Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)=[O:7].[CH3:21][NH:22][CH3:23]>O1CCCC1>[CH3:21][N:22]([CH3:23])[CH2:2][CH2:3][O:4][CH2:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)COCCBr)C1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CCOCC(=O)N[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A solution of (S)-3-[2-(2-bromoethoxy)acetyl]amino-1-(tert-butoxycarbonyl)pyrrolidine (195 mg) prepared in Step C in tetrahydrofuran (2 ml) was added with dimethylamine (2 M solution in tetrahydrofuran, 4.5 ml, Aldrich) at 0° C., and the mixture was stirred at room temperature for 23 hours. The volatile components were evaporated under reduced pressure, and the residue was added with saturated aqueous sodium hydrogencarbonate, and extracted five times with chloroform. The combined organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (180 mg).
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([OH:49])=O)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].ON1C2C=CC=CC=2N=N1.[OH:60][CH2:61][C@@H:62]([C@@H:64]([C@@H:66]([CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[OH:67])[OH:65])[NH2:63].C(N=C=NC(C)C)(C)C>O1CCCC1>[C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([NH:63][C@H:62]([C@@H:64]([C@@H:66]([CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[OH:67])[OH:65])[CH2:61][OH:60])=[O:49])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@@H](N)CO
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)[C@H](O)CCCCCCCCCCCCCC
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of 27-stearoyloxyheptacosanoic acid (8.88 g, 12.8 mmoles), tetrahydrofuran (120 ml), dried 1-hydroxybenzotriazole (4 g, 34.1 mmoles), phytosphingosine (3.91 g, 12.33 mmoles) and N,N'-diisopropylcarbodiimide (2.55 ml, 16.3 mmoles) was stirred under nitrogen for 2 hours at 40° C. and for another 4 hours at 50° C. After filtration and recrystallisation from hot chloroform 8.84 g of the title compound was obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]3[CH:14]=[CH:13][N:12](COCC[Si](C)(C)C)[C:8]=3[N:9]=[CH:10][N:11]=2)=[CH:2]1.[CH2:23]([S:25]([N:28]1[CH2:31][C:30](=[CH:32][C:33]#[N:34])[CH2:29]1)(=[O:27])=[O:26])[CH3:24].N12CCCN=C1CCCCC2>C(#N)C>[CH2:23]([S:25]([N:28]1[CH2:29][C:30]([CH2:32][C:33]#[N:34])([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[C:7]4[CH:14]=[CH:13][NH:12][C:8]=4[N:9]=[CH:10][N:11]=3)=[CH:2]2)[CH2:31]1)(=[O:26])=[O:27])[CH3:24]
Reactant: CCS(=O)(=O)N1CC(=CC#N)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cc[nH]c3)ncnc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCS(=O)(=O)N1CC(CC#N)(n2ccc(-c3ncnc4[nH]ccc34)c2)C1
Reaction time: 4 h

Procedure:
A solution of 4-(1H-pyrrol-3-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.100 g, 0.318 mmol) and [1-(ethylsulfonyl)azetidin-3-ylidene]acetonitrile (0.118 g, 0.636 mmol, prepared as in Example 68) in acetonitrile (1 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (24 μL, 0.16 mmol). The mixture was stirred for 4 hours. The solvent was evaporated. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution, then extracted with two further portions of ethyl acetate. The combined extracts were dried over sodium sulfate, decanted and concentrated. The crude product was stirred with 25% TFA/DCM (8 mL) overnight. The solvents were evaporated. The product was then stirred with ethylenediamine (0.3 mL) in methanol (5 mL). Preparative HPLC-MS (eluting with a gradient of methanol and water containing 0.15% NH4OH) was used to purify the product.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1nc2ccccc2s1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1nc2ccccc2s1)c1ccccc1

Procedure:
Using 2-amino-benzothiazole and benzoyl chloride in pyridine the title compound was obtained as a white solid (87% yield), MS: m/e=255.1 (M+H+).
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8][CH2:9]Br)[C:3]([O:5][CH3:6])=[O:4].C([O-])([O-])=O.[K+].[K+].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]([NH2:26])[CH3:25])=[CH:20][CH:19]=1.CCOC(C)=O>CC#N.O>[CH3:6][O:5][C:3]([C@@H:2]1[CH2:7][CH2:8][CH2:9][N:26]1[C@H:24]([C:21]1[CH:22]=[CH:23][C:18]([Br:17])=[CH:19][CH:20]=1)[CH3:25])=[O:4]
Reactant: COC(=O)C(Br)CCCBr
Reactant: C[C@H](N)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@@H]1CCCN1[C@@H](C)c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
The following procedure was adapted from W. A. J. Starmans, R. W. A. Walgers, L. Thijs, R. de Gelder, J. M. M. Smits, and B. Zwanenburg, Tetrahedron 54 (1998) 4991-5004. To a mixture of methyl 2,5-dibromopentanoate (0.401 ml, 2.56 mmol) and K2CO3 (706 mg, 5.11 mmol) in MeCN (7 ml) and water (0.7 ml) was added dropwise a solution of (S)-1-(4-bromophenyl)ethanamine (0.405 ml, 2.81 mmol) in MeCN (3.5 ml) at 80° C. After the addition, the reaction mixture was further stirred at 80° C. for 14 h then cooled to RT, diluted into AcOEt (50 ml) and washed with water (40 ml). The aqueous phase was further extracted with AcOEt and the combined organic fractions were dried over Na2SO4, filtered and evaporated to dryness. The resulting crude material was purified and both diastereoisomers separated by reversed phase prep-HPLC (gradient elution, MeCN/water containing 20 mM ammonium formate). Fractions containing pure material were combined and concentrated under vacuum. The resulting aqueous mixture was basified by the addition of Na2CO3 2M and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated to dryness to yield the title compounds as light yellow oils. Intermediate 89.1: 240 mg, 0.77 mmol, 30%; HPLC: AtRet=1.15 min, CtRet=4.07 min; LC-MS: m/z 314.4 [M+H]+; 1H NMR (400 MHz, CDCl3): 1.38 (d, J=6.6, 3H), 1.76-1.99 (m, 3H), 2.04-2.16 (m, 1H), 2.52 (q, J=8.1, 1H), 3.05-3.13 (m, 1H), 3.47 (dd, J=9.4, 3.5, 1H), 3.51 (s, 3H), 3.66 (q, J=6.6, 1H), 7.21-7.26 (m, 2H), 7.39-7.45 (m, 2H). Intermediate 89.2: 222 mg, 0.71 mmol, 28%; HPLC: AtRet=1.15 min, CtRet=5.18 min; LC-MS: m/z 314.4 [M+H]+; 1H NMR (400 MHz, CDCl3): 1.36 (d, J=6.8, 3H), 1.73-1.84 (m, 1H), 1.84-1.96 (m, 2H), 2.03-2.14 (m, 1H), 2.54-2.63 (m, 1H), 2.93-3.02 (m, 1H), 3.31 (dd, J=9.2, 4.0, 1H), 3.69 (s, 3H), 3.72 (q, J=6.6, 1 H), 7.17-7.22 (m, 2H), 7.42-7.47 (m, 2H). The configuration of each diastereoisomers was attributed by comparing the 1H NMR spectra with published 1H NMR data of close analogues (see R. Almansa, D. Guijarro and M. Yus Tetrahedron: Asymmetry 18, 2007, 2828-2840).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][NH:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)O.S(=O)(=O)(O)O>C(Cl)Cl>[Cl:22][C:20]1[CH:19]=[C:18]2[C:3](=[C:2]([Cl:1])[CH:21]=1)[CH2:4][NH:5][CH2:6][CH:7]2[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1
Reactant: O=[N+]([O-])c1cccc(C(O)CNCc2ccc(Cl)cc2Cl)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(C2CNCc3c(Cl)cc(Cl)cc32)c1
Temperature: 2.5 °C

Procedure:
To 2-(2,4-dichlorobenzylamino)-1-(3-nitrophenyl)ethanol (intermediate 171.2) (500 mg, 1.47 mmol, 1.00 equiv) in DCM (10 mL) was added conc. sulfuric acid (4 mL) dropwise with stirring at 0-5° C. The resulting solution was stirred for 12 h at room temperature. The reaction was then quenched by the addition of water/ice. The pH value of the solution was adjusted to 10 with sodium hydroxide. The resulting solution was extracted with 2×50 mL of DCM and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 300 mg (63%) of 6,8-dichloro-4-(3-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline as yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12]C)[N:10]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:17])[CH2:15][CH3:16].C[Si](Cl)(C)C.[I-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:17])[CH2:15][CH3:16]
Reactant: CCC(=O)c1cnc2ccc(OC)nc2c1O
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])([O-])=S
Agent: [I-]
Solvent: CC#N
Product: CCC(=O)c1cnc2ccc(O)nc2c1O
Temperature: 25 °C

Procedure:
To a suspension of 1-(4-hydroxy-6-methoxy-1,5-naphthyridin-3-yl)propan-1-one (5.2 g, 22.4 mmol) in acetonitrile (100 ml) was added trimethylsilylchloride (12 g, 112 mmol) and sodium iodide (10 g, 67 mmol) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to room temperature and satd. aq. sodium thiosulfate was added. The mixture was concentrated to remove acetonitrile, diluted with brine and the solids were filtered and dried to provide the intermediate 1-(4,6-dihydroxy-1,5-naphthyridin-3-yl)propan-1-one. This intermediate was suspended in dichloroethane (10 mL) followed by the addition of phosphorus oxychloride (10 mL) and catalytic N,N-dimethylformamide and the reaction mixture was stirred with heat at 80° C. for 2 h. The reaction mixture was cooled to room temperature and quenched by pouring slowly into ice-cold satd. aq. sodium bicarbonate or 3 N sodium hydroxide. The quenched reaction mixture was concentrated to remove the dichloroethane and the resulting solids were collected by filtration and purified by chromatography (silica, hexanes/ethyl acetate) to provide the desired product (3.2 g, 56% over 2 steps) as a brown solid: ESI MS m/z 255 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:22]3[CH:23]=[C:24]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=4)=[O:30])[CH:25]=[CH:26][CH:27]=3)=[N:10][N:11](CC3C=CC(OC)=CC=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1>FC(F)(F)C(O)=O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:22]3[CH:23]=[C:24]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:39])([F:40])[F:41])=[CH:34][CH:33]=4)=[O:30])[CH:25]=[CH:26][CH:27]=3)=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(Cn2cc(-c3ccnc(N)n3)c(-c3cccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc(-c2c[nH]nc2-c2cccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c2)n1
Temperature: 70 °C
Reaction time: 4 h
Yield: 73.2 %

Procedure:
800 mg (1.4 mmol) of 1-{3-[4-(2-aminopyrimidin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazol-3-yl]phenyl}-3-[4-(trifluoromethyl)phenyl]urea were dissolved in 20 ml of trifluoroacetic acid and the mixture stirred at 70° C. for 4 hours. The solvent was then removed under reduced pressure and the residue taken up with dichloromethane and washed with aqueous sodium hydrogenocarbonate. The organic phase was dried over sodium sulphate and evaporated. The product was finally purified by flash-chromatography on a silica gel column (CH2Cl2-CH3OH; from 99/1 to 95/5), giving 450 mg (73%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[F:35][C:36]([F:47])([F:46])[O:37][C:38]1[CH:43]=[CH:42][C:41]([NH:44][NH2:45])=[CH:40][CH:39]=1>>[CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21]/[C:22](/[C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[N:45]\[NH:44][C:41]3[CH:42]=[CH:43][C:38]([O:37][C:36]([F:35])([F:47])[F:46])=[CH:39][CH:40]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCC/C(=N\Nc3ccc(OC(F)(F)F)cc3)c3ccc([N+](=O)[O-])cc3)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-(4-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 626.2 (M+H)+.
Reaction SMILES: [C:1]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[CH2:24][O:25][P:26]([OH:29])([OH:28])=[O:27])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18]CC.C(O)(=O)CCCCCCC/C=C\CC=CCC=CCC>>[C:1]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[CH2:24][O:25][P:26]([OH:29])([OH:28])=[O:27])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH:12]=[CH:13][CH2:14][CH:15]=[CH:16][CH2:17][CH3:18]
Reactant: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@@H](COP(=O)(O)O)C(=O)O
Agent: CCC=CCC=CC/C=C\CCCCCCCC(=O)O
Product: CCC=CCC=CC/C=C\CCCCCCCC(=O)N[C@@H](COP(=O)(O)O)C(=O)O

Procedure:
This compound was prepared as described above for (6), using 0.5 mmol (139 mg) of cis-9,12,15-octadecatrienoic acid; yield 73 mg (33%); Rf 0.05-0.10 (system B); 1H-NMR (CD3SOCD3, 200 MHz) δ0.9-1.0 (t, 3H, ω-CH3); 1.3 (s, 8H, 4CH2); 1.4-1.5 (br s, 2H, CH2CH2CO); 2.0-2.2 (m, 6H, CH2CO and 2 CH2CH═CH); 2.7-2.9 (br s, 4H, 2HC═CH—CH2—CH═CH); 3.9-4.0 (br s, 2H, CH2OP); 4.3-4.4 (m, 1H, NH CHCO); 5.2-5.4 (br s, 6H, 3 HC═CH); 8.2-8.4 (m, 3H, NH and 2POH).
Reaction SMILES: [Cl:1][C:2]1[C:8]([F:9])=[CH:7][C:6]([CH3:10])=[C:5]([F:11])[C:3]=1[NH2:4].[Br:12]Br>CO>[Cl:1][C:2]1[C:8]([F:9])=[C:7]([Br:12])[C:6]([CH3:10])=[C:5]([F:11])[C:3]=1[NH2:4]
Reactant: BrBr
Reactant: Cc1cc(F)c(Cl)c(N)c1F
Solvent: CO
Product: Cc1c(F)c(N)c(Cl)c(F)c1Br
Reaction time: 12 h

Procedure:
A solution of 2-chloro-5-methyl-3,6-difluoroaniline (5.0 g, 28 mmol) in anhydrous methanol (25 mL) is treated with elemental bromine (5.0 g, 3,1 mmol) at room temperature. After stirring for 12 hours, most of the solvent is removed by rotary evaporator and the residue partitioned between EtOAc (250 mL) and water (250 mL). The organic phase is washed with brine (150 mL), dried (MgSO4) and concentrated by rotary evaporator. The crude product is purified using flash chromatography (7% EtOAc/hexanes) to give 2-chloro-4-bromo-5-methyl-3,6-difluoroaniline as a tan solid.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([O:36]C5CCCCO5)[CH:33]=[CH:32][C:31]=4[F:43])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([OH:36])[CH:33]=[CH:32][C:31]=4[F:43])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1cccc(COc2cnc(-c3cc(OC4CCCCO4)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CO
Product: CCOC(=O)CC(c1cccc(COc2cnc(-c3cc(O)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 50 °C
Reaction time: 20 h
Yield: 81.2 %

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-cyclopropyl-3-(3-(((6-(2-fluoro-5-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-5-neopentylpyridin-3-yl)oxy)methyl)phenyl)propanoate (984 mg) in methanol (8.35 mL) was added pyridinium p-toluenesulfonate (126 mg) at room temperature, and the mixture was stirred at 50° C. for 20 hr. The reaction mixture was cooled, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (685 mg) as a colorless gummy substance.
Reaction SMILES: Cl[C:2]1[C:3]([O:13][CH:14]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]2)=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:22]1(B(O)O)[CH2:24][CH2:23]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Pd]>[CH:22]1([C:2]2[C:3]([O:13][CH:14]3[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]3)=[CH:4][C:5]([F:12])=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:24][CH2:23]1
Reactant: COC(=O)c1cc(Cl)c(OC2CCC(F)(F)CC2)cc1F
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C2CC2)c(OC2CCC(F)(F)CC2)cc1F
Temperature: 25 °C
Yield: 74.9 %

Procedure:
To an argon-degassed solution of methyl 5-chloro-4-((4,4-difluoro-cyclohexyl)oxy)-2-fluorobenzoate (0.394 g, 1.22 mmol) in toluene (15 mL) and water (3 mL) was added cyclopropylboronic acid (0.639 g, 7.44 mmol), tribasic potassium phosphate (0.826 g, 3.89 mmol), tricyclohexylphosphine tetrafluoroborate (0.30 g, 0.97 mmol), and palladium acetate trimer (0.108 g, 0.481 mmol Pd). The mixture was heated to reflux under an argon atmosphere for 21 hours, cooled to ambient temperature. The mixture was filtered through a pad of diatomaceous earth that was rinsed with ethyl acetate (100 mL). The filtrate was washed with a 2:1 mixture of saturated aqueous ammonium chloride and water (150 mL), brine (150 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to dryness. The residue was purified by column chromatography with a gradient of ethyl acetate in hexanes (0-10%) to afford the title compound as a light yellow syrup (0.30 g, 76%): 1H NMR (300 MHz, CDCl3) δ 7.46 (d, J=8.4 Hz, 1H), 6.55 (d, J=12.6 Hz, 1H), 4.57 (br s, 1H), 3.86 (s, 3H), 2.44-1.88 (m, 9H), 0.93-0.86 (m, 2H), 0.64-0.59 (m, 2H); 19F NMR (282 MHz, CDCl3) 8-92.3 (d, J=238 Hz, 1F), −102.3 (d, J=237 Hz, 1F), −109.4 (s, 1F); MS (ES+) m/z 329.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:11])([CH2:7][C:8]([O-])=[O:9])[C:3]([O:5][CH3:6])=[O:4].CO>ClCCl.O1CCCC1>[F:1][C:2]([F:11])([CH2:7][CH2:8][OH:9])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(F)(F)CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(F)(F)CCO
Temperature: 80 °C

Procedure:
In a 4 L flask equipped with a reflux condenser and 1 L dropping funnel, a solution of BH3.Me2S complex (10M, 88 mL) in dry dichloromethane (1 L) is slowly added over a 2 hour period to a stirred solution of the methyl 2,2-difluorosuccinate (120 g, 0.714 moles) in dry tetrahydrofuran at 20° C. After refluxing (bath temperature 80° C.) for about 15 hours, the mixture is allowed to cool to room temperature and methanol (1 L) is slowly added. Evaporation yields methyl 2,2-difluoro-4-hydroxybutyrate as an oil which is stripped with methanol (1 L) and finally with CCL4 to yield a yellow oil: 100 g (92%).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[CH3:27][O:28][CH2:29][CH2:30][C:31](O)=O>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:31]([CH2:30][CH2:29][O:28][CH3:27])[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: COCCC(=O)O
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: COCCc1nc([C@@H]2CC(=NOC)CN2C(=O)c2ccc(-c3ccccc3)cc2)no1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and 3-methoxypropanoic acid, the title compound was obtained in 80% purity by HPLC. MS(ESI+): m/z=421.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]2[C:10]3([CH2:12][CH2:11]3)[CH2:9][O:8][C:7]=12.CN(C=O)C.Cl[C:20]1[N:25]=[CH:24][C:23]([N:26]2[C:30](=[O:31])[C@:29]([CH2:33][CH3:34])([CH3:32])[NH:28][C:27]2=[O:35])=[CH:22][N:21]=1>>[CH2:33]([C@@:29]1([CH3:32])[NH:28][C:27](=[O:35])[N:26]([C:23]2[CH:24]=[N:25][C:20]([O:13][C:5]3[C:6]4[C:10]5([CH2:9][O:8][C:7]=4[C:2]([CH3:1])=[CH:3][CH:4]=3)[CH2:12][CH2:11]5)=[N:21][CH:22]=2)[C:30]1=[O:31])[CH3:34]
Reactant: CC[C@@]1(C)NC(=O)N(c2cnc(Cl)nc2)C1=O
Reactant: Cc1ccc(O)c2c1OCC21CC1
Solvent: CN(C)C=O
Product: CC[C@@]1(C)NC(=O)N(c2cnc(Oc3ccc(C)c4c3C3(CC3)CO4)nc2)C1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
To a solution of 7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-ol (Intermediate 13, 18 mg, 0.1 mmol) in dry DMF (1 ml) potassium carbonate (27.6 mg, 0.2 mmol) and then (5R)-3-(2-chloropyrimidin-5-yl)-5-ethyl-5-methyl-imidazolidine-2,4-dione (Intermediate 22, 20 mg, 0.08 mmol) were added and the reaction mixture was stirred for 2 hours at 80° C. After cooling the reaction mixture was quenched with water (1 ml), diluted with brine (5 ml) and extracted with ethyl acetate (2×10 ml). The organic layer was dried over sodium sulfate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 7:3 to cyclohexane/ethyl acetate 3:7 as eluents affording the title compound (21 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[O:10][C:9]([C:11]3[CH:12]=[C:13]([NH:18][C:19]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[O:20])[CH:14]=[CH:15][C:16]=3[Cl:17])=[N:8][C:5]2=[N:6][CH:7]=1.Cl[C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28].N1C=CC=CC=1>COCCOC>[CH:30]([O:29][C:27](=[O:28])[NH:1][C:2]1[CH:3]=[C:4]2[O:10][C:9]([C:11]3[CH:12]=[C:13]([NH:18][C:19]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[O:20])[CH:14]=[CH:15][C:16]=3[Cl:17])=[N:8][C:5]2=[N:6][CH:7]=1)([CH3:32])[CH3:31]
Reactant: Nc1cnc2nc(-c3cc(NC(=O)N4CCCC4)ccc3Cl)oc2c1
Reactant: CC(C)OC(=O)Cl
Solvent: COCCOC
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1cnc2nc(-c3cc(NC(=O)N4CCCC4)ccc3Cl)oc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-[6-amino-[1,3]oxazolo[4,5-b]pyridin-2-yl]-4-chlorophenyl)pyrrolidine-1-carboxamide (100 mg, 0.28 mmol, 1.00 equiv), propan-2-yl chloroformate (68.3 mg, 0.56 mmol, 1.99 equiv), pyridine (111 mg, 1.40 mmol, 5.02 equiv) in ethylene glycol dimethyl ether (15 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). The collected fractions were combined and concentrated under vacuum. This resulted in 60.8 mg (49%) of propan-2-yl N-[2-(2-chloro-5-[[(pyrrolidin-1-yl)carbonyl]amino]phenyl)-[1,3]oxazolo[4,5-b]pyridin-6-yl]carbamate (75) as a yellow solid.