Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Br:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.CN(/[CH:24]=[N:25]/[C:26]1[N:27]=[CH:28][NH:29][C:30]=1[C:31](OCC)=[O:32])C.C1(O)C=CC=CC=1>C(Cl)Cl>[Br:19][C:17]1[CH:16]=[C:13]([CH:12]=[C:11]([O:10][C:5]2[C:6]([Cl:9])=[CH:7][CH:8]=[C:3]([CH2:2][N:1]3[C:31](=[O:32])[C:30]4[NH:29][CH:28]=[N:27][C:26]=4[N:25]=[CH:24]3)[C:4]=2[F:20])[CH:18]=1)[C:14]#[N:15]
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CCOC(=O)c1[nH]cnc1/N=C/N(C)C
Solvent: Oc1ccccc1
Solvent: ClCCl
Product: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(Cn3cnc4nc[nH]c4c3=O)c2F)c1
Yield: 38.1 %

Procedure:
The title compound was prepared in a manner similar to that described herein using 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (0.61 g, 1.715 mmol), ethyl 4-{[(1E)-(dimethylamino)methylidene]amino}-1H-imidazole-5-carboxylate (0.397 g, 1.887 mmol) and phenol (0.484 g, 5.15 mmol) in DCM (3 mL) to give 0.31 g (38%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.58 (br. s., 1H), 8.45 (s, 1H), 8.17 (br. s., 1H), 7.93 (s, 1H), 7.58 (d, 2H), 7.47 (d, 1H), 7.21 (t, 1H), 5.30 (s, 2H). LCMS m/z 474.1 (M−H).
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH:7]1[CH2:11][CH2:10][N:9](CC2C=CC=CC=2)[CH2:8]1)[C:3](=[O:5])[CH3:4].C([OH:21])C>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[C:3]([OH:5])(=[O:21])[CH3:4].[CH3:1][N:2]([CH2:6][CH:7]1[CH2:11][CH2:10][NH:9][CH2:8]1)[C:3](=[O:5])[CH3:4]
Reactant: CCO
Reactant: CC(=O)N(C)CC1CCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(=O)N(C)CC1CCNC1

Procedure:
0.05 mole of the compound obtained in stage C in 130 cm3 of ethanol and 3 cm3 of acetic acid is hydrogenated in the presence of 1.3 g of palladium dihydroxide at 50° C. and at a pressure of 5 kilograms/cm2. The mixture is evaporated and then filtered. 12 g of the expected compound are obtained.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:7]=[C:6]([OH:19])[CH:5]=1)([CH3:3])[CH3:2].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>>[CH:1]([C:4]1[CH:5]=[C:6]([O:19][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:30])[F:31])=[CH:29][CH:28]=2)[N:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(O)nc(-c2cccc([N+](=O)[O-])c2)n1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: CC(C)c1cc(OCc2ccc(C(F)(F)F)cc2)nc(-c2cccc([N+](=O)[O-])c2)n1

Procedure:
The title compound was prepared from 6-isopropyl-2-(3-nitro-phenyl)-pyrimidin-4-ol (which was obtained in Intermediate 8) and 4-(trifluoromethyl)benzyl bromide according to Method A; 1H NMR (DMSO-d6, 300 MHz) δ 1.30 (d, J=6.8 Hz, 6H), 3.00-3.10 (m, 1H), 5.69 (s, 2H), 6.95 (s, 1H), 7.75-7.85 (m, 4H), 7.84 (t, J=8.1 Hz, 1H), 8.38 (t, J=8.1 Hz, 1H), 8.80 (d, J=7.8 Hz, 1H), 9.08 (s, 1H); LC retention 4.18 min; MS: m/z (ESI) 418 (M+H).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH2:12])=[S:11])=[CH:5][CH:4]=1.[CH2:13]([O:15]C1C=CC(NC(N)=S)=CC=1)[CH3:14]>>[CH2:13]([O:15][C:7]1[C:6]([NH:9][C:10]([NH2:12])=[S:11])=[CH:5][CH:4]=[CH:3][CH:8]=1)[CH3:14]
Reactant: CCOc1ccc(NC(N)=S)cc1
Reactant: COc1ccc(NC(N)=S)cc1
Product: CCOc1ccccc1NC(N)=S
Yield: 95.6 %

Procedure:
The reaction is carried out as described in the preceding Example with the exception that instead of 4-methoxyphenylthiourea the equimolar amount of 4-ethoxyphenylthiourea is used. 6-Ethoxy-phenylthiourea melting at 174° C. is obtained in a 95.6% yield and with the same good purity.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:9]([O:11][C:12](=[O:29])[NH:13][C:14]2[C:15]([CH3:28])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][C:20]=2[O:26][CH3:27])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH2:32]([O:34][C:35]([C:37]1([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[CH2:39][CH2:38]1)=[O:36])[CH3:33]>>[CH2:32]([O:34][C:35]([C:37]1([C:40]2[CH:45]=[CH:44][C:43]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH3:28])[C:14]=4[NH:13][C:12]([O:11][C@@H:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:31])([F:30])[F:1])[CH:4]=4)[CH3:10])=[O:29])=[C:20]([O:26][CH3:27])[CH:21]=3)=[CH:42][CH:41]=2)[CH2:38][CH2:39]1)=[O:36])[CH3:33]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: COc1cc(Br)ccc1-c1onc(C)c1NC(=O)O[C@H](C)c1cccc(C(F)(F)F)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)c4cccc(C(F)(F)F)c4)c(OC)c3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using [5-(4-bromo-2-methoxy-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(3-trifluoromethyl-phenyl)-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23]([OH:25])=O)[CH:18]=2)[CH2:13][CH2:12]1.Cl.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH:28]1[C:36]([O:38][CH2:39][CH3:40])=[O:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23]([N:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][CH:28]3[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:25])[CH:18]=2)[CH2:13][CH2:12]1
Reactant: CCOC(=O)C1Cc2ccccc2N1
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1Cc2ccccc2N1C(=O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1

Procedure:
150 mg (0.44 mmol) 6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]pyrimidine-4-carboxylic acid, 110 mg (0.48 mmol) ethyl 2,3-dihydro-1H-indole-2-carboxylate hydrochloride, 150.0 mg (0.47 mmol) TBTU and 150 μL (1.1 mmol) triethylamine in 2 mL DMF were stirred overnight at RT. The mixture was filtered through a syringe filter and the solution was purified by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1)#[N:2].CN([C:15]([O:19][N:20]1N=NC2C=CC=N[C:21]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN>C(Cl)Cl.O>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:20]([O:19][CH3:15])[CH3:21])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
To a stirred solution of 4-cyanobenzoic acid (5.0 g, 34.0 mmol) in DCM (75 mL) were added HATU (19.40 g, 51.0 mmol), N-methoxy, N-methylamine (4.90 g, 51.0 mmol) and TEA (14.30 mL, 102.0 mmol) at RT under a nitrogen atmosphere. The reaction mixture was then stirred at RT for 3 h, diluted with water and the aqueous layer was extracted with DCM (3×100 mL). The combined organic extracts were washed with water (60 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford 4-cyano-N-methoxy-N-methylbenzamide (6.2 g, 96%) as a yellow color oil.
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:13])=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9])=[O:2].S(=O)(=O)(O)O.[CH3:19]O>>[CH:1]([C:3]1[C:4]([CH3:13])=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([O:10][CH3:19])=[O:9])=[O:2]
Reactant: CO
Reactant: Cc1cc(C)c(C(=O)O)cc1C=O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C=O)c(C)cc1C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Into a 250-mL round-bottom flask, was placed 5-formyl-2,4-dimethylbenzoic acid (compound 83.1, 2.00 g, 11.2 mmol) and methanol (50 mL). Concentrated sulfuric acid (2 mL) was carefully added drop-wise and the resulting solution was stirred for 2 h at 80° C., then cooled and the volatiles were removed under reduced pressure. The pH of the residue was adjusted to 9 with sodium bicarbonate (sat.), then the aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (2×20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to yield 2.0 g (crude) of the title compound as yellow oil. The crude product was used in next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][C:43]([OH:45])=[O:44])[CH2:10]2)=[CH:5][CH:4]=1.[N+](=[CH2:48])=[N-].S([O-])([O-])(=O)=O.[Mg+2]>CO.CCOCC>[CH3:48][O:44][C:43](=[O:45])[CH2:42][C@H:11]1[CH2:10][C@H:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=3[CH:31]=2)[CH2:13][N:12]1[S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:33])=[O:34]
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: C=[N+]=[N-]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: CO
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)OC)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
To a solution of 2.03 g of [(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-acetic acid (from example 25f) in 50 ml of methanol at 0° C. is added a 0.1M solution of diazomethane in ether until the conversion to the methyl ester is complete. The reaction mixture is treated with magnesium sulfate to destroy the excess of diazomethane. The solids are removed by filtration and the organic layer is concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a yellow oil. Rf=0.24 (EtOAc-heptane 1:1); Rt=5.24.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:32]([OH:34])=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:23][CH:22]=1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:43]>ClCCl>[C:1]([NH:18][C@H:19]([C:32]([F:43])=[O:34])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:23][CH:22]=1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)F)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
N-FMOC-O-t-Butyl-L-tyrosine (5 g, 10.88 mmol) (Bachem) was dissolved in dichloromethane (50 mL). Pyridine (0.88 mL, 10.88 mmol) (Aldrich) and cyanuric fluoride (1.47 g, 10.88 mmol) (Aldrich) were successively added at room temperature and the mixture was stirred for 5 hours. Ice cold water (100 mL) was added and the resulting slurry was filtered. The filtrate was poured into a separatory funnel and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford N-FMOC-O-t-butyl-L-tyrosyl fluoride as a white powder. (Yield 4.43 g, 88%).
Reaction SMILES: C(O)C.C[N:5](C)/[CH:6]=[CH:7]/[C:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)=O.O.[NH2:18]N>O>[NH:5]1[CH:6]=[CH:7][C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[N:18]1
Reactant: CN(C)/C=C/C(=O)c1ccncc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: c1cc(-c2cc[nH]n2)ccn1
Yield: 93 %

Procedure:
To 50 mL absolute ethanol was added (E)-3-(dimethylamino)-1-(pyridin-4-yl)prop-2-en-1-one (20 g; Example 1, Step 1). When all solids dissolved, 6.33 mL hydrazine monohydrate was added dropwise with stirring. After 30 minutes an additional 1.1 mL hydrazine hydrate was added. After 2 hours the reaction was treated with water and the yellow solution was concentrated under vacuum until a slurry formed. The resulting solid product was collected by vacuum filtration, washed with water, and dried under high vacuum overnight to yield 15.27 g (93% yield) of product as off-white crystals. 1H NMR (CDCl3) was consistent with a tautomeric mixture of the desired structure. LC/MS showed one peak with a M+1 molecular ion of m/z 146.4 by positive ESI.
Reaction SMILES: [CH3:1][N:2]([S:6]([CH3:9])(=[O:8])=[O:7])[C:3](Cl)=[O:4].C(N(CC)CC)C.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>O1CCCC1>[CH3:1][N:2]([S:6]([CH3:9])(=[O:8])=[O:7])[C:3]([NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([C:18]([F:17])([F:26])[F:27])[CH:20]=1)=[O:4]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CN(C(=O)Cl)S(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)Nc1cccc(C(F)(F)F)c1)S(C)(=O)=O
Reaction time: 16 h
Yield: 40.6 %

Procedure:
A solution OF 11.4 g of N-methyl-N-methylsulfonyl-carbamoyl chloride in 100 ml of tetrahydrofuran was slowly added at 10° C. to a mixture of 60 ml of tetrahydrofuran, 10.1 g of triethylamine and 16.1 g of 3-trifluoromethylaniline, and after stirring for 16 hours, the mixture was filtered. The filtrate was distilled to dryness under reduced pressure. The residue was added to isopropyl ether and the precipitate formed was recovered by vacuum filtration and was washed and dried to obtain 8 g of N-methyl-N-methylsulfonyl-N'-(3-trifluoromethylphenyl)-urea melting at 72° C. The melting point was unchanged after crystallization from isopropyl ether.
Reaction SMILES: [CH:1]([O:3][C:4](Cl)=[O:5])=[CH2:2].[P:7]([O:14]CC)([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10]>>[CH2:9]([O:8][P:7]([C:4]([O:3][CH:1]=[CH2:2])=[O:5])(=[O:14])[O:11][CH2:12][CH3:13])[CH3:10]
Reactant: C=COC(=O)Cl
Reactant: CCOP(OCC)OCC
Product: C=COC(=O)P(=O)(OCC)OCC
Temperature: 0 °C

Procedure:
2.0 g (19 mmol) of chloroformic acid vinyl ester were precharged into a 50 ml two-necked flask, and, while stirring at 0° C., 3.13 g (19 mmol) of triethyl phosphite were slowly added dropwise. After completion of the addition, the reaction mixture was stirred for further 2 hours at room temperature. For complete removal of the ethyl chloride formed during the reaction, the solution was heated to 40° C. for 30 minutes. Purification by vacuum destillation yielded 2.5 g (64% of th.) of the title compound as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[CH:34]=[CH:33][O:32][CH:31]=1)(=[O:29])=[O:28].[OH-].[NH4+:36]>O1CCOCC1>[NH2:36][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:9][C:8]=2[C:7]2[C:2]([Cl:1])=[C:3]([NH:26][S:27]([C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)(=[O:28])=[O:29])[CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:17][N:16]=1
Reactant: [NH4+]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1ccoc1
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2Cl)n1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-3-furansulfonamide (114 mg, 0.212 mmol) and ammonium hydroxide (4 mL) and 1,4-Dioxane (1 mL), the title compound was obtained as an off-white solid (82 mg, 70% yield). MS (ESI): 519 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[S:19](Cl)(=[O:21])=[O:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:23]>C1COCC1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[S:19]([NH2:23])(=[O:21])=[O:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Reactant: N
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
To a stirred solution of 10 g (0.0281 mole) of 1-phenylsulfonyl-1H-indole-2-sulfonyl chloride in 150 ml anhydrous THF was added at -78° 4 ml (0.192 mole) of anhydrous ammonia. The resulting slurry was allowed to warm to room temperature over 30 minutes, then was sparged with nitrogen to remove excess ammonia. The slurry was filtered and the filtrate evaporated in vacuo to afford 9.19 g of tan solid, m.p. 199°-200.5°, 1H NMR (CDCl3 /DMSO-d6) δ7.23-7.77 (m, 9H), 8.1-8.28 (m, 3H, C-3 proton and SO2NH2). The infrared spectrum of the product included absorptions at 3400 and 3280 cm-1 (SO2NH2).
Reaction SMILES: [C:1]1([C@H:7]([CH2:9][OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.C([O-])([O-])=O.[K+].[K+]>C(O)C.C(Cl)Cl>[N:8]1([C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][OH:10])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: OC[C@@H](c1ccccc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 138.3 %

Procedure:
A suspension mixture of (R)-(-)-2-phenylglycinol(686 mg, 5 mmol), 1,5-dibromopentane (0.82 ml, 6 mmol), and K2CO3 (1.38 g, 10 mmol) in ethanol (15 ml) was refluxed with stirring for 23 h. After cooling down to rt, the white solid was removed by filtration and the filtrate was concentrated to give white solid oil mixture. This was suspended in CH2Cl2 (30 ml), washed with water and saturated NaHCO3 aqueous solution, dried (Na2SO4), and concentrated to give 1.42 g of clear yellow oil. This was purified by column chromatography (silica gel: 50 g, CH2Cl1 /MeOH:30/1 to 20/1) to afford 955 mg (93%) of desired compound as clear light yellow oil.
Reaction SMILES: [Na].Cl[C:3]1[C:4]2[C:5](=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[N:11]=2)[N:6]=[CH:7][N:8]=1.[CH3:26][CH:27]([OH:29])[CH3:28]>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:9]2[N:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[N:11]=[C:4]3[C:3]([O:29][CH:27]([CH3:28])[CH3:26])=[N:8][CH:7]=[N:6][C:5]=23)=[CH:20][CH:21]=1
Reactant: Clc1ccc(-c2c3ncnc(Cl)c3nn2-c2ccccc2Cl)cc1
Reactant: CC(C)O
Agent: [Na]
Product: CC(C)Oc1ncnc2c(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)nc12
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Sodium (21 mg, 0.9 mmol) was added to 2-propanol (2 ml), and the resultant mixture was stirred at 65° C. for 16 hours. Next, 7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine I-2A-1c (75 mg, 0.2 mmol) was added in one portion, and the mixture was stirred at 65° C. for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate and concentrated. Purification of the residue by flash column chromatography (50% ethyl acetate in hexanes) provided the title compound 3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-isopropoxy-2H-pyrazolo[4,3-d]pyrimidine 8A-1 (41 mg): MS: 399.1 (M+1)+; 1H NMR (400 MHz, CDCl3) δ 8.6 (s, 1H), 7.6 (d, J=6.6 Hz, 1H), 7.5 (m, 5H), 7.3 (d, J=8.7 Hz, 2H), 5.8 (pentuplet, J=6.2 Hz, 1H), 1.5 (d, J=6.2 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:15][C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:17](=[O:18])[C:16]([CH3:21])([CH3:20])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 87.7 %

Procedure:
To a 5 L 3 necked round bottomed flask with an overhead stirrer was added 4-chloroaniline (127.57 g, 1 mole), 1200 mL of CHCl3, and 1200 mL of saturated aqueous Na2CO3 solution. An addition funnel was attached to the flask and charged with 2,2-dimethylpropanoyl chloride (129 mL, 1.05 mole). The acid chloride was added dropwise to the vigorously stirred mixture over 1 h. The resulting mixture was stirred at ambient temperature for an additional 23 h. Some of the product separated from the mixture as white crystals. These crystals were collected by filtration. The filtrate was transferred to a separatory funnel and the layers were separated. The chloroform layer was washed with water and brine. Drying (MgSO4), filtration, and removal of the solvent in vacuo gave additional product. The two portions of product were combined and recrystallized from boiling EtOAc-hexanes to give 185.6 g of N-(4-chlorophenyl)-2,2-dimethylpropanamide as a white crystalline solid.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:11]=[C:12]([Br:16])[CH:13]=[CH:14][CH:15]=1.[CH2:17]1[O:20][CH:18]1[CH3:19]>C1COCC1>[Br:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[C:11]=1[CH2:17][CH:18]([OH:20])[CH3:19]
Reactant: Clc1cccc(Br)c1
Reactant: CC1CO1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)Cc1c(Cl)cccc1Br
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of LDA (6 mL, 12 mmol) in THF (10 mL) was added 3-chlorobromobenzene (1.91 g, 10.0 mmol) in THF (5 mL) at −78° C. under nitrogen, the resulting mixture was stirred at −78° C. for 1 h, then a solution of propylene oxide (1.7 g, 30 mmol) in THF (5 mL) was added. The mixture was slowly warmed to rt. The mixture was quenched with sat. aq NH4Cl (10 mL), then extracted with EtOAc (50 mL). The organic phase was washed with brine (10 mL) and dried over anhydrous sodium sulfate. The crude material was purified by silica gel chromatography Hexane/EtOAc (80:20) to give the title compound as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ=1.34 (d, J=6.1 Hz, 3H), 1.49 (d, J=5.8 Hz, 1H), 3.11-3.26 (m, 2H), 4.20-4.31 (m, 1H), 7.03 (t, J=8.0 Hz, 1H), 7.36 (dd, J=8.0, 1.1 Hz, 1H), 7.50 (dd, J=8.0, 1.1 Hz, 1H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[C:15]1([C:21]2[CH:29]=[C:28]3[C:24]([CH2:25][C:26](=[O:30])[NH:27]3)=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1CCCCC1.C(O)C>[CH3:14][C:7]1[NH:8][C:9]([CH:12]=[C:25]2[C:24]3[C:28](=[CH:29][C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:22][CH:23]=3)[NH:27][C:26]2=[O:30])=[C:10]([CH3:11])[C:6]=1[CH2:5][CH2:4][C:1]([OH:3])=[O:2]
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cc(-c4ccccc4)ccc32)c(C)c1CCC(=O)O
Yield: 71.4 %

Procedure:
3-(2-carboxyethyl)-2,4-dimethyl-5-formylpyrrole (97.6 mg), 105 mg 6-phenyl-2-oxindole and 2 drops piperidine in 2 mL of ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 138 mg (71%) of the title compound as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:9])=[C:4]([Cl:10])[C:3]=1[CH3:11].[C:12](O)(=[O:16])[C:13](O)=[O:14]>Cl>[Cl:10][C:4]1[C:5]([Cl:9])=[CH:6][C:7]2[C:2](=[N:1][C:12](=[O:16])[C:13](=[O:14])[N:8]=2)[C:3]=1[CH3:11]
Reactant: Cc1c(N)c(N)cc(Cl)c1Cl
Reactant: O=C(O)C(=O)O
Agent: Cl
Product: Cc1c(Cl)c(Cl)cc2c1=NC(=O)C(=O)N=2
Yield: 66.3 %

Procedure:
A mixture of 2,3-diamino-5,6-dichlorotoluene (from step (c), 21.6 g, 0.137 mol) and oxalic acid (18.45 g, 0.206 mol) in hydrochloric acid (4M, 900 ml) was heated at reflux for 6 hours, cooled and filtered. The dark brown solid was suspended in diethyl ether, filtered and washed with more ether to give 6,7-dichloro-5-methyl-quinoxalin-2,3-dione (22.06 g, 66%).