Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[CH2:10][CH:9]([N:11]2[C:15]3[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH:22]4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:14]=3[N:13]=[N:12]2)[CH:8]([OH:34])[CH:7]1[OH:35])=[O:5])[CH3:2].[Cl:36][C:37]1[CH:38]=C([CH:42]=[CH:43][CH:44]=1)CN>>[Cl:36][C:37]1[CH:38]=[C:2]([CH2:1][NH:3][C:4]([CH:6]2[CH2:10][CH:9]([N:11]3[C:15]4[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]5[CH2:23][CH:22]5[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:14]=4[N:13]=[N:12]3)[CH:8]([OH:34])[CH:7]2[OH:35])=[O:5])[CH:42]=[CH:43][CH:44]=1
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCC)C(O)C3O)c2n1
Reactant: NCc1cccc(Cl)c1
Product: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCc4cccc(Cl)c4)C(O)C3O)c2n1

Procedure:
The subtitle compound was prepared according to the method of example 39, step a) using the product of example 1, step c) and 3-chlorobenzylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32]1([C:38]2([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:41]3[CH2:42][CH2:43][C:38]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:48])([CH3:50])[CH3:49])([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:39][CH2:40]3)=[O:22])[C:9]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccccc2)CCNCC1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)N2CCC(NC(=O)OC(C)(C)C)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Yield: 87 %

Procedure:
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1 eq., 201 mg, 0.53 mmol), triethylamine (3 eq, 0.22 mL, 0.157 mmol), tert-butyl N-(4-phenyl piperidin-4-yl)carbamate (1 eq, 146 mg, 0.53 mmol), and Benzotriazole-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (1 eq, 233 mg, 0.53 mmol) was stirred in tetrahydrofuran (10 mL) for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure tert-butyl N-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-yl)carbamate (295 mg, 87%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.37 (br. s., 9H) 2.11 (dd, J=12.67, 4.00 Hz, 2H) 2.21 (s, 3H) 2.24-2.34 (m, 1H) 2.34-2.56 (m, 1H) 3.26 (t, J=12.01 Hz, 1H) 3.56 (t, J=12.39 Hz, 1H) 4.32 (d, J=13.75 Hz, 1H) 4.64 (d, J=13.56 Hz, 1H) 4.96 (br. s., 1H) 7.08 (d, J=8.38 Hz, 2H) 7.13-7.49 (m, 10H).
Reaction SMILES: [CH2:1]([C:3]1[C:7](I)=[C:6]([CH:9]=[O:10])[NH:5][C:4]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH3:2].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[O:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH:28]=[C:27]1B(O)O>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(COC)OC>[O:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH:28]=[C:27]1[C:7]1[C:3]([CH2:1][CH3:2])=[C:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[NH:5][C:6]=1[CH:9]=[O:10]
Reactant: OB(O)c1cc2ccccc2o1
Reactant: CCc1c(C(=O)OC(C)(C)C)[nH]c(C=O)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCc1c(C(=O)OC(C)(C)C)[nH]c(C=O)c1-c1cc2ccccc2o1
Temperature: 85 °C

Procedure:
Tert-butyl 3-ethyl-5-formyl-4-iodo-1H-pyrrole-2-carboxylate was obtained following the procedures described in Example 1. To a mixture of tert-butyl 3-ethyl-5-formyl-4-iodo-1H-pyrrole-2-carboxylate (0.0597 g, 0.172 mmol), K3PO4 (0.180 g, 0.85 mmol), Pd(PPh3)4(0.0120 g, 0.010 mmol), and 1-benzofuran-2-ylboronic acid (0.0330 g, 0.21 mmol) under N2 was added dimethoxyethane (2.5 mL). The reaction was heated to 85° C. and refluxed for 5 h. After cooling to ambient temperature, the reaction was filtrated through a pad of silica gel and concentration. The resultant residue was purified by normal phase chromatography (5-15% ethyl acetate/hexanes). Proton NMR for the product was consistent with the title compound as a 2:1 mixture of atropdiastereomers. 1H NMR (500 MHz, CDCl3) δ 10.17 (s, 0.7 H); 9.59 (s, 0.3H); 7.64 (app. d, J=7.6 Hz, 1H); 7.52 (app. d, J=8.1 Hz, 1H); 7.34 (app. t, J=7.7 Hz, 1H); 7.28 (app. t, J=7.6 Hz, 1H), 6.92 (s, 0.7H); 6.80 (s, 0.3H); 3.00 (q, J=7.3 Hz, 1.4H); 2.79 (q, J=7.5 Hz, 0.6H); 1.62 (s, 6.3H); 1.59 (s, 2.7H); 1.28 (t, J=7.3 Hz, 2.1H); 1.23 (t, J=7.6 Hz, 0.9H). HRMS (ES) exact mass calculated for C20H21NNaO4 (M+Na+): 362.1362. Found 362.1362.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[C:7](O)=[O:8])[CH3:2].O=S(Cl)[Cl:18]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[C:7]([Cl:18])=[O:8])[CH3:2]
Reactant: CCOc1ccc(C(=O)O)cc1OCC
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOc1ccc(C(=O)Cl)cc1OCC

Procedure:
To a stirred solution of 3,4-diethoxybenzoic acid (0.71 mmol, 150 mg) in CH2Cl2 was added SOCl2 at room temperature; the reaction was refluxed for 1.5 h and the mixture concentrated under reduced pressure to yield 3,4-diethoxybenzoylchloride quantitatively. To a stirred suspension of Na2CO3 (1.42 mmol, 150.52 mg) and pyridine-4-carbohydrazide (0.71 mmol, 97 mg) in NMP (0.8 mL) was added a solution of the 3,4-diethoxybenzoylchloride in NMP (0.8 mL) and the reaction was stirred for 12 h at room temperature. The mixture was poured into 20 mL of cold H2O and filtered. The precipitated intermediate was dried in vacuum. The solid was added to POCl3 (5 mL) and heated to 70-72° C. for 6 h. The solution was poured into an ice-water container and neutralized with a solution of NaOH (2M). The precipitated product was filtered and purified by column chromatography using CH2Cl2:MeOH (9:1) to yield the product as white solid in 67% yield (150 mg). 1H NMR (400 MHz, CDCl3): δ 8.84 (bs, 2H), 7.99 (d, J=4.4 Hz, 2H), 7.67 (dd, J1=2.0, J2=8.4 Hz, 1H), 7.64 (d, J=2.0 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 4.18 (q, J=7.2 Hz, 2H), 1.51 (t, J=7.2 Hz, 3H), 1.50 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ165.81, 162.46, 152.51, 150.84, 149.20, 131.52, 128.05, 120.97, 115.77, 112.78, 111.58, 65.05, 64.80, 14.92, 14.85. MS (EI) m/z: 312 (M+), HRMS (EI) for C17H17N3O3 (M+): calcd 312.1343. found 312.1350.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:36][CH2:37][CH2:38][OH:39])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[OH:39][CH2:38][CH2:37][NH:36][S:33]([C:30]1[CH:31]=[CH:32][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:28][CH:29]=1)(=[O:35])=[O:34]
Reactant: O=S(=O)(NCCO)c1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=S(=O)(NCCO)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 4-bromo-N-(2-hydroxy-ethyl)-benzenesulfonamide (example B.29) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (370 mg, 66%). MS (ISP) 555.2 [(M+H)+]; mp 206–208° C.
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][NH:19][S:20]([CH:23]3[CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:16]=2)[CH2:11][CH2:10][CH:9]1[NH:27]C(=O)OC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:27][CH:9]1[CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17]2[CH:16]=[C:15]([CH2:18][NH:19][S:20]([CH:23]3[CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(CNS(=O)(=O)C3CCC3)cc2C1Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCc2ccc(CNS(=O)(=O)C3CCC3)cc2C1Cc1ccccc1

Procedure:
tert-Butyl 1-benzyl-7-(cyclobutanesulfonamidomethyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (0.732 g, 1.51 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (0.5 mL, 6.49 mmol) and stirred overnight at room temperature. The solution was evaporated and partitioned between saturated aqueous NaHCO3 and ethyl acetate. Water was extracted with ethyl acetate (2×30 mL). The collected organic extracts were dried on MgSO4 and evaporated under reduced pressure to give a brown oil. Product was obtained as a brown oil (0.487 g, 1.31, 98%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(OP([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(OCC)=O)C>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH2:1][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:3]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1cccnc1
Product: CCOC(=O)CCc1cccnc1

Procedure:
The procedure of Synthetic Example 4 was repeated using nicotinaldehyde and ethyl diethylphosphonoacetate to obtain ethyl 3-(pyridin-3-yl)propionate.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15][O:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1
Reactant: OCc1ccc(Cl)c(Cl)c1
Reactant: N#Cc1ccc(O)cc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1ccc(OCc2ccc(Cl)c(Cl)c2)cc1F
Temperature: 50 °C
Reaction time: 5 h
Yield: 89.5 %

Procedure:
2-Fluoro-4-hydroxybenzonitrile (350 mg, 2.55 mmol) and 3,4-dichlorobenzyl alcohol (542 mg, 3.06 mmol) were dissolved in tetrahydrofuran (7.0 mL), and triphenylphosphine (803 mg, 3.06 mmol) and a 40% diethyl azodicarboxylate toluene solution (1.40 mL, 3.06 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 5 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 65:35 (v/v)), whereby the objective title compound was obtained as a white solid (676 mg, yield: 89%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([C:13]2[O:14][C:15]3[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:10]=[CH:11][CH:12]=1.[H][H]>CO.O.[Pt](=O)=O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]1[CH:8]=[C:9]([C:13]2[O:14][C:15]3[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: NC(=O)c1cccc2nc(-c3cccc(-c4ccccn4)c3)oc12
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Solvent: O
Product: NC(=O)c1cccc2nc(-c3cccc(C4CCCCN4)c3)oc12
Yield: 33.3 %

Procedure:
2-(3-(Pyridin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide (90 mg, 0.28 mmol) and platinum (IV) oxide monohydrate (45 mg) in methanol (20 mL) was purged with 20 atm of hydrogen at 50° C. for 24 h. Then the mixture was filtered and adjusted to pH=9. The solvent was removed in vacuum. The crude was purified by chromatography (petroleum ether/ethyl acetate=1:1). 30 mg of 2-(3-(piperidin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained, yield: 33%. 1H-NMR (400 MHz, DMSO-d6) δ 1.35-1.38 (m, 1H), 1.45-1.47 (m, 2H), 1.58-1.60 (m, 1H), 1.75-1.82 (m, 2H); 2.68-2.69 (m, 1H); 3.08-3.10 (d, J=9.6 Hz, 1H); 3.66-3.69 (m, 1H); 7.48-7.50 (t, J=6.0 Hz, 1H), 7.55-7.58 (d, J=6.4 Hz, 1H), 7.63-7.64 (d, J=5.6 Hz, 1H); 7.79-7.81 (m, 1H); 7.86 (brs, 1H); 7.94 (brs, 1H); 7.95-7.97 (m, 1H); 8.16-8.18 (m, 1H); 8.302 (s, 1H); LC-MS (ESI) m/z: 322 (M+1)+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[O:12][CH3:13].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:11][C:9]1[CH:8]=[CH:7][C:6]([O:12][CH3:13])=[C:5]([CH:10]=1)[O:4][CH2:3][CH2:2][N:18]1[C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]2[C:14]1=[O:24]
Reactant: COc1ccc(F)cc1OCCCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(F)cc1OCCN1C(=O)c2ccccc2C1=O
Yield: 84.4 %

Procedure:
A suspension of 8.00 g of 2-(2-chloroethoxy)-4-fluoroanisole, 5.75 g of phthalimide and 3.24 g of potassium carbonate in 15 ml of N,N-dimethylformamide was heated for 2 hours at 120°-130° C. After cooling, the reaction mixture was poured into water. The precipitate was filtered to give 10.4 g of N-[2-(5-fluoro-2-methoxyphenoxy)ethyl]phthalimide as colorless crystals, which were recrystallized from ethanol as colorless needles, m.p. 134.5°-136° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:12]([CH3:13])=[C:11](O)[C:10]2[C:5](=[C:6]([C:15]([F:18])([F:17])[F:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.P(Br)(Br)([Br:23])=O>C1(C)C=CC=CC=1>[F:1][C:2]([F:20])([F:19])[C:3]1[C:12]([CH3:13])=[C:11]([Br:23])[C:10]2[C:5](=[C:6]([C:15]([F:18])([F:17])[F:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cc1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Reactant: O=P(Br)(Br)Br
Solvent: Cc1ccccc1
Product: Cc1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1Br
Yield: 81 %

Procedure:
A solution of 2,8-bis(trifluoromethyl)-3-methyl-4-quinolinol (5.9 g, 20 mmol) in toluene (20 mL) was treated with POBr3 (6.0 g, 21 mmol), heated to reflux for 30 min, cooled in ice, quenched with water and extracted with EtOAc (2×50 mL). The combined extracts were dried (MgSO4), concentrated in vacuo and the resulting brown solid purified by flash chromatography [SiO2; heptane] to give the product (5.8 g, 81%) as a white crystalline solid: mp 81.9-82.3° C.; IR νmax (Nujol)/cm−1 2955, 2924, 2854, 1574, 1465, 1364, 1299, 1281, 1213, 1189, 1141; NMR δH (400 MHz, CDCl3) 2.77 (3H, s), 7.78 (1H, t, J 8.1 Hz), 8.14 (1H, d, 7.4 Hz), 8.49 (1H, d, J 8.5 Hz).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18](Cl)[C:17]([CH3:22])=[CH:16]2>CN(C=O)C>[Br:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:17]([CH3:22])=[CH:16]2
Reactant: Cc1cc2cccc(Br)c2nc1Cl
Reactant: Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2cccc(Br)c2nc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 28.2 %

Procedure:
NaH (60% w/w in mineral oil; 390 mg, 9.75 mmol) was added to a solution of aniline (0.888 mL, 9.75 mmol) in DMF (4.0 mL) at 0° C. and the resulting suspension was stirred at 0° C. for 2 min, then warmed to 25° C. and stirred for 5 min. 8-Bromo-2-chloro-3-methylquinoline (Example 104b; 529 mg, 2.062 mmol) was added as a solid, and the resulting solution was stirred at 25° C. for 1.5 h, then at 80° C. bath for 2.5 h. The mixture was cooled to 25° C. and partitioned between EtOAc (100 mL) and saturated aq. NH4Cl (80 mL). The organic layer was separated and the aq. layer was extracted with EtOAc (2×50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-40% EtOAc/hexanes) furnished 8-bromo-3-methyl-N-phenylquinolin-2-amine (182.0 mg, 0.581 mmol, 28% yield) as a brown oil: m/z (ESI, +ve) 313.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.Cl.[C:13]([C:15]1[CH:28]=[CH:27][C:18]([CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:17][CH:16]=1)#[N:14].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:26][CH:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:18]3[CH:27]=[CH:28][C:15]([C:13]#[N:14])=[CH:16][CH:17]=3)[CH2:21][CH2:22]2)=[O:10])=[N:6][CH:7]=1
Reactant: N#Cc1ccc(CN2CCC(N)CC2)cc1
Reactant: O=C(O)c1ccc(Br)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN2CCC(NC(=O)c3ccc(Br)cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 5-bromopicolinic acid (0.50 g, 2.48 mmol, 1.0 eq) and 1-(4-cyanobenzyl)-4-aminopiperidine dihydrochloride (0.71 g, 2.48 mmol, 1.0 eq) in dimethylformamide (10 mL) was added triethylamine (1.21 mL, 8.66 mmol, 3.5 eq) and HATU (1.13 g, 2.97 mmol, 1.2 eq). The reaction mixture was stirred at room temperature 14 hours before partitioning between EtOAc (120 mL) and water (100 mL). The organics were washed with brine (100 mL), water (100 mL) and brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (0%, 5%, 10% MeOH—CH2Cl2, 0→5→25→35 min) yielded 5-bromo-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide as a waxy brown solid: 1H nmr (CDCl3) 8.60 (1H, d, J 2.0 Hz, pyH-6), 8.07 (1H, d, J 8.5 Hz, pyH-3), 7.97 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.84 (1H, d, J 7.5 Hz, NH), 7.63 (2H, d, J 8.5 Hz, 2H of C6H4CN), 7.50 (2H, d, J 8.0 Hz, 2H of C6H4CN), 4.00 (1H, m, pipH-4), 3.63 (2H, s, CH2C6H4CN), 2.88 (2H, m, 2H of pip), 2.30 (2H, m, 2H of pip), 2.04 (2H, m, 2H of pip), 1.70 (2H, m, 2H of pip); m/z 399, 401 [M+H]+. To a mixture of the 5-bromo-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide (0.040 g, 0.100 mmol, 1.0 eq) 4-(4-piperidinyloxy)benzonitrile (0.024 g, 0.120 mmol, 1.2 eq), sodium t-butoxide (0.019 g, 0.201 mmol, 2.0 eq) and S-Phos (0.004 g, 0.010 mmol, 0.1 eq) was added toluene (1.0 mL). The resulting mixture was degassed by bubbling argon through the mixture. Tris(dibenzylideneacetone)dipalladium (0.005 g, 0.005 mmol, 0.05 eq) was added and the mixture further degassed before sealing the reaction and heating to 105° C. for 14 hours. The reaction was filtered through celite, eluting with 5% MeOH—CH2Cl2 (3×15 mL). The filtrate was concentrated under reduced pressure. The crude material was purified by RP-HPLC to yield Compound 165: 1H nmr (CDCl3) δ 8.19 (1H, d, J 3.0 Hz, pyH-6), 8.04 (1H, d, J 9.0 Hz, pyH-3), 7.72 (1H, d, J 8.5 Hz, NH), 7.60 (4H, m, 2H of OC6H4CN, 2H of CH2C6H4CN), 7.45 (2H, d, J 8.0 Hz, 2H of CH2C6H4CN), 7.24 (1H, dd, J 8.0, 3.0 Hz, pyH-4), 6.97 (2H, d, J 9.0 Hz, 2H of OC6H4CN), 4.64 (1H, m, PhOpipH-4), 3.98 (1H, m, pipH-4), 3.63-3.57 (2H, m, 2H of PhOpipH-2, H-6), 3.55 (2H, s, CH2C6H4CN), 3.38-3.30 (2H, m, 2H of PhOpipH-2, H-6), 2.80 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.16-2.05 (2H, m, 2H of PhOpipH-3, H-5), 2.01-1.92 (4H, m, 2H of pipH-3, H-5, 2H of PhOpipH-3, H-5), 1.62 (2H, m, 2H of pipH-3, H-5); m/z: 522 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:32]=[CH:33][CH:34]=2)[C:12]([NH:14][C:15]2[CH:16]=[C:17]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27](Cl)[CH:26]=3)=[O:24])[CH:18]=[CH:19][C:20]=2[CH3:21])=[O:13])[CH2:4][CH2:3]1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:32]=[CH:33][CH:34]=2)[C:12]([NH:14][C:15]2[CH:16]=[C:17]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[CH:26]=3)=[O:24])[CH:18]=[CH:19][C:20]=2[CH3:21])=[O:13])[CH2:4][CH2:3]1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1NC(=O)c1cccc(CN2CCN(C)CC2)c1
Reactant: C1COCCN1
Solvent: O
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cccc(CN2CCN(C)CC2)c1
Temperature: 110 °C

Procedure:
Using an analogous procedure to that described in Example 3, a mixture of N-{3-[3-(4-methylpiperazin-1-ylmethyl)benzamido]-4-methylphenyl}-2-chloropyridine-4-carboxamide (0.5 g) and morpholine (5 ml) was stirred and heated to 110° C. for 16 hours. The resultant solution was cooled to ambient temperature and poured into water and extracted with methylene chloride. The organic phase was evaporated and the residue was purified by column chromatography on an isolute SCX ion exchange column using a 99:1 mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound (0.023 g); Mass Spectrum: M+H+529.
Reaction SMILES: [Cl-].[CH2:2]([CH:9]1[C:15]2[CH:16]=[C:17]([O:20][CH2:21][CH2:22][NH3+:23])[CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][CH2:11][N:10]1[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN(C1C=CC=CN=1)C.[CH3:38][N:39]1[CH:43]=[C:42]([S:44](Cl)(=[O:46])=[O:45])[N:41]=[CH:40]1>ClCCl.C(OCC)(=O)C>[CH2:2]([CH:9]1[C:15]2[CH:16]=[C:17]([O:20][CH2:21][CH2:22][NH:23][S:44]([C:42]3[N:41]=[CH:40][N:39]([CH3:38])[CH:43]=3)(=[O:46])=[O:45])[CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][CH2:11][N:10]1[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)N1CCCc2ccc(OCC[NH3+])cc2C1Cc1ccccc1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Agent: CN(C)c1ccccn1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCCc2ccc(OCCNS(=O)(=O)c3cn(C)cn3)cc2C1Cc1ccccc1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
To a solution of 0.12 mmol 2-(1-benzyl-2-(ethoxycarbonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yloxy)ethanaminium chloride in 3 ml dichloromethane were added 0.33 mmol dimethylaminopyridine and 0.17 mmol 1-methyl-1H-imidazole-4-sulfonyl chloride. The mixture was stirred at room temperature over night. The mixture was diluted with ethyl acetate and washed with NH4Cl solution (2×), water (1×), and brine (1×). The organic layer was dried over MgSO4 and filtered. Evaporation of the solvent gave 66 mg of crude material that was purified by flash chromatography to yield 60 mg of ethyl 1-benzyl-8-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-4,5-dihydro-1H-benzo[c]azepine-2(3H)carboxylate (95%).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:14]([O:18][CH3:19])(=[O:17])[CH2:15][SH:16].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:11][C:10]([F:13])([F:12])[C:8]1[CH:7]=[CH:6][C:3]2[CH:4]=[C:15]([C:14]([O:18][CH3:19])=[O:17])[S:16][C:2]=2[CH:9]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2ccc(C(F)(F)F)cc2s1
Temperature: 140 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
A mixture of 1.11 g of 2-fluoro-4-(trifluoromethyl)benzaldehyde, 739 mg of methyl thioglycolate, 1.3 g of potassium carbonate and 20 ml of DMF was stirred at 140° C. for 2 hours. The reaction mixture was cooled down to room temperature. To the reaction mixture was added water, and the mixture was extracted with tert-butyl methyl ether three times. The combined organic layers were washed with water and saturated saline, and dried over magnesium sulfate, then, concentrated under reduced pressure, to obtain 848 mg of methyl 6-(trifluoromethyl)benzo[b]thiophene-2-carboxylate (present condensed ring compound 2).