Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[C:6]1([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[O:23].C1(C)C=CC=CC=1>O1CCCC1>[OH:23][CH:22]([C:13]1[N:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:20]2[C:15]([CH:14]=1)=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:21]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C=O
Reactant: c1ccc(-n2ccc3ccccc32)cc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1cc2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 19 %

Procedure:
A solution of butyllithium (1.6 M, 1.19 mL, 1.9 mmol) was added at −78° C. to a solution of 1-phenyl-1H-indole (5a) (350 mg, 1.81 mmol) in tetrahydrofuran (10 mL) under a nitrogen atmosphere. After 45 minutes, a solution of ethyl glyoxylate in toluene (50%, 400 μL, 2 mmol) was added. The reaction mixture was slowly warmed to room temperature for 12 hours, quenched with water (2 mL) and concentrated in vacuo. The residue was partitioned between dichloromethane (30 mL) and water (10 mL). The organic layer was washed with water (2×10 mL), brine (10 mL), dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired alcohol (5b) as a white solid (100 mg, 0.33 mmol, 19%).
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[O:14]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][OH:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC=CC=1>C1C=CC=CC=1>[C:1]12([C:11]([O:25][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[C:21]([O:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:22]=3)=[O:12])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(OCc1cccc(Oc2ccccc2)c1)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 66 h
Yield: 98.7 %

Procedure:
1 g (5.03 mmol) of tricyclo[3.3.1.13,7 ]decane-1-carbonyl chloride, 1.01 g (5.04 mmol) of 3-phenoxybenzyl alcohol and 0.08 g (10.07 mmol) of anhydrous pyridine were dissolved in 30 ml of anhydrous benzene. The mixture was stirred at room temperature for 66 hours. Then the reaction was terminated. The resulting pyridine hydrochloride was removed by filtration and the filtrate was thoroughly washed with 1N hydrochloric acid, 5% sodium carbonate and then saturated saline solution, and dried over sodium sulfate. The solvent was removed to obtain 1.8 g of an oily material. Purification by column chromatography on silica gel employing a developer consisting of n-hexane and benzene (1:1) gave 1.69 g (yield 93%) of a colorless oily material.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.[Li]CCCC.[CH2:27]([N:34]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C@H:35]1[CH2:39][CH2:38][CH:37]([CH:40]=[O:41])[CH2:36]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[C:3]([CH:40]([CH:37]2[CH2:38][CH2:39][C@H:35]([N:34]([CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:36]2)[OH:41])=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: O=CC1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)C1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(I)c(Cl)cnc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(O)C3CC[C@H](N(Cc4ccccc4)Cc4ccccc4)C3)c(Cl)cnc21
Temperature: -78 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
A round-bottomed flask was charged with 5-chloro-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3.5 g, 8.05 mmol, Adesis) in THF (161 mL) to give a colorless solution. The solution was cooled to about −78° C. and n-BuLi (1.6 M in hexanes, 6.54 mL, 10.46 mmol) was added drop-wise over about 15 min. After addition of the n-BuLi solution was complete, (35)-3-(dibenzylamino)cyclopentanecarbaldehyde (2.48 g, 8.45 mmol) in THF (10 mL) was added drop-wise over about 5 min. The reaction mixture was stirred for about 4 h at about −78° C. Saturated aqueous NH4Cl (40 mL) was added slowly and the mixture was stirred for about 5 min. The organic solvent was removed under reduced pressure and EtOAc (100 mL) was added. The layers were separated and the organic layer was washed with brine (3×50 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give a yellow oil that was purified by silica gel chromatography eluting with a gradient of 5-10% EtOAc in heptane. The product containing fractions were combined and concentrated to give (5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)((3S)-3-(dibenzylamino)cyclopentyl)methanol (3.5 g, 72%): LC/MS (Table 2, Method n) Rt=2.97 min; MS m/z: 603 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[CH2:18]([C:21]1[N:25]([C:26]([CH3:29])([CH3:28])[CH3:27])[N:24]=[C:23]([CH:30]=O)[CH:22]=1)[CH2:19][CH3:20]>>[C:26]([N:25]1[C:21]([CH2:18][CH2:19][CH3:20])=[CH:22][C:23]([CH2:30][NH:17][CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=3[CH3:1])[CH2:14][CH2:13]2)=[N:24]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CCCc1cc(C=O)nn1C(C)(C)C
Reactant: Cc1cccc(N2CCN(CCN)CC2)c1C
Product: CCCc1cc(CNCCN2CCN(c3cccc(C)c3C)CC2)nn1C(C)(C)C
Yield: 90.7 %

Procedure:
Compound 15 was prepared using the same method as that of Example 1 except that 4-(2,3-dimethylphenyl)piperazin-1-ylethylamine and 5-propyl-1-t-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:19].[Br:22][C:23]([Br:27])=[CH:24][CH2:25]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH3:18])=[CH:14][CH:15]=2)[CH:6]=[CH:5][C:4]=1[O:19][CH2:25][CH:24]=[C:23]([Br:27])[Br:22]
Reactant: CCOc1ccc(Oc2ccc(O)c(C(F)(F)F)c2)cc1
Reactant: OCC=C(Br)Br
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOc1ccc(Oc2ccc(OCC=C(Br)Br)c(C(F)(F)F)c2)cc1
Yield: 32.8 %

Procedure:
To a solution prepared by dissolving 0.55 g of 2-trifluoromethyl-4-(4-ethoxyphenoxy)phenol, 0.40 g of 3,3-dibromoallyl alcohol and 0.49 g of triphenylphosphine in 10 ml of tetrahydrofuran, a solution prepared by dissolving 0.38 g of diisopropylazodicarboxylate in 5 ml of tetrahydrofuran was added dropwise at room temperature with stirring. After stirring at room temperature for 12 hours, the reaction solution was concentrated. Then, 20 ml of diethyl ether was added thereto, and the precipitate was filtered off. The resulting filtrate was concentrated, and subjected to silica gel column chromatography to give 0.30 g of 2-trifluoromethyl-4-(4-ethoxyphenoxy)-1-(3,3-dibromo-2-propenyloxy)benzene, yield 32%; nD24.0 1.5480.
Reaction SMILES: C(OC([N:8]1[CH2:16][C@@H:15]2[C@@H:10]([C@H:11]([F:29])[CH2:12][CH2:13][C:14]2([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)=O)(C)(C)C.[ClH:30]>O1CCOCC1>[ClH:30].[C:23]1([C:14]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12][C@@H:11]([F:29])[C@@H:10]3[C@H:15]2[CH2:16][NH:8][CH2:9]3)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2[C@H](F)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Agent: Cl
Solvent: C1COCCO1
Product: F[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of 2.25 g of (3aR, 7R,7aR)-2-t-butoxycarbonyl-4,4-diphenyl-7-fluoroperhydroisoindole in 25 cm3 of dioxane is treated with a 5.8N solution of hydrochloric acid in dioxane and stirred for 2 hours at 20° C. and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is concreted by adding 100 cm3 of isopropyl oxide, the solid is filtered and dried to give 1.8 g of (3aR, 7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride in the form of a cream-colored powder.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH3:19])([CH3:18])[CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])C.[CH3:21][NH2:22]>>[CH2:11]([O:10][C:8]([NH:7][CH2:6][C:5]([CH3:19])([CH3:18])[C:4]([NH:22][CH3:21])=[O:3])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN
Reactant: CCOC(=O)C(C)(C)CNC(=O)OCc1ccccc1
Product: CNC(=O)C(C)(C)CNC(=O)OCc1ccccc1

Procedure:
4.19 g of 3-benzyloxycarbonylamino-2,2-dimethylpropionic acid ethyl ester and 50 ml of 33% methylamine (in ethanol) are stirred for 8 days at 60° C. in a bomb tube. The reaction mixture is concentrated by evaporation and the residue is purified by FC (220 g of silica gel, dichloromethane/methanol=95:5). The title compound is obtained: Rf (dichloromethane/methanol=9:1)=0.51.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[I:17]I.N(OC(C)(C)C)=O>C1(C)C=CC=CC=1>[I:17][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: II
Reactant: COC(=O)c1cc(N)c(OC)c([N+](=O)[O-])c1
Agent: CC(C)(C)ON=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(I)c(OC)c([N+](=O)[O-])c1
Yield: 96.6 %

Procedure:
To a solution of methyl 3-amino-4-(methyloxy)-5-nitrobenzoate (D163) (370 mg, 1.64 mmol, 1 equiv) in toluene (20 ml) at 0° C. was added iodine (218 mg, 0.86 mmol, 0.5 equiv) then 1,1-dimethylethyl nitrite (200 mg, 1.75 mmol, 1.1 equiv) and the resulting mixture was stirred at room temperature for 15 h then partitioned between AcOEt and brine. The two layers were separated and the organic phase was dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel gave methyl 3-iodo-4-(methyloxy)-5-nitrobenzoate (D165) (280 mg, 51%) as a light brown solid. No molecular ion. RT=3.33 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[C:5]([C:12]#[N:13])=[CH:4][N:3]=1.[CH3:14][O:15][CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>CC(O)CC>[C:12]([C:5]1[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[N:7][C:2]([NH:26][C:25]2[CH:27]=[CH:28][C:22]([S:19](=[O:21])(=[O:20])[NH:18][CH2:17][CH2:16][O:15][CH3:14])=[CH:23][CH:24]=2)=[N:3][CH:4]=1)#[N:13]
Reactant: N#Cc1cnc(Cl)nc1NC1CC1
Reactant: COCCNS(=O)(=O)c1ccc(N)cc1
Solvent: CCC(C)O
Product: COCCNS(=O)(=O)c1ccc(Nc2ncc(C#N)c(NC3CC3)n2)cc1
Temperature: 90 °C
Yield: 77.2 %

Procedure:
2-Chloro-5-cyano-4-cyclopropylaminopyrimidine (Method 96; 295 mg, 1.28 mmol) was dissolved in hot 2-butanol (3 ml). A hot solution of 4-[N-(2-methoxyethyl)sulphamoyl]aniline (Method 5; 207 mg, 0.90 mmol) in 2-butanol (3 ml) was added and the reaction was stirred and heated at 90° C. for 1 hour. The reaction mixture was cooled and the volatiles evaporated to give a solid. The solid residue was triturated with hot ethyl acetate, cooled, and the resultant solid collected by filtration to give the title compound (270 mg, 77%). NMR: 0.68 (m, 2H), 0.80 (m, 2H), 2.88 (m, 3H), 3.14 (s, 3H), 3.28 (m, 2H), 7.48 (brs, 1H), 7.70 (d, 2H), 8.05 (d, 2H), 8.12 (brs, 1H) 8.41 (s, 1H), 10.31 (s, 1H); m/z: 389.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:4]([CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[NH:12]1[CH2:11][CH2:10][CH:9]([C:4]2[C:3]([C:2]([F:23])([F:1])[F:22])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncccc2C(F)(F)F)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1cccnc1C1CCNCC1
Temperature: 0 °C

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of tert-butyl 4-(3-(trifluoromethyl)pyridin-2-yl)piperidine-1-carboxylate (379.8 mg, 1.10 mmol, 1.00 equiv, 96%) in dichloromethane (10 mL). This was followed by the addition of trifluoroacetic acid (5 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 3 h at room temperature. The pH value of the solution was adjusted to 8-9 with sat sodium bicarbonate. The resulting solution was extracted with 6×50 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 237.4 mg (93%) of 2-(piperidin-4-yl)-3-(trifluoromethyl)pyridine as yellow oil.
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=[C:6](S(C)(=O)=O)[N:5]=1)([CH3:3])[CH3:2].O1CCOCC1.[CH2:25]1[CH:29]2[CH2:30][CH:31]([NH2:32])[CH:27]([CH2:28]2)[CH2:26]1>O>[C@H:27]12[CH2:28][C@H:29]([CH2:25][CH2:26]1)[CH2:30][C@H:31]2[NH:32][C:6]1[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=1
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1C(C)C
Reactant: NC1CC2CCC1C2
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cnc(N[C@@H]2C[C@H]3CC[C@@H]2C3)nc1C(C)C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a mixture of ethyl 4-isopropyl-2-(methylsulfonyl)pyrimidine-5-carboxylate (500 mg) and 1,4-dioxane (10 mL) was added exo-2-aminonorbornane (612 mg) at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture was added water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain ethyl rac-2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]-4-isopropylpyrimidine-5-carboxylate (470 mg) as a white solid.
Reaction SMILES: Cl[CH:2]([C:8]([CH3:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:11][C:12]([NH2:14])=[O:13]>CO>[NH2:14][C:12]1[O:13][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([CH3:10])[N:11]=1
Reactant: NC(N)=O
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CO
Product: CCOC(=O)c1oc(N)nc1C
Temperature: 66 °C

Procedure:
Ethyl 2-chloroacetoacetate (8.0 mL, 59 mmol) was added to a mixture of urea (10.6 g, 176 mmol) in MeOH (40 mL), and the reaction mixture was heated to 66° C. overnight. Upon cooling to room temperature, the solids were collected by filtration and suspended in 1 N aqueous NaOH (50 mL). This was extracted with EtOAc (100 mL). The aqueous layer was brought to pH ˜11 with NaOH and was extracted with EtOAc (3×100 mL). The EtOAc extracts were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. This gave 5.02 g (50%) of the title compound as a white solid. LC-MS: RT=5.1 min, [M+H]+=171.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([CH2:6]N(C)C)=[C:4]([OH:13])[CH:3]=1.[H][H]>C(O)(=O)C.[Pd]>[F:12][C:11]1[C:2]([F:1])=[CH:3][C:4]([OH:13])=[C:5]([CH3:6])[CH:10]=1
Reactant: [H][H]
Reactant: CN(C)Cc1cc(F)c(F)cc1O
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1cc(F)c(F)cc1O

Procedure:
214 g of 4,5-difluoro-2-hydroxy-N,N-dimethylbenzylamine are initially charged in 700 ml of acetic acid in an autoclave, admixed with 50 g of palladium/activated carbon (5%) and heated with 70 bar of hydrogen to 100° C. for 26 hours. The autoclave is cooled and decompressed. The catalyst is filtered off and washed with acetic acid, and the filtrate is admixed with 3 000 ml of water. This aqueous solution is extracted three times with methyl tert-butyl ether. The combined organic phases are washed once with water and dried, and the solvent is distilled off under reduced pressure. The crude product is fractionally distilled under reduced pressure. The distillate can be further purified by crystallization. 98 g (58% of theory) of a colourless solid are obtained having a melting point of 68-70° C. and a boiling point of 78-80° C. at 13 mbar.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[N:4][C:3]=1[C:14](=O)[NH2:15].P(Cl)(Cl)(Cl)=O.Cl>CN(C)C=O>[NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[N:4][C:3]=1[C:14]#[N:15]
Reactant: NC(=O)c1nnn(Cc2ccccc2)c1N
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1nnn(Cc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
11 Parts of the 5-amino-1-benzyl-4-carbamoyl-1,2,3-triazole obtained are suspended in 50 parts dimethylformamide. At 0°, 15.3 parts phosphorus oxychloride are added dropwise thereto and the mixture is stirred for 15 minutes at room temperature and 15 minutes at 80°. After cooling to 25°, 50 parts 1 N hydrochloric acid are added thereto and the whole is heated to 100° for approximately 5 minutes. On cooling to room temperature the desired product precipitates which is then filtered and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[F:13][CH:14]([F:28])[O:15][C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[S:24](Cl)(=[O:26])=[O:25])=[CH:18][CH:17]=1.N1C=CC=CC=1>ClCCl>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9]([NH2:12])(=[O:11])=[O:10])=[C:2]([NH:1][S:24](/[CH:23]=[CH:22]/[C:19]2[CH:20]=[CH:21][C:16]([O:15][CH:14]([F:13])[F:28])=[CH:17][CH:18]=2)(=[O:26])=[O:25])[CH:7]=1
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Reactant: O=S(=O)(Cl)/C=C/c1ccc(OC(F)F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccc(Cl)cc1NS(=O)(=O)/C=C/c1ccc(OC(F)F)cc1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
2-Amino-4-chlorobenzenesulfonamide (200 mg, 0.97 mmol) and (E)-2-(4-(difluoromethoxy)phenyl)ethenesulfonyl chloride (260 mg, 0.97 mmol) were dissolved in anhydrous dichloromethane (5 mL) and flushed with argon. Anhydrous pyridine (0.391 mL, 4.84 mmol) was added and the reaction was stirred at room temperature under an inert atmosphere over night. The reaction was quenched using 2 M hydrochloric acid (20 mL) and extracted with dichloromethane. The combined organic phase was washed with water, dried over magnesium sulfate and concentrated under vacuum to give 426 mg (100% yield) of the title compound.
Reaction SMILES: [CH:1]1([C@H:4]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@@H:5]([OH:10])[C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.[C:19](OC)([CH3:21])=[CH2:20].[NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1>C1C=CC=CC=1>[C:15]([O:14][C:12]([N:11]1[C@@H:4]([CH:1]2[CH2:3][CH2:2]2)[C@H:5]([C:6]([O:8][CH3:9])=[O:7])[O:10][C:19]1([CH3:21])[CH3:20])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: C=C(C)OC
Reactant: COC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C1CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: COC(=O)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of 2.63 g of methyl (2R,3S)-3-cyclopropyl-3-tert-butoxycarbonylamino-2-hydroxypropionate in 60 ml of benzene are added 1.94 ml of isopropenylmethylether and 0.25 g of p-toluenesulfonic acid pyridinium salt. The mixture is stirred at room temperature for one hour, and then refluxed for 40 minutes. After the mixture is cooled, 1.94 ml of isopropenylmethylether is added to the reaction mixture. The mixture is stirred at room temperature for 10 minutes, refluxed for 40 minutes, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; hexane:ethyl acetate=8:1) to give 2.69 g of methyl (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-cyclopropyl-5-oxazolidinecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10](=O)[C:11]([C:16]#[N:17])=[CH:12][NH:13]3)=[CH:8][C:7]=2[CH:19]=1.P(Cl)(Cl)([Cl:22])=O>CN(C)C=O>[Cl:22][C:10]1[C:9]2[C:14](=[CH:15][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][C:7]=3[CH:8]=2)[N:13]=[CH:12][C:11]=1[C:16]#[N:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2cc3[nH]cc(C#N)c(=O)c3cc2c1
Solvent: CN(C)C=O
Product: COc1ccc2cc3ncc(C#N)c(Cl)c3cc2c1
Yield: 64.7 %

Procedure:
A reaction mixture of 767.7 mg (3.1 mmol) of 7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile in 12 mL of phosphorus oxychloride and 5 drops of N,N-dimethylformamide (DMF) is refluxed for 2 hours. After cooling, the mixture is concentrated to dryness in vacuo to give a dark residue. The residue is partitioned between methylene chloride and ice-cooled saturated aqueous sodium carbonate solution. The organic layer is washed with ice-cooled brine and dried over sodium sulfate. The crude product is passed through a short column of silica gel, and further eluted with additional methylene chloride, followed by 95:5 methylene chloride/ethyl acetate. Removal of the solvent in vacuo yields 532.0 mg (64.7%) of 4-chloro-7-methoxybenzo[g]quinoline-3-carbonitrile as a bright yellow solid, mp 242-243° C.
Reaction SMILES: ClC(Cl)C.[Cl:5][C:6]1[C:7]([F:34])=[C:8]([F:33])[CH:9]=[C:10]2[C:15]=1[N:14]([C:16]1[CH:21]=[C:20]([N+:22]([O-])=O)[C:19]([F:25])=[CH:18][C:17]=1[F:26])[CH:13]=[C:12]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:11]2=[O:32].[C:35](OC(=O)C)(=[O:37])C>[Pd].C(O)=O>[Cl:5][C:6]1[C:7]([F:34])=[C:8]([F:33])[CH:9]=[C:10]2[C:15]=1[N:14]([C:16]1[CH:21]=[C:20]([NH:22][CH:35]=[O:37])[C:19]([F:25])=[CH:18][C:17]=1[F:26])[CH:13]=[C:12]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:11]2=[O:32]
Reactant: CCOC(=O)c1cn(-c2cc([N+](=O)[O-])c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: O=CO
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cn(-c2cc(NC=O)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 20 ml of dichloroethane and 10 ml of formic acid were added 2 g of ethyl 8-chloro-6,7-difluoro-1-(2,4-difluoro-5-nitrophenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate and 200 mg of 10% palladium on carbon. Under a hydrogen atmosphere, the solution was stirred at room temperature for 3 hours and after addition of acetic anhydride, further stirred overnight. The catalyst was removed by a membrane filter and the filtrate was concentrated in vacua. Diethyl ether was added to the residue whereupon the solid was collected by filtration and washed with ethanol and diethyl ether to give 1.9 g of the title compound.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11](=[N:24][CH:25]1[CH2:29][CH2:28][O:27][C:26]1=[O:30])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N:31]1[CH:36]=[CH:35][C:34]([CH2:37]Cl)=[CH:33][CH:32]=1>C1COCC1>[C:11](=[N:24][C:25]1([CH2:37][C:34]2[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=2)[CH2:29][CH2:28][O:27][C:26]1=[O:30])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1OCCC1N=C(c1ccccc1)c1ccccc1
Reactant: ClCc1ccncc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1OCCC1(Cc1ccncc1)N=C(c1ccccc1)c1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
Potassium bis-(trimethylsilyl)amide (2.67, 13.4 mMol) was dissolved in anhydrous THF (50 mL) under an atmosphere of dry N2. The mixture was cooled to -40° C. to which was added a solution of 3-(benzhydrylidene-amino)-dihydro-furan-2-one (3.38 g, 12.7 mMol) in THF (30 mL). The mixture was warmed to ambient temperature and stirred at this temperature for 30 minutes. The solution was then cooled to -40° C. and a solution of 4-picolyl chloride (1.70 g, 13.4 mMol) in THF (20 mL) was added. The reaction mixture was warmed to ambient temperature and stirred for 18 hours. The mixture was partitioned between ethyl acetate-(EtOAc) and water. The organic layer was dried over sodium sulfate (Na2SO4), filtered and concentrated under vacuum to give a yellow oil. The oil was chromatographed on flash silica gel eluting with a gradient of EtOAc-hexanes (50:50) to EtOAc-hexanes (60:40 ) to give 2.26 g of the titled compound as an oil which crystallizes to a white solid upon standing.