Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:38]([C:42]1[N:46]([CH2:47][CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[C:45]2[CH:54]=[CH:55][C:56]([S:58]([N:61]3[CH:65]=[C:64]([C:66](O)=[O:67])[CH:63]=[N:62]3)(=[O:60])=[O:59])=[CH:57][C:44]=2[N:43]=1)([CH3:41])([CH3:40])[CH3:39]>CN(C=O)C>[C:38]([C:42]1[N:46]([CH2:47][CH:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[C:45]2[CH:54]=[CH:55][C:56]([S:58]([N:61]3[CH:65]=[C:64]([C:66]([NH:4][CH2:1][CH2:2][CH3:3])=[O:67])[CH:63]=[N:62]3)(=[O:60])=[O:59])=[CH:57][C:44]=2[N:43]=1)([CH3:39])([CH3:40])[CH3:41]
Reactant: CCCN
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCNC(=O)c1cnn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)c1

Procedure:
Following the same procedure in Example 53, Step A, using n-propylamine (8 mg, 0.13 mmol), HATU (37 mg, 0.09 mmol), DIPEA (0.02 mL, 0.10 mmol) and 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (40 mg, 0.09 mmol) in DMF (5 mL). The crude product was purified by MPLC on silica gel using EtOAc/DCM (1:1) to provide the title compound as a white solid. The product was converted to its TFA salt. Yield: 32 mg (59%); 1H NMR (400 MHz, CD3OD) δ 0.93 (t, J=7.52 Hz, 3 H), 1.43-1.52 (m, 2 H), 1.52-1.62 (m, 4 H), 1.64 (s, 9 H), 2.25-2.37 (m, 1 H), 3.28-3.36 (m, 4 H), 3.91 (dd, J=11.43, 3.22 Hz, 2 H), 4.48 (d, J=7.62 Hz, 2 H), 7.99-8.11 (m, 3 H), 8.39 (d, J=1.37 Hz, 1 H), 8.77 (s, 1 H); MS (ESI) (M+H)+=487.8; Anal. Calcd for C24H33N5O4S+1.7 TFA+1.8H2O: C, 46.10; H, 5.41; N, 9.81. Found: C, 46.15; H, 5.56; N, 9.48.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:15][CH3:16])[CH2:11][CH2:12][CH2:13][OH:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:17][C:18]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:19]=1[CH2:20][NH:21][C:22](=[O:33])OC1C=CC([N+]([O-])=O)=CC=1>C1COCC1>[Si:1]([O:8][CH2:9][C@@H:10]([N:15]([CH3:16])[C:22]([NH:21][CH2:20][C:19]1[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:18]=1[F:17])=[O:33])[CH2:11][CH2:12][CH2:13][OH:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CN[C@@H](CCCO)CO[Si](C)(C)C(C)(C)C
Reactant: O=C(NCc1cccc(F)c1F)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CN(C(=O)NCc1cccc(F)c1F)[C@@H](CCCO)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
To a solution of (S)-5-(tert-butyldimethylsilyloxy)-4-(methylamino)pentan-1-ol (109.2 mmol) in THF (200 mL) was added 4-nitrophenyl 2,3-difluorobenzylcarbamate (43.72 g, 142.0 mmol). The resulting solution was stirred at RT for 1 h. The solvent was removed and the resulting residue was dissolved in EtOAc (800 mL). The organic mixture was washed with NaOH (1 N, 100 mL×3), HCl (0.5 N, 100 mL), NaHCO3 (sat.), and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column using a mixture of EtOAC and hexanes to give (S)-1-(1-(tert-butyldimethylsilyloxy)-5-hydroxypentan-2-yl)-3-(2,3-difluorobenzyl)-1-methylurea (35.1 g, 76%) as a pale yellow oil. LRMS (M+H+) m/z 417.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4](Cl)[N:3]=1.O.C(=O)(O)[O-].[Na+].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>C(COC)OC>[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([C:22]3[CH:23]=[CH:24][C:19]([C:18]([F:29])([F:28])[F:17])=[CH:20][CH:21]=3)[N:3]=2)=[CH:21][CH:20]=1
Reactant: N#Cc1cc(Cl)nc(Cl)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Yield: 30 %

Procedure:
2-6-dichloropyridine-4-carbonitrile 24 (3.7 g, 21.35 mmol) was dissolved in 100 ml of dimethoxyethane. To the solution were added 70 ml of water, sodium bicarbonate (3 equiv., 5.38 g), [4-(trifluoromethyl)phenyl]boronic acid (2.4 equiv., 9.74 g) and the mixture was stirred at rt for 5′. The mixture was degassed and put under argon. A catalytic amount of tetrakispalladium was added and the mixture was heated at 100° C. overnight. The solvents were evaporated off and the residue was dissolved with ethyl acetate, washed with water and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The crude was crystallized from ethyl acetate and petroleum ether to give 28A as a beige solid. (2.5 g, 30% yield)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]([F:18])([F:17])[F:16])[CH:9]=2)[C:5]([CH3:19])=[CH:4][N:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)[CH2:23][CH2:22]1>C(Cl)Cl.CO>[CH3:19][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]([F:18])([F:17])[F:16])[CH:9]=2)=[N:7][C:2]([NH:32][C:31]2[CH:30]=[CH:29][C:28]([CH2:27][N:24]3[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]3)=[CH:34][CH:33]=2)=[N:3][CH:4]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: Cc1cnc(Cl)nc1-c1cccc(OC(F)(F)F)c1
Solvent: CO
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc(CN3CCN(C)CC3)cc2)nc1-c1cccc(OC(F)(F)F)c1
Yield: 79 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-5-methyl-4-(3-(trifluoromethoxy)phenyl)pyrimidine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 79% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.32 (s, 1H), 7.57 (d, 3H, J=8.5 Hz), 7.52 (s, 1H), 7.50 (t, 1H, J=7.9 Hz), 7.29 (d, 1H, J=7.9 Hz), 7.25 (d, 2H, J: not calculated due to overlapping peaks), 3.45 (s, 2H), 2.47 (bs, 8H), 2.28 (s, 3H), 2.26 (s, 3H); MS (ESI): 458.3 [M+H]+, 229.7 [M+2H]2+.
Reaction SMILES: [NH2:1][C:2](=O)[C:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:5])[CH3:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C1(C)C=CC=CC=1>[NH2:1][C:2](=[S:24])[C:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:5])[CH3:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(N)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC(C)(C)C(N)=S
Temperature: 90 °C
Reaction time: 6 h
Yield: 109.9 %

Procedure:
To a mixture of tert-butyl 1-amino-2-methyl-1-oxopropan-2-ylcarbamate (10 g, 49 mmol) in toluene (200 mL) was added Lawesson's reagent (CAN 19172-47-5, 10 g, 25 mmol). The suspension was heated to 90° C. and stirred for 6 h. After evaporation of solvents, the residue was purified by column chromatography (silica gel, 120 g) eluting with 30% ethyl acetate in petroleum ether to yield the title compound (6 g, 56%); MS: m/e 241.2 [M+Na]+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2([OH:27])[C:17]3=[C:18]([Cl:26])[CH:19]=[N:20][C:21]4[CH:22]=[CH:23][C:24](=[O:25])[N:15]([C:16]=43)[CH2:14]2)(=O)=O)=CC=1.[NH:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:26][C:18]1[CH:19]=[N:20][C:21]2[CH:22]=[CH:23][C:24](=[O:25])[N:15]3[CH2:14][C:13]([CH2:12][N:28]4[CH2:29][CH2:30][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[CH2:32][CH2:33]4)([OH:27])[C:17]=1[C:16]=23
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCC2(O)Cn3c(=O)ccc4ncc(Cl)c2c43)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(CC2(O)Cn3c(=O)ccc4ncc(Cl)c2c43)CC1
Yield: 85.7 %

Procedure:
A mixture of [(4R/S)-(3-chloro-4-hydroxy-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl)methyl 4-methylbenzenesulfonate (465 mg, 1.15 mmol), 1,1-dimethylethyl 4-piperidinylcarbamate (218 mg, 1.1 mmol) and sodium carbonate (350 mg, 3.3 mmol) in ethanol (12.5 ml). After 1 day more 1,1-dimethylethyl 4-piperidinylcarbamate (100 mg) was added. After 1 hour the mixture was evaporated and the residue was partitioned between 20% methanol/dichloromethane and water. The organic extract was dried and evaporated. The crude material was chromatographed affording the product (410 mg, 82%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[N:7]=1)[CH2:2][CH:3]=[CH2:4].C(N(CC)CC)C.[C:29](Cl)(=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:31]([O:30][C:29]([N:19]1[CH2:20][CH2:21][N:16]([C:8]2[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH:3]=[CH2:4])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:17][CH2:18]1)=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CCCOc1nc(N2CCNCC2)nc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CCCOc1nc(N2CCN(C(=O)OCc3ccccc3)CC2)nc2ccccc12

Procedure:
To a solution of 4-[(3-buten-1-yl)oxy]-2-(1-piperazinyl)quinazoline (23.3 g) in dry methylene chloride (200 ml) is added triethylamine (22.9 ml) with stirring under ice-cooling, and thereto is further added dropwise a solution of benzyl chlorocarbonate (12.3 ml) in dry methylene chloride (30 ml). The mixture is stirred under ice-cooling for 5 hours. The reaction mixture is diluted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. The solution is evaporated to dryness under reduced pressure, and the residue is purified by medium pressure liquid column chromatography (eluent, chloroform) to give 2-[4-(benzyloxycarbonyl) piperazin-1-yl]-4-[(3-buten-1-yl)oxy]quinazoline (26.7 g) as crystals.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)([OH:10])[C:7]([OH:9])=[O:8].[CH3:21]I.O>C(O)C.C(OCC)C>[Cl:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)([OH:10])[C:7]([O:9][CH3:21])=[O:8]
Reactant: O=C(O)C(O)(c1cccc(Cl)c1)c1cccc(Cl)c1
Reactant: CI
Agent: [Na]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: COC(=O)C(O)(c1cccc(Cl)c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
From 100 ml of ethanol and 1.97 g (0.0855 mol) of sodium, a sodium ethoxide solution is prepared to which 26.6 g (0.0855 mol) of 3,3′-dichlorobenzilic acid in 50 ml of ethanol is added dropwise. The mixture is then stirred for 4 hours at ambient temperature. After the solvent has been distilled off, the residue is dissolved in 150 ml DMF and 24.27 g (0.171 mol) of methyl iodide is added dropwise, then stirred for another 24 hours. While cooling with ice, 300 ml of water and 200 ml of diethylether are added dropwise, the phases are separated, the aqueous phase is extracted with diethylether, then the organic phases are washed with Na2CO3 solution and shaken with water till neutral. After drying over Na2SO4, the mixture is evaporated to dryness. Yield: 22.91 g of yellow oil (82% of theory).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:62])[C:56]4[CH:57]=[N:58][NH:59][C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:62][C:55]2[CH:54]=[C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[C:52]4[C:47]=3[CH:46]=[CH:45][NH:44]4)[CH:61]=[C:60]3[C:56]=2[CH:57]=[N:58][NH:59]3)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: O=C(O)c1cccc(Cl)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.9 %

Procedure:
6-Chloro-2-pyridinecarboxylic acid (available from Fluorochem, 2540 mg, 16.1 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (6130 mg, 16.1 mmol) were dissolved in DMF (40 ml) and DIPEA (8.44 ml) was added. The mixture was stirred at room temperature for 30 mins then 6-(1H-indol-4-yl)-1H-indazol-4-amine (2000 mg, 8.06 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to ˜15 ml which was added to 4×50 g aminopropyl cartridges which had been preconditioned with MeOH. The reaction mixture remained on the cartridges for 3 h before being eluted with MeOH. The fractions were combined and the solvent was removed in vacuo to give a brown oil which was purified by chromatography on silica gel (2×100 g cartridges) eluting with 0-25% MeOH in dichloromethane over 40 mins. Appropriate fractions were combined and the solvent was removed in vacuo to give the title compound (809 mg) as an orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:32]=[C:31]([CH2:33][C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)[C:30](=[O:40])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17]([N:19]5[CH2:24][CH2:23][CH:22]([C:25]([O:27]CC)=[O:26])[CH2:21][CH2:20]5)=[O:18])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:32]=[C:31]([CH2:33][C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)[C:30](=[O:40])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17]([N:19]5[CH2:20][CH2:21][CH:22]([C:25]([OH:27])=[O:26])[CH2:23][CH2:24]5)=[O:18])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CCOC(=O)C1CCN(C(=O)COc2cc3c(=O)c(Cc4cccnc4)cn4c5ccc(Br)cc5c(c2)c34)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCN(C(=O)COc2cc3c(=O)c(Cc4cccnc4)cn4c5ccc(Br)cc5c(c2)c34)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42 %

Procedure:
10-bromo-2-(4-ethoxycarbonyl-1-piperidinocarbonylmethyloxy)-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (250 mg) obtained in Example 45 was suspended in ethanol (30 ml), and to the suspension was added 1 N aqueous solution of sodium hydroxide (8 ml) and the mixture was stirred for 90 minutes at room temperature. After evaporate the solvent under reduced pressure, water and ethyl acetate were added to extract the mixture. The aqueous layer was adjusted to pH 6 by adding 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: methylene chloride/methanol=5:1). The crude purification product was washed with ether and recovered by filtration to obtain the title compound (100 mg, 42%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[C:9]2[N:10]([CH2:17][CH3:18])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[S:7][CH2:6][CH2:5]1.C[OH:20]>C(Cl)Cl>[CH3:1][NH:2][CH2:3][CH:4]1[C:9]2[N:10]([CH2:17][CH3:18])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[S:7](=[O:20])[CH2:6][CH2:5]1
Reactant: CO
Reactant: CCn1c2c(c3ccccc31)SCCC2CNC
Solvent: ClCCl
Product: CCn1c2c(c3ccccc31)S(=O)CCC2CNC
Reaction time: 5 h
Yield: 92.8 %

Procedure:
A solution of 4-methylaminomethyl-5-ethyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole (1.3 g) in methanol (30 ml) is mixed with an aqueous solution (10 ml) of sodium periodide (1.12 g) and kept at room temperature for 5 hours. The precipitate is filtered off and the filtrate is condensed. The residue is dissolved in methylene chloride, washed with water, dried and evaporated to give the title compound (1.28 g) as an oil: Yield 92.8%.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6]([C:8]1([C:11]([O:13]CC)=[O:12])[CH2:10][CH2:9]1)=[O:7])C>CO>[CH3:3][O:5][C:6]([C:8]1([C:11]([OH:13])=[O:12])[CH2:10][CH2:9]1)=[O:7]
Reactant: CCOC(=O)C1(C(=O)OCC)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.9 %

Procedure:
KOH (420 mg, 7.5 mmol) was added to a solution cyclopropane-1,1-dicarboxylic acid diethyl ester (1 g, 6.3 mmol) in methanol (7 mL). The reaction mixture was stirred for 4 hours at ambient temperature then concentrated. The resulting residue was diluted with water, acidified with conc. HCl and the product was extracted with dichloromethane. The dichloromethane layer was dried over sodium sulfate and concentrated under reduced pressure to afford 680 mg (75%) of cyclopropane-1,1-dicarboxylic acid methyl ester. HOBt (764 mg, 5.6 mmol), DMAP (1.72 g, 14.15 mmol) and EDCI.HCl (1.08 g, 5.6 mmol) followed by biphenyl-4-ylamine (957 mg, 5.6 mmol) were added to a stirred solution of cyclopropane-1,1-dicarboxylic acid methyl ester (680 mg, 4.7 mmol) in DMF (7 mL) and the resulting mixture was stirred at ambient temperature overnight. The mixture was then diluted with water and the product was extracted with ethyl acetate. The ethylacetate layer was washed with brine solution and concentrated to afford 1.1 g (79%) of 1-(biphenyl-4-ylcarbamoyl)-cyclopropanecarboxylic acid methyl ester. LiOH.H2O (234 mg, 5.5 mmol) was added to a solution of 1-(biphenyl-4-ylcarbamoyl)-cyclopropanecarboxylic acid methyl ester (1.1 g, 3.7 mmol) in a mixture of methanol (5 mL), THF (11 mL) and H2O (3 mL) and the resulting mixture was stirred for 2 hours at ambient temperature. The reaction mixture was then concentrated and the residue was diluted with water, acidified with conc. HCl. The resulting precipitate was isolated by filtration and dried to afford 340 mg (33%) of 1-(biphenyl-4-ylcarbamoyl)-cyclopropane carboxylic acid.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH:23]1([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[N:37]=[CH:36][C:35]([C:38](OC)=[O:39])=[CH:34][N:33]=3)[CH2:28][CH2:27]2)[CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[CH:23]1([N:26]2[CH2:27][CH2:28][N:29]([C:32]3[N:37]=[CH:36][C:35]([C:38]([NH:22][C:19]4[NH:20][N:21]=[C:17]([CH2:16][CH2:15][C:9]5[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=5)[CH:18]=4)=[O:39])=[CH:34][N:33]=3)[CH2:30][CH2:31]2)[CH2:25][CH2:24]1
Reactant: COC(=O)c1cnc(N2CCN(C3CC3)CC2)nc1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCN(C5CC5)CC4)nc3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 13.6 %

Procedure:
Trimethylaluminium (2M in toluene, 1.92 mL, 3.85 mmol) was added dropwise to a stirred suspension of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (381 mg, 1.54 mmol) and methyl 2-(4-cyclopropylpiperazin-1-yl)pyrimidine-5-carboxylate (404 mg, 1.54 mmol) in toluene (7.7 mL) at 25° C. The resulting solution was stirred at ambient temperature for 18 h and then heated at 60° C. for 2 h. The reaction mixture was quenched with methanol (20 mL) and treated with HCl (2N aqueous solution). The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. The impure material was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (100 mg, 14%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21](/[C:23](=[N:27]/[C@H:28]([CH:33]([CH3:35])[CH3:34])[C:29]([O:31][CH3:32])=[O:30])/[S:24][CH2:25][CH3:26])[O:20][N:19]=2)=[CH:14][CH:13]=1>>[CH2:25]([S:24]/[C:23](=[N:27]\[C@H:28]([CH:33]([CH3:34])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])/[C:21]1[O:20][N:19]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:9]([NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[O:10])=[CH:13][CH:14]=2)[CH:22]=1)[CH3:26]
Reactant: O=C=Nc1ccccc1F
Reactant: CCS/C(=N\[C@@H](C(=O)OC)C(C)C)c1cc(-c2ccc(N)cc2)no1
Product: CCS/C(=N\[C@@H](C(=O)OC)C(C)C)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1
Yield: 76 %

Procedure:
The title compound was prepared according to the procedure as set forth in example 151, except that 1-fluoro-2-isocyanatobenzene was used in place of 1-fluoro-3-isocyanatobenzene and (R,Z)-methyl 2-((3-(4-aminophenyl)isoxazol-5-yl)(ethylthio) methyleneamino)-3-methylbutanoate was used in place of methyl 2-(3-(4-aminophenyl)isoxazole-5-carboxamido)-3-methylbutanoate to yield 76% of the title compound. MS (ESI): m/z 499 (M+H)+; 1HNMR (DMSO-d6, 300 MHz): δ 8.124 (s, 1H), 8.101 (d, 1H), 7.858 (s, 1H), 7.593 (m, 1H), 7.406 (m, 1H), 7.260 (s, 2H), 7.095 (m, 2H), 6.991 (m, 1H), 6.701(d, 1H), 4.583 (d, 1H), 3.843 (s, 3H), 3.075 (m, 2H), 2.450 (s, 1H), 1.331 (t, 3H), 1.076 (d, 6H).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:21][SiH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])([CH:18]=[CH2:19])[O:7][CH:6]1OC(=O)C)(=[O:3])[CH3:2].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.[C:55]([NH:63][C:64]1[N:72]=[CH:71][N:70]=[C:69]2[C:65]=1[NH:66][CH:67]=[N:68]2)(=[O:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>C(#N)C>[C:55]([NH:63][C:64]1[N:72]=[CH:71][N:70]=[C:69]2[C:65]=1[N:66]=[CH:67][N:68]2[CH:6]1[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH:9]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:20]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:21][SiH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])([CH:18]=[CH2:19])[O:7]1)(=[O:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: C=CC1(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(OC(C)=O)C(OC(C)=O)C1OCc1ccccc1
Reactant: O=C(Nc1ncnc2nc[nH]c12)c1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: C=CC1(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(n2cnc3c(NC(=O)c4ccccc4)ncnc32)C(OC(C)=O)C1OCc1ccccc1
Yield: 68 %

Procedure:
A flask was charged with Acetic acid 3-acetoxy-4-benzyloxy-5-(tert-butyl-diphenyl-silanyloxymethyl)-5-vinyl-tetrahydro-furan-2-yl ester, acetonitrile, the trimethylsilyl triflate (TMSOTf). To the reaction was added N6-benzoyl adenine. The reaction was stirred, extracted, and the solvent was evaporated to provide the titled compound in 68% yield.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:26]([C:40]2[CH:45]=[C:44]([O:46][CH2:47][CH3:48])[CH:43]=[C:42]([O:49][CH:50]([CH3:52])[CH3:51])[C:41]=2[F:53])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:38]=[C:37]([CH3:39])[O:36][N:35]=3)=[CH:30][CH:29]=2)[N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[F:54][C:55]([F:66])([F:65])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>CCOC(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>[CH2:47]([O:46][C:44]1[CH:43]=[C:42]([O:49][CH:50]([CH3:52])[CH3:51])[C:41]([F:53])=[C:40]([CH:26]([C:4]2[N:5]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:6]=[C:2]([C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=3[C:55]([F:66])([F:65])[F:54])[N:3]=2)[NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[N:38]=[C:37]([CH3:39])[O:36][N:35]=3)=[CH:32][CH:33]=2)[CH:45]=1)[CH3:48]
Reactant: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
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: CCOC(C)=O
Product: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3ccccc3C(F)(F)F)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
To a degassed mixture of Intermediate 66.3 (48 mg, 0.062 mmol), 2-trifluoromethylphenylboronic acid (18 mg, 0.093 mmol) and Na2CO3 (28 mg, 0.24 mmol) was added Pd(PPh3)4 (36 mg, 0.031 mmol). The mixture was stirred at 150° C. for 5 min in a microwave oven, then was diluted with EtOAc, washed with water and brine, dried (Na2SO4) and concentrated to afford Intermediate 77.1.