Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13](=[O:40])[CH2:14][O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]#[N:39])[CH:33]=4)[N:31]=2)[N:28]=[CH:27][CH:26]=[CH:25]3)[CH2:18][CH2:17]1)(C)(C)C>C(Cl)Cl>[C:38]([C:34]1[CH:33]=[C:32]([C:30]2[N:31]=[C:22]([N:19]3[CH2:20][CH2:21][CH:16]([O:15][CH2:14][C:13]([OH:40])=[O:12])[CH2:17][CH2:18]3)[CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)[CH:37]=[CH:36][CH:35]=1)#[N:39]
Reactant: CC(C)(C)OC(=O)COC1CCN(c2cc3cccnc3c(-c3cccc(C#N)c3)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(-c2nc(N3CCC(OCC(=O)O)CC3)cc3cccnc23)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
TFA (1 ml) is added to a solution of {1-[8-(3-cyano-phenyl)-[1,7]naphthyridin-6-yl]-piperidin-4-yloxy}-acetic acid tert-butyl ester (200 mg, 0.45 mmol) in CH2Cl2 (2 ml) at 0° C. The reaction mixture is stirred at 0° C. for 10 minutes then at room temperature for 1.5 hours and is then concentrated. The residue is partitioned between ethyl acetate and water and the aqueous layer is adjusted to pH 5 with 1M KOH. The aqueous layer is extracted with ethyl acetate (×3) and the combined ethyl acetate extracts are dried (MgSO4), filtered and concentrated. Purification by chromatography on silica gel, eluting with 1% MeOH in CH2Cl2 gives the product. MS (ES+) Observed [M+H]+3 89.05
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:39])[C@@H:28]([NH2:38])[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:23][CH2:22]1)=[O:20])[CH3:17].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:16]([O:18][C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:39])[C@@H:28]([NH:38][C:13]([C:4]2[CH:3]=[C:2]([OH:1])[N:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:5]=2)=[O:15])[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:25][CH2:26]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Reactant: O=C(O)c1cc(O)n(-c2ccccc2)n1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.3 g of 5-Hydroxy-1-phenyl-1H-pyrazole-3-carboxylic acid and 2.2 g of 4-((S)-2-Amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 80 ml of DMF, 0.9 g of HOBT and 1.3 g of EDC was added and the reaction mixture was stirred for 2 h at RT. Then, the reaction mixture was diluted with water and extracted with DCM. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 2.7 g.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12](Cl)=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][CH2:16]1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([C:22]2[CH:21]=[CH:20][C:19]3[O:15][CH2:16][CH2:17][C:18]=3[CH:23]=2)=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CCC(=O)Cl)CC1
Reactant: c1ccc2c(c1)CCO2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)N1CCC(CCC(=O)c2ccc3c(c2)CCO3)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To 200 ml of 1,2-dichloroethane were added 9.65 g (44 mmol) of 3-(1-acetylpiperidin-4-yl)propionic acid chloride and 10.65 g (89 mmol), of 2,3-dihydrobenzofuran. To the mixture was added 12.82 g (96 mmol) of aluminum chloride in limited amounts, then the mixture was stirred for 3 hours at room temperature. The reaction mixture was poured into ice-water, which was subjected to extraction with methylene chloride. Organic layers were combined and washed with water and dried over anhydrous sodium sulfate, followed by distilling off the solvent. The residue was purified by means of a silica gel column chromatography (ethyl acetate) to give 10.47 g (78%) of 5-[3-(1-acetylpiperidin-4-yl)-1-oxopropyl]-2,3-dihydrobenzofuran. Recrystallization from methylene chloride--diethyl ether gave colorless needles, m.p. 93°-95° C.
Reaction SMILES: [IH:1].CS[C:4]1[NH:5][CH2:6][CH:7]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[N:8]=1.[CH2:17]([CH2:19][NH2:20])[OH:18].CCOCC>C(O)C>[IH:1].[OH:18][CH2:17][CH2:19][NH:20][C:4]1[NH:5][CH2:6][CH:7]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[N:8]=1
Reactant: NCCO
Reactant: CSC1=NC(c2c(Cl)cccc2Cl)CN1
Agent: I
Solvent: CCOCC
Solvent: CCO
Product: OCCNC1=NC(c2c(Cl)cccc2Cl)CN1
Temperature: 130 °C

Procedure:
5.0 gm (0.0129 mol) of 2-methylmercapto-4-(2',6'-dichloro-phenyl)-2-imidazoline hydroiodide and 7.9 gm (0.13 mol) of ethanolamine were dissolved in 30 ml of ethanol, and the solution was heated in an autoclave for 3 hours at 130° C. Thereafter, the reaction solution was cooled and then admixed with ether, and the crystals precipitated thereby were collected, washed with acetone and recrystallized from ethanol/ether, yielding 1.5 gm (29% of theory) of the pure compound of the formula ##STR14##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[C:15](OCC)(=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].[Na]>>[CH2:19]([O:18][C:16](=[O:17])/[C:15](/[OH:21])=[CH:9]/[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:11]([F:12])([F:13])[F:14])[CH:4]=1)=[O:10])[CH3:20]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(F)c(C(F)(F)F)c1
Agent: [Na]
Product: CCOC(=O)/C(O)=C/C(=O)c1ccc(F)c(C(F)(F)F)c1

Procedure:
In analogy to the procedure described for example 11 a], 1-(4-fluoro-3-trifluoromethyl-phenyl)-ethanone was reacted with diethyl oxalate in the presence of metallic sodium to give (Z)-4-(4-fluoro-3-trifluoromethyl-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid ethyl ester as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1.[CH:27]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([NH:22][S:33]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)(=[O:35])=[O:34])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Reactant: O=S(=O)(Cl)C1CCCCC1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)C1CCCCC1
Reaction time: 8 h
Yield: 37.2 %

Procedure:
3-(5-(2-Chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline (200 mg, 0.510 mmol) was suspended in pyridine (2 mL) and after 5 min, cyclohexanesulfonyl chloride (0.148 mL 1.021 mmol) was added. The mixture was stirred overnight. Additional cyclohexanesulfonyl chloride (0.100 mL 0.69 mmol) was added and stirred overnight. Silica gel was added the reaction mixture and concentrated. The crude product was chromatographed on silica gel eluting with DCM and 9:1 (EtOAc:MeOH). The product was chromatographed again with 9:1 hexane:EtOAc increasing to 1:1 gradient. The clean fractions were concentrated to yield the title compound of Step A (102 mg, 37% yield). A second reaction was run (46 mg, 17% yield) same scale and combined to yield the title compound of Step A (148 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.70 (s, 1H) 8.34 (d, J=5.5 Hz, 1H) 7.55 (td, J=7.6, 2.0 Hz, 2H) 7.14-7.38 (m, 3H) 6.65 (d, J=5.5 Hz, 1H) 3.68 (t, J=4.7 Hz, 4H) 3.52 (t, J=4.6 Hz, 4H) 2.79-3.04 (m, 1H) 2.01 (d, J=11.4 Hz, 2H) 1.69 (d, J=13.0 Hz, 3H) 1.47-1.63 (m, 2H) 1.26-1.42 (m, 3H) 0.84 (t, J=7.4 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-])=O.[CH3:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20]O)[CH2:13]1.CO.O.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([OH:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(OCC)(=O)C>[S:31]([C:28]1[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=1)([OH:34])(=[O:33])=[O:32].[CH3:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][O:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:13]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: C[C@H]1CCCN(CCCO)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H]1CCCN(CCCOc2ccc(N)cc2)C1

Procedure:
4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}aniline was obtained as a light brown oily substance by the method according to Example 18, using 4-nitrophenol and 3-[(3S)-3-methylpiperidin-1-yl]propan-1-ol as starting materials. The obtained oily substance was dissolved in ethyl acetate, 1 Eq of a methanol solution of p-toluenesulfonic acid monohydrate was added, and the target compound was obtained as a light peach-colored solid by filtering off the solid produced.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.CC1(C)C(C)(C)OB([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[O:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)=[CH:3]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Brc1coc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2coc3ccccc23)CC1
Temperature: 85 °C
Reaction time: 17 h
Yield: 54.2 %

Procedure:
A mixture of commercially available 3-bromobenzofurane (2.50 g, 12.7 mmol) and commercially available tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (4.32 g, 14.0 mmol) in 1,2-dimethoxyethane (85 ml) and 2M sodium carbonate solution (21.1 ml, 42.3 mmol) was purged with argon in an ultrasonic bath during 5 min. Then triphenylphosphine (666 mg, 2.54 mmol) and palladium(II)acetate (285 mg, 1.27 mmol) were added and the reaction mixture was allowed to stir at 85° C. for 17 h. The reaction mixture was cooled to room temperature, poured into water (30 ml) and extracted with diethyl ether (2×120 ml). The combined organic layers were washed with brine (60 ml), dried (MgSO4) and evaporated. The crude product (5.78 g) was further purified by flash chromatography on silica gel (heptane/ethyl acetate 4:1) to yield tert-butyl 4-(benzofuran-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate as a yellow oil (2.06 g, 54%), MS (ISP) m/z=300.2 [(M+H)+].
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17]>>[C:16]([C:15]1[CH:14]=[C:13]([CH:20]=[CH:19][CH:18]=1)[O:12][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5])#[N:17]
Reactant: N#Cc1cccc(O)c1
Reactant: N#Cc1cc(C=O)ccc1F
Product: N#Cc1cccc(Oc2ccc(C=O)cc2C#N)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 3-hydroxybenzonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][N+:3]=1[O-].[OH-].[Na+]>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([CH3:11])=[CH:4][N:3]=1
Reactant: Cc1c[n+]([O-])c(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cnc(Br)cc1N
Temperature: 100 °C
Yield: 53.1 %

Procedure:
To a solution of 2-bromo-5-methyl-4-nitropyridine 1-oxide (0.5 g, 2.146 mmol) in acetic acid (10 mL) at 25° C. was added iron (0.479 g, 8.58 mmol). The reaction was heated to 100° C. for 30 minutes, then cooled to room temperature, poured into NaOH (1N, 30 mL), extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to dryness to give 2-bromo-5-methylpyridin-4-amine (213 mg, 53.1% yield) as a brown solid which was used without further purification. ESI-MS: m/z 187.0 (M+H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:24])[C:10](OC)=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C(=O)C)=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.[C:25](=O)([O-])[O-:26].[K+].[K+]>CO>[CH3:1][CH:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[C:16]([O:26][CH3:25])[CH:17]=2)[CH2:6][CH2:7]1
Reactant: COC(=Cc1ccc(OC(C)=O)cc1)C(=O)NC1CCC(C)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cc(C=CC(=O)NC2CCC(C)CC2)ccc1O
Yield: 83.4 %

Procedure:
Using 4.31 g of N-(4-methylcyclohexyl)-4-acetoxy-methoxycinnamamide (Example 61), 100 ml of methanol, and 10 g of potassium carbonate, a reaction similar to that conducted in Example 54 was carried out. As a result, 3.14 g of N-(4-methylcyclohexyl)-4-hydroxy-3-methoxycinnamamide (a compound of the present invention) was obtained as pale yellowish white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2([C:22]([NH2:24])=[O:23])[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[CH:25](OCC)(OCC)OCC>>[CH2:15]([N:12]1[CH2:11][CH2:10][C:9]2([N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[CH:25]=[N:24][C:22]2=[O:23])[CH2:14][CH2:13]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cccc(NC2(C(N)=O)CCN(Cc3ccccc3)CC2)c1
Reactant: CCOC(OCC)OCC
Product: Cc1cccc(N2C=NC(=O)C23CCN(Cc2ccccc2)CC3)c1
Temperature: 150 °C
Reaction time: 66 h

Procedure:
4-(3-methyl-phenyl-amino)-1-(phenylmethyl)-4-piperidine-carboxamide (12.94 g) was dissolved in 80 ml triethyl orthoformate and stirred at 150° C. for 66 hours. After cooling to 0° C., the reaction mixture was filtered and the light brown powder washed with ether to yield 8-benzyl-1-(3-methyl-phenyl)-1,3,8-triazaspiro[4,5]dec-2-en-4-one (2.1g). M.p. 301.5-302.6° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:30])[CH:24]=[CH:23][CH:22]=[C:21](/[CH:25]=[CH:26]/[C:27](O)=[O:28])[CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:27](=[O:28])/[CH:26]=[CH:25]/[C:21]3[CH:20]=[C:19]([CH3:30])[CH:24]=[CH:23][CH:22]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: Cc1cccc(/C=C/C(=O)O)c1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)/C=C/c3cccc(C)c3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and (E)-3-m-tolyl-acrylic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)=[C:10]([CH3:20])[S:9][C:4]=2[NH:5][C:6](=[O:8])[CH:7]=1.[C:21](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:20][C:10]1[S:9][C:4]2[N:5]=[C:6]([O:8][CH3:21])[CH:7]=[C:2]([NH2:1])[C:3]=2[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(-c2c(C)sc3[nH]c(=O)cc(N)c23)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc(-c2c(C)sc3nc(OC)cc(N)c23)c1
Temperature: 90 °C
Yield: 13.1 %

Procedure:
To a suspension of 4-amino-2-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-6(7H)-one (Description 36) (120 mg, 0.419 mmol) in DMF (3 mL) was added potassium carbonate (116 mg, 0.838 mmol) and methyl iodide (0.029 mL, 0.461 mmol). The suspension was then heated to 90° C. under nitrogen atmosphere for ca. 2 hand then cooled to RT, quenched with water (ca. 25 mL) and extracted with ethyl acetate (ca. 25 mL×2). The combined organic layers were passed through a phase separator and solvent concentrated in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-100% ethyl acetate in DCM followed by 0-20% MeOH in DCM, to afford the title compound (16.5 mg). LCMS (A) m/z: 301 [M+1]+, Rt 1.21 min (acidic).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27][N:26]=4)[CH2:21][CH2:20]3)=O)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH:19]3[CH2:20][CH2:21][N:22]([C:25]4[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27][N:26]=4)[CH2:23][CH2:24]3)[CH2:15][CH2:16]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1cc(N2CCC(C(=O)N3CCN(S(=O)(=O)c4ccc(Br)cc4)CC3)CC2)ncn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(N2CCC(CN3CCN(S(=O)(=O)c4ccc(Br)cc4)CC3)CC2)ncn1
Reaction time: 18 h
Yield: 45 %

Procedure:
1-(4-Bromophenylsulphonyl)-4-[1-(6-methylpyrimidin-4-yl)-4-piperidylcarbonyl]piperazine (630 mg) suspended in dry THF (10 ml) was treated with excess borane methyl sulphide complex (0.59 ml) at ambient temprature, then at 45° C. for 18 hours. 5M HCl (1.0 ml) was added and stirred for 2 hours. The reaction mixture was basified with 4M NaOH solution. then partitioned between ethylacetate and water. dried (MgSO4), and evaporated. The residue was chromatographed on Bondelut (CH2Cl2 then 1% MeOH/CH2Cl2,2% MeOH/CH2Cl2) to give 1-(4-bromophenylsulphonyl)-4-[1-(6-methylpyrimidin-4-yl)-4-piperidylmethyl]piperazine (276 mg) as a gum.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][N:7]=[CH:6]1.C(Br)(Br)(Br)[Br:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:11][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][N:7]=[CH:6]1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCN1C=NCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrCCCN1C=NCC1
Yield: 61.5 %

Procedure:
A solution of 1-(3-hydroxypropyl)-4,5-dihydroimidazole (1.0 g, 3.65 mmol) in tetrahydrofuran (15 ml) was reacted with carbon tetrabromide (1.43 g, 5.47 mmol) and triphenylphosphine (1.43 g, 5.47 mmol) at ambient temperature for 18 hours. Solvent evaporation in vacuo and purification by flash chromatography on silica gel, eluting with 10% methanol in dichloromethane, yielded 1-(3-bromopropyl)-4,5-dihydroimidazole (429 mg, 35% yield) as a white solid:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]2=[O:20])[C:3]=1[CH3:21].C=O.[C:24](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([BH3-])#N.[Na+]>ClC(Cl)C.C(Cl)Cl.O.CO>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([CH3:24])[CH2:16][C:15]2=[O:20])[C:3]=1[CH3:21]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1c(N2CCNCC2=O)nc2cc(F)cc(F)c2c1Cl
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1c(N2CCN(C)CC2=O)nc2cc(F)cc(F)c2c1Cl
Reaction time: 6.5 h

Procedure:
The 1-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)piperazin-2-one (52.0 mg, 0.167 mmol) and paraformaldehyde (5.01 mg, 0.167 mmol) were dissolved in 1.5 mL of a 2:1 dichloroethane:MeOH solution. The sodium triacetoxyborohydride (106 mg, 0.500 mmol) was added and the reaction mixture was stirred for 6.5 h. The reaction by LCMS had only progressed ˜30%. Some sodium cyanoborohydride (50 mg, 0.796 mmol) was added turning the mixture into a solution again and stirred overnight. The reaction was then diluted with DCM and water. The layers were separated and the organic layer was washed with brine (1×10 mL) and dried over magnesium sulfate to give crude 1-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-4-methylpiperazin-2-one. Mass Spectrum (ESI) m/e=312.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:30]3[CH2:29][CH2:28][CH2:27][NH:26][C:25]=3[CH:24]=[N:23]2)=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:30]3[CH2:29][CH2:28][CH2:27][N:26]([C:10](=[O:12])[CH2:9][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:13])=[CH:8][CH:7]=4)[C:25]=3[CH:24]=[N:23]2)=[CH:20][CH:21]=1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Product: O=C(Cc1ccc(C(F)(F)F)cc1)N1CCCc2c1cnn2-c1ccc(F)cc1
Yield: 64 %

Procedure:
The compound was prepared from 4-trifluoromethylphenylacetic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method B. The product mixture was washed with 1 M NaHSO4. The reaction slurry was purified by flash chromatography (SiO2, 24 g column, eluting with 5-50% EtOAc in hexanes) to provide 77 mg (64%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.45 (s, 0.8H), 7.62 (d, J=7.8 Hz, 2H), 7.55 (s, 0.2H), 7.40-7.49 (m, 4H), 7.15 (m, 2H), 4.08 (s, 0.3H), 3.96 (m, 2H), 3.75 (m, 1.7H), 2.80-2.86 (m, 2H), 2.00 (m, 2H); MS: (ES) m/z calculated for C21H18F4N3O [M+H]+ 404.1, found 404.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH:6]=[CH:5][C:4]=1[C:14]1[C:23]2[C:18](=[CH:19][C:20]([S:24]([NH:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][N:29]=3)(=[O:26])=[O:25])=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.[Cl:34]N1C(C)(C)C(=O)N(Cl)C1=O>CO>[Cl:34][C:11]1[S:10][C:9]([C:7]2[CH:6]=[CH:5][C:4]([C:14]3[C:23]4[C:18](=[CH:19][C:20]([S:24]([NH:27][C:28]5[CH:33]=[CH:32][N:31]=[CH:30][N:29]=5)(=[O:26])=[O:25])=[CH:21][CH:22]=4)[CH:17]=[CH:16][N:15]=3)=[C:3]([O:2][CH3:1])[CH:8]=2)=[N:13][CH:12]=1
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: COc1cc(-c2nccs2)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Solvent: CO
Product: COc1cc(-c2ncc(Cl)s2)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.7 %

Procedure:
A solution of 1-(2-methoxy-4-(thiazol-2-yl)phenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.100 g, 0.210 mmol) in 2 mL MeOH was treated with 1,3-dichloro-5,5-dimethylhydantoin (0.028 ml, 0.210 mmol) and was allowed to stir overnight at room temperature then was heated to reflux for two hours. LC/MS showed product, so the reaction mixture was concentrated. Purification of the crude residue by reverse phase column chromatography [Puriflash C18 30μ, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 1-(4-(5-chlorothiazol-2-yl)-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.006 g, 0.012 mmol, 5.59% yield). 1H NMR (MeCN-d3) δ: 8.60-8.64 (m, 1H), 8.52-8.56 (m, 1H), 8.10-8.13 (m, 1H), 8.05-8.09 (m, 1H), 7.95-8.00 (m, 1H), 7.91-7.95 (m, 1H), 7.87-7.91 (m, 1H), 7.74-7.78 (m, 1H), 7.66-7.74 (m, 2H), 7.57-7.61 (m, 1H), 7.42-7.47 (m, 1H), 3.76 (s, 3H); (M+H)+=510.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:49])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)[CH:36]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:49])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)[CH:36]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(COC3CCCCO3)c2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(COC4CCCCO4)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (4.40 g, 15.0 mmol) and (RS)-3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionic acid tert-butyl ester (Example K40) (6.24 g, 15.0 mmol) according to the general procedure M. Obtained as a light yellow foam (6.20 g, 65%).