Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[C:11]3[CH2:19][N:18]([CH3:20])[CH2:17][CH:16]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:12]3=[CH:13][CH:14]=2)[NH:9][CH:8]=1)([CH3:3])[CH3:2].FC(F)(F)C(O)=O.O.[OH-].[Na+]>O1CCCC1>[CH:1]([NH:4][CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[C:11]3[CH2:19][N:18]([CH3:20])[CH2:17][CH:16]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:12]3=[CH:13][CH:14]=2)[NH:9][CH2:8]1)([CH3:3])[CH3:2]
Reactant: CC(C)NCCc1c[nH]c2c3c(ccc12)C(c1ccccc1)CN(C)C3
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NCCC1CNc2c1ccc1c2CN(C)CC1c1ccccc1

Procedure:
2.1 g (0.00604 mol) of 3-(isopropylaminoethyl)-8-methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]-indole are dissolved in 25 ml (0.3275 mol) of trifluoroacetic acid, with stirring and in the absence of moisture, and a solution of 1.76 g (0.0241 mol) of trimethylaminoborane in 10 ml of tetrahydrofuran is then added dropwise at a temperature of 0°-+2° C. The mixture is subsequently stirred at 0° C. for 1 hour, a solution of 1.76 g (0.0241 mol) of trimethylamonoborane in 10 ml of tetrahydrofuran is then again added and the mixture is subsequently stirred for 2.5 hours. 150 ml of H2O are now added to the reaction mixture, the mixture is brought to pH 13 with NaOH and the oily product which deposits is extracted with CH2Cl2. The CH2Cl2 phase is washed with H2O, dried over Na2SO4 and then freed from the solvent on a rotary evaporator. The residue is chromatographed twice on silica gel (silica gel 60 from E. Merck, Darmstadt). Eluent: initially CH2Cl2 /MeOH/N(C2H5)3 (15:4:0.25), then diethyl ether/MeOH/N(C2H5)3 (15:3:0.25).
Reaction SMILES: [H][H].[OH:3][CH2:4][CH2:5][C:6]1[C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH2:14])[CH:9]=[CH:10][C:11]=1[NH:12][CH3:13].C(=O)([O-])[O-].[Ca+2].[CH2:23]([OH:26])[CH2:24]Br.Cl>O>[OH:26][CH2:23][CH2:24][C:10]1[C:11]([NH:12][CH3:13])=[C:6]([CH2:5][CH2:4][OH:3])[C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH2:14])[CH:9]=1
Reactant: OCCBr
Reactant: CNc1ccc(N)c([N+](=O)[O-])c1CCO
Reactant: [H][H]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: CNc1c(CCO)cc(N)c([N+](=O)[O-])c1CCO
Yield: 72.9 %

Procedure:
The substitution of a hydrogen of the amine function in the meta position of the nitro group is easily accomplished in the following manner. A mixture of 0.086 mols (18.1 g) of (2'-hydroxyethyl)-1-amino-2-nitro-4-methylamino benzene with 110 cm3 of water and 6.25 g of calcium carbonate is brought to reflux. 0.124 mols (8.75 cm3) of glycol bromohydrine is then introduced drop by drop, while stirring. Reflux is maintained for an hour and a half and then the reaction mixture is cooled and acidified with hydrochloric acid. The crystallized hydrochlorate is then dried, redissolved in water, and brought to an alkaline pH by adding ammonia. Drying yields 16 g of (2'-hyroxyethyl)-1-amino-2-nitro-(2'-hydroxyethyl)-4-methylamino benzene which melts at 99° C.
Reaction SMILES: CO.C[O-].[Na+].[SH:6][CH2:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][OH:11].[CH3:16][C:17]([CH3:35])=[CH:18][CH2:19][C@H:20]1[O:22][C@@:21]1([C@@H:24]1[C@:29]2([O:31][CH2:30]2)[CH2:28][CH2:27][C@@H:26]([OH:32])[C@H:25]1[O:33][CH3:34])[CH3:23]>O>[O:22]1[CH:20]([CH2:19][CH:18]=[C:17]([CH3:35])[CH3:16])[C:21]1([CH:24]1[CH:25]([O:33][CH3:34])[CH:26]([OH:32])[CH2:27][CH2:28][C:29]1([CH2:30][S:6][CH2:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][OH:11])[OH:31])[CH3:23]
Reactant: CO[C@@H]1[C@H](O)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Reactant: OCc1ccccc1CS
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1C(O)CCC(O)(CSCc2ccccc2CO)C1C1(C)OC1CC=C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
To an about 14% methanol solution (6 ml) of sodium methoxide were added, under ice-cooling, 2-mercaptomethylbenzylalcohol (655 mg) and fumagillol (1.00 g). The mixture was stirred for one hour at room temperature, to which was added water to suspend the reaction. The product was extracted with ethyl acetate, The extract solution was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 30 g, developing solvent : ethyl acetate - hexane=2:1) to give 2-(1,2-epoxy-1,5-dimethy-4-hexenyl)-1-(2-hydroxymethylbenzyl)thiomethyl-3-methoxy-1,4-cyclohexanediol (1.43 g : yield 92%) as a colorless oily substance.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH3:35][C:36]1[CH:37]=[CH:38][C:39]([O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])=[C:40]([CH2:42][OH:43])[CH:41]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:43][CH2:42][C:40]4[CH:41]=[C:36]([CH3:35])[CH:37]=[CH:38][C:39]=4[O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Reactant: C=CC[C@H](C)Oc1ccc(C)cc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4cc(C)ccc4O[C@@H](C)CC=C)nn23)CC1
Reaction time: 5 h
Yield: 22.3 %

Procedure:
(S)-Ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.45 g, 0.770 mmol) was dissolved in 1 mL DMF to this was added (S)-(5-methyl-2-(pent-4-en-2-yloxy)phenyl)methanol (0.191 g, 0.924 mmol) as a solution in 1 mL DMF. NaH-60% wt/wt in oil (47 mg, 1.16 mmol) was added and the reaction mixture was stirred for 5 hours. The reaction was quenched with 1N HCl then transferred to a separatory funnel where the product was extracted with ethyl acetate. The organic solution was dried over Na2SO4. After filtration the solvent was removed under vacuum and the product purified by silica gel chromatography using a Biotage apparatus to isolate the title compound as an oil (114 mg). 1H NMR (400 MHz, CDCl3) δ 1.21-1.24 (15H, overlapping s and m), 1.32 (3H, d), 1.65-1.8 (4H, br m), 2.35 (3H, s), 2.50 (2H, m), 2.61 (3H, s), 3.0-3.5 (4H, very broad m), 3.75 (2H, s), 4.21 (2H, m), 4.45 (1H, m), 4.66 (2H, br s), 4.77 (2H, s), 5.06-5.22 (4H, overlapping m), 5.32 (1H, s), 5.85-6.2 (2H, overlapping m), 6.59 (1H, s), 6.71 (1H, s), 6.77 (1H, d), 7.34 (1H, d).
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:24][O:23][CH2:22][CH2:21][O:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)C=CC=CC=1.N1C=CC=CC=1.[CH3:34][NH:35][C@@H:36]1[CH2:41][CH2:40][C@H:39]([OH:42])[CH2:38][CH2:37]1>C(Cl)(Cl)Cl>[O:20]1[CH2:21][CH2:22][O:23][CH2:24][CH:19]1[C:18]1[C:12]2[S:11][C:10]([NH:9][C:8](=[O:27])[N:35]([C@H:36]3[CH2:41][CH2:40][C@@H:39]([OH:42])[CH2:38][CH2:37]3)[CH3:34])=[N:14][C:13]=2[C:15]([O:25][CH3:26])=[CH:16][CH:17]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)Oc3ccccc3)nc12
Reactant: CN[C@H]1CC[C@@H](O)CC1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)N(C)[C@H]3CC[C@@H](O)CC3)nc12
Reaction time: 16 h

Procedure:
To a stirred solution of 100 mg (0.26 mmol) (+)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid phenyl ester and 0.06 ml (0.78 mmol) pyridine in 5 ml chloroform at room temperature was added 47 mg (0.36 mmol) cis-4-methylamino-cyclohexanol and stirring continued at 50° C. for 16 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (1/1 acetone/heptane then acetone) followed by trituration in ether and hexane afforded 75 mg (69%) (+)-cis-3-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-1-(4-hydroxy-cyclohexyl)-1-methyl-urea as a white solid. [α]D20=+18.8° (c=1.07, CHCl3), ES-MS m/e (%): 422 (M+H+, 100).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:10]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:9]1)=[O:7])(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Br:19][C:15]1[CH:14]=[C:13]([CH:12]2[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:10]([CH2:30][C:31]([CH3:33])([CH3:34])[CH3:32])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Br)c2)C1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Br)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 83 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2S,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 67a (1.3 g, 2.4 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2S,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.2 g, 83%).
Reaction SMILES: COC1C=C(C=CC=1OC)C[C:7]1[C:16]2[C:11](=[CH:12][C:13](OC)=[C:14](OC)[CH:15]=2)[CH:10]=[CH:9][N+:8]=1[O-:21].CN(C)C=O.COC1C=CC=CC=1N1CCNCC1>C(N(CC)CC)C>[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][N+:8]=1[O-:21]
Reactant: COc1ccc(Cc2c3cc(OC)c(OC)cc3cc[n+]2[O-])cc1OC
Agent: COc1ccccc1N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: [O-][n+]1ccc2ccccc2c1

Procedure:
A mixture of 2.5g 4-chloromethyl-1-(3,4-dimethoxybenzyl-6,7-dimethoxyisoquinoline 2-oxide, 35 ml dimethylformamide, 1.8 triethylamine and 1.29 g 1-(2-methoxyphenyl)piperazine was stirred and heated under nitrogen at 50° for 7 hours. After evaporation of the solvent, the residue was partitioned between methylene chloride and water. The methylene chloride solution was washed with water and dried. After removal of the solvent in vacuo, the residue (3.5 g) was crystallized from methylene chloride/ethyl acetate to yield 3.05 g of yellow, hygroscopic crystals of 1-(3,4)-dimethoxybenzyl)-6,7-dimethoxy-4-{]4'-(2-methoxyphenyl)-1'-piperazinyl]methyl} isoquinoline 2-oxide, mp 128°-129° (dec.).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C:13]([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])([CH2:14][O:15][S:16]([CH3:19])(=[O:18])=[O:17])[O:12][C@@H:11]([N:26]2[CH:34]=[C:32]([CH3:33])[C:30](=[O:31])[NH:29][C:27]2=[O:28])[C@@H:10]1[OH:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[CH2:1]([O:8][C@@H:9]1[C:13]([CH2:14][O:15][S:16]([CH3:19])(=[O:17])=[O:18])([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])[O:12][C@@H:11]([N:26]2[CH:34]=[C:32]([CH3:33])[C:30](=[O:31])[NH:29][C:27]2=[O:28])[C@@H:10]1[O:35][S:43]([CH3:42])(=[O:45])=[O:44])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cn([C@@H]2OC(COS(C)(=O)=O)(COS(C)(=O)=O)[C@@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]c1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cn([C@@H]2OC(COS(C)(=O)=O)(COS(C)(=O)=O)[C@@H](OCc3ccccc3)[C@H]2OS(C)(=O)=O)c(=O)[nH]c1=O
Temperature: 0 °C

Procedure:
Nucleoside 27 (20 g, 37 mmol) was dissolved in anhyd dichloromethane (100 mL) and anhyd pyridine (100 mL) was added. The solution was cooled to 0° C. and methanesulfonyl chloride (4.4 mL, 56 mmol) was added dropwise. After 2 h the reaction was quenched with sat. aq NaHCO3 (200 mL), and the phases were separated. The aq phase was extracted with dichloromethane (2×150 mL), and the combined organic phases were washed with aq HCl (1 M, 2×200 mL), sat. aq NaHCO3 (2×250 mL) and brine (250 mL). The organic phase was dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude product was co-evaporated with toluene affording 28 (22 g, 96%) as a white foam. Rf=0.41 (100% EtOAc); ESI-MS m/z found 635.0 ([MNa]+, calcd 635.1). All analytical data were identical to those previously reported. (Håkansson, A. E.; Koshkin, A.; Sørensen, M. D.; Wengel, J. J. Org. Chem. 2000, 65, 5161-5166)
Reaction SMILES: [C:1]([C:3](=[C:7](SC)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]([NH2:6])=[O:5])#[N:2].C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)C([O-])=O.[OH:30][CH2:31][CH2:32][CH2:33][NH2+:34][NH2:35].CO>C(Cl)Cl>[NH2:2][C:1]1[N:34]([CH2:33][CH2:32][CH2:31][OH:30])[N:35]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CSC(=C(C#N)C(N)=O)c1ccc(C)cc1
Reactant: N[NH2+]CCCO
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(-c2nn(CCCO)c(N)c2C(N)=O)cc1
Yield: 43.7 %

Procedure:
The title compound was prepared from 2-cyano-3-methylthio-3-(4-tolyl)acrylamide (464 mg, 2.0 mmol), sodium carbonate (424 mg, 4.0 mmol) and 1-(3-hydroxypropyl)hydrazinium trifluoroacetate (449 mg, 2.2 mmol) following the procedure used for the compound of Example 12. The crude product was subjected to column chromatography (SiO2, 8% methanol in CH2Cl2) and was recrystallised from ethyl acetate to give the title compound as white crystals (240 mg) m.p. 164-165°. δH (CDCl3) 7.43 (2H, d, J 8.1 Hz), 7.26 (2H, d, J 7.8 Hz), 5.73 (2H, br s), 5.18 (2H, br s), 4.12 (2H, t, J 6.1 Hz), 3.66 (2H, t, J 5.5 Hz), 2.40 (3H, s), 2.04 (2H, quintet, J 6.1 Hz) and 1.59 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[N:11]([C:13]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:14]=1[NH:15]C)=O.C(O)(=O)C.Br>O>[CH3:21][C:19]1[CH:20]=[C:13]2[C:14](=[CH:17][CH:18]=1)[N:15]=[C:6]1[NH:7][C:8]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=3[C:5]1=[N:11]2
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: CNc1ccc(C)cc1N=O
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc2nc3[nH]c4ccc(Cl)cc4c3nc2c1
Reaction time: 2 h

Procedure:
A solution of 1.68 g 5-chloroindol (0.01 mole) and 1.50 g 2-nitroso-N-methyl-p-toluidine (0.01 mole), 10 ml acetic acid is boiled under reflux for 1 hour. Finally hydrogen bromide is introduced and the mixture is boiled for further 2 hours. After cooling it is poured into water. The dried reaction product is recrystallized from acetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:21]2[CH2:26][CH2:25][O:24][C:23]3[CH:27]=[C:28]([S:31](=[O:48])(=[O:47])[N:32](CC4C=CC(OC)=CC=4)[C:33]4[S:34][CH:35]=[CH:36][N:37]=4)[CH:29]=[CH:30][C:22]2=3)=[C:6]([C:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]=2)[CH:7]=1.N(OC(C)(C)C)=O.[N:56]([Si](C)(C)C)=[N+:57]=[N-].[C:63]([OH:69])([C:65]([F:68])([F:67])[F:66])=[O:64]>C(#N)C>[F:66][C:65]([F:68])([F:67])[C:63]([OH:69])=[O:64].[F:66][C:65]([F:68])([F:67])[C:63]([OH:69])=[O:64].[N:1]([C:2]1[CH:3]=[CH:4][C:5]([N:21]2[CH2:26][CH2:25][O:24][C:23]3[CH:27]=[C:28]([S:31]([NH:32][C:33]4[S:34][CH:35]=[CH:36][N:37]=4)(=[O:48])=[O:47])[CH:29]=[CH:30][C:22]2=3)=[C:6]([C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]=2)[CH:7]=1)=[N+:56]=[N-:57]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc(N)cc2C2=CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CC(C)(C)ON=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: [N-]=[N+]=Nc1ccc(N2CCOc3cc(S(=O)(=O)Nc4nccs4)ccc32)c(C2=CCNCC2)c1
Reaction time: 0.33 h
Yield: 25.7 %

Procedure:
To a solution of tert-butyl 4-(5-amino-2-(7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.105 g, 0.152 mmol) in dry acetonitrile (1.522 mL) at 0° C. was added tert-butyl nitrite (0.026 mL, 0.213 mmol) followed by dropwise addition of azidotrimethylsilane (0.024 mL, 0.183 mmol). The resulting mixture was stirred for 20 minutes, at which time no conversion to the desired was observed. Additional tert-butyl nitrite (0.052 mL) and azidotrimethylsilane (0.048 mL) were added at 0° C. and the reaction was once again stirred at RT for 1 h. Conversion was observed, but starting material was still the major reaction component, so the reaction was recooled to 0° C. and 0.156 mL of t-Bu nitrite was added, followed by dropwise addition of 0.144 mL of TMS-azide. After 20 minutes at RT, the reaction was complete and was concentrated under a vacuum. DCM (1.0 mL) was added, followed by TFA (0.235 mL, 3.04 mmol), and the reaction was stirred at RT for 1 h. The material was concentrated under a vacuum and purified by reverse-phase preparative HPLC using a Phenomenex Luna column, 5 micron, C18(2), 100 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 25% to 90% over 20 min to provide 4-(4-azido-2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide bis(2,2,2-trifluoroacetate) (0.028 g, 0.039 mmol) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.30-2.44 (m, 2 H) 3.19 (m, J=5.20 Hz, 2 H) 3.47-3.56 (m, 2 H) 3.62-3.70 (m, 2 H) 4.29 (t, J=4.25 Hz, 2 H) 5.76-5.83 (m, 1 H) 6.29 (d, J=8.31 Hz, 1 H) 6.79 (d, J=4.50 Hz, 1 H) 7.02 (d, J=2.74 Hz, 1 H) 7.08-7.15 (m, 2 H) 7.17 (dd, J=8.56, 2.69 Hz, 1 H) 7.22 (d, J=4.60 Hz, 1 H) 7.38 (d, J=8.51 Hz, 1 H) 8.76 (br. s., 2 H) 12.53 (br. s., 1H); m/z (ESI) 496.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[C:6]([CH:9]=1)[C:7]#[N:8].[H-].[Na+].[CH3:22][C:23]1([CH3:26])[CH2:25][O:24]1>CN(C=O)C.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:22][C:23]([OH:24])([CH3:26])[CH3:25])[N:15]=[CH:14]3)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(F)ccc1Oc1ccc2[nH]ncc2c1
Reactant: CC1(C)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1ncc2cc(Oc3ccc(F)cc3C#N)ccc21
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 54.5 %

Procedure:
A solution of 5-fluoro-2-(1H-indazol-5-yloxy)-benzonitrile (0.100 g, 0.395 mmol) in DMF (4 mL) was treated with NaH (0.022 g, 60%, 056 mmol) and stirred for 5 minutes. 2,2-Dimethyloxirane (0.035 g, 0.48 mmol) was added and the solution was stirred at room temperature for 1 hour. The reaction mixture was then heated to 80° C. for 1.5 hours. The solution was cooled to room temperature, diluted with ether (50 mL), washed with water (3×5 mL), brine, dried over MgSO4, and concentrated under reduced pressure. The residue was chromatographed eluting with ethyl acetate/hexanes (1:1) to afford 0.070 g of product (47% yield).
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][P:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])(=[O:9])[O:7][CH3:8].[C:15]([O:23][CH3:24])(=[O:22])/[CH:16]=[CH:17]\[C:18]([O:20][CH3:21])=[O:19].Cl>CO>[CH3:4][O:5][P:6]([CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH:16]([C:15]([O:23][CH3:24])=[O:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19])(=[O:9])[O:7][CH3:8]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: COC(=O)/C=C\C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC(C(=O)OC)C(C(=O)OC)P(=O)(OC)OC

Procedure:
0.09 mol of sodium methylate in 25 cc of methanol was added within 45 minutes to a mixture of 136.5 g (0.75 mol) of carbomethoxy-methane-phosphonic acid dimethyl ester and 108 g (0.75 mol) of dimethyl maleate. The temperature was found to increase from 22° C to 41° C. The whole was allowed to further react for 30 minutes at 100° C. After neutralization by the addition of 5 cc of concentrated hydrochloric acid and filtration, all volatile matter was distilled off under vacuum at a base temperature up to 120° C. 1,2,3-tricarbomethoxy-propane-1-phosphonic acid dimethyl ester was obtained in a crude yield of 237 g (97 % of the theoretical). The ester had a boiling point of 169°-172° C under 0.7 mm of mercury. n25D = 1.4520.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:21])=[CH:22][CH:23]=1
Reactant: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)O)cn1
Reactant: C1COCCN1
Product: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)N2CCOCC2)cn1
Yield: 70 %

Procedure:
As described for example 313b, 6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (53 mg, 0.17 mmol) was converted, using morpholine instead of isopropylamine, to the title compound (45 mg, 70%) which was obtained as an off white foam. MS: m/e=382.4 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:19])([CH3:18])[CH2:3][C@H:4]([NH:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[C:5]([OH:7])=O.Cl.[NH2:21][CH:22]([CH2:33][CH3:34])[C@@H:23]([C:25]1[O:29][N:28]=[C:27]([CH:30]2[CH2:32][CH2:31]2)[N:26]=1)[OH:24].C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl>[CH:30]1([C:27]2[N:26]=[C:25]([CH:23]([OH:24])[C@@H:22]([NH:21][C:5]([C@@H:4]([NH:8][C:9]([N:11]3[CH2:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[O:10])[CH2:3][C:2]([F:1])([F:19])[CH3:18])=[O:7])[CH2:33][CH3:34])[O:29][N:28]=2)[CH2:31][CH2:32]1
Reactant: CCC(N)[C@H](O)c1nc(C2CC2)no1
Reactant: CC(F)(F)C[C@H](NC(=O)N1CCCOCC1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC[C@H](NC(=O)[C@H](CC(C)(F)F)NC(=O)N1CCCOCC1)C(O)c1nc(C2CC2)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
To a mixture of (S)-4,4-Difluoro-2-[(perhydro-1,4-oxazepine-4-carbonyl)-amino]-pentanoic acid (97 mg, 0.35 mmol), (S)-2-Amino-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-butan-1-ol hydrochloride (83 mg, 0.36 mmol) and diisopropylethyl amine (121 μL, 0.70 mmol) in dry dichloromethane (12 mL) is added 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (66 mg, 0.35 mmol) and 1-hydroxybenzotriazole hydrate (47 mg, 0.35 mmol). The mixture is stirred at room temperature for 16 hr then is diluted with dichloromethane (20 mL) and washed with dilute HCl (30 mL), then saturated NaHCO3 (30 mL). The organic layer is dried (Na2SO4) and concentrated in vacuum. The residue is purified over 12 g silica gel, eluting with ethyl acetate: heptane (gradient 50-100%) to afford Perhydro-1,4-oxazepine-4-carboxylic acid ((S)-1-{(S)-1-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-hydroxy-methyl]-propylcarbamoyl}-3,3-difluoro-butyl)-amide (120 mg, 75%) as a glassy solid. LC/MS 100% 460 (M+H).