Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:6]2.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[CH2:25]([O:24][C:22]([CH2:21][CH2:20][CH2:19][N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[C:5]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:23])[CH3:26]
Reactant: CCOC(=O)c1cc2c(C)cccc2[nH]1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1c(C(=O)OCC)cc2c(C)cccc21
Temperature: 25 °C

Procedure:
A mixture of ethyl 4-methyl-1H-indole-2-carboxylate (8.50 g, 41.8 mmol), 60% sodium hydride (1.67 g, 41.8 mmol) and N,N-dimethylformamide (150 ml) was stirred at room temperature until the reaction mixture became transparent. Subsequently, ethyl 4-bromobutyrate (8.16 g, 41.8 mmol) was added dropwise to the aforesaid mixture and the resulting mixture was stirred at 27-29° C. for another 8 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate, and the extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=3/97) to obtain ethyl 1-(3-ethoxycarbonylpropyl)-4-methyl-1H-indole-2-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[OH:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([O-])=[O:30])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1>>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:1][C:29](=[O:30])[C:28]4[CH:27]=[CH:26][C:25]([N:22]5[CH2:23][CH2:24][CH:19]([OH:18])[CH2:20][CH2:21]5)=[CH:33][CH:32]=4)=[CH:10][CH:9]=3)[CH:5]=[N:6]2)=[CH:12][CH:13]=1
Reactant: Nc1ccc(-n2ncc3cc(N)ccc32)cc1
Reactant: O=C([O-])c1ccc(N2CCC(O)CC2)cc1
Product: Nc1ccc(-n2ncc3cc(NC(=O)c4ccc(N5CCC(O)CC5)cc4)ccc32)cc1

Procedure:
Compound 515 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)indazole and 4-(4-hydroxypiperidin-1-yl)benzoate. [M+H]+ calcd for C25H25N5O2: 428.20; found: 427.93.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[CH3:7][CH:8]([C:11](=O)[CH2:12][CH2:13][CH2:14][CH3:15])[C:9]#[N:10]>C1(C)C=CC=CC=1>[NH2:10][C:9]1[N:3]2[N:4]=[CH:5][CH:6]=[C:2]2[N:1]=[C:11]([CH2:12][CH2:13][CH2:14][CH3:15])[C:8]=1[CH3:7]
Reactant: CCCCC(=O)C(C)C#N
Reactant: Nc1cc[nH]n1
Solvent: Cc1ccccc1
Product: CCCCc1nc2ccnn2c(N)c1C
Temperature: 115 °C

Procedure:
A toluene solution (2.5 ml) containing 1.8 g of 3-aminopyrazole and 3 g of 2-methyl-3-oxoheptanenitrile was heated at 115° C. for 3.5 hours. Toluene was distilled off under reduced pressure and the residue was recrystallized from ethyl acetate and washed with diethyl ether to provide 2.4 g of the title object compound as colorless crystals.
Reaction SMILES: [OH:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([N:16]3[CH:20]=[CH:19][N:18]=[C:17]3[CH3:21])=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][C:4](=[O:22])[C:3]1=[O:23].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C.P([O-])(O)(O)=O.[K+]>[CH2:24]([O:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([N:16]3[CH:20]=[CH:19][N:18]=[C:17]3[CH3:21])=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=2)[NH:5][C:4](=[O:22])[C:3]1=[O:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nccn1-c1cc2[nH]c(=O)c(=O)n(O)c2cc1C(F)(F)F
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CCO
Product: Cc1nccn1-c1cc2[nH]c(=O)c(=O)n(OCc3ccccc3)c2cc1C(F)(F)F
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To a solution of 5.3 g (~16.3 mmol) of 1-hydroxy-6-(2-methyl-1H-imidazol-1-yl)-7-trifluoromethylquinoxaline-2,3(1H,4H)-dione in a mixture of 80 ml ethanol and 80 ml 1M potassium dihydrogen phosphate buffer pH 7.4 was added 2.1 ml (17.7 mmol) benzylbromide. Stirring was continued at 25° C. for 1 h. The precipitate was filtered off and washed with water and a little ice-cooled ethanol to give the title compound (5.2 g; 78%). M.p. 156° C. (decomp.).
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][N:17]([CH3:35])[CH2:18][CH2:19][NH:20][C:21]1[N:22]=[N+:23]([O-:34])[C:24]2[CH:30]=[C:29]3[O:31][CH2:32][CH2:33][C:28]3=[CH:27][C:25]=2[N:26]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[O-:34][N+:23]1[C:24]2[CH:30]=[C:29]3[O:31][CH2:32][CH2:33][C:28]3=[CH:27][C:25]=2[N+:26]([O-:4])=[C:21]([NH:20][CH2:19][CH2:18][N:17]([CH3:35])[CH3:16])[N:22]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)OCC3
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCO3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 25.9 %

Procedure:
H2O2 (70%, 0.66 mL, ca. 13.2 mmol) was added dropwise to a stirred solution of TFAA (1.9 mL, 13.2 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 197 (363 mg, 1.3 mmol) and TFA (0.51 mL, 6.6 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 20° C. for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 198 (98 mg, 25%) as a red solid: mp (MeOH/EtOAc) 149-151° C.; 1H NMR δ 8.12 (s, 1H, H-5), 7.54 (s, 1H, H-9), 7.27 (br s, 1H, NH), 4.75 (t, J=8.3 Hz, 2H, H-7), 3.58-3.64 (m, 2H, CH2N), 3.43 (t, J=8.2 Hz, 2H, H-6), 2.62 (t, J=6.0 Hz, 2H, CH2N), 2.31 [s, 6H, N(CH3)2]; 13C NMR δ 159.9, 148.9, 141.6, 135.2, 130.9, 113.1, 97.4, 72.4, 57.5, 45.1 (2), 38.8, 29.7. Anal. calcd for C13H17N5O3.¼H2O: C, 52.8; H, 6.0; N, 23.7. Found: C, 52.8; H, 5.7; N, 23.5%.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:40][CH2:39][C:18]2([N:22]=[C:21]([C:23]3[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([O:33][CH2:34][CH2:35][CH:36]=[CH2:37])[CH:24]=3)[NH:20][C:19]2=[O:38])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH2:34]([O:33][C:25]1[CH:24]=[C:23]([C:21]2[NH:20][C:19](=[O:38])[C:18]3([CH2:39][CH2:40][NH:15][CH2:16][CH2:17]3)[N:22]=2)[CH:28]=[C:27]([C:29]([F:31])([F:30])[F:32])[CH:26]=1)[CH2:35][CH:36]=[CH2:37]
Reactant: C=CCCOc1cc(C2=NC3(CCN(C(=O)OC(C)(C)C)CC3)C(=O)N2)cc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCCOc1cc(C2=NC3(CCNCC3)C(=O)N2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102.1 %

Procedure:
Trifluoroacetic acid (27 ml) was added to a solution of 2-(3-but-3-enyloxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester (2.39 g, 5.12 mmol) in methylene chloride (54 ml), and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure with azeotropic distillation with toluene, and the resulting residue (trifluoroacetate) was then dissolved in methanol (50 ml). A 4 N solution of hydrochloric acid in dioxane (16 ml) was added and the mixture was concentrated under reduced pressure. The resulting residue was dissolved in a mixed solution of ethyl acetate (100 ml)-ethanol (5 ml), followed by washing with a 1 N aqueous K3PO4 solution. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give 2-(3-but-3-enyloxy-5-trifluoromethyl-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (1.92 g). This compound was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][CH2:14]Br.[OH-].[K+].O>CN(C)C=O>[N+:8]([C:7]1[C:2]2[NH:1][CH2:14][CH2:13][O:11][C:3]=2[CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: BrCCBr
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c1NCCO2
Temperature: 200 °C
Reaction time: 48 h
Yield: 14.3 %

Procedure:
To a solution of 2-amino-3-nitrophenol (15.0 g, 97 mmol) and 1,2-dibromoethane (29.1 g, 155 mmol) in dimethylformamide (80 mL) was added KOH (10.9 g, 194 mmol) at 180° C. After stirring at 200° C. for 2 days, the mixture was poured to 150 g water. The mixture was concentrated under reduced pressure. The crude product was purified using column chromatography to give the title compound (2.50 g) as a red solid. MS (ESI): m/z 181 [M+H]+
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[N:14]=[C:13]([CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[S:24][C:20]=3[C:19](=[O:31])[N:18]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[C:17]2=[O:38])[S:12][N:11]=1)[CH3:9].[CH2:39]([O:41][C:42]1[C:51]([O:52][CH3:53])=[CH:50][C:49]2[C:48]([C:54]3[CH:62]=[CH:61][C:57]([C:58](O)=[O:59])=[CH:56][CH:55]=3)=[N:47][C@@H:46]3[CH2:63][CH2:64][S:65][CH2:66][C@@H:45]3[C:44]=2[CH:43]=1)[CH3:40].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.S([O-])(O)(=O)=O.[K+]>C(Cl)Cl>[CH2:39]([O:41][C:42]1[C:51]([O:52][CH3:53])=[CH:50][C:49]2[C:48]([C:54]3[CH:55]=[CH:56][C:57]([C:58]([N:35]4[CH2:36][CH2:37][CH:32]([N:18]5[C:19](=[O:31])[C:20]6[S:24][C:23]([C:25]7[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=7)=[CH:22][C:21]=6[N:16]([CH2:15][C:13]6[S:12][N:11]=[C:10]([CH2:8][CH3:9])[N:14]=6)[C:17]5=[O:38])[CH2:33][CH2:34]4)=[O:59])=[CH:61][CH:62]=3)=[N:47][C@@H:46]3[CH2:63][CH2:64][S:65][CH2:66][C@@H:45]3[C:44]=2[CH:43]=1)[CH3:40]
Reactant: CCc1nsc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CCN=C=NCCCN(C)C
Agent: O=S(=O)([O-])O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nc(CC)ns5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 1-[(3-ethyl-1,2,4-thiadiazol-5-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione trifluoroacetate (250 mg; compound B46), 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (175 mg; compound C10), EDCI (84 mg) and HOBT hydrate (60 mg) in DCM (15 ml) DIPEA (0.23 ml) is added. After 14 h at RT additional EDCI (84 mg) and HOBT hydrate (60 mg) are added and the reaction mixture is stirred for additional 3 d at RT. Aqueous potassium hydrogen sulfate solution (10% w/w) is added and the mixture is filtered using a phase separator. The organic layer is concentrated under reduced pressure and the residue is purified by flash column chromatography [silica gel, eluation gradient: DCM/MeOH, 17/3 to 1/1 (v/v)] to afford the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11][C:10]2=[O:17])=[CH:5][CH:4]=1.[BrH:18].BrBr>O>[Br:18][C:9]1([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:10](=[O:17])[NH:11][C:12](=[O:16])[NH:13][C:14]1=[O:15]
Reactant: Br
Reactant: COc1ccc(C2C(=O)NC(=O)NC2=O)cc1
Agent: BrBr
Solvent: O
Product: COc1ccc(C2(Br)C(=O)NC(=O)NC2=O)cc1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-(4-methoxyphenyl)barbituric acid (222 mg) in 3 ml of water, cooled to 0-5° C. with ice bath, are added 136 μl of 48% hydrobromic acid and 56 μl of bromine, dropwise. After 1 hour at a temperature below 10° C., the solid which separated is collected by filtration and washed on the filter with water. The solid is dried for several hours under vacuum at 50° C., to give 283 mg of the product.
Reaction SMILES: O=[C:2]1[CH:7]=[CH:6][NH:5][C:4]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[N:3]1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1ccc(Nc2nc(=O)cc[nH]2)cc1
Product: N#Cc1ccc(Nc2nccc(Cl)n2)cc1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
A mixture of 4-[(1,4-dihydro-4-oxo-2-pyrimidinyl)amino]benzonitrile, (0.12 mol) in POCl3 (90 ml) was stirred and refluxed under Argon for 20 minutes. The reaction mixture was slowly poured onto 750 ml ice/water, and the solid was separated by filtration. The solid was suspended in 500 ml water, and the pH of the suspension was adjusted to neutral by adding a 20% NaOH solution. The solid was again separated by filtration, suspended in 200 ml 2-propanone, and 1000 ml CH2Cl2 was added. The mixture was heated until all solid had dissolved. After cooling to room temperature, the aqueous layer was separated, and the organic layer was dried. During removal of the drying agent by filtration, a white solid formed in the filtrate. Further cooling of the filtrate in the freezer, followed by filtration, yielded 21.38 g (77.2%) of 4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (interm. 10). b) Intermediate (10) (0.005 mol), 1-bromo-2,5-pyrrolidinedione (0.006 mol) and trichloromethane (10 ml) were combined in a sealed tube and heated at 100° C. overnight. The reaction mixture was allowed to cool to room temperature. Silica gel (2 g) was added, and the solvent was evaporated. The residue was purified by flash column chromatography over silica gel (eluent: CH2Cl2/hexanes 9/1). The pure fractions were collected and the solvent was evaporated, yielding 1.31 g (84.5%) of 4-[(5-bromo-4-chloro-2-pyrimidinyl)amino]benzonitrile (interm. 11).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[NH:19][N:18]=[N:17][N:16]=1)([CH3:4])([CH3:3])[CH3:2].[C:21](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:19]([CH3:21])[N:18]=[N:17][N:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1nnn[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nnnc1-c1ccccc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of [2-(1H-tetrazol-5-yl)-benzyl]-carbamic acid tert-butyl ester (0.23 g, 0.84 mmol, preparation described in example 14, Step C), crushed potassium carbonate (0.58 g, 4.2 mmol) and iodomethane (0.26 ml, 4.2 mmol) in dimethylformamide (4.7 ml) was stirred at room temperature for 1 h. Water was added and the reaction mixture was extracted with chloroform. Drying and solvent evaporation gave a mixture of regioisomers; separation and purification by reverse phase preparative HPLC (5% to 95% CH3CN in water containing 0.1% TFA, C18 PRO YMC 20×150 mm) gave [2-(1-methyl-1H-tetrazol-5-yl)-benzyl]-carbamic acid tert-butyl ester; 1H NMR (CDCl3, 400 MHz) δ 7.66 (d, 1H, J=7.4 Hz), 7.58 (m, 1H), 7.46 (m, 1H), 7.33 (d, 1H, J=7.6 Hz), 4.17 (d, 2H, J=6.3 Hz), 4.05 (s, 3H), 1.41 (s, 9H) and [2-(2-methyl-2H-tetrazol-5-yl)-benzyl]-carbamic acid tert-butyl ester; 1H NMR (CDCl3, 400 MHz) δ 8.06 (d, 1H, J=7.4 Hz), 7.61 (d, 1H, J=7 Hz), 7.44 (m, 2H), 5.82 (bs, 1H), 4.52 (d, 2H, J=6.5 Hz), 4.44 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][NH2:15]>C(Cl)Cl>[NH2:12][CH2:13][CH2:14][NH:15][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCN
Solvent: ClCCl
Product: NCCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of benzylchloroformate (1.3 mL, 9 mmol) in DCM (25 mL) was added over 1.5 h to a solution of 1,2-diaminoethane (6 mL, 90 mmol) in DCM (95 mL) cooled at 0° C. The solution was stirred for 2 h at 0° C., then the solution was washed with brine (40 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:30][C:31]([NH:33][CH2:34][C:35]([F:39])([F:38])[CH2:36][OH:37])=[O:32])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:30][C:31](=[O:32])[NH:33][CH2:34][C:35]([F:38])([F:39])[CH2:36][O:37][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:27])([F:28])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: O=C(NCC(F)(F)CO)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COCC(F)(F)CNC(=O)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Reaction time: 0.03 h
Yield: 42.7 %

Procedure:
(S)-1-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(2,2-difluoro-3-hydroxypropyl)urea (12 mg, 0.027 mmol), prepared as described in Procedures 3, 5, 6, 7 and 8, in THF (0.5 mL) was added NaH (4 mg, 60% in mineral oil, 0.1 mmol). After 2 min, tert-butyl 2-bromoacetate (6 mg, 0.04 mmol) was added. The reaction mixture was stirred for 15 min, filtered and concentrated in vacuo. The residue was purified by preparative HPLC Shimadzu-Phenomenex Luna C18 column, 21.2×100 mm eluting with 10-90% CH3CN (90% in H2O, 0.1% TFA) gradient over 15 min with flow rate 20 mL/min and UV detection at 220 nm to give (S)-tert-butyl 2-(3-(3-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)ureido)-2,2-difluoropropoxy)acetate as a white solid (8 mg, 43% yield). LCMS RT=4.12 min, [M+H] 694.35 (LCMS Method 1) NMR: 500 MHz 1H (CDCl3) 8.25 ppm, 1H, m; 7.67 ppm, 1H, m; 7.50 ppm, 1H, m; 7.17 ppm, 1H, d; 7.06 ppm, 6H, m; 6.89 ppm, 1H, m; 6.61 ppm, 2H, m; 5.87 ppm, 1H, t; 4.35 ppm, 1H, d; 4.07 ppm, 1H, d; 3.95 ppm, 1H, d; 3.88 ppm, 1H, m; 3.74 ppm, 2H, m; 3.55 ppm, 2H, m; 1.42 ppm, 9H, m.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH:12]([CH3:20])[C:13](=O)[CH2:14][C:15]([O:17][CH3:18])=[O:16]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:18][O:17][C:15](=[O:16])[CH2:14][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[O:7][C:12]=1[CH3:20]
Reactant: NC(=O)c1ccc(F)cc1
Reactant: COC(=O)CC(=O)C(C)Br
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)Cc1nc(-c2ccc(F)cc2)oc1C
Temperature: 25 °C
Yield: 25.7 %

Procedure:
A solution of 667 mg (4.80 mmol) of 4-fluorobenzamide and 1.0 g (4.80 mmol) of methyl 4-bromo-3-oxo-pentanoate in 6 mL of dry toluene was heated at 120° C. for 16 h. The resulting dark slurry was cooled to RT, diluted with 10 mL of EtOAc, and washed with NaHCO3 (1×10 mL). The organic layer was separated, dried (MgSO4), and the solvents removed in vacuo. Purification of the material by silica gel flash column chromatography using hexane/EtOAc 4/1 as eluent to afford 308 mg of the title compound as a clear oil: 1H NMR (CDCl3, 400 MHz) δ 7.97 (m, 2H), 7.11 (m, 2H), 3.73 (s, 3H), 3.56 (s, 2H), 2.36 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][NH:9][C:10]([C:11]3[CH:12]=[C:13](C=CC=3)C#N)=[C:6]2[C:5](=[O:19])[N:4]([CH3:20])[C:3]1=[O:21].I[C:23]1C=C[N:25](C)[N:24]=1>>[CH3:1][N:2]1[C:7]2=[CH:8][NH:9][C:10]([C:11]3[CH:12]=[CH:13][N:24]([CH3:23])[N:25]=3)=[C:6]2[C:5](=[O:19])[N:4]([CH3:20])[C:3]1=[O:21]
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)[nH]cc2n(C)c1=O
Reactant: Cn1ccc(I)n1
Product: Cn1ccc(-c2[nH]cc3c2c(=O)n(C)c(=O)n3C)n1

Procedure:
The title compound was prepared by a similar method to 3-(1,3-Dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Example 9.0 Step 4), replacing 3-bromobenzonitrile with 3-iodo-1-methyl-1H-pyrazole in Step 3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:29]([O:31]CC)=[O:30])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:34][CH3:35])=[CH:7][CH:6]=2.[ClH:36]>ClCCl.CO>[ClH:1].[ClH:36].[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:29]([OH:31])=[O:30])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:34][CH3:35])=[CH:7][CH:6]=2
Reactant: CCOC(=O)C1(CCCc2c(Cl)cnc3ccc(OC)cc23)CCN(CCSC2CCCC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2ncc(Cl)c(CCCC3(C(=O)O)CCN(CCSC4CCCC4)CC3)c2c1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 0.55 g of ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]-piperidine-4-carboxylate in 8 cm3 of aqueous 6 N hydrochloric acid was heated at a temperature in the region of 100° C., with stirring and under an inert atmosphere, for 5 hours. After stirring for 18 hours at a temperature in the region of 20° C., the solution obtained was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The evaporation residue obtained was taken up in 10 cm3 of a mixture of dichloromethane/methanol (90/10 by volume) and then concentrated under the same conditions as above. 0.59 g of 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-4-carboxylic acid dihydrochloride was obtained in the form of a foam melting at 129° C. with softening.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1)=[O:31]
Reactant: CSc1nc2ccc(Oc3ccnc4ccccc34)cc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Oc3ccnc4ccccc34)cc2s1
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 74.1 %

Procedure:
The reaction mixture of 2-(methylthio)-6-(quinolin-4-yloxy)benzo[d]thiazole (460 mg, 1.415 mmol) was dissolved in 8 ml of DCM and cooled to −5° C. A solution was made of 77% MCPBA (333 mg, 1.486 mmol) and 6 ml of DCM. This solution was added to above cooled reaction mixture dropwise over 3-4 minutes. The reaction was stirred at −5° C. for 10 minutes, stirred at RT. for 90 minutes. The reaction followed by LC indicated 95% completed and stalled. A new solution was made of 77% MCPBA (25 mg, 0.1132 mmol) and 1 ml of DCM. This solution was added to above RT. reaction mixture dropwise. The reaction was stirred for 90 minutes more with LC indicating the reaction was complete. The reaction was worked up by adding 80 ml of DCM and 25 ml of a 10% sodium thiosulfate solution and stirred at RT. for 10 minutes. Aqueous layer was extracted and the DCM layer was washed with 25 ml of saturated NaHCO3, 2×25 ml 5% NaHCO3 solution, 1×25 ml water, 1×25 ml saturated NaCl, dried with sodium sulfate. About 1 gram of Silica gel was added and stirred for 10 minutes. The mixture was filtered and concentrated in vacuo to give 2-(methylsulfinyl)-6-(quinolin-4-yloxy)benzo[d]thiazole as solid (357 mg). ES/MS m/z 341.0 (MH+).