Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][Si:3]([CH3:30])([CH3:29])[CH2:4][CH2:5][O:6][CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][N:20]([C:22]4([CH2:26][C:27]#[N:28])[CH2:25][NH:24][CH2:23]4)[CH:21]=3)=[C:11]2[CH:10]=[CH:9]1.Cl[C:32]1[N:33]=[CH:34][C:35]([C:38]([NH:40][C@H:41]([CH:43]2[CH2:45][CH2:44]2)[CH3:42])=[O:39])=[N:36][CH:37]=1.C(N(CC)C(C)C)(C)C>>[C:27]([CH2:26][C:22]1([N:20]2[CH:21]=[C:17]([C:16]3[CH:15]=[CH:14][N:13]=[C:12]4[N:8]([CH2:7][O:6][CH2:5][CH2:4][Si:3]([CH3:29])([CH3:2])[CH3:30])[CH:9]=[CH:10][C:11]=34)[CH:18]=[N:19]2)[CH2:23][N:24]([C:32]2[N:33]=[CH:34][C:35]([C:38]([NH:40][C@H:41]([CH:43]3[CH2:45][CH2:44]3)[CH3:42])=[O:39])=[N:36][CH:37]=2)[CH2:25]1)#[N:28]
Reactant: C[C@H](NC(=O)c1cnc(Cl)cn1)C1CC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ccnc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ccnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cn1)C1CC1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 96.2 %

Procedure:
A mixture of {3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile HCl salt (200 mg, 0.4 mmol) (Example 40, Step 3), 5-chloro-N-[(1S)-1-cyclopropylethyl]pyrazine-2-carboxamide (100 mg, 0.46 mmol) in N,N-diisopropylethylamine (0.7 mL, 4 mmol) in a sealed vial was stirred at 120° C. for 1.5 h. After cooling it was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in methylene chloride (0-5%) to afford the desired product (0.23 g).
Reaction SMILES: C[O-].[Na+].[CH2:4]([N:6]([CH2:32][CH3:33])[CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18](OC)=[O:19])=[CH:12][C:11]=1[NH:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:5].[OH:34][NH:35]Cl.Cl.CO>CO>[CH2:4]([N:6]([CH2:32][CH3:33])[CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:35][OH:34])=[O:19])=[CH:12][C:11]=1[NH:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:5]
Reactant: ONCl
Reactant: CCN(CC)CCSc1ccc(/C=C/C(=O)OC)cc1NCCCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCN(CC)CCSc1ccc(/C=C/C(=O)NO)cc1NCCCc1ccccc1
Reaction time: 0.46 h
Yield: 2.2 %

Procedure:
Under stirring, sodium methoxide (30% in methanol; 2.72 g, 15.1 mmol) was added to a methanol (1.6 mL) solution of (E)-methyl 3-(4-(2-(diethylamino)ethylthio)-3-(3-phenylpropylamino)phenyl)acrylate (229 mg, 0.54 mmol) and hydroxylamino hydrochloride (750 mg, 10.8 mmol). The resulted mixture was kept at room temperature for 5-50 min, then a pre-cooled HCl-MeOH solution was added and pH was adjusted to 7. Solvent was removed under reduced pressure. The product was purified by chromatography. 5 mg of (E)-3-(4-(2-(diethylamino)ethylthio)-3-(3-phenylpropylamino)-phenyl)-N-hydroxy-acrylamide (I) was obtained. Yield: 2%. TLC: Rf=0.23 (DCM:MeOH=9:1); HPLC: 93.1%; tR=8.16 min (LC/PDA: Diamonsil C18 5μ 150×4.6 mm, flow rate 1.0 mL/min, grade: 10-100% B, 20 minutes; mobile phase A: H2O; mobile phase B: acetonitrile; UV254); 1HNMR (400 MHz, DMSO-δ6) δ: 10.68 (1H, s), 9.00 (1H, s), 7.17-7.37 (6H, m), 6.77 (1H, d, J=8.0 Hz), 6.72 (1H, s), 6.40 (1H, d, J=16.0 Hz), 5.45 (1H, br), 3.20 (2H, q, J=6.4 Hz), 2.86 (2H, br), 2.69 (3H, t, 8.0 Hz), 1.90 (2H, m, 3.2 Hz), 0.92 (6H, br). MS (m/z): 428 (MH)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH3:18])[N:6]([CH3:17])[C:7]=1[S:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[CH:10]=1.[C-:19]#[N:20].[K+]>CN(C)C=O>[CH3:17][N:6]1[C:7]([S:8][C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[CH:10]=2)=[C:3]([CH2:2][C:19]#[N:20])[N:4]=[C:5]1[CH3:18]
Reactant: [C-]#N
Reactant: Cc1cc(C)cc(Sc2c(CCl)nc(C)n2C)c1
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(Sc2c(CC#N)nc(C)n2C)c1
Temperature: 50 °C
Yield: 42 %

Procedure:
In 5.6 ml of dry dimethylformamide was dissolved 280 mg (1.0 mmol)of 4-chloromethyl-1,2-dimethyl-5-(3,5-dimethylphenylthio)-1H-imidazole (42c). Added was 98 mg (1.5 mmol)of potassium cyanide, and the mixture was heated at 50° C. for 5 hours. To the reaction mixture, ice-water was added, extracted with diethyl ether, the extract was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate)to obtain 114 mg of [1,2-dimethyl-5-(3,5-dimethylphenylthio)-1H-imidazol-4-yl]acetonitrile (42d)(yield 42%). mp 81-82° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][NH2:39])[CH:33]=1>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:39][CH2:38][C:34]3[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=3)=[O:19])=[CH:20][CH:21]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:25])=[O:24]
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccccc1
Reactant: NCc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccccc1
Yield: 48.4 %

Procedure:
Method E. Reaction of oxalyl chloride (102 λL, 1.17 mmol) and benzoic acid 17 (280 mg, 0.78 mmol) with subsequent coupling to 3-pyridinylmethylamine (87 λL, 0.86 mmol) gave benzamide 18 (169 mg, 48%) as a white powder: mp (EtOAc) 196-198° C.; 1H NMR δ 9.20 (t, J=5.9 Hz, 1 H, CONH), 8.57 (br s, 1 H, H-2′), 8.46 (br s, 1 H, H-6′), 8.00 (br dd, J=8.6, 1.8Hz, 2 H, H-2, H-6), 7.89 (br dd, J=8.6, 1.8Hz, 2 H, H-3, H-5), 7.80 (br d, J=8.5Hz, 2 H, H-2″, H-6″), 7.71-7.76 (m, 2 H, H-4′, H-4″), 7.62 (br dd, J=8.2, 7.5 Hz, 2 H, H-3″, H-5″), 7.36 (dd, J=7.8, 4.8Hz, 1 H, H-5′), 4.68 (s, 2 H, CH2SO2), 4.50 (d, J=5.8Hz, 2 H, CH2N), 2.13 (s, 3 H, CH3); 13C NMR δ 165.4, 157.9, 149.9, 148.8, 148.0, 138.3, 135.3, 135.0, 134.8, 133.8, 129.1 (2), 128.7, 128.1 (2), 128.0 (2), 125.8, 125.3 (2), 123.4, 52.7, 40.4, 9.5; MS m/z 448.5 (MH+, 100%). Anal. calcd for C24H21N3O4S: C, 64.41; H, 4.73; N, 9.39. Found: C, 64.23; H, 4.71; N, 9.37%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][OH:11])[C:6]=2[CH:12]=1.[CH3:13][CH2:14][O:15][C:16]([C:18]1[N:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:20]2[C:25]([CH:26]=1)=[C:24](O)[CH:23]=[CH:22][CH:21]=2)=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(C(C)C)C(C)C)C>C1COCC1>[CH3:13][CH2:14][O:15][C:16]([C:18]1[N:19]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C:20]2[C:25]([CH:26]=1)=[C:24]([O:11][CH2:10][C:7]1[C:6]3[CH:12]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:9][CH:8]=1)[CH:23]=[CH:22][CH:21]=2)=[O:17]
Reactant: CCOC(=O)c1cc2c(O)cccc2n1C(=O)OC(C)(C)C
Reactant: OCc1coc2ccc(Cl)cc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2n1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
100 (4 g, 21.9 mmol), 102 (6.7 g, 21.9 mmol), triphenylphosphine (17.3 g, 65.8 mmol) and 40% diethyl azadicarboxylate solution (31.8 ml, 65.8 mmol) are dissolved in THF and cooled to 0° C. Then a solution of N-ethyldiisopropylamine (11.2 ml, 65.8 mmol) in THF is added dropwise. After the addition is completed, the mixture is stirred at room temperature for 2 h. Then the mixture is evaporated under reduced pressure. The residue is diluted with ethyl acetate, washed with saturated NaHCO3-solution and dried over Na2SO4. The crude product is purified by Flash-chromatography (ethyl acetate/hexanes (3:7), silicagel).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]1[F:18])=O)C1C=CC=CC=1.[CH3:19][O:20][C:21]1[N:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[C:24]2[C@@H:31]1[CH2:33][O:32]1>>[NH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:33][C@@H:31]([C:24]2[C:23]3[C:28](=[CH:29][CH:30]=[C:21]([O:20][CH3:19])[N:22]=3)[N:27]=[CH:26][CH:25]=2)[OH:32])[CH2:14][CH:13]1[F:18]
Reactant: O=C(N[C@H]1CCNC[C@H]1F)OCc1ccccc1
Reactant: COc1ccc2nccc([C@@H]3CO3)c2n1
Product: COc1ccc2nccc([C@@H](O)CN3CCC(N)C(F)C3)c2n1

Procedure:
This was prepared from cis-4-benzyloxycarbonylamino-3-fluoropiperidine Enantiomer 2 (7a) and (R)-2-(6-methoxy-[1,5]-naphthyridin-4-yl)oxirane (20d) (100% ee) by the method of Example (20e).
Reaction SMILES: [F:1][CH:2]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([NH:19][C:20]3[N:25]=[C:24]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:23]=[CH:22][N:21]=3)[CH:13]=2)=[O:10])=[CH:5][CH:4]=1.[CH3:38][CH:39]=O>>[CH2:38]([N:35]1[CH2:34][CH2:33][N:32]([CH:2]([F:1])[C:3]2[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([NH:19][C:20]4[N:25]=[C:24]([C:26]5[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=5)[CH:23]=[CH:22][N:21]=4)[CH:13]=3)=[O:10])=[CH:5][CH:4]=2)[CH2:37][CH2:36]1)[CH3:39]
Reactant: CC=O
Reactant: Cc1ccc(NC(=O)c2ccc(C(F)N3CCNCC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Product: CCN1CCN(C(F)c2ccc(C(=O)Nc3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc2)CC1

Procedure:
The product from Example 3 was ethylated via reductive amination with CH3CHO/NaBHCN afforded the title compound. Mass: (M+1), 526.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[S:8][C:4]=2[CH:3]=1.[C:15](Cl)(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:15]([O:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9](=[O:11])(=[O:10])[NH2:12])[S:8][C:4]=2[CH:3]=1)(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCC(=O)Cl
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCC(=O)Oc1ccc2nc(S(N)(=O)=O)sc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-hydroxy-2-benzothiazolesulfonamide (2.3 g., 0.01 mole) and 4-dimethylaminopyridine (100 mg.) in pyridine (15 ml.) is added octanoyl chloride (1.7 ml.) over a period of 5 minutes. The reaction mixture is stirred 11/2 hours, poured into ice water and dilute hydrochloric acid, extracted into ethylacetate, washed with water, dried over magnesium sulfate and chromatographed on 35 g of silica gel (ethyl acetatehexane 1:1) to give 0.65 g of 2-sulfamoyl-6-benzothiazolyl octanoate which melts at 114° C. after recrystallization from butyl chloride.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:14][CH2:15][CH2:16]Br>>[Br:14][CH2:15][CH2:16][O:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:8]=1
Reactant: CCCCCOc1cccc(O)c1
Reactant: BrCCBr
Product: CCCCCOc1cccc(OCCBr)c1
Yield: 90.9 %

Procedure:
Prepared according to the method described in Example E above from 3-(n-pentoxy)phenol (18.0 g; 0.1 mol; from Example C above) and 1,2-dibromoethane (100 ml; 1.16 mol). Following work up the residue was chromatographed on silica gel with diisopropyl ether as eluent to yield 26.1 g (91%) of the tide compound as an oil which subsequently crystallised (96% purity). MW=287 (GCMS)
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:16][C:17]1[S:18][C:19]([CH:23]=O)=[CH:20][C:21]=1[CH3:22]>C1(C)C=CC=CC=1>[Br:16][C:17]1[S:18][C:19]([CH:23]2[O:4][CH2:1][CH2:2][O:3]2)=[CH:20][C:21]=1[CH3:22]
Reactant: OCCO
Reactant: Cc1cc(C=O)sc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(C2OCCO2)sc1Br

Procedure:
Ethylene glycol (2.18 ml) and p-toluenesulfonic acid (0.74 g) is added to a solution of 2-brom-3-methyl-5-formylthiophene (4.0 g) in toluene (98 ml) in a Dean-Stark apparatus. After 18 hours at reflux, the reaction is quenched with water. The organic phase is separated and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried over Na2SO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 2-(5-bromo-4-methyl-thiophen-2-yl)-[1,3]dioxolane (4.04 g) as a yellow oil. MS (HPLC/MS): 250 (MH+). Retention time: 4.02 min.
Reaction SMILES: C1C=CC=CC=1.[C:7]1([C:13]2([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:19][C:20]([Cl:25])([Cl:24])[C:21](Cl)=[O:22]>C(N(CC)CC)C>[C:7]1([C:13]2([NH:18][C:21](=[O:22])[C:20]([Cl:25])([Cl:24])[Cl:19])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: NC1(c2ccccc2)CCCC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(NC1(c2ccccc2)CCCC1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 200 ml four-necked flask, there were charged benzene (100 ml), 1-phenylcyclopentylamine (8.1 g) and triethylamine (6.1 g), and trichloroacetyl chloride (9.1 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. After completion of the reaction, the reaction mixture was washed with water to remove triethylamine hydrochloride. The benzene layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethanol to give 12.4 g g of N-(1-phenylcyclopentyl)trichloroacetamide. M.P., 114°-115.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[CH:26]=[N:27][CH:28]=[N:29][CH:30]=3)[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([C:25]5[CH:30]=[N:29][CH:28]=[N:27][CH:26]=5)=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2ccc(-c3cncnc3)cc21
Product: CC1c2cc(-c3cncnc3)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-pyrimidin-5-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)[C:3]#[CH:4].Br[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:1][CH:2]([C:5]1[N:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)[C:3]#[C:4][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC(O)c1cccn1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3cccn3C)c21

Procedure:
Using Method D above, 3-hydroxy-3-(1-methyl-pyrrol-2-yl)-1-propyne (132 mg, 0.98 mmol) (from Example 27 above) was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (112 mg, 0.35 mmol) (Starting Material 2) using (Ph3P)2PdCl2 (31 mg)(Aldrich) and CuI (17 mg)(Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 28 h, yielding rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-(1-methyl-pyrrol-2-yl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 114 mg, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:6]([OH:8])=O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:6]([N:51]1[CH2:52][CH2:53][N:48]([CH3:47])[CH2:49][CH2:50]1)=[O:8]
Reactant: COc1ccc(COc2ccc(C(=O)O)cc2OC)cc1
Reactant: CN1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(C(=O)N3CCN(C)CC3)cc2OC)cc1
Reaction time: 3 h
Yield: 93 %

Procedure:
A mixture of 3-methoxy-4-p-methoxybenzyloxybenzoic acid (2.88 g: 10 mMol.), 1-hydroxybenzotriazole (1.49 g: 1.1 Eq.), and dicyclohexylcarbodiimide (2.27 g: 1.1 Eq.) in tetrahydrofuran (100 ml) is kept at room temperature for 3 hours. To this solution is added N-methylpiperazine (2.22 ml: 2 Eq.), and the mixture is kept at room temperature overnight to give 1-(3-methoxy-4-p-methoxybenzyloxybenzoyl)-4-methylpiperazine (3.45 g). Yield: 93%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[NH:14][N:13]=[N:12][N:11]=1.[C:15](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[N:11]=[N:12][N:13]([CH3:15])[N:14]=1
Reactant: Fc1cc(Cl)cc(Br)c1-c1nnn[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nnc(-c2c(F)cc(Cl)cc2Br)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of the above tetrazole (16.0 g, 57.7 mmol), potassium carbonate (12.0 g, 86.5 mol), and iodomethane (11.5 g, 80.7 mol) in 15 mL DMF was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water, and the organic extract was washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 0-10% ethyl acetate in hexanes to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 293.0 for M+H+.
Reaction SMILES: [CH:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4])=[CH2:2].[CH3:13][SnH:14]([CH3:16])[CH3:15]>O1CCCC1>[C:9]1([CH3:12])[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH2:2][Sn:14]([CH3:16])([CH3:15])[CH3:13])(=[O:5])=[O:4])=[CH:7][CH:8]=1
Reactant: C=CS(=O)(=O)c1ccc(C)cc1
Reactant: C[SnH](C)C
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)CC[Sn](C)(C)C)cc1
Reaction time: 14.75 h
Yield: 73.2 %

Procedure:
The procedure described in Example 1 was employed except that 7.74 g (42.5 mmoles) of 4-tolyl vinyl sulfone, 7.0 g (42.5 mmoles) of trimethyltin hydride and 10 ml of tetrahydrofuran were the reactants and solvent. The irradiation proceeded for 14.75 hours. Evaporation of solvent afforded an oil which crystallized on standing. Recrystallization of the product from cold petroleum ether gave 10.8 g of 2-(p-tolylsulfonyl)ethyltrimethylstannane, m.p. 55.5°-58°C. The presence of both the sulfonyl and trimethyltin groups was indicated by the strong infrared absorption bands at 1310 cm-1, 1295 cm-1, 1260 cm-1, 1145 cm-1 (--SO2 --) and 750 cm-1 ((CH3)3Sn) employing a KBr disc. Nuclear magnetic resonance spectroscopy (NMR) showed the following:
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[NH:16][C:17]([C:19]12[CH2:26][C:23]([CH2:27][OH:28])([CH2:24][CH2:25]1)[CH2:22][CH2:21][CH2:20]2)=O.[OH-].[Na+]>CO>[OH:28][CH2:27][C:23]12[CH2:26][C:19]([C:17]3[NH:16][C:3]4[C:4](=[O:15])[N:5]([CH2:12][CH2:13][CH3:14])[C:6](=[O:11])[N:7]([CH2:8][CH2:9][CH3:10])[C:2]=4[N:1]=3)([CH2:25][CH2:24]1)[CH2:20][CH2:21][CH2:22]2
Reactant: CCCn1c(N)c(NC(=O)C23CCCC(CO)(CC2)C3)c(=O)n(CCC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C34CCCC(CO)(CC3)C4)nc2n(CCC)c1=O
Temperature: 25 °C
Yield: 40 %

Procedure:
A solution of 5-hydroxymethyl-bicyclo[3.2.1]octane-1-carboxylic acid (6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide (0.51 mmol, 0.20 g) in 20°% NaOH (2.0 ml) and MeOH (10.0 ml) was stirred and refluxed overnight. The reaction was cooled to room temperature and then concentrated to remove MeOH. The aqueous was acidified (pH 2-3) with conc. HCl and then extracted with EtOAc. The combined EtOAc extracts were washed with saturated NaHCO3, H2O and brine, and dried (MgSQ4). Filtration and evaporation followed by flash chromatography eluting with 3:2 EtOAc/CH2Cl2 provided title compound (0:077 g, 40%) as an oil. 13C NMR (100 MHz, CDCl3): 11.53 (q), 11.74 (q), 20.26 (t), 21.71 (t), 31.62 (t) 34.15 (t), 37.29 (t), 43.49 (s), 45.54 (t), 45.67 (t), 46.14 (t). 46.90 (t), 70.51 (t), 71.11 (s), 107.03 (s), 149.25 (s), 151.54 (s), 155.88 (s), 162.58 (s).
Reaction SMILES: [B:1]([Cl:4])(Cl)Cl.[CH:5]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9])=[CH2:6]>C1(C)C=CC=CC=1>[Cl:4][B:1]1[CH:6]=[CH:5][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH:9]1
Reactant: ClB(Cl)Cl
Reactant: C=Cc1ccccc1N
Solvent: Cc1ccccc1
Product: ClB1C=Cc2ccccc2N1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
BCl3 (67.8 mL, 1.0 M in hexanes) was added to a solution if 2-vinylaniline (5.3 g, 44.3 mmol) in 40 mL of anhydrous toluene at 0° C. The mixture was stirred at 0° C. for 1 h and then refluxed for 2 h. The mixture was then evaporated to dryness and used immediately for next step.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH:15]1([NH2:19])[CH2:18][CH2:17][CH2:16]1>C1COCC1>[CH:15]1([NH:19][CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH3:8])=[O:6])[CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)/C=C/CBr
Reactant: NC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/CNC1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
To a solution of (E)-methyl 4-bromobut-2-enoate (5.37 g, 30 mmol) in THF (60 mL) was added potassium carbonate (8.34 g, 60 mmol), followed by cyclobutanamine (2.13 g, 30 mmol, in 30 mL THF) under N2 atmosphere. The resulting reaction mixture was stirred at RT overnight. Excess potassium carbonate was removed by filtration and the filtrate was diluted with EA and water. The organic layer was separated and the aqueous later was extracted with EA. The combined organic phase was dried over Na2SO4. Solvent was removed in vacuum and the crude mixture was purified by flash chromatography (0-5% DCM/MeOH) to provide (E)-methyl 4-(cyclobutylamino)but-2-enoate (19) (1.7 g, 33%) as an oil. LC-MS (ESI): m/z (M+1), 170.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[C:9](OC(OCC)OCC)(=O)C>C(OCC)(=O)C>[N:8]1[C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[NH:1][CH:9]=1
Reactant: CCOC(OCC)OC(C)=O
Reactant: Nc1ccncc1N
Solvent: CCOC(C)=O
Product: c1cc2nc[nH]c2cn1

Procedure:
3H-Imidazolo[4,5-c]pyridine was prepared by the method of Stanovik and Tisler, Synthesis, 2, 120 (1974). A mixture of 2.2 g (0.02 mole) of 3,4-diaminopyridine and 5 ml diethoxymethyl acetate was heated at reflux for two hours. The reaction mixture was cooled and diluted by addition of ethyl acetate. The solid precipitate was collected by filtration and sublimed at 170° C. and 50 torr to give 0.84 g of 3H-imidazolo[4,5-c]pyridine; mp 165°-168° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:15]=[C:14]([NH2:16])[N:13]([CH3:17])[N:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C([O:20][C:21](=O)[CH2:22][C:23](=O)[CH3:24])C>C(O)(=O)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]2[C:15]3[C:23]([CH3:24])=[CH:22][C:21](=[O:20])[NH:16][C:14]=3[N:13]([CH3:17])[N:12]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(OC)cc(-c2cc(N)n(C)n2)c1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Product: COc1cc(OC)cc(-c2nn(C)c3[nH]c(=O)cc(C)c23)c1
Yield: 60 %

Procedure:
A solution of 3-(3,5-dimethoxyphenyl)-1-methyl-1H-pyrazol-5-amine (1.3 g, 5.57 mmol) and 3-oxo-butyric acid ethyl ester (1.09 g, 8.36 mmol) in acetic acid (5 ml) was stirred at 150° C. for 18 h. The solution was evaporated under reduced pressure and the resulting crude product was purified by column chromatography (eluent 10% MeOH in CH2Cl2) to yield 1.0 g (60%) of the title compound. [1H-NMR (DMSO-d6, 360 MHz): δ 6.68 (d, 2H), 6.56 (s, 1H), 6.18 (s, 1H), 3.90 (s, 3H), 3.78 (s, 6H), 2.24 (s, 3H); UPLC-MS RtJ=0.79 min; [M+H]+=300.1]