Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC1(C)[O:19][CH:18]([CH2:20]OS(C)(=O)=O)[CH2:17][O:16]1.C(N(CC)CC)C>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH:11][CH2:20][CH:18]([OH:19])[CH2:17][OH:16])=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)OCC(COS(C)(=O)=O)O1
Reactant: Nc1ccc(C2CCCCC2)cc1
Solvent: CCN(CC)CC
Product: OCC(O)CNc1ccc(C2CCCCC2)cc1
Reaction time: 1 h
Yield: 19.8 %

Procedure:
8.05 g (44.6 mmol) of 4-cyclohexylaniline, 12.0 g (57 mmol) of methanesulfonic acid (RS)-2,2-dimethyl-1,3-dioxolan-4-yl-methyl ester and 11.2 ml (80 mmol) of triethylamine were held at 140° in a bomb tube for 4 h. The solvent was distilled off in a water-jet vacuum and the brown oily residue was treated with 50 ml of 3N hydrochloric acid and stirred at 50° for 1 hour. After cooling the mixture was extracted twice with 250 ml of ether each time, the aqueous phase was made alkaline with 3N sodium hydroxide solution and the product was taken up in ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and the solvent was distilled off. The oily residue crystallized upon treatment with ethyl acetate/hexane. 2.2 g of crystalline (RS)-3-(4-cyclohexyl-phenylamino)-propane-1,2-diol were obtained. M.p.: 121°-122° (dec.). A further 0.65 g of crystalline product was obtained from the mother liquor.
Reaction SMILES: [CH3:1][C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[CH2:20][O:21][C@H:22]([CH3:31])[C:23](N3CCOCC3)=[O:24])=[CH:14][CH:13]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:32]([C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1)=[O:33].C1C[O:44]CC1.[OH-].[Li+]>CO.O>[CH3:1][C:2]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15](/[CH:18]=[CH:19]/[CH2:20][O:21][C@H:22]([CH3:31])[C:23]([OH:44])=[O:24])=[CH:16][CH:17]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:32](=[O:33])[C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(C(=O)c2c(C)n(Cc3ccc(/C=C/CO[C@H](C)C(=O)N4CCOCC4)cc3)c3ncccc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)c2c(C)n(Cc3ccc(/C=C/CO[C@H](C)C(=O)O)cc3)c3ncccc23)cc1
Yield: 96 %

Procedure:
The compound of Example 74-1 (33 mg, 0.06 mmol) was dissolved in methanol (1 ml) and THF (1 ml) and thereto was added 2N aqueous lithium hydroxide solution (1 ml), followed by stirring under reflux for 8 hours. The mixture was diluted with water and washed with ethyl ether. The aqueous layer was adjusted to around pH 4 with 5% aqueous potassium hydrogen sulfate solution and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo to give the subject compound (28 mg, 96%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:21]3)=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:11])=[CH:6][C:5]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][C:22]([N:28]2[CH2:29][CH2:30][N:31]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:32][CH2:33]2)=[N:21]3)=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=S(=O)(Nc1cc(-c2ccc3ncc(N4CCNCC4)nc3c2)cnc1Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2cnc3ccc(-c4cnc(Cl)c(NS(=O)(=O)c5ccccc5)c4)cc3n2)CC1
Temperature: 50 °C
Reaction time: 18 h
Yield: 6.1 %

Procedure:
To a solution of N-{2-chloro-5-[3-(1-piperazinyl)-6-quinoxalinyl]-3-pyridinyl}benzenesulfonamide (0.23 mmol), triethylamine (0.92 mmol), in dichloromethane (5 ml) was added methanesulfonyl chloride (0.25 mmol), which stirred at 50° C. for 18 hours. The reaction was cooled to ambient temperature, concentrated, redissolved in methanol and purified on reverse phase HPLC (0.1% ammonium hydroxide/water in acetonitrile). The desired fractions were combined and concentrated to give the title compound (7.8 mg, 2%) as a white solid. MS(ES)+ m/e 560.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)[N:7]([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:6]=1[CH3:32])=O.[N:33]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[N:33]1([NH:39][C:3]([C:5]2[C:9]([CH3:10])=[C:8]([C:11]3[CH:12]=[C:13]([C:21]([F:23])([F:24])[F:22])[CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=3)[N:7]([CH2:25][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)[C:6]=2[CH3:32])=[O:2])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: COC(=O)c1c(C)c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n(CC2CCCCC2)c1C
Reactant: NN1CCCCC1
Product: Cc1c(C(=O)NN2CCCCC2)c(C)n(CC2CCCCC2)c1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was synthesized in analogy to example 203, from 5-(3,5-bis-trifluoromethyl-phenyl)-1-cyclohexylmethyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid methyl ester and 1-piperidinamine as R1R2NH, MS (ISP) 530.4 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].[Li]N([Si](C)(C)C)[Si](C)(C)C.[NH:34](C(OC(C)(C)C)=O)[C@H:35]([C:43]([O:45]N1C(=O)CCC1=O)=[O:44])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1>[NH2:34][C@H:35]([C:43]([OH:45])=[O:44])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 0.08 h

Procedure:
To a solution of oxycodone-freebase (1.0 eq) in tetrahydrofuran (THF) (10 ml/mmol) was added LiN(TMS)2 (3.5 eq). After 5 minutes, Boc-Phe-OSu (3.5 eq) was added. The reaction was stirred at ambient temperatures for 18 hours, quenched with water and solvents removed. Crude protected product was purified using reverse-phase HPLC. Deprotection occurred with 4N HCl in dioxane (20 ml/mmol) to obtain Phe-Oxycodone.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[N:6][C:5]=1[F:19].[AlH4-].[Li+].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[F:19][C:5]1[C:4]([CH2:3][OH:2])=[CH:9][CH:8]=[C:7]([NH:10][C:11]2[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[N:6]=1
Reactant: COC(=O)c1ccc(Nc2ccc(OC)nc2)nc1F
Agent: O=S(=O)([O-])[O-]
Agent: [AlH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Nc2ccc(CO)c(F)n2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To 2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-nicotinic acid methyl ester (54, 1.20 g, 4.33 mmol) in 50.0 mL of tetrahydrofuran, lithium tetrahydroaluminate (8.66 mL, 1.00 M in tetrahydrofuran, 8.66 mmol) is added and the reaction is stirred at room temperature for 3 hours. Sodium sulfate decahydrate (5 g) is added and after 1 hour, the reaction is filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (55, 700 mg). MS (ESI) [M+H+]+=250.1.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]=1[N+:19]([O-])=O)(=O)C.[OH-].[Na+]>CO>[NH2:19][C:6]1[CH:7]=[CH:8][C:9]([S:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:10][C:5]=1[NH2:4]
Reactant: CC(=O)Nc1cc(Sc2ccc(C)cc2)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(Sc2ccc(N)c(N)c2)cc1
Reaction time: 0.08 h

Procedure:
3.5 G. of 2-acetamido-4-(p-methylthiophenoxy)-1-nitrobenzene is treated on the steam bath with 7 ml. 5N sodium hydroxide and 50 ml. methanol for 1 hour. The mixture is concentrated, diluted with water and the 2-amino-4-(p-methylthiophenoxy)-1-nitrobenzene filtered off. This material is treated in 18 ml. concentrated hydrochloric acid with 18 g. stannous chloride on the steam bath for 5 minutes. The mixture is cooled, decanted and the solid washed with 18 ml. 6N hydrochloric acid. The free base is liberated by treatment with potassium bicarbonate and extracted into chloroform. Evaporation of the chloroform leaves crystalline 1,2-diamino-4-(p-methylthiophenoxy)-benzene.
Reaction SMILES: [N:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:14]3[O:15][CH2:16][CH2:17][CH2:18][C:13]3=[N:12][C:4]=1[CH:5]=[N+:6]2[O-].ClC(Cl)(Cl)C([N:23]=C=O)=O>ClCCl>[N:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:14]3[O:15][CH2:16][CH2:17][CH2:18][C:13]3=[N:12][C:4]=1[C:5]([NH2:23])=[N:6]2
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: [O-][n+]1cc2nc3n(c2c2ncccc21)OCCC3
Solvent: ClCCl
Product: Nc1nc2cccnc2c2c1nc1n2OCCC1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 9,10-dihydro-8H-[1,2]oxazino[2′,3′:1,2]imidazo[4,5-c][1,5]naphthyridine 5-oxide (0.13 g, 0.54 mmol) in dichloromethane (10 mL) was added trichloroacetyl isocyanate (0.08 mL, 0.67 mmol). After 1.5 hours, the solution was concentrated under reduced pressure and methanol (4 mL) and sodium methoxide (2 drops of a 25% w/w solution in methanol) were added with stirring. After 18 hours the solution was concentrated under reduced pressure. The resulting solid was recrystallized from methanol/ethyl acetate to provide 9,10-dihydro-8H-[1,2]oxazino[2′,3′:1,2]imidazo[4,5-c]-1,5-naphthyridin-6-amine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[C:12]([F:42])=[C:13]([C:35]2[C:36]([F:41])=[N:37][CH:38]=[CH:39][CH:40]=2)[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:32]=[CH:33][CH:34]=2)[C:22]([O:24]CC2C=CC=CC=2)=[O:23])(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[C].[Pd]>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[C:12]([F:42])=[C:13]([C:35]2[C:36]([F:41])=[N:37][CH:38]=[CH:39][CH:40]=2)[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:32]=[CH:33][CH:34]=2)[C:22]([OH:24])=[O:23])(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(C(=O)OCc3ccccc3)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CN(Cc1cn(S(=O)(=O)c2cccc(C(=O)O)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of benzyl 3-{[4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-3-fluoro-2-(2-fluoropyridin-3-yl)-1H-pyrrol-1-yl]sulfonyl}benzoate (1.03 g) in ethanol (5 mL) was added 10% palladium carbon (50% containing water, 200 mg), and the mixture was stirred for 1 hr under a hydrogen atmosphere. The reaction mixture was filtrated, and concentrated under reduced pressure to give the title compound as a colorless solid (yield 866 mg, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:17]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[CH:18][N:19]=1)[C:5]([NH:7][O:8][CH2:9][C@H:10]1[CH2:14]OC(C)(C)[O:11]1)=[O:6].FC(F)(F)[C:31](O)=[O:32].CCOC(C)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:17]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[CH:18][N:19]=1)[C:5]([NH:7][O:8][CH2:9][CH:10]([OH:11])[CH2:14][CH2:31][OH:32])=[O:6]
Reactant: O=C(O)C(F)(F)F
Reactant: CC1(C)OC[C@H](CONC(=O)c2cc(Br)ncc2Nc2ccc(I)cc2F)O1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NOCC(O)CCO)c1cc(Br)ncc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
2-Bromo-N-(2,4-dihydroxy-butoxy)-5-(2-fluoro-4-iodo -phenylamino)-isonicotinamide was synthesized as described in General method 3: To a solution of 2-bromo-N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-5-[(2-fluoro-4-iodophenyl)amino]-isonicotinamide (100.0 mg, 0.18 mmol) in dichloromethane (1 ml) was added trifluoroacetic acid (1 ml) at RT. The reaction mixture was stirred at RT for 30 min, and monitored by TLC (Hex:EtOAc=1:1 and contain TEA). Upon completion, the volatiles were evaporated, and the residue was dissolved in dichloromethane, washed with 5% aq. NaHCO3 to get a precipitate. The residue was filtered, washed with water, and dried to get 53 mg (56%) of 2-Bromo-N-(2,4-dihydroxy-butoxy)-5-(2-fluoro-4-iodo-phenylamino)-isonicotinamide. LC/MS: [8.76 min, 541 (M+1)]
Reaction SMILES: NC1N=C(C2C=CC3N(C4C=C(C5C=CC=CC=5CO)N=CN=4)C=NC=3C=2)C=CN=1.C1(NC(N2C[CH2:44][CH2:43][CH:42]([CH:46]([NH:48][C:49]3[N:54]=[C:53]([N:55]4[C:59]5[CH:60]=[CH:61][C:62](C6C=CN=C(N)C=6)=[CH:63][C:58]=5[N:57]=[CH:56]4)[CH:52]=[CH:51][N:50]=3)C)C2)=O)C=CC=CC=1>>[CH:42]1([CH2:46][NH:48][C:49]2[N:54]=[C:53]([N:55]3[C:59]4[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=4[N:57]=[CH:56]3)[CH:52]=[CH:51][N:50]=2)[CH2:43][CH2:44]1
Reactant: CC(Nc1nccc(-n2cnc3cc(-c4ccnc(N)c4)ccc32)n1)C1CCCN(C(=O)Nc2ccccc2)C1
Agent: Nc1nccc(-c2ccc3c(c2)ncn3-c2cc(-c3ccccc3CO)ncn2)n1
Product: c1ccc2c(c1)ncn2-c1ccnc(NCC2CC2)n1

Procedure:
2-[1-(1-(N-naphth-1-yl)carbamoyl)piperidin-3-yl)ethylamino]-4-[5-(2-aminopyrimidin-4-yl)benzimidazol-1-yl]-6-[2-hydroxymethylphenyl]pyrimidine; 2-[1-(1-(N-phenylcarbamoyl)piperidin-3-yl)ethylamino]-4-[5-(2-aminopyridin-4-yl)benzimidazol-1-yl]pyrimidine;
Reaction SMILES: [NH:1]1[CH2:16][CH2:15][CH2:14][CH:3]([C:4]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH2:2]1.F[C:18]1[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]>>[CH3:23][O:22][C:20]([C:19]1[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=1[N:1]1[CH2:16][CH2:15][CH2:14][CH:3]([C:4]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH2:2]1)=[O:21]
Reactant: COC(=O)c1ccccc1F
Reactant: O=C(OCc1ccccc1)C1CCCNC1
Product: COC(=O)c1ccccc1N1CCCC(C(=O)OCc2ccccc2)C1
Yield: 17.3 %

Procedure:
Using benzyl nipecotate (5.90 g, 26.9 mmol) and methyl 2-fluorobenzoate (3.70 mL, 29.0 mmol), the same procedure was followed as in Step 1c of Example 1 to give 1.64 g (17%) of the desired compound as a colorless oil.
Reaction SMILES: O1B([C@@H](NC(=O)[C@@H](NC(C2C=NC=CN=2)=O)CC2C=CC=CC=2)CC(C)C)[O:5][B:4]([C@@H:32]([NH:37][C:38](=[O:56])[C@@H:39]([NH:47][C:48]([C:50]2[CH:55]=[N:54][CH:53]=[CH:52][N:51]=2)=[O:49])[CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:33][CH:34]([CH3:36])[CH3:35])[O:3]B1[C@@H](NC(=O)[C@@H](NC(C1C=NC=CN=1)=O)CC1C=CC=CC=1)CC(C)C.[C:82](O)(=[O:90])[C@@H:83]([C@H:85]([C:87]([OH:89])=[O:88])[OH:86])O.CCCCCCC>CC(C)=O>[OH:86][C@H:85]([C@@H:83]1[C:82](=[O:90])[O:3][B:4]([C@@H:32]([NH:37][C:38](=[O:56])[C@@H:39]([NH:47][C:48]([C:50]2[CH:55]=[N:54][CH:53]=[CH:52][N:51]=2)=[O:49])[CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:33][CH:34]([CH3:35])[CH3:36])[O:5]1)[C:87]([OH:89])=[O:88]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B1OB([C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)c2cnccn2)OB([C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)c2cnccn2)O1
Solvent: CCCCCCC
Solvent: CC(C)=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B1OC(=O)[C@@H]([C@@H](O)C(=O)O)O1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of N,N′,N″-(boroxin-2,4,6-triyltris{[(1R)-3-methylbutane-1,1-diyl]imino[(2S)-1-oxo-3-phenylpropane-1,2-diyl]})tripyrazine-2-carboxamide (0.270 g, 0.246 mmol) and L-tartaric acid (149.5 mg, 0.33 mmol) were mixed in acetone (3 mL). The mixture was heated to form a solution. The solution was cooled uncontrolled until the internal temperature was about 25° C. Heptane (2.5 mL) was added. White solid precipitated out and the resultant slurry was agitated at ambient temperature for 1.5 h. The slurry was filtered to collect solid (R)-2-hydroxy-2-((R)-2-((R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido)butyl)-5-oxo-1,3,2-dioxaborolan-4-yl)acetic acid (0.388 g) which also contained a dimeric species. MS (m/z) in CH3CN: [M+H] calculated for C23H28BN4O8, 499.2000. found, 499.2.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:8]2[CH:9]=[C:10]([O:14][CH3:15])[C:11](Br)=[CH:12][C:7]=2[N:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][C:4]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:22][CH3:23])[CH2:3]1.C([O-])([O-])=O.[Cs+].[Cs+].[C:35]([O:39]CC)(=[O:38])[CH2:36][SH:37]>CN(C=O)C.O>[O:1]=[S:2]1(=[O:28])[C:8]2[CH:9]=[C:10]([O:14][CH3:15])[C:11]([S:37][CH2:36][C:35]([OH:39])=[O:38])=[CH:12][C:7]=2[N:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][C:4]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:22][CH3:23])[CH2:3]1
Reactant: CCOC(=O)CS
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OC)cc2S(=O)(=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(SCC(=O)O)c(OC)cc2S(=O)(=O)C1
Temperature: 25 °C
Reaction time: 0.13 h
Yield: 50.6 %

Procedure:
1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (113 mg, 0.24 mmol), Cs2CO3 (170 mg, 0.52 mmol) and ethyl thioglycolate (0.060 ml, 0.54 mmol) in DMF (4.0 ml) were subjected to microwave irradiation in a Smith Synthesiser at 80° C. for 3 min and then at 90° C. for 8 min. The reaction mixture was diluted with water (250 ml) and extracted with DCM (5×10 ml) and collected organic layers were dried (MgSO4), concentrated and purified on a short column (petroleum ether: EtOAc 4:1→2:1). The resulting product was dissolved in THF (2 ml) and water (2 ml) and NaOH (aq., 0.5 ml, 1 M) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with HCl (1 M) and the reaction mixture was diluted with water (10 ml) and extracted with DCM (3×3 ml). Purification with preparative HPLC yielded the title compound (58 mg, 59%). NMR (300 MHz, CD3OD) 0.81 (m, 6H), 1.00–1.70 (m, 8H), 3.21 (m, 2H), 3.42 (m, 2H), 3.71 (m, 2H), 3.92 (s, 3H), 6.88 (m, 2H), 7.02 (m, 2H), 7.23 (t, 2H), 7.40 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].C[Si]([C:15]#[N:16])(C)C.CCCCCC.CCOC(C)=O>CO>[OH:6][CH:5]([C:4]1[CH:7]=[CH:8][C:9]([F:10])=[C:2]([F:1])[CH:3]=1)[C:15]#[N:16]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: C[Si](C)(C)C#N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: N#CC(O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 3,4-difluorobenzaldehyde (2.86 g, 20.0 mmol) in MeOH (20 mL)in a round bottom flask was added trimethylsilyl cyanide (4.0 mL., 30.0 mmol) at 0° C. The reaction mixture was stirred at room temperature for 10 h when TLC analysis indicated that the reaction was complete (Rf=0.4, 3:2 hexane/EtOAc). Solvent was removed in vacuo and hydroxy-(3,4-difluorophenyl)-acetonitrile was obtained as a colorless liquid (crude wt.=3.4 g). It was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([C:16]#[N:17])=[C:4]([SH:18])[N:3]=1.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[S:24][CH:25]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[S:24][CH:25]=2)[N:3]=1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1C1CCCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2.00 g (5.42 mmol) of the compound from Example 33A are initially charged in 111 ml of dry DMF, and 1.46 g (5.96 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 1.82 g (21.68 mmol) of sodium bicarbonate are added. The reaction mixture is stirred at RT for 12 h. The mixture is then diluted with 20 ml of water and extracted twice with in each case 100 ml of ethyl acetate. The combined organic phases are washed once with 15 ml of saturated aqueous sodium bicarbonate solution and dried over magnesium sulfate. After removal of the solvent the residue is purified chromatographically on silica gel 60 (mobile phase: gradient cyclohexane/ethyl acetate 50:1→2:1).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[C:8]([F:16])[CH:7]=1)[CH2:3][CH2:4][OH:5].[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19].CCN(C(C)C)C(C)C.C(Cl)Cl>CN(C1C=CN=CC=1)C.O>[Si:21]([O:5][CH2:4][CH2:3][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[C:8]([F:16])[CH:7]=1)[NH2:1])([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NC(CCO)c1ccc(C(F)(F)F)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCCC(N)c1ccc(C(F)(F)F)c(F)c1
Yield: 70.9 %

Procedure:
solution of 276 (0.200 g, 0.843 mmol), TBDMS-Cl (0.153 g, 1.01 mmol), DIPEA (0.294 mL, 1.69 mmol), DMAP (0.0103 g, 0.0843 mmol) and DCM (6 mL) was stirred for 1 h at RT and then poured into H2O, and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (500:5) to afford 0.210 g (70.9%) of 3-(tert-butyldimethylsilyloxy)-1-(3-fluoro-4-(trifluoromethyl)phenyl)propan-1-amine (278).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].CN(C1C=CC=CN=1)C.[C:20](Cl)(=[O:23])[O:21][CH3:22].O>CN(C)C(=O)C>[Cl:10][C:7]1[CH:8]=[CH:9][C:2]([NH:1][C:20](=[O:23])[O:21][CH3:22])=[C:3]([C:4]#[N:5])[CH:6]=1
Reactant: N#Cc1cc(Cl)ccc1N
Reactant: COC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)Nc1ccc(Cl)cc1C#N
Temperature: 90 °C
Reaction time: 5 h

Procedure:
(Step 1) To a solution of 2-amino-5-chlorobenzonitrile (1.95 g) and dimethylaminopyridine (20.3 mg) in N,N-dimethylacetamide (15 ml) was added dropwise methyl chlorocarbonate (3.5 ml) at room temperature, and the mixture was stirred at 90° C. for 5 hr. The mixture was allowed to cool to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:20-1:4) to give methyl (4-chloro-2-cyanophenyl)carbamate (1.21 g) as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]=2[O:4][CH2:3]1.[CH:15](=O)[CH3:16].[BH3-]C#N.[Na+]>>[CH2:15]([N:7]1[C:6]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]=2[O:4][CH2:3][CH:2]1[CH3:1])[CH3:16]
Reactant: CC=O
Reactant: CC1COc2cc([N+](=O)[O-])ccc2N1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN1c2ccc([N+](=O)[O-])cc2OCC1C
Yield: 64.8 %

Procedure:
This compound was prepared by General Method 3 (EXAMPLE 1) from (±)-3,4-dihydro-3-methyl-7-nitro-2H-1,4-benzoxazine (200 mg, 1.0 mmol), acetaldehyde (455 mg, 10.3 mmol) and NaBH3CN (314 mg, 5.0 mmol) to afford 144 mg (63%) of 4-ethyl-3,4-dihydro-3-methyl-7-nitro-2H-1,4-benzoxazine. Data for (±)-4-ethyl-3,4-dihydro-3-methyl-7-nitro-2H-1,4-benzoxazine: Rf 0.80 (3:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 7.80 (dd, 1H, J=8.9, 2.6), 7.66 (d, 1H, J=2.6), 6.55 (d, 1H, J=9.2), 4.07 (dd, 1H, J=10.7,2.5), 3.96 (dd, 1H, J=10.7, 2.6), 3.60 (m, 1H), 3.55-3.35 (m, 2H), 1.29 (d, 3H, J=6.6), 1.24 (t, 3H, J=7.0).