Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]([CH2:12][OH:13])[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:13][CH2:12][CH:9]2[CH2:8][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=3[O:10]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: COc1cccc2c1OC(CO)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Temperature: 50 °C
Reaction time: 12 h
Yield: 68 %

Procedure:
To a solution of (±)-tert-butyl[(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methoxy]dimethylsilane (34.12 g; 0.116 mol) in tetrahydrofuran (700 mL) cooled to 0° C. was added via an addition funnel tetrabutylammonium fluoride (140 mL, 1.0 M solution in tetrahydrofuran) and the reaction mixture was allowed to stir at room temperature for 6 h. The reaction was diluted with water (500 mL) and extracted with ethyl acetate (2×300 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give (±)-(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methanol, a crude oil. The alcohol was dissolved in dichloromethane (700 mL) and p-toluenesulfonyl chloride (33.14 g, 0.174 mol) was added followed by triethylamine (21.11 g, 0.209 mol) and then 4-(dimethylamino)pyridine (2.12 g, 0.017 mol). The reaction mixture was allowed to stir at 50° C. for 12 h. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 3:7) provided 26.45 g (68%) of (±)-(7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white crystalline solid. Rf=0.38 (silica, ethyl acetate:hexanes 3:7); mp 98-103° C.; Anal. calcd. for C17H18O5S: C, 61.06; H, 5.43. Found: C, 60.80; H, 5.37.
Reaction SMILES: [N:1]1([C@H:7]2[CH2:24][C@@:23]3([CH3:25])[C@@H:10]([CH2:11][CH2:12][C@@H:13]4[C@@H:22]3[CH2:21][CH2:20][C@@:18]3([CH3:19])[C@H:14]4[CH2:15][C@H:16]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[C@@H:17]3[OH:26])[CH2:9][C@@H:8]2[OH:32])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41].C([O-])([O-])=O.[Na+].[Na+]>ClCCl.C(#N)C>[C:40]([O:26][C@H:17]1[C@@H:16]([N:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)[CH2:15][C@H:14]2[C@H:13]3[C@H:22]([CH2:21][CH2:20][C@:18]12[CH3:19])[C@:23]1([CH3:25])[C@H:10]([CH2:9][C@H:8]([OH:32])[C@@H:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH2:24]1)[CH2:11][CH2:12]3)(=[O:42])[CH3:41]
Reactant: C[C@]12C[C@H](N3CCOCC3)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@H]1[C@@H](N2CCCC2)C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5CCOCC5)C[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 2.5 °C
Yield: 66.8 %

Procedure:
To a suspension of 2β-(4-morpholinyl)-16β-(1-pyrrolidinyl)-5α-androstan-3α,17β-diol (2.067 Kg, 4.628 mol) in dichloromethane (103.35 L) at 20-22° C., was added triethylamine (1.935 L, 13.883 mol) under N2 atmosphere. The mixture was stirred until complete dissolution. Acetic anhydride (0.873 L, 9.255 mol) was charged slowly under continuous stirring and then the resulting reaction mixture was stirred for 22 h at a temperature of 20-22° C. A 5% Na2CO3 solution (41.34 L) was then added and the mixture was stirred for 5-10 min. The phases were separated and the organic phase was washed with water (2×41 L) at 15° C., dried with anhydrous Na2SO4 (10 Kg), and filtered under vacuum to remove salts, which were rinsed with dichloromethane (10 L). The solvent was removed under vacuum at a temperature lower than 20° C. until a final volume of 12 L was obtained. To the concentrated stirred solution at a maximum temperature of 20° C. was added wet acetonitrile (40 L), followed by concentrating under vacuum at a temperature lower than 15° C., to a total volume of 40 L of a suspension. The resulting suspension was cooled to 0-5° C., stirred for 1 h, filtered off under vacuum and washed with acetonitrile (3 L). The desired wet product was dissolved in dichloromethane (9.5 L) at 20-22° C., followed by addition of acetonitrile (38 L). The volume was reduced under vacuum at a temperature lower than 15° C. to a total volume of 39 L to give a suspension. The resulting suspension was cooled to 0-5° C. and stirred for 1 h. The obtained solid was filtered off under vacuum and the product was washed with acetonitrile (3 L). The pure product was dried in a vacuum oven at 40° C. for at least 15 h to give 1.51 Kg of a white solid. (68.8% molar yield and a purity of 99.9% by HPLC); M.P. 160° C.; [α]D20+55.5 (c=1.0 in CHCl3).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]([CH3:46])([CH2:43][CH2:44][CH3:45])[CH2:16][NH:17][C:18]([C:20]1[C:21]([CH3:42])=[N:22][N:23]2[C:28]([O:29][CH2:30][C:31]3[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=3[F:38])=[CH:27][C:26]([CH:39]3[CH2:41][CH2:40]3)=[CH:25][C:24]=12)=[O:19])(C)(C)C>ClCCl>[NH2:14][C:15]([CH3:46])([CH2:43][CH2:44][CH3:45])[CH2:16][NH:17][C:18]([C:20]1[C:21]([CH3:42])=[N:22][N:23]2[C:28]([O:29][CH2:30][C:31]3[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=3[F:38])=[CH:27][C:26]([CH:39]3[CH2:41][CH2:40]3)=[CH:25][C:24]=12)=[O:19]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(C3CC3)cc12)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C)(N)CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(C3CC3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 ml of trifluoroacetic acid were added to a solution of 125 mg (0.2 mmol) of rac-{1-[({5-cyclopropyl-7-[(2,6-difluorobenzyl)oxy]-2-methylpyrazolo[1,5-a]pyridin-3-yl}carbonyl)amino]-2-methylpentan-2-yl}carbamic acid tert-butyl ester (Example 150A) in 4 ml of dichloromethane. The reaction mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was purified by chromatography on SCX-2 silica gel (mobile phase: methanol then 20% (2 M ammonia in methanol) in dichloromethane). This gave 40 mg of the target compound (39% of theory).
Reaction SMILES: [Cl:1]/[C:2](=[C:6](\[Cl:10])/[C:7]([OH:9])=[O:8])/[C:3]([OH:5])=[O:4].[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C1C=CC=CC=1>>[Cl:1]/[C:2](=[C:6](\[Cl:10])/[C:7]([O-:9])=[O:8])/[C:3]([O-:5])=[O:4].[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH3+:16])=[CH:14][CH:13]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH3+:16])=[CH:14][CH:13]=1
Reactant: O=C(O)/C(Cl)=C(/Cl)C(=O)O
Reactant: Nc1ccc(F)cc1
Solvent: c1ccccc1
Product: O=C([O-])/C(Cl)=C(/Cl)C(=O)[O-]
Product: [NH3+]c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
9.25g (0.05 mol) of 2,3-dichloromaleic acid was dissolved in 50 ml of benzene. To the resulting solution 20 ml of benzene containing 5.55g (0.05 mol) of 4-fluoroaniline was added dropwise over a period of 20 min. at temperatures of 15°-25° C under agitation. After completing the addition, the mixture was agitated at that temperature for 30 min. during which time crystals formed, which were separated by filtration and washed with benzene to obtain 14.7g of 4-fluoroanilinium 2,3-dichloromaleate in the form of white crystal at a yield of 98.7%. The crystal had a melting point (decomposition point) of 207° C and is expressed by the following formula: ##STR2## The results of elementary analysis were as follows:
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.Cl.Cl.[NH2:15][CH:16]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C:17]([NH:19][C:20]1([C:27]#[N:28])[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=[O:18].C(N(CC)CC)C>C(#N)C>[C:27]([C:20]1([NH:19][C:17](=[O:18])[CH:16]([NH:15][C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:4](=[O:12])(=[O:11])[N:3]=2)[CH2:29][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]1)#[N:28]
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC2=NS(=O)(=O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.4 %

Procedure:
A suspension of 3-chloro-benzo[d]isothiazole 1,1-dioxide (300 mg, 1.49 mmol) and 2-amino-N-(-4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexylpropionamide bis hydrochloride salt (500 mg, 1.37 mmol) was prepared in 5.5 mL of acetonitrile. Triethylamine (575 μL, 4.10 mmol) was added and the reaction mixture was stirred at room temperature for 1 day. The suspension was filtered to remove triethylamine hydrochloride and the filtrate was concentrated. The resulting residue was chromatographed over 50 g of flash silica using dichloromethane/methanol 9:1 as the eluant to provide the desired product as a light yellow solid (310 mg, 49%). 1H NMR (400 MHz, CDCl3) δ 0.25-0.45 (m, 1H), 0.65-0.85 (m, 2H), 0.95-1.10 (m, 2H), 1.30-1.60 (m, 7H), 1.75-1.85 (m, 2H), 1.85-2.2 (m, 2H), 2.31 (s, 3H), 2.35-2.50 (m, 3H), 2.65-2.80 (m, 2H), 4.60-4.70 (m, 1H), 7.35-7.50 (m, 2H), 7.58 (t, J=7.3, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.81 (br s, 1H), 8.91 (br s, 1H). MS, m/z 458=M+1.
Reaction SMILES: [Na].[NH:2]([C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:20](OC)(=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CC([O-])C.CC([O-])C.CC([O-])C.[Al+3]>[C:20]([O:17][CH2:16][CH2:15][CH2:14][O:13][C:12]1[CH:18]=[CH:19][C:9]([NH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:10][CH:11]=1)(=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCC(=O)OC
Reactant: OCCCOc1ccc(Nc2ccccc2)cc1
Agent: CC(C)[O-]
Agent: [Al+3]
Agent: [Na]
Product: CCCCCC(=O)OCCCOc1ccc(Nc2ccccc2)cc1

Procedure:
Following the method of Example 1 using a mixture of sodium metal and aluminum isopropylate catalysts, the reaction of 24.3 g. of 3-(p-anilinophenoxy)propanol with 13 g. of methyl hexanoate was carried out at 140°-145° C. for several hours. The reaction mixture was dissolved in petroleum ether, washed with sodium bicarbonate solution and then with water and dried. After removal of solvent, the residue was recrystallized from isooctane to isolate the ester, 3-(p-anilinophenoxy)propyl hexanoate as a crystalline solid, m.p. 50°-51° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:17](=[O:18])[C:16]3[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:14][C:12]2=[O:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Product: O=c1[nH]c2ccccc2c(=O)n1S(=O)(=O)c1ccc(Cl)cc1
Yield: 95.5 %

Procedure:
3.10 g (14.3 mmol) of 4-chlorobenzenesulfonylisocyanate and 2.00 g (14.4 mmol) of 2-aminobenzoic acid were treated in the same way as in Example 1 to obtain 4.60 g of the above-identified compound (yield 94.4%). Properties: colorless crystal, Melting point: 214°-215° C., PMR (δppm, DMSO-d6): 7.10 (1H,d), 7.20 (1H,t), 7.66 (2H,d), 7.70 (2H,d), 7.84 (1H,d), 7.15 (2H,d).
Reaction SMILES: C([N:3](CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:24]2[C:19](=[CH:20][C:21]([CH3:26])=[C:22]([CH3:25])[CH:23]=2)[N:18]([CH3:27])[C:17](=[O:28])[C:16]=1C(O)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C1C=CC=CC=1>[NH2:3][C:16]1[C:17](=[O:28])[N:18]([CH3:27])[C:19]2[C:24]([C:15]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[Cl:8])=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=2
Reactant: Cc1cc2c(-c3ccccc3Cl)c(C(=O)O)c(=O)n(C)c2cc1C
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: Cc1cc2c(-c3ccccc3Cl)c(N)c(=O)n(C)c2cc1C
Yield: 69.2 %

Procedure:
Triethylamine (0.7 ml) was added dropwise to a mixture of 4-(2-chlorophenyl)-1,2-dihydro-1,6,7-trimethyl-2-oxo-3-quinolinecarboxylic acid (1.71 g), diphenylphosphoryl azide (1.65 g) and benzene (25 ml) under stirring. The mixture was further stirred for 15 minutes at room temperature and for 30 minutes under reflux, and then distilled to remove the solvent. The residue was dissolved in a mixture of dioxane (20 ml) and 1sodium hydroxide (7.5 ml) , followed by refluxing for 15 minutes. The resulting solution was acidified with 2N hydrochloric acid and then stirred for 20 minutes at room temperature. The mixture was made alkaline with 2N sodium hydroxide. The resultant crystals were collected by filtration to give 3-amino-4-(2-chlorophenyl)-1,6,7-trimethyl-2(1H)-quinolone (1.08 g, 69.2%), which was recrystallized from a mixture of chloroform and ethanol to give colorless needles. mp 242°-243° C.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.[C:25]1([NH:31]N)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[C:25]1([N:31]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NNc1ccccc1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Solvent: CCO
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 14.4 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (337 mg, 1.0 mmol) in ethanol (100 mL) was added phenylhydrazine (163 mg, 1.5 mmol). The mixture was stirred at 100° C. for 3 h, and the solvent was removed under reduced pressure. Preparative HPLC chromatography provided 3-(1-phenyl-1H-pyrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a gray solid (55 mg, 15%).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: COc1cc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2cc1O
Reactant: ClCCN1CCOCC1
Product: COc1cc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2cc1OCCN1CCOCC1

Procedure:
Similar procedure as described in example 329 was used, starting from 1-Isopropoxy-7-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol and N-(2-chloroethyl)-morpholine to give [1-Isopropoxy-7-methoxy-6-(2-morpholin-4-yl-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 442(MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12]([OH:14])[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:31])([F:30])[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:28](=O)[NH:27][CH:26]=[N:25]2)=[CH:20][CH:19]=1.FC1C=C(F)C=CC=1[C@]1(OC1)[C@H](N1C=NN(C2C=CC(OC(F)(F)F)=CC=2)C1=O)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([O:14][C:28]2[N:24]([C:21]3[CH:22]=[CH:23][C:18]([O:17][C:16]([F:30])([F:15])[F:31])=[CH:19][CH:20]=3)[N:25]=[CH:26][N:27]=2)[CH3:13])[CH2:11][O:10]1
Reactant: O=c1[nH]cnn1-c1ccc(OC(F)(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Agent: C[C@@H](n1cnn(-c2ccc(OC(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](Oc1ncnn1-c1ccc(OC(F)(F)F)cc1)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 29.8 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.53 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl] ethanol and 1.50 g of 2-(4-trifluoromethoxyphenyl)-3(2H,4H)-1,2,4-triazolone, 4-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-2-(4-trifluoromethoxyphenyl)-3(2H,4H)-1,2,4-triazolone (829 mg) and 778 mg of (2R)-2-(2,4-difluorophenyl)-2-[(1R)-1-[1-(4-trifluoromethoxyphenyl)-1H-1,2,4-triazol-5-yloxy]ethyl]oxirane were obtained.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>CN(C=O)C>[CH3:13][N:14](/[CH:16]=[C:3](\[C:2](=[O:1])[CH2:9][CH3:10])/[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:15]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=C/N(C)C)C(=O)CC
Yield: 100 %

Procedure:
According to Scheme 9 Step 1: A solution of ethyl 3-oxopentanoate (13.9 mmol, 2.00 g) and of 1,1-dimethoxy-N,N-dimethylmethanamine (13.9 mmole, 1.84 mL) in DMF (10 mL) was microwaved for 30 min at 120° C. After evaporation of the solvent, 2.76 g (13.9 mmol) of (E)-ethyl 2-((dimethylamino)methylene)-3-oxopentanoate were obtained and used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[CH3:33][N:34]([CH3:44])[C:35]1[CH:40]=[CH:39][C:38]([C:41](Cl)=[O:42])=[CH:37][CH:36]=1>N1C=CC=CC=1.ClCCl>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:41](=[O:42])[C:38]4[CH:37]=[CH:36][C:35]([N:34]([CH3:33])[CH3:44])=[CH:40][CH:39]=4)=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(N(C)C)cc1
Temperature: -5 °C
Reaction time: 2.5 h
Yield: 53.3 %

Procedure:
A suspension of 3-(4-Amino-3-methoxyphenyl)-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.398 g, 0.912 mmol) in pyridine (7 mL) at −5° C. was treated with a solution of 4-(dimethylamino)-1-benzenecarbonyl chloride (0.167 g, 0.912 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at −5° C. for 2.5 h, and the ice bath was removed. 1 N sodium hydroxide solution (10 mL) was added to the reaction mixture and stirred for 1 h. The organic layer was removed under reduced pressure, and dichloromethane (15 mL) was added. The layers were separated using an Empore extraction cartridge. The organic layer was removed under reduced pressure. The crude solid was purified two times by flash chromatography on silica gel using 12% (methanol with 5% ammonium hydroxide) in dichloromethane as eluent to give 0.284 g (53%) of N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(dimethylamino)benzamide. A hot solution of N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(dimethylamino)benzamide (0.284 g, 0.487 mmol) in ethyl acetate and a few drops of ethanol was treated with a hot solution of maleic acid (0.169 g, 1.46 mmol) in ethyl acetate. The precipitate formed was filtered under nitrogen and dried under high vacuum to give 0.409 g N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(dimethylamino)benzamide tris-maleate. 1H NMR (DMSO-d6, 400 MHz) δ 9.054 (s, 1H), 8.278 (s, 1H), 8.215-8.194 (m, 1H), 7.851-7.828 (m, 2H), 7.312-7.308 (m, 1H), 7.288-7.263 (m, 1H), 6.794-6.772 (m, 2H), 6.096 (s, 6H), 5.10-5.00 (m, 1H), 3.951 (s, 3H), 3.538 (s, 4H), 3.061 (s, 8H), 2.215-2.183 (m, 4H), 1.90-1.81 (m, 2H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 4.496 min (98%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[H-].[Na+].[H][H].Cl[CH2:18][C:19]([NH:21][C:22]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)([CH3:24])[CH3:23])=[O:20]>CS(C)=O>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:22]([NH:21][C:19](=[O:20])[CH2:18][O:1][C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4](=[O:5])[N:6]([CH3:8])[CH3:7])([CH3:23])[CH3:24])=[CH:30][CH:29]=1
Reactant: CC(C)(NC(=O)CCl)c1ccc(Cl)cc1
Reactant: [H][H]
Reactant: CN(C)C(=O)c1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)C(=O)c1ccccc1OCC(=O)NC(C)(C)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
A mixture of the 2-hydroxy-N,N-dimethylbenzamide (0.68 g) in DMSO (5 ml) was added to a stirred suspension of sodium hydride (163 mg of a 60% dispersion in mineral oil) in DMSO (5 ml) at ambient temperature over 5 minutes with stirring. The mixture was stirred until the evolution of hydrogen ceased and then a solution of 2-chloro-N-[1-(4-chlorophenyl)-1-methylethyl]-acetamide (prepared by reacting α,α-dimethylbenzylamine with chloroacetyl chloride) (1.0 g) in DMSO (5 ml) was added dropwise over 5 minutes with stirring. The mixture was stirred at ambient temperature for 16 hours and then poured into ice water (200 ml) and extracted with ethyl acetate to give a solid which was recrystallised from ethyl acetate/petroleum ether, b.p. 60°-80° C. to give N-(4-chloro-α,α-dimethylbenzyl)-2-(2-dimethylcarbamoyl-phenoxy)acetamide, m.p. 127°-9° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[CH3:21][C:22]1[N:23]=[CH:24][S:25][C:26]=1[CH:27]=O.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH2:27][C:26]3[S:25][CH:24]=[N:23][C:22]=3[CH3:21])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: Cc1ncsc1C=O
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: Cc1ncsc1CNc1ccc(F)c([C@@]2(C)N=C(N)N(C)C(=O)C2(C)C)c1

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 4-methylthiazole-5-carbaldehyde using decaborane yielded the title compound as a white solid. MS (ESI): m/z=390.3 [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.CS(C)=O.[C:26]([C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31])#[CH:27]>CO>[CH3:16][O:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[C:11]2[C:2]([NH:31][C:30]3[CH:32]=[CH:33][CH:34]=[C:28]([C:26]#[CH:27])[CH:29]=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: C#Cc1cccc(N)c1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Solvent: CO
Solvent: CS(C)=O
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Product: Cl
Temperature: 27.5 °C
Yield: 87.3 %

Procedure:
4-Chloro-6,7-bis-(2-methoxyethoxy)-quinazoline (50 gm) and dimethyl sulfoxide (250 ml) are added to methanol (500 ml) while stirred at 25-30° C., 3-ethynylaniline (20.5 gm) is added to the reaction mixture at 25-30° C. and then the contents are heated to 85° C. The reaction mass is stirred for 2 hours at 80-85° C., the mass is cooled to 25-30° C. and then stirred for 1 hour. The material is filtered, washed with a mixture of dimethyl sulfoxide (50 ml) and methanol (100 ml), and then dried at 60° C. under vacuum for 4 hours to give 60 gm of erlotinib hydrochloride [HPLC purity: 99.65%; Content of N-methoxyethyl impurity: 0.09% (at 1.14 RRT)].
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:11]([Cl:16])(Cl)(Cl)(Cl)[Cl:12].Cl.C(O)=[O:19]>C(Cl)(Cl)(Cl)Cl>[Cl:12][P:11]([Cl:16])([NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:19]
Reactant: NC(=O)Cc1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=CO
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Cc1ccccc1)NP(=O)(Cl)Cl
Reaction time: 0.5 h

Procedure:
A suspension of 50 g (0.37 mole) of phenylacetamide, 77 g (0.37 mole) of phosphorus pentachloride and 500 ml of AR carbon tetrachloride was heated at 70° for 25 min. or until the HCl gas evolution ceases. The resulting solution was cooled to 30°, then 17.6 g (0.37 mole) of 97% formic acid was added, dropwise. Stirred at 30° for 30 min. following the addition, then filtered, washed with AR carbon tetrachloride and air-dried to give 80 g, m.p. softens 79°, some melts 83°-94°, complete 120°.