Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([CH2:11][CH2:12][OH:13])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].C(=O)([O-])O.[Na+]>ClCCl>[S:26]([O:13][CH2:12][CH2:11][C:10]1[CH:9]=[CH:8][C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:15][CH:14]=1)(=[O:28])(=[O:27])[CH3:25]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccc(N2CCOCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccc(N2CCOCC2)cc1
Reaction time: 4 h

Procedure:
4-Morpholinophenethyl alcohol (2.35 g, 11.3 mmol) was dissolved in dichloromethane (20 ml). Diisopropylethylamine (2.60 ml, 14.8 mmol) and methanesulfonyl chloride (1.11 ml, 14.8 mmol) were added to the obtained solution at 0° C., and they were stirred for 4 hours. The reaction mixture was distributed into 5% aqueous sodium hydrogencarbonate solution and dichloromethane. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (3:1) and then with them (1:1) as the eluents, suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain 4-morpholinophenethyl mesylate in the form of a white solid (2.60 g, 81%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[N:3]1.[NH2:24][CH2:25][CH:26]([OH:31])[C:27]([F:30])([F:29])[F:28]>>[CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:24][CH2:25][CH:26]([OH:31])[C:27]([F:30])([F:29])[F:28])=[O:15])=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[N:3]1
Reactant: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)O)cn1
Reactant: NCC(O)C(F)(F)F
Product: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)NCC(O)C(F)(F)F)cn1
Yield: 62 %

Procedure:
As described for example 26b, 6-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid (75 mg, 0.24 mmol) was converted, using 3-amino-1,1,1-trifluoro-2-propanol instead of 4-aminotetrahydropyran, to the title compound (63 mg, 62%) which was obtained as a white solid. MS: m/e=423.1 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:3])[CH3:2].O.[I:16]Cl>CO>[C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([I:16])[C:6]=1[OH:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClI
Reactant: CC(C)(C)c1cc([N+](=O)[O-])ccc1O
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc([N+](=O)[O-])cc(I)c1O
Reaction time: 2 h
Yield: 96 %

Procedure:
To the product from Example 1, Part A (4.5 g, 23.05 mmol) dissolved in MeOH (120 ml) and water (30 mL) was added iodine monochloride (1.155 ml, 23.05 mmol) drop wise over a period of 10 min. The mixture was stirred for 2 h and diluted into 1 L of water and allowed to stand overnight. The solid material was collected by filtration and washed 3×50 mL with water and dried under vacuum overnight to give a tan solid (7.14 g, 96%).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[C:12]([S:13]2(=[O:17])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=12.ClC1C(=O)[C:25](C#N)=[C:26]([C:31]#[N:32])C(=O)C=1Cl.C(N)CC>C1COCC1>[CH2:31]([NH:32][C:15]1[C:2](=[O:1])[C:3]2[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=2[C:5]2[C:14]=1[S:13](=[O:17])(=[O:16])[C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[N:6]=2)[CH2:26][CH3:25]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: O=S1(=O)c2ccccc2Nc2c1cc(O)c1ccccc21
Solvent: CCCN
Solvent: C1CCOC1
Product: CCCNC1=C2C(=Nc3ccccc3S2(=O)=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 62.8 %

Procedure:
To a suspension of 5-hydroxy-12H-benzo[a]phenothiazine-7,7-dioxide (594 mg) in THF (10 ml) was added 2,3-dichloro 5,6-dicyano-1,4-benzoquinone (1.021 gram). The mixture was stirred at room temperature for 2 minutes, then there was added n-propyl amine (0.2 ml). The stirring was continued for 0.5 hour, then the mixture was evaporated to dryness. To the residue was added 50 ml dichloromethane and the mixture was stirred for 15 minutes and filtered. The filtrate was evaporated to dryness and the residue crystallized from a mixture of toluene and hexane to afford the title compound (442 mg) as a red-brown crystalline solid, m.p. 149°-151° C. (dec.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl.Cl.[CH3:16][N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([NH2:26])[C:20]=2[N:19]=[CH:18]1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:26][C:25]2[C:20]3[N:19]=[CH:18][N:17]([CH3:16])[C:21]=3[CH:22]=[CH:23][CH:24]=2)[CH:7]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: Cn1cnc2c(N)cccc21
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nnc(Cl)cc1Nc1cccc2c1ncn2C
Yield: 61.5 %

Procedure:
A heavy walled resealable tube, was charged with ethyl 4,6-dichloropyridazine-3-carboxylate (500 mg, 2.26 mmol) and 1-methyl-1H-benzo[d]imidazol-4-amine dihydrochloride (498 mg, 2.26 mmol) in acetonitrile (3.5 mL) with stirring. DIPEA (877 mg, 1.19 mL, 6.79 mmol) was added and the tube was heated with stirring in an oil bath at 80° C. for 24 h. Solvents evaporated and crude purified by flash chromatography (silica 20-45 μM, 80 g, Thomson, 0 to 20% acetone in dichloromethane, 20 min) to give ethyl 6-chloro-4-(1-methyl-1H-benzo[d]imidazol-4-ylamino)pyridazine-3-carboxylate (461 mg, 1.39 mmol, 61%) as a light yellow solid. 1H NMR (CHLOROFORM-d) δ: 10.42 (s, 1H), 7.92 (s, 1H), 7.30-7.45 (m, 2H), 7.23-7.28 (m, 1H), 7.20 (s, 1H), 4.59 (q, J=7.1 Hz, 2H), 3.91 (s, 3H), 1.51 (t, J=7.2 Hz, 3H); LC-MS 332.0 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:16]([O-])(=O)/[CH:17]=[CH:18]/[C:19]([O-])=O>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH:17]4[CH2:7][C:6]5[C:19](=[CH:2][CH:3]=[CH:4][CH:5]=5)[CH2:18]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: c1cc2c(cc1N1CCNCC1)CCO2
Product: c1ccc2c(c1)CC(CN1CCN(c3ccc4c(c3)CCO4)CC1)C2

Procedure:
Prepared as described in Example 9, starting from 4-(2,3-dihydrobenzofuran-5-yl)-piperazine. The fumarate of the title compound melts at 180°-182° C. (ethanol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][NH:6][C:7]([CH:9]1[CH2:12][NH:11][CH2:10]1)=[O:8].CS[C:16]1[S:17][CH2:18][C:19](=[O:21])[N:20]=1>>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][NH:6][C:7]([CH:9]1[CH2:10][N:11]([C:16]2[S:17][CH2:18][C:19](=[O:21])[N:20]=2)[CH2:12]1)=[O:8]
Reactant: COC(=O)CCNC(=O)C1CNC1
Reactant: CSC1=NC(=O)CS1
Product: COC(=O)CCNC(=O)C1CN(C2=NC(=O)CS2)C1

Procedure:
3-{[1-(4-Oxo-4,5-dihydro-thiazol-2-yl)-azetidine-3-carbonyl]-amino}-propionic acid methyl ester was prepared from 3-[(Azetidine-3-carbonyl)-amino]-propionic acid methyl ester and 2-Methylsulfanyl-thiazol-4-one following General Procedure D.
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[N:13][N:14]([CH3:28])[C:15]=1[CH2:16][O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][N:19]=1>O.C1COCC1>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[N:13][N:14]([CH3:28])[C:15]=1[CH2:16][O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3F)nnn2C)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nnc(-c2ccccc2F)c1COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A solution of lithium hydroxide monohydrate (23 mg, 0.56 mmol) in water (0.8 mL) was added dropwise to a suspension of methyl 6-((4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methoxy)nicotinate (95 mg, 0.28 mmol) in THF (0.8 mL). The reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was then evaporated and the residue dissolved in water, acidified with HCl (1N), and the resulting precipitate filtered off to afford the title product (68 mg, 75%) as a white solid. MS: m/e=327.1 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH:17]3[CH2:19][O:18]3)[CH:13]=2)[NH:8][C:7]=1[CH3:20])=[O:5])[CH3:2].[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[Li+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:21]=[N+:22]=[N-:23])[CH:13]=2)[NH:8][C:7]=1[CH3:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)[nH]c2ccc(OCC3CO3)cc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)[nH]c2ccc(OC[C@@H](O)CN=[N+]=[N-])cc12
Temperature: 25 °C
Yield: 38.8 %

Procedure:
A solution of 1.4 g (5.1 mmol) of 2-methyl-5-oxiranylmethoxy-1 H-indole-3-carboxylic acid ethyl ester (which was obtained in Example 139), 0.5 g (7.6 mmol) of sodium azide and 0.43 g (10.2 mmol) of lithium chloride in 15 mL anhydrous DMF was heated at 60° C. overnight. The mixture was cooled to room temperature and quenched with water. The aqueous mixture was extracted with ethyl acetate. The organic layer was washed twice with water, dried over sodium sulfate and concentrated in vacuo. The residue was then purified by flash chromatography (10% EtOAc in hexanes to 50% EtOAc in hexanes) to give 0.63 g of the title compound as a yellow solid; mp 75-77° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.34 (t, J=7.1 Hz, 3H), 2.66 (s, 3H), 3.42 (d, 4.6 Hz, 1H), 3.89-3.95 (m, 2H), 4.00-4.06 (m, 1H), 4.26 (q, J=7.1 Hz, 2H), 5.55 (d, J=5.1 Hz, 2H), 6.76 (dd, J=8.7, 2.7 Hz, 1H), 7.24 (d, J=8.7 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H), 11.65 (s, 1H); MS (ES) m/z: 319.0 (MH+); HRMS Calcd. for C15H18N4O4 (M+): 318.1328. Found: 318.1334.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([CH3:26])[CH:20]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:23][C:22]1[CH:24]=[CH:25][C:19]([Cl:18])=[CH:20][C:21]=1[CH3:26])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(Cl)ccc1N
Reactant: CCCC(=O)c1cnc2c(C)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(C)cccc2c1Nc1ccc(Cl)cc1C
Yield: 41.4 %

Procedure:
3-Butyryl-4-chloro-8-methylquinoline (1.24 g, 5 mmol) and 4-chloro-2-methylaniline (1.06 g, 7.5 mmol) in dioxan (5 ml) were heated at reflux for 30 minutes, then allowed to cool. The product was filtered off, converted to free base, and recrystallised from methanol, to give 3-butyryl-4-(4-chloro-2-methylphenylamino)-8-methylquinoline (0.73 g), m.p. 166°-167°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:17]=1)[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.[Na]>C(Cl)Cl.CC(O)C>[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:1][CH2:2][C:3]2[CH:4]=[C:5]([CH:15]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:17]=2)[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(CN)cc(Oc2ccc(F)cc2)c1
Reactant: O=Cc1ccc(F)cc1
Agent: [Na]
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCc1cc(CNCc2ccc(F)cc2)cc(Oc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 66.7 %

Procedure:
To a solution of tert-butyl 3-(aminomethyl)-5-(4-fluorophenoxy)benzylcarbamate (1.37 g, 3.96 mmol) in CH2Cl2 (15 mL) and 2-propanol (15 mL) was added 4-fluorobenzaldehyde (0.42 mL, 3.96 mmol). The reaction mixture was stirred at rt. under nitrogen for 40 min, and then treated with sodium triacetoxyhydroborate (1.76 g, 8.31 mmol). The resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated and the residue was partitioned between saturated NaHCO3 solution and ethyl acetate. The organic layer (clear solution) was washed with brine and dried over MgSO4. The filtrate was concentrated. The sample was purified by flash chromatography. Elution with 0-35% of ethyl acetate in CH2Cl2 gave the product as viscous oil (1.2 g, 67%). 1H NMR (CD3OD): δ 7.35-7.32 (m, 2H), 7.13-6.99 (m, 7H), 6.87 (s, 1H), 6.80 (s, 1H), 4.20 (s, 2H), 3.70 (s, 2H), 1.44 (s, 9H); MS (ESI): (M−H)−=513.1.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][OH:6])[CH2:3][CH2:2]1.[N+:7]([C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([N+]([O-])=O)[C:11]=1[C:12]#[N:13])([O-:9])=[O:8]>>[CH:1]1([CH2:4][CH2:5][O:6][C:14]2[CH:15]=[CH:16][CH:17]=[C:10]([N+:7]([O-:9])=[O:8])[C:11]=2[C:12]#[N:13])[CH2:3][CH2:2]1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: OCCC1CC1
Product: N#Cc1c(OCCC2CC2)cccc1[N+](=O)[O-]
Yield: 85 %

Procedure:
Prepared as in Example 187c from 2-cyclopropylethanol and 2,6-dinitrobenzonitrile in 85% yield as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 0.15-0.20 (m, 2H), 0.43-0.47 (m, 2H), 0.84-0.89 (m, 1H), 1.69 (q, J=6.8 Hz, 2H), 4.31 (t, J=6.4 Hz, 2H), 7.73-7.76 (m, 1H), 7.86-7.93 (m, 2H). MS 233 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18](OC)=[O:19].[NH2:22][C:23]1[S:24][C:25]([CH3:28])=[N:26][N:27]=1>>[OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18]([NH:22][C:23]1[S:24][C:25]([CH3:28])=[N:26][N:27]=1)=[O:19]
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Reactant: Cc1nnc(N)s1
Product: Cc1nnc(NC(=O)C2=C(O)c3sc4ccccc4c3S(=O)(=O)N2C)s1
Yield: 65 %

Procedure:
Prepared analogous to Example 1 from methyl 4-hydroxy-2-methyl-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 2-amino-5-methyl-1,3,4-thiadiazole with a yield of 65% of theory.
Reaction SMILES: [CH2:1]([CH:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[Br:12]Br>O>[Br:12][CH2:10][C:9](=[O:11])[CH:3]([CH2:1][CH3:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(CC)C(C)=O
Reactant: BrBr
Solvent: O
Product: CCOC(=O)C(CC)C(=O)CBr
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 2-ethyl-3-oxobutanoate (5.17 g, 32.7 mmol) in water (10 mL) at 0° C. was added bromine (1.684 mL, 32.7 mmol) dropwise over 2 h. The resulting solution was stirred at rt for 16 h. The mixture was extracted with ethyl acetate (100 mL) and the organic phase was dried over sodium sulfate and concentrated to give ethyl 4-bromo-2-ethyl-3-oxobutanoate. 1HNMR (500 MHz, CDCl3), δ4.327-4.284(m, 2H), 2.412(s, 2H), 2.320-2.212 (q, 2H), 1.338-10309 (m, 3H), 1.042-1.013 (t, J=7.3 Hz, 3H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8](C(=O)C3C=CC=CC=3)[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.O.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[C:20]1([C:2]2[N:7]=[C:6]3[NH:8][CH:9]=[CH:10][C:5]3=[CH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(c1ccccc1)n1ccc2ccc(Br)nc21
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: c1ccc(-c2ccc3cc[nH]c3n2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
A solution of 6-bromo-1-benzoyl-1H-pyrrolo[2,3-b]pyridine (0.19 g, 0.64 mmol) obtained in Example A47, Step 1 in 1,2-dimethoxyethane (5.0 mL) was successively added with water (2.0 mL), phenylboronic acid (0.16 g, 0.64 mmol), and sodium carbonate (0.20 g, 1.9 mmol). After the inside of the reaction vessel was replaced with argon, the reaction mixture was added with tetrakis(triphenylphosphine)palladium(0) (0.074 g, 0.064 mmol), and the mixture was stirred overnight at 110° C. in a sealed tube. The reaction mixture was extracted with ethyl acetate, and then the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (99:1→99:5)) to obtain 6-phenyl-1H-pyrrolo[2,3-b]pyridine (0.10 g, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5](Cl)[C:6](=O)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[S:22])=[CH:19][CH:18]=1.O>CCO>[CH2:1]([O:3][C:4]([C:5]1[S:22][C:21]([C:20]2[CH:24]=[CH:25][C:17]([Cl:16])=[CH:18][CH:19]=2)=[N:23][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:15])[CH3:2]
Reactant: CCOC(=O)CC(=O)C(Cl)C(=O)OCC
Reactant: NC(=S)c1ccc(Cl)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)OCC
Temperature: 75 °C
Reaction time: 5.5 h
Yield: 85.1 %

Procedure:
Dissolve 2-chloro-3-oxo-pentanedioic acid diethyl ester (1370 g, 5.50 mol) in EtOH (8.5 L) and add 4-chloro-thiobenzamide (885 g, 5.00 mol). Heat the mixture to 75° C. and stir mechanically for 5.5 h. Cool the mixture to 45° C., then slowly add water (3.5 L) and stir overnight. Collect the yellow precipitate and wash the solids with 50% EtOH/water (4 L). Dry in an oven to obtain 1505 g (81%) of the title compound. 1H NMR (CDCl3, 500 MHz): δ 7.90 (d, 2H, J=7.4), 7.41 (d, 2H, J=7.4), 4.34 (q, 2H, J=6.8), 4.24 (s, 2H), 4.19 (q, 2H, J=7.4), 1.36 (t, 3H, J=6.8), 1.27 (t, 3H, J=6.8).
Reaction SMILES: CS([O:5][C@@H:6]([CH3:16])[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])(=O)=O.CC(C)([O-])C.[K+].CS(C)=O.[Cl:27][C:28]1[CH:29]=[C:30](O)[CH:31]=[N:32][C:33]=1[O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[N:41]=[CH:40][N:39]=[C:38]2[NH:45][C:46]1[CH:50]=[CH:49][N:48]([CH3:51])[N:47]=1>O>[Si:9]([O:8][CH2:7][C@@H:6]([CH3:16])[O:5][C:30]1[CH:29]=[C:28]([Cl:27])[C:33]([O:34][C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[N:41]=[CH:40][N:39]=[C:38]3[NH:45][C:46]2[CH:50]=[CH:49][N:48]([CH3:51])[N:47]=2)=[N:32][CH:31]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: Cn1ccc(Nc2ncnc3ccc(Oc4ncc(O)cc4Cl)cc23)n1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)Oc1cnc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)c(Cl)c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 33.1 %

Procedure:
(1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl methanesulfonate (79 mg, 0.29 mmol) and potassium tert-butoxide (55 mg, 0.49 mmol) were added to a dimethyl sulfoxide solution (3 ml) of 5-chloro-6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-ol (90 mg, 0.24 mmol) obtained in Example 22, then stirred for 24 hours at 100° C. The reaction solution was cooled to room temperature, water was added, and extracted with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2 to 0:1) to obtain 6-{[5-((1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-3-chloropyridin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)quinazoline-4-amine (43 mg, yield: 33%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[CH3:14].[NH2:15][C:16]1[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=1)=[O:19].S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[OH:1][CH2:2][CH2:3][O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([C:9]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=3)[C:18](=[O:19])[C:17]3[C:16](=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:15]=2)=[CH:7][C:6]=1[CH3:14]
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Reactant: Nc1ccccc1C(=O)Nc1ccc(I)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(I)cc2)cc(C)c1OCCO
Temperature: 155 °C

Procedure:
To a mixture of 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (0.570 g, 2.96 mmol) and 2-amino-N-(4-iodo-phenyl)-benzamide (1.00 g, 2.96 mmol) in N,N-dimethylacetamide (10 mL) was added sodium hydrogen sulfite (0.470 g, 4.44 mmol) and p-toluenesulfonic acid (0.280 g, 1.48 mmol). The reaction mixture was heated at 155° C. for 14 hours. The reaction mixture was cooled to room temperature and diluted with cold water (20 mL) to produce the precipitate. The yellow solid was filtered, washed with cold water (2×20 mL), methanol and dried under vacuum to provide crude product, which was purified by column chromatography (silica gel 230-400 mesh; 10% EtOAc/hexane as eluent) to give the title compound as white solid. Yield: 0.20 g (13%). MP 101-103° C. 1H-NMR (400 MHz, CDCl3): δ 8.38 (d, 1H), 7.81-7.78 (m, 2H), 7.75 (d, 2H), 7.59-7.48 (m, 1H), 7.01-6.85 (m, 4H), 3.98-3.81 (m, 4H), 2.40 (s, 6H), 2.01 (t, 1H). MS (ES+) m/z: 513.09 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]1([NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:29]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:22])[NH:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH2:30])[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(C(=O)O)c2)CC1
Reactant: Nc1ccccc1N
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(C(=O)Nc3ccccc3N)c2)CC1
Temperature: 25 °C
Yield: 39.8 %

Procedure:
A solution of 4-(3-carboxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (5.80 g, 18.95 mmol) and 1,1-carbonyldiimidazole (CDI) (3.07 g, 18.95 mmol) in acetonitrile (120 mL) was stirred for 3 h at room temperature, then 1,2-phenylenediamine (2.25 g, 20.85 mmol) was added. The resulting suspension was refluxed for 3 h, then cooled to room temperature and the solvent removed under reduced pressure. The resulting residue was diluted with dichlomethane (200 mL), washed with water (3×40 mL) and the organic layer dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was recrystallized from EtOAc to obtain 2.99 g (40%) of the title compound.