Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[CH3:10])C=O.O.C1(C)C=CC(S(O)(=O)=[O:21])=CC=1.OO.S([O-])([O-])=O.[Na+].[Na+]>C1COCC1.CO>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([OH:21])[CH:7]=[C:8]([CH3:11])[C:9]=1[CH3:10]
Reactant: Cc1cc(C=O)c(C)c(Br)c1C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(O)c(C)c(Br)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 30 %

Procedure:
To a solution of 3-bromo-2,4,5-trimethylbenzaldehyde obtained in Reference Example 67 (32.0 g, 141 mmol) in THF (100 mL) was added methanol (200 mL) with ice-cooling, followed by addition of p-toluenesulfonic acid monohydrate (5.40 g, 28.4 mmol) with ice-cooling. Hydrogen peroxide (30%, 24.0 g, 212 mmol) was added dropwise to the reaction solution at 10° C. or lower, and the mixture was warmed to room temperature and stirred for 12 hours. Then the reaction solution was stirred at 50° C. for 36 hours, followed by addition of an aqueous sodium sulfite solution, and methanol and THF were distilled off under reduced pressure. The residue was extracted with ethyl acetate, the organic layer was washed with water and a saturated brine, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 9.1 g (yield 30%) of the title compound. Melting point: 86-88° C.
Reaction SMILES: C[C:2]1[C:10]2[C:6](=[N:7][NH:8][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[Cl:11][O-].[Na+]>>[Cl:11][N:9]1[C:10]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[N:7]=[N:8]1
Reactant: [O-]Cl
Reactant: Cc1cccc2n[nH]nc12
Agent: [Na+]
Product: Cln1nnc2ccccc21

Procedure:
The Performance of Tolytriazole in the Presence of Sodium Hypochlorite Under Simulated Field Conditions, NACE Corrosion/83, Paper No.283, (1983).
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.[C:29]([OH:34])(=[O:33])[CH:30]([CH3:32])O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[CH3:28][Si:2]([CH3:1])([CH3:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH:30]([C:29]([OH:34])=[O:33])[CH3:32])=[O:23])=[CH:25][CH:26]=1
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: CC(O)C(=O)O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(OC(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1)C(=O)O

Procedure:
A flask containing 10.0 g. 4-[14-(trimethylsilyl)tetradecylamino]benzoic acid, 3.4 g. lactic acid, 500 mg. toluenesulfonic acid and 500 ml. toluene is equipped with a Soxhlet extractor charged with activated 4A Linde molecular sieves. The solution is refluxed for 24 hours, during which time the Soxhlet extractor is charged twice more with fresh sieves. The hot solution is filtered and allowed to cool, whereupon the product separates as off-white crystals.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:10](OCC)=[O:11].B.CSC.[OH-].[Na+]>CC1CCCO1>[Br:1][C:2]1[N:6]([CH:7]([CH3:8])[CH3:9])[N:5]=[CH:4][C:3]=1[CH2:10][OH:11]
Reactant: CCOC(=O)c1cnn(C(C)C)c1Br
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: CC1CCCO1
Solvent: CSC
Product: CC(C)n1ncc(CO)c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a solution of ethyl 5-bromo-1-isopropyl-1H-pyrazole-4-carboxylate (163 g, 0.50 mol) in 2-methyl tetrahydrofuran (400 mL) was added borane-DMS (140 mL, 1.50 mol) at 0° C., under argon (effervescence ceased after 50 mL was added). The mixture was stirred at room temperature for 30 minutes and then heated to 70° C. for 2 hours, and then to reflux for 17 hours. Additional portion of borane DMS (40 mL) was added and the mixture was stirred at reflux for an additional 3 hours. The mixture was cooled to room temperature then added gradually to ice-cold methanol (500 mL) with stirring, over a period of 30 minutes. The mixture was stirred at room temperature for 30 minutes then 2 M aqueous sodium hydroxide (1.5 L) was added. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×500 mL). The organic layers were combined, washed with brine (500 mL), dried over magnesium sulfate, filtered and the solvent removed in vacuo. The crude product was purified by dry flash chromatography (0-50% ethyl acetate in heptane) to give (5-bromo-1-isopropyl-1H-pyrazol-4-yl)methanol (70.8 g, 65% over two steps). +ESI (M+H) 220.9; 1H NMR (400 MHz, CDCl3, δ): 7.52 (s, 1H), 4.67 (m, 1H), 4.47 (s, 2H), 2.59 (br. s., 1H), 1.41 (s, 6H).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[Br:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O>CN(C)C(=O)C>[Br:25][C:26]1[CH:27]=[C:28]([CH:29]=[N:1][N:2]2[C:7](=[O:8])[C:6]([C:9]3[NH:14][C:13]4[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=4[S:11](=[O:20])(=[O:19])[N:10]=3)=[C:5]([OH:21])[C:4]3[S:22][CH:23]=[CH:24][C:3]2=3)[CH:31]=[CH:32][CH:33]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1N=Cc1cccc(Br)c1
Temperature: 25 °C

Procedure:
The product of Example 268D (0.115 g, 0.30 mmol) was reacted with 3-bromobenzaldehyde (0.555 g, 3.0 mmol) in N,N-dimethylacetamide (2 mL) in a sealed tube at 135° C. for 30 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with ethyl acetate (3 mL) and filtered to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:43][C:44]1[C:45](F)=[CH:46][C:47]([F:71])=[C:48]([S:50]([N:53]([CH2:60][C:61]2[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][C:62]=2[O:69][CH3:70])[C:54]2[N:59]=[CH:58][CH:57]=[CH:56][N:55]=2)(=[O:52])=[O:51])[CH:49]=1>CS(C)=O>[Cl:43][C:44]1[CH:49]=[C:48]([S:50]([N:53]([CH2:60][C:61]2[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][C:62]=2[O:69][CH3:70])[C:54]2[N:55]=[CH:56][CH:57]=[CH:58][N:59]=2)(=[O:51])=[O:52])[C:47]([F:71])=[CH:46][C:45]=1[O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH:19]=1
Reactant: COc1ccc(CN(c2ncccn2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3cc(-c4ccc(C(F)(F)F)cc4)ccc3O)ccn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncccn2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc3-c3ccnc(N4CCN(C(=O)OC(C)(C)C)CC4)c3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.6 %

Procedure:
tert-Butyl 4-(4-(4-hydroxy-4′-(trifluoromethyl)biphenyl-3-yl)pyridin-2-yl)piperazine-1-carboxylate (Preparation 114, 240 mg, 0.480 mmol) was dissolved in dimethyl sulfoxide (3 mL) and then potassium carbonate (133 mg, 0.962 mmol) followed by 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-2-yl)benzenesulfonamide (Preparation 13, 219 mg, 0.480 mmol) were added. The reaction mixture was stirred at room temperature for 20 hours. The reaction was then partitioned between ethyl acetate (15 mL) and 2M HCl (5 mL). The organic layer was separated and dried over anhydrous MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel (gradient: 5-60% ethyl acetate in heptane) to give the title compound (380 mg, 84%) as a yellow foam.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]2[C:9]([C:10]=1[C:11](=[O:15])[C:12]([NH2:14])=[O:13])=[CH:8][C:7]([N+:16]([O-:18])=[O:17])=[CH:6][CH:5]=2.[BH4-].[Na+]>CCO>[CH3:1][C:2]1[N:3]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]2[C:9]([C:10]=1[CH:11]([OH:15])[C:12]([NH2:14])=[O:13])=[CH:8][C:7]([N+:16]([O-:18])=[O:17])=[CH:6][CH:5]=2
Reactant: Cc1c(C(=O)C(N)=O)c2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(C(O)C(N)=O)c2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a mixture of 1.04 g (3.1 mmol) of 2-methyl-5-nitro-1-(phenylmethyl)-1H-indole-3-glyoxylic acid amide in 30 mL of EtOH was added 148 mg (3.9 mmol) of NaBH4, the mixture stirred for 1.0 hour and concentrated at reduced pressure. The residue was stirred with water and EtOAc and the insoluble material filtered to give 1.05 mg (100% yield of 2-methyl-5-nitro-1-(phenylmethyl)-1H-indole-3-glycolic acid amide, mp, 120°-124° C.
Reaction SMILES: ClC1C=CC(C(C2C=CC(Cl)=CC=2)[N:9]2[CH2:12][CH:11]([CH2:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10]2)=CC=1.[BH4-].[Na+].C1(S(C=C2CNC2)(=O)=O)C=CC=CC=1.S([O-])([O-])(=O)=O.[Mg+2]>C(O)C.ClCCl.O>[C:17]1([S:14]([CH2:13][CH:11]2[CH2:12][NH:9][CH2:10]2)(=[O:16])=[O:15])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=S(=O)(CC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1ccccc1
Agent: O=S(=O)(C=C1CNC1)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: O=S(=O)(CC1CNC1)c1ccccc1
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
1-[Bis(4-chlorophenyl)methyl]-3-(phenylsulfonylmethyl)azetidine may be prepared by carrying out the procedure in the following manner: 13 mg of sodium borohydride are added, under argon, to a solution of 0.15 g of 1-[bis(4-chlorophenyl)methyl)]-3-(phenylsulfonylmethylene)azetidine in 3 cm3 of anhydrous ethanol and 3.5 cm3 of anhydrous dichloromethane. After stirring for 1 hour and 45 minutes, 14 mg of sodium borohydride are again added and then the mixture is kept stirring for 20 hours at 20° C. The reaction mixture is then heated to 50° C., supplemented with 9.5 mg of sodium borohydride and kept stirred for 2 hours and 30 minutes at 50° C. and then cooled to room temperature. 0.5 cm3 of water, 10 cm3 of dichloromethane and then 50 mg of magnesium sulfate are then added to the mixture, filtered and then evaporated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 15 cm, diameter 1 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 5-cm3 fractions. Fractions 12 to 19 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 29 mg of 1-[bis(4-chlorophenyl)methyl)]-3-(phenylsulfonylmethyl)azetidine are obtained in the form of a white solid [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): from 2.75 to 8.90 (mt: 3H); 3.32 (mt: 2H); 3.37 (d, J=7 Hz: 2H); 4.22 (s: 1H); from 7.20 to 7.30 (mt: 8H); 7.57 (broad t, J=7.5 Hz: 2H); 7.67 (tt, J=7.5 and 1.5 Hz 1H); 7.88 (broad d, J=7.5 Hz: 2H)].
Reaction SMILES: C1(COC([NH:11][CH2:12][C:13]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]2[C:21]([O:23]C)=O)=[O:14])=O)C=CC=CC=1>CO>[C:21]1(=[O:23])[NH:11][CH2:12][C:13](=[O:14])[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]12
Reactant: COC(=O)[C@H]1CCCCN1C(=O)CNC(=O)OCc1ccccc1
Solvent: CO
Product: O=C1NCC(=O)N2CCCC[C@H]12
Yield: 76.3 %

Procedure:
Methyl (2R)-1-(N-{[(phenylmethyl)oxy]carbonyl}glycyl)-2-piperidinecarboxylate (2.029 g, 6.068 mmol) was dissolved in MeOH (30 mL), degassed and placed under argon. 10% Pd/C (610 mg) was added, and the contents were thoroughly degassed and placed under a hydrogen balloon for 3 h. The contents were then degassed, and the Pd/C was removed by filtration through Celite, washing with MeOH. The filtrate was concentrated in vacuo to provide pure (9aR)-tetrahydro-2H-pyrido[1,2-a]pyrazine-1,4(3H,6H)-dione (779 mg, 76%). LCMS: (M+H)+: 169.1.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([S:11]([O:14][C:15]3[CH:16]=[C:17]([CH:24]=[C:25]([CH3:27])[CH:26]=3)[O:18][CH2:19][CH2:20][CH2:21][O:22][NH2:23])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[ClH:28].N1C=CC([C:34]([NH2:36])=[NH:35])=N1>CN(C)C=O>[ClH:28].[CH:1]1[C:10]2[C:5](=[C:6]([S:11]([O:14][C:15]3[CH:16]=[C:17]([CH:24]=[C:25]([CH3:27])[CH:26]=3)[O:18][CH2:19][CH2:20][CH2:21][O:22][NH:23][C:34]([NH2:36])=[NH:35])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Cc1cc(OCCCON)cc(OS(=O)(=O)c2cccc3cnccc23)c1
Reactant: N=C(N)c1cc[nH]n1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(OCCCONC(=N)N)cc(OS(=O)(=O)c2cccc3cnccc23)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.4 %

Procedure:
To a solution of 3-[3-(5-isoquinolinylsulfonyloxy)-5-methylphenoxy]propoxyamine (100 mg, 0.25 mmol), as prepared in the preceding step, in N,N-dimethylformamide (4 mL) was added 1H-pyrazole-carboxamidine hydrochloride (150 mg, 1.0 mmol). The reaction mixture was stirred at ambient temperature for two days. N,N-Dimethylformamide was removed under high vacuum. Acetonitrile (5 mL) was added and the solid was removed by filtration. The filtrate was concentrated in vacuo and the residue was dried under high vacuum. The residue was partitioned between water (20 mL plus 2 mL brine) and diethyl ether (10 mL). The water solution was extracted with diethyl ether (10 mL). The combined diethyl ether extracts were extracted with pH 5 water. The combined water solution was basified (pH 8-9) by using 2 N NaOH and extracted with ethyl acetate (3×30 mL). The ethyl acetate solution was washed with pH 7 buffer solution (2×20 mL) and brine (20 mL) then dried over Na2SO4. After removing the solvent, 0.6 N HCl methanol (3 mL) was added, and the solution was concentrated to give the title compound as colorless foam (95 mg, 81%). 1H-NMR (300 MHz, DMSO-d6) δ11.16 (br s, 1H), 9.75 (s, 1H), 8.89 (d, J=6.3 Hz, 1H), 8.73 (d, J=8.3 Hz, 1H), 8.46 (m, 4H), 7.93 (t, J=7.9 Hz, 1H), 7.72 (br s, 4H), 6.71 (s, 1H), 6.33 (s, 1H), 6.27 (s, 1H), 3.88 (m, 4H), 2.13 (s, 3H), 1.94 (m, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C20H22N4O5S: 431.1 (M+H), 453.1 (M+Na). Found: 431.2, 453.3.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CCCCCC.[S:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[CH2:19][CH2:18]1.C([C:30]([O:32][CH3:33])=[O:31])#N.[Cl-].[NH4+]>O1CCCC1>[O:27]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:17][CH2:18][CH:19]1[C:30]([O:32][CH3:33])=[O:31]
Reactant: O=C1CCSc2ccccc21
Reactant: COC(=O)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)C1CSc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dry tetrahydrofuran (60 ml) was cooled under nitrogen atmosphere to −50 to −60° C. 1M Lithium bis(trimethylsily)amide solution in hexane (56 ml, 56 mmol) was added. The temperature was kept at −50 to −60° C. and thiochroman-4-one was added dropwise over 20 min. Stirring was continued at low temperature for 60 min. Methyl cyanoformate (4.84 ml, 60.9 mmol) was added dropwise over 5 min to the reaction mixture. The obtained suspension was stirred at −50 to −60° C. for 80 min and then allowed to warm up to room temperature. Saturated ammonium chloride solution (100 ml) was added. The phases were separated, the aqueous phase extracted with ethyl acetate (2×100 ml). The combined organic phases were washed with water (50 ml), dried over magnesium sulphate, filtered and concentrated under vacuum. An orange oil was obtained and purified by column chromatography. The title compound was isolated as a yellow solid (4.70 g, 21.1 mmol, 42%). LCMS: m/z 221 [M−H]+. Intermediate 7: Preparation of 4-(3-Oxo-3a,4-dihydro-3H-thiochromeno[4,3-c]pyrazol-2-yl)-benzoic Acid
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:24]([CH3:25])=[C:23]([CH3:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[C:24]([CH3:25])=[C:23]([CH3:26])[S:22][C:12]=2[N:13]=1
Reactant: NCc1ccccc1
Reactant: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3ccccn3)nc(NCc3ccccc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-2-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-benzylamino-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=1[Cl:34])[C:20](=O)[CH3:21])C>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][C:25]=1[Cl:34])=[C:20]([CH3:21])[NH:13]2
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Reactant: CCOC(=O)C(Cc1ccc(S(C)(=O)=O)cc1Cl)C(C)=O
Solvent: O
Product: COC(=O)COc1ccc(Cl)c2[nH]c(C)c(Cc3ccc(S(C)(=O)=O)cc3Cl)c(=O)c12
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-chlorophenoxy)acetic acid methyl ester (0.85 g), 2-(2-chloro-4-methanesulfonylbenzyl)-3-oxobutyric acid ethyl ester (2.1 g) and polyphosphoric acid (10 g) was heated at 130° C. for 2 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel to afford title compound, 0.35 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([S:18]([CH3:21])(=[O:20])=[O:19])=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].CO.[OH-].[Na+].Cl>ClCCl.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([S:18]([CH3:21])(=[O:20])=[O:19])=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(-n2nnnc2S(C)(=O)=O)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COc1ccc(-n2nnnc2S(C)(=O)=O)cc1C(=O)O
Reaction time: 18 h

Procedure:
Combine methyl 2-methoxy-5-(5-methylsulfonyl-1H-tetrazol-1-yl)benzoate (5 mmol), methanol (10 mL), and a 1 M aqueous sodium hydroxide solution (6 mL, 6.0 mmol). After 18 hours, evaporate in vacuo to give a residue. Combine the residue, water (5 mL) and acidify by dropwise addition of a 1 M aqueous hydrochloric acid solution (6.5 mL). Evaporate in vacuo to give a residue. Combine the residue and dichloromethane and stir. Decant and add dichloromethane and stir. Decant and combine with the first decantate. Dry over Na2SO4, filter, and concentrate in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C2C(=CC=CC=2)C=CC=1.[Cl-].[CH2:31]([O:33][C:34](=[O:40])/[CH:35]=[CH:36]/[C:37](O)=[O:38])[CH3:32]>C(O)C>[C:34]([O:33][CH2:31][CH3:32])(=[O:40])/[CH:35]=[CH:36]/[C:37]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:38]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: CCOC(=O)/C=C/C(=O)O
Agent: [Cl-]
Solvent: c1ccc2ncccc2c1
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCOC(=O)/C=C/C(=O)OCC
Reaction time: 2 h

Procedure:
135 g (0.5 mole) of 1-octadecanol and 65 ml (0.55 mole) of quinoline are dissolved, with stirring, at 40° C. in 500 ml of ethanol-free chloroform. Over the course of one hour, 89.4 g (0.55 mole) of fumaric acid monoethylesterchloride were added drop by drop to the clear solution and it was boiled for 2 hours under reflux. The reaction mixture was diluted with 500 ml of petroleum ether and extracted twice with 0.5N hydrochloric acid, water, 5% potassium carbonate solution and water, dried over sodium sulfate and concentrated under reduced pressure. The solid residue was recrystallized from 95% ethanol. Yield: 139 g of product having a melting point of 42° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1)=O.[C:22]([O:29][CH3:30])(=[O:28])[CH2:23][CH2:24][C:25]([CH3:27])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:30][O:29][C:22](=[O:28])[CH2:23][C:24]1[C:11]([C:13]2[CH:21]=[CH:20][C:16]3[O:17][CH2:18][O:19][C:15]=3[CH:14]=2)=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:25]=1[CH3:27]
Reactant: COC(=O)CCC(C)=O
Reactant: Nc1sc2c(c1C(=O)c1ccc3c(c1)OCO3)CCCC2
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc2c(c1)OCO2)CCCC3
Yield: 82.9 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(benzo[d][1,3]dioxol-5-yl)methanone (0.301 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol), chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane furnished 0.328 g (83%) of the title compound as a yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH:13]1([Mg]Cl)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(OCC)C>[CH2:10]([O:9][C:7](=[O:8])[C:6]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([OH:12])[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH3:11]
Reactant: CCOC(=O)C(=O)c1cccs1
Reactant: Cl[Mg]C1CCCCC1
Solvent: CCOCC
Product: CCOC(=O)C(O)(c1cccs1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred, cooled (0° C.) solution of ethyl thiophene-2-glyoxylate (125.6 g, 0.683 mol) in diethyl ether (2 litres) is added dropwise 2M cyclohexyl magnesium chloride in ether (400 ml, 0.8 mol) over 1 hour. After stirring at room temperature for 2 hours, the reaction is quenched by addition of saturated ammonium chloride solution (1 litre of a 270 g/l solution) and water (1 litre) ensuring the temperature does not rise above 20° C. The organic portion is separated and washed with brine (1 litre), dried over magnesium sulphate and concentrated in vacuo, to yield the titled compound as an orange oil which is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16](=O)[NH:15][N:14]=1)=O.P(Cl)(Cl)([Cl:22])=O>S1(CCCC1)(=O)=O>[Cl:22][C:16]1[CH:17]=[CH:18][C:13]2[N:14]([C:9]([CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[N:11][CH:12]=2)[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(Cc1ccccc1F)NCc1ccc(=O)[nH]n1
Solvent: O=S1(=O)CCCC1
Product: Fc1ccccc1Cc1ncc2ccc(Cl)nn12
Temperature: 100 °C
Reaction time: 3 h

Procedure:
65.00 g (248.79 mmol) of the compound obtained in Example 2A were initially charged in sulfolane (780 ml), 185.52 ml (1.990 mol) of phosphorus oxychloride were added and the mixture was then stirred at 100° C. for 3 h. Excess phosphorus oxychloride was then distilled off under high vacuum, and the residue was taken up in ethyl acetate and added to a saturated aqueous sodium bicarbonate solution. The mixture was diluted with water and then extracted with ethyl acetate. The organic phases were combined, washed with water, dried and concentrated. The residue was purified by chromatography on silica gel (mobile phase:dichloromethane/methanol 20:1→5:1 (v/v)), then washed once more with water and purified once more by chromatography on silica gel (mobile phase:dichloromethane/methanol 100:1 v/v). This gave 23.6 g of the target compound (36% of theory).