Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]([F:48])([F:47])[C:35]1[CH:36]=[C:37]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:38]=[CH:39][CH:40]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:44]1[CH2:45][CH2:46][N:41]([C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([C:34]([F:33])([F:47])[F:48])[CH:36]=2)[CH2:42][CH2:43]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Product: O=C([C@@H]1C[C@H](NCc2ccc(F)cc2F)CN1Cc1ccccc1)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 11 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(3-trifluoromethyl-phenyl)piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (8.2 mg, 11%) as light yellow oil. MS m/e=559.4 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:38]=[CH:37][C:6]([CH2:7][C@@:8]2([CH3:36])[N:12]3[C:13]([C:16]([NH:18][C@@H:19]([CH2:23][C:24]([NH2:26])=[O:25])[C:20]([OH:22])=O)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=3)[C:9]2=[O:35])=[CH:5][CH:4]=1)#[N:2].Cl.[F:40][C:41]1([F:45])[CH2:44][NH:43][CH2:42]1.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[C:24]([CH2:23][C@H:19]([NH:18][C:16]([C:13]1[N:12]2[C@@:8]([CH2:7][C:6]3[CH:37]=[CH:38][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)([CH3:36])[C:9](=[O:35])[N:10]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=3)[C:11]2=[N:15][CH:14]=1)=[O:17])[C:20]([N:43]1[CH2:44][C:41]([F:45])([F:40])[CH2:42]1)=[O:22])(=[O:25])[NH2:26]
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)N[C@@H](CC(N)=O)C(=O)O)n21
Reactant: FC1(F)CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)N[C@@H](CC(N)=O)C(=O)N3CC(F)(F)C3)n21
Reaction time: 3 h
Yield: 45.3 %

Procedure:
A solution of the resulting intermediate (S)-2-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-succinamic acid (0.039 g, 0.070 mmol) in DMA (0.5 mL) was added to a solution of 3,3-difluoroazetidine hydrochloride (0.014 g, 0.135 mmol) in DMA (0.5 mL). A solution of HOAt (0.015 g, 0.110 mmol) in DMA (0.5 mL) was added to the reaction mixture, followed by HATU (0.04 g, 0.105 mmol) in 0.5 mL DMA. The reaction mixture was agitated on an orbital shaker for 3 h. Diisopropylethylamine (0.036 mL, 0.207 mmol) was added and the resulting solution was agitated on an orbital shaker for 14 h. The volatiles were removed in vacuo at 40° C. and the crude product was dissolved in DMSO (1 mL) and water (0.1 mL) and purified via reverse phase HPLC to afford 0.020 g (45%) of (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid [(S)-1-carbamoylmethyl-2-(3,3-difluoro-azetidin-1-yl)-2-oxo-ethyl]-amide as a white solid, m/z 632.3 [M+1]+.
Reaction SMILES: [CH:1]1[C:2]([C:10]([O:12][CH3:13])=[O:11])=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2>[Pd].CO>[CH:1]1[C:2]([C:10]([O:12][CH3:13])=[O:11])=[CH:3][N:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH2:5]2
Reactant: COC(=O)c1cc2ccccn2c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc2n(c1)CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
A 250-mL round-bottomed flask was purged with nitrogen and charged with 127b (2.0 g, 11.4 mmol), 10% palladium on carbon (50% wet, 200 mg), and methanol (50 mL). It was evacuated, charged with hydrogen gas, and stirred under 5 atm hydrogen at room temperature for 8 h. The hydrogen was then evacuated and nitrogen was charged into the flask. The catalyst was removed by filtration through a pad of CELITE® and the filtrate concentrated under reduced pressure to afford 127c as a white solid (1.1 g, 81%). MS-ESI: [M+H]+ 180.3. 1H NMR (500 MHz, DMSO-d6) δ 7.25 (d, J=2.0 Hz, 1H), 6.09 (s, 1H), 3.93 (t, J=6.0 Hz, 2H), 3.66 (s, 3H), 2.67 (t, J=6.0 Hz, 2H), 1.87-1.83 (m, 2H), 1.75-1.70 (m, 2H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([C@H:15]([NH:17][S:18]([C:21]2[O:25][C:24]([C:26]([O:28]C)=[O:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH3:16])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CC(O)=O>[C:1]([C:9]1[CH:10]=[C:11]([C@H:15]([NH:17][S:18]([C:21]2[O:25][C:24]([C:26]([OH:28])=[O:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH3:16])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)N[C@H](C)c2cccc(C(=O)c3ccccc3)c2)o1
Agent: Cl
Solvent: CC(=O)O
Product: C[C@@H](NS(=O)(=O)c1ccc(C(=O)O)o1)c1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C

Procedure:
To a solution of methyl 5-({[(1R)-1-(3-benzoylphenyl)ethyl]amino}sulfonyl)-2-furoate (0.1 g, 0.24 mmol) in glacial AcOH (10 mL) few drops of 37% HCl were added and the resulting solution was refluxed for 12 h. After cooling at room temperature solvents were evaporated under vacuum, the residue was diluted with a saturated solution of NaHCO3 (10 mL), washed with CHCl3 (2×5 mL), acidified to pH 1 by 37% HCl and extracted again with CHCl3 (2×5 mL). The collected organic extracts were dried over Na2SO4, filtered and evaporated under vacuum to give the pure compound 11 as a waxy solid (0.075 g, 78% yield). [α]D25 (c=0.5, CH2Cl2): −12°; 1H-NMR (CDCl3) δ 7.75 (d, 2H, J=7 Hz), 7.60 (d, 3H, J=7 Hz), 7.50-7.35 (m, 3H), 7.30 (m, 1H), 7.05 (d, 1H, J=7 Hz), 6.85 (d, 1H, J=7 Hz), 5.75 (bs, 1H, NH), 4.78 (q, 1H, J=7 Hz), 4.50 (bs, 1H, COOH), 1.57 (d, 3H, J=7 Hz).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH:14]([CH2:26][OH:27])[CH2:13]1.O>C(Cl)Cl>[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH:14]([CH:26]=[O:27])[CH2:13]1
Reactant: CN1CCC(c2ccc(Cl)c(Cl)c2)C(CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN1CCC(c2ccc(Cl)c(Cl)c2)C(C=O)C1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 111.3 %

Procedure:
To a solution of oxalyl chloride (3.3 mL, 37.9 mmol) in methylene chloride (100 mL) cooled below −40° C. was added dimethyl sulfoxide (5.6 mL, 79 mmol) in methylene chloride (5 mL). The reaction was stirred for another 30 min at −40° C. and 1-methyl-3-hydroxymethyl-4-(3,4-dichlorophenyl)piperidine (9.0 g, 33 mmol) in methylene chloride (100 mL) was added over 15 min while keeping the temperature below −40° C. The reaction was stirred for another 30 min at this temperature and then allowed to heat to room temperature. Water (100 mL) was added and the organic phase separated off. The aqueous phase was extracted with methylene chloride (2×100 mL). The combined organic extracts were dried over magnesium sulphate and evaporated to dryness to give 10 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10](Cl)=[CH:9][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:7][C:6]=12.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][NH2:33])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][NH:33][C:10]2[N:5]3[N:4]=[CH:3][C:2]([Br:1])=[C:6]3[N:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:9]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: Clc1ccccc1-c1cc(Cl)n2ncc(Br)c2n1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc(-c3ccccc3Cl)nc3c(Br)cnn23)CC1
Temperature: 75 °C
Yield: 101.2 %

Procedure:
3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine (300 mg, 0.875 mmoles) (prepared as described in Preparative Example 129) was dissolved in anhydrous 1,4-dioxane (6.8 mL). 4-(aminomethyl)piperidine-1-carboxylic acid tert-butyl ester (225 mg, 1.05 mmoles) and diisopropyl ethylamine (0.3055 mL, 1.75 mmoles) were added and the mixture was heated at 75° C. for 24h. The solution was evaporated to dryness and the residue was chromatographed on a silica gel column (15×5 cm) using dichloromethane as the eluant to give 4-{[3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]methyl}piperidine-1-carboxylic acid tert-butyl ester (461.2 mg, 100%): FABMS: m/z 520.1 (MH+); HRFABMS: m/z 520.1111 (MH+). Calcd. for C23H28N5O2BrCl: m/z 520.1115; δH (CDCl3) 1.30 (2H, m, CH2), 1.51 (9H, s, —COOC(CH3)3), 1.85 (2H, d, CH2), 1.95 (1H, m, CH), 2.76 (2H, m, CH2), 3.40 (2H, m, CH2), 6.37 (1H, s, H6), 6.55 (1H, m, NH), 7.42 (2H, m, Ar—H), 7.52 (1H, m, Ar—H), 7.76 (1H, m, Ar—H) and 8.07 ppm (1H, s, H2); δC (CDCl3) CH3: 28.5, 28.5, 28.5; CH2: 29.1, 29.1, 43.5, 43.5, 47.9; CH: 36.3, 87.5, 127.2, 130.2, 130.3, 131.6, 143.9; C, 79.7, 83.3, 132.1, 138.6, 145.4, 146.3, 154.7, 158.1.
Reaction SMILES: [OH-].[Na+].[N:3]#[C:4][NH2:5].Cl[CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12].C(Cl)Cl>O>[C:4]([N:5]1[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1=[O:12])#[N:3]
Reactant: N#CN
Reactant: O=C(Cl)CCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: N#CN1CCCCC1=O
Temperature: 0 °C

Procedure:
59.4 g (1.484 mols) of sodium hydroxide are dissolved in 370 ml of water, and 13.2 g (0.742 mol) of cyanamide are added in portions to the solution, after cooling to 0° C. 115.0 g (0.742 mol) of δ-chlorovaleric acid chloride are added dropwise to the clear and colourless cyanamide solution, in the course of one hour, at 0° to 8° C.; a strongly exothermic reaction is observed during this dropwise addition and the mixture must therefore be cooled intensively. After the dropwise addition has ended, the mixture is stirred for a further hour at 0° C. 740 ml of methylene chloride are then added and the reaction mixture is warmed at the reflux temperature (40° C.) for one hour. The two phases are separated in a separating funnel. The aqueous phase is extracted again with 740 ml of methylene chloride.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([S:26][CH3:27])=[CH:18]2)=[CH:13][CH:12]=1.O.C(Cl)Cl>CN(C=O)C>[Br:8][C:18]1[N:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[C:25]2[C:20]([C:19]=1[S:26][CH3:27])=[CH:21][CH:22]=[CH:23][CH:24]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(-n2cc(SC)c3ccccc32)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-n2c(Br)c(SC)c3ccccc32)cc1
Temperature: 25 °C
Yield: 66 %

Procedure:
NBS (529 mg, 2.97 mmol) was added to a cooled (0° C.) solution of 1-(4-methoxyphenyl)-3-(methylthio)-1H-indole (800 mg, 2.97 mmol) in 10 ml of DMF. The temperature was allowed to warm to RT and the mixture was stirred at RT for 30 min Water and DCM were added and the phases were separated. After evaporation of the solvents, the residue was purified by flash chromatography with heptane/EtAc 20:1 to provide 2-bromo-1-(4-methoxyphenyl)-3-(methylthio)-1H-indole in 66% yield. ES/MS m/z: 348.04, 350.01 (M+H).
Reaction SMILES: [CH2:1]([Si:3]([CH2:9]C)([CH2:7]C)[CH2:4][CH2:5][SH:6])C.CCN(C(C)C)C(C)C.[C:20]([O:24][C:25]([N:27]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35](Br)=[CH:34][C:33]=2[O:39][CH3:40])[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].OS([O-])(=O)=O.[K+].[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:20]([O:24][C:25]([N:27]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([S:6][CH2:5][CH2:4][Si:3]([CH3:1])([CH3:7])[CH3:9])=[CH:34][C:33]=2[O:39][CH3:40])[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1cc(Br)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Reactant: CC[Si](CC)(CC)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(SCC[Si](C)(C)C)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Yield: 66.1 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (32 mg, 0.03509 mmol), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (40 mg, 0.07017 mmol), 2-(triethylsilyl)ethanethiol (57 μL, 1.403 mmol) and DIPEA (0.257 mL, 2.807 mmol) were added to a solution of 3-(4-bromo-2-methoxy-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.50 g, 1.403 mmol) in 1,4-dioxane (10 mL). The reaction mixture was heated at reflux for 18 hours. The reaction mixture was cooled and a solution of 10% KHSO4/Na2SO4 was added. The resulting mixture was extracted with EtOAc, and the combined organic extracts were washed with water and brine; dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified via flash chromatography (hexane/EtOAc, 95/5) to give 0.380 g (66% yield) of 3-[2-methoxy-4-(2-trimethylsilanyl-ethylsulfanyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a clear oil.
Reaction SMILES: [NH2:1][S:2]([C:5]1[C:6]([Cl:21])=[CH:7][C:8]([NH:14][CH2:15][C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].O1CCOCC1.C(=O)([O-])[O-].[Cs+:32].[Cs+]>O>[NH2:1][S:2]([C:5]1[C:6]([Cl:21])=[CH:7][C:8]([NH:14][CH2:15][C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[C:9]([CH:13]=1)[C:10]([O-:12])=[O:11])(=[O:3])=[O:4].[Cs+:32]
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cc(C(=O)[O-])c(NCc2ccco2)cc1Cl
Yield: 191.3 %

Procedure:
Furosemide (10) (5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid, Aldrich) (4.0 g, 12.1 mmol) was added to dioxane (100 mL), and water (50 mL) was added with stirring to give a solution. Cesium carbonate (1.97 g, 6.0 mmol) was added, and the clear solution was stirred for 1 hour. The solvent was removed by spin evaporation, and the solid was dried overnight on a vacuum pump to afford 5.31 g of cesium 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoate as a white solid.
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([C:18]#[N:19])=[C:16]([NH2:20])[N:15]=[C:14]([S:21][CH2:22][C:23]3[N:28]=[C:27]([CH2:29][CH2:30][C:31](O)=[O:32])[CH:26]=[CH:25][CH:24]=3)[N:13]=2)=[CH:8][CH:7]=1)(=[O:4])[CH3:3].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.CCN=C=NCCCN(C)C.C(N(C(C)C)CC)(C)C>C(Cl)Cl.[Cl-].[Na+].O>[NH2:20][C:16]1[N:15]=[C:14]([S:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([CH2:29][CH2:30][C:31]([N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)=[O:32])[N:28]=2)[N:13]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([NH:5][C:2](=[O:4])[CH3:3])=[CH:7][CH:8]=2)[C:17]=1[C:18]#[N:19]
Reactant: CN1CCNCC1
Reactant: CC(=O)Nc1ccc(-c2nc(SCc3cccc(CCC(=O)O)n3)nc(N)c2C#N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(-c2nc(SCc3cccc(CCC(=O)N4CCN(C)CC4)n3)nc(N)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 45 (100 mg) was suspended in 2 mL of methylene chloride. To the suspension were added 34 μL of N-methylpiperazine, 79 mg of WSC and 72 μL of diisopropyl-ethylamine, and the mixture was stirred at room temperature overnight. To the reaction mixture was added brine, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (chloroform-methanol-28% aqueous ammonia=100:10:1) to give 95 mg of N-[4-(6-amino-5-cyano-2-{6-[3-(4-methylpiperazin-1-yl)-3-oxopropyl]pyridin-2-ylmethylsulfanyl}pyrimidin-4-yl)phenyl]-acetamide.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH2:3][CH2:4][NH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.C(N(CC)CC)C.[CH3:19][N:20]([CH3:24])[C:21](Cl)=[O:22]>C1C=CC=CC=1>[CH3:19][N:20]([CH3:24])[C:21]([N:5]([CH2:4][CH2:3][N:2]([CH3:11])[CH3:1])[C:6]1[S:7][CH:8]=[CH:9][N:10]=1)=[O:22]
Reactant: CN(C)C(=O)Cl
Reactant: CN(C)CCNc1nccs1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN(C)CCN(C(=O)N(C)C)c1nccs1

Procedure:
Following the procedure of Example 1C using 18.2 g. (0.1065 moles) of N,N-dimethyl-N'-(2-thiazolyl)-1,2-ethane diamine, 12.1 g. (0.120 moles) of triethylamine, 12.5 g. (0.116 moles) of dimethylcarbamoyl chloride and 135 ml. of dry benzene, there is obtained 20.1 g. of N,N-dimethyl-N'-(2-dimethylaminoethyl)-N'-(2-thiazolyl) urea as an oil which is distilled at 108°-110° C., at 0.02 mm. of Hg.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]1[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[N:17]12.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>CCCCCC.O1CCCC1>[O:26]=[C:22]1[N:17]2[C:18]3[C:14]([CH:15]=[C:16]2[CH2:25][CH2:24][CH:23]1[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:13][CH:21]=[CH:20][CH:19]=3
Reactant: CCOC(=O)Cl
Reactant: O=C1CCCc2cc3ccccc3n21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1CCc2cc3ccccc3n2C1=O
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
6.6 ml of a 1.6M solution of n-butyllithium in n-hexane were added to a stirred solution of 1.11 g of diisopropylamine in 150 ml of tetrahydrofuran at -78° C. under nitrogen. The mixture was allowed to warm to -20° C. for 5 minutes and was then again cooled to -78° C. Then, 1.85 g of 6,7,8,9-tetrahydropyrido[1,2-a]indol-6-one in 10 ml of tetrahydrofuran were added dropwise. After stirring at -78° C. for 0.5 hour, 1.19 g of ethyl chloroformate were added and the mixture was allowed to warm to room temperature. The solvent was removed by evaporation and the residue was partitioned between diethyl ether and 2M hydrochloric acid. The ethereal extracts were washed with saturated sodium bicarbonate solution, dried and concentrated to give an oil. This oil was purified by chromatography on silica gel with dichloromethane. Crystallization of the product from methanol gave 1.35 g of ethyl 6,7,8,9-tetrahydro-6-oxopyrido[1,2-a]indole-7-carboxylate of melting point 82°-84° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=[O:12].[H-].[Na+].[CH3:15]I.[Cl-].[NH4+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:15])[CH:6]=[C:5]2[CH:11]=[O:12]
Reactant: CI
Reactant: O=Cc1c[nH]c2ccc(F)cc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cn1cc(C=O)c2cc(F)ccc21
Temperature: 0 °C
Yield: 100 %

Procedure:
In DMF (60 ml) was dissolved 5-fluoroindole-3-carbaldehyde (5.00 g, 30.6 mmol). Under stirring at 0° C., sodium hydride (60% in oil, 1.35 g, 33.7 mmol) was added in portions. After the reaction mixture was stirred at the same temperature for 1 hour, methyl iodide (5.72 ml, 91.9 mmol) was added thereto. The resulting mixture was stirred further at 0° C. for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture to neutralize the same, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from ethyl acetate eluate fractions, 5-fluoro-1-methylindole-3-carbaldehyde (5.42 g, 100%) was obtained as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:7]([CH3:19])=[C:6]2[CH2:20][C:21]([NH:23]N)=[O:22].CCOC(C)=O.CO.CCOC(C)=O>[Ni].CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:7]([CH3:19])=[C:6]2[CH2:20][C:21]([NH2:23])=[O:22]
Reactant: COc1ccc2c(c1)c(CC(=O)NN)c(C)n2Cc1ccccn1
Agent: [Ni]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1ccccn1
Yield: 28.2 %

Procedure:
Using the procedure in Example 6, Part C, 200 mg (0.62 mmol) of 5-methoxy-2-methyl-1-[(2-pyridyl)methyl]-1H-indole-3-acetic acid hydrazide and approximately 1 gram of Raney nickel in 10 mL of EtOH were reacted to give after chromatographing twice on silica eluting with EtOAc followed by 5% MeOH/EtOAc, 54 mg (28% yield) of 5-methoxy-2-methyl-1-[(2-pyridyl)methyl]-1H-indole-3-acetamide, as a semi-solid material.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].C(N(CC)CC)C.NC1N=CN=C([N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)C=1>C(O)CCC>[O:8]=[C:3]1[CH:2]([N:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]2)[CH2:7][CH2:6][CH2:5][NH:4]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(N)ncn2)CC1
Reactant: O=C1NCCCC1Br
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C2CCCNC2=O)CC1
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
3-Bromopiperidin-2-one 51-1 (0.15 g, 0.87 mmol) was dissolved in n-butanol (4 mL) then triethyl amine (0.26 g, 2.60 mmol) was added followed by tert-butyl piperazine-1-carboxylate 12-1 (0.16 g, 0.87 mmol). This was then stirred at 150° C. for 1.5 hours and then the solid was filtered off, washed with n-butanol and then ethyl ether. Hi-Res MS: calc: 284.1969 found: 284.1966. 1H-NMR (CDCl3): 3.45 (br s, 2H); 3.26 (br s, 2H); 3.13 (complex, 3H); 2.74(m, 1H); 2.62(m, 1H); 1.98(m, 1H); 1.77(m, 1H); 1.55(complex, 3H); 1.45(t, 9H).
Reaction SMILES: N([O-])=[O:2].[Na+].[CH:5]1([CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][C:17](N)=[CH:18][C:13]=3[N:12]=[N:11]2)[CH2:8][CH2:7][CH2:6]1>S(=O)(=O)(O)O>[CH:5]1([CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][C:17]([OH:2])=[CH:18][C:13]=3[N:12]=[N:11]2)[CH2:8][CH2:7][CH2:6]1
Reactant: O=N[O-]
Reactant: Nc1ccc2c(c1)nnn2CC1CCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Oc1ccc2c(c1)nnn2CC1CCC1
Temperature: 25 °C

Procedure:
Sodium nitrite (61 mg, 0.89 mmol, 1.2 equiv) was added to a solution of 1-(cyclobutylmethyl)-1H-benzotriazol-5-amine (3-3, 150 mg, 0.74 mmol, 1 equiv) in 20% aqueous sulfuric acid solution (5 mL) and the resulting mixture was irradiated at 120° C. in a microwave reactor for 40 min. The reaction mixture was cooled to ambient temperature and then partitioned between water (300 mL) and ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (hexanes, grading to 100% ethyl acetate) to give 1-(cyclobutylmethyl)-1H-benzotriazol-5-ol (3-4) as a light yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.45 (d, 1H, J=2.1 Hz), 7.42 (d, 1H, J=8.9 Hz), 7.16 (dd, 1H, J=8.9, 2.1 Hz), 6.39 (br s, 1H), 4.61 (d, 2H, J=7.3 Hz), 2.99 (p, 1H, J=7.6 Hz), 2.08 (m, 2H), 1.91 (m, 4H) ppm. LRMS m/z (M+H) 204.0 found, 204.1 required.