Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11].[CH2:14]([S:17][C:18]([CH3:22])([CH3:21])[CH:19]=O)[CH:15]=[CH2:16].C([BH3-])#N.[Na+].Cl>CO.C(O)(=O)C>[CH2:14]([S:17][C:18]([CH3:22])([CH3:21])[CH2:19][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:11])[CH3:12])[CH:15]=[CH2:16]
Reactant: C=CCSC(C)(C)C=O
Reactant: CC(C)(S)CNc1ccccc1N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C=CCSC(C)(C)CNc1ccccc1NCC(C)(C)S
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
2-Amino-1-(2-mercapto-2-methylpropylamino)benzene (3.5 g, 1.78×10-2 mol) and 2-(allylthio)-2-methylpropanal (3.85 g, 2.67×10-2 mol, 150 M%) were dissolved in 200 ml methanol. Glacial acetic acid (2.05 ml, 3.56×10-2, 200 M%) and sodium cyanoborohydride (3.36 g, 5.35×10-2 mol, 300 M%) were then added. The reaction was stirred at room temperature for 18 hr, then 100 ml 0.5 M HCl was added and the mixture was extracted with 2×100 ml diethyl ether. The combined organic extracts were washed with 100 ml saturated NaHCO3, then with 100 ml saturated NaCl. The ether layer was dried over anhydrous Na2SO4, and the solvent was removed on the rotary evaporator. The crude product (6.7 g) was purified by filtration through a 600 ml sintered glass funnel filled silica bed, using 95% hexane/diethyl ether as the eluting solvent to give 4 g (70% yield) of 1-(2-allylthio-2-methylpropylamino)-2-(2-mercapto-2-methylpropylamino]benzene as a yellow oil.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:12]=1[O:13][C:14]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=1[F:24])[CH2:9][C:8]([CH3:31])=[CH:7]2)([CH3:3])[CH3:2].[H-].[K+].[Cl:34][Si:35](Cl)([CH3:37])[CH3:36]>C1COCC1>[Cl:34][Si:35]([CH:7]1[C:6]2[C:10](=[C:11]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:12]([O:13][C:14]3[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=3[F:24])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=2)[CH:9]=[C:8]1[CH3:31])([CH3:37])[CH3:36]
Reactant: CC1=Cc2cc(C(C)C)c(Oc3c(F)c(F)c(F)c(F)c3F)c(-c3ccccc3)c2C1
Reactant: C[Si](C)(Cl)Cl
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1=Cc2c(cc(C(C)C)c(Oc3c(F)c(F)c(F)c(F)c3F)c2-c2ccccc2)C1[Si](C)(C)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To a solution of 8.61 g (20.0 mmol) of 5-isopropyl-2-methyl-6-(pentafluorophenoxy)-7-phenyl-1H-indene in 200 ml of THF cooled to −25° C., 885 mg (22.1 mmol) of potassium hydride was added. The resulting mixture was stirred overnight at room temperature, filtered through glass frit (G3) to remove an excess of KH, then cooled to −25° C., and 13.0 g (101 mmol, 5 eq.) of dichlorodimethylsilane was added in one portion. The resulting solution was stirred overnight at room temperature, then evaporated to dryness. The residue was dissolved in 200 ml of toluene, and the formed suspension was filtered through glass frit (G3). The precipitate was additionally washed by 2×30 ml of toluene. The combined filtrate was evaporated to dryness to give 10.5 g (99%) of the title product which was further used without an additional purification.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=O)[CH2:15]Br)C.[C:19]1([CH2:25][C:26]([NH2:28])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:25]([C:26]1[O:27][CH:15]=[C:14]([C:8]2[CH:9]=[C:10]([Br:13])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4]([OH:3])=[O:18])[N:28]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC(=O)Cc1ccccc1
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)CBr
Product: O=C(O)COc1ccc(Br)cc1-c1coc(Cc2ccccc2)n1

Procedure:
Title compound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and 2-phenylacetamide according to GP5 and GP3: LC/MS (an10p8) Rt 2.47 min, m/z 388 [M+H]+; 1H NMR (CDCl3): δ 4.22 (s, 2H), 4.84 (s, 2H), 7.04 (d, 1H), 7.25 (m, 5H), 7.43 (d, 1H), 8.06 (s, 1H), 8.69 (s, 1H), 13 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4](Cl)[N:3]=1.[NH2:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([NH:18][CH3:19])=[O:17].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([NH:18][CH3:19])=[O:17])[C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CNC(=O)c1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Yield: 8 %

Procedure:
In a similar fashion as outlined in Example 191a, 2,6-dichloro-5-trifluoromethylpyrimidine was reacted with 2-amino-N-methylbenzamide and N,N-diisopropylethylamine in isopropyl alcohol (no microwave—20° C., 2 days) to afford 2-(2-chloro-5-trifluoromethyl-pyrimidin-4-ylamino)-N-methyl-benzamide as a white solid in 8% yield. Mp: (209° C.); MS: 331.05 (M+H); 1H NMR (chloroform-d): δ 11.63 (br s, 1H), δ 8.59 (d, J=8 Hz, 1H), δ 8.47 (s, 1H), δ 7.59 (t, J=8 Hz, 1H), δ 7.52 (d, J=8 Hz, 1H), δ 7.19 (t, J=8 Hz, 1H), δ 6.20 (br s, 1H), δ 3.04 (d, J=5 Hz, 3H).
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:20]([NH:22][CH2:23][CH2:24][C:25]([OH:27])=O)=[O:21].[CH2:28]1[C:36]2[C:31](=[CH:32]C=CC=2)[CH2:30][N:29]1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH3:30][CH:31]([CH3:32])[CH2:36][CH2:28][NH:29][C:25](=[O:27])[CH2:24][CH2:23][NH:22][C:20]([N:12]1[CH2:11][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)=[O:21]
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: O=C(O)CCNC(=O)N1Cc2ccccc2C1
Agent: NCCCc1ccccc1
Product: CC(C)CCNC(=O)CCNC(=O)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 1C, substituting 1,3-methylbutan-1-amine for 3-phenylpropan-1-amine and 3-(isoindoline-2-carboxamido)propanoic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.76-7.81 (m, 1H), 7.25-7.34 (m, 4H), 6.31-6.36 (m, 1H), 4.56 (s, 4H), 3.23-3.31 (m, 2H), 3.02-3.09 (m, 2H), 2.27 (t, J=7.0 Hz, 2H), 1.46-1.62 (m, 1H), 1.27 (q, J=7.1 Hz, 2H), 0.84 (d, J=6.6 Hz, 6H); MS (ESI(+)) m/e 304 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH:9]([CH:13]([CH3:15])[CH3:14])[CH2:8]2)=[CH:4][CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=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(O)C>[CH:13]([CH:9]1[NH:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:16]=[CH:17][C:2]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:19]([F:30])([F:29])[F:18])=[CH:3][CH:4]=2)[CH2:8]1)([CH3:15])[CH3:14]
Reactant: CC(C)C1CN(Cc2ccc(Br)cc2)CCN1
Reactant: OB(O)c1ccccc1C(F)(F)F
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: CCO
Solvent: Cc1ccccc1
Product: CC(C)C1CN(Cc2ccc(-c3ccccc3C(F)(F)F)cc2)CCN1
Temperature: 120 °C

Procedure:
100 mg of 1-(4-bromo-benzyl)-3-isopropyl-piperazine could be combined with 1 equiv. of 2-trifluoromethylphenyl boronic acid, 10 mol % of tetrakis(triphenylphosphine)palladium(0), 2M sodium carbonate solution, toluene and ethanol. The reaction mixture could be heated in a sealed tube at 120° C. overnight. The reaction mixture could be filtered through Celite and concentrated in vacuo. The residue could be diluted with water and extracted with ethyl acetate. The combined organic phases could be washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material could be purified by flash chromatography to afford 3-isopropyl-1-(2′-trifluoromethyl-biphenyl-4-ylmethyl)-piperazine.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:9][C:8]=2[C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CI.[C:40](OCC)(=O)C>CN(C=O)C>[CH:1]1([O:6][C:7]2[C:8]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[CH:9][C:10]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:11][C:12]=2[N:13]([CH3:40])[C:14](=[O:19])[C:15]([F:17])([F:16])[F:18])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCc1cc(NC(=O)C(F)(F)F)c(OC2CCCC2)c(-c2ccc3ccccc3c2)c1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CCc1cc(-c2ccc3ccccc3c2)c(OC2CCCC2)c(N(C)C(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of Intermediate 54 (208 mg) in DMF (5 ml) was added with 60% sodium hydride (21 mg) under ice cooling, and stirred for 20 minutes. This reaction mixture was added dropwise with methyl iodide (150 μl), stirred for 10 minutes, then warmed to room temperature, and further stirred for 1 hour. The reaction mixture was poured into ice water, and ethyl acetate (100 ml) was added for extraction. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate 5:1) to obtain the title compound (Intermediate 55, 200 mg).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:23])[NH:18][CH2:19][C:20]([OH:22])=O)[CH:12]=[C:13]([Cl:15])[CH:14]=1.Cl.[CH:25]([N:28]=[C:29]=[O:30])([CH3:27])[CH3:26]>ClC1C=CC=CC=1>[CH:25]([NH:28][C:29]([N:18]1[CH2:19][C:20](=[O:22])[N:16]([C:11]2[CH:12]=[C:13]([Cl:15])[CH:14]=[C:9]([Cl:8])[CH:10]=2)[C:17]1=[O:23])=[O:30])([CH3:27])[CH3:26]
Reactant: CC(C)N=C=O
Reactant: O=C(O)CNC(=O)Nc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Clc1ccccc1
Product: CC(C)NC(=O)N1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 100.6 %

Procedure:
101 g of triethylamine are added to a suspension of 263 g of 2-[3-(3,5-dichlorophenyl)-ureido]-acetic acid in 2,000 cm3 of chlorobenzene and 300 g of isopropyl isocyanate, which has been heated to 50° C, and the mixture is stirred for 4 hours at 80°-90°. After cooling, the reaction mixture is stirred for 30 minutes with 500 cm3 of a 7% strength (weight/volume) aqueous solution of hydrochloric acid. The organic solution is decanted, dried and concentrated under reduced pressure. 332 g of 1-isopropylcarbamoyl-3-(3,5-dichlorophenyl)-hydantoin melting at 130° C are thus obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH2:10][C:11](O)=[O:12])=[CH:5][CH:4]=1)#[N:2].[NH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([F:54])[C:28]=1[CH2:29][CH2:30][C@H:31]1[O:36][CH2:35][C@H:34]([CH2:37][O:38][C:39]([NH:41][CH2:42][C:43]([F:46])([F:45])[F:44])=[O:40])[N:33]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:32]1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH2:10][C:11]([NH:22][C:23]2[CH:24]=[N:25][CH:26]=[C:27]([F:54])[C:28]=2[CH2:29][CH2:30][C@H:31]2[O:36][CH2:35][C@@H:34]([CH2:37][O:38][C:39](=[O:40])[NH:41][CH2:42][C:43]([F:46])([F:44])[F:45])[N:33]([C:47]([O:49][C:50]([CH3:51])([CH3:53])[CH3:52])=[O:48])[CH2:32]2)=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc([C@@H](CC(=O)O)c2ccc(F)c(F)c2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cncc2F)OC[C@@H]1COC(=O)NCC(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)C[C@H](c2ccc(C#N)cc2)c2ccc(F)c(F)c2)OC[C@H]1COC(=O)NCC(F)(F)F
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
The product from step 1 (50 mg, 0.16 mmol) and the product from step 4 of Example 89 (78 mg, 0.16 mmol) were dissolved in pyridine (1 mL) and the stirred solution was cooled to −10° C. in an ice/acetone bath. To the cold solution was added POCl3 dropwise (0.02 mL, 0.18 mmol). The mixture was stirred at −10° C. for 30 min. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution (1 mL) and the mixture was allowed to warm to ambient temperature. The mixture was diluted with water (10 mL) and extracted with dichloromethane (3×10 mL). The combined dichloromethane phases were dried (Na2SO4), filtered, and the filtrate solvents were removed in vacuo. The residue was purified on a 12 g silica gel column using a gradient elution of 0-100% EtOAc:hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give the title compound as a gum. (M+H-Boc)+=650.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[CH2:11](C(CC)(CC)C([O-])([O-])[O-])[CH3:12]>C(O)(=O)C>[CH3:11][C:12]1[O:10][C:3]2[C:4]([CH3:9])=[CH:5][C:6]([NH2:8])=[CH:7][C:2]=2[N:1]=1
Reactant: Cc1cc(N)cc(N)c1O
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: CC(=O)O
Product: Cc1nc2cc(N)cc(C)c2o1
Temperature: 25 °C

Procedure:
1.00 g (7.20 mmol) 2,4-diamino-6-methyl-phenol, 5.00 mL acetic acid and 15.0 mL (81.8 mmol) triethylorthoacetate were combined and refluxed. The reaction mixture was cooled to RT overnight and evaporated down. The residue was extracted with 0.5 N sodium hydroxide solution and EtOAc and the organic phase was evaporated down. The flask residue was triturated with diethyl ether and the precipitate formed was suction filtered. The mother liquor was evaporated down and the residue was purified by flash chromatography. The product-containing fractions were combined and evaporated down.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[N:13]=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[N:15]=[C:16]([N:17]3[CH2:21][CH2:20][C@@H:19]([OH:22])[CH2:18]3)[C:11]=2[N:10]=[N:9]1)[C:2]1C=CC=CC=1.C(C1N=C(N2CC[C@@H](O)C2)C2N=NNC=2N=1)(C)(C)C.C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.ClC[C:70]1[N:74](C)[N:73]=[N:72][N:71]=1>[Pd]>[C:23]([C:14]1[N:15]=[C:16]([N:17]2[CH2:21][CH2:20][C@@H:19]([OH:22])[CH2:18]2)[C:11]2[N:10]=[N:9][N:8]([CH2:1][C:2]3[N:71]([CH3:70])[N:72]=[N:73][N:74]=3)[C:12]=2[N:13]=1)([CH3:25])([CH3:26])[CH3:24]
Reactant: Cn1nnnc1CCl
Reactant: CC(C)(C)c1nc(N2CC[C@@H](O)C2)c2nnn(Cc3ccccc3)c2n1
Agent: [Pd]
Agent: CC(C)(C)c1nc(N2CC[C@@H](O)C2)c2nn[nH]c2n1
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: Cn1nnnc1Cn1nnc2c(N3CC[C@@H](O)C3)nc(C(C)(C)C)nc21

Procedure:
(R)-1-(3-Benzyl-5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-ol was hydrogenated over Pd/C and the resulting (R)-1-(5-tert-Butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-ol was reacted in analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b) with 5-(chloromethyl)-1-methyl-1H-tetrazole. MS (m/e): 359.3 (MH+)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[N:12][C:13]([NH:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31].C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>O.Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[N:12][C:13]([NH:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)=[O:9])=[CH:6][C:5]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[C:29]([O:30][CH3:31])[CH:28]=2)=[CH:4][N:3]=1
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: COCCNc1ccc(C(=O)c2cc(Br)cnc2N)cn1
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COCCNc1ccc(C(=O)c2cc(-c3ccc(OC)c(OC)c3)cnc2N)cn1
Reaction time: 0.33 h
Yield: 74 %

Procedure:
To (2-amino-5-bromo-pyridin-3-yl)-[6-(2-methoxy-ethylamino)-pyridin-3-yl]-methanone, 3,4-dimethoxyphenylboronic acid (1.3 equiv.) and dichlorobis (triphenylphosphino)palladium (II) (6 mol %) in a Smith process vial was added a 3:2:1 mixture of acetonitrile, water, and a 2 m solution of sodium carbonate in water to achieve an overall concentration of the starting material of 0.10 m. The reaction was run in a Personal Chemistry® microwave reactor at 165° C. for 1200 s. Water was added and the mixture extracted three times with ethyl acetate. Purification on silica gel with a gradient of MeOH/CH2Cl2 afforded [2-amino-5-(3,4-dimethoxy-phenyl)-pyridin-3-yl]-[6-(2-methoxy-ethylamino)-pyridin-3-yl]-methanone as a yellow solid (74% yield). 1H NMR (DMSO-d6): δ 8.49 (d, J=2.0 Hz, 1H), 8.33 (d, J=2.5 Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.58 (broad s, 1H), 7.14 (s, 1H), 7.05 (m, 3H), 6.98 (d, J=8.5 Hz, 1H), 6.59 (d, J=9.0 Hz, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 3.50 (broad t, J=5.0 Hz, 2H), 3.46 (t, J=5.0 Hz, 2H), 3.26 (s, 3H); HPLC/MS m/z: 409.2 [MH]+.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:29])([CH3:28])[C:18]=3[CH:17]=2)[OH:15])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].P([O-])([O-])O.[Na+].[Na+].[CH2:36]=O>O1CCOCC1>[C:1]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:13][CH:14]([C:16]3[CH:25]=[CH:24][C:23]4[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:28])([CH3:29])[C:18]=4[CH:17]=3)[O:15][CH2:36]2)=[CH:10][CH:11]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: C=O
Reactant: CCOC(=O)c1ccc(NCC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [O-]P([O-])O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(N2COC(c3ccc4c(c3)C(C)(C)CCC4(C)C)C2)cc1
Yield: 61.3 %

Procedure:
1.58 g (4 millimoles) of N-(4-carbethoxyphenyl)-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-aminoethanol were stirred with 20 ml of 1N sodium hydrogen phosphite solution and 2 ml (20 millimoles) of formalin solution in 20 ml of dioxane for 1 hour at 60° C. The mixture was then poured onto water and extracted with ether, and the organic phase was washed with 2N sodium hydroxide solution and water, dried over magnesium sulfate and evaporated down. Recrystallization from methanol gave 1.0 g of the title compound, RF =0.51 (thin layer chromatography, silica gel; 7:1 n-heptane/ethyl acetate).
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=1>CN(C)C=O>[CH3:32][C:27]1[CH:26]=[C:25]([NH:24][C:4]([C:3]2[C:2](=[S:1])[NH:10][CH:9]=[CH:8][CH:7]=2)=[O:6])[CH:30]=[C:29]([CH3:31])[CH:28]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: O=C(O)c1cccnc1S
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)cc(NC(=O)c2ccc[nH]c2=S)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
2-Mercaptonicotinic acid (90 g, 0.58 mol) was suspended in N,N-dimethylformamide (660 mL) under ice-cooling, then carbonyldiimidazole (110 g, 0.70 mol) was added thereto, and the whole was stirred for 2 hours at room temperature. Water (5.4 mL) was added thereto, and the whole was stirred for 40 minutes, and then 3,5-xylidine (76 mL, 0.61 mol) was added thereto and the resulting mixture was stirred at 60° C. for 16 hours. The mixture was allowed to stand, and then water (1.3 L) was added, and the precipitated solid was filtered off. The solid was dried at 45° C. under reduced pressure to give 130 g of the title Reference Compound as a yellow solid (Yield: 89%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[SH:19]CCC(OC)=O.C[O-].[Na+].CO.CCCC(OC)=O>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([C@H:11]([SH:19])[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C[C@@H]1O[C@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: COC(=O)CCS
Agent: C[O-]
Agent: [Na+]
Solvent: CCCC(=O)OC
Solvent: CO
Product: C[C@@H](S)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 3 h

Procedure:
In methanol (25 ml) were dissolved (2S,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (1.0 g), methyl 3-mercaptopropionate (3.5 ml) and 28% sodium methoxide-methanol (3.07 g) and the solution was refluxed in an oil bath. After 2 and after 3 hours, methyl 3-methylpropionate (1.75 ml) and 28% sodium methoxide-methanol (1.5 g) were added at each time. The oil bath was removed after heating for 4 hours and the reaction mixture was neutralized with cold 1N hydrochloric acid (32 ml) and extracted with dichloromethane (200 ml). The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane-ethyl acetate=1:3). The desired fraction was concentrated and the resulting crystals were recrystallized from ethyl acetate-hexane to give (2S,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1 H-1,2,4-triazol-1-yl)-2-butanol (compound 117, 472 mg) as colorless needles.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CCOC(C)=O.[H][H]>[Pd].CO>[OH:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: [H][H]
Reactant: COc1ccc(C=CC(=O)O)cc1O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(CCC(=O)O)cc1O
Yield: 99 %

Procedure:
The mixture of 3-(3-Hydroxy-4-methoxy-phenyl)-acrylic acid (3 g), 10% Pd/C (0.5 g), EtOAc (50 ml) and MeOH (50 ml) was shaken in Parr apparatus for 5 hs under 30-40 psi of hydrogen. Then the solution was passed through a celite pad and was concentrated to give 3-(3-Hydroxy-4-methoxy-phenyl)-propionic acid (3 g). LC-MS: m/e 197 (MH+).
Reaction SMILES: [C@@H]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)O[C@H](CO)[C@@H](O)[C@H]1O.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C>CS(C)=O>[CH2:20]([N:12]1[C:13]2[C:14](=[O:15])[NH:16][CH:17]=[N:18][C:19]=2[N:10]=[CH:11]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=c1[nH]cnc2ncn(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
18.23 g of inosine was dissolved in 90 ml of dimethyl sulfoxide, and 16 ml of benzyl bromide was added thereto. The mixture was stirred at room temperature overnight. The reaction solution was poured into 3 L of ethyl acetate. The resulting supernatant was removed and the precipitated oil was dissolved in 10% hydrochloric acid (135 ml). The solution was heated at 70° C. with stirring for 4 hours. The solution was cooled to room temperature, and then neutralized to pH 7 using a 5N aqueous sodium hydroxide solution. The precipitated solid was collected by filtration, and dried to give 12.748 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[O:43][N:42]=[C:41]([CH3:44])[CH:40]=2)[CH:34]=1)=[O:32])(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]([C:18]([F:20])([F:21])[F:19])=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[O:43][N:42]=[C:41]([CH3:44])[CH:40]=2)[CH:34]=1)=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCC2)c(C(F)(F)F)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N4CCC4)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-5-azetidin-1-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J17) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K4) according to the general procedure M. Obtained as a light yellow foam (218 mg).