Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[C:18]([OH:19])=[C:17]([Br:20])[CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].CN(C=O)C.Cl[CH2:27][C:28]([NH2:30])=[O:29]>O>[Br:7][C:8]1[C:18]([O:19][CH2:27][C:28]([NH2:30])=[O:29])=[C:17]([Br:20])[CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: NC(=O)CCl
Reactant: CCOC(=O)c1ccc(Br)c(O)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Br)c(OCC(N)=O)c1Br
Temperature: 120 °C

Procedure:
0.853 g (6.20 mmol) of K2CO3, 0.154 g (0.90 mmol) of Kl and 1.000 g (3.10 mmol) of ethyl 2,4-dibromo-3-hydroxybenzoate were introduced into 15 ml of DMF. 0.346 g (3.70 mmol) of chloroacetamide was added at RT, and the mixture was heated for 6 hours at 120° C. The mixture was then poured into water and extracted with diisopropyl ether. The combined organic phases were washed with water, dried over Na2SO4 and concentrated completely. Drying in an oil-pump vacuum gave ethyl 2,4-dibromo-3-(aminocarbonylmethoxy)benzoate as a brown oil.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:51]2[CH:55]=[C:54]([C:56]#[N:57])[N:53]([CH3:58])[C:52]=2[CH3:59])[C:16]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=3[C:30]([N:32]3[C@H:41]([CH2:42][N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)[CH2:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:33]3)=[O:31])[N:20]([CH3:49])[C:19]=2[CH3:50])=[O:17])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.Cl>CCOCC>[ClH:29].[Cl:29][C:27]1[CH:26]=[CH:25][C:24]([C:30]([N:32]2[C@H:41]([CH2:42][N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)[CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)=[O:31])=[C:23]([C:21]2[N:20]([CH3:49])[C:19]([CH3:50])=[C:18]([C:16]([N:15]([C:51]3[CH:55]=[C:54]([C:56]#[N:57])[N:53]([CH3:58])[C:52]=3[CH3:59])[C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)=[O:17])[CH:22]=2)[CH:28]=1
Reactant: Cc1c(N(C(=O)c2cc(-c3cc(Cl)ccc3C(=O)N3Cc4ccccc4C[C@H]3CN3CCOCC3)n(C)c2C)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc(C#N)n1C
Agent: Cl
Solvent: CCOCC
Product: Cc1c(N(C(=O)c2cc(-c3cc(Cl)ccc3C(=O)N3Cc4ccccc4C[C@H]3CN3CCOCC3)n(C)c2C)c2ccc(O)cc2)cc(C#N)n1C

Procedure:
The compound of Step A is deprotected in accordance with the protocol described in Step D of Example 1. The product thereby obtained is finally subjected to a step of conversion into salt form in the presence of HCl in ether. After filtration and lyophilisation in a mixture of acetonitrile/water, the expected product is obtained.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O)#[N:6].[BH4-].[Na+]>C1(C)C=CC=CC=1>[OH:2][CH2:1][CH2:3][NH:4][CH2:10][C:9]1[CH:8]=[C:7]([CH:14]=[CH:13][CH:12]=1)[C:5]#[N:6]
Reactant: N#Cc1cccc(C=O)c1
Reactant: NCCO
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1cccc(CNCCO)c1
Temperature: 140 °C

Procedure:
To a stirred solution of ethanolamine (2.32 g, 0.0381 mol) in toluene (100 mL), was added 3-cyanobenzaldehyde (5 g, 0.0381 mol) under N2 and refluxed at 140° C. After complete distilling out of toluene, the reaction mass was cooled to RT and dissolved in dry methanol (100 mL). To this solution was added in portions sodium borohydride (2.17 g, 0.0571 mol) at 0° C. The reaction mass was evaporated under pressure, washed with water (100 mL), extracted in DCM (100 mL), dried using sodium sulphate and concentrated under reduced pressure. The obtained crude was purified using column chromatography on silica and chloroform/methanol as eluent to afford the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 7.76 (s, 1H), 7.65-7.69 (m, 2H), 7.49-7.52 (m, 1H), 4.45-4.48 (m, 1H), 3.74 (s, 2H), 3.42-3.46 (m, 2H), 2.51-2.54 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[S:17][CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[F:54][C:55]1[CH:62]=[CH:61][C:58]([CH2:59][NH2:60])=[CH:57][CH:56]=1>ClCCl>[F:54][C:55]1[CH:62]=[CH:61][C:58]([CH2:59][NH:60][C:21]([C:19]2[N:20]=[C:16]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[S:17][CH:18]=2)=[O:22])=[CH:57][CH:56]=1
Reactant: COc1cc(Nc2nc(C(=O)O)cs2)ccc1-n1cnc(C)c1
Reactant: NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1cc(Nc2nc(C(=O)NCc3ccc(F)cc3)cs2)ccc1-n1cnc(C)c1

Procedure:
To a suspension of 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazole-4-carboxylic acid (61.5 mg, purity 43%, 0.080 mmol) in dichloromethane (2 ml) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (24.5 mg, 0.128 mmol), 1-hydroxybenzotriazole hydrate (19.6 mg, 0.128 mmol), triethylamine (30.0 mg, 0.296 mmol) and a solution of 4-fluorobenzyl amine (12 mg, 0.096 mmol) in dichloromethane (1 ml). After 12 h at rt again 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (24.5 mg, 0.128 mmol), 1-hydroxybenzotriazole hydrate (19.6 mg, 0.128 mmol), triethylamine (30.0 mg, 0.296 mmol) and a solution of 4-fluorobenzyl amine (12 mg, 0.096 mmol) in dichloromethane (1 ml) were added. After 12 h at rt the reaction mixture was directly purified by silica gel chromatography using dichloromethane/methanol as eluent. The title compound was obtained as a off-white foam (23.0 mg, 66%). MS ISP (m/e): 438.2 (14) [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([Br:12])[C:5]2[S:9][C:8]([NH2:10])=[N:7][C:6]=2[CH:11]=1.C(N(CC)CC)C.[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23]>CS(C)=O.O>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([Br:12])[C:5]2[S:9][C:8]([NH:10][C:25]([NH:24][CH2:22][CH3:23])=[O:26])=[N:7][C:6]=2[CH:11]=1
Reactant: COc1c(Br)cc2nc(N)sc2c1Br
Reactant: CCN=C=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCNC(=O)Nc1nc2cc(Br)c(OC)c(Br)c2s1
Temperature: 25 °C
Reaction time: 3.75 h

Procedure:
5,7-Dibromo-6-methoxy-1,3-benzothiazol-2-amine (208 mg, 0.62 mmol) was dissolved in anhydrous DMSO (1 mL) and triethylamine (0.189 mL, 1.35 mmol) followed by ethyl isocyanate (0.058 mL, 0.74 mmol). The mixture was stirred at rt. A further aliquot of ethyl isocyanate (0.058 mL, 0.74 mmol) was added after 3 h. After 3.75 h, the mixture was diluted with water and extracted into EtOAc (3×30 mL). The combined organic phases were washed with water and brine, dried over Na2SO4 and concentrated to dryness under reduced pressure. The desired compound was obtained as a pale yellow solid, 234 mg (93%). The material was used without further purification in the next step. m/z: 407.83/409.83/411.81 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14](OC)=[O:15])=[C:12]([CH3:18])[N:11]=[C:10]([CH:19]([CH3:21])[CH3:20])[C:9]=2[C:22](OCC)=[O:23])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[K+]>O1CCCC1>[OH:23][CH2:22][C:9]1[C:10]([CH:19]([CH3:21])[CH3:20])=[N:11][C:12]([CH3:18])=[C:13]([CH2:14][OH:15])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1c(C(C)C)nc(C)c(C(=O)OC)c1-c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(C(C)C)c(CO)c(-c2ccc(F)cc2)c1CO
Temperature: 0 °C

Procedure:
20.7 g (57.7 mmol) of the compound from Example 26 dissolved in 50 ml of absolute tetrahydrofuran are slowly added dropwise under nitrogen to a suspension of 6 g (158 mmol) of lithium aluminum hydride in 200 ml of absolute tetrahydrofuran at 60° C. The mixture is heated to reflux for 1 h, cooled to 0° C. and 18 ml of water are cautiously added. 6 ml of 10% strength potassium hydroxide solution are added to the mixture, it is filtered off from the precipitate with suction and the residue is boiled twice using 250 ml of ether each time. The combined mother liquors are dried over magnesium sulphate and concentrated in vacuo, The residue is stirred with petroleum ether, filtered off with suction and dried in a desiccator.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:19]([O-:21])=[O:20])[CH:3]=1.[Li+].[OH-].Cl>CO>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=2)=[C:4]([N+:19]([O-:21])=[O:20])[CH:3]=1
Reactant: COC(=O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
The compound from Example 126a (29.6 g, 96.2 mmol) in 200 mL of MeOH was treated with aqueous LiOH (1 M) and heated under reflux for 1 hour. Cooled to room temperature and acidified with aqueous HCl (1 M). Precipitate was filtered, washed with H2O and air-dried giving the title compound as a yellow solid (28.2 g, 100%).
Reaction SMILES: [CH3:1][CH:2]([C:19]([NH:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])=[O:20])[C:3]([NH:5][C@@H:6]1[C:12](=[O:13])[N:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[NH:8][CH2:7]1)=[O:4].ClCCl.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl>C(N(CC)CC)C>[C:33]([N:8]1[CH2:7][C@H:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:1])[C:19]([NH:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:26])([F:25])[F:27])=[O:20])[C:12](=[O:13])[N:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]1=2)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@H]1CNc2ccccc2N(C)C1=O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@H]1CN(C(=O)c2ccccc2)c2ccccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.6 %

Procedure:
To a solution of 0.2 g (0.47 mmol) of 2-methyl-N-((3S)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide in 3 ml of dichloromethane 0.096 g (0.95 mmol) of triethylamine and 0.08 mg (0.57 mmol) of benzoylchloride were added. The mixture was stirred for 20 min at room temperature. Hydrochloric acid (10 ml of a 1 N solution) was added and the mixture was extracted two times with dichloromethane. The combined organic layers were extracted with 1N sodiumbicarbonate solution, dried (MgSO4) and concentrated in vacuo. The remaining oil was purified by column chromatography to yield 0.15 g (60%) of a white foam.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][NH:8][CH:7]([CH3:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:12].[Cl:13]N1C(=O)CCC1=O.[Cl-].[Li+]>CN(C=O)C>[NH2:1][C:2]1[C:10]2[O:9][NH:8][CH:7]([CH3:11])[C:6]=2[C:5]([Cl:13])=[CH:4][C:3]=1[F:12]
Reactant: CC1NOc2c1ccc(F)c2N
Reactant: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC1NOc2c(N)c(F)cc(Cl)c21
Reaction time: 18 h
Yield: 64.2 %

Procedure:
A solution of 7-amino-6-fluoro-3-methyl-1,2(2H)-benzisoxazole (3.5 g, 0.021 mole) in DMF (50 mL) was stirred, and a solution of N-chlorosuccinimide (2.8 g, 0.02 mole) in a minimum amount of DMF was added dropwise. Upon completion of addition, the reaction mixture was stirred for about 18 hours. After this time, the reaction mixture was poured into aqueous 10% lithium chloride and then thoroughly extracted with ether. The combined extracts were washed with aqueous 10% lithium chloride, dried with magnesium sulfate, and concentrated to a residue. The residue was subjected to silica gel column chromatography using 9:1 to 4:1 hexane and ethyl acetate to provide 2.6 grams of 7-amino-4-chloro-6-fluoro-3-methyl-1,2(2H)-benzisoxazole. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]([O:14]C)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[K+]>CO>[Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]([OH:14])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(OC)c(Cl)c(C)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(Cl)c(O)cc(C(=O)O)c1Cl
Temperature: 50 °C
Reaction time: 19 h
Yield: 95.2 %

Procedure:
Methyl 2,4-dichloro-5-methoxy-3-methylbenzoate (238 mg, 0.96 mmol) was dissolved in MeOH (30 mL) and flushed with argon. Potassium hydroxide (308 mg, 4.78 mmol) was added and the reaction mixture was stirred at 50° C. for 19 h. The solvent was evaporated and the residue was dried in vacuum. Hydrobromic acid 30 mL, 48%, aq) was added and the mixture was heated to 110° C. After 3 days most of the HBr was removed by vacuum-distillation. The crude product was mixed with H2O (10 mL), concentrated NH3 (1 mL) and EtOAc (40 mL) were added, the aqueous phase (pH 1) was extracted with EtOAc (2×20 mL) and the combined organic phase was washed with brine (10 mL) and dried (MgSO4). Evaporation of the solvent gave 202 mg of the title compound. 1H NMR (DMSO-D6): δ 10.68 (br, 1H), 7.15 (s, 1H), 2.42 (s, 3H); 13C NMR (DMSO-d6): δ 166.68, 151.82, 135.87, 131.24, 123.70, 121.17, 114.36, 17.93; MS (EI, 70 eV): m/z (rel.int.) 222/220 (M+, 56/100), 205/203 (36/59), 185(26).
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:16]=[C:15]([CH2:25][CH3:26])[C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[N:13][OH:14])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C)C=O>O>[CH2:33]([O:14][N:13]=[CH:12][CH2:11][O:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:4]1[C:15]([CH2:25][CH3:26])=[CH:16][C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:23])[Cl:24])=[CH:18][C:3]=1[CH2:1][CH3:2])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCCOCC=NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCCOCC=NOCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.6 %

Procedure:
First, 0.27 g of 4-(2,6-diethyl-4-(3,3-dichloro-2-propenyloxy)phenoxy)-butyloxyacetaldehyde oxime, 0.10g of potassium carbonate, 0.16 g of benzyl bromide, and 10 ml of N,N-dimethylformamide were placed in a reaction vessel. After stirring at room temperature for 24 hours, the reaction mixture was poured into water, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.21 g (yield, 56%) of 4-(2,6-diethyl-4-(3,3-dichloro-2-propenyloxy)phenoxy)-butyloxyacetaldehyde O-benzyloxime, nD22.5 1.5402.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH2:9])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Zn](CC)[CH2:17][CH3:18]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:17][CH3:18])[N:5]=[C:4]([NH2:9])[CH:3]=1
Reactant: CC[Zn]CC
Reactant: Nc1cc(Cl)cc(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1cc(Cl)cc(N)n1
Temperature: 70 °C
Yield: 33 %

Procedure:
To a solution of 4,6-dichloropyridin-2-amine (1.0 equiv.) in THF (0.1M) was added Pd(dppf)Cl2-DCM (0.1M), K2CO3 (3.0 equiv.), and Et2Zn (1.2 equiv.). The reaction was heated to 70° C. for 18 hrs. Upon cooling to room temperature, NH4Cl(sat.) was added, the mixture was extracted with EtOAc, dried with Na2SO4, and concentrated. The crude material was purified via SiO2 column chromatography eluting with DCM/MeOH (2%) to yield 4-chloro-6-ethylpyridin-2-amine in 33% yield. LCMS (m/z): 157.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1.[CH3:29][NH2:30]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13]([NH:30][CH3:29])[C:12]=2[CH2:11][CH2:10]1
Reactant: CN
Reactant: COc1ccccc1N1CCc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Solvent: O
Product: CNc1nc2c(OCC(F)(F)F)cccc2c2c1CCN2c1ccccc1OC
Temperature: 180 °C

Procedure:
1-(2-Methoxyphenyl)-4-chloro-6-β,β,β-trifluoroethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(598 mg, 1.5 mmol) was dissolved in aqueous solution of methylamine(40%, 5.0 ml) in the pressure tube, and the resultant was refluxed at 180° C. for 15 hours. The reaction mixture was dissolved in water, extracted with dichloromethane, and the organic layer was washed with water for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 312 mg of desired compound as solid in 53% of yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][CH2:20][OH:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]=1.[N:22]#[C:23][NH2:24].OS(C(F)(F)F)(=O)=O>C1COCC1>[C:23](=[NH:22])([O:21][CH2:20][CH2:19][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[N:10]=2)=[C:2]([F:1])[CH:3]=1)[NH2:24]
Reactant: OCCc1ccc(Oc2cccc(C(F)(F)F)n2)c(F)c1
Reactant: N#CN
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCOC1
Product: N=C(N)OCCc1ccc(Oc2cccc(C(F)(F)F)n2)c(F)c1
Temperature: 55 °C
Yield: 44 %

Procedure:
To a solution of 2-(3-fluoro-4-{[6-(trifluoromethyl)-2-pyridinyl]oxy}phenyl)ethanol (70 mg, 0.232 mmol) and cyanamide (11.72 mg, 0.279 mmol) in THF (5 mL) was added triflic acid (0.025 mL, 0.279 mmol) under argon. The mixture was heated at 55° C. for 3 h. Purification via reverse phase flash chromatography then afforded the title compound (50 mg, 0.102 mmol, 43.7% yield). LCMS: rt=2.53 min, [M+H+]=344
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[C:9](O)(=[O:12])[CH:10]=[CH2:11]>>[NH:1]1[C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=2[CH2:11][CH2:10][C:9]1=[O:12]
Reactant: C=CC(=O)O
Reactant: NC1=CC(=O)CCC1
Product: O=C1CCC2=C(CCCC2=O)N1
Temperature: 180 °C

Procedure:
5.00 g (0.675 mol) of 1-amino-cyclohexen-3-one and 65.65 g (1.35×0.675 mol) of acrylic acid are stirred for 3 hours under nitrogen in an oil bath heated to 180° C. The mixture is cooled and recrystallised from 1000 ml of methanol.
Reaction SMILES: [CH2:1]([NH:8][S:9]([NH2:12])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+:18]>>[K+:18].[CH2:1]([NH:8][S:9]([NH-:12])(=[O:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)NCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: [NH-]S(=O)(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.6 %

Procedure:
To a solution of benzylsulfamide (17.98 g) in McOH (300 mL) was carefully added potassium tert-butylate (10.8 g). The mixture was stirred at rt for 15 min before the solvent was evaporated. The remaining residue was dried under HV to give benzylsulfamide potassium salt as an off-white powder (21.73 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH3:11])=[CH:6][CH:5]=1)(=O)[CH3:2].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:2][C:1]([C:16]1[CH:17]=[CH:18][C:13]([OH:19])=[CH:14][CH:15]=1)([C:16]1[CH:17]=[CH:18][C:13]([OH:19])=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:11])([C:16]2[CH:17]=[CH:18][C:13]([OH:19])=[CH:14][CH:15]=2)[C:16]2[CH:17]=[CH:18][C:13]([OH:19])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: Oc1ccccc1
Reactant: CC(=O)c1ccc(C(C)=O)cc1
Product: CC(c1ccc(O)cc1)(c1ccc(O)cc1)c1ccc(C(C)(c2ccc(O)cc2)c2ccc(O)cc2)cc1

Procedure:
0.0215 mols of α,α′-dimethyl-α,α,α′,α′-tetrakis(4-hydroxyphenyl)-p-xylene (produced from 1,4-diacetylbenzene and phenol and having a melting point of 307° C.), 9.2 mols of bisphenol A, 9.4 liters of an aqueous solution of 2.0 N sodium hydroxide, and 8 liters of dichloromethane were put into a 50 liters container equipped with a stirrer, and stirred therein, to which phosgene was introduced for 30 minutes. Next, 0.44 mols of bisphenol A, 0.022mols of triethylamine, and 4.5 liters of an aqueous solution of 0.2 N sodium hydroxide were added thereto, and reacted for 40 minutes, and thereafter the aqueous phase and the organic phase in the reaction mixture were separated from each other. Thus was prepared a dichloromethane solution of an oligocarbonate.
Reaction SMILES: C(N(CC)CC)C.[C:8]1(/[CH:14]=[CH:15]/[S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:20][C:21]1[CH:33]=[C:32]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=[CH:30][C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(=O)([O-])O.[Na+]>C(Cl)Cl>[O:34]([C:32]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])=[C:21]([NH:20][S:16](/[CH:15]=[CH:14]/[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:18])=[O:17])[CH:33]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NS(=O)(=O)/C=C/c1ccccc1
Reaction time: 1 h

Procedure:
0.056 mL of triethylamine and 61 mg of ((E)-2-phenylvinyl)sulfonyl chloride were added to 5.0 mL of methylene chloride solution containing 57 mg of tert-butyl 2-amino-4-phenoxybenzoate at room, temperature sequentially and stirred at the same temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 4-phenoxy-2-(((E)-2-phenylvinyl)sulfonamido)benzoate.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:43]1[N:44]=[C:45]([NH:48]C=O)[S:46][CH:47]=1)[C:5]([NH:7][CH:8]1[C:41](=[O:42])[N:10]2[C:11]([C:25]([O:27][CH:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:18]=[N:19][N:20]([CH2:22][C:23]#[CH:24])[N:21]=3)[CH2:13][S:14][C@H:9]12)=[O:6].Cl.O1CCCC1>CO>[CH3:1][O:2][N:3]=[C:4]([C:43]1[N:44]=[C:45]([NH2:48])[S:46][CH:47]=1)[C:5]([NH:7][CH:8]1[C:41](=[O:42])[N:10]2[C:11]([C:25]([O:27][CH:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:18]=[N:19][N:20]([CH2:22][C:23]#[CH:24])[N:21]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: C#CCn1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NOC)c4csc(NC=O)n4)[C@H]3SC2)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: C#CCn1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NOC)c4csc(N)n4)[C@H]3SC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a mixture of benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[2-(2-propynyl)-2H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate (syn isomer) (2.7 g) in methanol (19.0 ml) were added conc. hydrochloric acid (0.75 g) and tetrahydrofuran (10 ml) and the mixture was stirred for 3 hours at room temperature. After the evaporation of the reaction mixture, to the residue were added water and ethyl acetate and then the resulting mixture was adjusted to pH 7.0 with a saturated aqueous solution of sodium carbonate. After the addition of tetrahydrofuran to the resulting mixture, the organic layer was separated, washed with a saturated aqueous solution of sodium chloride (×2), dried over magnesium sulfate and then evaporated. The residue was pulverized in isopropyl ether, collected by filtration, washed with isopropyl ether and then dried to give benzhydryl 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(2-propynyl)-2H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate (syn isomer) (2.0 g).