Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][C:28]#[N:29].O>CN(C)C=O>[C:28]([CH2:27][N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:13][CH2:12][CH2:11]1)#[N:29]
Reactant: c1ccc(C2(c3ccccc3)CCNCCO2)cc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCN1CCOC(c2ccccc2)(c2ccccc2)CC1

Procedure:
To the solution of 2.5 g of 7,7-diphenyl-hexahydro-1,4-oxazepine in 5 ml of dimethylformamide, 1.5 g of anhydrous potassium carbonate are added while stirring, followed by the dropwise addition of the solution of 0.85 g of chloroacetonitrile in 2 ml of dimethylformamide and the suspension is stirred for 5 hours at room temperature. It is poured onto a mixture of ice and water, the aqueous phase extracted twice with 20 ml of diethyl ether each, the extract dried, filtered and evaporated. The residue is recrystallized from ethanol, to yield the 4-cyanomethyl-7,7-diphenyl-hexahydro-1,4-oxazepine melting at 119°-121° (its hydrochloride melts at 178°-180° with decomposition).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.C1COCC1.[O:18]=[C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH:21]([C:30](O)=[O:31])[CH2:20]1.[BH4-].[Na+]>O>[OH:31][CH2:30][CH:21]1[CH2:22][N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19](=[O:18])[CH2:20]1
Reactant: O=C(O)C1CC(=O)N(c2ccccc2)C1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CC(CO)CN1c1ccccc1
Temperature: 25 °C

Procedure:
1,1′-Carbonylbisimidazole was added to a THF solution of 5-oxo-1-phenylpyrrolidine-3-carboxylic acid and stirred at room temperature for 1.5Hours. Successively sodium borohydride and 2.0 ml of water were added thereto and stirred at room temperature for 1Hour. Thereafter, its work-up and purification were carried out in the standard method to obtain 4-(hydroxymethyl)-1-phenylpyrrolidin-2-one. EP: 192.
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.C(O)(=O)C.[CH3:14][C:15]1[CH:16]=[C:17]([NH2:20])[NH:18][N:19]=1>COC(C)(C)C>[CH3:14][C:15]1[CH:16]=[C:17]2[NH:20][C:3]([CH3:5])=[CH:2][C:1](=[O:7])[N:18]2[N:19]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1cc(N)[nH]n1
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: Cc1cc2[nH]c(C)cc(=O)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.9 %

Procedure:
Add ethyl acetoacetate (128 g, 0.98 mol) dropwise to an acetic acid solution (500 mL) of 5-methyl-2H-pyrazol-3-ylamine (100 g, 0.95 mol), keeping the temperature at 25-28° C. Heat the mixture at reflux for 10 h and then cool to room temperature. Add the reaction to tert-butyl methyl ether (5 L) cooled to 5° C., keeping the temperature below 10° C. Stir for 1 h at 5° C., and filter. Dry the resulting material in vacuo overnight to provide a white solid (158 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:22]([N:24]1[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]1)=[O:23])[NH:6]2.[Cl:32][C:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35][N:34]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:10]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:22]([N:24]1[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]1)=[O:23])[N:6]2[C:37]1[CH:36]=[CH:35][N:34]=[C:33]([Cl:32])[CH:38]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2Cl)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(cc(C(=O)N4CCC(F)(F)CC4)n3-c3ccnc(Cl)c3)c2Cl)CC1
Yield: 34 %

Procedure:
The title compound was synthesized in analogy to example 66, from [4-chloro-2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 228), 2-chloropyridine-4-boronic acid, copper(II) acetate, pyridine and using chloroforme instead of dichloromethane as solvent, to give the desired product as a colorless foam (34%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:2]1.[H-].[Na+].BrCCC[N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].[CH2:33]1[CH2:37]OC[CH2:34]1>>[CH2:14]([O:13][C:11]([C:3]1[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:5][N:1]([CH2:34][CH2:33][CH3:37])[C:2]=1[N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32])=[O:12])[CH3:15]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: C1CCOC1
Reactant: CCOC(=O)c1c[nH]cc1C(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCCn1cc(C(=O)OCC)c(C(=O)OCC)c1N1C(=O)c2ccccc2C1=O
Temperature: 30 °C
Yield: 92 %

Procedure:
A solution of diethyl pyrrole-3,4-dicarboxylate (39 g, 0.185 mol) in THF (1600 mL) was treated with NaH (60%, 7.6 g, 0.19 mol). The reaction mixture was heated to reflux for 1 hour. The reaction was then cooled to 30° C. and N-(3-bromopropyl)phthalimide (52 g, 0.19 mol) was added. The reaction mixture was heated to reflux for 1 hour, cooled, filtered, and concentrated in vacuo. The resultant gum was partitioned between ETOAC/H2O and extracted with EtOAC (2×300 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The resultant solid was recrystallized from EtOAC to give the title compound 68 g (92%) (mp 100-101° C.). 1H NMR (DMSO) δ1.24 (t, 3H, CH), 2.06 (m, 2H, CH3), 3.57 (t, 2H, CH2), 4.14 (m, 4H, CH2), 7.49 (s, 2H, ArH), 7.86 (m, 4H, ArH)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(N(CC)CC)C.C([CH:21]([O:28]Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(O)=O.[C:30]([O-])([O-])=[O:31].[Na+].[Na+]>C(#N)C>[C:22]1([CH2:21][O:28][C:30](=[O:31])[NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: O=C(O)C(OCl)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2[nH]ccc2c1)OCc1ccccc1
Temperature: 23 °C
Reaction time: 60 h
Yield: 25.3 %

Procedure:
To a solution of 5-aminoindole (10.0 g, 76 mmol) and triethylamine (7.67 g, 76 mmol) in acetonitrile (400 mL) at 0° C. was added dropwise a solution of carboxybenzyloxychloride (12.93 g, 75.8 mmol) in acetonitrile (80 mL). After the addition was complete the reaction was allowed to warm to 23° C. and stand for 60 h. The solvent was removed in vacuo and the residue treated with water containing Na2CO3 (76 mmol). The mixture was extracted with four portions of CH2Cl2. The combined organic extracts were washed with a saturated NaCl solution, dried with K2CO3, filtered, and concentrated in vacuo. SiIica gel chromatography (4:1 to 1:1 hexane:ethyl acetate gradient) of the concentrate afforded phenylmethyl-(1H-indol-5-yl)carbamate (5.11 g, 25%).
Reaction SMILES: C1(S[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)CCCC1.ClC1[CH:23]=[CH:22][CH:21]=[C:20]([C:24](OO)=O)C=1.[S:28](=S)(=[O:31])([O-])[O-:29].[Na+].[Na+]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH:20]1([S:28]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)(=[O:31])=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=[N+]([O-])c1cccc(CSC2CCCC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(CS(=O)(=O)C2CCCC2)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 1-[(cyclopentylsulfanyl)methyl]-3-nitrobenzene (4.5 g) in DCM (180 mL) was treated at 0° C. with portions of m-chloroperbenzoic acid (9.3 g, 77%). The mixture was stirred at 0° C. for further 90 minutes and then 18 hours at room temperature. The reaction mixture was diluted with DCM before disodium sulfurothioate and sodium bicarbonate solution was added and extracted with DCM (2×). The combinded organic phases were washed and concentrated. The residue was purified by chromatography (hexane/ethyl acetate 12% 100%) to give the title compound (4.9 g).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][N:32]=[CH:31]2.CC(C)([O-])C.[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:33]3[C:34]4[C:30](=[CH:29][C:28]([C:27]([F:26])([F:38])[F:37])=[CH:36][CH:35]=4)[CH:31]=[N:32]3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: FC(F)(F)c1ccc2[nH]ncc2c1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4cc(C(F)(F)F)ccc43)nc12
Temperature: 125 °C
Yield: 44.1 %

Procedure:
To a stirred solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (200 mg, 468 μmol), 5-(trifluoromethyl)-1H-indazole (87.1 mg, 468 μmol) in dioxane (3.5 mL) was added sodium tert-butoxide (98.9 mg, 1.03 mmol) and bis(tri-tert-butylphosphine)palladium(0) (23.9 mg, 46.8 μmol). The mixture was degassed then heated in sealed tube at 125° C. for two days. The mixture was cooled, filtered through celite, the cake washed with ethyl acetate, and the combined filtrates were concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-30% ethyl acetate in hexanes) gave N-tert-butyl-2-(5-(trifluoromethyl)-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (110 mg, 44%). 1H NMR (CDCl3) δ: 9.20 (s, 1H), 8.69-8.74 (m, 2H), 8.42 (s, 2H), 8.39 (d, J=0.8 Hz, 1H), 8.33-8.36 (m, 1H), 8.18 (s, 2H), 7.70-7.74 (m, 1H), 5.73 (s, 2H), 3.59 (dd, J=8.9, 7.7 Hz, 2H), 1.63 (s, 9H), 0.92-0.98 (m, 2H), −0.04 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.CC1(C)COB([C:23]2[CH:24]=[CH:25][C:26]([F:37])=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=3)[CH:28]=2)OC1>>[F:37][C:26]1[CH:25]=[CH:24][C:23]([C:2]2[C:3]3[C:8](=[N:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[CH:28][C:27]=1[C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: CC1(C)COB(c2ccc(F)c(-c3ccc(C#N)cc3)c2)OC1
Product: N#Cc1ccc(-c2cc(-c3ccnc4nc(C(F)(F)F)ccc34)ccc2F)cc1
Yield: 24.3 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 5′-(5,5-dimethyl[1,3,2]dioxaborinan-2-yl)-2′-fluorobiphenyl-4-carbonitrile (87 mg, 0.28 mmol) as described in Example 7 part g), affording 2′-fluoro-5′-(7-trifluoromethyl[1,8]naphthyridin-4-yl)biphenyl-4-carbonitrile (21 mg, 25%). δH (360 MHz, CDCl3) 7.41-7.46 (1H, m), 7.52-7.60 (3H, m), 7.71-7.82 (4H, m), 7.85 (1H, d, J 8.4), 8.52 (1H, d, J 8.8), 9.30 (1H, d, J 4.6). m/z (ES+) 394 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>O.CC(OC)(C)C>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1nc[nH]c2nccc1-2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 88.9 %

Procedure:
To a flask equipped with a nitrogen inlet, addition funnel, thermowell, and mechanical stirrer was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 600 g, 3.91 mol) and dimethylacetimide (9.6 L). The mixture was cooled to −5° C. in an ice/brine bath and sodium hydride (NaH, 60 wt %, 174 g, 4.35 mol, 1.1 equiv) was added in portions as a solid. The mixture went to a dark solution during 15 minutes and trimethylsilylethoxymethyl chloride (2, 763 mL, 4.31 mol, 1.1 equiv) was added slowly via an addition funnel at a rate that the temperature did not exceed 5° C. The reaction was stirred for 30 minutes, determined to be complete by TLC and HPLC, and water (1 L) was slowly added to quench the reaction. The mixture was then diluted with water (12 L) and MTBE (8 L). The layers were separated and the aqueous was re-extracted with MTBE (8 L). The combined organic layers were washed with water (2×4 L) and brine (4 L), dried over sodium sulfate (NaSO4), and solvents removed under reduced pressure. The residue was dissolved in heptane (2 L), filtered and loaded onto a silica gel (3.5 kg) column eluting with heptane (˜6 L), 95% heptane/ethyl acetate (˜12 L), 90% heptane/ethyl acetate (10 L), and finally 80% heptane/ethyl acetate (10 L). The pure fractions were combined and concentrated under reduced pressure to give 4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (3a, 987 g, 1109.8 g theoretical, 88.9% yield) as a pale yellow oil that partially solidified to an oily solid on standing at room temperature. For 3a: 1H NMR (DMSO-d6, 300 MHz) δ ppm 8.67 (s, 1H), 7.87 (d, 1H, J=3.8 Hz), 6.71 (d, 1H, J=3.6 Hz), 5.63 (s, 2H), 3.50 (t, 2H, J=7.9 Hz), 0.80 (t, 2H, J=8.1 Hz), 1.24 (s, 9H); 13C NMR (DMSO-d6, 100 MHz) δ ppm 151.3, 150.8, 150.7, 131.5, 116.9, 99.3, 72.9, 65.8, 17.1, −1.48; C12H18ClN3OSi (MW 283.83), LCMS (EI) m/e 284/286 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])(C)C)=[O:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:23]([O-])=O.[H][H].[C:28](OCC)(=O)[CH3:29]>CO.[Pd]>[NH2:23][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:2]=1[NH2:1])[O:6][CH2:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]([O:16][CH2:17][CH2:20][CH2:28][CH3:29])=[O:15])[CH2:12][CH2:13]1
Reactant: CCOC(C)=O
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(N)c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CO
Product: CCCCOC(=O)N1CCC(COc2ccc(N)c(N)c2)CC1
Reaction time: 16 h
Yield: 100 %

Procedure:
tert-Butyl 4-((4-amino-3-nitrophenoxy)methyl)piperidine-1-carboxylate (3.58 g, 10.18 mmoles,) was dissolved in ethyl acetate (60 ml) and methanol (40 ml). The solution was treated with 600 mg of 10% palladium on carbon (50% water w/w). The slurry was then shaken on a Parr hydrogenator and treated with a 40 psi of hydrogen gas, at room temperature. After 16 hours, the slurry was filtered through a plug of Celite, which was subsequently washed with ethyl acetate (50 ml) and methanol (50 ml). The resulting filtrate was then evaporated at reduced pressure to give 3.42 g of tent-butyl 4-((3,4-diaminophenoxy)methyl)piperidine-1-carboxylate (100% yield). The material was used in the next step without any further purification. 1H-NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.49 (d, 1H), 7.24 (d, 1H), 5.32 (br s, 4H), 3.82 (d, 2H), 3.65 (m, 2H), 2.40 (s, 3H), 1.76 (m, 1H), 1.54 (m, 2H), 1.38 (s, 9H), 0.98 (m, 2H). MS (EI): 322 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][CH2:6][C:7]1[S:8][C:9]([N+:12]([O-])=O)=[CH:10][CH:11]=1>C(OCC)(=O)C.CO.[OH-].[Pd+2].[OH-]>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][CH2:6][C:7]1[S:8][C:9]([NH2:12])=[CH:10][CH:11]=1
Reactant: COC(=O)CCCc1ccc([N+](=O)[O-])s1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CCCc1ccc(N)s1
Reaction time: 48 h
Yield: 66.2 %

Procedure:
A mixture of 4-(5-nitro-thiophen-2-yl)-butyric acid methyl ester (2.29 g, 10.0 mmol) and palladium hydroxide (500 mg, 20% on carbon) in 30 mL of ethyl acetate and 30 mL of methanol is hydrogenated at 50 psi for 48 hours. The reaction mixture is filtered and concentrated. The residue is purified by flash column chromatography eluting with 1:3 ethyl acetate:hexane to provide 1.32 g of 4-(5-amino-thiophen-2-yl)-butyric acid methyl ester as a dark oil; 1H NMR (DMSO-d6) δ 1.74 (m, 2H), 2.38 (m, 2H), 2.54 (m, 2H), 3.59 (s, 3H), 5.66 (d, J=3 Hz, 1H), 6.24 (d, J=3 Hz, 1H); MS 200.2 (M+H)+.
Reaction SMILES: C[Mg]I.C(OCC)C.I[C:10]1[N:11]=[CH:12][N:13]2[CH:17]=[CH:16][S:15][C:14]=12.[CH2:18]([O:21][C:22]([N:24]1[C@H:28]([CH:29]=[O:30])[CH2:27][C@H:26]([S:31][C:32]2[C@H:33]([CH3:56])[C@@H:34]3[C@@H:44]([C@H:45]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[CH3:46])[C:43](=[O:55])[N:35]3[C:36]=2[C:37]([O:39][CH2:40][CH:41]=[CH2:42])=[O:38])[CH2:25]1)=[O:23])[CH:19]=[CH2:20].[Cl-].[NH4+]>C1COCC1>[CH2:18]([O:21][C:22]([N:24]1[C@H:28]([CH:29]([OH:30])[C:10]2[N:11]=[CH:12][N:13]3[CH:17]=[CH:16][S:15][C:14]=23)[CH2:27][C@H:26]([S:31][C:32]2[C@H:33]([CH3:56])[C@@H:34]3[C@@H:44]([C@H:45]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:49])[CH3:50])[CH3:46])[C:43](=[O:55])[N:35]3[C:36]=2[C:37]([O:39][CH2:40][CH:41]=[CH2:42])=[O:38])[CH2:25]1)=[O:23])[CH:19]=[CH2:20]
Reactant: Ic1ncn2ccsc12
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C=O)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(O)c3ncn4ccsc34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
A 2 M methylmagnesium iodide/diethyl ether solution (1.30 ml) is diluted with 10 ml of anhydrous THF, and a solution of 650 mg of 7-iodoimidazo[5,1-b]thiazole in 10 ml of anhydrous THF is added dropwise to the diluted solution in an argon atmosphere over a period of 4 min. The mixture is stirred in this state at room temperature for additional 30 min. The internal temperature is lowered to −48° C., and the solution is added dropwise to a solution of 1.003 g of allyl(1R,5S,6S)-2-((3S,5S)-1-allyloxycarbonyl-5-formylpyrrolidin-3-yl)thio-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-1-methylcarbapen-2-em-3-carboxylate in 10 ml of anhydrous THF over a period of 5 min. The mixture is stirred in this state at −48 to −40° C. for 40 min, and the temperature is then raised to −25° C. over a period of 50 min. Semi-saturated aqueous ammonium chloride (50 ml) is added thereto, the mixture is extracted with 90 ml of ethyl acetate, and the organic layer is dried over anhydrous magnesium sulfate, followed by filtration and the removal of the solvent by evaporation to give a yellow viscous material. This viscous material is successively purified by column chromatography on Sephadex LH-20 (dichloromethane:methanol=1:1) and on silica gel (toluene:ethyl acetate=1:9) to give 491.3 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-7-yl)methyl]pyrrolidin-3-yl]thio-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-1-methylcarbapen-2-em-3-carboxylate (a diastereomer mixture) as a yellow amorphous material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:10]2)=[CH:4][CH:3]=1.OO.[OH-:27].[Na+].C(O)(=[O:31])C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH2:10]2)(=[O:31])=[O:27])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(Sc3ccc(Cl)cc3)C2)cc1
Reactant: [OH-]
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)N2CCCC(S(=O)(=O)c3ccc(Cl)cc3)C2)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 37.96 g (0.10 mole) of 3-[(4-chlorophenyl)thio]-1-[(4-methylphenyl)sulfonyl]piperidine, 300 ml of glacial acetic acid, and 61.8 g of 30% hydrogen peroxide (0.6 mole) was stirred overnight at 90° C. The reaction mixture was cooled to room temperature and diluted with ice water. The diluted mixture was made alkaline with 50% aqueous sodium hydroxide and extracted with methylene chloride. The aqueous phase was discarded. The methylene chloride phase was washed with sodium sulfite to remove traces of peroxide. The methylene chloride solution was dried over magnesium sulfate, filtered and the solvent removed in vacuo to give a yellowish white solid. Recrystallization of an aliquot of the solid from methylene chloridehexanes gave the product, m.p. 186°-187° C. in 57.2% overall yield.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][C:8]2[CH:18]=[CH:17][C:11]3[N:12]=[C:13]([S:15][CH3:16])[S:14][C:10]=3[CH:9]=2)[CH:6]=1.ClC1C=C(C=CC=1)C(OO)=[O:24].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][C:8]2[CH:18]=[CH:17][C:11]3[N:12]=[C:13]([S:15]([CH3:16])=[O:24])[S:14][C:10]=3[CH:9]=2)[CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2ccc(Cn3cnc(Br)c3)cc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc(Br)c3)cc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 121.6 %

Procedure:
To a stirred mixture of 6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (105 mg, 0.3 mmol) from Step 5 of this Example in CH2Cl2 (15 mL) at 0° C. was added 70-75% 3-chloroperoxybenzoic acid (91 mg, 0.4 mmol). After the mixture was stirred at 0° C. for 2 h, saturated aq NaHCO3 (10 mL) was added. The mixture was stirred for 10 min and the CH2Cl2 layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (130 mg) as a white foam. The material was used in the next step without further purification. LCMS (ESI) m/z 356 and 358 (M+H)+.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH:20]=1.C1(C2SC3C=CC(O)=CC=3N=2)C=CC=CC=1>>[O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[C:20]2[S:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(-c2nc3cc(OCC4CO4)ccc3s2)cc1
Agent: Oc1ccc2sc(-c3ccccc3)nc2c1
Product: c1ccc(-c2nc3cccc(OCC4CO4)c3s2)cc1

Procedure:
Compound 63 was prepared in the manner of compound 59 substituting deprotected compound 28 for compound 29 in example 9.
Reaction SMILES: Br[CH2:2][C@H:3]1[C@@:5]2([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:9]3[C:19]([CH3:23])=[C:20]([CH3:22])[S:21][C:8]=3[N:7]3[C:24]([CH3:27])=[N:25][N:26]=[C:6]23)[CH2:4]1.Cl.[CH2:29]([NH2:31])[CH3:30].CCN(C(C)C)C(C)C>CN(C)C=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:19]([CH3:23])=[C:20]([CH3:22])[S:21][C:8]=3[N:7]3[C:24]([CH3:27])=[N:25][N:26]=[C:6]3[C@@:5]3([CH2:4][C@H:3]3[CH2:2][NH:31][CH2:29][CH3:30])[N:11]=2)=[CH:13][CH:14]=1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1CBr)c1nnc(C)n1-2
Reactant: CCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC[C@@H]1C[C@]12N=C(c1ccc(Cl)cc1)c1c(sc(C)c1C)-n1c(C)nnc12
Reaction time: 96 h
Yield: 69.6 %

Procedure:
To a solution of (1S,2R)-2-(bromomethyl)-4′-(4-chlorophenyl)-2′,3′,9′-trimethylspiro-[cyclopropane-1,6′-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine](50 mg, 0.108 mmol) in anhydrous N,N-dimethylformamide (3 mL) were added ethanamine hydrochloride (221 mg, 2.71 mmol) and Hunig's base (473 μl, 2.71 mmol) at rt. After 4 days at rt, silica gel was added to the reaction, and the solvent was removed under vacuum. The dry silica gel was packed and the product was purified by chromatography (Hexane/EtOAc 5:5 to 0:10 then DCM/MeOH 10:0 to 9:1). A second chromatography was performed (2-propanol 100% then DCM/MeOH 9:1) to give a tan solid (32 mg). LRMS (M+H)+: 426 m/z.