Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([CH:22]=[O:23])=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:24][C:25]1(C)[C:29](C)(C)OB(C(C)=C)O1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.O>O1CCOCC1.CC(O)=O.CC(O)=O.[Pd]>[CH:22]([C:3]1[C:2]([C:25]([CH3:29])=[CH2:24])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=1)=[O:23]
Reactant: COC(=O)c1ccc(-c2cc(C(F)(F)F)cc(Cl)c2C=O)cc1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)c1cc(C(F)(F)F)cc(-c2ccc(C(=O)OC)cc2)c1C=O
Temperature: 25 °C

Procedure:
Methyl 3′-chloro-2′-formyl-5′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate (430 mg, 1.3 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.59 mL, 3.1 mmol), S-PHOS (103 mg, 0.3 mmol), Pd(Oac)2 (28 mg, 0.1 mmol) and K3PO4hydrate (1.3 g, 6.3 mmol) were dissolved in 1,4-dioxane (5 mL) and water (0.3 mL) and the resulting mixture was heated to 90° C. After 16 h the resulting mixture was cooled to room temperature and filtered through CELITE. The filtrate was diluted EtOAc, washed with water and saturated aqueous NaHCO3, dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: [C:1](O)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11]([OH:14])(=O)C.C(N)=[NH:16].N>COCCO>[NH:4]1[C:3]2[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:1]=[N:16][C:11]1=[O:14]
Reactant: Nc1ccccc1C(=O)O
Reactant: N=CN
Reactant: CC(=O)O
Agent: N
Solvent: COCCO
Product: O=c1ncc2ccccc2[nH]1
Temperature: 125 °C

Procedure:
Anthranilic acid ED.5 (1.00 g, 4.27 mmol) is placed in 2-methoxyethanol (2.0 mL), combined with formamidine acetate (890 mg, 8.55 mmol) and heated to 125° C. for 20 h. The reaction mixture is added to aqueous NH3 (200 mL, 0.01 M), the precipitate is filtered off, dried and quinazolone Z.8 (817 mg, 79%) is obtained.
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8](C)[CH:7]=2)[CH2:3][CH2:2]1.IC1C=CC(C(OC)=O)=CC=1>>[CH:1]1([C:4]#[C:5][C:6]2[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:13][CH:14]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc(C#CC2CC2)ccc1C(=O)O
Agent: COC(=O)c1ccc(I)cc1
Product: O=C(O)c1ccc(C#CC2CC2)cc1

Procedure:
The above compound was prepared using the same procedure as 4-(cyclopropylethynyl)-2-methylbenzoic acid, except methyl 4-iodobenzoate was used as the starting material.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[C:5]([NH2:8])=[N:6][CH:7]=1.[O:19]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][NH:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:29]2[CH:30]=[CH:31][C:26]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:27][CH:28]=2)[N:3]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: COc1ccccc1CNc1nc(Br)cnc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccccc1CNc1nc(-c2ccc(Oc3ccccc3)cc2)cnc1N
Temperature: 90 °C
Reaction time: 10 h

Procedure:
A solution of 1.00 eq. of (4) in 1 mL toluene is treated with 10 mole percent tetrakis(triphenylphospine) palladium under nitrogen at room temperature. To this solution is added directly 2.50 eq. of 4-phenoxyphenyl boronic acid at room temperature and then 1 mL Na2CO3 (1.0 M) solution. The reaction vial is capped and the reaction stirred under nitrogen at 90° C. for 10 hours. The toluene layer is separated and removed under reduced pressure, and the resulting oil is purified via flash chromatography to provide (5).
Reaction SMILES: C(OC([N:8]1[CH2:20][CH:11]2[C:12]3[CH:13]=[C:14]([Br:19])[S:15][C:16]=3[CH:17]([CH3:18])[CH:10]2[CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[Br:19][C:14]1[S:15][C:16]2[CH:17]([CH3:18])[CH:10]3[CH2:9][NH:8][CH2:20][CH:11]3[C:12]=2[CH:13]=1
Reactant: CC1c2sc(Br)cc2C2CN(C(=O)OC(C)(C)C)CC12
Agent: Cl
Solvent: C1COCCO1
Product: CC1c2sc(Br)cc2C2CNCC12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from step b) (50 mg, 0.14 mmol) was dissolved in 2 mL of 4M HCl/dioxane and stirred at room temperature for one hour. The solvent was evaporated leaving a solid that was purified by preparative LC/MS. MS calculated for C10H12BrNS +H: 258, observed: 258 and 260. 1H NMR (CDCl3300 MHz) δ 1.29 (d, 3H), 1.98 (s, 1H), 3.14 (m, 3H), 3.32 (m 2H), 3.50 (m, 1H), 3.70 (m, 1H), 6.74 (s, 1H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2([CH2:17][CH2:16][CH2:15][N:14](CC3C=CC=CC=3)[C:13]2=O)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.CO.[C+4].[OH-].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-]>[C:1]([O:5][C:6]([N:8]1[C:12]2([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC12CCCN(Cc1ccccc1)C2=O
Agent: [Pd+2]
Agent: [C+4]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC12CCCNC2
Yield: 96.2 %

Procedure:
To a solution of 7-benzyl-6-oxo-1,7-diazaspiro[4.5]decane-1-carboxylic acid tert-butyl ester (76 mg) in tetrahydrofuran/methanol (1 ml/1 ml) was added 20% palladium hydroxide carbon (15 mg), and the mixture was hydrogenated under 4 atmospheres. The mixture was filtered through Celite under nitrogen, and the filtrate was concentrated under reduced pressure to give the titled compound (51 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[N:15]1([C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.N1CCCCC1>CO.CCOCC>[Br-:8].[CH2:9]([N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:25][C:24]1[CH:23]=[CH:22][C:21]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:28][CH:27]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=Cc1ccc(N2CCCCC2)cc1
Reactant: Cc1ccccn1
Reactant: CCCCCCBr
Solvent: CCOCC
Solvent: C1CCNCC1
Solvent: CO
Product: CCCCCC[n+]1ccccc1C=Cc1ccc(N2CCCCC2)cc1
Product: [Br-]
Yield: 16.3 %

Procedure:
2-Picoline (2.79 g, 0.03 mole) and 1-bromo-hexane (5.0 g, 0.03 mole) were heated in an oil bath at 130° C. for five hours. The resulting oil was cooled and dissolved in methanol (40 ml). 4-Piperidinobenzaldehyde (5.67 g, 0.03 mole) and piperidine (0.25 ml) were added and the mixture was refluxed under nitrogen for two hours. The addition of about 100 ml of ether to the cold solution gave red crystals which were collected and washed to give 1-hexyl-2-[(4-piperidino)styryl]-pyridinium bromide (2.1 g), melting point 212°-214° C. (decomposition).
Reaction SMILES: [O:1]1[C@@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=2)[C@@H:2]1[CH2:3][OH:4].C(Cl)Cl>CCCCCC.C(OCC)(=O)C>[O:1]1[C@@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=2)[C@@H:2]1[CH:3]=[O:4]
Reactant: COC(=O)c1cccc([C@@H]2O[C@H]2CO)c1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc([C@@H]2O[C@H]2C=O)c1

Procedure:
The title compound is prepared analogously to Example 5 from (2S,3S)-2,3-epoxy-3-(3-methoxycarbonylphenyl)-propanol; colourless oil; IR (methylene chloride): 2910, 2780, 1705, 1590, 1570, 1415, 1270, 1235 cm-1 ; Rf =0.36 (hexane/ethyl acetate 3:2).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.C(OC(=O)[N:34]([CH2:50][CH3:51])[C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=1)(C)(C)C>>[CH2:50]([NH:34][C:35]1[CH:40]=[CH:39][C:38]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)[S:8][C:6]=3[N:7]=2)=[CH:37][N:36]=1)[CH3:51]
Reactant: CCN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: CCNc1ccc(-c2nc(N3CCOCC3)c3cc(CN4CCN(S(C)(=O)=O)CC4)sc3n2)cn1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine was reacted with ethyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-carbamic acid tert-butyl ester in General Procedure A. Purification on silica yielded 365. NMR: (CDCl3): 1.31 (3H, t, J 7.2, Me), 2.65-2.68 (4H, m), 2.82 (3H, s, Me), 3.28-3.31 (4H, m), 3.38-3.44 (2H, m, CH2), 3.81 (2H, s, CH2), 3.88-3.90 (4H, m), 3.94-3.97 (4H, m), 4.71-4.74 (1H, m, NH), 6.45 (1H, d, J 8.7, Ar), 7.12 (1H, s, Ar), 8.46 (1H, dd, J 8.7 and 2.3, Ar) and 9.19 (1H, d, J 2.3, Ar). MS: (ESI+): MH+=518.22
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1>C1(C)C(C)=CC=CC=1>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:7]1
Reactant: Brc1ncccn1
Reactant: C[C@@H]1CNCCN1
Solvent: Cc1ccccc1C
Product: C[C@@H]1CN(c2ncccn2)CCN1
Reaction time: 15 h
Yield: 33.7 %

Procedure:
To a solution of (R)-2-methyl piperazine (4.0 g, 40 mmol) in xylene (100 mL) at 140° C. under nitrogen was added 2-bromo pyrimidine (6.36 g, 40 mmol) slowly over a period of 30 min. The heating was continued for additional 15 h and cooled. The solid precipitate was filtered and dried under suction and neutralized with a saturated aqueous solution of sodium bicarbonate. The product was extracted with DCM (2×50 mL), dried and evaporated to afford the title compound as a liquid (2.4 g, 34%). TLC—Chloroform/MeOH (8/2); Rf: 0.2.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([OH:22])=[O:21])(=[O:13])=[O:12])=[C:7]([OH:23])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>O1CCCC1.C(OCC)(=O)C>[C:31]([O:23][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:10]=[CH:9][C:8]=1[S:11]([NH:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([OH:22])=[O:21])(=[O:13])=[O:12])(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccsc2C(=O)O)c(O)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Oc1cc(C(C)(C)C)ccc1S(=O)(=O)Nc1ccsc1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.2 %

Procedure:
To a cooled (0° C.) solution of 35 (137.2 mg; 0.39 mmol) and triethylamine (0.06 mL; 0.46 mmol) in tetrahydrofuran (2 mL) was added acetyl chloride (0.03 mL; 0.46 mmol). After addition was complete, the reaction mixture was stirred at 0° C. for 30 minutes then allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water, aqueous saturated sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The crude residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes to yield the title compound as a white foam (67.0 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:17])[C:8]3[C:13]([S:14][C:15]=2[CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3)#[N:2].[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].[NH4+]>CN(C)C=O>[NH:18]1[C:1]([C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:17])[C:8]4[C:13]([S:14][C:15]=3[CH:16]=2)=[CH:12][CH:11]=[CH:10][CH:9]=4)=[N:2][N:20]=[N:19]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2c(=O)c3ccccc3sc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2ccccc2sc2cc(-c3nnn[nH]3)ccc12

Procedure:
A mixture of 3-cyanothioxanthone (2.56 g), sodium azide (0.84 g) and ammonium chloride (0.70 g) in dimethylformamide (20 ml) was heated on a steam bath for 5 hrs. The nitrile dissolved after 2 hrs., at the same time a precipitate of the product forming. Much solid crystallised out on cooling. The reaction mixture was poured into excess dilute hydrochloric acid, and the yellow precipitate was filtered off and washed with water. It was dissolved in dilute aqueous sodium hydroxide, filtered and reprecipitated with dilute hydrochloric acid. The product was filtered off and dried at 110° C., and then recrystallised from dimethylformamide and dried at 154° C./15 mm Hg, decomposes 290° C.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[CH:11]=[O:12].[F:13][CH:14]([F:22])[C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-:24].[K+].[K+]>>[F:9][CH:8]([F:10])[C:4]1[C:3]([C:11]([OH:12])=[O:24])=[C:2]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH:14]([F:22])[F:13])[CH:16]=2)[N:6]([CH3:7])[N:5]=1
Reactant: Oc1cccc(C(F)F)c1
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(C(F)F)c(C=O)c1Cl
Agent: [K+]
Product: Cn1nc(C(F)F)c(C(=O)O)c1Oc1cccc(C(F)F)c1

Procedure:
The title compound was prepared using 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde and 3-difluoromethylphenol in the manner similar to the method in Production Example 1 above except potassium carbonate was used instead of potassium hydroxide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1.[CH2:13]1[O:15][CH2:14]1.B(F)(F)F.CCOCC>ClCCl.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][CH2:13][CH2:14][OH:15])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: C1CO1
Agent: FB(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1ccc(COCCO)cc1
Temperature: 25 °C
Yield: 17 %

Procedure:
To a two-neck round bottom flask, which was equipped with a Dewar condenser, a solution of 4-hydroxymethylbenzoic acid methyl ester (2.50 g, 0.015 mol) in anhydrous dichloromethane (30 mL) was cooled to −10° C. in a salt/ice bath. Ethylene oxide (1.10 mL) was added to the cooled stirring solution dropwise followed by the addition of boron trifluoride etherate (0.51 ml). The reaction mixture was stirred for 45 minutes and then warmed to room temperature for 30 minutes to boil off any excess of ethylene oxide in the reaction mixture. The reaction mixture was then diluted with brine. The aqueous layer was extracted with dichloromethane (3 times). All of the organic layers were combined, dried over Na2SO4, filtered, and concentrated to provide an oil. The crude material was purified using silica gel chromatography (4:1 pentane:ethyl acetate) to provide the desired product (537 mg, 2.56 mmol) in 17% yield. 1H (CDCl38.36, 600 MHz): δ (2H, d, J=8.4 Hz), 7.41 (2H, d, J=8.5 Hz), 4.62 (3H, s), 3.92 (2H, s), 3.78 (m, 2H), 3.63 (2H, m); 13C (CDCl3167.1, 143.5, 130.0, 129.8, 127.5, 72.9, 72.0, 150 MHz): δ 62.1, 52.3.
Reaction SMILES: CC([N:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([O:26][CH3:27])[CH:22]=[CH:23][CH:24]=3)[C:19]([NH:28][S:29]([C:32]3[S:33][C:34]([Cl:37])=[CH:35][CH:36]=3)(=[O:31])=[O:30])=[N:18]2)=[CH:12][CH:11]=1)[C:6](=[O:8])[O-:7])(C)C.Cl>ClCCl>[CH:6]([OH:8])=[O:7].[NH2:5][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([O:26][CH3:27])[CH:22]=[CH:23][CH:24]=3)[C:19]([NH:28][S:29]([C:32]3[S:33][C:34]([Cl:37])=[CH:35][CH:36]=3)(=[O:31])=[O:30])=[N:18]2)=[CH:14][CH:15]=1
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1ccc(CN(C(=O)[O-])C(C)(C)C)cc1
Agent: Cl
Solvent: ClCCl
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1ccc(CN)cc1
Product: O=CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
To a solution of 1,1-dimethylethyl[(4-{[3-{[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1H-indazol-1-yl]methyl}phenyl)methyl]carbamate (for a preparation see Intermediate 29) (92 mg, 0.16 mmol) in dichloromethane (3 mL) was added dropwise hydrogen chloride (0.041 mL, 0.163 mmol). The resulting mixture was stirred at room temperature for 4 h, and then additional portion of hydrogen chloride (0.041 mL, 0.163 mmol) was added dropwise and the mixture was stirred at room temperature overnight. The solvents were then evaporated in a nitrogen blowdown unit. The residue was dissolved in 1:1 MeOH-DMSO (1 mL) and purified by Mass Directed AutoPrep (supelcosil ABZ+Plus column) eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid). The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the title compound (69 mg, 83%). LCMS (System E) RT=2.10 min, ES+ve m/z 463/465 (M+H)+.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]([C:13]2([OH:20])[N:17]([CH3:18])[C:16](=[O:19])[CH2:15][CH2:14]2)[CH:9]=[CH:10][C:11]=1[Cl:12].[S:21](=[O:23])=[O:22].[ClH:24]>O.C(O)(=O)C>[Cl:12][C:11]1[CH:10]=[CH:9][C:8]([C:13]2([OH:20])[N:17]([CH3:18])[C:16](=[O:19])[CH2:15][CH2:14]2)=[CH:7][C:6]=1[S:21]([Cl:24])(=[O:23])=[O:22]
Reactant: O=S=O
Reactant: CN1C(=O)CCC1(O)c1ccc(Cl)c(N)c1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN1C(=O)CCC1(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1

Procedure:
A solution of 9.9 g of sodium nitrite in 60 ml of water is metered into, below the surface of, a solution of 30.5 g of 5-(3-amino-4-chlorophenyl)-5-hydroxy-1-methyl-2-pyrrolidone in 300 ml of half-concentrated hydrochloric acid at at 0° to 5° C. The reaction mixture is stirred while cooling for a further 10 min, and then a mixture of 15.2 g of cooper(II)chloride dihydrate and 450 ml of a saturated solution of sulfur dioxide in glacial acetic acid is added in portions. The mixture is stirred for a further 30 min, and then the sulfonyl chloride is precipitated by addition of water, and the crystals are filtered off. Melting point 137°-139° C.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[CH2:16]([O:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[O:27]CCBr)[C:17]1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[ClH:1].[OH:27][C:26]1[CH:25]=[C:24]([CH:33]=[CH:32][CH:31]=1)[O:23][CH2:16][CH2:17][N:11]1[CH2:12][CH2:13][CH:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([CH3:2])=[CH:15][CH:14]=2)[CH2:9][CH2:10]1
Reactant: BrCCOc1cccc(OCc2ccccc2)c1
Reactant: Cc1ccc(CC2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(CC2CCN(CCOc3cccc(O)c3)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-methylbenzyl)piperidine hydrochloride (294 mg, 1.30 mmol), 2-(3-benzyloxyphenoxy)ethyl bromide (399 mg, 1.3 mmol) and potassium carbonate (449 mg, 3.2 mmol) in two steps as white-off solid (230 mg): mp 163-165° C. 1H NMR (CD3OD) 1.421 (m, 2 H), 1.733 (m, 2 H), 2.135 (s, 3 H), 2.424 (d, J=5.7 Hz, 2 H), 2.9 (m, 2 H), 3.370 (m, 2 H), 3.448 (m, 2 H), 4.147 (t, J=4.8 Hz, 2 H), 6.302 (m, 3 H), 6.937 (m, 5 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[CH2:9]([Sn](CCCC)(CCCC)C=C)[CH2:10]CC.C(OCC)(=O)C.[F-].[K+]>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([CH:9]=[CH2:10])[CH:5]=[CH:4][N:3]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Fc1cc(I)ccn1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=Cc1ccnc(F)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
A mixture of 2-fluoro-4-iodopyridine (2.23 g, 10.0 mmol), tributyl vinyl tin (3.8 g, 12 mmol), and Pd2Cl2(PPh3)2 (703 mg, 1.0 mmol) in dioxane (20 mL) was heated under nitrogen at 80° C. overnight. After cooled, ethyl acetate (40 ml) and saturated KF aqueous solution were added to the reaction mixture. The mixture was stirred for 30 min. The organic layer was separated and washed with water, dried (MgSO4), and concentrated. The resulting residue was purified by flash column chromatography eluting with hexane/ethyl acetate (20:1) to provide the title compound (463 mg, 38%). 1HNMR (500 MHz, CDCl3) δ ppm 5.55 (d, J=10.92 Hz, 1 H) 5.99 (d, J=17.47 Hz, 1 H) 6.67 (dd, J=17.47, 10.61 Hz, 1 H) 6.88 (m, 1 H) 7.17 (dt, J=5.30, 1.56 Hz, 1 H) 8.16 (d, J=5.30 Hz, 1 H).
Reaction SMILES: C(OC(N1CCC([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][C:24]3[CH:28]=[CH:27][O:26][CH:25]=3)[CH:15]=2)CC1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[O:26]1[CH:27]=[CH:28][C:24]([CH2:23][N:16]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:22]3[C:14]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:17]3)=[CH:15]2)=[CH:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cn(Cc3ccoc3)c3ncccc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cnc2c(c1)c(N1CCCCC1)cn2Cc1ccoc1

Procedure:
Over a solution of 1.4 g (3.7 mmol) of 4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester in 10 ml of dichloromethane, 2.85 ml of trifluoroacetic acid were carefully added. The crude mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the crude residue was dissolved in 10 ml of ethyl acetate and washed with saturated aqueous solution of sodium carbonate and brine. After drying over sodium sulphate, filtering and removing the solvent under reduced pressure, 0.62 g (60% of yield) of the expected product were obtained.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:22])[C:4]([C:19]([OH:21])=O)=[CH:5][N:6]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[CH3:10])[C:7]=1[CH3:8].[CH3:23][N:24](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN>CN(C=O)C.CO>[CH3:23][NH:24][C:19]([C:4]1[C:3](=[O:22])[C:2]([Br:1])=[C:7]([CH3:8])[N:6]([CH:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=2)[CH3:10])[CH:5]=1)=[O:21]
Reactant: Cc1c(Br)c(=O)c(C(=O)O)cn1C(C)c1ccc(C#N)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: CNC(=O)c1cn(C(C)c2ccc(C#N)cc2)c(C)c(Br)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-bromo-1-[1-(4-cyano-phenyl)-ethyl]-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 2b, 0.51 g, 1.41 mmol), HBTU (0.620 g, 1.64 mmol), DIPEA (0.50 mL, 2.93 mmol) in DMF (2.7 g) is stirred for 30 min. Then, methylamine (1.6 mL of 2M solution in THF, 3.20 mmol) is added and the reaction mixture is stirred for 18 h at room temperature. The reaction mixture is diluted with MeOH and purified by preparative reversed-phase HPLC (XBridge, gradient of acetonitrile in water, 0.3% NH4OH, 60° C.). Yield: 0.31 g (59% of theory); ESI mass spectrum: [M+H]+=374 (bromine isotope pattern); Retention time HPLC: 0.70 min (Z011_S03).
Reaction SMILES: [CH:1]1([CH:7]([NH:23][C:24]([C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)=[O:25])[CH:8]([NH:13][CH:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:15]([O:17]C)=[O:16])[C:9]([F:12])([F:11])[F:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si](C)(C)[O-].[K+]>O1CCCC1.C(OCC)(=O)C>[CH:1]1([CH:7]([NH:23][C:24]([C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)=[O:25])[CH:8]([NH:13][CH:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:15]([OH:17])=[O:16])[C:9]([F:11])([F:12])[F:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C(NC(C(NC(=O)c1cnccn1)C1CCCCC1)C(F)(F)F)C(C)(C)C
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(NC(C(NC(=O)c1cnccn1)C1CCCCC1)C(F)(F)F)C(=O)O
Temperature: 140 °C

Procedure:
The stereoisomer of methyl 2-(3-cyclohexyl-1,1,1-trifluoro-3-(pyrazine-2-carboxamido)propan-2-ylamino)-3,3-dimethylbutanoate designated as 7A1-isomer A (107 mgm), and potassium trimethylsilanolate (124 mgm, 4 eq) in tetrahydrofuran (2.5 mL) were heated to 140° C. in a microwave apparatus for 10 minutes. The reaction mixture was diluted with ethyl acetate, and washed successively with 1N hydrochloric acid, water, brine, and then dried over anhydrous sodium sulfate. Evaporation to dryness under reduced pressure gave crude 2-(3-cyclohexyl-1,1,1-trifluoro-3-(pyrazine-2-carboxamido)propan-2-ylamino)-3,3-dimethylbutanoic acid (8), designated as 8A1-isomer A.