Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:39]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:37]=[CH:36][C:16]=2[C:17]([NH:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][C:25]=2[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=2)=[O:27])=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:40]([C:38]1[CH:37]=[CH:36][C:16]([C:17]([NH:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][C:25]=2[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=2)=[O:27])=[O:18])=[C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:39]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)Nc2cnccc2C(=O)Nc2ccc(Cl)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)Nc2cnccc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
The 3-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(tert-butyl)benzoylamino]-N-(5-chloropyridin-2-yl)pyridine-4-carboxamide (60 mg, 0.1 mmol) was mixed with anisole (1 mL) and CH2Cl2 (2 mL) then treated with trifluoroacetic acid (1 mL). The reaction was stirred at ambient temperature for 4 h, concentrated under vacuum to dryness and mixed with CH2Cl2. This was filtered through a 1 g SCX ion exchange column using 2 M NH3 in MeOH. Concentration to dryness gave 32 mg of the title compound as a solid.
Reaction SMILES: CCN(S(F)(F)F)CC.[F:10][C:11]1[CH:35]=[CH:34][C:14]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([CH2:32]O)[CH:30]=4)[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.[Cl-:36].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:10][C:11]1[CH:35]=[CH:34][C:14]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([CH2:32][Cl:36])[CH:30]=4)[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1
Reactant: OCc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Reactant: [Cl-]
Agent: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Fc1ccc(CCN2CCC(N3CCc4ccc(CCl)cc43)CC2)cc1
Yield: 30 %

Procedure:
Diethylaminosulfatrifluoride (DAST, 160 mg) was added dropwise at −78° C. into a solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-hydroxymethylindoline (300 mg) inmethylene chloride (10 ml) and the resultant mixture was stirred for 1 hr. Then a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added thereto and the layers were separated. The organic layer was dried over anhydrous magnesium sulfate and the obtained residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate system) followed by conversion into a hydrochloride in a conventional manner to give the hydrochloride (100 mg) of the title compound as a white powder (yield: 30%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][C@H:12]([NH:14][CH2:15][C@H:16]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[C:17]2[CH:22]=[CH:21][C:20]([O:23]CC3C=CC=CC=3)=[C:19]([CH2:31][OH:32])[CH:18]=2)[CH3:13])[CH:6]=1>[Pd].C(O)C>[NH3:14].[CH3:1][O:2][C:3](=[O:41])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][C@H:12]([NH:14][CH2:15][C@H:16]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:31][OH:32])[CH:18]=2)[CH3:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c(CO)c2)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)Cc1cccc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c(CO)c2)c1
Product: N
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
A suspension of methyl(3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-[benzyloxy]-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetate (Preparation 22) (5.27 g, 9.12 mmol) and 10% palladium on carbon (1.00 g) in ethanol (50 ml) was stirred under an atmosphere of hydrogen (60 psi) at room temperature for 16 hours. The catalyst was filtered off through arbocel and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (96:4:0.4 changing to 95:5:0.5, by volume) to give the title compound as a pale yellow oil (1.99 g) which was used without further purification. 1H NMR (400 MHz, CD3OD): δ=7.21-7.17 (2H, m), 7.11-7.09 (1H, d), 7.03-6.98 (3H, m), 6.69-6.67 (1H, d), 4.71-4.68 (1H, t), 4.62-4.61 (2H, d), 3.67 (3H, s), 3.59 (2H, s), 2.96-2.86 (2H, m), 2.69-2.55 (3H, m), 1.07-1.05 (3H, d), 0.82 (9H, s), −0.01 (3H, s), −0.20 (3H, s) ppm. LRMS (electrospray): m/z [M+H]+ 488, [M+Na]+ 510, [M−H]− 486.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:30])[C@@H:19]([CH:20]=[C:21]2[CH2:25][CH2:24][S:23][C:22]2=[O:26])[C@H:18]1[C:27]([OH:29])=[O:28].[CH2:31]([C:38]1[S:39][C:40]([CH2:43]O)=[CH:41][N:42]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:16][C:17]1([CH3:30])[C@@H:19]([CH:20]=[C:21]2[CH2:25][CH2:24][S:23][C:22]2=[O:26])[C@H:18]1[C:27]([O:29][CH2:43][C:40]1[S:39][C:38]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:42][CH:41]=1)=[O:28]
Reactant: OCc1cnc(Cc2ccccc2)s1
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C=C1CCSC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)OCc2cnc(Cc3ccccc3)s2)[C@@H]1C=C1CCSC1=O
Temperature: 20 °C
Reaction time: 17 h
Yield: 48.3 %

Procedure:
0.1 g of 4-dimethylamino-pyridine and 0.94 g of dicyclohexylcarbodiimide were added to a solution of 1.1 g of (1R,3S) 2,2-dimethyl-3-[(dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-1-carboxylic acid in 10 ml of methylene chloride and then a solution of 1 g of (2-benzyl-5-thiazolyl)-methanol in 12 ml of methylene chloride was added to the mixture. The mixture was stirred for 17 hours at 20° C. and was filtered and the organic filtrate was washed with water, dried and evaporated to dryness under reduced pressure. The residue was taken upin 8 ml of a 7-3 cyclohexane-ethyl acetate mixture and the mixture was filtered. The filtrate was chromatographed over silica gel and was eluted with a 7-3 cyclohexane-ethyl acetate mixture to obtain 0.97 g of (2-benzyl -5-thiazolyl)-methyl (1R,3S) 2,2-dimethyl-3-[(dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+38°±2° (c=0.5% in benzene).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].I[CH2:26][CH3:27]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH2:26][CH3:27])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1CN(Cc2ccccc2)CCC1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 11.7 %

Procedure:
To a −78° C. solution of 1-benzyl-piperidin-4-one (3.79 g, 20 mmol) in anhydrous THF (20 mL) was added lithium hexamethyldisilazide (21 mL, 21 mmol of a 1.0 M solution in THF). After being stirred at −78° C. for 30 min, a solution of iodoethane (1.7 mL, 21 mmol) in THF (5 mL) was added to the reaction mixture. The resultant solution was stirred at 25° C. for 2 h and quenched with water. The aqueous layer was extracted with CH2Cl2. The organic extracts were combined, washed with brine and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product. The crude material was purified by flash column chromatography (hexane/EtOAc) to provide 0.51 g (11.5% yield) of 1-benzyl-3-ethyl-piperidin-4-one, which was converted into 1-benzyl-3-ethyl-piperidin-4-ylamine (3) using the same procedure as in Scheme 1-1. ((±)-cis:(±)-trans=1:1) LC/MS m/z : 219 (M+H)+. This material was used without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.[CH:22]([N:25]([CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[C:32]([O:39][CH3:40])[CH:31]=1)[CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(N(CC)CC)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:17][CH2:18][N:19]([C:34](=[O:35])[C:33]3[CH:37]=[CH:38][C:30]([CH2:29][N:25]([CH:26]([CH3:27])[CH3:28])[CH:22]([CH3:24])[CH3:23])=[CH:31][C:32]=3[O:39][CH3:40])[CH2:20][CH2:21]1)(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1cc(CN(C(C)C)C(C)C)ccc1C(=O)O
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(CN(C(C)C)C(C)C)ccc1C(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.6 %

Procedure:
To a solution of 1-(6-chloronaphthalene-2-sulfonyl)piperazine hydrochloride(100 mg), 4-diisopropylaminomethyl-2-methoxybenzoic acid (77 mg), triethylamine (35 mg) and HOBt (43 mg) in DMF (10 ml) was added WSC hydrochloride (61 mg) under ice-cooling, and the solution was stirred at room temperature for 4 hours and concentrated. To the residue were added ethyl acetate and sodium bicarbonate solution. The organic layer was separated, washed with water and extracted with 1 N hydrochloric acid. The extract was made alkaline with sodium hydroxide solution and extracted with dichloromethane. The extract was dried and concentrated and the residue was crystallized with ether to give colorless crystals of the title compound (99 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][N:3]=1.[CH3:18][C:19]1[NH:20][CH:21]=[CH:22][N:23]=1>>[ClH:1].[CH3:18][C:19]1[N:20]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:4][N:3]=2)[CH:21]=[CH:22][N:23]=1
Reactant: Clc1ncc(-c2ccccc2)c2ccccc12
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1ncc(-c2ccccc2)c2ccccc12
Product: Cl

Procedure:
Reaction analogous to 8d., from 1-chloro-4-phenylisoquinoline and 2-methylimidazole, M.p. 243° to 244° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[C:13]2[CH:20]3[CH2:21][CH:16]4[CH2:17][CH:18]([CH2:22][CH:14]2[CH2:15]4)[CH2:19]3)[O:9][CH2:10][CH2:11]I)[CH:5]=[CH:6][CH:7]=1.C1COCC1.[NH3:28]>C(=O)=O>[NH2:28][CH2:11][CH2:10][O:9][C:8](=[C:13]1[CH:20]2[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:22][CH:14]1[CH2:15]3)[CH2:19]2)[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1
Reactant: Oc1cccc(C(OCCI)=C2C3CC4CC(C3)CC2C4)c1
Reactant: N
Agent: O=C=O
Solvent: C1CCOC1
Product: NCCOC(=C1C2CC3CC(C2)CC1C3)c1cccc(O)c1
Temperature: 40 °C
Yield: 90 %

Procedure:
A solution of [(3-hydroxyphenyl)(2-iodoethoxy)methylene]adamantane (3.0 g, 0.01 mol) in a minimum amount of THF was added into 10 mL of liquid ammonia in a sealed tube which was kept in dry ice. After sealing the tube this was heated at 40° C. in an oil bath for 17 h. The reaction mixture was cooled down and solvent evaporated to obtain a white solid. This material was extracted with methylene chloride. The combined organic layers were washed with water, dried over MgSO4, and concentrated to give 2.0 g (90%) of the product as a white solid: mp 55° C.; 1H NMR (CDCl3) δ 1.77-1.96 (m, 12H), 2.68 (bs, 1H), 2.85 (t, 2H, J=4.8 MHz), 3.23 (bs, 1H), 3.48 (t, 2H, J=4.8 MHz), 4.46 (bs, 2H), 6.70-7.17 (m, 4H); 13C NMR (CDCl 3) δ 28.16, 30.28, 32.19, 36.99, 38.88, 39.04, 41.33, 70.45, 114.97, 116.17, 120.63, 129.02, 131.89, 136.69, 141.79, 156.86; MS m/e (rel intensity) 299 (10), 256 (100), 239 (5), 199 (6), 135 (12), 121 (27), 93 (12), 77 (5). Exact mass: calcd 299.1885, found: 299.1891. ##STR32##
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][NH:14]C(=O)OC(C)(C)C)[CH2:8]2)=[CH:3][CH:2]=1.C([Cl:25])(=O)C>C(O)C.C(OCC)C>[ClH:25].[ClH:25].[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][NH2:14])[CH2:8]2)=[CH:3][CH:2]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC1CCCN(c2ccncc2)C1
Solvent: CCOCC
Solvent: CCO
Product: Cl
Product: NCC1CCCN(c2ccncc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79 %

Procedure:
tert-Butyl (1-(pyridin-4-yl)piperidin-3-yl)methylcarbamate (0.35 g, 1.2 mmol, 1 eq) was dissolved in ethanol (4 ml), and acetyl chloride (0.42 ml, 6.0 mmol, 5 eq) was added, while cooling with ice. The reaction solution was stirred for 12 h at RT and then diluted with diethyl ether (20 ml). The resulting white solid was filtered off and dried in vacuo. Yield: 79%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:42]=[CH:41][C:25]([CH2:26][N:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH:29]([CH3:40])[CH2:28]3)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1>Cl.C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:42]=[CH:41][C:25]([CH2:26][N:27]3[CH2:32][CH2:31][NH:30][CH:29]([CH3:40])[CH2:28]3)=[CH:24][CH:23]=2)=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccc(F)cc3)cc2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC#N
Product: CC1CN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccc(F)cc3)cc2)CCN1
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A mixture of tert-butyl 4-(4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzyl)-2-methylpiperazine-1-carboxylate (70 mg, 0.123 mole) in 2 ml of HCl-acetonitrile was stirred for 2 hours. Concentrated and the residue was purified by prep-HPLC to afford the title produce as a white solid (30 mg, yield 52%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 0.87 (d, J=6.4 Hz, 3H), 1.49 (t, J=10 Hz, 1H), 1.83 (t, J=10 Hz, 1H), 2.55 (m, 2H), 2.64 (m, 2H), 2.75 (m, 1H), 3.32 (s, 3H), 4.34 (d, J=9.2 Hz, 1H), 4.72 (d, J=9.2 Hz, 1H), 6.97-7.01 (m, 2H), 7.13-7.24 (m, 7H), 7.37-7.41 (m, 2H), 7.55-7.59 (m, 1H), 12.15 (s, 1H); LC-MS (ESI) m/z: 470 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[NH2:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:28][CH:29]=1)=[O:14]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(O)c1ccc(CNC(=O)c2ccncc2Nc2ccc(I)cc2F)cc1

Procedure:
4-[({3-[(2-fluoro-4-iodophenyl)amino]isonicotinoyl}-amino)methyl]benzoic acid was synthesized according to the procedure for General Method 1, outlined above, starting with 0.3 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.45 mmol of 4-aminomethylbenzoic acid. LC/MS [9.25 min; 492 (M+1)]
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)O)=[C:8]([CH2:21][OH:22])[CH:7]=1)=[O:5])[CH3:2].O.CCOC(C)=O>OP(O)(O)=O>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH:12]2[C:9]3[C:8](=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=3)[CH2:21][O:22]2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1ccc(C(O)c2ccc(F)cc2)c(CO)c1
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)COC2c1ccc(F)cc1
Temperature: 80 °C

Procedure:
Crude (4-ethoxycarbonyl-2-hydroxymethylphenyl)(4-fluorophenyl)methanol (30 g) is dissolved in H3PO4 (60%, 250 ml) and the solution is heated to 80° C. for 1.5 hours. Water (300 ml) and EtOAc (100 ml) is added and the phases are separated. The aqueous phase is further extracted with EtOAc (100 ml). The organic phases are joined and the solvents are removed in vacuo. The yield of the remaining somewhat impure oil is 30 g.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([NH2:16])=[S:15])[CH2:3][S:2]1.[CH3:17][I:18]>CC(C)=O>[IH:18].[CH3:17][S:15][C:14](=[NH:16])[NH:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:4]1[CH2:5][CH2:6][O:1][S:2][CH2:3]1
Reactant: NC(=S)Nc1ccccc1N1CCOSC1
Reactant: CI
Solvent: CC(C)=O
Product: CSC(=N)Nc1ccccc1N1CCOSC1
Product: I

Procedure:
A mixture of 1-(2-thiamorpholinophenyl)thiourea (12.6 g), methyl iodide (7.1 g) and acetone (60 ml) was heated at 90°-95° C. for 21/2 hours. The solvent was removed by evaporation and the residue dried under vacuum (5 mm/Hg) to give 2-methyl-1-(2-thiamorpholinophenyl)-2-thiopseudourea hydroiodide (m.p. 176°-177° C.).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH3:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:17][N:18]([CH3:21])[C:19]#[N:20].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>C1C(O)=CC=CC=1C.CO>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[CH3:17][N:18]([CH3:21])[C:19]([NH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH3:10])=[CH:5][C:4]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[NH:20].[CH3:17][N:18]([CH3:21])[C:19]([NH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH3:10])=[CH:5][C:4]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[NH:20]
Reactant: CN(C)C#N
Reactant: CSc1ccc(N)c(-c2ccccc2)c1
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: Cc1cccc(O)c1
Product: CSc1ccc(NC(=N)N(C)C)c(-c2ccccc2)c1

Procedure:
Reaction of 2-amino-5-methylthiobiphenyl hydrochloride (1.6 g) with N,N-dimethylcyanamide (0.83 g) in m-cresol (1 ml) at 80° C. for 6 hours yielded a colourless solid which was dissolved in methanol (50 ml) and treated with a solution of fumaric acid (0.61 g) in methanol (50 ml) to give N,N-dimethyl-N'-(5-methylthio-2-biphenylyl)guanidine hemifumarate as a colourless solid (m.p. 207° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[C:13]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:12]=[C:11]([C:33]2[CH:41]=[C:40]3[C:36]([C:37]4[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][C:38]=4[NH:39]3)=[CH:35][CH:34]=2)[C:10]=1[CH2:53][CH3:54])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.[SiH](C(C)C)(C(C)C)C(C)C>[CH2:26]([O:25][C:13]1[N:12]=[C:11]([C:33]2[CH:41]=[C:40]3[C:36]([C:37]4[CH2:45][CH2:44][NH:43][CH2:42][C:38]=4[NH:39]3)=[CH:35][CH:34]=2)[C:10]([CH2:53][CH3:54])=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:14]=1[C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCc1c(-c2ccc3c4c([nH]c3c2)CN(C(=O)OC(C)(C)C)CC4)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1c(-c2ccc3c4c([nH]c3c2)CNCC4)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.9 %

Procedure:
To a solution of tert-butyl 7-(4,6-bis(benzyloxy)-5-(benzyloxycarbonyl)-3-ethylpyridin-2-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (130 mg, 0.18 mmol) in CH2Cl2 (0.3 mL) and TIPSH (0.3 mL) was added TFA (0.3 mL). The mixture was stirred at room temperature for 20 min. The solvents were removed and the residue was treated with 2N NH3 in MeOH (0.5 mL). The mixture was concentrated and chromatographed (0-5% 2N NH3 in MeOH/CH2Cl2) to give the title compound (111 mg, 99%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][C:7]2[S:8][C:9]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[CH:13][C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[N+](=[CH2:24])=[N-]>C(OCC)(=O)C.CCOCC>[C:1]([C:4]1[CH:21]=[CH:20][C:7]2[S:8][C:9]3[CH:16]=[C:15]([C:17]([O:19][CH3:24])=[O:18])[CH:14]=[CH:13][C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CC(=O)c1ccc2c(c1)CCc1ccc(C(=O)O)cc1S2
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)c1ccc2c(c1)Sc1ccc(C(C)=O)cc1CC2

Procedure:
To a solution of 2-acetyl-10,11-dihydro-dibenzo[b,f]thiepin-7-carboxylic acid (U.S. Pat. No. 4,536,507 (1985)) (600 mg, 2.01 mmol) in ethyl acetate (10 mL), was added dropwise a solution of diazomethane in ether until the yellow coloration persisted. Evaporation of the solvent gave the crude title compound as a solid which was used as such.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CC#N>[CH3:1][N:2]1[C:6]([C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:14])=[N:5][CH:4]=[N:3]1
Reactant: Cn1cncn1
Reactant: O=C(Cl)c1ccccc1
Solvent: CC#N
Product: Cn1ncnc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
To a solution of 1-methyl-1H-1,2,4-triazole (5.0 g, 60.17 mmol, 1 eq.) in 250 ml of MeCN cooled to −5° C. were added Benzoyl chloride (8.45 g, 60.17 mmol, 1 eq.) and TEA (6.39 g, 8.8 ml, 63.18 mmol, 1.05 eq.) dropwise. Upon complete addition the temperature was raised to r.t. and the reaction stirred overnight. The white solid was removed by filtration and the solvent evaporated. The yellow residue was triturated in EtOAc and the white solid removed by filtration. The solvent was evaporated and the resulting brown solid was recrystalised in EtOAc/IPE to give (1-methyl-1H-1,2,4-triazol-5-yl)(phenyl)methanone (6.5 g, 58% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[N:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1.[CH:21](=[O:25])[CH:22]([CH3:24])[CH3:23].O>O1CCCC1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]2[C:5]=1[NH:11][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)[C:22]([CH3:24])([CH3:23])[CH:21]2[OH:25])=[O:20]
Reactant: CC(C)C=O
Reactant: COC(=O)c1cc(F)ccc1N=Cc1cccc(Br)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2O
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a mixture of 2-{[1-(3-bromo-phenyl)-methylidene]-amino}-5-fluoro-benzoic acid methyl ester (50 g, 59.8 mmol) and ytterbium(III) triflate hydrate (3.7 g, 5.95 mmol) in dry tetrahydrofuran (30 mL) at 25° C. was added isobutyraldehyde (4.3 g, 59.5 mmol) and water (1.1 mL, 59.5 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-6-fluoro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (24.3 g, 100%) as a light yellow oil: LC/MS m/e calcd for C19H19BrFNO3 M+: 408.3, observed: 408.1.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.CC(C)C(O)=O.[CH3:14][N:15]([CH3:18])[CH:16]=O>>[CH3:14][N:15]([CH3:18])[CH:16]=[N:7][C:4]1[S:5][CH:6]=[C:2]([CH3:1])[N:3]=1
Reactant: CN(C)C=O
Reactant: Cc1csc(N)n1
Solvent: CC(C)C(=O)O
Product: Cc1csc(N=CN(C)C)n1

Procedure:
prepared by reaction of 4-methyl-thiazol-2-ylamine with N,N-dimethylformamide dimethyl acetate. LC-MS: tR=0.51 min; [M+H]+=170.1.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:4]3[N:5]([N:13]=[C:14]([CH2:16][OH:17])[CH:15]=3)[C:6](=[O:12])[NH:7][C:8]=2[CH:9]=[CH:10][CH:11]=1.[CH3:18]I.Cl>[Na].CO>[OH:17][CH2:16][C:14]1[CH:15]=[C:4]2[N:5]([C:6](=[O:12])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[C:2]([O:1][CH3:18])[C:3]=32)[N:13]=1
Reactant: O=c1[nH]c2cccc(O)c2c2cc(CO)nn12
Reactant: CI
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COc1cccc2[nH]c(=O)n3nc(CO)cc3c12
Reaction time: 3 h

Procedure:
To 4.2 g of 10-hydroxy-2-(hydroxymethyl)pyrazolo[1,5-c]-quinazoline-5(6H)-one in a solution of 0.58 g sodium dissolved in 100 ml dry methanol is added 2.9 g of methyl iodide. After stirring for 3 hours at 50°, the reaction is neutralized with one equivalent of 1N hydrochloric acid, evaporated and the residue recrystallized from absolute ethanol to give the title compound.