Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[S:38][C:8]2[C:9](=[O:37])[N:10]([C:12]3[C:13]([CH3:36])=[C:14]([C:18]4[CH:19]=[C:20]([NH:25][C:26]5[CH:35]=[C:29]6[CH2:30][N:31]([CH3:34])[CH2:32][CH2:33][N:28]6[N:27]=5)[C:21](=[O:24])[NH:22][N:23]=4)[CH:15]=[CH:16][CH:17]=3)[CH2:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:39]=[O:40]>CO>[C:1]([C:5]1[S:38][C:8]2[C:9](=[O:37])[N:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[CH:19]=[C:20]([NH:25][C:26]5[CH:35]=[C:29]6[CH2:30][N:31]([CH3:34])[CH2:32][CH2:33][N:28]6[N:27]=5)[C:21](=[O:24])[N:22]([CH2:39][OH:40])[N:23]=4)[C:13]=3[CH3:36])[CH2:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4)c(=O)[nH]n2)cccc1N1Cc2cc(C(C)(C)C)sc2C1=O
Reactant: C=O
Solvent: CO
Product: Cc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4)c(=O)n(CO)n2)cccc1N1Cc2cc(C(C)(C)C)sc2C1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 101 (2.50 g, 4.72 mmol), methanol (30 mL) and a 37% solution of formaldehyde in methanol (30 mL, 100 mmol). A reflux condenser was attached to the flask, and the reaction mixture was heated at 60° C. for 3 h under nitrogen atmosphere. After this time, the mixture was stirred at room temperature for 1 h and filtered through a Buchner funnel. The filter cake was washed with methanol (3×5 mL) and dried under vacuum at 40° C. for 12 h to afford 108a in a 93% yield (2.45 g) as a white solid: mp 185-187° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.33 (s, 1H), 7.79 (s, 1H), 7.47 (m, 1H), 7.39 (s, 1H), 7.38 (s, 1H), 7.14 (s, 1H), 6.77 (t, J=7.8 Hz, 1H), 5.99 (s, 1H), 5.43 (d, J=7.5 Hz, 2H), 4.78 (s, 2H), 3.97 (t, J=5.0 Hz, 2H), 3.51 (s, 2H), 2.79 (t, J=5.0 Hz, 2H), 2.35 (s, 3H), 2.13 (s, 3H), 1.41 (s, 9H); MS (ESI+) m/z 530.2 (M+H).
Reaction SMILES: [C:1](Cl)(=O)C.[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:15])[CH:7]=1>CO.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:1][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:6]([Br:5])=[CH:7][C:8]=1[CH3:15]
Reactant: CC(=O)Cl
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(Br)cc1C
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 97.8 %

Procedure:
Acetyl chloride (199 mL, 2.79 mol) is added to a solution of 4-bromo-2-methylbenzoic acid (500 g, 2.32 mol) in methanol (2500 mL) at 5° C. The mixture is heated at 65° C. for 7 hours. The mixture is cooled to room temperature and sodium carbonate (19 g, 0.18 mol) is added. The reaction mixture is stirred for 15 minutes. The slurry is filtered and the filtrate is concentrated under reduced pressure. The resulting residue is partitioned between MTBE (400 mL) and water (400 mL). The organic phase is washed with brine, dried over magnesium sulfate, and concentrated to give the title compound (520 g) as a golden oil. ES/MS m/e 216 (M+1).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[H-].[CH2:6]([Al+]CC(C)C)C(C)C.[Nd].C(Br)C=C>[Nd].CCCCCC.C(O)CCC>[CH2:1]=[CH:2][C:3](=[CH2:6])[CH3:4].[CH2:1]=[CH:2][CH:3]=[CH2:4]
Reactant: CC(C)C[Al+]CC(C)C
Agent: C=CC=C
Agent: [H-]
Agent: [Nd]
Solvent: C=CCBr
Solvent: CCCCCC
Solvent: CCCCO
Product: C=CC(=C)C
Temperature: 20 °C
Reaction time: 1 h

Procedure:
In this experiment, an isoprene-butadiene copolymer was synthesized using an alcohol modified neodymium catalyst system with a different catalyst component molar ratio than that described in Example 3. In this procedure, a one gallon (3.78 liter) reactor was charged with 1,088 grams of hexane containing 93.5 grams of butadiene and 668 grams of 1.23 molar diisobutylaluminum hydride (DIBAH) in hexane (i.e., 25% weight percent DIBAH). To this solution was added 26.22 grams of n-butanol with stirring and with temperatures maintained at 20° C. After stirring for thirty minutes, 107.5 grams of a 10.1% neodymium solution (neodymium neodecanoate), dilute with 158 grams of dry hexane, was charged to the reactor. The solution was stirred for another thirty minutes after which time 21.4 grams of allyl bromide was added. The cooling was stopped and the mixture allowed to warm up to ambient (and above) temperature. After the exotherm subsided, requiring about one hour, the catalyst solution was heat aged at 65° C. for ninety minutes. The aged catalyst was then cooled and stored in a dry container under nitrogen. The catalyst prepared had a [butanol-DIBAH] Nd-allyl bromide-butadiene molar component ratio of [4.7-15.5]-1-2.35-23, respectively, and a concentration of 0.025 molarity with respect to the neodymium.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br.CCO.O.[K+].[Br-]>O>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][N:15]1[C:14]2[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:13]=2[O:12][CH:11]([CH2:10][CH2:9][OH:1])[C:16]1=[O:17]
Reactant: Clc1cccc(CBr)c1
Reactant: COc1ccc2c(c1)NC(=O)C(CCO[Si](C)(C)C(C)(C)C)O2
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)N(Cc1cccc(Cl)c1)C(=O)C(CCO)O2

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-6-methoxy-3-oxo-2H-1,4-benzoxazine by methods F and G, alkylating with 3-chlorobenzyl bromide, in 80% overall yield. Isolated by crystallization from EtOH/water to afford a white powder, MS (CI) 348 (MH+); IR (KBr) 3501, 3053, 3021, 2959, 2933, 2876, 2838, 1664, 1618, 1600, 1575, 1512, 1466, 1445, 1435, 1390, 1361, 1337, 1313, 1272, 1237, 1201, 1173, 1107, 1078, 1049, 1030 cm-1 ; 1H NMR (CDCl3) δ7.27-7.20 (m, 3H), 7.13 (m, 1H), 6.94 (d, J=8.8 Hz, 1H), 6.52 (dd, J=9.1, 2.7 Hz, 1H), 6.41 (d, J=2.7 Hz, 1H), 5.12 (d, J=16.2 Hz, 1H), 4.79 (dd, J=8.2, 5.4 Hz, 1H), 3.92 (m, 2H), 3.68 (s, 3H), 3.39-2.16 (m, 2H), 2.17 (t, J=5.9 Hz, 1H). Anal. Calc'd for C18H18ClNO4.0.25 H2O: C 61.37, H 5.29, N 3.98. Found: C 61.35, H 5.14, N 3.95.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16](=[O:31])/[CH:17]=[CH:18]/[C:19]2[S:29][C:28]3[N:30]4[C:21](=[CH:22][N:23]=[C:24]4[CH:25]=[CH:26][CH:27]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32]>C(O)C>[ClH:32].[ClH:32].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16](=[O:31])/[CH:17]=[CH:18]/[C:19]2[S:29][C:28]3[N:30]4[C:21](=[CH:22][N:23]=[C:24]4[CH:25]=[CH:26][CH:27]=3)[CH:20]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)/C=C/C2=Cc3cnc4cccc(n34)S2)CC1
Agent: Cl
Solvent: CCO
Product: O=C(/C=C/C1=Cc2cnc3cccc(n23)S1)CCC1CCNCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To the above crude (E)-5-[1-(tert-butoxycarbonyl)-piperidin-4-yl]-1-(5-thia-1,8b-diazaacenaphthylen-4-yl)-1-penten-3-one was added 5 ml of concentrated hydrochloric acid and the mixture was stirred at room temperature for 15 minutes. To this reaction mixture was added ethanol, followed by stirring, and the resulting precipitate was recovered by filtration and rinsed serially with ethanol and diethyl ether to provide the title compound.
Reaction SMILES: CN(C)CCO.[Li]CCCC.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23]>CCCCCC.O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Sn:24]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH2:21][CH2:22][CH3:23])[N:15]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: COc1ccccn1
Agent: CN(C)CCO
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(OC)n1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-dimethylaminoethanol (3.50 mL, 16.36 mmol) in hexane (20.0 mL, HPLC grade) cooled at −5° C. was added drop wise n-BuLi (3.60 M, 9.0 mL, 32.40 mmol) under nitrogen atmosphere. After 30 min at 0° C., 2-methoxy-pyridine (0.60 g, 5.45 mmol) in hexane (20.0 mL) was added drop wise. After stirring the reaction mixture for 1 h at 0-5° C., the reaction medium was cooled to −78° C. followed by drop wise addition of tributyl tin chloride (3.70 mL, 13.62 mmol). The resulting reaction mixture was stirred at −78° C. for 30 min and then allowed to stir at 0-5° C. for 30 min. The reaction mixture was then allowed to come to room temperature. After the completion of reaction (TLC monitoring), the reaction mass was cooled to 0° C. and water was added slowly. The aqueous phase was extracted with diethyl ether (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness. The crude residue (1.80 g, 72%) was carried forward to the next step without further purification.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[C:9]([C:15]#[N:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17]N(C=O)C.[H-].[Na+].CI>O>[C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH3:17])[C:10](=[O:14])[C:9]([C:15]#[N:16])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1nn(-c2ccccc2)c(=O)[nH]c1=O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cn1c(=O)c(C#N)nn(-c2ccccc2)c1=O
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Intermediate c (9 g, 0.042 mol) was added to DMF (100 mL). To the mixture was added NaH (1.3 g, 0.054 mol) in batch under an ice bath. After stirring for 30 min, methyl iodide (2.74 mL, 0.042 mol) was added dropwise. After the dropwise addition, the reaction was conducted for 2 h. After completion of the reaction, the reaction solution was poured into water (600 mL). A great deal of red solid separated out and was filtered by suction. The filtered cake was washed with water and dried to produce an orange red solid (7.6 g) in a yield of 80.0%.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:20]2[C:21]([CH3:29])=[N:22][N:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=23)[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9](COCC[Si](C)(C)C)[N:8]=1.[OH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C([O-])(O)=O.[Na+].FC(F)(F)C(O)=O>C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[CH3:29][C:21]1[C:20]([C:4]2[S:5][C:6]([C:7]3[N:11]=[CH:10][NH:9][N:8]=3)=[C:2]([C:35]3[CH:36]=[CH:37][C:32]([CH2:31][OH:30])=[CH:33][CH:34]=3)[N:3]=2)=[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]2[N:22]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Cc1nn2ccccc2c1-c1nc(Br)c(-c2ncn(COCC[Si](C)(C)C)n2)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: COCCOC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nn2ccccc2c1-c1nc(-c2ccc(CO)cc2)c(-c2nc[nH]n2)s1
Temperature: 125 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
Into a microwave vial containing a mixture of 4-bromo-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)thiazole (0.030 g, 0.061 mmol) and 4-(hydroxymethyl)phenylboronic acid (0.026 g, 0.17 mmol) was added 1M aqueous NaHCO3 (0.15 mL, 0.15 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.0021 g, 0.003 mmol) and 1,2-dimethoxyethane (0.60 mL). The vial was flushed with nitrogen gas and the reaction mixture was heated at 125° C. in a Biotage Microwave reactor for 30 minutes. Upon cooling to room temperature, the reaction was concentrated in vacuo and the residue obtained was partitioned between water (2 mL) & a mixture of CHCl3/THF (4:1, 3 mL). Upon separation of the layers, the aqueous layer was extracted with additional CHCl3/THF (4:1, 3 mL), the combined layers were filtered and concentrated. The material obtained was dissolved in methylene chloride (0.75 mL) and to this solution was added trifluoroacetic acid (0.5 mL, 6.4 mmol). The resulting reaction mixture was stirred overnight at room temperature. The reaction was concentrated in vacuo, the residue re-dissolved in DMSO (1 mL), filtered and purified on Agilent A2 prep instrument mass triggered reverse phase chromatography (Waters Sunfire prep C18 10 mm 19×150 mm column). Concentration of fractions containing desired product afforded product (0.0061 g, 26% yield). LCMS: (FA) ES+ 390.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[CH:14]=[C:13]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:20][CH:19]=4)[O:17][C:12]3=[N:11][C:10]2=[O:29])[CH2:3]1.N1C=CC=CC=1.[O:36]([C:38]1[CH:59]=[CH:58][C:41]([C:42](Cl)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)=[CH:40][CH:39]=1)[CH3:37]>ClCCl>[CH3:50][O:49][C:46]1[CH:45]=[CH:44][C:43]([C:42]([C:41]2[CH:40]=[CH:39][C:38]([O:36][CH3:37])=[CH:59][CH:58]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[O:8][CH2:7][C@H:6]2[O:5][C@@H:4]([N:9]3[CH:14]=[C:13]4[CH:15]=[C:16]([C:18]5[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:22][CH:23]=5)[O:17][C:12]4=[N:11][C:10]3=[O:29])[CH2:3][C@@H:2]2[OH:1])=[CH:48][CH:47]=1
Reactant: CCCCCc1ccc(-c2cc3cn([C@H]4C[C@H](O)[C@@H](CO)O4)c(=O)nc3o2)cc1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCc1ccc(-c2cc3cn([C@H]4C[C@H](O)[C@@H](COC(c5ccccc5)(c5ccc(OC)cc5)c5ccc(OC)cc5)O4)c(=O)nc3o2)cc1

Procedure:
A 50 L reactor was charged with 2.8 kg (7.03 mol) of 3-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)-6-(4-pentylphenyl)furo[2,3-d]pyrimidin-2(3H)-one, 2.8 kg (35.4 mol) of pyridine and 22.4 kg of dichloromethane. The mixture was stirred and to it was added 2.86 kg (8.44 mol) 4,4′-dimethoxyltritylchloride (DMT-Cl) in 14.9 kg dichloromethane at room temperature (rt). After addition, the mixture was stirred for 0.5 h at rt. The mixture was filtered and the filtrate was washed with brine. The filtrate contained the desired product which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:12]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=1[F:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH2:15][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)[C:12]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:11]=3[N:10]=2)=[C:6]([CH:7]=1)[O:8][CH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=1[F:38]
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CCC1CCCCC1
Product: N#Cc1ccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CCC2CCCCC2)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-[1-(2-cyclohexyl-ethyl)-5,6-difluoro-1H-benzoimidazol-2-yl]-phenol and 4-bromomethyl-3-fluoro-benzonitrile (CAS Reg. No. 105942-09-4). Brown sticky solid (81%). MS (Turbo Spray): m/z=524.0 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:19][C:20](=[O:32])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)N2C=CC=N2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:35][CH2:36][C:37]([NH:39][CH:40]1[CH2:43][N:42]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:41]1)=[O:38].C(OCC)(=O)C>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]=[C:13]([NH:19][C:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:32])[NH:35][CH2:36][C:37]([NH:39][CH:40]2[CH2:43][N:42]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:41]2)=[O:38])=[O:11])=[CH:33][CH:34]=1)([O-:3])=[O:2]
Reactant: O=C(N=C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)n1cccn1)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CN)C1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=NC(=O)OCc2ccc([N+](=O)[O-])cc2)NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.6 %

Procedure:
Under ice cooling, a solution of 4-nitrobenzyl [(4-nitrobenzyloxy)carbonyliminopyrazol-1-ylmethyl]carbamate (1.42 g) in tetrahydrofuran (12 ml) was added to a solution of tert-butyl 3-(aminoacetylamino)-1-azetidinecarboxylate (785 mg) in tetrahydrofuran (13 ml) and the mixture was stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture. The resulting mixture was washed with water, an aqueous solution of potassium hydrogensulfate and saturated saline, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was crystallized from diisopropyl ether, followed by washing, whereby 1.94 g of the title compound were obtained as a colorless crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4]1.S(=O)(=O)(O)O.[C:15]([O-])(O)=O.[Na+]>CO>[OH:1][CH2:2][C:3]1([CH2:6][C:7]([O:9][CH3:15])=[O:8])[CH2:5][CH2:4]1
Reactant: O=C(O)CC1(CO)CC1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC1(CO)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5 g 2-[1-(hydroxymethyl)cyclopropyl]acetic acid (compound (13)) was dissolved in 65 ml methanol and 80 mg sulfuric acid was added. The reaction mixture was stirred overnight at room temperature; reaction progress was monitored by GC. The pH of the reaction mixture was adjusted to 7 with saturated NaHCO3. The reaction mixture was evaporated to dryness. 75 ml of ethyl acetate and 10 ml brine were added. The water layer was washed with 20 ml ethyl acetate. The combined organic layers were dried (Na2SO4) and evaporated to dryness, resulting in a yellow oil.
Reaction SMILES: N1C(C)=CC=CC=1C.B(Br)(Br)Br.COC(C1C=C(OC)C2CC(C)OC=2C=1)=O.[CH3:29][O:30][C:31]([C:33]1[CH:34]=[C:35]([O:43]C)[CH:36]=[C:37]2[O:41][CH:40]([CH3:42])[CH2:39][C:38]=12)=[O:32]>C(Cl)Cl>[CH3:29][O:30][C:31]([C:33]1[CH:34]=[C:35]([OH:43])[CH:36]=[C:37]2[O:41][CH:40]([CH3:42])[CH2:39][C:38]=12)=[O:32]
Reactant: COC(=O)c1cc(OC)cc2c1CC(C)O2
Agent: BrB(Br)Br
Agent: COC(=O)c1cc(OC)c2c(c1)OC(C)C2
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)c1cc(O)cc2c1CC(C)O2
Temperature: 0 °C
Yield: 23.2 %

Procedure:
2,6-Lutidine (2.64 mL, 22.7 mmol) and BBr3 (22.7 mL, 22.7 mmol, 1.0 M solution in CH2Cl2) were added to a mixture of 4-methoxy-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester and 6-methoxy-2-methyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (1d) (1.68 g, 7.58 mmol) in CH2Cl2 (30 mL) at 0° C. The mixture was stirred at 0° C. and the warmed to room temperature overnight. The mixture was quenched with H2O (80 mL) and extracted with CH2Cl2 (2×80 mL). The organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 20-30% EtOAc in hexanes to give a pale brown colored solid (366 mg, 23% yield). 1H NMR (400 MHz, CDCl3) δ 6.99 (d, J=2.27 Hz, 1 H) 6.49 (d, J=2.27 Hz, 1 H) 5.46 (s, 1 H) 4.86-5.07 (m, 1 H) 3.89 (s, 3 H) 3.57 (dd, J=16.93, 8.84 Hz, 1H) 3.03 (dd, J=16.93, 7.33 Hz, 1 H) 1.46 (d, J=6.32 Hz, 3 H); LCMS for C11H12O4 m/z 209.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:12]3[CH:20]=[CH:21][CH:22]=[CH:23][C:11]=3[N:10]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:6]1[CH:5]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:12]3[CH:20]=[CH:21][CH:22]=[CH:23][C:11]=3[N:10]=2)[CH:3]=[C:2]([C:26]2[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=2)[CH:7]=1
Reactant: Brc1cc(Br)cc(-c2nc3ccccc3n2-c2ccccc2)c1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1cc(-c2cccnc2)cc(-c2nc3ccccc3n2-c2ccccc2)c1

Procedure:
9.4 g (22.0 mmol) of 2-(3,5-dibromophenyl)-1-phenyl-1H-benzo[d]imidazole according to Synthesis Example 3, 2.7 g (22.0 mmol) of pyridine-3-boronic acid, 0.76 g (3 mol %) of tetrakis(triphenylphosphine)palladium (0), and 6.1 g (44.0 mmol) of potassium carbonate were dissolved in 300 ml of tetrahydrofuran/H2O mixed in a volume ratio of 2/1. The solution was reacted at 80° C. for 12 hours. The acquired reactant was extracted with ethyl acetate and treated under reduced pressure to remove the solvent therein. The reactant was separated through a column and dried, obtaining 5.15 g (Y=54%) of a yellow solid.
Reaction SMILES: [C:1](=O)([O:21]N1C(=O)CCC1=O)[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:20])[NH:16][CH:17]3[CH2:19][CH2:18]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:30][NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[CH:34]=1.C(N(CC)CC)C>ClCCl>[CH3:30][N:31]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[CH:41][N:42]=[CH:43][CH:44]=2)[CH:34]=1)[C:1](=[O:21])[O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:20])[NH:16][CH:17]3[CH2:19][CH2:18]3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CNCc1cccc(-c2ccncc2)c1
Reactant: O=C(Oc1ccc(-c2ccc(C(=O)NC3CC3)cc2)cc1)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(Cc1cccc(-c2ccncc2)c1)C(=O)Oc1ccc(-c2ccc(C(=O)NC3CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask was placed a solution of 4-[4-(cyclopropylcarbamoyl)phenyl]phenyl 2,5-dioxopyrrolidin-1-yl carbonate (600 mg, 1.52 mmol, 1.00 equiv) in dichloromethane (40 mL), N-methyl([[3-(pyridin-4-yl)phenyl]methyl])amine (301 mg, 1.52 mmol, 1.00 equiv) and triethylamine (153 mg, 1.51 mmol, 0.99 equiv). The resulting solution was stirred overnight at room temperature. The reaction mixture was washed with 2×20 mL of water and dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. The crude product (650 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-002(Agilent)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water and acetonitrile (10.0% acetonitrile up to 80.0% in 10 min, up to 100.0% in 1 min, down to 10.0% in 2 min); Detector, uv 220 & 254 nm. The title compound was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[O:3][C@H:4]([C:28]([F:31])([F:30])[F:29])[CH2:5][C@:6]([C:10]2[CH:11]=[C:12]([NH:17][C:18](=O)[C:19]3[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][N:20]=3)[CH:13]=[CH:14][C:15]=2[F:16])([CH2:8][F:9])[N:7]=1.C1(C)C=CC=CC=1.COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:48]2)=CC=1>CCOC(C)=O>[NH2:1][C:2]1[O:3][C@H:4]([C:28]([F:31])([F:30])[F:29])[CH2:5][C@:6]([C:10]2[CH:11]=[C:12]([NH:17][C:18]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][N:20]=3)=[S:48])[CH:13]=[CH:14][C:15]=2[F:16])([CH2:8][F:9])[N:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cc(Cl)cnc1C(=O)Nc1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)cnc1C(=S)Nc1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1
Temperature: 120 °C
Yield: 12.2 %

Procedure:
A sealable vial was charged with N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide (Example 4, 0.068 g, 0.147 mmol) and toluene (1 mL). 2,4-Bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (0.059 g, 0.147 mmol) was added and the reaction mixture was heated to 120° C. overnight. Upon cooling to room temperature, the reaction mixture was taken up in EtOAc (75 mL). The organic layer was washed with aqueous saturated NaHCO3 and with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified through silica gel (gradient 30%-50% EtOAc-hexane) affording the title compound as a yellow solid (8.4 mg, 0.018 mmol, 12%). MS m/z=479 [M+H]+. Calculated for C19H16ClF5N4OS: 478.