Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([NH2:11])=[CH:9][N:8]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1.[CH:31]([S:34]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)(=[O:36])=[O:35])([CH3:33])[CH3:32].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH:31]([S:34]([C:37]1[CH:42]=[CH:41][C:40]([C:2]2[N:3]=[C:4]3[C:10]([NH2:11])=[CH:9][N:8]([C:12]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:5]3=[N:6][CH:7]=2)=[CH:39][CH:38]=1)(=[O:35])=[O:36])([CH3:33])[CH3:32]
Reactant: CC(C)S(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Nc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
2-bromo-5-trityl-pyrrolo[2,3-b]pyrazin-7-amine (300 mg, 0.6588 mmol), (4-isopropylsulfonylphenyl)boronic acid (180.3 mg, 0.7906 mmol) and Na2CO3 (988.0 μL of 2 M, 1.976 mmol) combined in dioxane (3 mL) in a microwave tube and the mixture de-gassed (×2 vacuum-N2 cycles). Pd (tBu3P)2 (33.67 mg, 0.06588 mmol) added and the mixture de-gassed (×2 cycles) then heated at 65° C. (block temp), sealing tube with a crimp-top and left to stir for 1 hour. Reaction mixture cooled to ambient temperature and the mixture partitioned between DCM and water. Aqueous phase extracted with DCM and combined organics dried and concentrated. Residue purified by chromatography eluting with 0-30% MeOH-DCM. Brown/yellow solid obtained (332 mg, 90%). 1H NMR (400.0 MHz, DMSO) δ 8.67 (s, 1H), 8.35 (d, J=8.5 Hz, 2H), 7.91 (d, J=8.5 Hz, 2H), 7.35-7.25 (m, 15H), 7.01 (s, 1H), 4.59 (s, 2H), 3.57 (s, 1H), 3.49-3.40 (m, 1H), 1.29 (d, J=12.1 Hz, 2H) and 1.17 (d, J=6.8 Hz, 6H) ppm; MS (ES+) 559.17
Reaction SMILES: [NH2:1][N:2]1[CH:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:3]1[CH3:9].[C-:10]#[N:11].[Na+].[CH2:13]([O:20][CH2:21][CH:22]=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][CH2:21][CH:22]([NH:1][N:2]1[CH:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:3]1[CH3:9])[C:10]#[N:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [C-]#N
Reactant: O=CCOCc1ccccc1
Reactant: CC1CCCC(C)N1N
Agent: [Na+]
Product: CC1CCCC(C)N1NC(C#N)COCc1ccccc1
Yield: 81.2 %

Procedure:
12.8 g of 1-amino-2,6-dimethylpiperidine, 4.9 g of sodium cyanide and 15.0 g of benzyloxyacetaldehyde are reacted analogously to 8a). 23.3 g of 3-benzyloxy-2-((2,6-dimethylpiperidino)amino)propionitrile are obtained, which are employed in the following step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[C:24]([O:27][CH2:28][CH3:29])[C:25]=1F)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[O:16])[CH2:10][CH2:9]1)[CH3:2].C(OC1C=C(C=C(OCC)C=1[N:41]1[CH:45]=[CH:44][CH:43]=[CH:42]1)C=O)C.C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[C:24]([O:27][CH2:28][CH3:29])[C:25]=1[N:41]1[CH:45]=[CH:44][CH:43]=[CH:42]1)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[O:16])[CH2:10][CH2:9]1)[CH3:2]
Reactant: CCOc1cc(C=O)cc(OCC)c1-n1cccc1
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cncnc3)CC2)cc(OCC)c1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)c3cncnc3)CC2)cc(OCC)c1-n1cccc1

Procedure:
In analogy to the procedure described in example 50k), pyrimidine-5-carboxylic acid piperidin-4-ylamide (example 56) was reacted with 3,5-diethoxy-4-pyrrol-1-yl-benzaldehyde (example 40b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as light yellow solid. MS: 450.2 (MH+).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][O:14][C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][CH2:20][CH:21]2[NH2:24])=[CH:17][CH:16]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH2:33])(=[O:28])=[O:27]>>[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH:33][C:2]1[C:3]2[CH:4]=[CH:5][C:6]([NH:24][CH:21]3[C:22]4[C:18](=[CH:17][CH:16]=[C:15]([O:14][CH3:13])[CH:23]=4)[CH2:19][CH2:20]3)=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1)(=[O:27])=[O:28]
Reactant: Clc1ccc2c(I)cccc2n1
Reactant: CS(=O)(=O)c1cccc(CN)c1
Reactant: COc1ccc2c(c1)C(N)CC2
Product: COc1ccc2c(c1)C(Nc1ccc3c(NCc4cccc(S(C)(=O)=O)c4)cccc3n1)CC2

Procedure:
The title compound, MS: m/e=474.1 (M+H+), was prepared in accordance with the general method of example 6 from 5-iodo-2-chloroquinoline, 6-methoxyindan-1-ylamine (CAS 103028-81-5) and 3-(methylsulfonyl)benzylamine.
Reaction SMILES: Cl.[F:2][C:3]([F:34])([F:33])[C:4]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10](/[CH:13]=[C:14]2/C(NCC(O)=O)=[N:16][C:17](=[O:19])[S:18]/2)[CH2:9][CH2:8]1.C(N(C(C)C)C(C)C)C.[CH3:44][NH:45][CH2:46][CH2:47][OH:48].F[P-](F)(F)(F)(F)F.C(C(=NO[C+:66](N(C)C)[N:67]1CC[O:70][CH2:69][CH2:68]1)C(OCC)=O)#N>CN(C=O)C.O>[F:34][C:3]([F:2])([F:33])[C:4]1[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:25][C:5]=1[CH2:6][N:7]1[CH2:8][CH2:9][CH:10](/[CH:13]=[C:14]2/[C:44]([NH:45][CH2:46][C:47]([N:67]([CH2:68][CH2:69][OH:70])[CH3:66])=[O:48])=[N:16][C:17](=[O:19])[S:18]/2)[CH2:11][CH2:12]1
Reactant: O=C(O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CNCCO
Reactant: CCOC(=O)C(C#N)=NO[C+](N(C)C)N1CCOCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(CCO)C(=O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-2-oxo-2,5-dihydro-1,3-thiazol-4-yl]glycine hydrochloride (500 mg), N-ethyl-N-(1-methylethyl)propan-2-amine (0.49 mL) and 2-(methylamino)ethanol (0.23 mL) in DMF (5 mL) was added (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (403 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (35 mg).
Reaction SMILES: C([N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([S:46]([CH:49]2[CH2:53][CH2:52][CH2:51][CH2:50]2)(=[O:48])=[O:47])[CH:41]=1)[CH2:9][C@@H:10]([C:12]1[CH:13]=[CH:14][C:15]([O:21]CC2C=CC=CC=2)=[C:16]([NH:18][CH:19]=[O:20])[CH:17]=1)[OH:11])C1C=CC=CC=1.[C:54]([OH:57])(=[O:56])[CH3:55]>CCO.[Pd].[OH-].[OH-].[Pd+2]>[C:54]([OH:57])(=[O:56])[CH3:55].[CH:49]1([S:46]([C:42]2[CH:41]=[C:40]([CH2:39][CH2:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][NH:8][CH2:9][C@@H:10]([C:12]3[CH:13]=[CH:14][C:15]([OH:21])=[C:16]([NH:18][CH:19]=[O:20])[CH:17]=3)[OH:11])[CH:45]=[CH:44][CH:43]=2)(=[O:48])=[O:47])[CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: O=CNc1cc([C@@H](O)CN(CCCCCCOCCCCc2cccc(S(=O)(=O)C3CCCC3)c2)Cc2ccccc2)ccc1OCc1ccccc1
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=CNc1cc([C@@H](O)CNCCCCCCOCCCCc2cccc(S(=O)(=O)C3CCCC3)c2)ccc1O

Procedure:
5-{(1R)-2-[Benzyl(6-{4-[3-(cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-2-(benzyloxy)phenylformamide (17 mg) was dissolved in EtOH (10 ml) and glacial acetic acid (1 ml) added. The solution was hydrogenated using 10% palladium on carbon (50% water by weight, 7 mg) and 20% palladium hydroxide on carbon (7 mg) for 20 h. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was purified on an isolute aminopropyl cartridge (2 g), eluting with MeOH-DCM mixtures. Evaporation of the appropriate fractions with AcOH gave the title compound, (5 mg) LCMS RT=2.53 min, ES+ve 561 (MH)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH:17][CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].C1C=CC=CC=1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[O:17][CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])=[CH:4][CH:3]=1
Reactant: CC(=O)NCCO
Reactant: Fc1ccc(C(Cl)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)NCCOC(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
A mixture of 25.4 g (0.1 mole) of bis(p-fluorophenyl)methyl chloride, 10.3 g (0.1 mole) of N-(2-hydroxyethyl)acetamide (prepared according to F. J. McQuillin et. al., J. Chem. Soc. 1955, 2966), 14 g of potassium carbonate and 100 ml of benzene is refluxed for 5 hours. After cooling, the reaction mixture is poured into water. The aqueous layer is extracted with dichloromethane and the combined organic layers are dried over potassium carbonate and concentrated by evaporation of solvent. The residue is crystallised from toluene. N-{2-[B is(p-fluorophenyl)methoxy]ethyl}-acetamide, m.p. 112°-113.5° C., is obtained.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]3[C:33]([CH3:38])=[N:34][N:35]([CH3:37])[CH:36]=3)[N:26]=2)=[CH:21][C:20]1=[O:39])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C@H:10]([N:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]4[C:33]([CH3:38])=[N:34][N:35]([CH3:37])[CH:36]=4)[N:26]=3)=[CH:21][C:20]2=[O:39])[CH2:9][OH:8])=[CH:12][C:13]=1[F:18]
Reactant: Cc1nn(C)cc1Nc1nccc(-c2ccn([C@H](CO[Si](C)(C)C(C)(C)C)c3ccc(Cl)c(F)c3)c(=O)c2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(C)cc1Nc1nccc(-c2ccn([C@H](CO)c3ccc(Cl)c(F)c3)c(=O)c2)n1
Reaction time: 1 h
Yield: 73.3 %

Procedure:
(S)-1-(2-(tert-Butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.070 g, 0.12 mmol) was placed in THF (3 mL). TBAF (0.14 mL, 0.14 mmol) was added, and the mixture was stirred for 1 hour, then poured into water, and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by column chromatography (500:20-500:30 DCM/MeOH) to give the product (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.040 g, 71% yield). m/z (APCI-pos) M+1=455.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]1[CH2:9][CH2:8][CH:7]([CH3:22])[CH2:6][C:5]2=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]3[C:5]([C:4]=2[CH:3]=1)=[CH:6][C:7]([CH3:22])=[CH:8][CH:9]=3
Reactant: CC1CCc2c(c3cc(Br)ccc3n2C(=O)OC(C)(C)C)C1
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)c1cc(Br)ccc1n2C(=O)OC(C)(C)C
Yield: 83.1 %

Procedure:
To a mixture of 6-bromo-9-tert-butoxycarbonyl-3-methyl-1,2,3,4-tetrahydrocarbazole obtained in Example 24 (2.0 g, 5.49 mmol), 2,3-dichloro-4,5-dicyano-1,4-benzoquinone (2.62 g, 11.5 mmol) and activated 3 Å molecular sieves was added anhydrous benzene (17 mL) under a nitrogen atmosphere, and the mixture was refluxed for 20 h. The cooled reaction mixture was filtered and the filtrate evaporated. The crude product was chromatographed (PS with gradient elution up to PS:DCM 3:1) to afford 3-bromo-9-tert-butoxycarbonyl-6-methylcarbazole (1.64 g, 4.56 mmol, 83%) as a colourless solid. By-products were also obtained—6-bromo-9-tert-butoxycarbonyl-4-ethoxy-3-methylcarbazole (12 mg, 0.030 mmol, 0.5%) was obtained as a colourless oil, and 6-bromo-9-tert-butoxycarbonyl-1,2-dihydro-3-methylcarbazol-4-(3H)-one (52 mg, 0.144 mmol, 2.5%) was obtained as a pale yellow solid.
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[CH2:15][Mg]Cl>>[Cl:11][C:12]1[CH:13]=[C:14]([CH2:15][C:5](=[O:9])[CH2:6][CH2:7][CH:8]2[NH:4][C:3](=[O:10])[CH2:2][CH2:1]2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C1CCC2CCC(=O)N12
Reactant: Cl[Mg]Cc1cccc(Cl)c1
Product: O=C(CCC1CCC(=O)N1)Cc1cccc(Cl)c1
Yield: 51.5 %

Procedure:
Analogous to the procedure described for Compound 1A, Step A, tetrahydro-pyrrolizine-3,5-dione (2 g, 14 mmol) was reacted with 3-chlorobenzylmagnesium chloride (0.25M in Et2O, 62 mL, 15.5 mmol) over 2 h. Purification by medium pressure chromatography eluting with a solvent gradient (2:1 hexanes:EtOAc to EtOAc to 5% MeOH in CH2Cl2) provided 5-[4-(3-chloro-phenyl)-3-oxo-butyl]-pyrrolidin-2-one (1.9142 g). 1H NMR (CDCl3) δ 7.27 (m, 2H), 7.19 (m, 1H), 7.08 (m, 1H), 6.27 (br, 1H), 3.68 (s, 2H), 3.60 (m, 1H), 2.52 (t, 2H), 2.29 (m, 2H), 2.21 (m, 1H), 1.88-1.60 (m, 3H); MS 266.2 (M+1), 264.2 (M−1).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:6][C:5]=1[OH:18])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([N:12]2[CH2:13][CH2:14][N:15]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:16][CH2:17]2)=[CH:6][C:5]=1[OH:18])([CH3:3])[CH3:2]
Reactant: COc1cc(C(C)C)c(O)cc1N1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(C)C)c(O)cc1N1CCN(S(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.2 %

Procedure:
To a stirring solution of 2-Isopropyl-4-methoxy-5-piperazin-1-yl-phenol (0.47 g, 1.88 mmol) in dichloromethane at 0° C. under nitrogen was added triethylamine (0.26 mL, 1.89 mmol), followed by methanesulfonyl chloride (0.15 mL, 1.89 mmol). The reaction mixture was stirred at 0° C. for five minutes, and then allowed to warm to room temperature. The reaction mixture was partitioned between dichloromethane and water, and the organic layer was separated, washed with water, dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified via flash chromatography (hexanes:EtOAc 3:2) to afford 0.1 g (16%) of 2-Isopropyl-5-(4-methanesulfonyl-piperazin-1-yl)-4-methoxy-phenol as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[C:5]([NH:7][C:8]1[N:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=1)=[O:6].[H][H]>CCO.CO.[Pt]>[NH2:14][C:11]1[CH:12]=[N:13][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:17]=[CH:18][C:19]([F:20])=[C:2]([Cl:1])[CH:3]=2)=[N:9][CH:10]=1
Reactant: O=C(Nc1ncc([N+](=O)[O-])cn1)c1ccc(F)c(Cl)c1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Solvent: CO
Product: Nc1cnc(NC(=O)c2ccc(F)c(Cl)c2)nc1
Yield: 80 %

Procedure:
To 1C (1.16 g, 3.92 mmol) in a mixture of 60 mL EtOH and 10 mL MeOH was added 10% Pt/C (300 mg). The reaction was stirred under 1 atmosphere of hydrogen for 1.5 h, filtered, and concentrated to give 850 mg (80% yield) ID. RP HPLC ret. t.: 1.58 min. and (M+H)+: 267.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17]CC2C=CC(OC)=CC=2)=[O:16])[CH2:4]1)=O.[N:33]1[N:34]=[N:35][N:36]2[C:41]([CH2:42][CH2:43][CH2:44]N3CCCCC3)=[CH:40][CH:39]=[CH:38][C:37]=12.C(O[BH-](O[C:61](=O)[CH3:62])OC(=O)C)(=O)C.[Na+]>ClCCCl>[N:33]1[N:34]=[N:35][N:36]2[C:41]([CH2:42][CH2:43][CH2:44][CH:62]3[CH2:61][CH2:6][N:5]([CH2:1][C@@H:3]4[C@@H:7]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[CH2:6][N:5]([C@H:14]([CH:27]5[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]5)[C:15]([OH:17])=[O:16])[CH2:4]4)[CH2:4][CH2:3]3)=[CH:40][CH:39]=[CH:38][C:37]=12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: c1cc(CCCN2CCCCC2)n2nnnc2c1
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(CCCc3cccc4nnnn34)CC2)[C@@H](c2ccccc2)C1
Reaction time: 8 h
Yield: 27 %

Procedure:
A solution of 2-(R)-(3-(R)formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, (4-methoxy)benzyl ester (33 mg, 0.075 mmol, from EXAMPLE 33, Step E), 3-(tetrazolo[4,5-a]pyridin-5-yl)propylpiperidine.HCl (27 mg, 0.097 mmol from EXAMPLE 34, Step B) sodium triacetoxyborohydride, 32 mg (0.15 mmol) and TEA (0.014 mL, 0.097 mmol), in 1.0 mL 1,2-dichloroethane was stirred overnight. The solvent was removed and the product was purified by preprative HPLC (column: YMC Combiprep ODS-A 20×50 mm, gradient: 5% acetonitrile/H2O w/ 0.1% TFA for 1 min then ramp to 100% acetonitrile/H2O w/ 0.1% TFA over 6 min, flow: 20 mL/min). The material was stirred in 3 mL formic acid for 8 h. After removal of solvent the purification was accomplished by preprative HPLC (column: YMC Combiprep ODS-A 20×50 mm, gradient: 5% acetonitrile/H2O w/ 0.1% TFA for 1 min then ramp to 100% acetonitrile/H2O w/0.1% TFA over 6 min, flow: 20 mL/min) to give 11 mg (27%) of the title compound: 1H NMR (500 MHz) δ 1.02-1.98 (22H), 2.05-2.1 (m, 1H), 2.1-2.2 (m, 1H), 2.3-2.4 (m, 1H), 2.6-3.4 (8H), 3.8-3.9 (t, 2H), 4.51-4.55 (m, 1H), 7.2-7.33 (m, 5H), 7.48-7.49 (d, 1H, J=9 Hz), 7.94-7.96 (d, 1H, J=9 Hz): ESI-MS, M/z; (M+H)=545.5 (obs), 545.3 (calc.).
Reaction SMILES: [CH2:1]([CH:3]1[NH:7][C:6](=O)[CH2:5][CH:4]1[CH3:9])C.F[B-](F)(F)F.[CH3:15][O+:16]([CH3:18])C>C(Cl)Cl>[NH:7]([CH:3]1[CH:1]=[C:15]([O:16][CH3:18])[CH2:5][CH:4]1[CH3:9])[CH3:6]
Reactant: C[O+](C)C
Reactant: CCC1NC(=O)CC1C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CNC1C=C(OC)CC1C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a solution of 0.254 g (2 mmol) of 5-ethyl-4-methyl-2-pyrrolidone (from step B) in 3 mL of CH2Cl2 was added 0.355 g (2.4 mmol) of trimethyloxonium tetrafluoroborate under a N2 atmosphere. After stirring overnight the reaction mixture was quenched with saturated K2CO3 solution and diluted with Et2O. The solution was filtered and the filtrate was concentrated. The residue was purified by flash chromatography using Et2O-hexane to isolate 0.224 g (79%) of the title compound.
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1([CH3:24])[CH2:10][C:9]2[C:11]([CH3:23])=[C:12]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:13]([CH3:16])=[C:14]([CH3:15])[C:8]=2[O:7]1.Br[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C>[CH3:5][C:6]1([CH3:24])[CH2:10][C:9]2[C:11]([CH3:23])=[C:12]([N:17]3[CH2:18][CH2:19][N:20]([C:26]4[N:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:21][CH2:22]3)[C:13]([CH3:16])=[C:14]([CH3:15])[C:8]=2[O:7]1
Reactant: Brc1ncccn1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1c(C)c(N2CCN(c3ncccn3)CC2)c(C)c2c1OC(C)(C)C2
Temperature: 120 °C
Reaction time: 2 h
Yield: 42.6 %

Procedure:
To a solution of DMSO (12 mL) containing 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (1.1 g, 4.00 mmol) synthesized in Reference Example 61, 2-bromopyrimidine (954 mg, 6.0 mmol) and diisopropylethylamine (2.09 mL) were added, and the mixture was stirred at 120° C. for 2 hours. The reaction solution was diluted with ethyl acetate, and washed with water and saturated saline. The organic layer was dried using magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 9:1). The obtained solid was recrystallized from ethanol-water to obtain 600 mg of the title compound (yield 42%).
Reaction SMILES: C([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(OCC1C=CC=CC=1)=O.Br[CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30].[C:31](=[O:34])([O-])[O-:32].[K+].[K+].[I-].[Na+]>CC(C)=O.CN(C=O)C>[O:22]([C:19]1[CH:18]=[CH:17][C:16]([CH:15]([C:31]([O:32][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:34])[CH2:14][CH2:13][CH2:12][NH2:11])=[CH:21][CH:20]=1)[CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30]
Reactant: O=C([O-])[O-]
Reactant: COCCOCCBr
Reactant: O=C(NCCCCc1ccc(O)cc1)OCc1ccccc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: COCCOCCOc1ccc(C(CCCN)C(=O)OCc2ccccc2)cc1
Yield: 166 %

Procedure:
4-(4-Hydroxyphenyl)-N-benzyloxycarbonylbutylamine (29) (1.0 g, 3.3 mmol), 1-bromo-2-(2-methoxyethoxy)ethane (0.67 g, 3.7 mmol), and potassium carbonate (0.60 g, 4.3 mmol) were combined in acetone (20 mL), and stirred at reflux overnight. The reaction was allowed to cool, and then filtered and evaporated. The residue was re-subjected in methyl ethyl ketone (10 mL), 1-bromo-2-(2-methoxyethoxy)ethane (0.91 g, 5.0 mmol), potassium carbonate (0.74 g, 5.3 mmol), and sodium iodide (0.5 g, 3.3 mmol) with stirring at reflux for 2.5 h. The reaction was allowed to cool, and was filtered and evaporated. The residue was re-subjected in DMF (10 mL), with 1-bromo-2-(2-methoxyethoxy)ethane (1.8 g, 9.8 mmol), potassium carbonate (1.60 g, 11.6 mmol), and sodium iodide (0.4 g, 2.7 mmol), overnight with stirring at 70° C. The reaction was evaporated to remove the solvent and then was dissolved in ethyl acetate (70 mL). The organic extract was washed with water (3×20 mL), dried over potassium carbonate and filtered. Evaporation afforded 1.1 g of an oil which was purified by column chromatography (silica gel, 2:1 hexanes/ethyl acetate) to afford 800 mg (70%) of pure product 106. 1H NMR (300 MHz, CDCl3) δ 1.42-1.68 (m, 4H), 2.55 (t, J=7.5 Hz, 2H), 3.20 (q, J=6.2 Hz, 2H), 3.39 (s, 3H), 3.55-3.60 (m, 2H), 3.69-3.74 (m, 2H), 3.82-3.87 (m, 2H), 4.11 (t, 5.3 Hz, 2H), 4.71 (br s, 1H), 5.09 (s, 2H), 6.82 (d, J=8.5 Hz, 2H), 7.05 (d, J=8.5 Hz, 2H), 7.34 (s, 5H). CI MS m/z=402 [C23H31NO5+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:32]2[CH:33]=[CH:34][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=2)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]3)=[CH:20][CH:19]=1)([CH3:23])([CH3:22])[CH3:24]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CC(C)(C)c1ccc(-c2ccc3c(c2)cc(C(=O)O)n3-c2ccc(S(C)(=O)=O)cc2)cc1

Procedure:
The title compound was prepared in accordance with Example 8(c) using 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester and 4-(methylsulfonyl)phenylboronic acid, followed by hydrolysis in accordance with the procedure described in Example 1(c).
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[C:6]([CH3:16])=[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)#[N:2].C(O)(C)(C)C.C(Cl)(Cl)(Cl)[Cl:23].ClOC(C)(C)C>C1(C)C=CC=CC=1>[Cl:23][C:8]1[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([CH3:16])[C:5]([O:4][CH2:3][C:1]#[N:2])=[CH:10][CH:9]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1c(NS(C)(=O)=O)cccc1OCC#N
Agent: CC(C)(C)OCl
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: Cc1c(OCC#N)ccc(Cl)c1NS(C)(=O)=O
Temperature: -4 °C
Yield: 49 %

Procedure:
N-(3-cyanomethoxy-2-methylphenyl)-methanesulfonamide (1.87 g, 7.78 mmol) was suspended in a 1:1 mixture of t-butanol and carbon tetrachloride (80 ml) and cooled in an ice bath. t-Butyl hypochlorite (TCl, 0.85 g, 7.78 mmol) was added dropwise. The mixture was maintained at -4° C. overnight then warmed to room temperature. The volatiles were removed at reduced pressure. N-(6-chloro-3-cyanomethoxy-2-methylphenyl)-methanesulfonamide (1.05 g, 49% yield) was obtained by recrystallization from toluene.