Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:21][CH3:22])=[C:4]([CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH3:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[F:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>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>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([C:28]2[CH:27]=[N:26][CH:25]=[C:24]([F:23])[CH:29]=2)[C:3]([O:21][CH3:22])=[C:4]([CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH3:12])[CH:5]=1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Reactant: CCC(NC(=O)OC(C)(C)C)c1cc(Cl)c(C)c(Br)c1OC
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: O
Solvent: C1COCCO1
Product: CCC(NC(=O)OC(C)(C)C)c1cc(Cl)c(C)c(-c2cncc(F)c2)c1OC
Temperature: 90 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
The tert-butyl [1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)propyl]carbamate peak 2 (0.075 g, 0.19 mmol) was combined with 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.081 g, 0.29 mmol, Frontier Scientific, catalog #F2018) in 1,4-dioxane (4.6 mL) and potassium carbonate (0.053 g, 0.38 mmol) in water (1.5 mL) in a tube. This was degassed with nitrogen and the tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.02 mmol) was added. The reaction was degassed with nitrogen, sealed and heated to 90° C. in an oil bath. The reaction was complete after 18 h, and the reaction mixture was allowed to cool and partitioned between EtOAc and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give the crude product as an oil. The product was purified by chromatography on silica gel eluting with a hexane:EtOAc gradient to give tert-butyl {1-[5-chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]propyl}carbamate as a viscous oil (0.05 g, 77%). LCMS calculated for C21H27ClFN2O3 (M+H)+: m/z=409.1. found: 409.1.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[Mg]Br.[C:12](=[O:14])=[O:13]>C(OCC)C>[CH3:11][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:12]([OH:14])=[O:13]
Reactant: Cc1cc(C)c([Mg]Br)c(C)c1
Reactant: O=C=O
Solvent: CCOCC
Product: Cc1cc(C)c(C(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
20 mL of 2-mesitylmagnesium bromide (1.0 M in diethyl ether, 20 mmol) was added to a flask containing 60 mL of dry diethyl ether and solid carbon dioxide (dry ice). Additional dry ice was added throughout the course of the reaction as needed. After 30 min, the mixture was allowed to warm to room temperature and the solid was separated by filtration. The solid was dissolved in a 1 M KOH(aq) solution followed by neutralization to pH 1 using HCl. This resulted in the precipitation of a white powder that was collected by filtration and dried under vacuum at 80° C. (2.52 g, 77% yield).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([CH:13]=O)[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:22][CH2:23][CH2:24][CH2:25][P:26](=[O:29])([OH:28])[OH:27].[BH3-]C#N.[Na+]>CO>[C:1]1([C:7]2[N:12]=[C:11]([CH2:13][NH:22][CH2:23][CH2:24][CH2:25][P:26](=[O:27])([OH:29])[OH:28])[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCP(=O)(O)O
Reactant: Cc1ccc(-c2ccc(C=O)nc2-c2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(-c2ccc(CNCCCP(=O)(O)O)nc2-c2ccccc2)cc1

Procedure:
Following General Procedure M, 6-phenyl-5-p-tolylpyridine-2-carbaldehyde (Compound 55, 67 mg, 0.25 mmol), (3-aminopropyl)-phosphonic acid (34 mg, 0.25 mmol), Bu4NOH (0.2 ml, 0.25 mmol, 1 M in MeOH) and NaCNBH3 (15 mg, 0.25 mmol) in MeOH (3 ml) were reacted to produce the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=O)[CH2:4][C:5]#[N:6].[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[NH:18][NH2:19]>C(O)C>[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[N:18]1[C:5]([NH2:6])=[CH:4][C:3]([C:2]([F:9])([F:8])[F:1])=[N:19]1
Reactant: NNc1cccc(Cl)c1Cl
Reactant: N#CCC(=O)C(F)(F)F
Solvent: CCO
Product: Nc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1Cl
Yield: 39.4 %

Procedure:
To a stirred suspension of 4,4,4-trifluoro-3-oxobutanenitrile (20 g, 145.98 mmol, 1.0 eq.) in ethanol (200 mL) was added (2,3-dichlorophenyl)hydrazine (47.5 g, 145.98 mmol, 1.0 eq) and refluxed for 3 h. Ethanol was evaporated, the residue diluted with water and extracted with ethyl acetate (300 mL×2), dried (Na2SO4), and the solvent evaporated under vacuum. The crude product was purified by CC using EtOAc/PE (3:7) as eluent to get 1-(2,3-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-amine (17.02 g, 39.65%, yellow solid; TLC system: EtOAc/PE (1:1) Rf: 0.6).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Br:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=1[NH2:18]>>[Br:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:17]=1[NH:18][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Nc1ccc(Cl)cc1Br
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Cl)cc1Br

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-bromo-4-chloroaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:25]3[CH2:26][CH2:27][CH:22]([C:19]4[CH:18]=[CH:17][C:16]([CH3:15])=[CH:21][CH:20]=4)[CH2:23][CH2:24]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Reactant: Cc1ccc(C2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(C2CCN(C[C@H](O)COc3cccc4[nH]ccc34)CC2)cc1

Procedure:
The title compound was prepared in similar fashion from S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(4-methylphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 78% overall yield. FDMS m/e=364 (M+ of free base). α[D]589 =-11.77 (c=0.34, methanol).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH2:6]1[CH2:13][O:12][S:9](=[O:11])(=[O:10])[CH2:8][CH2:7]1>O1CCCC1>[C:1]([NH:5][CH2:13][CH2:6][CH2:7][CH2:8][S:9]([OH:12])(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S1(=O)CCCCO1
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Product: CC(C)(C)NCCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of tert-butylamine (1.0 mL, 9.5 mmol) in tetrahydrofuran (4 mL) was added 1,4-butane sultone (1.36 g, 10.0 mmol) at room temperature. The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×20 mL) and dried in vacuo. Yield: 690 mg (34%). 1H NMR (D2O, 500 MHz) δ ppm 2.92 (t, 2H, J=7.1 Hz), 2.82 (t, 2H, J=7.1 Hz), 1.68 (m, 4H), 1.22 (s, 9H). 13C (D2O, 125 MHz) δ ppm 57.07, 50.30, 40.95, 25.28, 24.96, 21.62. ES-MS 210 (M−1).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH:9]=[N:10][O:11][CH3:12])=[O:7])=[C:4]([CH3:15])[CH:3]=1.[CH:16]([O-])=[O:17].[Na+]>CN(C)C=O.O>[CH:16]([C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH:9]=[N:10][O:11][CH3:12])=[O:7])=[C:4]([CH3:15])[CH:3]=1)=[O:17]
Reactant: CON=CNC(=O)c1ccc(Br)cc1C
Reactant: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON=CNC(=O)c1ccc(C=O)cc1C
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 43.7 %

Procedure:
In a solution of 0.20 g of 4-bromo-N-(methoxyiminomethyl)-2-methyl benzoic acid amide in 5 ml of N,N-dimethylformamide, 0.065 g of sodium formate and 0.026 g of dichlorobis(triphenylphosphine) palladium (II) were added, and stirred under carbon monoxide atmosphere at 120° C. for 1.5 hour. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, and poured in 30 mL of water, and extracted with ethyl acetate (20 mL×2). The combined organic phases were washed with water, and dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that were eluated with ethyl acetate-hexane (gradient of 1:3 to 1:1) to obtain 0.071 g of the aimed product as colorless oily substance.
Reaction SMILES: Cl.[Br:2][C:3]1[C:11]([Cl:12])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([NH:13]N)[CH:4]=1.O=[C:16]1[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17]1.C(O)(=O)C>C1(C)C=CC=CC=1>[Br:2][C:3]1[C:11]([Cl:12])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]2[C:4]=1[C:21]1[CH2:20][CH2:19][CH:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][C:16]=1[NH:13]2
Reactant: CCOC(=O)C1CCCC(=O)C1
Reactant: NNc1cc(Br)c(Cl)cc1C(=O)O
Agent: Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCc2c([nH]c3c(C(=O)O)cc(Cl)c(Br)c23)C1
Temperature: 105 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
A suspension of 4-bromo-5-chloro-2-hydrazinylbenzoic acid hydrochloride (12.89 g, 37.6 mmol), ethyl 3-oxocyclohexanecarboxylate (7.03 g, 41.3 mmol), and acetic acid (6.45 mL, 113 mmol) in toluene (188 mL) was heated at 105° C. overnight. After 16 h, more acetic acid (6 mL) and ethyl 3-oxocyclohexanecarboxylate (2.00 g) were added and the mixture was heated at 110° C. for 4.5 h. The mixture was concentrated, and the residue was combined with toluene (100 mL) and TFA (20 mL). The suspension was heated at 90° C. overnight. The cooled mixture was concentrated and the residue was suspended in EtOAc. The resulting solid was collected by filtration, washed with EtOAc and air-dried to give 5-bromo-6-chloro-2-(ethoxycarbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid as a yellow solid (11.0 g, 73% yield). Mass spectrum m/z 400, 402 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 13.44 (br. s., 1H), 11.24 (s, 1H), 7.69 (s, 1H), 4.12 (qd, J=7.1, 2.3 Hz, 2H), 3.23-2.81 (m, 5H), 2.23-2.09 (m, 1H), 1.91-1.75 (m, 1H), 1.22 (t, J=7.0 Hz, 3H).
Reaction SMILES: C([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:21])=[C:18](Br)[CH:19]=1)(OC(C)(C)C)=O.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[NH:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][C:17]([Cl:21])=[C:18]([C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)[CH:19]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2cc(OC[C@@H]3CCN3)cnc2Cl)cc1
Yield: 124.3 %

Procedure:
To a solution of 3-(1-BOC-2-(S)-azetidinylmethoxy)-5-bromo-6-chloropyridine (650 mg, 1.73 mmol) and 4-chlorophenylboronic acid (284 mg, 1.82 mmol, Lancaster Chemical Co.) in toluene (10 mL) was added Pd(0) (37 mg) and Na2CO3 (5 mL of a 2 M solution), and the mixture was heated at reflux for 14 h. The solvent was removed under vacuum, and the residue was chromatographed (silica gel; EtOAc/hexane, 1:5 to 1:2) to afford the title compound (665 mg, 94 % yield): 1H NMR (CDCl3, 300 MHz) δ1.41 (s, 9H), 2.23-2.44 (m, 2H), 3.89 (t, J=7.5, Hz, 2H), 4.08-4.18 (m, 2H), 4.37 (m, 1H), 4.53 (m, 1H), 7.25 (d, J=3.0 Hz, 1H), 7.37-7.46 (m, 4H), 8.13 (d, J=3.0 Hz, 1H); MS (CI/NH3) m/z 409 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:25][C@@H:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36]3[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[C:38]([OH:46])[CH:37]=3)[CH:32]=2)[O:27]1)[CH2:9][C@H:10]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:48][CH:49]([CH3:51])[CH3:50].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]([CH2:25][C@@H:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36]3[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[C:38]([O:46][CH2:48][CH:49]([CH3:51])[CH3:50])[CH:37]=3)[CH:32]=2)[O:27]1)[CH2:9][C@H:10]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)CI
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@@H](CN(C[C@H](O[Si](C)(C)C(C)(C)C)c2cccnc2)C(=O)OC(C)(C)C)O3)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@@H](CN(C[C@H](O[Si](C)(C)C(C)(C)C)c2cccnc2)C(=O)OC(C)(C)C)O3)cc1OCC(C)C
Temperature: 60 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
To a solution of the compound of Example 181 (0.097 g, 0.0015 mmol, 1.0 eq.) in N,N-dimethylformamide (0.5 mL) were added 1-iodo-2-methylpropane (0.10 ml) and potassium carbonate (0.10 g). The reaction mixture was stirred at 60° C. for 16 hours. The mixture was diluted with distilled water (2 mL) and extracted with ethyl acetate (3×2 mL). The combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude as clear oil (0.076 g, 74%). LC-MS: 705.3 (MH+), retention time: 4.01 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[S:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)(=[O:14])(=[O:13])[NH2:12]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=[N:19][C:18]1[CH:20]=[CH:21][C:15]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:16][CH:17]=1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(N=Cc2ccc(Cl)c(Cl)c2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 3,4-dichlorobenzaldehyde and 4-sulfamoylaniline as starting materials, the title compound was obtained as a white powder (yield 52%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:27][CH3:28])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[C:12]1[N:13](COCC[Si](C)(C)C)[CH:14]=[CH:15][N:16]=1)=[CH:8][CH:7]=[C:6]([Cl:26])[N:5]=2.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[N:3]([CH2:27][CH3:28])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[C:12]1[NH:16][CH:15]=[CH:14][N:13]=1)=[CH:8][CH:7]=[C:6]([Cl:26])[N:5]=2
Reactant: CCn1c(N)c(-c2nccn2COCC[Si](C)(C)C)c(=O)c2ccc(Cl)nc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(N)c(-c2ncc[nH]2)c(=O)c2ccc(Cl)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
2-Amino-7-chloro-1-ethyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-1H-[1,8]naphthyridin-4-one (1.0 g, 2.38 mmol) was dissolved in 30 mL of dichoromethane. 30 mL of trifluoroacetic acid were added and the reaction mixture was stirred at room temperature for 3 h, until analytical HPLC showed complete consumption of the starting material. Solvents were removed under reduced pressure, and ethyl acetate was added to the residue. The solution was washed with saturated aqueous sodium bicarbonate. The formed precipitate was collected by filtration, then put to dry out overnight at 40° C. under vacuum, yielding 574 mg of beige powder.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:9][CH:8]=1>>[Cl:3][CH2:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:9][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cccc(CO)n1
Product: CCOC(=O)c1cccc(CCl)n1
Temperature: 12.5 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (13.8 ml) was added over ˜15 minutes to a stirred solution of ethyl 6-(hydroxymethyl)-2-pyridinecarboxylate (28.5 g) in MDC (200 ml) maintaining the temperature at 10-15° C. using an ice-water bath. On completion of the addition the mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue partitioned between toluene (200 ml)/saturated bicarb (sodium bicarbonate solution, 200 ml). The layers were separated and the organic phase washed with water (150 ml). The solvent was evaporated to leave a pale oil which solidified on standing. (31.3 g).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.[Cl:49][C:50]1[CH:57]=[C:56]([F:58])[CH:55]=[CH:54][C:51]=1[CH2:52][NH2:53]>>[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:53][CH2:52][C:51]2[CH:54]=[CH:55][C:56]([F:58])=[CH:57][C:50]=2[Cl:49])=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1
Reactant: NCc1ccc(F)cc1Cl
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(NCc1ccc(F)cc1Cl)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4-bromo-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 1, Step G) and 2-chloro-4-fluorobenzylamine and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C22H15BrClFN4O3S, 548.0; m/z found, 549/550 [M+H]+, 571/573 [M+Na]+. HPLC (reverse phase): RT=9.86 min. 1H NMR (500 MHz, CDCl3): 11.29 (s, 1H), 8.88 (dd, J=15.3, 6.0 Hz, 2H), 8.57 (dd, J=7.4, 1.4 Hz, 1H), 8.32 (dd, J=8.4, 1.8 Hz, 1H), 8.31 (d, J=1.8 Hz, 1H), 7.93 (d, J=1.8 Hz, 1H), 7.88 (dd, J=8.4, 7.4 Hz, 1H), 7.43 (dd, J=8.5, 6.0 Hz, 1H), 7.16 (dd, J=8.3, 2.6, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.07 (dd, J=8.5, 2.1 Hz, 1H), 7.01 (ddd, J=8.2, 8.2, 2.5 Hz, 1H), 6.38-6.33 (m, 1H), 4.57 (d, J=6.0 Hz, 1H).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH3:14])[C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])=[N+:2]=[N-:3].[C:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)#[CH:16]>CCO>[CH3:14][C:11]1[CH:10]=[C:6]([CH:5]=[C:4]([N:1]2[CH:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[N:3]=[N:2]2)[C:12]=1[CH3:13])[C:7]([OH:9])=[O:8]
Reactant: C#Cc1cccnc1
Reactant: Cc1cc(C(=O)O)cc(N=[N+]=[N-])c1C
Solvent: CCO
Product: Cc1cc(C(=O)O)cc(-n2cc(-c3cccnc3)nn2)c1C
Yield: 32.7 %

Procedure:
A suspension of 100 mg (0.52 mmol) of 3-azido-4,5-dimethyl benzoic acid (U.S. Ser. No. 04/102,492), 54 mg (0.52 mmol) of 3-ethynyl pyridine, and 200 μL of EtOH was heated to 120° C. in a sealed tube for 12 h. The mixture was cooled and diluted with 500 μL of EtOH. The mixture was filtered and the solids were washed with EtOH (3×0.5 mL). The solids were dried to provide 50 mg of 3,4-dimethyl-5-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzoic acid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18](Cl)[C:13]=3[C:12]([Br:20])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)(C)(C)C>[C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[C:13]=3[C:12]([Br:20])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCNCC1
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2c(Cl)ncnc21
Solvent: CC(C)(C)O
Product: O=S(=O)(c1ccccc1)n1cc(Br)c2c(N3CCCCC3)ncnc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A mixture of 2.0 g (5.37 mmol) of the product from Method U and 1.1 g (13.4 mmol) of piperidine in 10 mL of tert-butanol was heated with stirring at 60° C. for 2 h. After cooling to room temperature, the reaction mixture was partitioned between dichloromethane (25 mL) and water (25 mL). The dichloromethane layer was dried over sodium sulfate (Na2SO4) and concentrated to dryness in vacuo affording 2.2 g (97%) of the title compound. 1H NMR (400 MHz) (CDCl3) δ: 1.63-1.72 (m, 6H), 3.54-3.57 (m, 4H), 7.53 (t, 2H, J=2.0 Hz), 7.60 (s, 1H), 7.61 (t, 1H, J=2.0 Hz), 8.17-8.20 (m, 2H), 8.43 (s, 1H). LRMS: 422.7, 420.7 (M+1).
Reaction SMILES: [CH3:1][C:2]1([N:8]2[C:19]3[C:11](=[CH:12][N:13]=[C:14]4[C:18]=3[CH:17]=[CH:16][NH:15]4)[N:10]=[N:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:20](#[N:23])[CH:21]=[CH2:22]>C(O)C>[CH3:1][C:2]1([N:8]2[C:19]3[C:11](=[CH:12][N:13]=[C:14]4[C:18]=3[CH:17]=[CH:16][NH:15]4)[N:10]=[N:9]2)[CH2:7][CH2:6][N:5]([CH2:22][CH2:21][C:20]#[N:23])[CH2:4][CH2:3]1
Reactant: CC1(n2nnc3cnc4[nH]ccc4c32)CCNCC1
Reactant: C=CC#N
Solvent: CCO
Product: CC1(n2nnc3cnc4[nH]ccc4c32)CCN(CCC#N)CC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 71.3 %

Procedure:
A mixture of 1-(4-methyl-piperidin-4-yl)-1,6-dihydro-1,2,3,5,6-pentaaza-as-indacene (75.0 mg, 0.29 mmol) and acrylonitrile (95.5 μL, 1.45 mmol) in ethanol was stirred at 80° C. for 5 hours. The solvent was evaporated under vacuum and the residue purified by column chromatography on silica gel (gradient: 0 to 4.5% [2M NH3 in methanol] in DCM) to afford 64.0 mg (71%) of 3-[4-methyl-4-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-piperidin-1-yl]-propionitrile. LCMS (Method A, ESI): RT=1.91 min, m+H=310.3; 1H NMR (400 MHz, DMSO) δ: 12.41 (s, 1H), 9.04 (s, 1H), 7.59 (t, 1H), 7.08 (m, 1H), 2.85 (m, 2H), 2.66 (m, 4H), 2.58 (m, 2H), 2.49 (m, 2H), 2.11 (m, 2H), 1.85 (s, 3H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[NH:6][CH2:5]2.[Si:14]([O:21][C@:22]1([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([SH:35])[CH:30]=2)[CH2:27][CH2:26][O:25][C@@H:24]([CH3:28])[CH2:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>>[Si:14]([O:21][C@:22]1([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([S:35][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([CH3:12])[C:7](=[O:13])[NH:6][CH2:5]4)[CH:30]=2)[CH2:27][CH2:26][O:25][C@@H:24]([CH3:28])[CH2:23]1)([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:16])[CH3:15]
Reactant: C[C@H]1C[C@@](O[Si](C)(C)C(C)(C)C)(c2cccc(S)c2)CCO1
Reactant: CN1C(=O)NCc2cc(I)ccc21
Product: C[C@H]1C[C@@](O[Si](C)(C)C(C)(C)C)(c2cccc(Sc3ccc4c(c3)CNC(=O)N4C)c2)CCO1
Yield: 41 %

Procedure:
using an analogous procedure to that described in Example 5, 6-iodo-1-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline was reacted with (2S,4R)-4-(tert-butyldimethylsilyloxy)-4-(3-mercaptophenyl)-2methyltetrahydropyran to give (2S,4R)-4-(tert-butyldimethylsilyloxy)2-methyl-4-[3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-6-ylthio)phenyl]tetrahydropyran in 41% yield as a foam. A mixture of the material so formed (0.12 g) and tetrabutylammonium fluoride (1M in THF, 5 ml) was stirred and heated to reflux for 2 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic solution was dried (Na2SO4) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained (2S,4R)-4-hydroxy-2-methyl-4-[3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-6-ylthio)phenyl]tetrahydropyran (0.07 g) as a gum;