Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[C:17]([C:22]([F:25])([F:24])[F:23])=[N:16][N:15]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.O1CCCCC1[O:34][CH2:35][CH2:36][N:37]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[N:38]1.O1CCCCC1OC1CCCCO1.Cl>>[CH:19]([N:18]1[C:17]([C:22]([F:24])([F:25])[F:23])=[N:16][N:15]=[C:14]1[C:8]1[S:9][C:10]2[CH2:11][CH2:12][O:13][C:4]3[CH:3]=[C:2]([C:40]4[CH:39]=[N:38][N:37]([CH2:36][CH2:35][OH:34])[CH:41]=4)[CH:27]=[CH:26][C:5]=3[C:6]=2[N:7]=1)([CH3:21])[CH3:20]
Reactant: CC(C)n1c(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)nnc1C(F)(F)F
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Agent: C1CCC(OC2CCCCO2)OC1
Agent: Cl
Product: CC(C)n1c(-c2nc3c(s2)CCOc2cc(-c4cnn(CCO)c4)ccc2-3)nnc1C(F)(F)F

Procedure:
Similarly to as described in General Procedure C, 8-bromo-2-(4-isopropyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. Subsequent to the Suzuki coupling, deprotection of the tetrahydropyranyl ether was accomplished by adding 2N HCl to the crude reaction mixture. Purification by reverse phase HPLC gave 346 as a colorless solid (112 mg). LCMS: 491.1. 1H NMR (400 MHz, DMSO) δ 8.27 (d, J=13.7 Hz, 1H), 8.23 (s, 1H), 7.95 (s, 1H), 7.44 (dd, J=8.3, 1.7 Hz, 1H), 7.32 (d, J=1.7 Hz, 1H), 5.45-5.29 (m, 1H), 4.91 (t, J=5.3 Hz, 1H), 4.41 (t, J=5.0 Hz, 2H), 4.16 (t, J=5.6 Hz, 2H), 3.77 (q, J=5.5 Hz, 2H), 3.48 (t, J=5.0 Hz, 2H), 1.70 (t, J=11.9 Hz, 6H)
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+]>C(O)C.O>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[N:13][OH:14])([O-:3])=[O:2]
Reactant: NO
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccccc1C=NO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-nitrobenzaldehyde (115 g) and hydroxylamine hydrochloride (6.6 g) in ethanol (110 ml) and water (4 ml) was added sodium acetate (13.6 g) and the mixture was stirred at room temperature for 4 hours. The mixture was poured into water (500 ml) and the mixture filtered to give the title product.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.[Cl:26][C:27]1[N:28]=[C:29]([C:34]([NH:36][C@H:37]2[CH2:42][CH2:41][N:40]([C:43]3[S:44][C:45]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[C:46]([C:48]([OH:50])=O)[N:47]=3)[CH2:39][C@H:38]2[O:56][CH2:57][CH3:58])=[O:35])[NH:30][C:31]=1[CH2:32][CH3:33]>CC(N(C)C)=O.ClCCl.C(OCC)(=O)C>[Cl:26][C:27]1[N:28]=[C:29]([C:34]([NH:36][C@H:37]2[CH2:42][CH2:41][N:40]([C:43]3[S:44][C:45]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[C:46]([C:48](=[O:50])[NH:3][CH2:1][CH3:2])[N:47]=3)[CH2:39][C@H:38]2[O:56][CH2:57][CH3:58])=[O:35])[NH:30][C:31]=1[CH2:32][CH3:33]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)O
Reactant: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCNC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)sc1C(=O)OCC
Reaction time: 5 h
Yield: 81.3 %

Procedure:
Ethylamine (2.0 M solution in THF) (0.60 mL, 1.20 mmol), WSC hydrochloride (345 mg, 1.80 mmol) and 1-hydroxybenzotriazole (8 1 mg, 0.60 mmol) were added to a mixed solution of cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained in Example (50a) (300 mg, 0.60 mmol) in DMA/dichloromethane (6 mL/6 mL) at room temperature, followed by stirring for five hours. The reaction solution was diluted with ethyl acetate, and then the mixture was washed with a 1 N aqueous hydrochloric acid solution and 5% saline. The organic layer was dried over anhydrous magnesium sulfate. Following filtration, the filtrate was concentrated under reduced pressure. The resulting residue was suspended and washed in diethyl ether to obtain 257 mg of the title compound as a white solid (81%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([N:10]2[C:11]3[CH2:12][CH2:13][C:4]4[CH:3]=[C:2]([Cl:1])[CH:15]=[CH:14][C:5]=4[C:6]=3[CH2:7][CH2:8][CH2:9]2)=[O:30])=[CH:27][CH:26]=1
Reactant: Clc1ccc2c(c1)CCC1=C2CCCN1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCCC3=C2CCc2cc(Cl)ccc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
15.0 g (0.06 mol) of 8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline were dissolved in 150 ml of methylene chloride, treated with 6.68 g (0.066 mol) of triethylamine and 11.2 g (0.066 mol) of p-methoxybenzoyl chloride in 50 ml of methylene chloride were added dropwise thereto at 0°. After stirring at room temperature for 1 hour the mixture was extracted with water, dried with magnesium sulphate and the solvent was distilled off in vacuo. Crystallization (methylene chloride-ether) gave 4-(p-methoxybenzoyl)-8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline as white crystals of melting point 182°-183°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10]Cl>O1CCOCC1.O>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[NH:1][CH:10]=[CH:9]2
Reactant: Nc1c(Cl)cccc1C(=O)CCl
Solvent: O
Solvent: C1COCCO1
Product: Clc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dissolve 1-(2-amino-3-chlorophenyl)-2-chloroethanone (7.0 g, 34.30 mmol) in 10% aqueous 1,4-dioxane (75 mL). Carefully add NaBH (2.6 g, 68.6 mmol, 2 eq.) as a solid. Heat to reflux. After 4 hours, cool to room temperature, dilute with water (300 mL), and extract with dichloromethane (2×200 mL). Combine the organic layers, dry over MgSO4, filter, and remove the solvent in vacuo leaving a light brown oil in the flask. Purify the oil by HPLC (silica gel mobile phase: 100% hexane to 50% EtOAc in hexanes over 50 minutes), to give the title compound as a brown oil: 1H NMR (300 MHz, d6-DMSO-d6): 5.16 (m, 1H), 5.39 (d, 1H), 5.70 (bs, 1H), 6.59 (t, 1H), 7.09 (m, 2H); MS (ES+): m/z 154, 152 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([C@@H:4]([NH:9][C:10]([N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([CH2:21][CH2:22][S:23][CH3:24])[C:13]1=[O:25])=[O:11])[C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3].ClC1C=CC=C(C(OO)=[O:34])C=1.C([O-])(O)=O.[Na+]>ClCCl>[NH2:1][C:2]([C@@H:4]([NH:9][C:10]([N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([CH2:21][CH2:22][S:23]([CH3:24])=[O:34])[C:13]1=[O:25])=[O:11])[C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3]
Reactant: CSCCn1c(=O)n(C(=O)N[C@H](C(N)=O)C(C)(C)C)c2ccccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)CCn1c(=O)n(C(=O)N[C@H](C(N)=O)C(C)(C)C)c2ccccc21
Reaction time: 8 h

Procedure:
A mixture of N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[2-(methylthio)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide (Example 32, 150 mg), m-chloroperbenzoic acid (70%, 170 mg) and NaHCO3 (150 mg) in dichloromethane (5 mL) was stirred overnight and quenched with sat. Na2S2O3 aq. (25 mL) The whole was extracted with ethyl acetate (25 mL×2). The combined organic layers were washed with brine, dried over magnesium sulfate, filtrated and concentrated in vacuo. The residue was purified by preparative TLC to yield the titled compound. (180 mg)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]2[O:10][CH2:11][O:12][C:7]2=[CH:6][C:3]=1[CH:4]=O.[C:13](OCC)(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].N1CCCCC1.C(O)(=O)C>C(O)C>[CH2:11]1[O:10][C:8]2=[CH:9][C:2]3[O:1][C:13](=[O:20])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][C:3]=3[CH:6]=[C:7]2[O:12]1
Reactant: O=Cc1cc2c(cc1O)OCO2
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2cc3c(cc2oc1=O)OCO3
Yield: 70.5 %

Procedure:
A mixture of 2-hydoxy-4,5-methylenedioxybenzaldehyde (1.16 g), diethyl malonate (1.34 g), piperidine (0.3 g), acetic acid (0.035 ml) and ethanol (30 ml) was refluxed for 4 hours. After the reaction mixture was cooled, the resulting crystal was collected by filtration to yield ethyl 6,7-methylenedioxy-2-oxo-1-benzopyran-3-carboxylate (1.29 g, 70%) having a melting point of 200°-201° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.Cl[C:19](OC1C=CC=CC=1)=[O:20].C(N(CC)CC)C.[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][C:45]=1[C:46]([F:49])([F:48])[F:47])[NH:42][CH2:41][CH2:40]2>ClCCl>[N:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:1][C:19]([N:42]4[C:43]5[C:39](=[CH:38][C:37]([O:36][CH3:35])=[C:45]([C:46]([F:49])([F:47])[F:48])[CH:44]=5)[CH2:40][CH2:41]4)=[O:20])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)=[CH:13][CH:14]=1
Reactant: Nc1ccc2c(ccn2Cc2ccncc2)c1
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1ccc3c(ccn3Cc3ccncc3)c1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
A mixture of aminoindole (D49, 0.46 g, 2.1 mmol), phenyl chloroformate (0.26 mL, 2.1 mmol) and triethylamine (0.29 mL, 2.1 mmol) in dichloromethane (5 mL) was stirred at room temperature for 1 h. The mixture was then diluted with dichloromethane, washed with water, dried and evaporated. The residue was dissolved in acetonitrile (10 mL). 5-Methoxy-6-trifluoromethylindoline (D11, 0.45 g, 2.1 mmol) and triethylamine (0.29 mL, 2.1 mmol) were added and the mixture was stirred for 3 h at room temperature. The reaction was worked up as for Example 71, and the solid obtained after trituration was recrystallised from dichloromethane/petrol to give the title compound (0.26 g, 27%), m.p. 215-8° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH3:6])=[O:4].C/[C:8](/[C:14]([O-:16])=O)=[C:9](\C)/[C:10]([O-:12])=[O:11].[C:17]1(C)C(O)=CC=CC=1>ClC1C=CC=CC=1Cl>[CH3:1][N:2]1[C:8](=[CH:9][C:10]([O:12][CH3:17])=[O:11])[C:14](=[O:16])[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: C/C(C(=O)[O-])=C(\C)C(=O)[O-]
Reactant: Cc1ccccc1O
Reactant: CNC(=O)NC
Solvent: Clc1ccccc1Cl
Product: COC(=O)C=C1C(=O)N(C)C(=O)N1C

Procedure:
44 g of N,N'-dimethylurea were dissolved in 150 g of o-dichlorobenzene and reacted with 72 g of dimethylmaleate for 2 hours at 180°-185° C after the addition of 25 g of cresol. The solvent was removed from this reaction mixture and the residue was fractionated under vacuum, 85 g (= 85% of the theory) of the desired product distilling over at 0.07 Torr and 128° C. A purified product melting at 49.5° C could be obtained by dissolving the crude product in chloroform and reprecipitating it with ether. The structure of the purified product was confirmed by IR and NMR spectra and by elementary analysis.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].Br[CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21]>CN(C)C=O>[C:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][C:8]([CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CC(C#N)C#N)cc1
Reactant: FC(F)(F)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CC(C#N)(C#N)CCC(F)(F)F)cc1
Yield: 27.4 %

Procedure:
Using 1.00 g of (4-cyanobenzyl)malononitrile, 10 ml of N,N-di-methylformamide, 0.36 g of sodium hydride (60% in oil), and 2.37 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.42 g of 2-(4-cyanobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (22)).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])C.[Cl:9][C:10]1[CH:11]=[C:12]([C@@H:17]2[O:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][C@H:18]2[CH2:31][C:32](=O)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:13]=[CH:14][C:15]=1[Cl:16].C[NH:41]N>C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]([C@@H:17]2[O:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:19][C@H:18]2[CH2:31][C:32]2[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:3][N:4]([CH3:6])[N:41]=2)[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: CCOC(=O)CC(=O)C[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: CNN
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(C)nc1C[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 32.5 %

Procedure:
N,N-Dimethylformamide dimethyl acetal (0.210 mL, 1.58 mmol) was added to a solution of tert-butyl (6R,7R)-7-(3,4-dichlorophenyl)-6-(4-ethoxy-2,4-dioxobutyl)-1,4-oxazepane-4-carboxylate (500 mg, 1.05 mmol) in toluene (5 mL), and the mixture was stirred at 80° C. for 2 hr, and concentrated under reduced pressure. The residue was dissolved in ethanol (5 mL), and methylhydrazine (0.062 mL, 1.16 mmol) was added. The reaction mixture was stirred at 80° C. for 1.5 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (175 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH3:23][N:24]([CH3:45])[C:25]([CH:27]1[CH2:31][C:30]2[CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=[CH:35][C:29]=2[O:28]1)=[O:26].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:33]3[CH:34]=[CH:35][C:29]4[O:28][CH:27]([C:25]([N:24]([CH3:23])[CH3:45])=[O:26])[CH2:31][C:30]=4[CH:32]=3)[C:16]2=[CH:15][N:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
Reactant: CN(C)C(=O)C1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2O1
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: C1COCCO1
Solvent: O
Product: COc1cc(OC)c(Cl)c(-c2ncc3c(-c4ccc5c(c4)CC(C(=O)N(C)C)O5)n[nH]c3n2)c1Cl
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (18.0 mg, 0.0400 mmol), N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-2-carboxamide (19.0 mg, 0.0600 mmol), tetrakis(triphenylphosphine)palladium(0) (2.77 mg, 0.00240 mmol), and sodium carbonate (12.7 mg, 0.120 mmol) in 1,4-dioxane (0.42 mL) and water (0.14 mL) in a reaction vial was sealed, and degassed and recharged with nitrogen for three times. The mixture was stirred at 120° C. for 3 h. After cooling, the mixture was diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+=514.0/516.0. 1H NMR (300 MHz, DMSO-d6) δ: 9.77 (s, 1H), 8.02 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.06 (s, 1H), 6.97 (d, J=8.4 Hz, 1H), 5.76 (d, J=9.1, 7.4 Hz, 1H), 3.99 (s, 6H), 3.55-3.49 (m, 2H), 3.13 (s, 3H), 2.90 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:40])=[C:10]([NH:16][C:17]3[N:22]=[C:21]([N:23](CC)[CH2:24][C:25]4C=CC(OC)=CC=4)[C:20]4=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:19]4[N:18]=3)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][C@H:3]1[OH:41].C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:40])=[C:10]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH3:25])[C:20]4=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:19]4[N:18]=3)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][C@H:3]1[OH:41]
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](N)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](N)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
(+/−)-2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (390 mg, 0.681 mmol) was mixed with anisole (0.372 mL, 3.40 mmol) and DCE (3 mL). TFA (1.049 mL, 13.61 mmol) was added and the mixture was stirred at 25° C. for 1 hr. The mixture was concentrated to dryness under high-vac. 30 ml 2N NH3/MeOH was added and stirred for 30 min. The white precipitate was collected by filtration and washed with 20 ml cold MeOH, ether, and dried under air-suction for 2 hrs to give rac-2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (193 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([F:22])[C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][NH:11]2)=[CH:7][CH:6]=1.[H-].[Na+].Br[CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[C:14]([F:22])[C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:7][CH:6]=1.[Cl:1][C:2]1[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[C:14]([F:22])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:12]([CH:13]=1)=[N:11][N:10]([CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:9]=2
Reactant: CCOC(=O)C(C)Br
Reactant: Fc1cc(C(F)(F)F)cc(Cl)c1Oc1ccc2cn[nH]c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)n1cc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc2n1
Product: CCOC(=O)C(C)n1ncc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc21
Reaction time: 8.5 h

Procedure:
6-(2-Chloro-6-fluoro-4-trifluoromethylphenoxy)indazole (0.7 g) was dissolved in dry DMF (1.5 cm3) and cooled in a waterbath when 50% sodium hydride (0.1 g) was added portionwise with stirring. The mixture was stirred for 10 minutes and ethyl 2-bromopropionate (0.42 g) was added. The mixture was stirred with water cooling for 5 minutes and then at room temperature for 8.5 hours. The reaction was poured into water (15cm3) containing 2M hydrochloric acid (1 cm3) and the mixture extracted with ethyl acetate three times. The organic phase was combined, washed with water, dried (MgSO4), filtered, and the solvent removed from the filtrate under vacuum. The residue was purified by flash chromatography (hexane: TBME, 7:3) to give compound 1, ethyl 2-[6-(2-chloro-6-fluoro-4-trifluoromehylphenoxy)indazol-1-yl]propionate (0.51 g) as a colorless oil and compound 33 ethyl 2-[6-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)indazol-2-yl]propionate (0.154 g) as an oil.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:47]=[CH:46][C:15]([CH2:16][N:17]2[C:23](=[O:24])[C@H:22]3[CH2:25][CH2:26][CH2:27][C@H:21]3[N:20]([C:28](=[O:41])[CH2:29][N:30]3[C:34](=[O:35])[C:33]4=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]4[C:31]3=[O:40])[C:19]3[CH:42]=[CH:43][CH:44]=[CH:45][C:18]2=3)=[CH:14][CH:13]=1)=O)C1C=CC=CC=1.[BrH:48].C(O)(=O)C>C(Cl)(Cl)Cl>[BrH:48].[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][N:17]2[C:23](=[O:24])[C@H:22]3[CH2:25][CH2:26][CH2:27][C@H:21]3[N:20]([C:28](=[O:41])[CH2:29][N:30]3[C:31](=[O:40])[C:32]4=[CH:39][CH:38]=[CH:37][CH:36]=[C:33]4[C:34]3=[O:35])[C:19]3[CH:42]=[CH:43][CH:44]=[CH:45][C:18]2=3)=[CH:46][CH:47]=1
Reactant: O=C(Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (3aR*,10aS*)-9-[4-(benzyloxycarbonylamino)benzyl]-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (5.15 g, 8.2 mmol) in chloroform (80 mL) was added 25% hydrogen bromide/acetic acid (15 mL) and the mixture was stirred at room temperature for 45 minutes. This reaction mixture was concentrated under reduced pressure and the residue was crystallized from ethanol-diethyl ether to provide (3aR*,10aS*)-9-(4-aminobenzyl)-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][l,4]diazepin-10(1H)-one hydrobromide. This product was suspended in chloroform and treated with 0.5N-aqueous NaOH solution (40 mL). The aqueous layer was separated and the organic layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from chloroform-diethyl ether to provide 3.71 g (yield 91%) of the title compound. m.p. 286°-289° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:23])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20](=O)[CH3:21])[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:24])[C:5]([C:25]([OH:27])=[O:26])=[CH:4]1)[CH3:2].Cl.[NH2:29][OH:30].C(=O)(O)[O-].[Na+].C(Cl)Cl>CO.O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:23])=[C:10]([N:13]3[CH2:14][CH2:15][N:16]([CH2:19][C:20](=[N:29][OH:30])[CH3:21])[CH2:17][CH2:18]3)[CH:11]=2)[C:6](=[O:24])[C:5]([C:25]([OH:27])=[O:26])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(C)=O)CC3)cc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(C)=NO)CC3)cc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.7 %

Procedure:
To a suspension of the 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-[4-(2-oxopropyl)-1-piperazinyl]-quinoline-3-carboxylic acid [H. Kondo et. al., J. Med. Chem., 29, 2020 (1986)] (0.38 g, 1 mmol) in absolute methanol (20 ml) was added a solution of hydroxylamine hydrochloride (0.14 g, 2 mmol) and sodium bicarbonate (0.17 g, 2 mmol) in water (2 ml). The mixture was stirred for 20 hr at room temperature, then CH2Cl2 (50 ml) was added, and the layers were separated. The organic phase was washed successively with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to give a solid which was purified by flash column chromatography (silica gel, with CH2Cl2/methanol (10:1) as the eluant) and crystillization from CH2Cl2/methanol 5:1 to give 1-ethyl-6-fluoro-7-[4-(2-hydroxyiminopropyl)-1-piperazinyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as an off-white amorphous solid (0.28 g, 72%). Mp: 218° C. (dec). 1H NMR (DMSO-d6) δ1.41 (t, 3H, J=7.2), 1.81 (s, 3H), 2.54 (m, 4H), 3.03 (s, 2H2), 3.33 (m, 4H), 4.57 (q, 2H, J=7.2), 7.17 (d, H, J=7.2), 7.90 (d, 1H, J=13.6), 8.92 (s, 1H), 10,61 (s, 1H), 15.27 (br s, 1H). Anal. Calcd. for C19H23FN4O4•0.5 H2O: C, 57.14; H. 6.06; N, 14.03. Found: C, 57.43; H, 5.87; N, 13.83.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.CN(C)C(Cl)=O.[N:13]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:24])=[N+:21]([O-])[CH:22]=1)=[N+:14]=[N-:15].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[N:13]([CH2:16][C:17]1[C:22]([C:5]#[N:6])=[N:21][C:20]([CH3:24])=[CH:19][CH:18]=1)=[N+:14]=[N-:15]
Reactant: C[Si](C)(C)C#N
Reactant: Cc1ccc(CN=[N+]=[N-])c[n+]1[O-]
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(CN=[N+]=[N-])c(C#N)n1
Reaction time: 23 h
Yield: 77.4 %

Procedure:
Trimethylsilyl cyanide (6.4 ml, 48 mmol) and dimethylcarbamyl chloride (4.2 ml, 46 mmol) were added in that order to a solution of the 5-(azidomethyl)-2-methyl-1-pyridiniumolate (7.08 g, 43.2 mmol) in methylene chloride (80 ml) at room temperature and the mixture was stirred at the same temperature for 23 hours. After confirming completion of the reaction by thin layer chromatography, saturated aqueous sodium hydrogencarbonate (80 ml) was added and the mixture was stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate, the aqueous layer was separated and extraction was performed with ethyl acetate. The collected organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (5.79 g, 56%, two steps) as a colorless oil.