Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[O:18])[CH:12]=3)=[CH:10][C:3]=12.[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([C:37]2[C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][N:39]([CH2:51][CH3:52])[N:38]=2)=[CH:33][CH:32]=1)([O-:30])=[O:29].C(=O)(O)[O-].[Na+]>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.CN(C)C=O>[N+:28]([C:31]1[CH:32]=[CH:33][C:34]([C:37]2[C:41]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[N:8]([S:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)(=[O:21])=[O:20])[C:9]([C:11]5[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[O:18])[CH:12]=5)=[CH:10][C:3]=34)=[CH:40][N:39]([CH2:51][CH3:52])[N:38]=2)=[CH:35][CH:36]=1)([O-:30])=[O:29]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: O=Cc1cccc(-c2cc3c(Br)ccnc3n2S(=O)(=O)c2ccccc2)c1
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: CN(C)C=O
Product: CCn1cc(-c2ccnc3c2cc(-c2cccc(C=O)c2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
In a sealed pressure tube was added 4-bromo-2-(3-formylphenyl)-1-phenylsulfonyl-1H-pyrrolo[2,3-b]pyridine (1.6 mmol), 3-(4-nitrophenyl)-1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.7 mmol), N,N-dimethylformamide (15 mL), aqueous saturated sodium bicarbonate (4 mL) and tetrakis(triphenylphosphine)palladium(0) (0.09 mmol). The reaction was purged with nitrogen, capped, and stirred at 100° C. for 8 h. After cooling to room temperature, the reaction was concentrated under vacuum, taken up in ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered, and evaporated to dryness under vacuum. Purification by silica gel flash chromatography (5-10% ethyl acetate/methylene chloride) gave the title compound as a yellow solid (81%). ESMS [M+H]+: 578.3
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][C:6]1[C:12]([CH3:13])=[CH:11][C:9]([NH2:10])=[C:8]([CH3:14])[CH:7]=1.[CH2:19]([NH:21][CH3:22])[CH3:20].[CH:23](OC)(OC)OC>>[CH2:19]([N:21]([CH3:23])[CH:22]=[N:10][C:9]1[CH:11]=[C:12]([CH3:13])[C:6]([O:5][C:4]2[CH:15]=[CH:16][C:17]([Cl:18])=[C:2]([Cl:1])[CH:3]=2)=[CH:7][C:8]=1[CH3:14])[CH3:20]
Reactant: COC(OC)OC
Reactant: CCNC
Reactant: Cc1cc(Oc2ccc(Cl)c(Cl)c2)c(C)cc1N
Product: CCN(C)C=Nc1cc(C)c(Oc2ccc(Cl)c(Cl)c2)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
200 mg (0.71 mmol) of 4-(3,4-dichlorophenoxy)-2,5-dimethylaniline are refluxed in 5 ml of trimethyl orthoformate for 4 h. The reaction mixture is cooled to room temperature and concentrated under reduced pressure on a rotary evaporator. The residue is taken up in 50 ml of dichloromethane and admixed with 84 mg (1.42 mmol) of N-ethyl-N-methylamine. After 16 h of stirring at room temperature, solvent and unreacted amine are removed under reduced pressure and the product is purified by column chromatography (230 mg, 88% purity, 80% yield, log P (pH 2.3)=2.48).
Reaction SMILES: [CH2:1]([C@@H:3]1[O:5][CH2:4]1)Cl.[C:6]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:6]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:1][C@@H:3]2[CH2:4][O:5]2)=[CH:14][CH:15]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: ClC[C@H]1CO1
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)c1ccc(OC[C@@H]2CO2)cc1
Temperature: 45 °C
Reaction time: 96 h
Yield: 66.6 %

Procedure:
To a mixture of (R)-epichlorohydrin (12.4 g, 134 mmol) and 4-tert-butylphenol (10.0 g, 66.8 mmol) in acetone (50 ml) was added potassium carbonate (9.24 g, 66.8 mmol). The mixture was stirred at 45° C. for 96 hours. The reaction mixture was then concentrated to remove acetone. The residue was partitioned between ethyl acetate and water and extracted twice with ethyl acetate. The organic phases were combined and washed with water, brine, dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by flash chromatography (silica, methylene chloride/heptane) to give 9.18 g (67%) of (S)-2-(4-tert-butyl-phenoxymethyl)oxirane.
Reaction SMILES: [CH:1]1([CH2:8][CH2:9][NH:10][C:11](=[O:42])[C@H:12]([CH3:41])[C@H:13]([C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:40])[CH2:22][C@@H:23]([O:38][CH3:39])[C@@H:24]([N:29]([CH3:37])[C:30](=[O:36])[C@H:31]([CH:33]([CH3:35])[CH3:34])[NH2:32])[C@@H:25]([CH3:28])[CH2:26][CH3:27])[O:14][CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[CH:2]1.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH2:53][CH2:52][C@@:51]1([CH3:59])[C:56](O)=[O:57])=[O:49])([CH3:46])([CH3:45])[CH3:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[CH:1]1([CH2:8][CH2:9][NH:10][C:11](=[O:42])[C@H:12]([CH3:41])[C@H:13]([C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:40])[CH2:22][C@@H:23]([O:38][CH3:39])[C@@H:24]([N:29]([CH3:37])[C:30](=[O:36])[C@@H:31]([NH:32][C:56]([C@:51]2([CH3:59])[CH2:52][CH2:53][CH2:54][CH2:55][N:50]2[C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:49])=[O:57])[CH:33]([CH3:34])[CH3:35])[C@@H:25]([CH3:28])[CH2:26][CH3:27])[O:14][CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@]1(C)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCCN1C(=O)OC(C)(C)C)C(C)C

Procedure:
According to the general procedure D, from #176 (100 mg, 0.170 mmol, 1 eq.), #156 (53.8 mg, 0.221 mmol, 1.3 eq.), dichloromethane (4.5 mL), HATU (84.9 mg, 0.221 mmol, 1.3 eq.) and N,N-diisopropylethylamine (0.123 mL, 0.697 mmol, 4.1 eq.), was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0 to 100% ethyl acetate in heptane) to afford #177 (145 mg, assume quantitative yield) as a white solid. LC-MS (Protocol Q1): m/z 814.7 [M+H+], retention time=1.14 minutes.
Reaction SMILES: C(O)(=O)C.[N+:5]([C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)=[CH:10][C:9]=1[CH3:23])([O-])=O>C(O)C.O.[Fe]>[OH:22][C:18]1[CH:17]=[C:16]([S:15][C:11]2[CH:10]=[C:9]([CH3:23])[C:8](=[CH:13][C:12]=2[CH3:14])[NH2:5])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Sc1cccc(O)c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(Sc2cccc(O)c2)c(C)cc1N
Temperature: 60 °C

Procedure:
6.3 ml of glacial acetic acid (0.11 moles) are added to a solution of 20 g of the product obtained in Example 4 (0.076 moles) in 328 ml of ethanol and 33 ml of H2O; 29.7 g of Fe in powder form (0.53 moles) are carefully added to the reaction mixture kept under stirring at 60° C. The temperature is brought to 90° C. and the mixture is kept under stirring for 1.5 hours.
Reaction SMILES: [CH3:1][CH:2]([NH2:11])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Br[CH:13]([CH3:24])[C:14]([C:16]1[S:20][CH:19]=[C:18]([C:21]([NH2:23])=[O:22])[CH:17]=1)=[O:15].CC(=O)CC>CCOC(C)=O>[CH3:1][CH:2]([N:11]=[C:13]([CH3:24])[C:14]([C:16]1[S:20][CH:19]=[C:18]([C:21]([NH2:23])=[O:22])[CH:17]=1)=[O:15])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(Br)C(=O)c1cc(C(N)=O)cs1
Reactant: CC(N)CCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: CC(=NC(C)CCc1ccccc1)C(=O)c1cc(C(N)=O)cs1
Reaction time: 48 h

Procedure:
A solution of 1-methyl-3-phenylpropylamine (9.0 g) and 5-(2-bromo-1-oxopropyl)thiophene-3-carboxamide (7.6 g) was stirred for 2 h; butanone (75 ml) was added and stirring continued for 48 h. The resulting mixture was filtered and the filtrate evaporated to small volume (ca. 30 ml) and added to vigorously stirred light petroleum (b.p. 60°-80°: 500 ml) to precipitate a yellow gum (ca. 9 g) which was separated on a short path silica (7736H; 300 g) column eluted with ethyl acetate/2% isopropanol/20% triethylamine to give three products. TLC SiO2 (EtOAc/20% i-PrOH/2% Et3N) Rf 0.26, 0.39 and 0.5 respectively.
Reaction SMILES: O[N:2]=[C:3]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[NH:12][CH:11]=1)[C:4]([O:6]CC)=[O:5].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C.[Zn]>[Cl:19][C:17]1[CH:16]=[C:15]([Cl:20])[CH:14]=[C:13]2[C:18]=1[C:10]([CH2:9][C@@H:3]([C:4]([OH:6])=[O:5])[NH2:2])=[CH:11][NH:12]2
Reactant: CCOC(=O)C(Cc1c[nH]c2cc(Cl)cc(Cl)c12)=NO
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N[C@@H](Cc1c[nH]c2cc(Cl)cc(Cl)c12)C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 102.3 %

Procedure:
Dissolve ethyl 2-(hydroxyimino)-3-(4,6-dichloro-3-indolyl)propanoate (1.10g, 3.65mmol ) in acetic acid (200mL) and add activated zinc dust (1.25g, 19.2mmol). Stir at room temperature for 72 hours. Evaporate the acetic acid in vacuo to give a white oil. Take the white oil up in ethyl acetate (200mL) and treat with saturated sodium hydrogen carbonate (500mL). Filter t he resulting white precipitate and separate the organic phase. Wash with saturated sodium hydrogen carbonate (100mL) a nd brine (100mL). Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound as an amber oil (1.02g, 98%).
Reaction SMILES: [C:1]12([CH2:11][S:12]([OH:15])(=[O:14])=O)C(C)(C)C(CC1)CC2=O.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C@H:21]([NH2:26])[CH2:20]2.[CH2:27](Cl)Cl>>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C@H:21]([NH:26][S:12]([CH:11]([CH3:1])[CH3:27])(=[O:14])=[O:15])[CH2:20]2
Reactant: ClCCl
Reactant: N[C@H]1Cc2ccc(Br)cc2C1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(Br)cc2C1

Procedure:
N-[(2S)-5-bromo-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide was prepared using a similar method to that disclosed in WO 2006/015828; the initial solvent for conversion of (S)-5-bromo-2-aminoindane camphorsulfonate salt into the free base form was DCM.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=[N:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)([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.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH:1]([N:14]1[CH2:17][CH:16]([NH:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NN=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NNC1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 4 h
Yield: 94.1 %

Procedure:
The title compound was prepared as described in WO2010079443A1. To a solution of tert-butyl 2-(1-benzhydrylazetidin-3-ylidene)hydrazinecarboxylate (16.9 g, 48.1 mmol) in acetic acid (150 mL), sodium cyanoborohydride (3 g, 48.1 mmol) was added portionwise at 25° C. and stirred at the same temperature for 4 h under a nitrogen atmosphere. The solvent was completely evaporated off. The pH was adjusted to 8 to 10 with 1 M aqueous sodium hydroxide solution. The whole was extracted with dichloromethane (2×500 mL). Organic part was dried over sodium sulfate, filtered and concentrated in vacuum to give the crude tert-butyl 2-(1-benzhydrylazetidin-3-yl)hydrazinecarboxylate (16 g, 94%) as a white solid. This material was used as is for the next reaction. MS (ESI, positive ion) m/z (M+1): 354.4. 1H NMR (400 MHz, DMSO) δ 8.26 (s, 1H), 7.40 (d, J=7.5 Hz, 4H), 7.26 (t, J=7.5 Hz, 4H), 7.16 (t, J=7.2 Hz, 2H), 4.68 (t, J=4.6 Hz, 1H), 4.33 (s, 1H), 3.50 (dd, J=12.5, 6.2 Hz, 1H), 3.16 (t, J=7.0 Hz, 2H), 2.78 (t, J=6.9 Hz, 2H), 1.36 (s, 9H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([CH2:39][C:40]2[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:41]=2[F:47])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([CH2:39][C:40]2[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:41]=2[F:47])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(Cc2c(F)cccc2F)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(Cc2c(F)cccc2F)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
A mixture of hydroxylammonium chloride (0.49 g), sodium hydrogen carbonate (0.70 g) and dimethyl sulfoxide (8 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(2,6-difluorobenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.40 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.17 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.34 g, 75%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=CC(S(Cl)(=O)=O)=C[CH:2]=1.[Br:12][C:13]1(C(O)=O)[CH:18]=[CH:17][CH:16]=[CH:15][NH:14]1.N1C=CC=CC=1.[C:28](=[O:31])(O)[O-:29].[Na+]>C(O)(C)(C)C>[Br:12][C:13]1[N:14]=[C:15]([C:28]([O:29][C:1]([CH3:11])([CH3:6])[CH3:2])=[O:31])[CH:16]=[CH:17][CH:18]=1
Reactant: O=C([O-])O
Reactant: O=C(O)C1(Br)C=CC=CN1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 79 %

Procedure:
p-Toluenesulfonyl chloride (9.0 g, 47.2 mmol) was added portionwise to a mixture of 2-bromo-picolinic acid (4.02 g, 19.9 mmol) in tert-butanol (36 mL) and pyridine (10.8 mL, 134 mmol) at 0° C. and the mixture was stirred at rt for 14 hours. An aqueous solution of sodium bicarbonate was slowly added. The precipitate was filtered, washed with water and dried in vacuo to provide 4.04 g (79%) of the desired product tert-butyl 6-bromopicolinate (25A): 1H NMR (300 MHz, CDCl3) δ 7.97 (1H, dd), 7.64 (2H, m), 1.62 (9H, s).
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH2:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH2:6][C:5]1=[O:21])(=O)[CH3:2].Cl.[CH2:23]([O:25][NH2:26])[CH3:24].C(N(CC)CC)C.Cl>C(O)C.O>[CH2:23]([O:25][NH:26][C:1](=[C:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH2:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH2:6][C:5]1=[O:21])[CH3:2])[CH3:24]
Reactant: CC(=O)C1C(=O)CC(CCSc2ccc(C)cc2)CC1=O
Reactant: CCON
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CCONC(C)=C1C(=O)CC(CCSc2ccc(C)cc2)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.6 Gram of 2-acetyl-5-[2-(4-methylphenylthio)ethyl]cyclohexane-1,3-dione was dissolved in 60 ml of ethanol, and after adding 0.25 g of ethoxyamine hydrochloride and 0.26 g of triethylamine, the resulting solution was stirred overnight at room temperature. The reaction solution was poured into water, acidified with dilute hydrochloric acid and extracted with chloroform. After removing chloroform, the product obtained was purified by thin layer chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 0.4 g of 2-(1-ethoxyaminoethylidene)-5-[2-(4-methylphenylthio)ethyl]cyclohexane-1,3-dione [Compound (2)].
Reaction SMILES: [C:1]1([C:7](O)([C:9]#C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2.[CH:23]([NH:26][C:27]([C:29]1[C:38](=[O:39])[C:37]2[C:32](=[N:33][CH:34]=[CH:35][CH:36]=2)[N:31](C2C=CC=C(Br)C=2)[CH:30]=1)=[O:28])([CH3:25])[CH3:24]>>[CH:23]([NH:26][C:27]([C:29]1[C:38](=[O:39])[C:37]2[C:32](=[N:33][CH:34]=[CH:35][CH:36]=2)[N:31]([C:5]2[CH:4]=[CH:3][CH:2]=[C:1]([C:7]#[C:9][C:13]3[CH:14]=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:6]=2)[CH:30]=1)=[O:28])([CH3:25])[CH3:24]
Reactant: C#CC(C)(O)c1ccccc1
Reactant: CC(C)NC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Reactant: Brc1cnc2ccccc2c1
Product: CC(C)NC(=O)c1cn(-c2cccc(C#Cc3cnc4ccccc4c3)c2)c2ncccc2c1=O

Procedure:
Following the procedure of EXAMPLE 15, but substituting N-isopropyl-1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Step 2 of EXAMPLE 5 for 2-phenyl-3-butyn-2-ol, and 3-bromoquinoline for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, the title compound was obtained as a solid.
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].CC(C)([O-])C.[K+].F[C:14]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[S:28][C:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[N:26][C:25]=2[CH2:39][N:40]2[CH2:45][CH2:44][CH:43]([C:46]([F:49])([F:48])[F:47])[CH2:42][CH2:41]2)[C:19]([F:50])=[CH:18][C:15]=1[C:16]#[N:17].O>O1CCCC1.C(O)(C)(C)C>[F:50][C:19]1[C:20]([O:22][CH2:23][C:24]2[S:28][C:27]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:34]=3)=[N:26][C:25]=2[CH2:39][N:40]2[CH2:45][CH2:44][CH:43]([C:46]([F:49])([F:47])[F:48])[CH2:42][CH2:41]2)=[CH:21][C:14]([O:6][CH2:1][C:2]([F:5])([F:4])[F:3])=[C:15]([CH:18]=1)[C:16]#[N:17]
Reactant: OCC(F)(F)F
Reactant: N#Cc1cc(F)c(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCC(C(F)(F)F)CC2)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)(C)O
Product: N#Cc1cc(F)c(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCC(C(F)(F)F)CC2)cc1OCC(F)(F)F
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
To a solution of 190 mg of trifluoroethanol in 1.16 mL of tetrahydrofuran at 5° C. was slowly added 2.2 mL of a molar solution of potassium tert-butoxide in tert-butanol. After stirring at 5° C. for 30 minutes, the resulting solution was slowly added to a solution of 890 mg of 2,5-difluoro-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-benzonitrile in 3.1 mL of tetrahydrofuran at −60° C. The resulting mixture was stirred overnight allowing the temperature to warm up to room temperature. It was then poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was triturated with diisopropyl ether and filtered to give 410 mg of 5-fluoro-2-(2,2,2-trifluoro-ethoxy)-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-benzonitrile as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:51][O:52][C:53]1[CH:54]=[C:55]([CH:59]=[CH:60][CH:61]=1)[CH:56]([OH:58])[CH3:57]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:40](=[O:42])[O:58][CH:56]([C:55]2[CH:59]=[CH:60][CH:61]=[C:53]([O:52][CH3:51])[CH:54]=2)[CH3:57])=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cccc(C(C)O)c1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cccc(C(C)OC(=O)Nc2cc(C)c(Oc3ccnc4cc(OC)c(OC)cc34)cc2C)c1
Temperature: 25 °C
Yield: 55.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (90 mg) was added to toluene/triethylamine=10/1 (9 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (123 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-methoxy-α-methylbenzyl alcohol (64 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (78 mg, yield 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[CH2:18]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1)[CH2:19][CH3:20]>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(CCC)nc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 9.7 %

Procedure:
To a solution of 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g. 0.00045 mol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.20 g, 0.0036 mol) and allowed to stir for 10 min at RT. 2-propyl-5-vinyl-pyridine (0.2 g, 0.00136 mol) was added and stirred for further 24 h. at 100° C. After completion (TLC), reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was semi-purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch), Then further purified by preparative TLC, to give the desired compound as yellow oil (0.016 g, 9.6% yield). 8-Chloro-5-[2-(6-isopropyl-pyridin-3-yl)-ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.016 g, 0.0000435 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.005 g, 0.00007 mol) in THF (0.5 mL) was added and stirred for 30 min at RT. Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.010 g, 52% yield).
Reaction SMILES: [CH:1]1[C:6]([C:7]([CH2:9]Br)=O)=[CH:5][CH:4]=[C:3]([OH:11])[CH:2]=1.[NH2:12][C:13]1(C)[CH:18]=[CH:17][CH:16]=[CH:15][NH:14]1.[CH2:20](O)C>>[OH:11][C:3]1[CH:4]=[CH:5][C:6]([C:7]2[N:12]=[C:13]3[C:18]([CH3:20])=[CH:17][CH:16]=[CH:15][N:14]3[CH:9]=2)=[CH:1][CH:2]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: CCO
Reactant: CC1(N)C=CC=CN1
Product: Cc1cccn2cc(-c3ccc(O)cc3)nc12
Temperature: 25 °C

Procedure:
The product of step A (30 g) and 2-aminopicoline (15 mL) in ethanol (200 mL) was heated at reflux temperature for 4 hours then cooled to ambient temperature. The resulting precipitate containing the title compound was isolated via filtration (27 g).