Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.[NH2:33][C:34]1[CH:55]=[CH:54][C:53]([N:56]2[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]2)=[CH:52][C:35]=1[C:36]([NH:38][C:39]1[CH:43]=[CH:42][N:41]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[C:46]([CH3:51])[CH:45]=2)[N:40]=1)=[O:37]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:51][C:46]1[CH:45]=[C:44]([N:41]2[CH:42]=[CH:43][C:39]([NH:38][C:36]([C:35]3[CH:52]=[C:53]([N:56]4[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]4)[CH:54]=[CH:55][C:34]=3[NH:33][C:14]([C:13]3[CH:12]=[C:11]([CH:19]=[CH:18][CH:17]=3)[CH2:10][S:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:20])=[O:16])=[O:37])=[N:40]2)[CH:49]=[CH:48][C:47]=1[CH3:50]
Reactant: Cc1ccc(-n2ccc(NC(=O)c3cc(N4CCCCC4)ccc3N)n2)cc1C
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(-n2ccc(NC(=O)c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)OC(C)(C)C)c3)n2)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid (167 mg, 0.56 mmol, 1.10 equiv) in dichloromethane (10 mL), EDC.HCl (148 mg, 0.77 mmol, 1.50 equiv), 4-dimethylaminopyridine (95 mg, 0.77 mmol, 1.50 equiv), and 2-amino-N-(1-(3,4-dimethylphenyl)-1H-pyrazol-3-yl)-5-(piperidin-1-yl)benzamide (200 mg, 0.51 mmol, 1.00 equiv). The resulting solution was stirred for 4 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (10:1) to yield 150 mg (44%) of product as a green solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.C(O)(C(F)(F)F)=O.[CH3:20][O:21][C:22](=[O:47])[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH:29][C:30]1[CH:46]=[CH:45][C:33]([C:34]([NH:36][NH:37]C(OC(C)(C)C)=O)=[O:35])=[CH:32][CH:31]=1)=[O:28]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:37][NH:36][C:34]([C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][C:22]([O:21][CH3:20])=[O:47])=[CH:46][CH:45]=1)=[O:35]
Reactant: COC(=O)CCCCC(=O)Nc1ccc(C(=O)NNC(=O)OC(C)(C)C)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCCCC(=O)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 82 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid in the presence of 5% TFA was added tert-butyl 2-{4-[(6-methoxy-6-oxohexanoyl)amino]benzoyl)hydrazinecarboxylate. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 70° C. for 15 hrs gave 496 mg of the title compound (82%) as a yellow solid in 99.5% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH:1]([N-]C(C)C)([CH3:3])[CH3:2].[Li+].[CH3:9][O:10][C:11]([C:13]1([CH:20]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:17]([CH3:18])=[CH:16][C:15](=[O:19])[NH:14]1)=[O:12].Cl[Si](C)(C)C.C(Br)C=C>O1CCCC1>[CH3:9][O:10][C:11]([C:13]1([CH:20]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:29])[CH3:30])[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:17](=[CH2:18])[CH:16]([CH2:3][CH:1]=[CH2:2])[C:15](=[O:19])[NH:14]1)=[O:12]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C1(C(O[Si](C)(C)C(C)(C)C)C2CCCCC2)NC(=O)C=C1C
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC1C(=C)C(C(=O)OC)(C(O[Si](C)(C)C(C)(C)C)C2CCCCC2)NC1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
Lithium diisopropylamide solution (0.695 M solution in tetrahydrofuran, 5.66 ml, 3.93 mmol, 1.0 equiv) was added dropwise via syringe to a stirred solution of 2-[(tert-butyl-dimethyl-silanyloxy)-cyclohexyl-methyl]-3-methyl-5-oxo-2,5-dihydro-1H-pyrrole-2-carboxylic acid methyl ester (1.5 g, 3.93 mmol, 1.0 equiv) in tetrahydrofuran (45 ml) at −78° C. The reaction mixture was stirred at −78° C. for 30 min. Chlorotrimethylsilane (0.5 ml, 427 mg, 3.93 mmol, 1.0 equiv) was added and the resultant solution was stirred at −78° C. for 3 h. Another equiv of lithium diisopropylamide solution (0.695 M solution in tetrahydrofuran, 5.66 ml, 3.93 mmol, 1.0 equiv) was added dropwise at −78° C. The reaction mixture was stirred −78° C. for 30 min. Allyl bromide (0.68 ml, 0.951 g, 7.86 mmol, 2.0 equiv) was added dropwise via syringe at −78° C. The reaction mixture was stirred at −78° C. for 2 h. A buffer solution (pH=7, 100 ml) was added at −78° C. The mixture was extracted with ethyl acetate (50 ml×3). The combined organic layers were dried over sodium sulfate and the solids were filtered. The filtrate was concentrated. The residue was purified by flash column chromatography (10% ethyl acetate-hexanes initially, grading to 20% ethyl acetate-hexanes) to furnish 4-allyl-2-[(tert-butyl-dimethyl-silanyloxy)-cyclohexyl-methyl]-3-methylene-5-oxo-pyrrolidine-2-carboxylic acid methyl ester (0.757 g, 46%) as a white solid.
Reaction SMILES: COC([CH:5]1[C:14]2[N:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)=O.[OH-].[Na+]>>[CH3:15][C:11]1[CH:12]=[N:13][C:14]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: COC(=O)C1CCCc2cc(C)cnc21
Agent: [Na+]
Agent: [OH-]
Product: Cc1cnc2c(c1)CCCC2
Reaction time: 4 h

Procedure:
A solution of 15 % n-butyl lithium in hexane (51 ml. ca. 0.12 m) was added portionwise to a solution of 3-methyl-5,6,7,8-tetrahydroquinoline (14.7 g., 0.1 m) in ether (100 ml.) and the mixture allowed to stand at room temperature for 1 hour and then added dropwise to a cooled, stirred solution of methylchloroformate (9.45 g., 0.1 m) in ether (100 ml.). The mixture was stirred at 50° C for 1 hour. The reaction mixture was diluted with water (20 ml.) and then treated with 2N HCl until acidic. The ethereal solution was separated and washed with 2N HCl (2 × 25 ml.). The combined aqueous washings were extracted with ether and the ethereal extracts discarded. The aqueous solution was adjusted to pH 9.0 with Na2C03 and extracted with chloroform (3 × 50 ml.) and the combined extracts dried and evaporated to give a pale yellow oil (16 g) which on GLC examination (3% SE30) showed a mixture of unreacted tetrahydroquinoline (45%), the title compound (23%) and the 8,8-dicarboxylic ester (20%). The mixture was treated with 10% sodium hydroxide (75 ml.). and heated at reflux with stirring for 4 hours, cooled and extracted with ether (3 × 50 ml.). The combined ethereal extracts were dried, evaporated and distilled to give unreacted 3-methyl-5,6,7,8-tetrahydroquinoline (7 g.) b.p. 116°/18 mm Hg. The basic solution was adjusted to pH 8.5-9.0 with concentrated HC1 and evaporated to dryness and the residue treated with methanol previously saturated with dry HCl (50 ml.) and allowed to stand at room temperature for 5 hours. The solvent was removed and the residue dissolved in water (20 ml.) and extracted with ether (2 × 50 ml.). The aqueous solution was adjusted to pH 9.0 with Na2CO3 and extracted with chloroform (3 × 25 ml.) and the combined extracts dried and evaporated to give the title compound (3 gm.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[N+:5]([O-])=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]=12.P(Cl)(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]=12
Reactant: CC(C)Oc1cc(Cl)c2c([n+]1[O-])CCC2
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Product: CC(C)Oc1cc(Cl)c2c(n1)CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
To a solution of 4-chloro-2-isopropoxy-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (0.079 g, 0.35 mmol) in methylene chloride (5 mL) was added phosphorous trichloride (0.096 g, 0.70 mmol). The mixture stirred at rt for 30 min. After this time, the mixture was quenched with a saturated solution of NaHCO3 and extracted with methylene chloride. The organic layer were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.057 g, 77%) as a clear oil. MW=211.69. 1H NMR (CDCl3, 300 MHz) δ 6.47 (s, 1H), 5.27-5.18 (m, 1H), 3.01-2.84 (m, 4H), 2.11 (quin, J=7.5 Hz, 2H), 1.31 (d, J=6.0 Hz, 6H); APCI MS m/z 212 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[S:14]([O-:17])([O-:16])=[O:15].[Na+:18].[Na+]>C(O)C>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([NH:4][CH2:3][CH2:2][S:14]([O-:17])(=[O:16])=[O:15])=[CH:6][CH:7]=1)([O-:13])=[O:12].[Na+:18]
Reactant: O=[N+]([O-])c1ccc(NCCBr)cc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(NCCS(=O)(=O)[O-])cc1
Yield: 86 %

Procedure:
661 g (2.7 mol) of (2-bromoethyl)(4-nitrophenyl)amine (7) were partially dissolved in 3.7 L of 96% ethanol. At about 75-80° C., aqueous sodium sulfite solution (820 g, 6.5 mol of Na2SO3 in 2.4 L of water) was added. The mixture was stirred at reflux for 11 hours. The resulting mixture was filtered while boiling and the filtrate was allowed to cool. A yellow precipitate formed, which was filtered off by suction and washed with acetone. After drying, 623 g of product were isolated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH:12]([C:14]1[NH:18][C:17]([CH:19]([CH3:21])[CH3:20])=[C:16]([C:22]([OH:24])=[O:23])[C:15]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:14]1[NH:18][C:17]([CH:19]([CH3:21])[CH3:20])=[C:16]([C:22]([OH:24])=[O:23])[C:15]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)c1[nH]c(C=O)c(-c2ccccc2)c1C(=O)O
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: CC(C)c1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(-c2ccccc2)c1C(=O)O
Yield: 58.4 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (170 mg, 0.8 mmol) was condensed with 5-formyl-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid (205 mg) using method D to give 210 mg (58%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]1[S:5][C@@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[C@H:3]2[NH:13][C:14]([NH:16][C@@H:2]12)=[O:15].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[C:50]([NH:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][NH2:66])([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51]>CN(C=O)C>[C:50]([NH:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][NH:66][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][C@H:4]1[C@@H:3]2[C@@H:2]([NH:16][C:14]([NH:13]2)=[O:15])[CH2:1][S:5]1)([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51]
Reactant: CC(C)(C)OC(=O)NCCOCCOCCN
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCOCCOCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
A solution of vitamin H (Biotin) (2.2 g, 9 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (3 g, 8 mmol), and DIPEA (1.8 mL, 10 mmol) in DMF (100 mL) was stirred for 10 minutes at room temperature before being adding dropwise to a solution of N-Boc-3,6-dioxaoctane-1,8-diamine (1.5 g, 6 mmol, 1). The reaction mixture was stirred for 1 hour at room temperature, after which the DMF was removed in vacuo to give an oily residue, which was purified by flash silica gel column chromatography (CH2Cl2/CH3OH, 25/1, v/v) to afford N-Boc-N′-biotinyl-3,6-dioxaoctane-1,8-diamine (2.0 g, 90%). 1H NMR (300 MHz, CD3OD): δ 4.5 (m, 1H), 4.3 (m, 1H), 3.6 (s, 4H), 3.54 (tt, 4H), 3.39 (t, 2H), 3.26 (t, 2H), 2.9 (dd, 1H), 2.7 (d, 1H), 2.2 (t, 2H), 1.7-1.5 (m, 8H), 1.4 (s, 9H); MALDI HRMS: m/z 497.2416 [M+Na+]. Calcd for C21H38N4NaO6S 497.2410.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=O)[C:7]3=[C:8]2[C:3](=[C:4]([NH2:16])[CH:5]=[CH:6]3)[CH:2]=1)=[O:12].Cl.[NH2:18][OH:19]>N1C=CC=CC=1>[NH2:16][C:4]1[CH:5]=[CH:6][C:7]2[C:14](=[O:13])[N:18]([OH:19])[C:11](=[O:12])[C:9]3[C:8]=2[C:3]=1[CH:2]=[CH:1][CH:10]=3
Reactant: Nc1ccc2c3c(cccc13)C(=O)OC2=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Nc1ccc2c3c(cccc13)C(=O)N(O)C2=O
Yield: 97.4 %

Procedure:
4-Amino-1,8-naphthalic anhydride (0.2 g, 0.9 mmol) and hydroxylamine hydrochloride (0.1 g, 1.4 mmol) were reacted in pyridine (20 mL) following the procedure of Example 1 to give 0.2 g of the title compound, mp >360° C.;
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: Brc1ccccn1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Product: c1ccc(COc2ccc(Nc3ccccn3)cc2)cc1
Reaction time: 1 h

Procedure:
A mixture of 19.93 g. of 4-benzyloxyaniline and 4.77 ml. of 2-bromopyridine was stirred and gradually heated over a period of 21/2 hours to 150°C. The mixture was held at 160°C. for 1 hour and at 130°C. for one and three-quarters hours, and then steam distilled. The residue was filtered and the filtrate made alkaline. The combined solid products were recrystallized from cyclohexane to give N-(2-pyridyl)-4-benzyloxyaniline, tan prisms, m.p. 110°-111.5°C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C1COCC1>[CH3:20][S:21]([O:9][CH2:8][C:6]1[CH:5]=[CH:4][C:3]([N+:10]([O-:12])=[O:11])=[C:2]([CH3:1])[N:7]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(CO)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(COS(C)(=O)=O)ccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
(6-Methyl-5-nitropyridin-2-yl)methanol (12 g, 71 mmol), and triethylamine (9.4 g, 93 mmol) in THF (300 mL) was chilled in an ice bath to 10° C. and methanesulfonyl chloride (9.0 g, 79 mmol) was added dropwise and the solution was stirred for one hour, then filtered to remove triethylamine HCl, and the solvent was removed under reduced pressure on the rotovap (with the bath temperature at 35° C.) and (6-methyl-5-nitropyridin-2-yl)methyl methanesulfonate (17 g, 97%), a brown oil which was directly used as such. 1HNMR (CDCl3, 400 MHz) δ 2.87 (s, 3H), 3.16 (s, 3H), 5.83 (s, 2H), 7.55 (d, J=8.34, 1H), 8.38 (d, J=8.34, 1H); Exact mass calculated for C8H10N2O5: 246.03. found: 247.10 MS m/z (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][CH2:8][C@@H:9]([NH:20]C(=O)OC(C)(C)C)[CH2:10][N:11]2[CH2:18][CH:17]3[O:19][CH:13]([CH2:14][NH:15][CH2:16]3)[CH2:12]2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:31][CH2:32][N:33]1[CH:37]=[CH:36][CH:35]=[CH:34]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:20][C@@H:9]([CH2:10][N:11]1[CH2:18][CH:17]2[O:19][CH:13]([CH2:14][N:15]([CH2:31][CH2:32][N:33]3[CH:37]=[CH:36][CH:35]=[CH:34]3)[CH2:16]2)[CH2:12]1)[CH2:8][O:7][C:6]1[CH:28]=[CH:29][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: BrCCn1cccc1
Reactant: CC(C)(C)OC(=O)N[C@H](COc1ccc(C#N)cc1)CN1CC2CNCC(C1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OC[C@@H](N)CN2CC3CN(CCn4cccc4)CC(C2)O3)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.7 %

Procedure:
A mixture of tert-butyl (1S)-2-(4-cyanophenoxy)-1-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-ylmethyl)ethylcarbamate (Preparation J; 100.62 mg, 0.25 mmol), 1-(2-bromoethyl)pyrrole (52.21 mg, 0.30 mmol) and TEA (37.9 mg, 0.375 mmol) in DMF (2.5 mL) was stirred at rt for 2 days and then at 50° C. for 1 day. The solvent was evaporated and the resulting residue dissolved in ethyl acetate (0.5 mL). Ethyl acetate saturated with gaseous hydrochloric acid (2 mL) was added, and the reaction mixture stirred for 1.5 h at rt. The solvent was evaporated and the resulting residue dissolved in a mixture of MeCN (2.5 mL) and H2O (0.13 mL). Potassium carbonate (100 mg, 0.72 mmol) was added, and the mixture stirred overnight at rt. The mixture was filtered and the filtrate concentrated in vacuo. The resulting crude product was dissolved in DCM (2 mL), which solution was added to a ion-exchange solid-phase extraction plug (CBA, 2 g). After 80 min, the product was eluted with DCM:MeCN (4×2 mL of 4:1), followed by DCM:MeOH:TEA (8:1:1), to give 89.7 mg (90.7%) of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:18][C:17]([C:20]2[S:21][CH:22]=[C:23]([C:25]3[C:26]([O:40][CH:41]4[CH2:44][CH2:43][CH2:42]4)=[C:27]4[C:32](=[CH:33][CH:34]=3)[N:31]([C:35]([O:37][CH3:38])=[O:36])[C@@H:30]([CH3:39])[CH2:29][CH2:28]4)[N:24]=2)([F:19])[CH2:16]1)=O)(C)(C)C>ClCCl>[CH:41]1([O:40][C:26]2[C:25]([C:23]3[N:24]=[C:20]([C:17]4([F:19])[CH2:18][NH:15][CH2:16]4)[S:21][CH:22]=3)=[CH:34][CH:33]=[C:32]3[C:27]=2[CH2:28][CH2:29][C@H:30]([CH3:39])[N:31]3[C:35]([O:37][CH3:38])=[O:36])[CH2:42][CH2:43][CH2:44]1
Reactant: COC(=O)N1c2ccc(-c3csc(C4(F)CN(C(=O)OC(C)(C)C)C4)n3)c(OC3CCC3)c2CC[C@@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1c2ccc(-c3csc(C4(F)CNC4)n3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of (S)-methyl 6-(2-(1-(tert-butoxycarbonyl)-3-fluoro azetidin-3-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.059 g, 0.11 mmol) in dichloromethane (3 mL), and the resulting solution stirred for 2 h at room temperature and was then concentrated under vacuum. The residue was purified by preparative-HPLC with the following conditions (Waters I): Column, XBridge C18, 19×150 mm, 5 um; Mobile phase: water (0.05% ammonium bicarbonate) and acetonitrile (5% to 95% acetonitrile in 8 min; flow rate: 20 mL/min); Detector, UV 220&254 nm. This afforded (S)-methyl 5-cyclobutoxy-6-(2-(3-fluoro azetidin-3-yl)thiazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.025 g, 53%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.20 (d, J=6.40 Hz, 3H), 1.31-1.40 (m, 1H), 1.45-1.55 (m, 1H), 1.55-1.66 (m, 1H), 2.02-2.18 (m, 4H), 2.22-2.31 (m, 1H), 2.49-2.55 (m, 1H), 2.95-3.06 (m, 1H), 3.80 (s, 3H), 4.08-4.20 (m, 3H), 4.28-4.36 (m, 2H), 4.56-4.64 (m, 1H), 7.24-7.27 (m, 1H), 7.67-7.73 (m, 2H). MS (ESI, pos. ion) m/z 432 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:7][CH:6]=[CH:5][N:4]=1.[Br:14]N1C(=O)CCC1=O.O>C1COCC1>[Br:14][C:6]1[CH:7]=[C:8]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:3]([O:2][CH3:1])=[N:4][CH:5]=1
Reactant: COc1ncccc1CC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: COc1ncc(Br)cc1CC(C)(C)C
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
To a solution of 2-methoxy-3-neopentylpyridine (4.22 g) in THF (40 mL) was added N-bromosuccinimide (6.29 g) at room temperature, and the mixture was stirred at 100° C. for 20 min. Water was added to the reaction mixture at room temperature, and the reaction mixture was extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and 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 (NH, hexane) to give the title compound (4.38 g) as a pale-yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.O=[CH:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:7]([CH:4]1[CH2:5][CH2:6][N:1]([CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:2][CH2:3]1)#[N:8]
Reactant: N#CC1CCNCC1
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN1CCC(C#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
A mixture of piperidine-4-carbonitrile (1.10 g, 10 mmol), tert-butyl 2-oxoethylcarbamate (1.59 g, 10 mmol) and sodium triacetoxy borohydride (2.5 g, 12 mmol) in 25 ml of CH2Cl2 was stirred at room temperature overnight. Solvent was evaporated and ethyl acetate was added and washed with water. The solvent was removed in vacuo to provide oil. The crude oil was purified by column chromatography (100% ethyl acetate) to yield colorless oil (2.3 g, 91%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.FC(F)(F)C(O)=O.N>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][NH2:16])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCC1CCN(c2ccc(Br)cn2)CC1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCC1CCN(c2ccc(Br)cn2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 6.9 g (17.95 mmol) of tert-butyl 2-(5′-bromo-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-yl)ethylcarbamate obtained in step 8.1., in 100 ml of dichloromethane, cooled by an ice/water bath, is admixed slowly with 20.47 g (179.54 mmol) of trifluoroacetic acid. Stirring is continued at ambient temperature for 2 hours. The reaction mixture is poured into a mixture of ice-water and 28% aqueous ammonia. The mixture is decanted, the aqueous phase is extracted twice with dichloromethane, and the combined organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][O:18][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(C)Br
Reactant: OCCc1ccc(-c2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)OCCc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Sodium hydride (0.8 g., 80% w/w dispersion in mineral oil) was added to a stirred solution of 2-[4-(4-chlorophenyl)phenyl]-ethanol (5.0 g.) in dimethylformamide (20 ml.). The mixture was stirred at room temperature under nitrogen for 5 hours. Ethyl 2-bromopropionate (3 ml.) was then added and the mixture was stirred at room temperature. After 18 hours the mixture was partitioned between ethyl acetate (100 ml.) and 4-N-hydrochloric acid (100 ml.). The organic phase was separated, washed with water (30 ml.), and evaporated to give ethyl 2-{2-[4-(4-chlorophenyl)phenyl]ethoxy}propionate as an oil (7.0 g.).