Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([C:16]1[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=1[C:18](=[O:37])[N:19]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:20]3=[O:25])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:39](C1C=CC=CC=1)C.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.[Pd]>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[O:33][CH3:34])[CH2:26][N:19]1[C:18](=[O:37])[C:17]2[C:21](=[CH:22][CH:23]=[CH:24][C:16]=2[N:11]2[CH2:10][CH:9]3[N:8]([CH:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH3:39])[CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[C:20]1=[O:25]
Reactant: COc1ccc(CN2C(=O)c3cccc(N4CC5CCC(C4)N5Cc4ccccc4)c3C2=O)cc1OC
Reactant: CC(Br)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)c3cccc(N4CC5CCC(C4)N5C(C)c4ccccc4)c3C2=O)cc1OC
Temperature: 50 °C
Yield: 38.5 %

Procedure:
Compound 7 (50 mg, 0.10 mmol) was hydrogenated (50 psi H2) with 10% Pd/C (5 mg) in EtOAc (1.0 mL) for 5 h. The mixture was filtered through Celite®, and concentrated in vacuo. The crude oil was dissolved in THF (0.4 mL). A portion of 1-bromoethylbenzene (0.03 mL, 0.22 mmol) and K2CO3 (36 mg, 0.26 mmol) were added. The mixture was heated to 50° C. for 4 h. The mixture was cooled to room temperature, filtered through Celite®, and concentrated in vacuo. The crude oil was purified on a Gilson HPLC with a reversed phase Kromasil column (10μ, 100 Å C18, column length 250×50 mm, gradient 90:10-0:100 H2O:MeCN) to give the 19.7 mg (38%) of the title Compound 32 as a yellow solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:39])=[C:11]([N:16]4[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:36])[C@H:24]([CH:33]([CH3:35])[CH3:34])[NH:25]C(OC(C)(C)C)=O)[C:18]([CH3:38])([CH3:37])[CH2:17]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:40])[C:6]([C:41]([OH:43])=[O:42])=[CH:5]2)[CH2:3][CH2:2]1.[ClH:44]>>[ClH:44].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:39])=[C:11]([N:16]4[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:36])[C@H:24]([CH:33]([CH3:35])[CH3:34])[NH2:25])[C:18]([CH3:38])([CH3:37])[CH2:17]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:40])[C:6]([C:41]([OH:43])=[O:42])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: COc1c(N2CCC(NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(C)(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: Cl
Product: COc1c(N2CCC(NC(=O)[C@@H](N)C(C)C)C(C)(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 75 %

Procedure:
1-Cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-7-{4′-(N-t-butoxycarbonyl-L-valyl)amino-3′,3′-dimethylpiperidin-1-yl)-4-oxo-quinoline-3-carboxylic acid (0.4 gm) is hydrolysed with 6N HCl (20 ml) at room temperature for 1 hr. The mixture concentrated to furnish the titled product. Yield 75%, m.p 150–55° C., C26H35FN4O5.HCl m/z 503 (M+1).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30].O>C(OCC)(=O)C>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:29](=[O:30])[CH2:28][Cl:27])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
1.00 g of 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine was dissolved in 20 ml of ethyl acetate. 0.54 ml of triethylamine was added to the solution, and the resulting mixture was cooled in an ice bath. 0.31 ml of 2-chloroacetyl chloride was added, and the mixture was stirred for 1 hour at room temperature. At the end of this time, water was added, and the reaction mixture was extracted with ethyl acetate. The extract was condensed by evaporation under reduced pressure, and the residue was purified by silica gel chromatography, eluted with a 1:19 by volume mixture of methanol and ethyl acetate, to give 0.94 g (yield 73%) of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([O:17][C@@H:18]([C@H:20]3[CH2:24][NH:23][C:22](=[O:25])[CH2:21]3)[CH3:19])[C:14]3[NH:26][CH:27]=[N:28][C:13]=3[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([O-])([O-])=O.[Cs+].[Cs+].I[CH:36]1[CH2:39][O:38][CH2:37]1>CN(C=O)C.CCOC(C)=O.O.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([O:17][C@@H:18]([C@H:20]3[CH2:24][NH:23][C:22](=[O:25])[CH2:21]3)[CH3:19])[C:14]3[N:26]([CH:36]4[CH2:39][O:38][CH2:37]4)[CH:27]=[N:28][C:13]=3[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc3nc[nH]c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC
Reactant: IC1COC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3ncn(C4COC4)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To crude (R)-4-((R)-1-(6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.09 (0.064 mmol) as a solution in DMF (1 mL) was added Cs2CO3 (52 mg, 0.16 mmol) followed by 3-iodo-oxetane (7.0 μL, 0.078 mmol). After stirring 30 min, the reaction temperature was increased to 60° C. After an additional 40 min, 3-iodo-oxetane (7.0 μL, 0.078 mmol) was added and the reaction temperature was increased to 100° C. After stirring an additional 35 min at 100° C., 3-iodo-oxetane (3.0 μL, 0.034 mmol) was added. After an additional 40 min, the reaction mixture was cooled to r.t. and was diluted with EtOAc (20 mL), water (10 mL), and brine (10 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (20 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated, and the crude product was purified by silica gel chromatography (0% to 10% MeOH in DCM) to afford (R)-4-((R)-1-(6-(3,4-dimethoxyphenyl)-3-(oxetan-3-yl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.14.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:42])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)=O)(C)(C)C>>[N:33]1[CH:34]=[CH:35][C:30]([C:28]2[CH2:27][C:26](=[O:42])[NH:19][C:9]3[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=3[N:7]=2)=[CH:31][C:32]=1[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(-c2cccnc2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1ccnc(-c3cccnc3)c1)=N2

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (116 mg, 0.4 mmol) and 3-[2,3′]bipyridinyl-4-yl-3-oxo-propionic acid tert-butyl ester (Example K57) (119 mg, 0.4 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (95 mg).
Reaction SMILES: C(=O)([O-])O.[Na+].[Cl:6][C:7]1[CH:30]=[CH:29][C:10]([O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2B2OC(C)(C)C(C)(C)O2)=[CH:9][CH:8]=1.Br[C:32]1[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[CH:34][N:33]=1>O1CCOCC1.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>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[C:32]2[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[CH:34][N:33]=2)=[CH:29][CH:30]=1
Reactant: CC1(C)OB(c2cc(C#N)ccc2Oc2ccc(Cl)cc2)OC1(C)C
Reactant: COc1cccnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccnc1-c1cc(C#N)ccc1Oc1ccc(Cl)cc1
Temperature: 85 °C
Yield: 18.6 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.325 g, 0.28 mmol) and 1M aqueous solution of sodium hydrogen carbonate (5.6 mL, 5.6 mmol) were added to 4-(4-chlorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (Preparation 13, 1.0 g, 2.8 mmol) and 2-bromo-3-methoxypyridine (0.528 g, 2.8 mmol) in 1,4-dioxane (30 mL). The mixture was heated at 85° C. for 18 hours under a nitrogen atmosphere, then cooled, diluted with water (30 mL) and extracted with EtOAc (3×30 mL). The organic layer was washed with water (2×30 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford an oil. The crude product was purified by silica gel chromatography eluting with 10 to 80% tert-butyl dimethyl ether in heptane to yield the title compound as a white solid (0.175 g).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH2:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COCCO[AlH2-]OCCOC.[Na+].[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1(C)C=CC=CC=1>[CH2:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[CH2:11][NH2:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cccc(Cc2ccccc2)c1
Agent: COCCO[Al+]OCCOC
Agent: COCCO[AlH2-]OCCOC
Agent: [H-]
Solvent: Cc1ccccc1
Product: NCc1cccc(Cc2ccccc2)c1
Temperature: 60 °C

Procedure:
To a solution of 3-(benzyl)benzamide (0.0094 moles) from Step B in 70 of toluene was added 8 mL of Red-Al® (65+wt. % solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene, Aldrich) (CAUTION—reaction very exothermic). The reaction mixture was then heated at 60° C. for 2 hours and then poured over ice. The resulting mixture was extracted with ethyl acetate and the combined extracts were washed with water and brine. The organic layer was extracted with 1N HCl and the aqueous layer washed with ethyl acetate. The pH of the aqueous layer was then adjusted to about 9.0 with 1N NaOH and extracted with ethyl acetate. The organic extracts were washed with water and brine and then concentrated to give 3-(benzyl)benzyl amine.
Reaction SMILES: [CH:1](OCC)=[O:2].[OH:6][C@@:7]1([CH3:27])[CH:12]=[CH:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C:16](=[CH:17][C:18](=[O:26])[CH2:19][CH2:20]1)[CH2:15][CH2:14]3.[H-].[Na+].Cl>O1CCCC1.C1(C)C=CC=CC=1>[OH:6][C@@:7]1([CH3:27])[CH:12]=[CH:11][C@H:10]2[C@H:13]3[C@H:23]([CH2:24][CH2:25][C@:8]12[CH3:9])[C@:21]1([CH3:22])[C:16](=[CH:17][C:18](=[O:26])/[C:19](=[CH:1]\[OH:2])/[CH2:20]1)[CH2:15][CH2:14]3
Reactant: CCOC=O
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1C=C[C@]2(C)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@]12C/C(=C/O)C(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1C=C[C@]2(C)O
Temperature: 0 °C
Reaction time: 6 h

Procedure:
At room temperature, 4.6 ml of ethyl formate is added to 4.6 g of 17β-hydroxy-17α-methylandrosta-4,15-dien-3-one in 40 ml of tetrahydrofuran and 70 ml of toluene. Then 3.5 g of sodium hydride (60% paraffin suspension) is added in small portions. After 6 hours, the reaction mixture is gently stirred into ice/water which contains hydrochloric acid, the precipitated product is suctioned off, washed with water, dissolved in methylene chloride, dried, and concentrated under vacuum. After chromatography of the crude product on silica gel with a hexane-ethyl acetate gradient, 2.4 g of (Z)-17β-hydroxy-2-hydroxymethylene-17α-methylandrosta-4,15-dien-3-one is obtained, mp 176° C. (from acetone/hexane).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].[F:11][C:12]([F:26])([F:25])[CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:13][C:12]([F:26])([F:25])[F:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: Sc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)CSc1ccc(Br)cc1
Temperature: 0 °C
Yield: 44.5 %

Procedure:
Dissolve 4-bromo-benzenethiol (1.0 g, 5.3 mmol) in dry dimethylformamide (50 mL) and cool to 0° C. under nitrogen. Add dry sodium hydride (152 mg, 6.4 mmol), portionwise. After the vigorous gas evolution stops, add toluene-4-sulfonic acid 2,2,2-trifluoro-ethyl ester (2.0 g, 8.0 mmol) and stir the reaction overnight at room temperature. Slowly pour the reaction into water (400 mL) and extract with ethyl acetate (2×50 mL). Wash the combined organic layers with water (100 mL) and brine (100 mL). Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Chromatograph the resultant residue on a SiO2 column with hexanes to yield 640 mg of 1-bromo-4-(2,2,2-trifluoro-ethylsulfanyl)-benzene (45%).
Reaction SMILES: C1([NH2+]C2CCCCC2)CCCCC1.[C:14]([NH:24][C@H:25]([C:35]([O-:37])=[O:36])[CH2:26][CH:27]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O-:30])=[O:29])([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C1([NH2+]C2CCCCC2)CCCCC1.C(OCC)(=O)C.[CH3:57][N:58]([CH2:60][CH2:61]Cl)[CH3:59]>C1C=CC=CC=1>[CH3:57][N:58]([CH3:59])[CH:60]([O:36][C:35](=[O:37])[C@H:25]([CH2:26][CH:27]([C:31]([CH3:32])([CH3:33])[CH3:34])[C:28]([OH:30])=[O:29])[NH:24][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH3:61]
Reactant: CN(C)CCCl
Reactant: CC(C)(C)C(C[C@H](NC(=O)OCc1ccccc1)C(=O)[O-])C(=O)[O-]
Agent: C1CCC([NH2+]C2CCCCC2)CC1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(OC(=O)[C@H](CC(C(=O)O)C(C)(C)C)NC(=O)OCc1ccccc1)N(C)C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
To 28.2 g N-carbobenzyloxy-γ-tert.butyl-L-glutamic acid-dicyclohexyl ammonium salt, 360 ml ethyl acetate and 49.5 ml solution of dimethylaminoethylchloride in the amount of 11.7 g, which stoichiometrically corresponds to two times the molar volume, in benzene were added to be subjected to flux in oil bath at 90° C. for 16 hrs. After cooling, precipitated dicyclohexyl ammonium chloride was filtered off and ethyl acetate phase in the filtrate was washed with diluted hydrochloride to remove excessive dimethylaminoethylchloride contained therein. The filtrate was further washed with 10% aqueous solution of hydrogen sodium bicarbonate so as to remove the unreacted starting material and then with saturated brine to be neutral, which was then treated with sulfuric sodium anhydride for dehydration to be dried and subjected to reduced pressure distillation so as to distill off ethyl acetate and obtain the Intermediate I, N-carbobenzyloxy-γ-tert.butyl-L-glutamic acid-α-dimethylaminoethyl ester in the amount of 21.5 g (yield; 96.8%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=O)=[CH:27][CH:26]=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=1)[NH2:40].CN(C=O)C>O>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([NH:40][C:32](=[O:34])[CH2:31][C:28]2[CH:27]=[CH:26][C:25]([O:24][C:15]3[C:14]4[C:19](=[CH:20][C:21]([O:22][CH3:23])=[C:12]([O:11][CH3:10])[CH:13]=4)[N:18]=[CH:17][N:16]=3)=[CH:30][CH:29]=2)[CH:41]=[CH:42][CH:43]=1
Reactant: COc1cc2ncnc(Oc3ccc(CC(=O)O)cc3)c2cc1OC
Reactant: COc1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(NC(=O)Cc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2)c1

Procedure:
Diisopropylethylamine (0.073 ml) and 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (0.16 g) were added in turn to a stirred mixture of 2-[4-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]acetic acid (0.12 g), 3-methoxyaniline (0.047 ml) and DMF (3 ml) and the resultant mixture was stirred at ambient temperature for 2 hours. Water was added and the precipitate was recovered by filtration and purified by column chromatography on silica using a 19:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound as a solid (0.122 g); 1H NMR: (DMSOd6) 3.69 (s, 2H), 3.73 (s, 3H), 3.97 (s, 3H), 3.99 (s, 3H), 6.63 (m, 1H), 7.15 (d, 1H), 7.21 (m, 1H), 7.26 (d, 2H), 7.34 (m, 1H), 7.39 (s, 1H), 7.43 (d, 2H), 7.55 (s, 1H), 8.54 (s, 1H), 10.21 (s, 1H); Mass Spectrum: M+H+ 446.
Reaction SMILES: [Cl-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[OH:9][C:10]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13].O>C1COCC1>[CH3:18][C:17]1[C:10]2[O:9][CH2:2][CH:12]([OH:13])[C:11]=2[CH:14]=[CH:15][CH:16]=1
Reactant: C[S+](C)(C)=O
Reactant: Cc1cccc(C=O)c1O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc2c1OCC2O
Yield: 44.4 %

Procedure:
To a stirred suspension of trimethyl sulfoxonium chloride (3.78 g, 0.03 mole) in dry THF (60 ml) was added sodium hydride (1.16 g, 0.03 mole) and the whole warmed to reflux for 1 h. 2-Hydroxy-3-methyl-benzaldehyde (Lancaster) (4 g, 0.03 mole) was added in 30 ml THF via syringe and the resulting orange suspension stirred at reflux for 5 h. Water (50 ml) was added, and the organics were extracted with ether (3×50 ml). The combined organics were dried (MgSO4), filtered and evaporated in vacuo to an orange oil which was purified by column chromatography using 15-25% EtOAc in pentane to give the title product (2 g, 45%); 1HNMR (400 MHz, CDCl3) δ: 2.2 (s, 3H), 4.45 (m, 2H), 5.3 (m, 1H), 6.8 (t, 1H), 7.1 (d, 1H), 7.2 (d, 1H); LRMS: M+H, 151. (ES+).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[F:19])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:20][C:21]1[N:22]=[C:23]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][N:33]=2)[CH:29]=O)[S:24][CH:25]=1>>[F:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][N:33]=[C:26]([C:23]3[S:24][CH:25]=[C:21]([CH3:20])[N:22]=3)[CH:27]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: Cc1csc(-c2cc(C=O)ccn2)n1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OC
Product: COc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccnc(-c2nc(C)cs2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-fluoro-6-methoxyphenyl)-2-methylbutanoate with 2-(4-methylthiazol-2-yl)isonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.81 min.; [M+H]+: 411.99 g/mol.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5]>C1COCC1.CO>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc([N+](=O)[O-])cc1CO
Temperature: 80 °C
Yield: 114.6 %

Procedure:
To a solution of 2-methyl-5-nitrobenzoic acid (3.0 g, 16.6 mmol, Acros) in THF (60 ml) at ambient temperature under nitrogen was added dropwise 1.0 M borane-tetrahydrofuran complex (33.1 ml, 33.1 mmol, Aldrich). The solution was heated to 80° C. for 1.5 h. To the solution at ambient temperature was slowly added methanol (20 ml) and then heated to 80° C. for 30 min. The solvent was removed in vacuo to leave an oil. The residue was dissolved in methanol (approximately 30 ml) and the solvent removed in vacuo to give (2-methyl-5-nitrophenyl)methanol as a yellow solid (3.18 g).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([NH:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:19])=[O:18])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[S:3].I[CH3:35]>CO>[NH:1]=[C:2]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([NH:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:18])=[O:19])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)[S:3][CH3:35]
Reactant: CI
Reactant: CCOC(=O)CC(NS(=O)(=O)c1cccc(-c2cccc(NC(N)=S)c2)c1)c1ccccc1
Solvent: CO
Product: CCOC(=O)CC(NS(=O)(=O)c1cccc(-c2cccc(NC(=N)SC)c2)c1)c1ccccc1

Procedure:
2.42 g of Ethyl 3-[({3′-[(aminocarbothioyl)amino][1,1′-biphenyl]-3-yl}sulfonyl)-amino]-3-phenylpropanoate 14.1.1 were dissolved in 80 ml methanol and 0.89 g Iodomethan were added. After reflux for 2 h, the reaction mixture was concentrated and crystalized from ether to obtain 3.1 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][NH:23][C@H:22]([CH2:26][OH:27])[CH2:21]3)[CH:18]=2)[CH:13]=[N:12]1)[CH3:10].C(OC([N:35]1[CH2:39][CH2:38][CH2:37][C@@H:36]1[C:40](O)=[O:41])=O)(C)(C)C.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>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:40]([C@H:36]4[CH2:37][CH2:38][CH2:39][NH:35]4)=[O:41])[C@H:22]([CH2:26][OH:27])[CH2:21]3)[CH:18]=2)[CH:13]=[N:12]1)[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(N3CCN[C@H](CO)C3)cc21
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: ClCCl
Product: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(N3CCN(C(=O)[C@H]4CCCN4)[C@H](CO)C3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
To a stirred solution of the ((S)-4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-indazol-6-yl)piperazin-2-yl)methanol (0.072 g, 0.18 mmol) and (R)-1-(t-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.078 g, 0.36 mmol) in dichloromethane (2.0 mL) was added HATU (0.14 g, 0.36 mmol) and iPr2NEt (0.10 mL, 0.57 mmol). The reaction mixture was stirred at room temperature for 30 min, and was then diluted with dichloromethane. The mixture was washed with deionized water, and the aqueous layer was extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 30-100% ethyl acetate in hexanes) to afford the desired product (0.072 g, 0.12 mmol, 30% for 2 steps).
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[CH:20])[CH:12]=O.C([CH2:24][C:25]([NH:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([OH:32])=[O:31])=[O:26])(O)=O.CC(O)=O>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:24]/[C:25]([NH:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=[O:31])=[O:26])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[CH:20]
Reactant: C#CCOc1ccc(C=O)cc1OC
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: C#CCOc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 775.3 %

Procedure:
Piperidine (85.0 mL, 85.6 mmol) was added to a suspension of 3-methoxy-4-propargyloxybenzaldehyde (163 g, 85.6 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (182 g, 81.5 mmol) in toluene (1.0 L) and treated according to Procedure 2, acidifying with 50% AcOH. The crude product was recrystallised from EtOH (35 mL/g), filtered and washed with cold EtOH to afford (E)-2-[[3-(3-methoxy-4-propargyloxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (222 g, 77%) as a yellow crystalline solid; mp 191-193° C.; δH (400 MHz, DMSO-d6) 3.59 (t, J=2.4 Hz, 1H, HC≡C), 3.84 (s, 3H, OCH3), 4.84 (d, J=2.4 Hz, 2H, OCH2), 6.81 (d, J=15.6 Hz, 1H, CH═CHCO), 7.05 (d, J5′,6′=8.4 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.25 (d, J5′,6=8.4 Hz, 1H, H6′), 7.41 (s, 1H, H2′), 7.56 (d, J=15.6 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.31 (s, 1H, NH), 13.57 (br S, 1H, CO2H); δC (100 MHz, DMSO-d6) 55.6, 55.9, 78.6, 79.1, 110.8, 113.5, 116.6, 120.4, 120.4, 122.2, 122.7, 128.2, 131.2, 134.0, 141.0, 141.5, 148.3, 149.3, 164.1, 169.5; HRMS (ESI) calculated for C2OH17NO5 [M+H]+ 352.1179. found 352.1187; vmax 755, 1010, 1140, 1253, 1502, 1582, 1657, 3278, 3522 cm−1.