Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[CH:9]=[CH:10][C:3]=12
Reactant: Brc1ccnc2[nH]ccc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
4-Bromo-1H-pyrrolo[2,3-b]pyridine (10.0 g, 0.0508 mol, Aldrich: Cat. #703451) was dissolved in N,N-dimethylformamide (100 mL) and cooled under nitrogen to 0° C. Sodium hydride (3.00 g, 0.0750 mol, 60% dispersion in mineral oil) was added portion-wise. The reaction was stirred for 10 minutes. [β-(Trimethylsilyl)ethoxy]methyl chloride (10.8 mL, 0.0609 mol, Aldrich: Cat. #238902) was added slowly to the reaction mixture, stirred at 0° C. for 45 minutes, and allowed to warm to room temperature. The solvent was removed under reduced pressure. The residue was diluted with ethyl ether (100 mL), and washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexane (0-25%) to afford the desired product (16.04 g, 96.6%). LCMS (M+H)+: m/z=327.0/329.0
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[NH:4][N:3]=1.[CH3:12][S:13][C:14](SC)=[N:15][C:16]#[N:17]>>[NH2:17][C:16]1[N:3]2[N:4]=[C:5]([C:7]3[O:8][CH:9]=[CH:10][CH:11]=3)[N:6]=[C:2]2[N:1]=[C:14]([S:13][CH3:12])[N:15]=1
Reactant: CSC(=NC#N)SC
Reactant: Nc1n[nH]c(-c2ccco2)n1
Product: CSc1nc(N)n2nc(-c3ccco3)nc2n1
Temperature: 170 °C
Yield: 20.3 %

Procedure:
An intimate mixture of 3-amino-5-(2-furyl)-1,2,4-triazole (33.0 g) and dimethyl N-cyanodithioiminocarbonate (33.0 g) was heated at 170° C. for 1 hour, under a slow stream of argon. After cooling, the resulting solid was purified by column chromatography on silica (600 g) eluting with an increasing amount of ethyl acetate in dichloromethane (5-10% v/v) to give 7-amino-2-(2-furyl)-5-methylthio-[1,2,4]triazolo[1,5-a][1,3,5]triazine as a colourless solid (11.1 g), essentially pure by TLC, which was used without further purification. [A small amount of the above solid was recrystallised from ethanol to give, crystals, m.p. 238°-240° C.; microanalysis, found: C,44.0; H,3.3; N,33.7; C9H8N6SO. 0.05C2H5OH requires C,43.6; H,3.3; N,33.6; NMR 1.05 and 3.4 (t+q, ethanol of crystallisation), 2.5 (s, 3H, CH3S-- ), 6.7(dd, 1H, furyl-4H), 7.2(d, 1H, furyl-3H), 7.7(d, 1H, furyl-5H) 8.7-9.0(br d, 2H, NH2); m/e 248 (M+).
Reaction SMILES: Cl.[S:2]1[C:10]2[C:5](=[N:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH3:14]O>>[S:2]1[C:10]2[C:5](=[N:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: O=C(O)c1ccc2sccc2n1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc2sccc2n1
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of HCl (10%) in MeOH (10 mL) was added thieno[3,2-b]pyridine-5-carboxylic acid (1.0 g, 5.6 mmol, from Step 2, Example 1) and the mixture heated to reflux for 2 hr. After cooling to r.t., half the solvent was removed by evaporation and the remainder was partitioned between EtOAc and H2O. Solid NaHCO3 was added until the system remained basic. Separation, drying, and evaporation of the organic layer afforded 0.75 g (70%) of methyl thieno[3,2-b]pyridine-5-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=C[C:26]2N(O)N=[N:29][C:27]=2[CH:28]=1.CCN(C(C)C)C(C)C.C1(N)CC1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH:27]1([NH:29][C:16](=[O:18])[CH2:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:14][CH:13]=2)[CH2:28][CH2:26]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(=O)O)cc1
Reactant: On1nnc2ccccc21
Agent: NC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)Nc1ccc(CC(=O)NC2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
{4-[(tert-butoxycarbonyl)amino]phenyl}acetic acid (300 mg, 1.2 mmol) was dissolved in DMF (3 ml). EDC (275 mg, 1.4 mmol), HOBt (256 mg, 1.7 mmol), DIEA (450 mg, 3.6 mmol) and cyclopropyl amine (82 mg, 1.4) were added and the mixture stirred at RT for 2 hours. The mixture was diluted into a 10% solution of sodium bicarbonate (aq, 50 ml), extracted with EtOAc (3×30 ml), the organic fractions combined, dried over Na2SO4, filtered and the volatiles removed in vacuum to give the titled compound. LRMS calc: 290.16; obs: 397.27 (M+1).
Reaction SMILES: [CH:1]1([C@@H:7]2[NH:29][C:28](=[O:30])[O:27][CH2:26][C:25]([CH3:32])([CH3:31])[CH2:24][CH2:23][CH2:22][C:21]3[CH:33]=[C:34]4[C:18](=[C:19]([CH:37]=[CH2:38])[C:20]=3[O:35][CH3:36])[N:17]=[C:16]([O:39][CH2:40][CH3:41])[CH:15]=[C:14]4[O:13][C@H:12]3[CH2:42][N:9]([C@H:10]([C:43]([O:45][CH3:46])=[O:44])[CH2:11]3)[C:8]2=[O:47])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCO.[Pd]>[CH:1]1([C@@H:7]2[NH:29][C:28](=[O:30])[O:27][CH2:26][C:25]([CH3:32])([CH3:31])[CH2:24][CH2:23][CH2:22][C:21]3[CH:33]=[C:34]4[C:18](=[C:19]([CH2:37][CH3:38])[C:20]=3[O:35][CH3:36])[N:17]=[C:16]([O:39][CH2:40][CH3:41])[CH:15]=[C:14]4[O:13][C@H:12]3[CH2:42][N:9]([C@H:10]([C:43]([O:45][CH3:46])=[O:44])[CH2:11]3)[C:8]2=[O:47])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=Cc1c(OC)c2cc3c(cc(OCC)nc13)O[C@@H]1C[C@@H](C(=O)OC)N(C1)C(=O)[C@H](C1CCCCC1)NC(=O)OCC(C)(C)CCC2
Agent: [Pd]
Solvent: CCO
Product: CCOc1cc2c3cc(c(OC)c(CC)c3n1)CCCC(C)(C)COC(=O)N[C@@H](C1CCCCC1)C(=O)N1C[C@@H](C[C@H]1C(=O)OC)O2
Reaction time: 18 h

Procedure:
0% Pd/C (4 mg, 0.004 mmol) was added to a solution of the product from Step 1 (25 mg, 0.038 mmol) in EtOH (3 mL), and the mixture was placed under H2. After 18 hours, the mixture was filtered through a pad of glass wool, and the solvent was removed in vacuo. LRMS ESI+ (M+H)+ 654.5; calcd for C36H52N3O8: 654.4.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]1[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=1)[N:8]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:7][CH2:6]2.C(Cl)Cl>CO.C(Cl)Cl>[CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[CH:9]1[C:10]2[C:5](=[CH:4][C:3]([OH:2])=[CH:12][CH:11]=2)[CH2:6][CH2:7][N:8]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc2c(c1)CCN(c1ccccc1)C2c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc2c(c1)CCN(c1ccccc1)C2c1ccc2ccccc2c1

Procedure:
The title compound was prepared by analogy to Example 48 except that 6-methoxy-1-naphthalen-2-yl-2-phenyl-1,2,3,4-tetrahydroisoquinoline was used instead of 6-methoxy-1-(4-methoxy-phenyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline, and neat CH2Cl2 to 10% MeOH/CH2Cl2 was used as eluent for flash chromatography purification.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C(S(O)(=O)=O)=CC=CC=1.N1C=CC=CC=1.[O:24]=[C:25]1[CH2:42][C@@:40]2([CH3:41])[C@@H:36]([CH2:37][CH2:38][C@@H:39]2[OH:43])[C:35]2[CH2:34][CH2:33][C:32]3[CH:31]=[C:30]([O:44][CH3:45])[CH:29]=[CH:28][C:27]=3[C:26]1=2.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:45][O:44][C:30]1[CH:29]=[CH:28][C:27]2[C:26]3[C:25](=[O:24])[CH2:42][C@@:40]4([CH3:41])[C@@H:36]([CH2:37][CH2:38][C@@H:39]4[O:43][CH:6]4[CH2:5][CH2:4][CH2:3][CH2:2][O:1]4)[C:35]=3[CH2:34][CH2:33][C:32]=2[CH:31]=1
Reactant: C1=COCCC1
Reactant: COc1ccc2c(c1)CCC1=C2C(=O)C[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc2c(c1)CCC1=C2C(=O)C[C@]2(C)[C@@H](OC3CCCCO3)CC[C@@H]12
Reaction time: 2 h

Procedure:
47 ml of dihydropyran and 0.96 g of pyridine toluenesufonate were added at room temperature to 15.29 g of 11-keto-3-methoxy-estra-1,3,5(10),8-tetraen-17β-ol (1) in 35 ml of dichloromethane, and it was stirred for 2 hours. Then, the reaction solution was shaken several times with saturated sodium bicarbonate solution, washed with water and dried with magnesium sulfate. The solvent was evaporated in a vacuum, and the residue was purified on silica gel (solvent mixture: cyclohexane/ethyl acetate=8/2). 16.8 g (83%) of light yellowish, viscous oil was thus obtained.
Reaction SMILES: [C:1]([S:4][C:5]([S:28]C(=O)C)=[C:6]([N:18]1[CH:21]([S:22](CC=C)=O)[CH2:20][C:19]1=[O:27])[C:7]([O:9][CH2:10][O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:8])(=[O:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[C:1]([S:4][C:5]1[S:28][S:22][CH:21]2[N:18]([C:19](=[O:27])[CH2:20]2)[C:6]=1[C:7]([O:9][CH2:10][O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:8])(=[O:3])[CH3:2]
Reactant: C=CCS(=O)C1CC(=O)N1C(C(=O)OCOC(=O)C(C)(C)C)=C(SC(C)=O)SC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)SC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)CC2SS1
Yield: 53.6 %

Procedure:
A solution of 82 mg of pivaloyloxymethyl 3,3-di(acetylthio)-2-(4-allylsulphinylazetidin-2-on-1-yl)propenoate and 32 mg of 4-toluenesulphonic acid hydrate in 10 ml of dioxan was heated rapidly to reflux and maintained under reflux for 1 hour. The solvent was removed by evaporation and the residue chromatographed on silica gel using ethyl acetate/hexane mixtures as eluant. The product (35 mg, 54%) was obtained as a yellow oil.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)(=O)=O)=CC=1.BrCC1OC(C(F)(F)F)=CC=1.[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]2([C:44]3=[CH:45][C:46]4[O:50][CH2:49][O:48][C:47]=4[CH:51]=[C:43]3[O:42][CH2:41]2)[C:33]1=[O:52].CC1(C)COC2=CC3OCC4(C=3C=C12)C1C(=CC=CC=1)NC4=O>>[CH3:20][O:19][C:16]1[N:15]=[CH:14][C:13]([CH2:12][N:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]3([C:44]4=[CH:45][C:46]5[O:50][CH2:49][O:48][C:47]=5[CH:51]=[C:43]4[O:42][CH2:41]3)[C:33]2=[O:52])=[CH:18][CH:17]=1
Reactant: COc1ccc(COS(=O)(=O)c2ccc(C)cc2)cn1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)cn1

Procedure:
Following the procedure as described in EXAMPLE 10.21, and making non-critical variations using (6-methoxypyridin-3-yl)methyl 4-methylbenzenesulfonate to replace 2-bromomethyl-5-(trifloromethyl)furan, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, the title compound was obtained (45%): 1H NMR (300 MHz, CDCl3) δ 8.19 (d, 1H), 7.59 (dd, 1H), 7.26-7.12 (m, 2H), 7.02 (t, 1H), 6.83 (d, 1H), 6.74 (d, 1H), 6.50 (s, 1H), 6.07 (s, 1H), 5.89-5.82 (m, 2H), 5.00-4.90 (m, 2H), 4.76 (d, 1H), 4.65 (d, 1H), 3.93 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.6, 163.7, 155.9, 149.0, 145.3, 142.4, 141.6, 138.9, 132.2, 129.0, 124.4, 124.1, 123.7, 119.2, 111.7, 109.0, 102.9, 101.5, 93.7, 80.4, 58.2, 53.9, 41.1; MS (ES+) m/z 403.2 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]1(C)C=CC=CC=1.[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1)=[CH2:3]
Reactant: Cc1ccccc1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Solvent: O
Product: C=Cc1ccc(-c2ccccn2)cc1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Methyltriphenylphophonium bromide (25 g, 0.07 mol), sodium hydride (NaH, 3.36 g, 0.14 mol), and toluene (100 ml) were placed into 250 ml of 2-necked round-bottomed flask under N2. The reaction mixture was refluxed at 110° C. for 3 hr while changing the reaction solution to orange color. After cooling the reaction mixture, 2-(4-formyl-phenyl)pyridine (10 g, 0.0545 mol) was added and further refluxed at 110° C. for 12 hr. The reaction mixture was poured in 300 ml of water in beaker and extracted then with ether (3×150 ml). The ether layer was then dried over magnesium sulfate (10 g) by stirring for 30 min. The dried ether layer was evaporated in vacuo to dryness and purified further by column chromatography on silica gel with eluting hexane/ethylacetate (1/10) to yield 2-(4-vinyl-phenyl)pyridine (85%).
Reaction SMILES: [CH:1]1([N:4]2[C:12]([CH3:13])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])=[CH:10]3)=[N:5]2)[CH2:3][CH2:2]1.Cl[CH2:23][C:24]1[S:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([N:4]2[C:12]([CH3:13])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:23][C:24]5[S:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=5)=[CH:16][C:15]4=[O:21])=[CH:10]3)=[N:5]2)[CH2:2][CH2:3]1
Reactant: FC(F)(F)c1ccc(CCl)s1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c2cc(-n3ccc(OCc4ccc(C(F)(F)F)s4)cc3=O)ccc2nn1C1CC1
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a mixture of 1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (200 mg) and 2-(chloromethyl)-5-(trifluoromethyl)thiophene (171 mg) in DMF (4 ml) was added potassium carbonate (118 mg) at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was fractionated by HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% NH4HCO3)), and saturated aqueous sodium hydrogen carbonate solution was added to the obtained fraction. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from methanol-water to give the title compound (138 mg).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3](/[CH:11]=[CH:12]/[C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[CH:2]=1.O.[OH-].[Na+].Cl>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3](/[CH:11]=[CH:12]/[C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH:2]=1
Reactant: COC(=O)c1ccc(/C=C/c2cnc3ccccc3c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(/C=C/c2cnc3ccccc3c2)cc1

Procedure:
Methyl 4-[(E)-2-(3-quinolinyl)ethenyl]benzoate (0.840 mg, 3.36 mmol; see step (i) above) was suspended in methanol (10 mL) and water (20 mL) to which sodium hydroxide solution (NaOH 0.580 g, 14.5 mmol in water 10 mL) was added with stirring. The reaction mixture was heated under reflux for 2 h. At the beginning the starting material dissolved then white precipitate appeared. The reaction mixture was cooled in an ice bath then (dilute HCl was added dropwise with vigorous stirring until pH 2 was attained. The title compound formed as a yellow solid material, which was filtered off, washed with water and dried in vacuo at 60° C. (0.640 g, 69%), m.p.=287-290° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([CH2:15][C@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]2)[C:12](O)=[O:13])=[CH:7][C:6]=1[CH3:22])(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.[C:29]([Si:33]([CH3:44])([CH3:43])[O:34][CH2:35][CH2:36][N:37]1[CH:41]=[CH:40][C:39]([NH2:42])=[N:38]1)([CH3:32])([CH3:31])[CH3:30].N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[C:29]([Si:33]([CH3:44])([CH3:43])[O:34][CH2:35][CH2:36][N:37]1[CH:41]=[CH:40][C:39]([NH:42][C:12](=[O:13])[C@@H:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[C:6]([CH3:22])[CH:7]=2)[CH2:15][C@H:16]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]2)=[N:38]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: Cc1cc([C@@H](C[C@H]2CCC(=O)C2)C(=O)O)ccc1S(C)(=O)=O
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc([C@@H](C[C@H]2CCC(=O)C2)C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)n2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
(R)-2-(4-methanesulfonyl-3-methyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionic acid (85 mg, 0.26 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylformamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 140 μL, 0.27 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (2 mL) and added dropwise into a solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 63 mg, 0.26 mmol), 2,6-lutidine (62 μL, 0.52 mmol) and methylene chloride (2 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was quenched with a small amount of methanol and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) to afford (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(4-methanesulfonyl-3-methyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionamide (109 mg, 77%) as a yellow oil: [α]25589=−50.0° (c=0.21, methanol); ES-HRMS m/e calcd for C27H41N3O5SSi (M+H)+ 548.2609, observed 548.2609; 1H NMR (300 MHz, CDCl3) δ −0.06 (s, 6H, 2×SiCH3), 0.84 (s, 9H, 3×CH3), 1.57 (m, 1H, CH), 1.82-2.47 (m, 8H, 4×CH2), 2.72 (s, 3H, ArCH3), 3.09 (s, 3H, SO2CH3), 3.55 (t, J=7.3 Hz, 1H, ArCHCO), 3.85 (t, J=5.3 Hz, 2H, OCH2), 4.06 (t, J=5.3 Hz, 2H, NCH2), 6.64 (d, J=2.2 Hz, 1H, Ar), 7.35 (m, 3H, Ar), 7.75 (brs, 1H, NH), 8.03 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][C:13]3[S:14][C:15]([C:18](=[NH:21])[NH:19][OH:20])=[CH:16][N:17]=3)[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:22][C:23]([O:25]CC)=[O:24])[O:3]1.[OH-].[Na+]>CO.C1COCC1>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][C:13]3[S:14][C:15]([C:18](=[NH:21])[NH:19][OH:20])=[CH:16][N:17]=3)[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:22][C:23]([OH:25])=[O:24])[O:3]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ncc(C(=N)NO)s3)cc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Oc2ncc(C(=N)NO)s2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude ethyl 2-(1-hydroxy-6-(5-(N-hydroxycarbamimidoyl)thiazol-2-yloxy)-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate in MeOH/THF (10 mL, 1:1) was added aqueous NaOH solution (200 mg in 3 mL water). After stirring at room temperature for two hours, the reaction mixture was evaporated, acidified with 1N HCl to pH 5 and then concentrated. HPLC purification gave desired product as white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.2 (b, 2H), 9.20 (b, 1H), 7.70 (s, 1H), 7.37 (d, J=2 Hz, 1H), 7.22 (d, J=1.6 Hz, 1H), 5.48 (dd, J=9.2, 2 Hz, 1H), 3.02 (dd, J=15.6, 2.4 Hz, 1H), 2.26 (s, 3H), 2.28 (dd, J=15.6, 9.6 Hz, 1H). 2 protons assumed to be exchanged with solvents. MS (ESI) m/z=364 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[N:5][CH:6]=[CH:7][CH:8]=1.[C:17](Cl)(Cl)=[O:18]>O>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:9]1[C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:3]2[NH:2][C:17]1=[O:18]
Reactant: Nc1cccnc1Nc1ccccc1F
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: O
Product: O=c1[nH]c2cccnc2n1-c1ccccc1F

Procedure:
The product from step B (1.5 g.) was dissolved in 40 ml. of water and treated with phosgene as described in Example 1, Step C, to provide 3-(2-fluorophenyl)-1,3-dihydroimidazo[ 4,5-b] pyridin-2-one, m.p. 199°-200° C.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:30]3[N:34]([CH3:35])[C:33]4[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=4[N:31]=3)[CH:26]=[C:27]([CH2:28][CH3:29])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:40]=[N+:41]=[N-:42].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:42][N:41]=[N:40][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[CH:24]=[C:25]([C:30]3[N:34]([CH3:35])[C:33]4[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=4[N:31]=3)[CH:26]=[C:27]([CH2:28][CH3:29])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1nc2c(CC)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(CC)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[(2-n-propyl-4-ethyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:12]3[CH2:14][O:13]3)[CH:9]=2)[C:4](=[O:15])[O:3]1.BrC1C=C2C(=CC=1)C(=O)O[C@@H](C)C2>>[CH3:1][C@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:12]3[CH2:14][O:13]3)[CH:9]=2)[C:4](=[O:15])[O:3]1
Reactant: C[C@@H]1Cc2cc(C3CO3)ccc2C(=O)O1
Agent: C[C@H]1Cc2cc(Br)ccc2C(=O)O1
Product: C[C@H]1Cc2cc(C3CO3)ccc2C(=O)O1

Procedure:
(3S)-3-Methyl-6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one was prepared in an analogous fashion to that described for the synthesis of (3R)-3-methyl-6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one except starting from (3S)-6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]([C:14]([O:16]CC)=[O:15])=[C:5]2[O:19][CH3:20].[OH-].[Na+].O.Cl>O1CCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]([C:14]([OH:16])=[O:15])=[C:5]2[O:19][CH3:20]
Reactant: CCOC(=O)c1c(OC)c2cc(Cl)ccc2c(=O)n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1c(C(=O)O)n(C)c(=O)c2ccc(Cl)cc12
Temperature: 50 °C
Reaction time: 3 h
Yield: 76.9 %

Procedure:
To a solution of ethyl 6-chloro-4-methoxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (1.03 g, 3.5 mmol) in tetrahydrofuran (10 ml) and ethanol (10 ml) was added 1N sodium hydroxide (5 ml). The obtained mixture was refluxed under stirring at 50° C. for 3 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate diethyl ether to give 6-chloro-4-methoxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid (0.72 g, 77.4%) as crystals.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:20]([Sn](CCCC)(CCCC)CCCC)=[CH2:21]>O1CCOCC1.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>[CH:1]1([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[CH:20]=[CH2:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(OCC2CCCCC2)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1cc(C(=O)OC)ccc1OCC1CCCCC1
Temperature: 100 °C

Procedure:
To a solution of 23-3 (810 mg, 2.5 mmol) in 11.5 mL of dioxane was added 820 mg (2.6 mmol) of vinyltributyl tin followed by 58 mg (0.05 mmol) of Pd(PPh3)4. The resulting solution was then heated at 100° C. for 20 h. The solvent was distilled under reduced pressure and the residue was chromatographed to afford product 23-4.