Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]2[CH:26]=[C:27]([NH:31][C:32]3[C:35](=O)[C:34](=[O:37])[C:33]=3[O:38]CC)[CH:28]=[C:29]([CH3:30])[C:5]=2[N:4]=1)[CH3:2].[CH3:41][NH:42][CH3:43]>>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]2[CH:26]=[C:27]([NH:31][C:32]3[C:33](=[O:38])[C:34](=[O:37])[C:35]=3[N:42]([CH3:43])[CH3:41])[CH:28]=[C:29]([CH3:30])[C:5]=2[N:4]=1)[CH3:2]
Reactant: CCOc1c(Nc2cc(C)c3nc(CC)n(Cc4ccc(-c5ccccc5-c5nnn[nH]5)cc4)c3c2)c(=O)c1=O
Reactant: CNC
Product: CCc1nc2c(C)cc(Nc3c(N(C)C)c(=O)c3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 14b from 4'-[[2-ethyl-4-methyl-6-[(2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)-amino]-1H -benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)biphenyl and dimethylamine.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH:14]([CH3:16])[CH3:15])=[CH:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][C:3]=1[C:17](=[O:19])[CH3:18].I[CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:21]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH:14]([CH3:15])[CH3:16])=[CH:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][C:3]=1[C:17](=[O:19])[CH3:18])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCI
Reactant: CC(=O)c1cc2c(cc1O)OC(C)(C)C=C2C(C)C
Product: CCCCOc1cc2c(cc1C(C)=O)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure A, 1-(7-hydroxy-4-isopropyl-2,2-dimethyl-2H-chromen-6-yl)ethanone (Compound 62, 205 mg, 0.65 mmol) and 1-iodobutane (0.35 mL, 3.24 mmol) were reacted to produce the title compound as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=1)[C@@H:9]([OH:16])[C@@H:10]([OH:15])[CH2:11][CH2:12][CH2:13][CH3:14])(C)(C)C.[ClH:27]>O1CCOCC1>[F:24][C:22]1[CH:23]=[C:18]([CH:19]=[C:20]([F:25])[CH:21]=1)[CH2:17][C@H:8]([NH2:7])[C@@H:9]([OH:16])[C@@H:10]([OH:15])[CH2:11][CH2:12][CH2:13][CH3:14].[ClH:27]
Reactant: CCCC[C@H](O)[C@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCCC[C@H](O)[C@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
To a cooled (0-5° C.) solution of (1S,2R,3S)-[l-(3,5-Difluoro-benzyl)-2,3-dihydroxy-heptyl]-carbamic acid tert-butyl ester (1.19 g, 3.2 mmol) in dioxane (20 mL) was added HCl (4 M in dioxane, 80 mL, 320 mmol) over 30 min. The reaction mixture was stirred at 0-5° C. for 30 min, then room temperature overnight. The volatiles were removed in vacuo and the residue was evaporated from ether to afford (1S,2R,3S)-1-(3,5-difluorobenzyl)-2,3-dihydroxyheptylamine as an HCl salt. MS (ESI+) for C14H21F2NO2 m/z 274.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([NH:9][CH2:10][CH2:11][F:12])[S:8][C:4]=2[CH:3]=1.[CH3:15][N:16]([C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=1)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.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>[F:12][CH2:11][CH2:10][NH:9][C:7]1[S:8][C:4]2[CH:3]=[C:2]([C:27]3[CH:26]=[CH:25][C:24]([N:16]([CH3:15])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[CH:29][CH:28]=3)[CH:14]=[CH:13][C:5]=2[N:6]=1
Reactant: FCCNc1nc2ccc(Br)cc2s1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
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: CCOC(C)=O
Solvent: C1COCCO1
Product: CN(C(=O)OC(C)(C)C)c1ccc(-c2ccc3nc(NCCF)sc3c2)cc1
Temperature: 100 °C

Procedure:
A mixture of afford 6-bromo-N-(2-fluoroethyl)benzo[d]thiazol-2-amine (55 mg, 0.2 mmol), tert-butyl methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (66 mg, 0.2 mmol), and tetrakis(triphenylphosphine)palladium (7 mg, 0.006 mmol) in 2 mL dioxane and 0.5 mL of a 1 M Na2CO3 aqueous solution was heated at 100° C. in a microwave reactor for 10 min. After cooling to rt, it was diluted with EtOAc (30 mL) and washed with brine (30 mL), dried over MgSO4 and concentrated. The crude product was purified with silica chromatography (5% to 30% EtOAc in hexane) to afford tert-butyl 4-(2-(2-fluoroethylamino)benzo[d]thiazol-6-yl)phenyl(methyl)carbamate as a clear wax (25 mg, 31%). MS (ESI) m/z 402 (M+H+).
Reaction SMILES: C1(O)C=CC=CC=1.C1C2CC3C(=CC=CC=3)NC=2C=CC=1.OC1C[CH2:27][C:26]2([C:41]3[C:36]([CH:37]=[CH:38][C:39](=[O:42])[CH:40]=3)=[N:35][C:34]3[C:29]2=[CH:30][C:31]([OH:43])=[CH:32][CH:33]=3)[CH2:25]C1.C1(C2(C3C=CC=CC=3)C3C(C=CC(=O)C=3)=NC3C2=CC(O)=CC=3)C=CC=CC=1>S(=O)(=O)(O)O>[CH3:25][C:26]1([CH3:27])[C:41]2[C:36]([CH:37]=[CH:38][C:39](=[O:42])[CH:40]=2)=[N:35][C:34]2[C:29]1=[CH:30][C:31]([OH:43])=[CH:32][CH:33]=2
Reactant: O=C1C=CC2=Nc3ccc(O)cc3C3(CCC(O)CC3)C2=C1
Agent: O=C1C=CC2=Nc3ccc(O)cc3C(c3ccccc3)(c3ccccc3)C2=C1
Agent: O=S(=O)(O)O
Agent: c1ccc2c(c1)Cc1ccccc1N2
Solvent: Oc1ccccc1
Product: CC1(C)C2=CC(=O)C=CC2=Nc2ccc(O)cc21

Procedure:
Hill et al., The Phenol Dyestuff of Liehermann as an Acridan Derivative, J. Chem. Soc. (C) 2462 (1970), describes an acridan derivative, 7-hydroxyspiro [acridine-9,1'-cyclohexa-2', 5'-diene]-2(9H), 4'-dione, that has been used as an oxidation-reduction indicator. This compound and related acridan derivatives, 4',7-dihydroxyspiro [acridine-9,1'-cyclohexane]-2(9H)-one; 7-hydroxy-2',3',5',6'-tetramethylspiro[acridine-9,1'-cyclohexa-2', 5'-diene]-2(9H), 4'-dione; 9,9-diphenyl-7-hydroxyacridin-2 (9H)-one; and 9,9-dimethyl-7-hydroxyacridin-2(9H)-one, yield blue solutions in sulfuric acid which turn red on dilution, this color being due to protonation of the free base. The neutral forms of the compounds are yellow in most solvents. A method of synthesizing these compounds is also disclosed.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([Cl:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[O:13][CH2:14][CH3:15])#[N:2].Br[CH2:17]CC>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([Cl:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][CH3:17])#[N:2]
Reactant: CCCBr
Reactant: CCOc1cc(S(=O)(=O)Cl)ccc1C#N
Product: CCCOc1cc(S(=O)(=O)Cl)ccc1C#N

Procedure:
The titled compound was prepared analogously to 4-cyano-3-ethoxy-benzenesulfonyl chloride (Intermediate 127c) by replacing bromoethane with 1-bromopropane.
Reaction SMILES: B(F)(F)F.CCOCC.[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C@:18]12[CH2:27][O:26][C@@H:25]([CH:28]([OH:34])[CH2:29][CH2:30][C:31]([CH3:33])=[CH2:32])[CH2:24][C@H:23]1[CH2:22][S:21][C:20]([NH:35][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[N:19]2>ClCCl.O>[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C@:18]12[CH2:27][O:26][C@@H:25]([CH:28]3[CH2:29][CH2:30][C:31]([CH3:33])([CH3:32])[O:34]3)[CH2:24][C@H:23]1[CH2:22][S:21][C:20]([NH:35][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[N:19]2
Reactant: C=C(C)CCC(O)[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: CC1(C)CCC([C@H]2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3ccc(F)cc3F)CO2)O1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Boron trifluoride diethyl etherate (21 μL, 0.98 mmol) was added to a solution of N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(1-hydroxy-4-methylpent-4-en-1-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C77) (106 mg, 0.22 mmol) in dichloromethane (7 mL) at 0° C. The mixture was stirred at 0° C. for 5 minutes, then allowed to warm to room temperature and stirred for a further 5 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×20 mL). The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated to afford a yellow oil. Purification via silica gel chromatography (Gradient: 0% to 90% ethyl acetate in heptane) afforded the product as a white solid. By 1H NMR analysis, this was isolated as a single diastereomer. Yield: 30.1 mg, 28%. LCMS m/z 487.2 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.24 (br d, 7.0 Hz, 2H), 7.37-7.53 (m, 4H), 6.85-6.95 (m, 2H), 4.15 (d, J=12.1 Hz, 1H), 3.90 (ap. q, J=6.8 Hz, 1H), 3.79 (d, J=12.1 Hz, 1H), 3.53 (ddd, J=10.1, 6.6, 3.3 Hz, 1H), 3.10-3.15 (m, 1H), 3.01 (dd, J=12.8, 4.2 Hz, 1H), 2.66 (dd, J=12.7, 2.7 Hz, 1H), 2.03-2.12 (m, 1H), 1.86-1.99 (m, 3H), 1.68-1.78 (m, 2H), 1.27 (s, 3H), 1.22 (s, 3H).
Reaction SMILES: [C:1]([NH:5][C:6](=[S:23])[NH:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[NH2:22])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])([O:3][CH3:4])=[O:2].[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[C:1]([NH:5][C:6](=[S:23])[NH:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[NH:22][C:31]([NH:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:32])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])([O:3][CH3:4])=[O:2]
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)NC(=S)Nc1cc(C(=O)c2ccccc2)ccc1N
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1cc(C(=O)c2ccccc2)ccc1NC(=O)Nc1ccccc1
Reaction time: 8 h
Yield: 65 %

Procedure:
To a suspension of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (3.0 g.) in acetone (100 ml.) is added phenyl isocyanate (1.08 g.). The reaction mixture is refluxed for 11/2 hours and then allowed to stand at room temperature overnight. The precipitate is collected, washed with ether and dried to afford 2.65 g. (65% yield) of 3-(3-carbomethoxythioureido)-4-(3-phenylureido)benzophenone as a white solid, m.p. 212° C., dec.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][S:14]([CH2:17][C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1)(=[O:16])=[O:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24]O>C1(C)C=CC=CC=1.[Si](C=[N+]=[N-])(C)(C)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][S:14]([CH2:17][C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1)(=[O:15])=[O:16])[C:10]([O:12][CH3:24])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CO
Reactant: CC(C)(C)OC(=O)N[C@@H](CS(=O)(=O)Cc1cnccn1)C(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](CS(=O)(=O)Cc1cnccn1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
(R)-tert-Butoxycarbonylamino-3-(pyrazin-2-ylmethanesulfonyl)propionic acid (1.42 g, 4.53 mmol) was dissolved in mixture of MeOH (10 mL) and toluene (33 mL) and Me3SiCHN2 (2.0 M solution in hexanes, 3.06 ml) was added dropwise over 10 min. After stirring the reaction mixture overnight, the solvent was removed and the resulting residure was purified by flash chromatography with EtOAc/hexanes as eluent to afford methyl 2(R)-tert-butoxycarbonylamino-3-(pyrazin-2-ylmethanesulfonyl)propionate (0.755 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=O.[NH2:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]=1[F:25]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)/[CH:7]=[N:13]/[C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]=1[F:25]
Reactant: O=Cc1cc(Br)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)c1ccc(N)c(F)c1
Solvent: CCO
Product: CCOC(=O)c1ccc(/N=C/c2cc(Br)ccc2[N+](=O)[O-])c(F)c1

Procedure:
A mixture of 5-bromo-2-nitrobenzaldehyde (2.79 g, 12.13 mmol) and ethyl 4-amino-3-fluorobenzoate (2.22 g, 12.12 mmol) in ethanol (60 mL) was stirred at reflux for 2 h. After the solvent was removed under reduced pressure, the reaction mixture was purified by silica gel column chromatography to give (E)-ethyl 4-(5-bromo-2-nitrobenzylideneamino)-3-fluorobenzoate as pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H), 8.47 (d, J=2.0 Hz, 1H), 8.02 (d, J=8.6 Hz, 1H), 7.91 (dd, J=1.6, 2.3, 9.0 Hz, 1H), 7.85 (dd, J=1.6, 11.0 Hz, 1H), 7.80 (dd, J=2.3, 8.6 Hz, 1H), 7.24 (t, J=8.0 Hz, 1H), 4.40 (q, J=7.0 Hz, 2H), 1.42 (t, J=7.0 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −125.6.
Reaction SMILES: C(O[C:5]1[C:19]([O:20]C(=O)C)=[C:18]([O:24]C(=O)C)[CH:17]=[CH:16][C:6]=1[C:7]([CH:9]([C:13](=[O:15])[CH3:14])[C:10]([O-:12])=[O:11])=[O:8])(=O)C.Cl>O1CCCC1>[OH:24][C:18]1[C:19]([OH:20])=[C:5]2[C:6]([C:7](=[O:8])[C:9]([C:10]([OH:12])=[O:11])=[C:13]([CH3:14])[O:15]2)=[CH:16][CH:17]=1
Reactant: CC(=O)Oc1ccc(C(=O)C(C(C)=O)C(=O)[O-])c(OC(C)=O)c1OC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: Cc1oc2c(O)c(O)ccc2c(=O)c1C(=O)O
Temperature: 70 °C
Reaction time: 20.5 h
Yield: 47.2 %

Procedure:
The thus-obtained 2-(2,3,4-triacetoxybenzoyl)-3-oxobutanoate (3.2 g) was taken up in a mixture of tetrahydrofuran (160 ml) and 3N-HCl (160 ml) and agitated at 70° C. for 20.5 hours. The reaction mixture was concentrated to 20 ml and the resulting precipitate was collected by filtration. It was washed with water and then dried to give the desired product (0.94 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N1CCOCC1)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: C1COCCN1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(c1ccc(Br)c(F)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.5 %

Procedure:
A 500 mL flask was charged with 4-bromo-3-fluorobenzoic acid (5.00 g, 22.83 mmol), 100 mL DMF, morpholine (2.4 ml, 27.5 mmol), and 4-Ethylmorpholine (8.6 ml, 67.9 mmol). HOBt (4.32 g, 32.0 mmol) was added followed by EDC (5.25 g, 27.4 mmol) and the reaction allowed to stir at room temperature for 18 hours. The reaction was concentrated and the resulting orange syrup taken up in 100 mL EtOAc and 100 mL water. The organic layer was washed with 100 mL 2N HCl, 100 mL saturated sodium bicarbonate, and 100 mL saturated sodium chloride. The organic was then dried with MgSO4, filtered, and concentrated to give 6.476 g (98%) of a viscous yellow oil. This material was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].[S:10](=O)(=[O:13])([OH:12])[OH:11].[OH-].[K+]>>[CH3:9][C:6]1[CH:5]=[C:3]([NH2:4])[C:2]([CH3:1])=[CH:8][C:7]=1[S:10]([OH:13])(=[O:12])=[O:11]
Reactant: Cc1ccc(C)c(N)c1
Reactant: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: Cc1cc(S(=O)(=O)O)c(C)cc1N

Procedure:
To 121 g of 2,5-dimethylaniline, 100 g of sulfuric acid (d=1.84) was gradually added dropwise and the mixture was heated at 220° to 230° C. on an oil bath for 5 hours. To the reaction mixture, 2 l of an 1 N aqueous potasium hydroxide solution was added and the mixture was stirred with heating. After filtering the mixture while hot, 1 kg of hydrochloric acid (d=1.18) was added to the filtrate. The crystals thus precipitated were collected by filtration and washed with 1 l of acetone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[OH-].[Na+].Cl[C:15]([O:17][CH3:18])=[O:16].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][C:15]([O:17][CH3:18])=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COC(=O)Cl
Reactant: COc1ccc(N)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)Nc1ccc(OC)c(OC)c1
Temperature: -5 °C
Reaction time: 1.5 h
Yield: 90.7 %

Procedure:
A solution of 15.3 g (0.1 mol) of 3,4-dimethoxyaniline in 60 mL of methylene chloride was treated with 55 mL of 2N sodium hydroxide. The reaction mixture was cooled to -5° C. and 7.4 mL (0.096 mol) of methyl chloroformate was added keeping the reaction temperature between 15°-25° C. The reaction was stirred 1.5 hr at 10°-20° C. and then 50 mL of water was added. The layers were separated and the aqueous layer was extracted with 4×100 mL of methylene chloride. The combined methylene chloride layers were dried over sodium sulfate and Darco treated. Evaporation gave a paste which was recrystallized from 10 mL of ethyl acetate and 10 mL of hexanes to give 18.4 g (98%) of the product, mp 83°-87° C. NMR (CDCl3) δ 3.75 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 6.63 (br s, 1H, NH), 6.73 (m, 2H, ArH), 7.13 (m, 1H, ArH).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Br:22])[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[Br:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:11]1[C:10]([CH3:23])([CH3:24])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12]1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1Br)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccccc1Br
Temperature: 70 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
To a stirred mixture solution of 2-(2-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.5 g, 3.8 mmol) in methanol (5.0 mL) and tetrahydrofuran (5.0 mL) was added 50% sodium hydroxide in water (1.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(2-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (1.3 g, 90%) as a light yellow solid: LC/MS m/e calcd for C18H18BrNO2 (M+H)+: 361.25, observed: 360.0 & 362.0.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9]S[C:6]=2[CH:5]=[C:4]([C:11]([NH:13][O:14][CH2:15][CH2:16][O:17]C=C)=[O:12])[C:3]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[F:28].Cl.[OH:30]S(O)(=O)=O.FC(F)(F)C(O)=O.S1(CCCC1)(=O)=O>ClCCCl.ClCCl.CN1C(=O)N(C)CCC1.CN(P(N(C)C)(N(C)C)=O)C.CS(C)=O.CCOCC>[F:1][C:2]1[C:7]2[N:8]=[CH:9][O:30][C:6]=2[CH:5]=[C:4]([C:11]([NH:13][O:14][CH2:15][CH2:16][OH:17])=[O:12])[C:3]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[F:28]
Reactant: C=COCCONC(=O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F
Reactant: O=S(=O)(O)O
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NOCCO)c1cc2ocnc2c(F)c1Nc1ccc(I)cc1F

Procedure:
4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamide can be reacted in the presence of acid (such as HCl, H2SO4, trifluoroacetic acid) in appropriate solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer dichloromethane and 1,2-dichloroethane) for some time (1-12 h, prefer 3-10 h). 4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxy ethoxy)benzo[d]oxazole-6-carboxamide is obtained after conventional workup.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][O:13][C:14]1[CH:49]=[CH:48][C:17]2[NH:18][C:19](=[O:47])[N:20]([CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[C:33]([S:35][C:36]5[CH:45]=[C:44]([CH3:46])[C:39]6[NH:40][C:41](=[O:43])[O:42][C:38]=6[CH:37]=5)[N:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)[CH2:21][CH2:22][C:16]=2[CH:15]=1>ClCCl.CO>[CH3:12][O:13][C:14]1[CH:49]=[CH:48][C:17]2[NH:18][C:19](=[O:47])[N:20]([CH:23]3[CH2:24][CH2:25][N:26]([C:29]4[CH:34]=[C:33]([S:35]([C:36]5[CH:45]=[C:44]([CH3:46])[C:39]6[NH:40][C:41](=[O:43])[O:42][C:38]=6[CH:37]=5)=[O:6])[N:32]=[CH:31][N:30]=4)[CH2:27][CH2:28]3)[CH2:21][CH2:22][C:16]=2[CH:15]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(Sc4cc(C)c5[nH]c(=O)oc5c4)ncn3)CC1)C(=O)N2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(S(=O)c4cc(C)c5[nH]c(=O)oc5c4)ncn3)CC1)C(=O)N2

Procedure:
Under a nitrogen atmosphere 28 mg (0.11 mmol) 3-chloroperoxybenzoic acid (70%) in 5 mL dichloromethane was added dropwise to 60 mg (0.11 mmol) 7-methoxy-3-{1-[6-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylsulphanyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one in 5 mL dichloromethane and 1 mL methanol. After the reaction had ended the reaction mixture was evaporated down, dissolved in MeOH/DMF and purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: C(OC)(=[O:3])C.Cl.[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][CH2:13][NH:14][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[C:16]#[N:17].CO>>[ClH:24].[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][CH2:13][NH:14][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[C:16]([NH2:17])=[O:3]
Reactant: COC(C)=O
Reactant: N#CC(NCCc1cccs1)c1ccccc1Cl
Agent: Cl
Solvent: CO
Product: NC(=O)C(NCCc1cccs1)c1ccccc1Cl
Temperature: 22.5 °C
Reaction time: 6 h

Procedure:
Into 1200 ml of methyl acetate 204 g (5.6 mol) of hydrogen chloride gas is introduced at 15-25° C., and to the solution are added 221.4 g (0.8 mol) of the [2-(2-thienyl)ethylamino](2-chorophenyl)acetonitrile, prepared as described in Example 1., and 48 ml (1.2 mol) of methanol. The mixture is stirred at 20-25° C. for 6 hours. In the course of the reaction first the hydrochloride of the starting “nitrile”, then gradually the hydrochloride of the resulting “acid amide” precipitates, in the form of white crystals. The crystals are collected by filtration, washed with methyl acetate and dried. Weight: 249 g (94%) mp.: 231-232° C.
Reaction SMILES: [CH2:1]([O:7][CH2:8][CH:9]1[CH2:14][NH:13][CH2:12][CH2:11][NH:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:15]([N:17]1[C:26]2[C:21](=[CH:22][C:23]([F:28])=[C:24](F)[CH:25]=2)[C:20](=[O:29])[C:19]([C:30]([OH:32])=[O:31])=[CH:18]1)[CH3:16]>N1C=CC=CC=1>[CH2:15]([N:17]1[C:26]2[C:21](=[CH:22][C:23]([F:28])=[C:24]([N:13]3[CH2:12][CH2:11][NH:10][CH:9]([CH2:8][O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:14]3)[CH:25]=2)[C:20](=[O:29])[C:19]([C:30]([OH:32])=[O:31])=[CH:18]1)[CH3:16]
Reactant: CCCCCCOCC1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: c1ccncc1
Product: CCCCCCOCC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CC)CCN1

Procedure:
A 3 g portion of 2-[(hexyloxy)methyl]piperazine was added to 20 ml of pyridine in a pressure bottle, under argon. A 1.26 g portion of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added, the bottle sealed and the mixture heated at 80°-90° C. for 4 hours, then evaporated. The residue was evaporated twice from toluene, the residue triturated with ether and the solid collected, giving 2.03 g of the desired product, mp 12°-124° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C(N(CC)C(C)C)(C)C.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN1C(=O)CCC1.O>[CH2:19]([NH:26][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cc(Cl)nc(Cl)c1
Reactant: NCc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc(Cl)nc(NCc2ccccc2)c1
Temperature: 150 °C

Procedure:
2,6-Dichloro-4-methylpyridine (2.00 g, 12.3 mmol) was suspended in NMP (10 mL). N,N-Diisopropylethylamine (4.31 mL, 24.7 mmol) and benzylamine (1.42 mL, 13.0 mmol) were added, and the reaction mixture was heated to 150° C. in a microwave for 90 minutes. The reaction mixture was allowed to cool to room temperature, diluted with water, and extracted with diethyl ether (2×). The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (0-10% ethyl acetate/hexanes, linear gradient) to give N-benzyl-6-chloro-4-methylpyridin-2-amine. MS ESI calc'd. for C13H14ClN2 [M+H]+ 233. found 233.