Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]12[CH2:12][C:6]3([CH3:13])[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([C:14]45[CH2:24][C:18]6([CH3:25])[CH2:19][C:20]([CH3:23])([CH2:22][C:16](Br)([CH2:17]6)[CH2:15]4)[CH2:21]5)([CH2:5]3)[CH2:3]1)[CH2:9]2.[C:27]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O>[OH:33][C:27]1[CH:32]=[CH:31][C:30]([C:2]23[CH2:12][C:6]4([CH3:13])[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([C:14]56[CH2:24][C:18]7([CH3:25])[CH2:19][C:20]([CH3:23])([CH2:22][C:16]([C:30]8[CH:31]=[CH:32][C:27]([OH:33])=[CH:28][CH:29]=8)([CH2:17]7)[CH2:15]5)[CH2:21]6)([CH2:5]4)[CH2:3]2)[CH2:9]3)=[CH:29][CH:28]=1
Reactant: CC12CC3(C)CC(Br)(C1)CC(C14CC5(C)CC(C)(CC(Br)(C5)C1)C4)(C2)C3
Reactant: Oc1ccccc1
Solvent: O
Product: CC12CC3(C)CC(c4ccc(O)cc4)(C1)CC(C14CC5(C)CC(C)(CC(c6ccc(O)cc6)(C5)C1)C4)(C2)C3
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 99.1 %

Procedure:
Into a 5 liter four-necked separable flask equipped with a thermometer, a stirrer, an inlet for nitrogen gas and a reflux condenser, 48.4 g (0.1 mole) of 3,3′-dibromo-5,5′,7,7′-tetramethyl-1,1′-biadamantane and 688 g (7.3 moles) of phenol were placed, and the resultant mixture was heated under the refluxing condition at 155° C. for 30 minutes. After the mixture was cooled at the room temperature, 4.3 liters of pure water was added, and the obtained mixture was heated under the refluxing condition at 80° C. for 10 minutes. The formed precipitates were separated by filtration, and the solid substance was mixed with 7 liters of pure water and stirred for 10 minutes. The solid substance was separated by filtration and dried at 60° C. under a reduced pressure for 24 hours, and 50.6 g of 3,3′-bis(4-hydroxyphenyl)(5,5′,7,7′-tetramethyl)-1,1′-biadamantane was obtained (the yield: 99%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.[OH-].[Na+].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>O1CCOCC1.Cl>[CH2:14]([O:13][C:11]([N:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Reaction time: 18 h
Yield: 73 %

Procedure:
To a solution of azetidine-3-carboxylic acid (5.00 g, 49.5 mmol) in dioxane (325 ml) were added 1N sodium hydroxide (124 ml, 124 mmol) and benzyl chloroformate (8.44 ml, 59.3 mmol). The reaction was allowed to stir for 18 h. The reaction was diluted with 3N HCl until pH 2 was obtained. The product was extracted with EtOAc (2×), washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified via flash chromatography (silica, 0-70% methanol (0.5% acetic acid)/dichloromethane) to yield 1-[(benzyloxy)carbonyl]azetidine-3-carboxylic acid as a yellow oil (73%). 1H NMR (400 MHz, CD3OD) δ 7.37-7.26 (m, 5H), 5.08 (s, 2H), 4.18 (m, 2H), 4.11 (br s, 2H), 3.44 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:10])#[N:2].[N+:11]([O-])([O-:13])=[O:12].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:11]([C:5]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([C:1]#[N:2])[C:4]=1[OH:10])([O-:13])=[O:12]
Reactant: O=[N+]([O-])[O-]
Reactant: N#Cc1c(O)cccc1Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1c(Cl)ccc([N+](=O)[O-])c1O
Reaction time: 24 h
Yield: 28.9 %

Procedure:
2-cyano-3-chlorophenol(2.8 g, 18.3 mmol) was dissolved in methylene chloride(40 ml) followed by the addition of sodium nitrate (1.70 g, 20.1 mmol). The addition of sulfuric acid (15 ml/ 3M) is then made, followed by addition of a catalytic amount of sodium nitrite. The mixture is allowed to stir. After 24 hrs, the reaction mixture is diluted with methylene chloride and extracted with water. The organic layer is dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2Cl2) gave the desired product(1.05 g, 29.2%). 1H NMR (CD3COCD3): δ8.09 (d,1H), 6.55 (d, 1H).
Reaction SMILES: [NH2-].[Na+].[CH3:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[N:20]=[C:19]([C:30](OCC)=[O:31])[C:18]=2[CH3:35])=[CH:13][CH:12]=1.Cl>C1COCC1>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[N:20]=[C:19]([C:30](=[O:31])/[CH:3]=[C:4](\[OH:9])/[C:5]([CH3:8])([CH3:7])[CH3:6])[C:18]=2[CH3:35])=[CH:15][CH:16]=1
Reactant: CC(=O)C(C)(C)C
Reactant: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1C
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(C(=O)/C=C(\O)C(C)(C)C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 37.2 %

Procedure:
To a solution of sodium amide (215 mg, 5.5 mmol) in THF (5 mL) was added pinacolone (1.0 M THF solution, 5 mL, 5.0 mmol). The reaction mixture was refluxed at 80° C. for 30 min and then ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylate (4) (2.05 g, 5.0 mmol) in THF (15 mL) was added. The resulting solution was stirred and refluxed at 80° C. overnight. HCl aquous solution (11.0M, 50 mL) was added and extracted organic layer with ethyl acetate (50 mL twice). The combined organic phase was evaporated under vacuum. The crude residue was further purified by prep HPLC to provide 0.862 g (1.86 mmol, 37%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[CH:11][N:12](C)C)[C:7](=O)[C:6]=2[CH:16]=1.O.[NH2:18]N.C(O)(=O)C>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8]3[CH:11]=[N:12][NH:18][C:7]=3[C:6]=2[CH:16]=1
Reactant: CN(C)C=C1CSc2ccc(Cl)cc2C1=O
Reactant: NN
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc2c(c1)-c1[nH]ncc1CS2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 6-chloro-2,3-dihydro-3-dimethylaminomethylene-4H-1-benzothiopyran-4-one (7 g), hydrazine hydrate (2.01 ml), and acetic acid (2.37 ml) in methanol (140 ml) was stirred at room temperature for 5 hours and then evaporated in vacuo. To the residue was added aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue solid was recrystallized from ethyl acetate to give 8-chloro-1,4-dihydro[1]benzothiopyrano[4,3-c]pyrazole (2.85 g).
Reaction SMILES: [Cl-].[Li+].[CH:3]([O:6][C:7]([N:9]1[CH:14]([CH2:15][CH3:16])[CH:13](C(OCC)=O)[C:12](=[O:22])[C:11]2[S:23][CH:24]=[CH:25][C:10]1=2)=[O:8])([CH3:5])[CH3:4]>CS(C)=O.O>[CH:3]([O:6][C:7]([N:9]1[CH:14]([CH2:15][CH3:16])[CH2:13][C:12](=[O:22])[C:11]2[S:23][CH:24]=[CH:25][C:10]1=2)=[O:8])([CH3:4])[CH3:5]
Reactant: CCOC(=O)C1C(=O)c2sccc2N(C(=O)OC(C)C)C1CC
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CCC1CC(=O)c2sccc2N1C(=O)OC(C)C
Temperature: 160 °C
Yield: 57.7 %

Procedure:
Add lithium chloride (0.162 g, 3.83 mmol) in one portion to a mixture of 5-ethyl-7-oxo-6,7-dihydro-5H-thieno[3,2-b]pyridine-4,6-dicarboxylic acid 6-ethyl ester 4-isopropyl ester (0.520 g, 1.53 mmol) in dimethylsulfoxide (15 ml) and water (2 drops). Heat the mixture at 160° C. for 4 h. Cool the reaction to room temperature and partition between ethyl acetate (50 ml) and brine (50 ml). Separate the organic layer and wash with brine (3×50 ml). Dry the organic portion over sodium sulfate, filter and concentrate. Purify using silica gel column chromatography (gradient eluent, 0-15% ethyl acetate in hexane) to give 5-ethyl-7-oxo-6,7-dihydro-5H-thieno[3,2-b]pyridine-4-carboxylic acid isopropyl ester (0.236 g, 58% for two steps) as an oil. MS (ES+): 268 (M+H).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:2][CH3:3].[C:22]([C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)#[N:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:28][C:27]1[CH:30]=[CH:31][C:24]([C:22]#[N:23])=[CH:25][CH:26]=1)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=1)[CH2:20][CH3:21]
Reactant: CCCN(CCC)CCCCNCc1ccc(C#N)cc1
Reactant: N#Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCN(CCC)CCCCN(Cc1ccc(C#N)cc1)Cc1ccc(C#N)cc1
Temperature: -30 °C
Reaction time: 6 h
Yield: 96.6 %

Procedure:
1.0 g (3.47 mmol, 1.0 equivalent) of 4-[(4-dipropylaminobutyl)amino]methylbenzonitrile (2a), 10 ml of ethanol, and 684 mg (5.21 mmol, 1.5 equivalents) of 4-cyanobenzaldehyde were charged in a 100 ml three-necked flask. The mixture was cooled to −30° C. After the addition of 1.47 g (6.95 mmol, 2.0 equivalents) of sodium triacetoxyborohydride, the mixture was stirred for six hours and further stirred at room temperature for 12 hours. After confirming the disappearance of the raw material, the reaction solution was added into 50 ml of a saturated sodium bicarbonate aqueous solution, and extracted with 100 ml of chloroform. The chloroform layer was washed with 50 ml of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated, thereby obtaining 1.35 g of 4-[(4-dipropylaminobutyl)-4-cyanobenzylamino]methylbenzonitrile (12) as a colorless oily substance (yield: 97%, GC: 87%).
Reaction SMILES: [F:1][CH:2]1[CH:7]([N:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:11]=3[NH:10][C:9]2=[O:21])[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[C:23]1[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([C:30]([C:32]2[CH:42]=[C:41]([CH3:43])[C:35]3[N:36]([CH3:40])[C:37](=[O:39])[O:38][C:34]=3[CH:33]=2)=[O:31])[CH:24]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:40][N:36]1[C:35]2[C:41]([CH3:43])=[CH:42][C:32]([C:30]([C:25]3[N:26]=[C:27]([CH3:29])[N:28]=[C:23]([N:4]4[CH2:5][CH2:6][CH:7]([N:8]5[CH2:14][CH2:13][C:12]6[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:11]=6[NH:10][C:9]5=[O:21])[CH:2]([F:1])[CH2:3]4)[CH:24]=3)=[O:31])=[CH:33][C:34]=2[O:38][C:37]1=[O:39]
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1F)C(=O)N2
Reactant: Cc1nc(Cl)cc(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)nc(C)n3)CC1F)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
82 mg (0.28 mmol) 3-(3-fluoro-piperidin-4-yl)-7-methoxy-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one, 85 mg (0.27 mmol) 6-(6-chloro-2-methyl-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.10 mL (0.56 mmol) DIPEA were combined in 2 mL DMF and stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down. The residue was neutralised with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: C([O:4][CH:5]([CH:7]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:18]([OH:29])[CH:17]=1)[CH2:8][CH2:9][C:10]1C=CC=C[CH:11]=1)[CH3:6])(=O)C.[OH-].[Na+]>CO>[CH2:7]([O:29][C:18]1[CH:17]=[C:16]([CH:7]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:5]([OH:4])[CH3:6])[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(=O)OC(C)C(CCc1ccccc1)c1ccc(Oc2ccccc2)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(O)C(CCc1ccccc1)c1ccc(Oc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 96 %

Procedure:
160 mg of (2RS,3SR)-2-acetoxy-3-(3-hydroxy-4-phenoxyphenyl)-5-phenylpentane was dissolved in 5 ml of methanol, and 2.5 ml of a 1N sodium hydroxide aqueous solution was added, followed by stirring at room temperature for 3.5 hours. The reaction solution was concentrated under reduced pressure, and then, the residue was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract solution was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The drying agent was filtered off. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in 1 ml of methyl ethyl ketone. The solution was added to a suspension having 116 mg of potassium carbonate preliminarily suspended in 3 ml of methyl ethyl ketone, and 58 μl of benzyl bromide was further added at room temperature, followed by stirring under heating at 100° C. for 4 hours. The reaction solution was left to cool, then neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract solution was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The drying agent was filtered off. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain 173 mg (yield: 96%) of the above identified compound as a colorless oily substance.
Reaction SMILES: 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.Br[C:44]1[CH:49]=[CH:48][C:47]([CH:50]2[S:56][CH2:55][CH2:54][NH:53][C:52]3[N:57]([CH3:66])[N:58]=[C:59]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][N:61]=4)[C:51]2=3)=[C:46]([CH3:67])[CH:45]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:74][S:75]([O-:77])=[O:76].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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]>[CH3:66][N:57]1[C:52]2[NH:53][CH2:54][CH2:55][S:56][CH:50]([C:47]3[CH:48]=[CH:49][C:44]([S:75]([CH3:74])(=[O:77])=[O:76])=[CH:45][C:46]=3[CH3:67])[C:51]=2[C:59]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][N:61]=2)=[N:58]1
Reactant: CS(=O)[O-]
Reactant: Cc1cc(Br)ccc1C1SCCNc2c1c(-c1ccccn1)nn2C
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
Solvent: CCOC(C)=O
Product: Cc1cc(S(C)(=O)=O)ccc1C1SCCNc2c1c(-c1ccccn1)nn2C
Temperature: 120 °C
Yield: 3.8 %

Procedure:
To a degassed solution of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.057 g, 0.1 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.045 g, 0.025 mmol) in toluene (6 mL) was added 4-(4-bromo-2-methyl-phenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.400 g, 0.96 mmol, Example #4 step D), cesium carbonate (0.470 g, 1.5 mmol) and sodium methanesulfinate (0.118 g, 1.2 mmol). The resulting mixture was heated at about 120° C. overnight. After cooling to rt, the mixture was diluted with ethyl acetate (50 mL), washed with water (20 mL) and brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, DCM/methanol 1:1) followed by prep-HPLC (Table 2, Method b) to give 1-methyl-4-(2-methyl-4-methylsulfonyl-phenyl)-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.015 g, 0.036 mmol, 3%) as an off white solid: LC-MS (Table 1, Method a) Rt=2.98 min; m/z 415 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.65-2.73 (1H, m) 2.70 (3H, s) 2.81 (1H, ddd, J=15.0, 9.3, 2.4 Hz) 3.01 (3H, s) 3.23-3.32 (1H, m) 3.61-3.71 (1H, m) 3.84 (3H, s) 3.86 (1H, br s) 6.79 (1H, s) 7.09 (1H, ddd, J=7.4, 5.1, 1.0 Hz) 7.40 (1H, d, J=8.1 Hz) 7.58-7.64 (2H, m) 7.73 (1H, d, J=1.6 Hz) 7.86 (1H, d, J=8.0 Hz) 8.44 (1H, d, J=4.8 Hz).
Reaction SMILES: COC([N:5]1[N:15](C(OC)=O)[CH:14]2[CH:6]1[CH:7]1[CH:20]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:12]3([CH2:13]2)[CH:8]1[N:9]=[N:10][N:11]3[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)=O.[OH-].[Na+].[O-]Cl.[Na+]>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([N:11]2[N:10]=[N:9][CH:8]3[C:12]42[CH:20]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:7]3[CH:6]2[CH:14]([N:15]=[N:5]2)[CH2:13]4)=[CH:27][CH:28]=1
Reactant: COC(=O)N1C2CC34C(N=NN3c3ccc(Cl)cc3)C(C2N1C(=O)OC)C4OC(C)(C)C
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Product: CC(C)(C)OC1C2C3N=NC3CC13C2N=NN3c1ccc(Cl)cc1
Temperature: 85 °C
Reaction time: 6 h

Procedure:
400 parts of 3,4-dimethoxycarbonyl-8-(4-chlorophenyl)-12-t-butoxy-3,4,8,9,10-pentazatetracyclo[5,4,1,02,5,07,11 ]dodec-9-ene (Compound No. 9) were suspended in 1,000 parts of 25 percent strength aqueous sodium hydroxide solution, and the suspension was stirred for 6 hours at 85° C. Thereafter, 1,150 parts of 13 percent strength aqueous NaOCl were added at 60° C. in the course of 2 hours, and stirring was continued for 4 hours at 60° C. The mixture was cooled to 20° C., after which the solid product was filtered off under suction, washed with 3,000 parts of water and dried at 30° C. under 1 mbar. 270 parts (96 mole %) of 8-(4-chlorophenyl)-12-t-butoxy-3,4,8,9,10-pentazatetracyclo[5,4,1,02,5,07,11 ]dodeca-3,9-diene of melting point 178° C. (decomposition) were obtained (Compound No. 2). ##STR21##
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[C:22](=[O:23])[C:21]3[C:24]([CH3:31])=[C:25]([C:28](O)=[O:29])[CH:26]=[CH:27][C:20]=3[O:19][CH2:18][CH2:17]2)=[C:13]([CH3:32])[CH:12]=[C:11]([CH3:33])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:35][NH:36]C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[C:22](=[O:23])[C:21]3[C:24]([CH3:31])=[C:25]([C:28]([NH:36][CH3:35])=[O:29])[CH:26]=[CH:27][C:20]=3[O:19][CH2:18][CH2:17]2)=[C:13]([CH3:32])[CH:12]=[C:11]([CH3:33])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(CN2CCOc3ccc(C(=O)O)c(C)c3C2=O)c(OCc2ccccc2)n1
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc2c(c1C)C(=O)N(Cc1c(C)cc(C)nc1OCc1ccccc1)CCO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 74445.7 %

Procedure:
To a solution of 4-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-6-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-carboxylic acid (130f, 0.17 g, 0.38 mmol), dimethylamine hydrochloride (47 mg, 0.57 mmol) and DIPEA (0.25 g, 1.90 mmol) in DMF (10 mL) was added HATU (0.29 g, 0.76 mmol). The mixture was stirred at room temperature under N2 for 5 hours. To the reaction mixture was added H2O (30 mL). The mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (4×30 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc, 1/1) to give 4-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-N,6-dimethyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-carboxamide (130 g, 0.17 g, 94.6%) as a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([CH:23]([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:2]=[CH2:3].[O-][CH2:31]C.[Na+].CI>CCOCC>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([CH:23]([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:31])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:2]=[CH2:3]
Reactant: CC[O-]
Reactant: C=CCOc1ccccc1C(C(OCC)OCC)C(C(=O)OCC)C(=O)OCC
Agent: [Na+]
Solvent: CCOCC
Solvent: CI
Product: C=CCOc1ccccc1C(C(OCC)OCC)C(C)(C(=O)OCC)C(=O)OCC

Procedure:
A solution of ethyl 3-(2-allyloxyphenyl)-4,4-diethoxy-2-ethoxycarbonylbutanoate (described in Example 1(i)), in ether is treated with sodium ethoxide and subsequently with methyl iodide to give ethyl 3-(2-allyloxyphenyl)-4,4-diethoxy-2-ethoxycarbonyl-2-methylbutanoate, which is subsequently reacted in a manner similar to that described in Example 1(i) to give 4-(2-allyloxyphenyl)-5-ethoxy-3-methyl-2-oxotetrahydrofuran.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)(=O)C.[NH4+].[OH-]>CO>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:8]2[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([OH:4])[CH:6]=3)[N:11]=[CH:10][N:9]=2)=[CH:23][CH:22]=1
Reactant: COc1cc2ncnc(Nc3ccc(Cl)cc3)c2cc1OC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2ncnc(Nc3ccc(Cl)cc3)c2cc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6-acetoxy-4-(4-chloro-phenylamino)-7-methoxy-quinazoline (1.4 g, 4.07 mmol) (from Example 16, Step A, supra) in MeOH (35 mL) was added an aqueous solution of NH4OH (29%, 0.82 mL, 12.2 mmol). The reaction mixture was stirred at room temperature for 18 hours, then heated at 100° C. for 1.5 hours. The mixture was then cooled to room temperature and filtered. The precipitate was collected and dried in vacuo to give the desired 4-(4-chloro-phenylamino)-7-methoxy-quinazolin-6-ol as a gray solid. (Yield 0.67 g, 55%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([N:17]([CH2:27][CH3:28])[C:18](=[O:26])[C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)[CH3:16].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:22]2[CH:23]=[CH:24][C:19]([C:18]([N:17]([CH2:15][CH3:16])[CH2:27][CH3:28])=[O:26])=[CH:20][CH:21]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CCN(CC)C(=O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1ccc(NC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 80 °C
Yield: 77 %

Procedure:
To a dry flask containing 1-benzyl-piperidin-4-ylamine 6 (5.0 mL; 1.2 eq) in dry toluene (75 mL) was added N,N-diethyl-4-bromobenzamide (5.24 g; 1.0 eq), BINAP (383 mg; 0.03 eq), palladium acetate (92 mg; 0.02 eq) and sodium tert-butoxide (2.75 g; 1.4 eq). The reaction was heated to 80° C. under nitrogen. After 2 hours the reaction was cooled, diluted with ethyl acetate and washed with two portions water. The organics were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography eluting with 5% to 10% methanol in dichloromethane. The residue obtained was boiled in ethyl acetate, cooled and collected by filtration. A pale yellow solid was obtained (5.724 g; 77% yield).
Reaction SMILES: C(O[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])C.C(OCC)(=O)C.[CH3:19][NH2:20]>CO>[CH3:19][NH:20][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: CCOc1ccncc1[N+](=O)[O-]
Reactant: CN
Solvent: CO
Solvent: CCOC(C)=O
Product: CNc1ccncc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
4-Ethoxy-3-nitropyridine (10.0 g) was dissolved in a 40% methanol solution of methyl amine (100 mL), and this was heated at 80° C. for 60 hours. The solution was cooled, ethyl acetate (500 mL) was added, and the organic layer was washed twice with 300 mL of water and once with 300 mL of saturated aqueous sodium chloride solution. This was then dried over anhydrous magnesium sulfate. The solution was filtered, and concentrated under reduced pressure to give the title compound (7.00 g).