Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:12]=[C:11]([F:21])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30](Cl)[CH:29]=[CH:28][C:27]=1[N+:33]([O-:35])=[O:34].[CH3:37][N:38]([CH3:43])[CH2:39][CH2:40][CH2:41][NH2:42]>>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:12]=[C:11]([F:21])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30]([NH:42][CH2:41][CH2:40][CH2:39][N:38]([CH3:43])[CH3:37])[CH:29]=[CH:28][C:27]=1[N+:33]([O-:35])=[O:34]
Reactant: O=C(Nc1cc(F)cc(N2CCOCC2)c1)c1ccc(Cl)c(NC(=O)c2cc(Cl)ccc2[N+](=O)[O-])c1
Reactant: CN(C)CCCN
Product: CN(C)CCCNc1ccc([N+](=O)[O-])c(C(=O)Nc2cc(C(=O)Nc3cc(F)cc(N4CCOCC4)c3)ccc2Cl)c1
Yield: 76 %

Procedure:
Using an analogous procedure to that described in the sixth paragraph of the portion of Note a) immediately above which is concerned with the preparation of starting materials. 4-chloro-3-(5-chloro-2-nitrobenzamido)-N-(3-fluoro-5-morpholinophenyl)benzamide was reacted with 3-dimethylaminopropylamine to give 4-chloro-3-[5-(3-dimethylaminopropylamino)-2-nitrobenzamido]-N-(3-fluoro-5-morpholinophenyl)benzamide in 76% yield; NMR Spectrum: (DMSOd6) 1.62–1.74 (m, 2H), 2.12 (s, 6H), 2.27 (t, 2H), 3.08–3.13 (m, 4H), 3.18–3.22 (m, 2H), 3.69–3.74 (m, 4H), 6.58 (d, 1H) 6.67 (m, 2H), 7.15–7.2 (m, 2H), 7.42 (t, 1H), 7.69 (d, 1H), 7.68 (d, 1H), 7.82 (d, 1H), 8.04 (d, 1H), 8.26 (s, 1H), 10.32 (s, 1H); Mass Spectrum: M+H+ 599.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.B.O1CCCC1.CO>C1COCC1>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(F)cc1[N+](=O)[O-]
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])c1cc(F)c(F)cc1CO
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of to 4,5-difluoro-2-nitrobenzoic acid (25.9 g) in THF (90 ml), cooled to 0° C., was carefully added borane-tetrahydrofuran complex (319 ml, 1M in THF). After the addition was complete, the mixture was stirred at 60° C. for 3 h. Methanol (150 ml) was added to the mixture at 0° C. and after 10 minutes the mixture was concentrated in vacuo. The residue was poured into water and extracted with ethyl acetate. The organic layer was washed with sat. aq. NaCl, dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[C:10]([CH3:16])=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1.[ClH:17].[Cl:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1>>[ClH:18].[ClH:17].[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][N:20]=[C:19]2[NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[C:10]([CH3:16])[CH:11]=1
Reactant: Cc1cc(N)ccc1OCc1ccccn1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(C)c3)c2cc1OC
Yield: 60 %

Procedure:
Using an analogous procedure to that described in Example 1, 5-amino-2-tolyl 2-pyridylmethyl ether was reacted with 4-chloro-6,7-dimethoxyquinazoline hydrochloride to give 6,7-dimethoxy-4-[3-methyl-4-(2-pyridylmethoxy)anilino]quinazoline dihydrochloride salt in 60% yield, m.p. 239°-241° C.;
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(N(CC)CC)C.Cl.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>CN(C=O)C>[NH2:35][C:31]1[CH:30]=[C:29]([CH:26]2[CH2:27][CH2:28][N:23]([C:8](=[O:10])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:11]([F:14])([F:13])[F:12])=[N:5]3)[CH2:24][CH2:25]2)[CH:34]=[CH:33][CH:32]=1
Reactant: Nc1cccc(C2CCNCC2)c1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2cccc(N)c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (0.49 g, 2.35 mmol) in DMF (10 mL) is added triethylamine (0.65 mL, 4.7 mmol), followed by 1-hydroxy-7-benzotriazole (0.32 g, 2.35 mmol) and 1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (0.45 g, 2.35 mmol). After stirring 15 min at RT, 3-Piperidin-4-yl-phenylamine hydrochloride (0.50 g, 2.35 mmol) is added to the reaction mixture. After stirring overnight at RT, solvent is evaporated and the resulting yellow oil is dissolved in ethylacetate (20 mL), washed with saturated aqueous sodium bicarbonate solution (20 mL), and brine (20 mL). The organic layer is dried over sodium sulfate, filtered, and evaporated under reduced pressure to give 1-[4-(3-amino-phenyl)-piperidin-1-yl]-2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone as a crude mixture of good enough purity for the next step (0.86 g, quantitative). 1H-NMR (400 MHz, MeOD): δ=1.52-1.63 (m, 1H), 1.64-1.73 (m, 1H), 1.80-1.93 (m, 2H), 2.33 (s, 3H), 2.68-2.81 (m, 2H), 2.99 (s, 2H), 3.21-3.27 (m, 1H), 4.02-4.09 (m, 1H), 4.55-4.62 (m, 1H), 5.12-5.28 (q, 2H), 6.41 (s, 1H), 6.55-6.60 (m, 1H), 6.61-6.62 (m, 1H), 7.00-7.07 (t, 1H), 7.99 (s, 1H). MS: m/z=367 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:26](OC)(OC)(OC)[CH3:27].Cl.[NH+]1C=CC=CC=1>ClCCCl>[CH3:26][C:27]1[N:12]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CC(C)(C)OC(=O)NCCOCCNc1c(N)cnc2ccccc12
Reactant: COC(C)(OC)OC
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCCl
Product: Cc1nc2cnc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
A solution of tert-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (12.05 g, 34.8 mmol) in 200 mL of 1,2-dichloroethane was treated with trimethyl orthoacetate (5.50 mL, 43.2 mmol) and the reaction mixture was heated to reflux. A 100 mg portion of pyridinium hydrochloride was then added and refluxing was continued for 4 h. The reaction was then cooled and washed with water and brine. The organic portion was dried over Na2SO4 and concentrated to give an orange foam. The foam was triturated with ether and filtered to yield 10.76 g of tert-butyl 2-[2-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a tan solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:33])[CH:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:16][O:17]S(C)(=O)=O)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:34]1(O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:33])[CH:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:16][O:17][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(F)cc2)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2ccccc2)NS(=O)(=O)c2ccc(F)cc2)cc1
Yield: 80.4 %

Procedure:
The procedure described in Example 125 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzene-sulfonylamino)-3-methanesulfonyloxypropanamide (500 mg) was reacted with phenol (187 mg) to obtain (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-phenoxypropanamide (400.58 mg).
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]([CH2:31]I)=[CH2:30])[C@@H:9]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH2:1]([N:8]1[CH2:28][C:29](=[CH2:31])[CH2:30][C@H:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:9]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(CI)CN(Cc1ccccc1)[C@@H](CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C1C[C@H](C(=O)OC(C)(C)C)[C@@H](C(=O)OCc2ccccc2)N(Cc2ccccc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
To a cooled (−78° C.) solution of 1-benzyl 4-tert-butyl(2S)-2-{benzyl[2-(iodomethyl)prop-2-en-1-yl]amino}succinate from step 1c (9.2 g) in THF (50 mL) was added dropwise LiHMDS (1.0 M in THF, 20.2 mL) at −78° C. during a period of 30 min. The mixture was stirred at −78° C. for 1 h, and then was allowed to warm to −30° C. during 3 h. The reaction mixture was quenched with 10% citric acid (10 mL) and diluted with brine (100 mL). The mixture was extracted with ethyl acetate (4×75 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified through Combiflash (hexane and ethyl acetate: gradient 0 to 5% during 12 min) to give the desired 2-benzyl 3-tert-butyl(2S,3S)-1-benzyl-5-methylenepiperidine-2,3-dicarboxylate (3.45 g). MS (ESI): 422.3 (M+H+).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]2[C:7]([CH2:15][CH2:16][O:17][Si](C(C)(C)C)(C)C)=[CH:8][NH:9][C:10]=2[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:4].[C:25]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])(=O)[CH2:26][CH2:27][CH3:28].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][C:25]1([CH2:26][CH2:27][CH3:28])[C:8]2[NH:9][C:10]3[C:6]([C:7]=2[CH2:15][CH2:16][O:17]1)=[C:5]([C:3](=[O:4])[NH:2][CH3:1])[CH:13]=[CH:12][C:11]=3[CH3:14])[CH3:35]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: CNC(=O)c1ccc(C)c2[nH]cc(CCO[Si](C)(C)C(C)(C)C)c12
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)ccc(C(=O)NC)c21
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a solution of 3-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-7-methyl-1H-indole-4-carboxylic acid methylamide (100 mg, 0.289 mmol) and ethyl butyrylacetate (92 mL, 0.578 mmol) in CH2Cl2 (2 mL) was added BF3.OEt2 (0.11 mL, 0.867 mmol) dropwise at room temperature. After stirring overnight, the solution was diluted with CH2Cl2 (10 mL) and then washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic phase was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica, 50% EtOAc in hexanes) to give 88 mg (82%) of title compound as a yellow solid. 1H NMR (CDCl3): 300 MHz δ 9.54 (bs, 1H), 7.12 (d, J=7.38 Hz, 1H), 6.89 (d, J=7.38 Hz, 1H), 6.05 (d, J=4.71 Hz, 1H), 4.15 (m, 2H), 3.96 (m, 1H), 3.86 (m, 1H), 3.03–2.83 (m, 7H), 2.48 (s, 3H), 2.00 (m, 2H), 1.37 (m, 1H), 1.25 (t, J=6.84 Hz, 3H), 1.22 (m, 1H), 0.87 (t, J=7.17 Hz, 3H).
Reaction SMILES: [C:1]1(C(=CC=CC=1)O)[OH:2].[C:9]1([CH:16]=[CH:15][CH:14]=[C:12]([OH:13])[CH:11]=1)[OH:10].C1(C=CC(O)=CC=1)O>>[OH:10][C:9]1[CH:11]=[C:12]([OH:13])[CH:14]=[CH:15][C:16]=1[CH:1]=[O:2]
Reactant: Oc1cccc(O)c1
Reactant: Oc1ccccc1O
Agent: Oc1ccc(O)cc1
Product: O=Cc1ccc(O)cc1O

Procedure:
catechol; resorcinol; hydroquinone;
Reaction SMILES: C[Al](C)C.[NH2:5][CH2:6][CH2:7][NH2:8].C(O[C:12](=O)[CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[CH:16]=1)C.O>C1(C)C=CC=CC=1>[Cl:32][C:26]1[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=1[CH2:24][N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([CH2:14][CH2:13][C:12]2[NH:5][CH2:6][CH2:7][N:8]=2)=[CH:16]1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(Cl)cc2Cl)c2ccccc12
Reactant: NCCN
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccc(Cn2cc(CCC3=NCCN3)c3ccccc32)c(Cl)c1
Temperature: 0 °C

Procedure:
A 2M solution of trimethyl aluminium in toluene (3.32 ml) was diluted with dry toluene (30 ml), cooled to 0° C. and 1,2-diaminoethane (0.43 ml) was added. The mixture was brought to ambient temperature and a solution of 2.5 g of 3-[1-(2,4-Dichlorobenzyl)-1H-indol-3-yl]-propionic acid ethyl ester in dry toluene (20 ml) was added slowly. The reaction mixture was refluxed for 15 hours, cooled and carefully hydrolysed with water (20 ml). The organic phase was separated, dried over sodium sulphate and evaporated. The crude product was purified by column chromatography using successively methylene chloride/ethanol/aqueous ammonium hydroxide 50:49:1 and 50:43:7 respectively to yield the titled product.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]([NH:11][C:12]([CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:38]=[CH:39][CH:40]=1)[C:19]([C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[C:24]([C:35]([OH:37])=[O:36])=[CH:23][N:22]=1)=[O:20])=[O:13])([CH3:10])[CH3:9].[CH3:41][CH:42](N)[C:43]1C=CC=[CH:45][CH:44]=1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:34][O:33][C:27]1[CH:26]=[C:25]2[C:30](=[CH:29][C:28]=1[O:31][CH3:32])[C:21]([C:19](=[O:20])[C:18]1[CH:38]=[CH:39][CH:40]=[C:16]([O:15][CH2:14][C:12](=[O:13])[NH:11][CH:8]([C:10]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH3:9])[CH:17]=1)=[N:22][CH:23]=[C:24]2[C:35]([OH:37])=[O:36]
Reactant: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)NC(C)C)c3)c2cc1OC
Reactant: CC(N)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)NC(C)c4ccccc4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The resin bound activated ester (intermediate in the preparation of 1-[3-(Isopropylcarbamoyl-methoxy)-benzoyl]-6,7-dimethoxy-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid (Example 37)) (225 mg, 0.19 mmol) was combined with 3 ml of methylene chloride and 0.05 ml of α-methylbenzyl amine (0.4 mmol). The mixture was shaken for 15 minutes under argon at room temperature. The mixture was filtered and the filter cake was washed with methylene chloride. The filtrate was evaporated to dryness. The residue was saponified by dissolving in 1 ml of methanol containing 0.5 ml of 1N sodium hydroxide solution and several drops of tetrahydrofuran. The mixture was stirred at room temperature for 4 hrs and then evaporated to dryness. The residue was purified through a reverse phase preparative HPLC to give 6,7-Dimethoxy-1-{3-[(1-phenyl-ethylcarbamoyl)-methoxy]-benzoyl}-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid, as a fluffy solid (30 mg).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][CH2:59][C@H:60]([OH:62])[CH3:61]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][CH2:59][C@@H:60]([OH:62])[CH3:61])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: C[C@@H](O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC[C@H](C)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (R)-1-aminopropan-2-ol. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (d, J=6.1 Hz, 3H) 1.12-1.41 (m, 3H) 1.55-1.87 (m, 8H) 1.70-1.88 (m, 4H) 3.21 (q, J=6.3 Hz, 1H) 3.32 (s, 3H) 3.77 (m, 1H) 3.94 (s, 3H) 4.16 (t, J=13.0 Hz, 2H) 4.49 (quin., J=12.1 Hz, 1H) 7.53 (d, J=8.6 Hz, 1H) 7.58 (s, 1H) 8.14 (d, J=8.3 Hz, 1H) 8.23 (s, 1H) 8.41-8.47 (m, 1H) 8.51-8.57 (m, 1H). [M+H] calc'd for C25H32F2N6O4 519. found 519.
Reaction SMILES: [O:1]=[C:2]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH2:16])[CH:11]=2)[CH2:6][CH2:5]1.[H-].[Na+].Cl[C:25]1[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=1>>[O:1]=[C:2]([N:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1)[CH2:3][N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:25]3[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=3)[CH:11]=2)[CH2:8][CH2:9]1
Reactant: Nc1cc(N2CCN(CC(=O)N3CCCC3)CC2)ncn1
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cnc(Nc2cc(N3CCN(CC(=O)N4CCCC4)CC3)ncn2)s1

Procedure:
6-[4-(2-Oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]pyrimidin-4-amine 17-2 (0.60 g, 2.07 mmol) and sodium hydride (0.165 g, 4.13 mmol) and 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.299 g, 2.07 mmol) were treated as in Scheme 4 above. The product was purified on a silica column. Hi-Res MS: calc: 399.1710 found: 399.1706. 1NMR (CDCl3): 9.40 ppm (s, 1H); 8.45 ppm (s, 1H); 7.88 ppm (s, 1H); 5.98 ppm (s, 1H); 3.68 ppm (s, 4H); 3.50 ppm (m, 4H); 3.21 ppm (s, 2H); 2.68 ppm (t, 4H); 1.98 ppm (m, 2H); 1.87 ppm (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]#[CH:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>C(O)(C)C>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]#[CH:11])[CH:7]=[CH:8][CH:9]=1
Reactant: C#Cc1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Solvent: CC(C)O
Product: C#Cc1cccc(N)c1
Yield: 82 %

Procedure:
Example 6 was repeated using 50 grams of 3-nitrophenylacetylene (19% wt. conc.) in isopropanol in the presence of 8.0 grams of said cobalt polysulfide catalyst (weight ratio of NPA to Co of 50:1) for 1.1 hours at 120° C. and 1000 psig (6.9 MPa) of hydrogen pressure. Analysis showed quantitative conversion and 82% yield of 3-aminophenylacetylene. All byproducts were polymeric. The results are summarized in Table 1 below.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH:11]=[CH2:12])=[CH:4][CH:3]=1.B.C1C[O:17]CC1.OO>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][CH2:12][OH:17])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: C=C[C@H]1C[C@@H]1c1ccc(Br)cc1
Agent: B
Agent: OO
Product: OCC[C@H]1C[C@@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the alkene from Example 28D (1-bromo-4-[(1S,2R)-2-vinylcyclopropyl]benzene) in anhydrous THF (50 mL) under N2 was added borane-THF at 0° C. The mixture was stirred at room temperature for two hours and then chilled to 0° C. Aqueous hydrogen peroxide (30%) solution was added, the ice bath was removed, and the mixture was allowed to warm to room temperature with continued stirring for 10 minutes. The mixture was quenched with saturated aqueous NH4Cl and extracted with ether. The combined organic extracts were dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified on silica gel with 4:1 hexanes/ethyl acetate to provide the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:8][CH:7]=[N:6][C:5]=1[CH:9]=[O:10].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1COCC1>[CH:9]([C:5]1[N:6]=[CH:7][N:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:4]=1[CH3:3])=[O:10]
Reactant: Cc1[nH]cnc1C=O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1cnc(C=O)c1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
A 30% solution of sodium hydride (1.2 g, 32.6 mmol) was washed with pet ether (3×15 mL) and then slurried in THF (30 mL) under nitrogen. The slurry was cooled to 0° C. and 5-methylimidazole-4-carboxaldehyde (3 g, 27.2 mmol) was added in two portions. The mixture was stirred at ambient temperature for 2 hours, cooled to 0° C. and ethyl bromacetate (4.5 mL, 38.1 mmol) was added dropwise. The mixture was stirred at ambient temperature for 40 minutes and partitioned between ethyl acetate and water. The organic layer was isolated, washed with water, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was triturated with pet ether to provide ethyl 4-formyl-5-methylimidazol-1-ylacetate (5.3 g, 27 mmol) as a yellow solid. 1H-NMR (300 Mhz, DMSO-d6): 1.2 (t, 3H), 2.4 (s, 3H), 4.2 (q, 2H), 5.0 (s, 2H), 7.8 (s, 1H), 9.8 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[CH:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:13]([OH:15])=O>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][CH:13]([OH:15])[C:12]#[C:11][C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(C(C)(C)C)cc1
Reactant: O=CO
Product: CC(C)(C)c1ccc(C#CC(O)C#Cc2ccc(C(C)(C)C)cc2)cc1

Procedure:
In the first stage, (A) 4-tert-butylphenylacetylene, organic magnesium halide, and a formic acid derivative are used, thereby obtaining (B) 1,5-bis(4-tert-butylphenyl)-penta-1,4-diyn-3-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH:12]1[CH2:14][CH2:13]1)[C:6](=[O:15])[CH2:5]2.[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][C@H:24]1[CH2:26][O:25]1)([CH3:19])([CH3:18])[CH3:17].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C.C(OCC)(=O)C>[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][C@H:24]([OH:25])[CH2:26][NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH:12]1[CH2:13][CH2:14]1)[C:6](=[O:15])[CH2:5]2)([CH3:18])([CH3:17])[CH3:19]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CO1
Reactant: Nc1cc(F)c2c(c1)CC(=O)N2C1CC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC[C@H](O)CNc1cc(F)c2c(c1)CC(=O)N2C1CC1

Procedure:
5-Amino-1-cyclopropyl-7-fluoro-1,3-dihydro-indol-2-one (0.560 g, 2.72 mmol), (S)-oxiranylmethyl-carbamic acid tert-butyl ester (0.472 g, 2.72 mmol) and lithium trifluoromethanesulfonate (0.415 g, 2.72 mmol) in acetonitrile (5 ml) are heated at 85° C. for 4.5 hours. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated. Final purification by flash chromatography (70% Ethyl acetate/hexane) gives the title compound as a yellow solid. HPLC r.t. 3.98 min; MS for C19H26FN3O4 m/z 380.1 (M+H)+.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([O:14][P:15]([CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:34][CH:33]=2)[CH:25]=1)O)(=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:13])([CH3:12])[CH3:11].[OH-].[K+]>ClCCl>[C:10]([O:14][P:15]([CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:34][CH:33]=2)[CH:25]=1)[F:7])(=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OP(=O)(OC(C)(C)C)C(O)c1cccc(OCc2ccc(-c3ccccc3)cc2)c1
Reactant: CCN(CC)S(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)c1cccc(OCc2ccc(-c3ccccc3)cc2)c1
Temperature: -70 °C
Reaction time: 20 h
Yield: 36 %

Procedure:
Diethylaminosulfur trifluoride (2.2 ml, 8.2 mmol) was dissolved in dichloromethane (25 ml) and the solution was cooled to -70° C. and added dropwise to a solution of the above hydroxymethylphosphonic acid di-tert-butyl ester (4.0 g, 8.3 mmol) in dichloromethane (15 ml) at -70° C. The mixture was stirred at -70° C. for 3 h and at room temperature for 20 h. With stirring the mixture was poured into 1 N aqueous potassium hydroxide (200 ml) and the mixture was extracted with dichloromethane (1×300 ml) and (1×100 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (100 ml), dried (MgSO4), filtered and evaporated in vacuo affording 1.43 g (36%) of ((3-(biphenyl-4-ylmethoxy)-phenyl)fluoromethyl)phosphonic acid di-tert-butyl ester as a solid.