Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C=CC3C(=CC=CC=3)C=2C=CC=1[B:15]([OH:17])[OH:16].Br[C:19]1[C:32]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1>>[C:19]1([B:15]([OH:17])[OH:16])[C:32]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Brc1cccc2c1ccc1ccccc12
Reactant: OB(O)c1ccc2c(ccc3ccccc32)c1
Product: OB(O)c1cccc2c1ccc1ccccc12

Procedure:
Synthesis was performed in the same manner as in the synthesis of phenanthrene-2-boronic acid except that 1-bromophenanthrene was used instead of 2-iodophenanthrene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]23[CH2:16][CH2:15][CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH2:17])=[N:9]3)=[CH:4][C:3]=1[O:18]C.B(Br)(Br)Br>C(Cl)Cl.O>[NH2:17][C:10]1[S:11][CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16][C@:8]2([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([OH:18])[CH:4]=2)[N:9]=1
Reactant: COc1cc([C@]23CCCC2CSC(N)=N3)ccc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: NC1=N[C@@]2(c3ccc(F)c(O)c3)CCCC2CS1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
To a −78° C. solution of (7aS)-7a-(4-fluoro-3-methoxyphenyl)-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-amine (0.717 g, 2.56 mmol) in CH2Cl2 (15 mL) is added boron tribromide 11.20 g, 7.67 mmol). The reaction is warmed to 0° C. and is stirred for 2 hr. The reaction is diluted with water and the pH is adjusted to 7. The aqueous is extracted three times with EtOAc (some MeOH is added to help dissolve some solids during the extraction). The organic layer is dried over Na2SO4 and the solvent is removed under reduced pressure. The crude product is purified with a 10 g SCX column using 4:1 CH2Cl2:MeOH and then 2:1 CH2Cl2:7 N NH3 in MeOH to elute the product and give the title compound (0.56 g, 82%). ES/MS m/e: 267 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:29][N:30]([CH3:41])[CH2:31][CH2:32][NH:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36][CH2:35]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:29][N:30]([CH3:41])[CH2:31][CH2:32][N:33]([C@H:34]1[CH2:35][CH2:36][C@H:37]([CH3:40])[CH2:38][CH2:39]1)[C:6](=[O:8])[CH:5]=[CH:4][C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[Cl:1]
Reactant: O=C(O)C=Cc1ccccc1Cl
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCN(C(=O)C=Cc1ccccc1Cl)[C@H]1CC[C@H](C)CC1

Procedure:
Using 1.1 g of 2-chlorocinnamic acid, 1.4 ml of diethyl chlorophosphate, 1.4 ml of triethylamine, 60 ml of methylene chloride, 1.4 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexyl amine (Example 78), and 0.25 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 81 was carried out. As a result, 1.94 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-2-chlorocinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: C(=O)(O)O.[C:5]1([NH:11][C:12]([NH2:14])=[NH:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CN(C)[CH:17]=[CH:18][C:19]([C:21]1[CH:30]=[CH:29][C:28]2[NH:27][C:26](=[O:31])[C:25]3[NH:32][CH:33]=[CH:34][C:24]=3[C:23]=2[CH:22]=1)=O.[CH2:36]([C:38]([O-:40])=[O:39])[CH3:37]>CC(N(C)C)=O>[O:31]=[C:26]1[C:25]2[NH:32][CH:33]=[CH:34][C:24]=2[C:23]2[CH:22]=[C:21]([C:19]3[CH:18]=[CH:17][N:14]=[C:12]([NH:11][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:13]=3)[CH:30]=[CH:29][C:28]=2[NH:27]1.[CH2:36]([C:38]([O-:40])=[O:39])[CH3:37]
Reactant: N=C(N)Nc1ccccc1
Reactant: CN(C)C=CC(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: CCC(=O)[O-]
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]c2ccc(-c3ccnc(Nc4ccccc4)n3)cc2c2cc[nH]c12
Temperature: 130 °C
Reaction time: 48 h
Yield: 44.1 %

Procedure:
51 mg (0.38 mmol) of phenylguanidine carbonate is added to a suspension of 88 mg (0.25 mmol) of 8-(3-dimethylamino-acryloyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 2 mL of anhydrous dimethylacetamide. The mixture is stirred at 130° C. for 2 days then the solvent is evaporated. The residue is triturated with acetonitrile to give a solid which is collected by filtration then washed with acetonitrile then diisopropyl ether. After drying, 47 mg (44%) of 4-oxo-8-(2-phenylamino-pyrimidin-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a brown solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:49]1[C:57]2[C:52](=[C:53]([C:58]3[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=3)[CH:54]=[CH:55][CH:56]=2)[CH:51]=[CH:50]1>CN(C=O)C>[NH:49]1[C:57]2[C:52](=[C:53]([C:58]3[CH:59]=[C:60]([NH:64][C:22]([C:17]4[C:18](=[O:21])[O:19][C:20]5[C:15]([CH:16]=4)=[CH:14][CH:13]=[CH:12][C:11]=5[OH:10])=[O:24])[CH:61]=[CH:62][CH:63]=3)[CH:54]=[CH:55][CH:56]=2)[CH:51]=[CH:50]1
Reactant: Nc1cccc(-c2cccc3[nH]ccc23)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cccc3[nH]ccc23)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 50.5 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-indol-4-yl)-phenylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.013 g of product in 52% yield: LCMS (ESI) m/z 397 (MH+).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])=[CH:13][C:12]=1[Cl:24])[C:6](=O)[CH2:7][CH3:8])C.[CH3:26][O:27][C:28](=[O:39])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[C:33]([NH2:38])[CH:32]=1>>[CH3:26][O:27][C:28](=[O:39])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[C:33]2[C:32]=1[C:4](=[O:3])[C:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][C:12]=1[Cl:24])=[C:6]([CH2:7][CH3:8])[NH:38]2
Reactant: COC(=O)COc1ccc(F)c(N)c1
Reactant: CCOC(=O)C(Cc1ccc(C(=O)N2CCCC2)cc1Cl)C(=O)CC
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(C(=O)N2CCCC2)cc1Cl

Procedure:
The title compound was prepared by the method of Preparation 65c using 2-[2-chloro-4-(pyrrolidine-1-carbonyl)benzyl]-3-oxopentanoic acid ethyl ester and (3-amino-4-fluorophenoxy)acetic acid methyl ester.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:11][O-:12].[Na+].[CH3:14][OH:15]>>[CH3:11][O:12][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([O:15][CH3:14])[N:5]=[CH:4][N:3]=1
Reactant: CO
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: C[O-]
Agent: [Na+]
Product: COc1ncnc(OC)c1C=O
Yield: 20 %

Procedure:
43.6 g (246 mmol) of 4,6-dichloropyrimidine-5-carboaldehyde was dissolved in 200 ml of methanol, and 120 g (622 mmol) of 28% sodium methoxide was added under cooling with ice and then reacted for 2 hours at room temperature. After completion of the reaction, the solvent was distilled off, and an aqueous citric acid solution was added, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogencarbonate solution, an aqueous citric acid solution, water and an aqueous sodium chloride solution in this order, dried and concentrated, and the obtained crude crystals were washed with isopropyl ether to obtain 8.3 g (yield: 20%) of 4,6-dimethoxypyrimidine-5-carboaldehyde.
Reaction SMILES: C(O[C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C:19]1[CH:18]=[CH:17][C:16](OC2CCCCO2)=[CH:15][C:14]=1[CH2:13][C@H:12]3CCCCCNC)(=O)C.[H-].[Na+].Cl[CH2:40]CCC(SC(CCCCl)CCC(F)(F)C(F)(F)F)CCC(F)(F)C(F)(F)F.[C:68]([O:71][CH2:72][CH3:73])(=[O:70])[CH3:69]>CN(C=O)C>[O:71]1[CH2:72][CH2:73][CH2:40][CH2:69][CH:68]1[O:70][CH2:7][C@:6]12[CH2:22][CH2:21][C@H:20]3[C@@H:11]([CH2:12][CH2:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=43)[C@@H:8]1[CH2:9][CH2:10][CH2:5]2
Reactant: FC(F)(F)C(F)(F)CCC(CCCCl)SC(CCCCl)CCC(F)(F)C(F)(F)F
Reactant: CNCCCCC[C@@H]1Cc2cc(OC3CCCCO3)ccc2[C@H]2CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]12
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(COC3CCCCO3)CCC[C@@H]12
Temperature: 80 °C

Procedure:
A solution of 1.64 g of 17β-acetoxy-7α-(5-methylaminopentyl)-3-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-triene in 25 ml of absolute DMF is stirred with 159 mg of 80% sodium hydride under nitrogen for 2 hours at room temperature. 1.43 g of 3-chloropropyl-4,4,5,5,5-pentafluoropentylsulfide in 7 ml of absolute DnMnF is then added in drops and then stirred for 22 more hours at 80° C. The reaction solution is then diluted with ethyl acetate, washed with water, dried, concentrated by evaporation, and the residue is chromatographed on silica gel. 820 mg of 17β-acetoxy-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)-propylamino]-pentyl}-3-(tetrahydropyran-2-yloxy-estra-1,3,5(10)-triene is obtained as oil.
Reaction SMILES: [CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH2:20])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>ClCCCl.CO>[CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CO
Product: c1ccc(CN[C@H]2CC[C@@H](C(c3ccccc3)c3ccccc3)OC2)cc1
Yield: 86.5 %

Procedure:
Trans-5-amino-2-diphenylmethyl-tetrahydropyran 15 (0.03 g, 0.11 mmol) was reacted with benzaldehyde (0.012 g, 0.11 mmol) in the presence of glacial acetic acid (0.007 g, 0.11 mmol) in 1,2-dichloroethane (20 ml), and NaCNBH3 (0.009 g, 0.14 mmol) in methanol (5 ml) (Procedure D) to give compound 16k (0.034 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:19][CH:20]=3)[C:15](=[O:26])[N:14]2[CH3:27])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:28]=[C:29]1[NH:34][CH2:33][CH2:32][CH2:31][N:30]1[CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:19][CH:20]=3)[C:15](=[O:26])[N:14]2[CH3:27])[CH2:10][CH2:11][N:38]2[CH2:39][CH2:40][CH:35]([N:30]3[CH2:31][CH2:32][CH2:33][NH:34][C:29]3=[O:28])[CH2:36][CH2:37]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1C(=O)c2cc(S(C)(=O)=O)ccc2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C1NCCCN1C1CCNCC1
Product: CN1C(=O)c2cc(S(C)(=O)=O)ccc2C1C(CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 38.7 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(2-methyl-3-oxo-5-methylsulfonyl-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.35 g) was coupled to 4-(2-oxoperhydropyrimidine-1-yl)piperidine (0.15 g) by a method similar to that described in Example 8. The reaction product was not purified by chromatography but converted to the corresponding hydrochloride salt as described in the Example 8 to give the title compound (0.1 g); MS: m/z=593(M+1); NMR: 1.16 (m,5), 2.21 (m,5), 3.65 (m,1), 4.25 (m,1), 5.01 (d,1, J=3.9), 6.73 (m,2), 7.21 (m,1), 8.18 (m,3). Analysis for C28H34Cl2N4O24S.2.0 H2O: Calculated C, 53.14; H, 6.08, N, 8.89; Found: C, 53.58; H, 5.73; N, 8.56.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.P(Br)(Br)[Br:11]>ClCCl>[Br:11][CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1
Reactant: BrP(Br)Br
Reactant: OCc1cccc(O)c1
Solvent: ClCCl
Product: Oc1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer was charged 15 mL of dichloromethane. To the stirred solvent was added 3-hydroxymethyl-phenol (0.5 g, 4.03 mmol). The RM was brought to 0° C. and phosphorous tribromide (1.6 g, 0.56 mL, 6.04 mmol) was added drop wise. After addition, the RM was stirred at RT for 1 h. After 1 h, the RM was diluted with dichloromethane (25 mL) and the organic layer was washed with water (20 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as brown solid. (0.65 g, yield: 86.3%); MS (ESI, 120 eV): m/z=187.0 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 7.10-7.15 (t, 1H), 6.86-6.89 (d, 1H), 6.80 (d, 1H), 6.67-6.71 (m, 1H), 4.35-4.36 (d, 2H), 3.80-3.94 (bro s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:20])=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:13]([OH:20])=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:11]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(-c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1cc(-c2ccc(N)cc2)cc(C(C)(C)C)c1O
Yield: 105.3 %

Procedure:
A mixture of 5.0 g (15 mmol) of 4-(4'-nitrophenyl)-2,6-di-tert-butylphenol, 0.5 g of 5% palladium on carbon, and 250 mL of absolute ethanol was hydrogenated for one hour under 50 psig of hydrogen, filtered, and concentrated to give 4.7 g (quantitative yield) of 4-(4'-aminophenyl)-2,6-di-tert-butylphenol as a foam: 1H NMR (CDCl3) 1.48 (s, 18H), 3.25 (broad s, 2H), 5.20 (broad s, 1H), 6.67 (d, 2H, J=9 Hz), 7.36 (s, 2H), 7.36 (d, 2H, J=9 Hz). This compound may also be named 3,5-bis(1,1-dimethylethyl)-4'-amino-(1,1'-biphenyl)-4-ol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[C:6]([CH:18]=1)[C:7]([NH:9][CH2:10][C:11]1[NH:16][C:15](=[O:17])[CH:14]=[CH:13][CH:12]=1)=[O:8]>[Rh].CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21]([F:24])([F:22])[F:23])=[C:6]([CH:18]=1)[C:7]([NH:9][CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][C:15](=[O:17])[NH:16]1)=[O:8]
Reactant: O=C(NCc1cccc(=O)[nH]1)c1cc(O)ccc1OCC(F)(F)F
Agent: [Rh]
Solvent: CO
Product: O=C1CCCC(CNC(=O)c2cc(O)ccc2OCC(F)(F)F)N1
Reaction time: 0.83 h

Procedure:
A mixture of 0.16 g (0.468 mmole) of 6-[5-hydroxy-2-(2,2,2-trifluoroethoxy)benzamidomethyl]-2(1H)-pyridone, 0.05 g of 5% rhodium on alumina and 50 ml of methanol was hydrogenated on a Parr apparatus for 50 minutes. The mixture was filtered, the filtrate was evaporated, and the residue was dried to provide 5-hydroxy-N-(6-oxo-2-piperidylmethyl)-2-(2,2,2-trifluoroethoxy)benzamide.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9](C=O)[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.COC1C=C2C(N=CC(SCCN3CCC(N)CC3)=N2)=CC=1.C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCCl.CO>[O:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[NH:7][C:2](=[O:1])[CH2:3]1
Reactant: O=Cc1ccc2c(c1)NC(=O)CO2
Agent: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CO
Product: O=C1COc2ccccc2N1
Temperature: 25 °C
Reaction time: 15 h
Yield: 167.6 %

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde (354 mg, 2.00 mmol, 1.0 eq) is added at room temperature to a stirred solution of 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (0.65 g, 2.00 mmol, 1.0 eq) in 1,2-dichloroethane (4 mL) and methanol (1 mL), followed by acetic acid (0.11 mL, 2.00 mmol, 1.0 eq) and sodium cyanoborohydride (160 mg, 2.6 mmol, 1.4 eq). After 15 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×20 mL) and a saturated sodium hydrogen carbonate aqueous solution (20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 6-({1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amino)-methyl)-4H-benzo[1,4]oxazin-3-one as a white solid (500 mg, 52% yield).
Reaction SMILES: [F:1][CH:2]([F:21])[N:3]1[C:7]([C:8]2[CH:9]=[C:10]3[N:19]([CH3:20])[CH:18]=[CH:17][C:11]3=[N:12][C:13]=2[C@@H:14]([NH2:16])[CH3:15])=[CH:6][CH:5]=[N:4]1.Cl[C:23]1[N:31]=[C:30]([NH2:32])[N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][NH:27]2.C(N(C(C)C)C(C)C)C>C(#N)C>[F:21][CH:2]([F:1])[N:3]1[C:7]([C:8]2[CH:9]=[C:10]3[N:19]([CH3:20])[CH:18]=[CH:17][C:11]3=[N:12][C:13]=2[C@@H:14]([NH:16][C:23]2[N:31]=[C:30]([NH2:32])[N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][NH:27]3)[CH3:15])=[CH:6][CH:5]=[N:4]1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnn1C(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(N)nc2[nH]cnc12)c1nc2ccn(C)c2cc1-c1ccnn1C(F)F
Temperature: 120 °C

Procedure:
(S)-1-(6-(1-(Difluoromethyl)-1H-pyrazol-5-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (172 mg, 0.590 mmol), 6-chloro-9H-purin-2-amine (100 mg, 0.590 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.31 mL, 1.8 mmol) were combined in acetonitrile (6 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was taken up in DMF and was purified by preparative HPLC (acid mode) eluting with 5-20% ACN in water. The fractions containing the desired compound were combined and concentrated in vacuo. The residue was further purified by preparative HPLC (basic mode) eluting with 25-35% ACN in water. The fractions containing the desired product were combined and concentrated in vacuo to give the title compound as a white solid. 1H NMR (500 MHz, CD3OD) δ ppm 1.58 (d, J=6.83 Hz, 3 H), 3.87 (s, 3 H), 5.94-6.01 (m, 1 H), 6.64 (d, J=2.93 Hz, 1 H), 6.87 (d, J=2.44 Hz, 1 H), 7.46-7.76 (m, 2 H), 7.93 (s, 1 H), 8.18 (s, 1 H); ESI-MS m/z [M+H]+ calc'd for C19H18F2N10, 425; found 425.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:13])[CH:10]=CN=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:21])C(=O)C1.[C:22](#[N:24])C>>[Br:21][C:22]1[N:24]=[CH:10][N:9]([CH3:13])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: CC#N
Reactant: Cn1ccnc1-c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Product: Cn1cnc(Br)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
(4-Chlorophenyl)-1-methyl-1H-imidazole (3 g, 15.5 mmol) was dissolved in ACN (150 mL) and cooled to 0° C. NBS (2.76 g, 15.5 mmol) was added in 3 portions over 5 min. The reaction was stirred at 0° C. for 20 min then let warm to ambient temperature. Solvents were removed in vacuo and the residue partitioned between EtOAc and 20% aqueous KH2PO4. The organics were separated, washed with saturated aqueous NaHCO3, and dried with saturated aqueous NaCl. Solvents were removed in vacuo and the residue purified by column chromatography on silica to provide the desired product. MS (m/z) 273.1 [M+H]+.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[CH3:15][C:16]1[S:17][C:18]([C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[C:19]([C:21](O)=[O:22])[N:20]=1>>[F:13][C:10]([F:12])([F:11])[C:9]([NH:8][CH2:7][C@H:2]1[N:3]([C:21]([C:19]2[N:20]=[C:16]([CH3:15])[S:17][C:18]=2[C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[O:22])[CH2:4][C@H:5]2[C@@H:1]1[CH2:6]2)=[O:14]
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)C(F)(F)F
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)C(F)(F)F)c1

Procedure:
prepared by reaction of N-[(1S,2S,5R)-1-(3-Aza-bicyclo[3.1.0]hex-2-yl)methyl]-2,2,2-trifluoro-acetamide with 2-Methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH3:25])[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[C:16](=[C:18]([C:22](O)=[O:23])[CH:19]=[CH:20][CH:21]=3)[N:17]=2)=[CH:9][CH:8]=1.[NH4+:26].[OH-]>ClCCl>[C:7]1([CH3:25])[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[C:16](=[C:18]([C:22]([NH2:26])=[O:23])[CH:19]=[CH:20][CH:21]=3)[N:17]=2)=[CH:9][CH:8]=1
Reactant: [NH4+]
Reactant: Cc1ccc(-c2nc3c(C(=O)O)cccc3o2)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccc(-c2nc3c(C(N)=O)cccc3o2)cc1
Temperature: 50 °C
Yield: 69.8 %

Procedure:
Oxalyl chloride (0.04 g, 0.3 mmol) was slowly added to a solution of 2-p-tolylbenzo[d]oxazole-4-carboxylic acid (0.064 g, 0.25 mmol) in dichloromethane (10 mL) with stirring. The reaction mixture was warmed to 50° C. for 4 h and then cooled to 25° C. The solution was condensed in vacuum and then slowly added to 28% NH4OH (10 mL) and a solids precipitated out immediately. The mixture was warmed to 50° C. and stirred for another 2 h. Water (20 mL) was added to the reaction mixture and the slurry was cooled to 25° C. The product was filtered and the cake was washed with water, dried to afford 0.44 g 2-p-tolylbenzo[d]oxazole-4-carboxamide solid (Yield: 69.8%). 1H-NMR (300 MHz, DMSO-d6): 2.46 (s, 3H), 6.01 (s, 1H), 7.34-1.36 (d, J=5.7 Hz, 2H), 7.43-7.47 (t, J=6.0 Hz, 1H), 7.71-7.73 (d, J=6.0 Hz, 1H), 8.15-8.18 (m, 3H), 9.02 (s, 1H). MS (ESI) m/e 253 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:11]=[CH:10][N:9]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:4]=2[C:5](=[O:8])[NH:6][N:7]=1.[CH:21](=O)[CH2:22][CH3:23].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[C:17]1([CH3:18])[CH:16]=[C:15]([CH3:19])[CH:14]=[C:13]([CH3:20])[C:12]=1[N:9]1[C:4]2[C:5](=[O:8])[NH:6][N:7]=[C:2]([NH:1][CH2:21][CH2:22][CH3:23])[C:3]=2[CH:11]=[CH:10]1
Reactant: CCC=O
Reactant: Cc1cc(C)c(-n2ccc3c(N)n[nH]c(=O)c32)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCNc1n[nH]c(=O)c2c1ccn2-c1c(C)cc(C)cc1C
Reaction time: 3 h
Yield: 32.9 %

Procedure:
A mixture of 4-amino-1-mesityl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (50 mg, 0.19 mmol), propionaldehyde (0.034 ml, 0.47 mmol), AcOH (0.013 ml, 0.224 mmol) and dichloromethane (10 ml) was stirred for 30 min before addition of NaBH(OAc)3 (99 mg, 0-47 mmol). The mixture was stirred for 3 hours, then washed with saturated sodium bicarbonate (20 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (1:1-1:2) to give 19.4 mg (34%) of the title compound as crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17].C(O)(=O)C>C1CCCCC1>[C:11]([C:7]1[CH:8]=[C:9]([N+:16]([O-:18])=[O:17])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: O=[N+]([O-])O
Solvent: C1CCCCC1
Solvent: CC(=O)O
Product: CC(C)(C)c1cc([N+](=O)[O-])cc(C(C)(C)C)c1O
Reaction time: 0.25 h

Procedure:
2,6-di-t-butylphenol (8 g, 39 mmoles) is dissolved in 25 ml of cyclohexane at 10° C. A mixture (1/1) of nitric acid/acetic acid (5 ml) is added dropwise to the reaction medium maintained at this temperature. Then agitation is carried out for 15 minutes at ambient temperature, then the precipitate formed is filtered, followed by rinsing with water and with pentane. The 2,6-di-t-butyl-4-nitrophenol obtained (6.34 g, 65%) is dried in an oven and will be used without other purification in the following stages. Pale yellow powder. Melting point: 167-168° C.