Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.CSC.[CH2:5]([O:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH:16]1[CH:24]([C:26]#[N:27])[OH:25])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH2:5]([O:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH:16]1[CH:24]([OH:25])[CH2:26][NH2:27])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#CC(O)C1Cc2ccccc2N1C(=O)OCc1ccccc1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: CSC
Solvent: C1CCOC1
Product: NCC(O)C1Cc2ccccc2N1C(=O)OCc1ccccc1

Procedure:
Borane-dimethylsulfide (2M, 0.85 ml) is added to a mixture of (±) 1-benzyloxycarbonyl-2-(1-cyano-1-hydroxymethyl)indoline [VI diastereomer B, EXAMPLE 6, 0.431 g] in refluxing tetrahydrofuran (5 ml) slowly over 6 minutes. After one hour additional borane-dimethyl sulfide (2M, 0.5 ml) is added over 2 minutes. The mixture is continued to stir at reflux for 30 minutes then hydrochloric acid (3N, 1.8 ml) is added slowly with much effervescence over 2 minutes. The mixture is stirred for 15 minutes at reflux then cooled to 0° in an ice bath and sodium hydroxide (5N, 1.6 ml) is added slowly over 2 minutes. The solvent layers are separated and the aqueous layer is saturated with potassium carbonate and extracted with ethyl acetate (4×, 30 ml total). The organic layers are combined, dried over magnesium sulfate and then concentrated to give the title compound, NMR (methanol-d4, 300 MHz) 7.35, 7.15, 6.96, 5.26, 4.64, 3.87, 3.22, 3.03 and 2.43 δ; CMR (methanol-d4, 75.47 MHz) 30.5, 62.90, 68.8, 117.2, 124.48, 125.8, 128.24, 129.34, 129.68, 132.9 and 138.1 δ.
Reaction SMILES: [Cl:1][C:2]1[C:3](C2OC(C)(C)C(C)(C)O2)=[CH:4][C:5]([S:9]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[CH:20][CH:21]=[CH:22][C:13]2=3)(=[O:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.Br[C:33]1[C:34]([CH3:41])=[CH:35][C:36]([C:39]#[N:40])=[N:37][CH:38]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([S:9]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[CH:20][CH:21]=[CH:22][C:13]2=3)(=[O:11])=[O:10])=[CH:4][C:3]=1[C:33]1[C:34]([CH3:41])=[CH:35][C:36]([C:39]#[N:40])=[N:37][CH:38]=1
Reactant: CC1(C)OC(c2cc(S(=O)(=O)N3CCCCc4ccccc43)c(O)cc2Cl)OC1(C)C
Reactant: Cc1cc(C#N)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C#N)ncc1-c1cc(S(=O)(=O)N2CCCCc3ccccc32)c(O)cc1Cl
Temperature: 100 °C
Yield: 73.4 %

Procedure:
5-Chloro-2-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-4-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-phenol (153.0 mg, 0.33 mmol), 5-bromo-4-methyl-pyridine-2-carbonitrile (60 mg, 0.30 mmol), Pd(Ph3P)4 (38 mg, 0.03 mmol) and K2CO3 (138 mg, 1.0 mmol) in a mixture of dioxane (4 mL) and water (0.4 mL) was degassed with N2 for 5 min. The reaction vessel was sealed and then heated at 100° C. for 16 hrs. The mixture was then partitioned between ethyl acetate (20 mL) and water (10 mL). The organic layer was washed with brine (2×10 mL) and dried over MgSO4. After filtration and concentration, the material was purified by TLC plates eluting with ethyl acetate in hexanes (1/3) to give 5-[2-chloro-4-hydroxy-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenyl]-4-methyl-pyridine-2-carbonitrile 8-1 as a white solid (100 mg). MS: 453.9 (M+H)+; tR=8.37 min (method 2).
Reaction SMILES: [OH:1][C:2]1([CH3:26])[CH2:7][CH2:6][N:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]([O:11][C@H](C2C=CC=CC=2)C)=[O:10])[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[OH:1][C:2]1([CH3:26])[CH2:3][CH2:4][N:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]([OH:11])=[O:10])[CH2:6][CH2:7]1
Reactant: C[C@H](OC(=O)[C@@H](c1ccccc1)N1CCC(C)(O)CC1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(O)CCN([C@@H](C(=O)O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a solution of (S)-1-phenylethyl (R)-2-(4-hydroxy-4-methylpiperidin-1-yl)-2-phenylacetate (0.185 g, 0.52 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) and the mixture was stirred at room temperature for 2 hours. The volatiles were subsequently removed in vacuo and the residue was purified by reverse-phase preparative HPLC (Primesphere C-18, 20×100 mm; CH3CN—H2O-0.1% TFA) to give the title compound (as TFA salt) as a pale bluish solid (0.128 g, 98%). LCMS: Anal. Calcd. for C14H19NO3: 249. found: 250 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:16]=[N:15][C:5]2[NH:6][C:7](=[O:14])[N:8]([CH2:10][CH2:11][O:12][CH3:13])[CH2:9][C:4]=2[CH:3]=1.[CH3:17][C:18]1[NH:19][C:20]2[C:25]([C:26]=1[CH2:27][N:28]([CH3:33])[C:29](=[O:32])[CH:30]=[CH2:31])=[CH:24][CH:23]=[CH:22][CH:21]=2.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:33][N:28]([CH2:27][C:26]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][C:18]=1[CH3:17])[C:29](=[O:32])/[CH:30]=[CH:31]/[C:2]1[CH:16]=[N:15][C:5]2[NH:6][C:7](=[O:14])[N:8]([CH2:10][CH2:11][O:12][CH3:13])[CH2:9][C:4]=2[CH:3]=1
Reactant: C=CC(=O)N(C)Cc1c(C)[nH]c2ccccc12
Reactant: COCCN1Cc2cc(Br)cnc2NC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1Cc2cc(/C=C/C(=O)N(C)Cc3c(C)[nH]c4ccccc34)cnc2NC1=O
Yield: 35.4 %

Procedure:
A solution of 6-bromo-3-(2-methoxyethyl)-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one (0.86 g, 3.00 mmole), N-(2-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide (see Example 1 (a), 0.68 g, 3.00 mmole), Pd(OAc)2 (0.07 g, 0.30 mmole), tri-ortho-tolylphosphine (0.18 g, 0.60 mmole) and diisopropylethylamine (1.31 mL, 7.50 mmole) in propionitrile (50 mL) was deoxygenated, then was heated at reflux under N2 overnight. The dark mixture was filtered through a pad of Celite®, and the filter pad was rinsed with acetonitrile (250 mL). The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (10% EtOAc/EtOH). The title compound (0.46 g, 36%) was obtained as a light yellow solid after drying in vacuo: MS (ES) m/e 434 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:20])[CH:4]=[C:5]1[CH2:9][S:8][C:7]2=[C:10]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])[CH:11]([CH3:13])[CH2:12][N:6]12.C(Cl)(Cl)Cl.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(=O)([O-])O.[Na+]>O.O1CCCC1>[CH3:1][NH:2][C:3](=[O:20])[CH:4]=[C:5]1[CH2:9][S:8][C:7]2=[C:10]([C:14]([O:16][CH:17]([CH3:18])[CH3:19])=[O:15])[C:11]([CH3:13])=[CH:12][N:6]12
Reactant: CNC(=O)C=C1CSC2=C(C(=O)OC(C)C)C(C)CN12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CNC(=O)C=C1CSc2c(C(=O)OC(C)C)c(C)cn21
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
15.3 g of N-methyl-(7-isopropoxycarbonyl-6-methyl-2,3,5,6-tetrahydropyrrolo[2,1-b]thiazol-3-ylidene)acetamide was dissolved in a solvent mixture comprising 300 ml of chloroform and 120 ml of tetrahydrofuran. Then 11.7 g of 2,3-dichloro-5,6-dicyano-parabenzoquinone was added thereto under stirring and cooling with cold water. After 0.5 hour, a saturated aqueous solution of sodium hydrogencarbonate was added thereto. After stirring, the insoluble matters were filtered off with the use of celite and the filtrate was extracted with chloroform. The chloroform phase was washed with water and a saturated aqueous solution of sodium chloride and dried. After distilling off the solvent, the obtained crude crystals were recrystallized from ethanol. Thus 12.5 g of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:20])=[C:4]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[CH2:15][C:16]([NH:18][NH2:19])=[O:17])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C[Si]([N:25]=[C:26]=[O:27])(C)C>ClCCl.C(N(C(C)C)CC)(C)C>[C:26]([NH:19][NH:18][C:16](=[O:17])[CH2:15][CH:11]1[CH2:12][CH2:13][CH2:14][N:10]1[C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:20])(=[O:27])[NH2:25]
Reactant: Cc1c(N2CCCC2CC(=O)NN)ccc(C#N)c1Cl
Reactant: C[Si](C)(C)N=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(N2CCCC2CC(=O)NNC(N)=O)ccc(C#N)c1Cl

Procedure:
To a solution of 2-[1-(3-chloro-4-cyano-2-methylphenyl)pyrrolidin-2-yl]acetohydrazide (0.288 g, 1.030 mmol) in dichloromethane and diisopropylethylamine, add trimethylsilyl isocyanate (0.238 g, 2.060 mmol) and stir the reaction at 21° C. for 2 h. Partition the reaction is between ethyl acetate and brine. Dry the organic phase over magnesium sulphate, filter, and remove the solvent is under reduced pressure to yield the title compound. (0.303 g, 91%) mass spectrum (m/e): 322.1 (M+H); 1H NMR (300 MHz, CDCl3): δ 8.37 (s, 1H) 7.38 (d, 1H), 7.30 (s, 1H), 6.34 (d, 1H), 5.04 (s, 2H), 4.34 (t, 1H), 3.86 (m, 1H), 3.08 (m, 1H), 2.46 (m, 1H), 2.42 (s, 3H), 2.03 (s, 3H), 2.20-1.85 (m. 3H).
Reaction SMILES: [I:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-])=O.O.O.[Sn](Cl)Cl.C(O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[I:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[NH2:10]
Reactant: O=[N+]([O-])c1cc(F)cc(Br)c1I
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(F)cc(Br)c1I
Yield: 75.5 %

Procedure:
Treat 1-iodo-2-nitro-4-fluoro-6-bromobenzene (5.0 g, 14.46 mmol) with tin (II) chloride dihydrate (12 g, 58 mmol) in refluxing ethanol (150 mL). Stir at reflux for 24 hours, pour into a mixture of ethyl acetate (200 mL) and saturated sodium hydrogen carbonate (500 mL). Filter and wash the filtrate with saturated sodium hydrogen carbonate (200 mL) and water (200 mL). Dry (MgSO4), evaporate the solvent in vacuo and purify by silica gel chromatography to give the title compound as an off-white solid (3.45 g, 76%).
Reaction SMILES: C([O:4][C@H:5]([CH3:26])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[N:16]3[CH2:20][CH2:21][CH2:22][NH:23][C:15]3=[N:14][C:13]=2[N:12]([CH3:24])[C:11]1=[O:25])(=O)C.Cl.C(OCC)C>CO>[OH:4][C@H:5]([CH3:26])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[N:16]3[CH2:20][CH2:21][CH2:22][NH:23][C:15]3=[N:14][C:13]=2[N:12]([CH3:24])[C:11]1=[O:25]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc3n2CCCN3)n(C)c1=O
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: C[C@@H](O)CCCCn1c(=O)c2c(nc3n2CCCN3)n(C)c1=O
Yield: 80 %

Procedure:
A mixture of (R)-3-(5-acetoxyhexyl)-1-methyl-6,7,8,9-tetrahydro-pyrimido[2,1-f]purine-2,4(1H,3H)-dione (100 mg, 0.276 mmol) and a 1.0 M solution of hydrogen chloride in diethylether(1.0 ml, 1.0 mmol) in methanol (15 ml) was stirred at 70° C. for 3 hours. Concentration under reduced pressure provided (R)-3-(5-hydroxyhexyl)-1-methyl-6,7,8,9-tetrahydro-pyrimido[2,1-f]purine-2,4(1H,3H)-dione (CT-13431) (71 mg, 80% yield) as a white powder.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:35][CH2:34][C:33]([CH3:37])([OH:36])[CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[NH2:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([NH:45][CH3:46])=[O:44])=[CH:41][C:40]=1[CH3:49].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:36][C:33]1([CH3:37])[CH2:34][CH2:35][CH:30]([O:29][C:4]2[C:5]3[C:10]([C:11]4[CH:20]=[CH:19][C:14]5[N:15]=[C:16]([CH3:18])[O:17][C:13]=5[CH:12]=4)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=3[N:7]=[C:2]([NH:38][C:39]3[CH:48]=[CH:47][C:42]([C:43]([NH:45][CH3:46])=[O:44])=[CH:41][C:40]=3[CH3:49])[N:3]=2)[CH2:31][CH2:32]1
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CCC(C)(O)CC5)c34)cc2o1
Reactant: CNC(=O)c1ccc(N)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(Nc2nc(OC3CCC(C)(O)CC3)c3c(-c4ccc5nc(C)oc5c4)cn(COCC[Si](C)(C)C)c3n2)c(C)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a degassed mixture of 4-((2-chloro-5-(2-methylbenzo[d]oxazol-6-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-1-methylcyclohexanol (1 equiv), 4-amino-N,3-dimethylbenzamide (1.1 equiv) and cesium carbonate (3 equiv) in 1,4-dioxane (0.17 M) was added palladium acetate (0.1 equiv) and 2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (0.2 equiv). The reaction was stirred at 100° C. for 2 h. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (0-2% DCM in methanol) to afford the title compound 100% yield) as a red oil. MS (ESI) m/z 671.2 [M+1]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Cl[C:13]1[N:14]=[C:15]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[C:16]2[S:21][C:20]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([N:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]3)=[CH:19][C:17]=2[N:18]=1>CN(C=O)C.O>[N:1]1([C:13]2[N:14]=[C:15]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[C:16]3[S:21][C:20]([CH2:22][N:23]4[CH2:24][CH2:25][CH:26]([N:29]([CH3:31])[CH3:30])[CH2:27][CH2:28]4)=[CH:19][C:17]=3[N:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C1CCN(Cc2cc3nc(-n4ccc5ccccc54)nc(N4CCOCC4)c3s2)CC1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 32.8 %

Procedure:
A solution of indole (0.117 g) in DMF (8 mL) was cooled to 0° C. then sodium hydride (0.06 g) was added. After 15 min, [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.395 g) was added. The reaction flask was sealed, heated at 150° C. for 1 h, cooled to room temperature, and diluted with water. The solid precipitate was collected by filtration then purified by chromatography (silica, 0 to 20% of a 49:1 MeOH:NH4OH mixture in dichloromethane) to furnish the title compound (0.156 g, 33%) as an off-white solid. MS m/e 477 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.27-1.57 (m, 2H) 1.55-1.79 (m, 2H) 1.95-2.13 (m, 3H) 2.16 (s, 6H) 2.75-3.06 (m, 2H) 3.74-3.89 (m, 6H) 3.91-4.08 (m, 4H) 6.71 (d, J=3.39 Hz, 1H) 7.18 (s, 1H) 7.30 (s, 1H) 7.36 (s, 1H) 7.61 (s, 1H) 8.30 (d, J=3.77 Hz, 1H) 8.78 (d, J=7.91 Hz, 1H)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[NH:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[O:13].C(CN)O>O>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[C:17]1[NH:11][C:12](=[O:13])[NH:14][C:15]1=[O:16]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: O=C1CNC(=O)N1
Solvent: NCCO
Solvent: O
Product: O=C1NC(=O)C(=Cc2ccc(O)c(O)c2)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,4-dihydroxybenzaldehyde (2.072 g.) and hydantoin (1.50 g.) in water (15) was heated to 70° to give a clear solution. To this was added monoethanolamine (1.33 g.) and the magnetically stirred mixture was heated (90°-92°, bath temperature) for 4 hours. Within 10 minutes crystallization occurred. The product was allowed to cool to room temperature and was stored overnight. After immersing in an ice-bath, the mixture was acidified with HCl, refrigerated 5 hours, filtered, washed with cold (-10° ) 1:1 methanol-water and dried. The title compound was obtained as a pale brown solid: 2.776 g, m.p. 300°-310°. (Trituration with hot absolute ethanol gave a pale brown solid in ca 65% recovery, m.p. 320° decomp.)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[Na].[OH-].[Na+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O>[C:20]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:9]2)=[CH:4][CH:3]=1)([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]
Reactant: Nc1ccc2ccc(S(=O)(=O)O)cc2c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1ccc2ccc(S(=O)(=O)O)cc2c1)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a suspension of 7-aminonaphthalene-2-sulfonic acid, sodium salt (3.0 g, 12.2 mmol) in 70 mL of water is added solid NaOH (0.98 g, 24.0 mmol) at room temperature. The mixture is stirred for 30 minutes, and benzyl chloroformate (3.43 mL, 24.0 mmol) is then added. The resulting mixture is stirred over a period of 16 hours. The crude product is treated as in EXAMPLE 9, Part A, to give 4.18 g of crude N-CBz-7-aminonaphthalene-2-sulfonic acid, sodium salt. A mixture of the sulfonic acid, sodium salt (4.18 g, 11.0 mmol) in 12 mL of thionyl chloride is heated at 80° C. for 3 hours. The mixture is allowed to cool to room temperature and concentrated in vacuo. The residue is diluted with EtOAc and washed successively with water (2×), saturated NaHCO3 solution and saturated NaCl. The organic layer is dried over anhydrous MgSO4, filtered and concentrated to give a brown oil. The crude product is purified by column chromatography in a gradient of 10% EtOAc/hexanes to 30% EtOAc/hexanes to afford the title compound (1.76 g, 4.68. mmol) as a beige solid.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>O.Cl>[NH:12]([C:2]1[N:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:9][CH:10]=1)[NH2:13]
Reactant: NN
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: Cl
Solvent: O
Product: NNc1ccc(C(=O)O)cn1
Yield: 77 %

Procedure:
6-Chloronicotinic acid (8.0 g) was added to 85% hydrazine hydrate (35 ml). The reaction mixture was placed in a 100° C. oil bath for 4 hours. The homogeneous reaction mixture was concentrated to dryness to give a white solid. The solid was dissolved in water and on acidification to pH 5.5 with concentrated hydrochloric acid a precipitate formed. The precipitate was isolated by filtration and the solid was washed with 95% ethanol and ether to give 6.0 g of a pale brown solid; yield 77% m.p. 292°-293° C.;
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.[Cl-].[Na+].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[CH:38]([CH:40]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[O:39]>O>[CH2:46]([C@H:40]([CH2:38][OH:39])[C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CCOC(=O)C(C=O)Cc1ccccc1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Agent: [Cl-]
Solvent: O
Product: CCOC(=O)[C@@H](CO)Cc1ccccc1
Temperature: 30 °C
Reaction time: 72 h

Procedure:
Penicillium notatum NRRL 832 was cultivated on an agar slant with 7.5 ml of medium 5 consisting of 2 wt.% of sucrose, 1.5 wt.% of agar and 96.5 wt.% of beer wort (specific gravity 1.05-1.035) having a pH of 6.5. After incubation at 30° C. for 6 days the batch was treated with 9 ml of 0.9% (wt./vol.) sodium chloride solution and the cells were suspended. Subsequently, a shaking flask containing 100 ml of medium 6, which consisted of 1 wt.% of cornsteep, 1 wt.% of soya meal, 1 wt.% of glucose and 97 wt.% of distilled water, was inoculated with 1 ml of the suspension obtained. After an incubation period of 3 days while shaking at 30° C. 0.1 g of ethyl α-formyl-β-phenylpropionate was added directly to the pre-culture and incubated further while shaking at 30° C. After a reaction time of 1 hour the batch was extracted with ethyl acetate, there being obtained ethyl (R)-(+)-2-benzyl-3-hydroxypropionate in an optical purity of 88.5% ee.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:27])=[C:4]([N:8]2[C:16]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([NH2:25])[CH:19]=3)([OH:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:26])[CH:5]=[CH:6][CH:7]=1.[C:28](N1C=CN=C1)(N1C=CN=C1)=[S:29]>O1CCCC1>[Cl:1][C:2]1[C:3]([F:27])=[C:4]([N:8]2[C:16]([OH:17])([C:18]3[CH:23]=[CH:22][C:21]4[NH:24][C:28](=[S:29])[NH:25][C:20]=4[CH:19]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:26])[CH:5]=[CH:6][CH:7]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(C2(O)c3ccccc3C(=O)N2c2cccc(Cl)c2F)cc1N
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(O)(c2ccc3[nH]c(=S)[nH]c3c2)N1c1cccc(Cl)c1F
Reaction time: 4 h
Yield: 83.5 %

Procedure:
To a solution of 2-(3-chloro-2-fluorophenyl)-3-(3,4-diaminophenyl)-3-hydroxy-2,3-dihydro-1H-isoindol-1-one (575 mg, 1.49 mmol) in tetrahydrofuran (2.0 mL) was added 1,1′-thiocarbonyldiimidazole (400 mg, 2.25 mmol) at room temperature and stirred for 4 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (SiO2, hexanes/ethyl acetate) to afford 2-(3-chloro-2-fluorophenyl)-3-hydroxy-3-(2-thioxo-2,3-dihyro-1H-benzimidazol-5-yl)-2,3-dihyro-1H-isoindol-1-one (530 mg, 84%) as an off-white powder. 1H NMR (400 MHz, d6-DMSO): 12.58 (s, 1H), 12.50 (s, 1H), 7.90 (s, 1H), 7.89 (s, 1H), 7.70-7.60 (m, 2H), 7.51 (t, 1H), 7.32 (d, 1H), 7.30 (t, 1H), 7.19 (t, 1H), 7.14 (s, 1H), 7.05 (d, 1H), 6.94 (d, 1H); MS (EI) for C21H13ClFN3O2S: 426 (MH+).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[CH:8][C:7]([NH2:22])=[C:6]([NH2:23])[CH:5]=1.[C:24](=S)=[S:25].CC(O)=O>CCO.O>[C:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]([C:9]2[C:4]([Cl:3])=[CH:5][C:6]3[NH:23][C:24](=[S:25])[NH:22][C:7]=3[CH:8]=2)=[CH:15][CH:14]=1
Reactant: S=C=S
Reactant: Nc1cc(Cl)c(-c2ccc(-c3ccccc3)cc2)cc1N
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: S=c1[nH]c2cc(Cl)c(-c3ccc(-c4ccccc4)cc3)cc2[nH]1
Temperature: 110 °C

Procedure:
A 2 mL Biotage™ microwave was charged with solid KOH (18.0 mg, 0.326 mmol), water (0.2 mL), a solution of compound 2-2 (64.0 mg, 0.217 mmol) in EtOH (1.2 mL) and carbon disulfide (65 uL, 1.1 mmol). The vial was capped and stirred at rt until KOH dissolved then heated in a microwave synthesizer (Biotage Initiator™) at 110° C. for 10 min. Contents of the vial were transferred to a 20 mL scintillation vial, diluted with water (6 mL) and acidified by a dropwise addition of 10% aqueous AcOH. The resulting suspension was centrifuged, the supernatant was decanted and the resulting brownish precipitate was washed with 10% aqueous AcOH (3 mL) and water (three times, 3 mL). The precipitate was then dissolved in EtOAc and passed through a short plug of neutral alumina. The EtOAc solution was evaporated to dryness in vacuo to give the crude product as yellow solid. LR-MS (API-ES): calculated for C19H13ClN2S 336.1, observed m/e 337.0 (M+H)+ (Rt 3.12 min). The crude product was used in the next step without further purification.