Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:33](=[O:34])[C:32]2[CH:36]=[CH:37][CH:38]=[C:30]([F:29])[CH:31]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)c4cccc(F)c4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure VII as described above, the acylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with commercially available 3-fluorobenzoyl chloride gave the title compound. ES-MS m/e (%): 521.4 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:8]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[O:11][C:10]([CH3:18])([CH3:17])[C:9]2=[O:19])[CH:7]=1.[H-].[Na+].C([Li])CCC.C[O:29][B:30](OC)[O:31]C>O1CCCC1>[CH3:2][CH2:3][CH2:4][CH:5]([CH3:20])[CH3:6].[CH3:20][C:5]1[CH:4]=[CH:3][C:2]([B:30]([OH:31])[OH:29])=[CH:7][C:6]=1[CH:8]1[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[O:11][C:10]([CH3:18])([CH3:17])[C:9]1=[O:19]
Reactant: COB(OC)OC
Reactant: Cc1ccc(Br)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(C)C
Product: Cc1ccc(B(O)O)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
4-(5-Bromo-2-methyl-phenyl)-2,2,6,6-tetramethyl-pyran-3,5-dione (5 g, 0.0147 mol) is dissolved in anhydrous tetrahydrofuran (150 ml), the reaction mixture is cooled to 0° C. and sodium hydride (708 mg, 0.0294 mol, 60% dispersion in oil) is added. The mixture is stirred for 30 minutes, then cooled to −78° C. n-Butyl lithium (14.7 ml, 0.0294 mol, 2M solution in cyclohexane) is added, dropwise over approximately 10 minutes and reaction mixture is stirred for 15 minutes before trimethylborate (4.95 ml, 0.0442 mol) is added. The reaction mixture is stirred for a further 45 minutes, allowed to warm to ambient temperature and then stirred a further 1.5 hours before quenching with 2M aqueous hydrochloric acid. The reaction mixture is stirred for 1 hour and then extracted with dichloromethane. After separation of the organic phase solvents are removed under reduced pressure to give a pale yellow gum. Trituration with iso-hexane affords 4-methyl-3-(2,2,6,6-tetramethyl-3,5-dioxo-tetrahydropyran-4-yl)phenylboronic acid (2.01 g) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](O)=[CH:16][C:15]=1[F:21]>>[ClH:13].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:10][CH:5]2[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([CH3:1])[C:3]([CH3:12])([CH3:11])[CH2:4]2)=[CH:16][C:15]=1[F:21]
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Reactant: Oc1ccc(Cl)c(F)c1
Product: CN1C(C)(C)CC(Oc2ccc(Cl)c(F)c2)CC1(C)C
Product: Cl

Procedure:
Was prepared according to method A from 1,2,2,6,6-pentamethyl-piperidin-4-ol and 4-chloro-3-fluorophenol. Mp 187.2-190.7° C.
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].Cl[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:9].[OH-].[Na+].C([OH:34])(C)C>CCCCCC>[C:8](=[O:34])([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:9][O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OO
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)Cl
Reactant: CC(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCCCOC(=O)OOOC(C)(C)C

Procedure:
Tertiary-butylperoxy octadecyl carbonate was prepared by reaction of tertiary-butyl hydroperoxide with octadecyl chloroformate. Tertiary-butyl hydroperoxide, 70 percent (27.0 grams, 0.21 mole) was placed in a flask, and sodium hydroxide, 20 percent (43.3 grams, 0.22 mole) was added slowly at lower than 20° C., followed by the addition of 10.0 grams of isopropanol all at once. Octadecyl chloroformate (66.5 grams, 0.20 mole) and hexane (115.8 grams) were combined in an addition funnel and added over a period of 90 minutes at about 35° C. The resulting mixture wa phase-separated and the organic layer was washed with three 100 milliliter portions of water. Yield was 179.9 grams, 93.2 percent by weight of theoretical.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[N:21]1([CH:27]2[CH2:33][CH2:32][C:31]3[CH:34]=[C:35]([NH2:38])[CH:36]=[CH:37][C:30]=3[CH2:29][CH2:28]2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(O)(C)C.Cl.O1CCOCC1>>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:38][C:35]2[CH:36]=[CH:37][C:30]3[CH2:29][CH2:28][CH:27]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:33][CH2:32][C:31]=3[CH:34]=2)=[N:3][CH:4]=1
Reactant: CS(=O)(=O)NC1CCCCC1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)CCC(N2CCOCC2)CC3)ncc1Cl
Reaction time: 0.17 h

Procedure:
Into a microwave vial was placed N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (1.0E2 mg, 0.00029 mol) and 7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (0.080 g, 0.00032 mol) in isopropyl alcohol (4.0 g, 0.066 mol). To this mixture was added 4N HCl-dioxane (0.03 g, 0.0003 mol) and the contents subjected to microwaves at 120° C. for 10 min. The mixture was resubjected to the same conditions for an additional 15 min. for complete conversion of starting materials. A solid had precipitated out of solution and was redissolved in methylene chloride and washed with sat. aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo to a tan foam. The solid was dried at 50° C. in a vacuum oven overnight to give N-{(1R,2R)-2-[5-Chloro-2-(7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide isolated as a mixture of diasteromers as a beige foam (72 mg, 44% yield). 1HNMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 7.92 (s, 1H), 7.54 (d, 1H, J=7.6 Hz), 7.35 (t, 1H, J=8.34), 7.18 (dd, 1H, J=5.05, 8.6 Hz), 6.97 (d, 1H, J=8.1 Hz), 6.69 (d, 1H, J=7.6 Hz), 3.84 (m, 1H), 3.55 (broad s, 4H), 3.37 (m, 1H), 2.94 (s, 3H), 2.43-2.78 (m, 9H), 1.96-2.09 (m, 4H), 1.70 (d, 2H, J=8.6 Hz), 1.18-1.36 (m, 6H); MS (m/e) 549 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[C:10]([F:18])[CH:9]=2)=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:20][N:21]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[C:23]([CH3:35])=[N:22]1>>[NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:18])[CH:9]=2)=[CH:6][C:5]([C:24]2[C:23]([CH3:35])=[N:22][N:21]([CH3:20])[CH:25]=2)=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(-c2cc(Br)cnc2N)cc1F
Reactant: Cc1nn(C)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1nn(C)cc1-c1cnc(N)c(-c2ccc(C(=O)O)c(F)c2)c1

Procedure:
Following Steps 2 and 3 in Scheme 97, using methyl 4-(2-amino-5-bromopyridin-3-yl)-2-fluorobenzoate and 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 4-(2-amino-5-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-fluorobenzoic acid was obtained. LCMS (m/z): 327.2 (MH+), 0.47 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:5]=[CH:6][CH:7]=1.[C:25]1([S:35](Cl)(=[O:37])=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:4]2[CH:3]=[C:2]([NH:1][S:35]([C:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:28]=[CH:27][CH:26]=4)(=[O:37])=[O:36])[CH:7]=[CH:6][CH:5]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: Nc1cccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)c1
Product: O=C1CC(=O)N(c2cccc(NS(=O)(=O)c3cccc4ccccc34)c2)c2ccc3ccccc3c2N1
Yield: 100 %

Procedure:
By using 5-(3-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 53, (1), and naphthalene-1-sulfonyl chloride, the title compound (yield 100%) was obtained in the same manner as that of Example 150.
Reaction SMILES: [Br:1][CH:2]1[CH2:7][NH:6][CH:5](Br)[CH2:4]N1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15](=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:15]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: C1CNCCN1
Reactant: BrC1CNC(Br)CN1
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc(N2CCNCC2)nc1
Temperature: 25 °C

Procedure:
A solution of 2,5-dibromo piperazine (1.59 g, 8 mmole), and piperazine(1.45 g, 16 mmole), and potassium carbonate (6 g) in acetonitrile (50 mL) was heated at reflux for 48 h. The heating was discontinued and the solution allowed to cool to room temperature. The solid was filtered off and washed with acetonitrile (50 mL). The organics were concentrated to a tan solid. The product was purified by column chromatography on silica gel using dichloromethane:methanol:triethylamine (94:5:1) as eluent to provide (5-bromopyridin-2-yl)-piperazine as an offwhite solid (1.75 g, 95%). δH (300 MHz CDCl3) 1.75 (1H, br s), 2.95 (4H, m, piperaziny), 3.45 (4H, m, piperazinyl), 6.52 (1H, d, J=9.0), 7.51 (1H, dd, J=2.5 and 9.0), 8.17 (1H, d, J=2.4), ESMS 243 (MH+).
Reaction SMILES: C(F)(C(F)(F)F)=C(F)F.C(F)(C(F)(F)F)=C(F)F.C(F)(C(F)(F)F)=C(F)F.[F:28][C:29]([F:54])([F:53])[C:30](F)=[C:31]([C:42]([F:51])([C:47]([F:50])([F:49])[F:48])[C:43]([F:46])([F:45])[F:44])[C:32]([F:41])([C:37]([F:40])([F:39])[F:38])[C:33]([F:36])([F:35])[F:34].[C:55]1([Li])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>CCOCC>[C:55]1([C:30](=[C:31]([C:32]([F:41])([C:37]([F:38])([F:39])[F:40])[C:33]([F:34])([F:35])[F:36])[C:42]([F:51])([C:43]([F:46])([F:45])[F:44])[C:47]([F:50])([F:49])[F:48])[C:29]([F:54])([F:53])[F:28])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: [Li]c1ccccc1
Reactant: FC(=C(C(F)(C(F)(F)F)C(F)(F)F)C(F)(C(F)(F)F)C(F)(F)F)C(F)(F)F
Agent: FC(F)=C(F)C(F)(F)F
Solvent: CCOCC
Product: FC(F)(F)C(=C(C(F)(C(F)(F)F)C(F)(F)F)C(F)(C(F)(F)F)C(F)(F)F)c1ccccc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Under argon atmosphere, 1.0 mmol (459 mg) of hexafluoropropene trimer mixture [including 5 wt % of perfluoro-(3-ethyl-2,4-dimethyl-2-pentene)] comprising perfluoro-(4-methyl-3-isopropyl-2-pentene) as a main component was put in a 100 ml egg-plant-shaped flask with a three-way stopcock having a magnet stirrer made of Teflon (R) therein. Then, 10 ml of anhydrous ether dry-distilled on sodium was added into the mixture, and stirringly dissolved therein. 0.5 ml (1.0 mmol) of cyclohexane-ether solution containing 17% of phenyl lithium was dropped into the mixture from a dropping funnel in the interval of about 3 minutes, while maintaining the mixture at about −78° C. by cooling the reaction vessel in a dry ice-ethanol bath. After continuously stirring at about −50° C. for about 3 hours, the resulting reacted mixture became a yellow solution including a brown solid. The reaction mixture was poured into 30 ml of ice water. Then, 20 ml of ether was added therein to extract a target compound, and the extracted compound was rinsed with 30 ml of salt solution. After the reacted ether mixture was dried with magnesium sulfate for one night, the resulting mixture was subjected to reduced-pressure distillation under a vacuum of 5 mmHg to remove ether, and then subjected to reduced-pressure distillation under a vacuum of 10 mmHg. As a result, a mixture of 3 different conformational isomers of 2-phenyl-perfluoro-(4-methyl-3-isopropyl-2-pentene) was obtained. The respective structures of the obtained compounds were determined by 19F-NMR, 1H-NMR, GC-MS and others. The yields of conformational isomers A, B and C of 2-phenyl-perfluoro-(4-methyl-3-isopropyl-2-pentene) calculated from the integral ratio of the peak areas of the 19F-NMR spectrum were about 24% , 16% and 12%, respectively.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.F[C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24].O>CN(C=O)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=2[N+:23]([O-:25])=[O:24])=[CH:10][CH:9]=1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccc(Cl)cc2)c([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
1.4 g of potassium carbonate were added to a solution of 1.29 g of 4-chlorophenol in 8 ml of DMF and, after stirring for 30 minutes, 1.6 g of 4-fluoro-3-nitroaniline were added, and the mixture was stirred at 100° C. for 3 hours. After cooling, 80 ml of water were added and, after brief stirring, the precipitate was filtered off with suction and dried in vacuo at 40° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:32]#[N:33])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:34]=[C:35](Br)[CH:36]=[N:37][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C>[Pd].ClCCl>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:32]#[N:33])=[C:18]([O:19][CH:20]4[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:25]4)[C:13]=3[C:12]3[CH:34]=[CH:35][CH:36]=[N:37][C:11]2=3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)CCN1CCC(Oc2c(C#N)ncc3c2c2cc(Br)cnc2n3S(=O)(=O)c2ccccc2)CC1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)CCN1CCC(Oc2c(C#N)ncc3c2c2cccnc2n3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.5 %

Procedure:
A suspension of 9-benzenesulfonyl-3-bromo-5-[1-(2-methanesulfonyl-ethyl)-piperidin-4-yloxy]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (245 mg, 0.39 mmol) and palladium on carbon (10 wt %, 50 mg) in industrial methylated spirits (5 mL), dichloromethane (5 mL), and triethylamine (3 mL) was stirred at ambient temperature under an atmosphere of hydrogen for 24 hours. The reaction vessel was purged with nitrogen then the reaction mixture was filtered through a PTFE filter cup. The filtrate was evaporated in-vacuo and the resultant residue purified by flash chromatography (silica, 10 g column, ISCO, 0-50% ethyl acetate in dichloromethane) to afford the title compound as an off-white solid (140 mg, 65%). LCMS (Method C): RT=4.97 min, M+H+=400. 1H NMR (300 MHz, DMSO-d6): 9.49 (s, 1H), 8.76 (dd, J=4.8, 1.6 Hz, 1H), 8.63 (dd, J=7.9, 1.7 Hz, 1H), 8.25-8.24 (m, 2H), 7.76 (t, J=7.4 Hz, 1H), 7.64-7.63 (m, 3H), 4.76-4.75 (m, 1H), 3.26 (t, J=7.4 Hz, 2H obscured by solvent peak), 3.02 (s, 3H), 2.88 (d, J=11.3 Hz, 2H), 2.72 (t, J=6.8 Hz, 2H), 2.14-2.14 (m, 4H), 1.91-1.91 (m, 2H).
Reaction SMILES: [F:1][CH:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=O)[CH2:3]1.[OH-].[K+].[Cl:12][C:13]1[C:18]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:17][C:16]([N:23]=[C:24]=[S:25])=[C:15]([F:26])[CH:14]=1.C1(N=C=NC2CCCCC2)CCCCC1>CO.O.C(#N)C>[Cl:12][C:13]1[C:18]([O:19][CH:20]([CH3:21])[CH3:22])=[CH:17][C:16]([N:23]=[C:24]2[N:5]3[CH2:6][CH:2]([F:1])[CH2:3][CH:4]3[C:7](=[O:9])[S:25]2)=[C:15]([F:26])[CH:14]=1
Reactant: O=C(O)[C@@H]1CC(F)CN1
Reactant: CC(C)Oc1cc(N=C=S)c(F)cc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: CC(C)Oc1cc(N=C2SC(=O)C3CC(F)CN23)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A mixture of 1.31 g (0.01 mol) 4-fluoroproline, 30 mL 2N KOH in methanol and 10 mL water is prepared before 2.46 g (0.01 mol) 4-chloro-2-fluoro-5-isopropoxy-phenylisothiocyanate dissolved in 250 mL methanol is added dropwise. The reaction mixture is stirred overnight at room temperature, the aqueous phase adjusted to pH 2 and the resultant product (3.77 g, See Formula X) is filtered. The compound thus obtained is dissolved in 50 mL acetonitrile before 2.59 g (0.01 mol) dicyclohexylcarbodiimide is added at room temperature. The reaction mixture is stirred for 3 h and the crude product is purified by silica gel chromatography to give 3.24 g (85% yield) of the desired product.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:24]=[CH:23][C:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:16][C:10]=2[C:9]=1O.CI>CC(C)=O>[Br:7][C:8]1[CH:24]=[CH:23][C:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:22])[C:18]([F:19])([F:21])[F:20])[CH2:15][CH2:16][C:10]=2[C:9]=1[O:4][CH3:1]
Reactant: O=C(N1CCc2ccc(Br)c(O)c2CC1)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(Br)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Reaction time: 0.17 h
Yield: 98.8 %

Procedure:
Add potassium carbonate (10.214 g, 73.9 mmol) to a solution of 7-bromo-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (5.0 g, 14.8 mmol) in acetone (50 mL) and stir for 10 min. Add methyl iodide (4.2 g, 1.5 mL, 29.6 mmol) and stir the mixture overnight at room temperature. Remove the solvent in vacuo and partition the residue between water and DCM. Extract the aqueous phase twice with DCM. Combine the organic extracts, dry over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate as a solid (5.15 g, 99%). MS (ES+) m/z: 352 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][CH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][N:37](C(OC(C)(C)C)=O)[CH:38]=2)O1>>[ClH:1].[ClH:1].[ClH:1].[CH3:24][N:23]([CH2:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([NH:15][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:34]4[CH:35]=[N:36][NH:37][CH:38]=4)[N:3]=3)[N:8]=[CH:7][C:6]=2[C:12](=[O:14])[CH3:13])[CH2:17][CH2:18]1)[CH3:25]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1NC1CCC(CN(C)C)CC1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(=O)c1cnc2ccc(-c3cn[nH]c3)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Product: Cl

Procedure:
Following general procedure II, 1-(6-chloro-4-{4-[(dimethylamino)methyl]-cyclohexylamino}-1,5-naphthyridin-3-yl)ethanone (55 mg, 0.15 mmol) was reacted with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (66 mg, 0.225 mmol) followed by formation of the trihydrochloride salt to afford the desired product (32 mg, 42%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 9.10 (s, 1H), 8.34 (s, 2H) 8.30-8.23 (m, 2H), 5.64 (m, 1H), 3.14 (d, J=6.7 Hz, 2H), 2.94 (s, 6H), 2.75 (s, 3H), 2.47 (d, J=13.0 Hz, 2H), 2.09-1.97 (m, 3H), 1.73-1.61 (m, 2H), 1.45-1.33 (m, 2H); ESI MS m/z 393 [M+H]+; HPLC 98.3% (AUC), tR=8.60 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C.CO.Cl>C(Cl)Cl.CCOCC>[CH2:16]([N:14]([CH3:15])[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(Cc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: CN(Cc1ccccc1)C1CCNCC1

Procedure:
4-(Benzyl-methyl-amino)-piperidine-1-carboxylic acid tert-butyl ester was dissolved in DCM and methanol and 2.0M HCl in ether was added. After 3 hours the solvent was removed in vacuo and the residue was recrystallised from ethyl acetate/methanol to yield benzyl-methyl-piperidin-4-yl-amine (hydrochloride salt).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH:5]=O.[CH3:16][C:17]([CH3:19])=[O:18].CO.[OH-].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:16]/[C:17](=[O:18])[CH3:19])[CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=Cc1ccc(C2CCCCC2)c(Cl)c1
Reactant: CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)/C=C/c1ccc(C2CCCCC2)c(Cl)c1
Yield: 40 %

Procedure:
222.72 Gm (1.0 mol) of 3-chloro-4-cyclohexyl-benzaldehyde, 3,500 gm (60.3 mols) of acetone and 200 ml of methanol were charged into a 6-liter three-necked flask equipped with a stirrer, dropping funnel and internal thermometer. While thoroughly stirring the contents of the flask, a solution of 2.805 gm (0.05 mol) of potassium hydroxide in 16 ml of water was added dropwise thereto, while an internal temperature of 20° to 25°C was maintained. The mixture was then stirred for 3 hours more. The precipitate solid by-product was filtered off, and the filtrate was neutralized by dropwise addition of glacial acetic acid, and concentrated by evaporation in vacuo. The residue was shaken with a mixture of water and ether. The ether phase separated, dried over sodium sulfate, clarified with charcoal, and evaporated. The residual oil was distilled in a high vacuum (b.p. 162°-175°C at 0.2 mm Hg), crystallized by trituration with a small quantity methanol, and finally recrystallized once from methanol. The colorless crystals melted at 48°-49°C. Yield: 40 % of theory.
Reaction SMILES: [CH:1]1([C:4]#[CH:5])[CH2:3][CH2:2]1.[Li]CCCC.[NH2:11][C:12]1[C:17]([F:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=1[C:20](=[O:25])[C:21]([F:24])([F:23])[F:22]>C1(C)C=CC=CC=1.C1COCC1>[NH2:11][C:12]1[C:17]([F:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=1[C:20]([OH:25])([C:5]#[C:4][CH:1]1[CH2:3][CH2:2]1)[C:21]([F:22])([F:23])[F:24]
Reactant: C#CC1CC1
Reactant: Nc1c(F)cc(Cl)cc1C(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Nc1c(F)cc(Cl)cc1C(O)(C#CC1CC1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 48.5 %

Procedure:
To a stirred, cooled (0° C.) solution of 2.0 mL (7.0 mmol) of 3.5M cyclopropylacetylene in toluene was added 2 mL of THF followed by 2.8 mL (7.0 mmol) of 2.5M n-BuLi in hexanes over 2 min. The solution was stirred 5 min. at 0° C., warmed to RT, and stirred a further 20 min. The reaction was cooled to 0° C. and treated with a solution of 300 mg (1.24 mmol) of 2'-amino-5'-chloro-3'-fluoro-2,2,2-trifluoroacetophenone in 3mL of THF over 2 min. The solution was stirred an additional 10 min. and the cold bath was removed. The reaction was stirred 5 min and poured into 0.5N citric acid. The mixture was extracted with ether, and the organic extract was washed with water then brine, dried (MgSO4), and concentrated under reduced pressure. Chromatography on silica gel (elution with hexanes then 3:1 hexanes-ether) afforded 185 mg (49%) of (±)-2-amino-5-chloro-3-fluoro-α-(cyclopropylethynyl)-α-(trifluoromethyl)benzyl alcohol as an off-white solid, mp 131°-135° C. 1H NMR (300 MHz, CDCl3) δ7.34-7.36(m, 1H); 7.04(dd, 1H, J=10.4, 2.4 Hz); 4.58(br. s, 2H); 3.82(br. s, 1H); 1.35-1.44(m, 1H); 0.80-0.99(m, 4H). 19F NMR (282 MHz, CDCl3) δ-131.5(s, 1F), -80.5(s, 3F). High resolution mass spec: calculated for C13H11NOClF4 (M+H)+ : 308.0470, found: 308.0465.