Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:15])[CH2:13]Br)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[N-:16]=[N+:17]=[N-:18].[Na+].O>CN(C)C=O>[N:16]([CH2:13][C:12]([C:9]1[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=1)=[O:15])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(C(=O)CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a solution of 4′-ethoxycarbonyl-2-bromoacetophenone (2.0 g) in N,N-dimethylformamide (8 ml) was added sodium azide (480 mg) at 0° C., and stirred for 2 hours at room temperature. The reaction mixture was poured into water (100 ml), extracted with diethyl ether (200 ml×2), washed with brine, and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The product was purified by silica gel column chromatography (ethyl acetate:hexane=1:5) to give 2-azido-4′-ethoxycarbonylacetophenone (1.46 g).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21](I)[CH:20]=4)[CH2:14][CH2:13]3)[N:11]([CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])[C:10](=[O:31])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:32]([Sn](CCCC)(CCCC)CCCC)[CH:33]=[CH2:34]>CN(C=O)C.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:34]([C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][N:15]1[CH2:16][CH2:17][C:12]2([N:11]([CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])[C:10](=[O:31])[N:9]=[C:8]2[NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:13][CH2:14]1)[CH:33]=[CH2:32]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: C=CCCCN1C(=O)N=C(NC2CCCCC2)C12CCN(Cc1cccc(I)c1)CC2
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCCCN1C(=O)N=C(NC2CCCCC2)C12CCN(Cc1cccc(CC=C)c1)CC2
Temperature: 90 °C

Procedure:
To a solution of 4-(cyclohexylamino)-8-(3-iodobenzyl)-1-pent-4-en-1-yl-1,3,8-triazaspiro[4.5]dec-3-en-2-one (920 mg, 1.72 mmol, intermediate I.1.d.1) and trans-bis(triphenylphosphine)palladium(II) chloride (121 mg, 0.17 mmol) in degassed DMF (11.5 mL) was added allyl tri-n-butyltin (0.61 mL, 1.98 mmol) in one portion. The reaction mixture was stirred at 90° C., sealed, for 16 h, diluted with EtOAc, washed with aqueous LiCl twice, dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (90 g silica gel, EtOAc) to give the desired product. LRMS (M+1)=449.
Reaction SMILES: [NH2:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[CH2:4][CH:3]1[CH2:5][CH2:6][OH:7].[C:17]([N:21]=[C:22]=[S:23])([CH3:20])([CH3:19])[CH3:18]>C(#N)C>[C:17]([NH:21][C:22]([NH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[CH2:4][CH:3]1[CH2:5][CH2:6][OH:7])=[S:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: NC1(c2cccc([N+](=O)[O-])c2)CC1CCO
Reactant: CC(C)(C)N=C=S
Solvent: CC#N
Product: CC(C)(C)NC(=S)NC1(c2cccc([N+](=O)[O-])c2)CC1CCO
Temperature: 80 °C
Reaction time: 36 h
Yield: 67.3 %

Procedure:
To a solution of 2-((1SR,2SR)-2-amino-2-(3-nitrophenyl)cyclopropyl)ethanol (intermediate A2c) (1.44 g, 6.48 mmol, Eq: 1.00) in dry acetonitrile (30 ml) was added at 23° C. tert-butyl isothiocyanate (1.12 g, 1.23 ml, 9.72 mmol, Eq: 1.5) and the mixture was stirred at 80° C. for 36 h. Evaporated to dryness and chromatography. The residue was chromatographed on 50 g SiO2 with 0-50% ethyl acetate in dichloromethane to give the 1-tert-butyl-3-((1SR,2SR)-2-(2-hydroxyethyl)-1-(3-nitrophenyl)cyclopropyl)thiourea (1.47 g, 4.36 mmol, 67.2% yield) as a light brown solid. MS (ISP): m/z=338.4 [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[C:7]2[N:8]([CH2:12][CH2:13][O:14][CH3:15])[C:9]([CH3:11])=[N:10][C:6]=2[CH:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:3]=1[CH2:20][CH2:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[BH4-].[Na+]>C(O)C>[OH:1][C:2]1[C:7]2[N:8]([CH2:12][CH2:13][O:14][CH3:15])[C:9]([CH3:11])=[N:10][C:6]=2[CH:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:3]=1[CH2:20][CH2:21][CH:22]([OH:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COCCn1c(C)nc2cc(C(=O)OC)c(CCC(=O)c3ccccc3)c(O)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COCCn1c(C)nc2cc(C(=O)OC)c(CCC(O)c3ccccc3)c(O)c21
Reaction time: 4 h

Procedure:
To a solution of methyl 7-hydroxy-1-(2-methoxyethyl)-2-methyl-6-(3-oxo-3-phenylpropyl)-1H-benzimidazole-5-carboxylate (2.08 g, 5.25 mmol, Step 9) in ethanol (50 mL) was added sodium borohydride (298 mg, 7.87 mmol) at room temperature. After stirring at the same temperature for 4 hours, the solvent was evaporated, and the residue was poured onto saturated sodium hydrogencarbonate aqueous solution, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane/methanol (20:1) to afford the title compound as a brown amorphous (2.08 g, 99%).
Reaction SMILES: C(Cl)(Cl)=O.ClC(OCC)=O.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2C(=O)O[C:28](=[O:29])[C:27]3=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=[C:26]23)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:20][CH:21]=2)=[C:27]([CH:33]=1)[C:28]([N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)=[O:29]
Reactant: COc1ccc2c(c1)c(=O)oc(=O)n2-c1ccc(OCc2ccccc2)cc1
Reactant: C1CCNCC1
Agent: CCOC(=O)Cl
Agent: O=C(Cl)Cl
Product: COc1ccc(Nc2ccc(OCc3ccccc3)cc2)c(C(=O)N2CCCCC2)c1

Procedure:
It is contemplated that the foregoing product by reaction with phosgene or ethyl chloroformate can be converted to N-(4-methoxy-2-methylphenyl)isatoic anhydride [VIII; R=H, R"=2-CH3, OR°=4-OCH3 ], and the latter reacted with piperidine to give 1-[2-(4-methoxy-2-methylphenylamino)benzoyl]piperidine [IX; R=H, R"=2-CH3, N=Z=1-piperidinyl, OR°=4-OCH3 ] which can be de-etherified with boron tribromide to yield 1-[2-(4-hydroxy-2-methylphenylamino)benzoyl]piperidine [I; R and R'=H, R"=2-CH3, N=Z=1-piperidinyl, OH at 4-position].
Reaction SMILES: [OH:1][C@@H:2]1[C@H:8]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH2:6][CH3:7])[C:4](=[O:22])[CH2:3]1)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>N1C=CC=CC=1>[C:23]([O:1][C@@H:2]1[C@H:8]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH2:6][CH3:7])[C:4](=[O:22])[CH2:3]1)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](O)CC2=O
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(=O)c1ccccc1)CC2=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 102 g of 15α-hydroxy-18-methyl-4-estrene-3,17-dione in 500 ml of pyridine is combined under ice cooling with 50.9 ml of benzoyl chloride and stirred for one hour under cooling. Then 9 ml of water is added dropwise and the mixture is stirred for another hour. The reaction solution is then stirred into ice water, the thus-formed precipitate is suctioned off, washed with water, and dried, thus obtaining 146 g of crude 15α-benzoyloxy-18-methyl-4-estrene-3,17-dione.
Reaction SMILES: [Br-].[OH:2][CH2:3][CH2:4][CH2:5][N+:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:7]=1.[BH4-].[Na+]>CCO>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][CH2:3][OH:2])[CH2:7][CH:8]=1
Reactant: OCCC[n+]1ccc(-c2ccccn2)cc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Product: OCCCN1CC=C(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1-(3-hydroxypropyl)-4-[pyrid-2-yl]pyridinium bromide (8 g) in 100 mL EtOH was added NaBH4 (1.41 g, 37.2 mmol) in small portions. The reaction mixture was stirred at room temperature for 12 h and then quenched with drops of water. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:4 MeOH/EtOAc followed by 1:4 (2M NH3 in MeOH)/EtOAc as the eluting system (Rf=0. 6, (2M NH3 in MeOH)/EtOAc=1:4) to obtain 3-(3′,6′-dihydro-2′-H-[2,4′]bipyridinyl-1′-yl)-propanol as an oil (1.58 g, 39% over two steps).
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[C:18]([C:19]#[N:20])=[C:17]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[NH:16][N:15]=1.C(O)(=O)C>ClCCl>[CH3:10][C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:15]2[N:16]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:23][CH2:22]3)[C:18]([C:19]#[N:20])=[C:14]2[N:13]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: N#Cc1c(N)n[nH]c1N1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(-c2ccccc2)n2nc(N3CCN(Cc4ccccc4)CC3)c(C#N)c2n1
Yield: 74.8 %

Procedure:
A mixture of 2.9 g (0.018 moles) of 1-phenyl-1,3-butanedione, 5.0 g (0.018 moles) of 3-amino-5-(4-phenylmethyl-1-piperazinyl)-4-pyrazolecarbonitrile (prepared as described in Example 1) and 25 ml of glacial acetic acid was refluxed for 4 hours. The reaction mixture was evaporated in vacuo and gave a thick oil. The oil was dissolved in dichloromethane and partitioned with saturated sodium bicarbonate. The organic layer was separated, dried over anhydrous sodium sulfate and passed through magnesium silicate. The solution was evaporated in vacuo and gave a yellow solid which was recrystallized from isopropanol and cyclohexane and gave 5.5 g of the desired product as a light yellow solid, mp 160°-164° C.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[F:14])[C:8](O)=[O:9])(=[O:4])=[O:3].C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[F:14])[C:8]([Cl:18])=[O:9])(=[O:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(F)c(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(F)c(S(=O)(=O)Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 3-chlorosulfonyl-4-fluoro benzoic acid (2.5 g, 10 mmol) in methylene chloride at 0° C. is added oxalyl chloride (1.33 g, 11 mmol), followed by the addition of 1 drop of N,N,-dimethylformamide. The reaction mixture is warmed up to room temperature and stirred for an additional 4 h. The solvent is removed, and the residue is dried under vacuum for 1 hr to obtain the title compound as an oil, which is used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@H:5]2[CH2:7][CH2:8][CH2:9][C@H:10]([NH2:11])[C@H:4]2[O:3]1.[CH3:13][C:14]1([CH3:39])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]2[CH:19]=[C:18]([C:26]3[N:31]=[C:30]([N:32]4[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]4)[CH:29]=[CH:28][CH:27]=3)[CH:17]=[CH:16][C:15]1=2>C1COCC1>[CH3:1][C:2]1([CH3:12])[O:6][C@H:5]2[CH2:7][CH2:8][CH2:9][C@H:10]([NH:11][CH:35]3[CH2:34][CH2:33][N:32]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([C:18]5[CH:17]=[CH:16][C:15]6[C:14]([CH3:39])([CH3:13])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]=6[CH:19]=5)[N:31]=4)[CH2:37][CH2:36]3)[C@H:4]2[O:3]1
Reactant: CC1(C)O[C@H]2[C@H](CCC[C@@H]2N)O1
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(=O)CC4)n3)ccc21
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2[C@@H](NC3CCN(c4cccc(-c5ccc6c(c5)C(C)(C)CCC6(C)C)n4)CC3)CCC[C@@H]2O1

Procedure:
The preparation is carried out analogously to FS1008 in THF starting from 62 mg (0.360 mmol) of (3aR,4S,7aS)-2,2-dimethylhexahydrobenzo-1,3-dioxol-4-ylamine and 145 mg (0.360 mmol) of 6′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2,3,5,6-tetrahydro-1,2′-bipyridinyl-4-one. The purification is carried out by means of flash chromatography on silica gel.
Reaction SMILES: [C:1]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H-].[Na+].[CH:21]1([CH2:24][C@@H:25](OS(C(F)(F)F)(=O)=O)[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:23][CH2:22]1>COCCOC.ClCCl>[CH:21]1([CH2:24][C@@H:25]([C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])[CH:2]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[C:1]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:22][CH2:23]1
Reactant: O=C(OCc1ccccc1)[C@@H](CC1CC1)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)(C)OC(=O)C(C(=O)OCc1ccccc1)[C@@H](CC1CC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
A solution of 3.8 g of benzyl tert-butyl malonate in 50 ml of 1,2-dimethoxyethane was treated with 0.504 g of an 80% dispersion of sodium hydride in mineral oil. The mixture was stirred at room temperature for 30 minutes and then cooled to 0°. A solution of 5.37 g of benzyl 3-cyclopropyl-2(R)-trifluoromethylsulphonyloxypropionate in 20 ml of dichloromethane was added dropwise at 0°. The mixture was stirred at 0° for 2 hours and then left to warm to room temperature overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate the solvent was evaporated to give 6.54 g of 2,3-dibenzyl 3-tert-butyl 1-cyclopropyl-2(R),3(R,S),3-propane-tricarboxylate as a 1:1 mixture of diastereoisomers in the form of an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][CH3:22])=[C:19]([C:23](O)=[O:24])[C:18]([CH2:26][CH3:27])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[CH3:46][N:47]1[CH2:52][CH2:51][CH:50]([CH2:53][N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:49][CH2:48]1>CC#N>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][CH3:22])=[C:19]([C:23]([N:57]4[CH2:56][CH2:55][N:54]([CH2:53][CH:50]5[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]5)[CH2:59][CH2:58]4)=[O:24])[C:18]([CH2:26][CH3:27])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: CCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(CC)c1C(=O)O
Reactant: CN1CCC(CN2CCNCC2)CC1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(CC)c1C(=O)N1CCN(CC2CCN(C)CC2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 0.40 g (1.10 mmol) of 1-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenyl}-3,5-diethyl-1H-pyrazole-4-carboxylic acid (intermediate 1) and 0.18 g (1.1 mmol) of 2-chloro-4,6-dimethoxy-[1,3,5]triazine were dissolved in 10 ml of MeCN. The solution was then cooled down to 0° C. and 0.32 g=0.35 ml (3.2 mmol) of N-methylmorpholine was added drop by drop. After 2 hours stirring at 0° C., a solution of 0.21 g (1.1 mmol) 1-(1-methyl-piperidin-4-ylmethyl)-piperazine in 3 ml of MeCN was added drop by drop. Then, the mixture was warmed up to RT and stirring continued for 20 hours. Subsequently, it was poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0-7.5:2.5) to afford the title compound as colorless solid. MS: 560.2 (MH+, 1 Cl).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][CH2:12]Cl.[Si:14]([O:31][CH2:32][CH2:33][C@@H:34]([OH:55])[C@H:35]([C:46]1[CH:51]=[C:50]([F:52])[C:49]([F:53])=[C:48]([F:54])[CH:47]=1)[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCCl>[Si:14]([O:31][CH2:32][CH2:33][C@@H:34]([O:55][CH2:10][O:11][CH3:12])[C@H:35]([C:46]1[CH:51]=[C:50]([F:52])[C:49]([F:53])=[C:48]([F:54])[CH:47]=1)[C:36]([O:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:37])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)[Si](OCC[C@@H](O)[C@@H](C(=O)OCc1ccccc1)c1cc(F)c(F)c(F)c1)(c1ccccc1)c1ccccc1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COCO[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H](C(=O)OCc1ccccc1)c1cc(F)c(F)c(F)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
IPEA (0.742 mL) and chloromethyl methyl ether (0.324 mL) were added to a solution of benzyl (2S,3R)-5-(tert-butyldiphenylsilanyloxy)-3-hydroxy-2-(3,4,5-trifluorophenyl)pentanoate (840 mg) in 1,2-dichloroethane (20 mL) at 0° C. The reaction solution was stirred at 60° C. for 4 hours and then left to cool to room temperature and concentrated under reduced pressure. Ethyl acetate and a saturated ammonium chloride solution were added to the residue, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 875 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)[CH3:2].[H][H]>CO.[Pd]>[NH2:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:15])=[CH:11][CH:10]=1
Reactant: CCCCCCCN(CC)C(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCCCCN(CC)C(=O)Cc1ccc(N)cc1
Reaction time: 0.25 h

Procedure:
N-Ethyl-N-heptyl-4-nitrophenylacetamide (Preparation 18) (7.5 g) is hydrogenated on the Parr hydrogenator in two portions; i.e., 3.75 g in 150 ml methanol plus 0.4 g of 10% Pd/C catalyst at an initial hydrogen pressure of 50 psi. The hydrogen uptake ceases after 15 min; after 15 min more, the mixture is filtered through Celite. The filtrates of both runs are pooled and concentrated in vacuo. The residue is dissolved in 20 ml of EtOH, 200 ml of Et2O is added and the mixture treated with 12.0 ml of ca. 2.8M ethereal HCl with a resulting precipitate. This precipitate is collected and washed with ether to give the title compound; m.p. 172°-174° C.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](SC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH2:37].C1COCC1>>[C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:37][CH3:36])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4)c(F)cc3C)c(=O)n(C)c2n1
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4)c(F)cc3C)c(=O)n(C)c2n1
Yield: 94 %

Procedure:
Using a procedure analogous to Example A1, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.192 g, 0.39 mmol) and 2M methylamine in THF (1 mL; 5 eq) were combined to afford 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea as an off-white solid (0.174 g, 94% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.63 (s, 1H), 8.60 (s, 1H), 8.40 (d, J=1.6 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.80-7.77 (m, 2H), 7.66 (s, 1H), 7.36 (s, 1H), 7.10 (d, J=8.4 Hz, 1H), 3.59-3.51 (m, 3H), 2.90 (d, J=4.4 Hz, 1H), 2.05 (s, 3H), 1.45 (s, 9H); (ESI) m/z: 479.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C@@H:14]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:15]([OH:17])=[O:16])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH:27](O)([CH3:29])[CH3:28]>>[CH:27]([O:16][C:15](=[O:17])[C@@H:14]([NH:13][C@@H:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:9]([F:12])([F:11])[F:10])[CH2:18][CH:19]([CH3:21])[CH3:20])([CH3:29])[CH3:28]
Reactant: CC(C)C[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)O
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: CC(C)C[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)OC(C)C
Temperature: 80 °C
Yield: 88 %

Procedure:
To a stirred solution of (S)-2-[(S)-1-(4-bromo-phenyl)-2,2,2-trifluoro-ethylamino]-4-methyl-pentanoic acid, prepared as shown in Li, C. S. et al Bioorg. Med. Chem. Lett. 2006, 16, 1985, (1.80 g, 4.9 mmol) in isopropyl alcohol (100 mL) was added concentrated sulphuric acid (2 mL). The resulting solution was heated at 80° C. for 4 hours. The reaction mixture was allowed to cool and was then concentrated in vacuo. The resulting oil was dispersed in CH2Cl2 (100 mL), washed with saturated NaHCO3 (2×50 mL), dried (MgSO4) and concentrated in vacuo to yield the title compound as a brown oil (1.77 g, 88%). MS [M+H] 412.
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:21]3[O:20][C:19]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[N:18][C:17]=3[C:16]([O:28][CH:29]([F:31])[F:30])=[CH:15][CH:14]=2)=[O:12])=CC=1)([O-])=O.[NH2:32][C:33]1[N:37]([CH3:38])[N:36]=[CH:35][C:34]=1[C:39]#[N:40]>>[C:39]([C:34]1[CH:35]=[N:36][N:37]([CH3:38])[C:33]=1[NH:32][C:11]([C:13]1[C:21]2[O:20][C:19]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:18][C:17]=2[C:16]([O:28][CH:29]([F:30])[F:31])=[CH:15][CH:14]=1)=[O:12])#[N:40]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC(F)F)c2nc(N3CCCCC3)oc12
Reactant: Cn1ncc(C#N)c1N
Product: Cn1ncc(C#N)c1NC(=O)c1ccc(OC(F)F)c2nc(N3CCCCC3)oc12
Yield: 14.9 %

Procedure:
Starting from 4-difluoromethoxy-2-(piperidin-1-yl)-benzooxazole-7-carboxylic acid 4-nitro-phenyl ester (0.35 g) and 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (0.197 g). Purification by column chromatography on silica eluting with 50% ethyl acetate in heptane afforded the title compound as a white solid (50 mg).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:6]2[O:7][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[O:9][CH2:10][C@@H:5]2[CH2:4][C@H:3]1[N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].[CH:30]1[CH:35]=[CH:34][C:33]([O:36][C:37](Cl)=[S:38])=[CH:32][CH:31]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:37](=[S:38])([O:36][C:33]1[CH:34]=[CH:35][CH:30]=[CH:31][CH:32]=1)[O:1][C@@H:2]1[C@@H:6]2[O:7][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[O:9][CH2:10][C@@H:5]2[CH2:4][C@H:3]1[N:19]1[C:20](=[O:29])[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]1=[O:28]
Reactant: S=C(Cl)Oc1ccccc1
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](N4C(=O)c5ccccc5C4=O)[C@H](O)[C@@H]3O2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C2OC[C@@H]3C[C@@H](N4C(=O)c5ccccc5C4=O)[C@H](OC(=S)Oc4ccccc4)[C@@H]3O2)cc1
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a stirred solution of 2-[(4aS,6R,7S,7aR)-7-hydroxy-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]-1H-isoindole-1,3(2H)-dione (1.26 g, 3.19 mmol) in DCM (150. mL) was added DMAP (1.17 g, 9.54 mmol) and phenyl chlorothionoformate (0.661 mL, 4.78 mmol) under an atmosphere of argon. After 2 h, the mixture was concentrated in vacuo and the residue was purified via silica gel chromatography eluting with a gradient of 0 to 5% EtOAc in DCM to afford the title compound as a white amorphous solid (1.64 g, 97%). LC/MS: Rt=2.21 min, ES+ 532 (AA standard).