Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][NH2:10])=[O:8])=[CH:4][CH:3]=1.[N:11]([CH2:14][CH2:15][O:16][CH3:17])=[C:12]=[O:13]>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][NH:10][C:12]([NH:11][CH2:14][CH2:15][O:16][CH3:17])=[O:13])=[O:8])=[CH:4][CH:3]=1
Reactant: COCCN=C=O
Reactant: NNC(=O)c1ccc(Cl)s1
Solvent: C1CCOC1
Product: COCCNC(=O)NNC(=O)c1ccc(Cl)s1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
A quantity of 3.1 g (17.55 mmol) of 5-chlorothiophene-2-carbohydrazide was suspended largely finely in 30 ml of dry THF at 50° C. Then 1.81 g (17.90 mmol) of 1-isocyanato-2-methoxyethane in solution in 30 ml of THF were added dropwise. The mixture was stirred at 50° C. for 2.5 h. After cooling to RT, the solvent was removed on a rotary evaporator and the residue was admixed with diethyl ether. The crystals were filtered off with suction, washed with diethyl ether and dried in an HV. This gave 4.87 g (100% of theory) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[CH3:30][N:31]([CH:38]1[CH2:41][O:40][CH2:39]1)[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:35]4[CH2:36][CH2:37][CH:32]([N:31]([CH3:30])[CH:38]5[CH2:39][O:40][CH2:41]5)[CH2:33][CH2:34]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CN(C1CCNCC1)C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(N(C)C4COC4)CC3)n(C)c2n1
Reaction time: 16 h
Yield: 37 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (179 mg, 0.46 mmol), methyloxetan-3-ylpiperidin-4-ylamine (94 mg, 0.55 mmol) and 4 Å powdered molecular sieves (400 mg) in DCE (10 mL) was stirred at room temperature for 5 h before the addition of sodium triacetoxyborohydride (233 mg, 0.92 mmol). The reaction mixture was stirred for 16 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-15%) affording 418 as a cream solid (93 mg, 37%). LCMS (Method I): RT 2.31 min [M+H]+546.4. 1H NMR (CDCl3, 400 MHz): δ 8.03-7.99 (m, 1 H); 7.78-7.72 (m, 1 H); 7.29-7.22 (m, 2 H); 4.67 (t, J=6.5 Hz, 2 H); 4.60 (t, J=6.6 Hz, 2 H); 4.34 (m, 4 H); 3.98-3.88 (m, 1 H); 3.89-3.82 (m, 7 H); 3.72 (s, 2 H); 3.35 (q, J=7.5 Hz, 2 H); 2.94 (d, J=11.2 Hz, 2 H); 2.35-2.24 (m, 1 H); 2.21 (s, 3 H); 2.13 (t, J=11.2 Hz, 2 H); 1.64 (d, J=12.2 Hz, 2 H); 1.54 (m, 2 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:10](=[O:14])[CH2:11][CH2:12][CH:13]=1.CC(C)(O)[C:17]#[N:18].C(=O)([O-])[O-].[Na+].[Na+]>CO>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[C:10](=[O:14])[CH2:11][CH2:12][CH:13]1[C:17]#[N:18]
Reactant: CC(C)(O)C#N
Reactant: O=C1CCC=C1CCCCCCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: N#CC1CCC(=O)C1CCCCCCCO
Yield: 68.8 %

Procedure:
A mixture of 2-(7-hydroxyheptyl)cyclopent-2-en-1-one (17 g.), acetone cyanohydrin (8.5 g.), 6% aqueous sodium carbonate (8 ml.) and methanol (50 ml.) was stirred and heated under reflux for 4 hours. Methanol was removed in vacuo, water (100 ml.) was added and the mixture was extracted with diethyl ether and dried over magnesium sulphate. The solvent was removed by evaporation, and the residue was distilled under reduced pressure to give 2-(7-hydroxyheptyl)-3-oxocyclopentanecarbonitrile (13.3 g.), b.p. 144°-182° C./0.15 mm.Hg, nD25 1.4795.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@@H:16]([OH:19])[CH2:17][Br:18])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH2:9]([O:8][C:7]1[CH:6]=[CH:5][C:4]([C@@H:16]([OH:19])[CH2:17][Br:18])=[CH:3][C:2]=1[NH:1][S:27]([CH3:26])(=[O:29])=[O:28])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
A solution of (1R)-1-[3-amino-4-(benzyloxy)phenyl]-2-bromoethanol (Org. Process Research and Development, 1998, 2, 96) (30.8 g, 95.6 mmol) in dichloromethane (300 ml) was treated with pyridine (9.3 ml, 115 mmol). The resulting solution was cooled to 5° C. and a solution of methanesulfonyl chloride (7.8 ml, 100.7 mmol) in dichloromethane (10 ml) added dropwise. The mixture was stirred at 5° C. for a further 30 minutes and then allowed to warm gradually to room temperature over a period of 16 hours. The reaction mixture was washed with 2N hydrochloric acid (110 ml) and the organic phase separated, dried (magnesium sulfate) and the solvent removed in vacuo to give an orange oil. The residue was crystallized from hot toluene (100 ml) to give the title compound as a pale pink solid (33.7 g).
Reaction SMILES: S(Cl)(Cl)=O.[C:5](Cl)(=O)[C:6]([Cl:8])=[O:7].[O:11]([C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)C=1C(O)=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[O:11]([C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:5]=1[C:6]([Cl:8])=[O:7])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1c(Oc2ccccc2)cccc1Oc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1c(Oc2ccccc2)cccc1Oc1ccccc1

Procedure:
Fifteen parts of thionyl chloride or oxalyl chloride are added to 2 parts of 2,6-diphenoxybenzoic acid. The mixture is heated under reflux for 30 minutes, and the excess chloride is distilled. The residue crystallizes to give 2,6-diphenoxybenzoyl chloride, M.P. 72°-73°.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[C:16]([O:17][CH3:18])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.[C:19]1(=[O:25])[O:24][C:22](=[O:23])[CH2:21][CH2:20]1.O>C(Cl)Cl>[CH3:18][O:17][C:16]1[CH:15]=[C:14]2[C:9](=[CH:8][C:7]=1[O:6][CH3:5])[CH:10]=[C:11]([C:19](=[O:25])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:12]=[CH:13]2
Reactant: COc1cc2ccccc2cc1OC
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1cc2ccc(C(=O)CCC(=O)O)cc2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aluminium chloride (9.5 g) was added to a solution of 2,3-dimethoxynaphthalene (10 g) and succinic anhydride 7.1 g in methylene chloride (140 ml). The mixture was stirred at room temperature overnight and then treated with water and filtered. The resulting solid was taken into 1 M sodium hydroxide, washed once with methylene chloride, acidified and filtered. Yield: 8.3 g, melting point 215-229° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7](Cl)=[O:8].[NH:10]1[CH2:15][CH2:14][S:13][CH2:12][CH2:11]1>>[CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]([N:10]1[CH2:15][CH2:14][S:13][CH2:12][CH2:11]1)=[O:8]
Reactant: C1CSCCN1
Reactant: Cc1oncc1C(=O)Cl
Product: Cc1oncc1C(=O)N1CCSCC1

Procedure:
of melting point 64.5° to 65° C., prepared from 5-methyl-4-isoxazolecarboxylic acid chloride and thiomorpholine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([N:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][N:19]3[CH:27]=[CH:28][CH:29]=[C:18]3[CH2:17]2)=[O:15])[CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:36][C:37]([Cl:42])([Cl:41])[C:38](Cl)=[O:39]>O1CCCC1.C(OCC)(=O)C>[Cl:36][C:37]([Cl:42])([Cl:41])[C:38]([C:27]1[N:19]2[C:18]([CH2:17][N:16]([C:14]([C:10]3[CH:9]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])[CH:13]=[CH:12][CH:11]=3)=[O:15])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20]2)=[CH:29][CH:28]=1)=[O:39]
Reactant: Cc1ccccc1-c1cccc(C(=O)N2Cc3cccn3Cc3ccccc32)c1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.9 %

Procedure:
To a mixture of 10-[(2′-methyl-1,1′-biphenyl-3-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step B (1.7 g, 4.5 mmol) and sodium carbonate (0.95 g, 9.0 mmol) in dry tetrahydrofuran (40 mL) was added dropwise trichloroacetyl chloride (0.75 mL, 6.7 mmol) and the reaction mixture stirred at room temperature under nitrogen for 18 hours. The reaction mixture was then diluted with ethyl acetate (150 mL), washed with 1 M hydrochloric acid (150 mL), water (150 mL) and brine (150 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a dark foam. Purification by flash chromatography using a solvent gradient of 60% to 80% dichloromethane in hexane afforded a white solid that was recrystallized from hot ethyl acetate to give the title compound (1.2 g, 50%) as a white needles.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15](O)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.CCCCCC.S(Cl)([Cl:28])=O>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([Cl:28])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: CCCCCC
Product: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1

Procedure:
A mixture of 5.0 g of 4'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxylic acid in 5.0 ml of thionyl chloride is heated on a steam bath under Argon for 1 hour and hexane added. The resulting solid is collected and dried to give 5.36 g of the desired product as a colorless oil. M+ =280 as methyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]#[CH:16])=[CH:9][C:8]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=1)=O.[O-:31][C:32]#[N:33].[Na+]>CC(O)=O.O>[OH:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:7]2[C:8](=[CH:9][C:10]([O:13][CH2:14][C:15]#[CH:16])=[CH:11][CH:12]=2)[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[N:33][C:32]1=[O:31]
Reactant: C#CCOc1ccc(NCc2cccc(O)c2)c(C(=O)c2ccc(C(C)C)cc2)c1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3.0 g (7.51 mmol) of the product prepared in step A in 45 ml AcOH is treated with 732 mg (11.3 mmol) sodium cyanate. The dark red solution is stirred for 2 h at rt. The resulting yellow-orange suspension is diluted with water and filtered. The orange product is washed well with water and diethyl ether to yield an orange solid. m.p. 230° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:14]([O:20][CH2:21]Cl)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][N:8]([CH2:21][O:20][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]nc(I)c2c1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCn1nc(I)c2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
5-Bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine (3.00 g, 9.26 mmol) was dissolved in N,N-dimethylforamide (150 ml) at 4° C. To the solution was added sodium hydride (60%, 519 mg, 12.98 mmol) in small portions. The flask was warmed to room temperature and stirred for 1 hour. To the mixture was added chloromethyl pivalate (2.29 ml, 15.78 mmol). The reaction mixture was stirred for 2 hours at room temperature, and quenched with methanol. Saturated ammonium chloride solution was added, and the mixture was concentrated in vacuo. The residue was dissolved in dichloromethane, and the organic layer was washed four times with. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in acetone. The solution was filtered and the solid material collected was discarded. The filtrate was concentrated in vacuo. The crude material was re-crystallized in ether to give 2.80 g (69%) of 2,2-dimethyl-propionic acid 5-bromo-3-iodo-pyrazolo[3,4-b]pyridin-1-ylmethyl ester. 1H-NMR (250 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.20 (s, 1H), 6.43 (s, 2H), 1.14 (s, 9H); MS m/z 437.8, 439.8 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][C:12]([OH:14])=O)[N:4]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:30][O:31][C:32]([C:34]1[CH:44]=[CH:43][CH:42]=[CH:41][C:35]=1[CH2:36][S:37]([NH2:40])(=[O:39])=[O:38])=[O:33]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([CH2:11][C:12]([NH:40][S:37]([CH2:36][C:35]2[CH:41]=[CH:42][CH:43]=[CH:44][C:34]=2[C:32]([O:31][CH3:30])=[O:33])(=[O:38])=[O:39])=[O:14])[N:6]=1
Reactant: COC(=O)c1ccccc1CS(N)(=O)=O
Reactant: COc1cc(OC)nc(CC(=O)O)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccccc1CS(=O)(=O)NC(=O)Cc1nc(OC)cc(OC)n1
Reaction time: 1 h

Procedure:
A solution of 1.9 g of (4,6-dimethoxypyrimidin-2-yl)acetic acid in 40 ml of absolute dichloromethane is added dropwise at 0° C. to 2° C. to a solution of 1.9 g of dicyclohexylcarbodiimide, 100 mg of 4-dimethylaminopyridine and 2.1 g of 2-methoxycarbonylbenzylsulfonamide in 40 ml of absolute dichloromethane. Stirring is continued for 1 hour at 0° C., and the mixture is allowed to come to room temperature and stirred for another 0.5 hour. The solids are filtered off, and the filtrate is concentrated in a rotary evaporator. 100 ml of 2 N sodium carbonate solution are added to the residue, the mixture is stirred for 0.5 hour at room temperature, and the solids are filtered off with suction. The sodium carbonate alkaline phase is extracted twice using diethyl ether, and a pH of 2-3 is established using concentrated hydrochloric acid. Stirring is continued for 15 minutes, the solids are filtered off with suction, the filter residue is washed once with water and twice with ether, and dried in vacuo. This gives 2.4 g of N-[2-(4,6-dimethoxypyrimidin-2-yl)acetyl]-2-methoxycarbonylbenzylsulfonamide of melting point 98°-101° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][NH:9][C:10]2[N:11]=[C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH:5]=[CH:6][CH:7]=1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[C:31](Cl)=O>COCCOC>[Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][N:9]2[C:10]3[N:11]=[C:12]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[S:13][C:14]=3[C:15](=[O:16])[N:17]=[C:31]2[CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][O:25]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CCCCO1
Reactant: Cc1c(Cl)cccc1CNc1nc(N2CCOCC2)sc1C(N)=O
Solvent: COCCOC
Product: Cc1c(Cl)cccc1Cn1c(C2CCCCO2)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-{[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (100 mg, 0.273 mmol) in 1,2-Dimethoxyethane (DME) (1000 ul) was added tetrahydro-2H-pyran-2-carbonyl chloride (81 mg, 0.545 mmol) in 1,2-Dimethoxyethane (DME) (400 ul). The mixture was stirred at room temperature for 3 h, then irradiated (uwave) for 20 min at 90° C. The mixture was quenched with methanol, concentrated, and purified by reversed-phase HPLC to provide 4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)-5-(tetrahydro-2H-pyran-2-yl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one. (17 mg, 14%); LC/MS: MS (ES*) m/e 461 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (br. s., 3H), 1.62-1.72 (m, 1H), 1.78-1.98 (m, 2H), 2.45 (s, 3H), 3.45-3.57 (m, 5H), 3.66 (t, J=4.8 Hz, 4H), 3.81 (d, J=11.6 Hz, 1H), 4.28 (m, 1H), 5.51-5.66 (m, 2H), 6.49 (d, J=7.8 Hz, 1H), 7.13 (m, 1H), 7.36 (d, J=7.8 Hz, 1H).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:16][C:17]3[CH:26]=[CH:25][C:20]([C:21](OC)=[O:22])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:27][OH:28].[OH-].[Na+].C1COCC1>CO>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([NH:27][OH:28])=[O:22])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: COC(=O)c1ccc(CN2c3ccccc3C=Cc3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NO)c1ccc(CN2c3ccccc3C=Cc3ccccc32)cc1
Yield: 26 %

Procedure:
Title compound 350 (147 mg, 0.43 mmol), hydroxylamine (50% in water, 6 mL) and sodium hydroxide (138 mg, 3.40 mmol) were stirred in methanol (3 mL) and THF (3 mL) at room temperature overnight. The organic solvent was evaporated and the precipitate was filtered off and washed with a little bit of cold methanol to afford title compound 351 (39 mg, 26%) as a yellow solid. 1H NMR (DMSO-d6) δ (ppm): 11.06 (s, 1H), 8.96 (s, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.21 (td, J=1.6 and 7.2 Hz, 2H), 7.18-7.13 (m, 2H), 7.10 (dd, J=1.6 and 7.6 Hz, 2H), 6.6 (td, J=1.2 and 7.2 Hz, 2H), 6.85 (s, 2H), 5.00 (s, 2H). LRMS: 342.1 (calc). 343.2 (found).
Reaction SMILES: Cl[CH:2]([C:7]([CH3:9])=O)[C:3]([O:5][CH3:6])=[O:4].[C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[S:17])=[CH:14][CH:13]=1)#[N:11]>CO>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]2[S:17][C:2]([C:3]([O:5][CH3:6])=[O:4])=[C:7]([CH3:9])[N:18]=2)=[CH:19][CH:20]=1)#[N:11]
Reactant: N#Cc1ccc(C(N)=S)cc1
Reactant: COC(=O)C(Cl)C(C)=O
Solvent: CO
Product: COC(=O)c1sc(-c2ccc(C#N)cc2)nc1C
Temperature: 0 °C
Yield: 55.7 %

Procedure:
A suspension of methyl 2-chloroacetoacetate (30 g, 0.19 mol) and 4-cyanothiobenzamide (21.5 g, 0.13 mol) in MeOH (250 mL) was refluxed for 15 h. The reaction mixture was then cooled to 0° C., filtered after 20 h and washed with cooled (-20° C.) MeOH and with ether. The resulting off-white solid was dried to give methyl 2-(4-cyanophenyl)-4-methylthiazole-5-carboxylate (18.7 g, 55%). If desired, additional product may be recovered by flash chromatography of the washings: mp 186°-187° C.; 1H NMR (300 MHz, CDCl3) δ (TMS) 8.07 (dt, Jt =1.6, Jd =8.3, 2H, arom), 7.74 (dt, Jt =1.6, Jd =8.3, 2H, arom), 3.91 (s, 3H, OMe), 2.79 (s, 3H, Me-thiazole). Analysis calculated for C13H10N2O2S: C 60.45; H 3.90; N 10.85; S 12.41. Found: C 60.31; H 3.80; N 10.53; S 11.79.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:27][CH2:28]Cl>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2([C:12]([O:14][CH3:15])=[O:13])[CH2:28][CH2:27]2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccc(C(C)(C)C)cc1
Reactant: ClCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ccc(C(C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
4 g (19.4 mmol) of Methyl 4-tert-butylphenylacetate, 39 mL (1.0 m, 2 Eq.) of lithium bis(trimethylsilyl)amide, and 3 g (2 Eq.) of 1-bromo-2-chloroethane in 100 mL dry THF were reacted as described in Preparation 11, except that the reaction mixture was stirred for one hour at ambient temperature before work-up. This reaction yielded 4.21 g of a brown oil. This material was purified via silica gel chromatography eluting with a gradient solvent of hexanes to hexanes/EtOAc 19:1 to yield the title compound 1.57 g (35%) as a pale yellow solid m.p. 58°-60° C. Calculated for C15H20O2: Theory: C, 77.37; H, 8.81 Found: C, 77.54; H, 8.68.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[F:29][C:30]([F:37])([F:36])[CH2:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[C:16]1([CH:4]([NH:3][S:32]([CH2:31][C:30]([F:37])([F:36])[F:29])(=[O:34])=[O:33])[C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O[C@H]1CN2CCC1CC2)C(NS(=O)(=O)CC(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (120 mg, 0.36 mmol) in DCM (4 ml) and triethylamine (105 μl, 1.44 mmol), was added 2,2,2-trifluoroethanesulfonyl chloride (47.5 μl, 0.43 mmol). The reaction was stirred at RT for 3 hours, and then it was diluted with DCM and washed with water, brine and 1M K2CO3. The organic phase was dried with Na2SO4, filtered, and evaporated. The crude was purified with flash chromatography (DCM/MeOH=9/1) to obtain (R)-quinuclidin-3-yl 2-phenyl-2-(2,2,2-trifluoroethylsulfonamido)acetate (60 mg; 41% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][CH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH2:25][CH2:26][OH:27])[CH3:24])[CH2:18][CH2:17]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:28].[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:17][CH2:18][C@H:19]([CH2:22][N:23]([CH2:25][CH2:26][OH:27])[CH3:24])[CH2:20][CH2:21]2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1NC1CCC(CN(C)CCO)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](CN(C)CCO)CC1

Procedure:
Following general procedure II, 1-[6-chloro-4-(4-{[(2-hydroxyethyl)(methyl)-amino]methyl}cyclohexylamino)-1,5-naphthyridin-3-yl]ethanone (70 mg, 0.18 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (76 mg, 0.27 mmol) followed by formation of the dihydrochloride salt to afford the desired product (68 mg, 64%) as a light yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.15 (s, 1H), 8.46 (d, J=9.0 Hz, 1H), 8.34 (d, J=9.0 Hz, 1H), 8.12 (s, 2H), 5.74-5.71 (m, 1H), 3.90 (t, J=5.0 Hz, 2H), 3.39-3.37 (m, 1H), 3.28-3.26 (m, 2H), 3.06-3.02 (m, 1H), 2.97 (s, 3H), 2.76 (m, 3H), 2.46-2.43 (m, 2H), 2.13-2.03 (m, 3H), 1.69-1.66 (m, 2H), 1.44-1.42 (m, 2H); ESI MS m/z 517 [M+H]+; HPLC>99% (AUC), tR=9.74 min.
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH:7](=[O:11])[CH:8]([CH3:10])[CH3:9]>[Cl-].[Zn+2].[Cl-]>[C:7]([O:5][CH:1]([Cl:6])[CH:2]([CH3:4])[CH3:3])(=[O:11])[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)C=O
Reactant: CC(C)C(=O)Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(C)C(=O)OC(Cl)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a mixture of isobutyryl chloride (10 mL, 94.7 mmol) and zinc (II) chloride (25 mg, 186 mmol) was added isobutyraldehyde (10.4 mL, 113.6 mmol) at −20° C. The reaction was stirred at 0° C. for 1 h, then at rt for another 2 h. The mixture was filtered through a short silica gel column (100% PE). The solution was concentrated in vacuo at 40° C. and the resulted oil was distilled at 75° C. under reduced pressure to give the title compound as colorless oil (13.48 g, 79.3%). The title compound was characterized by 1H NMR as shown below: