Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]([CH:13]=O)=[CH:3]1.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18]>N1C=CC=CC=1.N1CCCCC1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4](/[CH:13]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:3]1
Reactant: O=C(O)CC(=O)O
Reactant: Cn1cc(C=O)c(=O)c2ccccc21
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: Cn1cc(/C=C/C(=O)O)c(=O)c2ccccc21

Procedure:
A mixture of 1-methyl-3-formyl-4(1H)-quinolone (5.61 g) and malonic acid (4.5 g) in pyridine (45 ml) with 3 drops piperidine was heated on a steam-bath for two hours. The pyridine was removed in vacuo and the solid residue washed with water and dried. Recrystallisation from DMF/H2O gave the title compound. NMR confirmed the structure as pure trans-isomer, m.p. 248°-250° (with decomposition).
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:28]([C:30]1[C:38]2[C:33](=[C:34]([C:39]#[N:40])[CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)=O>C(#N)C>[C:39]([C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:33]=1[NH:32][CH:31]=[C:30]2/[CH:28]=[CH:20]/[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])#[N:40]
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1cccc2c(C=O)c[nH]c12
Solvent: CC#N
Product: CC(C)(C)OC(=O)/C=C/c1c[nH]c2c(C#N)cccc12
Reaction time: 2.5 h
Yield: 77 %

Procedure:
1,1-Dimethylethyl (triphenyl-λ5-phosphanylidene)acetate (1.858 g) was added to a suspension of 3-formyl-1H-indole-7-carbonitrile (D3) (0.7 g) in acetonitrile (70 mL). The reaction mixture was heated to reflux and stirred for 2.5 hours. Another portion of 1,1-dimethylethyl (triphenyl-λ5-phosphanylidene)acetate (0.3 g) was added and the resulting suspension was refluxed for 2 more hours. The solvent was evaporated. The residue was purified by Biotage (25% EtOAc in hexane) to afford 1,1-dimethylethyl (2E)-3-(7-cyano-1H-indol-3-yl)-2-propenoate (D4) as a white solid (850 mg). δH (DMSO-d6, 400 MHz): 1.49 (9H, s), 6.40 (1H, d), 7.30 (1H, t), 7.71 (1H, dd), 7.79 (1H, d), 8.11 (1H, s), 8.25 (1H, dd), 12.59 (1H, br s). MS (ES): C16H16N2O2 requires 268; found 267.1 (M−H+).
Reaction SMILES: [NH:1]([C:3]1[C:8]([C:9](OCC)=O)=[CH:7][N:6]=[C:5]2[NH:14][N:15]=[CH:16][C:4]=12)[NH2:2].C(N1C2=[N:24][CH:25]=[C:26](C(OCC)=O)[C:27](NN)=[C:22]2C=N1)C>>[CH2:5]([NH:6][C:9]1[C:8]2[CH:7]=[N:6][C:5]3[NH:14][N:15]=[CH:16][C:4]=3[C:3]=2[N:1]2[N:2]=[C:27]([CH3:22])[CH:26]=[C:25]2[N:24]=1)[CH2:4][CH2:3][CH3:8]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1NN
Reactant: CCOC(=O)c1cnc2[nH]ncc2c1NN
Product: CCCCNc1nc2cc(C)nn2c2c1cnc1[nH]ncc12

Procedure:
By substituting an equivalent amount of 4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester for the 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester in the procedure of Example 1 a and continuing as in parts b, c and d, 5-chloro-2-methyl-8H-pyrazolo[1,5a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine and N-butyl-2-methyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5-amine respectively, are obtained.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:29]([C:31]1[CH:36]=[C:35](Cl)[N:34]=[CH:33][N:32]=1)=[O:30])[CH2:24][CH2:23]2.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:29]([C:31]1[N:32]=[CH:33][N:34]=[C:35]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:36]=1)=[O:30])[CH2:24][CH2:23]2
Reactant: O=C(c1cc(Cl)ncn1)N1CCc2cc(Br)ccc21
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 22 h

Procedure:
70 mg (0.24 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one dihydrochloride were added to 100 mg (0.30 mmol) (5-bromo-2,3-dihydroindol-1-yl)-(6-chloropyrimidin-4-yl)-methanone and 100 μL (0.58 mmol) DIPEA in 10 mL DMF. The reaction mixture was stirred for 22 h at RT and then evaporated down i. vac. The residue was combined with 20 mL water and stirred for 30 min at RT. The precipitated product was suction filtered. The purification was carried out using a silica gel column. The product fractions were combined and the solvent was eliminated using the rotary evaporator. The residue was stirred with water, suction filtered and dried at 40° C. in the CAD.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.C([Li])CCC.[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[Cl-].[NH4+]>C1(C)C=CC=CC=1.CCCCCC>[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][CH2:26][C:25]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=2)([OH:29])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Reactant: Cc1cc(Br)cnc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1cc(Br)cnc1C1(O)CCCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 39.5 %

Procedure:
To a solution of 2,5-dibromo-3-methylpyridine (3.88 g) in toluene (70 ml) was added dropwise a 1.6 M solution of n-butyllithium in n-hexane (10.6 ml) at −78° C., and stirred at the same temperature for 1 hour. Then, a solution of N-tert-butoxycarbonyl-hexahydroazepin-4-one (3.0 g) in toluene (16 ml) was added dropwise thereto, and stirred at the same temperature for 5 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added thereto, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated. The obtained residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 4-(5-bromo-3-methylpyridin-2-yl)-4-hydroxyazepane-1-carboxylic acid tert-butyl ester (2.14 g) as a colorless clear oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:14])=[C:8]([S:10](Cl)(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2].C([N:17](CC)C1C=CC=CC=1)C.C(C1C=CC(C)=C(S([O-])(=O)=O)C=1)(=O)C>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:14])=[C:8]([S:10]([NH2:17])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C)c(S(=O)(=O)Cl)c1
Reactant: CCN(CC)c1ccccc1
Agent: CC(=O)c1ccc(C)c(S(=O)(=O)[O-])c1
Product: CC(=O)c1ccc(C)c(S(N)(=O)=O)c1

Procedure:
Thus obtained 5-acetyl-2-methylbenzenesulfonyl chloride was dissolved in 790 g of tetrahydrofuran, then 81 g of ammonia gas was added at a temperature below 10° C. 800 Grams of water was added to this reaction mixture, and tetrahydrofuran was removed by evaporation to crystallized 5-acetyl-2-methylbenzenesulfonamide. The crystals were collected by filtration, and dried to obtain 176.8 g (0.83M) of 5-acetyl-2-methylmethylbenzenesulfonamide. Melting point: 150.5°-151.5° C. The yield was 95% on the basis of 5-acetyl-2-methylbenzenesulfonyl chloride, and was 83% on the basis of N,N-diethylaniline salt of 5-acetyl-2-methylbenzenesulfonate.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:18][CH:15]([CH:16]=[CH2:17])[CH:4]([CH:5]([O:9][CH:10]([O:12][CH2:13][CH3:14])[CH3:11])[CH2:6][CH:7]=O)[O:3]1.Cl.[NH2:21][OH:22]>N1C=CC=CC=1.CCOCC>[CH3:1][C:2]1([CH3:19])[O:18][CH:15]([CH:16]=[CH2:17])[CH:4]([CH:5]([O:9][CH:10]([O:12][CH2:13][CH3:14])[CH3:11])[CH2:6][CH:7]=[N:21][OH:22])[O:3]1
Reactant: NO
Reactant: C=CC1OC(C)(C)OC1C(CC=O)OC(C)OCC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: C=CC1OC(C)(C)OC1C(CC=NO)OC(C)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The obtained 4,5-(dimethylmethylenedioxy)-3-(1-ethoxyethoxy)-6-heptenal was dissolved in 2 ml of pyridine under a nitrogen atmosphere, and 442 mg of hydroxylamine hydrochloride was added at 0° C. The mixture was stirred at room temperature for 4 hours, and the obtained reaction mixture was diluted with ether. The diluted reaction mixture was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to afford 1.00 g of 4,5-(dimethylmethylenedioxy)-3-(1-ethoxyethoxy)-6-heptenal oxime.
Reaction SMILES: [H-].[K+].O1[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:8][S:9][CH2:10][S:11](=[O:13])[CH3:12].BrCCCCBr>C(Cl)Cl>[CH3:8][S:9][C:10]1([S:11](=[O:13])[CH3:12])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C1CCOC1
Reactant: CSCS(C)=O
Agent: [H-]
Agent: [K+]
Solvent: ClCCl
Solvent: BrCCCCBr
Product: CSC1(S(C)=O)CCCC1
Reaction time: 0.67 h

Procedure:
Potassium hydride (940 mg) was suspended in 15 ml. of tetrahydrofuran, and with ice cooling, 1.320g of formaldehyde dimethyl mercaptal S-oxide was added. With ice-cooling, the mixture was stirred for 40 minutes, and then 2.410 g of 1.4-dibromobutane was added. The mixture was stirred for 1 hour with ice cooling, and then for 19 hours at room temperature. Methylene chloride (70ml) was added, and the insoluble matter was separated by filtration. The filtrate was concentrated at reduced pressure, and the residue was separated by column chromatography (silica gel, eluted with CH2Cl2, 25% AcOEt-CH2Cl2, AcOEt, and MeOH) to afford 1.509 g of cyclopentanone dimethyl mercaptal S-oxide as a colorless oily substance. Furthermore, 208 mg of formaldehyde dimethyl mercaptal S-oxide was obtained from the MeOH fraction. The yield was 80%. The physical properties were as follows:
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.Cl[C:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11]>C1COCC1>[O:3]=[C:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11]
Reactant: O=C1CCCN1
Reactant: O=C(Cl)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCCN1C(=O)Oc1ccccc1
Temperature: -60 °C
Yield: 100.1 %

Procedure:
To a solution of 7.36 g (184 mmol) of NaH (60%) in 200 ml of THF was added 15.68 g (184 mmol) of 2-oxopyrrolidine with stirring under ice-cooling, and further the mixture was stirred at room temperature for 1 hr. until H2 gas ceased to evolve. The reaction solution was added to a solution of 29.7 g (190 mmol) of phenyl chloroformate in 100 ml of THF cooled at -60° C. and then stirred at room temperature for 4 hr. The reaction solution was poured into ice water, and then extracted with ethyl acetate. After drying, the solvent was removed by evaporation. When the crystalline residue was recrystallized from CH2Cl2 -ether, 37.8 g of the objective compound (II) melting at 120.0°-121.5° C. was obtained as crystals. Yield: 84.0%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]([OH:9])=[O:8])[CH2:2]1.C([O-])(O)=O.[Na+].[CH3:15][CH:16]([CH3:21])[CH2:17][C:18](Cl)=[O:19]>O.C1COCC1>[CH3:15][CH:16]([CH3:21])[CH2:17][C:18]([N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]([OH:9])=[O:8])[CH2:2]1)=[O:19]
Reactant: O=C(O)[C@@H]1CCCNC1
Reactant: CC(C)CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(=O)N1CCC[C@@H](C(=O)O)C1
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of (R)-piperidine-3-carboxylic acid (2.0 g, 15.48 mmol) in water (40 mL) and THF (20 mL) were added NaHCO3 (3.30 g, 38.70 mmol) and 3-methylbutanoyl chloride (2.8 mL, 23.2 mmol) at room temperature. The reaction was stirred overnight, concentrated under reduced pressure, diluted with water (50 mL) and extracted with EtOAc (1×). The aqueous layer was acidified with 1N HCl, extracted with EtOAc (3×) and the combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (2.53 g, 76%). MS 214 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:12][CH2:13][CH2:14][OH:15])[CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:3][CH2:2]1.[F:16][C:17]([F:47])([F:46])[C:18]1[CH:19]=[C:20]([CH2:28][CH2:29][N:30]([CH3:45])[C:31](=[O:44])[C@H:32](OS(C)(=O)=O)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1.C(N(CC)CC)C>CC(C)=O>[F:16][C:17]([F:46])([F:47])[C:18]1[CH:19]=[C:20]([CH2:28][CH2:29][N:30]([CH3:45])[C:31](=[O:44])[C@@H:32]([N:9]2[CH2:10][CH2:11][CH:6]([N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH2:12][CH2:13][CH2:14][OH:15])[CH2:7][CH2:8]2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:21]=[C:22]([C:24]([F:26])([F:27])[F:25])[CH:23]=1
Reactant: OCCCN(CC1CC1)C1CCNCC1
Reactant: CN(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)[C@H](OS(C)(=O)=O)c1ccccc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CN(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)[C@H](c1ccccc1)N1CCC(N(CCCO)CC2CC2)CC1
Yield: 46.2 %

Procedure:
4.7 g of 4-[cyclopropylmethyl-(3-hydroxy-propyl)-amino]-piperidine are stirred together with 9.6 g of (R)—N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-methanesulphonyloxy-N-methyl-2-phenyl-acetamide (prepared from D-(−)-mandelic acid) and 3.4 ml of triethylamine in 200 ml of acetone for four hours at 65° C. The mixture is concentrated by evaporation in vacuo, combined with 100 ml of saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined organic fractions are dried over sodium sulphate and the solvent is eliminated in vacuo. The residue is chromatographed with methylene chloride/methanol 1:1 over silica gel. The fractions found to be uniform by TLC are collected and the solvents are eliminated in vacuo. 5.5 g of (S)—N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-[cyclopropylmethyl-(3-hydroxy-propyl)-amino]-piperidin-1-yl}-N-methyl-2-phenyl-acetamide are obtained as a brownish-yellow oil, [α]D20=+35.1°
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[C:12](=[O:23])[CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN.[CH3:38][N:39](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N1C=CC=CC=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[C:12](=[O:23])[CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([NH:39][CH3:38])=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(N(CCc2ccc(C(F)(F)F)cc2)C(=O)C(C(=O)O)c2ccccc2)cc1OC
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CNC(=O)C(C(=O)N(CCc1ccc(C(F)(F)F)cc1)c1ccc(OC)c(OC)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.3 %

Procedure:
A mixture of 16.2 mg (0.033 mmol) N-(3,4-Dimethoxy-phenyl)-2-phenyl-N-[2-(4-trifluoromethyl-phenyl)-ethyl]-malonamic acid, 15.5 mg (0.049 mmol) methylamine (commercially available), 13.8 mg (0.043 mmol) TBTU and 7.8 mg (0.09 mmol) pyridine in 2 mL DMF was shaken for 4 h at room temperature. The mixture was evaporated to dryness, taken up in methanol, formic acid and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and acetic acid. The combined product fractions were evaporated to dryness to yield 2.7 mg (16%) of the title compound. MS(m/e): 501.3 (MH+), MH+ found: 501.3.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])=[C:5]([C:7]([NH2:9])=O)[N:6]=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])=[C:5]([C:7]#[N:9])[N:6]=1
Reactant: Cc1nc(C(N)=O)c(Nc2ccccc2[N+](=O)[O-])s1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1nc(C#N)c(Nc2ccccc2[N+](=O)[O-])s1
Temperature: 0 °C
Yield: 64.3 %

Procedure:
Combine 2-methyl-5-(2-nitroanilino)thiazole-4-carboxylic acid amide (60 g, 215 mmol) and toluene and add POCl3 (40 mL, 430 mmol) and reflux the reaction mixture. After 2.5 h cool to 0° C. Add saturated NaHCO3 solution to quench the extra POCl3 (Caution!!) until the aqueous was around pH 8. Add ethyl acetate (2×2 L) to extract the product. Combined organic layer and wash with brine (2×1 L), dry over MgSO4, and evaporate to give a reddish solid which triturated with 25% ethyl acetate in hexane to give a reddish solid (36 g). Evaporate the filtrate to half volume to give second batch of compound (3.2 g). Total yield (39.2 g, 70%): mass spectrum (m/e): 261 (M+1); 1HNMR(300 MHz, DMSO, ppm): 2.70 (s, 1H), 7.02 (t, 1H), 7.22 (d, 1H), 7.58 (t, 1H), 8.25 (d, 1H), 9.78 (s, 1H). ). 13CNMR(75MHz, DMSO, ppm): 20.4, 113.1, 116.2, 118.7, 121.2 127.0, 134.9, 136.6, 140.0, 148.6, 161.5. Formula: C11H8N4O2S
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[C:9]2[CH:10]=[N:11][C:12]([NH:14][C:15]([NH:17][C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[O:16])=[CH:13][C:8]=2[N:7](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:6]=1)[CH3:2].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH2:1]([O:3][CH2:4][C:5]1[C:9]2[CH:10]=[N:11][C:12]([NH:14][C:15]([NH:17][C@@H:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH3:19])=[O:16])=[CH:13][C:8]=2[NH:7][N:6]=1)[CH3:2]
Reactant: CCOCc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOCc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.3 %

Procedure:
To the solution of (R)-1-(3-(ethoxymethyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (130 mg, 0.223 mmol) and trifluoroacetic acid (0.856 ml, 11.17 mmol) in dichloromethane (2.0 ml) was added triethylsilane (39.0 mg, 0.335 mmol). The resulting mixture was allowed to stir at rt for 18 h. The reaction was concentrated in vacuo and submitted for reversed phase HPLC purification to provide the desired product (28.5 mg, 0.063 mmol, 28.1% yield). MS ESI calc'd. for C18H21N5O2 [M+H]+ 340, found 340.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[O:15](C(OC(C)(C)C)=O)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O>C(#N)C.CN(C1C=CN=CC=1)C>[O:7]=[C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][N:1]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:15]
Reactant: O=C1CCCCN1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCCC1=O
Reaction time: 0.17 h
Yield: 63.3 %

Procedure:
A solution of piperidin-2-one (25 g, 252.2 mmol) in acetonitrile (250 ml) was cooled to 0° C. and added DMAP (6.1 g, 50.4 mmol) and triethyl amine (25.5 g, 252.2 mmol) and stirred for 10 min at same temperature then added (BOC)2O (66 g, 302.6 mmol) and continue stirring for 2 h at room temperature. After completion of starting material, solvent was removed and residue was re-dissolved in ethyl acetate and washed with water, brine and dried over Na2SO4 and concentration to afford crude product as brown liquid (31.8 g) which was used directly for the next step. 1H NMR (300 MHz, CDCl3) δ 3.66-3.62 (2H, m), 2.52-2.47 (2H, m), 1.83-1.79 (4H, m), 1.52 (9H, s) ppm.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[CH2:9](Br)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18].[OH-].[K+]>C(O)C.O>[CH2:18]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=[CH2:9]
Reactant: Oc1ccc(O)cc1
Reactant: C=CCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCCCCCCCCOc1ccc(O)cc1
Yield: 36.4 %

Procedure:
Hydroquinone (37.65 g, 342 mmol) and dec-9-enyl bromide (25 g, 114 mmol) were dissolved in ethanol (150 ml) with warming under a nitrogen atmosphere. The solution was heated under reflux and a solution of potassium hydroxide (6.83 g, 121 mmol) in water (20 ml) was added dropwise over 1 h. The resulting suspension was heated under reflux (3 H) then poured on to water (500 ml) and extracted with ether (3×100 ml). The combined extracts were dried (MgSO4), evaporated in vacuo and the residue extracted with heptane (300 ml). On cooling, it afforded a first crop of the phenol (10.31 g). The remaining material was chromatographed (flash grade silica gel, petroleum ether 40-60° C./diethyl ether 3/2). 2 was isolated as white plates (Rf=0.57). Combined yield=15.61 g (55%). Mp=54° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([NH2:20])=[C:18](Br)[C:17]([Cl:22])=[C:16]([C:23]([F:26])([F:25])[F:24])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C1(C)C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([NH2:20])=[CH:18][C:17]([Cl:22])=[C:16]([C:23]([F:24])([F:25])[F:26])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(F)(F)F)c(Cl)c(Br)c2N)CC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C(F)(F)F)c(Cl)cc2N)CC1
Temperature: 85 °C
Yield: 96.6 %

Procedure:
A solution of the compound obtained in Step B (0.2 g), tris(trimethylsilyl)-silane (0.16 ml), and 2,2′-azobis(2-methylpropionitrile) (10 mg) in toluene (10 ml) was stirred at 85° C. for 2 hours under a nitrogen atmosphere. More tris(trimethylsilyl)silane (0.3 ml) and more 2,2′-azobis(2-methylpropionitrile) (5 mg) were then added and the reaction mixture was heated to 85° C. for 16 hours. The reaction mixture was cooled to ambient temperature, poured into water, extracted with ethyl acetate, dried over sodium sulfate and then concentrated in vacuo. Chromatography on silica gel (eluent: hexane/ethyl acetate 1:1) afforded 3-amino-5-chloro-6-trifluoromethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (0.160 g) as a solid. MS (ES+) 324/326 (M-isoprene); 1H NMR (400 MHz, CDCl3) 1.48 (s, 9H), 1.84 (m, 4H), 2.78 (m, 1H), 2.88 (m, 2H), 4.25 (m, 2H), 4.42 (s, 2H), 7.46 (s, 1H).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([SH:19])=[C:14]([CH3:20])[CH:13]=1.[Cl:21][C:22]1[N:27]=[C:26]([CH3:28])[C:25]([N+:29]([O-:31])=[O:30])=[C:24](Cl)[N:23]=1>C1COCC1>[Br:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([S:19][C:24]2[C:25]([N+:29]([O-:31])=[O:30])=[C:26]([CH3:28])[N:27]=[C:22]([Cl:21])[N:23]=2)=[C:14]([CH3:20])[CH:13]=1
Reactant: Cc1cc(Br)cc(C)c1S
Reactant: Cc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1Sc1nc(Cl)nc(C)c1[N+](=O)[O-]
Temperature: -100 °C
Reaction time: 2 h

Procedure:
A solution of LiHMDS in THF (77 mmol) is added to a mixture of 4-bromo-2,6-dimethylbenzenethiol (70 mmol) in THF (100 ml) at −78° C. over 15 minutes and the mixture stirred for an additional 2 hours. The mixture is cooled with liquid nitrogen to around −100° C. and a solution of 2,6-dichloro-4-methyl-5-nitropyrimidine (84 mmol) in THF (50 ml) is added rapidly. The reaction is maintained at around −100° C. for 1 hour and then allowed to warm to room temperature. The mixture is filtered and the isolated solid washed with ethanol. The filtrate may be concentrated and crystallized to obtain additional compound.