Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[NH:14])([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.N[C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1>C1(C)C=CC=CC=1>[C:1](=[N:14][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Cc1csc(N)n1
Solvent: Cc1ccccc1
Product: Cc1csc(N=C(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C

Procedure:
Benzophenone imine (39.8 g, 0.22 mol) is added to a solution of 2-Amino-4-methyl-1,3-thiazole (30 g, 0.261) in toluene (450 ml) and heated at reflux under an inert atmosphere for 18 h. The mixture is cooled to room temperature and washed with citrate buffer (2×250 ml), water (2×250 ml), brine (2×250 ml), dried (MgSO4 and decolourising charcoal), filtered and evaporated to an orange solid (42.9 g, 70%).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][O:5][CH:6]([C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[N:13][CH:14]=1)[C:7]#[N:8].C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC>C(Cl)Cl>[Br:17][CH2:2][CH2:3][CH2:4][O:5][CH:6]([C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[N:13][CH:14]=1)[C:7]#[N:8]
Reactant: Cc1ncc(C(C#N)OCCCO)cn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ncc(C(C#N)OCCCBr)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(3-hydroxypropoxy)-2-(2-methylpyrimidin-5-yl)acetonitrile (54 mg, 0.26 mmol) and CBr4 (259 mg, 0.782 mmol) in DCM (3 ml) was cooled at 0° C. Triphenylphosphine (205 mg, 0.782 mmol) in DCM (1 ml) was added dropwise over a period of 5 minutes. The reaction was stirred for 2 hours and then allowed to warm to room temperature. To the mixture was added Et2O (5 mL) and the cloudy solution was filtred through a plug of celite. The resulting solution was concentrated in vacuo and purified by flash chromatography to yield 2-(3-Bromopropoxy)-2-(2-methylpyrimidin-5-yl)acetonitrile.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][C:14]=1[Cl:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl.C(OCC)C>[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][Br:2])=[CH:15][C:14]=1[Cl:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCc1ccc(OCc2ccccc2)c(Cl)c1
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: ClCCl
Product: Clc1cc(CBr)ccc1OCc1ccccc1
Reaction time: 1 h

Procedure:
Phosphorous tribromide (2 mL) was added to a solution of (4-benzyloxy-3-chloro-phenyl)-methanol (CAB02127, 3.40 g, 13.7 mmol) in dichloromethane (50 mL) at 0° C. The mixture was stirred at this temperature for 1 h, diluted with diethyl ether (100 mL), transferred into a separation funnel and washed with water (50 mL) and brine (50 mL). The organic layer was dried over magnesium sulphate and concentrated under reduced pressure to give a white, analytical pure solid. Yield: 4.27 g (100%).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8]/[CH:9]=[C:10](\[CH3:14])/[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([O:12][C:11](=[O:13])/[C:10](/[CH3:14])=[CH:9]/[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: C/C(=C\C=C(c1ccccc1)c1ccccc1)C(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C/C(=C\C=C(c1ccccc1)c1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A solution of (E)-5,5-diphenyl-2-methyl-2,4-pentadienoic acid (1.85 g) and 4-nitrophenol (1.12 g) in dichloromethane (25 mL), stirred at 0°-5° C. in an ice-water bath, was treated with 1,3-dicyclohexylcarbodiimide (1.44 g). The mixture was stirred at 0°-5° C. for 30 minutes, then at room temperature for 1 hour. After the precipitated dicyclohexylurea was filtered off, the concentrated filtrate was passed through a short column of silica gel (~25 g) made up in dichloromethane-hexane (3:2). The appropriate fractions were combined and evaporated to give 2.4 g of (E)-5,5-diphenyl-2-methyl-2,4-pentadienoic acid 4-nitrophenyl ester. Crystallization of the material from 2-propanol furnished 1.64 g of (E)-5,5-diphenyl-2-methyl-2,4-pentadienoic acid 4-nitrophenyl ester mp 139°-141° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH2:7][CH2:8][C@@H:9]([C:25](N1[C@H](C)COC1=O)=[O:26])[CH2:10][C@H:11]1[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[N:12]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6](=[O:34])[CH2:7][CH2:8][C@@H:9]([CH2:25][OH:26])[CH2:10][C@H:11]1[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[N:12]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@@H]1COC(=O)N1C(=O)[C@H](CCC(=O)OC(C)(C)C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC[C@@H](CO)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.3 %

Procedure:
(S)-tert-butyl 4-((R)-5-tert-butoxy-2-((R)-4-methyl-2-oxooxazolidine-3-carbonyl)-5-oxopentyl)-2,2-dimethyloxazolidine-3-carboxylate (4.12 g, 7.36 mmol) was dissolved in 4:1 THF and methanol (200 mL) and cooled to 0° C. Sodium borohydride (557 mg, 2 eq) was added slowly. After 10 min., the mixture was warmed up to rt slowly. The mixture was stirred 2 hr at rt. The mixture was concentrated, redissolved in EtOAc (300 mL), washed with 1% HCl solution (100 mL), brine (60 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by ISCO (40 g column, 10-65% EtOAc in Hexanes gradient, check TLC with Ninhydrin stain) to afford 2.86 g of (S)-tert-butyl 4-((R)-5-tert-butoxy-2-(hydroxymethyl)-5-oxopentyl)-2,2-dimethyloxazolidine-3-carboxylate as a white solid. MS ESI +m/v 410 (M+Na).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16](C=O)=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]([O:26][CH3:27])([O:24][CH3:25])OC.C(N(CC)CC)C>CO>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH:21]([O:24][CH3:25])[O:26][CH3:27])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C=O)ccc1OCc1ccccc1
Reactant: COC(OC)OC
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cc(C(OC)OC)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
39.1 g of methyl 2-benzyloxy-5-formyl-benzoate was dissolved in 300 ml methanol. 60 ml trimethyl orthoformate and 2 g of p-toluenesulffonic acid were added thereto, followed by heating under reflux for 4 hours. After cooling to room temperature, 5 ml triethylamine was added thereto, and the mixture was evaporated. The residue was dissolved in ethyl acetate, successively washed with water and saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 39.08 g of methyl 2-(benzyloxy)-5-(dimethoxymethyl)benzoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]([NH:15][CH3:16])=[CH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]1=[O:19].[CH3:20][CH:21]([C:25]([OH:27])=O)[C:22]([OH:24])=O>C(OC(=O)C)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2[N:15]([CH3:16])[C:25](=[O:27])[C:21]([CH3:20])=[C:22]([OH:24])[C:13]=2[C:12](=[O:17])[N:11]([CH3:18])[C:10]1=[O:19]
Reactant: CNc1cc(=O)n(C)c(=O)n1-c1ccc(I)cc1F
Reactant: CC(C(=O)O)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1c(O)c2c(=O)n(C)c(=O)n(-c3ccc(I)cc3F)c2n(C)c1=O
Temperature: 95 °C
Yield: 37.2 %

Procedure:
To a 6:5 mixture (59.6 g) of 1-(2-fluoro-4-iodophenyl)-3-methyl-6-methylamino-1H-pyrimidine-2,4-dione 67 and 3-(2-fluoro-4-iodophenyl)-1-methyl-6-methylamino-1H-pyrimidine-2,4-dione 68 obtained in Step 4 and 2-methyl-malonic acid 54 (20.7 g) was added acetic anhydride (180 ml), and the mixture was stirred with heating at 95° C. for 1 hr. After allowing to cool to room temperature, the mixture was concentrated under reduced pressure. Tetrahydrofuran (350 ml) was added to the residue, and the mixture was stirred with heating under reflux for 1 hr. After allowing to cool to room temperature, the crystals were filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (chloroform:tetrahydrofuran=18:1). Toluene (150 ml) was added to the obtained solid, and the mixture was stirred with heating under reflux for 30 min. After allowing to return to room temperature, the crystals were collected by filtration and dried to give 1-(2-fluoro-4-iodophenyl)-5-hydroxy-3,6,8-trimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione 69 (27.0 g, yield 37%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3].[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:28]2[S:27][CH:31]=[CH:30][CH:29]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3]
Reactant: OB(O)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccs4)cc23)CC1
Yield: 54.7 %

Procedure:
Following the general procedure of Example 65, a mixture of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indazol-3-yl]-1-piperidinecarboxylate (Intermediate 5) (100 mg, 0.24 mmols), 2-thienylboronic acid (92 mg, 0.72 mmols), potassium carbonate (197 mg), and Pd(PPh3)4 (28 mg) in dioxane/water (3/1, 4 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (56 mg, 55%)
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][CH:5]=[CH2:6].[CH:8]1[CH2:12][CH:11]=[CH:10][CH:9]=1>>[CH2:4]([C:5]([CH3:6])=[C:9]1[CH:8]=[CH:12][CH:11]=[CH:10]1)[CH2:3][CH:2]=[CH2:1]
Reactant: C=CCCC(C)=O
Reactant: C1=CCC=C1
Product: C=CCCC(C)=C1C=CC=C1

Procedure:
A process according to claim 5 wherein 5-hexene-2-one is reacted with cyclopentadiene to yield 6-(3-butenyl)-6-methylfulvene which is then reacted with fluorenyllithium and then subjected to hydrolysis to yield 5-cyclopentadienyl-5-(9-fluorenyl )-1-hexene.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]#[N:11])=[C:4](Cl)[N:3]=1.[CH3:13][NH:14][CH3:15]>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]#[N:11])=[C:4]([N:14]([CH3:15])[CH3:13])[N:3]=1
Reactant: CNC
Reactant: N#Cc1nc(C#N)c(Cl)nc1N
Solvent: C1CCOC1
Product: CN(C)c1nc(N)c(C#N)nc1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The starting material, 2-amino-6-chloro-3,5-dicyanopyrazine (100 mg; 0.557 mM), is prepared in accordance with the method described by Perchais and Fleury in Tetrahedron, 30:999-1009 (1974), and stirring in 1 ml of dry tetrahydrofuran. There was then added dropwise 0 54 ml of a chilled solution of dimethylamine gas in tetrahydrofuran (93 mg/ml) over 10 minutes. The reaction mixture was then stirred at room temperature for 0.5 hours; the product was removed by centrifuging, and then recrystallized from 1:1 ethanol/i-propanol (50 mg); m.p. 201°-202° C.
Reaction SMILES: C1COCC1.[F:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([F:15])[CH:8]=1.C([Li])CCC.[F:21][C:22]([F:27])([F:26])[C:23]([CH3:25])=[O:24]>CCCCCC>[F:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([F:15])[C:8]=1[C:23]([OH:24])([CH3:25])[C:22]([F:27])([F:26])[F:21]
Reactant: COc1cc(F)cc(F)c1
Reactant: CC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(F)c(C(C)(O)C(F)(F)F)c(F)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a THF (100 ml) solution of 1,3-difluoro-5-methoxybenzene (7 g, 48.6 mmol) was added dropwise 1.6 M hexane solution of n-butyllithium (30 ml, 48.6 mmol) at −78° C. over 30 minutes and the mixture was stirred for 2 hours at −78 ° C. Then 1,1,1-Trifluoroacetone (6.5 g, 58.3 mmol) was added at −78° C. and the mixture was stirred for 2 hours at −78° C. After stirring at room temperature for an additional 1 hour, the reaction was quenched with water. The whole was extracted with EtOAc and the organic layer was dried over sodium sulfate, filterd, and concentrated in vacuo. Purification by silica gel column chromatography eluting with hexane/EtOAc (10:1) gave the title compound (9.7 g, 78% yield) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:38]=[CH:37][C:5]([CH:6]=[CH:7][C:8]([NH:10][CH2:11][C:12]([N:14]([C:16]2[C:17]([Cl:36])=[C:18]([C:32]([Cl:35])=[CH:33][CH:34]=2)[CH2:19][O:20][C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]3)[CH3:15])=[O:13])=[O:9])=[CH:4][C:3]=1[CH3:39].C(N(CC)CC)C.[C:47](Cl)(=[O:51])[CH:48]([CH3:50])[CH3:49]>ClCCl>[Cl:36][C:17]1[C:16]([N:14]([CH3:15])[C:12](=[O:13])[CH2:11][NH:10][C:8](=[O:9])[CH:7]=[CH:6][C:5]2[CH:37]=[CH:38][C:2]([NH:1][C:47](=[O:51])[CH:48]([CH3:50])[CH3:49])=[C:3]([CH3:39])[CH:4]=2)=[CH:34][CH:33]=[C:32]([Cl:35])[C:18]=1[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]2
Reactant: CC(C)C(=O)Cl
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(N)c(C)c4)c3Cl)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NC(=O)C(C)C)c(C)c4)c3Cl)c2n1
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To a solution of 8-[3-[N-(4-amino-3-methylcinnamoylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (200 mg) and triethylamine (35.9 mg) in dichloromethane was dropwise added isobutyryl chloride (41.6 mg) at 0° C. under nitrogen atmosphere, and the mixture was stirred for 30 minutes at the same temperature. The mixture was concentrated, and the residue was dissolved in methanol (3 ml). To the solution was added saturated sodium bicarbonate solution (1 ml), and the mixture was stirred for 2 hours at ambient temperature and concentrated. To the residue were added ethyl acetate and water, and the organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol=15:1, V/V) to give 8-[2,6-dichloro-3-[N-methyl-N-(4-isobutyramido-3-methylcinnamoylglycyl)amino]benzyloxy]-2-methylquinoline (195 mg) as an amorphous powder.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:15]([F:18])([F:17])[F:16])[CH2:14][CH2:13][C:6]2([NH:10]C(=O)N[C:7]2=[O:12])[CH2:5][CH2:4]1.Cl.[OH-:20].[Na+]>>[NH2:10][C:6]1([C:7]([OH:12])=[O:20])[CH2:5][CH2:4][C:3]([O:2][CH3:1])([C:15]([F:18])([F:17])[F:16])[CH2:14][CH2:13]1
Reactant: COC1(C(F)(F)F)CCC2(CC1)NC(=O)NC2=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: COC1(C(F)(F)F)CCC(N)(C(=O)O)CC1
Reaction time: 72 h

Procedure:
10.00 g (37.56 mmol) of 8-methoxy-8-(trifluoromethyl)-1,3-diazaspiro[4.5]decane-2,4-dione (Example 14A) were suspended in 125 ml of 3-molar aqueous sodium hydroxide solution and stirred under reflux conditions for 3 days. Subsequently, the pH was adjusted to 6 using concentrated aqueous hydrochloric acid, and the precipitated product was filtered off, washed with water and dried under reduced pressure. This gave 12.20 g (135% of theory; the product contains inorganic salts) of the title compound as a white powder.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[C:7]([CH3:14])[N:6]=1)([CH3:3])[CH3:2].[CH2:15](O)[CH3:16]>OS(O)(=O)=O>[CH2:15]([O:12][C:11]([C:9]1[CH:8]=[C:7]([CH3:14])[N:6]=[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])[N:10]=1)=[O:13])[CH3:16]
Reactant: CCO
Reactant: Cc1cc(C(=O)O)nc(NC(C)C)n1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(C)nc(NC(C)C)n1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 2-isopropylamino-6-methyl-pyrimidine-4-carboxylic acid (1.27 g, 6.53 mmol) in ethanol (20 mL), concentrated H2SO4 (4 mL) is added. The reaction mixture is stirred at 80° C. for 18 h and is then evaporated. The residue is dissolved in EtOAc, washed with sat. aq. NaHCO3 and water, dried over MgSO4, filtered and evaporated. The crude compound is purified by CC on silica gel (eluting with Heptane/EtOAc 4:1) to give 2-isopropylamino-6-methyl-pyrimidine-4-carboxylic acid ethyl ester as a yellow oil (1.46 g); LC-MS: tR=0.97; [M+H]+=224.49.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH:34]([CH3:36])[CH3:35]>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH:34]([CH3:36])[CH3:35])[C:18]([C:23]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)Br
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCOCC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c(C(=O)N2CCOCC2)cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc21
Yield: 31 %

Procedure:
The title compound was synthesized in analogy to example 51, from (4-cyclopentyl-piperazin-1-yl)-[2-(morpholine-4-carbonyl)-1H-indol-5-yl]-methanone (example 10), sodium hydride and 2-bromopropane in N,N-dimethylformamide, to give the desired product as a colorless foam (31%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26]C(=O)C)[C@@H:18]([O:19]C(=O)C)[C@H:13]3[O:14]C(=O)C)[C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].CC(O)=O>CO>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][OH:26])[C@@H:18]([OH:19])[C@H:13]3[OH:14])[C:6]=2[N:7]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3cnc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ncc2sc(=O)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a solution of 89 (0.52 g, 1.22 mmol) in MeOH (20 mL) was added K2CO3 (25 mg, 0.18 mmol). The reaction was stirred at room temperature overnight, then neutralized with AcOH (21 μL, 0.36 mmol). The resulting mixture was stirred at room temperature for additional 30 min, concentrated, and triturated with H2O (2 ml) to afford 0.33 g of compound 90 (89%) as a white solid: mp 220° C. (Dec); 1H (400 MHz, d6-DMSO) δ 8.34 (s, 1H), 6.85 (s, 2H), 5.90 (d, J=4.8 Hz, 1H), 5.31 (d, J=5.6 Hz, 1H), 4.98 (d, J=5.6 Hz, 1H), 4.81 (q, J=5.2 Hz, 1H), 4.67 (t, J=6.0 Hz, 1H), 4.11 (q, J=5.2 Hz, 1H), 3.77 (dd, J=10.8, 4.8 Hz, 1H), 3.58 (m, 1H), 3.44 (m, 1H); MS (+)-ES [M+H]+ m/z 301.1. Elemental Analysis calc'd for C10H12N4O5S.0.3 H2O: C, 39.29; H, 4.15; N, 18.33; S 10.49. Found: C, 39.51; H, 4.18; N, 17.95; S, 10.27.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[CH2:16][C:15]3[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([O:17][CH3:18])[CH:14]=3)[C:9]2=[O:21])[CH2:2]1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30]Br)=[CH:25][CH:24]=1>>[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]3[CH2:16][C:15]4[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([O:17][CH3:18])[CH:14]=4)[C:9]3=[O:21])[CH2:2]2)=[CH:25][CH:24]=1
Reactant: Cc1ccc(CCBr)cc1
Reactant: COc1cc2c(cc1OC)C(=O)N(CC1CCCNC1)C2
Product: COc1cc2c(cc1OC)C(=O)N(CC1CCCN(CCc3ccc(C)cc3)C1)C2

Procedure:
Prepared from 2-[(piperidin-3-yl)-methyl]-5,6-dimethoxy-1-oxo-isoindole and 2-(4-methyl-phenyl)-ethyl bromide analogously to Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[CH2:21]([NH2:24])[CH2:22][CH3:23]>>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:24][CH2:21][CH2:22][CH3:23])=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: O=C(Cl)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reactant: CCCN
Product: CCCNC(=O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Yield: 95.2 %

Procedure:
The product from Example 126c (1.0 g, 3.2 mmol) was reacted with propan-1-amine (568 mg, 9.61 mmol) for 12 h following the procedure from Example 126d giving the title compound (1.02 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:16][C:17]1[CH:31]=[CH:30][C:20]([CH2:21][P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[CH:19][CH:18]=1.[CH3:33][O-:34].[Na+]>CO>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:34][CH3:33])[N:6]2[CH2:16][C:17]1[CH:31]=[CH:30][C:20]([CH2:21][P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[CH:19][CH:18]=1
Reactant: C[O-]
Reactant: CCOP(=O)(Cc1ccc(Cn2c(Br)nc3c(N)nc(OCCOC)nc32)cc1)OCC
Agent: [Na+]
Solvent: CO
Product: CCOP(=O)(Cc1ccc(Cn2c(OC)nc3c(N)nc(OCCOC)nc32)cc1)OCC
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a solution of diethyl 4-((6-amino-8-bromo-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)benzylphosphonate in methanol (0.10 M) was added sodium methoxide (20 equiv.). The reaction mixture was then allowed to stir at 70° C. for 18 h. At this point the reaction mixture was allowed to cool to room temperature and then quenched by the addition of ammonium chloride. The mixture was then diluted with DCM, transferred to a separatory funnel and washed with DCM three times. The combined organic layers were then dried over anhydrous Na2SO4 and the volatiles were removed in vacuo. The resulting solid compound (38%) was carried onto the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].N1C=CC=CC=1.[Br:21]Br.Cl>C(Cl)Cl>[C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([Br:21])[C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(O)c(C(C)=O)c1
Reactant: BrBr
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(Br)c(O)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a stirred solution of methyl 3-acetyl-4-hydroxybenzoate (240 g, 1236 mmol) in DCM (2 L) was added pyridine (0.400 L, 4944 mmol) followed by a dropwise addition of dibromine (0.070 L, 1360 mmol) at 0° C. The reaction mixture was stirred at RT for 2 hrs then cooled to 5° C. and HCl 4N (0.927 L, 3708 mmol) was added dropwise. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated to afford a brown solid which was stirred in ether/petroleum ether (1:1, 1 L) for 1 hr. The solid was collected by filtration and dried to afford methyl 3-acetyl-5-bromo-4-hydroxybenzoate (270 g, 80%) as a beige powder.