Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]4[N:15]([CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[N:19]=4)[N:16]=3)[C:6]=2[CH:25]=1.[Li+].[OH-]>O.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]4[N:15]([CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=4)[N:16]=3)[C:6]=2[CH:25]=1
Reactant: CCOC(=O)c1cn2nc(Cn3nnc4ccc(Br)cc43)ccc2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cn2nc(Cn3nnc4ccc(Br)cc43)ccc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.4 %

Procedure:
To a solution of ethyl 6-((6-bromo-1H-benzo[d][1,2,3]triazol-1-yl)methyl)imidazo[1,2-b]pyridazine-2-carboxylate 13A (5 g, 12.46 mmol) in 10% H2O/MeOH (200 mL), LiOH (0.597 g, 24.92 mmol) was added. The reaction was stirred at ambient temperature for 18 hrs and then concentrated to remove the MeOH. H2O (100 mL) was added and the pH was adjusted to 4 with concentrated HCl. The resulting solid was collected by filtration, rinsed with water followed by EtOAc, and dried in vacuum over P2O5 to provide the title compound, 6-((6-bromo-1H-benzo[d][1,2,3]triazol-1-yl)methyl)imidazo[1,2-b]pyridazine-2-carboxylic acid 13B (3.6 g 9.65 mmol, 77%). The filtrate was extracted with EtOAc (3×150 mL) and the organics were combined, dried with MgSO4, filtered and concentrated to dryness to give an additional 0.6 g of product. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.24 (s, 2 H) 7.24 (d, J=9.35 Hz, 1 H) 7.58 (dd, J=8.84, 1.77 Hz, 1 H) 8.04-8.14 (m, 2H) 8.32 (d, J=1.01 Hz, 1 H) 8.47 (s, 1 H). MS:m/z 373.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:30][CH2:29][C:5]2[N:6]([CH2:14][CH:15]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH2:16][CH2:17]OS(C)(=O)=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:31][NH:32][CH3:33]>>[CH3:1][N:2]1[CH2:30][CH2:29][C:5]2[N:6]([CH2:14][CH:15]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH2:16][CH2:17][N:32]([CH3:33])[CH3:31])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CNC
Reactant: Cc1ccc2c(c1)c1c(n2CC(CCOS(C)(=O)=O)c2ccncc2)CCN(C)C1
Product: Cc1ccc2c(c1)c1c(n2CC(CCN(C)C)c2ccncc2)CCN(C)C1

Procedure:
Methanesulfonic acid-4-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butyl ester (200 mg, 0.468 mmol) in 10 mL of 40% aqueous dimethyl amine was heated at 100° C. for 1 h. The progress of reaction was monitored by TLC. After consumption of starting material, the reaction mixture was dried and the crude product was purified by reverse phase chromatography to obtain 170 mg of [4-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butyl]-dimethyl-amine as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.57 b (s, 2H), 7.65 (dd, 2H), 7.23 (d, 1H), 7.21 (s, 1H), 6.99 (d, 1H), 4.62 (m, 1H), 4.48 (m, 1H), 4.42 (m, 1H), 4.26 (t, 1H), 3.81 (m, 1H), 3.55 (m, 2H), 3.35 (m, 1H), 3.1 (m, 1H), 3.0 (s, 3H), 2.9 (m, 2H), 2.83 (s, 6H), 2.4 (m, 1H), 2.38 (s, 3H), 2.29 (m, 1H). Separation by chiral HPLC provides enantiomers II-232a-b.
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:9])[NH:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN(C)C=O>C1(C)C=CC=CC=1>[CH2:10]([N:8]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C1CCCCN1Cc1ccccc1
Temperature: 25 °C
Yield: 42.3 %

Procedure:
To a suspension of sodium hydride (80%, 3.3 g, 0.11 mol) in dry toluene (250 ml) under argon, was added dropwise a solution of δ-valerolactam (9.9 g, 0.10 mol) in toluene (50 ml). When the addition was complete, the mixture was heated under reflux for 1 h, then cooled to ambient temperature. A solution of benzyl bromide (13 ml, 18.8 g, 0.11 mol) in toluene (50 ml) containing dimethyl formamide (1 ml) was then added dropwise over 15 minutes. The resulting mixture was heated under reflux for 4 h. On cooling, the mixture was filtered and the filtrate was dried (Na2SO4) and evaporated in vacuo to give an oil. Bulb-to-bulb distillation gave the title compound (D26) as a yellow oil (8.0 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([S:10]CC[Si](C)(C)C)[CH:7]=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:5]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl.C(OCC)(=O)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:5]=[C:6]([C:17]([F:19])([F:20])[F:18])[CH:7]=[C:8]([SH:10])[CH:9]=1
Reactant: COC(=O)c1cc(SCC[Si](C)(C)C)cc(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(S)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-trifluoromethyl-5-(2-trimethylsilanyl-ethylsulfanyl)-benzoic acid methyl ester (580 mg, 1.72 mmol) in tetrahydrofuran (15 mL) was added tetrabutylammonium fluoride (1M solution in tetrahydrofuran, 11.6 mL, 11.6 mmol) and the yellow solution was stirred at room temperature for 1 hour. The reaction mixture was poured on aqueous 1M hydrochloric acid (30 mL) and ethyl acetate (30 mL) and the layers were separated. The aqueous layer was extracted a second time with ethyl acetate (30 mL). The organic layers were washed with 30 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 0:100). Yellow solid (295 mg, 72%). MS (ESI−): m/z=235.01 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].S(=O)(=O)(O)O.[N+:24]([O-])([OH:26])=[O:25]>O>[Cl:1][C:2]1[C:14]([C:15]([F:16])([F:17])[F:18])=[CH:13][C:12]([N+:24]([O-:26])=[O:25])=[C:4]([CH:3]=1)[CH:5]=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C=Cc1ccc(C(F)(F)F)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C=Cc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
To a solution of 100 mg of ethyl 3-chloro-4-trifluoromethylcinnamate and 1.8 ml of concentrated sulfuric acid was added 42 ml of 60% nitric acid at -15° C. After stirring at the same temperature for a few minutes, the reaction mixture was poured into a cold water, and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated. The residue was purified by a silica gel column chromatography to give 102 mg of ethyl 5-chloro-2-nitro-4-trifluoromethylcinnamate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([OH:33])=[CH:28][C:27]=2[CH3:34])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Cl[CH2:36][C:37]1[CH:42]=[CH:41][N:40]([CH3:43])[C:39](=[O:44])[CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:34][C:27]1[CH:28]=[C:29]([O:33][CH2:36][C:37]2[CH:42]=[CH:41][N:40]([CH3:43])[C:39](=[O:44])[CH:38]=2)[CH:30]=[C:31]([CH3:32])[C:26]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: Cn1ccc(CCl)cc1=O
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O)cc5C)ccc(F)c43)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCc6ccn(C)c(=O)c6)cc5C)ccc(F)c43)ccc21
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Methyl 2-((S)-6-((R)-7-fluoro-4-(4-hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (Intermediate 28-29) (46.3 mg) and 4-(chloromethyl)-1-methylpyridin-2(1H)-one (47.3 mg) were suspended in dimethylformamide (1.8 mL) and potassium carbonate (62 mg) was added. The reaction mixture was shaken for 24 h at 60° C. and than directly chromatographed by HPLC on reversed phase. The product fractions are collected and lyophilized to give the title compound. Yield: 49.6 mg; LC (method 23): tR=1.96 min; Mass spectrum (ESI+): m/z=584 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:14][CH2:15][CH:16]=[CH2:17]>C(O)C.O>[CH2:17]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[CH2:16][CH:15]=[CH2:14]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: C=CCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCCOc1ccc(C(=O)O)cc1

Procedure:
69.1 g (0.5 mol) of p-hydroxybenzoic acid were dissolved in 400 ml of ethanol and treated with a solution of 56.1 g (1 mol) of KOH in 250 ml of water. The reaction batch was heated under reflux. While so doing 74.26 g (0.55 mol) of 4-bromo-1-butene were slowly added dropwise. After 5 hours the ethanol was removed on a rotary evaporator. The aqueous phase was brought to a pH value of 10 with NaOH and extracted repeatedly with diethyl ether. The aqueous phase was poured into a mixture of 46 ml of concentrated HCl and 500 ml of ice-water. The separated acid was filtered off, washed with a small amount of water and recrystallized from methanol/water (2:1). After drying at 60° C. in a water-jet vacuum 40 g of 4-(but-3-enyloxy)-benzoic acid remained behind as a white powder; phase succession (° C.): C 120 N 141 I.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=2)[CH2:6]1)=[O:4].C([O-])(=O)C.[Na+].Cl.[NH2:23][OH:24]>CO.O>[CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[N:23][OH:24])=[CH:11][CH:10]=2)[CH2:6]1)=[O:4]
Reactant: NO
Reactant: COC(=O)C1CN(c2ccc(C=O)cc2)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C1CN(c2ccc(C=NO)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.9 %

Procedure:
To a stirred suspension of 1-(4-formyl-phenyl)-azetidine-3-carboxylic acid methyl ester (Preparation 9, 2.6 g, 11.87 mmol) in methanol (25 mL) and water (25 mL) was added sodium acetate (1.75 g, 21.36 mmol) followed by hydroxylamine hydrochloride (1.24 g, 17.80 mmol) at 0° C. Resulting reaction mixture was stirred at room temperature for 3 hours. After consumption of starting material, methanol was evaporated under reduced pressure and extracted with EtOAc (4×30 mL). Combined organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo to afford yellow colored solid (2.86 g, 99%). 1H NMR (400 MHz, CDCl3) δ: 3.55-3.59 (m, 1H), 3.75 (s, 3H), 4.05-4.13 (m, 4H), 6.42 (d, 2H, J=8.56 Hz), 7.41 (d, 2H, J=8.6 Hz), 8.03 (s, 1H); LC-MS (M+H): =235.00.
Reaction SMILES: C(B1O[C:8]([CH3:10])([CH3:9])[C:5]([CH3:7])(C)O1)=C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:20]([O:22][C:23]([C:25]1[CH:26]=[N:27][N:28]([C:31]2[C:36]([Cl:37])=CC(Br)=C[N:32]=2)[C:29]=1[CH3:30])=[O:24])[CH3:21]>CN(C)C=O.O>[CH2:20]([O:22][C:23]([C:25]1[CH:26]=[N:27][N:28]([C:31]2[C:36]([Cl:37])=[CH:9][C:8]([CH:5]=[CH2:7])=[CH:10][N:32]=2)[C:29]=1[CH3:30])=[O:24])[CH3:21]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)c1cnn(-c2ncc(Br)cc2Cl)c1C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1cnc(-n2ncc(C(=O)OCC)c2C)c(Cl)c1
Temperature: 100 °C
Reaction time: 7 h

Procedure:
Vinylboronic acid pinacol ester (1.37 ml), tripotassium phosphate (3.85 g) and 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (301 mg) were added to a solution of 1-(5-bromo-3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (2.52 g) described in Reference Example 44(2) in N,N-dimethylformamide (36 ml), and the mixture was stirred at 100° C. for seven hours. The reaction solution was cooled to room temperature, diluted with water, filtered through Celite and the filtrate was extracted with ethyl acetate three times. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-(3-chloro-5-vinylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.67 g).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[CH3:12][O:13][CH2:14][C@H:15]([CH3:35])[O:16][C:17]1[CH:18]=[C:19]([OH:34])[CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH3:33])[CH2:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[CH3:12][O:13][CH2:14][C@H:15]([CH3:35])[O:16][C:17]1[CH:18]=[C:19]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH3:33])[CH2:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:34][C:2]1[N:3]=[N:4][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(Cl)nn1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nn2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Reaction time: 1 h
Yield: 99.3 %

Procedure:
3-Chloro-6-(methylsulfonyl)pyridazine (41 mg, 0.27 mmol) synthesized in Example (118c) and 3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (80 mg, 0.24 mmol) synthesized in Example (116d) were dissolved in acetonitrile (2 mL), and cesium carbonate (158 mg, 0.48 mmol) was added, followed by stirring for 1 hour under nitrogen atmosphere. To the reaction solution, water (10 mL) was added, and extraction was carried out with ethyl acetate (10 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-4%) to afford the desired compound (116 mg, yield 98%) as a white solid.
Reaction SMILES: [OH:1][C@@H:2]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)[CH3:3]>C1(C)C=CC=CC=1>[C:2]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=[O:1])[CH3:3]
Reactant: C[C@@H](O)c1ccc(C#N)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(C#N)cc1

Procedure:
Prepared in an analogous manner to that of Preparation 247 starting with (R)-(+)-4-(1-Hydroxy-ethyl)-benzonitrile which is obtained from 4-acetylbenzonitrile using 1.0 M (S)-2-Methyl-CBS-oxazaborolidine in toluene in an analogous fashion as in Preparation 248.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](OS(C(F)(F)F)(=O)=O)=[C:8]([O:20][CH3:21])[CH:7]=1)[CH3:2].[CH3:23][N:24](C)C=O>O.C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:23]#[N:24])=[C:8]([O:20][CH3:21])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(OC)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)Cc1ccc(C#N)c(OC)c1
Temperature: 80 °C

Procedure:
Ethyl(3-methoxy-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)acetate (16.6 g) was dissolved in anhydrous dimethylformamide (100 mL). Zinc cyanide (3.4 g, 29 mmol) was added, and the solution was purged thoroughly with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (5.6 g, 4.9 mmol) was then added and the reaction mixture was heated to 80° C. for 4 h. After allowing the reaction mixture to cool to ambient temperature and diluting with water (200 mL), ethyl acetate (400 mL) was added and the mixture was filtered to remove any solids. The filtrate was transferred to a separatory funnel, and the layers separated. The aqueous layer was re-extracted with ethyl acetate (2×100 mL). The organic layers were combined and dried over magnesium sulfate. The dry organics were then filtered and evaporated to dryness under reduced pressure and excess dimethylformamide was removed by evaporation in vacuo at 65° C. for 1.5 h to yield crude product. The crude product was purified through silica gel chromatography (ethyl acetate/hexanes, 2:3) to yield ethyl(4-cyano-3-methoxyphenyl)acetate. 1H NMR (500 MHz, DMSO-d6), δ 7.67 (d, J=8.0 Hz, 1H), 7.18 (s, 1H), 7.0 (d, J=8.0 Hz, 1H), 4.10 (q, J=7.1 Hz, 2H), 3.89 (s, 3H), 3.78 (s, 2H), 1.19 (t, J=7.1 Hz, 3H); LC/MS (M+1)+=220.17; tR=1.36 min.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:13]2[N:14]=[C:15]([S:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=O)[NH:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1>[C:7]1([C:13]2[N:14]=[C:15]([S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[NH:16][C:17]=2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCCCCCNC(=O)CCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCNCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reaction time: 0.5 h

Procedure:
Part D. To a solution of lithium aluminum hydride, (1.52 g, 0.04 mol) in dry tetrahydrofuran (50 mL) was added, dropwise, a solution of 5-(4,5-diphenyl-1H-imidazol-2-ylthio)-N-heptylpentanamide (4.04 g, 0.009 mol) in tetrahydrofuran (25 mL) and the reaction mixture was stirred at reflux for 18 hours. The reaction mixture was cooled to 0°, quenched by the slow and careful sequential addition of water (1.52 mL), 15% sodium hydroxide (4.56 mL), and water (4.56 mL), and then stirred at 0° for 30 minutes. The solution was then dried over magnesium sulfate and concentrated under vacuum, and the residue was chromatographed with a gradient of 1:0 to 3:1 to 1:1 ethyl acetate-methanol. The resulting yellow oil was triturated with cold hexane to give N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-1-heptanamine as a white solid. A solution of this amine (0.80 g, 0.0018 mol) in ether (20 mL) was treated with a sufficient amount of ethereal HCl (about 25 mL) to cause complete precipitation of the amine as the hydrochloride salt. The reaction mixture was stirred for 15 minutes, and the supernatant liquid was decanted to afford a gummy solid, which was triturated with hot acetonitrile and then with cold hexane to give N-[5-(4,5-diphenyl-1H-imidazol-2 -ylthio)pentyl]-1-heptanamine hydrochloride (0.82 g, 0.0017 mol) as a white solid, mp 187°-190°. 1H NMR (CDCl3) δ9.3(s,2H), 7.7-7.3(m,10H), 3.7-3.5(m,2H), 3.0-2.7(m,4H), 2.0-1.2(m,16H), 0.9(1,3H,J=8Hz).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:14])=[CH:9][N:10]2[CH3:13])=[CH:6][C:5]=1[OH:15])([CH3:3])[CH3:2].I[CH2:17][C:18]#[N:19]>>[CH:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:14])=[CH:9][N:10]2[CH3:13])=[CH:6][C:5]=1[O:15][CH2:17][C:18]#[N:19])([CH3:3])[CH3:2]
Reactant: Cc1cn(C)c2cc(C(C)C)c(O)cc12
Reactant: N#CCI
Product: Cc1cn(C)c2cc(C(C)C)c(OCC#N)cc12

Procedure:
(6-Isopropyl-1,3-dimethyl-1H-indol-5-yloxy)-acetonitrile was prepared from 6-isopropyl-1,3-dimethyl-1H-indol-5-ol by treatment with iodoacetonitrile using the procedure of step 5 of Example 2 above.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:3]=1.[CH2:16]([NH2:18])[CH3:17].CO>>[CH2:16]([NH:18][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:3]=1)[CH3:17]
Reactant: CCN
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2nc1Cl
Solvent: CO
Product: CCNc1nc2ccc([N+](=O)[O-])cc2cc1C

Procedure:
The product (1 g, 4.5 mmol) from Step A and a solution of 2N ethylamine in methanol (5 mL, 25 mmol) were used to prepare the product according to the procedure of Example 1, Step C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[Cl:21][C:22]1[C:23]([F:38])=[C:24]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH2:30][C:31](=[O:37])[NH:32]3)[CH:25]=[CH:26][CH:27]=1>>[Cl:21][C:22]1[C:23]([F:38])=[C:24]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[C:30](=[CH:19][C:3]2[NH:4][C:5]4[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]5[CH2:14][CH2:15][CH2:16][CH2:17]5)[C:7](=[O:18])[C:6]=4[C:2]=2[CH3:1])[C:31](=[O:37])[NH:32]3)[CH:25]=[CH:26][CH:27]=1
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2F)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4F)c32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Yield: 28.5 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(3-chloro-2-fluoro-phenyl)-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 2-[4-(3-chloro-2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (24 mg, 28.5%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13]Cl)[CH:10]([CH2:15]Cl)[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[NH3:24]>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][NH:24][CH2:15][CH:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: N
Reactant: ClCCN1c2ccc(Cl)cc2C(c2ccccc2)=NCC1CCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCC1CNCCN21
Yield: 59 %

Procedure:
10 g 7-chloro-1-(β-chlorethyl)-2-chlormethyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine were reacted in 200 ml methanol with 20 g ammonia gas in a gas autoclave for 16 hours at 90° to 95° C. After heating of the solution under vacuum, the reaction material is yielded in chloroform and washed with dilute aqueous sodium hydroxide solution. After drying and evaporating of the solvent under vacuum the resultive oily reaction product is dissolved in ether. From the concentrated solution, 5 g of 1,2,3,4,4a,5-hexahydro-9-chloro-7-phenyl-pyrazino[1,2-a]-[1,4]benzodiazepine having a melting point of 132°-135° C. are obtained by crystallization.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.[CH2:12]([O:14][CH2:15][CH3:16])[CH3:13]>O>[CH2:12]([O:14][CH:15]([O:1][CH2:2][CH2:3][CH2:4][C:2]1([OH:1])[CH2:11][CH2:10][C:5]2([O:6][CH2:7][CH2:8][O:9]2)[CH2:4][CH2:3]1)[CH3:16])[CH3:13]
Reactant: CCOCC
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: O
Product: CCOC(C)OCCCC1(O)CCC2(CC1)OCCO2
Temperature: 25 °C

Procedure:
To the above lithiated intermediate there was added dropwise a solution of 85.8 g (0.55 mol) of 8-oxo-1,4-dioxaspiro[4.5]decane in one liter of dry diethyl ether (fresh cans, as above) over a period of about 2.5 hr. The resulting reaction mixture was allowed to warm slowly to room temperature and then poured into two liters of ice cold half saturated ammonium chloride in water solution. The phases were separated and the aqueous phase was extracted with one liter of diethyl ether. The ether layers were combined and washed with brine solution, dried over sodium sulfate, and then the ether solvent was removed under reduced pressure to leave, after drying to 45° C. (0.25 mm.Hg) for 14 hours, 142.15 g of a light yellow oil, the above named decan-8-ol acetal intermediate, which was of sufficient purity to use in the next step. A small sample of the named oil was distilled at reduced pressure to obtain a purer material bp 135°-140° C. (0.01 mmHg). The nuclear magnetic resonance spectrum (using CDCl3 solvent), was consistent with the above named decan-8-ol acetal compound.