Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]=[C:4]([CH3:7])[O:3]1.S(=O)(=O)(O)O.[CH2:13]=[O:14].[OH-].[Na+]>O>[OH:14][CH2:13][C:5]1[CH2:6][N:2]([CH3:1])[O:3][C:4]=1[CH3:7]
Reactant: C=O
Reactant: CC1=CCN(C)O1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1=C(CO)CN(C)O1
Temperature: 70 °C
Yield: 19.5 %

Procedure:
2,5-dimethylisooxazole (10.0 g) was dissolved in water (100 ml). To the solution were added concentrated sulfuric acid (35.3 g) and 40% aqueous formaldehyde solution (46.4 g) at 0° C., and the mixture was heated at 70° C. overnight. The mixture was neutralized with 1N sodium hydroxide solution at 0° C. and extracted with chloroform three times. The extract was dried with magnesium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was distilled under reduced pressure to give 4-hydroxymethyl-2,5-dimethylisooxazole (2.54 g) as colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:15])/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[F:8].[H][H]>C(O)C.O1CCCC1.[Pt]>[Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)/C=C/C(=O)c1ccc(F)c(Br)c1
Reactant: [H][H]
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCC(=O)c1ccc(F)c(Br)c1

Procedure:
A solution of 6.2 g (0.023 mol) of (E)-4-(3-bromo-4-fluorophenyl)-4-oxo-2-butenoic acid in a mixture of 200 ml ethanol and 25 ml tetrahydrofuran was hydrogenated in the presence of 1.0 g of 10% platinum/charcoal at ambient temperature under a pressure of 50 psi until the uptake of hydrogen was complete. The residue remaining after the catalyst and solvent had been eliminated crystallised spontaneously and after being washed thoroughly with diisopropylether yielded 1.7 g (27% of theoretical) of colourless crystals, m.p. 108–110° C. and Rf 0.73 (El F).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]([C:9]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[N:7]2[C:25](=[O:36])[C@@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C@H:6]2[S:5][CH:4]=1.[C:37]1([P:43]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(OCC)(=O)C>[Cl-:1].[C:13]1([CH:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:11][C:9]([CH:8]2[N:7]3[C:25](=[O:36])[C@@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)[C@H:6]3[S:5][CH:4]=[C:3]2[CH2:2][P+:43]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:10])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(CCl)=CS[C@H]12
Solvent: CCOC(C)=O
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)=CS[C@H]12
Product: [Cl-]
Yield: 14.6 %

Procedure:
A solution of diphenylmethyl 3-chloromethyl-7β-(2-thienylacetamido)ceph-2-em-4-carboxylate (2.3 g.) in ethyl acetate (20 ml.) was treated with triphenylphosphine (2.3 g., ca. 2 equivs.) and the mixture refluxed for 5 hours. The solution was cooled and the insoluble product isolated by filtration. This material was precipitated from acetone (containing some chloroform) solution by petroleum-ether to give the phosphonium salt (500 mg.) as an amorphous solid [α]D + 68.5° (CHCl3), λmax. (CHCl3) 269.5 and 276.5 nm. (ε 8,880 and 7,620), νmax. (CHBr3) 3440 (NH), 1780 (β-lactam), 1680 and 1510 (--CONH--), and 1445 (P-C aryl) cm,-1, τ(CDCl3) 3.61 (C(2) -H), 4.4 (C(7) -H, dd, J 4.5 and 9 Hz), 4.75 (C(6) -H, not well resolved), 5.04 and 5.18 (CH2 -P, part of two AB-q, JP-H 13 Hz.).
Reaction SMILES: [C:1]([C:5]1[N:6]([C:31]2[C:32](C[C@H](O)C)=[C:33](S([O-])(=O)=O)C=CC=2C)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH:14][C:15]([C:17]1([C:20]3[CH:30]=[CH:29][C:23]4[O:24][C:25]([F:28])([F:27])[O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]1)=[O:16])=[CH:9][CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[N-:46]=[N+:47]=[N-:48].[Na+].CN(C=[O:54])C>>[N:46]([CH2:33][C@H:32]([OH:54])[CH2:31][N:6]1[C:7]2[C:12](=[CH:11][C:10]([NH:14][C:15]([C:17]3([C:20]4[CH:30]=[CH:29][C:23]5[O:24][C:25]([F:27])([F:28])[O:26][C:22]=5[CH:21]=4)[CH2:18][CH2:19]3)=[O:16])=[CH:9][CH:8]=2)[CH:13]=[C:5]1[C:1]([CH3:2])([CH3:4])[CH3:3])=[N+:47]=[N-:48]
Reactant: Cc1ccc(S(=O)(=O)[O-])c(C[C@@H](C)O)c1-n1c(C(C)(C)C)cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc21
Reactant: CN(C)C=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2n1C[C@@H](O)CN=[N+]=[N-]
Temperature: 80 °C

Procedure:
To a stirred solution (R)-3-(2-tert-butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-1-yl)-2-hydroxypropyl-4-methylbenzenesulfonate (3.2 g, 5.0 mmol) in DMF (6 mL) was added sodium azide (2.0 g, 30 mmol). The reaction was heated at 80° C. for 2 h. The mixture was partitioned between 20 mL ethyl acetate and 20 mL water. The layers were separated and the organic layer was evaporated. The residue was purified using column chromatography (0-85% ethyl acetate/hexane) to give (R)—N-(1-(3-azido-2-hydroxypropyl)-2-tert-butyl-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-cyclopropanecarboxamide (2.48 g). LC/MS (M+1)=512.5. 1H NMR (400 MHz, CDCl3) δ 7.55 (d, 1H, J=2 Hz), 7.31 (m, 3H), 6.96 (s, 1H), 6.94 (dd, 1H, J=2, 8 Hz), 6.22 (s, 1H), 4.33 (m, 1H), 4.31 (dd, 1H, J=6, 15 Hz), 4.28 (dd, 1H, J=11, 15 Hz), 4.18 (m, 1H), 3.40 (dd, 1H, J=3, 6 Hz), 3.36 (dd, 1H, J=3, 6 Hz), 2.40 (br s, 1H), 1.74 (m, 2H), 1.40 (s, 9H), 1.11 (m, 2H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][CH:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH:22]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:28]3[C:23]2=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:15][CH:14]=1)[C:7]([O:9]CC)=[O:8])[CH3:4]>C(O)C>[CH2:3]([O:5][CH:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH:22]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:28]3[C:23]2=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:15][CH:14]=1)[C:7]([OH:9])=[O:8])[CH3:4]
Reactant: CCOC(=O)C(Cc1ccc(OCCC2c3ccccc3-c3ccccc32)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(Cc1ccc(OCCC2c3ccccc3-c3ccccc32)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Sodium hydroxide (1M, 2.5 ml, 2.5 mmol) was added to a solution of ethyl 2-ethoxy-3-{4-[2-(9H-fluoren-9-yl)-ethoxy]-phenyl}propionate (0.19 g, 0.44 mmol) in ethanol (5 ml) and the mixture stirred at room temperature for 20 h. The resulting mixture was partitioned between water (20 ml) and dichloromethane (20 ml), acidified to pH 1 by adding 1N hydrochloric acid, and the organic phase collected. The aqueous phase was further extracted with dichloromethane (3×20 ml) and the combined organics were washed with brine, dried (Na2SO4) and evaporated to give the title compound as a waxy solid; 0.17 g (95%).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][N:4]=[C:5]=[S:6].[NH2:9][C:10]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][OH:17])[N:11]=1>C(#N)C>[OH:17][CH2:16][CH2:15][N:12]1[CH:13]=[CH:14][C:10]([NH:9][C:5]([NH:4][CH2:3][C:2]([F:8])([F:7])[F:1])=[S:6])=[N:11]1
Reactant: Nc1ccn(CCO)n1
Reactant: FC(F)(F)CN=C=S
Solvent: CC#N
Product: OCCn1ccc(NC(=S)NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.1 %

Procedure:
A mixture of 2,2,2-trifluoroethylisothiocyanate (13.8 g.) and 3-amino-1-(2-hydroxyethyl)pyrazole (12.5 g.) in acetonitrile dried over 4A molecular sieve (30 ml.) was stirred at room temperature for 4 hours. A precipitate formed after 30 minutes. Filtration gave 1-(2-hydroxyethyl)-3-[3-(2,2,2-trifluoroethyl)thioureido]pyrazole (12.1 g.; 46%), m.p. 145°-146°.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[N:4]([C:5]([O:13][CH3:14])=[N:6][CH:7]=[C:8]2[O:11][CH3:12])[N:3]=1.[CH3:15][O:16][C:17]1[C:22]([S:23](Cl)(=[O:25])=[O:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=[CH:19][N:18]=1.N1C=C(C)C=C(C)C=1.Cl>C(#N)C.CS(C)=O>[CH3:14][O:13][C:5]1[N:4]2[N:3]=[C:2]([NH:1][S:23]([C:22]3[C:17]([O:16][CH3:15])=[N:18][CH:19]=[CH:20][C:21]=3[C:27]([F:30])([F:28])[F:29])(=[O:24])=[O:25])[N:10]=[C:9]2[C:8]([O:11][CH3:12])=[CH:7][N:6]=1
Reactant: COc1cnc(OC)n2nc(N)nc12
Reactant: COc1nccc(C(F)(F)F)c1S(=O)(=O)Cl
Agent: Cc1cncc(C)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: CC#N
Product: COc1nccc(C(F)(F)F)c1S(=O)(=O)Nc1nc2c(OC)cnc(OC)n2n1
Temperature: 40 °C
Reaction time: 17 h
Yield: 87.5 %

Procedure:
2-Amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine (19.5 g, 0.10 mol) and 2-methoxy-4-(trifluoromethyl)pyridine-3-sulfonyl chloride (27.5 g, 0.10 mol) were combined in acetonitrile (35 mL). To this was added 3,5-lutidine (32 g, 0.30 mol), followed by DMSO (0.23 g, 0.0030 mol). A slight exotherm was noted (to about 30° C.) in the initial hours as the reaction slurry was stirred at ambient conditions for 17 hours. The mixture was then warmed to 40° C. and treated with 2 N HCl (140 mL). The new slurry was stirred while being allowed to cool to room temperature over one hour. The solids were isolated by filtration, washed with water, and dried under vacuum to afford 38 g of product as a solid assaying at 97 wt % (85% yield).
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:10]([N:20]([CH3:32])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:9]1)C1C=CC=CC=1.ClC(OCC(Cl)(Cl)Cl)=O>CC#N>[Cl:19][C:15]1[CH:14]=[C:13]([CH:11]2[CH2:12][NH:8][CH2:9][CH:10]2[N:20]([CH3:32])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CN(Cc1ccc(C(F)(F)F)cc1)C1CN(Cc2ccccc2)CC1c1cccc(Cl)c1
Agent: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC#N
Product: CN(Cc1ccc(C(F)(F)F)cc1)C1CNCC1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
To a stirred solution of [(3RS,4SR)-1-benzyl-4-(3-chloro-phenyl)-pyrrolidin-3-yl]-methyl-(4-trifluoromethyl-benzyl)-amine (500 mg, 1.09 mmol) in CH3CN (7 ml) at RT, was added 2,2,2-trichloroethyl chloroformate (0.22 ml, 1.63 mmol). The reaction mixture was stirred at RT for 3 hours, concentrated under vacuo. The residue was dissolved in AcOH (5 ml) and zinc dust (200 mg) was added portion wise over 1 hours. The solvent was evaporated, the residue diluted in EtOAc and the organic phase was washed with an aqueous solution of NaHCO3. The organic phase was dried over Na2SO4 and concentrated under vacuo. The product was purified by column chromatography (CH2Cl2/MeOH: 9/1) to afford 305 mg (76%) of the tile compound as a colorless oil. ES-MS m/e: 369.2 (M+H+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]([CH3:38])([O:10][C:11]([NH:13][C@H:14]([C:18]([N:20]1[CH2:37][CH2:36][CH2:35][C@H:21]1[C:22]([NH:24][CH:25]([CH:32]([CH3:34])[CH3:33])[CH:26]([OH:31])[C:27]([F:30])([F:29])[F:28])=[O:23])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH3:9].CCN(CC)CC>ClCl.C(Cl)Cl.CS(C)=O>[CH3:9][C:8]([CH3:7])([O:10][C:11]([NH:13][C@H:14]([C:18]([N:20]1[CH2:37][CH2:36][CH2:35][C@H:21]1[C:22]([NH:24][CH:25]([CH:32]([CH3:33])[CH3:34])[C:26](=[O:31])[C:27]([F:28])([F:29])[F:30])=[O:23])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH3:38]
Reactant: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(O)C(F)(F)F
Agent: ClCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.1 h
Yield: 96.1 %

Procedure:
To a stirred solution of oxalyl chloride (0.31 mL, 3.56 mmol) in CH2 Cl2 (30 mL) cooled to -60° C. is added DMSO (0.51 mL, 7.12 mmol) dropwise. After 6 min, a solution of 49 (1.11 g, 2.37 mmol) in a mixture of CH2Cl2 (5 mL) and DMSO (3 mL) is slowly added and, 20 min later, Et3N (1.99 mL, 14.25 mmol) is added. The reaction mixture is allowed to warm to room temperature, diluted with CH2 Cl2 (100 mL) and washed with 0.5N aqueous HCl (2×150 mL), and half-saturated aqueous NaHCO3 (2×100 mL) followed by brine (75 mL). Drying (MgSO4) and concentration gives 50 (1.06 g, 96%, mixture of two diastereomers, ratio≈1:1) as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:49][O:50][C:51]1[CH:52]=[C:53]([CH:57]=[CH:58][CH:59]=1)[CH:54]([OH:56])[CH3:55]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:56][CH:54]([C:53]2[CH:57]=[CH:58][CH:59]=[C:51]([O:50][CH3:49])[CH:52]=2)[CH3:55])=[CH:18][CH:17]=1
Reactant: COc1cccc(C(C)O)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(C)OC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)c1
Temperature: 25 °C
Yield: 66.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (83 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (124 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-methoxy-α-methylbenzyl alcohol (64 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (88 mg, yield 66%).
Reaction SMILES: [CH2:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[OH:11]OS([O-])=O.[K+].C(OCC)(=O)C>ClCCl.O>[N:8]([C:7]1[CH:9]=[CH:10][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1)=[O:11]
Reactant: CCCc1ccc(N)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CCCc1ccc(N=O)cc1
Reaction time: 1 h

Procedure:
To a solution of 4-propylaniline (541 μl, 3.7 mmol) in dichloromethane (12.5 ml) was added a solution of oxone (4.55 g, 7.4 mmol) in H2O (50 ml). The biphasic mixture was stirred vigorously under nitrogen for 1 h, at which time the color had become deep aqua green and the reaction was judged as complete by TLC (1:1 hexanes:ethyl acetate; Rf=0.83). The mixture was transferred to a separatory funnel and the organic layer was removed. The aqueous layer was extracted twice with dichloromethane (20 ml). The combined organics were subsequently washed with 20 ml each of 1 M HCl, sat. NaHCO3, H2O, and brine and then dried over Na2SO4, filtered and removed of solvent in vacuo to provide nitrosyl-4-propylbenzene as a green oil. The crude product was immediately dissolved in glacial acetic acid (30 ml) and stirred under nitrogen, followed by the addition of 1,4-diaminobenzene (400 mg, 3.7 mmol) in dry DMSO (10 ml). The reaction was allowed to stir for 48 hrs, during which time the color turned orange-brown. The mixture was transferred to a separatory funnel containing 100 ml brine and extracted five times with ethyl acetate (50 ml). The combined organics were then washed with dilute NaCl (50 ml) six times to remove the DMSO and then dried of Na2SO4, filtered removed of solvent in vacuo. Silica gel chromatography through a wide column (40% ethyl acetate in hexanes) provided S6 as an orange solid (432 mg, 1.8 mmol, 49% yield): 1H (MeOD, 500 MHz): 0.95 (t, 3H, J=7.5); 1.66 (q, 2H, J=7.5); 2.62 (t, 2H, J=7.5); 6.74 (d, 2H, J=8.5); 7.26 (d, 2H, J=8) 7.70 (d, 4H, J=8.5). 13C (MeOD, 125 MHz): 12.7, 24.2, 37.4, 113.8, 121.7, 124.6, 128.7, 144.3, 144.4, 151.2, 151.8. HRMS (FAB+): calc'd for C15H18N3+—240.1495, found—240.1500 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:19])[C:9]1[CH:10]=[N:11][C:12]([C:15]([O:17]C)=[O:16])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+:20].[OH-]>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH3:19])[C:9]1[CH:14]=[N:13][C:12]([C:15]([O-:17])=[O:16])=[N:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+:20]
Reactant: COC(=O)c1ncc(N(C)C(=O)OC(C)(C)C)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cnc(C(=O)[O-])nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.9 %

Procedure:
A solution of methyl 5-((tert-butoxycarbonyl)(methyl)amino)pyrimidine-2-carboxylate (1.16 g, 4.35 mmol) in THF (15 mL) was treated with a 1.0 M aqueous solution of LiOH (4.6 mL, 4.6 mmol) and the solution was stirred at ambient temperature for 16 h. The mixture was concentrated and lyophilized from 1,4-dioxane to give lithium 5-((tert-butoxycarbonyl)(methyl)amino)pyrimidine-2-carboxylate (1.16 g, 100% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6): δ 8.63 (s, 2H), 3.24 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:13][C:12]([C:14](O)=[O:15])=[CH:11][C:10]=2[NH:17][C:18]2[C:19]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[N:24][C:20]=3[N:21]=[CH:22][N:23]=2)=[CH:4][CH:3]=1.C[NH:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[CH:41](N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CS(C)=O.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:13][C:12]([C:14]([NH:32][CH2:33][C@H:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH3:41])=[O:15])=[CH:11][C:10]=2[NH:17][C:18]2[C:19]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[N:24][C:20]=3[N:21]=[CH:22][N:23]=2)=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)sc3Sc3ccc(N)cc3)ncnc2n1
Reactant: CNCCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NC[C@@H](C)c4ccccc4)sc3Sc3ccc(N)cc3)ncnc2n1
Yield: 85.2 %

Procedure:
The product of Example 90F (62 mg, 0.142 mmol) in dimethyl sulfoxide (2 mL) under a nitrogen atmosphere was reacted with (S)-(−)-□-methylphenethylamine (23 mg, 0.170 mmol), N,N-diisopropylethylamine (0.123 mL, 0.708 mmol), and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (55 mg, 0.170 mmol at room temperature for 20 hours. The reaction mixture was diluted with water (10 mL), and extracted with ethyl acetate (50 mL). The organic extract was washed sequentially with water (3×10 mL), saturated aqueous sodium hydrogencarbonate (20 mL), and brine (20 mL), dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. Purification of the residue by silica gel flash chromatography eluting with 4:96 methanol/methylene chloride afforded the title compound (67 mg, 0.121 mmol, 85%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.19 (d, J=6.99 Hz, 3 H) 1.33 (d, J=6.99 Hz, 6 H) 2.91-3.07 (m, 1 H) 3.14-3.29 (m, 1 H) 5.50 (s, 2 H) 6.51 (d, J=8.46 Hz, 2 H) 7.12 (d, J=8.82 Hz, 2 H) 7.16-7.34 (m, 5 H) 7.63 (d, J=8.46 Hz, 1 H) 7.77 (s, 1 H) 8.50 (t, J=5.88 Hz, 1 H) 8.62 (s, 1 H) 8.82 (d, J=8.82 Hz, 1 H) 9.97 (s, 1 H); MS (ESI+) m/z 555 (M+H)+, 1109 (2M+H)+, MS (ESI−) m/z 553 (M−H)−.
Reaction SMILES: [OH-].[Na+].C(O)(=O)C.[CH3:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:39])[CH:25]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36](=[NH:38])[NH2:37])[CH:31]=2)[CH2:26][CH2:27][CH3:28])=[CH:19][CH:18]=1)(=[O:10])=[O:9].Cl[C:41]([O:43][CH3:44])=[O:42]>ClCCl>[CH3:44][O:43][C:41](=[O:42])[NH:38][C:36](=[NH:37])[C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([O:29][CH:25]([C:24](=[O:39])[NH:23][C:20]2[CH:19]=[CH:18][C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:8]([CH3:7])(=[O:9])=[O:10])=[CH:22][CH:21]=2)[CH2:26][CH2:27][CH3:28])[CH:31]=1
Reactant: CCCC(Oc1cccc(C(=N)N)c1)C(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCC(Oc1cccc(C(=N)NC(=O)OC)c1)C(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1

Procedure:
1 N NaOH is added up to a pH of 9 to a solution of 500 mg (1.07 mmol) of 2-(3-carbamimidoylphenoxy) pentanoic acid (2′-methanesulfonylbiphenyl-4-yl)amide acetate (3) in 40 ml of dichloromethane kept at 5° C. 0.108 ml (1.40 mmol) of methyl chloroformate is then added. During the following hour, the pH is kept at a value of 9 by addition of further 1 N NaOH. The organic phase is then separated off, washed with water, dried over sodium sulfate and evaporated. A colourless solid is obtained; FAB 524
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1[C:13]2[NH:14][C:15]3[CH:25]=[N:24][CH:23]=[CH:22][C:16]=3/[C:17](=[N:20]/O)/[C:18](=O)[C:12]=2[CH:11]=[CH:10][CH:9]=1.[Cl:26][C:27]1[CH:34]=[C:33]([S:35][CH2:36][CH3:37])[CH:32]=[C:31]([Cl:38])[C:28]=1[CH:29]=O.C([O-])(=O)C.[NH4+:43].P(OC(C)C)(OC(C)C)(OC(C)C)=O>C(O)(=O)C.C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:26][C:27]1[CH:34]=[C:33]([S:35][CH2:36][CH3:37])[CH:32]=[C:31]([Cl:38])[C:28]=1[C:29]1[NH:20][C:17]2[C:16]3[CH:22]=[CH:23][N:24]=[CH:25][C:15]=3[NH:14][C:13]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:18]=2[N:43]=1
Reactant: O=c1/c(=N\O)c2ccncc2[nH]c2ncccc12
Reactant: CCSc1cc(Cl)c(C=O)c(Cl)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: CC(C)OP(=O)(OC(C)C)OC(C)C
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CCSc1cc(Cl)c(-c2nc3c([nH]2)-c2ccncc2Nc2ncccc2-3)c(Cl)c1
Temperature: 130 °C

Procedure:
A solution of (6Z)-5H-dipyrido[2,3-b:4′,3′-f]azepine-5,6(11H)-dione 6-oxime trifluoroacetate (200 mg, 0.4 mmol), 2,6-dichloro-4-(ethylthio)benzaldehyde (200 mg, 0.85 mmol) and ammonium acetate (0.60 g, 8.0 mmol) were stirred in acetic acid (3 mL) and heated in a microwave for 5 minutes at 130° C. Evaporation gave the crude product which was dissolved in acetonitrile (1.0 mL) and triisopropyl phosphate (100 μL, 0.4 mmol) and heated in a microwave for 5 minutes at 180° C. Purification by preparative LCMS gave the desired product LC/MS: 440 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2].[Se](=O)=[O:28]>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([C:20](=[O:28])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: O=[Se]=O
Reactant: CCOC(=O)c1cnc(Cc2ccccc2)c2cc(OC)c(OC)cc12
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc(C(=O)c2ccccc2)c2cc(OC)c(OC)cc12
Yield: 87.1 %

Procedure:
The above 1-benzyl-6,7-dimethoxyisoquinoline-4-carboxylic acid ethyl ester (77.1 mg, 0.22 mmol) was dissolved in 5 ml of acetic acid. Then selenium dioxide (36.6 mg, 1.50 eq) was added and the mixture was refluxed for 1 hr until no more starting material was left. The mixture was evaporated to dryness and the residue was extracted with ethyl acetate and sodium bicarbonate solution. The organic layer was dried over sodium sulfate and then concentrated. The residue was dissolved in 5 ml of ethyl acetate and the solution was passed through a layer of silica gel. The solution was concentrated go give a pure 1-benzoyl-6,7-dimethoxyisoquinoline-4-carboxylic acid ethyl ester (70 mg, 87%).