Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[CH:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:3]1[CH3:9].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[N:20]=[C:19]([C:30](Cl)=[O:31])[CH:18]=2)=[CH:13][CH:12]=1>>[ClH:10].[CH3:9][CH:3]1[CH2:4][CH2:5][CH2:6][CH:7]([CH3:8])[N:2]1[NH:1][C:30]([C:19]1[CH:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][CH:15]=2)[N:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[N:20]=1)=[O:31]
Reactant: O=C(Cl)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1
Reactant: CC1CCCC(C)N1N
Product: CC1CCCC(C)N1NC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1
Product: Cl

Procedure:
This compound is prepared by the procedure described in EXAMPLE 1 starting from 1-amino-2,6-dimethylpiperidine and 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)pyrazole-3-carboxylic acid chloride. M.p.=195° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=O)=O)[CH:5]=[C:4](Br)[N:3]=1.[Na+].[I-:20].[IH:21]>O>[I:20][C:2]1[CH:7]=[C:6]([S:8][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH:5]=[C:4]([I:21])[N:3]=1
Reactant: I
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: O
Product: Nc1ccc(Sc2cc(I)nc(I)c2)cc1
Yield: 42 %

Procedure:
0.52 g (0.00133 Mol) 4-(2,6-Dibromo-pyridine-4-sulfonyl)-phenylamine and 0.45 g (0.003 Mol) NaI were stirred in aqueous HI (10 ml) at 120° C. for 5 h. Then the reaction mixture was diluted with water, extracted with ethyl acetate, the organic phase was washed with sat. bicarbonate and brine, dried over MgSO4 and evaporated. After chromatography on SiO2 with ethyl acetate hexane 1:3 and drying in a high vacuum it was obtained 0.255 g (42%) 4-(2,6-diiodo-pyridin-4-ylsulfanyl)-phenylamine as a brown solid; mp.: 175-176° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>>[F:11][C:9]1[C:8]([F:12])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([O:20][C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[CH:10]=1
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Reactant: Oc1ccc(F)cc1
Product: O=C(O)c1cc(F)c(F)cc1Oc1ccc(F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 66 from 2-chloro-4,5-difluorobenzoic acid and 4-fluorophenol: MS (ESI) m/z 222 (M−H)−.
Reaction SMILES: [BrH:1].[C:2]([O:5][CH2:6][C:7]1([CH2:29][O:30][C:31](=[O:33])[CH3:32])[O:16][CH:11](OC(=O)C)[C@H:10]([O:17][C:18](=[O:20])[CH3:19])[C@@H:9]([O:21][C:22](=[O:24])[CH3:23])[C@H:8]1[O:25][C:26](=[O:28])[CH3:27])(=[O:4])[CH3:3]>C(O)(=O)C>[C:2]([O:5][CH2:6][C:7]1([CH2:29][O:30][C:31](=[O:33])[CH3:32])[O:16][C@@H:11]([Br:1])[C@H:10]([O:17][C:18](=[O:20])[CH3:19])[C@@H:9]([O:21][C:22](=[O:24])[CH3:23])[C@H:8]1[O:25][C:26](=[O:28])[CH3:27])(=[O:4])[CH3:3]
Reactant: Br
Reactant: CC(=O)OCC1(COC(C)=O)OC(OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OCC1(COC(C)=O)O[C@@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Glacial acetic acid (60 ml) is saturated with dry gaseous HBr for 30 minutes at 18°-20° C. This solution is mixed with 5-C-acetoxymethyl-1,2,3,4,6-penta-O-acetyl-L-arabino-hexopyranose (7) (6.0 g, 0.013 ml) and is stirred at an ambient temperature for 3.5 hours. Workup of the reaction mixture involves: dilution with methylene chloride (150 ml), washing with ice-water, sat. sodium bicarbonate solution, and water again. After drying the methylene chloride solution with sodium sulfate (anhydrous), evaporation of the solvent produces crude 5-C-acetoxymethyl-2,3,4,6-tetra-O-acetyl-α-L-arabino-hexopyranosyl bromide (18) (3 g) which is dried under high vacuum for 30 minutes and is used for the glycosidation reactions without further purification.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH2:16])[C:5]2[N:6]([N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:7]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:25][CH:26]=[C:27]([C:2]2[N:3]=[C:4]([NH2:16])[C:5]3[N:6]([N:8]=[C:9]([C:11]4[O:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH:7]=2)[CH2:28][CH2:29]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Nc1nc(Br)cn2nc(-c3ccco3)nc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cn3nc(-c4ccco4)nc3c(N)n2)CC1
Temperature: 80 °C
Yield: 47.1 %

Procedure:
A mixture of 6-bromo-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine (112 mg, 0.4 mmol; see Examples 1 and 2), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (185 mg, 0.6 mmol; see Eastwood, P. Tetrahedron Letters 41:3705-3708 (2000) for its preparation), Pd(PPh3)3 (28 mg, 0.024 mmol), and aqueous Na2CO3 (2 M, 1 mL) in DMF (4 mL) was heated (at approximately 80° C.) for 16 hours. The reaction was filtered and then purified by HPLC (C18, H2O:MeCN gradient) to afford 4-(8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (72 mg, 47%). 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 2.47 (br. s, 2H), 3.54 (t, j=6.2 Hz, 2H), 4.05 (br. s, 2H), 6.7 (br. s, 1H), 6.7 (dd, J=3.3, 1.7 Hz, 1H), 7.12 (dd, J=3.5, 0.7 Hz, 1H), 7.91 (dd, J=1.7, 0.7 Hz, 1H), 8.18 (s, 1H). MS. m/z 383 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.COC1C=C(OC)C=CC=1CN(C1SN=CN=1)[S:24]([C:27]1[CH:36]=[CH:35][C:30]2[NH:31][C:32](=[O:34])[O:33][C:29]=2[CH:28]=1)(=[O:26])=[O:25]>C1COCC1>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:8][CH:9]=[CH:10][N:11]=1)[S:24]([C:27]1[CH:36]=[CH:35][C:30]2[NH:31][C:32](=[O:34])[O:33][C:29]=2[CH:28]=1)(=[O:26])=[O:25]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3[nH]c(=O)oc3c2)c(OC)c1
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3[nH]c(=O)oc3c2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 41-2 (2.79 g, 11.13 mmol) in THF (71 mL) was cooled to −78° C. Lithium hexamethyldisilizane (LHMDS, 21.4 ml, 21.4 mmol, 1.0M in THF) was added and the reaction was allowed to warm to RT and stir for 30 minutes. Commercially-available, solid 1-5 (4 g, 17.12 mmol) was then added in portions, maintaining the temperature of the reaction mixture at −78° C. The reaction was allowed to slowly warm to RT. After reaching RT, the reaction was quenched with saturated ammonium chloride solution at 0° C. and extracted into EtOAc (3×150 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by normal phase chromatography (0-60% EtOAc in hexane) yielded 41-3 as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])/[C:4](/[CH3:10])=[CH:5]\[C:6]([O:8][CH3:9])=[O:7].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:1][O:2][C:3](=[O:11])/[C:4](/[CH2:10][Br:12])=[CH:5]/[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)/C=C(/C)C(=O)OC
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)/C=C(\CBr)C(=O)OC
Temperature: 25 °C
Reaction time: 36 h
Yield: 85.5 %

Procedure:
To a solution of (Z)-2-methyl-2-butenedioic acid dimethyl ester (15.3 g) in carbon tetrachloride (300 ml) were added N-bromosuccinimide (25.8 g) and 2,2′-azobis(isobutyronitrile) (319 mg), and the mixture was stirred for 36 hours at reflux. After cooling the mixture to room temperature, the insoluble substance was filtered off, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 18/1) to give the titled compound (19.6 g).
Reaction SMILES: [CH3:1][N:2]1CCC[CH2:3]1.C=C([O:10][C:11](=O)[NH:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[C:18]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[C:26]([NH:31][C:32]([NH:34][CH2:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:33])[CH:25]=3)[C:19]([CH3:23])=[N:20]2)=[CH:15][N:14]=1)C.Cl.CNC>O1CCOCC1>[CH3:39][C:37]([CH3:38])([CH3:40])[CH2:36][CH2:35][NH:34][C:32](=[O:33])[NH:31][C:26]1[CH:25]=[C:24]([C:18]2[C:19]([CH3:23])=[N:20][C:21]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:12][C:11](=[O:10])[N:2]([CH3:3])[CH3:1])[CH:22]=3)[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: C=C(C)OC(=O)Nc1cc2nc(C)c(-c3ccc(F)c(NC(=O)NCCC(C)(C)C)c3)cc2cn1
Reactant: CN1CCCC1
Agent: CNC
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2cc(NC(=O)N(C)C)ncc2cc1-c1ccc(F)c(NC(=O)NCCC(C)(C)C)c1
Temperature: 60 °C
Yield: 50.9 %

Procedure:
Add 1-methylpyrrolidine (0.355 mL, 3.34 mmol) to a suspension of prop-1-en-2-yl(3-(3-(3-(3,3-dimethylbutyl)ureido)-4-fluorophenyl)-2-methyl-1,6-naphthyridin-7-yl)carbamate (0.2 g, 0.417 mmol) and dimethylamine hydrochloride (0.136 g, 1.668 mmol) in dioxane (4 mL) and heat at 60° C. overnight. Cool to RT, add satd. NaHCO3, extract with EtOAc (3×), dry the combined organics over MgSO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford 3-(3-(3-(3-(3,3-dimethylbutyl)ureido)-4-fluorophenyl)-2-methyl-1,6-naphthyridin-7-yl)-1,1-dimethylurea (99 mg, 51%). MS(ESI) m/z: 467.3 (M+H+). Treat the solid with MeCN (2 mL), add 0.1N HCl (2.33 mL, 0.233 mmol), freeze, lyophilize and dry to afford the title compound (76 mg, 71%). 1H NMR (400 MHz, DMSO-d6): δ 9.52 (s, 1H), 9.30 (s, 1H), 8.64 (s, 1H), 8.50 (s, 1H), 8.41 (s, 1H), 8.32 (dd, J=7.9, 2.4 Hz, 1H), 7.35 (dd, J=11.3, 8.4 Hz, 1H), 7.07 (m, 1H), 6.66 (m, 1H), 3.08 (m, 2H), 3.00 (s, 6H), 2.70 (s, 3H), 1.34 (m, 2H), 0.88 (s, 9H); MS(ESI) m/z: 467.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:26](I)[CH3:27]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:26][CH3:27])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCI
Reactant: COC(=O)c1cc(Cl)cc(NC2CCCCC2)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCN(c1cc(Cl)cc(C(=O)OC)c1C)C1CCCCC1
Temperature: 80 °C
Yield: 18.8 %

Procedure:
To a stirred solution of methyl 5-chloro-3-(cyclohexylamino)-2-methylbenzoate (1.2 g, 4.3 mmol) in dry DMF (15 mL), cesium carbonate (2.78 g, 8.5 mmol) and ethyl iodide (3.35 g, 21.47 mmol) were added. The resulting reaction mixture was heated at 80° C. for 18 h. On completion, the reaction mixture was cooled to room temperature and filtered, and the residue washed with ethyl acetate. The filtrate was concentrated and purified by column chromatography to afford methyl 5-chloro-3-(cyclohexyl(ethyl)amino)-2-methylbenzoate (0.25 g, 22.7%).
Reaction SMILES: [Br-].[CH2:2]([N+:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[C:11]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=2)[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+]>C(O)C>[CH2:2]([N:9]1[CH2:10][C:11]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:36])([F:37])[F:38])[CH:26]=2)=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH2:13][CH2:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccccc1-c1cc[n+](Cc2ccccc2)cc1COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccccc1C1=C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN(Cc2ccccc2)CC1
Temperature: 35 °C
Yield: 55 %

Procedure:
A solution of 1-benzyl-3-(3,5-bis-trifluoromethyl-benzyloxymethyl)-4-o-tolyl-pyridinium bromide (163 mg, 0.273 mmol) in 6 ml of ethanol was added sodium borohydride (10 mg, 0.26 mmol) at 0° C. The mixture was heated to 35° C. and stirred at this temperature over night. Another portion of sodium borohydride (10 mg, 0.26 mmol) was added and the mixture was heated to 50° C. for 2 h. After cooling to room temperature and quenching with water the mixture was diluted with a saturated aqueous solution of sodium carbonated and extracted with three portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 78 mg (55%) of the title compound as a light yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([C:21]2[C:26]([CH3:27])=[C:25]([C:28]#[N:29])[C:24]([NH:30]C(=O)C(F)(F)F)=[C:23]([O:37][CH3:38])[C:22]=2[F:39])[CH:18]=[CH:19][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[NH2:30][C:24]1[C:23]([O:37][CH3:38])=[C:22]([F:39])[C:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:16]=2)=[C:26]([CH3:27])[C:25]=1[C:28]#[N:29]
Reactant: COc1c(F)c(-c2cccc(OCc3ccccc3)c2)c(C)c(C#N)c1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1c(N)c(C#N)c(C)c(-c2cccc(OCc3ccccc3)c2)c1F
Temperature: 70 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
Aqueous potassium carbonate solution (20% w/v, 6.07 ml), methanol (12.1 ml) were added to N-(3′-benzyloxy-5-cyano-2-fluoro-3-methoxy-6-methylbiphenyl-4-yl)-2,2,2-trifluoroacetamide (I-53) (400 mg, 873 μmol), followed by stirring overnight at 70° C. After cooling, methanol was evaporated away under reduced pressure, saturated brine (50 ml) was added, the product was extracted with ethyl acetate (50 ml×2). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to obtain the entitled compound (276 mg, 87%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([CH:23]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([CH:16]=[CH:17][C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1)=[O:8].[H][H]>CO.[Pd].S([O-])([O-])(=O)=O.[Ba+2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([CH:23]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1ccc(C=CC(=O)O)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(CCC(=O)O)cc1

Procedure:
7.19 g. 4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-cinnamic acid are hydrogenated in methanol, with the use of 1 g. palladium/barium sulphate, at ambient temperature. After taking up 1 mol hydrogen/mol of starting material, the hydrogenation is discontinued and the solution is filtered, evaporated and the residue recrystallised from isopropanol/water. There are obtained 6.14 g. (about 85% of theory) β-{4-[2-(5-chloro-2-methoxybanzamido)-ethyl]-phenyl}-propionic acid; m.p. 118°- 120° C.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1)#N.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=1.[Mg].[Cl-].[NH4+].S(=O)(=O)(O)[OH:25]>CCOCC>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:1]([C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][N:4]=2)=[O:25])=[CH:16][CH:15]=1
Reactant: O=S(=O)(O)O
Reactant: Clc1ccc(Br)cc1
Reactant: N#Cc1nccc2ccccc12
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: O=C(c1ccc(Cl)cc1)c1nccc2ccccc12
Reaction time: 2 h
Yield: 76.6 %

Procedure:
To a solution of 3.1 g (20 millimoles) of 1-cyano-isoquinoline in anhydrous ether a Grignard reagent prepared from 5.75 g (30 millimoles) of 4-chloro-bromobenzene and 0.735 g (30 millimoles) of magnesium metal is added. The reaction mixture is allowed to stand for a night, thereafter the complex is decomposed with ammonium chloride solution, acidified with a 20% sulfuric acid and allowed to stand for 2 hours. After neutralization the ether phase is separated and the solvent is distilled off. 4.1 g (76.6%) of 1-(4-chlorobenzoyl)-isoquinoline are obtained.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:7][N:8]=1.[CH2:17]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1)/[CH:18]=[C:19](/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])\[CH3:20].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[CH2:17]([O:27][C:28]1[CH:29]=[CH:30][C:31]([C:32]([NH:3][C:4]2[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:7][N:8]=2)=[O:33])=[CH:35][CH:36]=1)/[CH:18]=[C:19](/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])\[CH3:20]
Reactant: CCN(CC)CCSc1nnc(N)s1
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCSc1nnc(NC(=O)c2ccc(OC/C=C(\C)CCC=C(C)C)cc2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.7 %

Procedure:
Sodium hydride (0.4 g) and 2-amino-5-diethylaminoethylthio-1,3,4-thiadiazole (1.4 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes while being cooled with ice. 4-Geranyloxybenzoic acid (1.6 g) and carbonyldiimidazole (1.1 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. The mixture was stirred for 4 hours at room temperature, and then concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 2.5 g of the aimed compound.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]3)=[N:9][CH:8]=[N:7][C:6]=2[NH:5][CH:4]=1.CCN(C(C)C)C(C)C.[CH3:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>C(Cl)Cl>[CH3:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]([NH:18][CH:15]1[CH2:16][CH2:17][N:12]([C:10]2[C:11]3[C:3]([CH3:2])=[CH:4][NH:5][C:6]=3[N:7]=[CH:8][N:9]=2)[CH2:13][CH2:14]1)=[O:32]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Cc1c[nH]c2ncnc(N3CCC(N)CC3)c12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1C(=O)NC1CCN(c2ncnc3[nH]cc(C)c23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine hydrochloride D11 (70 mg) and DIPEA (0.11 mL, 0.605 mmol) in DCM (1 mL) was added 2-methylbenzoyl chloride (70.2 mg, 0.454 mmol) and the reaction stirred at room temperature for 18 hours. The solvent was removed in vacuo and the mixture purified by MDAP to give the title compound E26 (25 mg) as a pale pink solid, 1H NMR (d6-DMSO) 11.55 (1H, brs), 8.26 (1H, d), 8.21 (1H, s), 7.30 (2H, m), 7.25 (2H, m), 7.06 (1H, s), 4.0 (3H, m), 3.06 (2H, t), 2.35 (3H, s), 2.35 (3H, s), 1.94 (2H, m), 1.67 (2H, m), MS(ES+) 350 [M+H]+.
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20]C)[CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)(Cl)Cl>[C:1]([N:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(C2CCCN2C(=O)c2ccccc2)c1
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)N1CCCC1c1cccc(O)c1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
To a solution of 1-benzoyl-2-(3-methoxyphenyl)pyrrolidine (1.0 g) in chloroform (40 ml) was added boron tribromide (99%, 1.0 ml) at -10° C., under nitrogen. The cooling bath was removed after 15 rains, and the reaction mixture was allowed to warm to ambient temperature. Crushed ice was added to the reaction mixture followed by 5:1-chloroform/2-propanol. The layers were separated, and the aqueous phase was extracted with 5:1-chloroform/2-propanol (2 times). The combined organic extracts were washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was crystallized from dichloromethane/petroleum ether to give 0.89 g (94%) of product. Recrystallization from 2-propanol/methanol gave the analytical sample, mp 167°-169° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:37])[CH2:11][N:12]2[N:18]=[C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=3[N:14]([CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:13]2=[O:36])[CH:6]=[CH:7][CH:8]=1.[NH2:38][C:39]([NH2:41])=[S:40].[Na+].[I-]>CC(C)=O>[C:39]([S:40][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:37])[CH2:11][N:12]2[N:18]=[C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=3[N:14]([CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:13]2=[O:36])[CH:6]=[CH:7][CH:8]=1)(=[NH:38])[NH2:41]
Reactant: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)Nc2cccc(CCl)c2)N=C(C2CCCCC2)c2ccccc21
Reactant: NC(N)=S
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)Nc2cccc(CSC(=N)N)c2)N=C(C2CCCCC2)c2ccccc21

Procedure:
N-(3-Chloromethyl-phenyl)-2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetamide (Example 49, step a) (52 mg, 0.0 mmol) was reacted with thiourea (7.6 mg, 0.0 mmol) and NaI (2 mg) in refluxing acetone (10 ml) for 3 h. After cooling, the solvents were concentrated in vacuo, affording the title compound as a yellow solid after trituration with Et2O (18 mg, 30%). 1H NMR (DMSO-d6) 9.89 (1H, br s), 8.99 (3H, br s), 7.75-7.46 (3H, m), 7.29-7.04 (5H, m), 4.77 (2H, m), 4.40 (2H, m), 4.38 (1H, m), 3.93 (1H, m), 2.86 (1H, m), 1.73-1.64 (6H, m), 1.21-1.08 (13H, m).
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([CH2:9][CH:10](O)C)[CH2:3]1.[Cl:13]N>>[ClH:13].[Cl:13][CH2:10][CH2:9][N:4]1[CH2:3][CH:2]([CH3:1])[O:7][CH:6]([CH3:8])[CH2:5]1
Reactant: CC(O)CN1CC(C)OC(C)C1
Reactant: NCl
Product: CC1CN(CCCl)CC(C)O1
Product: Cl

Procedure:
An amount, 389.3 grams, of 2,6-dimethyl-N-(2-hydroxypropyl) morpholine (2.25 moles) was condensed with the free chloroamine obtained from 481.5 grams N-chloroethyl-2,6-dimethylmorpholine hydrochloride (2.25 moles) as described above to give 415.9 grams (58.8%) of the catalyst, bp 127°-129° C. at 0.3 mm of Hg. The structure was confirmed as that of the title compound by elemental analysis, calc. 64.9 C, 10.9 H, 8.9 N; found 64.4 C, 10.6 H, 8.9 N.