Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]([C:9]([OH:11])=O)=[N:2]1.CCN=C=NCCCN(C)C.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.[NH2:40][C@H:41]([CH2:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([F:63])[CH:58]=2)=[CH:53][CH:52]=1)[CH2:42][C@:43]([CH2:48][OH:49])([CH3:47])[C:44]([OH:46])=[O:45]>CN(C=O)C>[C:44]([C@:43]([CH3:47])([CH2:48][OH:49])[CH2:42][C@H:41]([NH:40][C:9]([C:3]1[NH:2][N:1]=[C:5]([C:6]([OH:8])=[O:7])[CH:4]=1)=[O:11])[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([F:63])[CH:58]=2)=[CH:53][CH:52]=1)([OH:46])=[O:45]
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2cccc(F)c2)cc1)C(=O)O
Reactant: O=C(O)c1cc(C(=O)O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2cccc(F)c2)cc1)NC(=O)c1cc(C(=O)O)n[nH]1)C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 22.2 %

Procedure:
3,5-Pyrazoledicarboxylic acid (37.7 mg, 241 μmol, 1.0 eq.), EDCI (42.7 μL, 241 μmol, 1.0 eq.), 4-methylmorpholine (53.1 μL, 2.0 eq.) and 1 HOBt (32.6 mg, 241 μmol, 1.0 eq.) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. A predissolved solution of (2S,4R)-4-amino-5-(3′-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methyl-pentanoic acid (80 mg, 240 μmol, 1.0 eq.) and 4-methylmorpholine (53.1 μL) in DMF (0.3 mL) was added and the resulting mixture was stirred for 15 minutes. The reaction was quenched by adding AcOH and the product was purified by preparative HPLC and lyophilized to yield the title compound (25 mg). MS m/z [M+H]+ calc'd for C24H24FN3O6, 470.17. found 470.4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:33]=[CH:32][C:24]([O:25][C:26]2[N:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:33]=[CH:32][C:24]([O:25][C:26]2[N:27]=[CH:28][CH:29]=[CH:30][N:31]=2)=[CH:23][CH:22]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: Ic1ccc(Oc2ncccn2)cc1
Product: COC(=O)C(C/C=C/c1ccc(Oc2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 62.3 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (54.4 mg) was reacted with 2-(4-iodophenoxy)pyrimidine (59.2 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(pyrimidin-2-yloxy)phenyl]pent-4-enoic acid methyl ester (53.0 mg). Thin layer chromatography (silica gel, developing solvent: cyclohexane/ethyl acetate=10/1) was used for purification.
Reaction SMILES: [F:1][C:2]([F:16])([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[C:3](OCC)=[O:4].FC(F)(CCC1C=CC=CC=1)CO>>[F:1][C:2]([F:16])([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[CH2:3][OH:4]
Reactant: CCOC(=O)C(F)(F)c1cccc(OC)c1
Agent: OCC(F)(F)CCc1ccccc1
Product: COc1cccc(C(F)(F)CO)c1

Procedure:
Obtained from Intermediate 67 (4.35 g, 19 mmol) by the procedure described in Intermediate 2. The title compound was obtained (3.19 g, 90%) as oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[N:11]=[C:12]1[NH:16][CH2:15][CH2:14][N:13]1[OH:17].[CH2:18](Br)[C:19]#[CH:20]>CN(C)C=O>[ClH:3].[Cl:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[C:5]=1[N:11]=[C:12]1[NH:16][CH2:15][CH2:14][N:13]1[O:17][CH2:20][C:19]#[CH:18]
Reactant: ON1CCNC1=Nc1c(Cl)cccc1Cl
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCON1CCNC1=Nc1c(Cl)cccc1Cl
Product: Cl
Reaction time: 0.5 h

Procedure:
1.31 g. of sodium hydride (55% strength suspension) are added to a solution of 6.15 g. of 2-[(2,6-dichlorophenyl)imino]-1-hydroxyimidazolidine in 45 ml. of absolute dimethylformamide at a temperature of 25°. After 30 minutes, 4.16 g. of propargyl bromide are added dropwise. After 30 minutes, the mixture is poured onto 500 ml. of a saturated solution of sodium chloride and the aqueous phase is extracted with ether. The ether extracts are washed with aqueous hydrochloric acid. The aqueous extracts are then rendered basic with 3 N caustic soda solution and extracted with ether. After evaporating off the solvent, the residue is dissolved in ether, and hydrogen chloride in dioxane is added. The residue is recrystallized from methanol/acetonitrile, whereupon 2-[(2,6-dichlorophenyl)imino]-1-(2-propynyloxy)-imidazolidine hydrochloride, m.p. 198°-199° (from methanol/acetonitrile) is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([CH3:11])[N:3]=1.Br[CH2:13][CH2:14][O:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:16][O:15][CH2:14][CH2:13][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([CH3:11])[N:3]=1
Reactant: COCCBr
Reactant: COC(=O)c1cc(O)nn1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cc(C(=O)OC)n(C)n1
Yield: 94.3 %

Procedure:
Using methyl 3-hydroxy-1-methyl-1H-pyrazole-5-carboxylate (2.34 g, 15.0 mmol), 1-bromo-2-methoxyethane (3.13 g, 22.5 mmol), potassium carbonate (4.15 g, 30.0 mmol) and N,N-dimethylformamide (15 mL), and in the same manner as in Reference Example 57, the title compound (3.03 g, yield 94%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[F:11][C:12]([F:22])([F:21])[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.CC[O:25][C:26]([C:28]([CH2:30][C:31]([CH3:33])=[O:32])=[O:29])=O>>[C:31]([CH:30]1[CH:17]([C:16]2[CH:19]=[CH:20][C:13]([C:12]([F:22])([F:21])[F:11])=[CH:14][CH:15]=2)[N:1]([C:2]2[CH:3]=[C:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[C:26](=[O:25])[C:28]1=[O:29])(=[O:32])[CH3:33]
Reactant: Cc1cc(N)cn(C)c1=O
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(=O)CC(C)=O
Product: CC(=O)C1C(=O)C(=O)N(c2cc(C)c(=O)n(C)c2)C1c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 57.1 using 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2), 4-trifluormethylbenzaldehyde and ethyl acetopyruvate. tR: 0.76 min (LC-MS 2); ESI-MS: 407 [M+H]+ (LC-MS 2); ESI-MS: 405 [M−H]− (LC-MS 2).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C[NH+]=CC=1.[Br:26][Br-]Br>C1COCC1.C(Cl)(Cl)Cl>[CH3:19][O:18][C:16]([C:12]1[CH:11]=[C:10]2[C:15]([C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:8]([Br:26])[NH:9]2)=[CH:14][CH:13]=1)=[O:17]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
Adapting the procedure of L. Chu (Tet. Lett. 1997, 38, 3871) methyl 3-cyclohexyl-6-indole carboxylate (4.65 g, 18.07 mmol) was dissolved in a mixture of THF (80 mL) and CHCl3 (80 mL). The solution was cooled in an ice bath and pyridinium bromide perbromide (pyridine tribromide, 7.22 g, 22.6 mmol, 1.25 equivalent) was added. After stirring for 1.5 h at 0° C., the reaction was judged complete by TLC. It was diluted with CHCl3 (200 mL), washed with 1M NaHSO3 (2×50 mL), saturated aqueous NaHCO3 (2×50 mL) and brine (50 mL). After drying over Na2SO4, the solvent was removed under reduced pressure and the residue crystallized from TBME-hexane. The desired 2-bromoindole derivative was collected by filtration, washed with hexane and dried (3.45 g). Evaporation of mother liquors gave a red solid that was purified by flash chromatography using 15% EtOAc in hexane yielding an additional 3.62 g of pure material. Total yield was 5.17 g (85% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10]([CH2:12]C(O)=O)#[N:11].N1C=CC=CC=1>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)/[CH:5]=[CH:12]/[C:10]#[N:11]
Reactant: O=Cc1cccc(Cl)c1
Reactant: N#CCC(=O)O
Solvent: CC(C)O
Solvent: c1ccncc1
Product: N#C/C=C/c1cccc(Cl)c1

Procedure:
m-Chlorobenzaldehyde (210.75 g; 1.5 m), cyanoacetic acid (127.5 g; 1.5 m) and pyridine (150 ml.) were refluxed for two days. The solution was evaporated to give an oil which was distilled to give a mixture of isomers (72% trans/23% cis; 5% aldehyde), Yield (129 g; 53%), b.p. 70°-85°C. at 0.8 mm. The material was dissolved in isopropanol and allowed to fractionally crystallise at 0°C. The solid was filtered and freeze-dried. Yield of pure trans isomer was 15 g (6.1%) b.p. 104°-106°C. at 1 mm; m.p. 26°-28°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>>[ClH:1].[C:23]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:13](=[O:14])[CH:12]([NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[CH2:27][N:28]1[CH:32]=[CH:31][N:30]=[CH:29]1)([OH:25])=[O:24]
Reactant: COC(=O)CCCCCCCNC(=O)C(Cn1ccnc1)NS(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(O)CCCCCCCNC(=O)C(Cn1ccnc1)NS(=O)(=O)c1ccc(Cl)cc1
Yield: 185.9 %

Procedure:
The procedure described in Example 92 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)-N-(7-methoxycarbonylheptyl)propanamide (25.6 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(7-carboxyheptyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride (24.9 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH:31]=[O:32])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)=O>>[O:16]=[C:10]1[C:9](=[CH:17][C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH2:26][CH2:27][N:28]([CH:31]=[O:32])[CH2:29][CH2:30]3)=[CH:23][CH:24]=2)[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11]1
Reactant: O=Cc1ccc(N2CCN(C=O)CC2)cc1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: O=CN1CCN(c2ccc(C=C3C(=O)Nc4cccc(-c5ccncc5)c43)cc2)CC1

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 4-(4-formylphenyl)-piperazine-1-carbaldehyde to give the title compound.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:23][CH2:22][C@:12]34[C:13]5[C:14]6[O:21][C@H:11]3[C:10](=[O:24])[CH2:9][CH2:8][C@@:7]4([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[OH:20])[CH2:3][CH2:2]1.[CH3:39][I:40]>O>[I-:40].[CH:1]1([CH2:4][N@@+:5]2([CH3:39])[CH2:23][CH2:22][C@:12]34[C:13]5[C:14]6[O:21][C@H:11]3[C:10](=[O:24])[CH2:9][CH2:8][C@@:7]4([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[OH:20])[CH2:3][CH2:2]1
Reactant: CI
Reactant: O=C1CC[C@@]2(OCc3ccccc3-c3ccccc3)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Solvent: O
Product: C[N@+]1(CC2CC2)CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(OCc2ccccc2-c2ccccc2)[C@H]1C5
Product: [I-]

Procedure:
A solution of 17-cyclopropylmethyl-4,5α-epoxy-3-hydroxy-14β-[(2-phenylbenzyl)oxy]morphinan-6-one (0.39 g, 0.76 mmol) and methyl iodide (0.54 g, 3.79 mmol) in 6 ml of water-free acetonitrile was stirred under N2 at 40° C. (bath temperature) for 2 days and then evaporated down. The residue (0.5 g of brown oil) was purified using column chromatography (silica gel; CH2Cl2/MeOH 250:4). Yield: 0.02 g (4%) of beige crystals of the compound 50. Fp. 219-221° C.; MS (CI): 522 (M+); IR (KBr): 1725 (C═O) cm−1; 1H-NMR (DMSO-d6): δ 9.53 (s, OH), 7.68-7.25 (m, 9 arom. H), 6.67 (s, 2 arom. H), 4.73 (d, C14-OCH2), 4.61 (s, CH-5), 3.26 (s, CH3N+, axial).
Reaction SMILES: CO[C:3]1[C:4]([CH2:14][C:15]#[N:16])=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[BrH:17].[C:18]([OH:21])(=O)C>>[BrH:17].[CH3:18][O:21][C:7]1[C:8]([O:9][CH3:10])=[CH:3][C:4]2[CH2:14][C:15]([NH2:16])=[N:13][C:12]([Br:17])=[CH:11][C:5]=2[CH:6]=1
Reactant: COc1ccc(CC#N)c(CC#N)c1OC
Reactant: CC(=O)O
Agent: Br
Product: COc1cc2c(cc1OC)CC(N)=NC(Br)=C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
First 3,4-dimethoxy-o-phenylene-diacetonitrile (3.7 g, 0.017 mol) is suspended in glacial acetic acid (10 ml) and 30% hydrobromic acid in glacial acetic acid (12 ml) is added at 20° C. Then, the mixture is stirred for 3 hours at ambient temperature. The precipitate obtained is suction filtered, washed with glacial acetic acid and then with acetone/ether and dried. Yield: 5.3 g. Mp: 210°-211° C. (Decomp.)
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([CH2:13][CH2:14]Cl)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][N:24]=[C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:22]=2[CH:32]=1.Cl>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([CH2:13][CH2:14][N:29]3[CH2:28][CH2:27][CH:26]([C:23]4[C:22]5[CH:32]=[C:18]([Cl:17])[CH:19]=[CH:20][C:21]=5[O:25][N:24]=4)[CH2:31][CH2:30]3)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(CCCl)sc2C1
Reactant: Clc1ccc2onc(C3CCNCC3)c2c1
Agent: Cl
Product: CC(=O)N1CCc2cc(CCN3CCC(c4noc5ccc(Cl)cc45)CC3)sc2C1
Yield: 43.1 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 0.9 g of 6-acetyl-2-(2-chloroethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 1.0 g of 4-(5-chloro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.7 g of 6-acetyl-2-(2-(4-(5-chloro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine as an oil, m.p. 122°-124° C. (decomposition) as a hydrochloride thereof.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][C:8]2[CH:20]=[CH:19][C:11]([O:12][CH:13]([CH3:18])[C:14]([O:16]C)=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:23]([NH2:27])[CH2:24][CH2:25][CH3:26]>CO>[CH2:23]([NH:27][C:14](=[O:16])[CH:13]([O:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][O:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][CH:21]=2)=[CH:20][CH:19]=1)[CH3:18])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCN
Reactant: COC(=O)C(C)Oc1ccc(COc2ccc(Cl)cc2)cc1
Solvent: CO
Product: CCCCNC(=O)C(C)Oc1ccc(COc2ccc(Cl)cc2)cc1
Yield: 38.8 %

Procedure:
6.4 gm of methyl 2-[4-(4-chlorophenoxy-methyl)-phenoxy]-propionate were dissolved in 60 ml of methanol, 6.0 gm of n-butylamine were added to the solution, and the mixture was heated in an autoclave for 4 hours at a pressure of 15-16 atmospheres gauge. After cooling, the solvent was distilled off in vacuo, and the residue was recrystallized from ethanol, yielding 2.8 gm (39% of theory) of the amide named in the heading, which had a melting point of 98° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]#[N:21])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=1>CO.[Pd]>[OH:1][C:2]1[CH:3]=[C:4]([CH2:18][CH2:19][C:20]#[N:21])[C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)=[CH:7][C:6]=2[CH:17]=1
Reactant: N#CC=Cc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Agent: [Pd]
Solvent: CO
Product: N#CCCc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Yield: 25.1 %

Procedure:
A solution of 3-[5-hydroxy-2-(4-hydroxy-phenyl)-benzofuran-7-yl]-acrylonitrile 64 (0.028 g, 0.1 mmol) in methanol (1 mL) was purged with nitrogen and 10% palladium on carbon added. The reaction vessel was evacuated and a hydrogen balloon added. After an hour, the reaction was filtered and the solvent removed in vacuo. The product was purified via flash chromatography, eluting with 3% methanol in dichloromethane to give 0.007 g of 3-[5-hydroxy-2-(4-hydroxy-phenyl)-benzofuran-7-yl]-propionitrile 65: 1H NMR (DMSO-d6) δ 9.84 (s, 1 H), 9.17 (s, 1 H), 7.73 (d, 2 H, J=8.6 Hz), 7.02 (s, 1 H), 6.87 (d, 2 H, J=8.6 Hz), 6.79 (d, 1 H, J=2.3 Hz), 6.62 (d, 1 H, J=2.2 Hz), 3.12 (t, 2 H, J=7.1 Hz), 2.96 (t, 2 H, J=7.4 Hz); MS 280 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][O:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.S(C1C=CC(C)=CC=1)(O[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[CH3:35][N:34]([CH3:36])[C:31]1[CH:32]=[CH:33][C:28]([CH2:27][CH2:26][N:1]2[CH2:5][CH2:4][CH2:3][C@@H:2]2[CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)=[CH:29][CH:30]=1
Reactant: c1ccc2c(c1)COc1ccccc1N2C[C@H]1CCCN1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(N(C)C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CN(C)c1ccc(CCN2CCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 90 °C

Procedure:
(R)-5,11-dihydro-5-(2-pyrrolidinylmethyl)dibenzo[b,e][1,4]oxazepine (Preparation Example 1) (420 mg, 1.5 mmol), 2-(4-dimethylaminophenyl)ethyl tosylate (640 mg, 2 mmol), sodium carbonate (210 mg, 2 mmol) and sodium iodide (30 mg, 0.2 mmol) were added to acetonitrile (20 ml), and the mixture was heated under reflux at 90° C. for 14 hours. The solvent was evaporated under reduced pressure, and the residue was partitioned in ethyl acetate and water. The organic layer was washed with water and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was treated by the column chromatography and then eluted with dichloromethane and then with dichloromethane/2 M methanolic ammonia (50:1) as the eluents. A suitable fraction was collected, and the solvent was evaporated under reduced pressure to obtain the title compound in the form of a light yellow oil (240 mg, 37%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C(Cl)(Cl)[Cl:13].C(=O)([O-])[O-].[Na+].[Na+]>P(Cl)(Cl)(Cl)=O>[Cl:13][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:4][CH:3]=[C:2]([CH3:1])[C:10]=12
Reactant: Cc1c[nH]c2c1ccc[n+]2[O-]
Reactant: ClC(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c[nH]c2nccc(Cl)c12
Temperature: 25 °C

Procedure:
1.00 g (6.75 mmol) of 3-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxide is suspended in 5 ml of phosphoryl chloride. 2 ml of chloroform are then added, and the mixture is heated at reflux temperature overnight. The mixture is allowed to cool to RT and poured into ethyl acetate/ice-water. Solid sodium carbonate is then added. The phases are separated and the aqueous phase is washed with ethyl acetate. The organic phases are dried with sodium sulfate and concentrated. The residue is purified by column chromatography (silica gel 60, mobile phase: cyclohexane/methanol=4:1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12]([CH3:16])[CH:13]=[N:14][CH:15]=3)[CH:9]=2)[CH:4]=[CH:3]1.[C:17](Cl)(=O)[C:18](Cl)=[O:19].Cl.C([O:27][C:28](=[NH:43])[CH2:29][C:30]1[C:38]2[C:33](=[CH:34][C:35]([N+:39]([O-:41])=[O:40])=[CH:36][CH:37]=2)[N:32]([CH3:42])[CH:31]=1)(C)C.CCN(CC)CC>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12]([CH3:16])[CH:13]=[N:14][CH:15]=3)[CH:9]=2)[C:4]([C:17]2[C:18](=[O:19])[NH:27][C:28](=[O:43])[C:29]=2[C:30]2[C:38]3[C:33](=[CH:34][C:35]([N+:39]([O-:41])=[O:40])=[CH:36][CH:37]=3)[N:32]([CH3:42])[CH:31]=2)=[CH:3]1
Reactant: Cn1cncc1-c1ccc2ccn(C)c2c1
Reactant: CC(C)OC(=N)Cc1cn(C)c2cc([N+](=O)[O-])ccc12
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cncc1-c1ccc2c(C3=C(c4cn(C)c5cc([N+](=O)[O-])ccc45)C(=O)NC3=O)cn(C)c2c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 49 %

Procedure:
1-Methyl-6-(3-methyl-3H-imidazol-4-yl)-1H-indole (5.0 g, 23.7 mmol) was dissolved in CH2Cl2 (25 mL) (dried under 3A° molecular sieves) at 0° C. A solution of oxalyl chloride in CH2Cl2 (2 M, 23.7 mL, 47.4 mmol) was added dropwise over 10 min. The mixture was stirred at 0° C. for 2.5 h and evaporated. Ether (25 mL) was added to the solid residue and the mixture was stirred for 30 min. The resulting yellow solid was filtered off, washed with ether and dried under vacuum for 30 min. 2-(1-Methyl-6-nitro-1H-indol-3-yl)acetimidic acid isopropyl ester hydrochloride (7.02 g, 22.5 mmol) and CH2Cl2 (200 mL) were added to the yellow solid at 0° C. Et3N (dried over 3A° molecular sieves) (16.5 mL, 118.6 mmol) was added dropwise over 10 min., and the orange-red mixture was stirred at room temperature overnight. The mixture was diluted with CHCl3 and washed with aqueous Na2CO3. The aqueous layer was back extracted with CHCl3. The combined organic extracts were washed with brine, dried (K2CO3) and evaporated. MeOH (150 mL) and concentrated HCl (37%, 10 mL) were added. The mixture was heated at reflux for 2 h, then cooled, diluted with CHCl3 and washed with aqueous Na2CO3. The aqueous layer was back extracted with CHCl3. The combined organic extracts were washed with brine and dried (K2CO3). The mixture was passed through a pad of silica gel (10×10 cm) and the pad was washed with 10% methanol/EtOAc. Evaporation of the combined filtrates gave the crude product as an orange solid. Crystallization of the product from EtOH/CHCl3 gave 3-[1-methyl-6-(3-methyl-3H-imidazol-4-yl)-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione (5.65 g, 49%) as an orange solid.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[C:15]2[S:14](=[O:17])(=[O:16])[N:13]=[C:12]([CH2:18][C:19]([OH:21])=O)[NH:11][C:10]=2[S:9][CH:8]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1([O:38][C:39](N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.C(OC(=O)[C:57]([CH2:64][NH:65][CH:66]1[CH2:68][CH2:67]1)([CH3:63])[CH2:58][CH2:59][CH:60]([CH3:62])[CH3:61])C.[O-]CC.[Na+].C(O)C>CN(C)C=O>[CH:66]1([N:65]2[CH2:64][C:57]([CH3:63])([CH2:58][CH2:59][CH:60]([CH3:61])[CH3:62])[C:19]([OH:21])=[C:18]([C:12]3[NH:11][C:10]4[S:9][CH:8]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:15]=4[S:14](=[O:16])(=[O:17])[N:13]=3)[C:39]2=[O:38])[CH2:67][CH2:68]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)C(C)(CCC(C)C)CNC1CC1
Agent: CC[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)CCC1(C)CN(C2CC2)C(=O)C(C2=NS(=O)(=O)c3c(CNS(C)(=O)=O)csc3N2)=C1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 49 %

Procedure:
[7-(Methanesulfonylamino-methyl)-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-acetic acid (prepared as described in Example 2c; 0.148 g, 0.419 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.175 g, 0.460 mmol) and 4-methylmorpholine (0.092 mL, 0.837 mmol) were added sequentially to a solution of rac-2-cyclopropylaminomethyl-2,5-dimethyl-hexanoic acid ethyl ester (0.101 g, 0.418 mmol) in N,N-dimethylformamide (6 mL) at 25° C. The reaction mixture was stirred at 25° C. for 20 h, and then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was dissolved in ethanol (12 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (0.813 mL, 2.51 mmol) was added and the reaction mixture was heated to 70° C. for 26 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash chromatography (Teledyne Isco RediSep column; 50-100% ethyl acetate in hexanes) to afford rac-N-{3-[1-Cyclopropyl-4-hydroxy-5-methyl-5-(3-methyl-butyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.109 g, 0.205 mmol, 49%) as an orange oil. 1H NMR (400 MHz, DMSO-d6) δ: 0.70 (4H, bs), 0.84-0.86 (6H, m), 1.09 (3H, s), 1.12-1.15 (2H, m), 1.50 (2H, bs), 2.81 (1H, bs), 2.95 (3H, s), 3.27 (1H, d, J=13.5 Hz), 4.23 (2H, d, J=5.4 Hz), 7.26 (1H, s), 7.65 (1H, t, J=6.2 Hz). LC-MS (ESI) calculated for C21H30N4O6S3 530.13. found 531.0 [M+H+].