Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:36])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[C:11]([C:20]2[C:21]([CH3:35])=[CH:22][C:23]3[O:28][C:27]([CH3:30])([CH3:29])[C:26](=[O:31])[N:25]([CH2:32][CH3:33])[C:24]=3[CH:34]=2)[CH:10]=1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH2:32]([N:25]1[C:24]2[CH:34]=[C:20]([C:11]3[CH:10]=[C:9]([CH:8]=[CH:7][C:6]([OH:36])=[O:5])[CH:14]=[CH:13][C:12]=3[O:15][C:16]([F:19])([F:17])[F:18])[C:21]([CH3:35])=[CH:22][C:23]=2[O:28][C:27]([CH3:30])([CH3:29])[C:26]1=[O:31])[CH3:33]
Reactant: CCN1C(=O)C(C)(C)Oc2cc(C)c(-c3cc(C=CC(=O)OC(C)(C)C)ccc3OC(F)(F)F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN1C(=O)C(C)(C)Oc2cc(C)c(-c3cc(C=CC(=O)O)ccc3OC(F)(F)F)cc21
Yield: 98.2 %

Procedure:
A solution of Compound 1E (1.71 g, 3.4 mmol) in 15 mL of dichloromethane and 5 mL of trifluoroacetic acid was stirred at room temperature overnight. The reaction mixture was then concentrated on the rotary evaporator and redissolved in 20 mL of diethyl ether. To this solution, hexanes were added to give a cloudy solution from which 1.5 g (100%) of product precipitated out as a white solid (Compound 1). MS (electrospray): mass calculated for C23H22F3NO5, 449.15; m/z found 462.3, [M+H]+.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]#[C:17][CH2:18][CH:19]([C:21]1[CH:30]=[N:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1)O>C(Cl)Cl>[F:7][CH:19]([C:21]1[CH:30]=[N:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1)[CH2:18][C:17]#[C:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC(CC#Cc1ccccn1)c1cnc2ccccc2n1
Solvent: ClCCl
Product: FC(CC#Cc1ccccn1)c1cnc2ccccc2n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 32.7 %

Procedure:
DAST (19 μL, 0.15 mmol) was added dropwise to a solution of 4-pyridin-2-yl-1-quinoxalin-2-yl-but-3-yn-1-ol (30 mg, 0.11 mmol) in DCM (1.5 mL) at −78° C. The reaction mixture was stirred for 15 min. at −78° C., quenched by the addition of water at 0° C. and extracted twice with DCM. The organic phase was washed with water, dried over Na2SO4, filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 1:1) to yield 10 mg (36 μmol, 33%) of 2-(1-fluoro-4-(pyridin-2-yl)but-3-ynyl)quinoxaline as an orange semi-solid with a purity of 70%.
Reaction SMILES: O[CH2:2][C:3]([CH3:14])([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[CH3:15][C:16]1([CH3:28])[C:20]([CH3:22])([CH3:21])[O:19][B:18]([C:23]2[CH:24]=[N:25][NH:26][CH:27]=2)[O:17]1.C(P(CCCC)(CCCC)=CC#N)CCC>C1(C)C=CC=CC=1>[CH3:13][C:3]([CH3:14])([CH2:2][N:26]1[CH:27]=[C:23]([B:18]2[O:17][C:16]([CH3:28])([CH3:15])[C:20]([CH3:22])([CH3:21])[O:19]2)[CH:24]=[N:25]1)[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(CO)CNC(=O)OC(C)(C)C
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(CNC(=O)OC(C)(C)C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
A solution of tert-butyl (3-hydroxy-2,2-dimethylpropyl)carbamate (1.000 g, 4.92 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.145 g, 5.90 mmol) and 2-(tributylphosphoranylidene)acetonitrile (1.425 g, 5.90 mmol) were stirred together in toluene (20 ml) at 90° C. overnight. The reaction mixture was concentrated and purified by normal phase chromatography to give the title compound.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][CH:14]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:16][CH2:15]1>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][CH:14]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:16][CH2:15]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1COc2ccccc2C1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
46.14 g (242 mmol) of p-toluenesulphonyl chloride are added while stirring at room temperature to a solution of 36.12 g (220 mmol) of 3-hydroxymethylchroman in 100 ml of absolute pyridine, the slightly exothermic reaction being maintained at room temperature by means of an ice bath. The reaction mixture is stirred for a further 3 hours at room temperature and then poured onto ice-water. The crystals formed are filtered off with suction, washed with water and dried in vacuo. 65.84 g (94%) of 3-(p-toluenesulphonyloxymethyl)chroman having a melting point of 86°-87° are obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5](=[O:7])[N:4]([CH2:8][C:9](=O)[CH3:10])[N:3]=1.O.[NH2:13][NH2:14]>C(O)C>[C:2]([NH:3][N:4]1[CH2:8][C:9]([CH3:10])=[N:14][NH:13][C:5]1=[O:7])(=[O:6])[CH3:1]
Reactant: NN
Reactant: CC(=O)Cn1nc(C)oc1=O
Solvent: O
Solvent: CCO
Product: CC(=O)NN1CC(C)=NNC1=O

Procedure:
312 g of 2,3-dihydro-5-methyl-2-oxo-l,3,4-oxadiazol-3-ylacetone in 4 l of ethanol are stirred together with 200 g of hydrazine hydrate for 16 hours at 35° C. The solvent and the excess of hydrazine hydrate are evaporated in vacuo, and the residue is recrystallised from isopropanol to give 148 g (87% of the theoretical amount) of the title compound having a melting point of 197°-199° C.
Reaction SMILES: Cl.[N:2]1([CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[N:5][CH:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.[CH:24]1([N:27]2[C:36]3[C:31](=[CH:32][C:33]([F:39])=[C:34](F)[C:35]=3[F:37])[C:30](=[O:40])[C:29]([C:41]([OH:43])=[O:42])=[CH:28]2)[CH2:26][CH2:25]1>C(#N)C>[CH:24]1([N:27]2[C:36]3[C:31](=[CH:32][C:33]([F:39])=[C:34]([N:9]4[CH2:10][CH2:11][CH2:12][CH:7]([N:2]5[CH:6]=[N:5][CH:4]=[N:3]5)[CH2:8]4)[C:35]=3[F:37])[C:30](=[O:40])[C:29]([C:41]([OH:43])=[O:42])=[CH:28]2)[CH2:25][CH2:26]1
Reactant: c1ncn(C2CCCNC2)n1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCCC(n4cncn4)C3)c(F)cc2c1=O
Temperature: 90 °C

Procedure:
3-(1,2,4-triazol-1-yl)piperidine hydrochloride (300 mg, 1.59 mmol) and DBU (0.48 g, 3.18 mmol) were added to a suspension of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (180 mg, 0.63 mmol) in acetonitrile (15 ml). The reaction mixture was refluxed at 90° C. for 48 hrs and then concentrated under vacuum. The residue was diluted with water and aqueous solution was extracted with chloroform. The organic layer dried over Na2SO4, concentrated and the residue was diluted with water. The separated solid was filtered and washed with 2 ml of acetonitrile. Yield 13 mg, m.p. 217° C.; 1H NMR (TFA) δ: 9.75 (s, 1H), 9.40 (s, 1H), 8.78 (s, 1H), 8.20 (d, 1H), 5.10 (m, 1H), 4.58 (m, 1H), 3.52-4.40 (m, 4H), 2.55 (m, 2H), 2.20 (m, 2H), 1.30-1.70 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][CH2:6]P(OC)(OC)=O.[H-].[Na+].[CH2:16]([C@@:18]1([CH:38]=O)[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=3)[NH:28][CH:27]=2)[C:19]1=[O:37])[CH3:17]>O1CCCC1>[CH3:1][O:2][C:3](=[O:13])[C:4]([O:5][CH3:6])=[CH:38][C@:18]1([CH2:16][CH3:17])[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=3)[NH:28][CH:27]=2)[C:19]1=[O:37]
Reactant: COC(=O)COCP(=O)(OC)OC
Reactant: CC[C@@]1(C=O)CCCN(CCc2c[nH]c3ccc(OC)cc23)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@]1(C=C(OC)C(=O)OC)CCCN(CCc2c[nH]c3ccc(OC)cc23)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.185 g of dimethylphosphonomethoxyacetic acid methyl ester are added dropwise at room temperature to a suspension of 360 mg of sodium hydride in 10 cc of absolute tetrahydrofuran in the absence of moisture. After stirring at room temperature for 30 minutes, a solution of 3.284 g of (S)-3-ethyl-3-formyl-N-[2-(5-methoxy-indol-3-yl)-ethyl]-2-piperidone in 10 cc of absolute tetrahydrofuran is added dropwise at room temperature to the reaction solution while stirring for 30 minutes. The reaction mixture is subsequently stirred at room temperature for a further 2 hours, poured on ice and extracted with methylene chloride. The organic phases are dried and concentrated. A yellowish oil, consisting of a mixture of the Z and E isomers of 3-{(S)-3-ethyl-1-[2-(5-methoxy-indol-3-yl)ethyl]-2-oxo-3-piperidyl}-2-methoxy-propenoic acid methyl ester, is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CO[C:13](=O)[CH2:14][O:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([CH2:17][CH2:16][O:15][CH2:14][C:13]2[NH:6][C:4](=[O:5])[C:3]3[CH:7]=[CH:8][CH:9]=[N:10][C:2]=3[N:1]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: NC(=O)c1cccnc1N
Reactant: COC(=O)COCCc1cccc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(CCOCc2nc3ncccc3c(=O)[nH]2)c1

Procedure:
In analogy to example 91.3, 2-amino-nicotinamide and [2-(3-methoxy-phenyl)-ethoxy]-acetic acid methyl ester (prepared from 2-(3-methoxyphenyl)ethanol [5020-41-7] in analogy to example 91.1-91.2) reacted in the presence of LiHMDS in THF to yield after purification of the crude product with column chromatography (silica gel, EtOAc) 2-[2-(3-methoxy-phenyl)-ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one as white solid. MS (m/e): 312.2 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[O:25][N:24]=[C:23]([Br:26])[CH:22]=1.[Br:27]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[O:25][N:24]=[C:23]([Br:26])[C:22]=1[Br:27]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1cc(Br)no1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1onc(Br)c1Br
Reaction time: 24 h

Procedure:
To a solution of 5-amino-4-(3-bromoisoxazol-5-yl)-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (0.05 g) in acetonitrile (6 ml) was added N-bromosuccinimide (0.02 g). The mixture was left at room temperature for 24 hours during which time a precipitate formed which was isolated by filtration. Washing with methanol, followed by drying, afforded the title compound as a white solid, m.p. 279° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][C:10]#[N:11].[Li].O.[OH-].[Na+]>CCOCC>[NH2:11][CH2:10][CH2:9][CH:8]([O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC(CC#N)OC1CCCCO1
Agent: [Li]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCCCCC(CCN)OC1CCCCO1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
A solution of 3-(tetrahydro-2H-pyran-2-yloxy)caprylonitrile (4.05 g., 18 millimole) in dry ether (10 ml.) is added dropwise to a stirred suspension of lithium aluminumhydride (0.76 g., 20 millimole) in dry ether (90 ml.) maintained under a nitrogen atmosphere. Upon completing the addition, the reaction mixture is stirred and heated at reflux for 16 hours. After cooling to 25° C., the reaction mixture is treated successively with water (1 ml.) and 5% aqueous sodium hydroxide (3 ml.) added dropwise with caution, affording a fine suspension which is cooled to and maintained at 0°-5° C. for 30 minutes and filtered. In vacuo evaporation of the solvent leaves the title compound as a pale yellow oil (3.95 g., 95%), pmr (CDCl 3) δ 0.88 (3H, t), 2.79 (2H, m) and 4.68 (H, bs).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:68][O:69][C:70]1[CH:83]=[CH:82][C:73]([CH2:74][S:75][CH2:76][C@H:77]([C:79]([OH:81])=[O:80])[NH2:78])=[CH:72][CH:71]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:78][C@@H:77]([C:79]([OH:81])=[O:80])[CH2:76][S:75][CH2:74][C:73]3[CH:72]=[CH:71][C:70]([O:69][CH3:68])=[CH:83][CH:82]=3)=[O:35])=[O:31])=[CH:37][CH:38]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CSC[C@@H](N)C(=O)O)cc1
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1ccc(CSC[C@@H](NC(=O)CNC(=O)COc2ccc([C@@H]3[C@@H](SCC(O)c4ccc(F)cc4)C(=O)N3c3ccc(F)cc3)cc2)C(=O)O)cc1
Temperature: 30 °C
Reaction time: 0.58 h

Procedure:
To a stirred solution of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine, (21.3 mg, 0.039 mmol) in DMF (3 ml) was added N-methylmorpholine (20μl, 0.18 mmol). TBTU (15.1 mg, 0.047 mmol) was added and the mixture was stirred at 30° C. for 35 minutes. S-(4-methoxybenzyl)-D-cysteine (12.8 mg, 0.053 mmol) was added and the mixture was stirred 1 hour at 30° C. and 1.5 hours at ambient temperature. The formation of the ketone of the title compound was confirmed. M/z: 764.11 (M+1) and 762.06 (M−1). Methanol (3 ml) and sodium borohydride (15 mg, 0.40 mmol) were added and the mixture was stirred for 20 minutes. Ammonium acetate (25 mg) was added and the methanol was removed under reduced pressure. The remaining DMF-solution was purified with preparative HPLC on a C8 column, UV 240/260 nm. A gradient from 20 to 47% MeCN in 0.1M NH4OAc was used as eluent. The MeCN was removed from the collected fractions under reduced pressure. The remaining water solution was acidified to pH 1 with KHSO4 (2M) and extracted with DCM. The organic phase was concentrated under reduced pressure and the residue was dissolved in MeCN and water. After lyophilisation, the title compound was obtained as a white solid (10.7 mg, 36%). H-NMR (400 MHz, DMSO-d6): 2-60-2.80 (m, 2H), 2.83-2.97 (m, 2H), 3.63-3.66 (bd, 2H), 3.69 (s, 3H), 3.77-3.81 (bd, 2H), 4.24-4.33 (m, 2H), 4.52 (s, 2H), 4.67-4.76 (m, 1H), 5.03 (d, 0.5H), 5.06 (d, 0.5H), 5.60-5.90 (b, 1H), 6.82 (d, 2H), 6.98 (d, 2H), 7.05-7.25 (m, 8H), 7.30-7.38 (m, 4H), 8.00-8.10 (b, 1H), 8.30 (t, 1H). M/z: 764.07 (M−1).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:20]=[N:21][CH:22]=2)[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[C:6]([C:8]([OH:10])=O)[CH:7]=1.[CH3:23][C:24]1([CH3:32])[O:28][C@@H:27]([CH2:29][O:30][NH2:31])[CH2:26][O:25]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][C:24]1([CH3:32])[O:28][C@@H:27]([CH2:29][O:30][NH:31][C:8]([C:6]2[CH:7]=[C:2]([F:1])[C:3]3[N:4]([CH:20]=[N:21][CH:22]=3)[C:5]=2[NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[O:10])[CH2:26][O:25]1
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: O=C(O)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](CONC(=O)c2cc(F)c3cncn3c2Nc2ccc(I)cc2F)O1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.1 %

Procedure:
8-Fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (235 mg, 0.57 mmol), O-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (92 mg, 0.62 mmol), EDCI (120 mg, 0.62 mmol), HOBt (84 mg, 0.62 mmol) and DIPEA (0.1 mL, 0.62 mmol) were dissolved in DMF (10 mL) and the reaction mixture stirred at room temperature for 72 hours before being concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine (20 mL), dried with MgSO4 and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-10% methanol in DCM) to yield the title compound as a pale yellow solid (298 mg, 97%). LCMS (Method B): RT=3.34 min, [M+H]+=545.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=3[F:34])=[N:14][C:15]=2[O:17][CH2:18][C@H:19]2[CH2:23][O:22]C(C)(C)[O:20]2)[NH:10][N:9]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=3[F:34])=[N:14][C:15]=2[O:17][CH2:18][C@@H:19]([OH:20])[CH2:23][OH:22])[NH:10][N:9]=1
Reactant: CC1(C)OC[C@H](COc2nc(Oc3ccc(F)cc3F)nc3[nH]nc(-c4ccccc4Cl)c23)O1
Agent: Cl
Solvent: C1COCCO1
Product: OC[C@H](O)COc1nc(Oc2ccc(F)cc2F)nc2[nH]nc(-c3ccccc3Cl)c12
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 69.2 %

Procedure:
(S)-3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidine (1.395 g) was taken up in 30 mL dioxane, and 25 mL of 4N HCl was added. The reaction mixture was stirred at room temperature for 25 minutes, and then the reaction mixture was partitioned between water (100 mL) and EtOAc (300 mL). The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was eluted through silica gel with 30% EtOAc in methylene chloride to provide 886.4 mg of (S)-3-[3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-propane-1,2-diol. Mass Spec. M+H=449. Mp.=179.2-181.3° C.
Reaction SMILES: CS[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C@H:10]3[N:21]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH2:20][CH2:19][C@@:16]4([C:17]=2[CH:18]=1)[C@H:11]3[CH2:12][CH2:13][CH2:14][CH2:15]4.S(Cl)([Cl:35])(=O)=O>C(Cl)Cl>[CH2:25]([O:24][C:22]([N:21]1[CH2:20][CH2:19][C@@:16]23[C:17]4[CH:18]=[C:5]([O:4][CH2:3][Cl:35])[CH:6]=[CH:7][C:8]=4[CH2:9][C@@H:10]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][CH2:15]3)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CSCOc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(=O)OCc1ccccc1)CC3
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OCCl)cc13
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (+)[N-(Benzyloxycarbonyl)morphinan-3-yloxy]methyl methyl sulfide (1.78 g, 4.07 mmol) in DCM (40 mL) was added sulfuryl chloride (6.1 mL, 6.11 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. After removal of excess reagent and DCM by rotary evaporation, the product was dried under vacuum to afford (+)-[N-(benzyloxycarbonyl)morphinan-3-yloxy]methyl chloride as a yellow gum. Then, it was added to a stirred suspension of cesium carbonate (1.59 g, 4.88 mmol) and isobutyric acid (0.45 mL, 4.88 mmol) in acetone (20 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was filtered and evaporated under vacuum to provide the crude product, which was further purified by prep reverse-phase HPLC to afford the title compound (0.844 g, 43%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[NH:11][C:10](=[O:18])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:23]1([CH2:22][CH2:21][CH2:20][NH:19][C:14]([C:13]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:9][C:10](=[O:18])[NH:11][C:12]=2[CH3:17])=[O:16])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)NC(=O)N1
Reactant: NCCCN1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC1=C(C(=O)NCCCN2CCCC2)C(c2cccc(Cl)c2)NC(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
218 mg (0.817 mmol) of 4-(3-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 126 mg (0.981 mmol) of 1-(3-aminopropyl)pyrrolidine were dissolved in 10 ml of DMF. 235 mg (1.23 mmol) of WSC hydrochloride was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=50/1 to 10/1) to obtain the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[N:3]=1.Cl.[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[C:22]([NH:28][CH:29]2[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]2)[N:21]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[C:22]([NH:28][CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([C:2]3[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=4[Cl:17])[N:3]=3)[CH2:30]2)[N:21]=1
Reactant: N#Cc1ccc(-c2ccc(Cl)cc2Cl)nc1Cl
Reactant: N#Cc1ccc(NC2CCCNC2)nc1N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N#Cc1ccc(NC2CCCN(c3nc(-c4ccc(Cl)cc4Cl)ccc3C#N)C2)nc1N
Temperature: 120 °C

Procedure:
55 mg (0.19 mmol) of 2-chloro-6-(2,4-dichlorophenyl)pyridine-3-carbonitrile, 60.9 mg (0.23 mmol) of 2-amino-6-(piperidin-3-ylamino)pyridine-3-carbonitrile hydrochloride (Example 11A) and 0.169 ml (0.97 mmol) of N,N-diisopropylethylamine were initially charged in 2 ml of DMSO. The mixture was heated at 120° C. in a microwave for 30 min. The crude product was purified by means of preparative HPLC (method 13). 30 mg (33% of theory) of the product were obtained in solid form.
Reaction SMILES: [CH3:1][C@H:2]([O:9][C:10]([CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=2)[CH2:13]1)=[O:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(N[S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])C=CC=CC=1>ClCCl.C(N(CC)CC)C>[CH3:1][C@H:2]([O:9][C:10]([CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])[CH:18]=2)[CH2:13]1)=[O:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC[C@H](C)OC(=O)C1CCc2cc(O)ccc2C1
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC[C@H](C)OC(=O)C1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution 6-hydroxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (1S)-1-methylheptyl ester (37) (1 equi.), and N-phenyl trifluoromethanesulfonamide (1 equi.) in dichloromethane (10 mL/mmole), triethylamine (1.5 equi.) was added at −78 C. The reaction mixture was stirred at that temperature for 1 h and at room temperature for 24 h, quenched with water, extracted with ethyl acetate:hexane(1:1), washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (5% EtOAc/hexanes) gave 6-trifluoromethanesulfonyloxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (1S)-1-methylheptyl ester (45), as a colorless oil (92%).