Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH:14]=1)=[O:4].[OH-].[Na+]>>[CH3:13][N:10]1[C:9]2[CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]=2[N:12]=[N:11]1
Reactant: COC(=O)c1ccc2nnn(C)c2c1
Agent: [Na+]
Agent: [OH-]
Product: Cn1nnc2ccc(C(=O)O)cc21

Procedure:
The methyl ester (a) is hydrolysed with NaOH, yielding the title compound.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][NH2:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:15]1[N:20]=[C:19](Cl)[C:18]2[N:22]=[CH:23][N:24]([C@@H:25]3[O:29][C@H:28]([CH2:30][OH:31])[C@@H:27]([OH:32])[C@H:26]3[OH:33])[C:17]=2[N:16]=1>>[C:1]1([C:7]2([CH2:13][NH:14][C:19]3[C:18]4[N:22]=[CH:23][N:24]([C:17]=4[N:16]=[CH:15][N:20]=3)[C@@H:25]3[O:29][C@H:28]([CH2:30][OH:31])[C@@H:27]([OH:32])[C@H:26]3[OH:33])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCC1(c2ccccc2)CCCCC1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC4(c5ccccc5)CCCCC4)ncnc32)[C@H](O)[C@@H]1O
Yield: 42.4 %

Procedure:
(1-Phenylcyclohexyl)methylamine (1.80 g, 8 mmol) as prepared below, and 6-chloropurine riboside (2.36 g, 8 mmol) are reacted as described in Example 1. The solvent is removed under reduced pressure, and the residue dissolved up in CHCl3 and washed with water and dried (MgSO4). The solvent is removed under reduced pressure and the residual white foam is purified on silica gel chromatography eluting with 10% MeOH in CH2Cl2 to give N6-((1-phenylcyclohexyl)methyl)adenosine (1.49 g, 42%) as a white glass m.p. 87°-9° C. Found: C, 62.22; H, 6.96; N, 15.70%. C23H29N5O4 calculated requires: C, 62.87; H, 6.61; N, 15.95%.
Reaction SMILES: Br[C:2]1C=C(NC2C=CC(N3CCN(C(C)C)CC3)=CN=2)C(=O)N(C)C=1.[Br:26][C:27]1[N:28]=[C:29]([NH:35][C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)[CH2:41][NH:40][CH2:39]3)[C:30](=[O:34])[N:31]([CH3:33])[CH:32]=1>>[Br:26][C:27]1[N:28]=[C:29]([NH:35][C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)[CH2:41][N:40]([CH3:2])[CH2:39]3)[C:30](=[O:34])[N:31]([CH3:33])[CH:32]=1
Reactant: CC(C)N1CCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Reactant: Cn1cc(Br)nc(Nc2ccc3c(c2)CNC3)c1=O
Product: CN1Cc2ccc(Nc3nc(Br)cn(C)c3=O)cc2C1

Procedure:
Following the procedures as described for 220a and starting with 336 mg of 5-bromo-3-(isoindolin-5-ylamino)-1-methylpyrazin-2(1H)-one, compound 231f was obtained as a yellow solid (237 mg, 75%). MS: [M+H]+ 337. 1H NMR (500 MHz, CDCl3) δ 8.31 (s, 1H), 7.67 (s, 1H), 7.52 (t, J=7.0, 1H), 7.18 (d, J=8.0, 1H), 6.74 (s, 1H), 3.94 (s, 2H), 3.89 (s, 2H), 3.52 (s, 3H), 2.60 (s, 3H).
Reaction SMILES: [OH-].[Na+].Cl[CH:4]([NH:9][C:10](=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17]C(=O)C)[C:5]([Cl:8])([Cl:7])[Cl:6].CC(C)=O.[C:26]1([SH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[C:26]1([S:32][CH:4]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[C:5]([Cl:6])([Cl:7])[Cl:8])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)Oc1ccccc1C(=O)NC(Cl)C(Cl)(Cl)Cl
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(NC(Sc1ccccc1)C(Cl)(Cl)Cl)c1ccccc1O
Reaction time: 1 h
Yield: 80 %

Procedure:
10.3 g of a 20% acqueous NaOH solution was added dropwise to the mixture of 16.6 g of N-(1,2,2,2-tetrachloroethyl)-2-acetoxybenzamide, 70 ml of acetone and 5.3 g of phenyl mercaptan under stirring at 10°-15° C. The reaction was effected at room temperature for one hour. Water was added thereto, the dichloromethane layer was separated, and the solution was dried and concentrated. 100 ml of ethanol and 1.5 ml of 35% hydrochloric acid were added to the residue and the reaction was effected under reflux for two hours. The solvent was distilled off to obtain 14.5 g of N-(1-phenylthio-2,2,2-trichloroethyl)-2-hydroxybenzamide as white crystals.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[N:11]1[S:12][N:13]=[C:14]2[C:19]([S:20](Cl)(=[O:22])=[O:21])=[CH:18][CH:17]=[CH:16][C:15]=12>C([O-])(O)=O.[Na+].C(OCC)C.O>[N:11]1[S:12][N:13]=[C:14]2[C:19]([S:20]([O:5][C:4]3[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=3)(=[O:22])=[O:21])=[CH:18][CH:17]=[CH:16][C:15]=12
Reactant: Cc1cc(O)cc(O)c1
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc3nsnc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and benzo-2,1,3-thiadiazole-4-sulfonyl chloride (2.35 g, 10.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 5% ethyl acetate in dichloromethane) to give the title compound as a pale yellow solid (2.55 g, 79%). 1H-NMR (300 MHz, CDCl3) δ 8.34 (d, J=8.8 Hz, 1H), 8.26 (d, J=7.1 Hz, 1H), 7.72 (t, J=8.8 Hz, 1H), 6.53 (s, 1H), 6.47 (s, 1H), 6.37 (s, 1H), 5.24 (s, 1H), 2.19 (s, 1H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[C:5]([Si:9]([CH3:12])([CH3:11])Cl)([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CC=CN=1)C>[Si:9]([O:4][CH2:3][CH2:2][Br:1])([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:12])[CH3:11]
Reactant: OCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCBr
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of 2-bromoethanol (50 g, 0.40 mol) in CH2Cl2 (50 mL) was added t-butyldimethyl-chlorosilane (63.4 g, 0.42 mol), triethylamine (45.4 g, 0.45 mol) and dimethylaminopyridine (0.5 g). After stirring overnight the reaction mixture was washed 3× with water. The organic fraction was dried with Na2SO4, filtered, and concentrated in vacuo to provide 85 g of the title compound as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([N:22]2[C@H:31]([CH3:32])[CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23]2)=[O:21])=[C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH3:14])=[C:10]([C:15]([O:17]CC)=[O:16])[CH:9]=2)[CH:7]=1.[Li+].[OH-].[NH4+].[Cl-]>O1CCOCC1.O.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([N:22]2[C@H:31]([CH3:32])[CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23]2)=[O:21])=[C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH3:14])=[C:10]([C:15]([OH:17])=[O:16])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cc(Cl)ccc2C(=O)N2Cc3ccccc3C[C@H]2C)n(C)c1C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(C(=O)O)cc(-c2cc(Cl)ccc2C(=O)N2Cc3ccccc3C[C@H]2C)n1C
Temperature: 100 °C

Procedure:
To a solution of 1.7 g of the compound obtained in Step A (3.77 mmol) in 5 mL of dioxane there is added 0.317 g of LiOH (7.5 mmol) dissolved in 5 mL of water. The batch is heated in a microwave apparatus for 4 hours at 100° C. (power 140 W). The reaction mixture is then filtered and concentrated to dryness. The residue thereby obtained is taken up in dichloromethane (50 mL) and then saturated aqueous NH4Cl solution is added thereto. The organic phase is washed with water and then with brine, dried over MgSO4, filtered and concentrated to dryness. The title product is obtained in the form of a solid and is used directly in the next Step.
Reaction SMILES: [CH:1]1([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[Na].Cl>CO>[C:1]1([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: COC(=O)C1C=CCCC1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COC(=O)C1=CCCCC1
Yield: 87.5 %

Procedure:
Methyl 2-cyclohexene-1-carboxylate (4.0 g; 28.5 m. moles) was added to a solution of sodium (0.73 g; 31.7 m. moles) in methanol (20 ml) and the mixture was allowed to stand at room temperature for a period of 21/2 hours. The mixture was poured into dilute hydrochloric acid, extracted with ether (4×25 ml) and the combined extracts washed with dilute aqueous sodium carbonate and then water. The dried (MgSO4) extract was evaporated and the residue distilled to give methyl 1-cyclohexene-1-carboxylate (3.5 g; yield 87.5%), b.p. 84° C./15 mm.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][N:12]=1.C(O)(=O)[CH2:20][C:21]([OH:23])=[O:22].N1CCCCC1>N1C=CC=CC=1>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[N:12]=[CH:13][C:14](/[CH:15]=[CH:20]/[C:21]([OH:23])=[O:22])=[CH:17][CH:18]=1
Reactant: O=Cc1ccc(NC2Cc3ccccc3C2)nc1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1ccc(NC2Cc3ccccc3C2)nc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 100.9 %

Procedure:
To a stirred solution of 6-(2,3-dihydro-1H-inden-2-ylamino)nicotinaldehyde (160 mg) and malonic acid (84 mg) in pyridine (6 mL) was added piperidine (0.01 mL), and the mixture was stirred at 100° C. for 2 hours. The solvent was evaporated in vacuo and the resulting powder was collected by filtration to give (2E)-3-[6-(2,3-dihydro-1H-inden-2-ylamino)-3-pyridinyl]acrylic acid (190 mg) as a pale yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([NH:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][C:19]2=[O:24])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[Cl:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH:38]=[C:37]([S:42](Cl)(=[O:44])=[O:43])[CH:36]=[CH:35]2>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]([NH:17][N:18]2[CH2:23][CH2:22][N:21]([S:42]([C:37]3[CH:36]=[CH:35][C:34]4[C:39](=[CH:40][CH:41]=[C:32]([Cl:31])[CH:33]=4)[CH:38]=3)(=[O:43])=[O:44])[CH2:20][C:19]2=[O:24])=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)NN2CCNCC2=O)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)NN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(4-benzyloxycarbonyl-2-oxo-1-piperazinyl)-2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetamide (840 mg) and 10% Pd/C (500 mg) in methanol (35 ml) was stirred at room temperature for 15 hours under a hydrogen atmosphere. The catalyst was filtered off and the reaction mixture was concentrated to obtain N-(2-oxo-1-piperazinyl)-2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetamide as a colorless syrup. A solution of the resultant 2-[1-(tert-butoxycarbonyl)-4-piperidinyl]-N-(2-oxo-1-piperazinyl)acetamide in ethyl acetate (40 ml) and a 10% aqueous solution of sodium carbonate (40 ml) was combined at 0° C. with 6-chloronaphthalene-2-sulfonyl chloride (470 mg) and stirred at room temperature for 30 minutes. The organic phase was separated, washed with brine, dried and concentrated to obtain a residue, which was purified by a column chromatography on a silica gel (ethyl acetate) and crystallized from ethyl acetate to obtain the title compound (420 mg) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][N:14]1[CH:18]=[CH:17][C:16]([C:19](O)=[O:20])=[N:15]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:19]([C:16]3[CH:17]=[CH:18][N:14]([CH3:13])[N:15]=3)=[O:20])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cn1ccc(C(=O)O)n1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cn1ccc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.1 %

Procedure:
TEA (1.21 mL, 8.69 mmol) was added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (400 mg, 1.74 mmol, Example 1, Step H), 1-methyl-1H-pyrazole-3-carboxylic acid (260 mg, 2.09 mmol) and BOP-Cl (60 mg, 2.61 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 1 hour, and then a LiOH solution (3 mL, 2N) was added. The mixture was stirred for 30 minutes, and water (10 mL) was added. The solid formed was collected by filtration, washed with DCM (5 mL) and dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-1H-pyrazole-3-carboxamide (30 mg, 66% yield) as a solid.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[NH:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].[C:24]([O:28][C:29](=[O:40])[NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]Br)[CH:33]=1)([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C>[C:24]([O:28][C:29](=[O:40])[NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][N:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:2]([Br:1])[C:3]2=[O:17])[CH:33]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: O=c1[nH]ccc(OCc2ccc(F)cc2)c1Br
Reactant: CC(C)(C)OC(=O)NCc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cccc(Cn2ccc(OCc3ccc(F)cc3)c(Br)c2=O)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 20.2 %

Procedure:
To a solution of 3-bromo-4-(4-fluorobenzyloxy)pyridine-2(1H)-one (from Step 3, synthesis EXAMPLE 59) (0.2 g, 0.67 mmol) in DMF (11 mL) was added K2CO3 (0.26 g, 1.3 mmol) and 3-(bromomethyl)benzylcarbamic acid tert-butyl ester (0.23 g, 0.80 mmol), and the reaction mixture was stirred at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with a 50% aqueous solution of brine (24 mL), and extracted with CHCL3 (4×50 mL). The combined organics was washed water and then brine, dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 3:7 EtOAc/hexanes) and recrystallization from MeOH afforded {3-[3-bromo-4-(4-fluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]benzyl}carbamic acid tert-butyl ester as an off-white solid (0.07 g, 20%): mp 136-138° C.; 1H NMR (300 MHz, CDCl3) δ 7.42-7.37 (m, 2H), 7.30-7.20 (m, 5H), 7.08 (t, J=9 Hz, 2H), 6.04 (d, J=9 Hz, 1H), 5.16 (s, 2H), 5.14 (s, 2H), 4.28 (d, J=6 Hz, 1H), 1.44 (s, 9H). ES HRMS m/z 517.1124 (M+H C25H27BrFN2O4 requires 517.1133).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25](Br)[N:26]=3)[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[OH:37][C:38]1[CH:39]=[CH:40][CH:41]=[C:42]2[C:47]=1N=CC=C2.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(O)CCCCC1>CCOC(C)=O.[Cu]I>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([O:37][CH:38]4[CH2:39][CH2:40][CH2:41][CH2:42][CH2:47]4)[N:26]=3)[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: Oc1cccc2cccnc12
Reactant: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CCC(C#N)CC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: OC1CCCCC1
Product: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(OC3CCCCC3)nc12)C(=O)N1CCC(C#N)CC1
Temperature: 120 °C
Yield: 50 %

Procedure:
A 10 mL flask was charged with 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide (100 mg, 0.17 mmol, copper(I) iodide (1.7 mg, 0.009 mmol), 8-hydroxyquinoline (2.5 mg, 0.017 mmol) and potassium phosphate tribasic (74 mg, 0.34 mmol) under argon atmosphere. Cyclohexanol (1.82 mL, 17.3 mmol) was added and the reaction mixture was heated at 120° C. for 24 h. The reaction mixture was allowed to reach room temperature and then diluted with EtOAc (10 mL). The slurry was filtered over a celite pad and the filtrate was evaporated under vacuum. The crude residue was purified by preparative TLC (SiO2, Hex:EtOAc, 1:1×2) to give 52 mg (50%) of 2-cyclohexyloxy-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide. (M+Na)+=619.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Sc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CCO
Product: COc1ccc(Sc2ccc(N)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
To a solution of 13.06 g of 4-(4-methoxy-phenylsulfanyl)-nitrobenzene from step 1 in 100 mL of ethanol was added 33.85 g of SnCl2−2H2O. The resulting mixture was stirred for 30 minutes at room temperature, then heated to reflux for 2 hours. The mixture was then cooled to room temperature, concentrated in vacuo, and treated with 20% aqueous NaOH. The solution was extracted three times with ethyl acetate, and the combined extracts were washed with water followed by brine, dried (MgSO4), after which the ethyl acetate was removed in vacuo. The resulting solid was chromatographed on SiO2 (70%/30% dichloromethane/hexanes) to afford 7.87 g (68%) of 4-(4-methoxy-phenylsulfanyl)-phenylamine. Mp: 91–92° C. MS M+H: 232.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:19][CH2:18][C:13]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:12][CH:11]2O)=[C:6]([F:21])[C:5]=1[F:22])[CH3:2].O.C(O)CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:19][CH2:18][C:13]3([O:14][CH2:15][CH2:16][O:17]3)[CH2:12][CH:11]=2)=[C:6]([F:21])[C:5]=1[F:22])[CH3:2]
Reactant: CCOc1ccc(C2CCC3(CC2O)OCCO3)c(F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: OCCO
Solvent: O
Product: CCOc1ccc(C2=CCC3(CC2)OCCO3)c(F)c1F

Procedure:
609 g (about 1.94 mol) of crude 8-(4-ethoxy-2,3-difluorophenyl)-1,4-dioxaspiro[4.5]decan-7-ol in 2000 ml of toluene are heated on a water separator for 2 h together with 220 ml (3.93 mol) of ethylene glycol with addition of 36.1 g (0.19 mol) of p-toluenesulfonic acid monohydrate. After cooling, the batch is washed successively with water, sat. sodium hydrogencarbonate solution and sat. sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness. The crude product (507 g of orange oil) is crystallised from ethanol at −20° C., giving 8-(4-ethoxy-2,3-difluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene as yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N+:7]([CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)([O-])=O.CO.[OH-].[Na+]>C1COCC1.O>[F:19][C:18]([F:20])([F:21])[C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][NH2:7])=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])C=Cc1ccc(C(F)(F)F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: NCCc1ccc(C(F)(F)F)cc1
Yield: 31 %

Procedure:
Lithium aluminum hydride (0.558 g, 14. 7 mmol) was suspended in THF (10 ml), to which a solution of 1-(2-nitrovinyl)-4-trifluoromethylbenzene (1.596 g, 7.35 mmol) prepared in Reference Example 118 in THF (10 ml) was added dropwise while cooling in an ice-bath, and the mixture was heated under reflux for 2 hours. Methanol was slowly added to the mixture until it no longer foamed. Water (0.6 ml), 15% sodium hydroxide aqueous solution (0.6 ml) and water (1.8 ml) were added in this order, and the insoluble substances were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel with an amine-treated surface (Fuji Silysia; NH-DM1020, solvent; methylene chloride/n-hexane=4/1) to afford 2-(4-trifluoromethylphenyl)ethylamine (0.431 g, yield 31%) as an orange-colored oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:31][CH2:30][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[CH:27]=[CH:26][C:25]([CH:28]=[O:29])=[CH:24][CH:23]=5)=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4].[BH4-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:31][CH2:30][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=5)=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5ccc(C=O)cc5)cc4c3C2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5ccc(CO)cc5)cc4c3C2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.5 %

Procedure:
To a solution of Example 102 (0.150 g, 0.36 mmol) in DCM was added NaBH4 (0.069 g, 1.81 mmol) under nitrogen atmosphere at 0° C. The reaction mixture temperature was raised to room temperature and continued stirring for 3 hr. The progress of the reaction was monitored by TLC and upon completion, the mixture was partitioned between DCM (25 mL) and water (15 mL) and the organic layer was separated, dried over Na2SO4 filtered and the solvent was removed under reduced pressure to give crude residue, which was purified by column chromatography using silica gel to provide methyl-2-{8-[4-(hydroxymethyl)phenyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (0.050 g, 33.2%).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([C:7]1[CH:8]=[CH:9][C:10]([O:23]CC2C=CC=CC=2)=[C:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:12]=1)[OH:6])=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH2:4][C@@H:5]([C:7]1[CH:8]=[CH:9][C:10]([OH:23])=[C:11]([NH:13][S:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH:12]=1)[OH:6]
Reactant: [N-]=[N+]=NC[C@H](O)c1ccc(OCc2ccccc2)c(NS(=O)(=O)c2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: NC[C@H](O)c1ccc(O)c(NS(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Yield: 68.8 %

Procedure:
A mixture of N-[5-((1R)-2-azido-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-benzenesulfonamide (1.4 g, 3.3 mmol) (which was obtained in Example 31), HCO2NH4 (2.08 g, 3.3 mmol), and 10% Pd/C in absolute ethanol (15 mL) under nitrogen atmosphere was heated under reflux for 2.5 hours. The mixture was cooled to room temperature, filtered through celite pad, and filtrate concentrated and placed under high vacuum to give the titled compound as yellow solid (0.7 g, 69%); 1H NMR (300 MHz, DMSO-d6) δ 2.74 (d, J=15 Hz, 2H), 4.51 (d, J=6 Hz, 1H), 6.63 (d, J=9 Hz, 1H), 6.76 (d, J=9 Hz, 1H), 7.12 (s, 1H), 7.47 (m, 4H), 7.72 (d, J=6 Hz, 2H).
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[C:20](Cl)(=[O:22])[CH3:21]>>[C:20]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[CH2:7][O:6][C:5]1[CH:13]=[CH:14][CH:15]=[C:16]([N+:17]([O-:19])=[O:18])[C:4]=1[C:2]#[N:3])(=[O:22])[CH3:21]
Reactant: N#Cc1c(OC[C@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Agent: [Cl-]
Product: CC(=O)N1CCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 176b from (R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride and acetyl chloride in 100% yield as a yellow syrup. MS 290 (MH+).