Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.[Sn](Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:12]=[CH:11][N:10]([CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][O:22]3)[C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:15][CH:16]=1
Reactant: C1=COCCC1
Reactant: COc1ccc(-c2nc[nH]c2-c2ccc(OC)cc2)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(-c2ncn(C3CCCCO3)c2-c2ccc(OC)cc2)cc1
Yield: 81.6 %

Procedure:
14.17 g of 4,5-bis(4-methoxyphenyl)imidazole is suspended in 250 ml of absolute 1,2-dichloroethane and combined with 16 g of 3,4-dihydro-2H-pyran as well as 0.5 ml of tin tetrachloride. The mixture is heated to reflux under agitation for 12 hours, then allowed to cool, and poured into 500 ml of cold sodium bicarbonate solution. The organic phase is separated, dried over sodium sulfate, and concentrated under vacuum. The residue is dissolved in dichloromethane and subjected to hexane precipitation. The sediment is dissolved in ether. The solution is clarified with activated carbon, concentrated under vacuum, and made to crystallize, thus producing 15.03 g of 4,5-bis(4-methoxyphenyl)-1-(tetrahydropyran-2-yl)imidazole, mp 127°-128°.
Reaction SMILES: [C:1]([C:9]1[CH:37]=[CH:36][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:35]=[CH:34][C:23]([CH2:24][CH:25]([C:30]([O:32][CH3:33])=[O:31])[C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)[C:14](=[O:16])[O:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[OH:8][CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:37]=[CH:36][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:35]=[CH:34][C:23]([CH2:24][CH:25]([C:26]([O:28][CH3:29])=[O:27])[C:30]([O:32][CH3:33])=[O:31])=[CH:22][CH:21]=3)[C:14](=[O:16])[O:15][C:11]=2[CH:10]=1
Reactant: COC(=O)C(Cc1ccc(OCCn2c(=O)oc3cc(C(=O)c4ccccc4)ccc32)cc1)C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(Cc1ccc(OCCn2c(=O)oc3cc(C(O)c4ccccc4)ccc32)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The compound obtained in Example 21 is dissolved in methanol and 0.25 equivalents of sodium borohydride are added. The reaction mixture is stirred at ambient temperature for 24 hours, then the methanol is evaporated off in vacuo and the resulting residue is purified by flash chromatography using an ethyl acetate/cyclohexane mixture as eluant. The title compound obtained in that way is recrystallised from isopropyl ether.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=1[CH3:10])=[S:3].Br[CH2:16][C:17]([C:19]([F:22])([F:21])[F:20])=[O:18]>>[OH:18][C:17]1([C:19]([F:22])([F:21])[F:20])[CH2:16][S:3][C:2]([NH:4][C:5]2[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=2[CH3:10])=[N:1]1
Reactant: O=C(CBr)C(F)(F)F
Reactant: COC(=S)c1cc(NC(N)=S)c(C)s1
Product: COC(=S)c1cc(NC2=NC(O)(C(F)(F)F)CS2)c(C)s1
Yield: 53.8 %

Procedure:
Using a procedure similar to Example 204, step (a), 56 mg (0.21 mmol) of methyl 4-[(aminothioxomethyl)amino]-5-methylthiothiophene-2-carboxylate was allowed to react with 40 mg (0.21 mmol) of bromotrifluoroacetone (Aldrich Chemical Co., Milwaukee, Wis.) to afford 40.3 mg (54%) of methyl 4-{[4-hydroxy-4-(trifluoromethyl)(1,3-thiazolin-2-yl)]amino}-5-methylthiothiophene-2-carboxylate. Mass spectrum (ESI, m/z): Calcd. for C11H11F3N2O3S3, 373.00 (M+H), found 373.0.
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([Cl:46])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:26]=2[CH3:40])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:10][CH:9]=1.[C:47](=[O:59])([O:49][CH2:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1Br)[NH2:48]>>[C:20]([O:19][C:18](=[O:24])[NH:17][CH2:16][CH:15]([C:25]1[CH:30]=[CH:29][C:28]([C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=2[CH2:51][CH2:50][O:49][C:47]([NH2:48])=[O:59])=[CH:27][C:26]=1[CH3:40])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][O:4][C:3]2[C:41]([Cl:46])=[CH:42][C:43]([CH3:45])=[CH:44][C:2]=2[Cl:1])=[CH:9][CH:10]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3C)cc2)c(Cl)c1
Reactant: NC(=O)OCCc1ccccc1Br
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(-c4ccccc4CCOC(N)=O)cc3C)cc2)c(Cl)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 7, step 2 using tert-butyl {3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl}carbamate from EXAMPLE 9, step 1 and 2-(2-bromophenyl)ethyl carbamate (V.7) as starting materials. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (10 to 75% in 30 min) afforded the desired compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][CH:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[C:23]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)(=[O:25])[NH2:24]>>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[CH:12]([O:11][N:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:30]3[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=3)[C:23]([NH2:24])=[O:25])[CH:3]=2)[CH:8]=[CH:9]1)[CH3:13]
Reactant: CC(On1ccc2ncc(Br)cc21)c1c(Cl)ccc(F)c1Cl
Reactant: NC(=O)c1cccc(B(O)O)c1
Product: CC(On1ccc2ncc(-c3cccc(C(N)=O)c3)cc21)c1c(Cl)ccc(F)c1Cl

Procedure:
The entitled compound was prepared from 6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine and (3-carbamoylphenyl)boronic acid according to the procedure described in example 4.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:12])[CH2:6][CH2:5]2.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.O.C(OCC)(=O)C>CN1CCCC1=O>[F:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C:7]2=[O:12])=[CH:3][C:2]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=C1CCc2cc(F)c(F)cc21
Reactant: C1COCCN1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=C1CCc2cc(N3CCOCC3)c(F)cc21
Yield: 84.8 %

Procedure:
A solution of 5,6-difluoro-1-indanone (535 mg) and morpholine (554 mg) in 1-methyl-2-pyrrolidinone (6.0 mL) was stirred at 100° C. for 7 hours. After confirming that the raw materials disappeared, water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system) to obtain 635 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:14]=[CH:15][C:16]([CH3:33])=[C:17]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=3)[CH:18]=2)=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([O:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:33])=[C:17]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:28])[CH3:29])[CH:22]=3)[CH:18]=1)[N:10]=2
Reactant: N#C[S-]
Reactant: Cc1ccc(Oc2ccc(N)cn2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1ccc(Oc2ccc3nc(N)sc3n2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.4 %

Procedure:
Potassium thiocyanate (2.02 g, 20.8 mmol) was suspended in acetic acid (40 mL), and the mixture was stirred at room temperature for 10 min. A solution of N-{5-[(5-aminopyridin-2-yl)oxy]-2-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (2.0 g, 5.20 mmol) in acetic acid (40 mL) was added to the obtained solution, and the mixture was further stirred at room temperature for 10 min. A solution of bromine (914 mg, 5.72 mmol) in acetic acid (28 mL) was slowly added dropwise to the obtained solution. After the completion of the dropwise addition, the mixture was stirred at room temperature for 4 hr. The yielded yellow insoluble material was filtered off, and washed with acetic acid. The filtrate and washing solution were combined, and concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (300 mL), and the suspension was washed with 5% aqueous sodium hydrogen carbonate solution (300 mL), water (300 mL) and saturated brine (300 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=20/80→0/100), and the obtained solution was concentrated under reduced pressure to give the title compound (2.20 g, 95%) as a colorless amorphous substance.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:15])=[CH:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Cl[CH:17]([CH3:20])[C:18]#[N:19]>CN(C=O)C>[CH3:3][C:4]([CH3:15])=[CH:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH:17]([CH3:20])[C:18]#[N:19])=[CH:12][CH:13]=1
Reactant: CC(Cl)C#N
Reactant: CC(C)=CCOc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)=CCOc1ccc(OC(C)C#N)cc1
Temperature: 5 °C

Procedure:
To NaH (0.246 g, 10.2 mmol) in 10 ml of DMF at 20° is added 4-(3-methyl-2-butenoxy)phenol (1.33 g, 10.2 mmol) in 5 ml of DMF. After anion formation is complete, the reaction is cooled to 5° C. and 2-chloropropionitrile (1.095 g, 12.2 mmol) is added gradually. Then, the reaction mixture is warmed to RT and heated at 45° for 18 hrs. The reaction is cooled to RT, poured into ice water and extracted with ether. The combined organic layers are washed with 10% NaOH, followed with water until neutral, and with brine, and dried over calcium sulfate. Ether is removed under vacuum to give 2-[4-(3-methyl-2-butenoxy)phenoxy]propionitrile.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=3.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[C:16]1([C:2]2[CH:3]=[CH:4][C:5]3[NH:6][C:7]4[C:12]([C:13]=3[CH:14]=2)=[CH:11][C:10]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:13][CH:14]=2)=[CH:9][CH:8]=4)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc3[nH]c4ccc(-c5ccccc5)cc4c3c2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
Under a nitrogen gas atmosphere, to a flask, 3,6-dibromocarbazole (5 g, 15.4 mmol), phenylboronic acid (4.1 g, 33.9 mmol), tetrakis(triphenylphosphine)palladium (0.7 g, 0.6 mmol), toluene (45 ml) and 2M sodium carbonate (45 ml) were mixed in sequence, and were stirred for eight hours at 80 degrees C. An organic phase was separated and then concentrated under reduced pressure by an evaporator. The obtained residue thereof was refined by silica-gel column chromatography, so that 3.6-diphenylcarbazole (3.6 g, a yield of 74%) was obtained.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:36][C:37]1[N:42]=[CH:41][C:40]([C:43]2[CH:65]=[CH:64][C:46]3[N:47]([C:60]([CH3:63])([CH3:62])[CH3:61])[C:48]([C:50]4[CH:59]=[CH:58][CH:57]=[CH:56][C:51]=4[C:52]([NH:54]O)=[NH:53])=[N:49][C:45]=3[CH:44]=2)=[CH:39][N:38]=1>CN(C=O)C>[C:60]([N:47]1[C:46]2[CH:64]=[CH:65][C:43]([C:40]3[CH:41]=[N:42][C:37]([NH2:36])=[N:38][CH:39]=3)=[CH:44][C:45]=2[N:49]=[C:48]1[C:50]1[CH:59]=[CH:58][CH:57]=[CH:56][C:51]=1[C:52]1[N:54]=[C:1]([CH3:2])[O:4][N:53]=1)([CH3:63])([CH3:61])[CH3:62]
Reactant: CC(=O)O
Reactant: CC(C)(C)n1c(-c2ccccc2C(=N)NO)nc2cc(-c3cnc(N)nc3)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.7 %

Procedure:
To a solution of acetic acid (30 mg, 0.5 mmol) and HATU (189 mg, 0.5 mmol) in DMF (2 mL) is added triethylamine (0.07 mL, 0.5 mmol). The reaction mixture is stirred at room temperature for 10 minutes and 2-[5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-N-hydroxy-benzamidine (200 mg, 0.5 mmol) is added. The reaction mixture is stirred at room temperature for 0.5 hours then warmed to 80° C. and stirred for 15 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo. EtOAc (20 mL) is added and the organics washed with H2O (30 mL) then dried (Na2SO4), filtered and concentrated. Purification via prep HPLC (0.1% TFA/MeCN) affords the title compound (27 mg, 8%) as 2TFA salt. LCMS (ESMS): m/z 426.20 (M++1)
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:21]([CH3:23])[CH3:22])[CH:8]=2)[N:3]=1.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>N1C=CC=CC=1>[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:1]([C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)[C:2]2[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N:21]([CH3:23])[CH3:22])[CH:8]=3)[N:3]=2)=[O:31])=[CH:28][CH:27]=1
Reactant: CN(C)c1ccc2nc(N)c(C#N)c(NCc3cccs3)c2c1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N(C(=O)c2ccc(OC)cc2)c2nc3ccc(N(C)C)cc3c(NCc3cccs3)c2C#N)cc1
Temperature: 0 °C

Procedure:
To the solution of 0.4 g of 2-amino-3-cyano-4-[2-thienylmethylamino]-6-dimethylaminoquinoline in 2 mL of pyridine, 0.4 mL of 4-methoxybenzoyl chloride is added under stirring and cooling. The reaction mixture is stirred at 80° C. for 8 hours, then poured onto 5 mL of ice-water. The precipitated material is filtered off, washed twice with 3 mL of water. After drying 0.43 g of the title compound is obtained, m.p.: 171° C.
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[F:6][C:7]([F:24])([F:23])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:12]=1)=[O:9]>>[CH3:22][S:19]([CH2:18][CH2:17][C:13]1[CH:12]=[C:11]([NH:10][C:8](=[O:9])[C:7]([F:23])([F:6])[F:24])[CH:16]=[CH:15][C:14]=1[S:2]([OH:5])(=[O:4])=[O:3])(=[O:20])=[O:21]
Reactant: O=S(=O)(O)Cl
Reactant: CS(=O)(=O)CCc1cccc(NC(=O)C(F)(F)F)c1
Product: CS(=O)(=O)CCc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)O
Temperature: 25 °C
Yield: 43.1 %

Procedure:
Chlorosulfonic acid (5.8 g, 49 mmol) was cooled to 0° C., then 2,2,2-trifluoro-N-(3-(2-(methylsulfonyl)ethyl)phenyl)acetamide (2 g, 6.8 mmol) was added slowly. The reaction mixture was allowed to warm to room temperature. Two hours later, the reaction was poured onto ice. The aqueous layer was extracted with ethyl acetate 3 times. The combined organic phase was washed with brine, dried over sodium sulfate. The crude product was purified by pre-HPLC (column: Luna 300×50.0 mm, 10 um; liquid phase: [A-H2O+0.05% TFA; B-MeCN] B %: 0%-27%, 23 min) to give 2-(2-(methylsulfonyl)ethyl)-4-(2,2,2-trifluoroacetamido)benzenesulfonic acid (1.1 g, yield 28%).
Reaction SMILES: C(S)CCC.[H-].[Na+].Cl[C:9]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:12][S:11][N:10]=1.O>O1CCCC1>[S:11]1[N:10]=[CH:9][C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:12]1
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCS
Solvent: C1CCOC1
Product: c1cncc(-c2cnsn2)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-butanethiol (2.7 g, 30 mmol) and sodium hydride (1.2 g, 30 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (1.2 g, 6 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at -10° C. for 0.5 h. Water was added and the mixture was extracted with ether. The etherphase was dried and evaporated. The residue was purified by column chromatography (SiO2, eluent: ethyl acetate/methylene chloride (1:1))to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([Cl:13])[C:6](Cl)=[N:7]2.[CH3:14][C:15]([NH2:18])([CH3:17])[CH3:16].O.BrC1C=CC=C2C=1N=C(NC(C)(C)C)C(Cl)=N2>CS(C)=O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([Cl:13])[C:6]([NH:18][C:15]([CH3:17])([CH3:16])[CH3:14])=[N:7]2
Reactant: Clc1nc2cccc(Br)c2nc1Cl
Reactant: CC(C)(C)N
Agent: CC(C)(C)Nc1nc2c(Br)cccc2nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)Nc1nc2cccc(Br)c2nc1Cl
Temperature: 100 °C
Reaction time: 5 h
Yield: 64.5 %

Procedure:
A solution of 5-bromo-2,3-dichloroquinoxaline (LeadGen Labs, LLC, Orange, Conn.) (305 mg, 1.10 mmol) and 2-methylpropan-2-amine (Aldrich) (0.12 mL, 1.10 mmol) in DMSO (5.0 mL) was stirred under argon at 65° C. for 17 h (water-cooled reflux condenser attached to flask). Additional 2-methylpropan-2-amine (0.06 mL, 0.57 mmol) was added, and the resulting solution was stirred at 100° C. for 5 h. The reaction mixture was subsequently cooled to 25° C. and diluted with half-saturated aq. NaHCO3 (80 mL). The resulting mixture was extracted with DCM (2×80 mL), and the combined extracts were sequentially washed with water (2×50 mL), dried over Na2SO4, filtered, and concentrated onto silica gel. Chromatographic purification (silica gel, 0-10% EtOAc/hexanes) furnished a ˜2.5:1 mixture of 8-bromo-N-(tert-butyl)-3-chloroquinoxalin-2-amine and 5-bromo-N-(tert-butyl)-3-chloroquinoxalin-2-amine (224 mg, 0.71 mmol, 65% yield) as an off-white solid: 8-bromo-N-(tert-butyl)-3-chloroquinoxalin-2-amine: 1H NMR (400 MHz, CDCl3) δ ppm 7.86 (1H, dd, J=7.6, 1.0 Hz), 7.72 (1H, dd, J=8.2, 1.0 Hz), 7.21 (1H, t, J=7.9 Hz), 5.63 (1H, br. s.), 1.63 (9H, s). m/z (ESI, +ve) 314.0 (M+H)+. 5-bromo-N-(tert-butyl)-3-chloroquinoxalin-2-amine: 1H NMR (400 MHz, CDCl3) δ ppm 7.65 (1H, d, J=3.7 Hz), 7.63 (1H, d, J=3.3 Hz), 7.39 (1H, t, J=8.0 Hz), 5.60 (1H, br. s.), 1.57 (9H, s). m/z (ESI, +ve) 314.0 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]2[CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH2:16][C:4]=12)=O.Cl.[NH2:25]O>C(O)=O>[CH2:16]1[C:4]2=[C:3]([C:1]#[N:25])[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]2[CH2:12][CH2:13][NH:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(C=O)c3ccccc3n2CC1
Reactant: NO
Agent: Cl
Solvent: O=CO
Product: N#Cc1c2n(c3ccccc13)CCNCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of tert-butyl 11-formyl-1,2,4,5-tetrahydro-3H-[1,4]diazepino[1,7-a]indole-3-carboxylate in formic acid (1 mL) is treated with hydroxylamine hydrochloride (90 mg, 1.3 mmol) and heated to reflux. After 18 hrs, the reaction mixture is cooled to rt, quenched with 1M sodium hydroxide (15 mL), and extracted twice with ethyl acetate (20 mL). The combined organics are washed once with brine (20 mL), dried over MgSO4, filtered, and concentrated to give 224 mg of a crude solid. This material is purified by LC (230-400) silica gel eluting with 5% methanol/dichloromethane to afford 123 mg of 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole-11-carbonitrile as a red solid, mp 161-164° C. IR (drift) 3313, 2935, 2906, 2203, 1539, 1463, 1421, 1351, 1328, 1272, 1208, 1185, 822, 769, 752 cm−1.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20]([N:22]2[C:30]3[C:25](=[CH:26][C:27](B4OC(C)(C)C(C)(C)O4)=[CH:28][CH:29]=3)[CH2:24][CH2:23]2)=[O:21])[CH:16]=[CH:17][CH:18]=1>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20]([N:22]2[C:30]3[C:25](=[CH:26][C:27]([C:2]4[C:10]5[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=5[S:4][CH:3]=4)=[CH:28][CH:29]=3)[CH2:24][CH2:23]2)=[O:21])[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ncnc2scc(Br)c12
Reactant: Cc1cccc(CC(=O)N2CCc3cc(B4OC(C)(C)C(C)(C)O4)ccc32)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cccc(CC(=O)N2CCc3cc(-c4csc5ncnc(N)c45)ccc32)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A mixture of 5-bromothieno[2,3-d]pyrimidin-4-amine (90 mg, 0.391 mmol) and 1-[(3-methylphenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (148 mg, 0.391 mmol) in 1,4-Dioxane (6 mL) and sat. aq. NaHCO3 (2 mL) was degassed with N2 for 10 minutes. PdCl2(dppf)-CH2Cl2 adduct (15.97 mg, 0.020 mmol) was added, and the reaction mixture was stirred overnight at 100° C. in a sealed vessel. The reaction was cooled down to room temperature and poured onto water. The aqueous mixture was filtered, and the solid in the filter was purified via flash chromatography on SiO2 (gradient: 100% Hexanes to 100% EtOAc) to afford the desired product (119 mg) as a white solid. LC-MS (ES) m/z=401.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.31 (s, 3H), 3.22 (t, J=8.46 Hz, 2H), 3.84 (s, 2H), 4.23 (t, J=8.46 Hz, 2H), 7.04-7.16 (m, 3H), 7.20-7.29 (m, 2H), 7.34 (s, 1H), 7.42 (s, 1H), 8.17 (d, J=8.34 Hz, 1H), 8.34 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH:8]([CH3:10])[CH3:9].[N:11]1([C:17]2[C:22](=[O:23])[NH:21][CH:20]=[C:19]3[CH2:24][N:25]([CH2:28][CH2:29][C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]=4)[C:26](=[O:27])[C:18]=23)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C(#N)C>[CH:8]([N:21]1[C:22](=[O:23])[C:17]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)=[C:18]2[C:26](=[O:27])[N:25]([CH2:28][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)[CH2:24][C:19]2=[CH:20]1)([CH3:10])[CH3:9]
Reactant: CC(C)I
Reactant: O=C1c2c(c[nH]c(=O)c2N2CCOCC2)CN1CCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)n1cc2c(c(N3CCOCC3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2
Temperature: 105 °C
Reaction time: 24 h
Yield: 12.6 %

Procedure:
A solution of potassium carbonate (2.5 g, 18.09 mmol), 2-iodopropane (1.0 ml, 10.00 mmol) and 7-morpholin-4-yl-2-(2-quinolin-2-yl-ethyl)-3,5-dihydro-2H-pyrrolo[3,4-c]pyridine-1,6-dione (0.5 g, 1.281 mmol, see Example 15) were dissolved in acetonitrile (30 ml). The suspension was stirred at about 105° C. for about 24 h. After cooling to r.t., LC-MS analysis indicated complete conversion. The crude product was purified by preparative HPLC to afford the title compound (70 mg, 0.162 mmol, 12.64% yield).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[N:18]=[CH:19][N:20]=[C:21]3[C:28]=2[C:27]2[CH2:26][CH2:25][CH2:24][C:23]=2[S:22]3)[CH2:12][CH2:11]1)C(=O)OC(C)(C)C.[Cl:29]CCl>Cl>[ClH:29].[CH3:1][NH:2][CH:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[N:18]=[CH:19][N:20]=[C:21]3[C:28]=2[C:27]2[CH2:26][CH2:25][CH2:24][C:23]=2[S:22]3)[CH2:12][CH2:11]1
Reactant: ClCCl
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)CCC4)CC1
Agent: Cl
Product: CNC1CCC(Oc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of tert-butyl N-methyl-N-(4-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yloxy]cyclohexyl)carbamate (450 mg, 1.12 mmol, 1.00 equiv) in dichloromethane (50 mL), hydrochloric acid (1.0 mL, 12 M) was added and the resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum to provide N-methyl-4-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yloxy]cyclohexan-1-amine hydrochloride (350 mg 92%) as a white solid.