Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([C:5](=[O:9])[CH2:6][CH2:7][CH3:8])[CH2:3][CH3:4].[CH3:10][OH:11].C[O-].[Na+]>>[CH3:10][O:11][CH:2]([C:5](=[O:9])[CH2:6][CH2:7][CH3:8])[CH2:3][CH3:4]
Reactant: CCCC(=O)C(Cl)CC
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Product: CCCC(=O)C(CC)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.5 grams of 3-chloro-4-heptanone in 3ml anhydrous methanol (0.01 moles 3-chloro-4-heptanone) is placed into a 25 ml, three-necked, round bottom flask equipped with magnetic stirrer, pot thermometer, reflux condenser (with drying tube), 10 ml addition funnel with nitrogen inlet at top, an ice water-salt bath, and nitrogen bubbler. The 3-chloro-4-heptanone solution is cooled to a temperature of between 0° and 1° C. Into the 10 ml addition funnel is placed a solution of 0.54 grams of sodium methoxide dissolved in 7 ml anhydrous methanol (0.01 moles sodium methoxide). Over a period of one hour, while maintaining the reaction mass at a temperature of between 0° and 1° C the sodium methoxide solution is added to the 3-chloro-4-heptanone. The reaction mass is then permitted to warm up to room temperature. It is then vacuum filtered thereby separating the white precipitate from the filtrate. The white solid percipitate is washed with 25 ml methylene chloride, and the washings are combined with the filtrate prior to concentration. After concentration of the filtrate, the concentrate is dried over anhydrous sodium sulfate and further concentrated to a weight of 1.0 grams (white oil). The major peak is isolated by GLC trapping (8 feet × 1/4 inch SE-30 column). NMR, IR and mass spectral analyses confirm that the resulting material has the structure: ##STR89##
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][CH:40]([CH2:43][OH:44])[CH2:39][CH2:38]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][N:37]5[CH2:42][CH2:41][CH:40]([CH2:43][OH:44])[CH2:39][CH2:38]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCl
Reactant: OCC1CCNCC1
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCN1CCC(CO)CC1
Yield: 16.3 %

Procedure:
1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea from Example 35B (225 mg, 0.427 mmol) and piperidin-4-yl-methanol (0.103 mL, 1.281 mmol) were reacted in the manner described in Example 36 to afford 1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{7-[2-(4-hydroxymethyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinazolin-4-yloxy}-phenyl)-urea (41 mg, 16%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.65 (s, 1H), 9.15 (s, 1H), 8.55 (s, 1H), 7.55 (d, 2H), 7.38 (m, 2H), 7.25 (d, 1H), 6.95 (d, 1H), 6.45 (s, 1H), 4.45 (brs, 1H), 4.30 (m, 2H), 3.98 (s, 3H), 3.25 (m, 2H), 3.00 (m, 2H), 2.75 (m, 2H), 2.00 (m, 2H), 1.65 (d, 2H), 1.25 (s, 10H), 1.15 (m, 2H); LC-MS (ESI) m/z 591 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[CH3:14]O>>[CH3:14][O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)Cc1cc(Cl)cc(Br)c1
Agent: Cl
Product: COC(=O)Cc1cc(Cl)cc(Br)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of (3-bromo-5-chloro-phenyl)-acetic acid (0.400 g, 1.60 mmol) in MeOH (15 mL) was added 4N aqueous HCl (2 mL), and the reaction was stirred at 90° C. for 2 hours. The mixture was concentrated and purified by silica gel chromatography (0-5% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:9]([NH2:10])=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:14]([CH:16]=O)=O.O.[OH-].[NH4+]>C(O)(=O)C>[N+:11]([C:8]1[C:9]2[N:10]=[CH:16][CH:14]=[N:1][C:2]=2[C:3]([C:4]#[N:5])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: N#Cc1ccc([N+](=O)[O-])c(N)c1N
Reactant: O=CC=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc([N+](=O)[O-])c2nccnc12
Temperature: 22 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
2,3-Diamino-4-nitro-benzonitrile (0.050 g, 0.28 mmol, as prepared in WO-98/32439) was added to solution of glyoxal (40% in water, 0.032 mL, 0.28 mmol) in acetic acid (0.75 mL) and stirred at 22° C. for 3 h. The reaction was cooled to 0° C. and water (2.0 mL) was added and the pH was adjusted to 9.0 by addition of ammonium hydroxide which caused the product to precipitate. The mixture was then filtered and rinsed with cold water. Drying in vacuo gave 0.039 g (70%) of compound 468A as an orange solid. HPLC: 100% at 2.037 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C(=O)C>[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:18]([CH2:17][C:13]2[CH:12]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=3)[CH:16]=[CH:15][CH:14]=2)[S:19]([CH:22]([CH3:24])[CH3:23])(=[O:20])=[O:21])=[CH:28][CH:27]=1
Reactant: CC(C)S(=O)(=O)NCc1cccc(-c2cccc(S(C)(=O)=O)c2)c1
Reactant: Fc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)S(=O)(=O)N(Cc1ccc(F)cc1)Cc1cccc(-c2cccc(S(C)(=O)=O)c2)c1

Procedure:
In analogy to example 10, step 3, propane-2-sulfonic acid (3′-methanesulfonyl-biphenyl-3-ylmethyl)-amide (example 49, step 2) was reacted with 4-fluorobenzyl bromide, tetrabutylammonium iodide and cesium carbonate in N,N-dimethylacetamide to give propane-2-sulfonic acid (4-fluoro-benzyl)-(3′-methanesulfonyl-biphenyl-3-ylmethyl)-amide as a colorless solid. MS: 493.3 ([M+NH4]+)
Reaction SMILES: [C:1]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][O:9][C:10]2[CH:25]=[CH:24][C:13]3[C:14](=[O:23])[CH:15]=[C:16]([C:18]([O:20]CC)=[O:19])[O:17][C:12]=3[C:11]=2[CH2:26][CH2:27][CH3:28])=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+].C(O)C>O>[C:1]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][O:9][C:10]2[CH:25]=[CH:24][C:13]3[C:14](=[O:23])[CH:15]=[C:16]([C:18]([OH:20])=[O:19])[O:17][C:12]=3[C:11]=2[CH2:26][CH2:27][CH3:28])=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2]
Reactant: CCCc1c(COc2ccc3c(=O)cc(C(=O)OCC)oc3c2CCC)ccc(C(C)=O)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCc1c(COc2ccc3c(=O)cc(C(=O)O)oc3c2CCC)ccc(C(C)=O)c1O

Procedure:
A solution of 0.6 g. of the ethyl ester from Example 1 and 4.5 g. of sodium bicarbonate was heated to reflux in 100 ml. of ethanol and 25 ml. of water for four hours. The solution was then concentrated under reduced pressure. The residue was taken up in water. The solution was made acidic with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate was washed with water, dried over sodium sulfate, and evaporated to dryness. The residue was crystallized from ethanol/water to afford 0.2 g. of the desired title product, m.p. 195°-205° C.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Cl.[N:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][CH:14]=1>CCO>[N:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:5]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)=[CH:15][CH:14]=1
Reactant: ClCc1ccncc1
Reactant: C1CNCCNC1
Agent: Cl
Solvent: CC(=O)Cl
Solvent: CCO
Product: c1cc(CN2CCCNCC2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
A solution of acetyl chloride (6.34 mL, 0.084 mol, 4 equiv) dissolved in anhydrous EtOH (50 mL) was stirred for 0.5 h and added to a solution of homopiperazine (10.4 g, 0.1 mol, 5 equiv) in EtOH (250 mL). The reaction mixture was heated to reflux for 1 h, cooled to 25° C. and a solution of 4-picolyl chloride hydrochloride 93.44 g, 0.021 mol) in EtOH (40 mL) was added. The reaction mixture was heated to reflux for 16 h, cooled to 25° C. and the solvent was removed under vacuum. The residue was diluted with CH2Cl2 (300 mL) and was washed with 2N KOH (1×300 mL). The aqueous layer was extracted with CH2Cl2 (1×300 mL) and the organic phase was washed with 2N KOH (150 mL), dried (MgSO4) and concentrated. Chromatography (SiO2, 5% H2O-5% NH4OH—1PrOH) afforded the desired product (2.88 g, 4.01 g theoretical, 72%) as a yellow oil. TLC Rf 0.45 (5% H2O-5% NH4OH—1PrOH): 1H NMR (CDCl3, 300 MHz) δ 8.77 (d, J=5.9 Hz, 2H), 7.53 (d, J=5.7 Hz, 2H), 3.91 (s, 2H), 3,19 (m, 4H), 2.92 (m, 4H), 2.04 (m, 2H).
Reaction SMILES: [OH-].[K+].[O:3]=[C:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:5]C(OCC)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[CH:42]([C:44]1[CH:48]([OH:49])[CH2:47][C:46](=[O:50])[C:45]=1[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][C:57]([OH:59])=[O:58])=[O:43]>O.CO>[OH:49][CH:48]1[C:44]([CH:42]([OH:43])[CH2:5][C:4](=[O:3])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:45]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][C:57]([OH:59])=[O:58])[C:46](=[O:50])[CH2:47]1
Reactant: O=CC1=C(CCCCCCC(=O)O)C(=O)CC1O
Reactant: CCCCCC(=O)CC(=O)OCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCCCC(=O)CC(O)C1=C(CCCCCCC(=O)O)C(=O)CC1O
Reaction time: 72 h

Procedure:
To a cold solution of 0.8 part of potassium hydroxide in 10 parts of water is added 2 parts of ethyl 3-oxooctanoate and that mixture is stirred at 0°-5° until homogeneous. The homogeneous mixture is kept at 0°-5° for about 72 hours, then is neutralized to pH 7 by the addition of concentrated aqueous citric acid. To that mixture is then added successively 2.5 parts by volume of 1 M citrate buffer of pH 4.8 and a solution of 2.5 parts of 2-formyl-3-hydroxy-5-oxocyclopent-1-eneheptanoic acid in 4.8 parts of methanol containing 2.5 parts of water. The pH is adjusted to 4.5-5.0 and the mixture is stirred for approximately 3 hours at about 35°, then is allowed to stand at room temperature for about 16 hours. The reaction mixture is extracted with ether and the ether layer is separated, dried over anhydrous sodium sulfate and stripped of solvent under reduced pressure to afford, as a pale yellow glass, 11,13-dihydroxy-9,15-dioxoprost-8(12)-enoic acid, which compound displays an ultraviolet absorption maximum at about 233 millimicrons with a molecular extinction coefficient of about 11,500.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1/[CH:16]=[C:17](\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])/[C:18]([O:20]CC)=[O:19].COC1C2C(=CC=CC=2)C(OC)=CC=1/C=C(\C)/C(O)=O>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1/[CH:16]=[C:17](\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])/[C:18]([OH:20])=[O:19]
Reactant: CCCCCCCCC/C(=C\c1c(C)c(OC)c2ccccc2c1OC)C(=O)OCC
Agent: COc1cc(/C=C(\C)C(=O)O)c(OC)c2ccccc12
Product: CCCCCCCCC/C(=C\c1c(C)c(OC)c2ccccc2c1OC)C(=O)O

Procedure:
Compound 99c was prepared from 98c (0.164 g, 0.384 mmol) as described above for 29a to give 0.152 g (0.381 mmol, 96%) of the product as a colorless oil following flash chromatography (1:3 EtOAc:hexanes 0.5% AcOH).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH:4]2[CH:7]([CH:8]=1)[C:6](=[CH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]2.N12CCCN=C1CCCCC2.P([O-])(O)(O)=O.[K+].[N+:34]([CH3:37])([O-:36])=[O:35]>>[CH3:1][C:2]1[CH2:3][CH:4]2[CH:7]([CH:8]=1)[C:6]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH2:37][N+:34]([O-:36])=[O:35])[CH2:5]2
Reactant: C[N+](=O)[O-]
Reactant: CC1=CC2C(=CC(=O)OC(C)(C)C)CC2C1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Product: CC1=CC2C(C1)CC2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 6 h

Procedure:
Tert-butyl 3-methylbicyclo[3.2.0]hept-3-en-6-ylideneacetate (1.21 g, 5.50 mmol) was dissolved in nitromethane (7 mL). To the solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.91 mL, 6.0 mmol) was added, and the mixture was heated with stirring at 50 to 60° C. for 6 hours. The mixture was allowed to cool, and a saturated aqueous solution of potassium dihydrogen phosphate was then added thereto, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the compound of interest as a colorless oil substance (1.14 g, 74%).
Reaction SMILES: O[C:2]1[CH:15]=[C:14](O)[C:13]([C:17]([CH3:21])([CH3:20])[CH2:18][CH3:19])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[OH2:30]>C1(C)C(C)=CC=CC=1>[OH:30][C:2]1[CH:15]=[C:14]([CH2:17][CH2:13][CH2:14][CH2:15][CH2:2][CH:3]([CH3:12])[CH3:4])[C:13]([C:17]([CH3:21])([CH3:20])[CH2:18][CH3:19])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: O
Reactant: CCC(C)(C)c1cc(C(=O)c2ccccc2)c(O)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CCC(C)(C)c1cc(C(=O)c2ccccc2)c(O)cc1CCCCCC(C)C
Temperature: 110 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
A mixture of 10 g (35 mmol) of 2,4-dihydroxy-5-(1,1-dimethylpropyl)benzophenone, 7.9 g (38 mmol) of iso-bromooctane (mixture of isomers), 9.7 g (70 mmol) of potassium carbonate and 0.6 g (3.5 mmol) of potassium iodide in 30 ml of xylene is stirred at 110° C. for 8 h. The reaction mixture is cooled, then treated with 100 ml of water and extracted with ethyl acetate. The resulting solution is washed with water and then with saturated sodium chloride solution. The residue which remains after drying over MgSO4, filtering and concentrating by evaporation is distilled in a bulb tube (190° C./4 mbar). 11.2 g (86.4%) of the compound are obtained as a yellow liquid.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].C(N(C(C)C)CC)(C)C.[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31](Cl)=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1>ClCCl>[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([NH:6][CH2:5][CH2:4][CH2:3][Br:2])=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: NCCCBr
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCCBr)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of 3-bromopropylamine hydrobromide (5.0 g) and diisopropylethylamine (5.90 g) in dichloromethane (80 ml) was added portionwise 9-fluorenylmethoxycarbonyl chloride (5.91 g) and the mixture was stirred at ambient temperature for 3 hours and stand overnight. The resulting mixture was diluted with dichloromethane (50 ml) and the organic layer was washed successively with 1N hydrochloric acid and brine. Drying, filtering and removal of solvents afforded a crude product. The crude product was triturated with diethyl ether-hexane (1:5) to give 3-(9-fluorenylmethoxycarbonylamino)propyl bromide (7.82 g).
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH:6]1[CH2:10][O:9][C:8]2([CH:18](Br)[CH2:17][CH2:16][C:15]3[N:14]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[CH:13]=[CH:12][C:11]2=3)[O:7]1)([CH3:3])[CH3:2].B(Cl)(Cl)Cl>ClC(Cl)C>[OH:7][CH:6]([CH2:5][NH:4][CH:1]([CH3:3])[CH3:2])[CH2:10][O:9][C:8]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][N:14]2[S:20]([C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=1)(=[O:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2CCC(Br)C32OCC(CNC(C)C)O2)cc1
Agent: ClB(Cl)Cl
Solvent: CC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(OCC(O)CNC(C)C)cccc32)cc1
Temperature: 25 °C
Reaction time: 50 h
Yield: 71 %

Procedure:
To a solution of 4'-isopropylaminomethyl-5-bromo-1-p-toluenesulfonyl-4,5,6,7-tetrahydroindole-4-spiro-2'-[1,3]-dioxolane (100 parts) in dichloroethane (1000 parts) is added a solution of boron trichloride (2 molar equivalents) in dichloroethane (500 parts) at -19° C. The mixture is allowed to warm to room temperature and to stand for 50 hours. The reaction mixture is washed with aqueous sodium hydroxide at pH 10 and water, dried and concentrated. The residue is crystallized from hexane-benzene to give 4-(2-hydroxy-3-isopropylaminopropoxy)-1-p-toluenesulfonyl indole in 71% yield.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]([C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](O)=[O:16])=[O:8])=[CH:5][CH:4]=1.[NH2:22][OH:23].Cl>C(N(CC)CC)C>[OH:23][NH:22][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:7](=[O:8])[C:6]1[CH:18]=[CH:19][C:3]([C:2]([F:21])([F:20])[F:1])=[CH:4][CH:5]=1
Reactant: O=C(O)CCCCCCC(=O)c1ccc(C(F)(F)F)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(CCCCCCC(=O)c1ccc(C(F)(F)F)cc1)NO
Yield: 35 %

Procedure:
Following the procedure described in Example 14, step 3, but substituting carboxylic acid 50c for 37 and using 1.1 equivalent of NH2OH.HCl and triethylamine each, the title compound was obtained as light yellow solid in 35% yield: 1H NMR (300 MHz, CD3OD/CDCl3=5/1) δ 8.07 (d, J=8.4 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H), 3.02 (t, J=7.5 Hz, 2H), 2.12 (t, J=7.5 Hz, 2H), 1.75 (m, 2H) 1.65 (m, 2H), 1.40 (m, 4H); 13C NMR (75.4 MHz, CD3OD/CDCl3=5/1) δ 23.57, 25.03, 28.51, 28.59, 32.50, 38.50, 123.37(q, JCF=273 Hz),125.43 (q, JCF=3.7 Hz), 128.18, 134.09 (q, JCF=32.6 Hz), 139.32, 171.15, 199.93.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:18]([O:23][CH3:24])(=[O:22])[C:19]([CH3:21])=[CH2:20].CC(C)([O-])C.[K+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OC(C)C)(=O)C.[Cl-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[O:10])[CH2:20][CH:19]([CH3:21])[C:18]([O:23][CH3:24])=[O:22])[CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)C(=O)OC
Reactant: O=C(Cc1cccc(Cl)c1)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)C
Solvent: O
Product: COC(=O)C(C)CC(C(=O)c1ccc(Cl)cc1)c1cccc(Cl)c1
Temperature: 45 °C
Reaction time: 6 h

Procedure:
A solution of 2-(3-chlorophenyl)-1-(4-chlorophenyl)ethanone (Step A) (67.4 Kg, 255 mol) in THF (325 L) was dried azeotropically to achieve a water content by Karl Fisher of 0.05 wt %. Methyl methacrylate (25.8 Kg, 257 mol) was added to the solution and the mixture was heated to 45° C. A solution of potassium tert-butoxide (20 wt % in THF, 14.3 Kg, 25 mol) was added over the course of 30 minutes and the mixture was agitated for 6 h. The mixture was cooled to 10° C. and an aqueous solution of citric acid monohydrate (20 wt %, 35 L) was added in less than 5 minutes. Isopropyl acetate (400 L) and an aqueous sodium chloride solution (20 wt %, 300 L) were added. The mixture was agitated for 15 minutes and the phases were separated. The organic phase was distilled under reduced pressure to generate a distillate volume of 560 L while simultaneously adding isopropanol (350 L) and producing a solution of methyl 4-(3-chlorophenyl)-5-(4-chlorophenyl)-2-methyl-5-oxopentanoate in isopropanol (54 wt %, 140 kg total solution mass). The solution had a water content of 0.01 wt % by Karl Fisher. Additional isopropanol (420 L) and sulfuric acid (53 Kg, 535 mol) were added to the solution. The mixture was warmed to reflux and agitated for 12 h, during which time 200 L of solvent were distilled and 200 L of fresh isopropanol were added to the mixture. The mixture was cooled to 20° C. and water (180 L) was added over the course of 30 minutes. Isopropyl acetate (270 L) was added and the mixture was agitated for 30 minutes. The phases were separated and the aqueous phase was extracted using isopropyl acetate (100 L). The combined organic phases were washed with water (200 L) four times. The organic phase was distilled under reduced pressure to generate a distillate volume of 500 L while simultaneously adding isopropanol (50 L) and producing a solution of isopropyl 4-(3-chlorophenyl)-5-(4-chlorophenyl)-2-methyl-5-oxopentanoate in isopropanol (60 wt %, 134 kg total solution mass). The solution had a water content of 0.02 wt % by Karl Fisher. The title material was obtained in 81% overall yield as a roughly 1:1 mixture if diastereoisomers.
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1>C(#N)C>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Reactant: Nc1ccc(F)cc1
Solvent: CC#N
Product: Fc1ccc(Nc2ncnc3c2CN(Cc2ccccc2)CC3)cc1
Temperature: 200 °C
Yield: 97 %

Procedure:
6-Benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (Intermediate 2, 0.25 g, 0.97 mmol) was dissolved in anhydrous acetonitrile (3 mL) and 4-fluorobenzenamine was added (0.10 mL, 1.06 mmol). The mixture was heated at 200° C. for 600 s in a microwave (Emrys Optimizer model, Personal Chemistry). The solvents were removed under vacuum to give the desired product as a beige powder (0.313 g, 97%.).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl:17][C:18]1[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=1[CH:20]=[N+:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:17][C:18]1[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=1[CH:20]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ccccc1C=[N+]1CCCCC1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: [Cl-]
Product: Clc1ccccc1C(c1c(-c2ccccc2)[nH]c2ccccc12)N1CCCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-phenyl-1H-indole and 1-(2-chloro-benzylidene)-piperidinium chloride, which had been prepared in accordance with example 26.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1)(=O)C.[OH-].[Na+].Cl>O1CCCC1>[CH2:12]([O:11][C:7]1[CH:6]=[C:5]([OH:4])[CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)Oc1cccc(OCc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Oc1cccc(OCc2ccccc2)c1
Yield: 94.9 %

Procedure:
3-Benzyloxyphenyl acetate (4.84 g, 20 mmol), as prepared in the preceding step, in tetrahydrofuran (50 mL) was treated with 1 N NaOH (30 mL) at room temperature for 3 h. The mixture was acidified with 1 N HCl and extracted with ethyl acetate (3×100 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. The solvent was removed in vacuo and the residue purified by flash column chromatography (methylene chloride) to give the title compound as a colorless liquid (3.80 g, 96%). 1H-NMR (300 MHz, CDCl3) δ 5.01 (s, 2 H), 5.09 (s, 1 H), 6.47 (t, 2 H, J=2.2 Hz), 6.56 (dd, 1 H, J=1.1, 4.1 Hz), 7.11 (t, 1 H), and 7.39 (m, 5 H).