Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C2OC(C(F)(F)F)=C(C(NC3C=CC(N4CCN(C(C5CCCC5C(O)=O)=O)CC4)=CC=3)=O)N=2)C=CC=CC=1.[C:41]1([C:47]2[O:48][C:49]([C:78]([F:81])([F:80])[F:79])=[C:50]([C:52]([NH:54][C:55]3[CH:60]=[CH:59][C:58]([N:61]4[CH2:66][CH2:65][N:64]([C:67]([CH:69]5[CH2:74][CH2:73][CH2:72][CH:71]([C:75]([OH:77])=[O:76])[CH2:70]5)=[O:68])[CH2:63][CH2:62]4)=[CH:57][CH:56]=3)=[O:53])[N:51]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.COC(C1CCCC(C(N2CCN(C3C=CC(NC(C4N=C(C5C=CC=CC=5)OC=4C(F)(F)F)=O)=CC=3)CC2)=O)C1)=O.[OH-].[Li+]>>[C:41]1([C:47]2[O:48][C:49]([C:78]([F:79])([F:80])[F:81])=[C:50]([C:52]([NH:54][C:55]3[CH:60]=[CH:59][C:58]([N:61]4[CH2:66][CH2:65][N:64]([C:67]([C@@H:69]5[CH2:74][CH2:73][CH2:72][C@H:71]([C:75]([OH:77])=[O:76])[CH2:70]5)=[O:68])[CH2:63][CH2:62]4)=[CH:57][CH:56]=3)=[O:53])[N:51]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Nc1ccc(N2CCN(C(=O)C3CCCC(C(=O)O)C3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: COC(=O)C1CCCC(C(=O)N2CCN(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)C1
Agent: O=C(Nc1ccc(N2CCN(C(=O)C3CCCC3C(=O)O)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: [Li+]
Product: O=C(Nc1ccc(N2CCN(C(=O)[C@@H]3CCC[C@H](C(=O)O)C3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a method similar to that used for the preparation of rac-2-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid above, racemic 3-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid was prepared from 3-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid methyl ester and lithium hydroxide. The crude racemate was purified by chiral supercritical fluid chromatography (second eluting peak) to yield (1S,3R)-3-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid as an off-white solid. ES-MS calcd for C29H29F3N4O5 (m/e) 570.57, obsd 571.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1OC1C.CCN(CC)CC.C1OC1C>C(Cl)(Cl)Cl.CCN(CC)CC.CN(P(N(C)C)(N(C)C)=O)C>[CH3:13][O:12][C:11]1[C:2]([O:1][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:3]2[C:8](=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=1)[N:7]=[CH:6][CH:5]=[C:4]2[CH3:17]
Reactant: BrCCCCCCc1ccccc1
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1O
Agent: CC1CO1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCCc1ccccc1
Reaction time: 24 h
Yield: 58.3 %

Procedure:
To a stirred mixture of 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline (2.3 g, 0.01 mole), 1-bromo-6-phenylhexane (2.4 g, 0.01 mole) and HMPA (25 ml), at 130° C., was added dropwise, during 2 h, a mixture of Et3N (1 ml) and propylene oxide (9 ml). After four more hours, an additional 10 ml of the Et3N-propylene oxide mixture was introduced. Heating was continued for 24 h and 1.2 g (0.005 mole) of 1-bromo-6-phenylhexane was added followed by another 10 ml of Et3N-propylene oxide. This final mixture was heated for 6 h, allowed to cool, diluted with CHCl3 (50 ml), placed on a silica gel column and eluted with CHCl3. Concentration of the yellow eluate gave 2.3 g of 6-methoxy-4-methyl-8-nitro-5-(6-phenylhexoxy) quinoline as an oil which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11](Cl)=[O:12].[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:43])[CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[CH:17][N:16]=1>>[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:11]([C:3]4[N:2]([CH3:1])[C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)=[O:12])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:43])[CH2:35][CH2:36][N:37]2[CH2:38][CH2:39][O:40][CH2:41][CH2:42]2)=[CH:17][N:16]=1
Reactant: Cn1c(C(=O)Cl)cc2ccccc21
Reactant: COc1cc(-c2csc3c(NC(=O)CCN4CCOCC4)cnc(N)c23)ccc1N
Product: COc1cc(-c2csc3c(NC(=O)CCN4CCOCC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using 1-methyl-1H-indole-2-carbonyl chloride, N-[4-amino-3-(4-amino-3-methoxyphenyl)thieno[3,2-c]pyridin-7-yl]-3-morpholin-4-ylpropanamide, and the procedure described in General Procedure F. m/z (M+H)+ 585.4.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:5]2[N:15]=[C:16]([C:18]3[C:27]([CH3:28])=[N:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH:17]=[C:4]2[N:3]=1.Cl.[F:30][C@@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1.C(N(C(C)C)CC)(C)C.O>CN1CCCC1=O>[F:30][C@@H:31]1[CH2:35][CH2:34][N:33]([C:2]2[CH:7]=[C:6]([NH:8][CH:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[N:5]3[N:15]=[C:16]([C:18]4[C:27]([CH3:28])=[N:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[CH:17]=[C:4]3[N:3]=2)[CH2:32]1
Reactant: Cc1nc2ccccc2nc1-c1cc2nc(Cl)cc(NC3CCOCC3)n2n1
Reactant: F[C@@H]1CCNC1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1nc2ccccc2nc1-c1cc2nc(N3CC[C@@H](F)C3)cc(NC3CCOCC3)n2n1
Temperature: 80 °C

Procedure:
To a suspension of 5-chloro-2-(3-methylquinoxalin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (Example 1.001 (g)) (4.26 g, 10.8 mmol), (R)-3-fluoropyrrolidine hydrochloride (13.7 g, 108 mmol), and diisopropylethylamine (20.7 g, 160 mmol) in N-methyl-2-pyrrolidinone (108 mL) was heated 80° C. for 3 days. After being cooled to ambient temperature, the reaction mixture was poured into water. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over sodium sulfate, filtrate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (silica gel 800 g, hexane:ethyl acetate=1:1 to ethyl acetate) to give 5-[(3R)-3-fluoropyrrolidin-1-yl]-2-(3-methylquinoxalin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine. MS (APCI): m/z 448 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][NH:12]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:30](Cl)(=[O:33])[O:31][CH3:32]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][N:12]2[C:30]([O:31][CH3:32])=[O:33])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2cccc(C(C)(C)C)c2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2cccc(C(C)(C)C)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.2 %

Procedure:
Methyl 2-(3-tert-butylphenyl)piperidine-4-carboxylate (2.56 g, 9.30 mmol) was dissolved in DCM (100 mL) and DIPEA (2.429 mL, 13.94 mmol) added followed by methyl carbonochloridate (0.9 mL, 11.43 mmol) at 0° C. The solution was stirred at room temperature for 1 h. The reaction mixture was washed with 1 M aq HCl (pH 4) followed by brine, satd NaHCO3. The organic phase was passed through a phase separator and evaporated to yield dimethyl 2-(3-tert-butylphenyl)piperidine-1,4-dicarboxylate (3.17 g, quant.) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]([CH3:19])=[CH:16][C:17]([NH2:18])=[C:12]2[N:11]=[C:10]1[CH3:20].C(N(CC)C(C)C)(C)C.[Cl:30][CH2:31][C:32](Cl)=[O:33].C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]([CH3:19])=[CH:16][C:17]([NH:18][C:32](=[O:33])[CH2:31][Cl:30])=[C:12]2[N:11]=[C:10]1[CH3:20]
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(N)c2nc(C)n(-c3ccc(Cl)cc3Cl)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1cc(NC(=O)CCl)c2nc(C)n(-c3ccc(Cl)cc3Cl)c2n1
Temperature: 25 °C

Procedure:
Treat a solution of 3-(2,4-dichlorophenyl)-2,5-dimethylimidazolo[5,4-b]pyridin-7-ylamine (0.2 g, 0.65 mmol), and N,N-diisopropylethylamine, (0.12 mL, 0.72 mmol) in 1,2-dichloroethane (10 mL) with chloroacetyl chloride (0.06 mL, 30.72 mmol). Heat the solution to reflux for 2 h, cool to ambient temperature, and pour into an aqueous potassium carbonate solution. Extract the resulting mixture with CH2Cl2 and wash with saturated aq NaCl. Separate the organic layer, dry over Na2SO4, filter, and concentrate. Purify by preparative TLC (5% methanol in CH2Cl2) to obtain the title compound as a yellow solid.
Reaction SMILES: [ClH:1].Cl.[CH:3]1([N:7]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.C1C=CC2N(O)N=NC=2C=1.[O:54]=[S:55]1(=[O:70])[CH2:60][CH2:59][N:58]([C:61]2[CH:69]=[CH:68][C:64]([C:65](O)=[O:66])=[CH:63][CH:62]=2)[CH2:57][CH2:56]1>C(Cl)Cl.C(Cl)CCl>[ClH:1].[CH:3]1([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([C:65]([C:64]3[CH:63]=[CH:62][C:61]([N:58]4[CH2:57][CH2:56][S:55](=[O:70])(=[O:54])[CH2:60][CH2:59]4)=[CH:69][CH:68]=3)=[O:66])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: O=C(O)c1ccc(N2CCS(=O)(=O)CC2)cc1
Reactant: C1CC(N2CCCNCC2)C1
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Agent: Cl
Solvent: C=Cc1ccccc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(c1ccc(N2CCS(=O)(=O)CC2)cc1)N1CCCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.4 %

Procedure:
1-(Cyclobutyl)-hexahydro-1H-1,4-diazepine dihydrochloride (D4) (0.15 g) was stirred with diethylaminomethyl polystyrene (1.0 g), HOBT (0.045 g), 4-(1,1-dioxido-4-thiomorpholinyl)benzoic acid (0.186 g) in DCM (5 ml). EDC (0.165 g) was then added and the reaction was stirred at rt for 16 h. The polymer supported base was filtered off and the filtrate was diluted with DCM (10 ml) and washed with saturated sodium hydrogen carbonate (2×15 ml). The organic layer was then loaded directly onto a silica column and eluted with 0-10% MeOH (containing 10% 0.880 ammonia solution)/DCM. The isolated free base product was dissolved in DCM (5 ml) and treated with excess 1N HCl/diethyl ether solution (1 ml) and stirred for 10 min. The mixture was evaporated (co-evaporated with acetone 2×10 ml), triturated with acetone, then dried at 50° C. under high vacuum for 16 h to yield the title compound (E9) as a pale solid (0.086 g). MS electrospray (+ion) 392 (MH+). 1H NMR δ (DMSO-d6): 10.5 (1H, s), 7.37 (2H, d, J=8.4 Hz), 7.07 (2H, d, J=8.8 Hz), 4.18-3.24 (10H, m), 3.11 (4H, m), 3.10-2.85 (2H, m), 2.45-1.98 (7H, m), 1.80-2.54 (2H, m).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][C:9]([OH:11])=[O:10].C(N(CC)CC)C.[C:19]([O:23][C:24](N=[N+]=[N-])=[O:25])([CH3:22])([CH3:21])[CH3:20]>CC(C)=O>[C:19]([O:23][C:24]([NH:1][CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][C:9]([OH:11])=[O:10])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Reactant: NCc1ccsc1CC(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccsc1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
A mixture of 3-aminomethyl-2-thienylacetic acid 8 (3.1 g, 18 m moles) and triethylamine (8 g, 80 m moles) in 50% aqueous acetone (80 ml) was added dropwise t-butoxycarbonyl azide (5.7 g, 40 m moles) over a period of 20 mins. at 0° C. with vigorous stirring. The reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure. The concentrate was washed with ether (2×20 ml), adjusted to pH 2 with conc. HCl and extracted with ethyl acetate (2×50 ml). The ethyl acetate extracts were washed with saturated aqueous sodium chloride, dried over MgSO4, treated with charcoal and evaporated under reduced pressure. The residue was triturated with n-hexane and crystallized from n-hexane and benzene to give 4.5 g (92%) of colorless needles 9, melting at 62°-63° C.
Reaction SMILES: [C@@H:1]12[N:8]([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]=[C:2]2[C:10]([O:12]CC)=O.[Si](Cl)(C)(C)[CH3:16].[Li]C>C1COCC1>[C:10]([C:2]1[C@@H:1]2[N:8]([CH3:9])[C@H:5]([CH2:4][CH:3]=1)[CH2:6][CH2:7]2)(=[O:12])[CH3:16]
Reactant: CCOC(=O)C1=CC[C@@H]2CC[C@H]1N2C
Reactant: C[Si](C)(C)Cl
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(=O)C1=CC[C@@H]2CC[C@H]1N2C
Temperature: -100 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a mixture of ethyl trop 2-ene-2-carboxylate (3.43 g, 0.019 mol) and Me3SiCl (10.32 g, 0.095 mol) in THF (70 mL) cooled to -100° C., MeLi (1.4M, 17.07 mL, 0.0239 mol) was added dropwise. After warming up to room temperature, the reaction mixture was stirred for 16 hours. Excess Me3SiCl and THF was evaporated off and the resulting residue was stirred with EtOH (6 mL) followed by water (6 mL). The mixture was then made acidic (6N HCl) and extracted with ether. The aqueous layer was made basic (solid K2CO3) and extracted with chloroform, dried (K2CO3) and concentrated to give 3.14 g (81%) of 2-acetyltrop-2-ene as an oil: IR (neat) 1670 (COCH3); 1H NMR (CDCl3) δ6.7 (bt, 1H), 2.3 (s, NCH3), 2.2 (s, C(≡O)CH3).
Reaction SMILES: CI.[CH3:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:7]=1[NH:15][C:16]([NH:18][S:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])(=[O:21])=[O:20])=[O:17])[CH3:5].N12CCCN=C1CCCC[CH2:37]2>CC#N.CCOC(C)=O>[CH3:14][CH:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:4]([CH3:3])[CH3:5])[C:7]=1[NH:15][C:16]([N:18]([CH3:37])[S:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])(=[O:20])=[O:21])=[O:17])[CH3:13]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCCCCCCCCCCCCCS(=O)(=O)NC(=O)Nc1c(C(C)C)cccc1C(C)C
Solvent: CC#N
Solvent: CI
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCS(=O)(=O)N(C)C(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
CH3I (0.15 mL, 2.3 mmoles) was added dropwise to a room temperature solution of N-[2,6-bis(1-methylethyl)phenyl]-N'-(tetradecylsulfonyl)urea (1.0 g, 2.08 mmoles) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.34 mL, 2.3 mmoles), stirring in 10 mL of CH3CN. The solution was stirred overnight at room temperature, diluted with EtOAc, washed with 1M HCl, H2O, brine, and dried (MgSO4). Filtration and evaporation afforded an oil which was flash chromatographed (silica gel, 10:1 hexane-ethyl acetate) to provide 800 mg of a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][NH:32][CH:33]=2)O1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:8]2([C:5]3[CH:6]=[CH:7][C:2]([C:29]4[CH:30]=[N:31][NH:32][CH:33]=4)=[CH:3][CH:4]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:15][CH:16]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Clc1ccc(C2(c3ccc(Br)cc3)CCNCC2)cc1
Product: Clc1ccc(C2(c3ccc(-c4cn[nH]c4)cc3)CCNCC2)cc1

Procedure:
4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-piperidine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-A3) Rt 7.22 [M+H]+ 338.08. 1H NMR (Me-d3-OD) δ 2.64-2.74 (4H, m), 3.22-3.25 (4H, m), 7.33-7.45 (6H, m 7.65 (2H, d), 8.37 (2H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[O:4].Cl.OS(O)(=O)=O.[CH3:23][C:24](=[CH2:26])[CH3:25].C([O-])(O)=O.[Na+]>O1CCOCC1.CCOCC>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[CH2:8][C@@H:9]([C:11]([O:13][C:24]([CH3:26])([CH3:25])[CH3:23])=[O:12])[NH2:10])=[O:4]
Reactant: C=C(C)C
Reactant: COC(=O)c1cccc(C[C@H](N)C(=O)O)c1
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)c1cccc(C[C@H](N)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 74 %

Procedure:
A solution of 0.88 g of 3-methoxycarbonyl-L-phenylalanine.HCl, and 1.5 mL of conc. H2SO4 in 20 mL of 1,4-dioxane was added to 25 mL of liquid isobutylene (condensed at −78° C.) in a 300 mL pressure bottle equipped with a magnetic stirrer. The bottle was sealed and the mixture allowed to warm to RT with stirring. The initially heterogeneous mixture afforded a slightly cloudy solution after stirring for 18 h at RT. After 48 h the vessel was chilled in an ice water bath, opened, and the contents treated with 13 g of solid NaHCO3. The isobutylene was allowed to evaporate and the remaining mixture was concentrated in vacuo to dryness. The residue was suspended in 100 mL of water and extracted with EtOAc (4×40 mL). The combined EtOAc extracts were washed with 5% aqueous NaHCO3 (3×50 mL), dried over anhydrous MgSO4, and concentrated in vacuo to give an oil. This material was dissolved in 30 mL of ether and the solution was treated with 3.4 mL of 1M ethereal HCl. A white solid precipitated which was collected by filtration and dried in vacuo to afford 0.79 g (74%) of tert-butyl 3-methoxycarbonyl-L-phenylalaninate.HCl, m.p. 165° C. (dec).
Reaction SMILES: C1(S)C=CC=CC=1.C(Cl)(Cl)Cl.[CH3:12][C:13]([NH:21][C:22](=[O:43])[C@@H:23]([NH:35]C(OC(C)(C)C)=O)[CH2:24][S:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)([CH3:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>C(OCC)C.CCCCCC>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[CH3:20][C:13]([NH:21][C:22](=[O:43])[C@@H:23]([NH2:35])[CH2:24][S:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)([CH3:12])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(CSC[C@H](NC(=O)OC(C)(C)C)C(=O)NC(C)(C)c2ccccc2)cc1
Agent: Sc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COc1ccc(CSC[C@H](N)C(=O)NC(C)(C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.6 g of thiophenol was added to 20 ml of a chloroform solution containing 6.093 g of (2R)-N-(α,α-dimethylbenzyl)-2-(t-butoxycarbonylamino)-3-(p-methoxybenzylthio)propionamide (prepared as described in Preparation 6), and then the mixture was placed over an ice-water bath, and 15 ml of trifluoroacetic acid were added; the mixture was stirred for 20 minutes at the temperature of the ice-water bath. After additional stirring for 1.5 hours at room temperature, the solvent and excess reagents were distilled off under reduced pressure. The residue obtained was dissolved in 7 ml of diethyl ether and addition of 50 ml hexane afforded the title compound.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[H-].[Na+].CS(O[C@H:17]1[CH2:20][C@@H:19]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]1)(=O)=O>CN(C=O)C>[C:25]([O:24][C:22](=[O:23])[NH:21][C@H:19]1[CH2:18][C@H:17]([N:1]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[CH:3]=[CH:2]2)[CH2:20]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: c1cnc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](n2ccc3cccnc32)C1
Temperature: 100 °C

Procedure:
To a solution of 1H-pyrrolo[2,3-b]pyridine (44.5 mg, 0.377 mmol) in DMF (1.3 ml) at room temperature was added sodium hydride, 60% in oil (18 mg, 0.45 mmol), followed by cis-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate (100 mg, 0.38 mmol). The reaction mixture was heated at 100° C. for 16 h. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was back extracted with EtOAc (2×) and the combined organics was dried (MgSO4) and concentrated. The crude product was purified by ISCO (12 g), eluting with a gradient of EtOAc/hexane 0-50% to provide tert-butyl(trans-3-(1H-pyrrolo[2,3-b]pyridin-1-yl)cyclobutyl)carbamate (10 mg, 0.035 mmol, 9.23% yield) as off-white solid. ESI (M+1) 288.0.
Reaction SMILES: C(OP([CH:9]([CH2:17][C:18]1[N:19]=[CH:20][S:21][CH:22]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:25]=O>>[S:21]1[CH:22]=[C:18]([CH2:17][C:9](=[CH2:25])[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[N:19]=[CH:20]1
Reactant: C=O
Reactant: CCOP(=O)(OCC)C(Cc1cscn1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: C=C(Cc1cscn1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
To a stirred solution of tert-butyl 2-(diethoxyphosphoryl)-3-(1,3-thiazol-4-yl)propanoate (step 1, 7.17 g, 20.5 mmol) in tetrahydrofran (100 mL) was added sodiumhydride (60% dispersion in mineral oil, 820 mg, 20.5 mmol) at 0° C. under nitrogen. After 10 min, to the mixture was added paraformaldehyde (1.85 g, 61.5 mmol) and the mixture was stirred at room temperature for 45 min. The mixture was quenched with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (3/1) to afford 4.25 g (92%) of the title compound as a colorless oil:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[CH2:11]([O:18][C:19]1[CH:39]=[CH:38][C:22]([C:23]([CH:25]2[C:34]3[C:29](=[CH:30][C:31]([O:35][CH3:36])=[CH:32][CH:33]=3)[CH2:28][CH2:27][C:26]2=O)=[O:24])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:26]2[CH2:27][CH2:28][C:29]3[C:34]([C:25]=2[C:23](=[O:24])[C:22]2[CH:38]=[CH:39][C:19]([O:18][CH2:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:20][CH:21]=2)=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)=[CH:5][CH:4]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: COc1ccc2c(c1)CCC(=O)C2C(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C2=C(C(=O)c3ccc(OCc4ccccc4)cc3)c3ccc(OC)cc3CC2)cc1
Temperature: 45 °C

Procedure:
To a solution of about 50 grams (0.24 mole) of p-methoxyphenylmagnesium bromide in tetrahydrofuran (THF) were added at room temperature 30.2 grams (0.08 mole) of 1-(p-benzyloxybenzoyl)-6-methoxy-2-tetralone dissolved in THF. Upon completion of the addition, the entire mixture was warmed to 45° C. Analysis of a sample of the mixture by thin-layer chromatography (TLC) showed the absence of starting material. The mixture then was poured into aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate. The ethyl acetate extract was washed, dried, and evaporated. The resulting residue was dissolved in benzene, and a catalytic amount of p-toluene-sulfonic acid was added. The mixture was stirred at room temperature until a TLC of the mixture indicated the absence of any carbinol intermediate. The mixture then was washed with water, dried, and concentrated. The residue was chromatographed over one kg. of alumina using 6 l. of benzene. The product was eluted with a mixture of 2 percent ethyl acetate in benzene. The product, 3-(4-methoxyphenyl)-4-(4-benzyloxybenzoyl)-7-methoxy-1,2-dihydronaphthalene was obtained as an oil.