Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrBr.[NH:3]1[CH:7]=[C:6]([CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]2=[O:20])[N:5]=[CH:4]1.[OH-].[Na+]>C(O)(=O)C>[NH:3]1[CH:7]=[C:6]([CH2:8][C:9]2[C:10]([OH:20])=[C:11]([CH:12]=[CH:13][CH:14]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:5]=[CH:4]1
Reactant: CCOC(=O)C1CCCC(Cc2c[nH]cn2)C1=O
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)c1cccc(Cc2c[nH]cn2)c1O
Temperature: 20 °C
Reaction time: 2.5 h
Yield: 56 %

Procedure:
176 g (56.5 ml; 1.1 mole) of bromine dissolved in 400 ml of glacial acetic acid are added dropwise within 30 minutes, at 17° to 20° C. and under an atmosphere of argon, to a solution containing 37.5 g (0.55 mole) of ethyl 3-[(1H-imidazol-4-yl)methyl]-2-oxo-cyclohexanecarboxylate in 1.5 liter of glacial acetic acid. The reaction mixture is subsequently heated under reflux for 4 hours. The red solution becomes progressively blacker. The mixture is cooled to 20° C. and evaporated under reduced pressure. The residue is taken up in 1.2 liter of 50% aqueous acetic acid. There are then added a spatula tip of anion exchange resin (Amberlite IR 45 acetate), 25 g of 10% palladium on carbon and 25 g of 10% rhodium on carbon and hydrogenolysis is carried out for 150 minutes under a hydrogen pressure of 3.5 bars. The reaction mixture is filtered on Celite and the filtrate is evaporated under reduced pressure. The oil obtained is dissolved in 1 liter of an ice-water mixture and the solution is adjusted to a pH of 8 by the addition of a 2N aqueous sodium hydroxide solution and rapidly extracted 5 times with 400 ml of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by chromatography on silica (eluent: 93.5:6.0:0.5 v/v/v dichloromethane-ethanol-ammonia). There are obtained 75.9 g of ethyl 3-[(1H-imidazol-4-yl)methyl]-2-hydroxybenzoate in the form of an oil which crystallizes slowly. Yield: 55% of theory; M.P.: 133° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:62])[C:56]4[CH:57]=[N:58][NH:59][C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:62][C:55]2[CH:54]=[C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[C:52]4[C:47]=3[CH:46]=[CH:45][NH:44]4)[CH:61]=[C:60]3[C:56]=2[CH:57]=[N:58][NH:59]3)=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
To a solution of 5-bromo-2-pyridinecarboxylic acid (980 mg, 4.83 mmol, available from Alfa Aesar) in DMF (15 ml) was added HATU (1840 mg, 4.83 mmol) and DIPEA (2.53 ml, 14.50 mmol). The mixture was stirred at room temperature for 30 mins then 6-(1H-indol-4-yl)-1H-indazol-4-amine (600 mg, 2.41 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to approx. 5 ml volume and was applied to 2×50 g aminopropyl cartridges that had been pre-conditioned with MeOH. The reaction mixture remained on the cartridges for 2 h before being eluted with MeOH. The eluent was concentrated in vacuo and a precipitate formed, which was collected by filtration to give the title compound (430 mg) as a yellow solid.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([N:12]([C:50]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH:53]=[CH:52][CH:51]=2)[C:13]2[CH:25]=[CH:24][C:23]3[C:22]4[C:17](=[CH:18][C:19]([N:26]([C:37]5[CH:42]=[CH:41][CH:40]=[C:39]([CH:43]6OCC[O:44]6)[CH:38]=5)[C:27]5[C:36]6[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=6)[CH:30]=[CH:29][CH:28]=5)=[CH:20][CH:21]=4)[C:16]([CH3:49])([CH3:48])[C:15]=3[CH:14]=2)[CH:9]=[CH:10][CH:11]=1.Cl>CC(C)=O>[CH3:48][C:16]1([CH3:49])[C:17]2[CH:18]=[C:19]([N:26]([C:37]3[CH:38]=[C:39]([CH:40]=[CH:41][CH:42]=3)[CH:43]=[O:44])[C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)[CH:20]=[CH:21][C:22]=2[C:23]2[C:15]1=[CH:14][C:13]([N:12]([C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[CH:2]=[O:1])[C:50]1[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH:53]=[CH:52][CH:51]=1)=[CH:25][CH:24]=2
Reactant: CC1(C)c2cc(N(c3cccc(C4OCCO4)c3)c3cccc4ccccc34)ccc2-c2ccc(N(c3cccc(C4OCCO4)c3)c3cccc4ccccc34)cc21
Agent: Cl
Solvent: CC(C)=O
Product: CC1(C)c2cc(N(c3cccc(C=O)c3)c3cccc4ccccc34)ccc2-c2ccc(N(c3cccc(C=O)c3)c3cccc4ccccc34)cc21
Yield: 97.3 %

Procedure:
To a three-neck round-bottom flask, were added 8.0 g N2,N7-bis(3-(1,3-dioxolan-2-yl)phenyl)-9,9-dimethyl-N2,N7-di(naphthalen-1-yl)-9H-fluorene-2,7-diamine and in 100 mL acetone. 41.1 mL 2 M hydrochloric acid solution was added slowly to the reaction mixture through an addition funnel. After TLC showed the reaction was done, the solvent was removed by evaporation. 200 mL Ethyl acetate was added, and the reaction mixture was extracted using DI water (4×200 mL). The organic layer was dried over sodium sulfate. After filtration, the solvent was removed by evaporation. The product (6.9 g) was obtained after drying under vacuum, and was carried on to next step without further purification. The structure was confirmed by NMR.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]=[CH:9][NH:8][CH:7]=1.Br[CH2:12][C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].CCN(CC)CC>CCO>[CH2:17]([O:16][C:14]([C:13]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH2:5][CH2:4][NH:3][CH:12]=1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NCCc1c[nH]cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1=CNCCc2nc[nH]c21
Temperature: 25 °C

Procedure:
A mixture of histamine dihydrochloride (5.52 g, 30 mmol), ethyl bromopyruvate (5.0 mL, 36 mmol), and active carbon (500 mg) in anhydrous EtOH (80 mL) was refluxed under nitrogen for 24 hours. After cooling to room temperature, Et3N (30 mL) was added, and the mixture was refluxed at 90° C. for 6 hours. The active carbon was filtered off, and the filtrate was concentrated in vacuo. The residue was taken up in CHCl3, and washed twice with water, then dried over Na2SO4, and evaporated in vacuo. The residual oil was purified by column chromatography on silica gel eluting with hexane-EtOAc (60:40) to give the title compound as a pale-yellow solid. 1H-NMR (CDCl3): δ 7.49 (1H, d)), 7.00 (1H, s), 6.79 (1H, s), 4.85 (1H, br s), 4.30 (2H, q), 3.38 (2H, m), 3.06 (2H, m), 1.36 (3H, t); MS (ES): 208 (MH+).
Reaction SMILES: [OH-].[Na+].[SH:3][C:4]1[C:13]([CH3:14])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.Cl.[CH2:16]([N:18]([CH2:27][CH3:28])[C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Cl)[CH3:17]>O.C(O)C>[CH2:27]([N:18]([CH2:16][CH3:17])[C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][S:3][C:4]1[C:13]([CH3:14])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:28]
Reactant: Cc1nc2ccccc2nc1S
Reactant: CCN(CC)c1ccccc1CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCN(CC)c1ccccc1CSc1nc2ccccc2nc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
To a solution of 0.73 g of sodium hydroxide in a mixture of 2 ml of water and 50 ml of ethanol were added successively 1.5 g of 2-mercapto-3-methylquinoxaline and 1.99 g of 2-diethylaminobenzyl chloride hydrochloride. The resulting mixture was stirred at room temperature for 3 hrs., and the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was washed successively with 5% aqueous sodium hydroxide solution, water and saturated aqueous sodium chloride solution, and then dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was placed under reduced pressure to remove the solvent. The residual oil was purified by silica gel column chromatography (hexane/acetone) to give 1.74 g of 2-(2-diethylaminobenzylthio)-3-methylquinoxaline as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:24]2[CH:28]=[CH:27][C:26]([C:29](OC)=[O:30])=[N:25]2)[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][N:13]2[CH:21]=[CH:22][CH:23]=[C:12]2[CH2:11]1)=[O:9].[BH4-].[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:24]2[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[N:25]2)[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][N:13]2[CH:21]=[CH:22][CH:23]=[C:12]2[CH2:11]1)=[O:9]
Reactant: COC(=O)c1ccn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(Cl)c2)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1ccc(-n2ccc(CO)n2)cc1Cl)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Yield: 35.5 %

Procedure:
A stirred solution of methyl 1-[3-chloro-4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-1H-pyrazole-3-carboxylate (0.14 g, 0.31 mmol) in tetrahydrofuran (5 mL) was heated at reflux and treated with a solution of 2.0 M lithium borohydride in tetrahydrofuran (3 mL, 6.0 mmol) in three 1 mL aliquots over 1.5 hours. After cooling to room temperature, the reaction was quenched with 2 N hydrochloric acid, and extracted with ethyl acetate (3×). The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to a residue. Trituration of the residue with a mixture of methyl tert-butyl ether and hexane afforded a white amorphous powder which was purified by preparative normal phase high-performance liquid chromatography on a Primesphere® silica gel column (50 mm×250 mm), eluting with 100% methyl tert-butyl ether at a flow rate of 70 mL/min. to yield, after evaporation of the solvent, the title compound (0.05 g, 0.11 mmol, 37%) as a colorless amorphous solid, m.p. 85° C.;
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].[N:24]1([C:29]2[CH:30]=[C:31]([C:35]3[O:40]C(C)(C)[O:38][C:37](=O)[CH:36]=3)[CH:32]=[CH:33][CH:34]=2)[CH:28]=[CH:27][N:26]=[CH:25]1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH:22][C:37](=[O:38])[CH2:36][C:35]([C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[CH:30]=1)=[O:40])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Yield: 68.8 %

Procedure:
Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example G2) (154 mg, 0.5 mmol) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10) (135 mg, 0.5 mmol) according to the general procedure K. Obtained as an orange oil (179 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:52])[CH2:5][CH2:6][NH:7][C:8]([C@:10]12[CH2:48][CH2:47][C@@H:46]([C:49]([CH3:51])=[CH2:50])[C@@H:11]1[C@@H:12]1[C@@:25]([CH3:28])([CH2:26][CH2:27]2)[C@@:24]2([CH3:29])[C@@H:15]([C@:16]3([CH3:45])[C@@H:21]([CH2:22][CH2:23]2)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]2[CH:44]=[CH:43][C:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:34][CH:33]=2)=[CH:18][CH2:17]3)[CH2:14][CH2:13]1)=[O:9].[C:53]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])(=[O:60])[CH2:54][CH2:55][C:56](OC)=[O:57].C(Cl)CCl>ClCCl>[C:56]([O:1][CH2:2][CH2:3][N:4]([CH2:5][CH2:6][NH:7][C:8]([C@:10]12[CH2:48][CH2:47][C@@H:46]([C:49]([CH3:51])=[CH2:50])[C@@H:11]1[C@@H:12]1[C@@:25]([CH3:28])([CH2:26][CH2:27]2)[C@@:24]2([CH3:29])[C@@H:15]([C@:16]3([CH3:45])[C@@H:21]([CH2:22][CH2:23]2)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]2[CH:33]=[CH:34][C:35]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])=[CH:43][CH:44]=2)=[CH:18][CH2:17]3)[CH2:14][CH2:13]1)=[O:9])[CH3:52])(=[O:57])[CH2:55][CH2:54][C:53]([O:61][C:62]([CH3:64])([CH3:63])[CH3:65])=[O:60]
Reactant: COC(=O)CCC(=O)OC(C)(C)C
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(C)CCO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: ClCCl
Solvent: ClCCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(C)CCOC(=O)CCC(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 20 °C
Reaction time: 12 h

Procedure:
A mixture of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-((2-hydroxyethyl)(methyl)amino)ethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (40 mg, 0.056 mmol), tert-butyl methyl succinate (21.06 mg, 0.112 mmol), Hunig'sBase (0.049 mL, 0.280 mmol) and EDC (21.45 mg, 0.112 mmol) in dichloromethane (1 mL) was stirred at 20° C. for 12 hours. LCMS indicated the formation of desired product. The reaction mixture was quenched with distilled water, extracted with DCM (3×4 mL). All the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the crude including the title compound as a white solid (40 mg, 82%). LCMS: m/e 871.43 (M+H)+, 3.93 min (method 1).
Reaction SMILES: [Na].C(O[C:5](=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[C:12]([C:16](C)=[O:17])([CH3:15])([CH3:14])[CH3:13]>C(O)C>[CH2:9]([O:8][C:6](=[O:7])[CH2:5][C:16](=[O:17])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10]
Reactant: CC(=O)C(C)(C)C
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC(=O)C(C)(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 106.5 %

Procedure:
Sodium pellets (4.6 g, 200 mmol) were dissolved in ethanol (165 ml) under nitrogen at room temperature and a solution of diethyloxalate (27.2 ml, 200 mmol) in tert-butyl-methyl ketone (20.1 g, 200 mmol) was added dropwise at room temperature over 15 minutes. The reaction was diluted with ethanol (100 ml), heated to 60° C. and stirred at this temperature for 2 hours. After cooling to room temperature the reaction was stirred for 64 hours, poured onto ice-cold 2N HCl (200 ml) and extracted with diethylether (3×200 ml). The combined organic extracts were washed with water, dried over MgSO4 and concentrated under reduced pressure to give 4,4-dimethyl-3-oxo-pentanoic acid ethyl ester (36.7 g) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ=6.48 (1H, s), 4.26-4.37 (2H, quart), 1.29-1.38 (3H, t), 1.17 (9H, s) ppm. LRMS (electrospray): m/z [M+Na]+ 223, [M−H]+ 199.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19](=[O:27])[CH2:20][C:21]1[N:22]=[C:23]([NH2:26])[S:24][CH:25]=1)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:27])[CH2:20][C:21]1[N:22]=[C:23]([NH:26][C:13]([C:9]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:12]=[CH:11][CH:10]=2)=[O:15])[S:24][CH:25]=1)[CH3:17]
Reactant: O=C(O)c1cccn1Cc1ccccc1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NC(=O)c2cccn2Cc2ccccc2)n1
Yield: 65 %

Procedure:
(2-{[1-(Benzyl)-1H-pyrrole-2-carbonyl]-amino}-thiazol-4-yl)acetic acid ethyl ester (60 mg) was prepared from 1-benzyl-pyrrole-2-carboxylic acid (50 mg, 0.25 mmol) and 2-aminothiazol-4-yl acetic acid ethyl ester (47 mg, 0.25 mmol) following general procedure F.
Reaction SMILES: [CH3:1][C@@H:2]1[C:15](=[O:16])[NH:14][N:13]=[C:12]2[N:3]1[C:4]1[CH:5]=[C:6]3[N:19]([C@:20]4([CH3:25])[CH2:24][CH2:23][NH:22][CH2:21]4)[CH:18]=[CH:17][C:7]3=[CH:8][C:9]=1[O:10][CH2:11]2.C(OC(N1CC[C@](NC2C=C3C(=CC=2Br)OCC2N3[C@@H](C)C(=O)NN=2)(C)C1)=O)(C)(C)C>>[CH3:1][C@H:2]1[C:15](=[O:16])[NH:14][N:13]=[C:12]2[N:3]1[C:4]1[CH:5]=[C:6]3[N:19]([C@:20]4([CH3:25])[CH2:24][CH2:23][NH:22][CH2:21]4)[CH:18]=[CH:17][C:7]3=[CH:8][C:9]=1[O:10][CH2:11]2
Reactant: C[C@@H]1C(=O)NN=C2COc3cc4ccn([C@]5(C)CCNC5)c4cc3N21
Agent: C[C@H]1C(=O)NN=C2COc3cc(Br)c(N[C@]4(C)CCN(C(=O)OC(C)(C)C)C4)cc3N21
Product: C[C@H]1C(=O)NN=C2COc3cc4ccn([C@]5(C)CCNC5)c4cc3N21

Procedure:
Using a similar procedure as described in Example #162, Step F-G, (S)-1-Methyl-10-((R)-3-methyl-pyrrolidin-3-yl)-3,5-dihydro-10H-6-oxa-3,4,10,11b-tetraaza-cyclopenta[b]phenanthren-2-one (SFC (Table 1, Method 54) Rt=4.016 min, 0.019 g, 6%) was prepared from (R)-3-((S)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-3-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (Example #164, Step B, isomer D, SFC (Table 1, Method 54), Rt=1.752 min, 0.45 g, 0.9 mmol). 1H NMR (400 MHz, methanol-d4) δ 7.37 (s, 1H), 7.23 (s, 1H), 7.19 (s, 1H), 6.46 (s, 1H), 5.05 (q, J=6.4 Hz, 1H), 4.58 (m, 2H), 4.04 (d, J=12.0 Hz, 1H), 3.79 (d, J=12.0 Hz, 1H), 3.59-3.43 (m, 2H), 2.98 (m, 1H), 2.68 (m, 1H), 1.76 (s, 3H), 1.49 (d, J=6.8 Hz, 3H). LC/MS (Table 1, Method 4) Rt=1.290 min; MS (ESI): m/z 340 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][CH3:35])[CH:9]([CH3:23])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=1)[NH:16][CH2:15][CH2:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:43](Cl)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.O>C(Cl)Cl>[C:43]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([CH2:10][CH:9]([N:8]([CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH2:34][CH3:35])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH3:23])=[CH:19][C:18]=2[C:20]([NH2:22])=[O:21])[CH2:14][CH2:15]1)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc2c(c(C(N)=O)c1)NCC2
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc2c(c(C(N)=O)c1)N(C(=O)c1ccccc1)CC2

Procedure:
To a solution of 5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carboxamide (113 mg) in dry methylene chloride (1 ml) were added triethylamine (42 μl) and benzoyl chloride (26 μl) with stirring under ice cooling, and the mixture was stirred at room temperature for 2.5 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel by using a mixture of chloroform and methanol (20/1) as eluent to give 108 mg of 1-benzoyl-5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carboxamide as an oil.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)O1.B(O)O>>[N:8]1([C:6]2[N:7]=[C:2]([C:31]3[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=3)[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:4]=3[N:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CC1(C)OB(c2ccc(C#N)cc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1ccncc1
Agent: OBO
Product: N#Cc1ccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)cc1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile as a boronic acid, 4-(2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-benzonitrile was obtained, and subsequently 1 equivalent of 1M hydrochloric acid was added, followed by stirring at room temperature, which was concentrated under reduced pressure, to obtain the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH3:11])=[C:9]([C:12]([OH:14])=[O:13])[S:8][C:7]=2[CH:15]=1.Cl.[CH3:17]O>>[CH3:17][O:13][C:12]([C:9]1[S:8][C:7]2[CH:15]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[C:10]=1[CH3:11])=[O:14]
Reactant: COc1ccc2c(C)c(C(=O)O)sc2c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1sc2cc(OC)ccc2c1C

Procedure:
A solution of 6-methoxy-3-methylbenzo[b]thiophene-2-carboxylic acid (7.50 g.) in methanol (400 ml.) was saturated with hydrogen chloride gas and the solution was heated under reflux for 2 hours and then evaporated. The residue was dissolved in ethyl acetate and the solution was washed successively with water, sodium bicarbonate solution, water and dried (Na2SO4). Evaporation of the solvent gave a solid which was crystallized from methanol to give 6-methoxy-3-methylbenzo[b]thiophene-2-carboxylic acid methyl ester (5.59 g.), m.p. 118°-120° C.
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].C1CCCCC1.[OH-].[Na+:39]>CO>[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+:39]
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: CO
Solvent: C1CCCCC1
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Yield: 91.9 %

Procedure:
In a 3 neck flask were placed fluvastatin methyl ester (3.0 g) and cyclohexane (60 ml) then the mixture was heated to reflux. A solution of NaOH (0.29 g) in MeOH (3 ml) was added and the mixture was stirred at reflux for 1.6 h. The slurry was cooled to room temperature, cyclohexane (40 ml) was added and the mixture was stirred over night. The product was isolated by filtration under nitrogen, washed with cyclohexane (90 ml) and dried at 50° C. in a vacuum oven for 24 h to obtain 2.81 g (93%) of fluvastatin sodium Form XCVII.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]C1C=C(Cl)C(Cl)=CC=1Cl)=O.[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH2:29])[N:23]=1>CN(C)C=O>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:29][C:8](=[O:10])[CH2:7][N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[O:1])[N:23]=1)=[O:10]
Reactant: O=C(CN1CCCC1=O)Oc1cc(Cl)c(Cl)cc1Cl
Reactant: NCc1cccc(CN)n1
Solvent: CN(C)C=O
Product: O=C(CN1CCCC1=O)NCc1cccc(CNC(=O)CN2CCCC2=O)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
0.02 mol of 2,4,5-trichlorophenyl 2-oxo-pyrrolidineacetate is dissolved in 50 ml of dimethylformamide and reacted with a solution of 0.01 mol of 2,6-diaminomethylpyridine in 20 ml of dimethylformamide, at -5° C., whilst stirring and with the exclusion of moisture. After leaving the reaction solution to stand at room temperature for three hours, it is warmed to 60° C. for 2 hours, the solvent is then evaporated off, ether is added to the residue and the crystals which precipitate are filtered off. Melting point: 149° C., yield 57% of theory
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][OH:7].[F:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[CH2:12][NH:13][C:14]([NH:16][C:17]1[S:21][N:20]=[C:19]([CH2:22]Cl)[N:18]=1)=[O:15].ClCCl>C1COCC1>[F:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[CH2:12][NH:13][C:14]([NH:16][C:17]1[S:21][N:20]=[C:19]([CH2:22][O:7][CH2:6][CH2:5][O:4][CH3:3])[N:18]=1)=[O:15]
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CCl)ns1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCCOCc1nsc(NC(=O)NCc2cccc(F)c2)n1
Temperature: 0 °C

Procedure:
Sodium hydride (4 eq, 2.66 mmol, 0.13 g of a 50 wt-% suspension in oil) was suspended in THF (2 mL) and cooled to 0° C. 2-methoxy ethanol (3 eq, 1.99 mmol, 0.15 g) and 15-crown-5-ether (1 drop) were added. 1-(3-Fluorobenzyl)-3-(3-(chloromethyl)-1,2,4-thiadiazol-5-yl)urea (Intermediate XXV) was added and the mixture was stirred over night with temperature allowed to rise to room temperature. Dichloromethane (50 mL) was added. The mixture was washed with water (2×10 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude material (0.2 g of an oil) was further purified by preparative HPLC to give 0.101 g. 1H-NMR (300 MHz, CD3OD): δ 7.34 (m, 1H), 7.14 (d, 1H), 7.07 (d, 1H), 6.99 (m, 1H), 4.58 (s, 2H), 4.45 (s, 2H), 3.70 (t, 2H), 3.56 (t, 2H), 3.30 (s, 3H).