Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:29])[CH2:18][N:19]3[C:23]([CH3:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[N:20]3)[CH2:13][CH2:12]2)[S:9][CH:10]=1)=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1>[CH3:24][C:23]1[N:19]([CH2:18][C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=3)[CH2:16][CH2:15]2)=[O:29])[N:20]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:22]=1
Reactant: CCOC(=O)c1csc(N2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCN(c2nc(C(=O)O)cs2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A solution of ethyl-2-[4-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-1-piperazinyl]-4-thiazolecarboxylate (0.83 g, 1.93 mmol) (i.e. the product of Example 30, Step C) in a mixture of methanol (10 mL) and tetrahydrofuran (10 mL) was treated with a 1 N aqueous NaOH solution (4.0 mL, 4.0 mmol). The reaction mixture was stirred at room temperature for 2 h, then treated with 1 N aqueous hydrochloric acid solution (4.5 mL, 4.5 mmol). The resulting mixture was concentrated in vacuo and the resulting suspension was diluted with dichloromethane and filtered to give solid. The resulting solid was washed with dichloromethane and diethyl ether, and air dried to give 0.64 g of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])#[N:4].Br[CH2:14][CH2:15][O:16][CH2:17][CH2:18]Br>CN(C=O)C>[C:3]([C:5]1([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)#[N:4]
Reactant: BrCCOCCBr
Reactant: CC(C)(C)OC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1(C#N)CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
To a stirred suspension of NaH (17.7 g, 0.443 mol) in DMF (200 mL) was added dropwise tert-butyl cyanoacetate (25.0 g, 0.177 mol) in DMF (100 mL) at 0° C. under N2. The mixture was allowed to warm to ambient temperature, and stirred for 1 hour. Then, bis(2-bromoethyl)ether (49.3 g, 0.177 mol) was added to the mixture, and the resulting mixture was stirred at 90° C. for 24 h. After cooling to 0° C., the mixture was quenched with water (100 mL). The volatile components were removed by evaporation and the residue was precipitated with a mixture of EtOAc-Toluene (1:2, 500 mL) and water (500 mL). The organic phase was washed with water (500 mL) for three times, dried over Na2SO4, filtered and evaporated. The solid was washed with Hexane and dried in vacuo to give 19.0 g (57%) of the title compound as a white crystal.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12](B2OC(C)(C)C(C)(C)O2)=[C:11]([CH3:25])[CH:10]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].Br[C:27]1[C:28]([CH3:43])=[C:29]([CH:40]=[CH:41][CH:42]=1)[CH2:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][N:33]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[Si:5]([O:8][C:9]1[CH:10]=[C:11]([CH3:25])[C:12]([C:27]2[CH:42]=[CH:41][CH:40]=[C:29]([CH2:30][O:31][C:32]3[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][N:33]=3)[C:28]=2[CH3:43])=[C:13]([CH3:15])[CH:14]=1)([C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:6])[CH3:7]
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(Br)cccc1COc1ccc(C=O)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1-c1cccc(COc2ccc(C=O)cn2)c1C
Temperature: 60 °C

Procedure:
In an atmosphere of nitrogen, a mixture of tert-butyl [3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]dimethylsilane, 6-[(3-bromo-2-methylbenzyl)oxy]nicotinaldehyde, palladium acetate, dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine, tripotassium phosphate, toluene and water was stirred with heating at 60° C. for 3 days to obtain 6-[(4′-{[tert-butyl(dimethyl)silyl]oxy}-2,2′,6′-trimethylbiphenyl-3-yl)methoxy]nicotinaldehyde.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19]C)=[CH:16][CH:17]=3)[CH2:12][N:11]([CH3:21])[CH2:10]2)=[CH:5][CH:4]=1.[BrH:22]>>[BrH:22].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[CH2:12][N:11]([CH3:21])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)CN(C)CC2c1ccc(Cl)cc1
Agent: Br
Agent: Cl
Product: CN1Cc2cc(O)ccc2C(c2ccc(Cl)cc2)C1

Procedure:
The free base prepared from 12.2 g. of rac.-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline hydrochloride is stirred at reflux with 150 ml. of 48% hydrobromic acid solution for 2 hours at a bath temperature of 160°. After evaporation and recrystallization from methanol-ether there is obtained rac.-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-2-methyl-7-isoquinolinol hydrobromide of m.p. 292°-293°. The free base of this compound displays a m.p. of 189°-190° after recrystallization from ether, the hydrochloride after recrystallization from methanol-ether melts at 295°-297°.
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[C@H:5]([NH2:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1.[I:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([NH:27][S:28]([C:31]2[C:32]3[N:33]=[CH:34][CH:35]=[N:36][C:37]=3[CH:38]=[CH:39][CH:40]=2)(=[O:30])=[O:29])[CH:19]=1>>[Cl:14][C:9]1[CH:8]=[C:7]([CH2:6][C@@H:5]([NH:15][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([I:17])=[CH:19][C:20]=2[NH:27][S:28]([C:31]2[C:32]3[N:33]=[CH:34][CH:35]=[N:36][C:37]=3[CH:38]=[CH:39][CH:40]=2)(=[O:30])=[O:29])[C:4]([OH:3])=[O:16])[CH:12]=[CH:11][C:10]=1[Cl:13]
Reactant: COC(=O)[C@H](N)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: Cl
Product: O=C(N[C@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
(R)-2-(tert-Butoxycarbonylamino)-3-(3,4-dichloro-phenyl)-propionic acid was treated as in EXAMPLE 2, Part A, to produce (R)-2-amino-3-(3,4-dichloro-phenyl)-propionic acid methyl ester hydrochloride as a white solid. This ester was coupled to 4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoic acid as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC: RT=10.06 min. MS (ESI−): mass calcd. for C24H17Cl2IN4O5S, 669.93; m/z found, 669/671 [M−H]−. 1H NMR (500 MHz, CDCl3): 10.85 (s, 1H), 9.00,(d, J=1.8, 1H), 8.92 (d, J=1.7, 1H), 8.54 (dd, J=7.4, 1.2, 1H), 8.33-8.31 (m, 1H), 8.07 (d, J=1.5, 1H), 7.91-7.87 (m, 1H), 7.47-7.22 (m, 3H), 6.98 (dd, J=8.2, 2.0, 1H), 6.87 (d, J=8.3, 1H), 6.37 (d, J=7.7, 1H), 4.92-4.88 (m, 1H), 3.23 (dd, J=14.2, 5.9, 1H), 3.14 (dd, J=14.1, 6.1, 1H).
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:36][C:37]1[C:45]2[C:40](=[C:41]([NH:46][S:47]([C:50]3[S:51][CH:52]=[CH:53][CH:54]=3)(=[O:49])=[O:48])[CH:42]=[CH:43][CH:44]=2)[NH:39][C:38]=1[C:55]([NH:57][CH2:58][CH2:59][S:60]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O>ClCCl>[S:60]1[CH2:59][CH2:58][N:57]=[C:55]1[C:38]1[NH:39][C:40]2[C:45]([C:37]=1[CH3:36])=[CH:44][CH:43]=[CH:42][C:41]=2[NH:46][S:47]([C:50]1[S:51][CH:52]=[CH:53][CH:54]=1)(=[O:49])=[O:48]
Reactant: Cc1c(C(=O)NCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)[nH]c2c(NS(=O)(=O)c3cccs3)cccc12
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C2=NCCS2)[nH]c2c(NS(=O)(=O)c3cccs3)cccc12
Reaction time: 0.17 h
Yield: 41 %

Procedure:
To a solution of triphenylphosphine oxide (3.56 g) in dichloromethane (30 mL) was slowly added trifluoromethanesulfonic anhydride (1.10 mL) at 0° C. The mixture was stirred for 10 min, and 3-methyl-7-[(2-thienylsulfonyl)amino]-N-[2-(tritylthio)ethyl]-1H-indole-2-carboxamide (1.36 g) was added. The reaction mixture was stirred at room temperature for 3 hr and concentrated. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (0.33 g, yield 41%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:20→1:1, volume ratio). melting point 163-164° C.
Reaction SMILES: [Br:1][C:2]1[C:10](=[O:11])[C:6]([C:7]([OH:9])=[O:8])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]([CH3:18])[C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+:26]>CO>[Br:1][C:2]1[C:10](=[O:11])[C:6]([C:7]([O-:9])=[O:8])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]([CH3:18])[C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+:26]
Reactant: Cn1c(-c2ccccc2)c(Br)c(=O)c(C(=O)O)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(-c2ccccc2)c(Br)c(=O)c(C(=O)[O-])c1-c1ccccc1
Yield: 98.4 %

Procedure:
2.5 gms of 5-bromo-1-methyl-2,6-diphenyl-4-oxonicotinic acid, 0.286 gms of NaOH and 50 mls of dry methanol were mixed. Evaporation of the solvent provided 2.6 gms of sodium 5-bromo-1-methyl-2,6-diphenyl-4-oxonicotinate as a tan glassy solid.
Reaction SMILES: [OH-:1].[K+].Cl[C:4]1[C:5](=[O:16])[C:6]2[C:11]([C:12](=[O:15])[C:13]=1[CH3:14])=[CH:10][CH:9]=[CH:8][CH:7]=2>CO>[OH:1][C:4]1[C:5](=[O:16])[C:6]2[C:11]([C:12](=[O:15])[C:13]=1[CH3:14])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: [OH-]
Reactant: CC1=C(Cl)C(=O)c2ccccc2C1=O
Agent: [K+]
Solvent: CO
Product: CC1=C(O)C(=O)c2ccccc2C1=O

Procedure:
A solution of 10% aqueous potassium hydroxide (150 mL) was added to a solution of 2-chloro-3-methyl-1,4-naphthoquinone (10.3 g) in refluxing methanol (500 mL). After cooling and acidification with concentrated hydrochloric acid, the precipitated product was collected by filtration to give 2-hydroxy-3-methyl-1,4-naphthoquinone, m.p. 173°-174° C.
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].CN(C)[CH:8]=[CH:9][C:10](=O)[CH:11]([O:14][CH3:15])[O:12][CH3:13].C[O-].[Na+]>CO>[CH3:13][O:12][CH:11]([O:14][CH3:15])[C:10]1[CH:9]=[CH:8][N:5]=[C:2]([CH3:3])[N:4]=1
Reactant: CC(=N)N
Reactant: COC(OC)C(=O)C=CN(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ccnc(C)n1
Temperature: 40 °C
Yield: 91.3 %

Procedure:
Acetamidine hydrochloride (3 mol) and 4-dimethylamino-1,1-dimethoxy-but-3-en-2-one (2 mol) were mixed in methanol (500 ml) and the reaction mixture was warmed to 40° C. A solution of sodium methoxide in methanol (558 g, 30%) was added quickly and a brown suspension was formed. The reaction mixture was heated under reflux for 2 h, cooled to room temperature overnight followed by evaporation of methanol under reduced pressure. The resulting residue was taken up in dichloromethane (500 ml) and washed several times with water (100 mL). The solvent was removed to give 307 g of black oil. The distillation of this oil gave a colourless liquid of boiling point 55-58° C. (0.5 mbar).
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][C@H:9]1[C:19](O)=[O:20])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C(C)C)CC)(C)C.Cl.[NH2:32][C@:33]1([C:38]([NH:40][S:41]([CH:44]2[CH2:46][CH2:45]2)(=[O:43])=[O:42])=[O:39])[CH2:35][C@H:34]1[CH:36]=[CH2:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH:44]1([S:41]([NH:40][C:38]([C@@:33]2([NH:32][C:19]([C@@H:9]3[CH2:10][C@@H:11]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:12][N:8]3[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[O:20])[CH2:35][C@H:34]2[CH:36]=[CH2:37])=[O:39])(=[O:43])=[O:42])[CH2:46][CH2:45]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccccc2)C[C@H]1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](c2ccccc2)CN1C(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Reaction time: 14 h
Yield: 79.2 %

Procedure:
To a mixture of (2S,4S)-Boc-4-phenylpyrrolidine-2-carboxylic acid (0.711 g 2.44 mmol) (purchased from Chem-Impex International, Inc.), diisopropylethylamine (0.948 g, 7.33 mmol), and cyclopropanesulfonic acid (1-(R)-amino-2-(S)-vinyl-cyclopropanecarbonyl)amide HCl salt (0.561 g, 2.44 mmol) in dichloromethane (24 mL) was added HATU (1.21 g, 3.18 mmol). After stirring the reaction mixture for 14 hours, it was washed with 5% aqueous NaHCO3 (50 mL), and 5% aqueous citric acid (50 mL). Each aqueous layer was sequentially extracted with 2×25 mL dichloromethane. The combined organic layer was dried over MgSO4, filtered, and concentrated. The resulting brown viscous oil was purified by flash column chromatography (SiO2, 97:3, dichloromethane:methanol) to give (2S,4S)-tert-butyl 2-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-4-phenylpyrrolidine-1-carboxylate as a brown foamy solid (0.973 g, 79% yield). 1H NMR (CD3OD, 500 MHz) δ 0.91 (br s, 1H), 1.03 (d, J=6.4 Hz, 1H), 1.16-1.23 (m, 1H), 1.31-1.38 (m, 1H), 1.44 (dd, J=9.6, 5.6 Hz, 1H), 1.48 (s, 4H), 1.52 (s, 5H), 1.89 (t, J=6.4 Hz), 2.09 (q, J=8.4 Hz, 0.4H), 2.19 (q, J=8.6 Hz, 0.6H), 2.85-2.90 (m, 0.4H), 2.92-2.97 (m, 0.6H), 3.44 (t, J=9.6 Hz, 1H), 3.65 (p, J=8.0 Hz, 1H), 3.93-4.01 (m, 1H), 4.29 (dd, J=10.1, 6.7 Hz, 1H), 5.12 (d, J=10.1 Hz, 1H), 5.30 (d, J=18.0 Hz, 1H), 5.75-5.82 (m, 1H), 7.24 (t, J=6.9 Hz, 1H), 7.29-7.33 (m, 5H); MS m/z 504 (M+Na).
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C:13]1=[CH:19][C:20](=[N:27][C:28]3[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=3[CH3:36])[N:21]([CH2:24][CH2:25][NH2:26])[C:22](=[O:23])[N:12]1[CH2:11][CH2:10]2.Cl.[OH-].[Na+]>O>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C:13]1=[CH:19][C:20](=[N:27][C:28]3[C:29]([CH3:36])=[CH:30][C:31]([CH3:35])=[CH:32][C:33]=3[CH3:34])[N:21]([CH2:24][CH2:25][NH:26][C:2](=[O:1])[NH2:3])[C:22](=[O:23])[N:12]1[CH2:11][CH2:10]2
Reactant: COc1cc2c(cc1OC)-c1cc(=Nc3c(C)cc(C)cc3C)n(CCN)c(=O)n1CC2
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c(cc1OC)-c1cc(=Nc3c(C)cc(C)cc3C)n(CCNC(N)=O)c(=O)n1CC2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Sodium cyanate (6.0 g, 0.092 mol) in water (100 ml) was added dropwise to a stirred solution of 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one, prepared according to Preparation 4 above (20.0 g, 0.046 mol) in water (600 ml) and 1N HCl (92 ml) at 80° C. After stirring for 2 h at 80° C. the mixture was cooled in an ice-bath and basified with 2N NaOH. The mixture was extracted with dichloromethane (3×200 ml) and the combined extract was dried (MgSO4) and evaporated in vacuo. The resulting yellow foam was purified by column chromatography on silica gel eluting with CH2Cl2/MeOH (97:3) and triturated with ether to obtain the title compound as a yellow solid, 11.9 g, 54%.
Reaction SMILES: C(OCCCC)(=O)C.C(N(CC)CC)C.[CH2:16]([C:20]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]#[N:39])=[CH:28][CH:27]=2)[C:23](=[O:40])[C:22]2([CH2:44][CH2:43][CH2:42][CH2:41]2)[N:21]=1)[CH2:17][CH2:18][CH3:19].[N-:45]=[N+:46]=[N-:47].[Na+]>C(O)(=O)C>[CH2:16]([C:20]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[NH:47][N:46]=[N:45][N:39]=3)=[CH:28][CH:27]=2)[C:23](=[O:40])[C:22]2([CH2:41][CH2:42][CH2:43][CH2:44]2)[N:21]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCCCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 117.5 °C

Procedure:
A RB flask was charged with n-butyl Acetate (50 ml), triethyl amine (22 ml) and acetic acid (9 ml) and stirred. 2-(n-butyl)-3-[[2′-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one (10 g) and sodium Azide (3.4 g) was added to the flask and the reaction mixture was heated at 115-120° C. for 24 hrs, followed by cooling. The reaction was then quenched by addition of water (30 ml). The pH of the aqueous layer was adjusted between 10 to 11 with 30% Sodium hydroxide and then stirred for 10 min. Layers were separated and oily layer was treated with water and xylene. The pH of the aqueous layer was adjusted between 2 and 3 by the addition of hydrochloric acid and then stirred for 1 hour, filtered to obtain solid material which was washed with water (20 ml) and ethyl Acetate (5 ml) and dried at 90-100° C.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[C:35]([Si:39]([CH3:50])([CH3:49])[O:40][CH2:41][CH2:42][N:43]1[CH:47]=[CH:46][C:45]([NH2:48])=[N:44]1)([CH3:38])([CH3:37])[CH3:36]>C(Cl)Cl>[C:35]([Si:39]([CH3:50])([CH3:49])[O:40][CH2:41][CH2:42][N:43]1[CH:47]=[CH:46][C:45]([NH:48][C:8](=[O:10])[C@@H:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:44]1)([CH3:38])([CH3:37])[CH3:36]
Reactant: O=C(O)[C@H](CC1CCCC1)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-cyclopentyl-2(R)-(3-trifluoromethyl-phenyl)-propionic acid (92 mg, 0.32 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylfomamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 190 μL, 0.35 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes. After this time, the reaction was cooled to 0° C. and 2,6-lutidine (80 μL, 0.64 mmol) was added to the flask and it was stirred for 15 min. To this was then added a solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 78 mg, 0.32 mmol) in methylene chloride (1 mL) and the reaction was allowed to warm up to 25° C. and stirred for 2 h. After this time the reaction quenched with a small amount of methanol and then diluted with methylene chloride. The reaction was then transferred to a separatory funnel and washed with 1 N aqueous hydrochloric acid solution (1×10 mL) and then a saturated brine solution (1×10 mL). The organic layer was then dried over sodium sulfate and concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40M column, silica gel, 40% ethyl acetate/hexanes) (40S column, Silica gel, 20% ethyl acetate/hexanes) to afford N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2(R)-(3-trifluoromethyl-phenyl)-propionamide as a colorless gum: [α]25589=−14.5° (c=0.22, methanol); ES-HRMS m/e calcd for C26H38N3O2SiF3 (M+H)+ 510.2758, observed 510.2749; 1H NMR (400 MHz, DMSO-d6) δ ppm −0.09 (s, 6H, 2×SiCH3), 0.77 (s, 9H, 3×CH3), 1.06-1.18 (m, 2H, CH2), 1.37-1.79 (m, 8H, 4×CH2), 2.08-2.18 (m, 1H, CH), 3.84 (t, J=5.1 Hz, 2H, OCH2), 3.90 (dd, J=9.4, 5.3 Hz, 1H, ArCH), 4.04 (t, J=5.1 Hz, 2H, NCH2), 6.41 (d, J=2.3 Hz, 1H, Ar), 7.51 (d, J=2.3 Hz, 1H, Ar), 7.54-7.72 (m, 4H, Ar), 10.72 (s, 1H, NH).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:33])=[N:13][C:14]2[N:15]([N:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:26]=2)[C:16]=1[N:17]1[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH2:18]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:33])=[N:13][C:14]2[N:15]([N:24]=[C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:26]=2)[C:16]=1[N:17]1[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH2:18]1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3ccccc3)nn2c1N1CCC(C)(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2cc(-c3ccccc3)nn2c(N2CCC(C)(C)C2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.7 %

Procedure:
(S)-Methyl 2-(tert-butoxy)-2-(7-chloro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (50 mg, 0.13 mmol) was dissolved in DMF (1 mL) and treated with 3,3-dimethylpyrrolidine hydrochloride (17.5 mg, 0.13 mmol) followed by N,N-diisopropylethylamine (0.068 mL, 0.387 mmol). This reaction mixture was stirred at rt for 18 h. The reaction mixture was partitioned between ether and water, and the organic phase was washed with water (2×). The organic phase was dried (MgSO4) and concentrated to give 35 mg of the ester product as a yellow oil. (S)-methyl 2-(tert-butoxy)-2-(7-(3,3-dimethylpyrrolidin-1-yl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (34 mg, 0.075 mmol) was dissolved in ethanol (1 mL) and treated with 1M NaOH (0.226 mL, 0.226 mmol). The reaction mixture was stirred at rt for 18 h to complete the ester hydrolysis. The crude reaction mixture was partitioned between EtOAc and 1N HCl. The organic phase was dried (Na2SO4) and concentrated. The residue was purified by Biotage (2-10% MeOH/CH2Cl2) to give 12 mg of (S)-2-(tert-butoxy)-2-(7-(3,3-dimethylpyrrolidin-1-yl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)acetic acid as a white solid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]([C:14]3[C:15]4[CH:22]=[N:21][N:20]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[C:16]=4[CH:17]=[N:18][CH:19]=3)=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:30][S:31]([O-:33])=[O:32].[Na+].CNCCNC.[Cl-].[NH4+]>CS(C)=O.C(OCC)(=O)C.[I+].[Cu+]>[CH3:30][S:31]([C:2]1[N:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]([C:14]3[C:15]4[CH:22]=[N:21][N:20]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[C:16]=4[CH:17]=[N:18][CH:19]=3)=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)(=[O:33])=[O:32]
Reactant: O=C(NC1(c2ccc(Br)nc2)CC1)c1cncc2c1cnn2-c1ccc(F)cc1
Reactant: CS(=O)[O-]
Agent: [Cu+]
Agent: CNCCNC
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(C2(NC(=O)c3cncc4c3cnn4-c3ccc(F)cc3)CC2)cn1
Temperature: 130 °C
Reaction time: 0.75 h

Procedure:
A solution of 1-(4-fluoro-phenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [1-(6-bromo-pyridin-3-yl)-cyclopropyl]-amide (72.7 mg, 0.161 mmol), sodium methanesulfinate (32.8 mg, 0.321 mmol) and copper (I) iodine (61.2 mg, 0.321 mmol) in DMSO (1 mL) is evacuated and purged with argon three times and heated at 130° C. After 45 minutes, the reaction is cooled to room temperature and N,N′-dimethylethylenediamine (69 μL, 0.64 mmol) is added. The mixture is stirred for 30 minutes, diluted with ethyl acetate (20 mL) and stirred for 15 minutes. A saturated aqueous solution of ammonium chloride (20 mL) is added; the resulting mixture is sonicated for 30 minutes, and diluted with ethyl acetate (100 mL). Phases are separated and the aqueous layer is extracted with ethyl acetate (3×20 mL). The combined organic layers are washed with saturated aqueous ammonium chloride (2×50 mL), saturated aqueous sodium bicarbonate (50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated. The resulting residue is purified by silica gel chromatography eluting with a gradient of 0-8% methanol in methylene chloride to afford the title compound as a solid.