Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH2:15])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19].Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>N1C=CC=CC=1.C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH:15][C:22](=[O:23])[O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN(C)c1cc(-c2ccc3nc(N)sc3c2)cnc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)c1cc(-c2ccc3nc(NC(=O)Oc4ccccc4)sc3c2)cnc1Cl
Reaction time: 8 h

Procedure:
To a mixture of 6-(6-chloro-5-(dimethylamino)pyridin-3-yl)benzo[d]thiazol-2-amine (100 mg, 328 μmol) in pyridine (0.3 mL) and DCM (2 mL) was added phenyl chloroformate (200 μl, 1594 mmol). A clear solution formed. After overnight at rt, the slurry was diluted with EtOAc (10 mL) and filtered. The solid was washed with EtOAc, then H2O (2×3 mL). LCMS indicted that the organic liquid contains most of product and by-product. The small amount of solid remained on the filter was pure product (35 mg). MS (ESI, pos. ion) m/z: calc'd for C21H17ClN4O2S: 424.1. found: 425.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.85 (s, 6H) 7.33 (t, J=7.53 Hz, 3H) 7.48 (t, J=7.78 Hz, 2H) 7.76-7.88 (m, 3H) 8.35 (s, 1H) 8.43 (s, 1H) 12.73 (s, 1H).
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([SH:30])[CH:27]=[CH:28][CH:29]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:21])[C:2]=1[S:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Reactant: COc1cccc(S)c1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: COc1cccc(SC2=C(O)CC(c3ccccc3)(c3ccccc3)OC2=O)c1

Procedure:
The title compound was prepared as described in General Method 6 from 1.8 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 2.0 mmol of 3-methoxybenzenethiol, and 2.0 mmol of piperidine in 25 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform (m.p. 61°-62° C.). 1H NMR (DMSO-d6) δ 3.63 (s, 3 H), 3.76 (s, 2 H), 5.64 (bd, 1 H), 6,42 (s, 1 H), 6.54 (d, 1 H), 6.74 (t, 1 H), 7.32-7.47 (m, 10 H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2([CH2:20][C:21]([OH:23])=O)[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:25]([O:29][NH2:30])([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:25]([O:29][NH:30][C:21](=[O:23])[CH2:20][C:15]1([S:14][C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][CH:10]=2)[CH2:16][CH2:17][CH2:18][CH2:19]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)ON
Reactant: O=C(O)CC1(Sc2ccc(Oc3ccccc3)cc2)CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)(C)ONC(=O)CC1(Sc2ccc(Oc3ccccc3)cc2)CCCC1
Reaction time: 8 h

Procedure:
The 2-[1-(4-phenoxyphenylthio)-cyclopent-1-yl]-acetic acid obtained in Example 5 was dissolved in methylene chloride (8 ml) and treated with 4 -dimethylaminopyridine (180 mg), O-(tert-butyl) hydroxylamine hydrochloride (360 mg), triethylamine (540 μL), pyridine (400 μL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (750 mg). After stirring overnight the reaction mixture was partitioned between ethyl acetate and water, the organic layer separated, and the solvent removed under reduced pressure. Preparative TLC of the residue and elution with 2:1 hexane/ethyl acetate gave N-(tert-butoxy)-2-[1-(4-phenoxyphenylthio)cyclopent-1-yl]-acetamide (270 mg) as a white foam, which can be used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]21.[CH2:25]([Mg]Br)[CH3:26].[BH4-].[Na+].O>O1CCCC1.CC(O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH2:24])[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CC[Mg]Br
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCC(N)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 4 h
Yield: 132.4 %

Procedure:
To a solution of 9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbonitrile (1.496 g, 3.096 mmol) in tetrahydrofuran (40 mL) was added ethylmagnesium bromide (3.0 M solution in diethyl ether, 13.2 mL, 39.6 mmol) at 0° C. The reaction mixture was stirred at 50° C. for 4 hr, then the mixture was cooled to room temperature. A suspension of sodium tetrahydroborate (3.0 g, 79.3 mmol) in 2-propanol (40 mL) was added to the reaction mixture at room temperature. After the mixture was stirred at room temperature for 18 hr, water was added to the reaction mixture at 0° C. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, concentrated in vacuo to give title compound (1.68 g) as a pale yellow amorphous.
Reaction SMILES: [NH2:1][C:2]1[C:12]([Cl:13])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[Cl:14].[N:15]([O-])=O.[Na+].[Sn](Cl)Cl>Cl.O>[ClH:13].[Cl:14][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([Cl:13])[C:2]=1[NH:1][NH2:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1cc(Cl)c(N)c(Cl)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(Cl)c(NN)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 107.9 %

Procedure:
Part A: To a stirred suspension of 4.33 g (18.5 mmol) of ethyl 4-amino-3,5-dichlorobenzoate in 8 mL conc. HCl at 0° C. was added a solution of 1.28 g (18.5 mmol) of sodium nitrite in 8 mL water dropwise. After stirring at 0° C. for 45 min, a solution of 12.52 g (55.5 mmol) tin(II) chloride in 14 ML conc. HCl was added dropwise. The reaction was sealed and placed in the refrigerator for 18 h. The solid was collected by suction filtration, washed with brine and then 2:1 petroleum ether-diethyl ether, treated with 1 N NaOH, and filtered. This solid was dissolved in diethyl ether, acidified with 4 N HCl in dioxane, filtered and washed with diethyl ether to give 2.85 g (54%) of ethyl 3,5-dichloro-4-hydrazinobenzoate hydrochloride, mp 225-227 (dec)° C. Mass Spec.: (CI+) 249 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([S:23][CH3:24])[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:30]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([S:23]([CH3:24])=[O:30])[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(-c2c(-c3ccnc(F)c3)nn3ccccc23)n1
Solvent: ClCCl
Product: CS(=O)c1nccc(-c2c(-c3ccnc(F)c3)nn3ccccc23)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.1 %

Procedure:
To a cold (0° C.) solution of 2-(2-fluoro-4-pyridinyl)-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridine (1.81 g, 5.36 mmol) in dichloromethane (100 mL) was added 3-chloroperoxybenzoic acid (1.39 g, 70%, 5.63 mmol). The reaction mixture was warmed to room temperature and stirred 16 hours. The reaction mixture was diluted with 100 mL dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was concentrated in vacuo to give 1.84 g of 2-(2-fluoro-4-pyridinyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridine of 90% purity as a greenish grey solid. This material was carried on without further purification. 1H NMR (DMSO-d6) δ 8.92 (d, 1H), 8.75 (d, 1H), 8.54 (d, 1H), 8.38 (d, 1H), 7.63–7.59 (m, 2H), 7.48 (s, 1H), 7.32 (d, 1H), 7.24 (t, 1H), 2.87 (s, 3H); 19F NMR (DMSO-d6) δ −68.05; MS m/z 354 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[CH3:26][C:27]1[NH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:28]3[C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:35]=[C:27]3[CH3:26])=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9]
Reactant: Cc1cc2ccccc2[nH]1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1Cl
Product: Cc1cc2ccccc2n1Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2Cl)cc1
Yield: 81 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from 2-chloro-N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}benzenesulfonamide (Intermediate 8), and 2-methyl-1-H-indole, the title compound was isolated as a yellow solid in 81% yield (96% purity by HPLC).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:5]=1.O.[OH-].[Na+].Cl>O1CCOCC1>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][O:11][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[F:10])[C:3]([OH:21])=[O:2])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(F)c(OCCc2ccc(Cl)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(F)c(OCCc2ccc(Cl)cc2)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
0.75 g (2.43 mmol) of 3-[2-(4-Chloro-phenyl)-ethoxy]-4-fluoro-benzoic acid methyl ester was dissolved in 25 ml of dioxan. 5 ml of water and 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was heated at 60° C. for 2 h. The reaction solution was cooled to 0° C. and concentrated hydrochloric acid was added to give a pH of 1–2, whereupon the product precipitated from solution. The suspension was stirred for 30 min, then the product was filtered off and dried under reduced pressure.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:24][O:25][CH3:26])[C:20]([O:22]C)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O1CCOCC1>>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:24][O:25][CH3:26])[C:20]([OH:22])=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC
Solvent: C1COCCO1
Product: COC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O

Procedure:
To a solution of methyl (S)-(9-fluorenylmethyloxycarbonylamino)-3-methoxypropionate (2.18 g, 6.13 mmol) in dioxane (31 ml) 6M HCl (31 ml, 184 mmol) was added. This mixture was allowed to cool down and concentrated. The residue was purified by flash chromatography (silica gel; hexane: ethyl acetate: acetic acid (10:10:1).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:31]=[N:32][C:33]([N:36]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([C:45]([N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)=[O:46])[CH:43]=3)[C:38]([CH:53]([OH:55])[CH3:54])=[CH:37]2)=[N:34][CH:35]=1>ClCCl>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:35]=[N:34][C:33]([N:36]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([C:45]([N:47]4[CH2:48][CH2:49][O:50][CH2:51][CH2:52]4)=[O:46])[CH:43]=3)[C:38]([C:53](=[O:55])[CH3:54])=[CH:37]2)=[N:32][CH:31]=1
Reactant: CC(O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reaction time: 2 h

Procedure:
Dess-Martin periodinane reagent (437 mg, 1.008 mmol, 1.5 eq) was added at 0° C. to a stirred solution of (1-(5-(2-fluorophenyl)pyrimidin-2-yl)-3-(1-hydroxyethyl)-1H-indol-6-yl)(morpholino)methanone (synthesis example 28, 300 mg, 0.672 mmol, 1.0 eq) in dichloromethane (10 mL). Stirring was continued for 2 h at room temperature and the reaction mixture was then filtered through a bed of celite. The celite was washed with dichloromethane (10 mL) and the filtrate was dried over anhydrous sodium sulfate and evaporated in vacuo. White solid. Yield: 250 mg (72% of theory).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[C:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[CH:17]=[CH:18][C:12]=2[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].N1C=CC=CC=1.C(Cl)(=O)C([Cl:37])=O>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:37][C:23]([C:22]1[CH:26]=[CH:27][C:19]([C:16]2[CH:17]=[CH:18][C:12]3[O:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:14][C:13]=3[CH:15]=2)=[CH:20][CH:21]=1)=[O:24]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(C(=O)O)cc3)cc2C1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(C(=O)Cl)cc3)cc2C1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
To a cooled (0° C.) solution of 4-(4-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzoic acid (0.95 g, 2.6 mmol), pyridine (1.3 mL, 15 mmol) and oxalyl chloride (0.44 mL, 5.1 mmol) in toluene (10 mL) was added dimethylformamide (0.01 mL, 0.1 mmol) and the resulting mixture was warmed to room temperature. After 24 h the reaction mixture was concentrated to provide 1,1-dimethylethyl 7-[4-(chlorocarbonyl)phenyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.0 g, 100%) as a brown oil. MS (EI) for C21H22ClNO4: 388 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[C:7]([N:11]([C@@H:29]3[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]3)[C:12](=[O:28])[C:13]3[CH:18]=[CH:17][C:16](B4OC(C)(C)C(C)(C)O4)=[CH:15][CH:14]=3)[N:8]=[CH:9][CH:10]=[C:5]2[CH:4]=[CH:3]1.Br[C:43]1[CH:44]=[N:45][N:46]([CH3:53])[C:47]=1[C:48]([O:50][CH2:51][CH3:52])=[O:49].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:51]([O:50][C:48]([C:47]1[N:46]([CH3:53])[N:45]=[CH:44][C:43]=1[C:16]1[CH:17]=[CH:18][C:13]([C:12]([N:11]([C@@H:29]2[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:30]2)[C:7]2[N:8]=[CH:9][CH:10]=[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:6]=23)=[O:28])=[CH:14][CH:15]=1)=[O:49])[CH3:52]
Reactant: CCOC(=O)c1c(Br)cnn1C
Reactant: Cn1ccc2ccnc(N(C(=O)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)c21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)c1c(-c2ccc(C(=O)N(c3nccc4ccn(C)c34)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc2)cnn1C
Temperature: 85 °C
Yield: 86 %

Procedure:
To a solution of the compound from Step 1 (R)-tert-butyl 3-(N-(1-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)piperidine-1-carboxylate (0.5 g, 0.89 mmol) in 1,4-dioxane (10 mL) was added ethyl 4-bromo-1-methyl-1H-pyrazole-5-carboxylate (0.21 g, 0.90 mmol), Pd(dppf)Cl2 (0.065 g, 0.089 mmol) and Cs2CO3 (0.58 g, 1.78 mmol). The reaction was heated 85° C. for 16 h. The reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography eluting with a gradient of petroleum ether: EtOAc (5:1 to 0:1) to afford the title compound (0.45 g, 86%) as yellow solid.
Reaction SMILES: [Br:1]Br.[C:3]([O:6][CH2:7][CH2:8][N:9]1[CH:13]=[N:12][N:11]=[N:10]1)(=[O:5])[CH3:4]>C(Cl)(Cl)Cl.C(O)(=O)C>[C:3]([O:6][CH2:7][CH2:8][N:9]1[C:13]([Br:1])=[N:12][N:11]=[N:10]1)(=[O:5])[CH3:4]
Reactant: CC(=O)OCCn1cnnn1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)OCCn1nnnc1Br
Yield: 94.7 %

Procedure:
Bromine (69.1 g) in chloroform (80 ml) was added to a stirred refluxing solution of 1H-tetrazole-1-ethanol acetate (ester) (33.8 g) in acetic acid (200 ml) and chloroform (400 ml). After 72 h the mixture was cooled and evaporated, excess, saturated potassium carbonate solution was added and the mixture was extracted with ethyl acetate to give the title compound (48.2 g) as a cream solid, m.p. 55°-6° (from diethyl ether).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:22]([Si:26]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)Cl)([CH3:25])([CH3:24])[CH3:23].C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[Si:26]([O:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][CH2:6]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C1CCC(OCCO)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCC(OCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The crude product from Example 2A is dissolved in 20 ml of dichloromethane, and 0.83 ml (5.93 mmol) of triethylamine and 1.54 ml (5.93 mmol) of tert-butyldiphenylchlorosilane are added. After addition of 24.2 mg (0.20 mmol) of 4-N,N-dimethylaminopyridine the mixture is stirred at RT for 20 h. In each case 10 ml of ethyl acetate and of saturated aqueous sodium bicarbonate solution are then added. The phases are separated, and the combined organic phases are then dried over magnesium sulfate. The solvent is removed on a rotary evaporator and the residue is purified chromatographically on silica gel 60 (mobile phase: gradient cyclohexane/ethyl acetate 100:1→20:1).
Reaction SMILES: C([O:8][C:9](=[O:42])[CH2:10][CH:11]1[O:15][C:14]([CH:16]([NH:21][C:22](=[O:41])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])=[O:32])=[CH:26][CH:25]=2)[CH2:17][CH:18]([CH3:20])[CH3:19])=[N:13][CH2:12]1)C1C=CC=CC=1>C1COCC1.CO.[OH-].[Pd+2].[OH-]>[CH3:19][CH:18]([CH3:20])[CH2:17][CH:16]([C:14]1[O:15][CH:11]([CH2:10][C:9]([OH:42])=[O:8])[CH2:12][N:13]=1)[NH:21][C:22](=[O:41])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH3:40])=[O:32])=[CH:26][CH:25]=1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)C2=NCC(CC(=O)OCc3ccccc3)O2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)C2=NCC(CC(=O)O)O2)cc1
Reaction time: 2 h
Yield: 92 %

Procedure:
A mixture of [2-(3-methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-4,5-dihydro-oxazol-5-yl]-acetic acid benzyl ester (120 mg) and palladium hydroxide (40 mg) in 10 ml of THF and 10 ml of MeOH was shaken on a Parr Apparatus under 30 p.s.i. H2 for 2 h. The mixture was filtered through Celite and the filtrate concentrated under reduced pressure. The residue was suspended in EtOAc and concentrated under reduced pressure. Trituration with hot EtOAc gave 93 mg of the title compound as a light pink solid. MS [M+1]+481.3; 1H nmr (400 MHz, DMSO-d6) δ0.77-0.87 (m, 6H), 1.39-1.59 (m, 3H), 2.10-2.33 (m, 4H, including s at 2.21, 3H), 2.40-5.08 (m, 7H, including q at 3.36, J=14.2 Hz, 2H), 6.90 (t, J=7.4 Hz, 1H), 7.08-7.14 (m, 4H), 7.35 (d, J=6.8 Hz, 2H), 7.79 (d, J=8.1 Hz, 1H), 7.95-8.45 (m, 2H), 9.13-9.23 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:6](=[O:12])[CH2:5][C:4](=O)[CH2:3]1.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:22])=[C:19]([SH:21])[CH:20]=1>CS(C)=O>[Cl:14][C:15]1[CH:20]=[C:19]2[C:18](=[CH:17][CH:16]=1)[NH:22][C:4]1[CH2:3][CH:2]([CH3:1])[CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:6](=[O:12])[C:5]=1[S:21]2
Reactant: Nc1ccc(Cl)cc1S
Reactant: COC(=O)C1C(=O)CC(=O)CC1C
Solvent: CS(C)=O
Product: COC(=O)C1C(=O)C2=C(CC1C)Nc1ccc(Cl)cc1S2

Procedure:
A mixture of methyl 6-methyl-2,4-dioxocyclohexane-1-carboxylate, 7a (2.53 g, 13.7 mmole) and 5-chloro-2-aminobenzenethiol, 6 (X=Cl, 2.20 g, 13.7 mmole), in DMSO (10 mL) is placed in a preheated heating mantle. The reaction mixture is stirred and refluxed for 0.5 h. Upon cooling, the reaction mixture forms a solid. The crystals are filtered and the remaining mother liquid is poured into cold water, whereupon further precipitation occurs. Each precipitate is separately recrystallized twice from MeOH and proves to be identical. An analytical sample of 4e, (R=Cl), mp 226-227° C. occurs as light orange crystals; yield: 1.70 g (36.7%).
Reaction SMILES: [S:1]1[CH:6]2[C:7]([O:9][C:10](=[O:11])[CH:2]1[CH2:3][CH2:4][CH2:5]2)=O.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:19][CH2:18]1.C1(C)C=CC=CC=1>O>[N:24]1[CH:25]=[CH:26][CH:27]=[N:28][C:23]=1[N:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[C:7](=[O:9])[CH:6]3[S:1][CH:2]([CH2:3][CH2:4][CH2:5]3)[C:10]2=[O:11])[CH2:18][CH2:19]1
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Reactant: O=C1OC(=O)C2CCCC1S2
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1C2CCCC(S2)C(=O)N1CCCCN1CCN(c2ncccn2)CC1

Procedure:
Tetrahydrothiopyran-2,6-dicarboxylic anhydride (2.4 g., 14 mmole) and 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine (3.5 g., 15 mmole) were dissolved in 250 ml. of toluene and refluxed for 48 hours with water removal via a Dean-Shark trap. The solvent was removed in vacuum and replaced with chloroform. The mixture was filtered through 75 g. of silica gel and concentrated in vacuum and the residue was crystallized from isopropanol with addition of 4N isopropanolic HCl. A second crystallization from isopropanol gave 1. g. of the title compound as the monohydrochloride; m.p. 238°-241° C. (d).
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:41])[CH2:12][N:13]2[CH2:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@@:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.CO>[Cl:39][C:35]1[C:34]([F:40])=[C:33]([C@@H:14]2[C@:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:17][N:13]2[CH2:12][C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:42])=[O:2])=[CH:9][CH:8]=2)=[O:41])[CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)c1ccc(NC(=O)CN2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1CN(CC(=O)Nc2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To a mixture of rac-4-{2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetylamino}-benzoic acid methyl ester (30.0 mg, 0.05 mmol) in THF/MeOH (0.6 mL/0.2 mL) was added 2 N LiOH (0.2 mL), and the reaction mixture was stirred at rt for 2 hrs. The reaction mixture was concentrated and quenched with 2 NH2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to give rac-4-{2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetylamino}-benzoic acid (29.0 mg, 98.9%). LC-MS (ES+) m/z Calcd for C31H29Cl2F2N3O3+H [(M+H): 600.5; Found: 602.