Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(Cl)Cl.N1C=CC=CC=1.[N:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>O>[N:20]1([C:26]([O:10][C:3]2[C:4]([CH:5]=[O:6])=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=Cc1cccc(F)c1O
Reactant: O=C(Cl)N1CCOCC1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=Cc1cccc(F)c1OC(=O)N1CCOCC1
Yield: 94.1 %

Procedure:
To a 250 mL dry round bottom flask were added 3-fluoro-2-hydroxybenzaldehyde (4.90 g, 35.0 mmol), anhydrous CH2Cl2 (50 mL) and pyridine (3.40 mL, 42.0 mmol). The mixture was stirred in an ice-water bath, then 4-morpholinecarbonyl chloride (4.50 mL, 38.5 mmol) was added. The mixture was stirred at room temperature for 24 hours. Water (80 mL) was added to the reaction mixture. The CH2Cl2 layer was separated, and the aqueous layer was extracted continually with CH2Cl2 (100 mL×2). The combined CH2Cl2 solution was dried over Na2SO4. After removal of the solvent, the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give 2-fluoro-6-formylphenyl morpholine-4-carboxylate (8.34 g) as white solid. Yield: 94%. 1H NMR (CDCl3, 300 MHz): δ=10.06 (s, 1H), 7.58 (dt, J=7.8, 1.5 Hz, 1H), 7.39-7.22 (m, 2H), 3.69 (br, 6H), 3.50 (br, 2H). 13C NMR (CDCl3, 75.5 MHz, mixture of two isomers): δ=187.6, 187.5, 170.5, 156.4, 152.4 (d, J=100.7 Hz), 139.9 (d, J=12.8 Hz), 130.5, 126.5 (d, J=7.3 Hz), 125.2 (d, J=3.1 Hz), 121.7 (d, J=17.4 Hz), 66.1, 45.0, 44.3.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][C:16]=1[O:25][CH3:26])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:26][O:25][C:16]1[CH:17]=[C:18]([C:21]([O:23][CH3:24])=[O:22])[CH:19]=[CH:20][C:15]=1[C:14]#[C:13][CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1
Reactant: COC(=O)c1ccc(C#CC2CCCN2C(=O)OC(C)(C)C)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C#CC2CCCN2)c(OC)c1
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To a stirred solution of 1-(tert-butoxycarbonyl)-2-[2-(2-methoxy-4-methoxycarbonyl phenyl)ethynyl]pyrrolidine (395 mg, 1.1 mmol) in CH2Cl2 (3 mL) was added TFA (3 mL). The resulting mixture was stirred for 1 hr. The mixture was concentrated in vacuo and made basic by the addition of sat. NaHCO3, and extracted with CHCl3. The extract was washed with H2O, dried over MgSO4, and evaporated to give 238 mg (84%) 2-[2-(2-methoxy4-methoxycarbonylphenyl) ethynyl]pyrrolidine as a yellow oil. 1H-NMR (CDCl3) δ 1.81–2.16 (4 H, m), 2.97–3.17 (2 H, m), 3.91 (6 H, s), 4.13–4.15 (1 H, m), 7.41 (1 H, d, J=8.3 Hz), 7.51 (1 H, s), 7.56 (1 H, d, J=8.3 Hz).
Reaction SMILES: OC1C=CC2CCCCN3C=2C=1C(=O)CC3.C[O:18][C:19]1[CH:20]=[C:21]([N:29]([CH3:31])[CH3:30])[C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2>>[OH:18][C:19]1[CH:20]=[C:21]([N:29]([CH3:31])[CH3:30])[C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2
Reactant: COc1cc(N(C)C)c2ccccc2c1
Agent: O=C1CCN2CCCCc3ccc(O)c1c32
Product: CN(C)c1cc(O)cc2ccccc12

Procedure:
The title compound was synthesized in a similar manner as 11-hydroxy-2,3,5,6,7,8-hexahydro-1H-azepino[3,2,1-ij]quinolone starting from 3-methoxy-1-(dimethylamino)naphthalene: 1H NMR (DMSO-d6) δ 9.53 (s, 1H), 7.95 (d, 1H); 7.60 (d, 1H), 7.32 (ddd, 1H), 7.21 (ddd, 1H), 6.75 (d, 1H), 6.64 (d, 1H), 2.77 (s, 6H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12](=[O:13])[CH2:11][CH2:10][C:9](=[O:14])[C:8]2[CH:15]=[CH:16][CH:17]=[CH:18][C:7]1=2.[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:12](=[O:13])[CH2:11][CH2:10][C:9](=[O:14])[C:8]3[CH:15]=[CH:16][CH:17]=[CH:18][C:7]2=3)[CH2:29][CH2:28]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: O=C1CCC(=O)N(CCCCCl)c2ccccc21
Product: O=C1CCC(=O)N(CCCCN2CCN(c3cccc(Cl)c3Cl)CC2)c2ccccc21

Procedure:
Analogously to Example 3b, reaction of 1-(4-chlorobutyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione with 1-(2,3-dichlorophenyl)piperazine afforded the title compound.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=N1.OC1C2N=N[NH:34]C=2C=CC=1.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C.C(C1N=CC([C:57]2[C:69]3[C:68]4[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=4)[N:62]([C:70]4[CH:78]=[CH:77][C:73]([C:74](O)=[O:75])=[C:72]([NH:79][CH2:80][CH2:81][F:82])[CH:71]=4)[C:61]=3[CH:60]=[CH:59][CH:58]=2)=CC=1)#N>CN(C)C=O.O>[C:11]([C:16]1[N:8]=[CH:12][C:13]([C:57]2[C:69]3[C:68]4[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=4)[N:62]([C:70]4[CH:78]=[CH:77][C:73]([C:74]([NH2:34])=[O:75])=[C:72]([NH:79][CH2:80][CH2:81][F:82])[CH:71]=4)[C:61]=3[CH:60]=[CH:59][CH:58]=2)=[CH:14][CH:15]=1)#[N:10]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: N#Cc1ccc(-c2cccc3c2c2ccccc2n3-c2ccc(C(=O)O)c(NCCF)c2)cn1
Reactant: Oc1cccc2[nH]nnc12
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-c2cccc3c2c2ccccc2n3-c2ccc(C(N)=O)c(NCCF)c2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
58 mg of (1H-benzotriazol-1-yloxy)[tris(dimethylamino)]phosphonium hexafluorophosphate (BOP), 18 mg of hydroxybenzotriazole (HOBT), 9 mg of ammonium chloride and 0.07 ml of diisopropylethylamine are successively added to a solution of 40 mg of 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(2-fluoroethyl)amino]benzoic acid in 30 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 2 hours and then diluted with distilled water and extracted with ethyl acetate. The organic phase is subsequently washed with distilled water and a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a mixture of dichloromethane, acetonitrile and methanol (96/2/2 by volume), so as to gve 30 mg of 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(2-fluoroethyl)amino]benzamide in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:31])[C:10]([C@@H:12]1[CH2:17][C@@H:16]([NH:18][S:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:21])=[O:20])[C@H:15]([OH:30])[CH2:14][CH2:13]1)=[O:11].[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>C(#N)C>[CH3:32][S:33]([O:30][C@@H:15]1[CH2:14][CH2:13][C@H:12]([C:10](=[O:11])[N:9]([CH3:8])[CH3:31])[CH2:17][C@H:16]1[NH:18][S:19](=[O:20])(=[O:21])[NH:22][C:23]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:29])(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)C(=O)[C@H]1CC[C@@H](O)[C@H](NS(=O)(=O)NC(=O)OC(C)(C)C)C1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)[C@H]1CC[C@@H](OS(C)(=O)=O)[C@H](NS(=O)(=O)NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Acetonitrile (460 ml) and triethylamine (87.0 ml) were added to a solution of tert-butyl {[(1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl]sulfamoyl}carbamate (138.5 g) in acetonitrile (300 ml), and the obtained solution was then cooled to approximately 0° C. Methanesulfonyl chloride (38.5 ml) was added dropwise to the reaction solution, and the obtained mixture was then stirred for approximately 30 minutes. Thereafter, water (610 ml) was added to the reaction mixture, and the obtained mixture was stirred for approximately 30 minutes. Subsequently, water (930 ml) was added to the reaction mixture, and the obtained mixture was further stirred for approximately 3 hours. Thereafter, the precipitated solid was collected by filtration and was then washed with 27.5% aqueous acetonitrile (300 ml). The obtained solid was dried under reduced pressure to obtain the title compound (138.5 g, yield: 82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]([CH:17]([O:23][CH2:24][CH2:25][C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)[C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[CH:4][CH:3]=1.Cl.[C:33]([O:37][C:38](=[O:45])[C@H:39]([CH2:41][CH2:42][S:43][CH3:44])[NH2:40])([CH3:36])([CH3:35])[CH3:34].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]([CH:17]([O:23][CH2:24][CH2:25][C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)[C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[CH:14]=[CH:13][C:9]=2[C:10]([NH:40][C@@H:39]([CH2:41][CH2:42][S:43][CH3:44])[C:38]([O:37][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:45])=[O:12])=[CH:6][CH:7]=1
Reactant: CSCC[C@H](N)C(=O)OC(C)(C)C
Reactant: Cn1cncc1CCOC(c1ccc(C(=O)O)c(-c2ccc(F)cc2)c1)c1nccs1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CSCC[C@H](NC(=O)c1ccc(C(OCCc2cncn2C)c2nccs2)cc1-c1ccc(F)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(4-fluorophenyl)-4-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxymethyl]benzoic acid (0.44 g, 1.07 mmol) (from Example 65), DMAP (0.62 g, 5.03 mmol), L-methionine tert-butyl ester HCl (0.62 g, 5.03 mmol), EDC (0.39 g, 2.01 mmol) and HOBT (0.138 g, 1.01 mmol) in DMF (25 ml) was stirred at ambient temperature under a nitrogen atmosphere for 16 hours. The reaction was evaporated to dryness, the residue treated with aqueous citric acid (1M, 10 ml) and then extracted with dichloromethane (20 ml). The extracts were washed with saturated brine, dried and applied directly to a silica flash column eluting with dichloromethane/methanol (95:5, 9:1 and 85:15) to give a gum. This was dissolved in ethyl acetate and treated with ethereal 1M HCl (10 ml). The resulting solid was isolated by centrifuging, further washing with diethyl ether and drying under high vacuum to give tert-butyl (2S)-2-{2-(4-fluorophenyl)-4-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxymethyl]benzoylamino}-4-methylsulfanylbutyrate as a white solid, (0.373 g, 59%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[C:4]([CH3:14])[N:3]=1.[CH3:15]S(C)=O.CN>CN(C)C(=O)C.O>[CH3:15][NH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[C:4]([CH3:14])[N:3]=1
Reactant: Cc1nc(N)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CS(C)=O
Agent: CN
Solvent: O
Solvent: CC(=O)N(C)C
Product: CNc1nc(C)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 2-amino-6-methyl-3,5-dinitropyridine (24.9 g, 0.125 mole) and 175 ml dimethylsulfoxide in a 500 ml Parr bottle was added a solution of methylamine (20 g, 0.65 mole) in 75 ml N,N-dimethylacetamide. The reaction was shaken for 6 hours at ambient temperature and then heated 15 hours at 70° C. Upon cooling, the mixture was diluted with water, filtered, washed with methanol-water (1v/1v) and dried. 2-(methylamino)-6-methyl-3,5-dinitropyridine was obtained as a yellow solid (82% yield). Anal. Calcd. for C7H8N4O4 : C, 39.6; H, 3.8; N, 26.4. Found: C, 39.6; H, 3.9; N, 26.3.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10](N)[C:9]2[C:4](=[C:5]3[CH:20]=[CH:19][CH:18]=[CH:17][C:6]3=[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]3=2)[N:3]=1.[NH4+].[OH-:22]>Cl>[NH2:1][C:2]1[NH:11][C:10](=[O:22])[C:9]2[C:4](=[C:5]3[CH:20]=[CH:19][CH:18]=[CH:17][C:6]3=[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]3=2)[N:3]=1
Reactant: [OH-]
Reactant: Nc1nc(N)c2c3ccccc3c3ccccc3c2n1
Agent: Cl
Agent: [NH4+]
Product: Nc1nc2c3ccccc3c3ccccc3c2c(=O)[nH]1
Reaction time: 0.33 h

Procedure:
A suspension of 2,4-diaminodibenzo[f,h]quinazoline (0.20 g, 0.76 mmol) in 1N HCl (150 ml) was stirred at reflux for 24 h, then neutralized with NH4OH, The resulting solid was filtered, washed with water and methanol, then suspended in warm methanol (50 ml) for 20 minutes, filtered and dried at 90° C. under reduced pressure. The solid was nearly dissolved in ethanol (100 ml) and 1N NaOH (~1.5 ml), filtered, and the filtrate neutralized with acetic acid to give a precipitate which was filtered, washed with ethanol, and dried at 90° C. under reduced pressure. The solid was briefly heated to reflux in pivalic anhydride (4 ml), the solution concentrated in vacuo, and the residue subjected to chromatography on silica gel, eluting with methylene chloride containing a small percentage of ethyl acetate. The pivalamide (not characterized) was hydrolyzed in a solution of methanol (9 ml) and 1N NaOH (1 ml) at reflux for 1.5 hours. The solution was neutralized with acetic acid, and the precipitate filtered, washed with methanol and dried at 90° C. under reduced pressure to give 2-aminodibenzo[f,h]quinazolin-4-(3H)-one as a beige solid (0.10 g). 1H NMR (DMSO-d6, 200 MHz) δ: 6.69 (br s, 2H, NH2), 7.47-7.84 (m, 4H, Ar), 8.66-8.80 (m, 2H, Ar), 8.96 (dd, J=8, 1 Hz, 1H, Ar), 9.75-9.83 (m, 1H, Ar), 11.26 (br s, 1H, NH). Mass spectrum (CI-CH4) 262 (M+1, 100%). Anal. Calculated for C16H11N3O: C, 73.55; H, 4.24; N, 16.08. Found: C, 73.52; H, 4.27; N, 16.03.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:33][CH2:34][C:35]2[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=2)(=O)=O)=CC=1>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:33][CH2:34][C:35]3[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH2:15][C:16]([F:17])([F:19])[F:18])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(CC(F)(F)F)CC3
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(CC(F)(F)F)C1
Temperature: 25 °C

Procedure:
To a solution of 8-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.372 mmol) in DMF (2 mL) were added sodium hydride (50 mg, 1.11 mmol) and 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (271.3 mg, 0.932 mmol). The reaction mixture was irradiated in a microwave reactor at 90° C. for 1 h. The reaction mixture was cooled to RT, quenched with water and extracted with EtOAc (3×10 mL). The organic layer was washed with water (2×10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC. 1H NMR (CD3OD, TFA salt) d (ppm): 8.16 (s, 1H), 8.1 (d, 1H), 7.65 (d, 1H), 7.2 (s, 1H), 7.0 (d, 1H), 6.9 (d, 1H), 4.48 (s, 2H), 4.4 (t, 2H), 4.17 (q, 2H), 3.62 (t, 2H), 3.2 (t, 2H), 3.08 (t, 2H), 2.64 (s, 3H), 2.4 (s, 3H).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3].OC/C=C(/C)\CCC=C(C)C>>[CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH:10]=[O:11])[CH3:8])[CH3:3]
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: CC(C)=CCC/C(C)=C\CO
Product: CC(C)=CCCC(C)CC=O

Procedure:
geraniol and nerol: -
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(C(C)C)CC)(C)C.[F:24][C:25]([F:41])([F:40])[C:26]1[CH:30]=[CH:29][N:28]([C:31]2[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=2)[N:27]=1>ClCCl>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:35]([C:34]3[CH:33]=[CH:32][C:31]([N:28]4[CH:29]=[CH:30][C:26]([C:25]([F:41])([F:24])[F:40])=[N:27]4)=[CH:39][CH:38]=3)=[O:36])[CH2:6][C:5]=12
Reactant: O=C(Cl)c1ccc(-n2ccc(C(F)(F)F)n2)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(-n2ccc(C(F)(F)F)n2)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.3 %

Procedure:
To a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine (0.88 g) and diisopropylethylamine (0.66 g) in dichloromethane (50 ml) was added the 4-(3-trifluoromethylpyrazol-1-yl)benzoyl chloride (1.40 g). After stirring at room temperature for 18 hours, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (1.70 g), m.p. 166-167° C.; MS, m/z: 423.3 (M+H)+, 845.4 (2M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.[NH3:18].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: N
Reactant: O=C(O)c1c(O)cccc1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1c(O)cccc1F
Temperature: 0 °C
Reaction time: 20 h
Yield: 51.5 %

Procedure:
2-Fluoro-6-hydoxybenzoic acid (20.0 g, 0.128 mol) and oxalyl chloride (22.3 ml, 0.256 mol) were dissolved in ethyl acetate (300 ml) together with N,N-dimethylformamide (DMF) (2 drops) and the mixture was stirred under an atmosphere of nitrogen for 20 h. The solvent was removed by distillation under reduced pressure leaving the crude acid chloride which was redissolved in ethyl acetate (300 ml) and cooled to 0° C. Concentrated aqueous ammonia (d 0.88, 50 ml) was added dropwise and the mixture was stirred for a further 2 h. The mixture was poured into aqueous sodium bicarbonate solution. The organic phase was separated and the aqueous phase extracted with ethyl acetate (2×200 ml). The combined organic phases were dried (MgSO4) and concentrated leaving the crude compound (10.2 g, 51.5%). Mass spectrum (-ve CI)m /z 154 (M+ -H) .
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15]([C:26]#[C:27][C:28]([OH:31])([CH3:30])[CH3:29])=[CH:16][C:17]=3[C@@:18]32[CH2:24][O:23][C:22]([NH2:25])=[N:21]3)=[CH:9][C:8]=1[F:32])(=O)=O.[N:35]1[CH:40]=[C:39](B(O)O)[CH:38]=[N:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.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>[NH2:25][C:22]1[O:23][CH2:24][C@:18]2([N:21]=1)[C:19]1[CH:20]=[C:7]([C:39]3[CH:40]=[N:35][CH:36]=[N:37][CH:38]=3)[C:8]([F:32])=[CH:9][C:10]=1[O:11][C:12]1[C:17]2=[CH:16][C:15]([C:26]#[C:27][C:28]([CH3:29])([OH:31])[CH3:30])=[CH:14][CH:13]=1
Reactant: CC(C)(O)C#Cc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(OS(=O)(=O)C(F)(F)F)c(F)cc1O2
Reactant: OB(O)c1cncnc1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(O)C#Cc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)c(F)cc1O2
Temperature: 100 °C

Procedure:
A solution of (R)-2-amino-6′-fluoro-2′-(3-hydroxy-3-methylbut-1-ynyl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (0.317 g, 0.633 mmol), pyrimidin-5-ylboronic acid (0.157 g, 1.267 mmol), Pd(PPh3)4 (0.037 g, 0.032 mmol), and potassium carbonate (0.438 g, 3.17 mmol) in 1.5 mL dioxane was treated with 0.5 mL water and was heated to 100° C. overnight. The reaction mixture was cooled to rt and diluted with EtOAc. The layers were separated and the organic layer was dried over MgSO4 filtered and concentrated. Purification of the crude residue by column chromatography [0-80% (9:1:0.1—CH2Cl2:MeOH:NH4OH)/CH2Cl2] gave (R)-4-(2-amino-3′-fluoro-2′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl)-2-methylbut-3-yn-2-ol. MS m/z=431.0 [M+H].
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:12][N:13]2[C:17]3[CH:18]=[C:19]([CH3:23])[C:20]([CH3:22])=[CH:21][C:16]=3[NH:15][C:14]2=[O:24])=[CH:3]1.C([O-])([O-])=O.[K+].[K+].CC(N(C)C)=O.[C:37]([O:44][CH2:45][CH3:46])(=[O:43])/[CH:38]=[CH:39]/[CH2:40][CH2:41][CH3:42]>C(OCC)(=O)C>[CH2:45]([O:44][C:37](=[O:43])[CH2:38][CH:39]([N:15]1[C:16]2[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=2[N:13]([CH2:12][C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][C:6]=3[CH3:11])[N:2]([CH3:1])[CH:3]=2)[C:14]1=[O:24])[CH2:40][CH2:41][CH3:42])[CH3:46]
Reactant: CCC/C=C/C(=O)OCC
Reactant: Cc1cc2[nH]c(=O)n(Cc3cn(C)c4cccc(C)c34)c2cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2cc(C)c(C)cc21
Temperature: 130 °C

Procedure:
A mixture of 1-(1,4-Dimethyl-1H-indol-3-ylmethyl)-5,6-dimethyl-1,3-dihydro-benzimidazol-2-one (0.1 g, 0.31 mmol), K2CO3 (87 mg, 0.63 mmol) and ethyl trans-2-hexenoate (0.45 g, 3.1 mmol) was heated to 130° C. for 20 min in a microwave. Since the starting material was not soluble in ethyl trans-2-hexenoate even after heating, DMA (2 mL) was added to the reaction mixture and heated again at 150° C. for 30 min. Although the un-reacted starting material was present, the reaction mixture was diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting heterogeneous residue was purified by silica gel prep TLC using 4:1 hexanes:ethyl acetate as an eluent to afford 25 mg of the desired product as an oil. LCMS (ESMS): m/z 462.88 (M+H+).
Reaction SMILES: C1(N=C=N)CCCCC1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]([OH:20])=O.[NH2:21][C:22]1[S:23][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:25][N:26]=1>C(Cl)Cl>[CH:27]([C:24]1[S:23][C:22]([NH:21][C:18](=[O:20])[CH2:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[Br:10])=[N:26][CH:25]=1)([CH3:29])[CH3:28]
Reactant: CC(C)c1cnc(N)s1
Reactant: O=C(O)Cc1ccccc1Br
Agent: N=C=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)c1cnc(NC(=O)Cc2ccccc2Br)s1
Reaction time: 0.17 h

Procedure:
To a suspension of resin N-Cyclohexylcarbodiimide N′-methylpolystyrene (0.251 g, 2.39 mmol g, 0.6 mmol), previously washed with DCM (3×5 ml), in DCM (4 ml) at room temperature, 2-bromophenylacetic acid (0.086 g, 0.4 mmol) was added. After 10 min., a solution of 2-amino-5-isopropyl-1,3-thiazole (0.0284 g, 0.2 mmol) in DCM (4 ml) was added. The mixture was shaked for 24 hours at room temperature, the resin filtered and washed with DCM (3×10 ml). The filtrated were combined, washed with water, 5% HCl, water, saturated sodium bicarbonate and water, dried over sodium sulfate and evaporated.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.CC(N(C)C)=O.[C:17]12([CH2:27][NH2:28])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:17]12([CH2:27][NH:28][C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH2:1])[N:7]=3)=[O:10])[CH2:24][CH:23]3[CH2:22][CH:21]([CH2:20][CH:19]([CH2:25]3)[CH2:18]1)[CH2:26]2
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: Nc1cccc(C(=O)O)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Nc1cccc(C(=O)NCC23CC4CC(CC(C4)C2)C3)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 6-aminopyridine-2-carboxylic acid (10 g, 72.4 mmol) in DMF (200 mL) at RT, is sequentially added 25.2 mL of DMA (144.8 mmol), 12 g of 1-admantylmethylamine (72.4 mmol) and 38.4 g of BOP (86.88 mmol). The resulting mixture is stirred at RT for 16 h. The reaction mixture is added to 400 mL of ice/water. Filtration affords the title compound which is used in subsequent reactions without further purification.