Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:10][C:9]([CH2:11][OH:12])=[N:8][CH:7]=1.O[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)=[CH:16][CH:15]=1>>[N:23]1([CH2:22][CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([O:12][CH2:11][C:9]3[S:10][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[CH:7][N:8]=3)=[CH:15][CH:16]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: OCc1ncc(-c2cccs2)s1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: c1csc(-c2cnc(COc3ccc(CCCn4ccnc4)cc3)s2)c1
Yield: 66 %

Procedure:
In substantially the same manner as in Working Example 146, 5-(2-thienyl)-2-thiazolylmethanol was mesylated and then reacted with 1-[3-(4-hydroxyphenyl)propyl]imidazole to obtain 2-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-5-(2-thienyl)thiazole. The yield was 66%. Recrystallization from ethyl acetate-hexane gave orange prisms, mp 82-84° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]1(=[O:23])[O:22][C:20](=[O:21])[CH:19]=[CH:18]1>C1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([NH:11][C:17](=[O:23])/[CH:18]=[CH:19]\[C:20]([OH:22])=[O:21])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: O=C1C=CC(=O)O1
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(NC(=O)/C=C\C(=O)O)cc(C(C)(C)C)c1O
Reaction time: 2 h

Procedure:
N-(3,5-di tert.butyl-4-hydroxyphenyl)maleamic acid was prepared by adding to the benzene solution of 2,6-di tert.butyl-4-aminophenol in 15 minutes at 15° C. to 31° C. a solution of 9.8 grams of maleic anhydride in 50 milliliters of benzene. The mixture was stirred for 2 hours and the solid product was filtered off and dried. The yield was 19.5 grams and the product melted at 206° C. to 207° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH:9](O)[CH3:10])[C:3]=1[OH:12].[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]([C:18]2[CH:19]=[C:14]([F:13])[CH:15]=[CH:16][C:17]=2[OH:20])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(O)c1cc(Cl)cc(Cl)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(c1cc(F)ccc1O)c1cc(Cl)cc(Cl)c1O
Reaction time: 0.5 h

Procedure:
2,4-Dichloro-6-(1'-hydroxyethyl)phenol (10 g) was added in small portions to a melt of 4-fluoro phenol containing a trace of p-toluenesulphonic acid at 90° over a half hour period. The reaction mixture was stirred for a further 1/2 hr and cooled. The crystallization from benzene gave 1-(3,5-dichloro-2-hydroxyphenyl)-1-(5-fluoro-2-hydroxy phenyl) ethane (11 g, m.p. 150°).
Reaction SMILES: [NH2:1][C:2]12[C:8]([CH3:10])([CH3:9])[C:5]([CH3:11])([CH2:6][CH2:7]1)[C:4](=[O:12])[CH2:3]2.Cl[C:14]1[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([NH2:21])[C:15]=1[N+:22]([O-:24])=[O:23].CCN(C(C)C)C(C)C>CC(O)C>[NH2:21][C:16]1[C:15]([N+:22]([O-:24])=[O:23])=[C:14]([NH:1][C:2]23[C:8]([CH3:9])([CH3:10])[C:5]([CH3:11])([CH2:6][CH2:7]2)[C:4](=[O:12])[CH2:3]3)[C:19]([Cl:20])=[CH:18][N:17]=1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Reactant: CC12CCC(N)(CC1=O)C2(C)C
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC12CCC(Nc3c(Cl)cnc(N)c3[N+](=O)[O-])(CC1=O)C2(C)C
Temperature: 60 °C
Yield: 100 %

Procedure:
4-amino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (8) (1.1 g, 5.29 mmol)) and 4,5-dichloro-3-nitropyridin-2-amine (1 g, 4.81 mmol) were taken in IPA (30 ml) and DIPEA (4.6 ml, 26.44 mmol)) was added to the reaction mixture which was then heated at 60° C. for 24 h when TLC confirmed completion of reaction. The reaction mixture was cooled to rt and concentrated in vacuuo. Pure product (9) (1.63 g, 92%) was obtained as a yellow solid after purification by column chromatography using silica gel (100-200 mesh). NMR: δ (1H, 400 MHz, CDCl3): 0.87 (3H, s), 0.97 (3H, s), 1.05 (3H, s), 1.44-1.54 (1H, m), 1.70-1.80 (1H, m), 1.90-2.20 (1H, m), 2.30-2.40 (1H, m), 2.47 (1H, dd, J=3.2, 18.0 Hz), 2.88 (1H, d, J=18.4 Hz), 6.55 (2H, s), 7.85 (1H, s), 7.96 (1H, s) LCMS: (254 nm): [M+H]+ 339.10 (86.27%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[OH-].[K+].I[CH2:19][CH2:20][CH3:21]>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:19][CH2:20][CH3:21]
Reactant: c1ccc(CNCc2ccccn2)nc1
Reactant: CCCI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCN(Cc1ccccn1)Cc1ccccn1
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To a flask were added 1.0 g di-(2-picolyl)amine, 0.85 g of pulverized potassium hydroxide and 15 ml of N,N-dimethylformamide. After stirring for 1 hour under nitrogen, the mixture was cooled to 5 C and 1.7 g of 1-iodopropane were added. The mixture was heated to 35 C and stirred for 16 hours. After quenching with 30 ml water, the product was extracted with ethyl acetate and washed twice with water. Following removal of solvent, the product was purified by silica gel chromatography using ethyl acetate to give 0.65 g of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](OS(C(F)(F)F)(=O)=O)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:7]2[CH3:21].[Si]([O:37][C:38]([O:40][CH3:41])=[CH2:39])(C(C)(C)C)(C)C.C([O-])(=O)C.[Na+]>CN(C)C=O.C(OCC)(=O)C.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:41][O:40][C:38](=[O:37])[CH2:39][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:21])=[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:9]([CH3:12])=[N:10]2
Reactant: C=C(OC)O[Si](C)(C)C(C)(C)C
Reactant: Cc1nc2c(Cl)ccc(OS(=O)(=O)C(F)(F)F)c2c(C)c1Cc1ccc(Cl)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(Cl)c2nc(C)c(Cc3ccc(Cl)cc3)c(C)c12
Temperature: 120 °C

Procedure:
A mixture of trifluoromethanesulfonic acid 8-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinolin-5-yl ester (0.24 g), 1-(tert-butyldimethylsilyloxy)-1-methoxyethene (0.56 mL), sodium acetate (0.053 g), tris(dibenzylideneacetone) dipalladium (0) (0.024 g) and 1,1′-bis(diphenylphospino) ferrocene (0) (0.014 g) in N,N-dimethylformamide (2 mL) was heated by microwave irradiation at 120° C. for 10 minutes. The mixture was diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride solution and then dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:9 to 1:6 by volume) to afford title compound as a pink solid, 0.12 g.
Reaction SMILES: [BH4-].[Na+].[BH4-].[Li+].[O:5]1[C@H:7]2[CH:8]([OH:39])[CH2:9][C@H:10]3[C@:31]([CH3:32])([C@@H:6]12)[C@@H:30]1[C@H:13]([C@H:14]2[C@:27]([CH3:33])([CH2:28][CH2:29]1)[C@@H:17]([C@H:18]([CH3:26])[CH2:19][CH2:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[CH2:12][C@H:11]3[O:34][S:35]([CH3:38])(=[O:37])=[O:36].O>O1CCCC1>[OH:5][C@@H:6]1[C@@:31]2([CH3:32])[C@@H:10]([C@H:11]([O:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH2:12][C@@H:13]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:33])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[C@H:18]([CH3:26])[CH2:19][CH2:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])[CH2:9][CH:8]([OH:39])[CH2:7]1
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3C[C@@H](OS(C)(=O)=O)[C@H]4CC(O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3C[C@@H](OS(C)(=O)=O)[C@H]4CC(O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 10.9 %

Procedure:
To a mixture of 1-molar diborane-tetrahydrofuran complex (not stabilized with sodium borohydride, 157 ml) and lithium borohydride (3.4 g, 0.155 mole) cooled in an ice bath was added dropwise over about 25 minutes a solution of 1α,2α-epoxy-25-hydroxy-6β-methylsulfonyloxy-5α-cholestan-3-ol (20.0 g, 0.392 mole) in tetrahydrofuran (100 ml) with stirring under nitrogen. The suspension was stirred at 0° for about 6 hours, and then stored in a refrigerator (ca. 30° C) overnight. Water (200 ml) was added cautiously to the reaction mixture cooled in an ice bath. An additional 200 ml of water was added to the turbid solution and the solution was extracted with methylene chloride. The layers were separated and the organic phase was washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. Evaporation of the filtrate gave 22 g of 1α,25-dihydroxy-6β-methylsulfonyloxy-5α-cholestan-3-ol as a white foam.
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][C@H:13](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][C@H:11]2[CH2:26]Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:29][NH2:30]>CO>[C:1]1([CH3:28])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][C@@H:13]3[CH2:12][C@H:11]2[CH2:26][N:30]3[CH3:29])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](CCl)N(S(=O)(=O)c3ccc(C)cc3)C2)cc1
Reactant: CN
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2C[C@@H]3C[C@H]2CN3C)cc1
Temperature: 90 °C
Yield: 76 %

Procedure:
A Parr bottle was charged with 3.8 g (8.56 mmol) of (2S, 4R)-1-(4-toluenesulfonyl)-2-(chloromethyl)-4-(4-toluenesulfonyloxy)-pyrrolidine and 25 ml of methanol and the bottle was then tared. Methylamine gas was bubbled through the methanol solution until 2.65 g (85.6 mmol) of the gas had dissolved. The bottle was then sealed and heated to 90° C. After heating for 16 hours the reaction was cooled and the solvent was evaporated at reduced pressure. The residual solids were then partitioned between 50 ml of methylene chloride and 40 ml of 10% aqueous sodium hydroxide solution. The layers were separated and the organic layer was washed with 30 additional ml of 10% aqueous sodium hydroxide solution, and then dried over sodium sulfate. Evaporation of the solvent under reduced pressure provided 1.73 g of the desired product which represents a 76% yield. M.P.=87°-88° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C@H:8]1[CH2:13][C@@H:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH2:11][C:10]([CH3:26])([CH3:25])[CH2:9]1.[Br:27][C:28]1[N:33]=[C:32]([C:34](O)=[O:35])[CH:31]=[CH:30][C:29]=1[F:37]>CCOC(C)=O>[Br:27][C:28]1[N:33]=[C:32]([C:34]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C@H:8]2[CH2:13][C@@H:12]([N:14]3[C:15](=[O:24])[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:22]3=[O:23])[CH2:11][C:10]([CH3:26])([CH3:25])[CH2:9]2)=[O:35])[CH:31]=[CH:30][C:29]=1[F:37]
Reactant: O=C(O)c1ccc(F)c(Br)n1
Reactant: CC1(C)C[C@@H](c2ccncc2N)C[C@@H](N2C(=O)c3ccccc3C2=O)C1
Solvent: CCOC(C)=O
Product: CC1(C)C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(Br)n2)C[C@@H](N2C(=O)c3ccccc3C2=O)C1

Procedure:
Following Method 9, 2-((1R,5R)-5-(3-aminopyridin-4-yl)-3,3-dimethylcyclohexyl)isoindoline-1,3-dione and 6-bromo-5-fluoropicolinic acid were coupled and following addition of EtOAc and washing with H2O, NaCl(sat.) and drying over MgSO4, 6-bromo-N-(4-((1R,5R)-5-(1,3-dioxoisoindolin-2-yl)-3,3-dimethylcyclohexyl)pyridin-3-yl)-5-fluoropicolinamide was obtained. LCMS (m/z): 551/553 (MH+), Rt=0.95 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([C:23]#[N:24])[C:20]=1[O:21]C)[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:17])(=[O:16])[CH2:8]1)=[O:6].[Cl-].[Li+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([C:23]#[N:24])[C:20]=1[OH:21])[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9](=[O:16])(=[O:17])[CH2:8]1)=[O:6]
Reactant: COc1c(Cl)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1C#N
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(Cl)c1O
Temperature: 100 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
3-(3-chloro-5-cyano-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (180 mg) was dissolved in N,N-dimethylformamide (2 mL), and lithium chloride (87 mg) was added to the solution, and then the mixture was stirred at 100° C. for 1 hour. To the reaction solution, 1N hydrochloric acid was added, and then reaction mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from n-hexane-chloroform to obtain the title compound (146 mg) as a pale yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:39]=[C:40](F)[CH:41]=1)[C:25]([C:27]1[CH:37]=[C:36]([CH3:38])[C:30]2[N:31]([CH3:35])[C:32](=[O:34])[O:33][C:29]=2[CH:28]=1)=[O:26]>CN(C=O)C>[CH3:35][N:31]1[C:30]2[C:36]([CH3:38])=[CH:37][C:27]([C:25]([C:24]3[CH:39]=[C:40]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:41]=[C:22]([F:21])[CH:23]=3)=[O:26])=[CH:28][C:29]=2[O:33][C:32]1=[O:34]
Reactant: Cc1cc(C(=O)c2cc(F)cc(F)c2)cc2oc(=O)n(C)c12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(F)cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)c3)CC1)C(=O)N2
Temperature: 300 °C

Procedure:
440 mg (1.60 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 121 mg (0.40 mmol) 6-(3,5-difluoro-benzoyl)-3,4-dimethyl-3H-benzoxazol-2-one were combined and heated to 300° C. for approx. 10 min using the hot gun. Then the mixture was dissolved in DMF and purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down. The residue was neutralised with 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [CH2:1]([N:3]([CH2:9][CH3:10])[CH2:4][C:5](OC)=[O:6])[CH3:2].[NH2:11][NH2:12]>C(O)C>[NH2:11][NH:12][C:5](=[O:6])[CH2:4][N:3]([CH2:9][CH3:10])[CH2:1][CH3:2]
Reactant: CCN(CC)CC(=O)OC
Reactant: NN
Solvent: CCO
Product: CCN(CC)CC(=O)NN

Procedure:
To a solution of methyl 2-(diethylamino)acetate (4.167 mL, 27.55 mmol) in 4 mL of anhydrous ethanol was added anhydrous hydrazine (1.336 mL, 27.55 mmol). The solution was heated to reflux temperature overnight. The solvent was then removed under reduced pressure and the product was isolated as an oil in a quantitative yield and was used without further purification: 1H NMR (CDCl3) δ 8.3 (br s, 1H), 3.83 (br s, 2H), 3.08 (s, 2H), 2.51 (q, 4H), 1.00 (t, 6H); ES-MS (m/z) 146 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:23][C:10]2[N:11]=[CH:12][N:13]=[C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[C:9]=2[CH:8]=1.C1([O:30][C:31](=O)[NH:32][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)C=CC=CC=1>CS(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:23][C:10]2[N:11]=[CH:12][N:13]=[C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:31]([NH:32][C:33]4[S:34][CH:35]=[CH:36][N:37]=4)=[O:30])=[CH:18][CH:17]=3)[C:9]=2[CH:8]=1
Reactant: Nc1ccc(Oc2ncnc3[nH]c(-c4ccccn4)cc23)cc1
Reactant: O=C(Nc1nccs1)Oc1ccccc1
Solvent: CS(C)=O
Product: O=C(Nc1ccc(Oc2ncnc3[nH]c(-c4ccccn4)cc23)cc1)Nc1nccs1
Yield: 77.7 %

Procedure:
4-(6-(Pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenylamine (100 mg) and (thiazol-2-yl)carbamic acid phenyl ester (116 mg) were heated and stirred in dimethylsulfoxide (2.5 ml) at 80° C. for 1 hour, in the same manner as Example 224, to obtain the title compound (110 mg) as a solid.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([CH3:24])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9](C(OCC)=O)[C:8]1=[O:23].Cl>O1CCOCC1>[CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([CH3:24])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[CH:9][C:8]1=[O:23]
Reactant: CCOC(=O)C1=C(O)c2ccccc2C(C)(CCCCC(C)(C)C)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)CCCCC1(C)C(=O)C=C(O)c2ccccc21
Temperature: 25 °C
Yield: 72.1 %

Procedure:
A solution of Example 35F (1.84 g, 5.13 mmol) in 1,4-dioxane (20 mL) was treated with aqueous 1N hydrochloric acid solution (20 mL) and refluxed for 3 hours. The mixture was cooled to 25° C. and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated in hot hexane and filtered. The precipitate was dried to give the title compound (1.06 g, 72%). 1H NMR (300 MHz, CDCl3) δ ppm 0.57 (m, 1 H) 0.75 (s, 4.5 H) 0.80 (s, 4.5 H) 1.02 (m, 5 H) 1.51 (s, 1.5 H) 1.56 (s, 1.5 H) 1.84 (m, 1 H) 2.04 (m, 0.5 H) 2.25 (m, 0.5 H) 3.74 (s, 0.5 H) 3.75 (s, 0.5 H) 6.00 (s, 0.5 H) 7.51 (m, 3 H) 8.09 (m, 1 H). (ESI+) m/z 287 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[NH:14][C:13](=[O:15])[O:12][C:10](=O)[C:9]=12)([O-:3])=[O:2].[NH:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1C(O)=O>CS(C)=O.C(O)C>[N+:1]([C:4]1[C:9]2[C:10](=[O:12])[N:16]3[CH2:23][CH2:22][CH2:21][C@H:17]3[C:13](=[O:15])[NH:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=c1[nH]c2cccc([N+](=O)[O-])c2c(=O)o1
Solvent: CS(C)=O
Solvent: CCO
Product: O=C1Nc2cccc([N+](=O)[O-])c2C(=O)N2CCC[C@@H]12

Procedure:
10.6 g (50.9 mmol) of 6-nitroisatoic acid anhydride and 6.1 g (50.9 mmol) of L-proline in 70 ml of dimethyl sulphoxide are heated to 90° for 45 minutes, the mixture is subsequently evaporated in a high vacuum and the residue obtained is heated to 140° for 4 hours. The crystalline crude product is taken up in 100 ml of boiling ethanol, left to stand in the cold overnight, the material obtained is filtered off under suction while back-washing with cold ethanol and dried to constant weight. There is obtained (S)-1,2,3,11a-tetrahydro-6-nitro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione which has a decomposition point of 235°-237°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][C:6]=2[CH:15]=1.S(=O)(=O)(O)O.[CH3:21]O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:21])=[O:13])=[CH:7][C:6]=2[CH:15]=1
Reactant: CO
Reactant: O=C(O)C1=Cc2cc(Br)ccc2NCC1
Agent: O=S(=O)(O)O
Product: COC(=O)C1=Cc2cc(Br)ccc2NCC1
Temperature: 80 °C

Procedure:
To a suspension of 7-bromo-2,3-dihydro-1-benzazepine-4-carboxylic acid (68.2 g) in methanol (100 ml) was added concentrated sulfuric acid (37.3 g) at 0° C., and the mixture was heated at 80° C. for 10 hours. After allowing to cool, the solvent was evaporated under reduced pressure. Ethyl acetate and water were added thereto and 1N sodium hydroxide solution was added to pH=4 at 0° C. The solution was separated, and the organic phase was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was subjected to silica gel column to remove origin components (ethyl acetate), and the resulting solid was washed with diisopropyl ether to give methyl 7-bromo-2,3-dihydro-1-benzazepine-4-carboxylate (44.0 g). The filtrate was purified with silica gel column (hexane:ethyl acetate=4:1) to give methyl 7-bromo-2,3-dihydro-1-benzazepine-4-carboxylate (3.4 g).
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:4]=1[O:5][CH:6]([CH3:11])[C:7]([O:9][CH3:10])=[O:8])=[O:2].[BH4-].[Na+].Cl>CO.C[O-].[Na+]>[OH:2][CH2:1][C:3]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:4]=1[O:5][CH:6]([CH3:11])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C(C)Oc1cc(C)ccc1C=O
Agent: C[O-]
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: COC(=O)C(C)Oc1cc(C)ccc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
To a solution of 7.89 g (0.0355 mole) of methyl 2-(2-formyl-5-methylphenoxy)propionate in 20 mL of methanol, cooled to 5° C., was added a solution of 0.10 g (0.0018 mole) of sodium methoxide in 20 mL of methanol. While the temperature was maintained between 0° C. and 5° C., 0.36 g (0.0094 mole) of sodium borohydride was added to the reaction during a period of about 10 minutes. The reaction mixture was allowed to warm to ambient temperature, where it was stirred for two hours. At the end of this period, the reaction mixture was poured into 75 mL of 0.25N hydrochloric acid. This mixture was extracted twice with methylene chloride. The combined extracts were washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure, leaving a colorless oil as a residue. This oil was placed on a silica gel column and eluted first with methylene chloride/ethyl acetate (95/5) and then with the same solvents (90/10). After the product-containing fractions were combined and the solvents evaporated under reduced pressure, 5.76 g of methyl 2-(2-hydroxymethyl-5-methylphenoxy)propionate was isolated as a colorless oil. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:19]=1[NH2:20]>>[CH3:16][O:17][C:18]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:19]=1[NH:20][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: COc1ccc(OC)c(N)c1
Reactant: COc1cnc(-c2ccccn2)nc1Cl
Product: COc1ccc(OC)c(Nc2nc(-c3ccccn3)ncc2OC)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-5-methoxy-2-(2-pyridinyl)pyrimidine (50 mg, 0.226 mmol) and 2,5-dimethoxyaniline (35 mg, 0.226 mmol) similar to Example 11 and isolated as a gray solid (46 mg, 61%). 1H NMR (CDCl3): 8.77-8.74 (m, 1H), 8.72 (d, J=3.0 Hz, 1H), 8.43 (d, J=8.1 Hz, 1H), 8.10 (s, 1H), 8.03 (s, 1H), 7.83-7.77 (m, 1H), 7.33-7.29 (m, 1H), 6.84 (d, J=8.7 Hz, 1H), 6.56 (dd, J=3.0, 8.7 Hz, 1H), 4.04 (s, 3H), 3.90 (s, 3H), 3.89 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16]([NH2:19])[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].CN(C)[CH:22]=[O:23].C(OC(=O)C)(=O)C>C(O)=O>[CH3:9][N:8]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][N:6]=[C:7]1[C:10]1[N:14]2[N:15]=[C:16]([NH:19][CH:22]=[O:23])[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N)nn12
Reactant: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(NC=O)nn12

Procedure:
100 mg. 3-(5-nitro-1-methyl-2-imidazolyl)-6-amino-s-triazolo [4,3-b]pyridazine were suspended in 1.3 ml. dimethyl formamide and, after the addition of 1.5 ml. of the mixed anhydride obtainable from formic acid and acetic anhydride, stirred at ambient temperature until no more starting material could be detected by thin layer chromatography. The almost clear solution thus obtained was, after filtration, evaporated in a vacuum and the residue brought to crystallization with ether. There were thus obtained 72 mg. (65 percent of theory) 3-(1-methyl-5-nitro-2-imidazolyl)-6-formylamino-s-triazolo[4,3-b]pyridazine in the form of yellowish crystals which melt, with decomposition, at 200° - 204° C.