Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[C:17][C:18]([NH2:21])([CH3:20])[CH3:19])=[N:14][CH:15]=2)[CH:7]=[CH:6][N:5]=1)=O.[NH2:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]1>>[NH2:21][C:18]([CH3:20])([CH3:19])[C:17]#[C:16][C:13]1[N:14]=[CH:15][C:10]([C:8]2[CH:7]=[CH:6][N:5]=[C:4]([NH:22][CH:23]3[CH2:24][C:25]([CH3:32])([CH3:31])[NH:26][C:27]([CH3:30])([CH3:29])[CH2:28]3)[N:9]=2)=[CH:11][CH:12]=1
Reactant: CS(=O)c1nccc(-c2ccc(C#CC(C)(C)N)nc2)n1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Product: CC(C)(N)C#Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cn1

Procedure:
3-[5-(2-Methanesulfinyl-pyrimidin-4-yl)-pyridin-2-yl]-1,1-dimethyl-prop-2-ynylamine (500 mg, 1.76 mmol) and 4-amino-2,2,6,6-tetramethylpiperidine (0.61 ml, 3.54 mmol) were heated to 120° C. for 1 hour and the reaction mixture purified directly by chromatography on silicagel (TBME/MeOH/ammonia:95/4.5/0.5) to give the title compound as yellow crystals.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.CS(C)=O.[OH:11][CH2:12][C:13]([NH:16][C:17]1[S:18][CH:19]=[C:20]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[N:21]=1)([CH3:15])[CH3:14].C(N(CC)CC)C>C(Cl)Cl.O1CCCC1>[Cl:4][C:19]1[S:18][C:17]([NH:16][C:13]([CH3:15])([CH3:14])[CH:12]=[O:11])=[N:21][C:20]=1[C:22]1[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(CO)Nc1nc(-c2ccc(C#N)cc2)cs1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C=O)Nc1nc(-c2ccc(C#N)cc2)c(Cl)s1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 22 %

Procedure:
A dry round bottom flask under nitrogen was charged with oxalyl chloride (2M solution in methylene chloride (9.15 mL, 18.3 mmol) and methylene chloride (125 mL) and cooled to −78° C. Dimethylsulfoxide was added dropwise (2.6 mL, 36.6 mmol) and the mixture was stirred for 10 min. A solution of 4-{2-[(2-hydroxy-1,1-dimethylethyl)amino]-1,3-thiazol-4-yl}benzonitrile (2.5 g, 9.2 mmol), prepared in step 1 of Example 82, in 10 mL of tetrahydrofuran was added and the mixture stirred for 30 min. Triethylamine (7.9 mL, 55 mmol) was added and the mixture was stirred for 20 min and then allowed to warm to 25° C. The mixture was then diluted with methylene chloride and washed with H2O, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (20% acetone in hexane) afforded 4-{5-chloro-2-[(1,1-dimethyl-2-oxoethyl)amino]-1,3-thiazol-4-yl}benzonitrile (0.60 g, 22%) as a yellow solid. HRMS: calcd for C14H12ClN3OS+H+, 306.04623; found (ESI, [M+H]+), 306.0453; Analytical HPLC: purity see MS. MS & UV are same at 210-370 nm; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]2[N:9]=[CH:10][N:11]([C:12]3[S:16][C:15]([C:17]([NH2:19])=[O:18])=[C:14]([O:20][C@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH3:22])[CH:13]=3)[C:5]=2[CH:4]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>ClCCl>[CH3:33][S:34]([O:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]2[N:9]=[CH:10][N:11]([C:12]3[S:16][C:15]([C:17](=[O:18])[NH2:19])=[C:14]([O:20][C@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:30])([F:31])[F:32])[CH3:22])[CH:13]=3)[C:5]=2[CH:4]=1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example 49 (step 1), 120 mg of 5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-{(1S)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide, 57 mg of methanesulfonyl chloride, and 53 mg of triethylamine in 3 ml dichloromethane give [1-(5-carbamoyl-4-{(1S)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate as crude material that is used for step 2 without further purification.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([Br:19])=[CH:16][CH:17]=3)[C:12]([CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:39]=[CH:38][C:33]5[O:34][CH2:35][CH2:36][O:37][C:32]=5[CH:31]=4)[CH2:26][CH2:25]3)=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[K+]>C(O)C>[Br:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:10][CH:11]=[C:12]2[CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:25][CH2:26][N:27]([C:30]2[CH:39]=[CH:38][C:33]3[O:34][CH2:35][CH2:36][O:37][C:32]=3[CH:31]=2)[CH2:28][CH2:29]1
Reactant: O=S(=O)(c1ccccc1)n1cc(CCCCN2CCN(c3ccc4c(c3)OCCO4)CC2)c2cc(Br)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Brc1ccc2[nH]cc(CCCCN3CCN(c4ccc5c(c4)OCCO5)CC3)c2c1

Procedure:
4.7 g of 6-[4-(4-(1-benzenesulfonyl-5-bromoindol-3-yl)butyl)piperazino]-1,4-benzodioxane is boiled for 16 hours with 1.5 g of KOH in aqueous ethanol solution, worked up in the conventional manner and gives 6-[4-(4-(5-bromoindol-3-yl)butyl)piperazino]-1,4-benzodioxane.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=1[NH2:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[C:24](Cl)(Cl)=[S:25]>C(Cl)(Cl)Cl.O>[Si:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=1[NH:11][C:24]([NH:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:9]=1)=[S:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: S=C(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1cc([N+](=O)[O-])ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1cc([N+](=O)[O-])ccc1NC(=S)Nc1ccccc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
N-(2-tert-Butyldimethysilyloxy-4-nitrophenyl)-N′-phenyl-thiourea was prepared by treating a biphasic solution of 2-tert-butyldimethysilyloxy-4-nitroaniline(80 mg, 0.308 mmol) and NaHCO3 in CHCl3:H2O(2.5:1, 7 mL) with thiophosgene at 0° C. The solution was allowed to warm to 23° C. and the reaction was continued overnight The CHCl3 layer was separated and dried over sodium sulfate. The solution was concentrated in vacuo and the residue was dissolved in toluene and treated with aniline (100 uL) at 23° C. for 12 h. The reaction mixture was concentrated and the residue was purified by flash chromatography (10% EtOAc/hexanes) to afford the titled compound as a yellow solid (120.8 mg, 98%) mp: 144-145° C.; 1H NMR (CD3OD/CDCl3): δ 8.65 (d, 1H, J=10.0 Hz), 7.58 (d, 1H, J=10.0 Hz), 7.47 (d, 1H, J=1.25 Hz), 7.26 (m, 4H), 7.10 (m, 1H).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:26]([F:27])=[CH:25][C:24]([CH2:28][OH:29])=[C:23](Cl)[N:22]=3)[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:31]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:26]([F:27])=[CH:25][C:24]([CH2:28][OH:29])=[C:23]([CH3:31])[N:22]=3)[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CB1OB(C)OB(C)O1
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3nc(Cl)c(CO)cc3F)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1nc(N2CCC(=NOC3CCN(C(=O)OC(C)C)CC3)CC2)c(F)cc1CO
Temperature: 100 °C

Procedure:
55b (30 mg, 0.068 mmol), trimethylboroxine (25 mg, 0.2 mmol) and potassium carbonate (50 mg, 0.36 mmol) were combined in 0.5 mL of dioxane and heated at 100° C. for 20 h. The mixture was cooled, concentrated under a stream of nitrogen, diluted with water (2 mL) and extracted with ethyl acetate (2×2 mL). The combined extracts were dried under a stream of nitrogen and the residue was purified by preparative HPLC to afford 55-1 as a colorless oil: LC-MS 423.1 (MH+), tR=5.95 (Method 2). EC50: 206 nM.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].P(=O)([O-])[O-].C([Li])CCC.[C:17](OC)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1.CCCCCC.C(O)(=O)C>[O:24]=[C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)c1ccccc1
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)c1ccccc1)OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 51.1 %

Procedure:
A solution of 74.5 g (600 mmoles) dimethyl methylphosphonate (Aldrich) in 750 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 265 ml of 2.34 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 30 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 41 g (300 mmole) of methyl benzoate was added dropwise at a rate that kept the reaction temperature less than -70° (10 minutes). After 1 hour at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 35 ml acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 75 ml water, the aqueous phase extracted with 300 ml portions of ether (3x), the combined organic extracts were backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, b.p. 130°-5° (0.4 mm) to give 35 g (29%) dimethyl 2-oxo-2-phenylethylphosphonate (2a).
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8](=[O:35])[C:9]1[C:10](=[CH:30][CH:31]=[CH:32][C:33]=1[I:34])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=1[CH3:29])=[O:12])([CH3:6])[CH2:3][S:4][CH3:5].ClC1C=CC=C(C(OO)=[O:44])C=1>C(Cl)(Cl)Cl>[CH3:6][C:2]([NH:7][C:8](=[O:35])[C:9]1[C:10](=[CH:30][CH:31]=[CH:32][C:33]=1[I:34])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:21]([F:23])([F:22])[F:24])[C:25]([F:28])([F:26])[F:27])=[CH:16][C:15]=1[CH3:29])=[O:12])([CH3:1])[CH2:3][S:4]([CH3:5])=[O:44]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCC(C)(C)NC(=O)c1c(I)cccc1C(=O)Nc1ccc(C(C(F)(F)F)C(F)(F)F)cc1C
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(C(F)(F)F)C(F)(F)F)ccc1NC(=O)c1cccc(I)c1C(=O)NC(C)(C)CS(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
In 10 ml of chloroform was dissolved 0.63 g (1.0 mmol) of N2-(1,1-dimethyl-2-methylthioethyl)-3-iodo-N1-{2-methyl-4-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]phenyl}phthalamide, and the resulting solution was cooled to 0° C. To the solution was added 0.19 g (1.1 mmol) of meta-chloroperbenzoic acid. After stirring for one hour, the reaction mixture was washed with 10% aqueous solution of potassium carbonate and dried on anhydrous magnesium sulfate, and the solvent was dissolved off under reduced pressure. Thus, 0.45 g of the objective compound was obtained (yield: 69%).
Reaction SMILES: C([O:8][C:9]1[C:17]2[N:13]([C:14]([CH2:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[C:15]([CH2:23][CH3:24])[C:16]=2[C:18](=[O:22])[C:19]([NH2:21])=[O:20])[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1.CCCCCC.C[CH2:39][O:40][C:41]([CH3:43])=[O:42]>>[C:41]([CH2:43][O:8][C:9]1[C:17]2[N:13]([C:14]([CH2:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[C:15]([CH2:23][CH3:24])[C:16]=2[C:18](=[O:22])[C:19]([NH2:21])=[O:20])[CH:12]=[CH:11][CH:10]=1)([O:40][CH3:39])=[O:42]
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCc3ccccc3)cccn2c1CC1CCCCC1
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)cccn2c1CC1CCCCC1
Yield: 19 %

Procedure:
Mp, 149-150 C, (Hexane-EtOAc). 19% Yield from 49b.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[N+:7]([O-:9])[CH:8]=1.[N+:11]([O-])([OH:13])=[O:12]>>[CH3:1][O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[CH:5][C:6]([CH3:10])=[N+:7]([O-:9])[CH:8]=1
Reactant: COc1ccc(C)[n+]([O-])c1
Reactant: O=[N+]([O-])O
Product: COc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
21.2 g of 5-methoxy-2-methylpyridine 1-oxide are metered into 35 ml of 65% strength nitric acid and warmed to 60° C. in a manner such that the temperature of the reaction mixture does not rise above 80° C. The mixture is stirred at 80° C. for 1 hour, a further 13 ml of 100% strength nitric acid are added to bring the reaction to completion and the mixture is stirred at 60°-70° C. for a further 2 hours. For working up, the mixture is poured onto 300 g of ice. The yellow precipitate which separates out is filtered off over a suction filter, washed with water and dried. The dry solid is boiled up with 200 ml of methylene chloride, filtered off and dried. Further TLC-pure product is isolated by concentration of the filtrate. 22.3 g (87% of theory) of 5-methoxy-2-methyl-4-nitropyridine 1oxide of m.p. 201°-202° C. are obtained as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH:14][CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[S:12][CH:13]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:27][CH2:28][CH2:29][CH3:30].C(OCC)(=O)C>CN(C)C=O>[CH2:27]([N:14]([CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1)[C:11]1[S:12][CH:13]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCI
Reactant: COc1ccc(-c2csc(NCc3ccc(C#N)cc3)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCN(Cc1ccc(C#N)cc1)c1nc(-c2ccc(OC)cc2)cs1
Temperature: 25 °C

Procedure:
1.0 g 4-{[4-(4-Methoxy-phenyl)-thiazol-2-ylamino]-methyl}-benzonitrile was dissolved in 150 ml dimethylformamide. 150 mg sodium hydride (24% in mineral oil) were added and the reaction mixture stirred at room temperature for thirty minutes. Then 0.43 ml 1-Iodobutane were added and the reaction mixture stirred at room temperature for two hours. Then 100 ml ethyl acetate were added and the mixture was washed three times with portions of 50 ml water and then dried over MgSO4. The solvents were removed in vacuo to obtain 1.2 g 4-({Butyl-[4-(4-methoxy-phenyl)-thiazol-2-yl]-amino}-methyl)-benzonitrile.
Reaction SMILES: [CH2:1]([SH:5])[C:2]([OH:4])=[O:3].CS(O[CH2:11][CH2:12][C:13]#[CH:14])(=O)=O>>[CH2:14]([S:5][CH2:1][C:2]([OH:4])=[O:3])[CH2:13][C:12]#[CH:11]
Reactant: O=C(O)CS
Reactant: C#CCCOS(C)(=O)=O
Product: C#CCCSCC(=O)O

Procedure:
2-(But-3-ynylthio)acetic acid was prepared from thioglycollic acid and but-3-ynyl methanesulphonate using the methodology described in stage (i) of Example XIII.
Reaction SMILES: Cl.[CH:2]([Si:5]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[O:6][CH:7]([C:12]1[C:17]([CH:18]=[CH2:19])=[CH:16][CH:15]=[CH:14][N:13]=1)[CH2:8][CH2:9]C=C)([CH3:4])[CH3:3].N#N>C(Cl)Cl>[CH:20]([Si:5]([CH:23]([CH3:25])[CH3:24])([CH:2]([CH3:4])[CH3:3])[O:6][CH:7]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:17]2[CH:18]=[CH:19][CH2:9][CH2:8]1)([CH3:22])[CH3:21]
Reactant: C=CCCC(O[Si](C(C)C)(C(C)C)C(C)C)c1ncccc1C=C
Agent: Cl
Agent: N#N
Solvent: ClCCl
Product: CC(C)[Si](OC1CCC=Cc2cccnc21)(C(C)C)C(C)C
Temperature: 40 °C
Yield: 70.9 %

Procedure:
Hydrogen chloride (5.64 mL, 11.28 mmol)(10 mL, 2M diethyl ether solution) was added to the CH2Cl2 (25 mL) solution of 2-(1-(triisopropylsilyloxy)pent-4-enyl)-3-vinylpyridine (3.9 g, 11.28 mmol). The solvent was removed via vacuum and the corresponding HCl salt was azeotroped by benzene twice. The reaction was charged with CH2Cl2 (500 mL) and purged with N2 for 10 min before addition of Grubb II (0.192 g, 0.226 mmol). The reaction was heat to 40° C. for 3 hours, LCMS showed no starting material left. The reaction was washed with saturated NaHCO3 solution once. The CH2Cl2 was separated, dried (Na2SO4), filtered and concentrated. Flash column by ether in hexane from 0 to 25% gave the desired product as yellow oil (2.54 g, 71%yield). MS(ESI)[M+H+]=318.35.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([O:9]C)=[O:8].CO.[OH-].[Na+].Cl>O1CCOCC1>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1[nH]cnc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)c1[nH]cnc1Cl
Yield: 89.2 %

Procedure:
A solution of methyl 4-chloro-1H-imidazole-5-carboxylate (0.061 g, 0.4 mmol) was stirred in a solution of MeOH (2 mL), dioxane (2 mL) and 2N NaOH (1.9 mL, 3.8 mmol) at RT for 4 days. The reaction mixture was then acidified by addition of 1M HCl (20 mL) and extracted with EtOAc. The organic extracts were dried (Na2SO4), and the solvent was evaporated to provide 4-chloro-1H-imidazole-5-carboxylic acid (0.0523 g, 94%) as a white solid which was used without further purification. 4-Chloro-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide was prepared in a similar manner as described herein from 3-{[3-aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.054 g, 0.17 mmol), 4-chloro-1H-imidazole-5-carboxylic acid (0.026 g, 0.17 mmol), HATU (0.086 g, 0.23 mmol), DIPEA (0.039 mL, 0.23 mmol) and DMF (2 mL). Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.008 g, 10%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 13.16 (br. s., 1H), 8.24 (br. s., 1H), 7.82 (s, 1H), 7.78 (s, 1H), 7.45-7.54 (m, 3H), 7.35-7.42 (m, 1H), 4.54 (s, 2H). ES-LCMS: m/z 439.0, 441.0 (M+1).
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[N:20]([C:21]5[CH:22]=[C:23]([NH:28][C:29](=[O:48])[C:30]6[CH:35]=[C:34]([S:36]([F:41])([F:40])([F:39])([F:38])[F:37])[CH:33]=[C:32]([N:42]7[CH2:47][CH2:46][O:45][CH2:44][CH2:43]7)[CH:31]=6)[CH:24]=[CH:25][C:26]=5[CH3:27])[CH:19]=[CH:18][N:16]4[N:17]=3)[CH:10]=[N:9]2)=CC=1>FC(F)(F)C(O)=O>[CH3:27][C:26]1[CH:25]=[CH:24][C:23]([NH:28][C:29](=[O:48])[C:30]2[CH:35]=[C:34]([S:36]([F:39])([F:37])([F:38])([F:40])[F:41])[CH:33]=[C:32]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[CH:31]=2)=[CH:22][C:21]=1[N:20]1[C:15]2[N:16]([N:17]=[C:13]([C:11]3[CH:12]=[N:8][NH:9][CH:10]=3)[CH:14]=2)[CH:18]=[CH:19]1
Reactant: COc1ccc(Cn2cc(-c3cc4n(-c5cc(NC(=O)c6cc(N7CCOCC7)cc(S(F)(F)(F)(F)F)c6)ccc5C)ccn4n3)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)c2cc(N3CCOCC3)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cn[nH]c3)cc12

Procedure:
At 80° C., 98 mg (0.14 mmol) of the compound of Example 49A were stirred in 0.56 ml of trifluoroacetic acid for 3 h. The reaction was then concentrated, the residue was dissolved in ethyl acetate and the solution was washed with saturated sodium bicarbonate solution. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. After drying of the residue under high vacuum, the crude product was purified by preparative HPLC (Method 29). The product fractions were combined and concentrated, and the residue was taken up in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. Drying under high vacuum gave a first product fraction (39 mg). A second product fraction of a further 19 mg was obtained from the combined mixed fractions of the HPLC separation by concentrating these fractions followed by re-purification by the same method by preparative HPLC. This gave a total of 58 mg (69% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[CH2:28]([O:30][C:31](=[O:45])[CH:32]([C:38]1[CH:43]=[N:42][C:41]([NH2:44])=[CH:40][N:39]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH3:29].N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O.O1CCCC1>[CH2:28]([O:30][C:31](=[O:45])[CH:32]([C:38]1[CH:43]=[N:42][C:41]([NH:44][C:13](=[O:15])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:40][N:39]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH3:29]
Reactant: CCOC(=O)C(C(=O)OCC)c1cnc(N)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.6 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 170 mg, 0.51 mmol) in methylene chloride (10 mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (385 μL, 0.77 mmol) and catalytic N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 30 min and at 25° C. for 2 h. The solution was then concentrated in vacuo. The residue was dissolved in methylene chloride (10 mL), cooled to 0° C., and then treated with a solution of 2-(5-amino-pyrazin-2-yl)-malonic acid diethyl ester (130 mg, 0.51 mmol) and 2,6-lutidine (120 μL, 1.03 mmol) in tetrahydrofuran (10 mL). The reaction mixture was then stirred at 0° C. for 15 min and at 25° C. for 16 h. The reaction was then concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 1/1 ethyl acetate/hexanes) afforded the 2(R)-{5-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazin-2-yl}-malonic acid diethyl ester (76.9 mg, 26%) as a pale yellow oil. This material was further purified by dissolving it in methylene chloride and washing with a 1N aqueous hydrochloric acid solution (25 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the 2(R)-{5-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazin-2-yl}-malonic acid diethyl ester (51.3 mg, 18%) as a pale yellow oil: (ES)+-HRMS m/e calcd for C26H32ClN3O7S (M+H)+ 566.1722, found 566.1726.
Reaction SMILES: Br.[C:2]1([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2([C:21]([OH:23])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([N:18]1[CH2:17][CH2:16][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:21]([OH:23])=[O:22])[CH2:20][CH2:19]1)(=[O:26])[CH3:25]
Reactant: O=C(O)C1(c2ccccc2Sc2ccccc2)CCNCC1
Reactant: CC(=O)OC(C)=O
Agent: Br
Solvent: c1ccncc1
Product: CC(=O)N1CCC(C(=O)O)(c2ccccc2Sc2ccccc2)CC1

Procedure:
A mixture of 8 g of 4-(2-phenylthiophenyl)piperidine-4-carboxylic acid hydrobromide and 10 ml of acetic anhydride in 50 ml of pyridine is refluxed for 4 hours. Thereafter, any excess pyridine is removed by distillation under vacuum and the residue is triturated in 100 ml of 1 N hydrochloric acid before being extracted thrice with chloroform. The combined chloroform extracts are successively washed well with water, dried and concentrated under vacuum. The residue is recrystallized from boiling acetone to provide 1-acetyl-4-(2-phenylthiophenyl)piperidine-4-carboxylic acid.
Reaction SMILES: Cl.[CH3:2][N:3]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:4]1[N:9]=[C:8]([NH2:10])[N:7]=[C:6]([C:11]2[N:15]=[C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][NH:17]3)[O:13][N:12]=2)[N:5]=1.C([O-])(=O)C.[Na+].[F:32][C:33]([F:38])([F:37])[CH2:34][CH:35]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH3:2][N:3]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:4]1[N:9]=[C:8]([NH2:10])[N:7]=[C:6]([C:11]2[N:15]=[C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[CH2:35][CH2:34][C:33]([F:38])([F:37])[F:32])[O:13][N:12]=2)[N:5]=1
Reactant: O=CCC(F)(F)F
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc([C@@H]3CCCN3)n2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc([C@@H]3CCCN3CCC(F)(F)F)n2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.4 %

Procedure:
To a solution of 2-N-methyl-2-N-phenyl-6-{5-[(2S)-pyrrolidin-2-yl]-1,2,4-oxadiazol-3-yl}-1,3,5-triazine-2,4-diamine hydrochloride (Example 438, 0.2 g, 0.535 mmol) in DCE (5 mL) was added sodium acetate (0.07 g, 0.8 mmol) and 3,3,3-trifluoropropanal (0.12 g, 1.070 mmol) and the mixture was stirred for 1 h at room temperature. Sodium triacetoxyborohydride (0.17 g, 0.8 mmol) was added and the reaction mixture was stirred for 2 h at room temperature. DCM was added and the mixture was washed with saturated aq. sodium bicarbonate, and then brine. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by FCC, eluting with 20-100% EtOAc in heptane to afford the title compound (0.045 g, 19%).