Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][N:13]1[CH2:18][CH2:17][C:16]([CH2:25][NH2:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:26][CH2:25][C:16]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: CN1CCC(CN)(c2ccccc2)CC1
Product: CN1CCC(CNC(=O)c2cccc(Cl)c2Cl)(c2ccccc2)CC1

Procedure:
From 2,3-dichlorobenzoic acid and C-(1-methyl-4-phenyl-piperidin-4-yl)-methylamine. LCMS (MH+): m/z=376.9, tR (minutes, Method A)=0.69
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH2:20][C:21](=[O:27])[NH:22]2>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:20]1[C:19]2[C:23](=[CH:24][CH:25]=[CH:26][C:18]=2[CH3:17])[NH:22][C:21]1=[O:27])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: Cc1cccc2c1CC(=O)N2
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3cccc(C)c32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 4-methyl-2-oxindole to give 0.3 g of 3-(3,5-diisopropyl-4-methoxybenzylidene)-4-methyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].[CH3:22]I>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]=[C:7]2[N:12]([CH3:22])[C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[N:17][C:9]=3[S:8]2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=c1nc(Nc2ccc(Cl)cc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Product: Cn1c(=Nc2ccc(Cl)cc2)sc2ncccc2c1=O
Yield: 58.8 %

Procedure:
The reaction procedure of Example 11 was followed except that 900 mg (3.11 mmol) of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 25 mg of lithium hydride and 440 mg of methyl iodide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 554 mg of 2-[(4-chlorophenyl)imino]-2,3-dihydro-3-methyl-4H-pyrido[3,2-e]-1,3-thiazin-4-one (59%, recrystallized from a mixture of ether and hexane).
Reaction SMILES: [CH:1](=[N:3][O:4][CH2:5][C:6]1[N:7]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:8]2[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]3N=N[N:18]=[C:10]3[C:9]=2[N:19]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClC1C=CC=CC=1Cl>[NH2:18][C:10]1[C:9]2[N:19]=[C:6]([CH2:5][O:4][N:3]=[CH:1][CH3:2])[N:7]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:8]=2[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=1
Reactant: CC=NOCc1nc2c(c(C)c(C)n3nnnc23)n1CCCCNC(=O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Clc1ccccc1Cl
Product: CC=NOCc1nc2c(N)nc(C)c(C)c2n1CCCCNC(=O)c1ccccc1
Temperature: 125 °C
Reaction time: 8 h
Yield: 1.7 %

Procedure:
A mixture of N-{4-[8-({[ethylideneamino]oxy}methyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butyl}benzamide (2.0 g, 4.6 mmol), triphenylphosphine (2.4 g, 9.2 mmol), and 1,2-dichlorobenzene (50 mL) was heated at 125° C. for 2 days. The reaction mixture was allowed to cool to room temperature and was concentrated under reduced pressure. The residue was dissolved in methanol (40 mL) and 1 M aqueous hydrochloric acid (20 mL) was added. The mixture was heated at 50° C. for 6 hours. The mixture was allowed to stand at room temperature overnight and a white precipitate formed that was removed by filtration. The methanol was removed under reduced pressure and chloroform (20 mL) was added. The aqueous phase was adjusted to pH 12 with 1 M aqueous sodium hydroxide. The aqueous phase was extracted with chloroform (3×10 mL). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The material was purified by chromatography using a HORIZON HPFC system (silica gel, gradient elution with 10-35% CMA in chloroform). The appropriate fractions were combined and concentrated under reduced pressure to provide a solid that was triturated with acetonitrile, crystallized from acetonitrile, and purified again by chromatography as described above using 5-40% CMA in chloroform as the eluent to provide 32 mg of N-{4-[4-amino-2-({[ethylideneamino]oxy}methyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]butyl}benzamide as a white powder and as a mixture (approximately 1:1 mixture) of oxime isomers, mp 192.0-194.0° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]([O:21]CC)=O)[CH2:14][CH2:13]1.[NH2:24][NH2:25]>C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]([NH:24][NH2:25])=[O:21])[CH2:14][CH2:13]1
Reactant: NN
Reactant: CCOC(=O)CN1CCN(Cc2ccc3ccccc3c2)CC1
Solvent: CCO
Product: NNC(=O)CN1CCN(Cc2ccc3ccccc3c2)CC1

Procedure:
Synthesized according to General Procedure C: 6{25} (5.74 g, 18.4 mmol, 1 equiv.), anhydrous hydrazine (1.7 mL, 55.2 mmol, 3 equiv.), ethanol (37.2 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{25} (4.49 g, 82%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 8.17 (br s, 1H), 7.82-7.78 (m, 3H), 7.71 (s, 1H), 7.47-7.42 (m, 3H), 3.86 (br s, 2H), 3.64 (s, 2H), 3.06 (s, 2H), 2.53 (br s, 8H). 13C-NMR (125 MHz, CDCl3): δ 170.4, 135.4, 133.1, 132.6, 127.8, 127.5, 127.5, 127.2, 125.9, 125.5, 62.9, 60.5, 53.5, 53.0.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:23])[C:4]2[C:9]([C:10](=[O:22])[C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]C[Si](C)(C)C)=[CH:8][CH:7]=[CH:6][CH:5]=2.C(OC1C(=O)C2C(C(=O)C=1)=CC=CC=2)(=O)C1C=CC=CC=1.[CH3:45][Si:46](C(CCCCC)C(O)=O)([CH3:48])[CH3:47].C(=O)([O-])[O-].[Na+].[Na+].OO>O1CCOCC1.O.S([O-])([O-])(=O)=O.[Cu+2]>[OH:1][C:2]1[C:3](=[O:23])[C:4]2[C:9]([C:10](=[O:22])[C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][Si:46]([CH3:48])([CH3:47])[CH3:45])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CCCCCC(C(=O)O)[Si](C)(C)C
Reactant: C[Si](C)(C)CCCCCCC1=C(O)C(=O)c2ccccc2C1=O
Agent: [Cu+2]
Agent: O=C(OC1=CC(=O)c2ccccc2C1=O)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCCCCC1=C(O)C(=O)c2ccccc2C1=O
Temperature: 70 °C

Procedure:
2-Hydroxy-3(6'-trimethylsilylhexyl)-1,4-naphthoquinone (337 mg, 1.02 mmol), prepared from 2-benzoyloxy-1,4-naphthoquinone and trimethylsilylheptanoic acid by the method of Example 1 followed by the method of Example 2, was dissolved in dioxane (2.5 ml) under nitrogen. Sodium carbonate (120 mg) in water (2.5 ml) was added followed by an excess of 30% (w/v) hydrogen peroxide (200 μl). The mixture was heated at 70° C. for 40 minutes during which time the reaction mixture turned from red to colourless. The reaction mixture was allowed to cool and 20% (w/v) copper sulphate solution (100 μl) was added and the solution stirred until bubbling ceased. 25% (w/v) sodium hydroxide solution (2 ml) and 20% (w/v) copper sulphate solution (5 ml) were then added and the reaction mixture heated at 70° C. for 30 minutes. The mixture was allowed to cool and acidified to pH 2 with 1N hydrochloric acid. The product was extracted into diethyl ether and the ether extract was then washed with brine, dried over anhydrous magnesium sulphate and concentrated in vacuo. The crude material was chromatographed using 5% diethyl ether/hexane as eluent to give 2-hydroxy-3(5'-trimethylsilylpentyl)-1,4-naphthoquinone (202 mg) which was recrystallised from hexane, m. pt. 73-75° C. NMR peaks at: 184.6, 181.4, 153.0, 134.8, 132.9, 132.7, 129.4, 126.7, 126.0, 124.8; 33.6, 27.9, 33.7, 23.2, 16.5; -1.7.
Reaction SMILES: COP([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)(=O)OC.COP(C1C=CC2C(=CC=CC=2)C=1)(=O)OC>>[CH:15]1[C:16]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: COP(=O)(OC)c1cccc2ccccc12
Agent: COP(=O)(OC)c1ccc2ccccc2c1
Product: c1ccc2ccccc2c1

Procedure:
Working up is carried out analogously to Example 4 and gives, in addition to 3.3 g of naphthalene, 14.2 g (81%) of a mixture of isomers, dimethylnaphthalene-1-phosphonate (88.8% by area) and dimethylnaphthalene-2-phosphonate (9.7% by area). The current efficiency is 44%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:29][OH:30])[C:5]([CH2:21][O:22]C2CCCCO2)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2.[C:31]1(O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:1][C:2]1[C:10]2[N:9]([S:11]([C:14]3[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=3)(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=2[C:5]([CH:21]=[O:22])=[C:4]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:3]=1
Reactant: Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(CO)cc(C)c32)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)c(COc4ccccc4)cc(C)c32)cc1

Procedure:
The title compound was prepared from (±)-(7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indol-5-yl)methanol (Example 52-C) using phenol instead of phthalimide in the method depicted in Example 53. MS (ESI+) m/z 420.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:26]4[CH:31]=[CH:30][C:29]([O:32]CC5C=CC(Cl)=C(Cl)C=5)=[CH:28][CH:27]=4)[C:15](=[O:25])[NH:16]3)=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:26]4[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=4)[C:15](=[O:25])[NH:16]3)=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)NC(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)NC(=O)[C@H](c1ccc(O)cc1)O3

Procedure:
To a solution of (S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester (1 mmol) in methanol was added Pd/C (0.2 mmol). The mixture was hydrogenated using balloon for 2-4 h. The mixture was passed through a pad of celite and the filtrate was evaporated to furnish (S)-3-(4-Hydroxy-phenyl)-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester. This ester was converted to (S)-7-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-(4-hydroxy-phenyl)-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid tert-butyl ester using the general procedure A. LC-MS (m/z): 704.
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:16][CH2:17][C:18]#N>ClCCl>[C:1](=[N:14][CH2:18][C:17]#[N:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: N#CCN
Agent: Cl
Solvent: ClCCl
Product: N#CCN=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 157.5 %

Procedure:
A mixture of benzophenone imine (25 g, 0.138 mol, Aldrich) and aminoacetonitrile hydrochloride (25 g, 0.270 mol, Lancaster) in dichloromethane (1000 ml) was stirred in a 2 L Erlenmeyer flask under nitrogen at room temperature for 5 days. The reaction mixture was filtered to remove the precipitated ammonium chloride and the filtrate was evaporated to dryness in vacuo. The resulting residue was dissolved in ether (400 ml) washed with water (200 ml) and brine. After drying over magnesium sulfate the solution was evaporated to give (benzhydrylideneamino)-acetonitrile (47.89 g).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[C:17]([F:20])([F:19])[F:18])[CH2:5][CH2:4]1)=O.[CH2:21]([NH:24][C:25]1[CH2:29][S:28][C:27](=[O:30])[N:26]=1)[C:22]#[CH:23].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[O:30]=[C:27]1[N:26]=[C:25]([NH:24][CH2:21][C:22]#[CH:23])/[C:29](=[CH:1]/[CH:3]2[CH2:8][CH2:7][N:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=3[C:17]([F:20])([F:19])[F:18])[CH2:5][CH2:4]2)/[S:28]1
Reactant: C#CCNC1=NC(=O)SC1
Reactant: N#Cc1ccc(N2CCC(C=O)CC2)c(C(F)(F)F)c1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(c2ccc(C#N)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
To a solution of 4-(4-formylpiperidin-1-yl)-3-(trifluoromethyl)benzonitrile (800 mg) in 2-propanol (15 mL) were added 4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one (874 mg) and piperidinium acetate (420 mg). The reaction mixture was stirred at 60° C. overnight and concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (849 mg).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14](=[O:22])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=3F)[CH:11]=2)[C:6]([CH3:24])([CH3:23])[CH2:5]1)(=[O:3])[CH3:2].Cl.Cl.[NH:27]1[C:31]2=[N:32][CH:33]=[CH:34][C:35]([CH2:36][NH2:37])=[C:30]2[CH2:29][CH2:28]1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14](=[O:22])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=3[NH:37][CH2:36][C:35]3[CH:34]=[CH:33][N:32]=[C:31]4[NH:27][CH2:28][CH2:29][C:30]=34)[CH:11]=2)[C:6]([CH3:24])([CH3:23])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: NCc1ccnc2c1CCN2
Reactant: CC(=O)N1CC(C)(C)c2ccc(NC(=O)c3cccnc3F)cc21
Agent: Cl
Product: CC(=O)N1CC(C)(C)c2ccc(NC(=O)c3cccnc3NCc3ccnc4c3CCN4)cc21

Procedure:
The titled compound was prepared from N-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-fluoro-nicotinamide and C-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine dihydrochloride by the method described in Step A of Example 1. MS (ES+): 457 (M+H). Calc'd. for C26H28N6O2—456.55.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:21])[C:12]1[CH:17]=[C:16]([OH:18])[C:15]([OH:19])=[C:14]([OH:20])[CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CC(C)=O.O>[CH3:9][O:10][C:11](=[O:21])[C:12]1[CH:13]=[C:14]([O:20][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:15]([O:19][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:16]([O:18][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:17]=1
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
105 g (0.83 mol) of benzyl chloride are added dropwise at 56° C., under reflux, over a period of 10 minutes, to 18.4 g (0.1 mol) of 3,4,5-trihydroxybenzoic acid methyl ester, 50.0 g (0.48 mol) of sodium carbonate and 10.0 g (0.06 mol) of potassium iodide in 200 ml of acetone. After a further 20 hours at reflux, 500 ml of water are added at room temperature and the mixture is then extracted with ether. The crude product is worked up in customary manner, excess benzyl chloride is removed by distillation, and the residue is recrystallised from hexane/ethyl acetate. Colourless crystals, yield 45.0 g (98% of theory)
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].C(N(CC)C(C)C)(C)C.Cl[CH2:21][O:22][CH3:23]>C(Cl)Cl>[CH3:21][O:22][CH2:23][O:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([C:2](=[O:3])[CH3:1])[CH:9]=1
Reactant: COCCl
Reactant: CC(=O)c1cccc(O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cccc(C(C)=O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a stirred solution of 3-hydroxyacetophenone (20.40 g, 150 mmol) in CH2Cl2 (450 mL) at 0° C. under N2 was added N,N-diisopropylethylamine (52.25 mL, 300 mmol) followed by methyl chloromethyl ether (MOM chloride) (13.67 mL, 180 mmol) over a period of 30 min. The reaction was stirred at 0° C. for 30 min and then at room temperature for 2 h. The reaction was quenched with H2O (500 mL). The organic solution was separated, washed with H2O (2×500 mL), 0.5 N NaOH (2×100 mL), and again with H2O (200 mL). The organic solution was dried (Na2SO4) and concentrated. The resulting residue was purified by filtration through a pad of silica gel using n-hexanes through 2-5% EtOAc/n-hexanes to give the desired product (17.30 g, 64%); TLC Rf: 0.45 (20% EtOAc/n-hexanes).
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[NH:6][C:7](=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[NH2:21]>CN(C=O)C.CC(N(C)C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:9]2[C:4]3[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Reactant: O=c1ncc2cc(F)ncc2[nH]1
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Fc1cc2c(Nc3ccc(OCc4ccccn4)c(Cl)c3)ncnc2cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.3 %

Procedure:
A heterogeneous mixture of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one (200) (1.65 g, 10.0 mmol), thionyl chloride (30 ml) and a catalytic amount of DMF (3 drops) was stirred under reflux for 2 h 30 min to give a homogeneous mixture. It was evaporated under reduced pressure at 40° C. (bath temperature) to give a light brown solid. To this solid was added a solution of 3-chloro-4-(pyridin-2-ylmethoxy)aniline (2.58 g, 11.0 mmol) in dry DMA (15 ml). The residue of 3-chloro-4-(pyridin-2-ylmethoxy)aniline was washed down with more DMA (2×5 ml). The reaction mixture was stirred at room temperature for 18 h. It was poured into water (300 ml). The pH was adjusted to ca. 9 using an aqueous solution of Na2CO3 at room temperature. Petroleum ether (300 mL) was added and stirred at room temperature for 30 min. The petroleum ether layer was decanted. It was repeated once more with petroleum ether (300 mL). The solid was collected by filtration and washed with water (4×50 mL). It was stirred with hot (ca. 50° C.) acetone (300 mL) for 15 min. The insoluble materials was filtered off and the filtrate was evaporated under reduced pressure to give N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine (203) (3.18 g, 83%) as a yellow/orange solid, mp 216-219° C.; 1H NMR δ [(CD3)2SO] 10.04 (s, 1H), 8.94 (s, 1H), 8.69 (s, 1H), 8.63-8.57 (m, 1H), 8.22 (br s, 1H), 8.08 (d, J=2.6 Hz, 1H), 7.85 (td, J=7.7, 1.8 Hz, 1H), 7.75 (dd, J=9.0, 2.6 Hz, 1H), 7.59 (br d, J=7.8 Hz, 1H), 7.40-7.35 (m, 1H), 7.32 (d, J=9.0 Hz, 1H), 5.31 (s, 2H). Anal. Calcd for C19H13ClFN5O.0.9H2O: C, 57.34; H, 3.75; N, 17.60. Found C, 57.46; H, 3.82; N, 17.63.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:13]([C:24](OCC)=[O:25])[C:12]2=[O:29])=[CH:2]1.[CH3:30][C:31]([CH3:36])([CH2:34][OH:35])[CH2:32][OH:33]>CN(C)C(=O)C.[Zn]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:13]([C:24]([O:33][CH2:32][C:31]([CH3:36])([CH3:30])[CH2:34][OH:35])=[O:25])[C:12]2=[O:29])=[CH:2]1
Reactant: CCOC(=O)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Reactant: CC(C)(CO)CO
Agent: [Zn]
Solvent: CC(=O)N(C)C
Product: CC(C)(CO)COC(=O)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 17.7 %

Procedure:
A solution of the compound (0.10 g, 0.25 mmol) of Example 21, 2,2-dimethyl-1,3-propanediol (0.40 g, 3.8 mmol) and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.018 g, 0.019 mmol) in N,N-dimethylacetamide (1.5 mL) was stirred with the microwave synthesizer (Biotage Initiator™) at 130° C. for 24 h. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.020 g, y. 17%).
Reaction SMILES: C([Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=1)(C)C)(C)(C)C.C([N-]C(C)C)(C)C.[Li+].[CH3:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]=[O:31].C(O)C>O1CCCC1.CCCCCC.CCCCCCC.C(C1C=CC=CC=1)C>[OH:31][CH:30]([C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[CH3:27])[CH2:18][S:15]([C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1)(=[O:16])=[O:17]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(S(C)(=O)=O)cc1
Reactant: Cc1ccccc1C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Product: Cc1ccccc1C(O)CS(=O)(=O)c1ccc(O)cc1
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
Into a solution of 1.50 g (5.24 mmol) of tert-butyl-(4-methanesulfonylphenoxy)dimethylsilane in tetrahydrofuran (30 mL) was dropped, at −78° C. under an atmosphere of argon, 3.1 mL (6.20 mmol) of 2 mol/L lithium diisopropylamide in hexane-heptane-ethylbenzene (available from Aldrich), and stirred for 1 hour. Into this solution, 0.72 mL (6.23 mmol) of 2-methylbenzaldehyde was dropped at −78° C., and stirred for 30 minutes. Ethanol (30 mL) was added to the reaction mixture and stirred for 18 hours. The reaction mixture was concentrated under a reduced pressure. After addition of 1 N hydrochloric acid to the residue, it was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was removed. The obtained residue was purified by medium pressure column chromatography on silica gel (developing solvent: hexane:ethyl acetate=2:1 to 1:1) to obtain 930 mg (yield 60.8%) of 4-(2-hydroxy-2-o-tolylethanesulfonyl)phenol (XXXI-124) as a colorless crystal. Its physical property is shown below.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][N:15]=[C:16]([NH:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[C:26]([O:30][C:31](=[O:44])[NH:32][CH2:33][CH2:34][CH:35]([NH2:43])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1)([CH3:29])([CH3:28])[CH3:27].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C([O-])([O-])=O.[K+].[K+]>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]>[C:26]([O:30][C:31](=[O:44])[NH:32][CH2:33][CH2:34][CH:35]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1)[NH:43][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][N:15]=[C:16]([NH:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:11]3=[N:10][CH:9]=2)[N:7]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: Brc1cccc(-c2cnc3c(NCCN4CCOCC4)nccn23)n1
Reactant: CC(C)(C)OC(=O)NCCC(N)c1cccc(Cl)c1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCC(Nc1cccc(-c2cnc3c(NCCN4CCOCC4)nccn23)n1)c1cccc(Cl)c1
Temperature: 130 °C

Procedure:
A mixture of [3-(6-bromo-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 41 supra) (0.403 g, 1.0 mmol), [3-amino-3-(3-chloro-phenyl)-propyl]-carbamic acid tert-butyl ester (from Example 62 supra) (0.427 g, 1.5 mmol), Pd2(dba)3 (60 mg), Davephos (80 mg), K2CO3 (207 mg, 1.5 mmol) in dioxane (25 mL) in a sealed tube was bubbled with N2 for several minutes and then heated under N2 at 130° C. overnight. The solution was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative-HPLC to give (3-(3-chloro-phenyl)-3-{6-[8-(2-morpholin-4-yl-ethylamino)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-ylamino}-propyl)-carbamic acid tert-butyl ester. (Yield 50 mg). LC-MS: 607 [M+H]+ 607.