Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH2:4].[C:11](Cl)(=O)[CH3:12]>>[CH3:11][CH:12]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:2]([CH3:1])[CH2:3][NH:4]1
Reactant: CC(=O)Cl
Reactant: CC(CN)c1ccccc1
Product: CC1CNC(C)c2ccccc21

Procedure:
In accordance with the same procedures as in Preparation 1-1, except that 14.5 ml of β-methylphenethyl-amine(0.1M) and 7.8 ml of acetyl chloride(0.11M) were used as starting materials, 6.6 g of the title compound was prepared.
Reaction SMILES: [NH2:1][C:2]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:3]=1/[CH:4]=[CH:5]/[C:6]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14](=[O:22])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[CH3:28][O:27][C:26]1[CH:25]=[CH:24][CH:23]=[C:3](/[CH:4]=[CH:5]/[C:6]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14](=[O:22])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=2)[C:2]=1[NH:1][S:30]([CH3:29])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc(/C=C/c2nc3ccccc3c(=O)n2-c2ccccc2)c1N
Solvent: c1ccncc1
Product: COc1cccc(/C=C/c2nc3ccccc3c(=O)n2-c2ccccc2)c1NS(C)(=O)=O
Yield: 83.9 %

Procedure:
A solution of 14 (123 mg, 0.333 mmol) and MsCl (260 μL, 3.33 mmol) in pyridine (20 mL) was heated to ˜70° C. under N2 for 2 days. The mixture was concentrated in vacuo, and the residue was dissolved in CHCl3, washed with 10% citric acid, dried and concentrated in vacuo. The crude product was purified by flash chromatography eluting with EtOAc/DCM (5-20%) to give pure 15 as a white solid (125 mg, 84%). MS (APCI): m/z 448 (100%, [M+H]+).
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[N:5]=1)[CH3:2].S(OC)(O[CH3:18])(=O)=O>[OH-].[Na+]>[CH2:12]([N:3]([CH2:1][CH3:2])[C:4]1[N:5]=[C:6]([O:11][CH3:18])[CH:7]=[C:8]([OH:10])[N:9]=1)[CH3:13]
Reactant: CCN(CC)c1nc(O)cc(O)n1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: CCN(CC)c1nc(O)cc(OC)n1

Procedure:
500 cc of sodium hydroxide solution 1N are added while stirring to 91.5 g (0.5 mol) of 2-diethylamino-4,6-dihydroxy-pyrimidine. The solution is stirred at 50° for a short period and then cooled to 20° . 63 g (0.5 mol) of dimethyl sulphate are added dropwise, over the course of 1 hour, to the clear solution; by further addition of 1N sodium hydroxide solution the pH value is kept between 7.5 and 8. A total of approximately 100 cc of 1N sodium hydroxide solution is additionally required. The mixture is stirred for a further 5 hours at room temperature and the precipitated crystals are filtered off at 5°; then they are washed with water. The crystalline product is subsequently triturated with 1500 cc of carbon tetrachloride by means of a vibration mixer. The undissolved parts are suction filtered and the carbon tetrachloride solution is then concentrated by evaporation, whereupon crystallization commences; 200 cc of petroleum ether are then added.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH2:21][OH:22]>>[F:1][C:2]1[CH:3]=[C:4]([C:10](=[N:21][OH:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(=O)Cc2ccc(SC)cc2)cc1F
Reactant: NO
Product: COc1ccc(C(Cc2ccc(SC)cc2)=NO)cc1F
Yield: 91 %

Procedure:
1-(3-Fluoro-4-methoxyphenyl)-2-[4-(methylthio)phenyl]-ethan-1-one oxime was prepared in 91% yield by treatment of 1-(3-fluoro-4-methoxyphenyl)-2-[4-(methylthio)phenyl]-ethan-1-one from Step 1 with hydroxylamine: 1H NMR (CDCl3 /300 MHz) δ 7.40 (dd, J=12.69, 2.22 Hz, 1H), 7.30 (d, J=8.66 Hz, 1H), 7.18-7.12 (m, 4H), 6.88 (dd, J=8.66, 8.46 Hz, 1H), 4.10 (s, 2H), 3.87 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1.[Cl:27][C:28]1[N:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.Cl>C1COCC1>[Cl:19][C:6]1[CH:5]=[C:4]([NH:20][S:34]([C:31]2[CH:32]=[N:33][C:28]([Cl:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH:3]=[CH:2][C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccc(Sc2ccc3ccccc3c2)c(Cl)c1)c1ccc(Cl)nc1
Reaction time: 15 h
Yield: 57.3 %

Procedure:
To a 0.35M solution of 3-chloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (90) (150 mg, 0.53 mmol) in THF was added pyridine (Aldrich, 0.21 mL, 2.63 mmol) followed by 6-chloro-pyridine-3-sulfonyl chloride (Qorpark, 122 mg, 0.58 mmol). The resulting mixture was stirred for 15 hours. A 1M aqueous solution of HCl (20 mL) was added and the crude reaction mixture was extracted 3× with EtOAc (50 mL). The organic layers were combined and washed twice with a brine solution (100 mL), dried over Na2SO4, and concentrated under vacuum. The crude solid was chromatographed (5-15% EtOAc in hexane) to yield 140 mg (58%) of 94 as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:29])[C@@H:16]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:17]O)[CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[C:23]1([S:20]([N@:19]2[CH2:17][CH:16]2[C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:14][CH2:13]2)=[O:29])(=[O:22])=[O:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)[C@H](CO)NS(=O)(=O)c3ccccc3)CC2)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccc(C)c(N2CCN(C(=O)C3C[N@@]3S(=O)(=O)c3ccccc3)CC2)c1

Procedure:
In analogy to example 2, N-{(S)-2-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-1-hydroxymethyl-2-oxo-ethyl}-benzenesulfonamide was reacted with triphenylphosphine and diethylazodicarboxylate to give ((S)-1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH3:11])[CH3:2].[N+:12]([O-])([OH:14])=[O:13]>C(OC(=O)C)(=O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:12]([O-:14])=[O:13])=[CH:6][C:5]=1[CH2:10][CH3:11])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOc1ccccc1CC
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOc1ccc([N+](=O)[O-])cc1CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-ethoxy-2-ethyl benzene (3.5 g, Reference Example 51) in acetic anhydride (30 mL) was chilled in an ice-water bath. A solution of nitric acid (1.4 mL of 90%-30% excess) in acetic acid (25 mL) was added dropwise and the mixture was stirred overnight at ambient temperature. The reaction mixture was poured into ice water (300 mL) and the aqueous mixture was extracted with ethyl acetate (2×200 mL). The combined extracts were evaporated and the residue was chromatographed on silica gel (heptane with gradient of 5 to 10% ethyl acetate) to give 1-ethoxy-2-ethyl-4-nitrobenzene (1.4 g) as a clear liquid. LC-MS (Method E) RT=3.75 minutes, 196 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][NH:11][C:12]2[CH:31]=[CH:30][C:15]([C:16]([NH:18][C:19]([NH:21][NH:22]C(OC(C)(C)C)=O)=[O:20])=O)=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].O1CCOCC1.[ClH:38]>ClCCl>[ClH:38].[ClH:38].[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][NH:11][C:12]2[CH:31]=[CH:30][C:15]([CH2:16][NH:18][C:19]([NH:21][NH2:22])=[O:20])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CNc2ccc(C(=O)NC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(CNc2ccc(CNC(=O)NN)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a suspension of tert-butyl 2-{[4-({[2-(acetylamino)-1,3-thiazol-4-yl]methyl}amino)benzoyl]carbamoyl}hydrazinecarboxylate (306.2 mg, 0.705 mmol) in anhydrous dichloromethane (7 ml) was added 4M hydrogen chloride dioxane solution (7.0 ml, 28.0 mmol). The mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was concentrated again under reduced pressure. This operation was repeated 3 times to remove hydrogen chloride azeotropically. The residue was suspended in ethyl acetate, and the suspension was filtered, washed twice with ethyl acetate, and dried under reduced pressure. The residue was recrystallized by dissolving in methanol (3.6 ml) and then addition of ethyl acetate (12 ml). The crystals were collected by filtration, and dried under reduced pressure to give the title compound (272.8 mg, 0.670 mmol, yield 95.0%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:10]2)=[N:6][C:7]=1[NH2:8].[CH3:22][N:23]1[C:27]([C:28]2([C:31](=N)OCC)[CH2:30][CH2:29]2)=[N:26][CH:25]=[N:24]1.[S].C(O)(=O)C>C(O)C>[CH3:22][N:23]1[C:27]([C:28]2([C:31]3[NH:8][C:7]4=[N:6][C:5]([N:9]5[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]6[CH2:21][CH2:20][CH2:19][CH2:18]6)=[O:16])[CH2:10]5)=[CH:4][CH:3]=[C:2]4[N:1]=3)[CH2:30][CH2:29]2)=[N:26][CH:25]=[N:24]1
Reactant: CCOC(=N)C1(c2ncnn2C)CC1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: [S]
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1ncnc1C1(c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)CC1
Temperature: 80 °C
Yield: 18 %

Procedure:
(R)-(1-(5,6-Diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone, prepared during the previous step, was added to a suspension of ethyl 1-(1-methyl-1H-1,2,4-triazol-5-yl)cyclopropanecarbimidate (0.39 g, 2.0 mmol), sulfur (20 mg, 0.31 mmol) and acetic acid (0.96 mL, 15.5 mmol) in ethanol (10 mL) at room temperature. The reaction mixture was heated to 80° C. for 16 h. The mixture was concentrated under reduced pressure and the resulting crude was dissolved in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting crude was purified via preparative TLC to afford the title compound (120 mg, 18%). MS (ES+APCI) (M+H) 421.2; LCMS retention time: 3.311 min (Method Y1).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][CH:33]([N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:43]1[N:48]2[CH:49]=[CH:50][N:51]=[C:47]2[CH:46]=[CH:45][CH:44]=1>C1COCC1.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.[Cu]I>[N:51]1[CH:50]=[CH:49][N:48]2[C:43]([C:11]3[N:12]=[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[C:8]4[S:28][C:27]([CH2:29][N:30]5[CH2:35][CH2:34][CH:33]([N:36]6[CH2:41][CH2:40][O:39][CH2:38][CH2:37]6)[CH2:32][CH2:31]5)=[CH:26][C:9]=4[N:10]=3)=[CH:44][CH:45]=[CH:46][C:47]=12
Reactant: Brc1cccc2nccn12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCC(N4CCOCC4)CC3)cc2n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(-c2nc(N3CCOCC3)c3sc(CN4CCC(N5CCOCC5)CC4)cc3n2)n2ccnc2c1
Temperature: 140 °C
Yield: 42.3 %

Procedure:
A mixture of 4-morpholin-4-yl-6-(4-morpholin-4-ylpiperidin-1-ylmethyl)-2-(tributylstannanyl)thieno[3,2-d]pyrimidine (69 mg, 0.10 mmol), 5-bromoimidazo[1,2-a]pyridine (24 mg, 0.12 mmol), Pd(PPh3)4(11 mg, 0.01 mmol) and copper(I) iodide (23 mg, 0.12 mmol) in THF (1 mL) was purged with argon gas then heated at 140° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH then the product was eluted with 2 M NH3 in MeOH. The appropriate fractions were evaporated and the resulting residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 3:97) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 70:30 to 2:98) to give 687 as a white solid (22 mg, 42%). LCMS (Method F): RT 3.90 min; [M+H]+ 520. 1H NMR (400 MHz, CHCl3-d): δ 9.23 (s, 1 H); 7.95 (dd, J=7.2, 1.2 Hz, 1 H); 7.77 (d, J=8.9 Hz, 1 H); 7.75 (d, J=1.2 Hz, 1 H); 7.35 (s, 1 H); 7.31 (dd, J=8.9, 7.2 Hz, 1 H); 4.07 (t, J=4.7 Hz, 4 H); 3.91 (t, J=4.7 Hz, 4 H); 3.84 (s, 2 H); 3.74 (t, J=4.4 Hz, 4 H); 3.05 (d, J=11.4 Hz, 2 H); 2.57 (t, J=4.4 Hz, 4 H); 2.29-2.19 (m,1 H); 2.15 (t, J=11.4 Hz, 2 H); 1.87 (d, J=12.5 Hz, 2 H); 1.65-1.59 (m, 2 H)
Reaction SMILES: C(N(CC)CC)C.[S:8](Cl)([CH3:11])(=[O:10])=[O:9].[CH2:13]([N:17]1[C:25]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:24][C:23]2[C:18]1=[N:19][C:20]([C:38]1[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=1)=[N:21][C:22]=2[N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[CH:14]([CH3:16])[CH3:15]>CN1C(=O)CCC1>[CH2:13]([N:17]1[C:25]([N:26]2[CH2:31][CH2:30][N:29]([S:8]([CH3:11])(=[O:10])=[O:9])[CH2:28][CH2:27]2)=[N:24][C:23]2[C:18]1=[N:19][C:20]([C:38]1[CH:43]=[N:42][C:41]([NH2:44])=[N:40][CH:39]=1)=[N:21][C:22]=2[N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[CH:14]([CH3:16])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Cn1c(N2CCNCC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(C)Cn1c(N2CCN(S(C)(=O)=O)CC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reaction time: 1 h
Yield: 51 %

Procedure:
Triethylamine (143 μl) and mesyl chloride (50 μl, 0.63 mmol) were added to 5-(9-isobutyl-6-morpholin-4-yl-8-piperazin-1-yl-9H-purin-2-yl)pyrimidin-2-amine (2 ml of solution of 100 mg of this compound in 1 ml of NMP) and the resulting mixture was stirred for 1 hour. Mesyl chloride (50 μl, 0.63 mmol) was further added, the resulting mixture was stirred for 1 hour, then the reaction mixture was partitioned with ethyl acetate and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (135 mg, 51%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C=O)C>[Cl:1][C:2]1[N:6]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(Cl)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-1H-benzo[d]imidazole (10 g) and NaH (60% in oil, 3.15 g) in DMF (150 mL) was added ethyl bromoacetate (11.0 mL) at 0° C. After stirring overnight at room temperature, the reaction mixture was quenched with water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The precipitate was crystallized from AcOEt/hexane to give the title compound (12 g).
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=O.Cl.[CH3:15][O:16][NH2:17].C1(C)C(C)=CC=CC=1>O>[CH3:15][O:16][N:17]1[C:1](=[O:13])[CH2:2][C:3]2[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5]1=[O:7]
Reactant: CON
Reactant: O=C(O)Cc1ccccc1C(=O)O
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: O
Product: CON1C(=O)Cc2ccccc2C1=O

Procedure:
A mixture of homophthalic acid (9.0 g., 0.05 mole) and methyoxyamine hydrochloride (4.25 g., 0.05 mole) in 125 ml. of xylene was refluxed for 90 minutes, with water collected in Dean Stark trap as it formed. The reaction mixture was cooled and concentrated by vacuum to one half its original volume, then diluted with ethylacetate, washed with water and dried over sodium sulfate. Recrystallization from isopropanol and ethanol, followed by drying at 100° C. for 4 hours yielded pale pink crystals of 2-methoxyisoquinoline-1,3 (2H, 4H)-dione, m.p. 113°-114° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:10]1[N:11]=[CH:12][C:13]([C:16]([NH:18][C:19]2[NH:20][N:21]=[C:22]([CH2:24][CH2:25][C:26]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=3)[CH:23]=2)=[O:17])=[N:14][CH:15]=1>CS(C)=O.CO>[CH3:35][O:34][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][C:22]2[CH:23]=[C:19]([NH:18][C:16]([C:13]3[CH:12]=[N:11][C:10]([N:5]4[CH2:6][CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:15][N:14]=3)=[O:17])[NH:20][N:21]=2)[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=1
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Reactant: CN1CCCNCC1
Solvent: CO
Solvent: CS(C)=O
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCCN(C)CC4)cn3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
1-methyl-1,4-diazepane (0.20 ml, 1.60 mmol) was added to 5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (310 mg, 0.80 mmol) in DMSO (4.00 ml) at 25° C. The resulting solution was stirred at room temperature for 1 h. The reaction mixture was diluted with MeOH (5 ml) and the crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford crude product as an orange dry film. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (296 mg, 79%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:28])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][N:17]1[C:18](=[O:27])[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]1=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(O)cc1CN1C(=O)c2ccccc2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCc1ccc(O)cc1CN1C(=O)c2ccccc2C1=O
Temperature: 40 °C

Procedure:
A 1 gallon autoclave was charged with 3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-hydroxy-phenyl]-acrylic acid tert-butyl ester (196 g, 0.517 mol), ethyl acetate (2.6 L) and 5% palladium on carbon (75 g). The autoclave was kept at 25° C. under 60 psi of hydrogen for 21 h. The temperature of the reaction was increased to 40° C., and the pressure was increased to 75 psi for 5 h. The mixture was filtered through a pad of hyflo and concentrated to the title compound (186 g, 94.4%): MS (ESI) m/z 380.2 (M−H)−.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:10][C:11]([C:13]1[CH:14]=[C:15]([F:42])[C:16]([CH3:41])=[C:17]([C:19]2[CH:27]=[C:26]3[C:22]([C:23]([C:28]4[CH2:29][CH2:30][N:31](C(OC(C)(C)C)=O)[CH2:32][CH:33]=4)=[N:24][NH:25]3)=[CH:21][CH:20]=2)[CH:18]=1)=[O:12])[CH3:9]>ClCCl>[CH2:8]([NH:10][C:11](=[O:12])[C:13]1[CH:18]=[C:17]([C:19]2[CH:27]=[C:26]3[C:22]([C:23]([C:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH:33]=4)=[N:24][NH:25]3)=[CH:21][CH:20]=2)[C:16]([CH3:41])=[C:15]([F:42])[CH:14]=1)[CH3:9]
Reactant: CCNC(=O)c1cc(F)c(C)c(-c2ccc3c(C4=CCN(C(=O)OC(C)(C)C)CC4)n[nH]c3c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC(=O)c1cc(F)c(C)c(-c2ccc3c(C4=CCNCC4)n[nH]c3c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 2908.5 %

Procedure:
Trifluoroacetic acid (2.73 ml) was added dropwise to a solution of 1,1-dimethylethyl 4-(6-{5-[(ethylamino)carbonyl]-3-fluoro-2-methylphenyl}-1H-indazol-3-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (Intermediate 20, 50 mg) in dichloromethane (10 ml) at room temperature under nitrogen then stirred at room temperature for 1 h. More trifluoroacetic acid (1.73 ml) was added and the mixture was stirred at room temperature under nitrogen for a further 1 h. The solvent was removed and the residue was dissolved in methanol and applied to an SCX ion exchange cartridge. Elution with a solution of ammonia (0.88) in methanol gave the title compound as a white solid (1.15 g).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)=[C:8]([CH2:21][OH:22])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH:23]1([NH2:27])[CH2:26][CH2:25][CH2:24]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:27][CH:23]3[CH2:26][CH2:25][CH2:24]3)=[O:18])=[CH:14][N:13]=2)=[C:8]([CH2:21][OH:22])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1noc(CO)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCc1noc(CO)c1COc1ccc(C(=O)NC2CCC2)cn1
Temperature: 25 °C
Reaction time: 17 h
Yield: 62.6 %

Procedure:
To a solution of 6-[3-butyl-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (49 mg, 0.16 mmol) in DMF (2 mL) was added cyclobutylamine (25 mg, 0.35 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (82 mg, 0.26 mmol) and N-ethyldiisopropylamine (136 μL, 0.80 mmol) with DMF (1 mL). The reaction mixture was stirred for 17 h at room temperature. The reaction was partitioned between water and ethyl acetate. The aqueous phase was extracted two times with ethyl acetate and the combined organic phases were washed with brine, dried over sodium sulfate and concentrated to a yellow oil. The crude material was purified by chromatography (silica, dichloromethane:methanol 100:0 to 97:3) to afford the title compound (36 mg, 63%) as a colorless gum. MS: m/e=360.3 [M+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[C:34](Br)[C:35]([Cl:37])=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2].[CH3:39]B(O)O.[F-].[Cs+]>O1CCOCC1>[CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[C:34]([CH3:39])[C:35]([Cl:37])=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2]
Reactant: CB(O)O
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Cl)c(Br)cc21
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Cl)c(C)cc21
Temperature: 100 °C
Yield: 77.6 %

Procedure:
A mixture of 5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-7-bromo-8-chloro-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (0.118 g, 0.187 mmol), methyl boronic acid (0.0340 g, 0.561 mmol) and cesium fluoride (0.0990 mg, 0.655 mmol) in dioxane (2.00 ml) was purged with nitrogen for 10 minutes. To it was added PdCl2(dppf) (0.0240 g) in one portion. The mixture was heated at 100° C. overnight. The solid was removed by filtration, washed with ethyl acetate (30.0 ml) and the filtrate was concentrated in vacuo. Purification by silica gel chromatography (gradient eluent, 0-35% ethyl acetate in hexane) provided the titled compound (0.0820 g, 77%) as white foamy solid. MS (ES+): 565 (M+H).