Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2=[O:21])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[OH:21][CH2:11][CH:10]([C:14]1[C:13]([OH:12])=[C:18]([CH3:19])[C:17]([CH3:20])=[CH:16][CH:15]=1)[C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=1
Reactant: Cc1ccc2c(c1C)OC(=O)C2c1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(C(CO)c2ccc(C(C)C)cc2)c(O)c1C
Yield: 36 %

Procedure:
Using 3-(4-isopropylphenyl)-6,7-dimethyl-1-benzofuran-2 (3H)-one synthesized in Reference Example 3, the title compound was synthesized in the same manner as in Reference Example 8. Yield 36%. Melting point: 83-84° C. (ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:19][C:20]1[CH:41]=[CH:40][C:23]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][N:29]3[CH:37]=[CH:38][CH:39]=[C:28]3[CH2:27]2)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl.C(OCC)(=O)C>[CH:39]1[CH:38]=[CH:37][N:29]2[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=4[Cl:1])=[CH:41][CH:40]=3)=[O:25])[CH2:27][C:28]=12
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccc(Cl)cc1Cl
Reaction time: 0.05 h
Yield: 53.5 %

Procedure:
To a solution of 415 mg of 2,4-dichlorobenzoyl chloride in 5 ml of methylene chloride at 0° C. is added 346 μl of triethylamine. After stirring for 3 minutes, 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added. The bath is removed and the reaction mixture stirred at room temperature for 18 hours. The volatiles are concentrated in vacuo to give a residue which is dissolved in ethyl acetate, washed with water, 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried with Na2SO4, filtered and concentrated in vacuo to give a residue which is crystallized from ethyl acetate to give 420 mg of the desired product as a crystalline solid, m.p., 210°-212° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](O)=[C:11]3[CH2:14][S:15][CH2:16][CH2:17][C:10]3=[N:9]2)=[CH:4][CH:3]=1.P(Br)(Br)([Br:20])=O.C(=O)(O)[O-].[Na+]>C1(C)C(C)=CC=CC=1>[Br:20][C:12]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[C:10]2[CH2:17][CH2:16][S:15][CH2:14][C:11]=12
Reactant: O=P(Br)(Br)Br
Reactant: Oc1c2c(nn1-c1ccc(Cl)cc1)CCSC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: Clc1ccc(-n2nc3c(c2Br)CSCC3)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 10.6 parts of 2-(4-chlorophenyl)-3-hydroxy-2,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole, prepared according to the method of Example 1, and 12 parts of phosphorous oxybromide in 120 parts of xylene was refluxed for 7 hours and then stirred at room temperature for 12 hours. The suspension was neutralized with 5% sodium bicarbonate followed by extraction with chloroform (3 × 100 parts). The chloroform solution was washed with a saturated NaCl solution, dried over anhydrous magnesium sulfate and evaporated at a reduced pressure of 50 to 300 mm Hg, yielding a brown oil. This oil crystallized from acetone yielding 4.3 parts of the desired product, m.p. 138°-145° C.; a second recrystallization from acetone/methylene chloride gave 3.4 parts of pure 3-bromo-2-(4-chlorophenyl)-2,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazole, m.p. 143.5°-145° C.
Reaction SMILES: [Mg].Br[C:3]1[C:12]([O:13][CH2:14][CH3:15])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[Cl:16][CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.[Cl-].[NH4+].[H][H]>O1CCCC1>[ClH:16].[CH2:14]([O:13][C:12]1[C:3]([CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:15]
Reactant: [H][H]
Reactant: ClCc1ccncc1
Reactant: CCOc1cc2ccccc2cc1Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOc1cc2ccccc2cc1CC1CCNCC1
Product: Cl

Procedure:
To a suspension of 2.5 g (0.1 mole) of magnesium in 20 ml of tetrahydrofuran is added gradually a solution of 25 g (0.1 mole) of 2-bromo-3-ethoxynaphthalene in 25 ml of tetrahydrofuran. The agitated mixture is refluxed for 1 hour and a solution of 1.4 g (0.1 mole) of 4-chloromethylpyridine dissolved in tetrahydrofuran added gradually. The mixture is refluxed for 3 hours, a saturated ammonium chloride solution is added, the reaction mixture is extracted with ether, and the organic phase washed with sodium carbonate and dried over sodium sulfate. The ether is evaporated and the resulting 4-[(3-ethoxy-2-naphthyl)methyl]pyridine dissolved in acetic acid and agitated in a Parr apparatus in the presence of 1.5 g of platinum oxide. Hydrogen gas is introduced and the reaction continued until 0.3 mole of hydrogen is consumed. The solution is filtered and the solvent removed in vacuo. The residue is dissolved in ether and an excess of dry HCl bubbled through the solution to yield 4 -[(3-ethoxy-2-naphthyl)methyl]piperidine hydrochloride.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]([C:11]1[CH:12]=[C:13]([S:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[S:29][CH2:30][C:31](O)=[O:32])[CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])([CH3:10])[CH3:9].[CH3:34][NH:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1.C(N(CC)CC)C>C1C=CC=CC=1.O1CCCC1>[CH3:21][C:18]([C:15]1[CH:14]=[C:13]([S:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[S:29][CH2:30][C:31]([N:35]([CH3:34])[CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)=[O:32])[CH:12]=[C:11]([C:8]([CH3:7])([CH3:9])[CH3:10])[C:16]=1[OH:17])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2SCC(=O)O)cc(C(C)(C)C)c1O
Reactant: CNCCc1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN(CCc1ccccn1)C(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Oxalyl chloride (0.13 g, 0.00105 moles) was added to a cold (10° C.) solution of trans-[[2-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]cyclohexyl]thio]acetic acid (0.39 g, 0.00095 mole) in benzene (50 ml). The cold bath was removed and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo to an oil. The oil was dissolved in toluene (50 ml) and then concentrated once again. The process was repeated using tetrahydrofuran (25 ml) in place of toluene. To a solution of the oil in tetrahydrofuran (50 ml) was added 2-(2-methylaminoethyl) pyridine (0.13 g, 0.00095 moles) and triethylamine (1 ml) and the reaction mixture was stirred at room temperature for 44 hours. After removal of the while solid precipitate by filtration, the filtrate was concentrated to give the crude product as an oil. The product was purified by silica gel chromatography. The resulting oil was heated in vacuo at 100° C. for 3 hours to remove traces of solvent. The structure assignment was supported by NMR, infrared spectroscopy and elemental analysis.
Reaction SMILES: [C:1]12[C:12]([O:13][CH:14]3[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]3)=[N:11][CH:10]=[N:9][C:8]=1[S:7][C:6]1[CH2:5][CH2:4][CH2:3][C:2]2=1.Cl[CH2:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24]>C(O)C>[N:25]1([C:23](=[O:24])[CH2:22][NH:20][C@H:17]2[CH2:18][CH2:19][C@H:14]([O:13][C:12]3[C:1]4[C:2]5[CH2:3][CH2:4][CH2:5][C:6]=5[S:7][C:8]=4[N:9]=[CH:10][N:11]=3)[CH2:15][CH2:16]2)[CH2:29][CH2:28][CH2:27][CH2:26]1.[O:24]=[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:22][N:20]([C@H:17]1[CH2:18][CH2:19][C@H:14]([O:13][C:12]2[C:1]3[C:2]4[CH2:3][CH2:4][CH2:5][C:6]=4[S:7][C:8]=3[N:9]=[CH:10][N:11]=2)[CH2:15][CH2:16]1)[CH2:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24]
Reactant: O=C(CCl)N1CCCC1
Reactant: NC1CCC(Oc2ncnc3sc4c(c23)CCC4)CC1
Solvent: CCO
Product: O=C(CN(CC(=O)N1CCCC1)[C@H]1CC[C@H](Oc2ncnc3sc4c(c23)CCC4)CC1)N1CCCC1
Product: O=C(CN[C@H]1CC[C@H](Oc2ncnc3sc4c(c23)CCC4)CC1)N1CCCC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of 4-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yloxy]cyclohexan-1-amine (140 mg, 0.48 mmol, 1.00 equiv) in ethanol (20 mL) was added 2-chloro-1-(pyrrolidin-1-yl)ethan-1-one (72 mg, 0.49 mmol, 1.00 equiv) and KI (80 mg, 1.00 equiv) and the resulting solution was stirred for 8 h at 90° C. in an oil bath. After concentrated in vacuo, the crude product (160 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% HCOOH and CH3CN (6.0% CH3CN up to 52.0% in 14 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired trans-1-(pyrrolidin-1-yl)-2-[(4-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yloxy]cyclohexyl)amino]ethan-1-one (14.4 mg) as a off-white solid and trans-2-[[2-oxo-2-(pyrrolidin-1-yl)ethyl](4-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yloxy]cyclohexyl)amino]-1-(pyrrolidin-1-yl)ethan-1-one (32.8 mg) as a off-white solid, respectively.
Reaction SMILES: [O-]CC.[Na+].Cl.[NH2:6][C:7]([NH2:9])=[NH:8].ClCCl.[CH2:13]([O:15][C:16](=[O:27])[C:17]([C:21](=O)[C:22]([F:25])([F:24])[F:23])=[CH:18]OC)[CH3:14]>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[C:21]([C:22]([F:23])([F:24])[F:25])=[N:8][C:7]([NH2:9])=[N:6][CH:18]=1)=[O:27])[CH3:14]
Reactant: N=C(N)N
Reactant: CCOC(=O)C(=COC)C(=O)C(F)(F)F
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cnc(N)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
Sodium ethoxide (2 eq, 83.8 mmol, 5.7 g) was added in one portion to a solution of guanidine hydrochloride (4 g, 41.9 mmol) in absolute ethanol (100 ml) and the resulting mixture was stirred at ambient temperature for 1 hour. A dichloromethane solution of 3-methoxy-2-(2,2,2-trifluoro-acetyl)-acrylic acid ethyl ester was then added and the mixture was stirred at ambient temperature for an additional 20 hours. The solvent was then removed by evaporation, water was added to the residue, and the mixture was stirred vigorously for 2 hours then allowed to stand at room temperature. The resulting solid was isolated by filtration, washed with water then dried in vacuo to afford 6.10 g (62% yield) of 2-amino-4-trifluoromethyl-pyrimidine-5-carboxylic acid ethyl ester. m/z (M+H)=236.2.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].BrC1C=CC=C2C=1[C:25]1([C:36]3=CC4OCOC=4[CH:43]=[C:35]3[O:34][CH2:33]1)C(=O)N2.ClCC1OC=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[O:34]1[CH:33]=[CH:25][CH:36]=[C:35]1[CH2:43][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21]
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: ClCc1ccco1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2ccco2)c2ccccc2C12COc1cc3c(cc12)OCO3
Yield: 40 %

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 2-chloromethylfuran to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound (40%) as a colorless solid: mp 110-112° C.; 1H NMR (300 MHz, CDCl3) δ 7.35-7.33 (m, 1H), 7.29-7.23 (m, 1H), 7.15 (d, 1H), 7.06-7.00 (m, 2H), 6.50 (s, 1H), 6.34-6.31 (m, 2H), 6.10 (s, 1H), 5.85 (dd, 2H), 4.92 (ABq, 2H), 4.79 (ABq, 2H); 13C NMR (75 MHz, CDCl3) δ 177.1, 155.9, 149.0, 148.9, 142.6, 142.3, 141.8, 132.2, 128.9, 123.8, 123.5, 119.5, 110.6, 109.3, 108.7, 103.1, 101.5, 93.6, 80.4, 58.2, 37.1; MS (ES+) m/z 362.5 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[S:10]([CH2:13][CH:14]([CH3:16])[CH3:15])(=[O:12])=[O:11])[CH2:3][CH2:2]1.[CH3:20][C:21]1([CH3:26])[CH2:25][CH2:24][CH2:23][NH:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([N:22]3[CH2:23][CH2:24][CH2:25][C:21]3([CH3:26])[CH3:20])=[O:19])=[N:8][C:9]=2[S:10]([CH2:13][CH:14]([CH3:15])[CH3:16])(=[O:11])=[O:12])[CH2:2][CH2:3]1
Reactant: CC1(C)CCCN1
Reactant: CC(C)CS(=O)(=O)c1nc(C(=O)O)ccc1C1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CS(=O)(=O)c1nc(C(=O)N2CCCC2(C)C)ccc1C1CC1

Procedure:
In analogy to the procedure described in Example 47 b), 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid (Example 6 d)) was reacted with 2,2-dimethylpyrrolidine (CAN 35018-15-6) in the presence of TBTU and DIEA to obtain the title compound as colorless solid; MS (EI): m/e=365.5 [MH+].
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].N1C=CC=CC=1.C[C:12]1[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:15]2[CH:24]=[C:25]([C:28]3[CH:29]=[CH:30][C:31]4[O:37][CH2:36][CH2:35][NH:34][CH2:33][C:32]=4[CH:38]=3)[CH:26]=[CH:27][C:14]=2[N:13]=1>C(Cl)(Cl)Cl>[Cl:4][C:1]([N:34]1[CH2:33][C:32]2[CH:38]=[C:28]([C:25]3[CH:26]=[CH:27][C:14]4[N:13]=[CH:12][N:16]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C:15]=4[CH:24]=3)[CH:29]=[CH:30][C:31]=2[O:37][CH2:36][CH2:35]1)=[O:2]
Reactant: O=C(Cl)Cl
Reactant: Cc1nc2ccc(-c3ccc4c(c3)CNCCO4)cc2n1C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)n1cnc2ccc(-c3ccc4c(c3)CN(C(=O)Cl)CCO4)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
Phosgene (20 W % in toluene) (190 uL, 0.38 mmol) was added by syringe to a 0° C. cooled solution of pyridine (100 uL, 1.2 mmol) in chloroform (3 mL) followed by addition of 1,1-dimethylethyl 2-methyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazole-1-carboxylate as obtained in step 7 as a solution in chloroform (1 mL). The mixture was stirred for 15 minutes at 0° C. then partitioned with 10% aqueous citric acid. The organic phase was dried over anhydrous sodium sulfate then filtered and concentrated. The residue was purified by silica gel chromatography to give 1,1-dimethylethyl 6-[4-(chlorocarbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-1H-benzimidazole-1-carboxylate (62.6 mg, 59% yield) as a yellow amorphous residue. MS (EI) for C23H24ClN3O4: 442 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[C:4]([CH3:12])[N:3]=1.C(N(CC)CC)C.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:20]([NH:27][C:6]1[CH:5]=[C:4]([CH3:12])[N:3]=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(NCc2ccccc2)c([N+](=O)[O-])c(Cl)n1
Temperature: 25 °C
Yield: 26.6 %

Procedure:
2,4-Dichloro-6-methyl-3-nitro-pyridine (2 g, 9.7 mmol) and triethylamine (1.35 mL, 9.7 mmol) were dissolved in 40 mL THF and cooled (ice/water) to ˜5° C. A solution of benzylamine (1.04 g, 9.7 mmol) in 10 mL THF was added dropwise and the mixture was then allowed to warm gradually to room temperature overnight. The mixture was evaporated in vacuo, partitioned between EtOAc (50 mL) and water (20 mL). The organic layer was washed with saturated aqueous NaHCO3 (10 mL), dried (MgSO4) and evaporated in vacuo to an orange gum. This gum was preabsorbed onto silica gel and then purified by column chromatography, eluting with DCM:pentane 3:1. Appropriate fractions combined and evaporated in vacuo to yield the title compound as a yellow solid (716 mg).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14]2[C:15]([C:21]#N)=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[Cl:9].I[C:24]1[C:25]2[CH:32]=[CH:31][NH:30][C:26]=2[N:27]=[CH:28][N:29]=1.C1C[O:36]CC1>C1([Mg]Cl)C=CC=CC=1.C([Mg]Cl)(C)C>[Cl:2][C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14]2[C:15]([C:21]([C:24]3[C:25]4[CH:32]=[CH:31][NH:30][C:26]=4[N:27]=[CH:28][N:29]=3)=[O:36])=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)(=[O:11])=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Cc1cnc(C#N)c(NS(=O)(=O)c2ccc(Cl)c(Cl)c2)c1
Reactant: C1CCOC1
Reactant: Ic1ncnc2[nH]ccc12
Agent: CC(C)[Mg]Cl
Agent: Cl[Mg]c1ccccc1
Agent: [Na]
Product: Cc1cnc(C(=O)c2ncnc3[nH]ccc23)c(NS(=O)(=O)c2ccc(Cl)c(Cl)c2)c1

Procedure:
Prepared from 563 mg (1.55 mmol) of 3,4-dichloro-N-(2-cyano-5-methyl-pyridin-3-yl)-benzenesulfonamide sodium salt, 506 mg (2.01 mmol) of 97% 4-iodo-7H-pyrrolo[2,3-d]pyrimidine dissolved in 6 mL THF with 1.16 mL of 1.8 M phenylmagnesium chloride solution in THF and 1.06 mL of 2 M isopropylmagnesium chloride solution in THF added. The reaction yielded 471 mg of the final product as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Li]CCCC.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([B:19]([OH:24])[OH:20])=[CH:3][CH:4]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Brc1ccc(N2CCOCC2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OB(O)c1ccc(N2CCOCC2)cc1
Reaction time: 8 h

Procedure:
To a solution of the compound prepared in step 1 (0.3 g) in THF (15 mL) was added n-BuLi (0.74 mL, 2 M in pentane) at 78° C. After 1 h triisopropyl borate (0.86 mL) was added at −78° C. The solution was warmed up slowly from −78° C. to room temperature and was stirred overnight. The solution was added to aqueous NH4Cl, a white precipitate formed, and EtOAc was added. The organic solution was separated, concentrated and co-evaporated with toluene. The residue washed twice with THF and filtered. The filtrate was concentrated and dried under high vacuum to give 0.25 g of light yellow precipitate. LC/MS m/z 208 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[CH3:12][N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[N:3]=[C:4]([N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: CNc1ccccc1
Reactant: Clc1nc(Cl)c2ccsc2n1
Solvent: ClC(Cl)Cl
Product: CN(c1ccccc1)c1nc(N(C)c2ccccc2)c2ccsc2n1

Procedure:
2,4-Dichlorothieno[2,3-d]pyrimidine (2 g, 0.00975 mol) and N-methylaniline (5 ml) were heated in an oil bath at 150° for 2 hours. The reaction mixture was dissolved in chloroform (200 ml) and extracted with 2N hydrochloric acid (3×100 ml). The chloroform solution was then washed with sodium carbonate solution, dried over magnesium sulphate, filtered and evaporated to give an oil. The oil was purified by chromatography using dichloromethane as eluant. The solid obtained was recrystallized from ether/petroleum ether (b.p. 40°-60°) to give the title compound, (1.2 g) m.p. 85°-87°.
Reaction SMILES: CN(C)[CH:3]=[C:4]([N:9]=[CH:10]N(C)C)[C:5]([O:7][CH3:8])=[O:6].[CH2:15]([N:17]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18]1)[CH3:16]>C(O)(=O)C.C(O)(C(F)(F)F)=O>[CH2:15]([N:17]1[C:21]2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[N:9]=[CH:10][C:20]=2[C:19]([CH3:22])=[CH:18]1)[CH3:16]
Reactant: COC(=O)C(=CN(C)C)N=CN(C)C
Reactant: CCn1ccc(C)c1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCn1cc(C)c2cnc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.8 %

Procedure:
In a 500 ml round bottom flask, methyl 3-(dimethylamino)-2-((dimethylamino)methyleneamino)acrylate (1A, 12 g, 61 mmol) was dissolved in acetic acid (45 ml) and TFA (15 ml). 1-Ethyl-3-methyl-1H-pyrrole (6.7 g, 61 mmol) was added and the mixture was stirred at room temperature for an hour and then at 110° C. for 4 hours. Volatiles were then evaporated from the reaction mixture, the residue was cooled in an ice bath and ice cold saturated K2CO3 solution (˜200 ml) was slowly added to it. The mixture was extracted with EtOAc (3×250 ml). Combined organic layers were then washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified on a silica column using hexane-EtOAc (0-100%). Pure fractions were combined and evaporated to give the product methyl 1-ethyl-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (1N, 6.1 g, 46% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 1.34 (t, J=7.20 Hz, 3H) 2.34 (d, J=1.01 Hz, 3H) 3.88 (s, 3H) 4.26 (q, J=7.24 Hz, 2H) 7.48 (d, J=1.01 Hz, 1H) 8.20 (d, J=1.01 Hz, 1H) 8.85 (d, J=1.01 Hz, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C([O-])(O)=O.[Na+].[N:13]#[C:14]Br>ClCCl.O>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:14]#[N:13])[CH2:4][CH2:3]1
Reactant: N#CBr
Reactant: OC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#CN1CCC(O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Hydroxypiperidine (10 g) is dissolved in 20 ml dichloromethane and added dropwise to a solution of NaHCO3 (16.6 g) in H2O (10 ml) at 0° C. The mixture is stirred at 0° C. for 30 min then 3 M cyanogen bromide (36.3 ml) is added. The mixture is stirred at 0° C. for 30 min then warmed to room temperature for 12 h. The mixture is diluted with dichloroemthane (30 ml) and extracted. The organic layer is washed with brine (15 ml), dried over MgSO4, filtered and concentrated. The crude product is purified by silica gel chromatography (0% to 100% ethyl acetate/hexanes) to afford the title compound. LC (method 20): tR=0.49 min; Mass spectrum (APCI): m/z=127 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[NH2:3].N1C=CC=CC=1.C(#N)C.[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26](Cl)=[O:27]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26]([NH:3][N:2]([CH3:1])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)(=[O:5])=[O:6])=[O:27]
Reactant: O=C(Cl)c1c(F)cccc1Cl
Reactant: CN(N)S(=O)(=O)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC#N
Product: CN(NC(=O)c1c(F)cccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
Into a 100 mL three necked round bottom flask equipped with a magnetic stirrer and condenser, under an atmosphere of nitrogen, was added 2-methyl-2-[(4-chlorophenyl)sulfonyl] hydrazine (5.4 g, 24.5 mmol), pyridine (1.93 g, 1.98 mL, 24.5 mmol), 4-dimethylaminopyridine (0.15 g, 1.2 mmol), and acetonitrile (50 mL). The mixture was cooled to 10° C. and 2-fluoro-6-chlorobenzoyl chloride (4.65 g, 23.4 mmol) was added dropwise at a rate such that the temperature did not rise above 10° C. The mixture was allowed to stir at RT overnight. The solvent was removed from the reaction mixture in vacuo to give an off white solid and the solid was diluted with methylene chloride and extracted with 1N HCl (20 mL), saturated sodium bicarbonate (20 mL), dried (Na2SO4), and the solvent removed in vacuo to give 1-(2-fluoro-6-chlorobenzoyl)-2-methyl-2-[(4-chlorophenyl)sulfonyl] hydrazine as a yellow oil which was used without purification.