Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:11]2[C:20]([CH3:22])([CH3:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:23]([O:25]C)=[O:24])[CH:17]=3)[NH:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:11]2[C:20]([CH3:22])([CH3:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:23]([OH:25])=[O:24])[CH:17]=3)[NH:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)=O)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)Nc1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Yield: 33.1 %

Procedure:
To a mixture of methyl 2-(3-acetamidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (129 mg, 0.37 mmol) in methanol (10 mL) and water (5 mL) was added with a solution of sodium hydroxide (249 mg, 6.22 mmol) in water (5 mL). The resultant mixture was heated to reflux for 1.5 hours. The methanol was removed under vacuum. The residue was acidified with 2 M hydrochloric acid to pH=5-6. The precipitates were collected by filtration, purified by preparative Thin layer chromatography (silica gel, petroleum ether/ethyl acetate=3:1) to afford 2-(3-acetamidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a solid. (41 mg, yield: 33.1%). MS (ES+APCI) M+1=339.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:10][S@](C(C)(C)C)=O)[CH3:9])=[C:4]([F:17])[CH:3]=1.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[C:4]([F:17])[CH:3]=1
Reactant: CC(=N[S@@](=O)C(C)(C)C)c1ccc(Cl)cc1F
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.9 %

Procedure:
To a stirred solution of the crude (S)-N-(1-(4-chloro-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (6.8 g, 24.7 mmol) in THF (200 mL) at −45° C. was added a solution of lithium tri-sec-butylborohydride (L-Selectride, 1.0 M in THF, 62 mL, 61.8 mmol) dropwise. The reaction was slowly warmed to room temperature and stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, and the crude material was purified by flash chromatography (SiO2, 25-70% ethyl acetate in hexanes) to afford the desired product as a viscous oil (5.4 g, 19.5 mmol, 79%).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)=[O:29])=[CH:24][CH:23]=1.[OH-].[Na+]>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][CH:31]=3)=[O:29])=[CH:26][CH:27]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: O=C(c1ccc(O)cc1)c1cccc2ccccc12
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)c3cccc4ccccc34)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A wag treated with (4-Hydroxy-phenyl)-naphthalen-1-yl-methanone from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C30H28O6 [M+NH4]+: 507, [M+H]+485.
Reaction SMILES: CC1C=CC(C)N1C(C1C=[CH:12][C:13]([N:16]2[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=4)=[N:26][CH:25]=3)[CH2:18][CH2:17]2)=[N:14]C=1)=O.[N:38]1[CH:43]=[CH:42]C=C(N2CCC(N)CC2)N=1>>[F:36][C:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:23]([NH:22][CH:19]3[CH2:18][CH2:17][N:16]([C:13]4[N:14]=[N:38][CH:43]=[CH:42][CH:12]=4)[CH2:21][CH2:20]3)=[O:37])=[CH:25][N:26]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: CC1C=CC(C)N1C(=O)c1ccc(N2CCC(NC(=O)c3ccc(-c4cccc(F)c4)nc3)CC2)nc1
Reactant: NC1CCN(c2cccnn2)CC1
Product: O=C(NC1CCN(c2cccnn2)CC1)c1ccc(-c2cccc(F)c2)nc1

Procedure:
6-(3-fluorophenyl)-N-(1-pyridazin-3-ylpiperidin-4-yl)nicotinamide was prepared analogous to N-(1-{5-[(2,5-dimethyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]pyridin-2-yl}piperidin-4-yl)-6-(3-fluorophenyl)nicotinamide, except 1-(pyridazin-3-yl)piperidin-4-amine was used as R—NH2. M+H=378.3 observed, 378.17 expected.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[C:20]([NH:22][C:23]3[O:24][C:25]4[CH:31]=[CH:30][C:29]([O:32][C:33]5[CH:38]=[CH:37][N:36]=[C:35]([C:39](=[O:42])[NH:40][CH3:41])[CH:34]=5)=[CH:28][C:26]=4[N:27]=3)[CH:19]=[CH:18][C:17]=2[Cl:43])[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O>[CH3:41][NH:40][C:39]([C:35]1[CH:34]=[C:33]([O:32][C:29]2[CH:30]=[CH:31][C:25]3[O:24][C:23]([NH:22][C:20]4[CH:19]=[CH:18][C:17]([Cl:43])=[C:16]([O:15][CH2:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:21]=4)=[N:27][C:26]=3[CH:28]=2)[CH:38]=[CH:37][N:36]=1)=[O:42]
Reactant: CNC(=O)c1cc(Oc2ccc3oc(Nc4ccc(Cl)c(OCC5CCN(C(=O)OC(C)(C)C)CC5)c4)nc3c2)ccn1
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc(Oc2ccc3oc(Nc4ccc(Cl)c(OCC5CCNCC5)c4)nc3c2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-{2-Chloro-5-[5-(2-methylcarbamoyl-pyridin-4-yloxy)-benzoxazol-2-ylamino]-phenoxymethyl}-piperidine-1-carboxylic acid tert-butyl ester was dissolved in TFA (2 mL). After stirring for 2 h at RT, the mixture was concentrated in vacuo and taken up into EtOAc and washed with NaOH, then NaHCO3 (sat). The organic layer was dried with Na2SO4, filtered and evaporated. The title compound was obtained after purification by prepatory HPLC as a white solid. MS(MH+)=508.1; Calc'd 507.17 for C26H26ClN5O4.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:8]([O:34][CH3:35])=[C:9]([NH:11][C:12](=[O:33])[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N:20]3[CH:24]=[C:23]([C:25]4[CH:26]=[N:27][C:28]([CH:31]=[CH2:32])=[CH:29][CH:30]=4)[N:22]=[N:21]3)[CH:14]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:41][NH:42][CH3:43]>>[C:1]([C:5]1[CH:6]=[C:7]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[C:8]([O:34][CH3:35])=[C:9]([NH:11][C:12](=[O:33])[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N:20]3[CH:24]=[C:23]([C:25]4[CH:26]=[N:27][C:28]([CH2:31][CH2:32][N:42]([CH3:43])[CH3:41])=[CH:29][CH:30]=4)[N:22]=[N:21]3)[CH:14]=2)[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC
Reactant: C=Cc1ccc(-c2cn(-c3cc(C(=O)Nc4cc(C(C)(C)C)cc(NS(C)(=O)=O)c4OC)ccc3C)nn2)cn1
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4ccc(CCN(C)C)nc4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 163 was prepared from N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(6-vinyl-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzamide (Example 151) and dimethylamine in the same manner as Example 151. ESI MS m/z 606 [C31H39N7O4S+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[O:25]1[CH2:34][CH:26]1[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:34][CH:26]([OH:25])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CO2)cc1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1n(CC(O)Cc2ccccc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 85 °C
Yield: 70.4 %

Procedure:
To a stirred solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (500 mg, 1.4 mmol), prepared as described in Example 1, in 7 mL of DMF was added 2,3-epoxypropylbenzene (0.18 mL, 1.4 mmol) and 0.39 g of K2CO3. The resulting red solution was heated to 85° C. for 27 h and, upon cooling to room temp, the mixture was diluted with 200 mL of ethyl acetate and 200 mL of 1N HCL. The layers were extracted, and the organic layer was washed with 200 mL of saturated aqueous NaCl. The organic layer was dried over MgSO4, filtered and evaporated to a yellow oil. The material was purified by silica gel column chromatography using a gradient of 0-100% ethyl acetate/hexanes to give 484 mg of racemic 7,8-bis(4-chlorophenyl)-2-(2-hydroxy-3-phenylpropyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one as a yellow solid containing 15% starting material 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one. Separation of enantiomers was performed on 200 mg of material using Chiracel OD 5 cm×50 cm 20 micron column, flow rate 50 mL/min isocratic 65% heptane/17.5% ethanol/17.5% methanol, monochrome detection at 220 nm. Fraction A was collected at 49 min post injection to give 47 mg of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one enantiomer A as a yellow solid; Fraction B was collected at 55 min post injection to give 45 mg of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one enantiomer B as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:44]=[CH:43][C:7]([O:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:45][Mg]Br.Cl>O1CCCC1>[OH:3][C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)=[CH:43][CH:44]=1)([CH3:45])[CH3:2]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@@H](Oc3ccc(C(C)=O)cc3)CC2)c2ncnn12
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@@H](Oc3ccc(C(C)(C)O)cc3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
4′-({4-[cis-4-(4-Acetylphenoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.50 g) was dissolved in tetrahydrofuran (2 mL), methylmagnesium bromide (1.8 mL, 1.0 M tetrahydrofuran solution) was added dropwise, and the mixture was stirred at room temperature for 17 hr. Methylmagnesium bromide (1.0 mL, 1.0 M tetrahydrofuran solution) was further added dropwise, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.21 g, 41%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[C:21]([O:25][C:26](=[O:38])[CH2:27][CH2:28][CH2:29][S:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl.C1COCC1.CCOCC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([CH3:16])([CH3:15])[C:12]([O:14][C:34]2[CH:33]=[CH:32][C:31]([S:30][CH2:29][CH2:28][CH2:27][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:38])=[CH:36][CH:35]=2)=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(C)(C)C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)CCCSc1ccc(O)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)CCCSc1ccc(OC(=O)C(C)(C)c2ccc(C(C)(C)C)cc2)cc1
Reaction time: 8 h
Yield: 51.4 %

Procedure:
A mixture of 4-tert-butylphenylisobutyric acid (2.00 g, 0.0091 mol) and thionyl chloride (1.62 g, 0.0136 mol) in 16 ml of CH2Cl2 was allowed to stir overnight under Argon. The volatiles were removed under vacuum and the resulting solid was dissolved into THF (15 mL) and a solution of tert-butyl-4-(4'-hydroxyphenyl)mercaptobutyrate (2.44 g, 0.0091 mol), TEA (2.5 mL) in THF (15 mL) was added dropwise over 10 min. The mixture was stirred for 3 days, diluted with Et2O and extracted with 5% NaHCO3. The organics were washed with H2O, brine and dried (MgSO4). After evaporization the colored oil was separated (HPLC, silica gel 70:30 CH2Cl2 /hexane to CH2Cl2 linear graduent) to give the desired product as an oil (2.20 g, 51.5%). 1H NMR (CDCl3) δ 1.33 (s, 9H), 1.43 (s, 9H), 1.70 (s, 6H), 1.88 (tt, J=7.2 Hz, 2 H), 2.35 (t, J=7.2 Hz, 2H), 2.90 (t, J=7.2, 2H), 6.92 (d, J=8.6 Hz, 2H), 7.32 (d, J=8.6 Hz, 2H), 7.34-7.40 (m, 4H). 13C NMR (CDCl3) δ0 24.50, 26.42, 28.08, 31.31, 33.70, 34.11, 34.39, 46.40, 80.40, 121.92, 125.23, 125.46, 130.82, 133.03, 140.86, 149.58, 149.69, 172.21, 175.34.
Reaction SMILES: C(OC([N:8]1[C@H:17]([C:18]([NH:20][C@H:21]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)[C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=3[C:32]([O:34][CH3:35])=[O:33])[CH2:26][CH2:25]2)=[O:23])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>CCOC(C)=O>[CH2:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][C@@H:17]([C:18]([NH:20][C@H:21]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)[C:22]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=3[C:32]([O:34][CH3:35])=[O:33])[CH2:28][CH2:29]2)=[O:23])=[O:19])[NH:8]1
Reactant: COC(=O)c1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2)CC1

Procedure:
The title compound was prepared according to the procedure described in Preparation XVI by using methyl 2-{4-[(2R)-2-({(3S)-2-[(tert-butyl)oxycarbonyl](3-1,2,3,4-tetrahydroisoquinolyl)}carbonylamino)-3-(4-chlorophenyl)propanoyl]piperazinyl}benzoate (Preparation XVII) (140 mg, 0.21 mmol) and a satd soln of HCl in EtOAc (5 mL). The title compound was isolated by filtration as a white solid, and purified by preparative HPLC (62 mg). MS (ESI, pos.ion) m/z: 561 (M+H). Calc'd for C31H33ClN4O4: 560.22.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:31][CH2:32][CH:33]([OH:45])[CH2:34][N:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36]1>C(Cl)Cl>[CH2:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:43][CH2:44][N:35]1[CH2:34][CH:33]([OH:45])[CH2:32][NH:31][C:7](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
To a solution of picolinic acid (100 mg, 0.81 mmol) in DCM (10 mL), was added EDCI (187 mg, 0.97 mmol) and HOBT (132 mg, 0.98 mmol), which was stirred at 25° C. for 0.5 h before 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (167 mg, 0.81 mmol) was added and the resulting mixture was stirred at 25° C. for 2 h. The solution was concentrated in vacuo and the residue was purified by prep-HPLC to provide the title compound (68 mg, Yield 26.9%). 1H NMR (CD3OD, 400 MHz): δ 8.61 (d, J=3.9 Hz, 1H), 8.49 (brs, 1H), 8.10 (d, J=7.8 Hz, 1H), 8.01-7.92 (m, 1H), 7.56 (dd, J=5.1, 6.8 Hz, 1H), 7.31-7.20 (m, 3H), 7.19-7.13 (m, 1H), 4.44-4.27 (m, 3H), 3.66-3.47 (m, 4H), 3.31-3.12 (m, 4H). LCMS (m/z): 312.1 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]2[N:19]([CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=2)[CH:20]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Reactant: Nc1ccc(Cl)cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(Cl)ccc2n1
Yield: 53 %

Procedure:
As described for Example 1, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (140 mg, 0.5 mmol) was converted, using 2-amino-5-chloropyridine instead of 2-aminopyridine, to the title compound (82 mg, 53%) which was obtained as a yellow gum. MS: m/e=310.3[M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:9]=2[O:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][C:3]=1[S:25]([CH3:28])(=[O:27])=[O:26].[CH3:29][NH2:30].C1COCC1.[BH4-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:22]=[C:21]([CH2:23][NH:30][CH3:29])[CH:20]=[CH:19][C:9]=2[O:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][C:3]=1[S:25]([CH3:28])(=[O:27])=[O:26]
Reactant: CN
Reactant: CC(C)(C)OC(=O)COc1ccc(C=O)cc1-c1ccc(F)c(S(C)(=O)=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CNCc1ccc(OCC(=O)OC(C)(C)C)c(-c2ccc(F)c(S(C)(=O)=O)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Intermediate 29 (270 mg, 0.66 mmol, 1 eq) was stirred with methylamine (1.5 mL of a 0.88 M THF solution, 1.32 mmol, 2 eq.) in MeOH for 2 h. Sodium borohydride (50 mg, 0.66 mmol, 1 eq.) was added, and the resulting mixture was stirred at room temperature for an additional 2 h. Water (3 mL) was added and the MeOH was removed in vacuo. The resulting solution was extracted with EtOAc, dried (Na2SO4), and concentrated in vacuo to give 260 mg (93%) of t-butyl 2-(2-(4-fluoro-3-(methylsulfonyl)phenyl)-4-((methylamino)methyl)phenoxy)acetate (30) as oil.
Reaction SMILES: CC(C)=[O:3].[CH2:5]([C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][CH2:17][CH:18]2[C:21]([NH2:23])=[O:22])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O>O>[C:5]([C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][CH2:17][CH:18]2[C:21]([NH2:23])=[O:22])=[CH:14][CH:13]=1)(=[O:3])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NC(=O)C1CCc2ccc(Cc3ccccc3)cc21
Reactant: CC(C)=O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)C1CCc2ccc(C(=O)c3ccccc3)cc21
Reaction time: 8 h

Procedure:
To 150 ml. of acetone is added 12.5 g. of 6-benzylindan-1-carboxamide, followed by the dropwise addition of a solution of 5 g. of sodium dichromate in 24 ml. of 6N sulfuric acid. After the addition has been completed, the mixture is stirred overnight. Then, 200 ml. of water is added and the acetone is distilled off under reduced pressure. The residue is extracted with ethyl acetate. The extract is washed with water and dried, followed by removal of the solvent by distillation under reduced pressure. The residue is purified by column chromatography (500 g. of silica gel; eluted with a 7:3 solvent mixture of chloroform and acetone) and the resultant crude crystals are recrystallized from benzene. The procedure gives 6-benzoylindan-1-carboxamide as crystals melting at 195°-197° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:34][CH2:33][C:18]3([O:23][CH2:22][C:21](=[O:24])[N:20]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[CH2:19]3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[C].[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:34][CH2:33][C:18]3([O:23][CH2:22][C:21](=[O:24])[N:20]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[CH2:19]3)[CH2:17][CH2:16]2)=[CH:13][CH:14]=1
Reactant: COc1ccc(N2CC3(CCN(c4ccc(OCc5ccccc5)cc4)CC3)OCC2=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(N2CC3(CCN(c4ccc(O)cc4)CC3)OCC2=O)cc1
Yield: 82 %

Procedure:
The benzyloxy compound (529 mg, 1.15 mmol) obtained in (a) was dissolved in a mixed solvent of methanol/tetrahydrofuran (1/1), then 10% palladium-carbon (110 mg, 0.103 mmol) was added thereto and stirred overnight in a hydrogen atmosphere. The reaction solution was filtered through Celite, the Celite was washed with mixed solvent of chloroform/methanol, and the mother liquid was concentrated to obtain the entitled compound (350 mg, 82%) as a violet solid.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[O:25].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N>C(OCC)(=O)C.O.O1CCOCC1.CN(C)C=O>[O:25]=[C:21]1[CH2:22][CH2:23][CH2:24][N:20]1[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: O=C1CCCN1
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2N2CCCC2=O)C1
Temperature: 110 °C
Reaction time: 20 h
Yield: 78.2 %

Procedure:
tert-Butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (328 mg, 1.00 mmol), 2-pyrrolidone (85.1 mg, 1.00 mmol), tripotassium phosphate (318 mg, 1.50 mmol), N,N-dimethylformamide (3 ml), dioxane (3 ml) and 1,2-trans-cyclohexanediamine (0.025 ml) mixture were stirred at room temperature under a nitrogen atmosphere for 5 min. Copper iodide(I) (35.0 mg, 0.184 mmol) was added, and the mixture was stirred at 110° C. under a nitrogen atmosphere for 20 hr. The reaction mixture was poured into water (10 ml) and ethyl acetate (10 ml), and filtered through celite. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (260 mg, 86.4%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:5][C:6]=1[C:7]1[CH:12]=[C:11](F)[CH:10]=[C:9]([Cl:14])[CH:8]=1.BrC1C=C(C(OCC)=O)SC=1Br>>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:14])[CH:8]=1
Reactant: CCOC(=O)c1cc(Br)c(-c2cc(F)cc(Cl)c2)s1
Agent: CCOC(=O)c1cc(Br)c(Br)s1
Product: CCOC(=O)c1cc(Br)c(-c2cccc(Cl)c2)s1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 9A starting with the compound from Example 8A. 125 mg (57% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH2:6][CH2:7][C:8]([CH3:11])(O)[CH3:9].[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](C)([O-])=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:8]([CH3:11])([CH3:9])[CH2:7][CH2:6][O:5]2)=[CH:13][CH:14]=1
Reactant: CC(C)(O)CCOc1cccc(Br)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CC1(C)CCOc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
A solution of 4-(3-bromo-phenoxy)-2-methyl-butan-2-ol (5.741 g, 22.2 mmole) in 45 mL of nitromethane was added dropwise to a suspension of aluminum chloride (4.019 g, 30.1 mmole) in 45 mL of nitromethane. The reaction mixture was stirred at room temperature for two hours and then poured onto 300 mL of ice-water. The pH was adjusted to 2.0 with 10% HCl and the product was extracted with three 100 mL portions of ether. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a purple oil. The product was purified by flash chromatography (SiO2, 1% ethyl acetate in hexanes) to yield 4.667 g of 7-bromo-4,4-dimethyl-chroman as a colorless oil, which contained about 16% of 5-bromo-4,4-dimethyl-chroman.