Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=1>CS(C)=O>[N:1]([CH2:6][C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: O=c1[nH]cc(CCl)c(=O)[nH]1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1c[nH]c(=O)[nH]c1=O
Reaction time: 2 h
Yield: 98.5 %

Procedure:
Sodium azide (0.6 g, 9.34 mmol) was added to a solution of 5-(chloromethyl)-2,4(1H,3H)-pyrimidinedione (0.3 g, 1.67 mmol) in DMSO (5 ml) under nitrogen at room temperature. The reaction was stirred for 2 h then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give the 5-(azidomethyl)-2,4(1H,3H)-pyrimidinedione (0.275 g, 98%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[BrH:12]>CS(C)=O>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Br
Reactant: Cc1cccc(C(=O)O)c1N
Solvent: CS(C)=O
Product: Cc1cc(Br)cc(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of 2-amino-3-methylbenzoic acid (10.0 g, 66 mmol) in DMSO was added 48% aqueous hydrogen bromide (18.0 ml). The reaction solution was stirred at room temperature overnight and then quenched with saturated sodium bicarbonate. The resultant mixture was stirred overnight. Precipitation was collected by filtration and dried in vacuo to give 2-amino-5-bromo-3-methylbenzoic acid (13.0 g, 85%) as a pink solid: 1H NMR (500 MHz, DMSO) δ 7.69 (d, J=1.0 Hz, 1H), 7.33 (d, J=1.0 Hz, 1H), 2.10 (s, 3H); MS (ESI+) m/z 231 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=O)=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[Cl:25][C:26]1[CH:33]=[CH:32][C:29](/[CH:30]=[C:19]2\[N:18]=[C:16]([C:15]3[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[CH:24][CH:23]=3)[O:22][C:20]\2=[O:21])=[CH:28][CH:27]=1
Reactant: COc1ccc(CCOc2ccc(C(=O)NCC(=O)O)cc2)cc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(CCOc2ccc(C3=N/C(=C\c4ccc(Cl)cc4)C(=O)O3)cc2)cc1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 86.7 %

Procedure:
A mixture of N-{4-[2-(4-methoxyphenyl)ethoxy]benzoyl}glycine (329 mg, 1.00 mmol) prepared in Example 1 (1b), 4-chlorobenzaldehyde (148 mg, 1.05 mmol), sodium acetate (111 mg, 1.35 mmol), and acetic anhydride (467 μL, 5.00 mmol) was stirred at 120° C. for 20 minutes, and then water was added thereto to terminate the reaction. Then, continuously, the mixture was vigorously stirred until the mixture was cooled to room temperature. The deposited precipitate was collected by filtration, washed with water and hexane, and dried by heating under reduced pressure to give 376 mg of the title compound (yellow powder, yield: 87%).
Reaction SMILES: [CH2:1]([CH2:8][NH:9][C:10]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:1]([CH2:8][NH:9][C:10]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)[CH2:11][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(NCCc4ccccc4)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C#Cc2ccc(C3(NCCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
Using General Procedure I; a solution of ethyl 4-{4-[1-(benzylmethylamino)-cyclopropyl]-phenylethynyl}-benzoate (Compound 115, 65.0 mg, 0.16 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 45.0 mg (75%) of the title compound as a solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>>[CH:32]1([C:35]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]3[C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=5[O:27][CH2:28][CH:29]5[CH2:30][CH2:31]5)[C:13]=4[NH:12][CH:11]=3)=[O:9])[CH2:5][CH2:6]2)=[O:36])[CH2:34][CH2:33]1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c1
Reactant: O=C(Cl)C1CC1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)C5CC5)CC4)c[nH]c23)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A155) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH2:12][CH3:13].[Br:14][C:15]1[C:20]([NH2:21])=[CH:19][C:18]([Cl:22])=[CH:17][N:16]=1>N1C=CC=CC=1>[Br:14][C:15]1[C:20]([NH:21][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:12][CH3:13])[CH:4]=2)(=[O:10])=[O:9])=[CH:19][C:18]([Cl:22])=[CH:17][N:16]=1
Reactant: CCc1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: Nc1cc(Cl)cnc1Br
Solvent: c1ccncc1
Product: CCc1cc(S(=O)(=O)Nc2cc(Cl)cnc2Br)ccc1Cl

Procedure:
Prepared from 1.71 g (7.15 mmol) of 4-chloro-3-ethyl-benzenesulfonyl chloride and 1.34 g (6.47 mmol) of 2-bromo-5-chloro-pyridin-3-ylamine in 4 mL pyridine using procedure x. Yield: 2.35 g of a white solid. LC-MSD, m/z for C13H11BrCl2N2O2S [M+H]+=408.8, 410.8, 412.8
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].Br[CH2:12][CH:13](Br)C.[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:9]#[N:10])[CH2:13][CH2:12]1
Reactant: CC(Br)CBr
Reactant: N#CCc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1(c2ccccc2Cl)CC1

Procedure:
A solution of 13.1 g of 2-chlorophenylacetonitrile and 20.3 g of 1,2-dibromopropane in 142 ml of DMF is mixed with 9 g of sodium hydride [55–65% in oil] at room temperature. It is stirred for several hours and carefully added to water. After extraction with ethyl acetate and filtration by silica gel, the desired product is obtained: 13.1 g
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].C(N(CC)CC)C.Cl[CH2:19][C:20](Cl)=[O:21].[H-].[Na+]>C1COCC1>[Br:8][C:6]1[C:5]([CH3:9])=[CH:4][C:3]2[O:10][CH2:19][C:20](=[O:21])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(O)c(N)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc2c(cc1Br)NC(=O)CO2
Yield: 72.7 %

Procedure:
Prepared following the procedure for Intermediate 6 using 2-amino-4-bromo-5-methylphenol (4.73 g, 23.4 mmol), triethylamine (3.6 mL, 25.8 mmol) and chloroacetyl chloride (1.8 mL, 23.4 mmol) in THF (120 mL) followed by sodium hydride (1.9 g of a 60% suspension in oil, 49.2 mmol) to give the title compound (4.12 g, 73%) as a beige solid. δH (DMSO-d6) 2.23 (3H, s), 4.57 (2H, s), 6.97 (1H, s), 7.04 (1H, s), 10.72 (1H, s).
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:11])[CH2:6][CH2:7][C:8](Cl)=[O:9])(=[O:3])[CH3:2].N1C(C)=CC=CC=1C>[Pd].O1CCCC1>[C:1]([O:4][CH:5]([CH3:11])[CH2:6][CH2:7][CH:8]=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)CCC(=O)Cl
Agent: [Pd]
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: CC(=O)OC(C)CCC=O
Reaction time: 1 h

Procedure:
45.0 g (0.25 mol) of 4-acetoxypentanoic acid chloride are dissolved in 450 ml of abs. tetrahydrofuran. Then 31.9 ml (0.27 mol) of 2,6-lutidine and 9 g of 5% Pd/C are added and hydrogenation is carried out for 1 hour at 10°-15° C. Upon cessation of hydrogenation, the catalyst and the 2,6-lutidine are removed by filtration and the filtrate is concentrated by evaporation. Distillation of the residue gives 4-acetoxypentanal as a colourless liquid of b.p.34 98°-100° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[C:11]([CH3:23])([CH3:22])[C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)([CH3:14])[N:13]=1)(C)(C)C.[C:27]([C:29]1([C:32](O)=[O:33])[CH2:31][CH2:30]1)#[N:28]>>[NH2:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[C:11]([CH3:23])([CH3:22])[C@:12]([C:15]2[CH:16]=[C:17]([NH:21][C:32]([C:29]3([C:27]#[N:28])[CH2:31][CH2:30]3)=[O:33])[CH:18]=[CH:19][CH:20]=2)([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cccc(N)c2)N=C1NC(=O)OC(C)(C)C
Reactant: N#CC1(C(=O)O)CC1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cccc(NC(=O)C3(C#N)CC3)c2)N=C1N

Procedure:
The coupling of [(R)-4-(3-amino-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F1) and 1-cyano-cyclopropanecarboxylic acid followed by deprotection of the intermediate yielded the title compound as a white solid. MS (ESI): m/z=354.3 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.Cl.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[O:31][N:30]=[C:29]([C:32](O)=[O:33])[CH:28]=2)[CH2:22][CH2:21]1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:32]([C:29]3[CH:28]=[C:27]([CH2:26][N:23]4[CH2:22][CH2:21][O:20][CH2:25][CH2:24]4)[O:31][N:30]=3)=[O:33])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cc(CN2CCOCC2)on1
Agent: Cl
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(CN2CCOCC2)on1
Yield: 16.9 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(morpholinomethyl)isoxazole-3-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.690 mmol) and 5-(morpholinomethyl)isoxazole-3-carboxylic acid hydrochloride (206 mg, 0.828 mmol). The product was purified by reverse phase Flash-chromatography. Yield 16.9%. 1H-NMR (400 MHz; MeOD): δ 1.26 (d, 3H), 2.47-2.56 (m, 4H), 3.65-3.71 (m, 4H), 3.75 (d, 2H), 4.28-4.44 (m, 2H), 4.53-4.63 (m, 1H), 6.59 (t, 1H), 6.77 (d, 1H), 7.71 (d, 1H), 7.78 (dd, 1H), 7.88 (dd, 1H), 8.08 (dd, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9]1.N1C=CC=CC=1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38]>ClCCl>[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9]1)(=[O:39])=[O:38]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1N)N2
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NS(=O)(=O)c1ccccc1F)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
To an ice-cold mixture of methyl 2-(2-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (60 mg, 0.19 mmol, 1.0 eq.) and pyridine (0.3 mL, 3.8 mmol, 20 eq.) in dichloro methane (5 mL) was added 2-fluorobenzene-1-sulfonyl chloride (51 mg, 0.29 mmol, 1.5 eq.) under nitrogen. Then the reaction mixture was stirred at room temperature for two hours. Thin layer chromatography and LC-MS indicated that the starting material was consumed completely. The reaction was quenched with 20 mL water extracted with ethyl acetate (20 mL×2). The combined organic layers were concentrated and the residue was purified by silica gel (petroleum ether/ethyl acetate=2:1) to afford 62 mg of methyl 2-(2-(2-fluorophenylsulfonamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a pale yellow solid; yield: 70%; MS (ESI+APCI) M+1=469.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].Cl[CH2:11][O:12][CH3:13]>C(#N)C>[CH3:11][O:12][CH2:13][N:5]1[C:4]([CH3:3])=[C:8]([CH3:9])[N:7]=[CH:6]1
Reactant: Cc1nc[nH]c1C
Reactant: COCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: COCn1cnc(C)c1C

Procedure:
At a temperature of 60° C., 500 mg. of picrinic acid and 15.6 g. (0.39 mol) of sodium hydroxide were added to a solution of 31 g. (0.32 mol) of 4,5-dimethylimidazole (H, Bredereck and G. Theilig, Chem. Ber. 86, 88 (1953)) in 150 ml. of acetonitrile. Then 29 g. (0.36 mol) of chloromethoxymethane were added drop-wise, which made the temperature rise to 80° C. The reaction mixture was refluxed for 6 hours and filtered. The filtrate was concentrated by distilling off the solvent and the residue was distilled. 1-(Methoxymethyl)-4,5-dimethylimidazole was obtained. Boiling point 80°-100° C./1.0 mm. Hg. Melting point of the hydrogen oxalate 102°-103° C.
Reaction SMILES: N[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N([O-])=O.[Na+].C1C=CN=CC=1.[FH:22]>>[F:22][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cncc(N)c1
Reactant: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)c1cncc(F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a stirring solution of 243 mg (1.6 mmol) of methyl 5-aminonicotinate in 5 mL of HF-pyridine at 0° C. was added 119 mg (1.72 mmol) of NaNO2. The mixture was stirred at 0° C. for 30 min. and at 50° C. for 1 h. The reaction was quenched by ice and sat. NaHCO3 solution. The aqueous layer was extracted with CHCl3, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (1% MeOH/CHCl3) provided 139 mg of methyl 5-fluoronicotinate as a yellow solid in 56% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH:28]3[S:32][C:31](=[O:33])[NH:30][C:29]3=[O:34])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)[N:53]([CH3:55])[CH3:54])C2C=CC=CC=2N=N1.CNC>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10](=[O:11])[N:53]([CH3:55])[CH3:54])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH:28]3[S:32][C:31](=[O:33])[NH:30][C:29]3=[O:34])=[CH:23][CH:22]=2)=[CH:18][CH:19]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1)C(=O)O
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)C(Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 13.8 %

Procedure:
The compound, 2-tert-butoxycarbonylamino-3-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-propionic acid (4.2 g, 8.63 mmol) was dissolved in CH2Cl2 (30 mL) and stirred at room temperature under an atmosphere of argon. Triethylamine (1.44 mL, 0.014 mmol) and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 4.19 g, 9.5 mmol) were added and the reaction mixture was stirred for 15 min. Dimethylamine (2.0 M solution in THF, 5.6 mL, 11.2 mmol) was added and the resulting solution was stirred at room temperature for about 1 h. The solvent was removed under reduced pressure and the resulting oil was taken up in EtOAc (100 mL). The organic layer was extracted with 0.5 N NaOH (1×50 mL), water (1×100 mL) and brine (1×100 mL). Silica gel chromatography of the crude product with CHCl3-MeOH (19:1) yielded pure amide, (1-dimethylcarbamoyl-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-ethyl)-carbamic acid tert-butyl ester (0.61 g, 13.8%). 1H NMR (400 MHz, CDCl3): 7.17 (overlapped d, J=8.4 Hz, 2H), 7.16 (overlapped d, J=8.4 Hz, 2H), 6.92 (overlapped d, J=8.4 Hz, 2H), 6.90 (overlapped d, J=8.4 Hz, 2H), 5.51 (d, J=8.4 Hz, 1H), 4.81 (m, 1H), 3.02-3.13 (m, 2H), 2.83-2.95 (m, 5H), 2.76 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:23]([C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[C:30]([OH:35])[CH:29]=2)#[N:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.ClCCl>[C:23]([C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[C:30]([O:35][C:2]1[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=1)[CH:29]=2)#[N:24]
Reactant: N#Cc1cnc2cc(O)ccc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4cc(C#N)cnc4c3)ncnc2cc1OCC1CCN(C)CC1
Temperature: 95 °C
Yield: 86.4 %

Procedure:
4-Chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (200 mg, 0.62 mmol), (prepared as described for the starting material in Example 10), was suspended in DMF (3 ml) under argon. 3-Cyano-7-hydroxyquinoline (116 mg, 0.68 mmol) and potassium carbonate (129 mg, 0.93 mmol) were added and the reaction mixture was heated at 95° C. for 90 minutes. Upon cooling to ambient temperature the mixture was diluted with dichloromethane and poured on the top of an ISOLUTE silica column. Elution was done using successively dichloromethane, dichloromethane/methanol (95/5) and dichloromethane/methanol saturated with ammonia (95/5). Evaporation of the solvent and trituration of the solid in ether gave 4-(3-cyanoquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (244 mg, 86%).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2([CH3:31])[C:25](=[C:26]=[S:27])[C:24](=[C:28]=[S:29])[CH2:23][CH2:22][C:21]2=O)[CH:15]=1>O1CCCC1.C(OCC)(=O)C>[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2([CH3:31])[C:25](=[C:26]=[S:27])[C:24](=[C:28]=[S:29])[CH2:23][CH2:22][C:21]2=[CH:3][C:1]#[N:2])[CH:15]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC1(c2cccnc2)C(=O)CCC(=C=S)C1=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(c2cccnc2)C(=C=S)C(=C=S)CCC1=CC#N
Temperature: 25 °C
Yield: 26 %

Procedure:
A solution of diethyl cyanomethylphosphonate (18.2 g, 0.1 mol) in dry tetrahydrofuran (200 ml) at 25° C. was treated with sodium hydride (4.5 g of a 60% oil dispersion). After 30 mins at 25° C. the mixture was treated with 2-(pyrid-3-yl)-2-methyldithiocarbonylcyclohexanone (24.7 g, 0.93 mol) in dry tetrahydrofuran (100 ml). After 3 hrs at reflux the mixture was cooled to 25° C. over 30 mins, diluted with ethyl acetate (500 ml) and then washed with water (500 ml). The organic phase was removed and dried over magnesium sulphate and then filtered. Concentration in-vacuo (50° C.; 20 mm Hg) afforded a crude oil which wa purified by flash chromatography over silica gel, eluting with ethyl acetate/n-hexane (25:75) to give 2-(pyrid-3-yl)-2-methyldithiocarbonyl-1-cyanomethylenecyclohexane (7.4 g, 0.026 mol) as an orange gum.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[I:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12]>O1CCCC1>[CH2:1]([NH:7][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=1[I:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN
Reactant: O=C(Cl)c1ccccc1I
Solvent: C1CCOC1
Product: CCCCCCNC(=O)c1ccccc1I
Yield: 76.4 %

Procedure:
Solutions of 12.2 g hexylamine and 8.0 g o-iodobenzoyl chloride in a total of 20 ml tetrahydrofuran were reacted for 10 minutes. The tetrahydrofuran was removed by heating on a water bath at 65° for 10 minutes and 50 ml of water were added to precipitate the crude product. The precipitate was recovered as in Example 1 and recrystallized from a benzene/hexane mixture as white crystals, to yield 7.6 g of N-hexyl-o-iodobenzamide, m.p. 104°-105°, Rf 0.78.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:21]=[CH:20][C:8]2[N:9]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[NH:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].Cl>CO.C1COCC1>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:10]1[NH:11][C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:21]=[CH:20][C:8]=2[N:9]=1
Reactant: COC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(2,6-dichlorophenyl)-3H-benzoimidazole-5-carboxylic acid methyl ester (5.8 g) in 40 mL of MeOH/THF (1:1) was added 1N NaOH (20 mL). The mixture was stirred at RT for 18 h then 1N HCl was added until pH 3. The resulting precipitate was filtered, washed with water and dried under reduced pressure to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Br)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26].[I-].[Na+]>>[CH2:25]([N:27]([CH2:15][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:24][C:6]=3[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[N:8][CH2:9][C:10]2=[N:14][N:13]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: CCNCC
Reactant: Fc1ccc2c(c1)C(c1ccccc1F)=NCc1nnc(CBr)n1-2
Agent: [I-]
Agent: [Na+]
Product: CCN(CC)Cc1nnc2n1-c1ccc(F)cc1C(c1ccccc1F)=NC2

Procedure:
In the manner given in Example 1, 8-fluoro-1-(bromomethyl)-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine was reacted with diethylamine in the presence of sodium iodide to give 1-[(diethylamino)methyl]-8-fluoro-6-(o-fluorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[N:21]=[C:20]3[C:15]=2[CH:16]=[C:17]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:18](=[O:31])[NH:19]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[BH4-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[N:21]=[C:20]3[C:15]=2[CH2:16][CH:17]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:18](=[O:31])[NH:19]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc2c(C3CCCN(C(=O)OC(C)(C)C)C3)cc(-c3ccccc3O)nc2[nH]c1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1Cc2c(C3CCCN(C(=O)OC(C)(C)C)C3)cc(-c3ccccc3O)nc2NC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
To a cold (0° C.) suspension of ethyl 5-[1-(tert-butoxycarbonyl)-3-piperidinyl]-7-(2-hydroxyphenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate (0.050 g, 0.101 mmol) in THF (2.0 mL) under an argon atmosphere was added LiBH4 (0.004 g, 0.20 mmol). The mixture was allowed to warm to room temperature, and the stirring was continued for 3 hrs. The resulting mixture was quenched with water, and partitioned between ethyl acetate and a saturated ammonium chloride solution. The separated organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate, 3:2) to give Ethyl 5-[1-(tert-butoxycarbonyl)-3-piperidinyl]-7-(2-hydroxyphenyl)-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate. (0.027 g, yield; 54%)