Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[CH3:29][N:30]([CH3:37])[CH2:31]/[CH:32]=[CH:33]/[C:34](O)=[O:35]>>[NH2:13][C:9]1[N:10]=[CH:11][N:12]=[C:7]([O:6][C:5]2[CH:27]=[CH:28][C:2]([NH:1][C:34](=[O:35])/[CH:33]=[CH:32]/[CH2:31][N:30]([CH3:37])[CH3:29])=[CH:3][CH:4]=2)[C:8]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(Oc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)cc1
Reactant: CN(C)C/C=C/C(=O)O
Product: CN(C)C/C=C/C(=O)Nc1ccc(Oc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)cc1
Yield: 29 %

Procedure:
(E)-N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide was prepared from 6-(4-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine and (E)-4-(dimethylamino)but-2-enoic acid using Method E (29% yield). HPLC: 99%, RT=3.448 min. MS: m/z=482 [M+H]+, RT=3.40 min. 1H-NMR (DMSO-d6) δ 10.30 (s, 1H), 8.02 (s, 1H), 7.62 (d, 2H), 7.43-7.38 (m, 4H), 7.15 (tt, 1H), 7.10-7.01 (m, 6H), 6.73 (m, 1H), 6.49 (broad s, 2H), 6.44 (d, 1H), 3.93 (m, 2H), 2.80 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH2:12])[C:3]=1[NH2:13].C(O[C:17]([S-])=[S:18])C.[K+]>O>[CH3:1][C:2]1[C:3]2[N:13]=[C:17]([SH:18])[NH:12][C:4]=2[CH:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: CCOC(=S)[S-]
Reactant: Cc1c(N)c(N)cc2ccccc12
Agent: [K+]
Solvent: O
Product: Cc1c2ccccc2cc2[nH]c(S)nc12
Reaction time: 1 h
Yield: 48.5 %

Procedure:
16.9 g of 1-methyl-2,3-diamino-naphthalene (crude base) were suspended in 250 ml of alcohol in a 500 ml sulfonation flask equipped with stirrer, thermometer and reflux condenser and, after adding 25 ml of water as well as 18.8 g of potassium ethylxanthate, recrystallized from isopropanol, boiled at reflux overnight. The insoluble particles were removed by filtration, the solution was diluted with 200 ml of water and made neutral with 10-15 ml of glacial acetic acid. After stirring at 60°-70° C. for 1 hour, the mixture was cooled and suction filtered. There were obtained 10.2 g (48.5% of theory) of 4-methyl-1H-naphth(2,3-d)imidazole-2-thiol with a melting point above 300° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([NH:11][CH:12]3[CH2:15][CH2:14][CH2:13]3)=[N:8][C:7](Cl)=[N:6][C:5]=2[NH:4][CH:3]=1.[NH2:17][C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[N:23][NH:24]2)=[CH:20][CH:19]=1.C[Si](Cl)(C)C>C(O)CCC>[Br:1][C:2]1[C:10]2[C:9]([NH:11][CH:12]3[CH2:15][CH2:14][CH2:13]3)=[N:8][C:7]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[N:6][C:5]=2[NH:4][CH:3]=1
Reactant: Clc1nc(NC2CCC2)c2c(Br)c[nH]c2n1
Reactant: Nc1ccc2cn[nH]c2c1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: Brc1c[nH]c2nc(Nc3ccc4cn[nH]c4c3)nc(NC3CCC3)c12
Temperature: 116 °C
Reaction time: 4 h
Yield: 1.2 %

Procedure:
A mixture of 5-bromo-2-chloro-N-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (64 mg, 0.21 mmol), 6-aminoindazole (56 mg, 0.42 mmol) and TMSCl (0.050 mL, 0.40 mmol) in nBuOH (2 mL) was stirred at 116° C. for 4 h. It was then concentrated in vacuo. The residue was purified by HPLC to give a sample, which was further purified by preparative TLC using CH2Cl2/MeOH (95/5) as developing solvents to give the titled compound (1 mg). MS 398.3, 400.3 (M+H, Br pattern); UV 203.8, 247.4, 309.1 nm.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:7]=3[CH:8]=2)[NH:3]1.CC(C)([O-])C.[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH2:30]([N:3]1[C:4]2[C:9](=[CH:8][C:7]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16][C:6]=3[CH:5]=2)[CH2:10][CH2:11][C:2]1=[O:1])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)NC(=O)CC3
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)N(Cc1ccccc1)C(=O)CC3
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 600 mg of t-butyl 2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in 9 ml DMF were added 426 mg of potassium t-butoxide and 451 μl of benzyl bromide in an ice-bath, followed by stirring at room temperature for 3 hours. Water and ethyl acetate were added thereto, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 644 mg of t-butyl 1-benzyl-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate as a pale yellow solid.
Reaction SMILES: [CH:1](=O)[C:2]([CH3:4])=[O:3].[CH3:6][C:7]1([CH3:16])[CH2:12][CH:11]([NH2:13])[CH2:10][C:9]([CH3:15])([CH3:14])[NH:8]1>CC(OC)(C)C>[CH3:6][C:7]1([CH3:16])[CH2:12][CH:11]([N:13]=[CH:1][C:2](=[O:3])[CH3:4])[CH2:10][C:9]([CH3:15])([CH3:14])[NH:8]1
Reactant: CC(=O)C=O
Reactant: CC1(C)CC(N)CC(C)(C)N1
Solvent: COC(C)(C)C
Product: CC(=O)C=NC1CC(C)(C)NC(C)(C)C1
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
To a solution of pyruvaldehyde (40% w/w solution in water, 2.68 mL, 3.16 g, 17.5 mmol) in 30 mL of TBME at room temperature was added dropwise 2,2,6,6-tetramethyl-4-amino-piperidine (2.0 mL, 2.19 g, 14.0 mmol). After 30 min, the solution was diluted with 50 mL of TBME and washed with 3×25 mL of water and 25 mL of brine. The solution was concentrated in vacuo to yield 2.1 g (71%) of the imine product which was used as such in the subsequent step; 1H NMR (CDCl3) δ 7.64 (1H, s), 3.70 (1H, tt, J=3.9, 11.6 Hz), 2.34 (3H, s), 1.61 (2H, dd, J=3.9, 13.0 Hz), 1.32 (2H, t, J=12.2 Hz), 1.21 (6H, s), 1.14 (6H, s).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:25][C:26]([F:29])([F:28])[F:27])=[C:11]([CH:13]2[C:15]3([C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[O:17][C:16]3([CH3:24])[CH3:23])[O:14]2)[CH:12]=1>ClCCCl>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:25][C:26]([F:28])([F:29])[F:27])=[C:11]([CH:13]2[C:19](=[O:20])[C:18]([CH3:21])([CH3:22])[O:17][C:16]([CH3:24])([CH3:23])[C:15]2=[O:14])[CH:12]=1
Reactant: CC1(C)OC(C)(C)C2(OC2c2cc(Br)ccc2OC(F)(F)F)C1=O
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: CC1(C)OC(C)(C)C(=O)C(c2cc(Br)ccc2OC(F)(F)F)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
To an ice-cold solution of concentrated sulphuric acid (10 ml) is added a second solution of 2-(5-bromo-2-trifluoromethoxyphenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one (6.34 g, 15.00 mmol) in 1,2-dichloroethane (10 ml) dropwise over 5 minutes. This biphasic mixture is stirred vigorously for 2 hours at 0° C., then poured into ice-water, rinsing with a small amount of additional 1,2-dichloroethane/water. This mixture is then concentrated under vacuum to remove all organic solvents, until a free-flowing solid was produced. The solid is filtered, washed with water then isohexane, followed by drying under vacuum overnight. The solid is next redissolved in ethyl acetate, dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo to afford 4-(5-bromo-2-trifluoromethoxyphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (4.17 g, 68%).
Reaction SMILES: [CH:1]1([C:6]2[O:7][C:8]3[C:9](=[C:11]([CH:17]=O)[CH:12]=[CH:13][C:14]=3[O:15][CH3:16])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19]O.C([O-])=O.[Na+].C(OCC)(=O)C>C(O)=O>[CH:1]1([C:6]2[O:7][C:8]3[C:9](=[C:11]([C:17]#[N:19])[CH:12]=[CH:13][C:14]=3[O:15][CH3:16])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C=O)c2cc(C3CCCC3)oc12
Reactant: NO
Agent: O=C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=CO
Product: COc1ccc(C#N)c2cc(C3CCCC3)oc12
Temperature: 0 °C

Procedure:
27.6 g of 2-cyclopentyl-7-methoxybenzofuran-4-carbaldehyde are heated to reflux for 1.5 h with 11.6 g of hydroxylamine and 19.7 g of sodium formate in 250 ml of formic acid. The cooled solution is stirred in about 1.5 l of a 1:1 mixture of ice water and ethyl acetate, and the organic phase is separated off, dried over ignited potassium carbonate and evaporated in vacuo. The residual oil is sufficiently pure for further processing.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[C:16]([OH:28])[CH:15]=2)=[CH:9][C:8]=1[CH3:29])[CH3:2].[N:31]1([CH2:37][CH2:38]O)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[C:16]([O:28][CH2:38][CH2:37][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:29])[CH3:2]
Reactant: OCCN1CCOCC1
Reactant: CCOC(=O)COc1ccc(Sc2cc(O)cc(C#Cc3ccccc3)c2)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccccc3)cc(OCCN3CCOCC3)c2)cc1C
Reaction time: 16 h

Procedure:
[4-(3-Hydroxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (200 mg; 0.48 mmol), 2-morpholin-4-yl-ethanol (0.22 g; 0.67 mmol) and tributylphosphine (0.24 mL; 0.96 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. 1,1′-(Azodicarbonyl)dipiperidine (0.24 g; 0.96 mmol) was dissolved in THF (10 mL) and added to the reaction mixture. After stirring for 16 h the reaction mixture was evaporated to dryness and purified by flash chromatography (ethyl acetate:heptane (1:3-1:9). Yield: 150 mg. HPLC-MS: m/z: 532.6 (M+H); Rt: 2.07 min.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH2:9][C@H:10]2[CH2:13][CH2:12][N:11]2C(O[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=O)=[CH:6][CH:5]=[C:4]([CH3:24])[N:3]=1.O.C1(C)C([S:32]([OH:35])(=[O:34])=[O:33])=CC=CC=1>CCO.[Pd]>[S:32]([C:21]1[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=1)([OH:35])(=[O:34])=[O:33].[F:1][C:2]1[C:7]([O:8][CH2:9][C@H:10]2[CH2:13][CH2:12][NH:11]2)=[CH:6][CH:5]=[C:4]([CH3:24])[N:3]=1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: Cc1ccc(OC[C@H]2CCN2C(=O)OCc2ccccc2)c(F)n1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: Cc1ccc(OC[C@H]2CCN2)c(F)n1
Product: Cc1ccc(S(=O)(=O)O)cc1
Reaction time: 16 h
Yield: 48.5 %

Procedure:
2-Fluoro-6-methyl-3-(1-Cbz-2-(R)-azetidinylmethoxy)pyridine from step 118a (500 mg, 1.51 mmol) was combined with 10% Pd/C (50 mg) and p toluenesulfonic acid monohydrate (600 mg, 3.15 mmole) in 30 mL of EtOH, and the mixture was stirred under an H2 atmosphere for 16 hours. The mixture was filtered, concentrated, the residue was triturated with ether, and the product was recrystallized from ethyl acetate/ether to yield 270 mg (50%) of the title compound. mp 158-160° C. 1H NMR (D2O 300 MHz) δ 2.40 (s, 6H), 2.65-2.70 (m, 2H), 4.07-4.18 (m, 2H), 4.42 (d, J=4.5, 2H), 4.91-95 (m, 1H), 7.15 (d, J=8.0, 1H), 7.37 (d,J=8.0, 2H), 7.55 (dd, J=8.0, 2.0, 1H), 7.69 (d,J=8.5, 2H). MS (DCI/NH3) m/e 197 (M+H)+ 214 (M+NH4)+. Anal. calcd. for C10H13FN2O.C7H8O3S.0.4 H2O: C, 54.36 H, 5.85 N, 7.46. Found: C, 54.48 H, 5.81; N, 7.28; [α]D +2.05 (c 1, MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([O:27][CH3:28])[CH2:23][CH2:22]3)[C:17](O)=[O:18])[C:10](=[O:29])[CH:9]=2)[CH:7]=1.[NH2:32][C:33]1[CH:43]=[CH:42][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:35][CH:34]=1.CC(C)N=C=NC(C)C>CN(C)C=O.[Cl-].[Li+].C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([O:27][CH3:28])[CH2:23][CH2:22]3)[C:17]([NH:32][C:33]3[CH:34]=[CH:35][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:42][CH:43]=3)=[O:18])[C:10](=[O:29])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C[C@H]2CC[C@H](OC)CC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(NC(=O)C(C[C@H]2CC[C@H](OC)CC2)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1

Procedure:
1.70 g (purity 82%, 3.82 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(trans-4-methoxycyclohexyl)propanoic acid (racemate), 631 mg (3.82 mmol) of ethyl 4-aminobenzoate, 543 mg (3.82 mmol) of Oxima and 595 μl (3.82 mmol) of DIC in 38 ml of dimethylformamide were reacted according to General Method 5B. After complete conversion, the reaction solution was diluted with 213 ml of 10% strength lithium chloride solution and 170 ml of ethyl acetate and the phases were separated. The aqueous phase was extracted twice with 170 ml of ethyl acetate. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (ethyl acetate/cyclohexane gradient, 100 g silica cartridge, flow rate 50 ml/min), giving the title compound. Yield: 1.1 g (purity 78%, 49% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[NH:32][C:9]2=[N:10][CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]4[O:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C:18]=4[CH:31]=3)[CH:13]=[C:8]2[N:7]=1)=[O:4].C(#N)C.[ClH:36]>O1CCOCC1>[ClH:36].[O:23]1[C:17]2[CH:16]=[CH:15][C:14]([C:12]3[CH:13]=[C:8]4[NH:7][C:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])=[N:32][C:9]4=[N:10][CH:11]=3)=[CH:31][C:18]=2[CH2:19][NH:20][CH2:21][CH2:22]1
Reactant: COC(=O)Nc1nc2cc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CCO4)cnc2[nH]1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: COC(=O)Nc1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a mixture of 1,1-dimethylethyl 7-(2-{[(methyloxy)carbonyl]amino}-3H-imidazo[4,5-b]pyridin-6-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.52 g, 1.2 mmol) was taken into acetonitrile (5 mL) followed by addition of 4M hydrogen chloride in 1,4-dioxane (5 mL) and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated to give a white solid. It was washed with ether then dried to give methyl [6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridin-2-yl]carbamate hydrochloride salt (0.40 g, 100% yield), MS (EI) for C17H17N5O3: 340 (MH+).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([O:23][CH3:24])=[C:7]([O:21][CH3:22])[CH:8]=2)[N:3]=1.[CH2:25]([N:27](CC)CC)C.C(OCC)(=O)C.O1CCCC1>CN1CCCC1=O>[CH3:22][O:21][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:23][CH3:24])[N:3]=[C:2]([NH:27][CH3:25])[N:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: CCN(CC)CC
Reactant: COc1cc2nc(Cl)nc(-c3cccc([N+](=O)[O-])c3)c2cc1OC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CNc1nc(-c2cccc([N+](=O)[O-])c2)c2cc(OC)c(OC)cc2n1
Temperature: 130 °C
Reaction time: 18 h
Yield: 76.8 %

Procedure:
2.50 g of 2-chloro-6,7-dimethoxy-4-(3-nitrophenyl)quinazoline obtained in Production Example 1,4.89 g methylamine hydrochloride and 11.0 g triethylamine were suspended in 25 ml 1-methyl-2-pyrrolidinone and stirred at 130° C. for 18 hours in a sealed tube. Ethyl acetate and tetrahydrofuran were added thereto, and the reaction solution was washed with water 5 times and then with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified and separated by silica gel column chromatography (hexane:ethyl acetate=1:2). The product was recrystallized from tetrahydrofuran-ethyl acetate to give 1.89 g of the title compound as yellow crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH3:26][C:27]1[C:31](B(O)O)=[C:30]([CH3:35])[O:29][N:28]=1>CN(C=O)C>[CH3:26][C:27]1[C:31]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:30]([CH3:35])[O:29][N:28]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: Cc1noc(C)c1B(O)O
Solvent: CN(C)C=O
Product: Cc1noc(C)c1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 3,5-dimethylisoxazole-4-boronic acid (CAS RN 16114-47-9) and using DMF as reaction solvent. Light brown solid (20%). MS (ESI): m/z=444.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:11][C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13].[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[N:11]([CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:12]([O:14][CH:15]([CH3:16])[CH3:17])=[O:13]
Reactant: CCOC(=O)CCCBr
Reactant: COC(=O)c1c(F)cccc1NC(=O)OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCN(C(=O)OC(C)C)c1cccc(F)c1C(=O)OC
Reaction time: 1 h
Yield: 68 %

Procedure:
Add a solution of 2-Isopropoxycarbonylamino-6-fluor-benzoic acid methyl ester (3.0 g, 11.76 mmol) in DMF (43 mL) to a suspension of sodium hydride 60% dispersion mineral oil (471 mg, 11.76 mmol) in DMF (43 mL) at 0° C. under an atmosphere of nitrogen and allow to reach room temperature over 1 h. Add ethyl 4-bromobutyrate (2.5 mL, 17.64 mmol) and stir at room temperature for 14 h. Dilute with ethyl acetate, wash with 1M HCl, water and brine. Dry the organic layer over anhydrous magnesium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to provide the title compound (2.96, 68%). MS (ES+): 370 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16](B(O)O)=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.I[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28].C(=O)([O-])[O-].[Na+].[Na+]>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.CCO.COCCOC.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:26]=4[O:27][CH3:28])=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccncc1I
Reactant: OB(O)c1ccnc2c1cnn2-c1ccc(F)cc1
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
Solvent: CCO
Product: COc1ccncc1-c1ccnc2c1cnn2-c1ccc(F)cc1
Temperature: 105 °C
Yield: 31.4 %

Procedure:
Example 6 was prepared according to the general procedure of Example 1, except that the reaction mixture was heated at 105° C. for 2.25 h and using the following materials: Intermediate 5A (38.0 mg, 0.148 mmol), 3-iodo-4-methoxypyridine (86.2 mg, 0.367 mmol), sodium carbonate (56.1 mg, 0.529 mmol), degassed EtOH:DME:H2O (1.2:2.5:1.0 ratio) (1.5 mL) and tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.015 mmol). Example 6 was isolated as an off white solid (14.9 mg, 31.1%). Purification was done by preparative HPLC (Condition A) using a Phenomenex Luna Axia 30×100 mm S10 column from 10% Solvent B to 95% Solvent B over 12 min, ret. T=8.6 min. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.75 (1 H, d, J=4.88 Hz), 8.64 (1 H, d, J=5.80 Hz), 8.59 (1 H, s), 8.27-8.36 (3 H, m), 7.42-7.51 (3 H, m), 7.35 (1 H, d, J=6.10 Hz), 3.93 (3 H, s). LC/MS (Condition B): ret. T=2.84 min, (M+H)+ 321.05. Analytical HPLC: (Condition A): >99%, ret. T=22.96 min, (Condition B): >99%, ret. T=23.17 min, (Condition C): >99%, ret. T=9.33 min, (Condition D): >99%, ret. T=9.91 min.
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.[O:30]1[CH:34]=[CH:33][C:32]([C:35](O)=[O:36])=[N:31]1>>[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:35]([C:32]4[CH:33]=[CH:34][O:30][N:31]=4)=[O:36])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: O=C(O)c1ccon1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2ccon2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and isoxazole-3-carboxylic acid (17 mg, 0.15 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:16]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20](=[O:29])[C:19]2=[CH:30][CH:31]=[C:32]([Cl:33])[N:18]2[N:17]=1)[CH:13]1[CH2:15][CH2:14]1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:42]1([CH3:51])[CH:47]=[CH:46][C:45]([C:48](Cl)=[O:49])=[CH:44][CH:43]=1>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:16]1[N:21]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:20](=[O:29])[C:19]2=[CH:30][CH:31]=[C:32]([Cl:33])[N:18]2[N:17]=1)[CH:13]1[CH2:14][CH2:15]1)[C:48](=[O:49])[C:45]1[CH:46]=[CH:47][C:42]([CH3:51])=[CH:43][CH:44]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCCNC(c1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1)C1CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2nn3c(Cl)ccc3c(=O)n2Cc2ccccc2)C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 65.1 %

Procedure:
To a solution of (±)-(3-{[(3-benzyl-7-chloro-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]-triazin-2-yl)-cyclopropyl-methyl]-amino}propyl)carbamic acid tert-butyl ester (0.30 g, 0.62 mmol) and Et3N (0.13 mL, 0.93 mmol) in CH2Cl2 (10 mL) at rt was added p-toluoyl chloride (0.10 mL, 0.76 mmol) under N2 and it was stirred at rt for 50 min. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO3 solution, and dried over MgSO4. Concentration and purification of the residue by flash column chromatography (SiO2, EtOAc/hexane 1:4) gave the title compound as an oil (0.244 g, 66%): 1H NMR (CDCl3) δ 7.22 (m, 2H), 7.13 (m, 3H), 7.04 (d, 1H, J=4.4 Hz), 6.48 (d, 1H, J=4.4 Hz), 5.90 (d, 1H, J=15.95 Hz), 5.12 (d, 1H, J=9.9 Hz), 4.83 (d, 1H, J=15.95 Hz), 4.03 (m, 1H), 3.54 (m, 1H), 3.45 (m, 1H), 2.74 (m, 2H), 2.31 (s, 3H), 1.66 (m, 2H), 1.29 (s, 9H), 1.19 (m, 3H), 0.80 (m, 1H), 0.42 (m, 1H), 0.32 (m, 2H); 3C NMR (CDCl3) δ 172.9, 155.7, 154.6, 148.8, 139.8, 136.8, 133.2, 129.2, 128.8, 127.7, 126.8, 126.3, 117.7, 117.2, 110.3, 108.5, 57.9, 44.4, 42.7, 37.9, 30.9, 28.2, 21.4, 13.4, 5.24, 3.80; MS (ESI+) 626.16, 628.14 (M++Na).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[CH:20]=[C:19](F)[CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[N:6][C:7]=1[NH:8][CH3:9].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[CH:20]=[C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[N:6][C:7]=1[NH:8][CH3:9]
Reactant: CNc1ncc(Oc2cc(F)ccc2C(=O)OC)cc1Cl
Reactant: C1CNCCN1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CNc1ncc(Oc2cc(N3CCNCC3)ccc2C(=O)OC)cc1Cl

Procedure:
A solution of EXAMPLE 377E (0.230 g) and piperazine (0.255 g) in dimethylsulfoxide (3 mL) was heated to 85° C. for 1 hour. The reaction was cooled and diluted with ethyl acetate (75 mL). The organic layer was washed with water (3×50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated to give the title compound.