Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.Cl.[CH3:7][O:8][C:9](=[O:12])[CH2:10][NH2:11].[S:13]1[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15][S:14]1.P(C#N)(OCC)(OCC)=O>CN(C)C=O.C(N(CC)CC)C>[S:13]1[CH2:17][CH:16]([C:18]([NH:11][CH2:10][C:9]([O:8][CH3:7])=[O:12])=[O:19])[CH2:15][S:14]1
Reactant: COC(=O)CN
Reactant: O=C(O)C1CSSC1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)C1CSSC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 7.7 %

Procedure:
5 ml of anhydrous tetrahydrofuran, 1.01 ml of triethylamine and 398 mg of glycine methyl ester hydrochloride were added to 5 ml of a solution of 3.3 mmol of 1,2-dithiolane-4-carboxylic acid (prepared as described in Example 96) in anhydrous dimethylformamide, and 0.55 ml of diethyl cyanophosphate was then added to the resulting mixture, whilst ice-cooling, after which the mixture was stirred at room temperature for 5 hours. At the end of this time, the reaction mixture was left to stand at room temperature overnight, after which the solvent was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using, a 2:1 by volume mixture of ethyl acetate and hexane as the eluent. The solvent was then removed from the eluate solution by evaporation under reduced pressure, and the residue was recrystallized from a 1:2 by volume mixture of ethyl acetate and hexane, to obtain 54 mg of the title compound as pale yellow crystals melting at 73 to 75° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH:16]([NH2:22])[CH2:15][CH:14](CCC3C=CC=CC=3)[CH2:13][C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:32]1[CH:33]=[C:34]2[C:42](=[CH:43][CH:44]=1)N[C:40]1CCC(NCCC3C=CC=CC=3)C[C:35]2=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:13]1[CH2:14][CH2:15][CH:16]([NH:22][CH2:40][CH2:35][C:34]3[CH:42]=[CH:43][CH:44]=[CH:32][CH:33]=3)[CH2:17][C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CC(CCc2ccccc2)Cc2c1[nH]c1ccc(OCc3ccccc3)cc21
Reactant: Oc1ccc2[nH]c3c(c2c1)CC(NCCc1ccccc1)CC3
Product: c1ccc(CCNC2CCc3[nH]c4ccc(OCc5ccccc5)cc4c3C2)cc1

Procedure:
Beginning with 0.336 gm (0.85 mMol) 6-benzyloxy-3-(2-phenyleth-1-yl)-amino-1,2,3,4-tetrahydro-9H-carbazole, 0.175 gm (67%) of 6-hydroxy-3-(2-phenylethyl)amino-1,2,3,4-tetrahydro-9H-carbazole were prepared by the procedure described in detail in Example 35. The hydrochloride salt was prepared and crystallized from ethanol/diethyl ether to give the title compound.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][N:15]=[C:16]3[Cl:19])=[CH:11][CH:10]=2)[C:4]1=[O:20].C(N(CC)CC)C.[S:28]1[C:36]2[C:31](=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]1[S:37](Cl)(=[O:39])=[O:38]>CC#N>[Cl:19][C:16]1[C:17]2[C:12](=[CH:11][CH:10]=[C:9]([CH2:8][N:5]3[CH2:6][CH2:7][C@H:3]([NH:2][S:37]([C:29]4[S:28][C:36]5[C:31](=[N:32][CH:33]=[CH:34][CH:35]=5)[CH:30]=4)(=[O:38])=[O:39])[C:4]3=[O:20])[CH:18]=2)[CH:13]=[CH:14][N:15]=1
Reactant: N[C@H]1CCN(Cc2ccc3ccnc(Cl)c3c2)C1=O
Reactant: O=S(=O)(Cl)c1cc2ncccc2s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1[C@@H](NS(=O)(=O)c2cc3ncccc3s2)CCN1Cc1ccc2ccnc(Cl)c2c1
Reaction time: 8 h
Yield: 33.3 %

Procedure:
To a solution of 3-(S)-amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-one hydrochloride (0.15 g, 0.48 mmol) suspended in CH3CN (2.5 mL) is added triethylamine (0.23 mL, 1.6 mmol) followed by thieno[3,2-b]pyridine-2-sulfonyl chloride (0.14 g, 0.55 mmol). The mixture is stirred overnight, then concentrated. The residue is diluted with CH2Cl2 and washed with saturated NaHCO3 and brine. The organic layer is dried over MgSO4, filtered and concentrated to dryness. The crude product is purified by column chromatography eluting with 5% MeOH/CH2Cl2 to give the title compound (0.076 g, 0.16 mmol) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[C:10]([O:14][C:15](=[O:18])[CH2:16][NH2:17])([CH3:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>CC(N(C)C)=O.CCOCC>[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:17][CH2:16][C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:18])[CH:7]=1)#[N:9]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)CN
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CNc1cc(C#N)ccn1

Procedure:
A solution of 2-chloro-4-cyanopyridine (1.00 g, 7.2 mmol), glycine tert-butyl ester (1.5 mL, 10.8 mmol) and DIEA (4.9 mL, 28.9 mmol) in anhydrous DMA (15 mL) was heated at 150° C. for 48 hours. The reaction mixture was diluted with Et2O (100 mL) and washed with water (2×50 mL) and brine (50 mL). The organic layer was dried (MgSO4) and the solvents were removed under reduced pressure. After purification by flash chromatography (silica, DCM), the title compound was obtained as a yellow oil. HPLC (Method A), Rt: 3.1 min (purity: 94%). UPLC/MS, M+(ESI): 178.0 ([M-tBu+2H]+), M−(ESI): 232.1. 1H NMR (DMSO-d6, 300 MHz) δ 8.15 (d, J=5.2 Hz, 1H), 7.44 (t, J=6.2 Hz, 1H), 6.93 (brs, 1H), 6.85 (dd, J=5.2, 1.3 Hz, 1H), 3.94 (d, J=6.2 Hz, 2H), 1.38 (s, 9H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])[C:6]#[N:7].[CH2:18]([OH:20])[CH3:19].C(Cl)(=O)C>C(OC)(C)(C)C>[ClH:1].[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:15])([F:16])[F:17])[C:6](=[NH:7])[O:20][CH2:18][CH3:19]
Reactant: N#CC(CCCCl)c1ccccc1C(F)(F)F
Reactant: CCO
Solvent: COC(C)(C)C
Solvent: CC(=O)Cl
Product: CCOC(=N)C(CCCCl)c1ccccc1C(F)(F)F
Product: Cl
Temperature: 0 °C
Reaction time: 67 h

Procedure:
5-Chloro-2-(2-trifluoromethylphenyl)pentanenitrile (2.0 g, 7.64 mmol) was dissolved in ethanol (5.36 mL, 91.72 mmol) at room temperature under nitrogen atmosphere. Then, the solution was cooled to 0° C. Acetyl chloride (4.34 mL, 61.14 mmol) was added dropwise to the solution, and the reaction mixture was stirred at room temperature for 67 hours. The reaction mixture was cooled to 10° C. Traces of seed crystal of the title compound which was obtained by the method similar to this step and tert-butylmethylether (hereinafter referred to as “MTBE”) (40 mL) were added to the reaction mixture and the reaction mixture was stirred. The solid was collected by filtration, washed with MTBE to obtain the title compound (2.14 g, 81.6% yield).
Reaction SMILES: I[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.Cl.[C:31]([C:33]1([CH3:39])[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]1)#[CH:32]>>[CH3:27][O:26][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][CH2:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH2:9][N:6]1[C:5]2[CH:28]=[CH:29][C:2]([C:32]3[N:35]4[CH2:34][C:33]([CH3:39])([CH2:38][CH2:37][CH2:36]4)[CH:31]=3)=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: C#CC1(C)CCCNC1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(I)ccc43)cc2OC)cn1
Agent: Cl
Product: COc1ccc(COc2ccc(Cn3cnc4cc(C5=CC6(C)CCCN5C6)ccc43)cc2OC)cn1

Procedure:
1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(5-methyl-1-azabicyclo[3.2.1]oct-6-en-7-yl)-/H-benzo[d]imidazole was prepared from 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole and 3-ethynyl-3-methylpiperidine hydrochloride using the procedure outlined for the synthesis of Example 3-30: 1H NMR (500 MHz, CDCl3) δ 8.22-8.21 (m, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.69 (dd, J=8.5, 2.5 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.28-7.26 (m, 1H, partially obscured by CHCl3), 6.89 (d, J=8.5 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.75-6.73 (m, 2H), 5.93 (s, 1H), 5.28 (s, 2H), 5.04 (s, 2H), 3.95 (s, 3H), 3.80 (s, 3H), 3.21 (dd, J=9.5, 1.5 Hz, 1H), 2.92-2.90 (m, 2H), 2.79 (d, J=10.0 Hz, 1H), 1.87-1.83 (m, 1H), 1.57-1.43 (m, 3H), 1.14 (s, 3H) ppm; (M+1)=497.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([OH:23])[C@@H:6]([NH:14][C:15]1[C:16](=O)[C:17](=[O:21])[C:18]=1[O:19]C)[CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[N+:2]=[N-:3].Cl.[CH3:25][O:26][CH2:27][CH2:28][CH2:29][O:30][CH:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH:32]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]1.CCN(CC)CC>C(#N)C>[N:1]([CH2:4][C@@H:5]([OH:23])[C@@H:6]([NH:14][C:15]1[C:18](=[O:19])[C:17](=[O:21])[C:16]=1[N:34]1[CH2:35][CH2:36][CH2:37][CH:32]([CH:31]([O:30][CH2:29][CH2:28][CH2:27][O:26][CH3:25])[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:33]1)[CH2:7][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)=[N+:2]=[N-:3]
Reactant: COc1c(N[C@@H](CC2CCCCC2)[C@H](O)CN=[N+]=[N-])c(=O)c1=O
Reactant: COCCCOC(c1ccccc1)C1CCCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCCCOC(c1ccccc1)C1CCCN(c2c(N[C@@H](CC3CCCCC3)[C@H](O)CN=[N+]=[N-])c(=O)c2=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
3-((2S,3R)-4-Azido-1-cyclohexyl-3-hydroxybutan-2-ylamino)-4-methoxycyclobut-3-ene-1,2-dione (35 mg, 0.11 mmol), the HCl salt of 3-((3-methoxypropoxy)(phenyl)methyl)piperidine (48 mg, 0.16 mmol), and Et3N (100 μL, 0.7 mmol) were dissolved in acetonitrile (1 mL). The reaction was allowed to stir at rt overnight. The solvent was evaporated and the product was isolated by preparative HPLC to give 3-((2S,3R)-4-azido-1-cyclohexyl-3-hydroxybutan-2-ylamino)-4-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione (41 mg). MS m/z 554 (M+H+).
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](N1C=CN=C1)(N1C=CN=C1)=[S:13]>ClCCl>[C:1]1([N:7]2[CH2:8][CH2:9][CH2:10][NH:11][C:12]2=[S:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCNc1ccccc1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: S=C1NCCCN1c1ccccc1
Yield: 78 %

Procedure:
Prepared in the manner of Example 1, Step B from N-phenyl-propane-1,3-diamine of Step A and 1,1′-thiocarbonyldiimidazole, except that the cyclization was effected in dichloromethane. Workup consisted of washing with water, drying over magnesium sulfate, filtration and removal of solvent in vacuo. Purfication by flash chromatography on silica gel Merck-60 eluting with 1% methanol in dichloromethane followed by trituration with ethyl ether to provide the title compound as a white solid (2.74 g, 78%), m.p: 211-212° C., identical to the material described by Kashima et al., J. Chem. Soc. Perkin I, 1622 (1981).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH3:11])=[CH:6][CH:5]=1.[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17]>>[CH3:15][C:16]([S@:19]([NH:21][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=1)[CH3:11])=[O:20])([CH3:18])[CH3:17]
Reactant: CC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OC(F)(F)F)cc1
Yield: 77 %

Procedure:
The title compound is prepared in 77% yield (0.35 g, colorless oil) from 1-(4-(trifluoromethoxy)phenyl)ethanone (0.30 g, 1.47 mmol) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]([O:16][CH2:17][CH3:18])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][C:12]([O:14][CH3:15])=[O:13].[C:20]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]([O:16][CH2:17][CH3:18])=[C:6]2[C:10]=1[N:9]([CH3:20])[CH:8]=[C:7]2[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: CCOc1c(F)cc(Cl)c2[nH]cc(CC(=O)OC)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOc1c(F)cc(Cl)c2c1c(CC(=O)OC)cn2C
Temperature: 25 °C
Yield: 66.7 %

Procedure:
To a solution of 30-10 (2 g, 7 mmol) in acetone (40 mL) was added K2CO3 (3 g, 21 mmol) and MeI (1.2 g, 8.4 mmol). The reaction mixture was refluxed overnight before it was cooled to room temperature. The solid was filtered off and the filtrate was evaporated to give the crude product, which was purified on silica gel column chromatography eluting with hexane/ethyl acetate (1:5) to afford 30-11 (1.4 g, 67%) as a yellow solid. LRMS: calc 299.1 and found: 300.1 [M+1].
Reaction SMILES: [S:1](=[O:4])(=[O:3])=[O:2].[CH:5]1[CH:10]=[C:9]2[CH:11]=[CH:12][C:13]([NH2:19])=[C:14]([S:15]([OH:18])(=[O:17])=[O:16])[C:8]2=[CH:7][CH:6]=1.[S:20](=[O:24])(=[O:23])([OH:22])[OH:21]>>[NH2:19][C:13]1[CH:12]=[CH:11][C:9]2[C:10]([S:1]([OH:4])(=[O:3])=[O:2])=[CH:5][C:6]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:7][C:8]=2[C:14]=1[S:15]([OH:18])(=[O:16])=[O:17].[CH:11]1[C:9]2[C:8](=[C:7]([S:20]([OH:22])(=[O:24])=[O:21])[CH:6]=[C:5]([S:1]([OH:4])(=[O:3])=[O:2])[CH:10]=2)[CH:14]=[C:13]([NH2:19])[CH:12]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1ccc2ccccc2c1S(=O)(=O)O
Reactant: O=S(=O)=O
Product: Nc1ccc2c(S(=O)(=O)O)cc(S(=O)(=O)O)cc2c1S(=O)(=O)O
Product: Nc1ccc2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c2c1

Procedure:
We have now discovered that addition of sulfur trioxide to Tobias Acid in hot 100% sulfuric acid provides both 2-amino-1,5,7-naphthalenetrisulfonic acid and Amino G Acid. Separation of Amino G Acid and hydrolysis of the trisulfonic acid provides Amino J Acid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH2:14][OH:15])[NH:8][C:7]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:6][CH2:5]1.[CH2:16](Br)[C:17]#[CH:18].C(O)C>C1COCC1.C(OCC)C>[CH3:3][C:4]1([CH2:14][O:15][CH2:18][C:17]#[CH:16])[NH:8][C:7]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:6][CH2:5]1
Reactant: C#CCBr
Reactant: CC1(CO)COC2(CCCCC2)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOCC
Product: C#CCOCC1(C)COC2(CCCCC2)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (55% in dispersion in oil) (0.636 g) was added portion wise to a solution of (3-methyl-1-oxa-4-aza-spiro[4.5]dec-3-yl)-methanol (2.0 g) in dry THF (30 ml) at 0° C. The reaction mixture was stirred at room temperature for 1 h. Propargyl bromide (0.972 ml) was added dropwise at 0° C. and the resulting mixture was stirred at room temperature for 2.5 h. The reaction mixture was treated with ethanol (4 ml) and diluted with diethyl ether and the mixture was filtered. The filtrate was concentrated in vacuo to providing a crude residue which was purified by column chromatography (hexane/ethyl acetate 1:1) to give 2.33 g of 3-methyl-3-prop-2-ynyloxymethyl-1-oxa-4-aza-spiro[4.5]decane as an orange liquid. 1H NMR (CDCl3) δ ppm: 4.18 (2H, d); 3.82 (1H, d); 3.53 (1H, d); 3.43 (1H, d); 3.38 (1H, d); 2.42 (1H, t); 1.7-1.2 (10H, m); 1.25 (1H, s).
Reaction SMILES: N.[Na].[C:3](#[N:5])[CH3:4].[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]#[N:12]>O1CCCC1.CCOCC>[NH2:12][C:11]([C:7]1[S:6][CH:10]=[CH:9][CH:8]=1)=[CH:4][C:3]#[N:5]
Reactant: N#Cc1cccs1
Reactant: CC#N
Agent: N
Agent: [Na]
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#CC=C(N)c1cccs1
Reaction time: 0.5 h

Procedure:
About 100 ml. of ammonia is condensed in the reaction flask and a small piece of sodium is added, giving a blue color. The color is discharged with ferric chloride and 2.7 g. of sodium is added. When the blue color disappears, 4.91 ml. of acetonitrile in 10 ml. of ether is added. The reaction is cooled in a dry ice-acetone bath and 9.28 g. of 2-thiophenecarbonitrile in 25 ml. of tetrahydrofuran is added dropwise. Cooling is continued for 30 minutes, then the ammonia and solvent are allowed to evaporate. A 50 ml. portion of water is added and the mixture is extracted with methylene chloride. The methylene chloride extracts are dried over sodium sulfate and then passed through Magnesol. Hexanes are added and the filtrate is evaporated on a steam bath to an oil. The oil is dry column chromatographed on silica gel, eluting with methylene chloride. The fraction containing the desired product is taken up in methylene chloride, passed through Magnesol and the filtrate is evaporated on a steam bath with the addition of hexanes until an oil comes out. Cooling and seeding gives the desired product as crystals, mp. 50°-45° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[CH:14]=[CH:13]2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]1[C:35](B(O)O)=[C:34]([CH3:39])[O:33][N:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O.C(O)C>[CH3:30][C:31]1[C:35]([C:2]2[CH:3]=[C:4]([C:8]([CH3:28])([CH3:29])[CH2:9][C:10]([OH:27])([C:23]([F:24])([F:25])[F:26])[CH2:11][N:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=2)=[C:34]([CH3:39])[O:33][N:32]=1
Reactant: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cccc(Br)c1
Reactant: Cc1noc(C)c1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: Cc1noc(C)c1-c1cccc(C(C)(C)CC(O)(Cn2ccc(=O)c3ccccc32)C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A mixture of 1-[4-(3-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1-H-quinolin-4-one (30 mg, 0.064 mmol), 3,5-dimethylisoxazole-4-boronic acid (9 mg, 0.064 mmol, 1 equiv.), bisdichlorotriphenylphosphinopalladium (II) (catalytic amount) and cesium carbonate (21 mg, 0.064 mmol) in 1.1 mL of ethylene glycol dimethyl ether-water-ethanol (7:3:2) was degassed, sealed in a vial, and irradiated twice (microwave) at 160° C. for 300 seconds. The reaction was cooled to room temperature and filtered through CELITE® filter aid. The filtrate was diluted with water and extracted with diethyl ether. The combined organic layers were washed with brine and dried with sodium sulfate. Removal of the volatiles in vacuo provided a residue which was purified by HPLC to give 1-{4-[3-(3,5-dimethylisoxazol-4-yl)phenyl]-2-hydroxy-4-methyl-2-trifluoromethylpentyl}-1H-quinolin-4-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[CH2:27][C:28]([O:30]C)=[O:29])[O:5][CH2:6][CH2:7][C@@H:8]1[CH2:10][C@@H:9]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]2([CH3:23])[CH2:22][CH2:21]2)=[O:18])[CH2:13][CH2:12]1.CO.[OH-].[Li+].Cl>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]([O:5][CH2:6][CH2:7][C@@H:8]2[CH2:10][C@@H:9]2[CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]3([CH3:23])[CH2:21][CH2:22]3)=[O:18])[CH2:15][CH2:16]2)[CH:24]=[CH:25][C:26]=1[CH2:27][C:28]([OH:30])=[O:29]
Reactant: COC(=O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OC3(C)CC3)CC2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1(OC(=O)N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)c(F)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-methylcyclopropyl 4-[(1R,2S)-2-{2-[3-fluoro-4-(2-methoxy-2-oxoethyl)phenoxy]ethyl}cyclopropyl]piperidine-1-carboxylate (0.450 g, 1.04 mmol) in 14 ml anhydrous tetrahydrofuran was added by 7 ml methanol and 7 ml water. Lithium hydroxide (0.393 g, 16.39 mmol) was added into the reaction mixture, and the reaction was stirred at RT overnight. 1 M hydrochloric acid was added to adjust the pH to 4. The volatiles were removed under vacuum, and the remaining aqueous layer was extracted with dichloromethane (3×50 ml). The organics were combined, dried over magnesium sulphate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified on Biotage column (50 g silica gel) using a gradient eluent of 0-70% ethyl acetate in hexanes (700 ml) to afford the title compound. LC/MS (m/z) 420.2 (M+H)+.
Reaction SMILES: CO[C:3](=[O:24])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:25][NH:26][C:27]([NH2:29])=[O:28].C[O-].[Mg+2].C[O-].CO>C(OCC)(=O)C>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([C:20]([F:21])([F:23])[F:22])(=[O:19])=[O:18])[CH:12]=2)[C:3]([NH:29][C:27]([NH:26][CH3:25])=[O:28])=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)C(CC1CCCC1)c1cccc(S(=O)(=O)C(F)(F)F)c1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1cccc(S(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Yield: 45.4 %

Procedure:
3-Cyclopentyl-2-(3-trifluoromethanesulfonyl-phenyl)-propionic acid methyl ester (500 mg, 1.37 mmol) and methyl urea (305 mg, 4.12 mmol) were treated with a solution of magnesium methoxide in methanol (7.4 wt %, 5.9 mL, 4.12 mmol). The reaction mixture was then concentrated in vacuo to approximately one-half the volume of methanol. The resulting reaction mixture was then heated under reflux for 15 h. The reaction mixture was allowed to cool to 25° C., diluted with ethyl acetate (10 mL), and then filtered through celite. The celite was thoroughly washed with ethyl acetate. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2-(3-trifluoromethanesulfonyl-phenyl)-propionyl]-3-methyl-urea (253 mg, 45%) as a white foam: mp 59-62° C. (foam to gel); EI-HRMS m/e calcd for C17H21F3N2O4S (M+) 406.1174, found 406.1178.
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH:23]2[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25][N:24]2[C:36]([O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:37])[CH:16]=1>CO>[ClH:1].[ClH:1].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH:23]2[CH2:28][NH:27][CH2:26][CH2:25][N:24]2[C:36]([O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:37])[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Oc2ccccc2)C(COc2cccnc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Oc1ccccc1)N1CCNCC1COc1cccnc1
Reaction time: 1 h
Yield: 91 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of 4-tert-butyl 1-phenyl 2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate TFA salt (108.2 mg, 0.205 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure, yielding 72.3 mg (91%) of the desired product as a white solid. LC-MS: RT=3.89 min, [M+H]+=314.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:11]=2)=[O:9])[CH:3]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[N:34]=[N:35][N:36]([CH2:38][C:39](O)=[O:40])[CH:37]=1>>[Si:22]([O:21][CH2:20][C:19]([N:12]1[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:39](=[O:40])[CH2:38][N:36]3[CH:37]=[C:33]([C:32]([F:42])([F:31])[F:43])[N:34]=[N:35]3)[CH:7]=[CH:6][N:5]=2)=[O:9])=[CH:11]1)([CH3:30])[CH3:29])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cc(N)ccn2)c2cnccc21
Reactant: O=C(O)Cn1cc(C(F)(F)F)nn1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cc(NC(=O)Cn3cc(C(F)(F)F)nn3)ccn2)c2cnccc21

Procedure:
Prepared according to the method described for Method M (Example 206) using (4-aminopyridin-2-yl)[1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Preparation 27) and [4-(Trifluoromethyl)-1H-1,2,3-triazol-1-yl]acetic acid (Preparation 90). The residue was purified using alumina eluting with 3% MeOH in DCM to afford the title compound.