Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: CCCCCCN
Product: CCCCCCNCc1ccccc1
Yield: 88.1 %

Procedure:
A! 200 ml (1.49 moles) of hexylamine cooled to 5° C. were added with benzyl bromide (42.3 ml, 0.35 mole), and the resultant mixture was stirred for 1 hour at room temperature. The hexylamine in excess was then distilled off under vacuum, and the residue dissolved in 300 ml of ethyl ether and washed with 200 ml of 0.5N sodium hydroxide. The ether phase was anhydrified over sodium sulfate and evaporated to dryness thus yielding 75.5 g of a crude which, by distillation under vacuum, gave 59 g (yield: 89%) of N-benzyl-N-hexylamine (b.p.--90°-95° C./0.6 mmHg).
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][OH:6].Cl[CH2:11][C:12](OCC)=[O:13]>C1(C)C=CC=CC=1>[CH:7]([C@@H:4]1[NH:3][C:12](=[O:13])[CH2:11][O:6][CH2:5]1)([CH3:9])[CH3:8]
Reactant: CC(C)[C@H](N)CO
Reactant: CCOC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)[C@H]1COCC(=O)N1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
To an ice-cold, stirred suspension of sodium hydride (2.59 g, 64.8 mmol) in toluene (90 mL) was added dropwise a solution of (S)-2-amino-3-methylbutan-1-ol (3 g, 29.1 mmol) in toluene (60 mL). The reaction was then warmed to room temperature and a solution of ethyl chloroacetate (3.56 g, 29.1 mmol) in toluene (16 mL) was added dropwise. The resulting mixture was heated to reflux for 20 h under nitrogen and then concentrated under vacuum. The residue was purified by flash chromatography to afford 2.8 g of product (MS: (M+H)=144.3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1>O1CCCC1>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])/[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13]
Reactant: NCCCCCCN
Reactant: O=C1C=CC(=O)O1
Solvent: C1CCOC1
Product: NCCCCCCNC(=O)/C=C\C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
Under a nitrogen atmosphere, into a reaction vessel were charged 10.00 g (86.1 mmol) of 1,6-diaminohexane and 400 ml of tetrahydrofuran. A solution prepared by dissolving 8.44 g (86.1 mmol) of maleic anhydride in 25 ml of tetrahydrofuran was dropped into this under cooling with ice over a period of 2 hours, then, the mixture was stirred at room temperature overnight. After completion of the reaction, the deposited solid was isolated by filtration, and dried under reduced pressure. The resultant solid was dissolved in 100 ml of methanol, 100 ml of chloroform was added, and the solvent was distilled off under reduced pressure, the resultant solid was dried under reduced pressure at 35° C., to obtain 17 g of (2Z)-4-[(6-aminohexyl)amino]-4-oxo-2-butenoic acid as a white solid. NMR measurement thereof revealed a content of (2Z)-4-[(6-aminohexyl)amino]-4-oxo-2-butenoic acid of 38.4%. Net quantity: 8.1 g, yield: 43.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15](B4OC(C)(C)C(C)(C)O4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11]([CH3:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:31]1[CH:36]=[N:35][CH:34]=[CH:33][N:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([C:31]4[CH:36]=[N:35][CH:34]=[CH:33][N:32]=4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11]([CH3:29])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1Cc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Reactant: Clc1cnccn1
Product: CN1Cc2cc(-c3cnccn3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Yield: 47 %

Procedure:
A procedure similar to the one in Step A of Example 29 was used to couple (+)-4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline with 2-chloropyrazine. (+)-4-(3,4-Dichlorophenyl)-6-fluoro-2-methyl-7-(pyrazin-2-yl)-1,2,3,4-tetrahydroisoquinoline was obtained in 47% yield as a brown oil: ESI MS m/z 388 [M+H]+.
Reaction SMILES: [N:1]#[C:2]Br.[NH2:4][C:5]1[CH:6]=[C:7]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:8]=[CH:9][C:10]=1[OH:11].[OH-].[Na+]>O>[NH2:1][C:2]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:6][C:5]=2[N:4]=1
Reactant: N#CBr
Reactant: CC(C(=O)O)c1ccc(O)c(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)c1ccc2oc(N)nc2c1
Temperature: 25 °C
Reaction time: 41 h
Yield: 7.1 %

Procedure:
Cyanogen bromide (1.06 g., 0.1 mole.) was added to a stirred suspension of 2-(3-amino-4-hydroxyphenyl) propionic acid (1.8 g., 0.1 mole.) in water (100 ml.). The suspension was stirred at room temperature for a further 41 hours. The pH of the suspension was adjusted to 4 by the addition of 50% w/v sodium hydroxide solution. The suspension was filtered and the solid was washed (x2) with small volumes of water. Recrystallisation of the solid from 50% aqueous methanol gave 2-(2-amino-5-benzoxazolyl) propionic acid (1.46 g.), m.p. 225°-229°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH:10][C@H:11]([C:33]([O:35]C(C)(C)C)=[O:34])[CH2:12][NH:13][C:14](=[O:32])[C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](=[O:31])[NH:24][C:25]4[NH:26][CH2:27][CH2:28][CH2:29][N:30]=4)=[CH:17][CH:16]=3)=[N:7][C:6]=2[CH:40]=1.C(O)(C(F)(F)F)=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH:10][C@H:11]([C:33]([OH:35])=[O:34])[CH2:12][NH:13][C:14](=[O:32])[C:15]3[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23](=[O:31])[NH:24][C:25]4[NH:26][CH2:27][CH2:28][CH2:29][N:30]=4)=[CH:19][CH:20]=3)=[N:7][C:6]=2[CH:40]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)Nc1nc2cc(Br)ccc2o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCc1ccc(C(=O)NC[C@H](Nc2nc3cc(Br)ccc3o2)C(=O)O)cc1)NC1=NCCCN1
Yield: 117.9 %

Procedure:
Hydrolysis of the ester is carried out as in the previous examples, but starting from 56 mg of 10-7 and 2.5 ml of TFA in 2.5 ml of dichloromethane. 60 mg of 10-8 is obtained (in the form of the trifluoroacetic acid salt).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]1[NH:20][N:19]=[N:18][N:17]=1)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].Br[CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]1[N:17]=[N:18][N:19]([CH2:26][CH2:25][CH2:24][CH:23]=[CH2:22])[N:20]=1)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: C=CCCCBr
Reactant: CCCCc1nc(=O)c2cc(-c3nnn[nH]3)ccc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CCCCn1nnc(-c2ccc3[nH]c(CCCC)nc(=O)c3c2)n1
Yield: 53.2 %

Procedure:
A mixture of 3.0 g of 2-butyl-6-(1H-tetrazol-5-yl)-4(1H)-quinazolinone, 2.2 g of 5-bromo-1-pentene and 2 ml of N,N-diisopropylethylamine in 50 ml of tetrahydrofuran is refluxed for 24 hours. The volatiles are evaporated in vacuo to a residue which is partitioned between chloroform and water. The organic layer is dried over MgSO4, filtered and evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 3:2 ethyl acetate-hexanes to give a residue which crystallizes from ethyl acetate-hexanes to give 2.0 g of the desired product as a solid, m.p. 130° C.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])[C:10]2[CH:9]=[CH:8][N:7]3[C:17]([CH3:21])=[C:18]([CH3:20])[N:19]=[C:6]3[C:5]=2[NH:4][C@@H:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(OCC)C>[C:28]([O:1][C@H:2]1[C@@H:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])[C:10]2[CH:9]=[CH:8][N:7]3[C:17]([CH3:21])=[C:18]([CH3:20])[N:19]=[C:6]3[C:5]=2[NH:4][C@@H:3]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COCCO[C@H]1c2ccn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1O
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOCC
Product: COCCO[C@H]1c2ccn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1OC(=O)c1ccccc1

Procedure:
Analogously to example 6, 1.1 g of the title compound of melting point 78–80° C. (diethyl ether) are obtained by reaction of (7S,8R,9R)-8-hydroxy-7-(2-methoxyethoxy)-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine with benzoyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH:15]=[N:14][C:13]([C:16]([F:19])([F:18])[F:17])=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][NH:23][C@@H:22]1[CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:7](=[O:9])[C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[N:11]2[CH:15]=[N:14][C:13]([C:16]([F:19])([F:18])[F:17])=[N:12]2)[C@@H:22]1[CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)benzoic acid (0.24 g, 0.869 mmol), tert-butyl (((2S,3R)-3-methylpiperidin-2-yl)methyl)carbamate (0.22 g, 0.96 mmol) and DIPEA (0.3 mL, 1.738 mmol) in DCM (20 mL) was added HATU (0.33 g, 0.869 mmol). The mixture was stirred at rt for 1 h. The mixture was diluted with DCM and was washed with satd. NaHCO3 and brine and dried over Na2SO4. The solvent was removed in vacuo to obtain the title compound with no further purification for next step. ESI-MS (m/z): 482 [M+1]+.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:35]=[CH:34][C:33]([O:36][C@H:37]([CH:42]([CH3:44])[CH3:43])[C:38]([O:40][CH3:41])=[O:39])=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](O)=[O:28])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31]>>[Cl:14][C:15]1[CH:35]=[CH:34][C:33]([O:36][C@H:37]([CH:42]([CH3:44])[CH3:43])[C:38]([O:40][CH3:41])=[O:39])=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](=[O:28])[NH:13][C@H:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=3)[CH3:12])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31]
Reactant: COC(=O)[C@H](Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1)C(C)C
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: Cl
Product: COC(=O)[C@H](Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1)C(C)C

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (R)-1-(2-chloro-5-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [NH2:1][C@H:2]([P:6](=[O:9])([OH:8])[OH:7])[CH:3]([CH3:5])[CH3:4].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>[OH-].[Na+].O1CCCC1>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH:1][C@H:2]([P:6](=[O:8])([OH:7])[OH:9])[CH:3]([CH3:5])[CH3:4])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: CC(C)[C@H](N)P(=O)(O)O
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1)P(=O)(O)O
Temperature: 22 °C
Reaction time: 8 h

Procedure:
250 mg (1.6 mmol) of (R)-(1-amino-2-methylpropyl)phosphonic acid were dissolved in 6 ml of a 1 M NaOH and 6 ml of tetrahydrofuran. 560 mg (1.96 mmol) of 4-chlorobiphenyl-4′-sulfonyl chloride were then added and the mixture was stirred at 22° C. overnight. The reaction mixture was concentrated, acidified with 2 M HCl and extracted with ethyl acetate. The 4-chlorobiphenyl4′-sulfonic acid resulting as a by-product precipitated and was separated off. After drying and concentrating the ethyl acetate phase, a solid was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:33]=[C:32]([OH:34])[CH:31]=[CH:30][C:11]=3[C:12]=2[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:17][CH:16]=2)=[O:14])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:33]=[C:32]([OH:34])[CH:31]=[CH:30][C:11]=3[C:12]=2[CH:13]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[CH:19][CH:20]=2)[OH:14])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)oc2cc(O)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Oc1ccc(-c2oc3cc(O)ccc3c2C(O)c2ccc(OCCN3CCCCC3)cc2)cc1
Yield: 57.9 %

Procedure:
4.57 g (0.01 mol) of [2-(4-hydroxyphenyl)-6-hydroxybenzofuran-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl] methanone was dissolved in 250 mL of THF and 2 g (0.053 mol) of LiAlH4 was slowly added over a period of twenty minutes to the stirring solution. The reaction mixture was stirred and kept under a nitrogen atmosphere and the reaction was allowed to proceed for eighteen hours at room temperature and then it was concentrated to dryness in vacuo. 500 mL of EtOAc was slowly added along with 2 mL of water. After stirring for 10 minutes, 500 mL of water was added and the EtOAc layer was removed. The EtOAc layer was washed with an additional 500 mL of water and the layers were separated. The EtOAc layer was dried with anhydrous Na2SO4 and concentrated to dryness to yield 2.66 g of the title compound as tan amorphous powder.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[C:11]([NH2:20])[N:10]([CH3:21])[N:9]=1)(=O)C.[CH:22]([C:25]1[CH:26]=[CH:27][C:28]([S:31](Cl)(=[O:33])=[O:32])=[N:29][CH:30]=1)([CH3:24])[CH3:23].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[OH:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[C:11]([NH:20][S:31]([C:28]2[CH:27]=[CH:26][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:30][N:29]=2)(=[O:32])=[O:33])[N:10]([CH3:21])[N:9]=1
Reactant: CC(=O)OCCOc1nn(C)c(N)c1-c1ccc(C)cc1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)nc1
Agent: CN(C)c1ccncc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Reaction time: 8 h
Yield: 47.2 %

Procedure:
To a solution of 2-{[5-amino-1-methyl-4-(4-methylphenyl)-1H-pyrazol-3-yl]oxy}ethyl acetate (Preparation 5) (3.80 g) in anhydrous pyridine (25 ml) at room temperature and under an atmosphere of nitrogen was added 4-dimethylaminopyridine (0.85 g) and 5-isopropyl-2-pyridinesulfonyl chloride (2.00 g). After being left to stir overnight, the reaction mixture was poured onto saturated citric acid solution (300 ml) and extracted with ethyl acetate (2×200 ml). The organic fractions were washed with brine (200 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. To a solution of the residue (4.45 g) in ethanol (100 ml) was added sodium hydroxide solution (2.76 g in 10 ml water). The red solution which formed was stirred for 1 hour before being concentrated to approximately 20 ml under reduced pressure and partitioned between ethyl acetate (2×100 ml) and saturated citric acid solution (100 ml). Washing of the organic fractions with brine (100 ml), drying over magnesium sulfate, filtering and concentration under reduced pressure afforded a brown residue. Purification by column chromatography on silica gel (200 g), eluting in an isocratic fashion with dichloromethane:methanol (20:1) afforded the title compound as a brown foam (1.85 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1.[CH2:22](Br)[C:23]#[CH:24]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH2:24][C:23]#[CH:22])[C:12](=[O:14])[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1
Reactant: C#CCBr
Reactant: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.76 g of 50% sodium hydride in mineral oil were added to 250 ml. of dimethylforamamide cooled to about 0° C. The temperature of the suspension was maintained at about 0° C., while a solution of 27.05 g (0.1 mol) of 7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one in 50 ml. of dimethylformamide was added dropwise to it. The resulting mixture was stirred for 2 hours, and then 10 ml. of propargyl bromide were added dropwise while maintaining the temperature at 10°-15° C. The reaction mixture was stirred for about 4 hours and then poured over ice. The product was filtered and dissolved in chloroform; and the chloroform solution was separated from the aqueous layer, and dried over sodium sulphate. The chloroform was evaporated off from the solution and the residue was dissolved in the minimum quantity of a 7:3 (by volume) mixture of benzene and ethyl acetate. This solution was chromatographed on a column of silica gel and eluted with a 7:3 (by volume) mixture of benzene and ethyl acetate. The portion of eluate containing the desired product, as determined by thin-layer chromatography, was collected and evaporated under reduced pressure. The residue was recrystallized from a 1:1 (by volume) mixture of benzene and hexane, giving 16 g of the pure desired product with a melting point of 141°-143° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:21][C@H:20]([OH:22])[CH2:19][C@@H:18]1[C:23]([N:25]1[CH2:31][CH2:30][CH2:29][N:28]([CH:32]2[CH2:35][CH2:34][CH2:33]2)[CH2:27][CH2:26]1)=[O:24])=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]1[CH2:21][C@H:20]([O:22][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:19][C@@H:18]1[C:23]([N:25]1[CH2:31][CH2:30][CH2:29][N:28]([CH:32]2[CH2:33][CH2:34][CH2:35]2)[CH2:27][CH2:26]1)=[O:24])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)N1CCCN(C2CCC2)CC1
Reactant: N#Cc1ccc(Br)cc1
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2ccc(C#N)cc2)C[C@@H]1C(=O)N1CCCN(C2CCC2)CC1

Procedure:
The title compound was prepared from 4-bromobenzonitrile and (2R,4R)-2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as described for Example 59. MS (ESI): mass calcd. for C26H36N4O4, 468.27; m/z found, 469.4 [M+H]+. 1H NMR (CDCl3): 7.66-7.51 (m, 2H), 6.99-6.86 (m, 2H), 5.05-4.85 (m, 1H), 4.79-4.54 (m, 1H), 4.12-3.96 (m, 1H), 3.84-3.41 (m, 4H), 2.93-2.77 (m, 1H), 2.75-2.13 (m, 5H), 2.10-1.54 (m, 10H), 1.50-1.40 (m, 9H).
Reaction SMILES: Cl.CN.[CH2:4]([O:6][C:7]1[CH:8]=[C:9]([O:25][C:26]2[CH:27]=[N:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=2)[CH:10]=[C:11]2[C:15]=1[NH:14][C:13]([C:16]1[S:17][CH:18]([CH2:21][C:22](O)=[O:23])[CH2:19][N:20]=1)=[CH:12]2)[CH3:5].O[N:37]1[C:41]2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[CH2:4]([O:6][C:7]1[CH:8]=[C:9]([O:25][C:26]2[CH:27]=[N:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=2)[CH:10]=[C:11]2[C:15]=1[NH:14][C:13]([C:16]1[S:17][CH:18]([CH2:21][C:22]([NH:37][CH3:41])=[O:23])[CH2:19][N:20]=1)=[CH:12]2)[CH3:5]
Reactant: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)NC)S3)[nH]c12
Temperature: 0 °C
Yield: 98.4 %

Procedure:
To an ice-cooled and stirred mixture of methylamine hydrochloride (26 mg) and triethylamine (0.053 mL) in N,N-dimethylformamide (5 mL) were added [2-(7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (90 mg), 1-hydroxybenzotriazole (52 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (73 mg). After stirring at 4° C. to room temperature for 15 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated to give a pale yellow amorphous solid, which was crystallized from ethyl acetate-hexane to give the title compound (91 mg, 99%) as pale yellow crystals. MS 489 (MH+). mp 233-235° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[N:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:10])[F:11])[CH:3]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=Cc1ccccc1F
Solvent: Cc1ccccc1
Product: Fc1ccccc1C=Nc1cccc(C(F)(F)F)c1
Yield: 104.8 %

Procedure:
To a toluene (200 mL) solution of 3-aminobenzotrifluoride (10.4 grams, 0.06 mol) was added 2-fluorobenzaldehyde (8.0 grams, 0.06 mol). The mixture was heated under reflux with a Dean-Stark trap for 6 hours. The solvent was removed in a rotary evaporator to give 2-fluorobenzylidene 3-trifluoromethylaniline (16.8 grams, 97% yield, yellow liquid) whose structure was confirmed by nuclear magnetic resonance, infra-red spectroscopy, and mass spectroscopy analysis.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12](O)=[O:13])=[CH:6][CH:5]=1.C(Cl)(=O)C(Cl)=O.[NH3:23]>O1CCCC1.CN(C)C=O>[F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([NH2:23])=[O:13])=[CH:6][CH:5]=1
Reactant: O=C(O)C=Cc1ccc(OC(F)(F)F)cc1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)C=Cc1ccc(OC(F)(F)F)cc1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
To a suspension of 4.90 g (21.1 mmol) 3-(4-Trifluoromethoxy-phenyl)-acrylic acid in 30.0 ml tetrahydrofuran and 0.3 ml N,N-dimethyl formamide a solution of 2.70 ml (32.0 mmol) oxalyl chloride in 5.0 ml tetrahydrofuran was added dropwise at 0° C. within 10 min. Stirring was continued at 0-5° C. for 30 min. and 2 h at room temperature thereafter. The resulting solution was cooled to 0-5° C. again and then added within 15 min. to 75 ml of a 25% aqueous ammonia solution. After stirring for 30 min. the precipitated amide was collected, washed with water and dried at 40° C. in vacuo. 4.48 g (92%) 3-(4-Trifluoromethoxy-phenyl)-acrylamide.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[CH2:8][CH2:9][CH2:10][OH:11].O>N1C=CC=CC=1>[S:2]([O:11][CH2:10][CH2:9][CH2:8][CH:7]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[OH:6])([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC(O)c1ccc2ccccc2c1
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCCC(O)c1ccc2ccccc2c1

Procedure:
Methanesulfonyl chloride (0.77 g was added slowly with stirring to a cooled (-40° C.) solution of rac-delta-hydroxy-2-naphthalenebutanol (1.45 g) in dry pyridine (6 mL). The mixture was stirred at -40° C. for 5 hours, then was poured into water (20 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed in turn with water (2×10 mL), saturated magnesium sulfate solution (3×15 mL) and brine, then were dried (MgSO4) and evaporated. The resulting oil was purified by HPLC (ethyl acetate-hexane; 2:3) to provide 1.25 g of rac-alpha-(3-mesyloxypropyl)-2-naphthalenemethanol as an oil.