Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[OH:18])=[O:9])=[CH:6][C:5]([N+:19]([O-:21])=[O:20])=[CH:4][N:3]=1.N1C=CC=CC=1>O>[N+:19]([C:5]1[CH:4]=[N:3][C:2]2[O:18][C:12]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=3[NH:10][C:8](=[O:9])[C:7]=2[CH:6]=1)([O-:21])=[O:20]
Reactant: Cc1ccc(NC(=O)c2cc([N+](=O)[O-])cnc2Cl)c(O)c1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)Oc1ncc([N+](=O)[O-])cc1C(=O)N2
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 79.3 %

Procedure:
A mixture of 2-chloro-5-nitro-N-(3-hydroxytol-4-yl)-3-pyridinecarboxamide (6.3 g, 0.02 mol) and pyridine (100 ml) was heated under argon at 90° C. for 2.5 hours. The cooled solution was diluted with water and the yellow-orange precipitate collected and washed with water. The solid was then stirred in hot water (100 ml) for 45 min., filtered and washed with ethanol and ether to give 4.3 g of a tan-brown solid. Recrystallization from dimethylformamide/water afforded 3.76 g (69% of theory) of product.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([O:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[C:28]([Cl:32])=[N:27][CH:26]=[CH:25]3)[CH2:16]1)=O)(C)(C)C>ClCCl>[Cl:32][C:28]1[C:29]2[C:24](=[CH:23][C:22]([O:21][CH:17]3[CH2:18][CH2:19][CH2:20][NH:15][CH2:16]3)=[CH:31][CH:30]=2)[CH:25]=[CH:26][N:27]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Oc2ccc3c(Cl)nccc3c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1nccc2cc(OC3CCCNC3)ccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 67.2 %

Procedure:
Trifluoroacetic acid (1 ml) and dichloromethane (5 ml) were added to 3-(1-chloro-isoquinolin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester (370 mg) and the mixture stirred at ambient temperature for 48 h. The mixture was concentrated in vacuo then loaded onto a pre-acidified SCX column using methanol and eluted with 2M ammonia in methanol to afford 1-chloro-6-(piperidin-3-yloxy)isoquinoline (180 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=2)[O:9][N:8]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)[O:9][N:8]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cncc(-c2nc(-c3ccccn3)no2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(-c2cncc(-c3nc(-c4ccccn4)no3)c2)cc1
Yield: 30 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(5-bromo-pyrid-3-yl)-1,2,4-oxadiazole (152 mg, 0.5 mmol), phenylboronic acid (121.9 mg, 1.0 mmol) and Pd(PPh3)4 (57.8 mg, 0.05 mmol) in a solution of 2M sodium carbonate (3 mL) and ethylene glycol dimethyl ether (3 ml) was heated overnight at 105° C. Standard work up afforded 45 mg of 3-(2-pyridyl)-5-(5-phenyl-pyrid-3-yl)-1,2,4-oxadiazole.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>O1CCOCC1.CCOCC>[ClH:23].[F:21][C:19]([F:20])([F:22])[C:16]1[S:15][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(F)(F)F)s2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: FC(F)(F)c1cnc(N2CCNCC2)s1
Temperature: 90 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of 3.59 mmol 4-(5-trifluoromethyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in 20 ml dioxane was added dropwise 53.8 mmol hydrogen chloride solution (4 M in dioxane) and the mixture was stirred at 90° C. for 4 h. The reaction mixture was then cooled to 0° C. and diluted with ether. The resulting crystals were collected by filtration and washed with ether to afford the title compound as an off-white crystalline solid (yield 99%). MS (m/e): 238.1 (M+H+, 100%).
Reaction SMILES: [CH:1]1([C:4]([N:6]([CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([CH:30]([CH3:34])[C:31](O)=[O:32])[CH:21]=2)[CH2:7][CH3:8])=[O:5])[CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:38])=O>>[CH:1]1([C:4]([N:6]([CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([CH:30]([CH3:34])[C:31]([Cl:38])=[O:32])[CH:21]=2)[CH2:7][CH3:8])=[O:5])[CH2:3][CH2:2]1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C(=O)O)cc(C(F)(F)F)c1)C(=O)C1CC1
Reactant: O=C(Cl)C(=O)Cl
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C(=O)Cl)cc(C(F)(F)F)c1)C(=O)C1CC1

Procedure:
Prepared according to the procedure described in Example 218, Step 3, using the following starting materials: 2-{2′-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-5,4′-bis-trifluoromethyl-biphenyl-3-yl}-propionic acid and oxalyl chloride.
Reaction SMILES: Cl.[CH3:2][CH:3]([C:11]1([OH:23])[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[C:24]([Cl:27])(=[O:26])[CH3:25].[OH-].[Na+].Cl>CCOCC>[ClH:27].[C:24]([O:23][C:11]1([CH:3]([CH3:2])[CH2:4][N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:26])[CH3:25]
Reactant: CC(CN1CCOCC1)C1(O)CCCCC1c1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(=O)OC1(C(C)CN2CCOCC2)CCCCC1c1ccccc1

Procedure:
1-(1-Methyl-2-morpholinoethyl)-2-phenylcyclohexanol hydrochloride (Example XVIII) is converted to the free base and treated with acetyl chloride according to the procedure of Example I (c) using 14 ml acetyl chloride and a reaction time of 90 hours. The product is treated with NaOH to give the base which is dissolved in ether and acidified with HCl gas to give 10.7 g., m. 176.5-7.5 after recrystallization from isopropanol.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:12]([O-])=O)[CH:9]=2)[CH2:4]1.[CH3:16][C:17](OC(C)=O)=[O:18]>CCO.O.[Pd]>[CH3:1][N:2]([CH3:15])[CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:12][C:17](=[O:18])[CH3:16])[CH:9]=2)[CH2:4]1
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)C1Cc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc2c(c1)CC(N(C)C)C2
Temperature: 20 °C
Reaction time: 16 h
Yield: 73.5 %

Procedure:
A solution of crude nitroindanamine 108 (19.82 g, 95.8 mmol) in EtOH (200 mL) and Pd/C (500 mg) was stirred in 2×100 mL batches under H2 (60 psi) for 16 h. The combined batches were filtered through Celite, and washed with warm EtOH (1 L) and then DMF (100 mL). The solvent was evaporated and the residue suspended in dioxane (130 mL), and Ac2O (19 mL, 190 mmol) added dropwise. The mixture was stirred at 20° C. for 16 h, diluted with water (200 mL), the pH adjusted to 10 with cNH3, and the mixture stirred for 30 min. The precipitate was filtered, washed with water (50 mL) and dried to give pure 5-acetamide 109 (15.38 g, 73%) as tan powder: mp 94-96° C.; 1H NMR δ 7.42 (br s, 1H, NH), 7.08-7.14 (m, 3H, H-4, H-6, H-7), 2.97-3.08 (m, 3H, H-2, CH2), 2.78-2.89 (m, 2H, CH2), 2.30 [s, 6H, N(CH3)2], 2.15 (s, 3H, COCH3); 13C NMR δ 168.3, 142.8, 137.9, 136.3, 124.5, 118.5, 116.6, 68.1, 43.8 (2), 37.7, 37.1, 24.5. Anal. calcd for C13H18N2O.H2O: C, 66.1; H, 8.5; N, 11.9. Found: C, 66.1; H, 8.5; N, 11.9%.
Reaction SMILES: [N:1]1([CH2:7][C:8]([O:10]CC)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[ClH:14]>C1(C)C=CC=CC=1>[ClH:14].[N:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CN1CCCCC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)CN1CCCCC1
Yield: 83 %

Procedure:
Ethyl 2-(piperidin-1-yl)-acetate (5.5 g, 32.2 mmol), water (12 ml) and c HCl (3 ml) were heated under reflux for 20 hours. Volatile components were evaporated under reduced pressure to leave an off white solid. This solid was co-evaporated with toluene (50 ml×3) and dried in vacuo to give an off white powder (Yield 4.8 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH2:16]O)[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:25]([N:27](CC)CC)C.CS(Cl)(=O)=O.O>C1COCC1>[C:25]([CH2:16][CH:15]1[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:10][CH:9]1[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)#[N:27]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C(c2ccc(Cl)c(Cl)c2)C1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC(CC#N)C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (6RS,7SR)-6-(3,4-dichlorophenyl)-7-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (2.0 g) in THF (40 mL) were added triethylamine (2.22 mL) and methanesulfonyl chloride (0.82 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a solution of the obtained residue (1.6 g) in DMF (9.0 ml) was added sodium cyanide (345 mg), and the mixture was stirred at 80° C. for 2 days. The reaction solution was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (331 mg).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]3[CH:14]=[CH:13][C:12](C(O)=O)=[N:11][C:8]=3[CH:9]=2)[CH:4]=[CH:3][C:2]=1C(O)=O.C(=O)=O.N>COCCOCCO>[N:1]1[C:10]2[C:5](=[CH:6][C:7]3[CH:14]=[CH:13][CH:12]=[N:11][C:8]=3[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc2cc3ccc(C(=O)O)nc3cc2n1
Agent: N
Agent: O=C=O
Solvent: COCCOCCO
Product: c1cnc2cc3ncccc3cc2c1
Temperature: 165 °C

Procedure:
Diethylene glycol monomethyl ether (20 cc) was added to pyrido[3,2-g] quinoline-2,8-dicarboxylic acid (2.01 g, 7.5 mmol) from the above process and cuprous oxide (I) (50 mg, 0.35 mmol), and heated for 5.5 hours at 165° C. Carbon dioxide evolved during the reaction. After the addition of conc. aquous ammonia (25 cc), extracted with dichloromethane (3×100 ml) and dried on potassium carbonate and evaporated dichloromethane to yield pyrido[3,2-g]quinoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:24]([O:25][CH3:26])=[CH:23][C:6]2[CH:7]([O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.C(N(CC)CC)C.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:24]([O:25][CH3:26])=[CH:23][C:6]2[CH:7]([O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=3)[CH2:8][N:9]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)C(Oc1ccc(C(F)(F)F)cc1)CNCC2
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCc2cc(OC)c(OC)cc2C(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C

Procedure:
To a cooled solution of 7,8-dimethoxy-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine (5.5 g, 0.015 mole) and triethylamine (1.7 g, 0.017 mole) in chloroform (70 ml) was slowly dropped a solution of ethyl chloroformate (1.0 g, 0.017 mole) in chloroform (20 ml). After stirring twenty hours at ambient temperature the reaction mixture was concentrated to an oil which was dissolved in ether, washed with water, dilute HCl, again twice with water, then dried (saturated NaCl, anhydrous MgSO4). The solution was filtered then concentrated to a solid (5.0 g, 76%, m.p. 120° C.) of which a sample was twice recrystallized from hexanes to yield 7,8-dimethoxy-3-ethoxycarbonyl-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine, m.p. 130°-131° C.
Reaction SMILES: [CH:1]1(/[C:4](=[N:15]/[O:16][CH3:17])/[CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[C:18]([CH:20]([C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)[CH2:21][C:22]([O:24]C)=[O:23])#[N:19]>>[C:18]([CH:20]([C:26]1[CH:31]=[CH:30][C:29]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5]/[C:4](/[CH:1]3[CH2:3][CH2:2]3)=[N:15]\[O:16][CH3:17])=[CH:8][CH:9]=2)=[CH:28][CH:27]=1)[CH2:21][C:22]([OH:24])=[O:23])#[N:19]
Reactant: COC(=O)CC(C#N)c1ccc(O)cc1
Reactant: CO/N=C(\COc1ccc(CO)cc1)C1CC1
Product: CO/N=C(\COc1ccc(COc2ccc(C(C#N)CC(=O)O)cc2)cc1)C1CC1
Yield: 56.32 %

Procedure:
Compound 105 was synthesized from (4-{[(2Z)-2-cyclopropyl-2-(methoxyimino)ethyl]oxy}phenyl)methanol (0.5 g, 2.12 mmol) and methyl 3-cyano-3-(4-hydroxyphenyl)propanoate (0.44 g, 2.12 mmol) by following the procedure described in scheme 5 (0.008 g, yield: 56.32%); Purity: 84.26%.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([CH:38]=O)=[CH:34][CH:33]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:38][C:35]3[CH:36]=[CH:37][C:32]([C:31]([OH:40])=[O:30])=[CH:33][CH:34]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(O)c1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
This compound was prepared according to the procedure of Example 66 from 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 4-formyl-benzoic acid methyl ester MS (ESI) m/z 511.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15](O)=[O:16])[S:8][C:7]=3[C:6]=2[N:18]=1.C([N:22](CC)C(C)C)(C)C.[Cl-].[NH4+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]([NH2:22])=[O:16])[S:8][C:7]=3[C:6]=2[N:18]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cc2c(s1)-c1nc(Cl)ccc1OCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: NC(=O)c1cc2c(s1)-c1nc(Cl)ccc1OCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
A mixture of 9-Chloro-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene-2-carboxylic acid (24.6 g, 87.5 mmol), N,N-Diisopropylethylamine (68 g, 525 mmol), ammonium chloride (18.7 g, 350 mmol) and HATU (66.5 g, 175 mmol) in N,N-Dimethyl-formamide (200 mL) was stirred at r.t. for overnight. The reaction mixture was added saturated sodium bicarbonate. After filtered, the filtrate was concentrated to 23 g of 9-Chloro-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene-2-carboxylic acid amide (yield: 94%) 1H-NMR (DMSO, 400 MHz): δ7.96 (d, J=18.4 Hz, 1H), 7.56 (s, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.31 (d, J=4.8 Hz, 1H), 4.33 (t, J=4.8 Hz, 2H), 3.19 (t, J=4.8 Hz, 2H). LC-MS (ESI): m/z=281 [M+H]+
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)=[O:5].[C:19]1([Mg]Br)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH4+].[Cl-]>C1COCC1>[C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7]1)(=[O:5])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
A stirred solution of tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (2.27 g, 8.8 mmol) in dry THF (40 mL) was cooled in an ice bath and 1 M PhMgBr in THF (20 mL, 20.0 mmol) was added dropwise over 2 min. The mixture was stirred and the ice bath was allowed to melt. After 3 h, the mixture was poured into satd aq NH4Cl and extracted with ether (2×200 mL). The combined ether extracts were dried over MgSO4 and concentrated to leave an oil. Flash chromatography on a 40-g silica cartridge eluted with a 0 to 50% EtOAc in hexanes gradient afforded tert-butyl 3-benzoylpyrrolidine-1-carboxylate (2.04 g, 84%) as a clear colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][C:11]2(OCC[O:18]2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:5][N:4]=[N:3]1.O.Cl>C(O)(=O)C>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:18])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCCCC1(c2ccccn2)OCCO1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cn1nnnc1SCCCC(=O)c1ccccn1
Yield: 83.4 %

Procedure:
1-Methyl-5-[4,4-ethylenedioxy-4-(2-pyridyl)butyl]thio-1,2,3,4-tetrazole (0.7 g) is dissolved in acetic acid (5 ml). Water (2.5 ml) and conc. hydrochloric acid (0.5 ml) are added to the solution and the mixture is heated on a water bath for 1 hour. Water is added to the reaction mixture and the mixture is extracted with chloroform. The chloroform solution is washed with water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and dried over magnesium sulfate. Chloroform is distilled off and the residue is purified by silica gel column chromatography (Kieselgel 60). The column is eluted with benzene-ether (10:1) and the product is recrystallized from hexane-ether to obtain 1-methyl-5-[3-(2-pyridylcarbonyl)propyl]thio-1,2,3,4-tetrazole, (0.5 g) as colorless needles, m.p. 73°-75° C.
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:43]=[CH:42][C:37]([C:38]([O:40]C)=O)=[CH:36][C:35]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)[N:21]=3)[C@H:14]2[CH3:51])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:54][NH2:55]>C(O)C>[F:52][C:2]([F:1])([F:53])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:43]=[CH:42][C:37]([C:38]([NH:54][NH2:55])=[O:40])=[CH:36][C:35]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)[N:21]=3)[C@H:14]2[CH3:51])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2cnc(OC)c(-c3cnc(N4CCOCC4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Reactant: NN
Solvent: CCO
Product: COc1ncc(-c2ccc(C(=O)NN)cc2C)cc1-c1cnc(N2CCOCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
Methyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(morpholin-4-yl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoate (EXAMPLE 39 Step A, 0.114 g, 0.153 mmol) was dissolved in ethanol (1.0 mL). Added hydrazine (0.144 mL, 4.59 mmol), and stirred at 85° C. in a screw cap vial (Pressure type) under a nitrogen blanket. Once complete, the solvent was removed by rotary evaporation and the crude isolate was partitioned between ethyl acetate and water. Washed the organic twice more with water, then once with brine, dried over sodium sulfate, filtered and evaporated to give an off-white foam as the product. The compound was used without further purification. 1H NMR (CDCl3, 500 MHz): δ 8.18 (m, 2H), 7.88 (s, 1H), 7.71 (m, 3H), 7.61 (d, 1H), 7.45 (d, 1H), 7.35 (s, 1H), 7.31 (d, 1H), 5.63 (d, 1H), 4.74 (d, 1H), 4.33 (m, 1H), 4.10 (m, 2H), 4.00 (m, s, 4H), 3.86 (m, 4H), 3.80 (m, 4H), 2.37 (s, 3H), 0.72 (d, 3H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:29])=[CH:24][CH:23]=3)[C:18]2=[O:37])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:36][O:35][C:33]([CH2:32][CH2:31][NH:30][C:28]([C:25]1[CH:24]=[CH:23][C:22]([N:19]2[CH2:20][CH2:21][N:17]([CH:14]3[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]3)[C:18]2=[O:37])=[CH:27][CH:26]=1)=[O:29])=[O:34]
Reactant: [H][H]
Reactant: COC(=O)CCNC(=O)c1ccc(N2CCN(C3CCN(C(=O)OCc4ccccc4)CC3)C2=O)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCNC(=O)c1ccc(N2CCN(C3CCNCC3)C2=O)cc1

Procedure:
Prepared by treating 1-(1-benzyloxycarbonyl-4-piperidinyl)-3-[4-[(2-methoxycarbonyl-ethyl)-aminocarbonyl]-phenyl]-imidazolidin-2-one with hydrogen at 3 bars in the presence of 5% palladium/charcoal in methanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:21])=[C:8]2[CH:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Cl:29])C(=O)C1.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:21])=[C:8]2[C:14]([Cl:29])=[CH:13][N:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1ncc2c(ccn2-c2ccccc2)c1O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ncc2c(c(Cl)cn2-c2ccccc2)c1O
Yield: 40 %

Procedure:
A mixture of 4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (223 mg, 0.789 mmol), NCS (117 mg, 0.869 mmol) and BzOOBz (10 mg, 0.039 mmol) in carbontetrachloride (4 mL) was refluxed for 30 min. Then the reaction was cooled and concentrated, the resulting mixture was purified by column to give the desired product (100 mg). The title compound, 1H NMR (200 MHz, CDCl3): δ (ppm)=11.8 (s, 1H), 8.44 (s, 1H), 7.6-7.4 (m, 5H), 7.35 (s, 1H), 4.53 (q, 2H, J=7.4 Hz), 1.49 (t, 3H, J=7.4 Hz).
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:19]([C:22]1[C:23]([NH:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[N:24][C:25]([Cl:28])=[CH:26][CH:27]=1)(=[O:21])[CH3:20]>C1COCC1>[C:5]([O:4][C:1](=[O:3])[CH2:2][C:19]([C:22]1[C:23]([NH:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[N:24][C:25]([Cl:28])=[CH:26][CH:27]=1)([OH:21])[CH3:20])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(=O)c1ccc(Cl)nc1NC(=O)C(C)(C)C
Reactant: CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(C)(O)c1ccc(Cl)nc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A first intermediate compound, 7-Chloro-4-methyl-1H-[1,8]naphthyridin-2-one, was produced as follows: A solution of tert-butyl acetate (0.6 mL, 4.45 mmol) is added dropwise to a solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 4.2 mL, 4.2 mmol) in THF (5 mL) at −78° C. The yellow solution is stirred for 1 hour and N-(3-acetyl-6-chloro-pyridin-2-yl)-2,2-dimethyl-propionamide (0.503 g, 1.97 mmol) in THF (5 mL) is added dropwise to the mixture. The yellow suspension is stirred at −78° C. for 30 minutes and warmed to RT. The suspension clears to a yellow solution and the mixture is stirred at room temperature for 1.5 hours. The mixture is quenched with water and extracted with CH2Cl2. The organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to a brown liquid. The liquid is purified by column chromatography (2:1 hexanes/ethyl acetate) to afford 3-[6-chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-butyric acid tert-butyl ester (0.548 g, 75%) as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ 10.40 (br s, 1H), 7.37 (d, 1H), 6.98 (d, 1H), 5.61 (s, 1H), 3.03 (d, 1H), 2.67 (d, 1H), 1.56 (s, 3H), 1.45 (s, 9H), 1.32 (s, 9H). MS ES: m/z=370.86, 372.56.