Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:23]#[C:24][CH2:25][CH2:26][CH3:27].Cl>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:23]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)#[C:24][CH2:25][CH2:26][CH3:27]
Reactant: C#CCCC
Reactant: CCCC1CCC(C2CCC(c3ccc(Br)cc3)CC2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Product: CCCC#Cc1ccc(C2CCC(C3CCC(CCC)CC3)CC2)cc1
Temperature: 0 °C

Procedure:
8.0 g (22.0 mmol) of 4′-(4-bromophenyl)-4-propylbicyclohexyl are stirred at 60° C. for 60 h in 80 ml of NEt3 together with 4.4 ml (44.0 mmol) of 1-pentyne in the presence of 309 mg (0.44 mmol) of bis(triphenylphosphine)palladium(II) chloride and 42 mg (0.22 mmol) of copper(I) iodide. The batch is added to ice-water and acidified using hydrochloric acid. The mixture is extracted with MTBE, and the combined organic phases are washed with water and sat. sodium chloride solution. The solution is concentrated to completion, and the crude product is purified by column chromatography (SiO2, n-heptane). The further purification is carried out by recrystallisation from n-heptane (−20° C.). This gives 4′-(4-pent-1-ynylphenyl)-4-propylbicyclohexyl as a colourless solid (m.p. 47° C.).
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=2[CH3:21])[CH2:6]1)C.[CH3:22][NH:23][C:24]([NH2:26])=[NH:25].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:22][NH:23][C:24]1[N:26]=[CH:4][C:5]2[CH2:6][N:7]([C:12]3[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=3[CH3:21])[CH2:8][CH2:9][C:10]=2[N:25]=1
Reactant: CNC(=N)N
Reactant: Cc1ccc([N+](=O)[O-])cc1N1CCC(=O)C(=CN(C)C)C1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CNc1ncc2c(n1)CCN(c1cc([N+](=O)[O-])ccc1C)C2
Temperature: 25 °C

Procedure:
To a solution of 3-Dimethylaminomethylene-1-(2-methyl-5-nitrophenyl)piperidin-4-one (12.06 gm, 41.7 mmol)[as prepared in reference 1] in Ethanol (250 ml) were added N-Methyl guanidine (12.20 gm, 167 mmol) and sodium acetate (27.32 gm, 334 mmol) and solution was heated under reflux for 12 hours. After cooling to room temperature, the reaction mixture was diluted with water, extracted with ethyl acetate. The organic layer was washed with brine, dried [sodium sulfate] and concentrated under vacuum. The crude product obtained was further purified by silica gel chromatography using 5-10% Methanol/Chloroform as eluent to give pure desired product [41] i.e., Methyl-[6-(2-methyl-5-nitro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-amine as yellow solid. (Yield: 2.47 gm, 19.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][CH:5]1[CH2:10][CH:9]=[CH:8][NH:7][C:6]1=[O:11].O1CCCC1.C1(Cl)C(Cl)=C(Cl)C(=O)C(=O)C=1Cl>O>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[C:6](=[O:11])[NH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OC3CC=CNC3=O)c(Cl)cc2F)c1=O
Agent: O=C1C(=O)C(Cl)=C(Cl)C(Cl)=C1Cl
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc[nH]c3=O)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
A mixture of 144 mg of 3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-3,4-dihydro-1H-pyridin-2-one, 0.66 ml of tetrahydrofuran and 163 mg of o-chloranil was refluxed with stirring for one hour. The reaction mixture was cooled to room temperature, and then water was poured therein and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 72 mg of 3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-1H-pyridin-2-one.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[C:13](=[O:15])[CH3:14]>CO.O>[CH3:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH:13]([CH3:14])[OH:15]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1c(C(C)O)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.2 %

Procedure:
Sodium borohydride (0.02 g, 0.6 mmol) is added to a solution of 1-(2-methyl-3-nitrophenyl)ethanone (0.2 g, 1.1 mmol) in methanol (50 mL) at 0° C. The reaction mixture is stirred at room temperature for 1.5 hours, and then is diluted with water (100 mL). The aqueous mixture is stirred at room temperature an additional 5 hours followed by extraction with ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate, and evaporated. Flash chromatography of the residue (silica, methylene chloride) gives 2,α-dimethyl-3-nitrobenzenemethanol (0.14 g, 77%) as an oil.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:12]=1
Reactant: N#Cc1ncccc1Cl
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ncccc1Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A RBF was charged with 3-chloro-2-cyanopyridine (40 g, 289 mmol), 4-bromophenol (49.9 g, 289 mmol) and cesium carbonate (113 g, 346 mmol). The reactants were suspended in 50 mL of DMSO and allowed to stir at 85 C overnight. The reaction was cooled to RT and 600 mL of water was added to it. The reaction was filtered and the solid washed with water, then air dried to provide 3-(4-bromophenoxy)-picolinonitrile as a tan solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)=[C:4]([CH3:24])[CH:3]=1.[C:25](=[O:32])([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[NH2:26].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Cl-].[Na+].O>[CH:21]1([C:19]([NH:18][C:13]2[N:14]=[CH:15][C:16]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[C:8]([C:5]2[C:4]([CH3:24])=[CH:3][C:2]([NH:26][C:25](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:7][CH:6]=2)[CH:17]=3)=[O:20])[CH2:23][CH2:22]1
Reactant: Cc1cc(Cl)ncc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Reactant: CC(C)(C)OC(N)=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(NC(=O)OC(C)(C)C)ncc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 90 °C

Procedure:
A mixture of N-(7-(6-chloro-4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide (63.5 mg, 188 μmol, tert-butyl carbamate (46.7 mg, 399 μmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoeth yl)phenyl]palladium(II) (16.9 mg, 21 μmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl (10.6 mg, 20 μmol), and cesium carbonate (127 mg, 390 μmol) in 1,4-dioxane (1.0 mL) was heated in a sealed vessel at 90° C. for 20 hours. The mixture was treated with further portions of tert-butyl carbamate (67.1 mg, 537 μmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoeth yl)phenyl]palladium(II) (20.1 mg, 25 μmol) and 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl (12.9 mg, 24 μmol) and heated at 90° C. for a further 24 hours. The cooled mixture was diluted with brine, extracted twice into dichloromethane, and twice more with DCM to which methanol was added. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM, filtered through a celite pad and concentrated in vacuo to afford the impure title compound as a brown solid, used in the next step without purification. LCMS: M+H+=419.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[O:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]1[O:43][NH2:44]>C(Cl)CCl.CN(C=O)C.C(N(CC)CC)C.O>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([NH:44][O:43][CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42][O:37]3)=[O:19])=[CH:11]2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1)NOC1CCCCO1

Procedure:
Starting materials: (E)-3-[1-(biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-acrylic acid (compound 62) (0.300 g), HOBt?H2O (0.130 g), triethylamine (668 μl), DMF (20 ml), EDC?HCl (0.508 g), O-(tetrahydro-2H-pyran-yl)hydroxylamine (0.089 g). Reaction conditions: room temperature, 1 hour; room temperature, 18 hours.
Reaction SMILES: [CH:1]1[C:6]([C:7]2[C:16](=[O:17])[C:15]3[C:14](O)=[CH:13][C:12](O)=[CH:11][C:10]=3[O:9][CH:8]=2)=[CH:5][CH:4]=[C:3](O)[CH:2]=1.C([O-])([O-])=O.[K+].[K+]>>[O:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[O:17])[C:7]([C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=2)=[CH:8]1
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)cc(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=c1c(-c2ccccc2)coc2ccccc12
Temperature: 59 °C
Yield: 63.2 %

Procedure:
To a 100 mL round bottom flask was added genistein (500 mg, 1.85 mmol) and K2CO3 (1.02 g, 7.4 mmol). The flask was equipped with a reflux condenser and purged with N2. To the flask was added acetone (15 mL) and MeI (0.277 mL), and the reaction was heated to 59° C. Additional K2CO3 and MeI were added as needed to push the reaction. Upon completion, the reaction was allowed to cool to room temperature and was filtered to remove KI. Purified by flash column chromatography (SiO2, 2% MeOH/CH2Cl2) to afford 14 (260 mg, 45%) as an off-white solid. Analytical data for isoflavone 14: 1H NMR (500 MHz, CDCl3) δ 7.77 (s, 1H), 7.49 (d, J=9 Hz, 2H), 6.94 (d, J=9 Hz, 2H), 6.45 (s, 1H), 6.38 (s, 1H), 3.95 (s, 3H), 3.90 (s, 3H), 3.84 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 175.7, 164.1, 161.7, 160.2, 159.6, 150.2, 130.6, 126.2, 124.6, 113.9, 110.2, 96.4, 92.7, 56.6, 56.0, 55.5; LCMS: Mass calculated for C18H16O5, [M+H]+, 313. Found 313.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([NH2:18])[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH:19](=O)[CH2:20][CH2:21][CH2:22][CH:23]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO.C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:10]([O:11][C@H:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: Cc1c(O[C@@H]2CCC[C@H](N)C2)ccc2[nH]ncc12
Reactant: O=CCCCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1c(O[C@H]2CCC[C@@H](N3CCCCC3)C2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 72 %

Procedure:
Under nitrogen, the cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine (100 mg, 0.403 mmol) obtained in Example 411 and 25%-glutaraldehyde (187 mg, 0.448 mmol) were dissolved in methanol (10 ml), and the resulting solution was stirred at room temperature for 40 minutes. Then, sodium cyanoborohydride (51 mg, 0.815 mmol) and acetic acid (0.2 ml) were added thereto, and the resulting mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with chloroform and separated by the addition of a 1N-aqueous sodium hydroxide solution, and the desired compound was further extracted from the aqueous layer with chloroform. The combined chloroform layer was washed with water and then a saturated aqueous sodium chloride solution, dried by the addition of anhydrous magnesium sulfate, and then filtered. The solvent was distilled off under reduced pressure and the resulting concentration residue was purified by a silica gel column chromatography (eluent: acetonitrile/aqueous ammonia=100/0, 100/2, 100/4) to obtain 4-methyl-5-[(cis-3-piperidin-1-ylcyclohexyl)oxy]-1H-indazole (91 mg, yield 71.2%) as a white amorphous substance.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([N:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:41](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([N:33]5[CH2:38][CH2:37][N:36]([CH3:41])[CH2:35][CH2:34]5)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1ncnn2c(-c3ccc(N4CCNCC4)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(c2ccc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 57.2 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(4-piperazin-1-ylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (89 mg, 0.18 mmol) in dichloromethane (3 mL) was added formaldehyde (37% in water) (80 μL, 1.06 mmol) and sodium triacetoxyborohydride (113 mg, 0.53 mmol). The reaction was stirred (rt) for 17 h. The mixture was diluted with dichloromethane (25 mL) and was washed with H2O (1×20 mL), brine, and was dried (Na2SO4) and evaporated. The residue was purified by preparative HPLC using a gradient elution from 5% to 30% acetonitrile in water to obtain 53 mg (58%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.57 (s, 1 H), 7.99-7.91 (m, 3 H), 7.86-7.79 (m, 1 H), 7.69-7.63 (m, 1 H), 7.39-7.26 (m, 5 H), 7.23-7.17 (m, 1 H), 7.06-6.98 (m, 3 H), 5.66 (s, 2 H), 3.27-3.14 (m, 4 H), 2.47-2.40 (m, 4 H), 2.22 (s, 3 H); ES-MS m/z 515.32 [M+H]+, HPLC RT (min) 2.36.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH3:20]>C1COCC1.CN(C=O)C>[CH2:17]([N:9]1[CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCBr
Reactant: O=C1NC(Cc2ccccc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCN1C(=O)OCC1Cc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 5.005 g of 2-amino-3-phenylpropanol and 3 g of ethylene carbonate in 50 ml of toluene in a round bottom flask with a Dean-Stark trap was refluxed for 48 hours and the reaction was followed by tlc. At the end of the reaction the solution was washed with water and brine and concentrated to dryness to give 5.86 g of light yellow oil. The racemic 4-benzyloxazolidin- 2-one was dissolved in 20 ml of THF and was added to 1.98 g of 60% NaH in 40 ml of THF and 10 ml of DMF. After the initial reaction had subsided the reaction mixture was refluxed for 2 hours. After cooling to r.t. 5.44 g of 1-bromobutane in 20 ml of THF was added and the reaction mixture was refluxed overnight. It was then poured into ice-water and extracted twice with ethyl acetate. Combined organic extracts were washed three times with water, followed by brine. After drying, the solution was concentrated to give 7.625 g of crude oil. This was kugelrohr distilled (155°-160° C./0.3 mm) to give 6.54 g (84.7% overall yield) of product.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH:8]1[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC(NCCCCO)CC1
Agent: Cl
Solvent: C1COCCO1
Product: OCCCCNC1CCCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from step b (1.32 g, 4.65 mmol) is dissolved in 8 ml of dioxane, 16 ml of 4N HCl in dioxane are added, and the mixture is stirred at RT overnight. The reaction mixture is evaporated and dried under high vacuum.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=3)[CH:13]=[N:12]2)[CH:5]=1>CO.O>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([C:14]2[CH:13]=[N:12][N:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:24])=[O:2])[CH:15]=2)=[CH:21][CH:20]=1)#[N:23]
Reactant: COC(=O)c1cccc(Cn2cc(-c3ccc(C#N)cc3)cn2)c1
Solvent: CO
Solvent: O
Product: N#Cc1ccc(-c2cnn(Cc3cccc(C(=O)O)c3)c2)cc1
Yield: 82.4 %

Procedure:
Add LiOH monohydrate (0.03 g, 0.8 mmol) to a suspension of 3-[4-(4-cyano-phenyl)-pyrazol-1-ylmethyl]-benzoic acid methyl ester (0.2 g, 0.6 mmol) in 5 mL of a 4:1 MeOH-water mixture and stir the reaction at room temperature overnight. Concentrate the reaction to remove most of the MeOH, dilute with additional H2O and neutralize by the addition of 1 N aqueous HCl. Isolate the resulting solid by filtration and dry to afford 0.15 g, 71% yield of 3-[4-(4-cyano-phenyl)-pyrazol-1-ylmethyl]-benzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[C:6]([NH2:11])[CH:5]=1.[CH3:13][N:14](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]([NH2:11])[CH:5]=1
Reactant: COC(=O)c1ccc(Br)c(N)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1ccc(C#N)c(N)c1
Temperature: 120 °C
Yield: 94 %

Procedure:
Add zinc cyanide (1.5 g, 12.77 mmol), palladium tetrakis (675 mg, 0.584 mmol), to 3-amino-4-bromo-benzoic acid methyl ester (1.328 g, 5.77 mmol) in anhydrous DMF (3 ml). Purge with nitrogen for few minutes and keep under nitrogen atmosphere while heating to 120° C. overnight. Cool the mixture to room temperature and add water. Extract the product with EtOAc (×2). Wash the combined organic layers with 2N ammonium hydroxide solution (×2), water (×2), saturated aq. sodium chloride and dry over anhydrous sodium sulfate, filter and concentrate to yield the crude product. Purification by flash chromatography (Silica gel-hexane/EtOAc) yields 3-amino-4-cyano-benzoic acid methyl ester (94%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.O.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16](S(O)(=O)=O)=[CH:15][CH:14]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.CCOCC>C(O)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:23]([O:10][C:9]([C@H:6]1[CH2:5][CH2:4][C@H:3]([CH2:2][NH2:1])[CH2:8][CH2:7]1)=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: OCc1ccccc1
Product: NC[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1

Procedure:
Trans-4-Aminomethyl cyclohexane carboxylic acid (25 g; 160 mmol) in benzyl alcohol (100 cm3) and toluene (50 cm3) with para-toluene sulphonic acid monohydrate (30.2 g; 1 equivalent) was refluxed for 171/2 hours using a Dean and Stark apparatus to collect the water of condensation and from the toluene sulphonic acid monohydrate. The clear reaction mixture was poured into ether (600 cm3) and the resultant white solid filtered off, washed with ether and dried to afford 57 g (85%) of the title compound. Both infrared and nuclear magnetic resonance spectra were consistant with the desired compound.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[C@H:15]2[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C@@H:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:26]([F:29])([F:28])[F:27])[C:8]=2[C:7]1=[O:30].I[CH3:32]>C1COCC1.COC(C)(C)C>[CH3:32][O:3][CH2:4][CH2:5][N:6]1[C@H:15]2[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C@@H:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:26]([F:27])([F:29])[F:28])[C:8]=2[C:7]1=[O:30]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2c3cccc(C(F)(F)F)c3C(=O)N(CCO)[C@H]2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: COCCN1C(=O)c2c(cccc2C(F)(F)F)[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]21
Reaction time: 0.33 h
Yield: 37 %

Procedure:
To a suspension of sodium hydride (8 mg of 60% dispersion in mineral oil, hexane-washed, 0.20 mmol) in 2 mL of THF was added (3aR,9bS)-tert-butyl 4-(2-hydroxyethyl)-5-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate from Example 20, Part A (40 mg, 0.10 mmol) in 2 mL THF. The reaction was stirred for 20 min, at which time gas evolution had ceased. Then there was added iodomethane (0.125 mL of a 2M solution in tert-butyl methyl ether, 0.25 mmol) and the reaction was allowed to stir at ambient temperature for 18 h. TLC analysis showed that starting material remained. Additional sodium hydride (8 mg of 60% dispersion in mineral oil, 0.20 mmol) and iodomethane (0.125 mL of a 2M solution in tert-butyl methyl ether, 0.25 mmol) were added and the reaction was allowed to stir at 40° C. for 2 h. The reaction was quenched with 10 mL of 1N HCl and extracted with EtOAc. The organics were washed with sat'd aq NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (230-400 mesh silica gel, elution with 4:1 hexane/EtOAc) to afford 15 mg (37%) of the title compound. 1H NMR (CDCl3): δ 7.79 (d, 1H, J=7.7 Hz), 7.57-7.52 (m, 2H), 7.25-7.22 (m, 1H), 4.15-4.10 (m, 1H), 4.08-3.98 (m, 2H), 3.82-3.77 (m, 1H), 3.61-3.54 (m, 2H), 3.50-3.27 (overlapping m, 4H), 3.31 and 3.28 (singlets, 3H), 1.50 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:19]=[CH:20][N:21]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([C:8]([O:10]C)=[O:9])[CH:7]=1.[OH-].[Na+].O.Cl>O1CCCC1>[Cl:1][C:2]1[C:3]2[N:4]([CH:19]=[CH:20][N:21]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([C:8]([OH:10])=[O:9])[CH:7]=1
Reactant: COC(=O)c1cc(Cl)c2nccn2c1-c1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)c2nccn2c1-c1cccc(F)c1
Temperature: 20 °C
Reaction time: 6 h
Yield: 102.6 %

Procedure:
A solution of methyl 8-chloro-5-(3-fluorophenyl)imidazo[1,2-a]pyridine-6-carboxylate (0.18 g, 0.57 mmol) in tetrahydrofuran (3 mL) was treated with 1 M sodium hydroxide in water (1.7 mL, 1.7 mmol) and stirred at 20° C. for 6 hours. The reaction mixture was concentrated, diluted with water, cooled to 0° C., and treated with 1 M hydrogen chloride in water (2.3 mL, 2.3 mmol) dropwise. The resultant suspension was filtered to give the desired product (0.17 g, quantitative) that was used without further purification. LCMS calculated for C14H9ClFN2O2 (M+H)+: m/z=291.0. found: 290.9.