Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]([C:9](=O)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC(=O)c1cccc(OC)c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cccc(OC)c1C
Temperature: 60 °C
Yield: 83.8 %

Procedure:
To a solution ethyl 3-(3-methoxy-2-methylphenyl)-3-oxopropanoate (137.2 g, 595 mmol, from Step A) in ethyl alcohol (924 mL), 10% Pd—C (13.7 g) was added and 3 atm of hydrogen were applied. The mixture was heated to 60° C. for 20 hr, cooled to ambient temperature and filtered through Celite®. The filtrate was concentrated in vacuo and the residue purified by flash chromatography (2% EtOAc/hexanes) on SiO2 to afford 110.8 g of the title compound as a pale yellow liquid: 1H NMR (500 MHZ, CDCl3) δ 1.25 (t, 3H, J=7.1 Hz), 2.19 (s, 3H), 2.55 (t, 2H, J=8.0 Hz), 2.95 (t, 2H, J=8.0 Hz), 3.82 (s, 3H), 4.14 (q, 2H, J=7.1 Hz), 6.73 (d, 1H, J=8.2 Hz), 6.78 (d, 1H, J=7.6 Hz), 7.10 (d, 1H, J=7.9 Hz).
Reaction SMILES: ClC1C=CC(O[C:7]2[CH:31]=[CH:30][C:10]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:19]=[C:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]=4)[CH2:14][CH2:13]3)=[CH:9][CH:8]=2)=CC=1.[CH2:34]([N:36]1C2C=CC(CN3CCC(C4C=CC(NC(=O)C(C)C)=CC=4)CC3)=CC=2[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH3:35].C(N1C2C=CC(C=O)=CC=2C2C1=CC=CC=2)C.CC(C)C(NC1C=CC=C(C2CCNCC2)C=1)=O>>[CH2:34]([N:36]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:19]=[C:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]=4)[CH2:14][CH2:13]3)=[CH:30][C:31]=2[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH3:35]
Reactant: CCn1c2ccccc2c2cc(CN3CCC(c4ccc(NC(=O)C(C)C)cc4)CC3)ccc21
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(Oc4ccc(Cl)cc4)cc3)CC2)c1
Agent: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: CCn1c2ccccc2c2cc(C=O)ccc21
Product: CCn1c2ccccc2c2cc(CN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)ccc21
Yield: 95 %

Procedure:
According to the procedure used for the synthesis of N-(3-{1-[4-(4-CHLOROPHENOXY)BENZYL]-4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE (Example 108) N-(4-{1-[(9-ethyl-9H-carbazol-3-yl)methyl]-4-piperidinyl}phenyl)-2-methylpropanamide, 9-ethyl-9H-carbazole-3-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide afforded N-(3-{1-[(9-ethyl-9H-carbazol-3-yl)methyl]-4-piperidinyl}phenyl)-2-methylpropanamide (37 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 8.24–6.29 (m, 12H), 4.37 (q, 2H, J=7.2 Hz), 3.82 (s, 2H), 3.23–3.06 (m, 2H), 2.65–2.38 (m, 2H), 2.31–2.11 (m, 2H), 2.01–1.73 (m, 4H), 1.43 (t, 3H, J=7.2 Hz), 1.25 (d, 6H, J=4.0 Hz); ESMS m/e: 454.3 (M+H)+.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]2[CH2:21][C@@:11]3([C:19]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:12]3=[O:20])[CH2:10][C:7]2=[N:8][CH:9]=1.[CH3:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][O:26][CH2:27]Cl>CN(C=O)C>[I:3][C:4]1[CH:5]=[C:6]2[CH2:21][C:11]3([C:19]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:30])([CH3:29])[CH3:22])[C:12]3=[O:20])[CH2:10][C:7]2=[N:8][CH:9]=1
Reactant: O=C1Nc2ncccc2[C@@]12Cc1cc(I)cnc1C2
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3cc(I)cnc3C2)c2cccnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.242 g, 6.06 mmol) was added portionwise to a solution of (6S)-3-iodo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (described in Intermediate 4) (2.00 g, 5.51 mmol) in DMF (50 mL) at 0° C. After stirring for 10 min, 2-(trimethylsilyl)ethoxymethyl chloride (1.01 g, 6.06 mmol) was added dropwise. The resulting mixture was warmed slowly to ambient temperature and stirred for 48 h. The reaction was partitioned between water (20 mL) and EtOAc (100 mL). The organic layer was removed and the aqueous phase was extracted further with EtOAc (30 mL). The combined organic extracts were washed with brine, then dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—95:5 to 50:50, to give the title compound. MS: m/z=493.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[H-].[Na+].[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18]>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20]
Reactant: Clc1ccccc1CBr
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccccc1Cl
Yield: 75.1 %

Procedure:
Using 0.21 g of 2-chlorobenzyl bromide, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.22 g of 2-(2-chlorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (81)).
Reaction SMILES: [OH-].[K+].[C:3]1([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[CH:18]=[C:19]([C:21]([O:23]C)=[O:22])[S:20][C:10]2=3)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[C:3]1([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[CH:18]=[C:19]([C:21]([OH:23])=[O:22])[S:20][C:10]2=3)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cc2c3ccccc3n(-c3ccccc3)c2s1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1cc2c3ccccc3n(-c3ccccc3)c2s1
Yield: 94.3 %

Procedure:
Prepared from KOH (0.51 g), (51) (0.70 g) after reflux overnight yielding (58) 0.63 g (94%). M.p. 206°-207° C.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(N1CC[C@@H](N)C1)(OC(C)(C)C)=O.Br[C:19]1[CH:20]=[CH:21][C:22]([CH2:25][N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]3([C:46]4[C:37](=[CH:38][C:39]5[O:44][CH2:43][CH2:42][O:41][C:40]=5[CH:45]=4)[O:36][CH2:35]3)[C:27]2=[O:47])=[N:23][CH:24]=1.BrC1C=CC(CN2C3C(=CC=CC=3)C3(C4C=C(F)C(F)=CC=4OC3)C2=O)=CC=1>>[CH3:2][N:3]([CH3:4])[C:19]1[CH:20]=[CH:21][C:22]([CH2:25][N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]3([C:46]4[C:37](=[CH:38][C:39]5[O:44][CH2:43][CH2:42][O:41][C:40]=5[CH:45]=4)[O:36][CH2:35]3)[C:27]2=[O:47])=[N:23][CH:24]=1
Reactant: CNC
Reactant: O=C1N(Cc2ccc(Br)cn2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: Cl
Agent: O=C1N(Cc2ccc(Br)cc2)c2ccccc2C12COc1cc(F)c(F)cc12
Product: CN(C)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)nc1

Procedure:
Following the procedure as described in EXAMPLE 33.1 and making non-critical variations using dimethylamine hydrochloride to replace (R)-(+)-1-Boc-3-aminopyrrolidine, and 1′-[(5-bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 1′-(4-bromobenzyl)-5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 1′-{[5-(dimethylamino)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (23%) as a beige solid: mp 229-236° C.; 1H NMR (300 MHz, CDCl3) δ8.06 (d, J=2.7 Hz, 1H), 7.22-6.92 (m, 6H), 6.50 (s, 1H), 6.27 (s, 1H), 5.11 (d, J=15.3 Hz, 1H), 4.94 (d, J=9.0 Hz, 1H), 4.87 (d, J=15.3 Hz, 1H), 4.65 (d, J=8.7 Hz, 1H), 4.21-4.11 (m, 4H), 2.96 (s, 6H); 13C NMR (75 MHz, CDCl3) δ177.4, 155.3, 145.5, 144.5, 142.8, 142.4, 138.3, 134.1, 132.3, 128.8, 123.6, 123.2, 122.0, 121.2, 119.8, 111.7, 109.9, 99.3, 80.2, 64.5, 63.9, 58.1, 45.7, 40.1; MS (ES+) m/z 430.1 (M+1).
Reaction SMILES: CN(C)C=O.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[NH:30][C:31](=[O:41])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[Cl:40].[CH2:42](I)[CH3:43]>O>[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[N:30]([CH2:42][CH3:43])[C:31](=[O:41])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[Cl:40]
Reactant: CCI
Reactant: COc1cc2ncnc(Oc3ccc(NC(=O)OCc4ccccc4Cl)c(Cl)c3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)OCc1ccccc1Cl)c1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.1 %

Procedure:
Dimethylformamide (5 ml) was added to sodium hydride (11 mg), and 2-chlorobenzyl N-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}carbamate (65 mg) was added to the mixture. Subsequently, a dimethylformamide solution (2 ml) of ethyl iodide (84 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. Water was added to stop the reaction, and the reaction solution was then extracted with ethyl acetate, followed by washing with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (68 mg, yield 100%).
Reaction SMILES: NC1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(O)CO.[OH-].[K+].C1(C)C=CC=CC=1>C(O)(=O)C>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([SH:3])[CH:10]=1
Reactant: COc1ccc2nc(N)sc2c1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc(N)c(S)c1
Temperature: 25 °C
Yield: 86 %

Procedure:
A mixture of 2-amino-6-methoxybenzothiazole (15 g, 83.2 mmol), ethylene glycol (20.23 g, 0.33 mol) and 50% w/v KOH (100 ml) was heated under reflux for 24 h. On cooling to room temperature, toluene (60 ml) was added and the reaction mixture was cooled in an ice-bath and acidified with acetic acid (final pH 5-6). The reaction mixture was extracted with toluene (5×300 ml) and the combined organic extracts were washed with brine (2×200 ml), dried (MgSO4) and the solvent removed under reduced pressure to give the title compound (11.1 g, 86%) as a yellow solid which was used without further purification.
Reaction SMILES: CO[C:3]1[C:4](=[O:22])[C:5]([N:10]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH3:11])=[CH:6][CH:7]=[CH:8][CH:9]=1.[NH3:23]>CO>[NH2:23][C:3]1[C:4](=[O:22])[C:5]([N:10]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH3:11])=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccccc(N(C)S(=O)(=O)c2ccc(C)cc2)c1=O
Reactant: N
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N(C)c2ccccc(N)c2=O)cc1
Temperature: 80 °C

Procedure:
A solution at -25° C of 2-methoxy-7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatrien-1-one (described above, 4.0 g) in methanol (40 ml) is saturated with ammonia gas and heated in a pressure bottle at 80° C for 4 hours. The solution is cooled to -70° C, the bottle is opened and the solvent is evaporated to yield 2-amino-7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatrien-1-one, mp 221°-222° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:52]([CH3:53])=[CH:51][C:39]([O:40][CH2:41][CH2:42][NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:38][C:37]=1[CH3:54].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[C:46]([O:45][C:44]([NH:43][CH2:42][CH2:41][O:40][C:39]1[CH:38]=[C:37]([CH3:54])[C:36]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:10]3[C:6]=2[CH2:7][CH2:8][C@H:9]3[O:11][C:12]2[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=2)=[C:52]([CH3:53])[CH:51]=1)=[O:50])([CH3:49])([CH3:48])[CH3:47]
Reactant: Cc1cc(OCCNC(=O)OC(C)(C)C)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCCNC(=O)OC(C)(C)C)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and tert-butyl 2-(4-bromo-3,5-dimethylphenoxy)ethylcarbamate following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.92 min; Mass spectrum (ESI+): m/z=606 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14](F)=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][S-:23].[Na+].Cl>CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:23][CH3:22])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[S-]
Reactant: O=C(O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Yield: 82.4 %

Procedure:
A solution of 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid (prepared as in Example 87A, 1.52 g, 5.0 mmol) in N,N-dimethylformamide (10 mL) was treated with sodium methanethiolate (593 mg, 7.5 mmol). The reaction mixture was then heated to 100–110° C. for 14 h. At this time, the reaction was cooled to 25° C. and poured onto a 1N aqueous hydrochloric acid solution (25 mL) and extracted into ethyl acetate (3×25 mL) and diethyl ether (1×25 mL). The combined organic layers were then washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (3×75 mL), dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionic acid (1.37 g, 82.4%) as a pale yellow oil: EI-HRMS m/e calcd for C16H19F3O2S (M+) 332.1058, found 332.1057.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH2:11][CH2:12][NH:13][CH2:14][CH:15]=1.C(N(CC)CC)C.Cl[C:24]([O:26][CH3:27])=[O:25]>C(Cl)Cl>[F:1][C:2]1[C:7]([S:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH2:15][CH2:14][N:13]([C:24]([O:26][CH3:27])=[O:25])[CH2:12][CH:11]=1
Reactant: CSc1cccc(C2=CCNCC2)c1F
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CC=C(c2cccc(SC)c2F)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
To a solution of 4-[2-fluoro-3-(methylthio)phenyl]-1,2,3,6-tetrahydropyridine (1.35 g, 6.05 mmol) and triethyl amine (1.2 ml, 7.2 mmol) in methylen chloride (20 ml) at 0° C., a solution of methyl chloroformate (0.49 g, 6.6 mmol) in methylen chloride (5 ml), was added dropwise. The mixture was stirred for 15 min at 0° C. and for 1 h at ambient temperature. The reaction was quenched with aqueous sodium carbonate (10%, 50 ml), the phases were separated and the aqueous phase was extracted with methylen chloride (3×50 ml). The combined organic phases was dried (MgSO4), filtered and evaporated to dryness to give the title compound (0.95 g). MS m/z (rel. intensity, 70 eV) 281 (M+, 65), 267 (16), 266 (bp), 147 (27), 146 (25).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=4)[N:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Reactant: COc1cc(N)ccc1F
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(F)c(OC)c3)n2)cc1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 164 using 4-fluoro-3-methoxyaniline (Combi-Blocks Inc.) and 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine, and isolated as a brown solid (100%). 1H NMR (400 MHz, d6-DMSO) δ 11.91 (br. s., 1H); 8.80 (br. s., 1H); 8.35 (br. s., 1H); 7.55 (br. s., 1H); 7.24 (br. s., 4H); 7.11 (d, J=1.2 Hz, 1H); 6.77-6.94 (m, 6H); 4.79 (br. s., 4H); 3.77 (br. s., 3H); 3.72 (d, J=10.6 Hz, 6H); 2.56 (br. s., 3H). m/z (ESI, +ve ion) 567.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([O:8]N=C(C1C=CC=CC=1)C#N)=O)([CH3:4])([CH3:3])[CH3:2].Cl.[F:20][CH2:21][CH:22]([NH2:26])[CH2:23][CH:24]=[CH2:25].C(N(CC)CC)C.O>O1CCCC1>[F:20][CH2:21][CH:22]([NH:26][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:8])[CH2:23][CH:24]=[CH2:25]
Reactant: C=CCC(N)CF
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCC(CF)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
Tert-Butoxycarbonyloxyimino-2-phenylacetonitrile (3.34 g, 13.6 mmoles) in dry tetrahydrofuran (40 ml) is slowly added with ice cooling to a stirred mixture of 1-fluoro-2-amino-4pentene hydrochloride (1.9 g, 13.6 mmoles) prepared in Example 2 and triethylamine (2.78 g, 27.2 mmoles) in tetrahydrofuran (30 ml). After standing overnight (about 16 hours) at room temperature, water is added, the tetrahydrofuran is removed under reduced pressure, and the residue is extracted twice with ether. After washing with 1 N sodium hydroxide, then with water until neutral, the organic layer is dried and concentrated at reduced pressure to give 1-fluoro-2-tert-butoxycarbonylamino-4-pentene (2.33 g, 85%) as an oil which is used in Example 4 without further purification.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[CH:5]=[CH:4][CH:3]=1.[CH2:10]([N:14]1[N:18]=[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]2=[N:15]1)[CH2:11][C:12]#[CH:13]>>[N:15]1[N:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]2[N:7]=[C:6]([NH:8][CH3:9])[CH:5]=[CH:4][CH:3]=2)[N:18]=[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=12
Reactant: C#CCCn1nc2ccccc2n1
Reactant: CNc1cccc(Br)n1
Product: CNc1cccc(C#CCCn2nc3ccccc3n2)n1
Yield: 14.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from (6-bromo-pyridin-2-yl)-methyl-amine (105 mg, 0.56 mmol) and 2-but-3-ynyl-2H-benzo[d][1,2,3]triazole (96 mg, 0.56 mmol, Example 109(D)). Reaction time: 3 hours. The crude residue was purified by C18 flash chromatography (water to water/acetonitrile 3:2) to yield 22 mg (80 μmol, 14%) of 6-(4-(2H-benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)-N-methylpyridin-2-amine as a white solid (M.P.=150-154° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[C:8]=2[CH3:16])=[N:3]1.[H][H]>O1CCCC1.[Pd]>[CH3:1][C:2]1([CH3:17])[CH2:6][O:5][C:4]([C:7]2[C:8]([CH3:16])=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=2)=[N:3]1
Reactant: [H][H]
Reactant: Cc1c(C2=NC(C)(C)CO2)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1c(N)cccc1C1=NC(C)(C)CO1
Yield: 95 %

Procedure:
To 29.82 g of 4,5-dihydro-4,4-dimethyl-2-(2-methyl-3-nitrophenyl)oxazole in 500 ml of tetrahydrofuran is added 0.5 g of 10% palladium on barium sulfate. The mixture is exposed to hydrogen gas until the appropriate quantity of hydrogen is taken up, filtered and the solvent evaporated to give 24.7 g of 3-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-2-methylbenzenamine as a gum which crystallizes on cooling; mp 45° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:12]([C:13]([O:15]CC)=[O:14])=[C:11]([OH:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1>CCOCC>[F:20][C:2]([F:1])([F:19])[C:3]1[C:12]([C:13]([OH:15])=[O:14])=[C:11]([OH:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc2ccccc2c1O
Solvent: CCOCC
Product: O=C(O)c1c(C(F)(F)F)nc2ccccc2c1O
Yield: 97.2 %

Procedure:
Using the procedure of Step E of Example 8, 30 g of the product of Step D were reacted to obtain without ether purification 26.3 g of 2-trifluoromethyl-4-hydroxy-3-quinoline-carboxylic acid melting at 262° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[C:7]([NH2:9])=[S:8])[CH3:2].[CH2:16]([O:18][C:19]([C:21]1[C:26]([OH:27])=[CH:25][CH:24]=[C:23]([C:28](=O)[CH2:29]Br)[N:22]=1)=[O:20])[CH3:17]>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7]2[S:8][CH:29]=[C:28]([C:23]3[CH:24]=[CH:25][C:26]([OH:27])=[C:21]([C:19]([O:18][CH2:16][CH3:17])=[O:20])[N:22]=3)[N:9]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH3:2]
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Reactant: CCOC(=O)c1nc(C(=O)CBr)ccc1O
Solvent: CCO
Product: CCOC(=O)c1nc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)ccc1O
Yield: 56 %

Procedure:
0.7 g of 3,4-diethoxythiobenzamide and 20 ml of ethanol were added to 0.77 g of 2-ethoxycarbonyl-3-hydroxy-6-(2-bromoacetyl)pyridine. The mixture was refluxed for 3 hours. Ethanol was removed by distillation. To the residue was added ethyl acetate-dichloromethane to give rise to crystallization to obtain 0.62 g of 2-(3,4-diethoxyphenyl)-4-(5-hydroxy-6-ethoxycarbonyl-2-pyridyl)thiazole.
Reaction SMILES: [CH3:1][C:2]([Mg]Cl)([CH3:7])[CH2:3][CH2:4][CH2:5][CH3:6].ClC(C)(C)CCCC.[Cl:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23].Cl>CCOCC>[Cl:18][CH2:19][CH2:20][CH2:21][C:22](=[O:23])[C:2]([CH3:7])([CH3:1])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(Cl)CCCCl
Reactant: CCCCC(C)(C)[Mg]Cl
Agent: CCCCC(C)(C)Cl
Agent: Cl
Solvent: CCOCC
Product: CCCCC(C)(C)C(=O)CCCCl
Reaction time: 12 h

Procedure:
Four hundred ml. of a solution in ether of 1,1-dimethylpentylmagnesium chloride prepared from mangesium (24.3 g., 1.0 mole) and 1-chloro-1,1-dimethylpentane (134.5 g., 1.0 mole) according to the procedure of Whitmore and Badertscher [J. AM. CHEM. SOC., 55, 1559 (1933)] is added dropwise with stirring to 4-chlorobutyryl chloride (197.4 g., 1.4 moles) in ether (400 ml.) during 6 hours. The reaction mixture is stirred for an additional 12 hours. It is then poured into a mixture of ice and dilute hydrochloric acid. The ether layer is separated, washed with water, and dried over sodium sulfate. The ether is evaporated and the residue distilled at aspirator vacuum through a Vigreaux column to yield the product as a colorless oil.
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]([O:16][C:17]([N:19]1[CH2:26][C@H:25]([OH:27])[CH2:24][C@H:20]1[C:21]([OH:23])=O)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN1CCOCC1.[CH3:35][C:36]1[C:41]([C:42]([OH:44])=[O:43])=[C:40]([NH:45][C:46](=[O:52])[C@H:47]([CH:49]([CH3:51])[CH3:50])[NH2:48])[CH:39]=[CH:38][CH:37]=1.C(OC(N1CCC[C@H]1C(N[C@@H](C(NC1C=CC=C(C)C=1C(O)=O)=O)C(C)C)=O)=O)C1C=CC=CC=1>CN(C)C=O.O1CCCC1>[CH2:9]([O:16][C:17]([N:19]1[CH2:26][C@H:25]([OH:27])[CH2:24][C@H:20]1[C:21]([NH:48][C@H:47]([C:46]([NH:45][C:40]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:35])[C:41]=1[C:42]([OH:44])=[O:43])=[O:52])[CH:49]([CH3:51])[CH3:50])=[O:23])=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccc(NC(=O)[C@@H](N)C(C)C)c1C(=O)O
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cc1cccc(NC(=O)[C@H](NC(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)C(C)C)c1C(=O)O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)[C@@H](NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccccc2)C(C)C)c1C(=O)O
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
Isobutyl chloroformate (0.23 ml) was added to a tetrahydrofuran solution (3.5 ml) containing N-benzyloxycarbonyl-trans-4-hydroxy-L-proline (463 mg) and N-methylmorpholine (0.19 ml) at -15° C., and the mixture was stirred for 0.5 hour. An N,N-dimethylformamide solution (2.5 ml) containing 6-methyl-2-(L-valylamino)benzoic acid (291 mg) and N-methylmorpholine (0.15 ml) was added dropwise to the above mixture at -15° C., and the resultant mixture was stirred at -15° C. for 0.5 hour and then at room temperature for two hours. The reaction mixture was treated by the same procedures as in item (c) of Example 1 to obtain 2-[(N-benzyloxycarbonyl-trans-4-hydroxy-L-prolyl)-L-valyl]amino-6-methylbenzoic acid (570 mg).