Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[CH:7]([NH2:13])[CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1.[C:14]([O:18][C:19]([N:21]([CH2:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:14]([O:18][C:19](=[O:20])[N:21]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:34][NH:13][CH:7]2[C:6]3[N:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:11]=3[CH2:10][CH2:9][CH2:8]2)=[CH:36][CH:37]=1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C=O)cc1)Cc1ccccn1
Reactant: COc1cnc2c(c1)CCCC2N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cnc2c(c1)CCCC2NCc1ccc(CN(Cc2ccccn2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
To a solution of (3-methoxy-5,6,7,8-tetrahydroquinolin-8-yl)-amine (0.27 g, 1.5 mmol) and 4-[[N-(t-butoxycarbonyl)-N-(2-pyridinylmethyl)amino]methyl]benzaldehyde (prepared as described by Bridger et al, U.S. patent application Ser. No 09/535,314) (0.57 g, 1.7 mmol) in CH2Cl2 (15 mL) was added NaBH(OAc)3 (0.48 g, 2.3 mmol) and the mixture stirred at room temperature for 16 h. Purification of the crude material by column chromatography on silica gel (5% MeOH/CH2Cl2) gave {4-[(3-methoxy-5,6,7,8-tetrahydroquinolin-8-ylamino)-methyl]-benzyl}-pyridin-2-ylmethyl-carbamic acid tert-butyl ester (0.43 g, 58%). 1H NMR (CDCl3) δ1.45 (m, 9H), 1.77 (m, 2H), 2.00 (m, 1H), 2.12 (m, 1H), 2.77 (m, 2H), 3.80 (m, 1H), 3.81 (s, 3H), 3.85 (d, 1H, J=12.0 Hz), 3.95 (d, 1H, J=12.0 Hz), 4.44 (br s, 2H), 4.55 (br s, 2H), 6.88 (d, 1H, J=1.5 Hz), 7.15 (m, 2H), 7.23 (br s, 2H), 7.34 (d, 2H, J=6.0 Hz), 7.62 (t, 1H, J=7.5 Hz), 8.11 (d, 1H, J=1.5 Hz), 8.52 (d, 1H, J=6.0 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=[O:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[Br:16][CH2:17][CH2:18]Br.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:18][CH2:17][Br:16])[C:10]1[C:9](=[O:15])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: BrCCBr
Reactant: Cc1ccc2[nH]c3c(c2c1)CCCC3=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)c1c(n2CCBr)C(=O)CCC1

Procedure:
199 g. (1 mole) of 6-methyl-1,2,3,4-tetrahydro-carbazol-1-one and 376 g. (2 moles) of 1,2-dibromoethane are dissolved in 1000 ml. of toluene and stirred together with 1000 ml. of sodium hydroxide solution and 4.25 g. (12,5 m moles) of tetrabutylammoniumhydrogensulfate for 10 hours at 60° C. After evaporating the aqueous layer, distilling off the solvent and recrystallizing the residual crude product, 275 g. of 6-methyl-9-(2-bromoethyl)-1,2,3,4-tetrahydrocarbazol-1-one (90% of the theoretical) melting at 102° to 103° C. are obtained.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:7]([O:9][N:10]=[CH:11][C:12]1[CH:13]2[N:19]([CH3:20])[CH:16]([CH2:17][CH:18]=1)[CH2:15][CH2:14]2)C.C(C1C2N(C)C(CC=1)CC2)=O.Cl.C(ON)C>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][O:9][N:10]=[CH:11][C:12]1[CH:13]2[N:19]([CH3:20])[CH:16]([CH2:17][CH:18]=1)[CH2:15][CH2:14]2
Reactant: CCON=CC1=CCC2CCC1N2C
Agent: CCON
Agent: CN1C2CC=C(C=O)C1CC2
Agent: Cl
Product: CON=CC1=CCC2CCC1N2C

Procedure:
2-Ethoxyiminomethyl-8-methyl-8-azabicyclo[3.2.1]oct-2-ene oxalate from 2-formyl-8-methyl-8-azabicyclo[3.2.1]oct-2-ene and ethoxyamine hydrochloride. M.p. 127°-128° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O.C(OCC)C>CO>[CH2:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(F)c(Cc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: OCc1ccc(F)c(Cc2ccccc2)c1
Reaction time: 1 h
Yield: 79.3 %

Procedure:
A solution of 3-benzyl-4-fluorobenzaldehyde (5 g) in methanol (75 cm3) was cooled to 0° C. Sodium borohydride (1.34 g) was added in portions, and the mixture stirred for 1 hour. The reaction mixture was then poured cautiously into a mixture of water and diethyl ether, and the organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulphate. Evaporation of the solvents under reduced pressure gave a pale yellow oil which was purified by distillation in a kugelrohr apparatus to give 3-benzyl-4-fluorobenzyl alcohol (4.0 g).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[O:4][C:5]1[CH:10]=[N:9][N:8](C2CCCCO2)[C:7](=[O:17])[CH:6]=1.Cl.O>CO>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[O:4][C:5]1[CH:10]=[N:9][NH:8][C:7](=[O:17])[CH:6]=1
Reactant: O=c1cc(Oc2c(F)cccc2F)cnn1C1CCCCO1
Agent: Cl
Solvent: CO
Solvent: O
Product: O=c1cc(Oc2c(F)cccc2F)cn[nH]1
Temperature: 110 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
A solution of 5-(2,6-difluoro-phenoxy)-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (92.3 mg, 0.30 mmol) in methanol (0.6 mL, 0.5M) was treated with a 6N aqueous hydrochloric acid solution (0.25 L, 1.2M). The reaction was heated at 110° C. for 1 h and then stood at 25° C. overnight. At this point, the reaction was charged with water (10 mL). The solids were crushed, filtered, rinsed, and dried in vacuo to afford 5-(2,6-difluoro-phenoxy)-2H-pyridazin-3-one (45.7 mg, 68%) as an off-white solid; 1H-NMR (400 MHz, DMSO-d6) δ ppm 5.91 (s, 1H), 7.25-7.43 (m, 2H), 7.43-7.57 (m, 1H), 8.11 (d, J=2.6 Hz, 1H), 13.10 (brs, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:12]([OH:18])[CH2:13][CH2:14][CH2:15][CH2:16][OH:17]>>[Br:1][C:2]1[C:3]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][OH:18])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: OCCCCCO
Product: O=C(O)c1cnc(OCCCCCO)c(Br)c1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 31a, using 5-bromo-6-chloro-nicotinic acid and 1,5-pentanediol as starting materials to give the product as brownish oil, MS (ISP): 302.3 (M−H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[C:9]([NH2:19])=[N:10][N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][N:23]=1>N1C=CC=CC=1.C(Cl)Cl>[Cl:21][C:22]1[N:23]=[CH:24][C:25]([C:26]([NH:19][C:9]2[C:8]([NH:7][C:6](=[O:20])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:12][N:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:10]=2)=[O:27])=[CH:29][CH:30]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)Nc1cn(-c2ccccc2)nc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cn(-c2ccccc2)nc1NC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of t-butyl(3-amino-1-phenyl-1H-pyrazol-4-yl)carbamate (100 mg, 0.364 mmol) in pyridine (500 μL) was added 6-chloronicotinoyl chloride (53 mg, 0.304 mmol) in CH2Cl2 (2 mL). After 6 hours of stirring at room temperature, the reaction mixture was filtered and the solvent concentrated. Formation of t-butyl(3-{[(6-chloropyridin-3-yl)carbonyl]amino}-1-phenyl-1H-pyrazol-4-yl)carbamate (J) was confirmed by MS (ESI+): cal'd [M+H]+ 414.1, obs'd 414.1.
Reaction SMILES: [Br:1][C:2]1[C:8]([O:9]C)=[CH:7][C:5]([NH2:6])=[C:4]([O:11][CH3:12])[CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23]C)C(O)=O>>[Br:1][C:2]1[C:8]([OH:9])=[CH:7][C:5]2[N:6]=[C:12]([C:16]3[CH:20]=[CH:21][C:22]([OH:23])=[C:14]([F:13])[CH:15]=3)[O:11][C:4]=2[CH:3]=1
Reactant: COc1ccc(C(=O)O)cc1F
Reactant: COc1cc(Br)c(OC)cc1N
Product: Oc1ccc(-c2nc3cc(O)c(Br)cc3o2)cc1F

Procedure:
The title compound was prepared in substantially the same manner as described in Example 16, from 4-bromo-2,5-dimethoxyaniline, and 3-fluoro-4-methoxybenzoic acid and was obtained as a white solid, m.p. 224–226° C.; MS m/e 322 (M−H)+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:12]=[CH:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[N:9]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[Cl:20][C:15]1[CH:14]=[C:13]([N:10]2[CH:11]=[CH:12][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:9]2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: Clc1ccc(-n2ccc(OCCOCCBr)n2)cc1Cl
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(-n2ccc(OCCOCCN3CCCCC3)n2)cc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
A mixture of 3-(2-(2-bromoethoxy)ethoxy)-1-(3,4-dichlorophenyl)-1H-pyrazole (0.17 mg, 0.45 mmol), piperidine (62 mg, 0.72 mmol), potassium carbonate (0.25 g, 1.8 mmol) and sodium iodide (67 mg, 0.45 mmol) in dimethylformamide (5 ml) was stirred at 100° C. overnight in a dry nitrogen atmosphere. The solvent was evaporated in vacuo and water and ethyl ether was added. The aqueous phase was extracted several times with organic solvent and the combined organic phases washed with water, dried over sodium sulphate, filtered and evaporated to dryness in vacuo. The crude dark oil obtained, 138 mg, was purified by column chromatography on silica gel (eluent: ethyl acetate/petroleum ether 2:8 to 10:0 and ethyl acetate/CH3OH 9:1) yielding 118 mg of 1-(2-(2-(1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy)ethoxy)ethyl)piperidine as an oil
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=[O:15])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([O:16][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:15])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (2.5 g, 11.0 mmol) and Cs2CO3 (3.94 g, 12.1 mmol) in DMF (50 mL) at 0° C. benzylbromide (2.26 g, 13.2 mmol) was added dropwise. The reaction mixture was stirred overnight at RT under a nitrogen atmosphere. DMF was evaporated. The residue was dissolved in EtOAc and washed with a sat. aq. solution of NaHCO3, the layers were separated and the aqueous phase was extracted with EtOAc (×2). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 100:0 to 0:100) to give the desired material as a colorless oil. MS (LCMS): 318.2 [M+H]+; tR (HPLC conditions b): 2.23 min.
Reaction SMILES: [O:1]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH:19]=O)[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:9]=O.[C:26]([NH:29][NH2:30])([NH2:28])=[NH:27].[ClH:31]>CO.Cl.Cl.NNC(N)=N>[ClH:31].[ClH:31].[C:26]([NH:29][N:30]=[CH:19][C:18]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:16]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH:9]=[N:30][NH:29][C:26](=[NH:27])[NH2:28])[CH:17]=1)(=[NH:28])[NH2:27]
Reactant: COc1ccc(C=O)cc1OCCCOc1cc(C=O)ccc1OC
Reactant: N=C(N)NN
Agent: Cl
Solvent: CO
Product: COc1ccc(C=NNC(=N)N)cc1OCCCOc1cc(C=NNC(=N)N)ccc1OC
Yield: 86.5 %

Procedure:
3,3'-(trimethylenedioxy)di-p-anisaldehyde (1.032 g), aminoguanidine hydrochloride (0.829 g), and aminoguanidine dihydrochloride (0.02 g) were heated in 95% methanol (10.5 mL) for 16 hr. Cooling and filtration gave 1.372 g of 3,3'-(trimethylenedioxy)di-p-anisaldehyde bis(amidinohydrazone) dihydrochloride, mp 233°-5° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([CH3:19])[CH:18]=1)[N:15]=[C:14]([O:20][CH3:21])[CH:13]=[CH:12]2>ClCCl>[C:1]([NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([CH3:19])[CH:18]=1)[N:15]=[C:14]([O:20][CH3:21])[CH:13]=[CH:12]2)(=[O:3])[CH3:2]
Reactant: COc1ccc2cc(N)cc(C)c2n1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COc1ccc2cc(NC(C)=O)cc(C)c2n1

Procedure:
A solution of acetic anhydride (0.55 cm3) in dichloromethane (20 cm3) was added dropwise to a stirred solution of 6-amino-2-methoxy-8-methylquinoline (1.0 g) in dichloromethane (30 cm3) at room temperature. After 1 hour the solution was diluted with dichloromethane (50 cm3), washed with saturated sodium carbonate solution (10 cm3), and dried (MgSO4). Evaporation of the solution in vacuo afforded to a solid which was recrystallised from dichloromethane/hexane to give 6-acetamido-2-methoxy-8-methylquinoline, m.p. 193°-196° (1.143 g).
Reaction SMILES: [ClH:1].[CH3:2][CH2:3][O:4][C:5]([N:7]1[C:11]([NH:12][C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[CH:16][C:15]=2[N+:27]([O-:29])=[O:28])=[C:10]2[CH2:31][N:32](C(OC(C)(C)C)=O)[C:33]([CH3:35])([CH3:34])[C:9]2=[N:8]1)=[O:6]>O1CCOCC1>[ClH:1].[ClH:1].[CH2:3]([O:4][C:5]([N:7]1[C:11]([NH:12][C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[CH:16][C:15]=2[N+:27]([O-:29])=[O:28])=[C:10]2[CH2:31][NH:32][C:33]([CH3:34])([CH3:35])[C:9]2=[N:8]1)=[O:6])[CH3:2]
Reactant: CCOC(=O)n1nc2c(c1NC(=O)c1ccc(N3CCN(C)CC3)cc1[N+](=O)[O-])CN(C(=O)OC(C)(C)C)C2(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)n1nc2c(c1NC(=O)c1ccc(N3CCN(C)CC3)cc1[N+](=O)[O-])CNC2(C)C
Reaction time: 30 h

Procedure:
A solution of 4N HCl in 1,4-dioxane (4 eq., 18.4 mL, 73.6 mmol) was added to a stirred solution of 6,6-dimethyl-3-[4-(4-methyl-piperazin-1-yl)-2-nitro-benzoylamino]-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester (10.5 g, 18.4 mmol) in 1,4-dioxane (100 mL) at room temperature. Stirring was continued for 30 hours. After removal of the solvent, the crude material was treated with diethyl ether (2×100 mL) and evaporated to dryness. The title compound was obtained after crystallization from diethyl ether as yellow solid (10 g, quantitative).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5](/[CH:9]=[CH:10]/[S:11]([NH2:14])(=[O:13])=[O:12])[CH:4]=1.[Cl:15][C:16]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].O>O1CCOCC1>[Cl:15][C:16]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:17]=1[C:18]([NH:14][S:11](/[CH:10]=[CH:9]/[C:5]1[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=1)(=[O:12])=[O:13])=[O:19]
Reactant: NS(=O)(=O)/C=C/c1cccnc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NS(=O)(=O)/C=C/c1cccnc1)c1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil) (36 mg, 0.9 mmol) was added to a solution of (E)-2-Pyridin-3-yl-ethenesulfonic acid amide (56 mg, 0.3 mmol) in dioxane (1 mL) and the mixture was shaken for 30 minutes. A solution of 2,4-dichlorobenzoyl chloride (63 μL, 0.45 mmol) in dioxane (0.5 mL) was added to the mixture and the whole was shaken at room temperature for 18 hours. Water (0.1 mL) was added to the mixture and the whole was concentrated in vacuo. The resultant residue was purified by preparative HPLC to give (E)-2-pyridin-3-yl-ethenesulfonic acid 2,4-dichloro-benzoylamide (29.1 mg, 26%) as sodium salt.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([C@@H:8]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]2[OH:10])[CH:6]=[N:5][C:4]=1[C:17](=[N:19]O)[NH2:18].CO.[OH-].[Na+].[C:25](=S)=[S:26]>>[CH:6]1[N:7]([C@@H:8]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]2[OH:10])[C:3]2[C:4](=[C:17]([NH2:18])[NH:19][C:25]([N:2]=2)=[S:26])[N:5]=1
Reactant: NC(=NO)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1N
Reactant: S=C=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 95 %

Procedure:
10.0 g of 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide oxime hydrochloride was dissolved in 200 ml of an aqueous solution containing 175 ml of methanol, and the resulting solution was adjusted to a pH of 9 with sodium hydroxide. 50 ml of carbon disulfide was added to the solution, and the mixture was allowed to react in an autoclave at a temperature of 120° C for 5 hours under autogenous pressure (about 10 Kg/cm2) followed by working up in the same manner as described in Example 1 to obtain 9.7 g of 2-thioadenosine having a melting point of 198° C (with decomposition) in a 95% yield.
Reaction SMILES: [NH2:1]OS(O)(=O)=O.[NH2:7][C:8]1[NH:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1.[OH-].[K+]>O>[NH2:1][N:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[NH2:7]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: NOS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2ccccc2n1N
Reaction time: 0.5 h

Procedure:
Hydroxylamine O-sulphonic acid (tech. 23.25 g, 205 mmol) was added to a stirred solution of 2-aminobenzimidazole (25 g, 187.5 mmol) dissolved in water (600 ml) containing potassium hydroxide (24.6 g, 438 mmol) at 23° C. After a few moments a white solid began to precipitate. The mixture was stirred for 30 mins and the product collected by filtration, washed with water and dried in air at ambient temperature, 10.75 g. On standing overnight a second crop, 5.8 g was obtained. The total yield of product was 16.55 g, 60%, mp. 252°-254° C., (lit. 255°-259° C.). Spectroscopic analysis was consistent with the product but indicated a small amount of the starting material was also present. This was used without further purification (note 1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([CH3:15])[C:11](OC)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOC(C)=O.CCCCCC>C1COCC1>[CH2:1]([O:8][CH2:9][C@@H:10]([CH3:15])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](C)COCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@@H](CO)COCc1ccccc1
Temperature: 27.5 °C
Yield: 88.5 %

Procedure:
An oven dried three-necked 2 L round bottom flask was equipped with a mechanical stirrer, a reflux condenser and a 500 mL constant pressure addition funnel. The flask was charged with a solution of 62.252 g (0.299 mol) of methyl (S)-3-benzyloxy-2-methylpropanoate in 600 mL of anhydrous THF, and a 1.0 M solution of lithium aluminum hydride (300 mL; 0.3 mol) was transferred into the dropping funnel via a cannula. Stirring was started and the lithium aluminum hydride solution was added over 45 minutes to the reaction under an N2 atmosphere while the temperature of the reaction mixture was maintained between 25-30° C. using an external ice-water bath. After the addition was complete, the reaction was stirred an additional 6 h at room temperature at which point TLC analysis (20% EtOAc-hexane) indicated complete reaction. The reaction mixture was then cooled with an external ice-water bath and quenched by serial addition of 11.4 mL water, 11.4 mL of 15% aqueous NaOH, and 34.2 mL water. The reaction mixture was then filtered, the solids were washed with EtOAc, the filtrate and washings were combined and evaporated in vacuo. The residue was redissolved in EtOAc, washed with 10% aqueous NaHSO4, saturated NaCl, dried (MgSO4), filtered and evaporated. The residue was purified by Kugelrohr distillation to afford 47.67 g (89%) of the title compound as an oil.
Reaction SMILES: [CH:1]1([N:7]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)Cl>[CH:1]1([N:7]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(CO)cc1)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Solvent: ClCCl
Product: O=Cc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.7 %

Procedure:
A solution of 6-[cyclohexyl(cyclopropylmethyl)amino]-N-[4- (hydroxymethyl)phenyl]pyrimidine-4-carboxamide (Intermediate 23, 990 mg; 2.60 mmol) in DCM (100 ml) was treated with Mn02 (2262 mg; 26.0 mmol) and the reaction mixture was stirred at room temperature for 18 hours the mixture was filtered through celite and the solvent was removed under vacuum affording the title compound as a yellow solid (912 mg; 79%), which was used without further purification for the following steps.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22](Br)[CH:23]=3)[C:18](=[O:26])[N:17](S(C3C=CC=CC=3)(=O)=O)[CH:16]=2)[CH2:10][C@@H:9]1[CH2:36][OH:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:38]1([NH:41][C:42](=[O:60])[C:43]2[CH:48]=[C:47](B3OC(C)(C)C(C)(C)O3)[C:46]([CH3:58])=[C:45]([F:59])[CH:44]=2)[CH2:40][CH2:39]1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:47]4[CH:48]=[C:43]([C:42](=[O:60])[NH:41][CH:38]5[CH2:39][CH2:40]5)[CH:44]=[C:45]([F:59])[C:46]=4[CH3:58])[CH:23]=3)[C:18](=[O:26])[NH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:36][OH:37])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cn(S(=O)(=O)c3ccccc3)c(=O)c3ccc(Br)cc23)C[C@@H]1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)[nH]cc(CN3CCN(C(=O)OC(C)(C)C)[C@@H](CO)C3)c2c1
Temperature: 80 °C
Yield: 27.4 %

Procedure:
A solution of tert-butyl-(2R)-4-((6-bromo-1-oxo-2-(phenylsulfonyl)-1,2-dihydroisoquinolin-4-yl)methyl)-2-(hydroxymethyl)piperazine-1-carboxylate (Example 11e, 2.3 g) in DMF (20 mL) was treated with N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (1.24 g), Pd-118 (0.08 g) and potassium carbonate (0.86 g) under nitrogen. The resulting mixture was heated at 80° C. for 10 h. The reaction mixture was diluted with water (300 mL), acidified with acetic acid (to pH 5) and extracted with ethyl acetate (300 mL). The organic was dried (MgSO4), filtered and evaporated to afford crude product. Purification (SiO2 chromatography, elution with 1% AcOH in ethyl acetate) afforded the subtitle compound (0.60 g) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21]/[C:22](/[CH3:25])=[CH:23]/[CH3:24])=[C:6]([CH:19]=1)[CH2:7][N:8]1[C:12]([CH3:13])=[CH:11][C:10]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[N:9]1>CCOC(C)=O.CCCC(C)C.O=[Pt]=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][CH:22]([CH3:25])[CH2:23][CH3:24])=[C:6]([CH:19]=1)[CH2:7][N:8]1[C:12]([CH3:13])=[CH:11][C:10]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[N:9]1
Reactant: C/C=C(\C)COc1ccc(Br)cc1Cn1nc(CCC(=O)O)cc1C
Agent: O=[Pt]=O
Solvent: CCCC(C)C
Solvent: CCOC(C)=O
Product: CCC(C)COc1ccc(Br)cc1Cn1nc(CCC(=O)O)cc1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of 24 (0.1 g, 0.24 mmol) and PtO2 (0.02 g) in EtOAc (10 mL) and isohexane (10 mL), previously purged with nitrogen, was stirred under a hydrogen atmosphere (balloon) at RT for 90 min. The catalyst was removed by filtration through Hyflo, the filtrate was evaporated to dryness and the residue was purified on silica to yield the title compound 25, 0.027 g (26%).