Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C@@H:13](O)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.P(Br)(Br)[Br:19].Br>>[Br:19][C@@H:13]([C:5]1[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1)[CH3:14]
Reactant: C[C@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: BrP(Br)Br
Agent: Br
Product: C[C@@H](Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 20.5 °C
Reaction time: 0.5 h
Yield: 187.8 %

Procedure:
Under argon atmosphere, (S)-[3,5-bis(trifluoromethyl)phenyl]ethanol (1) (300 g, 1.16 mol, 96% ee) was added dropwise with phosphorous tribromide (157.3 g, 0.58 mol) at a temperature lower than 20° C. on a water bath, and the mixture was stirred at 19 to 22° C. for 30 minutes. The reaction mixture was cooled, and added dropwise with hydrogen bromide (30% solution in acetic acid, 228 mL, 1.16 mol) at a temperature lower than 0° C., and the mixture was stirred at 13 to 15° C. for 16 hours. The reaction mixture was poured into ice water, and the mixture was extracted with n-hexane (3 L×2). The organic layers were combined, successively washed with saturated aqueous sodium hydrogencarbonate (3 L), and saturated brine (3 L), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure (90 to 100 mmHg) to obtain 389.2 g of a crude product. The resulting crude product was purified by column chromatography (silica gel: 900 g, developing solvent: n-hexane) to obtain 349.8 g of (R)-1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane (2) as colorless oil (yield: 93.8%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([C@H:12]1[CH2:16][C@@H:15]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([Cl:27])=[N:21][C:22]=3Cl)[CH:14]=[CH:13]1)[C:8](=[O:11])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[CH3:29][CH2:30][CH:31]([NH2:34])[CH2:32][CH3:33]>C1COCC1>[C:1]([O:5][C:6](=[O:28])[N:7]([C@H:12]1[CH2:16][C@@H:15]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([Cl:27])=[N:21][C:22]=3[NH:34][CH:31]([CH2:32][CH3:33])[CH2:30][CH3:29])[CH:14]=[CH:13]1)[C:8](=[O:11])[CH2:9][CH3:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Reactant: CCC(N)CC
Solvent: C1CCOC1
Product: CCC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(NC(CC)CC)nc(Cl)nc32)C1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
[(1S,4R)-4-(2,6-Dichloro-purin-9-yl)-cyclopent-2-enyl]-propionyl-carbamic acid tert-butyl ester (700 mg, 1.64 mmol) is dissolved in THF (15 mL) under an atmosphere of argon. 3-Pentylamine (315 mg, 3.61 mmol) is added and the reaction mixture is stirred at 50° C. The reaction is shown to be complete by LCMS after 18 hours. The reaction mixture is partitioned between DCM (50 mL) and 0.1 M HCl (50 mL). The organic layer is washed with water (20 mL) and brine (20 mL), dried over MgSO4, filtered and the solvent is removed in vacuo to give the title compound.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([N:19]=[C:20]=[O:21])(=[O:18])=[O:17])=[CH:8][CH:9]=1)([O:3][CH3:4])=[O:2].[NH2:22][C:23]1[N:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[N:24]=1.C1N2CCN(CC2)C1>C(#N)C>[C:1]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([NH:19][C:20]([NH:22][C:23]2[N:24]=[C:25]([O:31][CH3:32])[CH:26]=[C:27]([O:29][CH3:30])[N:28]=2)=[O:21])(=[O:17])=[O:18])=[CH:8][CH:9]=1)([O:3][CH3:4])=[O:2]
Reactant: COc1cc(OC)nc(N)n1
Reactant: COC(=O)c1ccc(-c2ccccc2S(=O)(=O)N=C=O)o1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: COC(=O)c1ccc(-c2ccccc2S(=O)(=O)NC(=O)Nc2nc(OC)cc(OC)n2)o1
Reaction time: 8 h
Yield: 93.2 %

Procedure:
Under a nitrogen atmosphere, a mixture of 2.5 g of the product of Example 3, 0.9 g of 2-amino-4,6-dimethoxypyrimidine, and a few crystals of DABCO in 15 ml of dry acetonitrile was heated at 50°-55° for 1 hour, then stirred at 25° overnight. The solid was filtered off, washed with acetonitrile and 1-chlorobutane, and dried at 60° in vacuo to give 2.5 g of the title compound, mp=215°-217°(d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:24][O:25][C:26](=[O:29])[CH2:27]Br>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH3:24][O:25][C:26](=[O:29])[CH2:27][O:22][C:18]1[CH:17]=[C:16]([C:10]([OH:15])([C:11]([F:14])([F:13])[F:12])[CH:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH3:23])[CH:21]=[CH:20][N:19]=1
Reactant: CC(c1ccc(Cl)cc1Cl)C(O)(c1cc[nH]c(=O)c1)C(F)(F)F
Reactant: COC(=O)CBr
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)COc1cc(C(O)(C(C)c2ccc(Cl)cc2Cl)C(F)(F)F)ccn1
Temperature: 145 °C
Reaction time: 3.5 h

Procedure:
4-[2-(2,4-Dichloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1H-pyridin-2-one (Example 119, 158 mg) was dissolved in toluene (5 mL), and treated with bromo-acetic acid methyl ester (0.03 mL) and silver carbonate (53 mg). The reaction mixture was then stirred at 145° C. (Bath-temperature) for 3.5 h, cooled down to r.t., filtered-off and concentrated in vacuo. The residue was purified by flash chromatography (10 g silica gel, ethyl acetate/heptane 1:9) to give the title compound as colorless oil (30 mg). MS (m/e)=438.3 (MH+).
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:16]([F:17])=[C:15]([F:18])[C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][C:10]=2[CH:11]=[O:12])[CH2:3]1.I[C:29]1[CH:34]=[N:33][CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC#N.O>[CH3:8][CH:6]1[O:7][CH:2]([CH3:1])[CH2:3][N:4]([C:9]2[C:16]([F:17])=[C:15]([F:18])[C:14]([C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)=[CH:13][C:10]=2[CH:11]=[O:12])[CH2:5]1
Reactant: CC1CN(c2c(C=O)cc(B3OC(C)(C)C(C)(C)O3)c(F)c2F)CC(C)O1
Reactant: Ic1cnccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC1CN(c2c(C=O)cc(-c3cnccn3)c(F)c2F)CC(C)O1
Temperature: 85 °C
Yield: 68 %

Procedure:
2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (16 grams, 41 mmol), 2-iodopyrazine (Aldrich, 6 grams, 29.1 mmol), sodium carbonate (9.3 grams, 87 mmol) and Pd(PPh3)2Cl2 (Aldrich, 0.82 gram, 1.2 mmol) were suspended in a 1:1 mixture of CH3CN/H2O. The reaction mixture was then purged with nitrogen and heated at 85° C. overnight. Upon completion the reaction was partitioned between H2O and ethyl acetate and the aqueous layer was extracted twice with ethyl acetate. The combined extracts were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography eluting with 5-40% ethyl acetate in hexanes to obtain 6.6 grams of the desired product. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19 (d, J=6.2 Hz, 6H), 3.09 (m, 4H), 3.84 (m, 1H), 8.28 (dd, J=8.1, 2.1 Hz, 1H), 8.53 (d, J=2.5 Hz, 1H), 8.66 (dd, J=2.4, 1.7 Hz, 1H), 9.01 (s, 1 H), 10.22 (s, 1H); MS(APCl+) m/z 334 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3](C(OCC(C)C)=O)[C:4]2[C:5]([N:21]=1)=[N:6][CH:7]=[C:8]([C:10]1[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][NH:16][CH2:15][C:14]=3[CH:20]=1)[CH:9]=2.Cl[C:30]1[C:39]2[CH2:38][C:37]([CH3:41])([CH3:40])[CH2:36][CH2:35][C:34]=2[N:33]=[C:32]([CH2:42][NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[N:31]=1>>[CH3:40][C:37]1([CH3:41])[CH2:36][CH2:35][C:34]2[N:33]=[C:32]([CH2:42][NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[N:31]=[C:30]([N:16]3[CH2:15][C:14]4[CH:20]=[C:10]([C:8]5[CH:9]=[C:4]6[NH:3][C:2]([CH3:1])=[N:21][C:5]6=[N:6][CH:7]=5)[CH:11]=[CH:12][C:13]=4[O:19][CH2:18][CH2:17]3)[C:39]=2[CH2:38]1
Reactant: CC1(C)CCc2nc(CNS(C)(=O)=O)nc(Cl)c2C1
Reactant: Cc1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2n1C(=O)OCC(C)C
Product: Cc1nc2ncc(-c3ccc4c(c3)CN(c3nc(CNS(C)(=O)=O)nc5c3CC(C)(C)CC5)CCO4)cc2[nH]1

Procedure:
Prepared by the method of example 6 using 2-methylpropyl 2-methyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate and N-((4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)methyl)methanesulfonamide (reagent preparation 17) in step 3. 1H NMR (400 MHz, DMSO-d6) δ 8.52 (br s, 1H), 8.05 (br s, 1H), 7.74 (d, 1H), 7.56 (dd, 1H), 7.27 (t, 1H), 7.06 (d, 1H), 4.68 (s, 2H), 4.37-4.31 (m, 2H), 4.12 (d, 2H), 3.93-3.87 (m, 2H), 2.85 (s, 3H), 2.71 (t, 2H), 2.54 (s, 3H), 2.47 (s, 2H), 1.60 (t, 2H), 0.85 (s, 6H); MS (EI) for C28H33N7O3S: 548 (MH+).
Reaction SMILES: [NH:1]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]1.[CH:16]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[C:18]([C:24]([CH2:26]Br)=[O:25])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:23][C:19]1[CH:20]=[C:21]([Cl:22])[CH:16]=[CH:17][C:18]=1[C:24](=[O:25])[CH2:26][N:1]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]1
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(C(=O)OCC)n(CC(=O)c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5 g (23.6 mmol) of diethyl 1H-pyrazole-3,5-dicarboxylate were dissolved in 100 ml of acetone, and 6.3 g (23.6 mmol) of 2-bromo-2,4-dichloroacetophenone and 3.6 g (26 mmol) of potassium carbonate were added. The mixture was stirred at RT for 12 h. The reaction mixture was concentrated and the residue was taken up in water and dichloromethane. The organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated on a rotary evaporator. The residue was triturated with diethyl ether, and the solid was filtered off with suction. This gave 9.48 g (94% of theory) of the product as a solid.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=1.[K+].[C:25]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH-:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>>[C:25]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:38][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:3]=2)(=[O:36])=[O:37])=[CH:31][CH:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1Cl
Reactant: CC(C)(C)c1ccc(S([NH-])(=O)=O)cc1
Agent: [K+]
Product: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide was prepared as disclosed in EP 0 526 708 A1 from 4,6-dichloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine and p-tert.-butyl benzene sulfonamide potassium salt. LC-MS: tR=5.50 min, [M+1]+=526.29, [M−1]−=524.43.
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:10])[CH2:6][CH2:7][CH:8]=[O:9])(=[O:3])[CH3:2].[Cl-].[CH3:12][NH2+]C.C=O>>[C:1]([O:4][CH:5]([CH3:10])[CH2:6][C:7](=[CH2:12])[CH:8]=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)CCC=O
Reactant: C[NH2+]C
Agent: C=O
Agent: [Cl-]
Product: C=C(C=O)CC(C)OC(C)=O
Yield: 93.9 %

Procedure:
18.0 g (124.8 mmol) of 4-acetoxypentanal, 11.5 g (140.7 mmol) of dimethylammonium chloride and 11.0 ml (146 mmol) of a 37% solution of formaldehyde are stirred for 1 hour at a bath temperature of 110° C. The reaction mixture is allowed to cool and then extracted three times with CH2Cl2. The combined organic phases are dried over MgSO4, filtered and concentrated by evaporation, giving 18.3 g of 4-acetoxy-2-methylene-pentanal as a colourless oil which is further reacted without purification.
Reaction SMILES: [F:1][C:2]1[C:30]([F:31])=[C:29]([F:32])[CH:28]=[CH:27][C:3]=1[NH:4][C:5](=[C:16]([C:22](OCC)=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.CCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[OH:23][C:22]1[C:27]2[C:3](=[C:2]([F:1])[C:30]([F:31])=[C:29]([F:32])[CH:28]=2)[N:4]=[C:5]([S:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(C(=O)OCC)=C(Nc1ccc(F)c(F)c1F)SCc1ccc(OC)cc1
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c(SCc2ccc(OC)cc2)nc2c(F)c(F)c(F)cc2c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.1 %

Procedure:
A solution of diethyl [(2,3,4-trifluoroanilino)(p-methoxybenzylthio)methylene]malonate (80.9 g) in diphenyl ether (60 ml) heated at 110° C. was added dropwise to diphenyl ether (210 ml) kept at 250° to 260° C. with stirring under nitrogen stream over a period of 15 minutes. After the reaction mixture was further stirred at the same temperature for 5 minutes, the mixture was cooled to room temperature and added to hexane (3000 ml). The resulting precipitate was filtered to give the title compound (59.9 g), which was recrystallized from ethyl acetate to give yellow crystals, m.p. 174°-176° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:22]=1[CH3:23])[N:19]1[C:24]([CH:27]([CH:29]4[CH2:31][CH2:30]4)O)=[N:25][N:26]=[C:18]1[C:17](=[O:32])[NH:16]3)=[O:12])[CH2:6][CH2:5]2.ClCCl.C(N(S(F)(F)[F:42])CC)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:22]=1[CH3:23])[N:19]1[C:24]([CH:27]([CH:29]4[CH2:31][CH2:30]4)[F:42])=[N:25][N:26]=[C:18]1[C:17](=[O:32])[NH:16]3)=[O:12])[CH2:6][CH2:5]2
Reactant: Cc1cc2c(cc1C(=O)N1CCc3cc(Cl)ccc31)[nH]c(=O)c1nnc(C(O)C3CC3)n12
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(cc1C(=O)N1CCc3cc(Cl)ccc31)[nH]c(=O)c1nnc(C(F)C3CC3)n12
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A mixed solution of 60 mg of 7-[(5-chloro-2,3-dihydro-1H-indol-1-yl)carbonyl]-1-[cyclopropyl(hydroxy)methyl]-8-methyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one and 3 mL of dichloromethane was cooled to −70° C., and 100 μL of N,N-diethylaminosulfur trifluoride was added thereto, followed by slowly warming to −20° C. over 4 hours. The reaction liquid was returned to room temperature and stirred overnight. To the mixed liquid were added a saturated aqueous sodium hydrogen carbonate solution and chloroform, followed by extraction with chloroform, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 97/3). To the obtained solid was added 4 mL of methanol, followed by warming and washing. The precipitate was collected by filtration and dried under reduced pressure to obtain 31 mg of 7-[(5-chloro-2,3-dihydro-1H-indol-1-yl)carbonyl]-1-[cyclopropyl(fluoro)methyl]-8-methyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one as a white solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][CH2:11][C:12]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][CH2:13]1.[CH2:20]([N:27]=[C:28]=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH2:20]([NH:27][C:28](=[O:29])[NH:10][CH2:11][C:12]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][CH2:13]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCOC(=O)C1(CN)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1(CNC(=O)NCc2ccccc2)CC1
Yield: 95.7 %

Procedure:
According to the procedure described in the synthesis method of Compound V-1 with the modification that the reaction solvent was changed to CH2Cl2 and DIPEA (1.6 ml, 9.3 mmol) was added, ethyl 1-(aminomethyl)cyclopropanecarboxylate (880 mg, 6.2 mmol) was reacted with benzyl isocyanate (1.15 ml, 8.0 mmol) to obtain the title compound (1.64 g, 106%).
Reaction SMILES: [CH2:1]([CH:5]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([CH2:15][C:16]([OH:18])=O)[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][C:25]1([C:33](=[O:34])[NH:32][C:31](=[O:35])[NH:30]1)[CH2:24]2.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([CH:5]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([CH2:15][C:16]([NH:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[CH2:26][C:25]2([C:33](=[O:34])[NH:32][C:31](=[O:35])[NH:30]2)[CH2:24]3)=[O:18])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1Sc2ccccc2N(CC(=O)O)C1=O
Reactant: Nc1ccc2c(c1)CC1(C2)NC(=O)NC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC1Sc2ccccc2N(CC(=O)Nc2ccc3c(c2)CC2(C3)NC(=O)NC2=O)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(2-butyl-3-oxo-2H-benzo[b][1,4]thiazin-4(3H)-yl)acetic acid (0.2 mmol, 56 mg), 5′-amino-1′,3′-dihydrospiro[imidazolidine-4,2′-indene]-2,5-dione (0.2 mmol, 43 mg) and DIPEA (0.6 mmol, 104.5 μl) in DMF (1 ml) was added HATU (0.2 mmol, 76 mg) and the reaction mixture was stirred at room temperature for 16 h. Purification by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) gave the title compound. LC/MS (10% to 99%): M/Z (M+H)+ (obs)=479.2; tR=3.18. H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.55 (d, 1H), 7.42 (q, 1H), 7.25-7.33 (m, 2H), 7.16 (d, 1H), 7.07-7.15 (m, 2H), 4.86 (d, 1H), 4.60 (d, 1H), 3.59 (t, 1H), 3.27-3.34 (m, 2H), 2.97-3.04 (m, 2H), 1.6 (m, 1H), 1.24-1.28 (m, 5H), 0.83 (t, 3H).
Reaction SMILES: [Br:1]C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.[CH:23]1([C:26]2[C:27]([NH:35][C@@H:36]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH2:38][C@@H:37]3[OH:45])=[N:28][C:29]([CH:32]3[CH2:34][CH2:33]3)=[CH:30][N:31]=2)[CH2:25][CH2:24]1>>[Br:1][C:30]1[N:31]=[C:26]([CH:23]2[CH2:24][CH2:25]2)[C:27]([NH:35][C@H:36]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38][C@@H:37]2[OH:45])=[N:28][C:29]=1[CH:32]1[CH2:33][CH2:34]1
Reactant: O[C@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)cnc1C1CC1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: O[C@H]1Cc2ccccc2[C@@H]1Nc1nc(C2CC2)c(Br)nc1C1CC1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting (1R,2S)-1-[(3,6-dicyclopropylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.89–1.03, 1.27–1.30, 1.71–1.75, 2.36–2.39, 3.05–3.09, 3.25–3.30, 4.72–4.75, 5.45–5.46, 7.26–7.33; MS (ESI+) for C19H20BrN3O m/z 386 (M+H)+.
Reaction SMILES: [Cl:1]OC(C)(C)C.[CH2:7]([S:13][CH2:14][CH:15]=[CH2:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(Cl)Cl>[CH2:7]([S:13][CH:14]=[CH:15][CH2:16][Cl:1])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC(C)(C)OCl
Reactant: C=CCSCCCCCC
Solvent: ClCCl
Product: CCCCCCSC=CCCl
Temperature: 25 °C

Procedure:
Tert-butyl hypochlorite (2.06 g, 19.0 mmol) is added dropwise at -50° to a solution of 3-hexylthio-1-propene (3.0 g, 19.0 mmol) in 20 ml of methylene chloride. The mixture is allowed to warm to RT and is then stripped of solvent to give 3-hexylthio-2-propenyl chloride.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:21])[C:4]=2[CH:3]=1.[SH:22][CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[OH:25][CH2:24][CH2:23][S:22][C:2]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:21])[C:4]=2[CH:3]=1
Reactant: O=C1c2ccc(F)cc2C(=O)c2cc3ccccc3cc21
Reactant: OCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1c2ccc(SCCO)cc2C(=O)c2cc3ccccc3cc21

Procedure:
1 g (3.62 mmol) of 2-fluoronaphthacene-5,12-dione (prepared according to U.S. Pat. No. 4,522,754), 0.31 g (3.98 mmol) of 2-mercaptoethanol, 1.50 g (10.86 mmol) of potassium carbonate and 10 ml of DMSO are stirred at 25° C. for 3 minutes. The mixture is poured into water. The crystals are filtered off and dissolved in tetrahydrofuran/toluene, the solution dried over sodium sulfate and evaporated. The residue is recrystallized from THF/toluene/pentane. Yield 1 g (83%); melting point 195°-196° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:17]=[C:16]([CH3:18])[S:15][C:10]=2[NH:11][C:12](=[O:14])[N:13]=1.[H-].[Na+].[CH3:21]I.O>CN(C)C=O>[CH3:21][N:11]1[C:10]2[S:15][C:16]([CH3:18])=[CH:17][C:9]=2[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:13][C:12]1=[O:14]
Reactant: CI
Reactant: Cc1cc2c(-c3ccccc3F)nc(=O)[nH]c2s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(-c3ccccc3F)nc(=O)n(C)c2s1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 12.4 g of 4-(o-fluorophenyl)-6-methyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one in 248 ml of dimethylformamide is added 2.58 g of 67% sodium hydride. After stirring at 50°C for 1 hour and cooling to room temperature, 20.45 g of methyl iodide in 61.4 ml of dimethylformamide is added dropwise thereto. The mixture is stirred at room temperature for 1 hour, then poured into water and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel using chloroform as an eluent to give 1-methyl-4-(o-fluorophenyl)-6-methyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one as crystals having a melting point of 119° - 121°C (after recrystallization from chloroform-ethanol), and 3-methyl-4-(o-fluorophenyl)-6-methyl-3H-thieno[2,3-d]pyrimidin-2-one as crystals having a melting point of 239° - 241°C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Cl>C(OCC)C.[BH4-].[Zn+2].[BH4-]>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:27])([F:28])[CH:24]([F:25])[F:26])[CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1ccc(Cl)nc1
Agent: Cl
Agent: [BH4-]
Agent: [Zn+2]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Cl)nc1
Reaction time: 0.33 h

Procedure:
While stirring zinc chloride (10.8 g, 79.0 mmol) in diethyl ether (50 ml), sodium borohydride (5.98 g, 158 mmol) was added at room temperature, and the mixture was stirred as it was for 2 hrs. The insoluble material in the mixture was removed by filtration and washed with diethyl ether to give a solution of zinc borohydride in diethyl ether. To the obtained solution was added a solution of ethyl 3-(6-chloropyridin-3-yl)-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate (17.14 g, 39.51 mmol) in diethyl ether (50 ml) under ice-cooling, and the mixture was stirred as it was for 20 min. To the reaction solution was added dilute hydrochloric acid by small portions to decompose excess zinc borohydride, and the mixture was extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1-2/1) to give the objective substance.