Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].O[NH:14][C:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2)=[NH:16].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([O:7][NH:16][C:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2)=[NH:14])=[O:6]
Reactant: COc1ccc(C(=O)O)cc1Cl
Reactant: N=C(NO)c1ccc2[nH]ccc2c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(=O)ONC(=N)c2ccc3[nH]ccc3c2)cc1Cl
Temperature: 25 °C
Yield: 93.3 %

Procedure:
To a solution of the product of Step B (0.25 g; 1.43 mmol), and the product of Step C (0.23 g; 1.31 mmol) in anhydrous THF (5 ml), PyBroP (0.67 g; 1.44 mmol) was added followed by DIPEA (0.57 ml; 3.3 mmol), with stirring, at room temperature under N2. After 1 h of stirring, the mixture was diluted to 20 ml with EtOAc, washed with saturated NH4Cl (5 ml), brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by crystallization from EtOAc/hexane to give the title compound (0.42 g; 93%), as a creamy solid. 1H-NMR (CD3OD) 3.96 (s, 3H); 5.41 (s, 1H); 6.52 (d, 1H, J=3.2 Hz); 7.14 (d, 1H, J=8.7 Hz); 7.27 (d, 1H, J=3.2 Hz); 7.41-7.77 (m, 2H); 8.0 (s, 1H); 8.11 (dd, 1H, J=2; 8.7 Hz); 8.15 (d, 1H, J=2 Hz).
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]([OH:13])=[O:12].[CH3:14]O>>[ClH:3].[NH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: N[C@H]1CCC[C@H]1C(=O)O
Reactant: CO
Product: COC(=O)[C@@H]1CCC[C@@H]1N
Product: Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Thionyl chloride (2.64 mL, 36.22 mmol) was added slowly to anhydrous methanol (50 mL) at 0° C. under a nitrogen atmosphere. (1R,2S)-2-Amino-cyclopentanecarboxylic acid (4.0 g, 24.15 mmol) was added to above solution. The resulting mixture was allowed to warm to 25° C. and stirred for 5 h. The reaction mixture was concentrated in vacuo to afford the desired product, methyl (1R,2S)-2-aminocyclopentanecarboxylate hydrochloride (4.32 g, 24.15 mmol, quantitative), as a clear oil. The crude product was used directly in the next step. 1H NMR (400 MHz, CD3OD) δ: 1.72-2.05 (4H, m), 2.16 (2H, m), 3.13 (1H, m), 3.75 (3H, s), 3.77 (1H, m).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[N:28]1([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][CH2:31][CH2:30][CH2:29]1>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[S:18][C:17]([C:19]([N:36]5[CH2:37][CH2:38][CH:33]([N:28]6[CH2:32][CH2:31][CH2:30][CH2:29]6)[CH2:34][CH2:35]5)=[O:21])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: C1CCN(C2CCNCC2)C1
Product: O=C(c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)N1CCC(N2CCCC2)CC1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to 4-(pyrrolidin-1-yl)piperidine via General Procedure B. The product was purified via reverse phase HPLC to give 13.2 mg of 249. MS (Q1) 517.8 (M)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([NH:11][C:12]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)([CH3:14])[CH3:13])=[N:9][CH:10]=1)=O.[CH2:22]([O:24][C:25]([C:27]1[N:28]=[C:29]([NH2:32])[S:30][CH:31]=1)=[O:26])[CH3:23]>CC(CC)=O>[Cl:21][C:20]1[C:15]([C:12]([NH:11][C:8]2[N:7]=[CH:6][C:5]([C:3]3[N:32]=[C:29]4[N:28]([CH:2]=3)[C:27]([C:25]([O:24][CH2:22][CH3:23])=[O:26])=[CH:31][S:30]4)=[CH:10][N:9]=2)([CH3:14])[CH3:13])=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1csc(N)n1
Reactant: CC(C)(Nc1ncc(C(=O)CBr)cn1)c1ncccc1Cl
Solvent: CCC(C)=O
Product: CCOC(=O)c1csc2nc(-c3cnc(NC(C)(C)c4ncccc4Cl)nc3)cn12
Temperature: 90 °C
Reaction time: 8 h
Yield: 26.6 %

Procedure:
To a 20 dram vial was added 2-bromo-1-(2-(2-(3-chloropyridin-2-yl)propan-2-ylamino)pyrimidin-5-yl)ethanone (103 mg, 0.28 mmol), ethyl-2-aminothiazole-4-carboxylate (48 mg, 0.28 mmol), and methylethylketone (2 mL). The mixture was heated to 90° C. in a sealed tube and stirred overnight. The reaction was then concentrated and purified by silica gel chromatography (EtOAc/hex) to afford 33 mg of ethyl 6-(2-(2-(3-chloropyridin-2-yl)propan-2-ylamino)pyrimidin-5-yl)imidazo[2,1-b]thiazole-3-carboxylate as a tan solid. This compound was dissolved in methanol (1 mL) and ammonium hydroxide (3 mL) was added. The resulting mixture was heated in a microwave reactor to 135° C. and stirred for 15 min. The reaction was concentrated, followed by the addition of HBTU (68 mg, 179 μmol), HOBt (24 mg, 179 μmol), NH4Cl (48 mg, 1.1 mmol), DIPEA (78 μL, 441 μmol), and NMP (2 mL). The reaction was stirred for 2 h and then purified directly by reverse phase chromatography to afford 18 mg of 6-(2-(2-(3-chloropyridin-2-yl)propan-2-ylamino)pyrimidin-5-yl)imidazo[2,1-b]thiazole-3-carboxamide as an off-white solid (M+H=414.1).
Reaction SMILES: Cl[C:2]([NH:4][N:5]1[CH:13]=[C:11]([CH3:12])[C:9](=[O:10])[NH:8][C:6]1=[O:7])=[O:3].C(N(C(C)C)CC)(C)C.[CH2:23]([O:25][C:26](=[O:39])[CH2:27][NH:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH3:24]>C1COCC1.C(OCC)C>[CH2:23]([O:25][C:26](=[O:39])[CH2:27][N:28]([CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:2]([NH:4][N:5]1[CH:13]=[C:11]([CH3:12])[C:9](=[O:10])[NH:8][C:6]1=[O:7])=[O:3])[CH3:24]
Reactant: CCOC(=O)CNCCNC(=O)OC(C)(C)C
Reactant: Cc1cn(NC(=O)Cl)c(=O)[nH]c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)Nn1cc(C)c(=O)[nH]c1=O
Reaction time: 12 h

Procedure:
The product from Example 5, 8, is dissolved in THF (500 mL) and diisopropylethylamine (12.9 g, 0.1 mol) is added, followed by N-(2-t-butyloxycarbonylaminoethyl)glycine ethyl ester (24.6 g, 0.1 mol) and the solution stirred for 12 hours. The reaction is diluted with 1000 mL of diethyl ether and extracted 3 times with 0.1N HCl solution. The organic layer is washed with diluted sodium bicarbonate solution, dried, filtered and evaporated to give a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](O)=[N:6][CH:7]=1.P(Br)(Br)[Br:13].O>C1(C)C=CC=CC=1.CN(C=O)C>[Br:13][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(Br)cnc1Br
Temperature: 120 °C
Yield: 80 %

Procedure:
To a solution of 5-Bromo-3-nitro-pyridin-2-ol (10.0 g, 45.66 mmol) in 70 ml of toluene and 7 ml of DMF was added PBr3 (6.60 ml, 68.49 mmol) and the reaction mixture was heated at 120° C. for 20 min under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (100 mL) was added and extracted with ethyl acetate (3×200 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to get the desired product (10.30 g, 80.03%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:34]=[N:33][C:32]5[NH:31][C:30](=[O:35])[CH2:29][O:28][C:27]=5[CH:26]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:34]=[N:33][C:32]5[NH:31][C:30](=[O:35])[CH2:29][O:28][C:27]=5[CH:26]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4cnc5c(c4)OCC(=O)N5)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2nc(-c3ccnc(-c4cnc5c(c4)OCC(=O)N5)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetate (17.1 mg, 0.027 mmol) in THF (1.1 mL) and methanol (1.1 mL) was added 1N NaOH solution (0.8 mL, excess). The reaction mixture was stirred at 50° C. for 2 h and then purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H28ClN4O5S: 615.2; found: 615.2. 1H NMR (400 MHz, CD3OD) δ 8.74 (d, J=4.8 Hz, 1H), 8.61 (d, J=2.0 Hz, 1H), 8.43 (s, 1H), 7.99 (d, J=2.0 Hz, 1H), 7.94 (s, 1H), 7.91 (dd, J=5.2, 1.6 Hz, 1H), 7.71-7.68 (m, 1H), 7.62-7.59 (m, 3H), 5.28 (s, 1H), 4.72 (s, 2H), 2.63 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=NN=1.[C:21]1([CH2:27][CH:28]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[K+]>O1CCCC1.CO>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[N:10]=[N:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:28][C:27]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=CCc1ccccc1
Reactant: Clc1ccccc1-c1nnc(-c2ccccc2Cl)nn1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Clc1ccccc1-c1cc(-c2ccccc2)c(-c2ccccc2Cl)nn1
Reaction time: 0.08 h
Yield: 96.1 %

Procedure:
3,6-Bis(2-chlorophenyl)-1,2,4,5-tetrazine (4.6 g) and phenylacetaldehyde (2.0 g) were dissolved in tetrahydrofuran (60 ml). A solution of potassium hydroxide in methanol (1.5 ml, 1%) was added dropwise to the solution and left to stand for 5 minutes. The solution was evaporated to 20 mls volume and was then diluted with water (50 ml). The precipitated solid was filtered, washed with water and dried to give 5.5 g of desired product, mp 176°-178° C.
Reaction SMILES: [CH2:1]([N:7]([CH3:27])[C:8]([CH:10]1[CH2:14][CH:13]([OH:15])[CH2:12][CH:11]1[C:16]([NH:18][C:19]1([C:24]([OH:26])=[O:25])[CH2:21][CH:20]1[CH:22]=[CH2:23])=[O:17])=[O:9])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[H-].[Na+].Cl[C:31]1[C:40]2[C:35](=[CH:36][C:37](OC)=[CH:38][CH:39]=2)[N:34]=[C:33]([C:43]2[S:44][CH:45]=[C:46]([CH:48]([CH3:50])[CH3:49])[N:47]=2)[N:32]=1.Cl>C1COCC1.CCOC(C)=O>[CH2:1]([N:7]([CH3:27])[C:8]([CH:10]1[CH2:14][CH:13]([O:15][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=[C:33]([C:43]3[S:44][CH:45]=[C:46]([CH:48]([CH3:50])[CH3:49])[N:47]=3)[N:32]=2)[CH2:12][CH:11]1[C:16]([NH:18][C:19]1([C:24]([OH:26])=[O:25])[CH2:21][CH:20]1[CH:22]=[CH2:23])=[O:17])=[O:9])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)NC1(C(=O)O)CC1C=C
Reactant: COc1ccc2c(Cl)nc(-c3nc(C(C)C)cs3)nc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCCCCN(C)C(=O)C1CC(Oc2nc(-c3nc(C(C)C)cs3)nc3ccccc23)CC1C(=O)NC1(C(=O)O)CC1C=C
Reaction time: 0.17 h
Yield: 77.8 %

Procedure:
Compound 37 (26 mg, 70 μmol) was dissolved in THF (3 mL, dried with mol. siev.). To this solution was added NaH (60% in oil, 8.2 mg, 210 μmol) and the reaction was incubated for 10 min at ambient temperature. To the reaction mixture was then added compound 39 (17.6 mg, 61 μmol) followed by incubation at ambient temperature for 16 h. To the reaction was then added 0.1 M HCl (aq) and EtOAc, the phases separated and the aqueous phase extracted with another portion of EtOAc. The pooled organic phases were dried (MgSO4), filtered and concentrated in vacuo which gave a crude product which was further purified by flash-chromatography (Silica; DCM:MeOH) to afford the title compound (30 mg, 78%). LC/MS>95%, m/z (ESI+)=632 (MH+).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[N:12]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](/[CH:21]=[CH:22]/[C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][C:27]([Cl:33])=[CH:28][CH:29]=4)[N:24]=3)[CH:16]=1)[CH2:11][CH2:10]2)#[N:2].C(#N)C.C(O)(=O)C.C1COCC1.C([Sn]([N:59]=[N+:60]=[N-:61])(CCCC)CCCC)CCC>>[Cl:33][C:27]1[CH:26]=[C:25]2[C:30]([CH:31]=[CH:32][C:23](/[CH:22]=[CH:21]/[C:17]3[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=3)[CH2:14][N:12]3[C:13]4[C:9](=[CH:8][CH:7]=[CH:6][C:5]=4[CH2:4][CH2:3][C:1]4[NH:61][N:60]=[N:59][N:2]=4)[CH2:10][CH2:11]3)=[N:24]2)=[CH:29][CH:28]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#CCCc1cccc2c1N(Cc1cccc(/C=C/c3ccc4ccc(Cl)cc4n3)c1)CC2
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CC#N
Product: Clc1ccc2ccc(/C=C/c3cccc(CN4CCc5cccc(CCc6nnn[nH]6)c54)c3)nc2c1
Reaction time: 3.5 h
Yield: 36 %

Procedure:
A solution of 7-(2-cyanoethyl)-1-[3-[2-E-(7-chloroquinolin-2-yl)ethenyl]benzyl]-2,3-dihydroindole (600 mg) in tri-n-butyltin azide (2.0 mL) was heated in an oil bath at 95° C. for 23 hours. To the cooled solution was added acetonitrile (50 mL), acetic acid (20 mL), and THF (10 mL). The resulting solution was stirred for 3.5 hours and washed with hexane. The hexane layer was separated and discarded. The resulting mixture was concentrated in vacuo and the residue chromatographed (silica gel, 2% methanol/98% methylene chloride) to provide a solid that was recrystallized (ethyl acetate/ether) to provide 235 mg (36%) of the desired product: mp 141°-144° C. 1H-NMR (DMSO-d6) 8.48 (d, J=9 Hz, 1H), 8.08 (m, 2H), 7.85 (d, J=8 Hz, 1H), 7.75 (d, J=17 Hz, 1H), 7.59 (s, 1H), 7.54 (m, 2H), 7.33 (m, 3H), 7.07 (d, J=8 Hz, 1H), 6.95 (d, J=8 Hz, 1H), 6.77 (d, J=8 Hz, 1H), 4.49 (s, 2H), 3.28 (t, 2H, J=7 Hz), 3.17 (m, 2H), 3.08 (m, 2H), 2.83 (t, J=7 Hz, 2H); MS-FD m/e (493, p).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](O)=[C:5]([O:10][CH3:11])[CH:4]=1)#[N:2].[ClH:12].[CH3:13][OH:14]>>[CH3:13][O:14][N:2]=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([Cl:12])=[C:5]([O:10][CH3:11])[CH:4]=1
Reactant: COc1cc(C#N)ccc1O
Reactant: Cl
Reactant: CO
Product: CON=Cc1ccc(Cl)c(OC)c1

Procedure:
In 50 ml of anhydrous methanol, was dissolved 7.5 g of 4-cyano-2-methoxyphenol. The solution was saturated with dried gaseous hydrogen chloride, while being cooled in ice and stirred, and then stirred overnight at room temperature to precipitate yellow crystals. After addition of ethyl ether, the crystals were collected by filtration, washed with ethyl ether and dried to obtain 9.4 g of 4-methoxyiminomethyl-2-methoxyphenyl hydrochloride.
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][CH2:7][CH2:8][CH2:9][S@:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[NH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Br:30][C:31]1([CH:39]=[CH:38][CH:37]=[N:36][CH2:35]1)C(O)=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:67]([O-:70])(O)=O.[Na+]>CN(C=O)C>[Br:30][C:31]1[CH:35]=[N:36][CH:37]=[C:38]([CH:39]=1)[C:67]([N:12]=[S@@:10]([CH2:9][CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([CH3:20])[CH3:19])(=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:70]
Reactant: O=C(O)C1(Br)C=CC=NC1
Reactant: O=C([O-])O
Reactant: CC(C)(C)[Si](C)(C)OCCC[S@](=N)(=O)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCCC[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reaction time: 0.25 h
Yield: 97 %

Procedure:
To the solution of (S)-tert-butyl(dimethyl)[3-(S-phenylsulfonimidoyl)propoxy]silane (1.55 g, 4.95 mmol) in DMF (15 mL) at room temperature was added N,N-diisopropylethylamine (1.72 mL), 3-bromonicotinic acid (1.07 g), and finally the coupling reagent, (benzotriazol-1-yloxy)-tris(dimethylamino)-phosphonium hexafluorophosphate (2.48 g). The reaction was stirred for 15 min and then poured into saturated aqueous NaHCO3. The aqueous phase was extracted with EtOAC (1×), which was subsequently washed with aqueous NaHCO3, brine (1×), and dried with anhydrous Na2SO4. The organic layer was decanted, concentrated, and the oily residue was subject to a gradient column chromatography (EtOAc-Hex:from 1:20 to 1:6) yielding the title compound as an amber oil (2.39 g, 97%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:11](=[O:14])[CH:12]=[CH2:13])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]=[O:29].C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:11](=[O:14])[CH2:12][CH2:13][C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=2)=[O:29])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: O=Cc1ccccn1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(SC)c(F)c1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CSc1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccccn2)cc1F
Temperature: 25 °C
Yield: 42 %

Procedure:
To a solution of 4-[3-fluoro-4-(methylsulfanyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (225 mg) in ethanol (3.6 mL) were added pyridine-2-carbaldehyde (83.2 μL), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (21.6 mg) and triethylamine (43.7 μL), and the mixture was stirred with heating under reflux for 2 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (127 mg, yield 42%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: [CH3:1]I.[Mg].[CH3:4][CH:5]1[C:10]2([CH3:14])[CH:11]([CH3:13])[CH2:12][CH:7]([CH:8](C(OCC)=O)[CH2:9]2)[N:6]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH4+].[Cl-].CC[O:31][CH2:32][CH3:33]>>[CH3:1][C:32]([CH3:33])([CH:8]1[CH:7]2[CH2:12][CH:11]([CH3:13])[C:10]([CH3:14])([CH:5]([CH3:4])[N:6]2[CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:9]1)[OH:31]
Reactant: CCOC(=O)C1CC2(C)C(C)CC1N(Cc1ccccc1)C2C
Reactant: CCOCC
Reactant: CI
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Product: CC1CC2C(C(C)(C)O)CC1(C)C(C)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Methyl iodide (138.4 g, 0.98 mole) was added dropwise over 1.5 hours to magnesium turnings (23.7 g, 0.98 mole) in ether (300 mL). The solution was diluted to a total volume of 1 liter and was stirred at room temperature for 2 hours. The solution was filtered through a glass wool plug into a second flask under nitrogen and a solution of ethyl 3,4,8-trimethyl-2-(phenylmethyl)-2-azabicyclo[2.2.21-octane-6-carboxylate (87.9 g, 0.28 mole) in ether (400 mL) was added over 2 hours. The mixture was stirred at room temperature for 1 hour, poured into a mixture of saturated NH4Cl (100 mL) and ice-water (100 mL) and the organic layer was separated. The aqueous phase was extracted with ether (2×700 mL) and the combined organic layers were washed with water (2×500 mL) , then brine (500 mL) and were dried over anhydrous MgSO4. The solvent was removed in vacuo to afford 82.5 g (98%) of α,α,3,4,8-pentamethyl-2-(phenylmethyl)-2-azabicyclo[2.2.21octane-6-methanol.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[N:10]=[N:11][N:12]([CH2:14][C:15]([CH3:18])([OH:17])[CH3:16])[N:13]=2)=[CH:4][C:3]=1[CH3:19].[F:20][C:21]1[CH:22]=[CH:23][C:24](B2OC(C)(C)C(C)(C)O2)=[C:25]2[C:29]=1[C@H:28]([O:30][C:31]1[CH:44]=[CH:43][C:34]3[C@H:35]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH2:36][O:37][C:33]=3[CH:32]=1)[CH2:27][CH2:26]2.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([C:9]3[N:10]=[N:11][N:12]([CH2:14][C:15]([OH:17])([CH3:18])[CH3:16])[N:13]=3)=[CH:4][C:3]=2[CH3:19])=[C:25]2[C:29]=1[C@H:28]([O:30][C:31]1[CH:44]=[CH:43][C:34]3[C@H:35]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH2:36][O:37][C:33]=3[CH:32]=1)[CH2:27][CH2:26]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2nnn(CC(C)(C)O)n2)cc(C)c1Br
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6nnn(CC(C)(C)O)n6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from 1-(5-(4-bromo-3,5-dimethylphenyl)-2H-tetrazol-2-yl)-2-methylpropan-2-ol and methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 15): tR=1.24 min; Mass spectrum (ESI+): m/z=587 [M+H]+.
Reaction SMILES: C[Sn]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]3[C:27]([CH2:28][OH:29])=[C:26]([Cl:30])[N:25]=[C:24]3[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:18][CH:17]=2)=[N:8][N:7]=[N:6]1)(C)C.C(Cl)Cl.[OH-].[Na+].[C:40]1([C:46](Cl)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O.O1CCCC1>[C:40]1([C:46]([N:5]2[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[C:27]([CH2:28][OH:29])=[C:26]([Cl:30])[N:25]=[C:24]4[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:18][CH:17]=3)=[N:8][N:7]=[N:6]2)([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2[Sn](C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1-[(2'-(Trimethylstannyltetrazol-5-yl)-biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole (1.046 Kg), methylene chloride (5.00 L), tetrahydrofuran (0.85 L) and 10N sodium hydroxide (192 ml) were charged to a 12 liter round-bottomed flask equipped with mechanical stirrer, condenser with N2 inlet, and thermometer. After stirring five minutes at room temperature, triphenylmethyl chloride (0.530 Kg) was added and the mixture stirred three hours. 10N Sodium hydroxide (20 ml) and additional triphenylmethyl chloride (50 g) were added and the mixture stirred overnight. Deionized (D.I.) water (3.70 L) and 10N sodium hydroxide (30 ml) were added and the phases allowed to separate. The organic phase was washed twice with 2.0 L portions of water, dried with sodium sulfate (100 g) and filtered into a 12 L round-bottomed flask equipped for distillation. Methylene chloride (~2.0 L) was distilled. Heating was discontinued and heptane (5.0 L) was added. The resulting slurry was stirred at ambient temperature over the weekend (~68 hours). The mixture was cooled to ~5° C. and the product isolated by vacuum filtration, washed with heptane (1.0 L) and dried 48 hours in in vacuo at 40°-50° C. Yield: 959.5 g, 80%. M.P.: 167°-169° C. Purity by HPLC: 99.8%.