Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:10]([NH:20][C:21](=[O:39])[CH2:22][N:23]2[C:31]3[C:30]([F:33])([F:32])[CH2:29][CH2:28][C:27]([F:35])([F:34])[C:26]=3[C:25]([CH:36]([F:38])[F:37])=[N:24]2)[CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=[N:4][C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.BrC1C([C@@H](NC(=O)CN2C3C(F)(F)CCC(F)(F)C=3C(C(F)F)=N2)CC2C=C(F)C=C(F)C=2)=NC(S(C)(=O)=O)=NC=1.[CH3:81][O:82][CH2:83][CH2:84][O:85][CH2:86]CN>>[Br:1][C:2]1[C:3]([C@@H:10]([NH:20][C:21](=[O:39])[CH2:22][N:23]2[C:31]3[C:30]([F:33])([F:32])[CH2:29][CH2:28][C:27]([F:34])([F:35])[C:26]=3[C:25]([CH:36]([F:37])[F:38])=[N:24]2)[CH2:11][C:12]2[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:81][O:82][CH2:83][CH2:84][O:85][CH3:86])=[N:6][CH:7]=1
Reactant: COCCOCCN
Reactant: CNc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Agent: CS(=O)(=O)c1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Product: COCCOCCNc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1

Procedure:
The title compound (17A) was prepared according to the method presented for the synthesis of compound 14A of Example 14 utilizing 12C and 2-(2-methoxyethoxy)ethanamine. MS (m/z) 716.15 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]([CH:11]([C:18]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][C:25]=2[O:27][CH3:28])[NH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])C.O.[OH-].[K+]>C1COCC1.CCO>[CH3:28][O:27][C:25]1[CH:24]=[CH:23][N:22]=[C:21]2[NH:20][CH:19]=[C:18]([CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:5]([C:4]([OH:29])=[O:3])[C:6]([OH:8])=[O:7])[C:26]=12
Reactant: CCOC(=O)C(C(=O)OCC)C(c1ccccc1)c1c[nH]c2nccc(OC)c12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccnc2[nH]cc(C(c3ccccc3)C(C(=O)O)C(=O)O)c12
Temperature: 50 °C
Reaction time: 4 h
Yield: 94.3 %

Procedure:
To a suspension of 2-[(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-methyl]-malonic acid diethyl ester (1.0 g, 2.52 mmol) in a mixture of THF/EtOH (1/1, 24 ml) was added H2O (2 ml) followed by KOH (1.41 g, 25.2 mmol). The reaction mixture was stirred at 50° C. for 4 h, and then cooled to RT and concentrated. The solid residue was dissolved in H2O. The resulting solution was cooled to 0° C. and acidified to pH 4-5 by addition of HCl (I M). The white solid precipitate was collected by filtration, washed with cold H2O and dried to afford 2-[(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-methyl]-malonic acid (809 mg, 94% yield).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Br:25][CH2:26][C:27]([NH:29][C:30]1[CH:35]=[N:34][CH:33]=[C:32]([CH3:36])[N:31]=1)=[O:28]>C(#N)C>[Br-:25].[CH3:36][C:32]1[N:31]=[C:30]([NH:29][C:27]([CH2:26][N+:1]23[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]2)[C@@H:3]([O:9][C:10]([C:12]2([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:2]3)=[O:28])[CH:35]=[N:34][CH:33]=1
Reactant: Cc1cncc(NC(=O)CBr)n1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Solvent: CC#N
Product: Cc1cncc(NC(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)C2(c4ccccc4)CCCCCC2)C3)n1
Product: [Br-]
Reaction time: 8 h
Yield: 20.1 %

Procedure:
1-Phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 1e) (70 mg) and 2-bromo-N-(6-methylpyrazin-2-yl) acetamide (Example 2a) (49.2 mg) were dissolved in acetonitrile (1 mL) and left to stand overnight. Crystals separated on standing and were filtered and washed with acetonitrile (2×1 mL), ethyl acetate (2×3 mL) and diethyl ether (2×3 mL) and dried to yield the titled compound (24 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([OH:24])[CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1.[C:25](N1C=CN=C1)([N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1)=[S:26]>O1CCCC1.CN(C)C1C=CN=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:24][C:25]([N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1)=[S:26])[CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(O)c2nc3ccccc3s2)C1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(C(OC(=S)n2ccnc2)c2nc3ccccc3s2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.1 %

Procedure:
1.0 g (2.87 mmol) of tert-butyl 3-(benzothiazol-2-ylhydroxymethyl)piperidine-1-carboxylate were dissolved in 30 ml of tetrahydrofuran at room temperature. 0.35 g (2.87 mmol) of dimethylpyridin-4-ylamine and 1.53 g (8.61 mmol) of 1,1′-thiocarbonyldiimidazole were subsequently added. The reaction mixture was then stirred at room temperature for 18 h. Conventional work-up gave 1.08 g of tert-butyl 3-[benzothiazol-2-yl(imidazole-1-carbothioyloxy)methyl]piperidine-1-carboxylate; HPLC/MS (M+H)+=459 as oil.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]1([N+:12]2[C:17](Cl)=[CH:16][C:15]([NH2:19])=[CH:14][N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[NH2:21][NH2:22]>O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]1([N+:12]2[C:17]([NH:21][NH2:22])=[CH:16][C:15]([NH2:19])=[CH:14][N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1cn[n+](-c2ccccc2)c(Cl)c1
Reactant: NN
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Product: NNc1cc(N)cn[n+]1-c1ccccc1
Reaction time: 3 h

Procedure:
15.3 parts of 1-phenyl-4-amino-6-chloropyridazinium perchlorate is dissolved in 200 parts of water at 80° to 90° C; 5 parts of hydrazine hydrate is added and the whole is boiled for 3 hours. The reaction solution is concentrated to about half its volume and cooled. 13 parts (81.3% of theory, as hydrate) of 1-phenyl-4-amino-6-hydrazinopyridazinium perchlorate is obtained; C10H12O4N5Cl. H2O, obtained with 1 mole of water of crystallization when recrystallized from water. Melting point 63° to 65° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([NH2:22])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1>Br.C(O)(=O)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([N:22]5[CH2:15][CH2:14][NH:13][CH2:12][CH2:8]5)[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Nc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Clc1ccc(C2(C3=NCCc4ccc(N5CCNCC5)cc43)CCC2)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
1-[1-(4-Chloro-phenyl)-cyclobutyl]-3,4-dihydro-isoquinolin-7-ylamine (400 mg, 0.75 mmol) was dissolved in HBr/acetic acid (10 ml, 33%) and stirred for 3 h at 70° C. Another 10 ml of the HBr/acetic acid solution was added and the mixture was stirred for another 8 h at 70° C. The solvent was diluted with 1 N sodium hydroxid solution and extracted with dichloromethane. The combined organic layers were washed with saturated sodium chloride solution and dried with sodium sulphate. The residue was purified by flash column chromatography on silica with dichloromethane/methanol 98:2->95:5. The product was obtained as a brown oil (100 mg, 0.26 mmol, 35%) that was sufficiently pure for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](I)[C:5](I)=[CH:4][C:3]=1[Br:10].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C1(C)C=CC=CC=1.C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:4][C:3]=1[Br:10]
Reactant: Brc1cc(I)c(I)cc1Br
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Brc1cc(-c2ccccc2)c(-c2ccccc2)cc1Br
Temperature: 82 °C
Reaction time: 24 h
Yield: 159.8 %

Procedure:
To a 200 ml Schlenk reaction vessel were added under a nitrogen atmosphere 3.074 g (6.30 mmol) of 1,2-dibromo-4,5-diiodobenzene synthesized in Synthetic Example 3, 600 mg (0.519 mmol) of tetrakis(triphenylphosphine)palladium (manufactured by Tokyo Chemical Industry Co. Ltd.), and 1.920 mg (15.7 mmol) of phenylboronic acid (manufactured by Wako Pure Chemical Industries, Ltd.). Further, 50 ml of toluene, 13 ml of ethanol, and an aqueous solution composed of 4.007 g (37.8 mol) of sodium carbonate and 16 ml of water were added. The whole was heated to 82° C. and stirred for 24 hours. After cooling to room temperature, toluene and water were added and phase separation was conducted. The organic phase was concentrated and the resulting residue was dissolved in 26 ml of toluene. Then, 1.0 ml of a 70% tert-butyl hydroperoxide solution (manufactured by Wako Pure Chemical Industries, Ltd.) was added thereto, followed by 2 hours of stirring at room temperature. The toluene solution was washed twice with water and then the organic phase was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane) to obtain a white solid of 1,2-dibromo-4,5-diphenylbenzene (1.953 g, yield 80%).
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].[H-].[Na+].[H][H].I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>CN(C=O)C.O>[CH3:9][O:8][C:1]1[CH:7]=[CH:6][CH:5]=[CH:4][C:2]=1[O:3][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=1
Reactant: COc1ccccc1O
Reactant: N#Cc1ccc(OCCCCCI)cc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1OCCCCCOc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5.1 g (41 mmol) of guaiacol in 41 mL of DMF, cooled in an icebath, is added in portions, 20 g (41 mmole) of sodium hydride (50% dispersion in oil). The reaction is allowed to warm up to room temperature and stirred until no further hydrogen evolution is observed. The solution is then again cooled in an ice-bath and a solution of 13 g (41 mmol) 4-(5-iodopentoxy) benzonitrile in 82 mL DMF added. The reaction is allowed to warm up to room temperature and stirred for 18 h before pouring the mixture into water. The resulting solid is filtered off and dried to give 4-[5-(2-methoxyphenoxy)pentoxy] benzonitrile, m.p. 61°-63° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=1.ClC(N(C)C)=C(C)C.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][C:29]([CH3:34])([CH3:33])[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].CCN(C(C)C)C(C)C>C1COCC1.C([O-])(O)=O.[Na+]>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:9]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=2)=[O:11])[C:29]([CH3:34])([CH3:33])[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Reactant: COc1cccc(C(=O)O)n1
Agent: CC(C)=C(Cl)N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 410 mg (2.28 mmol) 6-methoxy-2-pyridinecarboxylic acid and 400 μL (3.02 mmol) 1-chloro-N,N,2-trimethylpropenylamine in 10 mL THF was stirred at RT. After 1.5 h, 600 mg (2.66 mmol) 3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester and 1.00 mL (5.81 mmol) DIPEA was added and the reaction mixture was stirred at RT for 30 min. The reaction mixture was diluted with saturated NaHCO3 solution and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (PE/EtOAc=1/1).
Reaction SMILES: [OH:1][C:2]([C:8]1[S:9][CH:10]=[C:11]([CH3:13])[N:12]=1)([CH3:7])[C:3]([NH:5][NH2:6])=O.[F:14][C:15]1[C:16]([CH2:22][N:23]2[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[S:30])=[N:24]2)=[N:17][CH:18]=[C:19]([F:21])[CH:20]=1.S(=O)(=O)(O)O.N>ClCCl>[F:14][C:15]1[C:16]([CH2:22][N:23]2[CH:27]=[CH:26][C:25]([NH:28][C:29]3[S:30][C:3]([C:2]([C:8]4[S:9][CH:10]=[C:11]([CH3:13])[N:12]=4)([OH:1])[CH3:7])=[N:5][N:6]=3)=[N:24]2)=[N:17][CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: Cc1csc(C(C)(O)C(=O)NN)n1
Reactant: Fc1cnc(Cn2ccc(N=C=S)n2)c(F)c1
Agent: N
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Cc1csc(C(C)(O)c2nnc(Nc3ccn(Cc4ncc(F)cc4F)n3)s2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of Intermediate 107, 2-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)propanohydrazide (63 mg, 0.313 mmol), and Intermediate 96, 3,5-difluoro-2-[(3-isothiocyanato-1H-pyrazol-1-yl)methyl]pyridine (79 mg, 0.313 mmol) in dichloromethane (anh) (3 mL) was stirred at room temperature overnight. Reaction mixture was concentrated, residue was treated with sulfuric acid (2 mL, 0.364 mmol) and stirred at room temperature during 1 h. Resulting mixture was neutralized with 32% NH3 (aq) under ice-bath until pH was basic. Mixture was partitioned between DCM (3×15 mL) and water (15 mL). Organic phase was separated, dried over magnesium sulfate and concentrated. Residue was purified by preparative HPLC using SUNFIRE column (C18, 3.5 μm, 19×150 mm) and linear gradient 25% to 75% water (0.1% HCOOH)-(0.1% HCOOH). Appropriate fractions were collected to give 1-[5-({1-[(3,5-difluoro-2-pyridinyl)methyl]-1H-pyrazol-3-yl}amino)-1,3,4-thiadiazol-2-yl]-1-(4-methyl-1,3-thiazol-2-yl)ethanol (50 mg, 0.109 mmol, 30.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.83 (s, 1H), 8.46 (d, 1H), 7.93-7.98 (m, 1H), 7.74 (d, 1H), 7.27 (s, 1H), 7.21 (m, 1H), 5.96 (d, 1H), 5.37 (d, 2H), 2.29 (d, 3H), 1.97 (s, 1H). [ES+MS] m/z 436 (MH+).
Reaction SMILES: [F:1][C:2]1[C:3](Br)=[C:4](Br)[CH:5]=[CH:6][C:7]=1[F:8].[O:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.[Li]CCCC>CCOCC>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[F:8])[CH:15]1[O:11][CH:12]2[CH:13]=[CH:14]1
Reactant: Fc1ccc(Br)c(Br)c1F
Reactant: c1ccoc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Fc1cc2c(cc1F)C1C=CC2O1
Temperature: -78 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To 3,4-difluoro-1,2-dibromo-benzene (0.75 g, 2.78 mmol) and furan (1 mL, 14.7 mmol) in Et2O (15 mL) at −78° C. was added BuLi (1.1 mL, 2.5M in hexanes, 2.75 mmol) dropwise. The reaction was stirred for two hours at −78° C. and then was allowed to warm to room temperature. After 2 hours, the reaction mixture was quenched with water dropwise and then was poured into water. The organic layer was separated and the aqueous layer was extracted three times with Et2O. The combined organic layers were washed with brine, dried over MgSO4, concentrated and chromatographed (25% ethyl acetate:hexanes) on silica gel to give 24 (350 mg, 70%) as a colourless oil. Rf=0.21 on silica gel (20% ethyl acetate:hexanes); bp 40° C. @ 0.5 mmHg]; IR (neat, cm−1), 3017 (M), 1624 (s), 1465 (s), 1365 (s), 1253 (s), 1190 (m), 1040 (s), 857 (s). 1H NMR (400 MHz, CDCl3) δ 7.06 (2H, dd, JH−F=7.7, 7.7 Hz), 7.01 (2H, s), 5.67 (2H, s); 13C NMR (400 MHz, CDCl3) δ 147.2 (dd, JC−F=247.9, 14.5 Hz), 145.1 (dd, JC−F=4.3, 4.3 Hz), 143.1, 110.8 (m), 82.1. HRMS calcd for C10H6O (M+): 180.0387. Found: 180.0394.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19](F)[C:18](Cl)=[CH:17][C:16]=2[C:23]2[N:27]([CH3:28])[C:26]([CH2:29][CH3:30])=[N:25][N:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.C(N(CC)CC)C.CN([CH:44]=[O:45])C.[CH3:46][OH:47]>>[CH3:46][O:47][C:44](=[O:45])[C:18]1[CH:19]=[CH:20][C:15]([NH:14][S:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:10][CH:9]=2)(=[O:12])=[O:13])=[C:16]([C:23]2[N:27]([CH3:28])[C:26]([CH2:29][CH3:30])=[N:25][N:24]=2)[CH:17]=1
Reactant: CO
Reactant: CCc1nnc(-c2cc(Cl)c(F)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Reactant: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nnc(-c2cc(C(=O)OC)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A 15 mL pressure vessel was charged with 4-tert-butyl-N-[4-iodo-2-(5-ethyl-4-methyl-4H-[1,2,4]triazol-3-yl)-phenyl]-benzenesulfonamide (prepared according to general procedure C, 551 mg, 1.05 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (1:1) (86 mg, 0.105 mmol), triethylamine (290 μL, 2.1 mmol), and DMF/MeOH (4:1) (5 mL). The vessel was placed under an atmosphere of CO (50 p.s.i.), heated to 80° C., and stirred overnight. The following day, the volatiles were removed in vacuo, the residue dissolved in EtOAc, and the organics washed twice with 1 M HCl. The aqueous solution was then extracted three times with EtOAc. The EtOAc extractions were then pooled together and washed with brine. The organic solvent was then removed and the resultant residue was purified by silica gel chromatography to afford 4-(4-tert-butyl-benzenesulfonylamino)-3-(5-ethyl-4-methyl-4H-[1,2,4]triazol-3-yl)-benzoic acid methyl ester as a yellow foam: MS (ES) M+H expected 457.2, found 457.1.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][N:16]([CH3:22])[CH2:17][CH2:18][CH2:19][NH:20][CH3:21].C([O-])(O)=O.[Na+]>C1COCC1.C(Cl)Cl>[CH3:15][N:16]([CH3:22])[CH2:17][CH2:18][CH2:19][N:20]([CH3:21])[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CNCCCN(C)C
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)CCCN(C)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 4-fluoro-3-nitrobenzotrifluoride (1.00 g, 4.78 mmol) in THF (25 mL) was added N1,N1,N3-trimethylpropane-1,3-diamine (0.84 mL, 5.7 mmol) and NaHCO3 (1.1 g, 13 mmol). The resulting mixture was stirred for 1 h at RT, diluted with CH2Cl2, and washed with H2O. The organic layer was dried (MgSO4), filtered and concentrated to afford the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:18])C=1>C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[O-:18])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)c1ccccn1
Solvent: ClCCl
Product: CC(C)c1cccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
A mixture of isopropylpyridine (2.1 g, 17.75 mmol) and m-CPBA (5.0 g, 1.3 eq.) in CH2Cl2 was stirred overnight at room temperature. Then, the reaction mixture was diluted with CH2Cl2 (twice the volume) and successively washed with aqueous sodium bicarbonate (twice) and brine, dried (Na2SO4) and evaporated to give 2.0 g (85%) of the title compound 104.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH:14]([OH:16])[C:13]([CH3:18])([CH3:17])[C:12]=2[CH:19]=1)#[N:7].C(N(CC)CC)C.O>C(OCC)C>[Cl:1][CH2:2][C:3]([O:16][CH:14]1[C:13]([CH3:17])([CH3:18])[C:12]2[CH:19]=[C:8]([C:6]#[N:7])[CH:9]=[CH:10][C:11]=2[O:15]1)=[O:4]
Reactant: CC1(C)c2cc(C#N)ccc2OC1O
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC1(C)c2cc(C#N)ccc2OC1OC(=O)CCl
Reaction time: 3 h
Yield: 34.2 %

Procedure:
Chloroacetyl chloride (3.6 g) was added dropwise to a solution of 5-cyano-2,3-dihydro-3,3-dimethyl-2-hydroxybenzofuran (5 g) prepared as in Example 10, and triethylamine (3.2 g) in diethyl ether (50 ml) with stirring and cooling. After 3 hours at room temperature, the mixture was shaken with water and an insoluble solid product was filtered off and dried to give 2.4 g of title compound, mp 138° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11]1([C@@H:17]2[N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][C:20](=[O:30])[O:19][C@@H:18]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]I.CN(P(N(C)C)(N(C)C)=O)C>C1COCC1.CCOC(C)=O>[C:26]([O:25][C:23]([N:22]1[C@@H:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:18]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:19][C:20](=[O:30])[C@@H:21]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][Cl:37])=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: ClCCCCCI
Reactant: CC(C)(C)OC(=O)N1CC(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](CCCCCCl)C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A 1.0M solution of sodium bis(trimethylsilyl)amide in THF (55.0 mL, 55.2 mmol) is added at −78° C. to a solution of (5S,6R)-5,6-diphenyl-4-tert-butoxycarbonyl-morpholin-2-one (13.0 g, 36.8 mmol), 1-chloro-5-iodo-pentane (25.0 g, 108.0 mmol) and HMPA (55.0 mL) in THF (200.0 mL). The reaction mixture is stirred at −78° C. for 2 hours and at room temperature for 1 hour. The reaction mixture is diluted with EtOAc, washed with water and brine. After drying the organic phase over anhydrous Na2SO4, the solvent is removed under reduced pressure to afford the crude product that is purified by silica gel column chromatography to afford the title compound; m/z 358 [M-Boc+H].
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[ClH:10].N([O-])=O.[Na+].[S:15](=[O:17])=[O:16]>C(O)(=O)C>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([S:15]([Cl:10])(=[O:17])=[O:16])=[CH:3][CH:4]=1
Reactant: O=S=O
Reactant: COc1ccc(N)cn1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(S(=O)(=O)Cl)cn1
Temperature: 25 °C
Yield: 51 %

Procedure:
5-Amino-2-methoxypyridine (1.24 g) was dissolved in acetic acid (8.3 mL), and the mixture was stirred under ice-cooling. Concentrated hydrochloric acid (8.3 mL) was added, and an aqueous solution (5 mL) of sodium nitrite (689 mg) was added dropwise over 15 min while keeping the inside temperature at not higher than 10° C. The reaction mixture was stirred for 10 min, and gradually added at 5° C. to a mixture of cuprous chloride (280 mg) and acetic acid (17 mL) saturated in advance with sulfur dioxide gas. The mixture was allowed to gradually warm to room temperature until the generation of gas stopped. The reaction mixture was concentrated to about 5 mL under reduced pressure, and the precipitate was collected by filtration to give the title compound (yield 1.0 g, 51%) as crude crystals. This compound was used for the next reaction without purification.
Reaction SMILES: I[C:2]1[C:3]([CH3:17])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:6]=1[CH3:7].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:3]([CH3:17])=[N:4][N:5]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=3)[C:6]=2[CH3:7])=[CH:21][CH:20]=1
Reactant: Cc1nn(-c2ccc(CCO)cc2)c(C)c1I
Reactant: OB(O)c1ccc(Cl)cc1
Product: Cc1nn(-c2ccc(CCO)cc2)c(C)c1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 12 from 2-[4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)phenyl]ethanol (step 2 of Example 11) and 4-chlorobenzeneboronic acid: MS (ESI) m/z 327 [M+H]+, 1H-NMR (CDCl3) δ 7.44-7.24 (8H, m), 3.89 (2H, t, J=6.6 Hz), 2.93 (2H, t, J=6.6 Hz), 2.31 (3H, s), 2.28 (3H, s).