Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:25]=[CH:24][C:9]([CH2:10][S:11][C:12]2[O:13][C:14]3[C:19]([C:20](=[O:23])[C:21]=2[CH3:22])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][CH:7]=1.[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>ClCCl.CN(C1C=CN=CC=1)C.O>[CH3:22][C:21]1[C:20](=[O:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:13][C:12]=1[S:11][CH2:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][O:1][S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c(SCc2ccc(CCCCO)cc2)oc2ccccc2c1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCCc2ccc(CSc3oc4ccccc4c(=O)c3C)cc2)cc1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
To a solution 2-[4-(4-hydroxy-butyl)-benzylsulfanyl]-3-methyl-chromen-4-one (300 mg, 0.85 mmol) dissolved in anhydrous dichloromethane (8.0 mL) was added TsCl (194 mg, 1.01 mmol), DMAP (124 mg, 1.01 mmol) and TEA (0.213 mL, 1.52 mmol). The reaction mixture continued stirring at room temperature. After 3 hours the reaction mixture was diluted with water. The aqueous layer was separated and extracted with ethyl acetate (3×). All combined organic layers were dried over Na2SO4, filtered, and concentrated to yield an oil. The crude material was purified using silica gel chromatography (1:1 pentane: ethyl acetate) to yield toluene-4-sulfonic acid 4-[4-(3-methyl-4-oxo-4H-chromen-2-ylsulfanylmethyl)-phenyl]-butyl ester (280 mg, 0.55 mmol) in moderate yield (65%).1H (CDCl3, 600 MHz): δ 8.18 (1H, dd, J=7.9, 1.3 Hz), 7.77 (2H, d, J=8.2 Hz). 7.62 (1H, m), 7.39 (2H, t, J=8.0 Hz), 7.33 (2H, d, J=8.0 Hz), 7.30 (2H, d, J=8.0 Hz), 7.07 (2H, d, J=8.0 Hz), 4.37 (2H, s), 4.02 (2H, t, J=5.8 Hz), 2.55 (2H, t, J=7.3 Hz), 2.05 (3H, s), 1.65 (4H, m); 13C (CDCl3, 150 MHz): δ 175.5, 162.2, 156.7, 144.9, 141.5, 134.1, 133.4, 133.0, 130.0, 129.1, 129.0, 128.1, 126.5 125.3, 122.9, 117.5, 117.0, 70.5, 35.3, 34.9, 28.6, 27.2, 21.8, 10.8.; HRMS calcd for C28H28O5S2 509.1450:, found 509.1441
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([N:14]=[CH:15][C:16]=3[C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[CH:13]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH2:31]([N:33]=[C:34]=[O:35])[CH3:32]>COCCOC>[CH2:31]([NH:33][C:34]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]2[CH:15]=[N:14][N:12]3[CH:13]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH:9]=[CH:10][C:11]=23)[CH:18]=1)=[O:35])[CH3:32]
Reactant: CCN=C=O
Reactant: Nc1cccc(-c2cnn3cc(-c4ccc(F)cc4)ccc23)c1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CCNC(=O)Nc1cccc(-c2cnn3cc(-c4ccc(F)cc4)ccc23)c1
Temperature: 60 °C
Yield: 91.8 %

Procedure:
A solution of 3-[6-(4-fluoro-phenyl)-pyrazolo[1,5-a]pyridin-3-yl]-phenylamine (Example 118, 50 mg, 0.16 mmol), Et3N (45 μL, 0.32 mmol) and ethyl isocyanate (26 μL, 0.32 mmol) in dry DME (2 ml) was stirred and heated at 60° C. under N2 for 24 hours [Further ethyl isocyanate (30 μL) was added after 7 hours]. The reaction mixture was evaporated and dried under vacuum to give the title compound (55 mg, solid). 1H NMR (400 MHz, DMSO-d6): 9.09 (1H, s), 8.53 (1H, s), 8.36 (1H, s), 8.02 (1H, d), 7.93-7.83 (3H, m), 7.72 (1H, dd), 7.38-7.29 (3H, m), 7.27-7.22 (2H, m), 6.15 (1H, t), 3.19-3.09 (2H, m), 1.08 (3H, t).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]([CH:7]=[C:8]([S:10][CH3:11])[CH:9]=1)[CH:5]=O.Cl.[NH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]1[NH:32][C:31]2[CH:33]=[CH:34][S:35][C:30]=2[C:29](=[O:36])[CH:28]=1>>[Br:1][C:2]1[C:3]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]([CH:7]=[C:8]([S:10][CH3:11])[CH:9]=1)[CH2:5][NH:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]1[NH:32][C:31]2[CH:33]=[CH:34][S:35][C:30]=2[C:29](=[O:36])[CH:28]=1
Reactant: CSc1cc(Br)c(OCCc2ccccc2)c(C=O)c1
Reactant: NCCCNc1cc(=O)c2sccc2[nH]1
Agent: Cl
Product: CSc1cc(Br)c(OCCc2ccccc2)c(CNCCCNc2cc(=O)c3sccc3[nH]2)c1

Procedure:
5-[3-(3-bromo-5-methylsulfanyl-2-phenethyloxy-benzylamino)-propylamino]-4H-thieno[3,2-b]pyridine-7-one was prepared by reductive amination of the aldehyde prepared in Example 3 with amine XVIII following method C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][OH:16])[CH:10]=1.O[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C1(C)C=CC=CC=1>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)[CH:10]=1
Reactant: Cc1cccc(C)c1-c1cccc(CO)c1
Reactant: O=Cc1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1-c1cccc(COc2ccc(C=O)cc2)c1
Yield: 80.5 %

Procedure:
To a solution of (2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methanol (1.0 g), 4-hydroxybenzaldehyde (0.58 g), and triphenylphosphine (1.48 g) in tetrahydrofuran (10 mL), a solution of 40% diisopropylazodicarboxylic acid diisopropyl in toluene (1.09 mL) was added under ice-cooling and the resultant reaction mixture was stirred under ice-cooling for 3 hours. A solution of diisopropyl azodicarboxylate in toluene (0.6 mL) was further added and the resultant reaction mixture was stirred at room temperature for 12 hours. From the reaction mixture, the solvent was distilled off under reduced pressure to give a residue and water was added to the resultant residue. The mixture was extracted with an organic solvent and the resultant organic phase was dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluent; n-heptane:ethyl acetate=100:0 to 100:20) to give the title compound (1.2 g) as a colorless oil.
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]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH:34]1[O:38][CH2:37][CH2:36][O:35]1.O>CN(C)C=O>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:33][CH:34]4[O:38][CH2:37][CH2:36][O:35]4)=[CH:23][CH:24]=3)[N:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3ccc(O)cc3)cc3ccccc23)CC1
Reactant: BrCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCN(c2nc(-c3ccc(OCC4OCCO4)cc3)cc3ccccc23)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
The resulting 1-(4-ethylpiperazin-1-yl)-3-(4-hydroxyphenyl)isoquinoline (0.53 g) was dissolved in N,N-dimethylformamide (5 ml), to which were added potassium carbonate (0.24 g) and 2-bromomethyl-1,3-dioxolane (250 ml), and the mixture was stirred at 90° C. overnight. Water was added to the reaction solution, and then the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.47 g of the title compound as a pale yellow oil.
Reaction SMILES: C(N1C2C(=[O:17])NC(=O)N(C)C=2N=C1)C1C=CC=CC=1.CN1C2N=CN(CCC)C=2C(=O)NC1=O.[CH3:35][N:36]1[C:44]2[N:43]=[CH:42][N:41]([CH2:45][CH2:46][CH3:47])[C:40]=2[C:39](=[O:48])[N:38]([CH2:49][CH2:50][CH2:51][CH:52]=[C:53]([CH3:55])[CH3:54])[C:37]1=[O:56]>>[OH:17][C:53]([CH3:55])([CH3:54])[CH2:52][CH2:51][CH2:50][CH2:49][N:38]1[C:39](=[O:48])[C:40]2[N:41]([CH2:45][CH2:46][CH3:47])[CH:42]=[N:43][C:44]=2[N:36]([CH3:35])[C:37]1=[O:56]
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Reactant: CCCn1cnc2c1c(=O)n(CCCC=C(C)C)c(=O)n2C
Agent: CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Product: CCCn1cnc2c1c(=O)n(CCCCC(C)(C)O)c(=O)n2C

Procedure:
The same compound was obtained, inter alia, by alkylation of the compound of Example 6 with 1-bromo- or 1-chloropropane analogously to Example 3, by reaction of 3-methyl-7-propylxanthine with the tertiary alcohol of Example 1a analogously to Example 2, or by acid-catalyzed hydration of 3-methyl-1-(5-methyl-4-hexenyl)-7-propylxanthine analogously to Example 14 below.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)[CH2:3][CH2:2]1.O=[CH:16][CH2:17][C:18]1([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)(=O)C>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][CH:4]2[CH2:5][CH2:6][N:1]([CH2:16][CH2:17][C:18]3([C:24]([O:26][CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:2][CH2:3]2)=[N:9][CH:10]=1
Reactant: O=CCC1(C(=O)OCc2ccccc2)CCCCC1
Reactant: Cc1ccc(NC2CCNCC2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ccc(NC2CCN(CCC3(C(=O)OCc4ccccc4)CCCCC3)CC2)nc1
Yield: 86.3 %

Procedure:
To a solution of 2-(piperidin-4-ylamino)-5-methylpyridine (277 mg) and benzyl 1-(2-oxoethyl)cyclohexanecarboxylate (360 mg) in tetrahydrofuran (15 mL) was added acetic acid (207 mg) and triacetoxyborohydride (731 mg) at room temperature. After stiring the solution for 18 hours, saturated aqueous sodium bicarbonate solution was added thereto and it was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and then, concentrated under reduced pressure. The resulting residue was purified by chromatography (NH silica gel, hexane:ethyl acetate=2:1) to give the title compound (520 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].Br[C:16]1[CH:25]=[CH:24][C:23]2[N:22]=[CH:21][C:20]3[N:26]([CH3:40])[C:27](=[N:37][C:38]#[N:39])[N:28]([C:29]4[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=4)[C:19]=3[C:18]=2[CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:16]2[CH:25]=[CH:24][C:23]3[N:22]=[CH:21][C:20]4[N:26]([CH3:40])[C:27](=[N:37][C:38]#[N:39])[N:28]([C:29]5[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=5)[C:19]=4[C:18]=3[CH:17]=2)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: Nc1ncc(B(O)O)cc1C(F)(F)F
Reactant: COc1ccc(-n2c(=NC#N)n(C)c3cnc4ccc(Br)cc4c32)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2c(=NC#N)n(C)c3cnc4ccc(-c5cnc(N)c(C(F)(F)F)c5)cc4c32)cn1
Temperature: 110 °C

Procedure:
6-amino-5-(trifluoromethyl)pyridin-3-ylboronic acid (1.677 mmol) and palladium dichlorobis triphenylphosphine (10 mol %) were added to a solution of N-(8-bromo-1-(6-methoxypyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (compound of step 5, 1.118 mmol) in dry DMF in an inert atmosphere. Saturated Na2CO3 (0.3 ml) was added to the reaction mixture and the resulting solution was heated at 110° C. for 3 h. The solvent was removed; the crude material was extracted in EtOAc, washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated and the crude solid was purified (silica gel column, EtOAc/MeOH as eluent) to obtain the title compound. 1H NMR (300 MHz, DMSO-d6): δ 9.20 (s, 1H), 8.66 (d, J=3 Hz, 1H), 8.38 (d, J=3 Hz, 1H), 8.22 (m, 2H), 8.06 (dd, J=9 Hz, 3 Hz, 1H), 7.55 (s, 1H), 7.19 (d, J=9 Hz, 1H), 7.03 (d, J=3 Hz, 1H), 6.79 (s, 2H), 3.99 (s, 3H), 3.84 (s, 3H); MS (m/z): 491.2 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11](=[O:33])/[CH:12]=[CH:13]/[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[CH2:18][CH2:17]2)=[O:15])[CH:5]=[CH:6][C:7]=1[N:8]([CH3:10])[CH3:9].C.[H][H].[K+].[Br-]>C(O)C.C1COCC1.[Pt]>[Cl:1][C:2]1[CH:3]=[C:4]([C:11](=[O:33])[CH2:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[CH2:18][CH2:17]2)=[O:15])[CH:5]=[CH:6][C:7]=1[N:8]([CH3:10])[CH3:9]
Reactant: [H][H]
Reactant: CN(C)c1ccc(C(=O)/C=C/C(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)cc1Cl
Agent: [Pt]
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)c1ccc(C(=O)CCC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)cc1Cl

Procedure:
A solution of 1.05 g (2.248 mmol) of (E)-3-{1-[4-(3-chloro-4-dimethylaminophenyl)-1,4-dioxo-2-buten-1-yl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone (Item no. 104) in 110 ml of an ethanol-THF mixture (10/1 v/v) was hydrogenated at ambient temperature in the presence of 0.5 g of platinum on active charcoal until the uptake of hydrogen had ended. The mixture was freed from catalyst and solvent and purified by chromatography on silica gel using dichloromethane/methanol/conc. ammonia (95/5/0.3 v/v/v) as eluant. 0.36 g (34% of theoretical) of a colourless substance were obtained, Rf 0.31 (El A). IR (KBr): 1672, 1660 (C═O) MS: M+=468/470 (Cl)
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17])[CH3:7].[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH:21]1[CH2:29][C:30]([CH3:33])([NH2:32])[CH3:31].Cl([O-])(=O)(=O)=O.[Li+].O>C1(C)C=CC=CC=1>[CH2:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][CH:21]1[CH2:29][C:30]([NH:32][CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17])[CH3:7])([CH3:31])[CH3:33]
Reactant: CC(C)(N)CC1Cc2ccccc2C1
Reactant: COC(=O)/C=C/c1ccccc1[C@@H](C)OC[C@H]1CO1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)/C=C/c1ccccc1[C@@H](C)OC[C@H](O)CNC(C)(C)CC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
A mixture of methyl (2E)-3-(2-{(1R)-1-[(2R)-oxiran-2-yl methoxy]ethyl}phenyl)prop-2-enoate (342 mg, 1.30 mmol) described in WO 2004/106280, 1-(2,3-dihydro-1H-inden-2-yl)-2-methylpropan-2-amine (234 mg, 1.24 mmol) described in WO 01/53254, and lithium perchlorate (79 mg, 0.74 mmol) in toluene (12 mL) was stirred at room temperature for 16 hours. Water (10 mL) was added to the reaction solution, which was then extracted with ethyl acetate (10 mL×3). After that, the organic layers were combined, washed with saturated brine, and washed with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound as a colorless oily substance (206 mg, yield 37%).
Reaction SMILES: [OH:1][CH:2]([CH2:16][CH2:17][OH:18])[CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:19][O:20][C:21]1[CH:42]=[CH:41][C:24]([C:25](Cl)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:23][CH:22]=1>N1C=CC=CC=1>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:18][CH2:17][CH2:16][CH:2]([OH:1])[CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:31][CH:30]=1
Reactant: O=C(NCCC(O)CCO)OCc1ccccc1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OCCC(O)CCNC(=O)OCc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Benzyl 3,5-dihydroxypentylcarbamate (7.3 g, 28.8 mmoles) is co-evaporated twice with anhydrous pyridine (100 mL each) and then is dissolved in anhydrous pyridine (300 mL). The solution is chilled in an ice bath, and 4,4′-dimethoxytritylchloride (9.8 g, 28.9 mmoles) is added. The reaction is allowed to warm to ambient temperature and is stirred for 16 hours. The yellow solution is then evaporated to near dryness, and the residue is dissolved in dry toluene (250 mL). The toluene mixture is chilled for 1 hour at 4° C., then filtered. The collected solid is washed with toluene (50 mL) and the combined toluene filtrates are evaporated to a dark yellow syrup. The syrup is dried in vacuo for at least 24 hours at ambient temperature. The crude product is purified on silica gel (500 mL bed volume) eluting with hexanes:ethyl acetate:triethylamine (90:5:5 [v/v/v], 300 mL, then 85:10:5 [v/v/v], 1000 mL, then 80:15:5 [v/v/v], 1000 mL, then 75:20:5 [v/v/v], 1000 mL, then 70:25:5 [v/v/v], 2000 mL, then 50:45:5 [v/v/v], 2000 mL). Fractions containing pure product by thin layer chromatography are pooled and evaporated to a pale yellow syrup. The syrup is dried well in vacuo. The yield is 15.4 g (96%).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.C(OCC)(=O)C>[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Br
Reactant: Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)c1[nH]c2ccccc2c1-c1ccccc1C

Procedure:
A mixture of EXAMPLE 31B (1.08 g), ortho-tolylboronic acid (1.1 g), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (140 mg) in dimethoxyethane:2N aqueous Na2CO3 (25 mL:5 mL) was stirred under nitrogen at 80° C. for 16 hours, diluted with ethyl acetate and was washed with water and brine. The organic phase was dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash chromatography on silica gel with 0-10% ethyl acetate/hexanes.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21])#[CH:17]>C(Cl)Cl.C(O)(C)C>[C:16]([C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:22]=[CH:23][CH:24]=1)#[CH:17]
Reactant: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1F
Reactant: C#Cc1cccc(N)c1
Solvent: CC(C)O
Solvent: ClCCl
Product: C#Cc1cccc(Nc2ncnc3cc(F)c([N+](=O)[O-])cc23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
4-chloro-7-fluoro-6-nitroquinazoline (12 g, 0.052 mol) was dissolved in 120 ml DCM. A solution of 3-ethynylaniline (7 g, 0.057 mol) in 200 ml isopropanol was added dropwise in an ice bath. The solution was stirred for 1 hour in the ice bath, then TEA (7 g, 0.069 mol) was added and allowed to stir for another 0.5 hour at room temperature. Yellow precipitate was formed and the solid was filtered and washed with 20 ml isopropanol twice, dried to give N-(3-ethynylphenyl)-7-fluoro-6-nitroquinazolin-4-amine 8.2 g as a yellow solid (50.3% yield).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Cl:15][O-].[Ca+2].Cl[O-].C(O)(=O)C>O>[Cl:15][C:8]1[CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][C:7]=1[NH:10][S:11]([CH3:14])(=[O:12])=[O:13]
Reactant: [O-]Cl
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)cc1
Agent: [Ca+2]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(Cl)c1
Reaction time: 24 h

Procedure:
To 2.13 g (10 mmole) of N-(4-acetylphenyl)methanesulfonamide in 50 ml of alcohol and 50 ml of water at 30° C. is added 1.43 g (10 mmol) of calcium hypochlorite. The solution is stirred for 24 hrs and an additional 1.43 g of calcium hypochlorite added. The mixture is stirred for 3 days at room temperature. The mixture is acidified with acetic acid to pH 6; concentrated and extracted into water-methylene chloride. The organic layer is dried, evaporated and the residue flash chromatographed on silica gel eluting in succession with 25% and 50% ethyl acetate-pet. ether. The solid product is recrystallized from Et2O-pet. ether; m.p. 129°-131° C. MW 247.71.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[F:29][C:30]1([F:44])[O:34][C:33]2[CH:35]=[CH:36][C:37](/[CH:39]=[CH:40]/[C:41](O)=[O:42])=[CH:38][C:32]=2[O:31]1>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:41](=[O:42])/[CH:40]=[CH:39]/[C:37]4[CH:36]=[CH:35][C:33]5[O:34][C:30]([F:44])([F:29])[O:31][C:32]=5[CH:38]=4)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: O=C(O)/C=C/c1ccc2c(c1)OC(F)(F)O2
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Agent: Cl
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2ccc3c(c2)OC(F)(F)O3)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J, and trans-3-(2,2-difluoro-1,3-benzodioxol-5-yl)prop-2-enoic acid, by the method of Example 1, step K, giving a solid that was mostly the more polar cyclohexyl diastereomer by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C31H34F2N4O4: 565 (M+H). Found: 565
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH2:33][CH3:34])=[C:17]([NH:20][C:21](=[O:31])[CH2:22]P(OCC)(OCC)=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[CH3:52][N:53]1[CH2:57][CH2:56][CH2:55][C@@H:54]1[CH:58]=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH2:33][CH3:34])=[C:17]([NH:20][C:21](=[O:31])/[CH:22]=[CH:58]/[C@H:54]4[CH2:55][CH2:56][CH2:57][N:53]4[CH3:52])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN1CCC[C@@H]1C=O
Reactant: CCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)CP(=O)(OCC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)/C=C/[C@H]1CCCN1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
N-[4-[(3-Chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-2-diethoxyphosphoryl-acetamide 7b (300 mg, 0.59 mmol) was dissolved in 10 mL of tetrahydrofuran. The mixture was cooled to −78° C. in a dry ice bath. Under argon, a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (1.2 mL, 1.18 mmol) was added dropwise. After the mixture was stirred for 30 minutes, (2R)-1-methylpyrrolidine-2-carbaldehyde 5c (133 mg, 1.18 mmol) was added, and the mixture was stirred for another 1 hour, then warm up to room temperature and stirred for 12 hours. The reaction mixture was concentrated, added with 10 mL of water, extracted with dichloromethane (25 mL×3). The combined organic extracts were washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[(3-chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide 9 (130 mg, yield 47.3%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8](=O)[CH2:9][CH3:10])[CH:7]=1.O.[NH2:14][NH2:15].O>CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:15][N:14]=[C:8]2[CH2:9][CH3:10]
Reactant: CCC(=O)c1cc(Br)ccc1F
Reactant: NN
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1n[nH]c2ccc(Br)cc12

Procedure:
A solution of 7.50 g (32.5 mmol) 1-(5-bromo-2-fluorophenyl)-1-propanone (Example 4A) in 1-methyl-2-pyrrolidone (NMP; 100 ml) was treated with 3.25 g (3.16 ml, 64.9 mmol) hydrazine hydrate and stirred at reflux temperature for 16 h. Upon cooling, the mixture was poured into a mixture of ice and water. The precipitate was collected by filtration and washed thoroughly with water to yield 4.56 g (62% of th.) of the title compound as a beige-coloured solid.