Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=3)[O:18][N:17]=2)[N:3]=1.C(Cl)(=O)C(Cl)=O.C[N:37](C=O)C>ClCCCl.CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([NH2:37])=[O:28])=[N:25][CH:26]=3)[O:18][N:17]=2)[N:3]=1
Reactant: CN(C)C=O
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(C(=O)O)nc3)n2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: CO
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(C(N)=O)nc3)n2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
To a solution of 5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)pyridine-2-carboxylic acid (Intermediate 124, 50 mg, 128 μmol) in DCE (10 mL) and DMF (100 μL) was added oxalyl chloride (22 μL, 256 μmol). The resulting solution was stirred at room temperature for 2 h, evaporated to dryness and re-suspended in a solution of ammonia in dioxane (7N, 10 mL). The reaction mixture was stirred overnight at room temperature and then poured into water (50 mL). The mixture was extracted with DCM (3×50 mL) and the combined organics were dried and concentrated under vacuum to afford a crude yellow solid. The crude material was suspended in MeOH, filtered and washed with further MeOH. The resulting solid was recrystallised in dioxane and water to afford the title compound as a white solid (15 mg, 30%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].I[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Ic1ccccc1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Product: O=[N+]([O-])c1ccc2ccn(-c3ccccc3)c2c1

Procedure:
Prepared by Procedure C and Scheme O using 6-nitro-1H-indole and iodobenzene: ESMS m/e: 238.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C@@H:17]([OH:20])[CH2:18][NH2:19])[CH:13]=2)[NH:8][C:7]=1[CH3:21])=[O:5])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]([CH:34]=[CH:35][C:36]=1[N:37]1[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]1)[CH2:26][CH:27]1[S:31][C:30](=[O:32])[NH:29][C:28]1=[O:33]>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C@@H:17]([OH:20])[CH2:18][NH:19][CH:40]3[CH2:41][CH2:42][N:37]([C:36]4[CH:35]=[CH:34][C:25]([CH2:26][CH:27]5[S:31][C:30](=[O:32])[NH:29][C:28]5=[O:33])=[CH:24][C:23]=4[F:22])[CH2:38][CH2:39]3)[CH:13]=2)[NH:8][C:7]=1[CH3:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)[nH]c2ccc(OC[C@@H](O)CN)cc12
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2F)CC1
Product: CCOC(=O)c1c(C)[nH]c2ccc(OC[C@@H](O)CNC3CCN(c4ccc(CC5SC(=O)NC5=O)cc4F)CC3)cc12

Procedure:
The title compound was prepared from 5-((2S)-3-amino-2-hydroxy-propoxy)-2-methyl-1H-indole-3-carboxylic acid ethyl ester (which was obtained in Example 141) and 5-[3-fluoro-4-(4-oxo-piperidine-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 61) according to the procedure of Example 73 as a yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 1.34 (t, J=7.1 Hz, 3H), 1.56-1.63 (m, 2H), 2.03 (m, 2H), 2.61 (s, 3H), 2.67-2.75 (m, 4H), 2.88-2.96 (m, 4H), 3.04-3.07 (m, 2H), 3.95-3.97 (m, 2H), 4.05 (m, 2H), 4.25 (q, J=7.1 Hz, 2H), 4.61-4.66 (m, 1H), 5.52 (brs, 1H), 6.79 (dd, J=8.7, 2.5 Hz, 1H), 6.94-7.03 (m, 2H), 7.24-7.29 (m, 2H), 7.46 (d, J=2.3 Hz, 1H) 11.65 (s, 1H); MS (ES) m/z: 599.1 (MH+); HRMS for C30H36FN4O6S(MH+): 599.2339. Found: 599.2333.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:27][CH2:26][C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([CH3:22])[CH:24]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: Cc1cccc(CCBr)c1
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cccc(CCN2CCC(C(C(N)=O)(c3ccccc3)c3ccccc3)C2)c1
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.5 g--see Preparation 8), 3-methylphenethylbromide (0.36 g--see J. Ind. Chem. Sac., 40, 327, (1963)) , anhydrous potassium carbonate (0.5 g) and acetonitrile (10 ml) was heated under reflux for 4 hours. On cooling to room temperature, water (60 ml) was added and the mixture was extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (2% up to 4%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as an oil, yield, 0.17 g.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[C:8](N)[CH:9]=[CH:10][C:2]1=2.[NH2:12]C1C=CC([N+]([O-])=O)=CC=1O>>[O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][C:2]1=2
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: Nc1ccc2c(c1)NCCO2
Product: Nc1ccc2c(c1)OCCN2

Procedure:
The above was prepared using the same procedure as for 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine, except 2-amino-5-nitrophenol was used as starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:3]=1[NH2:4].[OH-].[Na+].[CH2:14]([O:16][C:17](OCC)(OCC)OCC)[CH3:15]>C(O)C>[Cl:1][C:2]1[C:3]2[NH:4][C:17]([O:16][CH2:14][CH3:15])=[N:9][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(OCC)(OCC)OCC
Reactant: Nc1c(Cl)cccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1nc2cccc(Cl)c2[nH]1
Temperature: 130 °C
Reaction time: 12 h
Yield: 35.1 %

Procedure:
2-Chloro-6-nitroaniline (3.45 g, 20.0 mmol) and stannous chloride dihydrate (18.05 g, 80.0 mmol) were heated under reflux in ethanol (80 mL) for 3 hr. The reaction mixture was neutralized with aqueous sodium hydroxide solution, and the precipitate was filtered off. The filtrate was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was mixed with tetraethoxymethane (10 mL, 47.7 mmol) and the mixture was stirred at 130° C. for 12 hr. The reaction mixture was purified by silica gel column chromatography (hexane/ethyl acetate=50/50) to give the title compound (1.38 g, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14](I)=[CH:15][C:6]1=2.[N:22]1([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([C:35]3[CH:40]=[CH:39][C:38](B4OC(C)(C)C(C)(C)O4)=[CH:37][CH:36]=3)=[O:34])[CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14]([C:38]3[CH:39]=[CH:40][C:35]([C:33]([N:30]4[CH2:29][CH2:28][CH:27]([N:22]5[CH2:23][CH2:24][CH2:25][CH2:26]5)[CH2:32][CH2:31]4)=[O:34])=[CH:36][CH:37]=3)=[CH:15][C:6]1=2
Reactant: O=C1CNc2ncc(I)cc2N1Cc1cc(Cl)ccc1Cl
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC(N4CCCC4)CC3)cc2)OC1(C)C
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2Cl)C(=O)CN3)cc1)N1CCC(N2CCCC2)CC1
Yield: 42 %

Procedure:
1-(2,5-Dichlorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (62 mg) was reacted with (4-(pyrrolidin-1-yl)piperidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4B to give the title compound as a brown solid (42% yield). M.p.>200° C., LCMS: m/z=564.14 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 1.37 (2H, m), 1.67 (4H, m), 1.81 (2H, m), 3.22 (6H, m), 3.51 (3H, m), 4.22 (2H, s), 5.23 (2H, s), 7.22 (3H, m), 7.38 (3H, m), 7.55 (3H, m), 8.06 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[CH2:9]Cl.[C-:11]#[N:12].[Na+].O>CN(C=O)C>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][C:11]#[N:12])=[C:2]([F:1])[CH:7]=1
Reactant: Fc1cc(Br)ccc1CCl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.8 %

Procedure:
2-Fluoro-4-bromo-chloromethylbenzene (25.0 g, 112 mmol) and NaCN (6.32 g, 129 mmol) were dissolved in DMF (70 mL) and the solution was stirred under a N2 atmosphere for 18 hrs at ambient temperature. The solution was poured into water (300 mL), and was extracted with EtOAc (1×1 L, 4×300 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure, yielding the title compound (22.5 g, 105 mmol, 93%) as a yellow oil that contained some traces of DMF. 1H-NMR (CDCl3, 300 MHz): 3.75 (s, 2H); 7.20-7.4 (m, 3H)
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([NH2:7])[NH:4][N:3]=1.[C:8]([CH2:16][C:17](=O)[CH3:18])(=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)(=O)C>[CH3:18][C:17]1[CH:16]=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]2[N:4]=[C:5]([NH2:7])[N:6]=[C:2]2[N:1]=1
Reactant: Nc1n[nH]c(N)n1
Reactant: CC(=O)CC(=O)c1ccccc1
Solvent: CC(=O)O
Product: Cc1cc(-c2ccccc2)n2nc(N)nc2n1

Procedure:
A mixture of 14 g (141.4 mmol) of 3,5-diamino-1,2,4-triazole and 24.0 g (148.1 mmol) benzoylacetone was heated in 200 ml of glacial acetic acid at reflux for 2 hours. A solution soon formed after heating. The solvent was removed in vacuo and the residue dissolved in 400 ml of methylene chloride which was then washed with water (2X), brine and dried over magnesium sulfate. The solution was concentrated in vacuo (not to complete dryness) and ethyl acetate added to the residue. The precipitated solid was filtered and washed with ethyl acetate to give 16.0 g of reasonably pure intermediate 5-methyl-7-phenyl-1,2,4-triazolo[1,5-a]pyrimidin-2-amine which was able to be taken on directly to the next step without further purification m.p. 246°-250° .
Reaction SMILES: C(O)(=[O:3])C.[Cl:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][CH3:20])=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1.OO.O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19]([CH3:20])=[O:3])=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1
Reactant: CC(=O)O
Reactant: CSCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: OO
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reaction time: 2 h

Procedure:
To an acetic acid solution (30 ml) of 4-chloro-4'-methylmercaptomethylbenzophenone (8.3 g), aqueous 30% hydrogen peroxide solution (3.5 ml) was added, and the mixture was stirred for 2 hours while keeping at 10° C. To the reaction solution, water (200 ml) and toluene (200 ml) were added, and then the organic layer was separated, and washed successively with water, an aqueous sodium bicarbonate solution and an aqueous saturated sodium chloride solution, followed by drying over anhydrous magnesium sulfate. After distilling off the solvent, the crude product was purified by silicagel column chromatography (developing solvent: acetone:n-hexane=50:50) to obtain 4-chloro-4'-methylsulfinylmethylbenzophenone (5.3 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)=[O:21]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([O:17][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)=[O:21])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCCC1CC(=O)OCC(=O)c1cccc(Cl)c1
Yield: 81.4 %

Procedure:
The title compound (2.65 g) was prepared from (RS)-2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (2.0 g) and 2-bromo-3′chloroacetophenone (1.92 g) according to the method of description 36.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[C:7]([O:14][CH2:15][CH3:16])(=[O:13])[C:8]([O:10]CC)=O>C(O)C>[CH2:15]([O:14][C:7](=[O:13])[C:8]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:8](=[O:10])[C:7]([OH:14])=[O:13])=[O:10])[CH3:16]
Reactant: CCOC(=O)C(=O)OCC
Reactant: NCCCCN
Solvent: CCO
Product: CCOC(=O)C(=O)NCCCCNC(=O)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 1,4-diaminobutane (88.2 grams) in 100 mL ethanol was added to ice cooled diethyl oxalate (1461 grams) in ethanol (1400 mL) over 40 minutes, maintaining the internal temperature below 8° C. The reaction was allowed to gradually warm to ambient temperature, and after 48 hours, the crude solids (168 grams) were collected by filtration. The product (22 grams) was purified by flash column chromatography (EtOAc as the eluent) and then boiled in MTBE (200 mL) to obtain butylene-bis-oxamic acid ethyl ester as a white solid having a melting point in the range of 114.4 to 116.4° C. 1H NMR (CDCl3, 300 MHz) δ 7.23 (brs, 2H), 4.33 (q, J=7.1 Hz, 4H), 3.36 (q, J=6.5 Hz, 4H), 1.64-1.59 (m, 4H), 1.36 (t, J=7.2 Hz, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16](COCC[Si](C)(C)C)[CH:17]=3)[N:10]3[CH:26]=[CH:27][N:28]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.C(Cl)[Cl:30].Cl.O1CCOCC1>>[ClH:30].[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[N:10]3[CH:26]=[CH:27][N:28]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(COCC[Si](C)(C)C)c3)n2)cn1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-(1-Methyl-1H-pyrazol-4-yl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (75 mg, 0.19 mmol) was dissolved in DCM (950 μL, 0.19 mmol). To this was added 4N HCl in dioxane (950 μL, 0.95 mmol) and stirred at ambient temperature for 1 hour, and the mixture was concentrated down to dryness to provide the title compound. MS (apci) m/z=266.2 (M+H).
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8](=O)[CH3:9])[CH2:4][CH2:3]1.C([O-])(=O)C.[NH4+].[BH3-]C#[N:19].[Na+]>C1COCC1.CO>[F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([CH:8]([NH2:19])[CH3:9])[CH2:4][CH2:3]1
Reactant: CC(=O)C1CCC(F)(F)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(N)C1CCC(F)(F)CC1
Reaction time: 48 h
Yield: 54.1 %

Procedure:
To a solution of 1-(4,4-difluorocyclohexyl)ethanone (1 g, 6.17 mmol) in THF (5 mL) was added a solution of ammonium acetate (9.51 g, 123.4 mmol) and NaBH3CN (3.82 g, 61.7 mmol) in MeOH. The mixture was stirred for 48 hr. The reaction mixture was quenched with aqueous NaHCO3 and extracted with tert-Butyl-methyl ether (20 mL*3). The combined organic layers were washed with 1N HCl, and the organic and aqueous layer were separated. The aqueous layer was brought to above pH 8 with 2N NaOH and extracted with ethyl acetate (20 mL*3). The organic layer was washed with brine, dried over sodium sulfate. The organic layer was concentrated to give 1-(4,4-difluorocyclohexyl)ethanamine (545 mg, crude) for next step.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[BH4-].[Na+].C(O)(C)C.Cl>O>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C=O)cc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCOc1ccc(-c2ccc(CO)cc2)cc1
Temperature: 70 °C
Yield: 99.4 %

Procedure:
A mixture of 30 g of 4'-octyloxy-4-formylbiphenyl, 2.0 g of sodium borohydride and 300 ml of isopropanol was stirred on a water bath maintained at 70° C. for 3 hours. 20 ml of 6 N hydrochloric acid and 10 ml of water were added, and the resulting mixture was stirred for 2 hours. The reaction mixture was allowed to cool and filtered to collect solids. These solids were recrystallized from 300 ml of ethanol to obtain 30 g of 4'-octyloxy-4-hydroxymethyl-biphenyl. The total of 4'-octyloxy-4-hydroxymethyl-biphenyl, 100 ml of toluene and 40 g of thionyl chloride were uniformly mixed and allowed to stand overnight at room temperature. Then, the mixture was heated for 30 minutes on a water bath maintained at 70° C. After being allowed to cool, the mixture was poured into ice water and then extracted with 300 ml of toluene. The extract was washed with saturated saline water, with a saturated aqueous sodium hydrogen-carbonate and further with saturated saline water to make it neutral. Then, the extract was dried over anhydrous magnesium sulfate, concentrated and then recrystallized from 300 ml of ethanol to obtain 26 g of 4'-octyloxy-4-chloromethyl-biphenyl having a melting point of 97.3 to 98.0° C. Analysis of the compound by HPLC showed that the purity was 99.6%. (ii) Preparation of Objective Compound
Reaction SMILES: [ClH:1].[C:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20](=[NH:23])OC)=[CH:15][CH:14]=2)[N:10]=1)(=[O:4])[CH3:3].[Cl-].[NH4+:25].N>CCO.CO>[ClH:1].[NH2:25][C:20](=[NH:23])[CH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][C:9]2[N:10]=[C:6]([NH:5][C:2](=[O:4])[CH3:3])[S:7][CH:8]=2)=[CH:14][CH:15]=1
Reactant: [NH4+]
Reactant: COC(=N)Cc1ccc(CCc2csc(NC(C)=O)n2)cc1
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: CO
Solvent: CCO
Product: CC(=O)Nc1nc(CCc2ccc(CC(=N)N)cc2)cs1
Temperature: 25 °C
Yield: 58.9 %

Procedure:
Methyl 2-(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)ethanimidoate hydrochloride (600 mg) was dissolved in EtOH (12 ml). Then ammonium chloride (136 mg) and ammonia in methanol (2 ml) were added to the solution. The reaction mixture was refluxed for 4 hours under N2 atmosphere. After cooled to r.t., the suspension was filtered in vacuo. The filtrate was concentrated in vacuo, and the residue was solidified with EtOH/diethyl ether to give N-(4-{2-[4-(2-amino-2-iminoethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide hydrochloride (338.6 mg) as an off-white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH:12]([CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([N:24]3[C:28]4[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:27]=4[N:26]=[C:25]3[CH3:34])[CH:20]([CH2:35][OH:36])[CH2:19]1)[CH2:11]2)(C)(C)C>Cl.O1CCOCC1.C(Cl)Cl>[NH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH:12]([CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([N:24]3[C:28]4[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:27]=4[N:26]=[C:25]3[CH3:34])[CH:20]([CH2:35][OH:36])[CH2:19]1)[CH2:11]2
Reactant: Cc1ccc2c(c1)nc(C)n2C1CCN(CC2Cc3ccc(NC(=O)OC(C)(C)C)cc3C2)CC1CO
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)nc(C)n2C1CCN(CC2Cc3ccc(N)cc3C2)CC1CO
Reaction time: 1 h

Procedure:
{2-[4-(2,5-Dimethyl-benzoimidazol-1-yl)-3-hydroxymethyl-piperidin-1-ylmethyl]-indan-5-yl}-carbamic acid tert-butyl ester (191 mg) was dissolved in 4M HCl in dioxane and stirred for 1 h after which all volatiles were removed under reduced pressure to yield a heavy oil which was suspended in CH2Cl2 and washed with 0.1 M NaOH. The organic phase was dried over Na2CO3. Filtration and removal of volatiles yielded [1-(5-amino-indan-2-ylmethyl)-4-(2,5-dimethyl-benzoimidazol-1-yl)-piperidin-3-yl]-methanol as a heavy oil (86 mg; 59%)
Reaction SMILES: S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(C1C=CC(C)=CC=1)(=O)=O.[CH3:30][NH2:31]>O1CCCC1>[CH3:30][NH:31][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCC(=O)OC(C)(C)C)cc1
Reactant: CN
Solvent: C1CCOC1
Product: CNCCOCCOCCOCCC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
Into a 250-mL sealed bottle, was placed a solution of tert-butyl 3-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)propanoate (14 g, 32.41 mmol, 1.00 equiv) in tetrahydrofuran (5 mL), and CH3NH2 (66.9 g, 712.16 mmol, 21.98 equiv, 33% in ethanol). The resulting solution was stirred overnight at 50° C. The resulting mixture was concentrated under vacuum. The residue was dissolved in 150 mL of dichloromethane. The resulting mixture was washed with 2×150 mL of water and 1×150 mL of brine, dried over sodium sulfate, and concentrated under vacuum. This resulted in 8.2 g (87%) of product as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]1[C:17]([CH3:27])=[C:18]([CH:24]=[CH:25][CH:26]=1)[CH:19]=[CH:20][C:21](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:21](/[CH:20]=[CH:19]/[C:18]3[CH:24]=[CH:25][CH:26]=[C:16]([F:15])[C:17]=3[CH3:27])=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: Cc1c(F)cccc1C=CC(=O)O
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(F)c3C)nc2n(CC)c1=O
Yield: 50.5 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.50 g (13.9 mmol) of 3-fluoro-2-methylcinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 2.18 g (yield 51%) of Compound 180 as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7](SC)[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([N:20]3[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]3)[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1
Reactant: CSC1=Nc2ccc(Cl)cc2S(=O)(=O)N1
Reactant: CN1CCNCC1
Product: CN1CCN(C2=Nc3ccc(Cl)cc3S(=O)(=O)N2)CC1
Temperature: 140 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
A mixture of 3.2 g of 7-chloro-3-methylthio-2H-1,2,4-benzothiadiazine 1,1-dioxide and 1.1 g of 1-methylpiperazine is heated with stirring in an oil bath at 140° C. for 2 hours. After cooling, the resultant solid is recrystallized from a mixture of dimethylformamide and water to give 3.1 g of the desired product, m.p. above 300° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21][CH2:22][CH2:23][C:24]([O:26]C)=[O:25])(=[O:12])=[O:11].O[Li].O.Cl>C1COCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])(=[O:11])=[O:12]
Reactant: COC(=O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)propanoate (125 mg, 0.29 mmol) in THF (3 ml) was added a solution of LiOH.H2O (25 mg, 0.59 mmol) in H2O (1 ml). The reaction was stirred at room temperature for 1 hour, acidified with 1M HCl, and was extracted with EtOAc.