Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:14]=[CH:15][CH:16]=3)[C:11]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.ClS([N:36]=[C:37]=[O:38])(=O)=O>ClCCl>[CH2:25]([NH:24][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:37]([NH2:36])=[O:38])[CH:7]=[N:6][CH:5]=2)=[N:9][N:10]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1cncc(-c2nnc(NCc3ccccc3)c3c(-c4ccccc4)cccc23)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Product: NC(=O)Nc1cncc(-c2nnc(NCc3ccccc3)c3c(-c4ccccc4)cccc23)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3 %

Procedure:
To a solution of 4-(5-aminopyridin-3-yl)-N-benzyl-8-phenylphthalazin-1-amine (60.0 mg, 0.149 mmol) in dichloromethane (10 mL) was added chlorosulfonyl isocyanate (0.0191 mL, 0.223 mmol) dropwise at 0° C. and the reaction mixture allowed to stir for 2 h while warming to ambient temperature. The volatile components were evaporated under reduced pressure and the resulting residue was cooled to 0° C. 1.5N HCl was added and the reaction mixture stirred for an additional 2 h. The reaction mixture was adjusted to pH˜8 by the addition of aqueous sodium bicarbonate. The resulting solution was extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Condition 30 as described in general methods) to afford 1-(5-(4-(benzylamino)-5-phenylphthalazin-1-yl)pyridin-3-yl)urea (2.00 mg, 3.01%) as a white solid. LCMS (Condition 4): retention time 2.32 min, [M+1]=447.2. HPLC (Condition 28): retention time=6.13 min, purity 98.80%. 1H NMR (400 MHz, DMSO-d6) δ 4.51 (d, J=4.8 Hz, 2 H), 5.04 (t, J=4.8 Hz, 1 H), 6.10 (s, 2 H), 7.02 (dd, J=1.2 Hz, J=6.8 Hz, 2 H), 7.22-7.28 (m, 3 H), 7.43-7.51 (m, 5 H), 7.68 (dd, J=1.2 Hz, J=7.6 Hz, 1 H), 7.85-7.92 (m, 2 H), 8.24 (dd, J=2.0 Hz, J=2.4 Hz, 1 H), 8.37 (d, J=2.0 Hz, 1 H), 8.64 (d, J=2.4 Hz, 1 H), 8.94 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9](Cl)=[O:10].[CH:12]([NH:15][CH:16]([C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20])[CH3:17])([CH3:14])[CH3:13].C(N(CC)CC)C.O>ClCCl>[F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]([NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=1[CH:16]([NH:15][CH:12]([CH3:14])[CH3:13])[CH3:17])=[O:10]
Reactant: Cc1nn(C)c(F)c1C(=O)Cl
Reactant: CC(C)NC(C)c1ccccc1N
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(F)c1C(=O)Nc1ccccc1C(C)NC(C)C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of 0.27 g (1.5 mmol) 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride in 10 ml dichloromethane is added dropwise to a solution of 0.27 g (1.5 mmol) 2-[1-(isopropylamino)ethyl]aniline (III-4) and 0.42 ml (3.0 mmol) triethylamine in 5 ml dichloromethane. The reaction mixture is stirred for 2 hours at 50° C. and thereafter for 16 hours at room temperature. The reaction mixture is worked up by adding it to water, then the organic phase is dried over magnesium sulfate and concentrated under vacuum. Column chromatography (4:1 hexane/acetone) yielded 0.27 g (56% of the theoretical yield) 5-fluoro-N-{2-[1-(isopropylamino)ethyl]phenyl}-1,3-dimethyl-1H-pyrazole-4-carboxamide [log P (pH 2.3)=0.58].
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([C:19](=[N:21][OH:22])[NH2:20])[CH:16]=[C:15]([F:23])[C:3]=1[CH2:4][N:5]([CH3:14])[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([C:37](O)=O)=[CH:33][C:32]=1[C:40]([F:43])([F:42])[F:41].C(Cl)CCl>C(#N)C.N1C=CC=CC=1>[F:1][C:2]1[CH:18]=[C:17]([C:19]2[N:20]=[C:37]([C:34]3[CH:35]=[CH:36][C:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH3:24])=[C:32]([C:40]([F:41])([F:43])[F:42])[CH:33]=3)[O:22][N:21]=2)[CH:16]=[C:15]([F:23])[C:3]=1[CH2:4][N:5]([CH3:14])[CH2:6][C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C(F)(F)F
Reactant: CN(CC(=O)OC(C)(C)C)Cc1c(F)cc(C(N)=NO)cc1F
Solvent: ClCCCl
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1ccccc1-c1ccc(-c2nc(-c3cc(F)c(CN(C)CC(=O)OC(C)(C)C)c(F)c3)no2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Intermediate 76 (0.148 g, 0.45 mmol) and Intermediate 5 (0.107 mg, 0.375 mmol) in ACN (2.5 mL) was added EDC (0.101 g, 0.53 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with pyridine (2.5 mL) and heated at 150° C. in the microwave for 30 minutes. The solvent was removed in vacuo and the residue dissolved in DCM. The mixture was washed with water and the organic phase passed through a hydrophobic frit. The solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica, iso-hexane/EtOAc) to afford the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.62 (1H, d, J=1.7 Hz), 8.39 (1H, dd, J=8.0, 1.7 Hz), 7.76 (2H, d, J=7.1 Hz), 7.49 (1H, d, J=8.0 Hz), 7.38-7.22 (3H, m), 7.15 (1H, d, J=7.6 Hz), 3.99 (2H, s), 3.25 (2H, s), 2.45 (3H, s), 2.07 (3H, s), 1.50 (9H, s).
Reaction SMILES: [C:1]1([C@H:11]([NH:13][C@H:14]2[CH2:18][CH2:17][C@@H:16]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)[CH2:15]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[C:1]1([C@H:11]([NH:13][C@H:14]2[CH2:18][CH2:17][C@@H:16]([C:19]3[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=3)[CH2:15]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: C[C@@H](N[C@H]1CC[C@@H](c2ccc([N+](=O)[O-])cc2)C1)c1cccc2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@@H](N[C@H]1CC[C@@H](c2ccc(N)cc2)C1)c1cccc2ccccc12
Yield: 99.4 %

Procedure:
(1S,3R)-N-[(1R)-1-(Naphthalen-1-yl)ethyl]-3-(4-nitrophenyl)cyclopentanamine 0.99 g (2.71 mmol) was dissolved in 2 mL of ethyl acetate, followed by addition of 0.20 g of 10% palladium-carbon catalyst, and the mixture was subjected to catalytic hydrogen reduction for 1.5 hours at room temperature. The reaction solution was filtered, and the filtrate was concentrated to give the title compound (0.89 g, 97%).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.C1([O:16]C)C=CC=CC=1.[C:18]([C:20]1[N:24]([CH3:25])[C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:22][CH:21]=1)#N>O1CCCC1>[CH3:25][N:24]1[C:20]([C:18]([C:3]2[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=2)=[O:16])=[CH:21][CH:22]=[C:23]1[CH2:26][C:27]([OH:29])=[O:28]
Reactant: Cn1c(C#N)ccc1CC(=O)O
Reactant: Cc1ccc(Br)cc1
Reactant: COc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2ccc(CC(=O)O)n2C)cc1
Temperature: 115 °C
Yield: 77 %

Procedure:
To a solution of the Grignard reagent prepared from 0.71 g. (31 mmol) of magnesium and 5.3 g. (31 mmol) of 4-bromotoluene in a mixture of 20 ml. of anisole and 5 ml. of tetrahydrofuran was added over five minutes with stirring and heating a solution of 0.98 g. (6.0 mmol) of 5-cyano-1-methylpyrrole-2-acetic acid in a mixture of 5 ml. of anisole and 3 ml. of tetrahydrofuran. The reaction mixture was then heated under reflux (115° C.) for two hours, cooled, and partitioned between ether and dilute aqueous hydrochloric acid. Following a work-up procedure similar to that described for Example 1, there was obtained from the ether phase 60 mg. of purple liquid that contained only a trace of starting cyanoacid, and from the aqueous phase, 1.18 g. (77% yield) of 1-methyl-5-p-toluoylpyrrole-2-acetic acid as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.OS(O)(=O)=O.[N+:15]([O-])([OH:17])=[O:16].[NH4+].[OH-]>>[NH:1]([C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1)[N+:15]([O-:17])=[O:16]
Reactant: Cc1cc(C)nc(N)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc(C)nc(N[N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
2-Amino-4,6-dimethylpyridine (10.0 g, 81.8 mmol) was added portion-wise to 65 mL of H2SO4 (conc. d=1.84) which was stirred (mechanical) at 0° C. After complete addition, the mixture was warmed to room temperature until the mixture became homogeneous. The solution was then cooled to -10° C. and a pre-cooled (0° C.) mixture of concentrated HNO3 (11.5 mL, d=1.40) and H2SO4 (8.2 mL, d=1.84) was added at such a rate as not to raise the internal reaction temperature above -9° C. Ten minutes after the addition was complete this cooled (-10° C.) mixture was poured onto 400 g of crushed ice. The resulting slurry was neutralized by the addition of conc NH4OH (to pH 5.5) while cooling (ice bath). The solid was isolated by filtration, and dried at room temperature to give 13.3 g of 2-nitramino-4,6-dimethylpyridine as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]=O)[CH:8]=2)[O:3]1.[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2>>[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:14])([CH3:1])[CH2:11][CH2:10]2
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CC1(C)CCc2cc(C=O)ccc2O1
Product: CC1(C)CCc2cc(C=C3C(=O)Nc4ccc(Br)cc43)ccc2O1

Procedure:
2,2-Dimethyl-6-formylchromane (commercially available) was condensed with 5-bromo-2-oxindole to give 0.3 g of 5-bromo-3-(2,2-dimethylchroman-6-ylmethylene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[CH2:20][C:21]([O:23]CC2C=CC=CC=2)=[O:22])[CH2:4]1)=O.Cl.[CH2:32]([N:35]([CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)[C:36]1[N:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[CH:33]=[CH2:34].C(N(CC)CC)C>ClCCl.CCOC(C)=O>[CH2:32]([N:35]([CH:42]1[CH2:47][CH2:46][N:45]([CH2:1][C@@H:3]2[C@@H:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:6][N:5]([C@@H:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]3[CH2:20][C:21]([OH:23])=[O:22])[CH2:4]2)[CH2:44][CH2:43]1)[C:36]1[N:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[CH2:33][CH3:34]
Reactant: C=CCN(c1ncccn1)C1CCNCC1
Reactant: O=C[C@H]1CN([C@@H]2CCCCC2CC(=O)OCc2ccccc2)C[C@@H]1c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCN(c1ncccn1)C1CCN(C[C@H]2CN([C@@H]3CCCCC3CC(=O)O)C[C@@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
The title compound was prepared using 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, benzyl ester using (75 mg, 0.185 mmol; prepared above as Aldehyde 4), 4-(N-allyl-N-(pyrimid-2-yl)amino)piperidine hydrochloride (61 mg, 0.24 mmol) from Example 2, Step A, NaHB(OAc)3, (97 mg, 0.46 mmol) and triethylamine (0.026 ml, 0.24 mmol) in 3 ml dichloromethane. The mixture was stirred overnight at room temperature. The reaction was diluted with 100 ml EtOAc and washed with 1M NaOH and saturated NaCl. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The material was purified using flash chromatography (5% EtOAc in hexane) to provide 80 mg (71%) of the title compound. HPLC (Zorbax SB-C8 column, 4.6 mm×7.5 cm, Gradient: 90 H2O:10 CH3CN to 0 H2O:100 CH3CN over 7.5 minutes then hold at 100 CH3CN:0 H2O for 45 seconds, 2.25 mL/min, 220 nm): Retention Time: 4.4 minutes.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:6]([OH:39])([CH3:38])[CH2:7][CH2:8][CH:9]([OH:37])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:36])=[CH:20]/[CH:21]=[CH:22]/[C:23]([OH:35])([CH3:34])[CH2:24][CH:25]2[O:33][CH:26]2[CH:27]([CH3:32])[CH:28]([OH:31])[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2].C(N([CH2:45][CH3:46])CC)C.Cl[Si:48]([CH2:53][CH3:54])([CH2:51][CH3:52])[CH2:49][CH3:50]>ClCCl.C(OCC)(=O)C>[C:1]([O:4][CH:5]1[C:6]([OH:39])([CH3:38])[CH2:7][CH2:8][CH:9]([O:37][Si:48]([CH2:45][CH3:46])([CH2:51][CH3:52])[CH2:49][CH3:50])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:36])=[CH:20]/[CH:21]=[CH:22]/[C:23]([OH:35])([CH3:34])[CH2:24][CH:25]2[O:33][CH:26]2[CH:27]([CH3:32])[CH:28]([O:31][Si:48]([CH2:53][CH3:54])([CH2:51][CH3:52])[CH2:49][CH3:50])[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC[Si](Cl)(CC)CC
Reactant: CCC(O)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(C)=O)C=CC1C
Agent: CCC(O)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Agent: CCC(O[Si](CC)(CC)CC)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC(O[Si](CC)(CC)CC)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)C=CC1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (8E,12E,14E)-7-acetoxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (221 mg, 0.4 mmol), N,N-dimethylaminopyridine (25 mg, 0.2 mmol) and triethylamine (613 mg, 6 mmol) in dichloromethane (7 mL) was cooled to 5° C., a solution of chlorotriethylsilane (609 mg, 4 mmol) in dichloromethane (3 mL) was added dropwise thereto, and the reaction mixture was stirred at room temperature for one hour. The reaction mixture was diluted with ethyl acetate, washed with water and a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40 to 50 μm; ethyl acetate-hexane, 1:9 to 1:4 to 1:3) to give the title compound (320 mg, quantitative) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.O[CH2:18][C:19]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:20]=1[C:21]#[N:22]>>[C:21]([C:20]1[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:19]=1[CH2:18][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1)#[N:22]
Reactant: Cc1ccc(CO)c(C#N)c1
Reactant: COC(=O)c1ccnc(-n2nccc2O)c1
Product: COC(=O)c1ccnc(-n2nccc2OCc2ccc(C)cc2C#N)c1

Procedure:
The title compound was prepared from methyl 2-(5-hydroxypyrazol-1-yl)pyridine-4-carboxylate (PREPARATION 6) and 2-(hydroxymethyl)-5-methylbenzonitrile according to the procedure for the preparation of Example 125, part B. 1H NMR (400 MHz, CDCl3): δ 3.40 (3H, s), 3.97 (3H, s), 5.40 (2H, s), 5.83 (1H, d, J=1.2 Hz), 7.43 (1H, d, J=8.8 Hz), 7.50 (1H, s), 7.58-7.62 (2H, m), 7.76 (1H, d, J=5.2 Hz), 8.33 (1H, s), 8.68 (1H, d, J=5.2 Hz). [M+H] Calc'd for C19H16N4O3, 349; Found, 349.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][Si](C)(C)C)=[CH:9][CH:10]=2)[N:5]([CH3:18])[C:4](=[O:19])[C:3]=1[C:20]([NH:22][CH2:23][C:24]([O:26]C)=[O:25])=[O:21].CN(C)C=O.[F-].[Cs+].[H][H]>CO.[Pd]>[CH2:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([OH:1])=[C:3]([C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])[C:4](=[O:19])[N:5]2[CH3:18])=[CH:10][CH:9]=1)[CH3:13]
Reactant: [H][H]
Reactant: COC(=O)CNC(=O)c1c(O)c2ccc(C#C[Si](C)(C)C)cc2n(C)c1=O
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: CN(C)C=O
Product: CCc1ccc2c(O)c(C(=O)NCC(=O)O)c(=O)n(C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
To a stirred solution of methyl 2-(4-hydroxy-1-methyl-2-oxo-7-(2-(trimethylsilyl)ethynyl)-1,2-dihydroquinoline-3-carboxamido)acetate (0.59 g, 1.5 mmol) in N,N-dimethylformamide (5.0 mL, 1.5 mmol) and methanol (1.0 mL, 1.5 mmol) was added cesium fluoride (0.23 g, 1.5 mmol) under nitrogen. After stirring at room temperature for 1 hour, the mixture was concentrated to remove solvents. The resulting solid was adsorbed onto silica and purified using flash chromatography (15-80% EtOAc:Hex gradient) to afford a yellow solid. The solid was suspended in methanol (10 mL) with Pd/C (20 mol %) and exposed to hydrogen from a balloon for 16 h. The crude reaction mixture was filtered through Celite, and the filter pad was washed with dichloromethane (5×10 mL) under argon. The filtrate was concentrated to give a white solid that was further purified on silica by flash chromatography (100% chloroform). The solid was then treated with 5 N aqueous NaOH (3 mL) in THF (3 mL) for 5 hours. The mixture was acidified to pH 1 using 5 N aqueous HCl, and the resulting precipitate was collected by filtration. After washing the solid with water (5×10 mL) and ether (2×10 ml), the desired material was obtained after drying in a vacuum oven overnight at 50° C. (0.21 g, 38% yield, 3 steps).
Reaction SMILES: C1CCCCC1.[C:7]([O:11][C:12]([N:14]1[C:22]2[C:17](=[C:18]([C:23]#[C:24][Si](C)(C)C)[CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[CH3:29])=[O:13])([CH3:10])([CH3:9])[CH3:8].[OH-:30].[Na+].[OH:32]O>O1CCCC1>[C:7]([O:11][C:12]([N:14]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:23][C:24]([OH:32])=[O:30])[C:17]=2[CH:16]=[C:15]1[CH3:29])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: [OH-]
Reactant: OO
Reactant: Cc1cc2c(C#C[Si](C)(C)C)cccc2n1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Cc1cc2c(CC(=O)O)cccc2n1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of cyclohexane (16.1 ml) in tetrahydrofuran (160 ml) was cooled at −10° C., and then to the mixture was added dropwise borane-tetrahydrofuran complex (1M, 80 ml), and the mixture was stirred at 0° C. for 1 hour. To the solution was added dropwise a solution of 1-t-butoxycarbonyl-2-methyl-4-(2-trimethylsilylethynyl)indole (13.1 g; prepared in Reference Example 3) in tetrahydrofuran (60 ml), the mixture was stirred for 1 hour at room temperature. To a reaction solution was added dropwise 3N aqueous solution of sodium hydroxide (40 ml) and 30% hydrogen peroxide (in water, 45 ml), successively, and the mixture was stirred for 12 hours. The reaction mixture was extracted with water—diethyl ether. The aqueous layer was adjusted to acidic condition with hydrochloric acid and then extracted with ethyl acetate. The extraction was washed with water and a saturated aqueous solution of sodium chloride, successively, dried and concentrated under reduced pressure to give the title compound (10.4 g; crude).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:20](NC3C=CC=C(C#C)C=3)=[N:19][CH:18]=[N:17][C:9]2=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16].[ClH:30].[Cl:31]C1C2C(=CC(OCCOC)=C([O:42]CCOC)C=2)N=CN=1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16])[NH:17][C:18](=[O:42])[N:19]=[CH:20]2.[C:4]([Cl:31])(=[O:5])[C:3]([Cl:30])=[O:2]
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Reactant: Cl
Reactant: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Product: COCCOc1cc2cnc(=O)[nH]c2cc1OCCOC
Product: O=C(Cl)C(=O)Cl

Procedure:
As per the process described in U.S. Pat. No. 5,747,498 (hereinafter “the '498 patent”), erlotinib hydrochloride can be prepared by the reaction of 4-chloro-6,7-bis-(2-methoxyethoxy)-quinazoline, obtained by reaction of 6,7-bis(2-methoxy-ethoxy)-quinazolone with oxalylchloride in a solvent system containing chloroform and dimethylformamide, with 3-ethynylaniline or its hydrochloride salt in a solvent such as a (C1-C6)-alcohol, dimethylformamide, N-methylpyrrolidin-2-one, chloroform, acetonitrile, tetrahydrofuran, 1,4-dioxane, pyridine or another aprotic solvent, preferably isopropyl alcohol; in the presence or absence of a base, preferably an alkali or alkaline earth metal carbonate or hydroxide or a tertiary amine base, such as pyridine, 2,6-lutidine, collidine, N-methyl-morpholine, triethylamine, 4-dimethylamino-pyridine or N,N-dimethylaniline; at a temperature from about ambient to about the reflux temperature of the solvent, preferably from about 35° C. to about reflux; under an inert atmosphere such as dry nitrogen. The crude erlotinib hydrochloride (residue) obtained is then basified with saturated aqueous NaHCO3 in the presence of methanol and chloroform followed by flash chromatography on silica using 30% acetone in hexane to afford erlotinib free base, which is further treated with hydrochloric acid in the presence of diethyl ether and chloroform to give erlotinib hydrochloride.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH3:8][C:9]1([CH3:35])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](O)=[O:20])[CH:17]=2)[NH:12][CH:11]([C:22]2[CH:27]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:25]=[CH:24][C:23]=2[CH3:34])[CH2:10]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:8][C:9]1([CH3:35])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:20])[CH:17]=2)[NH:12][CH:11]([C:22]2[CH:27]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:25]=[CH:24][C:23]=2[CH3:34])[CH2:10]1
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(N2CCOCC2)cc1C1CC(C)(C)c2cc(C(=O)O)ccc2N1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(N2CCOCC2)cc1C1CC(C)(C)c2cc(C(=O)NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.1 %

Procedure:
To a suspension of 60% sodium hydride (560 mg, 14 mmol) in N,N-dimethylformamide (5 mL) was added methanesulfonamide (1.33 g, 14 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A22. A solution of 4,4-dimethyl-2-(2-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (800 mg, 2 mmol) and 1,1′-carbonyldiimidazole (690 mg, 4 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B22. Solution B22 was added to Solution A22 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[4,4-dimethyl-2-(2-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (239 mg, 26%) as a white solid: MS (ESI) M+1=458.1.
Reaction SMILES: CSC.B(F)(F)F.CCOCC.[CH3:13][O:14][C:15](=[O:38])[CH:16]([O:35][CH2:36][CH3:37])[CH2:17][C:18]1[C:26]2[O:25][CH:24]=[CH:23][C:22]=2[C:21]([O:27]CC2C=CC=CC=2)=[CH:20][CH:19]=1>ClCCl>[CH3:13][O:14][C:15](=[O:38])[CH:16]([O:35][CH2:36][CH3:37])[CH2:17][C:18]1[C:26]2[O:25][CH:24]=[CH:23][C:22]=2[C:21]([OH:27])=[CH:20][CH:19]=1
Reactant: CCOC(Cc1ccc(OCc2ccccc2)c2ccoc12)C(=O)OC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CSC
Solvent: CCOCC
Product: CCOC(Cc1ccc(O)c2ccoc12)C(=O)OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.8 %

Procedure:
Dimethyl sulfide (4.4 ml, 60 mmol) and boron trifluoride diethyl etherate (46% purity, 3.3 ml, 12 mmol) were added to a ice cold solution of [rac]-3-(4-benzyloxy-benzofuran-7-yl)-2-ethoxy-propionic acid methyl ester (0.85 g, 2.4 mmol) in dichloromethane (25 ml) under an argon atmosphere. The mixture was stirred for 6 h at ambient temperature, poured into ice water and extracted three times with dichloromethane. The combined extract was washed with brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a brown oil which was purified by column chromatography (silica gel, hexane/AcOEt=4/1) to give 0.45 g (1.7 mmol, 71%) of the title compound as light yellow oil.