Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:24])[N:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[N:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]1.C1(C(N)C2CCCCC2)CCCCC1.[CH3:39][OH:40]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:4]2[C:3](=[O:24])[C:2]3[C:39]([OH:40])=[C:9]4[C:10](=[O:15])[N:11]([CH3:14])[CH2:12][CH2:13][N:8]4[C:7]=3[CH:6]=[N:5]2)=[CH:18][CH:19]=1
Reactant: CN1CCN(c2cnn(Cc3ccc(F)cc3)c(=O)c2Br)CC1=O
Reactant: CO
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: NC(C1CCCCC1)C1CCCCC1
Product: CN1CCn2c(c(O)c3c(=O)n(Cc4ccc(F)cc4)ncc32)C1=O
Temperature: 90 °C

Procedure:
A mixture of 4-bromo-2-(4-fluorobenzyl)-5-(4-methyl-3-oxopiperazin-1-yl)pyridazin-3(2H)-one (0.2 g, 0.51 mmol), dicyclohexylmethylamine (0.15 g, 0.76 mmol), and bis-(tri-t-butylphosphine)palladium (0) (52 mg, 0.10 mmol) in anhydrous methanol (5 mL) was heated in a stainless steel pressure vessel under an atmosphere of carbon monoxide (250 psi) in an oil bath at 90° C. overnight. The resultant mixture was diluted with methanol, filtered through a pad of Celite. The filtrate was concentrated under vacuum. The residual oil was triturated with methanol. The white solid precipitated was filtered to provide the titled dione.
Reaction SMILES: [F:1][C:2]1([F:15])[O:7][C:6]2[CH:8]=[CH:9][C:10]([NH2:12])=[CH:11][C:5]=2[O:4][C:3]1([F:14])[F:13].[CH2:16](Br)[C:17]#[CH:18].C1(C)C=CC=CC=1>FC1C=CC=CC=1>[CH2:18]([NH:12][C:10]1[CH:9]=[CH:8][C:6]2[O:7][C:2]([F:1])([F:15])[C:3]([F:13])([F:14])[O:4][C:5]=2[CH:11]=1)[C:17]#[CH:16]
Reactant: C#CCBr
Reactant: Nc1ccc2c(c1)OC(F)(F)C(F)(F)O2
Solvent: Fc1ccccc1
Solvent: Cc1ccccc1
Product: C#CCNc1ccc2c(c1)OC(F)(F)C(F)(F)O2
Temperature: 50 °C

Procedure:
2,2,3,3-Tetrafluoro-6-aminobenzodioxane (6.694 g, 30.0 mmol) and Aldrich basic alumina (activated, Brockmann 1, 150 mesh, CAS#1344-28-1) (51 g) were mixed in fluorobenzene (100 mL) and then treated with 80% propargyl bromide in toluene (2.56 mL, 23.0 mmol). The resulting mixture was thoroughly stirred and heated at 50° C. for 17 hours. The mixture was cooled to ambient temperature and filtered. The alumina was rinsed thoroughly with dichloromethane (150 mL), the filtrate was reduced in volume under reduced pressure, washed with concentrated aqueous NH4OH (5 mL), dried (Na2SO4), concentrated and chromatographed on silica eluting with 0-10% EtOAc/hexanes to provide the titled compound. 1H NMR (CDCl3) δ ppm 2.24 (t, 1H), 3.92 (m, 2H), 3.96 (m, 1H), 6.43 (d, 1H), 6.45 (dd, 1H), 6.96 (d, 1H); MS (DCI) 262 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)=[CH:4][C:5]([Br:8])=[N:6][CH:7]=1.[CH:23](OCC)(OCC)OCC>>[Br:8][C:5]1[N:6]=[CH:7][C:2]2[N:1]=[CH:23][N:9]([CH:10]3[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]3)[C:3]=2[CH:4]=1
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2cc(Br)ncc2N)C1
Product: CC(C)(C)OC(=O)N1CCCC(n2cnc3cnc(Br)cc32)C1
Yield: 69.9 %

Procedure:
A mixture of tert-butyl 3-((5-amino-2-bromopyridin-4-yl)amino)piperidine-1-carboxylate (1.1 g, 3.0 mmol, 1.0 eq) in CH(OCH2CH3)3 (214 mg, 30 mmol, 10 eq) was refluxed for 40 h. Then the residual CH(OCH2CH3)3 was removed in vacuum and the crude product was purified by silica gel column chromatography with EtOAc in PE (½ v/v) to give the title compound (0.8 g, 70%) as yellow oil. 1H NMR (400 MHz, CDCl3) δ: 8.87 (s, 1H), 8.06 (s, 1H), 7.62 (s, 1H), 4.30-4.28 (m, 2H), 4.02-4.00 (m, 1H), 3.27-3.22 (m, 1H), 3.09-3.03 (m, 1H), 2.31-2.30 (m, 1H), 2.13-2.10 (m, 1H), 1.88-1.85 (m, 1H), 1.74-1.71 (m, 1H), 1.50 (s, 9H). ESI-MS (M+H+): 381.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([OH:11])=O)[CH:3]=1.[NH2:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1>>[NH:14]1[C:13]([NH:12][C:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=2)=[O:11])=[N:17][N:16]=[N:15]1
Reactant: Cc1cc(C)nc(C(=O)O)c1
Reactant: Nc1nnn[nH]1
Product: Cc1cc(C)nc(C(=O)Nc2nnn[nH]2)c1
Yield: 40.2 %

Procedure:
0.81 g of 4.6-dimethyl-2-pyridinecarboxylic acid, 0.86 g of N,N'-carbonyldiimidazole and 0.54 g of 5-aminotetrazole are treated in the same manner as described in Example 2. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and ethanol, whereby 0.47 g of N-(5-tetrazolyl)-4,6-dimethyl-2-pyridinecarboxamide is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:62])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:61])[C:48]([NH:56][C:57]([O:59][CH3:60])=[O:58])([C:50]6[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=6)C)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:63]([O:67]C(N1CCCC1C(O)=O)=O)(C)(C)C.COC(NC(C1C=CC=CC=1)C(O)=O)=O.COC(NC(C1C=CC=CC=1)(C)C(O)=O)=O>>[CH3:1][O:2][C:3](=[O:62])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH:45]([O:67][CH3:63])[CH2:44][N:43]6[C:47](=[O:61])[CH:48]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]6[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=6)=[N:40][CH:41]=5)=[CH:35][CH:36]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:7])[CH3:8]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(C)(NC(=O)OC)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Agent: COC(=O)NC(C(=O)O)c1ccccc1
Agent: COC(=O)NC(C)(C(=O)O)c1ccccc1
Product: COC(=O)NC(C(=O)N1CC(OC)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1

Procedure:
[1-(2-{5-[6-(4-{2-[4-Methoxy-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester was prepared following the procedure for [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester, substituting 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester for Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and Methoxycarbonylamino-phenyl-acetic acid for 2-Methoxycarbonylamino-2-phenyl-propionic acid. LCMS-ESI+: calc'd for C48H52N8O7: 852.40 (M+); Found: 853.43 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:5][CH2:6][C:7]#[N:8].N1C=CC=CC=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>O>[CH2:13]([O:12][C:11]1[CH:10]=[CH:9][C:4]([O:5][CH2:6][C:7]#[N:8])=[CH:3][C:2]=1[NH:1][S:27]([CH3:26])(=[O:29])=[O:28])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: N#CCOc1ccc(OCc2ccccc2)c(N)c1
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1cc(OCC#N)ccc1OCc1ccccc1
Reaction time: 1 h
Yield: 46.3 %

Procedure:
A solution of 5.9 g of (3-amino-4-benzyloxy-phenoxy)-acetonitrile and 24 ml of pyridine was cooled in an ice bath and treated at a dropwise rate with 3.46 g of methanesulfonyl chloride and stirred for 1 hour. The mixture was treated with 5 ml of water, removed the ice bath, and stirred at room temperature for 30 minutes. The mixture was poured into ethyl acetate, ice added, acidified with concentrated hydrochloric acid, washed with brine, dried (MgSO4), and evaporated. The residue was purified on silica gel eluting with ethyl acetate/hexane (2:5) and obtained 3.57 g of N-(2-benzyloxy-5-cyanomethoxy-phenyl)-methanesulfonamide as a cream solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:21]([CH3:23])[CH3:22])=[CH:4][CH:3]=1.[BH3:24].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH3:32][S:33]([O:20][CH2:19][CH2:18][CH:14]1[C:13]2[N:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:10]([CH:21]([CH3:23])[CH3:22])=[N:11][C:12]=2[CH2:17][CH2:16][CH2:15]1)(=[O:35])=[O:34].[BH3:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(CCO)CCC2
Agent: B
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(CCOS(C)(=O)=O)CCC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A stirred suspension of Intermediate 76 (830 mg) in Dichloromethane (DCM) (40 mL), under nitrogen, was treated with triethylamine (0.501 mL) then cooled to ca. 0° C. (ice bath). Methanesulfonyl chloride (0.222 mL) was added via syringe, then the cooling bath was removed and stirring continued for 2 h. The solution was partitioned between aqueous ammonium chloride (200 ml) and DCM (200 ml). The layers were separated and the aqueous phase was further extracted with DCM (200 ml). The combined organic extracts were washed with water (200 mL), dried (Na2SO4), filtered through a hydrophobic frit and evaporated in vacuo. The crude product was purified by column chromatography (silica, 0-25% Methanol in DCM). The appropriate fractions were combined and concentrated to afford the title compound, 368 mg. LC/MS (M-BH2)-411/413, Rt 2.18 mins (5 min run, TFA modifier).
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9](O)=[O:10])=[CH:4][CH:3]=1.S(N(C1C=C(C(O)=O)C(N(S(=O)(=O)N)C2C=CC=CC=2)=CC=1C(O)=O)C1C=CC=CC=1)(=O)(=O)N>>[CH3:1][C:2]1[CH:28]=[CH:27][C:5]2[NH:6][C:7]3[C:8]([C:9](=[O:10])[C:4]=2[CH:3]=1)=[CH:12][C:13]1[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=2[C:16](=[O:18])[C:14]=1[CH:15]=3
Reactant: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Agent: NS(=O)(=O)N(c1ccccc1)c1cc(C(=O)O)c(N(c2ccccc2)S(N)(=O)=O)cc1C(=O)O
Product: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1

Procedure:
Pigmentary 2,9-dimethylquinacridone was prepared exactly as described in comparison Example 1 except that 2% by weight, relative to the 2,5-di(4-methylanilino)terephthalic acid, of 2,5-di(sulfamoylanilino)terephthalic acid (1.4 g) was included in the ring-closure reaction. 2,9-Dimethylquinacridone (58 g) was obtained as a magenta pigment.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[S:7].[Cl-].[NH4+].CO>[Zn].O>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[S:7]
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=S)c1c(C)cccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=S)c1c(C)cccc1Cl
Temperature: 55 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a mixture of N-[(2-chloro-6-methylphenyl)thioxomethyl]-4-nitro-L-phenylalanine methyl ester (3.86 mmol, 1.52 g), zinc dust (˜325 mesh, 39.0 mmol, 2.55 g, 10 equiv.) and ammonium chloride (58.0 mmol, 3.09 g, 15 equiv.) was added methanol (50 mL) and water (25 mL) at room temperature. After addition of water, an exothermic reaction ensued and the temperature rose to between 45 and 50° C. After the suspension was stirred for 2 h at a bath temperature of 50-60° C., TLC analysis of the mixture indicated the absence of starting material. The reaction mixture was filtered through a pad of celite and the filter cake was washed with methanol (50 mL) and water (40 mL). The filtrate was concentrated under vacuum to remove methanol and the product was extracted into ethyl acetate (2×50 mL). The combined extracts were washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo to give 1.3 g (92%) of 4-amino-N-[(2-chloro-6-methylphenyl)thioxomethyl]-L-phenylalanine methyl ester as an amorphous yellow solid, which was used directly for next step. HRMS: Obs. mass, 363.0932. Calcd. mass, 363.0934 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:36])[CH2:9][CH2:10][CH:11]2[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:13]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33]F)=[CH:25][CH:24]=3)[C:12]2=[O:35])=[CH:4][CH:3]=1.[CH3:37][NH:38][CH2:39][CH2:40][S:41]([OH:44])(=[O:43])=[O:42].C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:36])[CH2:9][CH2:10][CH:11]2[C:12](=[O:35])[N:13]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][N:38]([CH3:37])[CH2:39][CH2:40][S:41]([OH:44])(=[O:43])=[O:42])=[CH:27][CH:28]=3)[CH:14]2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(OCCCCF)cc2)cc1
Reactant: CNCCS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(OCCCCN(C)CCS(=O)(=O)O)cc2)cc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 31 %

Procedure:
130 mg of 3-[3-(4-fluorophenyl)-3-hydroxypropyl]-1-[4-(4-fluorobutoxy)phenyl]-4-(4-methoxyphenyl)azetidin-2-one (7) were dissolved in 6 ml of absolute methanol. 120 mg of N-methyltaurine in 2 ml of water and 60 mg of potassium carbonate were then added. The mixture was stirred at 50° C. for 24 h. The reaction mixture was concentrated using a rotary evaporator and the residue was purified by preparative chromatography. Freeze-drying gave the product (50 mg) as an oil.
Reaction SMILES: [CH:1]([OH:3])=[O:2].F[C:5]1[CH:13]=[C:12]([NH:14][C:15]2[N:20]=[C:19]([NH:21][CH2:22][C:23]3[C:24]([N:29]([CH3:34])[S:30]([CH3:33])(=[O:32])=[O:31])=[N:25][CH:26]=[CH:27][CH:28]=3)[C:18]([C:35]([F:38])([F:37])[F:36])=[CH:17][N:16]=2)[CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8].NC1C=CC(C(N)=O)=CC=1[F:49]>C(O)=O>[CH:1]([OH:3])=[O:2].[F:49][C:13]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:14][C:15]1[N:20]=[C:19]([NH:21][CH2:22][C:23]2[C:24]([N:29]([CH3:34])[S:30]([CH3:33])(=[O:32])=[O:31])=[N:25][CH:26]=[CH:27][CH:28]=2)[C:18]([C:35]([F:36])([F:38])[F:37])=[CH:17][N:16]=1)[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1ccc(N)c(F)c1
Reactant: CN(c1ncccc1CNc1nc(Nc2ccc(C(N)=O)c(F)c2)ncc1C(F)(F)F)S(C)(=O)=O
Solvent: O=CO
Product: CN(c1ncccc1CNc1nc(Nc2ccc(C(N)=O)cc2F)ncc1C(F)(F)F)S(C)(=O)=O

Procedure:
Compound 14 was prepared in a manner similar to that described Example 13 for the preparation of 13 except that 4-amino-3-fluorobenzamide (1.5 equ/189 μM) was used instead of 4-amino-2-fluorobenzamide to provide the formic acid salt of 14 as a cream colored solid. Yield: 26 mg, 37%. LC-MS M+1=514. NMR (d6-DMSO) : 2.98 (3H, s), 3.09 (3H, s), 4.65 (2H, s), 7.35-7.66 (7H, m), 7.87 (1H, s), 8.23 (1H, s), 8.38 (1H, s), 9.19 (1H, s). FAK IC50: <0.000595 μM (Table 1, Example 322)
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1>C(Cl)Cl.CO>[NH2:1][CH2:2][CH:8]1[CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)CC1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CN)CC1

Procedure:
4-Amino-1-tert-butyloxycarbonylazacycloheptane colourless oil; RF : 0.36 (alumina; methylene chloride/methanol=9:1)
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[S:11][C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=2)[CH:3]=1.CCOC(C1(C(OCC)=O)NC(=O)CC1C1C=CC=CC=1)=O.[Cl:40][C:41]1[CH:47]=[CH:46][CH:45]=[C:44]([CH3:48])[C:42]=1[NH2:43].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[S:11][C:12]([C:15]([NH:43][C:42]3[C:44]([CH3:48])=[CH:45][CH:46]=[CH:47][C:41]=3[Cl:40])=[O:17])=[CH:13][N:14]=2)[CH:3]=1
Reactant: Cc1nc(Br)cc(Nc2ncc(C(=O)O)s2)n1
Reactant: Cc1cccc(Cl)c1N
Agent: CCOC(=O)C1(C(=O)OCC)NC(=O)CC1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(Br)cc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)n1
Temperature: 0 °C
Yield: 77.5 %

Procedure:
Under nitrogen atmosphere, 2-(6-bromo-2-methylpyrimidin-4-ylamino)thiazole-5-formic acid (Compound 12) (15.8 g, 0.05 mol), PDCP (9.0 mL, 0.06 mol) and 2-chloro-6-methylaniline (Compound 8)) (7.4 mL, 0.06 mol) were added into methylene dichloride (650 mL) by stirring and cooling, and then triethylamine (20.4 mL, 0.15 mol) was added by droplets at 0° C. When finish adding, it reacted by stirring at room temperature overnight. Saturated sodium bicarbonate aqueous solution was added and stirred for 15 mins and then filtrated. The cake was taken up and added in DMSO (80 mL) and heated to 60° C.-70° C. when stirring. After dissolving, the mixture of water and ethanol (1:1, 320 mL) was added in thermal insulation. Crystals precipitated by stirring and then cooled down to 0° C. to grow the grain for 1 h. After air pump filtration the cake was rinsed by water and then by the mixture of water and ethanol (1:1), and dried by air pump. With phosphorus pentoxide as an auxiliary desiccant, the cake was dried by vacuum (−0.095 MPa) at about 50° C. to give Compound 14 (17.0 g, yield: 77.5%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.[F:26][C:27]([F:45])([F:44])[C:28]1[CH:29]=[C:30]([C:38]([CH3:43])([CH3:42])[C:39](Cl)=[O:40])[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1>ClCCl>[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:39](=[O:40])[C:38]([C:30]2[CH:29]=[C:28]([C:27]([F:26])([F:44])[F:45])[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=2)([CH3:43])[CH3:42])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Nc1ccccc1S(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C(=O)Nc1ccccc1S(=O)(=O)c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
A solution of 233 mg (1.0 mmol) 2-aminophenyl phenyl sulfone and 0.25 ml (1.5 mmol) N-ethyldiisopropylamine in 2 ml dichloromethane was cooled in an ice bath and a solution of 350 mg (1.1 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 1 ml dichloromethane was added dropwise. The reaction mixture was stirred at room temperature overnight, evaporated and the residue was purified by flash chromatography to give 490 mg (95%) of the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:29])([F:28])[CH:20]([OH:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:27][CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:19]([F:18])([F:28])[F:29])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCC(O)C(F)(F)F
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC(OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In 20 ml of methylene chloride was dissolved 1.0 g of 4-benzyloxybenzoic acid chloride, and a solution of 0.67 g of optically active 1,1,1-trifluoro-2-octanol, 0.36 g of triethylamine, and a catalytic amount of dimethylaminopyridine in 10 ml of methylene chloride was slowly added thereto under ice-cooling. The reaction mixture was allowed to warm to room temperature, stirred at that temperature for 12 hours, poured into ice-water and extracted with methylene chloride. The methylene chloride phase was washed successively with diluted hydrochloric acid, water, an aqueous 1N sodium carbonate solution, and water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain a crude product. The crude product was purified by column chromatography using silica gel to obtain 0.65 g of 1,1,1-trifluoro-2-octyl 4-benzyloxybenzoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH2:11].[Br:12]Br.C([O-])(O)=O.[Na+]>CC(O)=O>[Br:12][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([F:1])[C:3]=1[NH2:11]
Reactant: BrBr
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1c(F)cc([N+](=O)[O-])cc1Br
Temperature: 20 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
To a solution of 2-fluoro-4-nitro-phenylamine (12 g, 77 mmol) in AcOH (50 mL) was added Br2 (3.9 mL, 77 mmol) dropwise at 0° C. The mixture was stirred at 20° C. for 3 h. The reaction mixture was basified with sat. aq. NaHCO3, and extracted with EtOAc (100 mL×3). The combined organics were dried over anhydrous Na2SO4 and evaporated under vacuum to give 2-bromo-6-fluoro-4-nitro-phenylamine (18 g, 97%). 1H NMR (400 MHz, CDCl3) δ 8.22 (m, 1H), 7.90 (dd, J=2.4, 10.8 Hz, 1H), 4.88 (brs, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[N:6][CH:7]=1.[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([N:8]([CH3:14])[S:9]([CH3:12])(=[O:10])=[O:11])=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(NS(C)(=O)=O)ncc1Br
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cc(N(C)S(C)(=O)=O)ncc1Br

Procedure:
The product from step (i) (2.23 g), potassium carbonate (2.33 g) and methyl iodide (0.7 ml) were stirred in DMF (20 ml) for 20 h. The reaction was quenched with water, extracted with EtOAc, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica eluting with 30% EtOAc/isohexane. Yield 1.5 g. Carried forward to step (ii) without characterisation.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([N:16]1[C:25](=[O:26])[C:24]2[NH:23][C:22]([C:27]3[N:31]([CH3:32])[N:30]=[C:29]([O:33][CH2:34][C:35](O)=[O:36])[CH:28]=3)=[N:21][C:20]=2[N:19]([CH2:38][CH2:39][CH3:40])[C:17]1=[O:18])[CH2:14][CH3:15]>>[CH3:40][CH2:39][CH2:38][N:19]1[C:17](=[O:18])[N:16]([CH2:13][CH2:14][CH3:15])[C:25](=[O:26])[C:24]2[C:20]1=[N:21][C:22]([N:23]=2)=[C:27]1[N:31]([CH3:32])[NH:30][C:29]([O:33][CH2:34][C:35]([N:10]2[CH2:11][CH2:12][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)=[O:36])=[CH:28]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CCC)c1=O
Product: CCCn1c(=O)c2c(n(CCC)c1=O)=NC(=C1C=C(OCC(=O)N3CCN(c4ccccc4)CC3)NN1C)N=2

Procedure:
Using N-phenyl-piperazine and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (Example 36), according to the method described in Example 36.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.Cl.[CH3:17][N:18]([CH2:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)[CH3:19]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:25][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:18]([CH3:19])[CH3:17])=[CH:27][CH:26]=1
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Agent: Cl
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN(C)C)cc1
Yield: 70 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (500 mg, 1.76 mmol) was reacted with 4-((dimethylamino)methyl)aniline hydrochloride (479 mg, 2.56 mmol) to afford the desired product (491 mg, 70%) as a yellow solid. ESI MS m/z 398 [C20H20BrN3O+H]+