Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl-].FC(F)(F)C(O)=O.[NH2:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41]([C:46]([NH:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[C:52]([O:57][C:58]3[CH:63]=[C:62]([C:64]#[N:65])[CH:61]=[C:60]([Cl:66])[CH:59]=3)[C:51]=1[F:67])=[O:47])=[CH:40]2.[CH3:68][C:69]([O:72][CH2:73][CH2:74][C:75](O)=[O:76])([CH3:71])[CH3:70].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][NH:48][C:46]([C:41]2[NH:42][C:43]3[C:39]([CH:40]=2)=[CH:38][C:37]([NH:36][C:75](=[O:76])[CH2:74][CH2:73][O:72][C:69]([CH3:71])([CH3:70])[CH3:68])=[CH:45][CH:44]=3)=[O:47])=[C:51]([F:67])[C:52]=1[O:57][C:58]1[CH:63]=[C:62]([C:64]#[N:65])[CH:61]=[C:60]([Cl:66])[CH:59]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Reactant: CC(C)(C)OCCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OCCC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
BOP chloride (0.079 g, 0.309 mmol) was added to a solution of 5-amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.060 g, 0.103 mmol), 3-[(1,1-dimethylethyl)oxy]propanoic acid (0.015 mL, 0.103 mmol) and diisopropylethylamine (0.090 mL, 0.514 mmol) in DMF (1 mL). the mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (hexane:ethyl acetate) to give the title compound (0.036 g, 58%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.49 (s, 1H), 9.69 (s, 1H), 8.95 (t, 1H), 7.95 (s, 1H), 7.77 (d, 1H), 7.40-7.52 (m, 3H), 7.36 (t, 1H), 7.26-7.32 (m, 1H), 7.21 (d, 1H), 7.06 (s, 1H), 4.52 (d, 2H), 3.57 (t, 2H), 2.41 (t, 2H), 1.09 (s, 9H). ES MS: m/z 597 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][O:11][CH3:12])[CH2:7][N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:4].[Li+].[OH-].Cl.BrC[C:25]([C:27]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=1)=[O:26].C(N(CC)CC)C>CO>[C:16]([O:15][C:13]([N:6]1[CH2:7][CH:8]([CH2:10][O:11][CH3:12])[CH2:9][CH:5]1[C:3]([O:2][CH2:1][C:25]([C:27]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=1)=[O:26])=[O:4])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: COCC1CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Product: COCC1CC(C(=O)OCC(=O)c2ccc(Br)cc2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.3 %

Procedure:
4-Methoxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (461 mg, 1.68 mmol) was dissolved in MeOH (17 mL) and LiOH (1 M in H2O, 8.5 mL, 8.5 mmol) was added. After stirring at RT for 5 h, the MeOH was removed under reduced pressure. The aqueous solution was poured into a separatory funnel, diluted with 1 M HCl (9 mL, 9 mmol) and extracted with DCM (3×). The combined organics were dried over MgSO4, filtered and concentrated. The residue was dissolved in MeCN (17 mL) and treated with 2,4′-dibromoacetophenone (514 mg, 1.85 mmol), and triethylamine (0.258 mL, 1.85 mmol). After stirring for 2 h, the solvent was removed and the solid was suspended in EtOAc. The organic layer was washed with saturated aqueous NaHCO3 and brine then dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (15% to 35% EtOAc/Hex) to afford the title compound (746 mg, 97%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:18])[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.C(N(CC)CC)C>O1CCOCC1>[C:1]1([C:7]2[N:8]=[C:9]([NH:18][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[S:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1nc(-c2ccccc2)c(-c2ccccc2)s1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc(C(=O)Nc2nc(-c3ccccc3)c(-c3ccccc3)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4,5-Diphenyl-thiazol-2-ylamine (50.5 mg, 0.200 mmol) and 4-methoxy-benzoyl chloride (34.1 mg, 0.200 mmol) were dissolved in 1,4-dioxane (2 mL) containing triethylamine (84.1 μL, 0.600 mmol). The reaction mixture was stirred overnight at room temperature. The crude product was filtered, evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (12.5 mg, 0.0323 mmol, 16.2%). ESI-MS m/z calc. 386.1, found 387.2 (M+1)+ Retention time 3.95 minutes.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH3:10])=[N+:5]([O-:9])[CH:6]=[CH:7][CH:8]=1)[CH3:2].S(=O)(=O)(O)O.[N+:16]([O-])([OH:18])=[O:17]>>[CH2:1]([C:3]1[C:4]([CH3:10])=[N+:5]([O-:9])[CH:6]=[CH:7][C:8]=1[N+:16]([O-:18])=[O:17])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCc1ccc[n+]([O-])c1C
Agent: O=S(=O)(O)O
Product: CCc1c([N+](=O)[O-])cc[n+]([O-])c1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
While cooling a mixture of 3-ethyl-2-methylpyridine 1-oxide (7.35 g, 53.6 mmol) and sulfuric acid (22.7 g, 231 mmol) in an ice bath, fuming nitric acid (3.64 ml, 87.9 mmol) was added dropwise, which was stirred at 80° C. for 8 hours. The reaction mixture was cooled to room temperature and then poured into ice. The obtained aqueous solution was extracted three times with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtrated and concentrated to obtain the title compound (3.37 g, yield: 34.5%) as yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C1COC=CC1.C1C2C(=CC=CC=2)C=CC=1.ClC1C2C(=CC=CC=2)CCC1>>[CH2:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:7][CH2:8][CH2:9]1
Reactant: Clc1cccc2ccccc12
Agent: C1=COCCC1
Agent: ClC1CCCc2ccccc21
Solvent: c1ccc2ccccc2c1
Product: c1ccc2c(c1)CCCC2

Procedure:
The method of example 6 was repeated (at 400° C. only) using 1:10 chloronaphthalene to DHP weight ratio. Conversion was 6% with 71% selectivity to naphthalene and 29% chlorotetralin. No tetralin was produced.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]1[CH2:10][C@@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].Br.[CH3:32][C@@H:33]1[CH2:37][CH2:36][CH2:35][NH:34]1>CN(C=O)C>[CH3:32][C@@H:33]1[CH2:37][CH2:36][CH2:35][N:34]1[CH2:6][CH2:7][C@H:8]1[CH2:10][C@@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: C[C@@H]1CCCN1
Reactant: CS(=O)(=O)OCC[C@H]1C[C@@H]1c1ccc(-c2ccc(C#N)cc2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN1CC[C@H]1C[C@@H]1c1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of the mesylate from Example 28G (methanesulfonic acid, 2-[(1R,2S)-2-(4′-cyano-biphenyl-4-yl)-cyclopropyl]-ethyl ester) and potassium carbonate in DMF was added (R)-2-methylpyrrolidine hydrobromide [CAS 117607-13-3]. The mixture was stirred at 50° C. overnight. The mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with brine, dried (MgSO4), and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel eluted with 7.5/20/70 MeOH/EtOAc/CH2Cl2 to provide the title compound. 1H NMR (300 MHz, CDCl3, free base): δ 0.88-1.0 (m, 2H), 1.18 (d, J=6 Hz, 3H), 1.4-2.4 (m, 11H), 2.9 (m, 1H), 3.15-3.23 (m, 1H), 7.15 (d, J=9 Hz, 2H), 7.47 (d, J=9 Hz, 2H), 7.66 (q, J=9 Hz, 4H). MS (DCl—NH3) m/z 331.2 (M+H)+. Anal, Calc. for C23H26N2.C4H6O6 1.25H2O (L-tartaric acid salt): C, 64.46; H, 6.91; N, 5.57. Found: C, 64.46; H, 6.91; N, 5.57.
Reaction SMILES: O[CH2:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1.[C:8]1(=[O:18])[NH:12][C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:13]=[C:11]1[C:10]2[C:9](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8](=[O:18])[N:12]1[CH2:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: N#CC1(CO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#CC1(CN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 68.3 %

Procedure:
A solution of 1-(hydroxymethyl)-cyclopropanecarbonitrile (5.52 g, 56.8 mmol), phthalimide (9.20 g, 62.5 mmol), and triphenylphosphine (16.4 g, 62.5 mmol) in THF (550 mL) was treated with DEAD (9.90 mL, 62.5 mmol) and stirred at room temperature for 17 hours. The reaction mixture was then concentrated and the resulting solids were triturated in diethyl ether (150 mL), and collected by filtration. Purification by flash chromatography (SiO2, 0-20% EtOAc in DCM) afforded 1-((1,3-dioxoisoindolin-2-yl)methyl)-cyclopropanecarbonitrile (8.8 g, 38.8 mmol, 68%) as a white solid: LCMS (m/z) 227.0 (MH+), tR=0.66 minute; 1H NMR (300 MHz, CDCl3) δ 7.90 (dd, J=5.4, 3.1 Hz, 2H), 7.77 (dd, J=5.4, 3.1 Hz, 2H), 3.81 (s, 2H), 1.30-1.44 (m, 2H), 1.28 (d, J=3.8 Hz, 2H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([C@@H:10]1[NH:15][CH2:14][CH2:13][N:12]([C:16]2[N:17]([CH2:38][C:39]([F:42])([F:41])[F:40])[C:18]3[C:23]([N:24]=2)=[C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:21]=[C:20]([C:31]2[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=2)[N:19]=3)[CH2:11]1)[CH3:9].C(N(CC)CC)C>C(Cl)Cl>[C:1]([N:15]1[CH2:14][CH2:13][N:12]([C:16]2[N:17]([CH2:38][C:39]([F:42])([F:41])[F:40])[C:18]3[C:23]([N:24]=2)=[C:22]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[N:21]=[C:20]([C:31]2[CH:36]=[N:35][C:34]([NH2:37])=[N:33][CH:32]=2)[N:19]=3)[CH2:11][C@@H:10]1[CH2:8][CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1C(C)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.8 %

Procedure:
Acetic anhydride (0.035 ml, 0.38 mmol) was added dropwise to a methylene chloride solution (6 ml) of 5-{8-[(3S)-3-ethylpiperazin-1-yl]-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl}pyrimidin-2-amine (123 mg, 0.25 mmol) and triethylamine (0.069 ml, 0.50 mmol) with ice cooling and the resulting mixture was stirred at room temperature for 1.5 hours. The resulting mixture was partitioned with ethyl acetate and saturated aqueous ammonium chloride solution and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (chloroform:methanol=95:5) to give the title compound (92 mg) as a pale yellow solid.
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]3[CH2:22][CH2:21][CH2:20]NC3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.C1(C(Cl)=[O:27])CC1>C(Cl)Cl>[N:1]1([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]3[CH:21]([CH:20]=[O:27])[CH2:22]3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2c(c1)nnn2-c1ccnc(NC2CCCNC2)n1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Product: O=CC1CC1Nc1nccc(-n2nnc3ccccc32)n1
Temperature: 25 °C

Procedure:
To DCM (8 mL) was added (4-benzotriazol-1-yl-pyrimidin-2-yl)-piperidin-3-ylamine (0.15 g), cyclopropylformyl chloride (40.5 μL) and TEA (0.285 mL), and the mixture stirred at RT. The product was purified by column chromatography on silica, using 100% DCM to 10% MeOH/DCM, then recrystallized from EtOAc to provide [3-(4-benzotriazol-1-yl-pyrimidin-2-ylamino)]-cyclopropylmethanone. Mp=99.0-100.0° C., 1H nmr (300 MHz, DMSO-d6): δ ppm 0.54-0.82 (m, 4H), 1.40-1.77 (m, 2H), 1.78-1.93 (m, 2H), 2.01-2.19 (m, 2H), 3.13 (t, J=11.11 Hz, 2H), 3.84-4.10 (m, 2H), 4.32 (d, J=11.68 Hz, 1H), 7.37 (d, J=5.27 Hz, 1H), 7.48-7.61 (m, 1H), 7.62-7.74 (m, 1H), 8.08-8.23 (d, 1H), 8.51 (d, J=5.27 Hz, 1H), 8.67 (d, J=8.29 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH2:17][CH:18]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)[CH2:19][CH2:20]S(C)(=O)=O)[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1.I.[NH:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[C:43]([CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=[O:44]>>[CH3:1][N:2]([CH2:17][CH:18]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)[CH2:19][CH2:20][N:48]1[CH2:49][CH2:50][CH:45]([C:43]([C:35]2[NH:34][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[N:36]=2)=[O:44])[CH2:46][CH2:47]1)[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1
Reactant: COc1cc(C(=O)N(C)CC(CCS(C)(=O)=O)c2ccc(Cl)c(Cl)c2)cc(OC)c1OC
Reactant: O=C(c1nc2ccccc2[nH]1)C1CCNCC1
Agent: I
Product: COc1cc(C(=O)N(C)CC(CCN2CCC(C(=O)c3nc4ccccc4[nH]3)CC2)c2ccc(Cl)c(Cl)c2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-(3,4-dichlorophenyl)-4-methanesulfonylbutyl)-3,4,5-trimethoxybenzamide and 4-(1H-benzimidazole-2-carbonyl)piperidine hydriodic acid salt to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([OH:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=1[CH3:15])=[O:5].[OH-].[Na+].Cl[CH:24]([F:26])[F:25]>C(COC)OC.O>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([O:12][CH:24]([F:26])[F:25])[C:9]([O:13][CH3:14])=[CH:8][C:7]=1[CH3:15])=[O:5]
Reactant: FC(F)Cl
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1OC(F)F
Temperature: 60 °C

Procedure:
To a solution of 2,6-dichloro-5'-hydroxy-4'-methoxy-2'-methyl-benzophenone (1.0 g; 3.2 mmol) in dimethoxyethane (7 ml) a solution of sodium hydroxide (0.6 g; 15 mmol) in water (1 ml) is added. The mixture is heated to 60° C. with stirring, then a stream of chlorodifluoromethane is introduced for 20 minutes. After further stirring for 1.5 hours the solvent is evaporated. The residue is extracted with a mixture of trichloromethane and water. The organic phase is separated, dried and the solvent is evaporated. For purification, a flash column with silicagel (30 g) is used (elution with mixtures of petrolether/ethylacetate 9:1, then 8:2, then 7:3 (v/v)). The resulting compound forms white crystalls (0.6 g; 51.8% y); mp. 126-128° C.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([C:13](Cl)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[C:16]([O:20][C:21]([N:23]1[CH2:27][C@@H:26]([CH2:28][N:29]([CH:46]([CH3:48])[CH3:47])[C:30](=[O:45])[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])[CH:32]=2)[C@H:25]([CH2:49][NH:50][CH:51]2[CH2:53][CH2:52]2)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[C:16]([O:20][C:21]([N:23]1[CH2:27][C@@H:26]([CH2:28][N:29]([CH:46]([CH3:47])[CH3:48])[C:30](=[O:45])[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])[CH:32]=2)[C@H:25]([CH2:49][N:50]([CH:51]2[CH2:52][CH2:53]2)[C:13]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:14])[CH2:24]1)=[O:22])([CH3:18])([CH3:19])[CH3:17]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC2CC2)C(C)C)ccc1OC
Reactant: O=C(Cl)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)N2CCCC2)C2CC2)C(C)C)ccc1OC
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Triethylamine (99 μL, 0.714 mmol) followed by 1-pyrrolidinecarbonyl chloride is added to a solution of ((3R*,4R*)-3-cyclopropylaminomethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (254 mg, 0.476 mmol) in CH2Cl2 (20 mL). The resulting solution is stirred at RT for 2 h and at 60° C. for another 24 h. Evaporation of the solvent affords the crude product which is purified by preparative HPLC (Waters C18 ODB, eluent: H2O/CH3CN 20 to 100%) to give the title compound. MS (LC-MS): 631.1 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 6.31 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]12(O)[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2.OS(O)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:9]12([C:6]3[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[OH:8])[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2
Reactant: Oc1ccc(Br)cc1
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Yield: 73.6 %

Procedure:
To a mixture of 4-bromophenol (34.60 g, 200 mmol) and 1-adamantanol (30.45 g, 200 mmol) in 100 mL of anhydrous CH2Cl2 at room temperature was added dropwise over 10–15 minutes concentrated H2SO4 (11 mL). After 1.5 hours a thick suspension resulted and the reaction was allowed to continue for a total of 24 hours. The suspension was carefully poured into ice water and neutralized with solid NaHCO3. The resulting layers were separated and the aqueous layer extracted with CH2Cl2 (2×). The combined organics were washed with brine, dried (MgSO4) and filtered. The solvent was removed under reduced pressure and the resulting solid was purified on silica gel (hexane:ethyl acetate 85:15), the impure fractions were further purified by recrystallization from hexane and the two lots combined to give 45.2 g (74%) of 2-(1-adamantyl)-4-bromophenol. 1H NMR (300 MHz; CDCl3): δ 1.77 (s, 6H), 2.08 (s, 9H), 4.81 (s, 1H), 6.53 (d, J=8.4 Hz, 1H), 7.14 (dd, J1=8.7 Hz, J2=2.4 Hz, 1H), 7.29 (d, J=2.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=O)=[C:4]([OH:13])[C:3]=1[F:14].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>CN(C)C=O>[C:26]([O:25][C:23](=[O:24])[CH2:22][O:13][C:4]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=[C:2]([Cl:1])[C:3]=1[F:14])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1CCCc2c1cc(Cl)c(F)c2O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1c(F)c(Cl)cc2c1CCCC2
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a stirred solution of 7-chloro-6-fluoro-5-hydroxy-3,4-dihydro-2H-naphthalen-1-one (0.90 g, 4.18 mmol) in dry N,N-dimethylformamide (10 mL) was added potassium carbonate (1.16 g, 8.36 mmol) and tert-butyl bromoacetate (1.22 g, 6.27 mmol) at room temperature and the resulting mixture was stirred for 2 hours, then extracted with ethyl acetate (25 mL×3), washed with water (25 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford (3-chloro-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (1.32 g, 96%), which was used in the next step without further purification. MS cald. for C16H18ClFO4 328, obsd. 329 [(M+H)+].
Reaction SMILES: [N:1]1([C:6]2[CH:31]=[CH:30][C:9]3[N:10]([C:13]4[CH:14]=[C:15]([NH:26]C(=O)C)[CH:16]=[C:17]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=5)[CH:18]=4)[CH:11]=[N:12][C:8]=3[CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[OH-].[Na+]>C(O)C>[N:1]1([C:6]2[CH:31]=[CH:30][C:9]3[N:10]([C:13]4[CH:14]=[C:15]([NH2:26])[CH:16]=[C:17]([C:19]5[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=5)[CH:18]=4)[CH:11]=[N:12][C:8]=3[CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2)cc(-n2cnc3cc(-n4cccn4)ccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(-c2ccc(F)cc2)cc(-n2cnc3cc(-n4cccn4)ccc32)c1
Temperature: 85 °C
Yield: 84 %

Procedure:
To a solution of the compound of Example 70 (0.6 g, 1.46 mmol) in ethanol (40 ml) was added aqueous solution of NaOH (1.0 g, 25 mmol, 17.1 eq.) and the mixture was heated at 85° C. for 5 h. The mixture was quenched and extracted as in Example 1(d). The combined organic layer was washed with water, brine and dried over sodium sulphate. The solvent was distilled off to afford the product in 84% yield (0.45 g).
Reaction SMILES: [F:1][C:2]1[CH:56]=[CH:55][C:5]([CH2:6][NH:7][C:8]([O:10][CH2:11][C@H:12]2[N:17](C(OC(C)(C)C)=O)[CH2:16][C@@H:15]([CH2:25][CH2:26][C:27]3[C:28]([NH:33][C:34](=[O:54])[C@H:35]([CH:41]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[NH:36][C:37]([O:39][CH3:40])=[O:38])=[N:29][CH:30]=[CH:31][CH:32]=3)[O:14][CH2:13]2)=[O:9])=[CH:4][CH:3]=1.C(Cl)Cl.[C:60]([OH:66])([C:62]([F:65])([F:64])[F:63])=[O:61]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([O:10][CH2:11][C@H:12]2[NH:17][CH2:16][C@@H:15]([CH2:25][CH2:26][C:27]3[C:28]([NH:33][C:34](=[O:54])[C@H:35]([CH:41]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[NH:36][C:37]([O:39][CH3:40])=[O:38])=[N:29][CH:30]=[CH:31][CH:32]=3)[O:14][CH2:13]2)=[O:9])=[CH:55][CH:56]=1.[C:60]([OH:66])([C:62]([F:65])([F:64])[F:63])=[O:61]
Reactant: COC(=O)N[C@H](C(=O)Nc1ncccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCc2ccc(F)cc2)CO1)C(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)Nc1ncccc1CC[C@@H]1CN[C@H](COC(=O)NCc2ccc(F)cc2)CO1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl (2R,5S)-5-({[(4-fluorobenzyl)carbamoyl]oxy}methyl)-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}pyridin-3-yl)ethyl]morpholine-4-carboxylate in a 1:1 mixture of CH2Cl2/TFA (0.1 M) was stirred at rt for 1 hr. The reaction mixture was concentrated under reduced pressure and the residue was co-evaporated twice with heptane and triturated in Et2O to afford the desired product as a TFA salt. Alternatively, the TFA salt, after concentration, could be neutralized with aqueous saturated NaHCO3, extracted with EtOAc, dried over Na2SO4, filtered and concentrated and then purified by automated SiO2 flash chromatography system using solvent gradient of 0% to 10% MeOH/CH2Cl2 to afford the desired compound. Alternatively, the free base could be purified by filtration on SCX SPE cartridge made of pTSA-SiO2 eluted first with MeOH to remove non basic impurities and eluted then with 10% NH4OH/MeOH to elute the free base and afford the desired compound after concentration under reduced pressure.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:17])[CH3:16])[CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[CH3:19][O:20][C:21]([C:23]1[O:24][C:25]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][C:26]=2[CH:27]=1)=[O:22]>>[F:18][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:17])[CH3:16])[CH:10]=2)=[N:7][C:2]([NH:32][C:29]2[CH:30]=[CH:31][C:25]3[O:24][C:23]([C:21]([O:20][CH3:19])=[O:22])=[CH:27][C:26]=3[CH:28]=2)=[N:3][CH:4]=1
Reactant: CC(C)c1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Product: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(C(C)C)c4)n3)ccc2o1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hyroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-isopropylphenyl)-4-pyrimidineamine and 2-methoxycarbonyl-5-aminobenzofuran were reacted to give 5-fluoro-N4-(3-isopropylphenyl)-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine. LCMS: retn, time: 26.05 min.; purity: 99%; MS (m/e): 420 (M+), 422 (MH+); 1H NMR (DMSO-d6): δ 10.00 (1H, s), 9.95 (1H, s), 8.31 (1H, d, J=4.8 Hz), 8.11 (1H, s), 7.74 (3H, m), 7.35 (1H, s), 7.35 (1H, t, J=7.2 Hz), 7.12 (1H, d, J=7.2 Hz), 3.99 (3H, s), 2.83 (1H, sept, J=6.9 Hz), 1.20 (6H, d, J=6.9 Hz).