Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:16][CH2:17][CH2:18]Br)=[CH:11][CH:10]=1.[I-].[K+]>CN(C)C=O.C(Cl)Cl>[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:16][CH2:17][CH2:18][N:1]2[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(C(CCCBr)c2ccc(F)cc2)cc1
Reactant: C1CNCCNC1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Fc1ccc(C(CCCN2CCCNCC2)c2ccc(F)cc2)cc1

Procedure:
24 g (0.24 mol) of 1,4-diazacycloheptane, 7.8 g (0.024 mol) of 4,4-bis(4-fluorophenyl)butyl bromide and 0.14 g of potassium iodide were stirred in 60 ml of dimethylformamide at room temperature for 4 hours. The solvent was stripped off in vacuo, the residue was taken up in methylene chloride, the mixture was extracted by shaking with 2N HCl, the acid phase was brought to pH 11 with concentrated NaOH and extracted with methylene chloride and the extracts were dried and concentrated.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Br[CH:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([O:9]CC)=O>C(O)C>[C:12]1([CH:6]2[NH:4][CH2:1][CH2:2][NH:3][C:7]2=[O:9])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: NCCN
Solvent: CCO
Product: O=C1NCCNC1c1ccccc1
Temperature: 25 °C
Yield: 54.3 %

Procedure:
To a stirred solution of 1928 g (32.1 mol) of ethylenediamine in 2 liters of absolute ethanol was added a solution of 3130 g (12.8 mol) of ethyl α-bromophenylacetate in 4 liters of absolute ethanol at such a rate so as to maintain reflux (~45 minutes addition time). The mixture was allowed to cool to ambient temperature and then concentrated to a thick yellow slurry. The slurry was stirred with 2 liters of chloroform, filtered, and the solid washed thoroughly with chloroform (total of 8 liters). The filtrate was concentrated to near dryness and the resulting residue stirred for a short time with 2 liters of isopropanol. The solid was collected by filtration, washed with 4 liters of isopropanol, and dried to give 1224 g (54%) of 3-phenyl-2-piperazinone. This material was used as such in the next step. [Pure material could be obtained by recrystallization from benzene and then from acetone to give a white solid (mp. 139.0°-139.5° C. ).]
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([C:19]#[N:20])=[CH:13]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>O1CCCC1>[C:19]([C:14]1[NH:15][C:16]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:2][O:1][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:18][CH:17]=2)#[N:20]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1cc2cc(C(CO)c3ccccc3)ccc2[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC(c1ccccc1)c1ccc2[nH]c(C#N)cc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 5-(2-hydroxy-1-phenyl-ethyl)-1H-indole-2-carbonitrile CCLXX (218 mg, 0.789 mmol) in tetrahydrofuran (10 mL) was added at 0° C. methanesulfonyl chloride (73 μL, 0.947 mmol) followed by triethylamine (0.16 mL, 1.183 mmol) and the resulting mixture was stirred at 0° C. for 3 hours. The precipitate which formed was filtered off and the filtrate was evaporated under reduced pressure. The crude residue was purified by flash chromatography to give 240 mg of methanesulfonic acid 2-(2-cyano-1H-indol-5-yl)-2-phenyl-ethyl ester CCLXXI.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([C:20]#[N:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[Br:22]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3([C:20]#[N:21])[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:12][CH:13]=2)=[N:6][C:7]=1[Br:22]
Reactant: N#CC1(c2ccc(-c3cnc(N)cn3)cc2)CCOCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(-c3cnc(N)c(Br)n3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-(5-aminopyrazin-2-yl)phenyl)tetrahydro-2H-pyran-4-carbonitrile (1.08 m, 3.84 mmol) in DMF (30 mL) was added N-bromosuccinimide (747 mg, 4.22 mmol) in one portion. The reaction was then stirred at room temperature for 1 h. At completion, the mixture was poured over ice (50 mL) and stirred for 20 min. After filtration and washing with water and drying under vacuum, 4-(4-(5-amino-6-bromopyrazin-2-yl)phenyl)tetrahydro-2H-pyran-4-carbonitrile was obtained as obtained as a dark brown solid (1.37 g, 100% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][N:15]3[C:19]4=[N:20][C:21]([C:24]5[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=5)=[CH:22][N:23]=[C:18]4[N:17]=[N:16]3)[CH2:9]2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:53]=[CH:52][C:41]([CH2:42][N:43]3[CH2:48][CH2:47][N:46]([C:49](=[O:51])[CH3:50])[CH2:45][CH2:44]3)=[CH:40][CH:39]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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]>[CH3:29][N:27]1[CH:28]=[C:24]([C:21]2[N:20]=[C:19]3[N:15]([CH2:14][C@H:10]4[CH2:11][CH2:12][CH2:13][N:8]([C:5]5[N:4]=[CH:3][C:2]([C:38]6[CH:53]=[CH:52][C:41]([CH2:42][N:43]7[CH2:48][CH2:47][N:46]([C:49](=[O:51])[CH3:50])[CH2:45][CH2:44]7)=[CH:40][CH:39]=6)=[CH:7][N:6]=5)[CH2:9]4)[N:16]=[N:17][C:18]3=[N:23][CH:22]=2)[CH:25]=[N:26]1
Reactant: Cn1cc(-c2cnc3nnn(C[C@H]4CCCN(c5ncc(Br)cn5)C4)c3n2)cn1
Reactant: CC(=O)N1CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1CCN(Cc2ccc(-c3cnc(N4CCC[C@H](Cn5nnc6ncc(-c7cnn(C)c7)nc65)C4)nc3)cc2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
(S)-1-((1-(5-bromopyrimidin-2-yl)piperidin-3-yl)methyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (50 mg, 0.11 mmol), 1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzyl)piperazin-1-yl) ethanone (45 mg, 0.13 mmol), Pd(dppf)2Cl2 (4.5 mg, 0.0054 mmol), and K2CO3 (45 mg, 0.33 mmol) were dissolved in dioxane (4 ml)+H2O (1 ml), and then degassed with N2(gas), followed by stirring at 80° C. for 2 hours. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (MeOH:MC=1:10), to give (S)-1-(4-(4-(2-(3-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)benzyl)piperazin-1-yl)ethanone (48 mg, 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[OH:12].Br[CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:16][CH2:15][CH2:14][O:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: ClCCBr
Reactant: COc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1OCCCl
Temperature: 90 °C
Yield: 56.3 %

Procedure:
A mixture of 2-methoxy-4-nitro-phenol (2.50 g, 14.8 mmol), 1-bromo-2-chloro-ethane (1.35 mL, 16.3 mmol) and potassium carbonate (4.08 g, 29.6 mmol) in DMF (50 mL) in a sealed tube was heated at 90° C. for 18 h. The reaction was cooled and filtered, washing with ethyl acetate. The filtrate was washed with sodium bicarbonate, water (4 times) and brine, was dried (sodium sulfate) and evaporated. Purification by flash chromatography (SiO2) eluted with 35:65 ethyl acetate:hexanes provided 1-(2-chloro-ethoxy)-2-methoxy-4-nitro-benzene (1.93 g, 56% yield) as an off-white solid. 1H-NMR (DMSO-d6, 500 MHz) 7.89 (dd, 1H), 7.76 (d, 1H), 7.21 (d, 1H), 4.41 (t, 2H), 4.00 (t, 2H), 3.90 (s, 3H) ppm; HPLC (Method A) 3.781 min.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([NH2:12])[CH2:9]2)C=CC=CC=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[NH:8]1[CH2:11][CH:10]([NH:12][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:9]1
Reactant: NC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC1CNC1
Reaction time: 0.5 h

Procedure:
A solution of 1-(diphenylmethyl)-3-azetidinamine (synthesized according to the methods of Arimoto et. al., J. of Antibiotics 39 (9), 1243-56, 1986)(197 mg, 0.83 mmol) in dichloromethane (10 mL) was treated with excess triethylamine at 0° C. followed by methanesulfonyl chloride (71 μL, 0.91 mmol). The reaction was stirred for 30 minutes and then concentrated and purified on silica gel (0-10% methanol/dichloromethane) to provide 185 mg of the desired product as a white solid. LC/MS: M+H 317.19 at 0.31 minutes, Method D.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[S:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1.C1(C)C=CC=CC=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.O.C(O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]3[O:28][CH2:29][O:30][C:26]=3[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:35]1[CH:36]=[CH:37][S:33][CH:34]=1)=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Reactant: OB(O)c1ccsc1
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)c2cc(-c3ccsc3)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Yield: 86.1 %

Procedure:
A mixture of 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg), 3-thiopheneboronic acid (120 mg), tetrakis(triphenylphosphine)palladium(0) (35 mg), toluene (6 ml), ethanol (0.8 ml) and 2M aqueous sodium carbonate solution (0.8 ml) was heated under reflux under a nitrogen atmosphere for 6 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The solvent was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-hexane:ethyl acetate=2:1) and recrystallized (ethyl acetate-hexane) to give the title compound (260 mg).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([CH3:16])([CH3:15])[O:13][C:12](=[C:17]([C:20]#[N:21])[C:18]#[N:19])[C:11]=2[C:22]#[N:23])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].O>C(O)C.S([O-])([O-])(=O)=O.[Cu+2]>[C:22]([C:11]1[C:12](=[C:17]([C:20]#[N:21])[C:18]#[N:19])[O:13][C:14]([CH3:15])([CH3:16])[C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([N:1]2[CH:31]=[C:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:3]=[N:2]2)=[CH:9][CH:8]=1)#[N:23]
Reactant: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1c1ccc(N=[N+]=[N-])cc1
Reactant: C#Cc1ccccc1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCO
Product: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1c1ccc(-n2cc(-c3ccccc3)nn2)cc1
Temperature: 50 °C

Procedure:
A mixture of 2-[4-(4-azido phenyl)-3-cyano-5,5-dimethyl-5H-furan-2-ylidene]malononitrile (100 mg, 0.33 mmol) and phenylacetylene (40 mg, 0.40 mmol) in 15 mL ethanol was stirred at 50° C. under N2. Sodium ascorbate (20 mg, 0.10 mmol in 2 ml water) solution was added followed by copper sulfate (12 mg, 0.048 mmol, 2 mL water) solution and stirred at 50° C. for 24 h. The reaction mixture was cooled, poured into cold water (100 mL) and was stirred at room temperature for 1 h. The precipitate formed was filtered off and air-dried. The crude product was further purified by recrystallization from EAC/1-propanol, Yield: 70 mg (52%) mp: 280° C. IR (neat) 3097, 2232, 1645, 1530 cm−1: 1H NMR (400 MHz, DMSO) δ 9.46 (s, 1H), 8.24 (d, J=8.8 Hz, 2H), 8.06 (d, J=8.8 Hz, 1H), 7.95-7.97 (m, 3H), 7.41-7.54 (m, 3H), 1.80 (s, 6H); 13C NMR (DMSO) δ 176.68, 176.52, 149.83, 147.27, 139.40, 130.17, 129.45, 128.86, 128.08, 126.9, 125.20, 120.34, 111.88, 111.00, 110.58, 103.71, 100.49, 54.80, 24.40; Anal. Calcd for C24H16N6O: C, 71.28; H, 3.99; N, 20.78. Found: C, 71.58; H, 3.84; N, 20.64. UV-Vis(CH2Cl2): λmax=369 nm, ε=2.05×104 L.mol−1cm−1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]3[S:21][CH:22]=[C:23]([C:25]([O:27]CC)=O)[N:24]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[CH3:30][NH2:31]>CCO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:12][CH2:13][N:14]([C:17]([NH:19][C:20]3[S:21][CH:22]=[C:23]([C:25]([NH:31][CH3:30])=[O:27])[N:24]=3)=[O:18])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: CCOC(=O)c1csc(NC(=O)N2CCC(N3CCc4ccc(F)cc43)CC2)n1
Solvent: CCO
Product: CNC(=O)c1csc(NC(=O)N2CCC(N3CCc4ccc(F)cc43)CC2)n1
Temperature: 39 °C

Procedure:
In a flask was placed ethyl 2-(4-(6-fluoroindolin-1-yl)piperidine-1-carboxamido)thiazole-4-carboxylate (83.6 mg, 0.2 mmol) and EtOH (2 mL) was added. Then, 40 wt % CH3NH2(aq) (10 mL) was added and the resulting mixture was heated to 38-40° C. for 4 h. The resulting mixture was concentrated to remove EtOH and then partitioned in CH2Cl2/H2O (30 mL/30 mL). The aqueous layer was extracted with CH2Cl2 (30 mL). The combined organic layer was dried (Na2SO4) and filtered. The solvent was removed by roto-evaporator and the resulting residue re-solidified from CH2Cl2/hexane to yield 2-(4-(6-fluoroindolin-1-yl)piperidine-1-carboxamido)-N-methylthiazole-4-carboxamide as a white solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].Br[CH2:16][C:17]1[CH:29]=[CH:28][C:20]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].Cl>CC(C)=O.O>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:16][C:17]2[CH:29]=[CH:28][C:20]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=2)=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=1[OH:10])(=[O:12])[CH3:13]
Reactant: CCOC(=O)COc1ccc(CBr)cc1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCCc1c(OCc2ccc(OCC(=O)OCC)cc2)ccc(C(C)=O)c1O

Procedure:
A solution of 1 g (5.15 mmoles) of 2,4-dihydroxy-3-propylacetophenone and 2.0 g (5.15 mmoles) of ethyl 4-bromomethylphenoxyacetate in 50 ml of dry acetone was stirred and refluxed with 800 mg of K2CO3 for 48 hours. The reaction mixture was diluted with H2O, rendered acidic with 6N HCl and extracted into CH2Cl2. Evaporation of the CH2Cl2 gave an oil that was chromatographed on silica gel by gradient elution with 50% CH2Cl2 /hexane to 75% CH2Cl2 /hexane to provide the title compound as a white solid.
Reaction SMILES: O=[C:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:15]1([NH:21]N)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)C.Cl>S(=O)(=O)(O)O.O>[C:9]1([C:8]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:21][C:2]=2[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C(=O)Cc1ccccc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1[nH]c2ccccc2c1-c1ccccc1
Temperature: 120 °C
Yield: 31.8 %

Procedure:
A mixture of Example 1A (7.81 g, 40.7 mmol) and phenylhydrazine (4.00 mL, 40.7 mmol) was treated with concentrated sulfuric acid (4 drops), heated to 120° C. for 15 minutes, cooled to room temperature, treated with ethanol (50 mL), treated with bubbling HCl gas for 2 minutes, and heated to reflux for 1 hour. The mixture was poured into water (100 mL) and extracted with diethyl ether. The combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was recrystallized from ethanol to provide 3.43 g (32%) of the desired product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][NH:11][CH3:12])[CH:8]=2)[CH:3]=[CH:2]1.Cl.Cl.[CH3:15][N:16]1[CH2:22][C:21]2[CH:23]=[C:24](/[CH:27]=[CH:28]/[C:29]([OH:31])=O)[CH:25]=[N:26][C:20]=2[NH:19][C:18](=[O:32])[CH2:17]1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][N:11]([CH3:12])[C:29](=[O:31])/[CH:28]=[CH:27]/[C:24]3[CH:25]=[N:26][C:20]4[NH:19][C:18](=[O:32])[CH2:17][N:16]([CH3:15])[CH2:22][C:21]=4[CH:23]=3)[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: CNCc1ccc2cc[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CC(=O)Nc2ncc(/C=C/C(=O)N(C)Cc3ccc4cc[nH]c4c3)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
To a solution of (1H-indol-6-ylmethyl)methylamine (98 mg, 0.6 mmol), (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid dihydrochloride (160 mg, 0.5 mmol) HOBt (81 mg, 0.5 mmol) and diisopropylethylamine (0.41 mL, 2 mmol) in DMF (12 mL) was added EDC hydrochloride (114 mg, 0.6 mmol). The mixture was stirred overnight at room temperature. Water (75 mL) was added and the solution stirred for 1 hr. The precipitate was collected by filtration and triturated with hexanes to afford (E)-N-(1H-indol-6-ylmethyl)-N-methyl-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylamide (89 mg, 37%) as a white solid and as a mixture of amide rotomers. 1H NMR (300 MHz, DMSO-d6) δ 11.03-11.01 (m, 1H), 10.33-10.30 (m, 1H), 8.52 (d, J=7.6 Hz, 1H), 8.13 (d, J=2.4 Hz, 1H), 7.60-7.22 (m, 5H), 6.92-6.86 (m, 1H), 6.37 (s, 1H), 4.88-4.68 (2×s, 2H), 3.78-3.74 (m, 2H), 3.08-2.89 (2×s, 3H), 2.36-2.33 (2×s, 3H); ESI MS m/z 390 [C22H23N5O2+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]=12.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=1>>[S:10]1[CH:11]=[CH:12][C:8]([C:6]2[N:5]=[C:4]3[CH2:13][CH2:14][CH2:15][C:3]3=[C:2]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=3)[CH:7]=2)=[CH:9]1
Reactant: Nc1ccc(CCO)cc1
Reactant: Clc1cc(-c2ccsc2)nc2c1CCC2
Product: OCCc1ccc(Nc2cc(-c3ccsc3)nc3c2CCC3)cc1
Yield: 29.7 %

Procedure:
Following general procedure B1, 4-chloro-2-(thiophen-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.060 g, 0.25 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.041 g, 0.30 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.025 g, 27%) as a white solid. MW=356.85. MW=372.91. 1H NMR (DMSO-d6, 500 MHz) δ 13.91 (s, 1H), 9.68 (s, 1H), 8.37-8.32 (m, 1H), 7.80-7.76 (m, 1H), 7.59-7.55 (m, 1H), 7.34 (d, J=8.5 Hz, 2H), 7.30 (d, J=8.5 Hz, 2H), 7.03 (s, 1H), 4.67 (s, 1H), 3.65 (t, J=7.0 Hz, 2H), 3.15 (t, J=7.5 Hz, 2H), 2.88 (t, J=7.0 Hz, 2H), 2.77 (t, J=7.0 Hz, 2H), 2.20 (quin, J=7.5 Hz, 2H); APCI MS m/z 337 [M+H]+.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:18])[N:5]([C:7]2[CH:12]=[N:11][N:10]([CH2:13][CH2:14]OC)[C:9](=[O:17])[CH:8]=2)[CH:6]=1.[Cl:19][C:20]1[CH:25]=[C:24]([C:26]#[C:27][Si](C)(C)C)[CH:23]=[CH:22][N:21]=1>>[Cl:19][C:20]1[CH:25]=[C:24]([C:26]#[C:27][C:2]2[N:3]=[C:4]([CH3:18])[N:5]([C:7]3[CH:12]=[N:11][N:10]([CH2:13][CH3:14])[C:9](=[O:17])[CH:8]=3)[CH:6]=2)[CH:23]=[CH:22][N:21]=1
Reactant: COCCn1ncc(-n2cc(I)nc2C)cc1=O
Reactant: C[Si](C)(C)C#Cc1ccnc(Cl)c1
Product: CCn1ncc(-n2cc(C#Cc3ccnc(Cl)c3)nc2C)cc1=O

Procedure:
The title compound, white crystalline solid, MS: m/e=370.1, 372.1 (M+H+), was prepared in accordance with the general method of example 35 from 5-(4-Iodo-2-methyl-imidazol-1-yl)-2-(2-methoxy-ethyl)-2H-pyridazin-3-one and 2-chloro-4-trimethylsilanylethynyl-pyridine.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[N:10][C:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[CH:21]=3)[C:16]([S:27][CH3:28])=[CH:15]2)=[N:12][CH:13]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.C(O)C>COCCOC.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>[CH3:29][O:30][C:31]1[CH:36]=[C:35]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]([O:25][CH3:26])=[O:24])[CH:21]=4)[C:16]([S:27][CH3:28])=[CH:15]3)=[N:12][CH:13]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COC(=O)c1ccc2c(SC)cn(-c3ncc(Br)cn3)c2c1
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: CCO
Solvent: COCCOC
Product: COC(=O)c1ccc2c(SC)cn(-c3ncc(-c4cccc(OC)c4)cn3)c2c1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.20 mmol) and a 2M solution of sodium carbonate (8 mL) were added at room temperature and under an argon atmosphere to methyl 1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indole-6-carboxylate (3.0 g, 7.96 mmol) in DME (50 mL). The addition of 3-methoxy phenyl boronic acid (1.53 g, 9.94 mmol) and ethanol (50 mL) followed 10 min later, and the resulting mixture was heated at 90° C. for 5 h. The reaction mixture was then cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated and the residue was purified by flash column chromatography [silica; ethyl acetate/hexane=3:7]. Yellow solid. Yield: 2.6 g (80% of theory)
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:11]([NH:15][C:16]1[CH:21]=[N:20][CH:19]=[C:18](Cl)[N:17]=1)([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:11]([NH:15][C:16]1[N:17]=[C:18]([N:3]2[C:4]3[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=3[N:1]=[CH:2]2)[CH:19]=[N:20][CH:21]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: CC(C)(C)Nc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)Nc1cncc(-n2cnc3ccc(N)cc32)n1
Temperature: 25 °C

Procedure:
A mixture of 1H-benzimidazol-5-amine (2.93 g, 22 mmol), N-(tert-butyl)-6-chloropyrazin-2-amine (3.71 g, 20=not) and cesium carbonate (9.12 g, 28 mmol) in DMF (20 mL) was heated under N2 for 48 h. Upon cooling to RT the mixture was filtered and the filtrate concentrated in vacuo. The residue was extracted with CHCl3 and the solvent removed under reduced pressure. The residue was chromatographed using CH2Cl2-MeOH (98:2-93:7) to give from the less polar fractions 1-[6-(tert-butylamino)pyrazin-2-yl]-1H-benzimidazol-6-amine (1.38 g):
Reaction SMILES: C(OC([NH:8][C:9]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[C:28]([CH:38]=[CH:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)[N:27]=1)=[N:10]C(OC(C)(C)C)=O)=O)(C)(C)C.[ClH:47]>CO.C(Cl)(Cl)Cl.C(OCC)(=O)C>[ClH:46].[ClH:47].[C:9]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[C:28]([CH:38]=[CH:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)[N:27]=1)(=[NH:8])[NH2:10]
Reactant: COc1ccc2nc(C=Cc3ccc(Cl)cc3)nc(N[C@H]3CCCC[C@H]3NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2c1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc2nc(C=Cc3ccc(Cl)cc3)nc(N[C@H]3CCCC[C@H]3NC(=N)N)c2c1

Procedure:
A solution of 570 mg of cis-N-[N,N′-bis(tert-butoxycarbonyl)]amidino-2-[2-(4-chlorostyryl)-6-methoxyquinazolin-4-yl]aminocyclohexylamine in 8 mL of methanol and 8 mL of chloroform was combined with 5 mL of a 4N solution of hydrogen chloride in ethyl acetate, and reacted at 50° C. for 48 hours. After concentrating, crystallization are performed with ethyl acetate to obtain 310 mg of the desirable compound as pale yellow crystals.