Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](O)=[O:19])[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:43][O:44][C:45](=[O:63])[C@@H:46]([NH2:62])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][N:57]=[C:56]([CH3:60])[C:55]=2[CH3:61])=[CH:50][CH:49]=1>>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:19])[NH:62][C@H:46]([C:45]([O:44][CH3:43])=[O:63])[CH2:47][C:48]2[CH:49]=[CH:50][C:51]([C:54]3[CH:59]=[CH:58][N:57]=[C:56]([CH3:60])[C:55]=3[CH3:61])=[CH:52][CH:53]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccnc(C)c2C)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Yield: 62.8 %

Procedure:
(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (0.33 g) was coupled with (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (0.20 g) according to General Procedure L to provide (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (0.30 g). LCMS (m/z): 853.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=1.[CH2:16]([CH2:18][NH2:19])[OH:17].CCN(C(C)C)C(C)C>CCCCO>[C:10]1([NH:9][C:5]2[N:6]=[CH:7][N:8]=[C:3]([NH:19][CH2:18][CH2:16][OH:17])[CH:4]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCCO
Reactant: Clc1cc(Nc2ccccc2)ncn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: OCCNc1cc(Nc2ccccc2)ncn1
Temperature: 200 °C
Yield: 97 %

Procedure:
50 mg of 6-chloro-N-phenylpyrimidin-4-amine hydrochloride, 14 mg of ethanolamine and 69 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 45 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc: MeOH 10:1. 2-(6-(Phenylamino)pyrimidin-4-ylamino)ethan-1-ol in the form of a colorless solid was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=O)[NH:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]2=3)=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[S:22])[NH:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]2=3)=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1CC(=O)N(c2ccc(Cl)cc2)c2ccccc2N1
Solvent: c1ccncc1
Product: O=C1CC(=S)Nc2ccccc2N1c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 49.5 %

Procedure:
A solution of 1-(4-chlorophenyl)-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione (2.00 g, 7.0 mmol) and P2S5 (1.87 g, 8.4 mmol) in pyridine (40 ml) was refluxed, with stirring for 1 h under N2 atmosphere. The solvent was evaporated in vacuo to afford a residue. The residue was purified by column chromatography (silica-gel, DCM:MEOH=40:1) to give 1-(4-chlorophenyl)-4-thioxo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (1.05 g, 49%). LRMS (M+H+) m/z: calcd 302.03. found 302.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[N:3]=1.Cl[CH2:21][CH:22]=O.O>C(O)C>[Cl:12][C:11]1[C:2]2[N:3]([CH:21]=[CH:22][N:1]=2)[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=1
Reactant: O=CCCl
Reactant: COC(=O)c1cc(Cl)c(N)nc1-c1cccc(F)c1
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(Cl)c2nccn2c1-c1cccc(F)c1
Yield: 87 %

Procedure:
A solution of methyl 6-amino-5-chloro-2-(3-fluorophenyl)nicotinate (0.19 g, 0.66 mmol) in ethanol (4 mL) at 60° C. was treated with 50 wt % chloroactaldehyde in water (0.34 mL, 2.6 mmol) dropwise. The reaction mixture was stirred at reflux for 2 hours. The reaction mixture was concentrated and purified by flash column chromatography with ethyl acetate in hexanes (0-60%) to give the desired product (180 mg, 87%). LCMS calculated for C15H11ClFN2O2 (M+H)+: m/z=305.0. found: 304.8.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16]C3CCCCO3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[OH:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)[S:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:38])=[O:37])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Ic1ccc(NCc2ccc(OC3CCCCO3)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)N(Cc1ccc(O)cc1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.3 %

Procedure:
To a solution of (4-iodo-phenyl)-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (3.43 g, 8.38 mmol) in 10 mL methylene chloride was added triethylamine (2.0 mL, 14.35 mmol) and benzenesulfonyl chloride (1.2 mL, 9.40 mmol). The reaction mixture was stirred at room temperature for 24 hr. The reaction mixture was quenched with water, was acidified with 1N HCl, and the aqueous solution was washed three times with methylene chloride. The combined organic extracts were washed with saturated aqueous sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated. The residue was dissolved in methanol and the solution was treated with a catalytic amount of 1N HCl. The reaction mixture was stirred at room temperature for 20 hr. The reaction mixture was made basic with saturated aqueous sodium bicarbonate and the aqueous solution was washed two times with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated. Medium pressure silica gel chromatography (10% ethyl acetate/hexanes to 20% ethyl acetate/hexanes) afforded 3.21 g (82%) of the title compound of Step B.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[NH2:35][C:36]1([CH3:48])[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]1>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:35][C:36]5([CH3:48])[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Reactant: CC1(N)CCN(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)CCN(C(=O)OC(C)(C)C)C4)c3n2)c2ccc(F)cc21
Reaction time: 16 h
Yield: 65.2 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.32 mmol) in 6 mL of DMF were added EDCI (123 mmol, 0.64 mmol), DMAP (110 mg, 0.90 mmol) and tert-butyl 3-amino-3-methylpyrrolidine-1-carboxylate (128 mg, 0.64 mmol) in one portion at room temperature and the mixture stirred for 16 hours. The solvent was evaporated at 70° C. under reduced pressure, the residue was triturated with petroleum ether then decanted and dried to give crude tert-butyl 3-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamido)-3-methylpyrrolidine-1-carboxylate (103 mg, 65.2%) as a yellow solid which was used for the next step without further purification.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].Br[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:28])=[O:27])=[CH:22][CH:21]=1>>[OH:4][CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[C:1]#[C:2][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:28])=[O:27])=[CH:22][CH:21]=1
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CS(=O)c1ccc(Br)cc1
Product: CS(=O)c1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
Following the basic procedure of Example 32, by reacting 1.21 g (5 mmol) of α-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol with 1.1 g (5 mmol) of 4-bromophenylsulfinylmethane, 177 mg (9%) of the expected sulfoxide compound, with a melting point of 121°-122° C., were obtained.
Reaction SMILES: C(OC([N:8]([CH2:16][CH:17]=[CH2:18])/[N:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:16]([NH:8]/[N:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:17]=[CH2:18]
Reactant: C=CCN(/N=C/C(=O)OCC)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCN/N=C/C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.5 %

Procedure:
To a solution of E-ethyl 2-(2-t-butoxycarbonyl-2-allylhydrazono)acetate (8.65 g, 33.7 mmol) in dichloromethane (60 ml) was added trifluoroacetic acid (15 ml) at 3° C. After being stirred at room temperature for 1 hour, concentrated in vacuo. The residue was added to a saturated aqueous sodium hydrogen carbonate solution (300 ml), and extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 1.87 g of E-ethyl 2-(2-allylhydrazono)acetate (yield 35%) as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24](O)=[O:25])=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:65][CH2:66][C:67]1[CH:68]=[CH:69][C:70]2[C:74]([CH2:77][F:78])([CH2:75][F:76])[O:73][B:72]([OH:79])[C:71]=2[CH:80]=1>CN(C=O)C>[F:78][CH2:77][C:74]1([CH2:75][F:76])[O:73][B:72]([OH:79])[C:71]2[CH:80]=[C:67]([CH2:66][NH:65][C:24]([C:21]3[C:20]4[N:16]([CH:17]=[CH:18][CH:19]=4)[C:15]([C:12]4[CH2:11][C:10]([C:4]5[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=5)([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=4)=[CH:23][CH:22]=3)=[O:25])[CH:68]=[CH:69][C:70]1=2
Reactant: NCc1ccc2c(c1)B(O)OC2(CF)CF
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccc2c(c1)B(O)OC2(CF)CF)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reaction time: 0.17 h

Procedure:
A solution of 5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.22 mmol) and DIPEA (114 mg, 0.88 mmol) in DMF (5 mL) can be stirred at rt for 5 min and then HATU (169 mg, 0.44 mmol) can be added. The mixture can be stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-bis(fluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (116 mg, 0.44 mmol). And the resulting mixture can be stirred at rt overnight. It can be then concentrated under vacuum, and the residue can be partitioned between 1N HCl and ethyl acetate. The organic layer separated can be concentrated under vacuum, and the residue can be purified by prep-TLC to provide the title product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]([OH:16])=O)=[CH:7][N:8]2[CH2:11][C:12]#[N:13])=[CH:4][CH:3]=1.OC1C2N=NNC=2C=CC=1.ClCCl.[CH3:30][NH:31][CH3:32]>CN(C=O)C>[CH3:30][N:31]([CH3:32])[C:14]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[N:8]([CH2:11][C:12]#[N:13])[CH:7]=1)=[O:16]
Reactant: N#CCn1cc(C(=O)O)c2ccc(Br)cc21
Reactant: CNC
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C(=O)c1cn(CC#N)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a reaction tube was added 26 mg (94 micromol) of 6-bromo-1-cyanomethyl-1H-indole-3-carboxylic acid, 138 mg (approximately 186 micromol of carbodiimide functionality) of polystyrene carbodiimide resin (Argonaut Technologies, Foster City Calif., Product No. 800371), 21.3 mg (158 micromol) of HOBT (hydroxybenzotriazole), 1.5 mL dichloromethane, and 3 drops of DMF. The tube was capped, swirled and allowed to shake on a mechanical shaker for 1 hour at room temperature. The cap was removed, and dimethylamine (1 equivalent, 78 micromol) was added to the tube. The tube was re-capped and shaken for 24 hours at room temperature. 200 microliters of DMF was then added to the tube, and the tube was re-capped and shaken for an additional 48 hours, after which 130 mg (230 micromol) of polystyrene isocyanate resin (Argonaut Technologies, Foster City Calif., Product No. 800260) was added, followed by 1 hour of shaking, to remove excess dimethylamine. The content of the tube was filtered through a Varian liquid extraction tube (pre-washed with 20 microliters of saturated sodium bicarbonate solution), and washed 3× with 1 mL dichloromethane. The combined organic fractions were evaporated under reduced pressure to yield 6-Bromo-1-cyanomethyl-1H-indole-3-carboxylic acid dimethylamide as an oil. Step 4
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C@@H:10]1[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1)=O)(C)(C)C>C(OCC)(=O)C.ClCCl>[ClH:1].[ClH:1].[ClH:1].[N:28]1([C:25]2[CH:24]=[CH:23][C:22]([C@H:10]3[CH2:11][NH:12][CH2:13][CH2:14][NH:9]3)=[CH:27][CH:26]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(N3CCCCC3)cc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: c1cc(N2CCCCC2)ccc1[C@H]1CNCCN1
Reaction time: 2 h
Yield: 98 %

Procedure:
Hydrogen chloride (4N, 1.5 ml) in ethyl acetate was added to a solution of (2S)-2-(4-piperidin-1-yl-phenyl)-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (455 g, 1.02 mmol) in dichloromethane (10 ml) and the solution was stirred for 2 hours. Filtration and washing with ethyl acetate of the precipitant gave (2S)-2-(4-piperidin-1-yl-phenyl)-piperazine trihydrochloride (353 mg, 98%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20]Cl)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH:30]([CH:32]1[CH2:36][CH2:35][CH2:34][NH:33]1)[OH:31]>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20][N:33]4[CH2:34][CH2:35][CH2:36][C@@H:32]4[C@H:30]([C:26]4[O:25][CH:29]=[CH:28][CH:27]=4)[OH:31])[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)sc21
Reactant: OC(c1ccco1)C1CCCN1
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCC[C@@H]3[C@@H](O)c3ccco3)sc21

Procedure:
Analogous to the procedures described in Example 2, N-(4-Chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Preparation 1) is treated with 2-furyl(pyrrolidin-2-yl)methanol (Preparation 4) to afford the title compound
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[CH3:19].CS(O[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)(=O)=O>>[C:15]([C:10]1[C:11](=[O:14])[N:12]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=2)[CH:9]=1)([OH:17])=[O:16]
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Reactant: CS(=O)(=O)OCCc1ccc(Cl)cc1
Product: Cc1cc(-c2cc(C(=O)O)c(=O)n(CCc3ccc(Cl)cc3)n2)ccc1F
Yield: 56.3 %

Procedure:
Following the procedure of Example 1(6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 2-(4-chlorophenyl)ethanol methanesulfonate were reacted to yield a crude product. Without purification, the crude product was reacted further in accordance with the procedure of Example 1 (7) to yield the title compound as a pale yellow solid (yield: 56.3%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][OH:5].[CH3:9][S:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[CH:19]=[C:18]([CH2:20][CH3:21])[N:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:15]=2[N:16]=1.C(Cl)Cl>C1C=CC=CC=1>[CH3:8][O:7][C:3](=[O:6])[CH2:4][O:5][C:13]1[C:14]2[CH:19]=[C:18]([CH2:20][CH3:21])[N:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:15]=2[N:16]=[C:11]([S:10][CH3:9])[N:12]=1
Reactant: COC(=O)CO
Reactant: CCc1cc2c(Cl)nc(SC)nc2n1Cc1ccccc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCc1cc2c(OCC(=O)OC)nc(SC)nc2n1Cc1ccccc1-c1ccccc1
Temperature: 25 °C
Yield: 46.9 %

Procedure:
To a suspension of 64 mg (2.66 mmol) of sodium hydride in 5 mL of benzene was added 200 mg (2.22 mmol) of methyl glycolate and a solution of 350 mg (0.89 mmol) of 2-(methylthio)-4-chloro-6-ethyl-7-([1,1′-biphenyl]-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine in 2.5 ml of benzene then the mixture heated to 60° C. The reaction was monitored for conversion to product by TLC (silica, methylene chloride). Additional sodium hydride (96 mg) and methyl glycolate (360 mg) were added in portions over 4 days. The reaction was cooled to ambient temperature and partitioned by the addition of 15 mL of 2 M sodium hydrogen sulfate and 15 mL of ethyl acetate. The aqueous phase was extracted twice with 7 mL portions of ethyl acetate. The combined organic phases were dried with sodium sulfate and concentrated. The product was purified by flash chromatography (53 g silica, hexanes-ethyl acetate gradient 100:0 to 85:15) to provide 187 mg (47%) of [[2-(methylthio)-6-ethyl-7-([1,1′-biphenyl]-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a solid. nmr (300 MHz, CDCl3) δ1.10 (t, 3H), 2.16 (q, 2H), 2.52 (s, 3H), 3.80 (s, 3H), 5.03 (s, 2H), 5.32 (s, 2H), 6.25 (s, 1H), 6.62 (d, 1H), 7.1-7.6 (m, 8H)
Reaction SMILES: O=[C:2]([CH2:7][C:8](=O)[CH3:9])[C:3]([O:5][CH3:6])=[O:4].O1CCCC1.[Cl:16][C:17]1[C:18]([NH:24][NH2:25])=[N:19][CH:20]=[C:21]([Cl:23])[CH:22]=1>C(O)(=O)C>[Cl:16][C:17]1[C:18]([N:24]2[C:2]([C:3]([O:5][CH3:6])=[O:4])=[CH:7][C:8]([CH3:9])=[N:25]2)=[N:19][CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: COC(=O)C(=O)CC(C)=O
Reactant: NNc1ncc(Cl)cc1Cl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1cc(C)nn1-c1ncc(Cl)cc1Cl
Yield: 50.7 %

Procedure:
To a 100 mL flask, methyl 2,4-dioxopentanoate (2.88 g, 0.020 mol), tetrahydrofuran (15 mL), acetic acid (30 mL), and 3,5-dichloro-2-hydrazinylpyridine (3.56 g, 0.020 mol) were added sequentially. The reaction mixture was heated to reflux for 2 hours and then the mixture was concentrated by rotary evaporator. Then ethyl acetate (150 mL) and water (100 mL) was added, the organic layer was washed with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate and concentrated by rotary evaporator. The residue was purified by silica gel column chromatography (Fluent: ethyl acetate/petroleum ether=1/5) to give the product (2.9 g) as a white solid in 50% yield. Melting point: 97-98° C. 1H NMR (300 MHz, CDCl3): 8.432 (d, 1H), 7.888 (d, 1H), 6.802 (s, 1H), 3.760 (s, 3H), 2.370 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH:4]=[CH:5][C:6]1[O:7][C:8]([CH3:13])=[C:9]([CH2:11]O)[N:10]=1.S(Cl)([Cl:20])=O>>[Cl:20][CH2:11][C:9]1[N:10]=[C:6]([CH:5]=[CH:4][C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=2[Cl:1])[O:7][C:8]=1[CH3:13]
Reactant: Cc1oc(C=Cc2ccccc2Cl)nc1CO
Reactant: O=S(Cl)Cl
Product: Cc1oc(C=Cc2ccccc2Cl)nc1CCl

Procedure:
2-(2-Chlorostyryl)-4-hydroxymethyl-5-methyloxazole (3.6 g) was added portionwise to thionyl chloride (18 ml) with ice-cooling and stirring. The mixture was stirred at room temperature for 20 minutes and the thionyl chloride was distilled off. To the residue was added aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off to give 4-chloromethyl-2-(2-chlorostyryl)-5-methyloxazole as crystals; yield 3.65 g (99.5%). Recrystallization from ethyl ether gave colorless needles melting at 109°-110° C.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[CH:6]([C:8]1[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:10][CH:9]=1)=[O:7].Cl>C(OCC)C.O1CCCC1>[OH:7][CH:6]([C:8]1[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[CH:10][CH:9]=1)[CH2:3][CH:2]=[CH2:1]
Reactant: C=CC[Mg]Br
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC(O)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
A 1.0M solution (200 ml, 200 ml) of allylmagnesium bromide in diethyl ether was dropped into a solution of t-butyl 4-formylbenzoate (30.9 g, 150 mmol) in anhydrous tetrahydrofuran, while stirring the latter under cooling with ice in a nitrogen stream. After the completion of the dropping, the obtained mixture was further stirred for 30 minutes, followed by the addition of 220 ml of 1N hydrochloric acid cooled with ice. The obtained mixture was vigorously stirred. The aqueous layer was further extracted with diethyl ether. The organic layers were combined, washed with an aqueous solution of common salt, dried and concentrated. The residue was purified by silica gel column chromatography to give t-butyl 4-(1-hydroxy-3-butenyl)benzoate. Yield: 8.2 g.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]#[N:12])=[CH:9][N:8]([C@@H:13]3[O:21][C@H:20]([CH2:22][O:23]C(=O)C4C=CC=CC=4)[C@@H:19]([CH3:32])[C@H:14]3[O:15]C(=O)C)[C:4]=2[N:5]=[CH:6][N:7]=1.N.[OH:34]O>>[NH2:1][C:2]1[C:3]2[C:10]([C:11]([NH2:12])=[O:34])=[CH:9][N:8]([C@@H:13]3[O:21][C@H:20]([CH2:22][OH:23])[C@@H:19]([CH3:32])[C@H:14]3[OH:15])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(=O)O[C@@H]1[C@H](C)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cc(C#N)c2c(N)ncnc21
Reactant: OO
Agent: N
Product: C[C@H]1[C@@H](O)[C@H](n2cc(C(N)=O)c3c(N)ncnc32)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the compound from Step B (51 mg, 0.12 mmol), ethanolic ammonia (5 mL, saturated at 0° C.), aqueous ammonia (5 mL, 30%) and aqueous hydrogen peroxide (1 mL, 35%) was stirred room temperature for 8 h. The solution was evaporated and the residue purified on silica gel column with a solvent system of CH2Cl2/MeOH: 10/1 to give the title compound as a white solid (28 mg).