Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[CH2:17]([O:19][C:20](=[O:40])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32][NH:31]1)[CH3:18].Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CN(C)C1C=CN=CC=1.CCOC(C)=O>[CH2:17]([O:19][C:20](=[O:40])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32][N:31]1[C:13](=[O:15])[CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH3:18]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCOC(=O)COc1ccc(F)cc1C1NCCc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(F)cc1C1c2ccccc2CCN1C(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of N-carbobenzyloxyglycine (1.07 g, 5.00 mmol, 1.0 eq.) and (±)-[4-fluoro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (1.93 g, 5.00 mmol, 1.0 eq.) in DMF (30 mL) was treated with 4-(dimethylamino)pyridine (2.44 g, 20.00 mmol, 4.0 eq.) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.44 g, 7.50 mmol, 1.5 eq.) and the resulting solution was stirred at r.t. for 18 hours. The reaction mixture was diluted with AcOEt (500 mL). The diluted solution was washed with 1N aq. HCl soln. (3×200 mL), sat. aq. NaHCO3 soln. (3×200 mL), sat. aq. NaCl soln. (1×200 mL), dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash master (column: 100 g, flow: 35 mL/min, heptane to heptane+AcOEt) to yield the title product as a white foam.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].[C:27]([C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34])([CH3:30])([CH3:29])[CH3:28].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>>[C:27]([C:31]1[CH:32]=[C:33]([NH:34][C:18]([C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:8][O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[CH:22][CH:21]=2)=[O:19])[CH:35]=[CH:36][CH:37]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.9 %

Procedure:
4-(6-Cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (90 mg, 0.255 mmol), 3-tert-butylaniline (38 mg, 0.255 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (43 mg, 0.280 mmol), and 1-hydroxy-7-azabenzotriazole (25 mg, 0.255 mmol) were combined in a round bottom flask and taken up in 5 ml dry of DMF. The reaction was stirred at ambient temperature for 12 hours and then poured into 10% HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified on silica gel. Elution with a gradient of 2-5% methanol-dichloromethane provided the title compound (100 mg, 81%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][O:20][Si](C(C)C)(C(C)C)C(C)C)=[CH:15][CH:14]=2)=[N:3]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:4]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=2)=[N:3]1
Reactant: CC(C)[Si](OCc1ccc(-c2nn(C)cc2-c2ccncc2)cc1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1cc(-c2ccncc2)c(-c2ccc(CO)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To a solution of 4-[1-Methyl-3-(4-triisopropylsilanyloxymethyl-phenyl)-1H-pyrazol-4-yl]-pyridine (1.75 g) in THF (16.2 mL) was added TBAF (1.0M THF, 5.2 mL) and the reaction mixture stirred at ambient temperature under inert atmosphere for 1 h. The reaction mixture was poured into saturated sodium bicarbonate, extracted 3× with chloroform, dried magnesium sulfate filtered and concentration. Purification via MPLC biotage chromatography eluting with 2% methanol/0.5% saturated ammonium hydroxide/50% ethyl acetate/hexanes provided the title compound (920 mg, 84%). MS: (M+H m/z=266.1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH:10]([CH3:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:19]=2)[CH:10]([CH3:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc(O)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2C)cc1
Temperature: 100 °C

Procedure:
A suspension of 6 g (0.0205 mol) of 4-tert-butyloxycarbonyl-1-(4-hydroxyphenyl)-2-methylpiperazine, 2.4 ml (0.0246 mol) of methyl bromoacetate and 3.4 g (0.0246 mol) of potassium carbonate in 50 ml of dimethylformamide is heated at 100° C. for 6 hours and, after cooling, concentrated to dryness in vacuo. The residue is partitioned between ethyl acetate and water and the aqueous phase is extracted once more with ethyl acetate. The combined ethyl acetate extracts are concentrated to dryness in vacuo. The residue is purified by means of chromatography on a silica gel column, ethyl acetate/cyclohexane being used as eluent. After evaporation, the residue is crystallized from ether/petroleum ether.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[NH2:25][C@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1.C(N(CC)CC)C>C(O)C>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:5]1[N:6]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[C:7]2[C:3]([N:4]=1)=[C:2]([NH:25][C@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1)[N:10]=[CH:9][N:8]=2
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)C1
Temperature: 80 °C
Yield: 95.1 %

Procedure:
To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purine (100 mg, 0.267 mmol, 1 eq.) in 3 mL of ethanol was added tert-butyl (3S)-3-aminopiperidine-1-carboxylate (64 mg, 0.32 mmol, 1.2 eq.) and triethylamine (0.06 mL, 0.4 mmol, 1.5 eq.). The reaction was heated to 80° C. for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 137 mg (95%) of tert-butyl (3S)-3-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}piperidine-1-carboxylate. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.43 (br. s., 9 H) 1.60-1.76 (m, 2 H) 1.77-1.93 (m, 1 H) 2.08-2.22 (m, 1 H) 3.30 (br. s., 2 H) 3.60 (br. s., 1 H) 3.98 (br. s., 1 H) 4.42 (br. s., 1 H) 5.96 (d, J=7.54 Hz, 1 H) 7.14-7.68 (m, 8 H) 8.48 (s, 1 H), [M+H]+ 539.4.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl>C(OCC)(=O)C>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[C:14]([O:16][C:4]2[CH:13]=[CH:12][CH:7]=[CH:6][CH:5]=2)=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)C1CCCc2ccc([N+](=O)[O-])cc21
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(Oc1ccccc1)C1CCCc2ccc([N+](=O)[O-])cc21
Reaction time: 0.5 h
Yield: 148.8 %

Procedure:
In 50 ml of ethyl acetate was dissolved 1.5 g of 7-nitro-1,2,3,4-tetrahydro-1-naphthoic acid. To the resulting solution was added at room temperature 1.3 g of phosphorus pentachloride, and the mixture was stirred for 30 minutes. The precipitates were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in 50 ml of fresh ethyl acetate. To the solution were added with cooling 1.0 g of phenol and 8.5 g of triethylamine. The resulting mixture was stirred for 24 hours. The reaction mixture was washed with a cold 5% sodium hydroxide solution and freed from the solvent by distillation to obtain 1.5 g of phenyl 7-nitro-1,2,3,4-tetrahydro-1-naphthoate having a melting point of 83°-84° C.
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:29])[CH:18]=[CH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[CH:14][CH:15]=2)[C:10]([CH3:31])([CH3:30])[CH2:9][C:8]1=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:33](N1C2C(=CC(C(=O)C)=CC=2)C(C)(C)CC1=O)[CH2:34]CCCCCC>>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:29])[CH:18]=[CH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[CH:14][CH:15]=2)[C:10]([CH3:31])([CH3:30])[CH2:9][C:8]1=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:33][CH3:34]
Reactant: CCCCCCCCN1C(=O)CC(C)(C)c2cc(C(C)=O)ccc21
Reactant: CCCCCCN1C(=O)CC(C)(C)c2cc(C(=O)C=Cc3ccc(C(=O)O)cc3)ccc21
Product: CCCCCCCCN1C(=O)CC(C)(C)c2cc(C(=O)C=Cc3ccc(C(=O)O)cc3)ccc21
Yield: 24 %

Procedure:
Following a procedure similar to that used for the preparation of Compound 8a but using N-octyl-6-acetyl-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (Intermediate 6c) as starting material afforded the title compound as a light yellow solid (24% yield).
Reaction SMILES: [C:1]([O:4][C@H:5]1[O:18][C@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:7]([O:8][C:9](=[O:11])[CH3:10])[C@H:6]1[N:24]=[N+]=[N-])(=[O:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:4][C@H:5]1[O:18][C@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:7]([O:8][C:9](=[O:11])[CH3:10])[C@H:6]1[NH2:24])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@H](OC(C)=O)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@H](OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 3 h
Yield: 101.5 %

Procedure:
To a solution of 1,3,4,6-tetra-O-acetyl-2-azido-2-deoxy-alpha-D-glucopyranose (TCI-US) (300 mg, 0.80 mmol) in 25 mL of EtOAc was added 180 mg of 10% Pd/C. This solution was stirred under an atmosphere of hydrogen gas (1 atm) for 3 hours. The mixture was filtered through a pad of Celite® and the pad was washed with EtOAc (20 mL). The solution was evaporated to afford the desired amine 149 (282 mg, 100%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)[CH:8]=1.[C:16](Cl)(=[O:18])[CH3:17].C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:2][C:3]1[CH:8]=[C:7]([O:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:18])[CH3:17])[CH2:11]2)[CH:6]=[N:5][CH:4]=1
Reactant: Brc1cncc(O[C@@H]2CCCNC2)c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCC[C@@H](Oc2cncc(Br)c2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
To a solution of 3-bromo-5-((R)-piperidin-3-yloxy)-pyridine hydrochloride salt (525 mg, 1.8 mmol) in DMF (10 mL) is added acetyl chloride (0.19 mL, 2.7 mmol) and N,N-diisopropylethylamine (1.4 mL, 8.0 mmol). The mixture is stirred at room temperature for 16 h. The reaction is partitioned between H2O and EtOAc and the layers are separated. The aqueous is extracted with EtOAc and the combined organic layers are dried and concentrated. The crude product is purified by flash column chromatography to provide 271 mg of 1-[(R)-3-(5-bromo-pyridin-3-yloxy)-piperidin-1-yl]-ethanone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4](I)[CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][C:13]=1/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29].C(=O)([O-])[O-].[Cs+].[Cs+]>COC1CCCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:19]([S:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=2[O:8][CH3:9])=[C:13](/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:14]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccc(Br)cc1I
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1N
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: COC1CCCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1cc(Br)ccc1OC
Temperature: 90 °C
Yield: 85.9 %

Procedure:
4-Bromo-2-iodo-1-methoxybenzene (6.07 g, 19.40 mmol), (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (5.066 g, 16.16 mmol), Pd2(dba)3 (0.370 g, 0.404 mmol), Xntphos (0.468 g, 0.808 mmol) and cesium carbonate (7.37 g, 22.63 mmol) were combined in CPME (32.3 ml) and the reaction was heated to 90° C. overnight. The reaction was cooled to RT, diluted with EtOAc and filtered over a pad of Celite (washing with EtOAc). The filtrate was concentrated in vacuo and the crude oil was then taken up in DCM and purified via MPLC, eluting with 0-20% ethyl acetate in heptanes to yield (E)-ethyl 3-(5-(benzylthio)-2-((5-bromo-2-methoxyphenyl)amino)phenyl)acrylate (6.92 g, 13.88 mmol, 86% yield) as a yellow solid. MS (ESI, pos. ion) m/z: [M+1] 498.0
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:42]=[C:41]([CH2:43][CH2:44][CH2:45][N:46]2[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]2)[CH:40]=[CH:39][C:37]=1[NH2:38].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]3[CH:39]=[CH:40][C:41]([CH2:43][CH2:44][CH2:45][N:46]4[CH2:47][CH2:48][N:49]([CH3:52])[CH2:50][CH2:51]4)=[CH:42][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: COc1cc(CCCN2CCN(C)CC2)ccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(CCCN2CCN(C)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 120 °C
Yield: 30.4 %

Procedure:
3-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (110 mg, 0.24 mmol), 2-(methyloxy)-4-[3-(4-methyl-1-piperazinyl)propyl]aniline (56 mg, 0.21 mol), and p-toluenesulfonic acid (109 mg, 0.57 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 40 hours. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (50 mg, 0.073 mmol, 34%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.22 (s, 1H), 9.39 (d, J=6.59 Hz, 1H), 8.50 (s, 1H), 8.31-8.34 (m, 1H), 8.25 (d, J=5.31 Hz, 1H), 8.02-8.06 (m, 1H), 7.79-7.82 (m, 1H), 7.73 (d, J=8.97 Hz, 1H), 7.56-7.64 (m, 2H), 7.45 (ddd, J=8.88, 6.78, 1.19 Hz, 1H), 7.35-7.41 (m, 1H), 7.20 (td, J=8.06, 5.13 Hz, 2H), 6.98 (t, J=6.87 Hz, 1H), 6.93 (d, J=1.47 Hz, 1H), 6.74 (dd, J=8.15, 1.56 Hz, 1H), 6.52 (d, J=5.13 Hz, 1H), 3.80 (s, 3H), 2.56 (t, J=7.60 Hz, 2H), 2.32-2.42 (m, 2H), 2.21-2.32 (m, 8H), 2.11 (s, 3H), 1.67-1.76 (m, 2H). MS (ESI): 689 [M+H]+.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[CH3:13][O:14][C:15](=[O:36])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24](Cl)[C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1>>[CH3:13][O:14][C:15](=[O:36])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(C(F)(F)F)sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCCc3ccc4c(c3)OCO4)c3cc(C(F)(F)F)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-methylenedioxyphenethylamine is reacted with 4-(4-chloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-methylenedioxyphenethylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].I[CH2:19][CH3:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:19][CH3:20])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:17])([F:15])[F:16]
Reactant: CCI
Reactant: FC(F)(F)c1cc(C2CCNCC2)ccc1Cl
Product: CCN1CCC(c2ccc(Cl)c(C(F)(F)F)c2)CC1

Procedure:
Beginning with 4-(4-Chloro-3-trifluoromethyl-phenyl)-piperidine and iodoethane, the title compound was recovered by the procedure described in Example 2. MS m/z (rel. intensity, 70 eV) 291 (M+, 6), 278 (29), 277 (11), 276 (bp), 70 (50).
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>CN(C)C=O>[C:20]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:18][C:17]([NH:16]/[CH:3]=[C:4]2\[C:5](=[O:15])[NH:6][C:7](=[O:14])[C:8]3[C:13]\2=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:22][CH:21]=1
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: COC=C1C(=O)NC(=O)c2ccccc21
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc2/C1=C/Nc1ccc(-c2ccccc2)cc1
Temperature: 105 °C
Yield: 35.2 %

Procedure:
A mixture of 0.500 g (2.46 mmol) of 4-methoxymethylene-4H-isoquinoline-1,3-dione and 0.416 g (2.46 mmol) of 4-aminobiphenyl in 8 mL of N,N-dimethylformamide is heated at 105° C. under N2 for 1.5 h. The reaction is then chilled in ice and the solid product is collected. It is washed with cold N,N-dimethylformamide (DMF) and Et2O and dried in vacuo to give 0.295 g (35%) of yellow crystals: mp 261-262° C.; 1H NMR (DMSO-d6) δ 12.5 (d, 1H, J=9 Hz), 11.4 (s, 1H), 9.94 (d, 1H, J=9 Hz), 8.21 (d, 1H, J=6 Hz), 8.05 (d, 1H, J=6 Hz), 7.68 (m, 7H), 7.47 (m, 2H), 7.36 (m, 2H); HRMS (ESI) m/z calcd for C22H16N2O2 341.12846. found 341.12811 (M+H)+1; Analysis for C22H16N2O2; Calcd: C, 77.63; H, 4.74; N, 8.23. Found: C, 77.36; H, 4.66; N, 8.25.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[C:11]([C:13](OCC)=[O:14])[N:12]=1.[H-].C([Al+]CC(C)C)C(C)C.[F-].[Na+].O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=1
Reactant: CCOC(=O)c1csc(-c2ccccc2Cl)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [F-]
Agent: [H-]
Solvent: O
Solvent: ClCCl
Product: OCc1csc(-c2ccccc2Cl)n1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
To a solution of ethyl 2-(2-chlorophenyl)-4-thiazolecarboxylate (1.34 g, 5.0 mmol), prepared as described above, in CH2Cl2 (20 mL) at −78° C. is added diisobutylaluminum hydride (10.5 mL of 1.0 M solution in toluene, 10.5 mmol) and the resulting reaction mixture is stirred at −78° C. for 1 hour after which time sodium fluoride (1.5 g) and water (0.5 mL) are added and the reaction mixture is allowed to warm to room temperature and filtered. The filtrate is concentrated to provide the crude reduction product which is purified by column chromatography (10% ethyl acetate in hexanes) to afford 138 mg of [2-(2-chlorophenyl)-1,3-thiazol-4-yl]carboxyaldehyde and 605 mg of [2-(2-chlorophenyl)-1,3-thiazol-4-yl]methanol. The of [2-(2-chlorophenyl)-1,3-thiazol-4-yl]carboxyaldehyde portion is then used for subsequent steps while the [2-(2-chlorophenyl)-1,3-thiazol-4-yl]methanol portion is converted to [2-(2-chlorophenyl)-1,3-thiazol-4-yl]carboxyaldehyde via standard oxidation conditions.
Reaction SMILES: C([O:5][C:6]([CH:8]1[NH:12][CH:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]2([C:25]3[C:20](=[CH:21][C:22]([Cl:27])=[C:23]([F:26])[CH:24]=3)[NH:19][C:18]2=[O:28])[CH:9]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=1[F:36])=[O:7])(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:27][C:22]1[CH:21]=[C:20]2[NH:19][C:18](=[O:28])[C:10]3([CH:9]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=4[F:36])[CH:8]([C:6]([OH:7])=[O:5])[NH:12][CH:11]3[CH2:13][C:14]([CH3:15])([CH3:16])[CH3:17])[C:25]2=[CH:24][C:23]=1[F:26]
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)c(F)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)c(F)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-5-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester (1.8 g, 3.4 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (7 mL). The reaction mixture was stirred at room temperature for 18 h, then concentrated. The residue was then triturated with ethyl ether hexanes, concentrated, dried in vacuo to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-5-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid as a off white solid (2 g, 93%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10]O)[C:5]=2[CH:6]=1.C(=O)=O>[OH-].[Na+]>[CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10][C:7]3[C:5]4[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=4[NH:9][CH:8]=3)[C:5]=2[CH:6]=1
Reactant: OCc1c[nH]c2ccccc12
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Product: c1ccc2c(Cc3c[nH]c4ccccc34)c[nH]c2c1
Yield: 77.7 %

Procedure:
Part (a). Indole-3-carbinol (1.0 g, 6.79 mmol) in 10% aqueous NaOH solution (100 mL) was refluxed for 1 h. The solution was cooled, neutralized with carbon dioxide and the white precipitate was collected by filtration, which was then crystallized from toluene to yield 3,3′-Diindolylmethane as a white solid (0.65 g, 77%): 1H NMR (300 MHz, CDCl3) δ 4.26 (s, 2, CH2), 6.94 (m, 2, PyH), 7.11 (m, 2, ArH), 7.21 (m, 2, ArH), 7.36 (m, 2, ArH), 7.64 (m, 2, ArH), 7.86 (br.s, 2, NH).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH3:33])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:9]2[CH2:10][CH2:11][C:6]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]#[C:32][CH3:33])=[CH:27][CH:28]=3)(=[O:22])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[CH:18][CH:17]=1
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(Br)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(Br)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-(4-Bromo-benzyl)-4-(4-but-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid was prepared starting from 1-(4-bromo-benzyl)-4-(4-but-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid ethyl ester (1.36 g, 2.54 mmol) dissolved in THF:methanol (100:50 ml) and 10 N NaOH (15 ml). The reaction mixture was stirred at room temperature for 24 hrs. The reaction mixture was then concentrated and residue was cooled and neutralized with concentrated HCl. The separated solid was extracted with chloroform:methanol (3:1) (300 ml) and washed with water. The chloroform layer was dried and concentrated. The product was crystallized from methanol. Yield 800 mg (62%); off white solid; mp 197° C.; MS: 507.9 (M+H)+