Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C@H:13]([OH:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][C:6]=1[NH:22][C:23](=[O:39])[CH2:24][CH:25]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:32][C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)([CH3:4])([CH3:3])[CH3:2].[C:40]1(=[O:47])[O:46][C:44](=[O:45])[CH2:43][CH2:42][CH2:41]1>>[C:40]([O:21][C@@H:13]([CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[C:6]([NH:22][C:23](=[O:39])[CH2:24][CH:25]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=3[O:32][C:33]3[C:38]2=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:7]=1)[CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)(=[O:47])[CH2:41][CH2:42][CH2:43][C:44]([OH:46])=[O:45]
Reactant: O=C1CCCC(=O)O1
Reactant: CC(C)(C)c1ccc(CC[C@H](O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Product: CC(C)(C)c1ccc(CC[C@@H](CC2CCCCC2)OC(=O)CCCC(=O)O)cc1NC(=O)CC1c2ccccc2Oc2ccccc21

Procedure:
Following a procedure similar to that described in Example 56, but using (S)-N-[2-t-butyl-5-(4-cyclohexyl-3-hydroxybutyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 102) and glutaric anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a foam-like material.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C:24]([C:26]1[C:27]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:25])[CH:17]=[CH:16]2)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:42](O)(=[O:45])[CH2:43][CH3:44].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.C(N(CC)CC)C>[C:4]1([C@H:3]([NH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([NH:23][C:24]([C:26]2[C:27]([C:32]4[CH:33]=[CH:34][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:36][CH:37]=4)=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:25])[CH:17]=[CH:16]3)=[O:12])[CH2:2][NH:1][C:42](=[O:45])[CH2:43][CH3:44])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NC[C@@H](NC(=O)c1ccc2nc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccc1
Reactant: CCC(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CCC(=O)NC[C@@H](NC(=O)c1ccc2nc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(S)-2-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-6-carboxylic acid (2-amino-1-phenyl-ethyl)-amide (N, 30 mg, 0.05 mM), proprionic acid (0.075 mM), EDC (14 mg, 0.075 mM), HOBT (11 mg, 0.075 mM), and triethylamine (0.03 mL, 0.21 mM) were taken up in CH2Cl2 (1 mL) and stirred at room temperature for 16 h. The mixture was concentrated and the residue was purified by flash chromatography (silica gel) eluting with EtOAc/hexanes. HPLC retention time, 2.87 min; ESMS (m+1), 611; calc. Mw, 610
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1.Cl.CCOCC>C(Cl)Cl.CCOCC>[ClH:1].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([N:10]2[CH2:11][CH2:12][C:7]3[NH:6][C:5]4[N:13]=[CH:14][C:2]([Cl:1])=[CH:3][C:4]=4[C:8]=3[CH2:9]2)=[O:33])=[CH:27][CH:26]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(Nc1ccc(Cl)cc1)N1CCc2[nH]c3ncc(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.2 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol), and DIEA (0.04 mL, 0.24 mmol) were dissolved in DCM (2 mL). 4-Chlorophenyl isocyanate (0.03 mL, 0.26 mmol) was added dropwise, and the reaction solution was stirred overnight at room temperature. The crude reaction mixture was concentrated, and converted to the HCl salt by dissolving the crude material in MeOH (2 ml) and adding 1 M HCl/ether (2 equiv). The resulting solution was refrigerated overnight. Additional ether was added to drive precipitate formation. The resulting precipitate was filtered and dried under vacuum to provide 29 (54 mg, 57% yield) as a yellow solid. LC-MS (M+H=362, obsd.=362).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[F:8][C:9]([F:42])([F:41])[C:10]1[CH:11]=[C:12]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:13][NH:14][CH:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]2[CH:29]=[C:30]([Br:33])[CH:31]=[CH:32][C:16]1=2.N1C=CC=CC=1>ClCCl>[C:1]([N:14]([CH2:13][C:12]1[CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=[C:10]([C:9]([F:8])([F:41])[F:42])[CH:11]=1)[CH:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]2[CH:29]=[C:30]([Br:33])[CH:31]=[CH:32][C:16]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(Br)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)(C)C)c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Add 3,5-bis(trifluoromethyl)benzylamine (1.49 g, 6.13 mmol) followed by titanium isopropoxide (1.60 mL, 5.47 mmol) to a solution of tert-butyl 8-bromo-5-oxo-2,3,4,5-tetrahydro benzo[b]azepine-1-carboxylate (1.49 g, 4.38 mmol) in tetrahydrofuran (17.5 mL) at room temperature under nitrogen and stir the solution for 14 h. Dilute the reaction with methanol (35 mL) and slowly add sodium borohydride (0.248 g, 6.57 mmol) to the reaction and stir at room temperature for 3 h. Add 2 N NaOH (20 mL) and water (20 mL) to the reaction and stir for 0.5 h. Filter the mixture and wash the solids with ethyl acetate (3×75 mL). Separate the filtrate and wash the organic layer with brine (25 mL), then dry the solution over sodium sulfate, filter and remove the solvent under reduced pressure to afford tert-butyl 5-(3,5-bistrifluoromethylbenzylamino)-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate as a white solid. Add acetic anhydride (6.0 mL, 64.0 mmol) dropwise to a suspension of tert-butyl 5-(3,5-bistrifluoromethylbenzylamino)-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (2.42 g, 4.26 mmol) and pyridine (5.2 mL, 64.0 mmol) in dichloromethane (17 mL) under nitrogen cooled to 0° C. After the addition is complete, remove the cooling bath and warm the reaction to room temperature and stir for 12 h. Dilute the mixture with dichloromethane (25 mL) and wash with 2 M potassium hydrogen sulfate and saturated aqueous sodium bicarbonate (25 mL each). Dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using chromatography on silica gel, eluting with hexanes/ethyl acetate (60:40), to afford the title compound as a white solid.
Reaction SMILES: [OH-:1].[Na+].BrBr.[F:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[C:14](=[O:16])C>O.O1CCOCC1>[F:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[C:14]([OH:16])=[O:1]
Reactant: [OH-]
Reactant: COc1ccc(C(C)=O)c(F)c1
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C(=O)O)c(F)c1
Yield: 82.7 %

Procedure:
23.30 g of sodium hydroxide was dissolved in 118 mL of water and was ice-cooled, to which 9.23 mL of bromine was added dropwise over 20 minutes and then a solution of 9.80 g of 1-(2-fluoro-4-methoxyphenyl)-1-ethanone in 88 mL of 1,4-dioxane was added dropwise over one hour at −10° C. The resultant reaction mixture was cooled to room temperature, to which water was added, and then an aqueous phase was separated therefrom. A solution of 7.23 g of sodium thiosulfate in 100 mL of water was added to the aqueous phase, and then 12M hydrochloric acid was further added until the pH value of this aqueous phase reached 2. The resultant precipitate was filtered therefrom and washed with water to yield 8.20 g of 2-fluoro-4-methoxybenzoic acid as white solid.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:22])[CH3:2].N.[Li].[Cl-].[NH4+]>NC1C=CC=CC=1.O1CCCC1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:22])[CH3:2]
Reactant: CC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CC[C@@H]2O
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: Nc1ccccc1
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reaction time: 2 h
Yield: 82.8 %

Procedure:
To 13β-ethyl-3-methoxy-gona-1,3,5(10), 8-tetraen-17β-ol (16.8 g.) dissolved in a mixture of aniline (150 cc.) and tetrahydrofuran (50 cc.) add liquid ammonia (400 cc.). Add lithium metal (6.0 g.) gradually in small pieces during 10 minutes, and stir the blue suspension obtained. After 2 hours, add ammonium chloride (50 g.) to the reaction mixture until a clear solution is obtained; then add water (600 cc.) and ether-extract the mixture. Evaporate the washed and dried extracts to obtain as residue a crystalline solid. Recrystallize from hexane (300 cc.), to obtain 13β-ethyl-3-methoxy-gona-1,3,5(10)-trien-17β-ol (14 g.), m.p. 126°-30°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([NH:21][NH:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=O)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.P(Cl)(Cl)(Cl)=O>>[CH2:17]([S:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:4]=[C:3]([C:19]3[O:30][C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:22][N:21]=3)[C:2]([NH2:1])=[N:7][CH:6]=2)[CH2:9][CH2:10]1)(=[O:16])=[O:15])[CH3:18]
Reactant: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)NNC(=O)c3ccccc3)n2)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3nnc(-c4ccccc4)o3)n2)CC1
Temperature: 100 °C
Yield: 101.9 %

Procedure:
A mixture of 3-amino-N′-benzoyl-6-(4-ethylsulfonylpiperazin-1-yl)pyrazine-2-carbohydrazide (50 mg, 0.1153 mmol) in phosphorus oxychloride (884.0 mg, 537.4 μL, 5.765 mmol) was heated at 100° C. for 3 hours. The mixture was allowed to cool to RT and added carefully to ice water. The mixture was extracted with EtOAc (3×10 mL) and the combined organics washed with 1N NaOH and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound (48.8 mg, 80% Yield). 1H NMR (400.0 MHz, DMSO) d 1.24 (3H, t), 3.11 (2H, q), 3.33-3.36 (4H, m), 3.56 (4H, masked signal), 6.95 (2H, br s), 7.63-7.69 (3H, m), 8.11-8.13 (2H, m), 8.28 (1H, s) ppm; MS (ES+) 416.01
Reaction SMILES: F[C:2]1[CH:3]=C(C2C=CC(OCCCCCCCC)=C(F)C=2)C=C[C:7]=1O.[CH2:25]([C@@H:30]1[CH2:33][C@H:32]([C:34]([Cl:36])=[O:35])[CH2:31]1)[CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:25]([CH:30]1[CH2:31][CH:32]([C:34]([Cl:36])=[O:35])[CH2:33]1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:7][CH2:2][CH3:3]
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)c(F)c2)cc1F
Reactant: CCCCC[C@H]1C[C@@H](C(=O)Cl)C1
Product: CCCCCCCCC1CC(C(=O)Cl)C1
Yield: 120.8 %

Procedure:
Except that 0.60 g of the crude 3,3'-difluoro-4-hydroxy-4'-octyloxybiphenyl obtained in Example 5-(c) was used in place of 0.7 g of the crude 3,3'-difluoro-4-hydroxy-4'-decyloxybiphenyl and 0.4 g of cis-3-pentylcyclobutanecarboxylic acid chloride obtained in (b) above in place of 0.5 g of the 3-octylcyclobutanecarboxylic acid chloride used in Example 9-(g) and purification was carried out by way of column chromatography on silica gel (eluent: hexane/benzene=2/1), the operation was performed in the same manner as in Example 9-(g) to obtain 0.58 g (yield 63.3%) of 3,3'-difluoro-4-octyloxybiphenyl-4'-yl cis-3-pentylcyclobutanecarboxylate.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3](O)=[O:4].S(Cl)([Cl:21])=O>C(Cl)Cl>[N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([Cl:21])=[O:4]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)[C@@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
A mixture of Z-L-Pro-OH E-1 (10.0 g, 40.1 mmol, 1 equiv.) and thionyl chloride (30 mL, 401.2 mmol, 10 equiv.) in DCM (200 mL) is heated to reflux under nitrogen for 20 minutes and concentrated in vacuo. The residual oil is coevaporated with toluene 3×, and concentrated to give Z-L-Pro-Cl as an opaque oil.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].Cl.[NH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].N1C=CC=CC=1.O>ClCCl>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([NH:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:3])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)CCNC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
180 mg of 4-nitrophenyl chloroformate was dissolved in 3.0 ml of dichloromethane, and 140 mg of ethyl 3-aminopropanoate hydrochloride and 0.15 ml of pyridine were added, followed by overnight stirring at room temperature. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and then concentrated under a reduced pressure. By purifying the resulting residue by silica gel column chromatography, 180 mg of ethyl 3-{[(4-nitrophenoxy)carbonyl]amino}propanoate was obtained. 180 mg of ethyl 3-{[(4-nitrophenoxy)carbonyl]amino}propanoate was dissolved in 2.0 ml of dichloromethane, and 220 mg of 3-amino-7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoroquinolin-4(1H)-one and 0.15 ml of pyridine were added, followed by overnight stirring at room temperature. Water was added, followed by extraction with chloroform. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then filtered and concentrated under a reduced pressure. By purifying the resulting residue by silica gel column chromatography, 120 mg of ethyl 3-[({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]amino}carbonyl)amino]propanoate was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:35]([O:41][CH2:42][CH3:43])(=[O:40])[CH2:36]C([O-])=O.[K+].[Cl-].[Mg+2].[Cl-]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH3:14])[C:10](=[O:12])[CH2:36][C:35]([O:41][CH2:42][CH3:43])=[O:40])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)CC(=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Reaction time: 144 h
Yield: 81.2 %

Procedure:
A solution of (2S,3R)-2-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)butanoic acid (614b) (1.01 g, 3.03 mmol) in THF (10 mL) was treated with 1,1′-carbonyldiimidazole (Aldrich) (0.59 g, 3.63 mmol) and heated at 60° C. for 2 h. A mixture of potassium ethyl malonate (Aldrich) (1.03 g, 6.06 mmol) and magnesium chloride (Aldrich) (0.58 g, 6.06 mmol) was added to the solution and heating was continued at 50° C. for 6 d. The suspension was extracted into EtOAc (2×100 mL) from saturated brine (100 mL) containing 1.0 M aq. HCl (25 mL). The combined organic extracts were washed with saturated aq. NaHCO3 (100 mL), back-extracting with EtOAc (100 mL). The organic extracts were dried (MgSO4) and concentrated to give (4S,5R)-ethyl 4-((tert-butoxycarbonyl)amino)-5-((tert-butyldimethylsilyl)oxy)-3-oxohexanoate (614) (995 mg, 2.46 mmol, 81% yield) as a pale yellow oil. LC-MS m/z 426.0, [M+Na]+.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH:20][S:28]([CH3:27])(=[O:30])=[O:29])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCN1CC2C(C1)C2(C)c1cccc(N)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(NS(C)(=O)=O)c1
Reaction time: 48 h
Yield: 82.3 %

Procedure:
To a solution of 3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation 12, 200 mg, 0.735 mmol) in dichloromethane (5 ml) at room temperature was added pyridine (0.15 ml, 1.84 mmol) then dropwise over 5 minutes methane-sulfonylchloride (0.11 ml, 158 mg, 1.38 nimol). The mixture was stirred for 48 h, concentrated in vacuo and the residue was purified by silica (10 g) column chromatography eluting with 90:10:1 ethyl acetate:methanol:ammonia solution (0.880), then in 80:20:1 ethyl acetate:methanol:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (212 mg, 82%).
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)[C:9]=1[C:42]#[N:43].[C:54]([OH:60])([C:56]([F:59])([F:58])[F:57])=[O:55].O>>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]2)[C:9]=1[C:42]#[N:43].[C:54]([OH:60])([C:56]([F:59])([F:58])[F:57])=[O:55]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2C#N)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N#Cc1c(C2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Reaction time: 0.17 h

Procedure:
Tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-cyano-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (190 mg) was treated with TFA/water (95:5, 3 ml) with stirring for 10 minutes. The reaction mixture was concentrated and lyophilized to yield the title compound as TFA salt.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]([CH:10]([F:12])[F:11])=[N:8][CH:9]=1.CCN(C(C)C)C(C)C.[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29]>C(Cl)Cl>[F:11][CH:10]([F:12])[C:7]1[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:5][C:4]([CH2:3][NH:2][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[CH:9][N:8]=1
Reactant: CC(C)C(=O)Cl
Reactant: CCOC(=O)c1cc(CN)cnc1C(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc(CNC(=O)C(C)C)cnc1C(F)F
Yield: 73.6 %

Procedure:
In a thermally controlled reactor stir a mixture of ethyl 5-(aminomethyl)-2-(difluoromethyl)pyridine-3-carboxylate hydrochloride (198 g, 742.4 mmol, 1.0 equiv), DCM (3040 mL), and DIPEA (520 mL, 2.98 mol, 4 equiv), then add a solution of isobutyryl chloride (95 mL, 903 mmol, 1.2 equiv) at such a rate so that the internal temperature is held between 18° C. and 22° C. Stir for 90 min. Extract the reaction mixture with NaHCO3 (sat., 1 L). Add water (1 L) and DCM (1 L), and filter the resulting suspension through diatomaceous earth. Combine all organic phases, and dry over MgSO4. Remove the solids by filtration, and concentrate the filtrate under reduced pressure. Purify the resulting material by slurrying with iso-hexane:Et2O [1:1, 1 L]. Collect the solids by filtration, wash with cold iso-hexanes (500 ml), and dry under vacuum at 50° C. to give the title compound as an off-white crystalline powder (164 g). MS (m/z) 301 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][CH:28]([F:31])[CH2:29][OH:30]>>[F:27][CH:28]([F:31])[CH2:29][O:30][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1
Reactant: OCC(F)F
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCC(F)F)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.184 mmol), intermediate 42.1, and 2,2-difluoroethanol (48 μl; 0.736 mmol), example 60 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:41])[C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=3)=[C:12]([NH:27][C:28]3[C:29]4[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[N:34][C:30]=4[N:31]=[CH:32][N:33]=3)[CH:11]=2)=[N:6][CH:7]=1.[C:42](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:43].[Na+].C(=O)C>ClCCl.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:41])[C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]([CH2:42][CH3:43])[CH2:24][CH2:25][CH3:26])=[CH:21][CH:22]=3)=[C:12]([NH:27][C:28]3[C:29]4[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[N:34][C:30]=4[N:31]=[CH:32][N:33]=3)[CH:11]=2)=[N:6][CH:7]=1
Reactant: CCCNc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cn3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCN(CC)c1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cn3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.1 %

Procedure:
To the product of Example 378 (31 mg, 0.05 mmol) and sodium triacetoxyborohydride (414 mg, 2.0 mmol) in dichloromethane/methanol (5 mL, 9:1) was added acetaldehyde (112 μL, 2.0 mmol). The mixture was stirred at room temperature for 16 hours and evaporated. The residue was partitioned between saturated sodium carbonate solution and ethyl acetate. The organic layer was washed with water, dried with magnesium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with dichloromethane/methanol (99:1) to give the title compound (25 mg, 77%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 0.90 (t, J=7.35 Hz, 3 H) 1.09 (t, J=6.99 Hz, 3 H) 1.34 (d, J=6.99 Hz, 6 H) 1.55 (m, 2 H) 3.24 (m, 3 H) 3.38 (q, J=6.99 Hz, 2 H) 6.71 (d, J=8.82 Hz, 2 H) 6.87 (d, J=8.82 Hz, 1 H) 7.26 (d, J=8.82 Hz, 2 H) 7.63 (d, J=8.46 Hz, 1 H) 7.88 (d, J=8.46 Hz, 1 H) 8.04 (d, J=2.57 Hz, 1 H) 8.07 (d, J=2.21 Hz, 1 H) 8.17 (m, 1 H) 8.49 (d, J=1.84 Hz, 1 H) 8.58 (s, 1 H) 8.89 (d, J=8.46 Hz, 1 H) 10.13 (s, 1 H) 10.91 (s, 1 H); (ESI+) m/z 656, 658 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[O:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[CH2:14]1.Cl>CCOCC>[F:9][C:2]([F:1])([F:8])[C:3]([CH:14]1[C:15](=[O:22])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:13]1)=[O:5]
Reactant: O=C1COc2ccccc21
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: O=C1c2ccccc2OC1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h
Yield: 86.5 %

Procedure:
Ethyl trifluoroacetate (1.90 g, 14 mmol) was dissolved in ether (15 mL) and treated with sodium methoxide (25%) (3.67 g, 17 mmol). To the stirred solution was added 3-coumaranone (1.50 g, 11 mmol). The reaction was stirred at room temperature overnight (19 hours) and treated with 3N HCl (8 mL). The organic layer was collected, washed with brine, dried over MgSO4, and concentrated in vacuo to give a reddish brown solid (2.19 g, 85%): mp 108°-111° C.; 1H NMR (CDCl3) 300 MHz 7.84 (d, J=8.1 Hz, 1H) 7.66 (m, 1H) 7.52 (d, J=8.7 Hz, 1H) 7.37 (m, 1H). Mass spectrum: M+H=231.