Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[F:9][C:10]([F:14])([F:13])[CH2:11][OH:12].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:12][CH2:11][C:10]([F:14])([F:13])[F:9])[N:5]=[CH:4][N:3]=1
Reactant: OCC(F)(F)F
Reactant: Clc1cc(Cl)ncn1
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)COc1cc(Cl)ncn1
Reaction time: 60 h

Procedure:
4,6-dichloropyrimidine (20 g) potassium carbonate (37 g) and 2,2,2-trifluoroethanol (10.3 cm3) were stirred together at ambient temperature in dry dimethyl formamide (DMF) (130 cm3) for seven hours. The mixture was stored at ambient temperature for 60 hours before being poured into water. The product was extracted with diethyl ether and the organic layer was washed with saturated brine and dried over magnesium sulfate. Evaporation under reduced pressure afforded 4-chloro-6-(2,2,2-trifluoroethoxy)-pyrimidine as a 1:1.5 mixture with residual DMF. 1H NMR (CDCl3): δ4.79-4.89(2H,q); 6.93(1H, s); 8.61(1H,s). This was used directly in step 2.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:15]1[C:28]2[C:27](=[O:29])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:20][C:19]=2[CH:18]=[CH:17][CH:16]=1.[F:30][C:31]([F:44])([F:43])[S:32]([O:35]S(C(F)(F)F)(=O)=O)(=[O:34])=[O:33]>ClCCl>[F:30][C:31]([F:44])([F:43])[S:32]([O-:35])(=[O:34])=[O:33].[C:9]1([S+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[CH:17]=[CH:18][C:19]3[O:20][C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:27](=[O:29])[C:28]=3[CH:15]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(c1ccccc1)c1ccccc1
Reactant: O=c1c2ccccc2oc2ccccc12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)([O-])C(F)(F)F
Product: O=c1c2ccccc2oc2ccc([S+](c3ccccc3)c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
To 320 ml of dichloromethane were dissolved 20.2 g (0.1 mol) of diphenylsulfoxide and 19.6 g (0.1 mol) of xanthene-9-one, and 28.2 g (0.1 mol) of trifluoromethanesulfonic anhydride was added dropwise thereto at −70 to −60° C., followed by gradually warming to room temperature and reacting with stirring for 4 hours. After completion of the reaction, the obtained reaction solution was washed with water (160 ml×4 times) and concentrated under reduced pressure, followed by purifying the obtained crude product with column chromatography to obtain 30.7 g of objective substance as pale brown glassy substance (yield: 58%).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH2:40])[CH:31]=[CH:32][C:33]=1[N:34]1[CH:38]=[N:37][C:36]([CH3:39])=[N:35]1.[CH2:41]([C:48]1[CH:53]=[C:52]([CH3:54])[N:51]=[C:50](Cl)[N:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:41]([C:48]1[CH:53]=[C:52]([CH3:54])[N:51]=[C:50]([NH:40][C:30]2[CH:31]=[CH:32][C:33]([N:34]3[CH:38]=[N:37][C:36]([CH3:39])=[N:35]3)=[C:28]([O:27][CH3:26])[CH:29]=2)[N:49]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: COc1cc(N)ccc1-n1cnc(C)n1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(C)cc(Cc3ccccc3)n2)ccc1-n1cnc(C)n1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 29.8 %

Procedure:
Palladium(II) acetate (5.9 mg, 0.026 mmol) and 2-(dicyclohexylphosphino)biphenyl (19 mg, 0.052 mmol) were dissolved under an atmosphere of nitrogen in dioxane (2 mL). The reaction was stirred for 25 minutes at room temperature. Sodium tert.-butylate (48 mg, 0.49 mmol), 3-methoxy-4-(3-methyl-[1,2,4]triazol-1-yl)-phenylamine (67 mg, 0.33 mmol) dissolved in dioxane (1.5 mL) and 4-benzyl-2-chloro-6-methyl-pyrimidine (79 mg, 0.36 mmol) were added. The reaction was heated three times for 30 minutes to 200° C. in a microwave oven. Water was added and the reaction was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methylenechloride/methanol (19:1 v/v) as eluent to yield the title compound as a yellow gum (38 mg, 30%). MS ISP (m/e): 387.3 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.49 (s, 1H), 7.97 (s, 1H), 7.56 (d, 1H), 7.26-7.33 (m, 5H), 6.98 (d, 1H), 6.51 (s, 1H), 3.97 (s, 2H), 3.83 (s, 3H), 2.48 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15]>O1CCOCC1>[NH3:4].[CH3:15][O:14][CH:13]([O:16][CH3:17])[CH2:12][NH:4][CH2:3][CH2:1][OH:2]
Reactant: COC(CBr)OC
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(CNCCO)OC
Product: N
Yield: 48.5 %

Procedure:
Ethanolamine (4 ml, 66.3 mmol) in dioxane (50 ml) in the presence of potassium carbonate (6.9 g, 50 mmol) was reacted with 2-bromo-1,1-dimethoxyethane (5 ml, 42.3 mmol) at 75° C. for 6 hours. The solid was filtered and washed with dioxane. The recovered organic phase was concentrated and purified by chromatography on silica gel. Elution with dichloromethane followed by increased polarity to dichloromethane:methanol (97:3), dichloromethane:methanolic ammonia (94:6) yielded 2-((2,2-dimethoxyethyl)amino)ethanol (2.4 g, 38% yield) as a pale yellow liquid:
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[N:24][CH:25]=2)[CH2:15][CH2:14]1.[H-].[Na+]>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([NH:26][C:23]2[CH:22]=[CH:21][C:20]([CH2:19][N:16]3[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]3)=[CH:25][N:24]=2)[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1
Reactant: Clc1cc(Br)c2nccn2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc(Nc3cc(Cl)nn4ccnc34)nc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.6 %

Procedure:
A mixture of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (214 mg, 921 μmol, Eq: 0.95) and 5-((4-methylpiperazin-1-yl)methyl)pyridin-2-amine (200 mg, 970 μmol, Eq: 1.00) in DMF (10.0 ml) was cooled to 0° C. To this was added sodium hydride (60% in mineral oil, 124 mg, 3.1 mmol, Eq: 3.2). The reaction was allowed to stir at 0° C. for 10 min and then allowed to warm to room temperature and stirred for 72 h. The reaction was quenched with saturated NaHCO3 (aq) and then diluted with water and EtOAc. The organic layer was separated and the aqueous phase was washed with EtOAc. The organic layers were combined, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in Et2O. The organic layer was washed with water and dried over MgSO4. The drying agent was removed by filtration. The resulting solution was concentrated in vacuo to give (6-chloro-imidazo[1,2-b]pyridazin-8-yl)-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amine (170 mg, 49%) as a solid. LC/MS-ESI observed [M+H]+ 358.
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6](=[O:15])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C(NC(C)C)(C)C.Cl[Si:29]([CH3:32])([CH3:31])[CH3:30]>C1COCC1.C([N-]C(C)C)(C)C.[Li+].O>[CH3:30][Si:29]([CH3:32])([CH3:31])[C:4]1[C:5]2[S:6](=[O:15])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][C:8]=3[Si:29]([CH3:32])([CH3:31])[CH3:30])[S:13][C:14]=2[CH:1]=[CH:2][CH:3]=1
Reactant: O=S1c2ccccc2Sc2ccccc21
Reactant: C[Si](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)c1cccc2c1S(=O)c1c(cccc1[Si](C)(C)C)S2
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.1 %

Procedure:
To a stirred solution of thianthrene-5-oxide (9.40 g, 40.5 mmole) in THF (200 mL), lithium diisopropylamide (prepared by the addition of n-butyl lithium (1.6 M, 64.0 mL, 101 mmole) to a solution of diisopropylamine (14.2 mL, 101 mmole) at −78° C.) in THF (100 mL) was added in portion at −78° C. under inert atmosphere. The reaction mixture was stirred at this temperature for 4 hrs and became dark green. Chlorotrimethylsilane (12.8 mL, 101 mmole) was then added to the cold solution. The solution was then turned into yellowish brown, warmed back to room temperature, and stirred overnight. Water (100 mL) was then added to the reaction mixture to quench the excess base. The solvent was removed and the crude mixture was redissolved in ether. The aqueous layer was extracted by ether and the organic layers were combined. It was further washed by water, brine, and dried with MgSO4. The solvent was then removed in vacuo. The crude product was further purified by column chromatography (hexane/CH2Cl2 4/1, and then 2/1) to afford light yellow crystals (5.50 g, 36%). mp 210˜211° C. (lit. 213˜214° C.). 1H NMR (300 MHz, CDCl3) δ: 7.69 (dd, 2H, J=7.8, 1.5 Hz), 7.60 (dd, 2H, J=7.8, 1.5 Hz), 7.41 (dd, 2H, J=7.8, 7.8 Hz), 0.57 (s, 18H). 13C NMR (125 MHz, CDCl3) δ: 144.1, 140.9, 134.0, 133.8, 129.9, 129.3, 1.55. HR-MS (ESI): calcd. for C18H24OS2Si2+Na 399.0699 [(M+Na)+]. found 399.0690.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[N:6]=[CH:5][N:4]=1.C(N(CCC)CCC)CC.[CH:24]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH2:28][CH2:27][CH2:26][CH2:25]1>N1C=CC=CC=1.C(OCC)(=O)C>[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:31](=[O:32])[CH2:30][CH2:29][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: Nc1ccc2ncnc(N)c2c1
Agent: CCCN(CCC)CCC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Nc1ncnc2ccc(NC(=O)CCC3CCCC3)cc12
Reaction time: 0.33 h
Yield: 49.8 %

Procedure:
A mixture of 4,6-diaminoquinazoline hydrochloride (10 g) and tripropylamine (26.4 g) in dry pyridine (100 ml) was stirred in an ice-bath for 20 minutes. To the mixture was added dropwise during 1.5 hours 3-cyclopentylpropionyl chloride (12.2 g). The mixture was stirred in an ice-bath for 1.5 hours. Crushed ice was added to the reaction mixture. The mixture was stirred for 5 minutes and concentrated under reduced pressure. After addition of water, sodium hydrogen carbonate was added in small portions to the mixture to give precipitates which were separated by filtration, washed with water and dried. The crude crystals were dissolved in a mixture of chloroform and methanol under heating. After the filtration of insoluble materials, the filtrate was treated with activated charcoal and concentrated under reduced pressure to give a residue. The residue was suspended in ethyl acetate. The suspension was stirred for 1 hour under heating and filtered to give crystalline 4-amino-6-(3-cyclopentylpropionamido)quinazoline (7.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]=[S:11].[NH2:12][CH2:13][C:14]([NH2:16])=[O:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[S:11])[NH:12][CH2:13][C:14]([NH2:16])=[O:15]
Reactant: Cc1cccc(Cl)c1N=C=S
Reactant: NCC(N)=O
Product: Cc1cccc(Cl)c1NC(=S)NCC(N)=O

Procedure:
2-[3-(2-Chloro-6-methylphenyl)-thioureido]-acetamide was prepared by the procedure described in Example 2 using 18.3 g of 2-chloro-6-methylphenylisothiocyanate and 12.0 g of glycinamide. 22.8 Grams of the product was obtained, m.p. 161°-163° C. (dec.). This compound was used without further purification in the next paragraph.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C:10](=[CH:11][CH2:12][C@@H:13]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:32])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[C@H:18]([CH3:23])[CH2:19][CH2:20][CH2:21][OH:22])[CH2:9]1.[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].N1C=CN=C1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Si:33]([O:22][CH2:21][CH2:20][CH2:19][C@H:18]([C@@H:17]1[C@:24]2([CH3:32])[C@H:14]([C@H:13]3[C@H:27]([CH2:26][CH2:25]2)[C@:28]2([CH3:31])[C:10]([CH2:9][C@@H:8]([O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[CH2:30][CH2:29]2)=[CH:11][CH2:12]3)[CH2:15][CH2:16]1)[CH3:23])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: C[C@H](CCCO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
Compound 2002 (7.6 g, 17 mmol) in dry CH2Cl2 (300 ml) was treated with a solution of t-butyldimethylsilylchloride (TBDMSCl, 1.0 M) and imidazole (0.5M) in dry CH2Cl2 (38.0 ml, 38.0 mmol TBDMSCl). The solution was stirred at room temperature under argon overnight. The resultant solution was poured into an aqueous saturated NaHCO3 solution and the mixture extracted with CH2Cl2 (3×). The combined organic layers were washed with saturated sodium chloride, dried over anhydrous MgSO4, filtered, and the solvent removed in vacuo. The resultant solid was purified by flash chromatography (SiO2, hexanes:EtOAc gradient from 20:1 to 5:1) giving compound 2003 (9.4 g, 17 mmol, 98%). 1H NMR (500 MHz, CDCl3) δ: 5.38-5.32 (m, 1H, C-6 H), 4.72 (brs, 1H, THP methine H), 3.95-3.88 (m, 1H, THP CH2O), 3.60-3.46 (m, 4H THP CH2O & C-3 H & C-24 H), 1.01 (s, 3H, C-19 H), 0.93 (d, J=6.6 Hz, C-21 H), 0.89 (s, 9H, t-Bu), 0.67 (s, 3H, C-18 H), 0.05 (s, 6H, TBDMS CH3); IR (CHCl3) 2900 cm-1 ; MS (CI/isobutane) m/z 559 (M+1, 1%), 474 (M+1-THP, 12%), 457 (M+1-THPOH, 18%), 343 (M+1-THP-TBDMSOH, 6%), 325 (M+1-THPOH-TBDMSOH, 100%); m.p. 116°-118° C.; Anal. calcd. for C35H62O33 Si: C=75.21, H=11.18; Found: C=75.37, H=11.24.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:28][S:29][CH2:30][CH3:31])[CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH:9]2C(=O)O[C:12](C)([CH3:16])[O:11][C:10]2=[O:18])=[CH:4][CH:3]=1>N1C=CC=CC=1.C(O)C.[Cu]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:28][S:29][CH2:30][CH3:31])[CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:9][C:10]([O:11][CH2:12][CH3:16])=[O:18])=[CH:6][CH:7]=1
Reactant: CCSCc1cccc2c(C(c3ccc(Cl)cc3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CC(c1ccc(Cl)cc1)c1c[nH]c2c(CSCC)cccc12
Yield: 93.7 %

Procedure:
2 mg (0.03 mmol) of copper powder were added to 1.38 g (3.00 mmol) of the compound from Example 14A in 15 ml of pyridine and 5 ml of ethanol. The reaction mixture was heated under reflux for 1 h. It was concentrated, and the residue was taken up in ethyl acetate, washed with 1N hydrochloric acid, dried over magnesium sulfate, filtered through silica gel and concentrated. 1.13 g of the target compound with a purity of 84% (78% of theory) were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([C:18]3([CH2:21][C:22]#N)[CH2:20][CH2:19]3)=[C:8]2[CH3:24])=[CH:4][CH:3]=1.Cl.[OH-:28].[Na+].[CH3:30][OH:31]>>[Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([C:18]3([CH2:21][C:22]([O:31][CH3:30])=[O:28])[CH2:20][CH2:19]3)=[C:8]2[CH3:24])=[CH:4][CH:3]=1
Reactant: CO
Reactant: [OH-]
Reactant: COc1ccc2c(c1)c(C1(CC#N)CC1)c(C)n2Cc1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Product: COC(=O)CC1(c2c(C)n(Cc3ccc(Br)cc3)c3ccc(OC)cc23)CC1
Temperature: 0 °C

Procedure:
To a -5° C. suspension of the nitrile from Step 6 (1.59 g, 3.88 mmol) in 15 mL methanol was added HCl gas to give a saturated solution. The mixture was then heated to reflux overnight, cooled and poured into ice water. The mixture was adjusted to pH 10 with 2.0N NaOH, and then extracted with ethyl acetate. The organic extracts were washed with saturated NaHCO3 and brine, dried over MgSO4 and evaporated. Purification by flash chromatography (15% ethyl acetate/hexanes) provided 1.63 g of the title compound.
Reaction SMILES: [O:1]([CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:27]=[CH:26][C:17]([O:18][C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.C(OCC)(=O)C>CN(C)C=O>[O:1]([CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:27]=[CH:26][C:17]([O:18][C:19]3[CH:20]=[CH:21][C:22]([NH:23][C:35]([NH:34][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:36])=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nc1ccccc1)Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Temperature: 100 °C
Yield: 21 %

Procedure:
A mixture containing 4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline (0.2 g, 0.56 mmol) and phenylisocyanate (0.136 g, 1.12 mmol) in 3 ml of dimethylformamide is heated at 100° C. for two hours. After returning to ambient temperature 20 ml of water and 30 ml of ethyl acetate are added followed by extraction, then the organic phase is washed with a saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and concentrated to dryness under vacuum. The solid obtained is purified on a silica column (eluent: dichloromethane-ethanol-ammonia 96-2-2) in order to obtain a white-coloured powder with a yield of 21%.
Reaction SMILES: [OH-].[Na+].O.Cl.[NH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][SH:8].[C:12](=S)=[S:13].Cl>O>[C:9]([CH:6]1[CH2:7][S:8][C:12](=[S:13])[NH:5]1)([OH:11])=[O:10]
Reactant: S=C=S
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CSC(=S)N1
Reaction time: 24 h
Yield: 26.2 %

Procedure:
Sodium hydroxide (40 g, 1.0 mol), cysteine hydrochloride hydrate (50 g, 0.285 mol) and carbon disulfide (30 g, 0.4 mol) were added in that order to 200 ml water at room temperature. This mixture was stirred for 24 hours. At the end of this period, the reaction mixture was acidified to pH 6 with hydrochloric acid and evaporated to yield a yellow foam. Trituration of this foam with concentrated hydrochloric acid caused crystallization to occur. The white solid thus obtained was recrystallized from 6 N hydrochloric acid to yield 12.2 g (21.2%) of 4-carboxythiazolidine-2-thione, m.p. 183°-184°C with decomposition.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>C(OCC)(=O)C.C1CCCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[C:29]([C:2]2[N:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(Br)nc2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)nc2)CC1
Yield: 65.3 %

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.3.). Starting with 1.28 g (3.43 mmol) of 2-(ethyloxy)-2-oxoethyl 4-(6-bromo-3-pyridyl)-1-piperazinecarboxylate, obtained in step 7.4., 1.96 g (10.29 mmol) of 3-(trifluoromethyl)phenylboronic acid, 2.91 g (13.72 mmol) of hydrated potassium phosphate and 0.40 g (0.34 mmol) of tetrakis(triphenylphosphine)palladium, and after chromatography on silica gel, eluting with a mixture 35/65 of ethyl acetate and cyclohexane, 0.98 g of pure product is obtained in the form of an oil that crystallizes at room temperature.
Reaction SMILES: [CH2:1]([C:3]1([CH2:28][CH3:29])[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[C:13]([N:15]3[CH2:19][CH2:18][C@@H:17]([O:20][CH3:21])[CH2:16]3)[CH:12]=[CH:11][C:10]=2[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:5][CH2:4]1)[CH3:2].[CH:30](=O)[CH2:31][CH2:32][CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[CH2:30]([N:25]1[CH2:24][CH2:23][N:22]([C:10]2[CH:11]=[CH:12][C:13]([N:15]3[CH2:19][CH2:18][C@@H:17]([O:20][CH3:21])[CH2:16]3)=[CH:14][C:9]=2[CH:6]2[CH2:7][CH2:8][C:3]([CH2:1][CH3:2])([CH2:28][CH3:29])[CH2:4][CH2:5]2)[CH2:27][CH2:26]1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCC=O
Reactant: CCC1(CC)CCC(c2cc(N3CC[C@@H](OC)C3)ccc2N2CCNCC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCCN1CCN(c2ccc(N3CC[C@@H](OC)C3)cc2C2CCC(CC)(CC)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a mixture of the crude product of (R)-1-[2-(4,4-diethylcyclohexyl)-4-(3-methoxypyrrolidin-1-yl)phenyl]piperazine produced in Example (98b) (160 mg), butyraldehyde (0.052 mL, 0.584 mmol) and tetrahydrofuran (7 mL) were added sodium triacetoxyborohydride (164 mg, 0.774 mmol) and acetic acid (0.022 mL, 0.384 mmol) in that order, followed by stirring for 1 hour at room temperature. Ethyl acetate and saturated aqueous solution of sodium hydrogencarbonate were added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 170 mg of (R)-1-butyl-4-[2-(4,4-diethylcyclohexyl)-4-(3-methoxypyrrolidin-1-yl)phenyl]piperazine as a light brown oil.
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9]C(C=C)=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.C[N+]1([O-])CC[O:24]CC1.S([O-])([O-])=O.[Na+].[Na+].[CH3:34][C:35]([CH3:37])=[O:36]>O.[Os](=O)(=O)(=O)=O.C(O)(C)(C)C>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:34]([CH:35]([OH:36])[CH2:37][OH:24])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1
Reactant: C=Cc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Reactant: CC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: NC(=O)c1ccc(Br)c2c1[nH]c1cc(C(O)CO)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Step 2 A solution of 4-bromo-7-vinyl-9H-carbazole-1-carboxamide (1.66 g, 4.74 mmol) and 4-methylmopholine N-oxide (0.833 g, 7.11 mmol) in acetone (172 mL) and water (17.2 mL) was treated with osmium tetroxide, 2.5 wt % in tert-butanol (0.238 mL, 0.019 mmol). The mixture was stirred at rt overnight, then was treated with additional 4-methylmorpholine N-oxide (0.8 eq., 0.42 g) and osmium tetroxide solution (0.004 eq., 0.2 mL). The mixture was stirred over a weekend, then was treated with sodium sulfite (2.99 g, 23.70 mmol) and stirred for 30 min. The mixture was filtered through a pad of Celite, and the solids were washed with acetone and THF. The filtrates were concentrated and purified by column chromatography (eluting with a gradient from 70:30 EtOAc-hexane to EtOAc, followed by 95:5 EtOAc-methanol) to afford 4-bromo-7-((RS)-1,2-dihydroxyethyl)-9H-carbazole-1-carboxamide as an off-white solid (1.47 g, 86%). 1H NMR (400 MHz, DMSO-d6) δ 11.45 (1 H, s), 8.33 (1 H, d, J=8.1 Hz), 8.00 (1 H, br. s.), 7.58-7.68 (2 H, m), 7.35 (1H, br. s.), 7.22 (1 H, d, J=8.1 Hz), 7.07 (1 H, d, J=8.4 Hz), 5.14 (1 H, d, J=4.0 Hz), 4.41-4.62 (2 H, m), 3.32 (2 H, t, J=5.7 Hz). Mass spectrum m/z 331, 333 (M+H—H2O)+.