Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:31])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:23][CH:22]([NH2:24])[CH2:21]3)[N:9]=2)[C:6]2[CH:25]=[CH:26][CH:27]=[C:28]([O:29][CH3:30])[C:5]=2[N:4]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[F:31][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH:22]([NH:24][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:23]3)[N:9]=2)[C:6]2[CH:25]=[CH:26][CH:27]=[C:28]([O:29][CH3:30])[C:5]=2[N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CC(N)C2)n1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CC(NS(C)(=O)=O)C2)n1
Yield: 86 %

Procedure:
Reaction of 1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinamine and methanesulfonyl chloride as in Example 28 gave N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}methanesulfonamide in 86% yield: mp 307-309° C.; 1H NMR (DMSO-d6) δ 7.98 (d, J=8.1 Hz, 1H), 7.92 (br s, 1H), 7.73 (t, JHF=53.0 Hz, 1H), 7.40 (t, J=8.2 Hz, 1H), 6.95 (d, J=7.7 Hz, 1H), 4.54-4.33 (m, 3H), 4.07-3.97 (m, 2H), 3.97 (s, 3H), 3.80-3.78 (m, 4H), 3.69 (m, 4H), 2.97 (s, 3H); Anal. Calcd. for C20H24F2N8O4S.0.25H2O: C, 46.6; H, 4.8; N, 21.8. Found: C, 46.7; H, 4.8; N, 22.0%.
Reaction SMILES: [C:1]([NH:4][N:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([NH:8][CH3:9])=[O:7])(=[O:3])[CH3:2].CI.[C:18](=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]([N:4]([CH3:18])[N:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([NH:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: CNC(=O)N(NC(C)=O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCO
Product: CNC(=O)N(c1ccccc1)N(C)C(C)=O
Yield: 55.1 %

Procedure:
A mixture of 17 g (0.082 mol) of the semicarbazide prepared above, 14.2 g (0.1 mol) methyl iodide, 14.0 g (0.1 mol) potassium carbonate, and 200 ml ethanol was refluxed for 2 hours, cooled, filtered and evaporated under reduced pressure. The resulting residue was diluted with dichloromethane, filtered to remove suspended solids, washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to give 10 g of crude 1-acetyl-1,4-dimethyl-2-phenyl-semicarbazide.
Reaction SMILES: [CH:1]1([N:4]([CH:6]2[C:15]3[C:10](=[CH:11][C:12]([C:16]#[C:17][Si](C)(C)C)=[CH:13][CH:14]=3)[C:9]([CH3:23])([CH3:22])[CH2:8][CH2:7]2)[CH3:5])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1]1([N:4]([CH:6]2[C:15]3[C:10](=[CH:11][C:12]([C:16]#[CH:17])=[CH:13][CH:14]=3)[C:9]([CH3:23])([CH3:22])[CH2:8][CH2:7]2)[CH3:5])[CH2:3][CH2:2]1
Reactant: CN(C1CC1)C1CCC(C)(C)c2cc(C#C[Si](C)(C)C)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc2c(c1)C(C)(C)CCC2N(C)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
A solution of cyclopropyl-(4,4-dimethyl-6-trimethylsilanylethynyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methyl-amine (Intermediate 167, 0.67 g, 2.62 mmol) in methanol (10 mL) was treated with potassium carbonate (1 g, 7.23 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The volatiles were evaporated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a light yellow oil (0.5 g, 75%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH:6]1([CH2:11][CH2:12][C:13]2[O:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][N:17]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl-].[Na+]>>[CH:6]1([CH2:11][CH2:12][C:13]2[O:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:20][CH:19]=3)=[CH:16][N:17]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: c1ccc(-c2cnc(CCC3CCCC3)o2)cc1
Reactant: O=S(=O)(O)Cl
Agent: [Cl-]
Agent: [Na+]
Product: O=S(=O)(Cl)c1ccc(-c2cnc(CCC3CCCC3)o2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
Neat chlorosulfonic acid (2 mL) was added to 2-(2-cyclopentylethyl)-5-phenyloxazole from Step B (500 mg, 2.07 mmol) at room temperature under nitrogen with stirring. To this brown solution was added sodium chloride (100 mg) in portions and then the mixture was heated at 50° C. in an oil bath. After 2 h at 50° C., the mixture was poured onto ice-water and extracted with ethyl acetate (3×10 mL). The combined organics were washed with saturated aqueous sodium bicarbonate solution, water, and brine, dried over sodium sulfate, and evaparated. The brown residue was chromatogaphed on silica gel (eluent: 2:3 ethyl acetate:hexanes) to give 500 mg (76.9%) of the title compound as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 8.05 (d, 2H, J=8.2 Hz), 7.81 (d, 2H, J=8.2 Hz), 7.45 (s, 1H), 2.85 (t, 2H, 7.5 Hz), 1.90-1.75 (m, 5H), 1.70-1.48 (m, H), 1.12 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][C:6]=1[CH3:7].[CH:13](=O)[CH:14]([CH3:16])[CH3:15]>O>[CH3:1][C:2]1[NH:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]=1[CH3:7]
Reactant: CCOC(=O)c1cc(C)c(C)[nH]1
Reactant: CC(C)C=O
Solvent: O
Product: CCOC(=O)c1[nH]c(C)c(C)c1CC(C)C

Procedure:
As in Example 32 but using 2,3-dimethyl-5-carbethoxy-pyrrole and isobutyraldehyde, pouring the mixture into water after 3 hrs and extracting the product from the alkaline mixture with ether. It was distilled (70°, 1 × 10-4 mm) and crystallized from pentane as colourless prisms (45%), m.p. 109°-111°. Anal. Calc. for C13H21NO2 : C, 69.92; H, 9.48; N, 6.27. Found: C, 70.23; H, 9.79; N, 6.27.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[C:5](=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7]>[OH-].[Na+]>[Cl:22][C:20]1[CH:21]=[C:16]([CH:17]=[C:18]([Cl:23])[CH:19]=1)[CH2:15][O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:24])=[O:2])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cccc(OCc2cc(Cl)cc(Cl)c2)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cccc(OCc2cc(Cl)cc(Cl)c2)c1C(=O)O
Yield: 83.1 %

Procedure:
A solution of 3-(3,5-dichloro-benzyloxy)-phthalic acid dimethyl ester (0.42 g, 1.2 mmol) in reagent alcohol (10 mL) and 3 N sodium hydroxide (10 mL) was refluxed for two hours. The solution was evaporated and the residue was dissolved in water (10 mL) and washed with methylene chloride (2×10 mL) then acidified to pH around 4. The resulting mixture was extracted with ethyl acetate (2×10 mL) and the combined organic layers was washed with water (2×10 mL), dried and concentrated to give 3-(3,5-dichloro-benzyloxy)-phthalic acid as an off-white solid (0.34 g, 88% yield). The product was used in the next step without further purification.
Reaction SMILES: C([C:3](CC)([C:7]([C:9]([O-:11])=[O:10])=O)[C:4]([O-])=[O:5])C.[Na+].[Na+].C(O)(=O)C.[CH:20]([NH2:22])=[NH:21].[OH-].[Na+].C>O>[OH:5][C:4]1[N:22]=[CH:20][N:21]=[C:7]([C:9]([OH:11])=[O:10])[CH:3]=1
Reactant: N=CN
Reactant: CCC(CC)(C(=O)[O-])C(=O)C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(O)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
63.5 g (0.3 mol) sodium diethyloxalacetate and 30.2 g (0.3 mol) formamidine acetate were added to 24.1 g (0.6 mol) NaOH in 3.6 L water. The mixture was stirred overnight at RT. Then activated charcoal was added and the mixture was refluxed for 1 h. It was filtered off while hot and after cooling acidified with a hydrochloric acid solution. The solution was concentrated to dryness by rotary evaporation. The residue contained the desired product and was used in the next step without any further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH:7]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]([CH3:15])=[C:5]([N+:16]([O-])=O)[C:4]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH3:19])[CH2:3]1>C(O)(=O)C.CO.[Fe]>[NH2:16][C:5]1[C:4]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([CH3:19])[CH2:3][C:2]([CH3:1])([CH3:28])[CH:7]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]=1[CH3:15]
Reactant: CC1=C([N+](=O)[O-])C(C)(NCc2ccccc2)CC(C)(C)C1Nc1ccccn1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: CC1=C(N)C(C)(NCc2ccccc2)CC(C)(C)C1Nc1ccccn1
Temperature: 70 °C

Procedure:
Add iron powder (7.0 g) to a solution of 6-methyl-3-nitro-4-[benzylamino](2-pyridyl)(2,4,6-trimethylphenyl)amine (8.75 g, 23.2 mmol) in acetic acid (14 mL) and MeOH (70 mL). Heat the resulting mixture at 70° C. for 1 h, cool to ambient temperature, and filter through a pad of celite. Evaporate the filtrate to dryness under reduced pressure. Treat he residue with 1N aq NaOH and extract with EtOAc. Wash the EtOAc extract with water and saturated aq NaCl. Separate the organic layer, dry over Na2SO4, filter, and concentrate to obtain the title compound as a brown solid which is used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([NH2:5])=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[C:7]1([NH:6][CH2:2][C:3]([NH2:5])=[O:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1ccccc1
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: NC(=O)CNc1ccccc1
Yield: 9.6 %

Procedure:
The mixture of 2-chloroacetamide (3.1 g), aniline (3.1 g), K2CO3 (4.5 g) and KI (1 g) in acetonitrile (50 mL) and water (10 mL) was stirred at room temperature for overnight. The solvent was evaporated to about 20 ml under vacuum and the residue was poured into water (40 mL). The solution was extracted with ethyl acetate (3×20 mL), dried over Na2SO4 and concentrated. The residue was purified with chromatography to give 0.48 g of 2-phenylamino-acetamide.
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:10][C:11]([CH:14]=[O:15])=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pt]=O>[CH2:1]([S:8][C:9]1[S:10][C:11]([CH2:14][OH:15])=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cnc(SCc2ccccc2)s1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: OCc1cnc(SCc2ccccc2)s1

Procedure:
325 mg of 2-benzylsulfanyl-thiazole-5-carbaldehyde in 35 ml of ethyl acetate are hydrogenated with 14 mg of FeCl2×4H2O and 175 mg of platinum oxide under normal pressure for 64 hours at room temperature under a hydrogen atmosphere. The reaction mixture is filtered off and extracted with water. The organic phase is dried over sodium sulfate and concentrated in vacua. The title compound is obtained in the form of an oil (compound 3.1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21](=[O:23])[NH2:22])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:35][CH2:36][CH3:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]([CH2:36][CH3:37])[C:25]([CH2:24][N:14]([S:11]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=1)(=[O:13])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([NH2:22])=[O:23])=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccccc2C(N)=O)cc1
Reactant: CCNCc1ccccc1
Product: CCN(Cc1ccccc1)C(=O)CN(c1ccccc1C(N)=O)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(2-carbamoyl-phenyl)-amino]-acetic acid with benzyl-ethyl-amine
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH2:11])=[N:7][C:6]=2[CH:5]=[C:4]([CH3:12])[C:3]=1[O:13][CH3:14].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[C:10]3[S:9][C:8]([NH2:11])=[N:7][C:6]=3[CH:5]=[C:4]([CH3:12])[C:3]=2[O:13][CH3:14])=[CH:18][CH:17]=1
Reactant: COc1c(C)cc2nc(N)sc2c1Br
Reactant: OB(O)c1ccc(Cl)cc1
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: COCCOC
Product: COc1c(C)cc2nc(N)sc2c1-c1ccc(Cl)cc1

Procedure:
The mixture of 7-bromo-6-methoxy-5-methylbenzo[d]thiazol-2-amine (8A) (1.72 g, 6.32 mmol), 4-chlorophenyl boronic acid (1.2 g, 7.67 mmol), K2CO3 (2.63 g, 18.9 mmol), Pd(PPh3)4 (364 mg, 0.315 mmol) in DME (8 ml) and H2O (4 ml) was reacted in microwave at 110° C. for 1 h. Then 4-chlorophenyl boronic acid (100 mg, 0.64 mmol), Pd(PPh3)4 (100 mg, 0.086 mmol) were added and reacted in microwave at 110° C. for 0.5 h and 120° C. for 20 min. The reaction mixture was washed by water, extracted by EtOAc. The organic phase was combined, dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in hexanes. LCMS-ESI+: calc'd for C15H13ClN2OS: 305.0 (M+H+). Found: 305.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:62]=[CH:61][C:28]([CH2:29][N:30]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=2)[C:31]2[N:36]=[CH:35][C:34]([C:37]3[C:38]4[CH2:51][CH2:50][NH:49][C:39]=4[N:40]=[C:41]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)[N:42]=3)=[CH:33][N:32]=2)=[CH:27][CH:26]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[C:20]([N:49]3[C:39]4[N:40]=[C:41]([N:43]5[CH2:44][CH2:45][O:46][CH2:47][CH2:48]5)[N:42]=[C:37]([C:34]5[CH:35]=[N:36][C:31]([N:30]([CH2:52][C:53]6[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=6)[CH2:29][C:28]6[CH:61]=[CH:62][C:25]([O:24][CH3:23])=[CH:26][CH:27]=6)=[N:32][CH:33]=5)[C:38]=4[CH2:51][CH2:50]3)[CH:19]=[CH:18][N:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cl)ccn2)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccnc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)c3)cn2)cc1
Yield: 57.7 %

Procedure:
Using 4-(4-chloro-pyridine-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (163 mg, 0.500 mmol) obtained in Step A instead of 4-chloropicolinic acid t-butylamide, and bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (245 mg, 445 mmol), in the same manner as Example 1-D-07, amination was carried out, to obtain a crude product of 4-[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridine-2-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (239 mg), and further PMB group and BOC group were removed according to the above Deprotection method 2, to obtain the desired compound (D-199) as a yellow powder (67 mg, 49%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](Cl)=[O:32])=[CH:26][CH:25]=1>C1COCC1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[O:32])=[CH:26][CH:25]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)Cc3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and (4-fluorophenyl)acetyl chloride: ESMS m/e: 440.3 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:10]1(Br)[CH2:14][CH2:13][CH2:12][CH2:11]1.[O-]CC.[Na+]>C(O)C>[CH:10]1([CH:3]([C:2](=[O:1])[CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)CC(C)=O
Reactant: BrC1CCCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C(C)=O)C1CCCC1
Temperature: 22.5 °C
Yield: 71.6 %

Procedure:
A mixture of ethyl 3-oxobutanoate (0.5 mol), cyclopentyl bromide (0.5 mol) and sodium ethoxide (0.5 mol) in ethanol (100 ml) was heated under reflux for 15 hours. The reaction mixture was cooled to about 20-25° C., and 71 g of the title compound were then isolated by distillation (96-100° C., 0.25 mbar).
Reaction SMILES: [CH2:1]([N:11]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:12]([C:14]1[CH:15]=[C:16]([N+:20]([O-])=O)[CH:17]=[CH:18][CH:19]=1)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H][H]>[Pd].C(OCC)(=O)C.C1COCC1>[CH2:23]([N:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:12]([C:14]1[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=1)=[O:13])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: [H][H]
Reactant: CCCCCCCCCCN(CCCCCCCCCC)C(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCN(CCCCCCCCCC)C(=O)c1cccc(N)c1
Yield: 107.2 %

Procedure:
To an ice bath cooled solution of 0.80 g (2.69 mmol) of di-decylamine and 0.75 mL (5.4 mmol) of triethylamine in 10 mL of anhydrous methylene chloride was added dropwise a solution of 0.50 g (2.69 mmol) of 3-nitrobenzoyl chloride in 5 mL of methylene chloride with stirring. The mixture was stirred at room temperature for 4 hours. Water was added, the organic layer was separated and dried. The solvent was removed at reduced pressure and the residual oil was purified by chromatography on 30 g of silica gel using 12.5% ethyl acetate-hexane to give 1.0 g of 3-(di-decylaminocarbonyl)-1-nitrobenzene as an oil. The nmr and mass spectra were consistent with the structure. A mixture of 1.0 g of 3-(di-decylaminocarbonyl)-1-nitrobenzene and 0.2 g of 10% palladium on carbon in 20 mL of ethyl acetate and 20 mL of THF was stirred under a hydrogen atmosphere at room temperature for 2 hours when hydrogen uptake ceased. The catalyst was removed by filtration and the filtrate was concentrated to give 1.0 g of 3-(di-decylaminocarbonyl)benzenamine as an oil. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:26]([CH3:28])[CH3:27])=[C:11]([CH2:13][CH2:14]OS(C2C=CC(C)=CC=2)(=O)=O)[N:12]=1.[I-:29].[Na+].O>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:26]([CH3:28])[CH3:27])=[C:11]([CH2:13][CH2:14][I:29])[N:12]=1
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3Cl)oc2C(C)C)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)c1oc(-c2ccccc2Cl)nc1CCI
Yield: 95.4 %

Procedure:
In acetone (2 mL) was dissolved 2-(2-chlorophenyl)-5-isopropyl-4-[2-(p-toluenesulfonyloxy)ethyl]oxazole (123 mg, 0.293 mmol). To the solution was added sodium iodide (176 mg, 1.17 mmol). The mixture was heated overnight under reflux. The reaction mixture was allowed to reach room temperature, poured into water, and extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine, dried over sodium sulfate, filtered, and concentrated, to obtain the desired compound (105 mg, 96%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-:19])=[O:18])=[C:6]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=O)[CH:7]=1.CSC.B>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-:19])=[O:18])=[C:6]([CH2:8][CH2:9][N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])c(CC(=O)N2CCOCC2)c1
Agent: B
Solvent: CSC
Solvent: Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])c(CCN2CCOCC2)c1
Yield: 79.1 %

Procedure:
2-(5-Methyl-2-nitro-phenyl)-1-morpholino-ethanone (267 mg, 1.01 mmol) was dissolved in toluene (10 mL) and treated with borane dimethylsulfide (983 mg, 1.23 mL, 11.7 mmol) and heated at reflux for 2 h. The reaction was concentrated in vacuo then resuspended in 2 N HCl (8 mL) and heated at reflux for 30 min. The reaction was diluted with 1N HCl and washed with ethyl acetate. The solution was basified (5 N NaOH) and the product extracted into dichloromethane (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide 4-[2-(5-methyl-2-nitro-phenyl)ethyl]morpholine as an oil (200 mg, 79% yield). LC/MS m/z 251.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2=[C:14](OS(C(F)(F)F)(=O)=O)[N:15]([CH:17]([CH3:19])[CH3:18])[N:16]=[C:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2=[C:14]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:15]([CH:17]([CH3:19])[CH3:18])[N:16]=[C:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(Cc1ccccc1)C2
Product: CC(C)n1nc2c(c1-c1ccccc1)CCN(Cc1ccccc1)C2
Yield: 32.9 %

Procedure:
The title compound (54 mg) was prepared as in Example 263 using 200 mg of trifluoro-methanesulfonic acid 6-benzyl-2-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-yl ester and 85 mg of phenylboronic acid. MS (ESI): exact mass calculated for C22H25N3, 331.20. found, m/z 332.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.60-7.48 (m, 7H), 7.39-7.37 (m, 2H), 4.59-4.48 (m, 3H), 4.44-4.34 (m, 2H), 3.81-3.79 (m, 1H), 3.46-3.40 (m, 1H), 2.94-2.84 (m, 2H), 1.46-1.29 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][C:5](=[O:7])[N:6]=1.[Cl:8][C:9]1[CH:27]=[C:26]([CH:28]=C2SC(=O)NC2=O)[CH:25]=[CH:24][C:10]=1[O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[C:20]([F:23])([F:22])[F:21]>>[Cl:8][C:9]1[CH:27]=[C:26]([CH:28]=[C:4]2[S:3][C:2](=[NH:1])[NH:6][C:5]2=[O:7])[CH:25]=[CH:24][C:10]=1[O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[C:20]([F:21])([F:22])[F:23]
Reactant: NC1=NC(=O)CS1
Reactant: N#Cc1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2Cl)c(C(F)(F)F)c1
Product: N#Cc1ccc(Oc2ccc(C=C3SC(=N)NC3=O)cc2Cl)c(C(F)(F)F)c1

Procedure:
4-[2-Chloro-4-(2-imino-4-oxo-thiazolidin-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile was prepared using 2-amino-thiazol-4-one and 4-[2-Chloro-4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-3-trifluoromethylbenzonitrile according to General Procedure C. 1H NMR (400 MHz, DMSO-d6) δ 9.56 (br, 1H), 9.24 (br, 1H), 8.40 (d, J=1.56 Hz, 1H), 8.08 (dd, J=8.6 and 1.95 Hz, 1H), 7.90 (d, J=1.96 Hz, 1H), 7.65 (d, J=2.35 Hz, 1H), 7.63 (s, 1H), 7.50 (d, J=8.61 Hz, 1H), 7.07 (d, J=8.61 Hz, 1H). LC/MS (m/z) [M+1]+424.2 (calculated for C18H10ClF3N3O2S 424.0).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.C(N(C(C)C)CC)(C)C>CCO>[Br:8][C:6]1[N:7]=[C:2]([NH:19][C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[NH:10][CH:11]=[CH:12]3)[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: Nc1ncc(Br)nc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1ncc(Br)nc1Nc1ccc2[nH]ccc2c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 42 %

Procedure:
To a stirred suspension of 3,5-dibromopyrazin-2-amine (3.48 g, 13.7 mmol) and 1H-indol-5-amine (2.00 g, 15.0 mmol) in EtOH (3.5 mL) was added diisopropylethylamine [DIEA] (2.60 mL, 15.0 mmol). The resulting mixture was stirred for 48 hr at 80° C., after which it was partitioned between EtOAc and H2O. The organic layer was separated, after which it was washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo to yield a residue that was purified via silica gel chromatography eluting with 1:1 EtOAc:hexanes to yield the title compound (1.75 g, 42%) as a red/brown solid. 1H NMR (DMSO-d6, 300 MHz): δ 10.98 (s, 1H), 8.22 (s, 1H), 7.83 (s, 1H), 7.31-7.28 (m, 3H), 7.19 (d, J=8.7 Hz, 1H), 6.43 (s, 2H), 6.36 (s, 1H); HPLC retention time: 2.07 minutes; MS ESI (m/z): 304.2/306.2 (M+1)+, calc. 303.