Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]([CH:11]=O)[CH2:9][CH2:8][N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)=O.C(O)(=O)C.[CH3:31][NH2:32].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[CH2:20]([C:5]12[C:3](=[O:2])[N:32]([CH3:31])[CH2:11][CH:10]1[CH2:9][CH2:8][N:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)C1(Cc2ccccc2)CN(Cc2ccccc2)CCC1C=O
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CN1CC2CCN(Cc3ccccc3)CC2(Cc2ccccc2)C1=O
Temperature: 70 °C

Procedure:
To a solution of the compound of Example 200, Step C (0.210 g, 0.60 mmol) in dichloroethane (5 mL) in a resealable tube was added acetic acid (0.188 mL, 3.28 mmol), methyl amine (2.0 M in MeOH, 1.64 mL, 3.28 mmol) and NaB(OAc)3H (0.951 g, 4.48 mmol), the tube was sealed and the reaction mixture was heated to 70° C. for 30 h. The reaction mixture was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate solution. The organic layer was removed and the aqueous layer was washed twice with CH2Cl2, the combined organic layers were washed with a saturated aqueous brine solution, dried over Na2SO4, filtered and concentrated under vacuum. Purification by silica gel chromatography employing 5-20% EtOAc/CH2Cl2 as the eluant afforded the less polar isomer of Example 200, Step D (0.034 g) as well as the more polar isomer (0.046 g). Example 200, Step D less polar isomer. +APcl MS (M+1)+ 335; 1H NMR (400 MHz, CDCl3) δ: 7.03-7.37 (arom, series of m, 10 H), 3.54 (m, 2H), 3.24 (m, 1H), 2.70 (s, 3H). More polar isomer: +APcl MS (M+1)+ 335; 1H NMR (400 MHz, CDCl3) δ: 7.15-7.33 (arom, series of m, 10 H), 3.59 (d, 1H), 3.43 (d, 1H), 2.74 (s, 3H).
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23](OC)=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.O[CH:30]([CH2:45]OC1C=CC=CC=1C)[CH2:31]NC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:30]([CH3:45])[CH3:31])=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:16])([CH3:17])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)C)cc2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 356 (M−15, 0.1), 251 (18), 250 (100), 163 (7), 121 (23), 117 (7), 114 (8).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[C:17]3[O:16][CH2:15][C:14](=[O:18])[NH:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.CS(O[CH2:24][CH2:25][O:26][C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[CH:29]=[N:30][C:31]([CH3:37])=[N:32]2)(=O)=O>>[CH3:37][C:31]1[N:30]=[CH:29][C:28]2[C:33](=[CH:34][CH:35]=[CH:36][C:27]=2[O:26][CH2:25][CH2:24][N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][C:8]3[C:17]4[O:16][CH2:15][C:14](=[O:18])[NH:13][C:12]=4[CH:11]=[CH:10][CH:9]=3)[CH2:3][CH2:2]2)[N:32]=1
Reactant: Cc1ncc2c(OCCOS(C)(=O)=O)cccc2n1
Reactant: O=C1COc2c(CC3CCNCC3)cccc2N1
Product: Cc1ncc2c(OCCN3CCC(Cc4cccc5c4OCC(=O)N5)CC3)cccc2n1

Procedure:
The title compound was prepared from 8-(piperidin-4-ylmethyl)-4H-benzo[1,4]oxazin-3-one and 5-(2-(methanesulphonyloxy)ethoxy)-2-methylquinazoline in a similar manner to Example 1.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C:19]#[N:20])[CH:10]=1)=O)(=[O:3])[CH3:2].C[Si]([N:25]=[N+:26]=[N-:27])(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCOC(C)=O>[C:1]([O:4][CH2:5][C:6]1[N:8]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C:19]#[N:20])[CH:10]=2)[N:27]=[N:26][N:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)Nc1cc(C#N)cc(C(F)(F)F)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)OCc1nnnn1-c1cc(C#N)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 90.7 %

Procedure:
To a solution of 2-{[3-cyano-5-(trifluoromethyl)phenyl]amino}-2-oxoethyl acetate (Intermediate 29, 3.38 g, 11.8 mmol) in tetrahydrofuran (100 mL) was added trimethylsilylazide (3.14 mL, 23.6 mmol), triphenylphosphine (6.20 g, 23.6 mmol) then di-isopropylazodicarboxylate (4.60 mL, 23.6 mmol). The reaction was warmed to 50° C. and stirred for 6 hours. The reaction was cooled and diluted with EtOAc (150 mL). The solution was washed with water (100 mL), passed through a hydrophobic frit and the solvent removed under vacuum. The residue was purified by silica chromatography (Biotage SP4, eluting 10% EtOAc in iso-hexane (4 column volumes) then a gradient from 10-35% EtOAc in iso-hexane (over 8 column volumes)) to yield the title compound as a yellow solid (3.33 g)
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:18](=O)(O)[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:18])=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C=Cc1ccc(Cl)cc1

Procedure:
25.9 g of p-chlorocinnamic acid was dissolved in 250 ml of methanol, to the solution was added 1.5 ml of concentrated sulfuric acid, and the mixture was refluxed for 2 hours. The reaction mixture was poured on ice, and the mixture was alkalized with sodium bicarbonate and extracted twice with 1000 ml of chloroform. The extract was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated to remove the solvent under a reduced pressure, and resulting residue was applied to a silica gel column and eluted with hexane/ethyl acetate (10:1), to obtain 26.5 g of the methyl p-chlorocinnamate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[N:31]=[C:18]4[C:19]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=5)=[CH:20][CH:21]=[CH:22][N:17]4[N:16]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:32][O-:33].[Na+]>CO>[F:30][C:25]1[CH:24]=[C:23]([C:19]2[C:18]3[N:17]([N:16]=[C:15]([NH:14][CH:11]4[CH2:12][CH2:13][N:8]([C:6]5[CH:5]=[CH:4][N:3]=[C:2]([O:33][CH3:32])[N:7]=5)[CH2:9][CH2:10]4)[N:31]=3)[CH:22]=[CH:21][CH:20]=2)[CH:28]=[CH:27][C:26]=1[F:29]
Reactant: C[O-]
Reactant: Fc1ccc(-c2cccn3nc(NC4CCN(c5ccnc(Cl)n5)CC4)nc23)cc1F
Agent: [Na+]
Solvent: CO
Product: COc1nccc(N2CCC(Nc3nc4c(-c5ccc(F)c(F)c5)cccn4n3)CC2)n1
Temperature: 120 °C
Yield: 104.7 %

Procedure:
To a solution of N-(1-(2-chloropyrimidin-4-yl)piperidin-4-yl)-8-(3,4-difluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (example 195) (88 mg, 0.155 mmol) in MeOH (2.0 mL) was added sodium methoxide solution (30% in MeOH, 41 μL, 0.22 mmol) and the reaction mixture was heated in the microwave at 120° C. for 2 h. The mixture was then evaporated. Purification by chromatography (silica gel, 20 g, 0 to 100% methanol in dichloromethane) afforded the title compound (71 mg, 81%) as a white foam.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]=2[N:8]=1)[C:4](O)=[O:5].Cl.Cl.[CH2:26]([O:33][C:34](=[O:46])[NH:35][C:36]([C:38]1[CH:43]=[CH:42][C:41]([CH2:44][NH2:45])=[CH:40][CH:39]=1)=[NH:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([O:33][C:34](=[O:46])/[N:35]=[C:36](/[NH2:37])\[C:38]1[CH:39]=[CH:40][C:41]([CH2:44][NH:45][C:4](=[O:5])[CH:3]([O:2][CH3:1])[C:7]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]=3[N:8]=2)=[CH:42][CH:43]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(C(=O)O)c1nc2ccccc2n1COCC[Si](C)(C)C
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(CN)cc1
Agent: Cl
Product: COC(C(=O)NCc1ccc(/C(N)=N\C(=O)OCc2ccccc2)cc1)c1nc2ccccc2n1COCC[Si](C)(C)C

Procedure:
According to general procedure C, (RS)-methoxy-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-acetic acid was reacted with [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid benzyl ester dihydrochloride (CAS 172348-75-3) to give (RS)-[1-amino-1-[4-({2-methoxy-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-acetylamino}-methyl)-phenyl]-meth-(E)-ylidene]-carbamic acid benzyl ester. Light yellow solid. MS 602.3 ([M+H]+)
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[C:8]([CH3:16])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([CH3:36])[CH:30]=2)[O:26][C:27]=1[CH3:28]>>[CH2:18]([O:17][CH:5]([CH2:6][C:7]1[C:8]([CH3:16])=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:22][C:23]1[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[C:31]([CH3:36])[CH:30]=3)[O:26][C:27]=1[CH3:28])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:20])[CH3:19]
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1C)OCC
Reactant: Cc1cc(-c2nc(CCl)c(C)o2)ccc1F
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccc(F)c(C)c3)oc2C)c1C)C(=O)O

Procedure:
In analogy to the procedure described in example 44, rac-2-ethoxy-3-(4-methyl-1H-indol-5-yl)-propionic acid ethyl ester [preparation 10h)] was reacted with 4-chloromethyl-2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazole to give rac-2-ethoxy-3-{-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethyl]-4-methyl-1H-indol-5-yl}-propionic acid as yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=O.P(Cl)(Cl)([Cl:21])=O>>[Br:1][C:2]1[C:3]2[C:4](=[C:5]([Cl:21])[C:17]3[C:12]([N:11]=2)=[C:13]([Br:18])[CH:14]=[CH:15][CH:16]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1cccc(Br)c1Nc1ccccc1Br
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1c2cccc(Br)c2nc2c(Br)cccc12
Yield: 74 %

Procedure:
A suspension of 7.43 g (20.0 mmol) of 3-bromo-2-(2-bromophenylamino)benzoic acid (XXII) in 19.5 ml (213 mmol) of distilled phosphoryl chloride was heated to reflux for 2.5 h. Subsequently, the excess phosphoryl chloride was distilled off at room temperature under vacuum. The resulting brown oil was dissolved in chloroform, and the solution was added dropwise to ice-cooled diluted aqueous ammonia with stirring. After the mixture had reached room temperature, the phases were separated. The aqueous phase was extracted twice with chloroform, and the combined organic phases were dried over sodium sulfate. The solvent was distilled off under vacuum, and the residue was dried under high vacuum. Fractional sublimation of 7.00 g of raw product under high vacuum yielded 5.5 g (74% of theory) of 4,5-dibromo-9-chloroacridine (XXIII) as an analytically pure yellow solid with a melting point of 195-196° C.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][O:11][C:12]([C@H:14]1[CH2:18][C@H:17](O)[CH2:16][N:15]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:13]>ClCCl>[CH3:10][O:11][C:12]([C@H:14]1[CH2:18][C@@H:17]([F:7])[CH2:16][N:15]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:13]
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)[C@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@@H](F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
Add (diethylamino)sulfur trifluoride (10.5 mL, 80 mmol) to a −78° C. cooled solution of 4-(S)-hydroxypyrrolidine-N1,2-(R)-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (9.83 g, 40 mmol) in dichloromethane (60 mL). Stir 2 h, then remove cooling bath and stir 18 h at room temperature. Heat to reflux for 30 min, then cool in ice bath and add saturated aqueous sodium bicarbonate solution. Warm to room temperature, dry (magnesium sulfate), concentrate (350 mbar, 25° C.) and purify (silica gel chromatography, eluting with diethyl ether and dichloromethane) and then concentrate at 120 mbar at 25° C. to give the title compound as an oil (9.09 g, 92%).
Reaction SMILES: [N:1]#[C:2][NH2:3].[CH3:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1.Cl>[OH-].[Na+].CCOCC>[CH3:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:1][C:2]#[N:3])=[O:10])=[CH:7][CH:6]=1
Reactant: N#CN
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(C(=O)NC#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84908.4 %

Procedure:
To a solution of cyanamide (1.05 g, 0.025 mmol) in 25 ml of sodium hydroxide (10%) was added slowly to a solution of 4-methylbenzoyl chloride (3.3 ml, 0.025 mmol) in ether (8 ml). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture then was cooled in ice bath and acidified with hydrochloric acid (10%) to pH 2. The white solid separated was filtered, washed with water, later hexanes and dried under high vacuum to give the N-(4-methylbenzoyl)cyanamide (3.4 g); m.p. 140–142° C. (lit m.p. 149–150° C.); purity 88% HPLC; 1H-NMR (CD3OD) δ 2.42 (s, 3H, CH3), 7.38 (d, 2H, ArH), 7.78 (d, 2H, ArH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12]O)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CS(Cl)(=O)=O.C(N(CC)CC)C.[CH3:26][NH:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][N:27]([CH2:28][CH2:29][CH2:30][CH3:31])[CH3:26])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCCCNC
Reactant: COC(=O)c1cc(Br)cc(CO)c1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCN(C)Cc1cc(Br)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of methyl 3-bromo-5-(hydroxymethyl)benzoate (4.1 g, 16.8 mmol) in anhydrous methylene chloride (35 mL) at −30° C. is added methanesulfonyl chloride (1.82 mL, 23.5 mmol) followed by triethylamine (4.7 mL, 33.6 mmol). The reaction mixture is stirred for 45 min at 0° C., and then filtered. The filtrate is added to N-methylbutylamine (6 mL, 50.4 mmol) and stirred at room temperature for 16 h. The solution is concentrated under reduced pressure, and the residue is purified by flash column chromatography (silica, 8% ethyl acetate/hexanes) to give the title compound. ESI MS m/z 314.1 [M+H]+.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:34])[N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][C:19]([F:24])=[CH:18][N:17]=2)=O)C>C1(C)C(C)=CC=CC=1>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:34])[N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][C:19]([F:24])=[CH:18][N:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1c(O)c2cc(F)cnc2n(Cc2ccc(OC)cc2)c1=O
Solvent: Cc1ccccc1C
Product: COc1ccc(Cn2c(=O)c(C(=O)NC3CCCCC3)c(O)c3cc(F)cnc32)cc1
Temperature: 140 °C
Yield: 65.4 %

Procedure:
Cyclohexylamine (6.14 mL, 53.65 mmol) was added to a stirred solution of 6-fluoro-4-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (74) (10 g, 26.82 mmol) in xylene and heated at 140° C. for 3 h. The solution was cooled and the solvent was evaporated under vacuum. The residue was suspended in water and extracted by dichloromethane. The combined organic phase was washed by water and brine, then dried over Na2SO4 and evaporated to yield 7.46 g (65%) of 6-fluoro-4-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid cyclohexyl amide (92) as white solids. MP: 176° C.; 1H-NMR (DMSO-d6): δ 1.25-1.41 (m, 5H), 1.54 (m, 1H), 1.66 (m, 2H), 1.87 (m, 2H), 3.68 (s, 3H), 3.86 (m, 1H), 5.51 (s, 2H), 6.81 (d, J=8.8 Hz, 2H), 7.20 (d, J=8.8 Hz, 2H), 8.31 (d, J=8.0 Hz, 1H), 8.83 (s, 1H), 10.24 (s, 1H); EIMS m/z 426 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[N:7]2[C:8]3[O:20][NH:19][C:18](=[O:21])[C:9]=3[C:10](=[O:17])[C:11]3=[CH:12][C:13]([F:16])=[C:14](F)[C:5](=[C:6]23)[O:4][CH2:3]1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>N1C=CC=CC=1>[CH3:1][CH:2]1[N:7]2[C:8]3[O:20][NH:19][C:18](=[O:21])[C:9]=3[C:10](=[O:17])[C:11]3=[CH:12][C:13]([F:16])=[C:14]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)[C:5](=[C:6]23)[O:4][CH2:3]1
Reactant: CC1COc2c(F)c(F)cc3c(=O)c4c(=O)[nH]oc4n1c23
Reactant: CN1CCNCC1
Solvent: c1ccncc1
Product: CC1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c4c(=O)[nH]oc4n1c23
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1.45 g of the preceding isoxazolo-pyrido-benzoxazine derivative (9) (R8 =CH3) in 30 ml pyridine is added in 2.5 ml N-methylpiperazine. It is then heated under nitrogen atmosphere at 50° C. for 24 hours. The mixture is evaporated to dryness and is then boiled in ethanol for 5 minutes and the mixture is filtered and washed with water yielding the 1-methyl-4-(4-methyl-1-piperazinyl)-5-fluoro-1,2,8,9-tetrahydro-7H-isoxazolo[4',5':5,6]pyrido[1,2,3-de][1,4]benzoxazine-7,8-dione (I) ##STR15## R=CH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)[CH:7]=[CH:6][C:4]=1[NH2:5].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)[CH:7]=[CH:6][C:4]=1[NH:5][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc2cc(-c3ccc(N)c(OC)c3)ccc2c1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2cc(-c3ccc(NC(=O)c4ccccc4)c(OC)c3)ccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a solution of 2-methoxy-4-(6-methoxy-2-naphthyl)aniline (82 mg, 0.29 mmol, 1 eq) in 10 ml of dry dichloromethane are added benzoyl chloride (0.1 ml, 123 mg, 0.88 mmol, 3 eq) and trace amounts of DMAP. After stirring for 18 h at RT, the reaction mixture is stopped by adding a 2% sodium carbonate solution, the phases are separated, and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated in vacuum on a rotary evaporator. Purification by column chromatography with a gradient of hexane/ethyl acetate 9/1 to 1/1 yielded the desired product in a yield of 90% (101 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:18][CH2:19][CH:20]=[CH2:21]>CO>[CH:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)=[CH:19][CH2:20][CH3:21]
Reactant: C=CCCBr
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCC=COc1ccc(-c2ccc(O)cc2)cc1
Reaction time: 24 h
Yield: 12 %

Procedure:
A solution containing 4,4'-Dihydroxybiphenyl (5 g,26.75 mmol), KOH (1.65 g, 29.5 mmol) and methanol (50 ml) was refluxed for 2 hours. 4-Bromo-1-butene (3.975 g, 29.5 mmol) in methanol (10 ml) was added dropwise over a period of 2 hours to the refluxing reaction mixture. The refluxation was continued for 24 hours. The solvent was then removed. The product was then extracted by dichloromethane (50 ml) and dichloromethane was then removed. The resulting solid was washed with 10% potassium hydroxide solution (17 ml), filtered and recrystallized from ethanol: water (1.1 v/v) mixture. Yield 12%, m.p. 155-157° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23]([O:25]CC)=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:28][CH2:29][CH:30]([F:32])[F:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:28][CH2:29][CH:30]([F:32])[F:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cnc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC(F)F)C2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ncc(C(=O)O)s3)C[C@H]2OCC(F)F)nc1Cl
Yield: 80.8 %

Procedure:
The same operation as in Example (91d) was performed using ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(2,2-difluoroethoxy)piperidin-1-yl)-1,3-thiazole-5-carboxylate obtained in Example (121g) (0.12 g, 0.24 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (4 mL) and THF (4 mL), to obtain 90 mg of the title compound as a colorless solid (80%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][C:14]([CH2:22][CH2:23][CH3:24])=[CH:15][C:16]=1[C:17](OCC)=[O:18]>>[O:18]=[C:17]1[N:7]2[CH:6]=[C:5]([C:8]([NH2:10])=[O:9])[CH:4]=[CH:3][C:2]2=[N:11][C:12]2[S:13][C:14]([CH2:22][CH2:23][CH3:24])=[CH:15][C:16]1=2
Reactant: CCCc1cc(C(=O)OCC)c(N)s1
Reactant: NC(=O)c1ccc(Cl)nc1
Product: CCCc1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Yield: 312 %

Procedure:
From 4.6 g (0.0029 mol) of 6-chloro-3-pyridinecarboxamide (Aldrich Chemical Company) and 8.6 g (0.040 mol) of 2-amino-5-propyl-3-thiophenecarboxylic acid, ethyl ester, following the procedure of Example 22 there is obtained 2.6 g of 4-oxo-2-propyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp 260-264° C. after recrystallization from pyridine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[O:21])=[CH:16][CH:15]=1.I[CH3:35]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([N:22]([CH3:35])[CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=2)=[O:21])=[CH:18][CH:19]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccc(C(F)(F)F)cc4)cc3)c2)o1
Reactant: CI
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)N(C)Cc4ccc(C(F)(F)F)cc4)cc3)c2)o1

Procedure:
2′-Methyl-N-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(4-trifluoromethylbenzyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(4trifluoromethylbenzyl)-1,1′-biphenyl-4-carboxamide and iodomethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H, d), 7.75,(3H, m), 7.59-7.46,(7H, m), 4.79-4.65,(2H, m), 2.94,(3H, s), 2.55,(3H, s), 2.32,(3H, s). LCMS; retention time 3.67 min, MH+ 466.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:18]>C(OCC)(=O)C>[Cl:18][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=[CH:13][N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Solvent: CCOC(C)=O
Product: Clc1cc(OCc2ccccc2)ccn1
Temperature: 0 °C
Yield: 28 %

Procedure:
4-Benzyloxy-2-pyridone (26.3 g, 0.131 mol) and POCl3 (200 mL) was heated at reflux for 2 h. The mixture was cooled and poured into 1 L of crushed ice and then 500 mL of ethyl acetate was added. The mixture was treated with decolorizing carbon, filtered and then treated with solid potassium carbonate until gas ceased to evolve. The mixture was filtered and the layers were separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were treated with decolorizing carbon, dried (MgSO4), filtered and the solvent was removed in-vacuo. The crude product was chromatographed to give 2-chloro-4-benzyloxypyridine (8 g, 28% yield) as a white solid, mp=91° C. -93° C. Anal. Calcd. for C12H10NO: C,65.61; H,4.59; N,6.38 Found: C,,65.59; H,4.55; N,6.39.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH:18]=[CH2:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:20]([O-])([N+]([O-])=O)=[O:21]>>[Cl:1][CH2:2][CH2:3][N:4]([N:20]=[O:21])[C:5]([N:7]([CH2:17][CH:18]=[CH2:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: C=CCN(C(=O)NCCCl)C1OC[C@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Product: C=CCN(C(=O)N(CCCl)N=O)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 65.4 %

Procedure:
3.2 g of 1-(2-chloroethyl)-3-(2-propenyl)-3-(L-arabinopyranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 31-(2). 2.3 g of 1-(2-chloroethyl)-1-nitroso-3-(2-propenyl)-3-(L-arabinopyranosyl)urea are thereby obtained as yellow caramel.