Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC(CC[C:9]([O:11]C)=[O:10])=CC=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][CH2:19][CH2:20][C:21]([O:23]C)=[O:22].[CH2:25]([C:29]1[N:30]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2Cl)[C:31]([CH:34]=O)=[CH:32][N:33]=1)[CH2:26][CH2:27][CH3:28].CN1C(C=O)=CN=C1.C(C1N(CC2C=CC=CC=2Cl)C(/C=C(\CC2SC=CC=2)/C(O)=O)=CN=1)CCC>>[CH2:25]([C:29]1[N:30]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:9]([OH:11])=[O:10])=[CH:39][CH:38]=2)[C:31](/[CH:34]=[C:20](\[CH2:19][CH2:18][C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)/[C:21]([OH:23])=[O:22])=[CH:32][N:33]=1)[CH2:26][CH2:27][CH3:28]
Reactant: COC(=O)CCc1ccncc1
Reactant: CCCCc1ncc(C=O)n1Cc1ccccc1Cl
Reactant: COC(=O)CCCc1cccs1
Agent: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1ccccc1Cl
Agent: Cn1cncc1C=O
Product: CCCCc1ncc(/C=C(\CCc2cccs2)C(=O)O)n1Cc1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared following the procedure of Example 20 replacing methyl 3-(4-pyridyl)propanoate with methyl 4-(2-thienyl)butanoate and 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde with 2-n-butyl-1-)4-carbomethoxyphenyl)methyl-1H-imidazol-5-carboxaldehyde; mp 244°-246° C. (d).
Reaction SMILES: C([Li:5])CCC.[CH:6]([CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)([CH3:8])[CH3:7]>CCCCCC>[CH:6]([C-:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)([CH3:8])[CH3:7].[Li+:5]
Reactant: [Li]CCCC
Reactant: CC(C)C1C=Cc2ccccc21
Solvent: CCCCCC
Product: CC(C)[c-]1ccc2ccccc21
Product: [Li+]
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
All operations are performed under an inert atmosphere and with dry, degassed solvents. A solution of 20.0 ml (32.0 mmoles) of 1.6 M butyl lithium in hexane is added to a stirred solution of 5.06 g (32.0 mmoles) of 1-isopropylindene in 100 ml of hexane at room temperature. A white precipitate appeared after 30 minutes at room temperature. Filtration after 2 days at room temperature produces 2.8 g of white solid product. The filtrate is concentrated to 20 ml and, after standing at room temperature another week, an additional 1.9 g of product is recovered for a total of 4.7 g (89 percent yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].[S-:11][C:12]#[N:13].[NH4+].BrBr>CC(O)=O>[Br:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[S:11][C:12]([NH2:13])=[N:5][C:4]=2[CH:3]=1
Reactant: N#C[S-]
Reactant: COc1ccc(N)cc1Br
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1cc2sc(N)nc2cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 3-bromo-4-methoxyaniline IV (2.0 g, 9.90 mmol) in AcOH (25.0 mL) was added ammonium thiocyanate (3.80 g, 49.50 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then cooled to 0° C. followed by addition of a solution of Br2 (0.60 mL, 11.0 mmol) in AcOH (10.0 mL). The reaction mixture was then allowed to stir at room temperature for 2 h. After the completion of the reaction (TLC monitoring), AcOH was distilled off, and the residue was cooled to 0° C. followed by basification with aqueous NH3 till pH 12 and extraction with EtOAc (2×250 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the desired product (2.0 g, 78%). 1H NMR (400 MHz, DMSO-d6): δ 3.80 (s, 3H), 7.41 (br s, 2H), 7.49 (s, 1H) and 7.50 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([CH3:19])=[C:11]2[N:16]([CH:17]=1)[N:15]=[CH:14][N:13]=[C:12]2[OH:18])(=[O:4])=[O:3].O=P(Cl)(Cl)Cl.[F:25][C:26]1[C:34](O)=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[C:29]([CH3:36])[NH:30]2.[H-].[Na+]>ClCCl.CN(C=O)C>[F:25][C:26]1[C:34]([O:18][C:12]2[C:11]3=[C:10]([CH3:19])[C:9]([O:8][CH2:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:17][N:16]3[N:15]=[CH:14][N:13]=2)=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[C:29]([CH3:36])[NH:30]2
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Reactant: Cc1c(OCCCS(C)(=O)=O)cn2ncnc(O)c12
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc2c(F)c(Oc3ncnn4cc(OCCCS(C)(=O)=O)c(C)c34)ccc2[nH]1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A mixture of 6-(3-methanesulfonyl-propoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-ol (620 mg, 2.17 mmol) and POCl3 (10 mL) was heated at 85° C. for 3 h. POCl3 was removed in vacuo to give a yellow solid, which was dissolved in dichloromethane, and washed successively with cold NaHCO3 solution and brine. The organics were dried, filtered and concentrated to afford the crude chloroimidate intermediate (610 mg), which was added to a pre-mixed solution of 4-fluoro-2-methyl-1H-indol-5-ol (664 mg, 4.02 mmol) and NaH (60% in mineral oil, 160 mg, 4.02 mmol) in DMF at 0° C. The resulting mixture was stirred at RT for 30 min, and diluted with dichloromethane, washed with 10% LiCl aqueous solution, dried concentrated. The residue was purified by flash column chromatography (silica gel, eluting from 10% ethyl acetate/dichloromethane to 30% ethyl acetate/dichloromethane). The desired fractions were combined and concentrated in vacuo to give a solid, which was washed with MeOH to afford the title compound as a white solid (610 mg, 65% yield). HRMS (M+H)+ Calcd. For C20H21FN4O4S: 432.12675. Found: 433.1329. 1H NMR (d-DMSO)δ 11.36 (br, 1H), 7.94 (s, 1H), 7.93 (s, 1H), 7.15 (d, 1H, J=8.4 Hz), 6.99 (m, 1H), 6.24 (s, 1H), 4.16 (t, 2H, J=6.16 Hz), 3.31 (t, 2H, J=5.7 Hz), 3.05 (s, 3H), 2.42 (s, 3H), 2.41 (s, 3H), 2.50 (m, 2H). Anal. Calcd. For C20H21FN4O4S: 0.4 H2O: C 54.58; H 4.84; N 12.56; S 7.29. Found: C 54.61; H 4.92; N 12.65; S 7.33.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22])[CH:15]=[O:16].[Cl-].[NH4+]>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]([CH:15]([C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[CH:5][CH:4]=2)[OH:16])[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22]
Reactant: CCc1ccc(Br)cc1
Reactant: CCOc1ccc(C=O)cc1Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOc1ccc(C(O)c2ccc(CC)cc2)cc1Br
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 87.2 %

Procedure:
THF (10 mL) was added to magnesium (353 mg, 14.5 mmol), and furthermore 1-bromo-4-ethylbenzene (2 mL, 14.5 mmol) was added dropwise thereto and the mixture was heated to reflux for one hour. The reaction mixture was cooled to 0° C., and a solution of 3-bromo-4-ethoxybenzaldehyde (2.21 g, 9.68 mmol) in THF (5 mL) was added thereto and the reaction mixture was stirred at the same temperature for 1.5 hours. To the reaction mixture, a saturated ammonium chloride aqueous solution was added and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The residue obtained by distilling the solvent under reduced pressure was purified by silica gel column chromatography [developing solution=n-hexane to n-hexane:ethyl acetate (3:1)] to obtain the title compound (2.83 g, 88%).
Reaction SMILES: [CH:1](=[O:8])[C:2]1C=CC=CC=1.NC(N)=S.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=O.[C:22]1([CH:28]2C(C(OCC)=O)=C[NH:31][C:30](=[S:39])[NH:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OC(=O)C)(=O)C>>[C:1]([N:29]1[CH:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:14]([C:13]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([CH3:17])[NH:31][C:30]1=[S:39])(=[O:8])[CH3:2]
Reactant: CCOC(=O)C1=CNC(=S)NC1c1ccccc1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Agent: NC(N)=S
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C1=C(C)NC(=S)N(C(C)=O)C1c1ccccc1

Procedure:
Utilizing the general procedure of Example 2 and starting with benzaldehyde, thiourea and ethyl acetoacetate, ethyl 4-phenyl-3,4-dihydropyrimidine-2(1H)thione-5-carboxylate was prepared and then acylated with acetic anhydride to afford the title product as a solid (mp 142°-5° C.).
Reaction SMILES: [Si]([O:8][CH:9]([CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([O:12]CC)=O)(C(C)(C)C)(C)C.[NH2:19][C:20]1[S:21][CH:22]=[C:23]([CH3:25])[N:24]=1>>[OH:8][CH:9]([CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([NH:19][C:20]1[S:21][CH:22]=[C:23]([CH3:25])[N:24]=1)=[O:12]
Reactant: Cc1csc(N)n1
Reactant: CCCCC(O[Si](C)(C)C(C)(C)C)C(=O)OCC
Product: CCCCC(O)C(=O)Nc1nc(C)cs1

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate A3, starting from ethyl 2-{[tert-butyl(dimethyl)silyl]oxy}hexanoate and 2-amino-4-methylthiazole, 1H NMR (300 MHz, CDCl3) δ 10.30 (br s, 1H), 6.54 (s, 1H), 5.12 (br s, 1H), 4.41 (m, 1H), 2.35 (s, 3H), 2.00 (m, 1H), 1.76 (m, 1H), 1.48 (m, 2H), 1.39 (m, 2H), 0.92 (t, 3H).
Reaction SMILES: O=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.Cl.[CH3:14][NH:15][CH:16]1[CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH:16]1([N:15]([CH3:14])[CH:2]2[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]2)[CH2:18][CH2:17]1
Reactant: CNC1CC1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C1CC1)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
Combined a solution of tert-butyl 3-oxoazetidine-1-carboxylate (175 mg, 1.022 mmol) and N-methylcyclopropanamine hydrochloride (121 mg, 1.124 mmol) in methylene chloride (5 mL) and added sodium triacetoxyborohydride (325 mg, 1.533 mmol) and the solution stirred at 20° C. for 30 min. The solution was concentrated in vacuo to give white solid which was taken up in ethyl acetate (50 mL), washed with saturated sodium bicarbonate (50 mL) and brine, dried with magnesium sulfate and concentrated in vacuo, and then purified on a 40 g silica gel column eluted with 0 to 50% ethyl acetate in hexanes to give the title compound (128 mg, 0.566 mmol, 55.3%) as a clear, colorless oil. MS: 227 (M+H). 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.41-0.47 (m, 2 H) 0.48-0.56 (m, 2 H) 1.43 (s, 9 H) 1.64 (tt, J=6.7, 3.9 Hz, 1 H) 2.28 (s, 3 H) 3.50 (tt, J=7.5, 5.7 Hz, 1 H) 3.84-4.01 (m, 4 H).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:29]([Cu])#[N:30]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:29]#[N:30])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(Oc3c(C)cccc3C)cc2c1O
Reactant: N#C[Cu]
Product: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3c(C)cccc3C)cc2c1O

Procedure:
The title compound was synthesized from 1-Bromo-6-(2,6-dimethyl-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and CuCN in analogy to example 3a; MS-(+)-ion: M+1=390.9.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:12](=[O:15])([O-])[O-].[K+].[K+].F[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>CN(C=O)C>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([O:15][C:12]2[CH:8]=[CH:9][C:4]([C:2]3[NH:1][C:5]4[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=4[N:3]=3)=[CH:5][CH:6]=2)=[CH:20][CH:21]=1)#[N:24]
Reactant: N#Cc1ccc(F)cc1
Reactant: N#Cc1ccc2[nH]cnc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(-c3nc4cc(C#N)ccc4[nH]3)cc2)cc1
Yield: 21 %

Procedure:
A mixture of 1H-Benzimidazole-5-nitrile, 2-(4-hydroxyphenyl)- (2.6 g, 0.011 mol), potassium carbonate (4.0 g, 0.029 mol), and 4-fluorobenzonitrile (1.2 g, 0.0099 mol) in DMF (100 mL) was refluxed for 18 h. The mixture was then filtered (to remove the potassium carbonate) into an ice/water bath. The precipitate was collected and recrystallized from ethyl acetate to afford 0.7 g (21%) of 2-[4-(4-cyanophenoxy)phenyl]-1H-benzimidazole-5-carbonitrile.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][C:27]([O:26][C:25]([F:24])([F:36])[F:37])=[CH:28][CH:29]=3)[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(CNC(=O)c3ccc(OC(F)(F)F)cc3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.5 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.49 g, 1.5 mmol) in acetonitrile (10 mL), was added 4-trifluoromethoxy-benzoyl chloride (0.34 mL, 2.2 mmol) and N,N-diisopropyl ethylamine (0.63 mL, 3.6 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-4-trifluoromethoxy-benzamide as a white solid (370 mg, 54% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.54 min (98.6%); mp, 258-260° C.; 1HNMR (DMSO-d6) 2.18-2.23 (m, 1H, CHH), 2.59-2.92 (m, 6H, CHCH2, CH3), 4.98-5.09 (m, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, Ch), 7.34-8.07 (m, 7H, Ar), 9.05 (t, J=5 Hz, 1H, CH2NH), 11.05 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.82, 23.29, 30.60, 42.22, 56.54, 117.66, 120.70, 124.15, 125.52, 129.59, 133.30, 133.96, 140.65, 148.51, 150.33, 154.84, 161.10, 165.05, 169.54, 172.63. LCMS MH=489; Anal Calcd For C23H19N4O5F3: C, 56.56; H, 3.92; N, 11.47; F, 11.67. Found: C, 56.32; H, 3.60; N, 11.23; F, 11.56.
Reaction SMILES: IC.[C:3]([NH:6][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[NH:23])[NH:21][OH:22])=[C:16]([F:24])[CH:15]=2)[CH2:9]1)(=[O:5])[CH3:4].[C:25](N=C(N(C)C)N(C)C)(C)(C)C>CN(C=O)C>[C:3]([NH:6][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[NH:23])[NH:21][O:22][CH3:25])=[C:16]([F:24])[CH:15]=2)[CH2:9]1)(=[O:5])[CH3:4]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C(=N)NO)c(F)c2)C(=O)O1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Solvent: CI
Product: CONC(=N)c1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Iodomethane (0.02 ml, 0.39 mmol) was added to a solution of 5-(S)-acetamidomethyl-3-[4′-(N-hydroxyamidino)-3′-fluorophenyl]oxazolidine-2-one (0.080 g, 0.26 mmol) and tert-butyl-1,1,3,3-tetramethylguanidine (0.058 ml, 0.39 mmol) in DMF (1.0 ml), and the mixture was stirred at r.t. overnight. Solvent was removed under vacuum, and the crude product purified by silica gel PTLC (10% methanol in DCM). HPLC: Rt 3.6 min. MS (m/z): [M+H]+=325.
Reaction SMILES: [CH3:1][I:2].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]1=[N:14][C:15]([CH3:21])=[C:16]([CH2:17][N:18]([CH3:20])[CH3:19])[N:9]1[CH:8]=[CH:7]2>C(O)C>[I-:2].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]1=[N:14][C:15]([CH3:21])=[C:16]([CH2:17][N+:18]([CH3:1])([CH3:20])[CH3:19])[N:9]1[CH:8]=[CH:7]2
Reactant: CI
Reactant: Cc1nc2c3ccc(Cl)cc3ccn2c1CN(C)C
Solvent: CCO
Product: Cc1nc2c3ccc(Cl)cc3ccn2c1C[N+](C)(C)C
Product: [I-]
Reaction time: 14 h
Yield: 84.2 %

Procedure:
Methyliodide (1.7 g) was added dropwise to a solution of 8-chloro-3-dimethylaminomethyl-2-methylimidazo[2,1-a]isoquinoline (2.8 g) in ethanol (34 ml) at room temperature and the mixture was stirred for 14 hours. The resulting precipitate was collected by filtration, washed with ethanol and dried in a desiccator to give 8-chloro-2-methyl-3-trimethylammoniomethylimidazo[2,1-a]isoquinoline iodide (3.58 g).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]2[C:26]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1.[CH3:35][NH2:36]>C(#N)C.CO>[CH3:35][NH:36][CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]2[C:26]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1
Reactant: CCOC(=O)c1cccc2nc(CCl)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Reactant: CN
Solvent: CC#N
Solvent: CO
Product: CCOC(=O)c1cccc2nc(CNC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Temperature: 60 °C
Yield: 61 %

Procedure:
To a solution of ethyl 2-chloromethyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.2 g) in acetonitrile (5 ml) was added a solution of 40% methylamine in methanol (0.33 g) and the mixture was heated at 60° C. for 77 hours. The reaction solution was cooled to give pale yellow prisms (0.12 g, 61%), m.p. 248-250° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:4][C:3]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:18]([CH:29]([CH3:31])[CH3:30])[C:17]1=O.CCN(CC)CC.[Si](Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl.CCOC(C)=O>[CH:29]([C@H:18]1[N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:20][CH2:21][N:16]2[C:3]3[CH:4]=[C:5]([S:12]([CH3:15])(=[O:13])=[O:14])[C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:7][C:2]=3[N:1]=[C:17]12)([CH3:30])[CH3:31]
Reactant: COC(=O)c1cc(N)c(N2CCN(C(=O)OC(C)(C)C)[C@H](C(C)C)C2=O)cc1S(C)(=O)=O
Agent: Cl[Si](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(C(=O)OC(C)(C)C)[C@@H]3C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a 1 L round-bottom flask containing (R)-tert-butyl 4-(2-amino-4-(methoxycarbonyl)-5-(methylsulfonyl)phenyl)-2-isopropyl-3-oxopiperazine-1-carboxylate (25 g, 0.0532 mol) in dichloromethane (500 mL) was added Et3N (64.5 g, 0.638 mol, 12 eq.) and SiCl4 (27.1 g, 0.160 mol, 3 eq.). The mixture was stirred at rt overnight. The mixture was added dropwise to aq. NaHCO3 solution (54.1 g in 1 L of water, 0.644 mol, 12.1 eq.) at 0° C. slowly and adjusted to pH=8. The mixture was filtered and the aqueous layer was extracted with dichloromethane (3×600 mL). The combined organic layers were washed with brine, and then dried over anhydrous Na2SO4. The mixture was filtered and concentrated under vacuum to give the residue. The residue was purified by column chromatography on silica gel eluting with PE:EtOAc 2:1 to give (R)-2-tert-butyl 8-methyl 1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2,8(1H)-dicarboxylate (13.2 g, 55% yield) as a pale yellow solid. Analytical chiral HPLC: tR=9.03 min in 15 min chromatography (Method: OD-3—3—5—40—2.5 ML). LC-MS MS (ESI) m/z 452.2 [M+H]+. 1H NMR (CD3OD 400 MHz): δ 8.31 (s, 1H), 8.01 (s, 1H), 5.30-5.18 (m, 1H), 4.70-4.52 (m, 1H), 4.47 (dd, J=3.2 and 12.4 Hz, 1H), 4.18 (dt, J=5.2 and 11.6 Hz, 1H), 3.98 (s, 3H), 3.70-3.52 (m, 1H), 3.44 (s, 3H), 2.50-2.38 (m, 1H), 1.53 (s, 9H), 1.25 (d, J=6.8 Hz, 3H), 1.06 (d, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27][S:28]([CH2:31][C:32]([OH:34])=O)(=[O:30])=[O:29])=[N:15][N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[CH3:35][N:36](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:37].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CNC>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27][S:28]([CH2:31][C:32]([N:36]([CH3:37])[CH3:35])=[O:34])(=[O:29])=[O:30])=[N:15][N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:11])[CH3:12])#[N:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@H]4NS(=O)(=O)CC(=O)O)s2)cc1C#N
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@H]4NS(=O)(=O)CC(=O)N(C)C)s2)cc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
Prepared using General Procedure 16: To (R)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetic acid (20 mg, 0.04 mmol) in DCM (0.4 mL) was added HATU (45 mg, 0.12 mmol) and DIEA (10.3 mg, 0.08 mmol). After 30 min, dimethylamine (2M solution in THF, 200 μL, 0.4 mmol) was added and the reaction stirred for 18 h at room temperature. The reaction was quenched with water (100 μL) and the solvent evaporated. The crude material was purified by preparative HPLC to afford 14 mg (66%) of (R)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)-N,N-dimethylacetamide 43 as white solid. LCMS-ESI (m/z) calculated for C25H27N5O4S2: 525.2; found 526.2 [M+H]+, tR=3.42 min. 1H NMR (400 MHz, CDCl3) δ 8.20 (dd, J=8.9, 2.3 Hz, 1H), 8.14 (d, J=2.3 Hz, 1H), 7.82 (d, J=7.7 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.40 (t, J=7.7 Hz, 1H), 7.09 (d, J=9.0 Hz, 1H), 5.50 (d, J=8.2 Hz, 1H), 5.07 (q, J=7.7 Hz, 1H), 4.76 (hept, J=6.1 Hz, 1H), 4.28 (d, J=14.6 Hz, 1H), 4.09 (d, J=14.6 Hz, 1H), 3.50 (ddd, J=17.0, 8.8, 3.4 Hz, 1H), 3.20 (dt, J=9.7, 7.1 Hz, 1H), 3.15 (s, 3H), 3.02 (s, 3H), 2.72 (dtd, J=11.4, 8.0, 3.5 Hz, 1H), 2.20 (dq, J=13.1, 8.4 Hz, 1H), 1.46 (d, J=6.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 166.99, 165.73, 163.22, 161.71, 144.17, 141.92, 133.44, 133.34, 129.31, 127.92, 127.33, 126.37, 122.70, 115.57, 113.91, 103.71, 72.56, 59.23, 54.92, 38.30, 35.99, 31.36, 21.74. Chiral HPLC: (R)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)-N,N-dimethylacetamide was eluted in 40% IPA in hexanes, 100% ee, tR=22.87 min.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][CH2:11][CH2:12][O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[NH:20]2)=[C:16]([NH2:25])[N:15]=1)[CH3:9].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:37][CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[CH2:8]([O:10][CH2:11][CH2:12][O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:37][CH:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[C:16]([NH2:25])[N:15]=1)[CH3:9]
Reactant: CS(=O)(=O)OCC1CCOCC1
Reactant: CCOCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCOCCOc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 50.2 %

Procedure:
To a solution of 2-[2-(ethyloxy)ethyl]oxy-8-(methoxy)-9H-purin-6-amine trifluoroacetic acid salt (500 mg) in dry N,N-dimethylformamide (4.5 ml) at room temperature and under nitrogen was added potassium carbonate (0.75 g) in one go. The reaction was stirred at 60° C. for 1.5 hours. Tetrahydro-2H-pyran-4-ylmethyl methanesulfonate (0.29 g) was added in one portion and the reaction heated at 90° C. for 3 hours. The reaction was cooled to room temperature and then diluted with ethyl acetate (20 ml) and washed with water (15 ml). The organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo. The product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (10-45%) to afford the title compound as a white solid (240 mg).
Reaction SMILES: CN(C[N:5]=[CH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22]Br)=[CH:16][CH:15]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH2:5][CH2:6][CH:7]1[CH2:8][CH2:9][N:10]([CH2:22][CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[CH2:11][CH2:12]1
Reactant: CN(C)CN=CC1CCNCC1
Reactant: Fc1ccc(OCCBr)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: NCC1CCN(CCOc2ccc(F)cc2)CC1

Procedure:
In a similar manner to Example 3, a mixture of 4-(dimethylaminomethyliminomethyl)piperidine (6.42 g), 2-bromoethyl 4-fluorophenyl ether (8.3 g), triethylamine (5.3 ml) and toluene (20 ml) was heated on a steam bath for 16 hours to give 4-aminomethyl-1-[2-(4-fluorophenoxy)ethyl]piperidine as an oil.