Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1.[CH:31](N(CC)C(C)C)([CH3:33])[CH3:32].C(Br)C=C>C(Cl)Cl>[CH2:33]([NH:20][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:11]([CH2:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH:21]2[C:30]3[N:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH2:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1)[CH:31]=[CH2:32]
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: C=CCBr
Solvent: ClCCl
Product: C=CCNCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1

Procedure:
To a solution of N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (200 mg, 0.39 mmol) in CH2Cl2 (˜0.4 mL) was added N,N-diisopropylethylamine (90 μL, 0.52 mmol). Allyl bromide (35 μL, 0.40 mmol) was dissolved in CH2Cl2 (˜9.6 mL) and added to the amine mixture at a rate of 5.5 mL/hour. The resultant mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed consecutively with H2O (5 mL), saturated aqueous NaHCO3 (5 mL) and saturated aqueous NaCl (5 mL). The aqueous layer was extracted with CH2Cl2 (20 mL) and the combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Purification by column chromatography on silica gel (200:1:1 followed by 100:1:1—EtOAc:MeOH:NH4OH) followed by radial chromatography on silica gel (250:1:1—EtOAc:MeOH:NH4OH) afforded AMD9725 (36 mg, 21%) as a light yellow foam. 1H NMR (CDCl3) δ 1.56-1.75 (m, 1H), 1.97-2.08 (m, 2H), 2.24-2.31 (m, 1H), 2.65-2.77 (m, 1H), 2.77-2.91 (m, 1H), 3.21 (d, 2H, J=5.7 Hz), 3.69 (s, 2H), 3.73 (s, 2H), 3.97 (d, 1H, J=16.8 Hz), 4.04-4.16 (m, 1H), 4.17 (d, 1H, J=16.8 Hz), 5.07 (d, 1H, J=9.9 Hz), 5.15 (dd, 1H, J=17.1, 1.2 Hz), 5.88 (ddt, 1H, J=17.1, 10.5, 6.0 Hz), 7.10-7.19 (m, 5H), 7.35 (d, 2H, J=7.8 Hz), 7.42 (d, 1H, J=7.5 Hz), 7.45-7.57 (m, 1H), 7.58-7.68 (m, 1H), 8.69 (d, 1H, J=4.2 Hz); 13C NMR (CDCl3) δ 20.83, 22.89, 28.67, 47.95, 51.11, 52.33, 53.17, 59.68, 110.37, 115.39, 118.11, 120.91, 121.66, 127.59, 128.07, 134.13, 136.17, 136.60, 137.48, 138.56, 146.38, 155.80, 156.94. ES-MS m/z 438.3 (M+H). Anal. Calcd. for C28H31N5. 0.8H2O: C, 74.40; H, 7.27; N, 15.49. Found: C, 74.36; H, 7.25; N, 15.31.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].ClC(Cl)C.[C:16]([O:20][C:21]([NH:23][CH:24]([C@H:30]1[CH2:34][CH2:33][N:32]([C@@H](C2C=CC=CC=2)C)[C:31]1=O)[C:25]1[O:26][CH:27]=[CH:28][CH:29]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([NH:23][CH:24]([C@@H:30]1[CH2:34][CH2:33][N:32]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH2:31]1)[C:25]1[O:26][CH:27]=[CH:28][CH:29]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: C[C@H](c1ccccc1)N1CC[C@H](C(NC(=O)OC(C)(C)C)c2ccco2)C1=O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)NC(c1ccco1)[C@@H]1CCN(C(=O)OCc2ccccc2)C1
Yield: 74.2 %

Procedure:
In an atmosphere of nitrogen, benzyl chloroformate (761 μl, 5.31 mmol) was added dropwise to a dichloroethane solution (15 ml) of 3-(R)-[1-tert-butoxycarbonylamino-1-(2-furyl)methyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1] (658 mg, 1.77 mmol) under ice-cooling and then the m was heated under refulx for 30 hours. After evaporation of the solvent under a reduced pressure, the residue was applied to a silica gel column chromatography. By eluting with chloroform to chloroform:methanol (97:3), 526 mg (74%) of the title compound was obtained as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([O:19][CH3:20])([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)[CH:4]([OH:6])[CH3:5].CN(C)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([O:6][CH:4]([CH3:5])[C:3]([O:19][CH3:20])([O:2][CH3:1])[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2cc(C(OC)(OC)C(C)O)ccc2c1
Agent: CN(C)C
Solvent: ClCCl
Product: COc1ccc2cc(C(OC)(OC)C(C)OS(C)(=O)=O)ccc2c1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
The crude oil, 1,1-dimethoxy-1-(6-methoxy-2-naphthyl)propan-2-ol, from Example 5 is dissolved in 250 ml of methylene chloride and cooled to 10° C. Then 12.2 g of trimethylamine is added and the reaction mixture is cooled to about 5° C. Over a 15 minute period, 10.55 g of methanesulfonyl chloride is added. The reaction mixture is stirred for about 30 minutes at 0°-5° C. Separation of the triethylamine hydrochloride as a precipitate is observed. The reaction mixture then is poured into 200 ml of water and extracted with methylene chloride. The organic phase is separated, dried over magnesium sulfate and evaporated under reduced pressure to yield 1,1-dimethoxy-1-(6-methoxy-2-naphthyl)prop-2-yl methanesulfonate as an oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:32]4[CH:31]=[N:30][C:29]([NH2:28])=[N:34][CH:33]=4)[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:5]=3[CH:10]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid pinacol ester in general procedure A. Purification by column chromatography yielded 5-[6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidin-2-yl]-pyrimidin-2-ylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[OH:22].Cl[C:24]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=1.[OH-].[K+]>C1(C)C=CC=CC=1.C1OCCOCCOCCOCCOCCOC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[O:22][C:24]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ncccc3[N+](=O)[O-])c(Cl)cc2F)c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
11.8 g of 2chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol and 5.2 g of 2-chloro-3-nitropyridine were dissolved in 10 ml of toluene, to this were added 2.3 g of potassium hydroxide and 56 mg of 18-crown-6, and the mixture was stirred for 3 hours at 90° C. The reaction solution was cooled to room temperature, then the solvent was distilled off, and the residue was poured into ice water, and the precipitated crystals were collected by filtration to obtain 11.5 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-nitropyridine.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc(O)n2nc(-c3ccc(OC)cc3)cc2n1
Product: CCOC(=O)c1cc(Cl)n2nc(-c3ccc(OC)cc3)cc2n1
Temperature: 115 °C
Yield: 60.4 %

Procedure:
Ethyl 7-hydroxy-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylate (1.26 g; 4.03 mmol) was suspended in phosphoryl chloride (8 mL; 88 mmol) and the mixture was heated to 115° C. for 1 h. The reaction mixture was allowed to cool to room temperature and then carefully quenched into a cold mixture of methylene chloride and saturated sodium bicarbonate. The basic aqueous layer was back extracted once with methylene chloride and the combined organic phases were washed with brine. Concentration afforded a crude solid which was triturated in methanol (15 mL) at 60° C. for 5 min. and then at room temperature for an hour. Filtration afforded 808 mg (60%) of the title compound. LCMS m/z 332.1 (M+H)+, ret. time=2.77 min.
Reaction SMILES: O.NN.[CH3:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][N:17]=2)[O:7][CH2:6]1>C(O)C.[Pd]>[CH3:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:15][C:16]2[N:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=2)[O:7][CH2:6]1
Reactant: CC1COc2cccc(Oc3ccc([N+](=O)[O-])cn3)c2C1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC1COc2cccc(Oc3ccc(N)cn3)c2C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
In a 50 ml round-bottomed flask 2-[(3-methyl-3,4-dihydro-2H-chromen-5-yl)oxy]-5-nitropyridine (Intermediate 118, 181 mg) was dissolved in ethanol (10 ml) to give a pale yellow solution. Pd/C (33.0 mg, 0.031 mmol) and hydrazine hydrate (0.030 ml, 0.310 mmol) were added. The reaction mixture was stirred at 90° C. After 1 hour, the reaction mixture was filtered and evaporated under vacuum to give the title compound (131.4 mg).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH:6]1[CH2:9][CH:8]([CH2:10][O:11][C:12]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:13]=2[C:14](/[N:16]=[C:17]2/[N:18]([CH2:27][C@H:28]3[CH2:32][CH2:31][CH2:30][O:29]3)[N:19]([CH3:26])[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:21]/2)=[O:15])[CH2:7]1.C(N(CC)CC)C>C1COCC1>[C:22]([C:20]1[N:19]([CH3:26])[N:18]([CH2:27][C@H:28]2[CH2:32][CH2:31][CH2:30][O:29]2)/[C:17](=[N:16]/[C:14](=[O:15])[C:13]2[CH:33]=[C:34]([C:37]([F:40])([F:39])[F:38])[CH:35]=[CH:36][C:12]=2[O:11][CH2:10][CH:8]2[CH2:9][N:6]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:7]2)/[CH:21]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2OCC2CNC2)n1C[C@H]1CCCO1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2OCC2CN(S(C)(=O)=O)C2)n1C[C@H]1CCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
Methanesulfonyl chloride (0.05 g, 0.4 mmol) was added to a solution of Example 54B (0.21 g, 0.4 mmol) in THF (5.0 mL) followed by triethylamine (0.17 mL, 1.2 mmol). The mixture was stirred for 1 hour at ambient temperature, then partitioned between EtOAc (15 mL) and saturated NaHCO3 (1 mL). The organic extract was washed with water and brine, dried with MgSO4, filtered and concentrated. The residue was purified by chromatography (SiO2, solvent A-hexane:EtOAc:Et3N (1:3:0.2), solvent B-hexane:EtOAc:MeOH:Et3N (1:3:1:0.2) 100% solvent A to 100% solvent B over 450 mL then isocratic for 180 mL) to afford the title compound (0.12 g, 0.21 mmol, 49% yield). 1H NMR (500 MHz, pyridine-d5) δ ppm 1.21 (s, 9H), 1.54-1.62 (m, 2H), 1.64-1.71 (m, 1H), 1.75-1.85 (m, 1H), 3.01-3.09 (m, 1H), 3.31 (s, 3H), 3.54-3.63 (m, 1H), 3.69-3.76 (m, 1H), 3.85 (s, 3H), 4.05 (t, J=8.1 Hz, 2H), 4.09 (d, J=4.3 Hz, 2H), 4.22-4.28 (m, 1H), 4.36-4.46 (m, 3H), 4.62 (dd, J=15.1, 3.2 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H), 7.46 (s, 1H), 7.65 (dd, J=8.7, 2.3 Hz, 1H), 8.48 (d, J=2.4 Hz, 1H); MS (ESI+) m/z 573.2 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH2:22].[F:25][C:26]1[CH:27]=[C:28]([CH2:33][C:34](O)=[O:35])[CH:29]=[C:30]([F:32])[CH:31]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[F:25][C:26]1[CH:27]=[C:28]([CH2:33][C:34]([NH:22][C@H:21]([C:20]([NH:19][C@@H:3]2[C:2](=[O:1])[NH:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C@@H:4]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:24])[CH3:23])=[O:35])[CH:29]=[C:30]([F:32])[CH:31]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a stirred solution of N1-[(2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]-L-alaninamide (6g) (765 mg, 2.351 mmol) in dichloromethane (10 mL) was added 3,5-difluorophenylacetic acid (450 mg, 2.614 mmol), HOBt (441 mg, 3.265 mmol), NMM (330 mg, 3.267 mmol) and EDAC-HCl (626 mg, 3.265 mmol). The mixture was stirred at ambient temperature under nitrogen overnight. The solvent was evaporated and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was separated and then washed in succession with 1N aqueous HCl and brine. The organic solution was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 2:1 (v/v) ethyl acetate:hexanes to afford the title compound (968 mg, 86%) as a white solid. TLC Rf=0.30 (2:1 ethyl acetate:hexanes). 1H NMR (300 MHz, DMSO-d6) δ1.11 (d, 3H, J=7.0 Hz), 3.46 (q AB, 2H, J=14.4 Hz), 4.24 (m, 1H), 4.95 (m, 1H), 5.61 (d, 1H, J=6.6 Hz), 6.94 (m, 2H), 7.02-7.29 (m, 5H), 7.32-7.40, (m, 6H), 8.32 (m, 1H), 10.29 (br, 1H). MS APCI, m/z=480 (M+1). LC/MS: 2.31 min.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C:5]2([CH2:11][CH2:10][N:9]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[N:20]=4)[N:15]=[CH:14][C:13]=3[F:24])[CH2:8][CH2:7]2)[CH2:4][C@H:3]1[OH:25].[O-]S([O-])(=O)=O.[Na+].[Na+].[O:33]=[C:34]1[CH2:39][S:38][C:37]2[CH:40]=[CH:41][C:42]([CH:44]=O)=[N:43][C:36]=2[NH:35]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCO>[F:24][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:12]=1[N:9]1[CH2:10][CH2:11][C:5]3([CH2:6][C@H:2]([NH:1][CH2:44][C:42]4[CH:41]=[CH:40][C:37]5[S:38][CH2:39][C:34](=[O:33])[NH:35][C:36]=5[N:43]=4)[C@H:3]([OH:25])[CH2:4]3)[CH2:7][CH2:8]1)=[N:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2ncc(F)c(N3CCC4(CC3)C[C@@H](O)[C@@H](N)C4)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2ncc(F)c(N3CCC4(CC3)C[C@@H](O)[C@@H](NCc3ccc5c(n3)NC(=O)CS5)C4)c2n1
Reaction time: 12 h
Yield: 83.8 %

Procedure:
To a solution of (2R,3S)-3-amino-8-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-8-azaspiro[4.5]decan-2-ol (0.26 mg, 75.1 μmol) in DCM-EtOH (1 mL, 1:1) were added Na2SO4 (16 mg, 0.112 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (15 mg, 75.1 μmol). After 12 h at 25° C., the imine was quenched by addition of NaBH(OAc)3 (32 mg, 0.150 mmol) in one portion. After an additional 1 h, the solution was partitioned between NaHCO3-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried (Na2SO4), concentrated and purified by column chromatography (silica, 1% MeOH in DCM (1% NH4OH)) affording the title compound (33 mg, 84%) as a light yellow oil: LCMS (ES) m/e 525 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=5.5 Hz, 1H), 8.11 (d, J=9.0 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.01 (d, J=9.0 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.12-4.19 (m, 1H), 4.03 (s, 3H), 3.92 (AB quart., 2H), 3.52-3.67 (m, 4H), 3.46 (s, 2H), 3.00-3.21 (m, 1H), 1.94-1.96 (m, 1H), 1.79-1.91 (m, 1H), 1.65-1.71 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[N:21][OH:22])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)s2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCC(=NO)c1ccc(-c2ccc(Cl)s2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.7 %

Procedure:
A stirred mixture of 4-[4-(5-chloro-thiophen-2-yl)-phenyl]-4-oxo-butyric acid (0.065 g, 0.00022 mol), hydroxylamine hydrochloride (0.0181 g, 0.000260 mol), sodium carbonate (0.0280 g, 0.000260 mol), and absolute ethanol was refluxed under nitrogen for 17 hours and allowed to cool. The resulting suspension was stirred at room temperature for 2 days and filtered. The filtercake was dissolved in methanol (5 mL) and water (5 mL), and the solution was filtered to remove a small amount of fines. The filtrate was acidified with 1.0 M aqueous hydrochloric acid (0.24 mL, 0.00024 mol), and the resulting suspension was rotary evaporated to remove methanol. The resulting aqueous suspension was filtered, washed with water, and dried in vacuo to give 0.0584 g of 4-[4-(5-chloro-thiophen-2-yl)-phenyl]-4-hydroxyimino-butyric acid as a pale yellow solid; mp 172-174° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH2:7][O:8][CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:13]=[CH:12][C:6]([CH2:7][O:8][CH2:9][CH2:10][O:11][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCOCc1ccc(C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.6 %

Procedure:
To a solution of 2-(4-trifluoromethyl-benzyloxy)-ethanol (1.0 g, 4.5 mmol) in dry DCM (20 ml) and DIPEA (2.36 ml, 13.5 mmol), at 0° C., under argon atmosphere, was added methanesulfonyl chloride (421 μl, 5.4 mmol). The reaction mixture was stirred at 0° C. for 10 minutes, then the ice-bath removed and the stirring continued for 2 hours at r.t. The mixture was then diluted with 70 ml of DCM and washed with 50 ml of NaHCO3 saturated solution, 100 ml of water, 100 ml of 2N HCl and 100 ml of water, dried over sodium sulfate and evaporated to dryness affording 1.35 g (yield: quantitative) of methanesulfonic acid 2-(4-trifluoromethyl-benzyloxy)-ethyl ester as a brown oil that was used as such for the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29]([OH:31])=O)[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].Cl.[CH3:36][O:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[CH3:36][O:37][CH:38]1[CH2:43][CH2:42][N:41]([C:29](=[O:31])[CH:28]([N:26]2[CH:27]=[C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:33])([F:34])[F:1])=[O:6])[CH:13]=[CH:12][CH:11]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)[CH:24]=[N:25]2)[CH3:32])[CH2:40][CH2:39]1
Reactant: COC1CCNCC1
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Agent: Cl
Product: COC1CCN(C(=O)C(C)n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and 4-methoxypiperidine hydrochloride (Matrix and Cat. No. 015567). LCMS (M+H)+: m/z=571.3.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH2:25][CH3:26])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:27][C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH2:25][CH3:26])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:34]([C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([CH3:27])[CH:29]=4)(=[O:36])=[O:35])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CCC1(C)C(=O)N(C2CCNCC2)N=C1c1ccc(OC)c(OC)c1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Product: CCC1(C)C(=O)N(C2CCN(S(=O)(=O)c3cccc(C)c3)CC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4-ethyl-4-methyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B9*HCl) and 3-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH:8]1[C:16]2[C:15]3[S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:14]=3[CH:13]=[CH:12][C:11]=2[NH:10][C:9]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH3:5][N:10]1[C:11]2[CH:12]=[CH:13][C:14]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[S:17][C:15]=3[C:16]=2[CH:8]=[C:9]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)c1cc2c(ccc3c4ccccc4sc23)[nH]1
Reactant: COS(=O)(=O)OC
Product: CCOC(=O)c1cc2c3sc4ccccc4c3ccc2n1C

Procedure:
Using the procedure outlined in Example 34A except that dimethyl sulfate was used as the alkylating agent, ethyl 3H-[1]benzothieno[2,3-e]indole-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc.) gave a nearly quantitative yield of crude ethyl 3-methyl-3H-[1]benzothieno[2,3-e]indole-2-carboxylate. This material was formylated using the procedure of A. Rieche et al., Chem. Ber. 93, 88 (1960) to give a crude mixture of aldehydes which was hydrolyzed and decarboxylated without purification using the procedure outlined in Example 15B to give a 19.0% yield of 3-methyl-3H-[1]benzothieno[2,3-e]indole-1-carbaldehyde.0.25 H2O, mp 223.5°-224°, (CH2Cl2 /hexane), (C,H,N).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([O:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([NH2:23])=[CH:18][C:17]=1[Cl:24])=[CH:8]2)=[O:4].[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34].N1C=CC=CC=1.C([O-])(O)=O.[Na+]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([O:15][C:16]1[C:17]([Cl:24])=[CH:18][C:19]([NH:23][S:33]([C:27]3[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=3[Cl:25])(=[O:35])=[O:34])=[CH:20][C:21]=1[Cl:22])=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ccc2ncc(Oc3c(Cl)cc(N)cc3Cl)cc2c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)c1ccc2ncc(Oc3c(Cl)cc(NS(=O)(=O)c4ccc(Cl)cc4Cl)cc3Cl)cc2c1
Yield: 44.5 %

Procedure:
A solution of 3-(4-amino-2,6-dichlorophenoxy)-quinoline-6-carboxylic acid methyl ester (96) (0.93 mmol) and 2,4-dichlorobenzenesulfonyl chloride (250 mg, 1.02 mmol) in pyridine (0.13 mL, 1.53 mmol) CH2Cl2 (3.7 mL) was stirred at room temperature for 12 h. Sat NaHCO3 was added to the reaction mixture, which was then extracted twice with AcOEt. Organic layer was washed by brine, dried over anhydrous MgSO4, and concentrated. Crude residue was purified by column chromatography (hexane/AcOEt=2/1, 80 g of silica gel) to afford compound 45 (237 mg, 41%, in 3 steps). 1H NMR (300 MHz, DMSO-d6) δ 3.90 (3H, s), 7.31 (2H, s), 7.72 (1H, dd, J=1.8, 7.8 Hz), 7.79 (1H, d, J=3.0 Hz), 7.96 (1H, d, J=1.8 Hz), 8.11 (2H, s), 8.18 (1H, d, J=7.8 Hz), 8.64 (1H, s), 8.99 (1H, d, J=3.0 Hz), 11.42 (1H, br s). MS (M+H) 571.