Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@H:17]([CH3:21])[C:18]([OH:20])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].O.[CH2:28](O)[CH2:29][OH:30]>S(=O)(=O)(O)O>[OH:30][CH2:29][CH2:28][O:19][C:18](=[O:20])[C@@H:17]([CH3:21])[N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: OCCO
Reactant: C[C@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: C[C@H](C(=O)OCCO)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 54 %

Procedure:
A solution of (R)-2-(4-chlorophenyl)-α-methyl-3H-imidazo [4,5-b]pyridine-3-acetic acid (4.22 g, 0.014 mole) and concentrated sulfuric acid (4 drops) in ethylene glycol (50 ml) was refluxed under nitrogen for three hours, and then poured into a saturated sodium bicarbonate solution (200 ml). Water (50 ml) was added and the product was extracted into three portions of ethyl acetate. The combined organic layers were washed twice with water and once with a saturated sodium chloride solution, dried over magnesium sulfate, treated with charcoal, filtered, and evaporated under reduced pressure to give 2.6 g (54% yield) of an oily glass. The glass was dissolved in hot isopropyl ether (with a little isopropyl alcohol added), filtered while hot, and cooled to room temperature with stirring, causing a solid to precipitate. The mixture was cooled in the freezer, and the solid was collected by filtration, rinsed with isopropyl ether and dried under high vacuum at room temperature to give 1.60 g of title compound, mp. 110°-113° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][C@H:4]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[CH:22]=1.C1C(=O)N([Cl:39])C(=O)C1>>[Cl:39][C:8]1[C:7]([O:6][CH2:5][C@@H:4]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:3][CH:2]([CH3:31])[CH3:1])=[CH:22][C:11]2[N:12]([CH3:21])[C:13](=[O:20])[C:14]3[C:19]([C:10]=2[CH:9]=1)=[CH:18][CH:17]=[N:16][CH:15]=3
Reactant: CC(C)C[C@@H](COc1ccc2c3ccncc3c(=O)n(C)c2c1)NC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Cl
Product: CC(C)C[C@@H](COc1cc2c(cc1Cl)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Yield: 61 %

Procedure:
(S)-tert-butyl (4-methyl-1-((6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (0.4 g, 0.714 mmol), prepared as described in Example 19, Part B, was subjected to chlorination using NCS as described in Example 41, to afford (S)-tert-butyl (1-((9-chloro-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.3 g, 0.437 mmol, 61% yield) as a yellow solid. LC/MS (ESI) m/e 460.2 [(M+H)+, calcd for C24H31ClN3O4, 460.2]; LC/MS retention time (Method C) tR=2.17 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[C:12]([Cu])#[N:13].O>CN(C)C=O.Cl.[Fe](Cl)(Cl)Cl>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: N#C[Cu]
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)CCC2=O

Procedure:
9.5 g of 5-bromoindan-1-one and 4.93 g of CuCN are suspended in 10 ml of dimethylformamide and the mixture is refluxed for 4 hours. A solution of 18 g of iron(III) chloride in 5 ml of conc. hydrochloric acid with 30 ml of water is added dropwise with stirring to the cooled, dark-brown, viscous suspension and the mixture is then stirred at 70° C. for 30 minutes. The reaction mixture is extracted three times by shaking with 50 ml of toluene, and the combined organic phases are extracted by shaking with 50 ml of 2N hydrochloric acid and 50 ml of 2N sodium hydroxide solution and then washed with water until neutral. The toluene extract is dried over magnesium sulfate and concentrated in vacuo, and the residue is recrystallized from n-heptane. 1-Oxoindan-5-carbonitrile of melting point 123-125° C. is obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[CH2:11]([O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)[CH3:12]>>[CH2:11]([O:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:7]([C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[NH:8])=[CH:16][CH:15]=1)[CH3:12]
Reactant: CSc1ccc(C#N)cc1
Reactant: CCOc1ccc(N)cc1
Product: CCOc1ccc(NC(=N)c2ccc(SC)cc2)cc1
Yield: 61 %

Procedure:
The title compound was prepared from 4-methylthiobenzonitrile (10.87 g, 73 mmol) and 4-ethoxyaniline (10 g, 73 mmol) by following the procedure described in preparation 10 (12.7 g, yield 61%, purity 96.27% by HPLC). 1H-NMR (CDCl3):δ 1.39-1.43 (t, 3H), 2.51 (s, 3H), 3.99-4.04 (q, 2H), 4.75 (bs, 2H, D2O exchangeable), 6.90 (s, 4H), 7.26-7.29 (m, 2H), 7.77-7.79 (d, 2H). MS m/z:287.2 (M+).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2].[AlH4-].[Li+]>O1CCCC1>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][NH2:24])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(C#N)ccc2-3)n(C(C)C)n1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(CN)ccc2-3)n(C(C)C)n1
Reaction time: 2 h
Yield: 47.2 %

Procedure:
To a solution of 2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbonitrile (0.500 g, 0.00142 mol) in Tetrahydrofuran (14 mL) was added Lithium tetrahydroaluminate (0.00569 mol, 1M in THF, 5.7 mL), dropwise at 0° C. The reaction was stirred for 2 hours and quenched with saturated Na2SO4 until H2 evolution ceased. MgSO4 was added and the whole was diluted with copious amounts of methylene chloride, filtered over celite, and concentrated in vacuo. The crude was purified by flash chromatography (1-15% MeOH in DCM spiked with Et3N) to afford 532 as a yellow solid (238 mg). MS (ESI+) 356.1
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([C:18]([O:20]CC)=O)=[CH:8][C:9]=1[NH:10]2.[CH2:23]([Mg]Cl)[CH3:24]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O>[Br:1][C:2]1[C:3]2[C:4]3[C:9](=[CH:8][C:7]([C:18]4([OH:20])[CH2:24][CH2:23]4)=[CH:6][CH:5]=3)[NH:10][C:11]=2[C:12]([C:15]([NH2:16])=[O:17])=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Reactant: CC[Mg]Cl
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Product: NC(=O)c1ccc(Br)c2c1[nH]c1cc(C3(O)CC3)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
Step 1 A solution of ethyl 5-bromo-8-carbamoyl-9H-carbazole-2-carboxylate (Intermediate 48-1, 0.275 g, 0.761 mmol) was treated with titanium (IV) isopropoxide (0.31 mL, 1.07 mmol), followed by ethylmagnesium chloride (2 M in THF, 3.81 mL, 7.61 mmol). The mixture was stirred at rt for 1 h, then was cooled on ice and treated with water (10 mL). After 30 min, the solid was removed by filtration and rinsed with ether (150 mL). The organic layer was dried and concentrated to give 4-bromo-7-(1-hydroxycyclopropyl)-9H-carbazole-1-carboxamide as a yellow solid (0.220 g, 79%). 1H NMR (400 MHz, DMSO-d6) δ 11.65 (1 H, s), 8.52 (1 H, d, J=8.4 Hz), 8.25 (1 H, br. s.), 7.84-7.89 (2 H, m), 7.61 (1 H, br. s.), 7.45 (1 H, d, J=8.1 Hz), 7.13 (1 H, dd, J=8.5, 1.7 Hz), 6.11 (1 H, s), 1.21-1.27 (2 H, m), 1.06-1.11 (2 H, m).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][CH2:14][OH:15])[CH2:9]1.C(N(CC)CC)C.[Mn]([O-])(=O)(=O)=O.FC1C=CC=CN=1>CO>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][CH2:14][OH:15])[CH2:9]1
Reactant: Fc1ccccn1
Reactant: OCC[C@@H]1CCNC1
Agent: O=[Mn](=O)(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CO
Product: OCC[C@@H]1CCN(c2ccccn2)C1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
(S)-2-(Pyrrolidin-3-yl)ethanol 2-fluoropyridine (6.95 mmol, 0.598 ml, 0.674 g) and triethylamine (17.36 mmol, 2.420 ml, 1.757 g) were dissolved in MeOH (2.5 ml) and heated to 150° C. for 1 hour in the microwave. TLC (permanganate stain) suggested SM remained. Further 2-fluoropyridine (6.95 mmol, 0.598 ml, 0.674 g) was added and heating continued for 1 hour. The reaction mixture was concentrated in vacuo. The resulting residue was purified by silica chromatography, eluting with DCM—3% MeOH/DCM to afford (S)-2-(1-(pyridin-2-yl)pyrrolidin-3-yl)ethanol. 1H NMR (CDCl3) δ: 8.14 (d, 1H), 7.44 (m, 1H), 6.51 (m, 1H), 6.33 (d, 1H), 3.71 (m, 3H), 3.55 (m, 1H), 3.38 (m, 1H), 3.05 (m, 1H), 2.42 (m, 1H), 2.17 (m, 1H), 1.78 (m, 2H), 1.66 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:23][NH2:24]>>[CH3:23][NH:24][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN(C)c1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: CN
Product: CNc1nc(N(C)c2ccc(N(C)C)cc2)c2ccccc2n1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-dimethylaminophenyl)-methylamine and methyl amine by a procedure similar to example 46. 1H NMR (CDCl3): 7.42-7.42 (m, 1H), 7.34 (ddd, J=8.1, 6.9, 4.0, 1H), 7.04 (m, 2H), 6.94 (m, 1H), 6.63-6.71 (m, 3H), 5.13 (s, broad, 1H), 3.49 (s, 3H), 3.10 (d, J=4.8, 3H), 2.97 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.[H-].[Na+].Cl[CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:18][C:19]=1[CH3:20].O>CN(C)C=O>[CH3:20][C:19]1[S:18][C:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:16][C:15]=1[CH2:14][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1
Reactant: COC(=O)c1cc(O)no1
Reactant: Cc1sc(-c2ccccc2)nc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2nc(-c3ccccc3)sc2C)no1
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
To a solution of methyl 3-hydroxyisoxazole-5-carboxylate (3.51 g) in N,N-dimethylformamide (100 mL) was added sodium hydride (60%, oil, 1.07 g) at 0° C. After stirring for 30 min., 4-chloromethyl-5-methyl-2-phenylthiazole (5.00 g) was added. After stirring at 60° C. for 2 hrs, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to give methyl 3-(5-methyl-2-phenyl-4-thiazolylmethoxy)-5-isoxazolecarboxylate (5.42 g, 74%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 89-90° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][CH2:14][OH:15])([O-:3])=[O:2].[F:16][C:17]([F:46])([C:42]([F:45])([F:44])[F:43])[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:41]=[CH:40][C:25]([C:26]([O:28][C:29]2[CH:34]=[CH:33][C:32](/[CH:35]=[CH:36]/[C:37](O)=[O:38])=[CH:31][CH:30]=2)=[O:27])=[CH:24][CH:23]=1.Cl.CN(C)CCCN=C=NCC.CCCCCC>CN(C)C1C=CN=CC=1.ClCCl>[F:16][C:17]([F:46])([C:42]([F:43])([F:44])[F:45])[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:41]=[CH:40][C:25]([C:26]([O:28][C:29]2[CH:34]=[CH:33][C:32](/[CH:35]=[CH:36]/[C:37]([O:15][CH2:14][CH2:13][C:5]3[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])=[O:38])=[CH:31][CH:30]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(O)/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)C(F)(F)F)cc2)cc1
Reactant: O=[N+]([O-])c1ccc(CCO)c([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)C(F)(F)F)cc2)cc1)OCCc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
2.50 g (11.8 mmol) of 2-(2,4-dinitrophenyl)ethanol, 5.24 g (11.8 mmol) of (2E)-3-(4-{[4-(4,4,5,5,5-pentafluoropentoxy)benzoyl]oxy}phenyl)acrylic acid, 144 mg (1.2 mmol) of 4-Dimethylaminopyridine are dissolved in 30 ml of dichloromethane. 2.48 g (13.0 mmol) of N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC hydrochloride) are added at 0° C. The solution is stirred for 1 h at 0° C. and allowed to stir at room temperature overnight. After 22 hours at room temperature the reaction mixture is partitioned between dichloromethane and water. The organic phase is washed repeatedly with water, dried over sodium sulphate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 200 g silica gel using toluene:ethyl acetate 95:5 as eluant and crystallization form ethylacetate:hexane mixture to yield 5.35 g (71%) 2-(2,4-Dinitrophenyl)ethyl (2E)3-{4-[(4-(4,4,5,5,5-pentafluoropentoxy)benzoyl)oxy]phenyl}acrylate as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH2:16][CH3:17])=[CH:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][C:5]=1/[C:18](/[CH3:31])=[C:19](/[F:30])\[CH:20]=[CH:21]\[C:22](\[CH3:29])=[CH:23]\[C:24]([O:26]CC)=[O:25])[CH3:2].[OH-].[Na+]>C(O)C.C1COCC1>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH2:16][CH3:17])=[CH:9][C:10]([CH3:14])([CH3:15])[O:11]2)=[CH:6][C:5]=1/[C:18](/[CH3:31])=[C:19](/[F:30])\[CH:20]=[CH:21]\[C:22](\[CH3:29])=[CH:23]\[C:24]([OH:26])=[O:25])[CH3:2]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(cc1OCC)OC(C)(C)C=C2CC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=C\C(=O)O)C(CC)=CC(C)(C)O2

Procedure:
Following General Procedure G, a solution of ethyl 7-(7-ethoxy-4-ethyl-2,2-dimethyl-2H-chromen-6-yl)-6-fluoro-3-methyl-octa-2E,4E,6E-trienoate (Compound 110, 9.0 mg, 0.02 mmol) in ethanol and THF was hydrolyzed with 1M NaOH. Purification by flash chromatography (silica gel, 75:25 hexane/ethyl acetate) afforded the title compound as a white solid.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[Br:7][C:8]1[CH:14]=[C:13]([F:15])[C:11]([NH2:12])=[C:10]([F:16])[CH:9]=1.C(N(CC)CC)C>C1COCC1>[Br:7][C:8]1[CH:14]=[C:13]([F:15])[C:11]([NH:12][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[C:10]([F:16])[CH:9]=1
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1c(F)cc(Br)cc1F)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cyclopropanecarbonyl chloride (1.05 ml) was added to a solution of 4-bromo-2,6-difluoroaniline (1.00 g) and triethylamine (1.61 ml) in THF (10 ml) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with brine and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, passed through NH silica gel pad and concentrated in vacuo. The solid was washed with IPE/hexane to give the title compound (1.08 g) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:14]3[C:13]([NH:15][C@H:16]([C:18]4[N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:22](=[O:30])[C:21]5=[C:31]([CH3:34])[CH:32]=[CH:33][N:20]5[N:19]=4)[CH3:17])=[N:12][CH:11]=[N:10][C:9]=3[N:8]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:7]=2)[CH:3]=[N:2]1.Cl[CH2:44][CH2:45][N:46]([CH3:48])[CH3:47].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:47][N:46]([CH3:48])[CH2:45][CH2:44][N:1]1[CH:5]=[C:4]([C:6]2[C:14]3[C:13]([NH:15][C@H:16]([C:18]4[N:23]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:22](=[O:30])[C:21]5=[C:31]([CH3:34])[CH:32]=[CH:33][N:20]5[N:19]=4)[CH3:17])=[N:12][CH:11]=[N:10][C:9]=3[N:8]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[CH:7]=2)[CH:3]=[N:2]1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cn[nH]c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cnn(CCN(C)C)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 75 °C
Reaction time: 3.5 h
Yield: 57 %

Procedure:
(S)-2-(1-((5-(1H-Pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (43 mg, 0.07 mmol) and 2-chloro-N,N-dimethylethanamine chlorhydrate (43 mg, 0.30 mmol) were dissolved in DMF (3 ml) and cesium carbonate (240 mg, 0.74 mmol) was added. After stirring the mixture at 75° C. for 3.5 h, the solvent was evaporated under reduced pressure and the residue was suspended in water and extracted with dichloromethane (×3). The organic phase was successively washed with water and brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. The residue was purified using SP1® Purification System (0% to 3%, dichloromethane-methanol) to obtain 31 mg (57% yield) of the title compound as a brown solid. Purity 90%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[N:12]1([CH2:18][CH2:19][O:20][C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]2[N:9]=[C:25]([C:24]3[CH:23]=[CH:22][C:21]([O:20][CH2:19][CH2:18][N:12]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]4)=[CH:28][CH:27]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(OCCN2CCCCC2)cc1
Reactant: COc1c(Cl)cnc(N)c1N
Product: COc1c(Cl)cnc2[nH]c(-c3ccc(OCCN4CCCCC4)cc3)nc12

Procedure:
By a procedure similar to Example 269 but using 5-chloro-4-methoxypyridin-2,3-diamine and 4-(2-piperidin-1-ylethoxy)benzaldehyde, the title compound was obtained as the bis(trifluoroacetate).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10]O)[N:9]=1)[CH3:3].S(Cl)(Cl)=O.C[N:17]([CH2:19][C:20]1[S:21]C=C(CCl)N=1)C.Cl.NCCS>>[CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:21][CH2:20][CH2:19][NH2:17])[N:9]=1)[CH3:3]
Reactant: CN(C)Cc1nc(CO)cs1
Reactant: CN(C)Cc1nc(CCl)cs1
Agent: Cl
Agent: NCCS
Solvent: O=S(Cl)Cl
Product: CN(C)Cc1nc(CSCCN)cs1

Procedure:
When 2-dimethylaminomethyl-4-hydroxymethylthiazole [prepared in Step D] is reacted with thionyl chloride and the resultant 2-dimethylaminomethyl-4-chloromethylthiazole is reacted with an equimolar amount of cysteamine hydrochloride and two equivalents of base according to the general procedure of Example 33, Step D, the title compound is thereby produced.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][NH2:23])[CH:18]=[CH:19][CH:20]=1.[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:23][CH2:22][CH2:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:13])([F:24])[F:25])[CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: NCCc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.4 %

Procedure:
A solution of 4-tert-butylbenzaldehyde (0.38 mL, 2.25 mmol) and 2-(3-trifluoromethyl-phenyl)-ethylamine (0.24 mL, 1.50 mmol) in methanol (4.5 mL) was stirred for 30 min at RT and subsequently refluxed for 4 h. After cooling, sodium borohydride (85 mg, 2.25 mmol) was added at RT, then after stirring for 5 min the reaction mixture was refluxed for 4 h. After cooling down to RT, the reaction mixture was treated with 1 M aq. hydrochloric acid solution (4 drops) and concentrated. The residue was dissolved in water/ethyl acetate. After separation of the organic phase, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with brine, dried with magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO2; ethyl acetate/heptane 1:2) to afford the title compound (450 mg, 89%). Colorless viscous oil, MS (ISP) 336.3 (M+H)+.
Reaction SMILES: [O:1]([CH2:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[NH2:15][C:16]1[CH:28]=[C:27]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(N(CC)CC)C>[O:29]([C:27]1[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])=[C:16]([NH:15][C:9](=[O:10])[CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:28]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Reactant: O=C(Cl)COc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)COc1ccccc1
Reaction time: 2 h

Procedure:
0.029 mL of 2-phenoxyacetyl chloride was added to 2.5 mL of methylene chloride solution containing 40 mg of tert-butyl 2-amino-4-phenoxybenzoate and 0.039 mL of triethylamine at room temperature and stirred at the same temperature for 2 hours. 0.25 g of aminomethylated polystyrene was added to the reaction mixture and after stirred at the same temperature overnight, 5 mL of 10% citric acid aqueous solution was added. The organic layer was separated and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate: acetic acid=20:5:1] to obtain tert-butyl 4-phenoxy-2-(2-phenoxyacetamido)benzoate.
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([C:24]([O:26]C)=O)=[CH:23][C:17]=4[N:16]=3)[CH2:11][CH2:10]2)=[O:8])=[CH:3][CH:2]=1.[CH3:34][NH2:35]>CCO>[C:1]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([C:24]([NH:35][CH3:34])=[O:26])=[CH:23][C:17]=4[N:16]=3)[CH2:11][CH2:10]2)=[O:8])=[CH:3][CH:2]=1
Reactant: CN
Reactant: COC(=O)c1ccc2[nH]c(C3CCN(C(=O)c4ccc(-c5ccccc5)cc4)CC3)nc2c1
Solvent: CCO
Product: CNC(=O)c1ccc2[nH]c(C3CCN(C(=O)c4ccc(-c5ccccc5)cc4)CC3)nc2c1

Procedure:
A solution of methyl 2-[1-(biphenyl-4-ylcarbonyl)piperidin-4-yl]-1H-benzimidazole-5-carboxylate (30 mg, 0.068 mmol) in 2M methylamine in EtOH (1 mL) is heated in at 50° C. for 18 h. The reaction is concentrated under reduced pressure and purified by preparative HPLC to give 13 mg of 2-[1-(biphenyl-4-ylcarbonyl)piperidin-4-yl]-N-methyl-1H-benzimidazole-5-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)CC[CH2:14]1)=[O:12].[CH3:28][O:29]C1C=CC=CC=1NC>CCCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:6]([C:11]([N:13]([C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:29][CH3:28])[CH3:14])=[O:12])=[CH:7][N:8]=[CH:9][CH:10]=1
Reactant: CNc1ccccc1OC
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1ccccc1N(C)C(=O)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and 2-methoxy-N-methylaniline (commercially available; CAS RN 10541-78-3) and using a gradient of n-heptane:ethyl acetate (100:0 to 40:60). The compound was further purified through a second preparative HPLC chromatography (Phenomenex Gemini column) using a gradient of acetonitrile:water (containing 0.05% formic acid) (50:50 to 95:5). White solid (57%). MS (ESI): m/z=403.062 [M+H]+.