Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([NH2:14])[S:11][N:10]=2)=[CH:5][CH:4]=1.C[Al](C)C.[CH3:19][C@@H:20]1[CH2:22][C@H:21]1[C:23](OCC1C=CC=CC=1)=[O:24].N#N>ClCCl.CC(OC)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:13]=[C:12]([NH:14][C:23]([C@@H:21]3[CH2:22][C@H:20]3[CH3:19])=[O:24])[S:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: C[C@@H]1C[C@H]1C(=O)OCc1ccccc1
Reactant: COc1ccc(-c2cc(N)sn2)cc1
Agent: C[Al](C)C
Agent: N#N
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: COc1ccc(-c2cc(NC(=O)[C@@H]3C[C@H]3C)sn2)cc1
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 74.5 %

Procedure:
To a stirred suspension of 3-(4-methoxyphenyl)isothiazol-5-ylamine (5.0 g, 24.3 mmol) in anhydrous dichloromethane (230 mL), cooled to 0-5° C., is added trimethylaluminum (2.0 M in toluene, 12.1 mL, 24.2 mmol) by syringe. The solution is stirred 5 min, and benzyl (R,R)-2-methylcyclopropanecarboxylate (4.6 g, 24.21 mmol) is added with the aid of anhydrous dichloromethane (10 mL). The mixture is then warmed to 40-45° C. with N2 flow (needle bleed valve) to slowly remove solvent. After 2 h, most of the dichloromethane has been removed, and the internal temperature rises to about 50° C. The solution is stirred further for 3 h, cooled, and quenched cautiously with dropwise addition of water followed by 0.1 N HCl under a good N2 stream. The resulting residue is then partitioned between ethyl acetate (400 mL) and 0.1 N HCl (400 mL). The organic layer is dried over potassium carbonate, filtered, and evaporated to a low volume. The resulting suspension is diluted with hexanes and the solid filtered to afford 5.9 g of crude product which is re-suspended in MTBE (100 mL), warmed to mild reflux for 1 h, and cooled to room temperature. After standing 1 h, the solid was filtered and dried (20 mm Hg, 40° C.) to afford (R,R)—N-[3-(4-methoxyphenyl)isothiazol-5-yl]-2-methyl-cyclopropanecarboxamide (5.2 g, 75%). 1H NMR (DMSO-d6) 7.86 (d, J=8.8 Hz, 2H), 7.20 (s, 1H), 7.00 (d, J=8.8 Hz, 2H), 3.78 (s, 3H), 1.62 (m, 1H), 1.34 (m, 1H), 1.10 (d, J=6.0 Hz, 3H), 1.09 (m, 1H), 0.80 (m, 1H); ES-MS m/e 289 (m+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:18]1([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>O1CCOCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:27]2[CH2:28][CH2:29][CH:24]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:25][CH2:26]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(N2CCC(N3CCCCC3)CC2)cc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
A solution of 1-fluoro-4-nitrobenzene (1.3 mL, 12.3 mmol), triethylamine (6.0 mL; 43.0 mmol) and 4-(piperidin-1-yl)piperidine (2.36 g; 14.0 mmol) in dioxane (10 mL) was heated at reflux for 18 hr. After cooling to room temperature the mixture was concentrated under reduced pressure and the residue dissolved in DCM (150 mL). The DCM solution was washed with saturated aqueous sodium bicarbonate and brine, then dried over magnesium sulfate and concentrated under reduced pressure to produce a yellow solid. Hexanes were added and the suspension briefly sonicated. The solid was collected by filtration and washed with hexanes to give 1-(4-nitrophenyl)-4-(piperidin-1-yl)piperidine (3.05 g) as a yellow solid. A solution of 1-(4-nitrophenyl)-4-(piperidin-1-yl)piperidine (3.05 g; 10.5 mmol) in ethanol (20 mL) was hydrogenated at atmospheric pressure with 10% palladium on carbon (0.251 g) at room temperature for 17 hr. The mixture was filtered through diatomaceous earth and concentrated under reduced pressure to give 4-[4-(piperidin-1-yl)piperidin-1-yl]benzenamine (2.01 g) as a purple/pink solid.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[CH2:6](Br)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-].[K+].O>CS(C)=O.O1CCCC1>[CH2:19]([O:4][CH2:3][CH2:2][CH2:1][OH:5])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH3:6]
Reactant: CCCCCCCCCCCCCCBr
Reactant: OCCCO
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCOCCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.6 %

Procedure:
In 70 ml of a mixture of dimethylsulfoxide-tetrahydrofuran (1:1) are dissolved 12.3 g of trimethylene glycol and 15 g of tetradecyl bromide. To the solution is added 12 g of powdery potassium hydroxide. The mixture is vigorously stirred for one hour at a room temperature, which is refluxed under heating for two hours. The reaction mixture is poured into 400 ml of cold water, which is neutralized and subjected to extraction with ethyl acetate, then washed with water and dried. The resultant is concentrated to dryness, and the residue is dissolved in methanol when hot. Cooling of the solution gives precipitation of crystals, which are removed by filtration. The filtrate is refined by means of chromatography employing silica-gel (eluent:chloroform) to give 5.1 g of the end-product.
Reaction SMILES: O.[CH3:2][C:3]1([CH3:12])[CH2:8][C:7](=[O:9])[CH2:6][C:5]([CH3:11])([CH3:10])[NH:4]1.[CH3:13][I:14]>C(O)(C)C>[IH:14].[CH3:13][N:4]1[C:5]([CH3:11])([CH3:10])[CH2:6][C:7](=[O:9])[CH2:8][C:3]1([CH3:12])[CH3:2]
Reactant: CI
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Solvent: CC(C)O
Solvent: O
Product: CN1C(C)(C)CC(=O)CC1(C)C
Product: I
Yield: 45.9 %

Procedure:
A solution of 2,2,6,6-tetramethyl-4-piperidone monohydrate (40 g, 23.1 mmol) and methyl iodide (98.31 g, 69.3 mmol) in isopropyl alcohol (25 mL) was stirred at RT for 48 hours. The resulting suspension was filtered, the solid residue was dried and recrystallized from MeOH. After filtration and repeated washings with MeOH the solid was dried giving pure title compound (31.6 g, 10.6 mmol, yield 46.0%) as pale brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][C:5]2=[CH:8][N:9]([CH2:11][C:12]([NH:16][C:17](=[O:29])[C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)([C:14]#[N:15])[CH3:13])[N:10]=[C:4]2[CH:3]=1.[Cl:30]N1C(=O)CCC1=O>C(#N)C>[C:14]([C:12]([NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=1)([CH3:13])[CH2:11][N:9]1[C:8]([Cl:30])=[C:5]2[N:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]2=[N:10]1)#[N:15]
Reactant: CC(C#N)(Cn1cc2ncc(Cl)cc2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CC(C#N)(Cn1nc2cc(Cl)cnc2c1Cl)NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 60 °C
Yield: 89 %

Procedure:
A mixture of N-[2-(6-Chloro-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide (134 mg described in Example 155), and N-chlorosuccinimide (51 mg) in acetonitrile (3.5 mL) was heated to 60° C. overnight. The mixture was concentrated under reduced pressure to yield a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound as white solid (129 mg, 89%). MS (ES): M/Z [M+H]=458. 1H NMR: (400 MHz, DMSO-d6): 1.78 (s, 3H), 5.10-5.20 (m, 2H), 7.53 (d, J=8.3 Hz, 2H), 7.97 (d, J=8.8 Hz, 2H), 8.43 (d, J=2.0 Hz, 1H), 8.59 (d, J=2.0 Hz, 1H) and 8.99 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −57.1 (s, 3F).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20].[CH3:30][O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:30][O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([CH2:8][C@@H:9]3[CH2:13][CH2:12][N:11]([N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[C:10]3=[O:20])=[C:6]([Cl:21])[CH:5]=2)=[CH:36][CH:35]=1)=[O:33]
Reactant: O=C1[C@H](Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1N1CCCCC1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCCCC4)C3=O)c(Cl)c2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
Bring a mixture of (R)-trifluoro-methanesulfonic acid 3,5-dichloro-4-(2-oxo-1-piperidin-1-yl-pyrrolidin-3-ylmethyl)-phenyl ester (0.236 g, 0.5 mmol), 4-methoxycarbonylphenylboronic acid (0.134 g, 0.75 mmol), sodium carbonate (0.158 g, 1.5 mmol) in THF (20 mL) and water (5 mL) to 60° C. To the mixture at 60° C., add Pd(PPh3)4 (0.029 g, 0.025 mmol), then raise the reaction temperature to 80° C., and stir for 3 hours. Cool the reaction, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify on silica gel column with 25% to 50% ethyl acetate in hexanes gradient to afford 0.22 g (95%) of the titled product. MS (m/z): 461 (M+).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][O:7][C@@H:6]([C@H:9]2[O:13][N:12]=[C:11]([C:14]3[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([C:21]([NH:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([O:32][CH3:33])[CH:26]=4)=[O:22])[CH:15]=3)[CH2:10]2)[CH2:5][O:4]1.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([NH:1][CH2:2][C@@H:3]1[CH2:8][O:7][C@@H:6]([C@H:9]2[O:13][N:12]=[C:11]([C:14]3[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([C:21]([NH:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([O:32][CH3:33])[CH:26]=4)=[O:22])[CH:15]=3)[CH2:10]2)[CH2:5][O:4]1)(=[O:36])[CH3:35]
Reactant: COc1cc(CNC(=O)c2cc(C3=NO[C@H]([C@H]4CO[C@H](CN)CO4)C3)nc(C)n2)ccc1F
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: COc1cc(CNC(=O)c2cc(C3=NO[C@H]([C@H]4CO[C@H](CNC(C)=O)CO4)C3)nc(C)n2)ccc1F
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
To a stirred solution of 6-((S)-5-((2R,5R)-5-(aminomethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide (0.08 g, 0.174 mmol, Preparation #J.1) in DCM (5 mL) at 0° C., was added TEA (0.073 mL, 0.522 mmol, Spectrochem) followed by acetyl chloride (0.015 mL, 0.209 mmol, Spectrochem). The reaction mixture was stirred for 30 min, was diluted with DCM (30 mL) and washed with water (2×20 mL). The organic layer dried over sodium sulphate and concentrated under reduced pressure. The resulting crude material was purified by preparative TLC eluting with 60% EtOAc in hexane to afford 6-((S)-5-((2R,5R)-5-(acetamidomethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide 0.065 g (74%); 1H NMR (400 MHz, DMSO): δ 9.50 (t, J=5.6 Hz, 1H), 8.13 (s, 1H), 7.93 (t, J=5.6 Hz, 1H), 7.17-7.11 (m, 2H), 6.89-6.81 (m, 1H), 4.81-4.75 (m, 1H), 4.48 (d, J=6.4 Hz, 2H), 3.88-3.86 (m, 1H), 3.81 (s, 3H), 3.78-3.63 (m, 2H), 3.46-3.36 (m, 4H), 3.32-3.22 (m, 2H), 3.08-3.00 (m, 2H) 2.75 (s, 3H), 1.79 (s, 3H); LC/MS (Table 1, Method e) Rt=2.69 min; MS: m/z 502 (m+H)+.
Reaction SMILES: [C:1]([CH:4]([N:8]1[CH:11]([S:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[CH:10]([NH:24][C:25](=[O:34])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]1=[O:35])[C:5]([CH3:7])=[CH2:6])([OH:3])=[O:2].[N+](=[CH2:38])=[N-].C(O)(=O)C>O1CCCC1.C(OCC)C>[CH3:38][O:2][C:1]([CH:4]([N:8]1[CH:11]([S:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[CH:10]([NH:24][C:25](=[O:34])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]1=[O:35])[C:5]([CH3:7])=[CH2:6])=[O:3]
Reactant: C=C(C)C(C(=O)O)N1C(=O)C(NC(=O)COc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C=C(C)C(C(=O)OC)N1C(=O)C(NC(=O)COc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Yield: 77.1 %

Procedure:
To a solution of 2.4 g (4.8 mmoles) of 1-(1-carboxy-2-methylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothio-azetidin-2-one in 20 ml of tetrahydrofuran was added a solution of 6 mmoles of diazomethane in diethyl ether. The clear solution was treated with acetic acid to remove excess diazomethane and was concentrated to a small volume. After addition of diethyl ether the formed precipitate was filtered off and dried to obtain 1.9 g (3.7 mmoles or 76% yield) of 1-(1-methoxycarbonyl-2-methylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothio-azetidin-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.C(N(CC)CC)C.[CH2:23]([CH2:25][NH2:26])[OH:24].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[OH:24][CH2:23][CH2:25][NH:26][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:13]([O-:15])=[O:14])(=[O:11])=[O:10]
Reactant: NCCO
Reactant: COc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NCCO)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
4-Methoxy-2-nitrobenzenesulfonyl chloride (3.1 g; 12.3 mmol; 1 eq) is dissolved in DCM (60 mL) in the presence of triethylamine (1.7 mL; 12.3 mmol; 1 eq) at 0° C. Ethanolamine (0.6 mL; 13.6 mmol; 1.1 eq) is then added and the reaction mixture is stirred at room temperature for 16 h. Water is added to the reaction mixture then aqueous Na2CO3. The organic phase is dried over MgSO4 and the solvent is evaporated under reduced pressure to give 2.9 g (85%) of the title compound as an orange oil, 1H NMR (DMSO-d6) δ 7.92 (d, J=3.2 Hz, 1H), 7.85-7.78 (m, 1H), 7.56 (d, J=2.5 Hz, 1H), 7.37 (dd, J=8.9, 2.6 Hz, 1H), 4.79-4.71 (m, 1H), 3.90 (s, 3H), 3.42-3.46 (m, 2H), 2.92-2.87 (m, 2H). HPLC (max plot) 52.3%; Rt 220 min. UPLCIMS: (ES+) 277.2, (ES−) 275.2.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=2)[CH:3]=1.[CH3:19][O:20][CH2:21][CH2:22][NH2:23].C([BH3-])#N.[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:23][CH2:22][CH2:21][O:20][CH3:19])[CH:12]=2)[CH:3]=1
Reactant: COCCN
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COCCNCc1cccc(Oc2cc(Cl)ccc2C#N)c1
Yield: 61.6 %

Procedure:
4-Chloro-2-(3-formylphenoxy)benzonitrile (0.20 g, 0.78 mmol), 2-methoxyethylamine (72 μL, 62 mg, 0.83 mmol) and sodium cyanoborohydride (60 mg, 0.96 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (20 mL) for 40 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.10 g, 0.86 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-{3-[(2-methoxyethylamino)methyl]phenoxy}benzonitrile fumarate (208 mg, 61%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:17])=[C:7]2[C:12](Cl)=[C:11]([C:14]#[N:15])[CH:10]=[N:9][N:8]2[CH:16]=1)=[O:4].[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21][CH2:20]1.COC(C1C(C)=C2C(NC3C=CC(OC4C=CC=CC=4OC(C(OC(C)(C)C)=O)(C)C)=CC=3)=C(C#N)C=NN2C=1)=O>>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:17])=[C:7]2[C:12]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:21][CH2:20]3)=[C:11]([C:14]#[N:15])[CH:10]=[N:9][N:8]2[CH:16]=1)=[O:4]
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: COC(=O)c1cn2ncc(C#N)c(Cl)c2c1C
Agent: COC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)OC(C)(C)C)cc3)c2c1C
Product: COC(=O)c1cn2ncc(C#N)c(NC3CCN(Cc4ccccc4)CC3)c2c1C

Procedure:
The title compound was prepared from 4-chloro-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acid methyl ester (prepared using the procedure of Example 1D) (65.0 mg, 0.246 mmol) and 4-amino-1-benzylpiperidine (52.6 μl, 0.258 mmol) by a route analogous to that used for the preparation of compound 388D. It (100 mg, 97%) was a white crystalline solid. LCMS Found: (M+H)+=418.2
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:11]2[CH2:16][C@H:15]([CH3:17])[C@@H:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@H:13]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:12]2)=[C:4]2[CH2:10][CH2:9][O:8][C:5]2=[N:6][CH:7]=1.[F:34][C:35]1[CH:40]=[C:39]([C:41]([OH:44])([CH3:43])[CH3:42])[CH:38]=[C:37]([F:45])[C:36]=1[C:46]1[N:51]=[C:50]([C:52](O)=[O:53])[CH:49]=[CH:48][C:47]=1[F:55].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Si:19]([O:18][C@@H:14]1[C@@H:15]([CH3:17])[CH2:16][N:11]([C:3]2[C:2]([NH:1][C:52]([C:50]3[CH:49]=[CH:48][C:47]([F:55])=[C:46]([C:36]4[C:35]([F:34])=[CH:40][C:39]([C:41]([OH:44])([CH3:43])[CH3:42])=[CH:38][C:37]=4[F:45])[N:51]=3)=[O:53])=[CH:7][N:6]=[C:5]3[O:8][CH2:9][CH2:10][C:4]=23)[CH2:12][C@H:13]1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([C:22]([CH3:23])([CH3:25])[CH3:24])([CH3:20])[CH3:21]
Reactant: CC(C)(O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Reactant: C[C@H]1CN(c2c(N)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cc(C(C)(C)O)cc4F)n3)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl ((3R,4R,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (200 mg, 0.418 mmol), 6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxylic acid (130 mg, 0.418 mmol), HATU (318 mg, 0.836 mmol) in DMF (1.5 mL) and DIPEA (218 μL, 1.25 mmol) was stirred at room temperature for 2 h. After quenched with water, the mixture was extracted with EtOAc (2×). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by purified by column chromatography on silica gel using CombiFlash® apparatus eluting with EtOAc/hexanes (50-100%), to yield an amide intermediate, tert-butyl ((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{5-[({6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-2,3-dihydrofuro[2,3-b]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[C:4]([C:8]2([O:13][CH3:14])[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.I[CH2:17][CH3:18].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[C:3]([F:15])=[C:4]([C:8]2([O:13][CH3:14])[CH2:12][CH2:11][N:10]([CH2:17][CH3:18])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC1(c2cccc(Cl)c2F)CCNC1
Reactant: CCI
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN1CCC(OC)(c2cccc(Cl)c2F)C1
Yield: 35.8 %

Procedure:
Preparation according to Example 2. (+3-(3-chloro-2-fluorophenyl)-3-methoxypyrrolidine (0.234 g, 1.02 mmol), tetrahydrofuran (20 ml), iodoethane (0.122 ml, 1.15 mmol) and triethylamine (0.285 ml, 2.04 mmol), the solution was stirred for 26 h. Purification by HPLC on waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 65:35) gave the title compound 0.094 g (35.9%). [a]D=−16.1° (methanol). The amine was converted to the fumaric acid salt and recrystallized from 2-propanol/diisopropyl ether: M.p. 131-133° C. MS m/z (rel. intensity, 70 eV) 257 (M+, 4), 242 (38), 227 (20), 157 (31), 71 (bp).
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][C:3]#[C:4][CH3:5].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:20][C:21]1[CH2:27][N:26]=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[C:24]2[CH:35]=[C:36]([Cl:39])[CH:37]=[CH:38][C:23]=2[N:22]=1>O1CCCC1.CN(C)C=O>[Cl:39][C:36]1[CH:37]=[CH:38][C:23]2[N:22]3[C:3]([CH2:4][CH3:5])=[CH:2][C:1](=[O:7])[N:20]=[C:21]3[CH2:27][N:26]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])[C:24]=2[CH:35]=1
Reactant: NC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Reactant: CC#CCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCc1cc(=O)nc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 16 carbonyldiimidazole β-pentynoic acid and 2-amino-7-chloro-5-(o-chlorophenyl)-3H-1,4-benzodiazepine were stirred in tetrahydrofuran-di-methylformamide to give 9-chloro-1-ethyl-7-(o-chlorophenyl) pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [CH2:1]([SH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C>[C:26]1([NH:32][C:33](=[O:34])[S:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCCCCCCCCCCCCCCCCCS
Reactant: O=C=Nc1ccccc1
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCCCSC(=O)Nc1ccccc1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
To a mixture of 15.69 g (54.8 mmol) of octadecanethiol, 250 ml of acetonitrile, and 5 ml (4.9 g, 62 mmol) of pyridine and under a nitrogen atmosphere, 6.52 g (0.54.8 mmol) of phenylisocyanate were added all at once. The mixture was heated to reflux for 2 hours, then cooled to room temperature. The product crystallized, was collected by filtration, and was recrystallized from acetonitrile to give 19.19 g of S-octadecyl phenylcarbamothioate (Compound PS-1), mp 85.5–86.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=3)[NH:8][C:7]=2[CH:20]=1.[C:21]1([NH2:28])[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1.[CH3:29][N:30]([CH3:40])[C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1>>[CH3:29][N:30]([CH3:40])[C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([NH:28][C:15](=[O:17])[C:14]3[CH:13]=[CH:12][C:11]([C:9]4[NH:8][C:7]5[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[N:10]=4)=[CH:19][CH:18]=3)=[CH:22][CH:23]=2)=[O:36])=[CH:33][CH:32]=1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Reactant: COc1ccc2nc(-c3ccc(C(=O)O)cc3)[nH]c2c1
Reactant: Nc1ccc(N)cc1
Product: COc1ccc2nc(-c3ccc(C(=O)Nc4ccc(NC(=O)c5ccc(N(C)C)cc5)cc4)cc3)[nH]c2c1

Procedure:
Compound 625 was prepared according to the procedure similar to that described in Scheme III from 4-(6-methoxy-1H-benzo[d]imidazol-2-yl)benzoic acid, 1,4-phenylenediamine, and 4-dimethylaminobenzoic acid. [M+H]+ calcd for C30H27N5O3: 506.21; found: 506.05.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][O:20][CH3:21])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][O:20][CH3:21])=[CH:13][CH:12]=2)[C:3]([OH:22])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COCC#Cc1ccc(C(CC2CCCC2)C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCC#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(3-methoxy-prop-1-ynyl)-phenyl]-propionic acid methyl ester (485 mg, 1.61 mmol) in tetrahydrofuran (10 mL) and water (10 mL) was treated with lithium hydroxide (775 mg, 18.5 mmol). The reaction mixture was stirred at 25° C. for 48 h. At this time, the reaction was concentrated in vacuo. The residue was re-dissolved in water (40 mL) which was then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2×40 mL). The aqueous layers were back extracted with ethyl acetate (1×40 mL). The combined organic extracts were then washed with a half-saturated aqueous sodium chloride solution (1×40 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-[4-(3-methoxy-prop-1-ynyl)-phenyl]-propionic acid (447 mg, 96.7%) as a white solid: mp 82-85° C.; EI-HRMS m/e calcd for C18H22O3 (M+) 286.1568, found 286.1563.