Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4]1[CH:5]=[C:6]([OH:19])[C:7](=[CH:17][CH:18]=1)[CH:8]=[N:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[NH2:16])[CH3:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([OH:32])[C:27](=[CH:30][CH:31]=1)[CH:28]=O>C(O)C>[CH2:20]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[C:6]([OH:19])[C:7](=[CH:17][CH:18]=1)[CH:8]=[N:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[N:16]=[CH:28][C:27]1[C:26](=[CH:25][C:24]([O:23][CH3:22])=[CH:31][CH:30]=1)[OH:32])[CH3:21]
Reactant: CCN(CC)c1ccc(C=N[C@@H]2CCCC[C@H]2N)c(O)c1
Reactant: COc1ccc(C=O)c(O)c1
Solvent: CCO
Product: CCN(CC)c1ccc(C=N[C@@H]2CCCC[C@H]2N=Cc2ccc(OC)cc2O)c(O)c1
Temperature: 60 °C

Procedure:
To a suspension of 2.5 g (8.64 mmol) of (R,R)-N-mono[4-(diethylamino)salicylidene]-1,2-cyclohexanediamine in 200 ml of ethanol is added dropwise over the course of 45 minutes at room temperature a solution of 1.3 g (8.64 mmol) of 4-methoxysalicylaldehyde in 200 ml of ethanol. The reaction solution is heated at 60° C. for 4 h. After the reaction solution has been cooled to room temperature it is concentrated to dryness. The crude product obtained is purified by column chromatography (ethyl acetate/methanol 9:1). Yield: 500 mg (14%), reddish orange oil, which slowly crystallizes.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]([Cl:13])[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([OH:15])[C:6]([OH:14])=[N:7]2.[CH:16](O)=O>O>[Cl:13][C:10]1[CH:9]=[C:8]2[C:3]([N:4]=[C:5]([OH:15])[C:6]([OH:14])=[N:7]2)=[C:2]2[NH:1][CH:16]=[N:12][C:11]=12
Reactant: Nc1c(Cl)cc2nc(O)c(O)nc2c1N
Reactant: O=CO
Solvent: O
Product: Oc1nc2cc(Cl)c3nc[nH]c3c2nc1O
Temperature: 25 °C
Yield: 67 %

Procedure:
A mixture of 0,3 g (1,35 mmol) 5,6-diamino-7-chloro-2,3-dihydroxyquinoxaline and 8 ml formic acid was refluxed for 2 h. After cooling to 25° C., the reaction mixture was poured into 30 ml water to give 0,21 g (67%) 4-chloro-7,8-dihydroxy-1H-imidazo(4,5-f)quinoxaline, m.p.>300° C. NMR (DMSO-d6): 7.37 (1H,s), 6.70 (1H,s).
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:13]C.[Cl-].[Al+3].[Cl-].[Cl-].N1C=CC=CC=1>CCOC(C)=O>[OH:13][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]=1[OH:1])[CH:6]=[O:7]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
To a vigorously stirred suspension of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde (47.0 g, 238 mmol) in EtOAc (450 mL) at room temperature, anhydrous aluminum chloride (38.1 g, 286 mmol) was added in one portion. Then pyridine (77 mL, 954 mmol) was added dropwise at 45-50° C. for 30 minutes. The reaction mixture was refluxed for 2 hours and allowed to cool down to 60° C. The reaction mixture was carefully poured into ice/concentrated HCl mixture (265 mL). After stirring at 50° C. for 1 hour, the reaction mixture was cooled to 0° C. The formed precipitate was separated by filtration, washed with water, and vacuum-dried to afford 3,4-dihydroxy-5-nitrobenzaldehyde (29.4 g, 161 mmol, 67.3% yield).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:34](=[O:35])[N:13]3[C:14]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20]Cl)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-:36].[Na+]>CC(C)=O>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:34](=[O:35])[N:13]3[C:14]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20][I:36])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(COC(=O)C2=C(C=CCCl)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(C=CCI)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Yield: 60.4 %

Procedure:
After 20.0 g of p-methoxybenzyl 7β-[2-phenylacetamido]-3-[3-chloro-1-propenyl]-3-cephem-4-carboxylate (E/Z=25/75) was suspended in 250 ml of acetone, 29 g of sodium iodide was added to the suspension. The mixture was reacted at 25-30° C. for 3 hours, while stirring. After the reaction was completed, the solution was concentrated at a temperature below 25° C. under a reduced pressure of 100 mmHg and 60 ml of acetone was distilled off. The formed crystals were collected by filtration and washed successively with 50 g of 5% sodium thiosulfate aqueous solution, next with 50 g of ion exchange water and finally with 50 g of acetone to give 14.24 g of p-methoxybenzyl 7β-[2-phenylacetamido]-3-[3-iodo-1-propenyl]-3-cephem-4-carboxylate (content, 97.0%; E/Z=99/1). The yield of E-form was 59%.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6])[CH:2]=[CH2:3].Cl.[C:17](=O)(O)[O-].[Na+]>CO>[CH3:17][O:14][C:13](=[O:15])[C@H:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6]
Reactant: C=CCOC(=O)N[C@@H](CC(C)C)C(=O)O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)N[C@@H](CC(C)C)C(=O)OC

Procedure:
A solution of 0.06 mol of N-(allyloxycarbonyl)leucine, prepared as described by F. Guibe, O. Dangles, and G. Balavione in Tetrahedron Letters, 1986, 27, 2365-2368, and 0.066 mol of HCl in 100 mL of CH3OH is stirred at reflux for 8 hours. The solution is then cooled and treated with 0.066 mol of sodium bicarbonate. The solvent is removed by rotary evaporator, and the residue is dissolved in diethyl ether, filtered, dried over MgSO4, and filtered. The solvent is removed by rotary evaporator to give N-(allyloxycarbonyl)leucine methyl ester
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:20]O>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH2:12][C:13]([O:15][CH3:20])=[O:14])=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)Cc1cccc2ccc(O)cc12
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cccc2ccc(O)cc12

Procedure:
Dissolve the compound obtained in Step A in 100 ml of methanol. Cool the mixture in an ice-bath. Add thionyl chloride dropwise and maintain the reaction mixture at that temperature for 20 minutes after the addition. Leave for 1 hour at room temperature with stirring. Remove the methanol by evaporation under reduced pressure, and recrystallise the resulting solid from a mixture of toluene/cyclohexane (4/1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:19][CH:20]=[CH2:21])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:24](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:19][CH:20]=[CH2:21])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:24])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: C=CCC(CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1
Agent: [K+]
Solvent: CI
Product: C=CCC(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-hex-5-enoyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless oil, MS (ESI+): m/z=360.1 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1)[CH2:3][OH:4].[N:18]#[C:19]Br>>[F:16][C:14]([F:17])([F:15])[C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][C@H:2]2[CH2:3][O:4][C:19]([NH2:18])=[N:1]2)=[N:9][CH:10]=1
Reactant: N[C@H](CO)CCOc1ccc(C(F)(F)F)cn1
Reactant: N#CBr
Product: NC1=N[C@@H](CCOc2ccc(C(F)(F)F)cn2)CO1

Procedure:
In analogy to example 1d (S)-2-amino-4-(5-trifluoromethyl-pyridin-2-yloxy)-butan-1-ol was reacted with cyanogen bromide to give (S)-4-[2-(5-trifluoromethyl-pyridin-2-yloxy)-ethyl]-4,5-dihydro-oxazol-2-ylamine. White solid. MS (ISP): 276.2 ([M+H]+).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][NH2:18]>[Ti](Cl)(Cl)(Cl)Cl.C1C=CC=CC=1>[CH3:17][N:18]=[C:6]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[CH:10]=[CH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]1=2
Reactant: CN
Reactant: O=c1c2ccccc2ccc2ccccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CN=c1c2ccccc2ccc2ccccc12
Temperature: 25 °C
Reaction time: 144 h
Yield: 95 %

Procedure:
Using the procedure following Example 1, a mixture of 100 g 0f 5H-dibenzo[a,d]-cyclohepten-5-one, 98 g of methylamine and 1000 ml of benzene is treated with 53 g of titanium tetrachloride. The mixture is worked up after stirring at room temperature for 6 days. Short-path distillation of the crude product at 120° bath temperature and 0.1 micron pressure gives 101.2 g (95% yield) of N-methyl-5H-dibenzo[a,d]cyclohepten-5-imine as a viscous oil that solidifies slowly on standing. Nmr spectrum (in CDCl3): multiplet at τ 2.3-2.9 (8H) and singlets at 3.2 (2H) and 6.7 (3H).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([C:40]3([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[C:20]1([C:3]2[N:4]=[C:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[NH:9][C:8]4[N:16]=[CH:17][CH:18]=[CH:19][C:7]=4[N:6]3[C:2]=2[C:34]2[CH:35]=[CH:36][C:37]([C:40]3([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:42][CH2:41]3)=[CH:38][CH:39]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Brc1c(-c2ccccc2)nc2n1-c1cccnc1Nc1ccccc1-2
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 73.3 %

Procedure:
A suspension of 3-bromo-2-phenyl-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepine (50 mg) and tert-butyl {1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl}carbamate (92 mg) and potassium phosphate (82 mg) and PdCl2(dppf)CH2Cl2 (11 mg) in dioxane (2.5 mL) and H2O (0.25 mL) was degassed for 5 min then stirred at 80° C. for 18 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (0-50% ethyl acetate in hexanes) gave the product (51 mg, 74%). 1HNMR (DMSO-d6) 400 MHz δ: 8.55 (s, 1H), 8.09-8.04 (m, 1H), 7.98-7.93 (m, 1H), 7.70 (br s, 1H), 7.48 (d, J=6.9 Hz, 2H), 7.39-7.06 (m, 10H), 6.94-6.87 (m, 1H), 6.78-6.65 (m, 1H), 1.44-1.08 (m, 13H). LCMS: 542 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([S:12]([NH2:15])(=[O:14])=[O:13])[N:4]([CH3:16])[N:3]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:21]([O:20][C:18]([NH:15][S:12]([C:5]1[N:4]([CH3:16])[N:3]=[C:2]([Cl:1])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:14])=[O:13])=[O:19])[CH3:22]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)c1c(Cl)nn(C)c1S(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)NS(=O)(=O)c1c(C(=O)OCC)c(Cl)nn1C
Yield: 88.4 %

Procedure:
Into 30 ml of dry acetone, there were added 5.35 g of 3-chloro-4-ethoxycarbonyl-1-methylpyrazole-5-sulfonamide, 2.5 g of ethyl chloroformate and 4.14 g of anhydrous potassium carbonate and the mixture was refluxed for three hours. After cooling, acetone was evaporated and the residue was added into ice-water. After separation of a trace of water insolubles, the filtrate was made acidic with hydrochloric acid. The reaction mixture was extrated with diethyl ether and organic layer was dried and the solvent was evaporated under reduced pressure to give 6.0 g of N-(ethoxycarbonyl)-3-chloro-4-ethoxycarbonyl-1-methylpyrazole-5-sulfonamide.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]2[C:19]3[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=3[N:17]([C:25](=[O:43])[C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:41])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH3:40])=[CH:28][C:27]=3[CH3:42])[CH2:16][CH2:15][CH2:14]2)(=O)=O)=CC=1.[I-].[Na+].[C:47]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)(=[O:49])[CH3:48].Cl>CN(C)C=O.C(OCC)C>[ClH:24].[C:47]([N:50]1[CH2:55][CH2:54][N:53]([CH2:11][CH2:12][CH:13]2[C:19]3[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=3[N:17]([C:25](=[O:43])[C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:41])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH3:40])=[CH:28][C:27]=3[CH3:42])[CH2:16][CH2:15][CH2:14]2)[CH2:52][CH2:51]1)(=[O:49])[CH3:48]
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCCN(C(=O)c3ccc(NC(=O)c4ccccc4C)cc3C)c3ccc(Cl)cc32)cc1
Reactant: CC(=O)N1CCNCC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)N1CCN(CCC2CCCN(C(=O)c3ccc(NC(=O)c4ccccc4C)cc3C)c3ccc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 121.5 %

Procedure:
To a solution of 5-[2-(p-toluenesulfonyloxy)ethyl]-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.25 g) in dry dimethylformamide (20 ml) are added sodium iodide (0.178 g) and 4-acetylpiperazine (0.152 g), and the mixture is stirred at room temperature for one hour. The mixture is heated at 50° C. for 2 hours, and further at 60° C. for 3 hours. To the reaction solution are added 1N-hydrochloric acid and diethyl ether, and the aqueous layer is collected and neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with dichloromethane. The dichloromethane layer is washed with water, dried, and the solvent is distilled off. To the resulting residue is added hydrochloric acid/ethanol to give 5-[2-(4-acetyl-1-piperazinyl)ethyl]-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride (150 mg) as colorless amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:32]=[CH:31][C:14]([CH2:15][C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:22](=[O:24])[CH3:23])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1.[OH-].[Na+]>C(O)C.O>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][C:16]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:22](=[O:24])[CH:23]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:31][CH:32]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)C(CCC(=O)O)(Cc1ccc(Cl)cc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCC(Cc1ccc(Cl)cc1)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
p-Chlorobenzaldehyde (2.81 g., 0.02 mole) in ethanol (10 ml.) is added to a solution of 4-(p-chlorobenzyl)-4-phenyl-5-oxohexanoic acid (3.0 g., .009 mole) and sodium hydroxide (0.56 g., 0.014 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. The reaction solution is cooled to room temperature, diluted with water (200 ml.), and extracted with ether to remove the excess p-chlorobenzaldehyde. Ether is expelled from the aqueous phase by warming. The solution is cooled in an ice bath, acidified with dilute hydrochloric acid (10 ml.), and the yellowish solid which precipitates is collected and air-dried to yield 3.1 g., m.p. 65°-145°C. Several recrystallizations from n-butyl chloride yields a material with m.p. 176°-178.5°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=O)[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:15][CH2:16][N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2(CC(=O)N(C)C)CC=CCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C2(CCN(C)C)C=CCCC2)c1

Procedure:
A solution of 1.0 g of 1-(m-methoxyphenyl)-N,N-dimethyl-3-cyclohexene-1-acetamide in 10 ml of absolute tetrahydrofuran is added to a suspension of 1 g of lithium aluminum hydride in 50 ml of absolute tetrahydrofuran, and the mixture is boiled at reflux overnight. After the addition of water, the separated precipitate is removed by filtration under suction and washed well with tetrahydrofuran, whereupon the filtrate is evaporated. The oil remaining behind is treated with 1 N hydrochloric acid. The neutral portion is taken up in ether. The acidic phase is made alkaline by the addition of concentrated ammonia and the liberated rac. 1-(m-methoxyphenyl)-N,N-dimethyl-2-cyclohexene-1-ethylamine is taken up in methylene chloride. The hydrochloride of this compound melts at 161°-162° C. (after recrystallization from ethyl acetate/ethanol).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][N:9]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[CH2:10][CH2:11][N:12](C)[C:13](=O)OC(C)(C)C)=[O:4].C(=O)(O)[O-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:27][C:23]1[CH:22]=[C:21]([N:9]([CH2:10][CH2:11][NH:12][CH3:13])[CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)NCCCN(CCN(C)C(=O)OC(C)(C)C)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCN(CCCNC(=O)OC)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
tert-butyl 2-((3-(methoxycarbonylamino)propyl)(3-chlorophenyl)amino)ethyl(methyl)carbamate (50 mg, 0.31 mmol) was dissolved in a solution of 20% (V/V) TFA/CH2Cl2 (4 mL). The reaction mixture was stirred at room temperature for 1 h, a solution of saturated sodium bicarbonate was added dropwise to adjust pH=7-8. The resulting mixture was extracted with CH2Cl2 (3×10 mL), washed with brine, dried over Na2SO4, concentrated in vacuo to afford methyl 3-((3-chlorophenyl)(2-(methylamino)ethyl)amino)propylcarbamate (40 mg, 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:6]=1.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29][Cl:30])=[CH:23][CH:24]=2)[N:19]=[CH:18][N:17]=1>C(O)(C)C.C(OCC)C>[Cl:30][CH2:29][CH2:28][CH2:27][O:26][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([NH:1][C:2]3[CH:3]=[N:4][N:5]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:6]=3)=[N:17][CH:18]=[N:19]2)=[CH:24][CH:23]=1
Reactant: ClCCCOc1ccc2c(Cl)ncnc2c1
Reactant: CC(C)(C)OC(=O)Cn1cc(N)cn1
Solvent: CC(C)O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Cn1cc(Nc2ncnc3cc(OCCCCl)ccc23)cn1
Temperature: 90 °C

Procedure:
A mixture of tert-butyl (4-amino-1H-pyrazol-1-yl)acetate (0.305 g, 1.55 mmol) and 4-chloro-7-(3-chloropropoxy)quinazoline (0.398 g, 1.55 mmol) in isopropanol (8 ml) was heated at 90° C. for 5 minutes and then allowed to cool to room temperature. The mixture was diluted with diethyl ether and then filtered to give tert-butyl (4-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)acetate as the hydrochloride salt (0.674 g, 96% yield):
Reaction SMILES: Cl.O1CCOCC1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([NH:24][C:25]([C:27]4([N:53]([CH:55]=[O:56])[CH3:54])[CH2:31][CH2:30][N:29]([CH2:32][C:33](=[O:52])[N:34]5[CH2:39][CH:38]=[C:37]([C:40]6[CH:45]=[CH:44][C:43]([C:46]7[N:51]=[CH:50][CH:49]=[CH:48][N:47]=7)=[CH:42][CH:41]=6)[CH2:36][CH2:35]5)[CH2:28]4)=[O:26])[CH:22]=3)[N:17](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:16]=2)=[CH:11][CH:10]=1>C(Cl)Cl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([NH:24][C:25]([C:27]4([N:53]([CH:55]=[O:56])[CH3:54])[CH2:31][CH2:30][N:29]([CH2:32][C:33](=[O:52])[N:34]5[CH2:35][CH:36]=[C:37]([C:40]6[CH:45]=[CH:44][C:43]([C:46]7[N:47]=[CH:48][CH:49]=[CH:50][N:51]=7)=[CH:42][CH:41]=6)[CH2:38][CH2:39]5)[CH2:28]4)=[O:26])[CH:22]=3)[NH:17][N:16]=2)=[CH:11][CH:10]=1
Reactant: CN(C=O)C1(C(=O)Nc2ccc3c(c2)c(-c2ccc(F)cc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN(CC(=O)N2CC=C(c3ccc(-c4ncccn4)cc3)CC2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN(C=O)C1(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)CCN(CC(=O)N2CC=C(c3ccc(-c4ncccn4)cc3)CC2)C1
Reaction time: 2 h
Yield: 85.2 %

Procedure:
Added 4M HCl/dioxane (2 ml) to a solution of 3-(Formyl-methyl-amino)-1-{2-oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1trityl-indazol-5-yl]-amide (7T) (89 mg, 0.098 mmol) in MeCl2 (2 ml) at room temperature, then stirred for 2 hours. The solvent was evaporated and the residue extracted with MeCl2 (50 ml), H2O (25 ml) and 3M NaOH (2 ml). The organic layer was separated, dried over MgSO4, filtered and solvent evaporated yielding a solid. Hexanes (2×50 ml) was added and the supernatant decanted. The residual solid was dried yielding 8T as a white solid (55 mg, 84%) LCMS (MH 659) Retention time=2.98 minutes.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[OH:21][CH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][CH2:27]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[OH:21][CH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][N:26]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=1[F:16])[CH2:27]2
Reactant: OCc1cccc2c1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4cccc(CO)c4C3)c(F)cc2c1=O
Yield: 41.3 %

Procedure:
283 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 179 mg of 4-hydroxymethylisoindoline, 304 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 170 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[NH:11][C:12](=[O:27])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:14]=1>ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[NH:11][C:12](=[O:27])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)[CH:14]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cc(CO)cc2Cl)cc1OC1CCCC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2c(Cl)cc(C=O)cc2Cl)cc1OC1CCCC1
Yield: 54.8 %

Procedure:
A solution of N-(2,6-dichloro-4-hydroxymethylphenyl)-3-cyclopentyloxy-4-methoxybenzamide (4.4 g) in dichloromethane (30 mL) is treated with activated manganese dioxide (6.2 g), and the mixture is stirred at reflux for 24 hours. The mixture is filtered, the flitrate is evaporated, and the resulting residue is subjected to flash chromatography on silica gel, eluting with ethyl acetate, to give N-(2,6-dichloro-4-formylphenyl)-3-cyclopentyloxy-4-methoxybenzamide (2.4 g), m.p. 96°-98° C. [Elemental analysis: C,59.0; H,5.1; N,3.1%; calculated: C,58.8; H,4.7; N,3.4%].