Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)CCl.Cl.[CH3:6][N:7]1[C:14](=[O:15])[CH2:13][CH2:12][NH:11][C:10]2[N:16]=[CH:17][C:18](/[CH:20]=[CH:21]/[C:22]([OH:24])=O)=[CH:19][C:9]=2[CH2:8]1.C1C=CC2N(O)N=NC=2C=1.[CH3:35][NH:36][CH2:37][C:38]1[S:42][C:41]2[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=2[C:39]=1[CH3:47].C(N(C(C)C)C(C)C)C>CN(C=O)C.C(#N)CC.C(OCC)(=O)C>[CH3:35][N:36]([CH2:37][C:38]1[S:42][C:41]2[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=2[C:39]=1[CH3:47])[C:22](=[O:24])/[CH:21]=[CH:20]/[C:18]1[CH:17]=[N:16][C:10]2[NH:11][CH2:12][CH2:13][C:14](=[O:15])[N:7]([CH3:6])[CH2:8][C:9]=2[CH:19]=1
Reactant: CNCc1sc2ccccc2c1C
Reactant: CN1Cc2cc(/C=C/C(=O)O)cnc2NCCC1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(C)C(=O)CCN3)sc2ccccc12
Temperature: 40 °C
Reaction time: 17 h

Procedure:
EDC (54 mg, 0.28 mmol) was added to a suspension of (E)-3-(5-methyl-4-oxo-1,2,3,4,5,6-hexahydropyrido[2,3-b][1,5]diazocin-8-yl)acrylic acid hydrochloride (70 mg, 0.23 mmol), HOBt (34 mg, 0.25 mmol), N-methyl(3-methylbenzo[b]thiophen-2-yl)methanamine (48 mg, 0.25 mmol) and (i-Pr)2EtN (0.20 mL, 1.2 mmol) in 5 mL of DMF:propionitrile (4:1). The mixture was allowed to stir for 17 h at 40° C. The mixture was cooled to room temperature and diluted with ethyl acetate (40 mL) and washed with water (50 mL) and NaHCO3 (50 mL), dried over MgSO4 and dried under high vacuum. The solid was then subjected to purification on Prep HPLC to obtain the product as a fluffy white solid. Yield 54 mg (54%); 1H NMR (400 MHz, CDCl3) δ 10.41 (bs, 1H), 8.08 (s, 1H), 7.79-7.68 (m, 3H), 7.59 (d, J=15.2 Hz, 1H), 7.40 (m, 2H), 6.95-6.86 (m, 1H), 4.96 (s, 2H), 4.72 (bs, 2H), 3.90 (s, 2H), 3.15 (m, 5H), 2.84 (s, 3H), 2.46 (s, 3H); ESI MS m/z 435 [C24H26N4O2S+H]+
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:22])[NH:5][C:6]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=1)[CH3:2].[CH3:23][CH2:24][N:25]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N)C>C1COCC1.CN(C1C=CN=CC=1)C>[CH2:24]([NH:25][C:10](=[O:12])[C:9]1[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][C:6]([NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:22])=[N:7][CH:8]=1)[CH3:23]
Reactant: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)O)cn1
Reactant: CCN=C=NCCCN(C)C
Agent: CCN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)NCC)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a solution of 6-(3-ethylureido)-4-(phenylamino)nicotinic acid (50 mg, 0.16 mmol, 1.0 eq) in THF (5.0 mL) was added EDCI.HCl (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, 46 mg, 0.24 mmol, 1.50 eq) followed by HOBt (N-hydroxybenzotriazole, 32 mg, 0.24 mmol, 1.50 eq), DMAP (4-dimethylaminopyridine, 29 mg, 0.24 mmol, 1.50 eq) and finally, ethyl amine (16 mg 70% solution, 0.24 mmol, 1.50 eq). The resulting reaction mixture was stirred overnight at room temperature. The reaction mass was then poured onto ice-cold water followed by extraction with EtOAc (3×20 mL). The organics were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified over silica gel (60-120 M, 1-2.5% MeOH-DCM) to obtain Compound 8 (48 mg, 92%), 1H NMR (300 MHz, DMSO-d6): δ 10.43 (br s, 1H), 9.03 (br s, 1H), 8.52 (t, J=5.20 Hz, 1H), 8.41 (5, 1H), 7.94 (br s, 1H), 7.39 (m, 2H), 7.22 (m, 3H), 7.13 (m, 1H), 3.26 (m, 2H), 3.13 (m, 2H), 1.12 (t, J=7.20 HZ, 3H) and 1.05 (t, J=7.20 Hz, 3H). [M+H]+ m/z=328.18.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:27])[C:11]2[C:16]([C:17]([CH3:19])=[CH2:18])=[CH:15][C:14]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:13][C:12]=2[F:26])=[CH:4][CH:3]=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:27])[C:11]2[C:16]([CH:17]([CH3:19])[CH3:18])=[CH:15][C:14]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[CH:13][C:12]=2[F:26])=[CH:4][CH:3]=1
Reactant: C=C(C)c1cc(N2CCOCC2)cc(F)c1C(=O)NCc1ccc(Cl)cc1
Solvent: CO
Product: CC(C)c1cc(N2CCOCC2)cc(F)c1C(=O)NCc1ccc(Cl)cc1
Reaction time: 0.75 h
Yield: 32.3 %

Procedure:
A stirred solution of N-[(4-chlorophenyl)-methyl]-2-fluoro-6-isopropenyl-4-morpholin-4-yl-benzamide (0.12 g, 0.31 mmol) in methanol (10 ml) is degassed and flushed with nitrogen before 10% palladium on carbon (25 mg) is added and the mixture is hydrogenated under hydrogen for 45 min at room temperature. After completion of the reaction (monitored by TLC), the mixture is filtered through a pad of celite and concentrated in vacuo. The resulting crude product is purified by preparative HPLC to obtain N-[(4-chlorophenyl)-methyl]-2-fluoro-6-isopropyl-4-morpholin-4-yl-benzamide (example 39) (0.04 g, 0.10 mmol, 33%). [M+H]+ 391.2.
Reaction SMILES: C[N:2]1[C:7]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:6]=2[C:5](=[O:15])O[C:3]1=O.C(O)C.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.C(N(CC)CC)C>[CH3:3][NH:2][C:7]1[S:8][C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:6]=1[C:5]([NH:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23])=[O:15]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: Cn1c(=O)oc(=O)c2c3c(sc21)CCCC3
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNc1sc2c(c1C(=O)N[C@@H](C)c1ccc(C(=O)OC)cc1)CCCC2
Temperature: 25 °C

Procedure:
To 1-methyl-5,6,7,8-tetrahydro-2H-[1]benzothieno[2,3-d][1,3]oxazine-2,4(1H)-dione (0.50 g) was added ethanol (20 mL), and triethylamine (0.44 mL) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride were sequentially added, followed by heating with reflux for 18 hours. The reaction mixture was cooled to room temperature, and a 10% aqueous citric acid solution (15 mL) was added thereto. To a mixture was added ethyl acetate, followed by washing with water, and the obtained organic layer was dried over anhydrous sodium sulfate. After filtering and concentrating under reduced pressure, the residue was purified by silica gel column chromatography (hexane/ethyl acetate: 90/10-75/25) to obtain methyl 4-[(1S)-1-({[2-(methylamino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)ethyl]benzoate (0.42 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH:11]=[CH:10]1.[NH2:28][CH2:29][CH2:30][CH2:31][OH:32]>>[CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13]([NH:28][CH2:29][CH2:30][CH2:31][OH:32])[C:12]=2[CH:11]=[CH:10]1
Reactant: Cc1cc(F)ccc1-n1ccc2c(Cl)nc3c(OC(F)(F)F)cccc3c21
Reactant: NCCCO
Product: Cc1cc(F)ccc1-n1ccc2c(NCCCO)nc3c(OC(F)(F)F)cccc3c21

Procedure:
1-(2-Methyl-4-fluorophenyl)-4-chloro-6-trifluoromethoxypyrrolo[3,2-c]quinoline(394 mg, 1.0 mmol) was dissolved in 3-amino-1-propanol(5 ml) in the pressure tube, and reacted at the same condition of Step 3 in the Example to obtain 460 mg of desired compound as solid in 83% of yield.
Reaction SMILES: [CH2:1]1[O:17][C:16]2[C:3](=[CH:4][C:5]3[CH:6]=[C:7]([C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36]C)=[O:35])=[O:27])[C:8]4[C:13]([C:14]=3[CH:15]=2)=[CH:12][C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:9]=4)[O:2]1.N>>[CH2:1]1[O:17][C:16]2[C:3](=[CH:4][C:5]3[CH:6]=[C:7]([C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:27])[C:8]4[C:13]([C:14]=3[CH:15]=2)=[CH:12][C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:9]=4)[O:2]1
Reactant: COC(=O)CCCCCNC(=O)c1cc2cc3c(cc2c2cc(OCc4ccccc4)ccc12)OCO3
Agent: N
Product: O=C(O)CCCCCNC(=O)c1cc2cc3c(cc2c2cc(OCc4ccccc4)ccc12)OCO3

Procedure:
General procedure e from 10 (100%); white needles; mp 198-200° C.; 1H NMR (400.13 MHz) δ 8.06 (d, J=4 Hz, 1H), 7.79 (d, J=2 Hz, 1H), 7.75 (s, 1H), 7.48 (s, 1H), 7.40 (d, J=4 Hz, 2H), 7.30 (t, J=4 Hz, 2H), 7.23 (m, 1H), 7.16 (dd, J=4 Hz, 2 Hz, 1H), 7.09 (s, 1H), 6.00 (s, 2H), 5.15 (s, 2H), 3.23 (m, 2H), 2.23 (t, J=6 Hz, 2H), 1.58 (m, 4H), 1.36 (m, 2H); MS (DCI/NH3) m/e: 486 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1([CH3:16])[CH2:15][CH2:14][O:13][CH2:12]1>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]1([CH3:16])[CH2:15][CH2:14][O:13][CH2:12]1
Reactant: CC1(c2cc([N+](=O)[O-])ccc2F)CCOC1
Agent: [Pd]
Solvent: CO
Product: CC1(c2cc(N)ccc2F)CCOC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3-(2-fluoro-5-nitrophenyl)-tetrahydro-3-methylfuran in methanol was added a catalytic amount of palladium on carbon (10%). The mixture was allowed to stir for 1 h at room temperature under hydrogen atmosphere. Mixture was filtered though celite and concentrated to afford 4-fluoro-3-(tetrahydro-3-methylfuran-3-yl)benzenamine.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([N:14]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:21]([OH:23])=O)=[O:13])([CH3:10])([CH3:9])[CH3:8].CCN(C(C)C)C(C)C.[C:43]1([NH:49][CH2:50][CH2:51][CH2:52][N:53]2[N:57]=[N:56][CH:55]=[N:54]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>ClCCl.CN(C1C=CN=CC=1)C.CN(C=O)C>[C:7]([O:11][C:12](=[O:13])[N:14]([CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([C:21](=[O:23])[N:49]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:50][CH2:51][CH2:52][N:53]2[N:57]=[N:56][CH:55]=[N:54]2)[CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)([CH3:9])([CH3:8])[CH3:10]
Reactant: c1ccc(NCCCn2ncnn2)cc1
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCn2ncnn2)c2ccccc2)c1)c1ccncc1
Reaction time: 0.17 h
Yield: 25.6 %

Procedure:
2M Oxalyl chloride solution in dichloromethane (0.11 ml), and dry DMF (0.005 ml) were added to a stirred suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.067 g) in dry dichloromethane (1 ml) under nitrogen. After 10 min, DIPEA (0.100 ml) was added followed after a further 40 min by phenyl-(3-tetrazol-2-yl-propyl)-amine (0.033 g) and DMAP (0.004 g). After 7 days the solvent was evaporated and the residue was purified by flash chromatography, eluting with dichloromethane:methanol (98:2 v/v) to give the title compound as a pale yellow oil (0.024 g).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:12]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl.C(Cl)(=O)C>Br.[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC.CO>[OH:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:12]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: COC(=O)Cc1cccnc1Oc1cccc(OC)c1
Agent: Br
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: CC(=O)Cl
Solvent: CO
Product: COC(=O)Cc1cccnc1Oc1cccc(O)c1
Reaction time: 3 h
Yield: 51.5 %

Procedure:
Methyl 2-(3-methoxyphenoxy)-3-pyridinylacetate (27.2 g) was heated at 115° C. in 47% hydrobromic acid (249 ml) containing hexadecyltributylphosphonium bromide (5.6 g). After 3 hours, the solution was cooled and potassium carbonate added until the pH of the solution was ca. 6. The reaction mixture was extracted (×5) with ethyl acetate. The organic extracts were dried, filtered and evaporated to give a pale orange solid. The solid was then treated with methanolic hydrogen chloride overnight (from methanol (500 ml) and acetyl chloride (50 ml)). The methanol was removed and the residue dissolved in water. The pH of the solution was adjusted to ca. pH6 with sodium bicarbonate and the solution extracted with ethyl acetate (×3). The combined organic extracts were dried, filtered ad evaporated. The resulting organge solid residue was re-dissolved in dichloromethane and filtered through a plug of silica (eluent ether dichloromethane). Evaporation afforded methyl 2-(3-hydroxyphenoxy)-3-pyridinylacetate as a pale yellow solid (13.28 g, 51%) which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[N+:23]([O-])=O)[NH:7][C:8]([CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)=[O:9])([O-])=O.[CH:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([C:26]2[NH:23][C:22]3[CH:21]=[CH:20][C:6]([NH:7][C:8]([CH:10]4[CH2:19][CH2:18][C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[CH2:11]4)=[O:9])=[CH:5][C:4]=3[N:1]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)C1CCc2ccccc2C1
Reactant: O=Cc1ccccc1
Product: O=C(Nc1ccc2[nH]c(-c3ccccc3)nc2c1)C1CCc2ccccc2C1

Procedure:
Compound 204 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(1,2,3,4-tetrahydronaphthalen-2-oyl)aniline and benzaldehyde. [M+H]+ calcd for C24H21N3O: 368.17; found: 368.00.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[OH:9])=[C:4]([Cl:16])[CH:3]=1.Cl.[Cl:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1>>[ClH:16].[ClH:18].[Cl:16][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[CH:8]([OH:9])[C:10]1[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=1)[NH:1][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1ccc(C(O)c2ccncc2)c(Cl)c1
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(C(O)c4ccncc4)c(Cl)c3)c2cc1OC
Yield: 12 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-amino-2-chlorophenyl)-1-(4-pyridyl)methanol was reacted with 4-chloro-6,7-dimethoxyquinazoline hydrochloride to give 4-{3-chloro-4-[1-hydroxy-1-(4-pyridyl)methyl]anilino}-6,7-dimethoxyquinazoline dihydrochloride salt in 12% yield;
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[N:22]([CH2:23][C:24]#[C:25][CH2:26]Cl)[C@@:16]2([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:17][CH2:18]3)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N-:36]=[N+:37]=[N-:38].[Na+]>CN(C)C=O.O>[N:36]([CH2:26][C:25]#[C:24][CH2:23][N:22]1[C@@H:19]2[CH2:18][CH2:17][C@@:16]1([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@H:15]([O:14][CH2:13][C:5]1[CH:4]=[C:3]([C:2]([F:35])([F:34])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1)[CH2:21][CH2:20]2)=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3CC#CCCl)cc(C(F)(F)F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC#CCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)CC2

Procedure:
(1R*,2R*,5R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-8-(4-chlorobut-2-ynyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Description 26; 254 mg, 0.49 mmol) and sodium azide (35 mg, 0.54 mmol) were stirred in dimethylformamide (3 ml) at room temperature overnight. The reaction mixture was diluted with water and the product extracted with ethyl acetate (×3), dried (MgSO4) and concentrated in vacuo to give the title compound as an orange oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([CH3:19])[S:18][C:12]2=[N:11][C:10]=1[C:20](O)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:24][CH2:25][C:26](=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1>>[Cl:35][C:30]1[CH:29]=[C:28]([CH2:27][C:26](=[O:36])[CH2:25][NH:24][C:20]([C:10]2[N:11]=[C:12]3[S:18][C:17]([CH3:19])=[CH:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:21])[CH:33]=[CH:32][C:31]=1[Cl:34]
Reactant: NCC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: Cc1cn2c(=O)c(OCc3ccccc3)c(C(=O)O)nc2s1
Agent: Cl
Product: Cc1cn2c(=O)c(OCc3ccccc3)c(C(=O)NCC(=O)Cc3ccc(Cl)c(Cl)c3)nc2s1

Procedure:
Adapted from example 2 using the product of example 1 and 1-amino-3-(3,4-dichloro-phenyl)-propan-2-one hydrochloride.
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([O:27][CH2:28][CH2:29][CH:30]([OH:52])[CH2:31][O:32]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O.O>[CH2:11]([O:27][CH2:28][CH2:29][CH:30]([O:52][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:31][OH:32])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCCCOCCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOCCC(CO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
To a suspension of 6.17 g of 50% sodium hydride (washed with hexanes) in 245 ml of dry dimethylformamide was added 19.45 g of benzyl bromide at 0° C. A solution of 56.65 g of 4-(hexadecyloxy)-1-(triphenylmethoxy)-2-butanol in 60 ml of dimethylformamide was added dropwise with stirring at 0° C. under argon. The mixture was stirred overnight at room temperature, then poured into 1000 ml of iced water and extracted with petroleum ether. The organic phase was dried, the solvent removed and the residue dissolved in a mixture of 235 ml of methanol and 125 ml of tetrahydrofuran. A 500 mg portion of p-toluene sulfonic acid was added, the mixture was allowed to stand overnight and then the solvent was removed. The residue was dissolved in petroleum ether, washed with saturated aqueous sodium bicarbonate, dried and the solvent removed giving an oil. This oil was again subjected to treatment with p-toluenesulfonic acid in the solvent system described above, again giving an oil which was purified by HPLC, giving 23 g of the desired compound as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([O:20][CH3:21])=[CH:18][N:17]=[CH:16][N:15]=2)[CH:10]([CH3:22])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.CCOCC>[CH3:21][O:20][C:19]1[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]2[CH3:22])=[N:15][CH:16]=[N:17][CH:18]=1
Reactant: COc1cncnc1N1CCN(C(=O)OC(C)(C)C)CC1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: COc1cncnc1N1CCNCC1C
Yield: 91.5 %

Procedure:
A solution of 1-(t-butoxycarbonyl)-4-(5-methoxy-4-pyrimidinyl)-3-methylpiperazine (1.70 g, 4.2 mmol) and trifluoroacetic acid (5 mL) in 50 mL of CH2Cl2 was stirred at r.t. under Ar for 18 h. The solution was evaporated, the residue was taken up in water and the mixture was basified (pHS) with 15% aqueous NaOH. The resulting (pH 8) mixture was extracted with ethyl acetate and the organic phase was washed (H2O, brine), dried (Na2SO4) and evaporated to give a semi-solid. This material was taken up in ether, filtered to remove insoluble material and the solution was evaporated to give the product (0.80 g, 92%) as an oil. It was used without further purification: IR (neat) 3300, 1580, 1540 cm-1 ; 1H nmr (200 MHz, CDCl3) δ 8.32 (S, 1H), 7.87 (s, 1H), 4.83-4.68 (m, 1H), 4.26-4.19 (m, 1H), 3.85 (s, 3H), 3.26-3.17 (m, 1H), 3.12-3.01 (m, 2H), 2.94-2.80 (m, 2H), 1.29 (d, J=6.8 Hz, 3H) .
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)=[O:3].C(O)C.[H-].[Na+].Cl.[C:20](=O)([O-:24])[O:21][CH2:22][CH3:23]>O>[O:3]=[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][CH:5]=1)[CH2:1][C:20]([O:21][CH2:22][CH3:23])=[O:24]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of 4-trifluoromethylacetophenone (57.8 g, 0.307 mol) and ethanol (1 ml) in ethyl carbonate (300 ml) was added sodium hydride (24.5 g, 60% in oil, 0.63 mol) by small portions. Because heat was generated gradually, the reaction solution was ice-cooled and thereafter stirred at room temperature for 2 hrs. 6N Hydrochloric acid was added thereto to stop the reaction. The mixture was diluted with water (300 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1-5:1) to give ethyl 3-oxo-3-(4-trifluoromethylphenyl)propionate (71.2 g, 89%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=3[O:18][CH3:19])=[N:9][N:10]=2)[CH:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][C:23]=1[OH:37]>>[OH:37][C:23]1[CH:24]=[C:25]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]4[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=4[O:18][CH3:19])=[N:9][N:10]=3)[CH:7]=2)[CH:26]=[CH:27][C:22]=1[O:21][CH3:20]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1O
Reactant: COc1cc(C)ccc1-c1nnc2ccc(Cl)cn12
Product: COc1ccc(-c2ccc3nnc(-c4ccc(C)cc4OC)n3c2)cc1O

Procedure:
The title compound was prepared from 6-chloro-3-(2-methoxy-4-methylphenyl)-[1,2,4]triazolo[4,3-a]pyridine and 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol using a procedure similar to those described for the synthesis of Example 1d, and was isolated as yellow solids. 1H NMR (DMSO-d6): 9.23 (s, 1H), 7.91-7.86 (m, 2H), 7.69 (dd, J=9.6 and 1.5 Hz, 1H), 7.49 (d, J=7.5 Hz, 1H), 7.16-6.99 (m, 5H), 3.84 (s, 3H), 3.80 (s, 3H), 2.45 (s, 3H). MS: m/z 362.2 [M+H+].
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[C:5]([CH:20]=[O:21])[CH:4]=1)#[N:2].[BH4-].[Na+]>CO>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[C:5]([CH2:20][OH:21])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
To a solution of 5-(4-cyano-2-formylphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (3.00 g, 10.8 mmol) in methanol (100 mL) was added sodium borohydride (400 mg, 10.8 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, 1 M HCl (50 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was treated with ethyl acetate/hexane to give 5-[4-cyano-2-(hydroxymethyl)phenoxy]-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (1.83 g, 60%).
Reaction SMILES: [C:1]1([C:7](=[N:14][C:15]2[CH:16]=[CH:17][C:18]3[C@H:23]([CH2:24][CH2:25][OH:26])[O:22][CH2:21][CH2:20][C:19]=3[CH:27]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].CS(OCC[C@H]1C2C=CC(C(N)=O)=CC=2CCO1)(=O)=O>>[CH3:28][S:29]([O:26][CH2:25][CH2:24][C@H:23]1[C:18]2[CH:17]=[CH:16][C:15]([N:14]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:27][C:19]=2[CH2:20][CH2:21][O:22]1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: OCC[C@@H]1OCCc2cc(N=C(c3ccccc3)c3ccccc3)ccc21
Agent: CS(=O)(=O)OCC[C@@H]1OCCc2cc(C(N)=O)ccc21
Product: CS(=O)(=O)OCC[C@@H]1OCCc2cc(N=C(c3ccccc3)c3ccccc3)ccc21

Procedure:
2-{(1S)-6-[(Diphenylmethylene)amino]-3,4-dihydro-1H-2-benzopyran-1-yl}ethanol was reacted with methanesulfonyl chloride, as described for the preparation of 2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl methanesulfonate, to yield 2-{(1S)-6-[(diphenylmethylene)amino]-3,4-dihydro-1H-2-benzopyran-1-yl}ethyl methanesulfonate.