Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.Br[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C)CC(O)=O>CS(C)=O.[Cu]I>[CH3:25][C:21]1[N:20]=[C:19]([O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]3)[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cccc(Br)n1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(O)cc2C1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: Cc1cccc(Oc2ccc3c(c2)C[C@@H](NS(=O)(=O)C(C)C)C3)n1

Procedure:
N-[(2S)-5-hydroxy-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (50 mg, 0.196 mmol, Description 3), copper(I) iodide (41.0 mg, 0.215 mmol), 2-bromo-6-methylpyridine (0.022 ml, 0.196 mmol), Cs2CO3 (191 mg, 0.587 mmol) and N,N-dimethylglycine (24.23 mg, 0.235 mmol), in dimethyl sulfoxide (2 ml) were heated under microwave conditions for 30 minutes at 190° C. The reaction mixture was partitioned between EtOAc (10 ml) and water (5 ml). The organic solution was dried (Na2SO4) and evaporated under reduced pressure to yield the impure product as a dark brown oil. The product was purified by reverse phase chromatography using the MDAP to afford the title compound as a white solid (17 mg).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[CH2:12]([N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCBr
Reactant: O=Cc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCn1ccc2c(C=O)cccc21
Temperature: 55 °C
Reaction time: 12.5 h
Yield: 60.5 %

Procedure:
There were dissolved, in 26 ml of dimethylformamide, 2.00 g of indole-4-carbaldehyde and 4.64 g of n-hexyl bromide, followed by addition of 9.52 g of potassium carbonate and heating the reaction solution to 55° C. with stirring for 12.5 hours. The reaction solution was poured into 500 ml of a 10% aqueous solution of ammonium chloride followed by extraction with ethyl acetate (150 ml×3). The resulting organic phase was washed with a saturated common salt solution, dried over anhydrous sodium sulfate, followed by removal of the solvent through evaporation under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 1.91 g of 1-hexylindole-4-carbaldehyde as a yellow oily substance. The yield thereof was found to be 61%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:21][CH:22]=1)[C:6]([CH3:11])=[CH:5]2
Reactant: Cc1cc2cc(F)ccc2[nH]1
Reactant: Ic1ccc(OCc2ccccc2)cc1
Product: Cc1cc2cc(F)ccc2n1-c1ccc(OCc2ccccc2)cc1
Yield: 23 %

Procedure:
5-Fluoro-2-methylindole (5.0 g, 33.5 mmol) and 4-benzyloxy iodobenzene (10.40 g, 33.5 mmol) were reacted according to the procedure used in Example 1a above to afford a white solid (23%): mp 94-95° C.; 1 H NMR (DMSO-d6): δ 2.23 (3H, s), 5.19 (2H, s), 6.39 (1H, s), 6.84-6.94 (2H, m), 7.19-7.29 (3H, m), 7.34-7.44 (5H, m), 7.51 (2H, d,J=7.1 Hz); MS m/z (M+H)+ 332. Anal. for C22H18NOF: Calc'd: C, 79.74; H, 5.47; N, 4.23. Found: C, 79.54; H, 5.54; N, 4.21.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccccc1Cl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4ccccc4Cl)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(2-chloro-phenyl)-1-methyl-propyl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:4]=2[N:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH2:23])=[CH:17][CH:16]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH:23][C:11]([C:9]2[CH:8]=[CH:7][C:5]3[NH:6][C:2]([CH3:1])=[N:3][C:4]=3[CH:10]=2)=[O:13])=[CH:17][CH:16]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: Cc1nc2cc(C(=O)O)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2cc(C(=O)NCCc3ccc(Cl)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
A suspension of 2-methyl-1H-benzo[d]imidazole-5carboxylic acid (0.750 g, 4.26 mmol), 2-(4-chlorophenyl)ethanamine (0.596 g, 3.83 mmol), HBTU (1.78 g, 4.68 mmol) and DIEA (1.11 mL, 6.39 mmol) in 10 mL of DCM was stirred at ambient temperature overnight. To the reaction was added DMF (10 mL) which caused a clear solution to form. The reaction was loaded onto a silica gel samplet and the product eluted using a gradient of 0.5% MeOH/DCM to 10% MeOH/DCM. Isolated N-(4-chlorophenethyl)-2-methyl-1H-benzo[d]imidazole-5carboxamide (0.65 g, 48.7% yield) as a yellow oil. MS(ESI)=314.4 (M+1).
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9]([O:11][CH2:12][C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:8][CH:7]=1)=[O:5])C.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[O:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:4]([C:6]2[S:10][C:9]([O:11][CH2:12][C:13]3[C:14]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:8][CH:7]=2)=[O:5])[CH2:27][CH2:28]1
Reactant: NC1CCOCC1
Reactant: CCOC(=O)c1cnc(OCc2c(-c3ccccc3)noc2C)s1
Product: Cc1onc(-c2ccccc2)c1COc1ncc(C(=O)NC2CCOCC2)s1
Yield: 56 %

Procedure:
As described for example 127, 2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-thiazole-5-carboxylic acid ethyl ester (100 mg, 0.28 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (65 mg, 56%) which was obtained as a white solid after purification by chromatography (silica, 0 to 3% methanol in dichloromethane). MS: m/e=398.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].C(N(C(C)C)CC)(C)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1)[C:26](Cl)=[O:27]>ClCCl>[C:9]([C:3]1[CH:4]=[C:5]([NH:8][C:26](=[O:27])[C:25]2[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=[C:23]([O:22][CH3:21])[CH:24]=2)[CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:11])[CH3:10]
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Reactant: CC(=O)c1cc(N)ccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC)cc(C(=O)Nc2ccc(Cl)c(C(C)=O)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a magnetically stirred solution of 2′-chloro-5′-amino-acetophenone (0.72 g, 4.2 mmol) in 20 ml of dichloromethane was added diisopropylethylamine (2.2 ml, 12.6 mmol). 3,5-dimethoxybenzoyl chloride (1.39 g, 6.9 mmol) in a single portion. The reaction was stirred for 2 h at room temperature, and a second portion of 3,5-dimethoxybenzoyl chloride (1.26 g, 6.3 mmol) was added, followed by diisopropylethylamine (1.0 ml, 5.7 mmol). The resulting solution was stirred an additional 3 h, and then quenched by the addition of 30 ml 1N HCl. The layers were separated and the aqueous layer was extracted with EtOAc (3×30 ml). The combined organics were washed with saturated NaHCO3 (1×20 ml), dried with solid anhydrous MgSO4, then concentrated. The crude product was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (0:1 to 2:5) to afford the desired N-(3-acetyl-4-chlorophenyl)-3,5-dimethoxybenzamide.
Reaction SMILES: [OH:1][C@@:2]1([CH3:41])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5][N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[C:30]4[CH:29]=[C:28]([C:31]5[CH:32]=[N:33][N:34]([CH2:36][C:37]([F:40])([F:39])[F:38])[CH:35]=5)[N:27]=[CH:26][C:25]=4[CH:24]=[N:23]3)[N:17]=2)[CH2:3]1.Cl>CO>[CH3:41][C@@:2]1([OH:1])[CH2:3][N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[C:30]4[CH:29]=[C:28]([C:31]5[CH:32]=[N:33][N:34]([CH2:36][C:37]([F:40])([F:39])[F:38])[CH:35]=5)[N:27]=[CH:26][C:25]=4[CH:24]=[N:23]3)[N:17]=2)[CH2:5][CH2:6][NH:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(-c5cnn(CC(F)(F)F)c5)cc43)n2)C[C@@](C)(O)C1
Agent: Cl
Solvent: CO
Product: C[C@]1(O)CNCCN(c2cccc(-n3ncc4cnc(-c5cnn(CC(F)(F)F)c5)cc43)n2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
To a solution of (R)-tert-butyl 6-hydroxy-6-methyl-4-(6-(6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (46 mg, 0.08 mmol) in MeOH (3 mL) was added HCl solution (conc. 3.0 mL) and stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure. The crude was purified by reverse phase preparative HPLC to afford 248 as a white solid (36 mg, 94%). 1H NMR (500 MHz, DMSO-d6) δ (ppm) 9.16 (s, 1H), 8.77 (s, 1H), 8.54 (s, 1H), 8.50 (s, 1H), 8.25 (s, 1H), 7.67 (t, 1H), 7.12 (d, 1H), 6.72 (d, 1H), 5.25-5.20 (t, 2H), 4.68 (s, 1H), 4.03-4.00 (m, 2H), 3.57-3.48 (m, 2H), 3.08-3.06 (m, 2H), 2.72 (d, 1H), 2.60 (d, 1H), 1.14 (s, 3H); MS (ESI) m/z: 473 [M+H]+.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>CN(C)C=O.C(OCC)C>[CH3:21][N:22]([CH3:24])[CH:23]=[C:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:8][CH:9]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCCCCCc1ccc(CC(=O)OCC)cc1
Reactant: COC(OC)N(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCc1ccc(C(=CN(C)C)C(=O)OCC)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
0.50 g (2.0 mmol) of ethyl 2-(4-hexylphenyl)acetate was dissolved in 7 mL of N,N-dimethylformamide, mixed with 0.31 mL (2.3 mmol) of N,N-dimethylformamide dimethyl acetal and stirred at 60° C. for 18 hours. After the stirring, the reaction mixture was further mixed with 0.65 mL (4.9 mmol) of N,N-dimethylformamide dimethyl acetal and stirred at 60° C. for 24 hours. After completion of the reaction, the reaction mixture was diluted with diethyl ether and washed with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the desired product as a brown liquid.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[Cl:61][CH2:62][C:63](=[O:70])[CH2:64][C:65]([O:67][CH2:68][CH3:69])=[O:66].[OH-].[Na+]>O.C(OCCCC)(=O)C>[Cl:61][CH2:62][C@@H:63]([OH:70])[CH2:64][C:65]([O:67][CH2:68][CH3:69])=[O:66]
Reactant: CCOC(=O)CC(=O)CCl
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Solvent: CCCCOC(C)=O
Solvent: O
Product: CCOC(=O)C[C@H](O)CCl
Yield: 87.4 %

Procedure:
To a 100 mL vessel connected to an automatic titrater by a pH electrode and a feeding tube for addition of base was charged a solution of glucose (12. g) in water (30 mL). To this solution was charged ketoreductase SEQ ID NO: 42 (100 mg); 50 mg GDH SEQ ID NO: 66 and NADP (6.25 mg). Butyl acetate (10 ml) was then charged. Ethyl 4-chloroacetoacetate (10 g) was then charged via syringe pump as follows: 1 mL was charged rapidly and the remainder was then charged at a rate of 1 mL/hr). The pH was maintained at 7 by the automatic titrater by the addition of 4M NaOH over 18 hours hrs. The stirring was stopped and the phases allowed to separate. The organic layer included some emulsion. The organic layer, including some emulsion, was separated and washed with 10 mL of water. The combined aqueous layers were extracted twice with 20 mL of butyl acetate. The organic extracts were combined and rotary evaporated under vacuum to remove water. Additional butyl acetate was added during the evaporation to help remove the water. When the water was removed the butyl acetate solution was decanted from solids in the flask. Evaporation of the solvent under vacuum then gave 8.85 g of ethyl (S)-4-chloro-3-hydroxybutyrate (87.4% yield) of very good purity.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[C:11]([NH2:12])=[C:10]([F:13])[C:9]([CH3:14])=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[Cl:5][C:6]1[C:11]([NH:12][C:1](=[O:3])[CH3:2])=[C:10]([F:13])[C:9]([CH3:14])=[CH:8][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(Cl)c(N)c1F
Solvent: Cc1ccccc1
Product: CC(=O)Nc1c(Cl)ccc(C)c1F

Procedure:
Acetylchloride (2.56 mL, 36.0 mmol) is added to a mixture of 6-chloro-2-fluoro-3-methyl-aniline (5.00 g, 31.3 mmol) and toluene (200 mL), additional toluene (50 mL) is added and the mixture is heated to reflux for 3 h. Then it is cooled with an ice bath and the formed precipitate is filtered off, washed with cold toluene and dried.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14](Cl)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([CH2:25][NH2:26])[OH:24].C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1.O.CC#N.CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.CS([O-])(=O)=O.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.[Pd+2]>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:26][CH2:25][CH2:23][OH:24])[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(cc(Cl)c3nnc(C)n32)n1Cc1ccccc1
Reactant: NCCO
Agent: [Pd+2]
Agent: COc1ccc(OC)c(P(C(C)(C)C)C(C)(C)C)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: CS(=O)(=O)[O-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CC#N
Product: Cc1cc2c(cc(NCCO)c3nnc(C)n32)n1Cc1ccccc1
Temperature: 100 °C

Procedure:
A degassed mixture of 6-benzyl-4-chloro-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (25.0 mg, 0.0804 mmol, Example 228, Step 7), ethanolamine (44 mg, 0.72 mmol, Aldrich), Cs2CO3 (79 mg, 0.24 mmol, Aldrich) and tBuBrettPhos Pd G3 (8.2 mg, 0.0096 mmol, Aldrich) in NMP (1 mL) and Water (38 μL) was heated at 100° C. overnight. Upon cooling, the reaction mixture was diluted with MeCN, filtered and purified via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (5.9 mg, 22%).
Reaction SMILES: [Na].[C@@H:2]1([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([OH:14])[C:12]=3[N:11]=[CH:10]2)[O:8][C@H:5]([CH2:6][OH:7])[CH:4]=[CH:3]1.[H][H]>[Ni].O>[CH:10]1[N:9]([C@@H:2]2[O:8][C@H:5]([CH2:6][OH:7])[CH2:4][CH2:3]2)[C:18]2[N:17]=[CH:16][NH:15][C:13](=[O:14])[C:12]=2[N:11]=1
Reactant: [H][H]
Reactant: OC[C@@H]1C=C[C@H](n2cnc3c(O)ncnc32)O1
Agent: [Ni]
Agent: [Na]
Solvent: O
Product: O=c1[nH]cnc2c1ncn2[C@H]1CC[C@@H](CO)O1
Temperature: 30 °C
Reaction time: 0.33 h
Yield: 66.4 %

Procedure:
2′,3′-Dideoxy-2′,3′-didehydroinosine sodium salt (50 gm) is added to water (180 ml) and stirred for 20 minutes at 25-35° C. Then the contents are hydrogenated under nitrogen atmosphere at 1.5-2.0 kg/cm2 hydrogen pressure at 15-20° C. using raney nickel catalyst for 7-8 hours. The reaction mass is filtered on a celite bed and washed with water (25 ml). To the filtrate activated carbon (2 gm) is added and stirred for 20 minutes. The mass is filtered on a celite bed and washed with water (25 ml). The filtrate is cooled to 5-15° C., the pH is adjusted to 7.0-8.0 with dilute hydrochloric acid (13 ml water+13 ml conc. HCl) at 5-15° C. and stirred for 2 hours 30 minutes. Filtered the mass, washed with water (40 ml). The resulting wet cake is added to water (120 ml), the temperature is raised to 65-75° C. and stirred for 20 minutes at the same temperature. The resulting solution is cooled to 25-35° C. and stirred for 1 hour 30 minutes. The reaction mass is then cooled to 10-15° C. and stirred for 1 hour 30 minutes. Filtered the solid, washed with the 40 ml of water and dried at 55-60° C. to give 30.5 gm of didanosine (HPLC Purity: 99.85%).
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:3]=1[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7].[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:3]=1[CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7]
Reactant: N#CC(C#N)=Cc1c(F)cc(F)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#CC(C#N)Cc1c(F)cc(F)cc1F
Yield: 90 %

Procedure:
Using 1.42 g of (2,4,6-trifluorobenzyliden)malononitrile, 50 ml of ethanol and 0.08 g of sodium borohydride, and according to the process described in the Reference Production Example 3, there was obtained 1.29 g of (2,4,6-trifluorobenzyl)malononitrile (the intermediate (21)).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[C@@H:16]([OH:31])[C@@H:17]([NH2:30])[CH2:18][O:19][P:20]([O:23][CH2:24][CH2:25][N+:26]([CH3:29])([CH3:28])[CH3:27])([O-:22])=[O:21].[C:32]([N:36]=[C:37]=[S:38])(C)(C)[CH3:33].C(=O)(O)[O-].[Na+]>CO.O.ClCCl>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[C@@H:16]([OH:31])[C@@H:17]([NH2:30])[CH2:18][O:19][P:20]([O:23][CH2:24][CH2:25][N+:26]([CH3:27])([CH3:29])[CH3:28])([O-:22])=[O:21].[CH2:32]([NH:36][C:37]([NH2:26])=[S:38])[CH3:33]
Reactant: CC(C)(C)N=C=S
Agent: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@@H](N)COP(=O)([O-])OCC[N+](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CCNC(N)=S
Reaction time: 0.17 h

Procedure:
100 mg of sphingosylphosphorylcholine were dissolved in 10 ml methanol:water, 2:1, in a 25 ml Erlenmeyer flask. To the stirred solution were added 100 mg of tertiary butyl isothiocyanate. The solution was stirred for 10 min, then 2.5 ml of 1N sodium bicarbonate were added. The solution was left to stir for 48 hours, transferred to a separatory funnel and 80 ml dichloromethane, 30 ml methanol and 40 ml water were added. The organic phase was washed with 40 ml of water, then dried over MgSO4, filtered and evaporated to dryness. The compound was purified by preparative TLC using dichloromethane:methanol:water, 65:35:5 for development. The silica spot containing the product was viewed by an ultraviolet lamp, scraped and eluted with dichloromethane: methanol:water, 1:2:1, in a small column. Yield: 80 mg; M.S. Na+=574.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[O:3]1.Br[CH2:15][C:16]1[C:28]([Cl:29])=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:18]([F:30])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:29][C:28]1[C:16]([CH2:15][O:12][C:6]2[CH:5]=[C:4]3[C:9]([CH2:10][CH2:11][C:2]([CH3:13])([CH3:1])[O:3]3)=[CH:8][CH:7]=2)=[CH:17][C:18]([F:30])=[C:19]([CH:27]=1)[C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(CBr)cc1F
Reactant: CC1(C)CCc2ccc(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(COc2ccc3c(c2)OC(C)(C)CC3)cc1F
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of 2,2-dimethylchroman-7-ol (100 mg, 0.561 mmol), tert-butyl 4-(bromomethyl)-5-chloro-2-fluorobenzoate (191 mg, 0.590 mmol) and potassium carbonate (194 mg, 1.40 mmol) in acetone (30 mL) was stirred at 50° C. for 16 hrs. After cooling to room temperature, the mixture was extracted with EtOAc (150×5 mL). The combined orgaic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product which was used in next step without further purification (290 mg, crude). LCMS (ESI) m/z: 420.8 [M+H].
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[N:21](C4CCCCO4)[C:20]4[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=4[N:18]=3)=[O:16])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)(C(F)(F)F)=O.N>CO.C1(C)C=CC=CC=1>[NH:18]1[C:19]2[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=2[N:21]=[C:17]1[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[C:2]([N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1)=[O:16]
Reactant: C1CCNCC1
Reactant: O=C(c1ccc(Oc2ncccc2Br)cc1)c1nc2ccccc2n1C1CCCCO1
Agent: N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(c1ccc(Oc2ncccc2N2CCCCC2)cc1)c1nc2ccccc2[nH]1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A heavy-walled vial was charged with (4-(3-bromopyridin-2-yloxy)phenyl)(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-2-yl)methanone (0.150 g, 0.314 mmol), piperidine (0.041 mL, 0.470 mmol), cesium carbonate (0.204 g, 0.627 mmol), (r)-binap (0.020 g, 0.031 mmol), Pd3 dba3 (0.014 g, 0.016 mmol) and Toluene (4 mL). Nitrogen was bubbled into the flask for 5 mins. The vial was capped and heated to 80° C. After 12 hours, the reaction was partitioned with ethyl acetate and water. The organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 20 to 60% EtOAc in hexanes to give a clear residue. The residue was dissolved in MeOH (10 mL) and treated with 1 mL of TFA. The mixture was allowed to stir at room temperature. 10 ml of 2N ammonia in MeOH was added to the reaction with was reduced in vacuo. The residue was partitioned in water and EtOAc. The organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and reduced. The residue obtained was triturated in 1:1 ethyl acetate:ether and then dried in a vacuum oven to give product as solid. MS (ESI, pos. ion) m/z: 398.8 (M+1). IC50 (uM) ++++.