Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[CH:14]1([N:7]2[CH2:8][CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:20][CH:21]4[CH2:22][CH2:23][N:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25][CH2:26]4)=[N:19][C:6]2=3)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Reactant: CCOC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOC(=O)N1CCC(Nc2ncc3c(n2)N(C2CCCC2)CCC(=O)N3C)CC1
Temperature: 105 °C
Yield: 12.1 %

Procedure:
2-Chloro-9-cyclopentyl-8,9-dihydro-5-methyl-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (100 mg, 0.357 mmol) and ethyl 4-aminopiperidine-1-carboxylate (129 μl, 0.714 mmol) in isopropylalcohol (2 ml) were heated at 90° C. for 24 hours. Diisopropylethylamine (125 μl, 0.714 mmol) was added and the reaction mixture was heated at 105° C. for another 24 hours. The crude mixture was concentrated in vacuo and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min] to afford the title compound (18 mg) as an off-white powder. NMR DMSO D6 1.20 (3H, t), 1.28-1.91 (14H, m), 2.80-2.96 (2H, m), 3.11 (3H, s), 3.50-3.58 (2H, m), 3.70-3.85 (1H, m), 3.90-3.98 (2H, m), 4.03 (2H, q), 4.60-4.70 (1H, m), 6.65 (1H, br s), 7.88 (1H, s); HPLC rt(min): 8.09; MS (ES+) 417, (ES−) 415.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:31]=[CH:30][C:21]([CH:22]=[C:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:31]=[CH:30][C:21]([CH2:22][CH:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Yield: 99.1 %

Procedure:
A solution of 0.5 g (1.14 mmole) 5-(4-[2-(4-tert-butyloxycarbonylaminophenyl)ethoxy]benzylidene)thiazolidine-2,4-dione in ethyl acetate was hydrogenated in the presence of 5% palladium on charcoal at room temperature and atmospheric pressure until hydrogen uptake ceased. The solution was filtered through celite, the filter pad was washed with ethyl acetate and the filtrate was evaporated to give 0.5 g (yield 99%) of 5-(-[4-[2-(4-tert-butyloxycarbonylaminophenyl)ethoxy]phenyl]methyl)thiazolidine-2,4-dione.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:7]2[CH2:8][CH2:9][CH:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: OCCC1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: OCCC1CCN(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(2-hydroxyethyl)piperidine (21.5 g), 4-fluorobenzaldehyde (17.5 ml) and p-toluene sulfonic acid (3 mg) in benzene (200 ml) was refluxed with separating water as the benzene azeotrope. After 2 hours, the mixture was evaporated in vacuo. The residue was dissolved in methanol (200 ml) and sodium borohydride (6.3 g) was added thereto at 5° C. After stirring at ambient temperature for 1 hour, the mixture was evaporated in vacuo. 4N Hydrochloric acid (200 ml) was added to the residue and washed with ethyl acetate. The aqueous layer was made basic to pH 10 with potassium carbonate and extracted with ethyl acetate. The extract was washed with water and brine, and dried over magnesium sulfate, and evaporated in vacuo to give 1-(4-fluorobenzyl)-4-(2-hydroxyethyl)piperidine (32.0 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([CH3:11])[C:5]=1[NH:12][C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14].[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:13]([O:15][CH:16]([CH3:17])[CH3:18])=[O:14]
Reactant: CCOC(=O)CCCBr
Reactant: COC(=O)c1ccc(Br)c(C)c1NC(=O)OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN(C(=O)OC(C)C)c1c(C(=O)OC)ccc(Br)c1C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
Add a solution of 2-Isopropoxycarbonylamino-4-bromo-3-methyl-benzoic acid methyl ester (3.36 g, 10.18 mmol) in DMF (37 mL) to a suspension of sodium hydride 60% dispersion mineral oil (407 mg, 10.18 mmol) in DMF (37 mL) at 0° C. under an atmosphere of nitrogen and allow to reach room temperature over 1 h. Add ethyl 4-bromobutyrate (2.2 mL, 15.27 mmol) and stir at room temperature for 14 h. Dilute with ethyl acetate, wash with 1M HCl, water and brine. Dry the organic layer over anhydrous magnesium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to provide the titled compound (3.47 g, 77%): MS (ES+): 445 (M+H).
Reaction SMILES: O[CH2:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:18][C:17]=2[O:26][CH3:27])=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[NH:8]2.C(N(CC)CC)C.CS([Cl:39])(=O)=O>ClCCl>[Cl:39][CH2:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][O:24][CH3:25])=[CH:18][C:17]=2[O:26][CH3:27])=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[NH:8]2
Reactant: CS(=O)(=O)Cl
Reactant: COCOc1ccc(-c2ccc3c(c2CO)NC(=O)C(C)(C)N3)c(OC)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOc1ccc(-c2ccc3c(c2CCl)NC(=O)C(C)(C)N3)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
8-Hydroxymethyl-7-(2-methoxy-4-methoxymethoxyphenyl)-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 9, 495 mg, 1.33 mmol) was dissolved in anhydrous dichloromethane (10 mL), and triethylamine (250 μL, 1.80 mmol) and methanesulfonyl chloride (113 μL, 1.46 mmol) were added thereto successively. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (239 mg) as a yellow amorphous product. (Yield 46%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([NH:11][C:12]1[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:15]=[CH:14][C:13]=1[F:24])[CH3:10].C(OC([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][C@@H:33]1[C:38](O)=[O:39])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([NH:11][C:12]1[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:38]([C@H:33]3[CH2:34][CH2:35][CH2:36][CH2:37][NH:32]3)=[O:39])[CH2:20][CH2:19]2)[CH:15]=[CH:14][C:13]=1[F:24])[CH3:10]
Reactant: C[C@@H](Nc1cc(N2CCNCC2)ccc1F)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1cc(N2CCN(C(=O)[C@H]3CCCCN3)CC2)ccc1F)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
To a stirred solution of the (R)—N-(1-(2,4-dichlorophenyl)ethyl)-2-fluoro-5-(piperazin-1-yl)aniline (0.085 g, 0.23 mmol) and (R)-1-(t-butoxycarbonyl)piperidine-2-carboxylic acid (0.053 g, 0.23 mmol) in DMF (1.5 mL) was added HATU (0.11 g, 0.28 mmol) and iPr2NEt (0.075 g, 0.58 mmol). The reaction mixture was stirred at room temperature for 2 h, and quenched with deionzied water. The aqueous layer was extracted with diethyl ether (2×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 10-70% ethyl acetate in hexanes) to afford the desired product (0.080 g, 0.14 mmol, 65%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:17][CH3:18])=[O:8])=[CH:10][CH:11]=1
Reactant: O=C(O)c1ccc(CO)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(CO)cc1

Procedure:
4 g (26.3 mmol) of 4-(hydroxymethyl)benzoic acid in 1,000 ml of absolute ethanol are heated under reflux of the solvent for 15 hours in the presence of approximately 1 g of concentrated sulfuric acid. The ethyl alcohol is then evaporated off and the residue taken up with water. After extraction of the aqueous phase with 3×100 ml of ethyl ether, the organic phases are washed to neutrality with saturated sodium hydrogen carbonate solution. After removal of the solvent, 4.56 g of a yellow oil, which soon crystallizes, remains.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][OH:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][CH2:11][OH:12]
Reactant: OCCBr
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1cccc(Br)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
In a nitrogen atmosphere, 3-bromophenol 5.0 g, 2-bromoethanol 5.42 g, and potassium carbonate 12.0 g were added to N,N-dimethylformamide 30 ml, and the mixture was stirred at 100° C. After 1 hour, the reaction mixture was cooled to room temperature and partitioned by adding water and diethyl ether. The organic layer was washed with water and then with brine, dried over magnesium sulfate anhydride and evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system), whereby the title compound (4.85 g, 77%) was obtained as a colorless oil.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([N:23]([CH3:25])[CH3:24])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)C=CC=CC=1.[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>O1CCOCC1>[CH3:24][N:23]([CH3:25])[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:8]([N:40]2[CH2:41][CH2:42][CH:37]([C:31]3[C:30]4[C:34](=[CH:35][CH:36]=[C:28]([Cl:27])[CH:29]=4)[NH:33][CH:32]=3)[CH2:38][CH2:39]2)=[O:7])[CH2:12][CH2:13]1
Reactant: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: CN(C)C1(c2ccccc2)CCC(CNC(=O)Oc2ccccc2)CC1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)N2CCC(c3c[nH]c4ccc(Cl)cc34)CC2)CC1
Yield: 10.6 %

Procedure:
The diastereoisomer mixture of (4-dimethylamino-4-phenylcyclohexylmethyl)-carbamic acid phenyl ester (774 mg, 2.2 mmole) was added to the suspension of 5-chloro-3-piperidine-4-yl-1H-indole (516 mg, 2.2 mmole) in dioxane (20 ml). The reaction mixture was a suspension also at 100° C., and was boiled under reflux for 40 hours. To work up the suspension the existing precipitate was filtered off, washed with dioxane (1×1 ml) and diethyl ether (3×2 ml) and dried in vacuo. The isolated solid (183 mg, 17%, m.p. 140°-150° C.) was a still unpurified part of the polar diastereoisomer of 4-(5-chloro-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide, which was purified by flash chromatography on silica gel [20 g, eluent: methanol (500 ml)]. The mother liquor and the wash phases were concentrated by evaporation in vacuo. The residue contained in addition to phenol, also the two diastereoisomers of 4-(5-chloro-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide. The diastereoisomers were separated and purified by flash chromatography on silica gel (75 g). Methanol/EE (1:1; 900 ml) was used as eluent. The non-polar diastereoisomer (335 mg, m.p. 205°-207° C., 31%) and the polar diastereoisomer of 4-(5-chloro-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (115 mg, m.p. 140°-143° C., 11%) were thereby obtained as pale yellow solids.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]=[C:12]=S)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.Cl.[NH2:23][CH2:24][C@@:25]1([OH:33])[CH:30]2[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]2)[CH2:26]1.C(N=C=NC(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:11][C:12]3[O:33][C@:25]4([CH2:24][N:23]=3)[CH:30]3[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]3)[CH2:26]4)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(N=C=S)n[nH]c2c1
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Fc1ccc2c(NC3=NC[C@@]4(CN5CCC4CC5)O3)n[nH]c2c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
To 6-fluoro-3-isothiocyanato-1H-indazole (0.20 g, 1.04 mmol) in DMF (15 mL) was added triethylamine (0.43 mL, 3.11 mmol) and (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.26 g, 1.14 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours. The reaction was cooled to room temperature and treated with N,N′-diisopropylcarbodiimide (0.48 mL, 3.11 mmol). The reaction was then heated to 70° C. for 2 hours. The reaction was cooled to ambient temperature and concentrated. The crude product was purified by column chromatography (85% chloroform, 14% methanol, 1% ammonium hydroxide) to afford (R)—N-(6-fluoro-1H-indazol-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.22 g, 0.66 mmol, 64% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 12.16 (s, 1 H), 8.00 (s, 1 H), 7.59-7.67 (m, 1H), 7.09 (dd, J=9.77, 2.14 Hz, 1 H), 6.81-6.88 (m, 1 H), 3.81 (d, J=9.16 Hz, 1 H), 3.56 (d, J=8.85 Hz, 1 H), 3.00 (s, 2 H), 2.78 (s, 2 H), 2.67 (t, J=7.32 Hz, 2 H), 2.01 (d, J=2.44 Hz, 1 H), 1.92 (s, 1 H), 1.59 (d, J=5.80 Hz, 2 H), 1.46 (s, 1 H). MS (LC/MS) R.T.=1.44; [M+H]+=316.16.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[N:11]=1.[F:20][C:21]([F:40])([F:39])[CH2:22][N:23]=[C:24]([NH2:38])[NH:25][C:26]1[S:27][CH:28]=[C:29]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]=C=S)[N:30]=1.[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]\[C:44]([OH:46])=[O:45]>CO.CC(C)=O>[F:19][C:2]([F:1])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][NH:6][C:7]([NH:11][NH:35][CH2:34][CH2:33][CH2:32][CH2:31][C:29]2[N:30]=[C:26]([NH:25][C:24]([NH2:38])=[N:23][CH2:22][C:21]([F:20])([F:39])[F:40])[S:27][CH:28]=2)=[S:8])[N:11]=1.[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]\[C:44]([OH:46])=[O:45]
Reactant: NC(=NCC(F)(F)F)Nc1nc(CCCCN=C=S)cs1
Reactant: NCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Solvent: CC(C)=O
Product: NC(=NCC(F)(F)F)Nc1nc(CCCCNNC(=S)NNCCCCc2csc(NC(N)=NCC(F)(F)F)n2)cs1
Reaction time: 8 h

Procedure:
A mixture of 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole (0.12 g.) and 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-isothiocyanatobutyl]thiazole (0.12 g.) in methanol (3 ml.) was allowed to stand at room temperature overnight. The mixture was then evaporated to dryness and purified by preparative thin layer chromatography using methanol/chloroform/ammonia 85:15:1 v/v/v as developing solvent. The appropriate band was extracted with chloroform/ethanol 1:1 v/v (200 ml.) and the resulting solution evaporated to give a brown gum. This was treated in acetone with excess maleic acid to give 1,3-di[4-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)butylamino]thiourea containing 2.25 equivalents of maleic acid. The n.m.r. spectrum in d6 dimethylsulphoxide containing tetramethylsilane as internal standard (δ=0) included the following resonances (δ): 1.5 (multiplet, 8H); 3.3 (multiplet, 4H); 4.1 (quartet, 4H); 6.5 (singlet, 2H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][C:9]=2[C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=1.O1CCCC1.B>CO>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][C:11]([CH2:12][OH:13])=[CH:10][C:9]=2[C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(C(=O)O)ccc1CCc1ccc(F)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(CO)ccc1CCc1ccc(F)cc1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
A mixture of 4-(4-fluorophenethyl)-3-methoxycarbonylbenzoic acid (16.5 g, 54.88 mmol), tetrahydrofuran(500 ml) and borane in tetrahydrofuran (1M, complex, 218 ml, 218 mmol) was stirred under an inert atmosphere at reflux for 6 hours. The reaction was cooled to ambient temperature and methanol (1 L) was added. It was then evaporated to dryness to give a dark oil which was purified by flash chromatography using iso-hexane/ethyl acetate (1:1) as eluant to give as a clear gum methyl 2-(4-fluorophenethyl)-5-hydroxymethylbenzoate (13.10 g).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH:9]1([NH:15][OH:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:17][C:18]1[O:19][CH:20]=[C:21]([CH3:26])[C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[CH:9]1([N:15]([C:23]([C:22]2[C:21]([CH3:26])=[CH:20][O:19][C:18]=2[CH3:17])=[O:24])[OH:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Cc1coc(C)c1C(=O)Cl
Reactant: ONC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1coc(C)c1C(=O)N(O)C1CCCCC1
Reaction time: 1 h

Procedure:
30 Parts of triethylamine is added to a suspension of 25 parts of N-cyclohexylhydroxylamine hydrochloride in 480 parts of benzene. After the mixture has been stirred for 1 hour, 20 parts of 2,4-dimethylfuran-3-carboxylic chloride is dripped in at room temperature. After the mixture has been stirred for a further 2 hours it is suction filtered, the residue is washed with benzene and the combined benzene phases are washed with water, dried with anhydrous sodium sulfate and evaporated. There is obtained 34 parts of N-cyclohexyl-2,4-dimethylfuran-3-hydroxamic acid in the form of an oil. This oil is dissolved in 370 parts of dichloromethane; at room temperature and while stirring, 18 parts of sodium hydroxide in 70 parts of water, and 28 parts of dimethyl sulfate are added to the solution. After the mixture has been stirred for 1 hour the organic phase is separated, washed with water, dried with sodium sulfate, evaporated and chromatographed using silica gel with a mixture of equal portions of ethyl acetate and cyclohexane. When the eluate is evaporated there is obtained 32 parts of O-methyl-N-cyclohexyl-2,4-dimethylfuran-3-hydroxamic acid having a boiling point at 0.01 mm Hg of 122° to 124° C and the refractive index nD25 : 1.5010. ##SPC13##
Reaction SMILES: [I:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][C:19]([CH3:22])(C)[CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:27]1(O)[CH2:32]CCC[CH2:28]1>CCO.CCO.CCO.CCO.[Ti]>[I:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH:19]3[CH2:20][CH2:32][CH2:27][CH2:28][CH2:22]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCCCC1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(I)cccc1-2
Agent: [Ti]
Solvent: CCO
Product: O=C(OC1CCCCC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(I)cccc1-2
Reaction time: 0.5 h

Procedure:
5 g (11 mmol) of tert.butyl (S)-11,12,13,13a-tetrahydro-8-iodo-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 30 g (300 mmol) of cyclohexanol and 1 g (4 mmol) of tetraethyl orthotitanate are stirred at 125° overnight, the solution is evaporated to dryness and the residue is taken up in chloroform. The solution is then stirred for 0.5 hour with 40 ml of a saturated potassium fluoride solution, the resulting emulsion is filtered over siliceous earth, the organic phase is separated, washed with water, dried over magnesium sulphate and evaporated. By crystallization from ethyl acetate there is obtained cyclohexyl (S)-11,12,13,13a-tetrahydro-8-iodo-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 181°-182°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][C:34](Cl)=[C:33]([C:38]([F:41])([F:40])[F:39])[CH:32]=1>CCCCCCC.C(OCC)(=O)C>[CH3:28][O:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][C:34]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:33]([C:38]([F:39])([F:41])[F:40])[CH:32]=1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: COC(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)c1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to Example 26, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and 4-chloro-3-trifluoromethyl-benzoic acid methyl ester (commercially available) after a reaction time of 6 h and using a gradient of n-heptane:Ethyl acetate (100:0 to 60:40). White solid (32%). MS (Turbo Spray): m/z=493.3 [M+H].
Reaction SMILES: O1CCCOC1.CC1(C)[O:13][C@H:12](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:11]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:10][O:9]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[OH:9][CH2:10][CH:11]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[C@H:12]([OH:13])/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1
Reactant: Cc1ccc(/C=C/[C@H]2OC(C)(C)OCC2NC(=O)OC(C)(C)C)cc1
Agent: C1COCOC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(/C=C/[C@@H](O)C(CO)NC(=O)OC(C)(C)C)cc1
Yield: 95 %

Procedure:
1,3-Dioxane, 2-boc amino (10B) and 10 mol % TsOH were combined in 5.0 mL THF and 5.0 mL H2O and stirred at reflux until the starting material was consumed as indicated by TLC. The reaction mixture was quenched with 5% NaHCO3 and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, and removed in vacuo. Purification by flash chromatography on silica gel afforded the desired product as a white solid (95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]([C:20]3[C:28]4[CH:27]=[N:26][CH:25]=[N:24][C:23]=4[N:22]([CH:29]([CH3:33])[C:30]([OH:32])=O)[CH:21]=3)=[O:19])[CH:15]=[N:16][CH:17]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:34][NH:35][CH3:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]([C:20]3[C:28]4[CH:27]=[N:26][CH:25]=[N:24][C:23]=4[N:22]([CH:29]([CH3:33])[C:30]([N:35]([CH3:36])[CH3:34])=[O:32])[CH:21]=3)=[O:19])[CH:15]=[N:16][CH:17]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CC(C(=O)O)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21
Product: CC(C(=O)N(C)C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Example 34 at 50° C. using racemic 2-{5-[(5-{[(4-chlorophenyl)acetyl]amino}pyridin-3-yl)carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}propanoic acid (Example 354) and dimethylamine.