Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:24]=[C:23]2[C:5]([CH2:6][CH2:7][C:8]3([C:16]42[NH:20][C:19](=S)[C:18]([CH3:22])=[N:17]4)[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=1.[NH3:25]>>[Br:1][C:2]1[CH:24]=[C:23]2[C:5]([CH2:6][CH2:7][C:8]3([C:16]42[N:20]=[C:19]([NH2:25])[C:18]([CH3:22])=[N:17]4)[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=1
Reactant: COC1CCC2(CCc3ccc(Br)cc3C23N=C(C)C(=S)N3)CC1
Reactant: N
Product: COC1CCC2(CCc3ccc(Br)cc3C23N=C(C)C(N)=N3)CC1
Temperature: 120 °C

Procedure:
(7′-Bromo-4-methoxy-5″-methyl-3′,4′-dihydrodispiro[cyclohexane-1,2′-naphthalene-1′,2″-imidazole]-4″(3″H)-thione (Intermediate 15, 0.191 g, 0.47 mmol) and ammonia (7M in MeOH, 2.5 mL, 17.5 mmol) were mixed in a microwave vial. The vial was sealed and the reaction was heated at 120° C. for 30 min in a microwave reactor. The mixture was concentrated and the residue was dissolved in ammonia (7M in MeOH, 2.5 mL, 17.5 mmol) and heated at 120° C. for 30 min in a microwave reactor. This was repeated six more times (8 runs in total). After evaporation of the solvent, the residue was partitioned between DCM and 2 M citric acid. The phases were separated and the organic layer was extracted with 2 M citric acid. The organic layer was discarded while the combined aqueous phases were basified to ˜pH 12 by addition of 50% aq. NaOH. The aqueous phase was then extracted with EtOAc three times. The combined organic layers were dried using a phase separator and concentrated. The product was purified by preparative HPLC to give two isomers:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23]O)[N:21]=1)=[CH:5]2.II.N1C=CN=C1.[NH:32]1[CH:36]=[CH:35][CH:34]=[N:33]1.[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][N:32]3[CH:36]=[CH:35][CH:34]=[N:33]3)[N:21]=1)=[CH:5]2
Reactant: c1cn[nH]c1
Reactant: OCC[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Agent: II
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCn4cccn4)CS3)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.7 %

Procedure:
2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol (81 mg, 0.11 mmol) prepared in Example 5 was dissolved in tetrahydrofuran (4 mL). Iodine (13.2 mg, 0.11 mmol) and imidazole (9.7 mg, 0.14 mmol) were added thereto, and the mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction mixture was filtered to remove solid moiety. The solvent was removed under reduced pressure, and tetrahydrofuran (4 mL) was added to the residue. Pyrazole (58 mg, 0.85 mmol) and sodium hydride (60% mineral oil, 21 mg, 0.85 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. The reaction was quenched by water, and the reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (24 mg, Yield 34%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([O:16][CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:13]([O:25][CH3:26])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Br:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31].[ClH:35].N1C=CC=CC=1>C(O)(C)C>[ClH:1].[ClH:35].[Br:27][C:28]1[CH:29]=[C:30]([NH:31][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[CH:15]=[C:14]([O:16][CH2:17][CH2:18][N:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)[C:13]([O:25][CH3:26])=[CH:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: Nc1cccc(Br)c1
Reactant: COc1cc2cc3c(Cl)ncnc3cc2cc1OCCN1CCOCC1
Agent: Cl
Solvent: CC(C)O
Solvent: c1ccncc1
Product: COc1cc2cc3c(Nc4cccc(Br)c4)ncnc3cc2cc1OCCN1CCOCC1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
To a suspension of 0.1 g (0.267 mmol) of 4-chloro-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinazoline in 3 mL of isopropanol is added 0.055 g (0.321 mmol) of 3-bromoaniline and 0.031 g (0.267 mmol) of pyridine hydrochloride. The mixture is brought to reflux for 15 minutes, then allowed to cool to room temperature. A yellow precipitate forms, which is filtered and washed with cold ethanol. Drying in vacuo provided 0.131 g of (3-bromophenyl)-[7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinazolin-4-yl]-amine dihydrochloride as a yellow solid, mp 266-269° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=1)=O.[C:19]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:21])[CH3:20].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.C(Cl)Cl>[C:19]([N:22]1[CH2:27][CH2:26][N:25]([CH2:1][C:3]2[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=2)[CH2:24][CH2:23]1)(=[O:21])[CH3:20]
Reactant: CC(=O)N1CCNCC1
Reactant: COc1cc(C=O)cc(NC(=O)OC(C)(C)C)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(CN2CCN(C(C)=O)CC2)cc(NC(=O)OC(C)(C)C)n1

Procedure:
To a solution of tert-butyl 4-formyl-6-methoxypyridin-2-ylcarbamate (15-3, 292 mg, 1.16 mmole) and 1-acetylpiperazine (178 mg, 1.39 mmole) in 2% glacial HOAc in CH2Cl2 (5 mL) was added NaBH(OAc)3 (270 mg, 1.27 mmole) at RT. After 1.5 hr the mixture was quenched with saturated NaHCO3 and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (gradient, 0-5% EtOH/EtOAc) gave the titled compound as a white foam. 1H-NMR (500 MHz, CDCl3) δ 7.41 (s, 1 H), 7.00 (bs, 1 H), 6.43 (s, 1 H), 3.83 (s, 3 H), 3.63 (bs, 2 H), 3.46 (bs, 4 H), 2.41 (m, 4 H), 2.08 (s, 3 H), 1.52 (s, 9 H); MS (ES) (M+H)+ 365.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](Br)=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:20][CH2:21][CH3:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]1(B(O)O)[CH2:25][CH2:24]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:18]([CH:23]2[CH2:25][CH2:24]2)=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:20][CH2:21][CH3:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)C1CC1
Reactant: CCOc1cc(OCc2ccccc2)c(Br)cc1C(=O)OC
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOc1cc(OCc2ccccc2)c(C2CC2)cc1C(=O)OC
Yield: 100 %

Procedure:
A mixture of methyl 4-(benzyloxy)-5-bromo-2-ethoxybenzoate (9.80 g), cyclopropylboronic acid (5.76 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (1.65 g), a 2 M aqueous sodium carbonate solution (40.2 mL), tris(dibenzylideneacetone)dipalladium(0) (1.72 g), and toluene (100 mL) was stirred overnight at 100° C. in an argon atmosphere. The reaction mixture was filtered, and then, the filtrate was poured to water, followed by extraction with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (8.76 g).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:33])[C@@H:22]([NH2:32])[CH2:23][C:24]2[CH:29]=[C:28]([OH:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:34][CH2:35][C:36]([F:39])([F:38])[F:37])[C@@H:16]1[CH3:40])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(C(C)C)CC)(C)C>ClCCl>[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:33])[C@@H:22]([NH:32][C:1](=[O:3])[CH3:2])[CH2:23][C:24]2[CH:29]=[C:28]([OH:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:34][CH2:35][C:36]([F:39])([F:37])[F:38])[C@@H:16]1[CH3:40])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H]1[C@H](OCC(F)(F)F)OC[C@H]([C@@H](O)[C@@H](N)Cc2cc(O)cc(F)c2)N1C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N[C@@H](Cc1cc(O)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](OCC(F)(F)F)[C@H](C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 65.7 %

Procedure:
Add acetic anhydride (0.142 mL, 1.51 mmol) to an ice cold solution of (2S,3S,5R)-5-[(1S,2S)-2-Amino-3-(3-fluoro-5-hydroxy-phenyl)-1-hydroxy-propyl]-3-methyl-2-(2,2,2-trifluoro-ethoxy)-morpholine-4-carboxylic acid tert-butyl ester (823 mg, 1.43 mmol) in dichloromethane (9 mL). Stir for 50 minutes and add diisopropylethylamine (0.125 mL, 0.717 mmol) and stir for 2 hours. Quench with aqueous 1N hydrochloric acid, wash with saturated aqueous sodium bicarbonate, dry with magnesium sulfate and purify on silica gel with dichloromethane/ethyl acetate mixtures to give the desired compound (493 mg). MS(ESI): m/z=525 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.Cl[C:17](=[O:24])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21]>O1CCCC1.O>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:17](=[O:24])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH3:3]
Reactant: CCOC(=O)CN
Reactant: COC(=O)CCC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)CCC(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
To a suspension of glycine ethyl ester hydrochloride (5.00 g, 35.8 mmol) in tetrahydrofuran (300 mL) were added triethylamine (9.99 mL, 71.6 mmol) and methyl 4-chloro-4-oxobutyrate (5.39 g, 35.8 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by recrystallization (ethyl acetate/hexane) to give the title compound (5.05 g, yield 65%).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([Cl:23])=[N:19][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:10][CH2:11][CH:5]2[NH:4][NH:3]1.CN(C)C=O.[H-].[Na+].Cl[CH2:32][C:33]#[N:34]>C(Cl)(Cl)Cl.O>[O:1]=[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([Cl:23])=[N:19][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:10][CH2:11][C:5]2=[N:4][N:3]1[CH2:32][C:33]#[N:34]
Reactant: N#CCCl
Reactant: O=C1NNC2CN=C(c3ccccc3Cl)c3nc(Cl)ccc3N12
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: N#CCn1nc2n(c1=O)-c1ccc(Cl)nc1C(c1ccccc1Cl)=NC2
Reaction time: 0.08 h

Procedure:
20 grams of 1-keto-6-(o-chlorophenyl)-8-chloro-1,3-dihydro-4H-s-triazolo-(4,3-a)-pyrido-(2,3-f)-(1,4)-diazepine were dissolved in 100 ml. of dimethyl formamide, 1.8 grams of sodium hydride (about 80%) added with cooling, further stirred for 5 minutes, then 5 grams of chloroacetonitrile added (the temperature increased from 30° C. to about 50° C.) and stirring continued for 30 minutes. Then it was poured into about 1 liter of water, shaken with chloroform, the chloroform paste washed with dilute aqueous sodium hydroxide and subsequently with water, dried, suction filtered over a silica gel layer and evaporated. The chloroform residue crystallized upon triturating with methanol and was recrystallized from methanol. M.P. 198°-200° C.; Yield 8 grams.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[CH3:25][CH:26]1[CH2:30][CH2:29][CH2:28][NH:27]1>CN1C(=O)CCC1>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:23]([CH3:24])=[C:12]([C:8]3[CH:7]=[C:6]4[C:11](=[CH:10][CH:9]=3)[C:2]([N:27]3[CH2:28][CH2:29][CH2:30][CH:26]3[CH3:25])=[N:3][N:4]=[CH:5]4)[CH:13]=2)[CH2:20][CH2:19]1
Reactant: CC1CCCN1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(Cl)nncc2c1
Solvent: CN1CCCC1=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCCC3C)nncc2c1
Temperature: 160 °C

Procedure:
A mixture of 3-(1-chlorophthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide (300 mg, 888 μmol) and 2-methylpyrrolidine (272 μl, 2664 μmol, Aldrich) in NMP (3 mL) was heated to 160° C. for 18 h. The solution was purified with reverse-phase chromatography (Phenomenex Synergi 4m Max RP 80 A column, 150×21 mM, 20 mL/min, 10-95% CH3CN/H2O, 0.1% TFA, 10.5 min gradient) to afford the title compound. Found MS (ESI, pos. ion) m/z: 387 (M+1).
Reaction SMILES: O[CH2:2][CH:3]([C:11]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[C:13]([CH3:19])[C:12]=1[OH:20])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1>CO>[Br:10][C:7]1[CH:6]=[CH:5][C:4]([CH:3]2[C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[C:13]([CH3:19])[C:12]=3[O:20][CH2:2]2)=[CH:9][CH:8]=1
Reactant: Cc1cc(C)c(C(CO)c2ccc(Br)cc2)c(O)c1C
Solvent: CO
Product: Cc1cc(C)c2c(c1C)OCC2c1ccc(Br)cc1
Yield: 95 %

Procedure:
Using 2-(2-hydroxy-1-(4-bromophenyl)ethyl)-3,5,6-trimethylphenol obtained in Reference Example 232, the title compound was synthesized in the same manner as in Reference Example 13. Yield 95%. Melting point: 72-73° C. (methanol).
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH:12]2[CH2:13][C:8]3([OH:15])[CH2:9][CH:10]([CH2:14][CH:6]1[CH2:7]3)[CH2:11]2)=[O:3].[CH3:16][C:17]1[O:18][C:19]([CH:22]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)=[N:20][N:21]=1>>[CH3:16][C:17]1[O:18][C:19]([CH:22]2[CH2:27][CH2:26][CH2:25][N:24]([C:2]([O:4][CH:5]3[CH:12]4[CH2:13][C:8]5([OH:15])[CH2:9][CH:10]([CH2:14][CH:6]3[CH2:7]5)[CH2:11]4)=[O:3])[CH2:23]2)=[N:20][N:21]=1
Reactant: O=C(Cl)OC1C2CC3CC1CC(O)(C3)C2
Reactant: Cc1nnc(C2CCCNC2)o1
Product: Cc1nnc(C2CCCN(C(=O)OC3C4CC5CC3CC(O)(C5)C4)C2)o1

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 19 Step 1 using 1-hydroxy-4-adamantyl chloroformate solution and 2-methyl-5-(piperidin-3-yl)-1,3,4-oxadiazole. LC-MS Method 1 tR=1.35 min, m/z=362.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH:13]2[CH2:40][CH2:39][C:16]3[N:17](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:18]=[N:19][C:15]=3[CH2:14]2)=[O:10])=[CH:4][CH:3]=1.ClC1C=CC(CC(NCC2CCC3N=CN(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)C=3C2)=O)=CC=1>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH:13]2[CH2:40][CH2:39][C:16]3[NH:17][CH:18]=[N:19][C:15]=3[CH2:14]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)cc1)NCC1CCc2c(ncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: O=C(Cc1ccc(Cl)cc1)NCC1CCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C1
Solvent: O
Solvent: CC(=O)O
Product: O=C(Cc1ccc(Cl)cc1)NCC1CCc2[nH]cnc2C1
Temperature: 90 °C

Procedure:
A solution of a mixture of 2-(4-chlorophenyl)-N-((1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazol-5-yl)methyl)acetamide and 2-(4-chlorophenyl)-N-((3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)methyl)acetamide (0.38 g, 0.80 mmol) in a mixture of acetic acid (5 ml) and water (0.6 ml) was heated to 90° C. for 2 hours. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using a mixture of DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 0.18 g of the title compound.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25](C(O)=O)[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:25]1[CH2:26][CH:23]([C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:18]=[C:9]([C:8]5[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=5)[S:10][C:11]=4[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[CH2:24]1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)O)C3)ccc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carboxylic acid tent-butyl ester (0.5 g, 1.1 mmol) in DCM (6.5 mL) was treated with TFA (6.5 mL). The reaction mixture was stirred at RT for 4 hours then concentrated in vacuo. The residue was azeotroped with DCM then dissolved in DCM and washed with an aqueous saturated sodium bicarbonate solution (×2) followed by brine. The mixture was passed through a phase separator cartridge and concentrated in vacuo to give 235 as a pale orange gum (397 mg, quant.). LCMS: RT=3.13 min, [M+H]+=368. 1H NMR δ (ppm) (DMSO-d6): 9.34 (1 H, s), 9.05 (1 H, s), 8.30 (1 H, d, J=8.19 Hz), 8.06 (1 H, d, J=0.58 Hz), 7.23 (1 H, dd, J=8.24, 1.89 Hz), 7.13 (1 H, d, J=1.84 Hz), 5.82-5.72 (1 H, m), 4.36-4.30 (2 H, m), 4.25-4.17 (2 H, m), 4.13-3.97 (3 H, m), 3.43-3.37 (2 H, m), 1.50 (6 H, d, J=6.59 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:32])[CH2:4][NH:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:30].N1C=CC=CC=1.[S:39](Cl)(Cl)=[O:40].Cl>ClCCl>[Cl:28][C:26]1[CH:27]=[C:22]([C:16]2([C:18]([F:20])([F:21])[F:19])[O:15][N:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([C:6]([NH:5][CH2:4][CH:3]4[O:32][S:39](=[O:40])[NH:1][CH2:2]4)=[O:31])=[C:8]([CH3:30])[CH:9]=3)[CH2:17]2)[CH:23]=[C:24]([Cl:29])[CH:25]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(O)CN
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC1CNS(=O)O1
Reaction time: 4 h

Procedure:
A solution of N-(3-amino-2-hydroxy-propyl)-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzamide (0.2 g) in dichloromethane (10 ml) was cooled to 0° C., treated with pyridine (0.32 ml) and thionyl chloride (0.06 ml), and stirred for 4 hours. The mixture was diluted with dichloromethane (50 ml), neutralized with 2N hydrochloric acid, and washed with water (50 ml). The organic layer was separated, dried over sodium sulfate and concentrated. Purification by chromatography on silica gel (eluent hexane/ethyl acetate 40:60) gave the title compound (20 mg). LCMS (Method G) 3.88 min, (M−H)− 534. 1HNMR (CDCl3, 400 MHz): 7.45-7.52 (m, 6H), 6.50 (m, 1H), 4.05 (d, 1H), 3.98 (m, 1H), 3.72 (d, 1H), 3.62 (m, 1H), 3.51 (m, 3H), 2.46 (s, 3H).
Reaction SMILES: C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:13](OCCC(C)C)=O.[C:21]([C:23]1[CH:28]=[CH:27][C:26]([NH:29]C(=O)C)=[C:25]([CH3:33])[C:24]=1[CH3:34])#[N:22]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH3:34][C:24]1[C:23]([C:21]#[N:22])=[CH:28][CH:27]=[C:26]2[C:25]=1[CH:33]=[N:13][NH:29]2
Reactant: CC(C)CCON=O
Reactant: CC(=O)Nc1ccc(C#N)c(C)c1C
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: Cc1c(C#N)ccc2[nH]ncc12
Reaction time: 7 h
Yield: 107.6 %

Procedure:
Acetic anhydride (2.1 ml, 22.3 mmol), tetra-n-butylammonium bromide (118 mg, 0.366 mmol), potassium acetate (1.44 g, 14.7 mmol) and isoamyl nitrite (1.3 ml, 9.68 mmol) were added to an ethyl acetate suspension (15 ml) of N-(4-cyano-2,3-dimethylphenyl)acetamide (1.38 g, 7.33 mmol) at room temperature, and then the reaction was carried out for 7 hours under reflux conditions. The reaction mixture was cooled, diluted with ethyl acetate, and then washed with a saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then distilled to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: n-hexane/chloroform) to obtain 4-methyl-1H-indazole-5-carbonitrile (1.24 g, 84.9%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33].CC(OC)(C)C>C(O)C>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: COC(C)(C)C
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 70 °C
Reaction time: 1.75 h
Yield: 71.2 %

Procedure:
Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq.) in ethanol (15 ml). The mixture was stirred at about 70° C. for 1.75 h, after which the starting material was no longer detectable by HPLC. Then, 40 ml of MTBE was dripped into the solution. The mixture was cooled slowly to room temperature and stirred overnight. The product could not be filtrated so another 100 ml of MTBE was added and the mixture was stirred over the weekend. The product was isolated by filtration under nitrogen and dried at 50° C. in a vacuum oven for 24 h to obtain 1.45 g (71.2%) of fluvastatin sodium Form XIV.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[OH-].[K+].CS(C)=O.Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>C(OCC)(=O)C.O>[N:20]1([CH2:19][CH2:18][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: ClCCN1CCCC1
Reactant: O=Cc1cccc(O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=Cc1cccc(OCCN2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a mixture of 3-hydroxybenzaldehyde (4.15 g, 33.98 mmol), KOH (4.93 g) and DMSO (50 ml) was added N-(2-chloroethyl)pyrrolidine hydrochloride (6.94 g). The reaction mixture was stirred at room temperature overnight, then was poured into water (750 ml) and ethyl acetate (350 ml) was added. The layers were separated, the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water (2×1000 ml), dried over MgSO4, filtered and stripped to afford 7.12 g of 3-[2-(1-pyrrolidinyl)ethoxy]benzaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[S:10]([N:13]1[C:21]2[C:16](=[C:17]([CH:22]=C)[CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11].N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:33].[Na+]>O1CCOCC1.O.O=[Os](=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[S:10]([N:13]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:22]=[O:33])[C:16]=2[CH2:15][CH2:14]1)(=[O:11])=[O:12]
Reactant: C=Cc1cccc2c1CCN2S(=O)(=O)c1cc(C)ccc1OC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1cccc(C)n1
Solvent: O
Product: COc1ccc(C)cc1S(=O)(=O)N1CCc2c(C=O)cccc21
Reaction time: 0.42 h

Procedure:
OsO4 (9 mg, 0.05 mmol) was added to a stirred mixture of 1-[(2-methoxy-5-methylphenyl)sulfonyl]-4-vinylindoline (240 mg, 0.73 mmol; Intermediate 10) and 2,6-lutidine (170 μL, 1.46 mmol) in dioxane (12 mL). The mixture turned from colorless to black in 1 minute. Sodium periodate (0.625 g, 2.92 mmol) in water (4 mL, warmed to dissolve) was added. A grey precipitation was immediately formed. The mixture was stirred for 25 min, combined with an earlier batch of this intermediate (followed this experimental and starting from Intermediate 10; 60 mg, 18 mmol), and partitioned between 2M aqueous HCl (25 mL) and DCM (25 mL). The organic layer was dried, filtered and concentrated to give the title compound (360 mg, still some dioxane according to HNMR) as a black sticky oil. MS (ESI+) for C17H17NO4S m/z 332 (M+H)+.