Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:50][C:51]1[CH:52]=[C:53]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[NH:63][C:64](=[O:66])[CH3:65])[CH:54]=[CH:55][CH:56]=1>CN(C=O)C>[C:64]([NH:63][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=1[C:53]1[CH:54]=[CH:55][CH:56]=[C:51]([NH:50][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])[CH:52]=1)(=[O:66])[CH3:65]
Reactant: CC(=O)Nc1ccccc1-c1cccc(N)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccccc4NC(C)=O)c3)c(=O)oc12
Temperature: 25 °C
Yield: 70.7 %

Procedure:
DIEA (0.013 mL, 0.073 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.015 g, 0.066 mmol) and HATU (0.028 g, 0.073 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, N-(3′-Amino-biphenyl-2-yl)-acetamide (0.015 g, 0.066 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.020 g of product in 69% yield: LCMS (ESI) m/z 429 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>ClCCl>[CH2:18]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: CCCCCCCCCCCBr
Reactant: C1CNCCN1
Solvent: ClCCl
Product: CCCCCCCCCCCN1CCNCC1

Procedure:
Excess piperazine (5 eq) and 1-bromoundecane (1.0 eq) are dissolved in dichloromethane and allowed to react overnight. The mixture is extracted with aqueous sodium bicarbonate and the organic layer dried with sodium sulfate. The mixture is filtered, the solvent removed in vacuo and the residue purified by column chromatography.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]1[CH2:18][C:19]([OH:21])=O.[N:22]1([CH2:28][C:29]([C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[C@H:37]([NH2:41])[CH2:36][CH2:35][CH2:34]3)=[CH2:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]1[CH2:18][C:19]([NH:41][C@H:37]1[C:38]2[C:33](=[CH:32][C:31]([C:29]([CH2:28][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH2:30])=[CH:40][CH:39]=2)[CH2:34][CH2:35][CH2:36]1)=[O:21]
Reactant: C=C(CN1CCCCC1)c1ccc2c(c1)CCC[C@H]2N
Reactant: Cc1ccc(S(=O)(=O)N2CCNC(=O)C2CC(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: C=C(CN1CCCCC1)c1ccc2c(c1)CCC[C@H]2NC(=O)CC1C(=O)NCCN1S(=O)(=O)c1ccc(C)cc1

Procedure:
To a 20 mL flask equipped with stirring was added [3-oxo-1-(toluene-4-sulfonyl)-piperazin-2-yl]-acetic acid (104 mg, 0.33 mmol), 6-(1-piperidin-1-ylmethyl-vinyl)-1,2,3,4-tetrahydro-naphthalen-1(R)-ylamine (Step g, 90 mg, 0.33 mmol), EDC (Aldrich, 96 mg, 0.50 mmol), HOBt (Aldrich, 45 mg, 0.33 mmol), and CH2Cl2 (2 mL). The reaction mixture was stirred at RT overnight and diluted with CH2Cl2 (50 mL). The organic phase was washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by preparative TLC in 10% MeOH-CH2Cl2 to afford the title compound as a mixture of two diastereomers. MS (ESI): 565 (M+H)+.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:22]=[CH:21][C:10]([O:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[C:9]([C:23]([F:26])([F:25])[F:24])[CH:8]=1.[B:27](OC(C)C)([O:32]C(C)C)[O:28]C(C)C>C1COCC1>[O:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[O:14][CH2:13][CH2:12][O:11][C:10]1[CH:21]=[CH:22][C:7]([B:27]([OH:32])[OH:28])=[CH:8][C:9]=1[C:23]([F:26])([F:25])[F:24]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)(F)c1cc(Br)ccc1OCCOC1CCCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(OCCOC2CCCCO2)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
BuLi (2.5M, 6 ml) was added dropwise to a solution of 2-(2-(4-bromo-2-(trifluoromethyl)phenoxy)ethoxy)tetrahydro-2H-pyran (5 g) in THF (50 ml) at −78° C. under N2 during 3 minutes. After stirring at −78° C. for another 10 minutes, triisopropyl borate (3.8 ml) was then added dropwise during 2 minutes at −78° C. The mixture was stirred at −78° C. for further 30 minutes, then slowly warmed up to room temperature and stirred at room temperature for 30 minutes. The mixture was then quenched with acetic acid (10% in water, 20 ml), extracted with EtOAc (300 ml), washed with water (200 ml×3), dried over sodium sulphate, solvent removed under reduced pressure, the residue was taken in to toluene and then solvent removed under reduced pressure to take out trace of acetic acid (repeat 3 times, until no acetic acid smell) (4.5 g).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]1([CH2:14][O:15][NH:16][CH:17]2[CH2:26][CH2:25][CH2:24][C:23]3[N:22]=[C:21]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:20]=[CH:19][C:18]2=3)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:35]CCl>>[ClH:35].[C:8]1([CH2:14][O:15][N:16]([CH:17]2[CH2:26][CH2:25][CH2:24][C:23]3[N:22]=[C:21]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:20]=[CH:19][C:18]2=3)[C:1](=[O:3])[CH3:2])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: ClCCl
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(CONC2CCCc3nc(OCc4ccccc4)ccc32)cc1
Product: CC(=O)N(OCc1ccccc1)C1CCCc2nc(OCc3ccccc3)ccc21
Product: Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 52 %

Procedure:
Acetic anhydride (3.77 g) was added to a solution of N,N-dimethylaminopyridine (0.2 g), N,2-bis(phenylmethoxy)-5,6,7,8-tetrahydro-5-quinolinamine (12.1 g) and dichloromethane (170 ml) at room temperature. The mixture was stirred at room temperature for 48 hrs, diluted with dichloromethane, and extracted with saturated sodium bicarbonate solution. The combined extracts were washed with water, brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was dissolved in methanol and acidified with 2-propanol/hydrochloric acid solution. The mixture was evaporated and the residue was recrystallized from ethanol/ethyl acetate to give 7.64 g (52%) of product, mp 125°-126° C.
Reaction SMILES: N[C:2]1([F:26])[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=3[Cl:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]2)=[CH:4][CH2:3]1.C(OC([N:34]1[CH2:41][CH:40]2[CH:36]([CH2:37][NH:38][CH2:39]2)[CH2:35]1)=O)(C)(C)C.C([N:44](CC)CC)C>C(#N)C>[ClH:19].[NH2:44][C:3]1[CH:4]=[C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:21])=[C:16]([N:34]4[CH2:41][CH:40]5[CH:36]([CH2:37][NH:38][CH2:39]5)[CH2:35]4)[C:17]=3[Cl:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]2)[C:6]([F:8])=[CH:7][C:2]=1[F:26]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: NC1(F)C=C(F)C(n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)=CC1
Solvent: CC#N
Product: Cl
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC5CNCC5C4)c(Cl)c32)c(F)cc1F
Temperature: 80 °C
Reaction time: 3 h
Yield: 181 %

Procedure:
In 3 ml of acetonitrile were dissolved 100 mg of 1-(4-amino-4,6-difluorophenyl)-8-chloro-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 104 mg of 3-t-butoxycarbonyl-3,7-diazabicyclo[3.3.0]octane, and 150 mg of triethylamine. The solution was stirred at 80° C. for 3 hours. The solvent was distilled off in vacua. The residue was extracted with 30 ml of chloroform. The organic layer was washed with 20 ml of 3% citric acid aqueous solution, dried, and then distilled. The residue was dissolved in 20 ml of dichloromethane, combined with 5 ml of 4N hydrochloric acid/dioxane, and stirred at room temperature for 2 hours. The solvent was distilled off in vacua. The residue was solidified with isopropyl ether and collected by filtration to give 120 mg of the title compound as a pale yellow powder.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:19](O)=[O:20])=[N:8][C:9]=2[NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH2:3][CH2:2]1.[CH3:22][O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[NH2:26]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:19]([NH:26][C:25]([CH3:28])([CH3:27])[C:24]([O:23][CH3:22])=[O:29])=[O:20])=[N:8][C:9]=2[NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH2:3][CH2:2]1
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(O)c1ccc(C2CC2)c(Nc2ccc(Cl)cc2Cl)n1
Product: COC(=O)C(C)(C)NC(=O)c1ccc(C2CC2)c(Nc2ccc(Cl)cc2Cl)n1

Procedure:
The title compound was synthesized in analogy to Example 4 b, using 5-cyclopropyl-6-(2,4-dichloro-phenylamino)-pyridine-2-carboxylic acid and 2-methyl-alanine methyl ester as starting materials, MS (EI): m/e 422.1 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[C:16](\[O:21][CH3:22])/[C:17]([O:19]C)=[O:18])[CH:12]=[CH:11][C:10]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:38])[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:31])[CH:24]=1)[CH3:4].O.Cl>O1CCCC1.CO>[CH2:3]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[C:16](\[O:21][CH3:22])/[C:17]([OH:19])=[O:18])[CH:12]=[CH:11][C:10]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:38])[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:31])[CH:24]=1)[CH3:4]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)OC)cc2OCCOCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)O)cc2OCCOCC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
17 mg (4.2 mmol) of sodium hydroxide are added to a solution of 211 mg (0.42 mmol) of methyl (Z)-3-[2-(2-ethoxyethoxy)-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]-2-methoxyacrylate in 5 mL of tetrahydrofuran and 0.5 mL of methanol. The reaction mixture is stirred overnight at room temperature. After addition of 10 mL of water and acidification to pH 3 with 1 N hydrochloric acid, the reaction medium is extracted with ethyl acetate. The organic phases are combined, dried over sodium sulfate and evaporated, and the residue obtained is then purified by chromatography on a column of silica eluted with a 98/2 dichloromethane/methanol mixture. 160 mg (74%) of (Z)-3-[2-(2-ethoxyethoxy)-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]-2-methoxyacrylic acid are obtained in the form of white crystals. (m.p.=78.2° C.).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:3]([OH:16])[CH2:4][N:5]([CH2:14][CH3:15])[NH:6][C:7]([O:9]C(C)(C)C)=O.[CH3:24][CH:25]([CH3:31])[CH2:26][CH2:27]C(O)=O.[CH3:32][C:33]1[CH:34]=[C:35]([C:42]([N:44]([CH2:48][CH2:49][CH3:50])[CH2:45][CH2:46][CH3:47])=[O:43])[CH:36]=[C:37]([CH:41]=1)[C:38]([OH:40])=O>>[CH2:17]([C@H:2]([NH:1][C:38](=[O:40])[C:37]1[CH:41]=[C:33]([CH3:32])[CH:34]=[C:35]([C:42]([N:44]([CH2:48][CH2:49][CH3:50])[CH2:45][CH2:46][CH3:47])=[O:43])[CH:36]=1)[C@@H:3]([OH:16])[CH2:4][N:5]([CH2:14][CH3:15])[NH:6][C:7](=[O:9])[CH2:27][CH2:26][CH:25]([CH3:31])[CH3:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCN(C[C@H](O)[C@@H](N)Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)O)c1
Reactant: CC(C)CCC(=O)O
Product: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)CN(CC)NC(=O)CCC(C)C)c1

Procedure:
Synthesized as described above from tert-butyl 2-((2S,3S)-3-amino-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate, 4-methylpentanoic acid and 5-methyl-N,N-dipropyl-isophthalamic acid (WO 02/02512). MS (ESI+) for C33H50N4O4 m/z 567.3 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:34]([O:38][C:39]([NH:41][C@H:42]1[C:50]2[C:45](=[CH:46][CH:47]=[C:48]([C:51]([OH:53])=O)[CH:49]=2)[CH2:44][CH2:43]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].[CH3:54][NH:55][CH:56]1[CH2:61][CH2:60][N:59]([C:62]2[CH:67]=[CH:66][N:65]=[CH:64][CH:63]=2)[CH2:58][CH2:57]1>C1COCC1.ClCCl>[CH3:54][N:55]([CH:56]1[CH2:57][CH2:58][N:59]([C:62]2[CH:63]=[CH:64][N:65]=[CH:66][CH:67]=2)[CH2:60][CH2:61]1)[C:51]([C:48]1[CH:49]=[C:50]2[C:45]([CH2:44][CH2:43][C@H:42]2[NH:41][C:39](=[O:40])[O:38][C:34]([CH3:35])([CH3:36])[CH3:37])=[CH:46][CH:47]=1)=[O:53]
Reactant: CNC1CCN(c2ccncc2)CC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2ccc(C(=O)O)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ccc2c(c1)[C@H](NC(=O)OC(C)(C)C)CC2)C1CCN(c2ccncc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
HATU (0.795 g, 2.09 mmol, 1 eq) and DIPEA (350 μA 2.04 mmol, 2.5 eq) were added to an ice-cooled solution of (R)-3-(tert-butoxycarbonylamino)-2,3-dihydro-1H-indene-5-carboxylic acid (368 mg, 2.09 mmol, 1 eq) in THF (5 ml), and stirring was carried out for 30 min. N-Methyl-1-(pyridin-4-yl)piperidin-4-amine (AMN-06) (400 mg, 2.09 mmol, 1 eq) was dissolved in THF (5 ml) and added dropwise to the reaction solution, and stirring was carried out for 16 h at RT. The reaction solution was diluted with dichloromethane (100 ml), washed with sat. sodium hydrogen carbonate solution (50 ml), sat. ammonium chloride solution (50 ml), water (50 ml) and sat. NaCl solution (50 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, 0.5% MeOH in dichloromethane), the desired product was obtained in the form of a yellowish solid. Yield: 64% (600 mg, 1.33 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[CH:5]=[C:4]([Cl:15])[N:3]=1.Cl.[F:17][C:18]1[CH:19]=[N:20][C:21]([C@@H:24]([NH2:26])[CH3:25])=[N:22][CH:23]=1>>[Cl:15][C:4]1[N:3]=[C:2]([NH:26][C@H:24]([C:21]2[N:22]=[CH:23][C:18]([F:17])=[CH:19][N:20]=2)[CH3:25])[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[CH:5]=1
Reactant: Cc1cc(Nc2cc(Cl)nc(Cl)n2)n[nH]1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Product: Cc1cc(Nc2cc(Cl)nc(N[C@@H](C)c3ncc(F)cn3)n2)n[nH]1

Procedure:
Following a similar procedure to that of Example 9, the title compound was synthesized from 2,6-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 17) and (5)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7). m/z 348.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15]3([CH2:17][O:16]3)[C:14]3[CH:13]=[C:12]([Cl:18])[N:11]=[C:10]([F:19])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[N:20]([Si](C)(C)C)=[N+:21]=[N-:22]>CN(C=O)C.CCOC(C)=O.O>[N:20]([C:15]1([CH2:17][OH:16])[C:14]2[CH:13]=[C:12]([Cl:18])[N:11]=[C:10]([F:19])[C:9]=2[O:8][C:5]2[C:4]1=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[N+:21]=[N-:22]
Reactant: Fc1nc(Cl)cc2c1Oc1ccc(Br)cc1C21CO1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC1(CO)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.7 %

Procedure:
To a solution of 7-bromo-3-chloro-1-fluorospiro[chromeno[2,3-c]pyridine-5,2′-oxirane] (23.5 g, 68.6 mmol) in DMF (600 mL) was added azidotrimethylsilane (54.6 mL, 412 mmol). The reaction mixture was stirred at RT for 6 hours. Additional azidotrimethylsilane (54.6 mL, 412 mmol) was added and the reaction was stirred at RT for 18 hours. The reaction mixture was diluted with EtOAc and water. The organic layer was separated, washed sequentially with a saturated aqueous LiCl solution and brine before drying over sodium sulfate. The solution was concentrated under reduced pressure to afford (5-azido-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)methanol (26.12 g, 67.7 mmol, 99% yield).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Br:14]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:14][C:3]1[C:4]2[CH:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=[CH:6][C:5]=2[S:1][CH:2]=1
Reactant: COC(=O)c1ccc2sccc2c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2scc(Br)c2c1
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a solution of methyl 1-benzothiophene-5-carboxylate (5.15 g, 26.8 mmol) in acetic acid (50 mL) was added dropwise bromine (2.06 mL, 40.2 mmol) at room temperature, and the resulting mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M aqueous sodium sulfite solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1), and crystallized from hexane/ethyl acetate to give the title compound (6.20 g, yield 85%) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([CH3:8])[CH2:4][C:5](O)=[O:6].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.Cl.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]1[O:41][N:40]=[C:39]([C:42]2[N:43]=[C:44]([CH:47]3[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)[S:45][CH:46]=2)[CH2:38]1.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]1[O:41][N:40]=[C:39]([C:42]2[N:43]=[C:44]([CH:47]3[CH2:52][CH2:51][N:50]([C:5](=[O:6])[CH2:4][CH:3]([CH3:8])[C:2]([F:10])([F:9])[F:1])[CH2:49][CH2:48]3)[S:45][CH:46]=2)[CH2:38]1
Reactant: Fc1ccccc1C1CC(c2csc(C3CCNCC3)n2)=NO1
Reactant: CC(CC(=O)O)C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4F)C3)cs2)CC1)C(F)(F)F
Reaction time: 0.08 h

Procedure:
To a solution of 4,4,4-trifluoro-3-methyl-butanoic acid (64 mg, 0.408 mmol) in dichloromethane (3 mL) was added 1-propanephosphonic acid cyclic anhydride solution (50% in ethyl acetate, 0.5 mL). After stirring for 5 minutes, 4-[4-[5-(2-fluorophenyl)-4,5-dihydro-3-isoxazolyl)-2-thiazolyl]piperidine hydrochloride (i.e. the product of Step C) (150 mg, 0.408 mmol), triethylamine (0.1 mL) and 4-dimethylaminopyridine (5 mg) were sequentially added The reaction mixture was stirred for 3 h, and then concentrated under reduced pressure. The resulting material was purified by column chromatography on silica gel to provide the title compound, a compound of the present invention, as an oil (151 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH3:15])[CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CN=C1>CN(C)C=O>[Si:16]([O:14][CH2:13][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:15])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](CO)NC(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Yield: 84.7 %

Procedure:
A procedure similar to that described in Preparation 8 was repeated, except that 12.54 g of (R)-2-benzyloxycarbonylaminopropanol (prepared as described in Preparation 23), 9.97 g of t-butyldimethylsilyl chloride, 4.90 g of imidazole and 150 ml of anhydrous dimethylformamide were used, to give 16.43 g of the title compound having an Rf value of 0.54 (on silica gel thin layer chromatography, using a 1:4 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][C:26]([F:29])([F:28])[F:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:31][CH2:32][NH2:33]>>[NH2:33][CH2:32][CH2:31][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][C:26]([F:27])([F:28])[F:29])[CH2:15][CH2:14]2)=[O:12])=[CH:7]1
Reactant: NCCCl
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2ccccc2OC(F)(F)F)CC1
Product: NCCn1cc(C(=O)N2CCC(c3ccccc3OC(F)(F)F)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-trifluoromethoxy-phenyl)-piperidin-1-yl]-methanone (prepared herein) with (commercially available) 2-chloro-ethylamine gave the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:10][C:11]([CH3:13])=O.[H][H].Cl>C(O)C.[Pd].O>[CH:11]([NH:1][C@@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([OH:9])=[O:8])([CH3:13])[CH3:10]
Reactant: CC(C)=O
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)C[C@H](NC(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 39.5 %

Procedure:
A mixture of L-leucine (5.0 g, 38 mmol) and acetone (5.6 mL, 76 mmol) was agitated in an atmosphere of hydrogen (pressure, 33-52 psi) at room temperature in absolute ethanol (100 mL) in the presence of Pd/C (20%, 1 g) until the absorption of hydrogen almost ceased. Four milliliters of concentrated HCl (aq, 36.5%) was then added and stirred for 10 minutes; the catalyst was then removed by filtration. The filtrate was treated with aqueous ammonium hydroxide (29.8%) to adjust the pH to 6.5. White solid precipitated out which was isolated via filtration. The white solid was mixed with 100 mL of water and heated to boiling on a hot plate. After cooling down to 0° C., the white solid was filtered and dried under vacuum. Forty percent (2.6 g) of the pure titled compound was isolated as a white solid; mp 293-296° C. APCI-MS m/z 174.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH:11]1[CH:16]=[CH:15][C:14]([CH2:17]Br)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].O>CC#N>[CH2:17]([O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[Cl:1])[C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=Cc1ccc(OCc2ccccc2)c(Cl)c1
Yield: 95 %

Procedure:
To a solution of 3-chloro-4-hydroxy-benzaldehyde (5.0 g, 32 mmol) and BnBr (6.6 g, 38 mmol) in CH3CN (100 mL) was added K2CO3 (8.8 g, 64 mmol). The mixture was heated at reflux for 2 hours. The resulting mixture was poured into water (100 mL), and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and evaporated under vacuum to give crude product, which was purified by column (petroleum ether/EtOAc 15:1) to give 4-benzyloxy-3-chloro-benzaldehyde (7.5 g, 95%). 1H NMR (CDCl3, 400 MHz) δ 9.85 (s, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.73 (dd, J=2.0, 8.4 Hz, 1H), 7.47-7.34 (m, 5H), 7.08 (d, J=8.8 Hz, 1H), 4.26 (s, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Br[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH3:45])=[C:39]([O:46][CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:38]=1>>[CH2:44]([O:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][O:1][CH:2]2[CH:7]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:10][CH:9]=3)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]2)=[CH:38][C:39]=1[O:46][CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH3:45]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: CCOc1ccc(CBr)cc1OCCCOC
Product: CCOc1ccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)cc1OCCCOC

Procedure:
Analogously to Method D, 0.496 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.502 g of 4-bromomethyl-1 ethoxy-2-(3-methoxypropoxy)benzene are reacted. The title compound is obtained as a colourless oil. Rf=0.26 (1:2 EtOAc-heptane); Rt=6.20.