Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>N1C=CC=CC=1>[F:21][C:3]1[C:2]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:20][C:6]2=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1.[OH2:15].[F:21][C:3]1[C:2]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:20][C:6]2=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1.[F:21][C:3]1[C:2]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:20][C:6]2=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: C1CNCCN1
Solvent: c1ccncc1
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNCC4)cc3nc21
Product: O

Procedure:
7-Fluoro-1-methyl-4-oxo-8-(1-piperazinyl)-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Reference Example 1 but starting from 10 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 28 g of piperazine in 100 cm3 of pyridine. 5.5 g of 7-fluoro-1-methyl-4-oxo-8-(1-piperazinyl)-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid hemihydrate are obtained in the form of a yellow solid melting at 370°-375° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([OH:12])[CH:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[CH2:21]([O:12][C:6]1[CH:5]=[C:4]([N:3]([CH2:1][CH3:2])[CH2:13][CH3:14])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)c1ccc(C=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To a suspension of 4-diethylamino-2-hydroxybenzaldehyde (300 mg, 1.55 mmol) and potassium carbonate (0.43 g, 3.1 mmol) in 1.6 mL of acetone was added benzyl bromide (300 mg, 1.55 mmol) at 0° C. After being stirred at room temperature overnight, the reaction mixture was filtered to remove inorganic salts. The filtrate was diluted with diethyl ether, and the solution was washed with saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10) to obtain the title compound as a yellow oil (292 mg, 67%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][CH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)[CH3:9].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:38][CH2:39][C:40]1[C:41]([OH:48])=[N:42][C:43]([CH3:47])=[CH:44][C:45]=1[CH3:46]>ClCCl>[OH:48][C:41]1[C:40]([CH2:39][NH:38][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([CH:8]([O:7][C:2]3[N:1]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH3:9])=[CH:18][CH:17]=2)=[C:45]([CH3:46])[CH:44]=[C:43]([CH3:47])[N:42]=1
Reactant: CC(Oc1ncccn1)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ncccn3)cc2)c(O)n1
Temperature: 20 °C
Reaction time: 13 h
Yield: 32.2 %

Procedure:
To a solution of 4-(1-(pyrimidin-2-yloxy)ethyl)benzoic acid (100 mg, 0.41 mmol), 1-hydroxybenzotriozole (83 mg, 0.61 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (118 mg, 0.61 mmol), triethylamine (0.2 mL) in dichloromethane (15 mL) was added 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (62 mg, 0.41 mmol). The reaction mixture was stirred at 20° C. for 13 hours. The mixture was washed with water (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-(pyrimidin-2-yloxy)ethyl)benzamide as a white solid (50 mg, 32%). LRMS (M+H+) m/z: 378.17. found 378. HPLC Purity (214 nm): 100%. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.30 (d, J=4.8 Hz, 1H), 8.06-8.04 (m, 1H), 7.80-7.68 (m, 2H), 7.44-7.42 (m, 2H), 6.93-6.84 (m, 2H), 6.17 (q, J=6.6 Hz, 1H), 5.84 (s, 1H), 4.27 (d, J=4.8, 2H), 2.15 (s, 3H), 2.11 (s, 3H), 1.55 (d, J=6.6 Hz, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].Br[C:11]1[S:12][CH:13]=[CH:14][N:15]=1>CN(C=O)C>[S:12]1[CH:13]=[CH:14][N:15]=[C:11]1[S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[OH:2]
Reactant: COc1ccccc1S
Reactant: Brc1nccs1
Solvent: CN(C)C=O
Product: Oc1ccccc1Sc1nccs1
Temperature: 100 °C
Yield: 81 %

Procedure:
To 2-methoxybenzenethiol (2.8 g, 20 mmol), and 2-bromothiazole (3.29 g, 20 mmol) in dry DMF (30 mL) under N2 (g) was added Me4N+OH-.5H2O (3.62 g, 20 mmol). The stirred mixture was heated to about 100° C. for 16 hours. Isolation of the methoxyphenyl intermediate, and its subsequent deprotection to the desired product with BBr3 was accomplished according to the method described in Preparation 16 (yield 81%; GC-MS m/z 209).
Reaction SMILES: N[C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])C.CO[C:11]1C=CC(C=O)=[CH:15][CH:16]=1.[Cl:19]CCl>>[Cl:19][C:16]1[CH:15]=[C:2]([CH:3]=[CH:5][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: COc1ccc(C=O)cc1
Reactant: CC(C)[C@@H](N)C(=O)O
Reactant: ClCCl
Product: O=C(O)c1cccc(Cl)c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
23.4 g (0.1 mol) of the Schiff base of D-valine and anisaldehyde prepared according to Ia) was dissolved, with stirring, in 130 ml of dry dichloromethane. The solution was cooled to 5° C. or lower. The stirring was continued and the temperature was allowed to rise to room temperature, after which the stirring was continued for 4 more hours. After about 0.5 hour's stirring at room temperature the mixture became turbid as a result of the crystallization of meta-chlorobenzoic acid. After the reaction, in which all the meta-chlorobenzoic acid formed crystallized, the reaction mixture was filtered and the filtered solution was evaporation until dry.
Reaction SMILES: [OH:1][C@@H:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10](Cl)=[CH:11][CH:12]=1)=[O:6].[N:20]1([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[OH:1][C@@H:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10]([N:23]2[CH2:24][CH2:25][N:20]([C:26](=[O:27])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:35])[F:36])[CH2:21][CH2:22]2)=[CH:11][CH:12]=1)=[O:6]
Reactant: O=C(NC[C@@H](O)c1ccccc1)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: O=C(NC[C@@H](O)c1ccccc1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use (S)-6-chloropyridazine-3-carboxylic acid (2-hydroxy-2-phenylethyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (64.5% yield). 1H NMR (500 MHz, CDCl3) δ 8.28, 8.05, 7.76, 7.64, 7.58, 7.44-7.32, 7.29, 7.00, 4.96, 4.08, 3.92-3.68, 3.61, 3.36. MS (ES+) m/z 500 (M+1).
Reaction SMILES: [C:1](=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)OC1C=CC=CC=1>Cl.[Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[C:1]([O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:16])[C:1]([O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:16]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: c1ccc([P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: O=C(Oc1ccccc1)C(=O)Oc1ccccc1

Procedure:
400 parts of distilled water were added to 200 parts of diphenyl carbonate, obtained through the decarbonylation reaction of diphenyl oxalate using a hydrochloride of tetraphenyl phosphonium chloride as a catalyst, and the mixture was heated to 90° C. and stirred for 1 hour to obtain diphenyl carbonate containing 5.8 ppm of hydrolyzable chlorine. An ester interchange reaction between this diphenyl carbonate and bisphenol A was carried out in the same manner as in Example 1 except that a disodium salt of bisphenol A was used in place of sodium hydroxide as an ester interchange catalyst in an amount of 2.0×10−6 mole, in terms of sodium, based on bisphenol A, to synthesize polycarbonate. A pellet of this polycarbonate was used for the measurement of its physical properties. The conditions and results are shown in Tables I-A and I-B below.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:10]([NH2:14])[CH:11]([NH2:13])[CH3:12]>C(O)(C)C.[Pt]>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH2:1][NH:14][CH2:10][CH:11]([NH:13][CH2:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[CH3:12]
Reactant: CC(N)CN
Reactant: O=Cc1ccccc1O
Agent: [Pt]
Solvent: CC(C)O
Product: CC(CNCc1ccccc1O)NCc1ccccc1O
Yield: 26.2 %

Procedure:
84.6 g of a bisazomethine prepared from 2 moles of salicylaldehyde and 1 mol of propylenediamine and having a melting point of 57°-58° C. are hydrogenated for 3 hours in 340 ml of isopropanol in an autoclave in the presence of 1.20 g of 5% platinum/charcoal at 45° C. and under a pressure of 50-60 atmospheres. The product crystallises out at room temperature and is dissolved by boiling, with the addition of a further 660 ml of isopropanol. The catalyst is filtered off and the diamine crystallises out on cooling. The crystals are collected by filtration, washed and dried, yielding 75.1 g of N,N'-bis-(2-hydroxybenzyl)-propylenediamine (87.5% of theory); melting point 109°-110° C.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:9]([O-:16])([O:13]CC)[O:10]CC.[H][H]>[Ni]>[CH2:1]([NH:8][CH:1]([P:9](=[O:10])([OH:13])[OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1
Reactant: [H][H]
Reactant: CCOP([O-])OCC
Agent: [Ni]
Product: O=P(O)(O)C(NCc1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of benzonitrile (75g; 0.73 mole) in diethyl phosphite (200g; 1.45 mole) was added W-2 Raney nickel (6g) and the whole mixture charged in an autoclave. The reactor was pressured to 600 psi with hydrogen and the mixture heated to 60° C. The pressure was maintained at 550-600 psi by addition of hydrogen as the reduction proceeded. After 18 hours, uptake of hydrogen had ceased. After cooling hydrogen was released and the catalyst filtered as the reaction product was removed from the reactor. Excess diethyl phosphite and unreacted benzonitrile was removed (135g) by distillation under reduced pressure. The residue was diethyl N-benzyl α-aminobenzylphosphonate. Hydrolysis of this residue with 18% HCl after crystallization yielded N-benzyl α-amino benzylphosphonic acid, 83g (82%), mp 233°-6°. ##STR10##
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([Br:14])=[CH:9][N:8]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:14][C:10]1[CH:11]=[C:12]([CH3:13])[C:7]([NH:6][C:3](=[O:4])[CH2:2][Cl:1])=[N:8][CH:9]=1
Reactant: Cc1cc(Br)cnc1N
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Br)cnc1NC(=O)CCl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.75 mL (22 mmol) chloroacetyl chloride are added to a solution, cooled to 0° C., of 3.74 g (20 mmol) 2-amino-5-bromo-3-methylpyridine in 50 mL DCM and then 6.1 mL (44 mmol) triethylamine are slowly added dropwise. After the addition has ended the ice bath is removed and the reaction mixture is stirred for 4 h at RT. It is poured onto water, extracted exhaustively with DCM, the combined organic phases are washed with water and saturated NaCl solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, cyc/EtOAc 2:1).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:18])[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[NH:11][C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21]I.O>CN(C)C=O>[NH2:1][C:2]1[C:7]2[C:8](=[O:18])[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[N:11]([CH3:21])[C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc2c(=O)[nH]c3ccccc3c(=O)c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2cccc(N)c2c(=O)c2ccccc21

Procedure:
To 5 g 10-amino-5,6-dihydro-11H-dibenzo(b,e)azepine-6,11-dione in 25 ml dimethylformamide are added 0.8 g 60% sodium hydride in mineral oil and then 1.5 ml methyl iodide. After leaving for 24 hours at ambient temperature, with stirring, the mixture is poured into water, filtered and dried: melting point 171°-3° C. (water).
Reaction SMILES: [H-].[Na+].C([O:7][C:8](=[O:20])[NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]=[N+:18]=[N-:19])(C)(C)C.[CH2:21](Br)[C:22]#[CH:23]>CCCCCC.CN(C=O)C>[N:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:9]([CH2:23][C:22]#[CH:21])[C:8](=[O:20])[OH:7])=[N+:18]=[N-:19]
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)NCc1ccccc1N=[N+]=[N-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C#CCN(Cc1ccccc1N=[N+]=[N-])C(=O)O
Reaction time: 0.5 h

Procedure:
Sodium hydride (5.0 mg, 0.120 mmol, 60% suspension in mineral oil) was washed with hexane (2 mL) in a flame dried round bottomed flask under nitrogen atmosphere. To the resulting free floating powder, was added a solution of (2-azido-benzyl)-carbamic acid tert-butyl ester (20 mg, 0.08 mmol) in dry DMF (1 mL) at 0° C. The reaction mixture was stirred at this temperature for 30 min. Propargyl bromide (0.021 mL, 0.24 mmol) was added and the reaction mixture was stirred at r.t. for 2 h. After the completion of reaction as confirmed by TLC, crude product was extracted with ethylacetate (10 mL). The organic layer was washed with water (2×5 mL). Organic layer was dried over Na2SO4 and concentrated in vacuo to afford the crude compound which was purified by column chromatography (silica gel; 1:9 EtOAc:Pet.Ether) to afford (2-azido-benzyl)-prop-2-ynyl-carbamic acid ten-butyl ester (20 mg, 87%) as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13](O)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1.C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]([Cl:23])=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Reaction time: 0.33 h

Procedure:
A sample of crude 1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (40.8 g, 0.14 mole) was dissolved in methylene chloride (300 mL). The solution was treated with oxalyl chloride (15.7 mL, 0.18 mole), followed by N,N-dimethylformamide (12 drops). Off-gassing began shortly after adding the N,N-dimethylformamide catalyst. The reaction mixture was stirred for about 20 minutes under ambient conditions, then was heated to reflux for a period of 35 minutes. Volatiles were removed by concentrating the reaction mixture on a rotary evaporator at a bath temperature of 55° C. The crude product, approximately 43 g of a light-yellow oil, was used directly in the next step.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]1([CH2:14][OH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH3:17][O:18][C:19](=[O:25])[C@@H:20]1[CH2:24][CH2:23][CH2:22][NH:21]1.Cl.[Cl-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[CH3:17][O:18][C:19](=[O:25])[C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[S:2]([NH:5][C:6]([O:15][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])(=[O:4])=[O:3]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: OCc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.8 %

Procedure:
To a stirred solution of 7.36 ml (84.8 mmol) of chlorosulfonyl isocyanate in 180 ml of methylene chloride was added phenylmethanol (8.82 ml, 84.9 mmol) at 0° C. over a period of 35 minutes. After stirring the above solution for 2 hours at this temperature, a solution of 15.54 g (93.28 mmol) of L-proline methyl ester hydrochloride in 500 ml of methylene chloride containing triethylamine (35.5 ml) was added at 0°-5° C., and the resulting mixture was stirred overnight allowing the mixture to warm to room temperature. The reaction mixture was poured into 600 ml of 10% aq. HCl solution, saturated with sodium chloride, and the organic layer was separated. The aqueous layer was extracted with methylene chloride (2×200 ml) and the combined organic layer was washed with brine, dried and concentrated in vacuo to yield 31 g of N-(carbobenzyloxyaminosulfonyl)-L-proline methyl ester (Formula XIV: R=CH3 ; R1 =H; R2 and R3 together=--(CH2)3 --) as an oil.
Reaction SMILES: [SH:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.[NH2:7][C:8]1[N:13]=[C:12]([CH2:14]Cl)[CH:11]=[C:10]([O:16][CH3:17])[N:9]=1>CO.O>[NH2:7][C:8]1[N:9]=[C:10]([O:16][CH3:17])[CH:11]=[C:12]([CH2:14][S:1][C:2]2[S:3][CH2:4][CH2:5][N:6]=2)[N:13]=1
Reactant: SC1=NCCS1
Reactant: COc1cc(CCl)nc(N)n1
Solvent: CO
Solvent: O
Product: COc1cc(CSC2=NCCS2)nc(N)n1
Reaction time: 1 h

Procedure:
11.9 g of 4,5-dihydro-2-mercapto-thiazole are suspended in 100 ml of methanol, and to the suspension are added 18.0 g of 30% methanolic sodium methylene solution. To the formed clear solution are subsequently added 17.4 g of 2-amino-4-chloromethyl-6-methoxy-pyrimidine, and refluxing is carried out for 1 hour. After the solution has cooled, it is diluted with about 1 liter of water, and the product which precipitates is separated and dried. The yield is 22.5 g (88% of theory) of 2-amino-4-methoxy-6-(4,5-dihydrothiazol-2-yl-thiomethyl)-pyrimidine, m.p. 122°-124° C.
Reaction SMILES: I[C:2]1[N:3]=[N:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1.[CH3:16][C:17]1([CH3:24])[CH2:22][CH2:21][NH:20][C:19](=[O:23])[CH2:18]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:16][C:17]1([CH3:24])[CH2:22][CH2:21][N:20]([C:2]2[N:3]=[N:4][C:5]([C:8]#[C:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:6][CH:7]=2)[C:19](=[O:23])[CH2:18]1
Reactant: Ic1ccc(C#Cc2ccccc2)nn1
Reactant: CC1(C)CCNC(=O)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC1(C)CCN(c2ccc(C#Cc3ccccc3)nn2)C(=O)C1
Yield: 18.8 %

Procedure:
To a well stirred suspension of 3-iodo-6-(phenylethynyl)pyridazine (Example 151, step 1) (80 mg, 261 mol), 4,4-dimethylpiperidin-2-one (66.5 mg, 314 μmol, 1.2 equiv.) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos) (6.05 mg, 10.5 μmol, 0.04 equiv.) in 2 ml of toluene were added under argon atmosphere tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), (4.79 mg, 5.23 μmol, 0.02 equiv.) and the mixture was stirred for 4 hours at 100° C. The crude mixture was directly purified by flash chromatography over a 20 g silicagel column using a heptane to 50% ethyl acetate in heptane gradient, and yielded 18 mg (23% yield) of the title compound as a white solid, MS: m/e=306.2 (M+H+).
Reaction SMILES: [F:1][CH:2]([F:30])[O:3][C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][O:7][C:8]1[CH:12]=[C:11]([N:13]2[C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:16]=3[N:15]=[CH:14]2)[S:10][C:9]=1[C:22]([O:24]C)=O.[NH3:31]>CO>[F:30][CH:2]([F:1])[O:3][C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][O:7][C:8]1[CH:12]=[C:11]([N:13]2[C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:16]=3[N:15]=[CH:14]2)[S:10][C:9]=1[C:22]([NH2:31])=[O:24]
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccccc1OC(F)F
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccccc1OC(F)F
Temperature: 125 °C
Reaction time: 4 h

Procedure:
A mixture of 37.5 mg of methyl 3-{[2-(difluoromethoxy)benzyl]oxy}-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate and 5 ml of a saturated solution of ammonia in methanol is stirred in a microwave vial at 125° C. for 4 h in the microwave cavity. The reaction mixture is concentrated to dryness, the resulting residue is dissolved in a mixture of acetonitrile and methanol (9:1 (v/v)) and purified by preparative HPLC (water/acetonitrile, elution gradient 9/1 to 1/9 (v/v)) to obtain the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10]CC)=[O:9])[CH2:3]1.[CH2:13](O)[CH2:14][OH:15].[OH-].[Na+]>C1C=CC=CC=1.C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:1]1[C:2]2([CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]2)[O:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)C1CCCC(=O)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccccc1
Solvent: O
Product: O=C(O)C1CCCC2(C1)OCCO2

Procedure:
A mixture of ethyl 3-oxocyclohexanecarboxylate (Nallet, J-P., et al, Bull. Soc. Chem. Fr., Part II, No. 3-4, pages 153-156 (1979)) (101.7 g) ethylene glycol (38.9 g) and para-toluenesulfonic acid (5.5 g) in 1000 mL of benzene is refluxed with a Dean-Stark trap for 4 hours. The solution is cooled, washed with 1N sodium hydroxide and brine, dried over magnesium sulfate, and evaporated in vacuo to give 113.1 g of a light oil which is dissolved in 1000 mL of ethanol, treated with sodium hydroxide (25.3 g) in 250 mL of water, and refluxed for 2.5 hours. The mixture is concentrated in vacuo, cooled in an ice bath, and acidified with ice-cold 1N aqueous hydrochloric acid solution to a pH of 2. The title compound is extracted with chloroform (2×500 mL), dried over magnesium sulfate, and concentrated in vacuo. The title compound (99.3 g) is obtained as a yellowish oil, which is determined to be 98% pure by gas chromatography and is carried on without further purification.
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:8](=[O:9])[CH2:7][N:6]([CH2:10][CH2:11][N:12]2[CH2:17][C:16](=[O:18])[N:15]([CH2:19][OH:20])[C:14](=[O:21])[CH2:13]2)[CH2:5][C:4]1=[O:22].[C:23](Cl)(=[O:33])[C:24]1[CH:32]=[CH:31][C:30]2[O:29][CH2:28][O:27][C:26]=2[CH:25]=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[CH2:28]1[O:29][C:30]2[CH:31]=[CH:32][C:24]([C:23]([O:20][CH2:19][N:15]3[C:14](=[O:21])[CH2:13][N:12]([CH2:11][CH2:10][N:6]4[CH2:7][C:8](=[O:9])[N:3]([CH2:2][O:1][C:23](=[O:33])[C:24]5[CH:32]=[CH:31][C:30]6[O:29][CH2:28][O:27][C:26]=6[CH:25]=5)[C:4](=[O:22])[CH2:5]4)[CH2:17][C:16]3=[O:18])=[O:33])=[CH:25][C:26]=2[O:27]1
Reactant: O=C1CN(CCN2CC(=O)N(CO)C(=O)C2)CC(=O)N1CO
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(OCN1C(=O)CN(CCN2CC(=O)N(COC(=O)c3ccc4c(c3)OCO4)C(=O)C2)CC1=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 20 h
Yield: 67.7 %

Procedure:
To a mixture of 1,2-bis(4-hydroxymethyl-3,5-dioxopiperazin-1-yl)ethane (0.94 g, 3.0 m mol) and pyridine (10 ml), piperonyloyl chloride (1.00 g, 6.0 m mol) dissolved in pyridine (10 ml) was added, and then the mixture was stirred for 20 hours at room temperature. To the reaction mixture, chloroform (250 ml) was added and the solution was washed with 10% sulfuric acid solution and successively with water, further was washed with aqueous sodium bicarbonate solution and successively with water. Then, the solvent was removed under reduced pressure to give the titled compound (1.12 g; yield 61%).