Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([CH2:9][CH2:10][C:11]([O:13]CC)=O)[CH2:3][C:4]([O:6]CC)=O.C[O:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([O:25]C)[CH:24]=1)[NH2:21]>>[OH:17][C:18]1[CH:24]=[C:23]([OH:25])[CH:22]=[C:20]2[C:19]=1[C:4](=[O:6])[CH2:3][CH:2]1[CH2:9][CH2:10][C:11](=[O:13])[N:21]12
Reactant: CCOC(=O)CCC(=O)CC(=O)OCC
Reactant: COc1cc(N)cc(OC)c1
Product: O=C1CC2CCC(=O)N2c2cc(O)cc(O)c21
Yield: 77 %

Procedure:
By the procedures of Examples 2 and 3, diethyl 3-oxohexanedioate [Tetrahedron 23, p. 897 (1967)] and 3,5-dimethoxyaniline were converted to title product, recrystallized from ethyl acetate/cyclohexane, in 77% yield, m.p. 254°-256° C.; m/e 233 (m+); ir (KBr) 3448, 2857, 1680, 1639 cm-1.
Reaction SMILES: I[CH2:2][I:3].N(OCCC(C)C)=O.NC1[C:14]2[C:37]([CH3:39])([CH3:38])[C:36](=[O:40])[NH:35][C:15]=2[N:16]=[C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([F:28])[CH:26]=3)[N:21]([CH2:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:20]=2)[N:18]=1>>[CH:30]1([CH2:29][N:21]2[C:22]3=[N:23][CH:24]=[C:25]([F:28])[CH:26]=[C:27]3[C:19]([C:17]3[N:18]=[C:2]([I:3])[C:14]4[C:37]([CH3:38])([CH3:39])[C:36](=[O:40])[NH:35][C:15]=4[N:16]=3)=[N:20]2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(CC4CCCC4)c4ncc(F)cc34)nc(N)c21
Reactant: ICI
Agent: CC(C)CCON=O
Product: CC1(C)C(=O)Nc2nc(-c3nn(CC4CCCC4)c4ncc(F)cc34)nc(I)c21
Temperature: 85 °C
Reaction time: 8 h

Procedure:
40.549 g (151.398 mmol) of diiodomethane and 4.420 g (37.738 mmol) of isopentyl nitrite were added to 711 mg (1.799 mmol) of 4-amino-2-[1-(cyclopentylmethyl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one. The mixture was stirred at 85° C. for 8 h. After cooling, the mixture was filtered, and the filtrate was diluted with cyclohexane and sucked through silica gel. The silica gel was washed with cyclohexane and the product was eluted with dichloromethane/methanol (v/v=50:2). The collected fractions were concentrated on a rotary evaporator, taken up in 20 ml of ethyl acetate and 5 ml of isopropanol, filtered and concentrated again. The residue was triturated with 5 ml of isopropanol. The solid was filtered off with suction and dried under high vacuum. This gave 230 mg (purity 92%, 23% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][O:13][CH3:14])[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:37]([NH2:46])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([CH3:39])[CH3:38]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][O:13][CH3:14])[C:5]([NH:46][C:37]([CH3:39])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH3:38])=[O:7]
Reactant: CC(C)(N)c1ccccc1
Reactant: COCOc1ccc(C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(C(=O)NC(C)(C)c2ccccc2)cc1Cl
Yield: 77.1 %

Procedure:
In a similar manner to Step 1 of Example 137, 3-chloro-4-methoxymethoxybenzoic acid (2.39 g, 11.0 mmol) was dissolved in DMF (47 mL), and the solution was treated with EDCI (4.23 g, 22.1 mmol), HOBT monohydrate (1.69 g, 11.0 mmol) and cumylamine (3.20 mL, 22.0 mmol). The reaction mixture was added with water. The precipitated solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 3-chloro-4-methoxymethoxy-N-(1-methyl-1-phenylethyl)benzamide (2.83 g, yield 77%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].[C:12]1([CH2:18][C:19](Cl)=[S:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>[OH-].[Na+]>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH:11][C:19](=[S:20])[CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: S=C(Cl)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(C(=O)O)c1NC(=S)Cc1ccccc1
Yield: 93.4 %

Procedure:
Benzenethiol and butyl bromoacetate were reacted by a conventional method and then hydrolyzed to obtain α-phenylthioacetatic acid. α-phenylthioacetatic acid was reacted with thionyl chloride by a convention method to obtain α-phenylthioacetyl chloride. 3-Methylanthranilic acid 5g (33 mmol) was dissolved in 10% aqueous sodium hydroxide solution 27 ml and to this solution, α-phenylthioacetyl chloride 5.5 ml (33 mmol) was added dropwise at 0° C. The resulting solution was stirred at room temperature for 1 hour and neutralized with 10% hydrochloric acid solution. Deposited crystals were collected by filtration and recrystallized from ethanol and water to obtain 3-methyl-N-(phenylthioacetyl)anthranilic acid (melting point: 148° to 150° C.) 8.8 g (yield: 89%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH3:21][OH:22]>>[CH3:21][O:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1
Reactant: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2c1
Reactant: CO
Product: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(OC)c2c1

Procedure:
Similar procedure as described in example 10 was used, starting from Methanol, (1-chloro-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (1-Methoxy-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 285(MH+).
Reaction SMILES: [CH:1]1([S:6]([C:8]2[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:29][C@@H:28]([C:30]4[CH:41]=[CH:40][C:33]5[O:34][C:35]([CH3:39])([CH3:38])[O:36][CH2:37][C:32]=5[CH:31]=4)[O:27]C3=O)[CH:11]=[CH:12][CH:13]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si](C)(C)[O-].[K+]>O1CCCC1>[CH:1]1([S:6]([C:8]2[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][CH2:29][C@@H:28]([C:30]3[CH:41]=[CH:40][C:33]4[O:34][C:35]([CH3:38])([CH3:39])[O:36][CH2:37][C:32]=4[CH:31]=3)[OH:27])[CH:11]=[CH:12][CH:13]=2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCCCc4cccc(S(=O)C5CCCC5)c4)C(=O)O3)ccc2O1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCCCc3cccc(S(=O)C4CCCC4)c3)ccc2O1
Yield: 82.1 %

Procedure:
A stirred mixture of (5R)-3-(6-{4-[3-(cyclopentylsulfinyl)phenyl]butoxy}hexyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (0.14 g) and potassium trimethyl silanolate (0.45 g) in tetrahydrofuran (10 ml) was heated to reflux for 2 h. The mixture was poured into phoshate buffer solution (pH 5, 50 ml) and extracted into ethyl acetate. The extracts were washed with water, dried (Na2SO4) and evaporated. The residual oil was purified on a biotage cartridge (8 g) using dichloromethane-ethanol-0.88 ammonia (100:8:1) as eluent. The appropriate fractions were evaporated to give the title compound (0.11 g) LCMS RT=2.89 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C[Si]([C:25]#[CH:26])(C)C>C(N(CC)CC)C.O.[Cu]I>[CH2:15]([N:14]([CH2:18][CH2:19][CH3:20])[C:12]([C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([C:25]#[CH:26])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:13])[CH2:16][CH3:17]
Reactant: CCCN(CCC)C(=O)c1cc(Br)cc(C(=O)OC)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: C#Cc1cc(C(=O)OC)cc(C(=O)N(CCC)CCC)c1
Reaction time: 3 h
Yield: 111.3 %

Procedure:
A mixture of methyl 3-bromo-5-[(dipropylamino)carbonyl]benzoate (XXI, 200 mg, 0.58 mmol), PdCl2(Ph3P)2 (16 mg, 0.03 mol %) and copper (I) iodide (6 mg, 0.05 mol %/o) in triethylamine (1.2 mL) is heated to reflux. (Trimethylsilyl) acetylene (100 microliter, 0.7 mmol) is added, and the mixture stirred for 3 hours, cooled to 20–25 degrees, diluted with water (20 mL), and extracted with chloroform (3×15 mL). The combined organic extracts are washed with saline (20 mL), dried over sodium sulfate and concentrated under reduced pressure to give methyl 3-[(dipropylamino)carbonyl]-5-ethynylbenzoate (XXXII, 185.5 mg), NMR (300 MHz, CDCl3): δ 7.95, 7.75, 7.43, 3.74, 3.25, 2.95, 1.49, 1.34, 0.79, 0.56 and 0.06.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:40])([C:31]([F:39])([F:38])[C:32]([F:37])([F:36])[CH:33]([F:35])[F:34])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[CH:28][NH:27][C:26]2=[O:30])=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:27]1[CH:28]=[CH:29][N:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:40])[C:31]([F:38])([F:39])[C:32]([F:37])([F:36])[CH:33]([F:35])[F:34])=[CH:24][CH:23]=2)[C:26]1=[O:30])[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]ccn1-c1ccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)cc1
Product: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 13.1 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.83 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.56 g of 1-[4-(2,2,3,3,4,4,5,5-octafluoropentoxy)phenyl]-2(1H,3H)-imidazolone, 0.30 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-(4-(2,2,3,3,4,4,5,5-octafluoropentoxy)phenyl]-2(1H,3H)-imidazolone was obtained as a colorless viscous oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[S:11])=[CH:5][CH:4]=1)#[N:2].[CH3:12][C:13]([CH3:18])([CH3:17])[CH:14]([NH2:16])[CH3:15]>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([NH:16][CH:14]([CH3:15])[C:13]([CH3:18])([CH3:17])[CH3:12])=[S:11])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(N=C=S)cc1
Reactant: CC(N)C(C)(C)C
Solvent: C1CCOC1
Product: CC(NC(=S)Nc1ccc(C#N)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a solution of 4-cyanophenyl isothiocyanate (2.00 g, 12.5 mmol) in THF (50 mL) at room temperature was added a solution of (±) 3,3-dimethyl-2-aminobutane (2.00 mL, 14.5 mmol) in THF (12 mL) and the reaction was stirred overnight at room temperature. The mixture was concentrated in vacuo and the resulting residue was triturated with diethyl ether and filtered to afford 3.12 g (96%) of 1-(4-cyanophenyl)-3-(1,2,2-trimethyl-propyl)-thiourea as a white solid which was used without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:54])[C@@H:5]([NH:21][C:22]([CH:24]1[CH2:33][C:32]2[CH:31]=[C:30]3[O:34][CH2:35][C@H:36]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]5[CH:51]=[CH:50][C:49]([CH3:52])=[C:48]([CH3:53])[CH:47]=5)=[CH:40][CH:39]=4)[O:37][C:29]3=[CH:28][C:27]=2[CH2:26][NH:25]1)=[O:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[C:55]([NH:58][C:59]1[S:60][C:61]([S:65](Cl)(=[O:67])=[O:66])=[C:62]([CH3:64])[N:63]=1)(=[O:57])[CH3:56]>>[CH3:2][O:3][C:4](=[O:54])[C@@H:5]([NH:21][C:22]([CH:24]1[CH2:33][C:32]2[CH:31]=[C:30]3[O:34][CH2:35][C@H:36]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]5[CH:51]=[CH:50][C:49]([CH3:52])=[C:48]([CH3:53])[CH:47]=5)=[CH:40][CH:39]=4)[O:37][C:29]3=[CH:28][C:27]=2[CH2:26][N:25]1[S:65]([C:61]1[S:60][C:59]([NH:58][C:55](=[O:57])[CH3:56])=[N:63][C:62]=1[CH3:64])(=[O:66])=[O:67])=[O:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(C)c(C)c2)cc1)CO3
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(C)c(C)c2)cc1)CO3
Yield: 73.1 %

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dimethyl-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester hydrochloride (11 mg) was reacted with 2-acetylamino-4-methyl thiazole-5-sulfonyl chloride (9 mg) according to General Procedure E to give (S)-2-({(S)-7-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dimethyl-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (10 mg). This was hydrolyzed according to General Procedures N and B to give the title compound (3 mg). LCMS: (m/z) 870.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[CH:19]=O)=[CH:13][CH:12]=1>CCCCCC>[C:14]1(/[CH:17]=[CH:18]/[CH:19]=[N:10]/[NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: O=C/C=C/c1ccccc1
Reactant: NNC(=O)c1ccccc1
Solvent: CCCCCC
Product: O=C(N/N=C/C=C/c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
A mixture of 1a (3.00 g, 22.0 mmol) and trans cinnamic aldehyde (4.35 g, 32.9 mmol, origin: Aldrich) in hexane (100 ml) was stirred at room temperature for 2 h. The reaction mixture was filtered, the residue washed with hexane and dried under vacuum to give 4.95 g (90%) of a white solid.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[C:4]([CH3:12])[C:3]=1[I:13].C([Mg]Cl)(C)C.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.[NH4+].[Cl-]>CCOCC.C1COCC1>[I:13][C:3]1[C:4]([CH3:12])=[C:5]([O:10][CH3:11])[C:6]([O:8][CH3:9])=[CH:7][C:2]=1[B:19]([OH:24])[OH:20]
Reactant: COc1cc(I)c(I)c(C)c1OC
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(B(O)O)c(I)c(C)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To a solution of 1,2-diiodo-4,5-dimethoxy-3-methylbenzene (Example 5(b), 2.0 g, 4.95 mmol) in 120 mL of a mixture of THF and Et2O (1:1) was added dropwise at −78° C., isopropylmagnesium chloride (2 M in THF, 2.72 mL, 5.44 mmol). After the mixture was stirred for 2 h at that temperature, B(OiPr)3 (10.50 ml, 14.84 mmol) was added. The solution was warmed to room temperature overnight; then a saturated solution of NH4Cl was added, and the resulting mixture was stirred for 30 min at room temperature. The aqueous layer was extracted with Et2O (50 mL, 3 times), dried over Na2SO4 and concentrated. To the concentrated sample, hexane was added and the resulting precipitate was isolated to give 0.90 g of the pure product (56%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:36])=[N:4][O:5][C:6]=1[N:7]([CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:20](O)[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[CH3:28])(=[O:10])=[O:9].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:36])=[N:4][O:5][C:6]=1[N:7]([CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[CH3:28])(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(O)c2ccc(C)cc2C)sc2ncccc12
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(Cc2ccc(C)cc2C)sc2ncccc12
Yield: 52.4 %

Procedure:
The title compound was prepared by the method of Example 5(A) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-[α-hydroxy-2,4-dimethylbenzyl]thieno[2,3-b]pyridine-3-sulfonamide (0.17 g, 0.31 mmoles), CH2Cl2 (5 ml), triethylsilane (0.5 ml, 3.1 mmoles) and boron trifluoride etherate (0.2 ml, 1.5 mmoles). Flash chromatography (40% EtOAc/hexanes) provided 87 mg (53%) of the title compound.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14]3[CH2:18][C:17]4([CH2:23][CH2:22][CH:21]([C:24]#[N:25])[CH2:20][CH2:19]4)[O:16][N:15]=3)=[CH:12][N:11]=[C:10]3[N:26]([CH2:30][CH3:31])[N:27]=[C:28](C)[C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:32]=[N+:33]=[N-:34].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:1]1([NH:7][C:8]2[C:9]3[CH:28]=[N:27][N:26]([CH2:30][CH3:31])[C:10]=3[N:11]=[CH:12][C:13]=2[C:14]2[CH2:18][C:17]3([CH2:23][CH2:22][CH:21]([C:24]4[NH:34][N:33]=[N:32][N:25]=4)[CH2:20][CH2:19]3)[O:16][N:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCn1nc(C)c2c(NC3CCCCC3)c(C3=NOC4(CCC(C#N)CC4)C3)cnc21
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCC(c5nnn[nH]5)CC4)C3)cnc21

Procedure:
3-[4-(Cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile (0.00098 mole) (example 40), sodium azide (0.00147 mole) and triethyl amine hydrochloride (0.00147 mol) is taken in toluene. The reaction mixture is refluxed overnight. Toluene is removed and water is added. The extraction is done with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure to give crude compound, which is purified by column chromatography
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH:10][C:11]2[CH2:12][O:13][C:14]([CH3:30])([CH3:29])[C:15]([F:28])([F:27])[C@:16]([C:19]3[CH:24]=[C:23](Br)[CH:22]=[CH:21][C:20]=3[F:26])([CH3:18])[N:17]=2)=[CH:5][CH:4]=1.[Cl:45][C:46]1[CH:47]=[C:48]([N:52]2[CH:56]=[C:55](B(O)O)[CH:54]=[N:53]2)[CH:49]=[CH:50][CH:51]=1.C(=O)([O-])[O-].[K+].[K+]>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.COCCOC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:10][C:11]2[CH2:12][O:13][C:14]([CH3:30])([CH3:29])[C:15]([F:28])([F:27])[C@:16]([C:19]3[CH:24]=[C:23]([C:55]4[CH:54]=[N:53][N:52]([C:48]5[CH:49]=[CH:50][CH:51]=[C:46]([Cl:45])[CH:47]=5)[CH:56]=4)[CH:22]=[CH:21][C:20]=3[F:26])([CH3:18])[N:17]=2)([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: OB(O)c1cnn(-c2cccc(Cl)c2)c1
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: [K+]
Solvent: COCCOC
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(-c4cnn(-c5cccc(Cl)c5)c4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 85 °C
Yield: 77.4 %

Procedure:
A dried pressure tube was consecutively charged with (R)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (intermediate B9.1) (199 mg, 299 μmol), 1,2-dimethoxyethane (4 ml), 1-(3-chlorophenyl)-1H-pyrazol-4-ylboronic acid (CAS 1072945-88-0) (102 mg, 448 μmol), and a solution of potassium carbonate (2M, 448·1). The tube was flushed with argon, thereafter tetrakistriphenylphosphinepalladium(0) (17.3 mg, 14.9 μmol) was added, the tube was sealed and the reaction mixture heated at 85° C. for 16 hours. For the workup, the reaction mixture was evaporated at reduced pressure and the residue directly purified by chromatography on an amine-silica phase using a gradient of heptane/ethyl acetate=100:0 to 80:20 as the eluent. The [bis-(4-methoxy-phenyl)-phenyl-methyl]-((R)-5-{5-[1-(3-chloro-phenyl)-1H-pyrazol-4-yl]-2-fluoro-phenyl}-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl)-amine (177 mg, 77% yield) was obtained as a white foam. MS (ISP): m/z=765.4 [M+H]+ and 767.4 [M+2+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1Cl.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[N:16]1[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]1
Reactant: CN1CCNCC1
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1ccc(N2CCN(C)CC2)c(Cl)c1

Procedure:
3',4'-Dichloroacetophenone (9.65 g., 0.05 mole) and N-methylpiperazine (10 g., 0.1 mole) are refluxed (165° C) for 24 hours. The solution is cooled and 100 ml. water containing 2 g. of sodium hydroxide is added. The oil is decanted and diluted with 200 ml. of toluene and washed first with dilute alkali then several times with water. The toluene layer is dried with magnesium sulfate and evaporated in vacuo to an oil. The residue is distilled 146°-150° at 0.1-0.3 mm., yield 3.0 g. This product is dissolved in ethyl ether and converted to the hydrochloride using isopropanolic hydrogen chloride and the salt crystallized from acetonitrile. The purified salt is reconverted to the base with dilute sodium hydroxide. The product is extracted using ethyl ether, separated, dried, evaporated to dryness to give 3'-chloro-4'-(4-methyl-1-piperazinyl)acetophenone as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:22]([OH:23])=[CH:21][C:5]2[C:6]([CH3:20])([CH3:19])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([Cl:18])[CH:10]=4.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:43][C:44]1([CH3:51])[O:48][C@H:47]([CH2:49]O)[CH2:46][O:45]1.C1(C)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[Cl:18][C:11]1[CH:10]=[C:9]2[C:14]([C:15]3[C:16](=[O:17])[C:4]4[CH:3]=[C:2]([Br:1])[C:22]([O:23][CH2:49][C@H:47]5[CH2:46][O:45][C:44]([CH3:51])([CH3:43])[O:48]5)=[CH:21][C:5]=4[C:6]([CH3:20])([CH3:19])[C:7]=3[NH:8]2)=[CH:13][CH:12]=1
Reactant: CC1(C)c2cc(O)c(Br)cc2C(=O)c2c1[nH]c1cc(Cl)ccc21
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(C)OC[C@H](COc2cc3c(cc2Br)C(=O)c2c([nH]c4cc(Cl)ccc24)C3(C)C)O1
Temperature: 40 °C
Reaction time: 12 h
Yield: 68.3 %

Procedure:
Under nitrogen atmosphere, 9-bromo-3-chloro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound S2-4, 112 mg, 0.29 mmol) and triphenylphosphine (227 mg, 3 eq.) were added with THF (2 ml), and ((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (114 mg, 3 eq.) and 2.19 N toluene solution (0.4 mL, 3 eq.) of diethyl azodicarboxylic acid were added dropwise thereto, followed by stirring at 40° C. for 12 hr under nitrogen atmosphere. The residues obtained from the reaction solution after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/dichloromethane) to obtain the title compound (white powder, 100 mg).
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][OH:6].C[O:8][C:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:30])/[CH:17]=[CH:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28]>CO>[OH:6][NH:5][C:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:30])/[CH:17]=[CH:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28])=[O:8]
Reactant: COC(=O)CCCCCNC(=O)/C=C/C=C/c1ccccc1[N+](=O)[O-]
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(/C=C/C=C/c1ccccc1[N+](=O)[O-])NCCCCCC(=O)NO
Reaction time: 0.17 h
Yield: 66.2 %

Procedure:
A solution of sodium methylate (6.0 mmol) in methanol (5 ml) was added to a solution of hydroxylamine hydrochloride (0.28 g, 4.0 mmol) (Acros) in methanol (8 ml). The mixture was stirred for 10 min. and the precipitate was filtered off. (2E,4E)-6-[5-(2-Nitrophenyl)penta-2,4-dienoylamino]hexanoic acid methyl ester (13a) (0.35 g, 1 mmol) was added to the filtrate and the obtained mixture was heated to the complete dissolving. The resultant mixture was stirred for 4 hours at ambient temperature and the solvent was removed under reduced pressure. The product was dissolved in water (10 ml) and the solution was acidified with 3% HCl. The precipitate was filtered and crystallized from acetonitrile to give the title compound (0.23 g, 66%) as a yellow solid. M.p. 131-133° C. 1H NMR (DMSO-d6, HMDSO), δ: 1.06-1.73 (6H, m, CH2); 1.87-2.09 (2H, m, CH2); 3.15 (2H, q, J=5.6 Hz, CH2N); 6.26 (1H, d, J=14.8 Hz, CH); 7.00-8.06 (8H, m, CH—CH═CH, C6H4, NH); 8.06 (1H, t, J=5.9 Hz, NH); 10.33 (1H, s, OH). HPLC analysis on Symmetry C18 column: impurities <1.0% (column size 3.9×150 mm; mobile phase acetonitrile−0.1M phosphate buffer (pH 2.5), 35:65; detector UV 220 nm; sample concentration 0.15 mg/ml). Anal. Calcd for C17H21N3O5, %: 58.78; H, 6.09; N, 12.10. Found, %: C, 58.26; H, 6.08; N, 11.87.