Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19]C4C=CC=CC=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1.O[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43]C(=O)OC(C)(C)C)=[CH:39][CH:38]=1>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][CH2:36][C:37]4[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CO)cc1
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)OCc1ccc(N)cc1
Temperature: 100 °C
Yield: 13.5 %

Procedure:
Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (51 mg, 0.111 mmol) was mixed with tert-butyl N-(4-(hydroxymethyl)phenyl)carbamate (119 mg, 0.533) in pyridine (0.8 mL). The reaction mixture was heated at 100° C. overnight. The solvent was removed and the residue was purified by preparative reverse phase LC/MS to give 4-aminobenzyl N-(4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl)carbamate (9 mg, 0.015 mmol). 1H NMR (CDCl-d) δ 1.52(s, 1H), 2.08(m, 4H), 3.65(m, 2H), 3.90(s, 3H), 4.14(m, 2H), 4.97(m, 1H), 5.17(s, 2H), 5.37(bs, 1H), 6.55(s, 1H), 6.95(s, 1H), 7.03(s, 1H), 7.06(m, 1H), 7.31(s, 1H), 7.38(m, 3H), 8.16(bs, 1H), 8.30(s, 1H). LC/MS: MH+589.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[N:22]=[CH:23][N:24]=[C:25]4[C:32]=3[C:31]3[C@@H:30]([CH2:33][C:34]#[N:35])[CH2:29][CH2:28][C:27]=3[S:26]4)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[OH:36][Li].O.OO>CO>[N:11]1([CH:14]2[CH2:15][CH2:16][CH:17]([O:20][C:21]3[N:22]=[CH:23][N:24]=[C:25]4[C:32]=3[C:31]3[C@@H:30]([CH2:33][C:34]([NH2:35])=[O:36])[CH2:29][CH2:28][C:27]=3[S:26]4)[CH2:18][CH2:19]2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: [Li]O
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCC(Oc3ncnc4sc5c(c34)[C@@H](CC#N)CC5)CC2)CC1
Agent: OO
Solvent: O
Solvent: CO
Product: NC(=O)C[C@H]1CCc2sc3ncnc(OC4CCC(N5CCNCC5)CC4)c3c21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl-4-(4-[[(3R)-3-(cyanomethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]oxy]cyclohexyl)piperazine-1-carboxylate (260 mg, 0.52 mmol, 1.00 equiv) in methanol (15 mL) were added LiOH.H2O (150 mg, 3.57 mmol, 6.84 equiv), H2O2 (30%) (0.8 mL). The resulting solution was stirred for 4 h at 0° C. The reaction was then quenched by the addition of 10 mL of Na2SO3 (aq.). The resulting solution was extracted with 3×30 mL of dichloromethane and the organic layers combined and concentrated under vacuum. This resulted in 120 mg (45%) of tert-butyl 4-(4-[[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]oxy]cyclohexyl)piperazine-1-carboxylate as a yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[CH3:6][N:7]1[C:16]2[NH:15][C:14]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:13]=3[N:12]([C:22]([CH:24]3[CH2:29][CH2:28][CH:27]([CH2:30][NH:31][C:32](=[O:40])[CH2:33][CH:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)[CH2:26][CH2:25]3)=[O:23])[CH2:11][C:10]=2[CH:9]=[N:8]1>ClCCl.C(N(CC)CC)C>[C:1]([N:37]1[CH2:38][CH2:39][CH:34]([CH2:33][C:32]([NH:31][CH2:30][CH:27]2[CH2:26][CH2:25][CH:24]([C:22]([N:12]3[CH2:11][C:10]4[CH:9]=[N:8][N:7]([CH3:6])[C:16]=4[NH:15][C:14]4[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:13]3=4)=[O:23])[CH2:29][CH2:28]2)=[O:40])[CH2:35][CH2:36]1)(=[O:3])[CH3:2]
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CNC(=O)CC2CCNCC2)CC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(CC(=O)NCC2CCC(C(=O)N3Cc4cnn(C)c4Nc4cc(C)ccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of acetyl chloride (0.39 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of N-[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-2-piperidin-4-yl-acetamide hydrochloride from Example E17 (2.57 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=521.5
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.S(Cl)([Cl:29])=O>C1(C)C=CC=CC=1>[Cl:29][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]2[N:11]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[S:8][CH:9]=2)=[CH:15][CH:16]=1
Reactant: OCc1ccc(OCc2csc(-c3ccccc3)n2)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: ClCc1ccc(OCc2csc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a mixture of [4-[(2-phenyl-4-thiazolyl)methoxy]phenyl]methanol (4.35 g), tetrahydrofuran (50 mL) and toluene (50 mL) was added a solution (5 mL) of thionyl chloride (1.5 mL) in toluene under ice-cooling, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The mixture was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give colorless crystals (4.10 g, 89%) of 4-(4-chloromethylphenoxymethyl)-2-phenylthiazole. melting point: 98-99° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[F:21][C:22]1[CH:23]=[C:24]([CH2:28][CH:29]=O)[CH:25]=[CH:26][CH:27]=1>>[F:21][C:22]1[CH:23]=[C:24]([C:28]2[CH:29]=[N:1][C:2]3[C:3]([C:12]=2[C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)=[CH:4][CH:5]=[CH:6][C:7]=3[C:8]([F:11])([F:10])[F:9])[CH:25]=[CH:26][CH:27]=1
Reactant: O=CCc1cccc(F)c1
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Product: Oc1cccc(-c2c(-c3cccc(F)c3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and (3-Fluoro-phenyl)-acetaldehyde following the procedure of Example 457: MS (ESI) m/z 384; HRMS: calcd for C22H13F4NO+H+, 384.10060; found (ESI, [M+H]+), 384.0992;
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[CH2:3].[C:6]1([CH3:12])[CH:11]=CC=C[CH:7]=1>>[C:6]([C:3]1[CH:2]=[C:1]([OH:5])[CH:3]=[CH:2][C:1]=1[OH:5])([CH3:7])([CH3:11])[CH3:12]
Reactant: C=CC(=O)O
Reactant: Cc1ccccc1
Product: CC(C)(C)c1cc(O)ccc1O
Yield: 5 %

Procedure:
Then, after adding a mixture of 17.2 g of acrylic acid and 150 g of toluene to the reaction mixture obtained above together with 1.0 g of t-butylhydroquinone, the reaction was further carried out under refluxing with stirring for 4 hours. After cooling to room temperature, the reaction mixture obtained was reprecipitated from 2 liters of methanol and the solid thus precipitated was collected by filtration and dried under reduced pressure to obtain 135 g of Macromonomer MM-1 having a weight average molecular weight of 6.8×103. ##STR51##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].Br[CH2:41][C:42]1[C:43]([C:50]2[C:55]([Cl:56])=[CH:54][CH:53]=[CH:52][C:51]=2[Cl:57])=[N:44][O:45][C:46]=1[CH:47]1[CH2:49][CH2:48]1>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([O:15][CH2:41][C:42]2[C:43]([C:50]3[C:51]([Cl:57])=[CH:52][CH:53]=[CH:54][C:55]=3[Cl:56])=[N:44][O:45][C:46]=2[CH:47]2[CH2:49][CH2:48]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)CC1
Reactant: Clc1cccc(Cl)c1-c1noc(C2CC2)c1CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(OCc2c(-c3c(Cl)cccc3Cl)noc2C2CC2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.2 %

Procedure:
To a solution of 36.11 g (167.7 mmol) of 4-hydroxy-azepane-1-carboxylic acid tert-butyl ester in 300 mL of tetrahydrofuran at 0° C. (ice bath), 18-crown-6 (63.43 g, 237.58 mmol) and potassium tert-butoxide (28.06 g, 250.04 mmol) are added. The resulting mixture is stirred for 20 min at room temperature under nitrogen, followed by addition of a solution of 48.5 g (139.75 mmol) of 4-Bromomethyl-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole in 100 mL tetrahydrofuran over a 1 hour period. The resulting mixture is stirred at room temperature under nitrogen atmosphere for 12 hours. Water (200 mL) is added to the reaction mixture and the solvent is removed under reduced pressure. The resulting brown oil is diluted with EtOAc (2×250 mL), and washed with brine (2×150 mL). The organic layer is dried (Na2SO4), filtered and concentrated to afford a crude which is purified on silica gel column chromatography (Eluting with Hexanes/EtOAc 8:2) to obtain 56 g of the title compound as a white/yellow oil. (83%). MS (m/e): 481 (M+1).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:15][C:14]=2[F:30])[CH:12]=1)=O>CN(C=O)C>[F:30][C:14]1[CH:15]=[C:16]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=[CH:18][C:13]=1[N:11]1[CH:12]=[C:8]([C:6]#[N:5])[CH:9]=[N:10]1
Reactant: NC(=O)c1cnn(-c2ccc(NC(=O)OCc3ccccc3)cc2F)c1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1cnn(-c2ccc(NC(=O)OCc3ccccc3)cc2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
Thionyl chloride (0.23 ml) was added to a stirred solution of benzyl 4-[4-(aminocarbonyl)-1H-pyrazol-1-yl]-3-fluorophenylcarbamate (Intermediate 40) (0.76 g, 2.14 mmol) in DMF (20 ml) at 0° C. The resulting mixture was warmed to room temperature and stirred for 1 hour. It was quenched with aqueous saturated sodium bicarbonate solution, extracted with ethyl acetate, dried over sodium sulfate and solvent was removed under vacuum to give the title product (0.71 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[CH:10][C:9]=1[CH3:16].[CH3:17][N:18]=[C:19]=[O:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:17][NH:18][C:19](=[O:20])[O:15][C:11]1[CH:10]=[C:9]([CH3:16])[C:8]([S:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[C:13]([CH3:14])[CH:12]=1
Reactant: CN=C=O
Reactant: Cc1cc(O)cc(C)c1Sc1ccccn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CNC(=O)Oc1cc(C)c(Sc2ccccn2)c(C)c1
Reaction time: 6 h

Procedure:
4-(2-Pyridylthio)-3,5-dimethylphenol (161 g.), prepared in part A, and methylisocyanate (48 g.) was dissolved in dry toluene (1500 ml.) containing triethylamine (10 ml.) and the mixture was then stirred under reflux overnight. Further quantities of methyl isocyanate (22 g.) and triethylamine (10 ml.) were then added and refluxing was continued for a further 6 hours.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:5](=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:11][C:12]=3[CH:13]=2)[NH:4][C:3]1=[O:22].[CH3:23][NH:24][CH:25]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([N:24]([CH3:23])[C:19](=[O:21])[CH2:18][CH2:17][CH2:16][O:15][C:10]2[CH:9]=[CH:8][C:7]3[N:6]=[C:5]4[NH:4][C:3](=[O:22])[N:2]([CH3:1])[C:14]4=[CH:13][C:12]=3[CH:11]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Cn1c(=O)[nH]c2nc3ccc(OCCCC(=O)O)cc3cc21
Reactant: CNC1CCCCCC1
Product: CN(C(=O)CCCOc1ccc2nc3[nH]c(=O)n(C)c3cc2c1)C1CCCCCC1

Procedure:
This compound, m.p. 234.5°-236.5° C., was prepared analogous to Example 15 from 4-[(2,3-dihydro-1-methyl-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butanoic acid and N-methylcycloheptylamine.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[CH:4][C:5]2[C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1.[C:18]([C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1)[CH2:25]Br)([CH3:21])([CH3:20])[CH3:19]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:17][CH2:25][C:24]1[CH:23]=[C:22]([C:18]([CH3:20])([CH3:19])[CH3:21])[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:27]=1)[C:6]([CH3:15])([CH3:16])[CH2:7][CH:8]=[C:9]2[CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1
Reactant: CC(C)C1=CCC(C)(C)c2cc(O)c(Br)cc21
Product: CC(C)C1=CCC(C)(C)c2cc(OCc3cc(C(C)(C)C)cc(C(C)(C)C)c3)c(Br)cc21
Yield: 72 %

Procedure:
Following General Procedure O, 3-bromo-5-isopropyl-8,8-dimethyl-7,8-dihydronaphthalen-2-ol (Compound 97, 0.14 g, 0.48 mmol) was reacted with 3,5-di-t-butylbenzylbromide to afford 0.074 g (72%) of the title compound as a yellow solid. PNMR (300 MHz, CDCl3) δ 1.20 (m, 12H), 1.37 (s, 18H), 2.15 (d, 2H, J=4.8 Hz), 2.85 (m, 1H), 5.20 (s, 2H), 5.72 (m, 3H), 6.95 (s, 1H), 7.40 (m, 3H), 7.55 (s, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([NH:19]N)=[C:8]3[C:16](=[O:17])[NH:15][NH:14][C:13](=[O:18])[C:9]3=[N:10][C:11]=2[CH:12]=1.Cl.[CH2:22]([O:24][C:25](=[O:29])[CH2:26][CH2:27]N)[CH3:23]>N1C=CC=CC=1.O>[CH2:22]([O:24][C:25]([CH2:26][CH2:27][NH:19][C:7]1[C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:12][C:11]=2[N:10]=[C:9]2[C:13](=[O:18])[NH:14][NH:15][C:16](=[O:17])[C:8]=12)=[O:29])[CH3:23]
Reactant: CCOC(=O)CCN
Reactant: NNc1c2ccc(Cl)cc2nc2c(=O)[nH][nH]c(=O)c12
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)CCNc1c2ccc(Cl)cc2nc2c(=O)[nH][nH]c(=O)c12
Yield: 11.3 %

Procedure:
A mixture of 7-chloro-2,3-dihydro-10-hydrazinopyridazino[4,5-b]-quinoline-1,4-dione hydrochloride (1.0 g, 2.9 mM, as prepared in Example 44) and beta alanine ethyl ester hydrochloride (49.0 g, 320 mM) in pyridine (52 mL) was refluxed for 23 hr. After cooling, the vigorously stirred reaction mixture was diluted slowly with water (100mL) and then filtered to separate a fine red solid. The collected solids were washed with water and chromatographed (eluant: methanol/methylene chloride; 5/95) over silica gel to provide the title ester (0.13 g, 13%) as a red powder, mp 258°-260° C.; MS(CI): 363 (M+H).
Reaction SMILES: [CH:1]1([C@@H:7]([NH:11][C:12](=[O:48])[CH2:13][NH:14][C:15](=[O:47])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C@@H:24]3[C@@H:27]([S:28][CH2:29][C:30]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)=[O:31])[C:26](=[O:39])[N:25]3[C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)=[CH:20][CH:19]=2)[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.C(O)(=O)C>[CH:1]1([C@@H:7]([NH:11][C:12](=[O:48])[CH2:13][NH:14][C:15](=[O:47])[CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C@@H:24]3[C@@H:27]([S:28][CH2:29][CH:30]([C:32]4[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=4)[OH:31])[C:26](=[O:39])[N:25]3[C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)=[CH:22][CH:23]=2)[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)NCC(=O)N[C@@H](C(=O)O)C1CCCCC1
Solvent: CO
Solvent: CC(=O)O
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)NCC(=O)N[C@@H](C(=O)O)C1CCCCC1
Yield: 79 %

Procedure:
(2R)-cyclohexyl[(N-([4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio)-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl)amino]acetic acid (0.0085 g, 0.013 mmol) was dissolved in methanol (2 ml). NABH4 (0.006 g, 0.159 mmol) was added and when the reaction was complete according to LC-MS a few drops of acetic acid was added. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on a Kromasil C8-column using a stepwise gradient of 35%, 40% then 50% MeCN in 0.1M ammonium acetate buffer as eluent. After freeze-drying, 0.007 g (82%) of the title product was obtained. NMR (500 MHz, CD3COOD) 1.05-1.33 (m, 5H), 1.60-1.87 (m, 6H), 2.91-3.07 (m, 2H), 3.94-4.06 (m, 3H), 4.32 (d, 1H), 4.60 (s, 2H), 4.79-4.86 (m, 1H), 4.90 (d, 0.5H), 4.92 (d, 0.5H), 6.96-7.03 (m, 4H), 7.03-7.08 (brd, 2H), 7.25-7.31 (m, 2H), 7.31-7.38 (m, 4H)
Reaction SMILES: N([O-])=O.[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([CH:10]=[C:11]([O:17][CH2:18][C:19]#[CH:20])[C:12]=1[O:13][CH2:14][C:15]#[CH:16])N.[ClH:21]>C(O)(=O)C.[Cu](Cl)Cl>[Cl:21][C:8]1[CH:10]=[C:11]([O:17][CH2:18][C:19]#[CH:20])[C:12]([O:13][CH2:14][C:15]#[CH:16])=[C:6]([Cl:5])[CH:7]=1
Reactant: Cl
Reactant: C#CCOc1cc(N)cc(Cl)c1OCC#C
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C#CCOc1cc(Cl)cc(Cl)c1OCC#C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium nitrite (1.33 g) was added to a solution of 3-chloro-4,5-dipropargyloxyaniline (4.47 g) in acetic acid (30 ml) and 35% hydrochloric acid (4 ml) at 0° C., followed by stirring at the same temperature for 1 hour. The resultant solution was poured into 35% hydrochloric acid (20 ml) containing copper chloride (2.35 g) at room temperature, and stirring was continued at 60° C. for 30 minutes. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with aqueous sodium carbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography using toluene as an eluent to give 1,3-dichloro-4,5-dipropargyloxybenzene (3.60 g) as white crystals. m.p. 61°-63° C.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][CH:10]=[C:11]([CH3:23])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH2:3][C:4]([O:6]C)=[O:5].[OH-].[Na+]>C(O)C>[OH:1][CH:2]([CH2:8][CH2:9][CH:10]=[C:11]([CH3:23])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: COC(=O)CC(O)CCC=C(C)CCC=C(C)CCC=C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(O)CC(=O)O

Procedure:
A solution of methyl 3-hydroxy-7,11,15-trimethylhexadeca-6,10,14-trienoate (139 mg, 430 μmol), ethanol (1 mL) and sodium hydroxide (1N, 440 μL, 440 μmol) was stirred at room temperature for two hours. The crude mixture was purified by flash chromatography on a 20 mm ID silica gel column. Elution of the column with choloform:acetic acid (40:1/v=v) gave title compound as a colorless gum.
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]>C(#N)C.O>[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: O
Solvent: CC#N
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Fluvastatin methyl ester (3.01 g) was dissolved in acetonitrile (60 ml) by heating and a solution of NaOH (0.28 g) in water (0.75 ml) was added at about 50EC. The mixture was stirred at about 40EC for 2 h, cooled to room temperature and stirred for another h. The product was isolated by filtration under nitrogen, washed with acetonitrile (40 ml) and dried at 50EC in a vacuum oven for 24 h to obtain 2.52 g (82.2%) of fluvastatin sodium crystal Form I.
Reaction SMILES: [CH3:1][SH:2].[Na].O.[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16]Br)=[CH:11][C:10]=1[O:19][CH3:20])(=[O:7])[CH3:6]>C1C=CC=CC=1>[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16][S:2][CH3:1])=[CH:11][C:10]=1[O:19][CH3:20])(=[O:7])[CH3:6]
Reactant: CS
Reactant: COc1cc(C(=O)CBr)ccc1OC(C)=O
Agent: [Na]
Solvent: c1ccccc1
Solvent: O
Product: COc1cc(C(=O)CSC)ccc1OC(C)=O
Reaction time: 20 h
Yield: 83 %

Procedure:
As shown in the above-described reaction formula, the mixture of 600 ml of sodium methyl mercaptan (8.56 ml) and three drops of aliquat/5 ml of water solution was added to the solution containing 2.46 g of 4-(2-bromoacetyl)-2-methoxyphenyl acetate (8.56 mM) dissolved in 10 ml of benzene. The mixture solution was stirred for 20 hours. The resulting product was extracted with ethylacetate, dried with anhydrous magnesium sulfate and the remaining solvent was removed. The remaining residue was performed to Silica gel column chromatography with a mobile phase (n-hexane:ethylacetate=4:1) to obtain white solid type of 2-methoxy-4-[2-(methylthio)acetyl]phenyl acetate (3; 2.18 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:12]([OH:25])[CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O)[CH:6]=[C:5]2[CH3:32].[CH3:33][NH2:34]>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@@H:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:12]([OH:25])[CH2:13][NH:34][CH3:33])[CH:6]=[C:5]2[CH3:32]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC(O)C(c2ccccc2)n2cc(C)c3cc(F)ccc32)cc1
Solvent: CO
Product: CNC[C@@H](O)[C@H](c1ccccc1)n1cc(C)c2cc(F)ccc21
Reaction time: 12 h

Procedure:
A solution of (2S,3S)-3-(5-fluoro-3-methyl-1H-indol-1-yl)-3-phenylpropane-1,2-diol (1.03 g, 3.4 mmol) and p-toluenesulfonyl chloride (0.78 g, 4.1 mmol) in anhydrous pyridine (11 ml) was stirred at room temperature under nitrogen for 12 hours. The reaction was poured into a 1N aqueous solution of hydrochloric acid (50 mL) and extracted with ethyl acetate (50 mL). The organics were dried over anhydrous sodium sulfate, filtered, and concentrated to give (2S,3S)-toluene-4-sulfonic acid 3-(5-fluoro-3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester. The product was used in the next step without further purification. To a solution of toluene-4-sulfonic acid 3-(5-fluoro-3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester (1.6 g, 3.4 mmol) in methanol (10 mL) was added a 2N solution of methylamine in methanol (8.6 mL, 17 mmol) and the reaction stirred for 12 hours. Upon completion, the reaction was partitioned between saturated sodium bicarbonate (50 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Biotage chromatography (FlasH40i, silica, 20% MeOH/dichloromethane) to give (1S,2R)-1-(5-fluoro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol as a clear oil. The free base was dissolved in a minimum amount of ethanol and treated with a 2N ethereal solution of hydrochloric acid and stirred for 1 hour. The ethanol was removed in vacuo and the clear oil was triturated with ether/dichloromethane to give (1S,2R)-1-(5-fluoro-3-methyl-1H-indol-1-yl)-3-(methylamino)-1-phenylpropan-2-ol hydrochloride as a white solid. MS (ESI) m/z 313.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][N+:9]([O-])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].C[Si](C)(C)[C:15]#[N:16].C(N(CC)CC)C>C(#N)C>[C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:15]#[N:16])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)C#N
Reactant: CC(=O)NCc1cc[n+]([O-])cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccnc(C#N)c1

Procedure:
A solution of 4-(acetylaminomethyl)pyridine N-oxide (17.5 g), trimethylsilanecarbonitrile (53 ml) and triethylamine (43 ml) in acetonitrile (180 ml) was refluxed for 7 hours with stirring. After evaporation of the solvent, the residue was diluted with water and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (430 g) by eluting with a mixture of ethyl acetate and methanol (50:1) followed by recrystallization with a mixture of ethyl acetate and diisopropyl ether to give 4-(acetylaminomethyl)-2-pyridinecarbonitrile (8.66 g).