Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:48]=[CH:47][N:46]=[C:45]([O:49][CH3:50])[CH:44]=2)=[CH:38][C:37]=1[CH3:51].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:8]=[CH:13][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:51])=[CH:38][C:39]([C:43]6[CH:48]=[CH:47][N:46]=[C:45]([O:49][CH3:50])[CH:44]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: COc1cc(-c2cc(C)c(Br)c(C)c2)ccn1
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ccnc(OC)c6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-(4-bromo-3,5-dimethyl-phenyl)-2-methoxy-pyridine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 9): tR=1.30 min; Mass spectrum (ESI+): m/z=554 [M+H]+.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13]([CH2:22][C:23]3[CH:24]=[C:25]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[CH:26]=[CH:27][CH:28]=3)[N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:21][O:20][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[C:11]([NH:10][S:7]([C:5]1[S:6][CH:2]=[CH:3][CH:4]=1)(=[O:8])=[O:9])=[N:12][N:13]2[CH2:22][C:23]1[CH:24]=[C:25]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[CH:26]=[CH:27][CH:28]=1
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(C)=O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc2c1c(NS(=O)(=O)c1cccs1)nn2Cc1cccc(CNC(C)=O)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
To a cooled (ice/water bath) solution of N-[(3-{[3-{[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1H-indazol-1-yl]methyl}phenyl)methyl]acetamide (for a preparation see Example 1) (30 mg, 0.06 mmol) in THF (1 mL) was added dropwise 2M lithium aluminium hydride in THF (0.074 mL, 0.149 mmol), and the suspension was stirred 10 min at 0° C. and then at room temperature for one hour. Reaction was quenched with 4 drops of water and then with aqueous solution of sodium hydroxide (2M, 0.5 mL). After stirring for 30 min, solid was removed and washed with THF (10 mL). The filtrate was concentrated under reduced pressure and the residue was dissolved in 1:1 MeOH-DMSO (1 mL) and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a TFA modifier (Method B). The solvent from appropriate fractions was evaporated under a stream of nitrogen in a Radleys blowdown apparatus to give the title compound (18 mg, 64%). LCMS (System A) RT=0.89 min, ES+ve m/z 471 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:28][O:29][CH2:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.CC(C)([O-])C.[K+]>COCCOC.O.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>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:35]4[CH:34]=[CH:33][CH:32]=[C:31]([CH2:30][O:29][CH3:28])[CH:36]=4)=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1
Reactant: COCc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COCc1cccc(-c2ccc(S(=O)(=O)Nc3cc(N4C[C@@H](C)N[C@@H](C)C4)ccc3OC)cc2)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]benzenesulfonamide (E106) (100 mg, 0.22 mmol) and {3-[(methyloxy)methyl]phenyl}boronic acid (75 mg, 0.45 mmol) in DME (3 ml) was added potassium tert-butoxide (220 mg, 1.96 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was then evaporated and purified by SCX followed by mass directed autoprep HPLC to afford the title compound (E117). MS (ES+) m/e 496 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[NH2:9].[BrH:16].BrBr>O>[NH2:9][C:8]1[C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][C:5]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][C:7]=1[Br:16]
Reactant: Br
Reactant: Nc1ccc(S(N)(=O)=O)cc1C(F)(F)F
Agent: BrBr
Solvent: O
Product: Nc1c(Br)cc(S(N)(=O)=O)cc1C(F)(F)F

Procedure:
A suspension of 0.69 g. (0.029 moles) of 3-trifluoromethyl-4-aminobenzenesulfonamide in 7 ml. of water and 7 ml. of 48% hydrobromic acid is treated dropwise with 0.16 ml. of liquid bromine and stirred for 3 hours at room temperature. The reaction mixture is filtered, the solid material washed with 10% aqueous sodium bicarbonate, water and dried. The dried solid is recrystallized from toluene affording 0.76 g. of 4-amino-3-bromo-5-trifluoromethylbenzenesulfonamide m.p. 248°-252° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:25][CH3:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:27]([CH2:29][NH2:30])[OH:28].C(N(C(C)C)CC)(C)C.Cl>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([CH2:21][C:22]([NH:30][CH2:29][CH2:27][OH:28])=[O:23])=[CH:19][CH:20]=3)[CH:11]=[C:10]([CH2:25][CH3:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: CCc1cc(Cc2ccc(CC(=O)Cl)cc2)nc(-c2cccc(Cl)c2)n1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cc(Cc2ccc(CC(=O)NCCO)cc2)nc(-c2cccc(Cl)c2)n1
Reaction time: 3 h
Yield: 43.9 %

Procedure:
To a stirred solution of crude 2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)acetyl chloride (˜0.20 mmol) in dichloromethane (8 mL) at 0° C. was added ethanolamine (0.060 mL, 1.00 mmol) followed by diisopropylethylamine (0.17 mL, 1.00 mmol). After stirring for 3 h, the reaction mixture was diluted with dichloromethane (50 mL) and water (5 mL). The mixture was acidified with 2N aqueous HCl until pH˜5. The organic layer was washed with saturated sodium chloride (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent followed by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford the title compound (0.036 g, 45%) as a white solid. MW=409.91. M.p. 136-138° C. 1H NMR (DMSO-d6, 500 MHz) δ 8.37-8.31 (m, 2H), 8.02-7.96 (m, 1H), 7.59 (dt, J=6.5, 2.0 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 7.25 (s, 1H), 7.20 (d, J=8.0 Hz, 2H), 4.63 (t, J=5.0 Hz, 1H), 4.09 (s, 2H), 3.40-3.35 (m, 4H), 3.90 (q, J=6.0 Hz, 2H), 2.77 (q, J=7.5 Hz, 2H), 1.26 (t, J=7.5 Hz, 3H); APCI MS m/z 410 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([CH:22]=[C:23]2[S:27][C:26](=[S:28])[NH:25][C:24]2=[O:29])[CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[C:14]([F:17])([F:16])[F:15].[CH3:30]I.[Al]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([CH:22]=[C:23]2[S:27][C:26]([S:28][CH3:30])=[N:25][C:24]2=[O:29])[CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[C:14]([F:17])([F:16])[F:15]
Reactant: CI
Reactant: COc1cc(C=C2SC(=S)NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Agent: [Al]
Solvent: CN(C)C=O
Product: COc1cc(C=C2SC(SC)=NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F

Procedure:
To a solution of 4-[2-Methoxy-4-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile (500 mg, 1.15 mmol) in DMF (5 mL) was added CH3I (15 mL) and the solution was heated to 40° C. in an aluminum heating block for 8 h. The solvent was concentrated in vacuo to afford the product. 1H NMR (400 Hz, CDCl3) δ 7.97 (bs, 1H), 7.68 (dd, 1H), 7.63 (s, 1H), 7.17 (m, 3H), 6.77 (d, 1H), 3.08 (s, 3H), 2.95 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]=[C:4]([CH:7]([O:10][CH3:11])[O:8][CH3:9])[C:5]#[N:6].[CH3:12][O-:13].[Na+]>C1(C)C=CC=CC=1.CO>[CH3:11][O:10][CH:7]([O:8][CH3:9])[CH:4]([CH:3]([O:13][CH3:12])[O:2][CH3:1])[C:5]#[N:6]
Reactant: C[O-]
Reactant: COC=C(C#N)C(OC)OC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(OC)C(C#N)C(OC)OC
Temperature: 25 °C

Procedure:
In a mixed solvent of 100 ml of toluene and 50 ml of methanol was dissolved 7.85 g (50 mmoles) of 2-methoxymethylene-3,3-dimethoxypropanenitrile. To the resulting solution was added 9.65 g (50 mmoles) of a 28 wt. % solution of sodium methylate in methanol and the mixture was stirred at room temperature for one and a half hours. Subsequently, the reaction mixture was concentrated under reduced pressure to remove the methanol by distillation. To the resulting residue was added 25 ml of water and the toluene layer was separated followed by drying over anhydrous sodium sulfate. The thus dried toluene solution was distilled to obtain 8.50 g (45 mmoles) of 2-dimethoxymethyl-3,3-dimethoxypropanenitrile as a colorless transparent oil boiling at 90°-93° C./2 mmHg.
Reaction SMILES: NC(N)=S.[C:5]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([F:31])=[C:13]([C@@:15]2([NH:23]C(=O)OC(C)(C)C)[C@:19]([F:22])([CH2:20][OH:21])[CH2:18][O:17][CH2:16]2)[CH:14]=1)(=[O:7])[CH3:6].FC(F)(F)C(O)=O.C(N(CC)CC)C.[C:46]([N:54]=[C:55]=[S:56])(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>ClCCl>[C:5]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([F:31])=[C:13]([C@@:15]2([NH:23][C:55]([NH:54][C:46](=[O:53])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[S:56])[C@:19]([F:22])([CH2:20][OH:21])[CH2:18][O:17][CH2:16]2)[CH:14]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Nc1ccc(F)c([C@]2(NC(=O)OC(C)(C)C)COC[C@@]2(F)CO)c1
Reactant: O=C(N=C=S)c1ccccc1
Agent: NC(N)=S
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccc(F)c([C@]2(NC(=S)NC(=O)c3ccccc3)COC[C@@]2(F)CO)c1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 82.8 %

Procedure:
Scheme 2, step I, (deprotection and thiourea formation): A solution of tert-butyl N-[(3S,4S)-3-(5-acetamido-2-fluoro-phenyl)-4-fluoro-4-(hydroxymethyl)tetrahydrofuran-3-yl]carbamate (2.70 g, 6.99 mmol) in dichloromethane (40 mL) and trifluoroacetic acid (8.00 mL, 106 mmol) is stirred at ambient temperature for 150 minutes. The reaction is concentrated under reduced pressure and azeotroped with toluene. The residue is dissolved in tetrahydrofuran and treated with triethylamine (1.10 mL, 7.89 mmol) and benzoyl isothiocyanate (1.00 mL, 7.41 mmol). The reaction is stirred at ambient temperature for 16.5 hours and is then quenched with a solution of saturated sodium bicarbonate in water, extracted with ethyl acetate and dichloromethane consecutively. The organic layers are combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by silica gel flash chromatography, eluting with methanol/dichloromethane (0:10) to methanol/dichloromethane (1:10) to give the title compound (2.60 g, 83%). ES/MS (m/e): 450 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[S:6][CH:7]=1.C(=O)(O)[O-].[Na+].[C:23]([C:25]1[C:26]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:27]2[CH2:34][CH2:33][CH2:32][C:28]2=[N:29][C:30]=1[S-:31])#[N:24].[Na+]>O>[C:23]([C:25]1[C:26]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:27]2[CH2:34][CH2:33][CH2:32][C:28]2=[N:29][C:30]=1[S:31][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[S:6][CH:7]=1)#[N:24]
Reactant: N#Cc1c([S-])nc2c(c1-c1ccccc1)CCC2
Reactant: COC(=O)c1ccc(-c2nc(CCl)cs2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(-c2nc(CSc3nc4c(c(-c5ccccc5)c3C#N)CCC4)cs2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
315 mg (1.18 mmol) of methyl 4-[4-(chloromethyl)-1,3-thiazol-2-yl]benzoate (prepared as described in WO 2005/011685) and 329 mg (3.92 mmol) of sodium bicarbonate are added to the reaction mixture from Example 18A, and the mixture is stirred at RT for 16 h. 50 ml of water were added, and the reaction was extracted with ethyl acetate. The organic phase was washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate and freed from the solvent on a rotary evaporator. The residue was purified by preparative HPLC (column: YMC GEL ODS-AQ S-5, 15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:22]([F:23])=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15]OS(C)(=O)=O)=[CH:10][C:9]=2[F:24])[C:6](=[O:25])[CH:5]=[CH:4][C:3]=1[C:26](=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34].[CH:36]1([O:41][C:42](=[O:49])[C@@H:43]([CH2:45][CH:46]([CH3:48])[CH3:47])[NH2:44])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[NH2:1][C:2]1[N:7]([C:8]2[C:22]([F:23])=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15][NH:44][C@@H:43]([C:42]([O:41][CH:36]3[CH2:37][CH2:38][CH2:39][CH2:40]3)=[O:49])[CH2:45][CH:46]([CH3:47])[CH3:48])=[CH:10][C:9]=2[F:24])[C:6](=[O:25])[CH:5]=[CH:4][C:3]=1[C:26](=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34]
Reactant: CC(C)C[C@@H](N)C(=O)OC1CCCC1
Reactant: CS(=O)(=O)OCCCOc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)c(F)c1
Product: CC(C)C[C@@H](NCCCOc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)c(F)c1)C(=O)OC1CCCC1

Procedure:
From Intermediate 4F and D-Leucine cyclopentyl ester, LCMS purity 95%, m/z 618 [M+H]+, 1H NMR (300 MHz, DMSO), δ: 10.10 (1H, brs), 9.40-9.10 (2H, m), 8.15 (1H, br s), 7.62-7.52 (1H, m), 7.47-7.31 (2H, m), 7.28-7.12 (1H, m), 7.07 (2H, d, J=10.5 Hz), 5.73 (1H, d, J=9.6 Hz), 5.30-5.20 (1H, m), 4.25-4.00 (3H, m), 3.30-3.00 (2H, m), 2.20-2.00 (2H, m), 1.95-1.80 (2H, m), 1.75-1.55 (10H, m), 1.00-0.90 (6H, m).
Reaction SMILES: CO[C:3](=[O:21])[C@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[NH2:5].[C:22]1([N:28]=[C:29]=[S:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:14]([O:13][C:11]([NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:4]1[NH:5][C:29](=[S:30])[N:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:3]1=[O:21])=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Reactant: S=C=Nc1ccccc1
Product: O=C(NCCCCC1NC(=S)N(c2ccccc2)C1=O)OCc1ccccc1

Procedure:
Using an analogous procedure to Example 1 Nε-benzyloxycarbonyl-L-lysine methyl ester may be reacted with phenyl isothiocynate to give the title compound.
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.[N+:24]([C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1)([O-:26])=[O:25].C(Cl)Cl.CO>C1COCC1>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]2[N:15]([CH:21]=[C:12]([C:9]3[CH:10]=[CH:11][C:6](/[CH:5]=[CH:31]/[C:30]4[CH:33]=[CH:34][C:27]([N+:24]([O-:26])=[O:25])=[CH:28][CH:29]=4)=[CH:7][CH:8]=3)[N:13]=2)[CH:16]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc2nc(-c3ccc(CO[PH](=O)[O-])cc3)cn2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc2nc(-c3ccc(/C=C/c4ccc([N+](=O)[O-])cc4)cc3)cn2c1
Yield: 24.2 %

Procedure:
Prepared as described in the Alkene Formation section using sodium hydride (60% dispersion in mineral oil, 7 mg, 0.307 mmol), diethyl[4-(6-methylimidazo[1,2-a]pyridin-2-yl)benzyl phosphonate (100 mg, 0.279 mmol) and 4-nitrobenzaldehyde (42 mg, 0.279 mmol) in THF (5 ml) to give the title compound (24 mg, 24%) as a yellow solid after work-up and flash chromatography (100:1 DCM/MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH2:17][CH2:16]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N2CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(N2CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Temperature: 80 °C

Procedure:
A mixture of EXAMPLE 2B (13 g) and lithium hydroxide hydrate (3.78 g) in dioxane (250 mL) and water (100 mL) at 95° C. was stirred for 16 hours and concentrated. The concentrate in water was heated at 80° C. and filtered. The filtrate was treated with 1M HCl (90 mL) and filtered.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH2:10])[S:9][C:5]=2[CH:4]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:36][O:37][C:38]1[CH:48]=[CH:47][C:46](/[CH:49]=[CH:50]\[C:51]2[CH:56]=[C:55]([O:57][CH3:58])[C:54]([O:59][CH3:60])=[C:53]([O:61][CH3:62])[CH:52]=2)=[CH:45][C:39]=1[O:40][CH2:41][C:42](O)=[O:43]>ClCCl.O>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH:10][C:42](=[O:43])[CH2:41][O:40][C:39]3[CH:45]=[C:46](/[CH:49]=[CH:50]\[C:51]4[CH:56]=[C:55]([O:57][CH3:58])[C:54]([O:59][CH3:60])=[C:53]([O:61][CH3:62])[CH:52]=4)[CH:47]=[CH:48][C:38]=3[O:37][CH3:36])[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)O
Reactant: Nc1nc2ccc(C(F)(F)F)cc2s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)Nc1nc2ccc(C(F)(F)F)cc2s1
Yield: 783.2 %

Procedure:
To a solution of 6-(trifluoromethyl)-2-aminobenzothiazole (218 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetic ac id (1) (374 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (8i) (450 mg, 80% yield)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)/[S:6][C:5]1=[O:32].[Cl:33][CH2:34][S:35](Cl)(=[O:37])=[O:36]>>[Cl:33][CH2:34][S:35]([NH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]([F:30])([F:29])[F:31])[N:15]=[CH:14]3)/[S:6][C:5]1=[O:32])(=[O:37])=[O:36]
Reactant: NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Reactant: O=S(=O)(Cl)CCl
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCNS(=O)(=O)CCl

Procedure:
1-Chloro-N-{2-[(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}-methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}methanesulfonamide was prepared from 3-(2-aminoethyl)-(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (from Example 49) and chloromethanesulfonyl chloride following General Procedure U.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)[CH:2]([CH3:4])[CH3:3].[CH2:14]([NH2:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([NH:22][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:10])[CH:2]([CH3:3])[CH3:4]
Reactant: NCCc1ccccc1
Reactant: CC(C)Cc1cccc(C(=O)O)c1
Product: CC(C)Cc1cccc(C(=O)NCCc2ccccc2)c1

Procedure:
Using preparation method 1, 94B (131 mg, 0.74 mmol) was reacted with phenethylamine (138 μL, 133 mg, 1.1 mmol). Purification by flash chromatography on SiO2 using CH2Cl2/hexanes 50:50 then CH2Cl2 100% afforded white crystals were obtained (177 mg, 86%). NMR 1H (ppm, CDCl3): 7.50 (s, 1H), 7.47 (dt, J3=7.0 Hz, J4=1.8 Hz, 1H), 7.33-7.21 (m, 7H), 6.28 (br. s, 1H), 3.72-3.66 (m, 2H), 2.92 (t, J3=7.0 Hz, 2H), 2.48 (d, J3=7.2 Hz, 2H), 1.90-1.81 (m, 1H), 0.88 (d, J3=6.6 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].Cl.[OH-].[NH4+].[CH:13](O)=O>>[CH3:9][C:3]1[C:2]2[N:1]=[CH:13][NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cccc(N)c1N
Reactant: O=CO
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cccc2[nH]cnc12

Procedure:
To a flask were added 2.0 g 2,3-diaminotoluene, 1.0 g 90% formic acid and 30 ml 5M hydrochloric acid and the mixture was heated to 90 C under nitrogen for 4 hours. After cooling to 22 C, the mixture was basified with aqueous ammonium hydroxide and the product was removed by filtration and washed with water. The product was purified by column chromatography using pure ethyl acetate resulting in 1.0 g brown solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=3Br)[C:21]#[N:22])=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:27])[CH:5]=1)(=[O:3])[CH3:2].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=3[N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:21]#[N:22])=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:27])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C#N)ccc3Br)CC2)c(F)c1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C#N)ccc3N3CCOCC3)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described for example 1 from 3-[4-(4-Acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-bromo-benzonitrile (example L) and morpholine (71%, white solid), MS (m/e): 437.2 (M+H, 100%)