Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4][N:5]([CH2:8][CH:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([Cl:25])=[CH:19][C:18]=3[Cl:26])[CH2:13][CH2:12]2)[NH2:10])[C:6]=1[CH3:7].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4][N:5]([CH2:8][CH:9]([NH:10][S:39]([CH3:38])(=[O:41])=[O:40])[CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([Cl:25])=[CH:19][C:18]=3[Cl:26])[CH2:13][CH2:12]2)[C:6]=1[CH3:7]
Reactant: COc1cc(N2CCC(C(N)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)c(Cl)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(N2CCC(C(Cn3nc(C(F)(F)F)c(Cl)c3C)NS(C)(=O)=O)CC2)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A 25-mL round bottom flask was charged with 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-1-(1-(2,4-dichloro-5-methoxyphenyl)piperidin-4-yl)ethanamine (23 mg, 0.047 mmol), anhydrous DCM (2 mL), and triethylamine (0.016 mL, 0.118 mmol). The resultant solution was treated with methanesulfonyl chloride (5.50 μL, 0.071 mmol) and stirred at RT for 1 h. After this time, the mixture was concentrated on a rotary evaporator, and the resultant residue was partitioned between EtOAc and saturated sodium bicarbonate. The organic phase was washed with brine, dried (MgSO4) and concentrated to give the crude product. The crude product was purified by flash chromatography (4 g silica gel cartridge, EtOAc/hexanes) to afford Example 4 g (22 mg, 0.039 mmol, 82% yield). LC-MS: 563.0 (M+H); tR=4.18 min (method c). 1H-NMR (400 MHz, CDCl3) δ ppm 7.16 (1 H, s), 6.49 (1 H, s), 4.59 (1 H, d, J=9.23 Hz), 4.20-4.26 (1 H, m), 4.09-4.15 (1 H, m), 3.76-3.81 (3 H, m), 3.59 (1 H, d, J=6.15 Hz), 3.30-3.39 (2 H, m), 2.65 (3 H, s), 2.48-2.54 (2 H, m), 2.23-2.32 (3 H, m), 1.91 (1 H, s), 1.75-1.81 (1 H, m), 1.55-1.62 (2 H, m).
Reaction SMILES: [Li+].[OH-].[CH:3]1[C:15]2[CH:14]([CH2:16][O:17][C:18]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[NH:31][C:30](=[O:32])[C:29]5[N:33]([CH2:36][C:37]([O:39]CC)=[O:38])[CH:34]=[N:35][C:28]=5[CH:27]=4)[CH2:22][CH2:21]3)=[O:19])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.O1CCCC1>O1CCCC1.O>[CH:12]1[C:13]2[CH:14]([CH2:16][O:17][C:18]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[NH:31][C:30](=[O:32])[C:29]5[N:33]([CH2:36][C:37]([OH:39])=[O:38])[CH:34]=[N:35][C:28]=5[CH:27]=4)[CH2:22][CH2:21]3)=[O:19])[C:15]3[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)Cn1cnc2cc(N3CCN(C(=O)OCC4c5ccccc5-c5ccccc54)CC3)[nH]c(=O)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cn1cnc2cc(N3CCN(C(=O)OCC4c5ccccc5-c5ccccc54)CC3)[nH]c(=O)c21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Aqueous 1N LiOH (5 equiv.) was added to a solution of 4-(3-ethoxycarbonylmethyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-6-yl)-piperazine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester, 6 dissolved in tetrahydrofuran/water (7:1) at room temperature Then the mixture was stirred at room temperature for 10 min. The solution was acidified (pH=3˜4) with 1 N HCl. Tetrahydrofuran was then added. Purification by silica gel chromatography gave 7.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)(O)=[O:2].CN(C=O)C.C(Cl)(=O)C([Cl:20])=O>C(Cl)(Cl)Cl.C(Cl)Cl>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([Cl:20])=[O:2])=[CH:5][CH:6]=1)=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=Cc1ccc(C(=O)Cl)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 4-carboxybenzaldehyde (4.50 g, 30 mmol) in CHCl3 (6 mL) and DCM (5 mL), containing a catalytic amount of DMF, was added oxalyl chloride (7.7 mL, 90 mmol). The mixture was stirred at 50° C. for 3 hours. The reaction was concentrated in vacuo and the residue was dried.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.O.[OH-].[Li+].Cl>C1COCC1.O.CO.C(OCC)C>[CH2:18]([C:13]1[C:12]([CH2:11][NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1noc(C)c1CNc1ccc(C(=O)OC)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCCCc1noc(C)c1CNc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a suspension of 6-[(3-butyl-5-methyl-isoxazol-4-ylmethyl)-amino]-nicotinic acid methyl ester (1.09 g, 4.0 mmol) in THF (11 mL) was added a solution of lithium hydroxide monohydrate (302 mg, 7.0 mmol) in water (11 mL) and methanol (11 mL). The resulting mixture was stirred at room temperature overnight. The mixture was acidified to pH 4 with HCl (1 N) and the resulting mixture diluted with diethylether. The aqueous phase was removed and the organic phase triturated with hexane-diethylether to afford the title compound (910 mg, 87%) which was obtained as a white solid. MS: m/e=288.4 [M−H]−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][NH:8][CH2:9][CH2:10][S:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[N:15]#[N:16].Cl.[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[CH:26]=[C:25]([S:32]([NH:35][C@H:36]([C:44](Cl)=[O:45])[CH2:37][CH2:38][CH2:39][NH:40][C:41](=[NH:43])[NH2:42])(=[O:34])=[O:33])[CH:24]=[CH:23]2>C(Cl)(Cl)Cl>[N:15]#[N:16].[C:1]([O:5][C:6](=[O:14])[CH2:7][N:8]([C:44](=[O:45])[C@H:36]([CH2:37][CH2:38][CH2:39][NH:40][C:41](=[NH:42])[NH2:43])[NH:35][S:32]([C:25]1[CH:24]=[CH:23][C:22]2[C:27](=[CH:28][C:29]([O:30][CH3:31])=[C:20]([O:19][CH3:18])[CH:21]=2)[CH:26]=1)(=[O:34])=[O:33])[CH2:9][CH2:10][S:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCSCCNCC(=O)OC(C)(C)C
Reactant: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)cc2cc1OC
Agent: Cl
Agent: N#N
Solvent: ClC(Cl)Cl
Product: CCSCCN(CC(=O)OC(C)(C)C)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Reaction time: 8 h

Procedure:
To a stirred solution of 4.80 g of N-(2-ethylthioethyl)-glycine tert-butyl ester in 40 ml of chloroform was carefully added N2 -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl chloride hydrochloride obtained above. The reaction mixture was allowed to stand at room temperature overnight. The reaction mixture was washed twice with 20 ml of saturated sodium chloride solution and evaporated to dryness. The residue was triturated with a small amount of water to give a powder. This was collected by filtration and reprecipitated with ethanol-diethyl ether to give 5.00 g of N2 -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-(2-ethylthioethyl)glycine tert-butyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH2:17][C:18](=[O:20])[CH3:19])[C:14](=O)[O:13]C1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:22]>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:15]([CH2:16][CH2:17][C:18](=[O:20])[CH3:19])[C:14]([NH2:22])=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CC(=O)CC[C@H]1C(=O)OCN1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(N)=O
Reaction time: 5 h
Yield: 82 %

Procedure:
Ten grams of the (S)-3-(benzyloxycarbonyl)-4-(3-oxobutyl)-5-oxazolidinone from Example 4 is dissolved in 480 ml of distilled tetrahydrofuran, followed by 160 ml of ammonia at 0° C. The reaction mixture is stirred at 0° for 5 hours, then at ambient temperature overnight. After stripping under vacuum to dryness, the reaction mixture yields a white solid which is recrystallized from hot ethyl acetate to give 8.8 g of (S)-2-(benzyloxycarbonylamino)-5-oxo-hexanamide as a white solid (82% yield), mp 142°-144°;
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1>C(OCC)(=O)C>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][C:3]=1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1
Reactant: CCOC(=O)n1c(C(=O)c2cccc(Cl)c2)c(N)c2cc([N+](=O)[O-])ccc21
Solvent: CCOC(C)=O
Product: Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2ccc([N+](=O)[O-])cc12

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 3-amino-2-(3-chlorobenzoyl)-1-(ethoxycarbonyl)-5-nitroindole (step 1). tlc: Rf=0.3 (33% ethyl acetate in hexanes)
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]([CH:26]=[CH:27][CH:28]=1)[C:5]([N:7]1[CH2:12][CH2:11][CH2:10][C@@H:9]([CH3:13])[C@H:8]1[CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])=[O:6].C([Sn](CCCC)(CCCC)[C:35]1[N:40]=[CH:39][CH:38]=[CH:37][N:36]=1)CCC.[F-].[Cs+]>CN(C=O)C.[Cu]I.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:1][C:2]1[C:3]([C:35]2[N:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[C:4]([CH:26]=[CH:27][CH:28]=1)[C:5]([N:7]1[CH2:12][CH2:11][CH2:10][C@@H:9]([CH3:13])[C@H:8]1[CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])=[O:6]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: C[C@@H]1CCCN(C(=O)c2cccc(F)c2I)[C@@H]1CN1C(=O)c2ccccc2C1=O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-c2ncccn2)[C@@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 74.1 %

Procedure:
A mixture of 2-(((2S,3R)-1-(3-fluoro-2-iodobenzoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (0.493 g, 0.974 mmol), 2-(tributylstannyl)pyrimidine (0.4 g, 1.07 mmol), CsF (0.3 g, 1.948 mmol), CuI (0.0185 g, 0.098 mmol) and Pd(PPh3)4 (0.112 g, 0.098 mmol) in DMF (5 mL) was degassed and heated at 100° C. oil bath for 16 h. The solvent was removed in vacuo to obtain the crude which was purified by silica gel chromatography (0˜100% EtOAc/hexanes) to yield the title compound as a white solid (0.331 g, 75%). MS (ESI) 459 (M+H).
Reaction SMILES: FC(F)(F)C1C=C[C:6]([C:7](O)=[O:8])=[CH:5]C=1.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25](C(=O)CC)=[CH:24][CH:23]=2)=[N:19][CH:20]=1>>[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[C:27]=2[CH2:5][CH2:6][C:7]3=[O:8])=[N:19][CH:20]=1
Reactant: CCC(=O)c1ccc(Oc2ccc(N)cn2)cc1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Product: Nc1ccc(Oc2cccc3c2CCC3=O)nc1

Procedure:
According to the same manner as that described in Example 1 except for using an equimolar amount of 4-trifluoromethylbenzoic acid in place of 3,4-dichlorobenzoic acid and using an equimolar amount of 1-{4-[(5-amino-2-pyridinyl)oxy]phenyl)-1-propanone obtained in Reference Example 27 in place of 4-[(5-amino-2-pyridinyl)oxy]-1-indanone, the reaction was carried out to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][CH:8]2[CH2:13][CH:12]3[CH2:14][CH:9]2[CH2:10][CH2:11]3)=[CH:4][CH:3]=1.[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18]>CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH:8]2[CH2:13][CH:12]3[CH2:14][CH:9]2[CH2:10][CH2:11]3)[C:20]([NH:19][CH2:17][CH3:18])=[O:21])=[CH:15][CH:16]=1
Reactant: Clc1ccc(CNC2CC3CCC2C3)cc1
Reactant: CCN=C=O
Solvent: CCCCCC
Product: CCNC(=O)N(Cc1ccc(Cl)cc1)C1CC2CCC1C2
Yield: 85.5 %

Procedure:
24 g of N-4-chlorobenzyl-2-norbornylamine was dissolved in 400 ml of hexane, and with stirring and cooling, a solution of 8 g of ethyl isocyanate in 30 ml of hexane was added dropwise to the solution. After the addition, the temperature of the mixture was gradually raised, and it was stirred for about 3 hours at 40° C. After cooling, the precipitated crystals were suction-filtered, and recrystallized from a mixture of hexane and ethanol to give 26.7 g of the desired 1-(4-chlorobenzyl)-3-ethyl-1-(2-norbornyl)urea. mp. 132°-133° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:13]([OH:15])=[O:14])([O-:9])=[O:8].[CH2:20](I)[CH3:21].Cl>CN(C=O)C>[Cl:19][C:18]1[CH:17]=[CH:16][C:12]([C:13]([O:15][CH2:20][CH3:21])=[O:14])=[CH:11][C:10]=1[N+:7]([O-:9])=[O:8]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To potassium carbonate (103 g) was added DMF (1 L), and a solution of 3-nitro-4-chlorobenzoic acid (125 g) in DMF (500 ml) was added thereto under ice-cooling. Ethyl iodide (116 g) was added thereto and the resulting mixture was stirred at 60° C. for 3 hours. The reaction solution was added to a 1N aqueous hydrochloric acid solution and the crystals precipitated were collected by filtration, washed with a 1N aqueous hydrochloric acid solution and water and then dried under reduced pressure to obtain ethyl 4-chloro-3-nitrobenzoate quantitatively.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.[O:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[O:20]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=1[C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=2)=[CH:18][CH:17]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1ccccc1Oc1ccccc1
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Product: O=C(O)c1csc(COc2ccc(-c3ccccc3Oc3ccccc3)cc2)n1

Procedure:
2-(2′-Phenoxy-biphenyl-4-yloxymethyl)-thiazole-4-carboxylic acid was prepared using the procedure described above for the preparation of Example 25 from 2-(4-iodo-phenoxymethyl)-thiazole-4-carboxylic acid ethyl ester (of Intermediate 2) and (2-phenoxy)phenylboronic acid (available from Aldrich Chemical Company, Inc., Milwaukee, Wis.). Mass spectrum MH+=404.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:10][CH:9]=2)[O:6][C:5](=[O:19])[NH:4]1.[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22]>>[Si:24]([O:1][CH2:2][C@H:3]1[C@H:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:12][CH:13]=2)[O:6][C:5](=[O:19])[NH:4]1)([C:21]([CH3:23])([CH3:22])[CH3:20])([CH3:26])[CH3:25]
Reactant: COCCOc1ccc([C@@H]2OC(=O)N[C@H]2CO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: COCCOc1ccc([C@@H]2OC(=O)N[C@H]2CO[Si](C)(C)C(C)(C)C)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for intermediate 10 [(4S,5S)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-5-(4-methoxyphenyl)oxazolidin-2-one] from (4S,5S)-4-(hydroxymethyl)-5-(4-(2-methoxyethoxy)phenyl)oxazolidin-2-one and TBDMS-Cl to afford after purification by column chromatography (using EtOAc in heptane from 5% to 50%) intermediate 11 as a light yellow oil. TLC (heptane/EtOAc 1:1) Rf=0.26; tR=1.28 min (UPLC 1); LC-MS: [M+H] 382.2; Rt 1.17 min; (LCMS method 2); 1H NMR (400 MHz, CDCl3): 7.30 (d, 2H), 6.97 (d, 2H), 5.44 (br s, 1H), 5.23 (d, 1H), 4.18 (dd, 2H), 3.70-3.85 (m, 5H), 3.48 (s, 3H), 0.91 (s, 9H), 0.11 (s,
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]3[CH2:28][CH2:27][CH:26]([CH:29]4[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][CH3:37])[CH2:31][CH2:30]4)[O:25][C:24]3=[O:38])=[C:19]([F:39])[C:18]=2[F:40])=[C:13]([F:41])[C:12]=1[F:42])[CH3:9].[H-].C([Al+]CC(C)C)C(C)C>C(O)=O>[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]3[CH2:28][CH2:27][CH:26]([CH:29]4[CH2:30][CH2:31][CH:32]([CH2:35][CH2:36][CH3:37])[CH2:33][CH2:34]4)[O:25][CH:24]3[OH:38])=[C:19]([F:39])[C:18]=2[F:40])=[C:13]([F:41])[C:12]=1[F:42])[CH3:9]
Reactant: CCCC1CCC(C2CCC(c3ccc(-c4ccc(OCC)c(F)c4F)c(F)c3F)C(=O)O2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O=CO
Product: CCCC1CCC(C2CCC(c3ccc(-c4ccc(OCC)c(F)c4F)c(F)c3F)C(O)O2)CC1
Reaction time: 3 h
Yield: 97 %

Procedure:
Toluene (20 ml) was added to 3-(4′-ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-yl)-6-(4-propylcyclohexyl)tetrahydropyran-2-one (11) (2.35 g) prepared in the ninth step. A toluene solution of diisobutylaluminum hydride (0.99 M; 9.6 ml) was added dropwise at −50° C. or lower, and the stirring was continued for 3 hours. The reaction mixture was poured into a 10% aqueous solution of formic acid (50 ml) to give two layers. The water layer was extracted with toluene (20 ml) twice and the combined organic layer was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to leave 3-(4′-ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-yl)-6-(4-propylcyclohexyl)tetrahydropyran-2-ol (12) (2.29 g) in 99% yield.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Clc1nc(NCc2ccc3c(c2)OCO3)c2c3c(sc2n1)CCCC3
Reactant: c1nc[nH]n1
Product: c1ncn(-c2nc(NCc3ccc4c(c3)OCO4)c3c4c(sc3n2)CCCC4)n1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-methylenedioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-methylenedioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1>>[F:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:3]=[C:4]3[CH2:10][C:9](=[O:11])[NH:8][C:5]3=[N:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=C1Cc2cc(Br)cnc2N1
Reactant: OB(O)c1cccc(F)c1
Product: O=C1Cc2cc(-c3cccc(F)c3)cnc2N1
Yield: 32 %

Procedure:
The title compound was prepared in 32% yield according to the procedure described in Example 2, starting from 5-bromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (prepared according to the procedure described in WO2003082868, Page 33) and 3-fluoro-phenyl boronic acid. 1H NMR is the same as the one reported in WO2003082868, page 34.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[C:10]([F:19])=[C:11]([C:15]([F:18])=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.[CH2:28]([Sn](CCCC)(CCCC)CCCC)[CH:29]=[CH2:30].O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:30]([C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[C:10]([F:19])=[C:11]([C:15]([F:18])=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH:29]=[CH2:28]
Reactant: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2Br)cc1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: C=CCc1sc(COc2ccc(F)c(C(N)=O)c2F)nc1-c1ccc(OC)cc1
Temperature: 120 °C
Yield: 144.1 %

Procedure:
To a solution of 3-[5-bromo-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.1 g, 0.0002 mol) in 5 ml of anhydrous DMF was added Allyl tributyltin (0.072 g, 0.0002 mol) and degassed the reaction mixture for the 10 minutes. Then added tetraphenylphosphine Palladium (0) (0.025 g, 0.00002 mol). The reaction mixture was heated at 120° C. for 12 h under the nitrogen atmosphere. Then reaction mixture was cooled to rt. 100 ml of water was added into it and extracted the compound with ethyl acetate, The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (230-400μ) using methanol/DCM (2:98) as the eluent to provide the title compound as brown solid (0.120 g, 60%). 1H NMR (DMSO-d6, 400 MHz): δ 3.79 (s, 3H), 5.11-5.14 (m, 1H), 5.16 (s, 1H), 5.48 (s, 2H), 5.57 (s, 1H), 5.99-6.06 (m, 1H), 7.03 (d, 2H, J=8.4 Hz (o-coupling), 7.11 (dt, 1H, J=9.2 Hz (o-coupling), 7.36-7.42 (m, 1H), 7.56 (d, 2H, J=8.8 Hz (o-coupling), 7.88 (broad s, 1H), 8.16 (broad s, 1H). MS ES+ (417.06), HPLC (method 5) Rt=16.96 min.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH:10](O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)/[C:7](=[N:18]/[C:19](=[O:29])[C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2[O:27][CH3:28])/[S:6]1)([CH3:4])([CH3:3])[CH3:2].C([SiH](CC)CC)C.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[CH2:10]([C:8]1=[CH:9][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6]/[C:7]/1=[N:18]\[C:19](=[O:29])[C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[O:27][CH3:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1C(O)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1Cc1ccccc1
Temperature: 60 °C
Yield: 25 %

Procedure:
The product from Example 31 (20 mg, 0.05 mmol) in TFA (0.5 mL) was treated with triethylsilane (54 mg, 0.5 mmol). The mixture was heated at 60° C. for 12 hrs, solvent evaporated and the residue purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous trifluoroacetic acid over 8 minutes (10 minutes run time) at a flow rate of 40 mL/minute to afford 4.8 mg (25%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.61 (s, 9H) 3.93 (s, 3H) 4.18 (s, 2H) 6.92 (d, J=8.90 Hz, 1H) 7.20-7.28 (m, 1H) 7.29-7.39 (m, 5H) 7.78 (s, 1H) 8.14 (d, J=2.76 Hz, 1H); MS (DCI/NH4+) m/z 415 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[C:13](=[O:17])[C:14]#[C:15][CH3:16].Cl.[O:19]1CCCC1>>[OH:19][CH2:16][C:15]#[C:14][C:13]([C:4]1[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1])=[O:17]
Reactant: CC#CC(=O)c1ccc(OC)c(OC)c1OC
Reactant: C1CCOC1
Agent: Cl
Product: COc1ccc(C(=O)C#CCO)c(OC)c1OC
Reaction time: 0.5 h

Procedure:
A solution of 8.3 g (27.6 mmol) of 4-1-ethoxytehoxy)- 1-(2,3.4-trimethoxyphenyl)-2 -butyn-1-one in 95 ml of tetrahydrofuran was treated at room temperature with 27.5 ml of 2N hydrochloric acid, whereupon the mixture was stirred for 30 minutes. The reaction mixture was then extracted twice with ethyl acetate. The combined organic phases were washed in succession with saturated sodium carbonate solution and with water, dried over magnesium sulphate and concentrated. Crystallization of the residue from ethyl acetate/hexane yielded 4-hydroxy-1-(2,3,4 -trimethoxyphenyl)-2-butyn-1-one of melting point 82°-83°.
Reaction SMILES: [F:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[CH2:10]=O.Cl>[Pd]>[F:1][C@H:2]1[CH2:6][N:5]([CH3:10])[C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1
Reactant: C=O
Reactant: O=C(O)[C@@H]1C[C@@H](F)CN1
Agent: [Pd]
Agent: Cl
Product: CN1C[C@H](F)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 54.2 %

Procedure:
A solution of (2S,4R)-4-fluoropyrrolidine-2-carboxylic acid (1.00 g, 7.52 mmol), formaldehyde (37% wt in water, 1.00 mL, 30.8 mmol), 12N HCl (0.5 mL) in IMS (38 mL) was purged with argon. To the solution was added Pd/C (100 mg), then the flask was evacuated and filled with H2 the resulting suspension was stirred at RT for 3 d. The reaction mixture was passed through a pad of Celite and the mixture was concentrated in vacuo to give the title compound as a pale yellow gum (600 mg, 54%). 1H NMR (300 MHz, d6-DMSO): 2.29-2.37 (1H, m), 2.63-2.67 (1H, m), 2.97 (3H, s), 3.44-3.53 (1H, m), 4.00-4.04 (1H, m), 4.58 (1H, dd, J 11.6, 7.11), 5.41-5.45 (1H, m).