Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[CH:10])=[CH:5][CH:4]=1.[CH:11]1[CH2:15][CH2:14][CH2:13][CH:12]=1.[C:16](OCC)(=[O:18])C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:16](=[O:18])[CH:11]3[CH:15]([CH:10]=2)[CH2:14][CH2:13][CH2:12]3)=[CH:5][CH:4]=1
Reactant: CCOC(C)=O
Reactant: C#Cc1ccc(OC)cc1
Reactant: C1=CCCC1
Solvent: Cc1ccccc1
Product: COc1ccc(C2=CC3CCCC3C2=O)cc1
Yield: 73 %

Procedure:
The method of Example 1 was used except that 4-methoxyphenylethyne (740 mg) was dissolved in ethyl acetate and added to Co2(CO)8 in toluene followed by cyclopentene and Me3NO.2H2O. After 48 h reaction time the title product (930 mg, 73%) was isolated as a pale yellow oil.
Reaction SMILES: Br[CH2:2][C:3](=[O:5])[CH3:4].[NH2:6][C@@H:7]([CH3:10])[CH2:8][OH:9].O>C(Cl)Cl>[OH:9][CH2:8][C@@H:7]([NH:6][CH2:2][C:3](=[O:5])[CH3:4])[CH3:10]
Reactant: C[C@H](N)CO
Reactant: CC(=O)CBr
Solvent: O
Solvent: ClCCl
Product: CC(=O)CN[C@@H](C)CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 145.7 %

Procedure:
A solution of 1-bromopropan-2-one (7.8 mL, 102 mmol) in DCM (15 mL) was added dropwise to a solution of (S)-2-aminopropan-1-ol (18.2 g, 0.243 mol) and anhydrous DCM (150 mL) at 0° C. The reaction stirred at 0° C. for 2 h. Water (150 mL) was added, and the organic phase was separated. The aqueous was extracted with DCM (3×40 mL), and the combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to give the crude product 19.5 g, which was used directly in the following step. LCMS: 132 (M+H)+.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:18]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:17][C:7]2[N:8]=[C:9]([S:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[NH:10][C:6]=2[CH:5]=1.[OH2:25].[O:26]1[CH2:30]C[CH2:28][CH2:27]1>C(N(CC)CC)C.BrCC(OC)=O>[Cl:3][C:4]1[C:18]([N:19]2[CH2:20][CH2:21][N:22]([CH2:28][C:27]([O:26][CH3:30])=[O:25])[CH2:23][CH2:24]2)=[CH:17][C:7]2[N:8]=[C:9]([S:11][CH:12]([CH2:13][CH3:14])[CH2:15][CH3:16])[NH:10][C:6]=2[CH:5]=1
Reactant: O
Reactant: C1CCOC1
Reactant: CCC(CC)Sc1nc2cc(N3CCNCC3)c(Cl)cc2[nH]1
Agent: COC(=O)CBr
Agent: Cl
Solvent: CCN(CC)CC
Product: CCC(CC)Sc1nc2cc(N3CCN(CC(=O)OC)CC3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 82 mg of the compound of Example 1 in 2 ml of tetrahydrofuran, 0.14 ml of triethylamine and 0.017 ml of methyl bromoacetate were added by the order stated, and stirred for 3 hours at room temperature. Water was added to the solution which then was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried on anhydrous sodium sulfate. After distilling the solvent off under reduced pressure, the residue was separated and purified on silica gel column chromatography (chloroform/methanol=20/1) to provide 80 mg of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O.C(O[C:40]1(O[Si](C)(C)C)[CH2:42][CH2:41]1)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][N:30]([CH:40]5[CH2:42][CH2:41]5)[CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ncnn2c(C3CCN(C4CC4)CC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 60 °C
Reaction time: 17 h
Yield: 50.7 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (85 mg, 0.20 mmol) in MeOH (2.25 mL) containing 3 Å molecular sieves was added AcOH (114 μL, 2.00 mmol), [(1-ethoxycyclopropyl)oxy]trimethylsilane (241 μL, 1.20 mmol) and sodium cyanoborohydride (57 mg, 0.90 mmol). The reaction was stirred at 60° C. for 17 h. The mixture was quenched with the addition of saturated, aqueous NaHCO3 (10 mL) and was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 47 mg (51%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 825 (s, 1 H), 7.60 (s, 1 H), 7.50 (d, 1 H), 7.28 (s, 1 H), 6.98-7.08 (m, 5 H), 6.84 (dd, 1 H), 6.27 (s, 1 H), 5.35 (s, 2 H), 3.04 (s, 2 H), 2.72 (s, 2 H), 1.99 (s, 2 H), 1.66 (s, 2 H), 1.27-1.38 (m, 2 H), 0.13 (s, 1 H), 0.11 (d, 1 H), −0.03-0.03 (m, 2 H); ES-MS m/z 464.32 [M+H]+, HPLC RT (min) 1.24.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11](C3N(CC4C=CC(CCC(O)=O)=CC=4)C4C=C(F)C(F)=CC=4N=3)=[CH:10][CH:9]=CN=2)CC1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:46](CC3CCCCC3)[C:45]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:44]=3[N:43]=2)=[C:38]([O:60][CH2:61]C2C=CC=CC=2Cl)[CH:37]=1.BrCC1CCOCC1>>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:46]([CH2:9][CH:10]3[CH2:1][CH2:4][O:5][CH2:6][CH2:11]3)[C:45]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:44]=3[N:43]=2)=[C:38]([O:60][CH3:61])[CH:37]=1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3OCc3ccccc3Cl)n(CC3CCCCC3)c2cc1F
Reactant: O=C(O)CCc1ccc(Cn2c(-c3cccnc3OCC3CC3)nc3cc(F)c(F)cc32)cc1
Agent: BrCC1CCOCC1
Product: COc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCOCC1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 19, intermediate c) and 4-bromomethyl-tetrahydro-pyran (CAS Reg. No. 125552-89-8). Light brown solid (29%). MS (Turbo Spray): m/z=393.3 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5](=[CH:8][CH:9]=1)[CH:6]=[O:7].Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][C:4]=1[O:10][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:7]
Reactant: Cc1ccc(C=O)c(O)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1cc(C)ccc1C=O
Yield: 91.8 %

Procedure:
By the method of Example 1, Step F, 8.27 g (0.060 mole) of 4-methylsalicylaldehyde and 11.15 g (0.073 mole) of methyl bromoacetate were reacted in the presence of 10.1 g (0.073 mole) of anhydrous potassium carbonate in 150 mL of acetone, yielding 11.47 g of methyl (2-formyl-5-methylphenoxy)acetate as a white solid, m. p. 63°-64° C. The NMR was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.Cl[C:18]1[N:19]([C:23]2[CH2:27][CH2:26][CH2:25][N:24]=2)[CH2:20][CH2:21][CH:22]=1>>[ClH:1].[Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:18]3[N:19]([C:23]4[CH2:27][CH2:26][CH2:25][N:24]=4)[CH2:20][CH2:21][CH:22]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc2c1Oc1ccccc1N2
Reactant: ClC1=CCCN1C1=NCCC1
Agent: Cl
Product: Clc1cccc2c1Oc1ccccc1N2C1=CCCN1C1=NCCC1

Procedure:
Reaction of 4-chlorophenoxazine with 2-chloro-(1-pyrrolin-2-yl)pyrroline hydrochloride according to the procedure of Example 7 affords 4-CHLORO-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOXAZINE HYDROCHLORIDE, m.p. 278°-282° C. (dec.), from ethanol-ether.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16][CH2:17]O>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([O:7][CH2:16][CH3:17])=[O:6]
Reactant: CCO
Reactant: O=C(O)c1ccc(F)c(Br)c1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(F)c(Br)c1
Yield: 90.3 %

Procedure:
To a solution of compound 3-bromo-4-fluoro-benzoic acid (430 g, 1.97 mol, 1 eq) in EtOH (2.3 L) was added dropwise thionyl chloride (287 mL, 3.94 mol, 2 eq) at 10° C. Then the mixture was heated to reflux overnight. The mixture was concentrated in vacuum to give a residue. The residue was dissolved in ethyl acetate (800 mL), washed with aqueous sodium hydrogen carbonate, brine (300 mL) and water (200 mL), then concentrated in vacuo to give title compound as a white solid (440 g, 1.78 mol, 90.3%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].Br[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20]>CN(C)C=O>[CH3:1][C:2]1[N:3]([CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[C:4]2[C:9]([C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CCOC(=O)c1c(C)[nH]c2ccccc12
Reactant: CC(Br)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)n(C(C)c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
A mixture of ethyl 2-methyl-1H-indole-3-carboxylate (400 mg, 1.97 mmol) and sodium hydride (47 mg, 2.0 mmol) in N,N-dimethylformamide (5.0 mL) was stirred at room temperature for 0.5 hours, and then (1-bromoethyl)benzene (361 mg, 2.0 mmol) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. Organic layers were combined and concentrated to give a residue. The residue was purified by chromatography (petroleum ether/ethyl acetate 5:1) to give ethyl 2-methyl-1-(1-phenylethyl)-1H-indole-3-carboxylate (340 mg, 56%). LRMS (M+H+) m/z: calcd 307.16. found 307.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([N:14]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:21]([OH:23])=O)=[O:13])([CH3:10])([CH3:9])[CH3:8].CCN(C(C)C)C(C)C.[C:43]1([NH:49][CH2:50][CH2:51][CH2:52][N:53]2[N:57]=[N:56][CH:55]=[N:54]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>ClCCl.CN(C1C=CN=CC=1)C.CN(C=O)C>[C:7]([O:11][C:12](=[O:13])[N:14]([CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([C:21](=[O:23])[N:49]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:50][CH2:51][CH2:52][N:53]2[N:57]=[N:56][CH:55]=[N:54]2)[CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)([CH3:9])([CH3:8])[CH3:10]
Reactant: c1ccc(NCCCn2ncnn2)cc1
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCn2ncnn2)c2ccccc2)c1)c1ccncc1
Reaction time: 0.17 h
Yield: 25.6 %

Procedure:
2M Oxalyl chloride solution in dichloromethane (0.11 ml), and dry DMF (0.005 ml) were added to a stirred suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.067 g) in dry dichloromethane (1 ml) under nitrogen. After 10 min, DIPEA (0.100 ml) was added followed after a further 40 min by phenyl-(3-tetrazol-2-yl-propyl)-amine (0.033 g) and DMAP (0.004 g). After 7 days the solvent was evaporated and the residue was purified by flash chromatography, eluting with dichloromethane:methanol (98:2 v/v) to give the title compound as a pale yellow oil (0.024 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH2:9])[N:6]=[C:5]2[NH:10][N:11]=[CH:12][C:4]=12.C([O-])(=O)C.[Na+].[I:18]Cl.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O>[I:18][C:12]1[C:4]2[C:5](=[N:6][C:7]([NH2:9])=[N:8][C:3]=2[O:2][CH3:1])[NH:10][N:11]=1
Reactant: ClI
Reactant: COc1nc(N)nc2[nH]ncc12
Agent: CC(=O)[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: COc1nc(N)nc2[nH]nc(I)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.8 %

Procedure:
A mixture of compound 4 (105 g, 0.636 mol), sodium acetate (263 g) and iodine monochloride (140 g) was mechanically stirred in 1.3 L of water at a temperature between 92-98° C. for 5 h. The mixture was cooled to room temperature and a solution of sodium metabisulfite (139 g in 500 ml of water) was added. The mixture was stirred for 10 minutes and then filtered. The solid was rinsed with water and dried. The resulting dried solid was dissolved in 840 ml of hot DMF and precipitate by addition of 800 ml of water. The mixture was cooled in an ice-bath and the solid was filtered and dried to provide 144 g (78% yield) of 3-iodo-4-methoxy-6-aminopyrazolo[3,4-d]pyrimidine (5).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:3]=1[C:4]([P:6]([C:15](=[O:24])[C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23])[C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[CH3:14])=[O:5].[OH:30]O.[PH3]=O>C(#N)C>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[C:15]([P:6](=[O:30])([C:4](=[O:5])[C:3]1[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:2]=1[Cl:1])[C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[CH3:14])=[O:24]
Reactant: OO
Reactant: Cc1ccc(C)c(P(C(=O)c2c(Cl)cccc2Cl)C(=O)c2c(Cl)cccc2Cl)c1
Agent: O=[PH3]
Solvent: CC#N
Product: Cc1ccc(C)c(P(=O)(C(=O)c2c(Cl)cccc2Cl)C(=O)c2c(Cl)cccc2Cl)c1
Temperature: 60 °C
Yield: 74 %

Procedure:
The crude bis-(2,6-dichlorobenzoyl)-2,5-dimethylphenylphosphine (50 grams) is dissolved in 1 liter acetonitrile, mixed with 150 ml of 30% hydrogen peroxide, and heated for one hour at 60° C. The formation of the phosphine oxide is accompanied by deepening of the color, and it precipitates in crystalline form, after the addition of water and cooling. Recrystallization from acetonitrile/water yields 37 grams of the captioned compound (74% of theoretical yield in 2 steps)
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=O)=[CH:12][CH:11]=1.CSC1C=CC(C=O)=CC=1.FC1C=CC(CCl)=CC=1>C1(C)C=CC=CC=1.CC(O)=O>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[C:6]3[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=3)[NH:7][C:17]=2[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)Cc2ccc(F)cc2)cc1
Reactant: NNc1ccccc1
Agent: CSc1ccc(C=O)cc1
Agent: Fc1ccc(CCl)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-c2[nH]c3ccccc3c2-c2ccc(F)cc2)cc1
Reaction time: 1 h

Procedure:
To phenylhydrazine (50 uL) in toluene-HOAc (2:1, 2 mL) was added 2-(4-fluorophenyl)-1-(4-(methylsulfonyl)phenyl)ethanone (105 mg) (prepared from 4-(methylthio)benzaldehyde and 4-fluorobenzyl chloride by the same method as described in Step 1 of Example 4). After 1 hr at 85° C., the reaction mixture was extracted with EtOAc and HCl. After drying over NaSO4 and evaporation in vacuo the title compound was purified by flash chromatography (67 mg).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH2:2][CH3:3].Br[CH:13]([CH3:25])[C:14]([C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([OH:23])=[C:18]([CH3:24])[CH:17]=1)=O>>[OH:23][C:19]1[C:18]([CH3:24])=[CH:17][C:16]([C:14]2[NH:9][C:8]3[C:10]([C:13]=2[CH3:25])=[CH:11][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[CH:6][CH:7]=3)=[CH:21][C:20]=1[CH3:22]
Reactant: Cc1cc(C(=O)C(C)Br)cc(C)c1O
Reactant: CCCOc1ccc(N)cc1
Product: CCCOc1ccc2[nH]c(-c3cc(C)c(O)c(C)c3)c(C)c2c1
Temperature: 0 °C

Procedure:
3 g of 4-n-propoxyaniline and 2.56 g of 4-(2-bromo-1-oxopropyl)-2,6-dimethylphenol were heated at 150° C. for 40 minutes in a stream of nitrogen. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was purified by silica gel column chromatography, and recrystallized from ether-hexane to give 2-(4-hydroxy-3,5-dimethylphenyl)-3-methyl-5-n-propoxyindole.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[NH:26]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[C@H:27]([C:35]([OH:37])=[O:36])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:34])[NH2:33].[NH2:48][C@H:49]([C:57]([NH:59][C@H:60]([C:70]([NH:72][C@H:73]([C:77]([NH:79][C@H:80]([C:84]([O:86][CH3:87])=[O:85])[CH:81]([CH3:83])[CH3:82])=[O:78])[CH:74]([CH3:76])[CH3:75])=[O:71])[CH2:61][CH2:62][C:63](=[O:69])[O:64]C(C)(C)C)=[O:58])[CH2:50][CH2:51][CH2:52][NH:53][C:54](=[NH:56])[NH2:55].Cl.Cl>CN(C)C=O>[NH:26]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[C@H:27]([C:35]([NH:48][C@H:49]([C:57]([NH:59][C@H:60]([C:70]([NH:72][C@H:73]([C:77]([NH:79][C@H:80]([C:84]([O:86][CH3:87])=[O:85])[CH:81]([CH3:82])[CH3:83])=[O:78])[CH:74]([CH3:75])[CH3:76])=[O:71])[CH2:61][CH2:62][C:63](=[O:64])[OH:69])=[O:58])[CH2:50][CH2:51][CH2:52][NH:53][C:54](=[NH:55])[NH2:56])=[O:37])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:34])[NH2:33].[CH3:27][C:35]([OH:37])=[O:36]
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@@H](N)CCCNC(=N)N)C(C)C)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)O
Product: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1)C(C)C)C(C)C
Reaction time: 8 h

Procedure:
0.68 g of HOBt and 1.1 g of DCC are added successively to 1.54 g of Z-Arg-OH and 3.44 g of the compound prepared in accordance with (B), in 40 ml of dimethylformamide. After stirring overnight, the mixture is filtered, the filtrate is concentrated in vacuo and the residue is digested with ethyl acetate. The tert.-butyl group is split off analogously to Example 1 with trifluoroacetic acid and the compound is converted into its acetate and purified by chromatography on Sephadex® LH 20. Yield 2.9 g, aminoacid analysis: Glu 1.00, Val 1.89 and Arg 2.01.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9](O)[CH3:10])=[N:7][CH:8]=1)[CH3:2].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].[OH2:24]>C(Cl)Cl>[CH3:19][S:20]([O:22][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=1)(=[O:24])=[O:21]
Reactant: CCc1ccc(C(C)O)nc1
Reactant: CS(=O)(=O)Cl
Reactant: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc(CCOS(C)(=O)=O)nc1
Yield: 100 %

Procedure:
In 800 ml of methylene chloride was dissolved 80 g of (5-ethyl-2-pyridyl)ethanol, to which was added 55 g of triethylamine. To this mixture was added dropwise gradually 73.2 g of methanesulfonyl chloride while stirring under cooling, and the mixture was stirred for 3 hours at room temperature. To the reaction mixture was added 400 ml of water. The aqueous layer was separated and subjected to re-extraction, which was combined with the extracted organic layer. The resultant organic layer was washed with 400 ml of a saturated aqueous solution of sodium hydrogencarbonate, then with a saturated aqueous saline solution, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 121 g (100 %) of (5-ethyl-2-pyridyl)ethyl methanesulfonate as a pale yellow oily product.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][N:22]=3)[C:16](OC)=[O:17])[CH:9]=[N:8]2)=[CH:4][CH:3]=1.[C-:25]#[N:26].[Na+]>C(N)C1C=CC=CC=1>[CH2:25]([NH:26][C:16](=[O:17])[C:15]1[CH:20]=[CH:21][N:22]=[C:13]([N:10]2[C:11](=[O:12])[N:7]([CH2:6][C:5]3[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=3)[N:8]=[CH:9]2)[CH:14]=1)[C:2]1[CH:24]=[CH:23][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: COC(=O)c1ccnc(-n2cnn(Cc3ccc(F)cc3)c2=O)c1
Agent: [Na+]
Solvent: NCc1ccccc1
Product: O=C(NCc1ccccc1)c1ccnc(-n2cnn(Cc3ccc(F)cc3)c2=O)c1
Yield: 6 %

Procedure:
A solution of methyl 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)isonicotinate and sodium cyanide (0.80 g, 1.43 mmol) in benzylamine (50 mL) was stirred at 100° C. for 23 hours and at 110° C. for 3 hours and concentrated in vacuo. The residue was dissolved in ethyl acetate (30 mL), washed with water (20 mL) and brine (20 mL). The organic solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography eluting with ethyl acetate in dichloromethane (0% to 50%) to give N-benzyl-2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)isonicotinamide as a colorless solid (0.29 g, 6%): mp 173-175° C.; 1H NMR (300 MHz, CDCl3) δ 8.56-8.55 (m, 1H), 8.49 (dd, J=5.1, 0.6 Hz, 1H), 8.41 (s, 1H), 7.73-7.70 (m, 1H), 7.32-7.22 (m, 7H), 7.00-6.95 (m, 3H), 4.90 (s, 2H), 4.60 (d, J=5.7 Hz, 2H); MS (ES+) m/z 403.9.
Reaction SMILES: [F:1][C:2]1[C:7](OS(C(F)(F)F)(=O)=O)=[CH:6][CH:5]=[C:4]([F:16])[C:3]=1[C:17]1[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][CH:18]=1.[CH3:27][Zn]C>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:1][C:2]1[C:7]([CH3:27])=[CH:6][CH:5]=[C:4]([F:16])[C:3]=1[C:17]1[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][CH:18]=1
Reactant: C[Zn]C
Reactant: COC(=O)c1cccc(-c2c(F)ccc(OS(=O)(=O)C(F)(F)F)c2F)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2c(F)ccc(C)c2F)n1
Temperature: 80 °C

Procedure:
To a solution of methyl 6-(2,6-difluoro-3-(trifluoromethylsulfonyloxy)-phenyl)picolinate (1.0 equiv.) in toluene was added Pd(dppf)Cl2-DCM (0.1 equiv.) followed by dimethyl zinc (3.0 equiv.). The solution turned from orange to bright yellow. The reaction was heated to 80° C. for 2 hours at which time, LC/MS analysis indicated complete conversion to product. The reaction was cooled to room temperature, diluted with ethyl acetate and washed with brine. The organic layer was dried with magnesium sulfate, filtered, and concentrated in vacuo to provide methyl 6-(2,6-difluoro-3-methylphenyl)picolinate as a brown oil in quantitative yield. LC/MS=264.0 (M+H), Rt=0.90 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.C([N:24](CC)CC)C.N>C(Cl)(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([NH2:24])=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)C1(c2ccc(Br)cc2)CC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: O
Solvent: ClC(Cl)Cl
Product: NC(=O)C1(c2ccc(Br)cc2)CC1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
To a −15° C. solution of 1-(4-bromophenyl)cyclopropanecarboxylic acid from Step 2 (1.5 g) in chloroform (60 mL) were slowly added isobutyl chloroformate (900 μL) and triethylamine (1.1 mL). The reaction mixture was stirred at −15° C. for 2 hours. Then it was saturated with ammonia gas and stirred at −15° C. for 10 minutes. The reaction mixture was allowed to stand at room temperature for 1 hour then poured into water (60 mL) and partitioned. The aqueous layer was extracted with dichloromethane (2×160 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue was purified by swish using diethyl ether and hexanes to yield the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.[CH2:21]1[CH:23]([CH:24](O)C#N)[CH2:22]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:23]1([CH2:24][N:1]2[CH2:2][CH2:3][CH:4]([CH2:7][CH:8]3[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]3)[CH2:5][CH2:6]2)[CH2:21][CH2:22]1
Reactant: N#CC(O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CC2CCNCC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CC2CCN(CC3CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl 4-(4-piperidinylmethyl)-1-piperidinecarboxylate (may be prepared as described in Description 2) (2.0 g), cyclopropyl carboxaldehyde (1.6 ml) and triethylamine (1.99 ml) were stirred in dichloromethane (70 ml) at room temperature. After 10 min sodium triacetoxyborohydride (3.1 g) was added and the reaction was stirred at room temperature overnight. The reaction mixture was washed with saturated potassium carbonate solution (2×50 ml), saturated sodium hydrogen carbonate solution (2×50 ml) and saturated brine (50 ml). The organic phase was dried (MgSO4) and evaporated to give the title compound (D9) (2.0 g).