Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[C:5]([C:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[CH:6]=[CH:7][C:8]=2[NH:12]C(=O)OC(C)(C)C)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:12][C:8]1[CH:7]=[CH:6][C:5]([C:20]([N:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[O:21])=[C:4]2[C:9]=1[C:10](=[O:11])[N:2]([CH3:1])[CH2:3]2
Reactant: CN1Cc2c(C(=O)N3CCCC3)ccc(NC(=O)OC(C)(C)C)c2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1Cc2c(C(=O)N3CCCC3)ccc(N)c2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl [2-methyl-3-oxo-7-(pyrrolidin-1-ylcarbonyl)-2,3-dihydro-1H-isoindol-4-yl]carbamate (Compound 116B) was added DCM (0.5 mL) and TFA (0.5 mL). The reaction mixture was stirred at room temperature for 30 minutes, after which it was concentrated to dryness an used without further purification. MS (ES+): m/z 260.30 (100) [MH+]; HPLC: tR=0.69 min (UPLC, Analytical).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.CI.[C:13](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:13])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(Cl)cc1C=O
Yield: 98.2 %

Procedure:
4.3 g of 5-chlorosalicylaldehyde, together with 7.8 g of methyl iodide and 5.7 g of potassium carbonate, in 100 ml of acetone are heated to reflux (1 hour). After filtration, the filtrate is concentrated. 4.6 g of the title compound are obtained as an oil.
Reaction SMILES: [C:1]1([S:7]([NH:10][C@@H:11]([CH2:15][NH2:16])[C:12]([OH:14])=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OS(O)(=O)=O.[CH3:22][C:23](=[CH2:25])[CH3:24].[ClH:26].CCOCC>C(Cl)(Cl)Cl.COCCOC>[ClH:26].[C:1]1([S:7]([NH:10][C@@H:11]([CH2:15][NH2:16])[C:12]([O:14][C:23]([CH3:25])([CH3:24])[CH3:22])=[O:13])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O
Reactant: C=C(C)C
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
In a Fischer-Porter tube, a mixture of 19-2 (10.2 g, 42 mmol) and DME (150 mL) was sequentially, treated with H2SO4 (6.4 mL, 0.12 mol), cooled to -78° C., and then condensed with isobutylene (75 mL). The cooling bath was removed. After 2 h, ice/water (250 mL) was added followed by washing with ether (2×). The aqueous phase was basified with aq 6N NaOH, saturated with NaCl, and extracted with EtOAc (3×). The combined extracts were washed with brine, dried (MgSO4), and concentrated to give a white solid. This was dissolved in CHCl3 then treated with 1N HCl/ether (22 mL) then concentrated to give 19-2a as a glossy yellow solid.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C.C1(C#C)C=CC=CC=1.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[C:27]#N>C(#N)C1C=CC=CC=1>[C:27]([C:18]1[CH:19]=[CH:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=1)#[C:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: C#CCCCCCC
Reactant: N#Cc1ccc2ccccc2c1
Solvent: C#Cc1ccccc1
Solvent: N#Cc1ccccc1
Product: CCCCCCC#Cc1ccc2ccccc2c1
Reaction time: 22 h
Yield: 99 %

Procedure:
The procedure was identical to Example 2, with the exception that 1-octyne (0.590 ml; 0.441 g; 4.00 mmol) was used as a substrate instead of phenylacetylene and 2-naphthonitrile (0.306 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 22 h at 65° C. showed the presence of 1.98 mmol (99% yield) of 2-(1-octynyl)naphthalene and no remaining 2-naphthonitrile in the reaction mixture.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[CH:18]2)([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH3:14])[CH:6]=1)[OH:4].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>N1C=CC=CC=1.CCOCC.O>[C:27]1([C:26]([N:20]2[C:21]3[C:17](=[CH:16][C:15]([C:3]([OH:4])([C:5]4[C:13]5[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=5)[N:7]([CH3:14])[CH:6]=4)[C:2]([F:1])([F:24])[F:25])=[CH:23][CH:22]=3)[CH:18]=[N:19]2)=[O:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cn1cc(C(O)(c2ccc3[nH]ncc3c2)C(F)(F)F)c2ccccc21
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cn1cc(C(O)(c2ccc3c(cnn3C(=O)c3ccccc3)c2)C(F)(F)F)c2ccccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
A mixture of 2,2,2-trifluoro-1-(1H-indazol-5-yl)-1-(1-methyl-1H-indol-3-yl)ethanol (0.162 mmol) and benzoyl chloride (0.324 mmol) in 1 mL pyridine was heated at 100° C. After 2 hours, the mixture was cooled to room temperature and diluted with ether and water. The organic layer was washed with aqueous HCl and brine and dried over magnesium sulfate. The volatiles were removed in vacuo and the residue purified by flash silica gel chromatography using 33% ethyl acetate in hexanes. The product-rich fractions were concentrated in vacuo to provide 0.093 mmol of the title compound, m.p. 102° C.-103° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:46][CH2:45][C:44]([CH3:58])([O:47][Si](C(C)C)(C(C)C)C(C)C)[CH2:43][CH2:42]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].N>C1COCC1.CO.C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:46][CH2:45][C:44]([OH:47])([CH3:58])[CH2:43][CH2:42]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC(C)(O[Si](C(C)C)(C(C)C)C(C)C)CC5)n4c3)c3ccccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC(C)(O)CC5)n4c3)c3ccccc32)cc1
Temperature: 25 °C
Yield: 39.7 %

Procedure:
To a solution of Intermediate 79f (210 mg, 0.260 mmol) in THF (4 mL) at −30° C. was added TBAF (1M in THF, 390 μL, 0.390 mmol) and the mixture was allowed to warm to RT over 1 h. The reaction mixture was applied to an SCX-2 cartridge (10 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, and then recrystallisation from boiling EtOAc (˜40 mL) gave the title compound as a white powder (67 mg, 40%). LCMS (Method 5): Rt 4.31 min, m/z 649.1 [MH+]. 1H NMR (400 MHz, d4-MeOH): 1.30 (3H, s), 1.33 (9H, s), 1.71-1.77 (2H, m), 1.84-1.93 (2H, m), 1.95-2.17 (3H, m), 2.25-2.32 (1H, m), 2.41 (3H, s), 3.20-3.28 (2H, m), 3.36-3.45 (2H, m), 4.72-4.92 (1H, m), 5.47 (1H, t, J 4.4), 6.36 (1H, s), 6.88 (1H, d, J 9.3), 7.21-7.40 (8H, m), 7.58 (1H, d, J 9.7), 7.62 (1H, d, J 1.7).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:33])[CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[NH:15][C:14]([CH:16]3[CH2:18][CH2:17]3)=[N:13][C:12]=2[C:19]2[C:20]([Cl:32])=[C:21]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:8]=[CH:7][N:6]=1.C([O-])(O)=O.[Na+].Cl[C:40]([O:42][CH3:43])=[O:41]>C1COCC1.O.O>[Cl:32][C:20]1[C:21]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])=[CH:22][CH:23]=[CH:24][C:19]=1[C:12]1[N:13]=[C:14]([CH:16]2[CH2:18][CH2:17]2)[NH:15][C:11]=1[C:9]1[CH:8]=[CH:7][N:6]=[C:5]([NH:4][CH2:3][C@@H:2]([NH:1][C:40](=[O:41])[O:42][CH3:43])[CH3:33])[N:10]=1
Reactant: CCCS(=O)(=O)Nc1cccc(-c2nc(C3CC3)[nH]c2-c2ccnc(NC[C@H](C)N)n2)c1Cl
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1cccc(-c2nc(C3CC3)[nH]c2-c2ccnc(NC[C@H](C)NC(=O)OC)n2)c1Cl
Reaction time: 0.08 h

Procedure:
To a mixture of (S)—N-(3-(5-(2-(2-aminopropylamino)pyrimidin-4-yl)-2-cyclopropyl-1H-imidazol-4-yl)-2-chlorophenyl)propane-1-sulfonamide in THF-water (1:1, 2 mL) at 0° C. was added solid NaHCO3 (137 mg, 1.6 mmol) and the resulting mixture was stirred for 5 minutes. Methyl chloroformate (14 μL, 0.18 mmol) was added and the reaction mixture was stirred at 0° C. for 15 minutes. The reaction was diluted with water and extracted with EtOAc (2×). The combined organic portions were washed with water, brine, dried (Na2SO4), and concentrated. The resulting residue was dissolved in DMSO and purified by reverse phase HPLC. Product fractions were combined and lyophilized to give (S)-methyl 1-(4-(4-(2-chloro-3-(propylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (19.9 mg) as the TFA salt (4A-3): LCMS (m/z) 548.0 (MH+), tR=0.61 minute, 1H NMR (400 MHz, CD3OD) δ 1.04 (t, J=7.4 Hz, 3H) 1.14 (d, J=6.6 Hz, 3H) 1.27 (t, J=4.5 Hz, 2H) 1.34-1.44 (m, 2H) 1.80-1.95 (m, 2H) 3.14-3.21 (m, 2H) 3.67 (br s, 3H) 3.97 (br s, 1H) 6.40 (br s, 1H) 7.45 (d, 7.0 Hz, 1H) 7.54 (m, 1H) 7.84 (d, J=7.4 Hz, 1H) 8.13 (d, J=5.1 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:15][C:16]3[O:17][C:18]4[C:23]([C:24](=[O:32])[C:25]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:9]=[C:10]([C:11]#[C:12][CH2:13][OH:14])[C:3]=12.ClCCl>CO.[Pd]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:15][C:16]3[O:17][C:18]4[C:23]([C:24](=[O:32])[C:25]=3[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:9]=[C:10]([CH2:11][CH2:12][CH2:13][OH:14])[C:3]=12
Reactant: Nc1ncnc2c1c(C#CCO)nn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Nc1ncnc2c1c(CCCO)nn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Reaction time: 48 h
Yield: 42 %

Procedure:
To a solution of example 59 (0.170 g, 0.401 mmoles) in methanol (4 ml), palladium on charcoal 1 (10%, 0.050 g) was added and hydrogenated at 5 kg/cm2 for 48 h. The reaction mixture filtered through celite pad and washed with methanol. The filtrate was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as brown solid (0.072 g, 42% yield). MP: 182-184° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.11(s,1H), 8.05(dd, J=8.0, 1.6Hz, 1H), 7.76(m,1H), 7.49(t, J=7.1Hz, 1H), 7.39-7.20(m, 8H), 4.62(t, J=4.6Hz, 1H),3.45(q, J=6.1Hz, 2H), 2.92(t, J=7.4Hz, 2H), 1.78(m,2H). Mass: 427.87(M+).
Reaction SMILES: Cl.[CH2:2]([C:6]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[CH:22][CH:21]=2)[C:9]2[CH2:10][NH:11][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:13][C:8]=2[N:7]=1)[CH2:3][CH2:4][CH3:5].[C:37]([CH2:39][C:40](O)=[O:41])#[N:38]>>[CH2:2]([C:6]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[CH:22][CH:21]=2)[C:9]2[CH2:10][N:11]([C:40](=[O:41])[CH2:39][C:37]#[N:38])[CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:13][C:8]=2[N:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: N#CCC(=O)O
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CNC(C(=O)OC)C2
Agent: Cl
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CN(C(=O)CC#N)C(C(=O)OC)C2

Procedure:
Methyl 2-n-butyl-3-{2'-(1H-tetrazol-5-yl)-biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]-pyridine-6-carboxylate hydrochloride and cyanoacetic acid are treated in the same manner as in Example 8-(1) to give methyl 2-n-butyl-5-cyanoacetyl-3-{2'-(1H-tetrazol-5-yl)-biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]-pyridine-6-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C(N(CC)CC)C.[S:19](Cl)([CH3:22])(=[O:21])=[O:20]>N1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]([NH:11][S:19]([CH3:22])(=[O:21])=[O:20])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(Br)c2cc[nH]c2c1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(Br)c2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
4-Bromo-6-amino indole (100 mg, 0.47 mmol) and triethylamine (0.1 ml, 0.71 mmol) were stirred together in pyridine at 0° C. Mesyl chloride (54 mg, 0.47 mmol) was then added and the mixture stirred for 1 hour, then allowed to warm to room temperature. The mixture was loaded directly onto an aminopropyl cartridge (10 g) and eluted with methanol. Solvent was evaporated and the residue was further purified by chromatography on silica (20 g cartridge) eluting with 0-25% methanol in DCM over 20 mins to afford the title compound as a orange/brown gum (110 mg).
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:8][S:9]([N:12]=C=O)(=[O:11])=[O:10]>C1C=CC=CC=1>[C:1]([NH:12][S:9]([Cl:8])(=[O:11])=[O:10])(=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: c1ccccc1
Product: CCCCC(=O)NS(=O)(=O)Cl
Yield: 100.2 %

Procedure:
n-Pentanoic acid (1.02 g, 10 mmol) was added slowly dropwise to chlorosulfonyl isocyanate (1.42 g, 10 mmol), with ice/water bath cooling as required to maintain gentle gas evolution. After the addition was complete, the residue was taken up in benzene (10 mL) and the mixture concentrated in vacuo to provide the title compound (2.0 g, quantitative) as a crystalline, hygroscopic solid.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:11][C:10]1=[O:22])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1>[CH3:7][CH:6]([CH3:8])[CH2:5][C@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:11][C:10]1=[O:22])[C:3]([OH:23])=[O:2]
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2ccccc2C)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)O)C1
Temperature: 20 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
To a solution containing (S)-4-methyl-2-(2-oxo-4-o-tolyloxy-2,5-dihydro-pyrrol-1-yl)-pentanoic acid methyl ester (1.50 g, 4.7 mmol) in tetrahydrofuran (30 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 20 mL, 10.0 mmol). The mixture was stirred at 20° C. for 3 h, and the solvents evaporated. The residue was dissolved in water and washed with diethyl ether, and the diethyl ether layer discarded. The aqueous phase was acidified with dilute hydrochloric acid (pH <2), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford (S)-4-methyl-2-(2-oxo-4-o-tolyloxy-2,5-dihydro-pyrrol-1-yl)-pentanoic acid (1.30 g, 91%) as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)([OH:16])[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].O.[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)([OH:16])[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)cnc1N1CC(O)(c2cccc(F)c2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(Cl)cnc1N1CC(O)(c2cccc(F)c2)C1
Temperature: 70 °C
Reaction time: 4 h
Yield: 96.7 %

Procedure:
To a solution of methyl 5-chloro-2-(3-(3-fluorophenyl)-3-hydroxyazetidin-1-yl)nicotinate (D80) (70 mg, 0.207 mmol) in a mixture 3:1 1,4-dioxane/water (2 ml), lithium hydroxide monohydrate (133 mg, 0.312 mmol) was added and the resulting mixture was stirred 4 h at 70° C. After solvent evaporation the residue was taken in a mixture water/1M HCl (10 ml/10 ml) and extracted with ethylacetate (2×30 ml). Collected organics after solvent evaporation afforded the title compound (D111) (64.6 mg).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[O:21])[CH2:13][CH2:12]3)=[CH:9][S:8][C:7]=2[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CO[CH:38](OC)[N:39]([CH3:41])[CH3:40].N1CC[CH2:46][CH2:45]1>CN(C)C=O>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19](=[CH:41][N:39]4[CH2:38][CH2:46][CH2:45][CH2:40]4)[C:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)=[O:21])[CH2:15][CH2:16]3)=[CH:9][S:8][C:7]=2[CH:29]=1
Reactant: COC(OC)N(C)C
Reactant: O=C(CCCN1CCC(c2csc3cc(F)ccc23)CC1)c1ccc(F)cc1
Reactant: C1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(C(=CN1CCCC1)CCN1CCC(c2csc3cc(F)ccc23)CC1)c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 3.5 h

Procedure:
A mixture of 0.15 g of 6-fluoro-3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]benzo[b]thiophene hydrochloride, 0.05 g of anhydrous potassium carbonate, 0.36 ml of N,N-dimethylformamide dimethyl acetal, 0.25 ml of pyrrolidine and 0.5 ml of N,N-dimethylformamide was stirred on an oil bath at 120° C. for 3.5 hours. The reaction mixture was cooled to room temperature and then separated with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed three times with a saturated aqueous sodium chloride solution. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain crude 6-fluoro-3-[1-[3-(1-pyrrolidinomethylene)-4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]benzo[b]thiophene.
Reaction SMILES: [NH:1]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:19]([O:26][C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=O)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OC1C=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)N1C(OCC)=O)C>O1CCCC1.C1(C)C=CC=CC=1>[CH2:19]([O:26][C:27]([NH:29][CH2:30][CH2:31][C:32]([N:1]1[CH2:18][CH2:17][N:16]([C:32](=[O:34])[CH2:31][CH2:30][NH:29][C:27]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:28])[CH2:15][CH2:14][N:13]([C:32](=[O:34])[CH2:31][CH2:30][NH:29][C:27]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:28])[CH2:12][CH2:11][N:10]([C:32](=[O:34])[CH2:31][CH2:30][NH:29][C:27]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:28])[CH2:9][CH2:8][N:7]([C:32](=[O:34])[CH2:31][CH2:30][NH:29][C:27]([O:28][CH2:46][C:45]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:26])[CH2:6][CH2:5][N:4]([C:32](=[O:34])[CH2:31][CH2:30][NH:29][C:27]([O:26][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:28])[CH2:3][CH2:2]1)=[O:34])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C1CNCCNCCNCCNCCNCCN1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(NCCC(=O)N1CCN(C(=O)CCNC(=O)OCc2ccccc2)CCN(C(=O)CCNC(=O)OCc2ccccc2)CCN(C(=O)CCNC(=O)OCc2ccccc2)CCN(C(=O)CCNC(=O)OCc2ccccc2)CCN(C(=O)CCNC(=O)OCc2ccccc2)CC1)OCc1ccccc1
Reaction time: 8 h

Procedure:
516 mg (2 mmol) of 1,4,7,10,13,16-hexaazacyclooctadecane (hexacyclene; Fluka) is azeotropically dehydrated with toluene. A solution of 3.35 g (15 mmol) of benzyloxycarbonyl-β-alanine (Sigma) in tetrahydrofuran (THF) as well as 3.71 g (15 mmol) of 2-ethoxy-l-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ; Fluka) are added to the cooled solution of hexacyclene in toluene at room temperature and stirred overnight. After the reaction is completed, the product is precipitated by adding hexane, and the precipitate is chromatographed on silica gel with dichloromethane/hexane/isopropanol (20:10:1).
Reaction SMILES: CCCCC.[H-].[Na+].[CH3:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[C:21]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:20][N:19]=[C:18]([S:26][CH3:27])[N:17]=2)[CH:12]=[CH:13][CH:14]=1.[CH:28]([N:31]=[C:32]=[O:33])([CH3:30])[CH3:29]>C1COCC1>[CH3:29][CH:28]([NH:31][C:32]([NH:25][S:22]([C:21]1[C:16]([NH:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([CH3:8])[CH:10]=2)=[N:17][C:18]([S:26][CH3:27])=[N:19][CH:20]=1)(=[O:23])=[O:24])=[O:33])[CH3:30]
Reactant: CC(C)N=C=O
Reactant: CSc1ncc(S(N)(=O)=O)c(Nc2cccc(C)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CSc1ncc(S(=O)(=O)NC(=O)NC(C)C)c(Nc2cccc(C)c2)n1
Reaction time: 1.5 h
Yield: 80.5 %

Procedure:
Pentane washed sodium hydride (3.99 mmol, 1.05 eq) was suspended in THF (50 mL), and 4-[(3-methylphenyl)amino]-2-(methylthio)-5-pyrimidinesulfonamide (1.18 g, 3.90 mm) was added slowly as a solid. The mixture was stirred for 90 minutes and isopropyl isocyanate (0.39 mL, 3.99 mmol, 1.05 eq) was added. After stirring 45 minutes an additional 0.1 mL of isopropyl isocyanate was added to complete the reaction. The THF was removed under reduced pressure and the residue was dissolved in dilute sodium hydroxide. Acetic acid was added until a pH of 4 and the aqueous solution was extracted with four 50 mL portions of ethyl acetate. The organic portions were combined, dried (Na2SO4), filtered and the solvent removed under reduced pressure to yield 1.61 g of crude solid. The crude solid was crystallized from ethanol and water to yield 1.21 g (3.06 mmoles, 80%) of white crystals, m.p. 160°-160.5° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[S:33](=[O:35])(=[O:34])[NH:32][C:31](=[O:36])[CH2:30]2)=[C:25]([Br:37])[CH:24]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[O:4].C(N(CC)C(C)C)(C)C.[N:47]1([C:53](Cl)=[O:54])[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>C(Cl)Cl.CN(C)C=O>[Br:37][C:25]1[CH:24]=[C:23]([CH2:22][C@H:2]([NH:1][C:53]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[O:54])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[O:4])[CH:28]=[CH:27][C:26]=1[CH:29]1[S:33](=[O:34])(=[O:35])[NH:32][C:31](=[O:36])[CH2:30]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@@H](N)Cc1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1)NC(=O)N1CCOCC1
Reaction time: 2 h
Yield: 84.2 %

Procedure:
To a solution of methyl 2-[4-((2S)-2-amino-3-[3-bromo-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]propanoylamino)butoxy]-6-hydroxybenzoate (30.0 mg, 0.0501 mmol) in methylene chloride (0.4 mL) and N,N-dimethylformamide (0.10 mL) was added N,N-diisopropylethylamine (26.4 μL, 0.152 mmol) and morpholine-4-carbonyl chloride (6.48 μL, 0.0556 mmol) at room temperature. The resulting solution was stirred for 2 h. The reaction was quenched with 1 N HCl solution and diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate twice. The combined organic solutions were dried over sodium sulfate, filtered, concentrated under reduced pressure. The residue was purified by preparative LCMS to afford a white solid (30 mg, 80%). 1H NMR (400 MHz, CD3OD): δ 7.61 (dd, J=9.6, 1.8 Hz, 1H), 7.47 (dd, J=11.3, 8.0 Hz, 1H), 7.35 (m, 1H), 7.24 (t, J=8.3 Hz, 1H), 6.48 (m, 2H), 5.36 (m, 1H), 4.44 (dd, J=8.8, 6.6 Hz, 1H), 3.98 (t, J=5.8 Hz, 2H), 3.87 (s, 3H), 3.59 (m, 4H), 3.43 (dd, J=17.6, 8.4 Hz, 1H), 3.23 (m, 1H), 3.16 (m, 3H), 2.96 (m, 1H), 1.64 (m, 4H). LCMS found for C29H36BrN4O10S (M+H)+: m/z=711, 713.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:24])/[CH:21]=[CH:22]/[CH3:23]>C(OCC)C>[C:20]([O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:10])[Cl:11])[N:3]=1)(=[O:24])/[CH:21]=[CH:22]/[CH3:23]
Reactant: C/C=C/C(=O)Cl
Reactant: Cc1cc(O)nc(C(Cl)(Cl)Cl)n1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C/C=C/C(=O)Oc1cc(C)nc(C(Cl)(Cl)Cl)n1
Yield: 30.5 %

Procedure:
To a solution of 3.0 g (0.02 mole) 4-hydroxy-6-methyl-2-trichloromethylpyrimidine and 1.3 g (0.02 mole) triethylamine in 75 ml diethyl ether was added 1.4 g (0.02 mole) crotonyl chloride. The reaction mixture was refluxed for 15 hours and filtered, and the filtrate was concentrated in-vacuo to give a viscous oil as residue. Trituration with petroleum ether caused the oil to solidify. Recrystallization from isopropyl alcohol gave 1.8 g (45% yield) of pure product; m.p. 55° C.