Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]([CH2:21][C:22]([C:24]3[C:32]4[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=4)[NH:26][C:25]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:23])[C:18](O)=[O:19])=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.[Cl:40][C:41]1[CH:49]=[C:48]2[C:44]([CH:45]=[C:46]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[NH:47]2)=[CH:43][CH:42]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]3[C:18](=[O:19])[O:23][C:22]([C:24]4[C:32]5[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=5)[NH:26][C:25]=4[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)([C:45]4[C:44]5[C:48](=[CH:49][C:41]([Cl:40])=[CH:42][CH:43]=5)[NH:47][C:46]=4[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[CH:21]=3)=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc(-c3ccccc3)[nH]c2c1
Reactant: O=C(CC(C(=O)O)c1c(-c2ccccc2)[nH]c2cc(Cl)ccc12)c1c(-c2ccccc2)[nH]c2cc(Cl)ccc12
Product: O=C1OC(c2c(-c3ccccc3)[nH]c3cc(Cl)ccc23)(c2c(-c3ccccc3)[nH]c3cc(Cl)ccc23)C=C1c1c(-c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
Following a procedure similar to that described above in part A of this example except that 2,4-bis(6-chloro-2-phenyl-3-indolyl)-4-oxobutanoic acid is used in place of 2,4-bis(1-n-propyl-2-methyl-3-indolyl)-4-oxobutanoic acid and 6-chloro-2-phenylindole is used instead of 1-n-propyl-2-methylindole, there is obtained 3,5,5-tris(6-chloro-2-phenyl-3-indolyl)-2(5H)-furanone (Formula III: R=R2 =H; R1 =R3 =C6H5 ; Y=Y1 =6-Cl).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:5].[Si]([O:30][CH2:31][CH2:32][O:33][C:34]1[C:41]([CH3:42])=[CH:40][C:37]([CH:38]=O)=[CH:36][C:35]=1[CH3:43])(C(C)(C)C)(C)C.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.[Cl-].[Li+]>[OH:30][CH2:31][CH2:32][O:33][C:34]1[C:41]([CH3:42])=[CH:40][C:37]([C:38]2[N:6]([C:7]3[CH:8]=[CH:9][C:10]([N:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)=[CH:11][CH:12]=3)[C:4](=[O:5])[C:3]3[C:2](=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:1]=2)=[CH:36][C:35]=1[CH3:43]
Reactant: Nc1ccccc1C(=O)Nc1ccc(N2CCOCC2)cc1
Reactant: Cc1cc(C=O)cc(C)c1OCCO[Si](C)(C)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(N3CCOCC3)cc2)cc(C)c1OCCO
Temperature: 120 °C
Reaction time: 17 h
Yield: 8.2 %

Procedure:
To a stirred solution of 2-amino-N-(4-morpholinophenyl)benzamide (1.71 g, 5.75 mmol) in DMA (20 mL) was added 4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylbenzaldehyde (1.77 g, 5.75 mmol), NaHSO3 (0.66 g, 6.33 mmol), and p-TsOH (0.22 g, 1.15 mmol). The reaction mixture was heated at 120° C. overnight, then heated to 140° C., and additional sodium bisulfite (2.60 g, 25 mmol) was added. After an additional 17 hours, the reaction mixture was cooled and diluted with 5% lithium chloride solution (120 mL), extracted with ethyl acetate (200 mL), and then washed with water (2×100 mL) and then brine (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was triturated with 1:1 hexanes/methylene chloride. Purification by flash chromatography on silica gel, eluting with 30% ethyl acetate/hexanes to 70% ethyl acetate/hexanes, afforded the title compound as a white solid (0.223 g, 8%). 1H-NMR (500 MHz, DMSO-d6) δ 8.16 (dd, J=7.98, 1.3 Hz, 1H), 7.87 (td, J=8.4, 1.5 Hz, 1H), 7.72 (d, J=7.9 Hz, 1H), 7.57 (td, J=8.1, 1.1 Hz, 1H), 7.11 (d, J=8.9 Hz, 2H), 7.03 (s, 2H), 6.86 (d, J=9.0 Hz, 2H), 4.82 (br s, 1H), 3.68-3.72 (m, 6H), 3.63-3.67 (m, 2H), 3.08-3.09 (m, 4H), 2.10 (s, 6H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=3)[N:18]=2)=[CH:13][CH:12]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=3)[N:18]=2)=[CH:13][CH:12]=1
Reactant: COCCCCCCCOc1ccc(-c2nc(-c3ccc(C(=O)OC)cc3)no2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCCCCCCOc1ccc(-c2nc(-c3ccc(C(=O)O)cc3)no2)cc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
A mixture of methyl 4-[5-[4-(7-methoxy-n-heptyloxy)phenyl]-1,2,4-oxadiazol-3-yl]benzoate (5.4 g) and 10% sodium hydroxide aqueous solution (15 ml) in ethanol (60 ml) and tetrahydrofuran (30 ml) was stirred at 60-70° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and water added to the residue and adjusted to pH 1 using hydrochloric acid. The precipitates were collected by filtration, washed with water and dried in vacuo to give 4-[5-[4-(7-methoxy-n-heptyloxy)phenyl]-1,2,4-oxadiazol-3-yl]benzoic acid (4.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6]1)=[O:4].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCC(OS(C)(=O)=O)C1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-hydroxy-cyclopentanecarboxylic acid methyl ester (1.6 g, 1.0 eq, cis/trans-mixture from step 1) in dichloromethane (25 mL) was cooled to −20° C. and treated with triethylamine (1.4 g, 1.3 eq) and methansulfonyl chloride (1.5 g, 1.2 eq). The mixture was stirred at −20° C. for 20 min and then partitioned between water and dichloromethane. The organic phase was washed with brine, dried over sodium sulfate and evaporated. The title compound was obtained as a yellow liquid (2.4 g, 97%) and was used crude in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:11][C:12]1[C:17]([CH:18]=[O:19])=[C:16]([F:20])[CH:15]=[CH:14][C:13]=1[NH:21][S:22]([CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:24])=[O:23].[OH-].[K+].[Cl-].[Na+]>C(OCC)(=O)C.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:18]([OH:19])[C:17]3[C:12]([F:11])=[C:13]([NH:21][S:22]([CH2:25][CH:26]([CH3:27])[CH3:28])(=[O:24])=[O:23])[CH:14]=[CH:15][C:16]=3[F:20])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: CC(C)CS(=O)(=O)Nc1ccc(F)c(C=O)c1F
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)CS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(Br)cc23)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
In a reaction vial, 5-bromo-1H-pyrrolo[2,3-b]pyridine (55, 287 mg, 1.46 mmol), 2-methyl-propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (59, 445 mg, 1.60 mmol) and potassium hydroxide (246 mg, 4.38 mmol) are combined with 7 mL of methanol and stirred at room temperature overnight. The reaction was combined with ethyl acetate and aqueous saturated sodium chloride, and extracted. The organic layer was washed with water, brine, and dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue was treated with 75 mL of acetonitrile:water 4:1 with 5% trifluoroacetic acid and stirred overnight at room temperature. The reaction was combined with ethyl acetate and aqueous saturated sodium chloride, and extracted. The organic layer was washed with water, brine, and dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound (68, 618 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[CH3:13].[CH:15]([C:18]1[N:19]=[C:20]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[S:21][C:22]=1[CH:23]([CH3:26])[CH:24]=O)([CH3:17])[CH3:16].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:26][CH:23]([C:22]2[S:21][C:20]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=3)=[N:19][C:18]=2[CH:15]([CH3:17])[CH3:16])[CH3:24])=[CH:8][C:7]=1[CH3:13]
Reactant: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)C=O
Reactant: COC(=O)CCc1ccc(N)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)CCc1ccc(NCC(C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C(C)C)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of 3-(4-Amino-2-methyl-phenyl)-propionic acid methyl ester (0.7.0 mmol) and 2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propionaldehyde (0.71 mmol) in anhydrous CH2Cl2 (5 mL) is added 4 Å molecular sieves followed by acetic acid (50 μL, 0.87 mmol). The mixture is stirred at RT for 2 h. Sodium triacetoxyborohydride (0.22 g, 1.04 mmol) is added, and the mixture is stirred at RT for 12 h. The reaction is quenched with saturated NaHCO3. The organics are separated and washed with saturated NaHCO3 and brine, and dried with MgSO4. The crude material is purified by flash chromatography to yield the title compound (0.21 g, 68%).
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]([CH3:32])([CH2:25][N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[C:33](OC(=O)C)(=[O:35])[CH3:34]>N1C=CC=CC=1>[C:33]([N:29]1[CH2:30][CH2:31][N:26]([CH2:25][C:22]2([CH3:32])[S:21][C:20]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:2]([CH3:1])[S:3]([C:6]3[S:7][CH:8]=[CH:9][CH:10]=3)(=[O:5])=[O:4])=[N:24][CH2:23]2)[CH2:27][CH2:28]1)(=[O:35])[CH3:34]
Reactant: CN(c1cccc2cc(C3=NCC(C)(CN4CCNCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1CCN(CC2(C)CN=C(c3cc4cccc(N(C)S(=O)(=O)c5cccs5)c4[nH]3)S2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A mixture of N-methyl-N-{2-[5-methyl-5-(piperazine-1-ylmethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (0.21 g), acetic anhydride (0.30 ml) and pyridine (6 ml) was stirred at 0° C. for 1 hr, and concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (0.19 g, yield 84%) as a colorless amorphous solid from a fraction eluted with ethyl acetate-methanol (6:1, volume ratio).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH3:14][O:15][N:16]=[CH:17][C:18]1[CH2:19][NH:20][CH2:21][CH2:22][CH:23]=1.C(N(CC)CC)C>ClCCl>[CH3:14][O:15][N:16]=[CH:17][C:18]1[CH2:19][N:20]([C:2]([O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)=[O:3])[CH2:21][CH2:22][CH:23]=1
Reactant: CON=CC1=CCCNC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON=CC1=CCCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.3 %

Procedure:
A solution of 97% 4-nitrophenyl chloroformate (1.5 g, 7.22 mmoles) in dichloromethane (15 mL) was added at 0° C. to a stirred solution of 1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime (0.92 g, 6.6 mmoles) and triethylamine (0.92 mL, 6.6 mmoles) in dichloromethane (20 mL). The reaction mixture was then stirred at room temperature for 20 minutes, the solvent was evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was dried (Na2SO4) and evaporated. The solid was recrystallized from benzene-cyclohexane to give 1.9 g (95%) of the desired product with mp 109°-110° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:13]Br>C(O)(=O)C>[Br:13][CH2:11][C:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:12]
Reactant: BrBr
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Temperature: 8 °C

Procedure:
To 82.5 g. of p-nitroacetophenone in 200 ml. of glacial acetic acid at 20°-25° C. is added 80 g. of bromine dropwise over 30 minutes. The resulting solution is cooled to 8° C. A precipitate forms during cooling which is filtered, washed and partially dried. 109 g. of wet alpha-bromo-p-nitroacetophenone is obtained. It is added to 109 g. of Na2S2O3.5H2O in 400 ml. of 70% methanol. The mixture is stirred, warmed to 60° C. and allowed to stand overnight. The mixture is cooled and a solid precipitates which is filtered and dried. The resulting cake is added to 600 ml. water, 600 ml. acetic acid and 300 ml. concentrated aqueous HCl. This mixture is stirred at refluxing temperature for 6 hours. An orange-red precipitate forms which is recovered and dried. NMR analysis indicates that the product is 2,5-di(p-nitrophenyl)dithiin having the structure: ##STR9##
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:25][C:23]([F:24])([F:26])[C:20]1[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCc2ccc(C(F)(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(CCCC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.9 %

Procedure:
4-[3-(4-Trifluoromethylphenyl)propyl]piperidine-1-carboxylic acid tert-butyl ester (13.45 g, 36.2 mmol) prepared in Reference Example 360 was dissolved in dichloromethane (50 ml). Trifluoroacetic acid (25 ml, 324 mmol) was added thereto and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and adjusted to a pH of 10 using a 5 N sodium hydroxide aqueous solution. The mixture was subjected to extraction with dichloromethane 4 times. The result was dried over anhydrous sodium sulfate and then concentrated to afford the title compound as a pale brown oil (10.2 g, quant).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[NH:10][NH2:11].[N:12]1[CH:17]=NC=N[CH:13]=1>CCO>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[N:10]1[CH:17]=[N:12][CH:13]=[N:11]1
Reactant: NNc1cc(F)ccc1Br
Reactant: c1ncncn1
Agent: Cl
Solvent: CCO
Product: Fc1ccc(Br)c(-n2cncn2)c1
Temperature: 90 °C
Yield: 61.3 %

Procedure:
Prepared according to the procedure described in J. Org. Chem., 1956, 21, 1037. A stirred mixture of (2-bromo-5-fluoro-phenyl)-hydrazine hydrochloride (31.9 g, 0.132 mol) and s-triazine (10.7 g, 0.132 mol; Aldrich) in EtOH (250 mL) was heated at 90° C. for 3 h. After cooling, the insoluble material was filtered off and the filtrate was concentrated. The residue was partitioned between CH2Cl2 (200 mL) and water (200 mL), and the aqueous phase was extracted once more with CH2Cl2 and the combined extracts were dried (MgSO4), filtered and concentrated to a red semi-solid which was triturated with hexanes to give 19.6 g of the title compound as an orange solid: HPLC rt=1.68 min. LC/MS m/z 242 (M+H); 1H NMR (CDCl3, 500 MHz) δ ppm 7.02-7.15 (1H, m, 5-CH), 7.29 (1H, dd, J=8.4, 2.9 Hz, 3-CH), 7.68 (1H, dd, J=8.8, 5.5 Hz, 6-CH), 8.10 (1H, s, 8-CH), 8.54 (1H, s, 7-CH); 13C NMR (CDCl3, 125.8 Hz) δ ppm 112.54, 112.57 (d, J=1.5 Hz, 1-C), 115.68, 115.88 (d, J=25 Hz, 3-CH), 118.07, 118.25 (d, J=22 Hz, 5-CH), 135.11, 135.18 (d, J=8.6 Hz, 6-CH), 137.43, 137.52 (d, J=11 Hz, 2-C), 144.4 (7-CH), 152.6 (8-CH), 160.95, 162.94 (d, J=251 Hz, 4-CF); HRMS (ESI) calcd for C8H6BrN3 (M+H) 241.9727; found 241.9733 (δ 1.6 ppm); UV (MeOH) λmax 275 nm (ε1.45×103); Anal. calcd for C8H5BrFN3: C, 39.69; H, 2.08; N, 17.36; found C, 39.63; H, 1.83; N, 17.22.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]2[S:10][C:9]([C:11]3[N:12]=[C:13]([NH2:16])[S:14][CH:15]=3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[C:33]3[CH:39]=[CH:38][NH:37][C:34]3=[N:35][CH:36]=2)O1>>[O:20]1[CH2:21][CH2:22][N:17]([C:4]2[C:5]3[S:10][C:9]([C:11]4[N:12]=[C:13]([NH2:16])[S:14][CH:15]=4)=[CH:8][C:6]=3[N:7]=[C:2]([C:31]3[CH:32]=[C:33]4[CH:39]=[CH:38][NH:37][C:34]4=[N:35][CH:36]=3)[N:3]=2)[CH2:18][CH2:19]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: Nc1nc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)cs1
Product: Nc1nc(-c2cc3nc(-c4cnc5[nH]ccc5c4)nc(N4CCOCC4)c3s2)cs1

Procedure:
4-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)thiazol-2-amine was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine via General Procedure B to give, after purification by reverse HPLC, 41 mg of 429. MS (Q1) 436 (M+)
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:28][CH2:29][CH3:30])=[C:4]([CH:21]=[CH:22][C:23]=1[C:24]([O:26]C)=[O:25])[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:20])[C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1.[OH-].[Na+]>CO>[C:24]([C:23]1[CH:22]=[CH:21][C:4]([O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:20])[C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)=[C:3]([CH2:28][CH2:29][CH3:30])[C:2]=1[OH:1])([OH:26])=[O:25]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)C(=O)O)cc2)ccc(C(=O)OC)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCOc2ccc(C(=O)C(=O)O)cc2)ccc(C(=O)O)c1O

Procedure:
A solution of 4-[3-[3-hydroxy-4-(methoxycarbonyl)-2-propylphenoxy)propoxy]-alphaoxobenzeneacetic acid (0.3 g) in methanol (30 mL) was treated with 4N sodium hydroxide (0.58 mL) was stirred at reflux for 46 hours. The methanol was removed in vacuo, then the mixture was acidified with 3N hydrochloric acid and extracted with dichloromethane-tetrahydrofuran (1:1). The dried (MgSO4) extracts were evaporated and the solid residue was crystallized from dichloromethane-hexane, and then from acetone-hexane to afford 4-[3-[4-carboxy-3-hydroxy-2-propylphenoxy)propoxy]-alpha-oxobenzeneacetic acid, mp 182°-185° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([OH:18])=[O:17])=[CH:10]2.[CH2:19](O)[CH3:20]>>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10]2
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc2cc(OC)ccc2[nH]1

Procedure:
1.91 ml (26.15 mmol) of thionyl chloride are added dropwise with stirring at 0° C. to a solution of 1 g (5.23 mmol) of 5-methoxy-1H-indole-2-carboxylic acid in 52 ml of ethanol. The reaction mixture is heated at reflux for 2 hours and then it is cooled and concentrated under reduced pressure. The residue is taken up in 100 ml of ethyl acetate and this solution is washed with two times 50 ml of water and then with 50 ml of a saturated sodium chloride solution. The solution is dried over magnesium sulfate and filtered, and then the filtrate is concentrated under reduced pressure. 1.2 g of product are obtained, which product is used as is in the following stage.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH:14]=[O:15])=[CH:13][C:8]=2[S:7][C:6]1=[O:16].CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH:14]=[O:15])=[CH:13][C:8]=2[S:7][C:6]1=[O:16])(=[O:27])=[O:26]
Reactant: O=Cc1ccc2c(c1)sc(=O)n2CCCO
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCn1c(=O)sc2cc(C=O)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a solution of 3-(3-hydroxypropyl)-2-oxo-2,3-dihydro-1,3-benzothiazole-6-carbaldehyde (Intermediate 71, 158 mg, 0.67 mmol) in CH2Cl2 (5 mL) was added Et3N (0.11 mL, 0.80 mmol) and the mixture was cooled to 0° C. To this solution, methanesulfonyl chloride was added dropwise (57 μL, 0.74 mmol) and the mixture was maintained at 0° C. for 90 min. CH2Cl2 and 4% aqueous sodium bicarbonate solution (10 mL) were added to the reaction mixture and stirred for 10 min. The two layers were separated and the organic phase was washed with water and brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give the title compound as a colourless oil (243 mg, 99% yield) which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:10]([C:14]2[N:15]([CH2:25][C:26]3[CH:31]=[C:30]([NH:32]CC4C=CC(OC)=CC=4)[N:29]=[C:28]([F:42])[CH:27]=3)[C:16](=[O:24])[NH:17][C:18](=[O:23])[C:19]=2[CH:20]([CH3:22])[CH3:21])[C:11](=[O:13])[CH3:12])[CH:6]=[C:7]([CH3:9])[CH:8]=1)#[N:2].C(O)(=O)C.[N+]([O-])([O-])=O.[NH4+]>C(#N)C.O>[NH2:32][C:30]1[CH:31]=[C:26]([CH2:25][N:15]2[C:14]([N:10]([C:5]3[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=3)[C:11](=[O:13])[CH3:12])=[C:19]([CH:20]([CH3:22])[CH3:21])[C:18](=[O:23])[NH:17][C:16]2=[O:24])[CH:27]=[C:28]([F:42])[N:29]=1
Reactant: COc1ccc(CNc2cc(Cn3c(N(C(C)=O)c4cc(C)cc(C#N)c4)c(C(C)C)c(=O)[nH]c3=O)cc(F)n2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(=O)N(c1cc(C)cc(C#N)c1)c1c(C(C)C)c(=O)[nH]c(=O)n1Cc1cc(N)nc(F)c1
Yield: 51 %

Procedure:
A solution of N-(3-cyano-5-methyl-phenyl)-N-{3-[2-fluoro-6-(4-methoxy-benzylamino)-pyridin-4-ylmethyl]-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl}-acetamide (58 mg, 0.10 mmol) in acetonitrile (0.7 mL) was treated with glacial acetic acid (0.275 mL), cerric (IV) ammonium nitrate (111 mg, 0.20 mmol) and water (10 drops). After 30 min the mixture was partitioned between water (5 mL) and ethyl acetate (10 mL). The solvent was removed from the organic phase in vacuo and the residue was subjected to flash chromatography (eluant: 0-70% ethyl acetate/hexanes). The product containing fractions were combined and the solvent was removed in vacuo to yield the product (23 mg, 0.051 mmol). C23H23FN6O3 calculated 450.2, observed [M+1]+451.1; rt=3.08 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[F:21][C:22]1[CH:23]=[CH:24][C:25]([CH3:31])=[C:26]([CH:30]=1)[C:27](Cl)=[O:28].CO.NCCNCCN>C(Cl)Cl.N1C=CC=CC=1>[F:21][C:22]1[CH:23]=[CH:24][C:25]([CH3:31])=[C:26]([CH:30]=1)[C:27]([NH:20][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:9]2)=[CH:7][C:2]=1[CH3:1])=[O:28]
Reactant: Cc1cc(N2CC[C@H](CN3CCC[C@@H]3C)C2)ccc1N
Reactant: Cc1ccc(F)cc1C(=O)Cl
Agent: NCCNCCN
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: Cc1cc(N2CC[C@H](CN3CCC[C@@H]3C)C2)ccc1NC(=O)c1cc(F)ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
(2S,3R)-2-Methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenylamine (92 mg, 0.34 mmol) was dissolved in DCM (4 mL) and pyridine (1 mL). The solution was cooled in an ice-water bath. To this solution was added a solution of 5-fluoro-2-methylbenzoyl chloride (from Alfa Aesar, 0.48 g, 2.77 mmol, 1.6 equiv.) in DCM (2 mL). The solution was stirred at r.t. for 2 h. The reaction was judged to be complete when TLC (10% MeOH in DCM) and LC/MS did not detect the SM at 274, but detected only the product peak at 410.2 and at retention time of 3.02 min. Polymer bounded diethylenetriamine (4 mmol/g, 0.12 g) was added and stirred at r.t. for 30 min., then filtered and rinsed with DCM. The solvent was evaporated to dryness, re-dissolved in DCM and NaHCO3 aqueous solution. The two layers were separated, and the aqueous layer was extracted with DCM (10 mL×2). The combined DCM extracts were successively washed with sodium bicarbonate (5 mL) and brine (5 mL×2), dried (anhydrous potassium carbonate), passed through a silica gel pad (self packed, ˜10 g), rinsed with DCM (no product) and then with 10% MeOH in DCM (contain product). The solution was concentrated in vacuo to obtain a crude product, which was purified on a silica gel column by eluting with 0 to 10% MeOH in DCM to obtain 48 mg (34% yield) of the title compound as a semi-solid. LC/MS: t=3.020 min, MS: 410.2. 1H NMR (300 MHz, CDCl3), δ (ppm): 7.49 (m, 1H), 7.23 (m, 1H), 7.11 (m, 2H), 6.41 (m, 1H), 3.70 (m, 2H), 3.57 (t, 6.2 Hz, 1H), 3.39 (m, 2H), 3.32 (m, 1H), 3.16 (m, 1H), 3.06 (m, 1H), 2.95 (m, 2H), 2.65 (m, 1H), 2.62 (s, 1H), 2.61 (s, 3H), 2.49 (m, 1H), 2.38 (s, 3H), 2.05 (m, 2H), 1.90 (m, 2H), 1.80 (m, 1H), 1.40 (d, 6.5 Hz, 3H).