Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21](/[N:24]=[N:25]/[C:26]3[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=O)=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)=[O:15])=[CH:4][C:3]=1[CH:36]([CH3:38])[CH3:37].[CH2:39]([NH2:42])[CH2:40][NH2:41]>CO.O.C(Cl)(Cl)Cl>[NH2:41][CH2:40][CH2:39][NH:42][C:30](=[O:32])[C:29]1[CH:28]=[CH:27][C:26](/[N:25]=[N:24]/[C:21]2[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][C:5]3[CH:6]=[C:7]([CH:8]([CH3:9])[CH3:10])[C:2]([OH:1])=[C:3]([CH:36]([CH3:38])[CH3:37])[CH:4]=3)=[CH:19][CH:20]=2)=[CH:35][CH:34]=1
Reactant: NCCN
Reactant: COC(=O)c1ccc(/N=N/c2ccc(CNC(=O)CCCc3cc(C(C)C)c(O)c(C(C)C)c3)cc2)cc1
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)c1cc(CCCC(=O)NCc2ccc(/N=N/c3ccc(C(=O)NCCN)cc3)cc2)cc(C(C)C)c1O

Procedure:
The solution of the compound 9 (258 mg, 0.50 mmol) and ethylenediamine (600 mg, 10 mmol) in methanol (10 mL), water (5 mL) and chloroform (2.5 mL) was refluxed for 24 h. The solvents were then evaporated, the residue was dissolved in 1N potassium hydroxide (15 mL), and the mixture extracted with methylene chloride (4×15 mL). The combined organic phases were washed with water and brine, dried over magnesium sulfate, concentrated under vacuum, and the residue chromatographed on silica gel using chloroform and chloroform-methanol (5%) step-gradient as an eluent to produce pure MCP088 (201 mg, 74%) as orange crystals. 1H NMR (360 MHz, CD3OD): δ 8.04-7.91 (m, 6H), 7.50 (d, J=8.4 Hz, 2H), 6.83 (s, 2H), 4.47 (s, 2H), 3.49 (t, J=6.4 Hz, 2H), 3.26 (septet, J=6.8 Hz, 2H), 2.90 (t, J=6.4 Hz, 2H), 2.55 (t, J=7.6 Hz, 2H), 2.30 (t, J=7.4 Hz, 2H), 1.92 (q, J=7.4 Hz, 2H), 1.19 (d, J=6.8 Hz, 12H). 13C NMR (90.55 MHz, CD3OD): δ 175.13, 168.66, 154.57, 152.02, 148.72, 143.39, 136.55, 135.84, 133.40, 128.42, 128.38, 128.20, 129.90, 123.21, 122.99, 122.65, 120.98, 120.02, 42.66, 42.48, 40.89, 35.54, 35.08, 28.21, 26.83, 22.48. HRMS (m/z): [M+H]+ calcd. for C32H41N5O3 544.3282. found 544.3308.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:19]1[CH2:26][NH:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[C:13]1([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[N:19]2[CH2:26][NH:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Reactant: C1CNCNCCN1
Product: O=Cc1c(N2CCNCCNC2)n(-c2ccccc2)c2ccccc12
Yield: 37 %

Procedure:
2-Chloro-1-phenyl-1H-indole-3-carboxaldehyde is reacted with [1,4,7]triazocane as described in Example 1 to afford 1-phenyl-2-[1,4,7]triazocan-1-yl-1H-indole-3-carboxaldehyde (37% yield) as a yellow solid. LC/MS: 321 (M+H−H2O); RT 2.96 min; NMR (CDCl3): 7.37 (1H, d), 7.18-7.30 (3H, m), 7.13 (1H, t), 6.97 (2H, d), 6.90 (1H, t), 6.79 (1H, t), 2.76-3.10 (12H, m).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=[O:4].[Na+].[I-].[N-:17]=[N+:18]=[N-:19].[Na+].O>CN(C=O)C.CCOC(C)=O>[N:17]([CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=[O:4])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1Cc2cc(C(=O)CCl)ccc2N1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.6 %

Procedure:
To a solution of 5-(2-chloroacetyl)indolin-2-one (1.0 g, 4.8 mmol) in DMF (20 ml) was added NaI (0.14 g, 0.96 mmol) and NaN3 (0.37 g, 5.7 mmol), and the mixture was stirred for 2 h at room temperature. H2O and EtOAc were added to the mixture, and the resulting precipitate was filtered and dried to afford 5-(2-azidoacetyl)indolin-2-one (0.38 g, 37%).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[N:16]([CH3:17])[C:15]([C:18]#[N:19])=[CH:14][CH:13]=3)[CH:10]=2)[NH:5][CH2:4]1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl.C(OCC)(=O)C>[CH3:2][C:3]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[N:16]([CH3:17])[C:15]([C:18]#[N:19])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:4]1
Reactant: Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)CN2
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)CN2S(C)(=O)=O
Reaction time: 3 h
Yield: 63.7 %

Procedure:
5-(3,3-dimethyl-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile hydrochloride (288 mg, 1.0 mmol) was dissolved in methylene chloride (5 mL) and triethylamine (0.43 mL, 3.0 mmol) was added. The mixture was treated with methanesulfonyl chloride (0.078 mL, 1.1 mmol) and stirred for 3 hours. The mixture was diluted with ethyl acetate, washed with water, 2N HCl, water, brine, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified via Isco chromatography (the Redisep® column, silica, gradient 10-60% ethyl acetate in hexane) to afford 5-[3,3-dimethyl-1-(methylsulfonyl)-2,3-dihydro-1H-indol-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile (0.21 g). MS (EI) m/z 329.8; HPLC purity 100.0% at 210-370 nm, 9.5 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5 acetonitrile+MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.FC1C=CC(I)=CC=1>>[F:33][C:30]1[CH:29]=[CH:28][C:27]([C:24]2[O:23][C:22]([C:9](=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:26][CH:25]=2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2ccc(F)cc2)o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: Fc1ccc(I)cc1
Product: O=C(CCCCCCc1ccccc1)c1ncc(-c2ccc(F)cc2)o1
Yield: 61 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)-5-(4-fluorophenyl)oxazole. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (81 mg, 0.122 mmol) and 1-fluoro-4-iodobenzene following General Procedure A. Flash chromatography (2% EtOAc/hexanes) yielded the title compound as a clear oil (40 mg, 61%): 1H NMR (CDCl3, 600 MHz) δ 7.63-7.61 (m, 2H), 7.27-7.24 (m, 4H), 7.17-7.11 (m, 4H), 4.88 (t, 1H, J=6.0 Hz), 2.58 (t, 2H, J=7.5 Hz), 1.95-1.90 (m, 2H), 1.62-1.59 (m, 2H), 1.46-1.35 (m, 6H), 0.89 (s, 9H), 0.10 (s, 3H), −0.01 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 165.9, 163.5 (d, J=258 Hz), 151.5, 143.6, 129.2, 129.1, 127.1 (d, J=8.3 Hz), 126.4, 124.8, 121.1, 117.0 (d, J=22 Hz), 69.4, 37.3, 36.8, 32.3, 30.0, 26.6, 26.6, 25.9, 19.1, −4.1, −4.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11]C)=[O:10])[CH:5]=[N:6][CH:7]=1.[N:13]1(C2C=C(CC(O)=O)C=CN=2)[CH:17]=[N:16][N:15]=[N:14]1>>[N:13]1([C:2]2[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[N:6][CH:7]=2)[CH:17]=[N:16][N:15]=[N:14]1
Reactant: O=C(O)Cc1ccnc(-n2cnnn2)c1
Reactant: COC(=O)Cc1cncc(Br)c1
Product: O=C(O)Cc1cncc(-n2cnnn2)c1

Procedure:
[5-(1H-Tetrazol-1-yl)pyridin-3-yl]acetic acid was prepared from methyl (5-bromopyridin-3-yl)acetate according to the procedure outlined for the preparation of intermediate [2-(1H-tetrazol-1-yl)pyridin-4-yl]acetic acid, except that in the final step the ester was hydrolyzed under basic conditions rather than acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9]2)=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.Cl.[CH3:28][N:29]([CH2:31][C:32](Cl)=[O:33])[CH3:30].C(=O)([O-])O.[Na+]>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][N:12]([C:32](=[O:33])[CH2:31][N:29]([CH3:30])[CH3:28])[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2CNc3ccccc3S2)cc1
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: CN(C)CC(=O)N1CC(c2ccc(Cl)cc2)Sc2ccccc21
Reaction time: 2.5 h
Yield: 165.5 %

Procedure:
To a solution of 2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine (0.52 g) ad N,N-dimethylaniline (0.97 g) in methylene chloride (15 ml) is added dimethylaminoacetyl chloride hydrochloride (0.63 g) under ice cooling, and the mixture is stirred at the same temperature for 2.5 hours. To the reaction mixture is added aqueous sodium hydrogen carbonate solution, and is extracted with chloroform. The chloroform layer is washed, dried and distilled to remove the solvent. The residue is treated with hydrochloric acid and the resulting salt is recrystallized from ethanol-ether to give 2-(4-chlorophenyl)-4-(dimethylamino)acetyl-3,4-dihyro-2H-1,4-benzothiazine hydrochloride (0.63 g, yield 86%).
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[S:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[ClH:23].Br[CH:25]1[CH2:34]CC2C(=CC=CC=2)[C:26]1=O>C(O)C>[ClH:23].[ClH:23].[O:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][NH:12][C:10]2[S:11][C:26]3[CH2:25][CH2:34][C:7]4[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:1]=3[N:9]=2)[CH2:16][CH2:17]1
Reactant: O=C1c2ccccc2CCC1Br
Reactant: O=C(NC(=S)NCCN1CCOCC1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc2c(c1)CCc1sc(NCCN3CCOCC3)nc1-2

Procedure:
3.66 g of N-benzoyl-N'-(morpholinoethyl)thiourea are refluxed in 17.5 ml of a 2.5N solution of sodium hydroxide under a nitrogen atmosphere for 15 minutes. After cooling, concentrated hydrochloric acid is added until the pH is 7. A solution of 3 g of 2-bromo-1,2,3,4-tetrahydronaphthalen-1-one in 20 ml of ethanol is added and the mixture is refluxed for 1 hour. After evaporation of the solvent, the residue is neutralized by the addition of sodium bicarbonate and extraction is carried out twice with methylene chloride. The organic phase is dried over magnesium sulfate and chromatographed on a silica column by elution with a methylene chloride/methanol mixture (95/5 vol/vol).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:18]1[C:35]([CH:36]2[CH2:38][CH2:37]2)=[CH:34][C:21]2[C:22]([C:32]#[N:33])=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[O:24][C:20]=2[CH:19]=1)[S:14]([CH3:17])(=[O:16])=[O:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:39][OH:40]>C(O)C>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([S:14]([CH3:17])(=[O:16])=[O:15])[C:18]1[C:35]([CH:36]2[CH2:38][CH2:37]2)=[CH:34][C:21]2[C:22]([C:32](=[NH:33])[NH:39][OH:40])=[C:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[O:24][C:20]=2[CH:19]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCCN(c1cc2oc(-c3ccc(F)cc3)c(C#N)c2cc1C1CC1)S(C)(=O)=O
Reactant: NO
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCCCN(c1cc2oc(-c3ccc(F)cc3)c(C(=N)NO)c2cc1C1CC1)S(C)(=O)=O
Temperature: 140 °C
Yield: 83.4 %

Procedure:
To a 20-mL microwave tube was added a solution of Example 11B (0.1346 g, 0.242 mmol) in ethanol (3 mL) followed by hydroxylamine (50 weight % in water, 3 mL, 50.9 mmol). The tube was sealed and the thick slurry was heated in a microwave reactor (Personal Chemistry (Biotage), Emrys Creator, 300 W maximum) for 30 minutes at 140° C. The reaction mixture was concentrated in vacuo to a cloudy solution that was taken up in ethyl acetate (60 mL), washed with 10% aqueous NaCl, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the title compound as a foamy white solid (0.119 g, 84%).
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[NH2:6][C:7]1[C:12]([C:13]#[N:14])=[CH:11][N:10]=[C:9]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([S:22](F)(=[O:24])=[O:23])=[CH:18][CH:17]=2)[N:8]=1>>[NH2:6][C:7]1[C:12]([C:13]#[N:14])=[CH:11][N:10]=[C:9]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([S:22](=[O:24])(=[O:23])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[CH:20][CH:21]=2)[N:8]=1
Reactant: N#Cc1cnc(Nc2ccc(S(=O)(=O)F)cc2)nc1N
Reactant: NC1CCC1
Product: N#Cc1cnc(Nc2ccc(S(=O)(=O)NC3CCC3)cc2)nc1N
Temperature: 40 °C
Reaction time: 18 h
Yield: 31 %

Procedure:
Cyclobutylamine (2 ml) was added to 4-amino-5-cyano-2-(4-fluorosulphonylanilino) pyrimidine (Method 1; 250 mg, 0.853 mmol), the mixture was heated at 40° C. for 1 hour and then stirred at ambient temperature for 18 hours. The volatiles were removed by evaporation and residue was purified by chromatography on silica gel eluting with ethyl acetate/hexane (50:50). The product was triturated with ether/hexane and the resulting solid collected by filtration to give the title compound (91 mg, 31%). NMR: 1.41-1.50 (m, 2H); 1.62-1.78 (m, 2H); 1.82-1.90 (m, 2H); 3.59 (m, 1H); 7.60 (s, 2H); 7.62 (d, 2H); 7.98 (d, 2H); 8.40 (s, 1H); m/z: 345 (MH)+.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[CH3:13].[Li]CCCC.[C:19](=[O:21])=[O:20].Cl>C1COCC1>[CH:10]([O:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([C:19]([OH:21])=[O:20])=[C:3]([CH3:13])[CH:4]=1)([CH3:12])[CH3:11]
Reactant: Cc1cc(OC(C)C)c(C)cc1I
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)c(C)cc1OC(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
A solution of 1-iodo-4-isopropoxy-2,5-dimethylbenzene (450 mg, 1.6 mmol) in THF (7.8 mL) was cooled to −78° C. before nBuLi (620 mL, 2.5 M, 1.6 mmol) was added dropwise. The mixture was allowed to warm to 0° C., then it was cooled to −78° C. before it was added dropwise to a flask containing crushed, dry CO2. The mixture was allowed to warm to room temperature and was stirred overnight. The mixture was poured over ice and was acidified with 1N HCl. The mixture was extracted with ethyl acetate (3×) and the combined organics were washed with brine, dried over sodium sulfate, and concentrated to give 4-isopropoxy-2,5-dimethylbenzoic acid (67 mg, 10%). ESI-MS m/z calc. 208.1, found 209.1 (M+1)+; Retention time: 1.55 minutes (3 min run).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[N:5][C:4]=1[CH2:16][O:17][C@H:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([CH2:24][O:25][C:26]([CH3:35])([CH3:34])[C:27]([O:29]C(C)(C)C)=[O:28])[CH2:19]1)[CH3:2]>FC(F)(F)C(O)=O>[CH2:1]([C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[N:5][C:4]=1[CH2:16][O:17][C@H:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([CH2:24][O:25][C:26]([CH3:34])([CH3:35])[C:27]([OH:29])=[O:28])[CH2:19]1)[CH3:2]
Reactant: CCc1oc(-c2cccc(OC)c2)nc1CO[C@H]1CCC[C@@H](COC(C)(C)C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Product: CCc1oc(-c2cccc(OC)c2)nc1CO[C@H]1CCC[C@@H](COC(C)(C)C(=O)O)C1

Procedure:
300 mg of tert-butyl 2-{(1R,3S)-3-[5-ethyl-2-(3-methoxyphenyl)oxazol-4-ylmethoxy]-cyclohexylmethoxy}-2-methylpropionate are left to stand in 1 ml of trifluoroacetic acid at RT overnight. The solution is completely evaporated, water is added to the residue, and the pH is adjusted to 3 with sodium bicarbonate solution. The solution is extracted with ethyl acetate, and the organic phase is washed twice with water, dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel (dichloromethane/methanol gradient), resulting in 256 mg of 2-{(1R,3S)-3-[5-ethyl-2-(3-methoxyphenyl)oxazol-4-ylmethoxy]cyclohexylmethoxy}-2-methylpropionic acid as yellow resin.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])(=[O:20])=[O:19]
Reactant: COc1ccccc1O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 2-methoxyphenol (50 g, 402.8 mmol) and triethylamine (84.2 mL, 604.2 mmol) in anhydrous dichloromethane (300 mL), was added methanesulfonyl chloride (37.6 mL, 483.3 mmol) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 2 hours, quenched with ice water (250 mL) and transferred to a separatory funnel. The organic phase was washed with a solution of NaOH (8 g) in ice water (200 mL), brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a colorless liquid (81.44 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ 3.32 (s, 3H), 3.83 (s, 3H), 6.96-7.0 (m, 1H), 7.18-7.2 (m, 1H), 7.27-7.33 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.N1([C:25](N2C=CN=C2)=[O:26])C=CN=C1>O1CCCC1>[Br:1][C:2]1[N:3]=[C:4]2[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[C:25](=[O:26])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)nc1NCc1cccc([N+](=O)[O-])c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2ncc(Br)nc2n1Cc1cccc([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a solution of 5-bromo-N3-(3-nitrobenzyl)pyrazine-2,3-diamine (100 mg, 0.31 mmol) in anhydrous tetrahydrofuran (10 mL) was added diimidazol-1-ylmethanone (250 mg, 1.51 mmol) at room temperature. After stirring overnight, the reaction was concentrated under reduced pressure. Purification of the resultant residue by flash chromatography [silica gel; hexanes/ethyl acetate (2:1)] afforded 6-bromo-1-(3- nitrobenzyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one as a red-brown solid (95 mg, 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[C:17]([N:25]=[C:26]=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[C:17]([NH:25][C:26]([NH:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[CH:4][CH:3]=1)=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=S)NC(=O)c2ccccc2)cc1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a stirred solution of tert-butyl N-(4-aminobenzyl)carbamate (6.00 g, 27.0 mmol) in anhydrous THF (50 ml) was added benzoylisothiocyanate (4.43 g, 27.0 mmol). The solution was stirred for 2 hours and the solvent removed in vacuo to yield 100% (10.4 g) of the protected thiourea as a yellow solid: m.p. 161-163° C.; 1H-NMR (CDCl3) δ 1.45 (9H, s), 4.33 (2H, d), 4.85 (1H, broad), 7.34 (2H, d), 7.60 (5H, m), 7.90 (2H, d), 9.13 (1H, s), 12.58 (1H, s); 386 (ESMS, MH+).
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:22])[CH:11]=[C:12]([CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[N:13]([CH3:15])[CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[C:10](=[O:22])[CH:11]=[C:12]([CH:16]([OH:21])[C:17]([F:18])([F:19])[F:20])[N:13]([CH3:15])[CH:14]=1
Reactant: Cn1cc(OCc2ccccc2)c(=O)cc1C(O)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: Cn1cc(O)c(=O)cc1C(O)C(F)(F)F
Reaction time: 0.33 h
Yield: 92 %

Procedure:
A mixture of 5-benzyloxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (3.1 g, 9.9 mmol) and methanol (60 mL) was sonicated to give a clear solution. To the solution was added Pd/C (10 wt. %, dry basis, on activated carbon, wet, Degussa type E101 NE/W, 0.58 g). The debenzylation reaction was conducted in a Parr hydrogenator under an atmosphere of hydrogen pressurized to 50 psi. The reaction was completed within 20 min. The reaction mixture was diluted with MeOH (100 mL), sonicated for about 20 min. A CELITE™ bed was prepared on a sintered glass, and washed with 6M HCl (100 mL), followed by water (7×50 mL) and then methanol (2×50 mL) under suction. The reaction mixture was filtered through the pre-treated CELITE™ bed. The filtrate was collected and concentrated in vacuo to give 5-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one as a solid product (2.05 g, 92% yield, HPLC Method 1 (Example 24), RT=7.4 min, HPLC purity (peak percent area): 99.4% at λ=280 nm). 1H NMR (DMSO-d6+D2O) δ ppm: 7.50 (s, 1H), 6.50 (s, 1H), 5.37 (q, J=6.5 Hz, 1H), 3.67 (s, 3H); MS-ESI (m/z) 224.2 [M+1]+, 206.2, 155.2 (100%), 140.1, 126.1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][C@@H:18]3[CH3:30])=[CH:13][CH:12]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([O:34][CH2:35][C:36]1[C:37]([N:45]2[CH2:56][CH2:55][N:54]3[C:47](=[CH:48][C:49]4[CH2:50][C:51]([CH3:58])([CH3:57])[CH2:52][C:53]=43)[C:46]2=[O:59])=[N:38][CH:39]=[CH:40][C:41]=1B(O)O)(=O)C.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C([O-])([O-])=O.[Cs+].[Cs+].O.[OH-].[Li+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[CH3:57][C:51]1([CH3:58])[CH2:50][C:49]2[CH:48]=[C:47]3[N:54]([CH2:55][CH2:56][N:45]([C:37]4[C:36]([CH2:35][OH:34])=[C:41]([C:2]5[CH:3]=[C:4]([NH:10][C:11]6[N:16]=[CH:15][C:14]([N:17]7[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][C@@H:18]7[CH3:30])=[CH:13][CH:12]=6)[C:5]([O:8][CH3:9])=[N:6][CH:7]=5)[CH:40]=[CH:39][N:38]=4)[C:46]3=[O:59])[C:53]=2[CH2:52]1
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: COc1ncc(Cl)cc1Nc1ccc(N2CCN(C(=O)OC(C)(C)C)C[C@@H]2C)cn1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ncc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2CO)cc1Nc1ccc(N2CCN(C(=O)OC(C)(C)C)C[C@@H]2C)cn1
Temperature: 110 °C
Reaction time: 4 h
Yield: 27.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 271a (650 mg, 1.50 mmol), {3-[(acetyloxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (1.79 g, 4.5 mmol), Pd2(dba)3 (137.2 mg, 0.15 mmol), P(cy)3(167.4 mg, 0.60 mmol), Cs2CO3 (978 mg, 3.0 mmol), dioxane (20 mL), and water (0.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 110° C. for 16 h. After this time the reaction was cooled to room temperature. Lithium hydroxide monohydrate (1.89 g, 45 mmol) and water (2.0 mL) were added. The resulting mixture was stirred at 45° C. for 4 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 3:1 ethyl acetate/petroleum ether to afford 271b (290 mg, 27%) as a yellow solid. MS-ESI: [M+H]+ 709.3
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[C:14]([Br:16])[CH:13]=[C:12]([F:17])[C:10]=1[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27]>CN(C=O)C>[CH3:29][O:28][C:26](=[O:27])[CH2:25][NH:11][C:10]1[C:12]([F:17])=[CH:13][C:14]([Br:16])=[CH:15][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1c(F)cc(Br)cc1OCc1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CNc1c(F)cc(Br)cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a mixture of 2.6 g (8.78 mmol) of 2-benzyloxy-4-bromo-6-fluoroaniline and 3.03 g (21.96 mmol) of potassium carbonate in 20 mL DMF in an oil bath at 60° C. is added 1.48 g (9.67 mmole) of methyl bromoacetate. The mixture is stirred at 60° C. for 2 h. HPLC analysis indicated that the reaction is 38% complete. Additional methyl bromoacetate equal to the molar amount of unreacted starting material is added and the mixture is stirred at 60° C. for 2 h. This process is repeated until the starting material is nearly consumed. The mixture is allowed to cool then is poured into water. The mixture is extracted with ethyl acetate and the organic phase is washed 3× with water. The organic solution is dried over sodium sulfate and the solvent is removed under reduced pressure. The residual dark oil is purified by flash chromatography using methylene chloride to elute the product as a dark oil. This is used directly in the next step.