Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)[NH2:2].[Cl:9][C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=1)[C:13]([CH:15]([C:21](=O)[CH3:22])[CH2:16][C:17]([O:19][CH3:20])=[O:18])=O>C(O)C>[Cl:9][C:10]1[CH:11]=[C:12]([C:13]2[N:1]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=3)[N:2]=[C:21]([CH3:22])[C:15]=2[CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:24]=[CH:25][CH:26]=1
Reactant: NNc1cccnc1
Reactant: COC(=O)CC(C(C)=O)C(=O)c1cccc(Cl)c1
Solvent: CCO
Product: COC(=O)Cc1c(C)nn(-c2cccnc2)c1-c1cccc(Cl)c1
Temperature: 130 °C
Reaction time: 1.5 h

Procedure:
0.577 g (4.233 mmol) of 3-hydrazinopyridine in 5.00 ml of ethanol was added to 0.650 g (2.419 mmol) of methyl 3-(3-chlorobenzoyl)-4-oxopentanoate, and the mixture was stirred in a closed vessel in a microwave oven at 130° C. for 1.5 h. The solvent was removed under reduced pressure, and the residue was taken up in dichloromethane and washed twice with in each case 25 ml of water. The combined organic phases were dried over sodium sulfate, and the solvent was removed under reduced pressure. Chromatography of the residue gave 0.364 g (42% of theory) of a light-yellow oil. 1H-NMR (CDCl3): see Table 2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([OH:21])=O)=[C:11]2[CH3:22])[CH3:9])=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC.[NH2:51][CH2:52][C:53]1[C:54]([OH:61])=[N:55][C:56]([CH3:60])=[CH:57][C:58]=1[CH3:59]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([NH:51][CH2:52][C:53]3[C:54]([OH:61])=[N:55][C:56]([CH3:60])=[CH:57][C:58]=3[CH3:59])=[O:21])=[C:11]2[CH3:22])[CH3:9])=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)O)c2ccccc2n1C(C)c1ccc(Cl)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2c(C)n(C(C)c3ccc(Cl)cc3)c3ccccc23)c(O)n1
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
To a solution of 1-(1-(4-chlorophenyl)ethyl)-2-methyl-1H-indole-3-carboxylic acid (200 mg, 0.64 mmol) in anhydrous DCM (5 mL) was added HOBt (130 mg, 0.96 mmol), EDCI (184 mg, 0.96 mmol) and Et3N (194 mg, 1.92 mmol) at room temperature under N2. The reaction was stirred for 30 min and then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (107 mg, 0.7 mmol) was added. The reaction was stirred at room temperature overnight. The mixture was diluted with water and adjusted to pH 7 and extracted with DCM. The crude product was purified by silica gel chromatography (Eluent: DCM:MeOH=30:1) to afford the title compound a yellow solid. (120 mg, yield 41.9%) 1H NMR (DMSO-d6, 400 MHz) δ 11.6 (s, 1H), 7.74-7.68 (m, 2H), 7.39 (dd, J1=2.0 Hz, J2=6.8 Hz, 2H), 7.16 (d, J=8.4 Hz, 2H), 7.06-6.93 (m, 3H), 5.92 (t, J=7.2 Hz, 2H), 4.33 (d, J=5.6 Hz, 2H), 2.59 (s, 3H), 2.26 (s, 3H), 2.11 (s, 3H), 1.87 (d, J=7.2 Hz, 3H); ESI-MS: m/z 447.8 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11](Br)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[Li]CCCC.[CH:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)=[O:26]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([CH:25]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[OH:26])[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: O=Cc1cccnc1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(C(O)c3cccnc3)cc3ccccc23)CC1
Temperature: 25 °C
Yield: 35.3 %

Procedure:
A solution of 1-(4-ethylpiperazin-1-yl)-3-bromoisoquinoline (0.39 g) obtained in Example 28-2, in tetrahydrofuran (10 ml) was cooled to −78° C., followed by the dropwise addition of 2.5M n-BuLi (0.6 ml). Fifteen minutes later, a solution of 3-formylpyridine (0.2 g) in tetrahydrofuran (3 ml) was added dropwise thereto. The temperature of the reaction solution was gradually raised to room temperature. The reaction solution was diluted with ethyl acetate, washed with brine, water and an aqueous solution of saturated sodium chloride, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give the title compound (0.15 g) as a pale yellow oil.
Reaction SMILES: [C:1](O[C@@H](C(N)(C)[C@H](O)C)C)(=[O:3])[CH3:2].[CH:13]([C:16]([N+:21]([O-])=O)([CH2:19][OH:20])[CH2:17][OH:18])([CH3:15])[CH3:14]>>[C:1]([O:18][CH2:17][C:16]([NH2:21])([CH:13]([CH3:15])[CH3:14])[CH2:19][OH:20])(=[O:3])[CH3:2]
Reactant: CC(C)C(CO)(CO)[N+](=O)[O-]
Reactant: CC(=O)O[C@H](C)C(C)(N)[C@@H](C)O
Product: CC(=O)OCC(N)(CO)C(C)C
Yield: 98 %

Procedure:
Using the procedure in 5D, 2-isopropyl-2-nitro-1,3-propanediol (11A) gave a 98% yield of 2-amino-2-isopropyl-1,3-propanediol acetate mp 155°-155.5°. H. S. Broadbent et al., J. Heterocyclic Chem., 13, 337 (1975) report the synthesis of this compound as the free base (mp 70°-72°)).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[C@H:19]([C:20]3[C:30]4=[C:31]5[C:26](=[CH:27][CH:28]=[CH:29]4)[CH2:25][CH2:24][CH2:23][N:22]5[CH:21]=3)[C:18](=[O:32])[NH:17][C:16]2=[O:33])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd]>[C:20]1([C@H:19]2[C@H:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[C:16](=[O:33])[NH:17][C:18]2=[O:32])[C:30]2=[C:31]3[C:26](=[CH:27][CH:28]=[CH:29]2)[CH2:25][CH2:24][CH2:23][N:22]3[CH:21]=1
Reactant: [H][H]
Reactant: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1ccc(O)cc1
Yield: 44.1 %

Procedure:
A mixture of (±)-trans-3-[4-(benzyloxy)phenyl]-4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)pyrrolidine-2,5-dione (0.2 g) and Pd/C (10% w/w, 0.076 g) was stirred under 1 atmosphere of hydrogen gas overnight. The catalyst was filtered off through a pad of celite and concentrated. The residue was purified by column chromatography on silica gel eluting with 30-40% ethyl acetate in hexane to provide (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(4-hydroxyphenyl)pyrrolidine-2,5-dione 0.07 g as a light yellow solid. Mp 105-107° C.; 1H NMR (acetone-d6) 400 MHz δ: 10.27 (s. 1 H), 8.34 (s, 1 H), 7.17-7.21 (m, 4 H), 6.80-6.91 (m, 4 H), 4.39 (d, J=7.0 Hz, 1 H), 4.22 (d, J=7.0 Hz, 1 H), 4.13 (d, J=5.6 Hz, 2 H), 2.92 (d, J=5.2 Hz, 2 H), 2.15-2.19 (m, 2 H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:16]=[CH:15][C:7](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.[CH3:17]COC(C)=O.CCCCCC>CS(C)=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C@@H:8]2[CH2:17][C@H:9]2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=1
Reactant: CCOC(=O)/C=C/c1ccc(Br)cc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(Br)cc1
Reaction time: 0.05 h
Yield: 46.7 %

Procedure:
To a vigorously stirring mixture of (CH3)3S(I)O (7.76 g, 35.3 mmol) in DMSO (75 mL) was added NaH (0.972 g, 36.5 mmol) in small portions over 5 min. Following complete addition, the reaction was left to stir for 10 min before the rapid dropwise addition of ethyl trans-4-bromocinnamate (2.21 mL, 11.8 mmol), which is commercially available from, for example, Sigma-Aldrich. After 3 h the reaction was partitioned between EtOAc (100 mL) and H2O (200 mL). The aq. phase washed with EtOAc (2×75 mL) wherein the combined organics were washed with H2O (2×50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting solid was absorbed onto Celite® and subjected to flash chromatography (SiO2—40 g; gradient elution: 5% EtOAc/Hexane isocratic for 3 min then 5-30% EtOAc/Hexane over 20 min at 40 mL/min to afford 1.48 g 13Ai as a white solid (46.7% yield). 1H NMR (500 MHz, CDCl3) δ 7.46-7.33 (m, 2H), 6.97 (d, J=8.6 Hz, 2H), 4.17 (q, J=7.2 Hz, 2H), 2.47 (ddd, J=9.2, 6.4, 4.3 Hz, 1H), 1.86 (ddd, J=8.5, 5.4, 4.2 Hz, 1H), 1.59 (dt, J=9.5, 4.8 Hz, 1H), 1.35-1.18 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[C:12]([CH:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)([CH3:15])([CH3:14])[CH3:13].N1CCCC1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:19]1([CH2:20][CH2:21][CH:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:17][CH2:18]1)[CH2:9][C:8]2=[O:10]
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)C1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Temperature: 60 °C
Yield: 73.8 %

Procedure:
To a 50 mL round bottom flask is added 1-(5-bromo-2-hydroxyphenyl)ethanone (2.0 g, 9.3 mmol), followed by 4-tert-butylcyclohexanone (1.43 g, 9.3 mmol). MeOH (20 mL) is added to give a clear solution, followed by pyrrolidine (1 mL). A condenser is attached to the RB flask, and the resulting solution is heated at 60° C. for two hours. MeOH is removed and the residue is redissolved in EtOAc (30 mL), washed with 1 N NaOH (10 mL), and 1 N HCl (10 mL), and dried over Na2SO4. Solvent is removed in vacuo to give 6-bromo-4′-t-butylspiro[chroman-2,1′-cyclohexan]-4-one (2.41 g, 74%), which is used for the next step without purification.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:6][C:5]=1[NH2:17].Cl.[CH:20](N)=[NH:21]>C(O)C>[Cl:16][CH2:15][CH2:14][CH2:13][O:12][C:7]1[CH:6]=[C:5]2[C:4]([C:3]([OH:2])=[N:21][CH:20]=[N:17]2)=[CH:9][C:8]=1[O:10][CH3:11]
Reactant: COC(=O)c1cc(OC)c(OCCCCl)cc1N
Reactant: N=CN
Agent: Cl
Solvent: CCO
Product: COc1cc2c(O)ncnc2cc1OCCCCl
Temperature: 140 °C
Yield: 56.2 %

Procedure:
To a solution of the intermediate from Step 3 (4.2 g, 15.35 mmol) in ethanol was added formamidine hydrochloride (2.97 g, 36.96 mmol). The mixture was heated at 140° C. in sealed tube for 12h. Completion of the reaction was monitored by LCMS. The precipitate formed was filtered and washed with ethanol and dried to afford the pure compound 7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-ol (2.32 g, 56%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 11.93 (brs, 1H), 7.99 (s, 1H), 7.45 (s, 1H), 7.16 (s, 1H), 4.23 (t, 2H), 3.88 (s, 3H), 3.80 (t, 2H), 2.23 (t, 2H), LC-MS (ESI)m/z 269 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[C:17]([NH2:19])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1>>[CH3:29][O:28][C:26](=[O:27])[C:25]1[CH:30]=[CH:31][C:22]([CH2:21][N:11]([C@@H:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[C:17](=[O:18])[NH2:19])[S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: NC(=O)[C@@H]1CCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Product: COC(=O)c1ccc(CN([C@@H]2CCC[C@@H]2C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 43 %

Procedure:
The titled compound (161 mg) was prepared in 43% yield from cis-2-(4-chlorobenzenesulfonylamino)-cyclopentanecarboxylic acid amide (250 mg, 0.83 mmol) and methyl 4-(bromomethyl)benzoate according to the N-alkylation procedure described in Example 11: 1H NMR (DMSO-d6) δ 7.82 (d, 2 H, J=8.0 Hz), 7.75 (d, 2 H, J=8.0 Hz), 7.58 (d, 2 H, J=8.0 Hz), 7.33 (d, 2 H, J=8.0 Hz), 7.02 (s br, 1 H), 6.75 (s br, 1 H), 4.67 (AB2,2 H,Δv=20,Jab=24 Hz), 4.33 (m, 1 H), 3.84 (s, 3 H), 2.84 (m, 1 H), 1.73 (m, 4 H), 1.48 (m, 2 H); MS m/e 451.01 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:22]([C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27])#[CH:23]>C(O)C>[CH3:16][O:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[C:11]2[C:2]([NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[C:24]([C:22]#[CH:23])[CH:25]=3)=[N:3][CH:4]=[N:5][C:6]2=[CH:7][C:8]=1[O:17][CH2:18][CH2:19][O:20][CH3:21].[ClH:1]
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Reactant: C#Cc1cccc(N)c1
Solvent: CCO
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Product: Cl
Temperature: 27.5 °C
Yield: 101.8 %

Procedure:
4-Chloro-6,7-bis-(2-methoxyethoxy)-quinazoline (2.5 gm) and ethanol (40 ml) are added to 3-ethynylaniline (1.25 gm) at 25-30° C. under stirring, the contents are heated to reflux and then refluxed for 1 hour 30 minutes to 2 hours. The reaction mass is cooled to 25-30° C. and stirred for 30 minutes. Filtered the material, washed with chilled isopropyl alcohol (20 ml) followed by n-hexane (20 ml) and then dried the material at 50-55° C. under vacuum to give 3.5 gm of crude erlotinib hydrochloride in polymorph form B [HPLC purity: 99.1%; Mean particle size (D50): 2.30 μm and 90 volume-% of the particles (D90): 7.74 μm].
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1([C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH3:23]O>>[CH:5]1([C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CO
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Temperature: 25 °C
Yield: 69 %

Procedure:
Thionyl chloride (1 mL) was added to a stirred mixture of 3-cyclohexyl-1H-indole-6-carboxylic acid (30.4 g, 0.125 mol) in methanol (300 mL). The mixture was stirred at reflux for 18 hours, treated with decolorizing carbon, and filtered. The filtrate was concentrated to about 150 mL at which point crystallization occurred. The filtrate was cooled to room temperature and filtered. The solid was washed with cold methanol followed by diethyl ether to provide the desired product as a pale purple solid (22.2 g, 69% yield). ESI-MS m/z 258 (MH+); 1H NMR (300 MHz, CDCl3.) δ 1.35 (m, 4H), 1.63 (s, 1H), 1.78 (m, 3H), 2.06 (d, J=8.05 Hz, 2H, 3.90 (m, 1H), 7.08 (d, J=1.83 Hz, 1H), 7.62 (s, 1H), 7.65 (s, 1H), 7.74 (d, J=1.46 Hz, 1H), 7.77 (d, J=1.46 Hz, 1H), 8.08 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:8]=[CH:9][CH:10]=[CH2:11]>>[CH2:1]([C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH2:8][CH:9]=[CH:10][CH3:11]
Reactant: Cc1ccncc1
Reactant: C=CC=C
Product: CC=CCCc1ccncc1
Temperature: 140 °C
Yield: 83 %

Procedure:
220 g of 4-methylpyridine and 1.0 g of solid base G were fed into a 1000 ml autoclave equipped with an electromagnetic stirrer under an atmosphere of nitrogen, and then heated to 140° C. with stirring at 700 r.p.m. Subsequently, 16.5 g of butadiene was added to the mixture in 1 hour. After the reaction, the autoclave was cooled and the catalyst was removed by filtration. The reaction solution was analyzed by gas chromatography. 4-(3-pentenyl)pyridine was obtained in a 83% yield based on 4-methypyridine consumed.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]([CH2:21]Cl)[CH:18]=[CH:17][C:3]=1[O:4][CH2:5][C:6]1[N:7]=[C:8]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[O:9][C:10]=1[CH3:11].[CH2:23]([N:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:32]([OH:40])=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([N:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:32]([O:40][CH2:21][C:19]2[CH:18]=[CH:17][C:3]([O:4][CH2:5][C:6]3[N:7]=[C:8]([C:12]4[O:13][CH:14]=[CH:15][CH:16]=4)[O:9][C:10]=3[CH3:11])=[C:2]([Br:1])[CH:20]=2)=[N:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(Br)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
A mixture of 4-{[2-bromo-4-(chloromethyl)phenoxy]methyl}-2-(2-furyl)-5-methyl-1,3-oxazole (3.52 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (2.27 g), potassium carbonate (1.27 g) and N,N-dimethylformamide (100 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give ethyl 1-benzyl-3-[(3-bromo-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate as colorless crystals (5.17 g, yield 95%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 158-159° C.
Reaction SMILES: O[C:2]1([C:12]#[N:13])[CH2:11][CH2:10][C:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][CH2:3]1.N1C=CC=CC=1.S(Cl)(Cl)=O.Cl>O1CCCC1>[CH2:9]1[C:5]2([CH2:10][CH2:11][C:2]([C:12]#[N:13])=[CH:3][CH2:4]2)[CH2:6][CH2:7][CH2:8]1
Reactant: N#CC1(O)CCC2(CCCC2)CC1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: N#CC1=CCC2(CCCC2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.8 %

Procedure:
To a solution of 8-hydroxy-spiro[4.5]decane-8-carbonitrile (3.9 g) obtained in Step 1 in tetrahydrofuran (30 mL) were added successively pyridine (4.4 mL) and thionyl chloride (1.8 mL), followed by stirring the reaction mixture at room temperature for 15 hours. Then, after addition of 1N aqueous hydrochloric acid solution, the reaction mixture was extracted with diethyl ether. The organic layer was washed successively with 1N aqueous hydrochloric acid solution and saturated brine, dried and concentrated to give spiro[4.5]dec-7-ene-8-carbonitrile (2.8 g).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C:8]2[C:9]([CH3:15])=[CH:10][CH:11]=[C:12]([O:13]C)[C:7]=2[CH2:6][C@@H:5]([CH2:16][NH2:17])[O:4]1.B(Br)(Br)[Br:19]>>[BrH:19].[BrH:19].[NH2:1][CH2:2][C@H:3]1[C:8]2[C:9]([CH3:15])=[CH:10][CH:11]=[C:12]([OH:13])[C:7]=2[CH2:6][C@@H:5]([CH2:16][NH2:17])[O:4]1
Reactant: BrB(Br)Br
Reactant: COc1ccc(C)c2c1C[C@@H](CN)O[C@H]2CN
Product: Br
Product: Cc1ccc(O)c2c1[C@H](CN)O[C@H](CN)C2

Procedure:
[1R,3S] 1,3-Bis(aminomethyl)-3,4-dihydro-5-methoxy-1H-2-benzopyran from Step 6 is treated with an excess of boron tribromide as described in Step 6 of Example 145 to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:13][CH:12]2[N:14](CC3C=CC=CC=3)[CH:8]([CH2:9][C:10](=[O:22])[CH2:11]2)[CH2:7]1)=[O:5])[CH3:2].[H][H]>CO.[OH-].[Pd+2].[OH-]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:13][CH:12]2[NH:14][CH:8]([CH2:9][C:10](=[O:22])[CH2:11]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC2CC(=O)CC(C1)N2Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)C1CC2CC(=O)CC(C1)N2
Reaction time: 12 h
Yield: 100.5 %

Procedure:
9-Benzyl-7-oxo-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid ethyl ester (11.1 g, 36.8 mmol) was dissolved in methanol (30 mL) and added to a suspension of palladium hydroxide (1 g) in methanol (10 mL) in a Parr bottle. The Parr bottle was filled with hydrogen (30 psi) and evacuated three times. The Parr bottle was refilled with hydrogen (30 psi) and shook for 12 h. The suspension was filtered through Celite and concentrated under vacuum to give 7.81 g (quantitative yield) of 7-oxo-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid ethyl ester as a yellow oil. Retention time (min)=0.369, method [1], MS (ESI) 212.1 (M+H).
Reaction SMILES: Br[C:2]1[N:3]([CH:18]([CH3:20])[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[C:32]([OH:36])(=[O:35])[CH:33]=[CH2:34]>O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]([CH:18]([CH3:20])[CH3:19])[C:2]=2/[CH:34]=[CH:33]/[C:32]([OH:36])=[O:35])=[CH:12][CH:13]=1
Reactant: C=CC(=O)O
Reactant: CC(C)n1c(Br)c(-c2ccc(F)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1c(/C=C/C(=O)O)c(-c2ccc(F)cc2)c2ccccc21
Reaction time: 0.5 h

Procedure:
2 g (6.02 mmol) of 2-bromo-3-(4-fluorophenyl)-1-isopropyl-1H-indole, 10 ml of DMF and 0.5 ml of water are introduced into a 50 ml three-necked, round-bottomed flask, which has been purged with nitrogen and is equipped with a magnetic stirrer, thermometer, reflux condenser, gas inlet tube and nitrogen delivery line, and degassing is carried out for 30 min. by introducing nitrogen. 24 mg (1.0 mol %) of the catalyst K4 from WO-A-99/47474 and 2.15 g (6.6 mmol) of caesium carbonate are then added and degassing is carried out for a further 1 hour. 1.0 g (13.8 mmol) of acrylic acid are subsequently added and the suspension is heated at reflux for 2 hours. The DMF is then distilled off, the residue is cooled, 10 ml of 1N hydrochloric acid are added and the aqueous phase is extracted three times with 50 ml of ethyl acetate. The combined organic phases are washed three times with 30 ml of saturated sodium carbonate solution, slightly acidified again using 1N hydrochloric acid, and washed three times with 50 ml of saturated sodium chloride solution in order to render neutral. Drying over magnesium sulfate, filtration and concentration by evaporation are then carried out. The residue (1.83 g) is dissolved in THF, 5 g of silica gel are added and the solution is concentrated by evaporation using a rotary evaporator. The charged silica gel is transferred into a glass frit, and non-polar secondary products are eluted using hexane/ethyl acetate=10:1 and then the product is eluted using ethyl acetate. Concentration by evaporation yields a yellow solid which, according to NMR, is the desired product in pure form.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[NH:4][N:3]=1.[C:13](/[CH:15]=[C:16](\[O-:18])/[CH3:17])#[N:14].[Na+].C(O)(=O)C.N1CCCCC1>ClCCl>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:11]=[C:15](/[C:16](=[O:18])[CH3:17])\[C:13]#[N:14])[CH:9]=2)[NH:4][N:3]=1
Reactant: C/C([O-])=C/C#N
Reactant: Cc1n[nH]c2ccc(C=O)cc12
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)/C(C#N)=C/c1ccc2[nH]nc(C)c2c1
Yield: 49.8 %

Procedure:
A mixture of 5.0 g (31.2 mmol) 3-methyl-1H-indazole-5-carbaldehyde (Example 1A), 3.61 g (34.3 mmol) sodium (1Z)-1-cyanoprop-1-en-2-olate, 2.23 ml (39 mmol) acetic acid and 0.31 ml (3.12 mmol) piperidine in dry dichloromethane (250 ml) containing 4 Å molecular sieve was stirred under reflux for 12 h. Upon cooling, a precipitate was formed which was collected by filtration and washed with saturated aqueous sodium bicarbonate solution and water. The solid was dissolved in ethanol, and the molecular sieve was filtered off. The filtrate was concentrated under reduced pressure, and the residue was treated with ethyl acetate and saturated aqueous sodium carbonate solution. The organic layer was washed with water, dried, and concentrated under reduced pressure to afford the title compound (3.5 g, 50% of th.) as a pale yellow solid which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:6]=1[C:7](OC)=[O:8])[CH:2]=[CH2:3].C([CH:18]([C:22](Cl)=[O:23])[C:19](Cl)=[O:20])C.[CH2:25]([O:27]CC)[CH3:26]>>[CH2:25]([O:27][C:22]([C:18]1[C:19](=[O:20])[N:4]([CH2:1][CH:2]=[CH2:3])[C:5]2[C:6]([C:7]=1[OH:8])=[CH:11][CH:12]=[C:13]([CH3:15])[N:14]=2)=[O:23])[CH3:26]
Reactant: C=CCNc1nc(C)ccc1C(=O)OC
Reactant: CCC(C(=O)Cl)C(=O)Cl
Reactant: CCOCC
Product: C=CCn1c(=O)c(C(=O)OCC)c(O)c2ccc(C)nc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2.88 g. (0.015 mole) of 2-allylamino-6-methylnicotinic acid, methyl ester in 50 ml. of anhydrous diethyl ether was added 1.12 g. (0.0075 mole) of ethyl malonyl chloride. The mixture was stirred at room temperature for 4 hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was dissolved in 5 ml. of ethanol and this solution was added to a solution of 0.23 g. (0.01 g. atoms) of sodium in 20 ml. of ethanol. The mixture was stirred at room temperature for 5 minutes. The mixture was diluted with water and was acidified with glacial acetic acid. The mixture was extracted with diethyl ether and the ether layer was dried over magnesium sulfate, filtered and was acidified with an etheral hydrochloric acid solution. The mixture was filtered and the filtrate was evaporated. The residue was recrystallized from heptane to give 10 mg. of the title compound, m.p. 110°-112° C.