Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:15][C:16]#[CH:17])C(=O)OC(C)(C)C)=[CH:5][N:4]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:6]([NH:7][CH2:15][C:16]#[CH:17])=[CH:5][N:4]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1
Reactant: C#CCN(C(=O)OC(C)(C)C)c1cn(-c2cccnc2)nc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#CCNc1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of tert-butyl (3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)(prop-2-yn-1-yl)carbamate (2.2 g, 6.61 mmol) in dichloromethane (DCM; 8.3 ml) was added 2,2,2-trifluoroacetic acid (12.06 g, 106 mmol) and the reaction mixture was stirred at ambient temperature for 1 h. The reaction was quenched by the addition of saturated sodium bicarbonate (NaHCO3). The organic layer was extracted with DCM (2×20 mL). The organic layers were combined and dried over sodium sulfate (Na2SO4), filtered and concentrated to afford the title compound as a beige solid (1.5 g, 6.12 mmol, 93%): 1H NMR (400 MHz, CDCl3) δ 8.89 (d, J=2.3 Hz, 1H), 8.50 (dd, J=4.7, 1.4 Hz, 1H), 8.01-7.93 (m, 1H), 7.54 (s, 1H), 7.37 (ddd, J=8.3, 4.8, 0.7 Hz, 1H), 3.90 (s, 2H), 3.38 (s, 1H), 2.44-2.09 (m, 1H); ESIMS m/z 233 ([M+H]+).
Reaction SMILES: S(NN=[C:13]1[CH2:18][CH2:17][C@H:16]2[C@H:19]3[C@H:30]([CH2:31][CH2:32][C@:14]12[CH3:15])[C@:27]1([CH2:28][OH:29])[C:22](=[CH:23][CH:24]([OH:33])[CH2:25][CH2:26]1)[CH2:21][CH2:20]3)(C1C=CC(C)=CC=1)(=O)=O.C([Li])CCC>O1CCCC1.CCCCCC>[OH:33][CH:24]1[CH2:25][CH2:26][C@@:27]2([CH2:28][OH:29])[C:22]([CH2:21][CH2:20][C@@H:19]3[C@@H:30]2[CH2:31][CH2:32][C@@:14]2([CH3:15])[C@H:16]3[CH2:17][CH:18]=[CH:13]2)=[CH:23]1
Reactant: Cc1ccc(S(=O)(=O)NN=C2CC[C@H]3[C@@H]4CCC5=CC(O)CC[C@]5(CO)[C@H]4CC[C@]23C)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=CC(O)CC[C@]3(CO)[C@H]1CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The tosylhydrazone (20) in tetrahydrofuran is treated with n-butyl lithium (BuLi, b) in hexane and the mixture is stirred at room temperature for 16 hours. Aqueous work up is followed by extraction and purification to yield the diene (21) .
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:13][C:12]3[C:11]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:10][CH:9]=[CH:8][C:7]=3[C:5]=2[N:6]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([S:1][C:2]1[S:3][C:4]2[CH2:13][C:12]3[C:11]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=[CH:8][C:7]=3[C:5]=2[N:6]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)COc1cccc2c1Cc1sc(S)nc1-2
Reactant: BrCc1ccccc1
Product: O=C(O)COc1cccc2c1Cc1sc(SCc3ccccc3)nc1-2
Yield: 21 %

Procedure:
Using ethyl [(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate and benzyl bromide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 21%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=O)[C:5](=[O:11])[NH:6]2.O.[NH2:14][NH2:15]>C(O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[N:14][NH2:15])[C:5](=[O:11])[NH:6]2
Reactant: NN
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Solvent: O
Solvent: CCO
Product: NN=C1C(=O)Nc2cccc(Cl)c21

Procedure:
To a stirred slurry of 43.3 g of 4-chloroisatin in 350 ml of ethanol was added 17.3 ml of hydrazine hydrate, and then the reaction mixture was cooled, and the precipitate was recovered by filtration to give 43.5 g of 4-chloro-3-hydrazono-2-oxindole, m.p. 235°-236° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[C:5]([CH3:25])[CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>ClCCl>[CH3:25][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[S:9]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)(=[O:11])=[O:10])[C:1]#[N:2]
Reactant: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C#N)ccc1S(=O)(=O)N1CCNCC1
Yield: 107.2 %

Procedure:
A solution of 1,1-dimethylethyl 4-[(4-cyano-2-methylphenyl)sulfonyl]-1-piperazinecarboxylate (may be prepared as described in Intermediate 8; 3.33 g, 9.11 mmol) and TFA (10 ml, 130 mmol) in dry dichloromethane (10 ml) was stirred at rt for 1 h, then concentrated in vacuo, azeotroping with toluene (25 ml) to give a brown oil. This was partitioned between DCM (50 ml) and sat. aq NaHCO3 (50 ml), then the aqueos layer extracted with DCM:EtOH (3:1, 40 ml). The combined organics were passed through a hydrophobic frit and concentrated in vacuo to give the title compound (2.59 g) as a yellow oil. The product became a pale yellow solid on standing.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C:12]2[C:13]([C:28](O)=[O:29])=[N:14][N:15]([C:18]3[C:19]([O:26][CH3:27])=[N:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=3)[C:16]=2[CH3:17])[CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([N:10]2[CH:11]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[C:12]3[C:13](=[N:14][N:15]([C:18]4[C:19]([O:26][CH3:27])=[N:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=4)[C:16]=3[CH3:17])[C:28]2=[O:29])[CH:3]=1
Reactant: COc1ncc(-n2nc(C(=O)O)c(C(Nc3cc(Cl)c(=O)n(C)c3)c3ccc(Cl)cc3)c2C)c(OC)n1
Solvent: CO
Solvent: ClCCl
Product: COc1ncc(-n2nc3c(c2C)C(c2ccc(Cl)cc2)N(c2cc(Cl)c(=O)n(C)c2)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-(((5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)(4-chlorophenyl)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-methyl-1H-pyrazole-3-carboxylic acid (Step 55.5). tR: 4.30 min (HPLC 1); tR: 0.98 min (LC-MS 2); ESI-MS: 527/529 [M+H]+ (LC-MS 2); Rf=0.37 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.91 (s, 3H) 3.44 (s, 3H) 3.92 (s, 3H) 3.96 (s, 3H) 6.24 (s, 1H) 7.29-7.42 (m, 4H) 7.93 (d, J=2.7 Hz, 1H) 7.97 (d, J=2.4 Hz, 1H) 8.53 (s, 1H).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([OH:32])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:20]2[CH:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:24][CH:25]=2)[O:17][C:18]=1[CH3:19])[CH2:2][CH2:3][CH3:4].Br[C:34]([CH3:41])([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:38]([O:37][C:35](=[O:36])[C:34]([O:32][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:21]=[C:22]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:23]=[CH:24][CH:25]=3)[O:17][C:18]=2[CH3:19])=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]=1)([CH3:41])[CH3:40])[CH3:39]
Reactant: CCCCc1cc(O)ccc1OCCc1nc(-c2cccc(-c3ccccc3)c2)oc1C
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCc1cc(OC(C)(C)C(=O)OCC)ccc1OCCc1nc(-c2cccc(-c3ccccc3)c2)oc1C
Temperature: 55 °C

Procedure:
A mixture of 3-butyl-4-[2-(5-methyl-2-biphenyl-3-yl-oxazole-4-yl)ethoxy]phenol (0.90 mmol), ethyl 2-bromo-2-methylpropanoate (2.25 mmol) and cesium carbonate (0.45 g, 1.38 mmol) in anhydrous DMF (4 mL) was heated for 24 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and water (40 mL), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 2% ethyl acetate/dichloromethane to give 2-{4-[2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethoxy]-3-butylphenoxy}-2-methylpropionic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ8.22 (d, J=1.5 Hz, 1H), 7.95 (dd, J=7.8, 1.5 Hz, 1H), 7.67-7.62 (m, 3H), 7.51-7.44 (m, 3H), 7.37 (t, J=6.8 Hz, 1H), 6.72-6.69 (m, 2H), 6.64 (dd, J=8.8, 2.9 Hz, 1H), 4.25-4.19 (m, 4H), 2.97 (t,J=6.6 Hz, 2H), 2.50 (t, J=7.6 Hz, 2H), 2.38 (s, 3H), 1.52 (s, 6H), 1.51-1.43 (m, 2H), 1.33-1.23 (m, 5H), 0.85 (t, J=7 Hz, 3H); Rf=0.24 (2% ethyl acetate/dichloromethane).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:19][N:20]=[C:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].[CH3:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[CH3:28][S:29]([O:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:16])=[O:17])=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:19][N:20]=[C:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(C)=NNc1ccc(Oc2ccc(S(C)(=O)=O)cn2)cc1O
Solvent: c1ccncc1
Product: CCOC(=O)C(C)=NNc1ccc(Oc2ccc(S(C)(=O)=O)cn2)cc1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of ethyl 2-[(2-hydroxy-4-{[5-(methylsulfonyl)pyridin-2-yl]oxy}phenyl)-hydrazono]propanoate (37.7 g) in pyridine (450 mL) was added methanesulfonyl chloride (8.9 mL) at 0° C., and the mixture was stirred at room temperature for 1 h. Methanesulfonyl chloride (8.9 mL) was added to the mixture at 0° C. again, and the mixture was stirred at room temperature for 1 h. Furthermore, methanesulfonyl chloride (8.9 mL) was added to the mixture at 0° C., and the mixture was stirred at room temperature for 15 h. The mixture was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed successively with 1M hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual solid was washed with diethyl ether to give the title compound (37.05 g, 83%) as an off-white solid. MS 472 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[N:11][C:10]([NH:13][NH2:14])=[CH:9][CH:8]=2)[CH:4]=[N:3]1.[OH-].[K+].[C:17](=S)=[S:18]>C(O)C.O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:17]([SH:18])=[N:14][N:13]=3)[N:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2ccc(NN)nn2)cn1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1cc(-c2ccc3nnc(S)n3n2)cn1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
To a solution of [6-(1-methyl-1H-pyrazol-4-yl)-pyridazin-3-yl]-hydrazine (18 g, 94.7 mmol) in ethanol (230 mL) and water (63 mL) was added KOH (5.63 g, 100 mmol), followed by CS2 (12 mL, 198 mmol). The mixture was stirred and heated to reflux for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in 1 N aqueous sodium hydroxide and the insolubles were filtered off. The filtrate was acidified to pH 2-3 with 1 N aqueous HCl. The resulting precipitate was collected, washed with water, and dried in vacuo to provide 17.7 g of 6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol as a yellow solid (80.5% yield): 1H NMR (DMSO-d6) δ 3.95 (s, 3H), 7.73 (d, 1H), 8.13 (s, 1H), 8.16 (d, 1H), 8.53 (s, 1H), 14.7 (s, 1H); MS (m/z) 233 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CS(O[CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=1)[O:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])(=O)=O>CN(C=O)C.CCOC(C)=O>[C:15]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:14])[N:12]([CH2:28][CH2:29][CH2:30][O:31][C:32]3[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=3)[O:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[N:13]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)n[nH]1
Reactant: CCOC(=O)COc1cccc(OCCCOS(C)(=O)=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(OCCCn2nc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
To a solution of 6-(diphenylmethyl)pyridazin-3(2H)-one (158 mg) in DMF (2 mL) was added NaH (60% in oil, 26 mg) at 5° C. After stirring for an hour at ambient temperature, to the reaction mixture was added a solution of ethyl (3-{3-[(methylsulfonyl)oxy]propoxy}phenoxy)acetate (200 mg) in DMF (0.5 mL), and the resulting mixture was stirred at ambient temperature for 12 hours and then was stirred at 50° C. for 5 hours. After cooling, the reaction mixture was diluted with EtOAc (5 mL) and washed with water (5 mL) and brine (5 mL) two times. The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo to give crude oil. The crude oil was purified by silica gel column chromatography (EtOAc:n-hexane=3:1) to give ethyl (3-{3-[3-(diphenylmethyl)-6-oxopyridazin-1(6H)-yl]propoxy}phenoxy)acetate (230 mg) as a pale yellow oil.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[F:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C:22]1[CH2:26][N:25]([C:27]([C@@H:29]([NH2:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:24]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:23]=1.C(N(CC)CC)C>C1COCC1>[F:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C:22]1[CH2:26][N:25]([C:27]([C@@H:29]([NH:34][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:24]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:23]=1
Reactant: CC(C)(C)[C@H](N)C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[C@H](NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1

Procedure:
A solution of 4-nitrophenyl chloroformate (300 mg, 1.49 mmol, 1.2 equiv) in THF (10 mL) was added drop wise to a stirred solution of (1S)-1-{[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-carbonyl}-2,2-dimethylpropylamine (16-1, 460 mg, 1.24 mmol, 1.0 equiv) and triethylamine (151 mg, 1.49 mmol, 1.2 equiv) in THF (10 mL) at 23° C. After 1 hr the reaction was filtered and the filtrate concentrated to a pale yellow gum which was purified by flash chromatography on silica gel. Elution with dichloromethane to 3% ethyl acetate/dichloromethane provided 2-hydroxyethyl (1S)-1-{[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}-2,2-dimethylpropylcarbamate (36-1) as a colorless foam. LRMS m/z (M+H) 536.5 found, 535.2 required.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.BrC1C2C(=NC=NC=2N)N(C(C)(C)C)N=1.[CH:39]1[C:47]2[C:46]3[CH:48]=[CH:49][CH:50]=[CH:51][C:45]=3[S:44][C:43]=2[CH:42]=[C:41](B(O)O)[CH:40]=1>>[CH:39]1[C:47]2[C:46]3[CH:48]=[CH:49][CH:50]=[CH:51][C:45]=3[S:44][C:43]=2[CH:42]=[C:41]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[N:4]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=2)[CH:40]=1
Reactant: OB(O)c1ccc2c(c1)sc1ccccc12
Reactant: Nc1ncnc2c1c(I)nn2[C@H]1CC[C@H](N2CCOCC2)CC1
Agent: CC(C)(C)n1nc(Br)c2c(N)ncnc21
Product: Nc1ncnc2c1c(-c1ccc3c(c1)sc1ccccc13)nn2[C@H]1CC[C@H](N2CCOCC2)CC1

Procedure:
The desired product was prepared by substituting (trans)-3-iodo-1-(4-morpholin-4-yl-cyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine prepared as described in WO 2005/074603 for 3-bromo-1-tert-butyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine and dibenzo(b,d)thiophen-3-ylboronic acid (purchased from Maybridge Chemicals) for EXAMPLE 188C in EXAMPLE 181. 1H NMR (300 MHz, methanol-d4) 8.56 (d, 1H), 8.40 (s, 1H), 8.34 (m, 1H), 8.12 (d, 1H); 7.96 (m, 1H); 7.80 (d, 1H); 7.54 (m, 2H); 4.95 (m, 1H); 4.12 (m, 2H); 3.80 (m, 2H); 3.58-3.38 (m, 4H); 2.44-2.38 (m, 2H); 2.38-2.25 (m, 4H); 1.94-1.82 (m, 2H).
Reaction SMILES: [CH2:1]=[O:2].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[OH:21].Cl>C(#N)C>[F:13][C:14]1[C:15]([OH:21])=[C:16]([C:17]([CH3:20])=[CH:18][CH:19]=1)[CH:1]=[O:2]
Reactant: C=O
Reactant: Cc1ccc(F)c(O)c1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(F)c(O)c1C=O
Temperature: 90 °C
Reaction time: 240 h

Procedure:
Paraformaldehyde (3.86 g, 133 mmol), magnesium chloride (6.32 g, 66.5 mmol) and triethylamine (11.6 ml, 83.3 mmol) were added to a solution of 2-fluoro-5-methylphenol (4.19 g, 33.3 mmol) in acetonitrile (100 ml), and the mixture was vigorously stirred at 90° C. for 10 days. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. After the organic layer was successively washed with 1N hydrochloric acid, water and a saturated aqueous NaCl solution, and dried with anhydrous sodium sulfate, it was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluting solvent: hexane/ethyl acetate=4/1) to obtain crude 3-fluoro-2-hydroxy-6-methylbenzaldehyde. According to a method similar to Example (28-3) and Example (28-4), from the crude compound obtained in the above, tert-butyl 2-[(tert-butoxycarbonyl)oxy]-3-fluoro-6-methylbenzoate was obtained (624 mg, three-step total yield: 6%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH3:9].CN[CH2:43][CH3:44]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:37])=[O:38])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH2:9][CH2:43][CH3:44]
Reactant: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Reactant: CCNC
Solvent: O=C(O)C(F)(F)F
Product: CCCCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Yield: 15.8 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting butyl(methyl)amine (87 mg, 1.0 mmol) for N-methylethanamine to afford 10 mg of the title compound (15.8%).
Reaction SMILES: [NH2:1][C@H:2]([C@H:4]([OH:20])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:3].[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22].C(N(CC)CC)C>ClCCl>[CH3:3][C@H:2]1[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[O:20][C:21](=[O:22])[NH:1]1
Reactant: CCCCCCCCCCCCCCC[C@@H](O)[C@H](C)N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCC[C@H]1OC(=O)N[C@H]1C
Reaction time: 5 h

Procedure:
(2S, 3R)-2-amino-3-octadecanol (155, 750 μg, 2.6 μmol) was dissolved in dichloromethane (100 μL) to which 1,1′-carbonyldiimidazole (0.85 mg, 5.3 μmol) and triethylamine (0.4 μL, 2.9 μmol) was added. The solution was stirred for 5 h and then the solvent removed by a stream of nitrogen. The crude product 158 was analyzed without purification: IR (NaCl) 36, 2919, 2851, 1742, 1713, 1551, 1470, 1395, 1321, 49, 1239, 1094, 1061, 1001, 768, 743, 664 cm−1; FABMS m/z 785, 623, 474, 406, 362, 328, 312, 286, 268. Anal. Calcd. For C19H38NO2: 312.2903 (M+H). Found: 312.2903 (HRFABMS).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][C:24]([CH3:26])=[CH2:25])=[C:6]([CH:21]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([NH:19][NH2:20])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].C(N(CC)CC)C.[C:34](Cl)(Cl)=[S:35]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][C:24]([CH3:26])=[CH2:25])=[C:6]([CH:21]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]2[O:18][C:34](=[S:35])[NH:20][N:19]=2)=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: S=C(Cl)Cl
Reactant: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(C(=O)NN)nn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(-c2n[nH]c(=S)o2)nn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 206.6 %

Procedure:
6-[N-(5-Bromo-2-(2-methylprop-2-en-1-yloxy)benzyl)-N-ethylamino]pyridazine-3-carbohydrazide (reference example 26) (750 mg, 1.78 mmol) was dissolved in THF (25 ml) and triethylamine (0.57 ml, 3.91 mmol) added followed by thiophosgene (0.1 ml, 1.96 mmol). The solution was stirred at ambient temperature under argon for 3 hours, then the THF removed in vacuo, water (75 ml) added, and then acetic acid was added dropwise till the mixture was at pH 5. The mixture was extracted with ethyl acetate(3×200 ml) and the combined organic phases washed with water and saturated brine (100 ml of each), dried (MgSO4) and concentrated in vacuo to give the title compound as a gum (1.7 g) which was purified by MPLC (98:2 dichloromethane:methanol), to give a solid foam (230 mg 28%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[O:16]1[C:18]2([CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH2:17]1>CO>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:17][C:18]2([OH:16])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CC2(CCO1)CO2
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCN(CC2(O)CCOCC2)CC1

Procedure:
To a stirred solution of tert-butyl(piperidin-4-ylmethyl)carbamate (22.3 g, 104 mmol) in methanol was added 1,6-dioxaspiro[2.5]octane (14.2 g, 124 mmol, Satyamurthy, Nagichettiar et al., Phosphorus Sulfur, 1984, 19, 113) at ambient temperature.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[C:11]([F:13])[C:10]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:9][C:5]=1[C:6](O)=[O:7])#[N:2].[NH2:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=1>>[F:13][C:11]1[CH:12]=[C:4]2[C:5](=[CH:9][C:10]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])[C:6](=[O:7])[NH:2][C:1]([NH:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=1)=[CH:3]2
Reactant: Cc1cc(N)n[nH]1
Reactant: COCCOc1cc(C(=O)O)c(CC#N)cc1F
Product: COCCOc1cc2c(=O)[nH]c(Nc3cc(C)[nH]n3)cc2cc1F

Procedure:
Similar procedure as described in example 2c was used, starting from 2-Cyanomethyl-4-fluoro-5-(2-methoxy-ethoxy)-benzoic acid and 3-amino-5-methylpyrazole to give 6-Fluoro-7-(2-methoxy-ethoxy)-3-(5-methyl-1H-pyrazol-3-ylamino)-2H-isoquinolin-1-one. LC-MS: m/e 333 (MH+).
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.[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>C(Cl)Cl>[C:16]1([CH:4]([NH:3][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[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: CC(C)(C)C(=O)Cl
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (140 mg, 0.42 mmol) in DCM (5 ml), were sequentially added triethylamine (175 μl, 1.26 mmol) and pivaloyl chloride (62.1 μl, 0.50 mmol). The reaction was stirred at RT for 2 hours, and then the solvent was evaporated. The residue was taken up with EtOAc and washed with Na2CO3, water and brine, dried over Na2SO4, filtered and evaporated to obtain (R)-quinuclidin-3-yl 2-phenyl-2-pivalamidoacetate (95 mg; 66% yield).