Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]([O:8]C(=O)C)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13].[CH:19](=[N:25]/O)\[C:20]1[O:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.O>N1C=CC=CC=1>[F:1][C:2]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]([O:8]/[N:25]=[CH:19]/[C:20]2[O:24][CH:23]=[CH:22][CH:21]=2)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13]
Reactant: CCOC(=O)C1(F)C(=O)NC(=O)NC1OC(C)=O
Reactant: O/N=C/c1ccco1
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)C1(F)C(=O)NC(=O)NC1O/N=C/c1ccco1
Temperature: 25 °C
Reaction time: 15 h
Yield: 52.4 %

Procedure:
In 20 ml of pyridine were dissolved 5.24 g (20 mmol) of ethyl 5-fluoro-6-acetoxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate and 2.62 g (23.6 mmol) of (E)-furfuraldoxime, and 2.02 g (20 mmol) of triethylamine was added to the solution, followed by stirring at room temperature for 15 hours. The reaction solution was poured into 200 ml of ice-cooled water, and crystals precipitated were collected by filtration and washed with water. The crystals were dried under reduced pressure and recrystallized from ethanol to give 3.28 g of ethyl 5-fluoro-6-(E)-furfurylideneaminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate. m.p. 189°-190° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6]2.[Na].C(O)CC(C)C.Cl>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH2:7][CH2:6]2
Reactant: COC(=O)C(C)c1ccc2cc(OC)ccc2c1
Agent: Cl
Agent: [Na]
Solvent: CCOCC
Solvent: CC(C)CCO
Product: COC(=O)C(C)C1=Cc2ccc(OC)cc2CC1

Procedure:
A mixture of 24.4 g. of methyl 6-methoxy-2-naphthyl-α-methylacetate, 25 g. of sodium metal, and 500 ml. of anhydrous iso-amyl alcohol are refluxed for 18 hours. The cooled reaction mixture is acidified by the addition of aqueous 1N hydrochloric acid. The product is isolated by diethyl ether extraction to give methyl 6-methoxy-3,4-dihydro-2-naphthyl-α-methylacetate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[NH:25])[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32]([O:34][C:35](=[O:41])[C:36](=O)[CH:37](Br)[CH3:38])[CH3:33]>C1COCC1>[CH2:32]([O:34][C:35]([C:36]1[N:25]=[C:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[N:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:13]=2)[C:37]=1[CH3:38])=[O:41])[CH3:33]
Reactant: CCOC(=O)C(=O)C(C)Br
Reactant: N=C(Nc1ccc(OCc2ccccc2)cc1)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(OCc3ccccc3)cc2)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To N-(4-benzyloxyphenyl)-2,4-dichlorobenzamidine, from Ex. 1, Step 1 (6.88 g, 18.5 mmol) dissolved in 50 ml THF was added potassium carbonate (2.56 g, 18.5 mmol) and the suspension was stirred for 10 minutes. Ethyl-3-bromo-2-oxobutanoate (4.65 g, 22.2 mmol) was dropwise added over 1 hour, and the mixture was stirred for 66 hours at room temperature. The solution was filtered and evaporated to dryness. The residue was dissolved in acetic acid and refluxed for 1 hour. The mixture was cooled to room temperature, 100 ml water added and the product extracted with EtOAc (2×200 ml). The combined organic phases were washed with saturated sodium hydrogen carbonate, dried (Na2SO4), filtered and concentrated. Flash chromatography (silica, hexane:EtOAc 70:30, 60:40) afforded 5.75 g (65%) of the title compound as a pale yellow solid.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](OCC)=[O:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:33]([O:50][CH2:51][CH2:52][NH2:53])([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C[Al](C)C.C(O)(=O)C.C(OCC)(=O)C>C1C=CC=CC=1>[Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:29])[NH:53][CH2:52][CH2:51][O:50][Si:33]([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:27]=2)[CH2:20]1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCCN)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: C[Al](C)C
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(C)(C)[Si](OCCNC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Subsequently, to a solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (1.16 g, 2.49 mmol) (obtained as described in Reference Example 2(1)) in benzene (8.5 ml) was added a solution of 0.67M 2-(t-butyldiphenylsilyloxy)ethylamine-trimethylaluminium in benzene (6.42 ml) at room temperature under an atmosphere of nitrogen. The mixture was heated under reflux for 5 hours. After checking the completion of the reaction, 10% aqueous acetic acid solution (50 ml) and ethyl acetate (200 ml) were added to the reaction mixture, and the resulting mixture was stirred at room temperature for 1 hour. After adding ethyl acetate thereto, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (3:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-{4-[2-(t-butyldiphenylsilyloxy)ethylcarbamoyl]-1,3-thiazol-2-yl}azetidine (1.68 g, yield 94%) as a pale brown solid.
Reaction SMILES: [OH:1][NH:2][CH2:3][CH2:4][CH2:5][P:6](=[O:9])([OH:8])[OH:7].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[OH:1][N:2]([CH2:3][CH2:4][CH2:5][P:6](=[O:8])([OH:7])[OH:9])[C:29](=[O:30])[NH:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=P(O)(O)CCCNO
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N(O)CCCP(=O)(O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 39 %

Procedure:
A mixture of 3-(N-hydroxyamino)propylphosphonic acid (1.64 g), dichloromethane (30 ml) and bis(trimethylsilyl)acetamide (10 g) was stirred at ambient temperature for 3 hours. The mixture was cooled to 0-5° C. and phenyl isocyanate (1.80 g) was added thereto. The reaction mixture was stirred at the same temperature for an hour and at ambient temperature for 3 hours and then allowed to stand overnight. The resultant mixture was concentrated under reduced pressure. To the residue was added water (60 ml), and then the mixture was stirred at ambient temperature for 3 hours. Insoluble materials were removed by filtration and the filtrate was washed twice with ethyl acetate (50 ml). To the aqueous layer was added an additional 90 ml of water, whereafter the aqueous solution was subjected to a column chromatography using activated charcoal. The object compound was eluted with 70% aqueous acetone. The eluate was evaporated to dryness under reduced pressure, whereafter the resulting crystals were washed with acetone and dried to give crystalline 3-(N-hydroxy-N-phenylcarbamoylamino)propylphosphonic acid (1.13 g). Mp 126-130° C. (dec.)
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[C:8](=[O:22])[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:10]=1[CH3:11])=O.[CH:37]([NH2:39])=[O:38].C1(C)C(C)=CC=CC=1.OS(O)(=O)=O>O.CC#N>[CH3:11][C:10]1[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[C:8](=[O:22])[C:7]([C:23]([NH:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:31][CH:32]=2)=[O:24])=[CH:6][C:5]=1[C:3]1[N:39]=[CH:37][O:38][CH:2]=1
Reactant: Cc1c(C(=O)CBr)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: NC=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Solvent: Cc1ccccc1C
Product: Cc1c(-c2cocn2)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 25.5 %

Procedure:
A mixture of 5-(bromoacetyl)-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (Example 50 (c), 100 mg, 0.17 mmol), formamide (135 μl, 3.4 mmol), xylene (300 μl) and conc. H2SO4 (10 μl) was heated with stirring for 2 h. The reaction was diluted with water and CH3CN and purified on preparative HPLC, affording the title compound (23 mg, 31%).
Reaction SMILES: C(O[C:4](=O)[CH:5]([Na])[C:6]([O:8]CC)=[O:7])C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:31])[C:21]2[CH:26]=C(Cl)[CH:24]=[CH:23][C:22]=2[N+:28]([O-:30])=[O:29])=[CH:16][CH:15]=1.O.C(O)(=O)C>C(OCC)(=O)CC(OCC)=O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([C:21]2[CH:26]=[C:4]([CH2:5][C:6]([OH:8])=[O:7])[CH:24]=[CH:23][C:22]=2[N+:28]([O-:30])=[O:29])=[O:31])=[CH:18][CH:19]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)C([Na])C(=O)OCC
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1ccc([N+](=O)[O-])c(C(=O)c2ccc(Cl)cc2)c1
Temperature: 90 °C

Procedure:
To a solution of 0.0175 mole of diethylsodiomalonate in 250 ml of diethyl malonate under nitrogen atmosphere at 80° C. was added 20.7 g (0.07 mole) of 4',5-dichloro-2-nitrobenzophenone. The mixture was heated at 90° C. for 2 hr, then poured into water and neutralized with glacial acetic acid. The mixture was extracted with diethyl ether and then washed and dried over sodium sulfate; extracts were concentrated and excess diethyl malonate removed by distillation. The residue was chromatographed eluting with 50-75% isopropyl ether in hexane and the appropriate fraction collected. This material was hydrolyzed by heating at reflux in a mixture of 150 ml of dioxane and 80 ml of 6N hydrochloric acid for 6 hr. The reaction mixture was diluted with water and extracted with diethyl ether. The ether extracts were washed with dilute sodium hydroxide and the basic washings were combined, acidified and extracted with diethyl ether-isopropyl ether to give after recrystallization from 80% aqueous methanol, 6.2 g of title compound as tan crystals, m.p. 182.0°-183.0° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([NH2:14])[C:3]=1[C:4]([OH:6])=[O:5].[C:15](=O)([O-])O.[Na+].C(=O)=O.S(OC)(OC)(=O)=O.[Na]>CC(C)=O.O>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([NH2:14])[C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: Cc1c([N+](=O)[O-])ccc(N)c1C(=O)O
Reactant: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COC(=O)c1c(N)ccc([N+](=O)[O-])c1C

Procedure:
49.7 g (0.253 mol) of 2-methyl-3-nitro-6-aminobenzoic acid are dissolved in 380 ml of acetone and 43 g (0.51 mol) of sodium hydrogen carbonate are added. The mixture is then heated to boiling until evolution of CO2 is complete. 35.3 g (0.28 mol) of dimethyl sulfate are then added in the course of two hours at the boiling point of acetone to the suspension of the sodium salt of 2-methyl-3-nitro-6-aminobenzoic acid thus obtained, and the mixture is subsequently refluxed 30 for a further three hours and then allowed to cool. After pouring the reaction mixture into 1.8 l of water, it is extracted with methylene chloride. After drying the organic phase, it is concentrated. The solid obtained is sufficiently pure for the subsequent reaction (NMR). Yield: 50 g (0.238 mol)=94% of theory, m.p.: 92°-94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([N:23]4[CH2:28][CH2:27][N:26]([CH2:29][C:30]([OH:32])=O)[CH2:25][CH2:24]4)=[O:22])=[CH:17][CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1.C1C=C[C:36]2N(O)N=[N:39][C:37]=2C=1.CCN=C=NCCCN(C)C.C(N)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([N:23]4[CH2:24][CH2:25][N:26]([CH2:29][C:30]([NH:39][CH2:37][CH3:36])=[O:32])[CH2:27][CH2:28]4)=[O:22])=[CH:19][CH:20]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CN1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(Cl)cc4)n3)cc2)CC1
Reactant: On1nnc2ccccc21
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)CN1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(Cl)cc4)n3)cc2)CC1
Reaction time: 0.5 h

Procedure:
2-{4-[(4-{[4-(4-Chlorophenyl)pyrimidin-2-yl]amino}phenyl) carbonyl]piperazinyl}acetic acid (0.200 g, 0.44 mmol) was dissolved in DMF then stirred for 15 minutes in ice-brine solution, then the HOBT (0.072 g, 0.53 mmol] then EDCI (0.102 g, 0.53 mmol) were added and stirred for another 30 minutes. Ethylamine (0.030 mL, 0.53 mmol) was added and the reaction was left to stir at room temp overnight. The reaction was quenched with 10 mL of water and a precipitate formed. The precipitate was colleted by filtration, and purified by preparative HPLC to yield 2-{4-[(4-{[4-(4-chlorophenyl)pyrimidin-2-yl]amino}phenyl)carbonyl]piperazinyl}N-ethylacetamide: HPLC Retention time; 9.508 min.(Method B) M+1; 479.2
Reaction SMILES: [Na].[Br:2][C:3]1[C:4](=[O:18])[N:5]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[N:6]=[CH:7][C:8]=1Br.[CH3:19][OH:20]>>[Br:2][C:3]1[C:4](=[O:18])[N:5]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[N:6]=[CH:7][C:8]=1[O:20][CH3:19]
Reactant: O=c1c(Br)c(Br)cnn1-c1cc(Cl)cc(Cl)c1
Reactant: CO
Agent: [Na]
Product: COc1cnn(-c2cc(Cl)cc(Cl)c2)c(=O)c1Br

Procedure:
Sodium (0.28 g, 0.012 moles) was dissolved in methanol (100 ml) and a suspension of 4,5-Dibromo-2-(3,5-dichlorophenyl)pyridazin-3-one (4.0 g, 0.01 moles) in methanol (60 ml) was added. Refluxed overnight. Evaporated to dryness and added water. Filtered off the solid and dried in a dessicator. Triturated with ether and dried in a dessicator. (3.1 g, 89%)
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:41][CH3:42])=[C:38]([OH:40])[CH:39]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]([O:41][CH3:42])=[C:38]([OH:40])[CH:39]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: COc1ccc(CCN)cc1O
Product: COc1ccc(CCNc2nccc(-c3cccc(CN(CCCN)S(C)(=O)=O)c3)n2)cc1O

Procedure:
Intermediate 4 from above was coupled with 5-(2-Amino-ethyl)-2-methoxy-phenol following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 486. 1H NMR (Varian 300 MHz, CDCl3—CD3OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.1 (m, 2H) 8.0 (d, 1H) 7.6 (m, 1H) 7.5 (m, 1H) 7.2 (m, 1H) 6.8 (s, 1H) 6.6 (s, 2H) 4.5 (s, 2H) 3.8 (m, 2H) 3.7 (s, 3H) 3.3 (m, 2H) 2.9 (m, 7H) 1.8 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=O.ClC(Cl)(O[C:17](=[O:23])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:32]1([NH:38][CH2:39][CH2:40][NH2:41])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[NH:38]([CH2:39][CH2:40][N:41]1[C:7](=[O:9])[C:6]2[CH:5]=[C:4]([CH2:11][CH3:12])[S:3][C:2]=2[NH:1][C:17]1=[O:23])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCc1cc(C(=O)OC)c(N)s1
Reactant: NCCNc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc2c(=O)n(CCNc3ccccc3)c(=O)[nH]c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
To a solution (40 mL) of methyl 2-amino-5-ethylthiophene-3-carboxylate (0.5 g) in methylene chloride were added triphosgene (0.32 g) and triethylamine (0.59 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added N-phenylethane-1,2-diamine (1 g), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (20 mL), sodium methoxide (28% methanol solution, 1.3 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was extracted with 1N hydrochloric acid and ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained solid was recrystallized from tetrahydrofuran-hexane to give the title compound as colorless crystals (0.22 g, 25%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].[C:13]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)#[N:14]>C(Cl)Cl>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([S:21]([C:18]2[CH:17]=[CH:16][C:15]([C:13]#[N:14])=[CH:20][CH:19]=2)(=[O:23])=[O:22])[CH2:6]1
Reactant: OC1CCNC1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)N2CCC(O)C2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90.3 %

Procedure:
4-hydroxypyrrolidine (12 g, 0.14 mol), DCM (300 ml) and 1N aqueous sodium carbonate solution (200 ml) were charged to a flask and cooled to <10° C. A solution of 4-cyanobenzenesulfonyl chloride (26.8 g, 0.133 mol) in DCM (100 ml) was added drop-wise, maintaining the temperature below 10° C. (typically addition takes 40-50 min). Cooling was removed and stirring at room temperature continued for 2 h. The layers were separated, the organic layer was washed with water (2×100 ml) and concentrated in vacuo to approximately 100 ml. Hexane (about 300 ml) was added to initialise crystallisation. The precipitate was aged at 0-5° C. for 10-30 min, filtered and washed with hexane (2×100 ml) to yield 30.3 g (86%) of sulfonamide 4-[(3-hydroxy-1-pyrrolidinyl)sulfonyl]benzonitrile 23a as white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)=O)[CH:7]=[CH:8][CH:9]=1)=O.[NH3:27]>CO>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[NH:27][C:3](=[O:2])[C:5]3[N:6]([CH:7]=[CH:8][CH:9]=3)[CH:10]=2)=[CH:14][CH:15]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cccn1CC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: N
Solvent: CO
Product: O=c1[nH]c(-c2ccc(OCc3ccccc3)cc2)cn2cccc12
Temperature: 25 °C

Procedure:
A suspension of 100 mg (0.286 mmol) 1-[2-(4-benzyloxy-phenyl)-2-oxo-ethyl]-1H-pyrrole-2-carboxylic acid methyl ester in a 7 M solution of ammonia in methanol is irradiated in a microwave apparatus at 90° C. for 18 h. The reaction mixture is cooled to room temperature and evaporated. The residue is chromatographed on a silica gel column with petrolether/ethylacetate as eluent to give 3-(4-benzyloxy-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one as beige crystals; HPLC/MS 2.26 min (A), [M+H] 317.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[C:14](Cl)(=[O:17])[CH2:15][CH3:16]>ClCCl>[O:4]1[CH2:5][CH2:6][CH:2]([NH:1][C:14](=[O:17])[CH2:15][CH3:16])[CH2:3]1
Reactant: NC1CCOC1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NC1CCOC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 50 g of 3-aminotetrahydrofuran in 200 ml of dichloromethane was mixed with 63.8 g (0.63 mol) of triethylamine. 58.4 g (0.63 mol) of propionyl chloride were added dropwise with ice-cooling. The mixture was stirred at room temperature for 2 days, resulting in a white precipitate. The solution was filtered and the filtrate was distilled. B.p. 145° C. (12 mm), yield 81 g. 1H NMR (270 MHz, in CDCl3): δ=1.14 (t, 3 H), 1.83 (m, 1H), 2.22 (q, 2H), 2.31 (m, 1H), 3.64 (dd, 1H), 3.72-3.98 (m, 3H), 4.50 (m, 1H), 6.57 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]2[N:14]=[C:15](S(C)(=O)=O)[N:16]=[CH:17][C:12]=2[S:11][C:10]=1[C:22]([O:24][CH3:25])=[O:23].[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([NH:39][CH:40]=[O:41])=[C:35]([O:42][CH:43]([CH3:45])[CH3:44])[CH:34]=2)[CH2:29][CH2:28]1.CC(N=P(N1CCCC1)(N1CCCC1)N1CCCC1)(C)C>CN(C=O)C>[CH:40]([N:39]([C:36]1[CH:37]=[CH:38][C:33]([N:30]2[CH2:29][CH2:28][N:27]([CH3:26])[CH2:32][CH2:31]2)=[CH:34][C:35]=1[O:42][CH:43]([CH3:45])[CH3:44])[C:15]1[N:16]=[CH:17][C:12]2[S:11][C:10]([C:22]([O:24][CH3:25])=[O:23])=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[C:13]=2[N:14]=1)=[O:41]
Reactant: COC(=O)c1sc2cnc(S(C)(=O)=O)nc2c1-c1ccccc1OC
Reactant: CC(C)Oc1cc(N2CCN(C)CC2)ccc1NC=O
Agent: CC(C)(C)N=P(N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: COC(=O)c1sc2cnc(N(C=O)c3ccc(N4CCN(C)CC4)cc3OC(C)C)nc2c1-c1ccccc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
A mixture of 1.80 g of methyl 7-(2-methoxyphenyl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidine-6-carboxylate, 1.37 g of N-[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]formamide and 4.44 g of 1-[N-(2-methylpropan-2-yl)-P,P-di(pyrrolidin-1-yl)phosphorimidoyl]pyrrolidine (BTPP) in 50 ml of anhydrous DMF is stirred at ambient temperature for 16 h. The mixture is then evaporated under vacuum at a temperature of 55° C., and the residue is diluted with ethyl acetate and water. The aqueous phase is extracted three times with ethyl acetate. The organic phases are washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product is purified on 100 g of silica, elution being carried out with 0-2.5% of methanol containing 10% by volume of 28% aqueous ammonia solution in dichloromethane, so as to obtain 2.264 g of methyl 2-{formyl[4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(2-methoxyphenyl)thieno[3,2-d]pyrimidine-6-carboxylate in the form of a brown solid.
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:10]=1[CH2:11][NH2:12].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH:26]=O.C1(C)C=CC(S(N)(=O)=O)=CC=1>O>[F:21][C:22]([F:35])([F:36])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=1)[CH:26]=[N:12][CH2:11][C:10]1[CH:13]=[C:14]([C:17]([F:18])([F:19])[F:20])[CH:15]=[CH:16][C:9]=1[Cl:8]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NCc1cc(C(F)(F)F)ccc1Cl
Agent: Cc1ccc(S(N)(=O)=O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)c1cc(C=NCc2cc(C(F)(F)F)ccc2Cl)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a 100 mL round bottom flask, equipped with a Dean Start Trap was charged 50 mL of toluene, 5.0 gm of 2-chloro-5-trifluoromethyl benzyl amine and 5.8 gm of 3,5-bis(trifluoromethyl)benzaldehyde and 50 mg of para-toluenesulfonamide. The reaction was heated until water no longer distilled off about 3 hours, then cooled to ambient temperature and the solvent removed in vacuum. The crude product was used directly in the next step without further purification. 10.0 gm.