Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[S:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:17]=3[N:18]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.CO.O.[SH-].[Na+]>O>[N:18]1[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[S:11][C:10]=1[C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc3ccncc3s2)c1
Agent: [Na+]
Agent: [SH-]
Solvent: O
Solvent: CO
Product: Nc1cccc(-c2nc3ccncc3s2)c1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
310 mg of 2-(3-nitrophenyl)thiazolo[5,4-c]pyridine (1.2 mmol) was mixed with 30 mL of MeOH along with 6 mL of water. Sodium hydrosulfide hydrate (6 eq, 7.24 mmol, 400 mg) was added and the reaction mixture was stirred under reflux for 3 hours. The reaction mixture was cooled to room temperature and concentrated. The aqueous layer was extracted with methylene chloride. The combined organic layers were dried (Na2SO4) and concentrated to afford 230 mg of 3-(thiazolo[5,4-c]pyridin-2-yl)benzenamine (84% crude yield) (MS, M++H=228).
Reaction SMILES: [CH2:1]([C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6]C1CCCCO1)[CH:2]=[CH2:3].C([Li])(CC)C.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C>C1COCC1>[CH2:1]([C:4]1[C:5]([OH:6])=[C:13]([B:26]([OH:27])[OH:25])[CH:14]=[CH:15][CH:16]=1)[CH:2]=[CH2:3]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: C=CCc1ccccc1OC1CCCCO1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: C=CCc1cccc(B(O)O)c1O
Reaction time: 0.17 h
Yield: 21 %

Procedure:
2-(2-allylphenoxy)tetrahydropyran (3.5 g, 16.03 mmol) was dissolved in dry THF (120 ml) and the solution cooled to −78° C. sec-Butyl lithium (1.3M in hexanes, 14.7 ml, 19.11 mmol) was added dropwise with stirring over 10 minutes, the reaction was stirred at −78° C. for 2 hours. Triisopropoxy borane (6.7 ml, 28.77 mmol) was added and stirring continued for 4 hours at −78° C. The reaction was quenched with water, acidified to pH 1 with 2N hydrochloric acid and extracted with ether (2×200 ml). The combined extracts were dried with magnesium sulphate and concentrated under vacuum. The oily solid produced was triturated with cyclohexane and the solid filtered off to give the title compound (600 mg, 21%); MS 177 (M-H)−; HPLC retention time (system 1) 3.09 minutes.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:9][O:10][C:11]2[C:19]3[C:18]4[CH:20]=[C:21]([C:24]#[N:25])[N:22]=[CH:23][C:17]=4[NH:16][C:15]=3[N:14]=[CH:13][CH:12]=2)([CH3:8])[CH2:4][CH2:3]1.[Cl:26]N1C(=O)CCC1=O>C(#N)C.C(O)(C)C>[Cl:26][C:12]1[CH:13]=[N:14][C:15]2[NH:16][C:17]3[CH:23]=[N:22][C:21]([C:24]#[N:25])=[CH:20][C:18]=3[C:19]=2[C:11]=1[O:10][CH2:9][C:5]1([CH3:8])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCC(C)(COc2ccnc3[nH]c4cnc(C#N)cc4c23)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Solvent: CC(C)O
Product: CN1CCC(C)(COc2c(Cl)cnc3[nH]c4cnc(C#N)cc4c23)CC1
Temperature: 40 °C
Reaction time: 16 h
Yield: 20.3 %

Procedure:
A mixture of 4-((1,4-dimethylpiperidin-4-yl)methoxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (50 mg, 0.16 mmol), N-chlorosuccinimide (60 mg, 0.45 mmol) in acetonitrile (0.8 mL) and isopropyl alcohol (0.23 mL) was stirred at 40° C. for 16 hours. The reaction mixture was diluted acetonitrile (1 mL) and the solid was collected by centrifugation, dissolved in dimethylsulfoxide (2 mL), and purified by preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the title compound as a white solid (12 mg, 20%). 1H NMR (500 MHz, d6-DMSO) δ 9.04 (s, 1H), 8.68 (s, 1H), 8.53 (s, 1H), 4.28 (s, 2H), 2.51-2.46 (m, 2H), 2.28 (m, 2H), 2.22 (s, 3H), 1.82 (m, 2H), 1.51 (m, 2H), 1.19 (s, 3H), NH signal not observed. LCMS (Method D): RT=8.445 min, M+H+=370.1.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[CH:13][NH:14]3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[F:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1>CN1C(=O)CCC1.ClCCl.[Cu]>[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:14]2[C:15]3[C:11](=[CH:10][CH:9]=[C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)[CH:16]=3)[CH:12]=[CH:13]2)=[CH:26][CH:25]=1
Reactant: Fc1ccc(I)cc1
Reactant: CN1CCN(c2ccc3cc[nH]c3c2)CC1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc3ccn(-c4ccc(F)cc4)c3c2)CC1
Yield: 36.7 %

Procedure:
A mixture of 6-(4-Methylpiperazinyl)-indole (14.8 mg, 0.0687 mmol), K2CO3 (37.9 mg, 0.275 mmol), CuBr (4.9 mg, 0.0353 mmol), a little copper powder and 1-Fluoro-4-iodobenzene (30.5 mg, 0.37 mmol) in 1 ml of NMP was heated at 170° C., under argon, overnight. After cooling, the mixture was diluted with dichloromethane and the organic layer washed with water 10 times before being passed through a silica gel column (eluting with 1% 2M ammonia/methanol in dichloromethane) to give the title product (7.8 mg, 37%).
Reaction SMILES: [C:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][S:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:15])=[O:14])#[N:2].Cl.[CH2:22]([O:24][C:25](=[O:30])[C@H:26]([CH2:28][SH:29])N)[CH3:23].C(O)C>O>[S:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[S:13]([NH:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[NH:4][C:3]([C:1]1[S:29][CH2:28][CH:26]([C:25]([O:24][CH2:22][CH3:23])=[O:30])[N:2]=1)=[CH:11]2)(=[O:14])=[O:15]
Reactant: CCOC(=O)[C@@H](N)CS
Reactant: N#Cc1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1CSC(c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)=N1
Yield: 25.5 %

Procedure:
A mixture of N-(2-cyano-1H-indol-7-yl)thiophene-2-sulfonamide (0.30 g), cysteine ethyl ester hydrochloride (0.22 g) and ethanol (10 mL) was heated under reflux overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.11 g, yield 25%) was obtained as pale-yellow crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 156-157° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:24]([O:25][CH3:26])=[CH:23][C:6]2[CH:7]([O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.C(N(CC)CC)C.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:24]([O:25][CH3:26])=[CH:23][C:6]2[CH:7]([O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=3)[CH2:8][N:9]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CCOC(=O)Cl
Reactant: COc1cc2c(cc1OC)C(Oc1ccc(C(F)(F)F)cc1)CNCC2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCc2cc(OC)c(OC)cc2C(Oc2ccc(C(F)(F)F)cc2)C1

Procedure:
To a cooled solution of 7,8-dimethoxy-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine (5.5 g, 0.015 mole) and triethylamine (1.7 g, 0.017 mole) in chloroform (70 ml) was slowly dropped a solution of ethyl chloroformate (1.0 g, 0.017 mole) in chloroform (20 ml). After stirring twenty hours at ambient temperatures the reaction mixture was concentrated to an oil which was dissolved in ether, washed with water, dilute HCl, again twice with water, then dried (saturated NaCl, anhydrous MgSO4). The solution was filtered then concentrated to a solid (5.0 g, 76%, m.p. 120° C.) of which a sample was twice recrystallized from hexanes to yield 7,8-dimethoxy-3-ethoxycarbonyl-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine, m.p. 130°-131° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=O)=[CH:5][CH:4]=1.COC1C=C[C:17]([C:20]2[C:24]([C:25]([OH:27])=[O:26])=[C:23](C)[N:22](C)[N:21]=2)=CC=1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[N:22]([CH3:23])[N:21]=[C:20]([CH3:17])[C:24]=2[C:25]([OH:27])=[O:26])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(-c2nn(C)c(C)c2C(=O)O)cc1
Product: COc1ccc(-c2c(C(=O)O)c(C)nn2C)cc1

Procedure:
From 3.59 g of 4-methoxybenzoyl chloride, 1.97 g (59%) of a mixture of the title compound (major) and 3-(4-methoxyphenyl)-1,5-dimethyl-1H-pyrazole-4-carboxylic acid (minor) was prepared. H1-NMR(CD3OD, 500 MHz) for the title compound: δ 7.27 (2H, d, J=9 Hz), 7.03 (2H,d, J=9 Hz), 3.84 (3H, s), 3.60 (3H, s), 2.43 (3H, s).
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:14]=[C:15]([CH:54]=[CH:55][CH:56]=3)[CH2:16][CH2:17][O:18][CH2:19][CH2:20][C:21]([N:23]([CH2:30][CH2:31][N:32]([CH2:40][CH2:41][C:42]3[C:47]4[O:48][CH2:49][C:50](=[O:52])[NH:51][C:46]=4[C:45]([OH:53])=[CH:44][CH:43]=3)[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:22])[CH2:8][CH2:7]2)[CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Si:66](Cl)([C:69]([CH3:72])([CH3:71])[CH3:70])([CH3:68])[CH3:67].C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1>[O:1]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:14]=[C:15]([CH:54]=[CH:55][CH:56]=3)[CH2:16][CH2:17][O:18][CH2:19][CH2:20][C:21]([N:23]([CH2:30][CH2:31][N:32]([CH2:40][CH2:41][C:42]3[C:47]4[O:48][CH2:49][C:50](=[O:52])[NH:51][C:46]=4[C:45]([O:53][Si:66]([C:69]([CH3:72])([CH3:71])[CH3:70])([CH3:68])[CH3:67])=[CH:44][CH:43]=3)[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:36])[CH3:37])[CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:22])[CH2:8][CH2:7]2)[CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(O)c2c1OCC(=O)N2)CCN(C(=O)CCOCCc1cccc(CN2CCC3(CC2)CNCCO3)c1)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N(CCc1ccc(O[Si](C)(C)C(C)(C)C)c2c1OCC(=O)N2)CCN(C(=O)CCOCCc1cccc(CN2CCC3(CC2)CNCCO3)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 2-(3-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)phenethoxy)-N-cyclohexylpropanamido)ethyl(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethyl)carbamate [Examples 81-175, step h] (0.97 g) was dissolved in NMP (10 mL) and treated with Hunig's base (1.0 mL) followed by tert-butyldimethylsilyl chloride (0.45 g). The resulting mixture was stirred at room temperature for 3 hours. The solution was poured into saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined extracts were washed three times with water, once with brine, then dried (MgSO4) and concentrated onto flash silica (20 mL) in-vacuo. The resulting powder was purified by flash chromatography on silica eluted with triethylamine:methanol:dichloromethane (1:5:94) to afford the subtitled compound as a white foam. Yield 0.81 g.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[SH:11][CH2:12][CH2:13][CH2:14][SiH2:15][CH:16]([O:19][CH3:20])[O:17][CH3:18].C(N(CC)CC)C>C1CCCCC1>[C:1]([S:11][CH2:12][CH2:13][CH2:14][SiH2:15][CH:16]([O:19][CH3:20])[O:17][CH3:18])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)Cl
Reactant: COC(OC)[SiH2]CCCS
Solvent: C1CCCCC1
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)SCCC[SiH2]C(OC)OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 96 %

Procedure:
Octanoyl chloride (18.0 g, 0.111 mol) is added dropwise over 30 minutes to a solution of 3-mercaptopropyldimethoxymethylsilane F with CAS number [31001-77-1] (20.0 g, 0.111 mol) and triethylamine (11.2 g, 0.111 mol) in cyclohexane (200 mL) kept at 5° C. under an inert atmosphere. The temperature of the reaction medium remains between 5 and 8° C. The reaction medium is then stirred for 15 hours at room temperature. The precipitate of triethylamine hydrochloride Et3N.HCl is filtered over celite. After evaporating the solvents under reduced pressure at 25° C., S-octanoylmercaptopropyldimethoxymethylsilane G with CAS number [828241-23-2] (32.6 g, 0.106 mol) is obtained in the form of a colourless oil with a yield of 96%.
Reaction SMILES: [CH2:1]1[C:6](=O)[CH2:5][CH2:4][N:3]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:2]1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][N:21]=[CH:20]2.C(O)(=O)C.C(=O)([O-])O.[Na+]>CO>[NH:22]1[C:23]2[C:19](=[CH:18][C:17]([NH:16][CH:6]3[CH2:5][CH2:4][N:3]([CH2:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH2:2][CH2:1]3)=[CH:25][CH:24]=2)[CH:20]=[N:21]1
Reactant: O=C1CCN(CCc2ccccc2)CC1
Reactant: Nc1ccc2[nH]ncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc(CCN2CCC(Nc3ccc4[nH]ncc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.5 %

Procedure:
1-(2-Phenethyl)-4-piperidone (142 mg), 5-aminoindazole (67 mg), and acetic acid (0.02 ml) were dissolved in methanol (1 ml), and a borane-pyridine complex (0.06 ml) was added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC [chloroform/methanol] to give the title compound (104 mg, yield 65%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]([N:17]1C=CN=C1)([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[S:11]>C(Cl)(Cl)Cl>[NH:1]=[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]1[NH:17][C:10]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[S:11]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(C)nc(N)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)n(NC(=S)n2ccnc2)c(=N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.4 %

Procedure:
An adaptation of the method described in WO 96/01826 was used. To a solution of ethyl O-mesitylsulfonylacetohydroxamate 7 (1.7 g, 6.0 mmol) in 1,4-dioxane (10 mL) cooled in an ice bath (freezes at 8-9° C.) was added 70% perchloric acid (7.5 mL) dropwise over 15 minutes, maintaining internal temperature below 15° C. The mixture was then diluted with ice water (100 mL) to precipitate the product O-(mesitylsulfonyl)hydroxylamine 8 which was filtered off, washed thoroughly with water, and immediately dissolved in chloroform (10 mL) while still wet (CAUTION! 8 is explosive when dry!). The organic layer was separated and was passed through a plug of Na2SO4 in a fritted syringe to remove water. The so obtained solution of O-(mesitylsulfonyl)hydroxylamine 8 was added dropwise to a solution of 2-amino-4,6-dimethylpyridine 9 (0.611 g, 5.00 mmol) in chloroform (10 mL) cooled in an ice bath. The mixture was then warmed to room temperature and was stirred for 2 hours to effect conversion to intermediate 10. Into the reaction mixture was then added 1,1′-thiocarbonyldimidazole 11 (1.16 g, 6.5 mmol) and the resulting mixture was stirred at 40° C. overnight. Volatiles were evaporated and the residue was chromatographed on silica gel (gradient elution with heptane:ethyl acetate 100:0→0:100) to yield imidazole-1-carbothioic acid (2-imino-4,6-dimethyl-2H-pyridin-1-yl)-amide 12 as an off-white solid (0.50 g, 40%) containing a minor amount of residual imidazole. 1H NMR (500 MHz, DMSO-d6): δ7.88 (s, 1H), 7.64 (s, 1H), 7.42 (br s, 2H), 6.93 (s, 1H), 6.69 (s, 1H), 6.67 (s, 1H), 2.28 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:7]=C([CH:11]=[CH:12][CH:13]=1)C#N)=[O:5].S(=O)(=O)(O)O.[C:30]([OH:33])(=[O:32])[CH3:31]>>[CH2:19]([O:18][C:16]1[CH:15]=[CH:14][C:3]([C:4]([C:6]2[CH:7]=[C:31]([CH:11]=[CH:12][CH:13]=2)[C:30]([OH:33])=[O:32])=[O:5])=[C:2]([CH3:1])[CH:17]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC(=O)O
Reactant: CCCCCCOc1ccc(C(=O)c2cccc(C#N)c2)c(C)c1
Agent: O=S(=O)(O)O
Product: CCCCCCOc1ccc(C(=O)c2cccc(C(=O)O)c2)c(C)c1
Temperature: 0 °C

Procedure:
Anhydrous aluminium chloride (38.35 g) is added to a solution of the acid chloride prepared from 3-cyanobenzoic acid (36.3 g) as described in Example 26 and nitrobenzene (200 ml). A solution of 3-n-hexyloxytoluene (39.5 g) in nitrobenzene (50 ml) is added and the resulting mixture heated to 110°-120° C. for 3 hours. The reaction mixture is cooled and poured into a mixture of ice water (1,000 ml) and concentrated hydrochloric acid (100 ml). The mixture is extracted with ether (3×300 ml) and the combined extracts concentrated and the nitrobenzene removed by steam distillation. The resulting residue is dissolved in ether, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue is chromatographed on silica gel (hexanes:ether; 70:30) to yield 3-(2-methyl-4-n-hexyloxybenzoyl)benzonitrile (21.1 g) as a dark brown oil and 3-(2-hydroxy-4-methylbenzoyl)benzonitrile, which is recrystallized from ethanol to give 5.78 g as a yellow solid (m.p. 126°-128°C.). The 3-(2-methyl-4-n-hexyloxybenzoyl)benzonitrile thereby obtained is heated under reflux in a mixture of acetic acid (160 g) and a solution of 75% sulfuric acid (160 g) for 1 hour. The cooled mixture is then poured into ice water (500 ml) and extracted with ether (3×200 ml). The extract is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue is chromatographed on silica gel (hexanes:ether:acetic acid; 50:50:1). The main fraction is collected and concentrated in vacuo. The residual yellow solid is crystallized from heptane to yield 3-(4-n-hexyloxy-2-methylbenzoyl)benzoic acid (9.62 g) as yellow needles m.p. 136°-138° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][N:43]([CH3:69])[CH2:44][CH2:45][O:46][C:47](=[O:68])[C@@:48]([CH2:66][OH:67])([CH3:65])[CH2:49][C@H:50]([NH2:64])[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:54][CH:53]=1>CN(C=O)C>[CH3:69][N:43]([CH3:42])[CH2:44][CH2:45][O:46][C:47](=[O:68])[C@@:48]([CH2:66][OH:67])([CH3:65])[CH2:49][C@H:50]([NH:64][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:51][C:52]1[CH:53]=[CH:54][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:56][CH:57]=1
Reactant: O=C(O)c1c[nH]nn1
Reactant: CN(C)CCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCOC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 26.1 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (0.0274 g, 0.242 mmol), DIPEA (169 μL, 969 μmol) and HATU (92 mg, 242 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 2-dimethylamino-ethyl ester (93 mg, 240 μmol), predissolved in DMF (0.2 mL) and DIPEA (0.5 eq.). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product was purified by preparative HPLC and lyophilized to yield the title compound (30 mg; purity 95%). MS m/z [M+H]+ calc'd for C26H33N5O4, 480.25. found 480.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](O)=[N:7][N:6]=[CH:5]2.P(Cl)(Cl)([Cl:15])=O.C(N(C(C)C)CC)(C)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:15])=[N:7][N:6]=[CH:5]2
Reactant: Oc1nncc2cc(Br)ccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nncc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
A mixture of 6-bromophthalazin-1(2H)-one (17, 2.6 g, 12 mmol) in phosphorous oxychloride (11 mL, 116 mmol) was treated with diisopropylethylamine (2.0 mL, 12 mmol). The mixture was stirred at room temperature for 30 min, then warmed up to a temperature of between about 95-100° C. and stirred under nitrogen. The suspension (reaction) became a deep brown solution in about 30 min, then a yellow solid precipitated out. After about 3 h, all of the starting material was converted, as appeared by TLC, to product (M+1=243, 245). After the mixture was cooled down to room temperature, it was diluted with 50 mL CHCl3 and cooled down to 0° C. The precipitate was filtrated, washed with 10 mL ice cool CHCl3, collected and dried under vacuum, to afford 1.96 g of 6-bromo-1-chlorophthalazine 18, as yellow solid. Found MS (ES+): 243, 245 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[C:27]1([O:33][C:34]([O:36][CH2:37]I)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:37][O:36][C:34]([O:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:35])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: O=C(OCI)Oc1ccccc1
Agent: [Na+]
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)Oc3ccccc3)=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Yield: 93.4 %

Procedure:
In the same manner as in Example 81, 278 mg of the title compound was prepared from 226 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 243 mg of phenyloxycarbonyloxymethyl iodide.
Reaction SMILES: C[O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9](Br)[CH:10]=1.[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[NH:19][CH2:18][CH2:17]2.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.[Cu]I>[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([C:9]1[CH:10]=[C:5]([CH2:4][C:3]([OH:2])=[O:12])[CH:6]=[N:7][CH:8]=1)[CH2:18][CH2:17]2
Reactant: O=C1NCCc2cc(Cl)ccc21
Reactant: COC(=O)Cc1cncc(Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)Cc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 150 °C
Yield: 72.6 %

Procedure:
(5-Bromo-pyridin-3-yl)-acetic acid methyl ester (230 mg, 1.0 mmol), 6-chloro-3,4-dihydro-2H-isoquinolin-1-one (intermediate A-2) (182 mg, 1.0 mmol), CuI (40 mg, 0.21 mmol), Cs2CO3 (650 mg, 2.0 mmol) and (+)-(1S,1S)-1,2-diaminocyclohexane (0.1 mL, 0.8 mmol) were dissolved in dioxane (4.0 ml) and the resulting reaction mixture was heated at 150° C. for 2 hours before it was poured into H2O (20 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product (230 mg, 72.5%) as light brown oil. MS: 317.1 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7](=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[CH:7]=[O:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
185 g of dimethylformamide and 82.8 g (0.6 mol) of potassium carbonate were placed in a flask, and 61 g (0.5 mol) of salicylaldehyde were added dropwise thereto. 75.9 g (0.6 mol) of benzyl chloride were then added dropwise to the resulting mixture at a temperature of 50° C. for one hour. After the addition, the mixture was stirred at a temperature of 70° C. for two hours. The resulting reaction mixture was washed with 185 g of toluene and 330 g of water. The solvent was distilled out of the mixture at an inside temperature of 90° C. under a reduced pressure of 10 mmHg thereby providing 104.5 g of 2-benzyloxybenzaldehyde as bottom in the form of brown liquid having a purity 97.9% in a yield of 96.5%.