Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]([F:28])=[C:12]([NH:18][C@H:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH3:20])[C:13]([F:17])=[CH:14][C:15]=3[NH2:16])[CH:5]=2)[CH2:3][CH2:2]1.[C:29](O)(=O)C.C(N)=N.C(=O)(O)[O-].[Na+].CCOC(C)=O>CCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([N:9]3[C:10]4[C:11]([F:28])=[C:12]([NH:18][C@H:19]([C:21]5[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=5)[CH3:20])[C:13]([F:17])=[CH:14][C:15]=4[N:16]=[CH:29]3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1c(F)cc(N)c(Nc2cc(C3CC3)[nH]n2)c1F)c1ccc(F)cc1
Reactant: CC(=O)O
Agent: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@H](Nc1c(F)cc2ncn(-c3cc(C4CC4)[nH]n3)c2c1F)c1ccc(F)cc1

Procedure:
(S)-N3-(5-Cyclopropyl-1H-pyrazol-3-yl)-2,6-difluoro-N1-(1-(4-fluorophenyl)ethyl)benzene-1,3,4-triamine (Method 101, 0.278 g, 0.718 mmol) and formamidine acetate (0.149 g, 1.44 mmol) in EtOH (10 ml) was heated at reflux for 1 hour. Saturated sodium bicarbonate solution (5 ml) and EtOAc (15 ml) were added. The organic layer was separated, washed with brine (3 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by chromatography (Hex-EtOAc=1:1) to give the title compound as off white solid (0.120 g, 42%). 1H NMR (400 MHz) 12.83 (s, 1H), 8.20 (s, 1H), 7.36 (m, 2H), 7.31 (d, J=11.2 Hz, 1H), 7.06 (t, J=8.8 Hz, 2H), 6.15 (s, 1H), 5.15 (d, J=10.4 Hz, 1H), 4.67 (m, 1H), 1.98 (m, 1H), 1.46 (d, J=6.8 Hz, 3H), 1.00 (m, 2H), 0.76 (m, 2H). MS: Calcd.: 397; Found: [M+H]+ 398.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][CH:6]([F:26])[O:7][C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[C:11]([NH:13][C:14]1[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:16]([OH:18])=[O:17])=O>ClCCCl>[F:5][CH:6]([F:26])[O:7][C:8]1[CH:9]=[C:10]([C:11]2[O:17][C:16](=[O:18])[C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[N:13]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Nc1ccccc1C(=O)O)c1cccc(OC(F)F)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: O=c1oc(-c2cccc(OC(F)F)c2)nc2ccccc12
Reaction time: 4 h

Procedure:
25 parts by weight of 3-difluoromethoxybenzoyl chloride and 12.2 parts by weight of triethylamine are added over 15 minutes, from 2 separate feeds, to a stirred mixture of 16.6 parts by weight of anthranilic acid in 360 parts by weight of 1,2-dichloroethane at 25°-30° C. After stirring for 2 hours at 25° C., the reaction mixture is extracted with 0.5 N hydrochloric acid and with water. The organic phase is then extracted with four times 100 parts of 0.5 N sodium hydroxide solution, and the extracts are stirred into dilute hydrochloric acid. After filtration and drying, 30.4 parts by weight, corresponding to 82% of theory, of N-(3-difluoromethoxybenzoyl)-anthranilic acid of melting point 186°-191° C. are obtained. 8.33 Parts by weight of thionyl chloride are introduced into a stirred mixture of 18 parts by weight of N-(3-difluoromethoxybenzoyl)anthranilic acid in 250 parts by weight of 1,2-dichloroethane at 25° C.; the mixture is then stirred for 4 hours under reflux. When it has cooled, the reaction mixture is extracted with 100 parts by volume of ice-water and 100 parts by volume of 0.5 N sodium hydroxide solution and is chromatographed over neutral aluminum oxide. 12 parts by weight, corresponding to 71% of theory, of 2-(3'-difluoromethoxy-phenyl)-3,1-benzoxazin-4-one, of melting point 84°-87° C., are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>>[Cl:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=2[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(B(O)O)cc1Cl
Reactant: CS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2Br)cc1
Product: COc1ccc(-c2cc(F)c(F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1Cl
Yield: 84.1 %

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 4.4 g (13 mmol) of 1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene (Step 2) was reacted with 3.1 g (17 mmol) of 3-chloro-4-methoxy phenylboronic acid (Example 5, Step 2). Purification by silica gel chromatography (Waters Prep-500A) with ethyl acetate/hexane (3:7) and subsequent recrystallization from ethyl acetate/hexane gave 4.47 g (95%) of 1-(3-chloro-4-methoxyphenyl)-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene as a colorless solid: mp 147.5°-148.5° C.; NMR (CDCl3) δ 3.05 (s, 3H), 3.88 (s, 3H), 6.75(d, J=9 Hz, 1H), 6.83 (dd, J=2, 9 Hz, 1H), 7.10(d, J=2 Hz, 1H), 7.17-7.32 (m, 4H), 7.83(d, J=9 Hz, 2H). MS (EI): m/e (rel intensity) 408 (33), 314 (15), 294 (52), 279 (63), 251 (100). Anal. Calc'd for C20H15ClF2O3 S.(0.27 ethyl acetate): C, 58.53; H, 3.99; F, 8.79. Found: C, 58.75; H, 3.71; F, 8.52.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.O.N([O-])=O.[Na+].[ClH:18]>>[Cl:18][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2
Reactant: Cl
Reactant: Nc1cccc2c1CCC(=O)N2
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C1CCc2c(Cl)cccc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
45 g of 5-amino-3,4-dihydrocarbostyril was suspended in 250 ml of a 15% hydrochloric acid and 250 ml of water having dissolved therein 20 g of sodium nitrite was added dropwise to the mixture followed by stirring at room temperature for 1 hour. The resulting solution was added dropwise to a solution prepared by dissolving 41.2 g of cuprous chloride in 120 ml of concentrated hydrochloric acid at room temperature while stirring. After completion of the addition, the mixture was heated on a water bath at 50° to 60° C. for 1 hour while stirring. After allowing the mixture to cool to precipitate crystals, they were collected by filtration and washed with water. The wet crystals were dissolved in chloroform and insoluble materials were removed by filtration. The residue was dried over anhydrous sodium sulfate. After removal of the solvent the residue was dissolved with heating and the solution was treated with activated carbon while hot. The ethanolic solution thus-treated was concentrated under reduced pressure. Recrystallization of the concentrate from ethanol gave 31.5 g of 5-chloro-3,4-dihydrocarbostyril having a melting point of 193° to 194° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9](O)[CH:10]([F:16])[N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.OS(O)(=O)=O.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[F:16][CH:10]([N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[C:27]1[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=1
Reactant: OC(c1ccc(Cl)cc1Cl)C(F)n1cncn1
Reactant: Fc1ccccc1
Agent: O=S(=O)(O)O
Product: Fc1ccc(C(c2ccc(Cl)cc2Cl)C(F)n2cncn2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
276 g of 1-(2,4-dichlorophenyl)-2-fluoro-2-(1H-1,2,4-triazol-1-yl)ethanol are introduced, with vigorous stirring, into a mixture, cooled to 0° C., of 1 liter of 98% H2SO4 and 300 ml of fluorobenzene in such a manner that the internal temperature does not exceed +10° C. The reaction mixture is subsequently stirred at room temperature for a further 6 hours; it is then poured onto about 1.5 kg of ice, and extracted three times with 300 ml of methylene chloride each time. The combined extracts are washed neutral with water, dried over sodium sulfate, filtered, and excess solvent and fluorobenzene are distilled off. The resulting light-brown resin is subjected to short-path distillation at 0.05 mbar and 160° C. (bath temperature). There are thus obtained 300 g (yield about 85%) of a light-coloured, glass-like substance. This glass can be caused to crystallise by means of cyclohexane/diethyl ether; melting range 96°-104° C. The analytical data show that the product obtained is a diastereoisomeric mixture of the compound No. 1.1.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:20])=[C:4]([Cl:23])[CH:3]=1.[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[Cl:23][C:4]1[CH:3]=[C:2]([NH:1][C:31]([NH:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:32])[CH:22]=[CH:21][C:5]=1[CH2:6][N:7]1[C:11]2=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH3:20]
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(N)cc3Cl)c2n1
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(NC(=O)Nc4ccccc4)cc3Cl)c2n1
Yield: 87.7 %

Procedure:
Methyl 3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (275 mg) was suspended in toluene (10 ml), and phenyl isocyanate (218 mg) was added at room temperature. The mixture was refluxed under heating for 5 hr and concentrated under reduced pressure. Hexane (20 ml) was added, and the mixture was heated and allowed to cool. The precipitated crystals were collected by filtration. The crystals were suspended in ethyl acetate (10 ml), heated and allowed to cool. The precipitated crystals were collected by filtration and dried under reduced pressure and by heating to give the objective compound (328 mg) as colorless crystals.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[C:17]=2[NH2:26])=[CH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N+:28]([O-])([O-])=O.[Na+].[OH-].[NH4+]>C(O)(=O)C.O>[CH2:9]([C:8]1[N:28]=[N:26][C:17]2[C:16]([C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH:21][CH:20]=[CH:19][C:18]=2[C:22]([F:24])([F:25])[F:23])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Nc1c(C(=CCc2ccccc2)c2ccccc2)cccc1C(F)(F)F
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc2c(-c3ccccc3)c(Cc3ccccc3)nnc12
Temperature: 40 °C

Procedure:
2-(1,3-Diphenyl-propenyl)-6-trifluoromethyl-phenylamine (0.08 g, 0.23 mmol) was dissolved in 5 mL of acetic acid, 4 mL of conc. hydrochloric acid in an ice bath. The mixture was treated with 2.5% of sodium nitrate in water. After addition the reaction was heated to ˜40° C. for 20 min, basified with ammonium hydroxide, and extracted with diethyl ether. The combined organics was dried over MgSO4 and concentrated. The material was purified by semi-preparative HPLC (Column: Phenomenex C18 Luna 2.1.6 mm×60 mm, 5 μM; Solvent A: Water (0.1% TFA buffer); Solvent B: Acetonitrile (0.1% TFA buffer); Solvent Gradient: Time 0: 0% B; 10 min: 100% B; Hold 100% B 5 min. Flow Rate: 22.5 mL/min). The product was collected based on UV absorption and concentrated to give the title compound as a brown solid. MS (ESI) m/z 365.
Reaction SMILES: [NH2:1][CH:2]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:3]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[S:5][C:4]=1[C:16]([OH:18])=O.Cl.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CO.C(Cl)Cl>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([CH:2]2[NH:1][C:16](=[O:18])[C:4]3[S:5][C:6]([N:10]4[CH2:15][CH2:14][O:13][CH2:12][CH2:11]4)=[C:7]([C:8]#[N:9])[C:3]2=3)=[CH:20][CH:21]=1
Reactant: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1C(N)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: N#Cc1c(N2CCOCC2)sc2c1C(c1ccc(Cl)cc1)NC2=O
Temperature: 25 °C
Reaction time: 21 h
Yield: 74.8 %

Procedure:
To a mixture of 3-[amino(4-chlorophenyl)methyl]-4-cyano-5-(morpholin-4-yl)thiophene-2-carboxylic acid.HCl (0.206 g, 0.497 mmol), 1-Hydroxybenzotriazole hydrate (92.1 mg, 0.601 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (188 mg, 0.981 mmol) in dry Methylene chloride (10.0 mL, 156 mmol) was added N,N-Diisopropylethylamine (0.252 mL, 1.45 mmol). The resulted clear solution was stirred at r.t. for 21 hours. The reaction solution was diluted with DCM (−30 mL), washed with water (3×), brine, dried over anhydrous Na2SO4, filtered and rotavaped to give a crude product. Chromatograph in a silica gel column using MeOH/DCM (0/100 to 3/97) afforded a racemic product (0.138 g, yield 74.8%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]CC)=[O:22])=[CH:16][C:15]=3[F:26])[C:9](=[O:27])[C:8]=2[C:7]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[C:6]2[CH:34]=[CH:35][CH:36]=[CH:37][C:5]=12)[CH3:2].C(O)(=O)C.Cl>O>[CH2:1]([O:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:15]=3[F:26])[C:9](=[O:27])[C:8]=2[C:7]([O:28][CH2:29][C:30]([F:31])([F:33])[F:32])=[C:6]2[CH:34]=[CH:35][CH:36]=[CH:37][C:5]=12)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC(F)(F)F)c4ccccc4c3OCC)C2=O)c(F)c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CCOc1c2c(c(OCC(F)(F)F)c3ccccc13)C(=O)N(c1ccc(CC(=O)O)cc1F)C2=O
Yield: 65.2 %

Procedure:
Ethyl (4-{4-(ethyloxy)-1,3-dioxo-9-[(2,2,2-trifluoroethyl)oxy]-1,3-dihydro-2H-benzo[f]isoindol-2-yl}-3-fluorophenyl)acetate (0.119 g, 0.23 mmol) was heated to 100° C. in a 1:1 mixture of acetic acid:2N aqueous hydrochloric acid (10 ml) for 2 hours. On addition of water, the resulting cream solid was collected by filtration and washed with water. This was purified by MDAP to give the title compound as a white solid (0.073 g, 0.15 mmol). LC/MS: Rt=3.38, [MH]+ 492.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[CH2:22][S:23][CH2:24][CH2:25][OH:26])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[CH2:22][S:23][CH2:24][CH2:25][O:26][C:28](=[O:30])[CH3:29])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CSCCO)NCCCCCOc1cc(CN2CCCCC2)ccn1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCCSCC(=O)NCCCCCOc1cc(CN2CCCCC2)ccn1
Yield: 90 %

Procedure:
Following a procedure similar to that described in Example 67(c), but using N-[5-(4-piperidinomethyl-2-pyridyloxy)pentyl]-2-(2-hydroxyethylthio)acetamide [prepared as described in step (a) above] and acetic anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 90% yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[NH:30])[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[N:16]([CH:17]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)[CH2:15][CH2:14][S:13][C:12]=2[CH:29]=1.Cl>CO>[NH:19]1[CH2:20][CH2:21][CH:17]([N:16]2[CH2:15][CH2:14][S:13][C:12]3[CH:29]=[C:8]([NH:7][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[NH:30])[CH:9]=[CH:10][C:11]2=3)[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCSc3cc(NC(=N)c4cccs4)ccc32)C1
Agent: Cl
Solvent: CO
Product: N=C(Nc1ccc2c(c1)SCCN2C1CCNC1)c1cccs1
Yield: 78.6 %

Procedure:
A solution of tert-butyl 3-(7-(thiophene-2-carboximidamido)-2H-benzo[b][1,4]thiazin-4(3H)-yl)pyrrolidine-1-carboxylate (0.24 g, 0.554 mmol) in MeOH (5 mL) was treated with 1N HCl solution (9.98 mL, 9.98 mmol) at room temperature. The resulting mixture was refluxed for 30 minutes and brought to room temperature. The mixture was filtered and quenched with 1N NaOH (10 mL). The mixture was diluted with water (50 mL) and extracted with CH2Cl2 (2×50 mL). The organic phase was washed with brine (50 mL) and dried (Na2SO4). The crude material was subject to flash chromatography on silica gel (5-20% 2M NH3 MeOH/CH2Cl2). The collected fractions gave compound 30 as yellow foam (0.15 g, 79%). 1H NMR (DMSO-d6) δ 7.69 (d, J=3.0 Hz, 1H), 7.56 (dd, J=0.9, 4.9 Hz, 1H), 7.07 (dd, J=3.9, 4.9 Hz, 1H), 6.79 (d, J=9.0 Hz, 1H), 6.52-6.49 (m, 2H), 6.31 (brs, 2H), 4.26-4.17 (m, 1H), 3.42-3.22 (m, 2H), 3.10-2.90 (m, 4H), 2.83-2.69 (m, 2H), 2.07-1.96 (m, 1H), 1.68-1.57 (m, 1H); ESI-MS (m/z, %): 347, 345 (MH+, 72), 278, 276 (100).
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:13](Cl)(=[O:24])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[CH3:8][S:7][C:1]1[CH:6]=[CH:5][C:4]([C:13](=[O:24])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([C:4]2[CH:5]=[CH:6][C:1]([S:7][CH3:8])=[CH:2][CH:3]=2)=[O:22])=[CH:3][CH:2]=1
Reactant: O=C(Cl)CCCCCCCC(=O)Cl
Reactant: CSc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CSc1ccc(C(=O)CCCCCCCC(=O)c2ccc(SC)cc2)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Thioanisole (23.5 ml, 0.20 mol) is added to a suspension of AlCl3 (27.3 g, 0.205 mol) in 200 ml of CH2Cl2. Azelaoyl chloride (19.7 ml, 0.10 mol) is added dropwise slowly, while the reaction mixture is cooled in an ice bath and the reaction solution is stirred for 19 h at room temperature. Then, the reaction solution is poured into ice-water. The produced white precipitate is filtered off and the crude product is extracted from the filtrate with CH2Cl2, washed with brine, dried over MgSO4, and concentrated. The residue is purified by recrystallization from i-Pr2O—CHCl3. The product is obtained as a white solid. 1H NMR (CDCl3), δ[ppm]: δ1.35-1.43 (m, 6H), 1.72 (t, 4H), 2.52 (s, 6H), 2.91 (t, 4H), 7.26 (d, 4H), 7.87 (d, 4H)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]12([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=3[O:26][CH3:27])[C:20](O)=[O:21])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1>[C:7]12([C:17]3[CH:18]=[C:19]([CH2:20][OH:21])[CH:23]=[CH:24][C:25]=3[O:26][CH3:27])[CH2:8][CH:9]3[CH2:15][CH:13]([CH2:12][CH:11]([CH2:10]3)[CH2:16]1)[CH2:14]2
Reactant: COc1ccc(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(CO)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
8 g (0.2 mol) of lithium aluminum hydride and 50 ml of anhydrous THF were introduced into a three-necked flask under a stream of nitrogen. A solution of 28.6 g (0.1 mol) of 3-(1-adamantyl)-4-methoxybenzoic acid in 260 ml of anhydrous THF was added dropwise and the mixture was heated at reflux for 16 hours. The reaction medium was cooled and hydrolyzed with 14.4 ml of sodium potassium tartrate solution. The salt was filtered off. The filtrate was evaporated and the solid obtained was triturated from hexane, filtered off and dried. 26.2 g (96%) of the expected benzyl alcohol, having a melting point of 134°-5° C., were recovered.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][N:5]1[C@H:14]2[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@H:13]2[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:25]([F:28])([F:27])[F:26])[C:7]=2[C:6]1=[O:29].O.[OH-].[Li+]>C1COCC1>[C:21]([O:20][C:18]([N:16]1[CH2:17][C@H:13]2[C@@H:14]([N:5]([CH2:4][C:3]([OH:30])=[O:2])[C:6](=[O:29])[C:7]3[C:8]([C:25]([F:27])([F:26])[F:28])=[CH:9][CH:10]=[CH:11][C:12]=32)[CH2:15]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)CN1C(=O)c2c(cccc2C(F)(F)F)[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H]2c3cccc(C(F)(F)F)c3C(=O)N(CC(=O)O)[C@H]2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of (3aR,9bS)-tert-butyl 4-(2-methoxy-2-oxoethyl)-5-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate from Example 18, Part A (105 mg, 0.25 mmol) in 4 mL of THF and 2 mL of water was added lithium hydroxide (12 mg, 0.49 mmol). The resulting mixture was allowed to stir at ambient temperature for 2 h. The reaction was quenched with 10 mL of 1N HCl and extracted with ethyl acetate. The organics were washed with brine, dried (MgSO4) and concentrated in vacuo to afford 100 mg (98%) of the title compound. LRMS (ESI): 415.20 (M+H)+.
Reaction SMILES: N(C(OCC)=O)=N[C:3](OCC)=O.C1(C)C=CC=CC=1.O[CH2:21][C@H:22]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N+:40]([O-:42])=[O:41])(=[O:33])=[O:32])[C@@H:23]1[CH2:27][C@@H:26]([CH3:28])[C:25](=[O:29])[O:24]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:28]([C@@H:26]1[CH2:27][C@@H:23]([CH:22]2[CH2:21][N@@:30]2[S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[N+:40]([O-:42])=[O:41])(=[O:33])=[O:32])[O:24][C:25]1=[O:29])[CH3:3]
Reactant: C[C@@H]1C[C@@H]([C@H](CO)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: CC[C@@H]1C[C@@H](C2C[N@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reaction time: 0.08 h

Procedure:
1.60 ml of a solution of diethyl azodicarboxylate in toluene (40%) (3.52 mmol) was added to a solution of 1.05 g of N-{(S)-2-hydroxy-1-[(2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide obtained in Example (106f) (2.93 mmol) and 923 mg of triphenylphosphine (3.52 mmol) in tetrahydrofuran (30 ml) under ice-cooling over five minutes, and the mixture was stirred at the same temperature for five minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: toluene/acetone=5/1) to obtain 916 mg of the title compound (yield: 92%).
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5]>C(O)C.[Pt]=O>[CH3:5][CH:4]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:10])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:3][CH2:2][OH:1]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Agent: O=[Pt]
Solvent: CCO
Product: CC(C)CCCC(C)CCCC(C)CCO
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.9 %

Procedure:
Farnesol (200 g) was dissolved in ethanol (1000 ml), added with platinum oxide (1 g) and stirred for 24 hours at room temperature under hydrogen atmosphere. After the completion of the reaction, insoluble material was removed by filtration through a Celite layer and the filtrate was concentrated under reduced pressure to obtain 3,7,11-trimethyldodecanol (195 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[N:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[CH3:13][O:12][C:10]1[CH:9]=[C:8]([O:14][CH3:15])[N:7]=[C:6]([C:4]([OH:5])=[O:3])[N:11]=1
Reactant: CCOC(=O)c1nc(OC)cc(OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(OC)nc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
17.1 g of 2-ethoxycarbonyl-4,6-dimethoxypyrimidine are dissolved in 300 ml of ethanol, and 3.4 g of sodium hydroxide in 50 ml of water are added. This solution is stirred for 4 hours at room temperature and refluxed for 1 hour. The mixture is cooled, and most of the ethanol is removed on a rotary evaporator. The residue is taken up in water and extracted using dichloromethane. The aqueous-alkaline phase is acidified to a pH of 2-3 using 6 N hydrochloric acid, and any precipitated product is filtered off with suction. This gives 9.6 g of 4,6-dimethoxypyrimidine-2-carboxylic acid of melting point 155°-157° C.