Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[C:16]([O:20][C:21](=[O:27])[C@@H:22]([CH:24]([CH3:26])[CH3:25])[NH2:23])([CH3:19])([CH3:18])[CH3:17].[CH:28]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]2[N:36]([S:42]([C:45]3[CH:51]=[CH:50][C:48]([CH3:49])=[CH:47][CH:46]=3)(=[O:44])=[O:43])[CH:37]=[C:38]([C:39](O)=[O:40])[C:31]=12)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C(Cl)Cl.C1COCC1.CCOC(C)=O>[CH3:26][CH:24]([CH3:25])[C@@H:22]([N:23]1[C:39](=[O:40])[C:38]2=[CH:37][N:36]([S:42]([C:45]3[CH:51]=[CH:50][C:48]([CH3:49])=[CH:47][CH:46]=3)(=[O:44])=[O:43])[C:32]3[C:31]2=[C:30]([CH:35]=[CH:34][N:33]=3)[CH2:28]1)[C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:27]
Reactant: CC(C)[C@@H](N)C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(C(=O)O)c3c(C=O)ccnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1ccc(S(=O)(=O)n2cc3c4c(ccnc42)CN([C@@H](C(=O)OC(C)(C)C)C(C)C)C3=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium triacetoxyborohydride (603 mg, 2.85 mmol) and D-valine-tert-butyl ester HCl salt (597 mg, 2.85 mmol) were combined in DCM (15 mL). The reaction mixture was stirred for 20 min at room temperature and then cooled to 0° C. 4-Formyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (700 mg, 2.03 mmol) was added, and the solution was stirred for 1 h. The solution was concentrated in vacuo to give a white foam, which was re-dissolved in THF (40 mL). HATU (1.16 g, 3.05 mmol) and N-methylmorpholine (339 μL, 3.05 mmol) were added, and the reaction mixture was stirred at 52° C. for 2 h. Additional HATU (580 mg, 1.53 mmol) and N-methylmorpholine (170 μL, 1.53 mmol) were added, and the reaction mixture was stirred for an additional 2 h at 52° C. The solution was subsequently cooled, diluted with EtOAc, and washed with brine. The organics were dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography (1:2:2 EtOAc/Hexanes/DCM) gave the title compound as a yellow oil, which solidified upon sitting (840 mg, 85%). 1H NMR (500 MHz, CDCl3) δ 0.86 (d, J=7.0 Hz, 3H), 1.08 (d, J=7.0 Hz, 3H), 1.42 (s, 9H), 2.25-2.34 (m, 1H), 2.35 (s, 3H), 4.77-5.14 (m, 3H), 7.05 (d, J=5.0 Hz, 1H), 7.28 (d, J=7.5 Hz, 2H), 8.05-8.10 (m, 3H), 8.45 (d, J=5.0 Hz, 1H). [M+H] calc'd for C25H29N3O5S, 484; found, 484.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O.O.NN.O>CO.O1CCCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:20][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Nc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
117.8 g (0.42 mol) of 2-(4-nitrophenoxymethyl)quinoline were dissolved in 1 l of methanol/tetrahydrofuran (1:1). About 5 g of Raney nickel were then added and the mixture was warmed to 35° C. 63.1 g (1.26 mol) of hydrazine hydrate ×H2O were then added dropwise and the mixture was stirred overnight. The residue was filtered off, the solution was concentrated in vacuo and the residue was taken up with methylene chloride. The mixture was then washed with water and conc. hydrochloric acid was added to the organic phase. The precipitate deposited was filtered off, washed with 2 N hydrochloric acid, dissolved in water and rendered alkaline with 20% strength NaOH. The residue was dried in vacuo.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][C@@H:5]([OH:8])[C@H:4]1[OH:9].CCN(C(C)C)C(C)C.[CH3:19][C:20]1([CH3:44])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]2[CH:25]=[C:24]([C:32]3[N:33]=[C:34]([N:37]4[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]4)[S:35][CH:36]=3)[CH:23]=[CH:22][C:21]1=2.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1COCC1.CN(C=O)C>[CH3:19][C:20]1([CH3:44])[CH2:29][CH2:28][C:27]([CH3:30])([CH3:31])[C:26]2[CH:25]=[C:24]([C:32]3[N:33]=[C:34]([N:37]4[CH2:42][CH2:41][CH:40]([NH:2][C@@H:3]5[CH2:7][CH2:6][C@@H:5]([OH:8])[C@H:4]5[OH:9])[CH2:39][CH2:38]4)[S:35][CH:36]=3)[CH:23]=[CH:22][C:21]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(=O)CC4)n3)ccc21
Reactant: N[C@@H]1CC[C@@H](O)[C@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N[C@@H]5CC[C@@H](O)[C@H]5O)CC4)n3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
24 mg (0.16 mmol) of (1R,2S,3R)-3-aminocyclopentane-1,2-diol hydrochloride are dissolved in 1 ml of THF and 2 ml of DMF, and 27 μl (0.16 mmol) of DIPEA are added. 60 mg (0.16 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-one are added. The mixture is stirred at room temperature for 30 min, 18 μl (0.32 mmol) of glacial acetic acid are added, and the mixture is stirred for a further 10 min. 70 mg (0.32 mmol) of sodium triacetoxyborohydride are subsequently added. The reaction mixture is stirred at room temperature overnight, a concentrated sodium hydrogencarbonate solution is added, and the mixture is extracted twice with EA. The organic phase is dried over sodium sulfate, filtered and evaporated. The residue is purified by means of preparative HPLC. The product is in the form of the hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=[O:10])=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1.[Li+].[OH-].Cl>C1COCC1.CO>[NH2:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(Br)ccc1N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Br)nc1C(=O)O
Reaction time: 16 h
Yield: 97 %

Procedure:
To a solution of methyl 3-amino-6-bromopicolinate (2.31 g, 10 mmoles) in 2:1 THF/MeOH (51 mL) was added 1.0 M LiOH (17 mL, 17 mmoles). After stirring for 16 hours, 1 N HCl (17 mL, 17 mmoles) was added and the THF/MeOH was removed in vacuo. The resulting solid was filtered, rinsed with cold H2O (4×20 mL) and pumped on yielding 3-amino-6-bromopicolinic acid (97%). LCMS (m/z): 216.9 (MH+); LC Rt=1.93 min.
Reaction SMILES: COC1N=C(C2CCC3C(=CC=C(OC)C=3)C2)C(N)=CC=1.Cl.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C:27](O)=O.FC1C=[C:45](C=CC=1OCCN1CCCCC1)[CH2:46][NH:47][C:48]1[C:49]([CH:56]2[CH2:65][CH2:64][C:63]3[C:58](=[CH:59][CH:60]=[C:61]([O:66][CH3:67])[CH:62]=3)[CH2:57]2)=[N:50][C:51]([O:54][CH3:55])=[CH:52][CH:53]=1>>[CH2:46]([N:47]([CH2:27][C:26]1[CH:30]=[CH:31][C:32]([O:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[C:24]([F:23])[CH:25]=1)[C:48]1[C:49]([CH:56]2[CH2:65][CH2:64][C:63]3[C:58](=[CH:59][CH:60]=[C:61]([O:66][CH3:67])[CH:62]=3)[CH2:57]2)=[N:50][C:51]([O:54][CH3:55])=[CH:52][CH:53]=1)[CH3:45]
Reactant: COc1ccc2c(c1)CCC(c1nc(OC)ccc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Agent: COc1ccc2c(c1)CCC(c1nc(OC)ccc1N)C2
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1ccc(OC)nc1C1CCc2cc(OC)ccc2C1

Procedure:
Synthesized from 6-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)pyridin-3-ylamine and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 282, [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][6-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)pyridin-3-yl]amine (548 mg) was used according to an analogous synthetic method to Example 36 to provide ethyl[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][6-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)pyridin-3-yl]amine (454 mg). This compound (452 mg) was used according to an analogous synthetic method to Example 111 to provide 6-{3-{ethyl[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amino}-6-methoxypyridin-2-yl}-5,6,7,8-tetrahydronaphthalen-2-ol (140 mg) and 5-{ethyl[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amino}-6-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)pyridin-2-ol (60 mg). 6-{3-{Ethyl[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amino}-6-methoxypyridin-2-yl}-5,6,7,8-tetrahydronaphthalen-2-ol
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH:7]1[C:17]2[CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[CH:12]([CH:22]([NH2:40])[CH2:23][O:24][CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.[NH3:41]>CO>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:1]([CH2:2][NH:40][CH:22]([CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:17]=2[CH2:16][CH2:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]1=2)[CH2:23][O:24][CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[C:28]([C:36]([F:37])([F:38])[F:39])[CH:27]=1)(=[O:6])[NH2:41]
Reactant: NC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1c2ccccc2CCc2ccccc21
Reactant: N
Agent: O=C(O)C(=O)O
Solvent: CO
Product: NC(=O)CNC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1c2ccccc2CCc2ccccc21
Reaction time: 48 h

Procedure:
A solution of the product of Example 6 in 5ml methanol saturated with ammonia was sealed in a reaction vessel and left at 0° C. for 48h. Solvent was removed in vacuo, and the residue dissolved in ethanol. Oxalic acid and water were added to give the title compound. mp 120°-122° C. 1H NMR (360MHz, DMSO-d6) 2.8-3.0 (2H, m), 3.3-3.7 (6H, m), 4.2-4.6 (4H, m), 7.00-7.4 (8H, m), 7.9 (1H, s), 7.95 (2H, s).,
Reaction SMILES: CN(C)C=O.[C:6]([C:8]1[C:13]([CH3:14])=[C:12](I)[C:11]([F:16])=[C:10]([O:17][CH3:18])[C:9]=1[NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])#[N:7].[CH2:26]([O:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>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.C(OCC)(=O)C>[CH2:26]([O:33][C:34]1[CH:39]=[C:38]([C:12]2[C:13]([CH3:14])=[C:8]([C:6]#[N:7])[C:9]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[C:10]([O:17][CH3:18])[C:11]=2[F:16])[CH:37]=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Reactant: COc1c(F)c(I)c(C)c(C#N)c1NC(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(F)c(-c2cccc(OCc3ccccc3)c2)c(C)c(C#N)c1NC(=O)C(F)(F)F
Temperature: 95 °C
Reaction time: 5.5 h
Yield: 73 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (287 mg, 249 μmol) was added to an N,N-dimethylformamide (16.5 ml) suspension of N-(2-cyano-5-fluoro-4-iodo-6-methoxy-3-methylphenyl)-2,2,2-trifluoroacetamide (I-35) (500 mg, 1.24 mmol), 3-benzyloxyphenylboronic acid (425 mg, 1.87 mmol), potassium phosphate n-hydrate (74-78%, 713 mg, 2.49 mmol), followed by stirring at 95° C. for 5.5 hours. The reaction liquid was cooled, then ethyl acetate (100 ml) was added, followed by washing with saturated brine (50 ml×3), drying over anhydrous magnesium sulfate, concentration under reduced pressure. The residue was purified twice by silica gel column chromatography (n-hexane:ethyl acetate=4:1), (n-hexane:ethyl acetate=6:1) to obtain the entitled compound (415 mg, 73%) as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH3:11].[C:12]([NH:14][C:15](=NC)[S:16][CH3:17])#[N:13]>>[C:12]([NH:14][C:15](=[N:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH3:11])[S:16][CH3:17])#[N:13]
Reactant: CN=C(NC#N)SC
Reactant: Cc1[nH]cnc1CSCCN
Product: CSC(=NCCSCc1nc[nH]c1C)NC#N

Procedure:
Furthermore, the final compound I can be obtained by reacting 4-[(2-aminoethyl)-thiomethyl]-5-methyl imidazole with N-cyano-N',S-dimethylisothiourea or with dimethylcyanodithioimido carbonate to form N-cyano-N'-{2-[(5-methylimidazole-4-yl)-methylthio]-ethyl}-S-methylisothiourea, which reacts with methylamine, thus yielding the final compound I.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:14]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)[CH2:13][N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:11][CH:10]2[CH2:34][O:35][CH3:36])=[CH:5][CH:4]=1.[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:37]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:14]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)[CH2:13][N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:11][CH:10]2[CH2:34][O:35][CH3:36])=[CH:5][CH:4]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: BrCc1ccccc1
Reactant: COCC1CN(C(=O)OC(C)(C)C)CC(OCc2ccc3ccccc3c2)C1c1ccc(CO)cc1
Product: COCC1CN(C(=O)OC(C)(C)C)CC(OCc2ccc3ccccc3c2)C1c1ccc(COCc2ccccc2)cc1

Procedure:
(ddd) In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3SR,4RS,5RS)-4-(4-hydroxymethyl-phenyl)-3-methoxymethyl-5-(naphthalen-2-yl-methoxy)-piperidine-1-carboxylate with benzyl bromide there was obtained tert-butyl (3SR,4RS,5RS)-4-(4-benzyloxymethyl-phenyl)-3-methoxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 582 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[NH4+:14].[OH-]>C(Cl)Cl>[OH:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[S:10]([NH2:14])(=[O:12])=[O:11]
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Agent: [OH-]
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(Cl)cc(Cl)c1O
Yield: 71 %

Procedure:
A solution of 39.16 g of the product from Example 3 in 100 ml CH2Cl2 was contacted with 250 ml of 28% NH4OH at 5°-8° C. Following removal of CH2Cl2 by a N2 sparge the mixture was acidified to pH 3. Filtration afforded 42.7 g of 61% pure 2-hydroxy-3,5-dichlorobenzenesulfonamide (D) (71% yield).
Reaction SMILES: [C:1]([O:7][CH2:8][CH:9]([CH2:14][O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])OCOC)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:22]([O:25][C:26](=[O:28])[CH3:27])(=[O:24])C.B(F)(F)F.CCOCC>C(Cl)Cl>[C:1]([O:7][CH2:8][CH:9]([CH2:14][O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[O:24][CH2:22][O:25][C:26](=[O:28])[CH3:27])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: COCOC(COC(=O)C(C)(C)C)COC(=O)C(C)(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)OCOC(COC(=O)C(C)(C)C)COC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
50 g of 1,3-dipivaloyl-2-methoxymethyl glycerol, 150 ml of methylene chloride, and 17 ml of acetic anhydride was cooled to about -5° C. Then 0.3 ml of boron trifluoride etherate was added and the mixture was stirred for an additional 1 hr at about 0° C. then allowed to warm to 25° C. over an additional 1.5 hr. After this period, 100 ml saturated aqueous Na2Cl3 was added to the mixture followed by 100 ml CH2Cl2. After vigorous stirring for 5 min, the organic layer was separated and washed once with 100 ml H2O, once with aqueous NaCl, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford 1,3-dipivaloyl-2-acetoxymethyl glycerol as a faintly colored oil.
Reaction SMILES: C=C=O.[OH:4][S:5]([C:8]([F:11])([F:10])[F:9])(=[O:7])=[O:6].[O:12](C(=O)C)[S:13]([C:16]([F:19])([F:18])[F:17])(=O)=[O:14].O(C(=O)C(C)C)S(C(F)(F)F)(=O)=O>>[S:5]([O:4][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:14])=[O:12])([C:8]([F:11])([F:10])[F:9])(=[O:7])=[O:6]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CC(=O)OS(=O)(=O)C(F)(F)F
Agent: C=C=O
Agent: CC(C)C(=O)OS(=O)(=O)C(F)(F)F
Product: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F

Procedure:
The process of the present invention may be operated in a batch, continuous or semi-continuous manner. For example, the process may be carried out by first reacting a ketene and triflic acid in a reaction vessel equipped with a distillation column. This vessel containing the mixed anhydride then may be heated to effect reactive distillation of the contents of the reaction vessel and recover triflic anhydride from the upper section of the distillation column. The process for the coproduction of triflic anhydride and a carboxylic acid anhydride, e.g., acetic or isobutyric anhydride, preferably is carried out in a continuous or semi-continuous manner comprising the steps of: (1) introducing a ketene reactant such as ketene or dimethylketene and triflic acid to a reaction vessel wherein the ketene reactant and triflic acid react to form a product comprising a mixed anhydride, e.g., acetyl triflate or isobutyryl triflate; (2) removing product from the reaction vessel and introducing it into the mid-section of a reactive distillation column wherein the mixed anhydride disproportionates to form triflic anhydride and a carboxylic anhydride, e.g. acetic or isobutyric anhydride; (3) removing triflic anhydride from the upper section of the reactive distillation column; and (4) removing a carboxylic anhydride from the lower section of the reactive distillation column.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21]([CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[N:20]=[CH:19]4)[N:12]=2)=[CH:7][C:6]=1[C:32]([F:35])([F:34])[F:33])[CH3:3].[OH-].[Na+]>C(O)C>[CH3:3][CH:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[N:20]=[CH:19]4)[N:12]=2)=[CH:7][C:6]=1[C:32]([F:34])([F:35])[F:33])[CH3:1]
Reactant: CCOC(=O)CCn1ncc2cc(-c3noc(-c4ccc(OC(C)C)c(C(F)(F)F)c4)n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(cnn4CCC(=O)O)c3)no2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
Ethyl 3-(5-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indazol-1-yl)propanoate (D59) (82 mg, 0.17 mmol) was dissolved in ethanol (4 ml) and then 2M aq. NaOH added (0.5 ml). The reaction was stirred at room temperature overnight and then the ethanol was evaporated in vacuo. Ethyl acetate was added but as the compound appeared to be in both aqueous and organic layers the mixture was evaporated. Purification by MDAP (in two batches) followed by freeze-drying gave the title compound (28.7 mg). δH (400 MHz, d6-DMSO) 1.36 (6H, d), 2.88 (2H, t), 4.65 (2H, t), 4.98 (1H, sept.), 7.59 (1H, d), 7.89 (1H, d), 8.07 (1H, dd), 8.27 (1H, d), 8.32 (1H, d), 8.41 (1H, dd), 8.57 (1H, dd). MS (ES): C22H19F3N4O4 requires 460; found (MH+) 461.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C@@H:14]([C:23](OCC(F)(F)F)=[O:24])[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]([N+:31]([O-:33])=O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N1C=CC=CC=1.[Pt]>[C:19]([O:18][C:16](=[O:17])[NH:15][C@@H:14]1[C:23](=[O:24])[N:31]([OH:33])[C:10]2=[N:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:12]=[C:11]2[CH2:13]1)([CH3:20])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cn(Cc2ccccc2)nc1[N+](=O)[O-])C(=O)OCC(F)(F)F
Agent: [Pt]
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@H]1Cc2cn(Cc3ccccc3)nc2N(O)C1=O
Reaction time: 3 h

Procedure:
To a solution of C8 (110 mg, 0.233 mmol) in pyridine (10 mL) was added 5% platinum on carbon (35 mg, 0.0090 mmol), and the reaction was subjected to hydrogenation at 30 psi for 3 hours on a Parr shaker. After filtration through Celite, the filter pad was rinsed with EtOAc (10 mL) and the combined filtrates were concentrated in vacuo. Purification using silica gel chromatography (Gradient: 0% to 100% EtOAc in heptane) provided C9 as a solid. Yield: 55 mg, 0.15 mmol, 64%. LCMS m/z 359.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.48 (s, 9H), 2.49 (br dd, J=14, 14 Hz, 1H), 3.30 (br dd, J=14, 7 Hz, 1H), 4.20-4.29 (m, 1H), 5.21 (AB quartet, JAB=15.2 Hz, ΔνAB=11.1 Hz, 2H), 5.61 (br s, 1H), 7.07-7.08 (m, 1H), 7.14-7.20 (m, 2H), 7.29-7.36 (m, 3H), 10.74 (br s, 1H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:2]1.[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28](O)=[O:29])=[CH:25][CH:26]=2)[C:21]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:20]1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28]([N:1]3[CH2:2][CH:3]([N:5]4[CH2:6][CH2:7][N:8]([C:11]([C:13]5[S:14][CH:15]=[CH:16][N:17]=5)=[O:12])[CH2:9][CH2:10]4)[CH2:4]3)=[O:29])=[CH:25][CH:26]=2)[C:21]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:20]1
Reactant: Cn1nc(-c2ccccc2)c2cc(C(=O)O)ccc21
Reactant: O=C(c1nccs1)N1CCN(C2CNC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1nc(-c2ccccc2)c2cc(C(=O)N3CC(N4CCN(C(=O)c5nccs5)CC4)C3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a mixture of compound 5e (42.9 mg, 0.132 mmol), compound 54c (30.3 mg, 0.12 mmol), and Et3N (0.084 mL, 0.6 mmol) in CH2Cl2 (1 mL) at room temperature was added HATU (70 mg, 0.168 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and H2O, washed with aq. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 2-4% MeOH/EtOAc) to give Cpd 1137 (48.1 mg). 1H NMR (400 MHz, CDCl3): δ 8.32 (s, 1H), 7.94 (d, J=7.3 Hz, 2H), 7.88 (d, J=3.2 Hz, 1H), 7.74 (d, J=9.5 Hz, 1H), 7.49-7.58 (m, 3H), 7.39-7.48 (m, 2H), 4.16 (s, 3H), 4.09-4.62 (m, 6H), 3.86 (m, 2H), 3.21-3.33 (m, 1H), 2.39-2.63 (m, 4H). MS m/z (M+H+) 487.2.
Reaction SMILES: [CH2:1]([O:19][C@@H:20]1[C@H:24]([OH:25])[C@@H:23]([CH2:26][OH:27])[O:22][C@H:21]1[N:28]1[C:38]2[N:37]=[C:35]([NH2:36])[NH:34][C:32](=[O:33])[C:31]=2[N:30]=[CH:29]1)[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].C[Si](Cl)(C)C.[C:44](Cl)(=[O:48])[CH:45]([CH3:47])[CH3:46].[OH-].[NH4+]>N1C=CC=CC=1.O>[C:44]([NH:36][C:35]1[NH:34][C:32](=[O:33])[C:31]2[N:30]=[CH:29][N:28]([C:38]=2[N:37]=1)[C@@H:21]1[O:22][C@H:23]([CH2:26][OH:27])[C@@H:24]([OH:25])[C@H:20]1[O:19][CH2:1][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])(=[O:48])[CH:45]([CH3:47])[CH3:46]
Reactant: CC(C)C(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21
Agent: C[Si](C)(C)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.9 %

Procedure:
2′-O-octadecylguanosine (1.9 g) in pyridine (150 ml) was cooled in an ice bath, and treated with trimethylsilyl chloride (2 g, 5 eq) and isobutyryl chloride (2 g, 5 eq). The reaction mixture was stirred for 4 hours, during which time it was allowed to warm to room temperature. The solution was cooled, water added (10 ml) and stirred for an additional 30 minutes. Concentrated ammonium hydroxide (10 ml) was added and the solution concentrated in vacuo. The residue was purified by silica gel chromatography (eluted with 3% MeOH/EtOAc) to yield 1.2 g of product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:18]3[O:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(OCC)(=O)C.[ClH:32]>C(OCC)(=O)C>[ClH:32].[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:18]3[O:17][CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2cccc(F)c2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1cccc(-c2cccc3c2OCCNC3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
A mixture of tert-butyl 9-(3-fluorophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (390 mg, 1.14 mmol), ethyl acetate (4 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (309 mg, 97.2%) as a solid.