Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][CH:4]([NH2:19])[C:3]1=[O:20].[Br:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[Br:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:19][CH:4]2[N:5]=[C:6]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:2]([CH3:1])[C:3]2=[O:20])=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Product: CN1C(=O)C(NC(=O)c2ccc(Br)cc2)N=C(c2ccccc2)c2ccccc21

Procedure:
The procedure of Example 134 was carried out employing equivalent amounts of 1,3-dihydro-1-methyl-3(RS)-amino-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-bromobenzoyl chloride. The product was purified by chromatography on silica gel (5% (v/v) Et2O in CH2Cl2 elution). The combined product fractions were evaporated to dryness in vacuo and crystallized to give the title compound which was dried at 65° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[NH:21][C:20]3[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17](Cl)=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([N:30](C(C)C)CC)(C)C.FC(F)(F)C1C=CC(CN)=CC=1>CN1C(=O)CCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[NH:21][C:20]3[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17]([NH:30][CH3:27])=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4ccccc4)c3)[nH]c2c1=O
Agent: NCc1ccc(C(F)(F)F)cc1
Solvent: CN1CCCC1=O
Product: CCCn1c(NC)nc2nc(-c3cnn(Cc4ccccc4)c3)[nH]c2c1=O
Temperature: 110 °C
Yield: 44.5 %

Procedure:
To a solution of 8-(1-Benzyl-1H-pyrazol-4-yl)-2-chloro-1-propyl-1,7-dihydro-purin-6-one (0.05 g, 0.136 mmol) in NMP (1 ml) under argon was added Diisopropyl ethyl amine (0.035 g, 0.27 mmol) and 4-Trifluoromethyl-benzylamine (0.035 g, 0.203 mmol). The reaction mixture was heated at 110° C. for overnight. The reaction mixture concentrated under reduced pressure. The residue was obtained was purified by preparative HPLC to obtain 8-(1-Benzyl-1H-pyrazol-4-yl)-2-methylamino-1-propyl-1,7-dihydro-purin-6-one (0.022 g, 32%) as a white solid.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[S:21][C:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:11][CH2:12][C:6]=2[CH:5]=1.[S-:22][C:23]#[N:24].[K+].BrBr>>[ClH:20].[ClH:1].[NH2:24][C:23]1[S:22][C:5]2[C:6]3[CH2:12][CH2:11][N:10]([CH2:13][C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)[CH2:9][CH2:8][C:7]=3[S:21][C:4]=2[N:3]=1
Reactant: Nc1cc2c(s1)CCN(Cc1ccc(Cl)cc1)CC2
Reactant: N#C[S-]
Agent: BrBr
Agent: Cl
Agent: [K+]
Product: Nc1nc2sc3c(c2s1)CCN(Cc1ccc(Cl)cc1)CC3

Procedure:
This compound was prepared from 2-amino-6-(4-chlorobenzyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine dihydrochloride, potassium thiocyanate and bromine analogous to Example 1.
Reaction SMILES: [CH2:1]([C:4]([C:18]#[N:19])([CH:15]([CH3:17])[CH3:16])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)[CH:2]=[CH2:3].N(C(C)(C)C#N)=NC(C)(C)C#N.[BrH:32].C(=O)([O-])[O-].[K+].[K+]>C1CCCCC1.CCCCCC>[Br:32][CH2:3][CH2:2][CH2:1][C:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)([CH:15]([CH3:17])[CH3:16])[C:18]#[N:19]
Reactant: C=CCC(C#N)(c1ccc(OC)c(OC)c1)C(C)C
Reactant: Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCCCC1
Solvent: CCCCCC
Product: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Yield: 94 %

Procedure:
To a solution of 50 g of α-allyl-α-isopropyl-3,4-dimethoxy- benzyl cyanide and 2 g of azobisisobutyronitrile in 400 ml of cyclohexane (or n-hexane) gaseous hydrogen bromide was introduced for 70 minutes, when, according to GLC, the reaction mixture did not contain the starting allyl derivative. During the introduction of the hydrogen bromide, the reaction temperature raised to 40° C. The reaction mixture was neutralized with 200 ml of 30% solution of potassium carbonate. The separated cyclohexane solution of the product was washed with water until neutral pH. After drying and evaporating the solvent under diminished pressure, the crude product (61.7 g, 94%) was obtained, which could be used without purification in further reaction step.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH:13]=2)O1.Cl[C:29]1[CH:34]=[N:33][N:32]2[C:35]([C:38]3[CH:39]=[C:40]([NH:44][C:45]([NH:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[O:46])[CH:41]=[CH:42][CH:43]=3)=[CH:36][N:37]=[C:31]2[CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.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>[F:52][C:49]([F:50])([F:51])[CH2:48][NH:47][C:45]([NH:44][C:40]1[CH:39]=[C:38]([C:35]2[N:32]3[N:33]=[CH:34][C:29]([C:9]4[CH:10]=[N:11][N:12]([CH:14]5[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:18][CH2:19]5)[CH:13]=4)=[CH:30][C:31]3=[N:37][CH:36]=2)[CH:43]=[CH:42][CH:41]=1)=[O:46]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(Cl)cnn23)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
A mixture of tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (0.830 g, 2.20 mmol, Combi-Block, Cat. No. FM-2957), N-[3-(7-chloroimidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (0.739 g, 2.00 mmol), tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.100 mmol) and sodium carbonate (0.636 g, 6.00 mmol) in dioxane (15 mL) and water (5 mL) was degassed and recharged with nitrogen three times, and heated and stirred at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexane (gradient: 0-50%) to afford the desired product (0.965 g, 82.5%). LCMS (M+H)+: m/z=585.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH2:16]I)[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].[C:31]([NH:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:33])[CH3:32].O>CN(C=O)C>[C:31]([NH:34][CH:35]1[CH2:40][CH2:39][N:38]([CH2:16][CH:15]2[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH:9]2[C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:37][CH2:36]1)(=[O:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCOC(CI)C(c2ccc(Cl)c(Cl)c2)C1
Reactant: CC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NC1CCN(CC2OCCN(C(=O)OC(C)(C)C)CC2c2ccc(Cl)c(Cl)c2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To a solution of tert-butyl (6SR,7RS)-6-(3,4-dichlorophenyl)-7-(iodomethyl)-1,4-oxazepane-4-carboxylate (300 mg) in DMF (5 mL) were added potassium carbonate (260 mg) and 4-acetamidopiperidine (130 mg), and the mixture was stirred at 80° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (190 mg).
Reaction SMILES: N#N.Cl[C:4]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]=[O:19])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[CH:9]2.[C:20]([Cu])#[N:21].Cl>C1(C)C=CC=CC=1.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.O.CN(C=O)C.CN1CCCC1=O>[CH:18]([C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4]([C:20]#[N:21])=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2)=[O:19]
Reactant: N#C[Cu]
Reactant: O=Cc1c2ccccc2c(Cl)c2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: N#N
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1c2ccccc2c(C=O)c2ccccc12
Reaction time: 1.5 h
Yield: 68 %

Procedure:
A 250 mL 2-neck round bottom flask fitted with thermometer, condenser, N2 inlet and bubbler, and stirring bar was charged with 10-chloro-9-anthraldehyde (Aldrich, 5 g, 21 mmol, CuCN (Fisher Scientific Company, 711 Forbes Ave., Pittsburgh, PA, 15219, 2.14 g, 24 mmol), N-methylpyrrolidinone (100 mL), DMF (15 mL), and bis(triphenylphosphine)palladium dichloride (Fluka, 0.08 g, 0.1 mmol). The mixture was warmed to 170° and stirred 15 h under N2. After 1.5 h, the mixture became homogeneous. The reaction was cooled to 70° and poured into a solution composed of 16 g of FeCl3.6H2O, (Mallinckrodt), 70 mL of 1.0M HCl and 400 mL H2O. The resulting mixture was stirred at 60°-70° for 1 h, filtered and a crude orange solid isolated. This material was dissolved in 1 L of hot PhCH3 and passed through a small plug (100 g) of SiO2. The filtrate was then concentrated to 75 mL and diluted with hexane (200 mL). The orange solid which formed was collected by filtration and dried at 50° to give 3.17 g (68%) of 10-formyl-9-anthracenecarbonitrile mp 270°-275°, (C, H, N).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=O)[CH3:20])[N:14]=1)[CH3:12].[F:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[N:25][C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[F:22])[CH3:20])[N:14]=1)[CH3:12]
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Reactant: Nc1ccccc1F
Solvent: Cc1ccccc1
Product: CC(=Nc1ccccc1F)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
Monoimine (1, 1.0 g, 3.57 mmol) and 2-fluoroaniline (398 mg, 3.57 mmol) (ex. Aldrich) were dissolved in 50 ml of toluene. To this solution, 4 Å molecular sieves were added. After standing for 20 hrs., with addition of more molecular sieves, the mixture was filtered. The solvent was removed in vacuum and the oily residue was warmed in ethanol (50° C.). The yellow solid, which precipitated after cooling at −20° C., was filtered off and dried in vacuo. Yield 300 mg (23%) of mixed diimine (4).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:11][CH3:12])[C:5]([O:13][CH3:14])=[C:4]([O:15][CH3:16])[CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:18].CCOCC>C1COCC1.CO>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:18])=[O:9])=[C:6]([O:11][CH3:12])[C:5]([O:13][CH3:14])=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: COc1cc(N)c(C(=O)O)c(OC)c1OC
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1c(N)cc(OC)c(OC)c1OC
Reaction time: 0.17 h
Yield: 99 %

Procedure:
A solution of 6-amino-2,3,4-tris(methyloxy)benzoic acid (2.7 g, 11.88 mmol) in THF (20 mL) and MeOH (20 mL) at 25° C. was treated with a solution of 2M TMS-diazomethane in Et2O (14.85 mL, 29.7 mmol) and stirred for 10 minutes before being concentrated to give methyl 6-amino-2,3,4-tris(methyloxy)benzoate (2.87 g, 99%) as a brown solid. MS (m/z) 242.1 (M+H+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[C:10]([CH2:11][OH:12])=[CH:9][N:8]=[CH:7]1.C(N(CC)CC)C.CCOC(C)=O>CS(C)=O>[I:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[C:10]([CH:11]=[O:12])=[CH:9][N:8]=[CH:7]1
Reactant: OCc1cncn1Cc1cccc(I)c1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=Cc1cncn1Cc1cccc(I)c1
Reaction time: 0.67 h

Procedure:
To a solution of the alcohol from Step B (ca. 10.4 mmol) in 100 mL of DMSO at room temperature was added triethylamine (14.5 mL, 104 mmol), then SO3-pyridine complex (8.27 g, 52 mmol). After 40 minutes, the reaction was poured into EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the aldehyde as an oily solid contaminated with triethylamine.
Reaction SMILES: [C:1]([C:3]1[C:26]([N+:27]([O-])=O)=[CH:25][CH:24]=[CH:23][C:4]=1[O:5][CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)=[O:14])#[N:2]>C1COCC1.C(O)(=O)C.[Fe]>[NH2:27][C:26]1[C:3]([C:1]#[N:2])=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[C:13]([NH:15][CH2:16][C:17]1[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=1)=[O:14]
Reactant: N#Cc1c(OC[C@H]2CCCCN2C(=O)NCc2ccncc2)cccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#Cc1c(N)cccc1OC[C@H]1CCCCN1C(=O)NCc1ccncc1
Temperature: 25 °C
Yield: 39.4 %

Procedure:
To a solution of (R)-2-((2-cyano-3-nitrophenoxy)methyl)-N-(pyridin-4-ylmethyl)piperidine-1-carboxamide (Example 27c, 365 mg, 0.98 mmol) in THF/acetic acid (20 mL, 1:1), was added iron powder (164 mg, 2.94 mmol). The reaction was heated to reflux over 15 min under nitrogen, and stirred at reflux for 30 min. Upon completion, the reaction was cooled to room temperature, concentrated, diluted with ethyl acetate and successively washed a saturated solution of NaHCO3, dried over Na2SO4, filtered, concentrated and flash chromatographed (0-10% methanol in dichloromethane) to provide the desired product (141 mg, 40%). MS=366 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][Cl:14].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#Cc1ccc(OCCCCl)cc1

Procedure:
A mixture of 0.47 g (0.004 mol) of 4-hydroxybenzonitrile, 0.63 g (0.004 mol) of 1-bromo-3-chloropropane and 1.95 g (0.006 mol) of caesium carbonate in 10 ml of acetonitrile is heated at reflux for 5 hours.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[C:22]([O:26][C:27]([N:29]1[CH2:33][C@H:32]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:31][C@H:30]1[CH2:42][C@H:43]1[CH2:47][N:46]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C@H:45]([CH2:55][OH:56])[CH2:44]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(OCC)(=[O:59])C>CN(C)C=O>[C:22]([O:26][C:27]([N:29]1[CH2:33][C@H:32]([O:34][Si:35]([C:38]([CH3:39])([CH3:41])[CH3:40])([CH3:37])[CH3:36])[CH2:31][C@H:30]1[CH2:42][C@H:43]1[CH2:47][N:46]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C@H:45]([C:55]([OH:59])=[O:56])[CH2:44]1)=[O:28])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1C[C@H](C[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)C[C@H]1CO
Reactant: CCOC(C)=O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 57 %

Procedure:
Pyridinium dichromate was added to a solution of (2R, 4R)-N-tert-butoxycarbonyl-2-[(2S, 4R)-N-tert-butoxycarbonyl-2-(hydroxymethyl)pyrrolidin-4-ylmethyl]-4 -(tert-butyldimethylsiloxy)pyrrolidine (3.00 g, 5.84 mmol, compound of Reference Example 2-6) in N,N-dimethylformamide (30 ml) and stirred at room temperature for 14 hours. Ethyl acetate was added to the reaction solution and washed sequentially with water and a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash column chromatography (Wakogel™ C-300, 80 ml, n-hexane-ethyl acetate (1:1)) to obtain (2R, 4R)-N-tert-butoxycarbonyl-2-[(2S, 4R)-N-tert-butoxycarbonyl-2-carboxypyrrolidin-4-ylmethyl]-4-(tert-butyldimethylsiloxy)pyrrolidine (1.77 g, yield: 57%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8](/[CH:12]=[C:13]2\[N:14]=C(C3C=CC=CC=3)[O:16][C:17]\2=[O:18])[C:3]=1[C:4](OC)=[O:5].[OH-].[K+]>C(OC(=O)C)(=O)C>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:5])[NH:14][C:13]([C:17]([OH:16])=[O:18])=[CH:12]2
Reactant: COC(=O)c1c(F)cccc1/C=C1\N=C(c2ccccc2)OC1=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1cc2cccc(F)c2c(=O)[nH]1
Yield: 41.9 %

Procedure:
A solution of crude (Z)-methyl 2-fluoro-6-((5-oxo-2-phenyloxazol-4(5H)-ylidene)methyl)benzoate (15 g) and potassium hydroxide (2.58 g, 46 mmol) in acetic anhydride (150 mL) was heated at 100° C. for 2 hours. The solvent was removed in vacuo, and the residue was diluted with water (30 mL). The resulting mixture was neutralized with 1M aqueous HCl (100 mL) and filtered. The solids were dried in vacuo to give 8-fluoro-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid (4 g, ESI-MS m/z [M+H]+ 208.0) which was converted to the methyl ester as described, below. The filtrate was concentrated under reduced pressure to give crude product which was purified by column chromatography eluting with a gradient of EtOAc (30-100%) and PE to give a first batch of the title compound (2 g, 19.6%). ESI-MS m/z [M+H]+=222.1.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[C:3]([O:5][CH2:6][C:7]([CH3:14])([CH3:13])[CH:8]([OH:12])[CH:9]([CH3:11])[CH3:10])=[O:4].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:12][CH:8]([CH:9]([CH3:10])[CH3:11])[C:7]([CH3:14])([CH3:13])[CH2:6][O:5][C:3](=[O:4])[CH:2]([CH3:15])[CH3:1])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: CC(C)C(=O)OCC(C)(C)C(O)C(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(C(C)C)C(C)(C)COC(=O)C(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Into a one-liter, four-necked, round bottom flask equipped with stirrer, condenser, and thermometer, 200.0 parts of pyridine and 54.0 parts of 3-hydroxy-2,2,4-trimethylpentyl 2-methylpropionate were mixed under a nitrogen blanket and cooled to 0° C. using an ice water bath. To this, 57.0 parts of para-toluenesulfonyl chloride were added in portions over a thirty minute period. The solution was stirred for one hour at 0° C. and then allowed to stand for twenty-four hours at 15° C. The mixture was subsequently poured into one liter of ice water, which was then extracted with 700 parts of methylene chloride. The organic layer was washed successively with cold 6N sulfuric acid (until the water layer was acidic to pH paper); dilute sodium bicarbonate (three times with 500 part-portions); and water (twice with 500 part-portions). It was then dried over sodium sulfate, filtered, and the solvent removed in vacuo to yield the 1-isobutyryloxy-2,2,4-trimethylpentane-3-yl para-toluenesulfonate.
Reaction SMILES: [Si:1]([O:8][CH:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17]CS([O-])(=O)=O)[CH2:13][CH2:12]1)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N-:23]=[N+:24]=[N-:25].[Na+].C(OCC)(=O)C>CN(C)C=O>[N:23]([CH2:17][C@H:14]1[CH2:15][CH2:16][C@H:11]([CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH3:10])[CH2:12][CH2:13]1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H](CCS(=O)(=O)[O-])CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H](CN=[N+]=[N-])CC1
Temperature: 110 °C
Reaction time: 0.75 h

Procedure:
In 50 ml of dry dimethylformamide was suspended 2.0 g of trans-4-(1-t-butyldimethylsilyloxyethyl)cyclohexylmethylmethanesulfonate and 1.85 g of sodium azide, and the resulting mixture was stirred at 110° C. for 45 minutes. To the reaction mixture were added 200 ml of ethyl acetate, and the mixture was washed three times with an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.7 g of the desired compound as a pale yellow oil. This oil was used for the subsequentareaction without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([O:12][C@@H:13]([CH3:22])[CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]>FC(F)(F)C(O)=O>[N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([O:12][C@@H:13]([CH3:22])[CH2:14][C:15]([OH:17])=[O:16])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[C@@H](CC(=O)OC(C)(C)C)OC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](CC(=O)O)OC(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 77.1 %

Procedure:
A solution of 5.10 g of tert-butyl (S)-3-(4-nitrobenzyloxycarbonyloxy)-butyrate in 20 ml of trifluoroacetic acid was stirred at 0° C. for 90 minutes. The solvent was evaporated in vacuo, and the residue was crystallized from methylene chloride/hexane to yield 3.28 g of (S)-3-(4-nitrobenzyloxycarbonyloxy)-butyric acid as white crystals of m.p. 78°-81° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:24][C:25](=[O:27])[NH2:26])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>CC(C)=O.O>[C:25]([O:24][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:36](=[O:37])[O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)(=[O:27])[NH2:26]
Reactant: NC(=O)OC(CCN1CCN(c2ccc(O)cc2)CC1)c1ccc(F)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: NC(=O)OC(CCN1CCN(c2ccc(OC(=O)OCc3ccccc3)cc2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The compound ‘carbamic acid 1-(4-fluoro-phenyl)-3-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-propyl ester (1 mmol) prepared in Example 88 was dissolved in acetone (20 mL), and triethylamine (2 mmol) was added and benzyl chloroformate (2.4 mmol) was added dropwise, and the resulting mixture was then stirred at a room temperature for 5 hours. The reaction mixture was diluted with water, and extracted several times with ethyl acetate to obtain an organic phase. The prepared organic phase was dried over magnesium sulfate, and concentrated under a reduced pressure. The resulting pellet was purified with column chromatography (hexane:ethyl acetate=1:1) to obtain a title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([F:23])[CH:22]=3)[C:9]([CH:11]([NH:13]C(=O)C)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl>>[Br:1][C:2]1[C:7]2[N:8]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([F:23])[CH:22]=3)[C:9]([CH:11]([NH2:13])[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)NC(C)c1nc2cccc(Br)c2n1-c1cncc(F)c1
Agent: Cl
Product: CC(N)c1nc2cccc(Br)c2n1-c1cncc(F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of N-(1-(7-bromo-1-(5-fluoropyridin-3-yl)-1H-benzo[d]imidazol-2-yl)ethyl)acetamide (1.5652 g, 4.15 mmol) and 2N HCl (31.1 mL, 62.2 mmol) was heated at 100° C. After 6 h, the mixture was cooled to rt and partitioned between DCM (50 mL) and water (50 mL). The acidic aqueous mixture was washed with DCM (50 mL×4) to remove organic impurities and then basified to ˜pH 12 with 10N NaOH (6 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with water (100 mL×1), brine (100 mL×1), dried over MgSO4, filtered, and concentrated in vacuo to give a dark red syrup. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep™ pre-packed silica gel column (80 g), eluting with a gradient of 0% to 50% DCM:MeOH:NH4OH (89:9:1) in DCM, to provide 1-(7-bromo-1-(5-fluoropyridin-3-yl)-1H-benzo[d]imidazol-2-yl)ethanamine as a brown syrupy solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.86 (1H, t, J=2.8 Hz), 8.73 (1H, dt, J=13.5, 1.4 Hz), 8.23-8.33 (1H, m), 7.75 (1H, dd, J=8.0, 1.0 Hz), 7.41 (1H, d, J=7.4 Hz), 7.21 (1H, t, J=7.9 Hz), 3.76 (1H, q, J=6.7 Hz), 1.93 (2H, br. s.), 1.36 (3H, d, J=6.7 Hz); LC-MS (ESI) m/z 334.9 [M+H (79Br)]+ and 337 [M+H (81Br)]+.