Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[N:9](COCC[Si](C)(C)C)[N:8]=[CH:7]3)[CH2:3][CH2:2]1.C(N)CN>ClCCl.FC(F)(F)C(O)=O>[CH:1]1([C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9][N:8]=[CH:7]3)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ncc2cc(C3CC3)ccc21
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc2[nH]ncc2cc1C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.3 %

Procedure:
In a 1 L round-bottomed flask, 5-cyclopropyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (1.7 g, 5.89 mmol) was dissolved in a solution of dichloromethane (292 mL) and trifluoroacetic acid (194 mL). After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane and ethylenediamine (24.2 mL, 5.89 mmol) was added. After stirring at room temperature overnight, the reaction mixture was poured onto water (50 mL) and extracted with EtOAc (2×100 mL). The organic layers were dried over MgSO4 and concentrated under reduced pressure to afford 1 g of 5-cyclopropyl-1H-indazole that was used without further purification.
Reaction SMILES: [C:1]([NH:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:28]([O:31][CH:32]([C:41]([CH3:48])([CH3:47])[CH2:42][O:43][C:44](=[O:46])[CH3:45])[C:33]([NH:35][CH2:36][CH2:37][C:38](O)=[O:39])=[O:34])(=[O:30])[CH3:29]>>[C:1]([NH:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:38](=[O:39])[CH2:37][CH2:36][NH:35][C:33](=[O:34])[CH:32]([O:31][C:28](=[O:30])[CH3:29])[C:41]([CH3:47])([CH3:48])[CH2:42][O:43][C:44](=[O:46])[CH3:45])=[CH:23][CH:22]=1)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccc(N)cc1
Reactant: CC(=O)OCC(C)(C)C(OC(C)=O)C(=O)NCCC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccc(NC(=O)CCNC(=O)C(OC(C)=O)C(C)(C)COC(C)=O)cc1
Yield: 68.5 %

Procedure:
4-Oleoylaminoaniline (744 mg) and 606 mg of 3-[N-(2,4-diacetoxy-3,3-dimethyl-1-oxobutyl)amino]propionic acid were reacted in the same manner as in Example 1 to obtain 900 mg of the title compound (yield: 69%).
Reaction SMILES: [CH:1]1([O:7][C:8]2[C:13](B(O)O)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=2)=[C:20]([F:31])[CH:19]=1>>[CH:1]1([O:7][C:8]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[N:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=4)=[C:20]([F:31])[CH:19]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1cccnc1OC1CCCCC1
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Product: Nc1cnc(-c2ccc(-c3cccnc3OC3CCCCC3)cc2F)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Example 369 using (2-(cyclohexyloxy)pyridin-3-yl)boronic acid and 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI): mass calcd. for C21H21FN4O, 364.17; m/z found, 365.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.64-8.57 (m, 1H), 8.18-8.10 (m, 2H), 8.00-7.92 (m, 1H), 7.70-7.63 (m, 1H), 7.52-7.43 (m, 2H), 6.94 (dd, J=5.0, 7.4, 1H), 5.26-5.16 (m, 1H), 4.66 (s, 2H), 2.05-1.91 (m, 2H), 1.82-1.68 (m, 2H), 1.66-1.24 (m, 6H).
Reaction SMILES: [H-].[Na+].C([O:7][C:8](=[O:21])[NH:9][CH:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1)[CH2:11]O)(C)(C)C>C1COCC1>[F:20][C:15]1[CH:14]=[C:13]([CH:10]2[CH2:11][O:21][C:8](=[O:7])[NH:9]2)[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: CC(C)(C)OC(=O)NC(CO)c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NC(c2ccc(F)c(F)c2)CO1

Procedure:
To a well stirred suspension of NaH (1.1 g, 45.8 mmol) in THF (40 mL) at room temperature was added a solution of [1-(3,4-difluorophenyl)-2-hydroxy-ethyl]-carbamic acid-tert-butyl ester (5.0 g, 18.3 mmol) in THF 20 mL via a dropping funnel at room temperature. The resulting suspension was stirred for 3 h and then quenched carefully with 10 mL of water. The biphasic mixture was extracted with 100 mL of Et2O, washed with brine, filtered and the solvent was removed in vacuo. The gummy residue thus obtained was purified by column chromatography over silica gel (Rf =0.15, 3:2 hexane-EtOAc) to obtain (+)-4-(3,4-difluorophenyl)-oxazolidin-2-one as a white flaky solid (2.8 g, 77%). The enantiomers were separated by using Chiralcel OD (4.6×250 mm) using 80% hexane/20% isopropyl alcohol/0.1% Diethylamine as the eluting system under isothermal conditions (U.V. 254 nM). The retention times for the two isomers were 16.19 min and 20.08 min respectively. First isomer:[α]D =+62.9 (c=0.67, acetone); Anal. Calcd. for C9H7NO2F2 : C, 54.28; H, 3.54; N, 7.03. Found: C, 54.16; H, 3.44; N, 6.96. Second isomer:[α]D =-56.9 (c=0.75, acetone); Anal. Calcd. for C9H7NO2F2 : C, 54.28; H, 3.54; N, 7.03. Found: C, 54.31; H, 3.46; N, 6.98. The first isomer was used in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](Br)=[C:13]([C:15]2[CH2:19][C:18]([CH2:25][C:26]([O:28][CH3:29])=[O:27])([CH2:20][C:21]([O:23][CH3:24])=[O:22])[O:17][N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:34])[CH:32]=[CH2:33].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CC(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:33]=[CH:32]/[C:31]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])=[C:13]([C:15]2[CH2:19][C:18]([CH2:25][C:26]([O:28][CH3:29])=[O:27])([CH2:20][C:21](=[O:22])[O:23][CH3:24])[O:17][N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OCc1ccccc1
Reactant: COC(=O)CC1(CC(=O)OC)CC(c2cc(OCc3ccccc3)ccc2Br)=NO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)CC1(CC(=O)OC)CC(c2cc(OCc3ccccc3)ccc2/C=C/C(=O)OCc2ccccc2)=NO1
Reaction time: 2 h
Yield: 65.8 %

Procedure:
A mixture of dimethyl 2,2′-(3-(5-(benzyloxy)-2-bromophenyl)-4,5-dihydro-1,2-oxazole-5,5-diyl)diacetate (1.00 g), benzyl acrylate (1.021 g), palladium acetate (II) (0.047 g), tris(2-methylphenyl)phosphine (0.128 g), triethylamine (0.878 mL), and DMA (7.5 mL) was stirred at 130 C for 2 hours under microwave irradiation under an argon atmosphere. To the reaction mixture, water was added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (0.770 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH3:29])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1.Cl[C:31]([C@@H:33]([O:35]C(=O)C)[CH3:34])=[O:32]>>[OH:35][C@@H:33]([CH3:34])[C:31]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH3:29])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1)=[O:32]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: CCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c13)OCO2
Product: CCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCN(C(=O)[C@H](C)O)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-ethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide (example A176) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound was obtained as colorless solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[CH:26](O)[CH3:27].CCOC(/N=N/C(OCC)=O)=O.O1CCCCC1[N:47]1[C:55]2[C:50](=[CH:51][C:52]([C:56]3[N:60]=[CH:59][N:58](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:57]=3)=[CH:53][CH:54]=2)[C:49]([C:80]2[CH:81]=[C:82]([OH:86])[CH:83]=[CH:84][CH:85]=2)=[N:48]1.Cl>O1CCCC1>[NH:57]1[C:56]([C:52]2[CH:51]=[C:50]3[C:55](=[CH:54][CH:53]=2)[NH:47][N:48]=[C:49]3[C:80]2[CH:85]=[CH:84][CH:83]=[C:82]([O:86][CH2:27][CH2:26][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][NH:20]3)[CH:81]=2)=[N:60][CH:59]=[N:58]1
Reactant: CC(O)C1CCCCN1
Reactant: Oc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OCCC2CCCCN2)cc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 48.2 %

Procedure:
Triphenylphosphine (0.694 g, 2.65 mmol), tetrahydrofuran (2.12 mL), 2-piperidylethanol (0.352 mL, 2.65 mmol) and diethylazodicarboxylate (0.418 mL, 2.65 mmol) were added to 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenol (0.400 g, 0.662 mmol). The mixture was stirred at ambient temperature for 23 h and poured into aqueous 6 N hydrochloric acid (30 mL). After stirring at ambient temperature for 4 h, the mixture was extracted with ether (3×). The aqueous fraction was added to aqueous 6 N sodium hydroxide (30 mL) and the pH adjusted to 11. The solution was extracted with ethyl acetate (3×) and the organic fractions were combined and dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica pretreated with 2% triethylamine/ethyl acetate elution followed by 0-20% methanol/ethyl acetate. The desired fractions were concentrated, dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated which gave the title compound (0.124 g, 48% yield). 1H NMR (CD3OD) δ 8.72 (m, 1H), 8.34 (s, 1H), 8.10 (dd, 1H), 7.67 (dd, 1H), 7.62 (dt, 1H), 7.58 (m, 1H), 7.47 (t, 1H), 7.04 (m, 1H), 4.27 (t, 2H), 2.89 (t, 2H), 2.63 (m, 4H), 1.68 (m, 4H), 1.51 (m, 2H). ES-MS (m/z) 389 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@H:4]([CH:5]=[C:6]2[CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:10]([OH:12])=[O:11].[CH2:14](O)[CH2:15][CH:16]=[CH2:17]>>[CH3:1][C:2]1([CH3:13])[C@H:4]([CH:5]=[C:6]2[CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:10]([O:12][CH2:17][CH2:16][CH:15]=[CH2:14])=[O:11]
Reactant: CC1(C)[C@H](C=C2CCC2)[C@H]1C(=O)O
Reactant: C=CCCO
Product: C=CCCOC(=O)[C@@H]1[C@@H](C=C2CCC2)C1(C)C

Procedure:
Using the procedure of Example 1, (1R,trans) 2,2-dimethyl-3-cyclobutylidenemethyl-cyclopropane-1-carboxylic acid and 3-buten-1-ol were reacted to obtain 3-buten-1-yl (1R,trans) 2,2-dimethyl-3-cyclobutylidenemethyl-cyclopropane-1-carboxylate.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([NH2:16])=O)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]#[N:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C#N)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
A solution containing 6.2 g (0.02 mole) of 2-[4-(4-trifluoromethylphenoxy)phenoxy] propanamide and 10.0 ml of phosphorus oxychloride in 50 ml of toluene is stirred at 50° until reaction is complete, as indicated by vpc techniques. The reaction mixture is cooled and poured into crushed ice, whereupon the toluene layer is washed with water, dried, and concentrated in vacuo. Purification is effected by elution through a pad of silica gel (50% toluene/hexane) to afford a colorless solid, mp 53°-56°.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH3:24])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([NH:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=1>>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=2)[C:9]2[C:10]([CH3:24])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nn(-c2ccc(C(F)(F)F)cc2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: Cc1nn(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 13.8 %

Procedure:
Using cyclohexyl{3-methyl-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}methanol (0.36 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.38 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (77.5 mg, 7%) was obtained as a white solid.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:29]=[CH:28][CH:27]=[CH:26][C:12]=2[CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21](OCC)=[O:22])[CH2:16][CH2:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:30][NH2:31].C(O)C>CO>[C:1]1([S:7]([CH2:10][C:11]2[CH:29]=[CH:28][CH:27]=[CH:26][C:12]=2[CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]([NH:30][NH2:31])=[O:22])[CH2:16][CH2:15]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CN1CCN(Cc2ccccc2CS(=O)(=O)c2ccccc2)CC1
Reactant: NN
Solvent: CO
Solvent: CCO
Product: NNC(=O)CN1CCN(Cc2ccccc2CS(=O)(=O)c2ccccc2)CC1

Procedure:
Synthesized according to General Procedure C: 6{29} (1.16 g, 2.77 mmol, 1 equiv.), anhydrous hydrazine (0.26 mL, 8.32 mmol, 3 equiv.), ethanol (15.6 mL), methanol (10 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{29} (0.88 g, 79%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 8.10 (br s, 1H), 7.66 (dd, 2H, J=0.5, 8.0 Hz), 7.64-7.61 (m, 1H), 7.47 (t, 2H, J=8.0 Hz), 7.24 (dt, 1H, J=1.0, 7.5 Hz), 7.17-7.12 (m, 2H), 6.95 (d, 1H, J=7.5 Hz), 4.80 (s, 2H), 3.83 (br s, 2H), 3.40 (s, 2H), 3.04 (s, 2H), 2.47 (br s, 4H), 2.35 (br s, 4H). 13C-NMR (125 MHz, CDCl3): δ 170.4, 138.6, 138.0, 133.7, 132.6, 131.1, 128.9, 128.7, 128.5, 128.0, 127.5, 61.1, 60.5, 59.1, 53.6, 53.0.
Reaction SMILES: [C:1]([CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=O)(=O)[CH3:2].Cl.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1>C(O)C.O>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:5]3[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[CH2:12][CH2:13][C:4]=3[C:1]([CH3:2])=[N:25]2)=[CH:20][CH:19]=1
Reactant: COc1ccc(NN)cc1
Reactant: CC(=O)C1CCc2ccccc2C1=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(-n2nc(C)c3c2-c2ccccc2CC3)cc1
Temperature: 80 °C

Procedure:
To a solution of 2-acetyl-1-tetralone (329 mg, 1.75 mmol) in ethanol (12 mL) was added 4-methoxyphenyl hydrazine hydrochloride. The stirred suspension was heated to 80° C. overnight. The reaction was cooled to room temperature and diluted with water (100 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water, 10% NaOH, 10% HCl, brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue purified on silica gel using a 5% EtOAc to 25% EtOAc in hexane gradient (yield 396 mg). LC-MS (C19H18N2O calculated 290) m/z 291 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1C1C=C(O)C=C2C=1CCC(=O)N2C1C(Cl)=CC=CC=1Cl.ClC1C=CC(F)=CC=1[C:37]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[C:43]2[C:38]=1[CH2:39][CH2:40][C:41](=[O:57])[N:42]2[C:49]1[C:54]([Cl:55])=[CH:53][CH:52]=[CH:51][C:50]=1[Cl:56].[BH-](OC(C)=O)(OC(C)=O)O[C:60](C)=O.[Na+]>>[Cl:55][C:54]1[CH:53]=[CH:52][CH:51]=[C:50]([Cl:56])[C:49]=1[N:42]1[C:43]2[C:38](=[C:37]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[CH3:60])[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=2)[CH2:39][CH2:40][C:41]1=[O:57]
Reactant: COc1cc(-c2cc(F)ccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C1CCc2c(-c3ccc(F)cc3Cl)cc(O)cc2N1c1c(Cl)cccc1Cl
Agent: [Na+]
Product: COc1cc(-c2ccc(F)cc2C)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2

Procedure:
Compound 9 (COMPOUND DMM-1) was converted to aldehyde 10 via standard Swern reaction. Aldehyde 10 was coupled with amine 11 via NaB(OAc)3H to afford 12. Treatment of 12 with TFA afford 13 (EXAMPLE DMM1). Mass spectrum (ESI) for 13, 573 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[CH2:18]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)[CH:17]=[CH2:16]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: C=CCOc1ccc(-c2ccc(C#N)cc2)cc1
Yield: 91.3 %

Procedure:
A solution prepared by adding 20 g of 4-cyano-4′-hydroxybiphenyl, 20 g of allyl bromide and 25 g of potassium carbonate to 250 ml of 2-butanone was refluxed for 7 hours. Water was added to the reaction solution for liquid-liquid separation, and the organic layer was washed with water and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the resulting residue was purified through silica gel column chromatography using toluene as an eluent solvent and then further recrystallized from ethanol to obtain 22 g of 4-allyloxy-4′-cyanobiphenyl.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[NH2:17].[C:18](OC)(OC)(OC)[CH2:19][CH2:20][CH2:21][CH3:22]>Cl.N1C=CC=CC=1>[CH2:19]([C:18]1[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:20][CH2:21][CH3:22]
Reactant: Nc1cnc2ccccc2c1NCCCCCl
Reactant: CCCCC(OC)(OC)OC
Agent: Cl
Solvent: c1ccncc1
Product: CCCCc1nc2cnc3ccccc3c2n1CCCCCl
Yield: 79.2 %

Procedure:
Using the general method of Example 1 Part D, N4-(4-chlorobutyl)quinoline-3,4-diamine (119.1 g, 0.48 mole) was cyclized using trimethyl orthovalerate (93 g, 0.57 mol) in the presence of pyridine hydrochloride (1.1 g, 0.0095 mol) to provide 120 g of 2-butyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinoline as an ivory powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH:8]([CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:9](O)=[O:10])[CH:7]=1.[NH2:26][C:27]1[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH:8]([CH2:12][CH:13]2[CH2:14][CH2:15]2)[C:9]([NH:26][C:27]2[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[CH:29][CH:28]=2)=[O:10])[CH:7]=1
Reactant: N#Cc1ccc(Cl)cc1-c1cc(=O)n(C(CC2CC2)C(=O)O)cc1Cl
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)C(CC2CC2)n2cc(Cl)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1

Procedure:
268 mg (0.68 mmol) of 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-cyclopropylpropanoic acid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 192 mg (51% of theory)
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][C:22]([NH:24][C:25]([NH:34]C(OC(C)(C)C)=O)=[N:26]C(OC(C)(C)C)=O)=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:42][C:43]1[CH:48]=[C:47]([C:49]#[N:50])[CH:46]=[CH:45][C:44]=1[NH:51][CH2:52][CH3:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][C:22]([NH:24][C:25]([NH2:34])=[NH:26])=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:42][C:43]1[CH:48]=[C:47]([C:49]#[N:50])[CH:46]=[CH:45][C:44]=1[NH:51][CH2:52][CH3:53])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3cc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)ccc3N2C)C(=O)N1Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3cc(NC(=N)N)ccc3N2C)C(=O)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a stirred solution of the product of Example 273 (116 mg, 0.15 mmol) in anhydrous DCM (6 mL) was added TFA (3 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, then at ambient temperature for 14 h. The solvent was removed in vacuo, and the residue was purified by reverse-phase HPLC (C18 column), eluting with 0.05% TFA in MeCN—H2O (1:9 to 9:1) to afford the title compound (25 mg, 30%) as a yellow solid. 1H-NMR (DMSO-d6): δ 9.65 (1H, s), 7.72 (1H, d), 7.48 (1H, d), 7.41–7.25 (8H, m), 7.15 (1H, d), 6.65 (1H, d), 5.14 (2H, s), 3.84 (3H, s), 3.07 (2H, m), 1.01 (3H, t); MS(ESI): 555 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:12]=[CH:11][C:10](/[C:13](/[C:23]2[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([O:33]C(C)(C)C)=[O:32])=[CH:25][CH:24]=2)=[C:14](\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)/[CH2:15][CH3:16])=[CH:9][CH:8]=1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([O:6][C:7]1[CH:8]=[CH:9][C:10](/[C:13](/[C:23]2[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32])=[CH:25][CH:24]=2)=[C:14](\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)/[CH2:15][CH3:16])=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Oc1ccc(/C(=C(/CC)c2ccccc2)c2ccc(/C=C/C(=O)OC(C)(C)C)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Oc1ccc(/C(=C(/CC)c2ccccc2)c2ccc(/C=C/C(=O)O)cc2)cc1
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a solution of 39 (0.51 g, 1.02 mmol) in CH2Cl2 (5 mL) at 0° C. was added TFA (5 mL) and the mixture was stirred for 1 h. Solvent was evaporated and coevaporated with CH2Cl2 (2×10 mL) and the residue dissolved in EtOAc and washed with water (2×10 mL). The organic layer was dried (Na2SO4) and evaporated. The residue was triturated with hexanes, filtered, and dried in vacuo to provide 37 (0.43 g, 96%) as an off-white solid. 1H NMR and MS as described in Example 23. Anal. calculated for C28H26O5: C, 76.00; H, 5.92; Found: C, 75.90; H, 6.12.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([CH:13]2[CH2:22][CH2:21][C:20]3[CH:19]=[C:18]([O:23]C(=O)C(C)(C)C)[CH:17]=[CH:16][C:15]=3[CH2:14]2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)[CH3:2].Cl.[N:31]1([CH2:38][CH2:39][C:40]2[CH:48]=[CH:47][C:43]([C:44](O)=O)=[CH:42][CH:41]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:38][CH2:39][C:40]2[CH:48]=[CH:47][C:43]([CH2:44][CH2:2][CH2:1][NH:3][C:4]3[C:5]([CH:13]4[CH2:22][CH2:21][C:20]5[CH:19]=[C:18]([OH:23])[CH:17]=[CH:16][C:15]=5[CH2:14]4)=[CH:6][C:7]4[O:11][CH2:10][O:9][C:8]=4[CH:12]=3)=[CH:42][CH:41]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(O)c1ccc(CCN2CCCCCC2)cc1
Reactant: CCNc1cc2c(cc1C1CCc3cc(OC(=O)C(C)(C)C)ccc3C1)OCO2
Agent: Cl
Product: Oc1ccc2c(c1)CCC(c1cc3c(cc1NCCCc1ccc(CCN4CCCCCC4)cc1)OCO3)C2
Yield: 63.8 %

Procedure:
Synthesized from pivalic acid 6-(6-ethylaminobenzo[1,3]dioxol-5-yl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (40 mg) and 4-(2-azepan-1-ylethyl)benzoic acid hydrochloride (80 mg) according to an analogous synthetic method to Example 337 described below, the title compound (34 mg) was obtained.