Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([NH2:6])=[N:4][CH:3]=[N:2]1.C(N(CC)CC)C.[S:14](Cl)(Cl)(=[O:16])=[O:15].Cl.[Br:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[CH2:33][CH2:34][NH:35][CH2:36]2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.C1COCC1>[Br:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[CH2:33][CH2:34][N:35]([S:14]([NH:6][C:5]1[S:1][N:2]=[CH:3][N:4]=1)(=[O:16])=[O:15])[CH2:36]2
Reactant: O=S(=O)(Cl)Cl
Reactant: Nc1ncns1
Reactant: FC(F)(F)c1ccc(-c2cccc3c2CCNC3)c(Br)c1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Nc1ncns1)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2Br)C1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A suspension of 1,2,4-thiadiazol-5-amine (2.67 g, 26.4 mmol) in 20 mL DCM was treated with triethylamine (3.68 ml, 26.4 mmol) and was allowed to stir for 10 minutes. The reaction mixture was then cooled to −78° C. and was treated with 1 equivalent of sulfuryl chloride. After stirring for 5 minutes, the cooling bath was removed, and the reaction mixture was allowed to stir for an additional hour. LC/MS showed mostly product so the reaction mixture was filtered then concentrated. The resulting residue was dissolved in 10 mL THF and was added to a solution of 5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate D, 4.70 g, 13.20 mmol) and triethylamine (4.05 ml, 29.0 mmol) in 10 mL THF. After stirring for an additional 4 hours, the reaction mixture was poured into 1 N citric acid solution and was extracted with EtOAc. The organics were washed with brine, dried over MgSO4 and concentrated. The resulting residue was triturated with DCM providing a white solid. The washings were purified by silica gel column chromatography (0 to 100% EtOAc/heptane) and combined with the white solid yielding 5-(2-bromo-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (6.90 g, 13.29 mmol). [M+H]+=518.9 1H NMR (400 MHz, Acetone-d6) δ ppm: 8.04 (s, 1H), 7.97 (s, 1H), 7.81 (d, J=7.9 Hz, 1H), 7.54 (d, J=7.9 Hz, 1H), 7.28 (t, J=7.5 Hz, 1H), 7.22 (d, J=7.1 Hz, 1H), 7.01 (d, J=6.1 Hz, 1H), 4.34 (s, 2H), 3.30 (m, 2H), 2.47-2.58 (m, 2H)
Reaction SMILES: [CH2:1]([N:3]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=2)=[CH:6][C:5]([C:17]2[CH:18]=[C:19]([C:23]([NH:26][S:27]([CH2:30][C:31]([F:34])([F:33])[F:32])(=[O:29])=[O:28])([CH3:25])[CH3:24])[CH:20]=[CH:21][CH:22]=2)=[N:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S([CH2:51][N+:52]#[C-:53])(=O)=O)=CC=1.[N+](CS(C1C=CC(C)=CC=1)(=O)=O)#[C-]>CO.O>[CH2:1]([N:3]1[C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[O:16][CH:53]=[N:52][CH:51]=3)=[CH:13][CH:14]=2)=[CH:6][C:5]([C:17]2[CH:18]=[C:19]([C:23]([NH:26][S:27]([CH2:30][C:31]([F:34])([F:32])[F:33])(=[O:28])=[O:29])([CH3:25])[CH3:24])[CH:20]=[CH:21][CH:22]=2)=[N:4]1)[CH3:2]
Reactant: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C=O)cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(-c2cnco2)cc1
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 3 %

Procedure:
N-(2-{3-[1-ethyl-5-(4-formylphenoxy)-1H-pyrazol-3-yl]phenyl}propan-2-yl)-2,2,2-trifluoroethanesulfonamide (340 mg, 0.69 mmol, 1 equiv) was added to a suspension of potassium carbonate (237 mg, 1.72 mmol, 2.5 equiv) stirring in MeOH (3.4 mL) at 22° C. 1-[(isocyanomethyl)sulfonyl]-4-methylbenzene isocyanomethyl 4-methylphenyl sulfone (161 mg, 0.82 mmol, 1.2 equiv) was added and the resulting mixture was stirred at 22° C. for 30 minutes. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (0-40% EtOAc:Hex). Fractions were identified, combined and concentrated in vacuo but the isolated material was not pure. The residue was then purified by reversed phase HPLC (0-95% acetonitrile:water with 0.025% TFA). Pure fractions were identified, combined, basified with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (3% yield). Calc'd (M+1)+: 535.1. Found: 535.1.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][C:11]([CH2:22][CH2:23][CH2:24][CH:25]([O:31]C(=O)C)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([S:17](OC)(=[O:19])=[O:18])C(OCC)=O)=[O:4].[Cl-].[Na+].[C:37](=O)=O>CCOCC.O.CS(C)=O>[CH3:37][S:17]([CH:11]([CH2:22][CH2:23][CH2:24][CH:25]([OH:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:10][C:9]#[C:8][CH2:7][CH2:6][CH2:5][C:3]([OH:2])=[O:4])(=[O:19])=[O:18]
Reactant: CCCCCC(CCCC(CC#CCCCC(=O)OC)(C(=O)OCC)S(=O)(=O)OC)OC(C)=O
Reactant: O=C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: CCCCCC(O)CCCC(CC#CCCCC(=O)O)S(C)(=O)=O

Procedure:
A solution of ethyl 2-(6-methoxycarbonyl-2-hexyn-1-yl)-2-(4-acetoxynonyl)-2-(methoxysulfonyl)-acetate (48.8 g., 0.1 mole), water (3.6 g., 0.2 mole), and sodium chloride (6.5 g., 0.11 mole) in 120 ml. of dimethyl sulfoxide is heated at 130°-150° C. for 6 hours until evolution of carbon dioxide is completed. The mixture is cooled, treated with 400 ml. of water and the oily product taken up in ether, washed with water and dried over sodium sulfate. Evaporation of the ether in vacuo leaves the title compound as a yellow viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[Cl:10].C(N(CC)CC)C.Cl[C:19]([O:21][CH3:22])=[O:20].O>C(C(C)=O)C>[Cl:10][C:3]1[C:4]([CH2:8][CH3:9])=[N:5][CH:6]=[CH:7][C:2]=1[NH:1][C:19](=[O:20])[O:21][CH3:22]
Reactant: COC(=O)Cl
Reactant: CCc1nccc(N)c1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCC(C)=O
Product: CCc1nccc(NC(=O)OC)c1Cl
Temperature: -10 °C
Yield: 64 %

Procedure:
5.7 g (36.4 mmol) of 4-amino-3-chloro-2-ethylpyridine was dissolved in 50 ml of methyl ethyl ketone. Then, 5.5 g (54.6 mmol) of triethylamine was added thereto, and the mixture was stirred at -10° C. Then, 8.6 g (91.0 mmol) of methyl chloroformate was gradually added thereto so that the temperature would not exceed -5° C. After completion of the dropwise addition, the mixture was stirred for one hour at a temperature of from -10° to -5° C. and for further one hour at room temperature. Then, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The obtained residue was recrystallized from isopropyl ether to obtain 5.0 g of the desired product as colorless prism crystals (melting point: 78° to 79° C.).
Reaction SMILES: C([N:11]1[CH2:18][C@@H:17]([F:19])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O.[BrH:20].CCOCC>C(O)(=O)C>[BrH:20].[F:19][C@@H:17]1[CH2:18][NH:11][C@H:12]([C:13]([OH:15])=[O:14])[CH2:16]1
Reactant: O=C(O)[C@@H]1C[C@H](F)CN1C(=O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(O)[C@@H]1C[C@H](F)CN1
Reaction time: 1 h

Procedure:
The cis-N-carbobenzyloxy-4-fluoro-L-proline (5.5 g., 0.021 mole) is treated with 28 ml. of hydrogen bromide in acetic acid (30-32%), stoppered loosely, and stirred for one hour. Ether (300 ml.) is added to the yellow mixture and when the crystalline product has settled the ethereal liquor is decanted and the material washed with 300 ml. of fresh ether by decantation. The product is finally heated in the steam bath with 70 ml. of methyl ethyl ketone, cooled for two hours, washed with cold methyl ethyl ketone and with ether, and dried in vacuo. The yield of nearly colorless solid, cis-4-fluoro-L-proline, hydrobromide is 3.8 g. (86%), m.p. 189°-191° (dec.), [α]D26 -19° (c=1, methanol).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:18][N:17]([CH2:19][CH2:20][O:21]C(=O)C)[CH2:16][CH2:15][N:14]([CH3:25])[C:13]=3[CH:26]=2)=[N:6][CH:7]=1.O1CCOCC1.[Li+].[OH-].N>CO.ClCCl>[Cl:1][C:2]1[C:3]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:36])=[O:37])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:18][N:17]([CH2:19][CH2:20][OH:21])[CH2:16][CH2:15][N:14]([CH3:25])[C:13]=3[CH:26]=2)=[N:6][CH:7]=1
Reactant: CC(=O)OCCN1CCN(C)c2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)ccc2C1
Agent: N
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(CCO)Cc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.2 %

Procedure:
To a 25 ml round bottom flask, acetic acid 2-{8-[5-chloro-4-((1R,2R)-2-methanesulfonylamino-cyclohexylamino)-pyrimidin-2-ylamino]-1-methyl-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl}-ethyl ester (50 mg, 0.09 mmole), dioxane (5 ml), and 1M LiOH (1 mL, 1 mmole) were added and stirred at room temperature for 18 hours. The reaction was then acidified to pH 2 with 1NHCl. The solvents were removed under vacuum to give a white solid. The desired product (10 mg, 21% yield) was isolated via column chromatography with dichloromethane and ammonia in methanol as eluant. NMR 1H-(CDCl3)-δ-7.93 (s, 1H), 7.15 (d, 1H, J=7.83 Hz), 7.04 (d, 1H, J=7.83 Hz), 6.93 (s, 1H), 6.89 (s, 1H), 5.38 (d, 1H, J=5.73 Hz), 5.29 (s, 1H), 3.82-3.95 (m, 1H), 3.80 (s, 2H), 3.61 (t, 2H, J=5.31 Hz), 3.15-3.30 (m, 1H), 2.99 (bs, 4H), 2.91 (s, 3H), 2.78 (s, 3H), 2.61 (t, 2H, J=5.30Hz), 2.10-2.30 (m, 2H), 1.75-1.90 (m, 2H), 1.30-1.50 (m, 4H)
Reaction SMILES: [C:1]([O-:4])([O-])=[O:2].[Na+].[Na+].S(O[C@:12]([C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[NH2:29])([C:17]#[C:18][CH:19]1[CH2:21][CH2:20]1)[C:13]([F:16])([F:15])[F:14])(=O)(=O)C.CS([O-])(=O)=O.[H][H].O=C(Cl)OC(Cl)(Cl)Cl>>[CH2:20]1[CH:19]([C:18]#[C:17][C@:12]2([C:13]([F:15])([F:14])[F:16])[O:4][C:1](=[O:2])[NH:29][C:23]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]2=3)[CH2:21]1
Reactant: O=C([O-])[O-]
Reactant: [H][H]
Reactant: CS(=O)(=O)O[C@@](C#CC1CC1)(c1cc(Cl)ccc1N)C(F)(F)F
Agent: CS(=O)(=O)[O-]
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Product: O=C1Nc2ccc(Cl)cc2[C@@](C#CC2CC2)(C(F)(F)F)O1
Temperature: 15 °C
Reaction time: 0.08 h
Yield: 94.2 %

Procedure:
Aqueous Na2CO3 (12%-w/w, 183 g, 0.206 mol) was charged to SD573-MSA ((S)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol mesylate (2:3 mol/mol)=methanesulfonate of the S-enantiomer of the compound of formula II, wherein R1 is trifluoromethyl, R2 is 2-cyclopropyl-ethynyl, R8 is 5-chloro, R9 is hydrogen and R10 is hydrogen; 100 g, 0.23 mol, corresponding to 66.8 g of SD573 free base, 99.6% ee, prepared accordingly to Example 1) in ethyl acetate/heptanes (203 g, 1.5:1 v/v). The mixture was stirred for 5 min at 15° C. Hydrolysis of the mesylate ended at about pH 9.0 of the aqueous phase. Then a phase separation was performed and the aqueous phase was removed. Aqueous Na2CO3 (12%-w/w, 232 g, 0.262 mol) was charged to the organic phase. To the biphasic mixture, liquid diphosgene (24 g, 120 mmol) was added in 90 min at 12° C. After a conversion of more than 99.7% was reached, according to Method C, heptanes (204 g) were charged. The reaction mixture was then heated to 20° C., the aqueous phase was separated and discarded, while the organic phase was washed with water (about 80 g). The organic layer was heated under reduced pressure, ethyl acetate distilled off and heptanes were charged to the reaction mixture to achieve a residual ethyl acetate content of 5.5%-w/w and a ratio of heptanes to organic matter of 10 L/kg in view of originally added SD573-MSA. Then the mixture was heated to dissolve all organic matter. The solution was seeded with 0.8 g of DMP-266 (DMP-266=S-enantiomer of the compound of formula I, wherein R1 is trifluoromethyl, R2 is 2-cyclopropyl-ethynyl, R8 is 6-chloro, R9 is hydrogen and R10 is hydrogen) at 55° C. and stirred for about 15 min at 55° C. The mixture was then cooled to 50° C. and hold for 120 min. Then the mixture was further cooled within 2 h from 50° C. to 25° C. and within another 2 h ramp to about −10° C. Finally, the mixture was stirred for about 1 h at −10° C. maximum and then filtered. The filter cake (wet product) was washed with pre-cooled heptanes (2×50 mL) at 0° C. maximum. The solid was dried in vacuo to yield 94.2% (68.4 g, 216 mmol) of DMP-266 at a purity of 99.9%-w/w according to Method D. The sample comprises 99.8%-w/w S-enantiomer, i.e. an enantiomeric excess (ee) of 99.6%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8].[S:26]1[CH2:30][CH2:29][C:28](=O)[CH2:27]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:28]3[CH2:29][CH2:30][S:26][CH2:27]3)[CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8]
Reactant: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCNCC2)nc1
Reactant: O=C1CCSC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCN(C3CCSC3)CC2)nc1
Temperature: 50 °C
Reaction time: 96 h
Yield: 77.3 %

Procedure:
A solution of 5-chloro-N-(5-methylpyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 99-A (0.45 g, 1.25 mmol) in 10 mL of 95:5 methanol-acetic acid was treated with excess tetrahydrothiophen-3-one (1.07 mL, 12.5 mmol), followed by sodium cyanoborohydride (5.0 ml of a 1 M solution in tetrahydrofuran, 6.0 mmol). After stirring at 50° C. for 96 h, the mixture was concentrated in vacuo; and the residue was subjected to silica gel chromatography. Elution with 9:1 dichloromethane-2 M ammonia in methanol afforded 0.43 g (77%) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:17](/[CH:18]=[CH:19]/[C:20](OCC)=[O:21])=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[C:3]=1[Cl:25]>C(Cl)(Cl)Cl.CO.[Pt](=O)=O>[Cl:25][C:3]1[C:4]2[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6][C:5]=2[CH:16]=[C:17]2[C:2]=1[NH:1][C:20](=[O:21])[CH2:19][CH2:18]2
Reactant: CCOC(=O)/C=C/c1cc2c(c(Cl)c1N)CCN(C(=O)OCC)CC2
Agent: O=[Pt]=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)N1CCc2cc3c(c(Cl)c2CC1)NC(=O)CC3
Reaction time: 20 h
Yield: 120.9 %

Procedure:
To a solution of 2.12 g of ethyl 7-amino-6-chloro-8-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate in 20 ml of chloroform and 20 ml of MeOH was added 65 mg of platinum(IV) oxide, followed by stirring for 20 hours at 1 atm under a hydrogen atmosphere. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to obtain 2.256 g of ethyl 11-chloro-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate as a milky white solid.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][C:6]1[N:7]=[CH:8][C:9]2[C:14]([CH:15]=1)=[C:13]([NH2:16])[CH:12]=[CH:11][CH:10]=2>CN(C)C1C=CN=CC=1.ClCCl.O1CCCC1>[CH3:5][C:6]1[N:7]=[CH:8][C:9]2[C:14]([CH:15]=1)=[C:13]([N:16]=[C:1]=[O:2])[CH:12]=[CH:11][CH:10]=2
Reactant: Cc1cc2c(N)cccc2cn1
Reactant: O=C(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc2c(N=C=O)cccc2cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of phosgene (20% in toluene, 2.9 mL, 5.5 mmol) of dichloromethane (30 mL) was cooled to 0° C. and treated dropwise with a solution of 4-dimethylaminopyridine (1.43 g, 11.7 mL) in dichloromethane (15 mL). A thick white suspension formed. A solution of 3-methyl-isoquinolin-5-ylamine (0.79 g, 5 mmol) in tetrahydrofuran (20 mL) was then added dropwise to this suspension. The reaction mixture was allowed to warm to ambient temperature and stirred overnight, the solvent was removed under reduced pressure, and the residue titurated with 50 mL of diethyl ether to give an approximately 0.1 M solution of 3-methyl-5-isocyanato-isoquinoline.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[S:6][C:7]([CH2:9][CH:10]3[CH2:14][CH2:13][N:12]([CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[C:11]3=[O:21])=[CH:8][C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27]>>[CH3:24][O:25][C:26](=[O:27])[C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:23]=[CH:22][C:5]3[S:6][C:7]([CH2:9][CH:10]4[CH2:14][CH2:13][N:12]([CH:15]5[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]5)[C:11]4=[O:21])=[CH:8][C:4]=3[CH:3]=2)=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: O=C1C(Cc2cc3cc(Br)ccc3s2)CCN1C1CCCCC1
Product: COC(=O)c1ccc(-c2ccc3sc(CC4CCN(C5CCCCC5)C4=O)cc3c2)cc1
Yield: 55.9 %

Procedure:
Using the procedure to synthesize Example 17 and using reagents 3-(5-bromo-benzo[b]thiophen-2-ylmethyl)-1-cyclohexyl-pyrrolidin-2-one (250 mg, 0.64 mmol) and 4-methoxycarbonylphenylboronic acid (200 mg, 1 mmol) afford the title compound as a white powder (160 mg, 78%): MS (APCI-pos mode) m/z (rel intensity): 342.2 (M+H, 100%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[C:6]([Cl:8])[CH:7]=1.[C:10]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C.[Cl-].[NH4+]>[Br:1][C:2]1[C:3](=[O:9])[N:4]([CH3:10])[N:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]nc(Cl)cc1Br
Agent: [Cl-]
Agent: [Cs+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nc(Cl)cc(Br)c1=O
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution of 4-bromo-6-chloropyridazin-3(2H)-one (1.0 equiv.) and Cs2CO3 (1.2 equiv.) in DMF (0.07 M) was added iodomethane (1.5 equiv.) drop-wise over 20 min. The resulting mixture was stirred for 3 h. The reaction mixture was then diluted with ammonium chloride, then extracted with ethyl acetate, dried over MgSO4 and concentrated in vacuo to yield as a brown solid. The oil was further purified via silica gel column chromatography eluting with 100% heptanes to 80% ethyl acetate:heptanes to yield 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one as an off-white solid in 79% yield. LCMS (m/z) (M+H)=222.9/224.9, Rt=0.54 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 3.77-3.86 (m, 3H) 7.56-7.69 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:12][C:11]1[C:2]([Cl:1])=[C:3]([CH:8]=[CH:9][C:10]=1[O:13][CH3:14])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(OC)c(C)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(OC)c(CBr)c1Cl
Reaction time: 4 h

Procedure:
To 50 ml carbon tetrachloride, was dissolved methyl 2-chloro-4-methoxy-3-methylbenzoate in an amount of 5.0 g (0.025 mole), and the resulting solution was then stirred for 4 hours under reflux and heating after the addition of N-bromosuccinimide in an amount of 4.9 g (0.028 mole) and benzoyl peroxide in an amount of 0.1 g into the solution. After cooling the mixture, insoluble material therein were separated by filtration, and the filtrate was washed with aqueous solution of sodium hydrogenbisulfite and then dried with anhydrous magnesium sulfate. The solvent remained in the filtrate was condensed under reduced pressure to obtain methyl 3-bromomethyl-2-chloro-4-methoxybenzoate in an amount of 7.5 g in crude crystalline form.
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: Cc1ccc(O)c([C@H](CCN(C(C)C)C(C)C)c2ccccc2)c1
Reactant: O=C(O)/C=C/c1ccccc1
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: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.Cl.[CH3:15][O:16][C:17]1[NH:21][N:20]=[C:19]([NH2:22])[CH:18]=1>C(O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:22][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([S:12][CH3:13])[N:3]=2)[NH:20][N:21]=1
Reactant: CSc1nc(Cl)cc(C(F)(F)F)n1
Reactant: COc1cc(N)n[nH]1
Agent: Cl
Solvent: CCO
Product: COc1cc(Nc2cc(C(F)(F)F)nc(SC)n2)[nH]n1
Temperature: 90 °C
Yield: 21.5 %

Procedure:
To a solution of 4-chloro-2-(methylthio)-6-(trifluoromethyl)pyrimidine (2.29 g) in absolute ethanol (50 mL) was added DIEPA (4.4 mL) and 5-methoxy-1H-pyrazol-3-amine hydrogen chloride salt (1.46 g). The resulting solution was heated at 90° C. for over night. The solvent was evaporated under reduced pressure. The crude compound was purified by Gilson (10-60% MeCN/H2O, 15 minutes) to give N-(3-methoxy-1H-pyrazol-5-yl)-2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-amine as solid (0.64 g). m/z 306. N-(3-methoxy-1H-pyrazol-5-yl)-2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-amine (240 mg) was dissolved in methylene chloride (5 mL), MCPBA (529 mg) was added. The resulting solution was stirred at room temperature for 0.5 hours and separate between methylene chloride and saturated sodium carbonate water solution. The organic layer was dried and solvent was removed under reduced pressure and low temperature. The crude product (270 mg) was carried on to do next step without further purification. m/z 338.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[O:10][CH3:11].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19].[CH3:20][C:21]1([CH3:34])[C@@H:23]2[CH2:24][C:25]3[C:29]([C@H:22]12)=[C:28]([CH3:30])[S:27][C:26]=3[C:31](O)=[O:32]>>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:31]([C:26]2[S:27][C:28]([CH3:30])=[C:29]3[C:25]=2[CH2:24][C@H:23]2[C:21]([CH3:34])([CH3:20])[C@H:22]23)=[O:32])=[C:4]([O:10][CH3:11])[CH:5]=1
Reactant: OCCCCCCBr
Reactant: COc1cc(O)ccc1CN
Reactant: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Product: COc1cc(OCCCCCCO)ccc1CNC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C

Procedure:
(1aS,5aR)-1,1,2-Trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-(6-hydroxy-hexyloxy)-2-methoxy-benzylamide is prepared starting from 4-aminomethyl-3-methoxy-phenol, 6-bromohexanol and (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid in analogy to the procedures given in Example 18. LC-MS: tR=1.08 min, [M+1]+=458.25.