Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39](=[O:47])[C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[N:42][CH:41]=1>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([C:44]2[CH:45]=[C:40]([CH:39]=[O:47])[CH:41]=[N:42][C:43]=2[CH3:46])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Reactant: CON(C)C(=O)c1ccc(C)nc1
Product: Cc1ncc(C=O)cc1-c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(Cl)c1F

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42) and N-methoxy-6,N-dimethyl-nicotinamide.
Reaction SMILES: [C:1](O)(=O)C.C([BH3-])#N.[Na+].[N:9]1([CH2:15][CH2:16][NH:17][C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[C:23]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[NH:24][C:25]3=[O:28])=[CH:20][CH:19]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(=O)(O)[O-].[Na+]>CO>[CH3:1][N:17]([CH2:16][CH2:15][N:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)[C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[C:23]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:24][C:25]2=[O:28])=[CH:20][CH:19]=1
Reactant: O=c1[nH]c(-c2ccccc2)cc2ccc(NCCN3CCOCC3)cc12
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN(CCN1CCOCC1)c1ccc2cc(-c3ccccc3)[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84 %

Procedure:
0.05 ml of acetic acid and 13.2 mg (0.168 mmol) of sodium cyanoborohydride were added to 0.5 ml of a methanol solution containing 14.7 mg (0.0241 mmol) of the 7-(2-morpholin-4-ylethylamino)-3-phenyl-2H-isoquinolin-1-one obtained in Example 15. The obtained mixture was stirred at a room temperature for 6 hours. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and was then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=20:1), so as to obtain 12.8 mg (84%) of 7-[methyl(2-morpholin-4-ylethyl)amino]-3-phenyl-2H-isoquinolin-1-one in the form of a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[NH:15]1[CH:19]=[CH:18][CH:17]=[N:16]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)[CH3:13])[CH2:11][O:10]1
Reactant: c1cn[nH]c1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1cccn1)[C@@]1(c2ccc(F)cc2F)CO1

Procedure:
Using (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (569 mg) and pyrazole, (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(1H-pyrazol-1-yl)ethyl]oxirane (166 mg) was obtained by the same way as in Reference Example 2.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([CH2:17][NH2:18])[N:13]([C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C[O:36][C:37](=O)[C:38]1[C:43]([O:44][CH3:45])=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:46]Cl>C(#N)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([CH2:17][N:18]3[CH2:46][C:39]4[C:38](=[C:43]([O:44][CH3:45])[CH:42]=[CH:41][CH:40]=4)[C:37]3=[O:36])[N:13]([C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1c(CCl)cccc1OC
Reactant: C[C@@H](c1ccccc1)N1Cc2sc(N)c(C(=O)OC(C)(C)C)c2C[C@H]1CN
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cccc2c1C(=O)N(C[C@@H]1Cc3c(sc(N)c3C(=O)OC(C)(C)C)CN1[C@@H](C)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.8 %

Procedure:
2-Amino-5-(S)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.55 g, 1.42 mmol) and triethylamine (396 μl, 2.84 mmol) was heated in acetonitrile (15 ml) under an atmosphere of nitrogen to 60° C. whereupon a solution of 2-chloromethyl-6-methoxy-benzoic acid methyl ester (0.32 g, 1.49 mmol) in acetonitrile (5 ml) was added dropwise over the course of 3 hours, keeping the reaction mixture at 60° C. The reaction was allowed to cool to room temperature and was left for 16 hours before the solvent was evaporated in vacuo. The product was purified by column chromatography (SiO2, Flash 40, ethyl acetate-petrol ether) to give 400 mg (53%) of 2-amino-5-(S)-(7-methoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-((S)-1-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([NH:6][CH:7]([CH:9]1[CH2:11][CH2:10]1)[CH3:8])=[O:5].[H-].[Na+].[Br:19]Br.Cl>CN(C)C=O>[NH2:1][C:2]1[C:15]([Br:19])=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([NH:6][CH:7]([CH:9]1[CH2:11][CH2:10]1)[CH3:8])=[O:5]
Reactant: BrBr
Reactant: CC(NC(=O)c1cc(Cl)ccc1N)C1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cc(Cl)cc(Br)c1N)C1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.1 g of 2-amino-5-chloro-N-(1-cyclopropylethyl)benzamide was dissolved in 3 ml of N,N-dimethylformamide and cooled to 0° C. 0.02 g of sodium hydride was added, followed by stirring for one hour, and 0.09 g of bromine was added, followed by stirring for 2 hours. The reaction liquid was added to a 1 M-HCl aqueous solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 1/1) to obtain 0.08 g of the pale yellow desired produce (melting point: 177° C.).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[C:17]1([C:14]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH2:8][NH:7][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])[CH2:16][CH2:15]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=C1CC(=O)O1
Reactant: NCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)NCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Reaction time: 48 h
Yield: 78.2 %

Procedure:
Diketene (0.44 mL, 5.68 mmol, 1.3 equiv, Aldrich) was added at room temperature to a stirred solution of 1-(3-aminopropyl) -4-,4-diphenylpiperidine (1.288 g, 4.37 mmol, 1.0 equiv) in anhydrous toluene (15 mL) under argon, and stirring was continued for 48 hours. The mixture was concentrated to give 1.294 g (78%) of white solid, which was used for the next reaction without purification: 1H NMR (300 MHz, CDCl3) δ 1.70 (tt, J=6.4, 6.4 Hz, 2H), 2.23 (s, 3H), 2.44 (br t, J=6.5 Hz), 2.49-2.67 (m, 8H), 3.32 (br t, J=5.8 Hz), 3.36 (s, 2H), 7.16 (m, 2H), 7.27 (m, 8H).
Reaction SMILES: CN(C)CCCN=C=NCC.[CH3:12][O:13][CH2:14][CH2:15][NH:16][C:17]1[C:18]([NH2:23])=[CH:19][CH:20]=[CH:21][CH:22]=1.[N:24]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)=[C:25]=S.C(OCC)(=O)C>O1CCCC1>[CH3:12][O:13][CH2:14][CH2:15][N:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]=[C:25]1[NH:24][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(N=C=S)cc1
Reactant: COCCNc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCn1c(Nc2ccc(C(=O)OC)cc2)nc2ccccc21
Temperature: 25 °C
Yield: 68.9 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide (EDC, 791 mg) is added to a solution of N1-(2-methoxyethyl)benzene-1,2-diamine (311 mg, 1.87 mmol) and methyl 4-isothiocyanatobenzoate (328 mg, 1.70 mmol) in tetrahydrofuran. The reaction may be heated to reflux for 2 hr and cooled to room temperature. The mixture may be diluted in an appropriate solvent such as ethyl acetate, filtered and concentrated. The residue may be purified by any appropriate method, including Biotage column chromatography to give methyl 4-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-ylamino)benzoate (381 mg).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]2[S:11][C:12]([CH:15]=O)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].N1C=CC=CC=1.Cl.[NH2:26][OH:27]>O>[CH:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]2[S:11][C:12]([CH:15]=[N:26][OH:27])=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(Oc2ncc(C=O)s2)cc1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)Oc1ccc(Oc2ncc(C=NO)s2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.5 %

Procedure:
To a solution of Example 1C (2.5 g, 0.0095 mol) in pyridine (15 mL, 0.19 mol) was added hydroxylamine hydrochloride (6.6 g, 0.095 mol) portion wise and the mixture was stirred at room temperature for 5 minutes and it solidified. The mixture was then heated at 70° C. for 0.5 hours. Water (300 mL) was added and the reaction was stirred for 20 minutes. The solid was filtered and air-dried to give 2.26 g of product as a white solid (85% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.28 (d, J=5.49 Hz, 6H) 4.54-4.68 (m, 1H) 7.00 (d, J=9.16 Hz, 2H) 7.28 (d, J=9.16 Hz, 2H) 7.68 (s, 1H) 7.77 (s, 1H) 11.89 (s, 1H). MS (ESI), m/z 279.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24].CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Temperature: 23 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-(4-chloro-phenyl)-3-iodo-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.4 step 2a and 2b) (13.96 g, 32.96 mmol), trimethylsilylacetylene (5.5 mL, 39.72 mmol) and Et3N (9.2 mL, 67.9 mmol) in dry DMF (33 mL) was stirred for 10 min at 23° C. while being purged with Argon, then PdCl2(PPh3)2 (116 mg, 0.5 mol %), PPh3 (43 mg, 0.5 mol %) and CuI (19 mg, 0.3 mol %) were added. Stirring was continued at 90° C. for 4 h. The react mixture was then cooled to 23° C., diluted with EtOAc, washed water (twice) and brine, dried over Na2SO4. Removal of the solvent left an orange solid (13.30 g, 102%). MS (ISP) 394.1 [(M+H)+] and 396.1 [(M+2+H)+]; mp 198° C.
Reaction SMILES: [CH3:1][C@H:2]1[C@@:6]([CH3:8])([OH:7])[CH2:5][CH2:4][NH:3]1.F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:18][CH3:19])[CH:11]=1.C(=O)([O-])[O-].[Li+].[Li+]>>[OH:7][C@@:6]1([CH3:8])[CH2:5][CH2:4][N:3]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:18][CH3:19])[CH:11]=2)[C@H:2]1[CH3:1]
Reactant: COc1cc(F)ccc1C#N
Reactant: C[C@@H]1NCC[C@]1(C)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: COc1cc(N2CC[C@](C)(O)[C@@H]2C)ccc1C#N

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2,3-dimethylpyrrolidin-3-ol 0.5 oxalate (228 mg), 4-fluoro-2-methoxybenzonitrile (317 mg) and lithium carbonate (206 mg), the title compound was obtained as a colorless solid (yield: 170 mg, yield: 49%).
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:30][C:31]1[C:32]([I:39])=[N:33][N:34]([CH:36]([CH3:38])[CH3:37])[CH:35]=1>O1CCCC1>[I:39][C:32]1[C:31]([CH2:30][C:4]2([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]2)=[CH:35][N:34]([CH:36]([CH3:38])[CH3:37])[N:33]=1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)n1cc(CBr)c(I)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2cn(C(C)C)nc2I)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 78.3 %

Procedure:
A solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (0.54 mL, 2.11 mmol) in tetrahydrofuran (15 mL) in a dry 100 mL round bottom flask under nitrogen was cooled to −78° C. and then treated with lithium bis(trimethylsilyl) amide (1 M toluene, 2.13 mL, 2.13 mmol). After stirring for 45 minutes at −78° C., 4-(bromomethyl)-3-iodo-1-isopropyl-1H-pyrazole (535 mg, 1.63 mmol) was added as a suspension in 10 mL tetrahydrofuran. The mixture was stirred 1 hour at −78° C. and then allowed to stir 18 hours at room temperature. The reaction mixture was quenched with 20 mL saturated aqueous ammonium chloride, stirred 30 minutes at room temperature, diluted with 50 mL water and then extracted with ethyl acetate (2×50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (10-80% ethyl acetate/heptanes, 25 g silica gel) to yield 1-tert-butyl 4-ethyl 4-((3-iodo-1-isopropyl-1H-pyrazol-4-yl)methyl)piperidine-1,4-dicarboxylate (645 mg) as a clear oil. +ESI (M-tBu) 450.1; 1H NMR (400 MHz, CDCl3, δ): 7.02 (s, 3H), 4.44 (spt, J=6.6 Hz, 1H), 4.17 (m, 2H), 3.92 (m, 2H), 2.86 (m, 2H), 2.62 (s, 2H), 2.08 (m, 2H), 1.46 (m, 17H), 1.25 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[CH:9]1([C:12]2[N:17]=[C:16]([C:18]([NH:20][C:21]3[CH:29]=[N:28][CH:27]=[CH:26][C:22]=3[C:23](O)=[O:24])=[O:19])[C:15]([NH:30][C:31]3[CH:32]=[N:33][CH:34]=[N:35][CH:36]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1>>[CH:9]1([C:12]2[N:17]=[C:16]([C:18](=[N:20][C:21]3[CH:29]=[N:28][CH:27]=[CH:26][C:22]=3[C:23]([N:5]3[CH2:6][CH2:7][CH:3]([N:2]([CH3:8])[CH3:1])[CH2:4]3)=[O:24])[OH:19])[C:15]([NH:30][C:31]3[CH:32]=[N:33][CH:34]=[N:35][CH:36]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1
Reactant: CN(C)C1CCNC1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: CN(C)C1CCN(C(=O)c2ccncc2N=C(O)c2nc(C3CC3)ccc2Nc2cncnc2)C1
Yield: 13 %

Procedure:
According to the general method described above (step 3), reaction of 3-dimethylamino-pyrrolidine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (13%) as sticky yellow solid
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[CH:2]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[CH3:18][O:17][N:16]([CH3:15])[C:11]([C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:13]
Reactant: CNOC
Reactant: O=C(O)c1cnc2ccccc2c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of the quinoline-3-carboxylic acid (480 mg, 2.77 mmol) and N,O-dimethyhydroxylamine hydrochloride (405 mg, 4.15 mmol), in dichloromethane (10 mL) was added triethyl amine (1.93 mL, 13.8 mmol) followed by bromo(trispyrrolidin-1yl)phosphonium hexafluorophosphate (1.55 g, 3.32 mmol). After stirring the reaction mixture at room temperature for 1 hour, it was quenched by the addition of water (10 mL). The resulting mixture was extracted with DCM. The organic layer dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 75% ethyl acetate-hexanes. 1H NMR (500 MHz, CDCl3): 8.25 (d, J=1.8 Hz, 1H), 8.67 (d, J=1.3 Hz, 1H), 8.18 (d, J=8.5 Hz, 1H), 7.96 (d, J=8.2 Hz, 1H), 7.84 (t, J=8.0 Hz, 1H), 7.65 (t, J=8.5 Hz, 1H), 3.61 (s, 3H), 3.48 (s, 3H). LC-MS: 1.24 min; (M+H)=217.1.
Reaction SMILES: [C:1]([NH2:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:9]([O:12]C(=O)C)(=[O:11])[CH3:10].N1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([NH2:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:9]([O-:12])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Agent: CC(C)(C)OC(N)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)[O-]
Reaction time: 3 h

Procedure:
To a solution of the Boc-amine (3, 540 mg, 0.451 mmol) in DCM (250 mL) is added acetic anhydride (0.100 mL, 0.979 mmol), pyridine (1.0 mL, 12.4 mmol) and DMAP (20 mg, 0.169 mmol). The reaction is stirred for 3 h, concentrated directly onto SiO2 and chromatographed (gradient elution: 50-70% EtOAc/hexanes) which provides 465 mg of Boc-amine-acetate (4). 1H NMR (400 MHz, d6-DMSO) δ 10.38 (br s, 1H), 9.20 (br d, 1H), 8.79 (br d, 1H), 8.61 (br d, 1H), 8.56 (s, 1H), 8.44-8.41 (m, 1H), 8.38 (d, 1H), 8.24 (s, 1H), 8.11 (d, 1H), 7.48 (br s, 1H), 7.42 (s, 2H), 7.35-7.29 (m, 6H), 6.14 (s, 1H), 5.47 (t, 1H), 5.31-5.26 (m, 1H), 5.19 (dd, 1H), 4.97 (s, 3H), 4.26 (dd, 1H), 3.72 (dd, 1H), 3.38 (s, 3H), 2.70-2.65 (m, 1H), 2.59 (s, 3H), 2.45 (d, 3H), 2.22-2.14 (m, 1H), 1.96 (s, 3H), 1.57-1.50 (m, 1H), 1.49 (s, 9H), 0.88 (d, 3H), 0.84 (d, 3H). LCMS: Rt=1.81 min, [M+H]+ 1238.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:21]I>CN(C)C=O>[Si:1]([O:8][CH2:9][C:10]1[N:11]([CH3:21])[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCc1nc2cnccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CO[Si](C)(C)C(C)(C)C)nc2cnccc21

Procedure:
A procedure similar to that described in Preparation 59 was repeated, except that 7.4 g of 2-t-butyldimethylsilyloxymethyl-1H-imidazo[4,5-c]pyridine (prepared as described in Preparation 71), 1.23 g of sodium hydride (as a 55% by weight dispersion. in mineral oil), 2.0 ml of methyl iodide and 200 ml of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 3.30 g of the title compound, melting at 93°-95° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:3]=1[C:4](Cl)=[O:5].FC(F)(F)C1C=C(C(F)(F)F)C=CC=1C(OC)=O.[CH3:37][C:38]([N:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1)([CH3:47])[CH:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:3]=1[C:4]([NH:46][CH:39]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:38]([CH3:47])([N:48]1[CH2:49][CH2:50][CH2:51][CH2:52]1)[CH3:37])=[O:5]
Reactant: Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)Cl
Reactant: CC(C)(C(N)c1ccccc1)N1CCCC1
Agent: COC(=O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC(c1ccccc1)C(C)(C)N1CCCC1
Reaction time: 8 h
Yield: 54 %

Procedure:
A mixture of 2-methyl-4,6-bis(trifluoromethyl)benzoyl chloride and methyl 2,4-bis(trifluoromethyl)benzoate (approximately 0.5 mmol) prepared as described in D53 was dissolved in dry DCM (3 ml) and treated with (+)-[2-methyl-1-phenyl-2-(1-pyrrolidinyl)propyl]amine D6 (109 mg, 0.50 mmol) and triethylamine (140 ul, 1.00 mmol) and left overnight at room temperature. The volatile components were removed under reduced pressure and the residue chromatographed on silica gel. Elution with 0-80% ethyl acetate in pentane gave the title product as an gum (127 mg, ca.54%). 1H NMR (CDCl3) δ: 0.90 (3H, s), 1.01 (3H, s), 1.70 (4H, overlapping m), 2.47 (3H, s), 2.63 (4H, overlapping m), 4.84 (1H, d, J=2.8 Hz), 7.16 (1H, br s), 7.26-7.38 (5H, overlapping m) 7.67 (1H, s), 7.77 (1H, s). Mass Spectrum (Electrospray LC/MS): Found 473 (MH+) C24H26F6N2O requires 472. Ret time 2.24 min.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:12]=[C:11]([Cl:13])[S:10][C:9]=2[Cl:14])[CH2:5][C:4](=[O:15])[CH:3]=1.[OH-].[K+]>C(O)C.C1(C)C=CC=CC=1>[Cl:14][C:9]1[S:10][C:11]([Cl:13])=[CH:12][C:8]=1[CH:6]1[CH2:7][C:2]2[N:1]=[CH:7][CH:2]=[C:3]([CH3:4])[C:3]=2[C:4](=[O:15])[CH2:5]1
Reactant: NC1=CC(=O)CC(c2cc(Cl)sc2Cl)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccnc2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Reaction time: 2 h
Yield: 148 %

Procedure:
A solution of 5-(2,5-dichlorothiophen-3-yl)cyclohexane-1,3-dione (42.0 g) and ammonium acetate (36.9 g) in ethanol (840 ml) was refluxed for 12 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added water. The crystals were filtered, washed with toluene and dried to give 1-amino-5-(2,5-dichlorothiophen-3-yl)cyclohexen-3-one (40.3 g). To a solution of 1-amino-5-(2,5-dichlorothiophen-3-yl)cyclohexen-3-one (37.0 g) in ethanol (700 ml) and toluene (1400 ml) were added 3-oxobutylaldehydedimethylacetal (46.6 g) and powdery potassium hydroxide (7.7 g), and the mixture was refluxed. To the mixture was added powdery potassium hydroxide (1.6 g) 30 minutes later; powdery potassium hydroxide (1.6 g) and 3-oxobutylaldehydedimethylacetal (3.7 g) 1 hour later; and powdery potassium hydroxide (1.6 g) 1.5 hours later; and then the mixture was stirred at the same temperature for 2 hours. After the mixture was cooled, the solvent was evaporated under reduced pressure and to the residue was added ethyl acetate. The mixture was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, ethyl acetate was evaporated, and the thus obtained oil containing crystals were subjected to silica gel column (EtOAc/hexane) to remove starting materials. The thus obtained crystals were recrystallized from ethyl acetate-hexane to give 7-(2,5-dichlorothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (32.6 g).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([NH:50][CH3:51])[N:43]=1>C(Cl)(Cl)Cl>[Cl:20][C:14]1[C:15]([F:19])=[C:16]([F:18])[CH:17]=[C:12]2[C:13]=1[N:41]([C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([NH:50][CH3:51])[N:43]=1)[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]2=[O:22]
Reactant: CNc1nc(N)c(F)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2nc(NC)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To 5 ml of chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.70 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added 430 mg of 2-amino-3,5-difluoro-6-(methylamino)pyridine. The solution was concentrated under reduced pressure. To the residue were added 0.3 g of anhydrous potassium carbonate and 2 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 10 minutes and allowed to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed twice with 300 ml distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and allowed to stand. The precipitate was collected by filtration, washed with ethanol and diisopropylether successively to obtain 784 mg of the title compound as a colorless powder.