Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[C:5](OCC)=[O:6].[CH2:17]([NH:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([NH:32][NH2:33])=[N:28][CH:27]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH2:17]([NH:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:5]([OH:6])=[C:4]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[CH:3]=[N:33]2)=[N:28][CH:27]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NNc1ccc(C(=O)NCc2ccccc2)cn1
Reactant: CCOC(=O)C(=CN(C)C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(NCc1ccccc1)c1ccc(-n2ncc(-c3ccncc3)c2O)nc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 35.6 %

Procedure:
Combined ethyl 3-(dimethylamino)-2-(pyridin-4-yl)acrylate (40.0 mg, 0.182 mmol) and N-benzyl-6-hydrazinylnicotinamide (33.8 mg, 0.140 mmol) in 2-propanol (0.698 mL) and stirred for 18 hours at room temperature. Hunig's base (0.219 mL, 1.257 mmol) was then added and the reaction was stirred for 24 hours at 50° C. The reaction mixture was then purified by preparative HPLC (SunFire™ C18, 5 μm, ID 30 mm×75 mm) eluting with ACN (with 0.035% TFA) in water (with 0.05% TFA) to give the title compound (18.5 mg, 35.7%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.58 (d, J=5.8 Hz, 2 H) 7.33 (dq, J=8.5, 4.3 Hz, 1 H) 7.37-7.45 (m, 4 H) 8.28 (d, J=6.3 Hz, 2 H) 8.45 (d, J=7.1 Hz, 2 H) 8.49-8.58 (m, 2 H) 8.63 (s, 1 H) 8.99 (s, 1 H) 9.33 (t, J=5.9 Hz, 1 H). MS m/z [M+H]+ 372.4.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[Si]([O:33][CH2:34][CH2:35][O:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([C:44]2[N:49]=[C:48]([C:50](O)=[O:51])[CH:47]=[CH:46][C:45]=2[F:53])=[C:39]([F:54])[CH:38]=1)(C(C)(C)C)(C)C>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:50](=[O:51])[C:48]2[CH:47]=[CH:46][C:45]([F:53])=[C:44]([C:40]3[C:41]([F:43])=[CH:42][C:37]([O:36][CH2:35][CH2:34][OH:33])=[CH:38][C:39]=3[F:54])[N:49]=2)[CH2:6][CH2:7]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3c(F)cc(OCCO)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,6-difluorophenyl)-5-fluoropicolinic acid (see US2012/225062) gave 209. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.26 (dd, J=8.6, 4.0 Hz, 1H), 8.11 (t, J=8.9 Hz, 1H), 7.92 (s, 1H), 6.93 (d, J=10.2 Hz, 2H), 4.98 (br, 1H), 4.82 (dd, J=10.3, 3.7 Hz, 1H), 4.24 (ddt, J=49.2, 6.1, 2.6 Hz, 1H), 4.11 (t, J=4.8 Hz, 2H), 4.07-3.84 (m, 2H), 3.80-3.69 (m, 5H), 3.15-3.01 (m, 1H), 2.12-2.01 (m, 1H), 1.83-1.58 (m, 3H). LCMS (ES+) m/z 524 (M+1).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].F[B-](F)(F)F.[N:22]1([O:31][C:32](N(C)C)=[N+](C)C)[C:26]2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CNOC>C(Cl)Cl>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([N:22]([CH3:26])[O:31][CH3:32])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CNOC
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.08 h

Procedure:
Boc-Leu-OH (1 g, 4.3 mmol) was dissolved in DCM (30 mL) and 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU)(1.380 g, 4.3 mmol), HOBt (0.581 g, 4.3 mmol) and DIPEA (743 μL, 4.3 mmol) were added at 0° C. After 5 min of stirring, 0,N-dimethylhydroxylamine hydrochloride (0.461 g, 4.73 mmol) and DIPEA (817 μL, 4.73 mmol) were added. All solid material dissolved within 10 min and the mixture was stirred overnight at RT. The solvent was evaporated, the reaction mixture redissolved in AcOEt and washed with H2O, 5% citric acid, H2O, 5% aqueous NaHCO3 solution, saturated NaCl solution several times. The solution was dried over MgSO4 and the solvent removed in vacuo. The desired compound was purified by silica gel column chromatography. ESI-MS: calcd. 269. found 292 [M+Na]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>CCO>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][S:15][C:13]2[O:14][C:10]([C:7]3[CH:8]=[CH:9][C:4]4[NH:3][CH:2]=[N:1][C:5]=4[CH:6]=3)=[N:11][N:12]=2)=[CH:19][CH:18]=1
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Reactant: Fc1ccc(CCl)cc1
Solvent: CCO
Product: Fc1ccc(CSc2nnc(-c3ccc4[nH]cnc4c3)o2)cc1

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.209 mL, 1.5 mmol) and 4-fluorobenzylchloride (0.17 mL, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26]([OH:28])=O)[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].[CH3:30][N:31]([CH3:38])[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26]([N:35]4[CH2:36][CH2:37][CH:32]([N:31]([CH3:38])[CH3:30])[CH2:33][CH2:34]4)=[O:28])[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OCC2)c1ccc(Cl)cc1Cl
Reactant: CN(C)C1CCNCC1
Product: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)N3CCC(N(C)C)CC3)ccc1OCC2)c1ccc(Cl)cc1Cl

Procedure:
2-[(2,4-Dichloro-phenyl)-methyl-carbamoyl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid and 4-(dimethylamino)piperidine were reacted by General Procedure B to give 247. NMR: (CDCl3): 1.45-1.62 (2 H, br m), 1.88-2.01 (2 H, br, m), 2.39 (6H, s, Me), 2.50-2.61 (1 H, br m), 2.82-3.10 (2 H, br m), 3.07-3.09 (2 H, m), 3.38 (3 H, s, Me), 3.80-4.01 (1 H, br m), 4.26-4.29 (2 H, m), 4.58-4.79 (1 H, br m), 6.85 (1 H, s, Ar), 7.02 (1 H, d, J 8.3, Ar), 7.25 (1 H, dd, J 8.2 and 2.0, Ar), 7.28-7.32 (1 H, m, Ar), 7.37-7.39 (1 H, m, Ar), 7.55 (1 H, s, Ar) and 7.60 (1 H, s, Ar). MS: (ESI+) MH+=558.14
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][CH2:17][C:18](O)=O>O>[CH2:1]([N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]=[C:18]1[CH2:17][Cl:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCl
Reactant: Nc1ccccc1NCc1ccccc1
Solvent: O
Product: ClCc1nc2ccccc2n1Cc1ccccc1
Temperature: 120 °C
Yield: 73.3 %

Procedure:
N-benzyl-o-phenylenediamine (3 g, 15 mmol), which is a known compound, was added to polyphosphoric ester (10 g), to which monochloroacetic acid (1.1 g, 12 mmol) was added and heated at 120° C. for 1 hour. Then water was added to the mixture to decompose remaining polyphosphoric ester. The resultant was refined in a conventional process and the title intermediate (2.25 g, 8.8 mmol) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>O1CCCC1>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:36])[O:18][C:15]2[CH:16]=[C:17]3[C:12]([CH2:11][CH2:10][CH2:9][N:8]3[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:13][CH:14]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)Oc2ccc3c(c2)N(Cc2ccccc2)CCC3)cc1
Temperature: 35 °C

Procedure:
A mixture of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (500 mg, 2.09 mM) and triethylamine in dry tetrahydrofuran (THF, 5 ml) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 4-methoxyphenyl isocyanate (407 mg/ml, 3.14 mM) was added at once and then the reaction mixture was further stirred for 72 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chlorophorm-hexane (1:9) to give 8j as solid. Yield: 0.588 g, 72.53%.
Reaction SMILES: [CH3:1][C:2]([C:4]([O:6][CH2:7][CH2:8][OH:9])=[O:5])=[CH2:3].[O-2].[Al+3].[O-2].[O-2].[Al+3].[CH3:15][Si:16]([CH3:19])([CH3:18])Cl>C(N(CC)CC)C>[CH3:15][Si:16]([CH3:19])([CH3:18])[O:9][CH2:8][CH2:7][O:6][C:4](=[O:5])[C:2]([CH3:1])=[CH2:3]
Reactant: C[Si](C)(C)Cl
Reactant: C=C(C)C(=O)OCCO
Agent: [Al+3]
Agent: [O-2]
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCO[Si](C)(C)C

Procedure:
HEMA monomer (with an impurity level lower than 0.8% purchased from Rohm) was mixed with triethylamine (≧99.5% pure, from Fluka) and petrol ether (bp 40-60° C.) passed through aluminum oxide and reacted with trimethyl chlorosilane (≧99.0% pure, from Fluka) to obtain trimethylsilyloxyethyl-methacrylate (TMS-HEMA). TMS-HEMA was purified by distillation from calciumhydride (once) and triethylaluminum (electronic grade, from Aldrich) (twice).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([Cl:7])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:6]=[C:5]([Cl:7])[N:4]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:3]=1
Reactant: Clc1cc(Cl)[nH]n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1nc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.1 %

Procedure:
A suspension of 3,5-dichloro-1H-pyrazole (690 mg, 5.0 mmol) (i.e. the product of Example 12, Step D), potassium carbonate (3 g, 21 mmol) in N,N-dimethylformamide (10 mL) was treated with ethyl bromoacetate (1.0 mL, 9.0 mmol) and stirred at ambient temperature for 12 h. The suspension was diluted with ethyl acetate, washed with water, and dried over MgSO4. The reaction mixture was then concentrated under reduced pressure giving 1.05 g of the title compound. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]([CH3:21])[C:10]([C:12]2[CH:20]=[CH:19][C:15]3=[N:16][O:17][N:18]=[C:14]3[CH:13]=2)=O)[CH2:5][CH2:4]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:23]>C1(C)C=CC=CC=1>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]([CH3:21])[C:10]([C:12]2[CH:20]=[CH:19][C:15]3=[N:16][O:17][N:18]=[C:14]3[CH:13]=2)=[S:23])[CH2:5][CH2:4]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CO[C@H]1CC[C@H](N(C)C(=O)c2ccc3nonc3c2)CC1
Solvent: Cc1ccccc1
Product: CO[C@H]1CC[C@H](N(C)C(=S)c2ccc3nonc3c2)CC1

Procedure:
N-(trans-4-Methoxycyclohexyl)-N-methyl-[2,1,3]-benzoxadiazole-5-carboxamide (0.91 g, 3.2 mmol) and phosphorus pentasulfide (1.42 g) were refluxed in toluene (40 ml) for 3 h. The mixture was cooled, filtered through a 2 cm layer of silica gel and washed with dichloromethane. Evaporation of the solvent and trituration with diethyl ether gave a yellow solid (0.1 g). Mp=137-138° C., 1H NMR (300 MHz, CDCl3, rotamers) δ 7.89-7.83 (m, 1H); 7.58-7.55 (m, 1H); 7.36-7.30 (m, 1H); 5.50-5.40 and 3.90-3.75 and 3.50-3.00 (m, 2H); 3.44 and 3.38 (s+s, 3H); 3.27 and 3.04 (s+s, 3H); 2.30-0.95 ppm (s, 8H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([OH:10])=[CH:7][CH:8]=[CH:9][C:2]1=2.[CH2:11](O)[CH:12]([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[CH2:11]([O:10][C:6]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH:9]=[CH:8][CH:7]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)CO
Reactant: Oc1cccc2sccc12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)COc1cccc2sccc12

Procedure:
Benzo[b]thiophen-4-ol (200, 4.3 g, 28.9 mmol) and iso-butanol (3.2 ml, 34.7 mmol) are dissolved under argon in 150 ml of toluene. After addition of triphenylphosphine (9.1 g, 34.7 mmol) and a 40% solution of DEAD in toluene (16.8 ml, 34.7 mmol), the mixture is stirred at 120° C. over night. After cooling down, the reaction mixture is subsequently washed with saturated aqueous NaHCO3 solution and NaCl solution, dried over Na2SO4 and evaporated under reduced pressure. Triphenylphosphinoxid is removed by crystallization from ethyl acetate and hexane and the crude product is further purified by flash chromatography (silica gel, hexane/ethyl acetate 9:1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:33]=[C:32]5[C:27]([CH2:28][CH2:29][N:30]([CH3:34])[CH2:31]5)=[CH:26][CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:35][C:36]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:37]=1[C:38](Cl)=[O:39]>C(Cl)Cl>[F:35][C:36]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:37]=1[C:38]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:33]=[C:32]5[C:27]([CH2:28][CH2:29][N:30]([CH3:34])[CH2:31]5)=[CH:26][CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:3]=1)=[O:39]
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: CN1CCc2ccc(Nc3nccc(-c4c(-c5cccc(N)c5)nn5ccccc45)n3)cc2C1
Solvent: ClCCl
Product: CN1CCc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)c6cc(F)ccc6F)c5)nn5ccccc45)n3)cc2C1
Reaction time: 16 h
Yield: 51 %

Procedure:
To a solution of N-{4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-2-methyl-1,2,3,4-tetrahydro-7-isoquinolinamine (96 mg, 0.21 mmol) and TEA (45 μL, 0.32 mmol) in DCM (2 mL) was added 2,5-difluorobenzoyl chloride (28 μL, 0.23 mmol). After 16 h at rt, the reaction mixture was adsorbed onto silica and purified by column chromatography to generate the title compound in 51% yield (63 mg, 0.11 mmol). 1H NMR (400 MHz, d6-DMSO) δ 10.65 (s, 1H), 9.44 (s, 1H), 8.87 (d, J=6.9 Hz, 1H), 8.47 (d, J=9.3 Hz, 1H), 8.26 (d, J=5.7 Hz, 1H), 8.05 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.34-7.55 (m, 8H), 7.13 (t, J=6.9 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.51 (d, J=5.3 Hz, 1H), 3.41 (s, 2H), 2.76 (t, J=5.7 Hz, 2H), 2.58-2.60 (m, 2H), 2.33 (s, 3H). HRMS=588.23178 (calculated for C34H27F2N7O=587.6313).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)[OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: Cc1cccc(C=O)c1OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2cccc(C)c2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
In a nitrogen stream, to a solution of 2-benzyloxy-3-methyl-benzaldehyde (1.87 g, 8.25 mmol) in THF (50 mL), a solution of 4-methoxyphenylmagnesium bromide in THF (0.5 M, 19.8 mL) was added dropwise under cooling with ice. The mixture was stirred at room temperature for one hour, and then a saturated ammonium chloride aqueous solution was added thereto under cooling with ice and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate: n-hexane (1:5)] to obtain the title compound (2.76 g, 100%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=O)[NH:9][C:8]=1[C:19]([O:21][CH3:22])=[O:20].P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:10]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[C:8]([C:19]([O:21][CH3:22])=[O:20])[N:9]=1
Reactant: COCCCCc1c(C(=O)OC)[nH]c(=O)n1-c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: COCCCCc1c(C(=O)OC)nc(Cl)n1-c1ccccc1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
Methyl 5-(4-methoxybutyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate (1.50 g) was dissolved in phosphorus oxychloride (18 ml) and the mixture was stirred at 100° C. for 10 hr. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (454 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][C@H:10]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[CH2:9][NH:8][C:7]1=[O:21])=[O:5])[CH3:2].F[B-](F)(F)F.[CH3:27][O+](C)C.C(=O)([O-])[O-].[K+].[K+].O>C(Cl)(Cl)Cl>[CH3:27][O:21][C:7]1[CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][C@H:10]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[CH2:9][N:8]=1
Reactant: CCOC(=O)C1C[C@H](CCc2ccc(Br)cc2)CNC1=O
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C1C[C@H](CCc2ccc(Br)cc2)CN=C1OC
Temperature: 25 °C
Yield: 53.4 %

Procedure:
A solution of 515 mg of the product of Example 4 and 236 mg of trimethyloxonium tetrafluoroborate in 3 ml of chloroform was heated under reflux for four hours. The mixture was then cooled to ambient temperature, and 2 ml of 50% aqueous potassium carbonate was added. Then 10 ml of water and 10 ml of chloroform were added, and the organic phase, containing solids, was dried with magnesium sulfate. The solids were removed by filtration, and the supernatant was concentrated under vacuum. The residue was purified by spinning plate thin layer chromatography on a 2 mm silica gel plate, with 1:1 ethyl acetate:hexane, to obtain 286 mg of (3RS,5S)-2-methoxy-3-ethoxycarbonyl-5-[2-(4-bromophenyl)ethyl]-3,4,5,6-tetrahydropyridine, as a 1:1 mixture of the 3-position diastereomers.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11](O)(=[O:15])[C:12](O)=[O:13]>Cl.O>[CH3:8][C:7]1[CH:6]=[C:5]2[C:4](=[CH:3][C:2]=1[CH3:1])[NH:10][C:12](=[O:13])[C:11](=[O:15])[NH:9]2
Reactant: O=C(O)C(=O)O
Reactant: Cc1cc(N)c(N)cc1C
Agent: Cl
Solvent: O
Product: Cc1cc2[nH]c(=O)c(=O)[nH]c2cc1C
Temperature: 25 °C
Yield: 938.5 %

Procedure:
A mixture of 2.72 g (2.0 mmol) of 4,5-dimethyl-1,2-phenylenediamine and 1.92 g (21.3 mmol) of oxalic acid in 30 mL of 2N HCl was refluxed for 2.5 h and cooled to room temperature. The mixture was diluted with 20 mL of H2O, filtered, washed with water, and dried to leave a pale-brown solid 3.57 g (94%); mp>250° C.; 1H NMR (DMSO-d6,2.161 (s,6), 6.869 (s,2), 11.78 (s,2).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])=[CH:7][C:6]=1[NH2:21])=O.C(O)(=O)C.[CH:26](N)=[NH:27]>COCCO.[OH-].[Na+]>[F:18][C:17]([F:20])([F:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[CH:7]=[C:6]2[C:5]([C:3](=[O:2])[NH:27][CH:26]=[N:21]2)=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)cc1N
Reactant: N=CN
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2cc(-c3ccccc3C(F)(F)F)ccc12

Procedure:
Heat a solution of 3-amino-2′-trifluoromethyl-biphenyl-4-carboxylic-acid methyl ester (5.0 g, 0.0169 mol) and formamidine acetate (2.8 g, 0.0203 mol) in 2-methoxyethanol at reflux for 8 hours. Cool the mixture and concentrate under reduced pressure to give a dark oil. Dissolve the residue in 10% NaOH and wash the aqueous with ether (3×). Bring the aqueous layer to pH 4 using 12N HCl to produce a milky solution. Extract the solution with EtOAc, wash the EtOAc with brine, dry (Na2SO4) and concentrate under reduced pressure to give 7-(2-Trifluoromethyl-phenyl)-3H-quinazolin-4-one as a beige solid.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[F-:12].[K+]>[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C>[Br:1][C:2]1[C:3]([F:12])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Reactant: [F-]
Agent: [Br-]
Agent: [K+]
Agent: c1ccc([P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=[N+]([O-])c1cnc(F)c(Br)c1
Yield: 56.8 %

Procedure:
3-Bromo-2-chloro-5-nitropyridine (119 g, 0.500 mol, prepared according to V. Koch and S. Schnatterer, Synthesis, 1990, 497-498), potassium fluoride (79.5 g, 1.37 mol), and tetraphenylphosphonium bromide (109 g, 0.260 mol) were combined in acetonitrile (1.5 L) and heated at reflux for 4 days until GLC indicated complete consumption of the 3-bromo-2-chloro-5-nitropyridine. The volume of the mixture was reduced to 750 mL in vacuo, then the residual liquid was diluted with 2 L of ether. The mixture was filtered and the filtrate concentrated. The residue was triturated with hot hexane, and the combined hexane extracts were concentrated to give 62.8 g (54%) of the title compound: 1H NMR (DMSO-d6 300 MHz) δ 9.14 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](O)=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:14][CH2:13][CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][CH:7]=1)=[O:24]
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Reactant: O=C(O)c1cccc(Cc2cccc(F)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2[nH]cc(CCNC(=O)c3cccc(Cc4cccc(F)c4)c3)c2c1
Yield: 51.3 %

Procedure:
3-(3-Fluorobenzyl)-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)benzamide was prepared according to method A with 2-(5-methoxy-1H-indol-3-yl)ethanamine (0.060 g; 0.315 mmol), 3-(3-fluorobenzyl)benzoic acid (0.073 g; 0.316 mmol), HATU (0.120 g; 0.316 mmol) and N,N-diisopropylethylamine (0.135 mL; 0.788 mmol) in DMF (5 mL). Flash chromatography on silica gel (eluent 1 to 20% ethyl acetate in dichloromethane) furnished 0.065 g (51%) of the title compound as a white solid.