Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17]N(C)C[C:14]=2[C:13]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=2F)=[N:12]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].[C:32]([N:39]1CCC(=O)[CH2:41][CH2:40]1)(OC(C)(C)C)=O.O=C1CCCCN(C(OC(C)(C)C)=O)C1.FC1C=C(F)C(F)=CC=1C(Cl)=O.FC1C=C(C=CC=1F)C(Cl)=O>>[F:27][C:25]1[CH:26]=[C:21]([C:13]2[C:14]3[N:39]([CH3:32])[CH2:40][CH2:41][CH2:17][CH2:18][C:19]=3[N:11]([C:9]([NH:8][C@@H:3]([C:2]([CH3:1])([CH3:30])[CH3:31])[C:4]([NH:6][CH3:7])=[O:5])=[O:10])[N:12]=2)[CH:22]=[CH:23][C:24]=1[F:28]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C
Agent: CC(C)(C)OC(=O)N1CCCCC(=O)C1
Agent: O=C(Cl)c1cc(F)c(F)cc1F
Agent: O=C(Cl)c1ccc(F)c(F)c1
Product: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCCCN2C)C(C)(C)C

Procedure:
Compound 69 was prepared according to the procedure described above for the synthesis of compound 37 except that 1-Boc-4-piperidone was replaced with tert-butyl 3-oxoazepane-1-carboxylate and 2,4,5-trifluorobenzoyl-chloride was replaced with 3,4-difluorobenzoylchloride. LCMS (+ESI) m/z=434.2 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([CH2:8][N:9]([CH2:17][C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)C(=O)OC(C)(C)C)=[N:5][C:4]2[CH2:23][CH2:24][O:25][CH2:26][C:3]1=2.Cl>CO>[S:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[CH2:17][NH:9][CH2:8][C:6]1[NH:7][C:2](=[O:1])[C:3]2[CH2:26][O:25][CH2:24][CH2:23][C:4]=2[N:5]=1
Reactant: CC(C)(C)OC(=O)N(Cc1nc2c(c(=O)[nH]1)COCC2)Cc1cccs1
Agent: Cl
Solvent: CO
Product: O=c1[nH]c(CNCc2cccs2)nc2c1COCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 111.3 %

Procedure:
To a solution of tert-butyl (4-oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methyl(thiophen-2-ylmethyl)carbamate (0.87 g, 2.3 mmol) in methanol (5 mL) was added hydrochloride acid (2.3 mL, 4M in dioxane). The mixture was stirred at ambient temperature for 24 h, filtered and washed with ether to give the title compound as a white solid (710 mg, 98% yield).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:15])[C:6]=1[NH:7][NH:8][C:9]([O:11][CH2:12][CH2:13][Cl:14])=[O:10].[CH3:16][O:17][CH2:18][C:19](Cl)=[O:20].Cl>C1(C)C=CC=CC=1>[CH3:16][O:17][CH2:18][C:19]([N:7]([C:6]1[C:5]([CH3:15])=[CH:4][S:3][C:2]=1[CH3:1])[NH:8][C:9]([O:11][CH2:12][CH2:13][Cl:14])=[O:10])=[O:20]
Reactant: Cc1csc(C)c1NNC(=O)OCCCl
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: COCC(=O)N(NC(=O)OCCCl)c1c(C)csc1C
Temperature: 25 °C

Procedure:
A solution of 24.85 g (0.1 mol) of 2-chloroethyl 2-(2,4-dimethylthien-3-yl)-hydrazinecarboxylate in 150 ml dry toluene is treated with 10.85 g (0.1 mol) methoxyacetylchloride, and the mixture is heated to 80° for 2 hours, vigorous HCl-formation starting at approx. 50° C. The mixture is cooled to room temperature, washed subsequently with water, 10% aqueous NaHCO3 -solution and water, dried over MgSO4 and evaporated in vacuo to yield the compound 2-chloroethyl 2-(methoxyacetyl)-2-(2,4-dimethylthien-3-yl)hydrazinecarboxylate, which may be directly reacted with NaOCH3 (see Step β).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+]>CN(C=O)C>[CH2:14]([N:1]([CH2:10][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(N)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-5-cyanobenzotrifluoride (1.0 g, 5.37 mmol, 1 eq) and benzyl bromide (2.55 mL, 21.5 mmol, 4.0 eq) in dry DMF (10 mL) was added at rt NaH (970 mg, 21.5 mmol, 4 eq) portion-wise under Ar(g). The reaction mixture was stirred at rt overnight, and was then partitioned with H2O (30 mL) and extracted with EtOAc (5×20 mL) and CH2Cl2 (20 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by silica gel column chromatography with hexane/EtOAc (1:0-9:1) to yield the product, 2, as a pale yellow solid (1.66 g, 85%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].C(O)C.O1CCOCC1.[C-:28]#[N:29].[K+]>O>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][C:28]#[N:29])[C:9]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Sc2ccccc2)c(CCl)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: N#CCc1cc([N+](=O)[O-])ccc1Sc1ccccc1

Procedure:
230 g of 3-nitro-6-(phenylthio)-benzyl chloride, 540 ml of ethanol and 320 ml of dioxane are treated with a solution of 70.5 g of potassium cyanide in 150 ml of water. The mixture is heated to reflux for 3 hours and subsequently concentrated under reduced pressure. The residue is diluted with water and extracted with benzene. The organic phase is washed with water and evaporated under reduced pressure. There is obtained 3-nitro-6-(phenylthio)-phenylacetonitrile as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:13]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[C:8](=O)[CH3:9].Cl.[NH2:25][OH:26].CC([O-])=O.[Na+]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[N:13]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[C:8](=[N:25][OH:26])[CH3:9]
Reactant: CC(=O)c1nc2ccn(S(=O)(=O)c3ccc(C)cc3)c2cc1Cl
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=NO)c1nc2ccn(S(=O)(=O)c3ccc(C)cc3)c2cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.4 %

Procedure:
A mixture of 1-(6-chloro-1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanone (480 mg, 1.38 mmol), hydroxylamine hydrochloride (478 mg, 6.88 mmol), NaOAc (1.13 g, 13.76 mmol) in EtOH (10 mL) was stirred at RT overnight. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (4:1) to afford 514 mg (94%) of 1-(6-chloro-1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanone oxime as white solid. MS (ESI): m/z=364.0 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[CH:5]=[CH:4][N:3]=1.ClC1[C:17]([CH2:18][OH:19])=[C:16](Cl)[CH:15]=[CH:14]N=1.ClC1C=NC=C(Cl)C=1CO.BrC1C=NC=C(Cl)C=1COC1CCCCO1>>[Cl:1][C:2]1[C:7]([CH2:8][O:9][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:19]2)=[C:6]([Cl:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1c(Cl)ccnc1Cl
Reactant: OCc1c(Cl)ccnc1Cl
Agent: Clc1cncc(Br)c1COC1CCCCO1
Agent: OCc1c(Cl)cncc1Cl
Product: Clc1ccnc(Cl)c1COC1CCCCO1

Procedure:
2,4-Dichloro-pyridine-3-carbaldehyde (1.565 g. 8.89 mmol) was reduced to (2,4-dichloro-pyridin-3-yl)-methanol according to the procedure described for the preparation of (3,5-dichloro-pyridin-4-yl)-methanol and subsequently protected with the THP-group according to the procedure described for the preparation 3-bromo-5-chloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridine to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH:15][NH2:16].C([O:19][C:20]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=O)=O)C>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C:22]=2[C:20](=[O:19])[NH:16]1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: NNc1cc(OC2CCCC2)c(Cl)cc1F
Solvent: CC(=O)O
Product: O=c1[nH]n(-c2cc(OC3CCCC3)c(Cl)cc2F)c2c1CCCC2
Reaction time: 2 h
Yield: 73.5 %

Procedure:
2-Fluoro-4-chloro-5-cyclopentyloxyphenylhydrazine (24.5 g, 0.10 mol), 2-ethoxycarbonylcyclohexanone (17.0 g, 0.10 mol) were dissolved in acetic acid (200 ml), and stirred for 2 hours while heating under refluxing. After completion of the reaction, the solvent was distilled off to obtain a crude product (37 g). The product was washed with a mixed solvent of benzene/hexane to obtain 2N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-1,2,4,5,6,7-hexahydro-3H indazol-3-one as a white solid (25.8 g, 72.3% yield).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:12]([C:19]#[N:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC(C)([O-])C.[K+]>CN(C=O)C>[C:13]1([CH:12]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[C:19]#[N:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CCc1ccccc1
Reactant: Clc1ccc2ccccc2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC(c1ccccc1)c1ccc2ccccc2n1

Procedure:
The compound was prepared substantially in accordance with the procedure detailed in Example 12A, using 2-chloroquinoline (5.0 g, 30.6 mmol), benzyl cyanide (3.5 ml, 30.6 mmol) and potassium t-butoxide (6.87 g, 61.2 mmol) in 40 ml of DMF.
Reaction SMILES: CCO[Si:4]([O:11][CH2:12]C)([O:8][CH2:9]C)[O:5][CH2:6]C.Cl.C[N:16]1C(=O)[CH2:19][CH2:18][CH2:17]1>>[NH2:16][CH2:17][CH2:18][CH2:19][Si:4]([O:5][CH3:6])([O:8][CH3:9])[O:11][CH3:12]
Reactant: CCO[Si](OCC)(OCC)OCC
Reactant: CN1CCCC1=O
Agent: Cl
Product: CO[Si](CCCN)(OC)OC

Procedure:
composite membranes of polyetherimide and nanodispersed silicium oxide, made by hydrolysis of TEOS in solutions of polyetherimide Ultem® in NMP by adding of 0.15 M HCl solution. After hydrolysis dense or phase inversed membranes are made from this polymer solution. Compatibility of the inorganic with the organic phase was obtained by extra addition of 3-aminopropyltrimethoxysilane (AS) (Membranes of poly(ether imide) and nanodispersed silica, S. P. Nunes, K. V. Peinemann, K, Ohlrogge, A. Alpers, M. Keller, A. T. N. Pires, J. Memb. Sci. 157 (1999) 219-226)).
Reaction SMILES: Br[C:2]1C=C(C2C=CC=CC=2OC)N2[C:10]=1C=NC(NC1C=CC(N3CCN(C)CC3)=CC=1)=N2.Br[C:34]1[CH:35]=[C:36]([C:57]2[CH:62]=[CH:61][C:60]([S:63]([CH3:66])(=[O:65])=[O:64])=[CH:59][CH:58]=2)[N:37]2[C:42]=1[CH:41]=[N:40][C:39]([NH:43][C:44]1[CH:49]=[CH:48][C:47]([N:50]3[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]3)=[CH:46][CH:45]=1)=[N:38]2>>[CH3:66][S:63]([C:60]1[CH:59]=[CH:58][C:57]([C:36]2[N:37]3[C:42]([CH:41]=[N:40][C:39]([NH:43][C:44]4[CH:45]=[CH:46][C:47]([N:50]5[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]5)=[CH:48][CH:49]=4)=[N:38]3)=[C:34]([CH:2]=[CH2:10])[CH:35]=2)=[CH:62][CH:61]=1)(=[O:64])=[O:65]
Reactant: COc1ccccc1-c1cc(Br)c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nn12
Reactant: CN1CCN(c2ccc(Nc3ncc4c(Br)cc(-c5ccc(S(C)(=O)=O)cc5)n4n3)cc2)CC1
Product: C=Cc1cc(-c2ccc(S(C)(=O)=O)cc2)n2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc12
Yield: 63 %

Procedure:
The tited compound was prepare in an analogous fashion to Example 103 replacing [5-Bromo-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine with [5-Bromo-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine to give [7-(4-Methanesulfonyl-phenyl)-5-vinyl-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (45 mg, 63%). LCMS (E/I+) 489.21 (M+H). NMR 1H (DSMO-d6)-9.23 (s, 1H), 8.99 (s, 1H), 8.48 (d, 2H, J=8.44 Hz), 8.07 (d, 2H, J=8.56 Hz), 7.66 (d, 2H, J=9.01 Hz), 7.00-7.18 (m, 2H), 7.00 (d, 2H, J=8.88 Hz), 5.82 (d, 1H, J=16.95 Hz), 5.21 (d, 1H, J=12.21 Hz), 3.80 (s, 3H), 3.02 (t, 4H, J=4.60 Hz), 2.44 (t, 4H, J=4.72 Hz), 2.21 (s, 3H).
Reaction SMILES: C(OC([C:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C:22]4=[O:27])=[CH:17][CH:16]=3)[C:10](=[O:28])[C:9]=2[N:8]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[N:7]=1)=O)C.C[Mg+].[Br-]>C1COCC1>[OH:35][C:32]([C:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C:22]4=[O:27])=[CH:17][CH:16]=3)[C:10](=[O:28])[C:9]=2[N:8]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[N:7]=1)([CH3:33])[CH3:31]
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(N3CCCCC3=O)cc1)C2=O
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C(C)(C)O)c3c2C(=O)N(c2ccc(N4CCCCC4=O)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
To 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (0.1 g, 0.2 mmol) in THF (15 mL) at 0° C. was added MeMgBr (0.21 mL, 0.6 mmol) and the reaction was stirred at rt for 24 h. The reaction was quenched with water and purified by HPLC to afford 47 mg (48%) of a white solid; Mass Spec (M+H)+ 475.
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:17][CH2:18][C:19]3[S:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)=[N:21][C:20]=3[CH3:34])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:34][C:20]1[N:21]=[C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=2)[S:23][C:19]=1[CH2:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[CH:9][N:8]2[CH2:7][C:6]([OH:35])=[O:5]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1cccc2c1ccn2CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1cccc2c1ccn2CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.1 %

Procedure:
To a solution of {4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester (50 mg, 99 μmol) in dichloromethane (4 ml) was added trifluoroacetic acid (1 ml). The reaction mixture was stirred for 2 h at ambient temperature. The solvent was removed under reduced pressure and the residue purified by preparative HPLC to give 5 mg (11 μmol, 11%) of the title compound as light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.N1([C:28](=[O:30])[CH3:29])C=CN=C1.CN(C=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:28](=[O:30])[CH3:29])[C:9]([O:11][CH3:12])=[O:10]
Reactant: CC(=O)n1ccnc1
Reactant: COC(=O)Cc1ccccc1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)C(C(C)=O)c1ccccc1Br
Reaction time: 1 h
Yield: 93.6 %

Procedure:
A round bottomed flask was charged with a magnetic stir bar and methyl 2-(2-bromophenyl)acetate (25 g, 109 mmol) and THF (50 mL). This solution was cooled to −78° C. before drop wise addition of a 1M solution of LiHMDS in THF (218 ml, 218 mmol). The reaction was stirred for 30 min at −78° C. before addition of 1-(1H-imidazol-1-yl)ethanone (14.42 g, 131 mmol) dissolved in a mixture of THF:DMF (112 mL THF, 24 mL DMF). The solution was stirred for 1 h before quenching with sat'd aqueous NH4Cl (˜250 mL) and diluting with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (˜2×250 mL). The combined organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified via silica gel chromatography using an eluent of ethyl acetate/hexanes (10:1) to afford methyl 2-(2-bromophenyl)-3-oxobutanoate (32.5 g, 102 mmol, 93% yield).
Reaction SMILES: O=[Si]=O.S(=O)(=O)(O)O.[C:9]([OH:13])(=[O:12])[CH:10]=[CH2:11].[C:14]1(=[O:21])[O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[C:22]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OC(=O)C=C)(=[O:25])[CH:23]=[CH2:24].CC(N=NC(C#N)(C)C)(C#N)C>O>[C:9]([OH:13])(=[O:12])[CH:10]=[CH2:11].[C:14]1(=[O:21])[O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[C:9]([O:13][CH:27]([O:26][C:22](=[O:25])[CH:23]=[CH2:24])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:12])[CH:10]=[CH2:11]
Reactant: C=CC(=O)OCCCCCCOC(=O)C=C
Agent: C=CC(=O)O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCCCCO1
Solvent: O
Product: C=CC(=O)OC(CCCCC)OC(=O)C=C
Temperature: 60 °C
Reaction time: 15 h

Procedure:
An aqueous mixture of 751 g deionized water, 101 g Ludox SM-30 (a colloidal silica dispersion, available from E.I. duPont de Nemours & Co.), and 5.5 g of a 50% solution of diethanol-adipic acid condensate (as promoter) was stirred in a glass jar and the mixture was adjusted to a pH of 4 by addition of 10% sulfuric acid. A monomer solution of 88.4 g caprolactone acrylate obtained from Sartomer Co. (Exton, Pa.), 354 g 1,6-hexandiol diacrylate, and 2.1 g VAZO 64 initiator (2,2'-azobis(isobutyronitrile)), available from E.I. duPont de Nemours & Co. was prepared separately. The aqueous mixture and the monomer solution were poured into a 5-liter split resin flask equipped with a marine-propeller type stirrer and mixed at about 1500 rpm (revolutions per minute) for 2 minutes. The mixture was then poured out of the flask and passed through a Manton-Gaulin Homogenizer available from the APV Gaulin Inc. (Everett, Mass.) at 700-900 psi (pounds per square inch, 4.8×106 -6.2×106Pascals) three times. The homogenized suspension was returned to the resin flask. The content was heated with infrared lamps to 60° C. under a nitrogen blanket and agitated at about 500 rpm (revolutions per minute) for 15 hours. A stable suspension of polymer particles was obtained. Analysis with Coulter N4 submicron particle size analyzer, available from Coulter Electronic Inc. (Hinleah, Fla.) showed an average particle size of 1.1 microns. The suspension was filtered with Whatmann #54 filter paper on a 24-cm Buchner funnel and washed several times with deionized water to give a wet cake. The wet cake was placed on glass trays and dried at ambient condition for several days. The dry cake was put in a gallon glass jar along with glass marbles and placed on a roller for several days to give free-flowing powder (average particle size=1.1 microns).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[CH2:12]([C@H:15]1[CH2:20][CH2:19][C@H:18]([C@H:21]2[CH2:26][CH2:25][C@H:24]([CH2:27][C:28](O)=[O:29])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1)[CH2:13][CH3:14].[OH-].[Na+]>O.C(OCC)(=O)C>[OH:29][CH2:28][CH2:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([C@H:18]2[CH2:19][CH2:20][C@H:15]([CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17]2)[CH2:22][CH2:23]1
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CC(=O)O)CC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCO)CC2)CC1
Temperature: 0 °C

Procedure:
Into a three-necked flask having a 500 ml capacity was added lithium aluminum hydride (2.8 g), and cooled down to 0° C., followed by dropwise adding tetrahydrofuran (50 ml) and a solution of trans-4-(trans-4-n-propylcyclohexyl)cyclohexyl-acetic acid (26.6 g, 0.1 mol) in this order, agitating the mixture at room temperature for 4 hours to obtain a mixture. To this mixture ethyl acetate (10 ml), water (10 ml) and 2N NaOH aqueous solution (10 ml) were added in this order and refluxed for 30 minutes, followed by cooling the resulting material, filtering, concentrating the filtrate under reduced pressure, adding water (100 ml) and toluene (100 ml), removing the resulting aqueous layer, washing the resulting organic layer with water till the washing water became neutral, drying over anhydrous sodium sulfate, removing a drying agent, concentrating under reduced pressure, passing the residue through an alumina column using dichloromethane solvent, distilling off dichloromethane, recrystallizing from heptane and drying to obtain the captioned compound (21.5 g). Its structure was confirmed by NMR spectra.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.[Al]>C1COCC1>[CH:7]1[CH:8]=[CH:9][C:4]([CH2:3][C@@H:2]2[NH:1][C:14](=[O:16])[O:12][C:10]2=[O:11])=[CH:5][CH:6]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Al]
Solvent: C1CCOC1
Product: O=C1N[C@@H](Cc2ccccc2)C(=O)O1
Temperature: 50 °C

Procedure:
A 1 L round bottom was dried in an oven prior to use (oven temp=120 ° C.). The glassware was cooled under an inert nitrogen atmosphere. Phenylalanine (50.0 g, 303 mmol) was added to the flask. Anhydrous THF (600 mL, 0.5 M) was charged to give a suspension of white solid. The mixture was heated to 50° C. and triphosgene (35.9 g, 121 mmol) was added as a solid. The suspension was stirred until the reaction was clear (−30 min). The reaction mixture was concentrated to an oil and then was slowly poured into 3 L of hexanes with rapid stirring to yield a white precipitate. The resulting suspension was capped using aluminum foil and placed in the freezer for a minimum of 3 h. The white precipitate was then filtered via vacuum filtration while maintaining an inert environment. The white solid was rinsed with hexanes (3×20 mL) to give the product. The white solid was collected and dried overnight under vacuum. 1H NMR (500 MHz, CHCl3-d): δ 7.37-7.30 (3 H, m); 7.18 (2 H, d, J=7.21 Hz); 6.23 (1 H, s); 4.53 (1 H, dd, J=8.18, 4.21 Hz); 3.27 (1 H, dd, J=14.14, 4.20 Hz); 3.00 (1 H, dd, J=14.13, 8.17 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][S:11][C:12]2[NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[N:20]=2)[CH:6]=[CH:7][CH:8]=1.ClC1C=C(C=CC=1)C(OO)=[O:26].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][S:11]([C:12]2[NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[N:20]=2)=[O:26])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCSc2nc3cnccc3[nH]2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cccc(CCS(=O)c2nc3cnccc3[nH]2)c1
Reaction time: 0.75 h
Yield: 54.5 %

Procedure:
2-[[(3-Methoxyphenyl)ethyl]thio]-1H-imidazo[4,5-c]pyridine (4.0 g, 0.014 mol) was dissolved in 60 mL of chloroform and cooled in an ice bath to 0°-5° C. m-Chloroperoxybenzoic acid (3.13 g, 0.015 mol) was added in portions to the reaction mixture. After 45 minutes, 10% aqueous sodium bicarbonate solution was added. The organic layer was removed and dried over magnesium sulfate, filtered and evaporated to dryness in a rotary evaporator. The crude product (4.2 g) when subjected to HPLC gave 2.3 g of pure product, m.p. 125°-128° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[CH2:18][C:19]([OH:21])=O)=[CH:12][CH:11]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[Br:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[C:58]([N:60]1[CH2:66][CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)=[O:59]>CN(C=O)C.O>[C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:22])[CH2:18][C:19]([N:63]2[CH2:64][CH2:65][CH2:66][N:60]([C:58](=[O:59])[C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=3[Br:51])[CH2:61][CH2:62]2)=[O:21])=[CH:14][CH:15]=1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Reactant: O=C(c1ccccc1Br)N1CCCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCCN(C(=O)c2ccccc2Br)CC1)Nc1ccc(-c2ccccc2)cc1
Reaction time: 0.03 h
Yield: 54.2 %

Procedure:
DIPEA (146 mg, 0.2 mL, 1.17 mmol) was added dropwise to N-biphenyl-4-yl-malonamic acid (100 mg, 0.39 mmol) in DMF (2 mL) followed by EDCI (90 mg, 0.47 mmol) and HOBT (63 mg, 0.47 mmol). After 2 minutes, (2-bromo-phenyl)-[1,4]diazepan-1-yl-methanone hydrochloride (150 mg, 0.47 mmol) was added and stirring was continued at room temperature overnight. Cold water was then added and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford 110 mg (54.18% yield) of N-biphenyl-4-yl-3-[4-(2-bromo-benzoyl)-[1,4]diazepan-1-yl]-3-oxo-propionamide. LC/MS [M+H]+: 520.12, 96.67%. 1H NMR (300 MHz, DMSO-d6): δ 10.3-10.2 (m, 1H), 7.8-6.7 (m, 13H), 4.1-3.4 (m, 9H), 3.3-3.0 (m, 2H), 2.0-1.8 (m, 1H), 1.7-1.5 (m, 1H).