Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br-].[F:10][C:11]1[CH:16]=[CH:15][C:14]([Zn+])=[CH:13][CH:12]=1.C(OCC)(=O)C.O>O1CCCC1>[Cl:8][C:6]1[CH:7]=[C:2]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[N:3]=[N:4][CH:5]=1
Reactant: Clc1cnnc(Cl)c1
Reactant: Fc1ccc([Zn+])cc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(-c2cc(Cl)cnn2)cc1
Temperature: -65 °C
Yield: 58 %

Procedure:
To a mixture of S-chloropyridazin-3(2H)-one (7.33 g, 56 mmol) was suspended in phosphorous oxychloride (55 ml, 594 mmol) and the mixture was heated at 80° C. for 3 hours. After cooling to room temperature the homogeneous dark solution was evaporated under reduced pressure and repartitioned between chloroform and water (50 ml each). The pH was adjusted to 8 by portionwise addition of saturated aqueous sodium carbonate solution and the phases were separated. After two further extractions the combined organic extracts were washed with water and brine and dried over sodium sulfate. After filtration the compound was adsorbed onto silica gel and purified by flash column (10% ethyl acetate-iso-hexane) to yield 3,5-dichloropyridazine (5.6 g, 67%) as a pale yellow solid. A sample of 3,5-dichloropyridazine (0.43 g, 2.9 mmol) was dissolved in tetrahydrofuran (10 ml) under nitrogen and cooled to −65° C. 1,2-(Bis(diphenylphosphino)ethane)-dichloronickel(II) (0.08 g, 0.15 mmol) was added followed by 4-fluorophenylzinc bromide (11.6 ml of a 0.5 M solution in tetrahydrofuran). The mixture was warmed to −10° C. over 4 hours and poured onto a mixture of ethyl acetate/water (30 ml/10 ml). The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and adsorbed onto silica gel. Purification by flask column chromatography (10% ethyl acetate-iso-hexane) gave the title compound (0.35 g, 58%) as a red solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([CH:13]([N:19]2[CH:23]=[C:22]([C:24]3[C:25]4[CH:32]=[CH:31][NH:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH:21]=[N:20]2)[CH2:14][CH:15]=[C:16]([F:18])[F:17])[CH2:12][CH2:11][CH2:10][CH2:9]1>CO.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([CH:13]([N:19]2[CH:23]=[C:22]([C:24]3[C:25]4[CH:32]=[CH:31][NH:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH:21]=[N:20]2)[CH2:14][CH2:15][CH:16]([F:17])[F:18])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: FC(F)=CCC(C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: FC(F)CCC(C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.2 %

Procedure:
4-[1-(1-Cyclopentyl-4,4-difluorobut-3-en-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]-pyrimidine trifluoroacetate salt (prepared as in Example 731) (20.0 mg, 0.041 mmol) was dissolved in methanol (3 mL), and a catalytic amount of 5% Pd on C was added. The mixture was stirred at room temperature for 2 hours, under an atmosphere of hydrogen provided by an affixed balloon. The mixture was filtered and purified via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) to afford product (4 mg, 21%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[N:13]C#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCNC1=N)C1C=CC=CC=1.Br[C:30]1[S:31][C:32]([C:36]([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[C:42]([F:47])[CH:41]=2)=[O:37])=[C:33]([CH3:35])[N:34]=1>>[CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:30]2[S:31][C:32]([C:36]([NH:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([F:46])=[C:42]([F:47])[CH:41]=3)=[O:37])=[C:33]([CH3:35])[N:34]=2)[C:9]1=[NH:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccc(F)c(F)c1
Reactant: N#CN=C1NCCN1Cc1ccccc1
Agent: N=C1NCCN1Cc1ccccc1
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=N)sc1C(=O)NCc1ccc(F)c(F)c1
Yield: 5 %

Procedure:
Following the procedure as described in Example 27, making variations as required to replace N-(1-benzylimidazolidin-2-ylidene)cyanamide with 1-benzylimidazolidin-2-imine to react with 2-bromo-N-(3,4-difluorobenzyl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 5% yield: mp 140-142° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.41 (t, J=5.8 Hz, 1H), 7.39-7.23 (m, 7H), 7.12-7.08 (m, 1H), 6.68 (m, 1H), 4.43 (s, 2H), 4.30 (d, J=5.8 Hz, 2H) 3.94 (m, 2H), 3.35-3.27 (m, 2H), 2.42 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.8, 158.3, 153.5, 151.1, 150.4, 148.0, 147.9, 138.2, 137.2, 129.0, 128.2, 127.8, 124.4, 117.7, 116.5, 48.4, 44.4, 43.9, 42.1, 17.6: MS (ES+) m/z 442.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH2:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.C([Li])CCC.[Cl-].[CH3:24][C:25]([NH:28][SiH:29]([CH3:31])[CH3:30])([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:10]([Si:29]([CH3:31])([CH3:30])[NH:28][C:25]([CH3:27])([CH3:26])[CH3:24])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:6][CH:7]=1
Reactant: Fc1ccc(CC2=Cc3ccccc3C2)cc1
Reactant: C[SiH](C)NC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Product: CC(C)(C)N[Si](C)(C)C1C(Cc2ccc(F)cc2)=Cc2ccccc21
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a mixture of 2-(4-fluorophenylmethyl)indene (2.21 g, 9.9 mmol) in 45 mL of hexanes were added 6.5 mL of butyl lithium (1.6 M hexane; 10.4 mmol). The mixture was stirred overnight, the mother liquor decanted and the solid dissolved in THF. To this was added N-(1,1-dimethylethyl)dimethylsilanamine chloride (1.80 g, 10.8 mmol) and the reaction heated at reflux for three hours. The volatiles were removed in vacuo, the residue extracted with hexane, filtered and the volatiles removed in vacuo to give 3.39 g (97 percent) of a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:7])[CH2:4][O:5][CH3:6].[C:8](Cl)(=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C.CN(C=O)C>C1COCC1.CN(C)C1C=CN=CC=1>[OH:7][CH:3]([CH2:4][O:5][CH3:6])[CH2:2][NH:1][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COCC(O)CN
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCC(O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5.0 g (47.6 mmol) of rac-1-amino-3-methoxypropan-2-ol were initially charged in THF (158 ml), and 7.36 ml (52.3 mmol) of benzyl chlorocarbonate, 24.85 ml (142.7 mmol) of N,N-diisopropyl ethyl amine and 1.16 g (9.5 mmol) of 4-dimethylaminopyridine were added. The reaction mixture was stirred at RT for 16 h. 3.7 ml (26.2 mmol) of benzyl chlorocarbonate and then 15 ml of DMF were added, and the reaction solution was stirred at RT overnight. The mixture was concentrated and diluted with ethyl acetate. The mixture was then washed with water, saturated aqueous sodium bicarbonate solution and with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, filtered off and concentrated. The aqueous phase was concentrated, the residue was taken up in ethyl acetate, the mixture was washed with saturated aqueous sodium bicarbonate solution and with saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered off and concentrated. Both fractions were combined and purified by silica gel chromatography (dichloromethane/methanol gradient: from 100:0 to 10:1). This gave 12.16 g (81% of theory, purity 76%) of the target compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCN(C2N=CC(Br)=CN=2)CC1)=O)(C)(C)C.[F:47][C:48]([F:59])([F:58])C1C=CC(B(O)O)=CC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:48]([F:59])([F:58])[F:47])=[CH:22][CH:21]=3)=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccc(C(F)(F)F)cc3)cn2)CC1
Yield: 95 %

Procedure:
Prepared according to the method for the preparation of 4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-carboxylic acid tert-butyl ester, from 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (0.346 g) and 4-(trifluoromethyl)benzeneboronic acid (0.211 g), to yield the title compound as a grey solid (0.392 g, 95%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].C[Si]([CH:12]=[N+:13]=[N-:14])(C)C.O>C1COCC1>[CH2:6]([O:5][C:1]([C:2]1[CH:3]=[CH:12][NH:13][N:14]=1)=[O:4])[CH3:7]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C#CC(=O)OCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc[nH]n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
A solution of ethyl propiolate (10.0 g, 0.10 mol) in THF (67 mL) was treated dropwise with (trimethylsilyl)diazomethane (51 mL, 0.10 mol) maintaining the temperature between 20-30° C. with ice bath cooling. The mixture was stirred at RT for 4 h then treated cautiously with water (250 mL) with cooling in an ice bath. The organics were evaporated in vacuo and the resulting precipitate was collected by filtration, washed with water and dried at RT in vacuo to give the title compound (13.5 g, 94%). LCMS (Method 3): Rt 2.22 min, m/z 141 [MH+].
Reaction SMILES: [F:1][C:2]1[C:3]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:4][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1>C(O)(C(F)(F)F)=O.ClCCl>[F:1][C:2]1[C:3]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH2:30])[CH2:25]2)=[N:4][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(F)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(F)c(N3CCC[C@H](N)C3)n2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
A mixture of tert-butyl N-[(3S)-1-[3-fluoro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate (0.1345 mmol; 113.1 mg) in TFA (1 mL) and dichloromethane (4 mL) was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 215 as an off-white solid (42.7 mg, 77%). 1H NMR (400 MHz, DMSO) δ 9.58-9.55 (s, 1H), 9.47-9.43 (s, 1H), 9.33-9.30 (s, 1H), 8.69-8.65 (s, 1H), 8.64-8.62 (s, 1H), 8.35-8.30 (s, 1H), 7.79-7.72 (dd, J=12.7, 8.5 Hz, 1H), 7.42-7.38 (dd, J=8.4, 2.0 Hz, 1H), 4.05-3.97 (d, J=8.5 Hz, 2H), 3.29-3.26 (d, J=10.8 Hz, 1H), 3.02-2.95 (m, 2H), 2.66-2.60 (s, 3H), 2.00-1.87 (t, J=14.1 Hz, 2H), 1.80-1.67 (m, 1H), 1.47-1.37 (d, J=10.5 Hz, 1H); MS (ESI) m/z: 405.1 [M+H]+
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:32]=[C:31]([CH2:33][N:34]([CH3:42])[CH:35]5CC[N:38](C)[CH2:37][CH2:36]5)[S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].CNC1CCN(C)CC1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:37]([CH2:36][CH2:35][N:34]([CH2:33][C:31]1[S:30][CH:29]=[C:28]([C:25]2[CH:26]=[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:16]2[CH2:17][CH2:18][N:13]([S:10]([CH2:8][CH3:9])(=[O:11])=[O:12])[CH2:14][CH2:15]2)[CH:32]=1)[CH3:42])#[N:38]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)C5CCN(C)CC5)c4)cc23)CC1
Agent: CNC1CCN(C)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)CCC#N)c4)cc23)CC1
Yield: 42.5 %

Procedure:
The title compound was prepared according to the general procedure for 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methyl-4-piperidinyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide trifluoroacetate, substituting 3-(methylamino)propanenitrile (84.12 mg, 1.0 mmol) for N,1-dimethyl-4-piperidinamine to afford 24 mg of the title compound (42.5%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]([CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][C:35]1=[O:39])[CH:15]1[CH:20]2[CH:16]1[CH2:17][N:18]([C:21]1[N:26]=[CH:25][C:24]([C:27]([O:29]CC)=[O:28])=[CH:23][N:22]=1)[CH2:19]2)(=[O:13])=[O:12].[O-]CC.[Na+].Cl.NO.O>CCO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]([CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][C:35]1=[O:39])[CH:15]1[CH:20]2[CH:16]1[CH2:17][N:18]([C:21]1[N:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][N:22]=1)[CH2:19]2)(=[O:12])=[O:13]
Reactant: CCOC(=O)c1cnc(N2CC3C(C2)C3N(CCN2CCCC2=O)S(=O)(=O)c2ccc3ccccc3c2)nc1
Agent: CC[O-]
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnc(N2CC3C(C2)C3N(CCN2CCCC2=O)S(=O)(=O)c2ccc3ccccc3c2)nc1
Temperature: 40 °C
Reaction time: 18 h
Yield: 31.8 %

Procedure:
To a solution of ethyl 2-(6-{(naphthalene-2-sulfonyl)-[2-(2-oxopyrrolidin-1-yl)ethyl]amino}-3-azabicyclo[3.1.0]hex-3-yl)pyrimidine-5-carboxylate (0.749 g, 1.4 mmol) in EtOH (8 ml) was added sodium ethoxide (1.08 g, 15.8 mmol) and hydroxylamine hydrochloride (1.30 g, 18.7 mmol). The mixture was stirred at 40° C. for 18 h, then water (20 ml) was added. The product was extracted with DCM (2×100 ml), and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The expected hydroxamate product was in fact proved not to have formed. The reaction yielded instead the acid. Purification by reverse phase HPLC yielded the title compound (232 mg, 32%). This was used directly in the next step without characterisation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][C:14]([NH2:16])=[O:15])[CH:7]=[CH:6]2.[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O>>[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]1[C:9]2[C:8](=[CH:7][CH:6]=[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]3=2)[CH2:13][C:14](=[O:15])[NH:16]1
Reactant: COc1ccc2cc(CC(N)=O)ccc2c1
Reactant: O=Cc1ccccc1F
Product: COc1ccc2c3c(ccc2c1)CC(=O)NC3c1ccccc1F

Procedure:
Prepared from 6-methoxy-2-naphthylacetamide and 2-fluorobenzaldehyde.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C@H:11]([N:15]1[CH:19]=[C:18]([C:20]([O:22]CC)=O)[N:17]=[CH:16]1)[CH2:12][CH2:13][OH:14])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:25]>CO>[Si:1]([O:8][C@H:9]([C@H:11]([N:15]1[CH:19]=[C:18]([C:20]([NH2:25])=[O:22])[N:17]=[CH:16]1)[CH2:12][CH2:13][OH:14])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: N
Reactant: CCOC(=O)c1cn([C@H](CCO)[C@H](C)O[Si](C)(C)C(C)(C)C)cn1
Solvent: CO
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CCO)n1cnc(C(N)=O)c1
Temperature: 100 °C
Yield: 83.8 %

Procedure:
To a solution of ethyl 1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-hydroxy-3-pentyl]imidazole-4-carboxylate (1.0 g, 2.8 mmol) in methanol (15 ml) was added aqueous 28% NH3 solution (15 ml). And the mixture was heated at 100° C. in a sealed steel tube for 15 h. After cooling, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel (35 g) chromatography eluting with chloroform/methanol (25:1 to 15:1) to give 1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-hydroxy-3-pentyl]imidazole-4-carboxamide (769.5 mg, 83.8%) as a white amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C:11](O)=[C:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9]1.Cl.[NH2:23][OH:24]>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C:11](=[N:23][OH:24])[CH:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9]1
Reactant: NO
Reactant: CC(C)(C)OC(=O)C1=C(O)C(=O)N(c2ccccc2F)C1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)C1CN(c2ccccc2F)C(=O)C1=NO
Temperature: 25 °C
Reaction time: 120 h
Yield: 57.4 %

Procedure:
To a solution of the title compound of Example H (3.16 g, 10.8 mmol) in pyridine (50 ml) was added hydroxylamine hydrochloride (3.73 g, 54 mmol) and the reaction was stirred for 5 days(d) at room temperature. After the reaction was concentrated in vacuo, H2O was added and the mixture was extracted with CH2Cl2. Drying of the organic phase (MgSO4) and concentration gave a solid which was chromatographed on silica gel eluting with 2% EtOH/CH2Cl2 to give the title compound (1.91 g, 57%). Anal calcd for C15H17N2O4F: C, 58.44; H, 5.56; N, 9.09. Found: C, 58.43; H, 5.62; N, 8.75. DSC=175.1°-180.2° C. at 225.6 J/g.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:19])=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCCc1ccc(-c2ccc(OC)c(Cl)c2F)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCCc1ccc(-c2ccc(O)c(Cl)c2F)cc1
Temperature: 25 °C
Yield: 86.2 %

Procedure:
22.0 g of the compound (b66) was dissolved in 200 mL of methylene chloride. 23.7 g of boron tribromide was added dropwise to the resulting solution in a temperature range of −27 to −20° C., and the temperature of the solution was gradually increased to room temperature, followed by stirring over night. The resulting reaction mixture was poured slowly to 300 mL of iced water, and the mixture was left at rest to separate into an organic layer and an aqueous layer, followed by extracting to the organic layer. The resulting organic layer was washed with a sodium chloride aqueous solution in three times, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was a yellowish solid. 19.7 g of the residue was purified by recrystallization from a mixed solvent of heptane and toluene (heptane/toluene=2/1 by volume) to obtain 18.0 g of 3-chloro-2-fluoro-4′-propylbiphenyl-4-ol (b67). The resulting compound (b67) was a white solid.
Reaction SMILES: O[CH:2]([C:4]1[S:8][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:5]=1)[CH3:3].C1(P([N:28]=[N+:29]=[N-:30])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:28]([CH:2]([C:4]1[S:8][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:5]=1)[CH3:3])=[N+:29]=[N-:30]
Reactant: CCOC(=O)c1ccc(C(C)O)s1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1ccc(C(C)N=[N+]=[N-])s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a mixture of ethyl 5-(1-hydroxyethyl)thiophene-2-carboxylate (1.01 g), diphenylphosphorylazide (1.67 g), and toluene (10 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (905 μL) under ice-cooling, followed by stirring for 30 minutes. The reaction mixture was warmed to room temperature, followed by stirring for 15 hours. The reaction liquid was washed with water and 1 M hydrochloric acid in this order, and dried over anhydrous sodium sulfate. Then, after concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain ethyl 5-(1-azidoethyl)thiophene-2-carboxylate (1.03 g) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH2:10][CH2:11][CH3:12])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:14][C@@H:15]([C:19]([OH:21])=[O:20])[C@H:16]([CH3:18])[OH:17].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[C:9]([CH2:10][CH2:11][CH3:12])=[C:8]([NH:14][C@H:15]([C@@H:16]([OH:17])[CH3:18])[C:19]([OH:21])=[O:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: CCCc1c(F)ccc(C#N)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Temperature: 80 °C
Reaction time: 40 h
Yield: 13.4 %

Procedure:
2-Chloro-4-fluoro-3-propylbenzonitrile (CAS 924626-89-1, 3.22 g, 16.3 mmol) was mixed together with H-D-Thr-OH (2.33 g, 19.6 mmol) in DMSO (30 mL) at room temperature. K2CO3 (4.73 g, 34.2 mmol) was added and the reaction mixture was stirred at 80° C. for 40 h. The reaction mixture was then cooled to room temperature and partitioned between water and EtOAc. The layers were separated and the aqueous extract was washed once with EtOAc. The aqueous extract was then acidified by slow addition of citric acid and stirred for 10 min at room temperature. The solution was extracted with EtOAc several times and the organic extracts were combined, washed with water, dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product (0.650 g, 13% yield), which was carried on to the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.C[Si](C)(C)[O:31][CH2:32][CH:33]([NH2:35])[CH3:34].CC([O-])(C)C.[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([NH:35][CH:33]([CH3:34])[CH2:32][OH:31])[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: CC(N)CO[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CC(CO)Nc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Temperature: 125 °C
Reaction time: 0.12 h
Yield: 12.2 %

Procedure:
A mixture of 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (300 mg, 0.72 mmol), 1-(trimethylsilyloxy)propan-2-amine (211 mg, 1.44 mmol), tBuONa (47 mg, 0.48 mmol), Pd(OAc)2 (16 mg, 0.1 mmol), and Xphos (68 mg, 0.144 mmol) in dioxane (2 mL) was bubbled N2 for 10 min and then stirred at 125° C. for 7 min under the irradition of microwave. The mixture was filtered over ceilite. The filtrate was concentrated to dryness and purified by pre-TLC (EtOAc) and pre-HPLC to afford 40 mg of 347. (yield: 13%). 1H NMR (CDCl3, 400 MHz): δ8.02 (s, 1H), 7.49 (q, J=5.6, 8.8 Hz, 1H), 7.12-6.99 (m, 4H), 6.21 (d, J=4.8 Hz, 1H), 4.20-3.04 (m, 8H), 2.28 (s, 1H), 1.19-1.15 (m, 3H). LC-MS (ESI): m/z=456 [M+H]+
Reaction SMILES: [N:1]1[C:2]([C:10](OCC)=[O:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[N:1]1[C:2]([CH2:10][OH:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCOC(=O)c1cn2ccccc2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cn2ccccc2n1
Temperature: 0 °C
Yield: 90.7 %

Procedure:
To an ice-cold solution of ethyl imidazo[1,2-a]pyridine-2-carboxylate (6.1 g, 32 mmol) in dry THF (300 mL) was added lithium aluminium hydride (LAH) (2.4 g, 64 mmol) in portions, and the temperature was maintained at <5° C. for 2 h. THF and water (50 mL, 1:1 v/v) were added slowly and the mixture was filtered. The filtrate was evaporated to dryness. The residue was re-dissolved in EtOAc (60 mL), and washed with brine (10 mL×3). The organic layers were combined, and the solvent was removed to give the title compound (4.3 g, yield 90%). ESI MS: m/z 149 [M+H]+.