Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([CH3:10])[CH:4]=1)#[CH:2].C(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[C:21](OS(C(F)(F)F)(=O)=O)[CH:22]=[N:23][CH:24]=1>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:18][C:19]1[CH:24]=[N:23][CH:22]=[C:21]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([F:9])=[C:5]([CH3:10])[CH:4]=2)[CH:20]=1
Reactant: C#Cc1ccc(F)c(C)c1
Reactant: O=S(=O)(Oc1cncc(Cl)c1)C(F)(F)F
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(C#Cc2cncc(Cl)c2)ccc1F
Temperature: 70 °C
Yield: 43.9 %

Procedure:
Add 4-ethynyl-1-fluoro-2-methylbenzene (0.56 g, 4.21 mmol), triethylamine (2.2 mL, 15 mmol), copper (I) iodide (36 mg, 0.19 mmol), and bis(triphenylphosphine)palladium (II) dichloride (110 mg, 0.15 mmol) to a solution of trifluoromethanesulfonic acid 5-chloropyridin-3-yl ester, (prepared as described in PREPARATION 25), (1.0 g, 3.8 mmol) in ethyl acetate (5 mL) under nitrogen. Heat the at 70° C. for 16 h and concentrate. Purify by silica gel chromatography, eluting with 100% dichloromethane, followed by a second silica gel chromatography eluting with 50:50 to 60:40 dichloromethane:hexanes, to give the title compound as a light yellow solid (410 mg, 44%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.F>C1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: F
Solvent: c1ccccc1
Product: Cc1ccc(C(c2ccccc2)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 64 h

Procedure:
1290 g of 2-(4-methylphenyl)hexafluoropropan-2-ol and 780 g of benzene were placed in a 5-liter steel autoclave and 1500 g of anhydrous hydrogen fluoride was pumped into the sealed autoclave. The reaction mixture was heated at 170°-175°C. with stirring for 64 hours. After completion of the reaction, hydrogen fluoride gas was allowed to escape at 80° C., and the liquid product was then washed twice with water, dried over calcium chloride, and fractionally distilled. Boiling point 135-136C./1.4 mbar. Yield: 1424 g (89.5%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.C(=O)([O-])[O-].[Na+].[Na+].[N:16]1([CH2:22][CH2:23][OH:24])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CN(C)C(=O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[N:19]1[CH2:20][CH2:21][N:16]([CH2:22][CH2:23][OH:24])[CH2:17][CH2:18]1
Reactant: Clc1cc(Cl)c(Cl)nn1
Reactant: OCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: OCCN1CCN(c2cc(Cl)nnc2Cl)CC1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
In a 50 mL round bottom flask, 9.18 g (0.05 mol) of 3,4,6-trichloro-pyridazine, 5.30 g (0.05 mol) of anhydrous sodium carbonate and 20 mL of N,N-dimethylacetamide (DMA) were added, stirred at room temperature, then 6.54 g (0.05 mol) of 2-(piperazin-1-yl)-ethanol (dissolved in 10 ml DMA) was added dropwise slowly, stirred overnight, filtered on the next day. 100 mL of distilled water was added into the filter cake and stirred, then filtered again to obtain 10.20 g of a white solid, yield: 73.6%, m.p. 139˜141° C. 1H-NMR (400MHz, CDCl3) δppm: 2.57(br, 1H), 2.66˜2.68(t, 2H, J=5.12Hz), 2.73˜2.76(t, 4H, J=4.76Hz), 3.36˜3.38(t, 4H, J=4.52Hz), 3.68˜3.71(t, 2H, J=5.04Hz), 6.88(s, 1H). 13C-NMR (400MHz, DMSO-d6) δppm: 155.14, 149.43, 148.70, 116.64, 60.00, 58.49, 52.44, 48.90.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[N:2]1.Cl.[CH3:10][NH:11][O:12][CH3:13].CN1CCOCC1.Cl.C(N(CC)CCCN=C=NCC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:13][O:12][N:11]([CH3:10])[C:6]([C:3]1[CH:4]=[CH:5][O:1][N:2]=1)=[O:8]
Reactant: CNOC
Reactant: O=C(O)c1ccon1
Agent: CCN=C=NCCCN(CC)CC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccon1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
A mixture of 3-isoxazolecarboxylic acid (4.2 g), 4-dimethylaminopyridine (5.1 g), N,O-dimethylhydroxylamine hydrochloride (4.0 g), N-methylmorpholine (4.2 g) and 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.5 g) in dichloromethane (175 ml) were stirred at ambient temperature overnight. The reaction mixture was then washed with 2N hydrochloric acid (100 ml), saturated sodium bicarbonate (100 ml), brine, dried over magnesium sulphate and evaporated to give the product as a dark orange oil (3.7 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:18]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[S:13][C:14]([Br:18])=[C:15]([CH3:17])[N:16]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@H](c2nc(C)cs2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@H](c2nc(C)c(Br)s2)CC1

Procedure:
A solution of cis/trans-4-(4-methyl-thiazol-2-yl)-cyclohexanecarboxylic acid ethyl ester (1:5) (319 mg, 1.26 mmol) and N-bromosuccinimide (247 mg, 1.38 mmol) in N,N-dimethylformamide (1.6 ml) was stirred for 1 h at room temperature. The reaction mixture was partitioned between tert-butyl methyl ether (25 ml) and 0.1 M aqueous sodium hydroxide solution (25 ml). The layers were separated. The aqueous layer was extracted with two 25-ml portions of tert-butyl methyl ether. The combined organic layers were washed with two 25-ml portions of water, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (371 mg, 89%) as light yellow solid, which was used in the next step without further purification. MS m/e: 334 ([M+H]+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][C:8](=[O:30])[N:9]3[CH2:13][C:12]([CH2:15][N:16]4[CH2:21][CH2:20][CH:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18][CH2:17]4)([F:14])[C:11]=1[C:10]=23.[ClH:31].O1CCOCC1>ClCCl.CO>[ClH:31].[ClH:31].[NH2:22][CH:19]1[CH2:18][CH2:17][N:16]([CH2:15][C:12]2([F:14])[C:11]3=[C:2]([F:1])[CH:3]=[N:4][C:5]4[CH:6]=[CH:7][C:8](=[O:30])[N:9]([C:10]=43)[CH2:13]2)[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2(F)Cn3c(=O)ccc4ncc(F)c2c43)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: NC1CCN(CC2(F)Cn3c(=O)ccc4ncc(F)c2c43)CC1

Procedure:
A solution of 1,1-dimethylethyl {1-[((4R/S)-3,4-difluoro-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl)methyl]-4-piperidinyl}carbamate (98 mg, 0.23 mmol) in dichloromethane (2 ml) and methanol (1.5 ml), was treated with hydrochloric acid in 1,4-dioxane (4M, 3.5 ml, 14 mmol). After 1.5 hours the mixture was evaporated affording the product (82 mg).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:18][CH:17]=2)[C:10](O)=[O:11])[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:36][CH:37]1[C:47](=[O:48])[N:39]2[C:40]([C:44]([OH:46])=[O:45])=[CH:41][CH2:42][S:43][C@H:38]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][NH:23][C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])=[CH:20][CH:21]=2)[C:10]([NH:36][CH:37]2[C:47](=[O:48])[N:39]3[C:40]([C:44]([OH:46])=[O:45])=[CH:41][CH2:42][S:43][C@H:38]23)=[O:11])[N:8]=1)=[O:2]
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reactant: CC(C)(C)OC(=O)NCc1ccc(CON=C(C(=O)O)c2csc(NC=O)n2)cc1
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(CON=C(C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)c2csc(NC=O)n2)cc1
Yield: 70.5 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-(4-tert-butoxycarbonylaminomethylbenzyloxyimino)acetic acid (syn isomer, 1.4 g.), N,N-dimethylformamide (0.29 g.), phosphoryl chloride (0.6 g.), 7-amino-3-cephem-4-carboxylic acid (0.65 g.), trimethylsilylacetamide (2.5 g.) and ethyl acetate (18 ml.) were treated in a similar manner to that of Example 11-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(4-tert-butoxycarbonylaminomethylbenzyloxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.4 g.).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][CH:21]=[C:20]([C:23](O)=[O:24])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[C:26]([O:30][C:31](=[O:40])[NH:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31](=[O:40])[NH:32][C@H:33]1[CH2:34][CH2:35][C@H:36]([NH:39][C:23]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:7]4[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:15]=3[NH:22][CH:21]=2)=[O:24])[CH2:37][CH2:38]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c[nH]c23)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c[nH]c23)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A75) and trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][C@H:4]([C:7]([NH:9][C:10]2[CH2:17][CH2:16][C:13]3([CH2:15][CH2:14]3)[CH2:12][C:11]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:8])[CH2:3]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[F:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][N:33]([C@@H:2]3[CH2:6][CH2:5][C@H:4]([C:7]([NH:9][C:10]4[CH2:17][CH2:16][C:13]5([CH2:15][CH2:14]5)[CH2:12][C:11]=4[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:8])[CH2:3]3)[CH2:32][CH2:31]2)=[CH:28][CH:29]=1
Reactant: CCOC(=O)C1=C(NC(=O)[C@H]2CCC(=O)C2)CCC2(CC2)C1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)C1=C(NC(=O)[C@H]2CC[C@@H](N3CCN(c4ccc(F)cc4)CC3)C2)CCC2(CC2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.9 %

Procedure:
To a solution of (S)-ethyl 6-(3-oxocyclopentanecarboxamido)spiro[2.5]oct-5-ene-5-carboxylate (0.7 g, 2.23 mmol) in 1,2-dichloroethane (10 ml) were added 1-(4-fluorophenyl)piperazine (0.43 g, 2.40 mmol), glacial acetic acid (0.14 g, 2.40 mmol) and sodium triacetoxy borohydride (0.7 g, 3.44 mmol). The mixture was stirred at RT for 24 h before removal of the solvent. The residue was treated with saturated sodium bicarbonate, extracted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude residue which was purified by column chromatography over silica gel using ethyl acetate in hexane as eluents to obtain a diastereomeric mixture (7:3) of title compound (0.9 g, 84%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[S:12]1[CH:16]=[CH:15][C:14]([C:17]([CH2:19][NH2:20])=[O:18])=[CH:13]1.C(=O)(O)[O-].[Na+].O>C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][CH2:19][C:17]([C:14]2[CH:15]=[CH:16][S:12][CH:13]=2)=[O:18])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NCC(=O)c1ccsc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CNC(=O)c1ccc(F)cc1)c1ccsc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.5 %

Procedure:
16 g of 4-fluorobenzoyl chloride are dissolved in 50 ml of ethyl acetate, and the solution is added at a temperature below 10° C. under stirring to a mixture of 17.8 g of N-[(3-thienylcarbonyl)methyl]amine hydrochloride, 25 g of sodium bicarbonate, 100 ml of ethyl acetate and 200 ml of water. The mixture is further stirred at room temperature for 3 hours. The precipitated crystalls are collected by filtration, washed with water and then dried, whereby N-(4-fluorobenzoyl)-N-[(3-thienylcarbonyl)methyl]amine is obtained. On the other hand, the filtrate is washed with water, dried and then condensed under reduced pressure to remove solvent. The residue is washed with ether, whereby N-(4-fluorobenzoyl)-N-[(3-thienylcarbonyl)methyl]amine is further obtained.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=O)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.[NH2:41][OH:42]>[Cl-].[Na+].O.CN(C=O)C>[CH:10]1[C:11]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:41][OH:42])=[O:27])=[O:16])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CCCCCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Reactant: NO
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(C=C1c2ccccc2-c2ccccc21)NCCCCCCCC(=O)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
8-(2-(9H-fluoren-9-ylidene)acetamido)octanoic acid (363 mg, 1 mmol), triethylamine (151 mg, 1.5 mmol) and 20 ml of DMF were stirred at 0° C. while ethyl chloroformate (163 mg, 1.5 mmol) was added. The mixture was stirred at 0° C. for 2 hours, and then 50% aqueous solution of hydroxylamine (1.32 g, 20 mmol) was added. The mixture was stirred for 3 hours at room temperature, and then diluted with 1000 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (166 mg, 44%) as a yellow solid. LC-MS (m/z) 379 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[NH:5][C:6](=[O:10])/[CH:7]=[CH:8]/[CH3:9].[Cl:14][C:15]1[CH:16]=[C:17]([N:22]=[C:23]=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21].C(N(CC)CC)C>C(OCC)(=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([NH:22][C:23]([O:1][C:2]2[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=2)[NH:5][C:6](=[O:10])/[CH:7]=[CH:8]/[CH3:9])=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: C/C=C/C(=O)Nc1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C/C=C/C(=O)Nc1cccc(OC(=O)Nc2ccc(Cl)c(Cl)c2)c1
Temperature: 55 °C

Procedure:
A reaction vessel is charged with 100 parts of ethyl acetate, 17.7 parts of 3'-hydroxycrotonanilide and 18.8 parts of 3,4-dichlorophenyl isocyanate. The reaction mixture is heated to about 55°C and one part of triethylamine is added. An additional 100 parts of ethyl acetate is added and the reaction mixture heated at reflux for about one-half hour, cooled and filtered. The solids are washed with ethyl acetate and air dried to give 31 parts of 3'-(3,4-dichlorophenylcarbamoyloxy)crotonanilide, m.p. 193°-194°C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[CH2:11][NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:4][N:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[CH2:11][N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[S:24]([CH3:23])(=[O:26])=[O:25])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc(-c2cccc(CNCc3ccccn3)c2)n1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)N(Cc1cccc(-c2ccnc(Cl)n2)c1)Cc1ccccn1

Procedure:
Intermediate 10 was coupled with methanesulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 389.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](CNCCN)[N:2]=1.[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][N:16]=[C:17]=[S:18]>>[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][NH:16][C:17]([NH:16][CH2:15][CH2:14][N:13]([C:3]1[N:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH3:12])=[S:18]
Reactant: NCCNCc1cccnn1
Reactant: CN(C)CCN=C=S
Product: CN(C)CCNC(=S)NCCN(C)c1cccnn1

Procedure:
Reacting N-(3-pyridazinylmethyl)ethylenediamine with 2-dimethylaminoethyl isothiocyanate by the procedure of Example 40 gives the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:32]=[CH:31][C:12]([O:13][CH2:14][CH:15]([OH:30])[CH2:16][NH:17][CH2:18][CH2:19][NH:20][C:21]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:22]=2[CH:23]=[N:24][NH:25]3)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH:15]([OH:30])[CH2:16][NH:17][CH2:18][CH2:19][NH:20][C:21]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:22]=2[CH:23]=[N:24][NH:25]3)=[CH:31][CH:32]=1
Reactant: OC(CNCCNc1cccc2[nH]ncc12)COc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: Oc1ccc(OCC(O)CNCCNc2cccc3[nH]ncc23)cc1

Procedure:
5.0 g. 1-(4-Benzyloxyphenoxy) 3-[2-(indazol-4-ylamino)-ethylamino]-propan-2-ol are hydrogenated in the presence of 0.5 g. palladium-charcoal (10%) in 100 ml. methanol. After filtering off the catalyst with suction, the filtrate is evaporated and the residue is triturated with ethanol. It is then dissolved in hot dimethylformamide, treated with active charcoal, mixed with double the amount of water, filtered off with suction and washed with water and then with ethanol. There are obtained 3.0 g. (76% of theory) of the desired product in the form of pale, pinkish crystals; m.p. 216°-218° C.
Reaction SMILES: O[CH2:2][C@H:3]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:4]([C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C:15]2=[O:20])=[C:10]([CH3:21])[CH:9]=1)[CH3:5].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[CH3:5][C@H:4]1[C:6](=[O:22])[N:7]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C:15]3=[O:20])=[C:10]([CH3:21])[CH:9]=2)[CH2:2][C@@H:3]1[NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cc(NC(=O)[C@H](C)[C@H](CO)NC(=O)OCc2ccccc2)ccc1N1CCOCC1=O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: Cc1cc(N2C[C@H](NC(=O)OCc3ccccc3)[C@@H](C)C2=O)ccc1N1CCOCC1=O

Procedure:
Prepared analogously to Example 2c from benzyl {(1R,2R)-1-hydroxymethyl-2-[3-methyl-4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-propyl}-carbamate with di-tert.-butyl azodicarboxylate and tributylphosphine in THF and subsequent purification by reversed-phase chromatography.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:20]1[N:25]=[C:24]([CH:26]=O)[CH:23]=[CH:22][CH:21]=1.[C:28]([NH2:32])([CH3:31])([CH3:30])[CH3:29].[BH3-]C#N.[Na+].ClCCl>C(O)C>[C:28]([NH:32][CH2:26][C:24]1[N:25]=[C:20]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][C:10]=2[CH2:9][NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH:21]=[CH:22][CH:23]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)N
Reactant: Cc1ccccc1NCc1ccc2ccccc2c1-c1cccc(C=O)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccccc1NCc1ccc2ccccc2c1-c1cccc(CNC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.79 g (5.09 mmol) of 6-(2-{[(2-methylphenyl)amino]methyl}-1-naphthyl)pyridine-2-carbaldehyde, 1.85 g (25.4 mmol) of tert-butylamine and 0.641 g (10.2 mmol) of NaBH3CN in 100 ml of dry ethanol was stirred overnight at room temperature. The resulting mixture was evaporated to dryness. The product was isolated from the residue by flash chromatography on neutral alumina (eluent: dichloromethane, then dichloromethane-ether=1:1, vol.). Yield 1.10 g (53%) of yellowish oil. Anal. calc. for C28H31N3: C, 82.11; H, 7.63; N, 10.26. Found: C, 82.34; H, 7.79; N, 10.11. 1H NMR (CDCl3): 7.90 (d, J=8.6 Hz, 1H, 4-H in naphthyl), 7.88 (m, 1H, 8-H in naphthyl), 7.79 (m, 1H, 4-H in Py), 7.65 (d, J=8.6 Hz, 1H, 3-H in naphthyl), 7.38-7.48 (m, 4H, 3-H in Py and 5,6,7-H in naphthyl), 7.32 (m, 1H, 5-H in Py), 7.01-7.04 (m, 2H, 3,5-H in ortho-tolyl), 6.63 (m, 1H, 4-H in ortho-tolyl), 6.52 (m, 1H, 6-H in ortho-tolyl), 4.22 (m, 2H, Naph-CH2N), 4.01 (m, 2H, Py-CH2N), 3.50 (br. s, 2H, NH), 2.11 (s, 3H, Me in ortho-tolyl), 1.18 (s, 9H, tBu).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([CH:8](C#N)[C:9]2[CH:10]=[CH:11][C:12]([F:17])=C([CH:16]=2)C#N)=[CH:4][C:3]=1[CH2:20][CH3:21].Cl.[CH3:23][C:24]([O-:26])=[O:25].[Na+].[OH-:28].[Na+]>CC(O)=O.O.CCOC(C)=O>[CH2:20]([C:3]1[C:2](=[O:28])[NH:7][N:6]=[C:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([F:17])=[C:23]([CH:16]=2)[C:24]([OH:26])=[O:25])[CH:4]=1)[CH3:21]
Reactant: [OH-]
Reactant: CCc1cc(C(C#N)c2ccc(F)c(C#N)c2)nnc1Cl
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCc1cc(Cc2ccc(F)c(C(=O)O)c2)n[nH]c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of A1 (1 eq) in AcOH, cone. HCl and H2O (1:2:1, 0.065 M) was heated at reflux overnight, then cooled to RT and diluted with H2O and EtOAc and separated. The aqueous phase was washed with EtOAc and the combined extracts were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude was dissolved in AcOH and NaOAc (2 eq) was added. The resulting solution was heated at reflux for 1 hr. The reaction mixture was cooled and the mixture was extracted with EtOAc. The organic phase was washed twice with brine, dried (Na2SO4) and the solvent removed under reduced pressure. The residue was taken up in H2O and to the resulting suspension was added an aqueous solution of 23 M NaOH (8 eq) and heated to 90° C. for 30 min. The reaction solution was cooled then acidified to pH 4 with 2 M HCl. The mixture stirred for 10 min and filtered. The resulting solid was washed sequentially with H2O, hexanes, Et2O, EtOAc and dried under high vacuum to give the title compound as a pale orange powder.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Br:23][C:24]1[CH:54]=[CH:53][C:27]([CH2:28][CH:29]([NH:42][C:43](=[O:52])[O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:30]([NH:32][CH2:33][CH:34]([OH:41])[CH2:35][C:36]([CH3:40])([CH3:39])[CH2:37][CH3:38])=[O:31])=[CH:26][CH:25]=1>C(Cl)Cl>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][CH:29]([NH:42][C:43](=[O:52])[O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:30]([NH:32][CH2:33][C:34](=[O:41])[CH2:35][C:36]([CH3:39])([CH3:40])[CH2:37][CH3:38])=[O:31])=[CH:53][CH:54]=1
Reactant: CCC(C)(C)CC(O)CNC(=O)C(Cc1ccc(Br)cc1)NC(=O)OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCC(C)(C)CC(=O)CNC(=O)C(Cc1ccc(Br)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dess-Martin periodinane (8.01 g, 18.9 mmol) was added to an ambient temperature solution of benzyl {1-(4-bromobenzyl)-2-[(2-hydroxy-4,4-dimethylhexyl)amino]-2-oxoethyl}carbamate (6.35 g, 12.6 mmol) in methylene chloride (200 mL). After stirring at ambient temperature for 2 h, the reaction mixture was quenched with saturated aqueous sodium thiosulfate/saturated aqueous sodium bicarbonate (1:1) and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-80% ethyl acetate/hexane afforded benzyl {1-(4-bromobenzyl)-2-[(4,4-dimethyl-2-oxohexyl)amino]-2-oxoethyl}carbamate.
Reaction SMILES: [C:1](N)(N)=N.C(N)(N)=N.C(O)(O)=O.Cl.[CH2:14]([CH2:17][NH:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH2:15][NH2:16]>O>[N:18]12[CH2:19][CH2:20][CH2:21][NH:22][C:1]1=[N:16][CH2:15][CH2:14][CH2:17]2
Reactant: NCCCNCCCN
Reactant: N=C(N)N
Agent: Cl
Agent: O=C(O)O
Solvent: O
Product: C1CN=C2NCCCN2C1
Reaction time: 5 h

Procedure:
In still another specific exemplary embodiment, as shown in Scheme 3 and Example 2 below, a guanidine carbonate salt (1) is dissolved in water and reacted with hydrochloric acid, followed by addition of dipropylene triamine (2). The resulting solution is warmed to reflux and stirred for 4-6 hours to yield the chloride salt of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (4) in water, as shown below: