Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCOCC1.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([OH:16])=O.ClC(OCC(C)C)=O.Cl.[CH3:26][NH:27][O:28][CH3:29]>ClCCl>[CH3:29][O:28][N:27]([CH3:26])[C:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=1)=[O:16]
Reactant: O=C(O)c1ccccn1
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccccn1
Temperature: -15 °C
Reaction time: 15 h
Yield: 80 %

Procedure:
N-Methylmorpholine (3.7 ml) is added to a solution of picolinic acid (2.05 g, 16.65 mmol) in anhydrous dichloromethane (50 mL) and cooled to −15° C. Isobutyl chloroformate (2.2 ml, 16.75 mmol) is added thereto, and the mixture is stirred for 15 hr, after which N,O-dimethylhydroxylamine hydrochloride (1.63 g, 16.71 mmol) is added. After 15 min, the cooling bath is removed and stirring is continued at room temperature for 4 hr. The reaction mixture is added to water (50 ml) and extracted with dichloromethane. The organic phases are washed with water and brine and dried over Na2SO4. The residue is chromatographed on silica gel to afford N-methoxy-N-methylpyridine-2-carboxamide as a colorless oil (2.2 g; 80% yield).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([N:13]1[C:17]([CH3:18])=[C:16]([Cl:19])[C:15]([C:20]([F:23])([F:22])[F:21])=[N:14]1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1.[Li+].[OH-]>C1COCC1.O>[Cl:19][C:16]1[C:15]([C:20]([F:22])([F:21])[F:23])=[N:14][N:13]([CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=2)[C:3]([OH:24])=[O:2])[C:17]=1[CH3:18]
Reactant: COC(=O)C(c1cccc(OC)c1)n1nc(C(F)(F)F)c(Cl)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(C(=O)O)n2nc(C(F)(F)F)c(Cl)c2C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-(3-methoxy-phenyl)-acetic acid methyl ester was then dissolved in THF (20 ml) and LiOH (0.39 g) in water (5 ml) were added. The mixture was stirred at room temperature for 4 h. After this period the THF was completely evaporated from the reaction mixture under vacuum. The remaining aqueous layer was extracted with ethyl acetate (3×5 ml) and the organic layer was discarded. The aqueous layer was cooled in ice and neutralized by using concentrated HCl. This neutral aqueous layer was extracted with ethyl acetate (3×10 ml), the organic layer dried over Na2SO4, concentrated and purified by flash chromatography (CHCl3/MeOH) to yield (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-(3-methoxy-phenyl)-acetic acid
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]1[S:8][C:9]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]#[N:21])[CH:16]=3)[C:10]=2[N:11]=1)([CH3:5])[CH3:4].CCCCCC.[C:28](OCC)(=[O:30])C>>[CH3:4][C:3]1([CH3:5])[CH2:2][O:1][C:28](=[O:30])[N:6]1[C:7]1[S:8][C:9]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]#[N:21])[CH:16]=3)[C:10]=2[N:11]=1
Reactant: CC(C)(CO)Nc1nc2c(s1)CCc1cc(C#N)ccc1-2
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CC1(C)COC(=O)N1c1nc2c(s1)CCc1cc(C#N)ccc1-2
Yield: 93 %

Procedure:
In the same manner as described in step 4 of Example 4, replacing 2-fluoro-4-{2-[(2-hydroxy-1,1-dimethyl-ethyl)amino]-1,3-thiazol-4-yl}benzonitrile with 2-[(2-hydroxy-1,1-dimethylethyl)amino]-4,5-dihydronaphtho[1,2-d][1,3]thiazole-7-carbonitrile, prepared in the previous step, and purification of the crude product on silica using a stepwise gradient of 6:1 to 1:1 hexane:ethyl acetate as the eluent gave the title compound (2.7 g, 93%), mp>230° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11](=[O:15])[NH:12][CH2:13][CH3:14])[CH:8]=[C:7]([Cl:16])[C:3]=1[C:4]([OH:6])=O.ON1C2N=CC=CC=2N=N1.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.[NH:60]1[C:68]2[CH:67]=[CH:66][N:65]=[C:64]([NH:69][C:70]([CH:72]3[CH2:74][CH2:73]3)=[O:71])[C:63]=2[CH:62]=[CH:61]1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CC=CC=1.O>[Cl:16][C:7]1[CH:8]=[C:9]([CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([N:60]1[C:68]2[CH:67]=[CH:66][N:65]=[C:64]([NH:69][C:70]([CH:72]3[CH2:73][CH2:74]3)=[O:71])[C:63]=2[CH:62]=[CH:61]1)=[O:6])[C:11]([NH:12][CH2:13][CH3:14])=[O:15]
Reactant: O=C(Nc1nccc2[nH]ccc12)C1CC1
Reactant: CCNC(=O)c1cc(Cl)c(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCNC(=O)c1cc(Cl)c(C(=O)n2ccc3c(NC(=O)C4CC4)nccc32)c(Cl)c1
Yield: 26.6 %

Procedure:
A well stirred mixture of 2,6-dichloro-4-(ethylcarbamoyl)benzoic acid (84.6 mg, 0.42 mmol), 1-hydroxy-7-azabenzotriazole (77 mg, 0.57 mmol), N,N-dimethyl aminopyridine (22 mg, 0.11 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (216 mg, 0.57 mmol) in N,N-dimethylaniline was treated with N-(1H-pyrrolo[3,2-c]pyridin-4-yl)cyclopropanecarboxamide (100 mg, 0.38 mmol) and N,N-diisopropylethylamine (0.1 ml, 0.95 mmol). The reaction was stirred overnight at room temperature. The contents were diluted with water and extracted with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography using methanol in dichloromethane (3%) as eluent to yield 3,5-dichloro-4-({4-[(cyclopropylcarbonyl)amino]-1H-pyrrolo[3,2-c]pyridin-1-yl}carbonyl)-N-ethylbenzamide (45 mg, 26%) as an off white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[C@@H:7]([NH:11][C:12]([C@H:14]1[C@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[C@:17]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)([C:26]#[N:27])[C@H:16]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:15]1)=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.C(OC(=O)[C@@H](NC([C@@H]1[C@@H](C2C=CC=C(Cl)C=2)[C@@](C2C=CC(Cl)=CC=2)(C#N)[C@@H](CC(C)(C)C)N1)=O)C(C)C)(C)(C)C>CO>[CH3:1][O:5][C:6](=[O:40])[C@@H:7]([NH:11][C:12]([C@H:14]1[C@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[C@:17]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)([C:26]#[N:27])[C@H:16]([CH2:35][C:36]([CH3:37])([CH3:39])[CH3:38])[NH:15]1)=[O:13])[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)[C@H](NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2)[C@H]1c1cccc(Cl)c1)C(=O)OC(C)(C)C
Agent: CC(C)[C@H](NC(=O)[C@H]1N[C@H](CC(C)(C)C)[C@@](C#N)(c2ccc(Cl)cc2)[C@@H]1c1cccc(Cl)c1)C(=O)OC(C)(C)C
Solvent: CO
Product: COC(=O)[C@@H](NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2)[C@H]1c1cccc(Cl)c1)C(C)C

Procedure:
Column separation from the above example (Example 10a) gave a mixture of (S)-2-{[(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methyl-butyric acid tert-butyl ester and (S)-2-{[(2S,3S,4S,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methyl-butyric acid tert-butyl ester (45.8 mg, 15.6%). The mixture was treated with 2NH2SO4 (catalytic) in MeOH (1 mL) at 120° C. for 10 min using CEM microwave reactor to give after purification by PR-HPLC: (S)-2-{[(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methyl-butyric acid methyl ester (15.5 mg, 36.5%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([CH3:14])[CH:6]=1)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C=O)C.ClCCl>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:11])=[C:7]([CH3:14])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)O)c(C)c1
Reactant: C1CCNC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(=O)N2CCCC2)c(C)c1
Temperature: 50 °C

Procedure:
25.0 g (124 mmol) N-acetyl-4-amino-2-methyl-benzoic acid are combined with 3 drops DMF in 1000 ml dichloromethane and a solution of 21.0 ml (30.56 g, 241 mmol) oxalyl chloride in 100 ml TEA is added dropwise with stirring and cooling in the ice bath. Then the mixture is heated to 50° C. for 4.5 hours. The reaction mixture is filtered and the filtrate is evaporated down completely i. vac. The residue is taken up in 100 ml dichloromethane and this solution is added dropwise to a mixture of 10.4 ml (8.86 g, 125 mmol) pyrrolidine and 34.4 ml (25.0 g, 247 mmol) TEA in 500 ml dichloromethane with stirring and cooling in the ice bath. The mixture is stirred for 16 hours at ambient temperature. After filtering the filtrate is washed with 1-molar hydrochloric acid and sat. sodium chloride solution, combined with activated charcoal and dried over sodium sulphate. After evaporation i. vac. the residue is purified by chromatography on silica gel.
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[NH:12][C:13]3[C:18]([C:19]([NH2:21])=[O:20])=[CH:17][N:16]=[C:15]4[NH:22][CH:23]=[CH:24][C:14]=34)[CH2:3]1)[CH2:9]2.[CH2:25]([C:28]#[N:29])[CH2:26][OH:27]>C(N(CC)CC)C>[C:28]([CH2:25][CH2:26][O:27][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[NH:12][C:13]3[C:18]([C:19]([NH2:21])=[O:20])=[CH:17][N:16]=[C:15]4[NH:22][CH:23]=[CH:24][C:14]=34)[CH2:3]1)[CH2:9]2)#[N:29]
Reactant: N#CCCO
Reactant: NC(=O)c1cnc2[nH]ccc2c1NC1C2CC3CC1CC(Br)(C3)C2
Solvent: CCN(CC)CC
Product: N#CCCOC12CC3CC(C1)C(Nc1c(C(N)=O)cnc4[nH]ccc14)C(C3)C2
Reaction time: 0.33 h

Procedure:
To 4-[(5-bromoadamantan-2-yl)amino]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (52 mg) were added ethylene cyanhydrin (250 μl) and triethylamine (56 μl), and the mixture was stirred for 20 minutes using a microwave reaction system at 150° C. The reaction solution was cooled and purified by silica gel column chromatography (chloroform:methanol). The obtained fraction was concentrated under reduced pressure, and water was added. The obtained solid was collected by filtration to obtain 4-{[5-(2-cyanoethoxy)adamantan-2-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (16 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.C(Cl)(Cl)[Cl:12]>>[Cl:12][C:6](=[N:7][OH:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: ClC(Cl)Cl
Reactant: ON=Cc1ccc(Cl)cc1
Product: ON=C(Cl)c1ccc(Cl)cc1
Yield: 94.7 %

Procedure:
31 g (0.2 mol) of 4-chlorobenzaldoxime was suspended in 200 g of chloroform and chlorine gas was bubbled through the suspension while maintaining the reaction mixture at a temperature of from 5° to 10° C. 3-Chlorobenzaldoxime went into solution while showing a green color upon reaction with chlorine to give a reaction mixture having a deep green color. The reaction mixture turned pale yellowish-brown upon standing; chloroform was then removed from the reaction mixture by distillation under reduced pressure to give 36 g of pale yellowish-brown crystals having a melting point of 75°-80° C. Yield, about 95%.
Reaction SMILES: COC1C=CC(C2(C3C=CC(OC)=CC=3)O[C:13]3[C:15]4[C:20]([C:21](O)=[C:22]([C:23](OC)=[O:24])[C:12]=3C=C2)=[CH:19][CH:18]=[CH:17][CH:16]=4)=CC=1.C(N([CH2:41][CH3:42])CC)C>C1COCC1>[CH:12]1[C:13]2[C:15]3[C:20]([CH:21]=[CH:41][C:42]=2[O:24][CH2:23][CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: COC(=O)c1c2c(c3ccccc3c1O)OC(c1ccc(OC)cc1)(c1ccc(OC)cc1)C=C2
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: C1=Cc2c(ccc3ccccc23)OC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,2-Bis(4-methoxyphenyl)-5-(methoxycarbonyl)-6-hydroxy-[2H]-naphtho[1,2-b]pyran (U.S. Pat. No. 5,458,814) (0.225 g, 0.48 mmol) was dissolved in anhydrous THF (25 ml) under nitrogen. To this solution was added triethylamine (0.13 ml) followed by the Acid Chloride Terminated Polydimethylsiloxane (Example 1, Step 2) (0.358 g), dropwise. The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through a short plug of silica gel and the solvent evaporated. The crude product (0.53 g) was then purified by column chromatography (silica gel, diethyl ether/hexane, 2:3→2:1) giving the bulk product, Naphthopyran Terminated Polydimethylsiloxane, as a viscous red oil. Analysis by 1H NMR gave an average molecular weight (Mn) of 2,297 (nPDMS=12.6). 1H NMR (200 MHz, d6-acetone) δ 8.40 (m, 2H), 7.95 (m, 2H), 7.63 (m, 4H), 7.45 (m, 8H), 6.97 (d, 2H), 6.88 (m, 8H), 6.41 (d, 2H), 4.23 (t, 4H), 3.95 (s, 6H), 3.75 (s, 12H), 3.62 (t, 4H), 3.41 (t, 4H), 3.04 (m, 4H), 2.80 (m, 4H), 1.60 (m, 4H), 0.58 (m, 4H), 0.13-0.08 (m, SiCH3).
Reaction SMILES: C([O:4][C:5]([C:7]1[O:8][C:9]2[CH:15]=[CH:14][C:13](OCC3C=CC=C(OCC4C=CC5C(=CC=CC=5)N=4)C=3)=[CH:12][C:10]=2[N:11]=1)=[O:6])CC.C(=O)(O)[O-].[Na+]>C(O)C.O>[O:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=[C:7]1[C:5]([OH:6])=[O:4]
Reactant: CCCOC(=O)c1nc2cc(OCc3cccc(OCc4ccc5ccccc5n4)c3)ccc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.64 g of n-propyl-5-(3-(quinolin-2-ylmethyloxy)benzyloxy)benzoxazole-2-carboxylate and 0.45 g of sodium bicarbonate in 20 ml of ethanol in 20 ml of water is refluxed for 1.5 hours, then stirred at room temperature overnight. The mixture is neutralized and the resulting solid is filtered off, washed with water and dried in vacuo to give 5-(3-quinolin-2-ylmethyloxy)-benzyloxy)benzoxazole-2-carboxylic acid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([Cl:10])=[C:8]([CH2:11][N:12]2[CH2:18][CH2:17][C:16](=[O:19])[N:15]([CH3:20])[CH2:14][CH2:13]2)[CH:7]=[CH:6][N:5]=1.Cl[C:22]1[S:23][C:24]([C:27]#[N:28])=[CH:25][N:26]=1>C1COCC1>[Cl:10][C:9]1[C:4]([NH:3][C:22]2[S:23][C:24]([C:27]#[N:28])=[CH:25][N:26]=2)=[N:5][CH:6]=[CH:7][C:8]=1[CH2:11][N:12]1[CH2:18][CH2:17][C:16](=[O:19])[N:15]([CH3:20])[CH2:14][CH2:13]1
Reactant: N#Cc1cnc(Cl)s1
Reactant: CN1CCN(Cc2ccnc(N)c2Cl)CCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccnc(Nc3ncc(C#N)s3)c2Cl)CCC1=O
Temperature: 25 °C

Procedure:
NaH (0.016 g, 0.40 mmol) was stirred in anhydrous THF, 1.5 mL, under N2. 1-(2-Amino-3-chloro-pyridin-4-ylmethyl)-4-methyl-[1,4]diazepan-5-one (0.045 g, 0.17 mmol) was added followed after 10 min by the addition of 2-chloro-thiazole-5-carbonitrile (0.034 g, 0.23 mmol) and the reaction was heated to reflux. After 4 h the reaction was cooled to RT and quenched by the addition of water. The pH was adjusted to 7 with 1M HCl and the mixture was extracted 3× with EtOAc. The organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative reverse phase HPLC to afford a colorless oil. The residue was azeotroped 3× with MeOH and the resulting residue was dissolved in a minimum of MeOH. The solvent slowly evaporated to afford a white solid which was further dried in vacuo. TFA salt: 1H NMR (CD3OD) δ8.46 (d, 1H, J=5.1 Hz), 8.12 (s, 1H), 7.34 (d, 1H, J=5.1 Hz), 4.43 (s, 2H), 3.75 (m, 2H), 3.36 (m, 4H), 3.02 (s, 3H), 2.88 (m, 2H). MS [M+H]+=377.2.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]([F:16])([F:15])[F:14])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:23][O:24][CH2:25]Br.CCOC(C)=O>CN(C=O)C.CCOCC.C(Cl)(Cl)Cl.CCCCCC>[CH3:23][O:24][CH2:25][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]([F:16])([F:14])[F:15])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=c1cc(C(F)(F)F)c2ccc(O)cc2o1
Reactant: COCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COCOc1ccc2c(C(F)(F)F)cc(=O)oc2c1
Reaction time: 0.75 h
Yield: 4 %

Procedure:
7-Methyloxymethyloxy-4-trifluorocoumarin (MOMFC) was prepared as follows: A mixture of 7-hydroxy-4-trifluoromethylcoumarin (230 mg, 1 mmol) and K2CO3 (248 mg, 1.5 mmol), in DMF (15 mL) was vigorously stirred at 0–5° C. for 25 min. Bromomethyl methyl ether (0.97 mL, 10.0 mmol), was then added quickly to the reaction. The bright yellow mixture was stirred at 0–5° C. for 45 min during which time the reaction turned to a colorless solution. The reaction was allowed to continue to stir at 0–5° C. while monitoring by TLC (Rf=0.54, 1:1 EtOAc/:Hexane and Rf=0.24, CHCl3) and stopped at the time when product decomposition was detected. The reaction was then brought up in Et2O (35 mL), extracted with 30 mL of a saturated NaHCO3 solution. The aqueous layer was extracted two more times with Et2O (30 mL), the ether fractions were then combined, dried with anhydrous NaSO4, filtered and evaporated under reduced pressure. Chromatography of the crude product on silica gel (gradient 0–5% MeOH in CHCl3) gave 11 mg of the purified 7-methyloxymethyloxy-4-trifluoromethylcoumarin (MOMFC) as a white solid. 1H NMR (500 MHz, CDCl3): δ 03.49 (s, 3H), 5.26 (s, 2H), 6.64 (s, 1H), 7.08–7.02 (m, 2H), 7.64 (d, 1H).
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][CH2:5][CH2:6][OH:7].S(O[CH:19]([CH2:21][O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:20])(C1C=CC(C)=CC=1)(=O)=O.Cl>O1CCOCC1>[OH:3][CH2:4][CH2:5][CH2:6][O:7][CH:19]([CH2:21][O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:20]
Reactant: OCCCO
Reactant: Cc1ccc(S(=O)(=O)OC(C)COC(C)(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(COC(C)(C)C)OCCCO
Yield: 43.8 %

Procedure:
Potassium hydroxide (274.27 g) and HO(CH2)3OH (371.93 g) were added to dioxane (3 L), and then TsOCH(CH3)CH2OC(CH3)3 (700 g) prepared in Example 2-1 was added gradually. The reaction solution was refluxed with heating for 16 hours, allowed to cool, and poured onto ice (500 g), neutralized with 2 N hydrochloric acid, concentrated and filtered to remove the precipitated salt. The filtrate was extracted with dichloromethane (250 mL), and the organic layer was washed with water (500 mL) repeatedly 17 times. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated with an evaporator, and the concentrate was purified by silica gel chromatography to give the title compound (203.77 g). The NMR spectrum data of the product were as follows.
Reaction SMILES: BrC1C=CC(S([O:11][C@@H:12]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]2)(=O)=O)=CC=1.[Br:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[NH:35][C:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[CH:33][C:32]2=O.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN1CCCC1.O>[Br:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[C:34]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH:33]=[C:32]2[O:11][C@H:12]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C@H:14]([C:24]([O:26][CH3:27])=[O:25])[CH2:13]1
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Reactant: COc1cc2[nH]c(-c3ccccc3)cc(=O)c2cc1Br
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)c(Br)cc23)CN1C(=O)OC(C)(C)C
Temperature: 45 °C
Reaction time: 15 h
Yield: 92.1 %

Procedure:
To a solution of the product from Step 4 (19.4 g, 41.7 mmol) and 6-bromo-7-methoxy-2-phenylquinolin-4(1H)-one (Step 3, 13.5 g, 40.9 mmol) in N-methylpyrrolidine (200 mL) was added cesium carbonate (20.0 g, 61.3 mmol). The reaction mixture was then heated at 45° C. with stirring for 15 hours and cooled to RT. The reaction mixture was poured into EtOAc and water, and the white solids removed by filtration. The layers were separated, and the organic phase washed with saturated aqueous NaHCO3, water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica (gradient elution 10% to 50% EtOAc in hexanes) to give the title compound (21.0 g) as a pale yellow solid. LRMS (M+H)+ Calcd.: 557.1; found 557.3.
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.[CH2:6]([NH:13][C:14]([C:16]1[S:20][C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH:23](Br)[C:22]2=[O:28])=[N:18][C:17]=1[CH3:29])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([NH:13][C:14]([C:16]1[S:20][C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([NH:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)[C:22]2=[O:28])=[N:18][C:17]=1[CH3:29])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCC1CC1
Reactant: Cc1nc(N2CCCC(Br)C2=O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(N2CCCC(NCC3CC3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 69 %

Procedure:
Following the procedure as described in Example 5, making variation as required to use cyclopropylmethanamine in place of 2-cyclopropylethanamine to react with N-benzyl-2-(3-bromo-2-oxopiperidin-1-yl)-4-methylthiazole-5-carboxamide in place of 2-(3-bromo-2-oxopyrrolidin-1-yl)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 69% yield: mp 125-126° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.38-7.29 (m, 5H), 5.95 (t, J=5.5 Hz, 1H), 4.56 (d, J=5.5 Hz, 2H), 4.37-4.26 (m, 1H), 4.04-3.91 (m, 1H), 3.54-3.45 (m, 1H), 2.63 (s, 3H), 2.59-2.44 (m, 2H), 2.31-1.82 (m, 4H), 1.81-1.68 (m, 1H), 1.01-0.89 (m, 1H), 0.57-0.41 (m, 2H), 0.23-0.08 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 171.5, 162.5, 156.7, 152.2, 137.9, 128.8, 127.9, 127.7, 119.6, 58.5, 52.5, 47.6, 44.1, 26.4, 20.5, 17.4, 11.2, 3.6, 3.3; MS (ES+) m/z 399.3 (M+1).
Reaction SMILES: O.[CH:2](/[CH:7]1[CH:11]=[CH:10][CH2:9][C:8]1=[O:12])=[CH:3]/[CH2:4][CH2:5][CH3:6].C(O)(=O)C.[C-:17]#[N:18].[Na+]>C(O)C>[CH:2](/[CH:7]1[CH:11]([C:17]#[N:18])[CH2:10][CH2:9][C:8]1=[O:12])=[CH:3]/[CH2:4][CH2:5][CH3:6]
Reactant: CCC/C=C\C1C=CCC1=O
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCC/C=C\C1C(=O)CCC1C#N
Temperature: 35 °C

Procedure:
Into a 500 ml reaction flash equipped with mechanical stir, immersion thermometer, water cool bubble condenser, 150 ml addition funnel and heating mantle is placed 10 grams (0.07 moles) of 2-(2-cis-pentenyl)-3-cyclopenten-1-one prepared according to Example B; (0.07 moles); 4.20 grams of glacial acetic acid (0.07 moles) and 245 ml of 95% aqueous ethanol. The reaction mass is heated to 35° C. and, dropwise with stirring while keeping the temperature between 35° and 37° C., 6.86 grams (0.14 moles) of sodium cyanide (dissolved in 75 ml water) is added. After addition, the reaction mass is stirred at a temperature of 35° C. for a period of 3.5 hours.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][CH2:26][CH2:27]Cl)=[CH:19][CH:18]=1>>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][CH2:26][CH2:27][O:1][C:2]2[C:3]([CH3:15])=[CH:4][C:5]3[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:12])([CH3:13])[C:6]=3[CH:14]=2)=[CH:19][CH:18]=1
Reactant: Cc1cc2c(cc1O)C(C)(C)OC(=O)N2
Reactant: Cc1ccc(SCCCCCl)cc1
Product: Cc1ccc(SCCCCOc2cc3c(cc2C)NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 4 from 6-hydroxy-4,4,7-trimethyl-4H-3,1-benzoxazin-2-one and 4-(4-methyl-phenylmercapto)-butylchloride.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][N:14](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:13]([C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6])#[N:14]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(C)nc(Cl)c1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(C)nc(C#N)c1
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
Under N2, methyl 2-chloro-6-methylisonicotinate (CAS 3998-90-1) (1.000 g, 5.39 mmol, Eq: 1.00), zinc cyanide (759 mg, 6.47 mmol, Eq: 1.2) and Tetrakis-triphenylphosphin-palladium (623 mg, 539 μmol, Eq: 0.1) were mixed in DMF (17 ml). The RM was stirred under microwave at 160° C. for 30 minutes. Control with TLC: the reaction was finished. The RM was partitioned between EtOAc and water; extracted; the organic phase was dried over MgSO4; filtered; concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 100 g, 5% to 30% EtOAc in heptane). Purple solid. MS (ISP): 177.2 ([M+H]+)