Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][O:3][NH2:4].[NH2:5][C:6]1[S:10][N:9]=[C:8]([C:11](=O)[C:12]([OH:14])=[O:13])[N:7]=1.[OH-].[Na+]>C(O)C.O>[NH2:5][C:6]1[S:10][N:9]=[C:8](/[C:11](=[N:4]/[O:3][CH2:2][F:1])/[C:12]([OH:14])=[O:13])[N:7]=1
Reactant: NOCF
Reactant: Nc1nc(C(=O)C(=O)O)ns1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nc(/C(=N/OCF)C(=O)O)ns1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To a mixture of a solution of fluoromethoxyamine (0.58 g) in ethanol (25 ml) and water (0.45 ml), 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-oxoacetic acid (1 g) was added. After adjusting the pH of the resulting mixture to 4-5 with a 10% aqueous solution of sodium hydroxide, the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, water (20 ml) and sodium chloride (10 g) were added, and the pH of the solution was adjusted to 1 with concentrated hydrochloric acid. The solution was extracted four times with ethyl acetate (30 ml). After washing the extract with saturated saline, anhydrous magnesium sulfate was added to the extract to dry the same. The solvent was distilled off and the residue was crystallized from a 1:3 mixture of acetone and isopropyl ether, thereby obtaining the target product (0.38 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]=O.O.NN.C(O)COCCO.[OH-].[K+]>O>[CH2:10]([C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:16]=1
Reactant: O=Cc1ccccc1-c1cc2ccccc2o1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: c1ccc(Cc2cc3ccccc3o2)cc1
Temperature: 25 °C
Yield: 73.1 %

Procedure:
A suspension of 2-benzofuranylphenyl-methanone (34.8 g, 0.157 mol), hydrazine monohydrate (31 mL, 0.639 mol) and diethylene glycol (72 mL) was heated to reflux for 10 min and cooled to room temperature. Potassium hydroxide (22.9 g, 0.408 mol) was added. The reaction mixture was heated in 130° C. oil bath for 1 h., cooled to room temperature and added to water. The oil was extracted with ether. Silica ge was added to the ether phase and the solvent was removed. The adsorbate was flash chromatographed eluent: (petroleum ether) to provide the title compound as an oil (23.9 g, 90%): NMR (CDCl3); δ7.5-7.1 (m, 9 H), 6.38 (s, 1 H), 4.10 (s, 2 H).
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=1.[Br:10]Br>C(O)(=O)C>[Br:10][C:6]1[C:7](=[O:9])[NH:8][C:3]([S:2][CH3:1])=[N:4][CH:5]=1
Reactant: BrBr
Reactant: CSc1nccc(=O)[nH]1
Solvent: CC(=O)O
Product: CSc1ncc(Br)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-methylsulfanyl-3H-pyrimidin-4-one (36 g, 0.25 mol) in glacial acetic acid (500 mL) was cooled to 0° C. in an ice bath and treated with Br2 (15.6 mL, 0.3 mol). The reaction mixture changed in color from yellow to brown within 0.5 hours, and was allowed to warm to room temperature where it stirred overnight. When all the starting material had been consumed (as indicated by TLC and HPLC UV detection at λ=254 nm), the reaction mixture was slowly poured into a mixture of ice/H2O (2 liters). The resulting white precipitate was collected by vacuum filtration and washed with H2O (200 mL) and Et2O (2×250 mL). The off-white solid was then suspended in anhydrous toluene (250 mL) and concentrated to dryness under reduced pressure in a 60° C. H2O bath. 5-Bromo-2-methylsulfanyl-3H-pyrimidin-4-one was obtained as a white solid (30.4 g, 55% yield).
Reaction SMILES: Cl[C:2]1[C:3]([S:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:27])=[O:26])=[CH:4][C:5]([S:16]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])=[C:6]([N:8]([CH2:14][CH3:15])[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[CH:7]=1.[C:34]1([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:14]([N:8]([C:6]1[CH:7]=[C:2]([N:43]2[CH2:44][CH2:45][N:40]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:41][CH2:42]2)[C:3]([S:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:26])=[O:27])=[CH:4][C:5]=1[S:16]([N:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)(=[O:18])=[O:17])[CH2:9][CH2:10][N:11]([CH3:12])[CH3:13])[CH3:15]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCN(CCN(C)C)c1cc(Cl)c(S(=O)(=O)N2CCCCC2)cc1S(=O)(=O)N1CCCCC1
Product: CCN(CCN(C)C)c1cc(N2CCN(c3ccccc3)CC2)c(S(=O)(=O)N2CCCCC2)cc1S(=O)(=O)N1CCCCC1
Temperature: 90 °C
Reaction time: 9 h

Procedure:
2.63 g (5.1 mmol) of N-[5-chloro-2,4-bis-(piperidine-1-sulfonyl)-phenyl]-N-ethyl-N′,N′-dimethylethane-1,2-diamine, prepared as described below, are dissolved in 12 ml of 4-phenylpiperazine, and the reaction mixture is stirred at 90° C. for 9 hours. Workup entails extraction with ethyl acetate/water, drying of the combined organic phases over sodium sulfate, and removing the extractant under reduced pressure in a rotary evaporator. This is followed by purification by chromatography on silica gel (40-63μ, Merck Darmstadt; mobile phase=dichloromethane/methanol=20/1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:18]([NH:20]C(=O)OC(C)(C)C)[CH3:19])[CH:5]=[CH:6][C:7]=1[C:8](=[O:17])[NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]1.[ClH:28].O1CCOCC1>CO>[NH2:20][C@H:18]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]2)=[O:17])=[C:2]([F:1])[CH:3]=1)[CH3:19].[ClH:28]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)N[C@H]2CC[C@H](O)CC2)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@H](N)c1ccc(C(=O)N[C@H]2CC[C@H](O)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl (S)-1-(3-fluoro-4-(trans-4-hydroxycyclohexylcarbamoyl)phenyl)ethylcarbamate (33 mg, 0.087 mmol) was added, HCl 4M in Dioxane (2 mL, 8.00 mmol) and MeOH (0.2 ml). The reaction was stirred at room temperature for 1 hour, followed by LCMS. The solvent was concentrated off to residue to give 4-((S)-1-aminoethyl)-2-fluoro-N-(trans-4-hydroxycyclohexyl)benzamide in quantitative yield (0.087 mmol) as HCl salt. LCMS m/z 281.1 (M+H)+, Rt 0.33 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5][OH:6].[CH3:11][S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C>ClCCl>[CH3:11][S:12]([O:6][CH2:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[C:8]([Cl:10])[CH:7]=1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cc(Cl)cc(Cl)c1

Procedure:
To a solution of 3.5 g of 3,5-dichlorobenzyl alcohol (Aldrich) in 75 mL of dichloromethane at 0° C. was added 1.8 mL of methane sulfonylchloride followed by 3.5 mL of triethylamine added dropwise. After 2 hours the solution was diluted to 150 mL with dichloromethane, washed with 3N HCl, saturated aqueous NaHCO3 dried with Na2SO4 and the solvents removed to yield the desired 3,5-dichlorobenzyl methanesulfonate as a yellow oil that was used without purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[F:16][C:17]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:18]=1CBr>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[C:23]2[CH:24]=[C:17]([F:16])[CH:18]=[CH:21][C:22]=2[F:25])=[CH:5][CH:4]=1)#[N:2]
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Product: N#Cc1ccc(N(c2cncnc2)c2cc(F)ccc2F)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and 2,5-difluorobenzyl bromide
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[F:10].C([O-])(=O)C.[NH4+].[N+:16]([CH3:19])([O-:18])=[O:17].O>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:19][N+:16]([O-:18])=[O:17])=[CH:4][C:3]=1[F:10]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(Cl)c(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1ccc(Cl)c(F)c1
Yield: 65.9 %

Procedure:
4-Chloro-3-fluorobenzaldehyde (13 g, 82 mmol) and ammonium acetate (14.6 g, 189 mmol) were dissolved in acetic acid (150 ml) and nitromethane (12.6 ml, 234 mmol) was added. The solution was heated to reflux for 1.5 h. After cooling to RT water (120 ml) was added. A solid precipitated. The reaction was extracted three times with methylene chloride. The combined organic layers were washed with water and sat. aq. NaCl solution, dried over magnesium sulfate, filtered and the solvent was removed in vacuo. The residue was purified by flash column chromatography (Ethyl acetate/cyclohexane:1/4). The crude product was suspended in heptane, filtered and dried to yield 1-chloro-2-fluoro-4-(2-nitro-vinyl)-benzene (10.9 g, 66%) as a light yellow solid. 1H NMR (CDCl3, 300 MHz): δ 7.29 (d, J=7.8 Hz, 1H), 7.33 (d, J=9.3 Hz, 1H), 7.50 (t, J=7.5H, 1H), 7.54 (d, J=13.6 Hz, 1H), 7.92 (d, J=13.6 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][N:5]([CH:17]1[CH2:22][C:21]([CH3:24])([CH3:23])[NH:20][C:19]([CH3:26])([CH3:25])[CH2:18]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:28][C:29]1([CH3:38])[CH2:34]C(O)[CH2:32][C:31]([CH3:37])([CH3:36])[NH:30]1.[NH2-].[Li+].CO>CCCCCCC>[CH3:28][C:29]1([CH3:38])[CH2:34][CH:1]([O:2][C:3](=[O:27])[CH2:4][N:5]([CH:17]2[CH2:22][C:21]([CH3:24])([CH3:23])[NH:20][C:19]([CH3:26])([CH3:25])[CH2:18]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:32][C:31]([CH3:37])([CH3:36])[NH:30]1
Reactant: CCCCCCCCCCCN(CC(=O)OC)C1CC(C)(C)NC(C)(C)C1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: [Li+]
Agent: [NH2-]
Solvent: CO
Solvent: CCCCCCC
Product: CCCCCCCCCCCN(CC(=O)OC1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1
Yield: 63.2 %

Procedure:
To the same flask as used in Example 1 were added 39.4 g (0.1 mole) of N-(2,2,6,6-tetramethyl-4-piperidinyl)-N-undecanylglycine methyl ester, 17.3 g (0.11 mole) of 2,2,6,6-tetramethyl-4-piperidinol, 0.23 g of lithium amide and 100 g of heptane. The temperature was raised with stirring, and reaction was carried out at 98° to 105° C. for 6 hours, during which methanol was removed from the reaction system by means of the Deanstark trap. After completion of the reaction, water was added to the reaction solution to dissolve the product in the heptane layer. The heptane layer was separated, and heptane in the layer was removed by distillation to obtain 32.1 g of N-(2,2,6,6-tetramethyl-4-piperidinyl)-N-undecanylglycine(2,2,6,6-tetramethyl-4-piperidinyl)ester as a pale brown liquid. Yield, 61% based on N-(2,2,6,6-tetramethyl-4-piperidinyl)-N-undecanylglycine methyl ester.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1.Cl[C:33]([C@@H:35]([O:37]C(=O)C)[CH3:36])=[O:34]>>[OH:37][C@@H:35]([CH3:36])[C:33]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1)=[O:34]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c13)OCO2
Product: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCN(C(=O)[C@H](C)O)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-butoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide (example A181) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=2)[C:10]([CH3:21])([CH3:20])[CH2:9][C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].I[CH2:24][CH2:25]C1C=CC=CC=1>>[C:3]1([CH2:2][CH2:1][N:7]2[C:16]3[C:11](=[CH:12][C:13]([C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=3)[C:10]([CH3:21])([CH3:20])[CH2:9][C:8]2=[O:22])[CH:25]=[CH:24][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCCCN1C(=O)CC(C)(C)c2cc(C(C)=O)ccc21
Reactant: ICCc1ccccc1
Product: CC(=O)c1ccc2c(c1)C(C)(C)CC(=O)N2CCc1ccccc1
Yield: 34 %

Procedure:
Following a procedure similar to that used for the preparation of Intermediate 6a but using (2-iodo-ethyl)benzene as the alkylating reagent the title compounds was obtained as a colorless oil (34% yield).
Reaction SMILES: [CH3:1][C:2]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)([CH3:5])[C:3]#[CH:4]>ClC1C=CC=CC=1Cl>[CH3:5][C:2]1([CH3:1])[O:6][C:7]2[C:8](=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[CH:10]3)[CH:4]=[CH:3]1
Reactant: C#CC(C)(C)Oc1ccc2ncccc2c1
Solvent: Clc1ccccc1Cl
Product: CC1(C)C=Cc2c(ccc3ncccc23)O1

Procedure:
A solution of 6-[(1,1-dimethyl-2-propynyl)oxy]quinoline (16.7 mmol) in 1,2-dichlorobenzene (10 mL) was stirred at 180° C. for 1 hour. Upon the completion of the reaction, the solvent was distilled off, and the residue was recrystallized with hexane-ethyl acetate to obtain the aimed compound (2-step, quant.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:16]=[CH:17]/[C:18]([NH:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:19])[CH:6]=[CH:7][C:8]=1[O:9]COCCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:9][C:8]1[CH:7]=[CH:6][C:5](/[CH:16]=[CH:17]/[C:18]([NH:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][CH:30]=3)[CH2:27][CH2:28]2)=[O:19])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COCCOCOc1ccc(/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COc1cc(/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)ccc1O
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
A mixture of 1-[2-[3-[3-methoxy-4-{(2-methoxyethoxy)-methoxy}phenyl]-(E)-propenoylamino]ethyl]-4-(3-indolyl)-piperidine (2 g) and p-toluenesulfonic acid monohydrate (1.05 g) in methanol (40 ml) was efluxed for 30 minutes under an inert atmosphere. After the solvent was removed under reduced pressure, the residue was treated with water (100 ml), adjusted to pH 10.0 with a sodium carbonate solution and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over magnesium sulfate. After removal of the solvent, the residue was subjected to column chromatography on silica gel (31 g) and eluted with a mixture of chloroform and methanol (8:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure to give 1-[2-{3-(4-hydroxy-3-methoxyphenyl)-(E)-propenoylamino}ethyl]-4-(3-indolyl)piperidine (0.89 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[N:21]1([C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][N:28]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][C:27]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[N:28][CH:29]=3)=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(N2CCOCC2)nc1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-6-morpholin-4-yl-nicotinamide was prepared starting from intermediate D and 6-morpholin-4-yl-nicotinic acid. MS calcd. for C26H23ClN4O3 [(M+H)+] 474.9, obsd. 474.9.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([NH:13][C:14]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[O:15])=[CH:12][C:7]=2[C:6]([CH3:28])([CH3:27])[CH2:5][CH2:4][C:3]1=[O:29].[OH-].[Na+]>C(O)C.O>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([NH:13][C:14]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=3)=[O:15])=[CH:12][C:7]=2[C:6]([CH3:27])([CH3:28])[CH2:5][CH2:4][C:3]1=[O:29]
Reactant: CCOC(=O)c1ccc(C(=O)Nc2ccc3c(c2)C(C)(C)CCC(=O)N3C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1C(=O)CCC(C)(C)c2cc(NC(=O)c3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
1.00 g of ethyl p-[(2,3,4,5-tetrahydro-1,5,5-trimethyl-2-oxo-1H-1-benzazepin-7-yl)carbamoyl]benzoate in 75 ml of ethanol/water (2:1) was treated with 0.40 g of sodium hydroxide and the reaction mixture was stirred at room temperature overnight. Thereafter, it was poured on to ice/conc. hydrochloric acid, extracted with ethyl acetate, the extract was washed with saturated sodium chloride solution, dried and concentrated up to crystallization. There was obtained 0.79 g of p-[(2,3,4,5-tetra- hydro-1,5,5-trimethyl-2-oxo-1H-1-benzazepin-7-yl)carbamoyl]benzoic acid, m.p. >275° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[N:8][C:7]([Sn:10]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:6][N:5]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C1COCC1>[CH3:23][S:24]([NH:3][C:4]1[CH:9]=[N:8][C:7]([Sn:10]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:6][N:5]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(N)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(NS(C)(=O)=O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.3 %

Procedure:
NaH (60%, 20 mg) was added into a solution of 2-amino-5-(tri-n-butylstannyl)pyrazine (0.2 g) in THF (30 mL) at room temperature. After the mixture stirred at room temperature for 30 minutes, to it was added methylsulfonyl chloride (63 mg). The reaction mixture was stirred at room temperature over 8 hours. The reaction was quenched with aqueous ammonium chloride solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic extract was dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to afford 2-methylsulfonylamino-5-(tri-n-butylstannyl)pyrazine (20 mg).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[C:13]1([S:19]([CH3:22])(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Br[CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.Cl>C1COCC1>[C:13]1([S:19]([CH2:22][CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCCC1CCCCC1
Reactant: CS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=S(=O)(CCCC1CCCCC1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 51.7 %

Procedure:
A solution of 2.5M nBuLi in hexanes (1.9 mL, 4.7 mmol) was added to a solution of diisopropylamine (660 μL, 4.7 mmol) in THF (9.0 mL) at ambient temperature. After 10 min, the mixture was cooled to −78° C. and methyl phenyl sulfone (700 mg, 4.5 mmol) was added to the reaction vessel. The cold bath was removed and after stirring for 30 min, 1-bromo-2-cyclohexylethane (1.3 g, 6.7 mmol) was added to the reaction mixture. The mixture was allowed to warm to ambient temperature and stir for 18 hours. A solution of 2N HCl was added to the reaction mixture followed by extraction with EtOAc (2×). The organic phases were combined, dried (MgSO4) and concentrated. The residue was chromatographed (silica gel; EtOAc/hexanes, 1:8) to afford a clear oil (620 mg, 52%). 1H NMR (CDCl3, MHz) δ 0.75-0.91 (m, 2H), 1.07-1.26 (m, 6H), 1.58-1.76 (m, 7H), 3.06 (t, J=8 Hz, 2H), 7.55-7.70 (m, 3H), 7.92 (m, 2H); MS (CI/NH3) m/z: (M+NH4)+ 284.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:23])[C:13](=[CH:19]OCC)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10].O>C(OCC)(=O)C>[CH2:7]([N:6]1[C:2]([NH:1][CH:19]=[C:13]([C:12]([O:11][CH2:9][CH3:10])=[O:23])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3][CH:4]=[N:5]1)[CH3:8]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCn1nccc1N
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CNc1ccnn1CC)C(=O)OCC
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of 5-amino-1-ethylpyrazole (1 gm, 0.0089 mole) and diethylethoxymethylenemalonate (1.9 ml, 0.0089 mole) was stirred at 120° C. for about 1 hour. The reaction mixture was poured into water and extraction was done with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give yellow oil. Yield: 2.5 g. m/z: (M++1) 282.0.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=[C:11]3[C:16]=2[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[C:28]([Cl:35])[CH:27]=1.C(N(CC)CC)C>ClCCCl>[CH3:23][O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]2[N:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:10]=[C:11]3[C:16]=2[CH2:15][CH2:14][CH2:13][CH2:12]3)=[O:34])=[C:28]([Cl:35])[CH:27]=1
Reactant: c1ccc(-n2nc3c(c2NC2CCCCC2)CCCC3)cc1
Reactant: COC(=O)c1ccc(N=C=O)c(Cl)c1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)N(c2c3c(nn2-c2ccccc2)CCCC3)C2CCCCC2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 1.2, cyclohexyl-(2-phenyl-4,5,6,7-tetrahydro-2H-indazol-3-yl)-amine (example 45) was reacted with 3-chloro-4-isocyanato-benzoic acid methyl ester (example 9.1) in 1,2-dichloroethane in the presence of triethylamine for 120 h under reflux conditions to give the title compound as yellow solid. MS: m/e=507.2 [M+H+].
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([CH2:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[S:23][C:17]=2[N:16]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:15]1=[O:39].[C:40](=[O:42])=[O:41].[OH-].[Na+]>O1CCCC1>[CH3:13][N:14]1[C:19](=[O:20])[C:18]2[C:21]([C:40]([OH:42])=[O:41])=[C:22]([CH2:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[S:23][C:17]=2[N:16]([CH2:35][CH:36]([CH3:37])[CH3:38])[C:15]1=[O:39]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cc(Cc3cccc4ccccc34)sc21
Reactant: O=C=O
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)O)c(Cc3cccc4ccccc34)sc21
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
n-Butyllithium (2.0M solution in hexanes, 1.90 ml) was added dropwise to a solution of diisopropylamine (0.069 ml) in anhydrous tetrahydrofuran (30 ml) at 0° C., under nitrogen. The solution was stirred for 5 minutes then cooled to −78° C. and a solution of 3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.50 g) in anhydrous tetrahydrofuran (15 ml) was added dropwise. After 15 minutes, the flask was transferred to a sealed bomb containing carbon dioxide pellets (2 g) and heated to 50° C. for 18 hours. The reaction mixture was cooled to room temperature then added to aqueous sodium hydroxide solution (0.25M, 75 ml) and washed with ether (2×75 ml). The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ether (2×75 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with isohexane:ethyl acetate (3:1) containing 1% acetic acid, to give the subtitle compound (0.337 g) as a solid.