Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:17]=O.Cl>CO>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: CO
Product: COc1cc(C=C2Oc3cc(O)ccc3C2=O)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 65.4 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-methoxy-4-benzyloxybenzaldehyde 1.79 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.63 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.[OH-].[K+]>CS(C)=O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:17]1[CH:18]=[C:14]([CH3:13])[N:15]=[CH:16]1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: Cc1c[nH]cn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc([N+](=O)[O-])ccc1-n1cnc(C)c1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 45.4 %

Procedure:
A solution of 2-chloro-5-nitroanisole (187 mg, 1 mmol), of 4-methyl-1H-imidazole (335 mg, 4 mmol) and of potassium hydroxide (99 mg, 1.5 mmol) in DMSO (0.86 mL) was stirred for 5 h at 80° C. under an atmosphere of nitrogen. After cooling to 20° C. the reaction was poured onto ice-water. A precipitation was formed and the suspension was stirred for 15 min. The solid was filtered off, washed with water, dissolved in dichloromethane, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield a yellow solid. The crude product was purified on silica gel using dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound (106 mg, 45%) as a pale-yellow solid. Alternatively the product can be also crystallized from the crude material from diethyl ether.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]3[C:18]=2C[N:16](C)[C:15]3=[O:20])[CH:7]=[N:6]1.NC1C=CC(C2C=NN(CCCO)C=2)=CC=1[C:53](NOC)=[O:54]>>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:29])[F:30])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:39][CH2:40][CH3:41])[O:42][CH2:43][CH3:44])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]([C:15](=[O:20])[NH:16][O:54][CH3:53])[CH:18]=2)[CH:7]=[N:6]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CONC(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)NOC)n2)c(OC)c1)OCC
Yield: 28 %

Procedure:
Prepared analogously to Compound 1B replacing Compound 1C with 2-amino-5-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-N-methoxybenzamide (Compound 26C, 169 mg, 583 μmol) to afford 114 mg of the title compound (28%). 1H NMR (400 MHz, CD3OD) δ=8.33 (s, 1H), 8.14 (s, 1H), 7.96 (d, J=0.5 Hz, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.71 (dd, J=2.2, 8.7 Hz, 1H), 7.00 (t, J=2.2 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 4.31 (t, J=7.0 Hz, 2H), 3.99-4.08 (m, 4H), 3.90 (s, 3H), 3.81 (s, 3H), 3.58 (t, J=6.1 Hz, 2H), 3.24 (d, J=21.0 Hz, 2H), 2.10 (quin. J=6.6 Hz, 2H), 1.24 (t, J=7.1 Hz, 6H). MS (ESI): m/z=708.72 [M+H]+. UPLC: tR=1.13 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[N:6][C:7]=1[CH3:8].CCN(C(C)C)C(C)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=2)[CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1ncc(N)cc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ncc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a 0.4 M solution of 5-bromo-6-methylpyridin-3-amine (1.00 equiv.) in DCM was added DIEA (1.00 equiv.) and 3-(trifluoromethyl)benzoyl chloride (1.00 equiv.). The mixture was stirred at ambient temperature for 3 hr. The reaction mixture was diluted with DCM, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated to give N-(5-bromo-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide as an off-white solid in 98% yield. LCMS (m/z) (M+H)=359.0/361.0, Rt=0.86 min.
Reaction SMILES: [CH3:1][C@H:2]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[CH:27]=[CH:26][C:21]3[NH:22][C:23](=[O:25])[O:24][C:20]=3[CH:19]=2)[CH2:14][CH2:13]1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:28](=O)[CH3:29].Cl>>[CH2:28]([N:11]([C@@H:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C@H:12]1[CH2:13][CH2:14][C@H:15]([C:18]2[CH:27]=[CH:26][C:21]3[NH:22][C:23](=[O:25])[O:24][C:20]=3[CH:19]=2)[CH2:16][CH2:17]1)[CH3:29]
Reactant: C[C@@H](CCc1ccccc1)N[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Reactant: CC=O
Agent: Cl
Product: CCN([C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1)[C@@H](C)CCc1ccccc1

Procedure:
Coupling of 6-{trans-4-[(S)-1-methyl-3-phenylpropylamino]cyclohexyl}-3H-benzoxazol-2-one (196 mg, 0.538 mmol) and acetaldehyde (24 mg, 0.538 mmol) following the procedure described in Example 24, followed by formation of the HCl salt, gave 6-(trans-4-{ethyl-[(S)-1-methyl-3-phenylpropyl]-amino}cyclohexyl)-3H-benzoxazol-2-one (110 mg, 50%), as a pale yellow solid (a mixture of diastereomers): mp 221-246° C.; IR (KBr): 3424, 2929, 1771, 1495 cm−1; 1H NMR (500 MHz, DMSO-d6): δ 11.52 (s, 2H), 9.11 (s, 2H), 7.35-7.21 (m, 10H), 7.18 (m, 4H), 7.00 (s, 2H), 3.20 (m, 2H), 2.81 (m, 2H), 2.54 (m, 2H), 2.20-1.51 (m, 28H), 1.44 (d, J=7 Hz, 3H), 1.32 (d, J=7 Hz, 3H), 126 (m, 6H); API-MS (methane) (m/z): 393 [M+H]+; HPLC: method C, 5.88 minutes (97.4%), method D, 11.32 minutes (>99%); Anal. Calcd for C25H32N2O2.HCl.H2O: C, 67.17; H, 7.89; N, 6.27. Found: C, 67.18; H, 7.69; N, 5.98.
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=2)=[N:5][N:4]2[CH2:14][CH2:15][CH2:16][C:3]=12.[CH2:17]1[O:25][C:24]2[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=2[O:18]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CO.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>[O:18]1[C:19]2[CH:20]=[CH:21][C:22]([C:2]3[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=4)=[N:5][N:4]4[CH2:14][CH2:15][CH2:16][C:3]=34)=[CH:23][C:24]=2[O:25][CH2:17]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: Cc1cccc(-c2nn3c(c2Br)CCC3)n1
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: CO
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2nn3c(c2-c2ccc4c(c2)OCO4)CCC3)n1
Temperature: 80 °C

Procedure:
A mixture of 3-bromo-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (99 mg, 0.36 mmol), 3,4-methylenedioxyphenylboronic acid (65 mg, 0.39 mmol), (PPh3)4Pd (20 mg, 0.02 mmol), 1 N aqueous sodium carbonate solution (500 μL, 0.5 mmol) in toluene (5 mL) and methanol (1 mL) is purged with argon for 10 min and heated at 80° C. under nitrogen for 30 h. The mixture is cooled and partitioned between water and ethyl acetate, and the organic portion washed with water and brine, dried (sodium sulfate), filtered, and concentrated in vacuo. The crude residue is chromatographed on SiO2 (ethyl acetate) to yield the title compound, 10 mg (9%), as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:11][O:10]C2=O)[CH:5]=[C:4]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)[CH:3]=1.[NH2:27][C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.O1CCOCC1>[F:19][C:16]1[CH:15]=[CH:14][C:13]([CH:12]([NH:8][C:6]2[CH:5]=[C:4]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[CH:3]=[C:2]([NH:27][C:28]3[CH:33]=[N:32][CH:31]=[CH:30][N:29]=3)[N:7]=2)[CH2:11][OH:10])=[CH:18][CH:17]=1
Reactant: Nc1cnccn1
Reactant: Cn1cc(-c2cc(Cl)nc(N3C(=O)OCC3c3ccc(F)cc3)c2)cn1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(Nc3cnccn3)nc(NC(CO)c3ccc(F)cc3)c2)cn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
80 mg of 3-[6-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]-4-(4-fluorophenyl)oxazolidin-2-one, 20 mg of 2-aminopyrazine, 20 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, mg of sodium t-butoxide and 22 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 2.5 ml of degassed 1,4-dioxane, and the mixture was stirred at 90° C. for 1 hour under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 34 mg of the objective compound as white powder.
Reaction SMILES: [CH3:1][C@@:2]12[C:18]([C:19]#[N:20])=[CH:17][CH2:16][C@@H:15]1[CH2:14][C@@H:13]1[C@H:4]([CH2:5][CH2:6][C@H:7]3[C@@:12]1([CH3:21])[CH2:11][CH2:10][C@H:9]([O:22]COC)[CH2:8]3)[CH2:3]2.Cl>CO.ClCCl>[CH3:1][C@@:2]12[C:18]([C:19]#[N:20])=[CH:17][CH2:16][C@@H:15]1[CH2:14][C@@H:13]1[C@H:4]([CH2:5][CH2:6][C@H:7]3[C@@:12]1([CH3:21])[CH2:11][CH2:10][C@H:9]([OH:22])[CH2:8]3)[CH2:3]2
Reactant: COCO[C@H]1CC[C@]2(C)[C@H](CC[C@@H]3C[C@]4(C)C(C#N)=CC[C@@H]4C[C@H]32)C1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: C[C@@]12CC[C@H](O)C[C@H]1CC[C@@H]1C[C@]3(C)C(C#N)=CC[C@@H]3C[C@H]12
Reaction time: 14 h
Yield: 93.7 %

Procedure:
To compound 26 (125 mg, 0.36 mmol) in methanol (9 mL) and dichloromethane (3 mL) was added 6 N HCl (10 ml) at room temperature. After 14 h, the mixture was extracted with dichloromethane (50 mL×2). The combined extracts were dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 25% EtOAc in hexanes) to afford compound 27 (101 mg, 93%): mp 170-172° C., [α]D25+5.4 (c 0.24, CHCl3); 1H NMR (CDCl3) δ 6.61 (t, J=2.8 Hz, 1H), 4.04-4.02 (m, 1H), 0.89 (s, 3H), 0.78 (s, 3H); 13C NMR (CDCl3) δ 147.7, 127.3, 116.0, 66.3, 55.1, 50.5, 48.1, 42.2, 39.1, 36.4, 35.7, 35.0, 34.8, 32.3, 32.0, 28.8, 28.7, 22.4, 16.6, 11.1; IR νmax 3391, 2216, 1448 cm−1. Anal. Calcd for (C20H29NO): C, 80.22; H, 9.76; N, 4.68. Found: C, 80.32; H, 9.70; N, 4.72.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[NH2:34][C:35]1[CH:36]=[C:37](S(N)(=O)=O)[CH:38]=[CH:39][CH:40]=1>>[CH2:2]1[C:37]2[C:38](=[CH:39][CH:40]=[C:35]([NH:34][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:36]=2)[CH2:5][CH2:4][NH:3]1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared by a procedure similar to Example 27, Step D using N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 3-aminobenzenesulfonamide: 1H NMR (400 MHz, DMSO-d6): δ 10.92 (s, 1H); 9.87 (s, 1H); 8.84 (d, 1H); 8.53 (d, 1H); 7.92 (d, 1H); 7.81 (d, 1H); 7.57 (m, 1H); 7.47 (m, 1H); 7.38 (m, 2H); 7.25 (m, 3H); 7.12 (m, 3H); 6.98 (s, 1H); 6.90 (d, 1H); 6.68 (d, 1H); 6.57 (d, 1H); 5.48 (br s, 1H). HRMS (ESI): (M+H)+ calculated 598.1473, found 598.1467.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](Cl)[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]3[C:28](=[O:29])[C:27]4=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]4[C:25]3=[O:34])=[CH:19][CH:18]=2)[C:5]1=[O:36])(=O)C.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[C:38]1([NH:37]/[C:16](=[C:6]2\[C:5](=[O:36])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][C:20]([CH2:23][N:24]3[C:25](=[O:34])[C:26]4=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]4[C:28]3=[O:29])=[CH:21][CH:22]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Nc1ccccc1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c2cc([N+](=O)[O-])ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccccc1)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1

Procedure:
Prepared analogously to Example 146 from 1-acetyl-3-[1-chloro-1-(4-phthalimidomethyl-phenyl)-methylidene]-5-nitro-2-indolinone, aniline, N-ethyl-N,N-diisopropyl-amine and DMF.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[CH2:18][C:19]#[N:20])#[CH:10]>C(#N)C.C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:10]#[C:9][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[CH2:18][C:19]#[N:20])[CH:5]=[CH:4][N:3]=1
Reactant: C#Cc1ccc(F)cc1CC#N
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#CCc1cc(F)ccc1C#Cc1ccnc(Cl)n1
Temperature: 80 °C
Yield: 65.3 %

Procedure:
2,4-Dichloropyrimidine (764 mg, 5.13 mmol) is dissolved in degassed acetonitrile (19.700 ml) and triethylamine (19.70 ml). Copper(I) iodide (75 mg, 0.395 mmol) is added, the mixture is degassed again for 10 min., and 2-(2-ethynyl-5-fluorophenyl)acetonitrile (628 mg, 3.95 mmol) and bis(triphenylphosphine)palladium(II) chloride (138 mg, 0.197 mmol) are then added successively to the greenish solution. The reaction phase is warmed at 80° C. for 30 min. The mixture is subsequently worked up, as described above, and the crude mass obtained is purified by chromatography on silica gel (petroleum ether/ethyl acetate=80/20 to 75/25), giving 700 mg of 2-(2-((2-chloropyrimidin-4-yl)ethynyl)-5-fluorophenyl)acetonitrile (2.58 mmol, 65.3% yield) as orange solid;
Reaction SMILES: [C:1]1([OH:9])[C:2]([CH3:8])=[CH:3][CH:4]=[C:5]([CH3:7])[CH:6]=1.S(=O)(=O)(O)O.[CH3:15][C:16](=[CH2:18])[CH3:17]>O.C([O-])(O)=O.[Na+]>[C:16]([C:4]1[CH:3]=[C:2]([CH3:8])[C:1]([OH:9])=[CH:6][C:5]=1[CH3:7])([CH3:18])([CH3:17])[CH3:15]
Reactant: Cc1ccc(C)c(O)c1
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(C(C)(C)C)c(C)cc1O
Yield: 49 %

Procedure:
2,5-Xylenol (90 g, 0.73 mol) was melted at 80° C., 1 mL of concentrated sulfuric acid was added, and the mixture was heated at 90° C. while isobutylene gas was introduced subsurface over 4 hours. The reaction appeared to stall at about 80% conversion. The reaction mass was diluted with water and neutralized with NaHCO3, and some starting xylenol was removed by steam-distillation. Since the steam-distillation did not completely remove the starting material, the residue was dissolved in hot hexanes, separated from the aqueous phase, and cooled in an ice-bath. The precipitated product was filtered and washed with cold hexanes to give 64 g (49%) of 4-t-Butyl-2,5-xylenol; lit. (Stevens, Ind. Eng. Chem. 1943, 655; Parc, Rev. Inst. Fr. Pet. 1960, 680) mp 70-72° C. 1H-NMR (CDCl3) δ 1.37, (s, 9H), 2.20 (s, 3H), 2.43 (s, 3H), 4.85 (s, 1H), 6.53 (s, 1H), 7.08 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](=[NH:7])[NH:5][NH2:6].[NH2:15][C:16](=S)[C:17](OCC)=[O:18]>C(O)C>[NH2:15][C:16]1[C:17](=[O:18])[NH:7][C:4]([C:3]2[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:2]=2[CH3:1])=[N:5][N:6]=1
Reactant: Cc1c(C(=N)NN)cccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(N)=S
Solvent: CCO
Product: Cc1c(-c2nnc(N)c(=O)[nH]2)cccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 2-methyl-3-nitrobenzimidohydrazide (2.10 g, 10.81 mmol) and ethyl 2-amino-2-thioxoacetate (3.60 g, 27.0 mmol) in ethanol (100 mL) was heated at reflux for 8 hr, during which period product precipitated. Upon cooling to rt, the product, 6-amino-3-(2-methyl-3-nitrophenyl)-1,2,4-triazin-5(2H)-one (2.18 g) was collected as a white solid by suction filtration and dried under vacuum. This product was 88% pure by HPLC. It was used in the next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:21][N:22]([CH2:24][CH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=O)[O:26]1)[CH3:23].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1>C(COC)OC.C1COCC1>[CH3:23][N:22]([CH2:24][CH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])[O:26]1)[CH3:21]
Reactant: O=C1Cc2ccccc2N1
Reactant: CN(C)CC1OC(=O)c2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: CN(C)CC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24.4 %

Procedure:
To a solution of oxindole (205 mg, 1.54 mmol) in dimethoxyethane (4.0 ml) at room temperature was added 1.0M LiHMDS in THF (1.54 ml). After stirring for 10 minutes at room temperature, 3-dimethylaminomethyl-3H-isobenzofuran-1-one (235 mg, 1.23 mmol) in dimethoxyethane (0.5 ml) was added and the mixture was stirred rapidly for 1 hour. Additional 1.0M LiHMDS/THF (1.54 ml) was added. After 2 hours the reaction was quenched into 10% HCl (50 ml) and 25 ml water added. The aqueous layer was washed with EtOAc and then basified with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with EtOAc. The EtOAc layer was washed with brine, dried over anhydrous Na2SO4, and rotary evaporated to provide a yellow solid. The yellow solid was chromatographed silica gel column (CHCl3 to 2.5% MeOH/CHCl3 gradient) and then recrystallized from MeOH to give 3-(3-dimethylaminomethy-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one as yellow needles (92 mg, 24%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])/[CH:5]=[CH:6]/[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)([CH3:9])[CH3:8])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)([CH3:8])[CH3:9])[CH3:2]
Reactant: CCOC(=O)/C=C/C(C)(C)c1cccc(OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC(C)(C)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
27.2 g (109.5 mmol) of ethyl-E-4-(3-methoxyphenyl)-4-methylpent-2-enoate is mixed in 293 ml of ethyl acetate with 2.72 g of palladium on carbon (10%) and stirred under hydrogen atmosphere for 18 hours at room temperature. The catalyst is removed by filtration through a glass-fiber filter, and the residue that remains after the concentration by evaporation (27.2 g=99.2%) is incorporated in crude form into the next stage.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:27]=[CH:26][C:9]2[N:10]=[C:11]([NH:14][CH:15]3[C:19]4[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:18]=4[O:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)([CH3:30])[CH3:29]>>[CH:28]([N:31]1[CH2:36][CH2:35][N:34]([CH2:2][C:3]([NH:5][C:6]2[CH:27]=[CH:26][C:9]3[N:10]=[C:11]([NH:14][CH:15]4[C:19]5[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:18]=5[O:17][CH2:16]4)[O:12][CH2:13][C:8]=3[CH:7]=2)=[O:4])[CH2:33][CH2:32]1)([CH3:30])[CH3:29]
Reactant: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CCl)cc3CO1)CO2
Reactant: CC(C)N1CCNCC1
Product: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CN4CCN(C(C)C)CC4)cc3CO1)CO2
Yield: 72.7 %

Procedure:
Prepared from rac-2-chloro-N-[2-(4-methoxy-2,3-dihydro-benzofuran-3-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 8) (50 mg, 0.129 mmol) and 1-(isopropyl)piperazine (330 mg, 2.578 mmol) according to the procedure described for Example 3 step B (here the reaction was sonicated for 2 min, which already lead to complete conversion). Obtained the title compound as a white solid (45 mg, 73%), MS (ISP) m/e=480.3 [(M+H)+].
Reaction SMILES: [N+]([N:4]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[N:6]=[CH:5]1)([O-])=O.C(=O)([O-])O.[Na+].[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[C:25][CH:26]=[C:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:19]=1>O.CC(C)=O>[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[C:25][CH:26]=[C:27]2[CH2:28][CH2:29][N:30]([C:8]3[NH:4][CH:5]=[N:6][C:7]=3[N+:9]([O-:11])=[O:10])[CH2:31][CH2:32]2)[N:19]=1
Reactant: O=[N+]([O-])c1cn([N+](=O)[O-])cn1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cccc(C#CC=C2CCN(c3[nH]cnc3[N+](=O)[O-])CC2)n1

Procedure:
To a solution of 1,4-dinitroimidazole (207 mg, 1.31 mmol) and sodium hydrogencarbonate (242 mg, 2.88 mmol) in 4 mL of water and 0.16 mL of acetone was added drop wise a solution of the compound of Example 3 (278 mg, 1.31 mmol) in acetone. The reaction mixture was refluxed for 2 h, poured into water and extracted with EtOAc. The crude residue was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with EtOAc-MeOH gradient from 1:0 to 92:8; affording the title compound not enough pure. So, it was purified again by preparative RP LC-MS chromatography, using MS-C18 XTerra column 30×50 mm eluting with ammonium bicarbonate 20 mM pH 8 buffer-acetonitrile gradient affording 4 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=[O:3].N1C[CH2:15][CH2:14][CH2:13]1.CC(C)=O>C1(C)C=CC=CC=1>[OH:11][C:7]1[CH:8]=[C:9]2[C:4]([C:2](=[O:3])[CH2:1][C:14]([CH3:15])([CH3:13])[O:10]2)=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: C1CCNC1
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)c2ccc(O)cc2O1
Yield: 33.8 %

Procedure:
To a solution of 2,4-dihydroxy acetophenone (6.00 g, 39.4 mmol) and pyrrolidine (15.0 mL, 181 mmol) in toluene (200 mL), acetone (22.9 g, 394 mmol) was added. After heated to reflux for 16 hrs, the solvents were removed and the residue was added HCl (2.0 N, 100 mL) and brine (200 mL) then the mixture was extracted with EtOAc (150×5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by SGC (eluting with petroleum ether/ethyl acetate=6/1) to give target compound (2.56 g, 33%) as a brown yellow solid. LCMS (ESI) m/z: 191.1 [M−H]+; 1H-NMR (500 MHz, CDCl3): δ 7.79 (d, J=8.0 Hz, 1H), 6.49 (dd, J=8.5, 2.0 Hz, 1H), 6.36 (d, J=2.0 Hz, 1H), 2.68 (s, 2H), 1.45 (s, 6H).