Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=2)[CH2:2]1.C1C(=O)N([Cl:21])C(=O)C1>C(#N)C.C(Cl)Cl>[Cl:21][C:12]1[C:7]([O:6][C@H:3]2[CH2:4][CH2:5][O:1][CH2:2]2)=[N:8][C:9]([NH2:13])=[N:10][CH:11]=1
Reactant: Nc1nccc(O[C@H]2CCOC2)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Solvent: ClCCl
Product: Nc1ncc(Cl)c(O[C@H]2CCOC2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of (S)-4-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-amine (intermediate 62, 100 mg, 0.552 mmol) in acetonitrile (4 ml) was treated with NCS (100 mg, 0.749 mmol) and stirred at 25° C. for 24 h. Then, the mixture was heated at 80° C. for 3 h. The resulting solution was cooled to room temperature, diluted with DCM and washed with NaOH (1 M in water) and brine. The org layer was dried over Na2SO4, filtered and concentrated. The crude was purified by normal phase chromatography (12 g gold silica gel cartridge, heptanes/EtOAc 100:0 to 8:92) to give the title compound as a white solid. (UPLC-MS 3) tR 0.64 min; ESI-MS 216.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:21]([Br:22])=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:10]=[N:11][C:12](F)=[CH:13][CH:14]=3)[O:8][C:4]=2[CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1COCC1>[NH2:1][C:2]1[C:21]([Br:22])=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:10]=[N:11][C:12]([O:30][C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)=[CH:13][CH:14]=3)[O:8][C:4]=2[CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)nc2)oc2cc(N)c(Br)cc12
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(Oc3ccc(F)cc3)nc2)oc2cc(N)c(Br)cc12
Temperature: 90 °C
Yield: 59.1 %

Procedure:
To a degassed solution of 6-amino-5-bromo-2-(6-fluoropyridin-3-yl)-N-methylbenzofuran-3-carboxamide (500 mg, 1.41 mmol) and 4-fluorophenol (460 mg, 5.21 mmol) in DMF/THF (1 mL/7 mL) was added K2CO3 (260 mg, 5.62 mmol) under N2. The mixture was heated at 90° C. for 8 h. The reaction mixture was concentrated in vacuo and it was extracted with EtOAc. It was washed with H2O, brine and dried over Na2SO4. After being concentrated, the residue was purified by column chromatography (PE:EA=4:1) to give the product of 6-amino-5-bromo-2-(6-(4-fluorophenoxy)pyridin-3-yl)-N-methylbenzofuran-3-carboxamide (380 mg, yield: 61%). 1H-NMR (CDCl3, 400 MHz) δ 8.61 (d, J=2.4 Hz, 1H), 8.23˜8.25 (m, 1H), 7.74 (s, 1H), 7.02˜7.09 (m, 4H), 6.91 (d, J=8.8 Hz, 1H), 8.85 (d, J=4.8 Hz, 1H), 5.76 (s, 1H), 4.20 (s, 2H), 2.95 (d, J=5.2 Hz, 3H). (M+H)+: 456/458.
Reaction SMILES: [CH2:1]([CH:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]#[N:16])=[CH:12][CH:13]=2)[C:7](=[O:8])[O:6]1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-:18].[K+].[K+].OO>CC(C)=O.O>[CH2:1]([CH:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([NH2:16])=[O:18])=[CH:12][CH:13]=2)[C:7](=[O:8])[O:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1OC(=O)c2cc(C#N)ccc21
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCC1OC(=O)c2cc(C(N)=O)ccc21
Reaction time: 8 h

Procedure:
To a solution of 0.8 g (3.72 mmol) of compound obtained in Example 18 in 100 ml of acetone there is added a solution of 0.55 g of potassium carbonate in 5 ml of water, to which there are added, at 20° C., 14 ml of 30% hydrogen peroxide. The mixture is put aside at room temperature overnight. The solvents are removed in vacuo and the residue is washed with water and crystallised from ethanol, giving the title compound.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[C:12]3=O)[CH2:5][CH2:4][O:3]1.C(O)(C(F)(F)F)=O.[H][H]>C(O)(=O)C.[Pd]>[O:1]=[C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)[CH2:5][CH2:4][O:3]1
Reactant: [H][H]
Reactant: O=C1Nc2ccc(CCN3CCOC3=O)cc2C1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: O=C1Cc2cc(CCN3CCOC3=O)ccc2N1

Procedure:
To a solution of the compound obtained in Step E (7.68 mmoles) in acetic acid (15 ml) there are added TFA (7 ml) and Pd/C 10% (400 mg). The reaction mixture is stirred at 50° C. under 4 bars of hydrogen overnight. The catalyst is filtered off on a bed of Celite and is then washed with acetic acid (20 ml). The filtrate is evaporated to dryness and the residual acetic acid is removed by azeotropic distillation with toluene. The solid obtained is recrystallised from a mixture of EtOH/ethyl ether to yield the title product after drying in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C([Li])CCC.[C:26](=[O:28])=[O:27]>CCCCC>[CH3:1][O:2][C:3]([C:5]1([C:26]([OH:28])=[O:27])[C:13]2[C:8](=[CH:9][C:10]([CH:14]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCc2cc(C3CCCCCC3)ccc21
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCC
Product: COC(=O)C1(C(=O)O)CCc2cc(C3CCCCCC3)ccc21

Procedure:
melting point 140°-141°C (from pentane), from 10 g of 5-cycloheptyl-1-indanecarboxylic acid methyl ester, 12.8 ml of a 2.6 N solution of butyl-lithium and carbon dioxide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].CN(C)C=O.S(Cl)([Cl:18])=O>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([Cl:18])=[O:8]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cncc(Br)c1
Temperature: 25 °C

Procedure:
To a mixture of 5-bromonicotinic acid (10 g) in thionyl chloride (25 mL) was added anhydrous dimethylformamide (DMF) (0.5 mL). The whole was heated to reflux for overnight. After cooling to RT, the excess thionyl chloride was removed under reduced pressure. A white solid (3) (11 g) was obtained, which was used for the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[OH:4].C(N(CC)CC)C.[C:26](Cl)(=[O:29])[CH2:27][CH3:28]>ClCCl>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH2:2][NH:1][C:26](=[O:29])[CH2:27][CH3:28])=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCC(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NCC(O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 112.2 %

Procedure:
The amine from example 24 (24.8 g, 0.10 mol) was dissolved in dichloromethane (700 ml) and to this was added triethylamine (20.86 ml, 0.15 mol). The reaction mixture was stirred and cooled to 0° C., before propionyl chloride (7.12 ml, 0.082 mol) was added dropwise. The reaction mixture was then allowed to warm to room temperature over 16 hours before quenching with 3M HCl (aq) (20 ml) and water (100 ml). The reaction mixture was then extracted with dichloromethane (3×200 ml) and the combined organic layers dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a clear viscous gum (27.5 g, 0.092 mol, 90%). 1H NMR (CDCl3, 400 MHz) δ: 1.10 (t, 3H), 2.19 (q, 2H), 3.32-3.43 (m, 4H), 4.81 (s, 2H), 5.11 (m, 1H), 6.99 (d, 2H), 7.25-7.42 (m, 7H). LRMS: m/z 298 (M-H−).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:4][N:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][N:37]([C:40](=[O:42])[CH3:41])[CH2:36][CH2:35]2)=[CH:30][CH:29]=1>CN(C=O)C.CCOC(C)=O>[CH2:12]([CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:27][C:28]1[CH:29]=[CH:30][C:31]([N:34]3[CH2:35][CH2:36][N:37]([C:40](=[O:42])[CH3:41])[CH2:38][CH2:39]3)=[CH:32][CH:33]=1)=[N:3][CH:4]=2)[CH2:14][CH3:15])[CH3:13]
Reactant: CCC(CC)n1cnc2cnc(Cl)nc21
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(CC)n1cnc2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Temperature: 140 °C
Yield: 24.5 %

Procedure:
To a mixture of 2-chloro-9-(1-ethyl-propyl)-9H-purine (90 mg, 0.4 mmol) and TsOH (1.6 mL, 0.2 M in 1,4-dioxane) in DMF (0.25 mL) is added 1-[4-(4-amino-phenyl)-piperazin-1-yl]-ethanone (105 mg, 0.5 mmol). The reaction mixture is sealed in a microwave reactor and heated at 140° C. for 30 min. The mixture is diluted with EtOAc and washed with NaHCO3 aqueous solution and brine. The organics are dried over Na2SO4, filtered and concentrated. The crude product is purified by preparative HPLC to give 40 mg of 1-(4-{4-[9-(1-ethyl-propyl)-9H-purin-2-ylamino]-phenyl}-piperazin-1-yl)-ethanone.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:26][C:27]([Si](C)(C)C)([F:29])[F:28].Cl>C1COCC1.C(OCC)(=O)C>[F:26][C:27]([F:29])([F:28])[CH:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[OH:7]
Reactant: O=Cc1nccs1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(c1nccs1)C(F)(F)F
Reaction time: 2 h

Procedure:
A solution of 2 g (17.68 mmol) of thiazole-2-carboxaldehyde and 0.88 ml (0.88 mmol) of a 1M solution of tetrabutylammonium fluoride in THF, in 88 ml of THF, is admixed slowly at approximately 0° (ice bath) with 2.7 g (19.44 mmol) of trifluoromethyltrimethylsilane (TMS-CF3). Stirring is continued at ambient temperature for 2 hours. The reaction mixture is admixed with 25 ml of 1N aqueous hydrochloric acid and ethyl acetate. The aqueous phase is separated off and extracted twice with ethyl acetate, and the combined organic phases are washed successively with saturated aqueous sodium bicarbonate solution and than with saturated aqueous sodium chloride solution and are dried over sodium sulphate. Following evaporation of the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]2=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1([OH:15])[CH2:14][CH2:13][NH:12][CH2:11]1.C(OB(O)OC(=O)C)(=O)C.[CH:37]1([N:40]2[C:49]3[C:44](=[CH:45][C:46]([F:53])=[C:47](F)[C:48]=3[O:50][CH3:51])[C:43](=[O:54])[C:42]([C:55]([OH:57])=[O:56])=[CH:41]2)[CH2:39][CH2:38]1.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[C:23]([NH:22][CH2:21][C@@H:19]1[O:18][C:17](=[O:26])[N:16]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]3([OH:15])[CH2:14][CH2:13][N:12]([C:47]4[C:48]([O:50][CH3:51])=[C:49]5[C:44]([C:43](=[O:54])[C:42]([C:55]([OH:57])=[O:56])=[CH:41][N:40]5[CH:37]5[CH2:39][CH2:38]5)=[CH:45][C:46]=4[F:53])[CH2:11]3)=[C:2]([F:1])[CH:3]=2)[CH2:20]1)(=[O:25])[CH3:24]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCNC3)c(F)c2)C(=O)O1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: CC(=O)OB(O)OC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(N2CCC(O)(COc3ccc(N4C[C@H](CNC(C)=O)OC4=O)cc3F)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
In analogy to example 76 with 143 mg N-{(5S)-3-[3-fluoro-4-(3-hydroxy-pyrrolidin-3-ylmethoxy)-phenyl]-2-oxo-oxazolidin-5-yl-methyl}-acetamide (MW: 367.38, 0.39 mmol), 165 mg of 1-cyclo-propyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline-carboxylic acid diacetylborate (MW: 423.137, 0.39 mmol) and 100 mg of ethyl diisopropylamine (MW: 129.25, 0.78 mmol) in 2 ml N-methyl-pyrrolidin-2-one. Yield: 143 mg, 57%. MS: 643.7 (M+H)+, 641.7 (M+H)−, Method ESI+, ESI−.
Reaction SMILES: C12N(C3C=NC4C(=CC=CC=4)N=3)CC1CCNC2.[C@@H:19]12[NH:26][CH2:25][C@@H:24]1[CH2:23][CH2:22][N:21]([C:27]([C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[N:36]1[N:40]=[CH:39][CH:38]=[N:37]1)=[O:28])[CH2:20]2.[NH2:41][C:42]1[N:47]=[C:46](Cl)[CH:45]=[C:44]([CH3:49])[N:43]=1>>[F:35][C:33]1[CH:32]=[CH:31][C:30]([N:36]2[N:40]=[CH:39][CH:38]=[N:37]2)=[C:29]([C:27]([N:21]2[CH2:22][CH2:23][C@@H:24]3[C@@H:19]([N:26]([C:46]4[CH:45]=[C:44]([CH3:49])[N:43]=[C:42]([NH2:41])[N:47]=4)[CH2:25]3)[CH2:20]2)=[O:28])[CH:34]=1
Reactant: O=C(c1cc(F)ccc1-n1nccn1)N1CC[C@H]2CN[C@H]2C1
Reactant: Cc1cc(Cl)nc(N)n1
Agent: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Product: Cc1cc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-n4nccn4)C[C@@H]32)nc(N)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using (1R,6S)-3,8-diazabicyclo[4.2.0]octan-3-yl(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-amino-4-chloro-6-methylpyrimidine. MS (ESI) mass calcd. for C20H21FN8O, 408.4; m/z found, 409.2 [M+H]+.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.Cl.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[NH:27][CH:28]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:29]([OH:31])=[O:30].C1C=CC2N(O)N=NC=2C=1.[N:48]12[CH2:55][CH2:54][CH:51]([CH2:52][CH2:53]1)[C@@H:50](O)[CH2:49]2>C1COCC1>[N:48]12[CH2:55][CH2:54][CH:51]([CH2:52][CH2:53]1)[C@@H:50]([O:30][C:29](=[O:31])[CH:28]([NH:27][C:20]1[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=1[O:18][CH3:17])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:49]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: COc1ccc(OC)c(NC(C(=O)O)c2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COc1ccc(OC)c(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
PS-DCC (715 mg, 0.951 mmol, loading: 1.33 mmol/g) is suspended in dry THF (10 mL). (2,5-Dimethoxy-phenylamino)-phenyl-acetic acid hydrochloride (I54) (154 mg, 0.48 mmol), HOBT (146 mg, 0.95 mmol) and (R)-quinuclidin-3-ol (181 mg, 1.43 mmol) are added and the mixture is shaken at RT overnight. PS-DCC is filtered off and the filtrate is evaporated. The residue is dissolved in EtOAc and washed with sat. NaHCO3, water and brine. The organic layer is dried over Na2SO4, filtered and evaporated to dryness. The crude compound is purified by flash chromatography (DCM/MeOH=95/5) to achieve the title compound as a colorless oil (108 mg, 57% yield, mixture of diastereoisomers).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].CC1(C)C(C)(C)OB([C:30]2[N:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=2)O1.C([O-])([O-])=O.[Na+].[Na+].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.COCCOC>[NH2:36][C:33]1[N:34]=[CH:35][C:30]([C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=2)[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[O:6])=[N:31][CH:32]=1
Reactant: CC1(C)OB(c2cnc(N)cn2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(Br)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: O
Solvent: COCCOC
Product: Nc1cnc(-c2cccc(C(=O)Nc3ccc(OC(F)(F)F)cc3)c2)cn1

Procedure:
3-Bromo-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 3.1, 50 mg, 0.139 mmol), 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazin-2-amine (0.180 mmol), 2 M Na2CO3 (0.104 mL, 0.208 mmol), (Ph3P)4Pd (8 mg, 6.94 μmol), water (0.8 mL) and DME (2.4 mL) were added to a vial, which was sealed and subjected to MW irradiation at 150° C. for 10 min. The RM was filtered through a PL-Thiol MP SPE cartridge (StratoSpheres™, 6 mL) and the cartridge was washed with MeOH (10 mL). The combined filtrates were evaporated to dryness under reduced pressure and the crude product was purified by preparative HPLC to afford the title compound. UPLC-MS (Condition 6) tR=1.84 min, m/z=375.3 [M+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:24]=3[F:33])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].Cl.[NH2:35][OH:36].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20](=[NH:21])[NH:35][OH:36])=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:24]=3[F:33])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3F)c2C#N)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3F)c2C(=N)NO)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
4-[5-Cyano-6-(2-fluoro-4-Methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (0.5 g, 1.04 mmol) was dissolved in the mixture ethanol/water (30 mL/14 mL) and heated to 80° C. Hydroxylamine hydrochloride (7.22 g, 104 mmol) and potassium carbonate (14.5 g, 105 mmol) were slowly added and the mixture kept stirring at 80° C. for 1 h. The crude was filtered and the retrieved solid was thoroughly washed with acetonitrile. The filtrate was concentrated under reduced pressure, yielding a yellow solid residue, which was purified by HPLC to afford Compound A99 (0.51 g, 78%). Exact mass calculated for C21H27FN6O6S 510.17, found 511.2 (MH+).
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[N+:29]([C:32]1[CH:33]=[C:34](O)[CH:35]=[CH:36][CH:37]=1)([O-:31])=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:20][CH:19]([CH3:21])[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@@H:2]([O:1][C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([N+:29]([O-:31])=[O:30])[CH:37]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:12]=1)=[O:22]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](Oc3cccc([N+](=O)[O-])c3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.7 %

Procedure:
A mixture of N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 3-nitrophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (2.80 mg, 40.8% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.76 (dm, 1H), 7.71 (t, 1H, J=1.8 Hz), 7.50-7.40 (m, 2H), 7.40-7.25 (m, 7H), 7.17 (apparent dd, 1H, J=2.4, 8.2), 6.97 (apparent d, 1H, J=7.7 Hz), 5.45 (apparent dd, 1H, J=5.0, 8.1 Hz), 3.45 (m, 2H), 2.89 (m, 2H), 2.53 (apparent sept, partially hidden, 2H, J=8.3 Hz), 2.30-2.10 (m, 6H), 1.92 (m, 2H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 502.3 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23].I[CH2:30][CH2:31][CH2:32][N:33]1[C:37]2[CH:38]=[CH:39][C:40](=O)[CH2:41][C:36]=2[NH:35][C:34]1=[O:43].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:30][CH2:31][CH2:32][N:33]3[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[NH:35][C:34]3=[O:43])[CH2:8][CH2:7]2)[CH:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)c1cccc(CN2CC(c3ccccc3)C3(CCNCC3)C2=O)c1
Reactant: O=C1C=Cc2c([nH]c(=O)n2CCCI)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN2CC(c3ccccc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)c1
Temperature: 65 °C
Reaction time: 16 h
Yield: 62.4 %

Procedure:
A mixture of methyl 3-((1-oxo-4-phenyl-2,8-diazaspiro[4.5]decan-2-yl)methyl)benzoate (500 mg, 1.206 mmol, 1 equiv), 1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one-one (364.4 mg, 1.206 mmol, 1 equiv), and potassium carbonate (500 mg, 3.62 mmol, 3 equiv) in N,N-dimethylformamide was stirred at 65° C. for 16 h. After cooling the reaction mixture, the crude mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified using the Biotage flash chromatography system (SNAP 50 g cartridge, Rf=0.4, gradient—10% methanol in dichloromethane) to afford the title compound as a white solid (416 mg, 62%); 1H NMR (400 MHz, DMSO-d6): δ 0.99 (bs, 1H); 1.57-1.59 (m, 2H); 1.67-1.74 (m, 3H); 1.86 (bs, 1H); 2.22-2.39 (m, 4H); 2.73-2.76 (m, 2H); 3.25-3.27 (m, 1H); 3.59-3.62 (m, 1H); 3.76 (t, 2H, J=6.8 Hz); 3.86 (s, 3H); 4.55 (s, 2H); 6.94-6.95 (m, 3H); 7.09-7.11 (m, 3H); 7.20-7.24 (m, 3H); 7.51-7.58 (m, 2H); 7.88-7.90 (m, 2H); 10.77 (s, 1H); MS for C33H36N4O4 m/z 553.11 (M+H)+.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9]2=[O:18])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:33]2[CH:47]=[CH:46][C:36]([O:37][CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:35][CH:34]=2)O1>O1CCOCC1.O>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:18])[C:8]2=[CH:7][C:5]1[O:6][C:2]([C:33]2[CH:47]=[CH:46][C:36]([O:37][CH2:38][CH2:39][N:40]3[CH2:41][CH2:42][O:43][CH2:44][CH2:45]3)=[CH:35][CH:34]=2)=[CH:3][CH:4]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(Br)o1
Reactant: CC1(C)OB(c2ccc(OCCN3CCOCC3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)o1
Temperature: 120 °C

Procedure:
To 3-((5-bromofuran-2-yl)methylene)-5-chloroindolin-2-one (50 mg, 0.155 mmol) in dioxane/water (5% water) was added Cs2CO3 (152 mg, 0.466 mmol) and 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)morpholine (62 mg, 0.186 mmol). The mixture was degassed with nitrogen for 5 minutes then heated in microwave for 20 minutes at 120° C. The solution was diluted with water and the solid formed was isolated by filtration. The solid was purified by HPLC to yield 5-chloro-3-((5-(4-(2-morpholinoethoxy)phenyl)furan-2-yl)methylene)indolin-2-one. LCMS (M+1=451).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=O.C(=O)(O)O.[NH2:15][C:16]([NH2:18])=[NH:17].O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:17]=[C:16]([NH2:18])[N:15]=[CH:7]2
Reactant: O=Cc1cc(Cl)ccc1F
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1ncc2cc(Cl)ccc2n1
Yield: 50 %

Procedure:
A mixture of 5-chloro-2-fluoro-benzaldehyde (109) (5 g, 31.6 mmol) and guanidine carbonate (7.5 g, 41.1 mmol) was heated at 140° C. in DMA (50 mL) for 3 h. 100 ml water was added and after refrigeration, a solid was isolated by filtration, and dried under vacuum to give the product (110) (2.8 g, 15.8 mmol, 50% yield). ESI-MS (M+1): 180 calc. for C8H6ClN3 179.