Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][C@H:14]([C:19]([NH:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][C:24]([OH:26])=[O:25])=[O:20])[C@H:15]([CH2:17][CH3:18])[CH3:16].C([O-])(O)=O.[Na+].O>CO>[CH2:2]([NH:13][C@H:14]([C:19]([NH:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][C:24]([OH:26])=[O:25])=[O:20])[C@H:15]([CH2:17][CH3:18])[CH3:16])[C:3]1([O:12][CH2:11][C@@H:9]([OH:10])[C@@H:7]([OH:8])[C@@H:5]1[OH:6])[OH:4]
Reactant: CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(=O)O)C(=O)O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC[C@H](C)[C@H](NCC1(O)OC[C@@H](O)[C@@H](O)[C@@H]1O)C(=O)N[C@@H](CC(=O)O)C(=O)O

Procedure:
30 g of anhydrous D-glucose were dissolved together with 3 g of isoleucyl-aspartic acid in 1.2 l of methanol, and 200 mg of NaHCO3 were added. The mixture was subsequently heated under reflux for 2 hours. The water which had formed was then removed by distillation with butanol, and the reaction mixture was diluted with methanol and again heated for 2 hours. After completion of the reaction, solvent was removed from the solution in vacuo, and the residue, in 300 ml of water, was applied to a 600 ml-capacity chromatography column (diameter 5 cm) packed with QAE-®Sephadex A-25. Whereas the excess glucose was located in the fore-run, it was possible to obtain selectively N-(1-deoxyfructopyranos-1-yl)-isoleucylaspartic acid using an acetic acid gradient (0 to 0.5 molar). These eluates from the column were collected and freeze-dried.
Reaction SMILES: O.[NH2:2][NH2:3].Br[CH:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)[CH2:6][CH2:7][CH3:8]>C(O)(C)C>[F:16][C:15]([F:18])([F:17])[C:12]1[CH:13]=[CH:14][C:9]([CH:5]([NH:2][NH2:3])[CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=1
Reactant: NN
Reactant: CCCC(Br)c1ccc(C(F)(F)F)cc1
Solvent: CC(C)O
Solvent: O
Product: CCCC(NN)c1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Hydrazine monohydrate (8.9 g) was dissolved in isopropanol (25 ml) and 1-(1-bromobutyl)-4-(trifluoromethyl)benzene (as prepared in WO 2005013985, 2.0 g, 7.12 mmol) added. The mixture was heated to 70° C. and stirred for 16 h. After this time the solvent was removed and the residue taken up in ethyl acetate and washed three times (H2O). The combined organics were dried (sodium sulfate) and concentrated to give the mixture of products as a white solid suspended in a clear oil. The mixture was triturated with diethyl ether to give a white solid; 1H NMR δ (ppm)(DMSO): 9.20 (1 H, s), 7.76 (2 H, d, J=8.1 Hz), 7.64 (2 H, s), 4.16 (1 H, s), 1.85 (1 H, s), 1.59 (1 H, s), 1.20-0.96 (2 H, m), 0.82 (3 H, t, J=7.3 Hz).
Reaction SMILES: [BH4-].[Na+].C(O)C.[Cl:6][C:7]1[CH:12]=[C:11](/[CH:13]=[CH:14]/[N+:15]([O-:17])=[O:16])[CH:10]=[C:9]([F:18])[CH:8]=1>O1CCOCC1>[Cl:6][C:7]1[CH:12]=[C:11]([CH2:13][CH2:14][N+:15]([O-:17])=[O:16])[CH:10]=[C:9]([F:18])[CH:8]=1
Reactant: O=[N+]([O-])/C=C/c1cc(F)cc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: O=[N+]([O-])CCc1cc(F)cc(Cl)c1
Yield: 58.5 %

Procedure:
Add sodium borohydride (0.75 g, 19.7 mmol) to a solution of 1,4-dioxane (10 mL) and absolute ethanol (2.5 mL) in a room temperature water bath. Next add 1-chloro-3-fluoro-5-((E)-2-nitrovinyl)-benzene (1.5 g, 8.98 mmol) in 1,4-dioxane (10 mL) dropwise and stir at room temperature for 1 hour (Bhattacharjya, Synthesis, 1985, 886-997). Add ice chips, glacial acetic acid (2 mL), water (2 mL), concentrate and dilute in dichloromethane/water. Wash the dichloromethane layer with water, saturated aqueous sodium chloride, dry (sodium sulfate), filter and purify (silica gel chromatography, eluting with 1:1 dichloromethane:hexanes) to give the desired compound as an oil (1.07 g 70%).
Reaction SMILES: [NH2:1][CH:2]([CH:7]([OH:23])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[C:31](Cl)(=[O:47])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>C1C=CC=CC=1>[C:31]([NH:1][CH:2]([CH:7]([OH:23])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:3]([O:5][CH3:6])=[O:4])(=[O:47])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCCCCCC(O)C(N)C(=O)OC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCC(=O)NC(C(=O)OC)C(O)CCCCCCCCCCCCCCC
Reaction time: 3 h
Yield: 87 %

Procedure:
10.7 g (0.033 mole) of methyl 2-amino-3-hydoxyoctadecanoate prepared according to Example 1 are dissolved in 200 cm3 of dry benzene and then 3.28 g of triethylamine are added. 8.92 g (0.033 mole) of palmitoyl chloride dissolved in 60 cm3 of benzene are added dropwise to this solution between 20 and 35° C. After 3 hours' stirring, the triethylamine hydrochloride is removed by filtration at 40° C. The organic phase is washed twice with 100 cm3 of water. The benzene solution is dried over sodium sulphate and then part of the benzene is removed by evaporation. 16.3 g of methyl 2-hexadecanoylamino-3-hydroxyoctadecanoate are isolated by crystallization.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:9]2.[F:30][CH:31]([F:34])[CH2:32]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[F:30][CH:31]([F:34])[CH2:32][N:15]([S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)(=[O:17])=[O:18])[C:13]1[CH:14]=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:9]2
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc(NS(=O)(=O)c3ccccn3)c2[nH]1
Reactant: OCC(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(OCCOC)cc(N(CC(F)F)S(=O)(=O)c3ccccn3)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a mixture of ethyl 5-(2-methoxyethoxy)-7-[(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylate (500 mg), 2,2-difluoroethanol (0.09 mL), tributylphosphine (0.59 mL) and toluene (30 mL) was added 1,1′-(azodicarbonyl)dipiperidine (600 mg), and the mixture was stirred at room temperature overnight. The insoluble substance was filtered off, and the filtrate was diluted with ethyl acetate and 1N aqueous hydrochloric acid solution. The organic layer was washed with aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography to give the title compound (211 mg, yield 37%) as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[NH:17][CH2:18][C@H:19]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])C.[NH:39]1[CH2:44][CH2:43][CH2:42][N:41]=[C:40]1[NH2:45]>CN(C)C=O>[C:23]([O:22][C:20](=[O:21])[C@@H:19]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:18][NH:17][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[C:14]=1[N:15]=[CH:16][N:8]2[CH2:7][CH2:6][CH2:5][C:4](=[O:3])[NH:45][C:40]1[NH:41][CH2:42][CH2:43][CH2:44][N:39]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)CCCn1cnc2c(NC[C@H](NC(=O)OCc3ccccc3)C(=O)OC(C)(C)C)ncnc21
Reactant: NC1=NCCCN1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CNc1ncnc2c1ncn2CCCC(=O)NC1=NCCCN1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
200 mg (0.38 mmol) of 4-[6-((2S)-2-benzyloxycarbonylamino-2-tert-butoxycarbonyl-ethylamino)-purin-9-yl]-butyric acid ethyl ester was dissolved in 2 ml of dimethylformamide and 188 mg (1.9 mmol) of 1,4,5,6-tetrahydro-pyrimidin-2-ylamine was added. The solution was stirred at room temperature for 16 hours. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and the solution was washed twice with 10% aqueous citric acid solution and twice with water. Product in the combined aqueous phase was extracted five times with dichloromethane. The combined organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane/methanol (10/1), followed by DCM/AcOH/water (85:15:1.5:1.5). Yield: 70.6 mg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[OH:11])=[CH:6][CH:5]=1.[C:20]([N:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[C:23]([O:22][C:20]([N:27]1[CH2:32][CH2:31][CH:30]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([CH:10]([OH:11])[C:7]3[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:19])=[CH:9][CH:8]=3)=[CH:13][CH:14]=2)[CH2:29][CH2:28]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(=O)c1ccc(C(O)c2ccc(N)cc2)cc1
Product: COC(=O)c1ccc(C(O)c2ccc(NC3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Yield: 85.1 %

Procedure:
Using general procedure A, 4-[(4-amino-phenyl)-hydroxy-methyl]-benzoic acid methyl ester (see EXAMPLE 100) (1.40 g, 5.44 mmol) and 1-Boc-4-piperidone (1.63 g, 8.18 mmol) gave 4-{4-[hydroxy-(4-methoxycarbonyl-phenyl)-methyl]-phenylamino}-piperidine-1-carboxylic acid tert-butyl ester as a pale solid (2.04 g, 85%).
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]2=[N:11][C:10]=1[C:18]([O:20]CC)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+:24]>C(O)C>[O:1]([CH2:8][C:9]1[N:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]2=[N:11][C:10]=1[C:18]([O-:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:24]
Reactant: CCOC(=O)c1nc2ccccn2c1COc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])c1nc2ccccn2c1COc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Ethyl 3-(phenoxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (889 mg) was dissolved in ethanol (50 ml), 2N aqueous sodium hydroxide solution (3 ml) was added, and the mixture was stirred at room temperature for 15 hr. The precipitated crystals were collected by filtration, and washed with ethanol to give sodium 3-(phenoxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (680 g). The obtained sodium 3-(phenoxymethyl)imidazo[1,2-a]pyridine-2-carboxylate (290 mg), tert-butyl (3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (370 mg) and N,N-diisopropylethylamine (862 μl) were dissolved in acetonitrile (20 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (561 mg) was added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (9:1) was concentrated under reduced pressure to give the object product (563 mg).
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:23][C@@:22]2([CH3:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:25])[CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6][C@@H:5]1[OH:27])[CH3:2].N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([O:27][C@@H:5]1[C@@H:4]([O:3][CH2:1][CH3:2])[CH2:23][C@@:22]2([CH3:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:25])[CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1OC(C)=O
Reaction time: 24 h

Procedure:
2β-Ethoxy-3α-hydroxy-5α-pregnane-11,20-dione (500 mg.) in dry methylene chloride (5 ml.) at 0° was treated with pyridine (2.0 ml.) and acetic anhydride (2.0 ml.). After 24 hours, methylene chloride was added, and the solution was washed with dilute hydrochloric acid and with water. It was then dried over sodium sulphate and evaporated to an oil. The title compound (350 mg.) was obtained as a colourless foam, [α]D + 132°.
Reaction SMILES: Br[CH:2]=[CH:3][CH3:4].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:21]([NH:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][CH:18]=3)=[CH:8][CH:7]=1.C(=O)([O-])O.[Na+]>C(O)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:21]([NH:22][CH:23]3[CH2:24][CH2:25][N:26]([CH2:4][CH:3]=[CH2:2])[CH2:27][CH2:28]3)=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][CH:18]=3)=[CH:8][CH:7]=1
Reactant: CC=CBr
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3cncnc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C=CCN1CCC(Nc2nc3cncnc3n2Cc2ccc(F)cc2)CC1
Reaction time: 1 h
Yield: 22 %

Procedure:
A mixture of 1.2 parts of bromo-1-propene, 3.26 parts of 9-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-9H-purin-8-amine, 1.5 parts of sodium hydrogen carbonate and 40 parts of ethanol was stirred for 1 hour at reflux temperature. The reaction mixture was filtered over diatomaceous earth while hot and the filtrate was evaporated. The residue was taken up in water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 0.8 parts (22%) of 9-[(4-fluorophenyl)methyl]-N-[1-(2-propenyl)-4-piperidinyl)-9H-purin-8-amine; mp. 144.8° C. (compound 120).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:2]1=2.C([Mg]Cl)(C)C.[C:16]1([CH:22]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[C:24]2=[O:33])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>O1CCCC1.ClCCCl>[C:34]1([CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([OH:32])([C:8]3[C:7]([OH:10])=[CH:6][C:3]4[CH:4]=[CH:5][S:1][C:2]=4[CH:9]=3)[C:24]2=[O:33])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Oc1ccc2sccc2c1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc2sccc2cc1O
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 59.3 %

Procedure:
To a solution of benzo[b]thiophen-5-ol (1.39 g, 9.25 mmol) in tetrahydrofuran (50 mL) at 5° C. was added a 2 M solution of isopropylmagnesium chloride in tetrahydrofuran (5.0 mL, 10 mmol). The reaction mixture was stirred at 5° C. for 15 min and concentrated in vacuo. To the residue were added 1,2-dichloroethane (100 mL) and 1-(diphenylmethyl)-1H-indole-2,3-dione (2.5 g, 8.0 mmol). The reaction mixture was heated at reflux for 3 h, allowed to cool to ambient temperature and stirred for 48 h. Saturated aqueous ammonium chloride (10 mL) was added and the phases were separated. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 0% to 20% gradient of ethyl acetate in dichloromethane to afford 1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-1-benzothiophen-6-yl)-1,3-dihydro-2H-indol-2-one (2.2 g, 59%) as an off-white solid: MS (ES+) m/z 486.0 (M+23).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])[C:3]=1[CH3:21].[I:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([CH3:33])([CH3:32])[CH2:28][NH:29]2)=[CH:25][CH:24]=1.Cl.O1CCOCC1>CN1C(=O)CCC1>[F:20][C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[C:4]1[C:3]([CH3:21])=[C:2]([N:29]2[C:30]3[C:26](=[CH:25][CH:24]=[C:23]([I:22])[CH:31]=3)[C:27]([CH3:33])([CH3:32])[CH2:28]2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: CC1(C)CNc2cc(I)ccc21
Reactant: Cc1c(-c2cc(F)ccc2F)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2cc(F)ccc2F)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(I)cc21
Temperature: 150 °C

Procedure:
Prepared according to procedure L using 4-chloro-2-(2,5-difluorophenyl)-7-fluoro-3-methylquinoline (150 mg, 0.49 mmol) (described herein), 6-iodo-3,3-dimethylindoline (160 mg, 0.59 mmol) (described herein), and 4.0 hydrochloric acid in 1,4-dioxane (120 μL, 0.49 mmol) in NMP (810 μL). The reaction mixture was stirred and heated at 150° C. for 3 h. Purification afforded 2-(2,5-difluorophenyl)-7-fluoro-4-(6-iodo-3,3-dimethylindolin-1-yl)-3-methylquinoline as a yellow solid. Mass Spectrum (ESI) m/e=545 (M+1).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]1[O:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6]1>O>[N+:1]([C:10]1[CH:11]=[CH:12][C:7]2[O:6][CH2:5][O:13][C:8]=2[CH:9]=1)([O-:4])=[O:2]
Reactant: c1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)OCO2
Temperature: 0 °C

Procedure:
To 150 mls. of concentrated nitric acid cooled to and maintained at 0°C. is added 100 gms. of methylenedioxybenzene dropwise with vigorous stirring. At the end of the addition, the reaction mixture is diluted with several volumes of water, the precipitated solids collected by vacuum filtration and washed with several portions of water. Recrystallization of the crude solids from methanol provided 1-nitro-3,4-methylenedioxybenzene, m.p. 130°-141°C.
Reaction SMILES: [NH2:1][C:2]1[N:3](C(=O)N)[N:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:9][CH:8]=1.[OH-].[Na+]>CO>[NH2:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)=[CH:11][CH:12]=2)=[CH:5][NH:4][N:3]=1
Reactant: COc1cccc(Cc2ccc(-c3cnn(C(N)=O)c3N)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(Cc2ccc(-c3c[nH]nc3N)cc2)c1
Yield: 50.7 %

Procedure:
To a solution of 3-amino-2-carbamoyl-4-[4-(3-methoxyphenylmethyl)phenyl]pyrazole (4.1 g) in methanol (50 ml) was added 5N sodium hydroxide solution (20 ml), and the mixture was refluxed for 30 minutes. Methanol was distilled away under reduced pressure. To the residue was added water (150 ml), and the mixture was neutralized (pH 7 to 8) with conc. hydrochloric acid, and extracted with chloroform. The extract was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The residue was separated and purified by using a silica-gel column chromatography (ethyl acetate:n-hexane=1:1, followed by ethyl acetate) to give the title compound (1.8 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]([NH2:19])[CH:15]=[C:16]([NH2:18])[CH:17]=1.C(N(CC)CC)C>C1COCC1>[NH2:19][C:14]1[CH:15]=[C:16]([NH:18][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[CH:17]=[C:12]([F:11])[CH:13]=1
Reactant: Nc1cc(N)cc(F)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1cc(F)cc(NC(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
Add slowly 4-fluorobenzoyl chloride (403 mg, 2.54 mmol) to a solution of 5-fluoro-benzene-1,3-diamine (Preparation 32 320 mg, 2.54 mmol) in triethylamine (514 mg, 0.71 mL, 5.08 mmol) and THF (10 mL) at 0° C. Stir the mixture overnight and gradually raise to room temperature. Quench the reaction with 0.1N NaOH solution, and extract the mixture with ethylacetate three times. Combine the organic layers and wash with saturated NaCl solution, dry over Na2SO4, filter and concentrate to give a solid. Purify by chromatography (silica gel, eluting with 25–40% ethylacetate in hexanes) gives 379 mg (60%) of N-(3-amino-5-fluoro-phenyl)-4-fluoro-benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11].[OH-].[Na+:26]>CO>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O-:12])=[O:11].[Na+:26]
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 105.4 %

Procedure:
5-(2-Chloro-4-trifluoromethylphenoxy)-2-nitrobenzoic acid (1.7 g, 0.0047 mole) is dissolved in methanol (25 ml) and sodium hydroxide (4.7 ml of 1 N NaOH in methanol, 0.0047 mole) is added rapidly. The solvent is then removed in vacuo to give 1.9 g of product that decomposes at 217° C.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[C:8]([OH:11])(=[S:10])[CH3:9].CS(O[CH:17]1[CH2:21][CH2:20][N:19]([C:22](=[N:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[O:26])[CH3:23])[CH2:18]1)(=O)=O>O>[C:8]([S:10][CH:17]1[CH2:21][CH2:20][N:19]([C:22](=[N:24][C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=2)=[O:26])[CH3:23])[CH2:18]1)(=[O:11])[CH3:9]
Reactant: CC(O)=S
Reactant: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCC(OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)SC1CCN(C(C)=NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
To 300 ml of anhydrous N,N-dimethylformamide were added 7.35 g of sodium hydride in the form of a 55% w/w/ dispersion in oil, followed by 12.5 g of thioacetic acid. The mixture was then stirred for 10 minutes, with ice-cooling, after which 40 g of 3-methanesulphonyloxy-1-(N-p-nitrobenzyloxycarbonylacetimidoyl)pyrrolidine were added. The mixture was then stirred for 3 hours at 65° C. After the reaction mixture had been allowed to cool, water was added and the mixture was extracted with ethyl acetate. The extract was washed with water and dried and then the solvent was distilled off under reduced pressure. The residue was purified by chromatography through a column of silica gel, eluted with a 2:1 by volume mixture of benzene and ethyl acetate, to give 30 g of the title compound.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[N:13]=[C:12]([N:14]([CH3:16])[CH3:15])[S:11][N:10]=1.[CH3:17][N:18]=[C:19]=[O:20]>C(Cl)(Cl)Cl>[CH3:17][NH:18][C:19]([N:10]1[C:9](=[O:8])[N:13]=[C:12]([N:14]([CH3:16])[CH3:15])[S:11]1)=[O:20]
Reactant: CN=C=O
Reactant: CN(C)c1nc(O)ns1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CNC(=O)n1sc(N(C)C)nc1=O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
0.53 ml of triethylamine were added to a solution of 18 g of 3-hydroxy-5-dimethylamino-1,2,4-thiadiazole in 150 ml of chloroform and 11.5 g of methyl isocyanate were added thereto in small fractions. The mixture was stirred for 30 minutes at 20° C and was filtered and the filtrate was evaporated to dryness. The residue was crystallized from ethyl acetate to obtain 18.5 g of 2-(N-methylcarbamoyl)-5-dimethylamino-1,2,4-thiadiazole-3-one melting at 164° C.