Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][C:19]([CH2:23][NH:24][S:25]([C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=3)(=[O:27])=[O:26])=[CH:20][CH:21]=2)[CH:16]=[N:15]1>>[Cl:8][C:7]1[C:2]([N:24]([CH2:23][C:19]2[CH:18]=[C:17]3[C:22](=[CH:21][CH:20]=2)[N:14]([CH3:13])[N:15]=[CH:16]3)[S:25]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][CH:37]=2)(=[O:27])=[O:26])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(cnn3C)c2)cc1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(cnn3C)c2)c2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 4-(N-((1-methyl-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-1 of Example 3).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[Cl:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[H][H]>C1COCC1>[CH2:1]([O:8][CH2:9][CH2:10][NH:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[Cl:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cl)c(NC(=O)COCc2ccccc2)c1
Reactant: [H][H]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Cl)c(NCCOCc2ccccc2)c1
Yield: 101.7 %

Procedure:
2-Benzyloxy-N-(2-chloro-5-methoxy-phenyl)acetamide (2) (18.9 g, 62.0 mmol) in THF (100 mL) was stirred and lithium aluminum hydride (4.9 g, 130.0 mmol) was added slowly over 15 min. There was a rapid evolution of hydrogen gas as the first of the lithium aluminium hydride was added. The reaction was then heated to reflux for 4 h and allowed to stand at RT over the weekend. The reaction was then quenched by the dropwise addition of water (50 mL) to the stirred solution. There was a violent evolution of hydrogen causing the reaction mixture to reflux. The reaction was then concentrated in vacuum to a slurry. Water (200 mL) and ethyl acetate (200 mL) were added and the mixture vigorously shaken. The reaction was then filtered through celite to remove the precipitated aluminium hydroxide and the ethyl acetate solution was separated, dried over magnesium sulfate and concentrated in vacuo to afford 18.4 g (quantitative) of (2-Benzyloxy-ethyl)-(2-chloro-5-methoxyphenyl) amine (3) as a gum. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 43.3, 55.3, 68.2, 73.0, 98.1, 101.8, 111.6, 127.6, 127.7, 128.4, 129.3, 137.9, 144.8, and 159.5.
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].F[C:11]1[CH:12]=[C:13]([C:19]([CH3:34])([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:14]=[CH:15][C:16]=1[CH:17]=O.O>CS(C)=O>[C:30]([O:29][C:27](=[O:28])[C:19]([C:13]1[CH:14]=[CH:15][C:16]2[CH:17]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[S:3][C:11]=2[CH:12]=1)([CH3:34])[C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])([CH3:31])([CH3:32])[CH3:33]
Reactant: CCOC(=O)CS
Reactant: CC(C)(C)OC(=O)C(C)(C(=O)OC(C)(C)C)c1ccc(C=O)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cc2ccc(C(C)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2s1
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.19 g, 4.75 mmol) was suspended in DMSO (2.5 mL) and ethyl mercaptoacetate (0.28 mL, 2.54 mmol) was added portionwise using a water bath to moderate the exotherm. On complete addition, the water bath was removed and stirring continued for 15 minutes. A solution of di-tert-butyl (3-fluoro-4-formylphenyl)(methyl)malonate (0.81 g, 2.30 mmol) in DMSO (0.5 L) was added in one portion. The orange solution was warmed with a heat gun to give a dark brown solution. H2O was added (150 mL) and the products were extracted into EtOAc (2×100 mL). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by MPLC gave the desired product (pale yellow solid). 1H NMR (CDCl3) δ 8.01 (s, 1H), 7.88 (d, J=1.8 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.48 (dd, J=8.4, 1.8 Hz, 1H), 4.39 (q, J=7.2 Hz, 2H), 1.84 (s, 3H), 1.47 (s, 18H), 1.40 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][C:16]([CH3:29])([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][C:16]([CH3:29])([C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=1)[CH2:15][CH:12]1[CH2:14][CH2:13]1)=[O:6]
Reactant: CC(CN)(CC1CC1)c1cnc(C(F)(F)F)nc1
Reactant: O=C(O)c1cccc(F)c1Cl
Product: CC(CNC(=O)c1cccc(F)c1Cl)(CC1CC1)c1cnc(C(F)(F)F)nc1

Procedure:
From 2-chloro-3-fluorobenzoic acid and 3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[O:14])([O-:3])=[O:2].[CH2:15](O)[CH2:16][CH2:17][OH:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]12[O:18][CH2:17][CH2:16][CH2:15][O:14]1)([O-:3])=[O:2]
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C1=O
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2C12OCCCO2

Procedure:
A mixture of 5-nitroisatin (5.00 g, 26.0 mmol), 1,3 propandiol (4.76 mL , 65 mmol, 2.5 eq) and p-toluenesulfonic acid mono-hydrate (0.989 g, 5.2 mmol, 0.2 mol %)) in benzene (500 mL) was refluxed with a Dean Stark Trap for 23 hr. The benzene was decanted off and concentrated. The crude product was purified on Biotage KP silica gel eluting with 50/50 petroleum ether/EtOAc to give the title compound as an off white solid (1.78 g, 27% yield). NMR (300 Mz, DMSO-d6): consistent.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4](=[O:10])/[CH:5]=[CH:6]/[C:7](=[O:9])[CH3:8])[CH3:2].[BH4-].[Na+]>CO>[CH2:11]([N:3]([CH2:1][CH3:2])[C:4](=[O:10])/[CH:5]=[CH:6]/[CH:7]([OH:9])[CH3:8])[CH3:12]
Reactant: CCN(CC)C(=O)/C=C/C(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCN(CC)C(=O)/C=C/C(C)O

Procedure:
To (E)-N,N-diethyl-4-oxo-2-pentenamide (0.73 g, 4.31 mmol) in methanol (10 ml) cooled to 0° C. is added sodium borohydride (0.18 g, 4.75 mmol) under nitrogen stirred for minutes, quenched with excess water, and extracted with ethyl acetate (3×50 ml). The organic extracts are combined, washed with saline (50 ml), dried over sodium sulfate, concentrated in vacuo to give the title compound, NMR (CDCl3) 6.89, 6.42, 4.49, 3.41, 2.51, 1.33, 1.17.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([O:11][CH3:12])[CH:10]=1)[NH:7][C:6](=[O:13])[C:5]2=[O:14].CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:26](O)[CH2:27][OH:28]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([O:11][CH3:12])[CH:10]=1)[NH:7][C:6](=[O:13])[C:5]12[O:28][CH2:27][CH2:26][O:14]1
Reactant: OCCO
Reactant: COc1cc(Br)cc2c1NC(=O)C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cc(Br)cc2c1NC(=O)C21OCCO1
Yield: 5 %

Procedure:
A stirred mixture of 5-bromo-7-methoxyindoline-2,3-dione (3.6 g, 14 mmol), p-TSA (1.14 g, 6 mmol) and toluene (100 mL) was refluxed using a Dean-Stark apparatus for 0.2 h. Ethylene glycol (9.3 g, 150 mmol, 10.7 eq.) was added and refluxed using a Dean-Stark apparatus for another 2 hours. The mixture was cooled and concentrated to 20 mL. EtOAc (100 mL) was added, washed with water (20 mL), brine (50 mL×2), dried over Na2SO4, filtered and concentrated under reduced pressure. Purified by column (CH2CL2/EtOAc=8:1) to give the desired product as a light brown solid (0.21 g, crude, 5%). 1H NMR (400 MHz, DMSO-d6): δH 10.66 (s, 1H), 7.48 (s, 1H), 7.26-7.27 (m, 1H), 7.13-7.14 (m, 1H), 4.25-4.31 (m, 4H), 3.86 (s, 3H). MS (ESI) m/e [M+1]+ 300/302.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[N:13]3[N:14]=[C:15]([O:22][CH2:23]C4N=CN(C)N=4)[C:16]4[C:21]([C:12]3=[N:11][N:10]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:5]=1.[CH3:30][N:31]1[C:35](CO)=[N:34][CH:33]=[N:32]1>>[CH3:1][O:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[N:13]3[N:14]=[C:15]([O:22][CH2:23][C:35]4[N:31]([CH3:30])[N:32]=[CH:33][N:34]=4)[C:16]4[C:21]([C:12]3=[N:11][N:10]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:5]=1
Reactant: COCc1cc(-c2nnc3c4ccccc4c(OCc4ncn(C)n4)nn23)no1
Reactant: Cn1ncnc1CO
Product: COCc1cc(-c2nnc3c4ccccc4c(OCc4ncnn4C)nn23)no1

Procedure:
The title-compound was prepared from the product of Example 116 part a and 1-methyl-1,2,4-triazole-5-methanol (prepared using the conditions of Itoh and Okongi, EP-A-421210) in a similar manner to Example 98, mp 206-207.56° C.; 1H NMR (360 MHz, CDCl3) δ 3.53 (3H, s, CH3), 4.12 (3H, s, CH3), 4.73 (2H, s, CH2), 5.87 (2H, s, CH2), 7.20 (1H, s, ArH), 7.42 (1H, s, ArH), 7.93 (1H, m, ArH), 8.06 (1H, m, ArH), 8.30 (1H, d, J=7.7 Hz, ArH), 8.70 (1H, d, J=7.2 Hz, ArH); MS (ES+) m/e 393 [MH]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1O>>[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[O:29][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Reactant: Oc1ccc(F)cc1F
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(F)cc3F)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 2,4-difluorophenol: ESMS m/e: 511.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)=[O:6].I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([C:28]1[C:33]([CH3:34])=[C:32]([O:35][CH3:36])[C:31]([CH3:37])=[C:30]([CH3:38])[C:29]=1[O:39][CH3:40])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>CN(C)C=O>[CH3:40][O:39][C:29]1[C:30]([CH3:38])=[C:31]([CH3:37])[C:32]([O:35][CH3:36])=[C:33]([CH3:34])[C:28]=1[CH:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]([O:4][CH3:3])=[O:6])=[CH:8][CH:9]=1
Reactant: COc1c(C)c(C)c(OC)c(C(CCCCCCI)c2ccccc2)c1C
Reactant: COC(=O)c1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCCCCC(c2ccccc2)c2c(C)c(OC)c(C)c(C)c2OC)cc1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 98.1 %

Procedure:
A 0.42 g (10×1.05 mmole) quantity of sodium hydride (60%, oily preparation) was added to a solution of 1.52 g (10.0 mmole) of methyl p-hydroxybenzoate in dimethylformamide (15 ml) under ice-cooling, followed by stirring for 5 minutes. The cooling bath was removed, and a solution of 4.80 g (10.0 mmole) of 1-iodo-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-7-phenylheptane in dimethylformamide (15 ml) was added to the mixture. Then, the temperature was raised to 50° C., and stirring was effected for 1 hour. After ice-cooling, dilute hydrochloric acid was added to suspend the reaction, and the product was extracted with isopropyl ether. The isopropyl ether layer was separated out, washed with aqueous sodium chloride solution, dried (magnesium sulfate) and evaporated. The residual solution was chromatographed on a silica gel column to perform purification (elution with hexane/isopropyl ether) to thereby give 4.95 g (98%) of methyl 4-[7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-7-phenylheptoxy]benzoate. Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 14.
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[C:3]([O:5][C@H:6]([O:10][C:11]([O:13]N1C(=O)[C@@H](OC(=O)C2C=CC=CC=2)[C@H](OC(=O)C2C=CC=CC=2)C1=O)=O)[CH:7]([CH3:9])[CH3:8])=[O:4].[NH2:40][CH2:41][CH2:42][CH2:43][P:44]([CH2:47][CH2:48][CH2:49][CH3:50])(=[O:46])[OH:45].C1COCC1>O>[C:3]([O:5][C@H:6]([O:10][C:11]([NH:40][CH2:41][CH2:42][CH2:43][P:44]([CH2:47][CH2:48][CH2:49][CH3:50])(=[O:45])[OH:46])=[O:13])[CH:7]([CH3:8])[CH3:9])(=[O:4])[CH:2]([CH3:1])[CH3:39]
Reactant: CC(C)C(=O)O[C@H](OC(=O)ON1C(=O)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)C1=O)C(C)C
Reactant: CCCCP(=O)(O)CCCN
Solvent: O
Solvent: C1CCOC1
Product: CCCCP(=O)(O)CCCNC(=O)O[C@@H](OC(=O)C(C)C)C(C)C
Temperature: 19 °C
Reaction time: 4 h

Procedure:
To a 3 L three necked round bottom flask fitted with a mechanical stirrer, temperature probe, and nitrogen inlet was added compound (25) (100 mmol), 3-aminopropyl(n-butyl)phosphinic acid (100 mmol), THF (1 L), and water (100 mL). The suspension was stirred under a nitrogen atmosphere at 18-20° C. for 4 h during which time the reaction mixture became homogeneous. The THF was removed in vacuo and the reaction mixture was diluted with methyl tert-butyl ether (250 mL) and washed with 1N HCl (1×500 mL) and water (2×200 mL). The organic phase was separated and concentrated in vacuo to leave a white solid. The solid was purified by flash chromatography to afford the product (39) as a white solid. 1H-NMR (400 MHz, CD3OD): δ 6.74-6.70 (q, J=5.2, 1H), 4.06-3.96 (m, 1H), 3.22-3.21 (m, 2H), 2.547-2.477 (m, 1H), 1.92-1.84 (m, 2H), 1.52-1.48 (s, 3H), 1.142-1.138 (d, J=1.6, 3.0H), 1.124-1.121 (dd, J=1.6, 3.0H). Phosphorus (162 MHz, CD3OD): δ1.04; MS (ESI) m/z 346 (M+H)+)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[C:27]([O:31][C:32](=[O:38])[NH:33][CH2:34][CH2:35][CH2:36]O)([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[C:27]([O:31][C:32](=[O:38])[NH:33][CH2:34][CH2:35][CH2:36][I:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCI
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of triphenylphosphine (28.5 g, 108.6 mmol) and imidazole (7.39 g, 108.6 mmol) in CH2Cl2 (400 mL) at RT, is added iodine (28.92 g, 113.95 mmol) portionwise. To this solution is added a solution of (3-hydroxypropyl)-carbamic acid tert-butyl ester (18.66 g, 106.49 mmol) (Synthesis 1990, 366) in CH2Cl2 (75 mL) dropwise and the mixture allowed to stir at RT for 14 h. The mixture is then filtered and the filtrate concentrated to a crude red oil, which is partitioned between ether and sat. sodium thiosulfate. The aqueous phase is extracted with ether. The combined organic layers are reduced to 200 mL and then filtered through a plug of silica, eluting with ether. Evaporation of solvent affords the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:39])[C:8]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]5[C@H:27]([C:28](C)(C)[O:29][SiH2]C(C)(C)C)[O:26]C(C)(C)[O:24]5)[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:39])[C:8]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([OH:24])[C@H:27]([OH:26])[CH2:28][OH:29])[CH:18]=[CH:17][C:9]=4[C:10]([CH3:15])([CH3:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: CC1(C)O[C@@H](C(C)(C)O[SiH2]C(C)(C)C)[C@@H](COc2ccc3c(c2)C(=O)c2c([nH]c4cc(Br)ccc24)C3(C)C)O1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)c2ccc(OC[C@@H](O)[C@H](O)CO)cc2C(=O)c2c1[nH]c1cc(Br)ccc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
3-Bromo-9-[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy]-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound JJ7-1, 13.7 mg, 0.0223 mmol) was dissolved in THF (0.15 mL) and methanol (0.1 mL), added with 0.5 M sulfuric acid (0.05 mL), and then stirred at 60° C. for 3 hr. After cooling, the reaction solution was added with saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After filtration and the concentration under reduced pressure, the resulting solid was washed with dichloromethane to obtain the title compound (white solid, 8.4 mg, 82%).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)=[N:4][C:3]=1[C:23]([O:25]C)=[O:24].O.[OH-].[Li+].C1COCC1>O>[OH:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)=[N:4][C:3]=1[C:23]([OH:25])=[O:24]
Reactant: COC(=O)c1nc(Cc2ccccc2-c2cccc(C)c2)[nH]c(=O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(-c2ccccc2Cc2nc(C(=O)O)c(O)c(=O)[nH]2)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 38.2 %

Procedure:
In a round-bottomed flask, methyl 5-hydroxy-2-((3′-methylbiphenyl-2-yl)methyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate (30 mg, 85.6 μmol) and lithium hydroxide hydrate (6.5 mg, 155 μmol) were combined with THF (2 ml) and water (1 ml) to give a colorless solution. The mixture was stirred at 50° C. for one day. Amberlyst (15, ion exchange resin) was added, the mixture was stirred for 10 min, filtered and evaporated to dryness. Trituration with EtOAc and hexanes provided the title compound as a white solid (0.011 g; 34%). LCMS: m/z=337 (MH+) 90% pure.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24]C(=O)OC(C)C)[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].CO.C(N(CC)CC)C>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:24])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(-c2ccc3c(c2)[C@H](N)C[C@H](C)N3C(C)=O)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
1-Methylethyl {(2S,4R)-1-acetyl-6-[3,4-bis(methyloxy)phenyl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (for a preparation see intermediate 95) (327 mg, 0.767 mmol) was added to a cold (ice bath) suspension of aluminium chloride (388 mg, 2.91 mmol) in dichloromethane (DCM) (4 mL). The reaction was stirred at approximately 0° C. for 30 min then an extra amount of aluminium chloride (102 mg, 0.767 mmol) was added and the resulting mixture was stirred at approximately 0° C. for 30 min. Aluminium chloride (102 mg, 0.767 mmol) was further added and the resulting mixture was stirred at approximately 0° C. for 30 min. Further Aluminium chloride (102 mg, 0.767 mmol) was added and the resulting mixture was stirred at approximately 0° C. for 30 min. The reaction mixture was then treated with a solution of methanol (0.884 mL) and triethylamine (2.312 mL, 16.59 mmol) and the resulting mixture was stirred further at approximately 0° C. for 20 min then was partitioned between EtOAc (35 mL) and a saturated NaHCO3 aqueous solution (35 mL). The reaction mixture was then filtered through celite and the insoluble were washed with EtOAc (25 mL) and NaHCO3 (25 mL). The filtered aluminum residues were suspended in MeOH and sonicated. The resulting suspension was filtered and the filtrate was concentrated in vacuovacuo. The white solid residue was loaded onto a 10 g SCX cartridge and eluted with MeOH and then with 2M NH3 in MeOH. The methanol fractions were combined and concentrated in vacuo to give (2S,4R)-1-acetyl-6-[3,4-bis(methyloxy)phenyl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (103 mg, 39%) and the combined ammonia fractions were combined to give (2S,4R)-1-acetyl-6-[3,4-bis(methyloxy)phenyl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (71 mg, 27%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[CH3:22][O:23][C:24]1[N:29]=[CH:28][C:27](B(O)O)=[CH:26][N:25]=1>>[F:21][C:4]1[CH:3]=[C:2]([C:27]2[CH:26]=[N:25][C:24]([O:23][CH3:22])=[N:29][CH:28]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: COc1ncc(B(O)O)cn1
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Product: COc1ncc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)cn1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 2-Methoxy-5-pyrimidine boronic acid. MS (M+H) 385.2
Reaction SMILES: Cl[C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].CC1(C)C(C)(C)OB([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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]>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[C:2]=1[C:22]1[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=1)=[O:5]
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Reactant: CCOC(=O)CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)CCNC(=O)c1ccc(-c2c(C=O)cccc2C(F)(F)F)cn1
Temperature: 100 °C

Procedure:
2-Chloro-3-(trifluoromethyl)benzaldehyde (199 mg, 0.96 mmol), ethyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamido)propanoate (410 mg, 1.2 mmol), Pd2(dba)3 (26 mg, 0.03 mmol), and 2M K3PO4 (aq) (1.0 mL, 2.0 mmol) were dissolved in 1,4-dioxane (2.9 mL) and heated to 100° C. After 2.5 h the resulting mixture was concentrated, taken up in DCM and the aqueous layer was extracted with DCM. The combined organics were dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH:1]1([O:7][C:8]([NH:10][CH2:11][C:12]([OH:14])=O)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:15]1[C:25]2[CH:24]=[CH:23][C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[C:20](=[C:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:19]=2[CH:18]=[CH:17][CH:16]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[CH:15]1[C:25]2[CH:24]=[CH:23][C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[C:20](=[C:30]3[CH2:31][CH2:32][N:33]([C:12](=[O:14])[CH2:11][NH:10][C:8](=[O:9])[O:7][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH2:34][CH2:35]3)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: C1=Cc2ccccc2C(=C2CCNCC2)c2ccccc21
Reactant: O=C(O)CNC(=O)OC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1)OC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
86.1 mg (0.428 mmol) of {[(cyclohexyloxy)carbonyl]amino}acetic acid, 176 mg (0.642 mmol) of 4-(5H-dibenzo[a,d][7]annulen-5-ylidene)piperidine and 98.5 mg (0.514 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride were suspended in 10 ml of dichloromethane. 0.086 ml (0.617 mmol) of triethylamine was added to the obtained suspension, and they were stirred at room temperature for 3 hours. The resultant mixture was concentrated under reduced pressure and then ethyl acetate was added to the residue. The resultant mixture was washed with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by the silica gel chromatography (hexane:ethyl acetate=95:5 to 1:4) to obtain the title compound.