Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]1[CH:7]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([CH3:18])[CH2:3]1.I.CS[C:22]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)=[NH:23]>C(O)C>[F:1][CH:2]1[CH:7]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:22]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)=[NH:23])[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([CH3:18])[CH2:3]1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)C(F)C1
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Product: CN1CCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)C(F)C1
Reaction time: 16 h
Yield: 89.2 %

Procedure:
A solution of compound 136 (0.07 g, 0.283 mmol) in dry ethanol (5 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.16 g, 0.566 mmol) at room temperature and stirred for overnight (16 h). Solvent was evaporated, crude was diluted with sat. NaHCO3 solution (25 mL) and product was extracted into CH2Cl2 (2×20 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 5:95) to obtain compound 137 (0.09 g, 90%) as a solid. mp 115-117° C.; 1H NMR (DMSO-d6) δ 1.79-2.09 (m, 4H), 2.26 (s, 3H), 2.74-2.90 (m, 2H), 3.13-3.17 (m, 1H), 4.68 (dddd, 1H, J=4.8, 9.6, 9.6, 48.5
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=O)[CH3:5].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[O-]S([O-])(=O)=O.[Mg+2]>>[C:9]1([N:8]=[C:4]([CH2:3][C:2](=[O:7])[CH3:1])[CH3:5])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccccc1
Reactant: CC(=O)CC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: CC(=O)CC(C)=Nc1ccccc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 69.1 %

Procedure:
500 g of 2,4-pentanedione, 600 g of aniline, and 1000 g of MgSO4 were mixed together at 100° C., and the mixed solution was stirred for 12 hours at 100° C. Then, the solid portion was precipitated, and the liquid portion was recrystallized upon addition of n-pentane to get 605 g of yellow 2-phenylimino-4-pentanone solid (70% yield). From the NMR analysis, the structure was confirmed; 1H-NMR(CDCl3) δ1.98(s, CH3), 2.10(s, CH3), 5.18(s, ═CH), 7.20(m, Ph), 12.6(brs, NH).
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][NH:21][CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:23]([S:25]([N:28]1[CH2:31][C:30](=[CH:32][C:33]#[N:34])[CH2:29]1)(=[O:27])=[O:26])[CH3:24].C1CCN2C(=NCCC2)CC1>CN(C)C=O.C1CCN2C(=NCCC2)CC1>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C:30]4([CH2:32][C:33]#[N:34])[CH2:31][N:28]([S:25]([CH2:23][CH3:24])(=[O:27])=[O:26])[CH2:29]4)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: CCS(=O)(=O)N1CC(=CC#N)C1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COC(=O)C(C)(C)C)cn2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
To a suspension of [4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (19, 10.0 g, 33.4 mmol) and 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (11, 6.22 g, 33.4 mmol, 1.0 equiv) in N,N-dimethylformamide (DMF, 20 mL) was added DBU (254 mg, 1.67 mmol, 0.05 equiv) drop wise to keep the reaction temperature between 15-25° C. After adding DBU, the reaction mixture became homogeneous within 90 min. The reaction mixture was stirred for 3 h at room temperature. When HPLC showed that the reaction was deemed complete, the reaction mixture was quenched with water (120 mL) and acetonitrile (80 mL). The resulting mixture was stirred at room temperature for an additional 30 min. The solids were collected by filtration, washed with a mixture of acetonitrile and water (2/3 by volume, 2×20 mL), and dried in vacuum oven at 40-45° C. for 24 h to afford crude (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 14.5 g, 16.2 g theoretical, 89.5% yield) as white solids, which was found to be sufficiently pure (>98.0% by HPLC) for the subsequent reaction without further purification. For 20: 1HNMR (CDCl3, 300 MHz), δ 8.87 (s, 1H), 8.43 (s, 1H), 8.37 (s, 1H), 7.51 (d, 1H, J=3.6 Hz), 6.76 (d, 1H, J=3.6 Hz), 6.26 (s, 2H), 4.64 (d, 2H, J=9.6 Hz), 4.25 (d, 2H, J=9.6 Hz), 3.41 (s, 2H), 3.09 (q, 2H, J=7.6 Hz), 1.42 (t, 3H, J=7.6 Hz), 1.17 (s, 9H) ppm; C22H27N7O4S (MW, 485.56), LCMS (EI) m/e 486 (M++H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:18])([CH3:17])[CH2:10]/[C:11](/[CH3:16])=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:41][N:42]([C@@H:59]([C:67](=[O:70])[NH:68][CH3:69])[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:43](=[O:58])[CH:44]([NH:56][CH3:57])[CH2:45][C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:18])([CH3:17])[CH2:10]/[C:11](/[CH3:16])=[CH:12]/[C:13](=[O:15])[N:56]([CH3:57])[C@@H:44]([C:43](=[O:58])[N:42]([CH3:41])[C@@H:59]([C:67](=[O:70])[NH:68][CH3:69])[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[CH2:45][C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C/C(=C\C(=O)O)CC(C)(C)NC(=O)OC(C)(C)C
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)C(Cc1ccc2ccccc2c1)NC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C(\C)CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.2 %

Procedure:
(2E)-5-tert-Butoxycarbonylamino-3,5-dimethylhex-2-enoic acid (0.30 g; 1.17 mmol.) was dissolved in methylene chloride (10 mL). 1-Hydroxy-7-azabenzotriazol (0.16 g; 1.17 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.26 g; 1.28 mmol) were added and the reaction mixture was stirred for 15 min at room temperature. N-Methyl-2-methylamino-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide (0.47 g; 1.67 mmol) was dissolved in methylene chloride (10 mL) and added. Diisopropylethylamine (0.20 mL; 1.66 mmol ) was added and the reaction was stirred for 12 hours at room temperature. Methylene chloride (10 mL) was added and the reaction was washed with water (10 mL), an aqueous solution of sodium hydrogen sulfate (10%; 10 mL) and an aqueous solution of sodium hydrogen carbonate (pH 8; 10 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (3×30 cm) using ethyl acetate/methylene chloride (1:1) as eluent to afford 0.37 g of ((3E)-1,1,3-trimethyl-4-(methyl-((1R)-1-(methyl-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamic acid tert butylester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([N:8]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:20][O:19]3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([N:8]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([OH:19])[CH2:20][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:14][CH:13]=2)(=[O:10])=[O:11])[CH:7]=1
Reactant: CC(C)CN(c1cc(Cl)ccc1F)S(=O)(=O)c1ccc(C2CO2)cc1
Reactant: C1COCCN1
Solvent: CCO
Product: CC(C)CN(c1cc(Cl)ccc1F)S(=O)(=O)c1ccc(C(O)CN2CCOCC2)cc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a stirred solution of N-(5-chloro-2-fluorophenyl)-N-isobutyl-4-(oxiran-2-yl)benzenesulfonamide (200 mg, 0.521 mmol) in ethanol (2 mL) at 25° C. was added morpholine (0.045 ml, 0.521 mmol) and the reaction mixture stirred at 50° C. for 24 hours. The mixture was then purified by mass directed autoprep (ammonium carbonate modifier). The appropriate fractions were combined and evaporated in vacuo to give the required product, 51.4 mg. LCMS [LCMS2] Rt 1.25 min, m/z (ES+) 471 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:18]=[C:19]([NH:27][C:28]2[N:37]=[CH:36][C:35]3[N:34]([CH3:38])[C:33](=[O:39])[CH2:32][N:31]([CH:40]([CH3:42])[CH3:41])[C:30]=3[N:29]=2)[CH:20]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:22]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13](=[O:15])[NH:16][C:17]2[CH:22]=[C:21]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:20]=[C:19]([NH:27][C:28]3[N:37]=[CH:36][C:35]4[N:34]([CH3:38])[C:33](=[O:39])[CH2:32][N:31]([CH:40]([CH3:42])[CH3:41])[C:30]=4[N:29]=3)[CH:18]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(N)cc(S(C)(=O)=O)c3)nc21
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)O)C1
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(NC(=O)[C@@H]4CCN(C(=O)OC(C)(C)C)C4)cc(S(C)(=O)=O)c3)nc21
Yield: 12 %

Procedure:
Starting from (R)-Pyrrolidine-1,3-dicarboxylic acid tert butyl ester (165 mg; 0.768 mmol) and 2-(3-amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (150 mg; 0.384 mmol), 27 mg (0.046 mmol; 12% yield) of the desired compound were obtained.
Reaction SMILES: C([C:4]1[CH:31]=[C:8]2[C:9]([N:11]([CH:14]([CH2:29][CH3:30])[C:15]([N:17]3[CH:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:19][NH:18]3)=[O:16])[C:12](=[O:13])[C:7]2=[CH:6][CH:5]=1)=[O:10])(O)=O.C(N1CC[O:37][CH2:36]C1)C.P(Cl)(Cl)(Cl)(Cl)Cl>O1CCCC1>[O:37]=[C:36]1[CH2:30][CH2:29][C@H:14]([N:11]2[C:12](=[O:13])[C:7]3=[CH:6][CH:5]=[CH:4][CH:31]=[C:8]3[C:9]2=[O:10])[C:15](=[O:16])[N:17]2[C@H:21]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:20][CH2:19][N:18]12
Reactant: CCC(C(=O)N1NCCC1C(=O)OC(C)(C)C)N1C(=O)c2ccc(C(=O)O)cc2C1=O
Reactant: CCN1CCOCC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCN2C(=O)CC[C@H](N3C(=O)c4ccccc4C3=O)C(=O)N12
Reaction time: 1 h
Yield: 33.3 %

Procedure:
A stirred solution of 3.45 g of tert.butyl 2-(5-carboxy-2-phthalimidobutyryl)-3-pyrazolidinecarboxylate and 0.92 g of N-ethylmorpholine in 50 ml of dry tetrahydrofuran was cooled to 0° C. and treated with 1.66 g of phosphorus pentachloride. After 1 hour, a further 0.92 g of N-ethylmorpholine and 1.66 g of phosphorus pentachloride were added and, after a further 1 hour, another 0.92 g of N-ethylmorpholine was added. The solvent was removed by evaporation and the residue was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate and evaporated. The oil obtained was chromatographed on silica gel. Elution with diethyl ether yielded firstly 1.1 g (33%) of tert.butyl 2,3,6,7,8,9-hexahydro-5,9-dioxo-8(S)-phthalimido-1H,5H-pyrazolo[1,2-α][1,2]diazepine-1(S)-carboxylate in the form of a white foam and then 0.52 g (15%) of tert.butyl 2,3,6,7,8,9-hexahydro-5,9-dioxo-8(S)-phthalimido-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1(R)-carboxylate in the form of a white solid of melting point 180°-181° C. (from ethyl acetate/n-hexane).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[CH3:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccc(Cl)nc1
Reactant: CN1CCNCC1
Product: CNC(=O)c1ccc(N2CCN(C)CC2)nc1
Temperature: 100 °C
Yield: 1011.7 %

Procedure:
A mixture of 52.0 g (30.5 mmol) 6-chloro-N-methyl-nicotinamide and 176 ml (1.58 mol) 1-methylpiperazine was heated at 100° C. for 1.5 h in an autoclave. After cooling to room temperature excess 1-methylpiperazine was removed by distillation. The residue was partitioned in 1000 ml dichloromethane/1 N aqueous sodium hydroxide solution. The layers were separated and the aqueous layer was extracted with three 500 ml portions of dichloromethane. Concentration and short column chromatography yielded 72.3 g (97%) of the title compound as a light brown solid.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[C:13]([CH2:16][C:17]([OH:19])=[O:18])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[C:20]([CH2:23]C1C=CC(OC2C=CC=CC=2C(O)=O)=CC=1)(O)=O>C(O)C>[O:1]=[C:2]1[C:15]2[CH:14]=[C:13]([CH2:16][C:17]([O:19][CH2:20][CH3:23])=[O:18])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: O=C(O)Cc1ccc(Oc2ccccc2C(=O)O)cc1
Reactant: O=C(O)Cc1ccc2oc3ccccc3c(=O)c2c1
Solvent: CCO
Product: CCOC(=O)Cc1ccc2oc3ccccc3c(=O)c2c1

Procedure:
9-Oxo-9H-xanthene-2-acetic acid, melting point 226°-228° C., is prepared from 2-(4-carboxymethylphenoxy)benzoic acid (Example 10f) analogously to Example 10c and is reacted with ethanol to give ethyl 9-oxo-9H-xanthene-2-acetate, melting point 97°-98° C.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[C:9]3[C:14]([CH:13]=[CH:12][CH:11]=[CH:10]3)=[C:6]2[N:5]=[C:4]([CH3:15])[C:3]=1[CH2:16][C:17]([O:19][CH3:20])=[O:18].CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:2]1[N:7]2[N:8]=[C:9]3[C:14]([CH:13]=[CH:12][CH:11]=[CH:10]3)=[C:6]2[N:5]=[C:4]([CH3:15])[C:3]=1[CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)Cc1c(C)nc2c3ccccc3nn2c1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COC(=O)Cc1c(C)nc2c3ccccc3nn2c1Cl
Temperature: 60 °C
Yield: 46 %

Procedure:
The methyl 2-(4-hydroxy-2-methylpyrimido[1,2-b]indazol-3-yl)acetate (1.34 g; 4.94 mmol) was suspended in phosphorus oxychloride (5.1 mL) and dimethylaniline (0.96 mL) was added under nitrogen atmosphere. The well-stirred reaction mixture was heated at 60° C. for 3 days. Phosphorus oxychloride in excess was removed under reduced pressure and the remaining oil was placed in an ice-bath. A cold saturated sodium hydrogenocarbonate solution was carefully added until neutralization. The aqueous layer was extracted with ethyl acetate, the organics were combined, dried over sodium sulfate, concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (1-20%) in dichloromethane furnished 0.659 g (46%) of methyl 2-(4-chloro-2-methylpyrimido[1,2-b]indazol-3-yl)acetate as a light yellow solid. ESI/APCI(+): 290-292 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[C:9]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:8][C:7]([CH3:16])=[N:6][C:5]=1[Cl:17].O[Li].O>O.O1CCOCC1>[Cl:17][C:5]1[N:6]=[C:7]([CH3:16])[CH:8]=[C:9]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:4]=1[C:3]([OH:18])=[O:2]
Reactant: CCC(CC)Nc1cc(C)nc(Cl)c1C(=O)OC
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CCC(CC)Nc1cc(C)nc(Cl)c1C(=O)O

Procedure:
The title compound was prepared by reaction of 2-chloro-4-(1-ethyl-propylamino)-6-methyl-nicotinic acid methyl ester with LiOH.H2O in a mixture of water and dioxane at room temperature. The desired product was acidified to pH 3 and extracted with ethyl acetate. The organic layer was dried and concentrated to dryness. The title compound was obtained as white crystals after titration with ethyl acetate. mp. 164-165° C.; anal. For C12H17Cl2O2 cacl. C, 56.14; H, 6.67; N, 10.91; found: C, 56.40; H, 6.53; H, 10.93.
Reaction SMILES: [CH3:1][C:2]1C=CC(C(C)C)=C[CH:7]=1.C([C:14]1[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:17]=[C:16](C(C)C)[CH:15]=1)(C)C>>[CH:2]([C:15]1[CH:14]=[CH:19][C:18]([CH:20]([CH3:21])[CH3:22])=[CH:17][CH:16]=1)([CH3:7])[CH3:1]
Reactant: Cc1ccc(C(C)C)cc1
Reactant: CC(C)c1cc(C(C)C)cc(C(C)C)c1
Product: CC(C)c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
[RuCl2 (1,3,5-triisopropylbenzene)]2 was prepared by stirring a suspension of [RuCl2 (P-cymene)]2 (3 g) in 120 mL 1,3,5-triisopropylbenzene (Aldrich, 97%) for a total of 8 hours at 190° C. under N2. The solution was cooled to room temperature and then placed in a refrigerator for 2-3 days. Solids were collected by cold filtration, washed with heptane, and dried in a vacuum oven at 70° C. A red-brown solid product was obtained (3.25 grams). 1H NMR analysis of this product was consistent with the material being 90+ % pure [RuCl2 (1,3,5-triisopropylbenzene)]2 with a small amount of unreacted [RuCl2 (p-cymene)]2. 1H NMR data for [RuCl2 (1,3,5-triisopropylbenzene)]2 (CDCl3 solvent): δ 1.3 (d, 18H), 3.1 (m, 3H), 5.2 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.I[CH2:31][CH3:32].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:31][CH3:32])[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: CCI
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN1CCC(c2cc(F)c(Nc3ncc(Cl)c(Nc4cc(C)[nH]n4)n3)cc2C)CC1
Temperature: 60 °C

Procedure:
A mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (400 mg, 0.96 mmol), iodoethane (92.5 μL, 1.2 mmol) and triethylamine (201.5 μL, 1.4 mmol) in 4 mL of DMF was heated at 60° C. for 2 h. The reaction mixture was partitioned between EtOAc and water. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by silica gel chromatography (MeOH/DCM: 1/9) to afford 5-chloro-N2-(4-(1-ethylpiperidin-4-yl)-2-fluoro-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine; 1HNMR (DMSO-d6) δ 8.01 (s, 1H), 7.35 (m, 1H), 7.02 (d, 1H), 6.22 (s, 1H), 2.97 (d, 2H), 2.62 (m, 1H), 2.34 (q, 2H), 2.21 (s, 3H), 2.13 (s, 3H), 1.98 (t, 2H), 1.64 (m, 4H), 1.01 (t, 3H); ESMS m/z 444.2 (M+H+).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[NH2:3].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.C(O)C>[CH:13](=[N:3][NH:2][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: NNc1ccccc1C(=O)O
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccccc1NN=Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution of 2-hydrazino-benzoic acid mono hydrochloric acid salt (13.66 g, 72.42 mmol) dissolved in water (580 mL) and ethanol (125 mL) was added a solution of benzaldehyde (7.35 mL, 72.42 mmol) in ethanol (20 mL) dropwise at room temperature. The reaction mixture was stirred at room temperature for an additional 3 hours. The resulting solid was collected by filtration and dried in a vacuum oven to provide 12.0 g (69%) of 2-(N′-benzylidene-hydrazino)-benzoic acid as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH2:20]1[C:24]2([CH2:28][CH2:27][NH:26][CH2:25]2)[CH2:23][CH2:22][NH:21]1>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:21]3[CH2:22][CH2:23][C:24]4([CH2:28][CH2:27][NH:26][CH2:25]4)[CH2:20]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: C1CC2(CCNC2)CN1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC4(CCNC4)C3)c(F)c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 103.3 %

Procedure:
A suspension of 0.81 g (3.0 mmol) 1-ethyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid in 40 ml acetonitrile was treated with 0.80 g (6.3 mmol) 2,7-diazaspiro[4.4]nonane [J. Org. Chem. 46, 2757 (1981)]and the mixture stirred two days at room temperature, refluxed 1.5 hours, cooled, and filtered to afford 1.17 g of the title compound, mp 234°-240° C. (dec). Analysis calculated for C19H21N3F2O3 ; C, 60.47; H, 5.61; N, 11.13. Found: C, 60.17; H, 5.46; N, 11.11.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:6]=[C:7]([C:11](=[O:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH:28]=[CH:29][C:30]#[C:31][C:32]([CH3:35])([CH3:34])[CH3:33]>>[CH3:33][C:32]([CH3:35])([CH3:34])[C:31]#[C:30]/[CH:29]=[CH:28]/[CH2:27][N:3]([CH2:4][C:5]1[CH:6]=[C:7]([C:11](=[O:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)[CH2:1][CH3:2]
Reactant: CCNCc1cccc(C(C)=O)c1
Reactant: CC(C)(C)C#CC=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(C(C)=O)c1
Yield: 62.4 %

Procedure:
The procedure described in Example 13 was repeated, except that 3′-(N-ethylaminomethyl)acetophenone (1.24 g; 7 mmol), sodium carbonate (instead of potassium carbonate) (745 mg; 7 mmol), and 1-bromo-6,6-dimethyl-2-hepten-4-yn (1.41 g; 7 mmol) were used, to thereby yield 1.30 g of the target compound (yield: 62.5%).
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[F:29][C:30]([F:43])([F:42])[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38](Cl)(=[O:40])=[O:39]>N.CO>[F:43][C:30]([F:29])([F:42])[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:40])=[O:39]
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1OC(F)(F)F)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 4.8 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 2-(Trifluoromethoxy)benzenesulfonyl chloride (26 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (1.0 mg). MS m/z 413 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:10][NH:11][CH3:12]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([N:11]([CH3:12])[CH3:10])[N:3]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: CNC
Solvent: CCO
Product: Cc1cc(N(C)C)nc(N)n1

Procedure:
2-Amino-4-methyl-6-chloropyrimidine (52 g, 0.36 mole) is heated at 160° C. for 18 hours with ethanol and an equimolar amount of dimethylamine in a pressure vessel. The reaction mixture is evaporated in vacuo taken up in 200 ml. of water containg 50 ml. 10 N sodium hydroxide and 300 ml. of methylene chloride. The mixture is extracted with methylene chloride and the organic layer dried and evaporated to dryness in vacuo affording 46 g of 2-amino-4-methyl-6-dimethylaminopyrimidine with a melting point of 172°-174° C.