Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[CH:7]1([C:10](Cl)=[O:11])[CH2:9][CH2:8]1.[NH2:13][C:14]1[CH:15]=[C:16]([C:21]2[C:25]([Cl:26])=[C:24]([O:27][CH:28]([F:30])[F:29])[N:23]([CH3:31])[N:22]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]>O1CCCC1>[Cl:26][C:25]1[C:21]([C:16]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([NH:13][C:10]([CH:7]3[CH2:9][CH2:8]3)=[O:11])[CH:15]=2)=[N:22][N:23]([CH3:31])[C:24]=1[O:27][CH:28]([F:30])[F:29]
Reactant: Cn1nc(-c2ccc(Cl)c(N)c2)c(Cl)c1OC(F)F
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cn1nc(-c2ccc(Cl)c(NC(=O)C3CC3)c2)c(Cl)c1OC(F)F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1.0 g (13 mmol) of pyridine and 0.7 g (6.5 mmol) of cyclopropanecarbonyl chloride were added to a solution of 2.0 g (6.5 mmol) of 3-(3-amino-4-chlorophenyl)-4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazole in 30 ml of tetrahydrofuran. The solution was stirred at room temperature overnight and at 50° C. for 2 hours, an then concentrated. The residue was taken up in ethyl acetate. The ethyl acetate was washed in succession with cold 1N hydrochloric acid, water and saturated sodium chloride solution, then dried over magnesium sulfate and finally concentrated. Yield: 2.2 g.
Reaction SMILES: [Br:1]Br.C(O)(=O)C.[CH3:7][C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([OH:19])[CH:11]=[CH:10][CH:9]=1>O.C(OCC)(=O)C>[Br:1][C:9]1[CH:10]=[CH:11][C:12]([OH:19])=[C:13]([C:8]=1[CH3:7])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1c(C)cccc1O
Reactant: BrBr
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(O)ccc(Br)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of bromine (5.05 ml, 0.099 mol) and acetic acid (15 ml) is added to a mixture of ethyl 6-methyl-2-hydroxybenzoate (17.05 g, 0.095 mol), and acetic acid (15 ml) at a temperature of 20° C. The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with water and ethyl acetate. The organic phase is washed with water twice, concentrated in vacuo and the residue is purified by flash chromatography (petrol ethers:ethyl acetate, 98:2 v/v) yielding the pure product as a yellow oil, 21.7 g, (88.2%).
Reaction SMILES: [C:1]([Mg]Br)#[C:2][CH3:3].C1COCC1.[N:11]12[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]1)[CH:13]([NH:19][C:20]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]3[O:30][C:29]([C:31]4[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=4)=[N:28][C:27]=13)=[O:21])[CH2:12]2>CN(C=O)C.[Cl-].[Zn+2].[Cl-].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:11]12[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]1)[CH:13]([NH:19][C:20]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]3[O:30][C:29]([C:31]4[CH:36]=[CH:35][C:34]([C:1]#[C:2][CH3:3])=[CH:33][CH:32]=4)=[N:28][C:27]=13)=[O:21])[CH2:12]2
Reactant: O=C(NC1CN2CCC1CC2)c1cccc2oc(-c3ccc(I)cc3)nc12
Reactant: CC#C[Mg]Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC#Cc1ccc(-c2nc3c(C(=O)NC4CN5CCC4CC5)cccc3o2)cc1
Reaction time: 0.17 h
Yield: 88 %

Procedure:
Zinc chloride (1.0 M in ether, 0.33 mL, 0.33 mmol) was added dropwise to a solution of 1-propynylmagnesium bromide in THF (0.5 M in THF, 0.66 mL, 0.33 mmol) at room temperature and the mixture was stirred under nitrogen for 10 min. N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-iodophenyl)benzoxazole-4-carboxamide (50 mg, 0.11 mmol) in DMF (2 mL) was added followed by bis(triphenylphosphine)dichloropalladium(II) (7.7 mg, 0.011 mmol). The resulting mixture was stirred under nitrogen at room temperature for 2 h, and then was quenched with saturated ammonium chloride, extracted with methylene chloride. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:10:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-propyn-1-ylphenyl)benzoxazole-4-carboxamide (36 mg, 88%) as a light yellow solid: 1H NMR (300 MHz, CDCl3) δ 9.56 (d, J=7.0 Hz, 1H), 8.23 (dd, J=8.0, 1.0 Hz, 1H), 8.17 (d, J=8.4 Hz, 2H), 7.73 (dd, J=8.0, 1.0 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.49 (t, J=8.0 Hz, 1H), 4.35-4.29 (m, 1H), 3.54 (ddd, J=14.0, 9.5, 2.0 Hz, 1H), 3.16-2.82 (m, 5H), 2.20-2.03 (m, 2H), 2.14 (s, 3H), 1.80-1.60 (m, 3H); MS (ESI+) m/z 386 (M+H); HPLC>99% (AUC), tR=13.24 min.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH:17]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:23][CH:22]=2)[C:18](O)=[O:19])[CH3:16])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:37][N:38]1C2C=CC=CC=2N=N1.NO>CN(C=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]([CH3:16])[CH:17]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:33])[O:34][CH2:35][CH3:36])=[CH:25][CH:26]=2)[C:18]([NH:38][OH:37])=[O:19])(=[O:14])=[O:13])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)O)c2ccc(OCCCNC(=O)OCC)cc2)cc1
Reactant: On1nnc2ccccc21
Agent: NO
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)NO)c2ccc(OCCCNC(=O)OCC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
To [{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino}(4-{3-[(ethoxycarbonyl)amino]propoxy]phenyl)acetic acid (0.35 g, 0.67 mmol) and 1-(3-dimethyl aminopropyl) 3-ethyl carbodiimide (0.2 g, 1.01 mmol) in DMF (8 ml), 1-hydroxybenzotriazole (0.13 g, 0.95 mmol) was added and the reaction was stirred at room temperature for 2 h. Hydroxylamine (0.23 ml of 50% in water, 3.71 mmol) was added and the reaction was stirred overnight. After evaporating the solvent, the residue was extracted with ethyl acetate and water, the organic layer was washed with saturated NaHCO3, water and brine, dried over Na2SO4, and concentrated. The residue was purified with preparative TLC plates (eluting with ethyl acetate:methanol (85:15) to provide 0.1 g of ethyl 3-{4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(hydroxyamino)-2-oxoethyl]phenoxy}propylcarbamate as a yellow solid. mp 60-62° C. Electrospray Mass Spec 532 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(O)C>[CH2:13]([NH:20][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([Cl:1])[CH:11]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1cc(Cl)c2ccccc2n1
Reactant: NCc1ccccc1
Solvent: O
Solvent: CCO
Product: Clc1cc(NCc2ccccc2)c2ccccc2n1
Yield: 34.8 %

Procedure:
2,4-Dichloroquinoline (0.70 g, 3.53 mmole) and benzylamine (3.79 g, 35.3 mmole) in ethanol (2 mL) were stirred at 110° C. in a microwave oven for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic phases were washed with saturated NaCl solution, dried and concentrated. The residue thus obtained was purified using silica gel chromatography, eluting with dichloromethane:methanol 95:5 to give a white solid (330 mg, 35%).
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: C#Cc1ccc(Br)cc1
Reactant: N#Cc1cnccc1Br
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1cnccc1C#Cc1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 4-bromo-nicotinonitrile (1.10 g, 6.00 mmol) in DMF (20 ml) are added bis(triphenylphosphine)-palladium(II)-chloride (211 mg, 0.30 mmol), copper(I) iodide (34 mg, 0.18 mmol), triethylamine (1.66 ml, 12.0 mmol) and 1-bromo-4-ethynyl-benzene (1.19 g, 6.6 mmol). The mixture is flushed with nitrogen, heated to 80° C. and stirred in a closed reaction vial at this temperature for 4 hours. The reaction mixture is allowed to cool to room temperature and partitioned between water and dichloromethane. The organic phase is washed with 1 N HCl, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 4-(4-bromo-phenylethynyl)-nicotinonitrile as light yellow powder; HPLC/MS 2.09 min (B), [M+H] 283/285.
Reaction SMILES: Br[C:2]1[S:15][C:5]2[C:6]3[N:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][N:18]=1.C(#N)C>C(=O)([O-])[O-].[Na+].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:14]1[C:6]2[C:5]3[S:15][C:2]([C:20]4[CH:21]=[CH:22][C:17]([NH2:16])=[N:18][CH:19]=4)=[CH:3][C:4]=3[CH2:10][CH2:9][O:8][C:7]=2[CH:11]=[CH:12][CH:13]=1
Reactant: Nc1ccc(B(O)O)cn1
Reactant: Brc1cc2c(s1)-c1ncccc1OCC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Nc1ccc(-c2cc3c(s2)-c2ncccc2OCC3)cn1
Yield: 36 %

Procedure:
A mixture of 9-bromo-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepine (113 mg, 0.400 mmol), 2-aminopyridine-5-boronic acid, pinacol ester (96.8 mg, 0.440 mmol) and bis(triphenylphosphine)palladium(II) chloride (14.0 mg, 0.0200 mmol) in 1.0 M of sodium carbonate in water (0.500 mL) and acetonitrile (3 mL, 60 mmol) was degassed and microwaved on 300 watts at 140° C. for 20 minutes. The reaction mixture was partitioned between ethyl acetate and water and filtered from inorganic salts. The organic layer was washed with water, brine, dried over MgSO4 and evaporated to dryness. The crude residue was purified on silicagel column, eluting with 50% of ethyl acetate in methylene chloride to give 142 (yield 43 mg, 36%). 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J=2.3, 1H), 8.21 (dd, J=1.4, 4.5, 1H), 7.68 (dd, J=2.5, 8.6, 1H), 7.38 (dd, J=1.4, 8.1, 1H), 7.21 (s, 1H), 7.17 (dd, J=4.5, 8.1, 1H), 6.50 (d, J=8.7, 1H), 6.21 (s, 2H), 4.32 (t, J=4.8, 2H), 3.19 (t, J=4.8, 2H). MS: (ESI+) 296.1
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:35])=[CH:17][N:16]=1>>[Cl:35][C:18]1[C:19]([NH:21][C:22]2[CH:31]=[CH:30][C:29]([N:32]([CH3:33])[CH3:34])=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Reactant: CNC(=O)c1cc(N(C)C)ccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cc(N(C)C)ccc1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3)ncc1Cl

Procedure:
2-[5-Chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-5-dimethylamino-N-methyl-benzamide was prepared from 8-amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-5-dimethylamino-N-methyl-benzamide in an analogous manner to Example 1410. Product isolated as a yellow solid (155 mg, 81%). m.p.=253-255° C.; LCMS (m/e) 480 (M+H); HNMR (d6-DMSO, 400 MHz) δ 11.46 (bs, 1H), 9.80-9.66 (m, 1H), 9.51 (s, 1H), 8.87-8.77 (m, 1H), 8.53-8.40 (m, 1H), 8.21 (s, 1H), 7.34 (s, 1H), 7.29-7.09 (m, 1H), 7.25 (d, 1H, J=8.0 Hz), 7.17 (d, 1H, J=8.5 Hz), 7.03-6.81 (m, 1H), 2.99 (s, 6H), 2.81 (d, 3H, J=3.8 Hz), 2.65 (t, 2H, J=6.8 Hz), 2.24-2.15 (m, 2H), 2.15-2.04 (m, 2H).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[C:14]([I:15])=[CH:13][NH:12][N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>C(#N)C>[C:1]1([NH:7][C:8]([C:10]2[C:14]([I:15])=[CH:13][N:12]([CH2:28][C:27]3[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[N:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccccc1)c1n[nH]cc1I
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(Cn2cc(I)c(C(=O)Nc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
A solution of 4-iodo-1H-pyrazole-3-carboxylic acid phenylamide (670 mg; 2.14 mmol) in acetonitrile (10 ml) was treated with potassium carbonate (360 mg; 2.57 mmol)) followed by 4-methoxybenzyl chloride (320 μl; 2.35 mmol). The mixture was stirred at room temperature overnight then evaporated under reduced pressure. The residue was partitioned between ethyl acetate and brine; the ethyl acetate layer was separated, dried (MgSO4), filtered and evaporated. The crude material was purified by flash column chromatography eluting with 1:3 ethyl acetate/hexane and the product containing fractions combined and evaporated to give 660 mg of 4-iodo-1-(4-methoxy-benzyl)-1H-pyrazole-3-carboxylic acid phenylamide.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[N+:10]([CH2:13][C:14]([C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[F:24])=[O:15])([O-:12])=[O:11].I[CH2:26][C:27]([CH2:29]I)=[CH2:28]>CN(C)C=O>[CH2:26]=[C:27]1[CH2:29][C:13]([N+:10]([O-:12])=[O:11])=[C:14]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=2[F:24])[O:15][CH2:28]1
Reactant: C=C(CI)CI
Reactant: O=C(C[N+](=O)[O-])c1cc(F)c(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=C1COC(c2cc(F)c(F)cc2F)=C([N+](=O)[O-])C1
Temperature: 60 °C

Procedure:
A mixture of 3-chloro-2-(chloromethyl)prop-1-ene (1.0 g, 8 mmol) and sodium iodide (6.6 g, 44 mmol) in acetone (60 mL) was stirred at room temperature for 20 hours, evaporated under reduced pressure and dissolved in dichloromethane (150 mL) and water (50 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to yield 3-iodo-2-(iodomethyl)prop-1-ene as a reddish oil (2.45 g). N,N-diisopropylethylamine (0.20 mL) was added to a solution of 2-nitro-1-(2,4,5-trifluorophenyl)ethanone (110 mg, 0.5 mmol) in N,N-dimethylformamide (3 mL) and 3-iodo-2-(iodomethyl)prop-1-ene (170 mg, 0.55 mmol) and the mixture was heated at 60° C. for 2.5 hours, evaporated and purified by chromatography on a Biotage Horizon® system (silica, gradient 0-30% dichloromethane in hexane) to yield 3-methylene-5-nitro-6-(2,4,5-trifluorophenyl)-3,4-dihydro-2H-pyran.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=O)=[CH:4][CH:3]=1>[Pd].C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(O)CCCc1ccc(F)cc1
Reaction time: 6 h
Yield: 97 %

Procedure:
A mixture of 3-(4-fluorobenzoyl)propanoic acid (42.3 g, 0.22 mol) and 10% Palladium on carbon (3 g) in acetic acid (250 mL) was hydrogenated at 50 psi and 25° C. for 6 h. The mixture was filtered and concentrated in vacuo. The residue was distilled at 0.02 mm Hg and the product crystallized to give 4-(4-fluorophenyl)butyric acid as a white solid (97%). m.p., 44°-46.2° C. (lit. J. Am. Chem. Soc. 89, 386, 1967; m.p., 45.5°-46.5° C.).
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.C[Si](C#C)(C)C.[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]#[C:21][C:22]1([O:30][Si](C)(C)C)[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1)=[O:13]>CCCCCC.O1CCCC1.C(OCC)(=O)C>[OH:13][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]#[C:21][C:22]1([OH:30])[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1)[C:1]#[CH:2]
Reactant: [Li]CCCC
Reactant: C[Si](C)(C)OC1(C#Cc2ccccc2C=O)CN2CCC1CC2
Agent: C#C[Si](C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C#CC(O)c1ccccc1C#CC1(O)CN2CCC1CC2
Temperature: -70 °C
Reaction time: 1 h

Procedure:
Butyl Lithium in hexane (1.6M, 3.4 ml) was added slowly to a stirred solution of trimethylsilylacetylene (1.0 g) in tetrahydrofuran (20 ml) at -70° C. under an atmosphere of argon. The reaction mixture was stirred at -70° C. for a further 60 minutes. A solution of 3-[2-(2-formylphenyl)ethynyl]-3-trimethylsilyloxyquinuclidine (1.3 g) in tetrahydrofuran (10 ml) was added slowly to the reaction mixture whilst maintaining the temperature at -70° C. The reaction mixture was allowed to warm to ambient temperature and then stirred for 20 hours. The reaction mixture was evaporated, potassium carbonate (4 g) and methanol (50 ml) added and the mixture was stirred vigorously at ambient temperature for 60 minutes. The inorganic salts were removed by filtration and the filtrate was evaporated to give a residue which was dissolved in ethyl acetate (150 ml). The solution was extracted with 2M hydrochloric acid (2×100 ml). The aqueous extracts were combined, washed with ether (2×200 ml) and then basified to pH 9 by addition of 5N sodium hydroxide solution. The aqueous mixture was extracted with ethyl acetate (2×100 ml), the ethyl acetate extracts combined, washed with water (100 ml), brine (100 ml), dried (MgSO4) and evaporated. The residue was purified by column chromatography on alumina (Alumina N 32-63) using a gradient of 2:98 to 5:95 (v/v) methanol in ethyl acetate as eluent to give a solid which was recrystallised from a mixture of tetrahydrofuran/hexane to give 3-[2-{2-(1-hydroxy-1-ethynylmethyl)phenyl}ethynyl]quinuclidin-3-ol (110 mg), m.p. 217° C.; microanalysis; found: C, 74.6; H, 7.2; N, 4.6%, C18H19NO2.0.5 H2O requires: C, 74.5; H, 6.9; N, 4.8%; NMR: 1.2-1.4 (1H, m), 1.45-1.7 (1H, m), 1.8-2.05 (3H, m), 2.55-2.8 (4H, m), 2.85 (1H, d), 3.15 (1H, d), 3.38 (1H, dd), 5.58 (1H, s), 5.6-5.7 (1H, m), 6.08 (1H, d), 7.25-7.46 (3H, m), 7.65 (1H, d), m/z 282 (M+H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH2:16][OH:17].C(N(CC)CC)C>CO>[C:1]([N:8]1[CH2:13][CH2:12][C:11](=[N:16][OH:17])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(=NO)CC1
Yield: 63.8 %

Procedure:
15.5 g (77.6 mmol) of N-Boc-4-piperidone was refluxed for one hour in methanol in the presence of 7.0 g (100.8 mmol) of hydroxylamine hydrochloride and 14.1 ml (100.8 mmol) of triethylamine. Then, methanol was distilled off, and the residue was thoroughly washed with water in chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 10.6 g of N-Boc-4-hydroxyiminopiperidine as white powder.
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[H][H]>CCO.Cl.[Rh]>[CH:1]1([C:11]([OH:13])=[O:12])[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][NH:2]1
Reactant: O=C(O)c1nccc2ccccc12
Reactant: [H][H]
Agent: [Rh]
Agent: Cl
Solvent: CCO
Product: O=C(O)C1NCCC2CCCCC21
Yield: 56.8 %

Procedure:
A solution of 1-isoquinolinecarboxylic acid (50 g, 0.288 mol) in EtOH (150 mL) and 60 mL of 5N HCl was reduced over 5% Rh/Al2O3 (14 g) at 52 bar (750 psi) of hydrogen in a high pressure apparatus at 50° C. for 17 hours. The reaction mixture was filtered through a pad of diatomaceous earth, and the filtrate was concentrated in vacuo. The solid was triturated with water, filtered and dried to give DL-perhydro-1-isoquinolinecarboxylic acid (DL-1-Piq-OH) (30 g, 48%)
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[C:12]1([N:13]2[CH:17]=[CH:16][CH:15]=[C:14]2[C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])[CH:4]=[CH:3][CH:2]=[CH:10][CH:9]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cn1cccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: O=C(O)c1ccccc1C(=O)c1cccn1-c1ccccc1

Procedure:
Proceeding in a manner similar to that described in part A of Example 16, 14.8 g (0.1 mole) of phthalic anhydride, 16.2 g (0.2 mole) of N-methylpyrrole and 39.0 g (0.3 mole) of aluminum chloride were interacted in 50 ml of chlorobenzene to obtain 2-[(1-methyl-2-pyrrolyl)carbonyl]benzoic acid (Formula IX: R0 =R1 =R2 =R3 =H; R7 =CH3) melting at 165°-167° C. A significant infrared absorption maximum appeared at 1710 cm-1 (C=O; s).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])[CH2:2][CH3:3].[NH2:14][C:15]1[C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(#N)C>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:14][C:15]1[C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=[CH:17][CH:16]=1)=[O:8])[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1C(=O)Cl
Reactant: NC(=O)c1cnccc1N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCOc1ccccc1C(=O)Nc1ccncc1C(N)=O

Procedure:
In a similar manner to Example 1 a) reaction of 2-propoxybenzoyl chloride (0.79 g), 4-aminonicotinamide (0.55 g) and triethylamine (0.40 g) in acetonitrile (12 ml) afforded a crude product which was recrystallised from ethanol-ether to afford 4-(2-propoxybenzamido)nicotinamide, 0.53 g, m.p. 164°-166° C.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH3:16])[C:10](=[O:17])[N:9]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[C:8]=2[N:7]=[C:6]1[N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH3:16])[C:10](=[O:17])[N:9]([CH2:18][C:19]([OH:21])=[O:20])[C:8]=2[N:7]=[C:6]1[N:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: CCn1c(=O)c2c(nc(N3CCCCC3)n2Cc2c(F)cccc2Cl)n(CC(=O)OC(C)(C)C)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1c(=O)c2c(nc(N3CCCCC3)n2Cc2c(F)cccc2Cl)n(CC(=O)O)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A solution of tert-butyl [7-(2-chloro-6-fluorobenzyl)-1-ethyl-2,6-dioxo-8-piperidin-1-yl-1,2,6,7-tetrahydro-3H-purin-3-yl]acetate (24 mg, 0.046 mmol) in 230 μL CH2Cl2 was treated with 230 μL TFA. The reaction was stirred at room temperature for 1 hr and then the solvent was removed by reduced pressure. The crude product was filtered through a silica plug and rinsed with 20% MeOH/EtOAc. The solvent was removed affording the title compound (19 mg, 90% yield) as a white solid: 1H NMR (CDCl3, 400 MHz) 7.22-7.16 (m, 1H), 7.14-7.10 (m, 1H), 6.98-6.91 (m, 1H), 5.51 (s, 2H), 4.80 (s, 2H), 3.95 (q, 2H, J=7.0 Hz), 3.11-3.01 (m, 4H), 1.54-1.41 (m, 6H), 1.12 (t, 3H, J=7.0 Hz); MS (ESP+) m/e 464 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12](O)=[O:13])[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:16]=1)[CH2:6][C:5]2([CH3:27])[CH3:26].[CH:28]1([S:31]([NH2:34])(=[O:33])=[O:32])[CH2:30][CH2:29]1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([NH:34][S:31]([CH:28]3[CH2:30][CH2:29]3)(=[O:33])=[O:32])=[O:13])[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:16]=1)[CH2:6][C:5]2([CH3:27])[CH3:26]
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)CC(c2cccc(N3CCCC3)c2)Nc2c(C(=O)O)cc(Cl)cc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc(N3CCCC3)c2)Nc2c(C(=O)NS(=O)(=O)C3CC3)cc(Cl)cc21
Yield: 20.1 %

Procedure:
A mixture of 6-chloro-4,4-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (200 mg, 0.52 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (140 mg, 0.78 mmol), 4-dimethylaminopyridine (95 mg, 0.78 mmol), cyclopropane sulfonic acid amide (190 mg, 1.56 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid [6-chloro-4,4-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carbonyl]-amide (51 mg, 20%) as a light yellow solid: MS (ESI) M+1=488.2.