Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1[C:10]([CH2:28][S:29][C:30]2[NH:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[N:31]=2)=[N:11][CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1([CH3:27])[O:26][CH2:25][C:20]2([O:24][CH2:23][CH2:22][O:21]2)[CH2:19][O:18]1.ClC1C=CC=C(C(OO)=[O:47])C=1>CO>[CH3:8][C:9]1[C:10]([CH2:28][S:29]([C:30]2[NH:31][C:32]3[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=3[N:34]=2)=[O:47])=[N:11][CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1([CH3:27])[O:18][CH2:19][C:20]2([O:21][CH2:22][CH2:23][O:24]2)[CH2:25][O:26]1
Reactant: Cc1c(OCC2(C)OCC3(CO2)OCCO3)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1c(OCC2(C)OCC3(CO2)OCCO3)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reaction time: 1.5 h
Yield: 38.4 %

Procedure:
To a toluene (8.1 ml) and methanol (0.9 ml) solution of the 2-(((3-methyl-4-((8-methyl-1,4,7,9-tetraoxaspiro[4.5]dec-8-yl)methoxy)pyridin-2-yl)methyl)thio)-1H-benzimidazole (372 mg, 0.84 mmol) obtained in the step (5f), a toluene (2.7 ml) and methanol (0.3 ml) solution of 3-chloroperbenzoic acid (200 mg, 0.76 mmol as the content was regarded as 65%) was added dropwise at −55° C. to −50° C. for 10 minutes in a nitrogen atmosphere. The mixture was stirred at −60° C. to −50° C. for 1.5 hours. The reaction was terminated by adding 12 ml of a saturated aqueous solution of sodium hydrogen carbonate at the same temperature. The mixture was extracted with 50 ml of chloroform twice, and then, the organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (NH silica gel, elution solvent: ethyl acetate/methanol=1/0-4/1 gradient) and desired fractions were concentrated. The obtained white foam was re-precipitated with chloroform and diethyl ether and filtered. The operation was repeated twice to obtain the title compound (148 mg, 38.4% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][S:8][C:9]2[N:13]=[CH:12][NH:11][N:10]=2)=[CH:5][CH:4]=1.[N+](=[CH2:18])=[N-]>CO.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[N:10]([CH3:18])[N:11]=[CH:12][N:13]=2)=[CH:14][CH:15]=1.[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[N:13]=[CH:12][N:11]([CH3:18])[N:10]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(CSc2nc[nH]n2)cc1
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(CSc2ncn(C)n2)cc1
Product: COc1ccc(CSc2ncnn2C)cc1
Reaction time: 1 h
Yield: 49 %
Yield: 34 %

Procedure:
To a solution of 3-p-methoxybenzylthio-1,2,4-triazole (10.0 g: 45.2 mMol.) in methanol (100 ml) is added under ice cooling a solution of diazomethane in ether (prepared from 15 g of N-nitrosomethylurea), and the mixture is stirred for 1 hour. The reaction mixture is concentrated and purified by Lobar column chromatography (toluene: ethyl acetate=1:2 to 1:3) to give 3-p-methoxybenzylthio-2-methyl-1,2,4-triazole [5.17 g: NMR δ(CDCl3) ppm: 3.63(s, 3H), 3.79(s, 3H), 4.34(s, 2H), 6.80-6.84, 7.19-7.24(A2B2, 4H), 7.88(s, 1H). IR ν(CHCl3) cm-1 : 1611, 1511, 1476, 1464, 1440, 1360, 1302. Yield: 49%] and 3-p-methoxybenzylthio-1-methyl-1,2,4-triazole [3.60 g: NMR δ(CDCl3) ppm: 3.78(s, 3H), 3.87(s, 3H), 4.31(s, 2H), 6.80-6.85, 7.30-7.34(A2B2, 4H), 7.99(s, 1H). IR ν(CHCl3) cm-1 : 1612, 1512, 1465, 1440, 1421, 1356, 1302. Yield: 34%].
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([NH:15]C(=O)OC(C)(C)C)[CH:12]=[CH:13][CH:14]=2)[CH:3]=1.[O:23]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>C(O)CCC>[NH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:34][C:33]3[CH:32]=[CH:31][C:30]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:36][CH:35]=3)[N:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Nc2cc(Cl)ncn2)c1
Agent: Cl
Solvent: CCCCO
Product: Nc1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Yield: 39.3 %

Procedure:
A solution of tert-butyl 3-(6-chloropyrimidin-4-ylamino)phenylcarbamate (200 mg, 0.6 mmol), 4-phenoxyaniline (346 mg, 1.8 mmol) and concentrated HCl (45 mg, 1.2 mmol) in n-butanol (8 mL) was subjected to microwave irradiation (160° C., 20 min). The reaction mixture was quenched with NaHCO3 solution (2 mL) and extracted with EtOAc (2×10 mL). The combined EtOAc extract was washed with water (5 mL), brine (5 mL), was dried over Na2SO4 and was concentrated under reduced pressure. The residue was further purified by column chromatography (SiO2, 60-120, Chloroform/methanol, 9/1) to give N4-(3-aminophenyl)-N6-(4-phenoxyphenyl)pyrimidine-4,6-diamine (87 mg, 37.8%) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([C:13]#[N:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:15]([O:17]C)=[O:16].O[Li].O.C1COCC1.O>C(=O)(O)[O-].[Na+].CO>[CH3:1][O:2][C:3]1[C:12]([C:13]#[N:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1c(OC)c(C#N)cc2ccccc12
Agent: O=C([O-])O
Agent: [Li]O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(C#N)cc2ccccc2c1C(=O)O

Procedure:
A solution of methyl 2-methoxy-3-cyano-1-naphthoate (0.113 g), LiOH.H2O (0.0196 g), THF (3 mL), water (1 mL) and methanol (1 mL) was stirred overnight at room temperature. The solution was diluted with saturated sodium bicarbonate and extracted with Et2O. The aqueous layer was acidified to pH 2 by addition of 1N HCl and extracted with Et2O. The organic layer was washed with water (30 mL) and brine (40 mL), dried (sodium sulfate), filtered, and concentrated to a white solid. 1H NMR (DMSO-d6): δ14.06 (broad, 1 H), 8.08-8.02 (m, 1 H), 7.83-7.76 (m, 2 H), 7.69-7.63 (m, 1 H), 4.02 (s, 3 H); MS m/z: 226 (M−1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:12]3[S:24][CH:23]=[CH:22][C:13]=3[NH:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:7][CH2:6]1.[C:25]([Cl:36])(=[O:35])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C1C=CC=CC=1>[ClH:36].[C:25]([O:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C:11]2[C:12]3[S:24][CH:23]=[CH:22][C:13]=3[NH:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:9][CH2:10]1)(=[O:35])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: OCCCN1CCN(C2=Nc3ccccc3Nc3ccsc32)CC1
Reactant: CCCCCCCCCC(=O)Cl
Solvent: c1ccccc1
Product: CCCCCCCCCC(=O)OCCCN1CCN(C2=Nc3ccccc3Nc3ccsc32)CC1
Product: Cl
Temperature: 75 °C

Procedure:
To a solution of 10-[4-(3-hydroxypropyl)-1-piperazinyl]-4H-thieno[3,2-b][1,5]benzodiazepine (1.71 g, 0.005 mol) in dry benzene (40 ml) was added decanoyl chloride (1.42 g, 0.0075 mol) in benzene (10 ml) dropwise with stirring and the solution heated at 75° C. until the reaction had gone to completion by TLC. The reaction mixture on washing gave the title compound.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:12][CH:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=2)[N:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:14]1=[O:31].O>CS(C)=O>[NH2:12][C:13]1([CH2:3][CH2:2][C:1]#[N:4])[C:21]2[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=2)[N:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:14]1=[O:31]
Reactant: C=CC#N
Reactant: COc1ccc2c(c1)N(c1ccc(F)cc1)C(=O)C2N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(c1)N(c1ccc(F)cc1)C(=O)C2(N)CCC#N
Temperature: 25 °C
Reaction time: 9 h

Procedure:
Under argon atmosphere, 1.2 ml of acrylonitrile and 4.48 g of potassium carbonate were added to a stirred suspension of 5.00 g of 3-amino-1-(4-fluorophenyl)-2,3-dihydro-6-methoxy-1H-indol-2-one hydrochloride in dimethyl sulfoxide (30 ml), and the mixture was stirred at room temperature for 9 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the extract was washed, dried and then filtered, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform-ethyl acetate (1:1)] to afford 3.48 g of 3-[3-amino-1-(4-fluorophenyl)-2,3-dihydro-6-methoxy-2-oxo-1H-indol-3-yl]propanonitrile as a pale yellow oil.
Reaction SMILES: C(OC(=O)C[C@@H](NC(OC(C)(C)C)=O)C([NH:14][C@H:15]([C:20](=[O:23])[NH:21]C)[C:16]([CH3:19])([CH3:18])[CH3:17])=O)C1C=CC=CC=1.FC(F)(F)C(O)=O.Cl.[CH2:41]([O:48][C:49](=[O:72])[CH2:50][C@@H:51]([N:55]1[CH:59]=[CH:58][C:57]([C:60]2[CH:65]=[CH:64][C:63]([C:66]3[CH:71]=[CH:70][N:69]=[CH:68][CH:67]=3)=[CH:62][CH:61]=2)=[CH:56]1)[C:52](O)=[O:53])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CN(C(ON1N=[N:88][C:83]2[CH:84]=[CH:85][CH:86]=[CH:87]C1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[CH2:41]([O:48][C:49](=[O:72])[CH2:50][C@@H:51]([N:55]1[CH:59]=[CH:58][C:57]([C:60]2[CH:61]=[CH:62][C:63]([C:66]3[CH:71]=[CH:70][N:69]=[CH:68][CH:67]=3)=[CH:64][CH:65]=2)=[CH:56]1)[C:52]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][C:85]1[CH:84]=[CH:83][N:88]=[CH:87][CH:86]=1)[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:53])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(C[C@H](C(=O)O)n1ccc(-c2ccc(-c3ccncc3)cc2)c1)OCc1ccccc1
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccncc3)cc2)c1)C(=O)Nc1ccncc1
Yield: 76 %

Procedure:
According to the procedure described in Example 1(b) for the preparation of N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)-3(R)-t-butoxycarbonylamino-succinamic acid benzyl ester, 2S-t-butoxycarbonylamino-3,3-dimethyl-N-(pyridin-4-yl)-butanamide (prepared as described in Example 5(d)) was deprotected with trifluoroacetic acid. The crude amine salt and 2(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinic acid 4-benzyl ester hydrochloride (prepared as described in Example 6(a)) were coupled with TBTU to provide after purification via column chromatography with 5% MeOH/CH2Cl2 and trituration with MTBE/hex, in 76% yield N-[2,2-dimethyl-1(S)-(pyridin-4-ylcarbamoyl)propyl]-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid benzyl ester as a pale yellow amorphous solid, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:10][C:40]([C:36]2[CH:35]=[C:34]3[C:39](=[CH:38][CH:37]=2)[N:31]([CH2:30][C:27]2[CH:26]=[CH:25][C:24]([C:19]4[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:29][CH:28]=2)[C:32]([CH3:44])=[C:33]3[CH3:43])=[O:41])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1cccc(F)c1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(F)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(3-fluorophenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 521 [M+H]+.
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[S:24][CH:23]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][CH:28]=[N:29][C:30]=3[Cl:34])[CH2:22][CH2:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:23]1([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][CH:28]=[N:29][C:30]=3[Cl:34])[S:24][C@H:20]([CH2:19][OH:18])[CH2:21][CH2:22]1
Reactant: CC(C)(C)[Si](OC[C@@H]1CCC(n2cnc3c(Cl)ncnc32)S1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OC[C@@H]1CCC(n2cnc3c(Cl)ncnc32)S1

Procedure:
A solution of 11 (0.315 g, 0.62 mmol), acetic acid (30 μL, 0.63 mmol) and tetrabutylammonium fluoride (1 M in THF, 0.65 mL, 0.65 mmol) in 3 mL THF was stirred for 10 minutes under nitrogen. The solvent was removed in vacuo and the residue flash chromatographed with dichloromethane followed by 19:1 chloroform/methanol to give 0.164 g (98%) of the anomers. The anomers were separated by centrifugal chromatography with 19:1 chloroform/methanol: yield of β-anomer 10 mg; mp. 125°-128° C.; [α]D25 +2.5° (c=0.1 CH3OH); FAB MS 271 (M+H)+ ; 1H NMR (CDCl3) δ 9.0 (s, 1, H-2), 8.8 (s, 1, H-8), 6.3 (m, 1, 5'-OH), 3.8 (m, 1, 5'-H), 3.65 (m, 2, 4'-H, 5'-H), 2.6 (m, 1, 2'-H), 2.45 (m, 1, 2'-H), 2.2 (m, 1, 3'-H), 2.0 (m, 1, 3'-H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)O1.[NH2:18][C@H:19]([CH2:29][F:30])[C@@H:20]([C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1)[OH:21].C([O-])([O-])=O.[Cs+].[Cs+]>C(COC)OC.O.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>[NH2:18][C@H:19]([CH2:29][F:30])[C@@H:20]([C:22]1[CH:23]=[CH:24][C:25]([C:9]2[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)=[CH:26][CH:27]=1)[OH:21]
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: N[C@H](CF)[C@H](O)c1ccc(I)cc1
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: [Cs+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccc(-c2ccc([C@@H](O)[C@H](N)CF)cc2)cn1
Temperature: 90 °C
Yield: 51 %

Procedure:
To a solution of 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl) -pyridine-2-carbonitrile (0.5 g, 2.17 mmol) in dimethoxyethane (10 mL) and water (3 mL) is added (1R,2S)-2-Amino-3-fluoro-1-(4-iodo-phenyl)-propan-1-ol (0.65 g, 2.20 mmol) and Cs2CO3 (2.15 g, 6.59 mmol), and degassed with nitrogen followed by addition of Pd(PPh3)4 (0.25 g, 0.21 mmol) and heated the reaction mixture to 90° C. for 1.5 hours. Solvent is evaporated in vacuo, to get crude material purified by column chromatography eluting in 2.5 to 3% methanol in CH2Cl2 to afford the title compound (0.3 g) as impure. 1H NMR (400 MHz, DMSO-d6) δ: 3.09-3.18 (m, 1H), 3.48 (s, 1H), 4.24-4.28 (m, 0.5H), 4.36-4.41 (m, 1H), 4.49-4.52 (m, 0.5H), 4.64 (d, J=6.16 Hz, 1H), 7.53 (d, J=8.16 Hz, 2H), 7.59 (d, J=8.24 Hz, 2H), 7.76 (d, J=8.2, 1H), 8.0 (dd, J1=8.16 Hz, J2=2.32 Hz, 1H), 8.93 (d, J=1.76 Hz, 1H). LC-MS (m/z): [M+H]=272.00.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\NC1C=CC(N2C[C@H](C)N[C@H](C)C2)=C(C(F)(F)F)C=1.BrC1C=C2C(=CC=1)[C:41](=[O:45])NC(=O)C2=CNC1C=CC(N2CC(C)NC(C)C2)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/[O:45][CH3:41]
Reactant: C[C@@H]1CN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc2C(F)(F)F)C[C@H](C)N1
Reactant: CC1CN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC(C)N1
Product: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21

Procedure:
Using the procedure described for the preparation of 4Z)-6-bromo-4-({[4-(3,5-dimethylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione, \2.28 g (62% yield) of yellow solid is obtained from 2.0 g (7.0 mmol) of (4E)-6-bromo-4-(methoxymethylene)isoquinoline 1,3(2H,4H)-dione, and 2.13 g (7.7 mmol) of 4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-(trifluoromethyl)phenyl]amine; mp: 224-225° C.; MS (ESI) m/z 523.1 (M+H)+1
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)#[CH:2].[CH2:19]1[CH2:29][CH2:28]N2[C:22](=NCCC2)[CH2:21][CH2:20]1.CN([CH2:33][CH2:34]N(C)C)C>Cl[Cu].C(#N)C>[CH2:1]([C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]#[C:14][C:15]#[C:16][C:17]3[S:9][C:8]([C:6]4[S:7][C:3]([CH2:28][CH2:29][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:33][CH:34]=4)=[CH:12][CH:18]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)[CH2:2][CH2:11][CH2:10][CH2:13][CH3:14]
Reactant: C#Cc1ccc(-c2ccc(CCCCCC)s2)s1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CN(C)CCN(C)C
Agent: Cl[Cu]
Solvent: CC#N
Product: CCCCCCc1ccc(-c2ccc(C#CC#Cc3ccc(-c4ccc(CCCCCC)s4)s3)s2)s1
Yield: 90 %

Procedure:
Glacer coupling reaction was carried out using 5-ethynyl-5′-hexyl-2,2′-bithiophene (0.23 g, 0.83 mmol), DBU (0.12 ml, 0.83 mmol), TMEDA (1.87 μl, 1.24 μmol), CuCl (1.60 mg, 1.66 μmol) and acetonitrile (20 ml), and the reaction product was treated in accordance with a conventional method thereby producing an intended product (yield: 90%).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][CH:8]([NH:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:9][OH:10])(C)(C)C.C(OC(=O)NC1CC(=O)OC1OCCC1C=CC=CC=1)C=C.[C:41]1([CH2:47][CH2:48][CH2:49]O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH2:15]([O:14][C:12](=[O:13])[NH:11][CH:8]1[CH2:7][C:6](=[O:5])[O:18][CH:9]1[O:10][CH2:49][CH2:48][CH2:47][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH:16]=[CH2:17]
Reactant: C=CCOC(=O)NC(CO)CC(=O)OC(C)(C)C
Reactant: OCCCc1ccccc1
Agent: C=CCOC(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: C=CCOC(=O)NC1CC(=O)OC1OCCCc1ccccc1
Yield: 32 %

Procedure:
Prepared from 3-allyloxycarbonylamino-4-hydroxy-butyric acid tert-butyl ester as described for compound 40 using 3-phenylpropanol to afford 1.15 grams (32% yield) of the title compound as a colorless oil. 1H-NMR (500 MHz, CDCl3) δ 1.82-2.05 (m, 2H), 2.38 (dd, 1H), 2.68 (m, 2H), 2.82 (dd, 1H), 3.55-3.65 (m, 1H), 3.82-3.92 (m, 1H), 4.48-4.72 (m, 3H), 5.12-5.59 (m, 3H), 5.82-6.03 (m, 1H), 7.11-7.45 (m, 5H). Analytical HPLC: 9.08 min. LC-MS (ES+): m/e=320.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][CH2:9][CH2:10][CH2:11][CH:12]([O:18][CH2:19]Cl)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].O>CCOCC>[Cl:8][CH2:9][CH2:10][CH2:11][CH:12]([O:18][CH2:19][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: Brc1ccccc1
Reactant: CCCCCC(CCCCl)OCCl
Solvent: O
Solvent: CCOCC
Product: CCCCCC(CCCCl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.7 %

Procedure:
A solution of bromobenzene (13.18 g., 0.084 mole) in ether (50 ml.) is added to a suspension of Mg (2.04 g., 0.084 mole) in ether (50 ml.) dropwise so as to maintain a gentle reflux. After complete addition of the bromobenzene, the mixture is heated on a steam bath for an additional hour. The reaction mixture is then cooled to 5°-10° C. by means of an ice-water bath, and 1-chloro-4-chloromethoxynonane (19.05 g., 0.084 mole) is added dropwise over 15 minutes. The resulting suspension is stirred for 18 hours at room temperature. The reaction mixture is diluted with ether (100 ml.), cooled to 0°-5° C., and cold water (75 ml.) is added with vigorous stirring while the temperature is kept below 5° C. Let stir a 0°-5° C. for about 15 minutes. The aqueous phase is separated from the ether phase (A), and the aqueous layer is extracted with ether (150 ml., B). Organic solution A is combined with B, washed with H2O (100 ml.), 5% K2CO3 (100 ml.), again with H2O (100 ml.), finally with saturated NaCl solution, and is dried over anhydrous Na2SO4. Removal of the solvent in vacuo yields 1-chloro-4-benzyloxynonane (19.28 g., 0.072 mole, 85.7% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:18])=[C:13]([C:15](=O)[CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](=O)([O-])[O-].[K+].[K+].BrC[C:27](=[O:31])[CH:28]([CH3:30])[CH3:29]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:18][C:16]([C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[C:15]([CH3:19])[C:13]=2[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cc(OCc2ccccc2)ccc1O
Reactant: CC(C)C(=O)CBr
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C(C)C)oc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 57.1 %

Procedure:
To a solution (200 mL) of 1-[5-(benzyloxy)-2-hydroxyphenyl]ethanone (16.1 g) synthesized in Example A82(1) in N,N-dimethylformamide were added at room temperature potassium carbonate (27.6 g) and 1-bromo-3-methylbutan-2-one (14.3 g) synthesized in Example A75(1), and the mixture was stirred for 15 hr. The reaction mixture was filtered through celite, water (200 mL) was added and the mixture was extracted with diethyl ether (100 mL×2). The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (100 mL), and DBU (9.9 mL) was added at room temperature. The reaction mixture was stirred at 100° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, 1N hydrochloric acid (150 mL) was added, and the mixture was extracted with diethyl ether (100 mL×2). The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol-diisopropyl ether to give the title object compound (11.7 g, 57%) as pale-yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14](SC)[N:13]=3)=[CH:10][N:9]([CH:20]([CH3:22])[CH3:21])[N:8]=2)=[CH:4][CH:3]=1.Cl[C:24]1C=CC=C(C(OO)=O)C=1.[S:34]([O-:37])([O-])=[O:35].[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([S:34]([CH3:24])(=[O:37])=[O:35])[N:13]=3)=[CH:10][N:9]([CH:20]([CH3:21])[CH3:22])[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(-c2cn(C(C)C)nc2-c2ccc(Cl)s2)n1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)n1cc(-c2ccnc(S(C)(=O)=O)n2)c(-c2ccc(Cl)s2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.1 %

Procedure:
To a solution of 4-[3-(5-chloro-2-thienyl)-1-isopropyl-1H-pyrazol-4-yl]-2-(methylsulfanyl)pyrimidine (1 eq, 12 mmol) in 315 mL of dichloromethane was added meta chloroperbenzoic acid 77% (2 eq, 24 mmol). The mixture was stirred at room temperature for 72 h and then quenched with water. Sodium sulfite (2.1 eq, 25 mmol) was added and the layers were separated. The organic layer was then washed twice with a 2M solution of potassium carbonate, dried over MgSO4 filtered and concentrated to afford 4 g of 4-[3-(5-Chloro-2-thienyl)-1-isopropyl-1H-pyrazol-4-yl]-2-(methylsulfonyl)pyrimidine (65% yield) in a 8:2 mixture with the corresponding sulfoxide. The crude material was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][CH:18]=1.[O:26]=[S:27]1(=[O:41])[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[O:41]=[S:27]1(=[O:26])[CH2:28][CH2:29][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:23]([C:20]3[CH:21]=[CH:22][C:17]([C:3]4[C:2]([CH3:1])=[CH:7][CH:6]=[C:5]([NH:8][C:9]([N:11]5[CH2:12][CH2:13][O:14][CH2:15][CH2:16]5)=[O:10])[CH:4]=4)=[CH:18][CH:19]=3)=[O:25])=[CH:36][CH:35]=2)[CH2:31][CH2:32]1
Reactant: Cc1ccc(NC(=O)N2CCOCC2)cc1-c1ccc(C(=O)O)cc1
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)N2CCOCC2)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1
Reaction time: 18 h
Yield: 48.8 %

Procedure:
A mixture of 2′-methyl-5′-[(morpholine-4-carbonyl)-amino]-biphenyl-4-carboxylic acid (40 mg), 4-(1,1-Dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-phenylamine (28 mg), triethylamine (0.033 ml) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (67 mg) in dry DMF (3 ml) was stirred at 20 C for 18 h. The mixture was then partitioned between water and dichloromethane. The dried extracts were evaporated and the residue purified on silica gel. Elution with dichloromethane:ethanol:0.880 ammonia; 200:8:1 gave an off-white solid (32 mg).