Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]#[CH:2].[Cl:3][SiH:4]([CH2:6][SiH:7]([Cl:9])[Cl:8])[Cl:5]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC=CC=1>[Cl:3][Si:4]1([Cl:5])[CH:2]=[CH:1][Si:7]([Cl:9])([Cl:8])[CH2:6]1
Reactant: C#C
Reactant: Cl[SiH](Cl)C[SiH](Cl)Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: Cl[Si]1(Cl)C=C[Si](Cl)(Cl)C1
Yield: 55.2 %

Procedure:
Hydrosilation of acetylene with bis(dichlorosilyl)methane in the presence of Pd(PPh3)4. Into the same apparatus as described in Example 1 were placed 10 g of bis(dichlorosilyl)methane, 0.103 g of Pd(PPh3)4, and 20 ml of dried benzene. Acetylene gas was blown into the flask at 90 ml/min for 3 hours. The products were vacuum distilled at 67 Pa to yield a mixture comprising 8.29 g of 1,1,3,3-tetrachloro-1,3-disilacyclopent-4-ene (TCD-GC area 55.2%); 3,3,5,5-tetrachloro-3,5-disilapent-1-ene (TCD-GC area 12.7%); 1,1,3,3-tetrachloro-1,3-disilacyclopentane (TCD-GC area 5.3%); and 1,1,3,3,6,6,8,8-octachloro-1,3,6,8-tetrasilaoctane (TCD-GC area 0.3%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[N:28]=[C:27]([CH2:29][NH:30][CH:31]([CH3:36])[C:32]([CH3:35])([OH:34])[CH3:33])[CH:26]=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([CH2:29][NH:30][CH:31]([CH3:36])[C:32]([OH:34])([CH3:33])[CH3:35])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CC(NCc1cccc(Br)n1)C(C)(C)O
Product: CC(NCc1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1)C(C)(C)O

Procedure:
The title compound was prepared by using the procedure listed in Example 1 with 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.080 g, 0.26 mmol) and 3-{[(6-bromopyridin-2-yl)methyl]amino}-2-methylbutan-2-ol (0.070 g, 0.26 mmol) as the starting materials.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[NH2:12])[N:4]=[CH:3]1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](O)=[O:23])=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:12][C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:5]2[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=2)=[O:23])=[CH:17][CH:16]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: Cn1cnc(-c2sccc2N)c1
Product: COc1ccc(CC(=O)Nc2ccsc2-c2cn(C)cn2)cc1

Procedure:
The title compound was prepared from 2-(1-methyl-1H-imidazol-4-yl)thiophen-3-amine and 2-(4-methoxyphenyl)acetic acid using protocol B and was purified by HPLC. Method [8] Retention time 3.55 min by HPLC (MH+ 328). 1H NMR (300 MHz, DMSO) δ 10.37 (s, 1H), 8.33 (s, 1H), 7.48 (3m, H), 7.26 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), (s, 6H), 3.60 (s, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]1[C:23](=[O:24])[CH2:22][S:21][C:20]1=[S:25]>>[CH3:4][C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:22]2[S:21][C:20](=[S:25])[N:19]([CH3:18])[C:23]2=[O:24])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:2])[CH3:3]
Reactant: CN1C(=O)CSC1=S
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Product: CN1C(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)SC1=S
Yield: 76 %

Procedure:
The title compound was prepared in 76% yield from 3,5-di-tert-butyl-4-hydroxybenzaldehyde and N-methylrhodanine following the procedure of Example 1, m.p. >230° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][C:3]=1[F:15].[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1>>[F:15][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1)[N:8]([CH3:11])[C:7](=[O:12])[C:6]2([CH3:13])[CH3:14]
Reactant: O=C(O)c1cccnc1
Reactant: CN1C(=O)C(C)(C)c2cc(F)c(N)cc21
Product: CN1C(=O)C(C)(C)c2cc(F)c(NC(=O)c3cccnc3)cc21

Procedure:
Prepared in analogy to example 17 from 6-amino-5-fluoro-1,3,3-trimethylindolin-2-one (example 20 f) and nicotinic acid. The title compound was obtained as off-white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:11]1[CH:12]2[N:19](C(OC(C)(C)C)=O)[CH:15]([CH2:16][C:17]=1[CH3:18])[CH2:14][CH2:13]2)(=[O:10])[CH3:9]>>[C:8]([C:11]1[CH:12]2[NH:19][CH:15]([CH2:16][C:17]=1[CH3:18])[CH2:14][CH2:13]2)(=[O:10])[CH3:9]
Reactant: CC(=O)C1=C(C)CC2CCC1N2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)C1=C(C)CC2CCC1N2

Procedure:
A solution of trifluoroacetic acid (18.8 mmol, 2.14 ml) and 2-acetyl-3-methyl-8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]oct-2-en (0.49 g, 1.88 mmol) was stirred at room temperature for about 0.5 hour. The solution was concentrated under reduced pressure. Hexane was added to the resulting residue, the resulting solution was concentrated under reduced pressure, and the process was repeated a second time to remove any residual trifluoroacetic acid. A concentrated solution of sodium carbonate was added to the residue to form a basic solution. The solution was extracted with methylene chloride, dried using sodium sulfate and purified by bulb-to-bulb distillation (80° C. (1.0 mmHg)) to give 2-acetyl-3-methyl-8-azabicyclo[3.2.1]oct-2-ene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:34])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[C:22]([O:31][CH2:32][CH3:33])=[N:23][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:25][CH:26]=3)=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:42](Cl)([Cl:44])=[O:43]>ClCCl.C1(C)C=CC=CC=1>[C:27]([C:24]1[N:23]=[C:22]([O:31][CH2:32][CH3:33])[C:21]([C:10]2[N:11]([C:42]([Cl:44])=[O:43])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([CH3:34])[N:9]=2)=[CH:26][N:25]=1)([CH3:28])([CH3:30])[CH3:29]
Reactant: O=C(Cl)Cl
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reaction time: 0.5 h

Procedure:
To a solution of rac-5-[(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-2-tert-butyl-4-ethoxy-pyrimidine (850 mg, 1.71 mmol) and triethylamine (600 uL, 4.28 mmol) in 10 mL of dichloromethane at 0° C. was added 1.88 mL solution of 20% phosgene in toluene (Fluka). After stirring for 30 min the mixture was concentrated to dryness under reduced pressure. Purification by flash column chromatography on silica gel, eluting with 10-20% of ethyl acetate in hexane provided 861 mg of rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride as an off-white solid.
Reaction SMILES: Cl.Cl.[C:3]([N:7]1[C:11]([NH:12][C:13]2[N:18]=[C:17]([CH2:19][C:20]3([C:26]4[O:30][C:29](=[O:31])[NH:28][N:27]=4)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=[N:8]1)([CH3:6])([CH3:5])[CH3:4].[Cl:32][C:33]1[C:34]([F:42])=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](O)=[O:37].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1>[C:3]([N:7]1[C:11]([NH:12][C:13]2[N:18]=[C:17]([CH2:19][C:20]3([C:26]4[O:30][C:29](=[O:31])[NH:28][N:27]=4)[CH2:21][CH2:22][N:23]([C:36](=[O:37])[C:35]4[CH:39]=[CH:40][CH:41]=[C:33]([Cl:32])[C:34]=4[F:42])[CH2:24][CH2:25]3)[CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=[N:8]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)n1nccc1Nc1cccc(CC2(c3n[nH]c(=O)o3)CCNCC2)n1
Reactant: O=C(O)c1cccc(Cl)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)n1nccc1Nc1cccc(CC2(c3n[nH]c(=O)o3)CCN(C(=O)c3cccc(Cl)c3F)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 40 mg of 5-(4-((6-((1-tert-butyl-1H-pyrazol-5-yl)amino)pyridin-2-yl)methyl)piperidin-4-yl)-1,3,4-oxadiazol-2(3H)-one dihydrochloride in 2 ml of pyridine were added 17.8 mg of 3-chloro-2-fluorobenzoic acid and 24.4 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at room temperature. The reaction mixture was stirred at room temperature overnight, followed by concentrating in vacuo. The reaction mixture was dissolved in ethyl acetate, and washed with water. The resulting ethyl acetate layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane to ethyl acetate) to give the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[C:4]([CH3:12])[N:3]=1.[C:13]([O:17][C:18](=[O:29])[NH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)([CH3:16])([CH3:15])[CH3:14]>C(N(CC)C(C)C)(C)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:28][C:25]2[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][NH:19][C:18](=[O:29])[O:17][C:13]([CH3:15])([CH3:14])[CH3:16])=[CH:27][CH:26]=2)[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2ccc(CCNC(=O)OC(C)(C)C)cc2)c([N+](=O)[O-])c(Cl)n1
Yield: 15.8 %

Procedure:
A mixture of 2,4-dichloro-6-methyl-3-nitro-pyridine (Chorvat, Robert J. et al., J. Med. Chem., 1999, 42, 833., 7.5 g, 36.2 mmol), [2-(4-amino-phenyl)-ethyl]-carbamic acid tert-butyl ester (Stark, Peter A. et al., J. Med. Chem., 1992, 35, 4264., 1.14 g, 4.83 mmol) in N,N-diisopropylethylamine (50 ml) was heated at reflux temperature for 16 h. After cooling, the mixture was concentrated. The residue was diluted with dichloromethane (200 ml) and washed with saturated aqueous NaHCO3 solution (50 ml×2). The organic layer was dried (MgSO4), and concentrated. Purification by flash column chromatography eluting with hexane/ethyl acetate (1:1) to afford 310 mg (16%) of the title compound as orange solids.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[CH:43][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[C:19]([C:22]5[CH:23]=[C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:25]=[CH:26][CH:27]=5)[CH:20]=4)[N:15](S(C4C=CC(C)=CC=4)(=O)=O)[CH:14]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[OH-].[Li+]>C1COCC1.O.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[C:21]4[C:16](=[N:17][CH:18]=[C:19]([C:22]5[CH:23]=[C:24]([NH:28][S:29]([CH3:32])(=[O:30])=[O:31])[CH:25]=[CH:26][CH:27]=5)[CH:20]=4)[NH:15][CH:14]=3)[CH:10]=[N:9]2)=[CH:43][CH:44]=1
Reactant: COc1ccc(Cn2cc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(-c5cccc(NS(C)(=O)=O)c5)cc34)cn2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(Cn2cc(-c3c[nH]c4ncc(-c5cccc(NS(C)(=O)=O)c5)cc34)cn2)cc1
Yield: 8.1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(3-(3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methane sulfon amide (250 mg, 0.39 mmol) was hydrolyzed with lithium hydroxide (66 mg, 1.6 mmol) in THF/water/methanol (4/3/1 ml) mixture to afford 15 mg (9.57% yield) of the pure product after purification by prep TLC using 2% methanol in DCM as eluent. 1H NMR (DMSO-d6, 300 MHz): δ 11.79 (s, 1H), 9.83 (s, 1H), 8.469 (s, 1H), 8.33-8.31 (d, 2H), 7.91 (s, 1H), 7.75 (s, 1H), 7.52-7.43 (m, 3H), 7.27-7.22 (t, 3H), 6.91-6.89 (d, 2H), 5.28 (s, 2H), 3.72 (s, 3H), 3.05 (s, 3H). MS: m/z=474.2 (M+1), HPLC: 94.18% in Method-C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH2:13])=[NH:12])=[CH:6][CH:5]=1.O.[NH2:15]N.[C:17]([NH:20][CH:21]([CH3:29])[C:22](=O)[C:23](OCC)=[O:24])(=[O:19])[CH3:18]>>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2[NH:13][C:23](=[O:24])[C:22]([CH:21]([NH:20][C:17](=[O:19])[CH3:18])[CH3:29])=[N:15][N:12]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(CC(=N)N)cc1
Reactant: CCOC(=O)C(=O)C(C)NC(C)=O
Reactant: NN
Agent: Cl
Solvent: O
Product: COc1ccc(Cc2nnc(C(C)NC(C)=O)c(=O)[nH]2)cc1

Procedure:
Analogously to Example 10A, 5.1 g (25.4 mmol) of 2-(4-methoxyphenyl)ethanamidine hydrochloride are reacted with 1.53 g (30.5 mmol) of hydrazine hydrate and 7.14 g (38.1 mmol) of ethyl 3-(acetylamino)-2-oxobutanoate to give N-{1-[3-(4-methoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}acetamide.
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[O:4][C:5]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[SH:30])([CH3:23])[CH3:22].N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:20])[C:2]=1[S:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)c1ccccc1S
Reactant: CC(C)CCC1(c2ccccc2)CC(O)=C(Br)C(=O)O1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)CCC1(c2ccccc2)CC(O)=C(Sc2ccccc2C(C)C)C(=O)O1

Procedure:
The title compound was prepared as described in General Method 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one (prepared in example CCC), 2.2 mmol of 2-isopropylbenzenethiol, and 2.2 mmol of piperidine in 30 mL of dichloromethane. The crude product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound (m.p. 64°-66° C.). 1H NMR (DMSO-d6) δ0.80 (m, 6H), 0.95 (m, 1H), 1.17 (t, 7H), 1.42 (m, 1H), 1.93 (m, 2H), 3.20 (m, 1H), 3.45 (2H+H2O), 5.84 (d, 1H), 6.55 (t, 1H), 6.93 (t, 1H), 7.12 (d, 1H), 7.40 (m, 5H).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@H:9]([N:10]=[N+:11]=[N-:12])[CH2:8][CH2:7][N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:4].[Li+].[OH-]>C1COCC1.O>[C:16]([O:15][C:13]([N:6]1[CH2:7][CH2:8][C@@H:9]([N:10]=[N+:11]=[N-:12])[C@H:5]1[C:3]([OH:4])=[O:2])=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)[C@@H]1[C@H](N=[N+]=[N-])CCN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (2S,3R)-3-azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester [361367-97-7] (210 mg, 0.777 mmol; Sunshine Ltd) in THF (6 mL) was added a solution of LiOH (55.8 mg, 2.33 mmol) in water (3 mL), followed by stirring at RT for 20 h. The reaction mixture was concentrated under reduced pressure and the residual aqueous phase was washed with EtOAc (3×). The water phase was adjusted to pH 2 to 3 by adding 1N aqueous HCl, followed by extraction with EtOAc (3×). The combined organics were dried (Phase separator) and concentrated in vacuo to give the crude title compound as a colorless oil. The crude product was used in the next reaction step without further purification. MS (LC/MS): 279 [M+Na]+, 200 [MH−tBu]+, 157 [MH−Boc]+; tR (HPLC conditions b): 2.77 min.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[C:22]([O:24]C)=[O:23])[CH:15]=[CH:14]1)[CH2:2]2.O.[OH-].[Li+:28]>O1CCCC1.O>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[C:22]([O-:24])=[O:23])[CH:15]=[CH:14]1)[CH2:2]2.[Li+:28]
Reactant: COC(=O)c1cccc2ccn(CCCN[C@H]3CN4CCC3CC4)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])c1cccc2ccn(CCCN[C@H]3CN4CCC3CC4)c12
Yield: 185.1 %

Procedure:
A mixture of (R)-methyl 1-(3-(quinuclidin-3-ylamino)propyl)-1H-indole-7-carboxylate (317 mg, 0.93 mmol) from Step C above and lithium hydroxide monohydrate (117 mg, 2.8 mmol) in tetrahydrofuran/water (1:1, 20 mL) was stirred at reflux until the reaction was complete by LC-MS. The solvent was removed under reduced pressure to give lithium (R)-1-(3-(quinuclidin-3-ylamino)propyl)-1H-indole-7-carboxylate as an off-white solid (574 mg, quantitative yield): 1H NMR (500 MHz, CD3OD) δ 7.49 (d, J=7.5 Hz, 1H), 7.26 (d, J=7.0 Hz, 1H), 7.19 (d, J=3.0 Hz, 1H), 6.98 (t, J=7.5 Hz, 1H), 6.43 (d, J=3.0 Hz, 1H), 4.51 (d, J=7.0 Hz, 2H), 3.05-2.99 (m, 1H), 2.83-2.68 (m, 5H), 2.49-2.32 (m, 3H), 2.01-1.92 (m, 2H), 1.71-1.61 (m, 3H), 1.51-1.47 (m, 1H), 1.36-1.28 (m, 1H); MS (ESI+) m/z 328 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C@H:9]2[CH2:14][C@H:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])=[CH:4][C:3]=1[F:27].[OH-].[Na+].[NH2:30]O.Cl>CO.O.C(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C@H:9]2[CH2:14][C@H:13]([C:15]3[O:22][NH:30][C:17](=[O:18])[CH:16]=3)[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])=[CH:4][C:3]=1[F:27]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2cc(F)c(Cl)c(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(F)c(Cl)c(F)c1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 96.3 %

Procedure:
Trans-methyl 2-(4-chloro-3,5-difluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (178 mg, 0.44 mmol) (from example 65, step 1) was dissolved in MeOH (2 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (18.51 mg, 0.46 mmol) dissolved in water (0.200 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.028 mL, 0.46 mmol) was added. The resulting solution was stirred at −40° C. for 1 h. The mixture was transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (2.278 mL, 13.67 mmol) and the mixture was stirred at 80° C. for 20 min. Water and DCM were added and the phases separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated. Crude trans-methyl 2-(4-chloro-3,5-difluorophenyl)-4-(3-oxo-2,3-dihydro-isoxazol-5-yl)piperidine-1-carboxylate (158 mg, 96%) was isolated as a light yellow oil. MS m/z 273 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2=[CH:15][N:16]([CH3:18])C)=[O:4].NC1[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2=[CH:15][NH:16][C:18]1[CH:25]=[CH:24][C:23]([S:26](=[O:28])(=[O:27])[NH2:29])=[CH:22][CH:21]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)C(=CN(C)C)C(=O)N2
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: COC(=O)c1ccc2c(c1)C(=CNc1ccc(S(N)(=O)=O)cc1)C(=O)N2
Yield: 41 %

Procedure:
A solution of 2.66 g (20.0 mmol) of ethyl (methylthio)acetate dissolved in 200 mL of dichloromethane was cooled with stirring to −70° C. and 2.7 g (20.0 mmol) of sulfuryl chloride was added. The reaction was stirred for 30 min. at −70° C., and a solution of 3.0 g (20 mol) of methyl 4-aminobenzoate and 4.3g (20 mmol) of Proton Sponge® in 250 mL of dichloromethane was added dropwise over 1 h. The resulting pink slurry was treated with 2.3 g (23 mmol) of TEA in one portion, and the solution was allowed to warm to rt. The solution was washed with three 250-mL portions of water, dried over MgSO4, and concentrated to give an oil. This was chromatographed on silica gel eluting with hexane:EtOAc (1:1) to yield 2.0 g (42% yield) of 3-methylthio-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester: 1H NMR (DMSO-d6): δ1.97 (s, 3H), 3.35 (s, 3H), 4.67 (s, 1H), 6.97 (d, J=8.2 Hz, 1H), 7.84 (s, 1H), 7.91 (d, J=8.2 Hz, 1H), 10.97 (s, 1H). A solution of 2.0 g (8.4 mmol) of 3-methylthio-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester in 20 mL of acetic acid was treated with 10 g of zinc powder. The reaction mixture was stirred for 2 h at rt, filtered through celite and concentrated to dryness. The residue was chromatographed on silica gel eluting with hexane:EtOAc (1:1) to yield 1.6 g (99% yield) of 2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester as a pink solid: 1H NMR (DMSO-d6): δ3.52 (s, 2H), 3.77 (s, 3H), 6.87 (d, J=8.2 Hz, 1H), 7.74 (s, J=1H), 7.80 (d, J=8.2 Hz, 1H), 10.72 (br s, 1H). Conversion to the 3-dimethylaminomethylene-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid methyl ester (mixture of E and Z isomers) was carried out via Procedure G in 49% yield: 1H NMR (DMSO-d6): δ3.29 Z (s, 6H), 3.31 E (s, 6H), 3.76 Z (s, 3H), 3.76 E (s, 3H), 6.74 Z (d, J=8.1 Hz, 1H), 6.81 E (d, J=8.2 Hz, 1H), 7.47-7.50 Z(m, 1H), 7.50-7.52 E (m, 1H), 7.57 E (dd, J=1.3, 8.2 Hz, 1H), 7.74 Z (s, 1H), 7.89 Z (s, 1H), 7.94 E (s, 1H), 10.33 Z (bs, 1H), 10.43 E (bs, 1H). The title compound was prepared in 41% yield from 3-[(dimethylamino)methylene]oxindole-5-carboxylic acid methyl ester and 4-aminobenzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ3.81 (s, 3H), 6.92 (d, J=8.2 Hz, 1H), 7.26 (s, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.2 Hz, 1H), 7.75 (d, J=8.4 Hz, 2H), 8.29 (s 1H), 8.86 (d, J=12.4 Hz, 1H), 10.80 (d, J=12.4 Hz, 1H), 10.94 (s, 1H); APCI−MS m/z372 (M−1)−. Anal. Calcd for C17H15N3O5S: C, 54.68, H, 4.05; N, 11.25; S 8.59. Found C, 54.65, H, 4.12; N, 11.17; S. 8.49.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[NH2:9][C:10]1[S:11][C:12]([CH2:20][CH3:21])=[CH:13][C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:15]1[C:14]2[CH:13]=[C:12]([CH2:20][CH3:21])[S:11][C:10]=2[N:9]=[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: N#Cc1ccccn1
Reactant: CCOC(=O)c1cc(CC)sc1N
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1cc2c(Cl)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 477, the reaction of 2-cyanopyridine and 2-amino-5-ethyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(pyridin-2-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH3:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>>[Br-:1].[CH2:2]([N+:17]1[CH:18]=[CH:19][N:15]([CH3:14])[CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCBr
Reactant: Cn1ccnc1
Product: CCCCCCCCCCCC[n+]1ccn(C)c1
Product: [Br-]
Temperature: 75 °C
Reaction time: 24 h
Yield: 94.4 %

Procedure:
A mixture of 1-Bromododecane (12.4 g, 50 mmol) and 1-methylimidazole (4.11 g, 50 mmol) was stirred at 75° C. for 24 h. The viscous liquid was washed with ethyl acetate several times and heated at 85° C. under vacuum for 24 h to produce waxy 1-dodecyl-3-methylimidazolium bromide (15.64 g, 83%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH3:14])=[CH:6][CH:5]=1.CNCC1C=CC2C(=CC=CC=2)C=1CCC.Cl.[O:32]=[C:33]1[NH:42][C:41]2[N:40]=[CH:39][C:38](/[CH:43]=[CH:44]/[C:45](O)=[O:46])=[CH:37][C:36]=2[CH2:35][CH2:34]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[CH3:1][N:2]([CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH3:14])=[CH:6][CH:5]=1)[C:45](=[O:46])/[CH:44]=[CH:43]/[C:38]1[CH:39]=[N:40][C:41]2[NH:42][C:33](=[O:32])[CH2:34][CH2:35][C:36]=2[CH:37]=1
Reactant: CNCc1ccc(C)c2ccccc12
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: Cc1ccc(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)c2ccccc12
Yield: 76 %

Procedure:
According to the procedure of Example 1 (a), except substituting methyl-(4-methyl-naphthalen-1ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.410 g, 76%) was prepared as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.67-10.62 (m, 1H), 8.38-8.29 (m, 1H), 8.15-7.94 (m, 3H), 7.60-7.55 (m, 3H), 7.36-7.02 (m, 3H), 5.30-5.06 (m, 2H), 3.04-2.73 (m, 5H), 2.65-2.45 (m, 5H); MS (ESI) m/e 386 (M+H)+.