Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[CH:19]=[C:20]([F:22])[CH:21]=1)[C:10]([CH3:32])([CH3:31])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([C:18]2[CH:19]=[C:20]([F:22])[CH:21]=[C:16]([CH:11]3[C:10]([CH3:32])([CH3:31])[CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:17]=2)=[CH:28][CH:27]=1)#[N:30]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(-c3ccc(C#N)cc3)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(F)cc(-c2ccc(C#N)cc2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 35.7 %

Procedure:
A mixture of 2-(4′-cyano-5-fluoro-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.15 g, 0.35 mmol), lithium hydroxide hydrate (0.15 g, 3.5 mmol), water (1 mL) in methanol (3 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-(4′-cyano-5-fluoro-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (50 mg, 36%) as a white solid: LC/MS m/e calcd for C25H21FN2O2 (M+H)+: 401.5, observed: 401.3.
Reaction SMILES: [O:1]=[C:2]1[O:6][C:5]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[NH:12]C(=O)OC(C)(C)C)=[N:4][NH:3]1.[ClH:20]>O1CCOCC1>[ClH:20].[NH2:12][C:11]1[CH:10]=[CH:9][S:8][C:7]=1[C:5]1[O:6][C:2](=[O:1])[NH:3][N:4]=1
Reactant: CC(C)(C)OC(=O)Nc1ccsc1-c1n[nH]c(=O)o1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccsc1-c1n[nH]c(=O)o1
Reaction time: 1 h

Procedure:
The mixture consisting of 100 mg of tert-butyl [2-(5-oxo-4,5-dihydro[1,3,4]oxadiazol-2-yl)thiophen-3-yl]carbamate and 5 ml of a 4 molar HCl solution in dioxane is stirred for one hour. Afterwards, the volatile fractions are removed under reduced pressure and the residue is stirred with 5 ml of tert-butyl methyl ether and the product is filtered off with suction and dried under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[CH2:6][CH2:5]2.[C:14]([NH:17][NH2:18])(=O)[CH3:15]>C(O)CCC>[Br:1][C:2]1[C:3]([Cl:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:14]([CH3:15])=[N:17][N:18]=[C:7]1[CH2:6][CH2:5]2
Reactant: CC(=O)NN
Reactant: S=C1CCc2c(ccc(Br)c2Cl)N1
Solvent: CCCCO
Product: Cc1nnc2n1-c1ccc(Br)c(Cl)c1CC2
Temperature: 120 °C

Procedure:
To a stirred solution of 6-bromo-5-chloro-3,4-dihydroquinoline-2(1H)-thione (143-6; 0.3 g, 0.0012 mol) in n-butanol (10 mL) was added acetic hydrazide (0.2 g, 0.00213 mol). Reaction mass was heated at 120° C. for 16 h. The reaction mixture was concentrated and directly purified by silica gel column chromatography to obtain title compound. MS (M+1): 298.0.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:11])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].[OH-].[Na+]>CO.[Pd]>[CH3:11][C:5]1[N:4]=[N:3][CH:2]=[C:7]([C:8]([OH:10])=[O:9])[CH:6]=1
Reactant: Cc1cc(C(=O)O)c(Cl)nn1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(=O)O)cnn1
Reaction time: 3 h
Yield: 30.1 %

Procedure:
To a stirred solution of 3-chloro-6-methyl-pyridazine-4-carboxylic acid (500 mg, 2.89 mmol) in MeOH (50 mL) was added NaOH (395 mg, 9.85 mmol) in pellets, followed by 150 mg of Pd/C (10%). The reaction mixture was put under a H2 atmosphere for 3 hours (atmospheric pressure). The reaction mixture was filtered on celite, acidified with aq. HCl (ph=6), and concentrated under vacuo. Column chromatography (SiO2, CH2Cl2/MeOH 7/3) yielded 120 mg (29%) of 6-methyl-pyridazine-4-carboxylic acid as a brown solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([O:11][C:12](=[O:49])[CH2:13][CH:14]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][CH3:35])=[S:33])=[CH:27][C:26]=1[O:36][CH2:37][CH2:38][C:39]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:40]=1[CH:41]=[CH:42][CH:43]=[N:44]2)(=[O:24])=[O:23])[C:15](N(OC)C)=[O:16])([CH3:10])([CH3:9])[CH3:8]>CCOCC.C1COCC1>[C:7]([O:11][C:12](=[O:49])[CH2:13][CH:14]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][CH3:35])=[S:33])=[CH:27][C:26]=1[O:36][CH2:37][CH2:38][C:39]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:40]=1[CH:41]=[CH:42][CH:43]=[N:44]2)(=[O:24])=[O:23])[CH:15]=[O:16])([CH3:10])([CH3:8])[CH3:9]
Reactant: CNC(=S)Nc1ccc(S(=O)(=O)NC(CC(=O)OC(C)(C)C)C(=O)N(C)OC)c(OCCc2cccc3ncccc23)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNC(=S)Nc1ccc(S(=O)(=O)NC(C=O)CC(=O)OC(C)(C)C)c(OCCc2cccc3ncccc23)c1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 505.8 %

Procedure:
A mixture of 2 mL THF and 0.8 mL 1M LiAlH4 solution in ether was cooled to −65° C. in a chloroform/dry ice bath. A mixture if 0.18 g (0.29 mmol) N-methoxy-N-methyl--3-[4-(3-methyl-thioureido)-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-succinamic acid tert-butyl ester in 3 mL THF was added dropwise and the reaction mixture was stirred 30 min at −65° C. TLC analysis showed starting material consumed. The reaction was quenched cold with 1 mL 1M aqueous potassium sodium tartrate solution and allowed to reach room temperature. The product was partioned between 75 mL brine and 50 mL EtOAc. The product was extracted with 50 EtOAc, the combined organic extracts dried over anhydrous magnesium sulfate, filtered, concentrated and purified on silica with 1:1 EtOAc:hexanes to give 0.84 g (52%) of 3-[4-(3-methyl-thioureido)-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid tert-butyl ester as a colorless glass. MS (APCI) m/z 573 (M+1).
Reaction SMILES: [C:1]1([CH:11]=[C:12]2[CH2:17][C:16](=[O:18])[O:15][C:13]2=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:19][OH:20]>ClCCl>[CH3:19][O:20][C:16]([CH2:17][C:12](=[CH:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C:13]([OH:15])=[O:14])=[O:18]
Reactant: O=C1CC(=Cc2cccc3ccccc23)C(=O)O1
Reactant: CO
Solvent: ClCCl
Product: COC(=O)CC(=Cc1cccc2ccccc12)C(=O)O

Procedure:
A solution of 300 mg of 2-(1-naphthylmethylene)succinic anhydride and 18 ml of methyl alcohol in 30 ml of dry dichloromethane was heated under reflux for 5 hours. The reaction mixture was washed successively with a diluted hydrochloric acid and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 336 mg of 3-methoxycarbonyl-2-(1-naphthylmethylene)propionic acid as a white powder.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([N:13]=[CH:14][C:15](=[O:19])[NH:16]2)=[CH:11][CH:10]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>O>[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([N:13]=[CH:14][C:15](=[O:19])[N:16]2[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:11][CH:10]=1
Reactant: CCOC(=O)CBr
Reactant: O=c1cnc2ccc(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1c(=O)cnc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen gas flow, to a mixture of NaH (55% in oil, 515 mg) and DMF (5 mL) was added a mixture of 7-chloroquinoxalin-2(1H)-one (2.00 g) and DMF (35 mL) under ice-cooling, followed by stirring at room temperature for 30 minutes. The reaction mixture was ice-cooled and ethyl bromoacetate (1.3 mL) was added thereto, followed by stirring at room temperature for 7 hours. The reaction mixture was added to water, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/MeOH=100/0-98/2). The obtained solid was washed with Hex to obtain ethyl (7-chloro-2-oxoquinoxalin-1(2H)-yl)acetate (2.21 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.CC(OC(C)=O)=O.[OH:18][S:19](O)(=[O:21])=[O:20]>CCOC(C)=O>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[S:19]([OH:21])(=[O:20])=[O:18]
Reactant: O=S(=O)(O)O
Reactant: Cc1csc2ccccc12
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: Cc1c(S(=O)(=O)O)sc2ccccc12
Yield: 13.9 %

Procedure:
A solution of 3-methyl-benzothiophene (900 mg, 6.1 mmol), Ac2O (1.75 mL, 18.5 mmol) and conc. H2SO4 (350 μL, 6.2 mmol) in EtOAc (5 mL) was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc. The organic phase was washed with water and brine and then dried. Upon evaporation of some of the solvent the product precipitated. Et2O was added, and the precipitate was collected giving 193 mg of 3-methylbenzothiophene-2-sulfonic acid (14%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.48 (s, 3 H) 7.33-7.41 (m, 2 H) 7.69-7.75 (m, 1 H) 7.83-7.88 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH2:8][CH:7]([OH:11])[C:6]=2[C:5]([CH:12]2[C@H:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@@H:16]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:15]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@@H:14]([CH2:42][O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[O:13]2)=[CH:4][C:3]=1[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH3:60])=[CH:54][CH:53]=1.I[CH3:62].[H-].[Na+]>CN(C=O)C.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[C:10]2[O:9][CH2:8][CH:7]([O:11][CH3:62])[C:6]=2[C:5]([CH:12]2[C@H:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@@H:16]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:15]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@@H:14]([CH2:42][O:43][CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[O:13]2)=[CH:4][C:3]=1[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH3:60])=[CH:54][CH:53]=1
Reactant: CCOc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC3O)cc1
Reactant: CI
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC3OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a mixture solution of 7-chloro-6-(4-ethoxybenzyl)-4-((3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)-2,3-dihydrobenzofuran-3-ol (260 mg, 0.314 mmole) and iodomethane (40 μL, 0.628 mmole) in DMF (10 mL) was added NaH (25.1 mg, 0.628 mmole) at 0° C. The resulting solution was stirred at rt overnight, diluted with sat. NaHCO3 and extracted with ethyl acetate. The organic layer was washed with water then brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified on Biotage® purification apparatus to yield the title compound (238 mg, 90%) as a yellow gum.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=O)[O:12]2)=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:22][NH2:23].[OH-].[Na+]>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:12])[NH:23][N:22]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(C=C2OC(=O)c3ccccc32)ccc1F
Reactant: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#Cc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F

Procedure:
from compound E by reaction with hydrazine hydrate; and (d) synthesising compound D from compound ED by reaction with sodium hydroxide.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[N:19]=[C:18]([C:20]([NH:22][CH2:23][CH2:24][CH3:25])=[O:21])[CH:17]=[CH:16][CH:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:12]([C:14]2[N:19]=[C:18]([C:20]([NH:22][CH2:23][CH2:24][CH3:25])=[O:21])[CH:17]=[CH:16][CH:15]=2)=[N:13]1
Reactant: CCCNC(=O)c1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCNC(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 80.4 %

Procedure:
A mixture of methyl thiosalicylate (4.2 g, 25 mmol), 6-cyano-N-propyl-2-pyridinecarboxamide (2.5 g, 13 mmol), triethylamine (4.0 ml, 28 mmol) and toluene (8 ml) was refluxed for 8 hrs as described in Example 1. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-tetrahydrofuran to give the titled compound (3.4 g, 78%) as crystals.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6].[N+]([O-])([O-])=O.[Na+].[Cl-:22].[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[OH-].[Na+]>Cl.O>[Cl:22][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6]
Reactant: [Cl-]
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1N
Agent: Cl
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: COc1ccc(C(=O)CCC(=O)O)cc1Cl

Procedure:
A solution of 3-(3-amino-4-methoxybenzoyl) propionic acid (5 g.) in concentrated hydrochloric acid (25 ml.) was diazotised at 0° C by the addition of a solution of sodium nitrate (1.54 g.) in water (5 ml.). This diazo solution was added with stirring to a solution containing hydrated copper sulphate (6.3 g.) and sodium chloride (5.4 g.) in water (20 ml.) to which had been added a solution containing sodium metabisulphite (1.4 g.) and sodium hydroxide (0.9 g.) in water (10 ml.). The mixture was then heated on the steam bath for 30 minutes when a solid separated. The mixture was cooled, the solid collected and washed with cold water. It was crystallised from methanol to yield the product (4.2 g.), m.p. 187°-189° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=O)[NH:4][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)[CH3:9])=[N:6][CH:7]=1.P(Cl)(Cl)([Cl:30])=O>>[Br:1][C:2]1[C:3]([Cl:30])=[N:4][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)[CH3:9])=[N:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(S(=O)(=O)N2CCN(C(C)c3ncc(Br)c(=O)[nH]3)CC2)cc1
Product: COc1ccc(S(=O)(=O)N2CCN(C(C)c3ncc(Br)c(Cl)n3)CC2)cc1
Temperature: 90 °C

Procedure:
In a flask containing of 5-bromo-2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-3H-pyrimidin-4-one (150.0 mg, 0.33 mmol) in phosphorus oxychloride (2 ml) was heated to 90° C. for 2 hours, then the solvent was concentrated under reduced pressure to give the 5-bromo-4-chloro-2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-pyrimidine that was used in the next step without any purification. MS m/z calc. 524.2 found (ESI); 526.2 (M+1)+. Retention time 2.91 minutes.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([C:12]1[NH:13][C:14]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][CH3:25])[CH:18]=2)[N:16]=1)([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[N:16]=[C:12]([C:9]([CH3:11])([CH3:10])[CH2:8][NH2:7])[NH:13][C:14]=2[C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)=[CH:18][C:19]=1[O:24][CH3:25]
Reactant: COc1cc(-c2nc(C(C)(C)CNC(=O)OC(C)(C)C)[nH]c2-c2ccncc2)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2nc(C(C)(C)CN)[nH]c2-c2ccncc2)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.5 %

Procedure:
A solution of Example 1 (112 mg, 0.245 mmol) in dichloromethane (2 ml) containing trifluoroacetic acid (1 ml) was stirred at room temperature for 3 hours. The solution was concentrated at reduced pressure and the residue was partitioned between saturated sodium hydrogen carbonate solution and ethyl acetate. The organic layers were then combined, washed with brine, dried over anhydrous magnesium sulphate, filtered and concentrated at reduced pressure to give the title compound (59 mg, 68%) as a solid; MS(ES+) m/e 357/359 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][C:15]([C:17](OCC)=[O:18])=[CH:16][C:4]=2[N:3]=1.[AlH4-].[Li+]>O1CCCC1>[NH2:1][C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[C:5]2[CH:13]=[CH:14][C:15]([CH2:17][OH:18])=[CH:16][C:4]=2[N:3]=1
Reactant: CCOC(=O)c1ccc2c(c1)nc(N)n2C1CCCCC1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1nc2cc(CO)ccc2n1C1CCCCC1
Yield: 91.6 %

Procedure:
In a 20 mL vial, ethyl 2-amino-1-cyclohexyl-1H-benzo[d]imidazole-5-carboxylate (101.5 mg, 0.0003532 mol) was dissoled in tetrahydrofuran (2 mL, 0.02 mol). While stirring under nitrogen, a solution of 1.0 M of lithium tetrahydroaluminate in tetrahydrofuran (1.0 mL) was added dropwise via a syringe to the reaction mixture. An initial reddish color occured followed by the reaction mixture becoming straw colored and a precipitate formed. After 1 hour the reaction was quenched by the dropwise addition of saturated ammonium chloride (1 mL). The mixture was extracted with ethyl acetate three times, the combined organic phases dried over sodium sulfate and concentrated to give the title compound (79.4 mg) as an off white solid.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][NH:10][CH2:9][C@H:8]2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>C(Cl)Cl>[CH:16]1([C:19]([N:10]2[CH2:11][CH2:12][C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C@H:8]([OH:13])[CH2:9]2)=[O:20])[CH2:18][CH2:17]1
Reactant: O=C(Cl)C1CC1
Reactant: O[C@@H]1CNCC[C@@H]1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(C1CC1)N1CC[C@H](c2ccccc2)[C@H](O)C1
Reaction time: 0.25 h

Procedure:
cis-4-Phenyl-3-piperidinol (9.0 g, 50.8 mmoles, described in Example 9) is dissolved in methylene chloride (200 ml) and a 30% solution of sodium hydroxide (100 ml) is added. Cyclopropanecarboxylic acid chloride (5.72 g, 55.0 mmoles) is added dropwise to the cooled solution (10° C.) and stirring is continued for 15 minutes. The organic phase is separated, washed with brine, dried (MgSO4) and evaporated. The residue is crystallized from ethyl acetate-ether to give cis-1-cyclopropylcarbonyl-4-phenyl-3-piperidinol, mp 175°-177° C.
Reaction SMILES: ClC(OCC(C)C)=O.[O:9]([CH2:17][C:18]#[C:19][C:20]([OH:22])=O)[Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].CN1CCOCC1.N#N.[NH2:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[N:39]=[CH:38][C:37]([C:43]#[N:44])=[C:36]2[NH:45][C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([Br:52])[CH:47]=1>O1CCCC1.N1C=CC=CC=1>[Br:52][C:48]1[CH:47]=[C:46]([NH:45][C:36]2[C:35]3[C:40](=[CH:41][CH:42]=[C:33]([NH:32][C:20](=[O:22])[C:19]#[C:18][CH2:17][O:9][Si:10]([C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:11])[CH3:12])[CH:34]=3)[N:39]=[CH:38][C:37]=2[C:43]#[N:44])[CH:51]=[CH:50][CH:49]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)OCC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N#N
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34.8 %

Procedure:
Isobutyl chloroformate (0.214 g, 1.57 mmol) was dropwise added into an ice cold solution of 4-t-butyldimethylsiloxy-2-butynoic acid (0.336 g, 1.57 mmol) and N-methylmorpholine (0.19 g, 1.88 mmol) in 15 mL of tetrahydrofuan under N2. After stirring for 30 min, the reaction mixture was added dropwise into a solution of 0.4 g (1.18 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 3 mL of tetrahydrofuran and 1.5 mL of pyridine and stirred at 0° C. for 1 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by column chromatography eluted with 60% ethyl acetate in hexane. The product was collected, and dried in vacuo to give 0.22 g (35%) of yellow solid;: mass spectrum (electrospray, m/e,): 535.1189 (M+.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6](=[O:18])[C:5]2=O.CCOCC>CCCCCC>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[CH2:5][C:6]1=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1C(=O)N(Cc2ccccc2)c2ccc(F)cc21
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C1Cc2cc(F)ccc2N1Cc1ccccc1
Yield: 75.2 %

Procedure:
In a manner similar to the method of N-benzylisatin, 5-fluoroisatin (10.0 g, 60.5 mmol) yielded 5-fluoro-N-benzylisatin as an orange red powder (14.5 g, 93%). The crude product was used for the next step without purification. 1H NMR (400 MHz, CDCl3) δ 7.33-7.21 (m, 5H), 6.95 (d, J=7.6 Hz, 1H), 6.84 (t, 1H), 6.60 (m, 1H), 4.89 (s, 2H); MS ESI 255.9 [M+H]+, calcd for [C15H10FNO2+H]+ 255.07. The title compound was prepared in a manner similar to the method of N-Benzyl-oxindole using 5-fluoro-N-benzylisatin (14.5 g, 56.8 mmol). Trituration using Et2O:hexane yielded the title compound as a pale yellow solid (10.3 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.30-7.26 (m, 5H), 7.00 (d, J=7.6 Hz, 1H), 6.87 (t, 1H), 6.63 (m, 1H), 4.91 (s, 2H), 3.63 (s, 2H); MS ESI 241.9 [M+H]+, calcd for [C15H10FNO2+H]+ 241.09.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:36](O)=[O:37])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:22]([CH3:35])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[CH2:72]([O:74][C:75]([CH:77]1[CH2:82][CH2:81][N:80]([CH:83]2[CH2:88][CH2:87][NH:86][CH2:85][CH2:84]2)[CH2:79][CH2:78]1)=[O:76])[CH3:73]>C1COCC1.CCOC(C)=O>[CH2:28]([O:27][C:23]1[C:24]([CH3:26])=[CH:25][C:20]([CH2:19][C@@H:18]([O:17][C:15]([N:12]2[CH2:11][CH2:10][CH:9]([N:8]3[CH2:7][CH2:6][C:5]4[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=4[NH:3][C:2]3=[O:1])[CH2:14][CH2:13]2)=[O:16])[C:36]([N:86]2[CH2:87][CH2:88][CH:83]([N:80]3[CH2:81][CH2:82][CH:77]([C:75]([O:74][CH2:72][CH3:73])=[O:76])[CH2:78][CH2:79]3)[CH2:84][CH2:85]2)=[O:37])=[CH:21][C:22]=1[CH3:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)C1CCN(C2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c(OCc4ccccc4)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 400 mg (0.70 mmol) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1g), 250 mg (0.78 mmol) TBTU and 0.12 mL (3.73 mmol) triethylamine in 20 mL THF were stirred for 1 h at RT. Then 0.4 mL (2.87 mmol) triethylamine and 270 mg (0.86 mmol) ethyl[1,4′]bipiperidinyl-4-carboxylate (used as the bis-hydrochloride salt) were added. The reaction mixture was stirred for 24 h at RT, diluted with EtOAc, washed with saturated NaHCO3 solution and the organic phase was dried on Na2SO4. After the elimination of the desiccant and solvent the residue was purified by chromatography (Alox activity stage II-III, gradient DCM/EtOH 40:1 to DCM/EtOH 30:1).