Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:22][CH2:23][CH2:24][C:25](OC)=O)[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].BrC[C:37]1C=C[CH:40]=[C:39]([Cl:43])[CH:38]=1.Cl>>[ClH:43].[Cl:43][C:39]1[CH:40]=[C:24]([CH:25]=[CH:37][CH:38]=1)[CH2:23][S:22][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH3:21])[N:20]=2)=[N:13][CH:12]=1
Reactant: Clc1cccc(CBr)c1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: Cc1csc(Nc2ncc(SCc3cccc(Cl)c3)cc2OCc2ccccc2)n1
Yield: 154 %

Procedure:
Methyl 3-(5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate (prepared according to Example 42; 70 mg, 0.17 mmol), KOtBu (0.59 mL, 0.59 mmol) and 1-(bromomethyl)-3-chlorobenzene (0.022 mL, 0.17 mmol) were reacted according to the method of Example 43 to afford 5-(3-chlorobenzylthio)-3-(benzyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine hydrochloride (64.2 mg, 77.70% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 10.85 (bs, 1H), 7.80 (d, 1H), 7.60-7.53 (m, 3H), 7.45-7.33 (m, 3H), 7.31-7.25 (m, 3H), 7.12 (m, 1H), 6.78 (s, 1H), 5.29 (s, 2H), 4.19 (s, 2H), 2.29 (d, 3H); Mass spectrum (apci) m/z=238.0 (100), 454.0 (95), 362.9 (80).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:19])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2cccnc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2cccnc2c1
Temperature: 100 °C
Yield: 57.9 %

Procedure:
To a solution of 7-methylquinoline (0.10 g, 0.70 mmol) in 5 ml of CCl4 was added NBS (0.14 g, 0.77 mmol) and AIBN (0.025 g, 0.15 mmol). The reaction mixture was heated at 100° C. for 2 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400M) using 1% ethyl acetate/hexane eluent to give the desired product (0.090 g, 58%).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][CH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=2)[C:18]([CH3:30])([CH3:29])[CH2:17]1)=O)(C)(C)C>C(Cl)Cl>[NH2:15][CH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=2)[C:18]([CH3:30])([CH3:29])[CH2:17]1
Reactant: COC(=O)c1ccc2c(c1)C(NC(=O)OC(C)(C)C)CC2(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)C(N)CC2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TFA (0.7 ml, 9 mmol, 13 eq.) was added to a stirred solution of methyl 3-(tert-butoxycarbonylamino)-1,1-dimethyl-2,3-dihydro-1H-indene-5-carboxylate (220 mg, 0.69 mmol, 1 eq.) in methylene chloride (10 ml) at 0° C. and the mixture was stirred at RT for 2 h. After complete deprotection (checked by TLC) the solvent was removed under reduced pressure. The residue was diluted with methylene chloride (50 ml) and washed with water (10 ml) and brine (10 ml). The organic part was evaporated under reduced pressure to give the crude product which was directly used for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:36]=[C:37]([C:43]2[CH:44]=[C:45]([CH2:60]OS(C)(=O)=O)[C:46](=[O:59])[N:47]([CH2:49][CH2:50][CH2:51][C:52]3[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=3)[N:48]=2)[CH:38]=[CH:39][C:40]=1[O:41][CH3:42].N1(C(OC(C)(C)C)=O)CCNCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:60][C:45]2[C:46](=[O:59])[N:47]([CH2:49][CH2:50][CH2:51][C:52]3[CH:53]=[CH:54][C:55]([F:58])=[CH:56][CH:57]=3)[N:48]=[C:43]([C:37]3[CH:38]=[CH:39][C:40]([O:41][CH3:42])=[C:35]([F:34])[CH:36]=3)[CH:44]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CCCc3ccc(F)cc3)n2)cc1F
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CCCc3ccc(F)cc3)n2)cc1F
Yield: 72.6 %

Procedure:
Following the procedure of Example 1 (10), 6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 72.6%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[C@H:3]1[CH2:10][C:11]#[N:12]>CCOC(C)=O.[Pd]>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C@H:3]1[CH2:10][C:11]#[N:12]
Reactant: C[C@@H]1C=CCC(C)(C)[C@H]1CC#N
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@@H]1CCCC(C)(C)[C@H]1CC#N
Temperature: 25 °C
Reaction time: 72 h
Yield: 98 %

Procedure:
To a solution of trans-(2,6,6-trimethyl-3-cyclohexen-1-yl)acetonitrile obtained in Example 3b) (3.0 g, purity 98%, 18 mmol) in AcOEt (30 ml) was added 10% Pd—C and the mixture was shaken under H2 (1 atm) at room temperature during 3 days. The catalyst was filtered off through celite and the filtrate was concentrated. Bulb-to-bulb distillation (oven temp 80° C./0.3 mbar) afforded trans-(2,6,6,trimethylcyclohexyl)acetonitrile (2.88 g, purity 99%, yield 98%).
Reaction SMILES: [CH3:1][C:2]1([CH3:53])[N:6]([CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH3:49])[C:5](=[O:50])[C:4]([CH3:52])([CH3:51])[NH:3]1.C(O[Cl:59])(C)(C)C>CO>[Cl:59][N:3]1[C:4]([CH3:52])([CH3:51])[C:5](=[O:50])[N:6]([CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH3:49])[C:2]1([CH3:53])[CH3:1]
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN1C(=O)C(C)(C)NC1(C)C
Reactant: CC(C)(C)OCl
Solvent: CO
Product: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN1C(=O)C(C)(C)N(Cl)C1(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a 0° C. solution of 2,2,5,5-tetramethyl-3-(2,5,8,11,14,17,20,23,26,29,32,35,38,41-tetradecaoxatritetracontan-43-yl)imidazolidin-4-one (1.13 g, 1.2 mmol) in methanol (150 ml) was added tert-butylhypochlorite (393 mg, 3.6 mmol). The mixture was stirred for 1 hour at 0° C. The reaction mixture was concentrated in vacuo, and crude material is purified by silica gel flash chromatography (0 to 10% methanol in dichloromethane) to give 764 mg (66%) of the title compound. 1H NMR (400 MHz, D2O) δ 3.70 (s, 54H), 3.64 (m, 2H), 3.56 (t, J=7.5 Hz, 2H), 3.39 (s, 3H), 1.54 (s, 6H), 1.37 (s, 6H). 13C NMR (100 MHz, D2O) δ 175.0, 83.6, 71.0, 69.4 (large peak), 67.7, 66.0, 58.0, 40.2, 24.1, 22.6.
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:22])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:23]([OH:31])(=[O:30])[C:24]([CH2:26][C:27](O)=[O:28])=[CH2:25]>C(OCC)(=O)C>[CH2:1]([NH:11][C:12](=[O:22])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[CH2:25][CH:24]([C:23]([OH:31])=[O:30])[CH2:26][C:27]2=[O:28])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: CCCCCCCCCCNC(=O)C=Cc1cccc(N)c1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCNC(=O)C=Cc1cccc(N2CC(C(=O)O)CC2=O)c1
Temperature: 25 °C

Procedure:
A mixture of 9.0 g. of N-decyl-3-(3-aminophenyl)propenamide and 3.9 g. of itaconic acid was heated as a melt at 140°-145° C. for 1 hour, and then ca. 70 ml. of ethyl acetate was added to the hot mass. The resulting mixture was stirred, and a solid appeared. The mixture was cooled to room temperature, and the solid was recovered by filtration to give 9.5 g. of the title compound. This product was recrystallized from acetonitrile to give 8.4 g. (69% yield) of product having a melting point of 152.5°-153.5° C.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N:14]([CH2:17][CH2:18][CH:19]([OH:24])[C:20]([F:23])([F:22])[F:21])=[N+:15]=[N-:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[N:14]([CH2:17][CH2:18][CH:19]([C:20]([F:21])([F:23])[F:22])[O:24][C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=NCCC(O)C(F)(F)F
Reactant: N#Cc1ccc(C(F)(F)F)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C(F)(F)F)nc1OC(CCN=[N+]=[N-])C(F)(F)F
Reaction time: 20 h
Yield: 91.3 %

Procedure:
A mixture of 2-chloro-6-(trifluoromethyl)nicotinonitrile (0.675 g, 3.27 mmol) and 4-azido-1,1,1-trifluoro-2-butanol (0.552 g, 3.26 mmol) in DMF (8.5 mL) was treated with caesium carbonate (2.18 g, 6.69 mmol) at ambient temperature. After 20 h, the mixture was diluted with water and extracted with diethyl ether. The combined organic extracts were washed (water, brine), dried, and-evaporated to give the product as a brown oil (1.01 g, 90%).
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH:4]=[CH:3]1>C(Cl)Cl.[Pd]>[O:1]=[C:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(C=CC(=O)CC2)CC1
Agent: [Pd]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of tert-butyl 9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate (5.2 g, 19.6 mmol) in DCM (80 mL) was added 10% Pd/C (0.5 g) and the suspension was stirred under a H2 atmosphere at room temperature overnight. The reaction mixture was filtered and concentrated in vacuo, then the residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/4) to give the product as brown oil (3.1 g, 59.0%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=O)[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[N:10]([CH3:16])[CH2:9]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[S:37])[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[N:10]([CH3:16])[CH2:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)N(C)C3)c(F)c2)C(=O)O1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC(=S)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)N(C)C3)c(F)c2)C(=O)O1
Temperature: 100 °C
Yield: 85.7 %

Procedure:
N-[[(5S)-3-[3-fluoro-4-(tetrahydro-2-methyl-1,1-dioxido-2H-1,2-thiazin4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (100 mg, 0.25 mmol) and Lawesson's Reagent (122 mg, 0.30 mmol) were dissolved in dioxane (10 mL) under nitrogen. The reaction is heated to 100° C. for 20 minutes then cooled to ambient and evaporated. The residue is partitioned between ethyl acetate (150 mL) and water (50 mL). The organic phase is washed 3 times with water (50 mL) and brine (50 mL), then dried over MgSO4, filtered and evaporated to a nearly colorless glass. The product is purified by radial chromatography over silica gel, eluting with 0-10% methanol-methylene chloride to give a white solid foam (89 mg, 85%). MP=95-98° C., decomposes.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[NH2:8][CH2:9][C:10]1[CH:40]=[C:39]([F:41])[C:13]([C:14]([NH:16][C@@H:17]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[C:29](=[O:38])[N:30]([CH3:37])[C:31](=[O:36])[N:32]([CH3:35])[C:33]=3[CH3:34])=[CH:24][CH:23]=2)[C:18]([OH:20])=[O:19])=[O:15])=[C:12]([F:42])[CH:11]=1.O=C1CCC(=O)N1[O:50][C:51](=O)[CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][O:72][CH2:73][CH2:74][O:75][CH2:76][CH2:77][NH:78][C:79](=[O:89])[CH2:80][CH2:81][N:82]1[C:86](=[O:87])[CH:85]=[CH:84][C:83]1=[O:88].CCN(C(C)C)C(C)C>>[F:5][C:4]([F:7])([F:6])[C:2]([OH:3])=[O:1].[O:88]=[C:83]1[CH:84]=[CH:85][C:86](=[O:87])[N:82]1[CH2:81][CH2:80][C:79]([NH:78][CH2:77][CH2:76][O:75][CH2:74][CH2:73][O:72][CH2:71][CH2:70][O:69][CH2:68][CH2:67][O:66][CH2:65][CH2:64][O:63][CH2:62][CH2:61][O:60][CH2:59][CH2:58][O:57][CH2:56][CH2:55][O:54][CH2:53][CH2:52][C:51]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([F:42])[C:13]([C:14]([NH:16][C@@H:17]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[C:29](=[O:38])[N:30]([CH3:37])[C:31](=[O:36])[N:32]([CH3:35])[C:33]=3[CH3:34])=[CH:26][CH:27]=2)[C:18]([OH:20])=[O:19])=[O:15])=[C:39]([F:41])[CH:40]=1)=[O:50])=[O:89]
Reactant: O=C(CCN1C(=O)C=CC1=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(F)cc(CN)cc3F)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(F)cc(CNC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCNC(=O)CCN4C(=O)C=CC4=O)cc3F)C(=O)O)cc2)c(=O)n(C)c(=O)n1C

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 11, starting from (S)-2-(4-aminomethyl-2,6-difluorobenzoylamino)-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid TFA salt (121 mg, 0.2 mmol), 3-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)- propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionic acid-2,5-dioxo-pyrrolidin-1-yl ester (100 mg, 0.145 mmol), and DIPEA (258 mg, 348 uL, 2.0 mmol), and after HPLC purification, resulted in a white solid (80 mg, 38%). ES(+)-HRMS m/e calcd. for C50H66F2N6O17 (M+H)+ 1061.4526, obsd. 1061.4521.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[C:10](=[O:11])[C@@H:9]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[C@H:8]1[C@@H:23]([OH:26])[CH2:24][OH:25].[C:32](N1C=CN=C1)(N1C=CN=C1)=[O:33]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[C:10](=[O:11])[C@@H:9]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[C@H:8]1[C@@H:23]1[CH2:24][O:25][C:32](=[O:33])[O:26]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2[C@@H](O)CO)cc1OC
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2[C@@H]2COC(=O)O2)cc1OC
Yield: 96.5 %

Procedure:
215.23 g (0.5 mol) of benzyl (2S,3S)-1-(3,4-dimethoxybenzyl)-2-[1 (R),2-dihydroxyethyl]-4-oxo-3-azetidinecarbamate were dissolved in 3 l of THF at the boiling temperature. 12.61 g (0.75 mol) of 1,1'-carbonyldiimidazole were added. The mixture was boiled under reflux for 4 hours. The THF was subsequently removed by concentration, the oily residue was taken up in 1.5 l of dichloromethane, washed once with 500 ml of 1N aqueous hydrochloric acid, twice with 1 l of water each time and once with 500 ml of saturated, aqueous sodium chloride solution and dried over magnesium sulphate with the addition of about 7 g of fuller's earth. The solvent was removed by concentration. After drying there were obtained without further purification 220.3 g (yield: 96%) of pure product. M.p.: 135°-136° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.C[N:19](C=O)C.[NH4+].[OH-]>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:19])=[O:5]
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)c1ccc(Cl)nc1Cl
Temperature: 25 °C

Procedure:
A suspension of 2,6-dichloronicotinic acid (5 g, 26.0 mmol) in CH2Cl2 (20 mL) was treated with oxalyl dichloride (3.97 g, 31.3 mmol) and few drops of DMF, and stirred at rt. The generation of bubbles was observed and the reaction mixture gradually became clear. The resulting clear solution was concentrated on a rotary evaporator to remove traces of oxalyl chloride, dissolved in CH2Cl2 (20 mL), treated with aqueous NH4OH (3.47 mL, 52.1 mmol) added drop-wise, and stirred at rt for 1 h. The resulting mixture was diluted with CH2Cl2 (white precipitate doesn't all dissolve), washed with satd. NaHCO3, and concentrated to obtain 2.97 g of 2,6-dichloronicotinamide as a white solid. LCMS: (M+H)+=190.96 (100%) 192.93 (70%) 194.93 (20%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([F:12])[C:3]=1[C:13]1[S:17][C:16]([NH:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([O:25]CC[Si](C)(C)C)[N:20]=2)=[C:15]([C:32]([NH2:34])=[O:33])[CH:14]=1>CO.Cl>[F:12][C:4]1[CH:5]=[C:6]([C:8]([OH:11])([CH3:9])[CH3:10])[CH:7]=[C:2]([F:1])[C:3]=1[C:13]1[S:17][C:16]([NH:18][C:19]2[CH:24]=[CH:23][NH:22][C:21](=[O:25])[N:20]=2)=[C:15]([C:32]([NH2:34])=[O:33])[CH:14]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccnc(OCC[Si](C)(C)C)n3)s2)c(F)c1
Agent: Cl
Solvent: CO
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cc[nH]c(=O)n3)s2)c(F)c1

Procedure:
5-[2,6-Difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-({2-[2-(trimethylsilyl)ethoxy]pyrimidin-4-yl}amino)thiophene-3-carboxamide (109 mg, 0.215 mmol) was stirred in a mixture of MeOH (10 mL) and 2N HCl (6 mL) at room temperature overnight. The solvent was removed in vacuo, saturated NaHCO3 was added and the reaction mixture was extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by reverse phase HPLC (40-100% MeCN—H2O) gave the title compound as a pale yellow solid after triturating in DCM.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O)([CH3:4])([CH3:3])[CH3:2].[O:14]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C1COCC1.CCCCCC.C(OCC)(=O)C>[O:14]([C:21]1[CH:22]=[C:23]([NH:24][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:7]=2)[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)Oc1cccc(C=O)c1
Reactant: Nc1cccc(Oc2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)Oc1cccc(CNc2cccc(Oc3ccccc3)c2)c1
Yield: 41.6 %

Procedure:
The 3-t-butoxybenzaldehyde (0.585 g, 3.27 nmmol) product from EX-654A and 3-phenoxyaniline (0.595 g, 3.21 mmol) were combined in 50 mL of THF, then solid NaBH(OAc)3 (0.860 g, 4.06 mmol) was added, and the mixture was stirred until uniform. Acetic acid (0.2 g, 3.33 mmol) was added, and the mixture was stirred at room temperature for 4 h, then quenched with 5% aq. NaHCO3. The aqueous layer was separated and extracted twice with ether. The combined ether layers were washed with water and brine, dried over MgSO4, filtered, and evaporated to give 1.29 g (115%) of crude product as a brown oil. Chromatography on silica gel eluting with 0-10% ethyl acetate in hexane gave 464 mg (40%) of the desired N-(3-phenoxyphenyl)[[3-(1,1-dimethyl-ethoxy)phenyl]methyl]amine product as a colorless oil, pure by TLC. MS m/z=347 [M+].
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1.[Cl:19][CH:20]([Cl:39])[C:21]([NH:23][C@H:24]([CH2:37][F:38])[C@H:25]([OH:36])[C:26]1[CH:31]=[CH:30][C:29]([Sn](C)(C)C)=[CH:28][CH:27]=1)=[O:22].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN1CCCC1=O.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]>[Cl:19][CH:20]([Cl:39])[C:21]([NH:23][C@H:24]([CH2:37][F:38])[C@@H:25]([C:26]1[CH:27]=[CH:28][C:29]([C:2]2[S:6][C:5]([CH:7]3[CH2:11][CH2:10][CH2:9][N:8]3[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=2)=[CH:30][CH:31]=1)[OH:36])=[O:22]
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(Br)s1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCCC1c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1
Temperature: 80 °C
Reaction time: 70 h
Yield: 46.5 %

Procedure:
To a stirred solution of tert-butyl 2-(5-bromothiophen-2-yl)pyrrolidine-1-carboxylate (0.750 g, 2.26 mmol), 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethylstannyl)phenyl)propan-2-yl)acetamide (1.0 g, 2.26 mmol), and tri(furan-2-yl)phosphine (105 mg, 0.452 mmol) in N-Methyl-2-pyrrolidone (10 mL) degassed with nitrogen is added Pd2(dba)3 (207 mg, 0.226 mmol). The reaction mixture is heated to 80° C. for 5 hours then left at ambient 70 hours. Reaction mixture partitioned between ethyl acetate (100 mL) and water (100 mL). Organic phase is isolated and concentrated in vacuo to give the crude material, which is purified by column chromatography on silica gel eluting in 0-100% ethyl acetate in heptane to give the title compound (559 mg): 1H-NMR (400 MHz, CDCl3) δ 1.32-1.52 (m, 9H), 1.89-2.15 (m, 3H), 2.21-2.37 (m, 1H), 2.59-2.78 (m, 1H), 3.40-3.66 (m, 2H), 4.25-4.38 (m, 1H), 4.43-4.49 (m, 0.5H), 4.54-4.62 (m, 1H), 4.66-4.73 (m, 0.5H), 5.01-5.25 (m, 2H), 5.89 (s, 1H), 6.83 (bs, 1H), 7.06 (d, J=8.6 Hz, 1H), 7.14 (d, J=3.5 Hz, 1H), 7.38 (d, J=8.1 Hz, 2H), 7.56 (d, J=8.1 Hz, 2H). m/z (Cl) M-boc+H 431.0.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24]>C(O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1cccc(CN)c1
Solvent: CCO
Product: COc1cccc(CNc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.1 %

Procedure:
A mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-methoxybenzylamine (37 μl, 0.290 mmol) in 10 ml of ethanol was stirred at room temperature for 48 h. The mixture was rotary evaporated to dryness and purified by preparative TLC with hexane:ethyl acetate (3:1) to give a yellow solid (14 mg, 20%). 1H NMR (CDCl3): 9.60-9.59 (m, 1H), 8.70-8.66 (m, 2H), 7.40-7.32 (m, 1H), 7.30 (d, J 7.8 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 6.91 (s, 1H), 6.85 (dd, J=2.7, 8.4 Hz, 1H), 6.62 (s, 1H), 5.75 (bs, 1H), 4.73 (s, 2H), 3.79 (s, 3H).
Reaction SMILES: [C@H:1]1([O:12][CH2:13][C:14]2[CH:15]=[C:16]([C:20]3[CH:21]=[C:22]([CH2:26][C:27]([OH:29])=[O:28])[CH:23]=[CH:24][CH:25]=3)[CH:17]=[CH:18][CH:19]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3].[CH3:30]O>S(=O)(=O)(O)O>[C@H:1]1([O:12][CH2:13][C:14]2[CH:15]=[C:16]([C:20]3[CH:21]=[C:22]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:23]=[CH:24][CH:25]=3)[CH:17]=[CH:18][CH:19]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: O=C(O)Cc1cccc(-c2cccc(CO[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)c2)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccc(-c2cccc(CO[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)c2)c1
Yield: 77 %

Procedure:
3-(3-(α-D-mannopyranosyloxymethyl)phenyl)phenylacetic acid (0.05 g, 0.12 mmol), methanol (10 ml), and concentrated sulfuric acid (2 drops) were heated reflux for 1 hour in a 25 ml flask, then quenched with saturated sodium bicarbonate solution, diluted with water (5 ml), extracted with methylene chloride (3×5 ml), washed with brine (10 ml), dried (MgSO4), concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 5:1/methylene chloride:methanol) which gave methyl 3-(3-(α-D-mannopyranosyloxymethyl)phenyl)phenylacetate (0.04 g, 77%); 1H NMR: (300 MHz, DMSO-d6) 7.2-7.6 (comp, 8H), 4.70 (s, 1H), 4.49-4.80 (comp, 7H), 3.75 (s, 2H), 3.62 (s, 3H), 3.30-3.50 (comp, 5H) ppm; IR: 3383, 1738, 1135, 1066 cm-1.