Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C@H:9]1[O:38][C@H:37]([CH2:39][O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@@H:28]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:10]1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=O)=O.[N-:48]=[N+:49]=[N-:50].C([N+](CCCC)(CCCC)CCCC)CCC>C(C#N)(C)=O>[CH2:12]([O:11][C@@H:10]1[C@@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:28]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C@@H:37]([CH2:39][O:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[O:38][C@@H:9]1[CH2:8][CH2:7][CH2:6][N:48]=[N+:49]=[N-:50])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)OCCC[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: CC(=O)C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: [N-]=[N+]=NCCC[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl)propyl methanesulfonate (3.78 g, 5.72 mmol) in AcCN (50 mL) was added tetrabutylammonium azide (1.66 g, 5.83 mmol). The resulting mixture allowed to reflux overnight. After cooled to rt, the reaction mixture was concentrated. The residue was dissolved in ether (50 mL), which was washed with water (2×50 mL), brine (25 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (120 g, eluting with 0-30% EtOAc in hexanes) to give the title compound. 1H NMR (CDCl3) δ 1.58-1.68 (m, 2H), 1.74-1.86 (m, 2H), 3.32-3.41 (m, 2H), 3.58-3.76 (m, 4H), 3.76-3.85 (m, 2H), 4.40 (m, 1H), 4.52 (t, J=10.4, 2H), 4.65 (dd, J=11.7, 2.5, 2H), 4.75 (d, J=11.7, 1H), 4.86 (m, 2H), 4.97 (d, J=10.8, 1H), 7.16 (m, 2H), 7.28-7.40 (m, 18H).
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Br:13][C:14]1[C:15]([C:19]([OH:21])=[O:20])=[CH:16][S:17][CH:18]=1.CN(P(N(C)C)(N(C)C)=O)C.CN([CH:36]=[O:37])C>C1COCC1>[Br:13][C:14]1[C:15]([C:19]([OH:21])=[O:20])=[C:16]([CH:36]=[O:37])[S:17][CH:18]=1
Reactant: O=C(O)c1cscc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=Cc1scc(Br)c1C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
To a solution of (i-Pr)2NH (1.09 g, 10.8 mmol) in anhydrous THF (15 mL) was added dropwise n-BuLi (5.0 mL, 12.5 mmol, 2.5M in hexane) at −30° C. The mixture was stirred at the same temperature for 0.5 h. Then, the mixture was cooled to −78° C. and the solution of 4-bromothiophene-3-carboxylic acid from example 1.1 (1.0 g, 4.85 mmol) and HMPA (0.17 g, 0.95 mmol) in anhydrous THF (20 mL) was added slowly. The mixture was stirred at the same temperature for 1 h, anhydrous DMF (0.6 g, 8.22 mmol) was added dropwise into the stirring mixture at −78° C. The reaction mixture was stirred for another 45 min at room temperature and then quenched with water. The aqueous layer was acidified with 5% aq. HCl to pH 1-2, the precipitate was collected by filtration, the filtrate was extracted with DCM (3×50 mL). The organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was washed with CH2Cl2 to give the title product (0.68 g, 60.2%) as a solid.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>O>[CH:11]1([NH:14][C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:13][CH2:12]1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: NC1CC1
Solvent: O
Product: c1nc(NC2CC2)c2cc[nH]c2n1
Yield: 28 %

Procedure:
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (9, 1.06 g, 6.90 mmol) is dissolved in cyclopropylamine (20, 2.42 mL, 34.5 mmol) and heated to reflux overnight. The reaction mixture is cooled and poured into water, then extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (21, 337 mg). MS (ESI) [M+H+]+=174.9. This is reacted similarly to step 2 of Scheme 4 to provide the desired compound 22.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[F:23])[CH:18]=O>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1ccc(F)c(Cl)c1
Product: O=c1cc(N2CCN(Cc3ccc(F)c(Cl)c3)CC2)nc[nH]1

Procedure:
6-[4-(3-Chloro-4-fluoro-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3-chloro-4-fluorobenzaldehyde. Mass spectrum (ES) MH+=323.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([NH2:13])[C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH:12]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([NH2:13])[C:7]2[CH:8]=[N:9][N:10]([S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[C:11]=2[CH:12]=1
Reactant: Nc1cc(Br)cc2[nH]ncc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1cc(Br)cc2c1cnn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To sodium hydride (1.886 g, 47.2 mmol) in DMF (10 ml) stirring at 0° C. was added a solution of 6-bromo-1H-indazol-4-amine (10 g, 47.2 mmol, available from Sinova) in DMF (30 ml) dropwise. NOTE—gas evolution. Upon complete addition the mixture was treated with benzene sulphonyl chloride (6.08 ml, 47.2 mmol) dropwise. The resulting mixture was stirred for 2 hrs at room temperature then the mixture was poured onto ice water (300 ml). The mixture was then extracted with ethyl acetate and the layers separated. The aqueous was re-extracted with ethyl acetate. The organics were then combined and washed with brine, dried over magnesium sulfate then filtered and evaporated to yield a brown gum that was triturated using DCM to yield the title compound as a peachy solid (8.72 g).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]2[CH:3]=[N:2]1.[F:11][C:12]1[C:20]([NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23])=[CH:19][CH:18]=[C:17]([F:28])[C:13]=1[C:14](O)=[O:15].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[F:11][C:12]1[C:20]([NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:23])=[O:24])=[CH:19][CH:18]=[C:17]([F:28])[C:13]=1[C:14]([NH:10][C:8]1[CH:9]=[C:4]2[CH:3]=[N:2][NH:1][C:5]2=[N:6][CH:7]=1)=[O:15]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Reactant: Nc1cnc2[nH]ncc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]ncc3c2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 599.5 %

Procedure:
1H-Pyrazolo[3,4-b]pyridin-5-amine (0.036 g, 0.027 mmol), 2,6-difluoro-3-(propylsulfonamido)benzoic acid (0.075 g, 0.27 mmol), EDCI (0.056 g, 0.30 mmol) and HOBt (0.040 g, 0.30 mmol) were dissolved in DMF (8 mL) and stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (200 mL), and the organic layers were washed with water (3×30 mL). The organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (1:1) to give 2,6-difluoro-3-(propylsulfonamido)-N-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide (0.064 g, 60%) as a solid. 1H NMR (400 MHz, CD3OD) δ 8.7 (s, 1H), 8.6 (s, 1H), 8.1 (s, 1H), 7.7 (m, 1H), 7.1 (m, 1H), 3.1 (m, 2H), 1.9 (m, 2H), 1.1 (t, J=7.6 Hz, 3H); m/z (APCI-neg) M−1=394.2.
Reaction SMILES: [CH:1]([N:4](C(C)C)[CH2:5]C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CNC.[CH:40]1[C:52]2[CH:51]([CH2:53][O:54][C:55]([N:57]3[CH2:66][CH2:65][C:64]4[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=4)[C@H:58]3[C:67]([OH:69])=O)=[O:56])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]=2[CH:43]=[CH:42][CH:41]=1>C(O)C.C(Cl)Cl.O.C(Cl)Cl>[CH3:1][N:4]([CH3:5])[C:67]([C@@H:58]1[C:59]2[C:64](=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH2:65][CH2:66][N:57]1[C:55]([O:54][CH2:53][CH:51]1[C:52]2[CH:40]=[CH:41][CH:42]=[CH:43][C:44]=2[C:45]2[C:50]1=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:56])=[O:69]
Reactant: O=C(O)[C@@H]1c2ccccc2CCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CN(C)C(=O)[C@@H]1c2ccccc2CCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 3 h
Yield: 84.7 %

Procedure:
1.61 g of diisopropylethylamine, 5.53 g of BOP and then 5 ml of a 5.6M solution of dimethylamine in ethanol are added to a solution of 5 g of (1S)-2-(9-fluorenylmethoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (commercial) in 100 ml of DCM and the mixture is left stirring for 3 hours at AT. The reaction mixture is taken up in a water/DCM mixture, after separation by settling the organic phase is washed with a 5% KHSO4 solution and dried over Na2SO4, and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, elution being carried out with a DCM/AcOEt (70/30, v/v) mixture. 4.5 g of the expected product are obtained in the form of an oil.
Reaction SMILES: C[O:2][C:3]([CH2:5][NH:6][C:7]1[N:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([N:17]([CH3:29])[CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]=2[CH3:28])=[O:16])=[CH:9][CH:8]=1)=[O:4].[OH-].[Na+].Cl>O1CCOCC1>[C:3]([CH2:5][NH:6][C:7]1[N:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([N:17]([CH3:29])[CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]=2[CH3:28])=[O:16])=[CH:9][CH:8]=1)([OH:4])=[O:2]
Reactant: COC(=O)CNc1ccc(/C=C/C(=O)N(C)Cc2c(C)[nH]c3ccccc23)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1[nH]c2ccccc2c1CN(C)C(=O)/C=C/c1ccc(NCC(=O)O)nc1
Reaction time: 18 h
Yield: 102.7 %

Procedure:
To a stirred solution of (E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide (0.5 g, 1.3 mmole) in dioxane (30 mL) was added 1 N NaOH (2 mL, 2 mmole). After stirring for 18 h the reaction was neutralized with 1 N HCl (2 mL, 2 mmole) and concentrated to near dryness. The resulting suspension was diluted with H2O and filtered. The solid was washed with H2O and dried under vacuum to give the title compound (505 mg, 100%) as a off-white solid: MS (ES) m/e 379.2 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]1[CH2:11][CH2:10][CH:9]([C:12]([O:14]CC)=[O:13])[CH2:8][CH2:7]1.[Li+:17].[OH-]>CO>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]1[CH2:11][CH2:10][CH:9]([C:12]([O-:14])=[O:13])[CH2:8][CH2:7]1.[Li+:17]
Reactant: CCOC(=O)C1CCN(c2nccs2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])C1CCN(c2nccs2)CC1
Reaction time: 8 h

Procedure:
To a methanol (30 mL) solution of 3 (3.6 g, 15 mmol) was added LiOH solution (1.0 M, 15 mL) at room temperature. The resulting solution was stirred overnight and then concentrated to yield a solid as 4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12]O.[CH3:14][O:15][C:16]([O:20][Si](C)(C)C)=[C:17](C)C.Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O>ClCCl.O>[CH3:14][O:15][C:16](=[O:20])[CH2:17][CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][CH:7]=1
Reactant: COc1ccc2[nH]cc(CO)c2c1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCc1c[nH]c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 100 %

Procedure:
To a solution of 5-methoxy-1H-indol-3yl-methanol 141 (115 mg, 0.643 mmol) dissolved in dichloromethane (3 ml), (1-methoxy-2-methyl-propenyloxy)-trimethylsilane (200 mg, 1 mmol) and magnesium perchlorate (164 mg, 0.74 mmol) were added. The reaction was allowed to stir at ambient temperature for 3-4 hours after after which the mixture was diluted with water (50 ml) and dichloromethane (DCM, 100 mL). The organic layer was separated and washed with water (50 mL; 3×). The organic layer was washed once with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give an oil and purified with flash chromatography (silica with 80% hexane, 20% ethyl acetate to afford 142 as a light colored oil (150 mg; 88% yield; M+1=262.3).
Reaction SMILES: Cl[CH:2]([C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:16][C:17]([NH2:19])=[S:18].CCOC(C)=O>CCO>[NH2:19][C:17]1[S:18][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:16]=1
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1
Reactant: NC(N)=S
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(N)nc1-c1ccccc1
Yield: 89 %

Procedure:
A solution of ethyl 2-chloro-3-oxo-3-phenylpropanoate (9.73 mmol) and thiourea (9.73 mmol) in EtOH (25 mL) was heated at reflux overnight. The resulting mixture was concentrated in vacuo, neutralized with 18M—NH4OH, and extracted with CH2Cl2. The organic phase was washed with brine, dried over anhyd. sodium sulfate, and concentrated to afford a yellow solid that was washed with MeOH (3 mL) and dried to afford the product in 89% yield as a pale yellow solid. MH+=249.1, Rf=0.29 (hexanes:EtOAc=1:1). MH+=249.1, retention time (LC-MS)=2.37 min.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:13]=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27]([Li])[CH2:28][CH2:29]C.ICCC.O>C1COCC1.CCOC(C)=O>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:13]([CH2:27][CH2:28][CH3:29])=[CH:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(OCc3ccccc3)ccc21
Reactant: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1cc2cc(OCc3ccccc3)ccc2n1S(=O)(=O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
To a solution a −78° C. cooled (dry ice/acetone bath) of 5-[(phenylmethyl)oxy]-1-(phenylsulfonyl)-1H-indole (1.1 g, 0.003 mol) in THF (anhydrous, 10 mL) was added n-butyllithium (2.3 mL of a 1.6 M solution in hexanes) dropwise. The mixture was then warmed to −10° C. over 30 min and then cooled to −78° C. and 1-iodopropane (1.5 eq., 0.005 mol, 0.77 g) was added dropwise. The mixture was warmed to rt over 1 h and then stirred at rt for 20 min. Water (10 mL) and EtOAc (100 mL) was added. The organic layer was separated, dried (MgSO4), and concentrated. Purification via semipreparative reverse-phase HPLC provided the desired product: MS (ES) m/z 406 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[N:6][CH:7]=1.[CH2:14]([NH2:18])[CH:15]([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:18][CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])=[N:6][CH:7]=1
Reactant: CC(C)(C(=O)O)c1ccc(Br)cn1
Reactant: CC(C)CN
Product: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cn1
Yield: 32 %

Procedure:
Prepared in a similar manner to example 27 from 2-(5-bromopyridin-2-yl)-2-methylpropanoic acid (example 46b) and isobutyl amine. Yield 32%. MS+H (301).
Reaction SMILES: F[C:2](F)(F)C(O)=O.[NH2:8][C@H:9]1[CH2:15][CH:14]=[CH:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]1=[O:22].C(OC(N[C@@H](CCC=C)C(O)=O)=O)(C)(C)C>>[NH2:8][C@H:9]1[CH2:15][CH2:14][CH:13]=[CH:12][CH2:2][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]1=[O:22]
Reactant: O=C(O)C(F)(F)F
Reactant: N[C@H]1CC=CCN(c2ccccc2)C1=O
Agent: C=CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: N[C@H]1CC/C=C\CN(c2ccccc2)C1=O
Product: N[C@H]1CCC=CCN(c2ccccc2)C1=O

Procedure:
(S,Z)-3-Amino-1-phenyl-1,4,5,8-tetrahydroazocin-2 (3H)-one (175 mg, 0.692 mmol) was synthesized as described for the preparation of Intermediate 52 using (S)-2-(tert-butoxycarbonylamino)hex-5-enoic acid in step A. Anal. Calcd. for C13H16N2O m/z 216.2. found: 217.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1.Br[CH2:14][C:15]1[CH:34]=[CH:33][C:18]2/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=3[O:22][CH2:23][C:17]=2[CH:16]=1>>[CH3:1][N:2]([CH3:12])[C:3]1[N:4]([CH2:14][C:15]2[CH:34]=[CH:33][C:18]3/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=4[O:22][CH2:23][C:17]=3[CH:16]=2)[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CN(C)c1nc2ccccc2[nH]1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(Cn3c(N(C)C)nc4ccccc43)cc2COc2cc(F)ccc21
Yield: 67.1 %

Procedure:
[step 2] Using N,N-dimethyl-1H-benzo[d]imidazole-2-amine (57 mg, 0.35 mmol) obtained in step 1 and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (129 mg, 0.36 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (103 mg, 66%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:63])[CH:48]([NH:55][C:56]([O:58][C:59](C)(C)C)=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].COC(N[CH:70](C1C=CC=CC=1)[C:71](O)=O)=O>>[CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH:46]7[CH2:45][CH:44]([CH2:70][CH2:71]7)[N:43]6[C:47](=[O:63])[CH:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]6[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:7])[CH3:8]
Reactant: COC(=O)NC(C(=O)O)c1ccccc1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC(C)(C)C)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Yield: 34.8 %

Procedure:
This compound was synthesized using the procedure used to make [1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using Methoxycarbonylamino-phenyl-acetic acid (0.047 g, 0.224 mmol) to give [1-(2-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-2-phenyl-acetyl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.044 g, 34.8% yield). LCMS-ESI+: calc'd for C49H52N8O6: 848.40 (M+); Found: 849.96 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:23])[N:9]([CH2:11][C:12]3[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:10]=[C:4]2[C:3]=1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:7]=[CH:6][N:5]3[C:8](=[O:23])[N:9]([CH2:11][C:12]4[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:16][CH:17]=4)[N:10]=[C:4]3[C:3]=2[C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:33][CH:32]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(Cl)ccn2c1=O
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: Cc1ccccc1
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(F)cc3)ccn2c1=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a suspension of 7-chloro-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (135 mg, 0.32 mmol), 4-fluorophenylboronic acid (180 mg, 1.29 mmol), and 2.0 M aqueous sodium carbonate (0.70 mL) in toluene (2.5 mL) was added (Ph3P)4Pd (55 mg, 0.048 mmol) in one portion, and the resulting yellow mixture was vigorously stirred under argon at 100° C. for 2 h. Analysis by HPLC/MS indicated about 10% of the starting 7-chloro-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one remained. Additional catalyst (15 mg, 0.013 mmol) was added. The reaction mixture was stirred at 100° C. for 1 h more. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The EtOAc layer was washed with water, then saturated aqueous NaCl twice, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluted with a gradient of EtOAc (0-80%) in hexanes to afford the desired product, which was contaminated with triphenylphosphine oxide. The product was further purified by preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 90% B over 15 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The yellow residue was dissolved in acetonitrile, frozen and lyophilized to afford 66 mg of the title compound as a light yellow powder. HPLC/MS: retention time=2.49 min, [M+H]+=480.0.
Reaction SMILES: CN.[C:3]([C:5]1[CH:6]=[CH:7][C:8]([F:36])=[C:9]([C@:11]23[CH2:20][O:19][C@@H:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[CH:22]=4)[CH2:17][C@H:16]2[CH2:15][S:14][C:13]([NH:27]C(=O)C2C=CC=CC=2)=[N:12]3)[CH:10]=1)#[N:4]>C(O)C>[NH2:27][C:13]1[S:14][CH2:15][C@@H:16]2[CH2:17][C@H:18]([C:21]3[O:25][N:24]=[C:23]([CH3:26])[CH:22]=3)[O:19][CH2:20][C@:11]2([C:9]2[CH:10]=[C:5]([CH:6]=[CH:7][C:8]=2[F:36])[C:3]#[N:4])[N:12]=1
Reactant: Cc1cc([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3cc(C#N)ccc3F)CO2)on1
Agent: CN
Solvent: CCO
Product: Cc1cc([C@H]2C[C@H]3CSC(N)=N[C@@]3(c3cc(C#N)ccc3F)CO2)on1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methylamine (8 M in ethanol, 1.34 mmol) was added to a solution of N-[(4aR,6R,8aS)-8a-(5-cyano-2-fluorophenyl)-6-(3-methyl-1,2-oxazol-5-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C37) (0.051 g, 0.11 mmol) in ethanol (4 mL). The resulting solution was allowed to stir at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give a yellow oily residue. Purification via silica gel chromatography (Gradient: 0% to 15% methanol in dichloromethane) afforded the product as an off-white solid. Yield: 25 mg, 63%. LCMS m/z 373.1 [M+H+]. 1H NMR (400 MHz, CD3OH) δ 7.78 (ddd, J=8.5, 4.5, 2.2 Hz, 1H), 7.69 (dd, J=7.2, 2.2 Hz, 1H), 7.35 (dd, J=8.6, 11.3 Hz, 1H), 6.26 (s, 1H), 4.89 (dd, J=11.9, 2.5 Hz, 1H), 4.25 (dd, J=11.2, 2.2 Hz, 1H), 3.80 (d, J=11.2 Hz, 1H), 3.08-3.14 (m, 1H), 2.89 (dd, J=12.7, 4.1 Hz, 1H), 2.78 (dd, J=12.7, 2.9 Hz, 1H), 2.28 (s, 3H), 2.10-2.22 (m, 1H), 1.91-1.96 (m, 1H).