Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[NH:16][C:17](=[O:25])[C:18](=[C:21]([S:23][CH3:24])[CH:22]=1)[C:19]#[N:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[NH:16][C:17](=[O:25])[C:18](=[C:21]([S:23]([CH3:24])=[O:34])[CH:22]=1)[C:19]#[N:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cc(-c2ccccc2OCc2ccccc2)[nH]c(=O)c1C#N
Solvent: ClCCl
Product: CS(=O)c1cc(-c2ccccc2OCc2ccccc2)[nH]c(=O)c1C#N
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To a cold (0° C.) solution of 6-[2-(benzyloxy)phenyl]-4-(methylthio)-2-oxo-1,2-dihydro-nicotinonitrile (4.00 g, 11.5 mmol) in CH2Cl2 was added m-chloroperbenzoic acid (mCPBA) (69%, 3.45 g, 13.8 mmol) in one portion. The reaction mixture was stirred at 0° C. to room temperature for 1 hr, quenched with saturated NaHCO3 solution (80 mL) including Na2S2O3.5H2O (5 g), and diluted with CH2Cl2. The separated organic phase was washed with saturated NaHCO3 solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residual solid was triturated with diisopropyl ether to give 6-[2-(benzyloxy)phenyl]-4-(methylsulfinyl)-2-oxo-1,2-dihydro-nicotinonitrile as a yellow solid (4.00 g, yield; 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])=[O:11])=[CH:4][CH:3]=1.C(O)C.C([O-])(=O)C.[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][C:10](=[O:11])[C:12]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:18]2)=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1ccc(Cl)cc1)c1ccccc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1CC(c2ccc(Cl)cc2)Oc2ccccc21
Reaction time: 8 h
Yield: 29 %

Procedure:
4-Chloro-2'-hydroxychalcone (5.17 g) was boiled under reflux with a mixture of ethanol (250 ml.) and a solution or sodium acetate (anhydrous, 4.10 g) in water (25 ml.) for 5 hrs. The reaction mixture was diluted with water and allowed to stand overnight. The solid precipitate was filtered off, washed with water and dried. Recrystallisation from petroleum ether (b.p. 80°-100° C.) gave 4'-chloroflavanone (1.50 g.), m.p. 96°-98° C.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH:10](=O)[CH2:11][CH:12]([CH3:14])[CH3:13].[OH-].[Na+]>[Pd].C(O)C>[CH3:13][CH:12]([CH2:11][CH3:10])[CH2:14][NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)CC=O
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(C)CN[C@@H](CC(C)C)C(=O)O
Yield: 32.6 %

Procedure:
A vessel containing 100 g of L-Leucine, 1600 mL of ethanol, 8 g of 2% Pd/C, and 131.5 g of isovaleraldehyde was shaken under hydrogen. After the reaction was finished, the ethanol solution was collected by filtration. Then 300 mL of concentrated HCl was added to the Pd/C-compound mixture, and the mixture was filtered again to give the second filtrate. The second filtration provided the product in concentrated HCl, and it was added NaOH to pH 6.5. The product precipitated out as a white solid, and it was collected by filtration. The crude product was washed with water (200 mL) and acetone (300 mL), then it was dried under vacuum to yield N-(2-methylbutyl)-leucine (50 g); mp 275° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([C:8]([OH:10])=[O:9])[CH:7]=1.[C:14]1([CH3:24])[CH:19]=[CH:18]C(S(O)(=O)=O)=CC=1>C(O)CCC>[CH2:3]([O:12][C:11]([C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[C:6]([C:8]([O:10][CH2:24][CH2:14][CH2:19][CH3:18])=[O:9])[CH:5]=1)=[O:13])[CH2:2][CH2:7][CH3:6]
Reactant: Nc1cc(C(=O)O)cc(C(=O)O)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: CCCCOC(=O)c1cc(N)cc(C(=O)OCCCC)c1
Temperature: 97 °C
Yield: 181.7 %

Procedure:
A mixture of 5-amino-1,3-benzenedicarboxylic acid (632 g, 3.49 mol), n-butyl alcohol (7.5 L) and p-toluenesulphonic acid (860 g, 4.52 mol) is loaded into a 10 L reaction vessel and heated to 97° C. under stirring under a reduced pressure of about 450 mBar removing the azeotrope n-butyl alcohol/water that forms. After 11 hours of heating the reaction mixture is concentrated to 2.4 L, cooled to 60° C. and neutralised by the addition of 5M NaOH (0.9 L). The mixture is further cooled to about 10° C. and diluted with water 3.4 L). After 15 hours at room temperature the solid is recovered by filtration, washed with water (2×1 L) and dried yielding the 5-amino-1,3-benzenedicarboxylic acid di-n-butyl ester (930 g, 3.17 mol, yield: 91%).
Reaction SMILES: [SH2:1].[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1.C(N(CC)CC)C>N1C=CC=CC=1>[NH2:2][C:3]1[C:8]([C:9](=[S:1])[NH2:10])=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1
Reactant: S
Reactant: CSc1ncc(C#N)c(N)n1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CSc1ncc(C(N)=S)c(N)n1
Reaction time: 1.75 h

Procedure:
Hydrogen sulfide is passed through a suspension of 4-amino-2-methylthio-5-pyrimidinecarbonitrile (16.621 g., 0.100 mole) in a mixture of pyridine (150 ml.) and triethylamine (14.0 ml., 0.100 mole) for 2 hours. The nitrile dissolves in the course of the reaction. After ca. 1.75 hours a solid begins to separate. The mixture is poured into water (500 ml.), and the yellow solid collected by filtration washed with water, dried at 100° C., house vac. The yield of product melting at 230° C. dec. (uncorr.) is 18.93 (94.5%). This material is recrystallized from dimethylformamide-water (Darco G-60) to give yellow rods melting at 229° C. dec. (uncorr.) in a yield of 15.685 g. (78.3%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]([F:48])([F:47])[C:35]1[C:36]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[N:37][CH:38]=[CH:39][CH:40]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:44]1[CH2:43][CH2:42][N:41]([C:36]2[C:35]([C:34]([F:33])([F:47])[F:48])=[CH:40][CH:39]=[CH:38][N:37]=2)[CH2:46][CH2:45]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Product: O=C([C@@H]1C[C@H](NCc2ccc(F)cc2F)CN1Cc1ccccc1)N1CCN(c2ncccc2C(F)(F)F)CC1
Yield: 7.5 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(3-trifluoromethyl-pyridin-2-yl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (5.7 mg, 7.5%) as light yellow oil. MS m/e=560.4 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([OH:14])[CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:17][C:18]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:19]=1[CH2:20][O:21][C@@H:22]1[O:27][C@@H:26]([CH2:28]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:25][CH2:24][CH2:23]1.O>CN(C)C=O>[Cl:17][C:18]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:19]=1[CH2:20][O:21][C@@H:22]1[O:27][C@@H:26]([CH2:28][O:14][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH2:25][CH2:24][CH2:23]1
Reactant: OC(Cn1ccnc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@H](OCc3ccc(Cl)cc3Cl)O2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(CO[C@H]2CCC[C@H](COC(Cn3ccnc3)c3ccccc3)O2)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.2 %

Procedure:
A solution of 106 mg of 1-phenyl-2-(1-imidazolyl)ethanol in 1 ml of dimethylformamide was stirred with 5 mg of 55% sodium hydride at 50° C. for 30 minutes and the mixture was then left to cool at room temperature. To the resulting mixture were added 3 ml of a dimethylformamide solution containing 300 mg of trans-6-(2,4-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran, prepared as described in Example 2(a); the mixture was then stirred at 80° C. for 4 hours and then at 90° C. for 1 hour. At the end of this time, the reaction mixture was cooled, poured into water and extracted with diethyl ether. The ethereal extract was washed with water, dried over anhydrous sodium sulphate and then concentrated to evaporation under reduced pressure. The residue was purified by column chromatography through silica gel eluted with a 30:1 by volume mixture of ethyl acetate and triethylamine, to give 107 mg of the title compound as a liquid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH:19]=[C:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1.C([O-])([O-])=O.[K+].[K+].CN1CCCC1=O>O>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH:19]=[C:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:27]5[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CS(=O)(=O)N1CC=C(c2cc3cc(C4CCNCC4)oc3cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)N1CC=C(c2cc3cc(C4CCN(c5ccc(C(F)(F)F)cn5)CC4)oc3cn2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-furo[2,3-c]pyridine (50 mg), 2-chloro-5-trifluoromethyl-pyridine (25 mg), K2CO3 (40 mg), and N-methylpyrrolidinone (1 mL) is stirred at 60° C. overnight. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are washed with brine, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 4:1→1:2) to give the title compound. LC (method 1): tR=1.05 min; Mass spectrum (ESI+): m/z=507 [M+H]+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([Sn](C)(C)C)=[N:38]1>O1CCOCC1.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.[Cu]I>[C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:39]4[C:40]5[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=5)[N:37]([CH3:36])[N:38]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cn1nc([Sn](C)(C)C)c2ccccc21
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4nn(C)c5ccccc45)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (35.0 mg, 0.066 mmol) and 1-methyl-3-(trimethylstannyl)-1H-indazole (24.0 mg, 0.079 mmol) in dioxane (0.9 mL) was added Pd(PPh3)4 (4.0 mg, 3.03×10−3 mmol) and CuI (4.0 mg, 0.018 mmol). The reaction was degassed for 5 minutes with N2 and then heated at 100° C. overnight. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 70% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C35H34ClN4O3S: 625.2; found: 625.3.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:10]=1[NH2:11].O>C(O)(=O)C>[Br:8][C:9]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:10]=1[NH:11][C:5](=[O:7])[CH3:6]
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic anhydride (1.4 mL, 13.8 mmol) was added dropwise to a stirring solution of 2-bromo-5-nitroaniline (3 g, 13.8 mmol) in glacial acetic acid (30 mL) at 25° C. The reaction mixture was stirred at room temperature overnight, and then poured into water. The precipitate was collected via filtration, washed with water and dried under vacuum to provide N-(2-bromo-5-nitrophenyl)acetamide as an off white solid (3.6 g, 90%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[Cl:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:24]=[O:25]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([Cl:16])=[C:11]([C:12]([F:15])=[CH:13][CH:14]=1)[CH:24]=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(OCc2ccccc2)c(Cl)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c(F)ccc(OCc2ccccc2)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
To a solution of 1-benzyloxy-2-chloro-4-fluoro-benzene (53, 5.8 g, 0.024 mol) in tetrahydrofuran (100 mL) was added 2.50 M of n-butyllithium (2.7 mL, 2.50 M in hexane, 0.029 mol) slowly at −78° C. over 15 minutes under nitrogen. The reaction mixture was stirred at −78° C. for 30 minutes. To the reaction mixture was then added N,N-dimethylformamide (4.2 mL, 0.054 mol). The reaction was allowed to warm to room temperature and was continued at room temperature overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with hydrochloric acid (10%), water, brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a white solid (54, 2.1 g, 32%). MS (ESI) [M+H+]+=265.08.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([S:47]([NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53](B3OC(C)(C)C(C)(C)O3)[CH:52]=2)(=[O:49])=[O:48])=[CH:43][CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:39][O:40][C:41]1[CH:42]=[CH:43][C:44]([S:47]([NH:50][C:51]2[CH:52]=[CH:53][CH:54]=[C:55]([C:2]3[C:10]4[C:9]([NH:11][C@H:12]([C:14]5[N:19]([C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=6)[C:18](=[O:26])[C:17]6=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]6[N:15]=5)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=4[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=3)[CH:56]=2)(=[O:49])=[O:48])=[CH:45][CH:46]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: COc1ccc(S(=O)(=O)Nc2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(S(=O)(=O)Nc2cccc(-c3cn(COCC[Si](C)(C)C)c4ncnc(N[C@@H](C)c5nn6ccc(C)c6c(=O)n5-c5ccccc5)c34)c2)cc1
Yield: 81 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (75 mg, 0.13 mmol) was treated with 4-methoxy-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (236 mg, 0.61 mmol), sodium carbonate (64 mg, 0.61 mmols) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (18 mg, 0.03 mmol) in 1,2-dimethoxyethane (1.2 ml) and water (0.30 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 35%, hexane-ethyl acetate) to give 82 mg (81% yield, 73% purity) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:12]2[N:13]=[CH:14][N:15]=[CH:16][C:11]=2[C:10](Br)=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:24]([O:26]CC)=[CH2:25])CCC.O>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:12]2[N:13]=[CH:14][N:15]=[CH:16][C:11]=2[C:10]([C:24](=[O:26])[CH3:25])=[CH:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)Cn1cc(Br)c2cncnc21
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1cn(CC(=O)OC(C)(C)C)c2ncncc12
Temperature: 25 °C

Procedure:
A solution of (5-bromo-pyrrolo[2,3-d]pyrimidin-7-yl)-acetic acid tert-butyl ester (220 mg, 0.71 mmol), tri-butyl(1-ethoxyvinyl)tin (285 μL, 0.85 mmol) and tetrakis(triphenylphosphine) palladium (16.28 mg, 14.1 μmol) in toluene (7 mL) was heated at 110° C. for 72 h under argon atmosphere. The mixture was allowed to cool to RT, poured into water and extracted with EtOAc (×2). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (CH2Cl2 to CH2Cl2/MeOH 94:6). TLC, Rf (CH2Cl2/MeOH 9:1)=0.54; MS (UPLC/MS): 276.3 [M+H]+, 320.4 [M+HCOO]−; tR (HPLC conditions f): 1.40 min.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(O)C>[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[CH2:16][CH2:15]1
Reactant: OCCN1CCNCC1
Reactant: CSc1ccc(CCl)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CSc1ccc(CN2CCN(CCO)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.6 %

Procedure:
A mixture of 4-(methylthio)benzyl chloride (28.6 g), 1-(2-hydroxyethyl)piperazine (21.6 g), triethylamine (16.8 g), and ethanol (250 ml) is stirred at room temperature for 5 hours. The ethanol is then removed in vacuo and water added to the residue. The product is extracted with ether, dried, and the ether evaporated to give 31.6 g of 1-(2-hydroxyethyl)-4-[4-(methylthio)benzyl] piperazine as an orange oil, suitable for use in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[H-].[Na+].[C:33]([O:37][C:38](=[O:41])[CH2:39]Br)([CH3:36])([CH3:35])[CH3:34]>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:39][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:41])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1cccc(O)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1cccc(OCC(=O)OC(C)(C)C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a solution of 0.40 g (0.94 mmol) of the product of Example 37 in 10 mL of DMF was added 0.047 g (1.171 mmol) of a 60% suspension of sodium hydride in minena oil. The resulting mixture was stirred at room temperature for 0.5 h and then 0.277 mL (1.873 mmol) of t-butylbromoacetate was added in one portion. Th reaction mixture was stirred for an additional 18 h and then diluted with ether, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with ether-hexanes to provide 0.423 g (83%) of the desired product as a white solid. Electrospray Mass Spec: 524.3 (M+H)+
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([O:12][C:13](=[O:18])[NH:14][CH2:15]OC)[CH:9]=[CH:10][CH:11]=1>C(Cl)(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]([O:12][C:13](=[O:18])[NH:14][CH2:15][Cl:3])[CH:9]=[CH:10][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: COCNC(=O)Oc1cccc(Cl)c1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(NCCl)Oc1cccc(Cl)c1
Temperature: 0 °C
Yield: 70.1 %

Procedure:
62 ml (0.85 mole) of thionyl chloride were added to 167 g (0.775 mole) of N-methoxymethylcarbamic acid 3-chlorophenyl ester in 200 ml of carbon tetrachloride. After the evolution of gas had ceased, the mixture was cooled to 0° C, while keeping the reaction mixture stirrable by adding carbon tetrachloride. The precipitate which had separated out was filtered off, rinsed with cold carbon tetrachloride and dried in vacuo at 40° C. 119.5 g (70% of theory) of N-chloromethylcarbamic acid 3-chlorophenyl ester of melting point 90° C were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[CH:13]=C[O:15][C:11]=2[CH:10]=[C:9]2[C:4]=1[C:5](=[O:18])[CH2:6][C:7]([CH3:17])([CH3:16])[O:8]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:38]=[O+][O-]>ClCCl>[OH:15][C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:18])[CH2:6][C:7]([CH3:17])([CH3:16])[O:8]2)=[C:3]([O:2][CH3:1])[C:12]=1[CH:13]=[O:38]
Reactant: O=[O+][O-]
Reactant: COc1c2c(cc3occc13)OC(C)(C)CC2=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1c(C=O)c(O)cc2c1C(=O)CC(C)(C)O2
Temperature: -78 °C
Reaction time: 2 h

Procedure:
500 mg (2.03 mmol) of 4-methoxy-7,7-dimethyl-6,7-dihydro-5H-furo[3,2-g]chromen-5-one (Example 1A) and 666 mg (2.54 mmol) of triphenylphosphine are initially charged, and 50 ml of dichloromethane are added. The mixture is cooled to −78° C., and ozone is then introduced for about 5 min. Once the color of the solution has turned to blue, excess ozone is flushed out with oxygen. The solution is stirred for another two hours and slowly warmed to room temperature. The mixture is concentrated and the residue that remains is purified on a silica gel column (mobile phase: cyclohexane/ethyl acetate 5:1) This gives 370 mg (72% of theory) of the title compound.
Reaction SMILES: [H-].[Na+].C[O:4][C:5]1[C:6](=[CH:13][CH:14]=[CH:15][C:16]=1[Cl:17])[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10].C1C[O:21]CC1>>[C:9]([C:8]1[O:4][C:5]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:6]=2[C:7]=1[OH:21])([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C=Cc1cccc(Cl)c1OC
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1oc2c(Cl)cccc2c1O
Reaction time: 1 h
Yield: 80 %

Procedure:
According to the procedure of D. C. Schroeder, et al., J. Org. Chem., 27, 586 (1962) to a stirred suspension of NaH (50% dispersion in mineral oil, washed with hexane) (4.5 g, 0.093 mol) in THF (20 mL) was added a solution of methyl (methyl 3-chlorosalicylyl)acetate (24.1 g, 0.093 mol) in THF (50 mL). Additional THF (60 mL) was added. After 1 hour, the mixture was heated under reflux for 1 hour, cooled, and partitioned between ether and H2O. The aqueous phase was acidified with 1N HCl and the precipitate was collected by filtration. This material was dissolved in ether. The solution was washed with H2O, dried (MgSO4), and concentrated to give a yellow solid (16.9 g, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:12]Cl)=[C:8]([CH2:10]Cl)[CH:9]=1)=[O:4].[S-2:14].[Na+].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH2:12][S:14][CH2:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(CCl)c(CCl)s1
Reactant: [S-2]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2c(s1)CSC2
Yield: 49.9 %

Procedure:
A solution of 4.8 g (20 mmol) (2) in 240 mL methanol was heated up and kept mild boiling. Sodium sulfide solution (1.7 g, 22 mmol) in 160 mL methanol was added dropwise in 2 h. After cooling of the reaction mixture, the precipitate was filtered off. The solvent was removed by evaporation and the residue was washed by water. Column chromatography on silica gel using dichloromethane yielded the pure title compound as a white solid 2.0 g (50%). 1HNMR (CDCl3): δ 3.87 (3H, s), 4.05-4.06 (2H, t, J=3 Hz), 4.19-4.20 (2H, t, J=3 Hz), 7.48 (1H, s). 13CNMR (CDCl3): 633.12, 33.47, 52.19, 127.90, 137.30, 143.90, 146.64, 162.51.