Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13](Cl)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].[O:19]([C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.COC(C1C(C)=C2C(NC3C=CC(OC4C=CC=CC=4OC(C(OC(C)(C)C)=O)(C)C)=CC=3)=C(C#N)C=NN2C=1)=O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:31][CH:30]=3)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1C
Agent: COC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)OC(C)(C)C)cc3)c2c1C
Product: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1C
Yield: 84.3 %

Procedure:
Compound 396A (1.85 g, 85%) was prepared from 4-chloro-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester (Example 1D) (1.4 g, 5.32 mmol) and 4-phenoxy-phenylamine (1.1 g, 5.94 mmol) by a route analogous to that used for the preparation of compound 388D.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[N:8]([CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=3)[CH:29]=[CH:28][CH:27]=2)[C:9]2[C:14]([C:15]=1[CH2:16][N:17](C(OCC)=O)C)=[CH:13][C:12]([F:24])=[CH:11][CH:10]=2)=[O:6])[CH3:3]>>[CH2:2]([O:4][C:5]([C:7]1[N:8]([CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=3)[CH:29]=[CH:28][CH:27]=2)[C:9]2[C:14]([C:15]=1[CH2:16][NH2:17])=[CH:13][C:12]([F:24])=[CH:11][CH:10]=2)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1c(CN(C)C(=O)OCC)c2cc(F)ccc2n1Cc1cccc2ccc(F)cc12
Agent: Cl
Product: CCOC(=O)c1c(CN)c2cc(F)ccc2n1Cc1cccc2ccc(F)cc12

Procedure:
salt with HCl (prepared according to Example 104.2.) was converted to 3-[(ethoxycarbonyl-methyl-amino)-methyl]-5-fluoro-1-(7-fluoro-naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid ethyl ester as described in Example 77.1. which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a white solid. MS: 451.5 ([M−H]−).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]([CH2:16][C:17]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][CH3:29])[C:20]=2[CH3:30])=O)[C:13]([OH:15])=[O:14])=[C:4]1[CH3:31])[CH3:2]>C(OC(=O)C)(=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH:16]=[C:17]([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH2:28][CH3:29])[C:20]=3[CH3:30])[O:15][C:13]2=[O:14])=[C:4]1[CH3:31])[CH3:2]
Reactant: CCn1c(C)c(C(=O)CC(C(=O)O)c2c(C)n(CC)c3ccccc23)c2ccccc21
Solvent: CC(=O)OC(C)=O
Product: CCn1c(C)c(C2=CC(c3c(C)n(CC)c4ccccc34)C(=O)O2)c2ccccc21
Temperature: 25 °C
Yield: 88.9 %

Procedure:
A mixture of 40.0 g (0.096 mole) of 2,4-bis(1-ethyl-2-methyl-3-indolyl)-4-oxobutanoic acid (prepared as in Example 3, part A) and 450 ml of acetic anhydride was stirred approximately seventeen hours at ambient temperature under an atmosphere of air. The solid that formed was collected by filtration and washed first with acetic anhydride and then with diethyl ether. After drying at 60° C in vacuo there was obtained 34.0 g of 3,5-bis(1-ethyl-2-methyl-3-indolyl)-2(3H)-furanone (Formula II: R=CH3CH2 ; R1 =CH3 ; Y=H) as a white solid which melted over the range 186°-188° C with decomposition.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:9]([NH:14][S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])([CH2:11][CH2:12][OH:13])[CH3:10].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+]>O.C(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:9]([NH:14][S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])([CH2:11][CH:12]=[O:13])[CH3:10]
Reactant: CC(C)(C)[S@@](=O)N[C@@](C)(CCO)c1cccc(F)c1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[S@@](=O)N[C@@](C)(CC=O)c1cccc(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
A mixture of (R)-N-((S)-2-(2-chloro-3-fluorophenyl)-4-hydroxybutan-2-yl)-2-methylpropane-2-sulfinamide (9.30 g, 28.9 mmol), dichloromethane (150 mL) and dess-martin periodinane (14.22 g, 33.5 mmol) was stirred at rt for 1 h. The mixture was diluted with water (150 mL), DCM and sodium bicarbonate (12.14 g, 144 mmol). The mixture was filtered through celite. The aqueous layer was extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel chromatography: 240 g, 5-25% EtOAc-hexane in 5 min, 25-80% in 20 min to give (R)-N-((S)-2-(2-chloro-3-fluorophenyl)-4-oxobutan-2-yl)-2-methylpropane-2-sulfinamide as yellow oil (8.98 g, 97%). MS m/z=320 [M+H]+. Calculated for C14H19ClFNO2S: 319.8.
Reaction SMILES: [CH2:1]=[O:2].[O:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH3:8])[CH3:5].N12CCCN=C1CCCCC2.Cl>>[CH3:8][C:7]([CH:6]([CH2:1][OH:2])[C:4](=[O:3])[CH3:5])=[CH2:9]
Reactant: C=O
Reactant: CC(=O)C=C(C)C
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Product: C=C(C)C(CO)C(C)=O
Yield: 27.7 %

Procedure:
30 g (1 mol) of paraformaldehyde were added to a mixture of 490 g (5 mols) of mesityl oxide and 15.2 g (0.1 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene over the course of 2 - 3 hours at 30° C. After completion of the addition of formaldehyde, the reaction mixture was stirred for about a further hour, then cooled to 0° C and neutralised with dilute hydrochloric acid. The organic phase was separated off and the aqueous phase was repeatedly extracted with methylene chloride. The combined organic phases were dried with zeolite, filtered off and then freed from methylene chloride. The residue (506 g) was fractionally distilled in a high vacuum at about 0.1 - 1 mm Hg. Thereby, 431 g of mesityl oxide were recovered. As a further fraction, 47 g of crude product of boiling point 45° - 85° C/l mm Hg were obtained. A further fractional distillation of this crude product gave 35.5 g of 2-methyl-3-hydroxymethyl-pent-1-en-4-one of boiling point 50° - 52° C/0.2 mm Hg (yield: 78%, relative to mesityl oxide converted), in the form of a colourless liquid.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][C:4]=2[CH:3]=1.[SH:21][C@@H:22]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]1.C(N(CC)C(C)C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][N:6]1[C:5]2[CH:19]=[CH:20][C:2]([S:21][C@@H:22]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]3)=[CH:3][C:4]=2[N:8]=[C:7]1[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(Br)ccc21
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](S)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN(C)CCn1c(CC(C)(C)C)nc2cc(S[C@@H]3CCN(C(=O)OC(C)(C)C)C3)ccc21
Temperature: 160 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A mixture of 2-(5-bromo-2-neopentyl-1H-benzo[d]imidazol-1-yl)-N,N-dimethylethanamine (prepared in STEP A of Example 1, 937 mg, 2.77 mmol), (R)-tert-butyl 3-mercaptopyrrolidine-1-carboxylate (prepared in STEP C of Example 18, c.a. 3.60 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (80.1 mg, 0.138 mmol), tris(dibenzylideneacetone)dipalladium(0) (63.1 mg, 0.0690 mmol) and N,N-diisopropylethylamine (725 microL, 4.15 mmol) in 1,4-dioxane (15 mL) was stirred at 160° C. for 1 h under microwave. The mixture was concentrated in vacuo and the residue was purified by amine gel column chromatography (hexane-ethyl acetate, gradient) to give the title compound (802 mg, 63% mmol) as a pale orange gum.
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:28]=[CH:27][C:10]2[CH2:11][CH2:12][CH:13]3[C:18]([C:9]=2[CH:8]=1)=[N:17][N:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[C:15](=[O:26])[CH2:14]3.[H-].[Na+].[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35]Cl>O>[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][O:6][C:7]1[CH:28]=[CH:27][C:10]2[CH2:11][CH2:12][CH:13]3[C:18]([C:9]=2[CH:8]=1)=[N:17][N:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[C:15](=[O:26])[CH2:14]3
Reactant: Cc1ccc(N2N=C3c4cc(O)ccc4CCC3CC2=O)cc1
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(N2N=C3c4cc(OCCCN(C)C)ccc4CCC3CC2=O)cc1
Temperature: 25 °C
Yield: 92.4 %

Procedure:
To 60 ml of dry dimethylformamide is added 6.1 g of 9-hydroxy-2-(4-methylphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one, and 0.96 g of 60% sodium hydride is added thereto while stirring at room temperature. After stirring at room temperature for 1 hour, 2.8 g of 3-dimethylaminopropyl chloride is added to the mixture. After the mixture is stirred over water bath under heating at 40°-50° C. for 5 hours, the reaction mixture is poured into a large amount of water, followed by extraction with chloroform. The organic layer is washed with water and dried over anhydrous magnesium sulfate. Then, the solvent is distilled off. The residue is subjected to column chromatography and the eluate is converted into its maleate, which is recrystallized from a mixed solvent of methanol and isopropyl ether to give 7.2 g of 9-(3-dimethylaminopropoxy)-2-(4-methylphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.maleate, m.p. 159°-162° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[S:27][C:10]2[CH2:11][CH2:12][CH:13]3[C:18]([C:9]=2[CH:8]=1)=[N:17][N:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[C:15](=[O:26])[CH2:14]3)(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[OH:4][CH2:5][CH2:6][C:7]1[S:27][C:10]2[CH2:11][CH2:12][CH:13]3[C:18]([C:9]=2[CH:8]=1)=[N:17][N:16]([C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1)[C:15](=[O:26])[CH2:14]3
Reactant: CC(=O)OCCc1cc2c(s1)CCC1CC(=O)N(c3ccc(C)cc3)N=C21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc(N2N=C3c4cc(CCO)sc4CCC3CC2=O)cc1
Yield: 97.4 %

Procedure:
To a suspension of 1.5 g of 8-(2-acetoxyethyl) -4,4a, 5,6-tetrahydro-2-(4-methylphenyl)thieno-[2,3-h]cinnolin-3(2H)-one in 50 ml of methanol was added 5 ml of aqueous solution of 0.7 g of potassium carbonate under ice-cooling. The mixture was stirred for an hour, and poured into water and then extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting solid was recrystallized from a mixed solvent of chloroform and ethanol to give 1.3 g of 4,4a,5,6-tetrahydro-8-(2-hydroxy-ethyl)-2-(4-methylphenyl)thieno-[2,3-h]cinnolin-3(2H)-one as a white powder, melting at 159°-160° C.
Reaction SMILES: O[C:2]1[C:7](CC=C)=[C:6]([O:11][CH2:12][O:13][CH3:14])[CH:5]=[C:4](OCOC)[C:3]=1[C:19](=[O:21])C>C(O)C>[CH3:14][O:13][CH2:12][O:11][C:6]1[CH:7]=[CH:2][C:3]([CH:19]=[O:21])=[CH:4][CH:5]=1
Reactant: C=CCc1c(OCOC)cc(OCOC)c(C(C)=O)c1O
Solvent: CCO
Product: COCOc1ccc(C=O)cc1
Yield: 119.8 %

Procedure:
In 40 ml of ethanol were dissolved 20.4 g of the 2'-hydroxy-4',6'-bis(methoxymethoxy)-3'-(2-propenyl)acetophenone obtained in Production Example 6 and 13.7 g of the p-methoxymethoxybenzaldehyde obtained in Production Example 23, and a 50% solution of potassium hydroxide in ethanol was added to the solution and the mixture was stirred at room temperature overnight to effect a reaction. After the reaction, the reaction mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate, and the solvent was removed from the ethyl acetate layer by distillation. The obtained residue was crystallized from methanol to obtain 26.3 g (yield=85.9%) of 2'-hydroxy-4,4',6'-tris(methoxymethoxy)-3'-(2-propenyl)chalcone in the form of a yellow prism.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@H:10]([OH:16])[C:11]([O:13]CC)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].OO.O.[OH-].[Li+]>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@H:10]([OH:16])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](O)[C@@H](CCCc1ccccc1)NC(=O)OC(C)(C)C
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CCCc1ccccc1)[C@H](O)C(=O)O

Procedure:
A solution of Example 9C (0.316 g, 0.90 mmol), 30% hydrogen peroxide (0.40 mL, 3.5 mmol), and lithium hydroxide monohydrate (0.076 g, 1.8 mmol) in 3:1 tetrahydrofuran/water (8 mL) was stirred at 0° C. for 3 hours and concentrated. The concentrate was dissolved in water and the pH adjusted to 10 with 1M NaOH. The solution was washed twice with diethyl ether, adjusted to pH 2 with 1M HCl, and extracted twice with ethyl acetate. The combined extracts were dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI) m/e 324 (M+H)+.
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][CH2:25][C:26]([OH:28])=O)=[C:17]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:16]=2)=[CH:11][N:10]=1)=O)(C)(C)C.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][CH2:25][C:26]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:28])=[C:17]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[N:16]=2)=[CH:13][N:14]=1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CCC(=O)O)c3n2)cn1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CCC(=O)N4CCOCC4)c3n2)cn1

Procedure:
3-(2-(2-(Tert-butoxycarbonylamino)pyrimidin-5-yl)-6-morpholino-9H-purin-9-yl)propanoic acid (50 mg) was reacted with morpholine via General Procedure F followed by Boc deprotection via General Procedure E to give 24.9 mg 113 as white solid following reverse phase purification. MS (Q1) 440.2 (M)+
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=2[O:14][CH3:15])[CH:6]=1.[C:16](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:17]>ClCCl>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[C:8]([O:14][CH3:15])=[CH:9][C:10]([N:13]=[C:16]=[S:17])=[CH:11][N:12]=2)[CH:6]=1
Reactant: COc1cc(N)cnc1-n1cnc(Cl)c1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: COc1cc(N=C=S)cnc1-n1cnc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
Step O (3): Dichloromethane (100 mL) was added to a flask charged with 6-(4-chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-amine (3.0 g, 13.35 mmol) and 1,1′-thiocarbonyldipyridin-2(1H)-one (3.10 g, 13.35 mmol). The resulting mixture was stirred for 18 h at rt. The reaction mixture was concentrated in vacuo. The crude products were purified using silica gel chromatography (0-5% EtOAc/chloroform, linear gradient) to afford 2-(4-chloro-1H-imidazol-1-yl)-5-isothiocyanato-3-methoxypyridine (2.89 g, 81% yield) as a yellow solid. LC-MS (M+H)+ 267.1. 1H NMR (500 MHz, chloroform-d) δ ppm 8.30 (s, 1 H) 8.02 (s, 1 H) 7.72 (s, 1 H) 7.20 (s, 1 H) 4.00 (s, 3 H).
Reaction SMILES: C1(C)C=CC(S([CH:10]([C@:12]2([O:23][CH2:22][C@@H:19]([O:20][CH3:21])[C@@H:16]([O:17][CH3:18])[C@@:14]2([C:24]([CH3:26])=[CH2:25])[OH:15])[OH:13])O)(=O)=O)=CC=1.[I-:28].[Na+]>CC(C)=O.C(OCC)C.CCCCC>[I:28][CH2:10][C@:12]1([O:23][CH2:22][C@@H:19]([O:20][CH3:21])[C@@H:16]([O:17][CH3:18])[C@@:14]1([C:24]([CH3:26])=[CH2:25])[OH:15])[OH:13]
Reactant: [I-]
Reactant: C=C(C)[C@@]1(O)[C@H](OC)[C@H](OC)CO[C@]1(O)C(O)S(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCCCC
Solvent: CCOCC
Product: C=C(C)[C@@]1(O)[C@H](OC)[C@H](OC)CO[C@]1(O)CI
Yield: 88 %

Procedure:
Following the procedure described for the preparation of Example 12, starting from 0.10 g (0.25 mmol) of the compound obtained in Example 30 and 0.18 g (1.20 mmol) of sodium iodide in 3 ml of acetone at room temperature, then purification by chromatography on silica gel (eluant: diethyl ether/pentane, 1.5:1), 0.079 g (0.22 mmol) of the desired product in the form of a pale-yellow-coloured solid is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[CH:17][C:16]=2[OH:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][CH2:39][Cl:40]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)(=[O:23])=[O:22])=[CH:17][C:16]=2[O:30][CH2:38][CH2:39][Cl:40])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(S(=O)(=O)c3ccccc3)cc2O)CC1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(S(=O)(=O)c3ccccc3)cc2OCCCl)CC1
Reaction time: 1.5 h
Yield: 78.8 %

Procedure:
To a solution of 4-(4-benzenesulfonyl-2-hydroxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.192 g., 0.444 mmol) in 1 mL acetonitrile is added potassium carbonate (0.245 g., 1.776 mmol) and then 1-bromo-2-chloro-ethane (0.044 mL, 0.535 mmol) dropwise. The suspension is refluxed under nitrogen for 3 hours, at which time is added 1-bromo-2-chloro-ethane (0.044 mL, 0.535 mmol) dropwise. Reflux is continued for another 1.5 hours. The reaction mixture is concentrated in vacuo and the resulting oil is dissolved in 75 mL ethyl acetate, washed with 2×50 mL water and 50 mL brine, then dried over sodium sulfate and concentrated in vacuo. The resulting crude oil is purified by flash chromatography (10% -30% ethyl acetate in hexanes) to give 0.175 g (0.35 mmol, 80%) of 4-[4-benzenesulfonyl-2-(2-chloro-ethoxy)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester as a clear oil. MS: 439 (M−tBu+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:24][CH:25]2[CH2:27][CH2:26]2)[C:5]2[C:10]([C:11](=[O:13])[CH3:12])=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:28][C:29]1[CH:37]=[C:36]2[C:32]([CH:33]=[N:34][NH:35]2)=[CH:31][CH:30]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:35]1[C:36]2[C:32](=[CH:31][CH:30]=[C:29]([NH:28][C:2]3[N:3]=[C:4]([NH:24][CH:25]4[CH2:26][CH2:27]4)[C:5]4[C:10]([C:11](=[O:13])[CH3:12])=[CH:9][NH:8][C:6]=4[N:7]=3)[CH:37]=2)[CH:33]=[N:34]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: CC(=O)c1cn(S(=O)(=O)c2ccc(C)cc2)c2nc(Cl)nc(NC3CC3)c12
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)c1c[nH]c2nc(Nc3ccc4cn[nH]c4c3)nc(NC3CC3)c12
Temperature: 116 °C
Reaction time: 18 h
Yield: 41.1 %

Procedure:
A mixture of 1-(2-chloro-4-(cyclopropylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethanone (85 mg, 0.21 mmol), 6-aminoindazole (56 mg, 0.42 mmol) and TMSCl (0.070 mL, 0.55 mmol) in nBuOH (3 mL) was stirred at 116° C. for 18 h. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (30 mg). MS 348.1 (M+H); UV 248.7, 305.7 nm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH3:23]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCOCCBr
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOCCOc1ccccc1Br
Temperature: 90 °C
Reaction time: 16 h

Procedure:
In DMF (120 ml) was dissolved 2-bromophenol (12 g), and to the solution were added potassium carbonate (14.4 g) and sodium iodide (10.4 g). To the mixture was added 2-bromoethylpropylether (10.4 ml), and the mixture was stirred at 90° C. for 16 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=12/1) to give 1-bromo-2-(2-propoxyethoxy)benzene (14.4 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]([O:15]CC2C=CC=CC=2)=[O:14])[N:7]=1)=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]([OH:15])=[O:14])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)n(CC(=O)OCc2ccccc2)n1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(CC(=O)O)n1
Reaction time: 21 h
Yield: 88.5 %

Procedure:
To a mixture of ethyl 2,4-dioxopentanoate (1.74 g, 11.0 mmol), ammonium acetate (1.16 g, 15.0 mmol) and ethanol (20 mL) was added benzyl hydrazinoacetate hydrochloride (2.17 g, 10.0 mmol), and the mixture was stirred at room temperature for 1 hr and at 80° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give benzyl [3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-1-yl]acetate (0.95 g, 31%) and benzyl [5-(ethoxycarbonyl)-3-methyl-1H-pyrazol-1-yl]acetate (1.56 g, 51%). To a solution of benzyl [3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-1-yl]acetate (0.95 g, 3.14 mmol) in ethanol (10 mL) was added 5% palladium/carbon (0.30 g), and the mixture was stirred under a hydrogen stream for 21 hr. The insoluble material was filtered off, and the filtrate was concentrated. The residue was recrystallized from ethyl acetate-hexane to give the title compound (0.59 g, 88%).
Reaction SMILES: [Na].C(O[C:5]([C:7]1[C:8]([N:15]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:9][C:10]([S:13][CH3:14])=[N:11][CH:12]=1)=[O:6])C.CC(C)([O-])C.[Na+].Cl>C1(C)C=CC=CC=1.C(O)(C)(C)C>[CH2:21]([O:20][C:18]([CH:17]1[CH2:16][N:15]([CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[C:8]2[N:9]=[C:10]([S:13][CH3:14])[N:11]=[CH:12][C:7]=2[C:5]1=[O:6])=[O:19])[CH3:22]
Reactant: CCOC(=O)CCN(c1nc(SC)ncc1C(=O)OCC)C1CCCCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CCOC(=O)C1CN(C2CCCCC2)c2nc(SC)ncc2C1=O
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
Sodium (25 wt % dispersion in paraffin wax, 0.10 g, 3.8 mmol) was added to t-butanol (1.8 mL) at rt. After 10 minutes, a solution of 4-[cyclohexyl-(2-ethoxycarbonyl-ethyl)-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (1.0 g, 2.5 mmol) in 10 mL of toluene was added to the sodium t-butoxide solution and the resulting mixture was heated at 90° C. for 30 minutes. The reaction mixture was then cooled and the solution was adjusted to pH 7 using a 1N HCl solution. The solution was then extracted with EtOAc (2×20 mL) and the organic layer was dried (MgSO4) and concentrated to provide 0.55 g (42%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:25]2[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: OB(O)c1ccncc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(Oc2ccncc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 10 h
Yield: 20.7 %

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-(4-hydroxy-phenyl)-propionic acid methyl ester (8.46 mmol), 4-pyridyl boronic acid (29.6 mmol), Cu(OAc)2 (16.9 mmol), and molecular sieves were suspended in 25 mL of DCM. Triethylamine (59.2 mmol) was added and the mixture stirred at rt for 10 h. The mixture was diluted with ethyl acetate and washed with 10% sodium carbonate (6×). The organic layer was dried and concentrated under reduced pressure. The residue was purified over silica gel (hexanes-EtOAc) to provide (S)-2-tert-Butoxycarbonylamino-3-[4-(pyridin-4-yloxy)-phenyl]-propionic acid methyl ester (653 mg). LC-MS (m/z) 374.