Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][C:12]([C:14]3[N:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:13][C:4]=2[CH2:3]1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1.[C:28]([CH:31]([CH:33]([C:35]([OH:37])=[O:36])[OH:34])[OH:32])([OH:30])=[O:29].ClC1C=CC(C2CCNCC3C=C(C4N=NC=CC=4)C=CC2=3)=CC=1>>[C:28]([CH:31]([CH:33]([C:35]([OH:37])=[O:36])[OH:34])[OH:32])([OH:30])=[O:29].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:9][CH:6]2[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]3[CH:13]=[C:12]([C:14]4[N:15]=[N:16][CH:17]=[CH:18][CH:19]=4)[CH:11]=[CH:10][C:5]2=3)=[CH:23][CH:22]=1
Reactant: CN1CCC(O)c2ccc(-c3cccnn3)cc2C1
Reactant: Oc1ccc(Cl)cc1
Agent: Clc1ccc(C2CCNCc3cc(-c4cccnn4)ccc32)cc1
Agent: O=C(O)C(O)C(O)C(=O)O
Product: CN1CCC(Oc2ccc(Cl)cc2)c2ccc(-c3cccnn3)cc2C1

Procedure:
This compound was prepared from (−)-2-methyl-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-ol from Step H in Example 1 and 4-chlorophenol, following the procedures of Steps J and K in Example 1. (+)-5-(4-Chlorophenyl)-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine, tartrate salt (AUC HPLC>99%) is a white solid: mp 106-108° C.; 1H NMR (CD3OD, 500 MHz) δ 9.18 (d, J=5.0 Hz, 1H), 8.20-8.17 (m, 2H), 8.07 (d, J=8.0 Hz, 1H), 7.80 (dd, J=8.7, 3.8 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.25 (d, J=9.0 Hz, 2H), 7.05 (d, J=9.0 Hz, 2H), 5.73 (d, J=7.6 Hz, 1H), 4.92-4.84 (m, 1H), 4.52-4.46 (m, 1H), 4.42 (s, 3H), 3.90-3.80 (m, 1H), 3.56-3.50 (m, 1H), 2.86 (s, 3H), 2.46-2.37 (m, 2H); ESI MS m/z 366 [M+H].
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH:9]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Cl>C(Cl)(Cl)(Cl)Cl>[CH:15]1([C:9]2[CH:10]=[CH:11][C:12]([C:5](=[O:7])[CH3:6])=[CH:13][CH:14]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CC(=O)Cl
Reactant: c1ccc(C2CCCCC2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1ccc(C2CCCCC2)cc1

Procedure:
To a suspension of anhydrous aluminum chloride (467 g,; 3.5 moles) in carbon tetrachloride (2 l.) is added acetyl chloride (275 g.; 249 cc., 3.5 moles) during fifteen minutes with vigorous stirring and cooling in an ice-bath. Cyclohexylbenzene (481 g,; 3.0 moles) is added dropwise over a period of three hours, keeping the temperature below 5°. After addition is complete, the product is stirred for another hour before hydrolyzing by pouring into ice and hydrochloric acid with stirring. The organic phase is washed with successive portions of dilute hydrochloric acid, sodium carbonate, and water, and distilled to give p-cyclohexylacetophenone, (b.p. 88°-95.5°/0.05 mm.)
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([N:12]3[CH2:17][CH2:16][S:15](=[O:18])[CH2:14][CH2:13]3)[C:6]=2[N:7]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[N:26]1([C:2]2[N:3]=[C:4]([N:19]3[CH2:20][CH2:21][S:22](=[O:25])[CH2:23][CH2:24]3)[C:5]3[N:11]=[CH:10][N:9]=[C:8]([N:12]4[CH2:17][CH2:16][S:15](=[O:18])[CH2:14][CH2:13]4)[C:6]=3[N:7]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: O=S1CCN(c2nc(Cl)nc3c(N4CCS(=O)CC4)ncnc23)CC1
Reactant: C1CNCCN1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(N4CCS(=O)CC4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 118 from 2-chloro-4,8-bis-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 295°-297° C.) and piperazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:17]=1)[C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7].[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([O:41][CH2:42][CH3:43])[C:35]=1[N:36]1[CH:40]=[CH:39][CH:38]=[CH:37]1)[CH:31]=O)[CH3:26].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([O:41][CH2:42][CH3:43])[C:35]=1[N:36]1[CH:40]=[CH:39][CH:38]=[CH:37]1)[CH2:31][N:12]1[CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[C:5]2[CH:15]=[C:16]([O:18][CH2:19][C:20]3[NH:21][N:22]=[N:23][N:24]=3)[CH:17]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:14][CH2:13]1)[CH3:26]
Reactant: COc1cc(OCc2nnn[nH]2)cc(C(=O)NC2CCNCC2)c1
Reactant: CCOc1cc(C=O)cc(OCC)c1-n1cccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OCc4nnn[nH]4)c3)CC2)cc(OCC)c1-n1cccc1

Procedure:
In analogy to the procedure described in example 50k), 3-methoxy-N-piperidin-4-yl-5-(1H-tetrazol-5-ylmethoxy)-benzamide (example 170c) was reacted with 3,5-diethoxy-4-pyrrol-1-yl-benzaldehyde (example 40b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as off-white solid. MS: 576.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:15]1[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[N:23]=2)[CH:16]=1>CN(C=O)C>[NH2:28][C:24]1[N:23]=[C:22]([NH:21][C:17]2[CH:16]=[C:15]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:20]=[CH:19][N:18]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccccc1
Reactant: Nc1cccc(Nc2cc(Cl)ncn2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1cccc(Nc2cc(Nc3ccccc3)ncn2)n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 36.9 %

Procedure:
To a stirred solution of 2 (4.35 g, 23.38 mmol) and Cs2CO3 (15.26 g, 46.76 mmol) in dry DMF (50 mL) was added 1 (5.0 g, 15.58 mmol) at rt and the reaction was stirred at 80° C. for 16 h under nitrogen atmosphere. The reaction mixture was cooled, concentrated under reduced pressure and the residue was diluted with ethyl acetate (50 mL). It was washed with water (2×10 mL), brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was further purified by column chromatography (SiO2, 60-120, pet ether/ethyl acetate, 5/5) to give 3 (1.6 g, 23.3%) as brown solid.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:12]3[CH:13]=[C:14]([O:17][C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:16][C:11]=3[NH:10][C:9]2=[O:22])[CH2:4][CH2:3]1.[O:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl-].[NH4+]>C(N(CC)CC)C.ClCCCl>[ClH:1].[O:23]1[CH2:28][CH2:27][CH:26]([N:2]2[CH2:7][CH2:6][CH:5]([N:8]3[C:12]4[CH:13]=[C:14]([O:17][C:18]([F:19])([F:21])[F:20])[CH:15]=[CH:16][C:11]=4[NH:10][C:9]3=[O:22])[CH2:4][CH2:3]2)[CH2:25][CH2:24]1
Reactant: O=c1[nH]c2ccc(OC(F)(F)F)cc2n1C1CCNCC1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=c1[nH]c2ccc(OC(F)(F)F)cc2n1C1CCN(C2CCOCC2)CC1

Procedure:
1-(4-Piperidinyl)-6-[(trifluoromethyl)oxy]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride D32 (0.6 g) 1,2-dichloroethane (50 mL) and triethylamine (10 mL), tetrahydro-4H-pyran-4-one (1.2 g), sodium triacetoxyborohydride (1.3 g) was stirred at room temperature over night. The mixture was poured into dilute ammonium chloride solution and extracted with dichloromethane. The organic phase was separated, washed with brine and dried with hydromatrix. The solvent was removed and the residue was chromatographed on silica gel eluted with dichloromethane/2M ammonia in methanol 0-10%. The resulting product was dissolved in a mixture of methanol and dichloromethane, treated with 1M hydrogen chloride in ether and the solvent was removed. Recrystallisation from methanol gave the title compound as a white solid (0.28 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([F:22])[C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:20]1[C:14]2[O:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[C:17]([F:22])=[CH:18][CH:19]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2c(F)ccc(Cl)c2o1
Product: Fc1ccc(Cl)c2oc(CCC#Cc3ccccn3)nc12
Yield: 12531.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (124 mg, 0.79 mmol) and 2-(but-3-ynyl)-7-chloro-4-fluoro-benzo[d]oxazole (176 mg, 0.79 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 30 mg (99 mmol, 13%) of 7-chloro-4-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown solid (M.P.=102-103° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)([CH2:16][CH3:17])/[CH:12]=[CH:13]/[C:14]#[N:15].CN1CCOCC1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)([CH2:16][CH3:17])/[CH:12]=[CH:13]/[C:14]#[N:15])=[CH:23][CH:22]=1
Reactant: CCC(/C=C/C#N)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(/C=C/C#N)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of compound from step B (123 mg, 0.367 mmol) and NMM (74 mg, 0.734 mmol) in DCM (15 mL) was added methanesulfonyl chloride (62 mg, 0.550 mmol) dropwise. Then the mixture was stirred at room temperature overnight. The reaction was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with PE/EA (10/1 to 3/1, v/v) to afford the title compound as a white solid. LC/MS m/z=436.1 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[N:15]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[N:13][CH:12]=1)[OH:10]>C(Cl)Cl.[O-2].[Mn+4].[O-2].O=[Mn]=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[N:15]([C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:14]=[N:13][CH:12]=1)=[O:10]
Reactant: Cc1cccc(C(O)c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Agent: O=[Mn]=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1cccc(C(=O)c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Temperature: 60 °C
Yield: 62 %

Procedure:
A mixture of (2,3-dimethylphenyl)(1-trityl-lH-imidazol-5-yl)methanol, (Intermediate 6) (2.4 g, 7.4 mmol) in CH2Cl2 (60 mL) was treated with manganese(IV) oxide, activated (commercially available from Aldrich): MnO2 (2.8 g, 32.3 mmol) at room temperature. The mixture was heated at 60° C. for 2 hours. The mixture was then cooled to room temperature and filtered through celite and the solvent was removed under vacuum. The residue was purified by MPLC with 3 to 5% MeOH:CH2Cl2 to give (2,3-dimethylphenyl)(l-trityl-lH-imidazol-5-yl)methanone, (Intermediate 7), 1.48 g, (62%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH:5]([N:11]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31]C(OC(C)(C)C)=O)=[CH:26][CH:25]=1)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].Cl.O1CCOCC1>C(O)C>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([N:11]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][NH2:31])=[CH:28][CH:29]=1)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH3:22])[C:4]([O:3][CH2:1][CH3:2])=[O:39])[CH3:10]
Reactant: CCCN(CCC)CCCCN(Cc1ccc(CNC(=O)OC(C)(C)C)cc1)C(C(=O)OCC)C(=O)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCCN(CCC)CCCCN(Cc1ccc(CN)cc1)C(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
The compound (421 mg) obtained in Example 89-1 was dissolved in anhydrous ethanol (4.0 ml) and added with a 4 mol/l hydrogen chloride/dioxane solution (4.00 ml) and the whole was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution and the whole was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (338 mg) as a pale-yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.[NH:19]1[C:27]2[C:22](=[C:23]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C@H:12]1[CH2:17][CH2:16][C@@H:15]([N:31]2[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[C:27]4[C:22]=3[CH:21]=[CH:20][NH:19]4)[CH2:29][CH2:30]2)[CH2:14][CH2:13]1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Reactant: COc1ccc2[nH]cc(C3CCC(=O)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc2[nH]cc([C@H]3CC[C@@H](N4CCN(c5cccc6[nH]ccc56)CC4)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
A solution of 4-(5-methoxy-1H-indol-3-yl)-cyclohexanone (1.2 g, 5 mmol), 1-(indol-4-yl)piperazine (1 g, 5 mmol), sodium triacetoxyborohydride (1.47 g, 6.2 mmol) and acetic acid (0.28 ml, 4 mmol) in 1,2-dichloroethane (20 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 1N sodium hydroxide (10 ml), extracted with methylene chloride (3×60 ml) and washed with brine (3×60 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (2.5% methanol-ethyl acetate) afforded 1.18 g (55%) of product as a white solid: mp 105-108° C.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH:16]([CH3:22])[N:15]([C:23](=[O:25])[CH3:24])[CH2:14][CH2:13][C:12]2=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C1(C)C=CC=CC=1>[C:23]([N:15]1[CH2:14][CH2:13][C:12]2[C:11]3[C:19](=[CH:20][CH:21]=[C:9]([O:8][CH3:7])[CH:10]=3)[N:18]([C:26](=[O:28])[CH3:27])[C:17]=2[CH:16]1[CH3:22])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2[nH]c3c(c2c1)CCN(C(C)=O)C3C
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc2c(c1)c1c(n2C(C)=O)C(C)N(C(C)=O)CC1
Yield: 22 %

Procedure:
N,N-Diethylaminopyridine (530 mg) and pyridine (1.1 mL) are added to a solution of 1-(6-methoxy-1 -methyl-2,3,4,9-tetrahydro- 1H-β-carbolin-2-yl)-1-ethanone (933 mg) in toluene (100 mL) and acetic anhydride (6 mL). The mixture is refluxed for 48 h. After evaporation of the toluene, the crude product is taken up in water and then extracted with dichloromethane and, after separation on silica gel (chloroform/methanol eluent), the 1-(2-acetyl-6-methoxy-1-methyl-2,3,4,9-tetrahydro-1 H-β-carbolin-9-yl) 1 -ethanone is obtained (22% yield).
Reaction SMILES: C([O:14][C:15]([C:17]1[N:18]2[C@H:21]([S:22][CH2:23][C:24]=1/[CH:25]=[C:26]1/[C:27](=[O:35])[N:28]([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:29][CH2:30]/1)[C@H:20]([NH:36]C(OC(C)(C)C)=O)[C:19]2=[O:44])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>ClCCl.C1(OC)C=CC=CC=1>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[NH2:36][C@@H:20]1[C:19](=[O:44])[N:18]2[C@@H:21]1[S:22][CH2:23][C:24](/[CH:25]=[C:26]1/[C:27](=[O:35])[N:28]([CH2:31][CH:32]([CH3:33])[CH3:34])[CH2:29][CH2:30]/1)=[C:17]2[C:15]([OH:16])=[O:14]
Reactant: CC(C)CN1CC/C(=C\C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]3SC2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CC(C)CN1CC/C(=C\C2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)C1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
(E)-(6R,7R)-7-tert-Butoxycarbonylamino-3-(1-isobutyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (21.9 g, 35.0 mmol) was dissolved in 240 ml dichloromethane and 23 ml anisole. At 20° C. 120 ml trifluoroacetic acid were added dropwise while maintaining the temperature below 50° C. After complete addition the ice-bath was removed and the solution was stirred at ambient temperature for 2.5 hours The volatile material was then removed under reduced pressure and the remaining yellow oil was added slowly to 400 ml of diethyl ether, in which the product started to precipitate. After 1.5 hours the suspension was filtered under argon atmosphere and the remaining crystals were stirred in 150 ml of ethyl acetate for 2 hours. The suspension was filtered under argon giving the desired product as a yellow crystalline powder.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[CH2:3][OH:4].C([O-])(=O)C.[Na+].[N:20]#[C:21]Br>CO>[C:9]1([CH:7]([CH3:8])[CH2:6][CH2:5][C@H:2]2[CH2:3][O:4][C:21]([NH2:20])=[N:1]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N#CBr
Reactant: CC(CC[C@H](N)CO)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC(CC[C@H]1COC(N)=N1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (2S)-2-amino-5-phenyl-hexan-1-ol (160 mg) in methanol (11 ml) at room temperature was added sodium acetate (136 mg). The mixture was cooled to 0° C. and a solution of cyanogen bromide (96 mg) in methanol (2 ml) was added dropwise. The mixture was stirred at 0° C. for 30 min and then at room temperature overnight before being concentrated in vacuo. The residue was resuspended in tetrahydrofuran/ethyl acetate (1/2) and washed sequentially with saturated aqueous sodium bicarbonate solution and saturated brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, heptane/dichloromethane/methanol gradient; eluant containing 1% aq. ammonia) to yield a colourlessoil, (128 mg, 71%); MS (ISP): 219.2 ([M+H]+).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([C:3]2[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=2)([OH:26])[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2ccc(C(F)(F)F)cc2)CCN(Cc2ccccc2)CC1
Yield: 41.2 %

Procedure:
This compound is prepared by the procedure described in step A of preparation 1.7, from 1.55 g of magnesium in 25 ml of THF, a solution of 14.25 g of 1-bromo-4-(trifluoromethyl)benzene in 15 ml of THF and a solution of 10 g of 1-benzyl-4-piperidinone in 30 ml of THF. This gives 7.3 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=C1CCCN1
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N2CCCC2=O)cc1Cl
Temperature: 100 °C

Procedure:
A mixture of 500 mg of 2-chloro-4-florobenzonitrile, 821 mg of 2-pyrrolidinone and 3 g of cesium carbonate in 5 mL of DMF was heated to 100° C. in a sealed microwave reactor for 15 min. The reaction mixture was diluted with ethyl acetate, washed with H2O, dried (MgSO4) and evaporated. Purified by silica gel chromatography (20-80% ethyl acetate/hexane) to afford 2-chloro-4-(2-oxopyrrolidin-1-yl)benzonitrile. 890 mg of 2-chloro-4-(2-oxopyrrolidin-1-yl)benzonitrile was reacted via Procedure T to give 2-chloro-4-(2-oxopyrrolidin-1-yl)benzoic acid. 80 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(2-oxopyrrolidin-1-yl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-oxopyrrolidin-1-yl)benzamide. MS (Q1) 426.2 (M)+.
Reaction SMILES: [CH2:1]([C@H:3]([NH:10][C:11](=[O:43])[C@@H:12]([C@@H:39]([CH2:41][CH3:42])[CH3:40])[NH:13][C:14](=[O:38])[C@H:15]([CH:27](CC1C=CC=CC=1)[C:28](=[O:30])[OH:29])[NH:16]C(OCC1C=CC=CC=1)=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]>CO.O.[Pd].[C]>[CH2:1]([C@H:3]([NH:10][C:11](=[O:43])[C@@H:12]([C@@H:39]([CH2:41][CH3:42])[CH3:40])[NH:13][C:14](=[O:38])[C@H:15]([CH2:27][C:28](=[O:29])[OH:30])[NH2:16])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC[C@H](NC(=O)[C@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O)[C@H](C)CC)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CC[C@H](NC(=O)[C@H](NC(=O)[C@@H](N)CC(=O)O)[C@H](C)CC)c1ccccc1
Reaction time: 5 h
Yield: 72.3 %

Procedure:
To a suspension of 2.81 g (4.7 mmols) of N-benzyloxycarbonyl-β-benzyl-L-aspartyl-D-isoleucine (S)-α-ethylbenzylamide in 150 ml of methanol and 50 ml of water was added 2.0 g of 10% Pd-carbon (water content 50%). The mixture was reduced under hydrogen at room temperature for 5 hours. The catalyst was removed by filtration, and the resulting filtrate was concentrated under reduced pressure to be 20 ml. The crystals thus precipitated were taken out by filtration and dried to obtain 1.22 g (3.4 mmols) of α-L-aspartyl-D-isoleucine (S)-α-ethylbenzylamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8](OC(=O)C)[O:9]C(=O)C)[C:5]([Br:17])=[CH:4][C:3]=1[CH:18](OC(=O)C)[O:19]C(=O)C.S(=O)(=O)(O)O>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[C:5]([Br:17])=[CH:4][C:3]=1[CH:18]=[O:19]
Reactant: CC(=O)OC(OC(C)=O)c1cc(Br)c(C(OC(C)=O)OC(C)=O)cc1Br
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: O=Cc1cc(Br)c(C=O)cc1Br
Temperature: -10 °C
Yield: 86.8 %

Procedure:
Unpurified 2,5-dibromo-α,α,α',α'-tetraacetoxy-1,4-xylene (60.5 g, 0.122 mole) was dissolved with stirring in three liters of hot ethanol. Then 450 ml of water was added followed by 75 ml of concentrated sulfuric acid which was added very slowly. After being allowed to reflux for an hour, the reaction mixture was diluted with 900 ml of hot water. Cooling overnight at -10° C. resulted in the recrystallization of 30.9 g (87% yield) of 2,5-dibromoterephthalaldehyde, mp 184°-189° C. (lit 189°-190.5° C.) which was isolated by filtration.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH2:12])[CH2:9][CH2:10][NH2:11].CC1C=CC=CC=1C(N)CCN.ClC1C=CC=CC=1C(N)CCN>>[C:3]1([CH:8]([NH2:12])[CH2:9][CH2:10][NH2:11])[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: NCCC(N)c1ccccc1F
Agent: Cc1ccccc1C(N)CCN
Agent: NCCC(N)c1ccccc1Cl
Product: NCCC(N)c1ccccc1

Procedure:
Analogously, 1-(2-fluorophenyl)-1,3-propanediamine, 1-(2-methylphenyl)-1,3-propanediamine and 1-(2-chlorophenyl)-1,3-propanediamine have been prepared by using the above procedure and the appropriate starting material.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:19]2[CH2:31][C:22]3[NH:23][C:24]4[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][C:29]=4[C:21]=3[CH2:20]2)([F:18])[C:11]2[O:15][N:14]=[C:13]([CH2:16][NH2:17])[N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:32][C:33]([F:38])([F:37])[C:34](O)=[O:35].N1C=CC=CC=1>C(Cl)Cl>[C:1]1([S:7]([C:10]([CH:19]2[CH2:31][C:22]3[NH:23][C:24]4[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][C:29]=4[C:21]=3[CH2:20]2)([F:18])[C:11]2[O:15][N:14]=[C:13]([CH2:16][NH:17][C:34](=[O:35])[C:33]([F:38])([F:37])[F:32])[N:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(F)(F)F
Reactant: NCc1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCc1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1)C(F)(F)F
Reaction time: 8 h
Yield: 10.8 %

Procedure:
To a stirred solution of 46 mg (0.1 mmol) of (RS,SR)-C-{5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-yl}-methylamine in 3 mL CH2Cl2 at RT, was added 10 μl (0.1 mmol, 1 eq) trifluoroacetic acid and 80 μl pyridine (1 mmol, 10 eq). Stirring was continued overnight, and the reaction mixture was evaporated to dryness. Column chromatography on silica gel (heptane/EtOAc 6:4) yielded 6 mg (12%) of (RS,SR)-N-{5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-ylmethyl}-2,2,2-trifluoro-acetamide as a light yellow powder, MS: 557 (MH+).