Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:10][C:11]([N:13]1[CH2:19][CH2:18][CH2:17][NH:16][C:15](=[O:20])[C@H:14]1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1)=[O:12])=O)(C)(C)C.[ClH:43]>O1CCOCC1>[ClH:43].[NH2:8][C@H:9]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:10][C:11]([N:13]1[CH2:19][CH2:18][CH2:17][NH:16][C:15](=[O:20])[C@H:14]1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:26][CH:27]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCCNC(=O)[C@H]1Cc1ccc(OC(F)(F)F)cc1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](CC(=O)N1CCCNC(=O)[C@H]1Cc1ccc(OC(F)(F)F)cc1)Cc1cc(F)c(F)cc1F

Procedure:
(3R)-4-[(3R)-3-[(tert-Butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]hexahydro-3-[4-(trifluoromethoxy)benzyl]-2H-1,4-diazepin-2-one was dissolved in 4M hydrogen chloride in dioxane and evaporated after 2.5 h to yield the desired product. LC/MS 504.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:6]([OH:8])=O.Cl.Cl.[CH:23]([O:26][C:27](=[O:49])[CH:28]([OH:48])[C@@H:29]([NH:37][C:38](=[O:47])[C@H:39]([CH2:41][C:42]1[N:46]=[CH:45][NH:44][CH:43]=1)[NH2:40])[CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)([CH3:25])[CH3:24].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH:23]([O:26][C:27](=[O:49])[CH:28]([OH:48])[C@@H:29]([NH:37][C:38](=[O:47])[C@H:39]([CH2:41][C:42]1[N:46]=[CH:45][NH:44][CH:43]=1)[NH:40][C:6](=[O:8])[CH:5]([CH2:4][C:3]1[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=1[F:1])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)([CH3:25])[CH3:24]
Reactant: O=C(O)C(Cc1ccccc1F)Cc1ccccc1F
Reactant: CC(C)OC(=O)C(O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)OC(=O)C(O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(Cc1ccccc1F)Cc1ccccc1F

Procedure:
In 5 ml of N,N-dimethylformamide were dissolved 67 mg of bis(2-fluorobenzyl)acetic acid and 100 mg of (2RS, 3S)-3-[N-(L-histidyl)amino]-4-cyclohexyl-2-hydroxybutyric acid isopropyl ester dihydrochloride, and to the solution were successively added 0.06 ml of diphenylphosphoryl azide and 0.1 ml of triethylamine with stirring under ice-cooling. The mixture was still stirred for 16 hours, and the reaction mixture was evaporated under reduced pressure. To the residue was added an aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: chloroform/methanol=10/1) to 23 mg of (2RS, 3S)-3-{N-[bis(2-fluorobenzyl)acetyl]-L-histidyl}amino-4-cyclohexyl-2-hydroxybutyric acid isopropyl ester having an Rf2 value of 0.59 as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH3:16])[CH2:13][CH:14]=O)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[C:17]([O:21][C:22]([N:24]1[CH2:31][CH:30]2[O:32][CH:26]([CH2:27][NH:28][CH2:29]2)[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(O)(=O)C.[BH3-]C#N.[Na+]>ClCCl>[C:17]([O:21][C:22]([N:24]1[CH2:25][CH:26]2[O:32][CH:30]([CH2:29][N:28]([CH2:14][CH2:13][N:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[CH3:16])[CH2:27]2)[CH2:31]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CN(CC=O)S(=O)(=O)c1ccc(C#N)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(CCN1CC2CN(C(=O)OC(C)(C)C)CC(C1)O2)S(=O)(=O)c1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of step (ii) product 4-Cyano-N-methyl-N-(2-oxo-ethyl)-benzenesulfonamide (4.97 g), and 9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (4.95 g; see WO 01/28992) and acetic acid (1.7 ml) in dry dichloromethane (50 ml) was stirred at RT for 3 h and then cooled to 0° C. NaBH3CN (1.96 g, 0.0312 mol) was added and stirring continued at RT overnight under nitrogen atmosphere. The reaction mixture was quenched with water, extracted with dichloromethane, washed with water and brine and dried over sodium sulfate. Solvent evaporated under reduced pressure and the residue was purified by column chromatography over silica gel using 28% ethyl acetate in petroleum ether eluent to give the sub-title compound (2.2 g) as a liquid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=2)=[O:36])[CH2:30][CH2:29]1.[OH-].[Na+]>CN(C=O)C.CO>[CH3:27][N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]([NH:37][C:38]2[CH:44]=[CH:43][C:41]([NH:42]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:40][CH:39]=2)=[O:36])[CH2:32][CH2:33]1
Reactant: CN1CCN(CC(=O)Nc2ccc(N)cc2)CC1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN1CCN(CC(=O)Nc2ccc(N/C(=C3\C(=O)Nc4ccc([N+](=O)[O-])cc43)c3ccccc3)cc2)CC1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(4-methylpiperazinomethylcarbonylamino)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:29][CH:30]=O)[CH2:10][N:11]2[C:17](=[O:18])[C:16]3[C:19]4[C:24]([CH:25]=[C:26]([C:27]#[N:28])[C:15]=3[S:14][CH2:13][CH2:12]2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:32]1([NH2:35])[CH2:34][CH2:33]1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:29][CH2:30][NH:35][CH:32]2[CH2:34][CH2:33]2)[CH2:10][N:11]2[C:17](=[O:18])[C:16]3[C:19]4[C:24]([CH:25]=[C:26]([C:27]#[N:28])[C:15]=3[S:14][CH2:13][CH2:12]2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC1CC1
Reactant: N#Cc1cc2ccccc2c2c1SCCN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C2=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc2ccccc2c2c1SCCN(C[C@@H](CCNC1CC1)c1ccc(Cl)c(Cl)c1)C2=O
Yield: 58.8 %

Procedure:
By the method described in Example 83, Intermediate 78a (70 mg, 0.15 mmol) and cyclopropylamine (13 mg, 0.23 mmol) were converted to 45 mg of the title compound as its trifluoroacetic acid salt.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][OH:20]>>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([O:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[O:16][CH3:15])[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: COc1ccccc1CO
Product: COc1ccccc1COc1cccc([N+](=O)[O-])c1C#N
Yield: 58 %

Procedure:
Prepared as in Example 111c from 2,6-dinitrobenzonitrile and 2-methoxybenzyl alcohol in 58% yield. 1H NMR (400 MHz, DMSO) δ 3.82 (s, 3H), 5.34 (s, 2H), 6.99 (t, J=7.6 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 7.37 (t, J=8.4 Hz, 1H), 7.46 (d, J=6.0 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.93-7.87 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([NH:17][S:18]([C:21]4[CH:42]=[CH:41][C:24]([C:25]([NH:27][C@H:28]([C:36]([O:38]CC)=[O:37])[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:26])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.Cl>[OH-].[Na+]>[NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([NH:17][S:18]([C:21]4[CH:22]=[CH:23][C:24]([C:25]([NH:27][C@H:28]([C:36]([OH:38])=[O:37])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:26])=[CH:41][CH:42]=4)(=[O:20])=[O:19])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(S(=O)(=O)Nc2ccc3ccc4nc(N)[nH]c(=O)c4c3c2)cc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc2ccc3ccc(NS(=O)(=O)c4ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc4)cc3c2c(=O)[nH]1
Temperature: 50 °C

Procedure:
A solution of diethyl N-(4-(((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)amino)sulfonyl)benzoyl)-L-glutamate (0.175 g, 0.3 mmoles) in 1N NaOH (12 ml) was stirred and heated to 50° C. under a nitrogen atmosphere for 24 hrs. After cooling,the solution was acidified (pH 3) with concentrated HCl to cause precipitation of the product which was filtered, washed with water and dried to give N-(4-(((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)-amino)sulfonyl)benzoyl)-L-glutamic acid as an off-white solid. (0.18 g, 99%) 1HNMR(DMSO-d6, 300 MHz) δ: 1.81-2.13(m, 2H, glu-CH2); 2.32(t, J=7.6 Hz, 2H, glu-CH2); 4.34(m, 1H, glu-CH); 6.58(br s, 2H, NH2); 7.16(d, J=8.9 Hz, 1H, Ar); 7.22(dd, J=8.6, 2 Hz, 1H, Ar); 7.74(d, J=8.7 Hz, 1H, Ar); 7.89(d, J=9.0 Hz, 1H, Ar); 7.96(m, 4H, Ar); 8.78(d, J=7.6 Hz, 1H, glu-NH); 9.49(d, J=2 Hz, 1H, Ar); 10.68(s, 1H, NH); 11.1(br s, 1H, NH); 12.3(br s, 2H, (CO2H)2). Anal. Calculated for C24H21N5O8S.3H2O: C, 48.56; H, 4.58; N, 11.80; S, 5.40. Found: C, 48.38; H, 4.30; N, 11.69; S, 5.34.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Br:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>C(O)C>[Br:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][N:8]=[C:9]([C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(Br)c1
Reactant: C[Si](C)(C)C#Cc1cc2c(Cl)c(C#N)cnc2cn1
Solvent: CCO
Product: C[Si](C)(C)C#Cc1cc2c(Nc3cccc(Br)c3)c(C#N)cnc2cn1
Temperature: 25 °C

Procedure:
To 626 mg of 4-chloro-6-trimethylsilanylethynyl-[1,7]naphthyridine-3-carbonitrile in 20 mL of absolute ethanol was added 1 mL of 3-bromoaniline. After refluxing the reaction under an inert atmosphere for 18 hours, the reaction mixture was cooled to ambient temperature, concentrated to 5 mL, diluted with ether, and the product filtered and washed with ether. Drying in vacuo yielded 500 mg of 4(3-bromo-phenylamino)-6-trimethylsilanylethynyl-[1,7]naphthyridine-3-carbonitrile as an off-white solid: melting point 125° C. (sublimed); mass spectrum (m/e): M+H 421.1, 423.2.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([N:53]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:49][CH:48]=2)(=O)=O)=CC=1.O.NN>CN(C=O)C.O>[C:1]([N:20]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][CH:48]=2)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Oc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(N3C(=O)c4ccccc4C3=O)cc2)cc1
Agent: NN
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(CCOc2ccccc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a solution of the 2-(1-trityl-1H-imidazol-4-yl)phenol (1.1 g, 2.73 mmol) in DMF (15 mL) was added NaH (83 mg, 3.28 mmol) at 0° C. and the mixture was stirred at room temperature for 1 h. 4-(1,3-dioxoisoindolin-2-yl)phenethyl 4-methylbenzenesulfonate (1.15 g, 2.73 mmol) was added to the mixture. After stirring overnight under a nitrogen atmosphere, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water (2×20 mL), brine (20 mL) and dried. The solvent was removed under reduced pressure and, the crude product was dissolved in ethanol (15 mL) and treated with hydrazine hydrate (0.3 mL, 5.46 mmol). The mixture was heated at 80° C. for 2 h and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (silica gel, 30%-50% EtOAc/hexanes as eluent) to afford the desired product as a yellow solid (862 mg, 60% over two steps). 1H NMR: 2.63 (t, 2H, J=7.6 Hz), 4.03 (t, 2H, J=7.6 Hz), 6.46 (d, 1H, J=8.4 Hz), 6.80 (dd, 2H, J=12.4 Hz, 8 Hz), 6.99 (t, 1H, J=7.6 Hz), 7.10-7.19 (m, 7H), 7.28-7.31 (m, 9H), 7.41 (s, 1H), 7.52 (s, 1H), 8.18-8.21 (m, 1H), 8.63 (s, 1H), 9.11 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:14])[C:4]([CH3:13])([CH3:12])[CH:5](Cl)[CH2:6]C(Cl)(Cl)Cl.ClCC(=O)C(CC(Cl)(Cl)Cl)C(Cl)(C)C>C(Cl)(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3](=[O:14])[C:4]([CH3:13])([CH3:12])[CH:5]=[CH2:6]
Reactant: CC(C)(C(=O)CCl)C(Cl)CC(Cl)(Cl)Cl
Agent: CC(C)(Cl)C(CC(Cl)(Cl)Cl)C(=O)CCl
Solvent: ClC(Cl)(Cl)Cl
Product: C=CC(C)(C)C(=O)CCl

Procedure:
The reaction is to be described as surprising, since the adduct mixture of 1,4,6,6,6-pentachloro- 3,3-dimethyl-hexane-2-one and 1,4-dichloro-4-methyl-3-(2,2,2-trichloroethyl)-pentan-2-one obtained from carbon tetrachloride and 1-chloro-3,3-dimethyl-pent-4en-2-one predominantly leads to cis-acids with bases (compare DE-OS (German Published Specification) 3,100,354 Example 4 and 5).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C@@H:5]12[C:14](=[O:15])[O:13][C:11](=[O:12])[C@H:6]1[CH2:7][CH2:8][CH2:9][CH2:10]2.Cl[CH2:17][CH2:18]Cl>>[O:12]=[C:11]([C@@H:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C@H:5]1[C:14]([OH:13])=[O:15])[CH:17]=[CH2:18]
Reactant: O=C1OC(=O)[C@H]2CCCC[C@H]12
Reactant: ClCCCl
Agent: [Al+3]
Agent: [Cl-]
Product: C=CC(=O)[C@@H]1CCCC[C@H]1C(=O)O

Procedure:
A mixture of aluminum chloride (66.7 g., 0.5 mole), trans-1,2-cyclohexanedicarboxylic anhydride (38.5 g., 0.25 mole) and 1,2-dichloroethane (1 liter) in a 2 liter 3-neck flask equipped with a gas inlet tube, a mechanical stirrer and a drying tube is stirred rapidly and ethylene is bubbled in for 4.5 hours. This mixture is poured into 900 ml. of 5% hydrochloric acid and ice. The layers are separated and the organic layer is washed with water and taken to dryness in vacuo. The aqueous layer is extracted with ether (300 ml.). This extract is washed with water and combined with material from the original organic layer and taken to dryness. The residue is heated with 300 ml. of 10% potassium carbonate on a steam bath for fifteen minutes. After cooling, the mixture is extracted three times with ether. The aqueous layer is acidified and the product trans-2-[1-oxo-2-propenyl]cyclohexanecarboxylic acid (31.6 g.) is extracted into ether, dried and concentrated in vacuo. The crude crystalline trans-2-(1-oxo-2-propenyl)cyclohexanecarboxylic acid is recrystallized from ether-hexane, m.p. 101°-102°.
Reaction SMILES: CC(C)([O-])C.[K+].C(OC(=O)[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]([O:21]CC)=O)[CH2:14]1)C>C1(C)C=CC=CC=1>[N:13]12[CH2:14][CH:15]([CH2:16][CH2:17][CH2:18]1)[C:19](=[O:21])[CH2:11][CH2:12]2
Reactant: CCOC(=O)CCN1CCCC(C(=O)OCC)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1CCN2CCCC1C2
Temperature: 25 °C

Procedure:
A suspension of potassium tert-butoxide (8.15 g, 72.6 mmol; Aldrich) in toluene (200 mL) was heated to reflux for 15 minutes, then a solution of ethyl 1-(3-ethoxy-3-oxopropyl)-piperidine-3-carboxylate (6.16 g, 23.9 mmol) in toluene (50 mL) was added dropwise over 1 hour to the refluxing reaction mixture. After the addition was complete, the reaction was heated to reflux for an additional 5 hours, cooled to ambient temperature, and extracted with water (3×50 mL). The combined aqueous layers were acidified with concentrated hydrochloric acid (40 mL), then heated to reflux for 22 hours. The reaction was basified with 45 weight % potassium hydroxide (˜35 mL) and extracted with chloroform (3×100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.50-1.81 (m, 2H), 1.90-1.96 (m, 2H), 2.39-2.43 (m, 1H), 2.49-2.54 (m, 2H), 3.08-3.41 (m, 6H); MS (DCI/NH3) m/z 140 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:14][CH2:15][N:16]3[C@H:21]4[CH2:22][CH2:23][C@@H:17]3[CH2:18][CH:19]([N:24]3[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[N:26]=[C:25]3[CH3:33])[CH2:20]4)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:34][C:35]1[CH:43]=[C:42]([F:44])[C:41]([S:45]([NH:48][CH3:49])(=[O:47])=[O:46])=[CH:40][C:36]=1[C:37](O)=[O:38]>>[Cl:34][C:35]1[C:36]([C:37]([N:11]2[CH2:10][CH2:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)([CH2:14][CH2:15][N:16]3[C@H:21]4[CH2:22][CH2:23][C@@H:17]3[CH2:18][CH:19]([N:24]3[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[N:26]=[C:25]3[CH3:33])[CH2:20]4)[CH2:13][CH2:12]2)=[O:38])=[CH:40][C:41]([S:45]([NH:48][CH3:49])(=[O:46])=[O:47])=[C:42]([F:44])[CH:43]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCNCC1
Reactant: CNS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F
Product: CNS(=O)(=O)c1cc(C(=O)N2CCC(CCN3[C@@H]4CC[C@H]3CC(n3c(C)nc5ccccc53)C4)(c3cccc(F)c3)CC2)c(Cl)cc1F
Yield: 47.6 %

Procedure:
5.36 g (12.0 mmol) 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole, 3.20 g (12.0 mmol) 2-chloro-4-fluoro-5-[(methylamino)sulfonyl]benzoic acid were combined following the general procedure in Example 5. 3.97 g recovered (47.6% yield). 1H NMR (300 MHz, DMSO-d6) δ 7.96-8.05 (br, 1H), 7.75-7.94 (m, 2 H), 7.38-7.56 (m, 3H), 7.24-7.30 (m, 2H), 7.07-7.18 (m, 3H), 4.48-4.60 (m, 1H), 3.91-4.03 (m, 1H), 3.23-3.49 (m, 6H), 3.04-3.13 (m, 1H), 2.52-2.60 (m, 4H), 2.33-2.44 (m, 2H), 2.12-2.32 (br, 2H), 2.01-2.09 (m, 2H), 1.76-1.95 (m, 8H), 1.60-1.66 (m, 2H). LC/MS m/z (M+H): 696
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[C:11]1([P:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:18]C)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClC1C=CC=CC=1Cl>[Br:1][C:2]1[C:3]([P:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:18])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: CSc1ncc(Br)c(Cl)n1
Reactant: COP(c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1Cl
Product: CSc1ncc(Br)c(P(=O)(c2ccccc2)c2ccccc2)n1
Yield: 49.3 %

Procedure:
To a stirred, refluxing mixture of 3.56 g of 5-bromo-4-chloro-2-methylthiopyrimidine in 100 ml of o-dichlorobenzene under nitrogen was added dropwise 10.00 g of methyl diphenylphosphinite. After the addition was completed, the mixture was refluxed for 6 hours and then allowed to cool. Volatiles were removed from the mixture under vacuum, and the residue was recrystallized from 30 ml of 1-chlorobutane and dried at 50° C./0.1 mm (13 Pa) to give 2.97 g of 5-bromo-4-diphenylphosphinyl-2-methylthiopyrimidine as white crystals, mp 124°-127° C. Anal. Calcd for C17H14BrN2OPS: C, 50.39; H, 3.48; N, 6.91. Found: C, 50.54; H, 3.67; N, 6.84.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:16][C:17]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:18]=1[O:19][C:20]1[CH:21]=[CH:22][C:23]([N+:38]([O-:40])=[O:39])=[C:24]([CH:37]=1)[O:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[O:28][CH2:29][C:30](Cl)=[O:31].O>O1CCCC1.C(Cl)Cl>[Cl:16][C:17]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:18]=1[O:19][C:20]1[CH:21]=[CH:22][C:23]([N+:38]([O-:40])=[O:39])=[C:24]([CH:37]=1)[O:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[O:28][CH2:29][C:30]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:31]
Reactant: OCc1ccccc1
Reactant: O=C(Cl)COc1ccccc1Oc1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=C(COc1ccccc1Oc1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-])OCc1ccccc1
Yield: 77.8 %

Procedure:
Benzyl alcohol (0.8 mL, 7.73 mmol) and triethylamine (1 mL, 7.17 mmol) are added to a mixture of {o-[5-(2,4-dichlorophenoxy)-2-nitrophenoxy]phenoxy}acetyl chloride (1.12 g, 2.38 mmol) in tetrahydrofuran. The reaction mixture is stirred for twenty minutes, poured into water and extracted with ether. The combined organic extracts are washed sequentially with one molar hydrochloric acid, water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain an oil. Column chromatography of the oil using silica gel and a hexanes in methylene chloride solution gives the title product as a yellow oil (1.0 g) which is identified by NMR spectral analyses.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[N:8]3[CH2:17][CH2:18][CH2:19][C@H:7]3[C:6]=12.[CH3:20][C:21]([OH:25])([C:23]#[CH:24])[CH3:22]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:25][C:21]([CH3:22])([CH3:20])[C:23]#[C:24][C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[N:8]3[CH2:17][CH2:18][CH2:19][C@H:7]3[C:6]=12
Reactant: O=C1c2ccccc2-n2cnc(I)c2[C@@H]2CCCN12
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CC(C)(O)C#Cc1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2

Procedure:
3.65 g (10 mmol) of (S)-11,12,13,13a-tetrahydro-1-iodo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one was heated to boiling under reflux for 1.5 hours with 1.26 g (15 mmol) of 2-methyl-3-butyn-2-ol, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 20 mg of copper(I) iodide in 30 ml of diethylamine. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. By recrystallization of the crude product from methanol and water there was obtained (S)-11,12,13,13a-tetrahydro-1-(3-hydroxy-3-methyl-1-butynyl)-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 128°.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([CH:14]=O)=[CH:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[NH:23][NH2:24].C(O)C>C(O)(=O)C.O>[CH2:27]([O:26][C:22]([NH:23][N:24]=[CH:14][C:13]1[C:9]([C:7]2[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:10][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=1)=[O:25])[CH3:28]
Reactant: O=Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reactant: CCOC(=O)NN
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)NN=Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Yield: 94 %

Procedure:
Stir 48 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxaldehyde together with 22 g of ethyl carbazate, 5 drops of glacial acetic acid and 500 ml of ethanol for 3 hours at 60° C. Add 500 ml of water dropwise to the resulting reaction mixture at room temperature. Vacuum filter and wash the obtained precipitate with ethanol/water and with water. Dry the precipitate and then admix it with toluene at 90° C to obtain a 94% yield of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxaldehyde-ethoxycarbonylhydrazone [m.p. 200° to 201° C].