Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[O:11]([C@H:15]1[CH2:20][CH2:19][C@H:18]([NH2:21])[CH2:17][CH2:16]1)[N+:12]([O-:14])=[O:13].C(OCC)(=O)C>O>[CH:1]([NH:21][C@H:18]1[CH2:17][CH2:16][C@H:15]([O:11][N+:12]([O-:14])=[O:13])[CH2:20][CH2:19]1)=[O:3]
Reactant: N[C@H]1CC[C@H](O[N+](=O)[O-])CC1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=CO
Product: O=CN[C@H]1CC[C@H](O[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6.8 ml (0.072 mol) acetic acid anhydride and 2.8 ml (0.072 mol) formic acid is heated for 2 h to 60° C. and thereafter mixed, with cooling at 5° C., with 1.9 g (0.012 mol) trans-4-nitroxycyclohexylamine. One leaves to stir overnight at room temperature, subsequently dilutes with 100 ml ethyl acetate and adds 100 ml of water thereto. After neutralisation with saturated sodium hydrogen carbonate solution, the organic phase is dried with sodium sulphate and distilled off in a vacuum. After trituration with ether, the crystals are filtered off with suction. One obtains 1.5 g of the title compound of the m p 148°-150° C., i.e. 66% of theory.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:9][C:10]([OH:12])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[ClH:13].[CH2:14](O)[CH3:15]>>[NH2:1][CH2:2][C:3]1([CH2:9][C:10]([O:12][CH2:14][CH3:15])=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[ClH:13]
Reactant: CCO
Reactant: NCC1(CC(=O)O)CCCCC1
Agent: Cl
Product: CCOC(=O)CC1(CN)CCCCC1
Reaction time: 8 h

Procedure:
10 g. of the 1-aminomethyl-1-cyclohexane-acetic acid, prepared according to Example 1, are dissolved in 50 ml. anhydrous ethanol and saturated at 0° C. with gaseous hydrogen chloride. The reaction mixture is left to stand overnight at ambient temperature, then evaporated in a vacuum and the residue recrystallised from ethanol/ether. Ethyl 1-aminomethyl-1-cyclohexane-acetate is obtained in the form of its hydrochloride; m.p. 161°-163° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:18]=[CH:17][O:16][C:15]=2[CH2:19]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[Cl:37][C:38]1[CH:39]=C(O)C=[CH:42][CH:43]=1.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]>CC#N>[Cl:37][C:38]1[CH:39]=[C:15]([CH:19]=[CH:42][CH:43]=1)[O:16][CH2:17][C:18]1[CH:47]=[CH:45][O:46][C:14]=1[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]
Reactant: Oc1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)OCc2occc2C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Clc1cccc(OCc2ccoc2C2CCNCC2)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
4-[2-(Toluene-4-sulfonyloxymethyl)furan-3-yl]piperidine-1-carboxylic acid t-butyl ester (65 mg, 0.15 mmol was dissolved in MeCN (770 μL) and added to a mixture of potassium carbonate (32 mg, 230 mmol, 1.6 eq.) and 3-chlorophenol (28.8 mg, 224 μmol, 1.5 eq.). The resulting mixture was shaken at 50° C. overnight. The mixture was then cooled and the solids removed. The supernatant was combined with TFA (12 μL, 160 mmol, 1.0 eq.) and the resulting mixture was shaken overnight at room temperature. The solution was concentrated using an evaporator, then dissolved in 1:1 AcOH:H2O (5.0 mL) then an additional 2.0 ml AcOH, filtered, and purified by preparative HPLC to yield the title compound as a TFA salt (4.3 mg, 98% purity). MS m/z: [M+H]+ calcd for C16H18ClNO2, 292.10. found 292.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[N:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23]>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([NH:1][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[F:19])[CH:3]=2)=[O:18])=[CH:12][N:13]=1
Reactant: Nc1cc(NC(=O)c2ccc(Cl)nc2)ccc1Cl
Reactant: O=C(O)c1ccccc1F
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2F)c1)c1ccc(Cl)nc1

Procedure:
N-(3-amino-4-chlorophenyl)-6-chloronicotinamide (0.16 mmol) was used in general procedure 2 with 2-fluorobenzoic acid (0.83 mmol). The product was purified by RP-HPLC to give 6-chloro-N-(4-chloro-3-(2-fluorobenzamido)phenyl)nicotinamide. MS (Q1) 404.3 (M)+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[NH2:29][C:28]1[CH:30]=[CH:31][C:25]([C:2]2[N:7]=[C:6]([NH:8][C@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH:5]=[N:4][CH:3]=2)=[CH:26][CH:27]=1
Reactant: C[C@H](Nc1cncc(Cl)n1)c1ccccc1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
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: O
Product: C[C@H](Nc1cncc(-c2ccc(N)cc2)n1)c1ccccc1

Procedure:
A mixture of 6-chloro-N-[(1S)-1-phenylethyl]pyrazin-2-amine (1.10 g, 4.71 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (1.10 g, 5.02 mmol), (PPh3)4Pd (580 mg, 0.5 mmol) and a Na2CO3 solution (2.6 ml, 2M solution) in toluene (20 ml) was heated under reflux for 40 h. Upon cooling, the mixture was diluted with water (30 mL) and the product extracted with ethyl acetate (3×40 ml). The organic layers were combined, washed with brine (30 ml), dried (Na2SO4), and the solvent removed in vacuo. The residue was purified by column chromatography, eluting with a hexane-ethyl acetate (2:3) to furnish the desired product from the polar fractions (0.86 g, 63%).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:29]=[CH:30][C:31]([O:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:32][CH:33]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OB(O)c1ccccc1
Reactant: Oc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(Oc2ccc(-c3nn4c(NC5CCCC5)cccc4c3-c3ccnc(NC4CCCC4)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 12 %

Procedure:
To a solution of 4-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol (100 mg, 0.22 mmol) in dichloromethane (5 mL) was added copper (II) acetate (40 mg, 0.22 mmol), phenylboronic acid (80 mg, 0.66 mmol), triethylamine (92 μL, 0.66 mmol) and molecular sieves. The mixture was stirred at room temperature for 24 hours. Solids were removed by filtration and the filtrate was concentrated, followed by purification by flash chromatography (2:3 ethyl acetate:hexanes) to give N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine (14 mg, 12%) as a yellow foam. 1H NMR (CDCl3): δ 8.05–6.85 (m, 12 H), 6.40 (d, 1H), 6.06 (m, 2H), 5.12 (d, 1H), 4.40 (m, 1H) 4.01 (m, 1H), 2.20–2.09 (m, 4H), 1.82–1.59 (m, 12H); MS m/z 531 (M+1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]1[CH2:51][O:50][C:13]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])([CH2:14][CH2:15][C@H:16]2[C@H:20]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH2:19][C@H:18]([OH:28])[C@@H:17]2[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])[O:12]1.C(N(CC)CC)C>ClCCl>[CH2:51]1[CH2:11][O:12][C:13]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])([CH2:14][CH2:15][C@H:16]2[C@H:20]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH2:19][C:18](=[O:28])[C@@H:17]2[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])[O:50]1
Reactant: CCCCCCCC1(CC[C@@H]2[C@@H](C/C=C\CCCCCC(=O)OC(C)C)[C@@H](O)C[C@H]2OC2CCCCO2)OCCO1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCC1(CC[C@H]2[C@H](OC3CCCCO3)CC(=O)[C@@H]2C/C=C\CCCCCC(=O)OC(C)C)OCCO1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 89.2 %

Procedure:
Oxalyl chloride (2M; 0.45 ml) and DMSO(0.13 ml) were added to dichloromethane (5 ml) which was previously cooled to −70° C. and the mixture was agitated for 15 minutes. The solution of isopropyl (Z)-9-[(1R,2R,3R,5S)-2-(3,3-ethylene dioxydecyl)-5-hydroxy-3-(tetrahydropyranyloxy)cyclopentyl]-7-nonenoate (3-a)(0.350 g) in dichloromethane (7 ml) was dropped into the mixture. The resultant mixture was warmed to −55° C. and agitated for 15 minutes, and then triethylamine (0.25 ml) was added to the mixture. The resultant mixture was warmed to 10° C. over 6 hours. The crude product obtained by the conventional treatment of the reaction mixture was purified on silica gel column to give the titled compound (5-a)[yield:0.311 g(89%)].
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:19][CH2:18][CH2:17][C:16]1([CH2:21][NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])[CH3:20])=O)(C)(C)C>C(Cl)Cl>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][NH:22][CH2:21][C:16]1([CH3:20])[CH2:17][CH2:18][CH2:19][NH:15]1
Reactant: CC(C)(C)OC(=O)N1CCCC1(C)CNCc1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(CNCc2ccccc2Cl)CCCN1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
TFA (4 mL) was added to the solution of (rac)-2-[(2-chloro-benzylamino)-methyl]-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.4 g) in DCM (15 mL) at 0° C. and stirred the reaction mixture at rt for 12 h. The reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure using a rotary evaporator and washed with ether (3×10 mL). The crude was basified with sodium bicarbonate and the aqueous layer was extracted with DCM (3×50 mL). The organic layer was dried over anhydrous Na2SO4 and distilled using rotary evaporator to give the desired (2-chloro-benzyl)-((rac)-2-methyl-pyrrolidin-2-ylmethyl)-amine as a sticky solid (Yield 40-70%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[F:20][C:21]([F:31])([F:30])[O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>>[C:14]1([C:4]2[N:3]=[C:2]([NH:27][C:26]3[CH:28]=[CH:29][C:23]([O:22][C:21]([F:20])([F:30])[F:31])=[CH:24][CH:25]=3)[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1cc(-c2ccccc2)nc(-c2ccccc2)n1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: FC(F)(F)Oc1ccc(Nc2cc(-c3ccccc3)nc(-c3ccccc3)n2)cc1

Procedure:
The title compound was prepared from 4-chloro-2,6-diphenyl-pyrimidine (0.25 g, 0.93 mmol) and 4-trifluoromethoxy aniline (0.16 g, 0.93 mmol) according to the procedure as described above.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([OH:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O>[CH2:8]([O:22][C:4]([CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[O:5])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCCCO
Reactant: O=C1CCC(=O)O1
Solvent: O
Product: CCCCCCCCCCCCCCOC(=O)CCC(=O)O
Temperature: 80 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
Succinic anhydride (24.2 g) and tetradecanol (42.9 g) were molten by heating them at 120° to 130° C. and stirred for 3 hours. After completion of the reaction, the reaction mixture was cooled to 80° C., and 50 ml of water was added thereto. The mixture was stirred for one additional hour. The reaction mixture was cooled to room temperature and extracted with 200 ml of ethyl acetate. The ethyl acetate solution was washed with 200 ml of water three times and concentrated to dryness under reduced pressure. There was obtained 60.9 g (96.8%) of 3-tetradecyloxycarbonylpropionic acid. Melting point: 48° to 49° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[O:11][CH2:12][C:13](O)=[O:14])=[O:9])[C:4](=[O:24])[O:3]1.C(Cl)(=O)C(Cl)=O.[CH3:32][NH:33][CH3:34].N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.CN(C)C=O>[CH3:32][N:33]([CH3:34])[C:13]([CH2:12][O:11][N:10]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:8](=[O:9])[CH:7]=[C:5]1[C:4](=[O:24])[O:3][C:2]([CH3:25])([CH3:1])[O:6]1)=[O:14]
Reactant: CC1(C)OC(=O)C(=CC(=O)N(Cc2ccc(F)cc2)OCC(=O)O)O1
Reactant: CNC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reaction time: 2 h
Yield: 50.4 %

Procedure:
A solution of [[2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-acetyl]-(4-fluorobenzyl)-aminooxy]-acetic acid (0.681 g, 1.93 mmol) in dichloromethane (20 ml) was treated at 22° C. with oxalyl chloride (0.34 ml, 3.9 mmol) and a trace of N,N-dimethylformamide and the resulting mixture was stirred for 1 h. The solvent and excess reagent were then evaporated in vacuo. The residual material was dissolved in dry dichloromethane (10 ml) and added dropwise to a cold (0° C.) solution of dimethylamine (0.18 g, 4.0 mmol) and pyridine (0.25 ml, 3.2 mmol) in dichloromethane. After 2 h, the reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent in vacuo and crystallisation of the residue from a mixture of ethyl acetate and hexane gave 0.370 g (50% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.77 (6H, s, CH3), 2.91 (3H, s, CH3), 2.97 (3H, s, CH3), 4.53 (2H, s, CH2), 4.93 (2H, s, CH2), 6.43 (1H, s, CH), 7.03 (2H, m, aromatics), 7.41 (2H, m, aromatics).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[O:25]=[C:26]1[NH:30][C@H:29]([CH2:31][O:32]C(=O)C2C=CC=CC=2)[CH2:28][O:27]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:30]4[C@H:29]([CH2:31][OH:32])[CH2:28][O:27][C:26]4=[O:25])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)cc3F)CC2)c(C)c1
Yield: 21.2 %

Procedure:
By reaction and treatment in the same manner as in Example 19 and using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.2 g) described in Preparation Example 65 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (849 mg), the title compound (278 mg) was obtained.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[SH:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cl-].[Na+].O>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1
Reactant: Fc1ccccc1S
Reactant: CN1CCC(Cl)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC(Sc2ccccc2F)CC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
A mixture of 4-chloro-1-methylpiperidine (110.1 g), 2-fluorothiophenol (117.3 g), and potassium carbonate (170.8 g) in N,N-dimethylformamide (1.0 l) was stirred at 90° C. for 2 hours and filtered. The filtrate was concentrated in vacuo to give an oily residue, which was diluted with brine and extracted three times with diethyl ether. The extracts were dried over magnesium sulfate, concentrated in vacuo, and distilled to give 4-[(2-fluorophenyl)thio]-1-methylpiperidine (111.1 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([OH:40])[CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:39][CH2:38][CH2:37][CH:36]([OH:40])[CH2:35]3)(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: O=S(=O)(c1ccccc1Br)N1CCCC(O)C1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCCC(O)C3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and racemic-1-((2-bromophenyl)sulfonyl)piperidin-3-ol. MS (ESI): mass calcd. for C21H21FN4O3S, 428.13; m/z found, 429.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.34 (s, 1H), 8.31 (d, J=1.4, 1H), 8.11-8.06 (m, 1H), 8.01-7.96 (m, 1H), 7.73-7.68 (m, 1H), 7.64-7.59 (m, 1H), 7.44-7.40 (m, 1H), 7.34-7.32 (m, 1H), 7.31-7.29 (m, 1H), 3.44-3.35 (m, 1H), 3.27-3.21 (m, 1H), 3.15-3.06 (m, 1H), 2.48-2.38 (m, 1H), 2.27-2.21 (m, 1H), 1.88-1.79 (m, 1H), 1.68-1.59 (m, 1H), 1.41-1.28 (m, 1H), 1.26-1.15 (m, 1H).
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9](C)C)[CH2:3][CH2:2]1.[F:13][C:14]1[C:21]([CH3:22])=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][N:6]([C:20]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([F:13])[C:21]=3[CH3:22])[C@H:5]2[CH3:9])[CH2:2][CH2:3]1
Reactant: Cc1c(F)ccc(C#N)c1F
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: Cc1c(N2CC[C@@](O)(C3CC3)[C@@H]2C)ccc(C#N)c1F

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3R)-3-cyclopropyl-2-methylpyrrolidin-3-ol 0.5 oxalate (260 mg), 2,4-difluoro-3-methylbenzonitrile (364 mg) and lithium carbonate (234 mg), the title compound was obtained as a colorless solid (yield: 106 mg, yield: 24%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:34])=[C:4]([CH2:8][N:9]([C:21]2[N:22]=[C:23]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[S:24][C:25]=2[C:26]#[N:27])[C:10](=O)[CH2:11][NH:12]C(=O)OC(C)(C)C)[CH:5]=[CH:6][CH:7]=1.B1([O-])O[O:36]1.O.O.O.O.[Na+].Cl.O1CCOCC1>CO.O.CCOC(C)=O>[NH2:12][CH2:11][C:10]1[N:9]([CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:34])[C:21]2[N:22]=[C:23]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[S:24][C:25]=2[C:26](=[O:36])[N:27]=1
Reactant: [O-]B1OO1
Reactant: Cc1c(Cl)cccc1CN(C(=O)CNC(=O)OC(C)(C)C)c1nc(N2CCOCC2)sc1C#N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1c(Cl)cccc1Cn1c(CN)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 55 °C
Reaction time: 2 h
Yield: 7.5 %

Procedure:
To a solution of 1,1-dimethylethyl (2-{[(3-chloro-2-methylphenyl)methyl][5-cyano-2-(4-morpholinyl)-1,3-thiazol-4-yl]amino}-2-oxoethyl)carbamate (150 mg, 0.296 mmol) in Methanol (5 mL) and Water (5.00 mL) was added sodium perborate tetrahydrate (137 mg, 0.889 mmol). The mixture was stirred at 55° C. for 2 hr and then diluted in 100 mL EtOAc. After washed with 100 mL H2O, the organic layer was concentrated and diluted in 10 mL DCM, to which was added 4M HCl in dioxane (0.371 mL, 1.482 mmol). The mixture was stirred at rt for 17 hr. One fourth of the crude material was purified by HPLC and then treated with HCl (6N) to give the titled compound 9 mg (26%). LC/MS (ES) m/z=406.4 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 7.42-7.40 (d, 1H, J=8.0 Hz), 7.18-7.12 (m, 1H), 6.55 (d, 1H, J=8.0 Hz), 5.65 (s, 2H), 4.21 (s, 2H), 3.79-3.76 (m, 4H), 3.68-3.62 (m, 4H), 2.52 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:10]([Cl:20])[C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]=1.[CH:21]([NH2:25])([CH2:23][CH3:24])[CH3:22]>CN(C=O)C>[CH:21]([NH:25][C:2]1[C:11]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:10]([Cl:20])[C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]=1)([CH2:23][CH3:24])[CH3:22]
Reactant: CCC(C)N
Reactant: Fc1cccc(Cl)c1-c1c(Cl)nc2ccncc2c1Cl
Solvent: CN(C)C=O
Product: CCC(C)Nc1nc2ccncc2c(Cl)c1-c1c(F)cccc1Cl
Temperature: 70 °C

Procedure:
The product from Step 3 (0.10 g) was dissolved in DMF (2 ml). Sec-butylamine (0.2 ml) was added and the mixture was refluxed in a sealed tube at 70° C. for 14 hours. The dark coloured reaction mixture was evaporated to give an oil, which was purified by flash column chromatography on silica gel (40-60) in ethyl acetate:hexane 1:1 to give N-sec-butyl-4-chloro-3-(2-chloro-6-fluorophenyl)-1,6-naphthyridin-2-amine as a light yellow gum (0.08 g).
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1>[Br:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]([OH:12])[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCNc2nc(Br)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC1CCNc2nc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 7-bromo-2,3-dihydro-1,8-naphthyridin-4(1H)-one (500 mg, 2.20 mmol) in THF (15 ml) was treated with NaBH4 (167 mg, 4.40 mmol) and stirred at 25° C. for 2 h. The reaction mixture was quenched with sat. aq. NH4Cl and extracted 2× with DCM. The org layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 50:50) to give the title compound as a white solid. (UPLC-MS 3) tR 0.59; ESI-MS 229.0, 231.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Cl:12]C[C:14]([NH:16]CO)=O.S(=O)(=O)(O)O>C(O)(=O)C.Cl.C(O)C.Cl>[ClH:12].[NH2:16][CH2:14][C:9]1[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH:6]=[CH:7][C:8]=1[OH:11]
Reactant: O=C(CCl)NCO
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)c1ccc(O)c(CN)c1
Temperature: 20 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
A mixture of 4-(1,1-dimethylethyl)phenol (75 g., 0.50 mole), 2-chloro-N-(hydroxymethyl)acetamide (61 g., 0.50 mole) and 96% sulfuric acid (50 ml.) in acetic acid (500 ml.) is stirred at 20° C. for 4 hours and then poured into ice water (2 l.) providing a heterogenous mixture. After decanting the aqueous solution, the insoluble white gum is extracted with ether. The organic extract is washed with water and saturated brine and evaporated in vacuo leaving a residual oil. A solution of the latter in 12N hydrochloric acid-ethanol (1:1; 400 ml.) is heated at reflux for 4 hours, diluted with 12N hydrochloric acid (200 ml.) and slowly cooled to -20° C. The deposited white crystalline solid is collected to provide pure 2-aminomethyl-4-(1,1-dimethylethyl)phenol hydrochloride (55 g.), m.p. 227°-229° C. (dec.).