Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[Cl:7][C:8]1[CH:9]=[C:10]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH:14]([CH2:18][NH:19][C:20]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:21])[CH2:13]1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:7][C:8]1[CH:9]=[C:10]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH:14]([CH2:18][NH:19][C:20]([NH:22][CH:23]2[CH2:24][CH2:25][N:26]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:27][CH2:28]2)=[O:21])[CH2:13]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)NC1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCC(NC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)CC1
Temperature: 23 °C
Reaction time: 5 h

Procedure:
Methane sulphonyl chloride (0.009 ml) was added to a solution of Intermediate 16 (0.04 g) and N,N-diisopropylethylamine (0.048 ml) in dichloromethane (3 ml). The solution was stirred for 5 h at 23° C. The solvent was removed in vacuo and the residue was purified by solid phase extraction (Isolute SCX sulphonic acid column) eluting with methanol followed by 10% 0.880 ammonia solution in methanol, to give the title compound as a pale yellow gum (0.034 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([C:15]1O[C:17](/[C:20](/[F:36])=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]3)=[C:24]([O:34][CH3:35])[CH:23]=2)=[N:18][N:19]=1)[C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[C:8]([F:14])[CH:7]=1.C([O-])(=O)C.[NH4+:41].C(OCC)(=O)C.O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[F:36]/[C:20](/[C:17]1[N:41]=[C:15]2[CH:5]([C:6]3[CH:11]=[C:10]([F:12])[C:9]([F:13])=[C:8]([F:14])[CH:7]=3)[CH2:4][CH2:3][CH2:2][N:19]2[N:18]=1)=[CH:21]\[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]2)=[C:24]([O:34][CH3:35])[CH:23]=1
Reactant: COc1cc(/C=C(\F)c2nnc(C(CCCCl)c3cc(F)c(F)c(F)c3)o2)ccc1-n1cnc(C)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C(\F)c2nc3n(n2)CCCC3c2cc(F)c(F)c(F)c2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 130.4 %

Procedure:
A solution of 2-[4-chloro-1-(3,4,5-trifluorophenyl)butyl]-5-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazole (81 mg) and ammonium acetate (358 mg) in acetic acid (2 mL) was stirred at 150° C. for three hours. The reaction solution was left to cool to room temperature. Then, ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=1:1→ethyl acetate) to obtain 98 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [OH:1][CH:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:13]([CH3:29])[O:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:18][C:16]=3[CH:17]=2)=[O:11])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:44])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[OH:1][CH:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N+:31]=1[O-:44])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[CH:13]([CH3:29])[O:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:18][C:16]=3[CH:17]=2)=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccccn4)cc2)C(C)O3)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])cc2)C(C)O3)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 41.6 %

Procedure:
To a solution of N-[4-[hydroxy(2-pyridyl)methyl]-phenyl]-6-(4-methylphenyl)-2-methyl-2H-1-benzopyran-3-carboxamide (300 mg) in tetrahydrofuran (10 ml) was added 3-chloroperbenzoic acid (70%, 0.24 g) at 0° C., and the mixture was stirred at room temperature for 24 hours. To the mixture was added sodium thiosulfate, and the mixture was stirred for a few minutes. was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:2) to give crystals, which were recrystallized from ethanol-ethyl acetate to give N-[4-[hydroxy(1-oxidopyridin-2-yl)-methyl]phenyl]-6-(4-methylphenyl)-2-methyl-2H-1-benzopyran-3-carboxamide (Compound 203) (129 mg) as pale yellow crystals.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:29]1([CH:32]=O)[CH2:31][CH2:30]1>>[CH:29]1([CH2:32][N:26]2[CH2:25][CH2:24][N:23]([CH2:22][C:16]3([C:13]4[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[CH:11][CH:12]=4)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[CH2:28][CH2:27]2)[CH2:31][CH2:30]1
Reactant: O=CC1CC1
Reactant: c1cc(C2(CN3CCNCC3)CCOCC2)ccc1OCCCN1CCCC1
Product: c1cc(C2(CN3CCN(CC4CC4)CC3)CCOCC2)ccc1OCCCN1CCCC1
Yield: 14 %

Procedure:
The title compound (26 mg, 14%) was prepared from 1-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}piperazine and cyclopropane carboxaldehyde similarly to the procedure used for example 54. 1H NMR (400 MHz, CDCl3) δ 0.02 (q, 2H), 0.43 (q, 2H), 0.76 (m, 1H), 1.74-1.76 (m, 4H), 1.83-1.89 (m, 2H), 1.95-1.99 (m, 2H), 2.03-2.06 (m, 3H), 2.13 (d, 2H), 2.19-2.21 (m, 4H), 2.26-2.40 (m, 5H), 2.47-2.51 (m, 4H), 2.59 (t, 2H), 3.49 (t, 2H), 3.68-3.72 (m, 2H), 3.98 (t, 2H), 6.82 (d, 2H), 7.17 (d, 2H). HRMS ESI+ m/z 442.3412 [MH]+.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[N:12]1([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>>[N:11]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH2:2][N:15]1[CH2:14][CH2:13][N:12]([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)[CH2:17][CH2:16]1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: ClCc1nc2cccnc2s1
Solvent: CCN(C(C)C)C(C)C
Product: Oc1ccc(N2CCN(Cc3nc4cccnc4s3)CC2)cc1

Procedure:
The product from Example 38A (150 mg, 0.81 mmol), 4-(1-piperazinyl)phenol (160 mg, 0.98 mmol), and DIEA (280 μL, 1.6 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.73 (m, 4H) 3.02 (m, 4H) 4.03 (s, 2H) 6.72 (m, 4H) 7.56 (dd, J=8.14, 4.75 Hz, 1H) 8.33 (dd, J=8.14, 1.70 Hz, 1H) 8.59 (dd, J=4.58, 1.53 Hz, 1H): (ESI) m/z 327 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:21][CH3:22])[S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>>[CH3:25][N:26]([CH3:28])[CH:27]=[CH:2][C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:21][CH3:22])[S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CCN(c1cccc(C(C)=O)c1)S(=O)(=O)c1ccc(C)cc1
Reactant: COC(OC)N(C)C
Product: CCN(c1cccc(C(=O)C=CN(C)C)c1)S(=O)(=O)c1ccc(C)cc1
Temperature: -10 °C
Reaction time: 18 h

Procedure:
A 31.2 g portion of N-(3-acetylphenyl)-N-ethyl-4-methylbenzenesulfonamide and 50 ml of dimethylformamide dimethylacetal were combined and stirred on a steam bath for 18 hours, then evaporated in vacuo to an oil. This oil was triturated with hexane at -10° C. The hexane was decanted and the residue dissolved in 125 ml of boiling dichloromethane and then filtered. The filtrate was reheated to boiling, 200 ml of hexane was added and the mixture cooled to -10° C. The precipitate was collected, washed with hexane and dried, giving 21.6 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethyl-4-methylbenzenesulfonamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][NH:6][CH2:7][CH2:8][O:9][CH3:10].[C:14]([O:18][C:19](=O)[O:20]C(C)(C)C)([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][N:6]([CH2:7][CH2:8][O:9][CH3:10])[C:19](=[O:20])[O:18][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: COCCNCc1cccc(Br)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCCN(Cc1cccc(Br)c1)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 56.5 %

Procedure:
To a solution of compound 64 (997 mg, 4 mmol) in CH2Cl2 (12 mL), di-tert-butylcarbonate (1.8 g, 8 mmol) was added and the reaction mixture was stirred for 3 hrs (scheme 14). DMAP (cat.) was added to the solution and the reaction mixture was allowed to stir for additional 76 hours. Solvent was removed under reduced pressure and the crude product was purified by column chromatography, eluent EtOAc/hexane (1:10) to afford the title compound 65 (778 mg, 56% yield) as a colorless oil. MS (m/z): 368.1/370.1 (M+Na).
Reaction SMILES: C(C1C=CC2N=C(N[C:16]([NH:18][CH2:19][CH3:20])=[O:17])SC=2C=1)C1C=CC=CC=1.[NH2:23][C:24]1[S:25][C:26]2[CH:32]=[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:30]=[CH:29][C:27]=2[N:28]=1.C(N(CC)CC)C.C(N=C=O)C>C1(C)C=CC=CC=1>[CH2:36]([O:35][C:33]([C:31]1[CH:30]=[CH:29][C:27]2[N:28]=[C:24]([NH:23][C:16]([NH:18][CH2:19][CH3:20])=[O:17])[S:25][C:26]=2[CH:32]=1)=[O:34])[CH3:37]
Reactant: CCNC(=O)Nc1nc2ccc(Cc3ccccc3)cc2s1
Reactant: CCOC(=O)c1ccc2nc(N)sc2c1
Agent: CCN=C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1nc2ccc(C(=O)OCC)cc2s1
Yield: 82 %

Procedure:
According to the General Procedure for 1-(6-substituted-2-benzothiazolyl)-3-ethylurea compounds, and similar to the synthesis of 1-(6-benzyl-2-benzothiazolyl)-3-ethylurea, a mixture of 2-amino-6-ethoxycarbonyl-benzothiazole, triethylamine and ethyl isocyanate in toluene was reacted to give the desired compound 2.40 g (82%). LC/MS 294.0 (M+1); LC retention time 4.29 min.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[N:3]=[CH:2]1.[F:9][C:10]1[N:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13]>>[F:9][C:10]1[N:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([N:3]1[C:4]([C:6]([OH:8])=[O:7])=[CH:5][S:1][CH2:2]1)=[O:13]
Reactant: O=C(O)c1cscn1
Reactant: O=C(O)c1cccnc1F
Product: O=C(O)C1=CSCN1C(=O)c1cccnc1F
Yield: 41.3 %

Procedure:
N-(2-Fluoronicotinoyl)thiazole-4-carboxylic acid is prepared as described in Example 5 from 11.03 g of thiazole-4-carboxylic acid and 11.7 g of 2-fluoronicotinic acid. 8.7 g of N-(2-fluoronicotinoyl)thiazole-4-carboxylic acid are thus obtained in the form of a cream solid. (Rf=0.33; thin layer chromatography on silica gel; eluent: ethyl acetate/acetic acid, 90/10 by volume).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[CH:6]([N:15]3[CH2:20][CH2:19][N:18]([C:21](SC)=[N:22][C:23]#[N:24])[CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3.[O:29]1[C:33]2[CH:34]=[CH:35][C:36]([CH2:38][NH2:39])=[CH:37][C:32]=2[O:31][CH2:30]1>O.C(Cl)Cl>[O:29]1[C:33]2[CH:34]=[CH:35][C:36]([CH2:38][NH:39][C:21]([N:18]3[CH2:19][CH2:20][N:15]([CH:6]4[C:7]5=[N:8][CH:9]=[CH:10][CH:11]=[C:12]5[CH2:13][S:14][C:4]5[CH:3]=[C:2]([Cl:1])[CH:28]=[CH:27][C:5]4=5)[CH2:16][CH2:17]3)=[N:22][C:23]#[N:24])=[CH:37][C:32]=2[O:31][CH2:30]1
Reactant: CSC(=NC#N)N1CCN(C2c3ccc(Cl)cc3SCc3cccnc32)CC1
Reactant: NCc1ccc2c(c1)OCO2
Solvent: O
Solvent: ClCCl
Product: N#CN=C(NCc1ccc2c(c1)OCO2)N1CCN(C2c3ccc(Cl)cc3SCc3cccnc32)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Methyl 4-(8-chloro-5,11-dihydro-[1]benzothiepino[4,3-b]pyridin-11-yl)-N-cyano-1-piperazine-carboximidothioate (184 mg, 0.428 mmol) was combined with 1 ,3-benzodioxol-5-ylmethylamine [piperonylamine] (1.07 ml, 8.56 mmol) in a 10 ml flask, and the mixture was stirred at 100° C. for three hours. The reaction mixture was cooled to room temperature and diluted with water and CH2Cl2. The layers were shaken together and separated, and the aqueous extract was extracted several times with CH2Cl2. The combined organic layers were washed with brine, dried (MgSO4), filtered through `Celite` and concentrated. The residue (over 2 g) was first filtered through a plug of silica gel and eluted with 15%acetone/CH2Cl2), and then further chromatographed more carefully and eluted with 2%EtOH/CH2Cl2, increasing gradually to 40%EtOH/CH2Cl2, to afford the pure product, 155 mg (68%); MS (FAB, M+H)=533.6.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][N:14]([CH2:18][CH2:19][OH:20])CCO)(OCC1C=CC=CC=1)=O.[ClH:21].[CH3:22][OH:23]>>[ClH:21].[OH:20][CH2:19][CH2:18][NH:14][CH2:13][CH2:12][NH:11][CH2:1][CH2:22][OH:23]
Reactant: O=C(NCCN(CCO)CCO)OCc1ccccc1
Reactant: CO
Agent: Cl
Product: OCCNCCNCCO
Reaction time: 16 h

Procedure:
A solution of diol 86 and conc. HCl (1 equiv) in methanol is degassed by bubbling nitrogen through it for 30 min. To this is added 10% palladized charcoal (5 wt. percent). The resulting mixture is shaken on a Parr apparatus under 50 psi of hydrogen gas for 16 h. The mixture is then filtered and the filtrate evaporated. The residue is flushed several times with chloroform to drive off traces of methanol. The crude product is carried on without further purification.
Reaction SMILES: [CH2:1]([Zn]CC)C.C1(C)C=CC=CC=1.ClCI.[CH3:16]/[C:17](=[CH:20]/[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1)[CH3:22])/[CH2:18][OH:19].S(=O)(=O)(O)O>>[CH3:16][C@:17]1([CH2:18][OH:19])[CH2:1][C@H:20]1[C@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1)[CH3:22]
Reactant: C/C(=C/C(C)c1cccc(C)c1)CO
Reactant: CC[Zn]CC
Agent: ClCI
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1cccc([C@H](C)[C@@H]2C[C@]2(C)CO)c1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
Under a nitrogen atmosphere, a diethylzinc solution in toluene (concentration: 15% by weight, 9.4 g, 0.0114 mol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to −15° C. Chloroiodomethane (4.02 g, 22.8 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between −15 and −20° C. After completion of the dropwise addition, the mixture was stirred at −10 to −15° C. for 20 minutes, and then cooled to −25° C. (Z)-2-Methyl-4-(3-methylphenyl)pent-2-en-1-ol (1.09 g, 5.7 mmol) was added dropwise at −20 to −25° C. over a period of 20 minutes. After completion of the dropwise addition, the stirring was continued at −15 to −25° C. for 40 minutes. Next, a 20% aqueous sulfuric acid solution (4.2 ml) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (10 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1). [(1S*,2S*)-1-Methyl-2-((R*)-1-(3-methylphenyl)ethyl)cyclopropyl]methanol (0.83 g, 4.1 mmol, 70% yield) was obtained as the main isomer, and [(1S*,2S*)-1-methyl-2-((S*)-1-(3-methylphenyl)ethyl)cyclopropyl]methanol (0.20 g, 0.99 mmol, 17% yield) was obtained as a minor isomer. The relative configurations of the main isomer and the minor isomer were determined by NOESY measurement.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([C:19]4[CH:27]=[CH:26][C:25]5[C:21](=[CH:22][N:23](COCC[Si](C)(C)C)[N:24]=5)[CH:20]=4)(O)[CH3:17])=[CH:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1.II.O[PH2]=O>C(O)(=O)C>[N:24]1[NH:23][CH:22]=[C:21]2[C:25]=1[CH:26]=[CH:27][C:19]([C@@H:16]([C:13]1[N:11]3[N:12]=[C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[CH:8]=[CH:9][C:10]3=[N:15][CH:14]=1)[CH3:17])=[CH:20]2
Reactant: Cn1cc(-c2ccc3ncc(C(C)(O)c4ccc5nn(COCC[Si](C)(C)C)cc5c4)n3n2)cn1
Agent: II
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: C[C@@H](c1ccc2n[nH]cc2c1)c1cnc2ccc(-c3cnn(C)c3)nn12
Temperature: 150 °C

Procedure:
To a solution of (rac)-1-[6-(1-Methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]-1-[2-(2-trimethylsilanyl-ethoxymethyl)-2H-indazol-5-yl]-ethanol (Stage 195.1, 194 mg, 0.396 mmol) in acetic acid (2.2 mL) were added iodine (201 mg, 0.792 mmol) and H3PO2 (0.436 mL of a 50% aqueous solution, 3.96 mmol). The mixture was then heated to 150° C. for 30 min. After cooling down to rt, the acetic acid was removed in vacuo and the residue was diluted with water and 10% Na2CO3-solution. The precipitate was filtered and washed with water and dried under vacuum overnight to afford the racemate. The mixture was then separated with a Preparative HPLC on a Chiralpak ADOOSC-JF004 (2.5×20 cm) column with a flow of 80 mL/min of n-heptane:EtOH:MeOH 70:25:10 (v/v). Oven 20° C., detection 210 nm (tR 41.3 min) to afford the title compound as a pure enantiomere (tR 3.64 min (conditions 3), MH+=344, 1H-NMR in DMSO-d6: 12.90 (s, 1H); 8.29 (s, 1H); 8.03-7.95 (m, 3H); 7.71 (s, 1H); 7.66 (s, 1H); 7.44-7.33 (m, 3H); 4.73 (q, 1H); 3.87 (s, 3H); 1.77 (d, 3H)).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]>[Pd].O1CCCC1>[NH2:15][C:14]1[C:5]([NH:4][CH2:3][CH2:2][OH:1])=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NCCO
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(N)c1NCCO
Temperature: 25 °C
Reaction time: 24 h
Yield: 0.2 %

Procedure:
A mixture of methyl 2-[(2-hydroxyethyl)amino]-3-nitrobenzoate (10.0 g, 41.6 mmol) and 10% palladium on carbon (0.10 g) in tetrahydrofuran (200 mL) was stirred under hydrogen atmosphere at room temperature for 24 hr. Catalyst was removed by filtration and the filtrate was concentrated in vacuo to give the title compound (36 mg, 0.090 mmol, 90%) as a pale yellow oil. This product was used next steps without purification.
Reaction SMILES: [OH:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[CH:5][C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[N:3]1.[CH3:23][N:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25](Cl)=[O:26]>>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:4]2[CH:5]=[C:6]([C:7]3[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=3)[N:2]([O:1][C:25](=[O:26])[N:24]([CH3:23])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:3]=2)=[CH:16][CH:17]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: COc1ccc(-c2cc(-c3ccc(OC)cc3)n(O)n2)cc1
Product: COc1ccc(-c2cc(-c3ccc(OC)cc3)n(OC(=O)N(C)c3ccccc3)n2)cc1

Procedure:
The title compound was prepared from 1-hydroxy-3,5-bis-(4-methoxyphenyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (29%, beige crystals).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH2:18][S:19][C:20]#[N:21])=[CH:13][CH:12]=1.C(N(CC)CC)C>C(O)C>[CH3:2][O:3][C:4](=[O:9])[CH:5]([NH:6][C:20]1[S:19][CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([Br:10])=[CH:12][CH:13]=2)[N:21]=1)[CH2:7][OH:8]
Reactant: N#CSCC(=O)c1ccc(Br)cc1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)C(CO)Nc1nc(-c2ccc(Br)cc2)cs1
Temperature: 60 °C
Yield: 77 %

Procedure:
Serine methyl ester hydrochloride (1.02 g, 4 mmol) was dissolved in 50 mL of ethanol and 2-(4-bromophenyl)-2-oxoethyl thiocyanate (0.686 g, 4.4 mmol), prepared in step 1 of Example 1, was added followed by triethylamine (0.63 mL, 4.4 mmol). The mixture was heated to 60° C. for 18 h and then cooled and concentrated under reduced pressure. Flash chromatography (1% methanol/chloroform) afforded 1.1 g of 2-[4-(4-bromophenyl)-1,3-thiazol-2-ylamino]-3-hydroxy-propionic acid methyl ester (1.1 g, 79%) as a white solid.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([NH:34][C:35]([NH2:37])=[O:36])=[C:12]([CH2:32][CH3:33])[N:13]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)(C)(C)C.FC(F)(F)C(O)=O>>[CH2:32]([C:12]1[N:13]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:14]2[C:10]([C:11]=1[NH:34][C:35]([NH2:37])=[O:36])=[C:9]([O:8][CH2:7][C:6]([OH:38])=[O:5])[CH:17]=[CH:16][CH:15]=2)[CH3:33]
Reactant: CCc1c(NC(N)=O)c2c(OCC(=O)OC(C)(C)C)cccc2n1Cc1ccccc1-c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1c(NC(N)=O)c2c(OCC(=O)O)cccc2n1Cc1ccccc1-c1ccc(F)cc1
Yield: 56.1 %

Procedure:
[[2-Ethyl-1-(2-(4-fluorophenyl)-phenylmethyl)-3-ureido-1H-indol-4-yl]oxy]acetic acid tert-butyl ester (0.4 g) was treated with 2 mL of trifluoroacetic acid at room temperature. After two hours the excess acid was removed under vacuum, 5 mL of 1N hydrochloric acid added, the mixture extracted with ethyl acetate, which was washed, dried, and concentrated. The residue was treated with 2 mL of 1 N hydrochloric acid and stirred for several hours. The resulting tan solid was isolated by filtration to afford 0.20 g of [[2-ethyl-1-(2-(4-fluorophenyl)-phenylmethyl)-3-ureido-1H-indol-4-yl]oxy]acetic acid. Mass spectrum: 461
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>Cl.O1CCCC1>[CH2:26]([NH:33][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[Cl:1])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cccnc1Cl
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(NCc1ccccc1)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
2-Chloronicotinic acid (25 grams, 158.67 mmol) is placed into a 2L 4-neck round bottom flask equipped with mechanical stirring, thermometer, nitrogen inlet and a rubber septum and is charged with 800 ml of tetrahydrofuran (THF). The reaction is chilled to 0° C. N-methylmorpholine (16.05 grams, 158.67 mmol) is added via syringe. The reaction is chilled to -10° C. and isobutyl chloroformate (21.67 grams, 158.67 mmol) is added to the reaction via syringe while maintaining the temperature at less than 0° C. The reaction is allowed to stir at -10° C. for 30 minutes. Benzylamine (18.70 grams, 174.54 mmol) is then added via syringe while maintaining the temperature below 0° C. The reaction is allowed to slowly warm to room temperature. After stirring for 18 hours IN HCl (300 ml) is added to the reaction. This is then extracted with ethyl acetate (2×350 ml). The organics are combined and washed with 1N HCl (1×300 ml) and 12% sodium hydroxide (2×300 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated to a white paste. The paste is triturated with diethyl ether to yield a solid. This is filtered and washed with diethyl ether (2×65 ml). The filtrates are concentrated and triturated with fresh diethyl ether to yield a second crop of compound which is combined with the first to yield 28.11 grams (71.8%) of N-benzyl-2-chloronicotinamide as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:27](Cl)(Cl)=[S:28].O>C1COCC1>[Cl:1][C:2]1[N:11]2[C:27](=[S:28])[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: Clc1nc(NNc2ccccc2)c2ccccc2n1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: S=c1n(-c2ccccc2)nc2c3ccccc3nc(Cl)n12
Reaction time: 0.08 h

Procedure:
To a mixture of 2-chloro-4-phenylhydrazinoquinazoline (example I) (600 mg, 2.2 mmol) and triethylamine (800 ml, 5.7 mmol) in THF (50 ml) was added thiophosgene (180 ml, 2.3 mmol) slowly and stirred for additional 5 min. The reaction mixture was poured into water and extracted with CH2 Cl2 (3×50 ml). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The residue was triturated with ethanol and the precipitate was filtered to afford 5-chloro-2-phenyl-1,2,4-triazolo[4,3-c]quinazolin-3-thione.