Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:14]([OH:16])=[O:15])[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>[OH-].[Na+].O.O1CCOCC1>[CH2:21]([O:20][C:18]([N:2]1[CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:1]1[C:14]([OH:16])=[O:15])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)C1NCCc2c1[nH]c1ccccc21
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C1c2[nH]c3ccccc3c2CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution, cooled in ice, of 3.0 g of 1,2,3,4-tetrahydropyrido[3,4-b]indole-1-carboxylic acid in 7 ml of 2M sodium hydroxide solution, 17 ml of water and 17 ml of dioxan were added in alternating portions 12.5 ml of 2M sodium hydroxide solution and a solution of 3.6 ml of benzyl chloroformate in 9 ml of dioxan. After completion of the additions the mixture was stirred at room temperature overnight and the dioxan-was then removed by evaporation under reduced pressure. The solution obtained was diluted with water, washed twice with diethyl ether, acidified with 25 ml of 1M sulphuric acid and extracted three times with ethyl acetate. The organic extracts were combined, washed twice with water, dried over anhydrous magnesium sulphate and evaporated to give 4.54 g of 2-benzyloxycarbonyl-1,2,3,4-tetrahydropyrido[3,4-b]indole-1-carboxylic acid, MS: m/e 351 [M+H]+, which was used without purification.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]=[CH:12][NH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][N:15]([CH3:19])[C:16](Cl)=[O:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([S:8][C:9]1[N:13]=[CH:12][N:11]([C:16](=[O:17])[N:15]([CH3:19])[CH3:14])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)Cl
Reactant: c1ccc(CSc2nc[nH]n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)n1cnc(SCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
A suspension of 3-benzylthio-1H-1,2,4-triazole (172 mg), dimethylcarbamoyl chloride (248 μl) and anhydrous potassium carbonate (621 mg) in dimethylformamide (4 ml) was stirred at room temperature for 80 minutes. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed three times with water and subsequently once with saturated aqueous sodium chloride solution, and then dried over sodium sulfate. After filtration, the solvent was distilled from the filtrate under reduced pressure to obtain a clear oil. The resultant oil was purified by a column chromatography (ethyl acetate/hexane=1/5) to yield the titled compound (88 mg) as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[CH2:10][CH2:9][CH2:8][O:7][C:6]=2[CH:13]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:13]=1)[O:7][CH2:8][CH2:9][CH:10]=[C:11]2[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: O=C1CCCOc2cc(Br)ccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)OCCC=C2N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
To a mixture of 8-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one (0.170 g, 0.705 mmol) and morpholine (0.307 mL, 3.53 mmol) in toluene (3 mL) at 0° C. was added titanium(IV) chloride (1.0 M in toluene) (0.388 mL, 0.388 mmol) dropwise. The ice-bath was removed, and the orange, heterogeneous reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered under reduced pressure through a pad of CELITE®, which was then rinsed with toluene (3×10 mL). The pale yellow filtrate was concentrated under reduced pressure to give (E)-4-(8-bromo-2,3-dihydrobenzo[b]oxepin-5-yl)morpholine (0.182 g, 0.587 mmol, 83% yield) as a yellow oil.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[O:4].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: C1=COCCC1
Reactant: O=C(CBr)c1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(CBr)c1ccc(OC2CCCCO2)cc1

Procedure:
2-Bromo-4'-hydroxyacetophenone (860 mg) was dissolved in dichloromethane (20 ml), and 3,4-dihydro-2H-pyran (550 μl) and pyridinium p-toluenesulfonate (100 mg) were added to the solution at room temperature with stirring. After reaction for 17 hours, the reaction mixture was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/ethyl acetate=10/1) gave 2-bromo-4'-((2RS)-2-tetrahydropyranyloxy)acetophenone (1.01 g) having a melting point of 102-104° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([CH:21]=O)([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:23]([C:26]2[CH:27]=[N:28][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[NH:38]1[CH2:42][CH2:41][C@H:40]([OH:43])[CH2:39]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([CH2:21][N:38]5[CH2:42][CH2:41][C@H:40]([OH:43])[CH2:39]5)([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:23]([C:26]2[CH:27]=[N:28][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:30][CH:31]=2)(=[O:24])=[O:25])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1
Reactant: O=C[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Reactant: O[C@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: O=S(=O)(c1ccc(N2CCOCC2)nc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(CN2CC[C@H](O)C2)C1
Reaction time: 20 h
Yield: 29.7 %

Procedure:
A solution of (R)-1-(4-fluorophenyl)-6-[6-morpholin-4-yl-pyridine-3-sulfonyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carbaldehyde (0.074 g) in dry dichloroethane (2.8 mL) was treated with (S)-pyrrolidin-3-ol (0.062 g) and 4A powdered molecular sieves (0.14 g) for 4 hours. Sodium triacetoxyborohydride (0.045 g) was added and the reaction mixture stirred for 20 hours. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution and brine. The organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC eluting with a mixture of acetonitrile and water containing 0.1% formic acid (1:19 to 7:3 by volume) to give the title compound as a white solid (0.025 g). 1H NMR (400 MHz, CHCl3-d): δ 8.54 (d, 1H), 8.24 (s, 1H), 7.81 (dd, 1H), 7.43-7.32 (m, 3H), 7.16 (t, 2H), 6.63 (d, 1H), 6.28 (d, 1H), 4.40 (s, 1H), 4.30 (d, 1H), 3.90 (d, 1H), 3.81 (t, 4H), 3.67 (t, 4H), 3.36-3.23 (m, 2H), 3.13-3.01 (m, 3H), 2.78-2.63 (m, 2H), 2.54 (d, 1H), 2.44-2.25 (m, 3H), 2.24-2.13 (m, 2H), 1.90 (dt, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:23]=2)[C:12]([NH:14][C:15]2[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=2)=[O:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:34](OC)[N:35]([CH3:37])[CH3:36]>>[CH3:34][N:35]([CH3:37])/[CH:36]=[CH:2]/[C:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:23]=2)[C:12]([NH:14][C:15]2[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=2)=[O:13])=[CH:6][CH:5]=1)=[O:3]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(C)=O)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: COC(OC)N(C)C
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)/C=C/N(C)C)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 100 °C
Yield: 83.3 %

Procedure:
A mixture of 3-(4-acetylphenoxy)-5-[(1S)-2-methoxy-1-methylethoxy]-N-(1′-methyl-1H-pyrazol-3-yl)benzamide (812 mg, 1.92 mmol) and N,N-dimethylformamide dimethyl acetal (10.2 mL, 77 mmol) was heated to 100° C. in a ‘Smith Creator’ microwave for 140 mins. The volatiles were removed under reduced pressure and the resulting oil purified by chromatography on silica, eluting with 0-20% methanol in DCM, to give the desired product (765 mg).
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])(=[O:13])=[O:12])[CH:3]=1.[CH2:22](C([Sn])=C(CCCC)CCCC)[CH2:23]CC>C(#N)C>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][S:11]([C:4]1[CH:3]=[C:2]([CH:22]=[CH2:23])[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=1)(=[O:13])=[O:12]
Reactant: Cc1ccccc1NS(=O)(=O)c1cc(I)c2occc2c1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Solvent: CC#N
Product: C=Cc1cc(S(=O)(=O)Nc2ccccc2C)cc2ccoc12

Procedure:
7-Iodo-N-(2-methylphenyl)-1-benzofuran-5-sulfonamide (0.41 g, 1 mmol; Intermediate 58), tributylvinyltin (0.32 mL, 1.1 mmol), bis(triphenylphosphine)palladium diacetate (10 mg) and acetonitrile (3 mL) were heated under microwave irradiation to 180° C. for 5 min. The mixture was cooled, filtered and evaporated. The resulting oil was washed with hexane (2×50 mL), dissolved in diethyl ether (50 mL), filtered and evaporated to give the crude product which was crystallized from ethanol:water (3:1). Yield 0.19 g (61%) of an off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.93 (s, 3H) 5.57 (dd, J=11.3, 1.0 Hz, 1H) 6.12 (dd, J=17.8, 1.0 Hz, 1H) 6.84-7.07 (m, 6H) 7.62 (d, J=1.8 Hz, 1H) 7.84 (d, J=1.8 Hz, 1H) 8.14 (d, J=2.3 Hz, 1H) 9.43 (s, 1H).
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].[H-].[Na+].Br[C:8]1[N:9]=[C:10]([NH:30][CH2:31][C:32]([OH:35])([CH3:34])[CH3:33])[C:11]2[N:12]([C:14]([C:17]3[CH:28]=[CH:27][C:20]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])=[C:19]([CH3:29])[CH:18]=3)=[CH:15][N:16]=2)[CH:13]=1>CS(C)=O>[CH:24]1([NH:23][C:21](=[O:22])[C:20]2[CH:27]=[CH:28][C:17]([C:14]3[N:12]4[CH:13]=[C:8]([S:4][CH2:1][CH2:2][CH3:3])[N:9]=[C:10]([NH:30][CH2:31][C:32]([OH:35])([CH3:33])[CH3:34])[C:11]4=[N:16][CH:15]=3)=[CH:18][C:19]=2[CH3:29])[CH2:25][CH2:26]1
Reactant: Cc1cc(-c2cnc3c(NCC(C)(C)O)nc(Br)cn23)ccc1C(=O)NC1CC1
Reactant: CCCS
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCSc1cn2c(-c3ccc(C(=O)NC4CC4)c(C)c3)cnc2c(NCC(C)(C)O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 80 mg (1.05 mmol) 1-propanethiol in 1.5 mL DMSO were added 50 mg (1.052 mmol) sodium hydride and the mixture was stirred for 2 h at rt. 100 mg (0.21 mmol) 4-{6-bromo-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-a]pyrazin-3-yl}-N-cyclopropyl-2-methylbenzamide were added and the mixture was heated at 120° C. for 2 h. The mixture was filtered and purified by HPLC.
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:13][NH2:14]>C(O)C>[NH2:11][C:10]1[CH:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:14][N:13]=1
Reactant: NN
Reactant: N#CCC(=O)c1ccccc1
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2ccccc2)[nH]n1

Procedure:
Benzoyl acetonitrile from part A hereinabove (10.0 g, 68.9 mmole) and hydrazine monohydrate (4.34 mL, 89.6 mmole) were combined in 95% ethanol (90 mL) and refluxed for 1.5 hours. The solvent was evaporated under vacuum and the crystalline subtitled compound, residue was crystallized from chloroform (three crops, 9.49 g, 86%, m.p. 125°-126.5°, lit., m.p. 123°-125°, Taylor, E. C. et al., J. Org. Chem., (1966), 31, page 1818.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:14](=[O:52])[CH2:15][N:16]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:19](=[O:33])[C@H:18]([CH2:34][C:35]4[C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[N:37](C(OC(C)(C)C)=O)[N:36]=4)[C:17]3=[O:51])[C:7]=2[CH:6]=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:35]([CH2:34][C@@H:18]2[C:17](=[O:51])[N:16]([CH2:15][C:14]([N:13]3[C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=4[CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:52])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:19]2=[O:33])=[N:36]1
Reactant: COc1cccc2c1CCCCN2C(=O)CN1C(=O)[C@@H](Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc2c1CCCCN2C(=O)CN1C(=O)[C@@H](Cc2n[nH]c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21
Reaction time: 1.25 h

Procedure:
A solution of tert-butyl 3-({(3R)-1-[2-(6-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-2-oxoethyl]-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl}methyl)-1H-indazole-1-carboxylate (93 mg) in methylene chloride (10 mL) was treated with trifluoroacetic acid (1 mL). Stirred for 1.25 hours and concentrated the solvent off. Chromatographed on silica gel (Hexane:Ethyl Acetate) then lyophilized to yield the title compound as a white film (64 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH2:7][OH:8].[CH2:11](I)[CH3:12].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH3:12])=[C:6]([CH:9]=1)[CH2:7][OH:8]
Reactant: OCc1cc(Br)ccc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(Br)cc1CO

Procedure:
5-Bromo-2-hydroxybenzylalcohol (5.0 g, 24.6 mmol), ethyl iodide (11.5 g, 73.8 mmol) and K2CO3 (3.4 g, 24.6 mmol) in 50 ml of acetone was stirred at +50° C. overnight. The mixture was filtered and evaporated. The product was purified by silica gel column chromatography (EtOAc/petroleum ether 30:100) to give 5-bromo-2-ethoxybenzyl alcohol.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(OCC)C.[CH:17]([Mg]Br)([CH3:19])[CH3:18].Cl>[Cu]Cl.O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](=[O:5])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)[Mg]Br
Reactant: O=C(Cl)c1ccc(F)cc1F
Agent: Cl[Cu]
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CC(C)C(=O)c1ccc(F)cc1F
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a mixture of 120 g (0.68 mmol) of 2,4-difluorobenzoyl chloride, 3.7 g (37 mmol) of copper (I) chloride, and 400 ml of diethyl ether was added dropwise 442 ml of diethyl ether containing 130.2 g (0.88 mol) of isopropylmagnesium bromide at -25° C. over 4 hours. The temperature was elevated up to -5° C., and the mixture was stirred at that temperature for 30 minutes. To the reaction mixture were added dropwise 150 ml of water and then 120 ml of 6N hydrochloric acid. The organic layer was separated, washed successively with 5% hydrochloric acid, a saturated sodium chloride aqueous solution, a saturated sodium carbonate aqueous solution, and a saturated sodium chloride aqueous solution, and dried. The solvent was removed by distillation under reduced pressure, and the residue was distilled under reduced pressure to obtain 104.3 g (83%) of 1-(2,4-difluorophenyl)-2-methylpropan-1-one as a colorless oily substance.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[H-].[Na+].CN(C)[C:15](=O)[CH3:16]>>[CH3:15][C:16]1[NH:6][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[N:10][C:2]=2[CH:1]=1
Reactant: CC(=O)N(C)C
Reactant: Cc1ncccc1C(N)=O
Agent: [H-]
Agent: [Na+]
Product: Cc1cc2ncccc2c(=O)[nH]1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 272.3 mg (2 mmol) of 2-methylnicotinamide (2) and 0.34 mL (2.2 mmol) of 95% N,N-dimethylacetamide, dimethylacetal is heated at 50° C. for 1.5 hours, then a vacuum is applied for 1 hour with heating as described above. The oil is diluted with 2 mL of dry N,N-dimethylacetamide, treated with 96 mg of 60% sodium hydride, and heated at 80° C. for 2.5 hours. The solution is treated with 70 mg more of 60% sodium hydride, heated for an addition 4.5 hours, then quenched with excess acetic acid. The mixture is concentrated at 2 mm/70° C. to leave a residual solid that is triturated in hot chloroform, then filtered through a pad of silica gel (230-400 mesh). The pad is eluted with chloroform, then acetone to collect the product. The filtrate is concentrated to a solid that is dissolved in a minimum volume of hot water. The solution is stored at 5° C. for 2 weeks, and the precipitated solids are collected by filtration, washed well with propanol, and dried to give 73 mg of pure product, mp 244°-245° C.
Reaction SMILES: N[C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:15][B-](F)(F)F.[H+].N([O-])=O.[Na+]>O>[F:15][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: F[B-](F)(F)F
Reactant: Nc1cc2ccccc2cc1C(=O)O
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc2ccccc2cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-amino-2-naphthoic acid (3.74 g, 20 mmol) and 48% fluoroboric acid (2.07 g, 30 mmol) in 10 mL of H2O cooled to 0° C. is added dropwise a solution of NaNO2 (2.07 g, 30 mmol) in 15 mL of H2O. The mixture is stirred at 0° C. for 1 hour. The mixture is filtered and the solids washed with cold H2O, then MeOH, then Et2O. The remaining solid is dried in vacuo at 40° C. for 2 days. The solid is suspended in xylene and heated to reflux for 8 hours and then cooled to room temperature. To the mixture is added hexane. The solid is filtered and washed with CH2Cl2, and dried to give 3-fluoro-2-naphthoic acid as a brown solid. A mixture of this solid and 80 mL of 1,4-dioxane is added to DPPA (4.5 mL, 20.9 mmol). Then 3.88 mL (27.9 mmol) of Et3N is added and the mixture is stirred for 2 hours at room temperature-under an atmosphere of nitrogen; Ethanol (8.1 mL, 139 mmol) is added, the mixture is heated to reflux for 2 hours, concentrated in vacuo and the residue diluted with 200 mL of EtOAc. The solution is washed with 5% aqueous Na2CO3 (50 mL), brine (50 mL), dried over MgSO4 and evaporated to dryness to give a solid that is purified by flash chromatography on silica gel (100% CH2Cl2) to give N-(3-fluoro-2-naphthyl)carbamic acid ethyl ester.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1.C[O:22][B:23](OC)[O:24]C.Cl>C1COCC1>[F:13][C:14]1[C:19]([B:23]([OH:24])[OH:22])=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1
Reactant: Fc1cccc(F)n1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OB(O)c1ccc(F)nc1F

Procedure:
0,6 M of n-butyllithium are added at -10° to 0,6 M of diisopropylamin in 600 ml THF. The mixture is cooled to -70°, 0,6 M of 2,6-difluoropyridin are added and after stirring for 15 minutes 0,6 M of trimethylborate are added at the same temperature. The mixture is allowed to warm up to -30°. Then the borate ester is hydrolysed with dilute HCl, the product extracted with ether, washed, dried and the solvent removed. Thus, 2,6-difluoro-pyridine-3-boronic acid is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][OH:12])=[C:4]([O:13][CH3:14])[CH:3]=1.[H][H]>C(OCC)(=O)C.O=[Pt]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[C:4]([O:13][CH3:14])[CH:3]=1
Reactant: [H][H]
Reactant: COc1cc(Cl)ccc1C#CCCO
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: COc1cc(Cl)ccc1CCCCO
Yield: 89.6 %

Procedure:
A solution of 4-(4-chloro-2-methoxy-phenyl)-but-3-yn-1-ol (2.2 g, 10.4 mmol) and PtO2 (200 mg) in ethyl acetate (15 mL) was hydrogenated under 50 psi hydrogen atmosphere until no more hydrogen uptake was observed. The reaction mixture was then filtered and concentrated in vacuo. The crude product was subjected to column chromatography on silica gel (gradient elution with 0%-40% EtOAc/hexane) to give 4-(4-chloro-2-methoxy-phenyl)-butan-1-ol as a colorless oil (2 g, 89.7%). 1H NMR (300 MHz, CDCl3) δ ppm 7.03 (d, J=8.2 Hz, 1H), 6.86 (dd, J=8.2, 1.6 Hz, 1H), 6.81 (d, J=1.6 Hz, 1H), 3.81 (s, 3H), 3.66 (t, J=6.0 Hz, 2H), 2.49-2.65 (m, 2H), 1.50-1.72 (m, 5H).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C@H:11]([CH2:12][C:13]2[S:17][C:16]3=[CH:18][N:19]=[C:20]([Cl:21])[N:15]3[CH:14]=2)[CH2:10][C@H:9]([S:22]C(=O)C2C=CC=CC=2)[CH2:8]1)=[O:6])[CH:2]=[CH2:3].C1(OP(O[C:48]2[C@H:49]([CH3:65])[C@@H:50]3[C@@H:60]([C@H:61]([OH:63])[CH3:62])[C:59](=[O:64])[N:51]3[C:52]=2[C:53]([O:55][CH2:56][CH:57]=[CH2:58])=[O:54])(OC2C=CC=CC=2)=O)C=CC=CC=1>>[CH2:1]([O:4][C:5]([N:7]1[C@H:11]([CH2:12][C:13]2[S:17][C:16]3=[CH:18][N:19]=[C:20]([Cl:21])[N:15]3[CH:14]=2)[CH2:10][C@H:9]([S:22][C:48]2[C@H:49]([CH3:65])[C@@H:50]3[C@@H:60]([C@H:61]([OH:63])[CH3:62])[C:59](=[O:64])[N:51]3[C:52]=2[C:53]([O:55][CH2:56][CH:57]=[CH2:58])=[O:54])[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](SC(=O)c2ccccc2)C[C@H]1Cc1cn2c(Cl)ncc2s1
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3cn4c(Cl)ncc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 58.9 %

Procedure:
The procedure of Example 23-a) is repeated, except that 303.0 mg of (3S,5S)-1-allyloxycarbonyl-3-benzoylthio-5-(5-chloroimidazo[5,1-b]thiazol-2-yl)methylpyrrolidine described in Synthesis Example 23 is used. Thus, 261.0 mg of a mercaptan compound is prepared as a yellow oil. Allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-(5-chloroimidazo[5,1-b]thiazol-2-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate (186.7 mg) is prepared as a colorless amorphous material from this mercaptan and 260.9 mg of allyl(1R,5R,6S)-2-(diphenylphosphono)oxy-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13]O)[S:11][CH:12]=2)=[CH:4][CH:3]=1.P(Br)(Br)[Br:16].O>C1(C)C=CC=CC=1>[Br:16][CH2:13][C:10]1[S:11][CH:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: BrP(Br)Br
Reactant: OCc1nc(-c2ccc(Cl)cc2)cs1
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2csc(CBr)n2)cc1
Temperature: 120 °C
Yield: 16.6 %

Procedure:
To the solution of [4-(4-Chloro-phenyl)-thiazol-2-yl]-methanol (0.80 g, 3.55 mmol) in 10 ml of toluene was added PBr3 (0.51 ml, 5.33 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 (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to get the desired product (0.17 g, 17%). The corresponding cyano derivative was also prepared by the same general method.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([F:14])=[C:4](Cl)[N:3]=1.[CH3:16][C:17]1[NH:21][N:20]=[C:19]([NH2:22])[CH:18]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([F:14])=[C:4]([NH:22][C:19]2[CH:18]=[C:17]([CH3:16])[NH:21][N:20]=2)[N:3]=1
Reactant: CN(c1nc(Cl)nc(Cl)c1F)S(C)(=O)=O
Reactant: Cc1cc(N)n[nH]1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(Cl)nc(N(C)S(C)(=O)=O)c2F)n[nH]1
Temperature: 50 °C
Yield: 94.5 %

Procedure:
To a solution of N-(2,6-dichloro-5-fluoropyrimidin-4-yl)-N-methylmethanesulfonamide (Method 31, 914 mg, 3.35 mmol) in n-BuOH (3 ml) was added 5-methyl-1H-pyrazol-3-amine (351 mg, 3.62 mmol, 97% purity) and DIPEA (1.2 ml, 6.9 mmol). The mixture was heated at 50° C. overnight. LC/MS showed the completion of the reaction. The solvent was evaporated and the residue was purified by silica gel chromatography (by ISCO Combiflash with gradient 0-5% methanol in DCM with 1% NH4OH) to afford the title compound as a light yellow solid (1.06 g, 95%). LC-MS, 335 (M+1). NMR (DMSO-d6, 400 MHz) δ12.27 (s, 1H), 10.53 (s, 1H), 6.32 (s, 1H), 3.27 (s, 3H), 3.20 (s, 3H), 2.25 (s, 3H).