Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:31][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][C:23]4[CH:28]=[CH:27][C:26](=[O:29])[N:25]([CH3:30])[CH:24]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCN(CC)CC.[C:40]([N:44]=[C:45]=[O:46])([CH3:43])([CH3:42])[CH3:41]>CO.CN(C=O)C>[C:40]([NH:44][C:45]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[NH:31][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][C:23]4[CH:28]=[CH:27][C:26](=[O:29])[N:25]([CH3:30])[CH:24]=4)[C:16]=3[CH:15]=2)[CH2:12][CH2:13]1)=[O:46])([CH3:43])([CH3:42])[CH3:41]
Reactant: Cn1cc(Nc2ncnc3[nH]c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc23)ccc1=O
Reactant: CC(C)(C)N=C=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: Cn1cc(Nc2ncnc3[nH]c(C4=CCN(C(=O)NC(C)(C)C)CC4)cc23)ccc1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-[4-(1-Methyl-6-oxo-1,6-dihydropyridin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (38.0 mg, 0.0845 mmol), 9M of Hydrogen chloride in Methanol (2 mL) and Methanol (2 mL) were combined, and the above miture was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo to obtain a black solid. DMF (3 mL), NEt3 (58.9 μL, 0.423 mmol) and tert-butyl isocyanate (14.5 μL, 0.127 mol) were added, and the mixture was stirred at rt under N2 for 1.5 h. Another portion of tert-butyl isocyanate was added and the reaction was stirred overnight. The mixture was concentrated in vacuo, and the residue was purified by HPLC to obtain the title compound as pink solid. 1H NMR (CD3OD, 400 MHz): δ=1.36 (s, 9H), 2.56 (brs, 2H), 3.61 (m, 2H), 3.62 (s, 3H), 4.07 (brs, 2H), 6.29 (brs, 1H), 6.58 (s, 1H), 6.60 (d, 1H, J=9.6 Hz), 7.71 (dd, 1H, J=2.8 & 9.6 Hz), 8.16 (brs, 2H), 8.19 (s, 1H), 8.25 (d, 1H, J=2.4 Hz). MS (ES+): m/z 422.12 (100) [MH+]. HPLC: tR=20.11 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][NH:6][C:5](=[N:8][N+:9]([O-:11])=[O:10])[NH:4][CH2:3]1.[H-].[Na+].[Cl:14][C:15]1N=[CH:19][C:18]([CH2:21]Cl)=[CH:17][N:16]=1.O.[CH3:24]N(C)C=O.CN(C=O)C>CN(C=O)C>[Cl:14][C:15]1[CH:24]=[CH:19][C:18]([CH2:21][N:6]2[CH2:7][N:2]([CH3:1])[CH2:3][NH:4][C:5]2=[N:8][N+:9]([O-:11])=[O:10])=[CH:17][N:16]=1
Reactant: ClCc1cnc(Cl)nc1
Reactant: CN(C)C=O
Reactant: CN1CNC(=N[N+](=O)[O-])NC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CN1CNC(=N[N+](=O)[O-])N(Cc2ccc(Cl)nc2)C1
Reaction time: 5 h

Procedure:
5-Methyl-2-nitroimino-hexahydro-1,3,5-triazine (3.0 g) was dissolved in dimethylformamide/DMF (20 ml), followed by portionwise addition of sodium hydride (950 mg: oil free) thereto at a temperature in the range of from 0° to 5° C. After one hour stirring at 0° to 5° C. a solution of 2-chloro-5-chloromethyl-pyrimidine (3.1 g) in 20 ml of DMF was added dropwise to the solution, the temperature was kept constant, followed by a five hour stirring. The reaction mixture thus obtained was poured into iced water, subjected to extraction with methylene chloride a few times and then the extract was dried with anhydrous magnesium sulfate which was removed from the solvent. The thus obtained residue was purified by silica gel column chromatography (eluant: ethanol: chloroform=1: 20), to obtain the desired 1-(2-chloro-5-pyridylmethyl)-5-methyl-2-nitroimino-hexahydro-1,3,5-triazine (3.7 g) having a melting point in the range of from 160° to 161° C.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[Br:9][C:10]1[N:15]=[CH:14][C:13]2[CH:16]=[C:17]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[NH:18][C:12]=2[CH:11]=1>CN(C=O)C>[Br:9][C:10]1[N:15]=[CH:14][C:13]2[C:16]([Cl:8])=[C:17]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[NH:18][C:12]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Solvent: CN(C)C=O
Product: Cn1cc(-c2[nH]c3cc(Br)ncc3c2Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
NCS (48 mg, 0.361 mmol) was added to a solution of 6-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22, 100 mg, 0.361 mmol) in DMF (1.1 mL). The reaction mixture was stirred overnight at room temperature before being filtered on an SCX-2 column and concentrated under vacuum. The residue was purified via Biotage silica gel column chromatography eluting with (DCM/EtOH 99/1 to 95/5) to afford the title product as a white solid (86 mg, 76%). 1H NMR (500 MHz, CD3OD) δ 4.01 (s, 3H), 7.54 (d, J=0.8 Hz, 1H), 8.05 (s, 1H), 8.28 (s, 1H), 8.47 (d, J=0.8 Hz, 1H). LC (Method B)-MS (ESI, m/z) tR 2.84 min, 312 [(M+H+), 100%].
Reaction SMILES: [CH3:1][C:2](=O)[CH3:3].[NH2:5][CH2:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]2[N:14]([C:29]3[C:30]4[C@H:37]([CH3:38])[CH2:36][CH2:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:15][C:16]3([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[C:8]=12.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[Cl:13][C:12]1[C:7]([CH2:6][NH:5][CH:2]([CH3:3])[CH3:1])=[C:8]2[C:16]3([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH2:15][N:14]([C:29]3[C:30]4[C@H:37]([CH3:38])[CH2:36][CH2:35][C:31]=4[N:32]=[CH:33][N:34]=3)[C:9]2=[CH:10][CH:11]=1
Reactant: CC(C)=O
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4c3ccc(Cl)c4CN)c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)NCc1c(Cl)ccc2c1C1(CCN(C(=O)OC(C)(C)C)CC1)CN2c1ncnc2c1[C@H](C)CC2
Reaction time: 8 h
Yield: 60.3 %

Procedure:
2-Propanone (12 mg, 0.20 mmol) was added to a solution of (R)-tert-butyl 4-(aminomethyl)-5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (20 mg, 0.041 mmol) in DCE (2 mL). The reaction was allowed to stir at room temperature for 15 minutes, at which point Na(OAc)3BH was added. The reaction was allowed to stir overnight. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 solution and brine, dried with MgSO4 and concentrated. The residue was purified by column chromatography (15:1, DCM:MeOH) to give (R)-tert-butyl 5-chloro-4-((isopropylamino)methyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (13 mg, 58%) as an oil. LCMS (APCI+) m/z 526/528 [M+H]+; Rt=4.72 min. This material was taken up into DCM (2 mL), and 2N HCl in ether was added (1 mL). The reaction was allowed to stir for 1 hour, at which point it was concentrated to give (R)—N-4-((5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)propan-2-amine trihydrochloride salt (13 mg, 59%) as a solid. 1H NMR (D2O, 400 MHz) δ 8.52 (s, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 4.51-4.38 (m, 4H), 4.15 (d, J=9.6 Hz, 1H), 3.71-3.5 (m, 5H), 3.16-2.96 (m, 5H), 2.46-2.18 (m, 3H), 2.06-2.00 (m, 1H), 1.89-1.74 (m, 2H), 1.34-1.32 (m, 6H). LCMS (APCI+) m/z 426/428 [M+H]+; Rt=2.38 min.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=[O:18])[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[N+](=[CH2:23])=[N-]>CO.CCOCC>[CH3:23][O:18][C:7]1[NH:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]=2[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9](=[O:17])[CH:8]=1
Reactant: O=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC1=CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1
Reaction time: 1 h

Procedure:
To 11.4 g of 7-chloro-5-phenyl-1H-1,5-benzodiazepine-2,4-dione stirred in 150 ml methanol is added, dropwise, approximately 2.1 g of diazomethane in ether. After addition is complete, the reaction is stirred for 1 hour and filtered. The filtrate is evaporated and the residue diluted with a small amount of ether. The suspension is filtered and the filtrate evaporated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.C(N(CC)CC)C>C1COCC1>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:1][C:2]2[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=2[C:4]([NH2:6])=[O:5])=[O:21])=[CH:18][CH:17]=1
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(NC(=O)c2ccc(Cl)cc2)c(C(N)=O)cc1OC

Procedure:
As shown in scheme Q, 2-amino-4,5-dimethoxybenzamide is reacted with 4-chlorobenzoyl chloride in presence of triethyl amine and THF to give 2-((4-chlorophenyl)carbonylamino)-4,5-dimethoxybenzamide. Which is cyclised using NaOH and then treated with thionyl chloride to give 4-chloro-2-(4-chlorophenyl)-6,7-dimethoxyquinazoline (McKee, R. L. et. al., J. Am. Chem. Soc., 1946, 68, 1902-1903). The 4-chlorocompound is treated with 5-(tert-butyl)selenophene-2-carboxamide in the presence of NaOH/DMF to give 3-(2-(4-chlorophenyl)-6,7-dimethoxyquinazolin-4-ylamino)-5-tert-butylselenophene-2-carboxamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:11][CH3:12])[O:9][CH3:10])=[CH:4][CH:3]=1.[Li][CH2:14][CH2:15][CH2:16][CH3:17].[O:18]1CC(=O)C1>O1CCCC1>[CH3:10][O:9][CH:8]([O:11][CH3:12])[C:5]1[CH:6]=[CH:7][C:2]([C:17]2([OH:18])[CH2:16][CH2:15][CH2:14]2)=[CH:3][CH:4]=1
Reactant: COC(OC)c1ccc(Br)cc1
Reactant: O=C1COC1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: COC(OC)c1ccc(C2(O)CCC2)cc1
Reaction time: 0.75 h

Procedure:
To a cold (−78° C.) solution of 1-bromo-4-(dimethoxymethyl)benzene BB1a (693 mg, 3 mmol) in anhydrous tetrahydrofuran (10 mL) is added n-BuLi (2.5 M in hexanes, 1.32 mL, 3.3 mmol) and the mixture is stirred for 45 min under nitrogen atmosphere. Oxetan-3-one (216 mg, 3 mmol) in anhydrous tetrahydrofuran (2 mL) is added and the cooling bath is removed. The reaction mixture is stirred for 2 h, saturated NH4Cl (5 mL) is added and the mixture is stirred for another 15 min. Tetrahydrofuran is evaporated, water is added and the mixture is extracted with ethyl acetate (4×). The combined organic phase is dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (hexanes/ethyl acetate gradient) affords 1-(4-(dimethoxymethyl)phenyl)cyclobutanol BB1b as white crystals: 1H-NMR (400 MHz, DMSO-d6) δ=7.60 (m, 2H), 7.40 (m, 2H), 6.37 (s, 1H), 5.39 (s, 1H), 4.76 (d, J=6.8 Hz, 2H), 4.67 (d, J=6.8 Hz, 2H), 3.24 (s, 6H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[S:5]1(=[O:14])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1.[Br:15][CH2:16][C:17](Cl)=[O:18]>CN(C)C=O>[Br:15][CH2:16][C:17]([C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[CH:6][S:5](=[O:14])[C:9]=2[CH:10]=1)=[O:18]
Reactant: O=C(Cl)CBr
Reactant: O=S1C=Nc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C(CBr)c1ccc2c(c1)S(=O)C=N2

Procedure:
210 g (1.60 mol) of aluminum chloride are introduced into a 500-cm3 ground-necked flask surmounted by a condenser, and 4 3cm3 of dimethylformamide are then added dropwise and with magnetic stirring via a dropping funnel. 30.2 g (0.2 mol) of benzothiazolinone are then added and, while the reaction medium homogenizes, the temperature is stabilized at 70° C. using an oil bath. 19.8 cm3 (0.24 mol) of bromoacetyl chloride are then introduced gradually. After the addition, the mixture is left stirring for one hour at a temperature of 70° C. The reaction medium is hydrolyzed by pouring it onto crushed ice and the precipitate obtained is drained, washed copiously with water and dried. The product is recrystallized in dioxane.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].[CH3:12][O:13][C:14](=[O:17])[CH2:15]Br.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[CH3:12][O:13][C:14](=[O:17])[CH2:15][O:10][C:8]1[CH:9]=[C:2]([Cl:1])[C:3]([CH:4]=[O:5])=[C:6]([Cl:11])[CH:7]=1
Reactant: COC(=O)CBr
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cc(Cl)c(C=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,6-dichloro-4-hydroxybenzaldehyde (1.9 g, 10 mmol) and bromoacetic acid methyl ester (1.1 ml, 11 mmol) in DMF (20 ml) was added K2CO3 (2.8 g, 20 mmol). The suspension was stirred at ambient temperature overnight then the reaction mixture was partioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were dried with MgSO4, filtered and concentrated. Purification by flash chromatography using heptane/EtOAc (8:1) as eluent gave (3,5-dichloro-4-formylphenoxy)-acetic acid methyl ester as a white solid.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[CH3:5][O:6][CH:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH:12]3[CH2:17][CH2:18][O:19][C:10]([C:11]=23)=[CH:9][N:8]1[O:20][CH3:21]>O.C(O)(=O)C>[CH3:5][O:6][CH:7]1[C:16]2[CH2:15][CH:14]([C:2]([NH2:3])=[O:1])[CH2:13][CH:12]3[CH2:17][CH2:18][O:19][C:10]([C:11]=23)=[CH:9][N:8]1[O:20][CH3:21]
Reactant: COC1C2=C3C(=CN1OC)OCCC3CCC2
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC1C2=C3C(=CN1OC)OCCC3CC(C(N)=O)C2
Reaction time: 6 h

Procedure:
A solution of sodium cyanate (2.0 g) in water (20 ml) is added dropwise to a solution of 1,2,3a,4,5,6-hexahydro-7,8-dimethoxypyrano[2,3,4-de]isoquinoline (2.0 g), described in Example 56, (2.0 g) in acetic acid (8.0 ml) and water (12.0 ml). The mixture is left at room temperature for 6 hr. and the precipitate is then collected, washed with water, and crystallized from methanol to give the title compound, m.p. 224° - 226° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH2:10])=[CH:8][S:7][CH:6]=1)=[O:4].C(N(C(C)C)C(C)C)C.[Br:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29](O)=[O:30])=[N:25][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:29](=[O:30])[CH2:28][O:27][C:24]2[CH:23]=[CH:22][C:21]([Br:20])=[CH:26][N:25]=2)=[CH:8][S:7][CH:6]=1)=[O:4]
Reactant: O=C(O)COc1ccc(Br)cn1
Reactant: COC(=O)c1cscc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cscc1NC(=O)COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
To a solution of 4-amino-thiophene-3-carboxylic acid methyl ester (0.5 g, 2.58 mmol) in dimethylformamide (25 mL) was added N-ethyldiisopropylamine (2.25 mL, 12.9 mmol), (5-bromo-pyridin-2-yloxy)-acetic acid ([79674-66-1], 0.6 g, 2.58 mmol) and HATU (Acros 365312, 1.24 g, 3.23 mmol). The reaction mixture was stirred for 2 hours at room temperature. After such time water was added to the reaction mixture until precipitation occurred (sonication was also used to ease precipitation). The precipitate was then isolated by filtration and washed with a mixture of water and ethanol (3:1) to yield the title compound as a light brown solid (0.96 g, 73%).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.N1C=CC=CC=1.[N+:15]([C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1)([O-])=O.[Sn](Cl)Cl>C(Cl)(Cl)Cl.Cl>[NH2:15][C:18]1[CH:19]=[C:20]([S:24]([O:7][C:6]2[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(OS(=O)(=O)c2cccc(N)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
To 50 g (0.463 mole) of p-cresol (4-methylphenol) and 37 mL (0.458 mole) of pyridine dissolved in 250 mL of chloroform was added 50 g (0.226 mole) of 3-nitrobenzenesulfonyl chloride. The reaction was allowed to stir at ambient temperature. After 2 hours, the reaction was judged complete by TLC and the volatiles were removed by rotary evaporation. The resulting residue was treated with 400 mL of 0.5 M sodium bicarbonate. The insoluble product was collected and washed with sodium bicarbonate (2 times, 200 mL each) and water (2 times, 300 mL each). The solid was then treated with methanol (200 mL) followed by water (200 mL). The solid was collected by vacuum filtration and washed with water. This solid was treated with 170 g (0.897 mole) of tin (II) chloride dissolved in 250 mL of concentrated HCl. The reaction was allowed to stir at ambient temperature for 40 hours. TLC indicated that the reaction was incomplete, so the reaction was heated at 50 C for 27 hours. The solid precipitate was collected by vacuum filtration and was washed with 6N HCl. The solid was extracted with ethyl acetate and water. The ethyl acetate layer was washed with brine, dried with magnesium sulfate, filtered, and the volatiles removed by rotary evaporation to yield 42.5 g of compound 5 as an oil that solidified on standing.
Reaction SMILES: [C:1](OC(OC(C)(C)C)N(C)C)(C)(C)C.[NH:15]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[CH2:17][C:16]1=[O:24].[S:25]([NH2:35])(=[O:34])([C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1)=[O:26].CS(O)(=O)=O.C([O-])(O)=O.[Na+]>CN(C=O)C.C(O)C.O>[O:24]=[C:16]1[NH:15][C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[C:17]1=[CH:1][NH:33][C:30]1[CH:29]=[CH:28][C:27]([S:25]([NH2:35])(=[O:34])=[O:26])=[CH:32][CH:31]=1
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: O=C1Cc2cccnc2N1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: NS(=O)(=O)c1ccc(NC=C2C(=O)Nc3ncccc32)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
Dimethylformamide di-tert-butyl acetal (180 mg, 0.89 mmol) was added to a solution of 1,2-dihydro-3H-pyrrolo[2,3-b]pyridin-2-one (70 mg, 0.52 mmol) in 0.25 ml DMF, and the reaction mixture was slowly warmed to 100° C. The cooled solution was then diluted with 5 ml of ethanol. Sulfanilamide (172 mg, 1.00 mmol) and methanesulfonic acid (60 mg, 0.63 mmol) were added, and the reaction mixture was stirred at reflux for 2 hours. The cooled solution was diluted with 4 ml of water, treated with NaHCO3 (70 mg, 0.83 mmol) and stirred 10 min. The resulting solid was filtered, washed with water and ethanol, and then suspended in boiling methanol and filtered upon cooling. Inorganics were removed by filtration through a short silica gel column, eluting with DMF. The resulting solution was diluted with an equal volume of ice water, and the suspension was refrigerated overnight. The solid was isolated by filtration and dried to give 36 mg (21%) of the title compound as a yellow solid: 1H NMR (400 MHz, DMSO-d6) (4:1 ratio of Z:E isomers): δ (Z) 11.07 (s, 1H), 10.76 (d, J=12.4 Hz, 1H), 8.67 (d, J=12.5 Hz, 1H), 7.92 (d, J=5.1 Hz, 1H), 7.84 (d, J=7.3 Hz,
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([CH:13]=O)=[C:8]2[C:3]=1[C:4](=[O:16])[CH:5]=[C:6]([CH3:15])[O:7]2.[C:17]([CH:19]=[C:20]([O-])[CH3:21])#[N:18].[Na+].[NH2:24][C:25]([CH3:35])=[CH:26][C:27](=[O:34])[CH2:28][CH2:29][CH:30]1[CH2:33][CH2:32][CH2:31]1.C(O)(=O)C>CC(O)C>[CH:30]1([CH2:29][CH2:28][C:27]([C:26]2[CH:13]([C:9]3[CH:10]=[C:11]([F:12])[C:2]([F:1])=[C:3]4[C:8]=3[O:7][C:6]([CH3:15])=[CH:5][C:4]4=[O:16])[C:19]([C:17]#[N:18])=[C:20]([CH3:21])[NH:24][C:25]=2[CH3:35])=[O:34])[CH2:31][CH2:32][CH2:33]1
Reactant: CC(N)=CC(=O)CCC1CCC1
Reactant: CC([O-])=CC#N
Reactant: Cc1cc(=O)c2c(F)c(F)cc(C=O)c2o1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2cc(F)c(F)c3c(=O)cc(C)oc23)C(C(=O)CCC2CCC2)=C(C)N1

Procedure:
A solution of 100 mg (0.45 mmol) of 5,6-difluoro-2-methyl-4-oxo-4H-chromene-8-carbaldehyde in 5 ml of 2-propanol is mixed with 46.9 mg (0.45 mmol) of sodium 1-cyanoprop-1-en-2-olate, 74.61 mg (0.45 mmol) of 5-amino-1-cyclobutylhex-4-en-3-one (example 15, stage a) and 0.04 ml (0.67 mmol) of acetic acid and stirred under reflux for 3 h. After cooling, the mixture is concentrated. The residue is purified on an Analogix cartridge (F12M) (mobile phase: cyclohexane/ethyl acetate 2:1). 71.2 mg (36.4% of theory) of the title compound are obtained as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:12][C:11](=[S:22])[N:10]=2)=[CH:5][CH:4]=1.[Na].[H-].[Na+].[CH2:26]([O:28][C:29](=[O:34])[CH2:30][C:31](Br)=[O:32])[CH3:27]>CN(C)P(=O)(N(C)C)N(C)C.C(OCC)C.CCCCCC>[CH2:26]([O:28][C:29](=[O:34])[CH:30]([S:22][C:11]1[S:12][C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1)[CH:31]=[O:32])[CH3:27]
Reactant: COc1ccc(C2=NC(=S)SC2c2ccc(OC)cc2)cc1
Reactant: CCOC(=O)CC(=O)Br
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CCOC(=O)C(C=O)Sc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.3 g of 4,5-bis-(p-methoxyphenyl)-thiazoline-2-thione are dissolved in 50 ml of hexamethylphosphoric acid triamide, the solution is cooled to 5° and converted into the sodium salt under nitrogen with sodium hydride (0.5 g of a 50% strength suspension in mineral oil, de-oiled with hexane). The product is allowed to warm to room temperature, 2.0 g of 2-bromoformylacetic acid ethyl ester are added dropwise and the mixture is stirred at 25° for 1 hour, poured into 750 ml of ice-water and taken up in diethyl ether. The ethereal phase is washed with water, dried over magnesium sulphate and concentrated to dryness by evaporation. 2-[4,5-bis-(p-methoxyphenyl)-thiazol-2-ylthio]-2-formylacetic acid ethyl ester is obtained, which can be used without further purification.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12]([C:14]1[CH:28]=[CH:27][C:17]([O:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=2)=[C:16]([O:29][CH2:30][CH3:31])[CH:15]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.C(OCC)(=O)C>[CH2:30]([O:29][C:16]1[CH:15]=[C:14]([CH2:12][N:9]2[CH2:10][CH2:11][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8]2)[CH:28]=[CH:27][C:17]=1[O:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=1)[CH3:31]
Reactant: c1ccc(C2CCNC2)cc1
Reactant: CCOc1cc(C=O)ccc1Oc1ccc(C#N)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOc1cc(CN2CCC(c3ccccc3)C2)ccc1Oc1ccc(C#N)cn1
Yield: 60.8 %

Procedure:
Using a method similar to Example 365 step 2, and using 3-phenyl-pyrollidine (0.150 g, 1.02 mmol), 6-(4-formyl-2-ethoxy-phenoxy)-nicotinonitrile (0.201 g, 0.749 mmol), sodium triacetoxyborohydride (0.237 g, 1.12 mmol), and acetic acid (0.064 mL, 1.12 mmol) in 1,2-dichloroethane (7.5 mL), after silica gel chromatography (1:1 hexanes:ethyl acetate), provides 0.182 g (61%) of the title compound as a clear syrup: mass spectrum (electrospray): m/z=400.2 (M+1); 1H NMR (CDCl3): 8.41 (d, 1H, J=2.0 Hz), 7.86 (dd, 1H, J=2.4, 9.3 Hz), 7.29-7.26 (m, 4H), 7.20-7.14 (m, 1H), 7.07-7.03 (m, 2H), 6.99 (d, 1H, J=7.8 Hz), 6.94 (dd, 1H, J=2.0, 7.8 Hz), 4.01-3.92 (m, 2H), 3.69 (d, 1H, J=13.2 Hz), 3.62 (d, 1H, J=13.2 Hz), 3.41-3.31 (m, 1H), 3.99 (dd, 1H, J=7.8, 8.8 Hz), 2.86-2.78 (m, 1H), 2.77-2.70 (m, 1H), 2.54 (dd, 1H, J=7.3, 9.3 Hz), 2.40-2.29 (m, 1H), 1.96-1.85 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:16])=[C:4]([C:8]([OH:15])=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:17]1(O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[C:17]1([O:6][C:5](=[O:7])[C:4]2[C:8]([OH:15])=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:10]=[C:2]([Br:1])[C:3]=2[CH3:16])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1c(Br)cc(C(C)(C)C)c(O)c1C(=O)O
Reactant: Oc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1c(Br)cc(C(C)(C)C)c(O)c1C(=O)Oc1ccccc1

Procedure:
From 3-bromo-5-tert-butyl-6-hydroxy-2-methyl-benzoic acid, phenol and phosphorus oxychloride in toluene; amber oil; 1H NMR (CDCl3): δ 11.10 (s, 1H), 7.64 (s, 1H), 7.50-7.42 (m, 2H), 7.36-7.28 (m, 1H), 7.22-7.17 (m, 2H), 2.74 (s, 3H), 1.40 (s, 9H); LC-MS: Major component: m/z 269/270 (acylium ion), 363/365 (M+H), 385/387 (M+Na); Rt=2.95 min. The crude product was used without purification.