Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl.[NH2:8][C@:9]([C:13]([OH:15])=[O:14])([CH3:12])[CH2:10][CH3:11].[Cl:16][C:17]1[N:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1.Cl>O.C(O)(C)C>[Cl:16][C:17]1[N:22]=[C:21]([NH:8][C@:9]([CH3:12])([CH2:10][CH3:11])[C:13]([OH:15])=[O:14])[CH:20]=[CH:19][N:18]=1
Reactant: CC[C@@](C)(N)C(=O)O
Reactant: Clc1ccnc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CC[C@@](C)(Nc1ccnc(Cl)n1)C(=O)O
Temperature: 87.5 °C
Reaction time: 0.17 h
Yield: 89.5 %

Procedure:
To a solution of K2CO3 (526.2 mg, 3.80 mmol) in water (1.6 mL, 6 volume) was added isovaline-HCl (292.4 mg, 1.90 mmol). The resulting solution was stirred for 10 minutes. A solution of [14C] enriched 2,4-dichloropyrimidine (11a**) (0.261 g, 90 mCi) in isopropanol (5.2 mL, 20 volume) was added dropwise at room temperature, and the resulting mixture was heated at 85-90° C. for 18 hours. The mixture was then concentrated to 4 volumes, then 1N NaOH (6 mL) and isopropyl acetate (6 mL) were added. The aqueous phase was separated and the organic phase was extracted with 1N NaOH (6 mL×2). The combined aqueous layer was acidified to pH=3.0-3.5 using 6N HCl (aq). The resulting solution was extracted with isopropyl acetate (15 mL×3). The collected organic layer was concentrated to 3-4 volumes, then 1N HCl etherate (1.73 mL, 1.73 mmol) was added drop wise at 0° C. and stirred for 15 minutes. The organic solvent was decanted and the solid was washed with isopropyl acetate (5 mL×2). The solid was dried under vacuum and obtained 360 mg of (R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid (2a**) with 70% radiochemical purity by instant imager to provide (R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid (2a**).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:3]=1[C:17]([OH:19])=O.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:42]1([C:48]2[CH:53]=[CH:52][C:51]([OH:54])=[CH:50][CH:49]=2)[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[OH:54][C:51]1[CH:50]=[CH:49][C:48]([N:42]2[CH2:47][CH2:46][N:45]([C:17]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[O:19])[CH2:44][CH2:43]2)=[CH:53][CH:52]=1
Reactant: Cc1onc(-c2cccc(C(F)(F)F)c2)c1C(=O)O
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Cc1onc(-c2cccc(C(F)(F)F)c2)c1C(=O)N1CCN(c2ccc(O)cc2)CC1
Yield: 55.4 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-methyl-3-(3-(trifluoromethyl)phenyl)isoxazol-4-carboxylic acid (500 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 4-(piperazine-1-yl)phenol (328 mg, 1.84 mmol), a white solid required compound (438 mg, 1.02 mmol, 55%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[CH:11][CH:12]=2)[CH2:7][NH:6]1)=[O:4].ClCCl.[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(N(CC)CC)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[CH:11][CH:12]=2)[CH:7]([C:23](=[O:24])[CH2:22][Cl:21])[NH:6]1)=[O:4]
Reactant: COC(=O)C1Cc2ccc([N+](=O)[O-])cc2CN1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1Cc2ccc([N+](=O)[O-])cc2C(C(=O)CCl)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.2 %

Procedure:
To a mixture of 7-nitro-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid methyl ester (Example 33 (a), 4.466 g, 18.9 mmol), dichloromethane (130 ml) and triethylamine (3.0 ml), cooled in an ice bath, was added dropwise chloroacetyl chloride (1.74 ml, 21.8 mmol). The resulting reaction mixture was stirred for 2 h at room temperature. The reaction mixture was then washed with dilute hydrochloric acid and then with water. The organic phase was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to yield 2-chloroacetyl-7-nitro-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid methyl ester (6.22 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.C1C(=O)N([Br:40])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:40][CH2:8][C:6]1[C:5]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:4]=2[CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C)c12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(CBr)c12
Temperature: 70 °C

Procedure:
6-Chloro-3-methoxy-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridine (1.5 g, 3.41 mmol) was dissolved in CCl4 (10 mL), charged with NBS (637 mg, 3.58 mmol) and AlBN (56.0 mg, 0.341 mmol), and heated to 70° C. overnight. The reaction was diluted with DCM (10 mL) and purified by flash chromatography (5-25% EtOAc/hexanes) to give 4-(bromomethyl)-6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine. MS ESI calc'd. for C27H21BrClN3O [M+1]+519. found 519.
Reaction SMILES: Br[C:2]1[N:3]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[CH:29]([C:31]1[S:32][CH:33]=[CH:34][C:35]=1B(O)O)=[O:30].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:25]([O:24][C:22](=[O:23])[CH2:21][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2)[C:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:2]1[C:35]1[CH:34]=[CH:33][S:32][C:31]=1[CH:29]=[O:30])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=Cc1sccc1B(O)O
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(=O)OC(C)(C)C)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccsc3C=O)n(CC(=O)OC(C)(C)C)c2c1

Procedure:
Methyl 2-bromo-1-(2-tert-butoxy-2-oxoethyl)-3-cyclohexyl-1H-indole-6-carboxylate (prepared as described in Example 1, Step 1) and (2-formyl-3-thienyl) boronic acid (1.5 eq) were dissolved in dioxane (0.07 M) and 2M aqueous Na2CO3 (6 eq) was added. The solution was degassed by bubbling argon, Pd(PPh3)2Cl2 (0.2 eq) was added, and the reaction mixture was refluxed for 45 min; after cooling EtOAc was added and the solution washed with water and brine, dried over Na2SO4 and concentrated. The title compound was isolated by chromatography (PE/EtOAc 9:1). Yield (84%); MS (ES+) m/z 504 (M+Na)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([CH2:9][CH2:10][CH2:11][C@H:12]([CH2:14][CH2:15][CH2:16]/[C:17](=[CH:19]/[CH2:20][OH:21])/[CH3:18])[CH3:13])[CH3:8])[CH3:3]>C(O)C.[Ni]>[CH2:20]([OH:21])[CH2:19][CH:17]([CH2:16][CH2:15][CH2:14][CH:12]([CH2:11][CH2:10][CH2:9][CH:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH3:8])[CH3:13])[CH3:18]
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: [Ni]
Solvent: CCO
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO

Procedure:
Phytol (5.0 g, 16.7 mmol) was stirred in ethanol (50 mL) in the presence of Raney nickel (1.0 g, 50% slurry in water) overnight under H2 atmosphere. The catalyst was filtered off and the solvent evaporated to give a clear oil. Yield: 4.9 g (97%)
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH2:9]1)(C)(C)C.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>C(Cl)Cl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[CH3:17][S:14]([C@H:11]1[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]1)(=[O:15])=[O:16]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](S(C)(=O)=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)[C@H]1CC[C@H](N)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of trans (4-methanesulfonyl-cyclohexyl)-carbamic acid tert-butyl ester (0.40 g, 1.40 mmol) in DCM (5 mL) was treated with trifluoroacetic acid (5 mL) and the mixture was stirred at ambient temperature for 30 minutes then concentrated under vacuum. The residue was azeotroped with toluene (×2) and the resulting oil was triturated (diethyl ether) to provide a solid which was washed with ether and dried to give 386 mg (93%) of trans 4-methanesulfonyl-cyclohexylamine trifluoroacetic acid salt as a white solid. 1H NMR (400 MHz, DMSO) δ: 7.86 (s, 3H), 3.11-2.98 (m, 2H), 2.92 (s, 3H), 2.18-2.02 (m, 4H), 1.56-1.43 (m, 2H), 1.43-1.28 (t, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=2[OH:16])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>>[C:24]1([S:30][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=3[OH:16])=[CH:4][CH:3]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Sc1ccccc1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(O)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(c1ccc(Sc2ccccc2)cc1)c1ccc(O)cc1O
Temperature: 200 °C
Reaction time: 2.5 h
Yield: 108 %

Procedure:
To 50 grams of 4′-chloro-2,4-dihydroxybenzophenone and 27.8 grams of potassium carbonate in 50 mL of 1-methyl-2-pyrrolidinone (NMP)is added 22.2 grams of thiophenol. The resulting suspension is heated at 200° C. with strrring for 2.5 hours. The reaction mixture is then allowed to cool to room temperature, made acidic with 10% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water and brine, dried over anhydrous magnesium sulfate and concentrated to leave 70 grams of a deep red syrup. The crude material is dissolved in an ethyl acetate/heptane mixture (1:1) and partially purified by filtration through a bed of silica gel to yield after concentration 66.6 grams of a light orange solid; 1H NMR and IR data are consistent with the tide compound; Mass. Spec m/z 322 (M+).
Reaction SMILES: [O:1]=[C:2]([NH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)[CH2:3][NH:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1.O=[C:24]1[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>CO.ClCCl>[F:13][C:12]([F:14])([F:15])[C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:5]([NH:4][CH2:3][C:2]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([CH:28]2[CH2:24][CH2:25][N:26]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:27]2)[CH2:19]1)=[O:1])=[O:16]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(C(=O)OCc3ccccc3)C2)C1
Reaction time: 16 h
Yield: 109.9 %

Procedure:
To a solution of N-{2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}-3-(trifluoromethyl)benzamide (500 mg, 1.59 mmol; prepared according to WO2004/050024A2) in methanol (5 mL) at room temperature was added benzyl 3-oxopyrrolidine-1-carboxylate (434 mg, 1.98 mmol) followed by sodium triacetoxyborohydride (470 mg, 2.22 mmol); the reaction mixture was stirred for 16 hours. To the mixture was added NaHCO3 (sat. aq., 10 mL) and dichloromethane (10 mL). The organic layer was separated and the aqueous layer was washed with an addition portion of dichloromethane (10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography (15% MeOH, 1% NH4OH in EtOAc) to afford, as a mixture of diastereomers, benzyl (3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidine-1′-carboxylate (906 mg, 88%) as a white solid. 1H-NMR (CDCl3) δ: 1.30-1.44 (m, 2H), 1.50-1.68 (m, 2H), 1.80-2.00 (m, 2H), 2.10-3.29 (m, 1H), 2.30-2.43 (m, 1H), 2.55-23.05 (m, 3H), 3.15-3.28 (m, 1H), 3.58-4.20 (m, 3H), 4.30-4.50 (m, 1H), 5.09 (s, 2H), 6.70-6.87 (m, 1H), 7.20-7.50 (m, 6H), 7.52 (t, J=8.7 Hz, 1H), 7.72 (d, J=7.2 Hz, 1H), 7.99 (d, J=7.2 Hz, 1H), 8.09 (s, 1H). MS m/z: 519 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=O)[CH:8]([CH3:11])[CH2:9][NH:10][C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>O1CCCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[S:24])[CH:8]([CH3:11])[CH2:9][NH:10][C:4]=2[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1CNc2cc(Br)ccc2NC1=O
Solvent: C1CCOC1
Product: CC1CNc2cc(Br)ccc2NC1=S
Yield: 77.9 %

Procedure:
A solution of 7-bromo-3-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (1.8 g, 7.1 mmol) and Lawesson's reagent (4.2 g, 10.4 mmol) in tetrahydrofuran (50 mL) was heated at 80° C. for 12 hours. The mixture was concentrated in vacuo. To the residue was added water (50 mL), extracted with ethyl acetate (50 mL×3). The combined layers were washed with brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to afford 7-bromo-3-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-thione (1.5 g, 79%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[C:19]([CH3:20])=[C:18]2[C:13]([CH:14]=[CH:15][C:16]([N:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)=[CH:23][C:22]3=[O:36])=[CH:17]2)=[N:12]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][O:27][C:24]2[CH:25]=[CH:26][N:21]([C:16]3[CH:15]=[CH:14][C:13]4[C:18](=[C:19]([CH3:20])[N:11]([CH2:10][CH2:9][OH:8])[N:12]=4)[CH:17]=3)[C:22](=[O:36])[CH:23]=2)=[CH:30][CH:31]=1
Reactant: Cc1c2cc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)ccc2nn1CCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c2cc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)ccc2nn1CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a solution of 1-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-methyl-2H-indazol-5-yl]-4-[(4-chlorobenzyl)oxy]pyridin-2(1H)-one (295 mg) in tetrahydrofuran (5 ml) was added tetra-n-butylammonium fluoride (1 M tetrahydrofuran solution, 1.13 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/methanol) to give the title compound (221 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[NH2:25][CH:26]([CH2:29][OH:30])[CH2:27][OH:28]>>[OH:28][CH2:27][CH:26]([NH:25][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=2)[CH:5]=1)[CH2:29][OH:30]
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: NC(CO)CO
Product: COc1ccc(C(=O)NC(CO)CO)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and 2-amino-1,3-propanediol in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([C:17]2[N:25]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)=[CH:5]1.[I-:36].[Na+]>C(C(C)=O)C>[I:36][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([C:17]2[N:25]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)=[CH:5]1
Reactant: [I-]
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCCl)c2cc1OC
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCI)c2cc1OC
Yield: 61.5 %

Procedure:
A solution of 2-[1-(2-chloroethyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.331 g; 649 μmol), described in example 1, and sodium iodide (0.195 g; 1.298 mmol) in methyl ethyl ketone (5 ml) is placed in a 10 ml round-bottomed flask. The reaction mixture is brought to reflux for 16 hours. After evaporation, the product is taken up in a mixture of water (15 ml) and ethyl acetate (15 ml). After separation by settling out and extraction with ethyl acetate (2×15 ml), the organic extracts are combined, dried over magnesium sulfate, and then evaporated under reduced pressure. The evaporation residue is chromatographed on silica gel, elution being carried out with a mixture of cyclohexane and ethyl acetate (50/50). The fractions containing the expected compound are combined and evaporated, giving 2-[1-(2-iodoethyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.24 g; 69%), the characteristics of which are as follows:
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]2=[N:8][S:9][N:10]=[C:4]2[CH:3]=1.[C:11]1(/[CH:17]=[CH:18]/B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>O>[C:11]1(/[CH:17]=[CH:18]/[C:2]2[CH:7]=[N:6][C:5]3=[N:8][S:9][N:10]=[C:4]3[CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1cnc2nsnc2c1
Reactant: OB(O)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C(=C/c1cnc2nsnc2c1)\c1ccccc1

Procedure:
To 6-bromo[1,2,5]thiadiazolo[3,4-b]pyridine (for a preparation see Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry (1979), 17B(1), 13-16) (1.9 g, 8.79 mmol), [(E)-2-phenylethenyl]boronic acid (1.561 g, 10.55 mmol) and tetrakistriphenylphosphine palladium(0) (0.508 g, 0.440 mmol) was added 1,4-dioxane (38 ml) and then potassium carbonate (1.276 g, 9.23 mmol) in water (19 ml). The reaction was then stirred at reflux for 1.5 hours. The cooled reaction was partitioned between chloroform and water. The phases were separated with a hydrophobic frit and the organic extracts concentrated to give a black solid/gum (˜2.4 g). This crude material was purified by chromatography on silica eluting with 20-50% EtOAc in cyclohexane to give the product as a yellow/brown solid (0.88 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[C:25](=[O:26])[C:24]3[N:27]4[C:17](=[CH:18][N:19]=[C:20]4[CH:21]=[CH:22][CH:23]=3)[C:16]2=[O:28])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:29]>C(O)C>[ClH:29].[ClH:29].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[C:25](=[O:26])[C:24]3[N:27]4[C:17](=[CH:18][N:19]=[C:20]4[CH:21]=[CH:22][CH:23]=3)[C:16]2=[O:28])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2c(=O)c3cccc4ncc(c2=O)n43)CC1
Agent: Cl
Solvent: CCO
Product: O=c1c2cccc3ncc(c(=O)n1CC1CCNCC1)n32
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 7.99 g (20.8 mmol) of 4,5-dihydro-4-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione in 50 ml of ethanol was added dropwise 25 ml of conc. HCl. The mixture was stirred for two hours at room temperature. The resulting crystalline precipitates were collected by filtration, washed with ethanol and then with ether to afford 7.07 g (87.4%, a colorless solid substance) of the desired compound
Reaction SMILES: [Br:1][C:2]1[C:3]([S:7]([N:10]2[C:14]([C:15]3[C:16]([F:21])=[N:17][CH:18]=[CH:19][CH:20]=3)=[C:13]([F:22])[C:12]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)=[CH:11]2)(=[O:9])=[O:8])=[CH:4][S:5][CH:6]=1.C(OCC)(=O)C.[ClH:39]>C(OCC)(=O)C.CC(O)C>[ClH:39].[Br:1][C:2]1[C:3]([S:7]([N:10]2[C:14]([C:15]3[C:16]([F:21])=[N:17][CH:18]=[CH:19][CH:20]=3)=[C:13]([F:22])[C:12]([CH2:23][NH:24][CH3:25])=[CH:11]2)(=[O:9])=[O:8])=[CH:4][S:5][CH:6]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cscc2Br)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cscc2Br)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
To a solution of tert-butyl {[1-[(4-bromo-3-thienyl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (195 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate-ethanol to give the title compound as a white solid (yield 114 mg, 66%).
Reaction SMILES: [OH:1][CH2:2][C@:3]12[CH2:10][C@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:8][C@H:4]1[O:5][CH2:6][CH2:7]2.CC(C)=[O:21].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>O>[C:14]([O:13][C:12]([NH:11][C@@H:9]1[CH2:8][C@H:4]2[O:5][CH2:6][CH2:7][C@@:3]2([C:2]([OH:21])=[O:1])[CH2:10]1)=[O:18])([CH3:15])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2OCC[C@@]2(CO)C1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of the product of Step H (426 g, 1.57 mol) and acetone (8.1 L) was added Jones reagent (710 mL) over 1 h 20 min. The resulting suspension was stirred at rt for 1 h, after which isopropyl alcohol (40 mL) was added, and the reaction stirred for 25 min at rt. Water was added, and the water/acetone was decanted off and evaporated. The insoluble material was dissolved separately in water and extracted with CH2Cl2. The green water/acetone concentrate was extracted with CH2Cl2 and the combined organic extracts were washed with brine, diluted with water and EtOAc and the organic layer was dried with Na2SO4. The organic layer was filtered, concentrated and the product was crystallized from MeCN, and the product of Step I was isolated by filtration as a white solid. 1H NMR (400 MHz, DMSO-d6) d=12.39-12.59 (m, 1H), 6.85-7.02 (m, 1H), 4.28 (d, J=5.4 Hz, 1H), 3.89-3.97 (m, 1H), 3.79-3.85 (m, 1H), 3.43-3.51 (m, 1H), 3.30-3.36 (m, 1H), 2.35-2.42 (m, 1H), 1.90 (d, J=11.0 Hz, 3H), 1.59-1.70 (m, 1H), 1.42-1.50 (m, 1H), 1.37 (s, 9H). Elemental anal calc for C13H21NO5: C, 57.55; H, 7.80; N, 5.16. Found: C, 57.34; H, 8.18; N, 5.08 mp: 147.4-149.1° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.C(=O)(O)[O-].[Na+].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>O.CC(C)=O>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:20])[CH2:7]1
Reactant: C[C@@H]1CNCCN1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(R)-2-methylpiperazine (13.85 g, 138 mmol) and sodium bicarbonate (52.3 g, 622 mmol) were partially dissolved in a mixture of water (182 ml) and acetone (112 ml). A solution of benzoyl chloride (17.7 ml, 152 mmol) in acetone (56 ml) was added dropwise over 1 hour with vigorous stirring. After stirring for 16 hours at RT, the acetone was stripped on the rotovap, water (400 ml) was added, and the solution acidified (6M HCl) to a pH less than 2. The aqueous phase was washed three times with dichloromethane (200 ml) and then 5M sodium hydroxide was added to bring pH over 12. The resulting solution was extracted three times with dichloromethane (200 ml), dried (MgSO4) and evaporated to give (R)-(3-methylpiperazin-1-yl)(phenyl)methanone 62 as a yellow oil, 15.1 g (54% of theoretical). LC/MS m/z=205 (M+H+).