Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:38])([CH3:37])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]2)[CH:9]=1.C1C(=O)N([I:46])C(=O)C1>CC#N>[CH3:36][Si:33]([CH3:35])([CH3:34])[CH2:32][CH2:31][O:30][CH2:29][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:37])[CH3:38])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:46])=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]2)[CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)C1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidine-1-carboxylate 3.95 g, 7.0 mmol) in CH3CN (30 mL) was added NIS (1.65 mg, 7.0 mmol). The mixture was stirred at rt for 2 h and diluted with EtOAC (50 mL) and washed with saturated sodium thiosulfate, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by Biotage (CH2Cl2/EtOAc, 100:1 to 10:1) to the title compound as a light brown oil. LC/MS RT=2.49 min. Mass calculated for, M+H 689.23, observed 389.17.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([NH2:28])=[O:27])=[C:24]([CH:29]([OH:33])[CH2:30][CH2:31][CH3:32])[N:23]=[C:22]2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.Cl>O1CCOCC1>[CH2:34]([C:22]1[N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:6]([OH:7])=[O:5])=[CH:19][CH:18]=2)[C:25]([C:26]([NH2:28])=[O:27])=[C:24]([CH:29]([OH:33])[CH2:30][CH2:31][CH3:32])[N:23]=1)[CH2:35][CH2:36][CH3:37]
Reactant: CCCCc1nc(C(O)CCC)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nc(C(O)CCC)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Following a procedure similar to that described in Example 45(d), but using 0.58 g of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxybutyl)imidazole-5-carboxamide [prepared as described in step (c) above] and 13 ml of a 4N solution of hydrogen chloride in dioxane, 0.55 g of the hydrochloride of the title compound was obtained as an amorphous powder, melting at above 110° C. (with softening).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:19][C:20]1[S:21][CH:22]=[CH:23][C:24]=1[C:25](Cl)=[O:26]>ClCCl.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][N:9]2[C:25]([C:24]2[CH:23]=[CH:22][S:21][C:20]=2[CH3:19])=[O:26])=[CH:4][CH:3]=1
Reactant: O=C1CCNc2cc(Cl)ccc21
Reactant: Cc1sccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1sccc1C(=O)N1CCC(=O)c2ccc(Cl)cc21
Yield: 83.2 %

Procedure:
To a mixture of 7-chloro-2,3-dihydro-4(lH)-quinolinone (20.0 g), pyridine (26 g) and dichloromethane (200 ml) was added dropwise 2-methyl-3-thienylcarbonyl chloride (26 g) at room temperature with stirring. The mixture was stirred under reflux for 4 hours. The reaction mixture was poured into 500 ml of water, then shaken with additional dichloromethane (1000 ml). The organic layer was washed once with 1 N HCl (100 ml), twice with water (200 ml each) and once with saturated aqueous NaCl solution, then dried over anhydrous sodium sulfate. Solvent was removed in vacuo and 7-chloro-2,3-dihydro-l-(2-methyl-3-thienylcarbonyl)-4(lH)-quinolinone (yield 28 g) was obtained as colorless oil.
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[N:8]=[C:9]([NH:12][C:13]([NH2:15])=[NH:14])[S:10][CH:11]=1)=[O:6])=[N+]=[N-].C(O)C.[ClH:19]>[Pd].O>[ClH:19].[ClH:19].[NH2:1][CH2:4][C:5]([C:7]1[N:8]=[C:9]([NH:12][C:13]([NH2:15])=[NH:14])[S:10][CH:11]=1)=[O:6]
Reactant: [N-]=[N+]=NCC(=O)c1csc(NC(=N)N)n1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: N=C(N)Nc1nc(C(=O)CN)cs1
Reaction time: 1 h
Yield: 92 %

Procedure:
A mixture of 12.0 g (53 mmol) of 2-azido-1-(2-guanidino-4-thiazolyl)ethanone, 1.0 g of 10% palladium on carbon, 100 ml of ethanol, 50 ml of water, and 20 ml of concentrated hydrochloric acid was hydrogenated at 3 atm. and room temperature for 1 hour. At this point another 50 ml of water and 300 mg of 10% palladium on carbon was added to the mixture and hydrogenation was continued at 3 atm for another 0.75 hour. The mixture was diluted with 200 ml of water, filtered to remove the catalyst, and the filtrate concentrated leaving 13.1 g (92%) of 2-amino-1-(2- guanidino-4-thiazolyl)ethanone dihydrochloride as a white powder mp >270°. nmr (DMSO-d6) (δ): 8.58 (b, 4H) 8.44 (s, 1H); 4.58 (b, 4H).
Reaction SMILES: [CH2:1]([S:3]([CH2:5][S:6][CH2:7][CH3:8])=[O:4])[CH3:2].C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.C(OC[C:34]1[N:38]([S:39]([C:42]2[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=2)(=[O:41])=[O:40])[CH:37]=[N:36][CH:35]=1)(=O)C>O1CCCC1.CCCCCC>[CH2:1]([S:3]([CH:5]([C:34]1[N:38]([S:39]([C:42]2[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=2)(=[O:41])=[O:40])[CH:37]=[N:36][CH:35]=1)[S:6][CH2:7][CH3:8])=[O:4])[CH3:2]
Reactant: CC(=O)OCc1cncn1S(=O)(=O)c1ccc(C)cc1
Reactant: CCSCS(=O)CC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCSC(c1cncn1S(=O)(=O)c1ccc(C)cc1)S(=O)CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10 mmole of [[(ethylsulfinyl)methyl]thio]ethane in 20 ml of dry tetrahydrofuran is heated at 0° C. with 10 mmole of lithium diisopropylamide, prepared from a solution of diisopropylamine M in tetrahydrofuran and butyllithium 2 M in hexane. After 30 minutes at 0° C. a solution of 12 mmole of 5-acetyloxymethyl-1-tosylimidazole in 10 ml of tetrahydrofuran is added. The reaction mixture is stirred at 25° C. overnight then is quenched with brine and extracted with ether. The organic phase is washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give [[(ethylsulfinyl)-1-tosylimidazol-5-ylmethyl]thio]ethane. To a solution of 20 mmole of [[(ethylsulfinyl)-1-tosylimidazol-5-ylmethyl]thio]ethane in 20 ml of dry tetrahydrofuran is added at 0° C. and under nitrogen a solution of 20 mmole of lithium diisopropylamide prepared from a solution of diisopropylamine M in tetrahydrofuran and butyl lithium 2 M in hexane. Stirring is continued for 30 minutes at 25° C. after which a stream of chlorodifluoromethane is bubbled into the reaction mixture for 1/2 hour. The reaction mixture is maintained at 40° C. for 3 hours then quenched with brine and extracted with ether. The organic phase is separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to afford [[(ethylsulfinyl)((difluoromethyl)-1-tosylimidazol-5-ylmethyl)]thio]ethane. To a solution of 30 ml of [[(ethylsulfinyl)((difluoromethyl)-1-tosylimidazol-5-ylmethyl)]thio]ethane in 33 ml of acetonitrile is added at 0° C. a 70% aqueous solution of perchloric acid (1.1 ml). After stirring for 2 hours at 0° C. the reaction mixture is poured into 60 ml of water then extracted with difluoromethane. The organic phase is washed with sodium bicarbonate then water, dried over magnesium sulfate and concentrated under reduced pressure to afford difluoromethyl 5-imidazolylmethyl ketone.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6](I)[C:5]([CH3:12])=[CH:4][CH:3]=1.[NH:13]1[CH:17]=[CH:16][N:15]=[N:14]1.CN[C@H]1CCCC[C@@H]1NC.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I>[F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([N:14]2[N:15]=[CH:16][CH:17]=[N:13]2)[C:5]([CH3:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)c(C(=O)O)c1I
Reactant: c1c[nH]nn1
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(C(=O)O)c1-n1nccn1
Temperature: 120 °C

Procedure:
A mixture of 6-fluoro-2-iodo-3-methylbenzoic acid (900 mg, 3.21 mmol), 1,2,3-triazole (208 μl, 4.82 mmol), (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (103 μl, 642 μmol), Cs2CO3 (1.57 g, 4.82 mmol) and CuI (61 mg, 321 μmol) in DMF (5 mL) was degassed and heated at 120° C. for 1 h in a microwave reactor. The reaction was cooled to rt, diluted with MeOH, and acidified with AcOH to pH 4˜5. The solvent was removed in vacuo to obtain the crude which was purified by silica gel chromatography (40% EtOAc in hexanes) to yield the title compound. MS (ESI) 222 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:12]O)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[CH3:8].CS(N1C2C(=CC=C(C[Br:28])C=2)C=C1)(=O)=O.CS(N1C2C(=CC=C(CO)C=2)C=C1)(=O)=O>>[Br:28][CH2:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]([CH3:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: CS(=O)(=O)n1ccc2ccc(CBr)cc21
Reactant: Cc1c(Cl)cc(CO)cc1[N+](=O)[O-]
Agent: CS(=O)(=O)n1ccc2ccc(CO)cc21
Product: Cc1c(Cl)cc(CBr)cc1[N+](=O)[O-]

Procedure:
5-Bromomethyl-1-chloro-2-methyl-3-nitrobenzene was prepared from (3-chloro-4-methyl-5-nitrophenyl)methanol in a manner similar to that described in Example 10 for the preparation of N-methanesulfonyl-6-bromomethylindole from N-methanesulfonyl-6-hyroxymethyl indole.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[C:3]=1[C:17]([NH2:19])=[O:18].[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.N1CCCCC1>C(O)C>[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[N:1][C:2]2[NH:6][N:5]=[C:4]([NH:7][C:8]3[CH:9]=[CH:10][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:12][CH:13]=3)[C:3]=2[C:17]([NH2:19])=[O:18])=[CH:23][CH:22]=1
Reactant: CC(C)c1ccc(Nc2n[nH]c(N)c2C(N)=O)cc1
Reactant: O=Cc1ccc(O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)c1ccc(Nc2n[nH]c(N=Cc3ccc(O)cc3)c2C(N)=O)cc1
Yield: 97 %

Procedure:
5-amino-3-((4-isopropylphenyl)amino)-1H-pyrazole-4-carboxamide (850 mg) was suspended in 15 mL of ethanol and 4-hydroxybenzaldehyde (601 mg, 1.5 eq.) and piperidine (0.50 eq, 168 μL) was added. Stirred the reaction at reflux until starting material was absent and confirmed by HPLC. After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-((4-hydroxybenzylidene)amino)-3-((4-isopropylphenyl)amino)-1H-pyrazole-4-carboxamide as a yellow to orange powder. The product was washed with ethanol to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr (1.15 g, 97% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[C:32]([C:34]1[S:38][C:37](B(O)O)=[CH:36][CH:35]=1)#[N:33]>>[C:32]([C:34]1[S:38][C:37]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:20][CH2:19]2)=[CH:36][CH:35]=1)#[N:33]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: N#Cc1ccc(B(O)O)s1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4ccc(C#N)s4)cc23)CC1

Procedure:
Following general procedure D, tert-butyl trans-4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexylcarbamate (49 mg, 0.100 mmol) was reacted with 5-cyanothiophen-2-ylboronic acid (31 mg, 0.200 mmol) to afford the desired product (24 mg, 47%) as a brown solid: ESI MS m/z 517 [C29H32N4O3S+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[C:24]([C:26]1[CH:35]=[CH:34][C:29]([C:30](=[O:33])[CH2:31]Br)=[CH:28][CH:27]=1)#[N:25]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:31]=1[C:30](=[O:33])[C:29]1[CH:34]=[CH:35][C:26]([C:24]#[N:25])=[CH:27][CH:28]=1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Product: COC(=O)Cc1c(C(=O)c2ccc(C#N)cc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 8 (Method B) from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 4-cyanophenacyl bromide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[O:12][CH2:13][CH3:14])[CH3:2].[Br:16]Br>O.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([Br:16])[C:8]([Cl:11])=[CH:7][C:6]=1[O:12][CH2:13][CH3:14])[CH3:2]
Reactant: CCOC(=O)c1ccc(Cl)cc1OCC
Reactant: BrBr
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)c(Cl)cc1OCC
Reaction time: 72 h
Yield: 64 %

Procedure:
To a solution of 4-chloro-2-ethoxy-benzoic acid ethyl ester (1.46 g, 6.4 mmol) in 13 mL of water and methylene chloride (1:1 mixture) was added bromine (360 uL, 7 mmol). The reaction was stirred for three days. The organic layer was separated. It was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Purification of the crude residue by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes) gave 5-bromo-4-chloro-2-ethoxy-benzoic acid ethyl ester (1.26 g, 64%). LC-MS: 307.1 [(M+H)+].
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[C:21]1[C:25]([C:26](Cl)=[O:27])=[C:24]([CH3:29])[O:23][N:22]=1>>[CH3:2][O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:26]([C:25]1[C:21]([C:15]2[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=2[Cl:13])=[N:22][O:23][C:24]=1[CH3:29])=[O:27]
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Reactant: COC(=O)CCCCCCN
Agent: Cl
Product: COC(=O)CCCCCCNC(=O)c1c(-c2c(F)cccc2Cl)noc1C
Yield: 99.5 %

Procedure:
Methyl-7-aminoheptanoate hydrochloride (733 mg, 3.75 mmol) and 3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-oyl chloride (1.03 g, 3.75 mmol) were converted to 1.48 g of the title compound by the procedure of Preparation 10. (100%). EA calculated for: C19H22N2O4ClF: C, 57.51; H, 5.59; N, 7.06. Found: C, 57.78; H, 5.70; N, 6.80. MS(FD) m/z 396.1 (M+).
Reaction SMILES: [CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22]>C(O)(=O)C>[C:21]([C:20]1[CH:19]=[C:18]([N:17]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[CH:1]=[C:2]2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:26]=[CH:25][CH:24]=1)([OH:23])=[O:22]
Reactant: O=C(CC1CCCCC1=O)c1ccccc1
Reactant: Nc1cccc(C(=O)O)c1
Solvent: CC(=O)O
Product: O=C(O)c1cccc(-n2c(-c3ccccc3)cc3c2CCCC3)c1

Procedure:
A solution of 10.8 g. (0.05 mole) of 2-phenacylcyclohexanone, 6.85 g. (0.05 mole) of m-aminobenzoic acid and 30 ml. of glacial acetic acid was heated under reflux for 6 hours, cooled and filtered. The filter cake was washed with water and recrystallized from ethanol to provide 5.7 g. (36%) of crystals, m.p. 191°-193°.
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:10]2[S:25][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:27][C:9]1=2)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH:19]1([C:11]2[C:10]3[S:25][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:27][C:9]=3[N:8]([CH2:7][C:6]([OH:32])=[O:5])[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccccc1)n2CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccccc1)n2CC(=O)O
Yield: 100 %

Procedure:
A solution (0.1 M) of methyl 4-(2-tert-butoxy-2-oxoethyl)-6-cyclohexyl-5-phenyl-4H-thieno[3,2-b]pyrrole-2-carboxylate in DCM/TFA (1:1) was stirred at RT for 4 h. Evaporation of the solvent gave the title compound (100%) as a solid.
Reaction SMILES: [N:1]12[CH2:9][CH:5]([C:6](=[O:8])[CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[C:10]12([CH2:20][S:21]([OH:24])(=[O:23])=[O:22])[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][C:11]2=[O:12]>O>[C:10]12([CH2:20][S:21]([OH:24])(=[O:22])=[O:23])[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][C:11]2=[O:12].[N:1]12[CH2:9][C@H:5]([C:6](=[O:8])[CH2:7]1)[CH2:4][CH2:3][CH2:2]2
Reactant: O=C1CN2CCCC1C2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: O
Product: O=C1CN2CCC[C@@H]1C2

Procedure:
This compound was made in exactly the same manner as described in example 1 using (±) 1-azabicyclo[3.2.1]octan-6-one and (-) camphorsulfonic acid. M.p. 267°-268° C. (decomp.) [α]D =-48° (water).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+].CO>O>[NH:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:11]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2c[nH]c3ncccc23)CC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Into a 50 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed tert-butyl 4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)piperazine-1-carboxylate (400 mg, 0.90 mmol). To this was added NaOH (90 mg, 2.25 mmol). Addition of methanol (20 mL) was next. To the mixture was added H2O (8 mL). The resulting solution was allowed to react, with stirring, for 4 hours while the temperature was maintained at 90° C. in a bath of oil. The mixture was concentrated by evaporation under vacuum using a rotary evaporator. A filtration was performed and the filter cake was washed with H2O. This resulted in 180 mg (66%) of tert-butyl 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperazine-1-carboxylate as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 1.40 (s, 9H), 2.96 (m, 4H), 3.56 (m, 4H), 6.73 (s, 1H), 6.97 (d, 1H), 7.88 (d, 1H), 8.22 (d, 1H), 8.97 (s, 1H). m/z 303 (M++1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[CH:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:8]=2[CH:21]=1)(=[O:3])[CH3:2].C([O:24]CC)C>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[CH:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=3[O-:24])[C:8]=2[CH:21]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)C(c1ccccn1)=CC(C)(C)O2
Reactant: CCOCC
Product: CC(=O)c1ccc2c(c1)C(c1cccc[n+]1[O-])=CC(C)(C)O2

Procedure:
In an analogous manner to that described in the first paragraph of Example 3, from 6-acetyl-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran there was obtained 2-(6-acetyl-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 165°-167° C. (from diethyl ether).
Reaction SMILES: [CH2:1]([S:5]([NH:8][C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[C:15]([C:17]1[CH:29]=[CH:28][C:20]([CH2:21][NH:22][C:23](=[O:27])[C@H:24]([CH3:26])[NH2:25])=[CH:19][CH:18]=1)#[N:16].Cl.[NH2:31][OH:32].CN1CCOCC1>CO>[CH2:1]([S:5]([NH:8][C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])(=[O:6])=[O:7])[CH2:2][CH2:3][CH3:4].[OH:32][NH:31][C:15]([C:17]1[CH:18]=[CH:19][C:20]([CH2:21][NH:22][C:23](=[O:27])[C@H:24]([CH3:26])[NH2:25])=[CH:28][CH:29]=1)=[NH:16]
Reactant: C[C@H](N)C(=O)NCc1ccc(C#N)cc1
Reactant: NO
Agent: CCCCS(=O)(=O)N[C@H](CO)C(=O)O
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CO
Product: C[C@H](N)C(=O)NCc1ccc(C(=N)NO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product in Example 7 (117 mg, 0.285 mmol) in 1.14 ml methanol was added hydroxylamine hydrochloride (33.7 mg, 0.485 mmol), followed by N-methylmorpholine (53 μl, 0.485 mmol). The reaction mixture was stirred overnight at ambient temperature and then at 50° C. for six hours. The reaction mixture was concentrated in vacuo. The crude product was taken to the next step (Example 9) without further purification. The product eluted at 6.5 minutes by reverse phase (C18) HPLC at 0.1% trifluoroacetic acid in 5-50% aqueous acetonitrile over 20 minutes.
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: CCCOC(=O)N1CCc2ccccc2[C@@H]1c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
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).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:5](OC)=[O:6].[CH3:23][NH:24][CH3:25]>CO>[CH3:23][N:24]([CH3:25])[C:5](=[O:6])[C:4](=[N:3][O:2][CH3:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CON=C(C(=O)OC)c1ccccc1OCc1ccccc1
Reactant: CNC
Solvent: CO
Product: CON=C(C(=O)N(C)C)c1ccccc1OCc1ccccc1
Yield: 66 %

Procedure:
A solution of 4.9 g (16.4 mmol) of methyl 2-methoxyimino-2-(2-benzyloxyphenyl)acetate and 0.9 g (20 mmol) of dimethylamine in 20 ml of methanol was stirred at about -25° C. for 60 hours. After removal of the solvent, the crude product was purified by chromatography on silica gel (methyl tert-butyl ether/n-hexane mixture as eluent). Yield: 66%;
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[F:30][CH2:31][CH2:32]O.C([C@@H](O)C1C=CC=C(OC2C=CC=CC=2)C=1)#N>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:9])[O:8][CH2:32][CH2:31][F:30])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Reactant: OCCF
Agent: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: c1ccccc1
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OCCF

Procedure:
Using the procedure of Step F of Example 9, the ester of Step A of Example 31 after reaction with 2-fluoroethanol and (S)α-cyano-3-phenoxy-benzyl alcohol was reacted to obtain (S)α-cyano-3-phenoxy-benzyl (IR,cis) 2,2-dimethyl -3-[(Z) 3-oxo-3-(2fluoroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+48° (c=0.25% in benzene).