Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]Br)[N:12]=1>O1CCCC1.O>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][S:3][CH2:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([Br:10])[N:12]=1)[CH3:9]
Reactant: BrCc1cccc(Br)n1
Reactant: CCOC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CSCc1cccc(Br)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.48 g, 11.96 mmol) was suspended in tetrahydrofuran (52.4 mL) and cooled to 0° C. Ethyl mercaptoacetate (0.48 mg, 3.99 mmol) was added and the solution was stirred for 30 minutes at 0° C. 2-Bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (1.0 g, 3.99 mmol) was added and the solution was allowed to stir until completion. The reaction mixture was then diluted with water and extracted with ethyl acetate (2×). The combined organics were dried over magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([F:13])=[CH:6][C:3]=1[C:4]#[N:5].[OH2:14]>ClCCl>[NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([F:13])=[CH:6][C:3]=1[C:4]([NH2:5])=[O:14]
Reactant: O
Reactant: N#Cc1cc(F)cc([N+](=O)[O-])c1N
Solvent: ClCCl
Product: NC(=O)c1cc(F)cc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A suspension of EXAMPLE 45B (13.9 g) in polyphosphoric acid (400 g) was stirred at 115° C. for 3 hours. After cooling, water and dichloromethane were added and the mixture stirred at ambient temperature for 10 minutes. The solid material was collected by filtration and recrystallized from methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18]I)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].C([O-])([O-])=O.[K+].[K+].[N:30]1[CH:35]=[C:34]([CH2:36][C:37]2[C:38](=[O:44])[NH:39][C:40](=[S:43])[NH:41][CH:42]=2)[CH:33]=[N:32][CH:31]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][S:43][C:40]3[NH:41][CH:42]=[C:37]([CH2:36][C:34]4[CH:33]=[N:32][CH:31]=[N:30][CH:35]=4)[C:38](=[O:44])[N:39]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21]
Reactant: N#Cc1cc(CCI)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1cncnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(CCSc2nc(=O)c(Cc3cncnc3)c[nH]2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 60 °C
Yield: 61.4 %

Procedure:
A mixture of 2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-(2-iodoethyl)benzonitrile (200 mg, 0.443 mmol), K2CO3 (122 mg, 0.886 mmol), and 5-(5-pyrimidinylmethyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (107 mg, 0.487 mmol) in DMF (4 mL) was heated with a microwave reactor at 60° C. for 15 min. Purification via reverse phase flash chromatography then afforded the title compound (148 mg, 61.4% yield). LCMS: rt=3.34 min, [M+H+]=544
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([O:15][C:16]([C@H:18]([C@@H:28]([CH2:44][CH:45]([CH3:47])[CH3:46])[C:29]([NH:31][N:32]1[C:36](=[O:37])[C:35]2([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[NH:34][C:33]1=[O:43])=[O:30])[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[C:1]1([S:7]([N:40]2[CH2:41][CH2:42][C:35]3([NH:34][C:33](=[O:43])[N:32]([NH:31][C:29](=[O:30])[C@@H:28]([C@@H:18]([C:16]([O:15][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:17])[CH2:19][CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:44][CH:45]([CH3:46])[CH3:47])[C:36]3=[O:37])[CH2:38][CH2:39]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)NC2(CCNCC2)C1=O)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Product: CC(C)C[C@@H](C(=O)NN1C(=O)NC2(CCN(S(=O)(=O)c3ccccc3)CC2)C1=O)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C

Procedure:
In a manner analogous to that described in Example 26, part (i) but using benzenesulphonyl chloride in place of methanesulphonyl chloride from 0.83 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methyl-N-[2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl]valeramide there was obtained 0.889 g of N-[8-(benzenesulphonyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decan-3-yl]-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methylvaleramide in the form of a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[NH:23][CH:24]=[C:25]([CH3:26])[C:18]=34)=[C:12]([F:27])[CH:11]=2)[CH:3]=1.C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[F:27][C:12]1[CH:11]=[C:10]([NH:9][C:4]2[CH:3]=[CH:2][N:7]=[C:6]([NH2:8])[N:5]=2)[CH:15]=[CH:14][C:13]=1[O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[NH:23][CH:24]=[C:25]([CH3:26])[C:18]=12
Reactant: [H][H]
Reactant: Cc1c[nH]c2nccc(Oc3ccc(Nc4cc(Cl)nc(N)n4)cc3F)c12
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1c[nH]c2nccc(Oc3ccc(Nc4ccnc(N)n4)cc3F)c12

Procedure:
50 mg (0.13 mmol) of 6-chloro-N4-{3-fluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine are dissolved in 10 ml of ethanol. 36 μl (0.26 mmol) of triethylamine and 28 mg (0.03 mmol) of 10% palladium-on-carbon are added, and the mixture is hydrogenated under atmospheric pressure in a hydrogen atmosphere overnight. The mixture is then filtered through Celite®, and the celite is washed with methanol. The solvent is removed under reduced pressure and the crude product is purified by preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[CH:3]=1.Cl.[CH3:14]O>>[Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([C:6]([O:8][CH3:14])=[O:7])=[C:9]([F:11])[CH:10]=1
Reactant: CO
Reactant: O=C(O)c1c(F)cc(Br)cc1F
Agent: Cl
Product: COC(=O)c1c(F)cc(Br)cc1F

Procedure:
A mixture of 4-bromo-2,6-difluorobenzoic acid (6.7 g, 28.3 mmol), MeOH (200 ml) and concentrated HCl (2.0 ml) was heated at reflux for 12 h. The reaction mixture was brought to ambient temperature and the volatiles were evaporated. EtOAc was added and the organic phase was extracted with a aquous solution of Na2CO3 (10%). The combined alkaline phases was acidified at 0° C. with aqueous HCl (10%) to pH 1 and extracted with EtOAc. The combined organic phases was dried (Na2SO4), filtered and concentrated in vacuo to afford pure title compound (3.1 g). MS m/z (rel. intensity, 70 eV) 252 (M+, 22), 250 (M+, 23), 221 (99), 219 (bp), 112 (44).
Reaction SMILES: B1C2CCCC1CCC2.[C:10]([O:14][C:15](=[O:34])[NH:16][C:17]1([CH2:31][CH:32]=[CH2:33])[CH2:22][CH2:21][CH:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[OH-:35].[Na+].OO>C1COCC1>[C:10]([O:14][C:15](=[O:34])[NH:16][C:17]1([CH2:31][CH2:32][CH2:33][OH:35])[CH2:22][CH2:21][CH:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])[CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11]
Reactant: [OH-]
Reactant: C=CCC1(NC(=O)OC(C)(C)C)CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(CCCO)CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
16.2 mL (8.12 mmol) of a 0.5M solution of 9-BBN in THF were added to a solution of 1.00 g (2.71 mmol) of [1-allyl-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-carbamic acid tert-butyl ester (31) in 5 mL THF at 0° C. The reaction mixture was allowed to warm to room temperature over night, before being cooled to 0° C. Then, 20 mL of 3M aqueous sodium hydroxide and 20 mL of 30% aqueous hydrogen peroxide were added slowly, and the mixture was stirred for 12 h. The mixture was extracted twice with ethyl acetate, washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. 0.85 g of the title compound 32 could be isolated as mixture of diastereoisomers in a purity sufficient for further conversion. Rt=2.03 min, 2.10 min (Method C). Detected mass: 388.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[S:14])[C:11]#[N:12])=[CH:5][CH:4]=1.I[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].CCN(C(C)C)C(C)C>C(#N)C>[C:11]([C:10]1[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[S:14][C:13]=1[N:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1)#[N:12]
Reactant: CCOC(=O)CI
Reactant: COc1ccc(C=C(C#N)C(=S)N2CCOCC2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1SC(N2CCOCC2)=C(C#N)C1c1ccc(OC)cc1
Reaction time: 0.17 h
Yield: 63 %

Procedure:
A mixture of 3-(4-methoxyphenyl)-2-(morpholin-4-ylcarbonothioyl)acrylonitrile (from step 1), ethyl iodoacetate (0.25 mL, 2.1 mmol) and DIPEA (0.5 mL, 2.9 mmol) was dissolved in ACN (2 mL) and subjected to MWI at 150° C. for 10 min. The mixture was allowed to cool and was concentrated. The residue was diluted with 5% sodium bisulfite solution and extracted with EtOAc. The organic solutions were combined, washed with sat NaHCO3 and brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give ethyl 4-cyano-3-(4-methoxyphenyl)-5-morpholin-4-yl-2,3-dihydrothiophene-2-carboxylate (0.168 g, 63% over two steps). LCMS: (AA) ES+ 375, ES− 373.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]#[N:19])[CH:14]=2)[N:9]([CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:8]1=[O:26].Cl.[OH-].[Na+]>C1COCC1.C(Cl)Cl>[NH2:19][CH2:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[C:8](=[O:26])[N:7]([CH2:6][C:5]1[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:16]2=[O:17]
Reactant: COc1ccc(Cn2c(=O)c3cc(C#N)ccc3n(C3CCOCC3)c2=O)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)c3cc(CN)ccc3n(C3CCOCC3)c2=O)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.4 %

Procedure:
A mixture of 0.55 g of the compound obtained in Step 12.1, and 2.94 ml of a 2M borane/dimethyl sulfide complex in THF, in 15 ml of THF is irradiated in a microwave field for 1 minute at 100° C. The reaction medium is taken up in DCM. 50 ml of 1N HCl are added and the mixture is stirred for 2 hours at room temperature. The resulting mixture is neutralized with 2N sodium hydroxide solution. This resulting mixture is extracted with DCM, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue is chromatographed on an RP18 column, eluting with a water/ACN mixture from (90/10, v/v) to (50/50, v/v) to give 0.23 g of the expected product.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[CH2:3]1.N1C=CC=CC=1.[C:17](Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>C(Cl)Cl>[C:17]([O:5][C:4]1[CH2:3][C:2]([CH3:10])([CH3:1])[CH2:9][C:7](=[O:8])[CH:6]=1)(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: CCCC(=O)Cl
Reactant: CC1(C)CC(=O)CC(=O)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)OC1=CC(=O)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
Dimedone (5,5-dimethylcyclohexane-1,3-dione, 99%, 14.2 g), pyridine (9 ml) and methylene chloride (100 ml) were mixed in a flask and butyryl chloride (11.4 g) was added dropwise. The mixture was stirred for 26 hours at room temperature and filtered. The filtrate was washed with HCl (6 N, 100 ml), water (100 ml), saturated Na2CO3 (50 ml), water (50 ml), dried (MgSO4). The solvent was removed under reduced pressure to yield 3-butyroxy-5,5-dimethylcyclohex-2-en-1-one as a yellow liquid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:15]2[CH:16]=[N:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:19]=2)O1.Br[C:29]1[CH:30]=[C:31]([NH2:35])[CH:32]=[N:33][CH:34]=1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O.O1CCCC1>[C:23]([O:22][C:20]([N:18]1[CH:19]=[C:15]([C:29]2[CH:34]=[N:33][CH:32]=[C:31]([NH2:35])[CH:30]=2)[CH:16]=[N:17]1)=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: Nc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cc(-c2cncc(N)c2)cn1
Reaction time: 2.75 h
Yield: 34.6 %

Procedure:
Water (0.5 ml), sodium carbonate (92 mg), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-carboxylate (203 mg), and bis(tri-tert-butylphosphine)palladium (30 mg) were added to a tetrahydrofuran (4.5 ml) solution containing 5-bromopyridin-3-amine (100 mg) in a nitrogen atmosphere, followed by stirring for 2.75 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (chloroform:methanol=1:0 to 30:1), and a white solid of tert-butyl-4-(5-aminopyridin-3-yl)-1H-pyrazol-1-carboxylate (52 mg) was thus obtained.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:27][C:28]([C:31]1[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=1)([F:30])[CH3:29]>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@H:24]([C:34]3[CH:35]=[CH:36][C:31]([C:28]([F:30])([F:27])[CH3:29])=[CH:32][CH:33]=3)[OH:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(F)(F)c1ccc(I)cc1
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1ccc(C(C)(F)F)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 1-(1,1-difluoroethyl)-4-iodobenzene.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:43])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[C:33]([CH2:34][O:35]C3CCCCO3)=[CH:32][N:31]=[N:30]2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:43])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[C:33]([CH2:34][OH:35])=[CH:32][N:31]=[N:30]4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3nncc3CO)c2)=Nc2cc(F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (RS)-[5-fluoro-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M34) (489 mg, 0.787 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (87 mg).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CN(C)C=O.Cl[CH:16]([N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)[CH:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[CH3:18]>O>[C:1]1([S:7][CH:16]([N:27]2[CH:31]=[N:30][CH:29]=[N:28]2)[CH:17]([O:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(OC(C)C(Cl)n2cncn2)cc1
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(OC(C)C(Sc2ccccc2)n2cncn2)cc1

Procedure:
13 q (0.12 mol of thiophenol were added slowly at 25° C. to a solution of 4.0 g of sodium hydride (80% strength by weight suspension in mineral oil) and 100 ml of N,N-dimethylformamide, followed, after stirring for 30 minutes, by 19.8 g (0.08 mol) of 1-chloro-1-(1,2,4-triazol-1-yl)-2-(4-methylphenoxy)-propane. After a reaction time of 24 hours at 25° C., 100 ml of water were added. Extraction with methyl tert-butyl ether was carried out, after which the organic phase was washed and was worked up in a conventional manner.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[C:12]([NH2:24])[C:11]=1[NH2:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC(C1C2N=C(N)[NH:36][C:35]=2C=CC=1)=O.BrC#N>CO>[CH2:1]([O:8][C:9]([C:10]1[C:11]2[N:25]=[C:35]([NH2:36])[NH:24][C:12]=2[CH:13]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=1)=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(OCc2ccccc2)cc(C(=O)OCc2ccccc2)c1N
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Agent: N#CBr
Solvent: CO
Product: Nc1nc2c(C(=O)OCc3ccccc3)cc(OCc3ccccc3)cc2[nH]1

Procedure:
2.5 g (7.2 mmol) of 2,3-diamino-5-benzyloxy-benzoic acid benzyl ester was subjected to a similar cyclization condition as illustrated in intermediate A by using 2.3 g (21.6 mmol) of BrCN in methanol to produce 2-amino-6-benzyloxy-1H-benzoimidazole-4-carboxylic acid benzyl ester. LCMS: 375 (M+1)+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH:35]1([CH2:38]Br)[CH2:37][CH2:36]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:38][CH:35]3[CH2:37][CH2:36]3)[C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2CC1CC1)N1CCN(C2CCCC2)CC1
Yield: 70 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), sodium hydride and cyclopropylmethyl bromide in N,N-dimethylformamide, to give the desired product as a light yellow solid (70%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][CH:8]=[CH:9][N:10]=1.CCCCCC.C([Li])CCC.CN(C)[CH:24]=[O:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][C:8]([CH:24]=[O:25])=[CH:9][N:10]=1
Reactant: c1csc(C2OCCO2)n1
Reactant: CN(C)C=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1cnc(C2OCCO2)s1
Temperature: -70 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
To a solution of 2-(1,3-dioxolan-2-yl)-1,3-thiazole (10.00 g) in tetrahydrofuran (150 mL) was slowly added a 1.6M n-butyllithium hexane solution (44 mL) at −70° C. under a nitrogen atmosphere. The reaction mixture was stirred at −70° C. for 1 hr and N,N-dimethylformamide (14 g) was added. The reaction mixture was warmed to room temperature, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (6.64 g, yield 56%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (3:2, volume ratio). MS: 186 (MH+).
Reaction SMILES: CN1C2C=CC=C(C([O-])=O)C=2C(CN[C@@H]2C3CCN(CC3)C2)=N1.[CH3:24][N:25]1[C:29]2[CH:30]=[N:31][CH:32]=[C:33]3[C:34](=[O:45])[C@H:35]([CH:37]4[CH:42]5[CH2:43][CH2:44][N:39]([CH2:40][CH2:41]5)[CH2:38]4)[CH2:36][C:27]([C:28]=23)=[N:26]1.[ClH:46]>>[ClH:46].[CH3:24][N:25]1[C:29]2[CH:30]=[N:31][CH:32]=[C:33]3[C:34](=[O:45])[C@@H:35]([CH:37]4[CH:42]5[CH2:41][CH2:40][N:39]([CH2:44][CH2:43]5)[CH2:38]4)[CH2:36][C:27]([C:28]=23)=[N:26]1
Reactant: Cn1nc2c3c(cncc31)C(=O)[C@H](C1CN3CCC1CC3)C2
Agent: Cl
Agent: Cn1nc(CN[C@H]2CN3CCC2CC3)c2c(C(=O)[O-])cccc21
Product: Cn1nc2c3c(cncc31)C(=O)[C@@H](C1CN3CCC1CC3)C2

Procedure:
Following general procedure GP-H, (R)-1-methyl-3-[(quinuclidin-3-ylamino)methyl)-1H-indazole-4-carboxylate was converted to (S)-2-methyl-7-(quinuclidin-3-yl]-7,8-dihydropyrazolo[3,4,5-de]isoquinolin-6(2H)-one, which was immediately treated with hydrochloric acid following general procedure GP-I to give (R)-2-methyl-7-(quinuclidin-3-yl)-7,8-dihydropyrazolo[3,4,5-de]isoquinolin-6(2H)-one, hydrochloride salt: 1H NMR (500 MHz, DMSO-d6) δ 10.20 (s, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.53 (t, J=7.0 Hz, 1H), 7.40 (d, J=6.5 Hz, 1H), 5.27 (d, J=17.0 Hz, 1H), 5.15 (d, J=16.5 Hz, 1H), 4.77 (t, J=9.0 Hz, 1H), 4.08 (s, 3H), 3.72-3.69 (m, 1H), 3.58-3.48 (m, 2H), 3.40-3.28 (m, 2H), 3.22-3.18 (m, 1H), 2.46-2.42 (m, 1H), 2.28-2.14 (m, 1H), 2.08-1.84 (m, 3H); MS (ESI+) m/z 297 (M+H); HPLC 98.7% (AUC), tR 13.39 min.
Reaction SMILES: O=[O+][O-].[O:4]=O.[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@@H:15]([O:18][C:19](=[O:21])[CH3:20])[CH:16]=C)=[O:12])([CH3:9])([CH3:8])[CH3:7].O=O.S(C)C>C(Cl)Cl>[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C@@H:15]([O:18][C:19](=[O:21])[CH3:20])[CH:16]=[O:4])=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: C=C[C@H](OC(C)=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: O=O
Agent: O=[O+][O-]
Solvent: CSC
Solvent: ClCCl
Product: CC(=O)O[C@@H](C=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
Ozone/oxygen was bubbled at -70° C. into a solution of (3S,4S)-N-[(tert-Butyloxy)carbonyl]-4-amino-3-acetoxy-5-phenylpentene (2.55 g, 8.0 mmol) [prepared by the method of Hanson et al., J. Org, Chem., 50, 5399 (1985)] in 100 mL of methylene chloride until a deep blue color persisted. Oxygen was introduced until the blue color completely faded, then 3.0 mL of Me2S was added and the solution was allowed to warm to 0°-5° C. and stand overnight. The solvent was removed at 0° C. under vacuum yielding the title compound as a thick yellow oil which was used without further purification.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:14]=[CH:13][C:8]2[S:9][CH:10]=[C:11]([CH3:12])[C:7]=2[CH:6]=1>CN1CCCC1=O>[C:2]([C:5]1[CH:14]=[CH:13][C:8]2[S:9][CH:10]=[C:11]([CH3:12])[C:7]=2[CH:6]=1)#[N:3]
Reactant: Cc1csc2ccc(Br)cc12
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: Cc1csc2ccc(C#N)cc12
Reaction time: 17 h
Yield: 90.1 %

Procedure:
To copper (I) cyanide (0.569 g, 6.35 mmol) was added 5-bromo-3-methyl benzo[b]thiophene (1.179 g, 5.19 mmol) in N-methylpyrrolidinone (10 ml) and the mixture was stirred at 180°-90° C. for 17 h. This was then partitioned between ether (75 ml) and ammonia solution (75 ml). The ether layer was separated, washed with more ammonia solution (2×50 ml), dried (Na2SO4) and evaporated in vacuo to leave 0.81 g of an off-white solid. Chromatography on flash silica, eluting with 10% ethyl acetate/petroleum ether yielded 0.76 g (85%) of the title compound as a white solid. δ (CDCl3) 2.47 (3H, s), 7.23 (1H, s), 7.55 (1H, dd, J=8.3 and 1.5 Hz), 7.93 (1H, d, J=8.4 Hz), 8.03 (1H, d, J=1.4 Hz).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.Br[CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(O)C>[OH:15][CH2:14][CH2:13][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: COc1cc(C=O)ccc1O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)=O
Product: COc1cc(C=O)ccc1OCCO
Yield: 40 %

Procedure:
25.9 g (170 mmol) vanillin (Aldrich), 33.3 g (266 mmol) 2-bromoethanol (Aldrich), 35.2 g (255 mmol) potassium carbonate (Sigma-Aldrich), and 20 g molecular sieves (Aldrich) were combined in a 1 liter round bottom flask equipped with magnetic stirrer and nitrogen inlet. Acetone (600 ml) (Chromasolv for HPLC, >99.9%, Sigma-Aldrich) was added and the reaction mixture was refluxed for 16 hours using an external glycerol heating bath set to 65° C. The solids were filtered and the solvent was removed via rotary evaporation to yield a yellow oil. White crystals were obtained by recrystallization in ethyl alcohol at −20° C. (40% yield).