Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16]([O:18][C:19](=[O:24])[CH2:20][CH2:21][CH2:22]Br)[CH3:17]>CN(C)C=O>[CH2:16]([O:18][C:19](=[O:24])[CH2:20][CH2:21][CH2:22][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH3:17]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 110.6 %

Procedure:
A mixture of 4-hydroxybenzaldehyde (9.21 g, 75 mmol), potassium carbonate (56 g, 410 mmol) and 4-bromobutyric acid ethyl ester (12.9 mL, 90 mmol) in N,N-dimethylformamide (250 mL) was stirred vigorously for 16 hours at room temperature. The mixture was filtered and concentrated in vacuo to afford 19.6 g (100%) of 4-(4-formylphenoxy)butyric acid ethyl ester as an oil. 1H-NMR (DMSO-d6): δ 1.21 (3H, t), 2.05 (2H, p), 2.49 (2H, t), 4.12 (4H, m), 7.13 (2H, d), 7.87 (2H, d), 9.90 (1H, s). HPLC-MS (Method A): m/z=237 (M+1); Rt=3.46 min.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:8][CH2:7][C:6]2([CH2:12][CH2:11][NH:10][CH2:9]2)[CH2:5]1.N12CCCN=C1CCCCC2.[F:24][C:25]1[C:26](F)=[C:27]2[O:32][CH2:31][CH:30]([CH3:33])[N:29]3[CH:34]=[C:35]([C:40]([OH:42])=[O:41])[C:36](=[O:39])[C:37]([CH:38]=1)=[C:28]23>C(#N)C>[F:24][C:25]1[C:26]([N:10]2[CH2:11][CH2:12][C:6]3([CH2:7][CH2:8][N:4]([CH3:3])[CH2:5]3)[CH2:9]2)=[C:27]2[O:32][CH2:31][CH:30]([CH3:33])[N:29]3[CH:34]=[C:35]([C:40]([OH:42])=[O:41])[C:36](=[O:39])[C:37]([CH:38]=1)=[C:28]23
Reactant: CN1CCC2(CCNC2)C1
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1COc2c(N3CCC4(CCN(C)C4)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
A suspension of 0.42 g (1.97 mmol) 2-methyl-2,7-diazaspiro[4.4]nonane dihydrochloride in 25 ml acetonitrile was treated with 0.85 g (5.80 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene and 0.52 g (1.85 mmol) 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]1,4-benzoxazine-6-carboxylic acid was added. The mixture was stirred carboxylic acid was added. The mixture was stirred two hours at room temperature and then refluxed overnight. The product which crystallized on cooling was filtered, washed with acetonitrile and recrystallized from acetonitrile to afford 0.45 g of the title compound, mp 227°-230° C. (dec). Analysis calculated for C21H22N3FO4 :
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4]1.[C:10](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:10]([O:1][CH2:2][C@H:3]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CCC[C@@H](CO)N1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)N1
Reaction time: 72 h

Procedure:
A mixture of (S)-39 (5.85 g, 45.3 mmol), trityl chloride (16.04 g, 57.5 mmol), i-Pr2NEt (11.6 mL, 66.6 mmol) and DMAP (0.527 g, 4.31 mmol) in DMF (21 mL) was stirred at r.t for 3 days. Reaction mixture was separated between brine (80 mL) and water (80 mL). The aqueous layer was extracted with AcOEt (4×80 mL). Combined organic solutions were washed with brine, dried (MgSO4), concentrated and separated by SGC with hexane:AcOEt (in gradient, up to 40% AcOEt) to afford (S)-40 as a foam; yield 12.20 g (73%). 1H NMR (250 MHz, CDCl3) δ 1.16-1.34 (m, 1H), 1.58-1.90 (m, 3H), 2.17-2.31 (m, 1H), 2.33-2.47 (m, 1H), 2.94 (t, J=9.1 Hz, 1H), 3.23 (dd, J=9.1, 3.1 Hz, 1H), 3.56-3.68 (m, 1H), 6.21 (s, 1H), 7.21-7.45 (m, 15H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=C2C(=O)Nc3cccc(-c4ccc(Br)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (88 mg, 68%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@:19]([O:49][Si:50]([CH3:53])([CH3:52])[CH3:51])([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][Si:32]([C:45]([CH3:48])([CH3:47])[CH3:46])([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH:26]=4)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.CCOC(C)=O.[Pd]>[C:1]1([C:7]2[N:8]=[C:9]([C@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@@:19]3([O:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][Si:32]([C:45]([CH3:48])([CH3:46])[CH3:47])([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH:26]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](Oc1cccc(C[C@]2(O[Si](C)(C)C)CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](Oc1cccc(C[C@]2(O[Si](C)(C)C)CCCC[C@@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 87.3 %

Procedure:
A mixture of (R)-2-(4,5-diphenyloxazol-2-yl)-1-trimethylsilyloxy-1-[3-(tertbutyldiphenylsiloxy)benzyl]-2-cyclohexene (24 g) and 10% Pd/C (10 g) in a mixture of MeOH (200 ml) and EtOAc (500 ml) was stirred under H2 for 8 hours. The catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silica gel to give (1R, 2S)-2-(4,5-diphenyloxazol-2-yl)-1-trimethylsilyoxy-1-[3-(tertbutyldiphenylsiloxy)benzyl]cyclohexane (21 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:20]O>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:3]=1[C:4]([O:6][CH3:20])=[O:5]
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C(F)(F)F)ccc1N
Temperature: 125 °C
Yield: 51 %

Procedure:
A solution of 2-amino-5-(trifluoromethyl)benzoic acid (1.07 g, 5.2 mmoles) in methanol (20 ml) was treated with concentrated sulphuric acid (0.5 ml) and heated under microwave conditions at 125° C. for 2 h. The mixture was evaporated to dryness and treated with water (100 ml) then basified to saturation with potassium carbonate and extracted with ethyl acetate (2×40 ml). The combined extracts were dried over sodium sulphate, filtered and evaporated to dryness. The residue was chromatographed on silica gel eluting with an ethyl acetate/isohexane gradient. This gave the title compound 1 as a colorless oil (0.59 g, 51%).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)(F)[CH2:4][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[OH:16]S(O)(=O)=O>>[Cl:1][C:2]1[C:3](=[O:16])[CH2:4][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(C2=C(Cl)C(F)(F)C2)cc1
Product: COc1ccc(C2=C(Cl)C(=O)C2)cc1
Reaction time: 0.33 h

Procedure:
2Chloro-1,1-difluoro-3-(p-methoxyphenyl)-2-cyclobutene (215 g., 0.93 mole) is poured gradually into 272 ml. of concentrated H2SO4 with stirring. The rate of addition is adjusted to maintain the reaction temperature below 40° C. When the reaction subsides, the cooling bath is removed, but stirring is continued for 20 min. The mixture is poured into 3 l. of water. A precipitate forms, and is collected on a filter, washed with water, and air-dried. recrystallization of this material twice from i-PrOH yields 128.8 g. (66%) of the desired intermediate, m.p. 96°-98° C. An analytical sample was prepared by chromatography an alumina (benzene) and recrystallized from heptane, m.p. 98-100° C.
Reaction SMILES: [CH2:1]([SiH:13]([Cl:15])[Cl:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:16]=[CH2:17]>C(O)(C)C>[CH2:1]([Si:13]([CH2:16][CH3:17])([Cl:15])[Cl:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C=C
Reactant: CCCCCCCCCCCC[SiH](Cl)Cl
Solvent: CC(C)O
Product: CCCCCCCCCCCC[Si](Cl)(Cl)CC
Reaction time: 25 h

Procedure:
Resultant n-dodecyldichlorosilane in an amount of 161.4 g (0.6 mol), 22.4 g of ethylene (0.8 mol) and a solution of H2PtCl6 ·6H2O in isopropanol (0.05 mol % relative to n-dodecyldichlorosilane) were charged in a pressure-proof stainless steel reactor. After sealing, reaction was carried out at 50° C. for 25 hours to give n-dodecylethyldichlorosilane [(n--C12H25)(C2H5)SiCl2 ].
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C:8]([CH3:29])([CH3:28])[CH2:9][N:10]1[C:15](=[O:16])[NH:14][C:13](=[O:17])[N:12]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[F:26])[C:11]1=[O:27])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[F:37][C:38]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[C:39]=1[CH2:40]Br>CN(C=O)C>[C:1]([O:5][C:6](=[O:30])[NH:7][C:8]([CH3:29])([CH3:28])[CH2:9][N:10]1[C:15](=[O:16])[N:14]([CH2:40][C:39]2[C:42]([C:46]([F:47])([F:49])[F:48])=[CH:43][CH:44]=[CH:45][C:38]=2[F:37])[C:13](=[O:17])[N:12]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[F:26])[C:11]1=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(-n2c(=O)[nH]c(=O)n(CC(C)(C)NC(=O)OC(C)(C)C)c2=O)c1F
Reactant: Fc1cccc(C(F)(F)F)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(-n2c(=O)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(CC(C)(C)NC(=O)OC(C)(C)C)c2=O)c1F
Reaction time: 14 h

Procedure:
{2-[3-(2-Fluoro-3-methoxy-phenyl)-2,4,6-trioxo-[1,3,5]triazinan-1-yl]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester (370 mg) was dissolved in 7 mL of anhydrous DMF. To this solution was added K2CO3 (2.0 eq, 226 mg) and 2-fluoro-6-(trifluoromethyl)benzyl bromide (1.0 eq, 222 mg). The reaction was complete by LC/MS after 14 hours. The DMF was removed in vacuo. The residue was partitioned between EtOAc and H2O. The EtOAc layer was collected and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography and eluted with 30% EtOAc/hexanes to yield 399 mg (76%). Rf=0.36 in 30% EtOAc/hexanes. 1H NMR (CDCl3) δ: 7.51 (d,1H), 7.39 (m,1H), 7.27 (d,1H), 7.15 (dt,1H), 7.06 (dt,1H), 6.88 (dt,1H), 5.42 (q,2H), 5.15 (bs,1H), 4.14 (q,2H), 3.9 (s,3H), 1.4 (s,9H), 1.39 (d,6H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCCl.[N+:11]([O-])([OH:13])=[O:12]>O>[N+:11]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([O-:13])=[O:12]
Reactant: c1ccccc1
Reactant: O=[N+]([O-])O
Solvent: ClCCCl
Solvent: O
Product: O=[N+]([O-])c1ccccc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A 100 mL three-necked reaction flask fitted with reverse dean-stark apparatus was charged with 7.8 g benzene (0.1 mol), 60 mL 1,2 dichloro ethane, and 1.56 g of catalyst as prepared in example 5. The flask was flushed with nitrogen. The reaction mixture was refluxed at 100° C. for 1 h followed by dropwise addition of 6.42 mL (0.1 mol) of 70% HNO3. The water formed during the reaction was removed using reverse dean-stark apparatus. The reaction was carried out for 8 h. The reaction was monitored by GC analysis. In this reaction 18.6% benzene conversion was obtained with 100% selectivity for mono nitro benzene.
Reaction SMILES: Br[C:2]1[C:3](C)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[O:12]1[CH2:16][CH2:15][O:14][CH:13]1[C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27]>C1(C)C=CC=CC=1.CCO>[O:12]1[CH2:16][CH2:15][O:14][CH:13]1[C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([NH2:7])=[O:6])[CH:3]=2)=[CH:19][C:18]=1[C:26]([F:27])([F:28])[F:29]
Reactant: Cc1c(Br)cccc1C(N)=O
Reactant: OB(O)c1ccc(C2OCCO2)c(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: NC(=O)c1cccc(-c2ccc(C3OCCO3)c(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared from 3-bromo-2-methylbenzamide (Ex IV-2) and 4-(1,3-dioxolan-2-yl)-3-(trifluoromethyl)phenylboronic acid (I-IX-8) according to the procedure described in Example IX-10, using PhMe/EtOH (4:1) as organic colsovent. LC/MS (method A) 2.36 min; m/z 351 (M+H).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH3:17][C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20]>>[CH:11]1([C:8]2[NH:7][C:6](=[O:16])[C:5]([CH:2]([NH:1][C:19](=[O:20])[C:18]([CH3:23])([CH3:22])[CH3:17])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Reactant: CC(C)(C)C(=O)Cl
Product: CCC(NC(=O)C(C)(C)C)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 150 mg (0.67 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 90 mg (0.74 mmol) 2,2-dimethylpropanoyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:13])[C:11]=1[OH:12])[O:8][CH2:7][CH2:6][CH:5]2[C:14]([O:16][CH2:17][CH3:18])=[O:15].F[C:20]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][C:21]=1[N+:33]([O-:35])=[O:34].C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[C:27]([O:26][C:24]([C:23]1[CH:31]=[CH:32][C:20]([O:12][C:11]2[C:10]([Cl:13])=[C:9]3[C:4]([CH:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:6][CH2:7][O:8]3)=[CH:3][C:2]=2[Cl:1])=[C:21]([N+:33]([O-:35])=[O:34])[CH:22]=1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(O)c2Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-])c2Cl
Temperature: 80 °C
Yield: 104.1 %

Procedure:
A mixture of ethyl 6,8-dichloro-7-hydroxychroman-4-carboxylate (35 g, 120.22 mmol), tert-butyl 4-fluoro-3-nitrobenzoate (31.1 g, 128.93 mmol), K2CO3 (24.923 g, 180.33 mmol), and 1-methyl-2-pyrrolidinone (500 mL) was purged with Argon (bubbled through) for 15 minutes. The mixture was heated to 80° C. for 4 hours under Argon atmosphere. The mixture was cooled to ambient temperature and poured into 3 liters of water. The pH was adjusted to pH 2 by addition of concentrated HCl (4×10 ml). A solid precipitated out as HCl was added and gas evolution was observed. The crude mixture was filtered and the solid was dissolved in EtOAc (1 liter). The EtOAc solution was washed with 2N HCl solution (200 ml), water (2×200 ml), and brine (200 ml), dried over MgSO4, filtered, and concentrated to provide 64.1 g of the title compound as a dark solid (104%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].CSC.B.C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][C:3]=1[Cl:11]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCc1cnc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
A slurry of 5,6-dichloronicotinic acid (25.3 g, 132 mmol) in THF (30 mL, 4.4 M) is cooled to 0° C. and carefully treated with 2 M borane dimethyl sulfide/THF (100 mL, 200 mmol) via syringe under a stream of nitrogen. After 1 h, the cooling bath is removed. After stirring overnight the colution is re-cooled to 0° C. and carefully quenched with water (20 mL). The reaction volume is reduced in vacuo, 50% NaHCO3 (150 mL) is added and the mixture is extracted with ethyl acetate (2×150 mL). The organic layer is washed with saturated aq NaCl (100 mL) and dried over Na2SO4. The product is purified by MPLC (30-90% ethyl acetate in n-heptane) to provide 5,6-dichloro-pyridin-3-yl-methanol as a white solid (19.1 g, 81%): Rf 0.57 (25% ethyl acetate in n-heptane), 1H NMR (CDCl3, 300 MHz) δ 8.27 (d, J=2.3 Hz, 1 H), 7.84 (d, J=2.3 Hz, 1 H), 4.74 (s, 2 H); ESI-LCMS m/z calcd for C6H5Cl2NO: 177.0; found 178.0 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[C@:17]1([CH2:36][F:37])[CH2:22][C@@H:21]([C:23]([F:26])([F:25])[F:24])[O:20][C:19]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:18]1.OO.O.C([O-])(O)=[O:42].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:42])=[CH:4][C:3]=1[C@:17]1([CH2:36][F:37])[CH2:22][C@@H:21]([C:23]([F:24])([F:25])[F:26])[O:20][C:19]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:18]1
Reactant: O=C([O-])O
Reactant: CC1(C)OB(c2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(NC(=O)c4ccccc4)=N3)c2)OC1(C)C
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1=N[C@](CF)(c2cc(O)ccc2F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Reaction time: 16 h
Yield: 56 %

Procedure:
To a solution of N-((4S,6S)-4-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (4.16 g, 7.93 mmol) in THF (22.67 mL) at 0° C. was added hydrogen peroxide 30% in water (2.431 mL, 23.80 mmol). The reaction mixture was stirred at 0° C. to room temperature for 16 h. The reaction mixture was acidified to pH 5-7 by addition of saturated NaHCO3, and extracted with EtOAc (2×). The combined organics were washed with water and brine, dried and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0-30% EtOAc in hexane, to provide N-((4S,6S)-4-(2-fluoro-5-hydroxyphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (1.84 g, 4.44 mmol, 56.0% yield) as white foam. MS m/z=415 [M]+. Calculated for C19H15F5N2O3: 414.33.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][C:14]1([S:17]([NH:20]C(=O)OC(C)(C)C)(=[O:19])=[O:18])[CH2:16][CH2:15]1>ClCCl>[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][C:14]1([S:17]([NH2:20])(=[O:19])=[O:18])[CH2:16][CH2:15]1
Reactant: COCCOCC1(S(=O)(=O)NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOCC1(S(N)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
TFA (5 ml) was added to the solution of the product of Step 1 (0.63 g) in dichloromethane (5 ml) at 0° C. The reaction was allowed to warm to room temperature and was stirred for 1.5 hour. The solvent was removed under reduced pressure to give the desired product (0.426 g) as a light brown oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 6.80-6.21 (m, 2H), 3.75 (s, 2H), 3.66-3.64 (m, 2H), 3.56-3.53 (m, 2H), 3.36 (s, 3H), 1.42-1.39 (m, 2H), 0.91-0.89 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](OCC)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32].[C-]#N.[K+]>>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:32][C@@H:27]3[CH2:28][CH2:29][CH2:30][CH2:31][C@H:26]3[CH3:25])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CCCC[C@H]1O
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: [C-]#N
Agent: [K+]
Product: C[C@@H]1CCCC[C@H]1OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 6 h

Procedure:
A mixture of 3.45 (10 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 11.4 g (100 mmol) of trans-2-methylcyclohexanol and 100 mg of powdered potassium cyanide is stirred at 130° for 6 hours, the solution obtained is evaporated to dryness and the residue is chromatographed on a silica gel column. By recrystallization from ethyl acetate there is obtained trans-2-methylcyclohexyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 213°-215° (1:1 mixture of the two diastereoisomers).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][CH2:23][OH:24].CN(C=O)C>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:22][CH2:23][OH:24])[CH:10]=2)[O:3]1
Reactant: OCCBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(CCO)c2)OC1(C)C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
To a flask charged with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.000 g, 5.154 mmol), Cs2CO3 (2.687 g, 8.246 mmol), and 2-bromoethanol (0.5479 mL, 7.730 mmol) was added 10 mL of DMF and the flask was sealed under nitrogen and heated to 100° C. for 48 hours. The reaction was diluted with ethyl acetate (100 mL) and stirred for 30 minutes before it was passed through a glass microfiber filter and the cake was washed with ethyl acetate. The organic was concentrated under reduced pressure. The crude was then purified by silica gel chromatography eluting with a gradient of 75-100% ethyl acetate in Hexanes to afford 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol (0.4290 g, 1.622 mmol, 31.47% yield). MS (apci) m/z=239.2 (M+H).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][OH:21])[O:16]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29](Cl)(=[O:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CN(C)C1C=CN=CC=1.C(#N)C>[CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][O:21][C:29](=[O:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[O:16]2)[CH2:2][CH2:3]1
Reactant: CCCCCCCCC(=O)Cl
Reactant: OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCC(=O)OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.3 %

Procedure:
6-(Cyclopropylmethylamino)-9-[(2R,5S)-tetrahydro-5-(hydroxymethyl)-2-furyl]-9H-purine (0.498 g, 1.7 mmoles), 4-dimethylaminopyridine (10 mg, 0.1 mmoles, Aldrich Chemical Co., Madison, Wis.), and triethylamine (2.0 mL, 14 mmoles, Aldrich Chemical Co., Madison, Wis.) were dissolved in 50 mL acetonitrile. Nonanoyl chloride (1.26 mL, 7.0 mmoles, Aldrich Chemical Co., Madison, Wis.) was added and the reaction was stirred at room temperature for 3 hours. The reaction was quenched with methanol and solvents were evaporated in vacuo. The residue was dissolved in 25 mL ethyl acetate and undissolved salts were removed by filtration. After evaporation of the ethyl acetate, the residue was dissolved in methanol and passed over a silica gel column (4.8×13 cm). The product containing fractions were combined, concentrated, and chromatographed on a Chromatotron (4 mm silica gel plate) in a mixture of hexane:acetone (80:20). Two separate subsequent runs on the Chromatotron (4 mm silica gel plate) with a mixture of chloroform:acetone (95:5) and a mixture of hexane:acetone (85:15) followed by lyophilization afforded 0.236 g of 6-(cyclopropylmethylamino)-9-((2R,5S)-5-[(nonanoyloxy)methyl]-tetrahydro-2-furyl)-9H-purine as an oil (32% yield).