Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(COC(=O)[NH:17][CH:18]([C:31]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][N+:39]([O-:41])=[O:40])=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CC#N>[NH2:17][C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:30])[C:31]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][N+:39]([O-:41])=[O:40])=[O:32]
Reactant: CC(C)(C)OC(=O)NCCCCC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCCCCO[N+](=O)[O-]
Solvent: C1CCNCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)OCCCCO[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of S)-4-(nitrooxy)butyl 1-(9H-fluoren-9-yl)-13,13-dimethyl-3,11-dioxo-2,12-dioxa-4,10-diazatetradecane-5-carboxylate (2.52 g, 4.30 mmol) in CH3CN (30 ml), piperidine (2.12 ml, 21.5 mmol) was added in the dark, the reaction was stirred at rt for 25 min. Then the mixture was concentrated to a small volume and diluted with EtOAc (150 ml) and washed with 5% aqueous NaHPO4 (2×70 ml). The organic layer was dried over sodium sulphate and concentrated under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:19][C:20]1[CH:21]=[C:22]([C:26]2[NH:30][N:29]=[N:28][N:27]=2)[CH:23]=[CH:24][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[NH:30][N:29]=[N:28][N:27]=4)[CH:21]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Yield: 18 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, with 3′,4′-dichloro[1,1′-biphenyl]-4-sulfonyl chloride (17.7 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 18% yield (4.1 mg). MS (ESI+) calcd mass for C19H13Cl2N5O2S 445.016701, found 445.016581.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.Cl.[CH3:27][C@H:28]1[O:33][CH2:32][CH2:31][NH:30][C@H:29]1[CH3:34].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:25][CH:23]([F:24])[C:15]1[N:14]([C:4]2[N:3]=[C:2]([N:30]3[CH2:31][CH2:32][O:33][C@@H:28]([CH3:27])[C@H:29]3[CH3:34])[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: C[C@@H]1NCCO[C@@H]1C
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1OCCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)[C@@H]1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
11.8 g (50 mmol) of 2,4-dichloro-6-morpholino-1,3,5-triazine, 8.41 g (50 mmol) of 2-difluoromethyl-benzimidazole and 55.3 g (400 mmol) of anhydrous potassium carbonate added to DMF (250 ml) were stirred at room temperature for 16 hours. The reaction solution was poured into water and the resulting precipitates were washed with DMF and ethanol to obtain 15.7 g (yield: 86%) of 4-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine. (2) 0.36 g (0.98 mmol) of the obtained 4-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine, 0.16 g (1.0 mmol) of cis-2,3-dimethylmorpholine hydrochloride and 0.3 g (2.2 mmol) of anhydrous potassium carbonate added to DMF (10 ml) were stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The separated organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain 0.38 g (yield: 87%) of the titled compound as colorless crystals.
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:20])[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:18]=[O:19])[CH:4]=1.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].O>CS(C)=O>[CH2:22]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([C:5]3[CH:4]=[C:3]([CH3:20])[CH:8]=[CH:7][CH:6]=3)=[CH:17][CH:16]=2)[C:12]([CH:18]=[O:19])=[CH:13]1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCBr
Reactant: Cc1cccc(-c2ccc3[nH]cc(C=O)c3c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCn1cc(C=O)c2cc(-c3cccc(C)c3)ccc21
Reaction time: 3 h
Yield: 62 %

Procedure:
NaH (60% in mineral oil dispersion, 6 mmol, 1.2 equiv.) was added to a stirred solution of aldehyde 8 (5 mmol, 1 equiv.) in anhydrous dimethylsulfoxide (DMSO) at room temperature. After 1 h of stirring at the same temperature, 1-bromooctane was added and the mixture stirred for another 3 h. Distilled water was added to the reaction mixture which was then extracted with CH2Cl2. The organic layer was washed with brine, dried (anhydrous Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography with EtOAc/hexane as eluting solvents as described in Section 5.4.1. Yield: 62%; 1 H NMR (300 MHz, CDCl3): δ 9.98 (s, 1 H), 8.53 (s, 1 H), 7.66 (s, 1 H), 7.57-7.46 (m, 3 H), 7.39-7.29 (m, 2 H), 7.13 (d, J=7.2H, 1 H), 4.1 (t, J=8.7 Hz, 2 H), 2.42 (s, 3 H), 1.86 (t, J=3 H), 1.29-1.24 (m, 10 H), 0.86 (t, J=6.6 Hz, 3 H); 13C NMR (75 MHz, CDCl3): δ 184.8, 143.7, 141.6, 138.9, 135.4, 135.1, 129.1, 128.9, 127.1, 119.3, 119.2, 118.5, 116.8, 111.6, 47.4, 32.7, 31.6, 29.6, 29.0, 26.7, 22.5, 14.0.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17].OS(O)(=O)=O.O>CC(O)=O>[C:1]([C:5]1[CH:10]=[C:9]([N+:16]([O-:18])=[O:17])[C:8]([OH:11])=[C:7]([C:12]([F:13])([F:14])[F:15])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)c1ccc(O)c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc([N+](=O)[O-])c(O)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4-tert-Butyl-2-trifluoromethyl-phenol (70 mg, 0.32 mmol) was dissolved in 3 mL AcOH/1.5 mL water and cooled to 0° C. HNO3 (1.5 mL) and catalytic H2SO4 were added and the reaction was allowed to warm to room temperature. Stirring was continued overnight, after which water was added and the compound was extracted into EtOAc. The organic layer was dried over MgSO4 and concentrated to yield 34 mg of final compound. Calculated mass=263. Observed mass=264
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1)[NH:8][CH2:7][CH2:6]2.[CH3:27][O:28][C:29](=[O:38])[CH:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)Br>>[CH3:27][O:28][C:29](=[O:38])[CH:30]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]1[CH2:15][CH2:16][C:17]1[CH:18]=[N:19][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:21][CH:22]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1cc2c(cc1OC)C(CCc1ccc(C(F)(F)F)nc1)NCC2
Reactant: COC(=O)C(Br)c1ccccc1
Product: COC(=O)C(c1ccccc1)N1CCc2cc(OC)c(OC)cc2C1CCc1ccc(C(F)(F)F)nc1

Procedure:
This compound is prepared by reaction of 6,7-dimethoxy-1-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-1,2,3,4-tetrahydroisoquinoline with α-bromo-phenyl-acetic acid methyl ester.
Reaction SMILES: [CH:1]([C:5]1[CH:6]=[C:7](/[CH:19]=[CH:20]/[C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:8]=[C:9]2[C:14]=1[O:13][C:12](=[O:15])[C:11]([C:16](O)=[O:17])=[CH:10]2)([CH2:3][CH3:4])[CH3:2].S(Cl)(Cl)=O.[CH2:34]([NH:36]CC)[CH3:35]>ClCCl>[CH:1]([C:5]1[CH:6]=[C:7](/[CH:19]=[CH:20]/[C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:8]=[C:9]2[C:14]=1[O:13][C:12](=[O:15])[C:11]([C:16]([NH:36][CH2:34][CH3:35])=[O:17])=[CH:10]2)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1cc(/C=C/C(=O)c2ccc(C)cc2)cc2cc(C(=O)O)c(=O)oc12
Reactant: CCNCC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCNC(=O)c1cc2cc(/C=C/C(=O)c3ccc(C)cc3)cc(C(C)CC)c2oc1=O
Reaction time: 0.75 h

Procedure:
To a suspension of (E)-8-sec-butyl-2-oxo-6-(3-oxo-3-p-tolylprop-1-enyl)-2H-chromene-3-carboxylic acid of the formula (V) (0.5 g, 1.28 mmol) in dichloromethane (20 mL). added thionyl chloride (1.0 mL), was refluxed for 1.5 h. The resulting solution was evaporated to dryness under reduced pressure, and the residue was dispersed in dichloromethane (10 mL). The solvent was eliminated under reduced pressure. Dispersion in dichloromethane and solvent elimination was repeated twice. The residue was dissolved in dichloromethane (15 mL) and added with stirring to a solution of the diethyl amine (0.09 g, 1.28 mmol). After 45 min at room temperature, the solvent was removed by evaporation under reduced pressure and extracted 3-fold with CHCl3 (25 mL). The combined organic layers were dried on Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was chromatographed over silica gel (SiO2, 230-400 flash), eluting with a gradient of 20% ethyl acetate in hexane to 40% ethyl acetate in hexane, which upon concentration provides (E)-8-sec-butyl-N,N-diethyl-2-oxo-6-(3-oxo-3-p-tolylprop-1-enyl)-2H-chromene-3-carboxamide (General Formula VI). (0.37 g, 65% yield). White solid, m. p. 146-147° C.; 1H NMR (CDCl3 300 MHz): δ 7.95, (d, J=8.1 Hz, 2H) 7.82-7.76 (m, 2H), 7.70 (d, J=1.8 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.51 (d, J=15.7 Hz, 1H), 7.33 (d, J=8.0 Hz, 2H), 3.58 (q, J=7.0 Hz, 2H), 3.45-3.41 (m, 1H), 3.33 (q, J=7.1 Hz, 2H), 2.45 (brs, 3H), 1.79-1.72 (m, 2H) 1.34-1.25 (m, 6H), 1.20 (t, J=7.1 Hz, 3H) 0.89 (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz): δ 189.7, 164.3, 157.8, 152.7, 144.0, 142.6, 141.4, 136.7, 135.5, 131.7, 129.8, 129.5, 128.8, 126.7, 126.0, 122.9, 118.7, 43.4, 39.6, 33.5, 29.8, 21.8, 20.6, 14.3, 12.9, 12.1; ESI-MS (m/z): 446 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10]CC2C=CC=CC=2)[C:5]([C:6]#[N:7])=[C:4]([F:18])[CH:3]=1.C(Cl)Cl.B(Br)(Br)Br>O>[Br:1][C:2]1[CH:9]=[C:8]([OH:10])[C:5]([C:6]#[N:7])=[C:4]([F:18])[CH:3]=1
Reactant: N#Cc1c(F)cc(Br)cc1OCc1ccccc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: N#Cc1c(O)cc(Br)cc1F
Temperature: 25 °C
Yield: 80.2 %

Procedure:
To a 500-mL RBF was added 4-bromo-2-fluoro-6-[(phenylmethyl)oxy]benzonitrile (5 g, 16.33 mmol) and CH2Cl2 (100 mL). The flask was cooled in an ice-water bath and BBr3 (49.0 mL, 49.0 mmol) (solution in CH2Cl2) was added dropwise via syringe. The red solution was allowed to warm to room temperature over 1 hour. The solution was poured into water (200 mL) and extracted with EtOAc (3×200 mL). The combined organics were concentrated to a yellow residue. The residue was treated with CH2Cl2, and a precipitate formed which was collected to afford the title compound (2.830 g) as a fine yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 7.03 (t, J=1.4 Hz, 1H), 7.29 (dd, J=9.0, 1.6 Hz, 1H), 12.23 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:20][N:21]([CH3:40])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[NH:29][C:30]3[CH:36]=[C:35]([C:37]([O-])=[O:38])[CH:34]=[CH:33][C:31]=3[N:32]=2)=[CH:24][CH:23]=1>>[CH3:1][N:2]([CH3:19])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:16]=[CH:15][C:13]([NH:14][C:37]([C:35]3[CH:34]=[CH:33][C:31]4[NH:32][C:28]([C:25]5[CH:24]=[CH:23][C:22]([N:21]([CH3:40])[CH3:20])=[CH:27][CH:26]=5)=[N:29][C:30]=4[CH:36]=3)=[O:38])=[CH:12][CH:11]=2)=[O:8])=[CH:17][CH:18]=1
Reactant: CN(C)c1ccc(C(=O)Nc2ccc(N)cc2)cc1
Reactant: CN(C)c1ccc(-c2nc3ccc(C(=O)[O-])cc3[nH]2)cc1
Product: CN(C)c1ccc(C(=O)Nc2ccc(NC(=O)c3ccc4[nH]c(-c5ccc(N(C)C)cc5)nc4c3)cc2)cc1

Procedure:
Compound 443 was prepared from 4-(4-dimethylaminobenzamido)aniline and 2-(4-dimethylaminophenyl)benzimidazole-5-carboxylate by standard conditions. [M+H]+ calcd for C31H30N6O2: 519.24; found: 519.04.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH2:11]1[CH2:16][O:15][CH:14]=[CH:13][CH2:12]1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>ClCCl>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:14]1[CH2:13][CH2:12][CH2:11][CH2:16][O:15]1)[N:6]=[CH:5]2
Reactant: Ic1ccc2[nH]ncc2c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Ic1ccc2c(cnn2C2CCCCO2)c1
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a mixture of 5-iodo-1H-indazole (0.90 g, 3.69 mmol) and DHP (1.57 g, 18.7 mmol) in dry dichloromethane (20 mL), was added PTSA (0.08 g, 0.41 mmol) at room temperature. The resulting mixture was stirred overnight. Upon completion, saturated aqueous NaHCO3 (30 mL) was added slowly into the reaction mixture. The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-5% EtOAc in petroleum ether) affording the title compound (1.0 g). 1H NMR (400 MHz, DMSO-d6): δ 8.21 (s, 1H), 8.08 (s, 1H), 7.67 (dd, 1H), 7.61 (d, 1H), 5.85 (dd, 1H), 3.88-3.85 (m, 1H), 3.78-3.72 (m, 1H), 2.41-2.29 (m, 1H), 2.05-1.95 (m, 2H), 1.77-1.72 (m, 1H), 1.61-1.56 (m, 2H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[C:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[C:22]([O:21][C:19]([N:26]1[CH2:31][CH2:30][N:29]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)[CH2:28][CH2:27]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Oc1cccc2cnccc12)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3cnccc23)CC1

Procedure:
The product from step (a) above (209 mg, 0.75 mmol) and 1-BOC-piperazine (210 mg, 1.1 mmol, Aldrich) was reacted under the conditions of Example 132b to give the title compound as yellow amorphous solid, which was used for the next step. MS (ESI, pos. ion) m/z: 314 (M+1)
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.CCO.Cl.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1>CCO>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:1]2[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:16][CH:17]=1)#[N:22]
Reactant: C1CNCCNC1
Reactant: N#Cc1ccc(CBr)cc1
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(CN2CCCNCC2)cc1

Procedure:
To a solution of homopiperazine (9.2 g, 92 mmol, 2 equiv). in EtOH (115 mL) was added 1 M HCl-EtOH (92 mL) dropwise over 1 h. The suspension was heated to 70° C. for 1 h at which point a homogeneous solution of monohydrochloride salt was obtained. α-Bromo-p-tolunitrile (9.0 g, 46 mnmol, 1 equiv) was added and the reaction mixture was heated to reflux for 5 h. After cooling, the solvent was removed by rotary evaporation and the residue was partitioned between CH2Cl2 (100 mL) and 2N aqueous KOH (100 mL). The aqueous layer was extracted with CH2Cl2 (5×50 mL) and the combined organic phase was washed with saturated aqueous NaCl (1×150 mL) and dried (MgSO4). Chromatography (SiO2, 4×20 cm, 20% CH3OH —5% Et3N—CH2Cl2) afforded the desired monoalkylated material (6.78 g, 10.1 g theoretical, 67%) as an amber oil.
Reaction SMILES: C[C:2]([CH3:16])([O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:9]#[N:10])[C:3]#[CH:4].[F-].[Cs+].Cl.[CH2:20](N(CC)C1C=CC=CC=1)C>>[CH3:15][O:14][C:13]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]2[C:6]=1[O:5][C:2]([CH:3]([CH3:4])[CH3:20])=[CH:16]2
Reactant: CCN(CC)c1ccccc1
Reactant: C#CC(C)(C)Oc1cc(C#N)ccc1OC
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Product: COc1ccc(C#N)c2cc(C(C)C)oc12

Procedure:
5.3 g of 3-(1,1-dimethylprop-2-yn-1-yloxy)-4-methoxybenzonitrile and 5.3 g of cesium fluoride are refluxed for 12 h in 30 ml of N,N-diethylaniline with nitrogen aeration. After cooling, the mixture is stirred into 300 ml of 4 N hydrochloric acid, the resulting emulsion is extracted three times with 5.0 ml of ethyl acetate, and the organic extracts are combined, dried over calcined potassium carbonate and evaporated in vacuo. The residue is chromatographed on silica gel using toluene. After evaporating the corresponding fractions, the title compound is obtained as an oil.
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:11]=[C:12]([NH2:24])[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH3:21].[Cl:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1/[CH:36]=[CH:37]/[C:38](O)=[O:39].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[Cl:9][C:10]1[CH:11]=[C:12]([NH:24][C:38](=[O:39])/[CH:37]=[CH:36]/[C:27]2[CH:28]=[CH:29][C:30]([C:32]([F:34])([F:33])[F:35])=[CH:31][C:26]=2[Cl:25])[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH3:21]
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1Cl
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc(NC(=O)/C=C/c2ccc(C(F)(F)F)cc2Cl)cc1Cl

Procedure:
0.29 mL (2.10 mmol) of triethylamine was added to a solution of 0.28 g (1.00 mmol) of 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine-hydrochloride (intermediate product Z1b), 0.25 g (1.00 mmol) of (E)-3-(2-chloro-4-trifluoromethyl-phenyl)-acrylic acid (Z37b) and 0.34 g (1.05 mmol) of TBTU in 10 mL abs. THF and the mixture was stirred for 1 hour at RT. The reaction mixture was evaporated down i. vac. and the residue was combined with dichloromethane and water. The org. phase was separated off, washed with sat. aqueous sodium bicarbonate solution and water and evaporated down i. vac. The residue was purified by column chromatography (silica gel, gradient dichloromethane/10% conc. aqueous ammonia in MeOH 100:0→5:95).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@:20]([OH:27])([C:24](O)=[O:25])[CH2:19]4)[C:14]([F:28])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:29][CH2:30][N:31](C(C)C)C(C)C.C(N)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@:20]([OH:27])([C:24]([NH:31][CH2:30][CH3:29])=[O:25])[CH2:19]4)[C:14]([F:28])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)[C@]1(O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Agent: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCNC(=O)[C@]1(O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(1S,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-1-hydroxy-cyclohexanecarboxylic acid, 64c, (0.040 g, 0.090 mmol) was dissolved in DMF (3 mL), then iPr2NEt (0.047 mL, 0.271 mmol) and ethanamine (0.135 mL of 2 M solution, 0.271 mmol) was added, followed by HATU (0.080 g, 0.210 mmol). The reaction was stirred at room temperature for another 2 hours. The solution was evaporated and the product was purified by Preparatory HPLC to afford 10 mg of (1S,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-N-ethyl-1-hydroxy-cyclohexanecarboxamide, 779.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[O:3]1.Br[CH2:18][CH2:19][OH:20].C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[C:11]([NH:12][CH2:18][CH2:19][OH:20])[CH:13]=[CH:14][CH:15]=2)[O:5]1
Reactant: OCCBr
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OB(c2cccc(NCCO)c2)OC1(C)C
Temperature: 25 °C
Yield: 29 %

Procedure:
A mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (219 mg, 1.00 mmol), 2-bromoethanol (82.7 μL, 1.10 mmol) and N,N-diisopropylethylamine (261 μL, 1.50 mmol) in toluene (2 mL) was refluxed for 22 hours. After cooling to room temperature, the mixture was concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane=2:1→1:1) to afford desired product (76.3 mg, 29.0%) as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([Br:12])=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[CH:13](O)=[O:14]>>[CH:13]([NH:1][C:2]1[CH:3]=[C:4]([C:8]([Br:12])=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])=[O:14]
Reactant: Cc1cc(Br)c(C(=O)O)cc1N
Reactant: O=CO
Product: Cc1cc(Br)c(C(=O)O)cc1NC=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-Amino-6-bromo-4-methylbenzoic Acid (19) (6.4145 g, 27.88 mmol) in 90% aqueous formic acid (36 mL) is heated to reflux for about 3 hours. The mixture is then cooled to ambient temperature, added to ice water (150 mL) and stirred for about 15 minutes. The solids that form are filtered and dried to provide 3-(Formylamino)-6-bromo-4-methylbenzoic Acid (20):, as a purple-pink solid (5.961 g, 82% Yield).
Reaction SMILES: [N+:1]([CH:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)([O-:3])=[O:2].[CH:9]([CH:11]=[CH2:12])=[O:10].[H-].[Na+]>O1CCCC1>[N+:1]([C:4]1([CH2:12][CH2:11][CH:9]=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]1)([O-:3])=[O:2]
Reactant: C=CC=O
Reactant: O=[N+]([O-])C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=CCCC1([N+](=O)[O-])CCCC1

Procedure:
Condense nitrocyclopentane (prepared from bromocyclopentane and sodium nitrite) and acrolein in tetrahydrofuran in the presence of sodium hydride to obtain 3-(1-nitrocyclopentyl)propionaldehyde. Treat this aldehyde with p-toluenesulfonic acid in methanol and isolate 3-(1-nitrocylopentyl) propionaldehyde dimethyl acetal. Hydrogenate this compound with Raney nickel. Isolate 3-(1-aminocyclopentyl)propionaldehyde dimethylacetal and dissolve in aqueous acetone in the presence of p-toluenesulfonic acid and heat under reflux, followed by addition of toluene and azeotrope the mixture to give 1-azaspiro[4.4]-Δ1 -nonane.
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:17])[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([Cl:16])[CH:10]=2)=O)C.[C:18]1([NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:24].C(=O)(O)[O-].[Na+]>>[N:24]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:25][C:4]=1[C:6]1[C:7](=[O:17])[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([Cl:16])[CH:10]=2
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Product: O=c1[nH]c2cc(Cl)ccc2cc1-c1nc2ccccc2[nH]1
Temperature: 200 °C

Procedure:
A mixture of 9-2 (30 mg, 0.12 mmol, 1 equiv) and 1,2-phenylenediamine (39 mg, 0.36 mmol, 3.0 equiv) in polyphosphoric acid (3 mL) was heated at 200° C. for 3 h. The hot reaction mixture was poured into ice water (20 mL), and the resulting mixture was allowed to stand until all polyphosphoric acid had dissolved. The acidic suspension was neutralized with saturated aqueous sodium bicarbonate solution, then extracted with ethyl acetate (2×50 mL). The organic layer were dried over sodium sulfate and concentrated. The residue was suspended in ethyl ether (50 mL) aided by sonication, and the solids were filtered to afford 3-(benzoimidazol-2-yl)-7-chloro-quinolin-2-one (9-3) as a yellow solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.63 (br s, 1H), 12.53 (br s, 1H), 9.13 (s, 1H), 8.01 (d, 1H, J=8.5 Hz), 7.72 (m, 1H), 7.65 (m, 1H), 7.22 (br s, 1H), 7.35 (dd, 1H, J=8.5, 1.9 Hz), 7.21 (m, 2H); HRMS (electrospray FT/ICR) calculated for C16H11N3O [M+H]+ 296.0585, found 296.0590.