Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:13]=[C:12]([CH:14]3[C:20]4[N:21]=[C:22]([CH3:24])[O:23][C:19]=4[CH:18]=[CH:17][C:16]4[CH:25]=[C:26]([O:29][Si](C(C)(C)C)(C)C)[CH:27]=[CH:28][C:15]3=4)[C:11](=[O:37])[NH:10][C:9]2=[O:38])[CH:5]=[CH:4][N:3]=1.[NH:39]1[CH2:42][CH:41]([C:43]([OH:45])=[O:44])[CH2:40]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:29][C:26]1[CH:27]=[CH:28][C:15]2[CH:14]([C:12]3[C:11](=[O:37])[NH:10][C:9](=[O:38])[N:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([N:39]5[CH2:42][CH:41]([C:43]([OH:45])=[O:44])[CH2:40]5)[N:7]=4)[CH:13]=3)[C:20]3[N:21]=[C:22]([CH3:24])[O:23][C:19]=3[CH:18]=[CH:17][C:16]=2[CH:25]=1
Reactant: Cc1nc2c(o1)C=Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1C2c1cn(-c2ccnc(Cl)n2)c(=O)[nH]c1=O
Reactant: O=C(O)C1CNC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c(o1)C=Cc1cc(O)ccc1C2c1cn(-c2ccnc(N3CC(C(=O)O)C3)n2)c(=O)[nH]c1=O

Procedure:
The product from step (ix) was treated with 3-azetidinecarboxylic acid (0.096 g) and N,N-diisopropylethylamine (0.445 ml) in N,N-dimethylformamide (10 ml) at 85° C. for 4 hours. The mixture was partitioned between 1N HCl and ethyl acetate. The aqueous layer was adjusted to pH 6 and extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated under reduced pressure to give a solid. Purification was by reverse phase chromatography eluting with 50% methanol in 0.1% aqueous ammonium acetate solution.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:15])=[N:10][CH:11]=[C:12](Br)[CH:13]=2)=[C:4]([F:16])[CH:3]=1.[CH3:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>O1CCOCC1.O.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>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:15])=[N:10][CH:11]=[C:12]([C:21]3[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=3)[CH:13]=2)=[C:4]([F:16])[CH:3]=1
Reactant: Nc1ccc(-c2cc(Br)cnc2N)c(F)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cnc(N)c(-c3ccc(N)cc3F)c2)cn1
Temperature: 100 °C
Yield: 93.6 %

Procedure:
The compound obtained in Step 1 of Example 29 (2 g), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.62 g), tetrakis(triphenylphosphine)palladium (0.41 g) and potassium carbonate (2.94 g) were suspended in dioxane (10 ml) and water (1 ml), and the suspension was heated under reflux at 100° C. for 61 hours. After leaving to cool, a saturated aqueous sodium bicarbonate solution was added, and the organic layer was extracted with ethyl acetate and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate:methanol=10:1 (v/v)] to give 1.88 g of the title compound as a solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.F[C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:31]=1[F:39].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[CH:1]1([C:4]2[C:5]([N:24]([C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:31]=3[F:39])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])cc3F)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 100 °C
Yield: 77 %

Procedure:
A mixture of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxamide (402 mg, 1 mmol), 1,2-difluoro-4-nitrobenzene (318 mg, 2 mmol) and potassium carbonate (414 mg, 3 mmol) in 1,2-dimethoxyethane (20 mL) and water (5 mL) was heated at 100° C. for 48 hours. The solution was cooled to room temperature and concentrated, diluted with ethyl acetate (50 mL) and washed with water. The organic layer was dried over sodium sulfate, filtered, concentrated to dryness, and purified by column chromatography to afford 5-cyclopropyl-6-(N-(2-fluoro-4-nitrophenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (420 mg, 0.77 mmol, 77% yield) as a yellow solid. LCMS (m/z, ES+)=542 (M+H+)
Reaction SMILES: C[O:2][C:3](=[O:28])/[C:4](/[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([C:23]([F:26])([F:25])[F:24])=[N:21][N:20]=[N:19]2)=[C:14]([Cl:27])[CH:13]=1)=[CH:5]/[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[Cl:27][C:14]1[CH:13]=[C:12](/[C:4](=[CH:5]\[CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)/[C:3]([OH:28])=[O:2])[CH:17]=[CH:16][C:15]=1[N:18]1[C:22]([C:23]([F:26])([F:24])[F:25])=[N:21][N:20]=[N:19]1
Reactant: COC(=O)/C(=C/C1CCCCC1)c1ccc(-n2nnnc2C(F)(F)F)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)/C(=C/C1CCCCC1)c1ccc(-n2nnnc2C(F)(F)F)c(Cl)c1
Temperature: 47.5 °C
Yield: 75.6 %

Procedure:
A solution of (E)-2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylic acid methyl ester (833 mg, 2 mmol) in ethanol (10 mL) was treated with a 1N aqueous sodium hydroxide solution (4 mL). The solution was heated at 45-50° C. for 15 h, at which time, thin layer chromatography analysis of the mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove ethanol, and the residue was diluted with water (20 mL) and extracted with diethyl ether (1×50 mnL) to remove any neutral impurities. The aqueous layer was acidified with a 1N aqueous hydrochloric acid solution. The resulting acid was extracted into ethyl acetate (2×50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford (E)-2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylic acid (606 mg, 75%) as a brown solid: FAB-HRMS m/e calcd for C17H16ClF3N4O2 (M+H)+ 401.0992, found 401.0987.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26]C)=[CH:16][S:15]2)[S:10][C:9]1=[N:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[NH:37][CH2:38][CH3:39])[C:32]#[N:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[OH:26])=[CH:16][S:15]2)[S:10][C:9]1=[N:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[NH:37][CH2:38][CH3:39])[C:32]#[N:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2SC=C(c3ccccc3OC)N2C)C(=O)N1Cc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2SC=C(c3ccccc3O)N2C)C(=O)N1Cc1ccccc1

Procedure:
The product of Example 192 was treated with boron tribromide in DCM at 25° C. After 15 min the product mixture was quenched with brine, concentrated and chromatographed (silica gel, 0-10% MeOH/DCM) to yield the title compound. MS(ESI): 540 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:17]=[CH:18][C:19]4[C:23]([CH:24]=3)=[N:22][N:21]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=4)[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]O)[N:6]2[N:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:52]>O1CCCC1>[CH2:25]([N:21]1[CH:20]=[C:19]2[C:23]([CH:24]=[C:16]([C:8]3[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][Br:52])[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:17]=[CH:18]2)=[N:22]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ncnn2c(CCCCO)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncnn2c(CCCCBr)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12

Procedure:
To a cooled (0° C.) solution of 4-(4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4)triazin-7-yl]butan-1-ol (2.54 g, 6.16 mmol) and triphenylphosphine (2.42 g, 9.24 mmol) in tetrahydrofuran (30 mL) was added carbon tetrabromide (2.45 g, 7.39 mmol).
Reaction SMILES: [C:1]1([O:7][P:8]([CH2:11][C:12]([CH3:35])=[CH:13][CH2:14][C:15]2[C:16]([O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[C:17]3[C:21](=[C:22]([CH3:26])[C:23]=2[O:24][CH3:25])[CH2:20][O:19][C:18]3=[O:27])(=[O:10])[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]([O:41][CH2:42][CH3:43])(=[O:40])[C@H:37]([CH3:39])O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>N1C=CC=CC=1>[CH2:42]([O:41][C:36](=[O:40])[CH:37]([O:10][P:8]([CH2:11][C:12]([CH3:35])=[CH:13][CH2:14][C:15]1[C:16]([O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:32])[CH3:33])=[C:17]2[C:21](=[C:22]([CH3:26])[C:23]=1[O:24][CH3:25])[CH2:20][O:19][C:18]2=[O:27])([O:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:9])[CH3:39])[CH3:43]
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CP(=O)(O)Oc1ccccc1)C(=O)OC2
Reactant: CCOC(=O)[C@H](C)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: c1ccncc1
Product: CCOC(=O)C(C)OP(=O)(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)Oc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
To a solution of {4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-phosphonic acid monophenyl ester (25 mg, 0.048 mmol) and ethyl (S)-(−)-lactate (34 mg, 0.288 mmol) in pyridine (1 mL) was added PyBOP (125 mg, 0.24 mmol). The solution was stirred at room temperature for 16 hours and concentrated. The residue was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 24 mg (83%) of the desired product. MS (m/z) 641 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.C(N(CC)CC)C.[C:17]([Si:21](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])([CH3:19])[CH3:18]>ClCCl>[CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][O:8][Si:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:17]([CH3:20])([CH3:18])[CH3:19])[CH2:4][O:3]1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC1(C)OC[C@@H](CO)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.2 %

Procedure:
To a solution of ((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)methan-1-ol (9 g, 68.6 mmol) in anhydrous dichloromethane (40 mL) were added triethylamine (11.2 mL), tert-butylchlorodiphenylsilane (19.8 g, 372 mmol), and N,N-dimethylaminopyridine (DMAP, 418 mg, 3.4 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. It was then diluted with additional dichloromethane and the reaction mixture was washed with water, brine, dried over sodium sulfate, filtered and evaporated to give the title compound (27 g) which was used in the next step without further purification.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[F:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1>CN(C=O)C>[F:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:23][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: Oc1cccc(F)c1
Reactant: N#Cc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2cccc(F)c2)cc1
Yield: 55.4 %

Procedure:
A DMF (83 mL) solution of K2CO3 (12.60 g, 91.3 mmol), 4-bromobenzonitrile (15.00 g, 83.0 mmol) and 3-fluorophenol (8.2 mL, 91.3 mmol) was stirred at reflux (24 h). DMF was removed by distillation and the residue was purified by flash column chromatography on silica gel with EtOAc/hexanes (0/10 to 5195) as the eluent to obtain 4-((3′-fluoro)phenoxy)benzonitrile as a white solid (9.81 g, 56%): Rf=0.54 (EtOAc/hexanes 5/95); mp 67-69° C.; IR (nujol) 3073, 2961, 2912, 2862, 2219, 1593, 1461, 1376, 1265, 1225, 1163, 1119, 954, 869, 830, 788, 677, 543 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.79 (dt, J=2.1, 9.9 Hz, 1 ArH), 6.84-6.98 (m, 2 ArH), 7.05 (d, J=9.0 Hz, 2H3), 7.32-7.41 (m, 1 ArH), 7.64 (d, J=9.0 Hz, 2H2); 13C NMR (75 MHz, CDCl3) δ 106.7 (C1), 107.9 (d, J=23.9 Hz, C2′ or C4′), 111.9 (d, J=21.1 Hz, C4′ or C2′), 115.6 (d, J=3.4 Hz, C6′), 118.5, 118.6 (CN, C3), 131.0 (d, J=9.7 Hz, C5′), 134.2 (C2), 156.2 (d, J=10.3 Hz, C1′), 160.7 (C4), 163.6 (d, J=247.1 Hz, C3′); HRMS (M+H+) (ESI+) not observed [M+H+] (calcd for C13H8FNOH+ 214.0668); Anal. Calcd. for C13H8FNO: C, 73.23; H, 3.78; F, 8.91; N, 6.57. Found: C, 73.18; H, 3.69; F, 8.68; N, 6.53.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:9]([OH:11])=[N:10][C:5]2=[N:4][CH:3]=1.CN1C[CH2:21][CH2:20][C:19]1=O.C(N(CC)CC)C.C([Sn](CCCC)(CCCC)/C=C/C)CCC>CCOC(C)=O.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>[CH3:14][CH2:13][CH:12]([N:8]1[C:6]2=[N:7][C:2](/[CH:19]=[CH:20]/[CH3:21])=[CH:3][N:4]=[C:5]2[N:10]=[C:9]1[OH:11])[CH2:15][CH3:16]
Reactant: CN1CCCC1=O
Reactant: CCC(CC)n1c(O)nc2ncc(Br)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C/C=C/[Sn](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C/C=C/c1cnc2nc(O)n(C(CC)CC)c2n1
Temperature: 120 °C
Yield: 15 %

Procedure:
A thick-walled microwave bottle equipped with a stirbar was charged with 6-bromo-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyrazin-2-ol (1.0 equiv) and (Ph3P)4Pd (0.15 equiv). The bottle was covered with a sheet of Parafilm and purged with nitrogen for 5-10 min, and N-methylpyrrolidone (11.7 volume equivalents), triethyl amine (2.0 equiv), and (E)-tributyl(prop-1-enyl)stannane (2.0 equiv) were added by syringe. The resulting mixture was immediately fitted with a septum and cap and heated to 120° C. in a microwave for 20 min. The reaction was then diluted with EtOAc, washed with three times with water and once with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Reverse-phase preparative HPLC provided the title compound (15%) as a foam. LCMS m/z (APCI)=247.1 (M+H).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][C:6](=[O:8])[CH2:5][C@@H:4]1[C:9](OCC)=[O:10])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[CH2:1]([C@H:3]1[C@@H:4]([CH2:9][OH:10])[CH2:5][CH:6]([OH:8])[CH2:7]1)[CH3:2]
Reactant: CCOC(=O)[C@H]1CC(=O)C[C@H]1CC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H]1CC(O)C[C@@H]1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of (1S,2R)-ethyl 2-ethyl-4-oxocyclopentanecarboxylate (5 g, 27.1 mmol, Example #22 step B) in THF (100 mL) at about −78° C. was added LAH (2 M in THF, 54.3 mL, 109 mmol). After about 1 h, the reaction mixture was allowed to warm to rt slowly. After about 4 h, water (4.8 mL) followed by aqueous NaOH (15% w/v, 4.8 mL) followed by water (9.6 mL) was added to the reaction mixture. After about 15 h, anhydrous Na2SO4 was added and the slurry was filtered and concd in vacuo to provide crude (3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentanol (3.9 g, 100%) as an oil which was used without further purification. LC/MS (Table 1, Method a) Rt=2.40 min; MS m/z: 145 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:12]>CO.[Pd]>[CH3:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: COc1cccc([N+](=O)[O-])c1C
Agent: [Pd]
Solvent: CO
Product: COc1cccc(N)c1C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a solution of 2-methyl-1-(methyloxy)-3-nitrobenzene (Intermediate 57, 1.67 g) in methanol (50 mL) was added Pd/C (10%, 50 mg) and the reaction mixture was stirred under H2 atmosphere for 1 hour. The mixture was filtered through a pad of celite. Evaporation afforded the title compound as a solid (1.31 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][OH:10])[CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH2:9][OH:10])[CH:3]=1
Reactant: OCc1cc(Cl)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCc1cc(Cl)ccc1OCc1ccccc1
Yield: 106.4 %

Procedure:
4-Chloro-2-(hydroxymethyl)phenol (5 g, 31 mmol), benzyl bromide (3.74 ml, 31 mmol), and potassium carbonate (4.78 g, 34 mmol) were refluxed in acetone (30 ml) for two hours. TLC showed no more SM (starting material). Cooled down, filtered off the solid and vacuumed down (the filtrate) to give a clear oil (8.2 g).
Reaction SMILES: [N:1](OCCCC)=O.[CH2:8]([CH:10]([NH:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([NH:21][C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=2[CH3:30])[C:15]=1[NH2:31])[CH2:11][CH3:12])[CH3:9].Cl.[OH-].[Na+]>C(#N)C>[CH2:8]([CH:10]([NH:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]2[N:21]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=3[CH3:30])[N:1]=[N:31][C:15]=12)[CH2:11][CH3:12])[CH3:9]
Reactant: CCCCON=O
Reactant: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCC(CC)Nc1cc(C)nc2c1nnn2-c1c(C)cc(C)cc1C
Temperature: 65 °C
Yield: 77.8 %

Procedure:
A mixture of butyl nitrite (119 mg, 1.15 mmol) and N4-(1-ethyl-propyl)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-triamine (250 mg, 0.766 mmol) in anhydrous acetonitrile (16 ml) was heated at 65° C. for 2 hours. The mixture was cooled to room temperature and 2N HCl (16 ml) was added. The mixture was neutralized with 2N NaOH and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give 250 mg of the crude product as a brown oil. The oil residue was purified through silica gel column using chloroform as eluent to give 201 mg of the title compound as golden yellow solid. Mp 131-133° C. 1H NMR (CDCl3) ä 7.022(s, 2H), 6.20(s, 1H), 5.44(d, 1H), 3.65(m, 1H), 2.50(s, 3H), 2.36(s, 3H), 1.96(s, 6H), 1.5-1.8(m, 4H), 1.03(t, 6H)ppm.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:6]([CH3:16])[N:5]=1.FC(F)(F)C(O)=O>O>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]2[N:6]([CH3:16])[N:5]=[C:4]([CH:3]=[O:2])[CH:8]=2)=[CH:14][CH:13]=1
Reactant: COC(OC)c1cc(-c2ccc(F)cc2)n(C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cn1nc(C=O)cc1-c1ccc(F)cc1

Procedure:
The compound from Step 1 (9 g) was treated with trifluoroacetic acid (30 mL) and water (30 mL). The trifluoacetic acid was removed in vacuo and the reaction mixture partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with saturated sodium bicarbonate (×2), brine and dried over MgSO4. The solvent was removed in vacuo to give a yellow oil which was crystallised from ethyl acetate/hexanes to give the title compound. 4.6 g 1H NMR (360, CDCl3) δ 9.97 (s, 1H), 7.38 (m, 2H), 7.20 (m, 2H), 6.80 (s, 1H), 3.95 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[CH3:33].[F-].[Cs+]>COCCOC.O.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>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:29]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:27]([CH3:26])[CH:28]=2)=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)cc1C
Reactant: CS(=O)(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=O)c2Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2c(-c3ccc(S(C)(=O)=O)cc3)cnn(Cc3ccccc3)c2=O)cc1C
Temperature: 25 °C
Yield: 56 %

Procedure:
2-Benzyl-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (150 mg, 0.4 mmol) prepared in Example 78 was dissolved in anhydrous DME (10 mL) and heated to reflux with 3,4-dimethylbenzeneboronic acid in presence of CsF (146 mg, 0.96 mmol) and tetrakis(triphenylphosphine)palladium (14 mg, 0.012 mmol) for 6 hours. After cooling to room temperature the reaction mixture was diluted with water and extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried over MgSO4, and evaporated in vacuo. The compound was purified on a silica gel column, eluting with 30% ethyl acetate in pentanes, providing the desired compound (yield: 100 mg, 56%). 1H NMR (300 MHz, CDCl3) δ 2.15, 2.20 (2s, 3H), 2.25, 2.30 (2s, 3H), 3.05, 3.08 (2s, 3H), 5.35, 5.40 (2s, 2H), 6.60-7.1, (m, 3H), 7.30-7.40 (m, 4H), 7.42-7.60 (m, 2H), 7.70-8, 02 (m, 4H). MS (DCI/NH3) m/z 445 (M+H)+. Anal. calc. for C26H24N2O3S.H2O: C, 67.51; H, 5.66; N, 6.05. Found: C, 67.45; H, 5.56; N, 5.85.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.Cl[CH2:25][C:26]1[C:27]([O:36][CH3:37])=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[N:15]([CH2:25][C:26]4[C:27]([O:36][CH3:37])=[N:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:4][CH:3]=1
Reactant: COc1nc(C(F)(F)F)ccc1CCl
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 70 °C
Reaction time: 3 h
Yield: 82.1 %

Procedure:
To a solution of 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (161.4 mg, 0.50 mmol) and 3-(chloromethyl)-2-methoxy-6-(trifluoromethyl)pyridine (169 mg, 0.75 mmol) in anhydrous DMF (3.0 mL) at room temperature was added anhydrous K2CO3 (138 mg, 1.0 mmol). The resulting yellow suspension was stirred at 70° C. for 3 h. Analysis by HPLC/MS indicated that starting 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one had been consumed. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (20 mL×2). The combined EtOAc extracts were washed with water, then saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluted with a gradient of ethyl acetate (30-100%) in hexanes to afford 210 mg (82%) of the title compound as a yellow solid. HPLC/MS: retention time=3.11 min, [M+H]+=512.2.