Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[C:14]3[N:20]=[C:19]([C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[NH2:23])[S:18][C:15]3=[N:16][CH:17]=2)[CH2:7][CH2:6]1.[C:28]1([C:34]2[N:35]=[C:36]([C:39](O)=[O:40])[S:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[C:14]3[N:20]=[C:19]([C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[NH:23][C:39]([C:36]4[S:37][CH:38]=[C:34]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:35]=4)=[O:40])[S:18][C:15]3=[N:16][CH:17]=2)[CH2:7][CH2:6]1
Reactant: O=C(O)c1nc(-c2ccccc2)cs1
Reactant: COCCN1CCN(Cc2cnc3sc(-c4ccccc4N)nc3c2)CC1
Solvent: O
Product: COCCN1CCN(Cc2cnc3sc(-c4ccccc4NC(=O)c4nc(-c5ccccc5)cs4)nc3c2)CC1

Procedure:
The title compound was prepared according to amide synthesis general method B, utilizing 2-(6-((4-(2-methoxyethyl)piperazin-1-yl)methyl)thiazolo[5,4-b]pyridin-2-yl)aniline and 4-phenylthiazole-2-carboxylic acid (1.5 eq). Addition of water to the crude reaction did not precipitate the product, therefore it was concentrated, triturated with hot MeCN, MeCN/EtOAc/MeOH mixture, and EtOAC/MeOH sequentially. The resulting pale yellow solid was lyophilized with a MeCN/water/HCl mixture and subsequently purified on prep HPLC. MS Calcd for C30H30N6O2S2: 570.19. Found (M+H)+ m/z=571.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21](O)=[O:22])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[O:3][CH2:2]1.C(Cl)(=O)C([Cl:35])=O>C1COCC1.CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21]([Cl:35])=[O:22])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2

Procedure:
2-(Benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (200 mg) was dissolved in THF (6.0 ml) and oxalyl chloride (71 μl) and DMF (1 drop) were added at 0° C. with stirring, and the mixture was stirred at room temperature for 2 hrs. and concentrated under reduced pressure. Toluene was added to the residue and they were boiled together several times and dried to give 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonyl chloride.
Reaction SMILES: [O:1]=[CH:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][CH:9]=1.[BH4-].[Na+].Cl>CO.[Cl-].[Na+].O>[OH:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][CH:9]=1
Reactant: COC(=O)c1cnc(CC=O)cn1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: COC(=O)c1cnc(CCO)cn1
Reaction time: 1 h
Yield: 26.1 %

Procedure:
To a solution of methyl 5-(2-oxoethyl)pyrazine-2-carboxylate (5.08 g) in methanol (50 mL) was added sodium borohydride (1.07 g) under ice-cooling, followed by stirring at the same temperature for 60 minutes. To the reaction mixture was added 1 M hydrochloric acid under ice-cooling to adjust the pH to 3. Saturated brine was added thereto, followed by extraction with a solvent (ethyl acetate:isopropyl alcohol=4:1). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-0:1, chloroform:methanol=1:0-30:1) to obtain methyl 5-(2-hydroxyethyl)pyrazine-2-carboxylate (1.34 g) as a red-brown oily substance.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][C:16]2[S:17][C:18]([C:21]#[N:22])=[CH:19][N:20]=2)[CH:9]=1)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[Cl:14][C:12]1[N:11]=[C:10]([NH:15][C:16]2[S:17][C:18]([C:21]#[N:22])=[CH:19][N:20]=2)[CH:9]=[C:8]([CH2:7][OH:6])[CH:13]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(Cl)nc(Nc2ncc(C#N)s2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cnc(Nc2cc(CO)cc(Cl)n2)s1
Temperature: 25 °C

Procedure:
2-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-6-chloro-pyridin-2-ylamino]-thiazole-5-carbonitrile (11-6) was dissolved in 5 mL of THF. HF-pyr (Aldrich), 0.5 mL was added and the reaction was stirred at room temperature. After 1.5 hours the reaction was diluted with water and adjuted to pH 7 by the gradual addition of solid K2CO3. The mixture was extracted 3× with DCM. Large amounts of solid were suspended in the DCM extracts so the extracts were filtered and washed with DCM to afford the desired product, 11-7. 1H NMR (DMSO-d6) δ 12.49 (s, 1H), 8.30 (s, 1H), 7.09 (s, 1H), 7.06 (s, 1H), 5.59 (t, 1H, J=5.8 Hz), 4.55 (d, 2H, J=5.5 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:35]=[CH:34][C:14]([CH2:15][C@@H:16]([C:25]([O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])=[O:26])[NH:17]C(OC(C)(C)C)=O)=[CH:13][CH:12]=1)([OH:3])=[O:2].Cl.O1CCOCC1>>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:35]=[CH:34][C:14]([CH2:15][C@@H:16]([C:25]([O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])=[O:26])[NH2:17])=[CH:13][CH:12]=1)([OH:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Nc2ccccc2C(=O)O)cc1)C(=O)OCC[Si](C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOC(=O)[C@@H](N)Cc1ccc(Nc2ccccc2C(=O)O)cc1
Yield: 109.6 %

Procedure:
2-(trimethylsilyl)ethyl 4-[(2-carboxyphenyl)amino]-N-(tert-butoxycarbonyl)-L-phenylalaninate (6.97 g, 13.9 mmol) was treated with 4N HCl (13.9 mL) in Dioxane (55.8 mmol) for one hour. The solvent was then removed under reduced pressure. The residue was precipitated with diethyl ether (2×35 mL) to provide the titled compound as a light yellow solid (6.1 g, 100%).
Reaction SMILES: C(C1C=CC=CC=1)C=C.[C:10]1([CH2:16]/[CH:17]=[CH:18]\[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([CH2:16][CH:17]=[CH:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C(=C\Cc1ccccc1)\Cc1ccccc1
Agent: C=CCc1ccccc1
Product: C(=CCc1ccccc1)Cc1ccccc1
Temperature: 25 °C

Procedure:
After the reaction was cooled to room temperature, the product was purified by silica column chromatography using hexanes as the eluant. The fraction containing the product was dried via rotavap to remove the solvent, affording the product as colorless liquid. The scale of a typical reaction was 2 mL of the substrate, allyl benzene. (Z)-1,4-diphenylbut-2-ene: 1H NMR (500 MHz, CDCl3) δ 7.30 (m, 10, Ar—H), 5.76 (m, 2, CH), 3.57 (d, 4, CH2, JHH=6 Hz); 13C NMR (125 MHz, CDCl3) δ 141.03, 129.31, 138.73, 128.63, 126.22, 33.74.
Reaction SMILES: [Li]CCCC.S1C2C=CC=CC=2N=C1.C1(NC([C:24]2[CH:60]=[CH:59][C:27]3[N:28]=[C:29]([C:31](=[O:58])[C@@H:32]([NH:41][C:42](=[O:57])[C@@H:43]([NH:48][C:49]([N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)=[O:50])[CH2:44][CH:45]([CH3:47])[CH3:46])[CH2:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[S:30][C:26]=3[CH:25]=2)=O)C=CC=CC=1>C1COCC1>[S:30]1[C:26]2[CH:25]=[CH:24][CH:60]=[CH:59][C:27]=2[N:28]=[C:29]1[C:31]([C@@H:32]([NH:41][C:42]([C@@H:43]([NH:48][C:49]([N:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1)=[O:50])[CH2:44][CH:45]([CH3:47])[CH3:46])=[O:57])[CH2:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:58]
Reactant: CC(C)C[C@H](NC(=O)N1CCOCC1)C(=O)N[C@@H](CCc1ccccc1)C(=O)c1nc2ccc(C(=O)Nc3ccccc3)cc2s1
Agent: [Li]CCCC
Agent: c1ccc2scnc2c1
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)N1CCOCC1)C(=O)N[C@@H](CCc1ccccc1)C(=O)c1nc2ccccc2s1
Reaction time: 0.25 h

Procedure:
Dry THF (1.5 mL), under Ar, was cooled to −78° C. with a dry-ice/acetone bath. n-BuLi (2.0 M in hexanes) (698 μL, 1.40 mmol) was added to reaction flask followed by dropwise addition of freshly distilled benzothiazole (180 mg, 1.40 mmol) as a solution in 0.5 mL of dry THF. The reaction was stirred for 15 min to give a suspension. A solution of N-(t-butoxycarbonyl)-(N′-methyl-N′-methoxy)-L-homophenylalaninamide (300 mg, 0.930 mmol) (prepared as described in Example 3) in 1 mL of dry THF was added all at once via syringe. The reaction was stirred for 5 min at which time TLC showed consumption of the amide. The reaction was quenched by the addition of water and the product extracted with 50 mL of EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to give a residue that was purified by preparative TLC (CH2Cl2) to give the desired ketone as a clear colorless oil.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].Cl.[NH2:14][OH:15].C(N(CC)CC)C>C(O)C>[F:1][C:2]([C:5]1[CH:12]=[CH:11][C:8]([C:9](=[N:14][OH:15])[NH2:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(F)c1ccc(C#N)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(F)c1ccc(C(N)=NO)cc1
Temperature: 25 °C

Procedure:
A solution of 4-(2-fluoropropan-2-yl)benzonitrile (Step 1, 675 mg, 4.14 mmol), hydroxylamine hydrochloride (632 mg, 9.10 mmol) and triethylamine (1.27 mL, 9.10 mmol) in ethanol (20 mL) was stirred and heated at reflux for 1 h. After being cooled to rt, the reaction mixture was evaporated to dryness. The resulting material was treated with ethyl acetate and the solid was filtered off. The ethyl acetate solution was washed with water and saturated sodium chloride solution, dried with anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the title compound was obtained (756 mg, 93%): 1H NMR (400 MHz, CDCl3) δ 7.62 (d, 2H), 7.41 (d, 2H), 4.89 (broad s, 2H), 1.72 (s, 3H), 1.68 (s, 3H); ES-MS m/z 197, HPLC RT (Method F) 1.04 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][CH:11]=[C:10]3[N:14]([CH3:18])[N:15]=[C:16]([NH2:17])[C:9]=23)=[CH:4][CH:3]=1.[N:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)=[C:20]=[O:21].FC1C=CC(C)=CC=1N=C=O>>[NH2:17][C:16]1[C:9]2[C:10](=[CH:11][N:12]=[CH:13][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:20]([NH:19][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=3)=[O:21])=[CH:7][CH:6]=2)[N:14]([CH3:18])[N:15]=1
Reactant: Cn1nc(N)c2c(-c3ccc(N)cc3)cncc21
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: Cc1ccc(F)c(N=C=O)c1
Product: Cn1nc(N)c2c(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cncc21

Procedure:
The title compound was prepared using the procedure described in Example 1E using the product from Example 6A and 1-isocyanato-3-trifluoromethyl-benzene instead of the product from Example 1D and 1-fluoro-2-isocyanato-4-methyl-benzene. MS (ESI(+)) m/e 427 (M+H)+; 1H NMR (500 MHz, DMSO-D6) δ ppm 3.92 (s, 3H) 4.66 (s, 2H) 7.33 (d, J=7.49 Hz, 1H) 7.48 (d, J=8.73 Hz, 2H) 7.53 (t, J=7.95 Hz, 1H) 7.61 (d, J=9.05 Hz, 1H) 7.65 (d, J=8.73 Hz, 2H) 7.95 (s, 1H) 8.04 (s, 1H) 8.87 (s, 1H) 8.98 (s, 1H) 9.10 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1.[CH3:12][C:13]1([CH3:20])[O:17][C@H:16]([CH2:18]O)[CH2:15][O:14]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:12][C:13]1([CH3:20])[O:17][C@H:16]([CH2:18][O:1][C:2]2[CH:3]=[C:4]([CH3:11])[C:5]([CH:6]=[O:7])=[C:8]([CH3:10])[CH:9]=2)[CH2:15][O:14]1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: Cc1cc(O)cc(C)c1C=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OC[C@@H]2COC(C)(C)O2)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-hydroxy-2,6-dimethylbenzaldehyde (150 mg, 1.0 mmol) and ((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (132 mg, 1.0 mmol) in THF (10 mL) was added PPh3-resin (553 mg, 2.13 mmol/g) and DEAD (0.54 mL of a 40% solution, 1.2 mmol) and the suspension was stirred at ambient temperature overnight. The reaction mixture was filtered and partioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the organic layer was dried with MgSO4, filtered and concentrated. Purification by flash chromatography using heptane/EtOAc (2:1) as eluent gave 4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2,6-dimethylbenzaldehyde as a white solid.
Reaction SMILES: C([O:8][C:9](=[O:38])/[CH:10]=[CH:11]/[CH2:12][CH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[O:29][C:28]([NH:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=4)=[N:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)C1C=CC=CC=1>CCOC(C)=O.CCO.[OH-].[OH-].[Pd+2]>[Cl:37][C:33]1[CH:32]=[C:31]([NH:30][C:28]2[O:29][C:25]([C:22]3[CH:23]=[CH:24][C:19]([CH:16]4[CH2:15][CH2:14][CH:13]([CH2:12][CH2:11][CH2:10][C:9]([OH:38])=[O:8])[CH2:18][CH2:17]4)=[CH:20][CH:21]=3)=[CH:26][N:27]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: O=C(/C=C/CC1CCC(c2ccc(-c3cnc(Nc4cccc(Cl)c4)o3)cc2)CC1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)CCCC1CCC(c2ccc(-c3cnc(Nc4cccc(Cl)c4)o3)cc2)CC1
Reaction time: 72 h
Yield: 86.1 %

Procedure:
To a solution of (E)-4-(4-{4-[2-(3-chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-but-2-enoic acid benzyl ester (139 mg, 0.283 mmol) in EtOAc/EtOH (5:1 v/v, 6 mL) is added Pd(OH)2 (100 mg) the mixture is stirred in an hydrogenated at 1 atm for 72 h. The catalyst is filtered and washed with EtOAc. The filtrated is then concentrated and dried under high vacuum to give the title compound (107 mg) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98-1.09 (m, 2H) 1.18-1.25 (m, 2H) 1.39-1.48 (m, 2H) 1.49-1.57 (m, 2H) 1.82 (d, J=10.11 Hz, 4H) 1.74-1.85 (m, 1H) 2.18 (t, J=7-33 Hz, 2H) 6.99 (ddd, J=7.96, 2.02, 0.88 Hz, 1H) 7.28-7.33 (m, 3H) 7.40 (s, 1H) 7.47-7.52 (m, 3H) 7.85 (t, J=2.02 Hz, 1H); (M+H)+=439.0.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].Cl[C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[C:13]([C:20]3[NH:28][C:27]4[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=4[CH:21]=3)[CH:14]=[CH:15][CH:16]=2)[N:11]=1>>[OH:2][C:1]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[O:5][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[C:13]([C:20]3[NH:28][C:27]4[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=4[CH:21]=3)[CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: Oc1cccc(O)c1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Oc5cccc(O)c5)nc34)cc21
Temperature: 90 °C
Yield: 77.4 %

Procedure:
Prepared according to Example 103 using resorcinol (125.5 mg, 1.140 mmol) and 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 50.0 mg, 0.168 mmol), heating at 90° C. for 18 h. Chromatographic purification (silica gel, 0-10% MeOH/DCM) furnished 2-(2-(3-hydroxyphenoxy)-quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (48.4 mg, 0.130 mmol, 78% yield) as a light-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.20 (1H, br. s.), 9.86 (1H, s), 8.47 (1H, d, J=8.8 Hz), 8.14 (1H, d, J=7.6 Hz), 7.78 (1H, d, J=7.2 Hz), 7.47 (1H, t, J=7.7 Hz), 7.35-7.42 (2H, m), 6.98 (1H, d, J=2.2 Hz), 6.94 (1H, br. s.), 6.83 (1H, m, J=7.8, 1.8 Hz), 6.79 (1H, dd, J=7.9, 1.7 Hz), 6.74 (1H, t, J=2.2 Hz), 3.31-3.37 (2H, m), 2.47-2.49 (2H, obsc. m). m/z (ESI, +ve) 372.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[N+:12]([O-])=O.[O-]S([O-])(=S)=O.[Na+].[Na+].Cl.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])([CH3:9])[CH3:11])=[CH:4][C:3]=1[NH2:12]
Reactant: CC(C)(C)c1ccc(Br)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: COCCO
Product: CC(C)(C)c1ccc(Br)c(N)c1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1-bromo-4-tert-butyl-2-nitrobenzene (2.1 g, 8.14 mmol, 1.00 equiv), sodium hyposulfite (6.6 g, 37.91 mmol, 3.50 equiv) and a solution of 2-methoxyethan-1-ol (12 mL) in water (12 mL). The resulting solution was stirred overnight at 130° C. Water (11 ml) and concentrated hydrochloric acid (11 ml) were added to the warm solution. After heated under reflux for 30 min, the reaction mixture was poured into ice water (25 ml), adjusted the pH value of the solution to 8-9 with sodium carbonate(s) and extracted with ether (3×50 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave the title compound, which was used directly for next step without further purification as a yellow liquid. 1H-NMR(400 MHz, DMSO-d6): δ ppm 1.298(s, 9H), 4.097(s, 2H), 6.682(dd, J=2 Hz, J=8.4 Hz, 1H), 6.827(d, J=2.4 Hz, 1H), 7.33(d, J=8.4 Hz, 1H).
Reaction SMILES: [C:1](#[N:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C@H:29](N)[CH3:30])[CH:26]=[CH:27][CH:28]=1.[BH4-].[Na+]>>[C:4]1([CH:3]=[CH:2][CH2:1][NH:10][C@@H:29]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=2)[CH3:30])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc([C@@H](C)N)c1
Reactant: N#CC=Cc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH4-]
Agent: [H-]
Product: COc1cccc([C@@H](C)NCC=Cc2ccccc2)c1

Procedure:
In a similar fashion, cinnamonitrile was treated with diisobutyl aluminum hydride and the intermediate aluminum-imine complex treated with (R)-1-(3-methoxyphenyl)ethylamine. The intermediate imine was treated with ethanolic sodium borohydride. Work-up and chromatography yielded (R)-N-(3-phenylprop-2-enyl)-1-(3-methoxyphenyl)ethylamine, 25E, as a clear colorless oil; m/z (rel. int.) 267 (M+. 3), 252 (14),176 (17), 135 (62),117 (100), 105 (28), 91 (56), 77 (33).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])O[C:4]([CH2:11][CH2:12][CH3:13])=[C:3]1[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].[CH2:23]([NH2:27])[CH2:24][CH2:25][CH3:26].C1(C)C=CC=CC=1.[OH-].[Na+]>CO.C(OC(=O)C)C.O>[CH2:23]([N:27]1[C:6]([CH2:8][CH2:9][CH3:10])=[CH:7][C:2](=[O:1])[C:3]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])=[C:4]1[CH2:11][CH2:12][CH3:13])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCN
Reactant: CCCc1cc(=O)c(C(=O)Nc2ccccc2)c(CCC)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCn1c(CCC)cc(=O)c(C(=O)Nc2ccccc2)c1CCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
To a mixture of 1 g (3.34 mmol) of 4-oxo-N-phenyl-2,6-dipropyl-4H-pyran-3-carboxamide, 0.37 g (5.01 mmol) of butylamine and 5 ml of toluene, 1 ml of 1N sodium hydroxide solution in methanol was added and stirred overnight at room temperature. After adding about 10 ml of water and about 10 ml of ethylacetate to the mixture, they were well shaken in a separatory funnel. The organic layer was washed with saturated sodium chloride solution, dried in an usual manner, concentrated and crystallized from toluene and cyclohexane to afford 737 mg of the title compound having m.p. 133.5°-136.5° C.
Reaction SMILES: O[CH2:2][C:3]1[C:8]([OH:9])=[C:7]([CH3:10])[CH:6]=[C:5]([CH3:11])[CH:4]=1.[C:12]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[OH:23])([CH3:15])([CH3:14])[CH3:13].[OH-].[Na+].Cl>O>[OH:23][C:17]1[C:16]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:21][C:20]([CH3:22])=[CH:19][C:18]=1[CH2:10][C:7]1[CH:6]=[C:5]([CH3:11])[CH:4]=[C:3]([CH3:2])[C:8]=1[OH:9]
Reactant: Cc1cc(C)c(O)c(CO)c1
Reactant: Cc1ccc(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C)c(O)c(Cc2cc(C)cc(C(C)(C)C)c2O)c1
Temperature: 100 °C
Yield: 51.9 %

Procedure:
In a 300 ml eggplant-type flask equipped with a Dimroth condenser, 10.4 g (0.068 mol) of intermediate 6-(hydroxymethyl)-2,4-dimethylphenol and 11.6 g (0.071 mol) of 2-t-butyl-4-methylphenol were suspended in 50 ml of water. To this suspension, an aqueous solution having 10.3 g (0.26 mol) of sodium hydroxide dissolved in 50 ml of water, was added, and the mixture was stirred by a magnetic stirrer. This mixture was heated to 100° C. and stirred at that temperature for 12 hours. The reaction mixture was cooled to room temperature, then acidified by concentrated hydrochloric acid and extracted with toluene. The obtained toluene solution was washed with water and then dried over anhydrous magnesium sulfate. From the solution having the anhydrous magnesium sulfate removed, toluene was distilled off, and the obtained residue was separated by silica gel chromatography to obtain 10.6 g (0.036 mol, yield: 51.9%) of (2-hydroxy-3-t-butyl-5-methylphenyl)-(2-hydroxy-3,5-dimethylphenyl)methane as a brown highly viscous liquid. By 1HNMR, the liquid was confirmed to be the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10](Cl)[C:4]=2[CH:3]=1.[C:18]([Cu])#[N:19]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]([C:18]#[N:19])[C:4]=2[CH:3]=1
Reactant: N#C[Cu]
Reactant: Clc1ccc2c(c1)C(Cl)c1ccccc1CO2
Solvent: Cc1ccccc1
Product: N#CC1c2ccccc2COc2ccc(Cl)cc21

Procedure:
2,11-Dichloro-6,11-dihydrodibenz[b,e]oxepin (7.7 g; 0.03 mole) of example 25-A is dissolved in dry toluene (120 ml) and placed under a positive dry nitrogen atmosphere. To this solution is added CuCN (5.2 g; 0.05 mole) in one portion and the reaction brought to reflux for 61/2 hours. The reaction mixture is filtered while hot (80° C.) and the salts washed with tolune. After removing the filtrate in vacuo the resulting solid is triturated with hexane and dried to yield 2-chloro-11-cyano-6,11-dihydrodibenz[b,e]oxepin, m.p. 113°-115° C.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=2[CH:15]=[O:16])=[CH:4][C:3]=1[CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=2[CH2:15][OH:16])=[CH:4][C:3]=1[CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1
Reactant: N#Cc1ccc(Oc2ccc(Br)c(COC3CCCCO3)c2)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(Oc2ccc(Br)c(COC3CCCCO3)c2)c(CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 4-[4-bromo-3-(2-tetrahydropyranyloxymethyl)phenoxy]-3-formylbenzonitrile obtained in Example 19w (D23) (14.6 g, 34.9 mmol) in methanol (100 mL) was added sodium borohydride (664 mg g, 17.5 mmol) portionwise at 0° C., and the mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure to a half volume, and the mixture was poured into ethyl acetate/water. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 4-[4-bromo-3-(2-tetrahydropyranyloxymethyl)phenoxy]-3-(hydroxymethyl)benzonitrile (14.6 g, 100%).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18](B(O)O)[CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>O.COCCOC.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>[F:14][C:6]1[C:5]([CH3:15])=[C:4]2[C:9]([CH:10]=[C:11]([CH:12]=[O:13])[C:2]([C:18]3[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: Cc1c(F)ccc2cc(C=O)c(Cl)nc12
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1c(F)ccc2cc(C=O)c(-c3cccnc3)nc12
Yield: 92.7 %

Procedure:
Prepared according to the procedure described for Intermediate 1, utilising 2-chloro-7-fluoro-8-methylquinoline-3-carbaldehyde (5.0 g, 22.36 mmol), 3-pyridylboronic acid (3.02 g, 24.6 mmol), tetrakis(triphenylphosphine)palladium(0) (127 mg, 0.11 mmol) and Na2CO3 (3.55 g, 33.54 mmol) in water (30 mL) and DME (60 mL). The title compound (5.52 g, 93%) was obtained as a beige solid. δH (DMSO-d6) 10.13 (s, 1H), 9.08 (s, 1H), 8.95 (dd, J 2.3, 0.8 Hz, 1H), 8.75 (dd, J 4.9, 1.7 Hz, 1H), 8.24 (dd, J 9.0, 6.4 Hz, 1H), 8.16-8.21 (m, 1H), 7.68 (t, J 9.2 Hz, 1H), 7.61 (ddd, J 7.9, 4.0, 0.8 Hz, 1H), 2.66 (d, J 2.4 Hz, 3H). LCMS (ES+) 267 (M+H)+, RT 2.16 minutes.