Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:8]([O:21][CH2:22][CH2:23][OH:24])=[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[CH:6]=1)C.[CH3:36][NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH3:36][N:37]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:4](=[O:3])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)[C:8]([O:21][CH2:22][CH2:23][OH:24])=[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=2)[CH:6]=1
Reactant: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: CNCCCCCCCCc1ccccc1
Product: CN(CCCCCCCCc1ccccc1)C(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
N-methyl-N-(8-phenyloctyl)-3,5-bis(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzamide was prepared as a white solid (0.238 g, 67%) from 3,5-bis-(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzoic acid ethyl ester and N-methyl-N-(8-phenyloctyl)amine using a procedure similar to step 2 of Example 175. 1H NMR (CDCl3) δ7.94 (s, 2H); 7.84 (d, 2H); 7.68-7.56 (m, 4H); 7.44 (s, 2H); 7.30-7.12 (m, 5H); 3.24 (t, 2H); 3.52 and 3.33 (2bt, 2H); 3.40 (t, 2H); 3.08 (2s, 3H); 2.58 (bt, 2H); 1.60 (m, 4H); 1.42-1.12 (m, 8H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].C[Al](C)C.C[O:9][C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([NH:18][C:19](=[O:38])[CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]34[CH2:37][CH:32]5[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]5)[CH2:29]3)[CH2:35]4)=[CH:24][CH:23]=2)[CH:12]=1.Cl>C1(C)C=CC=CC=1>[C:28]12([C:25]3[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:19]([NH:18][C:13]4[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=4[OH:17])[C:10]([N:2]([CH3:3])[CH3:1])=[O:9])=[O:38])=[CH:23][CH:24]=3)[CH2:35][CH:34]3[CH2:33][CH:32]([CH2:31][CH:30]([CH2:36]3)[CH2:29]1)[CH2:37]2
Reactant: CNC
Reactant: COC(=O)c1ccc(O)c(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CN(C)C(=O)c1ccc(O)c(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 33.1 %

Procedure:
Dimethyl amine (0.06 ml, 0.12 mmol) in anhydrous toluene 2 ml was treated with trimethyl aluminium (in 2.0 M Hexane, 0.15 ml, 0.31 mmol) under nitrogen. After 0.25 h, It was added 3-[2-(4-adamantan-1-yl-phenoxy)acetylamino]-4-hydroxy-benzoic acid methyl ester (30.1 mg, 0.07 mmol) in toluene 4 ml. The mixture was stirred for 3 h at 80° C. After cooling, the reaction mixture was treated with diluted HCl until no foaming more. The reaction mixture was separated with ethyl acetate and sodium bicarbonate. The organic phase was washed by brine, dried (MgSO4 anh), and concentrated. The residue was purified by preparative TLC(Hexane:EtoAC:MeOH=15:3:1) to give 3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-4-hydroxy-N,N-dimethyl-benzamide as a white solid (10.4 mg, 23.2% yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:15](=[O:28])[C:14]([C:29]#[N:30])=[C:13]2[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>N1C=CC=CC=1>[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[C:15](=[O:28])[C:14]([C:29]#[N:30])=[C:13]2[N:31]1[CH2:36][CH2:35][N:34]([C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:33][CH2:32]1
Reactant: N#Cc1c(N2CCNCC2)c2cc(F)ccc2n(Cc2ccc(F)cc2)c1=O
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccncc1
Product: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)ccc2n(Cc2ccc(F)cc2)c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
2-Furoyl chloride (148 μL, 1.5 mmol) was added to a stirred solution of Compound 49 (380 mg, 1 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethylacetate to yield 282 mg (85%) of white solids. M.P. 248° C. 1H NMR (DMSO-d6): δ 3.68 (m, 4H), 3.96 (m, 4H), 5.47 (s, 2H), 6.66 (dd, J=1.6, 3.6 Hz, 1H), 7.08 (d, J=3.4 Hz, 1H), 7.15 (m, 2H), 7.28 (m, 2H), 7.47 (dd, J=4.7, 9.6 Hz, 1H), 7.55 (m, 1H), 7.69 (dd, J=2.8, 9.7 Hz, 1H), 7.88 (s, 1H). EIMS m/z 497 (M+23). Anal. (C26H20FN4O3) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:14][C:15]1[N:20]=[C:19]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:18]([C:34]([F:37])([F:36])[F:35])=[CH:17][N:16]=1.C=O.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10][N:11]([CH3:40])[CH2:12][CH2:13]2)[CH:5]=[CH:4][C:3]=1[NH:14][C:15]1[N:20]=[C:19]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:18]([C:34]([F:37])([F:35])[F:36])=[CH:17][N:16]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2C)ncc1C(F)(F)F
Agent: C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C)CC3)cc2C)ncc1C(F)(F)F

Procedure:
Methyl 2-(2-(2-(2-((2-methyl-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (54) (1.10 g, 2.15 mmol) was dissolved in dry MeOH (20 mL) and formaldehyde solution (37% aq; 348 μL, 4.29 mmol) was added. Sodium triacetoxyborohydride (2.27 g, 10.7 mmol) was added under nitrogen and the resultant mixture was stirred at room temperature for 16 hours. Ethyl acetate (50 mL) was added and the mixture was washed with 10% NaHCO3 solution (20 mL). The organic layer was separated, dried (MgSO4) then the volatiles removed by evaporation under reduced pressure. Chromatography (SiO2, 0-50% MeOH/DCM) gave the title compound (I55) (480 mg, 42%) as a cream solid; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.83-7.73 (m, 1H), 7.35 (s, 1H), 7.32-7.19 (m, 3H), 7.19-7.09 (m, 2H), 7.07-6.97 (m, 1H), 3.76 (s, 2H), 3.70 (s, 3H), 3.23 (d, J=11.5 Hz, 2H), 3.17-3.04 (m, 4H), 2.61-2.51 (m, 1H), 2.50 (s, 3H), 2.35 (s, 3H), 2.33-2.24 (m, 2H), 2.02-1.84 (m, 4H). LCMS Method C: rt 5.25 min; m/z 527.2 [M+1]+.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27](#[N:30])[CH:28]=[CH2:29]>>[C:2]1([C:8]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH2:10][N:11]([CH2:29][CH2:28][C:27]#[N:30])[CH2:12][CH2:13]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC#N
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: N#CCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
To a suspension of 4,4-diphenylpiperidine hydrochloride (195 mg, 0.712 mmol, 1.0 equiv) in ETOh (1.5 mL) was added triethylamine (0.25 mL, 1.83 mmol, 2.6 equiv) followed by acrylonitrile (0.13 mL, 2.01 mmol, 2.8 equiv). The resulting solution was stirred at room temperature under argon for 15 minutes and then concentrated. Water was added, and the mixture was extracted three times with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated to give 170 mg (87%) of tan solid, which was used for the next reaction without purification. m.p. 95-96° C.; 1H NMR (300 MHz, CDCl3) δ 2.37 (m, 2H), 2,46 (m, 4H), 2.52 (m, 6H), 7.12 (m, 2H), 7.23 (m, 8H); 13C NMR (75 MHz, CDCl3) δ 16.65, 36.71. 45.08, 50.78, 54.13, 119.70, 126.48, 127.78, 129.11, 147.87; IR (neat) 2944.4, 2821.0, 1495.5, 1445.9 cm-1.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([S:11](Cl)(=[O:13])=[O:12])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl.O>[C:15]([NH:19][S:11]([C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10])(=[O:13])=[O:12])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 2-(acetylamino)-4-methyl-1,3-thiazole-5-sulfonyl chloride (1.0 g) in DCM (10 ml) was added tert-butylamine (0.92 ml) and the mixture was stirred at room temperature for 2 d. The mixture was diluted with H2O and extracted with DCM (×3). The combined organic extracts were dried (MgSO4), filtered and evaporated to give the subtitle compound as a beige foam. Yield 1.1 g.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=1>>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: COc1cccc(OCCCBr)c1
Product: COc1cccc(OCCCOc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3O)cc2)c1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.808 g of 1-(3-bromopropoxy)-3-methoxybenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.30 (1:2 EtOAc-heptane); Rt=5.18.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br.Br[CH2:42][C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1>CN(C=O)C>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:42][C:43]4[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=4)[N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Reactant: BrCc1cccnc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(Cc4cccnc4)c4ccc(OC(F)F)cc34)nc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
In a 25 ml round-bottomed flask, 2-(5-difluoromethoxy-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (120 mg, 0.23 mmol) was dissolved in DMF (1.7 ml). The light yellow solution was cooled to 0° C. and sodium hydride (60% in mineral oil, 37 mg, 0.93 mmol) was added. The reaction was stirred at 0° C. for 15 min then 3-(bromomethyl)pyridine hydrobromide (91 mg, 0.36 mmol) was added. The reaction mixture was stirred at 0° C. for 1 h then quenched with water and diluted with petroleum ether. The suspension was filtered, washed with water and petroleum ether and the product collected was dried under high vacuum to afford 126 mg (90%) of 2-(5-difluoromethoxy-1-pyridin-3-ylmethyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a yellow powder.
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14]>COCCOCCOC>[Cl:10][C:11]1[CH:12]=[C:13]([NH:14][C:3]2[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CSc1nccc(=O)[nH]1
Solvent: COCCOCCOC
Product: O=c1ccnc(Nc2cccc(Cl)c2)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
To 2-(methylthio)pyrimidine-4(3H)-one, 1, (4.88 g, 34.37 mmol) in diglyme (20 mL) is added 3-chloroaniline (4.3 mL, 68.74 mmol). The resulting mixture is heated to reflux and stirred for 18 hours. A solid forms upon cooling the mixture to room temperature. The solid is washed with hexanes to afford 5.0 g (66% yield) of the desired compound. 1H NMR (DMSO-d6, 300 MHz): δ 5.91 (d, J=5.7 Hz, 2H), 7.05 (d, J=7.5 Hz, 1H), 7.11 (br s, 1H), 7.32 (t, J=7.8, 15.9 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.86 (d, J=4.5 Hz, 1H), 7.94 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[C:22](=[O:23])[C:14]3=[CH:15][N:16]4[C:21]([CH2:20][CH2:19][CH2:18][CH2:17]4)=[C:13]3[CH:12]=[N:11]2)[N:5]=[CH:4][CH:3]=1.C([CH:26]1[CH2:31][N:30]([CH:32]2[CH2:35][O:34][CH2:33]2)[CH2:29][CH2:28][N:27]1[C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:43]2[C:44](=[O:59])[N:45]([CH3:58])[CH:46]=[C:47](B3OC(C)(C)C(C)(C)O3)[CH:48]=2)=[N:40][CH:41]=1)C.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>O>[CH3:58][N:45]1[C:44](=[O:59])[C:43]([NH:42][C:39]2[CH:38]=[CH:37][C:36]([N:27]3[CH2:28][CH2:29][N:30]([CH:32]4[CH2:33][O:34][CH2:35]4)[CH2:31][CH2:26]3)=[CH:41][N:40]=2)=[CH:48][C:47]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([N:10]3[C:22](=[O:23])[C:14]4=[CH:15][N:16]5[C:21]([CH2:20][CH2:19][CH2:18][CH2:17]5)=[C:13]4[CH:12]=[N:11]3)[N:5]=[CH:4][CH:3]=2)=[CH:46]1
Reactant: O=Cc1c(Cl)ccnc1-n1ncc2c3n(cc2c1=O)CCCC3
Reactant: CCC1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2ccnc(-n3ncc4c5n(cc4c3=O)CCCC5)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 50 °C
Yield: 40.8 %

Procedure:
A 50-mL round bottomed flask equipped with a reflux condenser was charged with 4-chloro-2-(4-oxo-7,8,9,10-tetrahydropyridazino[4,5-a]indolizin-3(4H)-yl)nicotinaldehyde 192c (118 mg, 0.36 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl-amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 101l (171 mg, 0.36 mmol), Na2CO3 (78 mg, 0.72 mmol), Pd (dppf)Cl2 (30 mg, 0.036 mmol), DMF (10 mL), and water (1 mL). After bubbling nitrogen through the mixture for 30 minutes, it was heated at 50° C. for 10 hours under N2 protection. It was then cooled to room temperature and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 20:1 dichloromethane/methanol to afford 198a (93 mg, 40%) as a brown solid. MS-ESI: [M+H]+ 634.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[F:23]
Reactant: Cc1n[nH]c(=O)c(-c2cccc(F)c2F)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2cccc(F)c2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
3.49 g of 5-(4-chlorophenyl)-4-(2,3-difluorophenyl)-6-methyl-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 3.66 g of 3-chloro-5-(4-chlorophenyl)-4-(2,3-difluorophenyl)-6-methyl pyridazine (hereinafter, referred to as compound (xii) of the present invention).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:32]=[CH:31][C:26]3[O:27][CH2:28][CH2:29][O:30][C:25]=3[CH:24]=2)[CH2:19][CH2:18]1)([O-])=O.[C:33](Cl)(=[O:35])[CH3:34]>C1COCC1>[C:33]([NH:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:32]=[CH:31][C:26]3[O:27][CH2:28][CH2:29][O:30][C:25]=3[CH:24]=2)[CH2:19][CH2:18]1)(=[O:35])[CH3:34]
Reactant: O=[N+]([O-])c1ccc2[nH]cc(CCCCN3CCN(c4ccc5c(c4)OCCO5)CC3)c2c1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2[nH]cc(CCCCN3CCN(c4ccc5c(c4)OCCO5)CC3)c2c1
Reaction time: 2 h

Procedure:
A solution of 4.21 g of 6-[4-(4-(5-aminoindol-3-yl)butyl)piperazino]-1,4-benzodioxane ("C") [obtainable as in Example 5] in 35 ml of THF is treated with a solution of 0.9 g of acetyl chloride in 10 ml of THF, and the mixture is stirred at 50° for 2 hours, evaporated and worked up in the conventional manner. 6-[4-(4-(5-Acetamidoindol-3-yl)butyl)piperazino]-1,4-benzodioxane is obtained.
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:10][C:4]=2[N:3]=1.[Cl-].Cl[CH2:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[CH:22][NH+:21]=1.O>C(O)C.[OH-].[Na+]>[CH3:27][O:26][C:24]1[C:23]([O:28][CH3:29])=[CH:22][N:21]=[C:20]([CH2:19][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]([F:16])([F:14])[F:15])=[CH:10][C:4]=3[N:3]=2)[CH:25]=1
Reactant: COc1c[nH+]c(CCl)cc1OC
Reactant: FC(F)(F)COc1ccc2[nH]c(S)nc2c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cnc(CSc2nc3cc(OCC(F)(F)F)ccc3[nH]2)cc1OC
Reaction time: 20 h

Procedure:
1.0 g of 2-mercapto-5-(2,2,2-trifluoroethoxy)-1H-benzimidazole is dissolved in 15 ml of ethanol and 8.5 ml of 1N sodium hydroxide solution, 0.90 g of 2-chloromethyl-4,5-dimethoxypyridinium chloride are added and the mixture is stirred for 20 hours. After addition of 30 ml of water, the mixture is extracted three times with 30 ml of methylene chloride each time, the methylene chloride phase is washed once with 5 ml of 0.1N sodium hydroxide solution, the combined organic phases are dried over magnesium sulfate and, after the drying agent has been filtered off, the filtrate is completely concentrated. 1.51 g (94% of theory) of the title compound are obtained as an amorphous solid residue of m.p. 55°-57° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[C@@H:7]([NH:23]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>N1CCCCC1.ClCCl>[C:1]([O:5][C:6](=[O:41])[C@@H:7]([NH2:23])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCc2ccccn2)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCc2ccccn2)cc1
Reaction time: 2 h

Procedure:
The product from Example H (3.90 g, 8.42 mmol) was suspended in 50 mL of 20% piperidine in dichloromethane at room temperature with stirring (2 h). The solution was concentrated under reduced pressure and partitioned between ethyl acetate and water (100 mL each) and separated. The organic layer was washed with 5% sodium bicarbonate (2×50 mL), brine (2×50 mL), dried with magnesium sulfate, filtered and concentrated under reduced pressure to an oil. The oil was purified by silica gel chromatography with ethyl acetate and methanol (3:1). Appropriate fractions were combined and concentrated under reduced pressure to a solid (1.34 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Br:11]Br.S(=O)(=O)(O)O>S([O-])([O-])(=O)=O.[Ag+2].O>[Br:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: BrBr
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(Br)c1
Reaction time: 16 h

Procedure:
28.2 g of p-fluoro-nitrobenzene were added to 20° C. to 10.4 ml of bromine and then 20 ml of water followed by 180 ml of concentrated sulfuric acid were added thereto at 0° C. 34 g of silver sulfate were added to the mixture and the temperature was allowed to rise to 20°-25° C. and the mixture was stirred for 16 hours and was poured into water. The mixture was filtered and the filter was washed with water and methylene chloride. The filtrate was extracted with methylene chloride and the organic phase was washed with water, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was dissolved in isopropyl ether and crystallized therefrom. The mixture was filtered and the product was washed to obtain 8.2 g of 3-bromo-4-fluoro-nitrobenzene melting at 59° C. Using the procedure of Example 1, the latter was reacted to obtain 0-(4-nitro-2-bromo-phenyl)-hydroxylamine melting at 122° C.
Reaction SMILES: C[O:2][C:3](=[O:15])[C@@H:4]([OH:14])[CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Li+]>>[CH2:7]([S:6][CH2:5][C@H:4]([OH:14])[C:3]([OH:15])=[O:2])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)[C@@H](O)CSCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)[C@@H](O)CSCc1ccccc1
Yield: 46 %

Procedure:
This reaction was performed as previously described by Deechongkit, S.; You, S.-L.; Kelly, J. W. Org. Lett. 2004, 6, 497, using (R)-3-Benzylsulfanyl-2-hydroxy-propionic acid methyl ester 110b and lithium hydroxide. (R)-3-Benzylsulfanyl-2-hydroxy-propionic acid 110c (3.08 g, 14.51 mmol, 46%) was isolated as a viscous oil: MS calcd. for C10H12O3S (M+Na+) 235.1. found 235.3.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([CH2:16][NH2:17])[OH:15].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:17][CH2:16][CH2:14][OH:15])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: NCCO
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCO)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a chilled solution (−10° C.) of 4-chloro-3-nitrobenzoyl chloride (1.85 g, 8.4 mmol) in anhydrous THF (60 mL) was added dropwise a solution of ethanolamine (0.48 mL, 8.0 mmol) in THF (20 mL) followed by TEA (1.1 mL, 8.0 mmol). After stirring 1 h while temperature was maintained at −10° C., the solution was combined with a 1:1 mixture of ice and satd NaHCO3 (100 mL) and then extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to give 4-chloro-N-(2-hydroxyethyl)-3-nitrobenzamide (1.74 g, 89%) as a white solid, which was used without purification. TLC (3:22 MeOH/DCM Rf 0.36).
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15]1[CH:16]=[C:17]([S:21][CH:22]([C:26](O)=[O:27])[C:23](O)=[O:24])[CH:18]=[CH:19][CH:20]=1>>[OH:27][C:26]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:9][C:23](=[O:24])[C:22]=1[S:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH3:14])[CH:16]=1
Reactant: Cc1cccc(SC(C(=O)O)C(=O)O)c1
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Product: Cc1cccc(Sc2c(O)cc(-c3ccccc3)oc2=O)c1

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g, 10.14 mmol) and diethyl ester of [(3-methylphenyl)thio]propanedioic acid (1.43 g, 5.07 mmol). m.p. 197-198° C.; 1H NMR (400 MHz, DMSO-d6) δ2.24 (s, 3H), 6.89 (s, 1H), 6.93 (t, 1H), 6.97 (s, 1H), 7.14 (t, 2H), 7.56 (m, 3H), 7.86 (m, 2H).