Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.[CH2:11]([N:13](CC)[CH2:14]C)C.S(Cl)(C)(=O)=O.CNC>ClC(Cl)C.CO.O>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][N:13]([CH3:14])[CH3:11])=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: OCCc1ccc(Br)nc1
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CO
Product: CN(C)CCc1ccc(Br)nc1
Temperature: 4 °C
Yield: 26.2 %

Procedure:
2-(6-Bromopyridin-3-yl)ethanol (40 mg, 0.20 mmol) was dissolved in dichloroethane (3 ml), 200 mg of triethylamine was added to the solution, and the mixture was stirred at 4° C. under ice cooling. Mesyl chloride (68 mg, 0.60 mmol) was added to the reaction solution. After the dropwise addition, the mixture was stirred at 4° C. for 1 hr under ice cooling and was further stirred at room temperature for 30 min. The reaction solution was poured into 10 ml of iced water, was extracted with ml of ethyl acetate, and the extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under the reduced pressure. The residue was dissolved in DMF (2 ml), and the solution was stirred at room temperature. A 2 M solution (1 ml) of dimethylamine (2 mmol) in methanol was added thereto, and the mixture was stirred at 5.0° C. for 4 hr. The reaction solution was poured into 10 ml of iced water and was extracted with 20 ml of ethyl acetate. The extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:methanol=10:1) to give 12 mg (yield 28.1%) of the title compound.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([CH:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20](=[O:28])(=[O:27])[NH:19]2)=[C:9]1[CH3:29])(C)(C)C.[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1>>[Cl:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:6]([OH:5])=[O:30])[C:9]([CH3:29])=[C:10]2[CH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[S:20](=[O:28])(=[O:27])[N:19]1[CH2:36][C:35]1[CH:38]=[CH:39][C:32]([F:31])=[CH:33][CH:34]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2cc(Cl)ccc2n1CC(=O)OC(C)(C)C
Product: Cc1c(C2c3ccccc3S(=O)(=O)N2Cc2ccc(F)cc2)c2cc(Cl)ccc2n1CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 6, step c) and 4-fluorobenzyl bromide. 1H NMR (DMSO-d6) 13.2 (bs, 1H), 8.05 (d, J=8.1 Hz, 1H), 7.67 (t, J=7.2 Hz, 1H), 7.62 (dt, J=1.5, 75 Hz, 1H), 7.44 (d, J=8.7 Hz, 1H), 7.19-6.96 (m, 6H), 6.83 (s, 1H), 5.83 (s, 1H), 5.01 (d, J=18.3 Hz, 1H), 5.00 (d, J=18.3 Hz, 1H), 4.50 (d, J=15.6 Hz, 1H), 3.83 (d, J=15.6 Hz, 1H), 2.11 (s, 3H); MS: ESI (negative): 497, 499 (M−H).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([C:11]2[CH2:15][C:14]([CH2:20][NH2:21])([C:16]([O:18][CH3:19])=[O:17])[O:13][N:12]=2)[CH:7]=[CH:8][C:9]=1[F:10])#[N:3].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[C:2]([C:4]1[CH:5]=[C:6]([C:11]2[CH2:15][C:14]([CH2:20][NH:21][S:30]([CH3:29])(=[O:32])=[O:31])([C:16]([O:18][CH3:19])=[O:17])[O:13][N:12]=2)[CH:7]=[CH:8][C:9]=1[F:10])#[N:3]
Reactant: COC(=O)C1(CN)CC(c2ccc(F)c(C#N)c2)=NO1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1(CNS(C)(=O)=O)CC(c2ccc(F)c(C#N)c2)=NO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(3-cyano-4-fluorophenyl)-5-(aminomethyl)-5-(carbomethoxy)isoxazoline hydrochloride salt (1.15 g) in CH2Cl2 (50 mL) was added triethylamine (1.27 mL) and methanesulfonyl chloride (0.31 mL). The mixture was stirred at RT under N2 for 1 h. The solvent was diluted with CH2Cl2 and washed with water, IN aqueous HCl, and saturated aqueous NaHCO3. It was dried over MgSO4 and concentrated to a yellow solid (1.13 g). 1H NMR (CDCl3) δ7.92 (m, 2H), 7.30 (t, 1H), 4.82 (t, 1H), 3.84 (s, 3H), 3.76-3.60 (m, 4H), 3.03 (s, 3H) ppm; ESI mass spectrum z (rel. intensity) 377.9 (M+H, 100).
Reaction SMILES: [BH4-].[Na+].Br.[Br:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7].Br>O.CO>[Br:4][CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[OH:7]
Reactant: O=C(CBr)c1ccccn1
Agent: Br
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC(CBr)c1ccccn1
Temperature: 0 °C
Yield: 82.2 %

Procedure:
2-Bromo-1-(2-pyridyl)ethanol can be obtained by adding, over the course of one hour, an ice-cold solution of sodium borohydride (17.2 g.) in water (310 cc.) to a solution of 2-(2-bromoacetyl)pyridine hydrobromide (82.9 g.) in methanol (830 cc.) kept at -10° C. The mixture is allowed to return to a temperature of about 20° C. and the pH is brought to 2 by adding 48% hydrobromic acid (70 cc.). The mixture is concentrated to dryness under reduced pressure (30 mm.Hg) at a temperature below 40° C. The residue is taken up in distilled water (400 cc.) and the solution is decolourised by treatment with decolourising charcoal. The solution is brought to pH 7-8 by adding sodium bicarbonate (50 g.). The mixture is extracted with diethyl ether (1,500 cc.) and the extracts are dried over anhydrous potassium carbonate. After filtration and concentration under reduced pressure (30 mm.Hg), 2-bromo-1-(2-pyridyl)-ethanol (49 g.) is obtained in the form of an oil.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][N:26]=3)[C:21]3=[N:28][O:29][C:30]([CH3:31])=[C:20]3[C:19]2=[O:32])[CH2:13]1)C1C=CC=CC=1.[I:34][Si](C)(C)C>ClCCl>[IH:34].[NH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][N:26]=3)[C:21]3=[N:28][O:29][C:30]([CH3:31])=[C:20]3[C:19]2=[O:32])[CH2:13]1
Reactant: C[Si](C)(C)I
Reactant: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)OCc3ccccc3)C1)c1ncccc21
Solvent: ClCCl
Product: Cc1onc2c1c(=O)n(C1CCCC(CN)C1)c1ncccc21
Product: I
Temperature: 25 °C

Procedure:
Dissolve [3-(3-methyl-4-oxo-5H-2-oxa-1,5,6-triaza-cyclopenta-[a]naphthalen-5yl)-cyclohexylmethyl]-carbamic acid benzyl ester (0.52 g, 0.0012 mol) in dry dichloromethane and cool in an ice bath under nitrogen. Add iodotrimethylsilane (0.50 mL, 0.0035 mol) and stir overnight while warming to ambient temperature. Quench the mixture with methanol (approx. 5 mL) and concentrate in vacuo. Take up the resulting residue in minimal dichloromethane and add diethyl ether. Concentrate and titrate from dichloromethane/diethyl ether to give a dark solid. Decant the solvent and dry the solid in vacuo to give a near quantitative yield of the crude amine salt as a dark solid. Use directly without purification. MS(ES): (M+1)+ 313.2, 314.2 m/z.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH2:25]([O:29][C:30]1[CH:40]=[CH:39][C:33]([CH2:34][C:35]2([NH2:38])[CH2:37][CH2:36]2)=[CH:32][CH:31]=1)[CH2:26][CH2:27][CH3:28].FC(F)(F)C([O-])=O>>[CH2:25]([O:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:34][C:35]2([NH:38][CH2:21][CH:20]([C:12]3[C:13]4[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=4[C:9]([OH:8])=[CH:10][CH:11]=3)[OH:24])[CH2:37][CH2:36]2)=[CH:39][CH:40]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCOc1ccc(CC2(N)CC2)cc1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Agent: O=C([O-])C(F)(F)F
Product: CCCCOc1ccc(CC2(NCC(O)c3ccc(O)c4c3OCC(=O)N4)CC2)cc1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 219 mg (1 mmol) 1-(4-butoxy-benzyl)-cyclopropylamine. Yield: 107 mg (20%, trifluoroacetate); mass spectroscopy: [M+H]+=427.
Reaction SMILES: Cl([O-])=O.[Na+].[CH2:5]([N:7]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][CH:14]=2)=[CH:10][C:9]([C:21]2[CH:22]=[C:23]([C:27]([NH:30][S:31]([CH2:34][C:35]([F:38])([F:37])[F:36])(=[O:33])=[O:32])([CH3:29])[CH3:28])[CH:24]=[CH:25][CH:26]=2)=[N:8]1)[CH3:6].CC(=CC)C.P([O-])(O)(O)=[O:45].[Na+]>CO>[CH2:5]([N:7]1[C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([OH:45])=[O:20])=[CH:17][CH:18]=2)=[CH:10][C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([CH3:29])([NH:30][S:31]([CH2:34][C:35]([F:38])([F:36])[F:37])(=[O:32])=[O:33])[CH3:28])[CH:22]=2)=[N:8]1)[CH3:6]
Reactant: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C=O)cc1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CO
Product: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C(=O)O)cc1
Reaction time: 1.5 h

Procedure:
Sodium chlorite (71 mg, 0.78 mmol, 4.0 equiv) was added to a mixture of N-(1-{3-[1-ethyl-5-(4-formylphenoxy)-1H-pyrazol-3-yl]phenyl}-1-methylethyl)-2,2,2-trifluoroethanesulfonamide (97 mg, 0.20 mmol, 1 equiv), 2-methyl-2-butene (1 mL), aqueous sodium dihydrogenphosphate solution (20% w/w, 0.7 mL) and methanol (2.8 mL). The biphasic mixture was stirred for 90 minutes, then was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated to afford 4-({1-ethyl-3-[3-(1-methyl-1-{[(2,2,2-trifluoroethyl)sulfonyl]amino}ethyl)phenyl]-1H-pyrazol-5-yl}oxy)benzoic acid. Calcd (M+1)+: 512.1. Found: 512.1.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([OH:11])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12]1([C:18]([C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[NH2:30])=NCCN)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl[CH:32](Cl)[CH3:33]>>[C:12]1([C:18]([C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[NH2:30])=[N:2][CH:3]([C:9]([O:11][CH2:32][CH3:33])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(Cl)Cl
Reactant: NCCN=C(c1ccccc1)c1cc(Cl)ccc1N
Reactant: CCOC(=O)C(N)C(=O)O
Agent: Cl
Product: CCOC(=O)C(N=C(c1ccccc1)c1cc(Cl)ccc1N)C(=O)OCC

Procedure:
16 g of dry ethyl amino-malonate hydrochloride are suspended in 200 ml of dichloroethane, then a solution of 10 g of 1-phenyl-1-(2-amino-5-chloro-phenyl)-2,5-diazapent-1-ene in 100 ml of dichloroethane is added and the whole is heated at 80° for 3 hours 30 minutes. The red colour at the start changes to yellow at the end of the reaction.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C@@H:12]3[C@@H:8]([CH2:9][C:10](=[O:19])[NH:11]3)[CH2:7]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:27](=O)([O:33]C(C)(C)C)[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]>ClCCl>[O:19]=[C:10]1[CH2:9][C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:4]3([CH2:7]2)[CH2:3][CH2:2][N:1]([C:27]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:33])[CH2:6][CH2:5]3)[NH:11]1
Reactant: O=C1C[C@H]2CC3(CCNCC3)c3ccccc3[C@H]2N1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C[C@@H]1CC(=O)N[C@@H]1c1ccccc12
Yield: 55.9 %

Procedure:
A solution of the (3aR,9bS)-1,3a,4,9b-tetrahydrospiro[benzo[g]indole-5,4′-piperidin]-2(3H)-one (900 mg, 3.51 mmol) in dichloromethane (100 ml) was treated with triethylamine (3 ml) and di-tert-butyl carbonate (1.5 g, 6.8 mmol) at room temperature for 1 h. The reaction mixture was diluted with dichloromethane, washed with aqueous saturated NH4Cl. The organic phase was separated and the aqueous phase was re-extracted with dichloromethane (2×). The combined organic phases were dried (Na2SO4), filtered and concentrated. The residue was purified by flasj chromatography (40 g silica gel, CH2Cl2/CH3CN up to 0:100%) to give (3aR,9bS)-tert-butyl 2-oxo-1,2,3,3a,4,9b-hexahydrospiro[benzo[g]indole-5,4′-piperidine]-1′-carboxylate 12 (700 mg). LC-MS: m/e=301.5 (M−t-Bu+H, 100%). Rt=3.04 min. 1H NMR (300 MHz, CDCl3): 7.36 (d, 1H), 7.25 (td, 1H), 7.21-7.13 (m, 2H), 6.32 (s, 1H, NH), 4.71 (d, J=5.8 Hz, 1H, CHN), 4.02 (br. d, 1H), 3.90 (br. d, 1H), 3.01 (td, J=13.4, 2.8 Hz, 1H), 2.89 (td, J=13, 3.1 Hz, 1H), 2.73-2.62 (m, 1H), 2.29 (td, J=12.7, 5.0 Hz, 1H), 2.23-2.44 (m, 3H), 1.66-1.59 (m, 1H), 1.51 (dd, J=13.2, 4.3 Hz, 1H), 1.41 (s, 9H), 1.37-1.30 (m, 2H).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([C:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=5)[CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].[CH3:32][CH:33]([CH3:39])[CH2:34][S:35](Cl)(=[O:37])=[O:36]>>[CH2:34]([S:35]([N:29]1[CH2:28][CH:27]=[C:26]([C:24]2[CH:23]=[CH:22][C:20]3[N:21]=[C:17]([O:16][CH:13]4[CH2:14][CH2:15][N:10]([C:7]5[N:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][N:6]=5)[CH2:11][CH2:12]4)[S:18][C:19]=3[CH:25]=2)[CH2:31][CH2:30]1)(=[O:37])=[O:36])[CH:33]([CH3:39])[CH3:32]
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)nc1
Product: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(S(=O)(=O)CC(C)C)CC5)cc4s3)CC2)nc1

Procedure:
Example 11 was prepared from Compound 1E and 2-methylpropane-1-sulfonyl chloride in a similar manner to the procedure described in Example 1. LCMS (M+H)+=556.
Reaction SMILES: [Br:1][CH:2]([CH2:15][CH3:16])[C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:7]=2[CH:6]=1)=O.[NH:17]1[CH2:21][CH2:20][NH:19][C:18]1=[S:22].C(O)C>C(O)(=O)C>[BrH:1].[Cl:14][C:13]1[C:7]2[CH:6]=[C:5]([C:3]3[N:19]4[CH2:20][CH2:21][N:17]=[C:18]4[S:22][C:2]=3[CH2:15][CH3:16])[S:9][C:8]=2[CH:10]=[CH:11][CH:12]=1
Reactant: S=C1NCCN1
Reactant: CCC(Br)C(=O)c1cc2c(Cl)cccc2s1
Solvent: CCO
Solvent: CC(=O)O
Product: Br
Product: CCC1=C(c2cc3c(Cl)cccc3s2)N2CCN=C2S1
Yield: 71.8 %

Procedure:
A mixture of 2-bromo-1-(4-chlorobenzo[b]thiophen-2-yl)butan-1-one (1.06 g), 2-imidazolidinethione (0.255 g) and ethanol (25 ml) was heated under reflux for 20 minutes. Acetic acid (12 ml) was added, the mixture was heated under reflux for 21 hours, then the solvents were removed in vacuo and the solid residue recrystallised from propan-2-ol (40 ml) to give 3-(4-chlorobenzo[b]thiophen-2-yl)-2-ethyl-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide (0.72 g) as a white solid, m.p. 187-189° C.
Reaction SMILES: [OH2:1].[N:2]1[C:15]2[C:6](=[CH:7][CH:8]=[C:9]3[C:14]=2[N:13]=[CH:12][CH:11]=[CH:10]3)[CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[N+]([O-])(O)=O.[OH-:25].[Na+]>>[N:2]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][N:13]=3)[C:8](=[O:1])[C:7](=[O:25])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=[N+]([O-])O
Product: O=C1C(=O)c2cccnc2-c2ncccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
25 g of 1,10-phenanthroline-hydrate was dissolved into 125 ml of 20% fuming sulfuric acid. The sulfuric acid was heated at the temperature of 110° to 125° C., and 33 ml of 72% concentrated nitric acid was added into the sulfuric acid. While the mixed solution was current-circulated at the temperature of 143° C. for 30 minutes, 66 ml of 72% concentrated nitric acid was added into the mixed solution. Then, the mixed solution was stirred for 1.5 hours to promote its reaction. After the reaction, the mixed solution was cooled to the room temperature, and it was poured into an ice. The ice-containing solution was neutralized by adding 30% sodium hydroxide solution. A precipitated by-product, 5-nitro-1,10-phenanthroline was filtered and removed from the neutralized solution. The filtered solution was extracted by chloroform, and the extracted chloroform solution was dried by sodium sulfate anhydride. Furthermore, the dried solution was vacuum-concentrated to obtain a yellow rough crystal of 1,10-phenanthroline-5,6-dione. The rough crystal was purified by recrystallization of ethanol.
Reaction SMILES: Cl[C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:12])[C:5]([Cl:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH:16]([NH2:19])([CH3:18])[CH3:17]>C(O)C>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH:19][CH:16]([CH3:18])[CH3:17])=[C:3]([N+:13]([O-:15])=[O:14])[C:4]=1[CH3:12]
Reactant: CC(C)N
Reactant: Cc1c(Cl)cc([N+](=O)[O-])c(Cl)c1[N+](=O)[O-]
Solvent: CCO
Product: Cc1c(Cl)cc([N+](=O)[O-])c(NC(C)C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 10.04 g. (0.04 mole) of 3,6-dichloro-2,4-dinitrotoluene in 50 ml. of ethanol is added 9.0 g. (0.15 mole) of isopropylamine. The mixture is stirred at room temperature for two hours and then at reflux for one hour. The solution is allowed to cool to room temperature and the crystalline precipitate is filtered and washed with a small amount of hexane to give 10.2 g. of the desired product as golden crystals having a m.p. of 69°-73° C. Two recrystallizations from methanol give the analytical sample, m.p. 69°-70° C. Analysis: Calcd. for C10H12ClN3O4 : C, 43.88; H, 4.42; Cl, 12.96; N, 15.35. Found: C, 44.09; H, 4.43; Cl, 13.02; N, 15.42.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[NH2:16][C@@H:17]([CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:18][OH:19].C(N(CC)CC)C>C(Cl)Cl.O>[CH2:22]([O:21][CH2:20][C@H:17]([NH:16][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH2:18][OH:19])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: N[C@H](CO)COCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2ccccc2c1N[C@H](CO)COCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.9 %

Procedure:
4-Chloro-3-nitroquinoline (41.0 g, 197 mmol) was added to a mixture of (2R)-2-amino-3-(benzyloxy)propan-1-ol hydrochloride (43.0 g, 197 mmol) and triethylamine (69.0 mL, 494 mmol) dissolved in 985 mL of CH2Cl2 at 0° C. The resulting yellow mixture was stirred for 18 hours at ambient temperature. The solvent was then removed under reduced pressure to afford a yellow solid. The solid was stirred in H2O (100 mL) and filtered to give 57 g of (2R)-3-(benzyloxy)-2-[(3-nitroquinolin-4-yl)amino]propan-1-ol as a bright yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[S:11].[Cl:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:12][C:2]1([CH3:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[S:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1C(=S)Nc2ccccc21
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(Cl)C(=S)Nc2ccccc21

Procedure:
A solution of 3-methylthiooxindole (1.70 g, 0.0095 mol) and N-chlorosuccinimide (1.34 g, 0.01 mol) in 100 ml of carbon tetrachloride was stirred at room temperature for 1 hour, the precipitate of succinimide was removed by filtration, and the filtrate was evaporated, yielding crude 3-chloro-3-methylthiooxindole. The residue, which was thus obtained, was dissolved in a minimum of tetrahydrofuran and added to a vigorously stirred slurry of red mercuric oxide powder (2.17 g, 0.01 mol) and boron trifluoride etherate (1.43 g, 0.01 mol) in 20 percent aqueous tetrahydrofuran (70 ml). After stirring at room temperature for 1 hour, 200 ml of ether was added, the reaction mixture was filtered through a pad of Celite and the organic phase of the filtrate was separated, dried over anhydrous magnesium sulfate, filtered, and this filtrate was evaporated to give isatin (1.07 g, 78%), mp 200°-202° after recrystallization from benzene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.FC(F)(F)S(O)(=O)=O.[SH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Sc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccccn2)CC1
Temperature: -78 °C
Reaction time: 0.02 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.01 g, 5.0 mmol)and diisopropylethylamine (2.6 mL, 15 mmol)in dry dichloromethane (30 mL) was added anhydrous trifluoromethanesulfonic acid (1.0 mL, 6.0 mmol) at −78° C. The mixture was stirred for 1 minute under ice cooling, and cooled to −78° C. To the reaction mixture was added 2-mercaptopyridine (1.67 g, 15 mmol), and the mixture was stirred at room temperature for 20 hours. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, successively, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (50 g, ethyl acetate-hexane 1:5) to give the titled compound as pale yellow oily substance (937 mg, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20]Cl)=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][NH:26][CH2:27][C@H:28]([C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)[OH:29].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20][N:26]([CH2:27][C@@H:28]([OH:29])[C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)[CH3:25])=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CCl)cc21
Reactant: CNC[C@@H](O)c1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cc2c(s1)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C)C[C@@H](O)c1cccnc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 57.2 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (167 mg, 0.44 mmol), (1S)-2-(methylamino)-1-pyridin-3-ylethanol (Preparation 29) (100 mg, 0.66 mmol) and diisopropylethylamine (115 μL, 0.66 mmol) in dry DMF (8 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 7 hours at that temperature. After cooling to room temperature, the solution was diluted with water (12 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight in the refrigerator. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from /water (dissolved with warming 5 mL of acetonitrile, then cooled to 0° C. and then diluted with 1 mL of water, left overnight) gave the title compound (125 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH:11]2[CH2:13][CH2:12]2)(=[O:10])=[O:9])[C:3]=1Cl.[NH2:15][C:16]1[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([OH:33])[CH:31]=2)[N:26]=[CH:25][N:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH:11]2[CH2:13][CH2:12]2)(=[O:10])=[O:9])[C:3]=1[O:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][N:24]=[C:23]2[NH:15][C:16]1[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=1
Reactant: O=S(=O)(c1cccc(Cl)c1Cl)C1CC1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: Cn1ccc(N)n1
Product: Cn1ccc(Nc2ncnc3ccc(Oc4c(Cl)cccc4S(=O)(=O)C4CC4)cc23)n1

Procedure:
The compound of Example 139 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 1,2-dichloro-3-(cyclopropylsulfonyl)benzene, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.