Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]=[CH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([S:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:7][C:8](=[O:13])[C:9]([CH3:10])([CH3:11])[CH3:12])=[CH:14][CH:15]=1
Reactant: Sc1ccccc1
Reactant: CC(C)(C)C(=O)C=Cc1ccc(Cl)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)CC(Sc1ccccc1)c1ccc(Cl)cc1
Reaction time: 4 h

Procedure:
To a mixture of 4-chlorobenzalpinacolone (22.3 g), triethylamine (5 drops) and ethanol (250 ml) was added thiophenol (12 g) and the mixture was kept to 70° C. for 4 hours. After ice-cooling, the resulted precipitates were collected by filtration, washed with cold ethanol and dried to give white crystals of the captioned compound (29 g; 84%). m.p. 127°-128° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[NH:12][C:11](=[O:19])[NH:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH2:37])[CH:35]=3)[NH:30][N:29]=2)=[CH:23][CH:22]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH:37][C:15]([C:14]4[CH:9]([C:4]5[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=5)[NH:10][C:11](=[O:19])[NH:12][C:13]=4[CH3:18])=[O:17])[CH:35]=3)[NH:30][N:29]=2)=[CH:25][CH:26]=1
Reactant: CC1=C(C(=O)O)C(c2cc(F)cc(F)c2)NC(=O)N1
Reactant: Nc1ccc2[nH]nc(Nc3ccc(F)cc3)c2c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Nc4ccc(F)cc4)c3c2)C(c2cc(F)cc(F)c2)NC(=O)N1

Procedure:
The titled compound was prepared following the procedure of Example 175 using 4-(3,5-Difluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, N3-(4-fluoro-phenyl)-1H-indazole-3,5-diamine, PyBroP and diisopropylethylamine in methylene chloride. MS (ESI) m/z=493 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:39])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][C:32]([CH:36]3[CH2:38][CH2:37]3)=[CH:33][C:34]=2[CH3:35])[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:36]1([C:32]2[N:31]=[CH:30][C:29]([C:25]3[CH:24]=[C:23]([C:21]4[CH2:20][C:19](=[O:39])[NH:18][C:9]5[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=5[N:7]=4)[CH:28]=[CH:27][CH:26]=3)=[C:34]([CH3:35])[CH:33]=2)[CH2:38][CH2:37]1
Reactant: Cc1cc(C2CC2)ncc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)ccc2NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C2CC2)ncc1-c1cccc(C2=Nc3ccc(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (2-{3-[3-(6-cyclopropyl-4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M264) (260 mg, 0.47 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (67 mg, 33%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[O:27]=[C:28]1[N:32]([C@@H:33]2[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][C@H:34]2[F:46])[C:31](=[O:47])[CH2:30][S:29]1>>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:30]3/[C:31](=[O:47])[N:32]([C@@H:33]4[CH2:38][CH2:37][NH:36][CH2:35][C@H:34]4[F:46])[C:28](=[O:27])[S:29]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N2C(=O)CSC2=O)[C@H](F)C1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CCNC[C@H]1F

Procedure:
(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[trans-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from [2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 6) and 1,1-dimethylethyl trans-4-(2,4-dioxo-1,3-thiazolidin-3-yl)-3-fluoropiperidine-1-carboxylate (from Example 273) following General Procedure F.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:10][C:7]2[CH:8]=[CH:9][C:2]([Br:1])=[C:3]([F:11])[C:4]=2[CH:5]=[O:6])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=Cc1c(O)ccc(Br)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)c(F)c2C=O)CC1
Yield: 93.9 %

Procedure:
In a manner similar to the method described in example 4a, 3-bromo-2-fluoro-6-hydroxy-benzaldehyde (3.69 g, 16.8 mmol) reacted with 4-(toluene-4-sulfonyloxy)-piperidine-1-carboxylic acid tert-butyl ester (4 g, 11.2 mmol, ASTATECH) and K2CO3 in N,N-dimethylformamide to give 4-(4-bromo-3-fluoro-2-formyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester as a brown oil (Yield 4.23 g, 94%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[C:1]([NH:8][C@H:9]([C:14]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])[CH2:10][CH2:11][S:12][CH3:13])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C1CCNC1
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1

Procedure:
2.50 g (10 mmol) BOC-methionine was coupled to 1.72 ml (20.6 mmol) pyrrolidine according to procedure B. Yield of crude product 3.38 g. The product was purified with a silica column using ethyl acetate as eluent. Yield 2.81 g (9.3 mmol, 93%).
Reaction SMILES: [C:1]([O:14][CH2:15][C:16]([CH3:20])([CH3:19])[CH:17]=[O:18])(=[O:13])/[CH:2]=[CH:3]\[C:4]([O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH:9]=[O:10])=[O:5].N1CCOCC1>C1(C)C=CC=CC=1>[C:1]([O:14][CH2:15][C:16]([CH3:20])([CH3:19])[CH:17]=[O:18])(=[O:13])/[CH:2]=[CH:3]/[C:4]([O:6][CH2:7][C:8]([CH3:11])([CH3:12])[CH:9]=[O:10])=[O:5]
Reactant: CC(C)(C=O)COC(=O)/C=C\C(=O)OCC(C)(C)C=O
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: CC(C)(C=O)COC(=O)/C=C/C(=O)OCC(C)(C)C=O
Temperature: 25 °C

Procedure:
Crude bis (2,2-dimethyl-3-oxopropyl) maleate was treated with a catalytic amount of morpholine (10 wt. %) in refluxing toluene for 4 hrs. The resulting solution was cooled to room temperature, washed with diluted hydrochloric acid and brine, then dried over magnesium sulfate. Evaporation of volatiles in vacuo gave crud bis (2,2-dimethyl-3-oxopropyl) fumarate in essentially quantitative yield. NMR* (CDCL3): 9.7 (s, 1H,--CHO), 6.93 (s, 2H, trans --CH=CH--), 4.33 (s, 2H, --CO2CH2 --), and 1.2 (s, 6H, --C(CH3)2 --).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].Cl[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: Cc1cccc(C)c1O
Product: Cc1cccc(C)c1Oc1ccc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Temperature: 70 °C
Yield: 79.8 %

Procedure:
Prepared according to Example 103 using 2,6-dimethylphenol (158 mg, 1.293 mmol) and 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 50.0 mg, 0.168 mmol), heating at 70° C. for 17 h. Chromatographic purification (silica gel, 0-10% MeOH/DCM) furnished 2-(2-(2,6-dimethylphenoxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (51.4 mg, 0.134 mmol, 80% yield) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ ppm 11.08 (1H, br. s.), 8.21 (1H, d, J=8.8 Hz), 8.03 (1H, dd, J=7.6, 1.3 Hz), 7.61 (1H, dd, J=7.9, 1.3 Hz), 7.42 (1H, t, J=7.8 Hz), 7.29 (1H, s), 7.21 (3H, s), 7.10 (1H, d, J=2.2 Hz), 5.33 (1H, br. s.), 3.51 (2H, td, J=6.8, 1.2 Hz), 2.47 (2H, t, J=6.9 Hz), 2.17 (6H, s). m/z (ESI, +ve) 384.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].I.[NH2:24][C:25]1[C:26]([C:33]([NH:35][C:36](=[NH:39])SC)=[O:34])=[N:27][C:28]([Cl:32])=[C:29]([NH2:31])[N:30]=1.C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:36]([NH2:39])=[N:35][C:33]([C:26]2[C:25]([NH2:24])=[N:30][C:29]([NH2:31])=[C:28]([Cl:32])[N:27]=2)=[O:34])=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(CCCCN)cc1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Yield: 92.5 %

Procedure:
{2-[4-(4-Aminobutyl)phenoxy]ethyl}carbamic acid tert-butyl ester 2 (1.7 g, 5.5 mmol), 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (2.6 g, 6.6 mmol), and triethylamine (3.1 mL) were combined in THF (18 mL). The reaction was stirred at reflux under argon for 1.5 h. The product mixture was allowed to cool, and the solvent was evaporated. Chromatography (silica gel, methylene chloride/methanol/concentrated ammonium hydroxide, 100:10:1) afforded 2.65 g (92%) of the pure product as a yellow foamy solid. 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 1.62 (m, 2H), 1.61 (m, 2H), 1.75 (br s, 2H), 2.56 (t, 2H), 2.71 (t, 2H), 3.51 (m, 2H), 3.99 (t, 2H), 5.07 (br s, 1H), 6.80 (d, 2H), 7.08 (d, 2H).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C@@H:11]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.[Cl:47][C:48]1[N:53]=[CH:52][C:51]([S:54](Cl)(=[O:56])=[O:55])=[CH:50][CH:49]=1>C(Cl)Cl>[Cl:47][C:48]1[N:53]=[CH:52][C:51]([S:54]([N:13]2[CH2:14][CH2:15][N:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:29])([F:31])[F:30])[C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=3)[C@@H:11]([CH2:10][S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[CH2:12]2)(=[O:56])=[O:55])=[CH:50][CH:49]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)[C@@H](CS(=O)(=O)c2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(C[C@H]1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.8 %

Procedure:
A 20 mL vial was charged with tert-butyl (3R)-3-((phenylsulfonyl)methyl)-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate (0.038 g, 0.065 mmol), TFA (0.50 mL, 6.5 mmol, Sigma-Aldrich, St. Louis, Mo.) and DCM (1 mL). The mixture was stirred at rt for 10 min. The volatile was removed and the residue was taken into DCM (1 mL). TEA (0.10 mL, 0.78 mmol) was added and the mixture was stirred at rt for 5 min. At this time, 6-chloropyridine-3-sulfonyl chloride (0.016 g, 0.073 mmol, Organic Process Research & Development 2009, 13, 875) was added and the mixture was stirred at rt for 10 min. The reaction mixture was directly purified by column chromatography (10 g of silica, 0 to 50% EtOAc in hexanes) to afford 2-(4-((2R)-4-((6-chloro-3-pyridinyl)sulfonyl)-2-((phenylsulfonyl)methyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.026 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8]2[N:9]=[C:10]([CH3:14])[S:11][C:12]=2[NH2:13])[CH:7]=1.[N:17]1[N:21]2[CH:22]=[CH:23][CH:24]=[N:25][C:20]2=[C:19]([C:26](Cl)=[O:27])[CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8]2[N:9]=[C:10]([CH3:14])[S:11][C:12]=2[NH:13][C:26]([C:19]2[CH:18]=[N:17][N:21]3[CH:22]=[CH:23][CH:24]=[N:25][C:20]=23)=[O:27])[CH:7]=1
Reactant: O=C(Cl)c1cnn2cccnc12
Reactant: COc1ccc(Cl)cc1-c1nc(C)sc1N
Product: COc1ccc(Cl)cc1-c1nc(C)sc1NC(=O)c1cnn2cccnc12

Procedure:
Using 4-(5-chloro-2-methoxyphenyl)-2-methylthiazol-5-amine and pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride the title compound was synthesized following the synthetic procedures described for N-(2-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(5-chloro-2-methoxyphenyl)thiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide with further purification by flash chromatography on silica gel (0 to 100% ethyl aceate in DCM) to give N-(4-(5-chloro-2-methoxyphenyl)-2-methylthiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as an orange solid. LCMS (ESI) m+H=400.0; 1H NMR (400 MHz, DMSO-d6): δ 10.43 (s, br, 1H); 9.38 (dd, 1H); 8.75-8.73 (m, 1H); 8.72 (s, 1H); 7.52 (dd, 1H); 7.47 (d, 1H); 7.34-7.32 (m, 2H); 3.79 (s, 3H); 2.62 (s, 3H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[F:18][C:19]([F:32])([F:31])[C:20]1[N:21]=[C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[S:23][CH:24]=1>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:28]1[CH2:29][CH2:30][N:25]([C:22]2[S:23][CH:24]=[C:20]([C:19]([F:32])([F:18])[F:31])[N:21]=2)[CH2:26][CH2:27]1)=[O:9])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1csc(N2CCNCC2)n1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc(C(F)(F)F)cs2)CC1
Yield: 55 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(4-trifluoromethyl-thiazol-2-yl)-piperazine. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in pentane to yield the title compound as a crystalline white solid (yield 55%). MS (m/e): 478.0 (M+H+, 100%).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]=1)=[O:4].Cl>[OH-].[Na+].CO>[NH:6]1[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=[C:5]1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1nc2ccccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
A mixture of 1H-benzoimidazole-2-carboxylic acid methyl ester (18) (0.89 g, 5.1 mmol) in 2 N aq. NaOH (10 mL) and MeOH (10 mL) was stirred at RT for 18 h. The mixture was acidified to pH=4 with 1 N aqueous HCl. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and evaporated to obtain compound (19) as a brown solid (0.67 g, yield 80%). ESI-MS (M+1): 163 calc. for C8H6N2O2 162.
Reaction SMILES: [N:1]1([CH2:7][C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:14][CH:15]([F:29])[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:24]=[C:25]([NH2:28])[NH:26][N:27]=1>>[F:29][CH:15]([F:14])[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:24]=[C:25]([NH:28][C:11]([C@@H:9]2[CH2:10][C@H:8]2[CH2:7][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:13])[NH:26][N:27]=1
Reactant: O=C(O)[C@@H]1C[C@H]1CN1CCCCC1
Reactant: Nc1cc(-c2ccccc2OC(F)F)n[nH]1
Product: O=C(Nc1cc(-c2ccccc2OC(F)F)n[nH]1)[C@@H]1C[C@H]1CN1CCCCC1
Yield: 25.5 %

Procedure:
The product was prepared according to the general synthetic method for the synthesis of ω-amino-alkanoic acid (1H-pyrazol-3-yl-5-aryl)-amides via the amino acid route, starting from trans (±)-2-piperidin-1-ylmethyl-cyclopropanecarboxylic acid (99.1 mg, 0.6 mmol, 1.3 eq) and 5-(2-difluoromethoxy-phenyl)-2H-pyrazol-3-ylamine (125.7 mg, 0.4 mmol, 1.0 eq). The crude product was purified through SiO2 column with gradient elution from 100% DCM to DCM-NH3 in MeOH 2 N 80:20. The title product (39.9 mg, 23% yield) was obtained.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([NH2:19])[CH:13]=1)(=[O:5])=[O:4].Cl.C(O[C:26](=N)[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=1)C>CCO>[F:21][C:2]([F:20])([F:1])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]2[NH:18][C:26]([CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:31][CH:30]=3)=[N:19][C:14]=2[CH:13]=1)(=[O:4])=[O:5]
Reactant: CCOC(=N)COc1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(-c2ccccc2S(=O)(=O)C(F)(F)F)cc1N
Agent: Cl
Solvent: CCO
Product: O=S(=O)(c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.7 %

Procedure:
A mixture of 2′-trifluoromethanesulfonyl-biphenyl-3,4-diamine (0.042 g, 0.133 mmol) and 2-(4-trifluoromethyl-phenoxy)-acetimidic acid ethyl ester hydrochloride (0.045 g, 0.159 mmol, Example 1.1) in EtOH (4 mL) was stirred at room temperature for 12 hours. The reaction was concentrated to give a residue, which was purified by chromatography (silica, hexanes: EtOAc, 1:2) to afford the product as brown oil (0.065 g, 98%). 1H NMR (400 MHz, CD3OD) δ (ppm): 8.25 (d, 1H, J=7.6 Hz), 7.92 (td, 1H, J=8.4 Hz, J=1.6 Hz), 7.77 (td, 1H, J=8.4 Hz, J=1.2 Hz), 7.65-7.54 (m, 3H), 7.27-7.20 (m, 4H), 7.14 (d, 1H, J=8.4 Hz), 5.45 (s, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C22H15F6N2O3S: 501.4 (M+H), Found 501.2.
Reaction SMILES: C[O:2][C:3](=[O:39])[C@H:4]([NH:11][C:12]([C:14]12[CH2:21][C:18]([C:22]3[NH:30][C:29]4[C:28](=[O:31])[N:27]([CH2:32][CH2:33][CH3:34])[C:26](=[O:35])[N:25]([CH2:36][CH2:37][CH3:38])[C:24]=4[N:23]=3)([CH2:19][CH2:20]1)[CH2:17][CH2:16][CH2:15]2)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Li+].[OH-]>C1COCC1>[O:35]=[C:26]1[N:25]([CH2:36][CH2:37][CH3:38])[C:24]2[N:23]=[C:22]([C:18]34[CH2:21][C:14]([C:12]([NH:11][C@H:4]([C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:3]([OH:39])=[O:2])=[O:13])([CH2:20][CH2:19]3)[CH2:15][CH2:16][CH2:17]4)[NH:30][C:29]=2[C:28](=[O:31])[N:27]1[CH2:32][CH2:33][CH3:34]
Reactant: CCCn1c(=O)c2[nH]c(C34CCCC(C(=O)N[C@@H](C(=O)OC)c5ccccc5)(CC3)C4)nc2n(CCC)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C34CCCC(C(=O)N[C@@H](C(=O)O)c5ccccc5)(CC3)C4)nc2n(CCC)c1=O
Yield: 47.9 %

Procedure:
A solution of (1RS,2R,5SR)-{[5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[3.2.1]octane-1-carbonyl]-amino}-phenyl-acetic acid methyl ester (0.022 mmol, 0.012 g) in THF (2 ml) was treated with 1N LiOH (0.22 ml) for 3d. The THF was removed on the rotovap, the aqueous residue acidified (pH 2) with 1N HCl and extracted with EtOAc. The combined organics were washed with H2O, brine and dried (MgSO4). Filtration and evaporation followed by reverse phase HPLC purification provide the desired product (0.0055 g, 48%) as a mixture of diastereomers. HPLC (10% to 90% MeCN (0.1% TFA)/H2O (0.1% TFA), YMC 120 A/S-5 ODS-AM column, 100 mm×4.6 mm, 1.5 ml/min: RT.=6.88 min.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].CO.[CH2:17]1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:17][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([CH2:2][Br:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=1
Reactant: O=C(O)c1ccc(CBr)c([N+](=O)[O-])c1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-bromomethyl-3-nitrobenzoic acid (2.6 g, 10 mmol), MeOH (320 mg, 10 mmol) and DMAP (122 mg, 1 mmol) in methylene chloride (40 mL) was added DCC (2.06 g, 10 mmol) and the resulting mixture was stirred at ambient temperature for 2 h. The resulting precipitate was filtered and the filtrate evaporated under reduced pressure. The resulting oil was filtered through a plug of silica gel using methylene chloride as eluent. The solvent was removed under reduced pressure to give 4-bromomethyl-3-nitrobenzoic acid methyl ester as a pale-yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.C[Al](C)C.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[N:19]1[C:24]2[N:25]=[C:26]([NH:37][CH2:38][C:39](OC)=[O:40])[N:27]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[CH3:36])[C:23]=2[CH:22]=[CH:21][C:20]1=[O:43]>>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[N:19]1[C:24]2[N:25]=[C:26]([NH:37][CH2:38][C:39](=[O:40])[N:1]3[CH2:6][CH2:5][S:4][CH2:3][CH2:2]3)[N:27]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[CH3:36])[C:23]=2[CH:22]=[CH:21][C:20]1=[O:43]
Reactant: COC(=O)CNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: C1CSCCN1
Agent: C[Al](C)C
Product: Cc1cc(F)ccc1-c1nc(NCC(=O)N2CCSCC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 86.5 %

Procedure:
Following the general procedure outlined in Example 193, thiomorpholine (0.22 mL, 2.2 mmol), trimethylaluminum (1.1 mL, 2.2 mmol) and the product of Example 190 (200 mg, 0.44 mmol) were reacted to give the desired product 200 mg (86%). LC-MS: 526.0 (MH+, m/z), 2.07 (Rt, min).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][C@@:11]2([C:16]([O:18]CCCC)=[O:17])[CH2:15][CH2:14][O:13][CH2:12]2)=[O:9])[CH:5]=[N:6][CH:7]=1.[OH-].[Na+]>>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][C@@:11]2([C:16]([OH:18])=[O:17])[CH2:15][CH2:14][O:13][CH2:12]2)=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: CCCCOC(=O)[C@]1(NC(=O)c2cncc(N)c2)CCOC1
Agent: [Na+]
Agent: [OH-]
Product: Nc1cncc(C(=O)N[C@@]2(C(=O)O)CCOC2)c1

Procedure:
Analogously to Example 1d), n-butyl(S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylate (69.9 mmol) was saponified with sodium hydroxide solution.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1>C1(C)C=CC=CC=1.[Pd]>[CH:8]1([CH:1]2[CH2:2][CH2:3][C:4](=[O:7])[CH2:5][CH2:6]2)[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: O=C1CCC(C2CCC(=O)CC2)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
A suspension of 50 g of 4,4′-biphenyldiol in 500 ml of toluene is hydrogenated at 5 bar and 125° C. in the presence of palladium on activated carbon. The reaction mixture is filtered and freed from water by azeotropic distillation. It is then treated with 29 g of pyridine sulfone and stirred at 50° C. for 1 hour. After filtration using basic alumina and removal of the solvent, 34.4 g (66% yield) of 4,4′-bicyclohexanedione remain as colourless crystals having a purity of 99.0% (GC).
Reaction SMILES: [CH3:1][CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(Cl)Cl.S(=O)(=O)(O)O.[C:25](O)([CH3:28])([CH3:27])[CH3:26]>[Cl-].[Na+].O>[C:25]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH:2]([CH3:1])[CH2:3][N:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)=[CH:12][CH:13]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)O
Reactant: CC(Cc1ccccc1)CN1CCCCC1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(Cc1ccc(C(C)(C)C)cc1)CN1CCCCC1
Temperature: 20 °C

Procedure:
100 g of 1-(2-methyl-3-phenyl-propyl)-piperidine are added to 375 ml of methylene chloride. 255 g of 95-96% sulfuric acid are then added dropwise over a 1.5 hour period with rapid stirring while cooling with brine to an internal temperature of 10° C. The mixture is warmed to 20° C. and 42.5 g of tert.-butanol are added dropwise. The mixture is reacted at room temperature for 2 hours. The work-up is analogous to that described in Example 1. The crude product is purified by fractional distillation on a Goodloe silver column to yield pure 1-[3-(p-tert.butyl-phenyl)-2-methyl-propyl]-piperidine, b.p. 118° C./0.07 Torr.