Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][C:37]=1[NH:51][S:52]([CH:55]1[CH2:57][CH2:56]1)(=[O:54])=[O:53]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:39]4[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[C:37]([NH:51][S:52]([CH:55]5[CH2:56][CH2:57]5)(=[O:54])=[O:53])[CH:38]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:26])=[O:25])[CH:9]=2)[CH:12]=[N:13]1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)C1CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(=O)(=O)C1CC1
Yield: 48.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Compound of step-i of −9) (150 mg, 2.85 mmol) was coupled with N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanesulfonamide (intermediate 19) (131 mg, 0.371 mmol), Pd(PPh3)2Cl2 (10 mg, 0.0142 mmol), Toluene/ethanol/water (15/10/5 ml) to afford 120 mg (62.82% yield) of the titled compound. MS: m/z=672.2 (M+1).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC[C:45]1[CH:50]=[CH:49][CH:48]=C[C:46]=1[S:51]([CH3:54])(=[O:53])=[O:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:48]=[CH:49][CH:50]=[CH:45][C:46]=3[S:51]([CH3:54])(=[O:53])=[O:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)c1ccccc1CBr
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccccc3S(C)(=O)=O)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-(methylsulfonyl)benzene and isolated as white solid. MS (m/e): 451.3 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH:9]1(B(O)O)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[CH:9]1([C:2]2[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=2)[NH2:5])[CH2:11][CH2:10]1
Reactant: OB(O)C1CC1
Reactant: Nc1cccc(Br)c1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cccc(C2CC2)c1
Yield: 38.3 %

Procedure:
Stir the mixture of 3-bromoaniline (400 mg, 2.35 mmol), cyclopropylboronic acid (240 mg, 2.79 mmol), tetrakis(triphenylphosphine)palladium(0) (140 mg, 0.12 mmol), cesium carbonate (1.5 g, 4.60 mmol) in dioxane (5 mL) and water (0.3 mL) under nitrogen atmosphere for 17 hrs at 100° C. Cool the reaction to room temperature, filter and concentrate the filtrate under reduced pressure. Purify by flash chromatography (silica gel, EtOAc:PE=3:7) to afford the title compound (120 mg, 38.8%). MS: (M+1): 134.0.
Reaction SMILES: [C:1]([Cl:4])(=[O:3])C.[O:5]1[CH2:9][CH2:8][O:7][CH2:6]1.[CH3:10]COCC>[Cl-].[Zn+2].[Cl-]>[C:6]([O:7][CH2:8][CH2:9][O:3][CH2:1][Cl:4])(=[O:5])[CH3:10]
Reactant: C1COCO1
Reactant: CC(=O)Cl
Reactant: CCOCC
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(=O)OCCOCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
A solution of acetyl chloride (43.2 g, 550 mmol) in 100 mL of dry ether was added dropwise over 1 hour to a solution of 1,3 dioxolane (37.1 g, 500 mmol) in 300 mL of ether containing a few crystals of zinc (II) chloride at room temperature under nitrogen. The reaction mixture was stirred at room temperature for an additional 2 hours and then concentrated in vacuo. The product was purified by distillation (0.6 mmHg, 56°-58° C.) to provide 67.9 g (89%) of 1-acetoxy-2-(chloromethoxy)ethane as a clear colorless oil. cf: Foye, W. O.; Kaufmann, J. M.; Kim, Y. H. J. Heterocyclic Chem. 1982, 19, 497.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].C(N(CC)CC)C>ClCCl>[F:20][C:19]([F:21])([F:22])[C:18]([NH:17][CH2:16][CH2:15][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=1)=[O:23]
Reactant: COc1ccc(CCNC(=O)C(F)(F)F)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)C(F)(F)F)cc1NS(C)(=O)=O
Reaction time: 18 h
Yield: 93.4 %

Procedure:
Methanesulphonyl chloride (5.75 g, 0.05 moles) in dry dichloromethane (-50 ml) was added dropwise with stirring to N-[2-(3-amino-4-methoxyphenyl)ethyl]-2,2,2-trifluoro acetamide (13.1 g, 0.05 moles) and triethylamine (10.1 g, 7.5 ml, 0.1 mole) in dry dichloromethane (250 ml). Stirring was continued at 20° for 18 hr and the solution was then washed with dilute hydrochloric acid, saturated sodium bicarbonate solution and water, dried and evaporated. The residue on recrystallisation from benzene gave the sub-title compound (15.9 g) as ivory-coloured plates mp 129°-130°.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][N:11]=[C:10]2[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH3:24])[CH:18]=1)=O.[NH3:35]>CO>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]([N:23]([CH3:24])[C:19]2[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=2)[CH2:16][NH:15][C:10]2[C:9]3[C:14](=[C:5]([C:3]([NH2:35])=[O:2])[CH:6]=[CH:7][CH:8]=3)[N:13]=[CH:12][N:11]=2)=[O:34])=[CH:31][CH:30]=1
Reactant: N
Reactant: COC(=O)c1cccc2c(NCc3cccc(N(C)C(=O)c4ccc(OC)cc4)c3)ncnc12
Solvent: CO
Product: COc1ccc(C(=O)N(C)c2cccc(CNc3ncnc4c(C(N)=O)cccc34)c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-{3-[(4-Methoxy-benzoyl)-methyl-amino]-benzylamino}-quinazoline-8-carboxylic acid methyl ester from step d was dissolved in 1 ml 7N NH3 in methanol in a sealed vessel and stirred for 24 h at room temperature. The reaction mixture was evaporated and purified using preparative HPLC. The product was treated with HCl in methanol and concentrated in the SpeedVac.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=2)[CH:9]=[C:8]1[C:21]([O:23][CH2:24][CH3:25])=[O:22].Br[CH:27]([CH3:30])[C:28]#[N:29]>CN(C=O)C>[C:28]([CH:27]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=2)[CH:9]=[C:8]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:30])#[N:29]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Reactant: CC(Br)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)C#N)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
A mixture of K2CO3 (7.9 g, 57.4 mmol) and diethyl 1H-indole-2,6-dicarboxylate (Intermediate A, 5.0 g, 19.1 mmol) in DMF (30 mL) is stirred at room temperature for 30 min. A solution of 2-bromo-propionitrile (3.4 mL, 38.3 mmol) in DMF (10 mL) is added. The reaction mixture is warmed to 80° C. for 6 h and then cooled to room temperature and stirred for another 16 h. Solvent is removed and the residue is partitioned between EtOAc and water. The organic layer is separated, dried and concentrated to afford crude compound which is purified by flash column chromatography using EtOAc in hexanes followed by trituration with acetonitrile to afford the title compound (5.5 g, 91%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[N:10]=2)=[N:6][CH:7]=1.C(N(C(C)C)C(C)C)C.[SH:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.O1CCOCC1>[CH3:49][O:48][C:46](=[O:47])[CH2:45][CH2:44][S:43][C:2]1[CH:3]=[C:4]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[N:10]=2)=[N:6][CH:7]=1
Reactant: COC(=O)CCS
Reactant: CC(C)(C)OC(=O)N1CCC(c2nsc(Nc3ncc(Br)cc3Oc3ccccc3)n2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCSc1cnc(Nc2nc(C3CCN(C(=O)OC(C)(C)C)CC3)ns2)c(Oc2ccccc2)c1
Temperature: 95 °C
Yield: 69.1 %

Procedure:
A 1 L flask was charged with tert-butyl 4-(5-(5-bromo-3-phenoxypyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate (Example 4, Step D, 24.4 g, 45.8 mmol), N-ethyl-N-isopropylpropan-2-amine (16.0 mL, 91.7 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (1.33 g, 2.29 mmol), and dioxane (450 mL). Nitrogen was bubbled through the solution for 30 minutes. Methyl 3-mercaptopropanoate (5.46 mL, 50.4 mmol) and Pd2dba3 (1.05 g, 1.15 mmol) were added and the reaction was heated at 95° C. overnight. The reaction was cooled to ambient temperature and the resultant solids were filtered through celite. The filtrate was concentrated and purified on silica (30 to 40% EtOAc in hexanes) to afford tert-butyl 4-(5-(5-(3-methoxy-3-oxopropylthio)-3-phenoxypyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate (18.1 g, 69.1% yield) as a white foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][CH:8](NCCNCCCC1C=CC=C(NCC2CC2)N=1)[C:9]1[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.O1CCOCC1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:35])[CH2:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(CC(=O)OC(C)(C)C)NCCNCCCc2cccc(NCC3CC3)n2)cn1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CCC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Yield: 147 %

Procedure:
To a solution of diamine 2-7 (12.5 g, 25.8 mmol) and DIPEA (13.5 mL, 77.5 mmol) in CH2Cl2 (750 mL) at 0° C. was added p-NO2PhOCOCl (5.47 g, 27.1 mmol) in 4 portions. The resulting mixture was warmed to room temperature and 1,4-dioxane (750 mL) was added and refluxed for 6 h. After cooling, the solution was washed with 10% K2CO3 (3×400 mL) then brine. The organic layer was dried (Na2SO4), filtered, concentrated in vacuo, and purified by flash chromatography (silica, 50% EtOAc/hexanes) affording 9.0 g of cyclic urea 2-8.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([C:11]2[CH:21]=[CH:20][C:14]([O:15][CH2:16][CH:17]3[O:19][CH2:18]3)=[CH:13][CH:12]=2)[NH:9][CH:10]=1.[NH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>C(O)(C)C>[OH2:15].[N:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][NH:22][CH2:18][CH:17]([OH:19])[CH2:16][O:15][C:14]2[CH:20]=[CH:21][C:11]([C:8]3[NH:9][CH:10]=[C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[N:7]=3)=[CH:12][CH:13]=2)=[CH:26][CH:27]=1.[N:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][NH:22][CH2:18][CH:17]([OH:19])[CH2:16][O:15][C:14]2[CH:20]=[CH:21][C:11]([C:8]3[NH:9][CH:10]=[C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[N:7]=3)=[CH:12][CH:13]=2)=[CH:26][CH:27]=1
Reactant: NCCc1ccncc1
Reactant: c1csc(-c2c[nH]c(-c3ccc(OCC4CO4)cc3)n2)c1
Solvent: CC(C)O
Product: O
Product: OC(CNCCc1ccncc1)COc1ccc(-c2nc(-c3cccs3)c[nH]2)cc1
Temperature: 70 °C
Reaction time: 23 h

Procedure:
A mixture of 3-{p-[4-(2-thienyl)-2-imidazolyl]phenoxy}-1,2-epoxypropane (5.0 g, 0.017 m) and 4-(2-aminoethyl)pyridine (3.18 g, 0.026 m) in isopropanol (90 ml) was stirred at 70° C. for 23 hours. The solvent was evaporated under reduced pressure and the residue chromatographed on silica gel and eluted with 5% MeOH--CHCl3 saturated with NH3, and then rechromatographed eluting with 10% MeOH--CHCl3 saturated with NH3. Compound 78 was isolated as an amorphous solid.
Reaction SMILES: Cl[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][C:14]=3[CH:27]=2)=[CH:6][CH:5]=1)=[O:3].CCN(C(C)C)C(C)C.[F:37][CH:38]([F:41])[CH2:39][NH2:40]>O1CCCC1>[F:37][CH:38]([F:41])[CH2:39][NH:40][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][C:14]=3[CH:27]=2)=[CH:6][CH:5]=1)=[O:3]
Reactant: NCC(F)F
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(C(=O)Cl)cc3)cc2C1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(C(=O)NCC(F)F)cc3)cc2C1
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a solution of 1,1-dimethylethyl 7-[4-(chlorocarbonyl)phenyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.0 g, 2.6 mmol) and DIPEA (2.2 mL, 13 mmol) in tetrahydrofuran (10 mL) was added 2,2-difluoroethylamine (0.21 g, 2.6 mmol). The reaction mixture was stirred for 2 h and then partitioned between ethyl acetate (20 mL) and 1M hydrochloric acid (20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by column chromatography on silica (30% ethyl acetate in hexanes) provided 1,1-dimethylethyl 7-(4-{[(2,2-difluoroethyl)amino]carbonyl}phenyl)-2,3-dihydro-1,4-benzoxazepine-4 (5H)-carboxylate (0.95 g, 85% yield). MS (EI) for C23H26F2N2O4: 433 (MH1).
Reaction SMILES: S(Cl)(Cl)=O.F[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:15])[CH:7]=1.[CH3:16][S-:17].[Na+]>CO>[CH3:15][C:8]1[CH:7]=[C:6]([S:17][CH3:16])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: C[S-]
Reactant: Cc1cc(F)ccc1C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: CSc1ccc(C(=O)O)c(C)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (2 mL, 27.4 mmol) was added dropwise to a solution of 4-fluoro-2-methyl-benzoic acid (1.25 g, 8.11 mmol) in methanol (10 mL). The reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated in vacuo and methyl 4-fluoro-2-methylbenzoate was used in the next step without further purification. Methyl 4-fluoro-2-methylbenzoate was dissolved in DMF (5 mL) and sodium thiomethoxide (1.1 g, 15.7 mmol) was added and the reaction mixture was heated to 80° C. for 2 hours. The reaction mixture was then partitioned between 1M hydrochloric acid and ethyl acetate. The layers were separated and the organic layer was washed with 1M hydrochloric acid, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 2-methyl-4-(methylthio)benzoic acid which was carried to the next step without further purification. 2-Methyl-4-(methylthio)benzoic acid was suspended in acetic acid (10 mL) and hydrogen peroxide (5 mL of 30% w/w) was added and the reaction mixture was heated to 80° C. for 2 hours. The reaction mixture was concentrated in vacuo, then partitioned between 0.2 M HCl (25 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous extracted with ethyl acetate (50 mL). The combined organics washed with brine (20 mL), dried over MgSO4 and concentrated in vacuo. The resulting solid was rinsed with ether (2×10 mL) and dried in vacuo to give 2-methyl-4-methylsulfonyl-benzoic acid (0.87 g, 50%) as a white solid. ESI-MS m/z calc. 214.0. Found 215.5 (M+1)+; Retention time: 0.48 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 7.99 (d, J=8.1 Hz, 1H), 7.87 (s, 1H), 7.82 (d, J=8.0 Hz, 1H), 3.25 (s, 3H), 2.59 (s, 3H).
Reaction SMILES: [C:1]([N:11]1[CH2:18][C@H:17]([OH:19])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:20][C:21](C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(Cl)Cl.C(N1CC(=O)C[C@H]1C(O)=O)(OCC1C=CC=CC=1)=O>CC(C)=O>[CH2:20]([O:14][C:13](=[O:15])[C@@H:12]1[CH2:16][C:17](=[O:19])[CH2:18][N:11]1[C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH3:21]
Reactant: CC(C)=O
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=C1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC(=O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
To a round bottom flask containing 14.0 g (52.8 mmol) of N-Cbz-4-hydroxy-L-proline 8 was added 26 mL acetone. The solution was cooled on ice bath where 8.12 mL (0.106 mmol; 2 eq) of Jones reagent (CrO3, H2SO4, 1.3 M in water) was added. The mixture was allowed to warm to room temperature and stir for 3 h where the reaction appeared to be complete, as determined by TLC. The reaction was quenched by the addition of 6 mL isopropanol. After stirring for another 2 h the flask was placed on a glass socket rotovap and the isopropanol/acetone was removed by reduced pressure. The remaining green residue was then diluted into 200 mL water, salted with NaCl and extracted with EtOAc (3×200 mL). The organic extracts were combined, dried with MgSO4, filtered and concentrated to an oil. The remaining yellow oil was then separated by silica gel (90% CH2Cl2, 9% MeOH, 1% AcOH, Rf=0.3). The fractions containing the product were combined and concentrated by rotovap to a solid residue and then recrystallized from CH2Cl2 leaving 9.86 g (37.5 mmol) of N-Cbz-4-keto-L-proline, a 71% yield. The product material was used in the next synthetic step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9]([C:11](O)=[O:12])=[CH:8][C:7]=1[CH3:14])=[O:5])[CH3:2].C[CH2:16][N:17](C(C)C)[CH:18](C)C.CNC.C1COCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:16][N:17]([CH3:18])[C:11]([C:9]1[NH:10][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([CH3:14])[CH:8]=1)=[O:12]
Reactant: CCOC(=O)c1[nH]c(C(=O)O)cc1C
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c(C(=O)N(C)C)cc1C
Yield: 5.6 %

Procedure:
To a solution of 5-[(ethyloxy)carbonyl]-4-methyl-1H-pyrrole-2-carboxylic acid (0.160 g, 0.812 mmol) in DMF (4 ml) was added DIPEA (0.140 mL, 0.790 mmol). The reaction mixture was stirred and the solution was divided into four equal portions, one of which was added to a glass vial with a stir bar. To the vial was added a 2M solution of dimethylamine in THF (0.10 mL, 0.2 mmol) and HATU (0.075 g, 0.197 mmol) and the reaction mixture stirred overnight. Purification was accomplished by RPHPLC (water:acetonitrile with 0.1% TFA). The desired fractions were collected and lypholized to afford ethyl 5-[(dimethylamino)carbonyl]-3-methyl-1H-pyrrole-2-carboxylate (0.010 g, 22%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.45 (br. s., 1H) 6.37 (d, 1H) 4.22 (q, 2H) 3.10 (br. s., 3H) 2.97 (br. s., 3H) 2.26 (s, 3H) 1.28 (t, 3H). MS: m/z 225.5 (M+1).
Reaction SMILES: C([S:9][CH:10]([CH3:21])[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])(=O)C1C=CC=CC=1>O.[OH-].[NH4+]>[SH:9][CH:10]([CH3:21])[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12]
Reactant: CC(SC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(S)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
1-(2-Benzoylthiopropanoyl)-L-proline (5.7 g.) is dissolved in a mixture of water (12 ml.) and concentrated ammonium hydroxide (9 ml.) with stirring. After 1 hour, the mixture is diluted with water (10 ml.) and filtered. The filtrate is extracted twice with ethyl acetate, concentrated to one-third of the original volume, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride, dried and concentrated to dryness in vacuo. The residue, 1-(2-mercaptopropanoyl)-L-proline, is crystallized from ethyl acetate-hexane, yield 3 g., m.p. (105) 116°-120°.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[S:10][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[CH2:13][CH2:12]2)=[N:8][N:7]=1.[H-].[Na+].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].Cl>CN(C=O)C>[F:25][C:24]([F:27])([F:26])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][CH:14]1[CH2:13][CH2:12][N:11]([C:9]2[S:10][C:6]([C:5]3[N:1]=[N:2][N:3]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:4]=3)=[N:7][N:8]=2)[CH2:16][CH2:15]1
Reactant: CCOC(=O)CBr
Reactant: FC(F)(F)c1ccccc1OC1CCN(c2nnc(-c3nn[nH]n3)s2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nnc(-c2nnc(N3CCC(Oc4ccccc4C(F)(F)F)CC3)s2)n1
Temperature: 0 °C

Procedure:
A solution of 1-[5-(2H-tetrazol-5-yl)-1,3,4-thiadiazol-2-yl]-4-[2-(trifluoromethyl)phenoxy]piperidine (262 mg, 0.66 mmol) in DMF (5 mL) was treated with NaH (60% in oil) (42 mg, 1.05 mmol) at −78° C. The mixture was warmed to 0° C. and, after 10 min, ethyl bromoacetate (150 μL, 1.35 mmol) was added dropwise. The final reaction mixture was warmed and stirred at room temperature until TLC indicated disappearance of the starting material. The reaction mixture was poured into aqueous 1 N HCl, extracted with EtOAc and washed with brine. The organic layer was dried (Na2SO4) and filtered. Solvents were removed in vacuo to afford the crude product, which was purified by column chromatography on silica gel (eluting with 10-50% EtOAc/hexanes) to afford ethyl [5-(5-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3,4-thiadiazol-2-yl)-2H-tetrazol-2-yl]acetate as the more polar regioisomer, Rf=0.2 (50% EtOAc/hexanes). 1H NMR (400 MHz, acetone-d6): δ7.70-7.61 (m, 2H), 7.40 (d, 1H), 7.14 (t, 1H), 5.81 (s, 2H), 5.10-5.04 (m, 1H), 4.31 (q, 2H), 3.94-3.85 (m, 2H), 3.86-3.77 (m, 2H), 2.29-2.20 (m, 2H), 2.11-2.03 (dd, 2H), 1.31 (t, 3H).
Reaction SMILES: [I:1]I.N1C=CN=C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:27]1([CH2:33][S:34]([CH2:37][CH2:38][CH2:39][CH2:40]O)(=[O:36])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[I:1][CH2:40][CH2:39][CH2:38][CH2:37][S:34]([CH2:33][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:36])=[O:35]
Reactant: II
Reactant: O=S(=O)(CCCCO)Cc1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=S(=O)(CCCCI)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of iodine (1.2 g, 4.5 mmol), imidazole (0.34 g, 4.4 mmol) and Ph3P (1.2 g, 4.4 mmol) in methylene chloride (10 mL) is added 4-phenylmethanesulfonylbutan-1-ol (0.99 g, 4.34 mmol) and the mixture is stirred at RT for 1 h. The mixture is filtered and the filtrate evaporated. The resulting oil is dissolved in EtOAc and washed with saturated sodium thiosulfate and brine. The organic phase is dried over magnesium sulfate and the solvent removed under reduced pressure. The resulting solid is washed with ether and the filtrate is evaporated to give the title compound as a white solid.