Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[CH:4]=1.[C-:16]#[N:17].[K+]>CN(C=O)C.O>[CH:13]1([CH2:12][O:11][C:5]2[CH:4]=[C:3]([CH2:2][C:16]#[N:17])[CH:8]=[CH:7][C:6]=2[O:9][CH3:10])[CH2:15][CH2:14]1
Reactant: COc1ccc(CCl)cc1OCC1CC1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CC#N)cc1OCC1CC1
Temperature: 60 °C
Yield: 87.4 %

Procedure:
A mixture of 4-(chloromethyl)-2-(cyclopropylmethoxy)-1-methoxybenzene (7.4 g) in DMF (68 ml) was stirred at 60° C. A mixture of potassium cyanide (4.26 g) in water (3.4 ml), previously heated to 80° C., was added dropwise. The resulting reaction mixture was stirred for 30 minutes at 60° C. The reaction mixture was cooled, treated with water (47 ml), and extracted with DIPE. The separated organic layer was dried (Na2SO4), filtered, and the solvent was evaporated, yielding 6.2 g (85%) of 3-(cyclopropylmethoxy)-4-methoxybenzeneacetonitrile (interm. 16).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].CN(C)[CH:33]=[O:34]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[C:14]=2[CH:33]=[O:34])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccc(F)cc1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)c(C=O)n1-c1ccc(F)cc1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
2-chloro-4-[1-(4-fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine (2.0 g, 6.42 mmol) was dissolved in 50 mL THF and cooled to −70° C. Lithiumdiisopropylamide 2M/THF (4.8 ml, 9.6 mmol) was added, and the mixture stirred for 15 min at −70° C. Dimethylformamide (0.69 ml, 9.0 mmol) was added and stirring was continued at −70° C. for 3 hrs. The reaction mixture was quenched with sat. NaHCO3− solution and extracted with water and ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethylacetate 1:2). The desired compound was obtained as a yellow solid (220 mg, 10%), MS: m/e=340.0 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:26])[C:4]([O:6][CH3:7])=[O:5].BrCC1C=CC(C2C=CC([N+]([O-])=O)=CC=2)=CC=1C(OC)=O.Cl.COC(=O)[C@@H](C(C)C)N>>[CH3:1][CH:2]([CH3:27])[C@@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:26])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2C1=O
Agent: COC(=O)[C@H](N)C(C)C
Agent: COC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)ccc1CBr
Agent: Cl
Product: COC(=O)[C@@H](C(C)C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2C1=O
Yield: 77 %

Procedure:
The compound of example 538 was prepared analogous to compound of example 5 by reaction of compound of example 4 with D-valine methyl ester hydrochloride.
Reaction SMILES: Cl[S:2]([OH:5])(=O)=[O:3].S(Cl)(Cl)=O.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH:15]1[CH:16]=[C:11]([Cl:10])[CH:12]=[C:13]([S:2]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([Cl:10])[CH:12]=2)(=[O:5])=[O:3])[CH:14]=1
Reactant: O=S(=O)(O)Cl
Reactant: Clc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=S(=O)(c1cccc(Cl)c1)c1cccc(Cl)c1
Temperature: 195 °C
Yield: 197.3 %

Procedure:
The filtrate from Example 1 is freed from methoanol by distillation, the residue is returned to the reaction vessel, and 562.5 g (5 mol) of chlorobenzene is added. chlorobenzenesulfonic acid chloride is formed by adding 476 g (4 mol) of chlorosulfonic acid and 466 g (4 mol) of thionyl chloride, the mixture is heated to 195° C., and 337.5 g (3 mol) of chlorobenzene is added at such a rate that the temperature does not fall. the charge is subsequently treated as described in Example 1, giving 850 g (74% yield) of dichlorodiphenyl sulfone of melting point 149°-150° C. Gas-chromatographic analysis of the product gives 99.6% 4,4'-isomer, 0.3% 2,4'-isomer, and 0.1% 3,4'-isomer.
Reaction SMILES: [NH:1]1[C:11]2C(=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[C:12]([OH:18])(=[O:17])[CH2:13][C:14](O)=O>C(O)(=O)C.C([O-])(O)=O.[Na+]>[OH:3][C:2]1[CH:4]=[C:13]([C:12]([OH:18])=[O:17])[C:14]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:1]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=C1Nc2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)c1cc(O)nc2ccccc12
Yield: 40 %

Procedure:
A stirred suspension of isatin, also called 1H-indole-2,3-dione, available from Sigma-Aldrich, (3.80 g, 25 mmol) and malonic acid (8.06 g, 77 mmol) in acetic acid (150 ml) was refluxed for 16 h. Acetic acid was removed under reduced pressure, the residue was suspended in water (150 ml), filtered and washed with water (100 ml) to give a brown solid. The solid was stirred in NaHCO3 saturated aqueous solution (200 ml) and the insoluble material was filtered off. The filtrate was acidified to pH 1-2 with concentrated HCl and the precipitate was filtered, washed with water and dried to obtain the desired product as a grey solid (2.2 g, 11.6 mmol, Yield 40%).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[N:19]([CH3:30])[C:20](=[O:29])[C:21]5[CH:27]=[CH:26][NH:25][C:24](=[O:28])[C:22]=5[N:23]=4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:32]([F:37])([F:36])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[N:19]([CH3:30])[C:20](=[O:29])[C:21]5[CH:27]=[CH:26][N:25]=[C:24]([O:28][CH:32]([F:37])[F:36])[C:22]=5[N:23]=4)=[CH:14][CH:13]=3)[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cn1c(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)nc2c(=O)[nH]ccc2c1=O
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cn1c(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)nc2c(OC(F)F)nccc2c1=O
Yield: 8.5 %

Procedure:
2-{4-[(1-Cyclobutylpiperidin-4-yl)oxy]phenyl}-3-methyl-3,7-dihydropyrido[3,4-d]pyrimidine-4,8-dione (50 mg, 0.123 mmol), sodium chlorodifluoroacetate (19 mg, 0.13 mmol) and potassium carbonate (34 mg, 0.25 mmol) were heated under reflux in acetonitrile (1 mL) for 6 hours. Sodium chlorodifluoroacetate (19 mg, 0.13 mmol) and acetonitrile (1 mL) were further added to the reaction solution and heated under reflux for 18 hours. After restored to room temperature, the reaction solution was diluted with ethyl acetate, washed with water and saturated saline water in that order, and the organic layer was dried with magnesium sulfate. The solvent was evaporated off, and the residue was purified through silica gel thin-layer chromatography (chloroform/methanol=9/1) to obtain a low-polar compound, 2-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-8-(difluoromethoxy)-3-methylpyrido[3,4-d]pyrimidin-4(3H)-one (4.8 mg, 9%), and a high-polar compound, 2-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-7-(difluoromethyl)-3-methyl-3,7-dihydropyrido[3,4-d]pyrimidine-4,8-dione (11.4 mg, 21%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:24]([O:26][C:27](=[O:30])[CH2:28]Br)[CH3:25]>CN(C=O)C>[CH2:24]([O:26][C:27](=[O:30])[CH2:28][O:17][C:11]1[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=1[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH3:25]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Cl)cc1CNC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A mixture of N-t-butoxycarbonyl-2-hydroxy-5-chlorobenzylamine (730 mg, 2.83 mmol), Cs2CO3 (923 mg, 2.83 mmol) and ethylbromoacetate (0.314 ml, 2.83 mmol) in DMF (5 ml) was stirred for 2 h. The crude reaction mixture was partitioned between ethyl acetate and water and the organic layer was washed with brine, dried (Na2SO4) and evaporated in vacuo to an oil which was used for the next step.
Reaction SMILES: FC1C=CC=CC=1NC(=S)NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44](=[S:70])[NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([O:65]C)=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[CH:48][CH:47]=2)=[CH:39][CH:38]=1>>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44](=[S:70])[NH:45][C:46]2[CH:47]=[CH:48][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:68])[CH3:69])[C:63]([OH:65])=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[CH:50][CH:51]=2)=[CH:39][CH:38]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccc(OC)cc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Product: COc1ccc(NC(=S)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)cc2)cc1
Yield: 85 %

Procedure:
The compound of example 58 was prepared analogous to compound of example 52 by hydrolysis of compound of example 57.
Reaction SMILES: [NH2:1][C:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[N:4]([CH3:9])[C:3]=1[C:10]([O:12]CC)=[O:11].[OH-].[K+:16]>CO>[NH2:1][C:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[N:4]([CH3:9])[C:3]=1[C:10]([O-:12])=[O:11].[K+:16]
Reactant: CCOC(=O)c1c(N)c(C)c(C)n1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(N)c(C(=O)[O-])n(C)c1C

Procedure:
36.6 g (0.187 mole) of ethyl 3-amino-1,4,5-trimethyl-1H-pyrrole-2-carboxylate and 11.4 g (0.213 mole) of potassium hydroxide are dissolved in 200 ml of methanol, and the obtained solution is boiled under reflux for 4 hours. The resulting solution is concentrated to dryness and used, without further purification, for the next reaction.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][N:13]=[C:14]([Cl:17])[CH:15]=2)[N:10]=[CH:9][CH:8]=1)(=O)=O.[NH:20]1[CH2:25][CH2:24][CH2:23][C@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][N:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[N:20]1[CH2:25][CH2:24][CH2:23][C@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]1
Reactant: O=S(=O)(Oc1ccnc2cnc(Cl)cc12)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccnc3cnc(Cl)cc23)C1
Yield: 61 %

Procedure:
A solution of 6-chloro-1,7-naphthyridin-4-yl trifluoromethanesulfonate (1.0 equiv.), (S)-tert-butyl piperidin-3-ylcarbamate (1.0 equiv.) and DIEA (1.5 equiv.) in CH2Cl2 (0.3 M) was stirred at rt for 120 hours. The solution was partitioned between EtOAc and Na2CO3(sat.). Upon separation, the organic layer was washed with NaCl(sat.), dried over MgSO4, concentrated and purified by silica gel chromatography (EtOAc eluant) to yield (S)-tert-butyl 1-(6-chloro-1,7-naphthyridin-4-yl)piperidin-3-ylcarbamate (61%). LC/MS=363.2 (M+H), LC=2.47 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[NH:10][C:9]2=O)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:20]>O=P(Cl)(Cl)Cl>[Cl:20][C:9]1[C:8]2[C:13](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=2)[N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[N:10]=1
Reactant: O=c1[nH]c(C(F)(F)F)nc2c([N+](=O)[O-])cccc12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc2c(Cl)nc(C(F)(F)F)nc12
Yield: 186.7 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-7, step-2 using 8-nitro-2-(trifluoromethyl)quinazolin-4(3H)-one (500 mg, 1.93 mmol) and PCl5 (477 mg, 2.32 mmol) in POCl3 (2.5 mL) to afford 1.0 g of the title product.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH2:10][CH2:11][CH3:12])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:14][C:15]([C@H:18]1[CH2:22][CH2:21][NH:20][C@H:19]1[CH3:23])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:1][C:2]1[C:9]([CH2:10][CH2:11][CH3:12])=[C:8]([N:20]2[CH2:21][CH2:22][C@H:18]([C:15]([OH:14])([CH3:17])[CH3:16])[C@@H:19]2[CH3:23])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Reactant: CCCc1c(F)ccc(C#N)c1Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CCCc1c(N2CC[C@H](C(C)(C)O)[C@@H]2C)ccc(C#N)c1Cl

Procedure:
Using 2-chloro-4-fluoro-3-propylbenzonitrile (538 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (615 mg) and lithium carbonate (259 mg), the title compound was obtained as a yellow solid (yield: 69 mg) by an operation similar to that in Example 3.
Reaction SMILES: [F:1][S:2]([C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][CH:31]=1)[C:8]([C:10]1[S:14][C:13]([NH:15]C(OCC(Cl)(Cl)Cl)=O)=[C:12]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:11]=1)=[O:9])(=[O:4])=[O:3]>[Zn].C(O)(C)C>[NH2:15][C:13]1[S:14][C:10]([C:8](=[O:9])[C:7]2[CH:29]=[CH:30][CH:31]=[C:5]([S:2]([F:1])(=[O:3])=[O:4])[CH:6]=2)=[CH:11][C:12]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)c1cc(C(=O)c2cccc(S(=O)(=O)F)c2)sc1NC(=O)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CC(C)O
Product: CCOC(=O)c1cc(C(=O)c2cccc(S(=O)(=O)F)c2)sc1N
Yield: 56 %

Procedure:
A solution of 175 g (0.33 mole) of ethyl 5-(m-fluorosulfonylbenzoyl)-2-(2,2,2-trichloroethoxycarbonylamino)-3-thenoate and 4200 ml of isopropyl alcohol was treated with 175 g of zinc dust at 75° to 77° C. over a 6-minute period. The mixture was held at gentle reflux for 50 minutes before a sudden onset of reaction, characterized by vigorous boiling of the solvent, was noticed. Heating was removed until the reaction subsided. Reflux was continued until all the urethane was consumed, as indicated by thin-layer chromatography in 30 percent acetone: 70 percent hexane. The mixture was filtered hot through Celite (diatomaceous earth) and the filtrate was evaporated slowly in an evaporating dish until about one liter of solvent had been removed. The solid was collected by filtration to yield 66 g (56 percent) of yellow solid, melting point 170° to 172° C. A second crop was obtained by further evaporation (melting point 153° to 168° C.), and this was recrystallized from isopropyl alcohol to yield 14.5 g (12 percent) of yellow solid, melting point 168° to 170° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[O:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:7]=[CH:8][CH:9]=1)([O-])=O.CO.O.[SH-].[Na+]>O>[N:18]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[O:11][C:10]=1[C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc3cccnc3o2)c1
Agent: [Na+]
Agent: [SH-]
Solvent: CO
Solvent: O
Product: Nc1cccc(-c2nc3cccnc3o2)c1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
2-(3-Nitrophenyl)oxazolo[5,4-b]pyridine (600 mg, 2.49 mmol) was mixed with 25 mL of MeOH and 4 mL of water along with 837 mg of sodium hydrosulfide hydrate (14.9 mmol). The reaction mixture was stirred under reflux for 3 hours. It was then cooled to room temperature and concentrated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4) and concentrated to afford 520 mg of 3-(oxazolo[5,4-b]pyridin-2-yl)benzenamine (quantitative crude yield) (MS, M++H=212).
Reaction SMILES: [NH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=1)[NH2:2].BrC1C=CC2N([C:18]([S:21][C:22]3[CH:23]=[CH:24][C:25]4[N:26]([CH:28]=[C:29]([NH:31][C:32]([CH:34]5[CH2:36][CH2:35]5)=[O:33])[N:30]=4)[N:27]=3)=NN=2)C=1>>[C:7]([C:6]1[CH:9]=[CH:10][C:3]2[N:4]([C:18]([S:21][C:22]3[CH:23]=[CH:24][C:25]4[N:26]([CH:28]=[C:29]([NH:31][C:32]([CH:34]5[CH2:36][CH2:35]5)=[O:33])[N:30]=4)[N:27]=3)=[N:2][N:1]=2)[CH:5]=1)#[N:8]
Reactant: N#Cc1ccc(NN)nc1
Reactant: O=C(Nc1cn2nc(Sc3nnc4ccc(Br)cn34)ccc2n1)C1CC1
Product: N#Cc1ccc2nnc(Sc3ccc4nc(NC(=O)C5CC5)cn4n3)n2c1

Procedure:
To a suspended mixture of 6-chloronicotinonitrile (7 g, 50.8 mmol) in EtOH (50 mL), was added NH2NH2 (10 g, 310.2 mmol). The mixture was stirred at room temperature for 10 min, and then 60° C. for 5 h. The mixture was cooled to room temperature. The solids were filtered out, washed with water and dried under high vacuum to give 6-hydrazinylnicotinonitrile (3.5 g). Compound 6 was prepared from 6-hydrazinylnicotinonitrile following the procedure of the synthesis of compound 4. 1H NMR (400 MHz, CDCl3-CD3OD 10:1) δ ppm 11.37 (s, 1H), 8.70 (t, J=1.2 Hz, 1 H), 8.14 (s, 1 H), 8.11(dd, J=1.04 and 9.52 Hz, 1 H), 7.96 (dd, J=1.12 and 9.52 Hz, 1 H), 7.61 (dd, J=1.52 and 9.48 Hz, 1 H), 7.38 (d, J=9.0 Hz, 1 H), 1.77 (m, 1 H), 1.06 (m, 2 H), 0.90 (m, 2H) ESI-MS:m/z 377.2 (M+H)+.
Reaction SMILES: ON=[C:3]([CH3:19])[C:4](=[N:14][NH:15][C:16]([NH2:18])=[S:17])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[C:20](=O)([O-])[O-].[K+].[K+]>O>[CH3:19][C:3]1[N:18]=[C:16]([S:17][CH3:20])[N:15]=[N:14][C:4]=1[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=NO)C(=NNC(N)=S)c1ccc([N+](=O)[O-])cc1
Agent: [K+]
Solvent: O
Product: CSc1nnc(-c2ccc([N+](=O)[O-])cc2)c(C)n1
Yield: 44.1 %

Procedure:
A mixture of 2-hydroxyimino-4'-nitropropiophenone thiosemicarbazone (15.8 g) and potassium carbonate (17.09 g) in water (145 ml) was refluxed for 30 minutes with stirring. After cooling, the mixture was filtered by suction and then methyl iodide (10.37 g) was added dropwise to the filtrate at room temperature with stirring. The resulting precipitates were collected by filtration, washed with water, and dried. The residue was purified by column chromatography on silica gel (100 g) with methylene chloride as an eluent to give yellow powder of 5-methyl-3-methylthio-6-(4-nitrophenyl)-1,2,4-triazine (6.49 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.S(Cl)([Cl:12])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][Cl:12])=[N:6][CH:7]=1
Reactant: OCc1ccc(Br)cn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the stirred solution of (5-Bromo-pyridin-2-yl)-Methanol (5 gm, 26.59 mmol, 1 eq) in DCM (50 mL) at 0° C. is added Thionyl chloride (3 mL) drop wise at RT then stirred at RT for 4 h. After completion, the reaction mixture quenched with saturated sodium bicarbonate solution and extracted with DCM (3×100 mL). The combined organic layer dried over sodium sulphate and evaporated under reduced pressure. The crude is purified by column chromatography using silica 100-200 mesh using 10% EtOAc: Hexane as eluent to afford title compound (4 g) as brown colored liquid. 1NMR (400 MHz, DMSO) δ: 4.77 (s, 2H), 7.54 (d, J=8.64 Hz, 1H), 8.09-8.12 (dd, J1=2.4 Hz, J2=8.32 Hz, 1H), 8.70 (d, J=5.96 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14]Cl)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39].[NH2:40][C:41]([CH3:45])([CH3:44])[CH2:42][OH:43].O>CN(C)C(=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][NH:40][C:41]([CH3:45])([CH3:44])[CH2:42][OH:43])=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OCCCCl)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: CC(C)(N)CO
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(CO)NCCCOc1cc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1Cl)CNC2=O
Yield: 38.2 %

Procedure:
In a similar manner to Step 2 of Example 440, 4-chloro-5-(3-chloropropoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (90.6 mg, 0.158 mmol) was dissolved in N,N-dimethylacetoamide (0.9 mL), and the solution was treated with 2-amino-2-methyl-1-propanol (0.159 mL, 1.58 mmol). The reaction mixture was added with water. The obtained solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-chloro-5-[3-(1-hydroxy-2-methyl-2-propylamino)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (37.7 mg, yield 38%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[S:11](Cl)(=[O:13])=[O:12].C1OC(C2C=CSC=2)OC1.[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30].C(N(CC)CC)C>C(=O)(O)[O-].[Na+]>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[S:11]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1sccc1C1OCCO1
Reactant: NCCCCO
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1cc(C2OCCO2)cs1
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCCCO)c1sccc1C1OCCO1
Reaction time: 1 h
Yield: 62 %

Procedure:
A solution of 3-(1,3-dioxolan-2-yl)-thiophene-2-sulfonyl chloride, prepared from thiophene-3-carboxaldehyde ethylene acetal (20.0 g, 128 mmol) as described in Example 6, Step A, was combined with 4-amino-1-butanol (17.1 g, 192 mmol) and triethylamine (15 g, 148 mmol). The reaction was stirred for 1 h, a saturated aqueous solution of sodium bicarbonate (200 mL) was added and this mixture was stirred for 1 h. The organic layer was separated, dried (MgSO4), and evaporated to a residue which was purified by column chromatography (silica, 50% ethyl acetate/hexane to ethyl acetate, gradient) to give an oil (26.45 g, 62%).
Reaction SMILES: C([O:5][NH:6][C:7](=[O:34])[CH:8]([NH:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH3:33])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:11][CH:10]=1)(C)(C)C>C(O)(C(F)(F)F)=O>[CH2:30]([O:29][C:26]1[CH:25]=[CH:24][C:23]([S:20]([NH:19][CH:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:11][CH:10]=2)[C:7]([NH:6][OH:5])=[O:34])(=[O:22])=[O:21])=[CH:28][CH:27]=1)[C:31]#[C:32][CH3:33]
Reactant: C#CCOc1ccc(C(NS(=O)(=O)c2ccc(OCC#CC)cc2)C(=O)NOC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: C#CCOc1ccc(C(NS(=O)(=O)c2ccc(OCC#CC)cc2)C(=O)NO)cc1
Yield: 17 %

Procedure:
The 75 mg (0.154 mmol) sample of ′N-(tert-butoxy)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-2-[4-(2-propynyloxy)phenyl]acetamide was stirred in neat TFA at room temperature for 72 h TFA was removed in vacuo. The residue was chromatographed on prep. TLC eluting with 1% HOAc in 10% MeOH/CH2Cl2 to provide 11.1 mg (17%) of 2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-[4-(2-propynyloxy)phenyl]acetamide as a white solid was obtained. High Resolution Mass Spec 429.11155 (M+H)+;
Reaction SMILES: [NH2:1][C:2]1([C:17]2[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][C:18]=2[O:26][CH3:27])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:12][C:13](=[O:15])[CH3:14])[C:3]1=[O:16].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>ClCCl>[CH:23]([C:20]1[CH:21]=[CH:22][C:17]([C:2]2([NH:1][C:35](=[O:37])[CH3:36])[C:10](=[O:11])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[NH:12][C:13](=[O:15])[CH3:14])[C:3]2=[O:16])=[C:18]([O:26][CH3:27])[CH:19]=1)([CH3:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: COc1cc(C(C)C)ccc1C1(N)C(=O)c2cccc(NC(C)=O)c2C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(C)C)ccc1C1(NC(C)=O)C(=O)c2cccc(NC(C)=O)c2C1=O
Reaction time: 8 h
Yield: 95.2 %

Procedure:
A solution of N-(2-amino-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-indene-4-yl)acetamide (0.20 g, 0.54 mmol) in dichloromethane (10 mL) and was added triethylamine (0.23 mL, 1.6 mmol) and acetyl chloride (0.040 mL, 0.56 mmol) and then stirred for overnight. The reaction mixture was extracted with dichloromethane and purified using silica gel column chromatography (50% ethylacetate in hexane) to afford the title compound (210 mg, 95%).