Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[O:10])=[CH:4][CH:3]=1.C1C=C[NH+]=CC=1.[O-:25][Cr](Cl)(=O)=O.N1C=CC=CC=1>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[O:10])=[CH:4][CH:3]=1
Reactant: O=[Cr](=O)([O-])Cl
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: O=C(C(=O)c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
2-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)ethanone (2.7 g, 9.01 mmol) was dissolved in 1,2-dichloroethane (25 ml) and freshly made PCC (3.89 g, 18.02 mmol), pyridine (1.43 g, 18.02 mmol) and molecular sieves were added. The reaction mixture was refluxed under inert atmosphere overnight. The solution was cooled to 25° C., filtered through Silica and then solvent was evaporated under reduced pressure. The crude product (1.9 g, 66%) was used directly in the next step. 1H NMR (500 MHz) δ 7.97 (d, 2H), 7.84 (d, 1H), 7.52 (d, 2H), 7.46 (s, 1H), 7.44 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]=[C:20]([NH2:30])[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=O>C(O)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][N:21]4[CH:33]=[C:34]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[N:30]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(N)ncc3-c3ccccc3)cc2)CCC1
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(-c5ccccc5)cn4cc3-c3ccccc3)cc2)CCC1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 48.4 %

Procedure:
A mixture of 5-1 (150 mg, 0.36 mmol) and 2-Bromo-1-phenyl-ethanone (110 mg, 0.54 mmol) in ethanol (2 mL) was heated to 100° C. and stirred for 45 mins under microwave radiation. The mixture was cooled to r.t. and diluted with 20 mL of DCM. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.TLC to give 90 mg of 5-2.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[C:17]([S:19]([N:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24][CH2:23]3)(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=1[Cl:32])[C:8](=[O:33])[NH:7]2>CN(C)C=O.C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[S:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[C:17]([S:19]([N:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24][CH2:23]3)(=[O:20])=[O:21])[CH:16]=[CH:15][C:14]=1[Cl:32])[C:8](=[O:33])[NH:7]2)=[O:1]
Reactant: O=c1[nH]c2csc(CO)c2c(=O)n1-c1cc(S(=O)(=O)N2CCCc3ccccc32)ccc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1scc2[nH]c(=O)n(-c3cc(S(=O)(=O)N4CCCc5ccccc54)ccc3Cl)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a solution of 5-hydroxymethyl-3-[2-chloro-5-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)phenyl]thieno[3,4-d]-pyrimidine-2,4(1H,3H)-dione (77 mg) in N,N-dimethylformamide (2.1 mL) was added manganese (IV) dioxide (0.77 g), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and the insoluble material was removed by filtration. The filtrate was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give the title compound (32 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([CH3:8])=[O:7])[CH3:2].N1C[CH2:13][CH2:12][CH2:11]1.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](=[O:7])[CH2:8][CH:12]([CH3:13])[CH3:11])[CH3:2]
Reactant: C1CCNC1
Reactant: CCOC(=O)CC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)CC(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.7 %

Procedure:
26 g of acetoacetic acid ethyl ester and 15 g of pyrrolidine were boiled in 70 ml of toluene on a water separator until the theoretical quantity of water was separated. The solution was added drop by drop at -40° C. to a suspension of 8.6 g of sodium amide in 300 ml of liquid ammonia. By heating to room temperature, the ammonia was removed. After the reaction solution had been cooled again to 0° C., isopropyl iodide dissolved in 100 ml of toluene was added at the same temperature. The solution was allowed to react for 3 hours at 0° C. The reaction solution was poured into 200 ml of water. The phases were separated and the toluene of the organic phase was removed using a rotary evaporator. Of the residue, 1.2 g of the first runnings was then distilled off at 1.5 torr (2×102Pa) and up to a still temperature of 60° C., which contained above all 2 -isopropyl acetoacetic acid ethyl ester. The brownish oil remaining behind was dissolved in 70 ml of methylene chloride, and 21 g of concentrated hydrochloric acid was added. The material was hydrolyzed for 1.5 hours at ambient temperature. The two phases were separated. The organic phase was dried, the solvent was removed and the residue was distilled. 28.1 g of 5-methyl-3-oxohexanoic acid ethyl ester (82 percent) was obtained.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][CH2:16][CH3:17])[C:10](=[O:18])C(C#N)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:22]([OH:25])(=[O:24])[CH3:23]>>[C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][CH2:16][CH3:17])[C:10](=[O:18])[C:23]([C:22]([OH:25])=[O:24])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCn1c(=O)c(C#N)nn(-c2ccccc2)c1=O
Reactant: CC(=O)O
Agent: Cl
Product: CCCCn1c(=O)c(C(=O)O)nn(-c2ccccc2)c1=O
Temperature: 120 °C
Yield: 45.7 %

Procedure:
Intermediate f (8.2 g, 0.035 mol) was added to a mixed solvent of glacial acetic acid (100 mL) and HCl (72 mL, 0.86 mol). The mixture was warmed up to 120° C. and reacted under reflux for 4 h. The solvent was evaporated off. To the obtained fraction was added water (200 mL). The mixture was filtered by suction and dried to produce Intermediate g (3.7 g) in a yield of 45.7%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].C(N(CC)C(C)C)(C)C.[CH3:21][O:22][CH2:23]Cl>CN(C)C=O>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:21][O:22][CH3:23])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: COCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(C(C)=O)c(O)c1
Reaction time: 0.33 h
Yield: 87.8 %

Procedure:
In 60 ml of dimethylformamide were dissolved 5.0 g of 2',4'-dihydroxyacetophenone and 6.37 g of N,N-diisopropylethylamine, and 2.72 ml of chloromethyl methyl ether was gradually added to the solution under ice cooling. The mixture was stirred under ice cooling for 20 minutes and a reaction was carried out at room temperature for 1.5 hours. After the reaction, the reaction mixture was extracted with 300 ml of diethyl ether, and the diethyl ether layer was washed with water (100 ml×2 times), shaken with a saturated aqueous solution of sodium chloride (50 ml×2 times), dried with anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by distillation and the residue was subjected to the silica gel chromatography (3.5 cm in diameter; 72.8 g; n-hexane/ethyl acetate=4/1; 0.3 kg/cm2) to obtain 5.66 g (yield=87.8%) of 2'-hydroxy-4'-methoxymethoxyacetophenone in the form of a colorless oil.
Reaction SMILES: [C:1]1([CH:7]([CH3:18])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([O:22][CH2:23][CH2:24][Li])(=[O:21])[CH3:20]>>[CH2:23]([O:22][C:19](=[O:21])[CH2:20][CH:16]([OH:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:18])[CH3:24]
Reactant: [Li]CCOC(C)=O
Reactant: CC(CCCCCCCCC=O)c1ccccc1
Product: CCOC(=O)CC(O)CCCCCCCCC(C)c1ccccc1
Yield: 70 %

Procedure:
When 78 g (0.317 mole) of 10-phenylundecanal was treated with lithioethyl acetate according to the procedure for the preparation of 3(R=CH3, m=12) 73.8 g (70% yield) of 3-hydroxy-12-phenyltridecanoic acid ethyl ester was obtained; δ (CDCl3) 1.28 (m, CH2), 2.1-2.6 (m, phenyl CH, CH2CO), 3.98-4.33 (CHOH, OCH2) and 7.20-7.22 (m, phenyl). This compound could be used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH:14]2[CH2:16][O:15]2)[CH2:8][CH2:7]1.[NH3:21]>CO>[NH2:21][CH2:16][CH:14]([OH:15])[CH2:13][CH2:12][N:9]1[CH2:10][CH2:11][CH:6]([O:5][C:4]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:2]([Cl:1])[CH:3]=2)[CH2:7][CH2:8]1
Reactant: N
Reactant: Clc1ccc(OC2CCN(CCC3CO3)CC2)cc1Cl
Solvent: CO
Product: NCC(O)CCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1

Procedure:
In a sealed metal tube, a solution of 4-(3,4-dichlorophenoxy)-1-(2-oxiran-2-ylethyl)piperidine (1.00 g) in 7N ammonia in methanol (25 ml) was heated at 70° C. for 12 h. The solvent was removed under vacuum and the residue purified on silicagel (0 to 10% 7N ammonia in methanol/dichloromethane) to afford the title compound as a yellow oil (0.55 g).
Reaction SMILES: [CH:1]1([CH2:5][N:6]2[CH:14]=[C:13]3[C:8]([CH:9]=[C:10]([C:15]4[CH:16]=[C:17]([CH:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[N:18]5[C:23]=4[C:22]([NH2:24])=[N:21][CH:20]=[N:19]5)[CH:11]=[CH:12]3)=[N:7]2)[CH2:4][CH2:3][CH2:2]1.Cl[CH2:32][C:33](N(C)C)=[O:34]>>[C:33]([N:28]1[CH2:29][CH2:30][CH:25]([C:17]2[N:18]3[C:23]([C:22]([NH2:24])=[N:21][CH:20]=[N:19]3)=[C:15]([C:10]3[CH:11]=[CH:12][C:13]4[C:8]([CH:9]=3)=[N:7][N:6]([CH2:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)[CH:14]=4)[CH:16]=2)[CH2:26][CH2:27]1)(=[O:34])[CH3:32]
Reactant: CN(C)C(=O)CCl
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(CC5CCC5)nc4c3)c12
Product: CC(=O)N1CCC(c2cc(-c3ccc4cn(CC5CCC5)nc4c3)c3c(N)ncnn23)CC1
Yield: 62 %

Procedure:
In a manner similar to the procedure described for Example 369 and using 5-[2-(cyclobutylmethyl)-2H-indazol-6-yl]-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and substituting acetyl chloride for 2-chloro-N,N-dimethylacetamide as starting materials, 48 mg, (62%) of the desired product was isolated. LC-MS [M+H]+=444.3, RT=2.37 min.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[P:38]([O:50][CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][N:56]([CH2:59][CH2:60][C@@H:61]([NH:70][C:71]2[CH:76]=[CH:75][C:74]([S:77](=[O:80])(=[O:79])[NH2:78])=[CH:73][C:72]=2[S:81]([C:84]([F:87])([F:86])[F:85])(=[O:83])=[O:82])[CH2:62][S:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH2:55][CH2:54]1)([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[P:38]([O:50][CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][N:56]([CH2:59][CH2:60][C@@H:61]([NH:70][C:71]2[CH:76]=[CH:75][C:74]([S:77](=[O:79])(=[O:80])[NH:78][C:20](=[O:21])[C:19]3[CH:18]=[CH:17][C:16]([N:13]4[CH2:12][CH2:11][CH:10]([C@@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3])[C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[C:31]5[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=5)[CH2:15][CH2:14]4)=[CH:24][CH:23]=3)=[CH:73][C:72]=2[S:81]([C:84]([F:87])([F:86])[F:85])(=[O:83])=[O:82])[CH2:62][S:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH2:55][CH2:54]1)([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CC(C)(C)OP(=O)(OCCN1CCN(CC[C@H](CSc2ccccc2)Nc2ccc(S(N)(=O)=O)cc2S(=O)(=O)C(F)(F)F)CC1)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OP(=O)(OCCN1CCN(CC[C@H](CSc2ccccc2)Nc2ccc(S(=O)(=O)NC(=O)c3ccc(N4CCC([C@@H](O[Si](C)(C)C(C)(C)C)c5ccccc5-c5ccc(Cl)cc5)CC4)cc3)cc2S(=O)(=O)C(F)(F)F)CC1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(R)-4-(4-((tert-butyldimethylsilyloxy)(4 ′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 13, 170 mg, 0.32 mmol), (R)-di-tert-butyl 2-(4-(4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)butyl)piperazin-1-yl)ethyl phosphate (INTERMEDIATE 61, 275 mg, 0.35 mmol), DMAP (116 mg, 0.95 mmol) and EDC (122 mg, 0.63 mmol) were dissolved in DCM (3.2 ml). The reaction mixture was stirred at r.t. for 72 hours. The mixture was diluted with DCM (10 ml) and washed with NaHCO3 solution (saturated, aq., 5 ml) and brine (5 ml). The collected organic layer was dried over Na2SO4 and concentrated to give the title compound (446 mg, yield: almost quantitative). The title compound was used in the preparation of EXAMPLE 10 without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:19])[F:18])[N:14]3[N:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27](O)=[O:28])[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:33]1[CH:37]2[CH2:38][NH:39][CH2:40][CH:36]2[CH2:35][N:34]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:19])([F:20])[F:18])[N:14]3[N:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27]([N:39]4[CH2:38][CH:37]5[CH2:33][N:34]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:35][CH:36]5[CH2:40]4)=[O:28])[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4cccc(C(=O)O)c4)cc3N2)cc1OC
Product: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4cccc(C(=O)N5CC6CN(C(=O)OC(C)(C)C)CC6C5)c4)cc3N2)cc1OC
Yield: 54.9 %

Procedure:
Example ER-896386 was prepared in two steps from 3-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)benzoic acid (119 mg, 0.266 mmol) and commercially available tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (226 mg, 1.06 mmol) in a manner similar to that of example D-6 to afford intermediate tert-butyl 5-(3-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (94 mg, 0.146 mmol, 55% yield). Then, this intermediate was resolved into its constituent enantiomers in a manner similar to that of ER-890044 (Section A) to afford tert-butyl 5-(3-((5S,7R)-5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (33 mg, 0.051 mmol) and tert-butyl 5-(3-((5R,7S)-5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (33 mg, 0.051 mmol). Then, intermediate tert-butyl 5-(3-((5S,7R)-5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (22 mg, 0.034 mmol) was treated with HCl in a manner similar to that of example ER-897560 to afford the desired product ER-896386 (19 mg, 96% yield).
Reaction SMILES: [OH:1][C:2]([CH:4]([C:6]1[CH:15]=[CH:14][C:9]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=1)[CH3:5])=[O:3].C1(C)C=CC=CC=1.[CH2:23]([NH:31][CH2:32][C@@H:33]([C@H:35]([C@@H:37]([C@@H:39]([CH2:41][OH:42])[OH:40])[OH:38])[OH:36])[OH:34])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>O>[CH2:23]([NH:31][CH2:32][C@@H:33]([C@H:35]([C@@H:37]([C@@H:39]([CH2:41][OH:42])[OH:40])[OH:38])[OH:36])[OH:34])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[OH:3][C:2]([C@H:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][CH:11]([CH3:12])[CH3:13])=[CH:14][CH:15]=1)[CH3:5])=[O:1]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: CCCCCCCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)Cc1ccc([C@H](C)C(=O)O)cc1
Temperature: 78 °C

Procedure:
Racemic ibuprofen (80 g, 390 mmol), toluene (200 mL), and water (0.5 mL) were stirred at 40° C., and N-octyl-D-glucamine (53.8 g, 183 mmol, N-octyl-D-glucamine/(S)-ibuprofen molar ratio=0.938) was added to the solution. The resulting thick slurry was heated to 78° C., forming a clear solution, and the solution then cooled to 15° C. over 3-4 hours. The resulting precipitate was recovered by filtration, washed with toluene (100 mL), and dried to give (S)-ibuprofen N-octyl-D-glucamine salt (72.2 g, 145 mmol, 74.6% yield, MR=136°-137° C.). The toluene liquors were saved for racemization and recycle of the contained (R)-ibuprofen.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH2:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20]>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][S:21]([CH2:19][CH3:20])(=[O:23])=[O:22])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: CCS(=O)(=O)Cl
Reactant: NCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCS(=O)(=O)NCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-nitro-benzylamine (47.2 mg, 0.25 mmol) in THF (250 μL) is added triethylamine (89 μL) and ethyl sulfonyl chloride (24 μL, 0.25 mmol). The reaction mixture is shaken at ambient temperature for 16 hours. The reaction mixture is then concentrated, methanol is added followed by Novabiochem AM resin to remove unreacted amine. This is then shaken for two hours, filtered, concentrated to yield ethanesulfonic acid 4-nitro-benzylamide, which is used as such for the subsequent reaction.
Reaction SMILES: [O:1]=[CH:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[Mg][CH2:10][CH:11]1[CH2:13][CH2:12]1>C1COCC1.C(OCC)(=O)C>[CH:11]1([CH2:10][CH:2]([OH:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:13][CH2:12]1
Reactant: Br[Mg]CC1CC1
Reactant: CCOC(=O)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(O)CC1CC1
Reaction time: 48 h

Procedure:
Under argon and with ice cooling, a solution of 5.4 g (purity 50%, 26.7 mmol) of ethyl oxoacetate in 50 ml of THF was quickly added dropwise to 7.6 g (48 mmol, 1.8 eq.) of bromo(cyclopropylmethyl)magnesium. The reaction mixture was stirred for another 48 h, diluted with ethyl acetate and quenched with water. Celite was added, and the reaction mixture was stirred for 5 min and then filtered. After phase separation, the organic phase was washed once with water, dried (sodium sulphate), filtered and concentrated under reduced pressure. Yield: 2.6 g (60% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][OH:9])=[NH:7])=[CH:4][N:3]=1.[F:12][C:13]([F:34])([F:33])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:23]=[C:22]([C:30](O)=O)[N:21]=2)=[CH:16][CH:15]=1>>[F:29][C:26]([F:27])([F:28])[C:24]1[CH:25]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:34])([F:33])[F:12])=[CH:15][CH:16]=2)[N:21]=[C:22]([C:30]2[O:9][N:8]=[C:6]([C:5]3[CH:10]=[CH:11][C:2]([NH2:1])=[N:3][CH:4]=3)[N:7]=2)[N:23]=1
Reactant: N=C(NO)c1ccc(N)nc1
Reactant: O=C(O)c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Product: Nc1ccc(-c2noc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)n2)cn1

Procedure:
The title compound was prepared from 6-amino-N-hydroxy-nicotinamidine (example C.3) (0.15 g, 1.0 mmol) and 4-(4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.2) (0.17 g, 0.5 mmol) according to the general procedure V. Obtained as a light yellow solid (0.13 g, 24%). MS (ISP) 453.1 [(M+H)+]; mp 218.5° C.
Reaction SMILES: [F:1][CH:2]([F:20])[C:3]1[CH:10]=[C:9]([O:11][CH2:12][C@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)[CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:21][C:22]1[C:30]([NH2:31])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C.O>[F:1][CH:2]([F:20])[C:3]1[CH:10]=[C:9]([O:11][CH2:12][C@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)[CH:8]=[CH:7][C:4]=1[C:5]1[NH:31][C:30]2[CH:29]=[CH:28][CH:27]=[C:23]([C:24]([OH:26])=[O:25])[C:22]=2[N:21]=1
Reactant: Nc1cccc(C(=O)O)c1N
Reactant: CC1(C)OC[C@H](COc2ccc(C=O)c(C(F)F)c2)O1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OC[C@H](COc2ccc(-c3nc4c(C(=O)O)cccc4[nH]3)c(C(F)F)c2)O1
Temperature: 110 °C
Reaction time: 18 h
Yield: 31.4 %

Procedure:
To a solution of (S)-2-(difluoromethyl)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzaldehyde (66; 1.83 g, 6.40 mmol) in DMF (150 ml) was added 2,3-diaminobenzoic acid (1; 0.97 g, 6.40 mmol), and Na2S2O5 (1.82 g, 9.60 mmol). The reaction mixture was stirred at 110° C. for 18 h. It was then cooled to room temperature and diluted with water. The resulting solids were collected by filtration and dried to afford (S)-2-(2-(difluoromethyl)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid 67 as dark yellow solid (0.84 g, 51%). MS (ESI) calcd for C21H20F2N5O5: 418.13; found: 419 [M+H].
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][CH2:11]/[C:12](=[CH:14]/[CH2:15][CH2:16]/[CH:17]=[C:18](/[CH2:20][CH2:21]/[CH:22]=[C:23](/[CH2:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])\[CH3:24])\[CH3:19])/[CH3:13])/[CH3:8])[CH3:3]>[Ni].C(CC(C)(C)C)(C)C.[H][H]>[CH3:30][CH:28]([CH2:27][CH2:26][CH2:25][CH:23]([CH2:22][CH2:21][CH2:20][CH:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH:12]([CH2:11][CH2:10][CH2:9][CH:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH3:8])[CH3:13])[CH3:19])[CH3:24])[CH3:29]
Reactant: [H][H]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C=C(\C)CC/C=C(\C)CCC=C(C)C
Agent: [Ni]
Solvent: CC(C)CC(C)(C)C
Product: CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C

Procedure:
A tubular reactor of 2.0 cm in inner diameter and 10 cm in length was packed with 20 g of carrier-supported nickel catalyst. Hydrogenation was carried out by feeding into the reactor the 50 wt % squalene solution in isooctane and hydrogen gas to obtain a squalane solution in isooctane. Samples were taken out for 30 hours after the temperature was stabilized at 210° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:6][C@@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[C@@H:4]([CH:11]=C)[O:3]1.[O:14]=[O+][O-]>ClCCl>[CH3:13][C:2]1([CH3:1])[O:6][C@@H:5]([CH2:7][CH:8]([CH3:9])[CH3:10])[C@H:4]([CH:11]=[O:14])[O:3]1
Reactant: C=C[C@H]1OC(C)(C)O[C@H]1CC(C)C
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: CC(C)C[C@@H]1OC(C)(C)O[C@H]1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A dichloromethane solution of the product of Example 16B (1 g) is cooled to -78° C. and a stream of ozone is passed through the solution until a blue color persists. Excess ozone is removed with nitrogen ebullition and dimethyl sulfide (1 mL) is added. The reaction is allowed to warm to room temperature and stirred overnight. The solvents are removed under reduced pressure, and the title compound is obtained following purification by silica gel chromatography.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][CH3:12])[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:3]=1[C:4]([OH:6])=O.ClC(N(C)C)=C(C)C.[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][C:26]=1[Cl:32].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[C:9]([NH:11][CH3:12])=[CH:10][C:2]=2[F:1])=[CH:27][C:26]=1[Cl:32]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CNc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]
Agent: CC(C)=C(Cl)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNc1cc(F)c(C(=O)Nc2ccc(F)c(Cl)c2)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
A mixture of 2-fluoro-4-methylamino-5-nitro-benzoic acid (0.500 g, 2.34 mmol), (1-chloro-2-methyl-propenyl)-dimethylamine (0.371 mL, 2.80 mmol) and DCM (50 mL) is stirred for 30 min, then 4-fluoro-3-chloro-aniline (0.340 g, 2.34 mmol) and DIPEA (0.549 mL, 3.15 mmol) are added and it is stirred for 2 h. The mixture is concentrated, water is added and the precipitate is filtered, washed with water and dried to give the subtitle compound.