Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8](Br)[CH:9]=[CH2:10]>C(OCC)C>[CH2:10]([N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:9]=[CH2:8]
Reactant: C1CCCNCC1
Reactant: C=CCBr
Solvent: CCOCC
Product: C=CCN1CCCCCC1
Temperature: 5 °C

Procedure:
198.4 9 of homopiperidine dissolved in 280 mL of diethyl ether was added to a 1 L, 3-necked round-bottomed flask. The mixture was cooled to 5° C. with an ice bath and while stirring, 121 g of allyl bromide in 40 mL of diethyl ether was added slowly to this amine solution. After addition was complete, the reaction mixture was allowed to stir at room temperature for 18 hours. The white precipitate thus formed was filtered and ether was removed at room temperature using a rotary evaporator. The residual liquid was fractionally distilled yielding 72 9 of N-allylhomopiperidine. To a 500 mL 3-necked round-bottomed flask was added 41.8 g of N-allylhomopiperidine dissolved in 50 mL of diethyl ether. After cooling to 5° C. with an ice bath, 36.3 g of allyl bromide in 30 mL diethyl ether was added slowly. After completion of the addition of allyl bromide, the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 24 hours. The solid thus formed was collected by filtration and was washed twice with 1.5 L of diethyl ether. The washed solid was dried under vacuum yielding 67 g of N,N-diallyl-homopiperidinium bromide as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[C:9]([C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([CH3:29])[CH3:28])[CH:21]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][CH2:39][CH2:40][OH:41]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:16][CH2:38][CH2:39][CH2:40][OH:41])[CH:14]=2)[C:9]([C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([CH3:29])[CH3:28])[CH:21]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(C(=O)c2cccc(OC(C)C)c2)c2cc(OC)c(O)cc12
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(C(=O)c2cccc(OC(C)C)c2)c2cc(OC)c(OCCCO)cc12
Temperature: 85 °C
Yield: 99.6 %

Procedure:
To a stirred solution of 6-hydroxy-1-(3-isopropoxy-benzoyl)-7-methoxy-isoquinoline-4-carboxylic acid ethyl ester (30 mg, 0.073 mmol) in N,N-dimethylformamide (1 mL) was added potassium carbonate (81.1 mg, 0.58 mmol) and 3-bromo-1-propanol (0.033 mL, 0.22 mmol) at room temperature. The reaction mixture was heated 85° C. for 2 hrs. The solvent was evaporated and the residue was purified on a flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) to afford product 6-(3-hydroxy-propoxy)-1-(3-isopropoxy-benzoyl)-7-methoxy-isoquinoline-4-carboxylic acid ethyl ester as a colorless oil (34 mg, 99% yield).
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]1[N:11]=[CH:10][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:8]=1)(=[O:3])[CH3:2].Cl.CO>C1COCC1>[C:1]([S:4][CH2:5][CH2:6][C:7]1[N:11]=[CH:10][NH:9][N:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)SCCc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)SCCc1nc[nH]n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-(2-Acetylthioethyl)-1-triphenylmethyl-1,2,4-triazole (0.50) was dissolved in THF (2.5 ml). To the solution were added 10% hydrochloric acid (0.5 ml) and methanol (10 ml). The mixture was stirred for 1.5 hour at 25° C. The reaction mixture was concentrated, to which was added NaHCO3, to make the solution to be weakly basic, followed by extraction three times with THF-ethyl acetate (1:1, 10 ml). Organic layers were combined and dried over anhydrous magnesium sulfate, followed by concentration. The concentrate was purified by means of a column chromatography (carrier: silica gel, 20 g, developing solvent: acetone) to afford the title compound (134 mg) as a crystalline product, m.p.84-86° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=3)[NH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:25].[Na+]>>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([NH2:24])=[O:25])[CH:21]=3)[NH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: N#Cc1ccc2[nH]cc(CC3CCN(Cc4ccccc4)C3)c2c1
Agent: [Na+]
Product: NC(=O)c1ccc2[nH]cc(CC3CCN(Cc4ccccc4)C3)c2c1

Procedure:
0.47 mmol of the compound obtained in Example 14 and 1 g of polyphosphoric acid are heated at 85° C. for 90 minutes. The combined mixture is then hydrolyzed with a water/ice mixture and the pH of this solution brought to 11-12 using concentrated sodium hydroxide solution. After extraction with a chloroform/methanol (80/15) mixture, drying and evaporation, the expected product is purified by chromatography on a silica column, using a THF/hexane/methanol/aqueous ammonia (80/18/2/0.2) mixture as solvent.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:16].C[Li].[Li+].[Br-].[Li]C(CC)C.CN([CH:29]=[O:30])C>C1COCC1.CCOCC.C1CCCCC1>[F:12][C:11]([F:14])([F:13])[C:10]([NH:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([CH:29]=[O:30])=[C:3]([CH3:16])[CH:4]=1)=[O:15]
Reactant: Cc1cc(NC(=O)C(F)(F)F)cc(C)c1Br
Reactant: CN(C)C=O
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Solvent: C1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)C(F)(F)F)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of N-(4-bromo-3,5-dimethylphenyl)-2,2,2-trifluoroacetamide (U.S. Pat. No. 6,391,865) (14.0 g. 47.3 mmol) in THF (200 mL) under nitrogen atmosphere at −78° C. was added slowly methyllithium/LiBr (44.1 mL of a 1.5 M solution in Et2O, 66.2 mmol). After 5 min of stirring, sec-BuLi (47.3 mL of a 1.4 M solution in cyclohexane, 66.2 mmol) was added slowly to the reaction solution at −78° C. After 5 min, anhydrous DMF (25.5 mL, 331 mmol) was added slowly then the solution was warmed to 25° C. After 30 min the reaction mixture was quenched with water. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were washed with water, brine, dried over MgSO4 and filtered. The solvent was removed under reduced pressure to give the title compound as a yellow solid. MS: m/z 246 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)[C:3]=1[C:4]#[N:5].[CH3:16][N+:17]([CH3:19])=[CH2:18].[I-]>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[C:14]([CH2:16][N:17]([CH3:19])[CH3:18])=[C:13]([CH3:15])[N:12]=[CH:11]2)[C:3]=1[C:4]#[N:5]
Reactant: C=[N+](C)C
Reactant: Cc1cn(-c2cccc(Cl)c2C#N)cn1
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2cccc(Cl)c2C#N)c1CN(C)C
Yield: 29 %

Procedure:
In analogy to example 5b, 2-chloro-6-(4-methyl-imidazol-1-yl)-benzonitrile was reacted with Eschenmoser's salt in DMF for 5 h at 90° C. Evaporation of the solvent, extractive workup and chromatography (SiO2, dichloromethane:methanol=100:0 to 98:2) afforded the title compound as a white solid (yield: 29%). MS: m/e=275.1 [M+H]+.
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[N:12]([O-])=[O:13].[Na+]>C(O)(=O)C.O>[OH:13][N:12]=[C:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: O=N[O-]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)C(=NO)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
t-Butyl acetoacetate (5.0 g, 31.6 mmol) was dissolved in acetic acid (4.5 mL), cooled by an ice water bath, and treated with sodium nitrite (2.45 g, 35.5 mmol) in water (5.5 mL) while the internal temperature was kept at <10° C. (see, e.g., U.S. Pat. No. 4,743,586). After the addition was complete, the mixture was stirred at rt for 30 minutes before water (16 mL) was added. After 2 h, extraction with ether (3×25 mL), which was washed with water (10 mL), sodium bicarbonate solution (3×10 mL), and water (20 mL), gave t-butyl 2-hydroxyimino-3-oxobutanoate as a white solid (5.52 g, 93%): 1H NMR (300 MHz, CDCl3) δ 8.61 (s, 1H), 2.39 (s, 3H), 1.58 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28]([C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)=O>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH:27]=[C:28]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)[N:20]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Reactant: O=C(CBr)c1ccc2ccccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(-n2cc(-c3ccc4ccccc4c3)nc2-c2ccc(Cl)cc2)cc1
Yield: 53.7 %

Procedure:
To a mixture of 4-chloro-N-(4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (400 mg, 1.29 mmol) and sodium bicarbonate (216 mg, 2.59 mmol) in isopropanol (30 mL), 2-bromo-2′-acetonaphthone (970 mg, 3.89 mmol) was added. After heating the reaction mixture at 80–85° C. for 20 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with aqueous sodium bicarbonate and water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product (1.2 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 2-(4-chlorophenyl)-1-(4-(methylsulfonyl)phenyl]-4-(2-naphthyl)-1H-imidazole (318 mg, 54%) as a pale yellow solid: mp 204–206° C. Anal Calc'd. for C26H19N2SO2Cl: C, 68.04; H, 4.17; N, 6.10; S, 6.99. Found: C, 67.65; H, 4.19; N, 5.96; S, 7.10.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1.[CH3:29][C@@H:30]1[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[NH:31]1>>[CH3:28][S:25]([C:4]1[CH:3]=[C:2]([N:31]2[C@H:30]([CH3:29])[CH2:34][CH2:33][S:32]2(=[O:36])=[O:35])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=2)[CH2:12][CH2:11]1)=[O:9])(=[O:27])=[O:26]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)nc1C
Reactant: C[C@@H]1CCS(=O)(=O)N1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4[C@H](C)CCS4(=O)=O)cc3S(C)(=O)=O)CC2)nc1C
Yield: 48.5 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (370 mg) described in Preparation Example 122 and (R)-3-methylisothiazolidine 1,1-dioxide (107 mg) described in Preparation Example 2 and by the reaction and treatment in the same manner as in Example 4, the title compound (200 mg) was obtained.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@H:10]1[C:18]2[C:13](=[CH:14][C:15]([CH3:22])=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=2)[CH2:12][CH2:11]1.[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>C(Cl)Cl>[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH:9][C@H:10]1[C:18]2[C:13](=[CH:14][C:15]([CH3:22])=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=2)[CH2:12][CH2:11]1)=[O:27]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Cc1cc2c(cc1C(=O)O)[C@H](N)CC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc2c(cc1C(=O)O)[C@H](NC(=O)c1ccccc1Cl)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
Triethylamine (4.707 mmol, 1.5 eq.) was added to a solution of (R)-3-amino-6-methyl-2,3-dihydro-1H-indene-5-carboxylic acid hydrochloride (commercially available from NetChem) (1 eq., 3.138 mmol) in methylene chloride (16 ml) at 0° C. 2-Chlorobenzoyl chloride (1.2 eq.) was added dropwise to the reaction mixture at the same temperature and the mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with methylene chloride (50 ml), and washed with NH4Cl solution (20 ml) and sat. NaCl solution (20 ml). The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo. The crude material was purified by column chromatography (silica, ethyl acetate/cyclohexane 3:2) to yield the desired product (E-12). Yield: 43%
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CS(C)=O.O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:2]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)=[CH:17][CH:18]=1
Reactant: C1CCNC1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCC3)nc2c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (130 mg, 0.41 mmol) in DMSO (2 mL) was added pyrrolidine (58 mg, 0.82 mmol) and DIEA (106 mg, 0.82 mmol). After stirring 2 h at 70° C., the reaction mixture was dissolved in water (100 mL), extracted with dichloromethane (3×30 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified via silica gel column chromatography (2% dichloromethane in petroleum ether) to afford methyl 2-(4-fluorophenyl)-3-(pyrrolidin-1-yl)quinoxaline-6-carboxylate as a light yellow solid (72 mg, 50%).
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+].C>ClCCl.C(OCC)C>[CH2:1]([S:8][CH2:9][CH:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(CO)CSCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)C(C=O)CSCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
A solution of 2-benzylthiomethyl-3,3-dimethylbutanol (3.7 g) in dry dichloromethane (15 ml) was added to a mechanically stirred suspension of pyridinium chlorochromate (10 g) and sodium acetate (1 g) in dichloromethane (100 ml) at 0° C. The resulting mixture was stirred at room temperature for two hours and then diethylether (300 ml) was added. The reaction mixture was passed through a short column of silica and charcoal (1:1) and then evaporated in vacuo to leave 2-benzylthiomethyl-3,3-dimethylbutanal as an oil (1.42 g).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH2:7])[CH:4]=[C:3]2[CH2:8][O:9][CH2:10][CH2:11][C:2]=12.[F:12][C:13]([F:31])([F:30])[C:14]([C:17]1[CH:26]=[CH:25][C:24]2[CH2:23][C@@H:22]([C:27](O)=[O:28])[CH2:21][CH2:20][C:19]=2[N:18]=1)([CH3:16])[CH3:15].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:1]1[CH:6]=[C:5]([NH:7][C:27]([CH:22]2[CH2:21][CH2:20][C:19]3[N:18]=[C:17]([C:14]([CH3:16])([CH3:15])[C:13]([F:31])([F:30])[F:12])[CH:26]=[CH:25][C:24]=3[CH2:23]2)=[O:28])[CH:4]=[C:3]2[CH2:8][O:9][CH2:10][CH2:11][C:2]=12
Reactant: CC(C)(c1ccc2c(n1)CC[C@H](C(=O)O)C2)C(F)(F)F
Reactant: Nc1cnc2c(c1)COCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(c1ccc2c(n1)CCC(C(=O)Nc1cnc3c(c1)COCC3)C2)C(F)(F)F
Temperature: 60 °C
Yield: 75.2 %

Procedure:
To a mixture of 7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-ylamine (36 mg, 0.24 mmol), (S)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (38 mg, 0.13 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (136 mg, 0.36 mmol) in DMF (1 mL), N,N-diisopropylethylamine (0.1 mL, 0.6 mmol) was added and the reaction was heated at 60° C. for 16 hours. The crude was purified by semi-preparative HPLC (55-75 gradient) to give the titled amide (41 mg, 74%). m/z=420.2 (M+1)+. HPLC: 10.31 min. NMR (400 MHz; d6-DMSO) δ 10.21 (s, 1H), 8.51 (d, 1H, J=2.5 Hz), 7.82 (d, 1H, J=2.3 Hz), 7.56 (d, 1H, J=8.1 Hz), 7.37 (d, 1H, J=8.1 Hz), 4.68 (s, 2H), 3.95 (t, 2H, J=5.9 Hz), 2.97-2.80 (m, 7H), 2.19-2.14 (m, 1H), 1.95-1.85 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:13][C:14]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:15]=1[C:16](O)=[O:17].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:16](=[O:17])[C:15]3[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:14]=3[F:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: Cc1ccc(F)c(C(=O)O)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(F)c(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)c1
Yield: 62.9 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 2-fluoro-5-methylbenzoic acid (281 mg, 1.83 mmol), BOP-Cl (465 mg, 1.83 mmol), and triethylamine (0.606 mL, 4.35 mmol) in DCM (5 mL) was processed as described in Example 62, Step A, to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-fluoro-5-methylbenzamide (200 mg, 63% yield).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[N:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CS(O[CH2:41][CH2:42][CH2:43][N:44]1[CH2:50][CH:49]([OH:51])[C:46]2([CH2:48][CH2:47]2)[CH2:45]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:51][CH:49]1[C:46]2([CH2:48][CH2:47]2)[CH2:45][N:44]([CH2:43][CH2:42][CH2:41][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]5[C:23](=[O:35])[N:24]([C:29]6[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=6)[N:25]([CH3:28])[C:26]=5[CH3:27])=[O:21])=[N:17][CH:18]=4)=[CH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)[CH2:50]1
Reactant: CS(=O)(=O)OCCCN1CC(O)C2(CC2)C1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)cn2)c(=O)n(-c2ccccc2)n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCCN5CC(O)C6(CC6)C5)ccc34)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
To a solution of N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (300 mg, 0.642 mmol) in DMA (3 mL) was added 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (240 mg, 0.963 mmol) and Cs2CO3 (417 mg, 1.284 mmol). The reaction was stirred at rt for 24 hrs. The solvent was removed and the residue was partioned between saturated NaHCO3 aqueous solution (15 mL) and CHCl3 (30 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (100:15:1(v/v/v)EtOAc/CH3OH/Et3N) to afford the title compound as a white solid (259 mg, 65%).
Reaction SMILES: C(N)CCCCC.C(C(CN)O)CCCCC.[CH2:18]([N:24](CCO)[CH2:25][CH2:26][OH:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>O>[CH2:18]([NH:24][CH2:25][CH2:26][OH:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCN(CCO)CCO
Agent: CCCCCCC(O)CN
Solvent: CCCCCCN
Solvent: O
Product: CCCCCCNCCO

Procedure:
This procedure outlines the steps involved in ethoxylating n-hexyl amine to n-hexyl ethanolamine and n-hexyl diethanolamine. A suitable reactor must have cooling water, a heat source of 350° F., and pressure rating of 100 psig. The material of construction may be carbon steel, stainless steel, or glass-lined steel.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:14])[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9][CH2:8]1)[CH3:3].C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>ClCCl>[CH2:2]([O:4][C:5](=[O:14])[CH2:6][C@H:7]1[CH2:8][CH2:9][C@H:10]([NH:13][C:22](=[O:24])[CH3:23])[CH2:11][CH2:12]1)[CH3:3]
Reactant: CCOC(=O)C[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1CC[C@H](NC(C)=O)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Trans-(4-Amino-cyclohexyl)-acetic acid ethyl ester hydrochloride (1.0 g, 4.51 mmol) (Example A, step 2) was dissolved in dichloromethane and triethylamine (1.89 ml, 13.5 mmol) was added. Acetyl chloride (0.35 ml, 4.96 mmol) was added drop wise and the reaction mixture stirred for 5 hours at room temperature. The reaction mixture was quenched with saturated NaHCO3-solution and extracted with dichloromethane. The organic extracts were washed with brine, dried with sodium sulfate, filtered and evaporated. The crude product (804 mg, 78%) [MS: m/e=228.3/229.3 (M+H+)] was obtained as a white solid and used without any further purification for the next step.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:10]([C:20]2[CH:25]=[C:24](C#N)[CH:23]=[CH:22][N:21]=2)[N:9]=1)(C)(C)C.[C:29]([OH:35])(C(F)(F)F)=[O:30]>>[NH2:7][C:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)[N:10]([C:20]2[CH:25]=[C:24]([C:29]([OH:35])=[O:30])[CH:23]=[CH:22][N:21]=2)[N:9]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccc(-c2cc(NC(=O)OC(C)(C)C)nn2-c2cc(C#N)ccn2)cc1
Product: Cc1ccc(-c2cc(N)nn2-c2cc(C(=O)O)ccn2)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
A solution of tert-butyl[1-(4-cyanopyridin-2-yl)-5-(4-methylphenyl)-1H-pyrazol-3-yl]carbamate (150 mg, 0.4 mmol) in TFA (2 mL) was heated to 50° C. for 30 min and evaporated to an oily residue. To the residue was added 10 N NaOH (2 mL) followed by MeOH (2 mL). The solution was stirred at 70° C. for 4 h and then cooled to rt. Solvent was evaporated, and the pH of the resulting aqueous phase was carefully adjusted to pH=5.5 using conc. HCl and then 1N HCl. The resulting mixture was extracted with EtOAc (2×20 mL). The organic layers were dried (MgSO4), filtered, concentrated to an oil, and purified by flash column chromatography (MeOH/EtOAc=5:95) to give the title compound (56 mg, 48%) as a beige solid. 1H NMR (400 MHz, DMSO-d6): δ 2.28 (3H, s), 5.73 (1H, s), 5.82 (1H, s), 7.05˜7.18 (4H, m), 7.51 (1H, d, J=5.2 Hz), 8.02 (1H, s), 8.22 (1H, d, J=5.2 Hz). [M+H] Calc'd for C16H14N4O2, 295; Found, 295.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.C(O)(=O)C.C(NC(=O)[O-])C.[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]2[CH:25]([CH3:33])[CH:26]3[CH2:30][NH:29][CH2:28][CH:27]3[C:31]=2[CH:32]=1>ClCCCl.C(Cl)Cl>[Cl:1][C:32]1[C:31]2[CH:27]3[CH2:28][NH:29][CH2:30][CH:26]3[CH:25]([CH3:33])[C:24]=2[CH:23]=[CH:22][C:21]=1[O:20][CH3:19]
Reactant: COc1ccc2c(c1)C1CNCC1C2C
Reactant: O=C1CCC(=O)N1Cl
Agent: CCNC(=O)[O-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc2c(c1Cl)C1CNCC1C2C
Temperature: 60 °C
Reaction time: 3 h
Yield: 7.3 %

Procedure:
N-chlorosuccinimide (0.39 g, 2.9 mmol) and acetic acid (3 mL) were added to a solution of N-ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 2, Step A) (0.80 g, 2.9 mmol) in DCE (3 mL). The resulting solution was stirred for 3 hours at 60° C. The reaction mixture was cooled to room temperature, diluted with CH2Cl2 (50 mL), and washed with H2O (50 mL). The organic extract was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (SiO2) using a 0-35% EtOAc-hexanes gradient to afford 50 mg (6%) of the subtitle compound (The major product is N-ethylcarbamate-5-methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole, 78%). MS calculated for C16H20ClNO3+H: 310, observed: 310.