Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH2:22][CH2:21][C:20]3[N:19]4[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]4)=[CH:13][C:12]=3[C:11]2=[O:23])[N:5]=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:56][O:55][CH2:54]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)[C:26]1=[O:57].CC([O-])=O.[Na+].C(#N)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:24][N:25]1[C:26](=[O:57])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:56][O:55][CH2:54]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)=[CH:28][C:29]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([N:10]3[CH2:22][CH2:21][C:20]4[N:19]5[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]5)=[CH:13][C:12]=4[C:11]3=[O:23])[N:5]=[CH:4][CH:3]=2)=[CH:30]1
Reactant: O=Cc1c(Cl)ccnc1N1CCc2c(cc3n2CCCC3)C1=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: Cn1cc(-c2ccnc(N3CCc4c(cc5n4CCCC5)C3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 100 °C
Yield: 49.9 %

Procedure:
A round-bottomed flask was charged with 139a (100 mg, 0.30 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 101 l (140 mg, 0.30 mmol), PdCl2(dppf) (25 mg, 0.03 mmol), K3PO4.3H2O (160 mg, 0.60 mmol), NaOAc (59 mg, 0.60 mmol), acetonitrile (10 mL), and H2O (5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified on flash column chromatography eluting with 1:3 petroleum/ethyl acetate to afford 139b as a yellow solid (95 mg, 50%). LCMS: [M+H]+ 635
Reaction SMILES: [CH3:1][NH2:2].O=[C:4]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])=[N:7][C:6]2[C:20]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[O:25])=[CH:21][CH:22]=[CH:23][C:5]1=2>CO>[CH3:1][N:2]1[C:4](=[O:9])[C:5]2[C:6](=[C:20]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[O:25])[CH:21]=[CH:22][CH:23]=2)[N:7]=[C:8]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:17])([F:18])[F:19]
Reactant: CN
Reactant: O=C(Nc1ccccn1)c1cccc2c(=O)oc(-c3ccccc3C(F)(F)F)nc12
Solvent: CO
Product: Cn1c(-c2ccccc2C(F)(F)F)nc2c(C(=O)Nc3ccccn3)cccc2c1=O
Temperature: 25 °C
Yield: 22 %

Procedure:
A solution of 30 wt % methylamine (7 mL) in MeOH and 4-oxo-N-(pyridin-2-yl)-2-(2-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]oxazine-8-carboxamide 25 (90 mg, 0.22 mmol) was heated under gentle reflux for 1 h then cooled to room temperature. The resulting precipitate was collected by filtration, rinsed with H2O, and dried under vacuum to give Compound 212 (20 mg, 22% yield) as a white solid. MS (ESI) calc. for C22H15F3N4O2: 424.11. found: 425 [M+H].
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]3[N:16]([CH2:19][C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[N:26]=[CH:25][CH:24]=[CH:23]5)[N:17]=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[CH2:30][OH:31].[CH3:32]I>CN(C=O)C>[F:3][C:4]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]3[N:16]([CH2:19][C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[N:26]=[CH:25][CH:24]=[CH:23]5)[N:17]=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[CH2:30][O:31][CH3:32]
Reactant: OCc1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
Sodium hydride (0.010 g, 0.259 mmol) was added at 0° C. to a solution of example 16 (0.100 g, 0.259 mmol) in DMF (1 ml) and stirred for 30 min. Methyl iodide (0.073 g, 0.518 mmol) was added and the reaction mixture was warmed to RT. After 12 h, the reaction mixture was poured into ice-cold water and extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as an off-white solid (0.033 g, 32%). M.P.: 200-201° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (dd, J=4.2, 1.7 Hz, 1H), 8.68 (d, J=8.8 Hz, 1H), 8.37 (d, J=8.4 Hz, 1H), 8.18 (d, J=8.8 Hz, 1H), 8.11-8.00 (m, 4H), 7.83 (dd, J=8.7, 1.9 Hz, 1H), 7.61 (t, J=7.7 Hz, 1H), 7.53 (dd, J=8.4, 4.2 Hz, 1H), 6.22 (s, 2H), 4.53 (s, 2H), 3.33 (s, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([N:10]2[C:14]3[CH:15]=[CH:16][C:17]([C:19]([NH:21][CH2:22][C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[O:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH:7]=[CH:8][CH:9]=1.[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30].CCN(CC)CC>C1COCC1>[CH3:36][C:35]1[CH:37]=[CH:38][C:32]([S:29]([NH:3][C:4]2[CH:5]=[C:6]([N:10]3[C:14]4[CH:15]=[CH:16][C:17]([C:19]([NH:21][CH2:22][C:23]5[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=5)=[O:20])=[CH:18][C:13]=4[N:12]=[CH:11]3)[CH:7]=[CH:8][CH:9]=2)(=[O:31])=[O:30])=[CH:33][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cccc(-n2cnc3cc(C(=O)NCc4cccnc4)ccc32)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Nc2cccc(-n3cnc4cc(C(=O)NCc5cccnc5)ccc43)c2)cc1
Reaction time: 72 h

Procedure:
A mixture of 1-(3-aminophenyl)-N-(pyridin-3-ylmethyl)-1H-benzimidazole-5-carboxamide dihydrochloride (47 mg, 0.14 mmol) and TsCl (27 mg, 0.14 mmol) was dissolved in anhydrous THF (3 mL) at 0° C. and treated with Et3N (95 μL, 0.68 mmol). The reaction mixture was stirred for 72 h and then filtered. The solid residue was washed with THF and the combined washings and filtrate were concentrated in vacuo. The resultant residue was purified by silica gel chromatography (0-7% MeOH in CH2Cl2). Further purification was achieved by trituration with MeOH to afford 1-(3-{[(4-methylphenyl)sulfonyl]amino}phenyl)-N-pyridin-3-ylmethyl-1H-benzimidazole-5-carboxamide as a white solid. 1H-NMR (DMSO-d6, 400 MHz): δ 2.35 (s, 3H), 4.54 (d, J=5.6 Hz, 2H), 7.20 (d, J=8.0 Hz, 1H), 7.32-7.44 (m, 4H), 7.50 (t, J=7.6 Hz, 1H), 7.68-7.81 (m, 3H), 7.89 (d, J=8.8 Hz, 1H), 8.36 (s, 1H), 8.47 (brs, 1H), 8.61 (s, 1H), 9.19 (brs, 1H). MS (ES+): m/z 498 [MH+].
Reaction SMILES: [C:1](=[O:7])([O:5][CH3:6])[O:2][CH2:3]Cl.[F:8][C:9]([S:12][CH2:13][C:14]([NH:16][CH:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH:24]([S:26][C:27]3[NH:31][N:30]=[N:29][N:28]=3)[CH3:25])[CH2:22][S:23][C@H:18]12)=[O:15])([F:11])[F:10].[Na]>CN(C=O)C>[F:8][C:9]([S:12][CH2:13][C:14]([NH:16][CH:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([O:34][CH2:3][O:2][C:1]([O:5][CH3:6])=[O:7])=[O:33])=[C:21]([CH:24]([S:26][C:27]3[NH:28][N:29]=[N:30][N:31]=3)[CH3:25])[CH2:22][S:23][C@H:18]12)=[O:15])([F:11])[F:10]
Reactant: COC(=O)OCCl
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CSC(F)(F)F)[C@H]2SC1
Agent: [Na]
Solvent: CN(C)C=O
Product: COC(=O)OCOC(=O)C1=C(C(C)Sc2nnn[nH]2)CS[C@@H]2C(NC(=O)CSC(F)(F)F)C(=O)N12

Procedure:
Chloromethyl methyl carbonate (0.02 mol) is reacted with sodium 7-trifluoromethylmercaptoacetamido-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (0.01 mol) in DMF for 20 hours. On work up as described in Example 1, methoxycarbonyloxymethyl 7-trifluoromethylmercaptoacetamido-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH2:10]O)=[CH:4][CH:3]=1.[BrH:18]>>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH2:10][Br:18])=[CH:4][CH:3]=1
Reactant: OCc1ccccc1CCc1ccc(Br)cc1
Reactant: Br
Product: BrCc1ccccc1CCc1ccc(Br)cc1

Procedure:
A suspension of 28.5 g. (0.098 mole) of 2-(4-bromophenethyl)-benzyl alcohol in 150 ml. of 48% hydrobromic acid is stirred at reflux for 3 hours. The cooled two-phase mixture is extracted with benzene. Evaporation of the washed and dried benzene extract under reduced pressure leaves the product as the residual solid, m.p. 63°-75° C. Recrystallization from hexane affords purified material, m.p. 76°-77.5° C. A sample for analysis melts at 76.5°-78° C. after further recrystallization from hexane.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[O:12]>C(=O)([O-])O.[Na+]>[OH:12][C@H:11]([CH2:3][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:1])[C:10]([O:14][CH3:15])=[O:13]
Reactant: C=C(C)c1ccccc1
Reactant: COC(=O)C=O
Agent: O=C([O-])O
Agent: [Na+]
Product: C=C(C[C@@H](O)C(=O)OC)c1ccccc1
Temperature: -30 °C
Yield: 97 %

Procedure:
A solution of an (R)-binaphthol-dichlorotitanium complex which had been prepared in the same manner as in Example 1 was cooled to -30° C. and added with 118 mg (1 mmole) of α-methylstyrene and 88 mg (1 mmole) of methyl glyoxylate, followed by reaction for 15 hours. Then, 10 ml of an aqueous sodium hydrogen-carbonate solution was added to terminate the reaction. The reaction mixture was filtered through Celite and extracted with two 20 ml portions of diethyl ether and two 20 ml portions of ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. Thereafter, the solvents were distilled off, and hexane was added to the residue to crystallize binaphthol. The remaining solution was purified by means of silica gel column chromatography to obtain 200 mg of methyl (R)-2-hydroxy-4-phenyl-4-pentenoate. The yield was 97%.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:7](Cl)=[C:8]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=2)[C:9](O)=[O:10])=[CH:4][C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2.[NH2:23][NH2:24]>C(O)(C)C>[S:1]1[C:5]([C:6]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:8]3[C:7]=2[NH:24][N:23]=[C:9]3[OH:10])=[CH:4][C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2
Reactant: NN
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(-c2cc3ccccc3s2)c1Cl
Solvent: CC(C)O
Product: O=[N+]([O-])c1cc(-c2cc3ccccc3s2)c2[nH]nc(O)c2c1
Temperature: 90 °C

Procedure:
A mixture of 3-Benzo[b]thiophen-2-yl-2-chloro-5-nitro-benzoic acid (0.11 g, 0.33 mmol), hydrazine (0.35 mL) and isopropyl alcohol (3 mL) was heated to about 90° C. for about 1 hour. The mixture was cooled then the solvents were evaporated under reduced pressure. The residue was treated with 6N aqueous hydrochloric acid (5 mL) the mixture was extracted with ethyl acetate (3×30 mL). The organic extracts were combined then concentrated to give 7-Benzo[b]thiophen-2-yl-5-nitro-1H-indazol-3-ol RP-HPLC (Table 1, Method e) Rt 1.41 min; m/z: (M−H)− 310.24.
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](SC2C(C)=C(S(O)(=O)=O)C(C)=C(N)C=2C)=[CH:4][C:3]=1S(O)(=O)=O.N1C(Cl)=NC(Cl)=NC=1Cl>N1C=CC=CC=1>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1c(N)c(C)c(S(=O)(=O)O)c(C)c1Sc1cc(S(=O)(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
1-Amino-4-(3'-amino-2',4',6'-trimethyl-5'-sulfophenylthio)anthraquinone-2-sulfonic acid (23.7 parts), cyanuric chloride (9.3 parts) and 1-aminobenzene-3-β-sulfatoethylsulfone (14.1 parts) were subjected to condensation reactions one after another in an aqueous medium in a usual manner, followed by condensation reaction with pyridine (4.5 parts) at 60° to 70° C. under a weak acid condition. Thereafter, salting out of the reaction mixture gave an anthraquinone compound of the following formula (free acid form). ##STR580##
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11](O)=O)=[CH:4][C:3]=2[O:2]1.C1C[O:17]CC1>>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([OH:17])[CH3:11])=[CH:4][C:3]=2[O:2]1
Reactant: C1CCOC1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Product: CC(O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 2-(3,4-methylenedioxy)phenylacetic acid (5 g, 25.75 mmol) in anhydrous THF (20 ml) at 0° C. was added BH3 THF (40 ml, 1.0 M in THF). The mixture was stirred at room temperature for 1 h. To work up, THF was evaporated on a rotavap. The residue was treated with water (100 ml) Acidified and extracted with ether (2×100 ml). Removal of the solvent under reduced pressure gave 2-(3,4-methylenedioxy)phenyl-1-ethanol as an oil (4.7 g, 98% yield).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([C:25]([O:27][CH3:28])=[O:26])[C:21]([CH3:24])=[N:22][CH:23]=2)[CH2:14][C@H:13]1[O:29][CH3:30])=O)C1C=CC=CC=1>[C].[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([C:25]([O:27][CH3:28])=[O:26])[C:21]([CH3:24])=[N:22][CH:23]=2)[CH2:14][C@H:13]1[O:29][CH3:30]
Reactant: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)cnc1C
Agent: [Pd]
Product: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)cnc1C
Yield: 74.3 %

Procedure:
The same operation as in Example (160c) was performed using methyl cis(±)-5-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-2-methylpyridine-3-carboxylate obtained in Example (171a) (225 mg) and a 10% palladium-carbon catalyst (250 mg), to obtain 113 mg of the title compound as a yellow oily substance. The resulting compound was used for the next reaction without purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:13]2[N:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1.C(N(CC)CC)C>C(Cl)Cl>[N:23]1([NH:22][C:19]([C:16]2[CH:17]=[N:18][C:13]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:14][CH:15]=2)=[O:21])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1
Reactant: NN1CCc2ccccc21
Reactant: O=C(O)c1cnc(-c2ccccc2)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NN1CCc2ccccc21)c1cnc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.8 %

Procedure:
Oxalyl chloride in DCM (2 M, 1.5 mL) is added to a solution of 2-phenyl-pyrimidine-5-carboxylic acid (200 mg, 2 mmol) in DCM (20 mL) and stirred at rt for 2 h. The reaction solution is concentrated in vacuo. The residue is dissolved in DCM (20 mL). N-amino-indoline (268 mg, 2 mmol) and triethylamine (404 mg, 4 mmol) are added and stirred at rt overnight. The mixture is concentrated in vacuo and the residue is purified by silica gel column chromatography eluting with 0-40% EtOAc in heptane to afford 2-phenyl-pyrimidine-5-carboxylic acid (2,3-dihydro-indol-1-yl)-amide (195 mg, 31%) as a solid. MS: 317 (M+H); 1H NMR (300 MHz, CD3OD): δ 3.07 (t, 2H), 3.77 (t, 2H), 6.76 (m, H), 6.82-6.95 (m, H) 7.09-7.24 (m, 2H), 7.54-7.63 (m, 3H), 8.52 (d, 2H), 9.28 (s, 2H) and 2-phenyl-pyrimidine-5-carboxylic acid (indol-1-yl)-amide (10 mg, 2%). MS: 315 (M+H). IC50=2 nM.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:22])[CH2:7][C@@H:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][O:9]1>CO.O>[C:18]([O:17][C:15]([NH:14][C@H:11]1[CH2:10][O:9][C@H:8]([CH2:7][C:6]([OH:22])=[O:5])[CH2:13][CH2:12]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)C[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)CO1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](CC(=O)O)OC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
Lithium hydroxide monohydrate (61 mg, 1.46 mmol, 2.0 eq) is added at room temperature to a stirred solution of (2S,5R)-(5-tert-butoxycarbonylamino-tetrahydro-pyran-2-yl)-acetic acid methyl ester (200 mg, 0.73 mmol, 1.0 eq) in methanol (10 mL) and water (5 mL) and the resulting mixture is stirred at room temperature for 2 hours. Then solvents are evaporated, the residue is acidified to pH 2 with 2.0 M hydrochloric acid aqueous solution and the resulting aqueous layer is extracted with ethyl acetate (3×20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford (2S,5R)-(5-tert-butoxycarbonylamino-tetrahydro-pyran-2-yl)-acetic acid as a colorless oil (150 mg, 79% yield).
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=1.Cl[C:23]1[C:24]([C:31]([OH:33])=[O:32])=[CH:25][N:26]([CH3:30])[C:27](=[O:29])[CH:28]=1>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:23]2[C:24]([C:31]([OH:33])=[O:32])=[CH:25][N:26]([CH3:30])[C:27](=[O:29])[CH:28]=2)=[C:16]([F:21])[CH:15]=1
Reactant: Cn1cc(C(=O)O)c(Cl)cc1=O
Reactant: Nc1ccc(Br)cc1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cn1cc(C(=O)O)c(Nc2ccc(Br)cc2F)cc1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
To a solution of i-Pr2NH (0.39 mL, 2.80 mmol) in THF (4 mL) at 0° C. was added n-BuLi (1.1 mL, 2.80 mmol, 2.5 M solution in hexanes). After stirring 15 minutes, the mixture was cooled to −78° C. 4-Bromo-2-fluorophenylamine (0.38 g, 2.0 mmol) was added. After vigorous stirring for 10 minutes, a mixture of the 4-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.15 g, 0.80 mmol) in THF (5 mL) was added. The dry-ice bath was removed after 30 minutes, and the reaction mixture was stirred for 17 hours at room temperature. The reaction mixture was treated with a 10% aqueous HCl solution (15 mL), extracted with EtOAc, dried (MgSO4), and concentrated. Trituration with methylene chloride gave 0.21 g (77%) desired product. MS APCI (−) m/z 339, 341 (M−, Br pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.53 (s, 1H), 7.69 (dd, 1H), 7.46 (m, 2H), 3.41 (s, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH3:30][C:31]1[N:36]=[C:35](Cl)[CH:34]=[CH:33][N:32]=1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:33]4[CH:34]=[CH:35][N:36]=[C:31]([CH3:30])[N:32]=4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: Cc1nccc(Cl)n1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(c2ccnc(C)n2)C3)cc1

Procedure:
Compound (dv) was prepared according to the procedure described in Example 2 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 2-methyl-4-chloropyrimidin. LC-MS: m/z=+489 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7](/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][C:18]3[CH:24]=[CH:23][C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[CH:20]([S:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:19]=3[CH:35]=1)[CH:6]=[CH:5]2.[OH-].[Na+:37]>O1CCCC1.CO>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7](/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][C:18]3[CH:24]=[CH:23][C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[CH:20]([S:29][CH2:30][CH2:31][C:32]([O-:34])=[O:33])[C:19]=3[CH:35]=1)[CH:6]=[CH:5]2.[Na+:37]
Reactant: O=C(O)CCSC1c2ccccc2C=Cc2ccc(/C=C/c3ccc4cc(F)c(F)cc4n3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C([O-])CCSC1c2ccccc2C=Cc2ccc(/C=C/c3ccc4cc(F)c(F)cc4n3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-{[3-[(E)-2-(6,7-difluoroquinolin-2-yl)ethenyl]-5H-dibenzo[a,d]cyclohepten-5-yl]thio}propionic acid obtained in Example 4(a) was dissolved as such in a mixed solution of 10 ml of tetrahydrofuran and 20 ml of methanol, 0.35 ml (0.35 mmol) of an aqueous 1N sodium hydroxide solution was added to the solution and the mixture was stirred at room temperature for 1 hour.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2S[CH2:11][CH2:10][O:9][N:8]=2)=[CH:4][CH:3]=1.[S:13]([O-:17])([O-])(=O)=[O:14].[Mg+2].ClC1C=C(C=CC=1)C(OO)=O>C=Cl.C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]2[S:13](=[O:17])(=[O:14])[CH2:11][CH2:10][O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)([O-])[O-]
Reactant: Clc1ccc(C2=NOCCS2)s1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Mg+2]
Solvent: ClCCl
Product: O=S1(=O)CCON=C1c1ccc(Cl)s1
Temperature: 30 °C
Yield: 103.3 %

Procedure:
3-(5-Chloro-2-thienyl)-5,6-dihydro-1,4,2-oxathiazine (12g, 0.055 mol) prepared in Example 1, in methylene chlorine (50 ml) and anhydrous magnesium sulphate (10 g) in suspension, was stirred while m-chloroperoxybenzoic acid (34g, 50-60% material) in methylene chloride (250 ml), was added dropwise, to prepare a reaction mixture. The reaction mixture was allowed to warm to 30° C. and after the dropwise addition was externally heated to 35° C. for 10 hours by which time a negative starch/Kl test was obtained. Unwanted m-chlorobenzoic acid was then removed from the reaction mixture by extraction with aqueous sodium bicarbonate. The remaining reaction mixture was washed with water, dried (MgSO4) and evaporated to dryness. The resultant residue was chromatographed on 500 g silica gel eluting with methylene chloride, to produce 3-(5-chloro-2-thienyl)-5,6-dihydro-1,4,2-oxathiazine-4,4-dioxide (mp 113-114° C., 14.3g, Found: C 33.27, H 2.33, N 5.55; C7H6ClNO3S2 requires C 33.40, H 2.39, N 5.57).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C@@H:3]2[CH2:7][CH2:8][O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C@H:2]12.[CH2:16](N(CC)CC)[CH3:17].C(Cl)(=O)C>C(Cl)Cl>[CH2:16]([N:4]1[CH2:5][CH2:6][O:1][C@H:2]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][C@@H:3]12)[CH3:17]
Reactant: CCN(CC)CC
Reactant: c1ccc2c(c1)OCC[C@H]1NCCO[C@@H]21
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CCN1CCO[C@H]2c3ccccc3OCC[C@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.01M of cis-3,4,4a,5,6,11b-hexahydro-2H-[1]benzoxepino[5,4-b]-1,4-oxazine and 0.011M of triethylamine in 25 ml of methylene chloride was cooled in ice and treated dropwise with 0.01M of acetyl chloride in 10 ml of methylene chloride. After stirring at room temperature overnight, the solution was extracted with dilute hydrochloric acid and dried over magnesium sulfate. Evaporation of the solvent left an oil which was dissolved in 10 ml of dry tetrahydrofuran and this solution added dropwise to a suspension of 0.01M of lithium aluminum hydride in 25 ml of tetrahydrofuran. After refluxing five hours, the mixture was cooled in ice and decomposed with 15% sodium hydroxide. After stirring overnight, the solids were filtered and the solvent removed from the filtrate. Kugelrohr distillation of the residue at 110°-116° C./0.2 mm gave the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([C@@H:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:9][CH2:10][N:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:7]=1.[OH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[C:36]([OH:38])=[O:37]>CC(C)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([C@@H:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:9][CH2:10][N:11]([CH:12]([CH3:14])[CH3:13])[CH:15]([CH3:16])[CH3:17])[CH:7]=1.[OH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[C:36]([O-:38])=[O:37]
Reactant: O=C(O)c1ccc2ccccc2c1O
Agent: Cc1ccc(O)c([C@H](CCN(C(C)C)C(C)C)c2ccccc2)c1
Solvent: CC(C)=O
Product: O=C([O-])c1ccc2ccccc2c1O
Reaction time: 0.5 h

Procedure:
3.25 g of tolterodine dissolved in 50 mL of acetone was mixed at room temperature (25° C.) with 1.88 g of 1-hydroxy-2-naphthoic acid, which was suspended in 50 mL of acetone, and then stirred for 30 minutes. Acetone in the above mixture was removed by nitrogen reflux apparatus, and when about 10˜20 mL of acetone was removed there started to appear a solid precipitate. After stirring the mixture at room temperature (25° C.) for 1 hour, the solid precipitate was filtered and then washed with hexane. The resultant was dried at room temperature (25° C.) for 24 hours and 4.32 g (theoretical yield: 84.1%) of the final product in light brown solid was obtained.