Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[CH:16]1[CH:21]=[N:20][CH:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=1.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[C:33]1([C:36]([N:38]2[CH2:42][CH2:41][C:40](=O)[CH2:39]2)=[O:37])[CH2:35][CH2:34]1.Cl>CCCCCC.C1COCC1>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[C:33]1([C:36]([N:38]2[CH2:39][CH2:40][C:41]3([C:17]4[CH:16]=[CH:21][N:20]=[CH:19][C:18]=4[C:22](=[O:24])[O:23]3)[CH2:42]2)=[O:37])[CH2:35][CH2:34]1
Reactant: O=C(O)c1cccnc1
Reactant: O=C1CCN(C(=O)C2(c3ccc(Cl)cc3Cl)CC2)C1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1OC2(CCN(C(=O)C3(c4ccc(Cl)cc4Cl)CC3)C2)c2ccncc21
Temperature: -55 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2,2,6,6-tetramethyl-piperidine, (1.18 mL, 0.00700 mol) in tetrahydrofuran (30 mL, 0.4 mol) at −78° C. was added n-butyllithium in hexane (2.5 M, 3.7 mL). After stirring for 15 min, a suspension of niacin (0.287 g, 0.00233 mol) in THF was added and the mixture was stirred at −78° C. for 10 min. The reaction mixture was then warmed to −55° C. for 60 min. A solution of 1-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-one (580 mg, 0.0019 mol) in THF (2 mL) was added to the above mixture and stirring was continued at −55 degrees celsius for 20 min. The reaction mixture was then allowed to warm to rt for 1 h and then acidified (pH ˜1) using 6M HCl aq. solution. The reaction mixture was stirred at rt overnight and then neutralized (pH ˜7). The product from the mixture was extracted with AcOEt. The organic extract was washed with brine, dried with MgSO4, and concentrated in-vane. The crude product was purified by Combiflash followed by separation of the enantiomers using a chrial column. LCMS: m/z 402.0 & 404.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)[N:14]=[C:13]([C:28](=O)[CH2:29][NH:30][NH:31][C:32]([NH2:34])=[O:33])[C:12]=2[N:11]2[CH2:36][CH2:37][N:38]([CH3:41])[C:39](=[O:40])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>C(O)C>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[F:26])[CH2:19][N:15]1[C:16](=[O:18])[C:17]2[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]3[C:39](=[O:40])[N:38]([CH3:41])[CH2:37][CH2:36][N:11]3[C:12]=2[C:13]([C:28]2[CH2:29][NH:30][NH:31][C:32](=[O:33])[N:34]=2)=[N:14]1
Reactant: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(C(=O)CNNC(N)=O)c32)C1=O
Solvent: CC(=O)O
Solvent: CCO
Product: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(C4=NC(=O)NNC4)c32)C1=O

Procedure:
A solution of the above hydrazinecarboxamide (0.20 g, 0.34 mmol) and glacial acetic acid (0.1 mL) in absolute ethanol (5 mL) was heated in a sealed tube in an oil bath at 100° C. overnight. The reaction mixture was concentrated under vacuum. The residue was partitioned between chloroform and aqueous sodium bicarbonate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the corresponding cyclized trazinyl intermediate. ES MS M+1=564
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:32])[C@@H:4]2[CH:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18](=[O:31])[N:5]2[C:6]=1[C:7]([O:9][CH2:10][O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:8].O1CCCC1.C(O)(=O)C>[Ni].C1(C)C=CC=CC=1.[Zn]>[CH3:1][CH:2]1[CH:6]([C:7]([O:9][CH2:10][O:11][C:12](=[O:17])[C:13]([CH3:14])([CH3:15])[CH3:16])=[O:8])[N:5]2[C:18](=[O:31])[CH:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:4]2[C:3]1=[O:32]
Reactant: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2C1=O
Agent: [Ni]
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1C(=O)[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCOC(=O)C(C)(C)C
Reaction time: 1 h

Procedure:
Freshly prepared pivaloyloxymethyl 2-methyl-1-oxo-6-(2-phenoxyacetamido)carbapen-2-em-3-carboxylate (prepared from 200 mg. of pivaloyloxymethyl 2-diazo-3-methyl-1-beta-oxo-7-(2-phenoxyacetamido)ceph-3-em-4-carboxylate (incorporating a 2 g. Raney nickel treatment into the isolation step) was taken up in 1 ml. of tetrahydrofuran and added to a stirred slurry of 2 g. of specially activated zinc powder (Example 2), in 6 ml. of acetic acid containing 30% tetrahydrofuran maintained at 0°-5° C. After stirring for 1 hour at this temperature, the reaction mixture was diluted with toluene and evaporated to dryness in vacuo to yield pivaloyloxymethyl 2-methyl-1-oxo-6-(2-phenoxyacetamido)carbapenam-3-carboxylate [Rf 0.34 (9:1 chloroform:ethyl acetate; ir (CH2Cl2) 1790, 1750, 1680 cm-1 ].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.C(C1C=NC=C(CCC(C)C)C=1)#N>>[NH2:9][CH2:8][C:6]1[CH:5]=[C:4]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=[C:2]([Br:1])[CH:7]=1
Reactant: N#Cc1cc(Br)cc(NC(=O)OCc2ccccc2)c1
Agent: CC(C)CCc1cncc(C#N)c1
Product: NCc1cc(Br)cc(NC(=O)OCc2ccccc2)c1

Procedure:
Benzyl 3-(aminomethyl)-5-bromophenylcarbamate was synthesized from benzyl 3-bromo-5-cyanophenylcarbamate following the general procedure as described for the 3-cyano-5-isopentylpyridine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=C)=[CH:7][CH:6]=1.[OH:13]C1C=CC(C=O)=CC=1>>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:13])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: C=Cc1ccc(OCCO)cc1
Product: O=Cc1ccc(OCCO)cc1

Procedure:
Woods et al. (U.S. Pat. No. 5,019,629) describe a two-step procedure for preparing p-(2-hydroxyethoxy)styrene starting with p-hydroxybenzaldehyde. In the first step, p-(2-hydroxyethoxy)benzaldehyde is formed by reacting p-hydroxybenzaldehyde with ethylene carbonate in the presence of potassium carbonate. In the second step, p-(2-hydroxyethoxy)styrene is formed by reacting the isolated p-(2-hydroxyethoxy)benzaldehyde with methyltriphenylphosphonium bromide in the presence of sodium amide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[N:18][C:17]([Cl:32])=[CH:16][CH:15]=3)=[O:10])=[CH:5][CH:4]=1.Cl[C:36](OCC)=[O:37]>>[Cl:32][C:17]1[CH:16]=[CH:15][C:14]2[N:13]=[CH:12][C:11]3[C:9](=[O:10])[N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:34][CH:33]=4)[C:36](=[O:37])[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=4)[C:20]=3[C:19]=2[N:18]=1
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(CNC(=O)c2cnc3ccc(Cl)nc3c2Nc2cccc(C(F)(F)F)c2)cc1
Product: COc1ccc(Cn2c(=O)c3cnc4ccc(Cl)nc4c3n(-c3cccc(C(F)(F)F)c3)c2=O)cc1
Reaction time: 120 h

Procedure:
N-(4-methoxybenzyl)-6-chloro-4-(3-(trifluoromethyl)phenylamino)-1,5-naphthyridine-3-carboxamide (4.5 g, 9.2 mmol) is suspended in ethyl chloroformate (50 mL). The resulting mixture was added to 90° C., stirred for 120 hrs, rotary-evaporated to remove the volatile substance, and separated by silicagel column chromatography (EtOAc/PE=0-1/4) to obtain a yellow oil of 9-chloro-3-(4-methoxybenzyl)-1-(3-(trifluoromethyl)phenyl)pyrimido[5,4-c][1,5]naphthyridine-2,4(1H,3H)-dione (700 mg).
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.[CH:15]1[C:16]([CH2:24][C@@H:25]([NH2:42])[CH2:26][C:27]([N:29]2[CH2:41][C:33]3=[N:34][N:35]=[C:36]([C:37]([F:40])([F:39])[F:38])[N:32]3[CH2:31][CH2:30]2)=[O:28])=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=1[F:21]>C(O)C>[CH:15]1[C:16]([CH2:24][C@@H:25]([NH2:42])[CH2:26][C:27]([N:29]2[CH2:41][C:33]3=[N:34][N:35]=[C:36]([C:37]([F:40])([F:39])[F:38])[N:32]3[CH2:31][CH2:30]2)=[O:28])=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=1[F:21].[C:1]([O-:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: CCO
Product: COc1cc(/C=C/C(=O)[O-])ccc1O
Reaction time: 0.25 h

Procedure:
Ferulic acid (2.0 gms) was dissolved in ethanol (10 ml) and sitagliptin free base (1.9 gms) was added to the clear solution and stirred for 15 min. Additional ethanol (10 ml) was added to the semi precipitated reaction mass and stirring was continued for 48 hours at room temperature. Precipitated solids were filtered off and dried at 70° C. to 75° C. for 24 hours to obtain the title compound. Yield: 1.37 gms.
Reaction SMILES: Cl.[C:2]([CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)#[N:3].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])Br.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])[N:10]1[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5][CH2:4][C:2]#[N:3])[CH2:12][CH2:11]1
Reactant: Clc1ccccc1C(Br)c1ccccc1Cl
Reactant: N#CCCCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: N#CCCCC1CCN(C(c2ccccc2Cl)c2ccccc2Cl)CC1

Procedure:
20 g (106 mmol) 4-(3-cyanoprop-1-yl)-piperidin hydrochloride, 40.2 g (127 mmol) bis(2-chlorophenyl)-bromomethane and 35.2 g (254 mmol) potassium carbonate are heated to boiling in 90 ml acetone for six hours. After cooling, the mixture is freed from solution under vacuum. The residue is dispersed between 90 ml tolueneand 90 ml water. The aqueous phase is extracted with 10 ml tolueneand the combined organic phases are washed with 10 ml water. The organic phase is concentrated and the residue is chromatographically purified over silica gel with CHCL3. Yield: 11.2 g (27%).
Reaction SMILES: [CH2:1]([C@H:10]1[O:12][C@H:11]1[C:13](O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:16]([N:18]([CH2:21][CH3:22])[CH2:19]C)[CH3:17].C([O:27]C(Cl)=O)C(C)C.C(NCC)C>C1COCC1.CCOCC>[CH2:16]([N:18]([CH2:21][CH3:22])[C:19]([CH2:13][C@@H:11]1[C@H:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[O:12]1)=[O:27])[CH3:17]
Reactant: CC(C)COC(=O)Cl
Reactant: CCN(CC)CC
Reactant: CCCCCCCCC[C@H]1O[C@H]1C(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCNCC
Product: CCCCCCCCC[C@@H]1O[C@@H]1CC(=O)N(CC)CC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 75 mg 90.35 mmole) of (2R-cis)-3-nonyloxiranecarboxylic acid and 0.148 ml (106 mg, 1.05 mmole) of triethylamine in 5 ml of THF was prepared under argon and cooled to 0° C. To this solution 50 mg (0.37 mmole) of isobutylchloroformate was added and the mixture was allowed to stir of 30 min. Diethylamine (0.109 ml, 76 mg, 1.05 mmole) was then added and the mixture stirred for an additional 2 hours. The reaction was diluted with 75 ml of Et2O, washed with 50 ml of saturated NaHCO3, 30 ml of brine, dried over MgSO4, filtered and evaporated to yield a clear residue. This residue was flash chromatographed (25 mm column; 5% MeOH:CHCl3) to afford 80 mg of a clear oil. 1H NMR δ 3.57 (d, 1, J=4 Hz), 3.6-3.3 (m, 4), 3.2 (m, 1), 1.6-1.2 (m, 19), 1.13 (t, 3, J=7 Hz), 0.88 (t, 3, J=7 Hz). Mass Spectra: M+(1.5)269, M-OH(1.3)252, M(100)100.1.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])#[N:2].ClCCCl.S(=O)(=O)(O)O.[N+:32]([O-])([O-:34])=[O:33].[K+]>O>[C:1]([C:3]1[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[CH:15][C:4]=1[O:5][C:6]1[CH:14]=[CH:13][C:12]([N+:32]([O-:34])=[O:33])=[C:8]([CH:7]=1)[C:9]([OH:11])=[O:10])#[N:2]
Reactant: N#Cc1cc(C(F)(F)F)ccc1Oc1cccc(C(=O)O)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCCl
Solvent: O
Product: N#Cc1cc(C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(C(=O)O)c1
Temperature: 0 °C

Procedure:
The product from (a) (9.22 g) was added in portions to a mixture of 1,2-dichloroethane (25 ml) and concentrated sulphuric acid (40 ml) stirred at 0° C. Potassium nitrate (3.13 g) was then added in portions with stirring at 0° C., over a period of 15 minutes. The mixture was then stirred at 0° C. for 30 minutes, allowed to warm to room temperature, and poured into 200 ml of ice and water. The mixture was stirred until the ice had melted, and filtered with suction. The solid which separated on evaporation of the dichloroethane was washed with water and taken up in ether. The ether solution was treated with charcoal, dried and petroleum (b.p. 40°-60° C.) added. The solid which separated was identified as the required benzoic acid derivative (7.8 g) having a melting point of 190°-192° C.
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[CH2:15]([CH:17]([N:20]1[C:28]2[N:27]3[N:29]=[C:30]([CH3:34])[C:31]([CH:32]=O)=[C:26]3[N:25]=[C:24]([CH3:35])[C:23]=2[CH2:22][CH2:21]1)[CH2:18][CH3:19])[CH3:16].[C:36]1([NH2:43])[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH2:42].[OH-].[Na+]>C(#N)C>[NH:42]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:43]=[C:32]1[C:31]1[C:30]([CH3:34])=[N:29][N:27]2[C:28]3[N:20]([CH:17]([CH2:18][CH3:19])[CH2:15][CH3:16])[CH2:21][CH2:22][C:23]=3[C:24]([CH3:35])=[N:25][C:26]=12
Reactant: Nc1ccccc1N
Reactant: CCC(CC)N1CCc2c(C)nc3c(C=O)c(C)nn3c21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCC(CC)N1CCc2c(C)nc3c(-c4nc5ccccc5[nH]4)c(C)nn3c21
Reaction time: 24 h
Yield: 17.5 %

Procedure:
DDQ (79 mg, 0.35 mmol) was added to a solution of 8-(1-ethylpropyl)-2,5-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidin-3-carbaldehyde (100 mg, 0.35 mmol) and 1,2-phenylenediamine (40 mg, 0.37 mmol) in acetonitrile (1 mL) at room temperature and the mixture was stirred for one day. Further, a 0.5N aqueous solution of sodium hydroxide was added thereto, followed by stirring for five hours. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by dry pack silica gel column chromatography (50% ethyl acetate/hexane), to give the title compound (23 mg) as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[Al](C)C.[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:15]=1[C:16]#[N:17]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.CO>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:16](=[NH:17])[C:15]2[C:14]([F:13])=[CH:21][CH:20]=[CH:19][C:18]=2[F:22])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: N#Cc1c(F)cccc1F
Agent: C[Al](C)C
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: N=C(Nc1ccc(Br)cc1)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
4-bromoaniline (1.72 g, 10 mmol) was placed into a three-neck reactor, and the reactor was flushed with argon for 20 min. 50 mL anhydrous toluene was added. After cooling to 0° C., trimethylaluminum (7.5 mL, 2.0M solution in toluene, 15 mmol) was added slowly to keep the inner temperature below 18° C. After addition, the reaction mixture was warmed to room temperature and then stirred for additional 2 hrs. A solution of 2,6-difluorobenzonitrile (2.78 g, 20 mmol) in 50 mL anhydrous toluene was added, and the reaction mixture was heated to 80° C. After 18 hrs, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in CHCl3/MeOH (4/1, VAT). After being stirring for 20 min, the mixture was filtered and the residue was washed with a mixture of CHCl3/MeOH (4/1, V/V). The combined filtrates were concentrated in vacuo, and the resulting solid was stirred with a solution of Hexane/Ether (3/1, V/V). The intermediate was filtered and washed with additional Hexane/Ether (3/1, V/V) to give a white solid (2.4 g, 79% yield), which was used directly for the next step without further purification.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].C(O[C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C.[CH2:24]([OH:26])[CH3:25]>O>[C:3]1([C:2]2[NH:10][C:24](=[O:26])[CH:25]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:9]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCO
Reactant: CCOC(=O)c1ccccc1
Reactant: N=C(N)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1cc(-c2ccccc2)nc(-c2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
Benzamidine hydrochloride (3.9 g, 24.9 mmol) was dissolved in a minimal amount of H2O (10 mL), to this was added sodium hydroxide pellets (1.0 g, 24.9 mmol, 1 eq.) dissolved in H2O (2 mL), followed by ethylbenzoate (4.53 mL, 26.1 mmol, 1.05 eq.). Ethanol was then added until a clear solution was obtained. The reaction mixture was then allowed to stir at room temperature overnight yielding a thick suspension, which was then filtered to give a white solid. After washing with diethyl ether to remove unreacted/excess β-ketoester the solid was dried in vacuo to give 57% of the desired product. 1H NMR δ (DMSO-d6): 8.31-8.18 (m, 5H, Ar), 7.60-7.54 (m, 5H, Ar), 6.92 (s, 1H, Ar).
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[O:29][CH2:28][C@:13]2([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])[N:14]=[C:15]([NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:16][C@H:17]([CH3:18])[C@@H:12]2[CH2:11]1)C1C=CC=CC=1.FC1C=C(F)C=CC=1[C@]12CO[C@@H](CO)C[C@H]1CSC(NC(=O)C1C=CC=CC=1)=N2>>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[C@:13]12[CH2:28][O:29][C@@H:10]([CH2:9][OH:8])[CH2:11][C@H:12]1[C@@H:17]([CH3:18])[S:16][C:15]([NH:19][C:20](=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[N:14]2
Reactant: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](COCc3ccccc3)C[C@@H]12
Agent: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CO)C[C@H]2CS1)c1ccccc1
Product: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CO)C[C@@H]12

Procedure:
The product was prepared from N-[(4R,4aR,6R,8aS)-6-[(benzyloxy)methyl]-8a-(2,4-difluorophenyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C18) according to the general procedure for the synthesis of N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(hydroxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (P1) in Preparation P1. In this case, the combined crude product from two similar reactions was triturated with dichloromethane rather than being purified by chromatography. The filtrate from the trituration was concentrated in vacuo, and a second crop of material was obtained via a second trituration with dichloromethane, affording the product in both cases as a white solid. Total yield: 23.12 g, 53.46 mmol, 79%. LCMS m/z 433.2 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 8.12 (br d, J=7 Hz, 2H), 7.51-7.57 (m, 1H), 7.40-7.49 (m, 3H), 7.02-7.11 (m, 2H), 4.15 (br d, J=12 Hz, 1H), 3.91 (d, J=11.9 Hz, 1H), 3.71-3.78 (m, 1H), 3.60 (d, J=5.2 Hz, 2H), 3.19-3.28 (br m, 1H), 2.97-3.06 (br m, 1H), 1.74-1.82 (m, 1H), 1.49-1.62 (m, 1H), 1.26 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:7]=[C:6]([OH:19])[CH:5]=1)([CH3:3])[CH3:2].Br[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=1>>[CH:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:7]=[C:6]([O:19][CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[CH:5]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)c1cc(O)nc(-c2cccc([N+](=O)[O-])c2)n1
Product: CC(C)c1cc(OCc2ccc(C(=O)O)cc2)nc(-c2cccc([N+](=O)[O-])c2)n1

Procedure:
The title compound was prepared from 6-isopropyl-2-(3-nitro-phenyl)-pyrimidin-4-ol (which was obtained in Intermediate 8) and methyl 4-(bromomethyl)benzoate according to Method A and Method B; LC retention time 3.40 min; MS: m/z (ESI) 394 (M+H).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[N:13][CH:12]=[CH:11]2)=[O:5].[CH3:17][Mg]Br>C1COCC1>[CH:14]1[C:15]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[C:4](=[O:5])[CH3:17])[CH:11]=[CH:12][N:13]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cccc2ccncc12
Solvent: C1CCOC1
Product: CC(=O)c1cccc2ccncc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of N-methoxy-N-methylisoquinoline-8-carboxamide (1.04 g, 4.81 mmol) in THF (40.1 ml) at 0° C. was treated with methylmagnesium bromide (11.22 ml, 33.7 mmol) in THF. Reaction was stirred at 0° C. for 1 hours before quenching with a saturated ammonium chloride solution (5 mL). After reaching RT, solution extracted with EtOAc (3×75 mL). Combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. Purified by normal phase chromatography (0-50% EtOAc in hexane) to yield 1-(isoquinolin-8-yl)ethanone as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[C:12]=2[C:21](OCC)=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[C:12]=2[C:21]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C1COCCN1
Reactant: CCOC(=O)C1=C(c2ccc(OC)c(OC)c2)c2ccccc2C1=O
Agent: Cl
Product: COc1ccc(C2=C(C(=O)N3CCOCC3)C(=O)c3ccccc32)cc1OC
Yield: 98 %

Procedure:
The indenone obtained in Example 108 (0.9 g) is heated with morpholine (10 ml) for 1 hour. The reaction mixture is poured into a solution of dilute hydrochloric acid and extracted with ethyl acetate, washed with water and concentrated. The product is obtained with a yield of 98% (m.p.=71.5°; compound no. 109).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[OH:17])[NH:8][CH:7]=1)=[O:5])C>[OH-].[Na+]>[OH:17][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][NH:8]2
Reactant: CCOC(=O)c1c[nH]c2cccc(O)c2c1=O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c[nH]c2cccc(O)c2c1=O
Yield: 87.7 %

Procedure:
A mixture of 5-hydroxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (700 mg, 3 mmol) in 10% NaOH (20 ml) was heated at reflux overnight. After cooling, the mixture was extracted with ether. The aqueous phase was separated and acidified with conc. HCl to pH 1-2. The resulting precipitate was collected via filtration to give 5-hydroxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (A-3) (540 mg, 87%). 1H NMR (DMSO-d6) δ 13.7 (br, 1 H), 13.5 (br, 1 H), 12.6 (s, 1 H), 8.82 (s, 1 H), 7.68 (t, J=8.1 Hz, 1 H), 7.18 (d, J=8.4 Hz, 1 H), 6.82 (d, J=8.4 Hz, 1 H); ESI-MS 205.9 m/z (MH+).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.C(N(CC)CC)C.[CH2:13]([C:17]1[CH:22]=[C:21](O)[N:20]2[N:24]=[CH:25][CH:26]=[C:19]2[N:18]=1)[CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1>[CH2:13]([C:17]1[CH:22]=[C:21]([Cl:3])[N:20]2[N:24]=[CH:25][CH:26]=[C:19]2[N:18]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1cc(O)n2nccc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCc1cc(Cl)n2nccc2n1

Procedure:
Phosphorus oxychloride (80 ml) and triethylamine (44 ml) were added to a toluene suspension (400 ml) containing 40 g of the crystals obtained in step (1). The reaction mixture was refluxed with heating for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was poured into ice water. The mixture was neutralized with sodium acetate and extracted with ethyl acetate. The organic layer was collected, washed with a saturated saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane=1:9) to provide 41 g of 5-n-butyl-7-chloropyrazolo[1,5-a]pyrimidine as a light yellow oily compound.