Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([NH:4][S:5](Cl)(=[O:7])=[O:6])[CH3:3].[CH2:9]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH3:10].C(N(CC)CC)C>ClCCl>[CH2:9]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:5]([NH:4][CH:2]([CH3:3])[CH3:1])(=[O:7])=[O:6])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH3:10]
Reactant: CCS(=O)(=O)c1ccc(N)cc1
Reactant: CC(C)NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(NS(=O)(=O)NC(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(1-Methylethyl)sulfamoyl chloride (6.63 g, 0.034 mol) was added dropwise to a solution of 4-(ethylsulfonyl)benzene amine (6 g, 0.032 mol) and triethylamine (4.87 ml, 0.035 mol) in dry dichloromethane (100 ml) at 0° C. under a nitrogen atmosphere. After addition, the resultant mixture was allowed to warm to room temperature and was stirred for 6 hr. The reaction mixture was then washed with water (2×50 ml). The organic extracts were combined, dried (MgSO4) and concentrated in vacuo to yield N-(4-ethylsulfonylphenyl)-N′-(1-methylethyl)sulfamide as a white solid. δ(1H NMR, DMSO, ppm): 1.05 (6H, d), 1.10 (3H, t), 3.25 (2H, q), 3.40 (1H, m), 7.40 (2H, d), 7.80 (3H, m).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:3].CN(CCC1CC=CC=1)C.[Cl-:25].[Cl-].[Cl-].[CH:28]1([Zr+3:33])[CH:32]=[CH:31][CH:30]=[CH:29]1.[Cl-].[Cl-].[Cl-].C[Zr](C)(C)(C)(C)C1C=CC=C1>>[Cl-:25].[Cl-:25].[CH3:1][N:2]([CH2:4][CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[Zr+2:33][CH:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1)[CH3:3]
Reactant: CN(C)CCC1C=Cc2ccccc21
Reactant: [Zr+3]C1C=CC=C1
Agent: C[Zr](C)(C)(C)(C)C1C=CC=C1
Agent: CN(C)CCC1=CC=CC1
Agent: [Cl-]
Product: CN(C)CCC1C([Zr+2]C2C=CC=C2)=Cc2ccccc21
Yield: 35 %

Procedure:
Example 1 was repeated in the same manner as described except that 1-(N,N-dimethylaminoethyl)indene was substituted for (N,N-dimethylaminoethyl)cyclopentadiene and that cyclopentadienylzirconium trichloride was substituted for pentamethylcyclopentadienylzirconium trichloride. The yield was 35.0%. The physical properties of the product are as follows:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:18]3[C:13](=[C:14]([F:20])[CH:15]=[CH:16][C:17]=3[F:19])[C:12](=[O:21])[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][N:38](C(OC(C)(C)C)=O)[CH:39]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C1COCC1.C(P([Pd]P(C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C.O>[F:20][C:14]1[CH:15]=[CH:16][C:17]([F:19])=[C:18]2[C:13]=1[C:12](=[O:21])[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][N:9]2[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([C:35]2[CH:36]=[N:37][NH:38][CH:39]=2)=[CH:7][N:6]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOC(=O)c1cn(Cc2ccc(Br)cn2)c2c(F)ccc(F)c2c1=O
Agent: CC(C)(C)[PH]([Pd][PH](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(Cc2ccc(-c3cn[nH]c3)cn2)c2c(F)ccc(F)c2c1=O
Temperature: 100 °C

Procedure:
To a solution of ethyl 1-[(5-bromopyridin-2-yl)methyl]-5,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (3.00 g, 7.09 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (5.42 g, 18.4 mmol), and 1 N cesium carbonate (14.2 mL, 14.2 mmol) in 50 mL of THF under nitrogen was added bis(tri-tert-butylphosphoranyl)palladium (10 mol %). The reaction mixture was heated to 100° C. for 20 hours, then cooled to room temperature. Ethyl acetate (100 mL) and water (100 mL) were added, and the resultant brown solid was collected to provide ethyl 5,8-difluoro-4-oxo-1-{[5-(1H-pyrazol-4-yl)pyridin-2-yl]methyl}-1,4-dihydroquinoline-3-carboxylate that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 411.0 for M+H+.
Reaction SMILES: C1C[O:4][CH2:3]C1.[NH2:6][C:7]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]([F:17])[C:8]=1[C:9]([OH:11])=[O:10].CCN(C(C)C)C(C)C.C(=O)(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl>O.C(#N)C>[F:17][C:12]1[C:8]([C:9]([OH:11])=[O:10])=[C:7]2[NH:6][C:3](=[O:4])[O:16][C:15]2=[CH:14][CH:13]=1
Reactant: Nc1c(O)ccc(F)c1C(=O)O
Reactant: C1CCOC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1c(F)ccc2oc(=O)[nH]c12

Procedure:
To a THF solution of 2-amino-6-fluoro-3-hydroxybenzoic acid (520 mg, 3.04 mmole) and n,n-diisopropylethylamine (942 mg, 7.29 mmole) was added bis(trichloromethyl) carbonate (1.08 g, 3.64 mmole) and stirred. Removal of solvent under vacuum afforded a residue, which was run on reversephase flash chromatography 10 to 90% acetonitrile water (0.01% TFA). The resulting fractions were evaporated.
Reaction SMILES: [CH2:1]([N:5]([CH3:24])[C:6]([C:8]1[CH:9]=[C:10]([C:21](O)=[O:22])[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:13]=1)=[O:7])[CH:2]([CH3:4])[CH3:3].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:48][C:49]1[N:54]=[CH:53][C:52]([CH2:55][NH2:56])=[CH:51][N:50]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:1]([N:5]([CH3:24])[C:6]([C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:11]=[C:10]([C:21]([NH:56][CH2:55][C:52]2[CH:51]=[N:50][C:49]([CH3:48])=[N:54][CH:53]=2)=[O:22])[CH:9]=1)=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N(C)CC(C)C)c2)cc1
Reactant: Cc1ncc(CN)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)nc3)cc(C(=O)N(C)CC(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(isobutyl(methyl)carbamoyl)-4′-methylbiphenyl-3-carboxylic acid (15 mg, 0.046 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (18 mg, 0.092 mmol), 1-hydroxybenzotriazole hydrate (7.0 mg, 0.046 mmol), and CH2Cl2 (2 mL) were added (2-methylpyrimidin-5-yl)methanamine (8.5 mg, 0.069 mmol) (WO 2008/130481) and N,N-diisopropylethylamine (12 μL, 0.069 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 40-70% MeCN/water[10 mM Et2NH]) to afford a white foam.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].CS(Cl)(=O)=O.[CH2:24](O)[CH2:25][CH2:26][OH:27]>>[F:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:26]([OH:27])[CH2:25][CH3:24]
Reactant: OCCCO
Reactant: OCCCCCCCCCCCCCCCCF
Agent: CS(=O)(=O)Cl
Product: CCC(O)OCCCCCCCCCCCCCCCCF

Procedure:
A general procedure for the preparation of terminal fluorinated alkoxyalkyl esters of acyclic nucleoside phosphonates is illustrated in Scheme 7, below. Fluoroalkoxyalkyl esters of acyclic nucleoside phosphonates such as 3-(16-fluoro-hexadecyloxy)propyl cidofovir (16-F-HDP-CDV) 49 and 3-(16-fluoro-hexadecyloxy)propyl (S)-HPMPA 50 (16-F-HDP-(S)-HPMPA) can be prepared using this process. Briefly, with reference to Scheme 7, the Grignard reagent prepared from 1-bromo-4-fluorobutane and magnesium is reacted with 12-bromododecanol 44 to obtain 16-fluorohexadecanol 45. Reaction of 45 with methanesulfonyl chloride followed by reaction with 1,3-propanediol provides 16-fluorohexadecyloxy-1-propanol 46. Coupling of 46 with cyclic cidofovir or cyclic (S)-HPMPA as described generally in Example 2 (step a), provides the cyclic esters (47 and 48, respectively) which can then be converted to the desired compounds (49 and 50, respectively) using the general method set forth in Example 2 (step b).
Reaction SMILES: [CH:1]1[C:17]2[CH:16]=[C:15]3[C:7](=[C:8]4[C:13](=[N:14]3)[CH:12]=[CH:11][CH:10]=[CH:9]4)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)(Cl)[Cl:33]>>[Cl-:33].[CH2:18]([N+:6]1[C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:14]([CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:15]=2[CH:16]=[C:17]2[C:5]=1[CH:4]=[CH:3][CH:2]=[CH:1]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc2[nH]c3c4ccccc4nc-3cc2c1
Reactant: BrCc1ccccc1
Reactant: ClC(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: [Cl-]
Product: c1ccc(Cn2c3ccccc3c3c2cc2ccccc2[n+]3Cc2ccccc2)cc1
Temperature: 140 °C
Yield: 32.7 %

Procedure:
A suspension of quindoline (1 g, 4.58 mmol) from Example 2, benzyl bromide (3 mL, 25.1 mmol) and dry chloroform (5 mL) was heated in a bomb at 140° C. for 48 hours. A solution of aqueous 5% Na2CO3 (100 mL) was added and the reaction mixture was extracted with chloroform (2×250 mL). The extract was evaporated to dryness. The residue was purified on a basic alumina column eluting with 1-2% MeOH in CHCl3, and the combined fractions were acidified with a solution of 1.0 M HCl in ether and concentrated to afford 0.65 g (32.7%) of the title compound as an orange solid, mp 244.4-244.7° C.; 1H NMR (DMSO-d6) δ 9.87 (s, 1H), 8.59 (d, J=8.0, 1H), 8.55 (d, J=9.2, 1H), 8.37 (d, J=8.4, 1H), 8.04-7.93 (m, 3H), 7.45 (t, J=7.2, 1H), 7.40-7.28 (m, 10 H), 6.87 (s, 2H), 6.06 (s, 2H); 13C NMR (DMSO-d6) δ 145.84, 138.05, 136.03, 135.36, 134.74, 134.46, 133.29, 133.14, 130.13, 129.19, 128.81, 128.18, 127.84, 127.65, 126.95, 126.49, 126.08, 125.63, 125.13, 122.13, 117.78, 113.11, 111.99,55.17, 46.28; MS (LSIMS, m/z) 399 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([O:6][CH3:7])([CH3:5])[CH3:4].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[I:25][C:26]1([CH2:29][C@H](O)CO)[CH2:28][CH2:27]1>ClCCl>[I:25][C:26]1([CH2:29][C@H:1]2[CH2:7][O:6][C:3]([CH3:5])([CH3:4])[O:2]2)[CH2:28][CH2:27]1
Reactant: OC[C@@H](O)CC1(I)CC1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC1(C)OC[C@H](CC2(I)CC2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,2-Dimethoxypropane and pyridinium p-toluenesulfonate are added to a solution of (S)-3-(1-iodocyclopropyl)propane-1,2-diol dissolved in dichloromethane and the mixture stirred at room temperature for 2 hours. Solvents are removed under reduced pressure and the crude product purified by flash chromatography using ethyl acetate/hexane (1:10) eluant.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][N:27]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]1[S:15][CH:16]([CH2:19][C:20](OCC)=[O:21])[CH2:17][N:18]=1)=[CH:10]2)[CH3:3].O1CCCC1.CO.[BH4-].[Li+]>O>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][N:27]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]1[S:15][CH:16]([CH2:19][CH2:20][OH:21])[CH2:17][N:18]=1)=[CH:10]2)[CH3:1]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cn4)cc(OC(C)C)c3[nH]2)S1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C3=NCC(CCO)S3)[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.7 %

Procedure:
To a mixture of ethyl {2-[7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (500 mg), tetrahydrofuran (20 mL) and methanol (5 mL) was added lithium borohydride (110 mg) at 0° C. The whole was stirred at room temperature for 2 h. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane=1:2 to 9:1, volume ratio) to give a pale yellow amorphous solid. The solid was crystallized from ethyl acetate-diethyl ether to give the title compound (210 mg, 46%) as pale yellow crystals. The crystals were recrystallized from ethyl acetate-diethyl ether to give pale yellow prisms. MS 476 (MH+). mp 172-173° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][C:11](=[O:41])[N:12]2[C:15]2[CH:20]=[C:19]([O:21][CH2:22][C:23]3[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[C:25]([F:31])[C:24]=3[F:32])[C:18]([O:33][CH2:34][C:35]([O:37]CC)=[O:36])=[CH:17][C:16]=2[Cl:40])=[C:8]([O:42][CH3:43])[N:7]=1)(=O)C.O.[OH-].[Li+].CO.Cl>O1CCCC1.O>[C:35]([CH2:34][O:33][C:18]1[C:19]([O:21][CH2:22][C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[C:25]([F:31])[C:24]=2[F:32])=[CH:20][C:15]([N:12]2[C:11](=[O:41])[NH:10][C:9]3[C:13]2=[N:14][C:6]([CH2:5][OH:4])=[N:7][C:8]=3[O:42][CH3:43])=[C:16]([Cl:40])[CH:17]=1)([OH:37])=[O:36]
Reactant: CCOC(=O)COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(COC(C)=O)nc32)cc1OCc1c(OC)ccc(F)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)c(F)c1COc1cc(-n2c(=O)[nH]c3c(OC)nc(CO)nc32)c(Cl)cc1OCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
A mixture of 2-acetyloxymethyl-9-[2-chloro-4-ethoxycarbonylmethoxy-5-(2,3-difluoro-6-methoxybenzyloxy)phenyl]-6-methoxy-7,9-dihydro-8H-purin-8-one (60 mg) and lithium hydroxide monohydrate (81 mg) in tetrahydrofuran (4 mL)-methanol (2 mL)-water (2 mL) was stirred at room temperature for 1 hour. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (42 mg).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26](Cl)(=[O:29])[C:27]#[CH:28]>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:26](=[O:29])[C:27]#[CH:28])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CC(=O)Cl
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C#CC(=O)OC1CCN(C)C(=O)N1c1nnc(C(C)(C)C)s1

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)- 3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Propynoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol- 2-yl)-3-methyl-6-propynoyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:15][CH:16]=2)[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:10]=1[C:29]([OH:31])=O)=[O:8].[NH2:36][CH2:37][CH2:38][OH:39].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:15][CH:16]=2)[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:10]=1[C:29]([NH:36][CH2:37][CH2:38][OH:39])=[O:31])=[O:8]
Reactant: CC(C)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(=O)O)n(Cc3ccccn3)c2c1
Reactant: NCCO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(=O)NCCO)n(Cc3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(3,4-difluorobenzylcarbamoyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylic acid (Compound 102, 73 mg, 0.12 mmol) in DMF (2 ml) was added 2-aminoethanol (11 μl, 0.17 mmol), BOP (64 mg, 0.14 mmol), and i-Pr2NEt 30 μl, 0.17 mmol). The reaction was stirred at room temperature for 16 h, diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as a yellow syrup.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.CN(C)C=O.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:19])=[O:11])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)Cc1ccc(F)cc1
Temperature: 40 °C
Yield: 89.5 %

Procedure:
A solution of 150 g (0.974 mol) of 4-fluorophenylacetic acid an 1 mL of N,N-dimethylformamide in 500 mL of toluene at 40° C. was treated with 20 mL of thionyl chloride and heated to 40° C. An additional 61.2 mL of thionyl chloride was added dropwise over 1.5 hours. After the addition, the solution was heated at 50° C. for 1 hour, the solvent was removed in vacuo and the residual oil was distilled at reduced pressure (1.5 mmHg) to afford 150.4 g (89.5%) of the title compound, bp=68-70° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]2[O:9][CH:13]=[CH:12][CH:11]=2)=[CH:3][CH:4]=1
Reactant: OB(O)c1ccco1
Reactant: Fc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Fc1ccc(-c2ccco2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
To a solution of 1-bromo-4-fluorobenzene (3.0 g, 17.14 mmol) in dioxane (100.0 mL) and water (3.0 mL) was added (furan-2-yl)boronic acid (5.76 g, 51.48 mmol), K3PO4 (10.76 g, 50.69 mmol) and Pd(PPh3)4 (980 mg, 0.85 mmol) with stirring for 2 h at 90° C. in an oil bath maintained under an inert atmosphere of nitrogen. The reaction mixture was concentrated under reduced pressure to give the residue, which was purified via silica gel chromatography (1% ethyl acetate in petroleum ether) to afford 2-(4-fluorophenyl)furan as colorless oil (2.5 g, 90%).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][N:6]=1)([F:4])[CH3:3].[O-:12][Mn](=O)(=O)=O.[K+].[OH2:18]>>[F:4][C:2]([C:5]1[CH:10]=[C:9]([CH:8]=[CH:7][N:6]=1)[C:11]([OH:12])=[O:18])([F:1])[CH3:3]
Reactant: O
Reactant: Cc1ccnc(C(C)(F)F)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: CC(F)(F)c1cc(C(=O)O)ccn1
Temperature: 80 °C
Yield: 12 %

Procedure:
To a solution of 2-(1,1-difluoroethyl)-4-methylpyridine (1 equiv.) in water (2.0 M) was added KMnO4 (3.0 equiv) and heated to 80° C. for 4 hrs. LCMS analysis indicated the formation of the desired product (MH+—188.0, Rt—0.52 min). The reaction was acidified to pH 3 with 1M HCl. The white precipitate was filtered and dried. Isolated 2-(1,1-difluoroethyl)isonicotinic acid in 12% yield. LCMS (m/z) (M+H)=188.0, Rt=0.52). 1H NMR (400 MHz, <cd3od>) δ ppm 2.01 (t, J=18.78 Hz, 3H) 8.00 (d, J=4.70 Hz, 1H) 8.16 (s, 1H) 8.80 (d, J=5.09 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[CH3:17][O:18][C:19]([C:21]1(Br)[CH2:24][CH2:23][CH2:22]1)=[O:20].O>CN(C=O)C.COC(C1(Br)CCC1)=O>[CH3:17][O:18][C:19]([C:21]1([O:10][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=2[CH:7]=[O:8])[CH2:24][CH2:23][CH2:22]1)=[O:20]
Reactant: COC(=O)C1(Br)CCC1
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(Oc2ccc(Cl)cc2C=O)CCC1
Temperature: 140 °C

Procedure:
To a mixture of 5-chloro-2-hydroxy-benzaldehyde (10 g, 64 mmol) and K2CO3 (13 g, 94 mmol) in DMF (100 mL) was added 1-bromo-cyclobutanecarboxylic acid methyl ester (15 g, 77 mmol, prepared according to Bulletin of the Chemical Society of Japan, 36, 145-7; 1963). The mixture was heated at 140° C. for 1.5 h. Then additional 1-Bromo-cyclobutanecarboxylic acid methyl ester (0.5 g, 2.6 mmol) was added and the mixture was heated at 140° C. for additional 10 min. The mixture was cooled to room temperature and poured into water (200 mL). The mixture was extracted with ethyl acetate twice. The organic layers were combined, washed with water (4×), dried over Na2SO4, concentrated to afford crude product 1-(4-chloro-2-formyl-phenoxy)-cyclobutanecarboxylic acid methyl ester as a dark oil (18 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO.C1COCC1.C(Cl)Cl>[F:18][C:17]([F:19])([F:20])[CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1
Reactant: FC(F)(F)/C=C/c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc(CCC(F)(F)F)cc1
Yield: 72.5 %

Procedure:
A solution of (E)-1-(benzyloxy)-4-(3,3,3-trifluoroprop-1-enyl)benzene (305 mg, 1.096 mmol) and palladium on carbon (305 mg, 10 wt. %, wet, Aldrich) in MeOH (15 mL) and THF (5 mL) was placed under hydrogen (1 Atm) for 4 hrs. The resulting mixture was diluted with CH2Cl2 and filtered through a pad of CELITE® 545 filter aid. The filtrate was evaporated under reduced pressure and then purified by flash chromatography on silica gel (0 to 30% EtOAc/hexanes) to yield the title compound (151 mg, 72%) as a colorless oil. MS (ESI) 189 (M−H).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][O:27][CH2:28][C:29](Cl)=[O:30]>>[CH3:26][O:27][CH2:28][C:29]([NH:25][C:23]1[CH:22]=[CH:21][C:20]2[N:16]([C:14]3[CH:13]=[N:12][CH:11]=[C:10]([NH:9][C@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:8])[N:15]=3)[CH:17]=[N:18][C:19]=2[CH:24]=1)=[O:30]
Reactant: C[C@H](Nc1cncc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Reactant: COCC(=O)Cl
Product: COCC(=O)Nc1ccc2c(c1)ncn2-c1cncc(N[C@@H](C)c2ccccc2)n1
Yield: 49.7 %

Procedure:
In a procedure analogous to example 32, reaction of 1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-5-amine (33 mg, 0.10 mmol) and methoxyacetyl chloride (12 mg, 0.11 mmol) furnished the product (20 mg, 50%) after chromatography.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(=O)=O.[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[N:14][CH:15]=1>CCOCC>[ClH:1].[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:3](=[O:4])[CH2:2][Cl:1])=[CH:15][N:14]=1
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(N)cn1
Agent: O=C=O
Solvent: CCOCC
Product: COc1ccc(NC(=O)CCl)cn1
Product: Cl
Yield: 90.3 %

Procedure:
Chloroacetyl chloride (8.0 ml, 0.10 mol) was added over a period of 10 minutes with cooling (dry ice bath) to a solution of 5-amino-2-methoxypyridine (11 ml, 0.10 mol) and ether (100 ml). After one hour the reaction wsa filtered and the solid collected and washed with ether to give 10.7 g of the title compound, m.p. 155°-160° C. The title product was identified by IR, NMR and MS analysis.