Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](N(OC)C)=[O:9])[CH:5]=[CH:4][N:3]=1.[CH:14]1([Mg]Br)[CH2:16][CH2:15]1>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([CH:14]2[CH2:16][CH2:15]2)=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: Br[Mg]C1CC1
Reactant: CON(C)C(=O)c1ccnc(Cl)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1ccnc(Cl)n1)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
To a solution of 2-chloro-N-methoxy-N-methylpyrimidine-4-carboxamide (893 mg, 4.43 mmol) in THF (9 mL) at −78° C. under nitrogen atmosphere was added cyclopropyl magnesium bromide (0.5 M in THF, 13.3 mL, 6.64 mmol) dropwise. The solution was warmed to 0° C. and stirred for an additional 30 min. The solution was diluted with EtOAc, washed with brine, dried with MgSO4, filtered, and concentrated to dryness. Purification on silica gel by flash chromatography (0-100% EtOAc/hexanes) afforded (2-chloropyrimidin-4-yl)(cyclopropyl)methanone (360 mg, 1.97 mmol, 45% yield) as a colorless oil. MS ESI: [M+H]+ m/z 183.1. 1H NMR (500 MHz, CDCl3) δ 8.85 (d, J=4.9, 1H); 7.82 (d, J=4.9, 1H), 3.45-3.31 (m, 1H), 1.30 (m, 2H), 1.22 (m, 2H).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH2:13])=[O:12])=[C:7]([O:16][CH2:17][C:18](=[O:20])[NH2:19])[CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].F[C:28]1[CH:29]=[C:30]([O:37][CH3:38])[CH:31]=[CH:32][C:33]=1[N+:34]([O-:36])=[O:35]>CC(N(C)C)=O.O>[C:18]([CH2:17][O:16][C:7]1[CH:6]=[C:5]([S:2]([NH:1][C:28]2[CH:29]=[C:30]([O:37][CH3:38])[CH:31]=[CH:32][C:33]=2[N+:34]([O-:36])=[O:35])(=[O:3])=[O:4])[CH:15]=[CH:14][C:8]=1[O:9][CH2:10][C:11]([NH2:13])=[O:12])(=[O:20])[NH2:19]
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Reactant: NC(=O)COc1ccc(S(N)(=O)=O)cc1OCC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc([N+](=O)[O-])c(NS(=O)(=O)c2ccc(OCC(N)=O)c(OCC(N)=O)c2)c1

Procedure:
A mixture of 4-aminosulfonyl-2-carbamoylmethoxyphenoxyacetamide (Intermediate A66, 12.1 g, 0.040 mol), potassium carbonate (11.0 g, 0.80 mol), and dimethylacetamide (160 mL) was heated at reflux as 3-fluoro-4-nitroanisole (6.84 g, 0.040 mol) in 40 mL dimethylacetamide was added dropwise over 40 min. After an additional 30 min at reflux, the mixture was allowed to cool overnight. It was then diluted with 200 mL of water and filtered with the aid of additional water. The filtrate was brought to pH 5, and the resulting solid was collected and washed with water. After air-drying, the product, title compound weighed 15 g (80%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1)([O-:16])=[O:15]>CN(C)C=O>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:25])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)=[CH:21][CH:22]=1)([O-:16])=[O:15]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 4.88 g of ethyl 2-aminothiazol-4-ylglyoxylate, 5 g of p-nitrophenyl isocyanate and 30 ml of dimethylformamide. The resulting product was a pale yellow powder having the following physical properties.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([Br:16])=[CH:10][CH:11]=3)[CH2:6][CH2:5][C:4]=2[CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([Br:16])=[CH:10][CH:11]=3)[CH:6]=[CH:5][C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)CCc1cc(Br)ccc1-2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: Brc1ccc2c(ccc3cc(Br)ccc32)c1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
Preparing 32.7 g of 2,7-dibromo-9,10-dihydrophenanthrene, 24.1 g of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) and 500 milliliter of benzene as a mixture solution, the solution was refluxed with heating under an ambient atmosphere of argon gas for 64 hours. The reacted solution was cooled down to a room temperature, and further filtered. Concentrating the filtrate by means of an evaporator, the residue was washed with a use of methanol. After refining the filtered product by means of a short column, the refined product was re-crystallized with a use of toluene and as a result, 15.5 g of 2,7-dibromophenanthrene was obtained as colorless needle crystals.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[CH:19][CH2:20]Br>CN(C)C=O.O>[N+:7]([C:6]1[CH:5]=[CH:4][C:3]([O:10][CH2:20][CH:19]=[C:18]([CH3:17])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[CH:2][CH:1]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)=CCCC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCCC(C)=CCOc1ccc([N+](=O)[O-])cc1
Reaction time: 12 h

Procedure:
To a solution of p-nitrophenol (2 g.) in dimethylformamide (10 ml.) is added anhydrous potassium carbonate (2 g.) and 3,7-dimethylocta-2,6-dienyl bromide (3.1 g.). The reaction is kept at 50° for 12 hours, diluted with water and extracted with ether. The ethereal extract is washed with 5% aqueous sodium hydroxide and dried over sodium sulfate. The crude product is purified by distillation to yield 3,7-dimethylocta-2,6-dienyl p-nitrophenyl ether.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])(=O)=O)=CC=1.[F:22][C:23]([F:32])([C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:25][CH2:26]O.CC(C)([O-])C.[K+].C(O)C>O1CCCC1>[F:22][C:23]([F:32])([C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:25][CH2:26][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: OCCCC(F)(F)C(F)(F)F
Reactant: CCOC(=O)CCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCCCCOCCCC(F)(F)C(F)(F)F
Temperature: 200 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
To a stirred solution of the product of step (a) (500 mg) and 4,4,5,5,5-pentafluoropentan-1-ol (284 mg) in tetrahydrofuran (10 ml) was added potassium tert-butoxide (1M in tetrahydrofuran; 1.6 ml) and the reaction was stirred at 200° C. for 2 hours. An additional charge of potassium tert-butoxide (1M in tetrahydrofuran; 1.6 ml) was added and the reaction was stirred for a further 18 hours. Ethanol (5 ml) was added and the reaction was stirred for 30 mlnutes. The reaction mixture was partitioned between dichloromethane (300 ml) and water (300 ml). The organic layer was dried over magnesium sulphate and the solvent was removed in vacuo. Purification by column chromatography on silica gel (5 g Bond Elut cartridge) eluting with 20% ethyl acetate in cyclohexane gave the title compound as a clear oil (100 mg).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9](=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([O-])=O>CCO.C1COCC1.[Zn]>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9](=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCC(=O)OCCCC[N+](=O)[O-]
Agent: [Zn]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCC(=O)OCCCCN

Procedure:
Hexadecanoic acid (4-nitrobutyl)ester was reduced with zinc in EtOH/THF/6 nHCl for 30 minutes at 35°-35°. Work up in the cold via basification with ammonia and extraction with methylene chloride yielded a crude residue. Crystallization from ether furnished off-white crystals, m.p. 59°-61°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=O)=[CH:4][CH:3]=1.[NH2:25][NH2:26].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[NH:26][N:25]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)C#Cc2ccc(Cl)cc2)CC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccc(Cl)cc3)n[nH]2)CC1
Temperature: 75 °C

Procedure:
To a solution of tert-butyl 4-[3-(4-chlorophenyl)prop-2-ynoyl]piperidine-1-carboxylate (5.28 g, 15.18 mmol) in ethanol (160 mL) was added hydrazine (0.953 mL, 30.4 mmol) and triethylamine (4.23 mL, 30 4 mmol). The mixture was heated at 75° C. for 3 h. The solvent was evaporated under reduced pressure, and dried under vacuum to give INTERMEDIATE 1. LC-MS m/z 362.19 [M+H]+, 306.14 [M−56+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][C:31]=1[O:39][CH3:40].C(=O)([O-])[O-].[K+].[K+].CO.C(OCC)(=O)C>C(O)CCC.C(Cl)(Cl)Cl.C(OCC)(=O)C.[I-].[K+]>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][C:31]=3[O:39][CH3:40])[CH2:11][CH2:10]2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)C2CCNCC2)cc1
Reactant: COc1cc(C(C)=O)ccc1OCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(C(C)=O)ccc1OCCCCCCN1CCC(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
A mixture of 4-[bis(4-fluorophenyl)methyl]piperidine (7.90 g, 0.0275 mole), 1-[4-(6-chlorohexyloxy)-3-methoxyphenyl]ethanone (7.82 g, 0.025 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated overnight at reflux in 400 ml of 1-butanol containing potassium iodide (0.2 g). The mixture was cooled to room temperature and filtered. Butanol was removed by rotary evaporation. The brown oil obtained was dissolved in chloroform and extracted several times with water. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a brown oil. This oil was dissolved in ethyl acetate and subjected to flask chromatography on silica gel using ethyl acetate and 5% methanol-ethyl acetate for elution. Fractions of similar purity were combined and solvent removed to give an oil. The oil was dried at 80° C. overnight in vacuo to give 7.28 g (54.4% yield) of title compound as a light brown oil.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:5]([CH3:15])=[C:6]([CH3:14])[C:7]2[N:8]([C:10]([NH2:13])=[N:11][N:12]=2)[N:9]=1.[CH2:16]([OH:19])[CH2:17][CH3:18]>CN(C=O)C>[CH3:15][C:5]1[C:4]([O:19][CH2:16][CH2:17][CH3:18])=[N:9][N:8]2[C:10]([NH2:13])=[N:11][N:12]=[C:7]2[C:6]=1[CH3:14]
Reactant: Cc1c(Cl)nn2c(N)nnc2c1C
Reactant: CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1nn2c(N)nnc2c(C)c1C

Procedure:
1-Propanol (28 ml) was deprotonated analogously to W1.056 with sodium hydride (1.3 g) and reacted with 6-chloro-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.006a, 1 g), dissolved in 1-propanol (10 ml) and DMF (10 ml), and worked up. 647 mg of the title compound were isolated in sufficient purity.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:36])=[CH:21][N:20]=1>>[CH2:1]([O:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:19]3[N:24]=[C:23]([NH:25][C:26]4[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=4[C:28](=[O:29])[NH:30][CH3:31])[C:22]([Cl:36])=[CH:21][N:20]=3)=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCOC(=O)N1CCCOc2cc(N)ccc21
Product: CCOC(=O)N1CCCOc2cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc21

Procedure:
3-[5-Chloro-4-(2-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide in an analogous manner to Example 1410. Product isolated as a yellow foam (102 mg, 52%). LCMS (m/e) 497 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.14-11.00 (m, 1H), 8.70-8.36 (m, 1H), 8.12 (s, 1H), 7.57-6.96 (m, 7H), 6.48-6.38 (m, 1H), 4.33-4.03 (m, 4H), 3.88-3.60 (m, 2H), 3.03 (d, 3H, J=4.4 Hz), 2.15-2.00 (m, 2H), 1.42-1.12 (m, 3H).
Reaction SMILES: [K].[C:2]([O:7][CH3:8])(=[O:6])/[CH:3]=[CH:4]/[CH3:5].[CH:9]([C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:13][CH:12]=1)=O.S([O-])(O)(=O)=O.[K+]>C(O)(C)(C)C.O.CCOCC>[C:18]([O:17][C:15]([C:14]1[CH:22]=[CH:23][C:11]([CH2:9][CH2:5][CH2:4][CH2:3][C:2]([O:7][CH3:8])=[O:6])=[CH:12][CH:13]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: C/C=C/C(=O)OC
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: COC(=O)CCCCc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
Under an atmosphere of argon, potassium (25 g) was dissolved completely in dried tert-butyl alcohol (820 ml) by refluxing by heating for 3 hours. The solution was cooled to 20° C., to which was added ether (300 ml) and then slowly a solution of methyl crotonate (63.93 g) and tert-butyl 4-formylbenzoate (71.0 g) in tert-butyl alcohol-ether mixture (2:1, 300 ml) while keeping the inner temperature at 10° C. The mixture was stirred at the same temperature for 2 hours, and 1 N potassium hydrogen sulfate in water (750 ml) was added with cooling to adjust the pH to 4. After extraction with ether, the ether layer was washed with saturated sodium chloride solution and the solvent was evaporated off under reduced pressure. The residue was dissolved in ethyl acetate (100 ml), to which was added 5% Pd-C (15 g: manufactured by Engelhard Co. Ltd.), and stirred vigorously at room temperature under hydrogen pressure of 4 kg/cm2 for 3 hours. The catalyst was filtered off, the solvent was evaporated off under reduced pressure, and dried methanol (200 ml), 4-(N,N-dimethylamino)pyridine (30 mg) and dichloromethane (250 ml) were added, to which a solution of 1,3-dicyclohexylcarbodiimide (132 g) in dichloromethane (250 ml) was added slowly dropwise at 0° C. After stirring at room temperature for 18 hours, the mixture was cooled to 0° C. Acetic acid (30 ml) was added and the mixture stirred at 0° C. for 30 minutes and then at room temperature for 30 minutes. The resulting precipitate was filtered off, the filtrate was concentrated to dryness under reduced pressure, and to the residue was added ethyl acetate (100 ml), which was left standing at 0° C. for 2 hours, and the resulting precipitate was again filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (carrier: silica gel, 500 g, ether-hexane, 1:15→1:5), to give the object compound (59.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7](=[CH:22][N:23](C)[CH3:24])[C:8]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=O)=[CH:4][CH:3]=1.C[NH:29]N>C(O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]2[C:8]([C@H:10]3[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:29][N:23]([CH3:24])[CH:22]=2)=[CH:4][CH:3]=1
Reactant: CNN
Reactant: CN(C)C=C(Cc1ccc(Cl)cc1)C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Solvent: CCO
Product: Cn1cc(Cc2ccc(Cl)cc2)c([C@H]2CCCN2C(=O)OC(C)(C)C)n1
Temperature: 70 °C
Yield: 69.2 %

Procedure:
To a solution of (R)-tert-butyl 2-(2-(4-chlorobenzyl)-3-(dimethylamino)acryloyl)pyrrolidine-1-carboxylate (120 mg, 0.3 mmol) in ethanol (4 mL) was added 1-methylhydrazine (60 μL, 2.4 mmol). The resulting solution was heated at 70° C. for 3 h and concentrated in vacuo. Purification of the resulting residue by silica gel column chromatography (hexanes/ethyl acetate gradient, 10-100% ethyl acetate) afforded (R)-tert-butyl 2-(4-(4-chlorobenzyl)-1-methyl-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate (78 mg, 75%). LCMS: calculated: 375, found (MH+): 376.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:41])[C@@H:12]([NH:20][C:21](=[O:40])[CH:22]([NH:32]C(OC(C)(C)C)=O)[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([F:31])[CH:24]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:41])[C@@H:12]([NH:20][C:21](=[O:40])[CH:22]([NH2:32])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([F:31])[CH:24]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)C(NC(=O)OC(C)(C)C)c2ccc(OC)c(F)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)C(N)c2ccc(OC)c(F)c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
2-{(S)-2-[2-tert-Butoxycarbonylamino-2-(3-fluoro-4-methoxy-phenyl)-acetylamino]-3-phenyl-propionylamino}-thiazole-4-carboxylic acid methyl ester (0.98 g, 2.28 mmol) was taken into dry dichloromethane (20 mL) under argon and cooled in an ice bath. To this was added trifluoroacetic acid (10 mL, 130 mmol) and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was then concentrated to dryness. The oil was dissolved in dichloromethane and precipited with ether and the resulting suspension stirred for 15 minutes. The precipitate was isolated by filtration, washed with ether and dried to give a tan solid. The solid was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic solution was dried over sodium sulfate, filtered, concentrated and dried to give 2-{(S)-2-[2-amino-2-(3-fluoro-4-methoxy-phenyl)-acetylamino]-3-phenyl-propionylamino}-thiazole-4-carboxylic acid methyl ester as a tan foam (0.70 g, 92%).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=1.C1(N2CCC3C=C(OC4C=CC(C#N)=CN=4)C=CC=3CC2)CCC1>>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][C:18]4[N:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=4)=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Agent: N#Cc1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Product: CC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1

Procedure:
Example 214 (E214) was prepared from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and 1-(6-chloropyridin-3-yl)ethanone using the method described for Example 100 (E100); MS (ES+) m/e 337 [M+H]+.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][N:10]1[CH:15]2[CH2:16][CH2:17][CH:11]1[C:12](=[O:18])[CH2:13][CH2:14]2>O1CCCC1>[CH3:9][N:10]1[CH:15]2[CH2:16][CH2:17][CH:11]1[C:12]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:18])[CH2:13][CH2:14]2
Reactant: CN1C2CCC(=O)C1CC2
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CN1C2CCC1C(O)(c1ccccc1)CC2
Temperature: 0 °C
Reaction time: 5 h
Yield: 65.1 %

Procedure:
To 5.4 ml (5.39 mmol) of a 1M phenyl-magnesium bromide solution under nitrogen at 0° C., was added drop-wise a solution of 500 mg 8-methyl-8-aza-bicyclo[3.2.1]octan-2-one (CAS 78477-91-5) in 5 ml tetrahydrofuran over mol-sieve. The reaction mixture was stirred at 0° C. for 5 hours. The mixture was quenched under ice bath cooling with a 20% ammonium chloride solution (5 ml). The organic layer was separated and the aqueous layer was extracted once with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified with flash column chromatography on silica (20 g) eluting with a gradient formed from n-heptane and ethyl acetate (0 to 100%) to provide 508 mg (65.1%) of the title compound as a light yellow oil. MS (m/e): 218.4 (M+H+).
Reaction SMILES: [OH-].[Na+:2].[Cl:3][C:4]1[N:9]=[N:8][C:7]([O:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH:18]2[CH2:20][CH2:19]2)=[C:6]([OH:21])[CH:5]=1>C(O)C>[Cl:3][C:4]1[N:9]=[N:8][C:7]([O:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH:18]2[CH2:20][CH2:19]2)=[C:6]([O-:21])[CH:5]=1.[Na+:2]
Reactant: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1[O-]
Temperature: 50 °C
Reaction time: 4 h
Yield: 100.3 %

Procedure:
0.18 mL (0.36 mmol) of 2 mol/L aqueous sodium hydroxide solution was added to an ethanol (2 mL) solution containing 100 mg (0.361 mmol) of 6-chloro-3-(2-cyclo-propyl-6-methylphenoxy)-4-pyridazinol, and the resulting mixture was stirred at 50° C. for 4 hours. The reaction mixture was concentrated to obtain 108 mg (0.361 mmol, Yield: 100%) of sodium 6-chloro-3-(2-cyclopropyl-6-methyl-phenoxy)-4-pyridazinolate (Compound No. 3805).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]([O:12]CC)=O)[CH:5]=[C:4]([CH3:15])[N:3]=1.[C:16]1([CH2:22][CH2:23][NH2:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]([NH:24][CH2:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12])[CH:5]=[C:4]([CH3:15])[N:3]=1
Reactant: CCOC(=O)CSc1cc(C)nc(N)n1
Reactant: NCCc1ccccc1
Solvent: CO
Product: Cc1cc(SCC(=O)NCCc2ccccc2)nc(N)n1
Yield: 76.7 %

Procedure:
A mixture of 7.50 g (33.0 mmol) of ethyl 2-[(2-amino-6-methylpyrimidin-4-yl)thio]acetate, 4.40 g (36.3 mmol) of 2-phenylethylamine and 25 ml of MeOH was heated at 120° for 18 hrs. in a steel bomb. The reaction mixture was evaporated to a residual solid which yielded crude solid product (7.65 g, 76.7%), m.p. 114°-121° upon trituration with Et2O. The analytically pure sample was obtained after one recrystallization from 2-propanol, m.p. 130°-132° (3.79 g, 38%).
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:7]3[C:30]([C:31]4[CH:36]=[CH:35][C:34]([C:37](=[O:40])[NH:38][CH3:39])=[CH:33][CH:32]=4)=[CH:29][N:28](COCC[Si](C)(C)C)[C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:25]=[CH:24][C:16]([C:17]([NH:19][CH:20]4[CH2:23][O:22][CH2:21]4)=[O:18])=[CH:15][C:14]=3[O:26][CH3:27])[N:11]=2)[CH2:4][CH2:3][CH2:2]1.ClC1N=C(OC2CCC2)C2C(C3C=CC(C(NC)=O)=CC=3)=CN(COCC[Si](C)(C)C)C=2N=1.NC1C=CC(C(NC2COC2)=O)=CC=1OC.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]1([O:5][C:6]2[C:7]3[C:30]([C:31]4[CH:32]=[CH:33][C:34]([C:37](=[O:40])[NH:38][CH3:39])=[CH:35][CH:36]=4)=[CH:29][NH:28][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:25]=[CH:24][C:16]([C:17]([NH:19][CH:20]4[CH2:23][O:22][CH2:21]4)=[O:18])=[CH:15][C:14]=3[O:26][CH3:27])[N:11]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Nc4ccc(C(=O)NC5COC5)cc4OC)nc(OC4CCC4)c23)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CCC4)c23)cc1
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(-c2c[nH]c3nc(Nc4ccc(C(=O)NC5COC5)cc4OC)nc(OC4CCC4)c23)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
4-((4-Cyclobutoxy-5-(4-(methylcarbamoyl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-(oxetan-3-yl)benzamide. To a degassed mixture of 4-(2-chloro-4-cyclobutoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylbenzamide (1 equiv), 4-amino-3-methoxy-N-(oxetan-3-yl)benzamide (1.1 equiv) and cesium carbonate (3 equiv) in 1,4-dioxane (0.09 M) was added palladium acetate (0.1 equiv) and 2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (0.3 equiv). The reaction was stirred at 100° C. for 2 h. The reaction mixture was cooled to room temperature, and concentrated. The residue was purified by silica gel chromatography (0-5% DCM in methanol) to afford the title compound (crude) as a yellow solid which was used in the next step without further purification. MS (ESI) m/z 673.1 [M+1]+.