Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[C:9]([NH2:11])=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl.CCOC(C)=O>CO>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([NH2:11])=[S:10])=[CH:17][CH:16]=1
Reactant: NC(=S)N(Cc1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: NC(=S)N(Cc1ccccc1)c1ccc(N)cc1
Temperature: 25 °C
Yield: 74.6 %

Procedure:
In Example 107, reduction of the nitro group in compound 342 by reaction with stannous chloride in methanol proceeded selectively and resulted in the formation of amino derivative 343 in high yield, as follows: A mixture of thiourea 342 (0.287 g, 1 mmol) and SnCl2.2H2O (0.5 g, 2.2 mmol) in MeOH (25 mL) was refluxed for 4 hours, cooled to room temperature, then poured into EtOAc (150 mL. The mixture was sequentially washed with saturated NaHCO3 (5×20 mL) and H2O (3×20 mL), dried over MgSO4, then evaporated. The residue was chromatographed over silica gel (2×15 cm, eluant: 1% MeOH in CHCl3) to produce (4-aminophenyl)-benzyl thiourea 343 (0.192 g, 75% yield) as a white powder. Relevant data: mp 153°-155° C. (from EtOAc); 1H NMR (DMSO-d6): δ4.65 (d, 2H, J=5.7 Hz), 5.05 (br.s., 2H, NH2), 6.50 (d, 2H, J=9 Hz), 6.85 (d, 2H, J=9Hz), 7.25 (m, 5H), 7.61 (br.s., 1H, NH), 9.15 (s, 1H, NH); 13C NMR (DMSO-d6) δ47.50, 114.72, 126.96, 127.23, 127.51, 128.66, 139.57, 146.88, 181.305; MS m/e (1%): 257 (M+, 42), 256 (17), 182 (25), 165 (6), 150 (100), 108 (75), 107 (37), 106 (47), 91 (92).
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[C:29](Cl)(=[O:33])[C:30](Cl)=[O:31].[OH2:35]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:18][CH:17]=4)=[CH:13][CH:14]=3)[C:9]([C:29](=[O:33])[C:30]([OH:35])=[O:31])=[CH:8]2)=[CH:27][CH:28]=1
Reactant: Cc1ccc(Cn2ccc3cc(-c4ccc(OC(F)(F)F)cc4)ccc32)cc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O
Product: Cc1ccc(Cn2cc(C(=O)C(=O)O)c3cc(-c4ccc(OC(F)(F)F)cc4)ccc32)cc1

Procedure:
The title compound was prepared from 1-(4-methylbenzyl)-5-[4-(trifluoromethoxy)phenyl]-1H-indole and oxalyl chloride in substantially the same manner, as described in Step 3 of Example 25. The product was obtained as a yellow solid, mp: 192-193° C. Mass spectrum (ESI, [M+H]+) m/z 454. 1HNMR (400 MHz, DMSO-d6): δ 13.50 (br s, 1H), 8.70 (s, 1H), 8.42 (s, 1H), 7.77 (d, 2H, J=8.7 Hz), 7.67 (d, 1H, J=8.5 Hz), 7.58 (dd, 1H, J=8.7 Hz and 1.8 Hz), 7.45 (d, 2H, J=8.3 Hz), 7.22 (d, 1H, J=7.9 Hz), 7.15 (d, 2H, J=8.1 Hz), 5.57 (s, 2H), and 2.25 ppm (s, 3H). Elemental Analysis for C25H18F3NO4.0.2 H2O: Calculated: C, 65.70; H, 4.06; N, 3.06. Found: C, 65.74; H, 4.05; N, 2.94.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([Cl:12])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[Cu][C:14]#[N:15].CN(C=O)C>CCOC(C)=O>[Cl:12][C:7]1[N:8]=[CH:9][C:10]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([C:14]#[N:15])[CH:11]=2
Reactant: N#C[Cu]
Reactant: Clc1cc2ccc(Br)cc2cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2cc(Cl)ncc2c1
Temperature: 150 °C

Procedure:
To a flask charged with 7-bromo-3-chloroisoquinoline (1.0 g, 4.1 mmol) and a stir bar was added copper(I) cyanide (550 mg, 6.2 mmol) and DMF (50 mL). The mixture was heated to 150° C. for 24 hours under an atmosphere of nitrogen. The reaction was diluted with EtOAc, washed with sat. NH4OAc and brine, dried over sodium sulfate, concentrated and purified by silica gel chromatography (Hexanes:DCM) and the solvent removed to afford the title compound. LC-MS (IE, m/z): 189 [M+1]+.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[NH:14][CH:13]=[CH:12]2.[CH2:20](I)[CH3:21]>O>[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH3:21])[CH:13]=[CH:12]2
Reactant: CCI
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ccc2cc(Br)ccc2c1=O
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 22 mg of 60% sodium hydride was added at 0° C. to 3 ml solution of dimethylformamide with 100 mg of 6-bromo-2H-isoquinoline-1-one, and the mixture was stirred for 30 min. 0.04 ml of ethyl iodide was added at 0° C., and the mixture was stirred at room temperature for 3 hours. Cold water was added to the reaction solution, extracted with chloroform. Chloroform layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. After distilling out the solvents under reduced pressure, the residues were separated and purified by thin-layer chromatography (hexane/ethyl acetate=3/1) to obtain 30 mg of the above compound as a white solid.
Reaction SMILES: COC(=O)CCCC1OC=C(C2C=CC=CC=2[N+]([O-])=O)N=1.Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33])=O.[CH3:35][O:36][C:37](=[O:43])[CH2:38][CH2:39][C:40]([NH2:42])=[O:41]>>[CH3:35][O:36][C:37](=[O:43])[CH2:38][CH2:39][C:40]1[O:41][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])[N:42]=1
Reactant: COC(=O)CCC(N)=O
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Agent: COC(=O)CCCc1nc(-c2ccccc2[N+](=O)[O-])co1
Product: COC(=O)CCc1nc(-c2ccccc2[N+](=O)[O-])co1
Yield: 35.7 %

Procedure:
Using a method similar to the procedure described for the preparation of 4-[4-(2-nitro-phenyl)-oxazol-2-yl]-butyric acid methyl ester; reaction of 2-bromo-2′-nitroacetophenone (15.43 g, 63.2 mmol) with succinamic acid methyl ester (14.4 g, 110 mmol) gives 3-[4-(2-nitro-phenyl)-oxazol-2-yl]-propionic acid methyl ester (6.24 g, 36%). MS (ES): (M+1)+ 277.1 m/z.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[NH:4][C:5](=O)[C:6]2[NH:7][CH:8]=[N:9][C:10]=2[N:11]=1.O=S(Cl)[Cl:17].CN(C=O)C>C(Cl)(Cl)Cl>[Cl:17][C:5]1[N:4]=[C:3]([C:2]([F:14])([F:13])[F:1])[N:11]=[C:10]2[C:6]=1[NH:7][CH:8]=[N:9]2
Reactant: O=c1[nH]c(C(F)(F)F)nc2nc[nH]c12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1nc(Cl)c2[nH]cnc2n1
Temperature: 25 °C
Yield: 45.5 %

Procedure:
A mixture of 15 g (73 mmol) of 2-trifluoromethylhypoxanthine and 300 mL of CHCl3 was warmed to reflux and treated with a solution of 26.7 mL (366 mmol) SOCl2 and 28.3 mL (366 mmol) DMF. The reaction was maintained at reflux for 1.5 h, cooled to room temperature, and poured into 1.2 L of ice-water. The organic layer was separated and washed with 2×300 mL of H2O. The pH of the combined aqueous phases was adjusted to 7 with saturated NaHCO3 and extracted with 3×1.2 L of ether. The combined ether and chloroform extracts were dried (MgSO4) and concentrated to dryness to give 7.4 g of crude product. 1H NMR (DMSO-d6) δ 14.45 (bs, 1H), 8.95 (s, 1H). MS (ES+) 222.96 (100%, M+H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1.Cl.[NH2:17][CH2:18][CH2:19][C:20]([CH3:23])([OH:22])[CH3:21].C(N(CC)CC)C>N1C=CC=CC=1>[CH3:21][C:20]([OH:22])([CH2:19][CH2:18][NH:17][C:2]1[N:3]=[N:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1)[CH3:23]
Reactant: Clc1ccc(C#Cc2ccccc2)nn1
Reactant: CC(C)(O)CCN
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)(O)CCNc1ccc(C#Cc2ccccc2)nn1
Yield: 26.9 %

Procedure:
A solution of 3-chloro-6-(phenylethynyl)pyridazine (CAS 77778-15-5) (125 mg, 0.582 mmol) and 4-amino-2-methylbutan-2-ol hydrochloride (244 mg, 1.75 mmol, 3 equiv.) and triethylamine (206 mg, 284 ml, 2.04 mmol, 2 equiv.) in 1.25 ml of pyridine was heated 20 hours at 85° C. The solvent was removed in vacuo. The residue was taken up in ethyl acetate/methanol, adsorbed onto 4 g of silica and purified on a 20 g flash chromatography column using a heptane/ethyl acetate 85:15 to 15:85 gradient to yield 44 mg (27% yield) of the title compound as a crystalline white solid, MS: m/e=282.2 (M+H+).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[C:13](C(OCC)=O)[C:12]2=[O:25])=[CH:2]1>CN(C)C(=O)C.O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[C:12](=[O:25])[CH:13]=[C:14]([NH:16][CH:17]([CH3:19])[CH3:18])[O:15]2)=[CH:2]1
Reactant: CCOC(=O)C1=C(NC(C)C)OC(=Cc2c[nH]c3ncccc23)C1=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)NC1=CC(=O)C(=Cc2c[nH]c3ncccc23)O1
Temperature: 25 °C
Yield: 13 %

Procedure:
A solution of the compound (0.15 g, 0.43 mmol) of Example 56 in N,N-dimethylacetamide (1.5 mL) was refluxed for 12 h. Cooled to ambient temperature, the reaction mixture was diluted with water and the precipitate was collected by filtration. The solid was washed with diethyl ether then dried to afford the titled compound as solid (0.015 g, y. 12%).
Reaction SMILES: [C:1]([O:6][CH3:7])(=O)[C@@H:2](C)O.[H-].[Na+].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].S(=O)(=O)(O)[OH:17]>C(OCC)C.CS(C)=O>[CH3:15][O:14][C:10]([CH:11]1[CH2:7][O:6][C@H:1]([CH3:2])[C:12]1=[O:17])=[O:13]
Reactant: COC(=O)[C@@H](C)O
Reactant: C=CC(=O)OC
Reactant: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: COC(=O)C1CO[C@H](C)C1=O
Temperature: -35 °C
Reaction time: 0.33 h
Yield: 37 %

Procedure:
A solution of methyl (R)-(+)-lactate (30 g) in diethyl ether (60 ml) was added dropwise to a stirred mixture of sodium hydride (65%, 10.42 g) and diethyl ether (180 ml) which had been cooled to -35° C. The mixture was allowed to warm to 0° C. and stirred for 20 minutes. The mixture was evaporated. To the residue so obtained there was added a solution of methyl acrylate (29.2 ml) in DMSO (120 ml) which had been cooled to 10° C. The mixture was stirred in an ice-bath for 30 minutes and at ambient temperature for 2 hours. The mixture was poured into cold dilute (5%) aqueous sulphuric acid and extracted with diethyl ether. The organic phase was washed with a cold aqueous sodium bicarbonate solution and with brine, dried (MgSO4) and evaporated. The residue was distilled to give (2R)-4-methoxycarbonyl-2-methyltetrahydrofuran-3-one (16.5 g, 37%), b.p. 66°-68° C. (0.5 mm Hg), [alpha]20 =+55.3° (conc.=1.16 g per 100 ml of chloroform).
Reaction SMILES: [N:1]1([C:6]([C:8]2[S:12][C:11]([C:13]3(O)[CH2:22][CH2:21][C:16]4([O:20][CH2:19][CH2:18][O:17]4)[CH2:15][CH2:14]3)=[N:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:26])=O>N1C=CC=CC=1>[Cl:26][C:13]1([C:11]2[S:12][C:8]([C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])=[CH:9][N:10]=2)[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14]1
Reactant: O=S(Cl)Cl
Reactant: O=C(c1cnc(C2(O)CCC3(CC2)OCCO3)s1)N1CCCC1
Solvent: c1ccncc1
Product: O=C(c1cnc(C2(Cl)CCC3(CC2)OCCO3)s1)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.4 %

Procedure:
To a mixture of 8-[5-(pyrrolidin-1-ylcarbonyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[4.5]decan-8-ol (0.2 g, 3.32 mmol) in pyridine (3 mL) at 0° C. was added thionyl chloride (0.5 mL, 6.86 mmol) under N2. The mixture was warmed to room temperature and stirred overnight. After the reaction solution was concentrated, water and EtOAc were added. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with saturated NaCl, dried (MgSO4), concentrated and flash chromatographed (50% EtOAc/hexane to EtOAc) to give 0.10 g of the title compound in 53% yield. MS (EI) calcd: (M+1)+=356.1; found: 357.0.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][NH2:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.ON1C2C=CC=CC=2N=N1.[C:33]([C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](O)=[O:39])#[N:34].C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:33]([C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38]([NH:20][O:19][CH:16]1[CH2:17][CH2:18][N:13]([S:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:9][CH:8]=2)(=[O:11])=[O:12])[CH2:14][CH2:15]1)=[O:39])#[N:34]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cccc(C(=O)NOC2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 35.9 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (160 mg, 0.84 mmol) was added to a solution of O-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yl)hydroxylamine (238 mg, 0.70 mmol), 1-hydroxybenzotriazole (114 mg, 0.84 mmol), 3-cyanobenzoic acid (103 mg, 0.70 mmol) and N,N-diisopropylethylamine (271 mg, 2.10 mmol) in N,N-dimethylformamide (6 ml). The reaction mixture was stirred at room temperature for 17 hours and quenched with H2O (10 ml) and aqueous 1 N HCl solution (pH=3). The aqueous phase was extracted with CH2Cl2 (20 ml×3) and the combined organic phase was washed with aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane: 33/67) to give 3-cyano-N-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yloxy)benzamide (118 mg, 36%) as a white solid: LCMS: 470 [M+1]+. 1H NMR (DMSO-d6) δ: 1.77 (s, 2H), 1.92 (s, 2H), 3.02 (s, 2H), 3.12 (s, 2H), 4.03 (s, 1H), 7.67 (m, 3H), 8.01 (m, 5H), 11.7 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[CH:10]3)=[C:4]([F:18])[CH:3]=1.Cl[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:23]=[C:22]([NH2:32])[N:21]=1.Cl.C(=O)(O)[O-].[Na+]>O>[NH2:32][C:22]1[N:21]=[C:20]([NH:1][C:2]2[CH:17]=[CH:16][C:5]([O:6][C:7]3[CH:8]=[C:9]4[C:13](=[CH:14][CH:15]=3)[NH:12][N:11]=[CH:10]4)=[C:4]([F:18])[CH:3]=2)[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:23]=1
Reactant: Nc1ccc(Oc2ccc3[nH]ncc3c2)c(F)c1
Reactant: Nc1nc(Cl)cc(-c2ccncc2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1nc(Nc2ccc(Oc3ccc4[nH]ncc4c3)c(F)c2)cc(-c2ccncc2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
600 mg (2.47 mmol) of 5-(4-amino-2-fluorophenoxy)-1H-indazole (from example XII) are suspended in 100 ml of water. 510 mg (2.47 mmol) of 4-chloro-6-(4-pyridinyl)-2-pyrimidineamine (from example XXIX) and 0.25 ml of concentrated aqueous hydrogen chloride solution are added, and the mixture is stirred at 100° C. overnight. For work-up, the reaction solution was made alkaline with saturated sodium bicarbonate solution and extracted 3× with ethyl acetate. The precipitate obtained contains crude product and is filtered off with suction. The organic phase is dried with sodium sulfate and concentrated using a rotary evaporator. The residue is combined with the precipitate and purified by preparative HPLC.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[C:14]4[CH:26]=[CH:25][CH:24]=[N:23][C:15]=4[NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:12]3=[N:11][N:10]=2)=[CH:5][CH:4]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29][CH2:28]1.C(N(CC)CC)C>CC(N(C)C)=O.O>[N:11]1[N:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:27]3[CH2:28][CH2:29][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:31][CH2:32]3)=[CH:8][CH:7]=2)[N:13]2[C:12]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:16][C:15]1[N:23]=[CH:24][CH:25]=[CH:26][C:14]2=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: ClCc1ccc(-c2nnc3n2-c2cccnc2Nc2ccccc2-3)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(-c3nnc4n3-c3cccnc3Nc3ccccc3-4)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of 3-(4-(chloromethyl)phenyl)-9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepine (1.3 g, 3.62 mmol), tert-butyl piperidin-4-ylcarbamate (0.71 g, 3.80 mmol), triethylamine (1 mL) in dimethylacetamide (15 mL) was stirred at 75° C. for 20 hours. The mixture wass diluted with water (30 mL). The resulting suspension was stirred at room temperature. The solid was collected by filtration, washed thoroughly with water and dried under high vacuum. The tert-butyl (1-(4-(9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)benzyl)piperidin-4-yl)carbamate was obtained as a yellow solid (1.3 g, 69%). M.p.=145-147° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.76 (s, 1H), 8.18 (dd, J=4.4, 1.2 Hz, 1H), 7.93 (dd, J=8.0, 1.2 Hz, 1H), 7.41 (td, J=8.0, 1.6 Hz, 1H), 7.35-7.30 (m, 5H), 7.15-7.08 (m, 2H), 6.87 (dd, J=8.0, 4.8 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 3.45 (s, 2H), 3.21-3.06 (m, 1H), 2.80-2.65 (m, 2H), 2.0-1.9 (m, 2H), 1.7-1.6 (m, 2H), 1.4-1.3 (m, 2H), 1.34 (s, 9H); LCMS [M+H]: 524.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[CH2:16]([NH:23][C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[F:32])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([NH:23][C:24](=[O:25])[C:26]1[CH:27]=[C:28]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)[CH:29]=[CH:30][C:31]=1[F:32])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: O=C(NCc1ccccc1)c1cc(B(O)O)ccc1F
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(F)c(C(=O)NCc2ccccc2)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 2) and 3-(benzylcarbamoyl)-4-fluorophenyl boronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C24H18FN5O, 412. Found, 412.
Reaction SMILES: [Cl:1][C:2]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:12]=2)[C:7]([CH3:18])=[N:6]1.[OH-].[K+:25]>C(O)C>[Cl:1][C:2]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([O-:17])=[O:16])[CH:12]=2)[C:7]([CH3:18])=[N:6]1.[K+:25]
Reactant: Cc1nn(Cc2cccc(Cl)c2Cl)c2cc(CC(=O)O)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(Cc2cccc(Cl)c2Cl)c2cc(CC(=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of the compound [99] (37 mg) in ethanol (2 mL) was added an aqueous solution of 1N-potassium hydroxide (106 μL) at room temperature, and then the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to give the titled compound (38 mg) as a white solid.
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:59][C:60]1[CH:61]=[C:62](B(O)O)[CH:63]=[CH:64][C:65]=1[F:66]>>[F:59][C:60]1[CH:61]=[C:62]([C:2]2[C:3](=[O:32])[C:4]3[C:9]([C:10]=2[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:24][CH2:23]2)[CH:5]=3)[CH:63]=[CH:64][C:65]=1[F:66]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(c2ccc(F)c(F)c2)=C3c2cc(F)cc(F)c2)CC1
Yield: 57 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-[2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy]-1H-inden-1-one obtained in Step 1 of Example 50 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, and 3,4-difluorophenylboronic acid instead of 3-pyridinylboronic acid, and being purified by prep HPLC (CH3CN/H2O=7:3) to obtain the title compound (57%).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([CH2:12][CH:13]3[NH:19][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:9]([C:21]([F:24])([F:23])[F:22])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH3:30][O+](C)C>>[CH3:30][O:20][C:18]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]([CH2:12][C:10]2[C:9]([C:21]([F:23])([F:22])[F:24])=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:11]=2)[N:19]=1
Reactant: O=C1CCCCC(Cc2cn(-c3ccccc3)nc2C(F)(F)F)N1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Product: COC1=NC(Cc2cn(-c3ccccc3)nc2C(F)(F)F)CCCC1

Procedure:
The title material of Example 140 is reacted with trimethyloxonium tetrafluoroborate by the method of Example 3 to generate the title compound.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.Cl.[C:13]([N:23]1[CH2:28][CH2:27][NH:26][CH:25]([C:29]([OH:31])=[O:30])[CH2:24]1)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C(N(CC)CC)C>CS(C)=O>[F:11][C:4]1[N:3]=[C:2]([N:26]2[CH2:27][CH2:28][N:23]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:24][CH:25]2[C:29]([OH:31])=[O:30])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: O=[N+]([O-])c1ccc(F)nc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1c1nc(F)ccc1[N+](=O)[O-]

Procedure:
In a similar procedure to that described in Example 1, from 6.0 g. of 2,6-difluoro-3-nitropyridine, 9.0 g. of 4-carbobenzoxypiperazine-2-carboxylic acid, hydrochloride, 20 ml. of triethylamine and 150 ml. of dimethyl sulfoxide, there is obtained 14 g. of the title product as a viscous orange glass. Thin layer chromatographic analysis of this material shows essentially one spot.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:14][C:15]([CH3:17])=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(Cl)[Cl:37]>[OH-].[Na+]>[ClH:37].[ClH:37].[CH:15]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)([CH3:17])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: ClCCl
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)N1CCNCC1
Product: Cl
Reaction time: 18 h

Procedure:
To a solution of tert-butyl piperazine-1-carboxylate (100 g) and acetone (48 mL) in CH2Cl2 (1 L) was added acetic acid (31 mL) and NaBH(OAc)3 (170 g). The reaction mixture was stirred for 18 h, then was diluted with 1 N NaOH (500 mL), and extracted with CH2Cl2 (500 mL×2). The combined organic layers were dried (Na2SO4) and concentrated to a residue. The residue was dissolved in MeOH (200 mL) and 4 M HCl in 1,4-dioxane (700 mL) was added to the reaction mixture over a period of several hours. After 18 h, the reaction mixture was concentrated to yield a solid, which was washed with Et2O (500 mL×2) and dried overnight to yield the title compound as a white solid.
Reaction SMILES: NC1C2C3C=CC=CC=3SC=2NC2C=C(F)C=CC=2N=1.[ClH:21].FC1C=CC2N=[C:28]([N:39]3[CH2:44][CH2:43][N:42](CCC)[CH2:41][CH2:40]3)[C:29]3C4C=CC=CC=4S[C:30]=3NC=2C=1>CS(C)=O>[ClH:21].[CH2:28]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[CH2:29][CH3:30]
Reactant: CCCN1CCN(C2=Nc3ccc(F)cc3Nc3sc4ccccc4c32)CC1
Agent: Cl
Agent: NC1=Nc2ccc(F)cc2Nc2sc3ccccc3c21
Solvent: CS(C)=O
Product: CCCN1CCNCC1

Procedure:
In the same manner as in Example 42 and using 12-amino-8-fluoro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine.1 hydrochloride (1.5 g), N-n-propylpiperazine (17 g), dimethyl sulfoxide (10 ml) and hydrochloric acid, crude crystals (850 mg) of 8-fluoro-12-(4-propylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine were obtained. The crude crystals were dissolved in ethyl acetate (12 ml) and a solution of 5.5 mol/1 hydrochloric acid in ether was added to give 8-fluoro-12-(4-propylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine.2 hydrochloride.1.5 hydrate (757 mg).