Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=1.[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.C(O)(=O)C.[BH4-].C([Na])#N>CO>[Cl:25][C:22]1[CH:23]=[CH:24][C:2]([NH:1][CH2:31][C:30]2[CH:33]=[CH:34][C:27]([F:26])=[CH:28][CH:29]=2)=[C:3]([CH:21]=1)[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH:6]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2N)c1
Agent: N#C[Na]
Agent: [BH4-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2NCc2ccc(F)cc2)c1
Yield: 86.3 %

Procedure:
In methanol (10 ml) were dissolved 2-amino-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol produced in Example (1) (0.5 g) and 4-fluorobenzaldehyde (0.2 g). To the solution were added acetic acid (0.1 g) and cyano sodium borohydride (0.1 g). The mixture was concentrated, to which were added water (60 ml) and ethyl acetate (50 ml), followed by extraction. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was then distilled off to leave 5-chloro-2-(4-fluorobenzylamino)-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (0.56 g) as a colorless oily product.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:10])([CH3:9])[C:5]([CH3:8])([OH:7])[CH3:6].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18](=O)[O:19]C1C=CC=CN=1>C1COCC1.CCOC(C)=O>[C:18](=[O:19])([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=1)[O:7][C:5]([CH3:8])([C:4]([F:10])([F:3])[CH3:9])[CH3:6]
Reactant: CC(C)(O)C(C)(F)F
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(F)(F)C(C)(C)OC(=O)Oc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.8 %

Procedure:
To a suspension of sodium hydride, 60% in mineral oil (0.652 g, 16.31 mmol) in THF (25 mL) was added 3,3-difluoro-2-methylbutan-2-ol (1.84 g, 14.82 mmol) at 0° C. After stirring 30 min, the solution was transferred to a solution of di(pyridin-2-yl)carbonate (3.20 g, 14.82 mmol) in THF (25 mL) through a cannula. The formed slurry was stirred at 0° C. for 30 min. The slurry was warmed to rt and stirred for 2 h. The reaction was diluted with EtOAc, washed with brine, dried over MgSO4, filtered, concentrated to give a residue that was purified by Biotage eluting with 10-50% EtOAc in hexanes to afford the desired product 3,3-difluoro-2-methylbutan-2-yl pyridin-2-yl carbonate (500 mg, 13.76%) as an oil that later crystallized to a white solid upon standing. 1H NMR (500 MHz, CHLOROFORM-d) δ 8.43 (ddd, J=4.9, 2.0, 0.7 Hz, 1H), 7.95-7.75 (m, 1H), 7.31-7.24 (m, 1H), 7.15 (dt, J=8.2, 0.8 Hz, 1H), 1.72 (s, 6H), 1.77-1.66 (m, 3H).
Reaction SMILES: CS(O[C@H:6]1[CH2:11][CH2:10][C@@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:23]=[C:22]4[N:24]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[C:25]([O:27][C@@H:28]5[CH2:32][O:31][C@@H:30]6[C@H:33]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH2:34][O:35][C@H:29]56)=[N:26][C:21]4=[CH:20][C:19]=3[Cl:52])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=O)=O.[N-:53]=[N+:54]=[N-:55].[Na+]>CN(C)C=O>[N:53]([C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[N:23]=[C:22]4[N:24]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:49])[CH3:50])[C:25]([O:27][C@@H:28]5[CH2:32][O:31][C@@H:30]6[C@H:33]([O:36][Si:37]([C:40]([CH3:43])([CH3:41])[CH3:42])([CH3:39])[CH3:38])[CH2:34][O:35][C@H:29]56)=[N:26][C:21]4=[CH:20][C:19]=3[Cl:52])=[CH:16][CH:17]=2)[CH2:10][CH2:11]1)=[N+:54]=[N-:55]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](OS(C)(=O)=O)CC4)cc3)nc2n1COCC[Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](N=[N+]=[N-])CC4)cc3)nc2n1COCC[Si](C)(C)C
Temperature: 80 °C
Reaction time: 12 h

Procedure:
(cis)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-Butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexyl methanesulfonate (295 mg) is dissolved in N,N-dimethylformamide (5 mL), treated with sodium azide (52 mg) and stirred for 12 hours at 80° C. The mixture is partitioned between ethylacetate and saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→60:40) to give the title compound. LC (method 5): tR=1.33 min; Mass spectrum (ESI+): m/z=741 [M+H]+.
Reaction SMILES: FC1C=CC(F)=CC=1[N+]([O-])=O.N[C@@H](CC)C(O)=O.[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C@H:27]([CH2:31][CH3:32])[C:28]([OH:30])=[O:29])=[C:22]([N+:33]([O-:35])=[O:34])[CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C@@H:27]([CH2:31][CH3:32])[C:28]([OH:30])=[O:29])=[C:22]([N+:33]([O-:35])=[O:34])[CH:21]=1
Reactant: CC[C@@H](Nc1ccc(F)cc1[N+](=O)[O-])C(=O)O
Agent: CC[C@H](N)C(=O)O
Agent: O=[N+]([O-])c1cc(F)ccc1F
Product: CC[C@H](Nc1ccc(F)cc1[N+](=O)[O-])C(=O)O

Procedure:
2,5-Difluoronitrobenzene was treated with (S)-2-aminobutyric acid according to the procedure for the preparation of (R)-2-(4-fluoro-2-nitrophenylamino)-butyric acid (see Example 1) to yield (2S)-2-[(4-fluoro-2-nitrophenyl)amino]butanoic acid. MS (ESI) m/z 243 ([M+H]+); MS (ESI) m/z 241 ([M−H]−).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:9]=2)[N:4]=1.I[C:23]1[C:31]2[S:30][N:29]=[C:28]([NH2:32])[C:27]=2[CH:26]=[CH:25][C:24]=1[CH3:33].C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>O.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>[NH2:32][C:28]1[C:27]2[CH:26]=[CH:25][C:24]([CH3:33])=[C:23]([C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[N:4]=[C:3]([NH:2][CH3:1])[N:12]=[CH:11]4)[C:31]=2[S:30][N:29]=1
Reactant: Cc1ccc2c(N)nsc2c1I
Reactant: CNc1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1ncc2cc(-c3c(C)ccc4c(N)nsc34)ccc2n1
Temperature: 150 °C

Procedure:
N-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (0.42 g, 1.5 mmol), 7-iodo-6-methylbenzo[d]isothiazol-3-amine (0.39 g, 1.3 mmol), dichlorobis(triphenyl-phosphine)palladium (II) (0.047 g, 0.067 mmol) and sodium carbonate (0.14 g, 1.3 mmol) were all placed in a clear microwave vial along with 5 ml of 9:1 DMF:water. The vial was capped and heated in a Personal Chemistry SmithSynthesizer to 150° C. for 10 minutes. The reaction was diluted with water and extracted with EtAOc. The organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 50 to 100% EtOAc in hexanes. The clean fractions were triturated with warm ether and the solid collected by suction filtration and dried to give 6-(3-amino-6-methylbenzo[d]isothiazol-7-yl)-N-methylquinazolin-2-amine as a tan solid. MS(M+H)+ 322.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]=[C:10]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C-:32]#[N:33].[Na+].O>CS(C)=O>[C:32]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]=[C:10]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)#[N:33]
Reactant: [C-]#N
Reactant: BrCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
1-(7-Bromoheptyl)-2,4,5-triphenylimidazole (7 g) in dry dimethylsulphoxide (15 ml) was added over 20 minutes to a mixture of sodium cyanide (0.87 g) in dimethyl-sulphoxide (25 ml). The reaction was stirred at 40° C. for 1 hour. The cooled reaction mixture was poured into water (800 ml) and extracted with diethyl ether (4×100 ml). The extracts were combined, washed with water, dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Recrystallisation from dichloro-methane/hexane gave 1-(7-cyanoheptyl)-2,4,5-triphenylimidazole (3.7 g,60%) as a white solid, m.p. 93°-94°; Found: C, 82.35; H, 6.90; N, 9.96%; C29H29N3 1% CH2Cl2 requires C, 82.43; H, 6.91; N, 9.91%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:19]O>>[CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([CH3:14])=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C)c([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a stirred solution of 2,5-dimethyl-4-nitrobenzoic acid (480 mg, 2.4 mmol) in dry methanol (8.2 mL) at 0° C. under dry nitrogen was added thionyl chloride (0.538 mL, 7.38 mmol). The resulting mixture as allowed to warm to room temperature and stirred for about 7 hours. Additional thionyl chloride (0.300 mL) was added and stirring was continued at room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. This solution was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide methyl 2,5-dimethyl-4-nitrobenzoate (578 mg) as a pale yellow solid. HPLC (10-70) Rt=4.61; 1H NMR (300 MHz, CDCl3) δ 2.57 (s, 3H), 2.61 (s, 3H), 3.94 (s, 3H), 7.82 (s, 1H), 7.87 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8](C3CCCCO3)[C:5]2=[CH:6][N:7]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=1>>[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:10]([C:24]4[CH:23]=[CH:22][CH:21]=[C:20]([C:19]([F:30])([F:29])[F:18])[CH:25]=4)=[N:9][NH:8][C:5]3=[CH:6][N:7]=2)[CH:32]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: Brc1cc2c(I)nn(C3CCCCO3)c2cn1
Product: FC(F)(F)c1cccc(-c2n[nH]c3cnc(-c4cccnc4)cc23)c1
Yield: 33 %

Procedure:
Following the Suzuki coupling procedure of Example 159, 5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and 3-(trifluoromethyl)phenylboronic acid were reacted and the product was consequently reacted under Suzuki coupling procedure of Example 10 with 3-pyridineboronic acid pinacol ester and deprotected by the procedure of Example 131. The mixture was obtained as a base and purified by crystallization from ethyl acetate to afford 56 mg (33%) of 126 over three steps. ESI MS m/z 341.1 (M+1)
Reaction SMILES: C(N(CC)CC)C.O[C@@H]([C@@H:11]1[C@@H:14]([CH2:15][C:16](=[O:31])[CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[NH:13][C:12]1=[O:32])C.C(C1C=CC(S([N:45]=[N+:46]=[N-])(=O)=O)=CC=1)(O)=O>C(#N)C>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:18]([C:17](=[N+:45]=[N-:46])[C:16](=[O:31])[CH2:15][CH:14]2[NH:13][C:12](=[O:32])[CH2:11]2)=[O:19])=[CH:23][CH:24]=1)([O-:30])=[O:29]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(C(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: [N-]=[N+]=C(C(=O)CC1CC(=O)N1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (263 mg, 2.6 mmol) is added by syringe to a mixture of (3S,4R)-3-[(R)-1-hydroxyethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxopropyl]azetidin-2-one (253 mg, 0.72 mmol) and p-carboxybenzene sulfonylazide (196 mg, 0.84 mmol) in dry acetonitrile (6 ml) at 0° C. When addition is complete the cooling bath is removed and the reaction mixture is stirred at room temperature for 1 hour. The mixture is then diluted with ethyl acetate (50 ml) and filtered. The filtrate is concentrated in vacuo and the residue is chromatographed on a short silica gel column (ethyl acetate) to yield 222 mg, (81% overall from (3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyl dimethylsilyloxy)ethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxopropyl]azetidin-2-one) of (3S,4R)-3-(R)-1-hydroxyethyl)-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxo-3-diazopropyl]azetidin-2-one as a white solid m.p. (dec.) 163° C. IR(CHCl3, CM-1) 3410, 2132, 1756, 1718, 1650, 1350, 1280, 1120; n.m.r. (CDCl3) δ7.9(2d-aromatic, 4), δ5.4(s, 2), δ6.2(brs, 1), δ4.1(m, 2), δ2.6-3.6(m, 4), δ1.32(d, 3, J=6.2).
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)=[O:4].[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17].C(N(CC)CC)C>O>[ClH:1].[CH2:16]([N:18]([CH2:2][C:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)=[O:4])[CH2:19][CH3:20])[CH3:17]
Reactant: CC(=O)Nc1ccc(OC(=O)CCl)cc1
Reactant: CCNCC
Solvent: CCN(CC)CC
Solvent: O
Product: CCN(CC)CC(=O)Oc1ccc(NC(C)=O)cc1
Product: Cl
Yield: 39.8 %

Procedure:
22.8 g of p-acetamidophenyl chloroacetate were added in small portions to a solution of 7.5 g of diethylamine in 30 c.c. of triethylamine with stirring, while the temperature was maintained at between 40° C. and 50° C. with a bath of cold water if necessary. The process described in Example 1 was then followed to obtain 12 g of p-acetamidophenyl diethylaminoacetate hydrochloride melting point = 228° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])=O.[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])[CH3:13].[OH-].[Na+].Cl>C(O)C.O>[O:14]=[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:13]=[CH:1][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc(C=CC(=O)c2ccccc2)c1
Yield: 84.5 %

Procedure:
A mixture of 3-formylbenzoic acid (2 g, 13.32 mmol), acetophenone (1.6 g, 13.32 mmol), and sodium hydroxide (1.06 g, 26.64 mmol) is stirred 18 hours in ethanol-water (175 mL, 1:1) and then acidified with concentrated hydrochloric acid. The resulting solid is collected by filtration and dried to provide 2.84 g of the title compound; mp 198°-201° C.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:33]=1)[C:18]1[CH:17]=[C:16]([C:19]3[C:20]([F:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:27]#[C:28][C:29]([CH3:32])([OH:31])[CH3:30])=[CH:9][C:10]=1[F:26].[H][H]>[Pd]>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:33]=1)[C:18]1[CH:17]=[C:16]([C:19]3[C:20]([F:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([CH2:27][CH2:28][C:29]([CH3:30])([OH:31])[CH3:32])=[CH:9][C:10]=1[F:26]
Reactant: [H][H]
Reactant: CC(C)(O)C#Cc1cc(F)c2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3F)ccc1O2
Agent: [Pd]
Product: CC(C)(O)CCc1cc(F)c2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3F)ccc1O2

Procedure:
A 100 ml flask was charged with (S)-4-(2-amino-5′-fluoro-2′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl)-2-methylbut-3-yn-2-ol (120 mg, 0.268 mmol) ethanol (4 ml). Palladium on carbon (86 mg, 0.080 mmol) was added under argon and the resulting mixture was hydrogenated under 1 atm of hydrogen gas for 1 hr. The mixture was filtered through celite and concentrated in vacuo to provide (S)-4-(2-amino-5′-fluoro-2′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl)-2-methylbutan-2-ol. MS m/z=454.0 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=O)[C:9]([CH3:25])([CH3:24])[CH2:8]2)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:38]1([S:44]([NH2:47])(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.N12CCCN=C1CCCCC2>O1CCCC1.C(OCC)(=O)C>[CH3:25][C:9]1([CH3:24])[CH2:8][C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=2)[NH:11][CH:10]1[C:15]1[CH:23]=[CH:22][CH:21]=[C:17]([C:18](=[O:20])[NH:47][S:44]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:46])=[O:45])[CH:16]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)O)c1)N2
Reactant: NS(=O)(=O)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)NS(=O)(=O)c3ccccc3)c1)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 119.7 %

Procedure:
A solution of 3-(6-(methoxycarbonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)-benzoic acid (150 mg, 0.44 mmol, 1.0 eq.) and 1,1′-carbonyldiimidazole (214 mg, 1.32 mmol, 3.0 eq.) in tetrahydrofuran (3 mL) was heated to 60° C. for 2 h, then was cooled to room temperature and treated with benzenesulfonamide (89.6 mg, 0.57 mmol, 1.3 eq.). After stirring for 10 min, the reaction mixture was treated with dropwise addition of a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (221 mg, 1.45 mmol, 3.3 eq.) in tetrahydrofuran (1 mL). Upon completion of addition, the resultant mixture was stirred overnight. Thin layer chromatography (petroleum ether:ethyl acetate=1:1) showed the reaction was complete. The reaction mixture was quenched with brine and acidified with 1N hydrochloric acid solution to pH=6, extracted with ethyl acetate (twice). The combined organic layers were washed with brine for 3 times, dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave 252 mg of methyl 3,3-dimethyl-2-(3-(phenylsulfonylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid, which was pure enough for next step without further purification. MS (ESI+APCI) M+1=479.2.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][C@H:18]2[C:31]([OH:33])=O)[C:13]1=[O:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:37]=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:19][C@H:18]2[C:31]([NH2:37])=[O:33])[C:13]1=[O:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](C(=O)O)C1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
A 3 L round bottom flask was charged with (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (75.5 g, 0.158 mol), EDC.HCl (33.5 g, 0.175 mol), 1-hydroxybenzotriazole (23.6 g, 0.175 mol), and dichloromethane (1 L). The reaction was stirred at room temperature for 2 h, during which time it changed from a white suspension to a clear solution. Ammonia (gas) was bubbled into the solution until the pH was strongly basic (paper) and the reaction was stirred for 10 min; this ammonia addition was repeated and the reaction was stirred for an additional 10 min. Water was added. The organic phase was washed with sat. NaHCO3, NaH2PO4, and brine before being concentrated in vacuo. The residue was slurried with acetonitrile (0.5 L) and then concentrated in to give (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)cyclohexanecarboxamide as a white solid (75.9 g, ˜100%), which was used in the next step without further purification. LC/MS for primary peak: [M-Boc+H]+=375.3; [M+H]+=475.4; [M-tBu+H]+=419.3. 1H-NMR (400 MHz, d-MeOH): δ 7.35 (m, 5H), 5.11 (s, 2H), 4.25 (m, 2H), 3.70 (m, 1H), 3.6 (m, 1H), 3.45 (m, 1H), 2.91 (m, 1H), 2.38 (m, 1H), 2.12 (m, 1H), 1.9-2.05 (m, 2H), 1.65-1.9 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([O:16]C)=[O:15])(C)C.C1COCC1.CO.O.[OH-].[Li+]>O>[C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([OH:16])=[O:15])#[CH:5]
Reactant: COC(=O)Cc1ccccc1C#C[Si](C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccccc1CC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
To a solution of ester 319 (4.65 g, 18.9 mmol) in 1:1 THF/methanol (100 mL) was added lithium hydroxide monohydrate (1.60 g, 38.1 mmol) in water (25 mL) and the mixture was stirred at r.t. for 30 min. It was then partially concentrated, the aqueous residue was washed with ether, then acidified with 3M HCl (aq) and extracted with ethyl acetate. The organic extract was washed with water, dried (anhydrous MgSO4), filtered and concentrated. The residue was dissolved in ethyl acetate, run through a short plug of silica gel, and concentrated to provide 320 (2.77 g, 92% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.40 (br s, 1H); 7.45 (d, J=8.0 Hz, 1H), 7.37-7.24 (m, 3H), 4.36 (s, 1H); 3.72 (s, 2H). LCMS: (M+Na) 183.1
Reaction SMILES: [C:1]([NH:4][CH:5]([CH3:10])[CH:6]=[C:7](Cl)Cl)(=[O:3])[CH3:2].[CH3:11][O-:12].[Na+]>CO>[CH3:2][C:1]1[O:3][C:6]([CH2:7][O:12][CH3:11])=[C:5]([CH3:10])[N:4]=1
Reactant: C[O-]
Reactant: CC(=O)NC(C)C=C(Cl)Cl
Agent: [Na+]
Solvent: CO
Product: COCc1oc(C)nc1C
Yield: 64.5 %

Procedure:
A solution of 1.8 g of 3-acetamido-1,1-dichlorobut-1-ene and 1,0 g of sodium methylate in 20 ml of methanol is heated at the boiling point under reflux for 24 hours. Thereafter, the methanol is distilled off, the residue is taken up in 5 ml of water and 30 ml of methylene chloride and the organic phase is separated off and distilled in vacuo. 0.9 g of 2,4-dimethyl-5-methoxymethyl-oxazole is obtained, boiling point 54° C./20 mbar.
Reaction SMILES: [Sn]=O.[Zr:3].[Sn].[S:5](=[O:9])(=[O:8])([OH:7])[OH:6]>>[S:5]([O-:9])([O-:8])(=[O:7])=[O:6].[Zr+4:3].[S:5]([O-:9])([O-:8])(=[O:7])=[O:6]
Reactant: [Zr]
Reactant: O=S(=O)(O)O
Agent: O=[Sn]
Agent: [Sn]
Product: O=S(=O)([O-])[O-]
Product: [Zr+4]

Procedure:
FIG. 1 is a view showing the relationship between the amount of tin oxide and the amount of coating deposition converted to zirconium in the case of treating tin-plated steel sheet (tin deposition amount on one surface: 2.8 g/m2), dipped in sulfuric acid (dipped in 2% sulfuric acid (25° C.) for 0 to 60 seconds) to remove the tin oxide, by zirconium sulfate electrolysis (electrolytic conditions: 1 A/dm2×5 seconds (40° C.)) to form a chrome-free foundation layer containing zirconium (zirconium compound coating).