Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:12]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[C:5]2[NH:6][C:7](=[O:11])[CH2:8][C:9](=[O:10])[N:4]2[N:3]=1.[C:24]1(=O)[O:29][C:27](=[O:28])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12>C(#N)C>[O:28]=[C:27]1[C:26]2[C:25](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:24](=[O:29])[N:1]1[C:2]1[C:12]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[C:5]2[NH:6][C:7](=[O:11])[CH2:8][C:9](=[O:10])[N:4]2[N:3]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1nn2c(c1Cc1cccc3ccccc13)NC(=O)CC2=O
Solvent: CC#N
Product: O=C1CC(=O)n2nc(N3C(=O)c4ccccc4C3=O)c(Cc3cccc4ccccc34)c2N1
Temperature: 80 °C
Reaction time: 120 h
Yield: 72.8 %

Procedure:
The solution of 2-amino-3-(1-naphthalenylmethyl)pyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione (2.7 g, 8.81 mmol), phthalic anhydride (3.00 g, 20.27 mmol) in Acetonitrile (100 mL) was stirred at 80° C. for 2 days. Additional phthalic anhydride (3.00 g, 20.27 mmol) was added in. The reaction was stirred at 80° C. for 5 days. The reaction was concentrated. To the crude was added DCM (20 mL). The insoluble solid was collected. The filtrate was purified on a silica column (20-60% EtOAc/Hexane) which was combined with the solid from filtration to give the product (2.8 g, 71%). LC/MS: MS (ES+) m/e 437.2 [M+H]+
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:7]=[C:8]([CH2:16][CH2:17][C:18]3[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=3)[O:9][C:10]=2[C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)=[CH:2]1.Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:7]=[C:8]([CH2:16][CH2:17][C:18]3[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=3)[O:24][CH2:26][C:27]([O:29][CH3:30])=[O:28])[O:9][C:10]=2[C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)=[CH:2]1
Reactant: COC(=O)CBr
Reactant: Oc1cccc(CCc2nc(-c3ccsc3)c(-c3ccsc3)o2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1cccc(CCc2nc(-c3ccsc3)c(-c3ccsc3)o2)c1
Reaction time: 15 h
Yield: 81.8 %

Procedure:
A mixture of 3-[2-[4,5-di(3-thienyl)-2-oxazolyl]ethyl]phenol (2.00 g, 5.6 mmol), methyl bromoacetate (1.04 g, 6.8 mmol), potassium carbonate (0.94 g, 6.8 mmol), potassium iodide (catalytic amount) and acetonitrile (100 mL) was stirred at reflux under an atmosphere of nitrogen. After 15 hours, the mixture was cooled, filtered and concentrated and the residue subjected to chromatography on a column of silica gel. Elution with a mixture of hexanes and ethyl acetate (7:2) gave methyl [3-[2-[4,5-di(3-thienyl)-2-oxazolyl]ethyl]phenoxy]acetate (1.95 g, 80%) as an oil.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)#[N:2].[C:12](OC)(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[SH:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([C:1]2[S:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[C:12](=[O:20])[N:2]=2)=[CH:4]1
Reactant: N#Cc1c[nH]c2ccccc12
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2c[nH]c3ccccc23)sc2ccccc12
Yield: 19.5 %

Procedure:
3-Cyanoindole (1.00 g, 7.0 mmol) and methyl thiosalicylate (1.20 g, 7.0 mmol) were dissolved in toluene (10 ml), and triethylamine (1.5 ml, 10.4 mmol) was added thereto. The reaction mixture was refluxed for 24 hrs. The solvent was evaporated. The residue was recrystallized from ethanol to give the titled compound (0.38 g, 20%) as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9](=O)[CH2:8][CH:7]1[CH3:27])=[O:5])[CH3:2].Cl.[NH2:29][OH:30].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9](=[N:29][OH:30])[CH2:8][CH:7]1[CH3:27])=[O:5])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)N1c2cc(OC)c(OCc3ccccc3)cc2C(=O)CC1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)N1c2cc(OC)c(OCc3ccccc3)cc2C(=NO)CC1C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
To a stirred solution of 6-benzyloxy-7-methoxy-2-methyl-4-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (1.99 g, 5.39 mmol) in 95% ethanol (20 mL) was added hydroxylamine hydrochloride (1.1 g, 16 mmol) and sodium acetate (1.1 g, 14 mmol), and the mixture was heated at reflux. After 2 h, water (50 mL) was added, and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give 2.05 g of the title compound (99%).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH2:28]([S:30]([O-:32])=[O:31])[CH3:29].[Na+]>>[CH2:24]([C:21]1[CH:20]=[N:19][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([C@H:10]3[CH2:11][C@H:9]3[CH2:8][O:7][CH2:6][C:5]3[CH:26]=[CH:27][C:2]([S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])=[CH:3][CH:4]=3)[CH2:13][CH2:14]2)=[N:23][CH:22]=1)[CH3:25]
Reactant: CCS(=O)[O-]
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(Br)cc3)CC2)nc1
Agent: [Na+]
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(S(=O)(=O)CC)cc3)CC2)nc1

Procedure:
This compound was prepared from the product of example 54 (step A), and sodium ethanesulfinate according to the procedure from example 56. MS (ESI) m/z 444 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(Cl)CCl.C(N(C(C)C)C(C)C)C.[CH2:28]([N:30]1[N:34]=[N:33][C:32]([C:35]2[S:39][C:38]([NH2:40])=[N:37][C:36]=2[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[N:31]1)[CH3:29]>CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([NH:40][C:38]2[S:39][C:35]([C:32]3[N:33]=[N:34][N:30]([CH2:28][CH3:29])[N:31]=3)=[C:36]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:37]=2)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCn1nnc(-c2sc(N)nc2-c2ccccc2)n1
Reactant: COc1ccc(CC(=O)O)cc1OC
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCn1nnc(-c2sc(NC(=O)Cc3ccc(OC)c(OC)c3)nc2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
200 μL of a 0.6M stock solution of (3,4-dimethoxy-phenyl)-acetic acid was mixed with 200 μL of a 0.3M stock solution of EDC containing 1 eq. of ethyl-diisopropyl-amine. Then 100 μL of a 0.3M stock solution of 5-(2-ethyl-2H-tetrazol-5-yl)-4-phenyl-thiazol-2-ylamine containing 1 eq. of DMAP was added. The reaction mixture was shaken overnight at ambient temperature. Purification was performed by preparative LC-MS. Yield: 13%.
Reaction SMILES: CON(C)[C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:7][CH:6]=1.[C:22]([Mg]Br)([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[CH3:23][C:22]([CH3:25])([CH3:24])[C:4]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[O:13][N:12]=2)=[CH:9][CH:10]=1)=[O:20]
Reactant: CC(C)(C)[Mg]Br
Reactant: CON(C)C(=O)c1ccc(-c2cc(C(F)(F)F)on2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1ccc(-c2cc(C(F)(F)F)on2)cc1
Yield: 7 %

Procedure:
Prepared from N-Methoxy-N-methyl-4-(5-trifluoromethyl-isoxazol-3-yl)-benzamide and a 1.7 N THF solution of tert-butylmagnesium bromide as described in Example 5. Chromatographed on silica gel with EtOAc/hexanes (5 then 10%) as eluant to afford product as a colorless solid (21 mg, 7%). 1H NMR (CDCl3) 1.37 (s, 9 H), 7.05 (s, 1 H), 7.79 (d, J=8.4, 2 H), 7.87 (d, J=7.9, 2 H). 19F NMR −64.6. LC/MS 7.28 min, [M+1]+298.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10](/[CH:12]=[CH:13]/[C:14]([O:16][CH3:17])=[O:15])[CH:9]=[CH:8][C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][CH3:25])[CH:19]=1)[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:9]=[CH:8][C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][CH3:25])[CH:19]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(/C=C/C(=O)OC)ccc1-c1cccc(NC)c1
Agent: [Pd]
Solvent: CO
Product: CCCCOc1cc(CCC(=O)OC)ccc1-c1cccc(NC)c1
Yield: 92.8 %

Procedure:
A solution of 3.63 g (10.7 mmol) of methyl (E)-3-(2-butoxy-3′-methylaminobiphenyl-4-yl)acrylate in 70 ml of methanol is stirred for 4 hours at room temperature in the presence of 363 mg (10% by mass) of 10% palladium-on-charcoal under a hydrogen atmosphere. The palladium is filtered off and the solvent is evaporated off. 3.39 g of methyl 3-(2-butoxy-3′-methylaminobiphenyl-4-yl)propanoate are obtained in the form of a yellowish oil. Yield=93%
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([CH3:26])=[C:6]([C:23]([OH:25])=O)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[CH:9]=1)[CH3:2].[NH2:27][CH2:28][C:29]1[C:30](=[O:37])[NH:31][C:32]([CH3:36])=[CH:33][C:34]=1[CH3:35].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O>[CH3:35][C:34]1[CH:33]=[C:32]([CH3:36])[NH:31][C:30](=[O:37])[C:29]=1[CH2:28][NH:27][C:23]([C:6]1[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[CH:9]=[C:4]([NH:3][CH2:1][CH3:2])[C:5]=1[CH3:26])=[O:25]
Reactant: CCNc1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)O)c1C
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CS(C)=O
Product: CCNc1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
5-(Ethylamino)-4-methyl-4′-(morpholinomethyl)[1,1′-biphenyl]-3-carboxylic acid (300 mg, 0.84 mmol) was dissolved in DMSO (2 mL) and 3-(amino methyl)-4,6-dimethylpyridin-2(1H)-one (257 mg, 1.69 mmol) was added to it. After 15 minutes stirring at room temperature PyBOP (660 mg, 1.26 mmol) was added to the reaction mixture and stirring was continued for overnight. After completion, the reaction mass was poured into ice, extracted with 10% MeOH/DCM (5 times). Combined organic layer was washed with water and dried over sodium sulphate. Removal of the solvent under reduced pressure followed by solvent washings afforded the title compound (100 mg, 24%). LCMS: 489.20 (M+1)+; HPLC: 96.41% (@254 nm) (Rt; 4.060; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 9.90 (s, 1H), 8.06 (t, 1H), 7.73 (d, 2H, J=7.6 Hz), 7.55 (d, 2H, J=7.2 Hz), 6.80 (d, 2H, J=7.6 Hz), 5.86 (s, 1H), 4.38 (s, 2H), 4.27 (d, 2H, J=4 Hz), 3.95 (m, 2H), 3.62-3.65 (m, 2H), 3.28-3.31 (m, 2H), 3.20-3.24 (m, 2H), 3.14-3.19 (m, 2H), 2.20 (s, 3H), 2.10 (s, 3H), 2.06 (s, 3H), 1.21 (t, 3H, J=6.8 Hz).
Reaction SMILES: Cl[CH2:2][C:3]1[N:14]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][C:22]#[N:23])[CH2:17][CH2:16]2)[C:6]2=[C:7]3[S:13][CH:12]=[CH:11][C:8]3=[N:9][CH:10]=[C:5]2[N:4]=1.[CH3:24][S:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:22]([CH2:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([N:14]2[C:6]3=[C:7]4[S:13][CH:12]=[CH:11][C:8]4=[N:9][CH:10]=[C:5]3[N:4]=[C:3]2[CH2:2][N:28]([S:25]([CH3:24])(=[O:26])=[O:27])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:16][CH2:17]1)#[N:23]
Reactant: CC(C)(C)OC(=O)NS(C)(=O)=O
Reactant: N#CC[C@H]1CC[C@H](n2c(CCl)nc3cnc4ccsc4c32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)CC1)S(C)(=O)=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of {trans-4-[2-(chloromethyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl]cyclohexyl}acetonitrile (from example 17, 22.2 mg, 0.0644 mmol) dissolved in N,N-dimethylformamide (0.2 mL) was added tert-butyl (methylsulfonyl)carbamate (19 mg, 0.096 mmol) and potassium carbonate (18 mg, 0.13 mmol). The reaction was stirred at 50° C. overnight. The mixture was diluted with water, extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated to give tert-butyl ({1-[trans-4-(cyanomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}methyl)(methylsulfonyl)carbamate. LCMS calculated for C23H30N5O4S2 (M+H)+: m/z=504.2. Found: 504.1. This crude intermediate was treated with trifluoroacetic acid (0.1 mL, 1 mmol) in methylene chloride (0.1 mL) at room temperature for 30 min, and then the solvent was removed in vacuo. The residue was then dissolved in MeOH and purified on prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (9.5 mg, 36%). LCMS calculated for C18H22N5O2S2 (M+H)+: m/z=404.1. Found: 404.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[F:13][C:14]1[CH:15]=[C:16](OB(O)O)[CH:17]=[CH:18][C:19]=1[F:20].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>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.C(O)C>[F:13][C:14]1[CH:15]=[C:16]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]3)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: OB(O)Oc1ccc(F)c(F)c1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Oc1ccc2cc(-c3ccc(F)c(F)c3)ccc2c1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
To 25.0 g of 6-bromo-2-naphthol and 22.0 g of 3,4-difluorophenylboric acid were added 100 ml of toluene, 50 ml of ethanol, 50 ml of a 2 N aqueous solution of potassium carbonate and 1.3 g of tetrakis(triphenylphosphine)palladium (0). The reaction mixture was heated under reflux for 3 hours. The reaction solution was then allowed to cool to room temperature. The resulting organic phase was separated, washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was then distilled off. The residue was purified through silica gel column chromatography (dichloromethane) to obtain 25.3 g of 6-(3,4-difluorophenyl)-2-naphthol.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][C:8]=1[F:17])(=O)=O.B([C:23]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:24]=1[O:25][C@@H:26]([CH3:30])[C:27]([OH:29])=[O:28])(O)O>>[F:17][C:8]1[CH:9]=[C:10]([S:13]([CH3:16])(=[O:14])=[O:15])[CH:11]=[CH:12][C:7]=1[C:31]1[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=[CH:23][C:24]=1[O:25][C@@H:26]([CH3:30])[C:27]([OH:29])=[O:28]
Reactant: C[C@H](Oc1ccc(C(F)(F)F)cc1B(O)O)C(=O)O
Reactant: CS(=O)(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1
Product: C[C@H](Oc1ccc(C(F)(F)F)cc1-c1ccc(S(C)(=O)=O)cc1F)C(=O)O

Procedure:
The title compound was prepared by the method of example 144 step (i) using the product from step (i) and the product from example 146 step (iv).
Reaction SMILES: [Si:1]([N:8]1[C:11](=[O:12])[CH2:10][C@H:9]1[C:13]([OH:15])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:26](Br)[CH:27]=[CH2:28]>C1COCC1>[CH2:28]([C@H:10]1[C:11](=[O:12])[N:8]([Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C@@H:9]1[C:13]([OH:15])=[O:14])[CH:27]=[CH2:26]
Reactant: C=CCBr
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@H]1C(=O)O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-1-(tert-butyldimethylsilyl)-4-oxoazetidine-2-carboxylic acid (4) (2.00 g, 8.73 mmol.) in anhydrous THF (20 mL) at −78° C. was added 1.0 M solution of LiHMDS (20 ml, 20.1 mmol, 2.3 eq.) in THF. After the solution was stirred for 30 min. at −78° C., it was warmed to 0° C. for 10 min. The solution was recooled to −78° C. and allyl bromide (1.28 g, 10.5 mmol, 1.2 eq.) was added slowly. The reaction solution was stirred at −78° C. for 1 h, then warmed up to room temperature and stirred for another hour. The reaction mixture was quenched with aqueous 10% KHSO4 solution (30 ml) and extracted with ethyl acetate (40 mL×3). The combined organic layers were washed with brine twice and dried over Na2SO4. After removal of solvent, compound 57 was obtained as crystalline solid (2.0 g, 85%); 78% purity by LCMS, 1HNMR (300 MHz, CDCl3): 0.12 (s, 3H), 0.30 (s, 3H), 0.95 (s, 9H), 2.55 (m, 2H), 3.41 (m, 1H), 3.80 (d, J=2.61 Hz, 1H), 5.16 (m, 2H), 5.72 (m, 1H). Anal. C13H23NO3Si, Mol. Wt.: 269.41. Found: ESI-MS: 270.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[CH2:10][N:11]1C2C=CC=CC=2NC[C@H](NC(OC(C)(C)C)=O)[C:12]1=[O:30])[C:2]1C=CC=CC=1.[O:32]=[C:33]1[N:39](CC(N[C@H]2CC(=O)OC2OCC2C=CC=CC=2)=O)[C:38]2[CH:58]=[CH:59][CH:60]=[CH:61][C:37]=2[N:36]([C:62](=[O:65])[CH2:63][OH:64])[CH2:35][C@@H:34]1[NH:66][C:67](=[O:77])[C:68]1C=[C:72](C)[C:71](O)=[C:70](C)[CH:69]=1>>[O:32]=[C:33]1[N:39]([C:12]([NH:11][C@H:10]2[CH2:34][C:33](=[O:32])[O:31][CH:9]2[O:8][CH2:1][CH3:2])=[O:30])[C:38]2[CH:58]=[CH:59][CH:60]=[CH:61][C:37]=2[N:36]([C:62](=[O:65])[CH2:63][OH:64])[CH2:35][C@@H:34]1[NH:66][C:67]([C:68]1[C:69]2[C:58](=[CH:59][CH:72]=[CH:71][CH:70]=2)[CH:38]=[CH:37][N:36]=1)=[O:77]
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Reactant: Cc1cc(C(=O)N[C@H]2CN(C(=O)CO)c3ccccc3N(CC(=O)N[C@H]3CC(=O)OC3OCc3ccccc3)C2=O)cc(C)c1O
Product: CCOC1OC(=O)C[C@@H]1NC(=O)N1C(=O)[C@@H](NC(=O)c2nccc3ccccc23)CN(C(=O)CO)c2ccccc21

Procedure:
(3S)-2-oxo-3-(isoquinolin-1-oyl)amino-5-hydroxyacetyl-N-[(2RS,3S)-ethoxy-5-oxo-tetrahydrofuran-3-yl]-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-carboxamide (696b) was synthesized from 600b via methods used to prepare 690a from 600b to afford 696b. 1H NMR (CDCl3) δ 0.9 (m, 3H), 1.15 (q, 3H), 1.15 (m, 1H), 1.65 (m, 1H), 2.5 (m, 1H), 2.8 (m, 1H), 2.95-3.0 (m, 2H), 3.6 (m, 2H), 3.7-3.85 (m, 4H), 4.0 (m, 2H), 4.3 (m, 1H), 4.55 (m, 1H), 4.65 (m, 1H), 4.85-4.95 (m, 1H), 5.05 (m, 1H), 5.35 (s, 1H), 5.45 (d, 1H), 6.85 (d, 1H), 7.25 (d, 1H), 7.35-7.85 (6H), 8.85 (dd, 2H), 9.05 (m, 1H), 9.35 (dd, 2H).
Reaction SMILES: [C:1]([CH2:3][C:4]([N:6]([CH:17]([CH3:19])[CH3:18])[C:7]1[CH:16]=[CH:15][C:10]2[N:11]=[C:12]([SH:14])[S:13][C:9]=2[CH:8]=1)=[O:5])#[N:2].[CH:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)=O.N1CCCCC1>C(O)C>[C:1]([C:3]([C:4](=[O:5])[N:6]([CH:17]([CH3:19])[CH3:18])[C:7]1[CH:16]=[CH:15][C:10]2[N:11]=[C:12]([SH:14])[S:13][C:9]=2[CH:8]=1)=[CH:20][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)#[N:2]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(C)N(C(=O)CC#N)c1ccc2nc(S)sc2c1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)N(C(=O)C(C#N)=Cc1ccc(C(=O)O)cc1)c1ccc2nc(S)sc2c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
α-cyano-N-isopropyl-N-(2-mercaptobenzothiazol-6-yl)acetamide (99 mg, 0.339 mmol) and 4-formylbenzoic acid (56 mg, 0.374 mmol) were combined in absolute ethanol (1.4 ml). The mixture was stirred 15 minutes with activated 4A molecular sieves in a sealed vessel. Piperidine (67 μL, 0.678 mmol) was added and the mixture was heated to 80° C. After 1 hour, the solution was concentrated in vacuo and purified by preparative TLC (10% methanol, 90% dichloromethane) to yield 49 mg (34%). 1H NMR(CDCl3) δ1.17 (d, 6H), 4.93 (m, 1H), 7.16 (dd, 1H), 7.28 (dd, 1H), 7.32 (d, 1H), 7.69 (d, 2H), 7.93 (s, 1H), 7.98 (d, 2H); ESIMS: m/z 422 (M−H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:9])=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13][CH2:12]1.CS(C)=O>C(OCC)(=O)C>[C:21]([O:20][C:19](=[O:25])[NH:18][CH2:17][C@H:14]1[CH2:13][CH2:12][C@H:11]([NH:10][C:5]2[CH:4]=[C:3]([I:9])[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:16][CH2:15]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](N)CC1
Reactant: Fc1cc(I)c(Cl)cn1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Nc2cc(I)c(Cl)cn2)CC1
Temperature: 95 °C
Reaction time: 26 h

Procedure:
A mixture of 5-chloro-2-fluoro-4-iodopyridine (517 mg, 2.008 mmol), tert-butyl (trans-4-aminocyclohexyl)methylcarbamate (550 mg, 2.410 mmol), DMSO (2 ml) and TEA (0.336 ml, 2.410 mmol) reaction mixture was stirred at about 95° C. for about 26 hours. The crude reaction mixture mixture was cooled to room temperature, mixed with 125 ml ethyl acetate, washed with saturated sodium bicarbonate (2×), water (3×), saturated salt solution (1×), dried sodium sulfate, filtered and concentrated under reduced pressure to yield a residue. The residue was purified by silica gel chromatography using a 40 g column, eluting from 0%-35% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, yielding 656 mg of titled compound as free base. LCMS (m/z): 466.1 (MH+), retention time=0.93 min.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)[N:10]=[N:9][C:8]=1[C:23]([NH:25][CH:26]1[CH2:28][CH2:27]1)=[O:24])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>C(#N)C.C(OCC)(=O)C>[CH:26]1([NH:25][C:23]([C:8]2[N:9]=[N:10][N:11]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:17]=3)[C:7]=2[CH2:6][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:24])[CH2:28][CH2:27]1
Reactant: C1CCNC1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1.83 h
Yield: 83.4 %

Procedure:
(4-[(Cyclopropylamino)carbonyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazol-5-yl)methyl methanesulfonate (204 mg, 0.501 mmol) obtained in Example 126a), potassium carbonate (69.2 mg, 0.501 mmol, 1.0 eq.) and pyrrolidine (0.084 ml, 1.00 mmol, 2.0 eq.) were suspended in acetonitrile (4.0 ml), and the mixture was stirred at room temperature for 110 min. The reaction mixture was diluted with ethyl acetate (30 ml), washed twice with 2% aqueous sodium carbonate solution and with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a colorless oil. The oil was crystallized from ethyl acetate and diethyl ether, and the precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (160 mg, 0.418 mmol, 83.5%).
Reaction SMILES: P(Br)(Br)[Br:2].N1C=CC=CC=1.[CH:11]([O:14][CH2:15][CH2:16][CH:17]([CH3:21])[CH2:18][CH2:19]O)([CH3:13])[CH3:12]>>[Br:2][CH2:19][CH2:18][CH:17]([CH3:21])[CH2:16][CH2:15][O:14][CH:11]([CH3:13])[CH3:12]
Reactant: CC(CCO)CCOC(C)C
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Product: CC(CCBr)CCOC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
13.6 g (0.05 mol) of phosphorus tribromide and 2.47 g (0.03 mol) of pyridine are mixed and cooled to 0°-5°C. 20 g (0.125 mol) of 5-isopropoxy-3-methyl-1-pentanol are added dropwise, whilst stirring, over the course of 1 hour. The turbid mixture is then heated to 25°C and after 2 hours at 12 mm Hg, the reaction mixture is distilled into a receiver containing ice cold saturated sodium bicarbonate solution. (B.P.: 92°-103° /12 mm). The distillate is taken up in ether, successively washed with saturated sodium bicarbonate solution, water, 2N sulphuric acid, water, dried with sodium sulphate and evaporated. The residue is distilled, whereby 1-bromo-5-isopropoxy-3-methyl-pentane is obtained. B.P.: 92°-95° /12 mm Hg.