Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.Cl.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:13]=1.ClCCl>C(=O)(O)[O-].[Na+]>[CH3:8][C:7]1[CH:9]=[C:2]([O:10][S:18]([C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)(=[O:20])=[O:19])[CH:3]=[C:4]([OH:5])[CH:6]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccnc2)c1
Yield: 58.1 %

Procedure:
A mixture of orcinol monohydrate (1.42 g, 0.01 mol) and 3-pyridylsulfonyl chloride hydrochloride (2.13 g, 0.01 mol), as prepared in J. Am. Chem. Soc., 114:4889 (1992), in saturated aqueous sodium bicarbonate (17.5 mL) and dichloromethane (50 mL) was stirred rapidly at ambient temperature for 2 days. The dichloromethane was separated and the aqueous layer was extracted with ethyl acetate (3×25 mL). The ethyl acetate and dichloromethane extracts were combined and washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was recrystallized from ether and hexane, collected by filtration, and dried under high vacuum to give 1.54 g of a white solid (58% yield). 1H-NMR (300 MHz, CDCl3) δ 9.03 (d, 1H), 8.88 (dd, 1H), 8.16 (dt, 1H), 7.5 (m, 1H), 6.57 (d, 1H), 6.42 (s, 1H), 6.32 (t, 1H), 2.24 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.[Li+].CCC[CH2-].[N:13]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:17][CH2:16][CH:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14]1.[I:31][CH2:32]I>C1COCC1>[I:31][CH2:32][C:15]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:16][CH2:17][CH2:18][N:13]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:14]1
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: ICI
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1(CI)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
A solution of diisopropylamine (14.6 mmol, 2.05 mL) in THF (15 mL) was cooled to −78° C. N-butyllithium (1.6 M in hexane) (16 mmol, 10 ml) was added dropwise and the solution was stirred for 30 minutes at 0° C. After cooling to −78° C. a solution of 1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (14.6 mmol, 3.75 g) in 20 ml THF was added and the solution was stirred for 3 h at −78° C. A solution of diiodomethane (16 mmol, 1.3 mL) in THF (10 mL) was added and the solution was stirred for 2 days at room temperature. The reaction was quenched by the addition of water and extracted twice with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude was purified by flash chromatography (heptane/EtOAc: 10 to 50%) yielding the title compound (C1) (4.5 g, 74%). MS (ES) C14H24INO4 requires: 397. found: 420.1 [M+Na]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][CH:10]2O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH:9]=[CH:10]2
Reactant: OC1CCc2c(-c3cccs3)cccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C1=Cc2cccc(-c3cccs3)c2C1
Yield: 96.3 %

Procedure:
A stirred solution of 2.4 g (0.011 mole) of 4-(2-thienyl)-1-indanol and 0.15 g of p-toluenesulfonic acid in 60 mL of toluene was heated under reflux, and the theoretical amount of water by-product was collected in a Dean-Stark trap. The reaction mixture was cooled and washed with two portions of 100 mL each of a 5% aqueous solution of sodium bicarbonate, then with two portions of 50 mL each of water. The organic layer was dried over magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 2.1 g of 7-(2-thienyl)-1H-indene as an oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:9]([OH:17])[CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:19].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9](=[O:17])[C:10]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CSc1cccc(C(O)Cc2ccncc2)c1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CSc1cccc(C(=O)C(=O)c2ccncc2)c1
Reaction time: 12 h
Yield: 5.5 %

Procedure:
To a solution of 1-(3-methylthiophenyl)-2-(4-pyridyl)ethanol (2.5 g, 10.2 mmol) in CH2Cl2 (150 mL) was added a mixture of celite (4.4 g) and pyridinium dichromate (4.4 g, 20.4 mmol). After stirring for 12 h, the mixture was filtered through celite. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with a solvent gradient of 40-50% EtOAc/Hex to provide the title compound (144 mg, 5.5%): 1H NMR (CDCl3): d 8.88 (br d, 2H); 7.85 (s, 1H); 7.78 (d, 2H); 7.67(d, 1H); 7.56 (d, 1H); 7.44 (t, 1H); 2.55 (s, 3H).
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13]OS(C3C=CC(C)=CC=3)(=O)=O)[N:11]=2)=[CH:3][CH:2]=1.[CH2:32]([O:34][C:35](=[O:47])[C:36]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([OH:46])[CH:41]=1)([CH3:38])[CH3:37])[CH3:33].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:32]([O:34][C:35](=[O:47])[C:36]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH2:13][CH2:12][C:10]2[N:11]=[C:7]([C:4]3[CH:5]=[CH:6][C:1]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:2][CH:3]=3)[O:8][C:9]=2[CH3:25])[CH:41]=1)([CH3:38])[CH3:37])[CH3:33]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1cccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)c1

Procedure:
A mixture of the toluene-4-sulfonic acid 2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethyl ester (24 g, 66.9 mmol) and 2-(3-hydroxyphenoxy)-2-methylpropanoic acid ethyl ester (Columbia University WO 9731530) (12.5 g, 55.71 mmol) and Cs2CO3 (22.7 g, 69.6 mmol) was heated at 55° C. in DMF (45 mL) for 18 h. The reaction was partitioned between ethyl acetate (160 mL) and H2O (180 mL), and the aqueous phase extracted with ethyl acetate (150 mL). The combined organic phases were dried (MgSO4) and concentrated under reduced pressure to an oil which was purified by column chromatography (1500 mL SiO2, 10% ethyl acetate/hexanes to 20% ethyl acetate/hexanes) to provide 2-{3-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic acid ethyl ester. Rf=0.63 in 35% ethyl acetate/hexanes; 1H NMR (400 MHz, CDCl3) δ8.03-8.00 (m, 2H), 7.65-7.60 (m, 4H), 7.43 (t, J 7.2 Hz, 2H), 7.34 (tt, J=7.2, 1.2 Hz, 1H), 7.07 (t, J 8.0 Hz, 1H), 6.52 (ddd, J=8.0, 2.4, 1.2 Hz, 1H), 6.43 (t, J=2.4 Hz, 1H), 6.36 (ddd, J=8.0, 2.4, 1.2 Hz, 1H), 4.20 (q, J=6.8 Hz, 2H), 4.18 (t, J=6.4 Hz, 2H), 2.95 (t, J=6.4 Hz, 2H), 2.36 (s, 3H), 1.56 (s, 6H), 1.21 (t, J=6.8 Hz, 3H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].[CH3:13]I.O>CN(C)C=O>[Cl:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: CI
Reactant: O=Cc1ccc(O)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C=O)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To suspension of sodium hydride (2.6 g; 62.6% in oil) in dimethylformamide (80 ml), a solution of 2-chloro-4-hydroxybenzaldehyde (10.0 g) in dimethylformamide (50 ml) was dropped over 15 minutes. The mixture was stirred for 30 minutes. Methyl iodide (4.2 ml) was dropped into the reaction mixture over 10 minutes at 0° C., and stirred for 1 hour. The reaction mixture was poured into water and extracted with hexane/ethyl acetate (1:1) The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the title compound (10.7 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][C:12]2[CH:17]=[C:16](F)[CH:15]=[CH:14][C:13]=2[S:19]([CH3:22])(=[O:21])=[O:20])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:23]1(C(OC(C)(C)C)=O)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][C:12]2[CH:17]=[C:16]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:15]=[CH:14][C:13]=2[S:19]([CH3:22])(=[O:21])=[O:20])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(Nc1cc(F)ccc1S(C)(=O)=O)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1cc(N2CCNCC2)ccc1S(C)(=O)=O)c1cc(Cl)cc(Cl)c1
Yield: 49 %

Procedure:
N-(1-(3,5-Dichlorophenyl)ethyl)-5-fluoro-2-(methylsulfonyl)benzenamine (600 mg, 1.62 mmol), t-butyl piperazine-1-carboxylate (0.29 mmol), N,N-diisopropylethylamine (0.58 mmol) were stirred at 60° C. in dry acetonitrile (20 mL) for 3 days. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 20% ethyl acetate in hexanes to afford the title compound (49% yield). 1H NMR (400 MHz, CDCl3): δ 9.31 (d, 1H), 7.63 (d, 1H), 7.25 (s, 1H), 7.22 (s, 2H), 6.18 (d, 1H), 5.53 (s, 1H), 4.48 (m, 1H), 3.48 (m, 4H), 3.25 (m, 4H), 1.60 (d, 3H), 1.47 (s, 9H); MS (ESI) m/z: Calculated for C19H23Cl2N3O2S: 428.3; Observed: 429.4 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH2:44][C@H:45]1[CH2:50][CH2:49][C@H:48]([CH2:51][C:52]([NH:54][C@H:55]([B:68]2[O:76][CH:75]3[C:70]([CH3:80])([CH:71]4[CH2:77][CH:73]([CH2:74]3)[C:72]4([CH3:79])[CH3:78])[O:69]2)[CH2:56][C:57]2[C:58]([O:66][CH3:67])=[C:59]([CH:63]=[CH:64][CH:65]=2)[C:60]([OH:62])=[O:61])=[O:53])[CH2:47][CH2:46]1>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:44][C@H:45]1[CH2:50][CH2:49][C@H:48]([CH2:51][C:52]([NH:54][C@H:55]([B:68]2[O:76][CH:75]3[C:70]([CH3:80])([CH:71]4[CH2:77][CH:73]([CH2:74]3)[C:72]4([CH3:79])[CH3:78])[O:69]2)[CH2:56][C:57]2[C:58]([O:66][CH3:67])=[C:59]([CH:63]=[CH:64][CH:65]=2)[C:60]([OH:62])=[O:61])=[O:53])[CH2:47][CH2:46]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1c(C[C@H](NC(=O)C[C@H]2CC[C@H](N)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)O
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1c(C[C@H](NC(=O)C[C@H]2CC[C@H](NC(=O)CNC(=O)OC(C)(C)C)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-(tert-butoxycarbonylamino)acetic acid (175 mg) in a flask was added HATU (380 mg) and N-methyl morpholine (0.56 mL). After stirring at RT for 1 hr, this solution was added to 3-((2R)-2-(2-(trans-4-aminocyclohexyl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoic acid from Step 1 of Example 53 (110 mg) in DMF (3 mL). The resultant reaction mixture was stirred at RT overnight. Water was added to the reaction mixture and extracted with EtOAc. The organic phase was dried and concentrated in vacuo to afford the crude product which was used in next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:51])=[C:6]([CH2:8][N:9]([CH3:50])[C:10]([CH:12]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[C:31]([N:35]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[N:30][CH:29]=[CH:28]3)[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH:7]=1.[C:52](Cl)(Cl)=[O:53]>C(#N)C.ClCCl.CN1C(=O)N(C)CCC1>[Br:51][C:5]1[CH:4]=[CH:3][C:2]2=[CH:7][C:6]=1[CH2:8][N:9]([CH3:50])[C:10](=[O:11])[C@H:12]([NH:24][C:25]1[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=1)[C:31]([N:35]([C:36]([O:37][C:38]([CH3:40])([CH3:41])[CH3:39])=[O:42])[C:43](=[O:44])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[N:30][CH:29]=[CH:28]3)[C:13]1[CH:14]=[C:15]([CH3:23])[C:16]([C@@H:19]([CH3:22])[CH2:20][O:21][C:52](=[O:53])[NH:1]2)=[CH:17][CH:18]=1
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)N(C)Cc2cc(N)ccc2Br)ccc1[C@@H](C)CO
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: CN1CCCN(C)C1=O
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1ccc(Br)c(c1)CN(C)C(=O)[C@@H]2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 16.5 %

Procedure:
A solution of 1A (1.173 g, 1.538 mmol) in acetonitrile (8 mL), dichloromethane (8 mL) and DMPU (0.6 mL) was cooled to 0° C. To this solution was added phosgene (20% in toluene, 0.837 mL, 1.692 mmol). The mixture was stirred at 0° C. for 15 min. and then bubbled with Ar for 10 min to remove excess phosgene. The resulting solution was added dropwise over 3 h (via a syringe pump) into a solution of TEA (2.144 mL, 15.38 mmol) in dichloromethane (400 mL) at 40° C. The yellow solution was stirred for an additional 30 min. Reaction mixture was concentrated, suspended in EtOAc (250 mL), washed with water (2×200 mL), brine (1×100 ml) and dried (Na2SO4). EtOAc was removed under reduced pressure and the residue was purified by Isco: (40 g) 50-100% EtOAc/hexanes. Fractions were combined and concentrated under reduced pressure to give product as a mixture of diastereomers. The diastereoisomers were separated by chiral HPLC (Chiral OD 10 um 4.6×250 mm; sol. A heptane; sol. B 50% MeOH-50% EtOH) to give 1B (0.200 g, 0.254 mmol, 33.0% yield): MS (ESI) m/z: 788.1 [M+1]+; Purity 95%; 1H NMR: (400 MHz, CD3OD) δ ppm 8.04 (1H, d, J=5.50 Hz), 7.68 (1H, d, J=6.05 Hz), 7.60 (1H, d, J=9.34 Hz), 7.51 (1H, d, J=6.05 Hz), 7.46 (1H, d, J=7.70 Hz), 7.40 (1H, d, J=8.24 Hz), 7.27 (1H, dd, J=8.79, 2.20 Hz), 7.22 (1H, s), 6.87 (1H, d, J=2.20 Hz), 6.63 (1H, dd, J=8.52, 2.47 Hz), 5.99 (1H, d, J=2.20 Hz), 5.71 (1H, s), 5.35 (1H, d, J=17.04 Hz), 4.65 (1H, t, J=11.27 Hz), 3.95 (1H, dd, J=10.99, 4.40 Hz), 3.65 (1H, s), 3.44-3.53 (1H, m), 3.34 (3H, s), 2.31 (3H, s), 1.31 (3H, d, J=7.15 Hz), 1.27 (18H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:29]3[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=3)[CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(Br)c1)N2
Reactant: OB(O)c1ccc(Cl)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: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-c3ccc(Cl)cc3)c1)N2
Yield: 78.6 %

Procedure:
To a mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (4.0 g, 10.3 mmol), 4-chlorophenylboronic acid (2.1 g, 13.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.1 mmol) in dioxane (10 mL) was added 2 M sodium carbonate solution in water (10 mL, 20 mmol). The resulting mixture was subjected to microwave irradiation for 60 min at 110° C. The mixture was diluted with ethyl acetate (150 mL), washed with saturated aqueous sodium bicarbonate solution (30 mL×2), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) afforded 2-(4′-chloro-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.4 g, 80%) as a white solid: LC/MS m/e calcd for C26H26ClNO2 (M+H)+: 420.96, observed: 420.5.
Reaction SMILES: [Cl-].[C:2]1([CH:8]([O:10][NH3+:11])[CH3:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([C:15]1[N:16]=[C:17]([CH:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:38])[CH2:27][N:28]3[C:32]([CH3:33])=[CH:31][C:30]([C:34]([F:37])([F:36])[F:35])=[N:29]3)[CH2:22][CH2:21]2)[S:18][CH:19]=1)(=O)[CH3:13]>C(O)C>[CH3:33][C:32]1[N:28]([CH2:27][C:26]([N:23]2[CH2:24][CH2:25][CH:20]([C:17]3[S:18][CH:19]=[C:15]([C:12](=[N:11][O:10][CH:8]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH3:9])[CH3:13])[N:16]=3)[CH2:21][CH2:22]2)=[O:38])[N:29]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:31]=1
Reactant: CC(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Reactant: CC(O[NH3+])c1ccccc1
Agent: [Cl-]
Solvent: CCO
Product: CC(=NOC(C)c1ccccc1)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Reaction time: 24 h

Procedure:
At room temperature, (1-phenylethoxy)ammonium chloride (91 mg) and Amberlyst A21 (300 mg) are added to a solution of 1-[4-(4-acetyl-1,3-thiazol-2-yl)piperidin-1-yl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (200 mg) in ethanol. The reaction mixture is stirred for 24 hours, and the solvent is then removed under reduced pressure. The residue is separated by column chromatography (silica gel, ethyl acetate:hexane 0%-100% elution gradient). This gives 2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[N-(1-phenylethoxy)ethanimidoyl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (230 mg, 89%) which consists of an about 9:1 mixture of trans and cis isomers (log P (pH2.7)=4.38 (89%), 4.54 (11%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[CH3:24][C:25]1([CH3:38])[S:30][CH2:29][CH2:28][NH:27][C@H:26]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].CN1CCOCC1>C(Cl)(Cl)Cl.CO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:27]2[CH2:28][CH2:29][S:30][C:25]([CH3:24])([CH3:38])[C@@H:26]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1NCCSC1(C)C
Reactant: O=S(=O)(Cl)c1ccc(O)cc1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a suspension of 20.0 g (0.104 mol) of 4-hydroxybenzenesulfonyl chloride in 200 mL of chloroform was added 28.25 mL (0.114 mol) of bis(trimethylsilyl)acetamide and the reaction was stirred at room temperature for 1 h, after which all of the solids have dissolved. To this mixture was added 20.0 g (0.087 mol) of tert-butyl (3S)-2,2-dimethyl-3-thiomorpholine carboxylate followed by 19.2 mL of 4-methylmorpholine and the reaction was stirred overnight at room temperature. After the addition of 400 mL of methanol to the reaction, the resulting mixture was stirred overnight at room temperature and then concentrated in vacuo. The residue was diluted with ethyl acetate and the organics were washed with water and 5% HCl solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting white solid was washed with ether/hexanes (1:2) and dried in vacuo to give 28.4 g (85%) of tert-butyl (3S)-4-[(4-hydroxyphenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholine carboxylate as a white solid. Electrospray Mass Spec 386.5 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:8])[CH3:9])[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1C
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cnn(C(C)(C)C)c1CBr
Yield: 85.2 %

Procedure:
5-Methyl-1-tert-butyl-1H-pyrazole-4-carboxylic acid, ethyl ester (30 grams, 0.14 mole) and N-bromosuccinimide (25.4 grams, 0.14 mole) were combined in 100 ml of carbon tetrachloride. A heating lamp was turned onto the reaction mixture, and the reaction mixture was refluxed for three hours. The reaction mixture was then cooled and filtered to remove the succinimide. The filtrate was washed with water, washed with saturated brine, and dried over sodium sulfate and filter paper. The solvent was then removed in vacuo, providing 34.5 grams of the 5-(bromomethyl)-1-tert-butyl-1H-pyrazole-4-carboxylic acid, ethyl ester.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1([F:36])[CH2:8][CH:7]([CH2:9][O:10][CH2:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]4)=[C:21]([O:31][CH3:32])[CH:20]=3)[N:15]=[C:14]([C:33](=[O:35])[CH3:34])[CH:13]=2)[CH2:6]1>O1CCCC1>[F:36][C:5]1([F:4])[CH2:8][CH:7]([CH2:9][O:10][CH2:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]4)=[C:21]([O:31][CH3:32])[CH:20]=3)[N:15]=[C:14]([C:33]([OH:35])([CH3:1])[CH3:34])[CH:13]=2)[CH2:6]1
Reactant: C[Mg]Br
Reactant: COc1cc(Nc2nc(COCC3CC(F)(F)C3)cc(C(C)=O)n2)ccc1-n1cnc(C)c1
Solvent: C1CCOC1
Product: COc1cc(Nc2nc(COCC3CC(F)(F)C3)cc(C(C)(C)O)n2)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Methylmagnesium bromide (0.105 mL, 0.31 mmol) was added to an ice-cold solution of 1-(6-(((3,3-difluorocyclobutyl)methoxy)methyl)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)-phenylamino)pyrimidin-4-yl)ethanone (16 mg, 0.03 mmol) in tetrahydrofuran (5 mL) under argon atmosphere. The mixture was stirred for 10 min. Methylmagnesium bromide (0.058 mL, 0.17 mmol) was added and the mixture was stirred for 10 minutes. The reaction was quenched with of ammonium chloride (aq, sat). The mixture was concentrated. The residue was extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC to give the title compound as a dry film (4 mg, 24%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9](/[CH:11]=[N:12]/[CH3:13])=[CH:8][C:6]=2[N:7]=1.[BH4-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1
Reactant: C/N=C/c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
To [1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-meth-(E)-ylidene]-methyl-amine (0.9 g) in methanol (25 ml) and tetrahydrofuran (10 ml) under nitrogen was added sodium borohydride (0.17 g) and molecular sieves. The reaction mixture was stirred at room temperature overnight. The solvents were removed in vacuo, quenched with brine, extracted with dichloromethane, dried (MgSO4) and the solvent removed in vacuo to give a crude product which was purified using flash chromatography to give (2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amine (342 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[NH:13][CH:12]=1)C(OC)=O)=[O:4].[I-].[Na+]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:20]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:10][CH2:5][C:3]([O:2][CH3:1])=[O:4])#[N:21]
Reactant: COC(=O)C(Cc1c[nH]c2ccc(C#N)cc12)C(=O)OC
Agent: [I-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)CCc1c[nH]c2ccc(C#N)cc12
Yield: 80.8 %

Procedure:
To a solution of 1.14 g (3.98 mmol, 1.0 equiv.) of methyl 2-methoxycarbonyl-3-(5-cyano-1H-indol-3-yl)propanoate in 20 mL of pyridine was added 1.19 g (7.96 mmol, 2.0 equiv.) of sodium iodide. The mixture was heated to reflux for sixteen hours. The solution was cooled and diluted with 150 mL of chloroform. The organic layer was washed once with 25 mL of saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was filtered through a plug of silica gel with 1:1 ethyl acetate:hexane to remove colored impurities to provide 0.734 g (81%) of methyl 3-(5-cyano-1H-indol-3-yl)propanoate.