Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH3:7])[N:6]=1.N1C=CC=CC=1.[C:14]1([CH:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:7][N:5]1[N:4]=[N:3][C:2]([NH:1][C:21](=[O:22])[CH:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:6]1
Reactant: Cn1nnc(N)n1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1nnc(NC(=O)C(c2ccccc2)c2ccccc2)n1
Reaction time: 2 h
Yield: 56 %

Procedure:
To a stirred solution of 5-amino-2-methyl-2H-tetrazole (0.50 g, 5.05 mmol), pyridine (0.48 g, 6.06 mmol) and DMAP (0.06 g, 0.51 mmol) in dichloromethane (30 ml) was added at 0° C. diphenylacetyl chloride (1.16 g, 5.05 mmol). Stirring was continued at RT for 2 h, the reaction mixture was poured into sat. NaHCO3 solution (50 ml) and extracted with dichloromethane (3×50 ml). The combined organic layers were washed with brine (70 ml), dried (Na2SO4) and evaporated. The crude product was crystallized from ethyl acetate/hexane to give the title compound (0.83 g, 56%) as a white solid, m.p. 218° C. (dec.) and MS: m/e=293.1 (M+H+).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[CH2:12])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)(Cl)Cl>[CH3:20][S:21]([O:1][N:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[CH2:12])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: C=Cc1ccc2nnn(O)c2c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=Cc1ccc2nnn(OS(C)(=O)=O)c2c1
Yield: 76.6 %

Procedure:
In chloroform (80 ml) are dissolved 1-hydroxy-6-vinyl-1,2,3-benzotriazole (8.0 g) and triethylamine (5.1 g) under stirring, and thereto is added dropwise a solution of methanesulfonyl chloride (5.73 g) in chloroform (20 ml) at a temperature of less than 10° C. The mixture is stirred at room temperature for 1.5 hours. The reaction mixture is washed with water, an aqueous sodium hydrogen carbonate and water in order, dried over anhydrous magnesium sulfate, treated with charcoal and then concentrated till about 40 ml. After dissolving the precipitated crystals by heating, the mixture is allowed to stand. The precipitated crystals are separated by filtration to give 1-methanesulfonyloxy-6-vinyl-1,2,3-benzotriazole (9.1 g), melting point: 129°-129.5° C. The filtrate is concentrated, and the resulting residue is recrystallized from benzene to give additionally the desired product (2.3 g).
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:13][C:14]=3[C:6]=2[C:5]([NH:16][CH3:17])=[N:4][CH:3]=1.[Cu][C:19]#[N:20]>CN1C(=O)CCC1.C(OCC)(=O)C>[F:15][C:12]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[C:2]([C:19]#[N:20])=[CH:3][N:4]=[C:5]([NH:16][CH3:17])[C:6]=3[C:14]=2[CH:13]=1
Reactant: CNc1ncc(Br)c2[nH]c3ccc(F)cc3c12
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CNc1ncc(C#N)c2[nH]c3ccc(F)cc3c12
Temperature: 225 °C

Procedure:
4-Bromo-8-fluoro-N-methyl-5H-pyrido[4,3-b]indol-1-amine (150 mg, 0.501 mmol) was combined with copper(I) cyanide (114 mg, 1.275 mmol) and dissolved in NMP (2.55 mL). The reaction was heated to 225° C. in a microwave for one hr. The solution was cooled to ambient temperature, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified on silica gel (EtOAc/hexanes).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)=O)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C[Si]([N:54]=[N+:55]=[N-:56])(C)C>O1CCCC1>[C:1]([O:4][CH2:5][C:6]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:56]=[N:55][N:54]=1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(=O)OCC(=O)Nc1ccc(C#N)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)OCc1nnnn1-c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.1 %

Procedure:
To a solution of 2-[(4-cyanophenyl)amino]-2-oxoethyl acetate (3.48 g, 15.95 mmol, Intermediate 7) in tetrahydrofuran (THF) (200 mL) was added triphenylphosphine (8.37 g, 31.9 mmol), di-isopropyl azodicarboxylate (6.20 mL, 31.9 mmol) and trimethylsilylazide (4.23 mL, 31.9 mmol). The reaction mixture was stirred at room temperature for 18 hours. The majority of the solvent was removed under vacuum and the residue purified by silica chromatography (Biotage SP4, eluting 30% EtOAc in iso-hexane (5 column volumes) then a gradient from 30-40% ethyl acetate in iso-hexane (over 7 column volumes)) to yield the title compound as a white solid (2.68 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.[C:11]([O:15][C:16]([CH2:18][S:19][C:20]([CH3:32])([CH3:31])[C@H:21]([NH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:22](O)=[O:23])=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[CH3:2][O:3][C:4]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:22](=[O:23])[C@@H:21]([NH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:20]([S:19][CH2:18][C:16]([O:15][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:17])([CH3:31])[CH3:32])=[O:10]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CCOC(=O)N[C@H](C(=O)O)C(C)(C)SCC(=O)OC(C)(C)C
Agent: Cl
Product: CCOC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OC)C(C)(C)SCC(=O)OC(C)(C)C
Yield: 52.4 %

Procedure:
Reaction of 0.44 g of (L)-proline methyl ester hydrochloride and 0.86 g of 3-tert.-butoxycarbonylmethylsulfanyl-2-(R)-ethoxycarbonylamino-3-methyl-butyric acid according to the procedure described in example 91b yielded 0.60 g (52%) of the title compound as a colorless oil. (+)-APCI-MS: 474 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33]C)=[C:6]([C:8]([CH3:32])([CH3:31])[CH2:9][C:10]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[C:22](=[O:23])[O:21][N:20]=[C:19]([CH3:24])[C:18]=3[CH:25]=2)=[O:12])[CH:7]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>ClCCl.B(Br)(Br)Br>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:33])=[C:6]([C:8]([CH3:32])([CH3:31])[CH2:9][C:10]([OH:30])([C:26]([F:27])([F:29])[F:28])[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[C:22](=[O:23])[O:21][N:20]=[C:19]([CH3:24])[C:18]=3[CH:25]=2)=[O:12])[CH:7]=1
Reactant: COc1ccc(Br)cc1C(C)(C)CC(O)(C(=O)Nc1ccc2c(=O)onc(C)c2c1)C(F)(F)F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1noc(=O)c2ccc(NC(=O)C(O)(CC(C)(C)c3cc(Br)ccc3O)C(F)(F)F)cc12
Yield: 80.8 %

Procedure:
43.2 mg of (+)-6-[4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)valeroylamino]-4-methyl-2,3-benzoxazin-1-one in 2.5 ml of dichloromethane and 0.4 ml of 1 M boron tribromide in dichloromethane are stirred for 1.5 hours at 0° C. and mixed with ethyl acetate and sodium bicarbonate solution. The organic phase is washed with water, dried, concentrated by evaporation, and the residue is chromatographed on silica gel (hexane/ethyl acetate, 1.5+1). After crystallization from diisopropyl ether, 34 mg of (+)-6-[4-(5-bromo-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)valeroylamino]-4-methyl-2,3-benzoxazin-1-one is obtained.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][S:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29](Cl)=[O:30])[CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:19].Cl>O1CCCC1.O>[OH:3][NH:2][C:29](=[O:30])[CH:28]=[CH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([S:18](=[O:20])(=[O:19])[NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])[CH:22]=1
Reactant: NO
Reactant: COc1ccccc1NS(=O)(=O)c1cccc(C=CC(=O)Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1NS(=O)(=O)c1cccc(C=CC(=O)NO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine hydrochloride (0.36 g, 5.20 mmol) in tetrahydrofuran (6 ml) a saturated NaHCO3 solution (4.5 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a solution of crude 3-[3-(2-methoxy-phenylsulfamoyl)-phenyl]-acryloyl chloride (16c) (0.37 g,1.05 mmol) in tetrahydrofuran (5 ml) was added and the mixture was stirred at ambient temperature for one hour. The reaction mixture was poured into water, the obtained solution was acidified with 2N HCl and extracted with ethyl acetate. The organic layer was washed successively with water and saturated NaCl, then the solvent was removed. The residue was crystallised from ethyl acetate and washed with diethyl ether affording the title compound (0.23 g, 64%). M.p. 181° C. 1H NMR (DMSO-d6, HMDSO) δ: 3.45 (3H, s); 6.49 (1H, d, J=16.0 Hz); 6.76-7.96 (9H, m); 9.09 (1H, br s); 9.54 (1H, s); 10.78 (1H, br s). HPLC analysis on Symmetry C8 column: impurities 1.3% (column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 35:65; sample concentration 0.15 mg/min; flow rate 1.2 ml/min; detector UV 230 nm). Anal. Calcd for C16H16N2O5S, % N C 55.16, H 4.63, N 8.04. Found, %: C 55.14, H 4.52, N 7.99.
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(O)C>CCO>[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: CC(C)O
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Yield: 94.7 %

Procedure:
In a 100 ml flask were placed Fluvastatin methyl ester (2.0 g) and a solution of NaOH (0.19 g) in EtOH (5 ml). The mixture was stirred at reflux for 3.5 h and propan-2-ol (40 ml) was added. The slurry was cooled to room temperature and stirred over night. The product was isolated by filtration under nitrogen, washed with propan-2-ol (20 ml) and dried at 50° C. in a vacuum oven for 24 h to obtain 1.93 g (95%) of fluvastatin sodium crystal Form XXXIX.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][Mg]Cl)=[CH:4][CH:3]=1.FC1C=CC(CCl)=CC=1.[Mg].Cl[Si:22]([CH2:25][Cl:26])([CH3:24])[CH3:23].Cl>CCOCC.CCCCCC>[Cl:26][CH2:25][Si:22]([CH3:24])([CH3:23])[CH2:6][C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: C[Si](C)(Cl)CCl
Reactant: Fc1ccc(C[Mg]Cl)cc1
Agent: Cl
Agent: Fc1ccc(CCl)cc1
Agent: [Mg]
Solvent: CCOCC
Solvent: CCCCCC
Product: C[Si](C)(CCl)Cc1ccc(F)cc1
Yield: 93 %

Procedure:
To the 4-fluorobenzylmagnesiumchloride, prepared from parafluorobenzylchloride (1.59 g, 11 mmol) and magnesium (0.25 g, 11 mmol) in ether (20 ml), was added dropwise, at 0° C., chloro-chloromethyl-dimethylsilane (1.43 g, 10 mmol )in ether (5 ml). Then the mixture was refluxed 6 hours, cooled to 0° C., hydrolyzed with 3N HCl (20 ml) and extracted with ether. The ether solution was washed with water, brine, dried and evaporated. Chromatography (silica gel, hexane) afforded chloromethyl-dimethyl-4-fluorobenzyl silane as an oil (2.01 g, 93% yield) 1H NMR, CDCl3, TMS) δ: 0.20 (s,6H), 2.27 (s,2H), 2.63 (s,2H), 6.90-7.13 (m,4H).
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]#[C:4][C:5](OCC)=[O:6].[CH3:11][NH:12][NH2:13]>C(Cl)Cl.C(OCC)(=O)C>[F:1][CH:2]([F:10])[C:3]1[N:12]([CH3:11])[N:13]=[C:5]([OH:6])[CH:4]=1
Reactant: CNN
Reactant: CCOC(=O)C#CC(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1nc(O)cc1C(F)F
Temperature: -78 °C
Reaction time: 8 h
Yield: 21.8 %

Procedure:
10.2 g (0.068 mol) of ethyl 4,4-difluoro-2-butynoate in 20 ml of methylene chloride was added dropwise to a stirred solution of 4 ml (0.075 mol) of methylhydrazine in 80 ml of methylene chloride cooled to -78° C. The resultant reaction mixture was stirred overnight and subsequently concentrated in vacuo to afford 8.63 g of a clear, yellow oil. The oil was dissolved in ethyl acetate and washed with 10% aqueous sodium bicarbonate. The organic layer was dried, concentrated and recrystallized from carbon tetrachloride to give 2.2 g (21.7% yield) of a white crystalline solid, m.p. 115°-119° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[C:15]2[CH2:14][CH2:13][N:12]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[Cl:22].[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].C(N(CC)CC)C.Cl>C(Cl)Cl>[Cl:22][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][CH2:11][N:12]([C:16](=[O:21])[C:17]([F:19])([F:18])[F:20])[CH2:13][CH2:14][C:15]=2[C:5]=1[O:4][CH2:3][CH2:2][NH:1][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[F:23]
Reactant: NCCOc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Reactant: O=C(Cl)c1ccccc1F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCOc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1ccccc1F
Yield: 81.5 %

Procedure:
Dissolve 6-(2-amino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (100 mg, 0.297 mmol) in DCM (5 mL). Add 2-fluorobenzoyl chloride (39 μL, 0.326 mmol), triethylamine (62 μL, 0.445 mmol) and stir at ambient temperature for 72 h under nitrogen atmosphere. Dilute with DCM, add 1M aqueous HCl and extract the aqueous phase with DCM. Dry the combined organic extracts over MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (7:3 and 2:1) to give 7-chloro-6-[2-(2-fluorobenzoylamino)-ethoxy]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (111 mg, 820%).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:47][C@@H:48]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:49]1[CH:50]=[C:51]([P:55]([CH3:60])(=[O:59])[O:56][CH2:57][CH3:58])[CH:52]=[CH:53][CH:54]=1>CC#N>[OH:1][C:2]1[C:7]([C:8]([NH:47][C@@H:48]([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:49]2[CH:50]=[C:51]([P:55]([CH3:60])(=[O:59])[O:56][CH2:57][CH3:58])[CH:52]=[CH:53][CH:54]=2)=[O:10])=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Reactant: CCOP(C)(=O)c1cccc([C@@H](N)c2ccccc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOP(C)(=O)c1cccc([C@@H](NC(=O)c2cnc(-n3cccn3)nc2O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 8-b, (12.3 g, 40 mmol) and Et3N (11 g, 109 mmol) in MeCN (200 ml) was added HATU (16.6 g, 43.8 mmol). The mixture was stirred for 10 min at room temperature and then ethyl 3-((S)-amino(phenyl)methyl)phenyl(methyl)phosphinate, 25-d, (10.55 g, 36.5 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with saturated NH4Cl. The organic layer was dried over sodium sulfate and concentrated under vacuum to provide the crude product, 25-e, (33 g) as red oil. The crude product was used for the next step directly.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:7][C:6]=2[CH:14]=1.C([Li])CCC.CN(C)[CH:22]=[O:23].[Cl-].[NH4+]>C(OCC)(=O)C.O1CCCC1>[F:11][C:10]([F:13])([F:12])[C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([CH:22]=[O:23])=[CH:14][C:6]=2[CH:7]=1
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cc2cc(Br)ccc2o1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1ccc2oc(C(F)(F)F)cc2c1
Temperature: 25 °C
Yield: 38 %

Procedure:
To a tetrahydrofuran solution (12 mL) of 5-bromo-2(trifluoromethyl)benzofuran (587 mg, 2.21 mmol), n-butyl lithium (hexane solution, 1.59 mol/L) (1.70 mL, 2.66 mmol) was added at −78° C. and the resultant solution was stirred for 40 minutes. To the reaction solution, N,N-dimethylformamide (257 μL, 3.32 mmol) was added and the resultant mixture was stirred for 3 hours while the temperature of the mixture was raised to room temperature. After completion of the reaction, saturated ammonium chloride aqueous solution was added to the reaction solution and extraction with ethyl acetate from the resultant mixture was performed. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (180 mg, yield 39%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[CH3:15]O>>[CH3:15][O:8][C:7]([C:6]1[S:5][N:4]=[N:3][C:2]=1[CH3:1])=[O:9]
Reactant: Cc1nnsc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1snnc1C

Procedure:
4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid (1.0 g, 6.94 mmol), concentrated H2SO4 (866 μL), and methanol (12 mL) were combined and heated to reflux for 15 h. The solvent was reduced by a rotary evaporator and the residue was poured into 15 g of ice. The reaction was neutralized with saturated aqueous NaHCO3. The solution was then extracted with CH2Cl2 (4×35 mL). The combined organics were dried over MgSO4, filtered, and concentrated on the rotary evaporator. The product was preadsorbed onto silica gel and purified by flash chromatography to afford the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[I:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:35][C:34]2[CH:37]=[CH:38][CH:39]=[C:32]([I:31])[CH:33]=2)[CH:6]=1
Reactant: BrCc1cccc(I)c1
Reactant: COC(=O)Cc1cccc(OCCCNCC(c2ccccc2)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(I)c2)CC(c2ccccc2)c2ccccc2)c1
Temperature: 45 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
To a solution of {3-[3-(2,2-diphenyl-ethylamino)-propoxy]-phenyl}-acetic acid methyl ester (3) (0.50 g, 0.0012 mol) in DMF (10 mL), was added 3-iodobenzyl bromide (0.36 g, 0.0012 mol) and powdered potassium carbonate (1.16 g, 0.0084 mol), the reaction mixture was heated and stirred at 45° C. for 18 hours. After cooling, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, concentrated to an oil, which was purified by flash chromatography (8:2 Hexanes/EtOAc) to give the desired product as oil 0.6 g in 81% yield. 1H NMR (CDCl3) δ 7.48 (d, 1H), 7.42 (s, 1H), 7.24 (m, 5H), 7.15 (m, 6H), 6.99 (d, 1H), 6.86 (m, 2H), 6.65 (s, 1H), 6.63 (dd, 1H), 4.16 (t, 1H), 3.67 (s, 3H), 3.60 (t, 2H), 3.58 (s, 2H), 3.52 (s, 2H), 3.05 (d, 2H), 2.61 (t, 2H), 1.81 (t, 2H); 13C NMR (CDCl3) δ 173.4, 160.5, 144.7, 143.7, 139.2, 137.3, 136.6, 131.2, 130.9, 129.8, 129.7, 129.6, 129.4, 127.8, 122.7, 116.9, 114.5, 95.6, 66.9, 61.1, 59.9, 53.5, 51.8, 51.1, 42.7, 28.2.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[C:31]([CH2:37][CH2:38][CH3:39])=[N:30][C:29]([OH:40])=[CH:28]2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[OH:40][C:29]1[N:30]=[C:31]([CH2:37][CH2:38][CH3:39])[C:32]2[C:27]([C:28]=1[CH2:3][C:4]1[C:5]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[N:6][C:7]3[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=3)=[CH:26][C:25]([O:24][CH3:23])=[C:34]([O:35][CH3:36])[CH:33]=2
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: COc1ccc2nc(NCCNC(C)=O)c(CCl)cc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NCCNC(C)=O)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of N-(2-((3-(chloromethyl)-6-methoxyquinolin-2-yl)amino)ethyl)acetamide hydrochloride SLA 41090 (128 mg, 0.372 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35134 (103 mg, 0.417 mmol) followed by a 2 N aq. LiOH solution (0.21 mL, 0.42 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL) and washed with brine (20 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 92:8) provided 19.4 mg of N-(2-(3-((3-hydroxy-6,7-dimethoxy-1-propylisoquinolin-4-yl)methyl)-6-methoxyquinolin-2-ylamino)ethyl)acetamide. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.0 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afforded N-(2-((3-((3-hydroxy-6,7-dimethoxy-1-propylisoquinolin-4-yl)methyl)-6-methoxyquinolin-2-yl)amino)ethyl)acetamide dihydrochloride 55 as a yellow solid (20 mg, 9% yield).
Reaction SMILES: [N:1]1([C:10]2[CH:23]=[CH:22][C:13]([C:14]([N:16]3[CH2:20][CH2:19][C@@H:18]([OH:21])[CH2:17]3)=[O:15])=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C(N(C(C)C)CC)(C)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH3:33][S:34]([O:21][C@@H:18]1[CH2:19][CH2:20][N:16]([C:14](=[O:15])[C:13]2[CH:22]=[CH:23][C:10]([N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[CH:2]3)=[CH:11][CH:12]=2)[CH2:17]1)(=[O:36])=[O:35]
Reactant: O=C(c1ccc(-n2cnc3ccccc32)cc1)N1CC[C@@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]1CCN(C(=O)c2ccc(-n3cnc4ccccc43)cc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A solution of (3R)-1-[4-(1H-benzimidazol-1-yl)benzoyl]pyrrolidin-3-ol (2.30 g, 7.48 mmol) in anhydrous dichloromethane at 0° C. is treated with diisopropylethyl amine (2.13 g, 16.46 mmol) and methanesulfonyl chloride (1.29 g, 11.22 mmol), stirred at 0° C. for 2 hours and concentrated to give a crude oil. Purification of this oil by flash column chromatography (silica, methanol:dichloromethane 5:95) provides the title product as a yellow solid, 2.3 g (81% yield), identified by NMR and mass spectral analyses. MS [386.5 m/e (M+H)].
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][CH:6]=1)=[O:4].[NH2:22][CH2:23][CH:24]([OH:26])[CH3:25]>>[OH:26][CH:24]([CH3:25])[CH2:23][NH:22][C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][CH:6]=1)=[O:4]
Reactant: CCCCc1noc(C)c1CCc1ncc(C(=O)OC)s1
Reactant: CC(O)CN
Product: CCCCc1noc(C)c1CCc1ncc(C(=O)NCC(C)O)s1
Yield: 69 %

Procedure:
As described for example 58, 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid methyl ester (90 mg, 0.29 mmol) was converted, using rac-1-amino-2-propanol instead of rac-2-amino-1-propanol, to the title compound (50 mg, 69%) which was obtained as a light yellow oil. MS: m/e=352.4 [M+H]+.