Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[O:6]/[C:5](=[C:7]2/[C:8](=[O:17])[NH:9][C:10]3[C:15]/2=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)/[CH:4]=[C:3]1[C:18]1[CH:19]=[N:20][C:21]([CH:24]=[CH2:25])=[CH:22][CH:23]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.O>CN(C=O)C>[CH3:1][C:2]1([CH3:26])[O:6]/[C:5](=[C:7]2/[C:8](=[O:17])[NH:9][C:10]3[C:15]/2=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)/[CH:4]=[C:3]1[C:18]1[CH:19]=[N:20][C:21]([CH2:24][CH2:25][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:22][CH:23]=1
Reactant: C1COCCN1
Reactant: C=Cc1ccc(C2=C/C(=C3\C(=O)Nc4cc(F)ccc43)OC2(C)C)cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(CCN2CCOCC2)nc1
Temperature: 96 °C

Procedure:
A mixture of (3E)-3-[5,5-dimethyl-4-(6-vinylpyridin-3-yl)furan-2(5H)-ylidene]-6-fluoro-1,3-dihydro-2H-indol-2-one (50 mg, 0.14 mmol) and morpholine (0.2 mL, 2.3 mmol) in 5 mL of DMF was heated in 96° C. bath under nitrogen for 3 hours. The mixture was cooled to room temperature and poured into 100 mL of water. The precipitates were filtered, washed with water and dried in vacuo to give (3E)-3-{5,5-dimethyl-4-[6-(2-morpholin-4-ylethyl)pyridin-3-yl]furan-2(5H)-ylidene}-6-fluoro-1,3-dihydro-2H-indol-2-one as a brown solid. Yield: 40 mg, 64%.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH:5]([C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1)[C:6]#[N:7].[OH-].[K+].C(OCC)(=[O:25])C.Cl>CC(O)(C)C>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]([C:8]1[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=1)[C:6]([NH2:7])=[O:25]
Reactant: CCOC(C)=O
Reactant: COc1cc(C(C#N)CCN(C)C)cc(OC)c1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: COc1cc(C(CCN(C)C)C(N)=O)cc(OC)c1OC

Procedure:
In 8 ml of 2-methyl-2-propanol was dissolved 0.84 g of 4-dimethylamino-2-(3,4,5-trimethoxyphenyl)butyronitrile, followed by addition of 1.0 g of ground potassium hydroxide. The mixture was refluxed for 1 hour. After cooling the reaction mixture, the insoluble matters were filtered off and the filtrate was concentrated under reduced pressure. To the residue thus obtained were added ethyl acetate and 10% hydrochloric acid. The aqueous layer was separated and made strongly basic with sodium hydroxide for salting-out and the basic substance was extracted with ethyl acetate. The ethyl acetate layer was washed with a mixture of water and saturated aqueous sodium chloride (1:1) and a saturated aqueous solution of sodium chloride in turn, then dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The crystalline residue thus obtained (0.59 g) was recrystallized from ethyl acetate to provide 0.35 g of 4-dimethylamino-2-(3,4,5-trimethoxyphenyl)butyramide.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[S:10][CH:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=2)[CH:3]=[N:2]1.CCN(C(C)C)C(C)C.[F:23][C:24]([F:37])([F:36])[CH2:25][N:26]1[CH:35]2[CH:30]([CH2:31][CH2:32][CH2:33][CH2:34]2)[NH:29][CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[NH:2]1[CH:3]=[C:4]([C:6]2[S:10][CH:9]=[C:8]([C:11]([N:29]3[CH:30]4[CH:35]([CH2:34][CH2:33][CH2:32][CH2:31]4)[N:26]([CH2:25][C:24]([F:36])([F:37])[F:23])[CH2:27][CH2:28]3)=[O:13])[CH:7]=2)[CH:5]=[N:1]1
Reactant: FC(F)(F)CN1CCNC2CCCCC21
Reactant: O=C(O)c1csc(-c2cn[nH]c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1csc(-c2cn[nH]c2)c1)N1CCN(CC(F)(F)F)C2CCCCC21
Reaction time: 24 h
Yield: 12.2 %

Procedure:
5-(1H-Pyrazol-4-yl)-thiophene-3-carboxylic acid (0.080 g, 0.41 mmol) was suspended in acetonitrile (2 mL) then DIPEA (0.158 mL, 0.90 mmol) and 1-(2,2,2-trifluoro-ethyl)-decahydro-quinoxaline (0.119 g, 0.54 mmol) were added followed by HATU (0.192 g, 0.50 mmol). The resulting mixture was stirred for about 24 hours and then further amounts of DIPEA (79 μL) and HATU (0.192 g) were added and stirring continued over the weekend. The mixture was evaporated and the residue was taken up in sodium hydroxide (1 N) and stirred for 30 minutes. HCl (1 N, 2.5 mL) was added and the solution extracted with ethyl acetate (×3). The organics were dried over sodium sulfate, filtered and evaporated. The material was purified by HPLC, eluting with 5%-95% acetonitrile in water (0.1% formic acid) and the fractions containing the desired product were combined and freeze-dried to give the title compound as a white solid (0.020 g). LCMS m/z 399.17 [M+H]+ R.T.=10.05 min (Analytical Method 2).
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1N1[C:18](=[O:19])[C:17]2[C:20]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=3[F:34])=[CH:21][C:22](=[O:25])[N:23]([CH3:24])[C:16]=2[N:15]=[CH:14]1)([O-])=O.[NH2:35][CH:36]([CH2:39][OH:40])[CH2:37][OH:38]>CN(C=O)C>[OH:38][CH2:37][CH:36]([N:35]1[C:18](=[O:19])[C:17]2[C:20]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=3[F:34])=[CH:21][C:22](=[O:25])[N:23]([CH3:24])[C:16]=2[N:15]=[CH:14]1)[CH2:39][OH:40]
Reactant: NC(CO)CO
Reactant: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)n(-c3ccc([N+](=O)[O-])cc3[N+](=O)[O-])cnc21
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)n(C(CO)CO)cnc21
Temperature: 80 °C

Procedure:
To a mixture of 3-(2,4-dinitrophenyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 24A (18 mg, 0.03 mmol, 1 eq) in DMF (0.3 mL) was added 2-aminopropane-1,3-diol (29 mg, 0.3 mmol, 10 eq). The reaction mixture was heated at 80° C. for 5 hours. The solvent was removed under vacuum and the residue was purified by preparatory LC/MS (30-55% CH3CN in H2O) to yield 3-(1,3-dihydroxypropan-2-yl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione Example 24 as an off-white solid (10 mg, 66% yield). 1H NMR (400 MHz, MeOD) δ ppm 3.65 (s, 3H) 3.87-3.95 (m, 2H) 4.04 (dd, J=11.87, 7.07 Hz, 2H) 4.88-4.90 (m, 1H) 5.74 (s, 1H) 7.29 (t, J=8.34 Hz, 1H) 7.57-7.69 (m, 2H) 8.50 (s, 1H). [M+H] calc'd for C17H16FIN4O4, 487; found, 487.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH2:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:13]([O:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11])[CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: C=CCCCCCC
Product: CCCCCC=CCON1C(C)(C)CC(O)CC1(C)C
Temperature: 100 °C
Reaction time: 24 h
Yield: 42.3 %

Procedure:
A mixture of 20.0 g (0.12 mol) of 1-oxyl-4-hydroxy-2,2,6,6-tetramethylpiperidine and 164.0 g (1.04 mol) of 1-octene is heated under a nitrogen atmosphere at 100° C. for 24 hours, and then for an additional 24 hours at 115° C. The reaction mixture is filtered to remove 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine, and the filtrate is washed with 10% (w/v) ascorbic acid (2×50 mL) and distilled water (2×50 mL). The organic phase is dried over anhydrous magnesium sulfate and the volatiles removed in vacuo. The residue is chromatographed to give 14.4 g (83% yield) of the title compound as an amber oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:21](C#N)=[C:20]([N:24]=[CH:25][N:26]([CH3:28])C)[NH:19][N:18]=2)=[CH:13][CH:12]=1>CO>[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:21]3[C:20](=[N:24][CH:25]=[N:26][C:28]=3[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[C:3]([Cl:2])[CH:4]=3)[NH:19][N:18]=2)=[CH:15][CH:16]=1
Reactant: CN(C)C=Nc1[nH]nc(-c2ccc(N)cc2)c1C#N
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: CO
Product: Nc1ccc(-c2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1

Procedure:
With the exclusion of moisture, 62 mg (0.38 mmol) of 3-chloro-aniline hydrochloride (see Step 14.4) are added to 92 mg (0.36 mmol) of N'-[3-(4-amino-phenyl)-4-cyano-1H-pyrazol-5-yl]-N,N-dimethylformamidine in 1 ml of methanol and the reaction mixture is boiled under reflux for 28 hours. The light-yellow reaction solution is cooled, concentrated by evaporation and chromatographed (SiO2, methylene chloride/ethanol [10:1]). Crystallization from isopropanol yields 3-(4-amino-phenyl)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine; TLC: Rf =0.33 (methylene chloride:methanol=10:1); FAB-MS: (M)+ =336; HPLC: TRet (Grad20-100)=9.2, TRet (Grad5-40)=18.8.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([O:15][C@@H:16]1[C@H:21]2[NH:22][C:23](=[O:25])[O:24][C@H:20]2[CH2:19][C@H:18](C(O)C)[C@H:17]1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:5]([O:4][CH:1]([C@@H:18]1[C@@H:17]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@H:21]2[NH:22][C:23](=[O:25])[O:24][C@H:20]2[CH2:19]1)[CH3:2])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CC(O)[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OC(C)[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic anhydride (3.3 g, 32 mmol) was added to a solution of 4 (1.0 g, 2.5 mmol) in pyridine (60 mL) and the solution was stirred overnight at room temperature. The mixture was concentrated in vacuo to give a residue, which was purified by a silica gel column, eluted with 2% MeOH in DCM to give 5 as yellow oil (900 mg, 81%, the ratio of diastereomers is 1:3 by 1H NMR). (ES, m/z): [M+H]+ 457.1; 1H NMR (300 MHz, CDCl3) δ 7.32-7.43 (m, 10H), 4.91-4.95 (m, 1H), 4.72-4.78 (m, 3H), 4.56-4.66 (m, 2H), 4.47-4.50 (m, 1H), 3.61-3.63 (m, 1H), 3.49-3.54 (m, 1H), 3.32-3.35 (m, 1H), 2.03 (s, 3H), 1.51-1.76 (m, 2H), 1.27 (d, J=6.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][S:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C@@H:15]23)[CH:20]=1>>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][S:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][NH:27][CH2:28][C@@H:15]23)[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Reactant: O=Cc1ccc(F)cc1F
Product: Fc1ccc(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c(F)c1

Procedure:
Using 2,4-difluorobenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part P was converted into the title compound of EXAMPLE 163. 1H NMR(CDCl3) δ: 7.30-7.20 (m, 1H), 6.80-6.70 (m, 2H), 6.27 (d, 1H, J=2.2 Hz), 6.15 (d, 1H, J=2.2 Hz), 4.20 (broad s, 2H), 3.59 (ABq, 2H, JAB=15.2 Hz), 3.53-3.40 (m, 2H), 3.29-3.21 (m, 1H), 3.20-3.10 (m, 1H), 3.02-2.77 (m, 5H), 2.52 (dd, 1H, J=12.8, 9.2 Hz), 1.82-1.70 (m, 2H). LRMS (ES)+: 388.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[C:14](=[O:17])[NH:15][N:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:23][CH:24]([CH3:26])[CH3:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[C:14](=[O:17])[N:15]([CH2:23][CH:24]([CH3:26])[CH3:25])[N:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1cc(-c2ccc(OC)c(OC)c2)n[nH]c1=O
Reactant: CC(C)CBr
Product: COC(=O)c1cc(-c2ccc(OC)c(OC)c2)nn(CC(C)C)c1=O
Yield: 86.6 %

Procedure:
Using 6-(3,4-dimethoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 1-bromo-2-methylpropane as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 86.6%.
Reaction SMILES: C[O:2][C:3]1[C:12]([O:13]C)=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:15].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[OH:2][C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:15]
Reactant: COc1ccc2c(c1OC)CCCC2=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1CCCc2c1ccc(O)c2O
Temperature: 80 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a solution 5,6-dimethoxy-1-tetralone (100 g) in toluene (958 ml) was added aluminum chloride (200 g) in small portions. After the addition was complete the reaction was heated to 80° C. and mechanically stirred for 2 hours. The reaction was cooled and slowly poured into ice and concentrated HCl. The resulting solids were filtered and washed with cold dilute HCl. The resulting solids were taken up into monoglyme, dried (MgSO4), filtered treated with charcoal, refiltered and concentrated. The residue was co-concentrated with acetonitrile to provide upon cooling 82.5 g of desired product as an off white solid, m.p. 191° C.-194° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:13]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][C:5]=1[C:14]([OH:16])=O)#[N:2].[NH2:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=1>>[CH3:23][C:21]1[NH:20][N:19]=[C:18]([NH:17][C:1]2[NH:2][C:14](=[O:16])[C:5]3[C:4](=[C:13]4[C:8](=[CH:7][CH:6]=3)[O:9][CH2:10][CH2:11][O:12]4)[CH:3]=2)[CH:22]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: N#CCc1c(C(=O)O)ccc2c1OCCO2
Product: Cc1cc(Nc2cc3c4c(ccc3c(=O)[nH]2)OCCO4)n[nH]1

Procedure:
Similar procedure as described in example 2c was used, starting from 5-Cyanomethyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid and 3-amino-5-methylpyrazole to give 6-(5-Methyl-1H-pyrazol-3-ylamino)-2,3-dihydro-7H-1,4-dioxa-7-aza-phenanthren-8-one. LC-MS: m/e 299 (MH+).
Reaction SMILES: [CH3:1][C:2]([OH:13])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][CH2:4][CH:5]=C.[O:14]=[O+][O-].O=O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[O:13][C:5](=[O:14])[CH2:4][CH2:3]1
Reactant: C=CCCC(C)(O)CCCCCC
Reactant: O=[O+][O-]
Agent: O=[Cr](=O)=O
Agent: O=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CCCCCCC1(C)CCC(=O)O1
Yield: 89 %

Procedure:
A solution of 5-methyl-1-undecen-5-ol (9.2 g., 0.05 mol) in acetone (100 ml) was cooled in a dry-ice-isopropanol bath while a stream of ozone was bubbling through it. When reaction was complete, excess ozone was expelled with oxygen and the reaction mixture was treated with Jones' reagent until an orange color persisted. Acetone was removed by evaporation and the residue was distributed between water and methylene chloride. The organic solution was separated, washed with water, and evaporated. The residue was distilled to give 4-methyl-4-decanolide (8.2 g., 89% yield; b.p. 108°-113°/0.5 torr).
Reaction SMILES: OC1C=CC(/C=C/[CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=CC=1OC.[F:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40]CBr)=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[CH:19][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:35][CH:34]=1
Reactant: COc1cc(/C=C/CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)ccc1O
Reactant: Fc1ccc(OCCBr)cc1
Product: Fc1ccc(OCCN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)cc1

Procedure:
The same procedure was followed as in Example 11 using the compound (9) synthesized in Example 2 and 2-(4-fluorophenyl)oxyethyl bromide to produce the above.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:29][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: NCc1ccccc1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NCc3ccccc3)cc2c1=O
Yield: 31 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (20 mg, 0.0628 mmol) is reacted with benzylamine according to the GPA affording 8 mg (31%) of a red powder. Rt=3.45 min.
Reaction SMILES: CO[C:3](=[O:21])[C:4]([OH:20])=[CH:5][C:6](=[O:19])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[O:8][CH3:9].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:30][N:31](C)[C:32](C1CN(C)C(=O)C=1O)=O>>[Cl:18][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[Cl:17])[CH2:10][N:7]([O:8][CH3:9])[C:6]([C:5]1[CH2:30][N:31]([CH3:32])[C:3](=[O:21])[C:4]=1[OH:20])=[O:19]
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(Cl)c(Cl)c1)OC
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: CN
Product: CON(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 49 %

Procedure:
3-[(3,4-Dichlorobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 47-C) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12, yielding the title compound as a white solid (49% yield); mp 149° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.11 (3H, s, NCH3), 3.75 (3H, s, OCH3), 4.15 (2H, s, NCH2), 4.82 (2H, s, NCH2), 7.18 (1H, dd, J=2.0 Hz, J=8.2 Hz, aromatic), 7.42 (1H, d, J=8.2 Hz, aromatic), 7.43 (1H, d, J=2.0 Hz, aromatic). Anal. calcd for C14H14Cl2N2O4: C, 48.72; H, 4.09; N, 8.12. Found: C, 48.81; H, 4.04; N, 7.99.
Reaction SMILES: Cl.[CH:2]1([NH+:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>O>[CH:2]1([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1CCC([NH+]2CCCC2)CC1
Agent: Cl
Solvent: O
Product: C1CCC(N2CCCC2)CC1

Procedure:
In some instances when some unreacted cyclohexanone is still in the reaction mixture, the product after hydrogenation was purified by adding 3M HCl solution to the mixture (after filtering out the palladium/carbon catalyst) and left to stir for 15-20 minutes. The resulting mixture is then extracted with diethyl ether to remove the cyclohexanone from the mixture and leaving behind the cyclohexylpyrrolidinium hydrochloride salt. The water layer containing cyclohexylpyrrolidinium hydrochloride salt is separated and then neutralized with NaOH solution to a pH of 9-10. The free cyclohexylpyrrolidine is extracted with ethyl acetate, dried over MgSO4 and concentrated on a rotary evaporator at reduced pressure to give the desired product free from any impurities.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:25]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)Nc2ccc(O)cc2)CC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(NC(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.5 %

Procedure:
A suspension of 4-(2-tert-butylphenyl)-N-(4-hydroxyphenyl)piperazine-1-carboxamide (Example 174, 0.290 g, 0.82 mmol), methyl bromoacetate (0.163 g, 1.07 mmol), and potassium carbonate (0.227 g, 1.64 mmol) in DMF (3 mL) was stirred at room temperature for 24 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3 solution and brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to give the crude product, which was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=90:10 to 50:50) to provide methyl [4-({[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}amino)phenoxy]acetate (0.260 g, 75%) as a white powder.
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]([O:14]CC2C=CC=CC=2)[CH2:12][N:11]([CH2:22][CH:23]([OH:26])[CH2:24][OH:25])[C@@H:10]1[CH2:27][O:28]CC1C=CC=CC=1)C1C=CC=CC=1.[ClH:36]>[Pd].C(O)C>[ClH:36].[OH:8][C@H:9]1[C@H:13]([OH:14])[CH2:12][N:11]([CH2:22][CH:23]([OH:26])[CH2:24][OH:25])[C@@H:10]1[CH2:27][OH:28]
Reactant: OCC(O)CN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: OCC(O)CN1C[C@@H](O)[C@H](O)[C@H]1CO

Procedure:
The title compound was synthesized as described for compound 9 using (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxymethyl-1-(2,3-dihydroxyprop-1-yl)pyrrolidine (Compound 17) (0.424 g, 0.89 mmol), ethanol (80 ml), 10% Pd/C (0.1g), and excess of 4 M hydrochloric acid to convert the amine to the hydrochloride salt. (2R,3R,4R)-3,4-Dihydroxy-2-hydroxymethyl-1-(2,3-dihydroxyprop-1-yl)pyrrolidine hydrochloride was obtained as white crystals (0.216 g, yield: 100%) with melting point above 230° C. (decomposition).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][CH:40]=[C:41]([CH:44]=2)[C:42]#[N:43])O1>>[C:42]([C:41]1[CH:44]=[C:37]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)[CH:38]=[N:39][CH:40]=1)#[N:43]
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Product: N#Cc1cncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@H](CO)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 75 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford an off-white solid. UPLC-MS (condition 1) tR=2.38 min, m/z=484.0 [M+H]+, m/z=482.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.47-1.67 (m, 1H) 1.78-1.91 (m, 1H) 2.16-2.30 (m, 1H) 2.96 (dd, J=11.00, 6.85 Hz, 1H) 3.12-3.19 (m, 2H) 3.19-3.26 (m, 1H) 3.25-3.31 (m, 1H) 3.33-3.39 (m, 1H) 4.62 (t, J=5.26 Hz, 1H) 7.35 (d, J=8.56 Hz, 2H) 7.85 (d, J=9.29 Hz, 2H) 8.08 (d, J=2.45 Hz, 1H) 8.40 (t, J=2.08 Hz, 1H) 8.79 (d, J=2.20 Hz, 1H) 8.91 (d, J=2.20 Hz, 1H) 9.02 (d, J=1.96 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[C:3]1[C:10]1[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=1.[NH2:16][C@@H:17]([CH3:33])[CH2:18][N:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([Cl:32])[CH:25]=2)=[N:20]1>>[Cl:32][C:26]1[CH:25]=[C:24]([C:21]2[CH:22]=[CH:23][N:19]([CH2:18][C@@H:17]([NH:16][C:7]([C:5]3[N:4]=[C:3]([C:10]4[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=4)[N:2]([CH3:1])[CH:6]=3)=[O:9])[CH3:33])[N:20]=2)[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Cn1cc(-c2nc(C(=O)O)cn2C)cn1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn(C)c(-c2cnn(C)c2)n1

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 1-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole-4-carboxylic acid (0.3 g, 1.44 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.377 g, 1.44 mmol). The product was purified by flash chromatography. Yield 200 mg. 1H-NMR (400 MHz; DMSO-d6): δ 1.10 (d, 3H), 3.72 (s, 3H), 3.91 (s, 3H), 4.23-4.45 (m, 3H), 6.95 (d, 1H), 7.63 (d, 1H), 7.83 (t, 2H), 7.99 (d, 1H), 8.03 (d, 1H), 8.07 (s, 1H), 8.17 (s, 1H).