Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[N:37]1[CH:42]=[CH:41][N:40]=[CH:39][C:38]=1[NH2:43]>ClCCl>[CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([NH:43][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][N:37]=2)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Reactant: Nc1cnccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnccn1)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 4b) (50 mg, 0.16 mmol) in dichloromethane (5 mL) was added oxalylchloride (0.02 mL, 0.25 mmol) at 0° C. and the reaction mixture was stirred at 25° C. for 3 h. Solvent was removed in vacuo and the residue was dissolved in dry dichloromethane. To this was added DIPEA (0.2 mL, 0.99 mmol) followed by 2-pyrazinamine (CAN 5049-61-6, 19 mg, 0.21 mmol) at 25° C. and the reaction mixture was stirred for 12 hours at that temperature. The solvent was removed in vacuo and the crude residue was purified by prep-HPLC to give 5-cyclohexyl-N-pyrazin-2-yl-6-(2,2,2-trifluoro-ethoxy)-nicotinamide as off white solid (10 mg, 15.9%); MS (ESI): 381.4 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][O:5][C:4](=[O:7])[CH2:3]1.[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:1][CH:2]1[CH2:6][O:5][C:4](=[O:7])[CH2:3]1
Reactant: O=C1CC(O)CO1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1CC(OC2CCCCO2)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
To a mixture of 4-hydroxy-dihydrofuran-2(3H)-one (10 g, 0.1 mol, Alfa) and dihydropyran (12.5 g, 0.15 mol, Alfa) in 250 mL of dry CH2Cl2 was added PPTS (2.5 g 0.01 mol), and the reaction mixture was stirred at rt overnight. The reaction mixture was washed with brine and extracted with CH2Cl2 (100 mL×3), and the combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (3:1 (v/v) EtOAc/n-Hexane) to give the title compound as colorless oil (15.6 g, 68%).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1([CH3:20])[CH3:19].[C:21](Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>>[C:11]([O:10][CH:5]1[CH2:6][C:7]([CH3:9])([CH3:8])[N:2]([O:1][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:3]([CH3:20])([CH3:19])[CH2:4]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Product: CC(C)(C)C(=O)ON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C
Yield: 70 %

Procedure:
Using 1-hydroxy-4-benzoyloxy-2,2,6,6-tetramethylpiperidine (prepared as described by: Kurumada T. et. al., loc. cit.) and pivaloyl chloride in a procedure otherwise similar to the preparation of the compound 101 gives a 70% yield of the compound 107 which is obtained in the form of colourless crystals; melting point: 107-110° C. (hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH3:22])=[CH:18][N:17]([CH3:23])[C:16]2=[O:24])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Br:25]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][Br:25])=[CH:18][N:17]([CH3:23])[C:16]2=[O:24])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: Cc1cn(C)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)OC(=O)c1cc(-n2c(=O)c(CBr)cn(C)c2=O)c(F)cc1Cl

Procedure:
A solution of 3.5 g of isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3,5-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate in 100 ml of carbon tetrachloride is heated to reflux temperature while stirring for 1 hour with 1.8 g of N-bromosuccinimide and some dibenzoyl peroxide. The reaction mixture is irradiated with a 150 W bulb. The succinimide is filtered off under suction and the filtrate is evaporated to dryness under reduced pressure. The residue is purified by chromatography on a silica gel column using methylene chloride/ethyl acetate (7:1) as the eluent. There is obtained isopropyl 2-chloro-4-fluoro-5-[5-bromomethyl-3,6-dihydro-3-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H-NMR (CDCl3, 400 MHz) 7.84 ppm (d, 1H), 7.58 ppm (s, 1H), 7.36 ppm (d, 1H), 5.24 ppm (m, 1H), 4.35 ppm (d, 1H), 4.29 ppm (d, 1H), 3.48 ppm (s, 3H), 1.37 ppm (2d, 6H).
Reaction SMILES: FC(F)(F)C(O)=O.C([NH:12][C:13](=[O:26])[C@@H:14]1[CH2:18][C@H:17](OC2C=CC=CC=2)[CH2:16][NH:15]1)(C)(C)C.[C:27]1([OH:37])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1.C1(O)C=CC=CC=1>>[C:27]1([O:37][N:15]2[CH2:16][CH2:17][CH2:18][C@H:14]2[C:13]([NH2:12])=[O:26])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: Oc1cccc2ccccc12
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](Oc2ccccc2)CN1
Solvent: O=C(O)C(F)(F)F
Solvent: Oc1ccccc1
Product: NC(=O)[C@@H]1CCCN1Oc1cccc2ccccc12

Procedure:
Following substantially the same procedure for synthesizing N-t-butyl-4(S)-phenoxy-L-prolineamide trifluoroacetic acid salt as outlined in Example 1, Steps 6 through 8, but substituting 1-naphthol for the phenol used therein, the 1-naphthyloxy proline amide was produced.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.O[CH:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[NH:6]1[C:7]2[C:3](=[C:2]([O:1][CH:16]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15]3)[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: Oc1cccc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-hydroxyindole (2.66 g, 20.0 mmol), t-butyl 3-hydroxy-1-pyrrolidinecarboxylate (7.5 g, 40.0 mmol) and triphenylphosphine (φ3P) (10.5 g 40.0 mmol) in THF is treated with diethyl azodicarboxylate (DEAC)(6.3 ml, 40.0 mmol) under nitrogen at room temperature, stirred for 2 h at room temperature and concentrated in vacuo. The resultant residue is stirred under ether, cooled and filtered. The filtercake is washed with cold ether. The filtrates are combined and concentrated in vacuo. The residue is purified by flash chromatography (silica gel, EtOAc/hexane: 2/80) to give the title compound as a white solid, 3.98 g, mp 164-165° C., identified by NMR and mass spectral analyses.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36]OS(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:36][CH2:35][C:33]2[N:34]=[C:30]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[O:31][C:32]=2[CH3:48])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:23]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(F)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Product: Cc1oc(C2CCCCC2)nc1CCOc1ccc(CC(C)(Oc2cccc(F)c2)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(3-fluoro-phenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester according to the method of Example 21.
Reaction SMILES: II.O[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1/[N:11]=[N:12]/[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([OH:20])=[CH:15][C:14]=1[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>O1CCCC1>[N:11]1[N:12]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([OH:20])=[CH:15][C:14]=2[CH3:21])[CH:4]=[C:5]2[C:6]=1[CH:7]=[CH:8][CH:9]=[CH:10]2
Reactant: Cc1cc(O)cc(C)c1/N=N/c1ccccc1CO
Agent: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(O)cc(C)c1-n1cc2ccccc2n1
Reaction time: 0.67 h

Procedure:
Iodine (3980 mg, 15.7 mmol) was added to the orange solution of (E)-4-((2-(hydroxymethyl)phenyl)diazenyl)-3,5-dimethylphenol (2680 mg, 10.46 mmol), triphenylphosphine (4110 mg, 15.7 mmol) and imidazole (2140 mg, 31.4 mmol) in tetrahydrofuran (30 mL) at room temperature. The mixture was stirred for 40 minutes. The solvent was evaporated. The crude was dissolved in EtOAc/MeOH and loaded to the column and purified by ISCO (40 g silica gel, EtOAc/heptane: 0→50%), leading to the desired product as a white/pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.85 (s, 6H) 6.49 (s, 2H) 7.07-7.21 (m, 1H) 7.32-7.42 (m, 1H) 7.75 (d, J=8.58 Hz, 1H) 7.80 (dd, J=8.78, 0.98 Hz, 1H) 7.96 (d, J=0.78 Hz, 1H) 7.99 (s, 1H). LCMS: m/z=239.2 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=O)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[O:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccccc1O)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc(-c2nc3ccccc3o2)cc1

Procedure:
In a 300 mL three-necked flask were placed 5.3 g (18 mmol) of 4-bromo-N-(2-hydroxyphenyl)benzamide, 8.0 g (46 mmol) of p-toluenesulphonic acid monohydrate, and 200 mL of toluene. This mixture was refluxed for 4 hours under nitrogen stream. After a predetermined time, water was added to the mixture that had been refluxed, and an aqueous layer and an organic layer were separated in the mixture. Then, an organic substance was extracted from the aqueous layer with ethyl acetate. The extract and the organic layer were neutralized together with a saturated aqueous sodium hydrogen carbonate solution, and washed with a saturated aqueous sodium chloride solution. Then, the organic layer was dried over magnesium sulfate. This mixture was subjected to suction filtration through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), and the filtrate was concentrated to obtain a solid. The obtained solid was recrystallized with ethyl acetate/hexane, so that 3.1 g of target white powder was obtained with a yield of 61%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][OH:11])=[C:6](Cl)[N:5]2[N:13]=[CH:14][CH:15]=[C:4]2[N:3]=1.C(N(CC)CC)C.[CH3:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1>C(O)(C)C>[Cl:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][OH:11])=[C:6]([NH:32][C:29]2[CH:30]=[CH:31][C:26]([O:25][CH2:24][CH3:23])=[CH:27][CH:28]=2)[N:5]2[N:13]=[CH:14][CH:15]=[C:4]2[N:3]=1
Reactant: OCCCc1c(Cl)nc2ccnn2c1Cl
Reactant: CCOc1ccc(N)cc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCOc1ccc(Nc2c(CCCO)c(Cl)nc3ccnn23)cc1
Temperature: 40 °C
Reaction time: 5 h
Yield: 67.2 %

Procedure:
To an isopropanol (3 mL) solution containing 3-(5,7-dichloropyrazolo[1,5-a]pyrimidin-6-yl)propan-1-ol (224 mg, 0.910 mmol), triethylamine (253 μL, 1.82 mmol) and phenethidine (128 μL, 1.00 mmol) were added, and this mixture was stirred at 40° C. for 5 hr. After the reaction, the solvent was distilled off, aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the filtrate was concentrated and the residue was purified with column chromatography (30% ethyl acetate-hexane) to obtain the title compound (212 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[CH2:16][C:15]2=[O:24])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[Cl:23][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[N:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:15](=[O:24])[CH2:16]2
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)Cc3cc(Cl)ccc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1Cc2cc(Cl)ccc2N1C1CCNCC1
Yield: 139.8 %

Procedure:
4-(5-Chloro-2-oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (3.4 g, 9.7 mmol) was set stirring in 1:1 TFA/CH2Cl2. After 45 min the mixture was evaporated and the golden oil brought up in Et2O. A solid formed and was filtered, washed with Et2O and air dried to give 3.4 g (97%) of a white solid. MS (electrospray): exact mass calculated for C13H15ClN2O, 250.09. m/z found, 251.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6); 7.45 (s, 2H), 7.31 (d, J=8.1 Hz, 1H), 4.55-4.45 (m, 1H), 3.68 (s, 2H), 3.50 (d, J=12.3, 2H), 3.14 (m, 2H), 2.70-2.55 (m, 2H), 1.87 (d, J=13.1 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Br[CH2:22][C:23]#[CH:24].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:24][C:23]#[CH:22])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C#CCn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Temperature: 25 °C

Procedure:
300 mg (0.98 mmol) of the compound from Example 4A were dissolved in 10 ml of acetonitrile, and 122 mg (1.02 mmol) of 3-bromo-1-propyne and 270 mg (1.95 mmol) of potassium carbonate were added. The mixture was heated at reflux for 1 h. For work-up, the reaction mixture was allowed to cool to RT and about 10 ml of water were added. The mixture was extracted twice with in each case 15 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 166 mg (49% of theory) of the target compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[F:14][C:15]1[CH:23]=[C:22]([F:24])[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C(Cl)Cl>[F:14][C:15]1[CH:23]=[C:22]([F:24])[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:16]=1[C:17](=[O:18])[C:8]1[CH:7]=[C:6]([CH3:5])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1F
Reactant: COc1ccc(C)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C)cc1C(=O)c1cc([N+](=O)[O-])c(F)cc1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
A mixture of aluminum chloride (62.3 g, 0.467 mol) and methylene chloride is cooled to −20° C. to −10° C., treated with 4-methylanisole (60.1 g, 0.492 mol), treated dropwise with a mixture of 2,4-difluoro-5-nitrobenzoyl chloride (111 g, 0.468 mol) and methylene chloride over a 10 minute period, warmed to 0° C., stirred overnight at ambient temperature, slowly poured onto ice with stirring, and diluted with methylene chloride. The organic layer is washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to a solid. The solid is recrystallized from acetonitrile to afford the title compound as a yellow solid (82.1 g, 54.0%) which is identified by NMR spectral analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:13](=[C:15]2\[C:16](=[C:22]([CH3:24])[CH3:23])[C:17](O[C:20]\2=[O:21])=[O:18])/[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[CH3:12][O:11][C:7]1[CH:6]=[C:5](/[C:13](=[C:15]2\[C:16](=[C:22]([CH3:23])[CH3:24])[C:17]([N:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]\2=[O:21])=[O:18])/[CH3:14])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(/C(C)=C2/C(=O)OC(=O)C2=C(C)C)cc(OC)c1OC
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc(/C(C)=C2/C(=O)N(c3ccccc3)C(=O)C2=C(C)C)cc(OC)c1OC
Reaction time: 2 h

Procedure:
(E)-α-(3,4,5-trimethoxyphenyl) ethylideneisopropylidene succinic anhydride (4 parts), prepared as in Example 3, in toluene (40 parts by volume), and aniline (1 part) were heated (12 hours) at 70°. Petrol was added and the liberated succinamic acid separated. The dry acid (1.8 parts) was dissolved in acetyl chloride (40 parts by volume) boiled for 2 hours and the solvent removed. Crystallization of the product from a toluene/petrol mixture gave (E)-α-(3,4,5-trimethoxyphenyl) ethylideneisopropylidene-N-phenylsuccinimide as pale yellow needles, melting point 169.5°. The compound shows similar photochromic properties to the corresponding (E)-anhydride.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[NH:7]([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][OH:10]>>[OH:10][CH2:9][CH2:8][N:7]([CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH2:11][CH2:12][OH:13]
Reactant: C=CC(=O)OC
Reactant: OCCNCCO
Product: COC(=O)CCN(CCO)CCO
Reaction time: 20 h
Yield: 98 %

Procedure:
At 20 to 30° C., 9.01 g of methyl acrylate was added to 10.0 g of diethanolamine. The resulting mixture was allowed to stand for 20 hours. The reaction mixture was concentrated under reduced pressure, whereby N,N-bis(2-hydroxyethyl)-2-(methoxycarbonyl)ethylamine was obtained (yield: 98%).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[N:7]=[N:8][C:9]([Cl:15])=[CH:10][C:11]=1[C:12](O)=[O:13].[Cl-].[Cl-].[Cl-].[Al+3].[CH3:20][C:21]1[C:26]2[NH:27][C:28](=[O:30])[O:29][C:25]=2[CH:24]=[CH:23][CH:22]=1>ClCCCl>[Cl:5][C:6]1[N:7]=[N:8][C:9]([Cl:15])=[CH:10][C:11]=1[C:12]([C:23]1[CH:22]=[C:21]([CH3:20])[C:26]2[NH:27][C:28](=[O:30])[O:29][C:25]=2[CH:24]=1)=[O:13]
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Reactant: Cc1cccc2oc(=O)[nH]c12
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: Cc1cc(C(=O)c2cc(Cl)nnc2Cl)cc2oc(=O)[nH]c12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2.00 mL (27.4 mmol) thionyl chloride were added to 1.92 g (9.95 mmol) 3,6-dichloro-pyridazine-4-carboxylic acid in 10 mL 1,2-dichloroethane and the mixture was refluxed for 2 h. The reaction mixture was evaporated to dryness and coevaporated with 1,2-dichloroethane. Then 5.30 g (39.8 mmol) aluminium trichloride and 1.56 g (10.5 mmol) 4-methyl-3H-benzoxazol-2-one were added and the mixture was stirred for 1 h at 100° C. under a nitrogen atmosphere. Then it was stirred for a further 2 h at 120° C., 3 h at 130° C. and then cooled for 48 h at RT. The mixture was decomposed with ice water and extracted with DCM. The organic phases were combined, washed with water, dried on sodium sulphate, filtered and evaporated down i. vac. The residue was triturated with DIPE, suction filtered and dried.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][N:3]=[CH:2]1.Cl[CH2:8][CH:9]=[O:10]>CC(C)=O>[N:3]1([CH2:8][CH:9]=[O:10])[CH2:4][CH2:5][CH2:6][N:1]=[CH:2]1
Reactant: O=CCCl
Reactant: C1=NCCCN1
Solvent: CC(C)=O
Product: O=CCN1C=NCCC1

Procedure:
A mixture of 8.4 g. of 1,4,5,6-tetrahydropyrimidine and 7.8 g. of chloroacetaldehyde is refluxed in 100 ml. of acetone for two hours. The solvent is removed in vacuo and the residue is taken up in water and neutralized with 1N sodium hydroxide. Extracting with chloroform, drying and removing the solvent in vacuo gives 1,4,5,6-tetrahydropyrimidine-1-acetaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:15][CH2:14][CH2:12][OH:13])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Product: O=S(=O)(NCCO)c1cccc(Br)c1
Yield: 97.3 %

Procedure:
Prepared by general procedure III from 3-bromobenzenesulfonyl chloride (5.0 g, 20 mmol) and ethanolamine (1.32 g, 22 mmol) to give the title compound (5.45 g, 99%) as a white solid. MS (ISP) 280.0[(M+H)+].
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]([C:23]1[NH:27][C:26]([CH3:28])=[C:25]([CH2:29][C:30]([OH:32])=[O:31])[C:24]=1[CH3:33])=O>>[CH3:28][C:26]1[NH:27][C:23](/[CH:21]=[C:14]2\[C:15](=[O:20])[NH:16][C:17]3[C:13]\2=[CH:12][C:11]([S:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:10])=[O:9])=[CH:19][CH:18]=3)=[C:24]([CH3:33])[C:25]=1[CH2:29][C:30]([OH:32])=[O:31]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4)cc32)c(C)c1CC(=O)O

Procedure:
5-Phenylmethanesulfonyl-1,3-dihydro-indol-2-one was condensed with (5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-acetic acid to give the titled compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]([CH3:14])=[CH:12][C:11](Cl)=[CH:10][CH:9]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]C)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Li+].[Li+].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:13]([CH3:14])=[CH:12][CH2:11][CH2:10][CH:9]1[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCC1C=C(Cl)C=C(C)N1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CO
Product: CCCCCC1CCC=C(C)N1C(=O)OC(C)(C)C

Procedure:
To a stirred solution of 1-(tert-Butoxycarbonyl)-4-chloro-6-methyl-2-n-hexyl-1,2-dihydropyridine (3.74 g, 11.91 mmol) in 250 mL of MeOH at 0° C. was added of lithium carbonate (0.88 g, 11.91 mmol) followed by 5% Pd/C. The mixture was placed under a positive pressure of hydrogen gas from a balloon, and the reaction progress was monitored by removing aliquots with a syringe, concentrating the aliquot in vacuo, and examining its 1H NMR spectrum. Upon completion, the mixture was filtered through Celite and evaporated. The residue was dissolved in ether (100 mL) and water (50 mL) was added, and the aqueous phase was extracted twice with ether. The combined organic extracts were washed with 1M NaOH and brine. The organic phase was dried with potassium carbonate, filtered through Celite, and concentrated in vacuo to give the crude product. Purification by column chromatography (silica gel, 5% EtOAc in hexanes) afforded 2.09 g (62%) as a clear oil that was homogeneous by TLC analysis. 1H NMR (300 MHz) δ 4.85 (br s, 1H), 4.43-4.38 (m, 1H), 2.01 (s, 3H), 1.99-1.91 (m, 2H), 1.83-1.12 (m, 23H), 0.89-0.84 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3](/[CH:9]=[CH:10]/[C:11]([O:13]C)=O)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C[O-].[Na+]>C(O)C>[Cl:8][C:6]1[CH:7]=[C:2]2[C:3]([CH:9]=[CH:10][C:11](=[O:13])[NH:1]2)=[N:4][CH:5]=1
Reactant: COC(=O)/C=C/c1ncc(Cl)cc1N
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1ccc2ncc(Cl)cc2[nH]1

Procedure:
A suspension of (E)-methyl 3-(3-amino-5-chloropyridin-2-yl)acrylate (1.2 g, 5.64 mmol) and sodium methoxide (0.786 ml, 14.11 mmol) in 20 mL of ethanol was refluxed for 3 h until the starting material disappeared. The reaction mixture was evaporated to dryness to give crude product 7-chloro-1,5-naphthyridin-2(1H)-one. To the crude residue was added phosphorus oxychloride (5.17 ml, 56.4 mmol) and the resulting mixture was stirred at 70° C. for 4 h. The excess POCl3 was removed under reduced pressure and the residue was directly submitted to flash column (DCM) to give 2,7-dichloro-1,5-naphthyridine (540 mg, 2.71 mmol, 48.1% yield) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=8.90 (d, J=2.2 Hz, 1H), 8.35 (d, J=8.8 Hz, 1H), 8.31 (d, J=1.8 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H). m/z=199 (M+1).