Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][NH:3]C(=O)C[Cl:6].[CH3:8][S:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=1[OH:20].S(=O)(=O)(O)O.Cl>C(O)(=O)C.C(O)C>[ClH:6].[NH2:3][CH2:2][C:12]1[CH:13]=[C:14]([C:16]([CH3:17])([CH3:19])[CH3:18])[CH:15]=[C:10]([S:9][CH3:8])[C:11]=1[OH:20]
Reactant: CSc1cc(C(C)(C)C)ccc1O
Reactant: O=C(CCl)NCO
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CC(=O)O
Product: CSc1cc(C(C)(C)C)cc(CN)c1O
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Pulverized N-hydroxymethyl-2-chloroacetamide (3.32 g., 0.027 mole) is added portionwise over 15 minutes to a solution of 2-methylthio-4-(1,1-dimethylethyl)phenol (5.3 g., 0.027 mole) and conc. sulfuric acid (10 ml.) in acetic acid (150 ml.) cooled in an ice bath. The resulting reaction mixture is stirred at 20° C. for 16 hours and then poured into ice-water (1 l.) whereupon a white gum is deposited. The gum is extracted with ether and the etheral extract, washed well with water and saturated brine. Removal of the solvent under reduced pressure leaves a residual solid which is dissolved in ethanol (30 ml.). The resulting solution is treated with 12 N hydrochloric acid (15 ml.) and heated at reflux for 4 hours. Evaporation in vacuo affords a residual solid which is triturated with ether and collected by filtration to give crude 2-aminomethyl-4-(1,1-dimethylethyl)-6-(methylthio)phenol hydrochloride (5.4 g., 76.4%), m.p. 150°-177° C. Two recrystallizations from ether-ethanol (10:1; v:v) followed by recrystallization from 12 N hydrochloric acid provides analytically pure 2-aminomethyl-4-(1,1-dimethylethyl)6-(methylthio)phenol hydrochloride as colorless crystals, m.p. 180°-181.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 83 %

Procedure:
1-(tert-Butoxycarbonyl)-4-[(2-hydroxyphenyl)amino]piperidine (50 mg) was dissolved in N,N-dimethylformamide (1 ml), added with methyl bromoacetate (17 μl) and potassium carbonate (25 mg) and stirred at room temperature for 17 hours. The reaction mixture was added with water (3 ml) and extracted twice with ethyl acetate (3 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: hexane:ethyl acetate=1:1) to obtain 51.8 mg of the title compound. Yield: 83%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]3[CH:19]=[C:20](Br)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([Sn](CCCC)(CCCC)CC=C)[CH2:25][CH2:26]C>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]3[CH:19]=[C:20]([CH2:26][CH:25]=[CH2:24])[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cnc3ccc(Br)cn23)CC1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=CCc1ccc2ncc(C3CCN(C(=O)OC(C)(C)C)CC3)n2c1
Temperature: 25 °C
Yield: 63.8 %

Procedure:
To a solution of 89 mg of 1-(t-butoxycarbonyl)-4-(6-bromo-imidazo [1,2-a]pyridin-3-yl)-piperidine (from Example 274, Step A) and 158 mg tributyl(allyl)tin in 6 mL of toluene was added 5.0 mg of dichlorobis (triphenyl phosphine)-palladium(II). The mixture was refluxed for 8 hours. The reaction was cooled down to r.t. and partitioned between CH2Cl2 and water. Aqueous layer was extracted with CH2Cl2 (3×). The combined organic phase was washed with brine and dried over MgSO4. After concentration, the residue was purified by prep TLC (100% EtOAc) to afford 51 mg of a viscous oil.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([O:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH3:14].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C1COCC1>[Si:29]([O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:17]([CH3:19])([CH3:18])[C:16]([O:15][CH2:13][CH3:14])=[O:20])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CCOC(=O)C(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)CCCCCCO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (32.8 mL) was added to a solution of diisopropylamine (1M in toluene, 11.64 mL) in THF (60 mL) at 0° C. to 5° C. over 15 minutes, and this mixture was stirred for 30 minutes. The reaction mixture was cooled to −78° C. then isobutyric acid ethyl ester (10 mL) was added dropwise over 15 minutes. The mixture was stirred at −78° C. for 1 hour, then (6-bromohexyloxy)-tert-butyldimethylsilane (23 mL) was added dropwise and the reaction mixture was stirred at −78° C. for a further 60 minutes. The cooling bath was removed and the mixture stirred at room temperature overnight before being poured onto a saturated aqueous solution of ammonium chloride (300 mL) and extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with water (250 mL), dried over magnesium sulfate, filtered and evaporated to give the crude product. Purification was by silica gel chromatography eluting with 0-40% ethyl acetate in cyclohexane to afford the subtitled compound as a pale amber liquid. Yield 20 g.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[S:19][C:20]([S:23]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=4)(=[O:25])=[O:24])=[CH:21][CH:22]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:36][CH2:37][C@H:38]([OH:48])[CH2:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=1>>[OH:48][C@H:38]([CH2:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=1)[CH2:37][NH:36][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[S:19][C:20]([S:23]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][N:27]=4)(=[O:25])=[O:24])=[CH:21][CH:22]=3)(=[O:16])=[O:17])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(S(=O)(=O)c4ccc(C(F)(F)F)cn4)s3)cc2)CC1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Product: O=S(=O)(Nc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)cc3)CC2)cc1)c1ccc(S(=O)(=O)c2ccc(C(F)(F)F)cn2)s1

Procedure:
The title compound was prepared from 5-(5-trifluoromethyl-pyridine-2-sulfonyl)-thiophene-2-sulfonic acid [4-(4-oxo-piperidine-1-yl)-phenyl]-amide (which was obtained in Example 229) and 4-((2S)-3-amino-2-hydroxy-propoxyl)-phenol (which was obtained in Example 5) according to the procedure of Example 278 as a grey solid; 1H NMR (300 MHz, DMSO-d6) δ 1.25-1.45 (m, 2H), 1.70-1.95 (m, 2H), 2.50-2.85 (m, 5H), 3.54 (brd, J=12.4 Hz, 2H), 3.65-3.95 (m, 3H), 6.60-6.90 (m, 8H), 7.92 (d, J=1.6 Hz, 1H), 8.41 (d, J=8.3 Hz, 1H), 8.48 (d, J=1.6 Hz, 1H), 8.61 (dd, J=8.3, 2.0 Hz, 1H), 8.89 (s, 1H), 9.23 (s, 1H); MS (ES) m/z: 713.1 (MH+); HRMS Calcd. for C30H32F3N4O7 S3 (MH+): 713.1385. Found: 713.1407.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH:35]1([CH2:38]Br)[CH2:37][CH2:36]1>CN(C)C=O>[CH:35]1([CH2:38][N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][CH:24]([N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:32])[CH2:3][CH2:4]2)=[O:9])[CH2:37][CH2:36]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCC2)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2CC1CC1)N1CCC(N2CCCC2)CC1
Yield: 53 %

Procedure:
The title compound was synthesized in analogy to example 51, from (4,4-difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 169), sodium hydride and cyclopropylmethyl bromide in N,N-dimethylformamide, to give the desired product as a yellow solid (53%).
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]4[CH2:20][CH2:19]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:21]=1.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C@:29]([OH:33])([C:31]#[CH:32])[CH3:30])[N:25]=1>>[CH:18]1([C:12]2[N:8]3[CH2:9][CH2:10][O:11][C:5]4[CH:4]=[C:3]([F:22])[C:2]([C:32]#[C:31][C@@:29]([OH:33])([C:26]5[N:25]=[C:24]([CH3:23])[O:28][N:27]=5)[CH3:30])=[CH:21][C:6]=4[C:7]3=[N:14][C:13]=2[C:15]([NH2:17])=[O:16])[CH2:20][CH2:19]1
Reactant: NC(=O)c1nc2n(c1C1CC1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Product: Cc1nc([C@](C)(O)C#Cc2cc3c(cc2F)OCCn2c-3nc(C(N)=O)c2C2CC2)no1
Yield: 14 %

Procedure:
10-bromo-3-cyclopropyl-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol via General Procedure E to yield 8.2 mg (14%) of 3-cyclopropyl-9-fluoro-10-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-ynyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide.
Reaction SMILES: [NH:1]1[CH2:5][C@H:4]([CH2:6][OH:7])[C@H:3]([CH2:8][OH:9])[CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>CO.O>[OH:9][CH2:8][C@H:3]1[C@@H:4]([CH2:6][OH:7])[CH2:5][N:1]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:2]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC[C@@H]1CNC[C@@H]1CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(OCc1ccccc1)N1C[C@@H](CO)[C@@H](CO)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 23 %

Procedure:
(cis)-3,4-Pyrrolidinediyldimethanol (970 mg, 7.4 mmol) was dissolved in a mixture of MeOH (20 mL) and water (7 mL) and cooled to 0° C. Na2CO3 (1.96 g, 19 mmol) was added followed by benzyl chloroformate (1.15 mL, 8.1 mmol) and the resulting solution was stirred for 4 hours, maintaining the temperature at 0° C. The reaction was concentrated under reduced pressure to remove most of the methanol, and the remaining aqueous solution was extracted twice with EtOAc. The combined organics were washed with brine and dried over sodium sulfate before being concentrated in vacuo. RP-HPLC yielded phenylmethyl (cis)-3,4-bis(hydroxymethyl)-1-pyrrolidinecarboxylate (450 mg, 22%, 1.7 mmol). LCMS: (M+H)+: 266.1.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[N:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25][CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH:23]1[CH2:24][CH2:25][N:26]([C:29]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[N:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:36])[CH3:34])[CH2:27][CH2:28]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(ON)CC1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.200 g, 0.723 mmol, US 2005/20572 A1) in DCM (6.0 mL) was added di-tert-butyl {[4-(aminooxy)piperidin-1-yl]methylylidene}biscarbamate 65 (0.389 g, 1.086 mmol), 1-hydroxybenzotriazole (0.147 g, 1.086 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.208 g, 1.086 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 66 (0.33 g, 74%) as a white solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[O:30][CH2:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][C:26]2([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[O:30][CH2:29]2)[CH2:27][CH2:28]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Yield: 39.7 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.055 g, 0.114 mmol) obtained in Example 125, step 2 and ethanesulfonamide (0.062 g, 0.569 mmol), the title compound (0.026 g, 47%) was obtained.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]1[CH3:20])[CH2:9][CH3:10]>C1C=CC=CC=1>[CH2:8]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:3]([CH2:2][C:1]([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]([CH2:8][CH2:9][CH3:10])[C:12]=2[CH3:20])=[O:7])[C:4]([OH:6])=[O:5])=[C:12]1[CH3:20])[CH2:9][CH3:10]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCn1c(C)cc2ccccc21
Solvent: c1ccccc1
Product: CCCn1c(C)c(C(=O)CC(C(=O)O)c2c(C)n(CCC)c3ccccc23)c2ccccc21
Temperature: 25 °C
Yield: 33.1 %

Procedure:
A stirred solution of 20.0 g (0.204 mole) of maleic anhydride and 70.0 g (0.408 mole) of 1-n-propyl-2-methylindole in 200 ml of benzene was heated at reflux for a period of approximately eighteen hours and then allowed to cool to ambient temperature. The solid which separated from the cooled solution was collected by filtration, washed with fresh chilled benzene and dried in vacuo at 60° C to obtain 30.0 g of 2,4-bis(1-n-propyl-2-methyl-3-indolyl)-4-oxobutanoic acid (Formula VII: R=CH3CH2CH2 ; R1 =CH3 ; Y=H) as a white solid melting over the range 210° to 215° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:14]1[S:15][C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=1.C(N(C(C)C)CC)(C)C>>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][N:11]([C:14]2[S:15][C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: CCOC(=O)c1sc(Br)nc1C
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2CC(NC(=O)OC(C)(C)C)C2)nc1C
Yield: 44.6 %

Procedure:
The same operation as in Example (217a) was performed using 3-tert-butoxycarbonylaminoazetidine (300 mg, 1.74 mmol), ethyl 2-bromo-4-methylthiazole-5-carboxylate (479 mg, 1.92 mmol) and diisopropylethylamine (0.61 mL, 3.48 mmol), to obtain 265 mg of the title compound as a pale yellow solid (45%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][C@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:3][CH:4]=1)[CH3:15]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Reactant: OB(O)c1ccccc1
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: Cc1ccccc1
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 95 °C
Reaction time: 14 h
Yield: 87.4 %

Procedure:
A mixture of (R)-ethyl 4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate (1.5 g, 3.88 mmol), phenylboronic acid (0.710 g, 5.82 mmol), Pd(Ph3P)4 (0.449 g, 0.388 mmol) and aqueous Na2CO3 (3.88 mL, 7.77 mmol) in toluene (25 mL) is allowed to stir at 95° C. under nitrogen for 14 hours. The reaction mixture is cooled to room temperature and quenched with brine. The mixture is extracted twice with ethylacetate, and the combined organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 50:50) to give (R)-ethyl-4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (1.30 g); HPLC retention time=1.61 minutes (condition B); MS (ES+)=328.0 (m-tBu+2); 284.1 (m-Boc+2; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J=7.1 Hz, 3 H) 2.48 (A of ABX, Jab=16.1 Hz, Jax=5.9 Hz, 1 H) 2.53 (B of ABX, Jab=16.0 Hz, Jbx=5.3 Hz, 1 H) 2.83-3.00 (m, 2 H) 4.14-4.19 (m, 3 H) 5.06 (br s) 7.26-7.27 (m, 2 H) 7.31-7.35 (m, 2 H) 7.43 (t, J=7.6 Hz, 2H) 7.52-7.58 (m, 4 H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].C([N-]C(C)C)(C)C.[Li+].Br[CH2:17]/[CH:18]=[C:19](/[C:30]1[N:35]=[C:34]([O:36][CH3:37])[C:33]([Cl:38])=[CH:32][CH:31]=1)\[C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1.O>O1CCCC1>[C:26]([C:23]1[CH:22]=[CH:21][C:20](/[C:19](/[C:30]2[CH:31]=[CH:32][C:33]([Cl:38])=[C:34]([O:36][CH3:37])[N:35]=2)=[CH:18]\[CH2:17][CH:4]2[CH2:5][CH2:6][N:2]([CH3:1])[C:3]2=[O:7])=[CH:25][CH:24]=1)([CH3:27])([CH3:28])[CH3:29]
Reactant: CN1CCCC1=O
Reactant: COc1nc(/C(=C/CBr)c2ccc(C(C)(C)C)cc2)ccc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(/C(=C/CC2CCN(C)C2=O)c2ccc(C(C)(C)C)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A solution of N-methylpyrrolidone (0.7 mL) in tetrahydrofuran (3 mL) was stirred at −78° C. in a nitrogen atmosphere, during which a lithium diisopropylamide solution (2.2 M, 0.5 mL) was added dropwise thereto. The mixture was stirred at the same temperature for 30 minutes. A solution of 6-[(1E)-3-bromo-1-(4-tert-butylphenyl)prop-1-en-1-yl]-3-chloro-2-methoxypyridine (182 mg) in tetrahydrofuran (2 mL) was slowly added dropwise thereto, and the mixture was stirred at −78° C. for one hour. Water was added to the reaction solution, which was then warmed to room temperature and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:10) to give 3-[(2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)prop-2-en-1-yl]-1-methylpyrrolidin-2-one as a colorless oil (176 mg, 93%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[C:13]([OH:20])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:20][C:13]1[C:14]([C:16]([O:18][CH3:19])=[O:17])=[N:15][C:10]([Br:9])=[CH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(Br)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Br)ccc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
Benzyl bromide (3.87 g, 22.6 mmol), was added to a suspension of methyl 6-bromo-3-hydroxypicolinate (5.00 g, 21.6 mmol) and K2CO3 (5.96 g, 43.1 mmol) in anhydrous DMF (40 mL). The reaction mixture was heated at 60° C. for 18 hours, cooled to rt, and poured into an ice/water mixture. After stirring for 2.5 hours, the precipitate was collected by filtration, washed with water, and dried to provide the desired product methyl 3-(benzyloxy)-6-bromopicolinate (29A).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][NH2:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].C(=O)(O)[O-].[Na+].CN(C)C=O>O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)(C)OC(=O)NC(CN)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1[N+](=O)[O-])C(=O)O
Temperature: 80 °C
Yield: 79.3 %

Procedure:
2-tert-Butoxycarbonylamino-3-aminopropionic acid (10 g, 49 mmol), 2-fluoronitrobenzene (5.7 ml, 54 mmol), and sodium bicarbonate (8.25 g, 98 mmol) was taken into 130 ml of dimethylformamide and heated at 80° C. for 18 hours. The reaction was evaporated in vacuo to give a viscous orange residue that was dissolved in 300 ml of water and extracted with diethyl ether (3×150 ml). The aqueous solution was acidified to pH 5 with 10% sodium hydrogen sulfate and extracted with ethyl acetate (3×250 ml). The combined extracts were dried over anhydrous sodium sulfate, filtered, and evaporated to give 12.64 g (83%) of the title compound as an orange amorphous solid. 1H NMR (CD3OD) δ 8.15-8.10 (1H,d), 7.54-7.48 (1H,t), 7.13-7.08 (1H, d), 6.73-6.65 (1H, t), 4.45-4.35 (1H, m), 3.9-3.8 (1H, dd), 3.65-3.55 (1H, dd), 1.45 (9H, s).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][C:8]=2[C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:3][CH2:2]1.Cl>CO.CCOCC>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[C:8]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=3)[CH2:21][CH2:20]2)=[O:18])[CH:9]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(C2=CCOCC2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CS(=O)(=O)c1ccc(C2CCOCC2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1

Procedure:
A suspension of [2-(3,6-Dihydro-2H-pyran-4-yl)-5-methanesulfonyl-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone, Example 60 (30 mg, 0.0607 mmol) in methanol (1.5 ml) was acidified to pH=1 with HCl solution in ether. The mixture was evaporated to dryness and the residue was taken up in Methanol (5 mL). Then Pd/C 10% (15 mg) was added and the mixture was hydrogenated at reflux temperature for 20 hours. The mixture was diluted with MeOH, filtered and the filtrate was concentrated in vacuo. The resulting mixture was purified on a SiO2: Eluent: Heptane/EtOAc 0% to 70% (20 minutes) then 70% (10 minutes) to provide the title compound (19 mg, white solid; Solid; M+H=497.2).