Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][NH2:3].C(O)(=O)C.[C:8]1([C:14]([CH:16]=O)=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O>[CH3:1][NH:2][N:3]=[CH:16][C:14](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CNN
Reactant: O=CC(=O)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CNN=CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.8 %

Procedure:
A mixed solution of methylhydrazine (0.554 mL, 10.5 mmol)/acetic acid (1 mL)/water (7.6 mL) was added to phenylglyoxal (1.34 g, 10 mmol) in water (130 mL), and the mixture was stirred at room temperature for 20 hours. The reaction solution was extracted with chloroform, and the extract was dried, filtered, evaporated and dried by means of a vacuum pump to give oxo(phenyl)acetaldehyde methylhydrazone (1.44 g (crude), yield 89%) as a yellow solid.
Reaction SMILES: Cl.[C:2]([CH:5]([CH:10]1[N:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]2=[N:12][C:11]1=[O:19])[CH2:6][C:7]([OH:9])=[O:8])([OH:4])=[O:3].[CH:20]([C:22]([CH3:24])=[O:23])=[CH2:21].CO>O>[C:2]([CH:5]([C:10]1([CH2:21][CH2:20][C:22](=[O:23])[CH3:24])[N:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]2=[N:12][C:11]1=[O:19])[CH2:6][C:7]([OH:9])=[O:8])([OH:4])=[O:3]
Reactant: O=C(O)CC(C(=O)O)C1C(=O)N=C2C=CC=CN21
Reactant: C=CC(C)=O
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(=O)CCC1(C(CC(=O)O)C(=O)O)C(=O)N=C2C=CC=CN21
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A mixture of 18.9 g (0.066 mole) of the hydrochloride of 3-(1,2-dicarboxyethyl)-imidazo[1,2-a]pyridin-2(3H)-one, 7 g (0.1 mole) of methyl vinyl ketone, 50 ml of methanol and 50 ml of water is stirred at room temperature for 36 hours. The product is then precipitated by the dropwise addition of approximately 15 ml of 4N aqueous sodium hydroxide solution. The precipitate is filtered with suction, washed with water, methanol and acetone and dried in vacuo at 50° C. 8 g (38% of the theoretical yield) of 3-(1,2-dicarboxyethyl)-3-(3-oxobutyl)-imidazo[1,2-a]pyridin-2(3H)-one having a melting point of 195° C. (decomposition) are obtained.
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].[CH2:10]=O>CCOCC>[CH2:10]=[N:1][C:2]([CH3:9])([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: C=O
Reactant: CCC(C)(N)C(=O)OC
Solvent: CCOCC
Product: C=NC(C)(CC)C(=O)OC
Reaction time: 4 h
Yield: 97.9 %

Procedure:
To methyl 2-amino-2-methylbutyrate (2.62 g) was dropped at room temperature 37% formalin (2.27 g), and the mixture was stirred for 4 h. Then the reaction mixture was dissolved in ether and washed with water. The organic phase was dried over magnesium sulfate, filtered and evaporated to get the captioned compound (2.80 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:15]=[CH:14][O:13][C:12]=2[CH3:16])=O)=[CH:4][C:3]=1[O:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21].C(=O)(O)[O-].[Na+].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:15]=[CH:14][O:13][C:12]=2[CH3:16])=[S:37])=[CH:4][C:3]=1[O:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)=CCOc1cc(NC(=O)c2ccoc2C)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)=CCOc1cc(NC(=S)c2ccoc2C)ccc1Cl
Temperature: 85 °C

Procedure:
A reaction mixture of N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furancarboxamide (4 g), sodium bicarbonate (7.4 g) and Lawesson's reagent (3.6 g) in toluene (168 mL) was gradually heated to 85° C. over 1 1/2 hours and then held at this temperature for a further 2 1/2 hours. The reaction mixture was then cooled and filtered through a plug of neutral aluminum oxide and eluted with ether:petroleum ether (1:1). Evaporation of the solvent gave the product, N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furancarbothioamide, 2.6 g.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]([CH3:21])[CH2:18][C:19]#[CH:20])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:22][C:23]1[CH:24]=[C:25]2[C:29](=[N:30][CH:31]=1)[NH:28][CH:27]=[CH:26]2>>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([O:22][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]([CH3:21])[CH2:18][C:19]#[CH:20])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:31][N:30]=2)[CH:26]=[CH:27]1
Reactant: C#CCN(C)CCOc1cc2ncnc(Cl)c2cc1OC
Reactant: Oc1cnc2[nH]ccc2c1
Product: C#CCN(C)CCOc1cc2ncnc(Oc3cnc4[nH]ccc4c3)c2cc1OC
Yield: 47.3 %

Procedure:
Using an analogous procedure to that described for the preparation of Example 5, 4-chloro-6-methoxy-7-[2-(N-methyl-N-prop-2-yn-1-ylamino)ethoxy]quinazoline (0.25 g, 0.817 mmol) was reacted with 5-hydroxy-7-azaindole (0.12 g, 0.899 mmol), (prepared as described for the starting material in Example 2), to give 4-(7-azaindol-5-yloxy)-6-methoxy-7-[2-(N-methyl-N-prop-2-yn-1-ylamino)ethoxy]quinazoline (0.156 g, 47%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][C:3]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23].[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28][NH2:29].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[O:15][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:29][CH2:28][CH2:27][CH2:26][N:25]([CH3:30])[CH3:24])[N:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:7]=[CH:6]2
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Reactant: CN(C)CCCN
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(NCCCN(C)C)cc21
Temperature: 100 °C
Yield: 69.2 %

Procedure:
A mixture of 6-bromo-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole (15d; Example 110, Steps A-E) (0.030 g, 0.079 mmol), 3-(dimethylamino)propylamine (0.012 g, 0.118 mmol), BINAP (0.009 g, 0.016 mmol), Pd2dba3 (0.007 g, 0.008 mmol), and NaOtBu (0.008 g, 0.087 mmol), in dioxane were mixed in a flask and purged with N2 three times. The reaction mixture was then heated to 100° C. for 16 hours. The mixture was cooled to room temperature and partitioned between ethyl acetate (20 mL) and brine (20 mL). The aqueous phase was extracted with ethyl acetate and the combined organics were dried over MgSO4 and concentrated under reduced pressure. The residue was chromatographed on silica eluting with acetone/ether (1:1.5) with 0.2% triethylamine. The product was chromatographed again eluting with 5% MeOH in dichloromethane to afford 0.022 g of the product as colorless oil (69% yield). MS (ESI+) m/z 403 (M+1) detected; 1H NMR (400 mHz, CDCl3) δ 7.70 (s, 1H), 6.95 (m, 3H), 6.80 (m, 1H), 6.40 (s, 1H), 5.48 (br. s, 1H), 4.06 (d, 2H), 3.28 (m, 2H), 2.43 (m, 2H), 2.35 (m, 1H), 2.20 (s, 6H), 1.86 (m, 2H), 0.94 (d, 6H).
Reaction SMILES: O(Br)[Br:2].[P+5].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[N:13]1[CH:23]=[C:16]2[CH:17]=[N+:18]([O-])[CH:19]=[C:20]([CH3:21])[C:15]2=[N:14]1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[Br:2][C:17]1[C:16]2=[CH:23][N:13]([C:7]3[C:6]([Cl:5])=[CH:11][CH:10]=[CH:9][C:8]=3[Cl:12])[N:14]=[C:15]2[C:20]([CH3:21])=[CH:19][N:18]=1
Reactant: BrOBr
Reactant: Cc1c[n+]([O-])cc2cn(-c3c(Cl)cccc3Cl)nc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [P+5]
Solvent: ClCCCl
Product: Cc1cnc(Br)c2cn(-c3c(Cl)cccc3Cl)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37.8 %

Procedure:
Phosphorus(V) oxybromide (921 mg, 3.43 mmol) was slowly added to a suspension of 2-(2,6-dichlorophenyl)-7-methyl-2H-pyrazolo[4,3-c]pyridine-5-oxide (404 mg, 1.37 mmol) in DCE (9.0 mL) at 0° C., under an atmosphere of nitrogen. The reaction mixture was stirred at 0° C. for 30 minutes and then at room temperature overnight. The orange suspension was poured onto saturated aqueous sodium carbonate solution and was stirred for 10 minutes. This was extracted with DCM and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-30% ethyl acetate in cyclohexane) to afford the title compound as a white solid (185 mg, 38% yield). 1H NMR (300 MHz, DMSO-d6): δ 9.20 (s, 1H), 7.90-7.89 (m, 1H), 7.84-7.80 (m, 2H), 7.76-7.72 (m, 1H), 2.45 (d, J=1.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:25]3[CH2:28][CH2:27][CH2:26]3)=[N:9][C:10]=2[C:11]2[CH2:12][CH2:13][N:14]([C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:18])[CH2:15][CH:16]=2)[CH:5]=[CH:6][N:7]=1.[F:29]C1C=CC=CC=1C(O)=O>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:25]3[CH2:26][CH2:27][CH2:28]3)=[N:9][C:10]=2[C:11]2[CH2:12][CH2:13][N:14]([C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:29])=[O:18])[CH2:15][CH:16]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c(C3CCC3)nc(C3=CCN(C(=O)c4ccccc4)CC3)c12
Reactant: O=C(O)c1ccccc1F
Product: Nc1nccn2c(C3CCC3)nc(C3=CCN(C(=O)c4ccccc4F)CC3)c12

Procedure:
Prepared according to a procedure analogous to that described for synthesis of [4-(8-amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-3,6-dihydro-2H-pyridin-1-yl]-phenylmethanone except using 2-fluorobenzoic acid. 1H NMR (400 MHz, CDCl3): δ=2.03 (ddd, J=11.75, 8.84, 3.16 Hz, 1H) 2.16 (ddd, J=14.46, 9.03, 5.56 Hz, 1H) 2.41-2.63 (m, 4H) 2.78 (br. s., 1H) 2.88 (br. s., 1H) 3.64 (t, J=5.05 Hz, 1H) 3.76 (quin, J=8.59 Hz, 1H) 4.11 (t, J=5.81 Hz, 2H) 4.51 (d, J=2.53 Hz, 1H) 5.82-6.12 (m, 1H) 6.64 (br. s., 2H) 6.87-6.98 (m, 1H) 7.04 (dd, J=5.31, 1.77 Hz, 1H) 7.15 (td, J=8.91, 3.66 Hz, 1H) 7.20-7.25 (m, 0H) 7.41-7.50 (m, 2H). MS (ES+): m/z 391.96 (100) [MH+]. HPLC: tR=2.16 min (OpenLynx polar—5 min).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C([O:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=1)(=O)C>O.CO>[OH:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=1
Reactant: CC(=O)OCCCc1ccnc(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: N#Cc1cc(CCCO)ccn1
Reaction time: 0.42 h

Procedure:
A solution of K2CO3 (1.67 g, 12.1 mmol) in H2O (30 ml) was added to a stirred solution of 3-(2-cyanopyridin-4-yl)propyl acetate (4.94 g, 24.2 mmol) in MeOH (130 ml). After 25 min, the MeOH was removed under reduced pressure, then the aqueous phase was extracted three times with EtOAc. The combined organic extracts were dried (MgSO4), filtered, and concentrated to give a residue that was purified by column chromatography (IH-EtOAc, 1:3) to furnish 4-(3-hydroxypropyl)pyridine-2-carbonitrile: m/z (ES+)=163.1 [M+H]+. A solution of this alcohol (500 mg, 3.1 mmol) in DMF (20 ml) was treated with PDC (7 g, 18.6 mmol) and H2O (0.5 ml). The reaction was stirred for 16 h, before being partitioned between H2O and EtOAc. The aqueous phase was extracted twice with EtOAc, then the combined organic extracts were washed with brine, before being dried (MgSO4), filtered, and concentrated to give the title compound: m/z (ES−)=177.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:55])[NH:4][C@@H:5]([CH:52]([CH3:54])[CH3:53])[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:17][C:16]2[C:18]3[C:23]([CH:24]=[CH:25][C:15]=2[N:14]=1)=[CH:22][C:21]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([NH:44]C(OC(C)(C)C)=O)[C:32]=2[NH:36]C(OC(C)(C)C)=O)[CH:27]=1)=[CH:20][CH:19]=3)=[O:7].[C:56]([OH:62])([C:58]([F:61])([F:60])[F:59])=[O:57]>ClCCl>[NH2:36][C:32]1[C:31]([NH2:44])=[CH:30][CH:29]=[C:28]2[C:33]=1[CH:34]=[CH:35][C:26]([C:21]1[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=1)[C:16]1[NH:17][C:13]([C@@H:9]4[CH2:10][CH2:11][CH2:12][N:8]4[C:6](=[O:7])[C@@H:5]([NH:4][C:3](=[O:55])[O:2][CH3:1])[CH:52]([CH3:54])[CH3:53])=[N:14][C:15]=1[CH:25]=[CH:24]3)=[CH:27]2.[C:56]([OH:62])([C:58]([F:61])([F:60])[F:59])=[O:57]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5c(NC(=O)OC(C)(C)C)c(NC(=O)OC(C)(C)C)ccc5c4)ccc3c2[nH]1)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5c(N)c(N)ccc5c4)ccc3c2[nH]1)C(C)C
Reaction time: 2 h

Procedure:
To (S)-1-((S)-2-(7-(5,6-bis(tert-butoxycarbonylamino)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester (165 mg, 0.22 mmol) in dichloromethane (2.2 mL) was added TFA (0.5 mL) and the reaction mixture stirred for 2 hours. The solvent was removed under reduced pressure to provide title compound as TFA salts.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:22][CH2:21][N:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)[CH:8]=[CH:7][C:5]=1[NH2:6].Cl[C:28]1[N:29]=[C:30]([NH:47][C:48]2[CH:56]=[CH:55][CH:54]=[C:53]([F:57])[C:49]=2[C:50](N)=[O:51])[C:31]2[CH:36]=[CH:35][N:34]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C:32]=2[N:33]=1.Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:57][C:53]1[CH:54]=[CH:55][CH:56]=[C:48]2[C:49]=1[C:50](=[O:51])[N:29]1[C:28]([NH:6][C:5]3[CH:7]=[CH:8][C:9]([N:11]4[CH2:16][CH2:15][CH:14]([N:17]5[CH2:18][CH2:19][N:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:21][CH2:22]5)[CH2:13][CH2:12]4)=[CH:10][C:4]=3[O:3][CH3:2])=[N:33][C:32]3[N:34]([S:37]([C:40]4[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=4)(=[O:38])=[O:39])[CH:35]=[CH:36][C:31]=3[C:30]1=[N:47]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(F)c4C(N)=O)nc(Cl)nc32)cc1
Reactant: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1Nc1nc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c2nc3cccc(F)c3c(=O)n12
Temperature: 25 °C
Yield: 89.1 %

Procedure:
A solution of 2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline hydrochloride (3 g, 7.41 mmol) and 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (3 g, 6.52 mmol) in trifluroroethanol (200 mL) and HCl in dioxane (14.16 ml, 56.6 mmol) and KI (300 mg, 1.807 mmol) was stirred at 90° C. in a 300 mL pressure vessel behind a blast shield for 15 hours. After cooling to rt, the solution was neutralized with aqueous NaHCO3 (400 mL), the black suspension was added to CH2Cl2 (500 mL), and the layers separated. Addition of brine (200 mL) helped to separate the organic and aqueous layers. The organic layers were concentrated under reduced pressure and then suspended in CH2Cl2 (20 mL) and Et2O (150 mL). The solid was filtered to obtain 8-fluoro-5-[(2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one as brown powder (4.5 g, 5.81 mmol, 89% yield). This material was used without further purification. ESIMS (M+H)+=775.32 (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]([CH2:17][CH3:18])[C:13]([O:15]C)=[O:14])=[CH:8][CH2:9]2)=[CH:5][CH:4]=1.[OH-].[K+]>CO.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]([CH2:17][CH3:18])[C:13]([OH:15])=[O:14])=[CH:8][CH2:9]2)=[CH:5][CH:4]=1
Reactant: CCC(C(=O)OC)C1=CCc2cc(OC)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(C(=O)O)C1=CCc2cc(OC)ccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a solution of the ester prepared in Example 1 (14.0 g, 58.9 mmol) in 140 mL MeOH, was added a solution of KOH (6.4 g, 113.8 mmol) in 5 mL water. The reaction mixture was stirred at 60° C. (pot temperature) for 2 hours. TLC showed 70% conversion. A solution of KOH (3.0 g, 53.6 mmol) in 100 mL water was then slowly added to the pot. After 1 hour, the reaction was completed. After cooling to room temperature, the solvents were removed at a reduced pressure. The residue was dissolved in 500 mL water, and then washed with EtOAc. The aqueous layer was cooled in an ice-water bath, and then acidified with conc. HCl to pH<3.0. The product was extracted into 300 mL CH2Cl2, washed with water (2×100 mL), then dried over Na2SO4. After Na2SO4 was filtered off, the CH2Cl2 solution was stirred with 3.0 g of charcoal for 2 hours. The charcoal was removed by filtration through a pad of Celite®. The title product (12.5 g, 95%) was obtained as a light brown solid after solvent removal and vacuum drying. 1H NMR (DMSO-d6) δ12.20(b, 1H), 7.30(d, 1H), 7.06(d, 1H), 6.82(dd, 1H), 6.22(s, 1H), 3.75(s, 3H), 3.45(t, 1H), 3.30(s, 2H), 1.90(m, 1H), 1.78(m, 1H), 0.90(t, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:26][CH3:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]=1[O:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[C:28]1([CH2:34]CO)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.S([O-])(O)(=O)=O.[K+].CO>C1(C)C=CC=CC=1>[C:4]1([CH2:3][CH2:27][O:26][CH:3]([O:2][CH2:1][CH2:34][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]=2[O:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(OC)c1cccc(OC(=O)OC(C)(C)C)c1OC(=O)OC(C)(C)C
Reactant: OCCc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Oc1cccc(C(OCCc2ccccc2)OCCc2ccccc2)c1OC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
An amount of 1.43 g (3.73 mmol) of 2,3-bis-tert.-butoxycarbonyloxy-benzaldehyde dimethylacetal was dissolved in 40 ml of dried toluene. After the addition of 0.91 g (7.46 mmol) of 2-phenylethanol and 18 mg of potassium hydrogen sulfate, the resulting mixture was stirred for 1 hour under reflux. The methanol formed was then distilled off slowly, while more toluene was added to the mixture. After complete removal of the methanol, the mixture was cooled down and the potassium hydrogensulfate was filtered off. The filtrate was concentrated in a rotary evaporator. This gave a yellowish, viscous oil which was dried in an oil pump vacuum.
Reaction SMILES: NC1C=CC(C=CC(O)=O)=CC=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>C(O)(C)C>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][N:15]=[CH:14]2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Nc1ccc(C=CC(=O)O)cc1
Solvent: CC(C)O
Product: COc1cc2cncnc2cc1OC
Temperature: 25 °C
Yield: 184 %

Procedure:
As an alternative, a solution of 4-aminocinnamic acid (199 mg, 1.00 mmol) and 4-chloro-6,7-dimethoxyquinazoline (224 mg, 1.00 mmol) in isopropanol (200 ml) was heated at reflux for 3 hours before the reaction was allowed to cool to ambient temperature. The solid which had precipitated was collected by suction filtration and washed with diethyl ether (2×50 ml). Drying of this material yielded 4-(4-(2-carboxy)ethenyl)anilino)-6,7-dimethoxyquinazoline (350 mg, 90% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:12]3[CH:13]=[C:14]([CH2:18][NH2:19])[CH:15]=[N:16][CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[F:20][C:21]([F:28])([F:27])[CH2:22][S:23](Cl)(=[O:25])=[O:24]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:12]3[CH:13]=[C:14]([CH2:18][NH:19][S:23]([CH2:22][C:21]([F:28])([F:27])[F:20])(=[O:25])=[O:24])[CH:15]=[N:16][CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1c(-c2cncc(CN)c2)cc2ccc(Cl)cc21
Reactant: O=S(=O)(Cl)CC(F)(F)F
Product: Cn1c(-c2cncc(CNS(=O)(=O)CC(F)(F)F)c2)cc2ccc(Cl)cc21

Procedure:
C-[5-(6-Chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-methylamine (Example 205a) and 2,2,2-trifluoro-ethanesulfonyl chloride are processed according to the method described in Example 186f to give 2,2,2-trifluoro-ethanesulfonic acid [5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide. 1H NMR (400 MHz, MeOD) δ ppm 3.75 (d, J=0.6 Hz, 3H), 4.16-4.28 (m, 2H), 4.44 (s, 2H), 6.67 (s, 1H), 7.07 (ddd, J=8.4, 1.8, 0.8 Hz, 1H), 7.50 (s, 1H), 7.55 (d, J=8.3 Hz, 1H), 8.04 (d, J=0.6 Hz, 1H), 8.58 (d, J=1.4 Hz, 1H), 8.68 (d, J=1.6 Hz, 1H). HRMS (ESI) m/z 418.06107 [(M+H)+ Calcd for C17H16N3O2F3SCl: 418.06039].
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([CH3:18])[C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:19]O>C(O)(=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:19])([CH3:18])[C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OO
Reactant: Cc1ncccc1C(=O)N(C)c1cccnc1Cl
Solvent: CC(=O)O
Product: Cc1ncccc1C(=O)[N+](C)([O-])c1cccnc1Cl
Temperature: 110 °C

Procedure:
A mixture of N-(2-chloro-3-pyridinyl)-N-methyl-2-methylnicotinamide (1.86 g) and H2O2 (30%, 5 mL) in acetic acid (10 mL) was heated at 110° C. for 75 minutes. The solvents were evaporated under reduced pressure. Chromatography of the residue over basic alumina (chloroform/ethanol) gave N-(2-chloro-3-pyridinyl)-N-methyl-2-methylnicotinamide N-oxide as an oil which crystallized on trituration with isopropyl ether/ethyl acetate, (1.42 g).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16](=[O:25])[CH:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH3:18])[CH3:14].IC>C1(C)C=CC=CC=1.CCCCCC>[CH2:13]([O:15][C:16](=[O:25])[C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)([CH3:1])[CH3:18])[CH3:14]
Reactant: CCOC(=O)C(C)N1CCOCC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CI
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)N1CCOCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 523.8 %

Procedure:
Diisopropyl amine (0.12 moles) was added to a flask and diluted with 40 mL of toluene. The resultant was cooled to −78° C. under nitrogen, and then a hexane solution of n-butyl lithium (0.11 moles) was added thereto, followed by stirring at −78° C. for 1 hour. To this, 2-morpholinopropionic acid ethyl ester (0.105 moles) was added and the resultant was further stirred for 1 hour, and iodomethane (0.21 moles) was added thereto and after the temperature was restored to room temperature, the mixture was stirred for 1 hour. The reaction mixture was quenched with ice water, extracted with ethyl acetate and washed with a saturated sodium chloride aqueous solution, and then the organic layer was dried over magnesium sulphate. The solvent was evaporated, and the residue was purified by column chromatography (hexane/ethyl acetate=4/1) to obtain α-morpholino isobutyric acid ethyl ester (0.55 moles).
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:10]1([CH2:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: c1c[nH]cn1
Reactant: BrCc1cccnc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cncc(Cn2ccnc2)c1

Procedure:
Synthesized from 3-(Bromomethyl)pyridine hydrobromide (500 mg, 1.97 mmol), imidazole (538 mg, 7.90 mmol) and K2CO3 (1.36 g, 9.85 mmol) in DMF according to Method B. Yield: 246 mg, 1.55 mmol, 78%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.15 (s, 2H), 6.90 (d, J=0.9 Hz, 1H), 7.11 (d, J=0.9 Hz, 1H), 7.29, (dd, J=7.9, 4.7 Hz, 1H), 7.40-7.43 (m, 1H), 7.56 (bs, 1H), 8.52-8.53 (m, 1H), 8.59 (d, J=4.7 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.3, 119.0, 123.8, 130.3, 131.8, 134.8, 137.3, 148.7, 149.9; MS (ESI): m/z=160.07 [M+H]+.