Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:15][C@H:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][C@H:17]1[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])(=O)C1C=CC=CC=1>O.C(O)C>[C:36]([O:35][C:33]([NH:32][C@H:17]1[C@@H:16]([OH:15])[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18]1)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1OC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1O
Temperature: 70 °C
Reaction time: 20 h
Yield: 88.6 %

Procedure:
A solution of potassium carbonate (3.70 g, 26.8 mmol) in water (80 mL) was added to a solution of cis-benzyl 4-(benzoyloxy)-3-((tert-butoxycarbonyl)amino)piperidine-1-carboxylate (8.11 g, 17.84 mmol) in ethanol (160 mL) and the mixture was stirred at 70° C. for 20 h. The reaction mixture was concentrated in vacuo to ⅓rd volume and the resultant suspension was diluted with water (50 mL) and extracted using DCM (3×70 mL). The collected organics were combined and dried (Na2SO4) and concentrated in vacuo to afford the crude product as a colourless oil. The crude product was then purified by column chromatography on a silica cartridge (340 g) using a 0-100% ethyl acetate/cyclohexane gradient. The appropriate fractions were combined and evaporated in vacuo to give the required product cis-benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxypiperidine-1-carboxylate (5.54 g, 15.81 mmol, 89% yield) as a white foam.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([O:27][CH2:28][C:29]([OH:31])=O)=[CH:26][C:20]=4[S:19](=[O:33])(=[O:32])[N:18]=3)[C:7]2=[O:34])[CH2:3][CH2:2]1.Cl.C[N:37]([CH3:46])[CH2:38][CH2:39][CH2:40][N:41]=C=NCC.ON1C2C=CC=CC=2N=N1.C(OC(=O)NC1CCNC1)(C)(C)C>CN(C)C=O.C(OCC)(=O)C>[NH2:41][CH:40]1[CH2:39][CH2:38][N:37]([C:29](=[O:31])[CH2:28][O:27][C:25]2[CH:24]=[CH:23][C:21]3[NH:22][C:17]([C:8]4[C:7](=[O:34])[N:6]([NH:5][CH2:4][CH:1]5[CH2:2][CH2:3]5)[C:15]5[C:10]([C:9]=4[OH:16])=[CH:11][CH:12]=[CH:13][CH:14]=5)=[N:18][S:19](=[O:32])(=[O:33])[C:20]=3[CH:26]=2)[CH2:46]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)COc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Agent: CC(C)(C)OC(=O)NC1CCNC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC1CCN(C(=O)COc2ccc3c(c2)S(=O)(=O)N=C(c2c(O)c4ccccc4n(NCC4CC4)c2=O)N3)C1
Reaction time: 24 h
Yield: 54.3 %

Procedure:
The product of Example 384B (24 mg, 0,05 mmole), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (16 mg, 0.08 mmol) and 1-hydroxybenzotriazole (14 mg, 0.1 mmol) in N,N-dimethylformamide (2 mL) was added pyrrolidin-3-yl-carbamic acid tert-butyl ester(19 mg, 0.1 mmol). The mixture was stirred for 1 day. The solution was poured into ethyl acetate (40 mL) and washed with saturated aqueous sodium bicarbonate, water, and brine, dried with magnesium sulfate, filtered and concentrated. The residue was triturated with methanol/water and filtered. The solid was treated with hydrochloric acid (1 M in dioxane, 2 mL) and stirred overnight, filtered and washed with ethyl acetate/hexane (1:1) to give title compound (15 mg, 51%). 1H NMR (500 MHz, BENZENE-d6) δ 0.16 (m, 2 H) 0.43 (m, 2 H) 1.01 (m, 1 H) 2.14 (m, 2 H) 2.29 (m, 1 H) 2.89 (d, J=6.84 Hz, 2 H) 3.36 (m, 2 H) 3.81 (m, 2 H) 4.88 (m, 2 H) 7.42 (m, 3 H) 7.61 (m, 1 H) 7.88 (m, 1 H) 8.09 (d, J=8.30 Hz, 1 H) 8.17 (d, J=8.30 Hz, 1 H) 8.28 (s, 3 H) 13.99 (s, 1 H). MS (ESI−) m/z 551 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1O[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[C:4](=[O:23])[CH:3]=1.[CH2:24]([NH2:31])[C:25]1C=C[CH:28]=[CH:27][CH:26]=1>C(O)C>[CH3:1][C:2]1[N:31]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[C:4](=[O:23])[CH:3]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc(=O)c(C(=O)Nc2ccccc2)c(-c2ccccc2)o1
Solvent: CCO
Product: CCCCCn1c(C)cc(=O)c(C(=O)Nc2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
1 g (3.23 mmol) of 6-methyl-4-oxo-N,2-diphenyl-4H-pyran-3-carboxamide and 590 mg (6.78 mmol) of benzylamine were dissolved in 10 ml of ethanol, and the resulted mixture was stirred over night at room temperature. Ethanol was removed under vacuo. The crystal residue was recrystallized from ethylacetate to afford 700 mg of the title compound having mp. 164°-165.5° C.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)[CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=1)[CH:10]([OH:15])[C:11]([F:12])([F:14])[F:13]
Reactant: OC(C(c1cccc(C(F)(F)F)c1)N(Cc1ccccc1)Cc1ccccc1)C(F)(F)F
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: NC(c1cccc(C(F)(F)F)c1)C(O)C(F)(F)F

Procedure:
In a continuous-flow hydrogenation apparatus (H-Cube from Thales Nano, Budapest, Model HC-2-SS), a solution of 168 mg (0.37 mmol) of the compound from Example 98A in 50 ml of methanol was hydrogenated (conditions: Pd(OH)2/C cartridge, flow rate of 1 ml/min, RT, standard hydrogen pressure). The reaction mixture was concentrated on a rotary evaporator and the residue was briefly dried in an HV. This was the title compound (93 mg, 92% of theory).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[N:20]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)=[N+:21]=[N-:22].S(=O)(=O)(O)O>C(Cl)Cl>[OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][NH:10][S:29]([C:26]2[CH:25]=[CH:24][C:23]([N:20]=[N+:21]=[N-:22])=[CH:28][CH:27]=2)(=[O:30])=[O:31])=[CH:6][CH:5]=1
Reactant: NCCc1ccc(CCO)cc1
Reactant: [N-]=[N+]=Nc1ccc(S(=O)(=O)Cl)cc1
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=Nc1ccc(S(=O)(=O)NCCc2ccc(CCO)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of 5.5 g. (33 mmole) 4-(2-hydroxyethyl)-phenethylamine, 100 ml. methylene chloride and 3.4 g. (33 mmole) triethylamine is slowly added dropwise a solution of 7.2 g. (33 mmole) 4-azidobenzenesulphonyl chloride in 50 ml. methylene chloride. Subsequently, the reaction is allowed to continue for 1 hour with ice cooling. The reaction mixture is now shaken out twice with dilute sulphuric acid, then twice with water, dried with anhydrous sodium sulphate and finally evaporated. The residue is recrystallised twice from toluene to give 7.8 g. (64% of theory) of desired product; m.p. 90°-92° C. (recrystallised from toluene).
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:6]1[C@H:11]([CH3:12])[CH2:10][N:9]([C@H:13]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[S:28][CH:29]=[C:30]([C:32]([O:34]CC)=[O:33])[N:31]=3)=[CH:23][CH:22]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[C@@H:8]([CH3:37])[CH2:7]1)[CH:4]=[CH2:5].CO.Cl>O1CCOCC1>[CH2:3]([N:6]1[C@H:11]([CH3:12])[CH2:10][N:9]([C@H:13]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[S:28][CH:29]=[C:30]([C:32]([OH:34])=[O:33])[N:31]=3)=[CH:23][CH:22]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[C@@H:8]([CH3:37])[CH2:7]1)[CH:4]=[CH2:5]
Reactant: C=CCN1C[C@H](C)N([C@H](c2ccc(-c3nc(C(=O)OCC)cs3)cc2)c2cccc(O)c2)C[C@H]1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: C=CCN1C[C@H](C)N([C@H](c2ccc(-c3nc(C(=O)O)cs3)cc2)c2cccc(O)c2)C[C@H]1C

Procedure:
Aqueous sodium hydroxide solution (3 ml, 2N) was added to a solution of the compound from Example 37 (580 mg), in dioxan (6 ml) and methanol (3 ml) and the reaction stirred at room temperature for 3 hours. The reaction mixture was acidified to pH 5 using 2N hydrochloric acid then evaporated to dryness in vacuo. The residue was purified by column chromatography over silica gel using gradient elution (85/15/2.5-80/20/3 dichloromethane/methanol/ammonium hydroxide). This material was further purified on a polystyrene reverse phase resin using gradient elution (100/0-50/50 water/acetonitrile). The acetonitrile was evaporated in vacuo and the remaining aqueous solution was frozen and lyophilised to afford the title compound, 410 mg.
Reaction SMILES: [BrH:1].[Br:2][C:3]1[C:4]([OH:13])=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6]O>C(O)(=O)C>[Br:2][C:3]1[C:4]([OH:13])=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][Br:1]
Reactant: COc1cc(Br)c(O)c(CO)c1
Reactant: Br
Solvent: CC(=O)O
Product: COc1cc(Br)c(O)c(CBr)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In the course of 30 minutes, at room temperature, 20 g of hydrogen bromide are introduced into a suspension of 50 g of 3-bromo-2-hydroxy-5-methoxy-benzyl alcohol in 300 ml of anhydrous acetic acid. The reaction mixture is stirred for 5 hours at room temperature and the resulting solution is concentrated by evaporation. The black-brown oily residue, which crystallises slowly when left to stand at room temperature, is crystallised from ethyl acetate/cyclohexane (5:1) with the addition of a small amount of activated charcoal. 3-Bromo-2-hydroxy-5-methoxy-benzyl bromide is thus obtained [1H-NMR (360 MHz, CDCl3): 3.75 (s, 3H, OCH3), 4.53 (s, 2H, CH2Br), 5.45 (s, 1H, OH), 6.85 (d, 1H), 7.00 (d, 1H) ppm].
Reaction SMILES: [NH2:1][C:2]([CH2:11][OH:12])=[CH:3][C:4](=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:13][C:14]1[C:15]([NH:20]N)=[N:16][CH:17]=[CH:18][CH:19]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[Cl:13][C:14]1[C:15]([N:20]2[C:4]([OH:10])([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][C:2]([CH2:11][OH:12])=[N:1]2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: NNc1ncccc1Cl
Reactant: CCOC(=O)C(=O)C=C(N)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C1(O)CC(CO)=NN1c1ncccc1Cl

Procedure:
A mixture of ethyl 4-amino-5-hydroxy-2-oxopent-3-enoate (2.5 g, 14 mmol), 3-chloropyridin-2-ylhydrazine (2.07 g, 14 mmol) and p-toluenesulphonic acid monohydrate (2.5 g, 13 mmol) was stirred in 25 ml of acetonitrile at 25° C. for 5 hours. The precipitate was isolated by filtration and the filtrate was concentrated under reduced pressure. The product was purified by column chromatography on SiO2 (eluent: hexane/ethyl acetate). Oil. Yield 4.2 g (90%).
Reaction SMILES: [N+](C1C=CC([N:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[C:11](=[O:13])[O-])=CC=1)([O-])=O.C(N(CC)C(C)C)(C)C.[NH2:35][C@@H:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:37][OH:38]>ClCCl>[OH:38][CH2:37][C@@H:36]([NH:35][C:11]([NH:10][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)=[CH:18][CH:19]=1)=[O:13])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: O=C([O-])N(c1ccc(-c2ccncc2)cc1)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2ccncc2)cc1)N[C@H](CO)c1ccccc1
Reaction time: 20 h
Yield: 81.6 %

Procedure:
To a solution of 4-nitrophenyl[4-(4-pyridinyl)phenyl]carbamate (7.50 g) and N,N-diisopropylethylamine (5.84 mL) in dichloromethane (150 mL) was added (2S)-2-amino-2-phenylethanol (4.60 g) at ambient temperature and the mixture was stirred at the same temperature for 20 hours. The resulting mixture was concentrated in vacuo and then water (45 mL) and ethyl acetate (45 mL) was added to the residue. The precipitated solid was collected by filtration and washed with water (30 mL×5) to obtain yellow crystals. The crystals were triturated with ethyl acetate (30 mL) to give 1-[(1S)-2-hydroxy-1-phenylethyl]-3-[4-(4-pyridinyl)phenyl]urea (6.1 g) as a slightly yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[C:10]([CH3:14])[NH:11]2)=[CH:7][CH:6]=1)=[O:4].[Cl:15][C:16]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:17]=1[CH2:18]Cl>O1CCOCC1.[Ag-]=O>[Cl:15][C:16]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:17]=1[CH2:18][C:9]1[C:8]2[C:12](=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[NH:11][C:10]=1[CH3:14]
Reactant: COC(=O)c1ccc2cc(C)[nH]c2c1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: O=[Ag-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(Cc3ccc(Cl)cc3Cl)c(C)[nH]c2c1
Temperature: 90 °C
Yield: 20.6 %

Procedure:
6-(Methoxycarbonyl)-2-methylindole (3.03 g), 2,4-dichlorobenzyl chloride (4.69 g) and silver(I) oxide (5.56 g) are suspended in 1,4-dioxane (50 ml), and stirred under heat at 90° C. for 19.5 hours. The solid is separated through filtration, and the filtrate is concentrated. The resulting residue is purified through silica gel column chromatography to obtain 3-(2,4-dichlorobenzyl)-6-(methoxycarbonyl)-2-methylindole (58) (1.15 g).
Reaction SMILES: [C:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7](=O)[O:6]C1=O)(=O)[CH3:2].[OH-].[NH4+:19]>>[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:6])[NH:19][C:1]([CH3:2])=[CH:4]2
Reactant: [NH4+]
Reactant: COc1ccc2c(c1)C(C(C)=O)C(=O)OC2=O
Agent: [OH-]
Product: COc1ccc2c(=O)[nH]c(C)cc2c1
Temperature: 25 °C
Yield: 74 %

Procedure:
The cyclic anhydride of step 1 (405 mg; 1.73 mmol) was dissolved in aqueous ammonium hydroxide, and heated at reflux for 1.5 hours. The mixture was cooled to room temperature and the solid was filtered then dried overnight to give 270 mg (74%) of 6-methoxy-3-methylisoquinolin-1(2H)-one.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:17])[CH3:16])[CH:5]=[C:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]=1[O:8][CH3:9].CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[CH:32]=[C:31]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:30]=[CH:29]3)O1>>[C:10]([C:6]1[CH:5]=[C:4]([NH:14][C:15](=[O:17])[CH3:16])[CH:3]=[C:2]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[CH:32]=3)[CH:27]=2)[C:7]=1[O:8][CH3:9])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC1(C)OB(c2ccc3cc(NS(C)(=O)=O)ccc3c2)OC1(C)C
Reactant: COc1c(Br)cc(NC(C)=O)cc1C(C)(C)C
Product: COc1c(-c2ccc3cc(NS(C)(=O)=O)ccc3c2)cc(NC(C)=O)cc1C(C)(C)C
Temperature: 90 °C

Procedure:
N-(3-bromo-5-tert-butyl-4-methoxyphenyl)acetamide (24 mg, 0.08 mmol) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-yl)methanesulfonamide (64 mg, 0.18 mmol), were reacted in the same manner as Example 43 Part C, heating in an oil bath at 90° C. for 18 hours to give crude product which was purified on an Isco 4 g silica cartridge eluting with 5% methanol/chloroform to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.39 (s, 9 H), 2.02 (s, 3 H), 3.06 (s, 3 H), 3.16 (s, 3 H), 7.34-7.76 (m, 5 H), 7.84-8.00 (m, 3 H), 9.91 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][CH2:11][C:12]2[S:16][C:15]([S:17](Cl)(=[O:19])=[O:18])=[CH:14][CH:13]=2)=[O:9])=[CH:4][CH:3]=1.[S:21]1[CH2:25][CH2:24][S:23][CH:22]1[C:26]1[CH:31]=[CH:30][C:29]([C:32]2[S:33][CH:34]=[C:35]([C:37]([NH:39][NH2:40])=[O:38])[N:36]=2)=[CH:28][CH:27]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][CH2:11][C:12]2[S:16][C:15]([S:17]([NH:40][NH:39][C:37]([C:35]3[N:36]=[C:32]([C:29]4[CH:28]=[CH:27][C:26]([CH:22]5[S:21][CH2:25][CH2:24][S:23]5)=[CH:31][CH:30]=4)[S:33][CH:34]=3)=[O:38])(=[O:19])=[O:18])=[CH:14][CH:13]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: NNC(=O)c1csc(-c2ccc(C3SCCS3)cc2)n1
Reactant: O=C(NCc1ccc(S(=O)(=O)Cl)s1)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccc(S(=O)(=O)NNC(=O)c2csc(-c3ccc(C4SCCS4)cc3)n2)s1)c1ccc(Cl)cc1
Yield: 80 %

Procedure:
A solution of sulfonyl chloride 1b (1.0 equivalents), 2-[4-(1,3-Dithiolan-2-yl)phenyl]-1,3-thiazole-4-carbohydrazide (1.1 equivalents), and pyridine (1.2-2 equivalents) in CHCl3 is heated to reflux for 2 h. Filtration over SiO2 (CH3CN) and evaporation yielded 80% of the desired sulfonyl hydrazide 1.
Reaction SMILES: Cl[CH2:2][C:3]([O:7][C:8](=[O:12])[N:9]([CH3:11])[CH3:10])=[N:4][O:5][CH3:6].[CH3:13][C:14]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:15]=1[CH2:16][P:17](=[O:22])([O-:21])[O:18][CH2:19][CH3:20].[K+].[I-].[K+]>C(C(C)=O)C>[CH3:13][C:14]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:15]=1[CH2:16][P:17](=[O:21])([O:18][CH2:19][CH3:20])[O:22][CH2:2][C:3]([O:7][C:8](=[O:12])[N:9]([CH3:11])[CH3:10])=[N:4][O:5][CH3:6]
Reactant: CCOP(=O)([O-])Cc1ccc(Cl)cc1C
Reactant: CON=C(CCl)OC(=O)N(C)C
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOP(=O)(Cc1ccc(Cl)cc1C)OCC(=NOC)OC(=O)N(C)C
Temperature: 25 °C

Procedure:
1-Chloro-2-(N,N-dimethylcarbamoyloxy)-2-methoxyiminoethane (10grams; 0.05 mole), methyl ethyl ketone (60ml), potassium O-ethyl 2-methyl-4-chlorobenzylphosphonate (15.6 grams; 0.05 mole) and a few crystals of potassium iodide are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 4 hours. After this time the reaction mixture is cooled to room temperature and is filtered to remove inorganic salts. The salts are washed with acetone and the washings combined with the filtrate. The resulting solution is stripped of solvent in a rotary evaporator. The remaining residue is dissolved in ether and the ether solution is washed with water and dried over anhydrous magnesium sulfate. The dried solution is filtered and stripped of ether to yield the desired product O-[2-(N,,N-dimethylcarbamoyloxy)-2-methoxyiminoethyl] O-ethyl 2-methyl-4-chlorobenzylphosphonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[N:6][CH:7]=1.[H-].[Na+].[CH3:14]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:11][CH3:14])([CH3:9])[CH3:10])=[N:6][CH:7]=1
Reactant: CC(C)(O)c1ccc(Br)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)(C)c1ccc(Br)cn1
Reaction time: 0.5 h
Yield: 108.6 %

Procedure:
2-(5-bromopyridin-2-yl)propan-2-ol (50 mg, 0.2 mmol, from Example 184, Step 3) was added to a mixture of NaH in mineral oil (10 mg, 0.5 mmol) in DMF (5 mL). The reaction was stirred for 30 min and the methyl iodide (30 μL, 0.5 mmol) was added and stirred for 2 hours. The reaction was partitioned between EtOAc and water. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give crude product 5-bromo-2-(1-methoxy-1-methylethyl)pyridine as an oil (0.05 g, 90%). LCMS calculated for C9H13BrNO (M+H)+: m/z=230.0, 232.0. found: 230.0, 231.8.
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1[O-])([O-])=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]2[O:21][CH2:22][CH2:23][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]1([C:36]#[C:37][C:38]([O:40][CH3:41])=[O:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O.O>[C:30]1([C:36]2[C:37]([C:38]([O:40][CH3:41])=[O:39])=[C:16]3[C:17]4[CH2:23][CH2:22][O:21][C:18]=4[CH:19]=[CH:20][N:15]3[N:14]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)C#Cc1ccccc1
Reactant: N[n+]1ccc2c(c1)CCO2
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)nn2ccc3c(c12)CCO3
Temperature: 25 °C
Reaction time: 14 h
Yield: 18.1 %

Procedure:
To a mixture of 5-amino-2,3-dihydrofuro[3,2-c]pyridin-5-ium 2,4-dinitrobenzenolate (1.00 g, 3.12 mmol) and potassium carbonate (640 mg, 4.37 mmol) in dimethylformamide (20 mL) was added methyl 3-phenylpropiolate (506 μL, 3.43 mmol) under ice-cooling, and the mixture was stirred at room temperature for 14 hr. The reaction solution was diluted with water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→40/60) to give the title compound (166 mg, yield 18%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C1N2CN3CN(C2)CN1C3.[C:20](O)(=[O:22])C>O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:20]=[O:22])=[CH:2]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: O=Cc1c[nH]c2ncccc12
Reaction time: 4 h

Procedure:
Into a 250 mL round bottom flask was placed 1H-pyrrolo[2,3-b]pyridine (10 g, 84.75 mmol). To this was added HMTA (hexamethylenetetramine) (17.8 g, 126.99 mmol). Addition of acetic acid (36 mL) was next. To the mixture was added H2O (70 mL). The resulting solution was allowed to react, with stirring, for 4 hours while the temperature was maintained at reflux in a bath of oil. The resulting solution was diluted with 200 mL of H2O. The reaction mixture was cooled. A filtration was performed and the filtrate cake was washed with H2O. This resulted in 7.5 g (61%) of 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[C:6]2O.O=P(Cl)(Cl)[Cl:19]>CN(C=O)C>[Cl:19][C:6]1[C:7]([N+:13]([O-:15])=[O:14])=[CH:8][N:9]=[C:10]2[C:5]=1[N:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11]2
Reactant: COc1ccc2ncc([N+](=O)[O-])c(O)c2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc2ncc([N+](=O)[O-])c(Cl)c2n1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 93 %

Procedure:
The compound of Example 2 (20 g, 1 eq.) was suspended in DMF (200 mL) at 20° C. To the suspension was added POCl3 (27.7 g, 2 eq.) over a period of 15 min. The mixture was stirred at 25° C. for 35 min, poured on ice (200 g) and filtered. After drying on a rotary evaporator at 70° C., a yellow solid (20.5 g; 93% yield) was obtained.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:26].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C=O)C>[CH2:1]([O:3][CH:4]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:5][CH2:6][CH2:7][CH2:8][C:9]([OH:26])=[O:10])[CH3:2]
Reactant: CCCCCCCCCCCCC#CC(OCC)OCCCCO
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCC#CC(OCC)OCCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.2 g of the product from example 22 in 15 ml of dry DMF was added in portions to a solution of pyridinium dichromate (4.4 g) in 30 ml of dry DMF. The solution was stirred at room temperature for 24 hours, then poured into water (300 ml). The aqueous mixture was extracted several times with Et2O, the combined extracts were washed with water and dried over Na2SO4. The reaction mixture was purified by column chromatography (SiO2) (1% MeOH/CHCl3). The partially purified product (0.54 g) was further purified by preparative thin layer chromatography (SiO2) (2%MeOH/CHCl3). Yield: 0.35 g.
Reaction SMILES: N#[C:2][Br:3].C(=O)([O-])[O-].[K+].[K+].[F:10][C:11]1[CH:31]=[CH:30][C:14]2[O:15][C:16]3[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=3[CH2:18][CH:19]([S:20][CH2:21]CN(C)C)[C:13]=2[CH:12]=1.CCCCCC>C(Cl)(Cl)Cl>[Br:3][CH2:2][CH2:21][S:20][CH:19]1[CH2:18][C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[O:15][C:14]2[CH:30]=[CH:31][C:11]([F:10])=[CH:12][C:13]1=2
Reactant: CN(C)CCSC1Cc2ccccc2Oc2ccc(F)cc21
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: Fc1ccc2c(c1)C(SCCBr)Cc1ccccc1O2
Reaction time: 0.33 h

Procedure:
To a mixture of 2.3 g of cyanogen bromide and 5.0 g of potassium carbonate in 40 ml of chloroform is added portion-wise over a 50 minutes span a solution of 4.8 of 2-fluoro-10,-11-dihydro-11-[β-(dimethylamino)ethylthio]dibenz[b,f]oxepin, free base of Example 32, in 85 ml of chloroform. After total addition, the mixture is stirred for 20 minutes before being filtered. The filtrate is evaporated to leave an oil which is treated with three portions of boiling hexane. The combined hexane portions are evaporated leaving an oil which is chromatographed through a silica gel column with an eluant of methylene chloride and is recrystallized from cold hexane to give a white powder, mp 46°-48° C. of 11-[β-(bromo)ethylthio]-2-fluoro-10,11-dihydrodibenz [b,f]oxepin.