Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH3:8])[S:6][CH:7]=1.[S:9]([O-:12])([O-:11])=[O:10].[Na+:13].[Na+]>O>[CH3:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][S:9]([O-:12])(=[O:11])=[O:10])[N:4]=1.[Na+:13]
Reactant: O=S([O-])[O-]
Reactant: Cc1nc(CCl)cs1
Agent: [Na+]
Solvent: O
Product: Cc1nc(CS(=O)(=O)[O-])cs1
Yield: 101.2 %

Procedure:
4-Chloromethyl-2-methylthiazole (250 mg, 1.69 mmol) is dissolved in H2O (2 mL) and treated with sodium sulfite (224 mg, 1.78 mmol). The reaction mixture is subjected to microwave irradiation for 20 minutes at 200° C. The reaction mixture is diluted with H2O (30 mL) and washed with EtOAc (2×25 mL). The aqueous layer is concentrated to afford 0.368 g of the desired product as a yellow solid. LC/MS ESI+ 194 (M+1, free acid).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[N:25]1([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: Fc1ccc2nnc(N3CCCCCC3)n2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCCCC4)n3c2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 55.2 %

Procedure:
To a solution of Intermediate A (137 mg, 0.84 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 68 mg, 1.7 mmol) and the mixture stirred at RT for 25 min. A solution of Intermediate 67a (197 mg, 0.84 mmol) in DMF (3 mL) was added and the mixture stirred at 60° C. for 1.25 h. The cooled mixture was diluted with water and extracted with DCM (5×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-14% [2M NH3 in MeOH] in DCM, to give the title compound as a dark brown gum (175 mg, 55%). LCMS (Method 3): Rt 2.22 min, m/z 378 [MH+].
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:18])[C:3]=1[CH:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21].C(O[C:29]([CH3:32])([CH3:31])[CH3:30])(=O)C.Cl(O)(=O)(=O)=O>C(Cl)Cl>[C:29]([O:24][CH:19]([C:3]1[C:4]([CH3:18])=[N:5][C:6]2[N:7]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[CH:10]=2)[C:2]=1[Cl:1])[C:20]([O:22][CH3:23])=[O:21])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)C(O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 0.1 %

Procedure:
To a suspension of methyl 2-(7-chloro-2-(3-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (3550 mg, 9.69 mmol) in tert-butyl acetate (50 mL, 9.69 mmol) at room temperature was added CH2Cl2 (30 mL) followed by perchloric acid (1.250 mL, 14.54 mmol). The reaction mixture was stirred for 5 h at room temperature. The reaction mixture was quenched with water and diluted with ethyl acetate. The organic phase was washed with saturated NaHCO3 and dried over sodium sulfate. The solvent was evaporated. Purification by silica gel chromatography provided the title compound (2.7 mg, 66%). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.07-8.00 (m, 1H), 7.89 (dt, J=6.7, 1.9 Hz, 1H), 7.48-7.37 (m, 2H), 6.93 (s, 1H), 5.68 (s, 1H), 3.75 (s, 3H), 2.69 (s, 3H), 1.29 (s, 9H).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:37])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][NH:26][S:27]([C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:29])=[O:28])[C:5]1=[O:36])[CH:2]=[CH2:3].[H-].[Na+].I[CH3:41].O>CN(C=O)C>[CH2:1]([C@@:4]1([CH3:37])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][N:26]([CH3:41])[S:27]([C:30]([CH3:31])([CH3:33])[CH3:32])(=[O:28])=[O:29])[C:5]1=[O:36])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)C(C)(C)C)C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-2-methylpropane-2-sulfonamide (100 mg, 0.177 mmol; Example 181, Step A) was dissolved in DMF (2.5 mL), and sodium hydride (60% dispersion in mineral oil, 19 mg, 0.45 mmol) was added in a single portion. After 25 minutes, this mixture was cooled to 0° C. in an ice-water bath, and iodomethane (0.04 mL, 0.643 mmol) was added dropwise by syringe. The mixture was allowed to gradually warm to ambient temperature, gradually becoming a pale yellow suspension. After 2 h water (2 mL) was added very carefully. The resulting mixture was partitioned between ethyl acetate and saturated aq. NH4Cl solution. The aqueous phase was back-extracted (2×) and the combined organics were washed with sat. aq. NaCl solution (2×), dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to an oily residue that was chromatographed on a 12 g silica column, eluting with a gradient of 0 to 35% EtOAc in hexanes. Fractions containing the sulfonamide product were pooled and concentrated to give the title compound. MS (ESI) m/z=579 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11](COCC[Si](C)(C)C)[N:10]=2)=[N:6][C:7]=1F.[NH:32]1[CH2:36][CH2:35][C@@H:34]([NH:37]C(=O)OC(C)(C)C)[CH2:33]1>>[Br:1][C:2]1[C:7]([N:32]2[CH2:36][CH2:35][C@@H:34]([NH2:37])[CH2:33]2)=[N:6][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[NH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)c(F)n2)c2cc(-c3cccnc3)ncc21
Product: N[C@@H]1CCN(c2nc(-c3n[nH]c4cnc(-c5cccnc5)cc34)ccc2Br)C1
Yield: 34 %

Procedure:
Following the procedures as described in Example 241 and starting with 3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and (R)-tert-butyl pyrrolidin-3-ylcarbamate, 287 was obtained as an off-white solid (12.2 mg, 34%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.27 (s, 1H), 9.22 (s, 1H), 9.02 (s, 1H), 8.60 (d, J=4.6 Hz, 1H), 8.41 (d, J=8.0 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.62 (dd, J=11.8, 7.2 Hz, 3H), 7.58-7.49 (m, 3H), 7.45 (d, J=8.0 Hz, 1H), 4.01-3.92 (m, 2H), 3.64-3.51 (m, 3H), 2.10 (dt, J=12.0, 5.9 Hz, 1H), 1.82-1.72 (m, 1H); ESI MS m/z=358.2 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:12]=[C:11](Cl)[C:10]=2[Cl:20])=[C:4]([Cl:21])[CH:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C.O>[N:22]([C:11]1[C:10]([Cl:20])=[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[Cl:21])[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:12]=1)=[N+:23]=[N-:24]
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc(N=[N+]=[N-])c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.3 %

Procedure:
Methyl 4-(4-bromo-2-chlorophenylamino)-5,6-dichloronicotinate (1.690 g, 4.14 mmol) was suspended in 30 ml DMF and the suspension was heated until everything went into solution. It was cooled down to room temperature and to that solution was added solid sodium azide (0.533 g, 8.2 mmol). The yellow solution was stirred for 17 h at room temperature and was diluted with water. The precipitate was filtered, washed with water and hexanes and dried in oil-pump vacuo at 50° C. for 2 h to obtain the title compound as a light-brown solid (1.5422 g, 90%). 1H-NMR (300 MHz, DMSO-D6): δ=9.85 (s, 1H), 8.90 (s, 1H), 7.80-7.79 (d, 1H), 7.46-7.40 (dd, 1H), 6.95-6.90 (d, 1H), 3.80 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][Cl:25])[CH:20]=2)[NH:15][C:14]=1[CH3:26])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C=O)C>[CH2:3]([O:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][Cl:25])[CH:20]=2)[N:15]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:14]=1[CH3:26])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCc1ccccc1
Reactant: Cc1[nH]c2ccc(OCCCl)cc2c1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)OCc2ccccc2)c2cc(OCCCl)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
To a suspension of NaH (0.959 mmol, 0.038 g, 60% in mineral oil, rinsed twice with hexanes) in 5 mL of DMF at 0° C. under N2 was added a solution of 5-(2-chloro-ethoxy)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.873 mmol, 0.300 g, Example 1, Step A) in 3.73 mL of DMF. The ice bath was removed and the solution was stirred for 2 hours at room temperature. Benzyl bromide (0.959 mmol, 0.114 mL, Aldrich) was added dropwise via syringe and the solution was stirred for 19 hours. Water (10 mL) was added and the mixture was stirred for 30 minutes. The resulting precipitate was filtered off, the filtrate was extracted with ethyl acetate (3×10 mL), and the extracts were washed with brine (1×10 mL), dried over MgSO4, and concentrated. The residue was combined with the solid and purified by silica gel flash column chromatography (10-20% ethyl acetate/hexanes) to give an off-white solid (0.236 g, 62%): 1HNMR (400 MHz, DMSO-d6) δ 2.64 (s, 3H, ArCH3),3.86-3.89 (m, 2H, CH2Cl), 4.09-4.12 (m, 2H, CH2OAr), 5.30 (s, 2H, CO2CH2Ph), 5.46 (s, 2H, NCH2Ph), 6.78 (dm, J=8.79 Hz, 1H, ArH), 6.96 (d, J=7.33 Hz, 2H, ArH), 7.18-7.30 (m, 3H, ArH), 7.32-7.40 (m, 4H, ArH), 7.44-7.49 (m, 3H, ArH); MS(APCI+): m/z 434.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=[O:13])=[CH:6][CH:5]=1)[CH3:2].C([O:19][N:20]=O)CC(C)C.Cl>C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][C:9](=[N:20][OH:19])[C:10]2=[O:13])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(C)CCON=O
Reactant: CCOc1ccc2c(c1)C(=O)CC2
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOc1ccc2c(c1)C(=O)C(=NO)C2
Temperature: 7.5 °C

Procedure:
A solution of 6-ethoxy-1-indanone and isoamylnitrite (1.5 eq.) in ethyl acetate arecooled to approximately 0° C. and concentrated hydrochloric acid (1.1 acid equivalents) is added at a rate to keep the temperature below 40° C. After the addition is completed the slurry is stirred at 5-10° C. until analysis indicated that all of the starting material is consumed. The product is filtered and rinsed with cold ethyl acetate. The oxime product (5) can be easily purified by refluxing as a slurry in anhydrous ethanol, cooling filtering, and then washing the solid with more ethanol and then drying (m.p. 220° C. decomp.).
Reaction SMILES: [C:1]([O:4][C:5]1([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[S:12]/[C:11]/2=[N:19]\[C:20]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[O:29][CH3:30])=S)[CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[N:38]#[C:39][NH2:40]>C(#N)C.[Hg](OC(C)=O)OC(C)=O>[C:1]([O:4][C:5]1([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[S:12]/[C:11]/2=[N:19]\[C:20]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[O:29][CH3:30])=[N:40][C:39]#[N:38])[CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(Cl)cc1C(=S)/N=c1\sc(C(C)(C)C)cn1CC1(OC(C)=O)CCC1
Reactant: N#CN
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C(=NC#N)/N=c1\sc(C(C)(C)C)cn1CC1(OC(C)=O)CCC1
Yield: 76.9 %

Procedure:
The product of Example 27D (1.2 g, 2.6 mmol), triethylamine (1.4 mL, 10 mmol), cyanamide (0.32 g, 7.7 mmol) and Hg(OAc)2 (1.6 g, 5.1 mmol) in acetonitrile (20 mL) were processed as described in Example 16E to provide the title compound (0.93 g, 2.0 mmol, 77% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.38 (s, 9H), 1.73-1.96 (m, 2H), 1.99 (s, 3H), 2.22-2.46 (m, 4H), 3.91 (s, 3H), 4.76 (s, 2H), 6.63 (s, 1H), 6.94 (d, J=8.8 Hz, 1H), 7.31-7.39 (m, 2H); MS (DCI/NH3) m/z 475 (M+H)+. Anal. calculated for C23H27ClN4O3S: C, 58.16; H, 5.73; N, 11.80. Found: C, 58.16; H, 5.66; N, 11.85.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:14][C:15]1[CH:27]=[CH:26][C:18]([O:19][CH:20]([CH2:24][CH3:25])[C:21](Cl)=[O:22])=[CH:17][C:16]=1[CH3:28]>C1C=CC=CC=1>[CH2:1]([NH:7][C:21](=[O:22])[CH:20]([O:19][C:18]1[CH:26]=[CH:27][C:15]([Cl:14])=[C:16]([CH3:28])[CH:17]=1)[CH2:24][CH3:25])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccco1
Reactant: CCC(Oc1ccc(Cl)c(C)c1)C(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCC(Oc1ccc(Cl)c(C)c1)C(=O)NCc1ccco1
Yield: 27.1 %

Procedure:
In 50 ml of benzene were dissolved 1.5 g (0.015 mole) of furfurylamine and 4.0 g (0.051 mole) of pyridine, and thereto was added dropwise a solution of 3.0 g (0.012 mole) of 2-(4-chloro-3-methylphenoxy)-butyroyl chloride in 20 ml of benzene at room temperature with stirring, followed by stirring for further 5 hours. Subsequently, after the same procedure as in Synthesis Example 4 and 5 was followed, the resultant crude crystals were recrystallized from ethanol to give 1.0 g of N-furfuryl-2-(4-chloro-3-methylphenoxy)-butyramide melting at 100°~102° C. as pale brown needles.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH:9]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:14]=[CH:13][N:12]=2)[CH2:8][CH2:7][CH2:6][N:5]1[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.N=C=N.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([C:46](O)=[O:47])[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].OC1C2N=NNC=2C=CC=1.C(=O)([O-])[O-]>ClCCl.CN(C)C=O>[N:17]1([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][CH:9]3[CH2:8][CH2:7][CH2:6][N:5]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[CH:4]3[CH2:3][CH2:2][NH:1][C:46]([CH:43]3[CH2:44][CH2:45][N:40]([C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[CH2:41][CH2:42]3)=[O:47])[N:16]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NCCC1C(Nc2nccc(N3CCCCCC3)n2)CCCN1C1CCCCC1
Agent: N=C=N
Agent: O=C([O-])[O-]
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCCC2C(Nc3nccc(N4CCCCCC4)n3)CCCN2C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[(2RS,3SR)-2-(2-aminoethyl)-1-cyclohexylpiperidin-3-yl]-4-azepan-1-ylpyrimidin-2-amine (63 mg) was dissolved in dichloromethane (3 mL), PS-carbodiimide (327 mg) was added and then 0.5 M of a solution (0.47 mL) of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid in dimethylformamide:dichloromethane=1:1 and 0.5 M of a mixture solution (0.53 mL) of hydroxybenzotriazole in dimethylformamide:dichloromethane=1:1 were added and stirred at room temperature for overnight. MP-carbonate (271 mg) was added into the reaction solution, stirred for 1 hour and then filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=90:10) to obtain the title compound (81 mg) having the following physical properties.
Reaction SMILES: COC1C=C(OC)C=CC=1[CH2:11][N:12]([CH2:14][C:15]1[C:19]([F:20])=[C:18]([C:21]2[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=2)[N:17]([S:28]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)(=[O:30])=[O:29])[CH:16]=1)C.C(Cl)(=O)OC(Cl)C.C(N(CC)CC)C>O1CCCC1>[F:20][C:19]1[C:15]([CH2:14][NH:12][CH3:11])=[CH:16][N:17]([S:28]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)(=[O:30])=[O:29])[C:18]=1[C:21]1[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1ccc(CN(C)Cc2cn(S(=O)(=O)c3cccnc3)c(-c3cccnc3F)c2F)c(OC)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNCc1cn(S(=O)(=O)c2cccnc2)c(-c2cccnc2F)c1F
Reaction time: 0.25 h
Yield: 77.1 %

Procedure:
To a solution of 1-(2,4-dimethoxyphenyl)-N-{[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}-N-methylmethanamine (5.68 g) in tetrahydrofuran (25 mL) was added a solution of 1-chloroethyl chlorocarbonate (1.58 g) in tetrahydrofuran (5 mL) at 0° C., and the mixture was stirred for 15 min. Triethylamine (4.63 mL) was added and the obtained mixture was stirred at 65° C. for 16 hr. The obtained solid was filtrated and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethanol (25 mL) was added to the residue, and the mixture was refluxed for 1.5 hr, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the precipitated solid was filtrated. To the obtained solid were successively added ethyl acetate, 1 mol/L aqueous sodium hydroxide solution and saturated aqueous sodium hydrogen carbonate solution, and the mixture was stirred at room temperature for 10 min. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane:ethyl acetate=1:1→1:4) to give the title compound as a colorless oil (yield 3.10 g, 77%).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[CH:17]=[C:16]([CH2:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[CH:15]=[CH:14][N:13]=2)=[N:3]1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[CH:17]=[C:16]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:15]=[CH:14][N:13]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)CCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85.4 %

Procedure:
tert-Butyl 3-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propionate (0.45 g, 1.2 mmol) was dissolved in trifluoroacetic acid (3.0 ml), and the mixture was stirred at room temperature for 2.5 hrs. Isopropyl ether was added to the reaction mixture to precipitate crystals, which were collected by filtration and washed with ethanol-hexane to give the titled compound (0.32 g, 84%) as white crystals.
Reaction SMILES: Cl[C:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[N:10][CH:9]=[CH:8][C:7]=3[C:6]=2[C:5]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:4]=2[N:3]=1.[NH2:22][CH2:23][CH2:24][N:25]([CH3:34])[CH2:26][CH2:27][CH2:28][N:29]([CH2:31][CH2:32][NH2:33])[CH3:30]>ClCCl>[NH2:33][CH2:32][CH2:31][N:29]([CH3:30])[CH2:28][CH2:27][CH2:26][N:25]([CH3:34])[CH2:24][CH2:23][NH:22][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[N:10][CH:9]=[CH:8][C:7]=3[C:6]=2[C:5]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:4]=2[N:3]=1
Reactant: CN(CCN)CCCN(C)CCN
Reactant: COc1ccc2c3c(c(Cl)nc2c1)C(=O)c1cnccc1-3
Solvent: ClCCl
Product: COc1ccc2c3c(c(NCCN(C)CCCN(C)CCN)nc2c1)C(=O)c1cnccc1-3
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of 6-chloro-3-methoxy-5,9-diaza-benzo[c]fluoren-7-one (50.8 mg) (the compound of Reference Example 1c-2) and N,N′-bis-(2-amino-ethyl)-N,N′-dimethyl-propane-1,3-diamine (0.5 ml) was stirred at 50° C. for 4 hours. The reaction mixture was diluted with dichloromethane. The solution was washed with saturated NaHCO3 solution and dried over magnesium sulfate. The organic layer was evaporated to dryness. The residue was purified by silica gel column chromatography developed by dichloromethane-methanol-ammonia water (25%)=90:10:1. The desired product (49 mg) was obtained as a reddish oil.
Reaction SMILES: [Br:1][C:2]1[C:7]2[NH:8][C:9](=O)[O:10][C:11](=[O:12])[C:6]=2[CH:5]=[C:4]([Cl:14])[CH:3]=1.[Cl:15][C:16]1[C:17]([N:22]2[C:26](C(Cl)=O)=[CH:25][C:24]([C:30]([F:33])([F:32])[F:31])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1.N1C=CC=CC=1>C(#N)C>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([C:26]3[N:22]([C:17]4[C:16]([Cl:15])=[CH:21][CH:20]=[CH:19][N:18]=4)[N:23]=[C:24]([C:30]([F:31])([F:32])[F:33])[CH:25]=3)[O:10][C:11](=[O:12])[C:6]=2[CH:5]=[C:4]([Cl:14])[CH:3]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: O=c1[nH]c2c(Br)cc(Cl)cc2c(=O)o1
Solvent: c1ccncc1
Solvent: CC#N
Product: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2c(Br)cc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
To a suspension of 8-Bromo-6-chloro-1H-benzo[d][1,3]oxazine-2,4-dione (5.0 g, 18.1 mmol) in acetonitrile (10 mL) was added a solution of 2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl chloride (6.45 g, 20.8 mmol) in acetonitrile (8 mL). After stirring for 5 min pyridine (10.4 mL) was added dropwise. The reaction was stirred for a further 30 min at room temperature, then heated to 100° C. for 4 h and stirred for a further 16 h at room temperature. The reaction was then cooled in an ice-bath and the resulting white solid filtered and washed with cold acetonitrile to obtain the title compound (5.88 g, 64%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][C:19]([O:21]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:25][NH2:26]>C(O)C>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][C:19]([NH:25][NH2:26])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)CSc1nc2ccccc2n1Cc1ccccc1
Solvent: O
Solvent: CCO
Product: NNC(=O)CSc1nc2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of ethyl 2-(1-benzyl-1H-benzo[d]imidazol-2-ylthio)acetate 4b (200 mg, 0.61 mmol, 1.0 eq.) in ethanol (5 mL), was added hydrazine monohydrate (61 mg, 1.23 mmol, 2.0 eq.), and the reaction mixture was heated to reflux and stirred at that temperature for 16 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The mixture was dissolved in ethyl acetate (20 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo giving 4c as a pale yellow solid which was used without further purification (200 mg, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])/[CH:5]=[CH:6]/[CH2:7]Br)[CH3:2].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:9])/[CH:5]=[CH:6]/[CH2:7][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH3:2]
Reactant: C1CCNCC1
Reactant: CCOC(=O)/C=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)/C=C/CN1CCCCC1
Yield: 79.6 %

Procedure:
A mixture of ethyl-4-bromocrotonate (193 mg), piperidine (94 mg) and potassium carbonate (276 mg) in acetonitrile (10 ml) was stirred and heated at reflux for 3 hours. The reaction mixture was cooled and the solvent was removed in vacuo. The residue was partitioned between water (2×15 ml) and ethyl acetate (20 ml). The organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as an orange oil (157 mg).