Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[OH-].[Na+]>O1CCOCC1.C(Cl)Cl>[Cl:20][C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=[CH:17][N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Clc1nccnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (10 g, 33.4 mmol, 1 eq) in 1,4-dioxane (160 mL) add a 4 M solution of hydrochloric acid in 1,4-dioxane (80 mL, 0.3 mol, 10 eq) and stir under nitrogen at room temperature overnight. Dilute with DCM (600 mL) then basify with 50% aqueous sodium hydroxide. Add water (100 mL), separate the layers and extract the aqueous twice with DCM (200 mL). Combine the organic extracts, wash with saturated aqueous sodium chloride, dry (magnesium sulfate), filter, and concentrate to give 3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl as a viscous oil which solidifies on standing (6.39 g, 96%). MS (ES): m/z=199.1, 201.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=2)[N:3]=1.O1CCCC1.[CH:24]1([Mg]Br)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[Cl-].[NH4+]>O1CCCC1>[CH:24]1([CH:7]([C:6]2[C:2]([CH3:1])=[N:3][N:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][N:10]=3)[CH:5]=2)[OH:8])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Br[Mg]C1CCCCC1
Reactant: Cc1nn(-c2ccc(C(F)(F)F)cn2)cc1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(O)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of 3-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carbaldehyde (2.6 g) synthesized above in tetrahydrofuran (40 mL) was added dropwise 1M cyclohexylmagnesium bromide tetrahydrofuran solution (15 mL) at 0° C. After stirring at 0° C. for 1 hr, aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (2.0 g, 36%) as a colorless solid.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#N)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].C([Al+]CC(C)C)C(C)C.C[OH:35].O>C1COCC1>[OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:35])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC(O)c1cccc(OCc2cccc(C#N)c2)c1
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC(O)c1cccc(OCc2cccc(C=O)c2)c1
Yield: 30 %

Procedure:
To a solution of 3-[[3-(1-hydroxyhexyl)phenoxy]methyl]benzonitrile (10.0 g.) in THF was added diisobutylaluminum hydride (15 g.) and the reaction was refluxed overnight. Methanol (10.2 ml) was slowly added followed by water (5.7 ml). The mixture was filtered and the filtrate was concentrated to an oil. The oil was dissolved in chloroform. The solution was washed with 5% aqueous hydrochloric acid (4 times), dried (MgSO4) and concentrated to an oil (3.0 g., 30% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2].S(=O)(=O)(O)O.[Br:19]Br>S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Ag+2].CO>[Br:19][C:12]1[CH:11]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: BrBr
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
A mixture of methyl 3-nitrobenzoate (122 g, 674 mmol), silver sulphate (100 g, 320.7 mmol) and concentrated sulfuric acid (750 mL) was stirred mechanically and heated at 90° C. To this mixture was added bromine (37 mL), dropwise, over 2 h. The reaction was stirred another hour, cooled and filtered. The filtrate was mixed with 2 L water and 1 Kg crushed ice. The solid was filtered and dried to afford a mixture of the desired methyl ester and free acid hydrolysis product. The mixture was taken up into methanol (1 L), treated with 10 drops concentrated sulfuric acid and refluxed for 12 h. The reaction mixture was allowed to cool and the crystals that were deposited were collected and dried in a desiccator to afford 126 g (72% yield) of methyl 3-bromo-5-nitrobenzoate (EX-119A): 1H NMR (300 MHz, CDCl3) δ 8.65 (s, 1H), 8.44 (s, 1H), 8.37 (s, 1H), 3.94 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C@:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[C:4]([F:31])[CH:3]=1.[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1.C(=O)([O-])[O-].[K+].[K+]>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>[Si:24]([O:23][CH2:22][C@:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:36]5[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=5)=[CH:3][C:4]=4[F:31])[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@]1(C)Cc2nnc(C3(c4ccc(Br)cc4F)CC3)n2CCS1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: Cn1cc(-c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)c(F)c2)cn1
Temperature: 25 °C
Yield: 100.2 %

Procedure:
A solution of the compound (3.86 g, 7.32 mmol) obtained in Example 81-1), 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (1.68 g, 8.06 mmol), tetrakis(triphenylphosphine)palladium(0) (850 mg, 0.73 mmol), and potassium carbonate (2.02 g, 14.65 mmol) in 1,2-dimethoxyethane (50 mL) and water (25 mL) was heated to reflux overnight with stirring. The reaction mixture was cooled to room temperature, water (20 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 70:30) to obtain the title compound (3.87 g, quant.) as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH:9]([C:10]([O:12][CH3:13])=[O:11])[C:2]=12.C1C=C(Cl)C=C(C(OO)=[O:22])C=1>ClCCl>[N+:1]1([O-:22])[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH:9]([C:10]([O:12][CH3:13])=[O:11])[C:2]=12
Reactant: COC(=O)C1CCc2cccnc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)C1CCc2ccc[n+]([O-])c21
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of 1.53 g (8.47 mmol) of methyl 6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxylate from step A above in 30 mL of dichloromethane was added 1.61 g (9.31 mmol) of m-CPBA. The solution was allowed to stir for 1 h and then quenched with 50 mL of a saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous phase extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo to yield the title compound as a light brown solid that was used without purification. LC-MS: m/z (E/S) 194.2 (MH)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([OH:8])=O)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]([CH2:40][C:41]2[CH:50]=[CH:49][C:44]([C:45]([NH:47]O)=[NH:46])=[CH:43][CH:42]=2)[CH:32]2[CH2:38][CH2:37][CH2:36][CH2:35][NH:34][C:33]2=[O:39])(=[O:30])=[O:29])=[CH:24][CH:23]=1.O>CN(C)C=O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([C:45]3[N:46]=[C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[O:8][N:47]=3)=[CH:49][CH:50]=2)[CH:32]2[CH2:38][CH2:37][CH2:36][CH2:35][NH:34][C:33]2=[O:39])(=[O:29])=[O:30])=[CH:24][CH:23]=1
Reactant: N=C(NO)c1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: CC(=O)OCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1nc(-c2ccc(CN(C3CCCCNC3=O)S(=O)(=O)c3ccc(Cl)cc3)cc2)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.1 %

Procedure:
To a solution of acetoxyacetic acid (0.13 g, 1.10 mmol) in 5 ml dimethylformamide were added 1,1′-carbonyl-diimidazole (0.18 g, 1.10 mmol). The mixture was stirred at room temperature for 10 minutes, heated to 40° C. for a few minutes and cooled to room temperature. 4-{[(4-Chloro-benzenesulfonyl)-(2-oxo-azepan-3-yl)-amino]-methyl}-N-hydroxy-benzamidine (0.45 g, 1.00 mmol) was added and the mixture was stirred at 100° C. for 5 hours and then poured into water. Filtration and chromatography on silicagel with ethylacetate/heptane (3/1) yielded 0.15 g (29%) acetic acid 3-(4-{[(4-chloro-benzenesulfonyl)-(2-oxo-azepan-3-yl)-amino]-methyl}-phenyl)-[1,2,4]oxadiazol-5-ylmethyl ester as white solid, MS: m/e (%)=533.0 (MH+, 100).
Reaction SMILES: ClC(Cl)(Cl)COC(=O)[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:32])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=3)=[CH:16][C:15]=2[NH:33][C:34]2[C:35]3[CH:43]=[CH:42][C:41]([CH:44]([CH3:46])[CH3:45])=[N:40][C:36]=3[N:37]=[CH:38][N:39]=2)=[CH:9][CH:8]=1.[OH-].[Na+].Cl>O1CCCC1.O>[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][N:23]=3)=[O:32])=[CH:16][C:15]=2[NH:33][C:34]2[C:35]3[CH:43]=[CH:42][C:41]([CH:44]([CH3:46])[CH3:45])=[N:40][C:36]=3[N:37]=[CH:38][N:39]=2)=[CH:9][CH:8]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(C(F)(F)F)cn4)ccc3Sc3ccc(NC(=O)OCC(Cl)(Cl)Cl)cc3)ncnc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(C(F)(F)F)cn4)ccc3Sc3ccc(N)cc3)ncnc2n1
Temperature: 60 °C

Procedure:
To a solution of the product of Example 175B in tetrahydrofuran and water (1:1) was added 1 M NaOH (5 equiv). The solution was heated at 60° C. for 40 minutes, cooled, adjusted to pH 6 with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product was purified by silica gel chromatography eluting with 2% methanol in dichloromethane to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=6.62 Hz, 6 H) 3.15-3.29 (m, 1 H) 5.63 (s, 2 H) 6.65 (d, J=8.46 Hz, 2 H) 6.84 (d, J=8.46 Hz, 1 H) 7.16 (d, J=8.46 Hz, 2 H) 7.64 (d, J=8.46 Hz, 1 H) 7.90 (d, J=6.99 Hz, 1 H) 8.06 (s, 1 H) 8.23 (dd, J=8.82, 1.47 Hz, 1 H) 8.39 (d, J=8.82 Hz, 1 H) 8.59 (s, 1 H) 8.76 (s, 1 H) 8.89 (d, J=8.46 Hz, 1 H) 10.14 (s, 1 H) 11.20 (s, 1 H).
Reaction SMILES: Cl.[CH2:2]([NH2:5])[C:3]#[CH:4].N1C=CC=CC=1.[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]>O1CCCC1>[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:5][CH2:2][C:3]#[CH:4])=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: C#CCN
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C#CCNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
To a stirred solution of propargylamine hydrochloride (5.0 g, 54.6 mmol) and pyridine (7.8 g, 99.1 mmol) in tetrahydrofuran (30 mL) was added 4-nitro-benzoylchloride (9.2 g, 49.6 mmol) in tetrahydrofuran (20 mL) and the mixture was heated at reflux for 16 h. The mixture was allowed to cool to ambient temperature and concentrated in vacuo. The crude residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water, brine, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to afford 4-nitro-N-prop-2-ynyl-benzamide (7.74 g, 77%) as a solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH:13][NH2:14])=[O:12])[CH:9]=2)[CH:4]=[CH:3]1.[OH-].[K+].[C:17](=S)=[S:18].Cl>O.CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:12][C:17]([SH:18])=[N:14][N:13]=3)[CH:9]=2)[CH:4]=[CH:3]1
Reactant: Cn1ccc2ccc(C(=O)NN)cc21
Reactant: S=C=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1ccc2ccc(-c3nnc(S)o3)cc21
Reaction time: 0.5 h

Procedure:
A mixture of 1-methyl-1H-indole-6-carboxylic acid hydrazide (2.8 g, 14.8 mmol), potassium hydroxide (0.91 g, 16.3 mmol) and methanol (50 ml) was stirred at room-temperature for 30 min. Carbon disulfide (2.25 g, 29.6 mmol) was added and the mixture was stirred for 15 h at reflux. The mixture was allowed to cool to room-temperature, water was added, pH was adjusted to 3 by adding concentrated aqueous hydrochloric acid. The crystalline product was isolated by filtration and washed with water. Yield 2.75 g (80%).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12]COC)[CH:3]=1.[CH3:16][CH:17]([S-:19])[CH3:18].[K+]>>[CH:17]([S:19][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1)([CH3:18])[CH3:16]
Reactant: COCOc1cc(F)ccc1C(=O)OC
Reactant: CC(C)[S-]
Agent: [K+]
Product: COC(=O)c1ccc(SC(C)C)cc1O

Procedure:
Using a procedure analogous to Example 66-A, methyl 4-fluoro-2-(methoxymethoxy)benzoate and potassium 2-propanethiolate gave the title compound.
Reaction SMILES: [C:1]1([C:11]2([C:16]#N)[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=[O:30])C>ClCCl.CCCCCC>[C:1]1([C:11]2([CH:16]=[O:30])[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: N#CC1(c2cccc3ccccc23)CCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Product: O=CC1(c2cccc3ccccc23)CCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 98 %

Procedure:
To a solution of 1-naphthalen-1-yl-cyclopentanecarbonitrile (338) (10.5 g, 47.4 mmol) in dichloromethane (150 mL) was added dropwise diisobutylaluminium hydride (25% in toluene, 67.5 mL, 118.6 mmol) at −78° C. and stirred for 2 h at the same temperature (silica TLC, 5% ethyl acetate in hexane; Rf=0.6). The reaction mixture was quenched with a saturated aqueous solution of potassium sodium tarterate (35 mL) and stirred for 17 h at room temperature. The reaction mixture was filtered and the residue was washed with dichloromethane. The organic phase was separated and the aqueous part was back extracted with dichloromethane (100 mL). The combined organic part was dried, filtered and concentrated in vacuo to get a crude mass which was purified by CombiFlash using gradient eluent mixture of ethyl acetate and hexane to obtain pure 1-naphthalen-1-yl-cyclopentanecarbaldehyde (339) (10.4 g, 98%) as a colorless sticky liquid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].[CH2:22]([S:29][C:30]([CH3:34])([CH3:33])[CH2:31][NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[CH2:22]([S:29][C:30]([CH3:34])([CH3:33])[CH2:31][NH:32][C:19]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])=[O:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(CN)SCc1ccccc1
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CNC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1)SCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.70 g), 2-(benzylthio)-2-methylpropylamine (0.47 g), 1H-1,2,3-benzotriazol-1-ol (0.35 g) and N,N-dimethylformamide (15 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.50 g) at 0° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (0.86 g, yield 77%) was obtained as yellow crystals from a fraction eluted with ethyl acetate-hexane (1:9-42:3, volume ratio). melting point 170-171° C.
Reaction SMILES: FC1C(O[C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[C:13]([F:17])=[C:12]([F:18])[C:11]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[Cl:27])=C(F)C(F)=C(F)C=1F.[CH3:33][C:34]1([CH3:42])[O:38][CH:37]([CH2:39][O:40][NH2:41])[CH2:36][O:35]1.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:16][C:14]1[C:13]([F:17])=[C:12]([F:18])[C:11]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[Cl:27])=[C:10]([CH:15]=1)[C:9]([NH:41][O:40][CH2:39][CH:37]1[CH2:36][O:35][C:34]([CH3:42])([CH3:33])[O:38]1)=[O:28]
Reactant: CC1(C)OCC(CON)O1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1cc(Cl)c(F)c(F)c1Nc1ccc(I)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)OCC(CONC(=O)c2cc(Cl)c(F)c(F)c2Nc2ccc(I)cc2Cl)O1
Reaction time: 20 h
Yield: 67.9 %

Procedure:
To a stirring solution of 5-chloro-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-benzoic acid pentafluorophenyl ester (5.80 g, 9.51 mmol) is freshly distilled tetrahydrofuran (40 mL) was added O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (1.54 g, 10.5 mmol) and diisopropylethylamine (1.8 mL, 10.5 mmol). After 20 hours, the mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with water and twice with saturated brine solution. The organic layer was collected, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by crystallization in ethyl acetate/hexanes affording 5-chloro-2-(2-chloro-4-iodo-phenylamino)-N-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,4-difluoro-benzamide as a white solid (3.7 g, 67.9%): 1H NMR (400 MHz; CDCl3) δ 9.82 (bs, 1H), 8.10 (bs, 1H), 7.68 (s, 1H), 7.47 (bs, 1H), 7.40-7.43 (m, 1H), 6.44-6.47 (m, 1H), 4.40 (bs, 1H), 3.97-4.20 (m, 3H), 3.77 (t, 1H, J=8.0), 1.44 (s, 3H), 1.37 (s, 3H); MS (APCI+)=573.0/575.0.
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[F:19][C:20]([F:50])([F:49])[C:21]1[CH:34]=[CH:33][C:32]2[S:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH2:35][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][C:41]([O:45][CH2:46][CH2:47][OH:48])([CH3:44])[CH2:40][CH2:39]3)[C:23]=2[CH:22]=1.C(N(CC)CC)C>C1C=CC=CC=1>[F:49][C:20]([F:19])([F:50])[C:21]1[CH:34]=[CH:33][C:32]2[S:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH2:35][CH2:36][CH2:37][N:38]3[CH2:39][CH2:40][C:41]([O:45][CH2:46][CH2:47][O:48][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([CH3:44])[CH2:42][CH2:43]3)[C:23]=2[CH:22]=1
Reactant: CC1(OCCO)CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCC(=O)OCCOC1(C)CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.7 %

Procedure:
A solution of 3.3 g of hexadecanoic acid chloride in 20 ml of anhydrous benzene was added dropwise at 10° C to a solution of 5 g of 2-trifluoromethyl-10-[3-(4-{2-hydroxyethoxy}-4-methyl-piperidino)-propyl]-phenothiazine in 50 ml of anhydrous benzene containing 1.2 g of triethylamine and the mixture was stirred for 20 hours at room temperature. The mixture was washed with water and then was stirred for 4 hours with 100 ml of an aqueous saturated sodium bicarbonate solution. The organic phase was decanted and concentrated. The oily residue was subjected to chromatography over silica gel with a 98-2 benzene-triethylamine mixture as eluant to obtain 6.4 g of 2-trifluoromethyl-10-[3-(4-{2-hexadecanoyloxyethoxy}-4-methyl-piperidino)-propyl]-phenothiazine in the form of a yellow oil.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:11]=[C:12]([C:17]([N+:20]([O-:22])=[O:21])=[CH:18][N:19]=1)[C:13]([O:15]C)=O)[CH2:3][CH2:2]2.[CH3:23][NH2:24]>CO>[N:1]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[N:4]([C:10]1[CH:11]=[C:12]([C:17]([N+:20]([O-:22])=[O:21])=[CH:18][N:19]=1)[C:13]([NH:24][CH3:23])=[O:15])[CH2:3][CH2:2]2
Reactant: COC(=O)c1cc(N2CCN3CCC2CC3)ncc1[N+](=O)[O-]
Reactant: CN
Solvent: CO
Product: CNC(=O)c1cc(N2CCN3CCC2CC3)ncc1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
Methyl 2-(1,4-diazabicyclo[3.2.2]nonan-4-yl)5-nitroisonicotinate (Intermediate 27A) (0.1 g, 0.46 mmol) and 2M methylamine in methanol (5 mL) were sealed in a tube and heated at 90° C. overnight. The reaction mixture was concentrated and purified by a 10 g silica column eluting with 0-10% methanol in DCM to afford 2-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-methyl-5-nitroisonicotinamide (96 mg, 0.31 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH3:13])[C:3]=1[C:4]#[N:5].[S:14](Cl)(=[O:17])(=[O:16])[NH2:15]>CC(N(C)C)=O>[S:14]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH3:13])[C:3]=1[C:4]#[N:5])(=[O:17])(=[O:16])[NH2:15]
Reactant: NS(=O)(=O)Cl
Reactant: CCCOc1cccc(N)c1C#N
Solvent: CC(=O)N(C)C
Product: CCCOc1cccc(NS(N)(=O)=O)c1C#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.2 %

Procedure:
To a solution of 2-amino-6-propoxybenzonitrile (Example 111b) (4.23 g, 24.01 mmol) in dimethylacetamide (20 mL) under N2 was added sulfamoyl chloride (5.56 g, 48.02 mmol). The reaction mixture was then stirred at room temperature under nitrogen for 4 hours. Upon completion, the reaction was quenched by addition of ice/water (250 mL). The resulting precipitate was collected by filtration, rinsed with water and dried to yield 2-sulfamoylamino-6-propoxybenzonitrile (4.73 g, 77%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 1.01 (d, J=7.2 Hz, 3H), 1.76 (sext, J=7.2 Hz, 2H), 4.08 (t, J=6.8 Hz, 2H), 6.96 (d, J=8.5 Hz, 1H), 7.15 (t, J=8.5 Hz, 1H), 7.28 (br s, 2H), 7.57 (d, J=8.5 Hz, 1H), 9.46 (s, 1H). MS 256 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[CH3:13][C:14]1([CH3:36])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:23][CH:22]=2)[O:15]1>C1COCC1.C(=O)([O-])[O-].[Ag+2].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>[CH3:19][C:18]1([CH3:20])[C:14]([CH3:13])([CH3:36])[O:15][B:16]([C:21]2[CH:26]=[CH:25][C:24]([C:2]3[CH:7]=[CH:6][C:5]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=3)=[CH:23][CH:22]=2)[O:17]1
Reactant: CS(=O)(=O)Cc1ccc(Br)cc1
Reactant: CC1(C)OB(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)OC1(C)C
Agent: [Ag+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(-c3ccc(CS(C)(=O)=O)cc3)cc2)OC1(C)C
Temperature: 80 °C

Procedure:
1-bromo-4-((methylsulfonyl)methyl)benzene (1.5 g, 6.02 mmol), 1,4-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene (4.97 g, 15.05 mmol), and silver carbonate (1.826 g, 6.62 mmol) were dissolved in THF (60.2 ml) and sparged with N2 for 15 min. Then Pd(PPh3)4 (0.348 g, 0.301 mmol) was added and the reaction was heated to 80° C. overnight. The reaction was then cooled to rt, filtered through Celite™ and concentrated in vacuo. The resulting residue was purified by column chromatography on a Biotage™ 50 g column by eluting with 5% to 50% EtOAc:Hex to yield the desired product. 1H NMR δ (ppm) 7.83 (d, 2H), 7.69 (d, 2H), 7.64 (d, 2H), 7.54 (d, 2H), 4.46 (s, 2H), 2.89 (s, 3H), 1.4 (12H).