Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:38]=[CH:37][CH:36]=[CH:35][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:34])[CH2:19][NH:20][C:21]([C:23]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:25][N:24]=2)=[O:22])[CH2:14][CH2:13]1)C1C=CC=CC=1.Cl.C(OOC1C=CC=CC=1NC1CCNCC1)C1C=CC=CC=1>CO.O.[Pd]>[OH:8][C:9]1[CH:38]=[CH:37][CH:36]=[CH:35][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18](=[O:34])[CH2:19][NH:20][C:21]([C:23]2[CH:27]=[C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[NH:25][N:24]=2)=[O:22])[CH2:16][CH2:17]1
Reactant: O=C(NCC(=O)N1CCC(Oc2ccccc2OCc2ccccc2)CC1)c1cc(-c2ccccc2)[nH]n1
Agent: [Pd]
Agent: Cl
Agent: c1ccc(COOc2ccccc2NC2CCNCC2)cc1
Solvent: CO
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2O)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 2 h
Yield: 71.5 %

Procedure:
10% Pd/C (10 mg) was added to a stirred solution of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-benzyloxy-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide (prepared from Intermediate 30 and (2-benzyloxyoxy-phenyl)-piperidin-4-yl-amine hydrochloride which was prepared according to the method used for the synthesis of Intermediate 15) (100 mg, 0.2 mmol) in a mixture of MeOH:H2O (1:1, 10 mL) under inert atmosphere and stirring was continued under H2 gas atmosphere for 2 hr. The reaction mixture was filtered through celite. The filtrate collected was concentrated under reduced pressure to afford the residue. The residue was purified by preparative HPLC to afford 60 mg (71.5% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-hydroxy-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 421.8, 96.21%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (b, 1H), 8.9 (b, 1H), 8.2 (b, 1H), 7.8 (m, 2H), 7.5 (m, 3H), 7.2 (s, 1H), 7.0 (d, 1H), 6.8 (m, 3H), 4.5 (m, 1H), 4.2 (m, 2H), 3.8 (m, 2H), 3.3 (m, 2H), 1.9 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.N#N.[O:12]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1)[CH3:13].C(OCC)(=O)C.CCCCCC>CN(C=O)C>[CH3:13][O:12][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:5]2[CH:6]=[CH:7][C:3]([C:2]([F:9])([F:8])[F:1])=[N:4]2)=[CH:16][CH:15]=1
Reactant: COc1ccc(CCl)cc1
Reactant: FC(F)(F)c1cc[nH]n1
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1ccc(Cn2ccc(C(F)(F)F)n2)cc1
Temperature: 0 °C
Yield: 69.5 %

Procedure:
NaH (33.08 g (19.85 mol, 60%) was washed with n-hexane, then dry DMF (500 mL) was added drop wise under N2 atmosphere and the mixture was stirred well. A solution of 3-(trifluoromethyl)-1H-pyrazole (75 g, 0.55 mol) in DMF (125 mL) was added drop wise under N2 atmosphere. Then a solution of 4-methoxylbenzyl chloride (86.3 g, 0.55 mol) in DMF (125 mL) was added drop wise and the overall reaction mixture was allowed to stir for 12 h at room temperature. Progress of the reaction was monitored by TLC (10% ethyl acetate/hexane, Rf˜0.4). On completion of the reaction, the reaction contents were poured into ice water (500 mL) and the product was extracted with ethyl acetate (2×400 mL). The ethyl acetate layer was washed with 2N HCl (2×200 ml). Then the contents were dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by CC with 10% ethyl acetate/n-hexane to yield 1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazole as a brown colored liquid (98 g, 70%).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](F)=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([OH:29])[CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([O:29][C:9]2[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:7][C:8]=2[C:13]([F:16])([F:15])[F:14])[CH:19]=1
Reactant: O=C(O)CCc1ccc(Cl)cc1O
Reactant: CCS(=O)(=O)c1ccc(F)c(C(F)(F)F)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(Cl)ccc2CCC(=O)O)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by the method of example 3 step viii) using the product from step i) and the product from example 35 step ii).
Reaction SMILES: [O-][Mn](=O)(=O)=O.[K+].[OH2:7].[CH3:8][C:9]1([CH3:17])[C@H:15]2[CH2:16][C@@H:10]1[CH2:11][CH2:12][C:13]2=C>C(Cl)Cl>[CH3:8][C:9]1([CH3:17])[CH:15]2[CH2:16][CH:10]1[CH2:11][CH2:12][C:13]2=[O:7]
Reactant: C=C1CC[C@H]2C[C@@H]1C2(C)C
Reactant: O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC1(C)C2CCC(=O)C1C2

Procedure:
KMnO4 (5.71 g) was ground into a fine powder and combined with acidic alumina (22.55 g) and water (5.6 mL) for 5 minutes in order to form a homogenous mixture. (−)-β-Pinene (1.16 mL), and methylene chloride (200 mL) were placed in a 250 mL roundbottom flask; the moistened KMnO4/acidic alumina was added in small portions slowly to the solution. As the KMnO4/acidic alumina was added, the reaction turned into a dark purple color solution. The reaction was allowed to continue to stir until TLC indicated all starting material had reacted. The solution was filtered through fritted glass, and the residue was washed twice with 50 mL of methylene chloride. The filtrate was concentrated and yielded 6,6-dimethyl-bicyclo[3.1.1]heptan-2-one as a light yellow oil. The oil was purified via column chromatography (85:15, Hex: EtOAc) and like fractions were combined. 1H NMR (300 MHz, CDCl3): (ppm) 0.96 (s, 3H), 1.34 (s, 3H), 1.59 (d, 1H), 1.86-2.13 (m, 2H), 2.20-2.30 (m, 1H), 2.31-2.43 (m, 1H), 2.45-2.68 (m, 3H). (ESI, Pos) m/z 161.0 (M+23).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[F:38][C:39]([F:49])([F:48])[C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][CH:47]=1)[CH2:43][NH2:44]>>[CH3:35][O:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:44][CH2:43][C:42]4[CH:45]=[CH:46][CH:47]=[C:40]([C:39]([F:48])([F:49])[F:38])[CH:41]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Reactant: NCc1cccc(C(F)(F)F)c1
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCc4cccc(C(F)(F)F)c4)n3Cc3ccccc32)ccc1-c1ccccc1C
Yield: 79 %

Procedure:
The title compound was prepared in 79% yield in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 3-trifluoromethylbenzylamine, m.p. 176-177° C. MS [(+)ESI, m/z]: 610 [M+H]+ Anal. Calcd for C36H30F3N3O3: C, 70.93; H, 4.96; N, 6.89. Found: C, 70.89; H, 5.02; N, 6.80.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([Cl:9])=[C:7]([Cl:10])[C:6]([CH2:11]Cl)=[C:5]([Cl:13])[C:4]=1[Cl:14].C[O:16][P:17]([O:20][CH3:21])[O:18][CH3:19].CCl>C1(C)C=CC=CC=1>[CH3:19][O:18][P:17]([CH2:2][C:3]1[C:8]([Cl:9])=[C:7]([Cl:10])[C:6]([CH2:11][P:17](=[O:16])([O:20][CH3:21])[O:18][CH3:19])=[C:5]([Cl:13])[C:4]=1[Cl:14])(=[O:16])[O:20][CH3:21]
Reactant: ClCc1c(Cl)c(Cl)c(CCl)c(Cl)c1Cl
Reactant: COP(OC)OC
Agent: CCl
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1c(Cl)c(Cl)c(CP(=O)(OC)OC)c(Cl)c1Cl)OC
Temperature: 25 °C
Yield: 56.2 %

Procedure:
A mixture of α,α',2,3,5,6-hexachloro-p-xylene (6.26 g, 0.02 mol) in toluene (60 mL) and trimethylphosphite (7.0 mL, 7.4 g, 0.06 mol) is heated to reflux temperature. The flask is set up with a condenser, Dean-Stark trap, and the nitrogen inlet positioned so that any methyl chloride produced in the reaction will be swept out the condenser. A clear solution resultes with heating and the solution is heated at reflux for 18 hours. The toluene is distilled from the flask via the Dean-Stark trap, more trimethylphosphite is added (7.0 mL), and the reaction is heated with an oil bath (~110° C.) for 48 hours. After standing at room temperature, a white solid formed in the flask. A TLC indicated that no starting material remained. Toluene (100 mL) is added to flask and the mixture is heated at reflux temperature with stirring until a clear solution is obtained. The reaction mixture is allowed to cool to room temperature and a white precipitate formed. The white solid is collected by filtration, washed with hexane, dried in a vacuum desiccator, to give 5.17 g of title compound, mp 179°-181° C. Recrystallization from ethyl acetate gives 2.44 g as white crystals, mp 181°-182° C. There are some problems keeping the product in solution during the filtration of the hot ethyl acetate solution so that a considerable amount of material crystallized out during filtration. These crystals are combined with the filtrate from the collection of the first crop and yielded. 2.27 g. This material is recrystallized from ethyl acetate giving a second crop of 2.22 g, mp 181°-182° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:37][C:38]1[CH:47]=[C:46]2[C:41]([C:42](=[O:55])[C:43](I)=[C:44]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[O:45]2)=[CH:40][C:39]=1[O:56][CH3:57]>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:43]3[C:42](=[O:55])[C:41]4[C:46](=[CH:47][C:38]([Br:37])=[C:39]([O:56][CH3:57])[CH:40]=4)[O:45][C:44]=3[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(=O)c(I)c(-c3ccccc3)oc2cc1Br
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COc1cc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2cc1Br
Yield: 52 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-bromo-3-iodo-6-methoxy-2-phenyl-chromen-4-one was reacted to give the title compound as a pale yellow foam (302 mg, 52%). LCMS (Method B): RT=5.02 min, [M+Na]+=598/600.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2.[CH:12]1([CH2:15][O:16][C:17]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=2[C:19](O)=[O:20])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:19]([C:18]1[CH:22]=[C:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:24]=[CH:25][C:17]=1[O:16][CH2:15][CH:12]1[CH2:14][CH2:13]1)=[O:20])[CH2:6][CH2:5]2
Reactant: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)O)c1
Reactant: Clc1ccc2c(c1)CCNC2
Product: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)N2CCc3cc(Cl)ccc3C2)c1

Procedure:
Prepared in analogy to example 1.1 from 6-chloro-1,2,3,4-tetrahydro-isoquinoline (CA [33537-99-4]) and 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (example 2.9). MS (m/e): 420.1 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:21](=[O:23])[CH3:22])[C:9]3[C:14]([S:15][C:16]=2[CH:17]=1)=[CH:13][C:12]([N+:18]([O-])=O)=[CH:11][CH:10]=3)([O-])=O.O.O.[Sn](Cl)Cl.C(=O)([O-])O.[Na+]>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:21](=[O:23])[CH3:22])[C:9]3[C:14]([S:15][C:16]=2[CH:17]=1)=[CH:13][C:12]([NH2:18])=[CH:11][CH:10]=3
Reactant: CC(=O)N1c2ccc([N+](=O)[O-])cc2Sc2cc([N+](=O)[O-])ccc21
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)N1c2ccc(N)cc2Sc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.1 %

Procedure:
A mixture of 1-(3,7-dinitro-phenothiazin-10-yl)-ethanone (2 g, 6.04 mmol), tin (II) chloride dihydrate (14.17 g, 62.8 mmol), and ethanol (50 cm3) was heated to reflux and stirred at this temperature for 5 hours. The mixture was then cooled to room temperature and poured over ice water. The pH was adjusted to 7 with 5% sodium hydrogen carbonate before the product was extracted with ethyl acetate (3×50 cm3). The extracts were washed with brine and dried over magnesium sulphate, filtered, and concentrated to give the title compound (1.64 g, 100%) as a purple blue solid; νmax (KBr)/cm−1: 3445 (NH), 3424 (NH), 3368 (NH), 3322 (NH), 3203 (NH), 3054 (CH), 2995 (CH), 1706 (C═O), 1650 (NO2), 1590 (NO2); δH (250 MHz; CDCl3): 2.01 (3H, s, CH3), 5.09-5.43 (4H, brd s, NH), 6.47-6.51 (2H, dd, J 1.5, 8.25, ArH), 6.61 (2H, s, ArH), 7.11-7.15 (2H, d, J 8, ArH); δC (62.9 MHz; CDCl3): 169.1 (C═O), 147.2 (ArC), 128.1 (ArC), 127.6 (ArC), 127.3 (ArC), 112.3 (ArC), 111.5 (ArC), 22.6 (CH3); m/z (ES) 293.9 (95%, [M+H, Na]+), 272.0 (20%, [M+H]+) 227.9 (100%, [M+H, −Ac]+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[CH2:23]Cl)[CH2:2][CH2:3][CH3:4].[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.[K].O>CN(C)C=O>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[CH2:23][N:29]1[C:25](=[O:35])[C:26]2[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28]1=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(CCl)n(CC(C)(C)C)c(=O)c2cc(F)ccc12
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1c(CN2C(=O)c3ccccc3C2=O)n(CC(C)(C)C)c(=O)c2cc(F)ccc12
Yield: 96.3 %

Procedure:
A solution of 4-butoxy-7-fluoro-3-chloromethyl-2-neopentyl-1(2H)-isoquinolinone (1.95 g, 5.5 mmol) and potassium phthalimide (1.54 g, 8.3 mmol) in N,N-dimethylformamide (20 ml) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 2-{(4-butoxy-7-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione (2.46 g, 96.5%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:12])[C:7]=1[CH2:8][C:9]([OH:11])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:25]1([CH2:30][C:31]2[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:39][CH2:40][NH2:41])[CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(CC)CC)C>C1COCC1>[CH:25]1([CH2:30][C:31]2[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:39][CH2:40][NH:41][C:9](=[O:11])[CH2:8][C:7]2[C:6]([Cl:12])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: O=C(O)Cc1c(Cl)cncc1Cl
Reactant: COc1cccc(CCN)c1CC1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(CCNC(=O)Cc2c(Cl)cncc2Cl)c1CC1CCCC1
Yield: 85.7 %

Procedure:
By working in a way similar to that described in example 4 but using (3,5-dichloro-pyridin-4-yl)-acetic acid (356 mg, 1.73 mmoles), carbonyldiimidazole (308 mg, 1.9 mmoles), THF (15 ml), 2-(2-cyclopentylmethyl-3-methoxy-phenyl)-ethylamine (390 mg, 1.44 mmoles), obtained as described in example 49, and triethylamine (0.24 ml, 1.73 mmoles), 520 mg of the title compound were obtained (yield: 86%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18](=[N:20][NH:21][C:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[O:23])[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1.CO.[OH-].[Na+].Cl>O>[OH:1][C:2]1[C:3]([C:18](=[N:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)=[O:23])[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([CH3:15])[CH3:16])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(CC(C)C)cc3)c2O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=NNC(=O)c1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(CC(C)C)cc2)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.7 %

Procedure:
To methyl 4-[(2-{1-[4-hydroxy-5-(4-isobutylphenyl)-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]benzoate (0.129 mmol, 57.7 mg), methanol (2.5 mL) was added, and 1 M aqueous sodium hydroxide (5 eq., 0.643 mL) was added at room temperature. After 15 minutes of stirring at room temperature and 1.5 hours of stirring at 60° C., the reactor was cooled to room temperature, and 1 M hydrochloric acid (5 eq., 0.643 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump, and the residue was further purified by silica gel thin layer chromatography (chloroform/methanol=10/1). After addition of chloroform/n-hexane, the precipitated solid was dried to give the desired product as a yellow solid (25.6 mg, yield 46%).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[S:15][C:14]=3[S:22]([NH2:25])(=[O:24])=[O:23])=[CH:9][CH:8]=2)[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28]>CN(C)C1C=CN=CC=1.C(N(CC)CC)C.C(OCC)(=O)C>[CH2:30]([O:29][C:27]([NH:25][S:22]([C:14]1[S:15][C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:17][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([CH2:6][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:8][CH:9]=1)(=[O:23])=[O:24])=[O:28])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCOC(=O)Cl
Reactant: CC(C)Cc1cc(-c2ccc(Cn3cncn3)cc2)c(S(N)(=O)=O)s1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1ccc(Cn2cncn2)cc1
Reaction time: 8 h
Yield: 9.2 %

Procedure:
59 mg (0.16 mmol) of the crude 3-(4-[1,2,4]triazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide from step (c) above was mixed with butyl chloroformate (31 μL, 0.24 mmol) and 4-dimethylaminopyridine (2 mg, 16 μmol) in 5 mL of triethylamine at 0° C. The reaction mixture was stirred overnight and then diluted with ethyl acetate, washed with water and dried over K2CO3. The reaction mixture was then separated on a silica column (dichloromethane+15% methanol), circular chromatography (dichloromethane+10-15% methanol and preparative LC-MS to yield 7.0 mg of the title compound (9% isolated yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([OH:14])=O)[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:34][CH2:35][C:36]([C:38]1[S:42][C:41]2[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=2[C:39]=1[CH3:47])=[O:37].C(N(CC)CC)C>CN(C=O)C.O>[CH3:47][C:39]1[C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[S:42][C:38]=1[C:36](=[O:37])[CH2:35][NH:34][C:12]([C:10]1[S:11][C:7]2[C:6]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:14]
Reactant: Cc1c(C(=O)CN)sc2ccccc12
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)O)nc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCOCC2)c2sc(C(=O)NCC(=O)c3sc4ccccc4c3C)nc12
Reaction time: 48 h
Yield: 24.4 %

Procedure:
0.30 g 4-Methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 0.19 g 1,1′-carbonyl-diimidazole in 18 ml DMF were stirred at room temperature for 4 hours. 0.27 g 2-amino-1-(3-methyl-benzo[b]thiophen-2-yl)-ethanone hydrochloride and 0.16 ml triethylamine were added and stirring was continued for two days at room temperature. Water was added and the mixture was extracted with ethylacetate. Chromatography on silicagel with ethylacetate/hexane 4:6 yielded 0.12 g (23%) 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid [2-(3-methyl-benzo[b]thiophen-2-yl)-2-oxo-ethyl]-amide as a yellow solid; M.p.: 186–187° C.; MS (ISP): m/e=482 (M+H+).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:8]=[CH:9][CH:10]=1)=[NH:4].C(N(C(C)C)CC)(C)C.[C:28]([CH2:32][CH2:33][C:34](Cl)=[O:35])([O:30][CH3:31])=[O:29]>C1COCC1>[C:14]([O:13][C:12]([NH:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:3]([NH:2][O:1][C:34](=[O:35])[CH2:33][CH2:32][C:28]([O:30][CH3:31])=[O:29])=[NH:4])=[O:18])([CH3:15])([CH3:17])[CH3:16]
Reactant: COC(=O)CCC(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=N)NO)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCC(=O)ONC(=N)c1cccc(NC(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 50-mL, one-neck, round bottomed flask equipped with a magnetic stirrer and a digital thermometer was charged with tert-butyl [3-(N-hydroxycarbamimidoyl)phenyl]carbamate (5.56 g, 22.1 mmol), diisopropylethylamine (4.29 g, 33.2 mmol) and THF (25 mL). The reaction mixture was then cooled to 0° C. in an ice/salt bath. 3-Carbomethoxypropionyl chloride (3.99 g, 26.6 mmol) was then added dropwise to the reaction mixture. Once the addition was complete, the cooling bath was removed and the mixture stirred at room temperature for an additional 3 h. The reaction was then concentrated under reduced pressure, the residue dissolved in ethyl acetate (60 mL), and the resulting solution washed with 2 M aqueous potassium carbonate solution (2×60 mL). Drying over sodium sulfate, filtration and concentration under reduced pressure afforded a quantitative yield of 3-tert-butyloxycarbonylamino-N-(3-carbomethoxypropionyloxy)benzamidine as a white solid that was used directly. 1H NMR (CDCl3) δ (ppm) 7.71 (s, 1H), 7.50 (m, 2H,), 7.33 (m, 2H), 6.58 (bs, 1H), 5.19 (bs, 2H), 3.71 (s, 3H), 2.83 (m, 2H), 2.75 (m, 2H), 1.52 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][CH:23]=[N:24][N:25]=2)=[N:10]1.C1C(=O)N([Br:33])C(=O)C1>>[Br:33][CH2:20][C:13]1[NH:12][C:11]([C:21]2[S:22][CH:23]=[N:24][N:25]=2)=[N:10][CH:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(C)NC(c2nncs2)=NC1c1ccc(F)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)C1=C(CBr)NC(c2nncs2)=NC1c1ccc(F)cc1Cl
Yield: 50 %

Procedure:
Ethyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(1,3,4-thiadiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.76 g, 2 mmol) was reacted with NBS (0.36 g, 2 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.46 g, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:22])[CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl.O1CCOCC1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:22])[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: CN(c1ccc(F)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN(c1ccc(F)cc1)C1CCNCC1
Yield: 70.9 %

Procedure:
To an N,N-dimethylformamide solution (5 ml) of tert-butyl 4-[(4-fluorophenyl)amino]piperidine-1-carboxylate (250 mg, 0.850 mmol) synthesized in Reference Synthesis Example 23, sodium hydride (37 mg, 0.93 mmol, purity 60%) and methyl iodide (58 μL, 0.93 mmol) were added at room temperature and the resultant solution was stirred at room temperature for 15 hours. After completion of the reaction, saturated ammonium chloride aqueous solution was added, and extraction with ethyl acetate was performed from the resultant mixture. The resultant organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product of tert-butyl 4-[(4-fluorophenyl)(methyl)amino]piperidine-1-carboxylate (286 mg). Subsequently, to the obtained tert-butyl 4-[(4-fluorophenyl)(methyl)amino]piperidine-1-carboxylate (130 mg, 0.420 mmol), 4 M hydrogen chloride/1,4-dioxane solution (2 mL) was added and the resultant mixture was stirred at room temperature for 1 day. After completion of the reaction, the resultant solid was collected by filtration and washed with dichloromethane. To the obtained solid, water was added and pH of the resultant solution was adjusted to 9 with 1 M sodium hydroxide aqueous solution, followed by extraction from the resultant mixture with ethyl acetate and chloroform. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (62 mg, yield 72%).