Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH:28]=[C:27]([O:32][CH2:33][C:34]#[N:35])[CH:26]=[CH:25]4)=[CH:20][N:21]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:36]=[N+:37]=[N-:38].[Na+].[Cl-].[NH4+].Cl>CN(C=O)C.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][C:34]5[NH:38][N:37]=[N:36][N:35]=5)[CH:28]=4)[CH:23]=3)=[CH:20][N:21]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCOc1ccc2cc(-c3cnc(-c4cn(Cc5ccccc5)c5ccccc45)o3)ccc2c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(Cn2cc(-c3ncc(-c4ccc5cc(OCc6nnn[nH]6)ccc5c4)o3)c3ccccc32)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 89.7 %

Procedure:
A mixture of ({6-[2-(1-benzyl-1H-indol-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)acetonitrile (104 mg, 0.228 mmol), prepared in the previous step, sodium azide (46.4 mg, 0.715 mmol) and ammonium chloride (36.9 mg, 0.69 mmol) in 10 mL of DMF was stirred at 100° C. for 5 h. Following the reaction by MS, starting material remained. Additional sodium azide (48.9 mg, 0.724 mmol) and ammonium chloride (37.6 mg, 0.71 mmol) were added and the reaction stirred at 100° C. for 2 h. This procedure was repeated until the MS showed that the reaction had gone to completion (three additional times). The reaction was acidified with 10 mL of 1N HCl and then diluted with 10 mL of H2O. The solid that formed was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (102 mg, 90%) as a tan solid, mp 244-246° C. Elemental Analysis for C30H22N6O2+0.31 H2O Calc'd: C, 71.48; H, 4.52; N, 16.67. Found: C, 69.55; H, 4.55; N, 16.15.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C([Li])(C)(C)C.[B:19](OCCCC)([O:25]CCCC)[O:20]CCCC>CCOCC>[C:9]([C:8]([C:4]1[CH:3]=[C:2]([B:19]([OH:25])[OH:20])[CH:7]=[CH:6][CH:5]=1)([CH3:13])[CH3:12])([OH:11])=[O:10]
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: CC(C)(C(=O)O)c1cccc(Br)c1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CC(C)(C(=O)O)c1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(3-bromo-phenyl)-2-methyl-propionic acid (2.18 mmol) in anhydrous ether (20 mL) is added tert-butyl lithium (1.7 M in pentane, 5.4 mL, 9.16 mmol) dropwise at −78° C. and this mixture is stirred for 30 minutes treated with tributyl borate (2.34 mL, 8.72 mmol). The reaction mixture is allowed to warm up to room temperature, stirred for 15 hours, diluted with ether, and quenched with 1 M H3PO4. After stirring for 30 minutes the ether layer is separated and extracted three times with 2 N NaOH (20 mL). The combined NaOH extracts are acidified with 6 N HCl to pH=1 and extracted three times with ether (50 mL). The combined organic extracts are washed with brine, dried over sodium sulfate and concentrated to afford 3-(1-carboxy-1-methyl-ethyl)-phenyl boronic acid, which is used without further purification. MS: 209 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].Cl.[CH:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH:8]1[NH2:17])[CH2:14]2.C(N(CC)CC)C>C(OCC)C.C(Cl)Cl>[CH:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH:8]1[NH:17][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:14]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: C=CC(=O)NC1C2CC3CC(C2)CC1C3
Reaction time: 12 h

Procedure:
A solution of acryloyl chloride (4.52 g, 0.05 mole) in ethyl ether (20 ml) was added dropwise to a stirring mixture of 2-adamantylamine hydrochloride (9.35 g, 0.05 mole) and triethylamine (30.65 ml) in methylene chloride (200 ml) and ethyl ether (200 ml) over a 30 minute period. The solution was stirred for 12 hours, the solid filtered and washed with ethyl ether and the filtrate stripped to an oily material which was taken up in ethyl acetate and hexane and allowed to stand overnight. The solid was filtered, the filtrate concentrated and chilled and the product as an orange solid filtered and dried. The structure was confirmed by NMR.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:6]2[N:5]=[C:4]([N:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[C:3]=1Br.[ClH:35]>O1CCOCC1>[Cl:35][C:3]1[C:4]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:5][C:6]2[N:7]([N:8]=[CH:9][C:10]=2[C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:2]=1[NH2:1]
Reactant: Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N)c2Br)CC1
Solvent: C1COCCO1
Product: Nc1c(Cl)c(N2CCNCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-(7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate (0.09 mmol) was charged to a 20 mL scintillation vial. To this vial was added 4N HCl in 1,4-dioxane. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and 6-chloro-5-(piperazin-1-yl)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1[C:7]([C:11]([OH:13])=O)=[CH:8][S:9][CH:10]=1.[Cl-].[CH3:18][O:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([NH3+:30])[CH3:29])=[CH:24][CH:23]=1)=[O:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1[C:7]([C:11]([NH:30][C@H:28]([C:25]2[CH:26]=[CH:27][C:22]([C:20]([O:19][CH3:18])=[O:21])=[CH:23][CH:24]=2)[CH3:29])=[O:13])=[CH:8][S:9][CH:10]=1
Reactant: COC(=O)c1ccc([C@H](C)[NH3+])cc1
Reactant: O=C(O)c1cscc1Cc1cccc(Cl)c1
Agent: [Cl-]
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cscc2Cc2cccc(Cl)c2)cc1

Procedure:
4-(3-Chlorobenzyl)thiophene-3-carboxylic acid from Example 3, Step 3 (380 mg, 1.50 mmol) was reacted with (1S)-1-[4-(methoxycarbonyl)phenyl]ethanaminium chloride from Example 1, Step 9 under conditions similar to Example 1, Step 10. After chromatography on silica gel (EtOAc/hexane 40:60 to 95:5), the desired product was obtained as a white solid.
Reaction SMILES: [CH2:1]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:27]([C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][C:39]=1OS(C(F)(F)F)(=O)=O)[C:33]([O:35][CH3:36])=[O:34])([O-:29])=[O:28].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.O.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>[CH2:1]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:39]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][C:30]=2[N+:27]([O-:29])=[O:28])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(B(O)O)cc1)Cc1ccccc1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
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: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(CCN(Cc3ccccc3)C(=O)OC(C)(C)C)cc2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 71.2 %

Procedure:
To a solution of [4-[2-[benzyl(tert-butoxycarbonyl)amino]ethyl]phenyl]boronic acid (3.1 g) in 1,2-dimethoxyethane (45 ml) were added methyl 3-nitro-4-[[(trifluoromethyl)sulfonyl]oxy]benzoate (3.0 g), tetrakis(triphenylphosphine)palladium (800 mg) and aqueous solution of sodium carbonate (2M, 9.1 ml), and the mixture was stirred at 80° C. for 4 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3/1) to give methyl 4′-[2-[benzyl(tert-butoxycarbonyl)amino]ethyl]-2-nitro-4-biphenylcarboxylate (3.05 g).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH2:15])[CH:6]=1)[CH3:3].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[C:30]([O:34][CH3:35])[CH:29]=2)=[CH:22][N:21]=1)([O-])=O>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:20]2[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]3[CH:33]=[CH:32][N:31]=[C:30]([O:34][CH3:35])[CH:29]=3)=[CH:22][N:21]=2)[CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccnc(CSCCN)c1
Reactant: COc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)ccn1
Solvent: c1ccncc1
Product: COc1cc(Cc2cnc(NCCSCc3cc(CN(C)C)ccn3)[nH]c2=O)ccn1
Yield: 61.9 %

Procedure:
A solution of 2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethylamine (1 g) and 2-nitroamino-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone (1.23 g) was refluxed in pyridine (6 ml) for 10 hours, concentrated in vacuo and chromatographed on silica gel column eluted with ethyl acetate-ethanol-28% W:W aqueous ammonia (by volume 10:15:2). Recrystallisation from acetonitrile:ether (1:5) gave 2-[2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethylamino-5-(2-methoxy-4-pyridylmethyl)-4-pyrimidone (1.21 g) m.p. 65°-74° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1.[CH2:11]([N:14]([CH3:18])[C:15](Cl)=[O:16])[CH:12]=[CH2:13]>>[CH2:11]([N:14]([CH3:18])[C:15]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1)=[O:16])[CH:12]=[CH2:13]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: C=CCN(C)C(=O)Cl
Product: C=CCN(C)C(=O)Nc1cc(C(C)(C)C)on1
Yield: 90.5 %

Procedure:
Using 3-amino-5-t-butylisoxazole and N-allyl-N-methylcarbamoyl chloride, the reaction is effected as in Example 1, whereby 1-allyl-1-methyl-3-(5-t-butyl-3-isoxazolyl)urea is obtained. Yield is 90.5%. Melting point is 90.0° to 91.0° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[C:9]=1[O:10][CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>C(O)C>[CH2:1]([C:8]1[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[C:9]=1[O:10][CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(COc2c(Br)cccc2Cc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(COc2c(Br)cccc2Cc2ccccc2)cc1
Reaction time: 72 h

Procedure:
Methyl 4-(2-benzyl-6-bromophenoxymethyl)benzoate (prepared below) was dissolved in ethanol (50 ml) and THF (15 ml) and treated with a solution of sodium hydroxide (1N, 32 ml). The reaction was stirred for 72 hours, partially evaporated and the residue diluted with water and acidified with ethyl acetate to give a precipitate. The precipitate was recrystallised from ethanol/water to give the title product. MS (CI+): 397(M+H)+Elemental analysis: Calc: 63.5%C, 4.31%H Found: 63.3%C, 4.3%H
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16](=[O:26])[C:17]1[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:18]=1[F:25].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH4+].[OH-]>C1COCC1.O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16](=[O:26])[C:17]1[CH:22]=[C:21]([CH2:23][N:35]2[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]2)[CH:20]=[CH:19][C:18]=1[F:25]
Reactant: O=Cc1ccc(F)c(C(=O)Nc2n[nH]c3ccc(Cc4cc(F)cc(F)c4)cc23)c1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCN(Cc2ccc(F)c(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c2)CC1

Procedure:
N-[5-(3,5-Difluoro-benzyl)-1H-indazol-3-yl]-2-fluoro-5-formyl-benzamide (150 mg, 0.367 mmol) in THF (4 mL), under a nitrogen atmosphere, at room temperature was treated with N-methylpiperazine ((0.039 mL, 0.367 mmol) and then with acetic acid (0.024 mL, 0.422 mmol). After 0.5 hours sodium triacetoxyborohydride was added and the reaction was stirred over night. EtOAc (25 mL) and water (25 mL) were added, pH was adjusted to 11 with concentrated NH4OH. The organic layer was separated and the aqueous layer was extracted twice with EtOAc (2×10 mL). The combines organic extracts were dried over sodium sulphate, evaporated to dryness and purified over silica gel (Eluent: DCM: 7N NH3 in MeOH 96:4) affording 177 mg of title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][N:11]([C:13]2[N:22]=[C:21]3[C:16]([C:17](=[O:32])[C:18]([C:27]([O:29]CC)=[O:28])=[CH:19][N:20]3[CH2:23][CH2:24][C:25]#[N:26])=[CH:15][C:14]=2[F:33])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.CO>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][N:11]([C:13]2[N:22]=[C:21]3[C:16]([C:17](=[O:32])[C:18]([C:27]([OH:29])=[O:28])=[CH:19][N:20]3[CH2:23][CH2:24][C:25]#[N:26])=[CH:15][C:14]=2[F:33])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(N3CC(NC(=O)OC(C)(C)C)C3)c(F)cc2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3CCC#N)C1
Reaction time: 3 h

Procedure:
A suspension of EXAMPLE 20A (0.41 g) in THF (60 mL) and methanol (30 mL) at reflux was treated with 1M LiOH (100 mL), stirred for 3 hours then cooled, concentrated to half volume, acidified with 10% citric acid (90 mL), and filtered.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][O:12][C:13]([CH2:15]P(=O)(OCC(F)(F)F)OCC(F)(F)F)=[O:14].C1OCCOCCOCCOCCOCCOC1.[F:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[N:59]([CH3:60])[N:58]=[CH:57][C:56]=2[CH:61]=O)=[CH:51][CH:50]=1.[Cl-].[NH4+]>O1CCCC1>[F:48][C:49]1[CH:50]=[CH:51][C:52]([C:55]2[N:59]([CH3:60])[N:58]=[CH:57][C:56]=2/[CH:61]=[CH:15]\[C:13]([O:12][CH3:11])=[O:14])=[CH:53][CH:54]=1
Reactant: Cn1ncc(C=O)c1-c1ccc(F)cc1
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)/C=C\c1cnn(C)c1-c1ccc(F)cc1
Reaction time: 8 h
Yield: 88 %

Procedure:
Potassium bis(trimethylsilyl)amide (20% toluene solution, 3.05 g) was added to a mixture of bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)phosphonate (973 mg), 18-crown-6 (4.04 g) and tetrahydrofuran (50 mL) at −78° C. Furthermore, 5-(4-fluorophenyl)-1-methyl-1H-pyrazole-4-carbaldehyde (312 mg) was added and the mixture was stirred overnight while allowing to warm from −78° C. to room temperature. Saturated aqueous ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to give methyl (2Z)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylate as crystals (0.35 g, yield 95%) from a fraction eluted with hexane-ethyl acetate (4:1-1:1, v/v) (recrystallized from ethyl acetate-hexane). melting point: 108-109° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])=[N:6][CH:7]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH:28]=[O:29])=[C:23](B(O)O)[CH:24]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:28]=[O:29])=[C:21]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])=[N:6][CH:7]=2)[CH:20]=1
Reactant: O=Cc1ccc(Cl)cc1B(O)O
Reactant: CCOC(=O)CCNC(=O)c1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C=O)cn1
Temperature: 25 °C

Procedure:
Ethyl 3-(5-bromopicolinamido)propanoate, prepared as in Example 1, (1.5 g, 5.0 mmol), (5-chloro-2-formylphenyl)boronic acid (1.0 g, 5.5 mmol), Pd(dppf)Cl2 (408 mg, 0.5 mmol), and K2CO3 (1.4 g, 10.0 mmol) were dissolved in 1,4-dioxane (20 mL) and water (5 mL) and heated to 80° C. After 3 h the resulting mixture was cooled to room temperature, diluted with EtOAc washed with water and brine, dried (Na2SO4), dry-packed onto silica gel and purified via column chromatography to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([S:12]([NH:15][CH2:16][C:17]2[C:18]([NH:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[C:19]3[CH:27]=[N:26][N:25]([CH2:28][CH3:29])[C:20]3=[N:21][C:22]=2[CH2:23][CH3:24])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:37][CH2:38][C:39]1[CH:40]=[CH:41][C:42]([F:66])=[C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][N:52]3[CH2:57][CH2:56][N:55]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C@@H:54]([CH3:65])[CH2:53]3)[CH:46]=2)[CH:44]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([S:12]([NH:15][CH2:16][C:17]2[C:18]([NH:30][CH:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[C:19]3[CH:27]=[N:26][N:25]([CH2:28][CH3:29])[C:20]3=[N:21][C:22]=2[CH2:23][CH3:24])(=[O:13])=[O:14])=[CH:7][C:3]=1[C:4]([NH:37][CH2:38][C:39]1[CH:40]=[CH:41][C:42]([F:66])=[C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][N:52]3[CH2:57][CH2:56][N:55]([C:58]([O:60][C:61]([CH3:62])([CH3:64])[CH3:63])=[O:59])[C@@H:54]([CH3:65])[CH2:53]3)[CH:46]=2)[CH:44]=1)=[O:5]
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CN)ccc3F)c2)CCN1C(=O)OC(C)(C)C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNS(=O)(=O)c1cc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)c3)c2)c(Cl)cc1F

Procedure:
345(b) The 2-chloro-5-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)sulfonyl]-4-fluorobenzoic acid, was dissolved in 3 mL of DCM with 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (41.3 mg, 0.1 mmol), and then added in HOBt (1.0 eq, 14.0 mg), and EDC (1.0 eq, 19.0 mg). The resultant solution was stirred overnight. The solution was then purified using a Gilson to give 1,1-dimethylethyl (2S)-4-[(5′-{[({2-chloro-5-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)sulfonyl]-4-fluorophenyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate.
Reaction SMILES: [Br:1]Br.[O:3]1[C:7]([C:8]2[C:9]([CH3:26])=[N:10][N:11]3[C:16]4[N:17]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:18][CH2:19][C:15]=4[C:14]([CH3:25])=[N:13][C:12]=23)=[CH:6][C:5]2[CH:27]=[CH:28][CH:29]=[CH:30][C:4]1=2.O>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:6]1[C:5]2[CH:27]=[CH:28][CH:29]=[CH:30][C:4]=2[O:3][C:7]=1[C:8]1[C:9]([CH3:26])=[N:10][N:11]2[C:16]3[N:17]([CH:20]([CH2:21][CH3:22])[CH2:23][CH3:24])[CH2:18][CH2:19][C:15]=3[C:14]([CH3:25])=[N:13][C:12]=12
Reactant: BrBr
Reactant: CCC(CC)N1CCc2c(C)nc3c(-c4cc5ccccc5o4)c(C)nn3c21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(CC)N1CCc2c(C)nc3c(-c4oc5ccccc5c4Br)c(C)nn3c21
Reaction time: 1 h
Yield: 96.7 %

Procedure:
Bromine (1.0 M solution in carbon tetrachloride 0.3 mL, 0.30 mmol) was added to a solution of 3-benzo[b]furan-2-yl-8-(1-ethylpropyl)-2,5-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (50 mg, 0.13 mmol) in N,N-dimethylformamide (0.3 mL) at 0° C., followed by stirring for one hour. Hypo water was added thereto, and the mixture was diluted with ethyl acetate, washed with an aqueous saturated solution of ammonium chloride and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (10% ethyl acetate/hexane), to give the title compound (57 mg) as white crystals.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([O:14][CH2:15][O:16][C@H:17]1[CH2:43][CH2:42][C@@:41]2([CH3:44])[C@@H:19]([C@@H:20]([OH:46])[CH2:21][C@@H:22]3[C@@H:40]2[CH2:39][CH2:38][C@@:37]2([CH3:45])[C@H:23]3[CH2:24][C@@H:25]3[O:30][C@@:29]4([O:36][CH2:35][C@H:33]([CH3:34])[CH2:32][CH2:31]4)[C@@H:27]([CH3:28])[C@@H:26]32)[CH2:18]1)[CH3:13]>ClCCl>[CH2:12]([O:14][CH2:15][O:16][C@H:17]1[CH2:43][CH2:42][C@@:41]2([CH3:44])[C@@H:19]([C:20](=[O:46])[CH2:21][C@@H:22]3[C@@H:40]2[CH2:39][CH2:38][C@@:37]2([CH3:45])[C@H:23]3[CH2:24][C@@H:25]3[O:30][C@@:29]4([O:36][CH2:35][C@H:33]([CH3:34])[CH2:32][CH2:31]4)[C@@H:27]([CH3:28])[C@@H:26]32)[CH2:18]1)[CH3:13]
Reactant: CCOCO[C@H]1CC[C@@]2(C)[C@H](C1)[C@@H](O)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]3[C@H](C[C@@H]12)O[C@]1(CC[C@@H](C)CO1)[C@H]3C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOCO[C@H]1CC[C@@]2(C)[C@H](C1)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]3[C@H](C[C@@H]12)O[C@]1(CC[C@@H](C)CO1)[C@H]3C
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.9 %

Procedure:
Pyridinium chlorochromate (1.98 g, 9.20 mmol) was added to a mixture of (3β,5α,6α,25R)-3-ethoxy methoxy-6-hydroxyspirostane (0.90 g, 1.8 mmol) and celite (8.0 g) in anhydrous dichloromethane at 0° C. The reaction mixture was gradually warmed to ambient temperature over 1 hour and allowed to stir for an additional 5 hours. The reaction mixture was then filtered through a plug of silica gel using ether as the eluent. The combined ether fractions were concentrated in vacuo to afford 0.80 g (91%) of the title compound as a colorless solid. 1H NMR (250 MHz; CDCl3) d 4.75 (m, 2H); 4.4 (m, 1H); 3.6 (q, 2H, J=7.0 Hz); 3.45 (m, 2H); 3.35 (t, 1H, J=11.0 Hz); 2.4-0.6 (m, 40H); 0.9 (d, 3H, J=7.0 Hz); 0.8 (d, 3H, J=7.0 Hz); 0.78 (s, 6H). MS: 489.0 (M+H)+ ; mp 191-1930C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5]1.C1CCN2C(=NCCC2)CC1.CN(C)C=O.[F:39][C:40]1[CH:41]=[C:42]2[C@:49]3([C:53](=[O:54])[NH:52][C:51](=[O:55])[NH:50]3)[CH2:48][C@@H:47]([C:56](Cl)=[O:57])[O:46][C:43]2=[CH:44][CH:45]=1>>[C:11]1([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:7]2[CH2:6][CH2:5][N:4]([CH2:3][CH2:2][NH:1][C:56]([C@@H:47]3[CH2:48][C@@:49]4([C:53](=[O:54])[NH:52][C:51](=[O:55])[NH:50]4)[C:42]4[C:43](=[CH:44][CH:45]=[C:40]([F:39])[CH:41]=4)[O:46]3)=[O:57])[CH2:9][CH2:8]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=C1NC(=O)[C@@]2(C[C@@H](C(=O)Cl)Oc3ccc(F)cc32)N1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1NC(=O)[C@@]2(C[C@@H](C(=O)NCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)Oc3ccc(F)cc32)N1
Temperature: -30 °C
Reaction time: 15 h
Yield: 65.3 %

Procedure:
A mixture of 1-(2-aminoethyl)-4-diphenylmethylpiperazine (10.0 g, 33.9 mmol), 1,8-diazabicyclo[5,4,0]-7-undecene (10.9 g, 71.7 mmol) and N,N-dimethylformamide (90.0 ml, 1.16 mol) was chilled to -30° C. To the mixture was added over 30 minutes a solution of (2S, 4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbonyl chloride (Reference Example 1, 10.0 g, 33.5 mmol) in N,N-dimethylformamide (90.0 ml, 1.16 mol) and the mixture was stirred for 15 hours at temperature of 15°-25° C. After distilling off the solvent, the reaction mixture was chromatographed on silica gel, eluted with CH2Cl2 /MeOH (9/1) and evaporated in vacuo to dryness to give the desired compound (12.2 g, 65.2%) as colorless amorphous substance.