Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]3[CH:14]=[CH:15][CH:16]=[CH:17][C:7]2=3)[CH2:3][CH2:2]1.[C:18]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCCl.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH:18]1([N:1]2[CH2:6][CH2:5][C:4]3([CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]4[CH:14]=[CH:15][CH:16]=[CH:17][C:7]3=4)[CH2:3][CH2:2]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1CCCCCC1
Reactant: O=C1CCC2(CCNCC2)c2ccccc2N1
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: CO
Solvent: ClCCCl
Product: O=C1CCC2(CCN(C3CCCCCC3)CC2)c2ccccc2N1
Temperature: 40 °C
Reaction time: 15 h

Procedure:
To a solution of 3,4-dihydrospiro[benzo[b]azepine-5,4′-piperidin]-2(1H)-one E (800 mg, 3.47 mmol) and cycloheptanone (1.12 g, 10 mmol) in 1,2-dichloroethane (25 ml) was added titanium tetraisopropoxide (2.5 ml, 8.8 mmol) and the resulting solution was stirred at 40° C. for 15 h, treated with sodium triacetoxyborohydride (2.12 g, 10 mmol) for 1 h, cooled to room temperature and MeOH (1 ml) was added and stirred for 1 h. After evaporation, the residue was dissolved in dichloromethane, washed with a mixture of brine and 6N NaOH (3 ml). The aqueous phase (suspension) was extracted with dichloromethane (3×). The extracts were dried over Na2SO4, concentrated and purified by silica gel chromatography (CH2Cl2/MeOH 9:1 to 8:2) to give 1′-cycloheptyl-3,4-dihydrospiro[benzo[b]azepine-5,4′-piperidin]-2(1H)-one (800 mg). LC-MS: m/e=327.1 (M+H, 100%). Rt=1.57 min. 1H-NMR (500 MHz, DMSO (d6)): 9.46 (s, 1H), 7.37 (d, 1H), 7.20 (t, 1H), 7.12 (t, 1H), 6.95 (d, 1H), 2.51 (m, 2H), 2.44-2.35 (m, 3H), 2.08 (t, 2H), 2.01 (t, 2H), 1.94 (m, 2H), 1.86 (m, 2H), 1.66 (m, 2H), 1.58 (m, 2H), 1.49-1.39 (m, 6H), 1.35-1.29 (m, 2H). The above product was suspended in water, filtration and the solid was dissolved in a diluted 1N HCl (6 ml), lyophilized to give a HCl salt 24 (723 mg). Two conformers were observed with ca. 1:2 ratios. 1H-NMR (500 MHz, DMSO-d6): 10.03 (m, 1H); 9.61, 9.57 (2s, 1H); 7.42 (d, 0.35H), 7.38 (d, 0.65H); 7.31, 7.26 (2t, 1H); 7.21, 7.16 (2t, 1H); 7.05, 7.01 (2t, 1H); 3.29 (d, 2H), 3.21 (q, 2H), 2.73 (d, 0.7H), 2.28 (d, 1.3H), 2.63-2.57 (m, 1H), 2.22-1.98 (m, 8H), 1.89-1.84 (m, 1H), 1.73-1.60 (m, 3H), 1.55-1.33 (m, 7H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16]([CH2:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)#[N:17]>>[C:16]([CH2:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:22][CH:21]=1)#[N:17]
Reactant: N#CCOc1ccc(N)cc1
Reactant: Cc1cccc(Nc2cc(Cl)ncn2)c1
Product: Cc1cccc(Nc2cc(Nc3ccc(OCC#N)cc3)ncn2)c1
Yield: 24 %

Procedure:
Using an analogous reaction procedure to that described in Example 6, 4-chloro-6-(3'-methylanilino)pyrimidine (1.0 g) was reacted with 4-cyanomethoxyaniline (0.6 g). The reaction product was chromatographed on silica to give 4-(4'-cyanomethoxyanilino)-6-(3'-methylanilino)pyrimidine in 24% yield, m.p. 207°-210° C.;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:20][N:21]1CCCC1=O>>[C:20]([C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6])#[N:21]
Reactant: CCCN(CCC)C(=O)c1cc(Br)cc(C(=O)O)c1
Reactant: CN1CCCC1=O
Product: CCCN(CCC)C(=O)c1cc(C#N)cc(C(=O)O)c1
Temperature: 175 °C
Reaction time: 2.5 h

Procedure:
A mixture of 3-bromo-5-[(dipropylamino)carbonyl]benzoic acid (PREPARATION 4, 0.596 g, 1.82 mmol) and copper nitrile (0.325 g, 3.63 mmol) in N-methylpyrrolidinone (1.5 mL) is stirred at 175 degrees C. for 2.5 hour, at which time the mixture is cooled and partitioned between ethyl acetate and hydrochloric acid (3N). The organic layer is washed twice more with hydrochloric acid (3N) and then twice more with saline which had been acidified with a small amount of hydrochloric acid (3N). The organic layer is dried over magnesium sulfate and concentrated under high vacuum to give the title compound, NMR (CDCl3) delta 0.80, 1.02, 1.60, 1.73, 3.17, 3.51, 7.90, 8.31 and 8.41; an aliquot is crystallized from ethyl ether/dichloromethane/hexane —IR (diffuse reflectance) 3017, 2970, 2937, 2898, 2877, 2473, 2432, 2350, 2318, 2236, 1721, 1608, 1588, 1206 and 1196 cm−1.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:9]Cl)=[N:5][CH:6]=[CH:7][CH:8]=1.BrCC1CCCCO1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:20]1=[O:40]>>[Cl:2][C:3]1[C:4]([CH2:9][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]3([C:39]4[C:30](=[CH:31][C:32]5[O:37][CH2:36][CH2:35][O:34][C:33]=5[CH:38]=4)[O:29][CH2:28]3)[C:20]2=[O:40])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: ClCc1ncccc1Cl
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Agent: Cl
Product: O=C1N(Cc2ncccc2Cl)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 3-chloro-2-(chloromethyl)pyridine hydrochloride to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[(3-chloropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (67%) as a colorless solid: mp 176-178° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.35-8.31 (m, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.27-7.15 (m, 3H), 7.09-7.02 (m, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.50 (d, J=1.5 Hz, 1H), 6.23 (d, J=1.4 Hz, 1H), 5.13 (d, J=16.8 Hz, 1H), 5.02-4.89 (m, 2H), 4.67 (dd, J=8.9, 1.3 Hz, 1H), 4.22-4.06 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.8, 155.4, 150.0, 148.9, 144.8, 141.4, 138.4, 136.9, 132.0, 129.1, 129.8, 124.2, 124.0, 123.0, 120.6, 111.4, 109.1, 99.6, 80.2, 64.5, 63.9, 58.1, 41.2.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:38][CH2:39][O:40][CH2:41][CH2:42]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCOCC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(N2CCOCC2)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(morpholin-4-yl)benzamido)-4-phenylbenzoate (0.060 g) in ethyl acetate (1.5 mL) and methanol (1.5 mL), 10% palladium-carbon (0.030 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 3 hours and 30 minutes. Ethyl acetate was added to the reaction mixture. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration to obtain 0.036 g of tert-butyl 2-(2-hydroxy-5-(morpholin-4-yl)benzamido)-4-phenylbenzoate as a yellow solid.
Reaction SMILES: CS(Cl)(=O)=O.C(O[C@H:15]1[C@H:20]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])[C@@H:19]([N:26]=[N+:27]=[N-:28])[CH:18]=[C:17]([C:29]([O:31][CH3:32])=[O:30])[CH2:16]1)(=O)C1C=CC=CC=1.[CH2:33](N(CC)CC)[CH3:34]>ClCCl>[N:26]([C@@H:19]1[C@@H:20]([O:21][S:22]([CH3:25])(=[O:23])=[O:24])[C@H:15]([CH:33]=[CH2:34])[CH2:16][C:17]([C:29]([O:31][CH3:32])=[O:30])=[CH:18]1)=[N+:27]=[N-:28]
Reactant: CCN(CC)CC
Reactant: COC(=O)C1=C[C@H](N=[N+]=[N-])[C@@H](OS(C)(=O)=O)[C@H](OC(=O)c2ccccc2)C1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: C=C[C@@H]1CC(C(=O)OC)=C[C@H](N=[N+]=[N-])[C@H]1OS(C)(=O)=O
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride can be added dropwise to a 0° C. solution of Example 13H and triethylamine in dichloromethane. The reaction mixture can be stirred for 2 hours, washed with saturated NaHCO3 solution, brine, dried (MgSO4), filtered and concentrated. The concentrate can be purified by flash chromatography to afford the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:28])=[C:4]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([CH3:8])=[CH:6][CH:7]=1.[C:29]1(=[O:43])[N:33]([CH2:34][C:35](Cl)=[O:36])[C:32](=[O:38])[C:31]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:30]12.O>N1C=CC=CC=1.CN(C)C=O>[Si:11]([O:10][CH2:9][C:4]1[C:5]([CH3:8])=[CH:6][CH:7]=[C:2]([NH:1][C:35](=[O:36])[CH2:34][N:33]2[C:32](=[O:38])[C:31]3=[CH:39][CH:40]=[CH:41][CH:42]=[C:30]3[C:29]2=[O:43])[C:3]=1[CH3:28])([C:24]([CH3:25])([CH3:27])[CH3:26])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(N)c(C)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(NC(=O)CN2C(=O)c3ccccc3C2=O)c(C)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a suspension of 3-amino-1-(tert-butyldiphenylsilyloxymethyl)-2,6-dimethylbenzene (42.4 g) in pyridine (17.2 g) and N,N-dimethylformamide (212 ml) was added phthalimidoacetyl chloride (25.6 g) over the period of 15 minutes under ice-cooling, and the mixture was stirred for 1 hour at the same temperature. Water was added thereto, and the resulting precipitate was collected by filtration and washed with acetone to give 1-(tert-butyldiphenylsilyloxymethyl)-2,6-dimethyl-3-(phthalimidoacetylamino)benzene (59.1 g) as colorless crystals.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:13][N:14]1[C@H:28]2[C@@H:18]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:29]=3[C:26]([CH2:27]2)=[CH:25][NH:24]4)[CH2:17][C:16](=O)[CH2:15]1>[Pd]>[CH3:13][N:14]1[C@H:28]2[C@@H:18]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:29]=3[C:26]([CH2:27]2)=[CH:25][NH:24]4)[CH2:17][CH:16]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[N:7][CH:8]=2)[CH2:15]1
Reactant: CN1CC(=O)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: CCCCOc1ccc(N)cn1
Agent: [Pd]
Product: CCCCOc1ccc(NC2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cn1

Procedure:
The following compounds (isomers Ia and Ib) are obtained in a manner analogous to that described in Example 3, from 2-n-butoxy-5-aminopyridine and 6-methyl-8-oxo-ergoline in the presence of palladium:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[CH:13][CH:14]=2)[N:9]([CH3:20])[CH:8]=1.C(N(CC)CC)C.O>ClCCl>[CH3:1][S:2]([O:6][C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[CH:13][CH:14]=2)[N:9]([CH3:20])[CH:8]=1)(=[O:4])=[O:3]
Reactant: COc1ccc2c(=O)c(O)cn(C)c2c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(=O)c(OS(C)(=O)=O)cn(C)c2c1

Procedure:
Methanesulphonyl chloride (0.88 ml) was added to a stirred suspension of 3-hydroxy-7-methoxy-1-methyl-4quinolone (0.7 g) and triethylamine (2.4 ml) in dry dichloromethane (100 ml) at ambient temperature and the resultant solution stirred for 3 hours. Water (50 ml) was added and the layers separated. The dichloromethane layer was dried over magnesium sulphate and the solvent evaporated. The residue was purified by flash chromatography on a silica gel column eluted with dichloromethane:methanol (19:1) followed by crystallisation from acetonitrile:methanol (20:1, 10 ml) to give the novel compound 7-methoxy-1-methyl-4-oxo-1,4-dihydroquinol-3-yl methanesulphonate, m.p. 163°.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]3([CH2:30][CH2:29][CH2:28][CH2:27]3)[C:19]2=[O:31])=[O:17])[CH2:10][CH2:9]1)[C:3]([O:5]C)=[O:4].OS(O)(=O)=O.C([O-])(O)=O.[Na+].C(Cl)Cl>C(O)(=O)C.O>[CH3:1][C:2]([CH3:32])([CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]3([CH2:30][CH2:29][CH2:28][CH2:27]3)[C:19]2=[O:31])=[O:17])[CH2:10][CH2:9]1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)CN1CCC(CNC(=O)N2C(=O)C3(CCCC3)c3ccccc32)CC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(CN1CCC(CNC(=O)N2C(=O)C3(CCCC3)c3ccccc32)CC1)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To a stirred solution of methyl 2,2-dimethyl-3-[4-({[(2′-oxospiro[cyclopentane-1,3′-indol]-1′(2′H)-yl)carbonyl]amino}methyl)piperidin-1-yl]propanoate (170 mg, 0.38 mmol, step 3 of Example 2) in acetic acid (2 mL), H2SO4 (113 mg) in water (2 mL) was added, and the mixture was refluxed for 36 h. The mixture was cooled to room temperature and solid NaHCO3 (500 mg) was added slowly. The resulting mixture was concentrated to give white solid. To the solid, CH2Cl2 (40 mL) was added and stirred for 10 min, dried over MgSO4. The solution was filtered and concentrated and then resulted yellow oil. The oil was chromatographed on a column of silica gel eluting with CH2Cl2/methanol (14:1) to give 130 mg (80%) of the title compound as white solid. Recrystallization from ethyl acetate/diethyl ether gave white powder.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].Br[C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][N:34]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>CO.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>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:33]3[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][N:34]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:30])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
Reactant: COC(=O)c1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)(C)C)C[C@H](C)N3C(C)=O)nc1

Procedure:
In a separate vial, Tert-butyl ((2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (for a preparation see Intermediate 61) (2.2 g, 5.11 mmol), methyl 6-bromonicotinate (1.325 g, 6.13 mmol), Pd(PPh3)4 (0.591 g, 0.511 mmol) and potassium carbonate (2.120 g, 15.34 mmol) were combined in methanol (10 mL) and DME (3 mL) and heated under microwave irradiation to 100° C. for 70 mins. The two reaction mixtures were combined and partitioned between water (150 mL) and DCM (3×150 mL). The aqueous layer was acidified to pH 3 via the addition of aq. HCl and extracted with DCM (3×100 mL). The combined organic layers were dried by passing through a hydrophobic frit, and concentrated in vacuo to give crude methyl 6-((2S,4R)-1-acetyl-4-((tert-butoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinate (2.2 g) which was used directly in the next step without further purification. LCMS: (Formate, 2 min), Rt=1.06 min, MH+440.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:24][CH3:25])=[C:18]([S:20](Cl)(=[O:22])=[O:21])[CH:19]=1>C(Cl)Cl>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:24][CH3:25])=[C:18]([S:20]([NH:5][CH2:4][CH2:3][Cl:2])(=[O:21])=[O:22])[CH:19]=1
Reactant: NCCCl
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Br)cc1S(=O)(=O)NCCCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 13.4 g (0.115 mol) of 2-chloroethylamine hydrochloride in 150 ml of CH2Cl2 there are added 34 ml (0.241 mol) of triethylamine and then, dropwise, 30 g (0.105 mol) of the product obtained in Step A above dissolved in 200 ml of CH2Cl2. The solution is stirred for 2 hours at ambient temperature and is then washed with 1N HCl solution, water and brine. The organic phase is dried over MgSO4 and evaporated. The solid is re-suspended in ethyl ether and filtered off to yield the title product.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]#[C:12][CH2:13][OH:14])[CH:2]=1.CC(C)([O-])C.[K+].[C:21]1([N:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH4+].[Cl-]>C1COCC1.CC(OC)(C)C>[C:21]1([N:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28]([O:14][CH2:13][C:12]#[C:11][C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[O:29])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: OCC#Cc1cnc2ccccc2c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: O=C(OCC#Cc1cnc2ccccc2c1)N(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a dry three-necked round-bottom flask equipped with nitrogen inlet and overhead stirrer was charged 3-(3-quinolyl)-2-propyn-1-ol (5 g, 27 mmol) in THF (50 ml) and the solution was cooled to 0° C. Potassium t-butoxide (3.6 g, 32 mmol) was then added followed by diphenylcarbamoyl chloride (6.9 g, 29.7 mmol). The mixture was stirred for 2 hours at 0° C. and then allowed to warm up to room temperature over a period of 6 hours by which time the reaction was determined to be complete. The reaction mixture was worked up with MTBE (100 ml) and 10% NH4Cl (50 ml) and was concentrated to ¼ the volume. Heptane (75 ml) was added and the product was crystallised out. Yield=8.3 g (80%).
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)[CH3:5])C.[NH:16]([C:18]1[N:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)[NH2:17].O>ClCCl.CO>[F:14][C:10]1[CH:9]=[C:8]([C:7]2[N:16]([C:18]3[N:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[N:17]=[C:4]([CH3:5])[N:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NNc1ccc(S(N)(=O)=O)cn1
Reactant: CCOC(C)=NC(=O)c1cccc(F)c1
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: Cc1nc(-c2cccc(F)c2)n(-c2ccc(S(N)(=O)=O)cn2)n1
Reaction time: 8 h
Yield: 53.1 %

Procedure:
N-(1-ethoxy-ethylidene)-3-fluoro-benzamide 438 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 6-hydrazinopyridine-3-sulfonic acid amide 433 mg (2.23 mmol) was added to the solution and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 6-[5-(3-fluoro-phenyl)-3-mehtyl-[1,2,4]triazole-1-yl]-pyridine-3-sulfonic acid amide (370 mg, yield: 53%) was obtained as a solid phase.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH3:15][O:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:15][O:16][CH2:17][CH2:18][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
A mixture of [A] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 0.5 mmol), 2-bromoethyl methyl ether (58 uL, 0.62 mmol, Aldrich, Cat. No. 238155), and cesium carbonate (500.0 mg, 1.5 mmol) in acetonitrile (1 mL) was stirred at 90° C. overnight. After cooling it was quenched with water, extracted with ethyl acetate. The extract was washed with water twice, brine once; dried over Na2SO4. After filtration the filtrate was concentrated to yield 90 mg of the product. LCMS (M+H)+: m/z=253.1
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[P:7]1[C:13]([CH3:15])([CH3:14])[CH2:12][CH2:11][C:10](=O)[CH2:9][C:8]1([CH3:18])[CH3:17].C(O)COCCO.O.NN.[OH-].[K+]>O.CCCCCCC>[C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[P:7]1[C:13]([CH3:14])([CH3:15])[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1([CH3:18])[CH3:17]
Reactant: CC1(C)CCC(=O)CC(C)(C)P1c1ccccc1-c1ccccc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: OCCOCCO
Solvent: O
Product: CC1(C)CCCCC(C)(C)P1c1ccccc1-c1ccccc1
Temperature: 210 °C
Reaction time: 7 h
Yield: 51 %

Procedure:
A round bottom flask was charged with 1-(biphenyl-2-yl)-2,2,7,7-tetramethylphosphepan-4-one (520 mg, 1.54 mmol, 1.0 equiv) and purged with nitrogen for 15 minutes. Then nitrogen-sparged diethylene glycol (8.0 mL, 85 mmol, 55 equiv) was added and the flask was equipped with a Claisen adapter and a Dean-Stark trap. The mixture was charged with hydrazine hydrate (0.680 mL, 7.68 mmol, 5 equiv, 55 wt % hydrazine) and potassium hydroxide (431 mg, 7.68 mmol, 5 equiv). The mixture was immersed in an oil bath at 175° C. The temperature of the bath was gradually increased to 210° C. over 30 minutes and kept at that temperature for 7 hours. The reaction mixture was cooled to room temperature under a positive pressure of nitrogen, and the reaction mixture was diluted with water (10 mL) and heptane (30 mL). The phases were partitioned, and the organic layer was collected. The aqueous layer was washed with heptane (2×20 mL). The combined organic fractions were washed once with aqueous saturated sodium chloride (20 mL), dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The crude product was crystallized from a saturated solution of ethanol and isolated by filtration to afford an off-white solid (254 mg, 90 area % by HPLC, 51% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.03-7.95 (m, 1H), 7.47-7.27 (m, 8H), 1.88-1.54 (m, 8H), 1.26 (d, J=4.0 Hz, 6H), 0.96 (s, 3H), 0.92 (s, 3H). 13C NMR (100 MHz, CDCl3) δ ppm 150.8 (d, J=34 Hz), 143.5 (d, J=7 Hz), 136.3 (d, J=3 Hz), 134.8 (d, J=32 Hz), 130.3 (d, J=4 Hz), 130.2 (d, J=6 Hz), 127.9, 126.7, 125.9, 125.3, 45.1 (d, J=18 Hz), 35.2, 34.9, 32.3, 32.0, 28.1 (d, J=3 Hz), 25.6 (d, J=3 Hz). 31P NMR (CDCl3, 202 MHz) δ ppm 14.4 (s). HRMS (TOF-ESI+) calcd for [M, C22H29P]+ 324.2007. found 324.2004.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](O)=[O:8])=[CH:5][C:4]([CH3:10])=[N:3]1.C(N(CC)CC)C.C(OC(Cl)=O)C.[N-:24]=[N+:25]=[N-:26].[Na+]>CC(C)=O.O>[N:24]([C:7]([C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH:5]=1)=[O:8])=[N+:25]=[N-:26]
Reactant: Cc1cc(C(=O)O)n(C)n1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N=[N+]=[N-])n(C)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 34.4 %

Procedure:
To a solution of 1,3-dimethylpyrazol-5-carboxylic acid (500 mg, 3.57 mmol) in a mixture of acetone (10 mL) and water (5 mL) was added triethylamine (0.75 mL, 7.13 mmol). The mixture was cooled to 0° C. in a ice-bath. Ethylchloroformate (774 mg, 7.13 mmol) was then added and the resulting mixture was stirred for 1.5 hours at 0° C. To the mixture was added sodium azide (0.844 g, 13.0 mmol), and the mixture was stirred for another 1.5 hours. The mixture was concentrated, the residue was diluted with dichloromethane and washed with water. The organic layer was dried over MgSO4 and concentrated to give desired product (203 mg, 34%). 1HNMR (CDCl3) (δ) 6.60 (s, 1H), 4.11 (s, 3H), 2.25 (s, 3H).