Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C@:13]([F:15])([CH3:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([C:29](O)=[O:30])=[N:22][N:23]([CH2:25][CH:26]([F:28])[F:27])[CH:24]=1>>[NH2:16][C:10]1[O:11][CH2:12][C@@:13]([F:15])([CH3:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:21]3[C:20]([Cl:19])=[CH:24][N:23]([CH2:25][CH:26]([F:28])[F:27])[N:22]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(N)ccc1F
Reactant: O=C(O)c1nn(CC(F)F)cc1Cl
Product: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(NC(=O)c2nn(CC(F)F)cc2Cl)ccc1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.3) and 4-chloro-1-(2,2-difluoro-ethyl)-1H-pyrazole-3-carboxylic acid (CAS 1006486-42-5) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=448.2 [M+H]+.
Reaction SMILES: Br[C:2]1[C:11]2[NH:10][C:9](=[O:12])[CH2:8][C:7]3([CH3:15])[CH2:13][NH:14][C:5]([C:6]=23)=[CH:4][CH:3]=1.[Cu][C:17]#[N:18]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][C:7]12[CH2:13][NH:14][C:5]3=[C:6]1[C:11](=[C:2]([C:17]#[N:18])[CH:3]=[CH:4]3)[NH:10][C:9](=[O:12])[CH2:8]2
Reactant: N#C[Cu]
Reactant: CC12CNc3ccc(Br)c(c31)NC(=O)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC12CNc3ccc(C#N)c(c31)NC(=O)C2
Temperature: 150 °C

Procedure:
A mixture of (±)-6-bromo-2a-methyl-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one (53 mg, 0.20 mmol, described in Intermediate 47), tetrakis(triphenylphosphine)palladium(0) (48 mg, 0.042 mmol), and copper(I) cyanide (27 mg, 0.30 mmol) in DMF (2 mL) was heated at 150° C. for 3 h. The cooled reaction mixture was quenched with aqueous NaHCO3 (10 mL) and extracted with EtOAc (30 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—60:40 to 0:100, to give the title compound in sufficient purity for use in the next step. MS: m/z=214 (M+1).
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C@H:17]([CH3:31])[CH2:18][CH2:19][NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)([O-])=O>CO.CO.ClCCl.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:3][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C@H:17]([CH3:31])[CH2:18][CH2:19][NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: C[C@H](CCNC(=O)OCc1ccccc1)Nc1c([N+](=O)[O-])cnc2ccccc12
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: C[C@H](CCNC(=O)OCc1ccccc1)Nc1c(N)cnc2ccccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.7 %

Procedure:
Sodium borohydride (110 mg, 2.8 mmol) was added to a solution of nickel (II) chloride hexahydrate (330 mg, 1.4 mmol) in 10 mL of methanol. A solution of benzyl (3R)-3-[(3-nitroquinolin-4-yl)amino]butylcarbamate (1.11 g, 2.81 mmol) in 20 mL of 1:1 methanol/dichloromethane was added, and the resulting dark mixture was stirred for 5 minutes at room temperature. Additional sodium borohydride was added in small portions until the reaction solution become colorless. The mixture was filtered through a layer of CELITE filter agent, and the filtrate was concentrated under reduced pressure. The resulting brown solid was triturated with dichloromethane, and the resulting mixture was filtered through a layer of CELITE filter agent. The filtrate was concentrated under reduced pressure to provide 0.96 g of benzyl (3R)-3-[(3-aminoquinolin-4-yl)amino]butylcarbamate as a brown foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[I-].FC(F)(F)[CH2:12][OH:13].[C]=O.O=O>ClC1C=CC=CC=1Cl>[C:2]1([N:1]=[C:12]=[O:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: OCC(F)(F)F
Agent: O=O
Agent: [C]=O
Agent: [I-]
Solvent: Clc1ccccc1Cl
Product: O=C=Nc1ccccc1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
In a 1000 ml high-pressure stirred autoclave 15.5 g of aniline, 7.6 g of the [Co-tBu-Salen]/Silica catalyst of Example 2, 1.78 g of NaI and 488 g of 2,2,2-trifluoroethanol (TFE) are charged. The autoclave is pressurized with carbon monoxide and oxygen in a volumetric ratio of 19/1. The temperature is increased to 120° C. and the total pressure is maintained constant at 40 bars. The reaction is maintained under constant vigorous stirring for three hours. After 3 hours the reactor is cooled to room temperature, depressurized and 97.8 g of 1,2-dichlorobenzene (DCB) is charged in the reactor. The temperature is increased to 180° C. under atmospheric pressure. The vapors of TFE are separated, condensed, and reused in the following example. In the bottom of the reactor a mixture of DCB and phenylisocyanate is obtained. From this mixture pheylisocyanate is recovered by distillation with 99% w/w purity.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].CS[C:14]1[NH:15][S:16](=[O:21])(=[O:20])[CH2:17][CH2:18][N:19]=1>>[CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:14]1[NH:15][S:16](=[O:21])(=[O:20])[CH2:17][CH2:18][N:19]=1
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CSC1=NCCS(=O)(=O)N1
Product: Cc1nc[nH]c1CSCCNC1=NCCS(=O)(=O)N1
Yield: 31.1 %

Procedure:
A mixture of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (4.0 g.) and 3-methylthio-5,6-dihydro-1,2,4-thiadiazine-1,1-dioxide (4.2 g.) was heated in an oil bath at 140° for 4 hours. The product was chromatographed on a column of silica gel with ethyl acetate-ethanol (3:2) as eluant and finally recrystallised from ethanol-ether to give 3-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-5,6- dihydro-1,2,4-thiadiazine-1,1-dioxide (2.2 g.) m.p. 146°-147°.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:33]1[CH:37]=[CH:36][C:35]([CH2:38][NH2:39])=[CH:34]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:39][CH2:38][C:35]5[CH:36]=[CH:37][S:33][CH:34]=5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCc1ccsc1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCc2ccsc2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 18 h
Yield: 23 %

Procedure:
A mixture of 0.070 g (0.16 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.035 (0.23 mmole) of 3-thiophenemethanamine 0.071 g (0.19 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.136 mL (0.78 mmole) of diisopropylethyl amine and 2.0 mL of dimethylformamide was stirred for 18 hours. The mixture was diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase silica gel chromatography, eluting with an acetonitrile-water (gradient, 20:80-100:0) to give 0.020 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-thiophen-3-ylmethyl-benzamide (I-33) as a light brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[C:16]([F:18])[C:15](Br)=[CH:14][C:13]=2[F:20])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH-].[NH4+].O.ClCCl.[CH3:27][N:28](C)C=O>>[C:27]([C:15]1[C:16]([F:18])=[CH:17][C:12]([C:9]2[CH2:8][CH2:7][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH:10]=2)=[C:13]([F:20])[CH:14]=1)#[N:28]
Reactant: CN(C)C=O
Reactant: CCOC(=O)N1CC=C(c2cc(F)c(Br)cc2F)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1CC=C(c2cc(F)c(C#N)cc2F)CC1

Procedure:
A mixture of 27.60 g (79.8 mmol) 1-ethoxycarbonyl-4-(4-bromo-2,5-difluorophenyl)-1,2,3,6-tetrahydropyridine and 9.00 g (89.6 mmol) cuprous cyanide in 300 ml N,N-dimethylformamide was stirred at reflux for 20 hours. The mixture was cooled and shaken with 800 ml concentrated ammonium hydroxide, 800 ml water and 1,000 ml of dichloromethane. The organic layer was washed with water, dried (MgSO4) and evaporated. The product was purified by chromatography on silica gel and crystallization from hexane to give the title compound, mp 85°-87° C.
Reaction SMILES: C1C=CC(C[O:8][C:9]([C@@H:11]([NH:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)=[O:10])=CC=1.[CH3:33][O:34][C:35]1[CH:40]=[C:39]([CH3:41])[C:38]([S:42](Cl)(=[O:44])=[O:43])=[C:37]([CH3:46])[C:36]=1[CH3:47].[OH-].[Na+]>ClCCl>[NH:22]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:11]([C:9]([OH:10])=[O:8])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([S:42]([C:38]2[C:37]([CH3:46])=[C:36]([CH3:47])[C:35]([O:34][CH3:33])=[CH:40][C:39]=2[CH3:41])(=[O:44])=[O:43])[CH:14]=1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)n2cc(C[C@H](NC(=O)OCc3ccccc3)C(=O)O)c3ccccc32)c(C)c1C

Procedure:
In the same manner as Example 5, Z-Trp-OBZl (15.0 g, 35 mM) and 4-methoxy-2,3,6-trimethylbenzenesulfonyl chloride were reacted in dichloromethane (500 ml) in the presence of sodium hydroxide (17.8 g, 0.44 M). The reaction product was then hydrolyzed with an aqueous solution of sodium hydroxide to give Z-Trp(Mtr)-OH. Yield 19.0 g (98.4%); m.p. 71°-74° C.; [α]D24 -41.6° (c=0.9, DMF).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].CO.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1>[CH2:1]([N:4]([CH2:8][C:9]1[CH:18]=[CH:17][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCCN(CCC)Cc1ccc(C(=O)OC)cc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
The compound (1.47 g) obtained in Example 80-1 was dissolved in anhydrous THF (50 ml). Then, the solution was added with lithium aluminum hydride (671 mg) in an ice bath, followed by stirring at room temperature for 1 hour. After completion of the reaction, the solution was added with methanol and then added with an aqueous potassium sodium tartrate solution, followed by stirring. The solution was extracted with chloroform and the extract was then washed with saturated saline solution. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off, thereby obtaining the subject compound (1.20 g) as a colorless liquid.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:4]=[C:5]([NH:9][CH2:10][C:11]([N:13]([CH2:21][CH3:22])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[O:12])[CH:6]=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.[C:33]([C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1)(=[O:35])[CH3:34]>C1COCC1>[C:33]([C:36]1[CH:37]=[CH:38][C:39]([S:42]([N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:23])[CH3:1])[CH:4]=2)[CH2:10][C:11]([N:13]([CH2:21][CH3:22])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[O:12])(=[O:44])=[O:43])=[CH:40][CH:41]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(Cc1ccccn1)C(=O)CNc1cccc(N(C)C)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1ccccn1)C(=O)CN(c1cccc(N(C)C)c1)S(=O)(=O)c1ccc(C(C)=O)cc1
Reaction time: 2 h
Yield: 36.4 %

Procedure:
A solution of 2-(3-dimethylamino-phenylamino)-N-ethyl-N-pyridin-2-ylmethyl-acetamide (2.50 mmol) and of DIPEA (5.00 mmol) in THF (10 mL) was added to a solution of 4-acetyl-benzenesulfonyl chloride (2.50 mmol) in THF (10 mL). The reaction mixture was stirred for 2 h, the solvents were removed and the residue was purified by preparative HPLC chromatography to give 451 mg (0.91 mmol, 36%) product as a brownish foam.
Reaction SMILES: Cl.[CH:2]1([C:5]#[C:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[CH2:12][C:11]2([CH2:20][CH2:19][CH:18]([O:21][CH3:22])[CH2:17][CH2:16]2)[C:10]3=[N:23]S(C(C)(C)C)=O)[CH2:4][CH2:3]1>O1CCOCC1>[CH:2]1([C:5]#[C:6][C:7]2[CH:8]=[C:9]3[C:13]([CH2:12][C:11]4([CH2:20][CH2:19][CH:18]([O:21][CH3:22])[CH2:17][CH2:16]4)[C:10]3=[NH:23])=[CH:14][CH:15]=2)[CH2:3][CH2:4]1
Reactant: COC1CCC2(CC1)Cc1ccc(C#CC3CC3)cc1C2=NS(=O)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC1CCC2(CC1)Cc1ccc(C#CC3CC3)cc1C2=N
Reaction time: 1 h
Yield: 104.8 %

Procedure:
4 M HCl in dioxane (1.5 mL, 6.00 mmol) was added to a solution of N-(5′-(cyclopropylethynyl)-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide (Example 20i Step 2, 470 mg, 1.18 mmol) in dry dioxane (5 mL) at 5° C. The reaction mixture was allowed to come to r.t. and stirred for 1 h, then it was stored at 0° C. overnight and then concentrated. The product (as the hydrochloride salt) was dissolved in DCM and washed with aq. sat. NaHCO3, dried over Na2SO4 and concentrated to give 363 mg of the title compound (quantitative yield). 1H NMR (500 MHz, CDCl3) δ ppm 0.78-0.85 (m, 2 H), 0.85-0.91 (m, 2 H), 1.34-1.49 (m, 3 H), 1.54-1.63 (m, 2 H), 1.68-1.84 (m, 2 H), 2.08-2.19 (m, 2 H), 2.98 (s, 2 H), 3.23-3.33 (m, 1 H), 3.38-3.43 (m, 3 H), 7.27 (m, 2 H), 7.46 (dd, 1 H), 7.69 (br. s., 1 H). MS (ES+) m/z 294 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11](=[O:13])[NH2:12].[C:14]1([CH2:20][C:21](O)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.ON1C2C=CC=CC=2N=N1.OC1C2N=NNC=2C=CC=1>ClCCl.CN(C)C=O>[C:11]([C:3]1[C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[S:6][C:2]=1[NH:1][C:21](=[O:22])[CH2:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])[NH2:12]
Reactant: NC(=O)c1c(N)sc2c1CCCC2
Reactant: O=C(O)Cc1ccccc1
Agent: Oc1cccc2[nH]nnc12
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1c(NC(=O)Cc2ccccc2)sc2c1CCCC2
Temperature: 20 °C
Reaction time: 170 h

Procedure:
A mixture of commercially available 2-amino-3-carbamoyl-4,5,6,7-tetrahydrobenzo[b]thiophene (5 mg, 0.026 mmol), phenylacetic acid (7 mg, 0.05 mmol), N-hydroxybenzotriazole (8.5 mg, 0.065 mmol), and N-cyclohexylcarbodiimide-N′-methylpolystyrene (loading about 1.5 mmol/g resin, 50 mg) in dichloromethane (2 ml)/dimethylformamide (0.5 ml) was agitated at 20° C. for 170 h. Afterward tris-(2-aminoethyl)-amine polystyrene (loading about 4 mmol/g resin 40 mg) was added for scavenging the hydroxybenzotriazole and the excess of acid, and the agitation was maintained for additional 24 h.
Reaction SMILES: C([Si]([C:8]#[C:9][C:10]1[C:15]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][N:13]=[CH:12][N:11]=1)(CC)CC)C.C(O)(=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([O-])(O)=O.[Na+]>C1COCC1.C(Cl)Cl>[C:9]([C:10]1[C:15]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][N:13]=[CH:12][N:11]=1)#[CH:8]
Reactant: CCOC(=O)Cc1cncnc1C#C[Si](CC)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: C#Cc1ncncc1CC(=O)OCC
Reaction time: 0.08 h
Yield: 54 %

Procedure:
To a solution of ethyl 2-(4-((triethylsilyl)ethynyl)pyrimidin-5-yl)acetate (I109) (1.174 g, 3.856 mmol) in dry THF (40 mL) under an atmosphere of nitrogen was added acetic acid (0.243 mL, 4.24 mmol) followed by TBAF (1.0 M in THF, 4.049 mL, 4.049 mmol) dropwise at 0° C. The reaction was stirred at this temperature for 5 minutes and was then poured into sat. aq. NaHCO3 (100 mL) and DCM (100 mL). The layers were separated and the aqueous layer was extracted with DCM (2×100 mL). The combined organics were washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give a brown oil. The crude material was purified by silica gel chromatography (Isolera Biotage, 40 g Si Cartridge, 0-60% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I110) (0.397 g, 54% yield) as a brown oil; 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 8.72 (s, 1H), 4.20 (q, J=7.1 Hz, 2H), 3.81 (s, 2H), 3.56 (s, 1H), 1.27 (t, J=7.1 Hz, 3H). LCMS Method C: rt 4.78 min; m/z 191.1 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([CH:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)#[N:14].Br[CH2:27][F:28]>C1COCC1>[C:13]([C:15]1([CH2:27][F:28])[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)#[N:14]
Reactant: CC(C)(C)OC(=O)N1CC(C#N)C1
Reactant: FCBr
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C#N)(CF)C1
Temperature: 0 °C
Yield: 88.6 %

Procedure:
To an oven-dried 25 mL round bottom flask equipped for stirring was added diisopropylamine (0.659 mL, 4.66 mmol) under nitrogen. THF (5 mL) was added and the colorless solution was cooled to 0° C. To this solution was added n-BuLi (2.92 mL, 4.66 mmol) and the solution was stirred at 0° C. for 30 min. The solution was cooled to −78° C. and a solution of tert-butyl 3-cyanoazetidine-1-carboxylate (0.5 g, 2.74 mmol) in THF (3 mL) was added and the solution was stirred at −78° C. for 30 min. Bromofluoromethane (0.403 g, 3.57 mmol) was added at −78° C. dropwise. The reaction mixture was stirred for 30 min and then allowed to warm to 25° C. and stirred for 16 h. The reaction mixture was quenched at 0° C. with aqueous NH4Cl (5 mL) and extracted with DCM (3×). The extracts were dried over Na2SO4. Purification by silica column chromatography (MeOH/DCM, 0-5%) afforded the title compound as a yellow oil (0.52 g, 94%).
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[C:4]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[N:3]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)C.O>[F:1][C:2]1[C:7]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:23][CH:22]=2)=[CH:6][CH:5]=[C:4]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[N:3]=1
Reactant: CCCCCCCCOc1ccc(Br)cc1
Reactant: CCCCCCCCOc1ccc(B(O)O)c(F)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(-c2ccc(OCCCCCCCC)nc2F)cc1
Yield: 41.5 %

Procedure:
2.00 g (7.44 mmol) of 2-fluoro-6-octyloxypyridine-3-boronic acid, 1.64 g (5.72 mmol) of 1-bromo-4-octyloxybenzene, 0.26 g (0.22 mmol) of tetrakis(triphenylphosphine)palladium(0) and 11.16 ml (22.32 mmol) of 2-molar sodium carbonate solution are refluxed in 20 ml of benzene and 10 ml of ethanol for 6 hours. After distributing the reaction mixture between water and diethyl ether, the organic phase is washed with water, dried over sodium sulfate, filtered and concentrated. Purification of the residue by chromatography (silica gel, 95:5 hexane/ethyl acetate) and recrystallization from acetonitrile give 1.02 g of 2-fluoro-6-octyloxy3-(4-octyloxyphenyl)pyridine. ##STR23##
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)[C:40]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([CH3:48])[N:44]=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[CH3:55][C:56]([CH3:65])=[CH:57]CN1C=CC(N)=N1.N1C(C)=CC=CC=1C>C(Cl)Cl.C(OCC)(=O)C>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:51][CH2:52][CH2:53][CH2:54]2)[C:40]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([CH2:48][CH:55]=[C:56]([CH3:65])[CH3:57])[N:44]=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36]
Reactant: CC(C)=CCn1ccc(N)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: CC(C)=CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Yield: 38.9 %

Procedure:
Triphenylphosphine (224 mg, 0.85 mmol) was dissolved in methylene chloride (3 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (172 mg, 0.97 mmol) and was stirred at 0° C. until it was completely dissolved and became light purple in color. The 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1; 188 mg, 0.57 mmol) was then added and it was stirred at 0° C. for 20 min and then warmed to 25° C. and stirred for another 30 min. After such time 1-(3-methyl-but-2-enyl)-1H-pyrazol-3-ylamine (86 mg, 0.57 mmol) and 2,6-lutidine (198 μL, 1.71 mmol) were added and the reaction was stirred at 25° C. for 16 h. The reaction was then diluted with ethyl acetate (50 mL), washed with water (2×15 mL), saturated aqueous brine solution (1×15 mL), dried over magnesium sulfate and concentrated in vacuo to give an orange oil. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 20% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) followed by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% ethyl acetate/methylene chloride to 20% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3-methyl-but-2-enyl)-1H-pyrazol-3-yl]-propionamide (103 mg 39%) as an off white powder: ESI-LRMS m/e calcd for C23H30ClN3O3S [M+] 463.17, found 464.23 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.06-1.23 (m, 2H, CH2), 1.46-1.93 (m, 8H, 4×CH2), 1.76 (s, 3H, CH3), 1.80 (s, 3H, CH3), 2.05-2.35 (m, 1H, CH), 3.28 (s, 3H, SO2CH3), 3.53 (t, J=7.6 Hz, 1H, CH), 4.59 (d, J=7.1 Hz, 2H, NCH2), 531-5.43 (m, 1H, vinylic), 6.66 (d, J=2.3 Hz, 1H, Ar), 7.27 (d, J=2.3 Hz, 1H, Ar), 7.46 (dd, Jo=8.1, Jm=1.7 Hz. 1H, Ar), 7.59 (d, Jm=1.7 Hz, 1H, Ar), 7.83 (s, 1H, NH), 8.10 (d, Jo=8.1 Hz, 1H, Ar).