Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:18])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][S:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:34])=[O:33])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN(CCc1ccccc1N)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(CCc1ccccc1NS(=O)(=O)c1ccccc1)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 16 h
Yield: 64.3 %

Procedure:
N-(2-(2-Aminophenyl)ethyl)-N-methylcarbamic acid tert-butyl ester (555 mg, 2.22 mmol) and triethylamine (0.40 ml, 2.66 mmol) were dissolved in dichloromethane (12 ml) and cooled to -78° C. A solution of benzenesulfonyl chloride (0.28 ml, 2.22 mmol) in dichloromethane (3 ml) was added dropwise. The solution was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (40 ml) and washed with 10% aqueous sodium hydrogen sulfate solution (20 ml). The aqueous phase was extracted with ethyl acetate (2×15 ml). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution (30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (30 g), using ethyl acetate/heptane 1:3 as eluent, to give 557 mg of N-[2-(2-(phenylsulfonylamino)phenyl)ethyl]-N-methylcarbamic acid tert-butyl ester.
Reaction SMILES: [N+](C1C=CC(C([O:10][CH2:11][C@H:12]2[O:16][C@@H:15]([N:17]3[C:36]4[N:35]=[CH:34][N:33]=[C:21]([NH:22]C(=O)COC5C=CC=CC=5)[C:20]=4[N:19]=[CH:18]3)[CH2:14][C@@H:13]2[OH:37])=O)=CC=1)([O-])=O.ClCCl.C(#N)C.C(N(P(N(C(C)C)C(C)C)OCCC#N)C(C)C)(C)C.N1[C-]=NN=N1.C([NH2+]C(C)C)(C)C>ClCCl>[C@@H:15]1([N:17]2[C:36]3[N:35]=[CH:34][N:33]=[C:21]([NH2:22])[C:20]=3[N:19]=[CH:18]2)[O:16][C@H:12]([CH2:11][OH:10])[C@@H:13]([OH:37])[CH2:14]1
Reactant: O=C(COc1ccccc1)Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](COC(=O)c2ccc([N+](=O)[O-])cc2)O1
Agent: CC(C)N(C(C)C)P(OCCC#N)N(C(C)C)C(C)C
Agent: CC(C)[NH2+]C(C)C
Agent: [c-]1nnn[nH]1
Solvent: ClCCl
Solvent: CC#N
Product: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Reaction time: 2 h

Procedure:
5′-O-p-Nitrobenzoyl-6-N-phenoxyacetyldeoxyadenosine (1 eq) is dried in a dichloromethane/acetonitrile mixture and reacted with 1.2 eq of bisdiisopropylaminocyanoethoxyphosphine and 0.5 eq of diisopropylammonium tetrazolide in anhydrous dichloromethane. After reacting for 2 hours, the reaction mixture is diluted and washed successively with 0.5 M sodium bicarbonate and saturated sodium chloride. The organic phase is evaporated to dryness. After precipitation in hexane, the product is dried under vacuum and stored under argon. This amidite is soluble in acetonitrile, a solvent in which oligonucleotide syntheses are conventionally carried out.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15](=[N:24][NH2:25])[NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[Cl:23])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[CH:27]([O-])([O-])OC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:16]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=5[Cl:23])[CH:27]=[N:25][N:24]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1
Reactant: NN=C(Nc1ccccc1Cl)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reactant: COC([O-])[O-]
Product: Clc1ccccc1-n1cnnc1-c1cc2c(s1)-c1ccc(Br)cc1OCC2
Temperature: 25 °C

Procedure:
A solution of crude 8-bromo-N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbohydrazonamide (150 mg) was heated in a sealed vessel with methyl orthoformate at 90° C. for 3 h. The mixture was cooled to room temperature and concentrated to give a crude residue that was purified by flash column chromatography (10-100% ethyl acetate in hexanes) to give 273. 1H NMR (dmso-d6, 400 MHz) δ 8.89 (s, 1H), 7.84 (m, 2H), 7.75 (m, 1H), 7.66 (m, 1H), 7.46 (m, 2H), 7.28-7.23 (m, 2H), 6.66 (s, 1H), 4.23 (t, 2H), 3.02 (t, 2H). MS (ESI) 460.0
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:25][CH2:24]2)=[CH:4][C:5]([N:20]([CH3:22])[CH3:21])=[C:6]([CH:19]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])=[O:8].C(N(CC)C(C)C)(C)C.[O:45]1[CH:49]=[CH:48][CH:47]=[C:46]1[C:50](Cl)=[O:51]>ClCCl.O>[CH3:21][N:20]([CH3:22])[C:5]1[C:6]([C:7](=[O:8])[NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])=[CH:19][C:2]([NH:1][C:50]([C:46]2[O:45][CH:49]=[CH:48][CH:47]=2)=[O:51])=[C:3]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:27][CH2:28]2)[CH:4]=1
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1ccccc1N1CCN(c2cc(N(C)C)c(C(=O)NCCCN3CCCC3=O)cc2N)CC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1N1CCN(c2cc(N(C)C)c(C(=O)NCCCN3CCCC3=O)cc2NC(=O)c2ccco2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.4 %

Procedure:
To a solution of 5-amino-2-dimethylamino-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide 7c (91.7 mg, 0.19 mmol, 100 mol %) and N,N-diisopropylethylamine (0.10 ml, 0.58 mmol, 300 mol %) in dichloromethane (4.0 ml) was added furan-2-carbonyl chloride (0.02 ml, 0.23 mmol, 120 mol %) and a catalytic amount of N,N-dimethylaminopyridine. The reaction was stirred for 16 h at room temperature and then diluted with water and extracted three times with dichloromethane. The combined organics were dried over sodium sulfate and concentrated to a residue that was purified by column chromatography (dichloromethane to 10% methanol/dichloromethane) to afford furan-2-carboxylic acid [4-dimethylamino-5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide 7d (50.0 mg; 0.09 mmol, 45.6%) as an off-white solid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:40][CH2:41][N:42]([CH3:44])[CH3:43]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([O:20][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reactant: CN(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)OCCN(C)C)cn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@H]1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 24 %

Procedure:
To a solution of 6-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinic acid (for a preparation see Intermediate 7) (54 mg, 0.126 mmol) in DMF (5 mL) were added K2CO3 (26.2 mg, 0.189 mmol) and 2-bromo-N,N-dimethylethanamine (28.8 mg, 0.189 mmol). The resulting mixture was stirred at room temperature for 3 h, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in a 1:1 MeOH/DMSO mixture and purified by MDAP (formate). The appropriate fractions were combined and concentrated in vacuo to give 2-(dimethylamino)ethyl 6-((2R,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinate (16.5 mg, 24%) as a viscous colourless oil. LCMS (Formate, 2 min), Rt=0.69 min, MH+=499.
Reaction SMILES: [C:1]([CH2:5][CH2:6][S:7][C:8]1[N:9]([CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[CH:10]=[CH:11][N:12]=1)([O:3]C)=[O:2].Cl>[OH-].[Na+]>[C:1]([CH2:5][CH2:6][S:7][C:8]1[N:9]([CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[CH:10]=[CH:11][N:12]=1)([OH:3])=[O:2]
Reactant: COC(=O)CCSc1nccn1Cc1cc(F)cc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCSc1nccn1Cc1cc(F)cc(F)c1

Procedure:
2-(2-Carbomethoxyethylthio)-1-(3,5-difluorobenzyl)imidazole (3.12, 0.010 mole) is stirred with 2.5N aqueous sodium hydroxide (20 ml) and the reaction mixture is heated at reflux for one hour and then cooled and neutralized with concentrated hydrochloric acid. The mixture is then extracted three times with ether and the combine ether extracts are concentrated. A crystalline solid is obtained by trituration of the residue with boiling hexane. This is recrystallized from ethyl acetate-hexane to give 2-(2-carboxyethylthio)-1-(3,5-difluorobenzyl)imidazole.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[C:34](=[O:35])[C:33]5[N:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH:27]=[CH:26]4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[I-]>N1C=CC=CC=1>[C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[C:34](=[O:35])[C:33]5[N:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH:27]=[CH:26]4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-n4ccc5cccnc5c4=O)c3)sc2c1-c1ccc(Cl)cc1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: Cc1cc2nc(-c3ccnc(-n4ccc5cccnc5c4=O)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 170 °C

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(8-oxo-1,7-naphthyridin-7(8H)-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetate (7.9 mg, 0.012 mmol) in pyridine (0.6 mL) was added LiI (75 mg, excess). The reaction mixture was heating in a microwave at 170° C. for 90 min. The mixture was concentrated in vacuo and then purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H28ClN4O4S: 611.2; found: 611.2. 1H NMR (400 MHz, CDCl3) δ 9.06 (d, J=2.8 Hz, 1H), 8.68 (d, J=5.2 Hz, 1H), 8.62 (s, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.99-7.92 (m, 3H), 7.76-7.69 (m, 2H), 7.55-7.49 (m, 3H), 6.66 (d, J=7.6 Hz, 1H), 5.34 (s, 1H), 2.58 (s, 3H), 1.01 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([CH2:15][F:16])([C:13]#[CH:14])[CH2:11][F:12])=[CH:5][CH:4]=1.COC(C)(C)C.CC(C)([O-])C.[K+].[Br:31]Br>CCCCCC.C(O)(C)(C)C>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([CH2:11][F:12])([C:13]#[C:14][Br:31])[CH2:15][F:16])=[CH:5][CH:4]=1
Reactant: BrBr
Reactant: C#CC(CF)(CF)Oc1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)(C)O
Solvent: COC(C)(C)C
Product: FCC(C#CBr)(CF)Oc1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
An amount (13.9 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-yl 4-trifluoromethylphenyl ether was dissolved in a solvent consisting of a mixture of tert-butyl methyl ether (100 ml) and tert-butyl alcohol (150 ml). To the solution under cooling with ice, potassium tert-butoxide (7.1 g) was added under a nitrogen atmosphere; after stirring for a while, bromine (3 ml) was added dropwise. After the end of the dropwise addition, the mixture was stirred for 30 minutes under stirring with ice. Hexane was added to the reaction mixture, which was then washed with water and a saturated aqueous solution of sodium chloride. The mixture was dried with anhydrous sodium sulfate and concentrated under reduced pressure to give the titled compound (18.1 g).
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[S:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>COCCOC.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.O>[CH3:25][N:17]([CH2:16][C:4]1[CH:3]=[C:2]([C:28]2[CH:29]=[CH:30][S:26][CH:27]=2)[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=1)[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2ccccc2)c1)C(=O)OC(C)(C)C
Reactant: OB(O)c1ccsc1
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: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CN(Cc1cc(-c2ccsc2)n(S(=O)(=O)c2ccccc2)c1)C(=O)OC(C)(C)C
Temperature: 105 °C
Reaction time: 7 h
Yield: 87.6 %

Procedure:
A suspension of tert-butyl {[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (1.02 g), 3-thienylboronic acid (0.61 g), tetrakis(triphenylphosphine)palladium (0.41 g) and sodium carbonate (0.75 g) in 1,2-dimethoxyethane (25 mL)-water (25 mL) was stirred at 105° C. for 7 hr. After cooling, saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as a colorless solid (yield 0.90 g, 88%).
Reaction SMILES: Br[C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[C:10]([OH:26])=[C:11]([C:23](=[O:25])[CH3:24])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:23]([C:11]1[C:10]2[O:26][C:2]([CH3:7])([CH3:6])[C:3](=[O:4])[NH:8][C:9]=2[C:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(N)c1O
Reactant: CC(C)(Br)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccc(OCc2ccccc2)c2c1OC(C)(C)C(=O)N2
Reaction time: 8 h

Procedure:
28 g (0.15 mol) 2-bromo-2-methyl-propionyl chloride are added dropwise to 25.7 g (0.10 mol) 1-(3-amino-4-benzyloxy-2-hydroxy-phenyl)-ethanone and 41 g (0.30 mol) potassium carbonate in 215 mL acetonitrile. After 8 hours stirring at reflux temperature the solid is filtered off, the filtrate is evaporated down and the residue is crystallised from ethanol. Yield: 11.2 g (35%); melting range=124-126° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([S:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])([CH3:10])[CH3:9])[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]2[CH3:26])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:41]2[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=2)O1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(OCC)(=O)C.COCCOC.C(O)C>[CH:14]1([S:11]([C:8]([C:6]2[CH:5]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]3[CH3:26])[N:3]=[C:2]([C:41]3[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=3)[N:7]=2)([CH3:10])[CH3:9])(=[O:13])=[O:12])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)C2CCCCC2)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)C2CCCCC2)nc(-c2ccc(N)cc2)n1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 83.8 %

Procedure:
A mixture of 2-chloro-4-(2-cyclohexylsulfonylpropan-2-yl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (1.18 g, 2.94 mmol), 2M aqueous sodium carbonate solution (5.5 mL, 11.00 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.907 g, 4.14 mmol) in a mixture of DMF (5 mL), water (12.50 mL), ethanol (5.00 mL) and DME (5.00 mL) was purged with nitrogen for 10 minutes before being treated with bis(triphenylphosphine)palladium(II) chloride (0.111 g, 0.16 mmol). The stirred mixture was heated to 80° C. and stirred under nitrogen for 2.5 hours. The reaction mixture was cooled and treated with ethyl acetate (50 mL) and water (50 mL). The organic layer was separated and the aqueous re-extracted with ethyl acetate (2×30 mL). The combined organics were washed with brine, dried (MgSO4) and evaporated to afford the crude product, which was purified by flash silica chromatography, elution gradient 25 to 75% ethyl acetate in isohexane, to give the desired material (1.130 g).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:21]=[C:20]([C:22]3[S:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[O:19][N:18]=1)[C:11]([C:28]([O:30]CC)=[O:29])=[CH:10]2)=[O:6])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.CO>[CH:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:21]=[C:20]([C:22]3[S:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[O:19][N:18]=1)[C:11]([C:28]([OH:30])=[O:29])=[CH:10]2)=[O:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(C(=O)OC(C)C)ccc2n1Cc1cc(-c2ccc(Cl)s2)on1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)OC(=O)c1ccc2c(c1)cc(C(=O)O)n2Cc1cc(-c2ccc(Cl)s2)on1
Reaction time: 2 h

Procedure:
To a solution of 6.21 g 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-indole-2,5-dicarboxylic acid 2-ethyl ester 5-isopropyl ester in 100 ml THF and 40 ml MeOH 52 ml of an aqueous 1 M LiOH solution were added and stirred for 2 h. The organic solvents were removed under reduced pressure and the residue acidified with 2 M hydrochloric acid to pH 2. The precipitated product was collected by filtration and dried over P2O5 in vacuo to yield a white solid. Yield: 5.77 g.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@@H:9]([NH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:10][CH2:11][S:12]2)=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+]>>[CH2:19]([O:18][C:16]([NH:15][C@@H:9]1[C:8]2[C:13](=[CH:14][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)[S:12][CH2:11][CH2:10]1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc2c(c1)SCC[C@@H]2NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(N[C@H]1CCSc2cc(C(=O)O)ccc21)OCc1ccccc1
Yield: 98 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 6 using (S)-4-(benzyloxycarbonylamino)thiochromane-7-carboxylic acid methyl ester (3.40 g) and potassium carbonate (2.63 g), the objective (S)-4-(benzyloxycarbonylamino)thiochromane-7-carboxylic acid (3.20 g) was obtained as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][C:18]([OH:20])=O)[C:12](=[O:21])[N:11]([CH3:22])[C:10]=3[N:9]=[C:8]2[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=2)=[CH:4][CH:3]=1.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN1C(=O)CCC1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][C:18]([N:41]4[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]4)=[O:20])[C:12](=[O:21])[N:11]([CH3:22])[C:10]=3[N:9]=[C:8]2[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:33])([F:34])[F:32])[CH:25]=2)=[CH:35][CH:36]=1
Reactant: CN1CCNCC1
Reactant: Cn1c(=O)n(CC(=O)O)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CN1CCN(C(=O)Cn2c(=O)c3c(nc(Oc4cccc(OC(F)(F)F)c4)n3Cc3ccc(Cl)cc3)n(C)c2=O)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 27.1 %

Procedure:
To a solution of 2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)acetic acid (80 mg, 0.152 mmol, example 9) in NMP (2 mL) was added TEA (0.1 mL, 0.614 mmol), 1-methylpiperazine (0.07 mL, 0.614 mmol) and O-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (87 mg, 0.231 mmol); then the mixture was stirred at 60° C. for 16 h. Then the mixture was diluted with ethyl acetate and water, the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give crude product. This crude material was purified by recrystallization from methanol to give 7-(4-chlorobenzyl)-3-methyl-1-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (25 mg, 27.5% yield) as white solid. 1H-NMR (DMSO-d6) δ 7.62-7.59(t, 1H), 7.55(s, 1H), 7.49-7.39(m, 5H), 7.36-7.34(d, 1H), 5.43(s, 2H), 4.71(s, 2H), 3.55-3.48(m, 4H), 3.30(s, 3H), 2.46-2.36(m, 4H), 2.21(s, 3H). LCMS retention time 2.298 min; LCMS MH+ 607.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:18]O)[C:13]=1[CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].S(Cl)([Cl:23])=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][Cl:23])[C:13]=1[CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccnc(CO)c1C
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCOc1ccnc(CCl)c1C
Yield: 91.5 %

Procedure:
19.8 g (0.058 mol, 1.0 eq.) of 4-decyloxy-2-hydroxymethyl-3-methylpyridine was dissolved in 300 mL of ethyl acetate, and 7.6 g (0.064 mol, 1.1 eq.) of thionyl chloride was added dropwise at 12 to 18° C. Subsequently, the mixture was allowed to react for 0.5 hours at room temperature, and then a 7% aqueous solution of sodium bicarbonate (220 g) was added to adjust the reaction liquid to pH 7.5. The organic layer was washed with a 5% aqueous solution of sodium bicarbonate (160 g), dried over anhydrous magnesium sulfate, and then concentrated to dryness under reduced pressure, to obtain 15.8 g of 4-decyloxy-2-chloromethyl-3-methylpyridine as a black oily matter.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[NH:20][C:19](=[O:24])[N:18]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:29]([O:32][CH2:33]Cl)[CH2:30][CH3:31]>CN(C)C=O.O.CO>[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:33][O:32][CH2:29][CH2:30][CH3:31])[C:19](=[O:24])[N:18]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=c1[nH]c(=O)n(CC2CC2)c2ncn(Cc3ccccc3)c12
Reactant: CCCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CCCOCn1c(=O)c2c(ncn2Cc2ccccc2)n(CC2CC2)c1=O
Reaction time: 1 h

Procedure:
1.12 g (8.1 mmol) of potassium carbonate were added at 60° C. to a solution of 1.5 g (5.06 mmol) of 7-benzyl-3-cyclopropylmethylxanthine from stage a) in 60 ml of dimethylformamide and the mixture was stirred at this temperature for one hour. 722 μl (6.58 mmol) of propoxymethyl chloride were then added dropwise and the mixture was stirred at 80° C. for 4 hours. 12 ml of water and 5 ml of methanol were added and the mixture was stirred at 50° C. for 2 hours. 60 ml of water were then added again, the mixture was extracted three times using methyl tert-butyl ether, and the combined organic phases were washed twice with water, dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column, dichloromethane/methanol (19.8/0.2).