Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: C1CCNC1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN2CCCC2)no1

Procedure:
Method as for preparation 5 using tert-butyl(3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (126 mg, 0.25 mmol) and pyrrolidine (1001, 1.20 mmol) as starting materials.
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.[CH3:21][C:22]1[O:26][N:25]=[C:24]([C:27]([NH2:34])([CH3:33])[CH2:28][S:29]([CH3:32])(=[O:31])=[O:30])[N:23]=1.Br>>[F:1][C:2]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([NH:34][C:27]([C:24]3[N:23]=[C:22]([CH3:21])[O:26][N:25]=3)([CH3:33])[CH2:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:14])=[N:10][CH:11]=2)[CH2:3][O:4][CH2:5]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2(F)COC2)cn1
Reactant: Cc1nc(C(C)(N)CS(C)(=O)=O)no1
Agent: Br
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(OCC(F)(F)F)c(C3(F)COC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3-fluorooxetan-3-yl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (Example 131b) and 2-(5-methyl-1,2,4-oxadiazol-3-yl)-1-methylsulfonyl-propan-2-amine;hydrobromide (enantiomer A) (example 124b) as starting materials and isolated (40 mg, 47%); MS (ESI, m/z): 497.5 (M+H+).
Reaction SMILES: [CH:1]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([OH:11])=[CH:3][C:2]=1[C:12]([F:15])([F:14])[F:13].[OH-].[K+].O.Cl[CH:20]([CH3:24])[C:21]([NH2:23])=[O:22]>CN(C)C=O>[F:15][C:12]([F:13])([F:14])[C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:7]([F:9])([F:8])[F:10])[CH:1]=1)[O:11][CH:20]([CH3:24])[C:21]([NH2:23])=[O:22]
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(Cl)C(N)=O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a stirred solution containing 5 g (0.22 mole) of 3,5-ditrifluoromethylphenol, 1.6 g (0.024 mole) of 85% potassium hydroxide, 10 ml of water and 200 ml of N,N-dimethylformamide, 0.024 mole of 2-chloropropionamide was added in one portion. The stirred reaction mixture was heated at 120°-130° C. for 46 hours. After cooling to 0° C., 600 g of ice water was added and stirring continued at 0°-10° C. for 30 minutes. The resulting solid was collected by filtration, washed with water until neutral to litmus and air-dried at 25°-30° C. A product with a melting point of 84°-85° C. (determined after recrystallization from heptane) was obtained with a 48% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]([C:31]2[CH:32]=[CH:33][C:34]([C:37](O)=[O:38])=[N:35][CH:36]=2)[N:23]=1>>[Cl:1][C:2]1[C:3]([N:8]([C:37]([C:34]2[CH:33]=[CH:32][C:31]([N:24]3[C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:30]4[N:22]=[N:23]3)=[CH:36][N:35]=2)=[O:38])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-n2nnc3cccnc32)cn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ncccc2Cl)C1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](N(C(=O)c2ccc(-n3nnc4cccnc43)cn2)c2ncccc2Cl)C1
Yield: 51.7 %

Procedure:
Prepared using General Procedures A and C starting from Preparation 1 tert-butyl (3R)-3-[(3-chloropyridin-2-yl)amino]piperidine-1-carboxylate (3.22 g, 10.3 mmol) and Preparation 7 5-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)pyridine-2-carboxylic acid (2.37 g, 9.83 mmol) to provide 2.72 g (52%) of the product isolated as a solid.
Reaction SMILES: O[CH2:2][C:3]1[C:13]2[O:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=2[C:11]([S:19][CH3:20])=[C:5]2[O:6][C:7]([CH3:10])([CH3:9])[O:8][C:4]=12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:41].CO>N1C=CC=CC=1>[Br:41][CH2:2][C:3]1[C:13]2[O:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=2[C:11]([S:19][CH3:20])=[C:5]2[O:6][C:7]([CH3:10])([CH3:9])[O:8][C:4]=12
Reactant: CSc1c2c(c(CO)c3c1OC(C)(C)O3)OC(C)(C)O2
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: c1ccncc1
Product: CSc1c2c(c(CBr)c3c1OC(C)(C)O3)OC(C)(C)O2

Procedure:
4-Hydroxymethyl-8-methylthio-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']bis(1,3)dioxole is dissolved in pyridine. The solution is chilled and triphenylphosphine followed by carbontetrabromide are added the reaction is stirred for an appropriate time. Methanol is added and the product is isolated by a suitable method.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][O:2]1.[N:11]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=1>CO>[N:11]1[CH:16]=[CH:15][C:14]([CH:17]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1](=[O:10])[O:2]2)=[CH:13][CH:12]=1
Reactant: O=C1OCc2ccccc21
Reactant: O=Cc1ccncc1
Solvent: CO
Product: O=C1OC(=Cc2ccncc2)c2ccccc21

Procedure:
In accordance with the procedure described in Lombardino, J.O.C. Vol. 32, pp. 1988-1992 (1967), a solution of isobenzofuran-1-one (13.4 g, 0.1 mol) and 4-pyridine carboxaldehyde (10.7 g, 0.1 mol) in 100 ml dry methanol are refluxed for 2 hours. The solvent is evaporated, and the product (3-(4-pyridylmethylene)isobenzofuran-1-one is used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][NH:5][CH:6]1[CH2:23][CH:22]([OH:24])[CH2:21][C:20]2[CH:19]=[C:18]3[C:9]([C:10](=[O:32])[C:11]4[CH:12]=[CH:13][CH:14](CC)[C:15]5(OCCO5)[C:16]=4[C:17]3=[O:25])=[C:8]([OH:33])[C:7]1=2.Cl.[CH3:36][C:37](C)=[O:38]>>[CH3:34][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][CH:6]1[CH2:23][C:22]([C:37](=[O:38])[CH3:36])([OH:24])[CH2:21][C:20]2[CH:19]=[C:18]3[C:9]([C:10](=[O:32])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[C:17]3=[O:25])=[C:8]([OH:33])[C:7]1=2
Reactant: CC(C)=O
Reactant: CCC1C=CC2=C(C(=O)c3cc4c(c(O)c3C2=O)C(NCCN(C)C)CC(O)C4)C12OCCO2
Agent: Cl
Product: CC(=O)C1(O)Cc2cc3c(c(O)c2C(NCCN(C)C)C1)C(=O)c1ccccc1C3=O

Procedure:
7-(2-Dimethylaminoethyl)amino-9-(1,1-ethylenedioxy)ethyl-6,9-dihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (60 mg) prepared in Example 13 (2) was added to a mixture of acetone (60 ml) and conc. hydrochloric acid (24 ml), and the resultant mixture was heated under reflux for 1 hour. After removal of acetone by distillation under reduced pressure, the water layer was washed with dichloromethane, adjusted to pH 8.0 with aqueous sodium hydroxide solution and extracted with dichloromethane. The extract was purified by silica gel chromatography using a mixture of chloroform and methanol (9:1) to give 7-(2-dimethylaminoethyl)amino-9-acetyl-6,9-dihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (55 mg). M.P., 170°-172° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][C:17]([F:20])([F:19])[CH3:18].[Cl:21][C:22]1[N:23]=[C:24]([C:29](O)=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:21][C:22]1[N:23]=[C:24]([C:29]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH2:16][C:17]([F:20])([F:19])[CH3:18])=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CC(F)(F)CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OCC(C)(F)F)nc1Cl
Yield: 94.3 %

Procedure:
The same operation as in Example (106d) was performed using tert-butyl cis(±)-4-amino-3-(2,2-difluoropropoxy)piperidine-1-carboxylate obtained in Example (128d) (0.68 g, 2.3 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 0.41 g, 2 mmol), WSC hydrochloride (0.77 g, 4 mmol), HOBt (0.41 g, 3 mmol), DMA (15 mL) and dichloromethane (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 0.85 g of the title compound as a colorless solid (94%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])=O.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[BH3-]C#N.[Na+]>CO>[C:21]([O:20][C:18]([N:12]1[CH2:17][CH2:16][N:15]([CH2:1][C:3]2[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=2)[C:6]([OH:8])=[O:7])[CH2:14][CH2:13]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(C(=O)O)c2)CC1
Temperature: 27 °C
Reaction time: 6 h
Yield: 54.6 %

Procedure:
The solution of 3-formylbenzoic acid (300 mg, 1.83 mmol) and tert-butyl piperazine-1-carboxylate (340 mg, 1.83 mmol) in MeOH (10 mL) was stirred at 27° C. for 1 h. Then NaBH3CN (138 mg, 2.19 mmol) was added to the solution and stirred at 27° C. for 6 h. The solution was concentrated and the residue was purified by column to give the title product (320 mg, Yield 50%). LCMS (m/z): 321.2 (M+1).
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].Br[CH:6]([CH3:11])[C:7]([O:9][CH3:10])=[O:8].C(=O)(O)[O-].[Na+]>O>[CH2:1]([NH:4][CH:6]([CH3:11])[C:7]([O:9][CH3:10])=[O:8])[C:2]#[CH:3]
Reactant: COC(=O)C(C)Br
Reactant: C#CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C#CCNC(C)C(=O)OC
Temperature: 80 °C
Yield: 37.7 %

Procedure:
Into a 250 ml round bottom flask are placed 26 g (0.47 mole) of propargylamine, 78.8 g (0.47 mole) of methyl 2-bromopropionate, and 39.7 g (0.47 mole) of sodium bicarbonate. The reaction mixture is heated at 80° C. overnight. It is cooled and poured into 200 ml of water. Extraction with ether provides 45 g of crude product which is further purified by vacuum distillation (94°-95°/3 mm) to give 25 g of desired product.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][CH:6]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[CH3:16][C:17]([S@:20]([NH:22][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([F:15])([F:14])[F:1])=[CH:6][CH:7]=1)[CH3:12])=[O:21])([CH3:19])[CH3:18]
Reactant: CC(=O)c1ccc(OCC(F)(F)F)cc1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OCC(F)(F)F)cc1
Yield: 76 %

Procedure:
The title compound is prepared in 76% yield (0.73 g, colorless oil) from 1-(4-(2,2,2-trifluoroethoxy)phenyl)ethanone (0.65 g, 2.99 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:22]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)=[N:4][C:5]2[N:6]([N:9]=[CH:10][C:11]=2[C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=1[NH2:8].CCN(C(C)C)C(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>CN(C=O)C>[Br:1][C:2]1[C:3]([CH:22]2[CH2:27][CH2:26][CH2:25][N:24]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:23]2)=[N:4][C:5]2[N:6]([N:9]=[CH:10][C:11]=2[C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=1[NH2:8]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1c(Br)c(C2CCCNC2)nc2c(-c3cnc4ccccc4c3)cnn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N)c2Br)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 6-bromo-5-(piperidin-3-yl)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine (HCl salt, 46 mg, 0.10 mmol) in DMF (2.0 mL) was added DIEA (0.10 mL, 0.30 mmol) and methylsulfonyl chloride (14 mg, 0.12 mmol). The reaction mixture was stirred at rt for 3 h and concentrated in vacuo. The residue was purified by prep-LC to give the title compound. LC/MS RT=2.49 min. Mass calculated for, M+H 486.05, observed 389.17.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[C:21]([C:23]([CH3:25])=[CH2:24])[CH:22]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:22]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)c1cncc(-c2cc3c(cn2)cnn3-c2cccc(F)n2)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1cncc(-c2cc3c(cn2)cnn3-c2cccc(F)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
To a solution of the aforesaid 1-(6-fluoro-2-pyridyl)-6-(5-isopropenyl-3-pyridyl)pyrazolo[4,3-c]pyridine in Ethanol (50 mL) in a 250 mL round bottom flask was added Pearlman's catalyst (0.3523 mmol; 247.4 mg). The flask was vacuumed and connected with a balloon of Hydrogen. The mixture was stirred at room temperature for 16 hours. The mixture was filtered through Celite. The filtrate was concentrated. The residue was purified on silica eluted with 0 to 5% MeOH in DCM to afford 1-(6-fluoropyridin-2-yl)-6-(5-isopropylpyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine (479.2 mg, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]=[C:12]([NH:16][C:17](=[O:45])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:44])[CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH2:37][CH3:38])([CH3:36])[CH3:35])=[CH:30][C:29]=3[C:39]([CH2:42][CH3:43])([CH3:41])[CH3:40])[CH:19]=2)[NH:11]1.[Br:46]Br.O>C(O)(=O)C>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14](=[O:15])[C:13]([Br:46])=[C:12]([NH:16][C:17](=[O:45])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:44])[CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH2:37][CH3:38])([CH3:36])[CH3:35])=[CH:30][C:29]=3[C:39]([CH2:42][CH3:43])([CH3:41])[CH3:40])[CH:19]=2)[NH:11]1
Reactant: CCC(C)(C)c1ccc(OCC(=O)Nc2cccc(C(=O)Nc3cc(=O)n(-c4c(Cl)cc(Cl)cc4Cl)[nH]3)c2)c(C(C)(C)CC)c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CCC(C)(C)c1ccc(OCC(=O)Nc2cccc(C(=O)Nc3[nH]n(-c4c(Cl)cc(Cl)cc4Cl)c(=O)c3Br)c2)c(C(C)(C)CC)c1

Procedure:
In 200 ml of acetic acid, 33 g of 1-(2,4,6-trichlorophenyl)-3-[3-(2,4-di-tert-amylphenoxyacetamido)benzamido]-5-pyrazolone was dissolved. 7.5 g of bromine was dropwise added to the solution with stirring. After the completion of the reaction, the reaction mixture was added to water, and the thus obtained crystals recovered by filtration and washed were recrystallized, after drying, from 150 ml of a mixture of ethyl acetate and ligroin (1:10 by volume) to obtain 26 g of 1-(2,4,6-trichlorophenyl-3-[3-(2,4-di-tert-amylphenoxyacetamido)benzamido]-4-bromo-5-pyrazolone having a melting point of 139° to 141° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:32][C:33]1[CH:34]=[C:35]([OH:40])[CH:36]=[CH:37][C:38]=1[Cl:39].O[CH:42]1[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]1>O1CCCC1>[Cl:32][C:33]1[CH:34]=[C:35]([CH:36]=[CH:37][C:38]=1[Cl:39])[O:40][CH:42]1[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.8 %

Procedure:
Diethyl azodicarboxylate (41.0 ml) was added to a solution of triphenylphosphine (62.9 g) in tetrahydrofuran (800 ml) at 0° C. After 15 minutes 3,4-dichlorophenol (39.1 g) was added, after a further 15 minutes tert-butyl 4-hydroxy-1-piperidinecarboxylate (48.3 g) in tetrahydrofuran (400 ml) was added dropwise over 30 min. The solution was stirred at room temperature for 16 hours and concentrated to a small volume. Purification by flash silica chromatography (ethyl acetate:iso-hexane 95:5) gave the sub-title compound as an oil (61.3 g).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])(=O)=O)=CC=1.[CH3:20][C:21]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:22]=1[NH2:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:21]([CH3:20])=[C:22]([NH:23][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])[CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)OCCN2CCOC2=O)cc1
Reactant: COc1ccc(C)c(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C)c(NCCN2CCOC2=O)c1
Temperature: 100 °C

Procedure:
To a flask was added 2.95 g (10.3 mmol) of Toluene-4-sulfonic acid, 2-(2-oxo-oxazolidin-3-yl)-ethyl ester, 1.56 g (11.4 mmol) of 2-methyl-5-methoxyaniline, 2.58 g (18.7 mmol) of potassium carbonate, and 22 mL of anhydrous dimethylformamide, and the mixture was heated at 100° C. for seven hours. The reaction was allowed to cool to room temperature, and was partitioned between ethyl acetate and water. The phases were separated, and the ethyl acetate phase was washed with brine, dried over Na2SO4, filtered, and concentrated to an oil. The oil was purified by chromatography (120 mL silica, 60 ethyl acetate/40 hexanes) to give the corresponding product as a clear oil that solidified upon drying: 1H NMR (DMSO-d6, 400 MHz) 6.81 (d, 1H), 6.11 (s, 1H), 6.04 (d, 1H), 4.92 (t, 1H), 4.21 (t, 2H), 3.65 (s, 3H), 3.59 (m, 2H), 3.31 (m, 2H), 3.23 (m, 2H), 1.95 (s, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH2:16][CH2:17][CH3:18])=[C:11]([C:13]([OH:15])=O)[N:12]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][N:25]=1>>[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[N:25]=[CH:26][C:27]([NH:30][C:13]([C:11]2[N:12]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])[O:9][C:10]=2[CH2:16][CH2:17][CH3:18])=[O:15])=[CH:28][CH:29]=1
Reactant: CCCc1oc(-c2ccccc2Br)nc1C(=O)O
Reactant: COCCN(C)c1ccc(N)cn1
Product: CCCc1oc(-c2ccccc2Br)nc1C(=O)Nc1ccc(N(C)CCOC)nc1

Procedure:
With a procedure similar to example 16 above, 2-(2-bromo-phenyl)-5-propyl-oxazole-4-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-(2-bromo-phenyl)-5-propyl-oxazole-4-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C22H25BrN4O3 (m/e) 473, obsd 474 (M+H).
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].[F:24][C:25]1([F:41])[O:29][C:28]2[CH:30]=[CH:31][C:32]([CH:34]=[CH:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:33][C:27]=2[O:26]1>>[F:41][C:25]1([F:24])[O:29][C:28]2[CH:30]=[CH:31][C:32]([C@H:34]3[C@H:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:2]3([CH3:4])[CH3:3])=[CH:33][C:27]=2[O:26]1
Reactant: CCOC(=O)C=Cc1ccc2c(c1)OC(F)(F)O2
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Product: CCOC(=O)[C@H]1[C@H](c2ccc3c(c2)OC(F)(F)O3)C1(C)C
Yield: 54.3 %

Procedure:
Isopropyltriphenylphosphonium iodide (4.32 g, 10 mmol) and ethyl 3-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-acrylate (2.56 g, 10 mmol) were reacted as described under General Procedure B to furnish the title compound (1.62 g, 54%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 6.96 (d, J=7.1 Hz, 1H), 6.89 (s, 1H), 6.87 (d, J=7.1 Hz, 1H), 4.18 (q, J=7.2 Hz, 2H), 2.66 (d, J=5.8 Hz, 1H), 1.88 (d, J=5.8 Hz, 1H), 1.36 (s, 3H), 1.30 (t, J=7.2 Hz, 3H), 0.92 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][O:8][C:9]2=[O:10])=[CH:5][CH:4]=1.[OH-].[Ca+2].[OH-].[H][H]>CO.O1CCOCC1.[Pd]>[CH3:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][O:8][C:9]2=[O:10])=[CH:5][CH:4]=1
Reactant: O=C1OCc2ccc(CBr)cc21
Reactant: [H][H]
Agent: [Pd]
Agent: [Ca+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc2c(c1)C(=O)OC2
Yield: 96 %

Procedure:
A total of 107 g (472 mmol) of 6-bromomethylphthalide was dissolved in 50 mL of methanol (dioxane was also used in different experiment). The solution was added to a parr bottle with 40 g (540 mmol) of calcium hydroxide and 2 g of 10% Pd/C. The suspension was hydrogenated at 40 psi until no more hydrogen uptake was recorded. All solids were filtered and filtrate was concentrated to a total of 67 g of brown solid in 96% yield. 1H NMR (CDCl3) (300 MHz) δ 2.53 (s, 3H), 5.30 (s, 2H), 7.49 (s 1H), 7.54 (d, 3JHCCH=7.9 Hz, 1H), 7.47 (d, 3JHCCH=7.9 Hz, 1H)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[OH:11].[CH2:12]1[CH2:17][O:16][CH:15]=[CH:14][CH2:13]1.CS(O)(=O)=O>C1COCC1>[Br:1][C:2]1[C:3]([OH:11])=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:15]1[CH2:14][CH2:13][CH2:12][CH2:17][O:16]1)[CH:6]=2
Reactant: C1=COCCC1
Reactant: Oc1cc2cn[nH]c2cc1Br
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Product: Oc1cc2cn(C3CCCCO3)nc2cc1Br
Temperature: 25 °C
Reaction time: 22 h
Yield: 162.3 %

Procedure:
To a solution of 6-bromo-5-hydroxy-1H-indazole (725.0 g, 3.4 mol) in THF (10.2 L) is added DHP (336.5 mL, 3.57 mol) and CH3SO3H (65.4 g, 0.68 mol) at RT. The resulting mixture is stirred at RT for 22 hours. The reaction mixture is quenched with distilled water (6 L) and extracted with EtOAc (6 L). Saturated aqueous NaHCO3 solution (1100 mL) is added to adjust the pH to 8. After phase separation, the organic phase is washed with water (4 L) and then saturated aqueous sodium chloride (3 L), dried over anhydrous Na2SO4, filtered, and concentrated to give the product as a solid (1.64 kg, 99.3% yield). MS (m/z): 299.0 (M+H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([OH:9])[CH2:2]2.[H-].[Na+].[C:12]1([C@H:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20][N:19]2[C:28](OCCC)=[O:29])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH:15]1[CH:16]=[CH:17][C:12]([C@@H:18]2[N:19]([C:28]([O:9][C@@H:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[O:29])[CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]2=3)=[CH:13][CH:14]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CCCOC(=O)N1CCc2ccccc2[C@@H]1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CN2CCC1CC2)N1CCc2ccccc2[C@@H]1c1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
(R)-quinuclidin-3-ol (0.66 g, 5.2 mmol) and sodium hydride (0.21 g, 0.52 mmol, 60%) are dissolved in anhydrous toluene and stirred for 1 hour at 80° C. A solution of propyl (1s)-1-phenyl-3,4-dihydro-2(1H)-isoquinoline-carboxylate (1.4 g, 4.75 mmol) in toluene (10 ml) is added and refluxed for 18 hours. Isopropyl alcohol is removed from the solution by azeotropic distillation during which toluene is necessarily added. The reaction is cooled to ambient temperature when propyl carboxylate is consumed completely according to TLC analysis. The toluene is washed with water and aq. HCl (1N)(10 ml), the organic phase is separated. Saturated sodium bicarbonate (20 ml) is added to the aqueous phase, then extracted with ethyl acetate (20 ml). The combined organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to afford yellow oil as crude Solifenacin base, 1.1 g, 63.9% with the following characteristics: HPLC: 95.8%; Chiral Purity: 99%; MS (ESI): m/z 363.2 (M+H+); 1-H-NMR (400 M, CDCl3): δ 7.32-7.17 (m, 9H), 6.55-6.17 (m, 1H), 4.20-2.90 (m, 1H), 3.36-2.86 (br, 10H), 2.18-1.47 (m, 5H).