Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24]O)[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:37])[N:34]([CH3:36])[CH3:35])=[CH:28][CH:27]=2)=[N:4]1)[CH3:2].[CH3:38][CH2:39][N:40](CC)[CH2:41][CH3:42].N1CCCC1>C(Cl)Cl>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24][N:40]5[CH2:41][CH2:42][CH2:38][CH2:39]5)[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:33](=[O:37])[N:34]([CH3:36])[CH3:35])=[CH:30][CH:31]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CCO)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCNC1
Product: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CCN5CCCC5)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a stirred solution of N′-[4-(1-ethyl-4-{2-[3-(2-hydroxyethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)phenyl]-N,N-dimethylurea (210 mg, 0.42 mMol) in CH2Cl2 (15 mL) was added at 0° C. Et3N (120 uL, 0.86 mmol) and methanesulfonyl lchloride (40 uL, 0.52 mmol). After stirring for 3 h, pyrrolidine (2 mL, 24 mmol) was added. The reaction was allowed to warm to RT, stirred for 18 h, and evaporated to dryness under vacuum. Purification by Gilson HPLC provided the title compound (25%) as a pale yellow solid. ESMS [M+H]+: 548.4.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]([CH:14]=[O:15])[CH3:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>O.[Pd]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([CH3:13])[CH:14]=[O:15])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C=O)=Cc1ccc(C(C)(C)C)cc1
Agent: [Pd]
Solvent: O
Product: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Temperature: 110 °C
Yield: 88.9 %

Procedure:
1420 g of 1-(p-tert.butylphenyl)-2-formyl-1-propene, prepared as described in paragraph (e), are mixed together with 6 g of 5% palladium/carbon and 6.8 g of soda in 20 ml of water at 70°-75° C. in a stirring autoclave. The autoclave is charged with hydrogen (8 atmospheres) and heated to 110° C. About 230 liters of hydrogen are absorbed after 12 hours. The crude 3-(p-tert.butyl-phenyl)-2-methyl-propionaldehyde is treated with ether, washed neutral with water and dried over sodium sulphate. After removing the ether, the product is fractionally distilled in vacuo. After separating a first running and a last running, there are obtained 1275 g of 3-(p-tert.butylphenyl)-2-methyl-propionaldehyde in 95% purity (about 88% of theory). Boiling point: 150°-152° C./15 mmHg; nD20 =1.5050.
Reaction SMILES: [NH2:1][C:2]12[CH2:13][C:6]3([CH3:14])[CH2:7][C:8]([CH2:11][OH:12])([CH2:10][C:4]([CH3:15])([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH2:16]([O:23][C:24](ON1C(=O)CCC1=O)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:16]([O:23][C:24]([NH:1][C:2]12[CH2:13][C:6]3([CH3:14])[CH2:7][C:8]([CH2:11][OH:12])([CH2:10][C:4]([CH3:15])([CH2:5]3)[CH2:3]1)[CH2:9]2)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC12CC3(C)CC(N)(C1)CC(CO)(C2)C3
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Product: CC12CC3(C)CC(CO)(C1)CC(NC(=O)OCc1ccccc1)(C2)C3
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of 1-amino-3,5-dimethyl-7-hydroxymethyl adamantane (60 mg) in THF (3 mL) was added N-(benzyloxycarbonyloxy)-succinimide (74 mg) and the mixture was stirred at room temperature overnight. THF was removed and the residue was dissolved in ethyl acetate. The solution was washed with water and brine. The product was purified by thin layer chromatography eluting with ethyl acetate and hexane (1:4, v/v) to give a white solid (80 mg). 1H NMR (DMSO-d6, ppm): 7.33 (m, 5H, C6H5), 6.89 (brs, 1H, NH), 4.94 (s, 2H, OCH2), 4.32 (t, 1H, OH, J=5.7 Hz), 3.04 (d, 2H, CH2OH, J=5.7 Hz), 1.46 (dd, 6H), 1.04 (dd, 6H), 0.84 (s, 6H, 2×CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[NH:12][C:11]1=[O:21].C([O-])(=O)C.[Na+].[Br:27]Br>C(O)(=O)C>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:15](=[O:16])[C:14]([Br:27])=[C:13]([C:17]([F:20])([F:19])[F:18])[NH:12][C:11]1=[O:21]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1c(Cl)cc(Cl)cc1Cl
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]c(C(F)(F)F)c(Br)c(=O)n1-c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Yield: 41 %

Procedure:
3.6 g of 3-(2,4,6-trichlorophenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione and 4.1 g of sodium acetate were added to 30 ml of acetic acid, followed by dropwise addition of 6.4 g of bromine with stirring at room temperature. The resulting solution was stirred at 110° C. for 5 hours and then the solvent was distilled away under reduced pressure. The residue was extracted with 100 ml of ethyl acetate, and the obtained organic layer was washed with water and dried. Then the solvent was distilled away to obtain a crude product. This crude product was washed with isopropyl ether and dried to obtain 1.8 g of the objective compound.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH:6]([CH3:10])[CH2:7][CH2:8][N:9]=1.[NH2:11][C:12]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[CH:17][C:13]=1[C:14](O)=[O:15]>CN(C=O)C.O>[CH3:10][CH:6]1[CH2:7][CH2:8][N:9]2[C:3](=[N:11][C:12]3[C:13]([C:14]2=[O:15])=[CH:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[CH:20]=3)[CH2:4][CH2:5]1
Reactant: COC1=NCCC(C)CC1
Reactant: Nc1cc(C(=O)O)ccc1C(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCc2nc3cc(C(=O)O)ccc3c(=O)n2CC1
Temperature: 25 °C
Yield: 2.2 %

Procedure:
A solution of (E)-7-methoxy-4-methyl-3,4,5,6-tetrahydro-2H-azepine (1.1 g) and 2-aminoterephthalic acid (1.4 g, 7.7 mmol) in DMF (30 mL) was stirred at 100° C. for 4 h. After it was cooled to room temperature, the reaction was diluted with water (80 mL) and extracted with ethyl acetate (2×60 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by silica gel chromatography to give 47 mg of desired product.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:35][C:19]3=[N:20][CH:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=4[CH3:34])[C:27]([O:29][CH3:30])=[O:28])[CH:23]=[C:18]3[CH:17]=2)=[CH:12][CH:11]=1>[Al].ClCCCl.CCOC(C)=O>[Br:8][C:17]1[C:18]2[C:19](=[N:20][CH:21]=[C:22]([C:24]3[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=3[CH3:34])[C:27]([O:29][CH3:30])=[O:28])[CH:23]=2)[O:35][C:16]=1[C:13]1[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(-c2cnc3oc(-c4ccc(F)cc4)cc3c2)c1
Agent: [Al]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)c1ccc(C)c(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1
Reaction time: 8 h

Procedure:
The reaction flask was wrapped in aluminum foil. NBS (175 mg, 0.983 mmol) was added to a stirring solution of methyl 3-(2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoate (289 mg, 0.800 mmol) in DCE (8 mL) at room temperature. It was allowed to stir overnight. The mixture was diluted with EtOAc and quenched with 10% sodium metabisulfate and washed with sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) the expected product consistent by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (1H, d, J=2.01 Hz), 8.16-8.26 (2H, m), 8.06 (1H, d, J=2.26 Hz), 7.95 (1H, dd, J=8.03, 1.76 Hz), 7.87 (1H, d), 7.45-7.57 (3H, m), 3.86 (3H, s), 2.34 (3H, s). LC-MS retention time: 2.85 min; m/z (MH+): 440, 442. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1.O1CCOCC1.CCN(C(C)C)C(C)C.[C:49]1([SH:55])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[C:49]1([S:55][C:2]2[CH:3]=[C:4]([CH:8]([N:12]3[CH:16]=[C:15]([C:17]4[C:18]5[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=5[N:20]=[CH:21][N:22]=4)[CH:14]=[N:13]3)[CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(Br)c4)c3)ncnc21
Reactant: Sc1ccccc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(Sc5ccccc5)c4)c3)ncnc21
Yield: 80.1 %

Procedure:
To the 3-(5-bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (0.130 g, 0.000248 mol) from Example 429 Step 2, in dry 1,4-dioxane (1.60 mL, 0.0205 mol) was added DIPEA (0.085 mL, 0.00049 mol). The solution was degassed with nitrogen, followed by addition of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.007 g, 0.00001 mol), is(dibenzylideneacetone)palladium(0) (0.0036 g, 0.0000062 mol), and benzenethiol (0.025 mL, 0.00025 mol). Again the solution was purged with nitrogen. The reaction mixture in a sealed tube was heated to reflux for 3 h. The reaction mixture was diluted with ethyl acetate, washed with water (2×), brine (1×), dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo. The crude product was triturated with hexane-ethyl acetate 9:1 to yield 3-[5-(phenylthio)pyridin-3-yl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (110 mg, 80%). LC/MS (M+H)+: m/z=554.2.
Reaction SMILES: [CH:1]1([C:4](=[O:19])[CH2:5][C:6]([C:8]2[C:16]3[O:15][C:14]([F:18])([F:17])[O:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[O:7])[CH2:3][CH2:2]1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[CH:1]1([C:4](=[O:19])[C:5](=[CH:22][N:23]([CH3:25])[CH3:24])[C:6]([C:8]2[C:16]3[O:15][C:14]([F:18])([F:17])[O:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: COC(OC)N(C)C
Reactant: O=C(CC(=O)C1CC1)c1cccc2c1OC(F)(F)O2
Solvent: Cc1ccccc1
Product: CN(C)C=C(C(=O)c1cccc2c1OC(F)(F)O2)C(=O)C1CC1
Reaction time: 8 h

Procedure:
A solution of 4-(3-cyclopropyl-1,3-dioxoprop-1-yl)-2,2-difluoro-1,3-benzodioxole (12.0 g) in dry toluene was treated with N,N-dimethylformamide dimethyl acetal and the mixture stirred overnight. After evaporation in vacuo and re-evaporation after addition of toluene the residue was recrystal from cyclohexane-ethanol to give 4-(3-cyclopropyl-2-dimethylaminomethylene-1,3-dioxopropyl)-2,2-difluoro-1,3-benzodioxole (6.5 g) as a pale yellow solid, m.p. 118°-119° C.
Reaction SMILES: [C:1]([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH3:15])[C:8]([CH3:17])([CH3:16])[CH2:7]1)(=[O:4])[CH:2]=[CH2:3].[C:18]([O:42][CH:43]1[CH2:48][C:47]([CH3:50])([CH3:49])[N:46]([OH:51])[C:45]([CH3:53])([CH3:52])[CH2:44]1)(=[O:41])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH:30]1[CH2:35][C:34]([CH3:37])([CH3:36])[N:33]([OH:38])[C:32]([CH3:40])([CH3:39])[CH2:31]1)=[O:28]>>[C:18]([O:42][CH:43]1[CH2:44][C:45]([CH3:53])([CH3:52])[N:46]([O:51][CH2:3][CH2:2][C:1]([O:5][CH:6]2[CH2:7][C:8]([CH3:16])([CH3:17])[N:9]([O:14][CH3:15])[C:10]([CH3:12])([CH3:13])[CH2:11]2)=[O:4])[C:47]([CH3:50])([CH3:49])[CH2:48]1)(=[O:41])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH:30]1[CH2:31][C:32]([CH3:39])([CH3:40])[N:33]([O:38][CH2:3][CH2:2][C:1]([O:5][CH:6]2[CH2:7][C:8]([CH3:17])([CH3:16])[N:9]([O:14][CH3:15])[C:10]([CH3:12])([CH3:13])[CH2:11]2)=[O:4])[C:34]([CH3:36])([CH3:37])[CH2:35]1)=[O:28]
Reactant: C=CC(=O)OC1CC(C)(C)N(OC)C(C)(C)C1
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Product: CON1C(C)(C)CC(OC(=O)CCON2C(C)(C)CC(OC(=O)CCCCCCCCC(=O)OC3CC(C)(C)N(OCCC(=O)OC4CC(C)(C)N(OC)C(C)(C)C4)C(C)(C)C3)CC2(C)C)CC1(C)C

Procedure:
The title compound is prepared from 1-methoxy-2,2,6,6-tetramethylpiperidin-4-yl acrylate and bis(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yl) sebacate according to the general procedure of Example 2.
Reaction SMILES: COC1C=CC=CC=1C1NC(=O)C2C(=CC=CC=2)N=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24].[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH:41]=O>>[CH3:36][O:37][C:38]1[CH:39]=[C:40]([C:41]2[NH:25][C:23](=[O:24])[C:22]3[C:21](=[CH:29][CH:28]=[C:27]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[CH:26]=3)[N:20]=2)[CH:43]=[CH:44][CH:45]=1
Reactant: NC(=O)c1cc(N2CCOCC2)ccc1N
Reactant: COc1cccc(C=O)c1
Agent: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Product: COc1cccc(-c2nc3ccc(N4CCOCC4)cc3c(=O)[nH]2)c1
Yield: 46.1 %

Procedure:
According to the preparation of 42, 29 (1.0 g, 4.5 mmol) and 3-methoxybenzaldehyde (34) (0.6 g, 4.5 mmol) were used to afford 59 (0.7 g, 48.3%) as pale yellow needles.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](Cl)[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[C:5]1=[O:27])(=O)C.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[NH:28](/[C:17](=[C:6]1\[C:5](=[O:27])[NH:4][C:12]2[C:7]\1=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)/[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1ccccc1
Reactant: COc1cc2c(cc1OC)N(C(C)=O)C(=O)C2=C(Cl)c1cccc(C#N)c1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccccc1)c1cccc(C#N)c1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-chloro-1-(3-cyanophenyl)-methylidene]-5,6-dimethoxy-2-indolinone and aniline
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[N:13][C:12]([NH2:15])=[N:11][C:10]=1[NH2:16].Cl[CH:18]([C:21]1([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[N:30]=[CH:29][CH:28]=[CH:27]3)[CH2:23][CH2:22]1)[CH:19]=O>C(O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([NH2:16])=[N:11][C:12]2[N:13]([C:18]([C:21]3([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[N:30]=[CH:29][CH:28]=[CH:27]5)[CH2:23][CH2:22]3)=[CH:19][N:15]=2)[N:14]=1
Reactant: Nc1nnc(-c2cccc(Cl)c2Cl)c(N)n1
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Solvent: CCO
Product: Nc1nc2ncc(C3(c4ccc5ncccc5c4)CC3)n2nc1-c1cccc(Cl)c1Cl
Temperature: 105 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
A mixture of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine (19 mg, 0.076 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (22 mg, 0.091 mmol) in ethanol (0.50 mL) was stirred at 105° C. overnight. The reaction mixture was purified by RP-HPLC (pH 10) to afford the desired product (12 mg, 35%). LCMS: (M+H)=447.3/449.2/451.2.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].C(=O)(O)[O-].[Na+].ClCC(N)=O>C(Cl)(Cl)Cl>[O:13]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:3](=[O:4])[CH2:2]1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1O
Agent: NC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C1COc2ccccc2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Chloroacetyl chloride (104 g) is added slowly to a stirred mixture of o-aminophenol (96 g), sodium bicarbonate (100 g) and chloroform (1400 ml). After the addition is complete the reaction mixture is stirred at room temperature for 2 hours. The resulting chloroacetamide derivative, which separates in the course of the reaction, is filtered and added with stirring to 1 liter of NaOH, producing 2H-1,4-benzoxazin-3(4H)-one, which is filtered and washed with H2O, m.p. 169°-170°. The latter (30 g) is added portionwise to a suspension of 26 g of LiAlH4 in 1500 ml of anhydrous ether, keeping the temperature at 10° during the addition. After the addition is complete the reaction mixture is heated to reflux for 2 hours. It is then cooled, decomposed with water and filtered. The organic layer is separated and dried over anhydrous sodium sulfate; the solvent is removed in the rotary evaporator and the oily product obtained distilled to yield 3,4-dihydro-2H-1,4 -benzoxazine (b760 265°-267°). In a like manner as in Example 1, the latter benzoxazine is converted to the corresponding 4-nitroso derivative, which is worked up as described in Example 110 to give 4-amino-3,4-dihydro-2H-1,4-benzoxazine hydrochloride [m.p. 160° (dec.)] and finally the title compound m.p. 255° (dec.).
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=[O:6])C=1C#N)#N.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[CH:19][C:18]=1[CH2:27][CH2:28][CH3:29]>O1CCOCC1.C(O)C>[CH3:29][CH2:28][C:27]([C:18]1[C:17]([O:16][CH3:15])=[CH:22][C:21]([O:23][CH3:24])=[C:20]([O:25][CH3:26])[CH:19]=1)=[O:6]
Reactant: CCCc1cc(OC)c(OC)cc1OC
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCO
Solvent: C1COCCO1
Product: CCC(=O)c1cc(OC)c(OC)cc1OC
Temperature: 25 °C
Yield: 59 %

Procedure:
A solution of DDQ (3.06-4.09 g) in dioxane (40 mL) was added dropwise over a period of 10 min to a ice cold and well stirred solution of 2,4,5-trimethoxyphenylpropane (1.89 g, 0.009 mol) in wet dioxane or ethanol (55 mL) and the resulting mixture was stirred at room temperature for over night. The precipitate was filtered and further washed twice with dioxane. The combined dioxane layer was evaporated and mixture was poured into water and extracted with dichloromethane (3×70 mL). The combined organic layer were washed with brine (3×15 mL) and dried over sodium sulphate. The residue obtained on evaporation of the solvents was chromatographed on silica gel column using hexane-ethyl acetate mixture with increasing proportion of ethyl acetate upto 40% to afford viscous liquid which was crystallized from ethylacetate/hexane to afford 1.19 g (59%) of white crystals of isoacoramone. The spectral data was found similar as mentioned above in Example III.
Reaction SMILES: [NH2:1][OH:2].[NH2:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:18])[C:11]=2[F:19])[N:7]=[C:6]([C:20](OC)=[O:21])[C:5]=1[Cl:24]>COCCOC>[NH2:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:18])[C:11]=2[F:19])[N:7]=[C:6]([C:20]([NH:1][OH:2])=[O:21])[C:5]=1[Cl:24]
Reactant: NO
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(N)c1Cl
Solvent: COCCOC
Product: COc1c(Cl)ccc(-c2cc(N)c(Cl)c(C(=O)NO)n2)c1F
Temperature: 23 °C
Reaction time: 96 h
Yield: 103.2 %

Procedure:
A 50% aq solution of hydroxylamine (4.4 mL, 72 mmol, 50 equiv) was added to a stirred suspension of methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate (500 mg, 1.4 mmol, 1.0 equiv) in 1,2-dimethoxyethane (1.0 mL) at 23° C. The resulting white suspension was stirred at 23° C. for 4 days (d). The reaction mixture was concentrated by rotary evaporation to afford a white powder (500 mg, 99%): mp 166-169° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.19 (br s, 1H), 7.68 (t, J=8 Hz, 1H), 7.42 (m, 1H), 7.20 (m, 1H), 6.73 (br s, 2H), 6.53 (br s, 1H), 3.93 (s, 3H); IR (neat film) 3322 (m), 2941 (w), 2878 (w), 1653 (s), 1632 (s) cm−1; ESIMS m/z 346.2 ([M+H]+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].[Cl:15][C:16]1[CH:21]=[C:20](I)[CH:19]=[CH:18][N:17]=1>>[Cl:15][C:16]1[CH:21]=[C:20]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)[CH:19]=[CH:18][N:17]=1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Reactant: Clc1cc(I)ccn1
Product: COC(=O)CCc1ccc(C#Cc2ccnc(Cl)c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (104 mg, 0.55 mmol) and 2-chloro-4-iodopyridine (141 mg, 0.59 mmol) according to the general procedure IC to give 96 mg (58%) of a pale yellow solid after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:5). Rf: 0.22 (EtOAc:hexanes, 1:5); 1HNMR (CDCl3) δ 8.36-8.35 (m, 1H), 7.48-7.45 (m, 2H), 7.42-7.41 (m, 1H), 7.29-7.26 (m, 1H), 7.24-7.21 (m, 2H), 3.67 (s, 3H), 3.01-2.96 (t, 2H, J=7.8 Hz), 2.67-2.62 (t, 2H, J=7.8 Hz); 13CNMR (CDCl3) δ 172.9, 151.7, 149.5, 142.4, 134.4, 132.1, 128.6, 125.9, 124.1, 95.4, 85.3, 51.8, 35.2, 30.8; EI-MS calcd for C17H15ClNO2 (M+): 299. found: 299.
Reaction SMILES: [OH-:1].[Li+].[CH:3]1[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][C:4]=1[O:16][CH:17]1[CH2:21][CH:20]([C:22]([O:24]C)=[O:23])[NH:19][C:18]1=[O:26].Cl>O.O1CCCC1>[CH:3]1[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][C:4]=1[O:16][CH:17]([C:18]([OH:26])=[O:1])[CH2:21][C@@H:20]([C:22]([OH:24])=[O:23])[NH2:19]
Reactant: [OH-]
Reactant: COC(=O)C1CC(Oc2ccc3c(c2)Cc2ccccc2-3)C(=O)N1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H](CC(Oc1ccc2c(c1)Cc1ccccc1-2)C(=O)O)C(=O)O
Temperature: 60 °C
Reaction time: 3.3 h

Procedure:
A mixture of lithium hydroxide (0.117 g) in water (1.5 ml) and tetrahydrofuran (4.7 ml) was treated with methyl 3-(2-fluorenoxy)-2-pyrrolidone-5-carboxylate (0.526 g), and heated to 60° C. After about 3.3 hours, the reaction mixture was allowed to cool to room temperature. The reaction mixture was treated with 5N HCl (976 ml). The resulting colloidal suspension was sonicated for ten minutes. The insolubles were collected by filtration, washed with 1:1 THF:water (10 ml), THF (10 ml), and water (10 ml). The insolubles were dried overnight in at vacuum oven at 60° C. to afford the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:22]3[N:21]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:28]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2ncccn2)c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2ncccn2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 3-(pyrimidin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.79 min.; [M+H]+: 403.86 g/mol.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][N:27]4C(OC(C)(C)C)=O)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:38])[NH:6]2.Cl>O1CCOCC1.CO>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][NH:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:38])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H]1CCCN1
Yield: 91.8 %

Procedure:
Using an analogous procedure to that described for the preparation of the starting material in Example 11, tert-butyl (2S)-2-[(4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline-7-yloxy)methyl]pyrrolidine-1-carboxylate (170 mg, 0.33 mmol) was reacted with hydrogen chloride in dioxane. The solid was dissolved in methanol and absorbed onto an Isolute SCX column which was washed through with methanol and then the product was eluted with 7N ammonia in methanol to give 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2S)-pyrrolidin-2-ylmethoxy]quinazoline (128 mg, 93%).