Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N([O-])=[O:16].[Na+].Cl>CN(C)C=O>[N:8]([N:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:16]
Reactant: O=N[O-]
Reactant: NN(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=NN(c1ccccc1)c1ccccc1

Procedure:
The compound 1,1-diphenylhydrazine is commercially available. The substituted 1,1-diphenylhydrazines can be made by reacting the corresponding 1,1-diarylamine with sodium nitrite and hydrochloric acid in dimethylformamide at about 10° C. to produce an N-nitrosodiphenylamine, then adding the N-nitroso compound in tetrahydrofuran to a suspension of lithium aluminum hydride in dry ether under nitrogen and maintaining the temperature at 25°-35° C. for about 11/2 hours. The procedure is analogous to that given for preparation of N-amino-iminodibenzyl in Cohen et al., U.S. Pat. No. 3,457,271.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][CH:3]=1.[CH3:9][S-:10].[Na+]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC>[CH3:9][S:10][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Clc1ccc(Cl)cc1
Reactant: C[S-]
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: CSc1ccc(Cl)cc1

Procedure:
A 4-necked, 1-liter flask equipped with a stirrer, a thermometer and a condenser tube was charged with 147.0 g (1.00 mole) of 1,4-dichlorobenzene and 67.9 g (0.10 mole) of an aqueous solution of 50 wt % tetra-n-butylphosphonium bromide. 233.6 g (1.00 mole) of an aqueous solution of 30 wt % sodium thiomethoxide was added dropwise at 80° C. over a period of 6 hours. After addition, the mixture was reacted at the same temperature for 10 hours. After completion of reaction, 157.4 g of a crude 1-methylthio-4-chlorobenzene was obtained by separation procedure.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]2[C:11](=[O:24])[N:12]([O:20]CC=C)[C:13](=[O:19])[C:14]3=[CH:15][CH:16]=[C:17]([Cl:18])[C:8]([C:9]=23)=[C:7]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:6]=1)(=[O:3])[CH3:2].C1([SiH3])C=CC=CC=1>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([NH:4][C:5]1[C:10]2[C:11](=[O:24])[N:12]([OH:20])[C:13](=[O:19])[C:14]3=[CH:15][CH:16]=[C:17]([Cl:18])[C:8]([C:9]=23)=[C:7]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: C=CCON1C(=O)c2ccc(Cl)c3c(N4CCCC4)cc(NC(C)=O)c(c23)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Product: CC(=O)Nc1cc(N2CCCC2)c2c(Cl)ccc3c2c1C(=O)N(O)C3=O
Reaction time: 1 h
Yield: 44.6 %

Procedure:
A solution of 4-acetylamino-2-allyloxy-7-chloro-6-(pyrrolidin-1-yl)benzo[de]isoquinoline-1,3-dione (0.24 g, 0.6 mmol, from Example H4) and phenylsilane (0.13 g, 1.2 mmol) in 15 mL of dichloromethane was cooled to 15° C. and treated with tetrakis(triphenylphosphine)palladium (27 mg, 0.02 mmol). The reaction was stirred for 1 hour and the solvent removed in vacuo. The residue was dissolved in methanol, filtered, and evaporated in vacuo. The residue was stirred with ether to give a fine precipitate which was filtered, washed with ether, and dried in vacuo to give 0.1 g of the title compound, mp 152-154° C.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1([CH2:20][CH:21]=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[C@@H:23]12[NH:30][C@@H:27]([CH2:28][CH2:29]1)[CH2:26][CH:25]([N:31]1[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]1[CH3:40])[CH2:24]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:1][N:2]([CH2:10][C:11]1([CH2:20][CH2:21][N:30]2[C@H:27]3[CH2:28][CH2:29][C@@H:23]2[CH2:24][CH:25]([N:31]2[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=[C:32]2[CH3:40])[CH2:26]3)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CN(CC1(CC=O)CCc2ccccc21)C(=O)OC(C)(C)C
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(CN(C)C(=O)OC(C)(C)C)CCc2ccccc21
Reaction time: 8 h
Yield: 70.9 %

Procedure:
tert-butyl methyl{[1-(2-oxoethyl)-2,3-dihydro-1H-inden-1-yl]methyl}carbamate (600 mg, 1.98 mmole) and 1-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1H-benzimidazole (622 mg, 1.98 mmole) was dissolved in 50 ml of DCE to which was added sodium triacetoxyborohydride (839 mg, 3.96 mmole) which was stirred overnight. A saturated solution of NaHCO3 was added to quench the remaining hydride. The organic layer was washed with water and evaporated. The resulting residue was absorbed into silica gel and 100% EtOAc was use to remove impurities followed by Methanol to remove the product affording 0.7425 g of tert-butyl methyl[(1-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2,3-dihydro-1H-inden-1-yl)methyl]carbamate (70% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[NH2:24])=[O:20]>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:24][C:23]2[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:21]([C:19]([O:18][CH3:17])=[O:20])[CH:22]=2)=[N:3][CH:4]=1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: COC(=O)c1cc(N)ccc1OC
Product: COC(=O)c1cc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)ccc1OC

Procedure:
In like manner to the preparation of 5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 3-methyloxycarbonyl-4-methoxyaniline were reacted to yield 5-fluoro-N4-(3-hydroxyphenyl)-N2-(3-methyloxycarbonyl-4-methoxyphenyl)-2,4-pyrimidinediamine R940301. 1H NMR (DMSO-d6): δ 9.93 (1H, s), 9.79 (1H, s), 9.54 (1H, s), 8.26 (1H, s, J=4.5 Hz), 7.92 (1H, s), 7.81 (1H, dd, J=9.3 Hz, J=2.7 Hz), 7.32 (1H, d, J=8.1 Hz), 7.20-7.13 (3H, m), 6.64 (1H, d, J=8.1 Hz), 3.89 (3H, s), 3.84 (3H, s); purity: 97%; MS (m/e): 385 (MH+).
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[N:14](C(OC(C)(C)C)=O)[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([NH:3][C:4]([CH:6]1[NH:14][C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCNC(=O)C1Cc2cccnc2N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)C1Cc2cccnc2N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.6 %

Procedure:
In a 100 mL round-bottomed flask, tert-butyl 2-(ethylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (402 mg, 1.38 mmol, Eq: 1.00) was combined with DCM (8 mL) to give a colorless solution. TFA (2 mL, 26.0 mmol, Eq: 18.8) was added and the reaction was stirred at rt for 6 h. The reaction mixture was concentrated in vacuo, saturated aqueous NaHCO3 (30 mL) was added and the resulting mixture was extracted with DCM (20 mL×3). The organic layers were dried over Na2SO4 and concentrated in vacuo to give 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethylamide as an off-white solid (210 mg), m/z=192 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:33]([CH3:36])([CH3:35])[CH3:34])[N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([NH:17][C:18](=[O:24])[O:19][C:20](C)(C)C)[CH3:16])[N:8]=1.Cl.C([O-])(O)=O.[Na+].ClC(OC)=O>CO.C1COCC1.O>[Br:1][C:2]1[N:3]=[C:4]([C:33]([CH3:34])([CH3:36])[CH3:35])[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([NH:17][C:18](=[O:24])[O:19][CH3:20])[CH3:16])[N:8]=1
Reactant: C[C@@H](CNc1nccc(-c2c(Br)nc(C(C)(C)C)n2COCC[Si](C)(C)C)n1)NC(=O)OC(C)(C)C
Agent: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC(=O)N[C@@H](C)CNc1nccc(-c2[nH]c(C(C)(C)C)nc2Br)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
To a solution of (S)-tert-butyl 1-(4-(4-bromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (2.66 g, 3.94 mmol, Example 7, Step 1) in MeOH (17 mL) was added aqueous concentrated HCl (1.97 mL, 23.65 mmol) and the resulting reaction was stirred at 60° C. for 1 hour. The reaction was allowed to cool to room temperature and concentrated in vacuo to give 2.28 g of crude residue. This material was then suspended in 1:1 THF-water (100 mL) followed by the addition of NaHCO3 (1.66 g, 19.70 mmol). The mixture was cooled to 5° C. and methyl chloroformate (1.0 M in THF, 4.33 mL, 4.33 mmol) was added dropwise. After 50 minutes, an additional charge of methyl chloroformate (1.0 M in THF, 4.33 mL, 4.33 mmol) was added and the reaction maintained for 45 minutes at 0° C. The reaction was quenched with water (300 mL) and the resulting layers were separated. The aqueous phase was extracted with EtOAc (2×200 mL) and the combined organic portions were washed with brine (2×400 mL), dried (Na2SO4), and concentrated. The resulting residue was triturated with 1:4 EtOAc-hexanes (10 mL) and washed with ether to provide 958 mg of (S)-methyl 1-(4-(4-bromo-2-tert-butyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate: LCMS (m/z) 411.0 (MH+), tR=0.65 minute.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C-:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH3:7].[Li+].[CH3:13][Si:14](Cl)([CH3:16])[CH3:15]>C1COCC1>[CH3:1][Si:2]([CH3:10])([CH3:11])[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH2:7][Si:14]([CH3:16])([CH3:15])[CH3:13]
Reactant: C[Si](C)(C)Cl
Reactant: CC(=[C-][Si](C)(C)C)C=C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=C[Si](C)(C)C)C=C(C)C[Si](C)(C)C
Reaction time: 8 h

Procedure:
To a solution initially at -35° C. of 3.609 g (20.7 mmol) of lithium (1-(trimethylsilyl)-2,4-dimethylpentadienide) in 30 mL of THF was added about 5 g (-46 mmol) of trimethylsilyl chloride. Copious precipitate formed immediately. After stirring overnight, the solvent was removed and the residue was extracted with pentane. After filtering, the solvent was removed under reduced pressure to give the product as a pale yellow liquid. The yield was 4.05 g, 81.3 percent. Major isomer: 1H NMR (C6D6) δ 5.72 (s, 1H), 5.50 (s, 1H), 1.88 (s, 3H), 1.85 (s, 2H), 1.69 (s, 3H), 0.20 (s, 9H), 0.06 (s, 9H). 13C NMR (C6D6) δ 151.8, 135.6, 128.9, 126.4, 27.8, 24.6, 23.5, 0.7, -0.2.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.O[N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19].CCN=C=NCCCN(C)C.Cl>O1CCCC1.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][N:13]2[C:17](=[O:18])[CH2:16][CH2:15][C:14]2=[O:19])=[O:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(ON1C(=O)CCC1=O)c1ccc(Br)cc1Cl
Yield: 91.6 %

Procedure:
A solution of 4-bromo-2-chlorobenzoic acid (2.00 g, 8.5 mmol), N-hydroxysuccinimide (1.07 g, 9.3 mmol) and EDCl (1.79 g, 9.3 mmol) in tetrahydrofuran/N,N-dimethylformamide (3:1; 40 mL) was stirred at room temperature for 18 h. The reaction was concentrated and water (50 mL) was added. The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were washed with brine, dried (Na2SO4), concentrated, and dried in vacuo to give 1-[(4-bromo-2-chlorobenzoyl)oxy]-2,5-pyrrolidinedione (2.59 g, 92%) as an off-white solid which was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([OH:33])([C:25]4[CH:30]=[CH:29][C:28]([CH2:31]O)=[CH:27][CH:26]=4)[C:19]4[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=4)[CH:16]=3)[N:11]([CH3:34])[C:10](=[O:35])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:38])=O>>[Cl:38][CH2:31][C:28]1[CH:29]=[CH:30][C:25]([C:18]([OH:33])([C:19]2[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=2)[C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[N:11]([CH3:34])[C:10](=[O:35])[CH:9]=[C:8]3[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:26][CH:27]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1cncc1C(O)(c1ccc(CO)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Product: Cn1cncc1C(O)(c1ccc(CCl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reaction time: 2 h
Yield: 100 %

Procedure:
A mixture of (±)-4-(3-chlorophenyl)-6-[hydroxy[4-(hydroxymethyl)phenyl](1-methyl-1H-imidazol-5yl)methyl]-1-methyl-2(1H)-quinolinone (described in Example B9) (0.000823 mol) in thionyl chloride (4 ml) was kept at room temperature for 2 hours. The solvent was evaporated till dryness. The residue was taken up in H2O. EtOAc was added. The mixture was basified with K2CO3 (10%) and extracted. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated, yielding 0.43 g (>100%) of (±)-6-[[4-(chloromethyl)phenyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4(3-chlorophenyl)-1-methyl-2(1H)-quinolinone.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:16])[C:13](O)=[O:14])=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[N:17]1(C(N)=O)[CH2:21]CC[CH2:18]1>>[CH3:18][N:17]([CH3:21])[C:13](=[O:14])[CH:12]([C:9]1[CH:10]=[CH:11][C:6]([C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[CH:7][CH:8]=1)[CH3:16]
Reactant: NC(=O)N1CCCC1
Reactant: CC(C(=O)O)c1ccc(C(=O)C2CC2)cc1
Product: CC(C(=O)N(C)C)c1ccc(C(=O)C2CC2)cc1

Procedure:
2-(4-Cyclopropanecarbonyl-phenyl)-proprionic acid, pyrrolidineamide;
Reaction SMILES: Cl.Cl.NC[C@H](N1CCN(S(C(C)C)(=O)=O)CC1)C(OC)=O.Cl.CC1C=C(COC2C=CC(S(Cl)(=O)=O)=CC=2)C2C(=CC=CC=2)N=1.[CH3:46][C:47]1[CH:56]=[C:55]([CH2:57][O:58][C:59]2[CH:64]=[CH:63][C:62]([S:65]([NH:68][CH2:69][C@H:70]([N:75]3[CH2:80][CH2:79][N:78]([S:81]([CH:84]([CH3:86])[CH3:85])(=[O:83])=[O:82])[CH2:77][CH2:76]3)[C:71]([O:73][CH3:74])=[O:72])(=[O:67])=[O:66])=[CH:61][CH:60]=2)[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[N:48]=1>>[CH3:46][C:47]1[CH:56]=[C:55]([CH2:57][O:58][C:59]2[CH:64]=[CH:63][C:62]([S:65]([NH:68][CH2:69][C@H:70]([N:75]3[CH2:80][CH2:79][N:78]([S:81]([C:84]([CH3:86])=[CH2:85])(=[O:82])=[O:83])[CH2:77][CH2:76]3)[C:71]([O:73][CH3:74])=[O:72])(=[O:67])=[O:66])=[CH:61][CH:60]=2)[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[N:48]=1
Reactant: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1)N1CCN(S(=O)(=O)C(C)C)CC1
Agent: COC(=O)[C@H](CN)N1CCN(S(=O)(=O)C(C)C)CC1
Agent: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Agent: Cl
Product: C=C(C)S(=O)(=O)N1CCN([C@@H](CNS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)C(=O)OC)CC1

Procedure:
In a manner analogous to example 17.6, using 620 mg (1.5 mmol) of methyl (S)-3-amino-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propanoate dihydrochloride and 830 mg (2.1 mmol) of 4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride hydrochloride (prepared as described in the example 17.2), 505 mg (54%) of methyl (S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propanoate are obtained in the form of a white solid.
Reaction SMILES: [Si]([O:8][C@H:9]1[C:18]2[C:13](=[CH:14][C:15]([O:27][CH:28]([CH3:30])[CH3:29])=[C:16]3[C:22]([CH2:23][CH2:24][CH3:25])=[CH:21][C:20](=[O:26])[O:19][C:17]3=2)[O:12][C@H:11]([CH3:31])[C@H:10]1[CH3:32])(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].O>C1COCC1.[Cl-].[Na+].O>[OH:8][C@H:9]1[C:18]2[C:13](=[CH:14][C:15]([O:27][CH:28]([CH3:30])[CH3:29])=[C:16]3[C:22]([CH2:23][CH2:24][CH3:25])=[CH:21][C:20](=[O:26])[O:19][C:17]3=2)[O:12][C@H:11]([CH3:31])[C@H:10]1[CH3:32]
Reactant: CCCc1cc(=O)oc2c3c(cc(OC(C)C)c12)O[C@H](C)[C@@H](C)[C@H]3O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cc(=O)oc2c3c(cc(OC(C)C)c12)O[C@H](C)[C@@H](C)[C@H]3O
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.6 %

Procedure:
To a solution of 6a (130 mg, 0.29 mmol) in THF (5 mL) was added Bu4NF (1.45 mL, 1M solution in THF) at 0° C. The reaction mixture was stirred at room temperature for 6 h. Water was added (2 mL), followed by brine (2 mL). The solution was extracted with ether (3×5 mL). The combined organic layers were dried (MgSO4), concentrated, and submitted for silica gel chromatography (Solvent B) to obtain 7a (92 mg, 91%) as a syrup: [α]D20 +26.5° (c 1.1, CHCl3); 1H NMR (CDCl3): δ 0.97 (t, 3 H, J=7.3 Hz, --CH2 CH2CH3), 1.08 (d, 3 H, J=7.0 Hz, --CHCH3), 1.37 [d, 9 H, J=6.2 Hz, --CH(CH3)2, CHCH3 ], 1.57 (m, 2 H, --CH2 CH2CH3), 1.70 (m, 1 H, H-9), 2.99 (m, 2 H, --CH2CH2 CH3), 4.22 (m,1 H, H-8), 4.59 [m, 1 H, --CH(CH3)2 ], 4.91 (d, 1 H, J=2.7 Hz, H-10), 5.88 (s, 1 H, H-3), 6.16 (s, 1 H, H-6): 13 C NMR (CDCl3): δ 12.49, 13.84, 18.83, 21.69, 21.74, 23.15, 38.38, 38.89, 61.65, 70.65, 72.87, 96.65, 104.20, 106.18, 110.10, 155.12, 156.36, 158.03, 159.09, 161.07. Anal. Calcd for C20H26O5 : C, 69.34; H, 7.56. Found: C, 69.15; H, 7.93.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1C=CC=CC=1>[CH2:24]([O:23][C:21]([CH2:20][N:15]1[CH2:16][CH2:17][CH2:18][CH:14]1[C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)=[O:22])[CH3:25]
Reactant: c1ccc(Oc2ccc(C3CCCN3)cc2)cc1
Reactant: CCOC(=O)CBr
Solvent: c1ccccc1
Product: CCOC(=O)CN1CCCC1c1ccc(Oc2ccccc2)cc1

Procedure:
To a solution of 23.9 parts of 2-(4-phenoxyphenyl) pyrrolidine in 80 parts of anhydrous benzene, there were quickly added 8.35 parts of ethyl bromacetate. The reaction mixture was then refluxed for 4 hours. After cooling and filtration, the residue was treated with 50 parts of water and 100 parts of ether. After decantation, then distillation, there were obtained 11.3 parts of 1-ethoxycarbonylmethyl-2-(4-phenoxyphenyl) pyrrolidine, B.P./0.1 mm Hg: 165° C., nD23 : 1.5524.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:8][C:9](=[O:14])[CH2:10][CH2:11][CH2:12]Cl)=[N:4][N:5]([CH3:7])[CH:6]=1.[H-].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[C:3]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(Br)c(NC(=O)CCCCl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cn1cc(Br)c(N2CCCC2=O)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.7 %

Procedure:
To a solution of N-(4-bromo-1-methyl-1H-pyrazol-3-yl)-4-chlorobutanamide (456 mg) in DMF (8.1 mL) was added a sodium hydride 60% dispersion in mineral oil (72 mg) under ice-cooling, and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (114 mg).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[C:26]([CH3:48])=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH:31]([CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])[N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18])#[N:9]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[C:26]([CH3:48])=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH:31]([CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])[NH:30][CH2:29][CH2:28]4)[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18])#[N:9]
Reactant: Cc1c(-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)ccc2c1CCN(C(=O)OC(C)(C)C)C2CCCC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)ccc2c1CCNC2CCCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
Trifluoroacetic acid (1.0 ml, 13.0 mmol) was added dropwise at 25° C. under nitrogen to a solution of 4-(6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2-{[(1,1-dimethylethyl)oxy]carbonyl}-5-methyl-1,2,3,4-tetrahydro-1-isoquinolinyl)butanoic acid (Preparation 32; 102 mg, 0.182 mmol) in dichloromethane (4.0 ml) and the resulting mixture was stirred at 25° C. for 1 h. The solvent was removed, and the residue co-evaporated with toluene followed by trituration with diethyl ether to give the title compound (76 mg) as a white solid.
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(C(C)C)C(C)C)[CH:7]=1.C(O)(=[O:34])/C=C/C1C=CC=CC=1.C1C(O)=CC=C(C)C=1>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:24][C:10](=[O:34])[CH2:9][CH:8]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:6]=2[CH:7]=1
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: Cc1ccc(O)c([C@H](CCN(C(C)C)C(C)C)c2ccccc2)c1
Agent: Cc1ccc(O)cc1
Agent: O=S(=O)(O)O
Product: Cc1ccc2c(c1)C(c1ccccc1)CC(=O)O2

Procedure:
U.S. Pat. No. 5,922,914 provides an alternate method for the preparation of tolterodine. The process involves the cyclization of trans-cinnamic acid with p-cresol in hot sulfuric acid to give 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one, which is reduced with diisobutyl aluminum hydride (DIBAL) in toluene to yield 6-methyl-4-phenyl-3,4-dihydro-2H-1-benzopyran-2-ol. This on reducto-condensation with diisopropylamine, by means of hydrogen over palladium on charcoal in methanol, affords racemic tolterodine of Formula I, which is resolved with L-(+)-tartaric acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([N+:20]([O-])=O)=[C:16]([CH:19]=2)[C:17]#[N:18])(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.O.[NH2:24]N>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:19]=[C:16]3[C:15](=[CH:14][CH:13]=2)[NH:20][N:18]=[C:17]3[NH2:24])(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: N#Cc1cc(S(=O)(=O)c2cc(F)cc(F)c2)ccc1[N+](=O)[O-]
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1n[nH]c2ccc(S(=O)(=O)c3cc(F)cc(F)c3)cc12
Yield: 73 %

Procedure:
5-(3,5-Difluoro-benzenesulfonyl)-2-nitro-benzonitrile (3.5 g, 10.8 mmol) was heated in anhydrous ethanol (175 mL) until completely dissolved. The solution was then treated with hydrazine hydrate (0.58 mL, 1.1 mol eq.) and refluxed for three hours. The reaction mixture was evaporated to dryness; the residue was dissolved in acetone, adsorbed onto flash chromatography-grade silica gel by rotoevaporation of the solvent. The silica was loaded onto a flash chromatography column conditioned with 10:1 dichloromethane/acetone. The column was then eluted with dichloromethane/acetone (gradient: from 10:1 to 2:1) followed by a final washing with dichloromethane/acetone/methanol. The pure fractions were collected and evaporated to afford the title compound as a whitish crystalline powder (2.44 g, 73%).
Reaction SMILES: [CH:1]([C:3]1([CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[O:2].C[Li].[C:28](=O)(O)[O-].[Na+]>C1COCC1.CCOCC>[OH:2][CH:1]([C:3]1([CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21])[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:7][CH2:8]1)[CH3:28]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)(CCO[Si](C)(C)C(C)(C)C)CC1
Agent: [Li]C
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)C1(CCO[Si](C)(C)C(C)(C)C)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-formyl-4-(2-(tert-butyldimethylsilyloxy)eth-1-yl)piperidine-1-carboxylate (6.3 g, 17 mmol) in THF (170 mL) at −70° C. was added 1.4M methyl lithium in ether (13.3 mL, 19 mmol). After 2 h, an additional amount of 1.4M methyl lithium in ether (2.5 mL) was added. After an additional 30 min, the reaction was poured into aq. sodium bicarbonate and extracted three times with ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the title product (6.6 g) which was used directly in the next step.