Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.Cl.[NH2:14][OH:15].[OH-].[Na+].Cl>CCO.O>[CH:1]1[C:10]2[C:5](=[CH:6][C:7](/[CH:11]=[N:14]/[OH:15])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: NO
Reactant: O=Cc1ccc2cnccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O/N=C/c1ccc2cnccc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
To a solution of isoquinoline-6-carbaldehyde (2.48 g, 15.8 mmol) (prepared as shown in Example 6) in 160 mL of 1:2 EtOH:H2O was added hydroxylamine hydrochloride (1.21 g, 17.4 mmol). The mixture was cooled to 0° C., and 50 wt % NaOH in H2O (3.2 mL, 0.2 mL per mmol of aldehyde) was added dropwise. The mixture was then stirred at 0° C. for 2 hours, at which time the pH was adjusted to about 6 with 10% aqueous HCl. The resulting biphasic mixture was then transferred to a separatory funnel and extracted five times with 150 mL of DCM. The combined organic layers were dried over MgSO4. Concentration under reduced pressure afforded (E)-isoquinoline-6-carbaldehyde oxime (2.14 g, 78.8% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 9.20 (s, 1H), 8.44 (d, J=5.9 Hz, 1H), 8.28 (s, 1H), 8.06 (s, 2H), 7.99 (s, 1H), 7.83 (s, 5.9 Hz, 1H).
Reaction SMILES: [CH3:1][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[OH:8][C:9]1([CH2:15][CH2:16][N:17]2[C:21](=[O:22])[CH2:20][S:19][CH:18]2[CH2:23][CH2:24][CH2:25][C:26]2[CH:34]=[CH:33][C:29](C(O)=O)=[CH:28][CH:27]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C>C(#N)C>[CH3:1][S:2]([NH:5][C:6](=[O:7])[C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][CH2:23][CH:18]2[N:17]([CH2:16][CH2:15][C:9]3([OH:8])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[C:21](=[O:22])[CH2:20][S:19]2)=[CH:34][CH:33]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N=C=O
Reactant: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)NC(=O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Reaction time: 4 h

Procedure:
A solution of methanesulfonylisocyanate (1.33 g., 0.011 mole) in acetonitrile (10 ml.) is added dropwise during 10 minutes to a solution of 4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid (3.9 g., 0.01 mole) and triethylamine (1.0 g., 0.01 mole) in acetonitrile (30 ml.). The resulting solution is stored at 25° C. for 4 hours and then evaporated at reduced pressure. The residue is treated with water. The crude product is extracted into chloroform and purified by chromatography on a silica gel column with elution by 4% methanol in chloroform.
Reaction SMILES: C([Si](C)(C)[O:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH2:9][CH2:8]1)(C)(C)C.[Li+].CC([N-]C(C)C)C.Br[CH2:30][C:31]1[S:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[C:32]=1[Cl:40].Cl>CO.O.C1COCC1>[Cl:40][C:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[S:35][C:31]=1[CH2:30][CH:15]1[CH2:16][CH2:17][N:13]([C@H:10]2[CH2:9][CH2:8][C@@H:7]([OH:6])[CH2:12][CH2:11]2)[C:14]1=[O:18]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCCC2=O)CC1
Reactant: Clc1c(CBr)sc2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C1C(Cc2sc3ccccc3c2Cl)CCN1[C@H]1CC[C@@H](O)CC1
Temperature: -78 °C

Procedure:
Charge a flask with cis-1-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-pyrrolidin-2-one (0.50 g, 1.68 mmol) (1.0 eq), dissolve with THF (0.2 M) and cool to −78° C. Add LDA (1.1 to 1.5 eq) and stir at −78° C. for 5 minutes. Add 2-bromomethyl-3-chloro-benzo[b]thiophene (U.S. Pat. No. 4,939,140) (0.53 g, 2.02 mmol) and warm to room temperature overnight. Dilute with methanol (0.2 M) and add concentrated HCl (10 eq.) and stir at room temperature. Pour into water after reaction complete by HPLC and extract with methylene chloride, dry over sodium sulfate, filter and concentrate in vacuo. Purification of the residue over silica gel (20% hexane in ethyl acetate) affords the title compound as a white powder (0.44 g, 71%): MS (APCI-pos mode) m/z (rel intensity) 364.1 (100), 366.1 (40).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[C:44]([CH2:46][C:47]2[CH:52]=[CH:51][C:50](Br)=[CH:49][CH:48]=2)[C:43]([CH3:54])=[CH:42][C:41]=1[O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:63]([O:66]C=C)(=[O:65])[CH3:64].[CH3:69][C:70]1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[C:44]([CH2:46][C:47]2[CH:52]=[CH:51][C:50](/[CH:69]=[CH:70]/[CH2:64][C:63]([OH:66])=[O:65])=[CH:49][CH:48]=2)[C:43]([CH3:54])=[CH:42][C:41]=1[O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=COC(C)=O
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Reactant: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(/C=C/CC(=O)O)cc1
Yield: 429.8 %

Procedure:
To an acetonitrile solution (8.8 mL) of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-(benzyloxy)-5-(4-bromobenzyl)-4-methylphenyl]-D-glucitol (780 mg, 0.876 mmol) were added vinyl acetate (184 mg, 2.14 mmol), palladium(II) acetate (20 mg, 0.0890 mmol), tri-O-tolylphosphine (54 mg, 0.177 mmol) and triethylamine (0.64 mL, 4.38 mmol), and reacted at 120° C. for 20 minutes with microwave manufactured by Biotage. The reaction solution was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=5:1, chloroform:methanol=40:1) to obtain the title compound (681 mg, 87%) as an orange-yellow amorphous compound.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:25])(=O)C.[C:26]([O:30][C:31]([NH:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27].[OH-].[Na+]>CN(C=O)C.CO>[C:26]([O:30][C:31]([NH:33][C:34]1[CH:35]=[CH:36][C:37]([NH:38]/[C:16](=[C:6]2\[C:5](=[O:25])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:39][CH:40]=1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: COC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-methoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-tert.butoxycarbonylamino-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:26][C:27]([Si](C)(C)C)([F:29])[F:28]>C1COCC1>[F:26][C:27]([F:29])([F:28])[CH:6]([C:4]1[N:3]=[CH:2][S:1][CH:5]=1)[OH:7]
Reactant: O=Cc1cscn1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1cscn1)C(F)(F)F
Yield: 33.4 %

Procedure:
The method described in Example 4 (step 4.5.) is followed. Starting from 1 g (8.84 mmol) of thiazole-4-carboxaldehyde, 0.10 ml (0.10 mmol) of a 1M solution of tetrabutylammonium fluoride in THF and 1.38 g (9.72 mmol) of trifluoromethyltrimethylsilane (TMS-CF3), and after chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, gives 0.54 g of pure product in the form of a colourless oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:5]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH3:12])=[O:6])[CH3:2].P([O-])([O-])([O-])=O.C([O-])(=O)C>>[CH2:1]([O:3][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)[C:5]([OH:7])=[O:6])[CH3:2].[CH2:1]([O:3][C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:5]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH3:12])=[O:6])[CH3:2]
Reactant: CCOCCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Product: CCOCCOC(=O)[C@@H](Cc1ccc(O)cc1)OCC
Product: CCO[C@@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 25 °C

Procedure:
Ethoxyethyl (2RS) (+/−) 2-ethoxy-3-(4-hydroxyphenyl)propanoate (0.5 ml of a solution containing 2 mg/ml in a phosphate, pH 7; 0.1 M, or acetate buffer, pH 5; 0.1 M) was added to the reaction vessel followed by an enzyme (0.5 ml enzyme solution). The reaction mixture was shaken at room temperature and analysed at different times (maximum 36 h). The reaction mixture was analysed without work up by the gradient HPLC method 1, chiral HPLC methods 2 and 5, and by the CCE method 1.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(O)(=O)C.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(CN2CCCCC2)ccc1F
Temperature: 0 °C
Reaction time: 18 h
Yield: 56.5 %

Procedure:
4-Fluoro-3-nitro-benzaldehyde (3.39 g, 0.0200 mol) was dissolved in methylene chloride (100 mL) and acetic acid (3.50 mL, 0.0616 mol) and the mixture was cooled to −10° C. Piperidine (2.4 mL, 0.024 mol) was then added to the cooled mixture over 10 minutes. Sodium triacetoxyborohydride (17.0 g, 0.0802 mol) was added in one portion. After stirring at 0° C. for 18 hours, the reaction was poured into a mixture of 1N aqueous HCl and ice. The organic phase was removed, and the aqueous layer was made basic by the addition of NaOH pellets. The aqueous layer was extracted twice with methylene chloride, dried over magnesium sulfate, filtered and concentrated. The residue was taken up in methylene chloride and purified by silica gel chromatography (ethyl acetate/hexanes as eluent) followed by further purification by preparative HPLC to yield 2.69 g of 1-(4-fluoro-3-nitro-benzyl)-piperidine as a TFA salt.
Reaction SMILES: Br[C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C@@H:17]([C:29]([OH:31])=[O:30])[C:18]([S:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)([CH3:20])[CH3:19])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[O:34]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35]1>C1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:34]1[CH:38]=[CH:37][C:36]([C:2]2[CH:3]=[CH:4][C:5]([O:6][C:7]3[CH:8]=[CH:9][C:10]([S:13]([NH:16][C@@H:17]([C:29]([OH:31])=[O:30])[C:18]([S:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)([CH3:20])[CH3:19])(=[O:14])=[O:15])=[CH:11][CH:12]=3)=[CH:32][CH:33]=2)=[CH:35]1
Reactant: CC(C)(SCc1ccccn1)[C@@H](NS(=O)(=O)c1ccc(Oc2ccc(Br)cc2)cc1)C(=O)O
Reactant: OB(O)c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: CC(C)(SCc1ccccn1)[C@@H](NS(=O)(=O)c1ccc(Oc2ccc(-c3ccoc3)cc2)cc1)C(=O)O
Temperature: 80 °C
Reaction time: 72 h
Yield: 77.1 %

Procedure:
To a suspension of 221 mg (0.40 mmol) of N-[4-(4-bromophenoxy) benzenesulfonyl]--S--[(pyrid-2-yl)methyl]-D-penicillamine (from example 3(d)) in 2 mL of benzene and 2 mL of 2M aqueous Na2CO3 solution was added a solution of 71 mg (0.48 mmol) of 3-furan boronic acid (J. Org. Chem. 1984, 49, 5237-5243) in 2 mL of EtOH. To the resulting mixture was added solid Pd(PPh3)4 (46 mg, 0.04 mmol) under a flow of Ar. The mixture was heated at 80° C. with vigorous stirring for 72 hours, cooled to room temperature, and partitioned between ehtyl acetate and AcOH/H2O buffer (pH 3). The aqueous layer was adjusted to pH of 3 by adding AcOH, then extracted with EtOAc (2×70 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residual yellow solid was chromatographed on silica gel, eluting first with CH2Cl2, then with 10% methanol in dichloromethane to elute the product fractions. After concentration of the product-containing fractions, the residue was triturated with hexane/t-butyl methyl ether, and the solid was collected by filtration. The solid was dried in high vacuum to give 166.1 mg (77%) of N-[4-(4-(furan-3-yl)phenoxy)benzenesulfonyl]--S--[(pyrid-2-yl)methyl]-D-penicillamine as a yellow solid: mp 185-189° C.; 1H--NMR (CDCl3) δ 1.40 (s, 3H) 1.44 (s, 3H), 3.32-4.01 (m, 3H), 6.83 (s, 1H), 7.10-7.13 (m, 4H), 7.22-7.23 (m, 2H), 7.57-7.92 (m, 8H), 8.42 (d, J=4 Hz, 2H).
Reaction SMILES: C(N(CC)CC)C.C[O:9][C:10](=[O:37])[C@H:11]([CH2:33][C:34]([OH:36])=[O:35])[N:12]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>CO>[CH2:26]([O:25][C:23]([NH:12][C@@H:11]1[C:10](=[O:9])[O:37][C:34](=[O:36])[CH2:33]1)=[O:24])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1.[CH2:16]([O:15][C:13]([NH:12][C@H:11]([C:10]([OH:37])=[O:9])[CH2:33][C:34]([OH:36])=[O:35])=[O:14])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)[C@H](CC(=O)O)N(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: O=C1C[C@H](NC(=O)OCc2ccccc2)C(=O)O1

Procedure:
Suitable amount of sample was withdrawn from the uniform reaction mixture thus obtained and dissolved in a methanol solution containing 5% by weight of triethylamine. α- and β-Isomers of N-benzyloxycarbonylcarbobenzoxy-L-aspartic acid methyl ester formed by the reaction of N-benzyloxycarbonyl-L-aspartic anhydride with methanol and residual N-benzyloxycarbonyl-L-aspartic acid were determined by high performance liquid chromatography. The content and yield of N-benzyloxycarbonyl-L-aspartic anhydride were calculated from measured values. Results are shown in Table 6.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[C:10]([CH2:13][CH:14]([NH2:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Cl:27][C:28]([Cl:35])([Cl:34])[CH2:29][O:30][C:31](Cl)=[O:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[C:10]([CH2:13][CH:14]([NH:20][C:31]([O:30][CH2:29][C:28]([Cl:35])([Cl:34])[Cl:27])=[O:32])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C(N)CC1=CCN(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)C(CC1=CCN(C(=O)OC(C)(C)C)C1)NC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Yield: 92.8 %

Procedure:
To an ice-cooled solution of 214 mg (0.75 mmol) 3-(2-amino-2-ethoxycarbonyl-ethyl)-2,5-dihydropyrrole-1-carboxylic acid tert.-butylester and 119 mg (1.5 mmol) pyridine in 2 ml methylene chloride was added a small amount of DMAP followed by 212 mg (1mmol) 2,2,2-trichloroethoxycarbonyl chloride. The mixture was allowed to warm to room temperature overnight. The mixture was diluted with ether, washed with water, sat. CuSO4, water and brine, dried over MgSO4 and evaporated. Purification of the residue by flash-chromatography (elution with petrol ether/ethyl acetate 3:1) gave 320 mg (93%) 3 -[2-(2,2,2-trichloroethoxycarbonyl-amino)-2-ethoxycarbonyl-ethyl]-2,5-dihydropyrrole-1-carboxylic acid tert.-butylester as a colorless oil, which was immediately used for the next step.
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][CH:6]=[C:5]1[O:11][C@H:12]1[CH2:16][N:15](C(OC(C)(C)C)=O)[C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]1)[CH:2]=[CH2:3].[ClH:28]>>[Cl-:28].[CH2:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][CH:6]=[C:5]1[O:11][C@H:12]1[CH2:16][NH2+:15][C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]1)[CH:2]=[CH2:3]
Reactant: C=CCn1c(O[C@@H]2C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C2)cccc1=O
Reactant: Cl
Product: C=CCn1c(O[C@H]2C[NH2+][C@H](C(=O)OC)C2)cccc1=O
Product: [Cl-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A 100 mL round bottom flask was charged with the product of Step 6 (1.91 g, 5.05 mmol). Added HCl (4.0M in dioxane) (30 mL, 120 mmol). Stirred at room temperature for 1 hour. Evaporated. Added ethanol. Evaporated. Repeated. The title compound remained as a pale foam. (1.59 g, 5.05 mmol, 100% yield). LCMS (ES+) m/z 279.3 (M+H)+.
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][C:11](/[CH:17]=[C:18]1/[C:19](=[O:33])[N:20]=[C:21]([NH:23][C@@H:24]3[CH2:26][C@H:25]3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[S:22]/1)=[CH:10][CH:9]=2)=[O:4].C[NH:35][CH2:36][CH2:37][NH:38][CH3:39].Cl.[CH:41](Cl)(Cl)Cl>>[CH3:41][N:38]([CH3:39])[CH2:37][CH2:36][NH:35][C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][C:11](/[CH:17]=[C:18]1/[C:19](=[O:33])[N:20]=[C:21]([NH:23][C@@H:24]3[CH2:26][C@H:25]3[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[S:22]/1)=[CH:10][CH:9]=2)=[O:4]
Reactant: CNCCNC
Reactant: COC(=O)c1cnc2ccc(/C=C3\SC(N[C@@H]4C[C@H]4c4ccccc4)=NC3=O)cc2c1OC
Reactant: ClC(Cl)Cl
Agent: Cl
Product: COc1c(C(=O)NCCN(C)C)cnc2ccc(/C=C3\SC(N[C@@H]4C[C@H]4c4ccccc4)=NC3=O)cc12
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To the suspension of 4-methoxy-6-[4-oxo-2-((1R,2S)-2-phenyl-cyclopropylamino)-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carboxylic acid methyl ester (example 1) (50 mg, 0.11 mmol) in chloroform (5 mL) was added dimethylethylenediamine (0.048 mL, 0.44 mmol). The mixture was stirring at 120° C. for 3 h. After cooling, the solid was collected by filtration and washed with methylenechloride. The solid was dissolved in acetonitrile and 1N hydrochloride acid (0.22 mL, 0.22 mmol) was added. The resulting solution was lyophilized to give 4-methoxy-6-[4-oxo-2-((1R,2S)-2-phenyl-cyclopropylamino)-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carboxylic acid (2-dimethylamino-ethyl)-amide; hydrochloride. LC-MS m/e 516 (MH+).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CC(C)=O.[CH3:11][C:12]1([CH3:30])[C:16]([CH3:18])([CH3:17])[O:15][B:14]([C:19]2[CH:20]=[C:21]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[O:13]1.CI>ClCCl>[CH3:1][N:25]([C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([B:14]2[O:13][C:12]([CH3:30])([CH3:11])[C:16]([CH3:17])([CH3:18])[O:15]2)[CH:20]=1)[S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: CC1(C)OB(c2cccc(NS(C)(=O)=O)c2)OC1(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Solvent: ClCCl
Product: CN(c1cccc(B2OC(C)(C)C(C)(C)O2)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A round bottom flask was charged with Potassium carbonate (1.1 g, 8.1 mmol) and Acetone (40 mL, 500 mmol). To the suspension was added N-[3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (2.0 g, 6.7 mmol) followed by Methyl iodide (0.50 mL, 8.1 mmol). The mixture was stirred at room temperature for 18 hours. The reaction was then diluted with dichloromethane (20 mL), filtered through a plug of diatomaceous earth, rinsed with dichloromethane and evaporated to a viscous oil. The material was subjected to high vacuum for 18 hours. The resulting white solid (2.00 g) was consistent for desired N-Methyl-N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide and was used without further purification. 1H NMR (400 MHz, DMSO, d6) δ 7.63 (m, 1H), 7.60 (m, 1H), 7.49 (m, 1H), 3.24 (s, 3H), 2.97 (s, 3H), 1.30 (s, 12H).
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[CH:12][C:13]([O:15]C)=[CH:14][C:6]=2[C:5]1=[O:17])[CH:2]=[CH2:3].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:6]=2[C:5]1=[O:17])[CH:2]=[CH2:3]
Reactant: C=CCN1CCCc2ccc(OC)cc2C1=O
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCN1CCCc2ccc(O)cc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
A solution of 2-allyl-8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one (1.10 g, 0.0047 mol) in CH2Cl2 (20 mL) was treated at 0° C. with BBr3 (1M in CH2Cl2, 9.50 mL), and the resulting mixture stirred at 0° C. for 30 minutes. The solution was poured over ice, NaHCO3 was added, and the solution was extracted with CH2Cl2. The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo to yield ca. 1.0 g (100%) of 2-allyl-8-hydroxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one as a colorless oil; 1H NMR(CDCl3) d8.2(brs, 1H), 7.47(s, 1H), 6.95(d, J=6 Hz, 1H), 6.84(dd, J=3, 6 Hz, 1H), 5.89(m, 1H), 5.22(m, complex, 2H), 4.20(d, J=6 Hz, 2H), 3.18(t, J=6 Hz, 2H), 2.66(t, J=6 Hz, 2H), 2.15(s,1H), 1.96(m, 2H); 13C NMR(CDCl3) d171.65(CO), 156.01,135.68, 133.27, 129.55, 128.46, 118.51, 118.05, 115.91, 53.46, 49.81, 45.83, 30.87, 29.76, 29.12.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=O.S(O)(O)(=O)=O.[NH2:16]O.C(Cl)Cl.C([O-])(O)=O.[Na+]>O>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[C:4]#[N:16]
Reactant: NO
Reactant: O=Cc1c(O)cccc1O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#Cc1c(O)cccc1O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 2,6-dihydroxybenzaldehyde (300 mg, 2.17 mmol) and hydroxylamine sulfate (758 mg, 6.51 mmol) in water (30 mL) is stirred at RT for 45 min. Methylene chloride (60 mL) is added followed by NaHCO3 (911 mg, 10.85 mmol) and the mixture is stirred at RT for 30 min. The organic phase is separated and dried over sodium sulfate and the solvent removed under reduced pressure to give the title compound as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([CH2:15][F:16])([C:13]#[CH:14])[CH2:11][F:12])=[CH:5][CH:4]=1.CCCCCC.C([Li])CCC.Cl[C:31]([O:33][CH3:34])=[O:32]>C(OCC)C>[F:16][CH2:15][C:10]([CH2:11][F:12])([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:18])[F:1])=[CH:4][CH:5]=1)[C:13]#[C:14][C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)Cl
Reactant: C#CC(CF)(CF)Oc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COC(=O)C#CC(CF)(CF)Oc1ccc(C(F)(F)F)cc1
Reaction time: 1 h
Yield: 78.9 %

Procedure:
An amount (0.53 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-yl 4-trifluoromethylphenyl ether was dissolved in diethyl ether (3 ml); to the solution under cooling with ice, a hexane solution (1.4 ml) of 1.69 M n-butyllithium was added dropwise under a nitrogen atmosphere. After the end of the dropwise addition, the mixture was stirred for 1 hour under cooling with ice. The resulting mixture was added dropwise to a solution of methyl chloroformate (0.38 g) in diethyl ether (3 ml) under a nitrogen atmosphere under cooling with ice. After stirring the mixture for 1 hour under cooling with ice, hexane was added, followed by washing with water and a saturated aqueous solution of sodium chloride. The mixture was dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluent; hexane/methylene chloride=1/1) to give the titled compound (0.51 g).