Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH2:12].[OH-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:12][CH2:11][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: C=Cc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Brc1ccc2[nH]cc(CCc3ccccn3)c2c1

Procedure:
To 5-bromoindole (5.9 g) in acetic acid (10 ml) solution, 2-vinylpyridine (3.6 ml) was added and the mixture was heated and refluxed for 15 hours. The reaction solution was cooled, then was diluted with ethyl acetate, the aqueous layer was made alkaline with 4N-aqueous sodium hydroxide solution and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off in vacuo, and the residue obtained was purified by silica gel column chromatography (hexane:ethyl acetate=1:1 to 17:33) to afford the above-identified compound (5.6 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:30]=[CH:29][C:24]3[O:25][CH2:26][CH2:27][O:28][C:23]=3[CH:22]=2)[CH2:17][CH2:16]1)#[N:2].[OH-].[Na+].C([O:35]CCOCCO)C>O>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:30]=[CH:29][C:24]3[O:25][CH2:26][CH2:27][O:28][C:23]=3[CH:22]=2)[CH2:19][CH2:20]1)(=[O:35])[NH2:2]
Reactant: N#Cc1ccc2[nH]cc(CCCN3CCN(c4ccc5c(c4)OCCO5)CC3)c2c1
Reactant: CCOCCOCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1ccc2[nH]cc(CCCN3CCN(c4ccc5c(c4)OCCO5)CC3)c2c1
Reaction time: 3 h

Procedure:
A mixture of 3.1 g of 6-[4-(3-(5-cyanoindol-3-yl)propyl)piperazino]-1,4-benzodioxane, 2.7 g of NaOH, 100 ml of water and 50 ml of diethylene glycol monoethyl ether is stirred at a bath temperature of 140° for 3 hours. It is cooled, worked up in the conventional manner and gives 6-[4-(3-(5-carbamoylindol-3-yl)propyl)piperazino]-1,4-benzodioxane.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][C@H:11]1[CH2:16][N:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20](B3OC(C)(C)C(C)(C)O3)[CH:19]=2)[CH2:14][CH2:13][N:12]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:22]2[CH:23]=[C:18]([CH2:17][N:15]3[CH2:14][CH2:13][N:12]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@@H:11]([CH3:10])[CH2:16]3)[CH:19]=[CH:20][CH:21]=2)[CH:7]=1)#[N:9]
Reactant: C[C@H]1CN(Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2)CCN1C(=O)OC(C)(C)C
Reactant: N#Cc1ccnc(Cl)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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1CN(Cc2cccc(-c3cc(C#N)ccn3)c2)CCN1C(=O)OC(C)(C)C
Temperature: 140 °C
Yield: 93.4 %

Procedure:
To 2-chloro-4-pyridinecarbonitrile (0.416 g, 3 mmol) was added 1,1-dimethylethyl (2S)-2-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperazinecarboxylate (1.499 g, 3.60 mmol) followed by K2CO3 (1.244 g, 9.00 mmol) and Pd(Ph3P)4 (0.139 g, 0.120 mmol) in 1,4-dioxane (15.00 mL) and water (5.00 mL). The mixture was heated in a microwave oven for 30 min at 140° C. The organic layer was collected and the aqueous layer was extracted once with EtOAc (3 mL). The combined organic layers were filtered, concentrated on Glas-Col, redissolved in hexane/DCM (3:1, 4 mL), loaded onto Redisep silica gel column (12 g) and purified with Combiflash chromatography. Fractions were collected and the solvent was removed under reduced pressure to afford 1.10 g (94%) of the title compound. LC-MS m/z 393 (M+H)+.
Reaction SMILES: C(O)C.Cl[C:5]1[N:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1.[CH3:14][NH2:15]>C1COCC1>[CH3:14][NH:15][C:5]1[N:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1
Reactant: CN
Reactant: CC(=O)c1ccc(Cl)nc1
Solvent: CCO
Solvent: C1CCOC1
Product: CNc1ccc(C(C)=O)cn1
Temperature: 130 °C

Procedure:
A mixture of 2 mL of ethanol, 280 mg (1.80 mmol) of 1-(6-chloropyrid-3-yl)ethanone and 4.50 mL (9 mmol) of a 2 M solution of methylamine in THF is heated in a Biotage microwave reactor at 130° C. for 30 minutes. The reaction medium is evaporated to dryness. The crude product is taken up in water and extracted with EtOAc. The organic phase is dried over magnesium sulfate and evaporated to dryness. 258 mg of 1-(6-methylaminopyrid-3-yl)ethanone are obtained, the characteristics of which are as follows:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=3)[C:11]([O:21][CH3:22])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:30]([CH2:32][CH3:33])[CH3:31]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH:30]([CH2:32][CH3:33])[CH3:31])[CH:15]=3)[C:11]([O:21][CH3:22])=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cnc(-c2ccc(F)cc2)nc1-c1cccc(O)c1
Reactant: CCC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(C)Oc1cccc(-c2nc(-c3ccc(F)cc3)ncc2OC)c1
Yield: 70.1 %

Procedure:
1.2 g of 2-(4-fluorophenyl)-4-(3-hydroxyphenyl)-5-methoxypyrimidine, 5.5 g of potassium carbonate, and 5.5 g of 2-bromobutane were added to 200 ml of acetone, and the resulting mixture was heated under reflux for 2 days. The solvent was distilled away under reduced pressure. The residue was washed with water, and then purified by column chromatography on silica gel, thereby obtaining 1.0 g of 2-(4-fluorophenyl )-4-[3-sec-butoxyphenyl)-5-methoxypyrimidine (Compound 50).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:14]([C:15]#[C:16][Si](C)(C)C)=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F-].[K+]>CO>[C:15]([C:14]1[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[N:11][NH:12][CH:13]=1)#[CH:16]
Reactant: C[Si](C)(C)C#Cc1c[nH]nc1-c1cccc([N+](=O)[O-])c1
Agent: [F-]
Agent: [K+]
Solvent: CO
Product: C#Cc1c[nH]nc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
300 mg (1.05 mmol) of 3-(3-nitrophenyl)-4-[(trimethylsilyl)ethynyl]-1H-pyrazole were suspended in 60 ml of methanol and 120 mg (2.1 mmol) of potassium fluoride were added and the mixture stirred at room temperature overnight. After this time the solvent was removed under reduced pressure and the residue taken up with dichloromethane and washed with water. The organic layer was then dried over sodium sulphate and evaporated. The crude was finally purified by flash-chromatography on a silica gel column (CH2Cl2-CH3COCH3 9/1), giving 150 mg (67%) of the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:19]1
Reactant: CC(C)CCBr
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCNC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCN(CCC(C)C)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(3-piperidinyl)propyl]-9H-purin-6-amine and 1-bromo-3-methylbutane.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([OH:9])=[C:7]([O:10][CH3:11])[CH:6]=[C:5]([CH:12]=[O:13])[CH:4]=1.S(OC)(O[CH3:18])(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(=O)=O>C1C=CC=CC=1.O>[CH3:11][O:10][C:7]1[CH:6]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:18])[CH:12]=[O:13]
Reactant: COS(=O)(=O)OC
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: COc1cc(C=O)cc(OC)c1OC
Temperature: 75 °C
Reaction time: 1 h

Procedure:
25.0g syringealdehyde (0.137 mol), 26.6g of dimethyl sulfate (0.211 mol), and 27.7 g. of potassium carbonate (0.201 mol) were heated with stirring as in Example 1. When the temperature reached 45° C the mixture became fluid and carbon dioxide was given off. The temperature was slowly increased to 75° C and held at this value for 1 hour. Addition of water, acidification, and benzene extraction gave a quantitative yield of 3,4,5-trimethoxybenzaldehyde which contained no detectable syringealdehyde or other impurities as determined by g.l.c. analysis.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])=[CH:11][CH:10]=1.C(N(CC)CC)C.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:21]=[C:30]=[O:32])=[CH:11][CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccccc1-c1ccc(COC2CCCCO2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C=Nc1ccccc1-c1ccc(COC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 200 mg (0.70 mmol) of 4-(tetrahydropyranyloxy)methyl-2'-amino-1,1'-biphenyl (Example 1, Step N) and 0.40 mL of triethylamine in 10 mL of methylene chloride under a nitrogen atmosphere was treated with triphosgene (420 mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 30 minutes when thin layer chromatography on silica (hexane/ethyl acetate; 2:1) revealed no remaining amine. The reaction mixture was evaporated under vacuum to yield the crude product which was used in the next step without purification.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7](=[O:38])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22][C:23]2[CH:28]=[CH:27]C(B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.Br[C:41]1[C:46](C)=C(C)[C:44](C)=[C:43](C)[C:42]=1[CH3:51]>>[CH3:27][C:28]1[C:43]([CH3:44])=[C:42]([CH3:51])[C:41]([CH3:46])=[C:24]([CH3:25])[C:23]=1[O:22][CH:14]([C:11]1[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:39])=[O:38])=[CH:13][CH:12]=1)[CH2:15][CH2:16][CH2:17][C:18]([F:19])([F:21])[F:20]
Reactant: Cc1c(C)c(C)c(Br)c(C)c1C
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Product: Cc1c(C)c(C)c(OC(CCCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)c(C)c1C

Procedure:
The title compound is prepared in a manner substantially similar to Example 359 starting from 3-(4-{5,5,5-trifluoro-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-pentyl}-benzoylamino)-propionic acid methyl ester and 1-bromo-2,3,4,5,6-pentamethyl-benzene. MS: 554.2 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]=[CH2:15])=[CH:8][CH:7]=1)[CH3:5].[H-].[Na+].[CH3:19]I>CN(C)C=O>[CH3:1][O:2][C:3](=[O:16])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH:14]=[CH2:15])=[CH:10][CH:11]=1)([CH3:19])[CH3:5]
Reactant: C=CCOc1ccc(C(C)C(=O)OC)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C(C)(C)C(=O)OC)cc1
Temperature: 0 °C

Procedure:
A 0° C. solution of the product of Example 46B (1.9 g, 8.6 mmol) in anhydrous dimethylformamide (10 mL) was treated portion-wise with 60% sodium hydride (410 mg, 10 mmol) in mineral oil. The reaction mixture was stirred twenty minutes at 0° C., and methyl iodide (1.4 mL, 22 mmol) was then added. Ice bath was removed, and reaction mixture stirred 16 hours at room temperature. Reaction mixture quenched with saturated ammonium chloride, and product extracted with ethyl acetate (2×). The combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. Residue purified by normal phase HPLC on silica gel eluting with 3% ethyl acetate/hexane to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([NH:13][C:14]([CH:16]1[CH2:18][CH2:17]1)=[O:15])=O.P([O-])([O-])(O)=O.[K+].[K+]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:10]=[C:11]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[N:8]=2)[N:7]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: O=C(CBr)NC(=O)C1CC1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cn2nc(Cl)ccc2n1)C1CC1

Procedure:
6-Chloropyridazin-3-amine, N-(2-bromoacetyl)cyclopropanecarboxamide, and potassium hydrogenphosphate were mixed in DMA at 75° C. to provide N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide. N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide was reacted with [1,2,4]triazolo[4,3-a]pyridine-3-thiol and K2CO3 in DMA at 145° C. and 100 psi N2 to provide N-(6-([1,2,4]triazolo[4,3-a]pyridin-3-ylthio)imidazo[1,2-b]pyridazin-2-yl)cyclo-propanecarboxamide.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C[O:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:14]2[CH:15]=[C:10]([OH:9])[CH:11]=[CH:12][CH:13]=2)[CH:3]=1
Reactant: Brc1cccnc1
Reactant: COc1cccc(B(O)O)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: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Oc1cccc(-c2cccnc2)c1
Temperature: 80 °C

Procedure:
A mixture of 3-bromopyridine, 3-methoxyphenylboronic acid (1.3 eq.), 2N sodium carbonate, and (PPh3)4Pd in toluene was stirred at 80° C. over night. The reaction mixture was taken up in ethyl acetate. The organic phase was washed with saturated sodium bicarbonate and then brine, dried, and concentrated. The residue was diluted in CDM and the solution was treated with boron tribromide at −78° C. (acetone-dry ice bath). The bath was allowed to warm up to room temperature over approximately 5 hr. Methanol was added to quench the reaction. The volatiles were removed under reduced pressure. The residue was taken up in ethyl acetate and the resultant solution was washed with saturated sodium bicarbonate. The organic phase was then extracted with 3 N hydrochloric acid, which was then basified with sodium bicarbonate The aqueous phase was extracted with ethyl acetate, which was washed with saturated brine, dried, and concentrated. The resultant white solid was pure by TLC, MS, and 1H-NMR and was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[CH2:9][C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[N:27][C:22]([NH:1][C:2]2[C:3]([O:19][CH3:20])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH:13]4[CH2:14][CH2:15]4)[CH2:9][C:8](=[O:16])[N:7]([CH3:17])[C:6]=3[CH:18]=2)=[N:23][CH:24]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)N(C)C(=O)CN(CC1CC1)C2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)N(C)C(=O)CN(CC1CC1)C2

Procedure:
The title compound was prepared from 8-Amino-4-cyclopropylmethyl-7-methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one and N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to example 730 (0.062 g, 47%) Mp131-132° C.; LCMS (m/e) 578 (M); 1H-NMR (DMSO, 400 MHz) δ 8.23 (s, 1H), 7.98 (s, 1H), 7.75 (s, 1H), 7.22-7.20 (d, 1H, J=8.59 Hz), 7.03 (s, 2H), 6.88-6.86 (d, 1H, J=7.83 Hz), 3.89 (s, 3H), 3.88-3.80 (m, 1H), 3.55 (d, 2H, J=3.03 Hz), 3.27 (s, 3H), 3.10-3.09 (d, 2H, J=3.82 Hz), 2.89 (s, 3H), 2.41-2.40 (d, 2H, J=6.82 Hz), 2.05-1.92 (m, 2H), 1.68-1.55 (m, 2H), 1.40-1.17 (m, 4H), 1.13-1.97 (m, 1H), 0.90-0.79 (m, 1H), 0.50-0.48 (d, 2H, J=7.83 Hz), 0.170-0.16 (d, 2H, J=4.55 Hz).
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([CH3:25])([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:27][C:28]1[O:32][C:31]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[N:30][C:29]=1[CH2:38][CH2:39]OS(C1C=CC(C)=CC=1)(=O)=O.[K+].[Br-]>>[CH3:25][C:5]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:39][CH2:38][C:29]2[N:30]=[C:31]([C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)[O:32][C:28]=2[CH3:27])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:26]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C(F)(F)F)cc1
Agent: [Br-]
Agent: [K+]
Product: Cc1oc(-c2cccs2)nc1CCOc1ccc(CC(C)(Oc2ccc(C(F)(F)F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from 3-(4-hydroxyphenyl)-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester using the procedure of Example 50. 1H NMR (400 MHz, CDCl3) δ 8.67 (bs, 1H), 7.66 (d, 1H, J=3.2 Hz), 7.48 (d, 2H, J=8.4 Hz), 7.43 (d, 1H, J=5.0 Hz), 7.16 (d, 2H, J=8.4 Hz), 7.08 (dd, 1H, J=5.0, 3.2 Hz), 6.95 (d, 2H, J=8.4 Hz), 6.80 (d, 2H, J=8.4 Hz), 4.16 (t, 2H, J=6.2 Hz), 3.28 and 3.16 (d of Abq, 2H, J=13.8 Hz), 3.00 (t, 2H, J=6.2 Hz), 2.37 (s, 3H), 1.49 (s, 3H). IR (KBr) 3420, 3000, 1714, 1614, 1513, 1327 cm−1. HRMS (ES+) m/z exact mass calcd for C27H25NO5F3S 532.1406, found 532.1412.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH:28]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:28][C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:18]=3)[CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(F)cc1)NC1CCNCC1
Reactant: O=Cc1ccc2ccccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=C(Cc1ccc(F)cc1)NC1CCN(Cc2ccc3ccccc3n2)CC1
Yield: 25.2 %

Procedure:
2-(4-Fluorophenyl)-N-(4-piperidinyl)acetamide (WO97/36871; 0.05 g), 2-quinolinecarbaldehyde (0.033 g) and sodium triacetoxyborohydride (0.067 g) in dichloroethane (3 ml) were stirred under nitrogen for 24 hours. Saturated sodium hydrogen carbonate was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure, triturated with diethyl ether/ethyl acetate and filtered to leave 2-(4-fluorophenyl)-N-[1-(2-quinolinylmethyl)-4-piperidinyl]acetamide (0.020 g).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:33]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=3)=[O:9])[NH:23][C:24]=2[C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(-c2nc(Sc3ccc(Cl)c(Cl)c3)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccc(Cl)c(Cl)c3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 4.57 g of 4,5-bis(4-methoxyphenyl)-2-(3,4-dichlorophenylthio)imidazole in 100 ml of dichloromethane. The solution is stirred for 3 hours at room temperature, washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane 2:3, thus obtaining 4.19 g of 4,5-bis(4-methoxyphenyl)-2-(3,4-dichlorophenylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=2[CH:14]=1.[CH3:15][CH2:16][CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>>[CH3:15][CH2:16][CH:17]([NH:21][C:11]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][C:7]=2[CH:8]=1)=[O:13])[CH2:18][CH2:19][CH3:20]
Reactant: CCCC(N)CC
Reactant: COc1ccc2oc(C(=O)O)cc2c1
Product: CCCC(CC)NC(=O)c1cc2cc(OC)ccc2o1
Yield: 32 %

Procedure:
Prepared in a similar manner to example 4 using 5-methoxybenzofuran-2-carboxylic acid and hexan-3-amine (example 28a). Yield: 32%. 1H NMR (500 MHz, CDCl3): δ 0.96 (m, 6H); 1.40-1.67 (m, 6H); 3.85 (s, 3H); 4.09 (m, 1H); 6.28 (d, 1H); 7.01 (dd, 1H); 7.08 (d, 1H); 7.38 (m, 2H). MS (276, M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:17][CH:16]([CH2:18][NH2:19])[CH2:15]1)=[N:9][C:8]([O:20][CH3:21])=[CH:7][CH:6]=2.[O:22]=[C:23]1[NH:28][C:27]2[N:29]=[C:30]([CH:33]=O)[CH:31]=[CH:32][C:26]=2[S:25][CH2:24]1.[BH4-].[Na+]>C(Cl)Cl.CCO>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:15][CH:16]([CH2:18][NH:19][CH2:33][C:30]3[CH:31]=[CH:32][C:26]4[S:25][CH2:24][C:23](=[O:22])[NH:28][C:27]=4[N:29]=3)[CH2:17]1)=[N:9][C:8]([O:20][CH3:21])=[CH:7][CH:6]=2
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2ncc(F)c(CCN3CC(CN)C3)c2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2ncc(F)c(CCN3CC(CNCc4ccc5c(n4)NC(=O)CS5)C3)c2n1
Reaction time: 12 h
Yield: 109 %

Procedure:
To a stirred solution of [(1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-azetidinyl)methyl]amine (138 mg, 0.47 mmole) in dry CH2Cl2 (40 mL) and dry EtOH (5 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde (91 mg, 0.47 mmole). After 12 h, NaBH4 was added to the reaction solution. After 4 hrs, silica gel was added to the reaction contents and the slurry was concentrated under vacuum to a dry solid. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (0.24 g, 50%) as light yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.59 (1H, s), 8.17 (1H, d, J=9.0 Hz), 7.55 (1H, d, J=7.8 Hz), 7.04 (1H, d, J=9.0 Hz), 6.93 (1H, d, J=7.8 Hz), 4.08 (3H, s), 3.79 (2H, s), 3.51 (2H, t, J=7.4 Hz), 3.44 (2H, s), 3.22 (2H, app t), 2.95 (2H, t, J=6.7 Hz), 2.82 (4H, m), 2.65 (1H, m). LC-MS (ES) m/e 467 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:37])([F:36])[C:20]([C:22]1[S:26][C:25]([C:27]2[CH:28]=[N:29][CH:30]=[C:31]([CH:35]=2)[C:32](O)=[O:33])=[CH:24][CH:23]=1)=[O:21]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:32](=[O:33])[C:31]3[CH:35]=[C:27]([C:25]4[S:26][C:22]([C:20](=[O:21])[C:19]([F:36])([F:18])[F:37])=[CH:23][CH:24]=4)[CH:28]=[N:29][CH:30]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cncc(-c2ccc(C(=O)C(F)(F)F)s2)c1
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Product: CC(C)(CNC(=O)c1cncc(-c2ccc(C(=O)C(F)(F)F)s2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 26 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 5-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)nicotinic acid as described in example 8 step 6 (45 mg, yield 26%). 1H NMR (400 MHz, DMSO-d6) δ 9.21 (d, J=2.1 Hz, 1H), 9.01 (s, 1H), 8.66-8.60 (m, 1H), 8.52-8.51 (t, J=2.0 Hz, 1H), 8.21-8.20 (m, 1H), 8.02-7.98 (m, 4H), 7.36-7.30 (m, 2H), 3.53-3.52 (d, J=6.1 Hz, 2H), 1.30 (s, 6H).