Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:20]=2[N:21]=1.[H-].[Na+].CN(C=O)C>C1COCC1.O>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([O:14][C:17]2[S:18][C:19]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:20]=3[N:21]=2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: COc1cccc2sc(Cl)nc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cccc2sc(O[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
trans-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester (2.15 g, 10 mmol) and 2-chloro-4-methoxybenzothiazole (1.99 g, 10 mmol) were dissolved in THF (50 ml) and cooled to 0° C. At this temperature, NaH dispersion (960 mg, 2.2 eq) was added portionwise and the mixture was heated at 60° C. for 2 h. DMF (20 ml) was added and heating was continued for 1 h. The mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. Purification by chromatograpy on SiO2 (hex/EtOAc 4:1, 2:1) gave 1 g (26%) of a beige solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:22])[N:14]([CH2:18][C:19]([OH:21])=O)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:64]([CH:66]([CH2:69][CH3:70])[CH2:67][NH2:68])[CH3:65]>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]1[C:13](=[O:22])[N:14]([CH2:18][C:19]([NH:68][CH2:67][CH:66]([CH2:69][CH3:70])[CH2:64][CH3:65])=[O:21])[CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O
Reactant: CCC(CC)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)CNC(=O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3.70 g of 2-(3-(benzyloxycarbonylamino)-2-oxopyridin-1(2H)-yl)acetic acid (˜11.2 mmol), 3.58 g of TBTU (11.2 mmol), 1.51 g of HOBt (11.2 mmol) is dissolved in 60 mL of DMF. By addition of 5.70 mL of DIPEA (33.5 mmol, 3 eq) a pH value is adjusted to ˜10. 1.50 mL of 2-ethyl-butylamine (11.2 mmol) is added and the mixture is stirred at RT overnight. The solvent is removed in vacuo and the obtained residue is taken up in 300 mL of DCM and subsequently washed with 10% citric acid (3×75 mL), saturated NaHCO3 solution (3×75 mL) and brine (75 mL). The organic phase is dried over Na2SO4, filtered and concentrated in dryness. Pale brown solid is obtained and it is suitable for further processing without further purification.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:7]([O:9]N1C(=O)CCC1=O)=O)[CH2:3][CH:4]([CH3:6])[CH3:5].C([O-])([O-])=O.[Na+].[Na+].[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34]>O1CCCC1>[C:20]([O:19][C:17]([NH:1][C@H:2]([C:7]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:18])([CH3:21])([CH3:22])[CH3:23]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: NCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCCC(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Boc-L-Leu-OSu (5 g, 15.24 mmol) was dissolved in a solution (200 ml) containing equal volumes of tetrahydrofuran and 5% Na2CO3. β-Alanine (2.71 g, 30.48 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. The organic solvent was removed in vacuo and the resulting aqueous solution was washed with diethyl ether (2×50 ml). On acidification with 5% NaHSO4, the product precipitated and was extracted into ethyl acetate (150 ml). The organic layer was washed with brine and dried over magnesium sulphate. On reduction to dryness, Boc-Leu-β-Ala was initially obtained as a clear oil but on standing at -20° C., formed an amorphous solid. The product was judged homogeneous by tlc in chloroform/methanol (4:1) (Rf 0.514) or chloroform/methanol (1:1) (Rf 0.554). Yield 2.89 g (63%), m.p. 91°-92° C. (Found: C, 55.61; H, 8.61; N, 9.29. C14H26O5N2 requires C, 55.63; H, 8.61; N, 9.27%).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][C:10]([NH2:13])([CH3:12])[CH3:11].[CH2:14]([O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26](Cl)=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=[N:29]2)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[NH2:13][C:10]([CH3:12])([CH3:11])[CH2:9][NH:8][C:26]1[C:25]2[C:30](=[CH:31][C:22]([O:21][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:23][CH:24]=2)[N:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33]
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Reactant: CC(C)(N)CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(N)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Reaction time: 8 h
Yield: 73.6 %

Procedure:
Triethylamine (12.8 mL, 92.0 mmol) and 1,2-diamino-2-methylpropane (5.29 mL, 50.6 mmol) were added sequentially to a solution of 7-benzyloxy-4-chloro-3-nitroquinoline (14.5 g, 46.0 mmol) in dichloromethane (400 mL). The reaction mixture was stirred overnight and then concentrated under reduced pressure. The residue was partitioned between water (200 mL) and dichloromethane (300 mL). The organic layer was washed with brine, dried over sodium sulfate, and then concentrated under reduced pressure to provide crude product as a brown solid. The crude product was passed through a layer of silica gel (eluting sequentially with chloroform and 96:4 chloroform:methanol) to provide 12.4 g of (2-amino-2-methylpropyl)(7-benzyloxy-3-nitroquinolin-4-yl)amine as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[N+:21]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:27](O)=O)([O-:23])=[O:22]>>[N+:21]([C:24]1[CH:25]=[C:26]([C:27]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1)([O-:23])=[O:22]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cc([N+](=O)[O-])cc(C(F)(F)F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 65 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-nitro-5-(trifluoromethyl)benzoic acid: MS (ESI): m/z 482 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35](O)=[O:36])[CH:12]=[CH:13][CH:14]=1.[NH2:39][C:40]1[CH:45]=[CH:44][N:43]([CH3:46])[C:42](=[O:47])[CH:41]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:46][N:43]1[CH:44]=[CH:45][C:40]([NH:39][C:35]([CH:16]2[CH:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:38])[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17]2)=[O:36])=[CH:41][C:42]1=[O:47]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Cn1ccc(N)cc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)cc1=O
Yield: 14.2 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 52c (0.2 g, 0.43 mmol) was vented with 4-amino-1-methyl-1H-pyridin-2-one (Molbridge) (0.11 g, 0.86 mmol), HATU (0.29 g, 0.77 mmol) and iPr2NEt (0.15 mL, 0.86 mmol) in CH2Cl2 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-amide as a white solid (35 mg, 14%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](Cl)(Cl)=[S:11].C(N(C(C)C)C(C)C)C>>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[N:4]=[C:10]=[S:11]
Reactant: Nc1ccc(F)cc1Cl
Reactant: S=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(N=C=S)c(Cl)c1
Yield: 46.6 %

Procedure:
The title compound was prepared following the procedure described for intermediate-2 using 2-chloro-4-fluoro aniline (5.0 g, 34.48 mmol), thiophosgene (3.95 g, 34.34 mmol), N-ethyl di-isopropyl amine (8.80 g, 68.00 mmol) to afford 3.0 g of the desired product.
Reaction SMILES: C([O:8][C:9]1[C:13]([O:14]CC2C=CC=CC=2)=[C:12]([C:22]2[N:23]=[N:24][NH:25][N:26]=2)[N:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:10]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36])C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[C:13]([OH:14])=[C:12]([C:22]2[N:23]=[N:24][NH:25][N:26]=2)[N:11]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C:10]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(-c2nn[nH]n2)n1-c1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1c(O)c(O)c(-c2nn[nH]n2)n1-c1ccc(OC)cc1

Procedure:
A solution of ethyl 3,4-bis(benzyloxy)-1-(4-methoxyphenyl)-5-(2H-tetrazol-5-yl)-1H-pyrrole-2-carboxylate (UL1-090) (85 mg, 0.16 mmol) in MeOH (6 mL) was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 40° C. under H2 (full H2 mode). The output was concentrated in vacuo. The crude material was dissolved in DCM (5 mL) and washed with 1M HCl (aq.), brine (5 mL), sat. NaHCO3 (aq.) (5 mL), the basic aqueous layer was acidified with 1M HCl (aq.) (5 mL) and washed with DCM (2×5 mL), the combined organics were dried (MgSO4), filtered and solvents removed in vacuo to afford ethyl 3,4-dihydroxy-1-(4-methoxyphenyl)-5-(2H-tetrazol-5-yl)-1H-pyrrole-2-carboxylate (UL1-089) (45 mg, 79%) as a white solid: m/z 346 (M+H)+ (ES+); 344 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 9.30 (br s, 1H), 8.67 (s, 1H), 7.10-7.05 (m, 2H), 6.87-6.81 (m, 2H), 4.02 (q, J=7.1 Hz, 2H), 3.76 (s, 3H), 0.99 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:2].[Br:11]Br>C(Cl)(Cl)Cl>[Br:11][C:8]1[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=[CH:6][C:7]=1[OH:10]
Reactant: BrBr
Reactant: CCOc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(O)c(Br)c1
Reaction time: 2 h

Procedure:
To a solution of 4-(ethyloxy)phenol (Commercial eg Aldrich) (1.0 g) in chloroform (5 ml) cooled to 0° C. was added bromine (1.26 g) dropwise over 20 min. The resulting mixture was stirred at 25 C for 2 h, before washing sequentially with aqueous sodium bicarbonate, and brine. The organics were dried over sodium sulphate, filtered and concentrated in vacuo to yield the title compound, 1.8 g
Reaction SMILES: [S:1]1[C:5]([CH2:6][C:7]([OH:9])=O)=[CH:4][N:3]=[CH:2]1.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:29][O:30][C:31](=[O:47])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][C@@H:39]2[CH2:44][CH2:43][CH2:42][CH2:41][C@H:40]2[CH3:45])=[C:34]([NH2:46])[CH:33]=1.Cl>CN(C=O)C.O.C(Cl)CCl>[CH3:29][O:30][C:31](=[O:47])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][C@@H:39]2[CH2:44][CH2:43][CH2:42][CH2:41][C@H:40]2[CH3:45])=[C:34]([NH:46][C:7](=[O:9])[CH2:6][C:5]2[S:1][CH:2]=[N:3][CH:4]=2)[CH:33]=1
Reactant: O=C(O)Cc1cncs1
Reactant: COC(=O)c1ccc(N[C@@H]2CCCC[C@H]2C)c(N)c1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(N[C@@H]2CCCC[C@H]2C)c(NC(=O)Cc2cncs2)c1
Reaction time: 48 h
Yield: 94.2 %

Procedure:
To a solution of 0.49 g of thiazol-5-yl-acetic acid in 10 ml of dry DMF 0.27 g of HOAT, 0.79 g of EDC and 1 ml of DIPEA were added at 0° C. After 30 min 0.9 g of 3-Amino-4-((1R,2R)-2-methyl-cyclohexylamino)-benzoic acid methyl ester were added, followed by the addition of 1 ml of DIPEA and the reaction was stirred at it for 48 h. The reaction was then poured into water, brought to pH3 by the addition of 2 M aqueous hydrochloric acid and extracted with ethyl acetate three times. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and concentrated to obtain 1.25 g (94%) of 4-((1R,2R)-2-Methyl-cyclohexylamino)-3-(2-thiazol-5-yl-acetylamino)-benzoic acid methyl ester, which was used without further purification.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]=1.[C:19]1([NH:25][C:26]#[N:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[ClH:1].[NH2:2][C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:26]([NH:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[NH:27])=[CH:12][CH:13]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]=1
Reactant: N#CNc1ccccc1
Reactant: Nc1ccc(-n2c(N)nc3ccccc32)cc1
Agent: Cl
Solvent: CC#N
Product: N=C(Nc1ccccc1)Nc1ccc(-n2c(N)nc3ccccc32)cc1

Procedure:
A mixture of 2-Amino-1-(4-aminophenyl)benzimidazole Hydrochloride (1.58 g, 6.06 mmol), phenylcyanamide (2.79 g, 23.6 mmol) and acetonitrile (10 ml) was refluxed for 3 days. The solid product was filtered off. The product was recrystallized from acetonitrile (300 ml). Yield 1.3 g, 57%. M.p. 265-267° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([C@H:12]1[O:16][C:15](=[O:17])[C@H:14]([CH2:18][CH2:19][CH3:20])[CH2:13]1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@H:10]([O:11][S:29]([CH3:28])(=[O:31])=[O:30])[C@@H:12]1[CH2:13][C@@H:14]([CH2:18][CH2:19][CH3:20])[C:15](=[O:17])[O:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC[C@@H]1C[C@@H]([C@H](O)COCc2ccccc2)OC1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCC[C@@H]1C[C@@H]([C@@H](COCc2ccccc2)OS(C)(=O)=O)OC1=O
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution of 12.1 g of (3R,5S)-5-[(R)-2-benzyloxy-1-hydroxyethyl]-3-propyldihydrofuran-2-one obtained in Example (116c) (43.5 mmol) in methylene chloride (300 ml) was cooled in an ice bath. Then, 13.2 g of triethylamine (131 mmol) and 7.30 g of methanesulfonyl chloride (63.7 mmol) were added thereto, and the mixture was stirred at the same temperature for one hour. 500 ml of water was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=4/1-1/1) to obtain 15.2 g of the title compound (yield: quant.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[CH2:10][C:11](Cl)=[O:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH:1]1[C:11](=[O:12])[CH2:10][O:8][C:3]2[N:4]=[CH:5][CH:6]=[CH:7][C:2]1=2
Reactant: O=C(Cl)CCl
Reactant: Nc1cccnc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1COc2ncccc2N1
Yield: 27.7 %

Procedure:
In a 20 ml flask equipped with a reflux apparatus, 3-amino-pyridin-2-ol (300 mg, 2.72 mmol) was dissolved in acetonitrile (27 ml). To the reaction solution was added chloroacetyl chloride (0.24 ml, 3.0 mmol) dropwise at room temperature, followed by Potassium carbonate (940 mg, 6.80 mmol). The mixture was heated at 1000 for 15 hours. After completion of the reaction, acetonitrile was evaporated under the reduced pressure. To the residue was added water and then the mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure to obtain white solid (113 mg, 28%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]1([O:16][C:17]2[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[NH2:20])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH:11]1([O:16][C:17]2[CH:18]=[C:19]([NH:20][C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=3)[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: COc1ccc(N)cc1OC1CCCC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(Nc2ncccc2[N+](=O)[O-])cc1OC1CCCC1
Yield: 32.9 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (2.17 g), 3-cyclopentyloxy-4-methoxyaniline (2.58 g) and potassium carbonate (2.6 g) in 1,4-dioxane (30 ml) was stirred under reflux for 20 hours. After cooling, insoluble materials were removed by filtration and the filtrate was concentrated. The resultant solid was collected and washed with isopropyl ether to give 2-[(3-cyclopentyloxy-4-methoxyphenyl)amino]-3-nitropyridine (1.35 g) as an orange solid.
Reaction SMILES: [NH2:1][C@H:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=O.B.C1COCC1.CO>C1COCC1>[C:13]1([C@@H:2]([NH2:1])[CH2:3][NH:4][CH2:5][CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N[C@@H](CNC(=O)C1CCOCC1)c1ccccc1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: N[C@@H](CNCC1CCOCC1)c1ccccc1
Temperature: 25 °C
Yield: 71.3 %

Procedure:
(R)-tetrahydro-pyran-4-carboxylic acid (2-amino-2-phenyl-ethyl)-amide (450 mg, 1.82 mmol) was dissolved in dry THF; and 5.45 ml of borane-THF complex (1M in THF, 5.45 mmol) was added. The solution was refluxed for 3 hours. The reaction was then cooled to room temperature. Methanol (7 ml) was added slowly through the condenser, and the reaction brought to reflux for a further 15 minutes. The reaction was again cooled to room temperature; and the volatiles were removed under high vacuum. More methanol was added and subsequently evaporated (3×15 ml). The resulting residue was dissolved in ethylenediamine (7 ml) and the solution was heated to 60° C. for 20 minutes. The reaction was then quenched with the addition of a saturated aqueous solution of NaHCO3. This aqueous phase was extracted with DCM; and the organic extracts dried over Na2SO4. The solvent was removed in vacuo to give the crude product. Purification by flash chromatography over silica gel afforded (R)-1-Phenyl-N2-(tetrahydro-pyran-4-ylmethyl)-ethane-1,2-diamine (304 mg, 72%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].[C:11](=O)(OC(Cl)(Cl)Cl)[O:12]C(Cl)(Cl)Cl.O1CCOCC1>CO>[Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([F:10])[C:3]=1[N:4]=[C:11]=[O:12]
Reactant: Nc1c(F)cc(Cl)cc1Br
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C=Nc1c(F)cc(Cl)cc1Br
Temperature: 100 °C

Procedure:
2-Bromo-4-chloro-6-fluoroaniline (5 mmol, 1.125 g), bis(trichloromethyl) carbonate (1.7 mmol, 0.50 g) and 1,4-dioxane (10 ml) were mixed together and the mixture was heated to 100° C. for 15 minutes; the mixture was then cooled to room temperature and it was filtered. The filtrate was concentrated to afford a mixture of products (2.2 g) containing the title compound, M++MeO=283 (LC-MS run in methanol).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[O:21][C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[N:19][N:18]=4)[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)[N:3]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][C:38]1=[O:43].CCN(CC)CC.[OH-].[Na+]>CN1C(=O)CCC1>[CH:23]([NH:22][C:20]1[O:21][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][CH:9]=[C:8]3[C:4]2[N:3]=[C:2]([N:40]3[CH2:41][CH2:42][N:37]([CH3:36])[C:38](=[O:43])[CH2:39]3)[CH:7]=[CH:6][N:5]=2)=[N:18][N:19]=1)([CH3:25])[CH3:24]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(Cl)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Reactant: CN1CCNCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)Nc1nnc(-c2ccc3[nH]cc(-c4nccc(N5CCN(C)C(=O)C5)n4)c3c2)o1
Temperature: 100 °C
Yield: 43.9 %

Procedure:
A glass microwave reaction vessel was charged with 5-(3-(4-chloropyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (80 mg, 0.157 mmol) and 1-methylpiperazin-2-one (17.94 mg, 0.157 mmol) in NMP (1.0 mL), followed by Et3N (65.6 μL, 0.472 mmol, Aldrich). The reaction was stirred and heated in a Initiator microwave reactor at 100° C. for 30 min. Then aq. NaOH (5 M, 0.3 mL) was added and the reaction was heated in microwave at 100° C. for 20 min. The mixture was purified with RP-HPLC (eluent: 10-60% MeCN in water with 0.1% TFA) and the fractions containing the product were combined and concentrated to remove AcCN. The remaining mixture was neutralized with sat. NaHCO3 and extracted with CHCl3/iPrOH (4:1). The combined organic layers were dried, filtered and concentrated to give 4-(2-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1H-indol-3-yl)pyrimidin-4-yl)-1-methylpiperazin-2-one (30.0 mg, 0.069 mmol, 44.1%) as a light yellow solid. MS (ESI, pos. ion) m/z: 433.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.88 (1H, br. s.), 9.10 (1H, s), 8.30 (1H, d, J=6.1 Hz), 8.23 (1H, d, J=2.7 Hz), 7.60-7.73 (2H, m), 7.56 (1H, d, J=8.4 Hz), 6.69 (1H, d, J=6.1 Hz), 4.40 (2H, br. s.), 3.93 (2H, br. s.), 3.75 (1H, dq, J=13.3, 6.5 Hz), 3.51 (2H, t, J=5.2 Hz), 2.97 (3H, s), 1.25 (6H, d, J=6.8 Hz), 1.24 (3H, s).
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[Cl:9][C:10]1[CH:26]=[CH:25][C:13]([CH:14]=[N:15][C@@H:16]([CH3:24])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1.[OH-].[Na+]>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C@@H:14]2[C:19]3[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][C@H:16]([CH3:24])[NH:15]2)=[CH:25][CH:26]=1
Reactant: C[C@@H](Cc1ccccc1)N=Cc1ccc(Cl)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: C[C@H]1Cc2ccccc2[C@@H](c2ccc(Cl)cc2)N1
Temperature: 120 °C
Reaction time: 19 h

Procedure:
To a flask with trifluoromethanesulfonic acid (3.00 mL, 34 mmol) at 0° C. was added dropwise (S)—N-(4-chlorobenzylidene)-1-phenylpropan-2-amine (1.20 g, 1.61 mmol) and the reaction was heated to 120° C. and stirred 19 h under N2. The reaction was cooled, poured into ice water (20 mL), and basisified with 5 N NaOH (6 mL). The aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with saturated NaCl (20 mL), dried (MgSO4), and concentrated to give a yellow/brown oil. The residue was purified by ISCO (40 g SiO2, 0-100% EtOAc/hexane) to give (1R,3S)-1-(4-chlorophenyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline as a light yellow oil.
Reaction SMILES: [CH2:1]([CH:3]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14](Cl)(Cl)Cl)[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29].C(N(CC)CC)C>C(O)C>[CH2:1]([CH:3]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14]1[O:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=1)[CH3:2]
Reactant: CCCCC(CC)Cn1c(C(Cl)(Cl)Cl)nc2ccccc21
Reactant: Nc1ccccc1O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCC(CC)Cn1c(-c2nc3ccccc3o2)nc2ccccc21

Procedure:
28.2 g (0.12 mol) of 1-(2-ethylhexyl)-2-trichloromethylbenzimidazole (prepared by reacting N-2-ethylhexyl-o-phenylenediamine with trichloroacetamido methyl ester), 13.1 g (0.12 mot) of o-aminophenol and 39.4 g (0.38 mot) of triethylamine in 150 ml of ethanol are stirred at room temperature for 15 hours. The ethanol is subsequently removed on a rotary evaporator, ethyl acetate is added to the residue which remains, and the mixture is washed with water and dried over sodium sulfate. 35% of product is identified by BPLC in the product mixture thus ob-5 tained; isolation can be carried out, for example, by column chromatography.