Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].CC1(C)COB([C:30]2[CH:31]=[CH:32][C:33]([F:38])=[C:34]([CH:37]=2)[C:35]#[N:36])OC1>>[F:38][C:33]1[CH:32]=[CH:31][C:30]([C:2]2[CH:3]=[C:4]([C:9]3[N:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]4=[N:11][CH:10]=3)[CH:5]=[CH:6][C:7]=2[F:8])=[CH:37][C:34]=1[C:35]#[N:36]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: CC1(C)COB(c2ccc(F)c(C#N)c2)OC1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(F)c(C#N)c4)c3)cnc2c1F
Yield: 5 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluorobenzonitrile were coupled in the same way as in Example 30 to give 4,2′-difluoro-5′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]biphenyl-3-carbonitrile as an off-white solid (9 mg, 5%): m/z (ES+) 408 [MH+].
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:20]C1C=CC=CC=1C=O>CCCCCCC.C(OCC)(=O)C>[Cl:20][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[CH:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=2)[O:9]1
Reactant: O=Cc1ccccc1Cl
Reactant: O=C1CC(c2cccc(F)c2)Oc2ccc(O)cc21
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C1CC(c2ccccc2Cl)Oc2ccc(O)cc21

Procedure:
2-(2-Chlorophenyl)-6-hydroxychroman-4-one was prepared as described for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 3.0 g of 2 ′,5′-dihydroxyacetophenone and 2.8 g of 2-chlorobenzaldehyde. The product was passed though silica gel using heptane-ethyl acetate as an eluant and then triturated with ethanol. 1H NMR (400 MHz, d6-DMSO) δ: 9.49 (s, 1H), 7.77 (dd, 1H, J 7.7, 2.0 Hz), 7.53 (dd, 1H, J 7.6, 1.8 Hz), 7.49-7.41 (m, 2H), 7.14 (d, 1H, J 2.9 Hz), 7.06 (dd, 1H, J 8.8, 2.9 Hz), 6.93 (d, 1H, J 8.8 Hz), 5.78 (dd, 1H, J 13.6, 2.6 Hz), 3.19 (dd, 1H, J −16.9, 13.6 Hz), 2.78 (dd, 1H, J −16.9, 2.6 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:2].[H][H]>C(O)C.[Ni]>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:2]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCC(Oc1cccc([N+](=O)[O-])c1)C(=O)OCC
Agent: [Ni]
Solvent: CCO
Product: CCCCCCCCCCCCC(Oc1cccc(N)c1)C(=O)OCC

Procedure:
A solution of 154 g (0.39 mol) of 2-(m-nitrophenoxy)-myristic acid ethyl ester in 500 ml of ethanol is placed in an autoclave. An amount of 8 ml of Raney nickel is added. Reduction of the nitro group is carried out with hydrogen gas at an initial pressure of 10-10.5 MPa and a temperature of 65° C. After the reduction (2 h) the solvent is removed by evaporation.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]2[NH:6][C:7](=O)[NH:8][C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:7]1[NH:6][C:5]2[CH:10]=[C:11]([CH3:12])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc2[nH]c(=O)[nH]c2cc1Cl
Product: Cc1cc2[nH]c(Cl)nc2cc1Cl

Procedure:
The benzimidazol-2-one from step (a) above (10.6 g, 58 mmol) reacted with POCl3 under the conditions of Example 1c to give the title compound as a brown solid. MS (ESI, pos. ion) m/z: 201.3 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5]([C:18]1[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=1)[CH2:6][C:7]#[C:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=O)C.[NH2:26][NH2:27].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C(OCC)(=O)C>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[N:27]([C:14]3[CH:15]=[CH:16][C:11]([CH3:9])=[CH:12][CH:13]=3)[N:26]=[C:7]([CH2:6][CH:5]([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[C:4]([OH:3])=[O:25])[CH:8]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(CC#CC(=O)c1ccc(Br)cc1)c1cccc(C)c1
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(CC(C(=O)O)c3cccc(C)c3)cc2-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 121.8 %

Procedure:
3-[5-(4-Bromo-phenyl)-1-β-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid ethyl ester. To a solution of 6-(4-bromo-phenyl)-6-oxo-2-m-tolyl-hex-4-ynoic acid ethyl ester (7.5 g, 19 mmol) in THF (40 mL) was added hydrazine (4.5 g, 28 mmol, 1.5 equiv) and Cs2CO3 (9.0 g, 28 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 12 h. The resulting mixture was diluted with ethyl acetate (30 mL), and a satd aq solution of cesium carbonate (50 mL) was added. The resulting aqueous layer was back-extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with satd aq NaHCO3 (50 mL) then brine (50 mL), and dried (MgSO4). The solvent was evaporated under reduced pressure, and the residue was purified by chromatography (silica gel, 25% ethyl acetate/hexanes) to afford the desired compound (5.5 g, 58%). TLC (silica gel, 3:7 EtOAc/hexanes): Rf=0.35. MS (ESI): mass calculated for C28H27BrN2O2, 502.13; m/z found, 503/505 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.39 (d, J=10.7 Hz, 2H), 7.25-7.01 (m, 10H), 6.17 (s, 1H), 4.19-4.03 (m, 3H), 3.52 (dd, J=14.7, 9.6 Hz, 1H), 3.09 (dd, J=14.7, 6.0, 1H), 2.35 (s, 6H), 1.19 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([C:11]([OH:13])=O)[CH:3]=1.Cl.Cl.Cl.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[S:25][C:26]([CH2:29][N:30]2[CH2:35][CH2:34][CH:33]([CH2:36][NH2:37])[CH2:32][CH2:31]2)=[CH:27][N:28]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([C:11]([NH:37][CH2:36][CH:33]2[CH2:34][CH2:35][N:30]([CH2:29][C:26]3[S:25][C:24]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[F:17])=[N:28][CH:27]=3)[CH2:31][CH2:32]2)=[O:13])[CH:3]=1
Reactant: N#Cc1c(N)cc(C(=O)O)nc1Cl
Reactant: NCC1CCN(Cc2cnc(-c3ccccc3F)s2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1c(N)cc(C(=O)NCC2CCN(Cc3cnc(-c4ccccc4F)s3)CC2)nc1Cl
Reaction time: 1 h

Procedure:
A solution of 1,1′-carbodiimidazole (0.15 g) and 4-amino-6-chloro-5-cyanopicolinic acid (0.14 g, prepared according to the reported preparation in Zhao, Hongyu, et al.; J. Med. Chem. 2006, 49(15), 4455-4458) in N,N-dimethylformamide (3.5 mL) was stirred one hour at room temperature. The compound prepared in Example 392 (0.30 g) and triethylamine (0.60 mL) were added and the reaction was stirred for one hour more. A saturated sodium bicarbonate solution was added and the mixture was vigorously stirred overnight. The mixture was diluted with water and then filtered. The solids were evaporated from acetone and then a 1:1 dichloromethane:toluene solution. The solids were triturated with dichloromethane to furnish the title compound (0.22 g) having the following physical data.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N+:15]([C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20])([O-:17])=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>[N+](C1C=CC=CC=1)([O-])=O>[N+:15]([C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)([O-:17])=[O:16]
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=[N+]([O-])c1ccccc1Nc1ccc(-c2ccc(Nc3ccccc3[N+](=O)[O-])cc2)cc1
Yield: 85 %

Procedure:
4,4'-Dibromobiphenyl (156 g., 0.5 mole) was condensed with o-nitroaniline (138 g., 1.0 mole) using cuprous iodide catalyst and anhydrous sodium carbonate as an acid acceptor in refluxing nitrobenzene (500 ml) during 16 hours. The resulting 4,4'-bis-(o-nitroanilino) biphenyl, obtained in 85% yield, was reduced with sodium sulfide in ethylene glycol at 150° to 200° C. The yield of 4,4'-bis(o-aminoanilino)biphenyl was 132 g. (72% yield, mp 211°-222° C.). The melting behavior of the compound is unusual. Differential Scanning Calorimetry (DSC) analysis provides two endotherms; one at 211° C. and one at 222° C. Depending on the thermal history of the amine, either melting point (or combination) is observed. The amine assay by acetylation was 16.2, theory 16.93. The elemental analysis provided the following:
Reaction SMILES: O[C:2]1([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][CH2:3]1>C1(C)C=CC=CC=1>[CH2:8]([CH:5]1[CH2:6][CH2:7][C:2]([C:13]2[CH:14]=[C:15]([F:20])[CH:16]=[C:17]([F:19])[CH:18]=2)=[CH:3][CH2:4]1)[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCC1CCC(O)(c2cc(F)cc(F)c2)CC1
Solvent: Cc1ccccc1
Product: CCCCCC1CC=C(c2cc(F)cc(F)c2)CC1
Yield: 56.7 %

Procedure:
Mixture of (1-hydroxy-4-pentylcyclohexyl)-3,5-difluorobenzene (300 mmol), the Amberlist 15E (4.0 g), and 1,000 ml of toluene was refluxed for 6 hours. After allowed to cool, the Amberlist 15E was filtered off, the solvent was distilled off, and the residue was purified by column chromatography (eluent: heptane) to give a (4-pentyl-1-cyclohexenyl)-3,5-difluorobenzene (170 mmol).
Reaction SMILES: [CH3:1][C@@H:2]([OH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(C)C>[CH:3]1([C@H:2]([OH:9])[CH3:1])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C[C@@H](O)c1ccccc1
Solvent: CC(C)O
Product: C[C@@H](O)C1CCCCC1
Reaction time: 4 h
Yield: 88.8 %

Procedure:
An autoclave was charged with (R)-alpha-methylbenzyl alcohol (980 g, synthesized as above) and isopropanol (100 g). Catalyst RuO2.H2O (0.2 g) was then added, and the reaction mixture was hydrogenated at a pressure of 20 bar and a temperature ranging from 70 to 80° C. for 4 hours. The catalyst was filtered. The organic layer was distilled first at 100 mmHg to remove isopropanol, and then at 5-10 mmHg to provide (R)-1-cyclohexylethanol (913 g) (optical rotation: [α]D−4.31°; optical purity: 83.3% ee).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][C:11]([O-:13])=[O:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:14]N(C)CCCN=C=NCC.CCOCC>CC#N.CN(C1C=CN=CC=1)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C([O-])Cc1ccc2c(c1)CCN2
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)Cc1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 1-(S-[4-tert-butoxycarbonyl)-4-(tert -butoxycarbonylamino)]butanoyl)indoline-5-acetate 7. Crude 3 (327 mg, 1.9 mmol) was prepared as described above (see compound 4), dissolved in dry MeCN (30 mL) and treated with DMAP (611 mg, 5 mmol) and N-tert-BOC-L-glutamic acid α-tert-butyl ester (607 mg, 2 mmol), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (422 mg, 2.2 mmol). The mixture was stirred at rt for 18 h, then evaporated and the residue was dissolved in EtOAc and washed successively with 0.5 M aq. HCl, saturated aq. NaHCO3 and brine, dried and evaporated to give a viscous oil. Flash chromatography [EtOAc-hexanes (55:45)] and trituration with ether gave. 6 as white crystals (626 mg, 69%), mp 80-81° C. (EtOAc-hexanes); IR: νmax/cm−1; 3340, 1730, 1680, 1655, 1625; 1H NMR: δH (400 MHz) 8.15 (d, J=8 Hz, 1H), 7.07-7.11 (m, 2H), 5.23 (d, J=6.9 Hz, 1H), 4.22 (m, 1H), 4.03 (2×t, J=8.5 Hz, 2H; rotamers), 3.68 (s, 3H), 3.57 (s, 2H), 3.17 (t, J=8.5 Hz, 2H), 2.43-2.59 (m, 2H), 2.18-2.31 (m, 1H), 1.98-2.07 (m, 1H), 1.47 (s, 9H) and 1.41 (s, 9H). Anal. Calcd for C25H36N2O7: C, 63.01; H, 7.61; N, 5.88. Found: C, 63.08; H, 7.81; N, 5.64.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:20][CH2:21][C:22]([F:24])([F:23])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:19])=[N:16][NH:17][CH:18]=1)[CH2:9][CH2:8]3.C(=O)([O-])[O-].[Cs+].[Cs+].I[C:32]1[C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=[CH:34][N:33]=1.CN[C@@H]1CCCC[C@H]1NC>[Cu-]=O.CN(C)C=O>[CH3:41][O:40][C:38](=[O:39])[C:37]1[CH:36]=[CH:35][CH:34]=[N:33][C:32]=1[N:17]1[CH:18]=[C:14]([CH2:13][N:10]2[CH2:11][CH2:12][C:7]3([C:5]4[S:6][C:2]([Cl:1])=[CH:3][C:4]=4[C:22]([F:23])([F:24])[CH2:21][O:20]3)[CH2:8][CH2:9]2)[C:15]([CH3:19])=[N:16]1
Reactant: Cc1n[nH]cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Reactant: COC(=O)c1cccnc1I
Agent: O=[Cu-]
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1cccnc1-n1cc(CN2CCC3(CC2)OCC(F)(F)c2cc(Cl)sc23)c(C)n1
Reaction time: 16 h
Yield: 75.4 %

Procedure:
To a screw-cap test tube are added copper(I) oxide (11 mg, 0.08 mmol), 2-chloro-4,4-difluoro-1′-[(3-methyl-1H-pyrazol-4-yl)methyl]spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine] (300 mg, 0.8 mmol), cesium carbonate (523 mg, 1.6 mmol), dry dimethylformamide (1.6 mL) and a stir bar. The reaction mixture is bubbled with nitrogen for 20 minutes and then methyl 2-iodopyridine-3-carboxylate (511 mg, 1.9 mmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (0.24 mmol; 34 mg) are added. The reaction tube is quickly sealed (caution: build-up of pressure possible; use a safety shield) and immersed in a preheated oil bath at 110° C. for 16 hours with the aid of a magnetic stirrer. Then, the mixture is poured on SCX column (10 g) and eluted with methanol and then 2N solution of ammonia in methanol. The basic fraction is concentrated and the resulting residue is purified by silica gel using normal phase Isco chromatography eluting with hexane:ethanol (gradient from 2 to 15% in ethanol) to give 307 mg of 2-(4-((2′-chloro-4′,4′-difluoro-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]-1-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-nicotinic acid methyl ester. MS (m/z): 309 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[C:16]4[C:23]3[S:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=3)=[CH:11][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[C:16]4[C:23]3[S:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2ccnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-c2ccnc3ccc(-c4c[nH]nc4-c4ccc(F)cc4)cc23)s1
Yield: 55.2 %

Procedure:
39 mg 6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-4-(5-methylsulfonyl 2-thienyl)quinoline obtained in Example 167 and 0.5 mL trifluoroacetic acid were reacted in the same manner as in Example 165, to give 14 mg of the title compound as pale yellow crystals.
Reaction SMILES: [CH3:1][O-:2].[Na+].[O:4]1[C@@H:6]2[CH2:7][C:8]3[C:13]([C@H:5]12)=[CH:12][CH:11]=[CH:10][CH:9]=3.O.Cl>CO>[CH3:1][O:2][C@@H:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C@H:6]1[OH:4]
Reactant: c1ccc2c(c1)C[C@H]1O[C@@H]21
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CO[C@@H]1c2ccccc2C[C@H]1O
Temperature: 30 °C
Reaction time: 1.5 h
Yield: 65.4 %

Procedure:
Into a 500 ml four-neck flask, 120 ml of methanol was introduced and 16.4 g (0.304 mol) of sodium methoxide powder was dissolved therein. At 30° C., 20.0 g (0.152 mol) of cis-(±)-1,2-epoxyindan (VI) dissolved in 80 ml of methanol was dropwise added thereto in a period of 90 minutes. After this mixture was stirred at 30° C. for 5 hours, 100 ml of water was added thereto. The resulting mixture was neutralized with 270 ml of 1N hydrochloric acid and then methanol was distilled off under reduced pressure. The remaining mixture was extracted twice with 200 ml of dichloromethane. The extracted phase was dried for one night with sodium sulfuric anhydride. The dichloromethane phase was concentrated under pressure to yield 28.5 g of an orange oily substance. When it was purified by a silica gel column chromatography in which chloroform was used as a developing solvent, 16.32 g (yield: 65.5%) of trans-(±)-1-methoxyindan-2-ol (I') was obtained as a pale yellow oil. Its purity determined by an HPLC analysis was 95.4%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][CH2:27][O:28][C:21]=3[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][CH2:27][O:28][C:21]=4[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccc4c(c3)OCCO4)c12
Reactant: c1cn[nH]c1
Product: Cc1csc2nc(-n3cccn3)nc(NCc3ccc4c(c3)OCCO4)c12

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[N:30]1[C:39]2[C:34](=[C:35]([NH:40][NH2:41])[CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1>>[N:23]1([S:20]([C:16]2[CH:15]=[C:14]([N:9]3[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]4[N:40]([C:35]5[CH:36]=[CH:37][CH:38]=[C:39]6[C:34]=5[CH:33]=[CH:32][CH:31]=[N:30]6)[N:41]=[CH:3][CH:4]=4)=[N:8]3)[CH:19]=[CH:18][CH:17]=2)(=[O:22])=[O:21])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NNc1cccc2ncccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N3CCCCC3)c2)ccc1=O
Product: O=c1ccn(-c2cccc(S(=O)(=O)N3CCCCC3)c2)nc1-c1ccnn1-c1cccc2ncccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[3-(piperidine-1-sulfonyl)-phenyl]-1H-pyridazin-4-one (A-26) and quinolin-5-yl-hydrazine according to the method described for example 91. MS: M=513.4 (M+H)+
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Cu]I>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([O:12][C:9]2[CH:10]=[CH:11][C:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[CH:7][CH:8]=2)=[CH:31][CH:32]=1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(I)cc1
Reactant: Oc1ccc(-c2nccs2)cc1
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(-c3nccs3)cc2)cc1
Yield: 51.3 %

Procedure:
A mixture of the product of step 2 (0.1 g, 0.56 mmol), the product of Example 130, step 2 (0.30 g, 0.73 mmol), N,N-dimethylgycine HCl salt (0.20 g, 1.46 mmol), copper(I) iodide (0.19 g, 1.01 mmol) and cesium carbonate (0.28 g, 0.85 mmol) in dioxane (2 ml) was heated 100° C. for 60 h under nitrogen. The solids were filtered off, and the filtrate was concentrated in vacuo. The residue was purified by a column chromatography on silica gel eluting with 25% EtOAc/hexanes to yield the title product (130 mg, 69%); 1HNMR (400 MHz, CDCl3) δ 7.88 (d, J=8.4 Hz, 2H), 7.84 (d, J=3.2 Hz, 1H), 7.30 (d, J=3.2 Hz, 1H), 7.24 (d, J=8.4 Hz, 2H), 7.10 (d, J=8 Hz, 2H), 6.86 (br d, J=8 Hz, 2H), 4.10 (br, 2H), 3.96 (s, 2H), 3.40 (br, 2H), 2.03-1.80 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].Cl.[NH2:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:23]2[CH:24]=[CH:25][C:20]([NH2:19])=[CH:21][CH:22]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: Nc1ccc(B(O)O)cc1
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Agent: Cl
Product: Nc1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 4-aminophenyl-boronic acid hydrochloride gives “A65”; method 2: HPLC/MS: 1.53 min, [M+H]=306;
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=2)[C:9](OCC)=[O:10])[CH:5]=[N:4][N:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.O1CCOCC1>[OH:10][CH2:9][C:8]1[CH:7]=[C:6]([N:1]2[CH:2]=[N:3][N:4]=[CH:5]2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1cccc(-n2cnnc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: OCc1cccc(-n2cnnc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
430 mg of ethyl 3-(1,3,4-triazol-1-yl)benzoate [synthesized substantially in accordance with the method described in J. Med. Chem., 5, 383 (1962)] was dissolved in a mixture of 20 ml of tetrahydrofuran and 20 ml of dioxane, and 100 mg of lithium aluminium hydride was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was distributed between ethyl acetate and water. The organic layer was separated and dried over anhydrous sodium sulfate. The desiccant was separated by filtration, and the solvent evaporated. The residue was purified by silica gel column chromatography [Wakogel C-200, 20 g; eluting solvent: chloroform/methanol=20/1] to give 240 mg (yield 69%) of 1(3-hydroxymethylphenyl)-1,3,4-triazole.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[N:14][C:15]([N:18]3[C:26]4[C:21](=[CH:22][C:23]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19]3)=[CH:16][CH:17]=2)[CH2:7][CH2:6]1)=[O:4].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH3:30][S:27]([C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[N:18]([C:15]1[N:14]=[CH:13][C:12]([O:11][CH:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH2:6][CH2:7]3)=[CH:17][CH:16]=1)[CH:19]=[CH:20]2)(=[O:28])=[O:29]
Reactant: CS(=O)(=O)c1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)CCl)CC3)cn2)c1
Reactant: C1COCCN1
Product: CS(=O)(=O)c1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)CN4CCOCC4)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-196 using 2-chloro-1-(4-((6-(5-(methylsulfonyl)-1H-indol-1-yl)pyridin-3-yl)oxy)piperidin-1-yl)ethanone and morpholine. (0.050 g, 56.18%).
Reaction SMILES: C([O:5][C:6](=[O:32])[CH:7]([C:25]([O:27]C(C)(C)C)=[O:26])[CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[O:12][C:13]=1[CH3:14])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:22][O:21][C:19]([C:18]1[CH:23]=[CH:24][C:15]([C:11]2[O:12][C:13]([CH3:14])=[C:9]([CH2:8][CH:7]([C:6]([OH:32])=[O:5])[C:25]([OH:27])=[O:26])[N:10]=2)=[CH:16][CH:17]=1)=[O:20]
Reactant: COC(=O)c1ccc(-c2nc(CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)o2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nc(CC(C(=O)O)C(=O)O)c(C)o2)cc1
Temperature: 35 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of methyl 4-(4-(3-tert-butoxy-2-(tert-butoxycarbonyl)-3-oxopropyl)-5-methyloxazol-2-yl)benzoate (4.0 g, 8.99 mmol, 1.00 equiv) in dichloromethane (20 mL) was added trifluoroacetic acid (20 mL). The reaction mixture was stirred overnight at 35° C. and then concentrated under vacuum to remove dichloromethane. Saturated sodium bicarbonate solution was added to the residue until the pH value of the solution was adjusted to 2-3. The resulting solution was extracted with 200 mL of ethyl acetate. The organic layer was washed with 2×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to yield 3.0 g (100%) of 2-((2-(4-(methoxycarbonyl)phenyl)-5-methyloxazol-4-yl)methyl)malonic acid as a light yellow solid. LC-MS: (ES, m/z): 334 [M+H]+, 272, 115.