Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:20]([CH3:19])(=[O:22])=[O:21])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(Br)cnc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)Nc1cc(Br)cnc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 5-bromo-2-chloropyridin-3-amine (1.0 g, 4.8 mmol) and diisopropylethylamine (1.85 mL, 10.6 mmol) in dichloromethane (25 mL) was cooled to 0° C., and then methanesulfonyl chloride (750 uL, 9.6 mmol) was added slowly. The reaction mixture was stirred at 0° C. for 15 min and was then warmed to rt. After stirring for 2 h, water was added, and then the biphasic mixture was partitioned. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was then dissolved in dioxane (10 mL) and water (10 mL). Potassium carbonate (2.76 g, 20 mmol) was added, and the reaction mixture was stirred for 15 h at rt. Water was then added to the mixture which was subsequently acidified with aqueous citric acid (10%). The aqueous mixture was extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (gradient, 100% hexanes to 50% hexanes: 50% ethyl acetate) to provide
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[C:4]=1B(O)O)#[N:2].C([O-])([O-])=[O:15].[K+].[K+].[CH3:20][O:21][C:22](=[O:50])[C@H:23]([CH2:35][C:36]1[CH:41]=[CH:40][C:39](OS(C(F)(F)F)(=O)=O)=[CH:38][CH:37]=1)[NH:24][C:25](=[O:34])[C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33]>COCCOC.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:20][O:21][C:22](=[O:50])[C@H:23]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:4]2[C:3]([C:1](=[O:15])[NH2:2])=[CH:8][CH:7]=[CH:6][C:5]=2[C:9]#[N:10])=[CH:38][CH:37]=1)[NH:24][C:25](=[O:34])[C:26]1[C:27]([Cl:33])=[CH:28][CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cccc(C#N)c1B(O)O
Reactant: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COC(=O)[C@H](Cc1ccc(-c2c(C#N)cccc2C(N)=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 80 °C
Yield: 65.5 %

Procedure:
To a mixture of 2,6-dicyanobenzene boronic acid (0.516 g) and anhydrous K2CO3 (0.52 g) in DME/H2O (10 mL/0.5 mL) under N2 was added N-(2,6-dichlorobenzoyl)-O-(trifluoromethanesulfonyl)-L-tyrosine methyl ester (0.5 g), The catalyst Pd(PPh3)4 (0.1 g) was added and the mixture was heated at 80° C. for 5 h. The mixture was cooled, diluted with EtOAc and washed successively with water and brine. The organic layer was dried (MgSO4), evaporated, and the residue was purified by column chromatography (silica gel; eluent: EtOAc/hexane 3/1)) to yield 325 mg of N-(2,6-dichlorobenzoyl)-4-(2-cyano-6-carbamoyl-phenyl)-L-phenylalanine methyl ester. ESMS: m/z 496 (MH+), 494 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[N:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7](Cl)=[O:8].[CH2:20](N(C(C)C)C(C)C)C.[Cl:29][C:30]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[C:32]([Cl:38])[C:31]=1[NH2:39].[H-].[Na+].IC>CN(C=O)C>[Cl:29][C:30]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[C:32]([Cl:38])[C:31]=1[N:39]([CH3:20])[C:7](=[O:8])[C:6]1[CH:10]=[C:11]([F:14])[CH:12]=[N:13][C:5]=1[O:4][C:3]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:2]=1[Cl:1]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)c1cc(F)cnc1Oc1cc(Cl)ccc1Cl
Reactant: COc1ccc(Cl)c(N)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(Cl)c(N(C)C(=O)c2cc(F)cnc2Oc2cc(Cl)ccc2Cl)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.9 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-5-fluoro-nicotinoyl chloride (76.6 mg, 0.24 mmol, 1.0 equiv) in anhydrous DMF (1 mL) was added N-ethyldiisopropylamine (155 mg, 205 μL, 1.2 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and 2,6-dichloro-3-methoxy-phenylamine (50.7 mg, 0.264 mmol, 1.1 equiv; [CAS RN 55285-43-3]) and the reaction mixture stirred at rt over night. To this solution was added sodium hydride (20.6 mg, 0.48 mmol, 2.0 equiv; 55% free-flowing powder moistened with oil; [CAS RN 7646-69-7]) and iodomethane (68.2 mg, 29 μL, 0.48 mmol, 2.0 equiv; [CAS RN 74-88-4]) and stirring of the reaction mixture at rt continued for 2 h. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 8.1 mg (7%) of the title compound as an off-white powder. MS (ISP): 490.9 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:6]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:5]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:4][C@H:3]1[OH:33].C1N=CN([C:39]([N:41]2[CH:45]=N[CH:43]=[CH:42]2)=[S:40])C=1.N1CCC[CH2:47]1>C(Cl)Cl>[CH2:9]([O:8][C@H:7]1[C@H:6]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:5]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:4][C@@H:3]([OH:33])[C@@H:2]1[NH:1][C:39]([N:41]1[CH2:42][CH2:43][CH2:47][CH2:45]1)=[S:40])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: N[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)C[C@H]1O
Reactant: C1CCNC1
Solvent: ClCCl
Product: O[C@@H]1C[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1NC(=S)N1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A mixture of (1R,2S,3R,4R,5R)-2-amino-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)cyclohexanol (0.210 g, 0.469 mmol), 1,1-thiocarbonyldiimidazole (Thio-CDI) (0.125 g, 0.704 mmol) in DCM (10 mL) was stirred at room temperature for 3 h. Pyrrolidine (0.10 mL) was then added, and the mixture was further stirred for 1 h. The solvent was removed under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 2:3 to 4:1), affording the product as a pale yellow solid (0.26 g, 99%). 1H NMR (400 MHz, CDCl3) δ 7.29-7.16 (m, 15H), 5.06 (d, J=7.5 Hz, 1H), 4.77 (d, J=12.0 Hz, 1H), 4.71 (d, J=10.8 Hz, 1H), 4.70-4.66 (m, 1H), 4.57 (d, J=12.0 Hz, 1H), 4.50 (d, J=10.8 Hz, 1H), 4.42 (s, 2H), 4.19 (s, broad, 1H), 3.65 (t, J=8.8 Hz, 1H), 3.56 (dd, J=4.5, 8.8 Hz, 1H), 3.51-3.40 (m, 3H), 2.07-2.02 (m, 1H), 1.76-1.62 (m, 6H).
Reaction SMILES: [O:1]=[C:2]1[CH:7](C(OCC)=O)[C:6](=[O:13])[CH:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:4][NH:3]1>C(#N)C.O>[C:14]1([CH:5]2[CH2:4][NH:3][C:2](=[O:1])[CH2:7][C:6]2=[O:13])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C1C(=O)NCC(c2ccccc2)C1=O
Solvent: CC#N
Solvent: O
Product: O=C1CC(=O)C(c2ccccc2)CN1
Yield: 62.2 %

Procedure:
Sodium (380 mg, 16.52 mmol) was dissolved in anhydrous ethanol (13 mL) and the resulting solution was treated dropwise with 3-(2-ethoxycarbonyl-acetylamino)-2-phenyl-propionic acid ethyl ester (4.23 g, 13.76 mmol) dissolved in anhydrous toluene (35 mL). The reaction was kept at 80° C. for 1.5 hours. After cooling, the mixture was extracted with water. The aqueous extracts were acidified with 2 N HCl, extracted with ethyl acetate and the organic layers were collected, dried over Na2SO4 and evaporated to dryness to obtain ethyl 2,4-dioxo-5-phenylpiperidine-3-carboxylate (1.73 g, Y=48%) which was used for the next step without further purification. Ethyl 2,4-dioxo-5-phenylpiperidine-3-carboxylate (1.73 g, 6.63 mmol) was dissolved in acetonitrile containing 1% of water (30 mL) and the resulting solution was refluxed for 2 hours. After evaporating to dryness, the crude material was chromatographed on silica gel, eluting with methylene chloride/methanol 92/8, to give the title compound (780 mg, Y=62%) as a solid.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:18]([OH:20])=O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:21][NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OC(=O)NC(C(N1CCC(C)CC1)=O)CCC1C=CC=CC=1Cl)(C)(C)C>>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:18](=[O:20])[N:22]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:21])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)O
Reactant: CNCc1ccccc1
Agent: CC1CCN(C(=O)C(CCc2ccccc2Cl)NC(=O)OC(C)(C)C)CC1
Product: CN(Cc1ccccc1)C(=O)[C@@H](CCc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
tert-Butyl{(1R)-1-[benzyl(methyl)carbamoyl]-3-phenylpropyl}carbamate is prepared from Boc-(D)-homophenylalanine and N-methylbenzylamine in the same manner that tert-butyl{3-(2-chlorophenyl)-1-[(4-methylpiperidin-1-yl)carbonyl]propyl}carbamate is synthesized.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]2[C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[NH:16][C:13]2=[N:14][CH:15]=1.C1CCCCC1>[Pd].C1(C)C=C(C)C=C(C)C=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:16][C:13]2=[N:14][CH:15]=1
Reactant: COc1ccc(F)c(-c2cnc3[nH]c4c(c3n2)CCCC4)c1
Agent: [Pd]
Solvent: Cc1cc(C)cc(C)c1
Solvent: C1CCCCC1
Product: COc1ccc(F)c(-c2cnc3[nH]c4ccccc4c3n2)c1
Temperature: 200 °C

Procedure:
A sealed tube containing 2-(2-Fluoro-5-methoxyphenyl)-6,7,8,9-tetrahydro-indolo[2,3-b]pyrazine (46 mg, 0.155 mmol), cyclohexane (10 equiv., 0.157 mL, 1.55 mmol), Pd black (35 mg) and mesitylene (10 mL) was heated to 200° C. in an oil bath and the contents stirred via a magnetic stir bar. The progress of the reaction was monitored by intermittently opening the cooled tube and taking out an aliquot for TLC analysis (30% ethyl acetate/hexanes eluent; the aromatized product has a slightly larger Rf value than that of the starting material). Upon completion of the reaction, the mixture was filtered through celite and the mesitylene removed using a high vacuum rotary evaporator. Recrystallization from hexanes/ethyl acetate afforded 2-(2-Fluoro-5-methoxyphenyl)-5H-indolo[2,3-b]pyrazine (Compound 2) as an off-white solid.
Reaction SMILES: [Na].[SH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.Br[CH:15]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16]([CH:15]([S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)C(Br)c1ccc(OC)cc1
Reactant: Sc1ccccc1-n1cccc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Sc1ccccc1-n1cccc1)c1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
To a solution of sodium (0.46 g, 0.02 g-atom) in 25 mL of anhydrous ethanol, a solution of 1-(2-mercaptophenyl)pyrrole (3.5 g, 0.02 mol) in 8 mL of anhydrous ethanol was added dropwise and the mixture was allowed to stirr for 1 h. After evaporation of the solvent the residue was dissolved in anhydrous tetrahydrofuran (25 mL) and ethyl α-bromo-p-methoxyphenylacetate (5.5 g, 0.02 mol) was slowly added. The reaction mixture was heated at 60° C. for 5 h and then was cooled and poured onto crushed ice, extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. The residue was purified by flash chromatography (dichloromethane as eluant) giving 5.05 g (69%) of the desired product. IR (neat) 1735 cm−1; 1HNMR (CDCl3) δ 1.06 (t, 3 H), 3.76 (s, 3 H), 4.07 (q, 2 H), 4.30 (s, 1 H), 6.35 (t, 2 H), 6.70-7.70 (m, 10 H).
Reaction SMILES: C1COCC1.[CH2:6]([N:9]([CH2:32][CH2:33][CH3:34])[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:23][NH:24][CH2:25][C:26]3[NH:27][CH:28]=[CH:29][N:30]=3)[CH:20]=2)[C:15]1=O)[CH2:7][CH3:8]>CO>[NH:27]1[CH:28]=[CH:29][N:30]=[C:26]1[CH2:25][NH:24][CH2:23][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([CH2:13][CH2:12][CH2:11][CH2:10][N:9]([CH2:6][CH2:7][CH3:8])[CH2:32][CH2:33][CH3:34])[CH2:22]2
Reactant: CCCN(CCC)CCCCN1Cc2cc(CNCc3ncc[nH]3)ccc2C1=O
Solvent: C1CCOC1
Solvent: CO
Product: CCCN(CCC)CCCCN1Cc2ccc(CNCc3ncc[nH]3)cc2C1
Temperature: 0 °C
Yield: 53.3 %

Procedure:
A THF solution (2.0 ml) containing the compound (24.3 mg) obtained in Example 7-7 was added with a 1 mol/l borane-THF complex/THF solution (0.41 ml). The whole was refluxed under heating for 16 hours. After having been cooled to 0° C., the solution was added with methanol to stop the reaction and concentrated. The residue was added with a 1 mol/l hydrochloric acid (4.0 ml) and the whole was refluxed under heating for 3 hours. After having been left standing for cooling, the resultant was added with a 1 mol/l sodium hydroxide aqueous solution (5 ml) and the whole was subjected to extraction with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and dried with anhydrous sodium sulfate. The residue obtained by distilling the solvent off was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (12.5 mg) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N+:10]([O-:11])=[N:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.[H-].[Na+].CS(O[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(OC)C=3)C=CC2=O)CC1)(C)(C)C>C(OCC)C>[C:33]([O:32][C:30](=[O:31])[NH:29][CH:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][N:7]2[C:6]3[CH:13]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[N+:10]([O-:11])=[N:9][C:8]2=[O:12])[CH2:24][CH2:25]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: O=c1n[n+]([O-])c2ccc(Cl)cc2[nH]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)n[n+]([O-])c3ccc(Cl)cc32)CC1

Procedure:
6-Chloro-1,2,4-benzotriazin-3(4H)-one 1-oxide (FR 2621583, 1.50 g) was deprotonated with sodium hydride (0.42 g, 60% in oil) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (1 equivalent) as described for Intermediate 2. The residue obtained after aqueous work up was suspended in diethyl ether and filtered to yield 1.30 g of product.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([CH:15]1[CH2:17][CH2:16]1)#[CH:14].C(N(CC)CC)C>O1CCCC1.[Cu](I)I>[CH:15]1([C:13]#[C:14][C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:9])[CH2:17][CH2:16]1
Reactant: C#CC1CC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(C#CC1CC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 250-mL round bottom flask was charged with bis(triphenylphosphine)palladium bischloride (151 mg, 0.216 mmol) and copper iodide (82 mg, 0.431 mmol), and the flask was degassed with nitrogen. Tetrahydrofuran (40 mL) was added through a septum, and nitrogen was bubbled through the mixture for 30 minutes. To this was added dropwise a nitrogen-degassed solution of 4-nitrobenzoyl chloride (2g, 10 8 mmol), ethynylcyclopropane (784 mg, 11.9 mmol) and triethylamine (1.31 g, 12.9 mmol) in tetrahydrofuran (15 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated to dryness. The residue was purified by normal phase chromatography to give the title compound.
Reaction SMILES: CCOCC.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[S:22][C:21]3[S:23][CH:24]=[CH:25][C:20]=3[C:19]([C:26](O)=[O:27])=[CH:18][C:17]=2[CH:29]=1.O1CCCC1>O>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[S:22][C:21]3[S:23][CH:24]=[CH:25][C:20]=3[C:19]([CH2:26][OH:27])=[CH:18][C:17]=2[CH:29]=1
Reactant: O=C(O)C1=Cc2cc(Cl)ccc2Sc2sccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCC1=Cc2cc(Cl)ccc2Sc2sccc21

Procedure:
To 40 ml of abs. ether is added at 3° under nitrogen 0.76 g (0.02 mole) of lithium aluminium hydride, and there is then added dropwise at 5° with stirring, in the course of half an hour, a solution of 2.9 g (0.01 mole) of 7-chlorobenzo[f]thieno [2,3-b]thiepin-4-carboxylic acid in 60 ml of abs. ether and 20 ml of abs. tetrahydrofuran. The mixture is subsequently stirred for 2 hours at room temperature; 4 ml of water is then slowly added dropwise at 5°, and the precipitate is filtered off with suction. The filtrate is concentrated in vacuo; the crude residue is chromatographed on a silica-gel column, and by elution with chloroform is yielded 7-chlorobenzo[f]thieno [2,3-b]thiepin-4-methanol, m.p. 117°-120°.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.CCN(C(C)C)C(C)C.CN(C(O[N:37]1[N:45]=NC2C=CC=[N:43][C:38]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NN1NC=[CH:56][S:55]1>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:43][C:38]2[S:55][CH:56]=[N:45][N:37]=2)=[O:7])=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: NN1NC=CS1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2nncs2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36.1 %

Procedure:
4-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (Intermediate 4) (2.0 g), DIPEA (4 ml) and HATU (3.05 g) were dissolved in DMF (20 ml) and stirred at room temp for 15 min. 2-Aminothiadiazole (810 mg) was added and the mixture was stirred at room temp for 18 h. The solvent was evaporated under vacuum and the residue was partitioned between ethyl acetate (250 ml) and hydrochloric acid (2N, 150 ml). The aqueous phase was extracted with ethyl acetate (2×250 ml). The combined organic extracts were dried (magnesium sulphate) and the solvent was removed under vacuum. The residue was absorbed onto silica and purified by flash column chromatography eluting with cyclohexane/ethyl acetate (4:1 then 1:1) to give the title compound (0.95 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:20]#[N:21])([CH3:19])[CH3:18])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C.[Cl:30][C:31]1[N:36]=[C:35]2[S:37][C:38]([C:40](Cl)=[O:41])=[CH:39][C:34]2=[N:33][CH:32]=1>C(Cl)Cl>[Cl:30][C:31]1[N:36]=[C:35]2[S:37][C:38]([C:40]([NH:1][C:2]3[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:20]#[N:21])([CH3:19])[CH3:18])[CH:12]=4)[CH:5]=[CH:6][C:7]=3[CH3:8])=[O:41])=[CH:39][C:34]2=[N:33][CH:32]=1
Reactant: O=C(Cl)c1cc2ncc(Cl)nc2s1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide 5 (2.56 mmol, 750 mg) and triethylamine (12.78 mmol, 1.782 mL) in CH2Cl21 ml at 0° C. was added 3-chlorothieno[2,3-b]pyrazine-6-carbonyl chloride 94 in 1 mL CH2Cl2 and stirred at rt for 1 h. The reaction mixture was quenched with water, extracted with CH2Cl2 (2×). The organic layer was dried and concentrated under reduced pressure. Purified with column chromatography (10-20% ethyl acetate in CH2Cl2) gave 3-chloro-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 95 (1.04 g, 83%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.26 (s, 3H), 7.32 (d, J=8.2 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.64 (dd, J=8.2 Hz and 2.0 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.87 (d, J=2.3 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 8.05 (s, 1H), 8.57 (s, 1H), 8.98 (s, 1H), 10.37 (s, 1H), 10.56 (s, 1H). (m/z)=490 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1[C:22](=[O:23])[CH2:21][CH2:20][C:19]1=[O:24].[CH:25]1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[O:23]=[C:22]1[CH2:21][CH2:20][C:19](=[O:24])[CH:25]1[O:15][C:14](=[O:16])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:10][CH:11]([CH3:12])[CH3:13]
Reactant: O=C1CCC(=O)N1O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CC#N
Product: CC(C)CC(NC(=O)OC(C)(C)C)C(=O)OC1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the mixture of N-(tert-Butoxycarbonyl)-L-leucine (1.03 g, 4.46 mmol) and N-Hydroxysuccinimide (0.74 g, 6.43 mmol) in acetonitrile (30 ml) was added 1,3-Dicyclohexylcarbodiimide (1.24 g, 6.01 mmol) and stirred for 4 hr, at room temperature. The resulting precipitate was filtered off and the acetonitrile filtrate containing 2 was carried on to the next step. MS, m/z (relative intensity): 327 [M+1H, 100%], 327 [M+1H —C(CH3)3, 100%].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:17].ClC(Cl)C>C(O)(C)(C)C>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:17][C:16]1[CH:18]=[CH:19][C:20]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:14]([CH3:13])[CH:15]=1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: Cc1cc(N)ccc1Oc1ccccc1
Solvent: CC(C)(C)O
Solvent: CC(Cl)Cl
Product: Cc1cc(Nc2ncnc3ccc(I)cc23)ccc1Oc1ccccc1
Temperature: 90 °C

Procedure:
The 4-chloro-6-iodo-quinazoline (5.0 g, 17.2 mmol) and the 3-methyl-4-phenoxyaniline (17.2 mmol) were mixed together in 1:1 dichloroethane and t-butanol (50 ml). The reaction mixture was heated at 90° C. for 4 hours whereupon a yellow precipitate was observed. The reaction was cooled down and the precipitate was collected and afforded (6-iodo-quinazolin-4-yl)-(3-methyl-4-phenoxy-phenyl)-amine. (8.0 g, 94%). M/z, 454. 1H NMR (CD3OD): δ: 9.12(s, 1H), 8.83(s, 1H), 8.39 (d, 1H, J=8.8 Hz), 7.63(d, 1H, J=8.8 Hz), 7.55 (d, 1H, J=2.1 Hz), 7.35(dd,1H, J1=J2=8.5 Hz), 7.28(t, 2H, J=8.1 Hz, ), 7.05 (t, J=8.5 Hz), 6.87(d, 1H, J=8.1 Hz), 3.81 (s, 3H).
Reaction SMILES: [CH:1]([CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14](C(OCC)=O)=[CH:13][C:12]=2[C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)=[O:2].C[O-].[Na+].[CH:34]([NH2:36])=[O:35]>>[CH:1]([CH2:3][NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:15][CH:14]=[C:13]([C:34]([NH2:36])=[O:35])[C:12]=2[C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:9][CH:10]=1)=[O:2]
Reactant: NC=O
Reactant: CCOC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(NCC=O)cc2)s1
Agent: C[O-]
Agent: [Na+]
Product: CS(=O)(=O)c1ccc(-c2c(C(N)=O)csc2-c2ccc(NCC=O)cc2)cc1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
A mixture of ethyl 5-[4-(N-formylmethylamino)phenyl]-4-[4-(methylsulfonyl)phenyl]thiophene-2-carboxylate (0.34 g) and sodium methoxide (0.13 g) in formamide (2 ml) was stirred at 100° C. for 2.5 hours. The mixture was poured into ice-water and the precipitates were collected to give 5-[4-(N-formylmethylamino)phenyl]-4-[4-(methylsulfonyl)phenyl]thiophene-3-carboxamide (0.3 g).