Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH3:9][C:10](C)([O-])[CH3:11].[K+].ICCC.O>ClCCl>[CH2:9]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:8])[CH2:10][CH3:11]
Reactant: CC(C)(C)[O-]
Reactant: OCCCCCCO
Agent: [K+]
Solvent: O
Solvent: CCCI
Solvent: ClCCl
Product: CCCOCCCCCCO
Temperature: 75 °C
Reaction time: 1 h
Yield: 24.6 %

Procedure:
a 500-mL, one-necked, round-bottom flask equipped with a magnetic stirrer was charged with 1,6-hexanediol (6.00 g), potassium tert-butoxide (5.413 g) at room temperature. The reaction mixture was stirred for one hour, and then 1-iodopropane (8.63 g) was added. The reaction mixture was heated to 70-80° C. and stirred overnight. The progress of reaction was monitored by TLC (Note 1). After completion of the reaction, water was added to the reaction mixture, and extracted with ethyl acetate (2×100 mL). The combined organic layers were concentrated in vacuo to get the crude product. The crude product was dissolved in dichloromethane and washed with water, and then brine, dried over sodium sulfate. The organic layer was concentrated in vacuo to get the crude product. The crude product was purified by column chromatography using 230-400 mesh silica gel. A solvent gradient of ethyl acetate in hexanes (10-45%) was used to elute the product from the column. All fractions containing the desired pure product were combined and concentrated in vacuo to give pure 6-propyloxy-1-hexanol (lot D-1029-048, 1.9 g, 25%) Completion of the reaction was monitored by thin layer chromatography (TLC); (eluent: 60% ethyl acetate in hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28](O)=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[CH3:32][N:33]1[CH2:37][CH2:36][C@@H:35]([NH2:38])[CH2:34]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([NH:38][C@@H:35]5[CH2:36][CH2:37][N:33]([CH3:32])[CH2:34]5)=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CN1CC[C@@H](N)C1
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CC[C@@H](NC(=O)c2ccc3c(n2)CCC2C3=NN(c3ccc(C#N)c(Cl)c3)C2C2CCCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
In a dried reaction flask, 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (0.421 g, 1.0 mmol), the crude (R)-1-methylpyrrolidine-3-amine hydrochloride (0.252 g), DIEA (0.26 mL, 1.5 mmol), and HATU (0.418 g, 1.1 mmol) were added to a mixed solvent of DMF (4 mL) and dichloromethane (8 mL). The mixture was stirred at room temperature for 2 hr and was concentrated under reduced pressure. Water was added to the residue. The mixture was filtered to obtain a crude yellow solid, which was washed with methanol to produce a purified product (0.28 g) in 55.7% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=1.Cl[CH2:14][C:15](Cl)=[O:16].[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19].[Na+].[I-]>CCO.O.C(O)(=O)C>[CH2:18]([N:20]([CH2:21][CH3:22])[CH2:14][C:15]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=1)=[O:16])[CH3:19]
Reactant: CCNCC
Reactant: CS(=O)(=O)Nc1ccc(N)cc1
Reactant: O=C(Cl)CCl
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCN(CC)CC(=O)Nc1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
To 100 mL of acetic acid under a nitrogen atmosphere add 12.9 g (69 mmol) of N-(4-aminophenyl)methanesulfonamide and 9.4 g (83 mmol) of chloroacetyl chloride. Stir the reaction mixture at ambient temperature. Monitor the progress of the reaction by thin-layer chromatography on silica gel (CH2Cl2MeOH, 19:1). Upon completion of the reaction, add 300 mL of H2O and suction filter the resulting solid. To 50 mL of EtOH is added 7.0 g (27 mmol) of the solid, 9.9 g (0.14 mol) of diethylamine, and 1 g of NaI. Stir the reaction mixture at ambient temperature. Monitor the progress of the reaction by thin-layer chromatography on silica gel (CHCl3 :MeOH, 9:1). Upon completion of the reaction remove the solvent in vacuo. To the resulting oil add 50 mL of H2O and 100 mL EtOAc. Separate the layers and dry the organic layer over anhydrous Na2SO4. Remove the drying agent by filtration and remove the solvent in vacuo. Chromatograph the resulting oil on 50 g of silica gel with CH2Cl2 :MeOH, 19:1. Combine the product fractions and remove the solvent in vacuo. Dissolve the residue in methanolic HCl and remove the solvent. Triturate the solid with EtOAc to afford the title compound.
Reaction SMILES: [CH3:1][CH:2]([O:4][CH2:5][CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][NH:7]1)[CH3:3].[CH2:12]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([F:25])=[C:21](F)[CH:22]=2)[C:17](=[O:26])[C:16]([C:27]([OH:29])=[O:28])=[CH:15]1)[CH3:13].N1C=CC=CC=1>CCOCC>[CH2:12]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([F:25])=[C:21]([N:10]3[CH2:9][CH2:8][NH:7][CH:6]([CH2:5][O:4][CH:2]([CH3:1])[CH3:3])[CH2:11]3)[CH:22]=2)[C:17](=[O:26])[C:16]([C:27]([OH:29])=[O:28])=[CH:15]1)[CH3:13]
Reactant: CC(C)OCC1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(COC(C)C)C3)cc21
Temperature: 80 °C
Yield: 107 %

Procedure:
A mixture of 2 g of 2-[(1-methylethoxy)methyl]-piperazine, 1.27 g of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 5 ml of pyridine was heated at 80° C. for 3 hours, then evaporated in vacuo. The residue was reevaporated three times from toluene, giving a gum. Ether was added to the gum which solidified. The solid was triturated with ether containing methanol and then dried giving 2.1 g of solid. A 1 g portion was purified by chromatography, giving 650 mg of the desired product, mp 144°-146° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:20][C:14]3[N:15]=[CH:16][N:17]=[C:18](Cl)[C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)[CH3:2].[CH3:22][O:23][C:24]1[N:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=1.COC1C=CC(C#N)=CN=1.N>CO.[Ni].CCN(CC)CC.C(O)CCC>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:20][C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH:31][CH2:30][C:27]4[CH:28]=[N:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)[C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: COc1ccc(CN)cn1
Reactant: CCOC(=O)c1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Agent: [Ni]
Agent: COc1ccc(C#N)cn1
Agent: N
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCCCO
Product: CCOC(=O)c1ccc(-c2cc3c(NCc4ccc(OC)nc4)ncnc3[nH]2)cc1
Reaction time: 6 h

Procedure:
A mixture of 5.0 g (16.6 mMol) 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acid ethyl ester (WO 97/02266) and 2.52 g (18 mMol) of 6-methoxy-pyridin-3-ylmethylamine (CAS: 262295-96-5; prepared from 6-methoxy-nicotin-nitrile by hydrogenation in the presence of Raney-Nickel in methanol containing NH3) in 3.5 ml (25 mMol) of Et3N and 100 ml n-butanol is heated for 8 h to 140° C. Then additional 0.69 g of 6-methoxy-pyridin-3-ylmethylamine and 1.2 ml of Et3N are added. Heating is continued for 6 h and the hot suspension filtrated and the residue washed with n-butanol and hexane to give the title compound; m.p. 305° C.; elemental analysis for C, H and N Within 0.5% of calculated value.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH2:5].[N:8]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=1)=[C:9]=[S:10].Cl>O1CCOCC1>[SH:10][C:9]1[N:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=2)[CH:3]=[CH:4][N:5]=1
Reactant: N#Cc1ccc(N=C=S)c2ccccc12
Reactant: COC(CN)OC
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(-n2ccnc2S)c2ccccc12
Temperature: 105 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
Aminoacetaldehyde dimethyl acetal (5.98 mL, 55.36 mmol) was added to a stirring slurry of 4-isothiocyanato-1-naphthonitrile (11.64 g, 55.36 mmol) in dioxane (55 mL), and stirring continued for 1 h (sizable exotherm observed). HCl was added (4.8 mL, 58.13 mmol) and the mixture heated to 105° C. for 18 h. The mixture was then concentrated, methanol added (100 mL), concentrated again, more methanol added (100 mL) and sonicated. Filtration provided 4-(2-mercapto-1H-imidazol-1-yl)-1-naphthonitrile as a tan solid (8.33 g, 60%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[C:4](O)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.S(Cl)(Cl)=[O:17].[CH2:20](O)[CH3:21]>>[OH:1][C:2]1[C:3]([C:13]([O:15][CH2:20][CH3:21])=[O:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([OH:17])[CH:8]=[CH:7][CH:6]=2
Reactant: O=S(Cl)Cl
Reactant: CCO
Reactant: O=C(O)c1c(O)cc2ccccc2c1O
Product: CCOC(=O)c1cc2cccc(O)c2cc1O

Procedure:
Dihydroxynaphthalene-2-carboxylic acid (25 g) was dissolved in 500 ml ethanol. To this was added 25 ml thionyl chloride. The solution was heated under reflux for 4 hours. Then the solvent was removed under reduced pressure and the resulting solid dissolved in 500 ml ethyl acetate. The organic phase was washed with aqueous potassium carbonate/potassium acetate (1M in each) (3×350 ml). The organic phase was dried over magnesium sulphate then the solvent removed under reduced pressure to yield ethyl 3,5-dihydroxynaphthalene-2-carboxylate as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@H:20]([NH2:23])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@H:20]([NH:23][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc([N+](=O)[O-])cn2)C1
Yield: 78.8 %

Procedure:
A mixture of 2-chloro-5-nitro-pyridine (3.4 g, 0.021 mol), (S)-(−)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (4 g, 0.021 mol), and potassium carbonate (14.5 g, 0.105 mol) in acetonitrile (50 mL) was heated at reflux for 24 h. The reaction was monitored by LCMS and additional (S)-(−)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester was added until the reaction was driven to completion. The reaction mixture was then filtered and concentrated to give (S)-3-(5-nitro-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (5.1 g, 78.6%) as a yellow solid. LCMS calcd for C14H20N4O4 (m/e) 308, obsd 307.1 (M−H).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].C(O)(=O)C.[I:16]N1C(=O)CCC1=O>>[CH2:1]([C:3]1[C:11]([I:16])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1cc2ccccn2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CCc1nn2ccccc2c1I
Yield: 75.2 %

Procedure:
2-Ethylpyrazolo[1,5-a]pyridine (4.1 g, 22 mmol) was stirred in acetic acid (2.6 g, 18 mmol) and N-iodosuccinimide (8 g, 40 mmol) was added in portions over 5 hrs. The mixture was evaporated and purified on silica gel with ethyl acetate in hexanes (0-15%) to give the desired compound (4.5 g, 93%). LCMS for C9H10N2 (M+H)+: m/z=273.1. 1H NMR (300 MHz, DMSO-d6): δ 8.62 (m, 1H), 7.40 (m, 1H), 7.27 (m, 1H), 6.82 (m, 1H), 2.72 (m, 2H), 1.22 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([C:13]([CH3:50])([CH3:49])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:36][CH2:35][CH2:34][C@H:33]3[CH2:37][N:38]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.NN>C(O)C.[OH-].[Na+]>[NH2:38][CH2:37][C@@H:33]1[CH2:34][CH2:35][CH2:36][N:32]1[C:21]1[N:20]=[CH:19][C:18]([N:16]([CH3:17])[C:14](=[O:15])[C:13]([C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:51])[F:52])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=2)([CH3:50])[CH3:49])=[C:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH:22]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2CCC[C@H]2CN2C(=O)c3ccccc3C2=O)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(F)ccc1-c1cc(N2CCC[C@H]2CN)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 103.6 %

Procedure:
A solution of 65 mg (0.089 mmol) (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-pyrrolidin-1-yl]-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide and 7.0 mg (0.14 mmol) hydrazine hydrate in 1 ml ethanol was stirred at room temperature over night. The reaction mixture was diluted with a 1 M aqueous sodium hydroxide solution and extracted with three portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulphate and concentrated to give 55 mg of crude (S)-N-[6-(2-aminomethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide. This material was dissolved in 2 ml dichloromethane, followed by the addition of 0.013 ml (0.092 mmol) triethylamine and 0.009 ml (0.09 mmol) acetic anhydride at 0° C. The cooling bath was removed 5 min. after completed addition, and stirring was continued at room temperature over night. The reaction mixture was diluted with a 0.5 M aqueous sodium hydroxide solution and extracted with three portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulphate and concentrated. Flash chromatography gave 44 mg (77%) of the title compound as an off-white solid.
Reaction SMILES: C1(C)C=CC(C([C@](C(O)=O)(O)[C@](C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=O)=CC=1.[CH3:29][N:30]([CH2:32][CH:33]1[C:38]([OH:47])([C:39]2[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][CH:40]=2)[CH2:37][CH2:36][CH2:35][CH2:34]1)[CH3:31]>C(O)C>[CH3:31][N:30]([CH2:32][C@@H:33]1[C@@:38]([OH:47])([C:39]2[CH:40]=[CH:41][CH:42]=[C:43]([O:45][CH3:46])[CH:44]=2)[CH2:37][CH2:36][CH2:35][CH2:34]1)[CH3:29]
Reactant: COc1cccc(C2(O)CCCCC2CN(C)C)c1
Agent: Cc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Solvent: CCO
Product: COc1cccc([C@@]2(O)CCCC[C@@H]2CN(C)C)c1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
The white solid was collected by filtration to give 58.3 g (75.4%) of (L)-(−)-DTTA which compared to an authentic sample. 77.3 g of Di-p-toluoyl-D-tartaric acid ((D)-(+)-DTTA) was taken up in 550 ml of ethanol at 70° C. in a jacketed vessel. To this solution was added the Tramadol free base in 200 ml of ethanol. A precipitate formed almost immediately. The vessel was gradually cooled to 25° C. over several hours to give a fine white solid. Stirring at 25° C. was maintained overnight. The resulting copious white solid was collected at the pump, washing with 500 ml of ethanol. This gave 111.6 g of (+)-Tramadol. Di-p-toluoyl-D-tartaric acid in 85.2% yield, with a de of 97.3%. Reslurrying of this salt from 500 ml of ethanol as above gave 108.5 g of the (+)-Tramadol-containing salt, with a de of >99% in 97.8% yield. [α]D 589=+103.30° (C=1.15, MeOH). MP=162.1-167.8° C. (DSC).
Reaction SMILES: [C:1]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Mg]Br)C=C.[CH2:19]1[CH2:23][O:22][CH2:21]C1>>[O:22]1[CH2:21][CH:23]1[CH2:19][C:1]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCOC1
Reactant: O=C1CCCCCCCCCCC1
Agent: C=CC[Mg]Br
Product: OC1(CC2CO2)CCCCCCCCCCC1
Temperature: 0 °C

Procedure:
An oven-dried 500-mL three-neck round-bottom flask was charged with cyclododecanone (6.00 g, 32.9 mmol) and 50 mL dry THF. A 100-mL addition funnel with allyl magnesium bromide (1.0 M solution in THF, 36.2 mL, 36.2 mmol) was attached and the flask was cooled in an ice bath for 10 minutes. The Grignard was slowly dripped in over the course of 30 minutes while stirring at 0° C. under nitrogen. After addition, the ice bath was removed and the reaction mixture was stirred for 4 hours at room temperature under nitrogen. Excess Grignard was quenched by slowly adding water to the reaction mixture cooled to 0° C., and the product was extracted three times with diethyl ether. The organic layer was dried over Na2SO4 and solvent was removed under vacuum to obtain the homoallylic alcohol that was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[N:11][C:10]([NH:13][NH2:14])=[CH:9][CH:8]=2)[CH:4]=[N:3]1.[C:15](N1C=CN=C1)(N1C=CN=C1)=[S:16].CCCCCC.C1COCC1>CN(C=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:15]([SH:16])=[N:14][N:13]=3)[N:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2ccc(NN)nn2)cn1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc3nnc(S)n3n2)cn1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
[6-(1-Methyl-1H-pyrazol-4-yl)-pyridazin-3-yl]-hydrazine (1.0 g, 5.3 mmol) and 1,1′-thiocarbonyldiimidazole (1.08 g, 6.1 mmol) were combined in DMF (10 mL) and heated at 50° C. for 2 h. After such time the mixture was allowed to cool to room temperature. Hexane (10 mL) was added followed by THF (4 mL), stirred for 10 mins then filtered and washed with THF (2 mL then 4 mL). Solid dried in vacuo to return 738 mg of 6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol as a yellow solid (60% yield).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]([OH:34])=O)[CH2:27][CH2:26]1.Cl.[NH2:36][C@@H:37]([C@H:42]([OH:44])[CH3:43])[C:38]([O:40][CH3:41])=[O:39].CN1CCOCC1>ClCCl>[OH:44][C@H:42]([CH3:43])[C@H:37]([NH:36][C:32](=[O:34])[CH2:31][N:28]1[CH2:27][CH2:26][O:25][CH2:30][CH2:29]1)[C:38]([O:40][CH3:41])=[O:39]
Reactant: O=C(O)CN1CCOCC1
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H](NC(=O)CN1CCOCC1)[C@@H](C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
HATU (7.66 g, 20.1 mmol) was added to a solution of 2-morpholinoacetic acid (2.44 g, 16.8 mmol) and (2S,3R)-methyl 2-amino-3-hydroxybutanoate hydrochloride (2.84 g, 16.8 mmol) in dichloromethane (20 mL) at 0° C. N-Methylmorpholine (5.1 g, 50.4 mmol) was added and the reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The mixture was concentrated and the residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=100:1 to 60:1) to afford (2S,3R)-methyl 3-hydroxy-2-(2-morpholinoacetamido)butanoate (2.1 g, 48% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4ccc(Br)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.1 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (78 mg, 60%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:32]1([CH3:60])[C:33]([C:38]([CH2:40][N:41]2[C:47]3[CH:48]=[C:49]([CH3:52])[CH:50]=[CH:51][C:46]=3[N:45]([CH2:53][CH:54]=[C:55]([CH3:57])[CH3:56])[CH2:44][CH:43]([NH2:58])[C:42]2=[O:59])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=1>O1CCCC1>[C:32]1([CH3:60])[C:33]([C:38]([CH2:40][N:41]2[C:47]3[CH:48]=[C:49]([CH3:52])[CH:50]=[CH:51][C:46]=3[N:45]([CH2:53][CH:54]=[C:55]([CH3:56])[CH3:57])[CH2:44][CH:43]([NH:58][C:14]([NH:1][C:2]3[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=3)=[O:16])[C:42]2=[O:59])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)=CCN1CC(N)C(=O)N(CC(=O)c2ccccc2C)c2cc(C)ccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(NC(=O)NC2CN(CC=C(C)C)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 120.1 %

Procedure:
Ethyl 3-aminobenzoate (221 mg) was dissolved in tetrahydrofuran (20 ml), under ice-cooling triphosgene (134 mg) was added, triethylamine (115 μl) was added thereto five times every 3 minutes,a solution of 1-(2-toluoylmethyl)-2-oxo-3-amino-5-(3-methyl-2-butenyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (477 mg) in tetrahydrofuran (20 ml) was added dropwise thereto, and the mixture was stirred for 30 minutes at same temperature and subsequently stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, water (50 ml) was added, and extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(chloroform:ethyl acetate=10:1), to thereby obtain 316 mg of the titled compound.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:24])[CH2:16][NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:2].[CH3:25][Mg]Br>O1CCCC1.C(OCC)C.O>[OH:2][CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:24])[CH2:16][NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:19])=[O:20])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)[CH3:25]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(C=O)cc2)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(O)c1ccc(-c2ccc(C(C)CNS(=O)(=O)C(C)C)cc2)cc1
Reaction time: 16 h
Yield: 74 %

Procedure:
To a solution of 0.2 g (0.4 mmol) of material from Example 45 in 3 mL of tetrahydrofuran at ambient temperature was added 0.3 mL (0.9 mmol) of a 3.0M solution of methylmagnesium bromide in ethyl ether. The mixture was stirred for 16 hours, diluted with 5 mL of water and extracted four times with 5 mL each of ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography (10 g silica gel, 45% ethyl acetate/hexane) of the residue afforded 0.1 g (74%) of the title compound.
Reaction SMILES: [Cl-:1].[CH3:2][N+:3]1[CH:7]=[CH:6][N:5]([CH2:8][CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH:4]=1>C(O)C.[Pd]>[ClH:1].[Cl-:1].[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[CH2:8][N:5]2[CH:6]=[CH:7][N+:3]([CH3:2])=[CH:4]2)=[CH:15][CH:16]=1
Reactant: C[n+]1ccn(CC2CCCN2c2ccc([N+](=O)[O-])cc2)c1
Agent: [Pd]
Agent: [Cl-]
Solvent: CCO
Product: C[n+]1ccn(CC2CCCN2c2ccc(N)cc2)c1
Product: Cl

Procedure:
3 g (0.093 mol) of 1-methyl-3-[1-(4-nitrophenyl)pyrrolidin-2-ylmethyl]-3H-imidazol-1-ium (2) dissolved in 350 ml of ethanol were hydrogenated in the presence of palladium-on-charcoal under a hydrogen pressure of 10 bar at a temperature of 30° C.; after filtering off the catalyst, the expected derivative (3) was isolated in the form of the hydrochloride. 2.6 g of a white powder were obtained.