Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][C:7]2[NH:15][C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH:8]=2)[CH2:2]1.[CH3:16]COCC>CO.C(N(CC)CC)C>[CH3:16][N:1]1[CH2:5][CH2:4][CH:3]([CH2:6][C:7]2[NH:15][C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH:8]=2)[CH2:2]1
Reactant: CCOCC
Reactant: c1cnc2[nH]c(CC3CCNC3)cc2c1
Solvent: CCN(CC)CC
Solvent: CO
Product: CN1CCC(Cc2cc3cccnc3[nH]2)C1

Procedure:
Compound 66 (0.3 g, 1.49 mmol) was converted to compound 67, using the methodology described for compound 9. Yield 0.362 g (80.7%). (TLC ether Rf 0.11), which was used as such to generate the title compound (68) using the methodology as described for compound 28.(Yield 0.17 g, 65%), mp 96-97° C. 1H-NMR (400 MHz, CDCl3): δ N1—H invisible, 8.16 (dd, J=5 Hz, 2 Hz, 1H), 7.77 (dd, J=8 Hz, 2 Hz, 1H), 6.98 (dd, J=8 Hz, 5 Hz, 1H), 6.16 (bs, 1H), 2.92-2.84 (m, 2H), 2.76-2.64 (m, 2H), 2.62-2.50 (m, 2H), 2.34 (s, 3H), 2.40-2.31 (m, 1H), 2.11-2.01 (m, 1H), 1.63-1.53 (m, 1H). (TLC MeOH/triethylamine (97/3) Rf 0.2).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH:8]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>C(OCC)(=O)C.CCCCCCC>[C:17]([O:16][C:14]([N:13]([CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: C=CC(=O)OCC
Reactant: NC1CCCC1
Reactant: CC(C)(C)OC=O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCOC(=O)CCN(C(=O)OC(C)(C)C)C1CCCC1

Procedure:
The title compound was prepared from ethyl acrylate (1.09 ml, 10 mmol) and cyclopentylamine (0.99 ml, 10 mmol) according to Example 2a. Yield: 2.28 g (80%). ESI-MS: 286.2 (M+H)+, 230.2 (M+H—C4H8)+, 186.2 (M+H-Boc)+. Rf (silica gel; ethyl acetate/heptane, 1:4, v/v): 0.45.
Reaction SMILES: CO[C:3](=[O:36])[CH:4]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH2:5][C:6]1[C:7]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:8][C:9]([NH:12][C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[N:10][CH:11]=1.S(=O)(=O)(O)O>C(O)(=O)C.C(OCC)(=O)C>[CH3:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([CH:4]2[C:3](=[O:36])[N:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:7]3[N:8]=[C:9]([NH:12][C:13]4[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=4)[N:10]=[CH:11][C:6]=3[CH2:5]2)=[CH:29][CH:30]=1
Reactant: COC(=O)C(Cc1cnc(Nc2ccc(OC)nc2)nc1Nc1ccccc1)c1ccc(OC)cc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(C2Cc3cnc(Nc4ccc(OC)nc4)nc3N(c3ccccc3)C2=O)cc1
Temperature: 80 °C

Procedure:
To a solution of 3-[2-(6-methoxy-pyridin-3-ylamino)-4-phenylamino-pyrimidin-5-yl]-2-(4-methoxy-phenyl)-propionic acid methyl ester (45.0 mg, 0.09 mmol) (from Example 12c supra) in glacial acetic acid (1 mL) was added concentrated sulfuric acid (0.1 mL) in one portion. After heating at 80° C. for 3 hours, the reaction mixture was diluted with ethyl acetate (50 mL) and quenched with 2 N aqueous sodium hydroxide solution. The organic layer was separated and successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by preparative thin layer chromatography to give 6-(4-methoxy-phenyl)-2-(6-methoxy-pyridin-3-ylamino)-8-phenyl-5,8-dihydro-6H-pyrido[2,3-d]pyrimidine-7-one as brown powder. (Yield 5.2 mg, 12.4%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O.NN>C(O)C.[Ni].O>[N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(NCCCN2CCOCC2)cc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc(NCCCN2CCOCC2)cc1
Temperature: 50 °C

Procedure:
A suspension of 5.00 gms. of (3-morpholin-4-yl-propyl)-(4-nitro-phenyl)-amine in 110 mL of ethanol is heated to 50° C. Once dissolution is achieved 5.49 mL hydrazine monohydrate is added to the solution. A Raney nickel slurry in water is added to the 50° C. solution dropwise, waiting after each addition for the bubbling to cease. Sufficient quantities of Raney nickel have been added when continued addition of Raney nickel causes no further gas evolution. The reaction is then maintained at 50° C. for an additional hour, and subsequently is cooled to room temperature. The reaction mixture is filtered through a pad of celite (rinsing the pad with methanol). N-(3-Morpholin-4-yl-propyl)-benzene-1,4-diamine (4.39 gms.) is isolated upon evaporation of the filtrate, and is subsequently used without purification in the reaction of Example 297.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[N:8]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22][CH3:23])[CH:17]=1)[C:7]([C:24]([O:26][CH3:27])=[O:25])=[C:6]2[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=1.ClC1C=CC=C(C(OO)=[O:48])C=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[N:8]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([CH3:23])=[O:48])[CH:17]=1)[C:7]([C:24]([O:26][CH3:27])=[O:25])=[C:6]2[C:28]1[CH:29]=[C:30]([O:38][CH3:39])[C:31]([O:36][CH3:37])=[C:32]([O:34][CH3:35])[CH:33]=1
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(OC)cc2c(=O)n1-c1cccc(SC)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(OC)cc2c(=O)n1-c1cccc(S(C)=O)c1
Reaction time: 1 h
Yield: 850.3 %

Procedure:
To a solution of the compound obtained in Example 121 (200 mg) in chloroform (15 ml) is added a solution of m-chloroperbenzoic acid (78 mg) in chloroform (10 ml) at room temperature, and the mixture is stirred for one hour. The reaction mixture is washed with a 5% aqueous sodium hydroxide solution, dried, and concentrated under reduced pressure to give 6,7-dimethoxy-3-methoxycarbonyl-2-(3-methylsulfinylphenyl)-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone (1750 mg) as listed in Table 11.
Reaction SMILES: [NH2:1]/[C:2](=[N:13]\[O:14][C:15](=O)[C:16]([CH3:19])([CH3:18])[CH3:17])/[CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>C1COCC1>[C:16]([C:15]1[O:14][N:13]=[C:2]([CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[N:1]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCC/C(N)=N/OC(=O)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCc1noc(C(C)(C)C)n1
Reaction time: 2 h
Yield: 98 %

Procedure:
To a stirred suspension of tert-butyl ((3Z)-3-amino-3-{[(2,2-dimethylpropanoyl)oxy]imino}propyl)carbamate, obtained in step II as describe above (51 g; 177 mmol; 1 eq.), in dry THF (1000 ml) under N2, is added dropwise at RT a solution of tetrabutylammonium fluoride solution (177.5 ml; 1 M; 177.5 mmol; 1 eq.) in dry THF (400 ml). At the end of addition, the initial white suspension becomes a yellow solution. The reaction is followed by NMR. After 2 h the reaction is complete. The reaction mixture is poured into EtOAc (1 l) and is washed with water (3×700 ml) and brine (3×700 ml). The organic layer is dried over MgSO4, filtered off and evaporated, affording the title compound as a beige solid (46.6 g, 98%).
Reaction SMILES: [NH2:1][C@@H:2]([C@@H:6]([CH3:9])[CH2:7][CH3:8])[C:3]([OH:5])=[O:4].[OH-].[Na+].Cl[C:13]([O:15][CH3:16])=[O:14]>O1CCOCC1.CCOC(C)=O>[CH3:16][O:15][C:13]([NH:1][C@@H:2]([C@@H:6]([CH3:9])[CH2:7][CH3:8])[C:3]([OH:5])=[O:4])=[O:14]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To a solution of (2S,3S)-2-amino-3-methylpentanoic acid (1.0 g, 7.62 mmol) in dioxane (10 mL) at 0° C. was added NaOH (12.58 g, 25.2 mmol) followed by dropwise addition of methyl chloroformate (1.18 mL, 15.25 mmol). The solution was warmed to room temperature with stirring over 2 h, diluted with EtOAc, washed with 1 N HCl, brine, dried (Na2SO4), filtered and solvent removed in vacuo to give the title compound (1.4 g, 7.4 mmol, 97%). 1H NMR (400 MHz, CDCl3) δ ppm 1.27-1.39 (m, 1H) 1.38-1.53 (m, 2 H) 1.58-1.72 (m, 3H) 1.82-1.94 (m, 2H) 2.04 (d, J=3.8 Hz, 2H) 3.70 (s, 3H) 4.94 (br s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:34])[NH:13][C:14](=[O:33])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26]COS(C)(=O)=O)[CH:17]=2)=[CH:3]1.C[S-].[Na+].[CH3:38][S:39]([CH3:41])=O>O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:34])[NH:13][C:14](=[O:33])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH2:38][S:39][CH3:41])[CH:17]=2)=[CH:3]1
Reactant: CS(C)=O
Reactant: Cn1cc(C2=C(c3cn(CCCOS(C)(=O)=O)c4ccccc34)C(=O)NC2=O)c2ccccc21
Agent: C[S-]
Agent: [Na+]
Solvent: O
Product: CSCCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 0.5 h

Procedure:
100 mg of the product of Example 58 in 5 ml of DMSO were treated with 30 mg of sodium methanethiolate. The solution was stirred for 30 minutes and then diluted with water. The precipitate was filtered off, washed with water and dried to give 52 mg of 3-(1-methyl-3-indolyl)-4-[1-[3-(methylthio)propyl]-3-indolyl]-1H-pyrrole-2,5-dione, m.p. 222°-224° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[N:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([B:22]4[O:26]C(C)(C)C(C)(C)[O:23]4)=[C:18]([CH:31]=O)[CH:17]=3)[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].Cl.O>CO>[CH:1]1([O:6][C:7]2[N:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]4[B:22]([OH:26])[O:23][CH2:31][C:18]=4[CH:17]=3)[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OB(c2ccc(Oc3ccc(C#N)c(OC4CCCC4)n3)cc2C=O)OC1(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)nc1OC1CCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-cyclopentyloxy-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile (2.0 g, 4.60 mmol) in methanol (15 mL) at 0° C. was added sodium borohydride (0.26 g, 6.90 mmol). After 1 h at rt, 2 M HCl was added to it at 0° C. until pH reached to 3˜4. The resulting mixture was stirred at 0° C. for 30 min and then sonicated to give white solid which was filtered and lyophilized to yield Z (0.85 g, 56%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1 H), 8.20 (d, J=8.2 Hz, 1 H), 7.77 (d, J=7.8 Hz, 1 H), 7.27 (d, J=1.2 Hz, 1 H), 7.18 (dd, J=8.2, 1.9 Hz, 1 H), 6.69 (d, J=8.2 Hz, 1 H), 4.97 (br. s., 3 H), 1.75-1.54 (m, 6 H), 1.52-1.33 (m, 2 H); MS (ES) m/z: 337 (M+1)+; HPLC purity 99.36% (Maxplot), 99.35% (220 nm); Elemental analysis for C18H17BN2O4.0.25 H2O: Calculated C=63.46%, H=5.18%, N=8.22%; Found C=63.34%, H=5.17%, N=8.34%.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[S:21](Cl)(=[O:23])=[O:22].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][CH:27]=1>>[O:5]=[C:4]1[C:6]2([CH2:7][CH2:8][N:9]([S:21]([C:17]3[S:16][CH:20]=[CH:19][CH:18]=3)(=[O:23])=[O:22])[CH2:10][CH2:11]2)[CH2:12][CH2:13][N:25]1[C:26]1[CH:31]=[CH:30][C:29]([O:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CS(=O)(=O)Oc1ccc(N)cc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: CS(=O)(=O)Oc1ccc(N2CCC3(CCN(S(=O)(=O)c4cccs4)CC3)C2=O)cc1

Procedure:
Off-white solid. MS (ESI): 471.07 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), thiophene-2-sulphonyl chloride and methanesulfonic acid 4-amino-phenyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=2)[CH:7]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:25][C:26]1[CH:27]=[C:28]([C:33]2[N:37]=[C:36]([CH:38]3[CH2:41][N:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]3)[O:35][N:34]=2)[CH:29]=[CH:30][C:31]=1[CH3:32]>ClCCl.N1C=CC=CC=1>[CH3:32][C:31]1[CH:30]=[CH:29][C:28]([C:33]2[N:37]=[C:36]([CH:38]3[CH2:39][N:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:41]3)[O:35][N:34]=2)=[CH:27][C:26]=1[NH:25][C:11]([C:8]1[N:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)=[O:13]
Reactant: Cc1ccc2ncc(C(=O)O)n2c1
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(N)c3)no2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5ccc(C)cn45)c3)no2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring suspension of 6-methylimidazo[1,2-a]pyridine-3-carboxylic acid (24j) (35 mg, 0.196 mmol) in anhydrous dichloromethane (2 mL) at 0° C. under Argon was added dropwise oxalyl chloride (17 uL, 0.206 mmol). Then, a drop of anhydrous N,N-dimethylformamide was added and the reaction mixture was stirred at 0° C. for 1 hour. The solvent was concentrated. A stirring mixture of the acid chloride and methyl 3-(3-(3-amino-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (31) (28 mg, 0.098 mmol) in anhydrous pyridine (1.5 mL) was stirred at room temperature for 2 hours. The solvent was concentrated and the crude product was purified by silica chromatography to give methyl 3-(3-(4-methyl-3-(6-methylimidazo[1,2-a]pyridine-3-carboxamido)phenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F62). 1H NMR (400 MHz, d6-DMSO) δ 10.15 (s, 1H), 9.36 (s, 1H), 8.67 (s, 1H), 8.11 (d, J=2.0 Hz, 1H), 7.85 (dd, J=2.0, 8.0 Hz, 1H), 7.81 (d, J=9.2 Hz, 1H), 7.57 (dd, J=1.2, 9.2 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 4.39-4.34 (m, 2H), 4.31-4.24 (m, 1H), 4.22-4.17 (m, 2H), 3.59 (s, 3H), 2.41 (s, 3H), 2.37 (s, 3H). MS m/z 447.17 (M+1)+.
Reaction SMILES: C1(CO[C:9](=O)[NH:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=3)[NH:15][CH:14]=2)C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(OCC)(=O)C>C1COCC1>[CH3:9][NH:10][CH2:11][CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][NH:23][S:24]([CH3:27])(=[O:25])=[O:26])[CH:20]=2)[NH:15][CH:14]=1
Reactant: CS(=O)(=O)NCc1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNCCc1c[nH]c2ccc(CNS(C)(=O)=O)cc12
Yield: 107 %

Procedure:
A solution of phenylmethyl[2-[5-[[(methylsulphonyl)amino]methyl]-1H-indol-3-yl]ethyl]carbamate (0.02 g) in dry THF (1 ml) was added to a stirred suspension of lithium aluminium hydride (0.1 g) in THF (2 ml) and the mixture was refluxed under nitrogen for 3 h. The mixture was cooled and excess reagent was decomposed by the addition of 10% water in THF. Salt and ethyl acetate (20 ml) were added and the organic layer was dried (Na2SO4) and evaporated in vacuo to leave the title compound as a brown oil (0.015 g).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[NH:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[K+].Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>CS(C)=O>[CH2:1]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:12][CH2:11]2)[N:8]([CH2:27][CH2:28][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1c[nH]c(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)Cc1cn(CCN2CCCC2)c(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 106.9 %

Procedure:
Combine tert-butyl 4-(4-isobutyl-1H-imidazol-2-yl)piperidine-1-carboxylate (1.50 g, 4.88 mmol) and potassium hydroxide (1.65 g, 6.0 eq) (freshly powdered) in dimethyl sulfoxide (30 mL). Heat the reaction mixture to 45° C. under nitrogen. After 5 minutes, add 1-(2-chloroethyl)pyrrolidine hydrochloride (1.08 g, 1.3 eq). Stop heating after 2 hours. Add water and extract with ethyl acetate. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo to give the title compound as a yellow oil (2.11 g, 100%). MS (ES) m/z=405 [M]+.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.Cl[CH2:10][C:11]1[N:12]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[C:18]([O:25][CH2:26][CH3:27])[CH:17]=2)[S:14][CH:15]=1>C(#N)C>[CH2:26]([O:25][C:18]1[CH:17]=[C:16]([C:13]2[S:14][CH:15]=[C:11]([CH:10]=[O:5])[N:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][CH3:24])[CH3:27]
Reactant: CCOc1ccc(-c2nc(CCl)cs2)cc1OCC
Reactant: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: CCOc1ccc(-c2nc(C=O)cs2)cc1OCC
Temperature: 25 °C
Yield: 85.9 %

Procedure:
N-methylmorpholine-N-oxide (16.5 g, 141 mmol) was added to a solution (200 ml) of 4-chloromethyl-2-(3,4-diethoxyphenyl)thiazole (13.99 g, 47 mmol) in acetonitrile, followed by heating under reflux for 1.5 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the residue was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated salt solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2). The solvent was distilled off under reduced pressure, to thereby obtain 11.2 g (yield: 86%) of 2-(3,4-diethoxyphenyl)thiazole-4-carboxaldehyde as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C.CCOC(C)=O.O>[CH2:31]([N:8]([C:7]1[C:2]([Br:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=S(=O)(Nc1cccnc1Br)c1ccc(Oc2ccccc2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(c1ccc(Oc2ccccc2)cc1)N(Cc1ccccc1)c1cccnc1Br

Procedure:
To a suspension of N-(2-bromo-pyridin-3-yl)-4-phenoxy-benzene-sulfonamide (0.38 g, 0.94 mmol) from step A and K2CO3 (0.39 g, 2.81 mmol) in dry DMF (10 mL) was added benzylbromide (0.13 mL, 1.13 mmol). The resulting mixture was heated at 80 C overnight. The cooled reaction was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc (×3) and the combined organics were washed with water and brine, dried over anhydrous Na2SO4, and filtered through Celite. The filtrate was concentrated under the reduced pressure and purified by chromatography (silica gel, 25% EtOAc/hexanes). MS: 495, 497 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH2:12]=[C:13]1[O:17][C:15](=O)[CH2:14]1.C(Cl)(Cl)(Cl)Cl.C(OC(=O)C)(=O)C>CC(C)=O>[CH3:11][C:7]1[C:3]2[C:4](=[O:6])[O:5][C:15]([CH2:14][C:13](=[O:17])[CH3:12])=[N:1][C:2]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: C=C1CC(=O)O1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)=O
Product: CC(=O)Cc1nc2cccc(C)c2c(=O)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a solution of 2-amino-6-methylbenzoic acid (20 g, 0.132 mol) in acetone (100 mL), diketene (15.3 mL, 0.198 mol) was added dropwise at room temperature, and the mixture was stirred overnight at room temperature. The reaction solvent and excess diketene was evaporated under reduced pressure. To the residue, carbon tetrachloride (80 mL) and subsequently acetic anhydride (27 g, 0.265 mol) were added, and the mixture was heated under reflux for 3 hours. The reaction solvent and excess acetic anhydride were evaporated and concentrated under reduced pressure, and the resulting powder was collected by filtration and washed with diethylether to give crude 5-methyl-2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one (13.75 g, 48% yield). A solution of the compound (12.99 g, 0.06 mol) and 2-hydrazinopyridine (7.18 g, 0.066 mol) in ethanol (100 mL) was heated under reflux for 1 hour. The reaction solution was allowed to cool to room temperature, and the reaction solvent was evaporated and concentrated under reduced pressure. A solution of the residue in phosphorous oxychloride (45.8 g, 0.3 mol) was heated and stirred at 100° C. for 1 hour. After the reaction solution was cooled to room temperature, the reaction solvent was evaporated and concentrated under reduced pressure, and the residue was poured into iced water, which was made basic by the addition of a sodium hydroxide solution, and organic matter was extracted with chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate:methanol=98:2) to give the title compound (4.4 g, 24% yield).
Reaction SMILES: [NH2:1][C:2](=[O:36])[C:3](=[O:35])[CH:4]([NH:13][C:14](=[O:34])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])=[N:22]1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.Br[CH2:38][CH2:39][OH:40].N12CCCN=C1CCCCC2.O>CN(C)C=O>[NH2:1][C:2]([C:3]1([CH:4]([NH:13][C:14](=[O:34])[C:15]2[CH:20]=[CH:19][CH:18]=[N:17][C:16]=2[N:21]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[Cl:33])=[N:22]2)[CH2:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)[O:40][CH2:39][CH2:38][O:35]1)=[O:36]
Reactant: OCCBr
Reactant: NC(=O)C(=O)C(Cc1ccc(F)cc1)NC(=O)c1cccnc1-n1ccc(-c2ccc(Cl)cc2Cl)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)C1(C(Cc2ccc(F)cc2)NC(=O)c2cccnc2-n2ccc(-c3ccc(Cl)cc3Cl)n2)OCCO1
Temperature: 25 °C

Procedure:
N-[3-amino-1-(4-fluorobenzyl)-2,3-dioxopropyl]-2-[3-(2,4-dichlorophenyl)-1H-pyrazol-1-yl]nicotinamide (0.09 g, 0.171 mmol) was dissolved in dimethylformamide (DMF, 1.7 ml) forming a slight yellow solution. Then, 2-bromoethanol (0.059 ml, 0.838 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.090 ml, 0.598 mmol) were added with stirring at room temperature. Stirring was continued over night. Water was added to reaction mixture resulting in precipitation of the desired product. The suspension was stirred for 30 min. at 0-5° C. The suspension was filtered under reduced pressure, the precipitate washed three times with ice cold water, and subsequently dried at 40° C. under reduced pressure. The remaining residue (85 mg) was treated with a dichloromethane/methanol mixture (97:3 v/v) and the resulting suspension was stirred at room temperature for 30 min. The precipitate was filtered under reduced pressure. washed with few amounts of dichloromethane and subsequently dried at 40° C. under reduced pressure resulting in 19 mg off-white powder. An additional amount of pure desired product could be obtained by column chromatography of the evaporated filtrate.