Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH:16]=O)[CH:5]=1)[CH:2]=[CH2:3].[CH2:18]([NH:20][C:21](=[O:34])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1)[CH3:19]>>[CH2:1]([C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH2:16][N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([C:21]([NH:20][CH2:18][CH3:19])=[O:34])=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C=O)cc2c1OC(C)C(=O)N2
Reactant: CCNC(=O)c1ccc(N2CCNCC2)cc1
Product: C=CCc1cc(CN2CCN(c3ccc(C(=O)NCC)cc3)CC2)cc2c1OC(C)C(=O)N2

Procedure:
Using 356A and N-ethyl-4-(piperazin-1-yl)benzamide 283 in the general procedure for reductive aminations, the title compound was obtained as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (t, J=7.20 Hz, 3H) 1.39 (d, J=6.82 Hz, 3H) 2.43-2.49 (m, 4H) 3.18-3.29 (m, 6H) 3.30-3.32 (m, 2H) 3.39 (s, 2H) 4.61 (q, J=6.82 Hz, 1H) 5.01-5.07 (m, 2H) 5.93 (m, J=16.86, 10.17, 6.57, 6.57 Hz, 1H) 6.77 (d, J=2.02 Hz, 1H) 6.73 (d, J=2.02 Hz, 1H) 6.92 (m, 2H) 7.71 (m, 2H) 8.18 (t, J=5.56 Hz, 1H) 10.60 (br. s., 1H). ESI-MS: m/z 449.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[NH2:34][CH2:35][CH2:36][S:37]([CH3:40])(=[O:39])=[O:38]>Cl>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[S:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:9]2[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:34][CH2:35][CH2:36][S:37]([CH3:40])(=[O:39])=[O:38])[N:7]=2)[CH:17]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)CCN
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Agent: Cl
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(NCCS(C)(=O)=O)n2)s1
Temperature: 60 °C
Yield: 41.5 %

Procedure:
A neat mixture of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (0.15 g, 0.30 mmol) and 2-aminoethyl-methyl-sulfone (0.20 g, 1.62 mmol) was heated at 60° C. overnight. The reaction mixture was diluted with 1M HCl and extracted with DCM twice. The organic layer was dried over MgSO4 and evaporated onto silica gel. Purification by ISCO chromatography (0 to 40% 1:9 MeOH:EtOAC in DCM) afforded the title compound (74 mg, 40.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.04 (s, 1H), 8.06 (d, J=5.1 Hz, 1H), 7.65-7.75 (m, 1H), 7.46 (t, J=5.7 Hz, 1H), 7.35 (t, J=7.9 Hz, 1H), 7.16-7.30 (m, 5H), 6.09 (br. s., 1H), 3.60-3.73 (m, 2H), 3.34-3.38 (m, 2H), 3.25-3.30 (m, 1H), 3.02 (s, 3H), 1.36 (d, J=6.9 Hz, 6H). MS (ESI): 594.2 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[C:33]([CH3:38])=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:18])([F:20])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[C:33]([CH3:38])=[N:34][CH:35]=[CH:36][CH:37]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1ncccc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(N(C)C)cc2NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncccc1-c1cccc(C2=Nc3cc(N(C)C)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (5-dimethylamino-2-{3-[3-(2-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M10) (380 mg, 0.683 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (215 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[C:12](OC)=[O:13].CCO.[Li+].[BH4-]>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[CH2:12][OH:13]
Reactant: COC(=O)c1cc2c(cc1F)NC(=O)C2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C1Cc2cc(CO)c(F)cc2N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of the compound obtained in Step B (2.68 mmoles) in anhydrous THF (20 mL) is maintained under nitrogen in the presence of 0.3 mL of EtOH. The solution is cooled to 0° C. and then 5.28 mmol of LiBH4 are added. The reaction mixture is stirred for 2 hours at ambient temperature; a second portion of LiBH4 (6.20 mmol) is then added and stirring is maintained for a further 3 hours. EtOH (0.3 mL) and a third portion of LiBH4 (9.14 mmol) are added and the reaction mixture is stirred overnight. The reaction mixture is quenched with 10 mL of water, and then saturated aqueous NH4Cl solution (30 mL) is added. Extraction with EtOAc is carried out, and the organic phases are dried over Na2SO4, filtered and evaporated in vacuo. The residue obtained is purified by flash chromatography (DCM/MeOH 10:1) to yield the title product.
Reaction SMILES: [Li].[F:2][C:3]1[CH:4]=[C:5]([C:9]([O-])=[CH:10][C:11](=O)[C:12]([O:14]CC)=[O:13])[CH:6]=[N:7][CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[Cl:42][C:43]1[CH:44]=[C:45]([NH:50][NH2:51])[CH:46]=[CH:47][C:48]=1[F:49]>>[Cl:42][C:43]1[CH:44]=[C:45]([N:50]2[C:9]([C:5]3[CH:6]=[N:7][CH:8]=[C:3]([F:2])[CH:4]=3)=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[N:51]2)[CH:46]=[CH:47][C:48]=1[F:49]
Reactant: NNc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cncc(F)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cncc(F)c2)n(-c2ccc(F)c(Cl)c2)n1

Procedure:
1.42 g (4.33 mmol) of the compound of Example 13A is reacted analogously to the synthesis of the compound of Example 20A with 1.28 g (6.50 mmol) of 3-chloro-4-fluorophenylhydrazine hydrochloride. After hydrolysis, 854 mg (59% of theory) of the title compound is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2[CH:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=2[C:11]([CH:27]=[O:28])=[N:10]1.CC(C)=[O:31]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2[CH:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=2[C:11]([C:27]([OH:31])=[O:28])=[N:10]1
Reactant: CC(C)=O
Reactant: O=Cc1nn(-c2ccc(F)cc2F)c2c1CCCCC2Cc1cccc(F)c1
Product: O=C(O)c1nn(-c2ccc(F)cc2F)c2c1CCCCC2Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Jone's Reagent (5.75 mL, 8.6 mmol) was added to a solution of 1-(2,4-difluoro-phenyl)-8-(3-fluoro-benzyl)-1,4,5,6,7,8-hexahydro-cycloheptapyrazole-3-carbaldehyde Compound 1h (1.65 g, 4.31 mmol) in acetone (20 mL) at 0° C. under a N2 atmosphere. The resulting suspension was stirred overnight, while warming to r.t., then filtered through a pad of celite to afford 1-(2,4-difluoro-phenyl)-8-(3-fluoro-benzyl)-1,4,5,6,7,8-hexahydro-cycloheptapyrazole-3-carboxylic acid Compound 2a as a solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:21]=[CH:20][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>C(#N)C.CN(C)C1C=CN=CC=1>[S:29]([O:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:21]=[CH:20][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:8][CH:7]=1)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC#Cc1ccc(OCCCN2CCCCC2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OCCC#Cc2ccc(OCCCN3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81975.1 %

Procedure:
To a solution of 1-{3-[4-(4-hydroxybut-1-yn-1-yl)phenoxy]propyl}piperidine (393 mg) in acetonitrile (10 mL) are added successively triethylamine (0.446 mL), 4-dimethylaminopyridine (18 mg) and tosyl chloride (617 mg). The mixture is stirred overnight at room temperature, concentrated under reduced pressure and purified by chromatography over silica gel to give 495 g of 1-{3-[4-(4-tosyloxybut-1-yn-1-yl)phenoxy]propyl}piperidine.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]=[CH:15][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:16]([O:18][CH3:19])=[O:17])=[CH:5][C:4]=2[N:3]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([F:28])[CH:27]=1)[NH2:24].O>CN1C(=O)CCC1>[F:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[N:12]=[CH:13][N:14]=[CH:15][C:10]=3[C:9]3[CH:8]=[CH:7][C:6]([C:16]([O:18][CH3:19])=[O:17])=[CH:5][C:4]=3[N:3]=2)[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: COC(=O)c1ccc2c(c1)nc(Cl)c1ncncc12
Reactant: Nc1cc(F)cc(F)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)nc(Nc1cc(F)cc(F)c1)c1ncncc12
Temperature: 120 °C

Procedure:
methyl 5-chloropyrimido[4,5-c]quinoline-8-carboxylate (10 mg) was mixed with 3,5-difluoroaniline (100 mg) in NMP (0.1 ml). The mixture was heated under microwaves at 120° C. for 10 minutes. Water was added and the material extracted with CH2Cl2. The solvent was removed. Trituration in a mixture of ethylacetate and hexanes and filtration provided methyl 5-(3,5-difluorophenylamino)pyrimido[4,5-c]quinoline-8-carboxylate. This material was suspended in a 1:1 mixture of THF and MeOH (2 ml) and a 5N aqueous solution of Lithium Hydroxide was added. The mixture was vigorously stirred at room temperature for 5 hours. Water and 6N hydrochloric acid were added to induce precipitation of the expected material. The solid was filtered, washed with water, dried and suspended in MeOH. Filtration and drying gave 5-(3,5-difluorophenylamino)pyrimido[4,5-c]quinoline-8-carboxylic acid as a yellow solid (4 mg, 31% yield). LCMS (ES): 95% pure, m/z 353 [M+1]+. 1H NMR (DMSO-d6, 400 MHz) δ 6.90 (br t, J=9.6, 1H), 8.02 (dd, J=1.6, J=8.0, 1H), 8.18 (br d, J=10.8, 2H), 8.34 (d, J=1.6, 1H), 8.86 (d, J=8.4, 1H), 9.65 (s, 1H), 10.40 (s, 1H), 10.44 (s, 1H) ppm.
Reaction SMILES: [H][H].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH:10]=2)[CH:4]=1>[Pt]=O>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10]2)[CH:4]=1
Reactant: O=C1C=C(c2cccnc2)CCC1
Reactant: [H][H]
Agent: O=[Pt]
Product: O=C1CCCC(c2cccnc2)C1
Reaction time: 2 h
Yield: 33.8 %

Procedure:
To a solution of 3-pyridin-3-yl-cyclohex-2-enone (1.25 g in 50 mL ethanol) was added 164 mg of platinum oxide catalyst and the mixture subjected to hydrogen at 40 psi. After 2 hours, the catalyst was removed by filtration and the filtrate concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (ethyl acetate:hexane, 1:1) gave the title compound (427 mg).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[CH:18]=[C:17]([O:19]C)[C:16]([O:21]C)=[C:15]([O:23]C)[CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9]C.Cl.N1C=CC=CC=1.[K+].[Br-]>>[OH:2][C:3]1[CH:4]=[C:5](/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]([OH:23])[C:16]([OH:21])=[C:17]([OH:19])[CH:18]=2)[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(C=Cc2cc(OC)c(OC)c(OC)c2)cc1OC
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: c1ccncc1
Product: Oc1ccc(/C=C/c2cc(O)c(O)c(O)c2)cc1O

Procedure:
Demethylation: The 1-(3,4-dimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl) ethylene (1.3 g) on demethylation with pyridine hydrochloride (7 g) under the conditions noted in example 1 gave 1, pp. 222–224° C.; IR (KBr) νmax 3450, 3338, 1608, 1535, 1449, 1320, 1177, 1119, 1035, 956, 848, 797 cm−1; 1H NMR (CH3OD, 400 MHz) δ 6.76 (1H, s), 6.61 (1H, d, J=8.0 Hz), 6.55 (1H, d, J=16.0 Hz), 6.54 (1H, d, J=8.0 Hz), 6.50 (1H, d, J=16.0 Hz), 6.33 (2H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]1[C:27]([O:29]CC)=[O:28].[OH-].[Na+]>C(O)C>[CH3:32][N:2]([CH3:1])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:6]1[C:27]([OH:29])=[O:28]
Reactant: CCOC(=O)c1c(C(c2ccccc2)c2ccccc2)c2ccccc2n1CCN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCn1c(C(=O)O)c(C(c2ccccc2)c2ccccc2)c2ccccc21
Reaction time: 4 h
Yield: 86.7 %

Procedure:
Compound 92 (7.0 g, 16.5 mmol) obtained in Example 92 was dissolved in ethanol (50 ml), and a 2N aqueous sodium hydroxide solution (25 ml) was added thereto, followed by heating under reflux. After 4 hours, a 2N aqueous sodium hydroxide solution (10 ml) was added thereto, followed by heating under reflux for one hour. The reaction solution was concentrated under reduced pressure, water was added, and the pH of the solution was adjusted to 5. A little amount of chloroform was added to the mixture followed by stirring. The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to give 5.7 g (yield: 87%) of the title compound.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([C@@H:15]2[CH2:19][C:18](=[N:20][O:21][CH3:22])[CH2:17][N:16]2[C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:27][CH:26]=2)=[O:24])[N:11]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+].[CH3:53][N:54]([CH2:56][C:57]([OH:59])=O)[CH3:55].C(Cl)CCl>CN(C1C=CN=CC=1)C>[C:28]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:26][C:25]([C:23]([N:16]2[CH2:17][C:18](=[N:20][O:21][CH3:22])[CH2:19][C@H:15]2[C:12]2[N:11]=[C:10]([CH2:9][NH:8][C:57](=[O:59])[CH2:56][N:54]([CH3:55])[CH3:53])[O:14][N:13]=2)=[O:24])=[CH:30][CH:29]=1
Reactant: CON=C1C[C@@H](c2noc(CNC(=O)OC(C)(C)C)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CN(C)CC(=O)O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CON=C1C[C@@H](c2noc(CNC(=O)CN(C)C)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
4-{[(2S,4EZ)-2-(5-{[(tert-butoxycarbonyl)amino]methyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl (Example 50) was treated with a 25% TFA/DCM solution at 0° C. The reaction was monitored by LC/MS and stopped after completion. The reaction was then made basic with sodium carbonate solution (10%) and extracted with DCM. The combined organic phases were dried over magnesium sulfate. Solvent removal afforded a crude product, which was used without purification in the next step. The residue was dissolved in DCM at room temperature, DMAP (1.1 equivalent) and (dimethylamino)acetic acid (1 equivalent) were added. The reaction mixture was then cooled down to 0° C. and EDC (1.1 equivalent) was added portion-wise. After stirring for 1 hour at 0° C., the reaction mixture was allowed to warm to room temperature. The reaction was monitored by TLC and LC/MS. Usually after 12 hours stirring at RT, the reaction mixture was hydrolyzed, washed with sodium carbonate solution (10%), dried over MgSO4, and evaporated in vacuo to give a crude product. Flash chromatography on silica gel, eluting with 60% EtOAc in hexane, gave the title compound as a mixture of E- and Z-isomers in 45% yield (88.1% purity by HPLC).
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([C:7]1[CH2:8][N:9]([CH2:14][C:15]2[C:18]3[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=3[CH:16]=2)[CH2:10][CH2:11][C:12]=1[OH:13])=[O:6])[CH3:3]>C(O)C.[Pt]=O>[ClH:1].[CH2:2]([O:4][C:5]([C@H:7]1[C@@H:12]([OH:13])[CH2:11][CH2:10][N:9]([CH2:14][C:15]2[C:18]3[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=3[CH:16]=2)[CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)C1=C(O)CCN(CC2=Cc3ccc(OC)cc32)C1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)[C@@H]1CN(CC2=Cc3ccc(OC)cc32)CC[C@@H]1O

Procedure:
11.7 g (33 mmol) of 4-hydroxy-1-[(5-methoxybenzocyclobuten-1-yl)methyl]-1,2,5,6-tetrahydro-pyridine-3carboxylic acid ethyl ester hydrochloride are hydrogenated at 4.105Pa and room temperature with the addition of 1.2 g of platinum oxide in 300 ml of ethanol. The catalyst is filtered off and the reaction solution is concentrated. Crystallisation from ethanol/diethyl ether yields cis-4-hydroxy-1-[(5-methoxybenzocyclobuten-1-yl)methyl]-piperidine-3carboxylic acid ethyl ester hydrochloride of m.p. 156°-160°.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[N:10]=[C:11]=[S:12])[CH3:2].[CH2:13]([NH:15][CH2:16][C:17](O)=[O:18])[CH3:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:13]([N:15]1[CH2:16][C:17](=[O:18])[N:10]([C:4]2[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:1][CH3:2])[C:11]1=[S:12])[CH3:14]
Reactant: CCc1cccc(C)c1N=C=S
Reactant: CCNCC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1cccc(C)c1N1C(=O)CN(CC)C1=S

Procedure:
The title compound was prepared by the procedure described in Example 10 using 17.7 g of 2-ethyl-6-methylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 300 mL of chloroform. The residue was further purified by flash chromatography on silica gel (20% ethyl acetate in hexane). The title compound was obtained (8.6 g) as a light peach solid, m.p. 82°-84° C. Anal. Calcd. for. C14H18N2OS: C, 64.09; H, 6.92; N, 10.68. Found: C, 64.27; H, 7.04; N, 10.60. Mass spectrum (EI, M.+) m/z 262.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[C:21](Br)[CH:20]=[CH:19][C:18]=1[F:24].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[C:21]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])[CH:20]=[CH:19][C:18]=1[F:24]
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: COC(=O)c1cc(Br)ccc1F
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cc(N2CCN(c3cnccc3C)C2=O)ccc1F
Yield: 88.7 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 315 mg, 1.78 mmol) was reacted with 5-bromo-2-fluoro-benzoic acid methyl ester (500 mg, 2.14 mmol), 1,4-dioxane (30 mL), copper iodide (34 mg, 0.178 mmol), trans-1,2-diamino cyclohexane (0.08 mL, 0.534 mmol) and potassium phosphate (935 mg, 4.45 mmol) to afford 520 mg of 2-Fluoro-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzoic acid methyl ester (88.8% yield).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[Cl:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](=O)[CH2:20]Br)=[CH:17][CH:16]=1.CN(C)C=O>C(O)C>[Cl:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]2[N:2]=[C:1]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[O:3][CH:20]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(C(N)=O)cc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CCO
Product: COC(=O)c1ccc(-c2nc(-c3ccc(Cl)cc3)co2)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 17.7 %

Procedure:
A mixture of methyl 4-carbamoylbenzoate (4.67 g), 4-chlorophenacyl bromide (6.50 g) and N,N-dimethylformamide (5 ml) was stirred at 130° C. for 2 hours. Hot ethanol was added to the reaction mixture, which was filtered. The filtrate was cooled to obtain crystals of methyl 4-[4-(4-chlorophenyl)-2-oxazolyl]benzoate (1.45 g, Yield: 18%). The product was recrystallized from ethanol. Pale yellow prisms. Melting Point: 183 to 184° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13]C)=[O:12])[C:5]=2[C:4]([CH2:15][NH:16][CH:17]2[CH2:23][CH:22]3[N:24]([CH3:25])[CH:19]([CH2:20][CH2:21]3)[CH2:18]2)=[N:3]1.O.[OH-].[Li+:28]>C1COCC1.O>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O-:13])=[O:12])[C:5]=2[C:4]([CH2:15][NH:16][CH:17]2[CH2:23][CH:22]3[N:24]([CH3:25])[CH:19]([CH2:20][CH2:21]3)[CH2:18]2)=[N:3]1.[Li+:28]
Reactant: COC(=O)c1cccc2c1c(CNC1CC3CCC(C1)N3C)nn2C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1C2CCC1CC(NCc1nn(C)c3cccc(C(=O)[O-])c13)C2
Temperature: 90 °C
Yield: 287.9 %

Procedure:
To a solution of methyl 1-methyl-3-((8-methyl-8-azabicyclo[3.2.1]octan-3-ylamino)methyl)-1H-indazole-4-carboxylate (0.54 g, 1.6 mmol) from Step A above in THF (5 mL) was added lithium hydroxide monohydrate (1.6 g, 38 mmol) in water (5 mL). The mixture was heated at 90° C. for 1 h and then concentrated under reduced pressure. The residue was dried overnight under vacuum to afford crude lithium 1-methyl-3-((8-methyl-8-azabicyclo[3.2.1]octan-3-ylamino)methyl)-1H-indazole-4-carboxylate (1.54 g), which was used in the next step without further purification: LC/MS (ESI+) m/z 329 (M+H).
Reaction SMILES: N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.[CH3:28][C:29]1[CH:33]=[CH:32][O:31][C:30]=1[C:34]([OH:36])=O.C(N(C(C)C)CC)(C)C.[CH3:46][O:47][C:48]1[CH:49]=[C:50]([NH:58][C:59]2[N:60]=[CH:61][C:62]3[CH2:68][NH:67][CH2:66][CH2:65][C:63]=3[N:64]=2)[CH:51]=[C:52]([O:56][CH3:57])[C:53]=1[O:54][CH3:55]>CN(C=O)C.CCOC(C)=O>[CH3:28][C:29]1[CH:33]=[CH:32][O:31][C:30]=1[C:34]([N:67]1[CH2:66][CH2:65][C:63]2[N:64]=[C:59]([NH:58][C:50]3[CH:49]=[C:48]([O:47][CH3:46])[C:53]([O:54][CH3:55])=[C:52]([O:56][CH3:57])[CH:51]=3)[N:60]=[CH:61][C:62]=2[CH2:68]1)=[O:36]
Reactant: COc1cc(Nc2ncc3c(n2)CCNC3)cc(OC)c1OC
Reactant: Cc1ccoc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2ncc3c(n2)CCN(C(=O)c2occc2C)C3)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
A solution of (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium-hexafluorophosphate (0.035 g, 0.079 mmol) in anhydrous DMF (2 mL) was treated sequentially with 3-methylfuran-2-carboxylic acid (0.013 g, 0.103 mmol) and diisopropylethylamine (0.035 mL, 0.159 mmol). The reaction mixture was allowed to stir for 30 minutes at room temperature. After 30 minutes, N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, Intermediate 1 (0.025 g, 0.079 mmol) was added to the reaction mixture. The reaction was allowed to stir for 3 hours at room temperature. The reaction mixture was then diluted with EtOAc and washed three times with brine. The combined aqueous layers were then washed twice with EtOAc. The organic layers were combined, dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude product was then purified over silica using a MeOH/CHCl3 gradient affording the final product in 47.3% yield (0.014 g, 0.037 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25]([OH:27])=O)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:28][C:29]1[CH:30]=[C:31]([S:35]([NH:38][C:39]([CH3:43])([CH3:42])[CH2:40][OH:41])(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[OH:41][CH2:40][C:39]([NH:38][S:35]([C:31]1[CH:30]=[C:29]([NH:28][C:25]([C:24]2[CH:23]=[N:22][N:15]3[C:16]([C:18]([F:19])([F:20])[F:21])=[CH:17][C:12]([C:4]4[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:11])[F:10])=[C:2]([F:1])[CH:3]=4)=[N:13][C:14]=23)=[O:27])[CH:34]=[CH:33][CH:32]=1)(=[O:37])=[O:36])([CH3:43])[CH3:42]
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(F)c3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(F)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3-fluoro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.18) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Light yellow solid. MS (ISP) 620.3 [(M+H+]; mp 221° C.