Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[C:11](=O)[CH:12]([CH3:18])[C:13](OCC)=[O:14]>>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[N:6]=[C:11]([C:10]([F:21])([F:20])[F:9])[C:12]([CH3:18])=[C:13]2[OH:14]
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)C(=O)C(F)(F)F
Product: Cc1c(C(F)(F)F)nc2ccc(Cl)cc2c1O

Procedure:
Prepared according to procedure R using 4-chloroaniline (6.44 g, 50.47 mmol) and ethyl 4,4,4-trifluoro-2-methyl-3-oxobutanoate (10 g, 50.47 mmol) to give 6-chloro-3-methyl-2-(trifluoromethyl)quinolin-4-ol as an off-white solid: Mass Spectrum (ESI) m/e=262.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Br-:10].[Br-:11].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>C(Cl)Cl.CO>[Br:10][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([Br:11])[C:6]=1[OH:9]
Reactant: [Br-]
Reactant: COc1ccc(O)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(Br)c(O)c(Br)c1
Yield: 101.2 %

Procedure:
To 4-methoxyphenol (10.00 g, 80.6 mmol) in CH2Cl2 (70 mL), add a stirred solution of benzyltrimethylammonium tribromide (69.10 g, 177.2 mmol) in CH2Cl2 (500 mL) and MeOH (200 mL). Stir the reaction for 12 hours and remove the solvent in vacuo. Add methyl tert-butyl ether (MTBE) (600 mL) and collect the precipitate (benzyltrimethylammonium bromide) by filtration and wash with MTBE (200 mL). Filter the organics through Celite® and concentrate to provide the subtitled product (23.0 g, >95%) as an orange solid that may be used without purification. 1H NMR (DMSO-d6) δ 3.69 (s, 3H), 7.14 (s, 2H), 9.32 (s, 1H).
Reaction SMILES: C1([C:7]2[N:16]3[C:10]([C:11](=O)[C:12]4[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=4[CH2:14][CH2:15]3)=[N:9][N:8]=2)C=CC=CC=1.[H][H].[CH2:24](O)[CH3:25]>[Pd]>[CH3:10][N:16]1[CH2:25][CH2:24][CH:13]([CH:11]2[C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[CH2:14][CH2:15][N:9]3[N:8]=[CH:7][N:16]=[C:10]23)[CH2:14][CH2:15]1
Reactant: CCO
Reactant: O=C1c2ccccc2CCn2c1nnc2-c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Product: CN1CCC(C2c3ccccc3CCn3ncnc32)CC1
Yield: 83 %

Procedure:
Compound (5) (0.00767 mol) in ethanol (200 ml) was hydrogenated with palladium on activated carbon (2.2 g) as a catalyst at 50° C. over a 5 hours period under a 3 bar pressure in a Parr apparatus. After uptake of hydrogen (1 eq.), the catalyst was filtered through celite and the filtrate was evaporated. The residue (2.1 g) was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH/NH4OH 94/6/0.5 to 90/10/0.5) (15-40 μm). The pure fractions were collected and evaporated. The residue was crystallized from 2,2'-oxybispropane, yielding 1.22 g (83%) of (±)-6,11-dihydro-11-(1-methyl-4-piperidinyl)-5H-[1,2,4]triazolo[5,1-b][3]benzazepine; mp. 133.8° C. (comp. 44).
Reaction SMILES: CN1CCOCC1.[C:8]([C:10]1[CH:27]=[CH:26][C:13]([O:14][CH2:15][CH:16]([NH:18][C:19](=[O:25])[C@H:20]([CH:22]([CH3:24])[CH3:23])[NH2:21])[CH3:17])=[CH:12][CH:11]=1)#[N:9].Cl[C:29]([S:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[S:30].O>C(Cl)Cl>[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH:16]([NH:18][C:19](=[O:25])[C@H:20]([CH:22]([CH3:23])[CH3:24])[NH:21][C:29]([S:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[S:30])[CH3:17])=[CH:26][CH:27]=1)#[N:9]
Reactant: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](N)C(C)C
Reactant: S=C(Cl)Sc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](NC(=S)Sc1ccccc1)C(C)C
Temperature: 25 °C
Yield: 68.6 %

Procedure:
0.5 g of N-methylmorpholine was added to a suspension containing 1.4 g of N1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide suspended in 40 ml of methylene chloride, at -15° C. After 0.9 g of phenyl chlorodithioformate was added to the mixture at -15° C., the reaction mixture was allowed to sit and, warm naturally to room temperature while being stirred, and was stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.4 g of the desired product in the form of a yellow glutinous substance (yield: 66%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].Cl.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]([OH:19])[C:14](=[NH:18])[O:15]CC.O1CCCC1>C1(C)C=CC=CC=1>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[O:19][C:1](=[O:2])[NH:15][C:14]1=[O:18]
Reactant: O=C(Cl)Cl
Reactant: CCOC(=N)C(O)c1ccccc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(c2ccccc2F)O1

Procedure:
By the procedure of Example 3, except that a reaction time of 2 hours at room temperature was employed following the phosgene perfusion step, ethyl 1-(2-fluorophenyl)-1-hydroxymethanecarboximidate hydrochloride (14.5 g., 0.062 mole) in 500 ml. of tetrahydrofuran was converted to toluene recrystallized 5-(2fluorophenyl)oxazolidine-2,4-dione (7.32 g., 60%; m.p. 129°-131° C.).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:18]=O)[CH3:13].Cl.O>CO>[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([CH:18]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH3:13]
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: O
Solvent: CO
Product: CCOc1cc(C=C2Oc3cc(O)ccc3C2=O)ccc1OC
Temperature: 25 °C
Yield: 47.6 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-ethoxy-4-methoxybenzaldehyde 1.33 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and water 150 ml was added. Precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 0.99 g.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][OH:15].Cl[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=1>C1COCC1>[CH3:11][C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][O:15][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=1
Reactant: CC(C)(C)CCO
Reactant: N#Cc1ccc(Cl)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)CCOc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
Add sodium bis(trimethylsilyl)amide (3.95 mL, 7.9 mmol, 2M solution in THF) to a solution of 3,3-dimethyl-butan-1-ol (960 □L, 7.9 mmol) in anhydrous THF (10 mL). Stir for 30 min at room temperature and then add a solution of 6-chloro-nicotinonitrile (1 g, 7.2 mmol) in anhydrous THF (5 mL). Stir at room temperature overnight and then quench the reaction mixture with saturated aqueous NaHCO3 (100 mL). Extract the aqueous layer with dichloromethane (3×100 mL) and wash the organic layer with brine (100 mL). Dry the combined organic extracts over MgSO4 and concentrate in vacuo to give the desired intermediate as a yellow solid (1.4 g, 94%). GC-MS m/z: 204 (M+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:6]=[N:7][CH:8]=1.C1CCN2C(=NCCC2)CC1.[CH:32]([S:35](Cl)(=[O:37])=[O:36])([CH3:34])[CH3:33]>ClCCCl>[C:18]([C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:20])[C:9]=1[C:5]1[CH:4]=[C:3]([CH2:2][NH:1][S:35]([CH:32]([CH3:34])[CH3:33])(=[O:37])=[O:36])[CH:8]=[N:7][CH:6]=1)#[N:19]
Reactant: Cn1c(-c2cncc(CN)c2)c(C#N)c2ccccc21
Reactant: CC(C)S(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCCl
Product: CC(C)S(=O)(=O)NCc1cncc(-c2c(C#N)c3ccccc3n2C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A flask is charged with 2-(5-aminomethyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (130 mg, 0.5 mmol), DBU (304 mg, 2.0 mmol) and DCE (15 mL), and isopropylsulfonyl chloride (142 mg, 1.0 mmol) is added. The mixture is stirred at room temperature for 1 h and concentrated in vacuo. The residue is purified by silica gel flash chromatography (dichloromethane-methanol, 1:0 to 97:3) to give propane-2-sulfonic acid [5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24 (d, J=6.8 Hz, 6H), 3.18-3.26 (m, 1H), 3.79 (s, 3H), 4.37 (d, J=6.1 Hz, 2H), 7.34-7.38 (m, 1H), 7.41-7.46 (m, 1H), 7.70-7.79 (m, 3H), 8.08 (t, J=2.0 Hz, 1H), 8.77 (d, J=2.3 Hz, 1H), 8.81 (d, J=2.3 Hz, 1H). HRMS (ESI) m/z 369.1389 [(M+H)+ Calcd for C19H21N4O2S: 369.1385].
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:19]O>>[I:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1I
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1I

Procedure:
In a 5 liter 3 necked flask, 2-iodo-5-nitro-benzoic acid (100 grams) was dissolved in methanol (3000 ml). The flask was fitted with a reflux condenser and 50 ml of concentrated sulfuric acid was added carefully with cooling. After the completion of the addition, the contents were refluxed for 3 days until completion of the reaction. The reaction was followed by TLC. After the completion of the reaction, the reaction mixture was concentrated to 1000 ml and allowed to cool. The product crystallized as a light yellow colored powder. The solid material was filtered and washed with water and methanol and air-dried. The yield was 90 grams.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].Cl[C:17]1[N:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([NH2:21])=[O:20].N1C=CC=CC=1>BrC1C=CC=CC=1>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:17]3[C:18]([C:19]([NH2:21])=[O:20])=[CH:22][CH:23]=[CH:24][N:25]=3)[CH:3]=2)[NH:7][CH:6]=1
Reactant: NC(=O)c1cccnc1Cl
Reactant: CN(C)CCc1c[nH]c2ccc(N)cc12
Solvent: Brc1ccccc1
Solvent: c1ccncc1
Product: CN(C)CCc1c[nH]c2ccc(Nc3ncccc3C(N)=O)cc12
Temperature: 156 °C
Yield: 36 %

Procedure:
5-Amino-3-(2-dimethylaminoethyl)indole and 2-chloronicotinamide were used. Pyridine was used as base, bromobenzene was used as solvent, and the reaction was heated at reflux (156° C.) for 18 hours. Chromatography followed by recrystallization (methanol/water) of the resulting solid in afforded the title compound (36%) as a yellow solid: mp, 127.0°-129.0° C.; 13C NMR (CD3OD) δ173.0, 157.9, 152.2, 139.0, 135.4, 132.4, 129.0, 123.9, 119.1, 113.7, 113.2, 113.0, 112.5, 111.3, 61.4, 45.4, 24.3; HRMS calculated for C18H21N5O 323.1748, found 323.1726. Anal. calcd. for C18H21N5O.H2O; C, 63.33; H, 6.79; N, 20.51. Found: C, 63.19; H, 6.50; N, 20.30.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([NH:8][NH2:9])=[O:7])#[N:2].C1COCC1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>CN(C=O)C>[Cl:18][CH2:19][C:20]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[CH:4]=1)=[O:21]
Reactant: N#Cc1cccc(C(=O)NN)c1
Reactant: O=C(Cl)CCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1cccc(C(=O)NNC(=O)CCl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
3-cyanobenzohydrazide (1.6 g, 10.0 mmol) was added to THF (40 ml) and DMF (10 ml). TEA (1.4 ml, 10.0 mmol) was added at 0° C. followed by chloroacetyl chloride (1.0 ml, 12.6 mmol) and the reaction mixture was stirred at 0° C. for 1 h and at rt for 2 h. The THF was evaporated, water was added to the remaining mixture, followed by filtratation over celite and purification with prep. HPLC to give the title compound (1.6 g, 69%). 1H NMR (DMSO-d6): 10.62 (br s, 2 H), 8.28 (m, 1 H), 8.18 (m, 1 H), 8.08 (m, 1 H), 7.75 (t, 1 H), 4.22 (s, 2 H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[Cl:39])[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12](=[O:35])[CH2:13][NH:14][C:15](=[O:34])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[NH:26]C(OC(C)(C)C)=O)[CH2:7]1.[CH3:40]O.C=O.[BH3-][C:45]#[N:46].[Na+]>C(O)(=O)C>[NH2:26][C:17]1[CH:18]=[CH:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:16]=1[C:15]([NH:14][CH2:13][C:12]([NH:11][C@@H:8]1[CH2:9][CH2:10][N:6]([CH2:5][C:4]2[CH:3]=[CH:2][C:38]([Cl:39])=[C:37]([N:46]([CH3:45])[CH3:40])[CH:36]=2)[CH2:7]1)=[O:35])=[O:34]
Reactant: [BH3-]C#N
Reactant: CO
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)c(N)c2)C1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)c1cc(CN2CC[C@@H](NC(=O)CNC(=O)c3cc(C(F)(F)F)ccc3N)C2)ccc1Cl
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of (R)-1-(3-amino-4-chlorobenzyl)-3-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (44.9 mg), methanol (0.95 mL), aceticacid (0.05 mL), and 37% aqueous HCHO solution (0.15 mL) was added NaBH3CN (38 mg). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature and evaporated. To the residue was added 2 N aqueous NaOH solution and ethyl acetate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried and concentrated, and the residue was loaded onto Varian™ SCX column and washed with CH3OH. Product was eluted off using 2 N NH3 in CH3OH and concentrated. The residue was dissolved in 50% conc. HCl/dioxane and the solution was stirred at room temperature for 1 h. The reaction mixture was adjusted to pH 10 with 5 N aqueous NaOH solution and extracted with ethyl acetate (2 times). The combined extracts were dried over Na2SO4, filtered, and evaporated. Preparative TLC (SiO2, 20% MeOH/AcOEt) gave (R)3-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}amino]-1-{4-chloro-3-(dimethylamino)benzyl)pyrrolidine (Compound No. 2133). (10.9 mg, 28%): The purity was determined by RPLC/MS (95%); ESI/MS m/e 498.3 (M++H, C23H25ClF3N5O2).
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[CH:9][C:10]([O:12]C(C)(C)C)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)Cl.FC(F)(F)C(O)=O>[C:1]1([CH2:7][CH:8]=[CH:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C=CCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C=CCc1ccccc1
Yield: 99.8 %

Procedure:
A solution of 6.3 g (28.86 mmol) of t-butyl 4-phenylbut-2-enoate in 100 mL of CH2Cl2 and 30 mL of trifluoroacetic acid is stirred at 25° C. for 18 hours. The reaction is concentrated in vacuo to afford 4.67 g (99.85%) of 4-phenylbut-2-enoic acid as a yellow crystalline solid.
Reaction SMILES: [CH:1]1([CH2:5][N:6]2[CH:10]=[CH:9][N:8]=[C:7]2[CH2:11]O)[CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:15])=O>>[ClH:15].[Cl:15][CH2:11][C:7]1[N:6]([CH2:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)[CH:10]=[CH:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1nccn1CC1CCC1
Product: Cl
Product: ClCc1nccn1CC1CCC1
Temperature: 90 °C

Procedure:
To 1-cyclobutylmethyl-2-hydroxymethylimidazole (2.90 g) was added thionyl chloride (29 ml) at 0° C., and the mixture was heated for 30 minutes under nitrogen atmosphere at 90° C. The mixture was allowed to be at room temperature. The solvent was distilled off under reduced pressure and the obtained residue was dissolved in methanol and the solvent was distilled off again under reduced pressure. The obtained solid was recrystallized from ethyl acetate, to give 2-chloromethyl-1-cyclobutylmethylimidazole hydrochloride (3.54 g) as brown crystals.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.C(N(CC)CC)C.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>CN(C=O)C.[Pd].[Cu]I>[Br:8][C:6]1[N:7]=[C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1nc(Br)cnc1N
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a solution of 3,5-Dibromo-pyrazin-2-ylamine (3.00 g, 11.86 mmol) in DMF (35 ml) was added triethylamine (16 ml), then tetrakistriphenylphine palladium (0) (685 mg, 0.59 mmol) and copper(I) iodide (271 mg, 1.42 mmol) were added sequentially. Finally trimethylsilylacetylene (2.0 ml, 14.3 mmol) was added dropwise. The reaction mixture was stirred at 120° C. for 30 minutes and then directly adsorbed onto silica gel. Purification by flash chromatography on silica gel with a gradient of ethyl acetate/hexane afforded the title compound (2.30 g, 71% yield) as yellow oil. MS: m/z 270.0/272.0 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[C:37]1(O)[CH:42]=[CH:41]C=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][C:26]2[CH:41]=[CH:42][CH:37]=[CH:38][CH:39]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Oc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)c(C)c3C)c2cc1OC
Yield: 53.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (139 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 10 min. Next, phenol (44 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (73 mg, yield 49%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[S:10][C:11]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[O:16])=[C:12]([CH3:14])[N:13]=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(CC)CC>C(O)C>[CH3:14][C:12]1[N:13]=[C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:2][S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])[S:10][C:11]=1[C:15](=[O:16])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1ccccc1C(=O)c1sc(NCCCCCN)nc1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccccc1C(=O)c1sc(NCCCCCNS(=O)(=O)c2ccccc2)nc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.1 %

Procedure:
A solution of 18 mg (0.05 mmol) [2-(5-Amino-pentylamino)-4-methyl-thiazol-5-yl]-o-tolyl-methanone hydrochloride in 1 ml ethanol was treated with 10.6 mg (0.06 mmol) benzenesulfonylchloride and 21 ml NEt3. The mixture was allowed to stir for 15 h at room temperature and afterwards subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient. Evaporation of the product fractions yielded 12.6 mg (55%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([CH2:12][Cl:13])=[CH:7][C:6]=2[CH:14]=1.[NH2:15][C:16]([NH2:18])=[S:17]>C(O)C>[ClH:13].[C:16]([S:17][CH2:12][C:8]1[CH2:9][CH2:10][CH2:11][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:6]=2[CH:7]=1)(=[NH:15])[NH2:18]
Reactant: NC(N)=S
Reactant: ClCC1=Cc2cc(Br)ccc2CCC1
Solvent: CCO
Product: Cl
Product: N=C(N)SCC1=Cc2cc(Br)ccc2CCC1
Yield: 91 %

Procedure:
To a solution of 2-bromo-8-(chloromethyl)-6,7-dihydro-5H-benzo[7]annulene from step A6 (60 mg, 0.221 mmol) in ethanol (1 mL) was added thiourea (16.82 mg, 0.221 mmol). The mixture was heated at reflux for 4 h. The solvent was removed, and the solid residue was triturated with hexanes and dried in vacuo to give (2-bromo-6,7-dihydro-5H-benzo[7]annulen-8-yl)methyl carbamimidothioate hydrochloride (70 mg, 0.201 mmol, 91% yield). To a solution of (2-bromo-6,7-dihydro-5H-benzo[7]annulen-8-yl)methyl carbamimidothioate, hydrochloride (60 mg, 0.173 mmol) in TFA (1 mL) was added triflic acid (0.2 mL) at 0° C. The mixture was stirred at rt for 18 h and then heated to 80° C. for 4 h. Another 2 mL of TFA and 0.2 mL of trifilic acid were added, and the mixture was stirred at 60° C. for 20 h. The solvent was removed. The residue was dissolved in 50 mL of EtOAc and the organic layer was washed with saturated sodium bicarbonate/water, dried over sodium sulfate, filtered, and concentrated in vacuo to afford crude product (60 mg, 0.193 mmol, 112% yield), which was used for the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[Br:11]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:10][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: Cc1ccc(F)cc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(F)ccc1CBr
Temperature: 25 °C
Yield: 101.7 %

Procedure:
A mixture of 5-fluoro-2-methylbenzonitrile (10.0 g, 74.0 mmol), N-bromosuccinimide (NBS, 13.2 g, 74.0 mmol), benzoyl peroxide (0.2 g, 0.82 mmol), and carbon tetrachloride (100 mL) was refluxed for 18 h. The reaction mixture was then cooled to room temperature and filtered through fritted glass. The solid in the funnel was washed with carbon tetrachloride (3×50 mL) and evaporated to dryness under vacuum to provide 16.1 g, 102% yield of product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[C:21]([OH:26])(=[O:25])[C:22]([CH3:24])=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:22]([C:21]([OH:26])=[O:25])[CH3:24])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: CC(=O)C(=O)O
Solvent: C1CCOC1
Product: CC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)C(=O)O
Reaction time: 2.5 h

Procedure:
To a solution of 2.85 g. (0.01 mole) of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 100 ml. of tetrahydrofuran under nitrogen is added with stirring, 0.847 ml. (0.012 mole) of pyruvic acid. After 2.5 hours at room temperature and overnight at 0° C. 7-chloro-2-[(1-carboxyethylidene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine is obtained.
Reaction SMILES: [I-:1].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O>[I:1][C:7]1[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=1.[I:1][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:3]
Reactant: Nc1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: O
Product: Nc1ccc(I)cc1
Product: Nc1ccccc1I
Reaction time: 4 h

Procedure:
The anode compartment of the cell described in Example 19 was charged with 150 ml of water, 22.5 g of sodium iodide and 139.5 ml of aniline. The cathode compartment was charged with 300 ml of water and 45 g of sodium iodide. The cell was operated at 0.25 ampere (25 ma/cm2) at 25°C for 4 hours, and the anode solution was extracted with methylene chloride and analyzed by glc. A total of 3.30 g of p-iodoaniline and 0.14 g of o-iodoaniline were produced. This corresponds to a p-iodoaniline current efficiency of 81% and a para to ortho ratio of 95.9 to 4.1.