Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([O:12][C:13]1[CH:20]=[CH:19][C:16](/[CH:17]=[C:6]2\[CH2:7][CH2:8][CH2:9][C:10]3[CH:11]=[C:2]([CH3:1])[CH:3]=[N:4][C:5]\2=3)=[CH:15][CH:14]=1)(=[O:23])[CH3:22]
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(/C=C2\CCCc3cc(C)cnc32)cc1

Procedure:
5,6,7,8-Tetrahydro-3-methylquinoline (6.6 g) was dissolved in acetic anhydride (10 ml) and 4-hydroxybenzaldehyde (7.35 g) was added. The mixture was allowed to reflux for 18 hours after which the solvent was removed under reduced pressure. The residue was added to 1M NaOH (300 ml) and the solid extracted with dichloromethane (3×150 ml) and dried (Na2SO4). Solvent was removed under reduced pressure. The solid residue was recrystallised from ethyl acetate to give the title compound (4.5 g). m.p. 119°-122° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:17]1([S:16][C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:15])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Sc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Sc1ccccc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.6 %

Procedure:
To a solution of 4-phenylsulfanylcarbonyl-piperidine-1-carboxylic acid tert-butyl ester (1.11 g, 3.45 mmol) in 10 mL of DCM, was added 2 mL of TFA. The reaction mixture was stirred at ambient temperature for 2.5 hours then solvent was removed by reduced pressure to yield the title product (0.75 g, 3.4 mmol). MS (ESI) m/z 221.8 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.29 min.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1.O>C1COCC1>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][CH:10]([O:12][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)[CH2:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 23 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
0.5 g (2 mmol) of 1-(diphenylmethyl)-3-hydroxyazetidine is added under an argon atmosphere to a suspension of 0.06 g (2.3 mmol) of Na in 20 ml of dry THF. After agitation for one hour at 23° C., a solution of 0.29 g (2.1 mmol) of 4-fluoronitrobenzene in 5 ml of dry THF is added dropwise to the reaction mixture. Agitation is maintained for another 2 hours at 23° C. and the whole is finally poured into 25 ml of water. The product is extracted twice with 25 ml of ethyl acetate, the organic phase is then washed twice with 25 ml of salt water, dried over magnesium sulphate, filtered and concentrated under vacuum. The product is purified on a silica column (eluant: 12% of ethyl acetate in heptane). The pure fractions are evaporated in order to produce a colourless oil with a yield of 40%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:20][O:21][CH2:22][CH2:23][CH2:24]Br>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH2:24][CH2:23][CH2:22][O:21][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCCBr
Reactant: O=Cc1ccc(OCc2ccccc2)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCOc1cc(C=O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 28.8 g of 4-benzyloxy-3-hydroxy-benzaldehyde in 100 ml of dimethyl-formamide is added dropwise to a suspension of 5.54 g of NaH (60% dispersion in mineral oil) in 150 ml of absolute dimethylformamide. The reaction mixture is stirred at room temperature. After 30 minutes, a solution of 29 g of 3-methoxybromopropane in 120 ml of dimethylformamide is added thereto, and the mixture is stirred at room temperature for a further 4 hours and is then concentrated by evaporation under reduced pressure. The residue is partitioned between diethyl ether and water. The combined organic phases are dried over sodium sulfate and concentrated by evaporation, and the residue is purified by FC (100 g of silica gel, dichloromethane), yielding the title compound, which crystallises spontaneously: Rf (dichloromethane/diethyl ether)=0.44.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:10]([NH:13][CH:14]([CH3:16])[CH3:15])([CH3:12])[CH3:11].[CH2:17]=O.Cl>CO.O>[OH:3][CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:2][CH2:17][N:13]([CH:14]([CH3:16])[CH3:15])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)NC(C)C
Reactant: C=O
Reactant: CC(=O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)N(CCC(O)c1ccccc1)C(C)C

Procedure:
20.0 g of acetophenone is reacted with 18.7 g of diisopropylamine and 40 ml of water solution of formaldehyde in presence of 20 ml of conc. HCl in 360 ml of methanol for 2 hours at reflux temperature. After evaporation of most of methanol water and ethylacetate is added. After separation the organic phase was concentrated by evaporation and diluted with methanol. The dissolved compound is reduced with 4.2 g of sodium borohydride to yield 3-hydroxy-N,N-diisopropyl-3-phenylpropan-1-amine which may be converted into N,N-diisopropyl-3-phenylpropyl-2-ene-1-amine by treating with strong alkali.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[O:15]=[C:16]1[C:25]2([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].CO>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:28]3[CH2:27][CH2:26][C:25]4([C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH2:18][CH2:17][C:16]4=[O:15])[CH2:30][CH2:29]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: O=C1CCc2ccccc2C12CCNCC2
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1CCc2ccccc2C12CCN(C[C@H](O)COc1cccc3[nH]ccc13)CC2

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 3,4-dihydro-2-oxospiro[naphthalene-1(2H),4′-piperidine]. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 68% overall yield. FDMS m/e=404 (M+ of free base). α[D]589=−15.81 (c=0.51, methanol)
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5]O.Cl.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][CH:14]([C:16]([OH:18])=[O:17])[NH2:15]>>[ClH:3].[CH3:5][O:17][C:16](=[O:18])[CH:14]([CH2:13][C:9]1[S:8][CH:12]=[CH:11][CH:10]=1)[NH2:15]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: NC(Cc1cccs1)C(=O)O
Agent: Cl
Product: COC(=O)C(N)Cc1cccs1
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
3.78 g (0.0318 mole) of thionyl chloride were added dropwise at -5° C. to 10.2 g (0.318 mole) of methanol. After 5 minutes, 3.3 g (0.0159 mole) of 3-(2-thienyl)-DL-alanine hydrochloride were added gradually to this solution, whilst keeping the temperature at -5° C. The mixture was then stirred for 3 hours at this temperature, and then left standing for 24 hours at room temperature. The reaction product was then condensed by evaporation under reduced pressure, and ethanol was added to the residue. The mixture was then condensed by evaporation under reduced pressure and 3.53 g (yield 100%) of 3-(2-thienyl)-DL-alanine methyl ester hydrochloride melting at 110°-112° C. were obtained as the residue.
Reaction SMILES: [NH2:1][C:2]1[CH2:29][O:28][CH2:27][C:4]2([C:17]3[CH:16]=[C:15]([OH:18])[CH:14]=[C:13]([F:19])[C:12]=3[O:11][C:10]3[C:5]2=[CH:6][C:7]([C:20]2[C:21]([F:26])=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:8][CH:9]=3)[N:3]=1.CN(C=O)C.FC(F)(F)S(O[CH2:41][C:42]([F:45])([CH3:44])[CH3:43])(=O)=O>O>[F:19][C:13]1[C:12]2[O:11][C:10]3[C:5](=[CH:6][C:7]([C:20]4[C:21]([F:26])=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:8][CH:9]=3)[C:4]3([N:3]=[C:2]([NH2:1])[CH2:29][O:28][CH2:27]3)[C:17]=2[CH:16]=[C:15]([O:18][CH2:41][C:42]([F:45])([CH3:44])[CH3:43])[CH:14]=1
Reactant: NC1=NC2(COC1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(O)cc12
Reactant: CC(C)(F)COS(=O)(=O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(F)COc1cc(F)c2c(c1)C1(COCC(N)=N1)c1cc(-c3cccnc3F)ccc1O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
To a solution of 5-amino-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-2′-ol (200 mg, 0.506 mmol) in DMF (2529 μL) cesium carbonate (330 mg, 1.012 mmol), KI (25.2 mg, 0.152 mmol) and 2-fluoro-2-methylpropyl trifluoromethanesulfonate (125 mg, 0.556 mmol) were added sequentially and the resulting mixture was stirred overnight at RT. The mixture was diluted with 5 ml of water and stirred for 5 minutes. The solvents were decanted from a precipitated gummy solid. 10 ml of water was added and the mixture was stirred for 1 hr at RT at which point a fine precipitate formed. The solids were filtered, washed with water and dried on air for 3 hr, then overnight in vacuo to afford racemic 4′-fluoro-2′-(2-fluoro-2-methylpropoxy)-7′-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (175 mg, 73% yield).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[C:8](OC)=[O:9].CO>O>[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[CH2:8][OH:9]
Reactant: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reaction time: 2 h

Procedure:
At room temperature, sodium borohydride (35.7 mg) was suspended in IPE (0.2 ml). Then a solution (0.8 ml) of methyl (2S)-2-(2,3,4-trifluoroanilino)propionate (200 mg, 99.8% ee) in IPE was added to the solution. After adding methanol (137.4 mg), the liquid reaction mixture was stirred for 2 hours. Then water was added to the liquid reaction mixture followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography to thereby give 176 mg (99.8% ee) of the title compound as an oily substance. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 51.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[N:17]1([C:23]2[S:24][CH:25]=[C:26]([C:28]3[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=3)[C:31]#[N:32])[N:27]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:31]([C:30]1[CH:29]=[C:28]([C:26]2[N:27]=[C:23]([N:17]3[CH2:22][CH2:21][N:20]([C:9]([NH:8][C:5]4[O:4][N:3]=[C:2]([CH3:1])[C:6]=4[CH3:7])=[O:16])[CH2:19][CH2:18]3)[S:24][CH:25]=2)[CH:35]=[CH:34][CH:33]=1)#[N:32]
Reactant: N#Cc1cccc(-c2csc(N3CCNCC3)n2)c1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4cccc(C#N)c4)cs3)CC2)c1C
Temperature: 70 °C
Reaction time: 15 h
Yield: 39.6 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (277 mg, 0.964 mmol), 3-(2-piperazin-1-yl-1,3-thiazol-4-yl)benzonitrile (237 mg, 0.877 mmol) and diisopropylethylamine (0.305 ml, 1.75 mmol) in dimethyl sulfoxide (2.9 ml) was stirred at 70° C. for 15 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), and recrystallized from a mixed solvent of hexane and ethyl acetate to give 142 mg (39.6%) of the desired product as a solid.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]=1.[CH:25](OCC)=[O:26]>O1CCCC1>[Cl:16][C:17]1[N:22]=[C:21]([O:23][CH3:24])[C:20]([CH:25]=[O:26])=[CH:19][N:18]=1
Reactant: CCOC=O
Reactant: COc1ccnc(Cl)n1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc(Cl)ncc1C=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 48.3 %

Procedure:
2,2,6,6-Tetramethylpiperidine (2.7 ml, 2.25 g, 16.0 mmol) was added to a solution of n-butyl lithium (n-BuLi) (10 ml, 16.0 mmol, 1.6M in hexanes) in tetrahydrofuran (THF) (100 ml) at -78° C. The solution was allowed to warm to 0° C. and stirred for 45 minutes, cooled to -78° C. and 2-chloro-4-methoxypyrimidine (726 mg, 5.04 mmol) in THF (20 ml) was added dropwise. The solution was then stirred for 1 hour. Then, ethyl formate (0.50 ml, 0.46 g, 6.2 mmol) in THF (20 ml) was added dropwise and the solution was stirred for 1.5 hours. The reaction mixture was quenched with acetic acid (HOAc) (conc.) at -78° C., diluted with water and extracted with ethyl acetate (EtOAc) (3 times). The combined extracts were washed with saturated brine, dried (MgSO4), filtered and concentrated in vacuo to give 1.06 g of crude material. Preparative radial chromatography (SiO2 ; hexane/EtOAc gradient elution) afforded 420 mg (48%) of 2-chloro-4-methoxypyrimidine-5-carboxaldehyde.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:11]1[C:20]2[CH:21]=[CH:22][S:23][C:19]=2[C:18]2[CH:17]=[CH:16][C:15]([C:24]#[N:25])=[CH:14][C:13]=2[N:12]=1.O>CN(C=O)C>[O:7]([C:11]1[C:20]2[CH:21]=[CH:22][S:23][C:19]=2[C:18]2[CH:17]=[CH:16][C:15]([C:24]#[N:25])=[CH:14][C:13]=2[N:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: N#Cc1ccc2c(c1)nc(Cl)c1ccsc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)nc(Oc1ccccc1)c1ccsc12

Procedure:
Phenol (2.0 eq, 85 mg) was dissolved in anhydrous DMF. 60% sodium hydride (2.0 eq, 36 mg) was added and the reaction mixture stirred for a few minutes. 4-chlorothieno[3,2-c]quinoline-7-carbonitrile (1.0 eq, 110 mg) was added to the mixture and the whole reaction was stirred at 100° C. for two days. Water was added and the solid was filtered and dried. 4-phenoxythieno[3,2-c]quinoline-7-carbonitrile was isolated as a solid (114 mg). LCMS (ES)>95% pure, m/z 303 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][S:4]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25]C)=[CH:22][CH:23]=3)[CH:18]=[C:17]([CH3:27])[C:16]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:10][CH:9]=1)(=[O:6])=[O:5].B(Br)(Br)Br.CCOC(C)=O>C(Cl)Cl>[F:35][C:2]([F:1])([F:34])[CH2:3][S:4]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=3)[CH:18]=[C:17]([CH3:27])[C:16]=2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:10][CH:9]=1)(=[O:5])=[O:6]
Reactant: COc1ccc2c(Oc3ccc(NS(=O)(=O)CC(F)(F)F)cc3)c(-c3ccccc3)c(C)cc2c1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc2cc(O)ccc2c(Oc2ccc(NS(=O)(=O)CC(F)(F)F)cc2)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
To a stirring solution of 273 (0.14 g, 0.31 mmol) in CH2Cl2 (6 mL), chilled to −20° C. under N2, was added BBr3 (0.24 g, 0.94 mmol) dropwise, via syringe, over 1 minute. After 90 min at −20° C. the r×n was poured over 50 g ice followed by EtOAc (50 mL). The EtOAC layer was washed with brine (50 mL), dried (Na2SO4) and concentrated to a viscous yellow oil that was purified by column chromatography using a gradient of 100% CH2Cl2 to 1% MeOH: CH2Cl2 to yield a foam. The foam was crystallized from EtOAc/hexanes to yield the title compound 274, as a light yellow solid (72 mg, 55%). 1H NMR (400 MHz, DMSO-d6): δ 2.13 (s, 3H), 4.33 (q, J=9.8 Hz, 2H), 6.57 (d, J=9.0 Hz, 2H), 6.96 (d, J=9.0 Hz, 2H), 6.97 (dd, J1=2.4 Hz, J2=9.1 Hz, 1H), 7.12-7.30 (m, 5H), 7.53 (s, 1H), 7.55 (d, J=9.8 Hz, 1H), 9.40 (s, 1H), 9.84 (s, 1H), 10.06 (s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([O:12][CH2:13][N:14]([CH3:15])[N:8]3[CH:7]=[C:6]([C:16]([OH:18])=O)[C:5]2=[O:19])[CH:11]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>O1CCCC1.CCOCC>[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH:38][C:16]([C:6]2[C:5](=[O:19])[C:4]3[C:9]4=[C:10]([O:12][CH2:13][N:14]([CH3:15])[N:8]4[CH:7]=2)[CH:11]=[C:2]([I:1])[CH:3]=3)=[O:18])=[CH:35][CH:34]=1
Reactant: CN1COc2cc(I)cc3c(=O)c(C(=O)O)cn1c23
Reactant: NCc1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1COc2cc(I)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Temperature: 25 °C
Yield: 57 %

Procedure:
A solution of 9-iodo-3-methyl-7-oxo-2,3-dihydro-7H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxylic acid (Preparation 31, 0.900 g) in tetrahydrofuran (25 mL) is refluxed with 1,1′-carbonyldiimidazole (0.631 g) for 5 h. The reaction mixture is cooled to room temperature and treated with 4-chlorobenzylamine (0.828 g). The reaction mixture is diluted with ether (75 mL), filtered, and the filtrate is concentrated at reduced pressure. The crude product is purified by chromatography, using 75 g of silica gel packed and eluted with EtOAc/CH2Cl2/heptane (1/4/5), to afford a 57% yield of the title compound. Physical characteristics: 1H NMR (DMSO-d6) δ10.15, 8.67, 8.12, 7.75, 7.37, 5.29, 4.54, 2.98; MS (EI) m/z 495 (M+); HRMS (FAB) m/z 495.9935 (C19H15ClIN3O3+H). Anal. Found: C, 45.97; H, 3.14; N, 8.39.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[C:15](OC(=O)C)(=[O:17])[CH3:16].C>CO.CO.ClCCl>[C:15]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7])(=[O:17])[CH3:16]
Reactant: NCCCCCO
Reactant: CC(=O)OC(C)=O
Agent: C
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A solution of 5-amino-1-pentanol (0.650 g, 6.31 mmol) in methanol (15 ml) was cooled to 0° C. and treated with triethylamine (1.62 ml, 11.6 mmol) followed by acetic anhydride (0.891 ml, 9.45 mmol). The reaction mixture was stirred at room temperature overnight. TLC analysis (8% methanol/dichloromethane) then revealed some unreacted material, so additional triethylamine (1.6 ml, 11.6 mmol) and acetic anhydride (0.9 ml, 9.5 mmol) were added at room temperature and the solution was stirred 16 h further. Concentration in vacuo and flash chromatography (7% methanol/dichloromethane) afforded III-20 (1 g, 94% yield) as a pale yellow oil: IR (film) 3300 (s), 3100 (m), 2940 (s), 2870 (m), 1650 (s), 1560 (s), 1439 (m), 1372 (m), 1295 (m), 1220 (w), 1180 (w), 1050 (m), 1010 (w) cm-1 ; 1H NMR (500 MHz, CDCl3) δ6.21 (s, 1 H), 3.62 (t, J=6.4 Hz, 2 H), 3.23 (dd, J=12.9, 7.0 Hz, 2 H), 2.87 (s, 1 H), 1.97 (s, 3 H), 1.60-1.50 (m, 4 H), 1.43-1.37 (m, 2 H); high resolution mass spectrum (Cl, CH4) m/z 146.1164 [(M+H)+ ; calcd for C7H16NO2 : 146.1181].
Reaction SMILES: C(C1C=CC(NC2C(F)=CN=C(NC3C=CC4OC(C(O)=O)CC=4C=3)N=2)=CC=1)(C)(C)C.C([O:34][C:35]([C:37]1[NH:38][C:39]2[C:44]([CH:45]=1)=[CH:43][C:42]([NH:46][C:47]1[N:52]=[C:51]([NH:53][C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([OH:60])[CH:55]=3)[C:50]([F:61])=[CH:49][N:48]=1)=[CH:41][CH:40]=2)=[O:36])C.[Li+].[OH-]>>[C:35]([C:37]1[NH:38][C:39]2[C:44]([CH:45]=1)=[CH:43][C:42]([NH:46][C:47]1[N:52]=[C:51]([NH:53][C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([OH:60])[CH:55]=3)[C:50]([F:61])=[CH:49][N:48]=1)=[CH:41][CH:40]=2)([OH:36])=[O:34]
Reactant: CCOC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2[nH]1
Agent: CC(C)(C)c1ccc(Nc2nc(Nc3ccc4c(c3)CC(C(=O)O)O4)ncc2F)cc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(O)c4)n3)ccc2[nH]1

Procedure:
In a manner similar to the preparation of N4-(4-tert-butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine, N2-(2-ethoxycarbonylindol-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine upon LiOH treatment gave N2-(2-carboxyindol-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.83 (m, 1H), 7.73 (s, 1H), 7.50 (bd, 1H, J=8.7 Hz), 7.30-7.11 (m, 5H), 6.68 (bd, 1H); LCMS: ret. time: 16.50 min.; purity: 97%; MS (m/e): 380 (MH+)
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17]I)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].[OH:25][C:26]1[CH:30]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[O:28][N:27]=1.CN(C=O)C>CCOCC>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][O:25][C:26]2[CH:30]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[O:28][N:27]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCI)CC1
Reactant: COC(=O)c1cc(O)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1cc(OCCCCC2CCN(C(=O)OC(C)(C)C)CC2)no1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.2 %

Procedure:
A mixture of 4-3 (3.0 g, 8.1 mmol), Cs2CO3 (2.6 g, 8.1 mmol), methyl 3-hydroxy-5-isoxazolecarboxylate (Aldrich) (1.2 g, 8.1 mmol), and DMF (20 mL) was stirred at ambient temperature for 20 h. The reaction mixture was diluted with ether and then washed with H2O and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 3% acetone/CH2Cl2) gave 4-4 (2.7 g) as a colorless solid. Rf 0.17 (silica, 3% acetone/CH2Cl2).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13]3[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=3[CH2:11][C:10]=2[CH:26]=1.C(=O)(O)[O-].[Na+].Br[C:33]1[N:38]=[CH:37][CH:36]=[CH:35][N:34]=1>C(O)C>[N:34]1[CH:35]=[CH:36][CH:37]=[N:38][C:33]=1[NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13]3[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=3[CH2:11][C:10]=2[CH:26]=1
Reactant: CCOC(=O)CC1Cc2ccc(OCCCN)cc2Cc2ccccc21
Reactant: Brc1ncccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC1Cc2ccc(OCCCNc3ncccn3)cc2Cc2ccccc21
Yield: 39.4 %

Procedure:
A mixture of ethyl (±)-10,11-dihydro-3-(3-amino-1-propyloxy)-5H-dibenzo[a,d]cycloheptene-10-acetate (0.4 g, 1 mmole), sodium bicarbonate (0.5 g, 6 mmole), 2-bromopyrimidine (0.34 g, 2 mmole) and ethanol (10 mL) was heated at reflux under argon for 18 hr. The solution was then decanted and concentrated. The residue was purified by chromatography on silica gel (0.2-2% MeOH/CH2Cl2) to give the title compound (0.17 g, 34%) as a pale yellow oil: MS (ES) 432.3 (M+H)+.