Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].N1C=CN=C1.[Si:14](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[CH3:7][O:6][C:4](=[O:5])[CH2:3][C@H:2]([O:1][Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:8]
Reactant: COC(=O)C[C@@H](C)O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)C[C@@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Methyl (R)-(−)-3-hydroxybutyrate (0.31 g, 2.61 mmol) (Aldrich) was dissolved in dichloromethane (3.5 mL, dried over molecular sieves). Imidazole (0.25 g, 3.66 mmol) (Aldrich) was added. When all had dissolved, tert-butyldiphenylsilyl chloride (0.69 mL, 2.63 mmol) (Aldrich) was added dropwise and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was diluted with additional dichloromethane, washed with water (2×) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography (Biotage 40M, 5:95 ethyl acetate-hexanes) gave (R)-3-(tert-butyl-diphenyl-silanyloxy)-butyric acid methyl ester. (Yield 0.85 g, 91.2%).
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)(=O)C.II>C1(C)C=CC=CC=1.[Zn].[Pd]>[CH2:6]([O:5][C:3](=[O:4])[C:2]([CH3:9])([CH3:8])[CH2:18][C:17]1[CH:16]=[CH:15][C:14]([OH:13])=[CH:21][CH:20]=1)[CH3:7]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC(=O)Oc1ccc(C=O)cc1
Agent: [Pd]
Agent: II
Agent: [Zn]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Cc1ccc(O)cc1
Reaction time: 24 h
Yield: 14.6 %

Procedure:
A slurry containing 24.6 g of zinc dust in 100 ml dry toluene was treated dropwise with a solution containing 73.5 g of ethyl bromoisobutyrate and 65 g of 4-acetoxybenzaldehyde in 200 ml dry toluene. A crystal of iodine was added to initiate the reaction and the mixture was heated to reflux overnight. An additional equivalent of ethyl bromoisobutyrate was added and reflux was continued for 24 hours. After cooling, the filtrate was hydrogenated over palladium and the residue purified by flash chromatography to give 12.2 g of 3-(4-hydroxyphenyl)-2,2-dimethylpropanoic acid ethyl ester as an oil.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[CH:27]O>>[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[CH:27][NH:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:14][CH:13]=1
Reactant: O=C1Nc2ccc(F)cc2C1=CO
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Product: O=C1Nc2ccc(F)cc2C1=CNc1ccc(OCCN2CCCC2)cc1
Yield: 68.8 %

Procedure:
In a manner similar to that described in Example 231, 4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamine (690 mg, 1.2 equiv.) and 5-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 2.79 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (705 mg, 69%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][CH2:23][CH2:24][OH:25])[N:16]=1>CN(C=O)C>[F:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][C:19]1[CH:20]=[CH:15][N:16]=[C:17]([NH:21][CH2:22][CH2:23][CH2:24][OH:25])[N:18]=1
Reactant: OCCCNc1nccc(Cl)n1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc(NCCCO)n2)c(F)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
358 mg (14.2 mmol) 95% sodium hydride was given to a solution of 2.12 g (13.5 mmol) 2-fluoro-4-nitrophenol in 25 ml DMF. Stirring was continued for 30 min. at room temperature. 2.53 g (13.5 mmol) 3-(4-Chloro-pyrimidin-2-ylamino)-propan-1-ol were added and the mixture heated to 140° C. for 24 h. The reaction mixture was evaporated, taken up with water and extracted with dichloromethane. The organic phase was extracted with sodium carbonate solution, dried (sodium sulphate) and evaporated. The obtained material was purified by chromatography over silica (dichloromethane/ethanol 95:5) to give 2.92 g (70%) 3-[4-(2-fluoro-4-nitro-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol as slightly yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:15])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[NH2:21][C:22]1[N:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[CH:24][CH:23]=1>Cl>[OH2:12].[ClH:1].[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[N:7][C:8]=1[CH3:15])[N:5]=[CH:4][C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:2]2[NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([O:28][CH2:29][CH3:30])[N:27]=1)[CH3:14].[ClH:1].[ClH:1].[CH2:19]([O:18][C:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([O:28][CH2:29][CH3:30])[N:27]=1)=[CH:10][C:9]([O:12][CH2:13][CH3:14])=[C:8]([CH3:15])[N:7]=2)=[O:17])[CH3:20].[OH2:12]
Reactant: CCOc1cccc(N)n1
Reactant: CCOC(=O)c1cnc2nc(C)c(OCC)cc2c1Cl
Agent: Cl
Product: CCOC(=O)c1cnc2nc(C)c(OCC)cc2c1Nc1cccc(OCC)n1
Product: O

Procedure:
A mixture of ethyl 4-chloro-6-ethoxy-7-methyl-1,8-naphthyridine-3-carboxylate (1.3 g), 6-amino-2-ethoxy pyridine (0.68 g), IMS (25 ml) and concentrated hydrochloric acid (2 drops) was boiled under reflux for 18 hours. The mixture was cooled and filtered to give ethyl 6-ethoxy-4-(6-ethoxy-2-pyridylamino)-7-methyl-1,8-naphthyridine-3-carboxylate sesquihydrochloride hydrate, m.p. 195°-200° C. Active (1/1) at 30 mg/kg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45](Br)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:49]([C:51]1[CH:52]=[C:53](B(O)O)[CH:54]=[CH:55][CH:56]=1)#[N:50]>>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:55]3[CH:54]=[CH:53][CH:52]=[C:51]([C:49]#[N:50])[CH:56]=3)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(Br)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Reactant: N#Cc1cccc(B(O)O)c1
Product: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(-c3cccc(C#N)c3)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1

Procedure:
Aryl halide 9 was coupled to 3-cyanophenylboronic acid to give 29 on a 0.1 mmol scale via General Procedure H (58 mg, 60%): δH (400 MHz, CDCl3) 2.33 (s, 3H, CH3), 2.76 (s, 3H, CH3), 3.62 (s, 2H, CH2), 4.78 (s, 2H, CH2), 4.97 (s, 2H, CH2), 5.28 (s, 2H, CH2), 6.60-6.62 (m, 2H, CH), 7.14-7.28 (m, 12H, CH), 7.25-7.28 (m, 2H, CH), 7.38 (d, J=8.0 Hz, 2H, CH), 7.44-7.49 (m, 1H, CH), 7.54-7.57 (m, 3H, CH), 7.71 (dt, J=7.6 and 1.2 Hz, 1H, CH), 7.76 (s, 1H, CH), 7.78 (s, 1H, CH); δC (100 MHz, CDCl3) 21.4, 36.0, 51.4, 52.7, 67.0, 70.7, 112.9, 114.0, 118.6, 120.0, 120.9, 127.0, 127.1, 127.4, 128.0, 128.2, 128.2, 128.5, 128.6, 128.7, 129.5, 129.5, 129.6, 130.5, 130.8, 131.2, 133.1, 135.6, 135.7, 136.8, 138.2, 141.7, 143.3, 158.8, 165.2, 167.1, 167.7; LRMS (ES+) calcd for [C45H39N3O6S+H] 750.26. found 750.26.
Reaction SMILES: [OH:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([CH2:8][NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[CH:18]2[CH2:27][CH2:26][C:25]3[CH:24]=[C:23]([O:28]C(=O)C(C)(C)C)[CH:22]=[CH:21][C:20]=3[CH2:19]2)=O)=[CH:4][CH:3]=1.[N:37]1([C:41](=O)[CH2:42]Cl)[CH2:40][CH2:39][CH2:38]1>>[N:37]1([CH2:41][CH2:42][O:1][C:2]2[CH:36]=[CH:35][C:5]([CH2:6][CH2:8][NH:9][C:10]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=3[CH:18]3[CH2:27][CH2:26][C:25]4[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21][C:20]=4[CH2:19]3)=[CH:4][CH:3]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: O=C(CCl)N1CCC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)cc2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3CCC3)cc2)c1
Yield: 19.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 1-azetidin-1-yl-2-chloroethanone (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (4.8 mg) was obtained.
Reaction SMILES: N1([C:6]([C:8]2[C:9]([CH3:16])=[C:10]([CH:14]=O)[NH:11][C:12]=2[CH3:13])=[O:7])C=CN=C1.[NH2:17][CH2:18][C@H:19]([OH:27])[CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[Cl:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33](=[O:38])[CH2:32]2.C1COCC1>C(N(CC)CC)C>[Cl:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33](=[O:38])/[C:32]/2=[CH:14]\[C:10]1[NH:11][C:12]([CH3:13])=[C:8]([C:6]([NH:17][CH2:18][C@H:19]([OH:27])[CH2:20][N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:7])[C:9]=1[CH3:16]
Reactant: NC[C@H](O)CN1CCOCC1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)n1ccnc1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(Cl)cc32)c(C)c1C(=O)NC[C@H](O)CN1CCOCC1
Temperature: 60 °C
Reaction time: 68 h
Yield: 38.1 %

Procedure:
4-(1H-imidazol-1-ylcarbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (6.8 g, 31.3 mmol), (2S)-1-amino-3-morpholin-4-ylpropan-2-ol (10.0 g, 62.5 mmol), 5-chlorooxindole (5.3 g, 31.6 mmol), and THF (100 ml) were mixed and heated to 60° C. After stirring for 68 h at 60° C., triethylamine (14 ml) was added and stirred for 5 h at 60° C. Added 4.6 g of (2S)-1-amino-3-morpholin-4-ylpropan-2-ol, and stirred for 20 h at 60° C. The yellow slurry was cooled to room temperature and filtered. The cake was washed with 2×50 ml THF and dried overnight at 50° C. under house vacuum. 5-[(Z)-(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (5.48 g) was obtained with 38% yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[C:4](=[O:18])[CH:3]=1.[CH3:19][C@H:20]1[CH2:25][C@H:24](OS(C)(=O)=O)[CH2:23][CH2:22][N:21]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[CH3:19][CH:20]1[CH2:25][CH:24]([O:1][C:2]2[CH:7]=[CH:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=3)[C:4](=[O:18])[CH:3]=2)[CH2:23][CH2:22][N:21]1[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32]
Reactant: CS(=O)(=O)c1ccc(-n2ccc(O)cc2=O)cc1
Reactant: C[C@H]1C[C@H](OS(C)(=O)=O)CCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC1CC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CCN1C(=O)OC(C)(C)C
Temperature: 110 °C
Yield: 52.6 %

Procedure:
A mixture of 4-hydroxy-1-(4-(methylsulfonyl)phenyl)pyridin-2(1H)-one (125 mg, 0.471 mmol), trans-tert-butyl 2-methyl-4-(methylsulfonyloxy)piperidine-1-carboxylate (138.2 mg, 0.471 mmol, Example 1) and potassium carbonate (163 mg, 1.178 mmol) in DMF (4.0 mL) was heated at 110° C. for 20 hrs. The reaction mixture was cooled to room temperature and diluted with EtOAc and water. The aqueous layer was extracted further with EtOAc (3×). The combined organic layers were washed with brine/water (1:1, 2×), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-100% EtOAc in hexane) to yield cis isomer of tert-butyl 2-methyl-4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (114.6 mg, 52% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3). δ 8.07 (d, J=8.80 Hz, 2H), 7.62 (d, J=8.25 Hz, 2H), 7.24 (d, J=7.70 Hz, 1H), 6.06 (dd, J=7.70, 2.75 Hz, 1H), 5.95 (d, J=2.20 Hz, 1H), 4.64-4.70 (m, 1H), 4.35-4.45 (m, 1H), 3.91-3.98 (m, 1H), 3.18-3.28 (m, 1H), 3.09 (s, 9H), 1.95-2.04 (m, 2H), 1.89-1.96 (m, 1H), 1.75-1.84 (m, 1H), 1.48 (s, 9H), 1.27 (d, J=7.15 Hz, 3H). MS (ESI) 463 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:19](=[O:28])[NH:20][C:21]3[S:22][C:23](SC)=[CH:24][N:25]=3)[C:5]2=[CH:6][CH:7]=1.Cl[C:30]1C=CC=C(C(OO)=O)C=1.[S:40]([O-:43])([O-])=[O:41].[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:19](=[O:28])[NH:20][C:21]3[S:22][C:23]([S:40]([CH3:30])(=[O:43])=[O:41])=[CH:24][N:25]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: COC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(SC)s1)c1ccc(Cl)cc12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(S(C)(=O)=O)s1)c1ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
The methyl 5-chloro-1-((5-(methylthio)thiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (41.0 mg, 0.093 mmol) obtained in Example 127 was dissolved in methylene chloride (4 mL). Thereafter, meta-chloroperbenzoic acid (64.0 mg, 0.37 mmol) was added to the above obtained solution, and the thus obtained mixture was then stirred at room temperature for 2 hours. Thereafter, the reaction solution was diluted with an aqueous solution of sodium sulfite, and was then extracted with chloroform. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain the captioned compound (22.0 mg, 50%) in the form of a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([N:22]3[CH2:27][C@@H:26]4[CH2:28][C@H:23]3[CH2:24][N:25]4C(OC(C)(C)C)=O)=[O:21])=[CH:17][CH:18]=2)[N:13]([C:36]2[N:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=3)=[CH:38][N:37]=2)[CH:12]=1)=[O:10]>ClCCl>[C@H:23]12[CH2:28][C@H:26]([NH:25][CH2:24]1)[CH2:27][N:22]2[C:20]([C:16]1[CH:15]=[C:14]2[C:19]([C:11]([S:9]([CH3:8])=[O:10])=[CH:12][N:13]2[C:36]2[N:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=3)=[CH:38][N:37]=2)=[CH:18][CH:17]=1)=[O:21]
Reactant: CS(=O)c1cn(-c2ncc(-c3ccccn3)cn2)c2cc(C(=O)N3C[C@@H]4C[C@H]3CN4C(=O)OC(C)(C)C)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)c1cn(-c2ncc(-c3ccccn3)cn2)c2cc(C(=O)N3C[C@@H]4C[C@H]3CN4)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4 M solution of trifluoroacetic acid in dichloromethane (5.1 mL, 20.78 mmol, 40 eq) was added at 0° C. to 244d) (0.29 g, 0.51 mmol, 1 eq) in dichloromethane (10 mL). The reaction mixture was then stirred for 3 h at room temperature. The solvent was removed under vacuum and the residue was co-distilled twice with dichloromethane, diluted with dichloromethane (50 mL) and washed with saturated potassium carbonate solution (2×20 mL) and brine (20 mL). The organic layer was dried over sodium sulfate, concentrated and finally chromatographed by preparative HPLC. White solid. Yield: 0.200 g (84% by theory)
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1.CN(C)[CH:18]=[O:19].Cl>CCCCCC.C(OCC)C>[S:10]1[CH:11]=[C:7]([CH:18]=[O:19])[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]1=2
Reactant: CN(C)C=O
Reactant: Brc1csc2ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=Cc1csc2ccccc12
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 17 ml of a 1.6M solution of n-butyl lithium in hexane and 100 ml of dry diethyl ether at -70° C. was added a solution of 5.3 g of 3-bromobenzo[b]thiophene in 65 ml of diethyl ether. After stirring for about 30 minutes, 2.2 ml of dry dimethylformamide in 2.5 ml of dry diethyl ether were added. The mixture was stirred for about 3.5 hours at -70° C., and then allowed to warm to -5° C. Approximately 100 ml of 1N hydrochloric acid were added and the reaction mixture was stirred at 0° C. for 15 minutes. The layers were separated and the aqueous layer was extracted with one liter of ether. The organic extracts were combined, dried over magnesium sulfate, and evaporated in vacuo. The resulting oil was held at 0° C. overnight at which time an orange solid had formed. Approximately 4.6 g of this solid was recovered and identified by proton NMR to be the desired subtitle carboxaldehyde intermediate. The carboxaldehyde intermediate was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[N:24]4[N:25]=[CH:26][CH:27]=[C:28]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[C:23]4=[N:22][C:21]=3[C:35](OCC)=[O:36])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1>>[OH:36][CH2:35][C:21]1[N:22]=[C:23]2[C:28]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[CH:27][CH:26]=[N:25][N:24]2[C:20]=1[C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[N:19][CH:18]=1
Reactant: CCOC(=O)c1nc2c(N3CCOCC3)ccnn2c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(CO)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Compound 20b (2.07 g, 3.85 mmol) was placed in a 100 mL round bottom flask equipped with a stir bar and then the flask was evacuated and backflushed with argon. Dry THF (40 mL) was added via syringe and then the solution was cooled to 0° C. in an ice bath. 1 M LiAlH4 in THF (3.85 mL, 3.85 mmol) was added via syringe and then the ice bath was removed and the reaction was allowed to warm to rt. The reaction was stirred at rt for 1 h and then poured into saturated NH4Cl solution (100 mL). The aqueous mixture was extracted with EtOAc (4×50 mL) and then the combined organic extracts were dried over MgSO4 and filtered. The solvent was removed under reduced pressure to afford compound 21a. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.48 (d, J=2.2 Hz, 1H), 8.01 (d, J=5.4 Hz, 1H), 7.90 (dd, J=8.8, 2.4 Hz, 1H), 6.77 (d, J=9.0 Hz, 1H), 6.09 (d, J=5.6 Hz, 1H), 4.83 (s, 2H), 3.93 (d, J=3.4 Hz, 8H), 3.51-3.66 (m, 8H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H33N7O4: 496.3 (M+H). Found: 496.3.
Reaction SMILES: [CH2:1]([CH:3]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]#[N:15])=[CH:8][CH:7]=1)[CH3:2].N>[Ni].O1CCCC1>[CH2:1]([CH:3]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:14][NH2:15])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCCCC(CC)COc1ccc(C=C(C#N)c2ccccc2)cc1
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Product: CCCCC(CC)COc1ccc(CC(CN)c2ccccc2)cc1
Yield: 60 %

Procedure:
95.6 Grams of the above nitrile, 25 g of Raney nickel, 150 ml of anhydrous ammonia and 225 ml of tetrahydrofuran were stirred at 140° C. for 12 hours at a pressure of 1500 psi. The catalyst and solvent were then removed and the residual was vacuum distilled to yield (60 percent) 4-[(2-ethylhexyl)oxy]-β-phenylbenzenepropanamine, b.p. 180°-185° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:17].[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26](=[NH:30])OCC>C(O)C>[ClH:17].[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26](=[NH:30])[CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH3:18])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1COc1cccnc1N
Reactant: CCOC(=N)Cc1ccccc1C
Agent: Cl
Solvent: CCO
Product: Cc1ccccc1COc1cccnc1NC(=N)Cc1ccccc1C
Yield: 14.8 %

Procedure:
A mixture of 2-amino-3-(2-methylbenzyloxy)pyridine (5.2 g, 24.2 mmol) and ethyl 2-methylphenylacetimidate hydrochloride (5.7 g, 26.7 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was purified by flash chromatography (chloroform/methanol) to obtain the product (1.37 g), m.p. 147°-154° C.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][CH:11]1[O:16][CH:15]([CH3:17])[CH2:14][N:13]([C:18]2[CH:19]=[C:20]([CH:24]3[C:33]([CH3:35])([CH3:34])[CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:36](O)=[O:37])[CH:30]=4)[NH:25]3)[CH:21]=[CH:22][CH:23]=2)[CH2:12]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:10][CH:11]1[O:16][CH:15]([CH3:17])[CH2:14][N:13]([C:18]2[CH:19]=[C:20]([CH:24]3[C:33]([CH3:35])([CH3:34])[CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:36]([NH:9][S:6]([CH:3]5[CH2:5][CH2:4]5)(=[O:8])=[O:7])=[O:37])[CH:30]=4)[NH:25]3)[CH:21]=[CH:22][CH:23]=2)[CH2:12]1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1CN(c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)CC(C)O1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(c2cccc(C3Nc4ccc(C(=O)NS(=O)(=O)C5CC5)cc4CC3(C)C)c2)CC(C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.6 %

Procedure:
To a suspension of 60% sodium hydride (149 mg, 3.7 mmol) in N,N-dimethylformamide (2.5 mL) was added cyclopropanesulfonamide (460 mg, 3.8 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-[3-(2,6-dimethyl-morpholin-4-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (150 mg, 0.38 mmol) and 1,1′-carbonyldiimidazole (125 mg, 0.76 mmol) in N,N-dimethylformamide (1.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. 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% ammonium hydroxide in water) afforded cyclopropanesulfonic acid {2-[3-(2,6-dimethyl-morpholin-4-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-amide (56 mg, 30%) as a white solid: LC/MS m/e calcd for C27H35N3O4S (M+H)+: 498.66, observed: 498.0.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].[NH2:39][C:40]1[CH:45]=[CH:44][N:43]=[C:42](Cl)[CH:41]=1.[Br-].[Na+]>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>[NH2:39][C:40]1[CH:45]=[CH:44][N:43]=[C:42]([C:33]2[CH:34]=[CH:35][C:30]([C:2]([C:6]3[N:7]=[CH:8][N:9]([C:11]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:10]=3)([OH:1])[CH:3]([CH3:5])[CH3:4])=[CH:31][CH:32]=2)[CH:41]=1
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Nc1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Na+]
Product: CC(C)C(O)(c1ccc(-c2cc(N)ccn2)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 53.7 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (5.78 g), 4-amino-2-chloropyridine (1.00 g), sodium bromide (810 mg) and tetrakis(triphenylphosphine)palladium(0) (0.190 g), the title compound (2.30 g) was obtained as a yellow amorphous powder.