Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:40])=[N:4][O:5][C:6]=1[N:7]([CH2:34][O:35][CH2:36][CH2:37][O:38][CH3:39])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:20]([OH:33])[C:21]1[CH:26]=[C:25]2[O:27][CH2:28][O:29][C:24]2=[CH:23][C:22]=1[CH2:30][CH2:31][OH:32])(=[O:10])=[O:9].[C:41](OC(=O)C)(=[O:43])[CH3:42].[CH3:48][CH2:49][O:50]C(C)=O>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH3:40])=[N:4][O:5][C:6]=1[N:7]([CH2:34][O:35][CH2:36][CH2:37][O:38][CH3:39])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:20]([O:33][C:49](=[O:50])[CH3:48])[C:21]1[CH:26]=[C:25]2[O:27][CH2:28][O:29][C:24]2=[CH:23][C:22]=1[CH2:30][CH2:31][O:32][C:41](=[O:43])[CH3:42])(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(O)c2cc3c(cc2CCO)OCO3)sc2ncccc12
Reactant: CCOC(C)=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(OC(C)=O)c2cc3c(cc2CCOC(C)=O)OCO3)sc2ncccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyeth-oxymethyl)-2-[α-hydroxy-2-(2-hydroxyethyl)-4,5-(methylenedioxy)benzyl]thieno[2,3-b]pyridine-3-sulfonamide (0.11 g, 0.19 mmoles) in pyridine (2 ml) was added acetic anhydride (0.18 ml, 1.9 mmoles). The reaction solution was stirred 2 hours at ambient temperature, then diluted with EtOAc (50 ml) and washed with 2% HCl (2×100 ml). The organic layer was dried (MgSO4), filtered and concentrated to collect 0.13 g (100%) of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[C:8]([CH3:14])=[C:7]([CH3:15])[C:6]=1[O:16][CH3:17])[OH:4].O=[C:19]([CH3:55])[CH2:20][O:21][C:22]1[CH:54]=[CH:53][C:25]([CH2:26][CH:27]2[S:31][C:30](=[O:32])[N:29](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:28]2=[O:52])=[CH:24][CH:23]=1.O.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[CH3:17][O:16][C:6]1[C:7]([CH3:15])=[C:8]([CH3:14])[C:9]([O:12][CH3:13])=[C:10]([CH3:11])[C:5]=1[CH:3]([OH:4])[CH2:2][NH:1][CH:19]([CH3:55])[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][CH:27]2[S:31][C:30](=[O:32])[NH:29][C:28]2=[O:52])=[CH:53][CH:54]=1
Reactant: COc1c(C)c(C)c(OC)c(C(O)CN)c1C
Reactant: CC(=O)COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: COc1c(C)c(C)c(OC)c(C(O)CNC(C)COc2ccc(CC3SC(=O)NC3=O)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.2 %

Procedure:
A solution of 1.23 g of 2-amino-1-(2,5-dimethoxy-3,4,6-trimethylphenyl)ethanol [prepared as described in Preparation 14] and 3.0 g of 5-[4-(2-oxopropoxy)benzyl]-3-triphenylmethylthiazolidine-2,4-dione [prepared as described in Preparation 20] in 300 ml of benzene was heated under reflux for approximately 4 hours, during which time the water produced throughout the reaction was eliminated as a benzene azeotrope. The reaction mixture was then freed from benzene by distillation under reduced pressure. The residue was dissolved in a mixture of 100 ml of absolute methanol and 100 ml of absolute ethanol, after which 8.5 g of sodium borohydride were added to the solution. The resulting mixture was then heated under reflux for one hour. At the end of this time, the reaction mixture was freed from the alcohol by distillation under reduced pressure. The residue was then mixed with water and then it was extracted with ethyl acetate. The ethyl acetate layer was then washed twice with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure, and 50 ml of trifluoroacetic acid were then added to the residue, whilst ice-cooling. The resulting mixture was then stirred at room temperature for one hour. At the end of this time, the trifluoroacetic acid was distilled off under reduced pressure and the residue was mixed with water. The aqueous mixture thus obtained was then neutralized with an aqueous solution of potassium carbonate, after which it was extracted with ethyl acetate. The extract was washed twice with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, after which the residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of ethyl acetate and ethanol as the eluent, to give 160 mg of the title compound, having an Rf=0.3 (thin layer chromatography on silica gel, using a 5:1 by volume mixture of ethyl acetate and ethanol as the developing solvent).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]3[C:10]([CH2:11][NH:12][C:13](=O)[C:4]=2[CH:3]=1)=[C:9]([C:15]1[N:19]=[C:18]([CH:20]2[CH2:22][CH2:21]2)[O:17][N:16]=1)[N:8]=[CH:7]3.CN(C)C1C=CC(C)=CC=1.P(Cl)(Cl)([Cl:37])=O>ClC1C=CC=CC=1>[Cl:37][C:13]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=2[N:6]2[C:10]([CH2:11][N:12]=1)=[C:9]([C:15]1[N:19]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[O:17][N:16]=1)[N:8]=[CH:7]2
Reactant: O=C1NCc2c(-c3noc(C4CC4)n3)ncn2-c2ccc(Cl)cc21
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccc(N(C)C)cc1
Solvent: Clc1ccccc1
Product: ClC1=NCc2c(-c3noc(C4CC4)n3)ncn2-c2ccc(Cl)cc21
Yield: 62.2 %

Procedure:
8-Chloro-3-(5-cyclopropyl-[1,2,4]oxadiazol-3-yl)-4,5-dihydro-2,5,10b-triaza-benzo[e]azulen-6-one (0.84 g, 2.5 mmol) was suspended in chlorobenzene (8 mL), N,N-dimethyl-p-toluidine (1.1 mL, 7.4 mmol) and phosphorus oxychloride (0.34 mL, 3.7 mmol) were added and the mixture was refluxed overnight. The resulting solution was evaporated and the residue was purified by chromatography on silica gel in CH2Cl2/acetone 10:1. One obtained a white solid (0.56 g, 63%). mp 200° C. m/z 359(M).
Reaction SMILES: CON(C)[C:4](=[O:21])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=1.[CH3:23][Li]>C1COCC1.CCOCC>[CH:16]1([O:15][C:9]2[CH:8]=[C:7](/[CH:6]=[CH:5]/[C:4](=[O:21])[CH3:23])[CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: [Li]C
Reactant: COc1ccc(/C=C/C(=O)N(C)OC)cc1OC1CCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(/C=C/C(C)=O)cc1OC1CCCC1
Reaction time: 0.08 h
Yield: 90 %

Procedure:
To a solution of (E)-N-methoxy-N-methyl-3-(3-cyclopentoxy-4-methoxyphenyl)-prop-2-enamide (318 mg, 1.05 mmol) in 2.5 mL of THF cooled to 0° C. was added CH3Li (1.5 mL of 1.4M ether solution). The resulting solution was stirred for 5 min, diluted with ether and transferred to a separatory funnel. After washing with H2O, 1M H3PO4, and brine, the organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (3:1, hexanes:ethyl acetate) provided (E)-4-(3-cyclopentoxy-4-methoxyphenyl)-but-3-en-2-one as a white solid (234 mg, 90%). 1H-NMR (300 MHz): δ 2.38 (s, 3), 3.89 (s, 3), 6.59 (d, 1, J=16), 7.46 (d, 1, J=16).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:31])[NH:9][C:10]2[CH:30]=[CH:29][C:13]([C:14]([N:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[O:15])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>ClCCl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[C:1]1([NH:7][C:8]([NH:9][C:10]2[CH:30]=[CH:29][C:13]([C:14]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])=[CH:12][CH:11]=2)=[O:31])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(NC(=O)Nc3ccccc3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1)Nc1ccc(C(=O)N2CCNCC2)cc1
Reaction time: 8 h

Procedure:
tert-Butyl 4-(4-(3-phenylureido)benzoyl)piperazine-1-carboxylate (15.0 g, 35.34 mmol) was stirred with 50% trifluoroacetic acid in dichloromethane (200 ml) at room temperature for 1 hour. The reaction was concentrated under vacuum and then dryed overnight on high vacuum to afford the title compound (15.5 g). MS (ESI) m/z 325.0 [M+H]+
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH2:37])[CH:28]=[CH:29][C:30]=1[N:31]1[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]1>>[CH3:1][N:2]([CH3:22])[C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:8]=[C:7]([NH:37][C:27]2[CH:28]=[CH:29][C:30]([N:31]3[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]3)=[C:25]([O:24][CH3:23])[CH:26]=2)[N:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nc(C(=O)N(C)C)cc(-c3ccc(C(F)(F)F)cc3)n2)ccc1-n1cnc(C)c1
Yield: 51 %

Procedure:
Using in analogous manner the procedure described in example 1e), 2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine-4-carboxylic acid dimethylamide (99 mg, 0.3 mmol) was reacted with 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (61 mg, 0.3 mmol) to give the title compound as yellow solid (76 mg, 51%). MS ISP (m/e): 497.4 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.21 (d, 2H), 7.77 (d, 2H), 7.74 (d, 1H), 7.66 (s, 1H), 7.45 (s, 1H), 7.41 (s, 1H), 7.23 (d, 1H), 7.18 (dd, 1H), 6.90 (s, 1H), 3.89 (s, 3H), 3.18 and 3.15 (2 s, 2×3H), 2.31 (s, 3H).
Reaction SMILES: [CH:1]1([C:7]2([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:12][CH2:11][N:10]([C:13](=[O:27])[C@H:14]([N:24]=[C:25]=[S:26])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:33][CH2:34][CH2:35][C:36]1[N:40]=[CH:39][NH:38][CH:37]=1.N12CCCN=C1CCCCC2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH:1]1([C:7]2([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:12][CH2:11][N:10]([C:13](=[O:27])[C@H:14]([NH:24][C:25]([NH:33][CH2:34][CH2:35][C:36]3[N:40]=[CH:39][NH:38][CH:37]=3)=[S:26])[CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NCCc1c[nH]cn1
Reactant: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(OC)cc2)N=C=S)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=S)NCCc2c[nH]cn2)CC1
Reaction time: 2 h
Yield: 53.5 %

Procedure:
To 400 mg (0.87 mmol) of ethyl 4-cyclohexyl-1-[(R)-2-isothiocyanato-3-(4-methoxy-phenyl)propionyl]piperidine-4-carboxylate in 5 mL of DMF are added 97 mg (0.87 mmol) of histamine and then 0.130 mL (0.87 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction medium is stirred for 2 hours and then hydrolysed by adding aqueous 5% citric acid solution. The organic compounds are extracted with dichloromethane. The organic phase is dried over MgSO4, filtered and concentrated. The crude product obtained is chromatographed on silica gel (eluent: 80/20 CH2Cl2/MeOH). 265 mg of ethyl 4-cyclohexyl-1-[(R)-2-{3-[2-(1H-imidazol-4-yl)ethyl]thioureido}-3-(4-methoxyphenyl)propionyl]piperidine-4-carboxylate in the form of a pale yellow powder are obtained in a yield of 53%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][N:3]=1.[BH4-].[Na+]>CO.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([CH:10]2[CH2:11][CH2:12]2)[OH:9])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(c1ccnc(Cl)n1)C1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: OC(c1ccnc(Cl)n1)C1CC1
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
To a solution of (2-chloropyrimidin-4-yl)(cyclopropyl)methanone (150 mg, 0.821 mmol) in MeOH (3 mL) at 0° C. was added sodium borohydride (31 mg, 0.821 mmol) and stirred for 30 min. The solution was diluted with EtOAc, washed with brine, dried with MgSO4, filtered, and concentrated to dryness to afford (2-chloropyrimidin-4-yl)(cyclopropyl)methanol (150 mg, 0.812 mmol, 99% yield). MS ESI: [M+H]+ m/z 185.1. 1H NMR (500 MHz, CDCl3) δ 8.60 (d, J=4.0, 1H), 7.41 (d, J=4.0, 1H), 4.12 (d, J=7.9, 1H), 1.12 (m, 1H), 0.64 (m, 2H), 0.56 (m, 2H).
Reaction SMILES: C1(C)C=CC=CC=1.C(#N)C.[Cl:11][C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[N:16][C:17]=1[Cl:18].[C:20]([O:23][C@@H:24]1[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:28]([O:34][C:35](=[O:37])[CH3:36])[CH2:27][S:26][C@@H:25]1Br)(=[O:22])[CH3:21]>[Cl-].[Zn+2].[Cl-].C(N(CC)CC)C>[C:20]([O:23][C@@H:24]1[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:28]([O:34][C:35](=[O:37])[CH3:36])[CH2:27][S:26][C@H:25]1[O:19][C:14]1[CH:15]=[N:16][C:17]([Cl:18])=[C:12]([Cl:11])[CH:13]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: Oc1cnc(Cl)c(Cl)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cnc(Cl)c(Cl)c1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 50 %

Procedure:
5.1 g (37.5 mM) of zinc chloride are melted under reduced pressure, the melt is cooled under an inert atmosphere and then 12 ml of toluene, 12 ml of acetonitrile, 3 g of 4 Å molecular sieve and 2.45 g (15 mM) of 5,6-dichloro-3-pyridinol are added. The temperature of the mixture is brought to 90° C. and 3.78 g (37.5 mM) of triethylamine and 5.86 g (16.5 mM) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide are added. The reaction medium is stirred at 90° C. for 20 minutes and is then cooled and filtered to remove the inorganic salts, which are washed with ethyl acetate. The combined organic phases are washed with a 0.5 N sodium hydroxide solution and then the pH is brought to a value of 3 using a 0.1 N hydrochloric acid solution. The organic phase is subsequently washed with a saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The product is crystallized from ethyl ether and the desired product is obtained in the form of a light brown solid with a yield of 50%.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C(OC([N:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:35]([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[CH:41][CH:42]=2)=[O:36])[CH2:30][CH2:29]1)=O)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:43][C:40]3[CH:41]=[CH:42][C:37]([C:35](=[O:36])[NH:34][CH:31]4[CH2:32][CH2:33][NH:28][CH2:29][CH2:30]4)=[CH:38][N:39]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(N)nc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)NC4CCNCC4)cn3)nc2n1C1CCCC1
Yield: 40.2 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (25 mg, 0.85 mmol) and 4-[(6-amino-pyridine-3-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (27 mg, 0.094 mmol), followed by deprotection using 0.6 mL of TBAF in 2 mL of THF to give 7-cyclopentyl-2-[5-(piperidin-4-ylcarbamoyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (18 mg, 72%). MS (ESI) m/z 424.2 (M+H)+
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([CH:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)C(Cl)=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([NH:42][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6](=[O:7])[CH:25]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:18])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: NCc1ccccc1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NCc2ccccc2)N(C(=O)C(c2ccccc2)c2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, diphenylacetyl chloride, and benzylamine the title compound was obtained in 82% purity by LC/MS. MS(ESI+): m/z=442.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([SH:10])=[C:7]([CH3:11])[C:6]=2[CH:12]=1.Cl[C:14]1[N:15]=[N:16][C:17](OC)=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([S:10][C:17]3[N:16]=[N:15][CH:14]=[CH:19][CH:18]=3)=[C:7]([CH3:11])[C:6]=2[CH:12]=1
Reactant: Cc1c(S)oc2ccc(Cl)cc12
Reactant: COc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Sc2cccnn2)oc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a solution containing 5-chloro-2-mercapto-3-methyl benzofuran (10 mmol, 1.98 g and 3-chloro-6-methoxy pyridazine (10 mmol, 1.44 g) in dimethylformamide (DMF, 10 mL) was added potassium carbonate (20 mmol, 2.76 g) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with H2O (200 mL), the precipitated yellow solid was collected and the solid was purified by silica gel chromatography (eluent: hexanes:EtOAc::9:1) to obtain 6-(5-chloro-3-methyl-benzofuran-2-sulfenyl)-pyridazine (93%, 2.87 g); mp 131° C.-134° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(OCC)C>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([O:12][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-hydroxy-cyclohexanecarboxylic acid ethyl ester (10.32 g, 59.92 mmol) in dimethylformamide (50 mL) was added imidazole (8.16 g, 119.8 mmol), followed by tert-butyldimethylsilyl chloride (9.94 g, 65.9 mmol). The resulting mixture was stirred at room temperature for 16 hours. Diethyl ether was added (150 mL), and the mixture was washed with 1M HCl (150 mL). The aqueous layer was extracted with diethyl ether (150 mL). The combined organic layers were washed with 1M HCl (100 mL) and saturated sodium chloride solution (100 mL), dried over magnesium sulfate, filtered and concentrated to afford a clear oil. MS (CI) m/z 287 (M+1)+
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1>O>[N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:9][CH:10]=1
Reactant: C1CNCCN1
Reactant: Clc1ccnc2ccccc12
Solvent: O
Product: c1ccc2c(N3CCNCC3)ccnc2c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 105.9 %

Procedure:
Piperazine (13.2 g) was melted by heating at 140° C., and 4-chloroquinoline (2.5 g) was added thereto. The mixture was stirred at 140° C. for 30 min. The reaction mixture was added to iced water, and the mixture was extracted with chloroform to give 1-(4-quinolyl)piperazine (3.45 g) as a pale-yellow oil.
Reaction SMILES: O[CH:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][C:4]1[C:9]([CH:10]=[CH:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][N:5]=1>C(O)C.C(O)(=O)C.[Pd]>[CH2:3]([C:4]1[C:9]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)[CH2:2][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(C=Cc2cccnc2CC(O)c2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)c1ccc(CCc2cccnc2CCc2ccccc2)cc1

Procedure:
Methyl 4-[2-(2-(2-hydroxy-2-(phenyl)ethyl)-3-pyridyl)ethenyl]benzoate (0.463 g, 1.29 mmol) was dissolved in ethanol (15 ml), acetic acid (3 drops) and 10% palladium on carbon (0.05 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]1([Mg]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:12][CH2:11][CH2:10][C:9](=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCC(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7.03 g, 38 mmol) in THF (130 mL) was added phenylmagnesium bromide (1.0 M solution, 50 mL) at −78° C. After stirring for 2 hour at −78° C., HCl (2 M, 35 mL) was added to quench the reaction, which was then warmed to room temperature and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organics were washed with brine (50 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to afford 9.56 g (96% yield) of the desired product.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[CH3:13][O:14][C:15]1[N:20]=[C:19]([C:21]2[CH:22]=[C:23]([C:27]3([C:33](O)=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:24]=[CH:25][CH:26]=2)[CH:18]=[C:17]([NH:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][C:46]([F:49])([F:48])[F:47])=[CH:41][CH:40]=2)[N:16]=1.[CH3:50][S:51]([NH2:54])(=[O:53])=[O:52]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:13][O:14][C:15]1[N:20]=[C:19]([C:21]2[CH:22]=[C:23]([C:27]3([C:33]([NH:54][S:51]([CH3:50])(=[O:53])=[O:52])=[O:34])[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[CH:24]=[CH:25][CH:26]=2)[CH:18]=[C:17]([NH:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][C:46]([F:49])([F:48])[F:47])=[CH:41][CH:40]=2)[N:16]=1
Reactant: COc1nc(NCCc2ccc(OC(F)(F)F)cc2)cc(-c2cccc(C3(C(=O)O)CCOCC3)c2)n1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1nc(NCCc2ccc(OC(F)(F)F)cc2)cc(-c2cccc(C3(C(=O)NS(C)(=O)=O)CCOCC3)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (39 mg, 0.2 mmol) is added to a stirred ice cold solution of N-[4-(3-{2-methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-tetrahydro-pyran-4-carboxylic acid (100 mg, 0.19 mmol), methanesulfonamide (19.3 mg, 0.2 mmol) and 4-dimethylaminopyridine (23.6 mg, 0.19 mmol) in dry DCM under nitrogen. The reaction mixture is stirred overnight at room temperature and concentrated in vacuo. The residue is dissolved in ethyl acetate, washed with 0.1N HCl, brine and water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography (SiO2 packed column), eluting with ethyl acetate/heptane to afford N-[4-(3-{2-methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-tetrahydro-pyran-4-carbonyl]-methanesulfonamide [86 mg, Example 84(a)]. LCMS: RT=2.52 minutes, LCMS: 595 (M+H). IC50=0.7 nM