Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[NH2:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19][CH2:20][C@@H:21]([C:30]([OH:32])=O)[NH:22][O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].CN(C=O)C>CCOC(C)=O>[CH3:26][C:25]([CH3:28])([CH3:27])[C:24]([O:23][NH:22][C@@H:21]1[C:30](=[O:32])[NH:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[S:19][CH2:20]1)=[O:29]
Reactant: CC(C)(C)C(=O)ON[C@@H](CSc1cccc(F)c1N)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)ON[C@H]1CSc2cccc(F)c2NC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 10.8 %

Procedure:
0.366 mL of diethyl cyanophosphonate (0.393 mg, 2.41 mmol) is placed in a 25 mL three-necked flask containing 670 mg of 49 (2.028 mmol) and 10 mL of DMF, at 0° C., followed by addition, after 10 minutes, of 0.273 mL of TEA (1.943 mmol). The reaction medium is stirred at 0° C. for 2 hours. 30 mL of EtOAc are added and the mixture is then washed with twice 30 mL of distilled water. The organic phase is dried over MgSO4, filtered and then evaporated to dryness. The crude product is chromatographed on a silica cartridge (70 g) with a heptane/EtOAc eluent (as an EtOAc gradient: 8% to 50%). 68.4 mg of expected product 50 are obtained (white solid).
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][C:21](=[O:29])[O:20]1>>[CH:1]1([C:5]2[N:6]=[C:7](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([NH:18][C:21](=[O:29])[CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[CH2:19][OH:20])[CH:15]=[CH:16][CH:17]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Reactant: O=C1Cc2ccccc2CO1
Product: O=C(Cc1ccccc1CO)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1

Procedure:
A solution of 0.256 g of (E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzeneamine and 0.148 g of 3-isochromanone was heated in a 126° C. oil bath for 17 hr. The residual materials were purified by silica gel chromatography using ethyl acetate-hexane (1:4 v/v) as the eluant to yield (E)-2-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzyl alcohol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:5][NH:6][C:7]([CH:9]([CH3:27])[C:10]([NH:12][CH:13]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:8].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.[CH3:52][O:53][C:54]1[CH:55]=[C:56]2[C:61](=[CH:62][CH:63]=1)[CH2:60][NH:59][CH2:58][CH2:57]2.CC#N>CN(C=O)C.C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:5][NH:6][C:7](=[O:8])[CH:9]([CH3:27])[C:10]([NH:12][CH:13]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[C:14]([N:59]1[CH2:58][CH2:57][C:56]2[C:61](=[CH:62][CH:63]=[C:54]([O:53][CH3:52])[CH:55]=2)[CH2:60]1)=[O:15])=[O:11]
Reactant: CC(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)O
Reactant: COc1ccc2c(c1)CCNC2
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1ccc2c(c1)CCN(C(=O)C(Cc1c[nH]c3ccccc13)NC(=O)C(C)C(=O)NCc1cc(F)cc(F)c1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[2-(3,5-Difluoro-benzylcarbamoyl)-propionylamino]-3-(1H-indol-3-yl)-propionic acid (64 mg, 0.15 mmol) was placed in a disposable polypropylene tube and dissolved in DMF (1 ml). TPTU (O-[2-oxo-1(2H)-pyridyl]-N,N,N′,N′-tetramethyluronium-tetrafluoroborate, 49 mg, 0.165 mmol) and 6-methoxy-1,2,3,4-tetrahydro-isoquinoline (24 mg, 0.15 mmol) were added, and the mixture was shaken overnight at r.t. The title compound, MS: m/e=575.3 (M+H+), was isolated from the reaction mixture by automated, preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].Cl[C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1>CN(C=O)C>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:14]2[N:13]=[CH:12][CH:20]=[CH:19][C:15]=2[C:16]([NH2:18])=[O:17])=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(Oc2ncccc2C(N)=O)cc1
Temperature: 25 °C
Yield: 20 %

Procedure:
4-Hydroxyacetophenone (1 equiv), 6-chloronicotinamide (1 equiv) and K2CO3 (1.4 equiv) in anhydrous DMF (0.4 M) was heated at 150° C. under nitrogen during 2.5 days. After cooling down to room temperature, toluene was added and solvents were evaporated. The residue was partitioned in water/EtOAc. The aqueous layer was thoroughly extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum (toluene was added to aid DMF evaporation). The crude mixture was purified by flash chromatography using EtOAc/CH2Cl2/2 M NH3 in MeOH (12:7:1) as eluent in 20% yield.
Reaction SMILES: [CH2:1]=[C:2]([CH2:5][OH:6])[CH2:3][OH:4].C([Sn](=O)CCCC)CCC.CN1C=CN=C1.[S:23](Cl)([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>C1(C)C=CC=CC=1.O>[C:29]1([CH3:30])[CH:31]=[CH:32][C:26]([S:23]([O:4][CH2:3][C:2](=[CH2:1])[CH2:5][OH:6])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: C=C(CO)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCCC[Sn](=O)CCCC
Agent: Cn1ccnc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(CO)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.4 %

Procedure:
2-Methylene-1,3-propanediol (480 mg) and dibutyltinoxide (1,7 g) were dissolved in toluene (30 ml) and the resulting suspension was refluxed for 1 hour eliminating water with the help of a Dean-Stark apparatus. The flask was cooled down to room temperature and then, N-methyl-imidazol (797 ml) and tosyl chloride (1,56 g) were added. After 15 minutes stirring, the reaction crude was directly purified by column chromatography (hexane-ethyl acetate v/v from 7:1 to 1:1). The title compound (428 mg) was obtained as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([C:34](=[O:37])[CH:35]=[CH2:36])[C@@H:11]([C:15]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](=[O:32])[C:22]2[C:17](=[CH:18][C:19]([Cl:33])=[CH:20][CH:21]=2)[N:16]=1)[CH:12]([CH3:14])[CH3:13])(C)(C)C.C(OC(=O)NCCN[C@@H](C1N(CC2C=CC=CC=2)C(=O)C2C(=CC(Cl)=CC=2)N=1)C(C)C)(C)(C)C>>[CH2:25]([N:24]1[C:23](=[O:32])[C:22]2[C:17](=[CH:18][C:19]([Cl:33])=[CH:20][CH:21]=2)[N:16]=[C:15]1[C@H:11]([N:10]1[C:34](=[O:37])[CH2:35][CH2:36][NH:7][CH2:8][CH2:9]1)[CH:12]([CH3:13])[CH3:14])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C=CC(=O)N(CCNC(=O)OC(C)(C)C)[C@@H](c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C
Agent: CC(C)[C@@H](NCCNC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Product: CC(C)[C@H](c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N1CCNCCC1=O

Procedure:
(2-{Acryloyl-[(R)-1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-amino}-ethyl)-carbamic acid tert-butyl ester: According to the procedure of Example 1c above, {2-[(R)1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propylamino]-ethyl}-carbamic acid tert-butyl ester (211 mg, 0.44 mmol) was converted to the title compound as a white solid: MS (ES) m/e 539.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=1[F:39])\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[F:39])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(F)c1F
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(F)c2F)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 26.4 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (640 mg, 0.003 mol) in N,N-dimethylformamide (7 mL) was added N,N-diisopropylethylamine (2.00 g, 0.015 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(2,3-difluoro-phenoxy)-but-2-enoic acid ethyl ester (1.00 g, 0.003 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(2,3-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (300 mg, 23%) as yellow oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH2:36][CH2:37][OH:38])[CH:33]=2)[NH:28][C:27]=1[C:39]([OH:41])=O.[NH2:42][CH2:43][C:44]1[C:45]([F:61])=[C:46]([O:51][C:52]2[CH:53]=[C:54]([CH:57]=[C:58]([Cl:60])[CH:59]=2)[C:55]#[N:56])[C:47]([Cl:50])=[CH:48][CH:49]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH2:36][CH2:37][OH:38])[CH:33]=2)[NH:28][C:27]=1[C:39]([NH:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[C:46]([O:51][C:52]2[CH:53]=[C:54]([C:55]#[N:56])[CH:57]=[C:58]([Cl:60])[CH:59]=2)[C:45]=1[F:61])=[O:41]
Reactant: O=C(O)c1[nH]c2ccc(OCCO)cc2c1Br
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[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: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c4ccc(OCCO)cc4c3Br)c2F)c1
Reaction time: 8 h
Yield: 51.3 %

Procedure:
HATU (0.061 g, 0.161 mmol) was added to a DMF (2 mL) solution of 3-bromo-5-[(2-hydroxyethyl)oxy]-1H-indole-2-carboxylic acid (0.048 g, 0.161 mmol), 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol) and DIPEA (0.028 mL, 0.161 mmol). The solution was stirred overnight and partitioned between water and EtOAc. The organic was washed with a 15% aqueous solution of Na2CO3, dried over MgSO4 and filtered. Evaporation of the EtOAc and trituration in acetone afforded the title compound (0.049 g, 47%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.91 (s, 1H), 8.49 (t, 1H), 7.77-7.89 (m, 1H), 7.51-7.57 (m, 2H), 7.43-7.51 (m, 2H), 7.37 (d, 1H), 6.96 (ddd, 1H), 6.89 (s, 1H), 4.86 (t, 1H), 4.62 (d, 2H), 4.02 (t, 1H), 3.69-3.82 (m, 1H). LCMS: m/z=592.2 (M+1).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]([C:11]#[N:12])[CH2:6][CH2:7][CH2:8][C:9]#[N:10])#[N:2].[C:13]([N:15]=[C:16]([NH2:18])[NH2:17])#[N:14].C[O-].[Na+]>CS(C)=O>[NH2:14][C:13]1[N:15]=[C:16]([NH2:18])[N:17]=[C:1]([CH2:3][CH2:4][CH:5]([C:11]2[N:17]=[C:16]([NH2:18])[N:15]=[C:13]([NH2:14])[N:12]=2)[CH2:6][CH2:7][CH2:8][C:9]2[N:17]=[C:16]([NH2:18])[N:15]=[C:13]([NH2:14])[N:10]=2)[N:2]=1
Reactant: N#CCCCC(C#N)CCC#N
Reactant: N#CN=C(N)N
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1nc(N)nc(CCCC(CCc2nc(N)nc(N)n2)c2nc(N)nc(N)n2)n1
Temperature: 130 °C
Yield: 70.6 %

Procedure:
161 g (1 mole) of 1,3,6-tricyanohexane and 277.2 g (3.3 moles) of dicyandiamide were added to 750 g of dimethyl sulfoxide as the reaction medium, followed by further addition of 68 g (1 mole) of sodium methylate as the catalyst. The mixture was stirred under heating at 130° C for 3 hours in a nitrogen atmosphere. After completion of the reaction the reaction mixture was cooled to 25° C to precipitate the reaction product, followed by separating the crude reaction product by filtration. Purification was conducted by dissolving the crude product in excess amount of dimethyl sulfoxide at 135° C and then precipitating the product by cooling. After repeating this procedure 5 times, 292 g of 1,3,6-tris(4,6-diamino-1,3,5-triazine-2-yl)hexane as a white powder were obtained.
Reaction SMILES: [F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4](Cl)=[O:5].[NH2:10][NH2:11]>CCOCC>[F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4]([NH:10][NH:11][C:4](=[O:5])[CH2:3][C:2]([F:1])=[C:7]([F:9])[F:8])=[O:5]
Reactant: O=C(Cl)CC(F)=C(F)F
Reactant: NN
Solvent: CCOCC
Product: O=C(CC(F)=C(F)F)NNC(=O)CC(F)=C(F)F
Temperature: -78 °C
Yield: 52.8 %

Procedure:
A solution of 3,4,4-trifluoro-3-butenoyl chloride (2.4 g, 0.0151 mole) in dry ether (20 mL) is treated dropwise with anhydrous hydrazine (0.48 g, 0.15 mole) with stirring at -78° C. The mixture is allowed to reach room temperature and the white precipitate is filtered and dissolved in ethyl acetate. The ethyl acetate solution is washed with 5% sodium bicarbonate and dried. Evaporation of the solvent gave 1.1 g of the desired product as a white solid, a 47% yield. m.p. 191°-193° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([CH2:15][O:16][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:11][C@@H:10]1[NH:34][C:35]([C:37]1[S:38][C:39]2[CH2:40][N:41]([CH3:46])[CH2:42][CH2:43][C:44]=2[N:45]=1)=[O:36])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([CH2:15][OH:16])[CH2:11][C@@H:10]1[NH:34][C:35]([C:37]1[S:38][C:39]2[CH2:40][N:41]([CH3:46])[CH2:42][CH2:43][C:44]=2[N:45]=1)=[O:36])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCc2nc(C(=O)N[C@H]3C[C@H](CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CC[C@@H]3NC(=O)OC(C)(C)C)sc2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN1CCc2nc(C(=O)N[C@H]3C[C@H](CO)CC[C@@H]3NC(=O)OC(C)(C)C)sc2C1
Yield: 67.5 %

Procedure:
(1S,2S,4R)-N1-tert-Butoxycarbonyl-4-(tert-butyldiphenylsilyloxymethyl)-N2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine (1.25 g) was dissolved in tetrahydrofuran (30 ml), and tetrabutylammonium fluoride (1 M solution, 2.5 ml), and the mixture was stirred at room temperature for 3 days. After the solvent was distilled off under reduced pressure, dichloromethane was added, and the reaction mixture was washed with water, the resultant organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methanol:dichloromethane=1:20-1:10) to obtain the title compound (540 mg) as a pale yellow amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:13][C:14]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])[CH3:15].[Cl-].[NH4+]>C1COCC1>[C:14]([Si:17]([CH3:19])([CH3:18])[N:8]1[C:5]2=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=[CH:9]1)([CH3:16])([CH3:15])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Clc1cnc2[nH]ccc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)n1ccc2cc(Cl)cnc21
Temperature: 0 °C
Yield: 82.4 %

Procedure:
In a sealed tube equipped with a septa under nitrogen was added 42 (600 mg, 0.00396 mol) and 20 mL of dry THF and the solution cooled to 0° C. NaH (110 mg, 0.00435 mol) was added portionwise and after 15 min. of stirring at 0° C., TBSCl (656 mg, 0.00435 mol) was added. The septa was replaced by a Teflon screw cap and the sealed tube heated at 80° C. for 3 h. Cooled and neutralized with ammonium chloride solution and extracted with hexanes. The organic phase was dried and concentrated in vacuo to an oil that was subjected to a short plug filtration (10% EtOAC-90% hexanes) to give 871 mg (82%) of compound 43. 1H NMR (500 MHz, CDCl3) 8.2 (s, 1H), 7.8 (s, 1H), 7.25 (s, 1H), 6.4 (s, 1H), 0.9 (s, 9H), 0.6 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7](F)=[C:6]([S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:23])[C@:16]([OH:22])([CH3:21])[C:17]([F:20])([F:19])[F:18].[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[C:7]([O:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:6]([S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:23])[C@:16]([OH:22])([CH3:21])[C:17]([F:20])([F:19])[F:18]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1Oc1ccccc1
Temperature: 150 °C
Yield: 19.8 %

Procedure:
(R)-N-[2-Chloro-3-fluoro-4-(ethylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 15; 0.308 g) was added to a stirred suspension of phenol (0.150 g) and anhydrous potassium carbonate (0.220 g) in anhydrous DMF (2 ml). The reaction mixture was heated to 150° C. under argon for 17 hours and allowed to cool to ambient temperature. EtOAc (50 ml) was added and the organic phase was washed with brine (4×50 ml), separated, dried and volatile material was removed by evaporation. The residue was purified on a 8 g silica Biotage cartridge eluting 40% EtOAc/isohexane to give the title compound (0.073 g) as a pale yellow foam. NMR (CDCl3): 1.18 (t, 3H), 1.69 (s, 3H), 3.23-3.30 (q, 2H), 3.48 (s, 1H), 6.78 (d, 2H), 7.02 (t, 1H), 7.24 (t, 2H), 7.97 (d, 1), 8.50 (d, 1H), 9.24 (brs, 1H); m/z: 450.
Reaction SMILES: [C:1]1(=[C:8]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[P:17](=[O:24])([O:21]CC)[O:18][CH2:19][CH3:20])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CCO>[C:1]1(=[C:8]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[P:17](=[O:21])([OH:24])[O:18][CH2:19][CH3:20])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOP(=O)(/C=C/c1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOP(=O)(O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
To a solution of diethyl (E)-2-{-4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}ethenylphosphonate (63) (0.051 g, 0.115 mmol) in EtOH (4 mL) was added aqueous NaOH (1 mL of a 5M solution, 5 mmol). The solution was heated to reflux for 4 h, then cooled to RT and concentrated. The residue was dissolved in water (1 mL) and the pH adjusted to ˜2 with with1 N aqueous HCl. The mixture was extracted with EtOAc (2×10 mL). The organics were dried (Na2SO4) and concentrated to provide compound 64 (0.041 g, 86%) as a waxy yellow solid. 1H NMR (DMSO-d6): δ 9.28 (s, 1H), 7.53 (d, J=8.1 Hz, 2H), 7.20 (dd, J=22.0 Hz, 17.6 Hz, 1H), 7.10 (d, J=8.1 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 6.65 (d, J=8.4 Hz, 2H), 6.41 (t, J=17.6 Hz, 1H), 3.90-3.84 (m, 2H), 2.20 (m, 4H), 1.50 (m, 8H), 1.18 (t, J=6.9 Hz, 3H). LRMS (ESI): m/z 411 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[C:6]([CH:12]([O:14][CH2:15][C:16]3([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=O)[CH2:18][CH2:17]3)[CH3:13])[CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][N:3]=1.C([BH3-])#N.[Na+].C=O.C(O)(=O)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:10]2[C:5](=[C:6]([CH:12]([O:14][CH2:15][C:16]3([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH3:13])[CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][N:3]=1
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2c(Cl)n[nH]c12
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CC(OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(Cl)cc2c(Cl)n[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-tert-Butyl 4-((1-(3,5-dichloro-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (120 mg, 0.23 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 2 mL) and stirred at room temperature for 1 h. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2 M ammonia in methanol and concentrated. The resulting residue was dissolved in acetonitrile (2 mL), cooled to 0° C., and treated with sodium cyanoborohydride (72 mg, 1.15 mmol) and formalin (0.84 mL). After 5 min, the reaction was treated with a drop of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was concentrated and purified by preparative HPLC to afford 30 mg (30%) as a clear oil. 1H-NMR (CD3OD, 500 MHz) δ 7.53 (d, J=1.8 Hz, 1H), 7.33-7.45 (m, 2H), 6.99-7.14 (m, 3H), 4.66 (q, J=6.7 Hz, 1H), 3.41-3.52 (m, 2H), 3.38 (qAB, JAB=9.2 Hz, 2H), 2.81-2.90 (m, 2H), 2.77(s, 3H), 2.61-2.69(m, 2H), 2.07-2.18 (m, 2H), 1.48 (m, 3H). Mass spec.: 442.44 (MH)+.
Reaction SMILES: ClC1C=CC(Cl)=CC=1CN1C2C=NC(C(OC)=O)=CC=2C2C1=CC=CC=2.S(=O)(=O)(O)O.[Cl:32][C:33]1[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][C:34]=1[CH2:35][N:36]1[C:48]2[CH:47]=[N:46][C:45]([C:49]([O:51][CH2:52][CH2:53][CH2:54]C)=[O:50])=[CH:44][C:43]=2[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2>C(O)CC>[Cl:32][C:33]1[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][C:34]=1[CH2:35][N:36]1[C:48]2[CH:47]=[N:46][C:45]([C:49]([O:51][CH2:52][CH2:53][CH3:54])=[O:50])=[CH:44][C:43]=2[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2
Reactant: CCCCOC(=O)c1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Agent: COC(=O)c1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Agent: O=S(=O)(O)O
Solvent: CCCO
Product: CCCOC(=O)c1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Yield: 74 %

Procedure:
Methyl 9-(2,5-dichlorobenzyl)-9H-β-carboline-3-carboxylate (195 mg, 0.5 mmol) was refluxed with n-propanol (15 mL) and concetrated sulfuric acid (1.5 mL) as described for the synthesis of the butyl 9-(2,5-dichlorobenzyl)-9H-β-carboline-3-carboxylate, affording an ivory-colored solid (152 mg, 74%). 1H NMR (CDCl3) δ8.94 (s, 1H), 8.85 (s, 1H), 8.28 (d, J=8.3 Hz, 1H), 7.64 (t, J=7.5 Hz, 1H), 7.45-7.40 (m, 3H), 7.22 (dd, J=8.5, 2.3 Hz, 1H), 6.55 (s, 1H), 5.66 (s, 2H), 4.45 (t,J=7 Hz, 2H), 1.93 (m, 2H), 1.07 (t, J=7 HZ, 3H); MS (APCI; (M+H)+) m/z 413.
Reaction SMILES: [C:1](=[O:13])([S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:2][CH:3](Cl)[CH3:4].[C:14]([OH:19])(=[O:18])[CH:15]([CH3:17])[CH3:16].C(N(CC)CC)C.[I-].[Na+]>C(OCC)C>[C:1](=[O:13])([S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:2][CH:3]([O:19][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[CH3:4]
Reactant: CC(Cl)OC(=O)Sc1ccccc1
Reactant: CC(C)C(=O)O
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(OC(=O)Sc1ccccc1)OC(=O)C(C)C
Temperature: 50 °C
Yield: 97 %

Procedure:
A mixture of compound (4) (10 g, 46 mmol), isobutyric acid (30 mL), triethylamine (30 mL) and sodium iodide (2 g) was stirred and heated in an oil bath at 50° C. for 3 days. The reaction mixture was diluted with diethyl ether (200 mL) and washed successively with water (3×100 mL), saturated aqueous sodium bicarbonate (2×100 mL) and 0.1 M aqueous potassium bisulfate (2×100 mL). The organic phase was separated, then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound (9) as a pale yellow liquid (12 g, 97%). 1H NMR (CDCl3, 400 MHz): δ 1.2 (d, 6H), 1.5 (d, 3H), 2.55 (m, 1H), 6.95 (q, 1H), 7.4-7.5 (m, 5H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14](O)=[O:15])=[CH:11][CH:12]=2)[C@H:7]([O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2].[NH3:26]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH2:26])=[O:15])=[CH:11][CH:12]=2)[C@H:7]([O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](Oc2ccc(Cl)cc2)C[C@@H]1C
Reactant: N
Product: CC(=O)N1c2ccc(C(N)=O)cc2[C@H](Oc2ccc(Cl)cc2)C[C@@H]1C

Procedure:
Reactions and treatments were carried out in the same manner as in Example 118, using 41.1 mg of (2S,4R)-1-acetyl-4-(4-chlorophenoxy)-2-methyl-1,2,3,4-tetra hydroquinoline-6-carboxylic acid instead of (2S,4R)-1-acetyl-2-methyl-4-(4-morpholinophenoxy)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid, and using aqueous ammonia instead of monomethylamine. Thus, 58.5 mg (95.6%, cis-form only) of the title compound was obtained as a white crystalline powder.