Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]([O:21][CH3:22])[C:3]=1[O:23]C.CS(O)(=O)=O.N[C@H](C(O)=O)CCSC>>[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([S:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:4]([O:21][CH3:22])[C:3]=1[OH:23]
Reactant: COc1c(Cl)c2c(c(Sc3ccccc3)c1OC)CCN(C)CC2
Agent: CS(=O)(=O)O
Agent: CSCC[C@H](N)C(=O)O
Product: COc1c(O)c(Cl)c2c(c1Sc1ccccc1)CCN(C)CC2

Procedure:
To a solution of 0.8 g. (0.0022 mole) of 9-chloro-7,8-dimethoxy-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine (prepared as in Example 15) in 10 ml. of methylsulfonic acid at room temperature is added 0.35 g. (0.0023 mole) of solid methionine all at once and the mixture is stirred for 4 hours. The reaction mixture is quenched in ice/water and made basic (pH 7.5) with concentrated ammonium hydroxide. The basic solution is extracted with methylene chloride and washed with saturated sodium chloride solution. The organic layer is dried and evaporated in vacuo to leave 9-chloro-8-hydroxy-7-methoxy-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: S(Cl)([Cl:3])=O.[S:5]1[C:9]([C:10](O)=[O:11])=[CH:8][C:7]2[CH:13]=[CH:14][CH:15]=[CH:16][C:6]1=2>CN(C=O)C.C1(C)C=CC=CC=1>[S:5]1[C:9]([C:10]([Cl:3])=[O:11])=[CH:8][C:7]2[CH:13]=[CH:14][CH:15]=[CH:16][C:6]1=2
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc2ccccc2s1

Procedure:
The Benzo[b]thiophene-2-carbonyl chloride was prepared by adding toluene (2 mL), DMF (2 drops) and thionyl chloride (50 μL) to benzo[b]thiophene-2-carboxylic acid. Heating the mixture to reflux for 5 hours followed by removal of the solvent afforded the crude product, which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]([CH3:18])[CH3:17])[C:6]=2[N:19]=1.[NH2:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([NH:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:26])=[CH:23][C:22]=1[O:37][CH3:38].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(O)(C)C>[F:14][C:9]1([F:15])[CH2:8][N:7]([CH:16]([CH3:18])[CH3:17])[C:6]2[N:19]=[C:2]([NH:20][C:21]3[CH:36]=[CH:35][C:24]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]4)=[O:26])=[CH:23][C:22]=3[O:37][CH3:38])[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: CC(C)N1CC(F)(F)C(=O)N(C)c2cnc(Cl)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C(C)C)CC(F)(F)C(=O)N2C
Yield: 30.6 %

Procedure:
A mixture of 0.07 g (0.24 mmole) of 2-chloro-7,7-difluoro-9-isopropyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-292b), 0.070 g (0.26 mmole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.069 g (0.36 mmole) of p-toluenesulfonic acid monohydrate and 4 mL of isopropanol was heated in a pressure tube at 140 degrees overnight. After cooling, dichloromethane and saturated sodium carbonate were added. The mixture was extracted with dichloromethane twice. The combined organic layers were washed three times with sodium carbonate, times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-40:60) gave 0.038 g of 4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-293) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1>>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([C:22]3[CH:23]=[CH:24][S:20][CH:21]=3)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccsc1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cl)cc21
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(-c3ccsc3)cc21

Procedure:
Prepared from 6-chloro-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester and thiophen-3-boronic acid using a procedure similar to Prep 379. MS [M+H]+ 331.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH2:21]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>O1CCOCC1>[CH2:29]([N:28]([CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C1Nc2cccnc2N(C(=O)CN(Cc2ccccc2)Cc2ccccc2)c2ccccc21

Procedure:
6 gm of 11-chloroacetyl-5,11-dihydro-6H-pyrido [2,3-b][1,4]benzodiazepin-6-one, 4.2 gm of dibenzylamine and 2.1 gm of triethylamine were refluxed in 100 ml of absolute dioxane for 15 hours. After cooling, the formed triethylamine hydrochloride was separated, and the filtrate was evaporated in vacuo to dryness. The residue was then recrystallized twice from ethanol.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][C:12]([CH2:21][CH3:22])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13]2)=[CH:8][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:43]>CC#N>[Br:43][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][C:12]([CH2:21][CH3:22])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13]2)=[CH:8][CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)C1(CC)CCc2ccc(OCCCO)cc2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCOC(=O)C1(CC)CCc2ccc(OCCCBr)cc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a 100 ml CH3CN solution of ethyl 7-(3-hydroxypropoxy)-2-ethylchromane-2-carboxylate (2.88 g, 9.4 mmol) was added triphenylphosphine (3.21 g, 12.2 mmol) and carbon tetrabromide (4.05 g, 12.2 mmol) upon cooling in an ice-water bath. After stirring at rt for 1 hr, the solvent was removed under reduced pressure. The residue was suspended in dichloromethane and was charged onto a silica gel column. Elution with 10% AcOEt/hexanes gave the title compound 3.36 g (96%).
Reaction SMILES: [ClH:1].[F:2][C:3]([F:15])([F:14])[C:4]1[CH:13]=[CH:12][C:7]([O:8][CH2:9][C:10]#[N:11])=[CH:6][CH:5]=1.[CH2:16]([OH:18])[CH3:17]>CCOCC>[ClH:1].[CH2:16]([O:18][C:10](=[NH:11])[CH2:9][O:8][C:7]1[CH:12]=[CH:13][C:4]([C:3]([F:14])([F:15])[F:2])=[CH:5][CH:6]=1)[CH3:17]
Reactant: N#CCOc1ccc(C(F)(F)F)cc1
Reactant: CCO
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)COc1ccc(C(F)(F)F)cc1
Temperature: 0 °C

Procedure:
A 5-L 3-neck round bottom flask equipped with a mechanical stirrer, 1-L pressure-equalizing addition funnel and gas outlet adapter, Claisen head with a thermocouple and nitrogen inlet adapter, in an ice bath, was charged with HCl in ether (2 M, 815 mL) via addition funnel. The addition funnel was replaced with a clean 500-mL addition funnel, and the solution was stirred until the internal temperature was approximately 0° C. To the addition funnel was added (4-trifluoromethyl-phenoxy)-acetonitrile (neat, 273.0 g, 1.36 mol) followed by ethanol (86.9 mL, 1.49 mol). The solution of (4-trifluoromethyl-phenoxy)-acetonitrile was added drop-wise over 20 min, so not to exceed 2.6° C. The stirring was continued for 20 min in the ice bath after the addition was complete. The ice bath was removed and the reaction was stirred at room temperature for 6 h. At 15° C., the orange solution became hazy, followed by sudden precipitation of a thick solid. Once room temperature was achieved, ether (800 mL) was added, a spatula was used to free the solid from the sides of the flask, and the solid was filtered with a Buchner funnel. The yellowish solid became white after washing with ether (500 mL), and the solid was air-dried for 12 h at rt. The collected solid was transferred to an amber bottle and afforded 306.0 g (79.5% isolated yield, 67% HPLC purity). 1H-NMR (400 MHz, CD3Cl) δ (ppm) 7.60 (d, 2H, J=8.8 Hz) 7.18 (d, 2H, J=8.4 Hz) 5.01 (s, 2H) 4.87 (q, 2H, J=7.1 Hz) 1.25 (t, 3H, J=7.0 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:8]=[C:9]([N:11]2[C:15]([C:16]([F:19])([F:18])[F:17])=[N:14][N:13]=[N:12]2)[CH:10]=1)=[O:4].O[Li].O>C1COCC1.O>[CH3:26][C:23]1[CH:24]=[CH:25][C:20]([C:7]2[CH:8]=[C:9]([N:11]3[C:15]([C:16]([F:18])([F:19])[F:17])=[N:14][N:13]=[N:12]3)[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)cc(-n2nnnc2C(F)(F)F)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(-n3nnnc3C(F)(F)F)c2)cc1
Temperature: 25 °C
Yield: 97 %

Procedure:
To a stirred solution of 4′-methyl-5-(5-trifluoromethyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid methyl ester (3.7 mmol, 1.34 g) in 50 ml of THF was added a solution of LiOH.H2O (18.5 mmol, 776.3 mg) in 12 mL of water. The reaction mixture was heated to reflux for 3.5 hours, then cooled to room temperature. Solvent was removed under reduced pressure, and the pH of the liquid residue was adjusted to 2.0 by addition of 2N aqueous HCl solution. The mixture was extracted with ethyl acetate and the combined ethyl acetate layers were dried over anhydrous Na2SO4 and concentrated in vacuo to give 4′-methyl-5-(5-trifluoromethyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid as light yellow solid (1.25 g, 97% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:10])[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][C:3]=1[C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1.O[C:30]1[CH:39]=[CH:38][C:33]([O:34][CH:35]([OH:37])[CH3:36])=[CH:32][CH:31]=1>CN(C)C1C=CN=CC=1.ClCCl>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:10])[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][C:3]=1[C:20]1[CH:28]=[CH:27][C:23]([C:24]([O:26][C:30]2[CH:39]=[CH:38][C:33]([O:34][CH:35]([OH:37])[CH3:36])=[CH:32][CH:31]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: CCCCCC[C@H](C)Oc1cc(N)c(-c2ccc(C(=O)O)cc2)cc1[N+](=O)[O-]
Reactant: CC(O)Oc1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCC[C@H](C)Oc1cc(N)c(-c2ccc(C(=O)Oc3ccc(OC(C)O)cc3)cc2)cc1[N+](=O)[O-]

Procedure:
0.6 g of 4-[4-(2-amino-5-nitro-4-[(S)-2-octyloxy]phenyl)benzoic acid and 0.2 g of (4-hydroxyphenoxy)ethanol, 0.04 g of 4-dimethylaminopyridine, 0.4 g of N,N'-dicyclodicyclohexyldicarbodimide and 50 ml of dichloromethane are reacted in an analogous manner to Example 1 to give 0.4 g of (4-[4-(2-amino-5-nitro-4-[(S)-2-octyloxy]phenyl)benzoyloxy]phenoxy)ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:12]([F:13])([F:14])[F:15]
Reactant: COc1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: COc1ccc(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 106.2 %

Procedure:
To a solution of 2-methoxy-5-nitrobenzotrifluoride (5.08 g, 23.0 mmol) in methanol (200 ml) was added 10% Pd—C (containing 50% water, 250 mg), and the resulting mixture was stirred for 3.5 hours under a hydrogen atmosphere at room temperature and atmospheric pressure while maintaining the temperature. The mixture was filtered by the use of Celite and the filtrate was concentrated to dryness under reduced pressure to obtain 4-methoxy-3-(trifluoromethyl)aniline (4.67 g, 100%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:11][CH2:10][C:9]([CH3:13])([CH3:12])[O:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:37])[CH3:36])=[CH:30][CH:29]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:9]1([CH3:13])[O:8][C:6]2[N:7]=[C:2]([C:28]3[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:37])[CH3:36])=[CH:30][CH:29]=3)[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:5]=2[O:11][CH2:10]1
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CC1(C)COc2c(nc(Cl)nc2N2CCOCC2)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)OCC(C)(C)O3)cc1
Temperature: 120 °C
Yield: 57.8 %

Procedure:
A microwave vial was charged with 2-chloro-7,7-dimethyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine from Example 104 (50 mg, 0.18 mmol), N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetamide (69 mg, 0.26 mmol), Pd(PPh3)2Cl2 (12 mg, 0.02 mmol) and sodium carbonate (0.5 mL, 0.5 mmol, 1M aqueous solution) in acetonitrile (1.5 mL) then was evacuated and back filled with nitrogen before being heated at 120° C. for 30 minutes using microwave irradiation. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient of acetonitrile 5-98%) affording 112 as a white solid (40 mg, 59%). LCMS: RT=2.73 min, [M+H]+=344. 1H NMR (400 MHz, CDCl3): δ 8.28 (2H, d, J=8.8 Hz), 7.54 (2H, d, J=8.8 Hz), 7.22 (1H, broad s), 3.90 (2H, s), 3.87-3.78 (8H, m), 2.19 (3H, s), 1.46 (6H, s)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:7][C:8]=1[CH3:9])#[N:2].[CH3:14][N:15](C=O)C.C([O-])(=O)C.[NH4+].N>O.C(O)C>[NH2:2][C:1]1[C:3]2[C:8](=[CH:7][C:6]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:5][CH:4]=2)[CH:9]=[CH:14][N:15]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(C(C)(C)C)ncc1C#N
Agent: CC(=O)[O-]
Agent: N
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc2ccnc(N)c2cn1

Procedure:
Procedure analogous to A. Zhang et al., J. Combi. Chem. 2007, 9, 6, 916: A mixture of 17.4 g (100 mmol) of 3-cyano-4-methyl-6-tert-butylpyridine [942938-45-6], 14.0 ml (105 mmol) of N,N-dimethylformamind dimethyl acetal [4637-24-5] and 150 ml of DMF is heated under reflux for 16 h. The DMF is then removed at 70° C. in vacuo. 46.3 g (600 mmol) of anhydrous ammonium acetate are added to the oily residue, the mixture is homogenised, heated to melt ing in an oil bath (temperature about 135° C.) and stirred for 3 h. After cooling, the melt is taken up in a mixture of 200 ml of water and 100 ml of ethanol, rendered alkaline (pH about 9) by addition of conc. ammonia solution and extracted three times with 300 ml of dichloromethane each time. The combined org. phases are washed twice with 300 ml of water each time and dried over sodium sulfat e. Aft er evaporation of the org. phase in vacuo, the residue remaining is subjected to sublimation (p about 1×10−2 mbar, T=150° C.). Yield: 13.7 g (68 mmol), 68%. Purity: >95% according to 1H-NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:17](=[O:25])[CH2:18][CH2:19][N:20]3[CH:24]=[CH:23][N:22]=[CH:21]3)[C:4]=2[CH:3]=1.[OH:26]O>C(O)(=O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12](=[O:26])(=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:17](=[O:25])[CH2:18][CH2:19][N:20]3[CH:24]=[CH:23][N:22]=[CH:21]3)[C:4]=2[CH:3]=1
Reactant: O=C(CCn1ccnc1)N1c2ccccc2S(=O)c2ccc(Cl)cc21
Reactant: OO
Solvent: CC(=O)O
Product: O=C(CCn1ccnc1)N1c2ccccc2S(=O)(=O)c2ccc(Cl)cc21
Reaction time: 3 h

Procedure:
A mixture of 1 g of 2-chloro-10-[3-(imidazol-1-yl)-propionyl]-phenothiazine-5-oxide, 4 ml of 30% H2O2 and 40 ml of acetic acid is stirred for 3 hours at 45° and is worked up in the customary manner to give 2-chloro-10-[3-(imidazol-1-yl)-propionyl]-phenothiazine-5,5-dioxide, melting point 134°-135° (decomposition). Hydrochloride, melting point 200°-201°.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.[C:24]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)(=[O:32])[CH2:25][C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27].C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[C:25]([C:24]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=2)=[O:32])[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)cc1
Reactant: CC(C)OC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)OC(C)C)cc1
Yield: 78.5 %

Procedure:
To a solution of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde (3.59 g, 11.7 mmol) synthesized according to the method described in WO95/18125 in toluene (40 ml) were added 4-nitrobenzyl isopropyl malonate (4 g, 14 mmol) obtained in Step 1, acetic acid (351 mg) and piperidine (498 mg). While removing water through Dean-Stark trap, the mixture was refluxed under heating. Two hours later, toluene was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=65:35) and the fraction containing the objective substance was concentrated under reduced pressure to give the title compound (5.24 g, yield 66%) as a yellow oil.
Reaction SMILES: BrC(C)C.[OH:5][CH:6]([C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][CH2:11]1)[CH:7]([CH3:9])[CH3:8]>>[OH:5][CH:6]([CH:10]1[CH2:11][CH2:12][CH:13]([C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:14][CH2:15]1)[CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)C(O)[C@H]1CC[C@H](C(C)(C)C)CC1
Solvent: CC(C)Br
Product: CC(C)C(O)C1CCC(C(C)(C)C)CC1
Yield: 73 %

Procedure:
This compound was similarly prepared using 2-bromopropane. Distillation of the product yielded a 1:1 mixture of cis and trans-1-(1-hydroxy-2-methylprop-1-yl)-4-t-butylcyclohexane; 77 g, 73% yield; bp 98-110 (3 mm); mol wt 212 (ms); nmr, 0.82 (15 H,s, t-butyl and isopropyl methyl H), 3.0-3.8 (1H, broad, αH); ir, 3360, 1360, 1110, 1000, 980.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]([OH:15])=O)[N:4]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:33]3[CH2:32][CH2:31][CH2:30][NH:29][C:28]=3[CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[C:33]3[CH2:32][CH2:31][CH2:30][N:29]([C:13](=[O:15])[CH2:12][N:5]4[C:6]5=[N:7][CH:8]=[CH:9][CH:10]=[C:11]5[C:3]([C:2]([F:1])([F:17])[F:16])=[N:4]4)[C:28]=3[CH:27]=[N:26]2)=[CH:23][CH:24]=1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2cccnc21
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Product: O=C(Cn1nc(C(F)(F)F)c2cccnc21)N1CCCc2c1cnn2-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2-(3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method B. The reaction slurry was purified by flash chromatography (SiO2, 24 g column, eluting with 5-70% EtOAc in hexanes) to provide 58 mg of the title compound as a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.65 (dd, J=2.6, 4.7 Hz, 1H), 8.32 (s, 0.8H), 8.24 (d, J=8.2 Hz, 1H), 7.72 (s, 0.2H), 7.44-7.52 (m, 2H), 7.33 (dd, J=4.3, 8.2 Hz, 1H), 7.13-7.23 (m, 2H), 5.76 (s, 0.4H), 5.65 (s, 1.6H), 3.93 (m, 2H), 2.89 (t, J=6.3 Hz, 2H), 2.17 (m, 1.6H), 2.06 (m, 0.4H); MS: (ES) m/z calculated for C21H17F4N6O [M+H]+ 445.1, found 445.1.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[F:28]>>[C:4]([O:3][C:1]([NH:8][C@H:9]([CH2:10][C:11]1[CH:12]=[C:13]([C:24]2[CH:25]=[CH:26][C:27]([F:28])=[C:22]([Cl:21])[CH:23]=2)[CH:14]=[CH:15][CH:16]=1)[C:18]([OH:20])=[O:19])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cccc(Br)c1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@H](Cc1cccc(-c2ccc(F)c(Cl)c2)c1)C(=O)O
Yield: 81.4 %

Procedure:
2-(R)-tert-Butoxycarbonylamino-3-(3′-chloro-4′-fluoro-biphenyl-3-yl)-propionic acid (0.93 g) was prepared from (R)-N-Boc-3-bromophenylalanine (1.0 g, 2.9 mmol) and 3-chloro-4-fluorophenylboronic acid (1.0 g, 5.8 mmol) following general procedure D.
Reaction SMILES: I[C:2]1[CH:25]=[CH:24][C:5]2[NH:6][C:7]([N:9]3[CH2:14][CH2:13][C:12]4([C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16](=[O:23])[O:15]4)[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.[CH3:26][N:27]1C(=O)CCC1>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N>[C:26]([C:2]1[CH:25]=[CH:24][C:5]2[NH:6][C:7]([N:9]3[CH2:14][CH2:13][C:12]4([C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16](=[O:23])[O:15]4)[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1)#[N:27]
Reactant: CN1CCCC1=O
Reactant: O=C1OC2(CCN(c3nc4cc(I)ccc4[nH]3)CC2)c2ccccc21
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ccc2[nH]c(N3CCC4(CC3)OC(=O)c3ccccc34)nc2c1
Temperature: 130 °C

Procedure:
Add zinc cyanide (0.016 g, 0.13 mmol) and tetrakistriphenylphosphine palladium(0) (0.018 g, 0.02 mmol) to a solution of 1′-(5-iodo-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one (0.1 g, 0.22 mmol) in NMP (2 mL). Heat the reaction mixture at 130° C. for 19 hours. After cooling to ambient temperature, dilute the mixture with EtOAc (20 mL), and wash with water (20 mL) and saturated aqueous NaCl (20 mL). Dry the organic portion over Na2SO4, filter and concentrate. Purify by preparative TLC (80% EtOAc-hexane) to obtain 1′-(5-cyano-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[CH:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:7][CH:8]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:7][CH:8]=1
Reactant: CCOC(=O)C(=CC1CCOCC1)c1ccc(SC)cn1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)C(CC1CCOCC1)c1ccc(SC)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.4 %

Procedure:
To a solution of ethyl 2-[5-(methylsulfanyl)pyridin-2-yl]-3-(tetrahydro-2H-pyran-4-yl)-2-propenoate (2.41 g) in methanol (20 mL) was added sodium borohydride (890 mg), and the mixture was stirred at room temperature for 3 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium to sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the title compound (1.44 g, yield 59%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: C1(C2(C#N)CCC(N3CCCC3)=CC2)C=CC=CC=1.C(N=C=S)C.[C:25]1([C:31]2([C:47]#[N:48])[CH2:36][CH2:35][C:34]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[C:33]([C:42](=[S:46])[NH:43][CH2:44]C)[CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([C:31]2([C:47]#[N:48])[CH2:36][CH2:35][C:34]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[C:33]([C:42](=[S:46])[NH:43][CH3:44])[CH2:32]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCNC(=S)C1=C(N2CCCC2)CCC(C#N)(c2ccccc2)C1
Agent: N#CC1(c2ccccc2)CC=C(N2CCCC2)CC1
Solvent: CCN=C=S
Product: CNC(=S)C1=C(N2CCCC2)CCC(C#N)(c2ccccc2)C1

Procedure:
Using the procedure of step B at example 10 and starting from 126.4 g 4-phenyl 4-cyano 1-pyrrolidino cyclohex-1 ene and 40 g ethyl isothiocyanate, 107.25 g of 4-phenyl 4-cyano 2-ethylthiocarbamoyl 1-pyrrolidino cyclohex-1 ene are obtained after the usual purifications.