Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:21][CH:22]2[CH:26]([CH2:27][CH3:28])[CH2:25][CH:24]([NH:29][S:30]([CH:33]3[CH2:35][CH2:34]3)(=[O:32])=[O:31])[CH2:23]2)=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[CH3:36][C@H](NC([C@H]1N(C([C@@H](NC([C@@H](N)CC2C=CC(O)=CC=2)=O)CC(O)=O)=O)CCC1)=O)C(N1[C@H](C(N2[C@H](C(N3[C@H](C(N4[C@H](C(N5[C@H](C(N6[C@H](C(O)=O)CCC6)=O)CCC5)=O)CCC4)=O)CCC3)=O)CCC2)=O)CCC1)=O>CO.CCOC(C)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:27]([CH:26]1[CH:22]([N:21]2[C:3]3=[C:4]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=5)(=[O:12])=[O:13])[C:5]4=[N:6][CH:7]=[C:2]3[N:1]=[CH:36]2)[CH2:23][CH:24]([NH:29][S:30]([CH:33]2[CH2:35][CH2:34]2)(=[O:31])=[O:32])[CH2:25]1)[CH3:28]
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)O)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCC1CC(NS(=O)(=O)C2CC2)CC1Nc1c(N)cnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC1CC(NS(=O)(=O)C2CC2)CC1n1cnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c21
Temperature: 65 °C
Yield: 100.1 %

Procedure:
To a solution of N-(3-(5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-4-ethylcyclopentyl)cyclopropanesulfonamide (0.095 g, 75% purity, 0.142 mmol, prepared using L from Preparation #27 and Preparation #000.1 with DIEA, K.1 with TsCl and NaH, and BBB) and TMOF (0.016 mL, 0.147 mmol) in MeOH (3.09 mL) was added toluene-4-sulfonic acid hydrate (0.0003 g, 0.0015 mmol). The reaction was heated at about 65° C. for about 14 h. The reaction was cooled to ambient temperature and concd under reduced pressure to give a crude solid. The solid was dissolved in EtOAc (10 mL) and was washed with saturated aqueous NaHCO3 (5 mL), water (5 mL), and brine (5 mL). The organic portion was separated and dried over anhydrous MgSO4, filtered, and concd under reduced pressure to afford N-(3-ethyl-4-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclopentyl)cyclopropanesulfonamide (0.075 g, 99%) as a yellow solid: LC/MS (Table 1, Method a) Rt=2.15 min; MS m/z: 514 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([S:18][CH2:19][C:20]([NH2:22])=[O:21])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([S:18]([CH2:19][C:20]([NH2:22])=[O:21])=[O:31])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: NC(=O)CSc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: NC(=O)CS(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
2-{[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]thio}acetamide (0.12 g, 0.36 mmol) was dissolved in chloroform (300 ml), and a solution of 3-chloroperbenzoic acid (77%, 0.082 g, 0.36 mmol) in chloroform (10 ml) was added dropwise thereto. The mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.071 g, 57%) as white crystals.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][C:16]3[C:22]4=[C:23]([NH:27][C:28]5[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]6[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=6)=[C:30]([Cl:43])[CH:29]=5)[N:24]=[CH:25][N:26]=[C:21]4[S:20][C:17]=32)=[N:12]1)(C(C)(C)C)(C)C.Cl>C1COCC1>[Cl:43][C:30]1[CH:29]=[C:28]([NH:27][C:23]2[C:22]3[C:16]4[CH2:15][CH2:14][C:13]5[C:18](=[CH:19][N:11]([CH2:10][CH2:9][OH:8])[N:12]=5)[C:17]=4[S:20][C:21]=3[N:26]=[CH:25][N:24]=2)[CH:33]=[CH:32][C:31]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1
Reactant: CC(C)(C)[Si](C)(C)OCCn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Agent: Cl
Solvent: C1CCOC1
Product: OCCn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 25 °C
Yield: 88.8 %

Procedure:
To 250 mL THF cooled to 0° C. was added 2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6-amine (7.70 g, 10.9 mmol). To the homogeneous mixture was then added aq HCl 2M, 6.5 mL), upon which the contents darken. The contents were stirred with warming to rt over a 4 h period, after which time the solvent was removed under reduced pressure. The crude residue was diluted with aq Na2CO3 (2M, 100 mL) to attain a pH=11 solution which was vigorously stirred, and the contents then filtered to a light brown solid which was dried under hi-vac. The collected product was triturated two times from hot ethanol to afford the final product (5.05 g, 89%) as a light tan solid. 1H-NMR (DMSO-d6) δ 2.90 (t, 2H), 3.36 (t, 2H), 3.72 (m, 2H), 4.06 (t, 2H), 4.90 (s, 1H), 5.24 (s, 2H), 7.14-7.34 (m, 4H), 7.41-7.54 (m, 2H), 7.78 (d, 1H), 7.95 (s, 1H), 8.35 (s, 1H), 8.40 (s, 1H); LCMS RT=3.39 min; [M+H]+=522.2.
Reaction SMILES: [Br-].[CH2:2]([N+:9]1[C:13]([CH3:14])=[CH:12][S:11][C:10]=1[CH:15]1OCCO1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:20]([O-:24])(=[O:23])(=[O:22])=[O:21].[Na+]>O>[Cl:20]([O-:24])(=[O:23])(=[O:22])=[O:21].[CH3:14][C:13]1[N+:9]2=[CH:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=3[CH:15]=[C:10]2[S:11][CH:12]=1
Reactant: Cc1csc(C2OCCO2)[n+]1Cc1ccccc1
Agent: [Br-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Product: Cc1csc2cc3ccccc3c[n+]12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 25 g of polyphosphoric acid heated at 110° C. was added with stirring 3-benzyl-2-(1,3-dioxolan-2-yl)-4-methylthiazolium bromide (2.31 7 g, 7.9 mmol) and the mixture was stirred for 3 h. The mixture was cooled to room temperature, poured into 200 ml of water, and treated with 3 g of sodium perchlorate. The precipitated product was filtered, washed with water, ether and dried in vacuo to afford 1.5 g (64%) of 3-methylthiazolo[3,2-b]isoquinolinium perchlorate (Formula II: A=3-methylthiazolo; R1 =R6 =H; X- =ClO4-).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][NH:14]3)=[O:8])=[C:5]([OH:21])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28]([CH:30]1[O:32][CH2:31]1)Cl>CC(C)=O>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][NH:14]3)=[O:8])=[C:5]([O:21][CH2:28][CH:30]2[CH2:31][O:32]2)[CH:4]=1
Reactant: COc1ccc(C(=O)Nc2cccc3[nH]ccc23)c(O)c1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(=O)Nc2cccc3[nH]ccc23)c(OCC2CO2)c1

Procedure:
Using the procedure of Step D of Example 52, 5 g of the product of Step A, 150 ml of acetone, 2.45 g of potassium carbonate and 14 ml of epichlorohydrin were reacted to obtain 7.3 g of 4-methoxy-2-[(2-oxiranyl)-methoxy]-N-(1H-indol-4-yl)-benzamide melting at 157° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[CH:10][C:9]=2[C:13]2[S:14][CH:15]=[C:16]([CH2:18][C:19]([O:21]CC)=[O:20])[N:17]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[CH:10][C:9]=2[C:13]2[S:14][CH:15]=[C:16]([CH2:18][C:19]([OH:21])=[O:20])[N:17]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1csc(-c2cn[nH]c2-c2ccc(F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1csc(-c2cn[nH]c2-c2ccc(F)cc2)n1
Yield: 74.9 %

Procedure:
To a solution of the compound (178 mg, 0.537 mmol) obtained in step 7 in ethanol (2.2 mL) was added 6N aqueous sodium hydroxide solution (0.269 mL, 1.61 mmol) at room temperature, and the mixture was heated under reflux for 1 hr. The organic solvent was evaporated, and 2N hydrochloric acid was added until the mixture became pH2. The precipitate was collected by filtration to give {2-[5-(4-fluorophenyl)-1H-pyrazol-4-yl]-1,3-thiazol-4-yl}acetic acid (122 mg, 75%) as a yellow powder.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][OH:24].[CH3:26][O:27][C:28](=[O:53])[CH:29]([N:37]([S:39]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]#[C:51][CH3:52])=[CH:44][CH:43]=1)(=[O:41])=[O:40])[CH3:38])[C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:26][O:27][C:28](=[O:53])[CH:29]([N:37]([S:39]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]#[C:51][CH3:52])=[CH:44][CH:43]=1)(=[O:40])=[O:41])[CH3:38])[C:30]1[CH:35]=[CH:34][C:33]([O:24][CH2:23][CH2:22][N:21]([CH3:25])[CH3:20])=[CH:32][CH:31]=1
Reactant: CN(C)CCO
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)c2ccc(O)cc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)c2ccc(OCCN(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
To a solution of 0.390 g (1.489 mmol) of triphenylphosphine in 8 mL of THF was added 0.150 mL (1.489 mmol) of N,N-dimethylethanolamine followed by 0.400 g (0.993 mmol) of methyl[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino](4-hydroxyphenyl)acetate (from Example 179) and 0.234 mL (1.489 mmol) of diethyl azodicarboxylate. The reaction was stirred overnight at room temperature and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:3) to give 0.246 g of methyl[{[4-(2-butynyloxy)phenyl]-sulfonyl}(methyl)amino]{4-[2-(dimethylamino)ethoxy]phenyl}acetate as a white solid. Electrospray Mass Spec 475.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])[N:6]2[CH2:12][C:13]([NH2:15])=O.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])[N:6]2[CH2:12][C:13]#[N:15]
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3Cl)n(CC(N)=O)c2n1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(Cl)c2nc(-c3ccccc3Cl)n(CC#N)c2n1
Yield: 78.6 %

Procedure:
Heat a solution of 2-[6-chloro-8-(2-chlorophenyl)-2-methyl-purin-9-yl]acetamide (0.3 g, 0.8 mmol) and phosphoryl chloride (2.5 mL) at 110° C. for 16 h. Quench the reaction with aqueous sodium bicarbonate solution and extract with dichloromethane. Wash the organics with water and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give the title compound (0.2 g). ES/MS m/z 318 (M+1).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][S:6]([C:9]2[CH:26]=[CH:25][C:12]3[N:13]([CH2:21][CH:22]4[CH2:24][CH2:23]4)[C:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:15][C:11]=3[CH:10]=2)(=[O:8])=[O:7])[CH2:2]1.C(N(CC)CC)C.C[Si]([N:38]=[C:39]=[O:40])(C)C>ClCCl>[CH:22]1([CH2:21][N:13]2[C:12]3[CH:25]=[CH:26][C:9]([S:6]([CH2:5][CH:3]4[CH2:2][N:1]([C:39]([NH2:38])=[O:40])[CH2:4]4)(=[O:8])=[O:7])=[CH:10][C:11]=3[N:15]=[C:14]2[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:23][CH2:24]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CNC3)ccc2n1CC1CC1
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CN(C(N)=O)C3)ccc2n1CC1CC1
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To the solution of 5-(azetidin-3-ylmethylsulfonyl)-1-(cyclopropylmethyl)-2-neopentyl-1H-benzo[d]imidazole (STEP F, 350 mg, 0.780 mmol) and triethylamine (395 microL, 2.81 mmol) in dichloromethane (5 mL) was added trimethylsilyl isocyanate (162 microL, 1.02 mmol) at room temperature. The resulting solution was stirred for 1 h. The reaction mixture was concentrated in vacuo. The residue was extracted with ethyl acetate (15 mL) and washed with water (30 mL). The organic layer was dried over magnesium sulfate. The crude product was purified with silica gel column chromatography (ethyl acetate-methanol=100:1 to 100:8) to give the title compound (198 mg, 61%).
Reaction SMILES: [C:1]([CH:4]([CH3:16])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([OH:3])=[O:2].[CH2:17](O)[CH3:18]>>[C:1]([CH:4]([CH3:16])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([O:3][CH2:17][CH3:18])=[O:2]
Reactant: CC(CCCCCC1=CCCC1=O)C(=O)O
Reactant: CCO
Product: CCOC(=O)C(C)CCCCCC1=CCCC1=O

Procedure:
Esterification with ethanol of the acid chloride derived from 2-(6-carboxyheptyl)-2-cyclopentenone in the manner of Example 31 is productive of the subject compound.
Reaction SMILES: [CH2:1]([NH:4][S:5]([CH2:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)(=[O:7])=[O:6])[C:2]#[CH:3].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([F:24])=[CH:19][N:18]=1>CO.O.C(OCC)(=O)C>[Cl:16][C:17]1[N:22]=[C:21]([NH:13][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][S:5]([NH:4][CH2:1][C:2]#[CH:3])(=[O:6])=[O:7])=[CH:15][CH:14]=2)[C:20]([F:24])=[CH:19][N:18]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: C#CCNS(=O)(=O)Cc1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: C#CCNS(=O)(=O)Cc1ccc(Nc2nc(Cl)ncc2F)cc1
Yield: 45.8 %

Procedure:
4-(Prop-2-ynylaminosulfonylmethyl)aniline (0.353 g, 1.57 mmol) and 2,4-dichloro-5-fluoropyrimidine (0.471 g, 2.81 mmol) were stirred in methanol:water (4:1, 10 mL) at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate (75 mL) and washed with 1N HCl (25 mL) and brine (10 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane ramped to methanol:dichloromethane (3:100)) to provide 2-chloro-5-fluoro-N4-[4-(prop-2-ynylaminosulfonylmethyl)phenyl]-4-pyrimidineamine as an off-white solid (0.255 g). 1H NMR (DMSO-d6): δ 10.03 (s, 1H), 8.31 (d, J=3.0 Hz, 1H), 7.68-7.63 (m, 3H), 7.36 (d, J=8.4 Hz, 2H), 4.35 (s, 2H), 3.78 (dd, J=2.4 and 5.7 Hz, 2H), 3.34 (t, J=2.4 Hz, 1H); LCMS: purity: 90%; MS (m/e): 356 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].F[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Reactant: Fc1ccc(C(F)(F)F)cc1
Product: N#Cc1ccc(N(c2ccc(C(F)(F)F)cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl) amino]pyrimidine and 4-fluorobenzotrifluoride
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([CH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8]1)[CH3:6])C.[OH-].[Na+]>>[C:17]([O:16][C:14]([CH2:13][CH:10]1[CH2:9][CH2:8][CH:7]([CH:5]([CH3:6])[C:4]([OH:21])=[O:3])[CH2:12][CH2:11]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)C(C)C1CCC(CC(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)C1CCC(CC(=O)OC(C)(C)C)CC1
Yield: 77.2 %

Procedure:
2-(4-Tert-butoxycarbonylmethyl-cyclohexyl)-propionic acid ethyl ester (2.46 g) obtained in Example (106a) was hydrolyzed with 1 N NaOH in the same way as in (Example 2) to obtain the title compound (1.72 g, 78%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([CH3:34])[CH2:29]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:26]([CH3:25])[CH2:27][CH:28]4[CH2:33][CH2:32][CH2:31][N:30]([CH3:34])[CH2:29]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: CNCC1CCCN(C)C1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N(C)CC3CCCN(C)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and N-methyl-1-(1-methylpiperidin-3-yl)methanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09-1.27 (m, 1H) 1.45-1.92 (m, 3H) 2.15 (br. s., 2H) 2.37-2.47 (m, 4H) 2.57-2.75 (m, 3H) 2.96 (s, 4H) 3.28 (dd, J=12.88, 5.81 Hz, 3H) 3.49 (d, J=15.41 Hz, 1H) 7.47 (d, J=8.53 Hz, 1H) 7.52 (s, 1H) 7.84 (s, 1H) 7.89 (br. s., 1H) 8.20 (d, J=8.34 Hz, 1H) 8.49 (br. s., 1H) 8.52 (d, J=8.84 Hz, 1H); ESI-MS m/z [M+H]+ 445.2.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.Cl[CH2:19][C:20]([N:22]([CH3:24])[CH3:23])=[O:21].C1(C)C=CC=CC=1.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:23][N:22]([CH3:24])[C:20](=[O:21])[CH2:19][O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Reactant: CN(C)C(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)C(=O)COC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
Benzyl 4-hydroxypiperidine-1-carboxylate (5 g, 21.25 mmol), tetrabutylammonium hydrogensulfate (0.361 g, 1.06 mmol) and 2-chloro-N,N-dimethylacetamide (4.13 g, 27.63 mmol) were added to toluene (50 mL) to this was added sodium hydroxide (21 g, 210.02 mmol) in water (30 mL) and the reaction was stirred at 25° C. overnight. The reaction mixture was quenched with water (100 mL), extracted with Et2O (3×75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford the desired compound as an orange liquid (6.00 g, 88% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.65-1.55 (2H, m), 1.93-1.86 (2H, m), 2.95 (3H, s), 3.03 (3H, s), 3.25-3.18 (2H, m), 3.63-3.57 (1H, m), 3.85-3.79 (2H, m), 4.17 (2H, s), 5.12 (2H, s), 7.38-7.30 (5H, m).
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=O)[NH:10][C:9]([S:13][CH3:14])=[N:8][C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:5])C.O=P(Cl)(Cl)Cl.[SH:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CCCCCCC.C(OCC)(=O)C>[OH:5][C:4]1[C:6]2[C:7]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:8][C:9]([S:13][CH3:14])=[N:10][C:11]=2[S:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)CS
Reactant: CCOC(=O)c1c(-c2ccccc2)nc(SC)[nH]c1=O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1sc2nc(SC)nc(-c3ccccc3)c2c1O

Procedure:
Treatment of 5-ethyloxycarbonyl-2-methylthio-4-phenyl-6-oxopyrimidine (63 mg) with POCl3 (304 μl) and subsequent reaction of the product with ethyl 2-mercaptoacetate were performed according to the methods described in example 1. The pure title compound was obtained after chromatography on silicagel in heptane/ethyl acetate 100/0=>60/40 (v/v) as eluent.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[C:25]([O:32][CH3:33])[CH:24]=3)[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>[Zn].C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([O:32][CH3:33])[CH:24]=3)[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(N2CCC(N3CCN(C(=O)OCc4ccccc4)CC3)CC2)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(N2CCC(N3CCN(C(=O)OCc4ccccc4)CC3)CC2)ccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
A mixture of 4-[1-(3-Methoxy-4-nitro-phenyl)-piperidin-4-yl]-piperazine-1-carboxylic acid benzyl ester (0.20 g, 0.44 mmol), Acetic acid (2 mL, 30 mmol), Ethanol (2 mL) and Zinc (0.20 g, 3.0 mmol) was stirred at room temperature for 3 hours. The reaction was filtered and evaporated. To the residue was added a saturated sodium bicarbonate solution and DCM, separated, dried and evaporated to give 4-[1-(4-Amino-3-methoxy-phenyl)-piperidin-4-yl]-piperazine-1-carboxylic acid benzyl ester as a dark blue solid (0.155 g, 82%). LCMS (m/e) 424 (M); 1H-NMR (DMSO-d6, 400 MHz) δ7.387.36 (m, 5H), 6.48 (s, 2H), 6.13 (s, 1H), 5.07 (s, 2H), 4.20 (br, 2H), 3.73 (s, 3H), 3.39 (m, 6H), 1.80 (m, 2H, 0.80 (m, 2H).
Reaction SMILES: CC1SC(C2C3C(=CC4C(C=3)=C(C3C=CC(C(O)=O)=CC=3)C=CC=4)C(C)(C)CC=2)=CC=1.[CH3:32][C:33]1([CH3:65])[CH:42]=[C:41]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[C:40]2[C:35](=[CH:36][C:37]3[CH:53]=[CH:52][C:51]([C:54]4[CH:64]=[CH:63][C:57]([C:58]([O:60]CC)=[O:59])=[CH:56][CH:55]=4)=[CH:50][C:38]=3[CH:39]=2)[O:34]1>>[CH3:32][C:33]1([CH3:65])[CH:42]=[C:41]([C:43]2[CH:44]=[CH:45][C:46]([CH3:49])=[CH:47][CH:48]=2)[C:40]2[C:35](=[CH:36][C:37]3[CH:53]=[CH:52][C:51]([C:54]4[CH:64]=[CH:63][C:57]([C:58]([OH:60])=[O:59])=[CH:56][CH:55]=4)=[CH:50][C:38]=3[CH:39]=2)[O:34]1
Reactant: CCOC(=O)c1ccc(-c2ccc3cc4c(cc3c2)C(c2ccc(C)cc2)=CC(C)(C)O4)cc1
Agent: Cc1ccc(C2=CCC(C)(C)c3cc4cccc(-c5ccc(C(=O)O)cc5)c4cc32)s1
Product: Cc1ccc(C2=CC(C)(C)Oc3cc4ccc(-c5ccc(C(=O)O)cc5)cc4cc32)cc1

Procedure:
By following the procedure employed for the preparation of 4-[1(5-methyl-thien-2-yl)3,4-dihydro-4,4-dimethyl-anthracen-8-yl]-benzoic acid (Compound 4), ethyl 4-[2,2-dimethyl-4-(tol-4-yl)-benzo(1,2-g)-chrom-3-en-7-yl]benzoate (Compound 9, 10 mg, 0.02 mmol), was converted into the title compound using LiOH in water (0.2 mL, 0.2 mmol). The title compound was obtained as an off white solid.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[NH2:2].C([O:14][C:15]([C:17]1[CH:18]=[N:19][C:20]2[C:25]([C:26]=1Cl)=[CH:24][CH:23]=[CH:22][C:21]=2[F:28])=O)C.[OH-].[Li+].Cl>C(O)CCC.O1CCCC1.O>[F:28][C:21]1[C:20]2[NH:19][CH:18]=[C:17]3[C:15](=[O:14])[N:1]([C:3]4[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=4)[C:6]([OH:8])=[O:7])[N:2]=[C:26]3[C:25]=2[CH:24]=[CH:23][CH:22]=1
Reactant: NNc1cccc(C(=O)O)c1
Reactant: CCOC(=O)c1cnc2c(F)cccc2c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.2 %

Procedure:
3-Hydrazinobenzoic acid (1.91 g, 0.013 mol) was added in one portion to a stirred solution of 4-chloro-8-fluoro-quinoline-3-carboxylic acid ethyl ester (2.93 g, 0.011 mol) in n-butanol (60 ml) at room temperature. The solution was heated to reflux for 16 h, cooled to room temperature and the resulting yellow solid filtered, washed with tert-butyl methyl ether and then dried. The solid was redissolved in a solution of tetrahydrofuran:water (2:1; 21 ml) and lithium hydroxide (1.27 g, 0.031 mol) was then added. After stirring at room temperature for 16 h, concentrated hydrochloric acid (3 ml) was added dropwise to the mixture to precipitate a yellow solid which was filtered and dried under vacuum to give the title compound (intermediate 3) (2.32 g, 63%) as a bright yellow solid.