Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@@H:18]([C:25]([NH2:27])=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:11][C:12](=[O:14])[OH:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(N(CC)CC)C.[NH:35]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C@H:36]([C:47](ON1C(=O)CCC1=O)=[O:48])[CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[NH:40][CH:39]=1>CN(C=O)C>[NH:35]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C@H:36]([C:47]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@@H:18]([C:25]([NH2:27])=[O:26])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[CH2:11][C:12](=[O:13])[OH:14])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:48])[CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[NH:40][CH:39]=1
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(N)=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(N)=O)c1ccccc1
Reaction time: 4 h
Yield: 72.8 %

Procedure:
2.25 g (5.93 mmoles) of H-Leu-Asp-D-Phg-NH2, prepared as described in Example 5, Step 2, are dissolved in a mixture of 50 ml of DMF and 10 ml of HMFA, and 0.84 ml (5.93 mmoles) of triethylamine and 2.65 g (6.6 mmoles) of BOC-Trp-OSu are added to the solution. The reaction mixture is stirred for 4 hours, whereupon a clear mixture is obtained. The mixture is allowed to stand overnight, and then DMF is evaporated in vacuo. The residual mixture containing HMFA is diluted with water, the obtained suspension is allowed to stand at a cool place, and then the precipitate is filtered off. The resulting crude product, weighing 4.31 g, is boiled twice in ethyl acetate, and the suspension is filtered when hot. 2.87 g (72.8%) of BOC-Trp-Leu-Asp-D-Phg-NH2 are obtained; m.p.: 195°-200° C., Rf5 : 0.55. The product is used in the next step without further purification.
Reaction SMILES: Br[CH:2]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[S-:21][C:22]#[N:23].[Na+]>C(O)C>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH:2]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:23]=[C:22]=[S:21])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)C(Br)c2ccc(OC)cc2)cc1
Reactant: N#C[S-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(=O)C(N=C=S)c2ccc(OC)cc2)cc1

Procedure:
100 g of 2-bromo-1,2-bis-(p-methoxyphenyl)-ethanone are mixed with 700 ml of 96% strength ethanol and 25.4 g of sodium thiocyanate and the mixture is heated at 45° for 2 hours. The mixture is then concentrated to dryness by evaporation under reduced pressure, 500 ml of ice-water are added, the mixture is filtered with suction and the residue is then washed twice with ice-water. The crude product is taken up in 1500 ml of methylene chloride, the remaining water is removed and the product is dried over magnesium sulphate. The product is then concentrated to approximately 200 ml, allowed to cool, filtered with suction again, then washed with a little methylene chloride and dried under reduced pressure. 1,2-bis-(p-methoxyphenyl)-2-isothiocyano-ethanone having a melting point of 155° is obtained.
Reaction SMILES: [N:1]1([C:7]2[N:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:15]=[C:11]3[N:10]=[C:9]([NH:22][NH2:23])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:24][C:25]1[O:26][C:27]2[C:33]([CH:34]=O)=[CH:32][CH:31]=[CH:30][C:28]=2[CH:29]=1.C(O)(=O)C>C(O)C>[CH3:24][C:25]1[O:26][C:27]2[C:33]([CH:34]=[N:23][NH:22][C:9]3[CH:8]=[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:12]4[N:13]=[C:14]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[CH:15]=[C:11]4[N:10]=3)=[CH:32][CH:31]=[CH:30][C:28]=2[CH:29]=1
Reactant: Cc1cc2cccc(C=O)c2o1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc2cccc(C=NNc3cc(N4CCOCC4)n4nc(-c5ccccc5)cc4n3)c2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.8 %

Procedure:
To a solution of 7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl-hydrazine (25 mg, 0.081 mM) in absolute ethanol (2.0 mL), there were added 2-methyl-7-formyl-benzofuran (19 mg, 0.12 mM) and acetic acid (2.0 μL) and the mixture was stirred at room temperature for 3 hours. The precipitated solid was recovered through filtration and washed with ethanol to thus give the title compound (28 mg, yield: 78%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][NH:8][C:9]1[S:10][CH2:11][C:12](=[O:14])[N:13]=1.[CH2:15]([O:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([CH:28]=O)[CH:26]=2)[N:21]=[C:20]([NH:30][CH3:31])[N:19]=1)[CH3:16].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH2:15]([O:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([CH:28]=[C:11]3[S:10][C:9]([NH:8][CH2:7][C:3]4[S:4][CH:5]=[CH:6][C:2]=4[CH3:1])=[N:13][C:12]3=[O:14])[CH:26]=2)[N:21]=[C:20]([NH:30][CH3:31])[N:19]=1)[CH3:16]
Reactant: Cc1ccsc1CNC1=NC(=O)CS1
Reactant: CCOc1nc(NC)nc2ccc(C=O)cc12
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOc1nc(NC)nc2ccc(C=C3SC(NCc4sccc4C)=NC3=O)cc12
Temperature: 150 °C

Procedure:
To a suspension of 2-[(3-methyl-thiophen-2-ylmethyl)-amino]-thiazol-4-one (36.2. mg, 0.16 mmole), and 4-ethoxy-2-methylamino-quinazoline-6-carbaldehyde (example 12f, 45.5 mg, 0.20 mmole) in 2 mL of toluene in a microwave tube were added benzoic acid (2.0 mg, 0.016 mmole) and piperidine (1.5 mg, 0.02 mmole). The reaction mixture was heated to 150° C. with microwave for 45 min. The reaction mixture was then cooled to r.t. and the solid was filtered off, washed with toluene, MeOH and ether to give 5-(4-ethoxy-2-methylamino-quinazolin-6-ylmethylene)-2-[(3-methyl-thiophen-2-ylmethyl)-amino]-thiazol-4-one as a brown solid: 56.5 mg (80.4%), MS: m/e 440 (MH+).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=[C:6]([Br:20])[N:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C:8]=12)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[Br:20][C:6]1[N:7]2[CH2:12][CH2:11][NH:10][CH2:9][C:8]2=[C:4]([C:1]([NH2:2])=[O:3])[C:5]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(Br)c(-c3cccc(F)c3)c(C(N)=O)c2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1c(-c2cccc(F)c2)c(Br)n2c1CNCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a solution of 1.24 g (2.83 mmol) of tert-butyl 8-carbamoyl-6-bromo-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in 10 ml of dichloromethane are added slowly 2.8 ml (28 mmol) of trifluoroacetic acid. After stirring for 1 hour at room temperature, the solvent is evaporated off under reduced pressure, the residue is taken up in water and the aqueous phase is basified by addition of aqueous ammonia. The solid formed is separated out by filtration and rinsed with water, to give 0.92 g of 6-bromo-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide in the form of a beige-coloured powder after drying under reduced pressure in the presence of potassium hydroxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[NH:11][N:10]=2)=[CH:4][C:3]=1[C:20]([N:22]1[CH2:27][CH2:26][N:25]2[C:28]([C:33]([F:36])([F:35])[F:34])=[N:29][C:30]([CH2:31]O)=[C:24]2[CH2:23]1)=[O:21].S(Cl)([Cl:39])=O>>[Cl:39][CH2:31][C:30]1[N:29]=[C:28]([C:33]([F:36])([F:35])[F:34])[N:25]2[CH2:26][CH2:27][N:22]([C:20]([C:3]3[CH:4]=[C:5]([CH2:8][C:9]4[C:18]5[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=5)[C:12](=[O:19])[NH:11][N:10]=4)[CH:6]=[CH:7][C:2]=3[F:1])=[O:21])[CH2:23][C:24]=12
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2c(C(F)(F)F)nc(CO)c2C1
Reactant: O=S(Cl)Cl
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2c(C(F)(F)F)nc(CCl)c2C1
Yield: 96.6 %

Procedure:
4-[[4-Fluoro-3-[1-(hydroxymethyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 6 (200 mg, 0.40 mmol) was dissolved in 5 mL of thionyl chloride. The reaction mixture was heated to reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, added with 10 mL of H2O, extracted with dichloromethane (10 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 4-[[3-[1-(chloromethyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 9a (200 mg, yield 96.6%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[N:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:37][N:36]=[CH:35][CH:34]=2)=[CH:29][CH:28]=1>CN(C=O)C.O>[O:37]1[C:33]([C:30]2[CH:31]=[CH:32][C:27]([CH2:26][N:16]3[C:15](=[O:18])[N:4]4[N:5]=[CH:6][C:7]([C:8]5[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=5)=[C:2]([Cl:1])[C:3]4=[N:17]3)=[CH:28][CH:29]=2)=[CH:34][CH:35]=[N:36]1
Reactant: O=c1[nH]nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Reactant: BrCc1ccc(-c2ccno2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1n(Cc2ccc(-c3ccno3)cc2)nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Temperature: 70 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 8-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (300 mg, 1.07 mmol), prepared as described in Example 354, in DMF (5 mL) was added K2CO3 (180 mg, 1.3 mmol) followed by 5-(4-(bromomethyl)phenyl)isoxazole (305 mg, 1.28 mmol), prepared as described in Example 250A. The reaction mixture was stirred at 70° C. for 2 h. The reaction mixture was cooled to RT, diluted with water (25 mL) and a precipitate formed. The solid was collected by filtration. The solid was washed with water (2×25 mL) followed by hexanes (20 mL). The solid was dried in a vacuum oven at 40° C. The title compound 2-(4-(isoxazol-5-yl)benzyl)-8-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (450 mg, 96%) was obtained as a yellow solid. HPLC: 3.50 min; M+H=438.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.N#N.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(N(CC)CC)C.O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:11]1([C:17]#[C:18][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C#Cc1ccccc1
Reactant: Brc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Brc1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 99.2 %

Procedure:
1-Bromo-4-iodobenzene (20.0 g, 70.7 mmol), bis(triphenylphospine)palladium(II) dichloride (PdCl2(PPh3)2) (250 mg), and CuI (68 mg) were suspended in 50 mL triethylamine (NEt3) and 100 mL tetrahydrofuran (THF). The suspension was treated with 3 cycles of evacuation and refilling with N2. Phenylacetylene (7.21 g, 7.75 mL, 1.0 eq) was added in 0.5 mL portions every 5 minutes to the stirred suspension. The solution was then stirred at room temperature for 22 hours. The solvents were then evaporated. Methylene chloride (100 mL) and 1 M HCl (aqueous) (50 mL) were added, the organic layer was retained, and then was washed again with 1 M HCl (aqueous) (50 mL) and 2×50 mL water, dried (MgSO4), filtered, and the solvent evaporated in vacuum to give 18 g of the title compound as a yellow solid, which was used without further purification.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[C@H:31]([OH:32])[CH2:30][NH:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:29]1[CH2:30][C@@H:31]([OH:32])[C@H:27]([NH:26][C:24]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:8]4[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:15]=3[NH:22][C:21]=2[CH3:23])=[O:25])[CH2:28]1)(=[O:35])[CH3:34]
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CNC[C@H]1O
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1C[C@@H](O)[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f10) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[N:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:22][NH2:23]>C1COCC1>[N:1]1[CH:6]=[CH:5][C:4]([C:7]([NH:22][NH2:23])=[O:9])=[N:3][CH:2]=1
Reactant: NN
Reactant: O=C(O)c1ccncn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: NNC(=O)c1ccncn1
Temperature: 25 °C

Procedure:
To a solution of pyrimidine-4-carboxylic acid (1.0 g, 8.0 mmol) in THF (15 mL), N,N-Carbonyldiimidazole (1.4 g, 8.9 mmol) was added. After refluxing for 2 hours, hydrazine (0.8 g, 20 mmol) was added to the reaction mixture slowly with a syringe at 0° C. The reaction mixture was allowed to warm to room temperature slowly and then concentrated to yield the desired product as white solid. LCMS calculated for C5H7N4O (M+H): 139.1; found: 139.1.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]([NH2:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])(C(C)(C)C)(C)C.[C:20]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:25]=[CH:24][C:23]([CH:26]2[C:31]3([CH2:34][O:33][CH2:32]3)[O:30][C:29](OC)=[N:28][S:27]2(=[O:38])=[O:37])=[CH:22][CH:21]=1>ClCCl>[C:20]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:25]=[CH:24][C:23]([CH:26]2[C:31]3([CH2:32][O:33][CH2:34]3)[O:30][C:29]([NH:19][C@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[CH2:10][CH2:9][OH:8])=[N:28][S:27]2(=[O:37])=[O:38])=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H](N)c1ccccc1F
Reactant: COC1=NS(=O)(=O)C(c2ccc(-c3ccccc3)cc2)C2(COC2)O1
Solvent: ClCCl
Product: O=S1(=O)N=C(N[C@@H](CCO)c2ccccc2F)OC2(COC2)C1c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a round-bottom flask, 9-biphenyl-4-yl-6-methoxy-2,5-dioxa-8-thia-7-azaspiro[3.5]non-6-ene 8,8-dioxide was dissolved under inert gas in 2 ml of dichloromethane, and 151 mg of (S)-3-(tert-butyldimethylsilanyloxy)-1-(2-fluorophenyl)propylamine were added. After concentration by rotary evaporation, the residue was left to stand at room temperature for 18 hours. To detach the protecting group, the residue was taken up in 1 ml of methanol and, after addition of 0.05 ml of concentrated hydrochloric acid, stirred at room temperature for 1 hour. After concentration by rotary evaporation, the residue was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined and freed of the solvent under reduced pressure. This gave the product (8 mg) with a molecular weight of 496.6 g/mol (C26H25FN2O5S); MS (ESI): m/e=497 (M+H+).
Reaction SMILES: [H-].[Na+].[N:3]1([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.O>CN(C)C=O>[N:3]1([C:8]2[N:9]([CH2:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=3)[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: c1ccc2[nH]c(N3CCCC3)nc2c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Cn2c(N3CCCC3)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (402 mg, 11 mmol) was added to a suspension of 2-pyrrolidino-1H-benzimidazole (1.9 g, 10.1 mmol) in dry N,N-dimethylformamide (30 mL). All solids dissolved. The solution was allowed to stir at ambient temperature for 15 minutes following the cessation of foaming. The solution was cooled to 5° C. and a solid formed. Methyl 4-(bromomethyl)benzoate (2.1 g, 01 mol) was added to the suspension and all the solids dissolved. The solution was allowed to stir at ambient temperature and a solid formed. The mixture was stirred at ambient temperature overnight and then it was poured into cold water. A solid was isolated by filtration, washed with water and dried to provide 3.0 g of crude product as an off-white solid. This material was recrystallized from methanol to provide methyl 4-[(2-pyrrolidinyl-1H-benzimidazol-1yl)methyl]benzoate. Analysis: Calculated for C20H21N3O2: %C, 71.62; %H, 6.31; %N, 12.53; Found: %C, 71.44; %H, 6.41; %N, 12.50.
Reaction SMILES: [OH-].[Na+].[SH:3][C:4]1[S:5][C:6]([SH:9])=[N:7][N:8]=1.Br[CH:11]([CH2:17][CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>CO.O>[SH:9][C:6]1[S:5][C:4]([S:3][CH:17]([CH3:18])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:8][N:7]=1
Reactant: Sc1nnc(S)s1
Reactant: CCOC(=O)C(Br)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC(=O)CC(C)Sc1nnc(S)s1
Reaction time: 3 h
Yield: 76.5 %

Procedure:
To a solution of 9.92 g of sodium hydroxide in 160 ml of methanol-water (10:1) was added 37.2 g of 2,5-dimercapto-1,3,4-thiadiazole to dissolve. Then 40 g of ethyl bromobutyrate was added to the solution followed by stirring for 3 hours. The reaction mixture was settled overnight. The formed solid was taken by filtration, washed with methanol-water (10:1) and dried under reduced pressure to obtain 41.5 g of ethyl 3-[(5-mercapto-1,3,4-thiadiazol-2-yl)thio]butyrate. Melting point: 107°~108° C.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)(O)[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:9]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:8]=2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Br:42])(=O)C.CO>C1(C)C=CC=CC=1>[Br:42][C:11]1([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:9]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:8]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(C2(O)C(c3ccccc3)=C(c3ccccc3)C(c3ccccc3)=C2c2ccccc2)cc1
Reactant: CC(=O)Br
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc(C2(Br)C(c3ccccc3)=C(c3ccccc3)C(c3ccccc3)=C2c2ccccc2)cc1

Procedure:
54.19 g (0.11 mol) of 1,2,3,4-tetraphenyl-5-p-methoxyphenylcyclopenta-1,3-dien-5-ol were suspended in 300 ml of toluene. 74 g (0.6 mol) of acetyl bromide were added dropwise in the course of 20 minutes at room temperature and the reaction batch was then refluxed for 2 hours. Toward the end of the reaction, 2 ml of methanol were also added dropwise. Excess acetyl bromide and toluene were distilled off in vacuo. The remaining oil crystallized after addition of 100 ml of petroleum ether. The orange precipitate was filtered off with suction, rinsed with petroleum ether and dried. The product was used for the further syntheses. Analytically pure orange product was obtained by recrystallization from toluene. (Yield: 54. 32 g (89%); elemental analysis for C36H27OBr: found: C, 77.06%, H, 4.90%. calculated: C, 77.84%, H, 4.90%).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH:13]1([C:19]2[C:20]3[CH:21]=[CH:22][C:23]([C:38](O)=[O:39])=[CH:24][C:25]=3[N:26]3[CH2:32][CH:31]([OH:33])[CH2:30][C:29]4[CH:34]=[CH:35][CH:36]=[CH:37][C:28]=4[C:27]=23)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:41][N:42]([CH3:47])[S:43]([NH2:46])(=[O:45])=[O:44]>CN(C1C=CN=CC=1)C.CN(C=O)C.C(Cl)Cl>[CH:13]1([C:19]2[C:20]3[CH:21]=[CH:22][C:23]([C:38]([NH:46][S:43]([N:42]([CH3:47])[CH3:41])(=[O:45])=[O:44])=[O:39])=[CH:24][C:25]=3[N:26]3[CH2:32][CH:31]([OH:33])[CH2:30][C:29]4[CH:34]=[CH:35][CH:36]=[CH:37][C:28]=4[C:27]=23)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CN(C)S(N)(=O)=O
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(O)Cc1ccccc1-3
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(O)Cc1ccccc1-3
Temperature: 22 °C
Reaction time: 18 h

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (11.5 mg, 0.06 mmol) was added to a solution of (±)13-cyclohexyl-6,7-dihydro-6-hydroxy-5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (7.5 mg, 0.02 mmol) and DMAP (7.4 mg, 0.06 mmol) in DMF (0.5 mL) and CH2Cl2 (0.5 mL) at 22° C. The vial was shaken for a minute at 22° C. N,N-Dimethylsulfamide (4.9 mg, 0.04 mmol) was then added. Stirring was continued for 18 hr. The solution was filtered and purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave the titled compound as a white film (3.0 mg, 30%). ESI-MS m/z 482 (MH+); 1H NMR (500 MHz, MeOD) δ 1.26-1.34 (m, 1 H) 1.40-1.55 (m, 2 H) 1.63 (m, 1 H) 1.82 (m, 2 H) 1.96 (m, 1 H) 2.01-2.19 (m, 3 H) 2.36 (m, 1 H) 2.95-3.08 (m, 2 H) 3.03 (s, 6 H) 3.76 (dd, J=15.26, 3.36 Hz, 1H) 4.41-4.69 (m, 2 H) 7.40-7.50 (m, 4 H) 7.60 (m, 1 H) 7.93 (m, 1 H) 8.11 (m, 1 H).
Reaction SMILES: [O:1]=[C:2]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:3](Cl)=[O:4].[CH3:11][N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([OH:18])[CH2:13]1>C(Cl)Cl>[CH3:11][N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([O:18][C:3](=[O:4])[C:2](=[O:1])[C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)[CH2:13]1
Reactant: O=C(Cl)C(=O)c1cccs1
Reactant: CN1CCC[C@@H](O)C1
Solvent: ClCCl
Product: CN1CCC[C@@H](OC(=O)C(=O)c2cccs2)C1
Reaction time: 0.33 h

Procedure:
To a solution of oxo-thiophen-2-yl-acetyl chloride (8.9 g, 51.2 mmol) at 5° C. in DCM (50 ml) is added a solution of (R)-1-Methyl-piperidine-3-ol (5.87 g, 51 mmol) in DCM (50 ml), dropwise with stirring over 20 minutes. The resulting mixture is stirred for 18 hours at room temperature. Washing with 1 Molar sodium bicarbonate solution, drying over magnesium sulphate, filtration and evaporation then gives the title compound as a dark oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:12](Cl)[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[C:15]1([CH:14]=[CH:13][CH2:12][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCC=Cc1ccccc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C(=Cc1ccccc1)Cn1cncn1
Reaction time: 12 h

Procedure:
A mixture of 14 parts by weight of 1,2,4-triazole, 200 parts by weight of acetonitrile, 32 parts by weight of potassium carbonate and 39.2 parts by weight of cinnamyl chloride is stirred for 12 hours, and then filtered. The filtrate is concentrated, dissolved in dichloromethane, washed with water, evaporated and distilled. There is obtained 26 parts by weight of 1-(3-phenyl-2-propenyl)-1,2,4-triazole; b.p. (0.27 mbar): 130°-134° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:15][CH2:14][C:13](=[O:16])[NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:19][O:20][C:21](=[O:28])[CH:22](Br)[CH2:23][CH2:24][CH2:25][Br:26]>>[CH3:19][O:20][C:21](=[O:28])[CH:22]([N:12]1[C:13](=[O:16])[CH2:14][CH2:15][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=2)[CH2:10][CH2:11]1)[CH2:23][CH2:24][CH2:25][Br:26]
Reactant: COC(=O)C(Br)CCCBr
Reactant: O=C1CCN(c2cccc(C(F)(F)F)c2)CCN1
Product: COC(=O)C(CCCBr)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Yield: 97 %

Procedure:
In analogy to the procedure described in example 15B, 1-(3-trifluoromethyl-phenyl)-[1,4]diazepan-5-one (example 15 A) and (rac)-2,5-dibromo-pentanoic acid methyl ester gave the title compound in 97% yield as yellow oil. MS: 453.1 (1Br, MH+).