Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][N:8]([CH3:42])[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][N:20]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=1)[C:21](=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[H][H]>C(O)C.[Pd]>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[NH2:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][CH2:31][N:20]([CH2:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9][N:8]([CH3:42])[CH3:7])[C:21](=[O:30])[CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:34][CH:35]=1
Reactant: [H][H]
Reactant: CN(C)CCCOc1ccccc1CN(CCc1ccc([N+](=O)[O-])cc1)C(=O)C=Cc1ccccc1
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: CN(C)CCCOc1ccccc1CN(CCc1ccc(N)cc1)C(=O)C=Cc1ccccc1

Procedure:
A suspension of 10 parts of N-[[2-[3-(dimethylamino)propoxy]phenyl]methyl]-N-[2-(4-nitrophenyl)ethyl]-3-phenyl-2-propenamide, oxalate salt (1:1) in 100 ml of ethanol is treated with 1 part of 5% palladium on carbon and placed under 3 atmospheres of gaseous hydrogen. The mixture is shaken until one equivalent of hydrogen is consumed, filtered and the solvent evaporated under reduced pressure to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[CH:16]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[C:20]=2[CH:19]=[CH:18][N:17]=1>ClCCl>[NH:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][S:26]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:20]=2[CH:19]=[CH:18][N:17]=[CH:16]3)(=[O:27])=[O:28])[CH2:4][CH2:5]1
Reactant: NCC1CCNCC1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCC1CCNCC1)c1cccc2cnccc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Dissolve 5.02 g of 4-aminomethylpiperidine and 22 g of triethylamine in 50 ml of dichloromethane. Add dropwise over 30 minutes 5.0 g of 5-isoquinoline sulfonyl chloride dissolved in 50 ml of dichloromethane while cooling the mixture in an ice bath. Stir at room temperature for 72 hours. Filter the reaction mixture and evaporate the filtrate. Chromatograph the residue over 400g of silica gel eluting with dichloromethane/methanol (9/1). Obtain the title compound by evaporating the appropriate fractions, as determined by thin layer chromatography. Dissolve the product in ethanol saturated with HCl and evaporate to obtain the title compound as the dihydrochloride salt. FAB MS (M+1)e =306.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:21][CH:22]=2)=[CH:11][C:10]=1[CH2:29][OH:30])([CH3:4])([CH3:3])[CH3:2].[CH:32]1([N:37]=[C:38]=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33]1.Cl.CCOCC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[O:21][CH:22]=2)=[CH:11][C:10]=1[CH2:29][O:30][C:38](=[O:39])[NH:37][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=NC1CCCC1
Reactant: CC(C)(C)OC(=O)CCc1ccc(OCCc2coc(-c3ccccc3)n2)cc1CO
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CCc1ccc(OCCc2coc(-c3ccccc3)n2)cc1COC(=O)NC1CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 15 mL round bottomed flask was charged with 3-{2-hydroxymethyl-4-[2-(2-phenyloxazol-4-yl)ethoxy]phenyl}propionic acid tert-butyl ester (0.10 g, 0.23 mmol), cyclopentylisocyanate (0.15 mL, 1.38 mmol), and anhydrous CH2Cl2 (0.75 mL). A 1.0 M HCl solution in ether (0.115 mL, 0.115 mmol) was added, and the reaction mixture was stirred at ambient temperature under a nitrogen atmosphere for 24 h. The reaction mixture was diluted with CH2Cl2, (30 mL), washed with brine, dried (Na2SO4), and concentrated to an oil. The crude product was purified using radial chromatography (EtOAc:hexanes 10:90 to 35:65) to a colorless oil (0.105 g, 83%). 1H NMR (400 MHz, CDCl3) 1.42 (s, 9H), 1.56-1.65 (m, 4H), 1.94-2.04 (m, 2H), 2.37 (s, 3H), 2.46 (t, J=7.6 Hz, 2H), 2.87 (t, J=8.1 Hz, 2H), 2.96 (t, J=6.6 Hz, 2H), 3.97 (br s, 1H), 4.22 (t, J=6.6 Hz, 2H), 4.76 (br s, 1H), 5.07 (s, 2H), 6.90 (dd, J=8.3, 2.4 Hz, 1H), 6.89 (s, 1H), 7.10 (d, J=8.8 Hz, 1H), 7.40-7.45 (m, 3H), 7.96-7.98 (m, 2H). MS (ES) m/e 549 (M+1).
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C@@H:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:10])=[O:7])=[CH:4][N:3]=1.[CH:17]1([NH:20][C:21]([C:23]2[CH:24]=[C:25]([F:33])[C:26]([CH3:32])=[C:27](B(O)O)[CH:28]=2)=[O:22])[CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>CC(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:17]1([NH:20][C:21]([C:23]2[CH:24]=[C:25]([F:33])[C:26]([CH3:32])=[C:27]([C:2]3[N:3]=[CH:4][C:5]([C:6]([NH:8][C@H:9]([CH3:10])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])=[CH:15][CH:16]=3)[CH:28]=2)=[O:22])[CH2:19][CH2:18]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B(O)O
Reactant: C[C@@H](NC(=O)c1ccc(Cl)nc1)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@H](C)C(C)(C)C)cn1
Temperature: 90 °C

Procedure:
6-Chloro-N-[(R)-3,3-dimethyl-2-butyl]nicotinamide (Intermediate 11, 100 mg), {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (Intermediate 6, 100 mg), tetrakis(triphenylphosphine)palladium (10 mg) and aqueous sodium hydrogen carbonate (4 ml) were mixed in propan-2-ol (8 ml) and heated at 90° C. under nitrogen for 18 hrs. The solvents were evaporated from the cooled reaction under vacuum and the residue dissolved as far as possible in ethylacetate. The solution was applied to an SPE (SCX, 10 g) and washed with ethyl acetate. The product was eluted from the column with methanol/0.880 ammonia, and the solvents evaporated in vacuo. The residue was redissolved in ethyl acetate and filtered through an SPE (silica, 0.5 g). The filtrate was reduced to dryness under vacuum and triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1R)-1,2,2-trimethylpropyl]-3-pyridinecarboxamide.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:8][CH:7]=1)(=[NH:4])[CH2:2][CH3:3].Br.Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=1)=O>>[CH2:2]([C:1]1[N:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:8][CH:7]=2)[CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[N:4]=1)[CH3:3]
Reactant: Cc1cccc(C(=O)CBr)n1
Reactant: CCC(=N)Nc1ccc(CCNC(=O)OC(C)(C)C)cc1
Agent: Br
Product: CCc1nc(-c2cccc(C)n2)cn1-c1ccc(CCNC(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 4 of Example 26 from tert-butyl 2-[4-(propanimidoylamino)phenyl]ethylcarbamate and 2-bromo-1-(6-methylpyridin-2-yl)ethanone hydrobromide (J. Med. Pharm. Chem., 1961, 3, 561). MS (ESI) m/z 407 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[C:23](OCC)(=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].O>CCOCC>[O:29]=[C:23]([CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][C:9]1[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=1[Br:7])[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)CCc1cc(OC)ccc1Br
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(=O)C(Cc1cc(OC)ccc1Br)C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
Potassium t-butoxide (6.72 g) was suspended in 30 ml of anhydrous ether and cooled to 0° C. A solution of 14.35 g of ethyl 3-(2-bromo-5-methoxyphenyl)propionate and 10.95 g diethyl oxalate in 10 ml ether was added dropwise over 15 min. After 2 h at 25° C., the reaction was poured into 100 ml H2O and the aqueous layer was separated, acidified to pH 1 and extracted with ether. The ether layer was dried (MgSO4) and the solvent was evaporated to yield 17.48 g of the desired product as a colorless oil (90%). NMR (CDCl3) δ 1.20 (t, 3H), 1.35 (t, 3H), 3.32 (dd, 2H), 3.76 (s, 3H), 4.18 (q, 2H), 4.32 (q, 2H), 4.53 (t, 1H), 6.67 (dd, 1H), 6.80 (d, 1H), 7.40 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[C:10]([O:12]CC)=[O:11])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:23])[C:18]([O:20]CC)=[O:19].Cl>[OH-].[Na+].O>[Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:23])[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)C(=O)Nc1cccc(NC(=O)C(=O)OCC)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(=O)Nc1cccc(NC(=O)C(=O)O)c1Cl

Procedure:
Diethyl N,N'-(2-chloro-m-phenylene)dioxamate (0.50 gram) is heated at reflux in 1.0N aqueous sodium hydroxide (10 ml.) for one hour. The reaction mixture is diluted with water (15 ml.). Concentrated hydrochloric acid is added to pH 3 and the solid product collected by filtration (0.27 grams, M.P. >320°).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19](O)=[O:20])[CH:15]=2)[C:10]1=[O:22].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:44][C:45]1[CH:46]=[C:47]([CH:49]=[CH:50][C:51]=1[CH3:52])[NH2:48]>CN(C=O)C.O>[CH3:44][C:45]1[CH:46]=[C:47]([NH:48][C:19]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[C:10](=[O:22])[N:9]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])[C:17]3=[O:18])=[O:20])[CH:49]=[CH:50][C:51]=1[CH3:52]
Reactant: Cc1ccc(N)cc1C
Reactant: Cc1cccc(C)c1N1C(=O)c2ccc(C(=O)O)cc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc3c(c2)C(=O)N(c2c(C)cccc2C)C3=O)cc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 2-(2,6-dimethylphenyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid (130 mg), EDCI (85 mg) and HOBt (60 mg) in DMF (3 mL) was added 3,4-dimethylaniline (53 mg) and the mixture was stirred at room temperature for 24 h. The mixture was poured into water and was extracted with EtOAc. The organic phase was washed with water (3×) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography using CH2Cl2 as eluent to give 2-(2,6-dimethylphenyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid (3,4-dimethylphenyl)-amide as a pale-yellow solid, mp=223-225° C.; MS (m/z) 397 (M−1); 1H NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 8.09 (d, J=8.34 Hz, 1H), 7.81 (s, 1H), 7.45 (s, 1H), 7.37-7.15 (m, 5H), 2.30 (s, 3H), 2.27 (s, 3H), 1.54 (s, 6H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][C@@:8]12[C:24](=O)[CH2:23][CH2:22][C@H:21]1[C@H:20]1[C@@H:11]([C:12]3[CH:13]=[CH:14][C:15]([OH:26])=[CH:16][C:17]=3[CH2:18][CH2:19]1)[CH2:10][CH2:9]2>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:1]=[C:24]1[CH2:23][CH2:22][C@H:9]2[C@H:10]3[C@H:11]([CH2:20][CH2:21][C@:8]12[CH3:7])[C:12]1[CH:13]=[CH:14][C:15]([OH:26])=[CH:16][C:17]=1[CH2:18][CH2:19]3
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
To a suspension of methyl triphenylphosphonium bromide (8.93 g, 25.0 mmol) in THF (120 mL) was added potassium tert-butoxide (2.69 g, 24 mmol) and stirred for 30 min at room temperature. The reaction mixture was added estrone (18, 2.70 g, 10 mmol), stirred for 19 h at room temperature. The reaction mixture was quenched with saturated aqueous NH4Cl at 0° C. and extracted with EtOAc. The combined organic layers were washed with H2O, then with saturated aqueous NaCl, and dried (Na2SO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:EtOAc (5:1→3:1, v/v) to afford 2.24 g of 19 (84% yield), m.p. 135°-136° C.
Reaction SMILES: [H-].[Na+].[S:3]1[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[C:6](=[O:16])[CH:5]=[CH:4]1.[CH3:17]I>CCCCCC.CN(C)C=O>[CH3:17][N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:15]2[S:3][CH:4]=[CH:5][C:6](=[O:16])[C:7]1=2
Reactant: CI
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cn1c2ccccc2c2sccc(=O)c21
Reaction time: 3 h

Procedure:
Sodium hydride (2.3 g of 50% suspension in mineral oil, 0.05 mole) is washed with hexane and suspended in 25 ml of dimethylformamide (DMF). Thiopyrano [3,2-b]indol-4(5H)-one, 10.0 g (0.05 mole) in 130 ml of DMF is added and the mixture stirred for 3 hours. Methyl iodide (14.2 g, 0.1 mole) is added and the mixture stirred for 3 hours and then poured over ice. The white precipitate is filtered, dried and recrystallized from hexane to give 9.3 g of product, mp 113°-114° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:16][C@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][N:18]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH2:4][N:21]1[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:17]([CH3:16])[CH2:22]1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=Cc1ccc(N2CCOCC2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: C[C@H]1CN(Cc2ccc(N3CCOCC3)cc2Cl)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
A 100 mL round-bottom flask was charged with 2-chloro-4-(morpholin-4-yl)benzaldehyde (0.800 g, 3.54 mmol, 1.00 equiv), tert-butyl (2S)-2-methylpiperazine-1-carboxylate (0.783 g, 3.91 mmol, 1.10 equiv), 1,2-dichloroethane (20 mL). The mixture was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (2.26 g, 10.7 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with H2O (30 mL), extracted with dichloromethane (3×30 mL) and the organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (25/75) to provide 1.20 g (74% yield) of tert-butyl (2S)-4-[[2-chloro-4-(morpholin-4-yl)phenyl]methyl]-2-methylpiperazine-1-carboxylate as a white solid. LCMS (ESI, m/z): 410 [M+H]+.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.I[C:14]1[CH:15]=[C:16]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]([CH2:30][N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)[CH:28]=[CH:29][C:23]=3[N:22]=2)[CH:17]=[CH:18][C:19]=1[CH3:20]>>[CH:1]1([NH:4][C:5]2[N:6]=[N:7][C:8]([C:11]#[C:12][C:14]3[CH:15]=[C:16]([C:21]4[NH:25][C:24]5[CH:26]=[C:27]([CH2:30][N:31]6[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]6)[CH:28]=[CH:29][C:23]=5[N:22]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1
Reactant: C#Cc1ccc(NC2CC2)nn1
Reactant: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1I
Product: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1C#Cc1ccc(NC2CC2)nn1

Procedure:
The title compound was synthesized from N-cyclopropyl-6-ethynylpyridazin-3-amine and 2-(3-iodo-4-methylphenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole (as prepared in Example 1) in a manner similar to that described for in Example 1. The intermediate compound N-cyclopropyl-6-ethynylpyridazin-3-amine was made as for Example 1 (Step 1 to 3) with the spectra below: 1H NMR (300 MHz, CDCl3) δ: 7.38-7.41 (1H, d, J=9.0 Hz), 6.96-6.99 (1H, d, J=9.0 Hz), 5.99 (1H, s), 3.25-3.27 (1H, m), 2.57 (1H, s), 0.87-0.89 (2H, s), 0.61-0.63 (2H, s).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:12])[CH3:11])[CH2:4][CH2:3]1.[OH-].[K+].NN>C(O)COCCO>[N:5]1([CH2:8][CH2:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:12])[CH3:11])[CH2:4][CH2:3][CH2:2][CH2:7][CH2:6]1
Reactant: CC(O)(CCN1CCC(=O)CC1)c1ccccc1-c1ccccc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Product: CC(O)(CCN1CCCCC1)c1ccccc1-c1ccccc1
Reaction time: 4 h

Procedure:
A mixture of 3.23 g of 1-(4-oxopiperidino)-3-p-biphenylyl-butan-3-ol (obtainable from 1-chloro-3-p-biphenylyl-butan-3-ol and 4-piperidone), 1.5 g of KOH, 2.5 ml of 85% hydrazine and 25 ml of diethylene glycol is warmed at 100° for 1 hour. The temperature is raised slowly until the hydrazone is decomposed, and the mixture is boiled for a further 4 hours, cooled and worked up in the customary manner to give 1-piperidino-3-p-biphenylyl-butan-3-ol, m.p. 102°-104°.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([C:8]2[C:16]3[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=[C:14]([C:17]4[CH:21]=[C:20]([CH:22]=O)[S:19][CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1(=[O:28])=[O:27].[NH:30]1[CH2:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[N:30]1([CH2:22][C:20]2[S:19][CH:18]=[C:17]([C:14]3[CH:15]=[C:16]4[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=3)[NH:10][CH:9]=[C:8]4[CH:6]3[CH2:5][CH2:4][S:3](=[O:28])(=[O:27])[C:2]([CH3:1])([CH3:29])[CH2:7]3)[CH:21]=2)[CH2:33][CH2:32][CH2:31]1
Reactant: C1CNC1
Reactant: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CCS1(=O)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCC5)c4)cc23)CCS1(=O)=O
Yield: 36.3 %

Procedure:
3-(2,2-Dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (30 mg, 0.070 mmol) was dissolved in dimethyl sulfoxide (1.5 mL) and put in a microwave vial. The mixture was stirred and 1-2 drops of acetic acid and azetidine (0.047 mL, 0.697 mmol) was added. The mixture was left stirring 30 minutes at 23° C., before adding sodium triacetoxyborohydride polymer bound (299 mg, 0.697 mmol). The vial was sealed using a silicon septum, and the mixture left stirring 16 h at 23° C. Based on LCMS only 60-70% of conversion was observed. The sodium triacetoxyborohydride polymer bound was removed by filtration. The crude product was purified by preparative HPLC (NH4OH buffer). The desired fractions were concentrated, giving 12 mg of the title compound.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([N:3]1[C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:11][C:9]1[CH:10]=[CH:4][CH:5]=[CH:7][CH:8]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccc2nc(S)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2nc(SCc3ccccc3)n(Cc3ccccc3)c2c1
Yield: 166.9 %

Procedure:
To a flask were added 2.0 g 2-mercapto-5-methylbenzimidazole, 4.2 g potassium carbonate, 30 ml N,N-dimethylformamide and 3.9 g benzyl chloride. The reaction mixture was heated to 60 C for 16 hours, then cooled to 50 C and quenched with 60 ml water and cooled to 5 C. The solid was filtered and washed with water and then recrystallized by dissolving in 50 ml hot acetonitrile and adding 10 ml of water. After cooling to 5 C, the product was filtered, washed and dried resulting in 3.5 g white solid as a mixture of the 5-methyl and 6-methyl isomers.
Reaction SMILES: N[C:2]1[C:3]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:12]=[CH2:13]>[Pd]>[CH2:12]=[CH:13][C:2]1[C:3]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1S(=O)(=O)O
Reactant: C=C
Agent: [Pd]
Product: C=Cc1ccccc1S(=O)(=O)O

Procedure:
EP-A 0 508 264 relates to a process for preparing arylolefins by reaction of aryldiazonium salts with olefins in the presence of a palladium catalyst. Although the use of heterogeneous palladium catalysts is mentioned (cf. EP-A 0 508 264 A1 page 4, lines 2 to 3), it is experimentally verified in only one case, namely the reaction of aniline-2-sulfonic acid with ethylene to give styrene-2-sulfonic acid (Example 6). However, as shown by comparison with Example 4 carried out using Pd(OAc)2, the yield decreases considerably when using a supported palladium catalyst (10% Pd on carbon) (Example 4: 87% yield; Example 7: 74% yield). In both examples the reaction is carried out with the addition of a base which is used in excess based on the aniline-2-sulfonic acid. As the experimental finding proves (see comparative experiment in the experimental section), the method practiced in the examples of EP-A 0 508 264, of preparing the aryldiazonium salts in situ and subsequently processing further, cannot be generally applied to the use of palladium-containing supported catalysts. The comparative experiment verifies that the desired aromatic olefin is not formed even in small amounts.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[C:9]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:10][CH:11]=[CH:12][CH:13]=1.[F:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24](F)=[CH:23][C:22]=1[NH:31][C:32](=[O:34])[CH3:33].CN(C)C=O>O>[F:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24]([O:7][C:8]2[C:9]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:23][C:22]=1[NH:31][C:32](=[O:34])[CH3:33]
Reactant: COC(=O)COc1ncccc1O
Reactant: CC(=O)Nc1cc(F)c([N+](=O)[O-])cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ncccc1Oc1cc(NC(C)=O)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
First, 2.08 g of potassium carbonate was added to a solution of 3.0 g of 3-hydroxy-2-(methoxycarbonyl)methoxypyridine, 2.95 g of N-(2,5-difluoro-4-nitrophenyl)acetamide, and 40 ml of N,N-dimethylformamide. The mixture was stirred at 60° C. to 70° C. for 2 hours, cooled to room temperature, and then poured into water. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated to give crude crystals. The crude crystals were washed with diisopropyl ether to give 3.67 g of N-[2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}-4-nitrophenyl]acetamide.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[F:4][C:5]1([F:37])[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[N:23]=[CH:22][C:21]4=[CH:24][CH:25]=[C:26]([C:27]5[C:28]([O:33][CH3:34])=[N:29][CH:30]=[CH:31][CH:32]=5)[N:20]4[N:19]=3)=[C:13]([O:35][CH3:36])[CH:12]=2)[CH2:9][CH2:8][NH:7][CH2:6]1>>[F:37][C:5]1([F:4])[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[N:23]=[CH:22][C:21]4=[CH:24][CH:25]=[C:26]([C:27]5[C:28]([O:33][CH3:34])=[N:29][CH:30]=[CH:31][CH:32]=5)[N:20]4[N:19]=3)=[C:13]([O:35][CH3:36])[CH:12]=2)[CH2:9][CH2:8][N:7]([CH2:1][CH2:2][OH:3])[CH2:6]1
Reactant: COc1cc(C2CCNCC2(F)F)ccc1Nc1ncc2ccc(-c3cccnc3OC)n2n1
Reactant: C1CO1
Product: COc1cc(C2CCN(CCO)CC2(F)F)ccc1Nc1ncc2ccc(-c3cccnc3OC)n2n1

Procedure:
Ethylene oxide and (±)-[4-(3,3-difluoro-piperidin-4-yl)-2-methoxy-phenyl]-[7-(2-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine (Example 12, 68 mg) were converted to the title product by a procedure similar to the one described for Example 8 to give a yellow foam (51 mg, 68% yield). 1H NMR (CDCl3): 8.72 (s, 1H), 8.48 (d, J=7.4 Hz, 1H), 8.28 (d, J=8.1 Hz, 1H), 8.24 (d, J=4.3 Hz, 1H), 7.51 (s, 1H), 7.14 (d, J=3.6 Hz, 1H), 7.08 (m, 1H), 6.84 (m, 2H), 4.02 (s, 3H), 3.92 (s, 3H), 3.68 (m, 2H), 3.25 (m, 1H), 3.10 (m, 1H), 2.90 (m, 1H), 2.74 (m, 1H), 2.65 (m, 1H), 2.46 (dd, J=28.3 (F-H vic. coupling), 11.7 Hz, 1H), 2.27 (m, 3H), 1.90 (m, 1H); LC/MS (ESI+): 510.54 (M+H).