Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]/[C:2](/[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)=[CH:3]\[C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14](=S)[S:15]C)=[O:5].C[O-].[Na+].Cl>CO>[OH:5][C:4]1[C:6]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:12])[CH:11]=2)[NH:13][C:14](=[S:15])[C:3]=1[C:2]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)=[O:1]
Reactant: CSC(=S)Nc1ccc(C)cc1C(=O)/C=C(\O)c1ccc(C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(C(=O)c2c(O)c3cc(C)ccc3[nH]c2=S)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
Keto-enol 7 (2.12 g, 5.93 mmol) was added to 100 mL of a 0.5 M solution of sodium methoxide in methanol and the mixture was stirred at 0° C. for 3 hours. A 1.0 M solution of hydrochloric acid (53 mL) was poured onto the reaction and the mixture was concentrated to less than half its volume under reduced pressure. The obtained slurry was stirred for 30 min at room temperature and then filtrated. The precipitate was washed with 20 mL of water and 20 mL of methanol, subsequently. The crude product was precipitated from acetone to give 13 as a yellow solid (1.70 g, 93%). mp: 280° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:12](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O.N>C(O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(O)cc(Cl)c1
Agent: N
Agent: [K+]
Solvent: CCO
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COc1cc(Cl)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
10 g 3-chloro-5-nitrophenol are dissolved in 250 ml of ethanol. 11.9 g potassium carbonate and 6 ml dimethylsulphate are added and the mixture is stirred for 12 hours at ambient temperature. Then 3 ml of a 33% ammonia solution are added and then the ethanol is eliminated in vacuo. The residue is taken up in water and the precipitated solid is suction filtered and dried.
Reaction SMILES: Br[CH2:2][CH3:3].[C:4]([O:8][C:9](=[O:30])[NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]1[C:17]2[C:22]([CH:23]=[C:24]3[C:29]=1[CH:28]=[CH:27][CH:26]=[CH:25]3)=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH3:7])([CH3:6])[CH3:5].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:4]([O:8][C:9](=[O:30])[NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:15][C:16]1[C:17]2[C:22]([CH:23]=[C:24]3[C:29]=1[CH:28]=[CH:27][CH:26]=[CH:25]3)=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:2][CH3:3])([CH3:7])([CH3:5])[CH3:6]
Reactant: CCBr
Reactant: CC(C)(C)OC(=O)NCCCNCc1c2ccccc2cc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CCCNC(=O)OC(C)(C)C)Cc1c2ccccc2cc2ccccc12
Temperature: 75 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Bromoethane (489 mg, 4.48 mmol) was dissolved in anhydrous acetonitrile and was added to the stirring mixture of compound 12a (545 mg, 1.5 mmol) and anhydrous K2CO3 (620 mg, 4.48 mmol). The mixture was then stirred at 75° C. under a N2 atmosphere overnight. After the confirmation of the disappearance of the 12a by TLC, the solution was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (20 mL) and washed three times with aqueous sodium carbonate. The organic layer was separated, dried with anhydrous Na2SO4, filtered and concentrated under vacuum. Flash column chromatography of the residue gave 12b as a light yellow oil. Yield 80%; Rf=0.35 (3% MeOH/CHCl3); 1H NMR (CDCl3) δ 8.39 (d, 2H), 8.30 (s, 1H), 7.90 (d, 2H), 7.40 (m, 4H), 4.54 (br t, 1H), 4.37 (s, 2H), 2.74 (q, 2H), 2.60 (q, 2H), 2.39 (t, 2H), 1.44 (q, 2H), 1.31 (m, 9H), 1.12 (t, 3H); 13C NMR (CDCl3) δ 155.7, 131.3 (2C), 131.2 (2C), 130.4 (2C), 129.0 (2C), 127.5 (2C), 125.7 (2C), 124.8 (2C), 78.3, 50.6, 50.5, 47.7, 39.1, 28.6 (3C), 26.6, 11.8. HRMS (FAB) m/z calcd. for C25H32N2O2 (M+H)+ 393.2537; found 393.2523.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[N:15][N:16]([CH3:18])[N:17]=2)=[CH:9][CH:8]=1)[C:4]([OH:6])=O.C(N(CC)C(C)C)(C)C.COCCN(S(F)(F)F)CCOC.Cl.[CH3:42][NH:43][O:44][CH3:45].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:45][O:44][N:43]([CH3:42])[C:4](=[O:6])[CH:3]([O:2][CH3:1])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[N:15][N:16]([CH3:18])[N:17]=2)=[CH:9][CH:8]=1
Reactant: COC(C(=O)O)c1ccc(-c2nnn(C)n2)cc1
Reactant: CNOC
Agent: COCCN(CCOC)S(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(C(=O)N(C)OC)c1ccc(-c2nnn(C)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.7 %

Procedure:
To a solution of 2-methoxy-2-(4-(2-methyl-2H-tetrazol-5-yl)phenyl)acetic acid (0.87 g, 3.5 mmol) in anhydr CH2Cl2 (10 ml) was added N,N-diisopropylethylamine (1.36 g, 10.5 mmol) while cooling over an ice bath. bis(2-Methoxyethyl)aminosulfur trifluoride (0.93 g, 4.2 mmol) was added and stirred 15 min. N,O-Dimethylhydroxylamine HCl (0.512 g, 5.25 mmol) was added and the mixture was allowed to stir overnight while warming to room temp. Saturated aqueous NaHCO3 (15 ml) was added and stirred for 5 min. The organic layer was dried over Na2SO4 and evaporated to dryness. Purification by chromatography (60% EtOAc-hexanes) gave N,2-dimethoxy-N-methyl-2-(4-(2-methyl-2H-tetrazol-5-yl)phenyl)acetamide as a clear oil (0.425 g, 42% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C@@:19]3([CH2:27][O:26][C@H:25]([CH2:28][O:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]5[CH:41]=[CH:40][C:39]([C:42]([O:44]C)=[O:43])=[CH:38][CH:37]=5)=[CH:32][CH:31]=4)[C@@H:23]([OH:24])[C@@H:21]3[OH:22])[OH:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4]>[OH-].[Na+].CO>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][C@@:19]3([CH2:27][O:26][C@H:25]([CH2:28][O:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]5[CH:37]=[CH:38][C:39]([C:42]([OH:44])=[O:43])=[CH:40][CH:41]=5)=[CH:32][CH:31]=4)[C@@H:23]([OH:24])[C@@H:21]3[OH:22])[OH:20])=[CH:15][CH:16]=2)=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(-c2ccc(OC[C@H]3OC[C@@](O)(COc4ccc(-c5ccc(C(=O)OC)cc5)cc4)[C@@H](O)[C@@H]3O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-c2ccc(OC[C@H]3OC[C@@](O)(COc4ccc(-c5ccc(C(=O)O)cc5)cc4)[C@@H](O)[C@@H]3O)cc2)cc1

Procedure:
0.67 g of 1,6-bis-O-(4'-methoxycarbonyl-biphenyl-4-yl)-2,5-O-methylene-D-mannitol was heated under reflux for 16 hours in 15 ml of concentrated sodium hydroxide solution and 15 ml of methanol; thereupon the mixture was evaporated and the residue was acidified with dilute hydrochloric acid. The precipitate of 1,6-bis-O-(4'-carboxy-biphenyl-4-yl)-2,5-O-methylene-D-mannitol which thereby formed was filtered off, dissolved in 5 ml of acetic anhydride and 5 ml of pyridine and stirred at room temperature for 16 hours. Now, the mixture was again evaporated, the residue was poured into dilute hydrochloric acid and the mixture was filtered; there was thus obtained 3,4-di-O-acetyl-1,6-bis-O-(4'-carboxy-biphenyl-4-yl)-2,5-O-methylene-D-mannitol in the form of colorless crystals, MS: m/z 669.4 ([M-H]-).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH:5]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][N:9]=1)[C:6]#[N:7].[C:22](OC(=O)C)(=[O:24])[CH3:23]>C1C=CC=CC=1>[C:22]([O:1][CH2:2][CH2:3][S:4][CH:5]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][N:9]=1)[C:6]#[N:7])(=[O:24])[CH3:23]
Reactant: COc1cc2c(cc1OC)C(C(C#N)SCCO)=NCC2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)C(C(C#N)SCCOC(C)=O)=NCC2

Procedure:
To 1.0 g. of α-(2-hydroxyethylmercapto)-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile 5 ml. of acetic anhydride and 15 ml. of benzene are added and the reaction mixture is refluxed for 4 hours. The mixture is then evaporated to dryness and to the residue carbon tetrachloride is added. 0.6 g. of α-(2-acetoxyethyl-mercapto)-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile are obtained, melting at 157° C. after recrystallization from butanol.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7](Cl)[C:6]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4].[IH:21].[Na+].[I-]>CC(C)=O>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]([I:21])[C:6]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: I
Reactant: CCCCc1nc(C)nc(Cl)c1Cc1ccc(I)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCc1nc(C)nc(I)c1Cc1ccc(I)cc1
Temperature: 40 °C
Yield: 99.3 %

Procedure:
To a solution of 380 mg (0.947 mmol) 6-butyl-4-chloro-2-methyl-5-[(4-iodophenyl)methyl]-pyrimidine in 10 mL acetone were added 0.119 mL 57% HI (0.900 mmol) and 851 mg (5.68 mmol) NaI. The mixture was warmed to 40° C. for 2.5 hours. As the reaction proceeds, NaCl can be seen precipitating out of solution. The mixture was diluted with brine and saturated NaHCO3 solution. The mixture was extracted 3 times with ether. The combined organic material was dried over MgSO4 and decolorized with activated charcoal, was stripped of solvent in vacuo, then was medium pressure chromatographed on silica gel using 10% EtOAc/hexane to give 440 mg of 6-butyl-4-iodo-2-methyl-5-[(4-iodophenyl)methyl]pyrimidine, 947% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.B(OC(C)C)(OC(C)C)[O:23]C(C)C.C(NC(C)C)(C)C.C([Li])CCC.C([O-])([O-])=O.C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].OS([O-])=O.[Na+]>O.C1COCC1>[Cl:1][C:2]1[C:7](=[O:23])[CH:6]=[CH:5][NH:4][C:3]=1[N:8]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccnc1N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Agent: OO
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=c1cc[nH]c(N=C(c2ccccc2)c2ccccc2)c1Cl
Temperature: 0 °C

Procedure:
To a 4-L CHEMGLASS® reactor (fitted with addition funnel, nitrogen blanket) was added: crude 3-chloro-N-(diphenylmethylene)pyridin-2-amine and triisopropyl borate (196.38 mL, 852 mmol). The resulting solution was the cooled to 0° C. In a separate reactor was added diisopropylamine (169.78 mL, 1207 mmol) and THF (1.05 L). This solution was cooled to 0° C. and n-butyl lithium (683.22 mL, 923 mmol) was added slowly. After stirring at 0° C., this solution was added slowly to the first solution. The reaction mixture was stirred for 30 min without the cooling bath (HPLC indicated consumption of starting material). Water (1.05 L) was added to the mixture, followed by the addition of sodium percarbonate (336.34 g, 1065 mmol) in one portion. This mixture was allowed to stir at 20° C. for 1 h. A saturated solution of NaHSO3 (˜1 L) was added slowly. The aqueous layer was removed and DMF (840.00 mL) was added to the organic layer and the THF was distilled off (solvent swap from THF to DMF). The DMF was used without further purification. 1H NMR (CDCl3) δ 6.02 (d, 1H, J=7.1 Hz), 7.10 (d, 1H, J=7.1 Hz), 7.20-7.80 (m, 10H); MS (ESI+) m/z 309.07 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[N:20][N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=3)=[CH:14][CH:13]=2)=[CH:7][C:8]=1[C:9]([NH2:11])=[O:10])([O-])=O>CO.CN(C=O)C.[Pt]>[NH2:1][C:4]1[S:5][C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[N:20][N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=3)=[CH:14][CH:13]=2)=[CH:7][C:8]=1[C:9]([NH2:11])=[O:10]
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccc(-c3cc(C(N)=O)c([N+](=O)[O-])s3)cc2)nn1
Agent: [Pt]
Solvent: CO
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(-c2ccc(-c3cc(C(N)=O)c(N)s3)cc2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-nitro-5-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,3-triazol-4-yl)phenyl]thiophene-3-carboxamide (440 mg, 0.99 mmol) in MeOH (15 mL) was added 3% Pt/C doped with 0.6% V (64 mg, 9.9 μmmol). The reaction was stirred under a hydrogen balloon at room temperature overnight. The solution was diluted with MeOH and DMF, filtered through Celite, and evaporated. The crude was triturated with MeOH and filtered to isolate the title compound as a gray solid. The mother liquor was concentrated, triturated with CH2Cl2, and filtered to isolate additional product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:15][CH2:14]1>CCOC(C)=O.CO.[Pt]>[CH3:1][C:2]1[C:3]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][S:21]([CH3:24])(=[O:22])=[O:23])[CH2:15][CH2:14]2)=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(C)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(C)cc1N
Reaction time: 48 h
Yield: 83.6 %

Procedure:
To 1-[2-methyl-5-(methyloxy)-4-nitrophenyl]-4-[2-(methylsulfonyl)ethyl]piperidine (26 g, 73 mmol) in EtOAc (1 L) and MeOH (200 mL) was added platinum on carbon (sulfided) (14 g, 73 mmol) as a slurry in EtOAc (100 mL). The mixture was stirred under H2 (1 atm.) for 2 days. The catalyst was filtered off and rinsed with EtOAc, MeOH, and DCM and the filtrate was rotovapped down. The resultant solid was triturated with diethyl ether to provide the title compound of Step J (20 g, 61 mmol, 82%). 1H NMR (400 MHz, DMSO-d6) δ 6.50 (s, 1H), 6.39 (s, 1H), 4.24 (s, 2H), 3.66 (s, 3H), 3.05-3.16 (m, 2H), 2.92 (s, 3H), 2.83 (d, 2H), 2.39-2.54 (m, 2H), 2.01 (s, 3H), 1.55-1.76 (m, 4H), 1.32-1.46 (m, J=10.6, 7.0, 3.5, 3.5 Hz, 1H), 1.24 (qd, J=11.7, 3.4 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C@H:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([O:19][Si](C(C)(C)C)(C)C)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]2C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[F:36][C:37]([F:60])([F:59])[C:38]1[CH:43]=[CH:42][C:41]([C:44]2[N:45]=[C:46]([C:49]3[CH:54]=[CH:53][C:52]([S:55](Cl)(=[O:57])=[O:56])=[CH:51][CH:50]=3)[S:47][CH:48]=2)=[CH:40][CH:39]=1>>[OH:19][C@H:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@@H:9]1[NH:8][C@@H:7]([CH2:6][C:5]2[CH:34]=[CH:35][C:2]([NH:1][S:55]([C:52]3[CH:53]=[CH:54][C:49]([C:46]4[S:47][CH:48]=[C:44]([C:41]5[CH:42]=[CH:43][C:38]([C:37]([F:60])([F:59])[F:36])=[CH:39][CH:40]=5)[N:45]=4)=[CH:50][CH:51]=3)(=[O:57])=[O:56])=[CH:3][CH:4]=2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(N)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(-c2nc(-c3ccc(C(F)(F)F)cc3)cs2)cc1
Product: O=S(=O)(Nc1ccc(C[C@H]2CC[C@H]([C@H](O)c3ccccc3)N2)cc1)c1ccc(-c2nc(-c3ccc(C(F)(F)F)cc3)cs2)cc1

Procedure:
The title compound was prepared from tert-butyl (2R,5R)-2-(4-aminobenzyl)-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]pyrrolidine-1-carboxylate (i-4-b) and 4-{4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}benzenesulfonyl chloride (i-6) according to the procedure of Example 212, step A. The crude product was purified by preparative TLC plate eluting with 40% ethyl acetate in hexane to afforded the product (8.1 mg, 81%). m/z (ES) 865 (MH)+, 765 (M-Boc)+.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]1[N:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:14]=1[C:15]([NH:17][C:18]1([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=2)[CH2:20][CH2:19]1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>O1CCOCC1>[CH2:1]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]1[N:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:14]=1[C:15]([NH:17][C:18]1([C:21]2[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)[CH2:20][CH2:19]1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCCC3Cc3ccccc3)CC2)cc1
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCCC3Cc3ccccc3)CC2)cc1
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 80.9 %

Procedure:
To a solution of methyl 4-(1-(2-(2-benzylpyrrolidin-1-yl)-5-chloronicotinamido)cyclopropyl)benzoate (D144) (60 mg, 0.122 mmol) in 1,4-dioxane (3 ml) and water (1 ml) lithium hydroxide monohydrate (7.7 mg, 0.18 mmol) was added and the resulting mixture was stirred at 150° C. under microwave irradiation for 10 min (2 cycles of 5 min each). Solvents were evaporated in vacuo, and the residue was diluted with water (5 ml) and 1M HCl (15 ml) and extracted with ethylacetate (3×20 ml). Collected organics, after solvent evaporation, afforded the title compound (E7) (racemic mixture) (47 mg).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[N+:19]([C:22]1[C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]([CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[N:23]=1)([O-:21])=[O:20].[F-].[K+]>O1CCCC1.C(P([Pd-2]P(C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C>[N+:19]([C:22]1[C:26]([C:2]2[CH:3]=[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[CH:5]=[CH:6][C:7]=2[OH:8])=[CH:25][N:24]([CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[N:23]=1)([O-:21])=[O:20]
Reactant: Oc1ccc(-c2cccc(C(F)(F)F)c2)cc1I
Reactant: CC1(C)OB(c2cn(C3CCCCO3)nc2[N+](=O)[O-])OC1(C)C
Agent: CC(C)(C)[PH]([Pd-2][PH](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1nn(C2CCCCO2)cc1-c1cc(-c2cccc(C(F)(F)F)c2)ccc1O
Temperature: 65 °C
Yield: 60.3 %

Procedure:
A mixture of 3-iodo-3′-(trifluoromethyl)biphenyl-4-ol (Preparation 2, 0.5 g, 1.3 mmol), 3-nitro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.42 g, 1.3 mmol), potassium fluoride (0.39 g, 0.65 mmol) in tetrahydrofuran (10 mL) was degassed. Bis-(tri-t-Butylphosphino)palladium (0) (35 mg, 0.068 mmol) was added and the reaction heated at 65° C. for 4 hours. After cooling the solvent was removed in vacuo and the residue was purified by silica gel chromatography (ethyl acetate:heptane 1:10) to provide the title compound (0.34 g, 61%) as a colourless oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[C:12]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21](F)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1.[CH3:39][NH:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]1>CC(N(C)C)=O>[Cl:10][C:11]1[C:12]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([N:40]([CH3:39])[CH2:41][CH2:42][N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1
Reactant: CNCCN1CCN(C)CC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N(C)CCN2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 140 °C
Yield: 67.4 %

Procedure:
DIPEA (0.105 mL, 0.60 mmol) was added to a mixture of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 20, 0.207 g, 0.5 mmol) and N-methyl-2-(4-methylpiperazin-1-yl)ethanamine (Intermediate 109, 0.079 g, 0.50 mmol) in DMA (5 mL). The mixture was heated in a microwave at 140° C. for 3 h. An additional portion of N-methyl-2-(4-methylpiperazin-1-yl)ethanamine (8 mg, 0.05 mmol) was added and the mixture was heated in a microwave at 140° C. for a further 1 h before being cooled to r.t. The mixture was then concentrated in vacuo and the residue was dissolved in CH3OH. Purification by ion exchange chromatography, using an SCX column and eluting with 1M methanolic ammonia provided crude material after concentration of appropriate fractions in vacuo. Further purification by FCC, eluting with 2-8% CH3OH in CH2Cl2 gave the title compound (0.186 g, 67%) as an orange foam; 1H NMR: (CDCl3) 2.26 (3H, s), 2.32-2.45 (4H, m), 2.45-2.57 (4H, m), 2.61 (2H, t), 2.89 (3H, s), 3.29 (2H, t), 3.98 (3H, s), 6.65 (1H, s), 6.93-7.00 (1H, m), 7.38 (1H, ddd), 7.44 (1H, s), 8.40 (1H, s), 8.49 (1H, d), 8.55 (1H, d), 8.91 (2H, d); m/z: ES+ MH+ 552.59.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[O:7][N:6]=[C:5]([CH:8](O)[CH2:9][CH3:10])[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:34]>C(OCC)C>[Br:34][CH:8]([C:5]1[CH:4]=[C:3]([C:2]([F:13])([F:12])[F:1])[O:7][N:6]=1)[CH2:9][CH3:10]
Reactant: BrC(Br)(Br)Br
Reactant: CCC(O)c1cc(C(F)(F)F)on1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CCC(Br)c1cc(C(F)(F)F)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
1.63 g of 1-(5-trifluoromethyl-isoxazol-3-yl)propanol was dissolved in 45 ml of diethyl ether, and 4.20 g of triphenylphosphine and 5.31 g of carbon tetrabromide were then added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was subjected to silica gel column chromatography to obtain 1.00 g of 3-(1-bromopropyl)-5-trifluoromethylisoxazole.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:46][C:47]1[S:48][C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=1.N1C=CC=CC=1>C(Cl)Cl.O>[S:48]1[C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=[C:47]1[NH:46][C:35](=[O:37])[C@@H:34]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=1)[CH2:33][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nc2ccccc2s1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1nc2ccccc2s1)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 75.3 %

Procedure:
A solution of triphenylphosphine (274 mg, 1.04 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (211 mg, 1.18 mmol). The resulting brownish-purple mixture was stirred at 0° C. for 5 min until the reaction mixture was homogeneous. The reaction mixture was then treated with 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid (200 mg, 0.70 mmol). The resulting reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminobenzothiazole (157 mg, 1.04 mmol) and pyridine (0.17 mL, 2.09 mmol), and the reaction mixture was allowed to stir at 25° C. for 20 h. The resulting reaction mixture was diluted with water (15 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 85/15 hexanes/ethyl acetate) afforded N-benzothiazol-2-yl-3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionamide (221 mg, 76%) as a yellow foam: [α]23589=−42.4° (c=0.092, chloroform); EI-HRMS m/e calcd for C21H20Cl2N2OS (M+) 418.0673, found 418.0672.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][C:5]2=[C:4]([C:13]([NH:15][C@@H:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:17]([NH:19][CH3:20])=[O:18])=[O:14])[N:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:22][C:21]([CH3:24])([CH3:23])[C@H:16]([NH:15][C:13]([C:4]1[N:3]=[C:2]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][CH3:25])[N:6]2[CH2:7][CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][C:5]=12)=[O:14])[C:17]([NH:19][CH3:20])=[O:18]
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(Br)n2c1CN(C)CCC2)C(C)(C)C
Reactant: COc1ccccc1B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2OC)n2c1CN(C)CCC2)C(C)(C)C
Temperature: 100 °C

Procedure:
A mixture of Compound 324 (7.7 mg), 2-methoxyphenylboronic acid (0.038 mmol), palladium tetrakis(triphenylphosphine) (2.5 mg) and potassium carbonate (3 mg) in dioxane/water was heated at 100° C. for two hours. The mixture was filtered through a thiol-based palladium scavenger and purified by preparative LC-MS to give Compound 325. LCMS (+ESI) m/z 428.2 [M+H]+.