Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8](Cl)=[O:9])[CH2:3][CH2:2]1.[NH4+:11].[OH-]>C1COCC1>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([NH2:11])=[O:9])[CH2:3][CH2:2]1
Reactant: O=C(Cl)CC1CCOCC1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)CC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 116 %

Procedure:
A 0° C. solution of tetrahydropyran-4-ylacetyl chloride (0.500 g, 3.07 mmol) in THF (25 mL) was treated drop-wise with NH4OH (˜15M, 2.05 mL, ˜30.7 mmol), allowed to warm to RT and stirred overnight. The mixture was concentrated to dryness, co-evaporated with IPA (2×), then suspended in IPA and the solids removed via filtration. The filtrate was concentrated to dryness to afford 2-(tetrahydro-2H-pyran-4-yl)acetamide (510 mg, 116%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.25 (s, 1H), 6.73 (s, 1H), 3.78 (dd, J=11.4, 4.1 Hz, 2H), 3.29-3.19 (m, 2H), 2.15-1.92 (m, 2H), 1.91-1.78 (m, 1H), 1.58-1.48 (m, 2H), 1.23-1.06 (m, 2H); MS (ESI) m/z: 144.1 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][CH2:21][CH2:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][N:25]=1>>[CH3:19][O:20][CH2:21][CH2:22][NH:23][C:24]1[N:25]=[CH:26][C:27]([NH:30][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:28][CH:29]=1
Reactant: COCCNc1ccc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: COCCNc1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-methoxy-ethylamino)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-pyridine-2,5-diamine. LCMS calcd for C19H17F3N4O3 (m/e) 406, obsd 407 (M+H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][CH2:6]O.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]([C:25]2[NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[N:26]=2)=[O:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH2:19][CH:20]([C:23]([C:25]2[N:26]([CH2:6][CH2:5][O:4][CH2:3][C:2]([F:1])([F:8])[F:9])[C:27]3[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=3[N:29]=2)=[O:24])[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3[nH]2)CC1
Reactant: OCCOCC(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3n2CCOCC(F)(F)F)CC1

Procedure:
Prepare by the method of Preparation 9 using 2-hydroxyethyl 2,2,2-trifluorethyl ether and 1-(t-butoxycarbonyl)-4-(1H-benzimidazole-2-carbonyl)piperidine (2.0 g, 6.1 mmol) to give 1-(t-butoxycarbonyl)-4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9](Cl)(=O)=O)[CH:8]=1)#[N:2]>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([SH:9])[CH:8]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 15 h

Procedure:
Under argon, 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (52 mg, 105 μmol) was dissolved in dichloromethane (10 ml). Triphenylphosphine-polystyrene resin (capacity 1 mmol/g, 315 mg, 315 μmol, 3 eq.) was added, and the mixture was shaken for 15 h. More triphenylphosphine-polystyrene resin (1 mmol/g, 105 mg, 105 μmol, 1 eq.) was then added, and the mixture was shaken for a further 5 h. The reaction mixture was then filtered, the filtrate was concentrated under reduced pressure and the residue was dried under high vacuum. The title compound was obtained as a solid (90 mg, purity 50%, quant.) which was used without further purification in the subsequent reactions.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][C:18]#[CH:19]>CC(C)=O>[CH2:19]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:18]#[CH:17]
Reactant: C#CCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1ccc(C=O)cc1
Temperature: 60 °C
Yield: 69 %

Procedure:
To a stirred suspension of 4-hydroxybenzaldehyde (425.8 g) and K2CO3 (807.6 g) in acetone (2,960 ml) at reflux temper-ature of about 60° C. under a nitrogen atmosphere, was added dropwise 3-bromo-propyne (502.4 g) over a period of 2 hours. The reaction was heated at reflux for 3 more hours. After cooling to room temperature the reaction mixture was filtered and the excess of K2CO3 removed and washed several times with acetone. The filtrate was washed with saturated aqueous solution of NaHCO2 and NaCl. The aqueous phase was extracted with diethyl ether. The combined organic extracts were dried over Na2SO4, filtered and concentrated to a volume of 1 liter. The solution was kept in the refrigerator overnight. The crystals were filtered out and washed with cold diethyl ether. The filtrate was kept in the refrigerator and some more crystals were formed and removed. This procedure was repeated 3 times resulting in 1,385.26 g of 4-(2-propynyloxy) benzaldehyde in 83% yield. The material was analysed by gas chromatography, and shown to be 99.9% pure. Infrared and mass spectroscopic analysis confirmed the structure.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:9]([CH2:12][CH:13]3[CH2:15][CH2:14]3)=[N:10][N:11]=2)[CH:5]=[CH:6][C:7]=1I.[N:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:24][CH:23]2[CH2:25][NH2:26])=[CH:18][CH:17]=1>>[Cl:1][C:2]1[C:3]2[N:4]([C:9]([CH2:12][CH:13]3[CH2:15][CH2:14]3)=[N:10][N:11]=2)[CH:5]=[CH:6][C:7]=1[NH:26][CH2:25][CH:23]1[CH2:24][CH:22]1[C:19]1[CH:18]=[CH:17][N:16]=[CH:21][CH:20]=1
Reactant: NCC1CC1c1ccncc1
Reactant: Clc1c(I)ccn2c(CC3CC3)nnc12
Product: Clc1c(NCC2CC2c2ccncc2)ccn2c(CC3CC3)nnc12
Yield: 48.4 %

Procedure:
A mixture of 8-chloro-3-(cyclopropylmethyl)-7-iodo-[1,2,4]triazolo[4,3-a]pyridine (50 mg, 0.150 mmol) and (2-(pyridin-4-yl)cyclopropyl)methanamine (26.7 mg, 0.180 mmol) was reacted in a manner similar to Example 1 to give 8-chloro-3-(cyclopropylmethyl)-N-((2-(pyridin-4-yl)cyclopropyl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-7-amine (25.7 mg, 47.5%). 1H NMR (500 MHz, DMSO-d6) δ 8.35 (d, J=6.1 Hz, 2H), 8.23 (d, J=7.6 Hz, 1H), 7.06 (d, J=6.1 Hz, 2H), 6.90 (d, J=7.6 Hz, 1H), 6.42 (t, J=6.1 Hz, 1H), 2.95 (d, J=6.7 Hz, 2H), 1.95 (dd, J=8.7, 4.4 Hz, 1H), 1.48 (br. s., 1H), 1.19-1.09 (m, 2H), 1.09-1.00 (m, 1H), 0.50 (d, J=6.4 Hz, 2H), 0.25 (d, J=4.6 Hz, 2H). LCMS: M+1=354.2.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[S:8])[NH:5][C:4]([CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([C:20]([OH:22])=[O:21])=[CH:15][CH:14]=[CH:13]3)=[CH:3]1.[OH-].[Na+].[CH3:25]I>C1COCC1.O>[OH:1][C:2]1[N:7]=[C:6]([S:8][CH3:25])[N:5]=[C:4]([CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([C:20]([OH:22])=[O:21])=[CH:15][CH:14]=[CH:13]3)[CH:3]=1
Reactant: CI
Reactant: O=C(O)c1cccc2cc(Cc3cc(=O)[nH]c(=S)[nH]3)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CSc1nc(O)cc(Cc2ccc3c(C(=O)O)cccc3c2)n1
Reaction time: 15 h

Procedure:
2.30 g (7.37 mMol) 6-(6-oxo-2-thioxo-1,2,3,6-tetrahydro-pyrimidin-4-ylmethyl)-naphthalene-1-carboxylic acid are suspended in 160 ml THF. Then a solution of 452 mg (11.3 mMol) NaOH in 9 ml water is added, followed by 556 μl (8.93 mMol) methyliodide. After 15 h, the reaction mixture is concentrated in vacuo. The residue is used without further purification in Step 3.8. Pure title compound can be obtained by chromatography (Combi Flash; CH2Cl2→CH2Cl2/MeOH 7:1): TLC (CH2Cl2/MeOH 4:1): Rf=0.46.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:25])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH:20](Br)[C:19](=[O:24])[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[C:26]([O-:29])(=[O:28])[CH3:27].[K+]>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:25])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH:20]([O:29][C:26](=[O:28])[CH3:27])[C:19](=[O:24])[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CN(CCc1ccc(F)cc1)S(=O)(=O)c1csc2c1CCC(Br)C2=O
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)OC1CCc2c(S(=O)(=O)N(C)CCc3ccc(F)cc3)csc2C1=O
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
To a solution of 6-bromo-7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-3-sulfonic acid [2-(4-fluorophenyl)ethyl]-methyl-amide (246 mg) in dimethylsulfoxide (2 mL) was added potassium acetate (108 mg). After stirring for 30 minutes, the solution was diluted with, and extracted with ethyl acetate. After drying the organic layer with anhydrous sodium sulfate, the solvent was removed by evaporation to provide the title compound (200 mg) as a yellow oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[C:25]([Sn](CCCC)(CCCC)CCCC)=[N:26][CH:27]=[CH:28][CH:29]=1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:12]=[N:13][CH:14]=2)=[CH:3][C:2]=1[C:25]1[C:24]([F:23])=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: COc1ccc(-c2nncc(-c3ccc(F)c(Br)c3)n2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccc1F
Product: COc1ccc(-c2nncc(-c3ccc(F)c(-c4ncccc4F)c3)n2)cc1
Yield: 38 %

Procedure:
5-(3-Bromo-4-fluorophenyl)-3-(4-methoxyphenyl)-[1,2,4]triazine (100 mg, 0.28 mmol) was coupled to 3-fluoro-2-tributylstannylpyridine (129 mg, 0.33 mmol) using the method described in Example 22 to give 5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-3-(4-methoxyphenyl)-[1,2,4]triazine as a pale yellow solid (40 mg): δH (400 MHz, CDCl3) 3.91 (3H, s), 7.04-7.08 (2H, m), 7.39-7.47 (2H, m), 7.56-7.61 (1H, m), 8.41-8.45 (1H, m), 8.54 (1H, dd, J 2.3, 6.7 Hz), 8.60-8.64 (3H, m), 9.57 (1H, s); m/z (ES+) 377.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]([CH3:14])=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2].[Li]CCCC.CON(C)[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)=[O:25].O>C1COCC1>[CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]([CH3:14])=[C:7]([C:9]2[S:10][C:11]([C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[O:25])=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2]
Reactant: CON(C)C(=O)c1ccccn1
Reactant: CCc1cc(-c2cccs2)c(C)[nH]c1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(-c2ccc(C(=O)c3ccccn3)s2)c(C)[nH]c1=O
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-ethyl-6-methyl-5-thiophen-2-yl-1H-pyridin-2-one prepared in accordance with the procedures of Example 24, Step 3 (100 mg, 0.456 mmol) in anhydrous THF (3 ml) is cooled to −78° C., and n-BuLi (2.5 M in hexane, 0.4 ml, 1 mmol) is added. The resulting dark green mixture is stirred for 20 min, and then N-methoxy-N-methylpyridine-2-carboxamide (83 mg, 0.5 mmol) in THF (1 ml) is added. The reaction mixture is then added to water (5 ml) and extracted with ethyl acetate. The organic phases are washed and dried, and the residue is purified on silica gel. The product is dissolved in a minimal amount of methanol and treated with HCl in diethyl ether. The resulting brown precipitate is filtered off with suction and dried (12 mg, as hydrochloride). MS: m/e=325 (M+H). 1H-NMR (D6-DMSO, δ ppm) 11.85 (s, 1H); 8.81 (d, 1H); 8.30 (d, 1H); 8.12 (m, 2H); 7.71 (m, 1H); 7.44 (s, 1H); 7.29 (d, 1H) 3.37 (m, 2H); 2.50 (s, 3H); 1.14 (t, 3H, J=7.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12](Cl)[C:11]([F:15])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[F-:16].[K+]>[Cl-].C[N+](C)(C)C>[Cl:1][C:2]1[CH:13]=[C:12]([F:16])[C:11]([F:15])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: [F-]
Reactant: CC(C)OC(=O)c1cc(F)c(Cl)cc1Cl
Agent: C[N+](C)(C)C
Agent: [Cl-]
Agent: [K+]
Product: CC(C)OC(=O)c1cc(F)c(F)cc1Cl
Yield: 85.2 %

Procedure:
Into a 1 l glass reactor equipped with a condenser, 251.0 g (1 mol) of isopropyl 2,4-dichloro-5-fluorobenzoate, 87 g (1.5 mol) of spray-dried potassium fluoride, 25.1 g of tetramethyl ammonium chloride and 500 g of sulforane were charged and reacted at 150° C. for 9 hours under vigorous stirring. After cooling, the inorganic salt was removed by filtration, and the filtrate was distilled under reduced pressure to obtain 199.8 g (yield: 85.2%) of isopropyl 2-chloro-4,5-difluorobenzoate. This compound was analyzed, and the results are as follows.
Reaction SMILES: [Cl:1][C:2]1[S:17][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1[CH:27]=O>>[Cl:1][C:2]1[S:17][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:12][CH2:13][N:14]([CH2:27][C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][C:19]=4[F:18])[C:23]#[N:24])[CH2:15][CH2:16]3)[C:4]=2[CH:3]=1
Reactant: Clc1cc2c(NC3CCNCC3)ncnc2s1
Reactant: N#Cc1ccc(F)c(C=O)c1
Product: N#Cc1ccc(F)c(CN2CCC(Nc3ncnc4sc(Cl)cc34)CC2)c1

Procedure:
The title compound was prepared (119 mg, 45%) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (150 mg, 0.56 mmol) and 4-fluoro-3-formylbenzonitrile (83 mg, 0.56 mmol) by following the general procedure described for Preparation 11. 1H NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 7.85 (m, 1H), 7.60 (m, 1H), 7.15 (t, 1H), 7.00 (s, 1H), 5.00 (d, 1H), 4.20 (m, 1H), 3.60 (s, 2H), 2.90 (m, 2H), 2.35 (m, 2H), 2.15 (m, 2H), 1.60 (m, 2H). MS (ESI) m/z: Calculated: 401.09; Observed: 402.1 (M++1).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:20][CH2:19][C:18]3[CH:21]=[CH:22][C:15]([Br:14])=[CH:16][CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: NCc1ccc(Br)cc1
Product: Nc1cc2ncnc(NCc3ccc(Br)cc3)c2cn1
Temperature: 140 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (234 mg, 1.22 mmol) (described in a previous experimental) and 4-bromobenzylamine (0.84 g, 4.52 mmol) is stirred under N2 at 140° C. for 1 h, and the resulting product chromatographed on silica gel (10% EtOH/EtOAc) to give 7-amino-4-(4-bromobenzylamino)pyrido[4,3-d]pyrimidine (192 mg, 48%) as a cream solid. 1H NMR (DMSO) δ 9.09 (1H, s), 8.87 (1H, t, J=5.7 Hz), 8.25 (1H, s), 7.51 (2H, d, J=8.3 Hz), 7.31 (2H, d, J=8.3 Hz), 6.46 (2H, brs), 6.37 (1H, s), 4.70 (2H, d, J=5.8 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[CH:15]=[C:16]([C:18]4[CH:27]=[CH:26][C:21]([C:22]([NH:24][CH3:25])=[O:23])=[CH:20][CH:19]=4)[S:17][C:10]=23)=[CH:4][CH:3]=1.C[Si]([N-:32][Si](C)(C)C)(C)C.[Li+]>>[NH2:32][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[CH:15]=[C:16]([C:18]4[CH:27]=[CH:26][C:21]([C:22]([NH:24][CH3:25])=[O:23])=[CH:20][CH:19]=4)[S:17][C:10]=23)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CNC(=O)c1ccc(-c2cc3nccc(Oc4ccc(Cl)nc4)c3s2)cc1
Agent: [Li+]
Product: CNC(=O)c1ccc(-c2cc3nccc(Oc4ccc(N)nc4)c3s2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 14.8 %

Procedure:
To a stirred mixture of 4-(7-(6-chloropyridin-3-yloxy)thieno[3,2-b]pyridin-2-yl)-N-methylbenzamide (Example 130, Step B, 78 mg, 0.197 mmol), lithium bis(trimethylsilyl)amide (LHMDS, 0.433 mL, 0.433 mmol, 1M in hexanes), and Pd2(dba3) (9.02 mg, 0.00985 mmol), was added P,P-dicyclohexyl(3-(2-N, N-dimethylaminophenyl)-phenyl)phosphine (7.75 mg, 0.0197 mmol). The mixture was sparged with nitrogen for 2 minutes, and then heated to 80° C. for 18 hours. After cooling to room temperature, 2N aqueous HCl (0.5 mL) was added and stirring was continued for 1 hour at room temperature. The mixture was partitioned between dichloromethane (5 mL) and 1:1 saturated aqueous NaHCO3/water (5 mL). The phases were separated, and the aqueous phase was re-extracted with dichloromethane (2×2 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated. The crude was purified by preparative TLC plate (1 mm thickness, Rf=0.45) eluting with 15% MeOH/CHCl3. The product was obtained as a beige, waxy solid (11 mg, 12%). 1H NMR (400 MHz, 1:1 CDCl3/CD3OD) δ 8.44 (d, J=5 Hz, 1H), 7.84-7.95 (m, 6H), 7.41 (m, 1H), 6.71 (d, J=9 Hz, 1H), 6.63 (d, J=5 Hz, 1H), 2.97 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:11])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23].Cl>N1C=CC=CC=1>[Cl:11][C:4]1[S:3][C:2]([NH:1][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([Cl:12])=[C:14]([N+:22]([O-:24])=[O:23])[CH:15]=2)=[N:6][C:5]=1[C:7]([F:10])([F:8])[F:9]
Reactant: Nc1nc(C(F)(F)F)c(Cl)s1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1nc(C(F)(F)F)c(Cl)s1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 43.5 %

Procedure:
2-Amino-5-chloro-4-trifluoromethylthiazole (1.0 g) was dissolved in pyridine (5 ml) and 4-chloro-3-nitrobenzoylchloride (1.1 g) was added at room temperature with stirring. The mixture was stirred for 1 day at room temperature. The mixture was poured into ice water and acidified with aqueous hydrochloric acid then extracted with chloroform. The chloroform layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The solid thus obtained was recrystallized from methanol to give N-(5-chloro-4-trifluoromethylthiazol-2-yl)-4-chloro-3-nitro-benzamide (0.83 g), m. p. 183-184° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].[CH2:33](I)[CH3:34]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:33][CH3:34])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CCI
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (0.3 g) obtained in Example 2 was suspended in dimethyl sulfoxide (20 ml), and to the suspension was added potassium carbonate (0.2 g), and the mixture was stirred at room temperature for 30 minutes. Ethyl iodide (0.13 ml) was added and the mixture was stirred at 80° C. in a hot water bath for 6 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, washed with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: ethyl acetate) to obtain the title compound (0.16 g, 45%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:11]([CH3:22])=[C:10]([CH2:23][OH:24])[CH:9]=2)=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:11]([CH3:22])=[C:10]([CH:23]=[O:24])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1c(CO)cc(-c2ccc(F)cc2)n1S(=O)(=O)c1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: Cc1c(C=O)cc(-c2ccc(F)cc2)n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
[5-(4-Fluorophenyl)-2-methyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (1.08 g) was dissolved in acetonitrile (20 mL), tetra-n-propylammonium perruthenate (100 mg), N-methylmorpholine N-oxide (0.52 g) and molecular sieves 4A powder (1.00 g) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:1) to give the title compound as colorless crystals (yield 0.71 g, 66%).
Reaction SMILES: [C:1]1([P:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8]CC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17][C:18]([F:22])([F:21])[CH2:19]I>>[F:17][C:18]([F:22])([F:21])[CH2:19][P:7](=[O:8])([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOP(c1ccccc1)c1ccccc1
Reactant: FC(F)(F)CI
Product: O=P(CC(F)(F)F)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 51 %

Procedure:
Ethyl diphenylphosphinite (b1; 20.0 g) and 1,1,1-trifluoro-2-iodoethane (b2; 36.5 g) were put into a reaction vessel under an argon atmosphere, and stirred at room temperature for 4 days. The resulting mixture was purified by means of fraction-collecting column chromatography using ethyl acetate as the eluent and silica gel as the stationary phase powder, and further purified by recrystallization from a mixed solvent of toluene and heptane (volume ratio of toluene:heptane=1:1), and then dried, whereby 12.6 g of 2,2,2-trifluoroethyl diphenylphosphine oxide (b3) was obtained. The yield based on the compound (b1) was 51.2%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:10])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 12.25 h

Procedure:
To a solution of 0.8 g (4.4 mmol) of 4-bromo-3-methylphenol in 20 mL of acetone was added 1.5 g (10.9 mmol) of potassium carbonate. A yellow slurry was obtained to which was added 0.55 mL (1.25 g, 8.8 mmol) of methyl iodide. The resultant reaction mixture was stirred at ambient temperature for 12.25 hours, filtered and extracted between ethyl ether and water. The layers were separated and the organic phase was washed with sat. Na2SO3 (aq.) solution, dried over MgSO4, filtered and then concentrated in vacuo to a yellow oil. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) gave the title compound as a yellow oil.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][C:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)=[O:7].O.[NH2:20][NH2:21].O>CCO>[NH:20]([C:3](=[O:2])[CH2:4][NH:5][C:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)=[O:7])[NH2:21]
Reactant: COC(=O)CNC(=O)c1cccc2ccccc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)CNC(=O)c1cccc2ccccc12
Temperature: 25 °C
Yield: 81.6 %

Procedure:
The above compound 2a (3.3 g, 13.1 mmol) was heated at 60° C. with hydrazine hydrate (3.5 mL, 65 mmol) in EtOH (30 mL) for 2 hours. After cooling at room temperature, water (10 mL) was added. The resulting white precipitate was filtered and dried under vacuum to give hydrazide derivative 3a (2.6 g, 79%). 1H NMR (acetone-d6) δ 3.91 (d, J=5.9 Hz, 2H, CH2), 7.55-7.58 (m, 3H, Ar), 7.68 (dd, J=1.1 and 7.0 Hz, 1H, Ar), 7.98 (d, J=8.0 Hz, 1H, Ar), 8.02 (d, J=8.3 Hz, 2H, Ar), 8.35 (m, 1H, NH), 8.74 (t, J=6.3 Hz, 1H, NH), 9.31 (bs, 1H, NH); 13C NMR (acetone-d6) δ 41.08 (CH2), 124.88, 124.92, 125.13, 125.72, 126.12, 126.56, 128.07, 129.67, 129.80, 129.83, 133.08, 134.46, 168.34 (CO), 168.91 (CO).