Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH:16]=[CH:17][C:11]=2[N:10]([CH3:26])[C:9]1=[O:27])(=[O:3])[CH3:2].C1C(=O)N([Br:35])C(=O)C1>C(Cl)Cl.O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[CH:16]=[C:17]([Br:35])[C:11]=2[N:10]([CH3:26])[C:9]1=[O:27])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCn1c(=O)c2c(ccn2Cc2ccc(Cl)cc2)n(C)c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: CC(=O)OCCCn1c(=O)c2c(c(Br)cn2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3(2H, 4H,5H)-yl)propyl acetate (1.50 g, 3.85 mmol) in DCM (1 mL) was added NBS (0.68 g, 3.85 mmol). The reaction was stirred at RT for 1 h then diluted with DCM (10 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (5:1 to 1:1) to give 3-(7-bromo-5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (1.2 g, 66.5% yield) as a solid. LCMS: MH+ 468 and TR=1.777 min. Used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:9]2=[O:26])=[CH:4][CH:3]=1.[C:27]([CH2:30][NH:31][CH2:32][C:33](O)=[O:34])(=[O:29])[CH3:28]>>[C:27]([CH2:30][NH:31][CH2:32][C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:9]2=[O:26])=[CH:6][CH:7]=1)=[O:34])(=[O:29])[CH3:28]
Reactant: Nc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1
Reactant: CC(=O)CNCC(=O)O
Product: CC(=O)CNCC(=O)Nc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1

Procedure:
1-(4-Aminophenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one was reacted with (acetylmethylamino)acetic acid as described in example 217. The product with the molecular weight of 456.51 (C26H24N4O4); MS (ESI): 457 ([M+H] ) was obtained as hydrotrifluoroacetate in this way.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[CH2:24]([N:29]=[C:30]=[O:31])[CH2:25][CH2:26][CH2:27][CH3:28]>O1CCCC1>[OH:16][CH2:15][C:3]1([CH2:2][O:1][C:30](=[O:31])[NH:29][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14]
Reactant: CCCCCN=C=O
Reactant: O=C1c2ccccc2OCCC1(CO)CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCNC(=O)OCC1(CO)CCOc2ccccc2C1=O

Procedure:
To a solution of 4,4-bis(hydroxymethyl)-3,4-dihydro-2H-benzo[b]oxepin-5-one (260 mg, 1.17 mmol) in 15 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.18 ml, 1.3 mmol) and n-pentyl isocyanate (332 μl, 2.57 mmol). The mixture was heated to reflux for 24 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:2 ethyl acetate/hexane). The product was obtained in a yield of 210 mg (54%).
Reaction SMILES: ClC1C=[C:6]([C:7](O)=[O:8])C(C(O)=O)=C(Cl)C=1C(O)=O.[Cl:18][C:19]1([CH3:27])[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]1[CH3:26].[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(=O)C>>[C:7]([C:21]1[CH:20]([CH3:26])[C:19]([Cl:18])([CH3:27])[CH:24]=[CH:23][C:22]=1[Cl:25])(=[O:8])[CH3:6]
Reactant: O=C(O)c1cc(Cl)c(C(=O)O)c(Cl)c1C(=O)O
Reactant: CC1C=C(Cl)C=CC1(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(=O)Cl
Product: CC(=O)C1=C(Cl)C=CC(C)(Cl)C1C
Temperature: 25 °C

Procedure:
Synthesis of dichlorotrimellitic acid—The reaction scheme for this synthesis is depicted in FIG. 7. Into a 250 ml round bottom flask was put 2,5-dichloroxylene (5 g, 28.6 mmol) and aluminum chloride (4.6 g, 34.3 mmol). Solids were thoroughly mixed, then acetyl chloride (2.0 mL, 28.6 mmol) was added and the reaction immersed in an oil bath at 70° C. After cessation of gas evolution (approx 30 min), reaction was allowed to cool to room temperature and partitioned between ethyl acetate (100 mL) and water (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to yield 5 g of 6-acetyl-2,5-dichloroxylene as a yellow oil. This crude was used directly for the subsequent oxidation without purification.
Reaction SMILES: C(O[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[O:8][N:7]=1)=[O:5])C.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([C:4]([C:6]2[CH:10]=[C:9]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[O:8][N:7]=2)=[O:5])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)c1cc(CNC(=O)OC(C)(C)C)on1
Reactant: C1CCNC1
Product: CC(C)(C)OC(=O)NCc1cc(C(=O)N2CCCC2)no1
Temperature: 85 °C
Yield: 79 %

Procedure:
3-Ethoxycarbonyl-5-[N-(tert-butyloxycarbonyl)aminomethyl]isoxazole (Method 73; 500 mg, 1.85 mmol) was dissolved in pyrrolidine (4 ml) and the mixture heated for 3 hours at 85° C. The volatiles were removed by evaporation and the residue was triturated with diethyl ether to give the title compound (432 mg, 79%) as a white solid. NMR (DMSO): 1.38 (s, 9H), 1.85 (m, 4H), 3.50 (t, 2H), 3.62 (t, 2H), 4.29 (d, 2H), 6.47 (1H), 7.53 (s, 1H); m/z 240 (M-C4H8)+.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3([CH3:18])[O:17][CH2:16][CH2:15][O:14]3)[CH:10]=[CH:9][C:8]=2[NH:19][C:20]([C:22]2[N:23](COCC[Si](C)(C)C)[CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3([CH3:18])[O:14][CH2:15][CH2:16][O:17]3)[CH:10]=[CH:9][C:8]=2[NH:19][C:20]([C:22]2[NH:26][C:25]([C:27]#[N:28])=[CH:24][N:23]=2)=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC1(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)OCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(c2ccc(NC(=O)c3ncc(C#N)[nH]3)c(C3=CCCCC3)c2)OCCO1
Temperature: 25 °C
Reaction time: 14 h
Yield: 93 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(2-methyl-[1,3]dioxolan-2-yl)-phenyl]-amide (as prepared in the previous step, 45 mg, 0.088 mmol) in 3 mL of THF was added tetrabutyl ammonium fluoride (TBAF) (69 mg, 0.264 mmol). The reaction was stirred for 14 h at room temperature, at which time the temperature was raised to 60° C. for 15 min and then diluted with EtOAc (25 mL) and washed with water (3×25 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. Purification of the residue using preparative TLC (10% MeOH—CHCl3) afforded 31 mg (93%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 9.76 (s, 1H), 8.28 (s, 1H), 7.97 (d, 1H, J=8.3 Hz), 7.33 (dd, 1H, J=8.3, 2.0 Hz), 7.21 (s, 1H, J=2.0 Hz), 5.77 (s, 1H), 3.98 (m, 2H), 3.72 (m, 2H), 2.20-2.15 (m, 4H), 1.75-1.66 (m, 4H), 1.56 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C21H22N4O3, 379.1 (M+H). found 379.1.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH2:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH2:9]1[CH2:15][S:12](=[O:14])(=[O:13])[O:11][CH2:10]1>O1CCCC1.O>[C:6]([C@@H:2]([NH:1][CH2:10][CH2:9][CH2:15][S:12]([OH:14])(=[O:13])=[O:11])[CH:3]([CH3:5])[CH3:4])(=[O:7])[NH2:8]
Reactant: CC(C)[C@H](N)C(N)=O
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@H](NCCCS(=O)(=O)O)C(N)=O
Temperature: 25 °C

Procedure:
To a solution of L-valinamide (1.57 g, 13.5 mmol) in tetrahydrofuran (20 mL) was slowly added 1,3-propane sultone (1.61 g, 12.9 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, washed with acetone (2×25 mL). The crude product was dissolved in water (60 mL) and treated with ion exchange resin Dowex Marathon C (strongly acidic, 15 g). The mixture was stirred for 15 minutes. The resin was removed by filtration. The filtrate was poured into EtOH (250 mL). The solid product, after the completion of the precipitation, was collected by filtration, and dried in vacuo, to afford compound EQ (1.6 g, 51%). 1H NMR (D2O, 500 MHz) δ ppm 3.63 (d, 1H), 3.05 (m, 2H), 2.85 (m, 2H), 2.05 (m, 4H), 0.93 (d, 3H), 0.88 (d, 3H). 13C NMR (D2O, 125 MHz) δ ppm 170.24, 65.92, 48.16, 46.31, 29.59, 21.31, 18.02, 17.07. [α]D=+10.5° (c=0.0027 in water), ES-MS 237 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C@H:13]([OH:15])[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:16][N:17]1[C:21](S(C)(=O)=O)=[N:20][N:19]=[C:18]1[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:16][N:17]1[C:21]([O:15][C@@H:13]([C:10]2[N:11]=[N:12][N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[N:9]=2)[CH3:14])=[N:20][N:19]=[C:18]1[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: Cc1cccc(-n2nnc([C@@H](C)O)n2)c1
Reactant: Cn1c(-c2ncccn2)nnc1S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cccc(-n2nnc([C@@H](C)Oc3nnc(-c4ncccn4)n3C)n2)c1
Temperature: 65 °C
Reaction time: 15 h
Yield: 72.9 %

Procedure:
A mixture of (1R)-1-[2-(3-methylphenyl)-2H-tetrazol-5-yl]ethanol (251 mg, 1.23 mmol), 2-[4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]pyrimidine (239 mg, 1.00 mmol) and cesium carbonate (911 mg, 2.80 mmol) in N,N-dimethylformamide (10 mL) was stirred at 65° C. for 15 h. After cooling to room temperature, the product was partitioned between ethyl acetate (300 mL) and water (50 mL). The organic layer was washed with water (3×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was concentrated in vacuo. Flash chromatography (silica gel, 2-3% methanol in dichloromethane) yielded the title compound (265 mg, 73%, oil).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[CH:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[CH:9]2)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[CH:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[CH:9]2
Reactant: CCOC(=O)c1ccc2cccc([N+](=O)[O-])c2c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc2cccc(N)c2c1
Yield: 72 %

Procedure:
According to the procedure of W. Adcock, et al. Aust. J. Chem. 18, 1351 (1965), a suspension of ethyl 8-nitro-2-naphthoate prepared according to Price, et al. J. Am. Chem. Soc. 74, 3652 (1952) (8.2 g, 0.033 mol) in ethanol (240 mL) was hydrogenated at 50 psi over 10% Pd/C (820 mg) for 4 hours. The mixture was filtered through Solka floc® and concentrated. Recrystallization of the residue from EtOH/H2O gave a yellow solid (5.2 g, 72%), m.p. 97°-98° C.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12]([Br:16])=[C:11]([O:17][CH2:18][C:19]#[N:20])[CH:10]=[CH:9]3)=[CH:4][C:3]2[CH:21]=[CH:22][CH:23]=[CH:24][C:2]1=2.[C:25](Cl)(=[O:30])[CH2:26][CH:27]([CH3:29])[CH3:28].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Br:16][C:12]1[C:13]2[C:8](=[CH:7][C:6]([C:5]3[S:1][C:2]4[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=4[C:4]=3[C:25](=[O:30])[CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:11]=1[O:17][CH2:18][C:19]#[N:20]
Reactant: N#CCOc1ccc2cc(-c3cc4ccccc4s3)ccc2c1Br
Reactant: CC(C)CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)CC(=O)c1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)sc2ccccc12
Temperature: 25 °C
Yield: 7.1 %

Procedure:
To a 0° C. mixture of (6-benzo[b]thiophen-2-yl-1-bromo-naphthalen-2-yloxy)-acetonitrile (11.3 g, 32.4 mmol) in chloroform (560 mL) was added isovaleryl chloride (4.7 mL, 39 mmol) and tin (IV) chloride (5.8 mL, 49 mmol). The reaction mixture was then refluxed for 23 hours. During this time, isovaleryl chloride (12.7 mL, 103 mmol) in three portions and tin (IV) chloride (13.4 mL, 113 mmol) were added in three portions. After cooling to ambient temperature, the reaction mixture was poured into ice water. It was diluted with more chloroform, and the organic phase was washed with water and brine. It was dried with anhydrous magnesium sulfate, filtered and solvent evaporated. The residue was stirred in ether and filtered. The filtrate was concentrated and purified by flash chromatography using 25–50% methylene chloride in hexane and then by HPLC using 89% acetonitrile (0.1% trifluoroacetic acid) in water as the mobile phase. Evaporating the solvent and extracting with ethyl acetate, washing with water and brine, drying with anhydrous magnesium sulfate, filtering, concentrating and drying in vacuo at 70° C. for 50 minutes yielded {1-bromo-6-[3-(3-methyl-butyryl)-benzo[b]thiophen-2-yl]-naphthalen-2-yloxy}-acetonitrile (1.1 g, 7.10%) as a yellow semi-solid. mass spectrum (−EI, [M−H]−) m/z 476/478. 1H NMR (500 MHz, DMSO-d6): δ8.19–8.25 (m, 2H), 8.16 (d, 1H, J=1.83 Hz), 8.04–8.07 (m, 1H), 7.91–7.94 (m, 1H), 7.78 (dd, 1H, J=8.78 Hz and 1.95 Hz), 7.69 (d, 1H, J=9.15 Hz), 7.42–7.49 (m, 2H), 5.43 (s, 2H), 2.28 (d, 2H, J=6.71 Hz), 1.93–2.00 (m, 1H), 0.64 ppm (d, 6H, J=6.71 Hz). Elemental Analysis for C25H20BrNO2S: Calcd: C, 62.77; H, 4.21; N, 2.93; Found: C, 62.79; H, 4.18; N, 2.82.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:45]=[CH:44][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:31][C:32](=[O:41])[C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[C:24]([O:26]C(C)(C)C)=[O:25])=[CH:18][C:17]=2[O:42][CH3:43])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:45]=[CH:44][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:31][C:32](=[O:41])[C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[C:24]([OH:26])=[O:25])=[CH:18][C:17]=2[O:42][CH3:43])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CC(NC(=O)c3ccc(OC)cc3)C(=O)OC(C)(C)C)cc2OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CC(NC(=O)c3ccc(OC)cc3)C(=O)O)cc2OC)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
A crude solution of 4-(3-(tert-butoxy)-2-(4-methoxybenzamido)-3-oxopropyl)-2-methoxyphenyl 4-(heptyloxy)benzoate in DCM (1 mL) was treated with TFA (0.1 mL) and stirred overnight at 30° C. The solvent was evaporated and the residue was purified by preparative HPLC to give 16.9 mg (48%) of 3-(4-((4-(heptyloxy)benzoyl)oxy)-3-methoxyphenyl)-2-(4-methoxybenzamido)propanoic acid 2. LCMS-ESI (m/z) calculated for C32H37NO8: 563; found 564 [M+H]+, tR=11.01 min (Method 2). 1H NMR (400 MHz, DMSO) δ 12.79 (s, 1H), 8.57 (d, J=8.1 Hz, 1H), 8.00 (d, J=9.0 Hz, 2H), 7.82 (d, J=8.9 Hz, 2H), 7.13 (d, J=1.7 Hz, 1H), 7.11-7.03 (m, 3H), 6.99 (d, J=8.9 Hz, 2H), 6.92 (dd, J=8.1, 1.7 Hz, 1H), 4.61 (ddd, J=10.8, 8.1, 4.4 Hz, 1H), 4.07 (t, J=6.5 Hz, 2H), 3.80 (s, 3H), 3.69 (s, 3H), 3.20 (dd, J=13.8, 4.2 Hz, 1H), 3.08 (dd, J=13.7, 10.7 Hz, 1H), 1.84-1.66 (m, 2H), 1.51-1.17 (m, 8H), 0.87 (t, J=6.9 Hz, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:13])[N:10]=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14]N1C(=O)CCC1=O>>[Cl:14][C:12]1[N:11]=[N:10][C:9]([NH2:13])=[N:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nncc(-c2ccccc2)n1
Reactant: O=C1CCC(=O)N1Cl
Product: Nc1nnc(Cl)c(-c2ccccc2)n1
Yield: 92.4 %

Procedure:
6-Chloro-5-phenyl-1,2,4-triazin-3-amine (0.38 g, 65%) was prepared from 5-phenyl-1,2,4-triazin-3-amine (0.50 g, 1.99 mmol) and N-chlorosuccinimide (0.50 g, 3.7 mmol) according to the general procedure of Preparation 3.
Reaction SMILES: N1C=CC=CC=1.[Si:7](Cl)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[CH:15]1([OH:21])[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]1>C(Cl)Cl>[C:10]([Si:7]([O:21][CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]1)([CH3:9])[CH3:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1C=CCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC1C=CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
Pyridine (4.74 g, 60 mmol) and tert-butyldimethylsilyl chloride (4.83 g, 32 mmol) were added to a solution of cyclohex-2-enol (1.96 g, 20 mmol) in DCM (40 mL). The reaction mixture was stirred at RT overnight. The mixture was concentrated and the residue was dispersed in EtOAc and water. The organic phase was separated and washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by silica flash chromatography eluting with EtOAc and petroleum ether (5-10% EtOAc) to give the title compound as an oil (4.1 g, 97%). 1H NMR (400 MHz, CDCl3) δ ppm 0.06-0.09 (m, 6 H), 0.92 (s, 9 H), 1.50-1.57 (m, 2 H), 1.74-1.89 (m, 2 H), 1.93-2.03 (m, 2 H), 4.21-4.23 (m, 1 H), 5.61-5.64 (m, 1 H), 5.72-5.76 (m, 1 H).
Reaction SMILES: C[CH:2]([C:13]([CH:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)C)=O)C1C=CC(OC)=C(OC)C=1.[NH2:27][CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1)[OH:30].C(OC(C)C)(C)C>[Pt]=O.C(O)(C)C>[Cl:37][C:33]1[CH:32]=[C:31]([C@@H:29]([OH:30])[CH2:28][NH:27][C@H:13]([CH3:2])[CH2:15][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: NC[C@H](O)c1cccc(Cl)c1
Reactant: COc1ccc(C(C)C(=O)C(C)c2ccc(OC)c(OC)c2)cc1OC
Agent: O=[Pt]
Solvent: CC(C)OC(C)C
Solvent: CC(C)O
Product: COc1ccc(C[C@@H](C)NC[C@H](O)c2cccc(Cl)c2)cc1OC
Reaction time: 24 h
Yield: 62 %

Procedure:
To a mixture of 5.83 g of methyl-3,4-dimethoxyphenylmethyl ketone, 5.15 g of (R)-2-amino-1-(3-chlorophenyl)ethanol and 50 mg of platinum oxide were added 15 ml of isopropyl alcohol and 30 ml of diisopropyl ether, and the reducing reaction was carried out at room temperature, at 1 atm under hydrogen atmosphere for 24 hours. After removing off platinum oxide by filtration, the solvent was distilled off under reduced pressure to give 6.51 g of white oil of (R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol (yield 62%). The optical purity of the (R,R)-isomer was 65%.
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].[H-].[Na+].[CH3:8][N:9]1[C@H:13]2[C:14]([C:17](OC)=O)=[CH:15][CH2:16][C@@H:10]1[CH2:11][CH2:12]2>C1COCC1>[CH3:2][C:1]1[N:3]=[C:17]([C:14]2[CH:13]3[N:9]([CH3:8])[CH:10]([CH2:16][CH:15]=2)[CH2:11][CH2:12]3)[O:5][N:4]=1
Reactant: CC(N)=NO
Reactant: COC(=O)C1=CC[C@@H]2CC[C@H]1N2C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(C2=CCC3CCC2N3C)n1

Procedure:
Acetamide oxime (500 mg, 6.75 mol) suspended in THF (50 mL) under nitrogen was heated at 60° C. with NaH (132 mg, 5.5 mmol in oil dispersion) for 1 h. Anhydroecgonine methyl ester (2.76 ml) and 4 A° molecular sieves (2 g) were added and the reaction mixture heated under reflux for 3 h. After cooling, the reaction mixture was filtered and the solvent removed in vacuo. The residue was chromatographed on a silica gel column eluting with CHCl3 --CH3OH (95:5) to give the free base.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].Cl[C:13]1[N:14]=[CH:15][S:16][CH:17]=1>C(O)C>[C:2]1([CH2:1][S:8][C:13]2[N:14]=[CH:15][S:16][CH:17]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: Clc1cscn1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(CSc2cscn2)cc1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 37.8 %

Procedure:
Benzylmercaptan (24.8 g) was added slowly to a solution of 10.8 g of sodium methoxide in 100 ml ethanol. After 10 minutes, the reaction mixture was heated to 65° C. and a solution of 23.8 g of 4-chlorothiazole [prepared by the method of P. Reynaud et al., Bull. Soc. Chim. France, 1735 (1962)] in 25 ml ethanol was added dropwise. When addition was complete, the reaction mixture was refluxed 36 hours. The reaction mixture was cooled, and the bulk of the solvent evaporated. Cold water (300 ml) was added to the residue, and the aqueous mixture was extracted with 200 ml ether followed by 200 ml methylene chloride. The combined organic solution was washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated. Distillation of the resulting yellow oil gave 15.6 g of 4-(phenylmethylthio)thiazole, bp 122-134 (0.6 mm).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O>C(O)C.[Ni]>[CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11]
Reactant: CNCCc1ccccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CNCCc1ccccc1N
Reaction time: 2 h

Procedure:
A mixture of N-methyl-N-(2-(2-nitrophenyl)ethyl)amine (WO 9803473, pg 100) (3 g, 16.65 mmol) and Raney® nickel (500 mg) in ethanol (50 ml) was hydrogenated at 60 psi and room temperature for 2 hours. The mixture was filtered through Celite® and the filtrate evaporated under reduced pressure to give the title compound as an oil.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:12]2[CH2:13][C:14]([F:18])([F:17])[CH2:15][CH2:16][C@H:11]2[O:10]C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[K+]>C(O)C>[CH2:1]([NH:8][C@@H:12]1[CH2:13][C:14]([F:17])([F:18])[CH2:15][CH2:16][C@H:11]1[OH:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1O[C@@H]2CCC(F)(F)C[C@H]2N1Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O[C@@H]1CCC(F)(F)C[C@H]1NCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a solution of trans-3-benzyl-5,5-difluorohexahydro-1,3-benzoxazol-2(3H)-one (980 mg) in ethanol (60 mL)/water (6 mL) was added potassium hydroxide (411 mg). The reaction mixture was stirred at 80° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/dichloromethane) to give the title compound (540 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCC)[NH:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][O:33][CH2:34][CH2:35][NH:36][CH2:37][CH2:38][O:39][CH3:40]>>[CH3:32][O:33][CH2:34][CH2:35][N:36]([CH2:37][CH2:38][O:39][CH3:40])[C:20]1[S:21][C:17](=[CH:16][C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:7]([CH2:6][C:5]2[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=2[C:28]([F:30])([F:31])[F:29])[N:8]=[CH:9]3)[C:18](=[O:25])[N:19]=1
Reactant: COCCNCCOC
Reactant: CCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: COCCN(CCOC)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
2-[Bis-(2-methoxy-ethyl)-amino]-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazolidin-4-one and Bis-(2-methoxy-ethyl)-amine following General Procedure C.
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)/[C:6](/[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=2)=[CH:7]\N(C)C)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:27][C:28]([NH2:30])=[NH:29]>CN(C=O)C>[CH:1]1([CH2:4][C:5]2[C:6]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)=[CH:7][N:27]=[C:28]([NH2:30])[N:29]=2)[CH2:2][CH2:3]1
Reactant: CSc1nccc(/C(=C/N(C)C)C(=O)CC2CC2)n1
Reactant: N=C(N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1nccc(-c2cnc(N)nc2CC2CC2)n1
Temperature: 120 °C
Reaction time: 0.75 h

Procedure:
To a solution of (Z)-1-cyclopropyl-4-(dimethylamino)-3-(2-(methylthio)pyrimidin-4-yl)but-3-en-2-one (3) (2.07 g, 7.46 mmol) in DMF (62.2 ml) was added potassium carbonate (3.09 g, 22.39 mmol) and guanidine hydrochloride (1.065 g, 11.19 mmol). The resulting suspension was stirred at 120° C. After 45 minutes, the reaction was complete. The reaction mixture was concentrated in vacuo, then was taken up in EtOAc. The organic solution was washed with water, followed by brine, dried over sodium sulfate, then concentrated in vacuo. The crude residue was dried over high vacuum for 18 h to obtain the desired product as a bright orange product (2.17 g, quant. yield). MS (ES+): m/z=250.1 (50) [MH+]. HPLC: tR=1.13 min over 3 min. Purity: 100% [HPLC (LC/MS) at 220 nm]. 1H NMR (400 MHz, DMSO-d6) d ppm 0.06-0.13 (m, 2H) 0.33-0.41 (m, 2 H) 0.96-1.11 (m, 1 H) 2.52-2.57 (m, 3 H) 2.79 (d, J=7.07 Hz, 2 H) 7.03 (s, 2 H) 7.39 (d, J=5.56 Hz, 1 H) 8.44 (s, 1 H) 8.60 (d, J=5.56 Hz, 1 H).