Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:22][CH:21]=3)=[N:15][CH:16]=2)[N:11]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][CH2:41]OS(C)(=O)=O)[CH:35]=2)[C:10]1=[O:47].[C:48]1(=[O:58])[NH:52][C:51](=[O:53])[C:50]2=[CH:54][CH:55]=[CH:56][CH:57]=[C:49]12.[K]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][N:29]([CH2:30][CH3:31])[CH2:32][CH3:33])=[CH:24][CH:25]=3)=[N:15][CH:16]=2)[N:11]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][CH2:41][N:52]3[C:48](=[O:58])[C:49]4=[CH:57][CH:56]=[CH:55][CH:54]=[C:50]4[C:51]3=[O:53])[CH:35]=2)[C:10]1=[O:47]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(c2cccc(CCOS(C)(=O)=O)c2)C(=O)N(c2ccc(Cl)cc2Cl)C3)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(c2cccc(CCN4C(=O)c5ccccc5C4=O)c2)C(=O)N(c2ccc(Cl)cc2Cl)C3)cc1
Temperature: 90 °C
Yield: 95.2 %

Procedure:
A solution of 50 mg (0.07 mmol) of 3-(2,4-dichlorophenyl)-7-[4-[2-(diethylamino) ethoxy]anilino]-3,4-dihydro-1-[3-(2-methanesulfonyloxyethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one in 5 ml of dimethylformamide was treated with 17 mg (0.09 mmol) of potassium phthalimide and the mixture was heated at 90° C. for 1 hour. The mixture was cooled and evaporated. The residue was partitioned between 20 ml of ethyl acetate and 20 ml of water. The organic phase was dried over magnesium sulfate and evaporated to yield 50 mg (95%) of 3-(2,4-dichlorophenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-[3-(2-phthalimidoethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid. [Mass spectrum (ESI) MH+ =750].
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24](N)=[CH:23][CH:22]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(N)cc1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(Nc2ncnc3ccc4nc(C#N)sc4c23)cc1
Yield: 20 %

Procedure:
Prepared from VII and 4-methoxyaniline. Flash chromatography eluent (DCM-EtOAc, 8:2). Yield: 20%; orange solid, mp>260° C.; IR (KBr) νmax/cm−1 3346, 2977, 2361, 2227, 1644, 1609, 1581, 1503, 1460, 1377, 1354, 1303, 1239, 1164, 1129, 1051, 1032, 975, 829; 1H NMR (300 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.95 (d, 1H, J=9.0 Hz), 7.70 (d, 1H, J=9.0 Hz), 7.45 (d, 2H, J=9.0 Hz), 6.99 (d, 2H, J=9.0 Hz), 3.76 (s, 3H); HRMS calcd for C17H12N5OS (M+H+): 334.0763, found 334.0758.
Reaction SMILES: Br[C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: Cc1ccc(B(O)O)c(C)c1
Reactant: CSc1ncc(Br)c(=O)n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CSc1ncc(-c2ccc(C)cc2C)c(=O)n1C
Temperature: 90 °C
Yield: 82.3 %

Procedure:
A mixture containing 0.2 g (0.84 mmol) of 5-bromo-3-methyl-2-(methylthio)pyrimidin-4(3H)-one, 0.19 g (1.3 mmol) of 2,4-dimethylphenyl boronic acid, 0.35 g (2.5 mmol) of potassium carbonate, 0.15 ml (8.4 mmol) of water, and 0.25 g (0.21 mmol) of tetrakis(triphenylphosphine)palladium(0) in 10 ml of dioxane was heated to 90° C. under a nitrogen atmosphere overnight. The reaction was cooled to room temperature, diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 30% ethyl acetate/hexanes gave 0.18 g (86%) of product.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH3:14][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cc(Cl)c(N)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-amino-5-chloro-2-methoxybenzoic acid (1.008 g, 5.0 mmol) in a mixture of toluene (9 mL) and methanol (1 mL) at 0° C. was added (trimethylsilyl)diazomethane (2.0 M in hexane, 3.0 mL, 6.0 mmol) dropwise. The reaction mixture was then warmed to room temperature and stirred for 16 h. Excess (trimethylsilyl)diazomethane was quenched by adding acetic acid until the bright yellow color of the reaction mixture disappeared. The mixture was then concentrated in vacuo to give the title compound as an off-white solid, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[O:20][CH3:21].[Al+3].[Cl-].[Cl-].[Cl-]>>[Cl:19][C:18]1[C:13]([Cl:12])=[C:14]([O:20][CH3:21])[CH:15]=[CH:16][C:17]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=1[CH3:1])=[O:5]
Reactant: Cc1cccc(C(=O)Cl)c1C
Reactant: COc1cccc(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)c2cccc(C)c2C)c(Cl)c1Cl

Procedure:
The Friedel-Crafts procedure of Example 24a is repeated with 33.7 g of 2,3-dimethylbenzoyl chloride, 54 g of 2,3-dichloroanisole and 26.7 AlCl3 being reacted to form 2,3-dichloro-4-methoxy-2',3'-dimethylbenzophenone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[N:30]1[N:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]2=[CH:32][C:31]=1[C:39](O)=[O:40]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:39]([C:31]4[CH:32]=[C:33]5[N:34]([N:30]=4)[CH:35]=[CH:36][CH:37]=[CH:38]5)=[O:40])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc2ccccn2n1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cc3ccccn3n2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and pyrazolo[1,5-a]pyridine-2-carboxylic acid (24 mg, 0.15 mmol).
Reaction SMILES: C(OC(C1SC(C2C=NC=C(N(CCOC3C=CC(F)=CC=3)C)N=2)=NC=1C)=O)C.C([O:32][C:33]([C:35]1[S:39][C:38]([C:40]2[CH:45]=[N:44][CH:43]=[C:42]([N:46]([CH2:48][C:49]3[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=3)[CH3:47])[N:41]=2)=[N:37][C:36]=1[CH3:56])=[O:34])C>>[F:55][C:52]1[CH:53]=[CH:54][C:49]([CH2:48][N:46]([CH3:47])[C:42]2[N:41]=[C:40]([C:38]3[S:39][C:35]([C:33]([OH:34])=[O:32])=[C:36]([CH3:56])[N:37]=3)[CH:45]=[N:44][CH:43]=2)=[CH:50][CH:51]=1
Reactant: CCOC(=O)c1sc(-c2cncc(N(C)Cc3ccc(F)cc3)n2)nc1C
Agent: CCOC(=O)c1sc(-c2cncc(N(C)CCOc3ccc(F)cc3)n2)nc1C
Product: Cc1nc(-c2cncc(N(C)Cc3ccc(F)cc3)n2)sc1C(=O)O
Yield: 90 %

Procedure:
Part B. Following the procedure described in Example 25 (Part C), making variations as required to replace 2-(6-{[2-(4-fluoro-phenoxy)-ethyl]methyl-amino}-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid ethyl ester with 2-{6-[(4-fluoro-benzyl)-methyl-amino]-pyrazin-2-yl}-4-methyl-thiazole-5-carboxylic acid ethyl ester to give 2-{6-[(4-fluoro-benzyl)-methyl-amino]-pyrazin-2-yl}-4-methyl-thiazole-5-carboxylic acid in 90% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([NH:9][C:10]2([C:19]([OH:21])=[O:20])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)=[O:8])=[CH:5][C:4]=1[O:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([S:33][CH3:34])[CH:28]=1.[OH:35]O>C(O)(=O)C.O>[CH3:34][S:33]([C:29]1[CH:28]=[C:27]([CH2:26][CH2:25][O:24][C:4]2[CH:5]=[C:6]([CH:22]=[CH:23][C:3]=2[O:2][CH3:1])[C:7]([NH:9][C:10]2([C:19]([OH:21])=[O:20])[CH2:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:18]2)=[O:8])[CH:32]=[CH:31][CH:30]=1)=[O:35]
Reactant: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1OCCc1cccc(SC)c1
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1OCCc1cccc(S(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of example 16 (35 mg, 0.078 mmol) was dissolved in acetic acid (2.5 ml), hydrogen peroxide (43 mg of a 30% solution in water, 0.38 mmol) was added and the mixture was stirred at room temperature for 2 h. The mixture was partitioned between EA and a 1% aqueous sodium sulfite solution, the aqueous phase extracted with EA, and the combined organic extracts were dried over sodium sulfate, filtered and evaporated to dryness to give 36 mg of the title compound.
Reaction SMILES: [CH:1]1([C@H:4]([N:8]2[C:13](=[O:14])[C:12]([NH:15][C:16]3[C:17]([CH3:24])=[N:18][C:19]([OH:23])=[C:20]([CH3:22])[CH:21]=3)=[N:11][C:10]([C:25]#[N:26])=[CH:9]2)[CH2:5][O:6][CH3:7])[CH2:3][CH2:2]1.[F-].[Cs+].[F:29][C:30]([F:42])(S(F)(=O)=O)C(O[Si](C)(C)C)=O>C(#N)C>[CH:1]1([C@H:4]([N:8]2[C:13](=[O:14])[C:12]([NH:15][C:16]3[C:17]([CH3:24])=[N:18][C:19]([O:23][CH:30]([F:42])[F:29])=[C:20]([CH3:22])[CH:21]=3)=[N:11][C:10]([C:25]#[N:26])=[CH:9]2)[CH2:5][O:6][CH3:7])[CH2:3][CH2:2]1
Reactant: COC[C@H](C1CC1)n1cc(C#N)nc(Nc2cc(C)c(O)nc2C)c1=O
Reactant: C[Si](C)(C)OC(=O)C(F)(F)S(=O)(=O)F
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: COC[C@H](C1CC1)n1cc(C#N)nc(Nc2cc(C)c(OC(F)F)nc2C)c1=O
Reaction time: 1 h

Procedure:
A mixture of pure (S)-4-(1-cyclopropyl-2-methoxyethyl)-6-(6-hydroxy-2,5-dimethylpyridin-3-ylamino)-5-oxo-4,5-dihydropyrazine-2-carbonitrile (2.3 g, 6.5 mmol) and CsF (395 mg, 2.6 mmol) was added to acetonitrile (65 mL). To the resulting suspension, trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (3.82 mL, 19.4 mmol) was slowly added (use extreme caution! The reagent can cause dermatological damage and should always be handled in hood). LC-MS analysis after 1 h showed the reaction to be complete (89% conversion to required product). Volatiles were evaporated in vacuo and the residue was partitioned between EtOAc (3×120 mL) and H2O (˜100 mL). The organic layer was washed with water (2×50 mL) and brine (50 mL), and dried over Na2SO4. The ethyl acetate was evaporated in vacuo and the residue was dissolved in DMF (10 mL). The solution was applied to C18 silica gel column (14 cm×5 cm) equilibrated with MeCN:H2O (1:2). The column was eluted with 33% MeCN/H2O (500 mL), 45% MeCN/H2O (500 mL), 60% MeCN/H2O (1000 mL), 70% MeCN/H2O (500 mL). Individual fractions were analyzed by LC-MS (product comes out in between 60%-70% MeCN/H2O). Fractions containing pure product were combined and concentrated in vacuo to give pure (S)-4-(1-cyclopropyl-2-methoxyethyl)-6-(6-(difluoromethoxy)-2,5-dimethylpyridin-3-ylamino)-5-oxo-4,5-dihydropyrazine-2-carbonitrile (2.28 g, 87% yield) as pale yellow solid: 1H NMR (CDCl3) δ 8.43 (s, 1H); 8.01 (s, 1H); 7.56 (s, 1H); 7.49 (t, JH-F=73.8 Hz, 1H); 4.15-4.18 (m, 1H); 3.76 (dd, JAB=10.4, JAX=5.2 Hz, 1H); 3.68 (dd, JBA=10.4, JBX=3.1 Hz, 1H); 3.37 (s, 3H); 2.46 (s, 3H); 2.30 (s, 3H); 1.35-1.42 (m, 1H); 0.82-0.88 (m, 1H); 0.64-0.69 (m, 1H); 0.53-0.58 (m, 1H); 0.31-0.36 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 153.0, 151.5, 147.8, 143.8, 133.3, 129.4, 125.6, 119.1, 117.2, 114.8 (t, J=256.1 Hz, 1 C), 107.6, 72.7, 62.6, 59.6, 20.0, 15.5, 11.4, 6.4, 4.2; 19F NMR (CDCl3) δ −88.73 (d); LRMS (ESI) m/e 406 [(M+H)+, calcd for C19H22N5O3F2 406]; tR=2.7 min (Solvent A: MeOH:H2O:TFA 10:90:0.1; Solvent MeOH:H2O:TFA=90:10:0.1; 40% B in A to 100% B in A linear gradient in a 3 min run with 1 min hold time at the end, λ=280 nm).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2([C:10]#[N:11])[CH2:9][CH2:8]2)[CH:4]=[N:3][CH:2]=1.[ClH:12].[CH2:13]([OH:15])[CH3:14]>>[ClH:12].[N:1]1[CH:6]=[C:5]([C:7]2([C:10](=[NH:11])[O:15][CH2:13][CH3:14])[CH2:8][CH2:9]2)[CH:4]=[N:3][CH:2]=1
Reactant: CCO
Reactant: N#CC1(c2cncnc2)CC1
Agent: Cl
Product: CCOC(=N)C1(c2cncnc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(Pyrimidin-5-yl)cyclopropanecarbonitrile (28 mg, 0.19 mmol) was suspended into ethanol (2 mL) previously saturated with gaseous hydrogen chloride. Hydrogen chloride was bubbled for an additional 30 seconds through the mixture and the resulting mixture was stirred for 18 h at room temperature. The solvent was removed under a flow of nitrogen to afford the title compound as a white solid (43 mg) which was used without further purification. 1H NMR (500 MHz, CD3OD) δ 1.45 (t, 3H), 1.70-1.76 (m, 2H), 1.98-2.07 (m, 15H), 4.43 (q, 2H), 8.96 (s, 2H), 9.24 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[N:7][CH:6]=1)[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21]O)[CH:17]=[CH:18][CH:19]=1>>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[C:9]([O:11][CH2:21][CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([Cl:13])[CH:15]=2)[CH:8]=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cncc(O)c1
Reactant: OCCc1cccc(Cl)c1
Product: CCOC(=O)c1cncc(OCCc2cccc(Cl)c2)c1

Procedure:
5-Hydroxy-nicotinic acid ethyl ester and 2-(3-chlorophenyl)ethanol were etherified in a Mitsunobu reaction in analogy to step 3 of example 3 to yield the title compound.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@H:26]5[CH2:30][CH2:29][CH2:28][NH:27]5)[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.[CH2:32]=O>C(O)=O>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@H:26]5[CH2:30][CH2:29][CH2:28][N:27]5[CH3:32])[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: C=O
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC[C@H]3CCCN3)cc2c1=O
Solvent: O=CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC[C@H]3CCCN3C)cc2c1=O

Procedure:
N-Cyclopropyl-4-methyl-3-[4-oxo-6-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-3(4H)-yl]benzamide (0.15 g) and 38% aqueous formaldehyde (0.284 ml) were stirred in formic acid (3 ml) at 90° C. for 4 hours and then concentrated. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution. The organic layer was washed with brine, dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting with 10% methanol/ethyl acetate followed by 10% methanol/ethyl acetate+1% aqueous ammonia solution to give the title compound (0.128 g) as a pale yellow foam solid; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.70 (m, 2H), 1.70 (m, 3H), 1.99 (m, 1H), 2.14 (s, 3H), 2.21 (m, 1H), 2.40 (s, 3H), 2.61 (m, 1H), 2.85 (m, 1H), 2.96 (m, 1H), 3.99 (m, 1H), 4.10 (m, 1H), 7.52 (m, 2H), 7.60 (s, 1H), 7.73 (d, 1M), 7.85 (s, 1H), 7.91 (d, 1H), 8.20 (s, 1H), 8.43 (d, 1H); Mass Spectrum: M+H+ 433.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15](B4OC(C)(C)C(C)(C)O4)=[C:16]([F:19])[CH:17]=3)[CH2:12][N:11](C)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.ClC(OC(Cl)C)=O>CN(C)C=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:32]=4)=[C:16]([F:19])[CH:17]=3)[CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CS(=O)(=O)c1cccc(Br)c1
Reactant: CN1Cc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc2C(c2ccc(Cl)c(Cl)c2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(Cl)OC(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(-c2cc3c(cc2F)C(c2ccc(Cl)c(Cl)c2)CNC3)c1

Procedure:
Following the procedure of Step A and Step B of Example 19, 4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (500 mg, 1.1 mmol), 1-bromo-3-(methylsulfonyl)benzene (517 mg, 2.2 mmol), cesium carbonate (1.08 g, 3.3 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (44 mg, 0.06 mmol) in N,N-dimethylformamide (10 mL) and water (3 mL) followed by N-de-methylation with N1,N1,N8,N8-tetramethylnaphthalene-1,8-diamine (240 mg, 1.12 mmol) and 1-chlorethyl chloroformate (0.31 mL, 2.8 mmol) gave after purification by preparative HPLC followed by preparative thin layer chromatography (90:10:1 diethyl ether/methanol/concentrated ammonium hydroxide) 4-(3,4-dichlorophenyl)-6-fluoro-7-(3-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (38 mg, 15%) as a colorless oil: 1H NMR (CDCl3, 500 MHz) δ 8.10 (s, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.84 (d, J=7.5 Hz, 1H), 7.65 (dd, J=8.0, 8.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.26 (s, 1H), 7.20 (d, J=7.5 Hz, 1H), 7.01 (dd, J=8.0, 2.0 Hz, 1H), 6.71 (d, J=11.0 Hz, 1H), 4.20-4.09 (m, 3H), 3.43 (dd, J=13.0, 5.5 Hz, 1H), 3.10 (s, 3H), 3.07 (dd, J=13.0, 6.5 Hz, 1H), 2.04 (br s, 1H); ESI MS m/z 450 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][CH2:16][CH2:17][CH2:18][C:19]1[C:26]([CH3:27])=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[CH3:28].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:15][CH2:16][CH2:17][CH2:18][C:19]1[C:26]([CH3:27])=[CH:25][C:22]([C:23]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:21][C:20]=1[CH3:28]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: Cc1cc(C=O)cc(C)c1CCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(CCCO)c(C)c3)nc2c1
Temperature: 115 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-4,6-dimethoxy-benzamide (0.80 g, 4.00 mmol) and 4-(3-hydroxy-propyl)-3,5-dimethyl-benzaldehyde (0.98 g, 5.1 mmol) in N,N-dimethylacetamide (15 mL) were added NaHSO3 (58.5 wt %, 0.80 g, 4.40 mmol) and p-TSA (0.155 g, 0.81 mmol) and the reaction mixture was heated at 115° C. for 16 hours, then cooled to room temperature. N,N-dimethylacetamide was removed under reduced pressure. The residue was diluted with water (50 mL), stirred for 30 minutes, and then filtered and washed with water. The crude compound was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in dichloromethane as eluent) to give 2-[4-(3-hydroxy-propyl)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one as an off-white solid. Yield: 1.10 g (73%).
Reaction SMILES: C(=O)([O:7][C:8]1[CH:25]=[CH:24][C:11]2[N:12]([CH2:21][O:22][CH3:23])[C:13](=[O:20])[C:14]3[CH:15]=[CH:16][CH:17]=[N:18][C:19]=3[C:10]=2[CH:9]=1)OC(C)(C)C.O1CCOCC1.Cl>O1CCOCC1>[OH:7][C:8]1[CH:25]=[CH:24][C:11]2[N:12]([CH2:21][O:22][CH3:23])[C:13](=[O:20])[C:14]3[CH:15]=[CH:16][CH:17]=[N:18][C:19]=3[C:10]=2[CH:9]=1
Reactant: COCn1c(=O)c2cccnc2c2cc(OC(=O)OC(C)(C)C)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: COCn1c(=O)c2cccnc2c2cc(O)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.3 %

Procedure:
The compound (580 mg, 1.627 mmol) prepared in step 4 was dissolved in 1,4-dioxane (10 ml), added with 3.7 N hydrochloric acid 1,4-dioxane solution (6 ml). The resulting mixture was stirred for one day at room temperature and the precipitate was collected by filtration to obtain the title compound (410 mg, yield: 98%, yellow solid).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([CH2:17][CH2:18][CH2:19][CH3:20])[CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[H-].[Na+].[C:24]([O:28][C:29](=[O:39])[NH:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][N:32]=1)([CH3:27])([CH3:26])[CH3:25].C(O)C>CN(C=O)C.O>[CH2:10]([O:9][C:7](=[O:8])[C:6]([CH2:37][C:34]1[CH:33]=[N:32][C:31]([NH:30][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:39])=[CH:36][CH:35]=1)([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]([CH2:17][CH2:18][CH2:19][CH3:20])[C:4]([O:3][CH2:1][CH3:2])=[O:21])[CH3:11]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Reactant: CCCCC(C(=O)OCC)C(C(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CCCCC(C(=O)OCC)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Yield: 78.6 %

Procedure:
A solution of 2-butyl-3-ethoxycarbonyl-succinic acid diethyl ester (1 g, 3 mmol) and NaH (119 mg, 5 mmol) in DMF (20 ml) was stirred for 60 minutes at 0° C. under argon. (5-Bromomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (1.425 g, 5 mmol) was added and the mixture was stirred at room temperature for one week. Ethanol (1 ml) was added and the reaction was poured into H2O and extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The product was purified by column chromatography (heptane/ethyl acetate, 4:1 to 1:1) to give 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-3-butyl-2-ethoxycarbonyl-succinic acid diethyl ester (1.2 g, 71.3%).
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:18]1=[O:36]>C1(C)C=CC=CC=1.[Pd]>[CH2:14]([O:13][C:11]([CH:10]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[C:18]1=[O:36])[CH2:9][CH:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:12])[CH3:15]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CCc2ccccc21
Reactant: CCOC(=O)C=CC(=O)c1ccccc1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CC(O)c1ccccc1)NC1CCc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Reaction time: 18 h

Procedure:
Ethyl 3-benzoylacrylate (13a) (55.6 g, 250 mmoles) is dropped into a solution of (3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one (11) (66.2 g, 227 mmoles) in 200 ml of toluene, at room temperature in 1 h. The resulting mixture is left under stirring for 18 h, then added with 10% Pd—C (26 g, 22 mmoles) and hydrogenated at 3 atm for 18 h at room temperature. The solvent is evaporated off and the residue is purified by chromatography (eluent: hexane-ethyl acetate 7:3). A mixture of isomeric products is isolated.