Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:12][C:11](=[O:13])[CH2:10][O:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].Cl.Cl[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][N:12]1[C:11](=[O:13])[CH2:10][O:9][C:8]2[CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]1=2
Reactant: CN(C)CCCl
Reactant: O=C1COc2cc([N+](=O)[O-])ccc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCN1C(=O)COc2cc([N+](=O)[O-])ccc21
Temperature: 100 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
A suspension of 7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (0.5 g, 2.575 mmol), 2-chloro-N,N-dimethylethanamine hydrochloride (0.37 g, 2.575 mmol), and K2CO3 (1.06 g, 7.726 mmol) in dry DMF (5 mL) was stirred at 100° C. overnight (18 hours). The reaction was brought to room temperature, diluted with water (100 mL), and the product was extracted into ethyl acetate (2×25 mL). The combined ethyl acetate layers were washed with brine (20 mL) and then dried (Na2SO4). The solvent was evaporated, and the crude material was purified by column chromatography (3:97 (2M NH3 in MeOH):CH2Cl2) to obtain the title compound (0.52 g, 76%) as a yellow solid. 1H NMR (DMSO-d6) δ 2.17 (s, 6H), 2.42 (t, 2H, J=6.6 Hz), 4.07 (t, 2H, J=6.6 Hz), 4.79 (s, 2H), 7.45 (d, 1H, J=9.0 Hz), 7.80 (d, 1H, J=2.7 Hz), 7.96 (dd, 1H, J=2.4, 9.0 Hz); ESI-MS (m/z, %): 266 (MH+, 100), 221 (66).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][C:15]=2[N:16]=1.FC(F)(F)S(O[C:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH:37]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>CN(C=O)C.O.CCOC(C)=O.O>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([C:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH:37]=3)=[CH:17][C:15]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: CC1(C)OB(c2ccc3oc(-c4ccc(S(C)(=O)=O)cc4F)nc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3oc(-c4ccc(S(C)(=O)=O)cc4F)nc3c2)CC1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 44.1 %

Procedure:
2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxa borolan-2-yl)benzo[d]oxazole (50 mg, 0.12 mmol), tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (39 mg, 0.12 mmol) and sodium carbonate (38 mg, 0.36 mmol) were dissolved in DMF (2 ml) under N2 atmosphere. This mixture was degassed with nitrogen for 30 mins and added Pd(dppf)2Cl2.CH2Cl2 (10 mg, 0.009 mmol). This mixture stirred at 80° C. for 90 mins in microwave. Reaction mixture diluted with water and work up (AcOEt/H2O) afforded the crude. Crude was purified by combiflash using a mixture of AcOEt and Petether (27:73) to afford the titled compound (25 mg) as an off-white solid. M.P.: 149-151° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.47 (t, J 7.4, 1H), 7.93-7.80 (m, 3H), 7.65-7.57 (m, 1H), 7.53-7.45 (m, 1H), 6.20-6.02 (m, 1H), 4.12 (bs, 2H), 3.68 (t, J 5.3, 2H), 3.13 (s, 3H), 2.65-2.55 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:11]=[C:10]([CH3:26])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:27]([NH:31][S:32]([C:35]1[S:36][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:39]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[S:36][C:37]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24][CH3:25])[CH:15]=4)[CH:11]=[C:10]([CH3:26])[N:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:38][CH:39]=1)(=[O:33])=[O:34])([CH3:30])([CH3:28])[CH3:29]
Reactant: COc1cc(-c2cc(C)nc(-c3ccnc(Cl)c3)c2)ccc1C(F)(F)F
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: COc1cc(-c2cc(C)nc(-c3ccnc(-c4ccc(S(=O)(=O)NC(C)(C)C)s4)c3)c2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2′-chloro-4-(3-methoxy-4-trifluoromethylphenyl)-6-methyl-[2,4′]bipyridinyl (example E.99) (0.378 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.380 g, 1.1 mmol) according to the general procedure VI. Obtained as a white solid (0.142 g, 25%). MS (ISP) 562.3 [(M+H)+]; mp 209° C. (dec.).
Reaction SMILES: [C:1]1([C:7]23[CH2:14][CH2:13][C:10]([C:15]([OH:17])=O)([CH2:11][CH2:12]2)[CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl.CN(C=O)C>[C:1]1([C:7]23[CH2:14][CH2:13][C:10]([C:15]([Cl:21])=[O:17])([CH2:11][CH2:12]2)[CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C12CCC(c3ccccc3)(CC1)CC2
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C12CCC(c3ccccc3)(CC1)CC2
Temperature: 25 °C

Procedure:
To an ice-water cooled solution of 4-phenylbicyclo[2.2.2]octane-1-carboxylic acid (479 mg, 2.07 mmol) in DCM (20 mL) was added DMF (2-3 drops) followed by oxalyl chloride (0.20 mL, 2.14 mmol). The reaction mixture was allowed to warm to ambient temperature overnight and then solvent was evaporated under reduced pressure to leave crude 4-phenylbicyclo[2.2.2]octane-1-carbonyl chloride which was used directly in the next stage.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH2:21][CH2:20]3)=[N:14][CH:15]=2)[N:10](COCC[Si](C)(C)C)[C:9]1=[O:38].Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH2:21][CH2:20]3)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:38]
Reactant: C[Si](C)(C)CCOCN1C(=O)N(c2ccccc2Cl)Cc2cnc(N[C@H]3CC[C@H](NS(C)(=O)=O)CC3)nc21
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)N[C@H]1CC[C@H](Nc2ncc3c(n2)NC(=O)N(c2ccccc2Cl)C3)CC1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a solution of the 3-(2-chlorophenyl)-7-[trans-4-(methanesulfonylamino)cyclohexylamino]-1-[2-(trimethylsilyl)ethoxymethyl]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (290 mg, 0.5 mmol) in 5 mL methanol was added 4.0 mL of 10% aqueous hydrochloric acid. The reaction mixture was stirred at 40° C. for 24 hours, and was concentrated in vacuo. Repeated triturations of the colorless. oil with ethyl acetate gave 3-(2-chlorophenyl)-7-[trans-4-(methanesulfonylamino)cyclohexylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one a white solid which was collected by vacuum filtration.
Reaction SMILES: [O:1]1[C@H:3]2[CH:4]=[C:5]3[C@@H:21]([C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:2]124)[CH2:20][CH2:19][C@@:18]1([CH3:29])[C@H:6]3[CH2:7][CH2:8][C@@H:9]1[C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[NH2:30][CH2:31][CH2:32][CH2:33][NH2:34].C(O)CCC>COC(C)(C)C>[OH:1][C@:2]12[CH2:26][C@@H:25]([OH:27])[CH2:24][CH2:23][C@:22]1([CH3:28])[C@@H:21]1[C:5]([C@H:6]3[C@:18]([CH3:29])([CH2:19][CH2:20]1)[C@@H:9]([C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]3)=[CH:4][C@H:3]2[NH:30][CH2:31][CH2:32][CH2:33][NH2:34]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C[C@@H]4OC45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C
Reactant: NCCCN
Solvent: COC(C)(C)C
Solvent: CCCCO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C[C@@H](NCCCN)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 65.8 %

Procedure:
5,6α-epoxicholest-7-en-3β-ol (8.9 g, 22.1 mmol, 1 eq) and 1,3-diaminopropane (3.3 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give 5α-Hydroxy-6β-(3-aminopropylamino)-cholest-7-en-3β-ol as a white solid (6.9 g, 66%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 21% yield.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@@:18]3(O)[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=4)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cccc(C[C@@H]2CCCC[C@]2(O)c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 4 h
Yield: 59.6 %

Procedure:
A mixture of (1R,2S)-1-(4,5-diphenyloxazol-2-yl)-1-hydroxy-2-(3-methoxybenzyl)cyclohexane (28 g) and p-toluene-sulfonic acid (2.5 g) in toluene (300 ml) was stirred for 4 hours under reflux. The solution was washed with water, sat. NaHCO3 and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford (S)-2-(4,5-diphenyloxazol-2-yl)-1-(3-methoxybenzyl)-2-cyclohexene (16 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([C:27](O)=[O:28])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:38]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1)=[CH:17][C:16]([C:27]([NH2:38])=[O:28])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(C(=O)O)ccc2c1=O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(C(N)=O)ccc2c1=O
Yield: 84.3 %

Procedure:
A solution of 3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylic acid (1.21 g, 2.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.96 g, 5 mmol) and 1-hydroxybenzotriazole ammonium salt (0.76 g, 5 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide (1.02 g, 85.0%) as crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][NH:8][C:9]2=[O:14])([O-])=O.[Cl-].[NH4+].O>C(O)C.O1CCCC1.[Zn]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][NH:8][C:9]2=[O:14]
Reactant: O=c1[nH]ccc2c([N+](=O)[O-])cccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cccc2c(=O)[nH]ccc12
Temperature: 32.5 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
268.3 mg (1.51 mmol) of 5-nitroisoquinolin-1(2H)-one is added with 376.5 mg of ammonium chloride and 2.6 ml of water in 14 ml of ethanol and 5.4 ml of tetrahydrofuran. After the addition of 1.23 g of zinc powder in portions (heating to 30 to 35° C.), it is stirred for two hours. The reaction mixture is suctioned off via a glass fiber filter and rewashed with ethyl acetate. After the filtrate is washed with water and saturated sodium chloride solution, the organic phase is dried as usual. Filtering off the desiccant and spinning-off the solvent produce 196.5 mg (88.1%) of the desired amine.
Reaction SMILES: FC1N(C)C(O)CN(C2C=CC(N[C:17]3[N:22]=[C:21]([C:23]4[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH:26]=[CH:27][CH:28]=4)[C:20]([NH:34][C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=4)=[CH:19][N:18]=3)=CC=2)C1.[Cl:42]C1N=C(Cl)C(NC2C=CC=C(F)C=2)=CN=1.C(NC1C=C(B(O)O)C=CC=1)(=O)C=C>[Pd]>[Cl:42][C:17]1[N:22]=[C:21]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH:26]=[CH:27][CH:28]=2)[C:20]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)=[CH:19][N:18]=1
Reactant: Fc1cccc(Nc2cnc(Cl)nc2Cl)c1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CC(O)N(C)C(F)C4)cc3)ncc2Nc2cccc(F)c2)c1
Agent: [Pd]
Agent: C=CC(=O)Nc1cccc(B(O)O)c1
Product: C=CC(=O)Nc1cccc(-c2nc(Cl)ncc2Nc2cccc(F)c2)c1

Procedure:
As an example, N-(3-(2-((4-(3-fluoro-5-hydroxy-4-methylpiperazin-1-yl)phenyl)amino)-5-((3-fluorophenyl)amino)pyrimidin-4-yl)phenyl)acrylamide can be prepared according to Route I. Beginning with 2,4-dichloro-N-(3-fluorophenyl)pyrimidin-5-amine, a palladium catalyzed coupling reaction with (3-acrylamidophenyl)boronic acid provides N-(3-(2-chloro-5-((3-fluorophenyl)amino)pyrimidin-4-yl)phenyl)acrylamide under mild conditions. Reaction of this product with 4-(4-aminophenyl)-6-fluoro-1-methylpiperazin-2-ol under palladium catalyzed aminolysis conditions can yield the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:3]=1.[O:22]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:22]([C:29]1[CH:30]=[CH:31][C:32]([NH:33][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]3)[CH:3]=2)=[CH:34][CH:35]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2cc(Cl)ncn2)C1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)C1
Yield: 40.6 %

Procedure:
A solution of tert-butyl 3-(6-chloropyrimidin-4-ylamino)piperidine-1-carboxylate (0.15 g, 0.48 mmol), 4-phenoxyaniline (0.089 g, 0.48 mmol), Pd(OAc)2 (0.010 g, 0.048 mmol), BINAP (0.014 g, 0.024 mmol) and Cs2CO3 (0.39 g, 1.2 mmol) in degassed toluene (toluene was purged with N2 for 15 min) was heated for 12 h at 100° C. under N2 atmosphere. The reaction mixture was cooled, was diluted with EtOAc (20 mL) and was washed with water (4 mL) and brine brine (2 mL) and was dried over Na2SO4. The crude product obtained was purified by column chromatography (SiO2, 230-400, chloroform/methanol:99/1) to give tert-butyl 3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)piperidine-1-carboxylate (90 mg, 40.9%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C@H:11]1[CH2:16][O:15][C@H:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][O:12]1)[C:5]([OH:7])=[O:6].[CH2:22]([C@H:25]1[CH2:30][CH2:29][C@H:28](O)[CH2:27][CH2:26]1)[CH2:23][CH3:24].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)C>[CH2:22]([C@H:25]1[CH2:30][CH2:29][C@H:28]([O:6][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([C@H:11]3[CH2:16][O:15][C@H:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][O:12]3)=[C:2]([F:1])[CH:3]=2)[CH2:27][CH2:26]1)[CH2:23][CH3:24]
Reactant: CCCCC[C@@H]1CO[C@@H](c2ccc(C(=O)O)cc2F)CO1
Reactant: CCC[C@H]1CC[C@H](O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: CCCCC[C@@H]1CO[C@@H](c2ccc(C(=O)O[C@H]3CC[C@H](CCC)CC3)cc2F)CO1

Procedure:
A mixture of 2.96 g. 3-fluoro-4-(trans-5-pentyl-1,4-dioxane-2-yl)benzoic acid (obtainable from the nitrile, cf. Example 7), 1.42 g. trans-4-propylcyclohexanol and 2.06 g. dicyclohexylcarbodiimide is boiled in 50 ml. diethyl ether for 6 hours. After cooling, one filters, works up as usual and obtains 3-fluoro-4-(trans-5-pentyl-1,4-dioxan-2-yl)benzoic acid trans-4-propylcyclohexyl ester.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:16]=3)[N:11]([CH:23]([CH3:25])[CH3:24])[CH:10]=2)=[CH:5][CH:4]=1)=O.Cl.[NH2:27][OH:28].C(O)C.O1CCCC1>C(OCC)(=O)C.N1C=CC=CC=1>[OH:28][N:27]=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:16]=3)[N:11]([CH:23]([CH3:25])[CH3:24])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: CC(C)n1cc(-c2ccc(C=O)cc2)c2ccc(NS(C)(=O)=O)cc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)n1cc(-c2ccc(C=NO)cc2)c2ccc(NS(C)(=O)=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
Method Z-2 Place N-[3-(4-formyl-phenyl)-1-isopropyl-1H-indol-6-yl]-methanesulfonamide and hydroxylamine hydrochloride into a round bottom flask under nitrogen. Add ethanol (10 mL), tetrahydrofuran (10 mL) and pyridine. Warm to 60° C., and stir for 2 hours. Dilute with ethyl acetate (20 mL), and wash with 1N hydrochloric acid. Dry the organic layer over sodium sulfate, and concentrate in vacuo. Purify the residue by flash chromatography on silica (5-40% ethyl acetate in dichloromethane) to give N-{3-[4-(Hydroxyimino-methyl)-phenyl]-1-isopropyl-1H-indol-6-yl}-methanesulfonamide (241.1 mg, 69%). LRMS (API ES+)=372.0 (M+H).
Reaction SMILES: [C:1]1([N:7]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]([C:10]2[CH:31]=[CH:30][C:13]3[N:14]([CH3:29])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=4[O:27][CH3:28])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:39].C(O)C.C(=O)([O-])[O-].[NH4+:47].[NH4+]>ClCCl.C(O)C>[ClH:39].[C:1]1([N:7]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]([C:10]2[CH:31]=[CH:30][C:13]3[N:14]([CH3:29])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:47])[NH2:26])=[CH:21][C:20]=4[O:27][CH3:28])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1OC)n2C)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1OC)n2C)c1ccccc1
Yield: 89 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyano-2-methoxyphenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 89% of theory, C29H32N6O4 (528.6); Rf value: 0.13 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=529; (M+H+Na)++=276; (M+2H)++=265.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[H][H]>[Pd].C(O)C>[C:4]1([NH:7][C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccccc1Nc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1Nc1ccccc1

Procedure:
To a pressure reaction bottle was added 10 g 2-nitrodiphenylamine, 0.5 g 5% palladium on carbon and 100 ml 95% ethanol. The mixture was hydrogenated at 22 C and 40 psi hydrogen for 2 hours. Following filtration through celite and solvent removal, an oil was obtained that crystallized on standing.
Reaction SMILES: [CH3:1][CH:2](O)[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([CH3:12])=[O:11])=[CH:5][CH:4]=1.C(OC(=O)C)(=O)C.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.P(=O)(O)(O)O>>[C:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[CH2:1])=[CH:4][CH:5]=1)(=[O:11])[CH3:12]
Reactant: CC(=O)Oc1ccc(C(C)O)cc1
Agent: O=P(O)(O)O
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CC(=O)OC(C)=O
Product: C=Cc1ccc(OC(C)=O)cc1

Procedure:
Crude 4'-acetoxyphenylmethylcarbinol (Compound II) [0.58 mol] was mixed with acetic anhydride (0.64 mol), phenothiazine (0.1 wt. %) and 85% by weight phosphoric acid (0.32 mol %). This reaction mixture was fed continuous at a rate of about 2.0 g/minute to the hot reaction vessel, as employed in Examples 1-25, and the product was collected overhead through a distillation column. The reaction vessel was immersed in hot oil maintained at 220°-230° C. and the residue temperature was maintained 180°-190° C. The product (155.4 g) containing Compound I was collected overhead through the distillation column and the residue (24.6 g) was accumulated in the hot reaction vessel. 4-Acetoxystyrene (Compound I) was isolated in 74.1% yield.
Reaction SMILES: [O:1]=[C:2]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)[CH2:3][N:4]1[CH2:8][CH2:7][CH:6]([C:9](O)=[O:10])[CH2:5]1.CN(C(O[N:38]1[N:46]=[N:45][C:40]2[CH:41]=[CH:42][CH:43]=[N:44][C:39]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[NH:4]1[CH:5]=[C:39]([C:40]2[C:41]3[C:7](=[CH:6][CH:9]=[C:43]([NH:44][C:9]([CH:6]4[CH2:7][CH2:8][N:4]([CH2:3][C:2](=[O:1])[N:12]5[CH2:17][CH2:16][N:15]([C:18]6[CH:19]=[CH:20][C:21]([C:24]7[N:25]=[CH:26][CH:27]=[CH:28][N:29]=7)=[CH:22][CH:23]=6)[CH2:14][CH2:13]5)[CH2:5]4)=[O:10])[CH:42]=3)[NH:46][N:45]=2)[N:38]=[CH:3]1
Reactant: O=C(O)C1CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1ccc2[nH]nc(-c3c[nH]cn3)c2c1)C1CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 28.1 %

Procedure:
Amine 24 (82 mg, 0.41 mmol) and carboxylic acid 12 (81 mg, 0.21 mmol) were dissolved in CH2Cl2 (2 mL) and DMF (2 ML). To the crude was added TEA (1.16 mL), and HATU (156 mg, 0.41 mmol). The crude was stirred at rt for 22 hrs under a stream of nitrogen. The crude was quenched with sat. NaHCO3 at rt and filtered over a plug of silica gel. The crude was evaporated and purified via preparation plates to give 17 mg of the product.
Reaction SMILES: [Na+].[CH3:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O-:25])(=O)=[O:23])=[CH:18][CH:17]=1.S(Cl)([Cl:28])=O>>[CH3:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([Cl:28])(=[O:25])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(S(=O)(=O)[O-])cc1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Thionyl chloride (50 mL) is added to the title B compound, 4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonic acid sodium salt (18.1 g, 52.46 mmol) at 0° C. After 10 min, the ice bath is removed and the mixture is stirred at RT for 30 min. An additional 50 mL of thionyl chloride is added, followed by about 1 mL of DMF. The solid dissolves within 10 min. Stirring is continued for an additional 2.5 h and the mixture is then concentrated under vacuum. The resulting yellow solid is partitioned between 250 mL of water and 250 mL of EtOAc (warm). The organic layer is further washed with water (3×250 mL), 0.1 N aqueous NaOH (4×250 mL) and brine (1×250 mL). The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to give 4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl chloride as a yellow solid: ESI-MS 363.99 [M+1]+.