Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:5]1[O:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:17][N:18]=[C:19]=[S:20]>CN(C)C=O>[NH:1]([C:5]1[O:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:19]([NH:18][CH3:17])=[S:20])[CH:11]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(-c2cccc(N)c2)co1
Reactant: CN=C=S
Solvent: CN(C)C=O
Product: CNC(=S)Nc1cccc(-c2coc(NC(=N)N)n2)c1

Procedure:
Reaction of 2-guanidino-4-(3-aminophenyl)-oxazole with methylisothiocyanate in dimethylformamide gave 2-guanidino-4-[3-(3-methylthioureido)phenyl]oxazole having the following n.m.r. in d6DMSO: 2.8(d,4H); 3.25(s,H2O); 6.9(s,4H); 7.2-7.7(m,5H); 7.8(s,1H); 9.5(s,1H).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:23]([CH:25]([CH3:27])[CH3:26])[CH3:24])[CH2:19][C@H:18]2[C:28]([O:30][CH3:31])=[O:29])[C:13]1=[O:32])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:23]([CH:25]([CH3:27])[CH3:26])[CH3:24])[CH2:19][C@H:18]2[C:28]([O:30][CH3:31])=[O:29])[C:13]1=[O:32]
Reactant: COC(=O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Yield: 98.8 %

Procedure:
A solution of (1R,2S,5R)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)-cyclohexanecarboxylate (0.6 g, 1.3 mmol) in methanol was treated with 150 mg of 10% Pd/C and hydrogenated at 55 psi of H2 in a Parr shaker overnight. The catalyst was filtered and the filtrate concentrated in vacuo to give 0.4 g of (1R,2S,5R)-methyl 2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)cyclohexanecarboxylate as a white solid. This was used without further purification. MS found: (M+H)+=312.3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][C:10]=2[O:22][CH3:23])=[N:6][CH:7]=1.N1C=CC=CC=1.[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][C:39]=1[Cl:40])[C:34](Cl)=[O:35].Cl>ClCCl>[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][C:39]=1[Cl:40])[C:34]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][C:10]=2[O:22][CH3:23])=[N:6][CH:7]=1)=[O:35]
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(N)cn2)c(OC)c1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CCc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)c(OC)c1
Reaction time: 1 h

Procedure:
Under ice cooling, to a solution of ethyl 3-(4-(5-aminopyridin-2-yloxy)-3-methoxyphenyl)propionate (1.43 g, 4.5 mmol) in dichloromethane (30 mL) was added pyridine (0.44 mL, 5.4 mmol), and then 3,4-dichlorobenzoyl chloride (0.99 g, 4.7 mmol). The resulting solution was stirred for 1 hour under ice cooling, and then for 10 hours at room temperature. To the resulting reaction solution was added 10% hydrochloric acid, and extracted with dichloromethane. The dichloromethane layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated. To the residue was added diethyl ether, and stirred. The precipitates were collected by filtration. After washing with water and diethyl ether, the precipitates were air dried at 60° C., to thereby yield 0.52 g of the title compound.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:10]([OH:26])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]2[O:23][CH2:24][O:25][C:19]=2[CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CN=C1.[C:39]([Si:43]([CH3:46])([CH3:45])Cl)([CH3:42])([CH3:41])[CH3:40].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CO.C1COCC1.O>[C:1]([NH:8][C@@H:9]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:10]([O:26][Si:43]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:46])[CH3:45])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]2[O:23][CH2:24][O:25][C:19]=2[CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc2c(c1)OCO2)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@@H](Cc1ccc2c(c1)OCO2)C(=O)O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 271 mg of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(3,4-methylenedioxyphenyl)methyl]hexanoic acid in 2.13 ml of DMF is treated, while being stirred, with 338 mg of imidazole and 415 mg of tert-butyldimethylchlorosilane. After having been stirred at RT for 20 h, the reaction solution is poured onto ice-water, and this mixture is extracted with ethyl acetate. The organic phase is washed with 10% citric acid solution and saline. A crude product is obtained which is dissolved in 7.13 ml of methanol and 2.75 ml of THF, with this solution then being treated, at RT, with a solution of 485 mg of potassium carbonate in 2.75 ml of water. The reaction mixture is stirred at RT for 2 h, concentrated down to approximately half its volume and poured onto 10% citric acid solution and ice; this mixture is then extracted with ethyl acetate. The organic phase is washed with (cold) saline. After drying over sodium sulfate, the solvent is evaporated and the residue is chromatographed on silica gel (eluent C), and the title compound is obtained. TLC Rf (C)=0.27. FAB-MS (M+H)+ =572.
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:14])=[O:15])[CH2:10][N:9]1[C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([F:23])=[CH:25][CH:26]=1)=[O:7])#[N:3]
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1
Reactant: O=C(O)c1ccc(F)cc1
Agent: Cl
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)c1ccc(F)cc1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride from experiment K1 was coupled with 4-fluorobenzoic acid in analogy to experiment A1 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(4-fluoro-benzoyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a colorless oil. MS: 450.1 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(#N)C.O>[N:18]1([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:2])=[O:9])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COC(=O)CCCCBr
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(O)CCCCN1CCCCC1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
5-Bromopentanoic acid methyl ester (1.22 g) was dissolved in acetonitrile (24.4 ml) and added with potassium carbonate (1.30 g), potassium iodide (0.104 g), and piperidine (0.928 ml) and the whole was stirred at 70° C. for 2.5 hours. The reaction solution was added with water and the whole was subjected to separation/extraction with chloroform. The organic layer was washed with a saturated saline solution and then dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was again dissolved in 18% hydrochloric acid (20 ml) and the whole was refluxed under heating for 3 hours. The reaction solution was concentrated under reduced pressure. Recrystallization was performed with acetone/acetic acid, thereby obtaining a hydrochloride (1.15 g) of the subject compound as a colorless crystal.
Reaction SMILES: C(Cl)Cl.C(O)(C(F)(F)F)=O.[OH:11][C:12]1[CH:20]=[CH:19][C:18]2[N:17]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:16]=[C:15]3[CH2:30][CH2:31][N:32](C(OC(C)(C)C)=O)[CH:33]([CH3:34])[C:13]=1[C:14]=23>>[CH3:34][CH:33]1[C:13]2=[C:14]3[C:18](=[CH:19][CH:20]=[C:12]2[OH:11])[N:17]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:16]=[C:15]3[CH2:30][CH2:31][NH:32]1
Reactant: CC1c2c(O)ccc3c2c(cn3S(=O)(=O)c2ccccc2)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1NCCc2cn(S(=O)(=O)c3ccccc3)c3ccc(O)c1c23
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 50/50 mixture of DCM/TFA (1 mL) was added to tert-butyl 7-hydroxy-6-methyl-1-(phenylsulfonyl)-1,3,4,6-tetrahydro-5H-azepino[5,4,3-cd]indole-5-carboxylate, Intermediate 15 (16 mg, 0.036 mmol) and the mixture was stirred at room temperature for one hour. The solvent was evaporated at reduced pressure and the crude product was purified by preparative HPLC (Xterra C18, 10 mM NH4CO3 (pH 10)-CH3CN) to give 6.9 mg of the title compound. MS m/z 343 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([N:23]4[CH2:28][CH2:27][N:26]([CH2:29][C:30]([OH:32])=O)[CH2:25][CH2:24]4)=[O:22])=[CH:17][CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1.C1C=C[C:36]2N(O)N=[N:39][C:37]=2C=1.CCN=C=NCCCN(C)C.C(N)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([N:23]4[CH2:24][CH2:25][N:26]([CH2:29][C:30]([NH:39][CH2:37][CH3:36])=[O:32])[CH2:27][CH2:28]4)=[O:22])=[CH:19][CH:20]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)CN1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(Cl)cc4)n3)cc2)CC1
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)CN1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(Cl)cc4)n3)cc2)CC1
Reaction time: 0.5 h

Procedure:
2-{4-[(4-{[4-(4-Chlorophenyl)pyrimidin-2-yl]amino}phenyl) carbonyl]piperazinyl}acetic acid (0.200 g, 0.44 mmol) was dissolved in DMF then stirred for 15 minutes in ice-brine solution, then the HOBT (0.072 g, 0.53 mmol] then EDCI (0.102 g, 0.53 mmol) were added and stirred for another 30 minutes. Ethylamine (0.030 mL, 0.53 mmol) was added and the reaction was left to stir at room temp overnight. The reaction was quenched with 10 mL of water and a precipitate formed. The precipitate was colleted by filtration, and purified by preparative HPLC to yield 2-{4-[(4-{[4-(4-chlorophenyl)pyrimidin-2-yl]amino}phenyl)carbonyl]piperazinyl}N-ethylacetamide: HPLC Retention time; 9.508 min.(Method B) M+1; 479.2
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:20][C:21]1[CH:22]=[CH:23][C:24](O)=[N:25][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OC(C)C)=O)(C(OC(C)C)=O)=[N-]>O1CCCC1>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:24]2[CH:23]=[CH:22][C:21]([Br:20])=[CH:26][N:25]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: Oc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Agent: CC(C)OC(=O)[N+](=[N-])C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(Br)cn2)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.3 %

Procedure:
2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (2.12 g) synthesized in Example 4 and 5-bromopyridin-2-ol (1.22 g) were dissolved in tetrahydrofuran (20 mL), triphenylphosphine (2.02 g) and diisopropyl diazodicarboxylate (40% toluene solution, 4.14 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and hexane (about 10 mL) was added. The precipitated crystals were removed by filtration, and the solvent of the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1) to give the title compound (1.84 g) as a pale-yellow oil.
Reaction SMILES: [C:1]1([CH:7](Br)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:27]=2[N+:33]([O-:35])=[O:34])[CH2:18][CH2:17]1.OC1CCN(CCCOC2C=CC=CC=2[N+]([O-])=O)CC1>>[C:1]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:27]=3[N+:33]([O-:35])=[O:34])[CH2:20][CH2:21]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: Cc1cccc(OCCCN2CCC(O)CC2)c1[N+](=O)[O-]
Agent: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: Cc1cccc(OCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1[N+](=O)[O-]

Procedure:
The procedure of Example 1 (a) was repeated except for using diphenylmethyl bromide and 4-hydroxy-1-[3-(3-methyl-2-nitrophenoxy)propyl]piperidine instead of diphenylmethyl bromide and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-diphenylmethoxy-1-[3-(3-methyl-2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@:4]([N:15]=[C:16]=[O:17])([CH3:14])[CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[N+:19](=[C:21]1[N:25]=[CH:24][N:23]=[C:22]1[C:26]([NH2:28])=[O:27])=[N-:20]>CS(C)=O>[CH3:1][O:2][C:3](=[O:18])[C@:4]([N:15]1[C:16](=[O:17])[N:25]2[CH:24]=[N:23][C:22]([C:26](=[O:27])[NH2:28])=[C:21]2[N:19]=[N:20]1)([CH3:14])[CH2:5][O:6][Si:7]([C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:9])[CH3:8]
Reactant: COC(=O)[C@](C)(CO[Si](C)(C)C(C)(C)C)N=C=O
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Solvent: CS(C)=O
Product: COC(=O)[C@](C)(CO[Si](C)(C)C(C)(C)C)n1nnc2c(C(N)=O)ncn2c1=O
Reaction time: 2 h

Procedure:
To a solution of (S)-3-(tert-butyl-dimethyl-silanyloxy)-2-isocyanato-2-methyl-propionic acid methyl ester (510 mg, 1.86 mmol) in dry DMSO (1.5 mL) was added 5-diazoimidazole-4-carboxamide (135 g, 0.98 mmol) at room temperature under nitrogen. The reaction mixture was stirred for 2 hours whereupon it was poured onto crushed ice. The resultant white precipitate was collected by vacuum filtration. The filter cake was washed with water (2×1 reaction volume), EtOAc (1 reaction volume) and then Et2O (1 reaction volume) to give (S)-3-(tert-Butyl-dimethyl-silanyloxy)-2-(8-carbamoyl-4-oxo-imidazo[5,1-d][1,2,3,5]tetrazin-3-yl)-2-methyl-propionic acid methyl ester as a pale off white solid (140 mg, 34%). 1H NMR (400 MHz, d6-DMSO) δ ppm: 8.96 (CH, s, 1H), 7.91 (CONH2, s, 1H), 7.77 (CONH2, s, 1H), 5.77 (CH, dd, J=8.8 Hz, 5.6 Hz, 1H), 4.36 (CH2, dd, J=10.6 Hz, 5.6 Hz, 1H), 4.23 (CH2, dd, J=10.6 Hz, 8.8 Hz, 1H), 3.72 (CO2CH3, s, 3H), 0.72 (SiC(CH3)3, s, 9H), 0.03 (SiCH3, s, 3H), −0.06 (SiCH3, s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:26])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1.[CH:27](=O)[CH:28]([CH3:30])[CH3:29].[BH3-]C#N.[Na+].NC1C=CC=CC=1>CCOC(C)=O.[Cl-].[Cl-].[Zn+2].[BH3-]C#N.[Na+].[Cl-].[Cl-].[Zn+2].CO.C1COCC1>[CH2:27]([NH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:26])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)C=O
Reactant: COc1cccc(OCC(=O)Nc2ccc(OCCC(C)C)cc2N)c1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Product: COc1cccc(OCC(=O)Nc2ccc(OCCC(C)C)cc2NCC(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.1 %

Procedure:
A 1 L 3-neck flask fitted with a stir-bar, addition funnel, and an Ar inlet was charged with aniline 49b (11.0 g, 30.7 mmol), THF (110 mL), and MeOH (30 mL). To the resultant solution was added isobutyraldehyde (3.10 g, 3.92 mL, 43.0 mmol), and the mixture stirred 15 min at rt. Meanwhile, in a 250 mL flask fitted with a stir-bar and septum with an Ar inlet, NaCNBH3 (1M in THF, 43 mL, 43.0 mmol) was added to MeOH (100 mL) followed by ZnCl2 (1M in Et2O, 21.5 mL, 21.5 mmol) forming a cloudy mixture. After stirring 20 min, this mixture was added to the above aniline solution. The mixture was stirred overnight at rt. Another 4.0 mL isobutyraldehyde was added, followed by a second addition of the same volume of the NaCNBH3/ZnCl2 mixture as made previously. The mixture stirred at rt overnight. Another 2 mL of isobutyraldehyde was then added, and the mixture stirred overnight again. The cloudy solution was diluted with EtOAc (500 mL) and washed with saturated NaHCO3 (2×400 mL) and brine (250 mL). The solution was filtered through phase separation paper and concentrated in vacuo to a waxy, orange solid. The solid was collected with hexanes (20 mL) and rinsed with hexanes (2×10 mL). The material dried to give 10.7 g of 50b as a pale orange solid. A second crop of 1.20 g was collected (94%). 1H NMR (300 MHz, CDCl3): δ 7.85 (s, 1H), 7.31-7.23 (m, 1H), 7.16 (d, 1H), 6.65-6.56 (m, 3H), 6.33-6.24 (m, 2H), 4.70 (s, 2H), 3.96 (t, 2H), 3.82 (s, 3H), 3.75 (bt, 1H), 2.84 (t, 2H), 1.83 (nonet, 2H), 1.67 (qt, 2H), 0.97 (d, 6H), 0.95 (d, 6H) ppm. HPLC analysis (5:10:85 H2O:A1:MeOH) showed a purity of 98% with a retention time of 6.9 min.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1.[N+:12]([O-])([O-:14])=[O:13].[K+].[OH-].[Na+]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])[O-]
Reactant: Brc1ccc2c(c1)CNCC2
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc2c(cc1Br)CNCC2
Temperature: -5 °C
Yield: 96.2 %

Procedure:
In a 5 liter three neck round bottom flask, 173 g (0.813 mol) of 7-bromo-1,2,3,4-tetrahydroisoquinoline was dissolved carefully into 950 mL of concentrated sulfuric add. The resulting solution was cooled to -5° C. and a solution of 82.7 g (0.816 mol) of potassium nitrate in 1 liter of concentrated sulfuric add was added dropwise. After addition, the reaction was maintained at -5° C. for 15 minutes and poured onto 3 liters of ice. The resulting mixture was basified to pH 14 with 50% sodium hydroxide solution. The basic solution was extracted three times with 1 liter of methylene chloride. The combined organic layers were washed with 1 liter each of water and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to yield 201 g of an oil. The oil, preadsorbed onto silica gel, was charged onto a column of 4 kg of silica gel and eluted with a gradient of 1-5% methanol/methylene chloride. The fractions containing product were combined and concentrated to yield 115 g of a solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH-].[Na+]>O>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([C@@H:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CN(CCCCN)C2CCCc3cccnc32)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cnc(CN(CCCCN)[C@H]2CCCc3cccnc32)c(C)c1

Procedure:
To a solution of (S)—(N1-(3,5-dimethyl-pyridin-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine (HCl salt) (440 mg, 0.83 mmol) in water (2 mL) was added 1.0 N NaOH (5 mL). The mixture was extracted with CH2Cl2 (5×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated and provided (S)-N1-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine in quantitative yield.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH:22]=[CH2:23])=[CH:17][C:16]=3[O:24][CH3:25])[O:10]C2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(C2C=CC=CC=2)N2CC(C[Cl:45])OC2)C=CC=CC=1.C1(OC)C=C(CC=C)C=C(C([O-])=O)C=1O.[Na+].Cl>>[ClH:45].[CH3:25][O:24][C:16]1[CH:17]=[C:18]([CH2:21][CH:22]=[CH2:23])[CH:19]=[CH:20][C:15]=1[O:14][CH2:13][CH:11]([OH:10])[CH2:12][NH:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: ClCC1CN(C(c2ccccc2)c2ccccc2)CO1
Reactant: C=CCc1ccc(OCC2CN(C(c3ccccc3)c3ccccc3)CO2)c(OC)c1
Agent: C=CCc1cc(OC)c(O)c(C(=O)[O-])c1
Agent: Cl
Agent: [Na+]
Product: C=CCc1ccc(OCC(O)CNC(c2ccccc2)c2ccccc2)c(OC)c1

Procedure:
3-Diphenylmethyl-5-(2-methoxy-4-allyl-phenoxymethyl)oxazolidine from 3-diphenylmethyl-5-chloromethyl-oxazolidine and sodium eugenolate*; this produce is hydrolysed with alcoholic-aqueous hydrochloric acid to give 1-(2-methoxy-4-allyl-phenoxy)-2-hydroxy-3-diphenylmethylaminopropane hydrochloride with a melting point of 143°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])=[O:12])=[C:6](B(O)O)[CH:7]=1.[CH2:20]([O:24][C:25]1[C:30](I)=[C:29]([NH2:32])[CH:28]=[C:27]([CH3:33])[N:26]=1)[CH2:21][CH2:22][CH3:23].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:32][C:29]1[CH:28]=[C:27]([CH3:33])[N:26]=[C:25]([O:24][CH2:20][CH2:21][CH2:22][CH3:23])[C:30]=1[C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[C:11]([N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])=[O:12]
Reactant: CCCCOc1nc(C)cc(N)c1I
Reactant: CC(C)N(C(=O)c1ccc(Br)cc1B(O)O)C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCCCOc1nc(C)cc(N)c1-c1cc(Br)ccc1C(=O)N(C(C)C)C(C)C

Procedure:
To a stirred solution of {5-bromo-2-[(diisopropylamino)carbonyl]phenyl}boronic acid (0.26 g, 0.8 mmol) in dioxane (10 mL) was added 2-butoxy-3-iodo-6-methylpyridin-4-amine (0.24 g, 0.8 mmol), Cs2CO3 (0.78 g, 2.4 mmol) and Pd(dppf)Cl2 (40 mg) under a nitrogen atmosphere. The reaction mixture was stirred under reflux for 3 h, and then diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (20 mL×3). The combined extracts were washed with brine (10 mL), dried over Na2SO4, evaporated. Column chromatography (EtOAc/petroleum ether) was used for purification to afford 2-(4-amino-2-butoxy-6-methylpyridin-3-yl)-4-bromo-N,N-diisopropylbenzamide. 1HNMR (300 MHz, CDCl3) δ 7.50 (dd, J=7.9 Hz, 1.9 Hz, 1H), 7.38 (d, J=1.9 Hz, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.12 (s, 1H), 4.12 (m, 2H), 3.64 (m, 1H), 3.31 (m, 1H), 1.53 (m, 2H), 1.47 (d, J=6.8 Hz, 3H), 1.29 (m, 2H), 1.17 (d, J=6.8 Hz, 3H), 0.99 (d, J=6.8 Hz, 3H), 0.87 (t, J=7.6 Hz, 3H), 0.76 (d, J=6.4 Hz, 3H). LRMS calc'd for (C23H32BrN3O2) [M+H]+, 462; found 462.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:23]2[C:24]([F:41])=[C:25]([NH:29][S:30]([C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[F:40])(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:5]=[CH:4][N:3]=1.[NH4+:42].[OH-].C(Cl)Cl>CO>[NH2:42][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:23]2[C:24]([F:41])=[C:25]([NH:29][S:30]([C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[F:40])(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CS(=O)(=O)N1CCN(c2nc(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)N1CCN(c2nc(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c(-c3ccnc(N)n3)s2)CC1
Yield: 101.7 %

Procedure:
A solution of N-(3-{5-(2-chloro-4-pyrimidinyl)-2-[4-(methylsulfonyl)-1-piperazinyl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,5-difluorobenzenesulfonamide (0.14 g, 0.22 mmol) in NH4OH (2.5 mL, 65 mmol) was sealed in a microwave vial and irradiated at 140° C. for 12 min. LCMS analysis indicates complete conversion to product. The reaction mixture was transferred to a round bottom flask with DCM and MeOH. A precipitate formed while attempting to remove the volatiles in vacuo and it was collected by vacuum filtration. The pale yellow solid was dried in vacuo to afford the title compound (0.14 g, 100% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.76 (br. s., 1H), 7.84 (d, J=5.3 Hz, 1H), 7.46-7.61 (m, 3H), 7.38-7.46 (m, 1H), 7.22-7.34 (m, 2H), 6.59 (br. s., 2H), 5.64 (d, J=5.1 Hz, 1H), 3.60 (br. s., 4H), 3.26 (br. s., 4H), 2.92 (s, 3H). MS (ES+): 626 [M+H]+.