Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]([OH:19])=O)[N:6]=1)=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH3:35].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH2:32]([N:36]([CH2:37][CH2:38][CH2:39][CH3:40])[C:17](=[O:19])[CH2:16][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:5]([C:3](=[O:4])[C:2]([CH3:20])([CH3:1])[CH3:21])=[N:6]1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCNCCCC
Reactant: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)O)c2c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCCN(CCCC)C(=O)Cn1nc(C(=O)C(C)(C)C)c2ccc(OC)cc21
Temperature: 25 °C

Procedure:
To a solution of 28.3 mg [3-(2,2-dimethylpropanoyl)-6-methoxy-1H-indazol-1-yl]acetic acid from the Step E above in 1 mL DMF was added 23.0 mg HOBt, 19.4 mg dibutylamine, 38.3 mg EDC, and 45.2 mg DIEA in that order. The mixture was stirred at room temperature over night and purified by RP-HPLC using 65˜100% MeCN gradient. The pure product fractions were pooled and lyophilized to give the title compound as white solid. LC-MS: 4.33 min. (m/Z=402.3, 424.3).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[N:10]=[C:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:26]2[C:25]([CH3:27])=[CH:24][N:23]=[C:22]([NH2:28])[C:21]=2[N:20]=[C:19]1[CH2:29][O:30][CH2:31][CH3:32]>>[NH2:28][C:22]1[C:21]2[N:20]=[C:19]([CH2:29][O:30][CH2:31][CH3:32])[N:18]([CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:11]([NH:10][C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:12])[C:26]=2[C:25]([CH3:27])=[CH:24][N:23]=1
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Reactant: CCOCc1nc2c(N)ncc(C)c2n1CCCCN
Product: CCOCc1nc2c(N)ncc(C)c2n1CCCCNC(=O)N[C@@H]1C[C@H]1c1ccccc1

Procedure:
Using the method of Examples 147-164, trans-2-phenylcyclopropyl isocyanate was reacted with 1-(4-aminobutyl)-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 437.2668.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH2:8][CH:7](O)[C:6]=2[CH:11]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:11]=1
Reactant: OC1CSc2ccc(Br)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: Brc1ccc2sccc2c1
Yield: 96.9 %

Procedure:
To acetone (600 mL) solution of 300 g of 5-bromo-2,3-dihydro-1-benzothiophen-3-ol was added 12.4 g of p-toluenesulfonic acid monohydrate, which was then refluxed for 2 hours. To the reaction solution was added 15.0 g of activated carbon, which was then stirred. Insoluble matter was filtered off and washed with 300 mL of acetone. The filtrate and washings were combined, to which was dropwise added 2700 mL of water at 5 to 15° C. The precipitate was collected by filtration to provide 268 g of 5-bromo-1-benzothiophene as pale purple solid form.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[S:23][C:22]([C:24](Cl)=[O:25])=[CH:21][CH:20]=1>>[F:18][C:19]1[S:23][C:22]([C:24]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:25])=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccc(F)s1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(F)s4)nc23)CC1
Yield: 17 %

Procedure:
Beginning with 0.414 gm (1.8 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 2.73 mMol 5-fluoro-2-thiophenecarbonyl chloride, 0.11 gm (17%) of the title compound were prepared essentially by the procedure described in Example 4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH:17]=[CH2:18]>CN(C)C=O.O>[CH2:16]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH:17]=[CH2:18]
Reactant: COc1ccccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccccc1OC
Reaction time: 0.5 h
Yield: 79 %

Procedure:
124 g of 2-methoxyphenol and 152 g of potassium carbonate in 500 ml of dimethylformamide are brought to 60° C. with stirring for 30 minutes. 127 g of allyl bromide are introduced and the reaction medium is then left at 60° C. for 1 hour. It is diluted with 2 l of water and extracted with ethyl ether and the organic phase is washed with sodium hydroxide. The organic phase is dried and the ether evaporated off. The product is then distilled at 115° C. and at 20 mmHg to obtain 129.6 g of the expected compound.
Reaction SMILES: [NH2:1][NH2:2].[N+:3]([O-:6])([OH:5])=[O:4].[N:7]#[C:8][NH2:9].C(O)C>>[N+:3]([O-:6])([O-:5])=[O:4].[NH2:1][N+:2]([NH2:3])=[C:8]([NH2:9])[NH2:7]
Reactant: NN
Reactant: O=[N+]([O-])O
Reactant: N#CN
Solvent: CCO
Product: NC(N)=[N+](N)N
Product: O=[N+]([O-])[O-]
Temperature: 20 °C

Procedure:
64% Hydrazine solution (50 g, 1 mole) and 70% nitric acid (45 g, 0.5 mole) were carefully mixed in 200 ml of ethanol. 50% Aqueous cyanamide solution (42 g, 0.5 mole) was added and the mixture refluxed two hours. The solution was cooled to 20° C. precipitating the product which was then recrystallized from methanol giving 15 g of white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:15]([O-])([OH:17])=[O:16]>C(OCC)(=O)C.CCCCCC>[N+:15]([C:4]1[CH:5]=[CH:6][C:1]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:2][CH:3]=1)([O-:17])=[O:16]
Reactant: O=C(O)CCCCCc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(O)CCCCCc1ccc([N+](=O)[O-])cc1
Temperature: -10 °C

Procedure:
6-Phenylhexanoic acid (30 g) was added dropwise over 6.5 hours to 125 ml of 90% nitric acid with cooling to -30° to -20° C. When the addition was complete, the mixture was allowed to warm to -10° C. for 30 minutes and it was then poured into ice water. The resulting mixture was extracted with diethyl ether and the ether extract was washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was then evaporated to leave a crude yellow solid which was subjected to high pressure liquid chromatography using ethyl acetate/hexane/glacial acetic acid as the eluent. This chromatography removed dinitrated material and gave a yellow slush which was recrystallized from a mixture of toluene and hexane to give 6-(4-nitrophenyl)hexanoic acid.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:31])[CH2:4][S:5][CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][C@@H:14]2[CH3:19])[N:10]=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:30])[NH:28][CH3:29])=[CH:22][CH:21]=2)[N:8]=1.C1C=C(Cl)C=C(C(OO)=[O:40])C=1.[Mn]([O-])(=O)(=O)=O.[Na+].[OH2:49]>O1CCOCC1>[CH3:1][NH:2][C:3](=[O:31])[CH2:4][S:5]([CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][C@@H:14]2[CH3:19])[N:10]=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:30])[NH:28][CH3:29])=[CH:22][CH:21]=2)[N:8]=1)(=[O:40])=[O:49]
Reactant: CNC(=O)CSCc1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)NC)cc2)n1
Reactant: O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CNC(=O)CS(=O)(=O)Cc1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)NC)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Methyl-2-[[2-[4-(methylcarbamoylamino)phenyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methylsulfanyl]acetamide (0.35 mmol) was dissolved in 1,4-Dioxane (5 mL) and water (1 mL). m-CPBA (75%) (121 mg) followed immediately by sodium permanganate (140 mg) were added to the solution and the reaction stirred at RT for 1 h. Further m-CPBA (75%) (121 mg) followed immediately by sodium permanganate (140 mg) were added to the solution and stirred at RT for 1 h. Again further m-CPBA (75%) (121 mg) followed immediately by sodium permanganate (140 mg) were added and the reaction stirred at RT for 1 h. The reaction was loaded onto a SCX-3 (10 g) column, which was washed with methanol and the product eluted with 7N ammonia in methanol. The material was further purified by prep-HPLC (basic) to give the desired material (30 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=[O:5].C(OC(=O)C)(=[O:29])C.C[C:35]1[CH:40]=CC=CC=1>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([CH:12]2[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][N:6]3[C:4](=[O:5])[C:3]4[C:2](=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:1]=[C:40]3[CH3:35])[CH2:10][CH2:11]2)=[O:29])=[CH:21][CH:20]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1C(=O)NCCN1CCC(Cc2ccc(F)cc2)CC1
Reactant: Cc1ccccc1
Product: Cc1nc2ccccc2c(=O)n1CCN1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 69 %

Procedure:
A mixture of 6 parts of 2-amino-N-[2-[4-(4-fluorobenzyl)-1-piperidinyl]ethyl]benzamide, 10 parts of acetic acid anhydride and 108 parts of methylbenzene is stirred and refluxed overnight. The reaction mixture is evaporated and water is added to the oily residue. The whole is alkalized with a dilute sodium hydroxide solution and extracted with trichloromethane. The extract is dried, filtered and evaporated. The oily residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered off and recrystallized from 2-propanol, yielding 4.4 parts (69%) of 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2-methyl-4(3H)-quinazolinone; mp. 164.9° C.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([O:21][CH3:22])=[CH:15][C:14]=2[O:23][CH3:24])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:25]I>>[CH3:1][C:2]1[N:11]=[C:10]([N:12]([C:13]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([O:21][CH3:22])=[CH:15][C:14]=2[O:23][CH3:24])[CH3:25])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1cc(OC)c(Nc2nc(C)nc3ccccc23)c(OC)c1
Reactant: CI
Product: COc1cc(OC)c(N(C)c2nc(C)nc3ccccc23)c(OC)c1

Procedure:
The title compound was prepared from (2-methyl-quinazolin-4-yl)-(2,4,6-trimethoxy-phenyl)-amine (56 mg, 0.17 mmol) and methyl iodide (0.1 ml, 1.6 mmol) by a procedure similar to Example 36. 1H NMR (CDCl3): 7.70 (d, J=8.4 Hz, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.09 (d, J=8.7 Hz, 1H), 6.93 (t, J=8.1 Hz, 1H), 6.18 (s, 2H), 3.86 (s, 3H), 3.63 (s, 6H), 3.44 (s, 3H), 2.70 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[F:24][C:25]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:26]=1[C:27](Cl)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[F:24][C:25]1[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:30][C:26]=1[C:27]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(F)(F)F)ccc2F)n1
Temperature: 150 °C
Yield: 45.1 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (3.0 mL) under N2, was added 2-fluoro-5-(trifluoromethyl)benzoyl chloride (0.279 g, 1.23 mmol) and N,N-diisopropylethylamine (0.50 mL, 5.21 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.069 g (45% yield) of pure product: MS (ES) m/z 496 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[C:25](Cl)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.S(S([O-])=O)([O-])=O.[Na+].[Na+]>ClCCl.O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([OH:11])[C:6]([CH3:12])=[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:4]=1[OH:24]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(O)c(C)c(CCCCCCCCCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c(O)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 138.1 %

Procedure:
2,3-Dimethoxy-6-(10-hydroxydecyl)-5-methylbenzoquinone (33.8 g) was dissolved in dichloromethane (250 ml). Trityl chloride (30 g) followed by triethylamine (10 g) was added, and the mixture was stirred at room temperature overnight. Then water (250 ml) containing sodium hydrosulfite (40 g) was added, and the mixture was stirred at room temperature for 1 hour. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired compound (80.4 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:31])[CH2:18][C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)=[CH:12][C:11]=2[N+:32]([O-:34])=[O:33])[O:7][C:6]=1[CH3:35])=[O:4].[Li+].[OH-].Cl>C1COCC1.CO.CCOC(C)=O>[CH3:35][C:6]1[O:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:31])[CH2:18][C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)=[CH:12][C:11]=2[N+:32]([O-:34])=[O:33])=[CH:9][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cc(-c2ccc(NC(=O)Cc3cc(OC)c(OC)c(OC)c3)cc2[N+](=O)[O-])oc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(CC(=O)Nc2ccc(-c3cc(C(=O)O)c(C)o3)c([N+](=O)[O-])c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 74.4 %

Procedure:
Dissolve 2-Methyl-5-{2-nitro-4-[2-(3,4,5-trimethoxy-phenyl)-acetylamino]-phenyl}-furan-3-carboxylic acid methyl ester (41) (50 mg, 0.10 mmol) in THF (11.0 mL) and MeOH (0.5 mL) at rt and add 1M aqu LiOH (525 μL, 0.52 mmol). Stir the reaction mixture for 17 h at rt. Add dropwise 1M aqu. HCl (580 μL, 0.58 mmol) and extract the mixture with EtOAc (3 times), wash the combined organic layer with brine and dry it with Na2SO4. Purify the obtained crude product by preparative TLC (silica gel, EtOAc/MeOH 9+1) to obtain 2-Methyl-5-{2-nitro-4-[2-(3,4,5-trimethoxy-phenyl)-acetylamino]-phenyl}-furan-3-carboxylic acid (42) (35 mg, 71%) as a brown sticky solid. 1H NMR (400 MHz, CDCl3): 2.61 (s, 3H); 3.70 (s, 2H); 3.86 (s, 3H); 3.87 (s, 6H); 6.51 (s, 2H); 6.85 (s, 1H); 7.29 (br.s, 1H); 7.58 (d, 1H, J=8.6 Hz); 7.62 (dd, 1H, J1=9.0 Hz, J2=2.2 Hz); 7.98 (d, 1H, J=2.0 Hz).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:28][C:15]3[N:16]=[C:17](SC)[N:18]=[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[C:29]1([C:35]2[CH:36]=[N:37][CH:38]=[C:39]([Sn](CCCC)(CCCC)CCCC)[CH:40]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>COCCOC.C(OCC)(=O)C.CSC.[Cu]Br.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>[CH3:1][S:2]([N:5]1[CH2:6][CH2:7][N:8]([CH2:11][C:12]2[S:28][C:15]3[N:16]=[C:17]([C:39]4[CH:38]=[N:37][CH:36]=[C:35]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:40]=4)[N:18]=[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]=3[CH:13]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: CSc1nc(N2CCOCC2)c2cc(CN3CCN(S(C)(=O)=O)CC3)sc2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(-c2ccccc2)c1
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CSC
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cncc(-c5ccccc5)c4)nc3s2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-yl-thieno[2,3-d]pyrimidine (135 mg) in 1,2-dimethoxyethane (10 mL) was added 3-phenyl-5-tributylstannanyl-pyridine (270 mg) and copper(I)bromide-dimethyl sulfide (125 mg) and the reaction mixture was stirred at room temperature for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (18 mg) was then added and the reaction mixture was heated at reflux for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (20 mL) and washed with water (2×20 mL) and brine (2×20 mL). The organic phase was dried (MgSO4), reduced in vacuo and purified by column chromatography to give 403. NMR: (CDCl3): 3.17 (3H, s, Me), 3.93-3.95 (4H, m), 4.13-4.16 (4H, m), 5.28 (2H, s, NH), 7.83 (1H, t, J 7.0, Ar), 7.92 (1H, s, Ar), 8.26 (2H, td, J 7.7 and 1.5, Ar), 8.53-8.54 (1H, m, Ar) and 9.30 (2H, s, Ar). MS: (ESI+): MH+ 497.08
Reaction SMILES: CC(C)([O-])C.[K+].COCCOC.[C:13]([C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1)(=O)[CH3:14].C1(C)C=CC(S([CH2:33][N+:34]#[C-])(=O)=O)=CC=1>C(O)C>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([CH2:13][CH2:14][C:33]#[N:34])=[CH:17][CH:18]=1)#[N:21]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)c1ccc(C#N)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: N#CCCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
1.40 g (1.25 mmole) of potassium tert-butoxide was added to a 17 ml ethylene glycol dimethyl ether solution containing 0.73 g (5 mmole) of 4-acetylbenzonitrile, 0.5 ml of ethanol and 1.27 g (6.5 mmole) of p-toluenesulfonylmethylisocyanide under ice-cooling; then the mixture was stirred at room temperature for 0.5 hour and then at 40° C. for an additional hour. After the reaction mixture was cooled by allowing to stand at room temperature, it was filtered under reduced pressure and the filtrate was purified by silica gel chromatography to obtain 0.55 g (yield: 70.4 %) of 2-(4-cyanophenyl)ethylcyanide.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C@@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][N:29]=[CH:28]3)[O:19]1.CC[O:37][C:38]([CH3:40])=[O:39].CO>N.O>[C:38]([OH:37])(=[O:39])/[CH:40]=[CH:14]/[C:9]([OH:19])=[O:8].[NH:30]1[C:31]2[C:27](=[CH:26][C:25]([C:2]3[N:7]=[N:6][C:5]([O:8][C@@H:9]4[CH:14]5[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]5)[CH2:10]4)=[CH:4][CH:3]=3)=[CH:33][CH:32]=2)[CH:28]=[N:29]1
Reactant: Clc1ccc(O[C@H]2CN3CCC2CC3)nn1
Reactant: CCOC(C)=O
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)OC1(C)C
Agent: N
Solvent: CO
Solvent: O
Product: O=C(O)/C=C/C(=O)O
Product: c1cc2[nH]ncc2cc1-c1ccc(O[C@H]2CN3CCC2CC3)nn1

Procedure:
The product of Example 9A (481 mg, 2.01 mmol) was coupled with the product of Example 49A (968 mg, 3.96 mmol) according to the procedure of Example 26B. The free base of the title product was purified by chromatography (SiO2, EtOAc/MeOH (with 2 v. % NH3.H2O) (385 mg, 1.19 mmol, yield, 59.5%). It was then treated with fumaric acid (134 mg, 1.2 mmol) in 15 ml EtOAc/EtOH (10:1 v.) at room temperature for 16 hours. The title product was obtained as a solid (414.6 mg, yield, 59.7%). 1H NMR (300 MHz, CD3OD) δ 1.90-2.24 (m, 3H) 2.32-2.47 (m, 1H) 2.61-2.70 (m, 1H) 3.32-3.52 (m, 5H) 3.96 (dd, J=13.73, 8.31 Hz, 1H) 5.53-5.60 (m, 1H) 6.69 (s, 2H) 7.36 (d, J=9.49 Hz, 1H) 7.69 (d, J=8.82 Hz, 1H) 8.08 (dd, J=8.82, 1.70 Hz, 1H) 8.16-8.23 (m, 2H) 8.38 (s, 1H) ppm. MS (DCI/NH3) m/z 322 (M+H)+. Anal. Calculated for C18H19N5O.1.4C4O4H4.0.6H2O: C, 57.30; H, 5.26; N, 14.16. Found: C, 57.24; H, 5.08; N, 14.24.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][C:7]2[CH:8]=[C:9](C3C=C4C(=C(C(N)=O)C=3)NC=C4C3CCN(S(CC)(=O)=O)CC3)[CH:10]=[N:11][CH:12]=2)[CH2:3][CH2:2]1.[CH3:36][C:37]1([CH3:52])[C:41]([CH3:43])([CH3:42])[O:40][B:39](C2C=C(C=O)C=NC=2)[O:38]1.C(N)C(C)C.[BH3-]C#N.[Na+]>>[CH3:3][CH:1]([CH3:2])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]([B:39]2[O:40][C:41]([CH3:43])([CH3:42])[C:37]([CH3:52])([CH3:36])[O:38]2)[CH:8]=1
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCC5CC5)c4)cc23)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)CN
Product: CC(C)CNCc1cncc(B2OC(C)(C)C(C)(C)O2)c1

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), isobutylamine (0.013 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 21 mg of crude (2-methylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude (2-methylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminormethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 12.5 mg of the title compound (35%).
Reaction SMILES: [Al+3].[Cl-:2].[Cl-].[Cl-].[CH2:5]1[O:9][C:8]2[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[C:12]([CH:14]=[O:15])=[CH:13][C:7]=2[O:6]1.N#N.O>ClC(Cl)C>[Cl:2][CH2:5][O:6][C:7]1[C:8]([OH:9])=[CH:10][C:11]([N+:16]([O-:18])=[O:17])=[C:12]([CH:13]=1)[CH:14]=[O:15]
Reactant: O=Cc1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: [Cl-]
Agent: N#N
Agent: [Al+3]
Solvent: O
Solvent: CC(Cl)Cl
Product: O=Cc1cc(OCCl)c(O)cc1[N+](=O)[O-]
Reaction time: 1.25 h
Yield: 96.7 %

Procedure:
AlCl3 (6 g) and dry dichloroethane (15 ml) are added to a three-neck round bottom flask, which has been purged with N2, and the dispersion is cooled to -5°. A solution of 6-nitropiperonal (3 g; 0.0154 mol) (available from Aldrich Chemical Co.) in 12 ml dry dichloroethane is added to the dispersion, in one portion, while the temperature and N2 atmosphere are maintained. The reaction mixture is stirred for 1.25 hours, and 100 ml H2O (0°) is added. The emulsion is stirred for 15 minutes, then extracted with 3×100 ml ethyl acetate. The combined organics are washed with saturated NaCl, then dried over Na2SO4. After filtration, the ethyl acetate is removed at reduced pressure. Recrystallization from ethyl acetate gives 3.45 g (97%) of (10): mp 160°-161° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)#[CH:14]>C(N(CC)CC)C.[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:15]1([C:13]#[C:14][C:2]2[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=3[N:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C#Cc1ccccc1
Reactant: O=C1CCCc2nc(Cl)ccc21
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C1CCCc2nc(C#Cc3ccccc3)ccc21
Yield: 14.7 %

Procedure:
To a solution of 2-chloro-7,8-dihydro-6H-quinolin-5-one (0.2 g, 1.1 mmol) and ethynylbenzene (0.17 g, 1.6 mmol) in triethylamine (7 ml) under an argon atmosphere was added tetrakis (triphenylphosphine) palladium (0.02 g, 0.062 mmol). The mixture was heated at reflux for 3 h. Then it was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to give the title compound (0.04 g, 15%).