Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[N:10][CH:11]=[N:12][C:7]=2[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:3]1.[C:23]([NH:30][C@H:31]([C:39](O)=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.C(N(CC)CC)C>[C:26]([O:25][C:23]([NH:30][C@@H:31]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:39]([NH:1][CH:2]1[C:8]2[CH:9]=[N:10][CH:11]=[N:12][C:7]=2[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[C:4]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:3]1)=[O:40])=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: NC1N=C(c2ccccc2)c2ccccc2-c2ncncc21
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NC1N=C(c2ccccc2)c2ccccc2-c2ncncc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Crude 5(R,S)-amino-7-phenyl-5H-pyrimido[5,4-d][2]benzazepine (1.37 g), Boc-L-phenylalanine (1.37 g, 5.17 mmole), 1-hydroxybenzotriazole (HBT) (0.70 g, 5.17 mmole), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) (0.99 g, 5.17 mmole) are combined in DMF (30 ml) and stirred at room temperature. The pH of the mixture is adjusted to 9.5 with triethylamine. After about 1/2 hour, the DMF is removed in vacuo and the residue is partitioned between methylene chloride and 10% citric acid solution. The layers are separated and the organic phase is washed with saturated NaHCO3 solution, water and brine, then dried over Na2SO4, filtered, and evaporated to dryness in vacuo. The residue is chromatographed on silica gel and the combined product fractions evaporated to dryness in vacuo to give the title compound as a mixture of diastereomers.
Reaction SMILES: [C:1]1([C@H:7]2[C:12](=[O:13])[O:11][CH2:10][CH2:9][N:8]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[F:35][C:36]([F:51])([F:50])[C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[C:40](Cl)=[O:41]>C1COCC1>[F:35][C:36]([F:50])([F:51])[C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([C:46]([F:49])([F:47])[F:48])[CH:45]=1)[C:40]([O:13][C@H:12]1[O:11][CH2:10][CH2:9][N:8]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:41]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1OCCN(Cc2ccccc2)[C@H]1c1ccccc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O[C@H]1OCCN(Cc2ccccc2)[C@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.75 h
Yield: 79.7 %

Procedure:
A solution of 2.67 g (10.0 mmol) of 3-(S)-phenyl-4-benzyl-2-morpholinone (from Example 14) in 40 mL of dry THF was cooled to -78° C. The cold solution was treated with 12.5 mL of 1.0M L-Selectride®, solution in THF, maintaining the internal reaction temperature below -70° C. Alternatively, only a 6% excess of L-Selectride® may be required. The resulting solution was stirred cold for 45 minutes and the reaction was charged with 3.60 mL (20.0 mmol) of 3,5-bis(trifluoro-methyl)benzoyl chloride. The resulting yellow mixture was stirred cold for 30 minutes and the reaction was quenched with 50 mL of saturated aqueous sodium bicarbonate solution. Alternatively, acetic acid may be used for the quench. The quenched mixture was partitioned between 300 mL of ether and 50 mL of water and the layers were separated. The organic layer was dried over magnesium sulfate. The aqueous layer was extracted with 300 mL of ether; the extract was dried and combined with the original organic layer. The combined organics were concentrated in vacuo. Flash chromatography on 150 g of silica gel using 37:3 v/v hexanes/ether as the eluant afforded 4.06 g (80%) of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6]/[C:5]/2=[CH:15]\[C:16](OCC)=[O:17].[CH:21]1([O:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[NH2:29])[CH2:25][CH2:24][CH2:23][CH2:22]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6]/[C:5]/2=[CH:15]\[C:16]([NH:29][C:28]1[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=1[O:26][CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:17]
Reactant: Nc1ccccc1OC1CCCC1
Reactant: CCOC(=O)/C=C1\CC2(CCC2)Oc2ccc(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(/C=C1\CC2(CCC2)Oc2ccc(Cl)cc21)Nc1ccccc1OC1CCCC1

Procedure:
The title compound was prepared by the coupling ethyl (2E)-(6-chlorospiro[chromene-2,1′-cyclobutan]-4(3H)-ylidene)acetate (Step 2 of Intermediate 1) with 2-(cyclopentyloxy)aniline (120 mg, 0.681 mmol) (150 mg, 0.565 mmol) in presence of EDCI.HCl (163 mg, 0.851 mmol), HOBt (130 mg, 0.851 mmol) and triethylamine (157 μl, 1.134 mmol) in dichloromethane (5 ml) as described in Method A to give 95 mg of the product as a white solid; 1H NMR (300 MHz, CDCl3) δ 1.53-1.65 (m, 8H), 1.74-1.90 (m, 4H), 2.22-2.30 (m, 2H), 2.47-2.57 (m, 2H), 3.50 (s, 2H), 4.67 (br s, 1H), 6.75 (d, J=8.1 Hz, 2H), 6.85-6.96 (m, 2H), 7.04-7.10 (m, 2H), 8.32 (d, J=7.8 Hz, 1H).
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=4)[C:25](O)=[O:26])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH:39]=[CH:38][N:37]=[CH:36]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=4)[C:25]([NH:31][CH2:32][CH2:33][CH2:34][N:35]4[CH:39]=[CH:38][N:37]=[CH:36]4)=[O:26])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: NCCCn1ccnc1
Reactant: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cncc(C(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cncc(C(=O)NCCCn2ccnc2)c1
Yield: 73.5 %

Procedure:
To solution of 5-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-nicotinic acid (40 mg, 0.098 mmol), 1-(3-aminopropyl)-imidazole (24.65 mg, 0.196 mmol) and DMAP (24.06 mg, 0.196 mmol) in DMF was added PyBOP (102.47 mg, 0.196 mmol) at room temperature, and stirred. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The resultant crude product was purified by PLC (MeOH:MC=1:9) to afford 5-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-N-(3-imidazole-1-yl-propyl)nicotinamide as a colorless solid (37 mg, 49% yield).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][C@@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@H:7]1[OH:20])#[N:2].C(N(CC)CC)C.[CH2:30]([OH:32])[CH3:31]>>[C:1]([N:3]=[C:4]([O:32][CH2:30][CH3:31])[NH:5][C@@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@H:7]1[OH:20])#[N:2]
Reactant: CCO
Reactant: CSC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Solvent: CCN(CC)CC
Product: CCOC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O

Procedure:
A mixture of trans-4-(3-cyano-2-methyl-1-isothioureido)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.48 g) and triethylamine (0.635 ml) in ethanol (5.0 ml) was stirred under reflux for 7 hours. The solvent was removed under reduced pressure. The residue was extracted with ethyl acetate (15 ml), and washed successively with 5% hydrochloric acid (15 ml) and saturated aqueous solution of sodium chloride (15 ml). The organic solution was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was subjected to a column chromatography on silica gel (17 g), eluting with a mixture of methanol and chloroform (1:50 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was recrystallized from a mixture of ethanol 1.5 ml) and n-hexane (3 ml) to give trans-4-(3-cyano-2-ethyl-1-isoureido)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.22 g).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[NH:15][C:16]([C:18]1[N:19]([CH2:24][C:25](=[O:41])[NH:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:20]=[C:21]([NH2:23])[CH:22]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42]1([S:48](Cl)(=[O:50])=[O:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>N1C=CC=CC=1.[Cl-].[Na+].O>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[NH:15][C:16]([C:18]1[N:19]([CH2:24][C:25](=[O:41])[NH:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:20]=[C:21]([NH:23][S:48]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)(=[O:50])=[O:49])[CH:22]=1)=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(C(=O)NC2CCCCC2OCc2ccccc2)n(CC(=O)NC2CCCCC2OCc2ccccc2)n1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: O=C(Cn1nc(NS(=O)(=O)c2ccccc2)cc1C(=O)NC1CCCCC1OCc1ccccc1)NC1CCCCC1OCc1ccccc1
Reaction time: 1 h

Procedure:
5-Amino-2-[(2-benzyloxy-cyclohexylcarbamoyl)-methyl]-2H-pyrazole-3-carboxylic acid (2-benzyloxy-cyclohexyl)-amide (40 mg, 0.067 mmol) was dissolved in 1 ml of dry pyridine. Benzenesulfonyl chloride (0.0085 ml) was added and the reaction mixture stirred for 1 hour. The mixture was added to brine and extracted with dichloromethane. The dichloromethane extract was dried over magnesium sulfate, filtered. 29 mg of title compound was obtained after preparative thin layer chromatography using 50% ethyl acetate/hexanes as the eluent. ESI M+1=700.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]2([C:13]#[N:14])[CH2:12][CH2:11]CC2)=[C:4]([CH:17]=O)[CH:3]=1.[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1.N1CCCC1>CO>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]2([C:13]#[N:14])[CH2:12][CH2:11]2)=[C:4](/[CH:17]=[C:24]2\[C:25](=[O:29])[NH:26][C:27]3[C:23]\2=[CH:22][CH:21]=[C:20]([Cl:19])[CH:28]=3)[CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: N#CC1(COc2ccc(Cl)cc2C=O)CCCC1
Solvent: CO
Solvent: C1CCNC1
Product: N#CC1(COc2ccc(Cl)cc2/C=C2\C(=O)Nc3cc(Cl)ccc32)CC1
Yield: 53.4 %

Procedure:
In a manner similar to the method described in Example 1b, 1-(4-chloro-2-formyl-phenoxymethyl)-cyclopentanecarbonitrile (4.7 g, 20 mmol) was reacted with 6-chlorooxindole (2.78 g, 16.67 mmol) and pyrrolidine (1.54 g, 21.67 mmol) in methanol to give the title compound as a yellow solid (3.43 g).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:27]=1[CH2:28]Cl.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C(F)=CC=CC=3F)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:28][C:27]3[C:26]([F:25])=[CH:33][CH:32]=[CH:31][C:30]=3[F:34])[N:13]=2)=[CH:23][CH:22]=1
Reactant: Fc1cccc(F)c1CCl
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CC(C)(C)OC(=O)N1CCc2nn(Cc3c(F)cccc3F)c(-c3ccc(Cl)cc3)c2CC1
Product: Fc1cccc(F)c1Cn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Yield: 18.7 %

Procedure:
The title compound (0.07 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 1 mmol) using 2,6-difluorobenzyl chloride (1.5 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chlorophenyl)-2-(2,6-difluoro-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C20H18ClF2N3, 373.12; found, m/z 374.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.34-7.30 (m, 5H), 6.93-6.90 (m, 2H), 5.34 (s, 2H), 3.59-3.57 (m, 2H), 3.39-3.37 (m, 4H), 2.94-2.92 (m, 2H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([NH:20]C(OCC4C=CC=CC=4)=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H][H]>CO.C1COCC1.[C].[Pd]>[N:1]1([CH2:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:15][CH2:16][CH:17]([NH2:20])[CH2:18][CH2:19]3)=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: O=C(NC1CCN(c2ccc(CCn3ccnn3)cc2)CC1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: NC1CCN(c2ccc(CCn3ccnn3)cc2)CC1

Procedure:
The N-(4-(2-(1,2,3-triazol-1-yl)-ethyl)-phenyl)-4-benzyloxycarbonylaminopiperidine (1.3 g, 50 mmol) obtained in Example 7 (6) was dissolved in methanol (13 ml) and THF (13 ml), and 10% palladium-carbon (hereinafter referred to as Pd—C) (130 mg) was added, followed by stirring at room temperature in an atmosphere of hydrogen gas for 24 hours. After the insoluble material was filtered with Celite, the solvent was evaporated from the filtrate under reduced pressure, thereby obtaining N-(4-(2-(1,2,3-triazol-1-yl)-ethyl)-phenyl)-4-aminopiperidine (870 mg, 99%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.COCCOC.[Cl:17][C:18]1[CH:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=1>O>[Cl:17][C:18]1[CH:23]=[C:22]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:21]=[CH:20][N:19]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Clc1cc(Cl)ncn1
Solvent: COCCOC
Solvent: O
Product: Fc1cccc(-c2cc(Cl)ncn2)c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 24.7 %

Procedure:
A reaction vessel was charged with 0.303 g of tetrakistriphenylphosphine palladium, 1.344 g of 3-fluorophenylboronic acid, and 3.707 g of tripotassium phosphate n-hydrate, to which 36 ml of 1,2-dimethoxyethane, 9 ml of water, and 1.301 g of 4,6-dichloropyrimidine were added, followed by stirring at 80° C. under an atmosphere of a nitrogen gas for 7 hours. The reaction mixture was then left for cooling to room temperature, and water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.45 g of 4-chloro-6-(3-fluorophenyl)pyrimidine.
Reaction SMILES: CS(O[CH2:6][C@H:7]([N:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:34])[C:15]=2[NH:19][C:20](=[O:33])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([F:32])[CH:23]=2)[C:10]1=[O:35])[CH3:8])(=O)=O.[CH3:36][NH:37][CH2:38][CH:39]=[CH2:40].C(N(CC)CC)C.C(Cl)Cl>>[CH2:38]([N:37]([CH3:36])[CH2:6][C@H:7]([N:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:34])[C:15]=2[NH:19][C:20](=[O:33])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[C:24]([F:32])[CH:23]=2)[C:10]1=[O:35])[CH3:8])[CH:39]=[CH2:40]
Reactant: Cc1ccc2c(=O)n([C@H](C)COS(C)(=O)=O)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Reactant: C=CCNC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN(C)C[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(C)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-2-(5-(2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamido)-6-methyl-1-oxoisoquinolin-2(1H)-yl)propyl methanesulfonate (100 mg, 0.0002 mol), N-methylprop-2-en-1-amine (30 mg, 0.4 mmol), triethylamine (200 mg, 0.002 mol) and methylene chloride (6 mL, 0.09 mol) was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the mixture was purified by reverse phase preparative HPLC to afford the desired product as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][CH2:7][CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C([Mg]Cl)(C)C.C([Li])CCC.N1(C=O)CC[O:33][CH2:32]C1>C1COCC1>[Si:10]([O:9][CH2:8][CH2:7][O:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:19]=[CH:18][CH:17]=1)[CH:32]=[O:33])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: O=CN1CCOCC1
Reactant: CC(C)(C)[Si](C)(C)OCCOCc1cccc(Br)c1
Agent: CC(C)[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCOCc1cccc(C=O)c1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
(2-(3-Bromobenzyloxy)ethoxy)(tert-butyl)dimethylsilane [Aromatic Intermediate 25, step b] (2.3 g) was dissolved in THF (15 mL) and the solution cooled to −10° C. Isopropylmagnesium chloride (2M in THF, 1.2 mL) was added, followed by butyllithium (2.1M in hexanes, 2.4 mL). The mixture was stirred for 10 min before being added to a solution of morpholine-4-carbaldehyde (1.4 mL) in THF (15 mL). The mixture was stirred for 1 hour, then poured onto ammonium chloride solution (30 mL) and extracted into ether (2×30 mL). The combined ether extracts were washed with water and dried over sodium sulphate. The solvent was evaporated in vacuo to give the titled compound as a colourless oil. Yield 1.8 g.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23](Br)[CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)[CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN1CCNCC1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2cccc(Br)c2)[C@H](c2ccccc2)C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CCN(c2cccc([C@H]3CCN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)C[C@H]3c3ccccc3)c2)CC1
Yield: 37.9 %

Procedure:
To a solution of rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(3-bromo-phenyl)-3-phenyl-piperidin-1-yl]-methanone (500 mg, 0.899 mmol) in 5 mL dry toluene was added 1-methyl-piperazine (0.123 mL, 1.08 mmol), sodium tert.-butoxide (125 mg, 1.26 mmol), bis(dibenzylidenacetone)palladium (2.1 mg, 0.002 mmol) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (4.3 mg, 0.007 mmol) and than refluxed overnight. The reaction mixture was diluted with 10 mL water and extracted three times with 20 mL ethyl acetate. Organic phases were pooled, dried with magnesium sulfate and evaporated. Flash chromatography on silica gel with hexane/ethyl acetate/triethyl amine 10:10:1 gave the desired product (196 mg, 38%), MS: m/e=576.1 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:30]([F:33])([F:32])[F:31])=[C:10]([C:12]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]4)=[N:19][CH:20]=3)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:34][S:35]([NH:38][C:27]([CH:24]1[CH2:25][CH2:26][N:21]([C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:30]([F:33])([F:31])[F:32])=[O:13])=[CH:20][N:19]=2)[CH2:22][CH2:23]1)=[O:28])(=[O:37])=[O:36]
Reactant: CS(N)(=O)=O
Reactant: O=C(Nc1ccc(N2CCC(C(=O)O)CC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)C1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
To a suspension of 5′-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid (39.4 mg, 0.085 mmol) in methylene chloride (5 mL) was added methanesulfonamide (8.2 mg, 0.086 mmol). Then 4-dimethylaminopyridine (10.45 mg, 0.085 mmol) and EDCl (16.4 mg, 0.085 mmol) was added. The mixture was stirred at room temperature overnight. Solvents were evaporated and the residue was purified by flash column chromatography using a linear gradient of ethyl acetate containing 1% acetic acid in hexanes (20% to 100% in 15 minutes) to give the desired compound as a pale yellow solid (16.5 mg). 1H-NMR is consistent with the desired structure. LRMS for C23H22F3N5O5S (m/e) calcd 537.13, obsd 538.1 (M+1).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:32]=[CH:31][C:7]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][C:22]=4[OH:30])[CH2:13][CH2:12]3)=[N:9][O:10][C:6]=2[CH:5]=1.[CH3:33]I.O>CN(C)C=O>[F:3][C:4]1[CH:32]=[CH:31][C:7]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][C:22]=4[O:30][CH3:33])[CH2:13][CH2:12]3)=[N:9][O:10][C:6]=2[CH:5]=1
Reactant: CC(=O)c1ccc(NCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(O)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1NCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 164.5 %

Procedure:
To a stirred suspension of sodium hydride (0.37 g, 7 mmol of a 50% oil dispersion) in dimethylformamide (20 ml) was added, dropwise, 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propylamino]-3-hydroxyphenyl]ethanone (2.9 g, 7 mmol) dissolved in dimethylformamide (25 ml). The reaction was stirred at ambient temperature for 15 minutes, and then it was cooled with an ice bath to about 5° C., whereupon methyl iodide (1.0 g, 7 mmol) in dimethylformamide (1 ml) was added dropwise. The reaction was stirred at ambient temperature for 30 min, and then water was added. The resulting aqueous mixture was extracted with ethyl acetate, the extract washed with water, dried (MgSO4), and the solvent was concentrated to afford 4.9 g of a brown oil, which solidified on standing. The solid was flash chromatographed on silica gel. The appropriate fractions were concentrated to yield 2.7 g of product as a yellow solid. Recrystallization from toluene-hexane yielded 2.0 g (67%) of analytically pure 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propylaminol-3-methoxyphenyl]ethanone as a yellow solid, m.p.=96°-98° C.
Reaction SMILES: [CH2:1]1[N:6]2[C:7]3[C:12]([NH:13][C:14](=[O:15])[CH:5]2[CH2:4][NH:3][CH2:2]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24]Cl)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.C(N(CC)CC)C>[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][N:3]2[CH2:2][CH2:1][N:6]3[C:7]4[C:12]([NH:13][C:14](=[O:15])[CH:5]3[CH2:4]2)=[CH:11][CH:10]=[CH:9][CH:8]=4)=[CH:18][CH:17]=1
Reactant: O=C1Nc2ccccc2N2CCNCC12
Reactant: ClCCCc1ccncc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C1Nc2ccccc2N2CCN(CCCc3ccncc3)CC12

Procedure:
A solution of 6.1 g. (0.03 mole) of 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one, 6.3 g. (0.04 mole) of 3-(4-pyridyl)-1-chloropropane, 10 g. of potassium carbonate, 5 g. of potassium iodide and 0.5 ml. of triethylamine was stirred and refluxed in 200 ml. of acetone for 48 hours, then cooled and filtered. The solvent was removed, and the residue was dissolved in ethanol-ether and treated with dry hydrogen chloride saturated ether. The product hyrochloride was filtered and recrystallized two times from methanol. Dried at 100° C./0.1 mm. Yield: 6.2 g. (44%) as the dihydrochloride salt, m.p. 188°-190° C.