Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[O:15]=[S:12]1(=[O:16])[CH2:13][CH2:14][CH:9]([NH2:8])[CH2:10][CH2:11]1
Reactant: [H][H]
Reactant: O=S1(=O)CCC(NCc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: NC1CCS(=O)(=O)CC1

Procedure:
N-Benzyl-1,1-dioxotetrahydro-2H-thiopyran-4-amine (2.00 g) was added to ethanol (40 mL) in a pressure bottle. Palladium hydroxide on carbon (0.587 g) was added and the solution was stirred under 30 psi of hydrogen at room temperature for 2 hours. The mixture was filtered though a nylon membrane and the solvent was removed under vacuum.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([C:24](=[O:35])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=4)[CH:16]([CH2:36][CH2:37][CH2:38][CH2:39][C:40](O)=[O:41])[CH2:15]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH2:44]([O:46][C:47](=[O:51])[CH2:48][CH2:49][NH2:50])[CH3:45].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH:1]1[C:13]2[N:12]([CH:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([C:24](=[O:35])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=4)[CH:16]([CH2:36][CH2:37][CH2:38][CH2:39][C:40]([NH:50][CH2:49][CH2:48][C:47]([O:46][CH2:44][CH3:45])=[O:51])=[O:41])[CH2:15]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C(=O)N2c3ccccc3C(n3c4ccccc4c4ccccc43)CC2CCCCC(=O)O)cc1OC
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)CCCCC1CC(n2c3ccccc3c3ccccc32)c2ccccc2N1C(=O)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
5-[4-(9H-9-Carbazolyl)-1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-2-quinolinyl]-pentanoic acid (0.50 g, 0.89 mmol) prepared in Example 128 was mixed with β-alanine ethyl ester hydrochloride (0.15 g, 1 mmol), N,N-dimethylformamide (10 ml), 1-hydroxybenzotriazole (0.14 g, 1 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) (0.19 g, 1 mmol), followed by stirring overnight at room temperature. After distilling off the solvent, the residue was partitioned between ethyl acetate and saturated brine, washed and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was applied to silica gel column chromatography (developing solvent: ethyl acetate/hexane=1/7) to give the titled compound (0.48 g, yield: 81%) as a white powder (cis:trans=3:1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].[CH3:10][NH2:11].C([O-])(O)=O.[Na+]>N1C=CC=CC=1.C1COCC1>[CH3:10][NH:11][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6]
Reactant: CN
Reactant: N#Cc1ccnc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CNc1cc(C#N)ccn1
Temperature: 120 °C

Procedure:
To a solution of 2-chloroisonicotinonitrile (22.0 g, 159 mmole) in pyridine (500 mL) was added methylamine in THF (2N, 160 mL), and NaHCO3 (54 g). The mixture was heated to 120° C. in a sealed vessel for 40 h. After cooled to RT, the mixture was filtered and the filter cake was washed with CH2Cl2. The combined filtrated was concentrated in vacuo to give a yellow solid (21 g) as the desired compound.
Reaction SMILES: [O-:1][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].[C:9]1([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O+]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:33]([C:45]1[CH:51]=[CH:50][C:48]([NH2:49])=[CH:47][CH:46]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>C(O)C>[O-:4][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:3])=[O:1].[CH2:33]([C:45]1[CH:46]=[CH:47][C:48]([N+:49]2[C:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:20][C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:18][C:17]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:50][CH:51]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: c1ccc(-c2cc(-c3ccccc3)[o+]c(-c3ccccc3)c2)cc1
Reactant: CCCCCCCCCCCCc1ccc(N)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCO
Product: CCCCCCCCCCCCc1ccc(-[n+]2c(-c3ccccc3)cc(-c3ccccc3)cc2-c2ccccc2)cc1

Procedure:
A 2.3-g portion (0.005 mole) of 2,4,6-triphenylpyrylium triflate is placed in a 500-ml round-bottom flask. To this, 200 ml of ethanol is added and then 1.3 g (0.005 mole) of p-dodecylaniline is added. The mixture is refluxed for about 20 hours. The ethanol is removed by evaporation to give a yellow waxy substance. This material is washed with ether which causes some yellow crystals to precipitate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][C:17]1[CH:18]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([O:33][C:34]([NH:36][C:37]1[CH:38]=[N:39][CH:40]=[C:41]([CH:45]=1)[C:42](O)=[O:43])=[O:35])([CH3:32])([CH3:31])[CH3:30].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N1C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[C:29]([O:33][C:34](=[O:35])[NH:36][C:37]1[CH:38]=[N:39][CH:40]=[C:41]([C:42]([N:26]2[CH2:25][CH2:24][CH:23]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([CH2:16][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:18]=3)[CH2:28][CH2:27]2)=[O:43])[CH:45]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)Nc1cncc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(C2CCNCC2)c1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cncc(C(=O)N2CCC(c3cccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c3)CC2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a 0° C. solution of 4-{3-[N,N-bis-(tert-butoxycarbonyl)aminomethyl]-phenyl}-piperidine (0.1545 g, 0.3956 mmol, EXAMPLE 1B), 5-tert-butoxycarbonylamino-nicotinic acid (0.0966 g, 0.4055 mmol), 1-hydroxy-7-azabenzotriazole (0.0290 g, 0.2131 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.1500 g, 0.7824 mmol) in dimethylformamide (5.0 mL) was added pyridine (0.065 mL, 0.8037 mmol). The reaction mixture was stirred 30 minutes at 0° C., then allowed to warm to room temperature under inert atmosphere. After 16 hours at ambient temperature the reaction solution was diluted with ethyl acetate (30 mL), washed with saturated ammonium chloride (2×15 mL), saturated sodium bicarbonate (15 mL), and brine (15 mL). The organic phase was dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate and methylene chloride (1:1, v/v) to give {5-[1-(4-{3-[N,N-bis-(tert-butoxycarbonyl)aminomethyl]-phenyl}-piperidin-1-yl)methanoyl]-pyridin-3-yl}carbamic acid tert-butyl ester as a colorless oil (0.1812 g): TLC, 50:50-methylene chloride:ethyl acetate, Rf=0.20. 1H NMR (300 MHz, CDCl3) δ 8.67 (d, J=2.6 Hz, 1H), 8.34 (d, J=1.4 Hz, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.21-7.35 (m, 1H), 7.08-7.18 (m, 3H), 4.81-4.93 (m, 1H), 4.78 (s, 2H), 3.81-3.93 (br m, 1H), 3.11-3.28 (br m, 1H), 2.70-2.96 (m, 2H), 1.51 (s, 9H), 1.45 (s, 18H), 1.40-2.02 (m partially obscured, 4H); 13C NMR (75 MHz, CDCl3) δ 167.5, 152.6, 152.5, 144.8, 141.3, 141.0, 138.9, 135.7, 131.8, 128.5, 125.6, 125.3, 125.2, 124.1, 82.4, 81.0, 77.2, 49.3, 42.5, 28.1, 27.8; MS (CI) m/z 611 (M+H).
Reaction SMILES: [CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH:43]2[CH2:45][CH:40]1[CH2:41][NH:42]2)=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH:43]2[CH2:45][CH:40]1[CH2:41][N:42]2[C:22]([C:21]1[CH:20]=[N:19][C:18]([NH:17][C:14]2[N:15]=[CH:16][C:11]3[CH:10]=[C:9]([C:27](=[O:31])[N:28]([CH3:29])[CH3:30])[N:8]([CH:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[C:12]=3[N:13]=2)=[CH:26][CH:25]=1)=[O:24])=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCCCC1
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CC4CN5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCCCC1
Yield: 72.6 %

Procedure:
Following general amide formation method 1, 6-(7-Cycloheptyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (52.5 mg, 0.124 mmol, 1.0 eq) was combined with 2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (32.0 mg, 0.162 mmol, 1.5 eq) which gave 5-[6-(7-Cycloheptyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (59 mg, 0.09 mmol, 76% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 9.12 (br s, 1H) 8.85 (s, 1H) 8.73 (br s, 1H) 8.61 (br s, 1H) 7.98 (br s, 1H) 6.48 (s, 1H) 4.47-4.65 (m, 2H) 3.72 (br s, 1H) 3.52-3.69 (m, 2H) 3.46 (t, J=8.59 Hz, 1H) 3.18 (s, 6H) 2.58-2.74 (m, 2H) 1.99-2.09 (m, 2H) 1.83-1.99 (m, 5H) 1.65-1.83 (m, 4H) 1.55-1.65 (m, 2H) 1.37-1.55 (m, 9H)
Reaction SMILES: C(OC([N:8]1[CH:14]([C:15]([F:18])([F:17])[F:16])[CH2:13][CH2:12][N:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([N:27]2[CH2:41][C:30]3=[C:31]4[N:36]([N:37]=[C:29]3[CH2:28]2)[C:35]([CH3:38])=[C:34]([Cl:39])[C:33]([CH3:40])=[N:32]4)=[O:26])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>>[Cl:39][C:34]1[C:33]([CH3:40])=[N:32][C:31]2[N:36]([N:37]=[C:29]3[CH2:28][N:27]([C:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:11]4[CH2:12][CH2:13][CH:14]([C:15]([F:17])([F:18])[F:16])[NH:8][CH2:9][CH2:10]4)=[O:26])[CH2:41][C:30]3=2)[C:35]=1[CH3:38]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1N1CCC(C(F)(F)F)N(C(=O)OC(C)(C)C)CC1)C3
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1N1CCNC(C(F)(F)F)CC1)C3
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.9 %

Procedure:
A suspension of 4-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-phenyl]-7-trifluoromethyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester (90 mg; 0.15 mmol; 1 eq.) in a 4M solution of HCl in 1,4-dioxane (0.38 mL; 1.52 mmol; 10 eq.) was stirred at room temperature for 3 hours. A 4M solution of HCl in 1,4-dioxane (0.38 mL; 1.52 mmol; 10 eq.) was added and the reaction mixture was stirred at room temperature for a 45 minutes. After concentration in vacuo, purification by mass directed preparative HPLC afforded the title compound (14 mg, 17%) as a white solid. 1H NMR (DMSO-d6) 10.12 (br s, 2H), 7.46-7.35 (m, 1H), 7.35-7.26 (m, 1H), 7.18-7.10 (m, 1H), 7.04 (t, J=7.4 Hz, 1H), 4.85 (d, J=8.3 Hz, 2H), 4.67-4.28 (m, 3H), 4.22-3.74 (m, 4H), 3.62-3.45 (m, 2H), 2.85 (s, 1.5H), 2.81 (s, 1.5H), 2.62 (s, 1.5H), 2.56 (s, 1.5H), 2.34-2.19 (m, 1H), 2.17-1.98 (m, 1H). HPLC (max plot) 94.6%, Rt 2.94 min. UPLC/MS: (MS+) 493.2 ([M+H]+).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]([C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]([C:22]2[CH:23]=[N:24][C:25]([NH:28][NH2:29])=[CH:26][CH:27]=2)[C:18]([F:21])([F:20])[F:19])[CH2:13]1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])N.[CH3:34][O:35][C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:45]=1[N:44]=[C:43]([CH:46]=O)[CH:42]=[CH:41]2>>[F:1][CH2:2][CH2:3][N:4]([C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]([C:22]2[CH:27]=[CH:26][C:25]3[N:24]([C:46]([C:43]4[CH:42]=[CH:41][C:40]5[C:45](=[C:36]([O:35][CH3:34])[CH:37]=[CH:38][CH:39]=5)[N:44]=4)=[N:29][N:28]=3)[CH:23]=2)[C:18]([F:21])([F:19])[F:20])[CH2:13]1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: COc1cccc2ccc(C=O)nc12
Reactant: CC(C)(C)OC(=O)N(CCF)[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Agent: NC(=O)[O-]
Product: COc1cccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](N(CCF)C(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12

Procedure:
Prepared as described in Example 9B, Step F, using tert-butyl 2-fluoroethyl((S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-yl)carbamate (0.10 g, 0.237 mmol) in place of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-yl)carbamate and 8-methoxyquinoline-2-carbaldehyde (0.044 g, 0.237 mmol). LCMS APCI (+) m/z 589 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9](OC3CCOCC3)[C:10]=2[N:11]=1.[CH:19]1([SH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([S:25][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:10]=2[N:11]=1
Reactant: SC1CCCCC1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Clc1ccc2ncnc(SC3CCCCC3)c2n1
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.1 g, 0.500 mmol) in ACN (2.500 ml) were added cyclohexanethiol (0.058 g, 0.500 mmol) and K2CO3 (0.069 g, 0.500 mmol) at room temperature. After stiffing overnight at room temperature, the reaction mixture was diluted with water and extracted with EtOAc (2×50 mL). The combined organic layers were washed with 1N aq. NaOH and then washed with 1N aq. HCl. The organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=5:1) to give 6-chloro-4-(cyclo hexylthio)pyrido[3,2-d]pyrimidine (0.129 g, 92%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.36-1.42 (1H, m), 1.48-1.69 (5H, m), 1.80-1.86 (2H, m), 2.14-2.20 (2H, m), 4.10-4.16 (1H, m), 7.73 (1H, d, J=8.8 Hz), 8.19 (1H, d, J=8.8 Hz), 8.98 (1H, s).
Reaction SMILES: S[C:2]1[NH:3][C:4](=[O:13])[C:5]2[CH2:10][CH2:9][CH:8]([O:11][CH3:12])[C:6]=2[N:7]=1.N>[Ni].O>[CH3:12][O:11][CH:8]1[C:6]2[N:7]=[CH:2][NH:3][C:4](=[O:13])[C:5]=2[CH2:10][CH2:9]1
Reactant: COC1CCc2c1nc(S)[nH]c2=O
Agent: [Ni]
Agent: N
Solvent: O
Product: COC1CCc2c1nc[nH]c2=O
Yield: 83.1 %

Procedure:
1.58 g of 6,7-dihydro-2-mercapto-7-methoxy-3H,5H-cyclopenta[d]pyrimidin-4-one [prepared as described in step (c) above] and 4 g of Raney nickel were suspended in 15 ml of distilled water, and then 3 ml of concentrated aqueous ammonia were added to the resulting suspension. The mixture was then heated under reflux for 3 hours, after which time the resulting insoluble materials were filtered off from the hot reaction mixture. The filtrate was then evaporated under reduced pressure, to give 1.1 g of the title compound as colorless crystals.
Reaction SMILES: C([N:8]([C@@H](C1C=CC=CC=1)C)[C@@H:9]1[CH2:13][CH2:12][CH2:11][C@:10]1([CH3:18])[C:14]([O:16][CH3:17])=[O:15])C1C=CC=CC=1>[Pd].C(O)=O.CO>[NH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@:10]1([CH3:18])[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)[C@@]1(C)CCC[C@H]1N(Cc1ccccc1)[C@H](C)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: COC(=O)[C@@]1(C)CCC[C@H]1N
Yield: 93.2 %

Procedure:
According to the procedure of Example 53, Step 2, using methyl (1S,2R)-2-{benzyl[(1R)-1-phenylethyl]amino}-1-methylcyclopentanecarboxylate (1.025 g, 2.92 mmol), 4.4% HCO2H/MeOH (30 mL) and 10% Pd/C (1.058 g), methyl (1S,2R)-2-amino -1-methylcyclopentanecarboxylate (527 mg, 2.72 mmol, 93%) was obtained as a colorless solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.29 (s, 3H) 1.56-1.62 (m, 1H) 1.64-1.76 (m, 3H) 2.07-2.13 (m, 1H) 2.15-2.22 (m, 1H) 3.24-3.31 (m, 1H) 3.64-3.71 (m, 3H) 8.18 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[CH:22]1([CH2:28][C:29](O)=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(OCC)C.C(Cl)Cl.CO.CN(C)C=O>[CH:22]1([CH2:28][C:29]([NH:1][C:2]2[CH:3]=[C:4]3[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]4=[C:7]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:8][C:9]([CH:10]=2)=[C:5]34)=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)CC1CCCCC1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CC1CCCCC1)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 36.1 %

Procedure:
Preparation of example 28 from the title compound of Example 7 (0.025 g, 0.09 mmol), Cyclohexyl-acetic acid (0.015g, 0.11 mmol), triethylamine (0.05 mL, 0.4 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (38 mg, 0.1 mmol) and N,N-dimethylformamide (0.05 M, 1.8 mL) was carried out analogously to Example 11. Silica gel chromatography (95:5 CH2Cl2/methanol) also in an analogous manner followed by diethyl ether trituration afforded the title compound (13 mg) as a yellow powder in 36% yield.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:10][S-:11].[Na+]>CN(C)C=O>[CH3:10][S:11][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CCCBr
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCSC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 4-bromobutyrate (0.269) in N,N-dimethylformamide (3 ml) was treated with sodium thiomethoxide (0.103 g), and the mixture stirred at room temperature overnight. The mixture was partitioned between water (10ml) and dichloromethane (10 ml), and the organic layer was washed with 1:1 saturated aqueous sodium chloride and water (10 ml). The organic layers were evaporated in vacuo to give the title compound as a clear oil (0.135 g).
Reaction SMILES: C([O:3][C:4](=[O:42])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[C:30]([Cl:31])=[CH:29][C:28]([C:32](=[O:34])[CH3:33])=[C:27]([OH:35])[C:26]=2[CH2:36][CH2:37][CH3:38])[C:10]=1[CH2:39][CH2:40][CH3:41])C.[OH-].[Na+]>CO>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:42])=[O:3])=[C:10]([CH2:39][CH2:40][CH3:41])[C:11]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[C:30]([Cl:31])=[CH:29][C:28]([C:32](=[O:34])[CH3:33])=[C:27]([OH:35])[C:26]=1[CH2:36][CH2:37][CH3:38])(=[O:17])[CH3:16]
Reactant: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCCCCCOc1c(C(C)=O)ccc(OCCCC(=O)OCC)c1CCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCCCCCOc1c(C(C)=O)ccc(OCCCC(=O)O)c1CCC
Yield: 92.1 %

Procedure:
A solution of 0.978 g (0.0016 mole) of 4-[4-acetyl-3-[5-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]butanoic acid ethyl ester in 50 ml of methanol and 8.1 ml (0.0081 mole) of 1.0N sodium hydroxide was stirred at reflux for 2 hours. Most of the solvent was removed in vacuo and the pH of the residue was adjusted to 2.0. The product was extracted with methylene chloride and the dried (magnesium sulfate) extract was concentrated in vacuo to give 0.850 g (91% yield) of 4-[4-acetyl-3-[5-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]butanoic acid as an oil.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][CH2:7][NH2:8])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.C[C:19]1[C:27]([S:28](Cl)(=[O:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=[O:22]>C1COCC1>[CH:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][S:28]([C:27]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22])(=[O:30])=[O:29])([CH3:3])[CH3:2]
Reactant: Cc1c(C(=O)O)cccc1S(=O)(=O)Cl
Reactant: CC(C)OCCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)OCCCNS(=O)(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C

Procedure:
3-Isopropoxypropylamine (1.1 eq.) is dissolved in THF with stirring at room temperature. N,N-diisopropylethylamine (1 eq.) is added followed by methyl 3-(chlorosulfonyl)benzoic acid (1 eq.). The reaction mixture is stirred at room temperature for 2 hours before the solvent is evaporated in vacuo to yield the crude titled product.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[C:17]([CH3:18])=[C:16]([C:19]2[NH:23][N:22]=[N:21][N:20]=2)[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[C:14]([CH:31]([NH2:33])[CH3:32])[CH:13]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:11][C:12]1[C:17]([CH3:18])=[C:16]([C:19]2[NH:23][N:22]=[N:21][N:20]=2)[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[C:14]([CH:31]([NH:33][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:32])[CH:13]=1
Reactant: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1-c1nnn[nH]1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c(-c2cccc(F)c2)c1-c1nnn[nH]1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (30 mg, 0.15 mmol), 1-[4-chloro-3′-fluoro-5-methyl-6-(1H-tetrazol-5-yl)biphenyl-2-yl]ethanamine (45 mg, 0.14 mmol), and N,N-diisopropylethylamine (0.047 mL, 0.27 mmol) in isopropyl alcohol (0.5 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C21H18ClFN9 (M+H)+: m/z=450.1. found: 450.1.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH:5]1[C:9]2=[C:10]([NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[N:11]=[CH:12][CH:13]=[C:8]2[CH:7]=[CH:6]1.[Br:20][C:21]1[CH:29]=[C:28]([Cl:30])[C:24]([C:25](Cl)=[O:26])=[C:23]([Cl:31])[CH:22]=1.CO>ClCCl>[Br:20][C:21]1[CH:22]=[C:23]([Cl:31])[C:24]([C:25]([C:7]2[C:8]3[C:9](=[C:10]([NH:14][C:15]([CH:17]4[CH2:18][CH2:19]4)=[O:16])[N:11]=[CH:12][CH:13]=3)[NH:5][CH:6]=2)=[O:26])=[C:28]([Cl:30])[CH:29]=1
Reactant: O=C(Nc1nccc2cc[nH]c12)C1CC1
Reactant: O=C(Cl)c1c(Cl)cc(Br)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: O=C(c1c(Cl)cc(Br)cc1Cl)c1c[nH]c2c(NC(=O)C3CC3)nccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
Aluminium chloride (4.3 g, 32.2 mmol) was added to a solution of N-(1H-pyrrolo[2,3-c]pyridin-7-yl)cyclopropanecarboxamide (0.65 g, 3.2 mmol) in dichloromethane (100 mL) under Argon atmosphere. The mixture was stirred at room temperature under inert atmosphere for about 1 hour, followed by drop wise addition of 4-bromo-2,6-dichlorobenzoyl chloride (4.6 g, 15.9 mmol) in dichloromethane (20 mL). After complete addition the reaction mixture was stirred at room temperature for about 16 hours. Methanol (100 mL) was poured in the reaction mixture and stirred well. Solvent was evaporated under vacuum, water (250 mL) was added and extracted with ethyl acetate (3×200 mL). The organic layer was washed with aqueous sodium bicarbonate (10%) solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by silica gel (100-200 mesh) column chromatography using 2% methanol in dichloromethane as an eluant to afford N-[3-(4-bromo-2,6-dichlorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]cyclopropanecarboxamide (0.8 g, 54%).
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:8]([C@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=[O:22])[CH3:21])[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=O)C)C=O)(=[O:3])[CH3:2].[CH2:28]([S:30][Si](C)(C)C)[CH3:29].FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(Cl)Cl>[C:25]([O:24][C@@H:23]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:8]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[O:9][C@H:10]1[S:30][CH2:28][CH3:29])(=[O:27])[CH3:26]
Reactant: CCS[Si](C)(C)C
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H](C=O)OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCS[C@@H]1O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
A mixture of galactose pentaacetate (38.00 g, 97.43 mmol), (ethylthio)trimethylsilane (19.60 g, 146.15 mmol) and trimethylsilyl trifluoromethanesulfonate (23.60 g, 106.20 mmol) in CH2Cl2 (150 ml) was stirred overnight at room temperature. The reaction mixture was diluted with CH2Cl2 (150 ml) and washed with 1M Na2CO3 solution (300 ml), water (300 ml), dried over MgSO4 and concentrated. The residue was crystallised from hexane/di-isopropyl ether 1:1 (v/v) to give ethyl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-galactopyranoside (34.00 g, 89%).