Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]#[N:9].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:16](=[O:17])[C:15]2[CH:19]=[CH:20][C:12]([C:11]([F:10])([F:21])[F:22])=[CH:13][CH:14]=2)=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]#[N:9]
Reactant: Cn1cccc1CC#N
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Product: Cn1c(CC#N)ccc1C(=O)c1ccc(C(F)(F)F)cc1

Procedure:
A solution of 14.4 g. (0.12 mole) of 1-methylpyrrole-2-acetonitrile and 25 g. (0.12 mole) of p-trifluoromethylbenzoyl chloride in 120 ml. methylene chloride is chilled to -25° C. (external bath). Then 14 ml. (0.12 mole) stannic chloride is added dropwise over a half hour. The resultant suspension is permitted to come to room temperature and poured into ice-dilute hydrochloric acid. The aqueous phase is separated and washed successively with N,N-dimethyl-1,3-propane-diamine, 3N hydrochloric acid and a saturated solution of sodium chloride. The solvent is evaporated, and the product is isolated from the residual oil by column chromatography using acid-washed alumina. The solvents hexane, benzene, and ether are used as eluents. The first compound-bearing fraction not giving a positive Enrlich's test (in benzene) is collected. The solvent is evaporated and the resultant solid, 1-methyl-5-(p-trifluoromethylbenzoyl)-pyrrole-2-acetonitrile, in purified by recrystallization from isopropanol, m.p. 95-97.5° C.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([NH:13][CH:14]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=2[N:16]([CH2:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:15]1=[O:40])=[O:12])[CH3:10])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:8][C@H:9]([C:11]([NH:13][CH:14]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=2[N:16]([CH2:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:15]1=[O:40])=[O:12])[CH3:10]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)c2ccccc2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)c2ccccc2)C1=O
Reaction time: 2 h
Yield: 93.7 %

Procedure:
3-(N′-(tert-Butoxycarbonyl)-L-alaninyl)amino-2,3-dihydro-1-(2-oxo-2-phenylethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one (2.5 g, 4.63 mmol) was added to 100 mL of a stirring solution of 15% TFA/methylene chloride in one portion. After stirring 2 h, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in 150 mL of methylene chloride. This solution was washed twice with saturated sodium bicarbonate, once with brine and then dried over sodium sulfate. Purification of the crude product using silica gel column chromatography (1-10% methanol/methylene chloride) gave 1.91 g (94%) of the title compound as a white foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[N:14][N:15]2[CH2:18][C@@H:19]([OH:21])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:24]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])([CH3:26])[CH3:25].[Na+].[I-]>C1COCC1.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[N:14][N:15]2[CH2:18][C@@H:19]([O:21][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:30])[CH3:29])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](O)Cn1ncc2ccc(OCc3ccccc3)cc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@@H](Cn1ncc2ccc(OCc3ccccc3)cc21)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a mixture of (S)-1-(6-benzyloxyindazol-1-yl)-propan-2-ol (2.03 g, 7.20 mmol) in anhydrous THF/DMF (100 mL/35 mL) under nitrogen was added sodium hydride (60% in mineral oil, 0.40 g, 10.0 mmol). After 30 min tert-butyl-chloro-dimethyl-silane (1.52 g, 110 mmol) and a catalytic amount of NaI were added and the mixture was stirred overnight at ambient temperature. Additional NaH (5 mmol) and tert-butyl-chloro-dimethyl-silane (5 mmol) were added to the reaction mixture, which was stirred for 6 h. The reaction mixture was evaporated to a residue that was mixed with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (2×200 mL). Purification by chromatography (silica, EtOAc/hexane) gave an oil (2.81 g, 99%).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li]CCCC.[CH3:15][C:16]([CH:18]1[CH2:20][CH2:19]1)=[O:17].[F:21][CH:22]([F:27])[C:23](OC)=[O:24]>C(OCC)C>[CH:18]1([C:16](=[O:17])/[CH:15]=[C:23](\[OH:24])/[CH:22]([F:27])[F:21])[CH2:20][CH2:19]1
Reactant: CC(=O)C1CC1
Reactant: COC(=O)C(F)F
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(/C=C(\O)C(F)F)C1CC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 35.4 %

Procedure:
Hexamethyldisilazane (1 g, 6.2 mmol) and diethylether were taken in RBF and cooled to −78° C. under nitrogen atmosphere. n-BuLi (7.7 ml) was added and stirred for 15 mins Cyclopropyl methyl ketone (0.66 ml, 6.8 mmol) was added and stirred at −78° C. for 45 mins. At this stage methyl 2,2-difluoroacetate (1.62 ml, 18.58 mmol) was added and brought the reaction mixture to rt and allowed to stir for overnight. Reaction mixture quenched with water, ether layer separated and aqueous layer was acidified with 1N HCl. Aqueous layer extracted with diethyl ether and ether was dried over anhydrous Na2SO4. Diethyl ether was removed on rotavapour to obtain the title compound (390 mg) which was used in the next step without further purification. 1H-NMR (δ ppm, CDCl3, 400 MHz): 6.08 (s, 1H), 5.95 (t, J 54.2, 1H), 1.84-1.76 (m, 1H), 1.34-1.29 (m, 2H), 1.10-1.03 (m, 2H).
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH2:3][CH3:4].[Na].[O:8]1[CH:10]([CH2:11][CH3:12])[CH2:9]1.S(=O)(=O)(O)O>>[OH:5][CH:2]([CH2:3][CH3:4])[CH2:1][O:6][CH2:9][CH:10]([OH:8])[CH2:11][CH3:12]
Reactant: CCC(O)CO
Reactant: CCC1CO1
Agent: O=S(=O)(O)O
Agent: [Na]
Product: CCC(O)COCC(O)CC
Temperature: 100 °C

Procedure:
A 500 ml, three neck, round bottom flask equipped with magnetic stirrer, internal thermometer, addition funnel, condenser, argon supply, and heating mantle, is flushed with argon. Then 1,2-butanediol (about 270 g, about 3 moles, Aldrich) is added and sodium metal (about 1.2 g, about 0.05 moles, Aldrich) is added and the sodium is allowed to dissolve. Then the reaction mixture is heated to about 100° C. and epoxybutane (about 71 g. about 1 mole, Aldrich) is added dropwise with stirring. Heating is continued until the reflux of epoxybutane has ceased and heating is continued for an additional hour to drive the conversion to completion. The reaction mixture is neutralized with sulfuric acid, the salts are removed by filtration, and the liquid is fractionally distilled under vacuum to recover the excess butanediol. The desired ether is obtained as a residue. Optionally, it is purified by further vacuum distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([CH2:17][C:18]([OH:20])=O)=[C:11]3[N:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=[CH:24]1)=O.CNC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]([CH2:17][C:18]([N:23]([CH3:24])[CH3:21])=[O:20])=[C:11]3[N:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cc1c(-c2ccc(Cl)cc2)nn2cccnc12
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)Cc1c(-c2ccc(Cl)cc2)nn2cccnc12
Reaction time: 4 h
Yield: 83.1 %

Procedure:
A mixture of 4.0 g (0.013 mole) of 2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidine-3-acetic acid and 2.25 g (0.013 mole) of 1,1'carbonyldiimidazole in 150 ml of anhydrous tetrahydrofuran was stirred for 4 hours while a stream of nitrogen was bubbled through the mixture. A solution of dimethylamine in tetrahydrofuran (14.1 ml; 0.0417 mole; 2.59M) was added, and the reaction was stirred for 17 hours under nitrogen atmosphere. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane, washed with water, aqueous 7% sodium bicarbonate, and water, and dried over magnesium sulfate and re-evaporated under reduced pressure. The crystalline residue (4.0 g) was recrystallized from isopropanol to give 3.4 g (79%) of product, mp 174°-175.5° C.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C@H:2]1[CH2:5][O:6][C:7]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:8]=1[C:9](/[N:11]=[C:12]1/[N:13]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[N:14]([CH3:21])[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:16]/1)=[O:10].C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43].O>C(Cl)Cl>[C:17]([C:15]1[N:14]([CH3:21])[N:13]([CH2:22][CH:23]2[CH2:24][CH2:25]2)/[C:12](=[N:11]/[C:9](=[O:10])[C:8]2[CH:26]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:28]=[CH:29][C:7]=2[O:6][CH2:5][C@@H:2]2[CH2:3][CH2:4][N:1]2[S:42]([CH3:41])(=[O:44])=[O:43])/[CH:16]=1)([CH3:19])([CH3:18])[CH3:20]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2OC[C@@H]2CCN2)n1CC1CC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2OC[C@@H]2CCN2S(C)(=O)=O)n1CC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
To a solution of Example 63B (220 mg, 0.474 mmol) and triethylamine (0.132 ml, 0.947 mmol) in CH2Cl2 (6 ml) was added methanesulfonyl chloride (0.055 ml, 0.710 mmol) dropwise. The mixture was stirred at ambient temperature for 2 hours then portioned between CH2Cl2 and water. The organic extract was washed with brine and concentrated. Purification by chromatography (silica gel, MeOH/Et3N (9:1) in CH2Cl2 in 0-30% gradient) provided 160 mg (62% yield) of the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 0.41-0.68 (m, 4H), 1.01-1.18 (m, 1H), 1.41-1.49 (m, 9H), 2.25-2.45 (m, 2H), 2.91 (s, 3H), 3.71-3.80 (m, 1H), 3.83 (s, 3H), 3.93-4.07 (m, 1H), 4.14-4.33 (m, 4H), 4.59-4.80 (m, 1H), 6.95-7.06 (m, 2H), 7.50 (dd, J=8.82, 1.70 Hz, 1H), 7.92 (d, J=2.37 Hz, 1H); MS (DCI/NH3) m/z 543 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[CH:7][S:8][CH:9]=1)(=[O:3])[CH3:2].[C:10]([O-])(=[O:12])[CH3:11].[Na+].C(Cl)(Cl)Cl>C(OC(=O)C)(=O)C.N1C=CC=CC=1>[C:1]([N:4]([C:10](=[O:12])[CH3:11])[C:5]1[N:6]=[CH:7][S:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cscn1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N(C(C)=O)c1cscn1
Temperature: 100 °C

Procedure:
A solution of 4-acetylaminothiazole (2.85 g, 20 mM) in a mixture of acetic anhydride (30 ml) and pyridine (10 ml) was heated at 100° C. for 16 hours. The reaction mixture was cooled and poured onto an ice cold mixture of 20% aqueous sodium acetate (200 ml) and chloroform (200 ml.). The layers were separated the organic layer was washed with water, dried (MgSO4) and the solvents removed under vacuum to give an oil. Trituration with hexane followed by recrystallisation from di-isopropyl ether gave the title compound (1.8 g, 49%) m.p. 55° C. (Found: C, 45.8; H, 4.4; N, 15.5%. C7H8N2O2S requires: C, 45.6; H, 4.4; N, 15.2%)
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[C:3]([O:5][C@H:6]([O:10][C:11]([O:13]N1C(=O)[C@@H](OC(=O)C2C=CC=CC=2)[C@H](OC(=O)C2C=CC=CC=2)C1=O)=O)[CH:7]([CH3:9])[CH3:8])=[O:4].[NH2:40][CH2:41][CH2:42][CH2:43][P:44]([CH3:47])(=[O:46])[OH:45].C1COCC1>O>[C:3]([O:5][C@H:6]([O:10][C:11]([NH:40][CH2:41][CH2:42][CH2:43][P:44]([CH3:47])(=[O:45])[OH:46])=[O:13])[CH:7]([CH3:8])[CH3:9])(=[O:4])[CH:2]([CH3:1])[CH3:39]
Reactant: CC(C)C(=O)O[C@H](OC(=O)ON1C(=O)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)C1=O)C(C)C
Reactant: CP(=O)(O)CCCN
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=O)O[C@H](OC(=O)NCCCP(C)(=O)O)C(C)C
Temperature: 19 °C
Reaction time: 4 h

Procedure:
To a 3 L three necked round bottom flask fitted with a mechanical stirrer, temperature probe, and nitrogen inlet is added (25) (100 mmol), 3-aminopropylmethylphosphinic acid (100 mmol), THF (1 L), and water (100 mL). The suspension is stirred under a nitrogen atmosphere at 18-20° C. for 4 h during which time the reaction mixture becomes homogeneous. The THF is removed in vacuo and the reaction mixture is diluted with methyl tert-butyl ether (250 mL) and washed with 1N HCl (1×500 mL) and water (2×200 mL). The organic phase is separated and concentrated in vacuo to leave a white solid. The solid is purified by flash chromatography to afford the title compound (119) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH2:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:29]1([CH2:35][C:36](Cl)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH:28][C:36](=[O:37])[CH2:35][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNC(=O)Cc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-[4′-(4-aminomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and phenylacetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([CH2:11][CH2:12][OH:13])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:14].CC(O)=[O:17]>CC(O)C.OS(O)(=O)=O.O>[Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([OH:17])=[O:13])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:14]
Reactant: OCCn1cnc2ccc(F)c(Cl)c21
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: O=C(O)Cn1cnc2ccc(F)c(Cl)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(7-Chloro-6-fluoro-1H-benzimidazol-1-yl)ethanol (550 mg, 2.57 mmol) is dissolved in AcOH (20.0 mL). Jones reagenta (3.31 mL, 3.00 mmol, 0.907 M) is added drop wise, and the solution is stirred for 1 hour at room temperature. The solution is diluted with iPrOH (50.0 mL), and the solvents are evaporated. 6N NaOH is added to the solution until the pH is 11. The aqueous phase is washed with EtOAc (50.0 mL), and the organic phase is extracted 3 times with water (3×50.0 mL). The combined aqueous phases are acidified with 12N HCl until the pH is 3. The aqueous phase is then extracted 4 times with EtOAc (4×50.0 mL). The combined organic phases are dried with MgSO4, filtered and concentrated. The product is sufficiently pure by 1H NMR (236 mg, 40%). 1H NMR (400 MHz, DMSO-D6) δ ppm 5.18 (s, 2H) 7.24 (dd, J=10.16, 8.79 Hz, 1H) 7.64 (dd, J=8.79, 4.49 Hz, 1H) 8.13-8.30 (m, 1H). a Jones reagent is prepared by mixing 997 mg of CrO3 in 1.00 mL of H2SO4 and 10.0 mL of water.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:2].Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([C:3]1[C:8]([B:9]2[O:10][C:11]([CH3:17])([CH3:16])[C:12]([CH3:14])([CH3:15])[O:13]2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH:18]1[CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:20][CH2:19]1)[CH3:2]
Reactant: CCc1c(B2OC(C)(C)C(C)(C)O2)cccc1C1CCNCC1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN1CCC(c2cccc(B3OC(C)(C)C(C)(C)O3)c2CC)CC1
Temperature: 60 °C
Yield: 48.9 %

Procedure:
To a solution of 4-[2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (D119) (300 mg, 0.952 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added ethyl 4-bromobutanoate (0.272 mL, 1.903 mmol) and potassium carbonate (526 mg, 3.81 mmol). The reaction solution was heated to 60° C. overnight. Ethyl acetate was added and the resulting solution was washed with water, brine. The organic layer was dried over anhydrous Na2SO4 and concentrated to afford ethyl 4-{4-[2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-piperidinyl}butanoate (D121) (200 mg). MS (ES): C25H40BNO4 requires 429.3. found 430.1 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([CH3:11])[CH:4]=1.[CH:12]1([N:15]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:14][CH2:13]1>>[CH:12]1([N:15]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([CH3:11])[CH:4]=3)[CH2:27][CH2:26]2)[S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:18])[CH2:14][CH2:13]1
Reactant: COc1ccc(CBr)cc1C
Reactant: O=S(=O)(c1ccccc1)N(C1CCNCC1)C1CC1
Product: COc1ccc(CN2CCC(N(C3CC3)S(=O)(=O)c3ccccc3)CC2)cc1C

Procedure:
N-Cyclopropyl-N-[1-(3-methyl-4-methoxybenzyl)piperidin-4-yl]benzenesulfonamide was prepared from 4-bromomethyl-1-methoxy-2-methylbenzene and N-cyclopropyl-N-piperidin-4-yl-benzenesulfonamide according to the above procedure. LC: 100%. MS: m/z=415.2, 416.2 (M+H+). 1H NMR (400 MHz, CDCl3): δ 7.82 (2H, d, J=8.0 Hz), 7.60 (1H, m), 7.52 (2H, m), 7.29 (1H, m), 7.21 (1H, s), 6.85 (1H, d, J=8.8 Hz), 4.13 (2H, s), 4.05 (1H, s), 3.85 (3H, s), 3.54 (2H, m), 2.63 (4H, m), 2.22 (3H, s), 1.75 (3H, m), 0.93 (2H, m), 0.86 (2H, m).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH2:8])[CH2:3]1.C[Al](C)C.C([O:15][C:16]([C:18]1[C:22]([NH:23][C:24]([NH2:26])=[O:25])=[CH:21][N:20]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH:19]=1)=O)C>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:16]([C:18]2[C:22]([NH:23][C:24]([NH2:26])=[O:25])=[CH:21][N:20]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[CH:19]=2)=[O:15])[CH2:3]1
Reactant: CCOC(=O)c1cn(-c2cccc(F)c2)cc1NC(N)=O
Reactant: CN1CCC[C@H](N)C1
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: CN1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 17 %

Procedure:
To a solution of (S)-1-methyl-piperidin-3-yl amine (120 mg, 1.05 mmol) in THF (8.0 mL), under nitrogen, was added 2N trimethylaluminium in hexanes (1.0 mL, 2.0 mmol), and the reaction mixture was allowed to stir at room temperature for 1.5 hours. After this time, a THF (5.0 mL) solution of 1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carboxylic acid ethyl ester (291 mg, 1.0 mmol), was added and the reaction mixture was heated at 65-70° C. for a period of 18 hours. After this time, the reaction mixture was allowed to cool to room temperature and was then quenched by addition of a saturated solution of Rochelle's salt. After 0.5 hours, the mixture was extracted with DCM (3×10 mL) and EtOAc (1×10 mL). The combined organic layer was dried (MgSO4) and concentrated in vacuo. The resultant residue was then purified by flash chromatography (silica, 5 g column, Isolute, 0-20% MeOH in DCM) to afford the title compound (60 mg, 0.17 mmol, 17%). LCMS (method A), RT=5.13 min, M+H+=360; 1H NMR (DMSO-D6, 400 MHz): 8.97 (s, 1H), 8.05 (d, J=2.6 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.56 (d, J=2.6 Hz, 1H), 7.55-7.48 (m, 1H), 7.39 (dt, J=10.6, 2.3 Hz, 1H), 7.36-7.33 (m, 1H), 7.12 (td, J=8.5, 2.4 Hz, 1H), 6.29 (s, 2H), 3.95-3.88 (m, 1H), 2.85-2.77 (m, 1H), 2.65-2.57 (m, 1H), 2.18 (s, 3H), 1.92-1.73 (m, 3H), 1.74-1.67 (m, 1H), 1.58-1.46 (m, 1H), 1.33-1.19 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([N+]([O-])=O)[CH:9]=[CH:8][N+:7]=1[O-:15].C[O-].[Na+].CO.C[C:22](O)=[O:23]>>[OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([O:23][CH3:22])[CH:9]=[CH:8][N+:7]=1[O-:15]
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(NCCCO)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc[n+]([O-])c(NCCCO)c1
Yield: 116 %

Procedure:
A solution of 2-[(3-hydroxy-1-propyl)amino]-4-nitropyridine-N-oxide (0.275 g, 1 mmol) and 0.5 M NaOMe in MeOH (16 mL, 8 mmol) was heated at reflux under argon for 3 hr. The reaction was then allowed to cool, and glacial AcOH (0.5 mL, 8 mmol) was added. The solution was concentrated to dryness and the residue was triturated with CH2Cl2. The insoluble materials were removed by filtration and the filtrate was concentrated. Silica gel chromatography (5-15% MeOH/CH2Cl2) gave the title compound (0.23 g, 90%) as a colorless oil: MS (ES) m/e 199.0 (M+H)+.
Reaction SMILES: O[C:2]1([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C(N(S(F)(F)[F:22])CC)C.[OH-].[Na+]>ClCCl.O>[F:22][C:2]1([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: N#Cc1ccc(C2(O)CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(C2(F)CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-(4-hydroxytetrahydro-2H-pyran-4-yl)benzonitrile (Step 1 of Intermediate 1,300 mg, 1.48 mmol) in dichloromethane (28 mL) was added dropwise N-ethyl-N-(trifluoro-λ4-sulfanyl)ethanamine (586 mg, 1.77 mmol, dissolved in 2 mL dichloromethane) at a temperature of −78° C. After 30 minutes at this temperature, the reaction mixture was rapidly warmed to −20° C. by the aid of a water/ice bath for no longer than 30 seconds whereupon NaOH (1N aq., 10 mL) was added and the reaction mixture was allowed to warm to rt. The mixture was diluted with water (100 mL) and extracted with diethyl ether. The organic extract was dried with anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the crude product was purified by MPLC (silica, cyclohexane/ethyl acetate 20:1→4:1) to afford the title compound in pure form (267 mg, 88%): 1H NMR (400 MHz, CDCl3) δ 7.68 (d, 2H), 7.50 (d, 2H), 3.98-3.83 (m, 4H), 2.23-2.05 (m, 2H), 1.91-1.85 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:17])=[C:4]([NH:10][C:11]2C=CC=CC=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[N-]=C=[O:20].C(C1C2C(=CC=CC=2)C=CC=1)#N>>[Cl:1][C:2]1[C:3]([CH3:17])=[C:4]([N:10]=[C:11]=[O:20])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(Nc2ccccc2)ccc(C#N)c1Cl
Reactant: [N-]=C=O
Agent: N#Cc1cccc2ccccc12
Product: Cc1c(N=C=O)ccc(C#N)c1Cl

Procedure:
The title compound was prepared from compound 4D in a manner similar to that described in the preparation of compound 1B.
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:4]=2[O:3]1.[BH4-].[Na+].O>C1COCC1>[F:13][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:4]=2[O:3]1
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)OC(F)(F)O2
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a solution of 2,2-difluorobenzo[d][1,3]dioxole-5-carbaldehyde (125 g, 0.67 mol) in anhydrous THF (400 mL) was added NaBH4 (28 g, 0.74 mol) in portions at 0° C. The mixture was stirred for 1 h at 0° C., then poured into 500 mL of water. The mixture was extracted with ethyl acetate (200 mL×3). The organic phase was dried over Na2SO4 and concentrated in vacuo to give (2,2-difluorobenzo[d][1,3]dioxol-5-yl)methanol as colorless oil (120 g, 95%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[O:16].[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:26]3[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][C:27]=3[O:29][CH3:30])[C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[O:16]
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: CCCNC(=O)c1nnc2c(Br)c(C#N)ccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3ccc(OC)cc3OC)c(C#N)ccc2c1N

Procedure:
Using Method G, 4-amino-8-bromo-7-cyano-N-propyl-cinnoline-3-carboxamide and 2,4-dimethoxyphenyl boronic acid were reacted to afford the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.51 (br, 1H), 7.87 (m, 2H), 7.27 (m, 1H), 6.66 (m, 2H), 3.88 (s, 3H), 3.74 (s, 3H), 3.45 (m, 2H), 1.64 (apparent sextet, 2H), 0.99 (t, J=7.0 Hz, 3H). MS APCI, m/z=392 (M+H).