Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=1[CH3:17].O=P(Cl)(Cl)Cl>>[CH3:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: Cc1ccccc1C
Reactant: O=C(O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(C(=O)c2ccccc2)cc1C
Temperature: 140 °C

Procedure:
Synthesis of the novel compounds was carried out according to the following method. Benzoic acid (1.68 moles) was added to 3.96 moles of o-xylene and 0.6 mole POCl3 and refluxed at 140° C. for 11 hours. The reaction product was cooled to room temperature, washed once with 500 ml. of water, twice with 300 ml. of 5% of Na2CO3 and twice again with 500 ml. of water. After washing, the xylene was distilled and the residue was vacuum distilled to obtain 3,4-dimethylbenzophenone. A mixture of 3,4-dimethylbenzophenone (1.0 mole), benzoyl peroxide (5 grams), chlorobenzene (800 ml.) and 3.0 moles of sulfuryl chloride was heated at 90° C. for 3-1/2 hours. During the last 30 minutes of the reaction nitrogen was passed through the reactor to remove the excess sulfuryl chloride. The resultant mixture was cooled and 50 grams of carbon black was added and the mixture stirred for 30 minutes, after which the carbon black was removed by filtration. The product 3,4-bis(chloromethyl)benzophenone was isolated by stripping of the solvent. Analysis found: 62.1% C, 4.3% H, and 27.1% Cl. Theoretical: 64.5% C, 4.3% H, and 25.5% Cl.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[C:19](Cl)(=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CCCCCCC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-(−)-4-benzyl-2-oxazolidinone (3.3 g, 18.6 mmol) in THF (50 mL) at −78° C. was added dropwise n-BuLi (7.4 mL, 2.5M solution in hexane, 18.6 mmol). After stirring for 30 min at the same temperature, the reaction mixture was then treated with heptanoyl chloride (2.76 g, 18.6 mmol). The reaction mixture was stirred and allowed to warm to 10° C. over 5 h, and then quenched with saturated aqueous NH4Cl solution (100 mL). The aqueous layer was extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine, and dried over MgSO4. Removal of the solvent under reduced pressure yielded the title compound. 1H NMR (400 MHz, CDCl3) δ 7.37-7.22 (m, 5H), 4.69 (m, 1H), 4.19 (m, 2H), 3.31 (dd, J=13.4, 3.3 Hz, 1H), 2.95 (m, 2H), 2.79 (dd, J=13.4, 9.7 Hz, 1H), 1.71 (m, 2H), 1.42-1.32 (m, 6H), 0.92 (t, J=6.8 Hz, 3H). MH+290.
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([S:6]([OH:9])(=[O:8])=[O:7])[C:3]1=[O:10].[C:11]1([CH2:17][C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])O.[Na+:25].P(=O)(O)(O)O>O.O1CCCC1>[C:11]1([CH2:17][C:18]([NH:1][CH:2]2[CH2:5][N:4]([S:6]([O-:9])(=[O:8])=[O:7])[C:3]2=[O:10])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+:25]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NC1CN(S(=O)(=O)O)C1=O
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)NC1CN(S(=O)(=O)[O-])C1=O
Yield: 45.6 %

Procedure:
In 1 ml of water is dissolved 50 mg of the above 3-amino 2-oxoazetidine-1-sulfonic acid, followed by addition of a solution of 69 mg of phenylacetyl chloride in 1 ml tetrahydrofuran and 101 mg of sodium hydrogen carbonate in alternate portions with ice-cooling and stirring. After stirring at room temperature for 30 minutes, the mixture is adjusted to pH 5.8 with phosphoric acid. The tetrahydrofuran is then distilled off under reduced pressure. The water layer is washed with ethyl acetate and purified by XAD-II chromatography, whereby 42 mg of sodium 3-phenylactamido-2-oxoazetidine-1-sulfonate is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([C:13](Cl)=[O:14])[C:10](Cl)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].I.[CH3:17][S:18][C:19](=[NH:25])[NH:20][N:21]=[C:22]([CH3:24])[CH3:23]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[NH:25][CH:19]([S:18][CH3:17])[N:20]([N:21]=[C:22]([CH3:24])[CH3:23])[C:10]2=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CSC(=N)NN=C(C)C
Reactant: O=C(Cl)N(C(=O)Cl)c1ccc(Cl)c(Cl)c1
Agent: I
Solvent: CCN(CC)CC
Product: CSC1NC(=O)N(c2ccc(Cl)c(Cl)c2)C(=O)N1N=C(C)C

Procedure:
Analogously to Example 1, N-(3,4-dichlorophenyl)-bis(chlorocarbonyl)-amine and acetone-S-methyl-isothiosemicarbazone hydroiodide, with addition of triethylamine, yielded 1-(3,4-dichlorophenyl)-3-isopropylideneamino-4-methylmercapto-tetrahydro-1,3,5-triazine-2,6-dione as a colorless powder of melting point 181°-182° C.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.COCN[C:15]([C@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)=[O:16].[Cl-].[Na+]>O1CCCC1.O>[S:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:15]([C@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)=[O:16]
Reactant: c1cscn1
Reactant: COCNC(=O)[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)c2nccs2)C1
Temperature: 0 °C
Yield: 88.6 %

Procedure:
136.6 g (0.32 mol) of n-butyllithium (15% in n-hexane) were added dropwise at −68° C. to a solution of 25 g (0.291 mol) of thiazole in 1 l of tetrahydrofuran. The mixture was warmed to 0° C. and subsequently cooled to −40° C. This mixture was then added dropwise to a solution of 79.2 g (0.291 mol) of tert-butyl (S)-3-(methoxymethylcarbamoyl)piperidine-1-carboxylate in 1.4 l of tetrahydrofuran at −50° C. The reaction mixture was then slowly warmed to 0° C., and 2 l of ice-water were added. After addition of 2 l of water and 2 l of saturated sodium chloride solution, the crude mixture was extracted with a total of 4 l of ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The crude product (87 g) was chromatographed over a silica-gel column, giving 76.4 g of tert-butyl (S)-3-(thiazole-2-carbonyl)piperidine-1-carboxylate as brown resin; rotation value in methanol [α]20D=+27.4°; 1H NMR (500 MHz, DMSO) δ 8.22 (d, J=3.0, 1H), 8.17 (d, J=3.0, 1H), 4.22-3.86 (m, 1H), 3.84-3.69 (m, 2H), 3.60-3.52 (m, 1H), 3.20-3.05 (m, 1H), 2.08-1.92 (m, 2H), 1.89-1.60 (m, 2H), 1.35 (s, 9H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[NH:14][C:15](=[O:23])[C:16]2[CH2:22][O:21][CH2:20][CH2:19][C:17]=2[N:18]=1)(C(C)(C)C)(C)C.[C:24]1([CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>ClCCl>[OH:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]1[NH:14][C:15](=[O:23])[C:16]2[CH2:22][O:21][CH2:20][CH2:19][C:17]=2[N:18]=1)[C:32](=[O:33])[CH2:31][CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)OCCNCc1nc2c(c(=O)[nH]1)COCC2
Reactant: O=C(Cl)CCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCc1ccccc1)N(CCO)Cc1nc2c(c(=O)[nH]1)COCC2
Reaction time: 24 h
Yield: 22.2 %

Procedure:
To a solution of 2-((2-(tert-butyldimethylsilyloxy)ethylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (10 mg, 0.029 mmol) in dichloromethane (0.1 mL) was added 3-phenylpropanoyl chloride (4.4 μL, 0.029 mmol) and then triethylamine (12 μL, 0.088 mmol) at 0° C. The mixture was stirred at 0° C. to ambient temperature for 24 h. Tetra-N-butylammonium fluoride (29 μL, 0.029 mmol, 1 M in THF) was added and the reaction was stirred at ambient temperature for 1 h. The mixture was concentrated in vacuo then purified via prep thin layer chromatography to provide the title compound (2.3 mg, 22% yield). 1H NMR (400 MHz, CDCl3) δ 7.18-7.34 (m, 3H), 7.14 (d, J=7.5 Hz, 2H), 4.56 (s, 2H), 4.38 (s, 2H), 3.95 (t, J=5.5 Hz, 2H), 3.65-3.82 (m, 2H), 3.58 (t, J=4.5 Hz, 2H), 2.87-3.06 (m, 2H), 2.81 (t, J=7.5 Hz, 2H), 2.67 (br. s., 2H). HRMS calculated for C19H23N3O4 358.1767. found (ESI, [M+H]+), 358.1767. Retention time=0.99 min.
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[N:28][C:27]([C:30]([OH:34])([CH3:33])[CH2:31][OH:32])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:42](Cl)([CH3:45])(=[O:44])=[O:43]>C1COCC1>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[CH:29]=[N:28][C:27]([C:30]([OH:34])([CH3:33])[CH2:31][O:32][S:42]([CH3:45])(=[O:44])=[O:43])=[CH:26][N:25]=3)[CH2:22][CH2:23]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)(CO)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)cn1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(O)(COS(C)(=O)=O)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)cn1
Temperature: 0 °C
Reaction time: 96 h
Yield: 99.9 %

Procedure:
2-[4-(4-Benzyl-phthalazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl]-propane-1,2-diol (100 mg, 0.219 mmol) is combined with THF (1.5 mL). The reaction is chilled to 0° C. and triethylamine (95 μL, 0.329 mmol) is added followed by mesyl chloride (100 μL, 0.2 M in THF, 0.263 mmol). The reaction is allowed to warm to room temperature and stir for 96 h. Reaction is quenched with saturated ammonium chloride solution (0.5 mL), diluted with additional water and extracted with EtOAc. Wash combined organics with brine. Concentrate organics in vacuo to afford the title compound (117 mg, 99%).
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([O:18][CH2:19][CH2:20][O:21][CH3:22])[CH:17]=2)[C:13]#[N:14])=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2.O.N>CO.C1COCC1.[Ni]>[N:1]1[C:2]([C:10]2[CH:11]=[C:12]([CH2:13][NH2:14])[CH:15]=[C:16]([O:18][CH2:19][CH2:20][O:21][CH3:22])[CH:17]=2)=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2
Reactant: COCCOc1cc(C#N)cc(-c2cn3ncccc3n2)c1
Agent: [Ni]
Agent: N
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COCCOc1cc(CN)cc(-c2cn3ncccc3n2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.2 %

Procedure:
3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzonitrile (6 mmol) in 40 ml MeOH and 30 ml THF was added Raney-Ni (0.6mmol) and 1 ml ammonia hydrate solution and stirred at room temperature for 4 h. Raney-Ni was removed and the filtrate was concentrated to yield (3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)methanamine (70.2%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([CH3:11])[C:3]=1[C:12]#[N:13].[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>ClCCl.N1C=CC=CC=1.C(OCC)(=O)C>[CH2:7]([N:6]1[C:2]([NH:1][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[F:14])=[C:3]([C:12]#[N:13])[C:4]([CH3:11])=[N:5]1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCn1nc(C)c(C#N)c1N
Reactant: O=C(Cl)c1ccccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCn1nc(C)c(C#N)c1NC(=O)c1ccccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.7 %

Procedure:
5-Amino-1-butyl-3-methyl-1H-pyrazole-4-carbonitrile (10.0 g, 56 mmole) was dissolved in a mixture of dichloromethane/pyridine (45 ml/15 ml) and cooled to 0° C. 2-fluorobenzoyl chloride (8.87 g, 56 mmole) was added dropwise and reaction mixture stirred for 1 hour at 0° C., the at room temperature overnight. Removed solvent under vacuum. Residue was taken up in ethyl acetate, washed with dilute hydrochloric acid, 0.1M sodium hydroxide, water and dried over sodium sulfate (anh). Removed solvent and triturated solid in 30% ethyl acetate/hexanes. Filtered product to obtain 4.16 g product (yield: 24%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14].[OH-].[K+].[CH3:22]I>CN(C=O)C>[Br:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH3:22])[CH:6]=[C:5]2[CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14]
Reactant: COc1c(Br)cc(F)c2[nH]cc(CC(=O)N(C)C)c12
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1c(Br)cc(F)c2c1c(CC(=O)N(C)C)cn2C
Reaction time: 1 h

Procedure:
To the solution of 8-10 (7.0 g, 21.3 mmol) in anhydrous DMF (20 mL) was added KOH (4.34 g, 78.0 mmol), and MeI (4.55 g, 32.0 mmol) at room temperature. After the mixture was stirred for 1 h, TLC showed that the reaction was completed. The mixture was quenched with water and extracted with ethyl acetate (150 mL×3). The organic layers were combined and concentrated in vacuo. 8-11 (7.2 g, crude) was obtained as yellow oil and used for the next step without further purification.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])(C)C.[OH:6][C:7]1[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[CH:11][C:8]=1[CH:9]=O.[C:17]1(C)C=CC=C[CH:18]=1>>[CH2:1]([NH:5][CH2:9][C:8]1[CH:11]=[C:12]([CH:15]=[CH2:16])[CH:13]=[CH:14][C:7]=1[OH:6])[CH2:4][CH2:17][CH3:18]
Reactant: Cc1ccccc1
Reactant: C=Cc1ccc(O)c(C=O)c1
Reactant: CC(C)(C)N
Product: C=Cc1ccc(O)c(CNCCCC)c1
Yield: 79 %

Procedure:
73 g (1 mole) of tert-butylamine were added to a solution of 74 g (0.5 mole) of 2-hydroxy-5-vinylbenzaldehyde in 750 ml of toluene, and this mixture was refluxed for 2 hours. After extraction with twice 500 ml of ice water, the toluene was distilled off. 80 g (79%) of 2-butylaminomethyl-4-vinylphenol were obtained as a yellow oil.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].N1C=CC=CC=1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:15]>C(Cl)Cl>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][C:14]([O:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])=[O:15])=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.6 %

Procedure:
A mixture of 640 mg of methyl glycolate, 0.60 mL of pyridine, and 10 mL of methylene chloride was added to 10 mL of a methylene chloride solution including 1.44 g of 4-nitrophenyl chloroformate at room temperature, followed by stirring for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and diethyl ether and water were added to the residue and an organic layer was separated. The organic layer was sequentially washed with water and saturated brine and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (using chloroform only), thereby obtaining 320 mg of methyl {[(4-nitrophenoxy)carbonyl]oxy}acetate.
Reaction SMILES: [F:1][C:2]([F:14])([C:10]([F:13])([F:12])[F:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>ClCCl>[CH3:22][S:23]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:14])([F:1])[C:10]([F:11])([F:12])[F:13])(=[O:25])=[O:24]
Reactant: OCCCCCCC(F)(F)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCCC(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
7,7,8,8,8-Pentafluorooctan-1-ol (25 g, 113 mmol) was dissolved in dichloromethane (250 ml) and cooled to 0° C. To this solution, triethylamine (47.4 ml, 339 mmol) and methanesulfonyl chloride (17.6 ml, 227 mmol) were added dropwise, followed by stirring for 1 hour. After the reaction was completed, water was added to the reaction mixture, which was then extracted twice with dichloromethane. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/10) to give 1-methanesulfonyloxy-7,7,8,8,8-pentafluorooctane (30 g, Yield 89%).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:24])[C@H:6]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[O:14])[NH2:12])[NH2:7])[CH:2]=[CH2:3].C([BH3-])#N.[Na+].[C:29]([CH:36]([NH2:39])[CH:37]=O)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].Cl>CO.CCOCC.C(O)(=O)C>[CH2:1]([O:4][C:5](=[O:24])[C@H:6]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[O:14])[NH2:12])[NH:7][CH2:37][CH:36]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[NH2:39])[CH:2]=[CH2:3]
Reactant: CC(C)(C)OC(=O)C(N)C=O
Reactant: C=CCOC(=O)[C@@H](N)CCCC(N)C(=O)OCc1ccccc1Cl
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: CC(=O)O
Product: C=CCOC(=O)[C@H](CCCC(N)C(=O)OCc1ccccc1Cl)NCC(N)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
ε-(2-chlorobenzyloxycarbonyl)-lysine allyl ester (from example 18) was dissolved in methanol (50 mL) and cooled to 0° C. To the resulting solution was added sodium cyanoborohydride (5.9 mmol) followed by acetic acid (0.75 mL). After 5 minutes BOC-amino-acetaldehyde (13.3 mmol) was added and the reaction mixture was stirred for an additional 1 h. The methanol was removed in vacuo and the oil was dissolved in ethyl acetate (40 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated to give a clear colorless oil. This oil was dissolved in dry ether (80 mL), cooled to −20° C., and a molar equivalent of HCl in ether was added slowly. The resulting white solid was collected by filtration and air dried Precipitation of tie air-dried white solid from dry ember gave analytically pure title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10](O)(=O)[CH2:11][OH:12]>>[Cl:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:10]([CH2:11][OH:12])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Cl)cnc1N
Reactant: O=C(O)CO
Product: OCc1nc2cc(Cl)cnc2[nH]1

Procedure:
A procedure similar to that described in Preparation 43 was repeated, except that 7.67 g of 5-chloro-2,3diaminopyridine (prepared as described in Preparation 62) and 18.6 g of glycolic acid were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 8.83 g of the title compound, melting at 209°-211° C.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11](CC1C=CC=CC=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:9]([N:14]1[CH:13]=[C:12]2[C:7](=[CH:8][CH:9]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=3)[C:10](=[O:22])[NH:11]2)[C:6]([OH:33])=[C:5]1[C:3]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccc(C(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)C1=C(O)C2=CC(c3ccc(C(F)(F)F)cc3)C(=O)NC2=CN1Cc1ccccc1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.066 mmol), β-alanine (589 mg, 6.6 mmol) and NaOMe solution (10.6 mL, 5.3 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-50% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2, and the resulting precipitate was isolated by filtration to give 15 mg of the title compound as a light yellow solid. MS: (+) m/z 512.34 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[Cl:9][C:10]1[CH:11]=[C:12]([N:16]=[C:17]=[O:18])[CH:13]=[CH:14][CH:15]=1>CN(C)C=O>[Cl:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]([N:8]=[C:7]2[NH:6][C:4](=[O:5])[CH2:3][N:2]2[CH3:1])=[O:18])[CH:13]=[CH:14][CH:15]=1
Reactant: CN1CC(=O)N=C1N
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: CN(C)C=O
Product: CN1CC(=O)NC1=NC(=O)Nc1cccc(Cl)c1
Reaction time: 2 h

Procedure:
To a suspension of creatinine (5.66 g, 0.05 mole) in 150 ml. of dry dimethylformamide (DMF) is added 7.68 g (0.05 mole) of m-chlorophenylisocyanate. The mixture is stirred for 2 hours and heated on a steam bath for 30 minutes. During this time the solution becomes clear (yellow). The solution is filtered and the filtrate cooled. Ice and ice-water are added to the filtrate. A light yellow solid precipitates and is filtered off. After recrystallizations from acetone-methanol and tetrahydrofuran-ether, the pure product, 1-m-chlorophenyl-3-(1-methyl-4-oxo-2-imidazolidinylidene)urea, is obtained, mp 180°-180.5°C.
Reaction SMILES: C([O:8][N:9]=[C:10]1[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=2)[NH:11]1)C1C=CC=CC=1.[C:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)#[N:26]>C(#N)C1C=CC=CC=1>[C:25]([C:27]1[CH:28]=[C:29]([C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[N:9][OH:8])[C:18]23[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:30]=[CH:31][CH:32]=1)#[N:26]
Reactant: Brc1ccc2c(c1)C1(CCCCC1)C(=NOCc1ccccc1)N2
Reactant: N#Cc1cccc(B(O)O)c1
Solvent: N#Cc1ccccc1
Product: N#Cc1cccc(-c2ccc3c(c2)C2(CCCCC2)C(=NO)N3)c1
Yield: 69.2 %

Procedure:
3-[Spiro[cyclohexane-1,3′-[3H]indol]-(1′H)-one-2′-(O-benzyloxime)]benzonitrile [3H]indol]-5-yl]benzonitrile Prepared from 5′-bromospiro{cyclohexane-1,3′-[3H]indol}-2′(1′H)-one 2′(O-benzyloxime) (1.0 g, 2.6 mmol) and 3-cyanophenyl boronic acid (0.76 g, 5.2 mmol) according to Example 45 procedure A. The product was purified by flash silica gel chromatography (eluant: 10:0.5 hexane: ethyl acetate) to give the desired product (0.75 g, 1.8 mmol, 71%) as a viscous oil. 1H NMR (500 MHz, DMSO-d6) δ 1.41-1.81 (8H, m) 1.96-2.03 (2H, q) 5.01 (2H, s) 6.86 (1H, d) 7.28-7.33 (9H, m) 7.95-7.97 (1H, d) 8.12 (1H, s) 9.65 (1H, s); MS (ESI(−ve)) m/z 406 (M−H)−.
Reaction SMILES: [CH:1]([N:4]([C:6]#[N:7])[NH2:5])([CH3:3])[CH3:2].C(Cl)([Cl:10])=O.N.[O:13]1[CH2:17]CCC1>>[CH:1]([N:4]1[C:6]([Cl:10])=[N:7][C:17]([OH:13])=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: C1CCOC1
Reactant: CC(C)N(N)C#N
Agent: N
Product: CC(C)n1nc(O)nc1Cl

Procedure:
A preferred embodiment of the improved process according to the present invention comprises reacting 1-isopropyl-1-cyanohydrazine in the form of a 6-8 percent solution in tetrahydrofuran with phosgene at a temperature of between 0°-30° C., treating the reaction mixture with anhydrous ammonia to form the ammonium salt of 1-isopropyl-3-hydroxy-5-chloro-1,2,4-triazole, which precipitates almost totally from the tetrahydrofuran reaction mass, and liberating from said isolated salt 1-isopropyl-3-hydroxy-5-chloro-1,2,4-triazole in a yield ranging from 85.8-92.1% of theory and in a very pure state, such as of 98% assay, by treating it with 32-37% hydrochloric acid.