Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:7]([NH:9][C@H:10]([C:15]([OH:17])=O)[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])(=[O:3])[CH3:2].[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>C1COCC1.C(Cl)Cl>[C:27]1([NH:26][C:15](=[O:17])[C@H:10]([CH2:11][CH:12]([CH3:13])[CH3:14])[NH:9][C:7](=[O:8])[CH:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccccc1
Reactant: CC(=O)SCC(CCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(=O)SCC(CCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
To a solution of N-(2-acetylthiomethyl-4-phenylbutanoyl)-(L)-leucine (derived from the higher Rf TLC fraction) (182 mg, 0.5 mmole) in 2 mL of THF at 0° C. was added aniline (93 mg, 1.0 mmole) and 1-hydroxybenzotriazole hydrate (HOBT′H2O), 101 mg, 0.75 mole) and N-methylmorpholine (202 mg, 2.0 mmole). The mixture was stirred at 0° C. for 15 minutes, then 192 mg of 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (EDC.HCl, 1.0 mmole) was added and the mixture stirred overnight. The solution was worked up by adding 7 mL methylene chloride and the mixture extracted with 3×3 ml of 5% sodium bicarbonate, then 2×2 mL of brine. The organic layer was dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with methylene chloride/ethyl acetate (90/10) to obtain 110 mg of product (yield=50%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:13]1([NH2:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1>O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:23][CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NC1CCCc2ccccc21
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(NC1CCCc2ccccc21)c1ccc([N+](=O)[O-])cc1
Yield: 90 %

Procedure:
A solution of 18.9 g of 4-nitrobenzoyl chloride in 100 ml of tetrahydrofuran was added rapidly to a solution of 10.0 g of 1,2,3,4-tetrahydro-1-naphthylamine in 200 ml of tetrahydrofuran and 180 ml of 20% aqueous potassium carbonate. The reaction mixture was stirred vigorously and heated at reflux for 2 hours. After cooling, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic portions were washed with water, 1N hydrochloric acid, water, and a saturated sodium chloride solution, dried over sodium sulfate, and concentrated in vacuo. The resulting solid was recrystallized from benzene to afford the title intermediate in 90% yield as a colorless solid, m.p. 156°-157° C.
Reaction SMILES: [N:1]1([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[S:23][N:22]=[C:21]([OH:24])[C:20]=3[C:25]#[N:26])=[CH:14][CH:13]=2)=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH2:27][CH:28]([CH3:31])[CH2:29][OH:30]>CCO>[N:1]1([C:10]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]3[S:23][N:22]=[C:21]([OH:24])[C:20]=3[C:25]([NH:27][CH:28]([CH3:31])[CH2:29][OH:30])=[NH:26])=[CH:16][CH:17]=2)=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(N)CO
Reactant: N#Cc1c(O)nsc1Nc1ccc(C(=O)N2CCc3ccccc32)cc1
Solvent: CCO
Product: CC(CO)NC(=N)c1c(O)nsc1Nc1ccc(C(=O)N2CCc3ccccc32)cc1
Temperature: 80 °C

Procedure:
To 5-[4-(2,3-dihydro-indole-1-carbonyl)-phenylamino]-3-hydroxy-isothiazole-4-carbonitrile 5 (0.362 gm, 1 mmol) in 10 ml anhydrous EtOH was added (2-amino-propan-1-ol (0.375 gm, 5 mmol). The reaction mixture was maintained at 80° C. for 16 h. with stirring, then concentrated to dryness and purified by column chromatography to provide 5-[4-(2,3-dihydro-indole-1-carbonyl)-phenylamino]-3-hydroxy-N-(2-hydroxy-1-methyl-ethyl)-isothiazole-4-carboxamidine 6.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:22]([C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27])[CH3:23]>CC(O)C>[CH2:22]([C:24]1[CH:25]=[C:26]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:28]=[CH:29][CH:30]=1)[CH3:23]
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Reactant: CCc1cccc(N)c1
Solvent: CC(C)O
Product: CCc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
4-Chloro-6,7-bis(2-methoxyethoxy)quinazoline (50 g, 160 mmol), 3-ethylaniline (21.34 g, 176 mmol) and propan-2-ol (500 mL) was heated at 78-82° C. for 16 hours. The mixture was cooled to cool to 5-10° C. and stirred for 1 hour. The solid was collected by filtration, and mixed with water (200 mL) and ethyl acetate (500 mL). The mixture was adjusted to pH 10-12 with 50% aqueous sodium hydroxide to give to clear layers. The organic layer was separated and washed with water (200 mL), brine (200 mL) and dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The oil was allowed to solidify and dried under vacuum at 20-25° C. to give the title product (57.2 g, 90%) as a white solid. mp 72-74° C.;
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C:15](=[O:16])[C@@H:14]3[C@H:17]([OH:20])[CH2:18][CH2:19][N:13]3[C:12]2=[O:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:22]N1C(=O)N(C)CCC1.[Li+].CC([N-]C(C)C)C.IC>C1COCC1>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C:15](=[O:16])[C@:14]3([CH3:22])[C@H:17]([OH:20])[CH2:18][CH2:19][N:13]3[C:12]2=[O:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CN1CCCN(C)C1=O
Reactant: Cc1c(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)ccc(C#N)c1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(N2C(=O)N3CC[C@@H](O)[C@@]3(C)C2=O)ccc(C#N)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirring suspension of compound 23G (600 mg, 1.96 mmol) in anhydrous THF (10 mL) at rt was added DMPU (4 mL). The resulting clear solution was cooled to −78° C., then a 2.0 M solution of LDA in THF (1.96 mL, 3.92 mmol) was added slowly so that the reaction temperature was maintained below −72° C. The resulting dark brown solution was stirred at −78° C. for 30 min, then iodomethane (0.36 mL, 3.92 mmol) was added dropwise. After addition, the reaction was stirred at −78° C. for 30 min, then at 0° C. for 3 h. The reaction was quenched with 5% aqueous KHSO4 and extracted with EtOAc (3×). The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was chromatographed (silica gel), eluting with 1% MeOH in EtOAc/CH2Cl2 (1:9) to give a mixture of compound 25 and compound 26 (150 mg), which was further purified using preparative HPLC to afford the title compound (20 mg). HPLC: 99% at 4.40, 5.20 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O-10% MeOH-0.1% H3PO4 and B=10% H2O-90% MeOH-0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). Chiral HPLC: retention time=7.9 min (99%); Conditions: OD (4.6×250 mm); Eluted with 20% isopropanol in hexane for 30 min at 1 mL/min, MS (ES) m/z 320 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([OH:20])=[C:10]([C:16]([O:18][CH3:19])=[O:17])[N:11]=[C:12]2I)=[CH:7][CH:6]=1.[C:25]([Cu])#[N:26].C(Cl)Cl>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([OH:20])=[C:10]([C:16]([O:18][CH3:19])=[O:17])[N:11]=[C:12]2[C:25]#[N:26])=[CH:7][CH:6]=1
Reactant: COC(=O)c1nc(I)c2cc(Oc3ccccc3Cl)ccc2c1O
Reactant: N#C[Cu]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3Cl)ccc2c1O
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
Methyl 7-(2-chlorophenoxy)-4-hydroxy-1-iodoisoquinoline-3-carboxylate (0.2 g, 0.44 mmol) and CuCN (79 mg, 0.88 mmol) were suspended in DMF (1.8 mL). The resulting mixture was heated at 120° C. for 7 minutes and then cooled to room temperature. The reaction crude was poured into CH2Cl2 (30 mL) and then stirred vigorously for 10 minutes at room temperature. The resulting suspension was filtered through a pad of celite and the filtrate was washed with H2O and brine sequentially. The organic layer was dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 150 mg. MS: (−) m/z 353.24 (M−1).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][N:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[OH-].[Li+]>>[CH3:29][S:26]([N:23]1[CH2:22][CH2:21][CH:20]([N:10]([C:11]([CH:13]2[CH2:14][CH2:15][CH:16]([CH3:19])[CH2:17][CH2:18]2)=[O:12])[C:9]2[CH:8]=[C:7]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])[CH2:25][CH2:24]1)(=[O:27])=[O:28]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCN(S(C)(=O)=O)CC1
Agent: [Li+]
Agent: [OH-]
Product: CC1CCC(C(=O)N(c2cc(-c3ccccc3)sc2C(=O)O)C2CCN(S(C)(=O)=O)CC2)CC1
Yield: 74.6 %

Procedure:
A solution of 3-[(1-Methanesulfonyl-piperidin-4-yl)-(4-methylcyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (40 mg, 0.077 mmol) was hydrolysed as described before with lithium hydroxide (2M, 114 μL, 5.5 mg, 0.23 mmol) to give after acidic work-up 3-[(1-Methanesulfonyl-piperidin-4-yl)-(4-methylcyclohexane-carbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid (29 mg, 74%) as a colourless powder; 1H (300 MHz, MeOD) 0.56-0.72 (m, 1H), 0.79 (d, J=4.8 Hz, 3H), 1.23-1.44 (m, 5H), 1.51-1.79 (m, 6H), 1.92-1.98 (m, 1H), 2.04-2.14 (m, 2H), 2.78-2.90 (m, 2H), 2.80 (s, 3H), 3.66-3.74 (m, 1H), 3.75-3.81 (m, 1H), 4.52-4.62 (m, 1H), 7.39 (s, 1H), 7.40-7.90 (m, 3H), 7.73-7.77 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH:11]1[C:16](=[O:17])[CH2:15][C:14]([CH3:19])([CH3:18])[CH2:13][C:12]1=[O:20].S>[OH-].[NH4+].C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH:11]1[C:16](=[O:17])[CH2:15][C:14]([CH3:18])([CH3:19])[CH2:13][C:12]1=[O:20]
Reactant: CC1(C)CC(=O)C(c2ccc([N+](=O)[O-])cc2Cl)C(=O)C1
Agent: S
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC(=O)C(c2ccc(N)cc2Cl)C(=O)C1
Reaction time: 24 h

Procedure:
A solution of 20.0 g (0.067 mol) of 2-(2'-chloro-4'-nitrophenyl)-5,5-dimethyl-1,3-cyclohexanedione in 150 ml of concentrated ammonium hydroxide and 150 ml of ethanol was stirred at room temperature while passing hydrogen sulfide gas through the solution at such a rate that all of the H2S was absorbed. When the solution was saturated with H2S, the temperature was raised to the reflux point and H2S continuously passed slowly through the refluxing solution for 24 hours. The reaction mixture was filtered to remove sulfur, and the filtrate evaporated under reduced pressure. To the residue was added 300 ml of 0.25 N NaOH, and the solution filtered once more. The filtrate was cooled and carefully acidified to pH=4 with 6 N HCl. 2-(2'-Chloro-4'-aminophenyl)-5,5-dimethyl-1,3-cyclohexanedione was collected by suction filtration.
Reaction SMILES: C([O:5][C:6](=[O:31])[CH:7]([C:9]([C:11]1[C:12]([O:29][CH3:30])=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[C:14]2/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:10])[NH2:8])(C)(C)C.FC(F)(F)C(O)=O.O>ClCCl>[F:28][C:25]1[CH:26]=[CH:27][C:22](/[CH:21]=[CH:20]/[C:14]2[C:13]3[C:17](=[CH:18][CH:19]=[C:11]([C:9]([CH:7]([NH2:8])[C:6]([OH:31])=[O:5])=[O:10])[C:12]=3[O:29][CH3:30])[NH:16][N:15]=2)=[CH:23][CH:24]=1
Reactant: COc1c(C(=O)C(N)C(=O)OC(C)(C)C)ccc2[nH]nc(/C=C/c3ccc(F)cc3)c12
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C(=O)C(N)C(=O)O)ccc2[nH]nc(/C=C/c3ccc(F)cc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
472 mg of {3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carbonyl}-aminoacetic acid tert-butyl ester was dissolved in 5 mL of dichloromethane, 2.5 mL of trifluoroacetic acid was added, and stirred overnight at room temperature. The reaction solution was added with water, and extracted with a mixed solution of ethyl acetate:tetrahydrofuran=1:1. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, to give 384 mg of the title compound as a pale yellow solid.
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@H:10]([O:22][C:23]([C:25]2[C:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[C@@H:9]([CH2:37][O:38][Si:39]([C:52]([CH3:55])([CH3:54])[CH3:53])([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:8][C@H:5]1SC)=[N+:2]=[N-:3].[CH2:56]1[O:66][C:65]2[CH:64]=[CH:63][C:60]([CH2:61][OH:62])=[CH:59][C:58]=2[O:57]1.COS(C(F)(F)F)(=O)=O>ClCCCl>[N:1]([C@@H:4]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@H:10]([O:22][C:23]([C:25]2[C:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[C@@H:9]([CH2:37][O:38][Si:39]([C:52]([CH3:55])([CH3:54])[CH3:53])([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[O:8][CH:5]1[O:62][CH2:61][C:60]1[CH:63]=[CH:64][C:65]2[O:66][CH2:56][O:57][C:58]=2[CH:59]=1)=[N+:2]=[N-:3]
Reactant: COc1ccc(CO[C@@H]2[C@@H](N=[N+]=[N-])[C@H](SC)O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@H]2OC(=O)c2ccccc2-c2ccccc2)cc1
Reactant: OCc1ccc2c(c1)OCO2
Agent: COS(=O)(=O)C(F)(F)F
Solvent: ClCCCl
Product: COc1ccc(CO[C@H]2[C@H](OC(=O)c3ccccc3-c3ccccc3)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)OC(OCc3ccc4c(c3)OCO4)[C@@H]2N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
A mixture of methyl 2-azido-4-O-biphenylcarbonyl-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (11) (200 mg, 0.26 mmol), 3,4-methylenedioxybenzyl alcohol 59 mg, 0.39 mmol), molecular sieves 4A (1 g) and methyltriflate (106 mg, 0.65 mmol) in 1,2-dichloroethane (10 mL) was stirred at room temperature overnight. The reaction mixture was neutralized with TEA (0.5 mL) and evaporated. The residue was purified by chromatography using EtOAc—hexane 15:85 as the mobile phase to give 3,4-methylenedioxybenzyl 2-azido-4-O-biphenylcarbonyl-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl)-α,β-D-glucopyranoside (43) (173 mg, 76%).
Reaction SMILES: [CH2:1]1[O:16][C:15]2[C:3](=[C:4]([CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]([O:9]CC)=[O:8])[O:2]1.[OH-].[K+]>CO.O>[CH2:1]1[O:16][C:15]2[C:3](=[C:4]([CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]([OH:9])=[O:8])[O:2]1
Reactant: CCOC(=O)C=Cc1cccc2c1OCO2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C=Cc1cccc2c1OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
A solution of ethyl 2,3-methylenedioxycinnamate (3.40 g) in methanol (25 mL) and water (5 mL) was treated with a solution of potassium hydroxide (4.3 g) in water (25 mL). The mixture was stirred overnight at room temperature before being concentrated in vacuo to half its original volume. The concentrate was then acidified with concentrated HCl to give 2,3-methylenedioxycinnamic acid as a colourless solid (2.81 g, 95%) which was collected by filtration and dried overnight under a vacuum.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14]N(C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].BrC1C=CC([N+]([O-])=[O:31])=NC=1.N1CCOCC1>>[N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][O:31][CH2:14][CH2:15]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Solvent: C1COCCN1
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cn1

Procedure:
Following the procedures as described for 188a and starting with 2 g of 5-bromo-2-nitropyridine and 968 mg morpholine, 255a was obtained as a yellow solid (1 g, 50%). MS: [M+H]+ 210. 1H NMR (500 MHz, CDCl3) δ 8.18 (d, J=9.0, 1H), 8.15 (d, J=3.0, 1H), 7.22 (dd, J=3.0, 1H), 3.90 (t, J=5.0, 4H), 3.42 (t, J=5.0, 4H).
Reaction SMILES: C(OC([N:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[CH2:15][OH:16])[CH2:7]1)=O)C.[OH-].[K+]>C(O)(C)C.O>[OH:16][CH2:15][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[CH2:14][NH:6][CH2:7]2
Reactant: CCOC(=O)N1Cc2cccc(CO)c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: OCc1cccc2c1CNC2
Yield: 72.4 %

Procedure:
3.03 g of 2-ethoxycarbonyl-4-hydroxymethylisoindoline and 2.91 g of potassium hydroxide were dissolved in a mixture of 25 ml isopropyl alcohol and 2.5 ml of water. The mixture was heated under refluxing for 3 days. After the addition of water, the resulting reaction mixture was extracted with chloroform. The extract was washed with brine, concentrated, and recrystallized from carbontetrachloride to give 1.48 g of 4-hydroxymethylisoindoline.
Reaction SMILES: Br.[CH3:2][N:3]([CH:5]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:6]1[CH2:11][CH2:10][N:9](C(OCC2C=CC=CC=2)=O)[CH2:8][CH2:7]1)[CH3:4]>C(O)(=O)C>[CH3:2][N:3]([CH3:4])[CH:5]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:6]1[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1
Reactant: CN(C)C(c1ccccc1)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: Br
Solvent: CC(=O)O
Product: CN(C)C(c1ccccc1)C1CCNCC1
Reaction time: 1.5 h

Procedure:
33% hydrogen bromide in glacial acetic acid (20 ml) was added to a solution of benzyl 4-((dimethylamino)(phenyl)methyl)piperidine-1-carboxylate (2.32 g, 6.58 mmol) in glacial acetic acid (20 ml), and stirring was carried out for 1.5 h at room temperature. A solid was precipitated by addition of diethyl ether. The supernatant solution was decanted off; diethyl ether was added repeatedly to the residue, and the supernatant solution was decanted off again each time. The residue was dried in vacuo and dissolved in methanol (20 ml); strongly basic ion exchanger Dowex 1×2-200 was added thereto, and stirring was carried out for 1 h at room temperature. The mixture was then filtered, the filter residue was washed with methanol, and the filtrate was concentrated in vacuo.
Reaction SMILES: C1(N2C3C(=CC(F)=C(N4CCC(NC5CCNCC5)CC4)C=3OC)C(=O)C(C(O)=O)=C2)CC1.C(OC([N:41]1[CH2:46][CH2:45][CH:44]([N:47]([CH2:53][CH:54]2[CH2:58][CH2:57][N:56]([C:59]3[C:68]([O:69][CH3:70])=[C:67]4[C:62]([C:63](=[O:77])[C:64]([C:74]([OH:76])=[O:75])=[CH:65][N:66]4[CH:71]4[CH2:73][CH2:72]4)=[CH:61][C:60]=3[F:78])[CH2:55]2)[CH2:48][CH2:49][N:50]([CH3:52])[CH3:51])[CH2:43][CH2:42]1)=O)(C)(C)C>>[CH:71]1([N:66]2[C:67]3[C:62](=[CH:61][C:60]([F:78])=[C:59]([N:56]4[CH2:57][CH2:58][CH:54]([CH2:53][N:47]([CH2:48][CH2:49][N:50]([CH3:52])[CH3:51])[CH:44]5[CH2:45][CH2:46][NH:41][CH2:42][CH2:43]5)[CH2:55]4)[C:68]=3[O:69][CH3:70])[C:63](=[O:77])[C:64]([C:74]([OH:76])=[O:75])=[CH:65]2)[CH2:73][CH2:72]1
Reactant: COc1c(N2CCC(CN(CCN(C)C)C3CCN(C(=O)OC(C)(C)C)CC3)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: COc1c(N2CCC(NC3CCNCC3)CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Product: COc1c(N2CCC(CN(CCN(C)C)C3CCNCC3)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
The title compound was prepared by using the same procedure as described for the preparation of 1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-7-[4-(piperidin-4-ylamino)-piperidin-1-yl]-1,4-dihydro-quinoline-3-carboxylic acid in Example 4, Step 3 except 7-(3-{[(1-tert-butoxycarbonyl-piperidin-4-yl)-(2-dimethylamino-ethyl)-amino]-methyl}-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid was used in place of 7-[4-(1-tert-butoxycarbonyl-piperidin-4-ylamino)-piperidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid. The title compound was obtained as light yellow oil. ESI MS m/z 459 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 7.46 (d, .J=14.2 Hz, 1H), 4.11 (br s, 1H), 3.70 (m, 1H), 3.57 (m, 1H), 3.54 (s, 3H), 3.46 (m, 4H), 2.99 (m, 4H), 2.88 (m, 2H), 2.71 (s, 6H), 2.52 (m, 1H), 2.12 (q, J=5.5 Hz, 1H), 2.00 (dd, J=12.7 Hz, 19.4 Hz, 2H), 1.78 (q, J=11.6 Hz, 2H), 1.71 (q, J=8.4 Hz, 2H), 1.24 (m, 2H), 1.09-0.95 (m, 4H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:11][C:12](=[O:28])[NH:13][C@H:14]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1)[CH3:15])([CH3:10])([CH3:9])[CH3:8].Br[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH3:38])=[CH:32][CH:31]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:7]([O:11][C:12](=[O:28])[NH:13][C@H:14]([C:16]1[CH:17]=[CH:18][C:19]([CH:22]2[CH2:27][CH2:26][N:25]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH3:38])=[CH:32][CH:31]=3)[CH2:24][CH2:23]2)=[CH:20][CH:21]=1)[CH3:15])([CH3:8])([CH3:9])[CH3:10]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C2CCNCC2)cc1
Reactant: CCOc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1ccc(N2CCC(c3ccc([C@H](C)NC(=O)OC(C)(C)C)cc3)CC2)cc1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
6.21 g (19.1 mmol) cesium carbonate are added to a mixture of 5.80 mg (19.1 mmol) (S)-[1-(4-piperidin-4-yl-phenyl)-ethyl]-carbamic acid tert-butyl ester (V.5), 4.21 g (21.0 mmol) 1-bromo-4-ethoxy-benzene, 454 mg (0.953 mmol) X-Phos and 214 mg (0.953 mmol) palladium(II) acetate in 50 mL toluene/10 mL tert-butanol. The mixture is stirred for 3 h at 120° C. under inert gas atmosphere. After that time, the mixture is poured into water and extracted with ethyl acetate. The organic layer is washed with water and dried over magnesium sulphate. The solvent is removed in vacuo and the residue is recrystallized from acetonitrile.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8](P(C)(C)=O)=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[P].[CH3:18][CH:19]([OH:21])C>>[NH:5]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:19](=[O:21])[CH3:18])[CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CP(C)(=O)c1cc2ncnc(Cl)c2cc1O
Reactant: CC(C)O
Agent: [P]
Product: CC(=O)Oc1ccc2ncnc(Nc3ccccc3)c2c1
Temperature: 90 °C

Procedure:
A mixture of 4-chloro-7-dimethylphosphinyl-6-quinazolinol, acetate ester (See e.g. PCT lnt. Appl.(2001) WO 0104102 for the 7-methoxy analog and subsequent examples below for conversion of quinazinols to triflates followed by displacement with “J”, our phosphorus-containing moiety) (3.2 mmol) and 3-chloro-4-flluoro aniline (3.3 mmol) in 2-propanol (20 mL) is heated at 90° C. for 10 hr. After this time the reaction mixture is cooled and the resulting product recovered to afford the 4-anilino-6-acetoxy quinazoline product. This material is then treated with MeOH (17 mL) followed by concentrated ammonium hydroxide and the resulting solution stirred for 17 h. After this time the reaction mixture is evaporated and the residue chromatographed on silica gel (10% MeOH/DCM) to afford deacetylated product.