Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)(=O)C.[ClH:7].[O:8]=[C:9]([C:30]1[CH:31]=[C:32]2[C:37]3=[C:38]([CH2:40][CH2:41][N:36]3[C:35](=[O:42])[CH2:34][CH2:33]2)[CH:39]=1)[CH2:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)C(=O)OC(C)(C)C>C(O)C>[ClH:7].[C:24]1([CH2:23][CH2:22][NH:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:30]2[CH:31]=[C:32]3[C:37]4=[C:38]([CH2:40][CH2:41][N:36]4[C:35](=[O:42])[CH2:34][CH2:33]3)[CH:39]=2)=[O:8])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N(CCCCC(=O)c1cc2c3c(c1)CCN3C(=O)CC2)CCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(CCCCNCCc1ccccc1)c1cc2c3c(c1)CCN3C(=O)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 4N hydrogen chloride-ethyl acetate solution was added to a solution of tert-butyl 5-oxo-5-(4-oxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)pentyl(2-phenylethyl)carbamate (3.00 g) obtained in Reference Example 19 in ethanol (5 ml), and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the resulting residue was crystallized from ethanol-ethyl acetate to give the title compound as colorless crystals (1.98 g) having a melting point of 166 to 168° C.
Reaction SMILES: [CH2:1]([CH:8]1[S:13][CH2:12][CH2:11][CH2:10][S:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][Si:15](Cl)([CH3:17])[CH3:16]>>[CH2:1]([C:8]1([Si:15]([CH3:17])([CH3:16])[CH3:14])[S:9][CH2:10][CH2:11][CH2:12][S:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CC2SCCCS2)cc1
Reactant: C[Si](C)(C)Cl
Product: C[Si](C)(C)C1(Cc2ccccc2)SCCCS1
Yield: 75 %

Procedure:
The title compound of this step was prepared in 75% yield, by the procedure described in JACS 89, (1967), 4347 by E. J. Corey, et al., using 2-benzyl-1,3-dithiane and trimethylsilyl chloride. The product was recrystallized from diethyl ether/pentane.
Reaction SMILES: CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.[CH:19]1([N:23]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([N:32]3[CH2:35][CH:34]([OH:36])[CH2:33]3)=[O:31])[CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20]1.Br[C:38]1[CH:39]=[CH:40][C:41]([C:44]([F:47])([F:46])[F:45])=[N:42][CH:43]=1>>[CH:19]1([N:23]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([N:32]3[CH2:33][CH:34]([O:36][C:38]4[CH:43]=[N:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=4)[CH2:35]3)=[O:31])[CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20]1
Reactant: O=C(N1CCCN(C2CCC2)CC1)N1CC(O)C1
Reactant: FC(F)(F)c1ccc(Br)cn1
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Product: O=C(N1CCCN(C2CCC2)CC1)N1CC(Oc2ccc(C(F)(F)F)nc2)C1

Procedure:
In a similar fashion (Route 21, GP J) except for replacing phenantroline with 3,4,7,8-tetramethylphenantroline, 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-ol (50 mg, 0.20 mmol) and 5-bromo-2-trifluoromethylpyridine (59 mg, 0.26 mmol) gave the title compound as a brown oil after purification by preparative HPLC (15 mg, 14%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:15][CH:16]([CH3:32])[CH2:17][NH:18][CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]1.P(C#N)(=O)(OCC)OCC.O>ClCCCl>[NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([N:18]([CH2:17][CH:16]([CH3:32])[CH3:15])[CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:20]1)=[O:6]
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: CC(C)CNC1CCCN(C(=O)OC(C)(C)C)C1
Agent: CCOP(=O)(C#N)OCC
Solvent: ClCCCl
Solvent: O
Product: CC(C)CN(C(=O)c1ccc(C(F)(F)F)cc1N)C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
2-amino-4-(trifluoromethyl)benzoic acid (0.32 g) and tert-butyl 3-[(2-methylpropyl)amino]piperidine-1-carboxylate (0.4 g) were dissolved in 1,2-dichloroethane (20 ml), diethyl phosphorocyanidate (0.31 g) was added and the mixture was stirred at 70° C. overnight. The reaction mixture was poured into water, 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, and the residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (0:10-1:1) was concentrated under reduced pressure to give the object compound (0.33 g).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:11][C:12]1[CH:16]=[CH:15][S:14][CH:13]=1.O>CN(C=O)C>[O:7]([CH2:11][C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCc1ccsc1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(OCc2ccsc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
A solution of phenol (13.16 g) in DMF (10 ml) was added in portions over 10 minutes to a stirred suspension of sodium hydride (3.12 g) in DMF (100 ml). After 2 hours, a solution of 3-(chloromethyl)thiophene (14.50 g) in DMF (30 ml) was added in one portion and the resulting mixture was stirred at room temperature for 3 hours then poured into water and extracted with ether. The extracts were washed successively with water, dilute aqueous sodium hydroxide, and aqueous sodium chloride, then dried and concentrated to give 3-(phenoxymethyl)thiophene (18.86 g, 91% yield) as a white solid. An analytical sample, recrystallised from methanol, had mp 49°-50° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[NH:10][CH:9]=[N:8][C:7]=1[CH3:11].[CH2:12]([C:19]1[C:20](=[O:28])[NH:21][C:22](SC)=[N:23][C:24]=1[CH3:25])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:11][C:7]1[N:8]=[CH:9][NH:10][C:6]=1[CH2:5][S:4][CH2:3][CH2:2][NH:1][C:22]1[NH:21][C:20](=[O:28])[C:19]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:24]([CH3:25])[N:23]=1
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CSc1nc(C)c(Cc2ccccc2)c(=O)[nH]1
Product: Cc1nc[nH]c1CSCCNc1nc(C)c(Cc2ccccc2)c(=O)[nH]1
Yield: 65.9 %

Procedure:
An intimate mixture of 5-(2-aminoethyl)thiomethyl-4-methylimidazole (1.28 gms) and 5-benzyl-6-methyl-2-methylthio-4-pyrimidone (1.84 gms) was heated at 150°-160° C. (oil-bath temperature) for 41/2 hours. The mixture was cooled, washed with water and recrystallised from isopropanol to give 2-[-2-(4-methyl-5-imidazolylmethylthio)ethylamino]-5-benzyl-6-methyl-4-pyrimidone (1.82 gms) m.p.= 140°-141.5° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:9][C:4]=2[CH2:3]1.[NH:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH:22]=O>N1CCCCC1.CC(O)C>[O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:9][C:4]=2/[C:3]/1=[CH:22]/[C:18]1[NH:17][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)c1cc2c(s1)NC(=O)C2
Reactant: O=Cc1ccc[nH]1
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)c1cc2c(s1)NC(=O)/C2=C\c1ccc[nH]1
Temperature: 75 °C
Yield: 15.8 %

Procedure:
tert-Butyl 5,6-dihydro-5-oxo-4H-thieno[2,3-b]pyrrole-2-carboxylate (32 mg, 0.2 mmol) was dissolved in a solution of 1% piperidine in 2-propanol (1 ml). Pyrrole-2-carboxaldehyde (0.39 mmol, 37 mg) was added in one portion and the mixture heated at 75° C. for 1 hour. The reaction mixture was poured into an ice/water mixture (6 ml) and the precipitated solid was collected by filtration and washed with water to give 10 mg of tert-butyl (Z)-5,6-dihydro-5-oxo-4-[(1H-pyrrol-2-yl)methylene]-4H-thieno[2,3-b]pyrrole-2-carboxylate as a yellow solid. MS(ES): m/e 317 [M+H].
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:34][O:35]CC1C=CC=CC=1)[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH:25]C(=O)C1C=CC=CC=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO>ClCCl>[OH:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:34][OH:35])[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH2:25]
Reactant: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@@]2(COCc3ccccc3)CO[C@@H]1[C@@H]2OCc1ccccc1)c1ccccc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@@]2(CO)CO[C@@H]1[C@@H]2O
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a stirred solution of nucleoside 61 (0.80 g, 1.42 mmol) in anhydrous dichloromethane (30 cm3) at −78° C. was dropwise during 30 min added BCl3 (1 M solution in hexane; 11.36 cm3, 11.36 mmol). The mixture was stirred for 4 h at −78° C., additional BCl3 (1M solution in hexane, 16.0 cm3, 16.0 mmol) was added drop-wise, and the mixture was stirred at −78° C. for 3 h. Then the temperature of the reaction mixture was raised slowly to room temperature and stirring was continued for 30 min. Methanol (25.0 cm3) was added at −78° C., and the mixture was stirred at room temperature for 12 h. The mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using dichloromethane/methanol (92:8, v/v) as eluent to give nucleoside 61A as a white solid material (0.332 g, 84%). δH ((CD3)2SO) 8.22 (1H, s, 8-H), 8.15 (1H, s, 2-H), 7.33 (2H, s, NH2), 5.89 (1H, s, 1′-H), 5.83 (1H, d, J 4.2, 3′-OH), 5.14 (1H, t, J 5.9, 5′-OH), 4.14 (1H, s, 2′-H), 4.25 (1H, d, J 4.2, 3′-H), 3.92 (1H, d, J 7.8, 1″-Ha), 3.81-3.41 (3H, m, 5′-Ha, 1″-Hb). Oc ((CD3)2SO) 155.90 (C-6), 152.64 (C-2), 148.35 (C-4), 137.72 (C-8), 118.94 (C-5), 88.48, 85.17 (C-1′, C-4′), 79.09, 71.34, 69.83, 56.51 (C-2′, C-3′, C-1″, C-5′). FAB-MS m/z 280 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=[CH:3][C:2]=1[OH:11].[H-].[Na+].[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[CH:17]=[O:18].Cl>CN(C)C=O>[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:11][C:2]2[CH:3]=[N:4][C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=3[N:1]=2)[C:16]=1[CH:17]=[O:18]
Reactant: O=Cc1c(F)cccc1Cl
Reactant: Oc1cnc2c(n1)CCCC2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1c(Cl)cccc1Oc1cnc2c(n1)CCCC2
Temperature: 100 °C
Reaction time: 3 h
Yield: 45.1 %

Procedure:
0.3 g of 5,6,7,8-tetrahydroquinoxalin-2-ol were dissolved in 5 ml of dimethylformamide. 0.1 g of sodium hydride were added thereto. 0.35 g of 2-chloro-6-fluoro-benzaldehyde were added to the reaction solution followed by stirring for 3 hours at 100° C. 1 N hydrochloric acid was then added to the reaction solution. Subsequently, the reaction solution was extracted with ethyl acetate and the organic layer was concentrated followed by purifying by silica gel column chromatography to obtain 0.26 g of 2-chloro-6-(5,6,7,8-tetrahydro-quinoxalin-2-yloxy)-benzaldehyde.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=2[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.CN(C1C=CC=CN=1)C.Cl>C(Cl)Cl.C(Cl)CCl>[C:1]1([S:7]([NH:10][C:11]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=2[C:13]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=2)=[O:15])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: COC(=O)c1ccc(N)cc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.8 %

Procedure:
To a suspension of 2-phenylsulfonylamino-5-chlorobenzoic acid (250 mg; prepared in Reference Example 3.) and methyl p-aminobenzoate (133 mg) in methylene chloride (5 ml), EDC (168 mg) and dimethylaminopyridine (20 mg) were added. The mixture was stirred for 3 days at room temperature. The reaction mixture was poured into diluted HCl and extracted with ethyl acetate. The organic layer was washed, dried over and concentrated under reduced pressure. The residue was purified on silica gel column chromatography (AcOEt-benzene) to give the title compound (142 mg) having the following physical data.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.CN([C:30]([O:34][N:35]1N=NC2C=CC=N[C:36]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CONC.Cl>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15](=[O:17])[N:35]([O:34][CH3:30])[CH3:36])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)CC1CCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
A solution of 2-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (Beckett et al, J. Med. Chem., 563, 1969) (2.29 g, 10 mmol) in DMF (20 ml) was treated sequentially with N,N-diisopropylethylamine (4.0 ml), HATU (3.8 g, 10 mmol) and O,N-dimethyl-hydroxylamine.HCl (0.98 g, 10 mmol). The reaction mixture was stirred under argon at room temperature for 16 h. The volatiles were removed in vacuo and the residue was chromatographed (silica gel, diethyl ether) to afford the title compound as a white solid (2.60 g, 90%).
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17](N)=[O:18])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl.C(O)(=[O:23])C>>[N:1]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:18])=[O:23])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: NC(=O)Cc1ccc(-c2cn3ccccc3n2)cc1
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)Cc1ccc(-c2cn3ccccc3n2)cc1

Procedure:
A mixture of 1 g of 4-(imidazo[1,2-a]pyridin-2-yl)phenylacetamide, 5 ml of glacial acetic acid and 5 ml of concentrated hydrochloric acid is heated under reflux for 1 hour. The solvent is distilled off under reduced pressure, and water is added to the residue. The mixture is alkalified with 10% sodium hydroxide, and then filtered. The filtrate is adjusted to pH 6 by addition of 10% hydrochloric acid. The crystalline precipitate is filtered off and washed with water to give 0.8 g of 4-(imidazo[1,2-a]pyridin-2-yl)phenylacetic acid as colorless crystals melting at 220°-222°C with decomposition.
Reaction SMILES: O[C@H:2]([CH2:22][CH3:23])[C@H:3]([NH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:9])[C:4]([OH:6])=[O:5].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:8](=[O:9])[NH:7][C@H:3]2[C:4](=[O:6])[O:5][C@H:2]2[CH2:22][CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC[C@@H](O)[C@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H]1OC(=O)[C@@H]1NC(=O)OCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 64 %

Procedure:
Under nitrogen atmosphere, to a stirred mixture of (2S*,3R*)-3-hydroxy-2-(5-phenylpentoxy-carbonylamino)-pentanoic acid (0.07 g, 0.22 mmol) in dry CH2Cl2 (10 mL), at 0° C., Et3N (0.091 mL, 0.65 mmol) and subsequently TBTU (0.083 g, 0.26 mmol) were added. The mixture was left stirring at 0° C. for 1 h and at rt for 15 h. The organics were then removed under reduced pressure, and the resulting crude product purified by column chromatography, using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (from 90:10 to 70:30) to afford the pure title compound (0.043 g, 65%), as a white solid. MS (ESI) m/z: 323 [M−NH4]+; (ESI) m/z: 304 [M−H]−. 1H NMR (DMSO-d6) δ 0.89 (t, J=7.43 Hz, 3H), 1.27-1.41 (m, 2H), 1.45-1.64 (m, 4H), 1.64-1.95 (m, 2H), 2.58 (t, J=7.66 Hz, 2H), 4.01 (t, J=6.49 Hz, 2H), 4.60 (dt, J=6.08, 8.01 Hz, 1H), 5.45 (dd, J=6.02, 9.42 Hz, 1H), 7.05-7.38 (m, 5H), 8.23 (d, J=9.41 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:11]([O:13][CH3:14])=[O:12])=[C:5]([CH3:7])[N:6]=1.[CH2:19]([O:26][CH2:27]CC1NC(I)=C(C)N=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.IC1NC(C)=NC=1C>>[CH2:19]([O:26][CH2:27][CH2:1][C:2]1[NH:3][C:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:11]([O:13][CH3:14])=[O:12])=[C:5]([CH3:7])[N:6]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(C)c(-c2[nH]c(C)nc2C)c1
Reactant: Cc1nc(CCOCc2ccccc2)[nH]c1I
Agent: Cc1nc(C)c(I)[nH]1
Product: COC(=O)c1ccc(C)c(-c2[nH]c(CCOCc3ccccc3)nc2C)c1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.6, except 2-(2-(benzyloxy)ethyl)-5-iodo-4-methyl-1H-imidazole (compound 227.2) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CN(C=O)C>C1COCC1>[CH2:19]([O:12][C:3]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(F)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 27.5 %

Procedure:
In THF (200 ml) was dissolved 2,3-difluoro-6-nitrophenol (10.0 g, 57.1 mmol), followed by the addition of potassium carbonate (15.8 g, 114.2 mmol) and benzyl bromide (7.47 ml, 62.8 mmol) at room temperature. The reaction mixture was stirred at 60° C. for 6 hours. DMF (100 ml) was added to the reaction mixture and the mixture was stirred at 60° C. for 24 hours. After cooling to room temperature, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was diluted with ether (100 ml), washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 100 g), whereby from the hexane/ethyl acetate (4/1) eluate fractions, the title compound (4.17 g, 28%) was obtained as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][C:9]3[CH:15]=[C:14]([C:16]4[C:20]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=5[F:28])=[N:19][NH:18][N:17]=4)[S:13][C:10]=3[C:11]=2[N:12]=1.[CH3:29][N:30](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:29]([C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][C:9]3[CH:15]=[C:14]([C:16]4[C:20]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=5[F:28])=[N:19][NH:18][N:17]=4)[S:13][C:10]=3[C:11]=2[N:12]=1)#[N:30]
Reactant: CN(C)C=O
Reactant: Fc1ccc(-c2n[nH]nc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(n1)-c1sc(-c3n[nH]nc3-c3ccc(F)cc3F)cc1CCO2
Temperature: 200 °C
Yield: 84 %

Procedure:
To solution containing 4-(2-chloro-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepin-9-yl)-5-(2,4-difluorophenyl)-2H-1,2,3-triazole (0.085 g, 0.20 mmol), zinc cyanide (47.9 mg, 0.408 mmol;), and tetrakis(triphenylphosphine)palladium(0) (11.8 mg, 0.0102 mmol;) in N,N-dimethylformamide (2.83 mL, 36.6 mmol;) was evacuated then back-filled with nitrogen. The reaction mixture was heated in microwave to 200° C. for 10 min. The reaction mixture was quenched with sat. NH4Cl then extracted EtOAc (3×). The crude product was purified by column chromatography (EtOAc/Hex) to give 367 (84% yield). MS: (ESI+)=408.2
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][CH2:5][NH:6][C:7](=[O:12])[C:8]([F:11])([F:10])[F:9].[CH2:17]=O.S(=O)(=O)(O)O>C(O)(=O)C>[Br:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:3]=1[CH2:4][CH2:5][N:6]([C:7](=[O:12])[C:8]([F:10])([F:11])[F:9])[CH2:17]2
Reactant: O=C(NCCc1ccccc1Br)C(F)(F)F
Reactant: C=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(N1CCc2c(Br)cccc2C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of N-(2-bromophenethyl)-2,2,2-trifluoroacetamide (8.88 g, 30 mmol) and paraformaldehyde (13.5 g, 0.45 mol) in 45 mL of glacial acetic acid at room temperature was slowly added 30 mL of sulfuric acid (96.6%). After stirring at room temperature overnight, the reaction mixture was quenched with ice water and extracted with EtOAc, washed with brine and Sat. NaHCO3 and dried over Na2SO4. After concentration, flash chomatography (SiO2, hexane/DCM=1:1) gave of 1-(5-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone as a white solid.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([CH3:32])[CH2:10][C:11]1[CH:31]=[CH:30][C:14]2[O:15][CH:16]([CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[O:17][C:13]=2[CH:12]=1)C)(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[CH2:23]([O:22][C:20](=[O:21])[NH:19][CH2:18][CH:16]1[O:15][C:14]2[CH:30]=[CH:31][C:11]([CH2:10][CH:9]([NH:7][CH3:6])[CH3:32])=[CH:12][C:13]=2[O:17]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(Cc1ccc2c(c1)OC(CNC(=O)OCc1ccccc1)O2)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(C)Cc1ccc2c(c1)OC(CNC(=O)OCc1ccccc1)O2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 0.41 g (0.89 mmol) of 1G in 2 mL of dichloromethane was added 2 mL of trifluoroacetic acid. The resulting solution was allowed to stir at room temperature for 90 minutes and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography using 20% methanol in ethyl acetate to give 0.29 g (0.64 mmol, 69%) of 1H as a colorless thick gum (M+Na, 357).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.ClC(Cl)(Cl)[C:12]([NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH:23]=[N:22][CH:21]=[CH:20]2)=[O:13].C1CCN2C(=NCCC2)CC1>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:12]([NH:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[CH:23]=[N:22][CH:21]=[CH:20]3)=[O:13])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Br)cc1
Reactant: O=C(Nc1cccc2ccncc12)C(Cl)(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: O=C(NCc1ccc(Br)cc1)Nc1cccc2ccncc12

Procedure:
The title compound was prepared using 4-bromobenzylamine, the product from Example 57D, DBU and the procedure described in Example 1B. MS (ESI+) m/z 356 (M+H)+; 1H NMR (DMSO-d6) δ 9.52 (s, 1H), 9.15 (s, 1H), 8.49 (d, 1H), 8.11 (d, 1H), 7.77 (d, 1H), 7.67 (t, 1H), 7.55 (m, 3H), 7.32 (d, 2H), 7.25 (t, 1H), 4.34 (d, 2H); Anal. Calcd for C17H14BrN3O.0.25H2O.0.16 MeOH: C, 56.34; H, 4.17; N, 11.49. Found C, 56.32, H, 4.45, N, 11.70.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:5]([C:21]([OH:23])=O)=[N:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9].[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([NH:47][C:21]([C:5]2[C:4]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=3)=[CH:3][C:2]([CH3:1])=[C:7]([C:8]([N:10]3[CH2:11][CH2:12][CH:13]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[CH2:14][CH2:15]3)=[O:9])[N:6]=2)=[O:23])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)O)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of example 1, 5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (example 47) was reacted with 4-amino-piperidine-1-carboxylic acid tert-butyl ester, Et3N and HATU in DMF to give the title compound as light yellow solid. MS: 644.3 (MH+).