Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:13][CH2:14][C:15]([NH2:17])=[O:16])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.C[O:19][C:20](=O)[C:21]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=O.CC(C)([O-])C.[K+].Cl>O1CCCC1.C(OCC)(=O)C>[C:1]1([CH2:13][C:14]2[C:15](=[O:16])[NH:17][C:20](=[O:19])[C:21]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][CH:24]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: NC(=O)CCc1cn2c3c(cccc13)CCC2
Reactant: COC(=O)C(=O)c1c[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1NC(=O)C(c2c[nH]c3ccccc23)=C1Cc1cn2c3c(cccc13)CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
To a solution of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-propionamide (249 mg, 1.1 mmol) and (1H-indol-3-yl)-oxo-acetic acid methyl ester (244 mg, 1.2 mmol) in anhydrous tetrahydrofuran (10 ml) at 0° C. was added potassium tert-butoxide (4.36 ml, 4.36 mmol; 1M in tetrahydrofuran). The mixture was allowed to warm to room temperature for 2 hours. Concentrated hydrochloric acid (4 ml) was added and the mixture stirred at room temperature for a further 30 minutes. The mixture was poured into ethyl acetate (250 ml), washed with water (750 ml) and purified by flash column chromatography (SiO2, 30 to 40% EtOAc in hexanes) to afford 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-ylmethyl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione as an orange foam (226 mg). 400 MHz 1H NMR (CDCl3) δ: 8.54 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.53 (d, J=3.2 Hz, 1H), 7.42 (m, 1H), 7.3-7.25 (m, 1H), 7.21-7.17 (m, 1H), 7.09 (dd, J=1.6 and 7.2 Hz, 1H), 6.92-6.86 (m, 2H), 4.15-4.04 (m, 4H), 2.95 (t, J=6.4 Hz, 2H), 2.22-2.16 (m, 2H); LCMS: 382 [M+H].
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[C:12](Cl)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cu](C#N)[C:19]#[N:20]>CN(P(N(C)C)(N(C)C)=O)C>[C:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:19]#[N:20])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#C[Cu]C#N
Reactant: Clc1cccc2c(-c3ccccc3)nccc12
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#Cc1cccc2c(-c3ccccc3)nccc12

Procedure:
1-Amino-2-(2-chlorophenyl)ethane and benzoyl chloride were reacted in the same way as in step (a) of Example 13 to afford 1-benzoylamino-2-(2-chlorophenyl)-ethane having a melting point of 70.1° to 71.0° C. (b) 1-Benzoylamino-2-(2-chlorophenyl)ethane, phosphorus oxychloride and phosphorus pentoxide were reacted in the same way as in step (b) of Example 13 to afford 1-phenyl-5-chloro-3,4-dihydroquinoline as an oil. (c) 1-Phenyl-5-chloro-3,4-dihydroisoquinoline and diphenyl disulfide were reacted in the same way as in step (c) of Example 13 to afford 1-phenyl-5-chloroisoquinoline as colorless needles having a melting point of 66.0° to 66.6° C. (d) 1-Phenyl-5-chloroisoquinoline, copper cyanide and hexamethylphosphotriamide were reacted in the same way as in step (d) of Example 13 to afford 1-phenyl-5-cyanoisoquinoline as an oil. (e) 1-Phenyl-5-cyanoisoquinoline was treated in the same way as in step (e) of Example 13 to afford 1-phenyl-5-methoxycarbonylisoquinoline as colorless needles having a melting point of 102.2° to 103.1° C. (f) 1-Phenyl-5-methoxycarbonylisoquinoline and dihydrobis(2-methoxyethoxy)aluminum sodium (in 70% benzene) were reacted in the same way as in step (f) of Example 13 to afford 1-phenyl-5-hydroxymethylisoquinoline as colorless plates having a melting point of 97.3° to 97.9° C. (g) 1-Phenyl-5-hydroxymethylisoquinoline was treated in the same way as in step (g) of Example 13 to afford 1-phenyl-5-chloromethylisoquinoline having a melting point of 104.0° to 104.2° C. (h) 1-Phenyl-5-chloromethylisoquinoline was treated by the same way as in step (h) of Example 13 to afford 1-phenylisoquinoline-5-acetonitrile as an oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[C:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)#[N:22]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([C:21]#[N:22])=[CH:24][CH:25]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: N#Cc1ccc(C(=O)NCC(=O)NC(c2ccccc2)c2ccc(Cl)cc2)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-cyanobenzoic acid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[N+:6]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1O)=[CH:16][CH:15]=[C:14]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:13]=2)([O-:8])=[O:7]>CN(C)C=O>[Cl:3][C:18]1[C:17]2[C:12](=[CH:13][C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: O=[N+]([O-])c1cnc2cc(-c3ccccc3)ccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2cc(-c3ccccc3)ccc2c1Cl
Reaction time: 1.5 h

Procedure:
A solution of phosphorous oxychloride (3.1 g, 20 mmol) in anhydrous N,N-dimethylformamide (DMF, 14 mL) was added to a suspension of 3-nitro-7-phenylquinolin-4-ol (5.0 g, 18.8 mmol) in 80 mL of DMF over 3 min. The reaction was allowed to stir for 1.5 h and then poured into 250 mL crushed ice. The resulting precipitate was collected by filtration, washed with H2O, and dried under vacuum for 2 h. The crude 4-chloro-3-nitro-7-phenylquinoline thus obtained was used without further purification.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][CH3:20])[C:7]2=[O:21])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[N:37][C:38]([NH2:41])=[CH:39][CH:40]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[N:37][C:38]([NH:41][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([CH2:19][CH3:20])[C:7](=[O:21])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:39][CH:40]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Solvent: Cc1ccccc1
Product: CCc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 105 °C
Yield: 15 %

Procedure:
4-[6-(8-Cyclopentyl-6-ethyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester was prepared by addition of 8-cyclopentyl-6-ethyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.80 g, 2.62 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.82 g, 6.55 mmol) to toluene (10 ml) followed by heating to 105° C. over 10 hours. The resulting suspension was filtered, the solid washed with toluene and dried in vacuo yielding 4-[6-(8-Cyclopentyl-6-ethyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a solid (0.204 g). MS (APCI); M++1; Calc'd 520.3. Found 520.1.
Reaction SMILES: [N:1]#[C:2]Br.[C:4]1([C:10]2([CH2:19][CH2:20][N:21](C)[CH3:22])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][CH2:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)(Cl)Cl>[C:4]1([C:10]2([CH2:19][CH2:20][N:21]([C:2]#[N:1])[CH3:22])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#CBr
Reactant: CN(C)CCC1(c2ccccc2)COc2ccccc21
Solvent: ClC(Cl)Cl
Product: CN(C#N)CCC1(c2ccccc2)COc2ccccc21
Yield: 83.5 %

Procedure:
A solution of 10.9 g (103 mmole) cyanogen bromide and 23 g (86 mmole) of 2-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N,N-dimethylethylamine in 500 ml CHCl3 was refluxed for 4 hours. The solvent was evaporated and the resultant oil warmed to reflux in 500 ml water. After cooling, the mixture was extracted with CH2Cl2 (2×1 liter), and the organics were washed with 1N HOAc (3×1 liter) and dried over K2CO3. Evaporation gave 20 g of an oil, which was chromatographed on 200 g silica gel using CH2Cl2 as an eluent to give 11 g of an oil which solidified on standing. Recrystallization from acetone/hexane gave 7.1 g (30%) of crystals, m.p. 88°-92°.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:10]=[O:11])=[C:5](Cl)[C:6]=1[C:7]#[N:8].[S:12]([O-:15])([O-:14])=[O:13].[Na+:16].[Na+].Cl>O>[NH2:1][C:2]1[S:3][C:4]([CH:10]=[O:11])=[C:5]([S:12]([O-:15])(=[O:14])=[O:13])[C:6]=1[C:7]#[N:8].[Na+:16]
Reactant: N#Cc1c(N)sc(C=O)c1Cl
Reactant: O=S([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#Cc1c(N)sc(C=O)c1S(=O)(=O)[O-]
Temperature: 0 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
93.3 parts of 2-amino-4-chloro-3-cyano-5-formylthiophene, 126 parts of sodium sulfite and 300 parts of water are heated at the boil for 2 hours, after which 200 parts of concentrated hydrochloric acid are added to the ice-cooled mixture, and the mixture is left to stand overnight. Thereafter, the mixture is filtered under suction, and the residue is washed with a little ice water and dried. 85 parts (67% of theory) of sodium 2-amino-3-cyano-5-formylthien-4-ylsulfonate are obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].CS[C:17]1[NH:22][C:21](=[S:23])[C:20]([CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[CH:19][N:18]=1>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]2[NH:22][C:21](=[S:23])[C:20]([CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[CH:19][N:18]=2)[N:9]=1)[CH3:1]
Reactant: CSc1ncc(Cc2cccnc2)c(=S)[nH]1
Reactant: CN(C)Cc1nc(CSCCN)cs1
Solvent: c1ccncc1
Product: CN(C)Cc1nc(CSCCNc2ncc(Cc3cccnc3)c(=S)[nH]2)cs1

Procedure:
Following the procedure of Example 12, a mixture of 1.11 g. of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine and 1.24 g. of 2-methylthio-5-(3-pyridyl)methyl-4-pyrimidinethione in 15 ml. of pyridine was refluxed for 2 days. The desired reaction product was purified by gradient elution high pressure liquid chromatography over silica using an ethyl acetate/ethanol/ammonium hydroxide solvent system as the eluant. Fractions shown by tlc to contain 2-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(3-pyridyl)methyl-4-pyrimidinethione free base were combined and the solvent removed by evaporation.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[NH:16][CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)=[CH:3][CH:2]=1.[H-].[Na+].[C:19]1([S:25][CH2:26][CH2:27]Br)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[ClH:29]>O.CN(C)C=O>[ClH:29].[C:19]1([S:25][CH2:26][CH2:27][N:16]2[C:9]3=[N:8][C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[CH:12][C:11](=[O:13])[N:10]3[CH2:14][CH2:15]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=c1cc(-c2ccncc2)nc2n1CCN2
Reactant: BrCCSc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(-c2ccncc2)nc2n1CCN2CCSc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.2 g (0.93 mmol) of 7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one in ml of anhydrous N,N-dimethylformamide was added 48.5 mg (1.21 mmol) of sodium hydride (60% suspension in mineral oil) and the resulting mixture was heated at 70° C. during 30 min. There was added 0.32 g (1.49 mmol) of 2-bromoethyl phenyl sulfide and heating was continued at 130° C. during 1 h. Water was added to the cooled mixture and the resulting solution extracted with ethyl acetate. The combined extracts were washed with water and evaporated. The crude product was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol/diethylamine in the proportions 98/2/0.2 to obtain pure compound as free base. The compound was converted to the hydrochloride salt by addition of hydrochloric acid to an isopropylic solution of the free base. There is obtained 0.11 g of product as a yellow solid.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:4]=1)[NH2:2].[C:19](OC(OCC)OCC)(=O)C>>[F:16][C:15]([F:18])([F:17])[C:11]1[CH:10]=[C:9]([C:5]2[N:4]3[CH:19]=[N:2][N:1]=[C:3]3[CH:8]=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: NNc1ccnc(-c2cccc(C(F)(F)F)c2)n1
Reactant: CCOC(OCC)OC(C)=O
Product: FC(F)(F)c1cccc(-c2nccc3nncn23)c1

Procedure:
The general procedure of Example 1 is repeated: A solution of 0.300 g. of 4-hydrazino-2-[3-(trifluoromethyl)phenyl]pyrimidine and 1 ml. of diethoxymethyl acetate is stirred at room temperature for 24 hours. The mixture is diluted with an excess of petroleum ether and the precipitate which forms is collected after 20-30 minutes to give 0.182 g. of the product of the example; m.p. 145°-146° C. when recrystallized from chloroform/hexane.
Reaction SMILES: [CH2:1]([C:3]([CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=O)([CH:6]=[CH:7][CH2:8][CH3:9])[CH:4]=O)[CH3:2].Cl.C(Cl)Cl>COCCOC.[Zn]>[CH2:6]([C:3]1([CH2:1][CH3:2])[CH:4]=[CH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][CH2:10]1)[CH2:7][CH2:8][CH3:9]
Reactant: CCC=CC(C=O)(CC)CSc1ccccc1C=O
Agent: Cl
Agent: [Zn]
Solvent: ClCCl
Solvent: COCCOC
Product: CCCCC1(CC)C=Cc2ccccc2SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 141.6 %

Procedure:
A mixture of 2.6 g (0.04 mole) of zinc dust, 7.2 g (0.047 mole) of TiCl3, and 50 mL of DME was held at reflux for 2 h and cooled to room temperature. To this mixture was added 2.4 g (8.6 mmole) of 17 in 20 mL of DME in 10 min. The reaction mixture was stirred at room temperature for 2 h and held at reflux for 1 h then was let standing at room temperature over weekend. The reaction mixture was poured into dilute HCl and was stirred with methylene chloride. The methylene chloride-water mixture was filtered through Celite. The methylene chloride layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give 3.0 g of residue. Purification by HPLC gave 0.41 g (20%) of 18 as an oil in the early fraction.
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3[C:29]2[CH:34]=[C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[N:32]=[C:31](S(C)(=O)=O)[N:30]=2)=[N:8][N:9]=1)([CH3:3])[CH3:2].[CH:49]([NH2:52])([CH3:51])[CH3:50]>CN1C(=O)CCC1.O>[CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3[C:29]2[CH:34]=[C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[N:32]=[C:31]([NH:52][CH:49]([CH3:51])[CH3:50])[N:30]=2)=[N:8][N:9]=1)([CH3:2])[CH3:3]
Reactant: CC(C)N
Reactant: COc1ccc(COc2cc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ccc(-c5nnc(NC(C)C)o5)cc34)nc(S(C)(=O)=O)n2)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(COc2cc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ccc(-c5nnc(NC(C)C)o5)cc34)nc(NC(C)C)n2)cc1
Temperature: 120 °C
Yield: 86.1 %

Procedure:
A glass microwave reaction vessel was charged with N-isopropyl-5-(3-(6-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (120 mg, 0.174 mmol) and isopropylamine (0.075 mL, 0.871 mmol) in NMP (1.0 mL). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 1 h. The mixture was diluted with water and filtered. The remaining solid was dried to give the crude product (100 mg), which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 668.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][NH2:8])=[CH:4][C:3]=1[O:11][CH3:12].C([O:15][C:16](=O)[CH:17]=[C:18]([NH2:22])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:22][C:18]1[NH:8][N:7]([CH2:6][C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([O:11][CH3:12])[CH:4]=2)[C:16](=[O:15])[CH:17]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: COc1cc(CNN)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: COc1cc(Cn2[nH]c(N)cc2=O)ccc1Cl
Reaction time: 8 h

Procedure:
59 g of 4-chloro-3-methoxybenzylhydrazine were added dropwise, under nitrogen, to a solution of 50.5 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1.5 g of p-toluenesulphonic acid in 250 ml of ethanol. After standing overnight, the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 148°, 30 g. (38%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[N:8]([CH3:11])C=O.[F:12]/[CH:13]=[C:14](\[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)/CO.O>C1(C)C=CC=CC=1>[NH2:8][CH2:11]/[C:14](=[CH:13]/[F:12])/[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1
Reactant: OC/C(=C/F)CCc1ccc(F)cc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: NC/C(=C/F)CCc1ccc(F)cc1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
Combine oxalyl chloride (25.2 g, 0.198 mol) and toluene (200 mL). Cool to -5° C. Add N,N-dimethylformamide (15.0 g, 0.21 mol) as a solution in toluene (20 mL). Warm to 25° C. After 30 minutes, add a solution of (E)-2-(fluoromethylene)-4-(p-fluorophenyl)butan-1-ol (24.7 g, 30% by weight in toluene, 0.124 mol). After 18 hours, add water (500 mL) and stir for 30 minutes. Separate the organic layer, dry over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:42])C=1>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N+:8]([O-:42])=[CH:7][C:6]=2[N:15]=1)[CH3:2]
Reactant: CCc1nc2cnc3ccccc3c2n1CCCCN(C(=O)OC(C)(C)C)C1CCOCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCc1nc2c[n+]([O-])c3ccccc3c2n1CCCCN(C(=O)OC(C)(C)C)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl [4-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]tetrahydro-2H-pyran-4-ylcarbamate in chloroform was added m-chloroperbenzoic acid (4 eq.) and stirred at ambient temperature for 2 hrs. Reaction mixture was then diluted with chloroform and washed with saturated sodium bicarbonate solution. Organic layer was dried over sodium sulphate and concentrated under reduced pressure to yield sticky mass. Product was then purified using silica gel column chromatography to afford tert-butyl [4-(2-ethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)butyl]tetrahydro-2H-pyran-4-ylcarbamate.
Reaction SMILES: [F:1][CH:2]([F:37])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([F:36])=[C:17]([C@:19]34[O:27][CH2:26][CH2:25][C@H:24]3[CH2:23][S:22][C:21]([NH:28]C(=O)OC(C)(C)C)=[N:20]4)[CH:18]=2)=[O:11])=[N:8][CH:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][C:21]1[S:22][CH2:23][C@@H:24]2[CH2:25][CH2:26][O:27][C@:19]2([C:17]2[CH:18]=[C:13]([NH:12][C:10](=[O:11])[C:7]3[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:37])[F:1])=[CH:9][N:8]=3)[CH:14]=[CH:15][C:16]=2[F:36])[N:20]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(NC(=O)c4ccc(OC(F)F)cn4)ccc3F)OCC[C@H]2CS1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1=N[C@@]2(c3cc(NC(=O)c4ccc(OC(F)F)cn4)ccc3F)OCC[C@H]2CS1
Yield: 145.1 %

Procedure:
A solution of tert-butyl ((4aR,7aR)-7a-(5-(5-(difluoromethoxy)picolinamido)-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (6 mg, 0.011 mmol) and TFA (17.17 μL, 0.223 mmol) in DCM (111 μL) was stirred at rt for 3 h, and the solvents were removed to give N-(3-((4aR,7aR)-2-amino-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-(difluoromethoxy)picolinamide (7 mg) as its TFA salt as a colorless oil. 1H NMR (500 MHz, METHANOL-d4) 8.60 (br. s., 1H), 8.29 (br. s., 1H), 8.18 (dd, J=7.1, 2.7 Hz, 1H), 7.94-7.87 (m, 1H), 7.84 (dd, J=8.6, 1.6 Hz, 1H), 7.31-7.22 (m, 1H), 7.10 (t, J=75 Hz, 1H), 4.33-4.19 (m, 2H), 3.46 (dd, J=13.6, 3.8 Hz, 1H), 3.34-3.25 (m, 1H), 3.18-3.09 (m, 1H), 2.32 (q, J=7.0 Hz, 2H). MS (M+H)+: 439.11.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@@H:11]2[CH2:13][C@H:12]2[CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[N:3]1.[Xe](F)[F:20]>C(#N)C.C(=O)([O-])O.[Na+]>[F:20][C:10]1[N:2]([CH3:1])[N:3]=[C:4]2[C:9]=1[C:8]([C@@H:11]1[CH2:13][C@H:12]1[CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:7][CH:6]=[CH:5]2
Reactant: F[Xe]F
Reactant: CC(=O)NC[C@@H]1C[C@H]1c1cccc2nn(C)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)NC[C@@H]1C[C@H]1c1cccc2nn(C)c(F)c12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 5.6 %

Procedure:
To a solution of trans-N-{[2-(2-methyl-2H-indazol-4-yl)cyclopropyl]methyl}acetamide (400 mg, 1.644 mmol) in acetonitrile (16 mL) was added xenon difluoride (306 mg, 1.808 mmol), and the mixture was stirred under nitrogen atmosphere at room temperature for 4.5 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=50/50→100/0), HPLC and TLC to give the title compound (24 mg, yield 6%).
Reaction SMILES: [CH2:1]([C:3]1[S:19][C:6]2[N:7]=[C:8]3[CH:15]=[CH:14][C:13]([C:16]([NH2:18])=O)=[CH:12][N:9]3[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[S:19][C:6]2[N:7]=[C:8]3[CH:15]=[CH:14][C:13]([C:16]#[N:18])=[CH:12][N:9]3[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(=O)n3cc(C#N)ccc3nc2s1
Yield: 96.3 %

Procedure:
From 1.3 g (0.0048 mol) of 2-ethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide (Example 22), 30 ml of phosphorus oxychloride and 30 ml of chloroform and refluxing on a steam bath for six hours, following the procedure of Example 27, there is obtained 1.18 g of 2-ethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile; mp 223°-224° C. after recrystallization from glacial acetic acid.
Reaction SMILES: COC(=O)C1C=CC=C([Cl:10])C=1OC.I[C:15]1[CH:20]=[CH:19][C:18]([C:21](C)([CH3:28])[CH2:22][C:23](=[O:27])[C:24]([OH:26])=[O:25])=[C:17]([O:30][CH3:31])[CH:16]=1>>[Cl:10][C:16]1[C:17]([O:30][CH3:31])=[C:18]([CH:21]([CH3:28])[CH2:22][C:23](=[O:27])[C:24]([OH:26])=[O:25])[CH:19]=[CH:20][CH:15]=1
Reactant: COc1cc(I)ccc1C(C)(C)CC(=O)C(=O)O
Reactant: COC(=O)c1cccc(Cl)c1OC
Product: COc1c(Cl)cccc1C(C)CC(=O)C(=O)O

Procedure:
This ester is reacted analogously to the process that is described for 4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid. 8 g of the title compound is obtained as a light yellow oil.