Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:29][CH3:30])=[C:25]([OH:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1.[N:31]1([CH2:37][CH2:38]O)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:29][CH3:30])=[C:25]([O:28][CH2:38][CH2:37][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: COc1cc2ncnc(Cl)c2cc1O
Reactant: OCCN1CCOCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2ncnc(Cl)c2cc1OCCN1CCOCC1
Reaction time: 2 h
Yield: 75.9 %

Procedure:
Di-tert-butyl azodicarboxylate (1.44 g, 6.26 mmol) was added portionwise at room temperature to a stirred suspension of 4-chloro-7-methoxyquinazolin-6-ol (1.20 g, 5.70 mmol), 2-morpholin-4-ylethanol (0.82 g, 6.26 mmol) and triphenylphosphine (1.8 g, 6.87 mmol) in dichloromethane (25 ml). The reaction mixture was stirred for 2 hour and then the resulting orange solution was purified directly by silica gel chromatography eluting with a mixture of 3% methanol in dichloromethane and then purified further by chromatography on neutral alumina eluting with a 3% mixture of methanol in dichloromethane to give 4-chloro-7-methoxy-6-(2-morpholin-4-ylethoxy)quinazoline (1.40 g, 76% yield) as a pale yellow solid:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][NH:6][O:7][CH2:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11].[CH2:19](O)[CH3:20]>>[ClH:2].[Cl:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][NH:6][O:7][CH2:8][C:9]([CH3:14])([CH3:13])[C:10]([O:12][CH2:19][CH3:20])=[O:11]
Reactant: CC(C)(CONCc1ccccc1Cl)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(C)(C)CONCc1ccccc1Cl
Reaction time: 8 h

Procedure:
Dry hydrogen chloride gas was passed through a stirred solution of 2-(2-chlorobenzylaminooxymethyl)-2-methylpropanoic acid (2.0 grams; 0.01 mole) in absolute ethanol (100 mL) at ambient temperature for two minutes. The reaction mixture was stirred overnight under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by passing it through a silica gel column, eluting first with methylene chloride (200 mL) and then with 95:5 methylene chloride:methanol. Appropriate fractions were combined and then concentrated under reduced pressure to afford 0.45 grams of ethyl 2-(2-chlorobenzylaminooxymethyl)-2-methylpropanoate hydrochloride as a colorless gum.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:7][C:6]=12.[CH2:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)[CH3:26]>>[CH2:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:7][C:6]=12)[CH3:26]
Reactant: CCc1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccn2ncc(Br)c2n1
Product: CCc1ccccc1-c1cnn2ccc(NC[C@@H]3CCCN3C(=O)OC(C)(C)C)nc12
Yield: 77 %

Procedure:
The Suzuki coupling of (5)-tert-butyl 2-(((3-bromopyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)pyrrolidine-1-carboxylate with (2-ethylphenyl)boronic acid under the same conditions as described in example 5.6.5 to give 77% of the titled compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.20 (t, J=7.58 Hz, 3 H) 1.49 (s, 9 H) 1.79-1.95 (m, 3 H) 1.95-2.05 (m, 1 H) 2.82 (q, J=7.58 Hz, 2 H) 3.34-3.44 (m, 3 H) 3.44-3.53 (m, 1 H) 4.15 (br. s., 1 H) 6.08 (d, J=6.82 Hz, 1 H) 7.23-7.31 (m, 3 H) 7.32-7.38 (m, 1 H) 7.51 (dd, J=7.20, 1.39 Hz, 1 H) 7.91 (s, 1 H) 8.20 (d, J=6.32 Hz, 1 H); LRMS (ESI) m/e 422.0 [(M+H)+, calcd for C24H31N5O2 421.0].
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][S:39]([C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1)(=[O:41])=[O:40].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:45]2[CH:46]=[CH:47][C:42]([S:39]([CH3:38])(=[O:41])=[O:40])=[CH:43][CH:44]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 41 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (500 mg, 0.93 mmol), 4-methylsulfonyl phenylboronic acid (560 mg, 2.78 mmol), and dichlorobis(triphenylphosphine)palladium (II) (65.3 mg, 0.09 mmol) in dioxane (4 mL) was added an aqueous sodium carbonate solution (2 M, 1.40 mL, 2.8 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by flash column chromatography (silica gel from QingDao, 200-300 mesh, 25% ethyl acetate/hexanes) to afford 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-fluoro-1H-pyrrolo[2,3-b]pyridine (200 mg, 41%) as a light yellow solid: LC/MS m/e calcd for C27H25FN2O4S2 [M+H]+ 525.64, observed 525.1.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C1COCC1>[CH2:1]([O:8][C:9](=[O:18])[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([O:17][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine trans-(4-hydroxy-cyclohexyl)-carbamic acid benzyl ester (16.0 g, 0.064 mol), immidazol (13.9 g, 0.10 mol), and anhydrous THF (300 mL), add tert-butyldimethylsilyl chloride (14.5 g, 0.10 mol) and stir at room temperature for 18 hours. Wash the reaction mixture with water (250 mL), saturated aqueous NaHCO3 (250 mL) and dry the organic layer over anhydrous Na2SO4. Remove the solvent and purify the residue by chromatography over silica gel (eluting with 0 to 30% EtOAc in hexane) to obtain trans-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-carbamic acid benzyl ester as clear oil (23.0 g, 98%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][N:19]3[C:24]([C:25]=2[CH3:26])=[C:23]([CH:27]2[CH2:29][CH2:28]2)[CH:22]=[C:21]([C:30]([O:32]C)=[O:31])[C:20]3=[O:34])=[CH:12][C:11]=1[F:35])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][N:19]3[C:24]([C:25]=2[CH3:26])=[C:23]([CH:27]2[CH2:29][CH2:28]2)[CH:22]=[C:21]([C:30]([OH:32])=[O:31])[C:20]3=[O:34])=[CH:12][C:11]=1[F:35])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(CNC(=O)OC(C)(C)C)c(F)c3)ccn2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(-c2ccc(CNC(=O)OC(C)(C)C)c(F)c2)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
Methyl 8-(4-((tert-butoxycarbonylamino)methyl)-3-fluorophenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (24 mg, 0.050 mmol) was dissolved in MeOH (2 mL) and 1M aqueous sodium hydroxide (0.5 mL, 0.5 mmol) was added. The mixture was stirred at 50° C. for 2 h. After cooling, the MeOH was removed in vacuum and the residue was dissolved in water (5 mL) and neutralized with 1M HCl (˜0.5 mL). The precipitate formed was extracted with DCM (3×4 mL). The organic layer was concentrated to afford the title compound as a yellow solid (20 mg, 86%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:23]=[CH:22][C:17]([CH2:18][NH:19][O:20][CH3:21])=[CH:16][CH:15]=1.N1C=CC=CC=1>ClCCl>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:19]([CH2:18][C:17]2[CH:22]=[CH:23][C:14]([F:13])=[CH:15][CH:16]=2)[O:20][CH3:21])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCc1ccc(F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A solution of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride, Compound 1-B, (2.45 g, 12.9 mmol) in dichloromethane (15 ml) was added dropwise over 10 minutes to a cold (0-5° C.) mixture of N-4-fluorobenzyl-O-methyl-hydroxylamine (2.0 g, 12.9 mmol) and pyridine (2.1 ml, 25.7 mmol) in dichloromethane (50 ml). The cooling bath was then removed and the solution was stirred at 22° C. for 30 minutes. The reaction mixture was then quenched by the addition of water and ethyl acetate. The organic phase was washed successively with 0.1 N hydrochloric acid, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and chromatography of the residue on silica gel (toluene-ethyl acetate, 8:2) gave 3.72 g (93% yield) of the title amide as white crystals: mp 111° C. (ethyl acetate-hexane). 1H NMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s), 3.68 (3H, s), 4.79 (2H, s), 6.38 (1H, s), 7.0 (2H, m), 7.34 (2H, m). Anal. calcd for C15H16FNO5: C, 58.25; H, 5.21; N, 4.52. Found: C, 58.33; H, 5.38; N, 4.51.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:14][C@H:15]2[CH2:19][N:18](C(OC(C)(C)C)=O)[C@H:17]([C:27]([O:29][CH3:30])=[O:28])[CH2:16]2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.Cl.O1CCOCC1>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[C:3]([O:14][C@H:15]2[CH2:19][NH:18][C@H:17]([C:27]([O:29][CH3:30])=[O:28])[CH2:16]2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2nc3cc(OC)ccc3nc2Cl)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](Oc2nc3cc(OC)ccc3nc2Cl)CN1
Temperature: 20 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A solution (0.62 M) of 1-tert-butyl 2-methyl (2S,4R)-4-[(3-chloro-7-methoxyquinoxalin-2-yl)oxy]pyrrolidine-1,2-dicarboxylate in CH2Cl2 was treated with a solution (4 M) of HCl in dioxane (5 eq). The mixture was stirred at 20° C. for 2 h, then treated with a solution (4 M) of HCl in dioxane (2 eq). After 5 h, the reaction was judged complete and the mixture was concentrated under reduced pressure. The residue was triturated with Et2O to give the title compound (95%) as a solid. MS (ES+) m/z 338 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH3:14])=[CH:10][C:11]([OH:13])=[O:12].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[CH2:40](O)[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O1CCCC1.CN(C)C1C=CN=CC=1>[CH2:40]([O:12][C:11](=[O:13])/[CH:10]=[C:9](/[C:3]1[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=1[OH:1])\[CH3:14])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(=CC(=O)O)c1ccc(O)cc1O
Reactant: OCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: C/C(=C\C(=O)OCCc1ccccc1)c1ccc(O)cc1O
Temperature: 22 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. solution of 9.7 g (0.050 mol) of 3-(2,4-dihydroxyphenyl)but-2-enoic acid in 500 mL of anhydrous tetrahydrofuran (THF) is added 10.3 g (0.050 mol) of 1,3-dicyclohexylcarbodiimide (DCC). After stirring for 10 min, 6.8 g (0.050 mol) of 1-hydroxybenzotriazole (HOBt), 5.5 g (0.045 mol) of phenethyl alcohol and 1.1 g (0.009 mol) of 4-(dimethylamino)pyridine (DMAP) is added and stirred at 0° C. for 1 h, warmed to 22° C. and stirred for an additional 72 h. The mixture is cooled to 0° C., filtered and the solvent is removed under vacuum. The residue is diluted with ethyl acetate and washed three times with saturated sodium bicarbonate, followed by 10% citric acid and brine. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to give (E)-3-(2,4-dihydroxyphenyl)-but-2-enoic acid phenethyl ester as a yellow oil that is purified by flash chromatography.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([OH:5])=[O:4].[CH3:12]O.Cl>>[OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH3:12])=[O:4]
Reactant: CO
Reactant: CCCCCCC(O)C(=O)O
Agent: Cl
Product: CCCCCCC(O)C(=O)OC
Reaction time: 1.5 h

Procedure:
2-Hydroxyoctanoic acid (1.0 g) was stirred in 10% hydrogen chloride methanol solution (20 ml) at room temperature. After 1.5 hours, the reaction mixture was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with aqueous NaHCO3 solution and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave methyl 2-hydroxyoctanoate (0.684 g) as a colorless oil.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:22][CH:21]2[O:23][CH:17]([CH2:18][NH:19][CH2:20]2)[CH2:16]1)[C:7]#[N:8].[C:24]([O:28][C:29](=[O:35])[NH:30][CH2:31][CH2:32][CH2:33]Br)([CH3:27])([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:24]([O:28][C:29](=[O:35])[NH:30][CH2:31][CH2:32][CH2:33][N:19]1[CH2:20][CH:21]2[O:23][CH:17]([CH2:16][N:15]([CH2:14][CH2:13][O:12][C:11]3[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=3[F:3])[CH2:22]2)[CH2:18]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: N#Cc1ccc(OCCN2CC3CNCC(C2)O3)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCN1CC2CN(CCOc3ccc(C#N)cc3F)CC(C1)O2
Temperature: 60 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
A suspension of 3-Fluoro-4-[2-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-ethoxy]-benzonitrile hydrochloride hydrochloric acid salt (5 g, 0.0137 mol, from step N (vii) above ), (3-Bromo-propyl)-carbamic acid tert-butyl ester (4.24 g, 0.0178 mol, from step (i) above) and potassium carbonate (7.57 g, 0.0548 mol) in dry acetonitrile (100 ml) was stirred at 60° C. overnight under nitrogen atmosphere. The reaction mixture was filtered through celite and solvent concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using 5% methanol in dichloromethane as eluent to give the sub-title compound (5.8 g) as yellow oil.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:42][C@H:43]1[CH2:49][CH2:48][CH2:47][CH2:46][N:45]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[CH:51]=2)[C:44]1=[O:57]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:42][C@H:43]1[CH2:49][CH2:48][CH2:47][CH2:46][N:45]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[CH:51]=2)[C:44]1=[O:57])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: N[C@H]1CCCCN(c2cccc(Cl)c2)C1=O
Agent: Cl
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(c4cccc(Cl)c4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((S)-1-(3-chlorophenyl)-2-oxoazepan-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (7.0 mg, 0.012 mmol) and Intermediate 49 (3.4 mg, 0.012 mmol) to give a white solid (5.1 mg, 51% yield). Anal. Calcd. for C43H51ClN4O6S m/z 786.4. found: 787.5 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.29 (d, J=8.25 Hz, 1H), 7.25-7.18 (m, 5H), 7.18-7.10 (m, 7H), 7.03 (d, J=7.70 Hz, 1H), 6.89 (d, J=6.60 Hz, 1H), 6.79 (d, J=6.60 Hz, 1H), 5.32 (t, J=4.40 Hz, 1H), 5.17-5.12 (m, 1H), 5.03-4.93 (m, 1H), 4.75 (dd, J=9.90, 7.15 Hz, 1H), 3.93 (dd, J=15.40, 11.55 Hz, 1H), 3.68 (s, 3H), 3.58 (dd, J=15.12, 4.67 Hz, 1H), 3.21-3.09 (m, 1H), 2.90-2.76 (m, 3H), 2.76-2.67 (m, 2H), 2.44-2.27 (m, 3H), 2.02-1.97 (m, 2H), 1.97-1.90 (m, 1H), 1.90-1.77 (m, 3H), 1.76-1.46 (m, 11H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH:5]=[C:6]1[CH2:10][CH2:9][NH:8][C:7]1=[O:11].[H-].[Na+].[CH3:18][O:19][CH2:20][CH2:21]Cl.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH:5]=[C:6]1[CH2:10][CH2:9][N:8]([CH2:21][CH2:20][O:19][CH3:18])[C:7]1=[O:11]
Reactant: COCCCl
Reactant: COc1ccccc1C=C1CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCN1CCC(=Cc2ccccc2OC)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The intermediate 3-(2′-methoxybenzylidene)-2-pyrrolidone (5.0 g) obtained in Example 317 was dissolved in dimethylformamide (50 ml) and sodium hydride (0.99 g) was added under ice-cooling. The mixture was stirred at room temperature for 30 min. To the reaction mixture was again added 2-methoxyethyl chloride (2.3 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hr and at 70° C. for 1 hr. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oily title compound (2.8 g).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[C:15]([C:16]#[N:17])=[CH:14][N:13]=1.N1C=CC=CC=1>C1COCC1>[C:5]1([O:4][C:2](=[O:3])[NH:11][C:12]2[CH:19]=[C:18]([O:20][CH2:21][C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: N#Cc1cnc(N)cc1OCc1cccs1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#Cc1cnc(NC(=O)Oc2ccccc2)cc1OCc1cccs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Phenyl chloroformate (3.46 ml, 27.6 mmol) was added drop wise to a mixture of 6-amino-4-(thiophen-2-ylmethoxy)nicotinonitrile (intermediate 284, 2.90 g, 12.54 mmol) and pyridine (4.46 ml, 55.2 mmol) in THF (100 ml) at room temperature. The reaction mixture was stirred for 16 h at room temperature and then partitioned between EtOAc and saturated aqueous NaHCO3 solution, the organic layer washed with saturated brine, dried over MgSO4 and evaporated. The residue was purified by normal phase chromatography: 80 g RediSep® column, eluting with a gradient from heptane to EtOAc. Product containing fractions were combined and evaporated to give the title compound as a beige solid. (UPLC-MS 3) tR 1.14; ESI-MS 352.0 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=1>C1COCC1>[CH:1]([C:4]1[N:5]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2ccccc2[nH]1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1nc2ccccc2n1Cc1ccc(N)cc1
Reaction time: 2 h

Procedure:
A solution of 2-isopropylbenzimidazole (4.0 g, 25 mmol) in THF was treated with sodium hydride (1.00 g, 25 mmol, 60% dispersed in oil) under N2 atmosphere and stirred for 2 hr. 4-Chloromethyl-1-nitrobenzene (4.3 g, 25 mmol) was added and the reaction stirred for 16 hr. The reaction was worked by extraction from NaHCO3 with EtOAc×3, the combined organic layers were dried with MgSO4, filtered, and concentrated. This material was converted to the aniline as shown in Example 200. MS found: (M+H)=267.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)O1.B(O)O>>[N:8]1([C:6]2[N:7]=[C:2]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[C:4]=3[N:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1cccnc1
Agent: OBO
Product: c1cncc(N2CCc3c(-c4ccncc4)nc(N4CCOCC4)nc32)c1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-3-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as a boronic acid, the desired compound was obtained.
Reaction SMILES: [H][H].[O:3]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[CH:13]([OH:16])[C:14]#[CH:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCOCC1>[O:3]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[CH:13]([OH:16])[CH:14]=[CH2:15])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: [H][H]
Solvent: C1COCCO1
Product: C=CC(O)c1cccc(Oc2ccccc2)c1

Procedure:
With stirring, at room temperature and under normal pressure, hydrogen was introduced (3.37 l H2 ; 0° C./760 mm Hg) in a solution of 33.7 3-phenoxy-α-ethynylbenzylalcohol in 340 ml dioxan and 1.7 g Lindlar catalysator.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][NH:2]1.[OH-].[Na+]>O1CCCC1.O>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: C1=Cc2ccccc2CN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2c(c1)CCNC2
Temperature: -30 °C

Procedure:
A solution of 467 mg (3.5 mmol) of AlCl3 in 10 ml of THF is added dropwise at room temperature to a suspension of 400 mg (10.5 mmol) of LiAlH4 in 20 ml of tetrahydrofuran (THF), as a result of which AlH3 is formed. After 15 minutes the solution is cooled to -30° C. and a solution of 2.5 g (6.74 mmol) of the dihydroisoquinoline according to b. in 100 ml of THF is added dropwise in 15 minutes. The reaction mixture is then slowly heated to room temperature. After 1.5 hours an NaOH solution in H2O is added until everything has dissolved. The organic phase is separated, and the aqueous phase is washed once with ethyl acetate/ether and four times with ether. The combined organic phases are washed with saline solution and dried with Na2SO4. After evaporation the tetrahydroisoquinoline (melting-point 160° C.) is obtained as a light-yellow powder (2.45 g, i.e. (2.45 g, i.e. 97%).
Reaction SMILES: [CH2:1]([C:5]1([CH3:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])[CH:2]([CH3:4])[CH3:3].[Br:13]C1CC(C(C)C)CCC1=O>>[Br:13][CH:7]1[C:6](=[O:11])[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])([CH3:12])[CH2:10][CH2:9][CH2:8]1
Reactant: CC(C)CC1(C)CCCCC1=O
Reactant: CC(C)C1CCC(=O)C(Br)C1
Product: CC(C)CC1(C)CCCC(Br)C1=O

Procedure:
The bromination of 2-isobutyl-2-methyl-cyclohexanone takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization.