Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([C:9]([OH:11])=O)[CH:5]=[N:4]1)[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:31]=[C:27]1[CH2:26][C:25]2[C:29](=[CH:30][C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:9]([C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]=4[CH3:8])=[O:11])[CH:34]=[CH:33][CH:32]=3)=[O:21])=[CH:23][CH:24]=2)[NH:28]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: CCn1ncc(C(=O)O)c1C
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCn1ncc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)c1C
Temperature: 79 °C
Reaction time: 3 h
Yield: 59.2 %

Procedure:
A dry flask was charged with 1-Ethyl-5-methyl-1H-pyrazole-4-carboxylic acid (0.159 g, 1.03 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (10 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.260 g, 1.03 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and filtered. The solid residue was washed with 0° C. THF and collected to afford the 1-Ethyl-5-methyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.236 g, 0.61 mmol, 59%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]([CH3:18])[CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=2)=[O:9])[CH:4]=[C:3]1[C:19]([O:21]C)=[O:20].[Li+].[OH-]>CC(N(C)C)=O.O>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]([CH3:18])[CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=2)=[O:9])[CH:4]=[C:3]1[C:19]([OH:21])=[O:20]
Reactant: COC(=O)c1cc(NC(=O)c2cc([N+](=O)[O-])cn2C)cn1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1cc(NC(=O)c2cc([N+](=O)[O-])cn2C)cc1C(=O)O
Reaction time: 8 h
Yield: 73.4 %

Procedure:
Methyl 1-methyl-4-(1-methyl-4-nitro-1H-pyrrole-2-carboxamido)-1H-pyrrole-2-carboxylate (2.0 g, 6.53 mmol) in 50 ml of DMA was added 2 g of LiOH in 30 ml of water. The mixture was stirred overnight, concentrated, diluted with water, extracted with EtAc/Hexane (1:1). The aqueous solution was adjusted to pH 4.0 with 20% H3PO4 to form precipitates. The precipitates were filtered, washed with water and dried over P2O5 with vacuum to afford 1.4 g (73%) of the title product. 1H NMR (DMF-d7) 10.34 (br, 1H), 8.17 (s, 1H), 7.62 (s, 1H), 7.51 (s, 1H), 7.00 (s, 1H), 4.09 (s, 1H), 3.91 (s, 1H); 13C NMR 158.47, 135.61, 129.11, 127.77, 123.65, 121.57, 121.50, 109.48, 108.52, 38.38, 37.05; MS m/z− 291.0 (M−H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1)#[N:2].Br[CH:20]1[CH2:25][CH2:24][CH2:23][C:22]([CH2:33][C:34]#[N:35])([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[C:21]1=O>C(O)C>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:22]2([CH2:33][C:34]#[N:35])[C:21]3[N:18]=[C:16]([NH:15][C:5]4[CH:6]=[CH:7][C:8]([N:9]5[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]5)=[C:3]([CH:4]=4)[C:1]#[N:2])[S:17][C:20]=3[CH2:25][CH2:24][CH2:23]2)=[CH:31][CH:30]=1
Reactant: N#CCC1(c2ccc(Cl)cc2)CCCC(Br)C1=O
Reactant: Cc1cn(-c2ccc(NC(N)=S)cc2C#N)cn1
Solvent: CCO
Product: Cc1cn(-c2ccc(Nc3nc4c(s3)CCCC4(CC#N)c3ccc(Cl)cc3)cc2C#N)cn1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
A suspension of [3-cyano-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (39.4 mg, 0.15 mmol) and of [3-bromo-1-(4-chloro-phenyl)-2-oxo-cyclohexyl]-acetonitrile (50.0 mg, 0.15 mmol) in ethanol (2 mL) was heated to reflux under an atmosphere of nitrogen for 2 days. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane/methanol/concentrated aqueous NH4OH solution (9:1:0.1 v/v/v) as eluent to yield the title compound (34 mg, 46%) as a yellow gum. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.41 (s, 1H), 7.95 (s, 1H), 7.89 (d, 1H), 7.69 (s, 1H), 7.31 (t, 2H), 7.12 (d, 2H), 7.00 (d, 1H), 3.23 (d, 1H), 3.02 (d, 1H), 2.73 (m, 2H), 2.31 (s, 3H), 2.17 (m, 1H), 1.88 (m, 2H), 1.60 (m, 1H).
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])=[C:6]([CH:28]([CH3:30])[CH3:29])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])=[C:6]([CH:28]([CH3:30])[CH3:29])[N:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccccc1/C=C/c1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccccc1CCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6diisopropyl-3-hydroxymethyl-(4-fluorophenyl)-5-[2(E)-(2-methylphenyl)ethenyl]pyridine (Example 40) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.16 (m, 4 H), 7.06 (m, 3 H), 6.81 (m, 1 H), 4.35 (d, J=4 Hz, 2 H), 3.42 (sept, J=6.6 Hz, 2 H), 2.57 (m, 4 H), 1.97 (s, 3 H), 1.36 (d, J=6.6 Hz, 6 H), 1.35 (d, J=6.6 Hz, 6 H), 1.19 (m, 1 H). FAB-MS: calculated for (C27H32FNO) 405, found 406 (M+H). Anal. Calcd for C27H32FNO: C, 79.96; H, 7.95; N, 3.45. Found: C, 80.08; H, 8.05; N, 3.46. mp 125-126° C. Rf=0.3 (20% ethyl acetate/hexane).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@H:24]([OH:39])[CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([OH:38])=[C:31]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:32]=1>>[OH:39][C@H:24]([CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([OH:38])=[C:31]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:32]=1)[CH2:23][NH:22][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN)ccc1O
Product: CCCCS(=O)(=O)Nc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from butane-1-sulfonic acid [4-(4-oxo-piperidine-1-yl)-phenyl]-amide (which was obtained in Example 228) and N-[5-((2S)-3-amino-2-hydroxy-propoxy)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 14) according to the procedure of Example 278 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.83 (t, J=7.3 Hz, 3H), 1.25-1.40 (m, 2H), 1.55-1.70 (m, 2H), 1.80-1.95 (m, 2H), 2.50-2.80 (m, 5H), 2.92 (s, 3H), 2.85-3.30 (m, 2H), 3.50-3.65 (m, 2H), 3.70-3.90 (m, 3H), 6.61 (dd, J=8.8, 2.9 Hz, 1H), 6.70-6.80 (m, 2H), 6.88 (d, J=8.9 Hz, 2H), 7.05 (d, J=8.9 Hz, 2H); MS (ES) m/z: 571.0 (MH+); HRMS Calcd. for C25H39N4O7S2 (MH+): 571.2261. Found: 571.2279.
Reaction SMILES: [CH2:1]([C:4]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3C(OC(C)(C)C)=O)=[CH:29][CH:28]=2)[C:7]2[CH:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:9]([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)[C:48]([OH:50])=[O:49]>C(Cl)Cl>[CH2:1]([C:4]1[N:25]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:31]([C:48]([OH:50])=[O:49])[CH:32]=2)[C:7]2[CH:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:9]([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)C(C(=O)OCC)N(C(=O)CC(=O)OCC)CC2
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3)c(C(=O)O)c1)C(C(=O)OCC)N(C(=O)CC(=O)OCC)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of ethyl 2-n-propyl-3-{2'-(tert-butoxycarbonyl)biphenyl-4-yl}methyl-5-ethoxycarbonylacetyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (657 mg), trifluoroacetic acid (3 ml) and methylene chloride (10 ml) is stirred overnight at room temperature. The reaction mixture is washed with saturated sodium hydrogen carbonate solution and brine, dried and evaporated to remove the solvent. The crude residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 2-n-propyl-3-(2 -carboxybiphenyl-4-yl)methyl-5-ethoxycarbonylacetyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (516 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]([CH:15]=O)=[C:13]([CH3:14])[C:7]=2[C:6]1=[O:17].[O:19]=[C:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([NH:29][CH:30]=[O:31])[CH:26]=2)[NH:21]1>>[CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]([CH:15]=[C:28]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([NH:29][CH:30]=[O:31])[CH:26]=4)[NH:21][C:20]3=[O:19])=[C:13]([CH3:14])[C:7]=2[C:6]1=[O:17]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CC2
Reactant: O=CNc1ccc2c(c1)CC(=O)N2
Product: Cc1c(C=C2C(=O)Nc3ccc(NC=O)cc32)[nH]c2c1C(=O)N(CCN(C)C)CC2
Yield: 69.3 %

Procedure:
The title compound was prepared under the same conditions as described in Example 112 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-formamide as starting materials to give N-{3-[5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-formamide (43 mg, 69.3%) as a yellow solid.
Reaction SMILES: [CH:1]1([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[OH:17])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.CCN(C(C)C)C(C)C.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>C(Cl)Cl>[CH2:31]([O:30][C:28]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:1]1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[OH:17])=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Oc1ccc(F)cc1C1NCc2ccccc21
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1Cc2ccccc2C1c1cc(F)ccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an-ice cooled solution of (±)-2-(2,3-dihydro-1H-isoindol-1-yl)-4-fluoro-phenol (13 mg, 0.055 mmol, 1.00 eq.) and DIPEA (37 μL, 0.218 mmol, 4.00 eq.) in DCM (2 mL), benzyl chloroformate (8 μL, 0.057 mmol, 1.05 eq.) was added dropwise. Upon completion of the addition, the cooling bath was removed and the solution was stirred at r.t. for 3 hours. The reaction was quenched with 1M aq. citric acid soln. (5 mL). The layers were separated. The aq. phase was extracted with DCM (3×2 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give (±)-1-(5-fluoro-2-hydroxy-phenyl)-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][C:6]=1[O:13][CH2:14][CH3:15])[CH3:2].S(=O)(=O)([OH:19])N.Cl([O-])=O.[Na+]>CN(C)C=O.O.[Cl-].[Na+].O>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([CH:8]=[CH:7][C:6]=1[O:13][CH2:14][CH3:15])[C:11]([OH:19])=[O:12])[CH3:2]
Reactant: NS(=O)(=O)O
Reactant: CCOC(=O)c1cc(C=O)ccc1OCC
Agent: [Cl-]
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(C(=O)O)ccc1OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a stirring solution of 2-ethoxy-5-formyl-benzoic acid ethyl ester (1.0 g, 4.5 mmol) in 10 mL of dimethylformamide was added dropwise sulfamic acid (610.4 mg, 6.3 mmol) in 5 mL of water. After addition of sulfamic acid, sodium chlorite (737.2 mg, 8.2 mmol) in 5 mL of water was added dropwise. Reaction was allowed to stir for 2 h at room temperature. Reaction was diluted with brine and extracted with ethyl acetate. Organic extract was dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 4-ethoxy isopthalic acid 3-ethyl ester as a white solid (900 mg, 84%). LC-MS: 239.2 [(M+H)+].
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)Cl>[CH3:1][S:2]([CH2:3][C:4]1[N:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:25]
Reactant: CSCc1cc2c(cn1)[nH]c1ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)Cc1cc2c(cn1)[nH]c1ccccc12

Procedure:
160 mg of 3-methylthiomethyl-β-carboline are stirred in 15 ml of methylene chloride with 163 mg of m-chloroperbenzoic acid for 3 hours at room temperature. After extraction with semiconcentrated sodium bicarbonate solution, the organic phase is dried, filtered and concentrated. The residue is stirred with ethyl acetate/ethanol. 76 mg of 3-methylsulfinylmethyl-β-carboline with a 175°-178° C. melting point are obtained as a residue.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[NH:15][CH:16]=[CH:17][N:18]=2)=[CH:9][CH:8]=1)C.[NH3:20]>C(O)C>[NH:18]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([NH2:20])=[O:3])=[CH:8][CH:9]=1
Reactant: CCOC(=O)COc1ccc(Cc2ncc[nH]2)cc1
Reactant: N
Solvent: CCO
Product: NC(=O)COc1ccc(Cc2ncc[nH]2)cc1

Procedure:
A solution of 4-(1-imidazolylmethyl)phenoxyacetic acid ethyl ester (2.0 g) in ethanol (10 ml) and concentrated aqueous ammonia (SG 0.880) were heated under reflux for 2 hours and then evaporated. The residue was crystallised from a mixture of methanol and 2-butanone to give 4-(1-imidazolylmethyl)phenoxyacetamide (1.31 g) m.p. 173°-174° C. Found: C, 62.42, H, 5.76, N, 17.40. C12H13N3O2 requires: C, 62.32, H, 5.67, N, 18.17%.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[CH:5]=[O:6].S(=O)(=O)([OH:16])N.[O-]Cl=O.[Na+]>CC#N.O>[CH3:13][O:12][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([I:1])[C:9]=1[O:10][CH3:11])[C:5]([OH:16])=[O:6]
Reactant: NS(=O)(=O)O
Reactant: COc1cc(C=O)cc(I)c1OC
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: COc1cc(C(=O)O)cc(I)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a stirred solution of 3-iodo-4,5-dimethoxybenzaldehyde (25.0 g, 85.6 mmol) in CH3CN (800 mL) at room temperature, was added a solution of sulfamic acid (10.65 g, 109 mmol) in H2O (135 mL). To this was added, dropwise, a solution of NaClO2 (12.65 g, 112 mmol) in H2O (135 mL) over 20 min period. After stirring for a further 30 min at room temperature, the solvent was removed in vacuo. The reaction was diluted with 1.0 M aqueous HCl (700 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (600 mL), dried over Na2SO4 and concentrated in vacuo to give 3,4-dimethoxy-5-iodobenzoic acid (26 g). The product was used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:15])(=O)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Cl:11][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH2:3][Cl:15])=[CH:10][CH:9]=1
Reactant: CC(C)(C)c1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CC(C)(CCl)c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 56.5 %

Procedure:
To 25 g of 4-tert-butylchlorobenzene synthesized in (1) above were added 20 g of sulfuryl chloride and a catalytic amount of benzoyl peroxide, and the temperature was elevated and the mixture was maintained at 100° C. for 1 hour. Then, the mixture was distilled under reduced pressure to give 17.0 g of 2-(4-chlorophenyl)-2-methyl-1-chloropropane (bp.: 121°-123° C./10 mmHg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[CH2:12]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CCCCCC>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:19]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[O:11])=[CH:26][CH:25]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCNCc1ccc(CCCC)cc1
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: CCCCCC
Product: CCCCCCCN(Cc1ccc(CCCC)cc1)C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1.55 g of 2,4-diflurophenylisocyanate in hexane was added to a solution of 2.61 g of N-heptyl-4-butylbenzenemethanamine in 15 ml of hexane and the solution was stirred at room temperature for 4 hours, then evaporated. The residual oil was distilled to yield 1-[(4-butylphenyl)methyl]-1-(n-heptyl)-3-[2,4-difluorophenyl]urea as a colorless oil, bp 160°-165° C./120μ.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3([C:16]([OH:18])=[O:17])[CH2:15][CH2:14][CH2:13]3)[CH:8]=2)[NH:3]1.O.[C:20]1(C)C=CC(S(O)(=O)=O)=C[CH:21]=1>C(O)C>[O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3([C:16]([O:18][CH2:20][CH3:21])=[O:17])[CH2:13][CH2:14][CH2:15]3)[CH:8]=2)[NH:3]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C1Nc2ccc(C3(C(=O)O)CCC3)cc2C1=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(c2ccc3c(c2)C(=O)C(=O)N3)CCC1
Temperature: 80 °C
Yield: 334.1 %

Procedure:
7.2 g of 1-(2,3-dioxoindolin-5-yl)cyclobutanecarboxylic acid are dissolved in 100 ml of ethanol, and 500 mg of toluene-4-sulfonic acid monohydrate are added. The mixture is heated at 80° C. for 1 h and subsequently evaporated in vacuo. The residue is taken up in 100 ml of water and 100 ml of ethyl acetate, and the aqueous phase is separated off. The aqueous phase is washed a further twice with 100 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue is purified by column chromatography (reversed phase), giving 2.4 g (30%) of ethyl 1-(2,3-dioxoindolin-5-yl)cyclobutanecarboxylate;
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:5]=2[CH2:4][CH2:3]1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])[C:19]([Cl:33])=[CH:18][N:17]=1.C(O)(C)C.Cl.O1CCOCC1>>[Cl:33][C:19]1[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])=[N:21][C:16]([NH:13][C:10]2[CH:11]=[CH:12][C:5]3[CH2:4][CH2:3][C:2]([F:14])([F:1])[CH2:8][CH2:7][C:6]=3[CH:9]=2)=[N:17][CH:18]=1
Reactant: Nc1ccc2c(c1)CCC(F)(F)CC2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(F)(F)CC3)ncc1Cl
Reaction time: 0.17 h
Yield: 27.7 %

Procedure:
Into a microwave vial was placed 7,7-difluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (79 mg, 0.00040 mol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (100 mg, 0.0003 mol) in isopropyl alcohol (4 mL, 0.05 mol). 4N HCl-dioxane (0.04 g, 0.0003 mol) was added to the reaction mixture and the contents subjected to microwaves at 120° C. for 10 min. The reaction mixture was resubjected to the same microwave conditions for an additional 10 min. A solid had precipitated out of the reaction mixture, was collected by filtration then redissolved in methylene chloride (6 mL) and washed with sat. aqueous sodium bicarbonate (1×5 mL) and water (2×5 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give 2-[5-Chloro-2-(7,7-difluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a brown solid (38 mg, 29%). MP: 160-168° C.; 1HNMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 9.46 (s, 1H), 8.80 (d, 1H, J=4.5 Hz), 8.74 (d, 1H, J=7.6), 8.26 (s, 1H), 7.79 (d, 1H, J=7.8 Hz), 7.61 (s, 1H), 7.53 (t, 1H, J=7.6), 7.45 (d, 1H, J=7.8), 7.2 (t, 1H, J=7.3), 2.85 (d, 3H, J=4 Hz), 2.69-2.77 (m, 4H), 2.06 (m, 4H); MS (m/e) 458 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]#[C:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH2:23]O)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]#[C:20][C:21]([CH3:25])([CH3:26])[CH2:22][CH2:23][N:31]3[C:27](=[O:37])[C:28]4[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:30]3=[O:32])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1C#CC(C)(C)CCO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1C#CC(C)(C)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 126.3 %

Procedure:
To a solution of 5-(2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)-3,3-dimethyl-4-pentyn-1-ol (F15, 75 mg), phthalimide (93 mg) and triphenylphosphine (165 mg) in tetrahydrofuran (3.5 mL), a 1.9 mol/L solution of diisopropyl azodicarboxylate in toluene (332 μL) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, 92 to 52% hexane in ethyl acetate) to obtain 2-(5-(2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)-3,3-dimethyl-4-pentyn-1-yl)isoindoline-1,3-dione (F16, 129 mg) as pale yellow solid.