Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]2.S(Cl)(Cl)=O.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[NH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:33][C:30]([F:31])([F:32])[C:28]1[CH:29]=[C:25]([C:24]([F:23])([F:34])[F:35])[N:26]([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[CH2:8][C@@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]3)[N:27]=1
Reactant: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(CO)cc2C1
Reactant: FC(F)(F)c1cc(C(F)(F)F)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(Cn3nc(C(F)(F)F)cc3C(F)(F)F)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 1.9 %

Procedure:
(R)—N-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (50 mg, 0.19 mmol) was dissolved in DCM (5 mL) and cooled to 0° C. before thionyl chloride (110 mg, 0.93 mmol) was added. The reaction mixture was stirred at room temperature for 1 h before being concentrated to dryness. The whole was dissolved in DMF (3 mL) to this was added 3,5-bis(trifluoromethyl)-1H-pyrazole (38 mg 0.19 mmol) followed by potassium carbonate (51 mg, 0.37 mmol). The reaction mixture was heated to 60° C. for 2 h before being quenched with water (2 mL) and the organics extracted with EtOAc (3×5 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated under reduced pressure. Purification by preparative acidic HPLC gave (R)—N-(5-((3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (1.7 mg, 3.7 μmol, 2.0%). MS (ESI): m/z [M+H]+ 456.1
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].N[C@@](C)([C@H](O)C)CO.[CH:13]([C:16]([N+:21]([O-])=O)([CH2:19]O)[CH2:17][OH:18])([CH3:15])[CH3:14]>>[C:1]([O:4][CH2:19][C:16]([NH2:21])([CH:13]([CH3:15])[CH3:14])[CH2:17][OH:18])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(C)C(CO)(CO)[N+](=O)[O-]
Agent: C[C@@H](O)[C@](C)(N)CO
Product: CC(=O)OCC(N)(CO)C(C)C
Yield: 98 %

Procedure:
Using the procedure in 5E, 2-isopropyl-2-nitro-1,3-propanediol (52A) gave a 98% yield of 2-amino-2-isopropyl-1,3-propanediol acetate mp 155°-155.5°. H. S. Broadbent et al., J. Heterocyclic Chem., 13, 337 (1975) report the synthesis of this compound as the free base (mp 70°-72°)).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(C(C)C)CC)(C)C.[F:21][C:22]([F:31])([F:30])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([F:21])([F:30])[F:31])=[CH:24][CH:25]=1)=[O:5]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(Cl)cc1Cl
Yield: 83.8 %

Procedure:
Part A: 2,4-Dichlorobenzoyl chloride (40.0 g, 0.19 mol) is dissolved in tetrahydrofuran (1 L). To the resulting stirred solution is successively added diisopropylethylamine (DIPEA) (73.4 mL, 2.2 molar equivalent) and 4-(trifluoromethyl)phenylamine (30.7 g, 0.19 mol). After one hour the mixture is concentrated in vacuo to give an oil. This oil is crystallised from ethanol to give pure 2,4-dichloro-N-(4-(trifluoromethyl)phenyl)benzamide (53.2 g, 83% yield). 1H-NMR (200 MHz, DMSO-d6): δ 10.90 (br s, 1H), 7.91 (br d, J=8 Hz, 2H), 7.63–7.77 (m, 4H), 7.57 (dt, J=8 Hz, J=2 Hz, 1H).
Reaction SMILES: CC([O-])(C)C.[K+].Cl.[NH2:8][OH:9].[CH2:10]([C:14]1[C:21]([CH3:22])=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1)[CH:11]([CH3:13])[CH3:12]>CO>[OH:9][NH:8][C:18](=[NH:19])[C:17]1[CH:20]=[C:21]([CH3:22])[C:14]([CH2:10][CH:11]([CH3:12])[CH3:13])=[N:15][CH:16]=1
Reactant: Cc1cc(C#N)cnc1CC(C)C
Reactant: NO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: Cc1cc(C(=N)NO)cnc1CC(C)C
Temperature: 25 °C
Yield: 95.2 %

Procedure:
To a solution of potassium tert-butylate (3.04 g, 27.1 mmol) in MeOH (60 mL), hydroxylamine hydrochloride (1.62 g, 23.2 mmol) is added at 0° C. To this suspension, 6-isobutyl-5-methyl-nicotinonitrile (1.35 g, 7.75 mmol) is added. The mixture is refluxed for 3 h, cooled to rt, filtered and the filtrate is evaporated to dryness. The residue is suspended in a small amount of water and then extracted with EA. The org. extract is concentrated and dried under high vacuum to give N-hydroxy-6-isobutyl-5-methyl-nicotinamidine (1.53 g) as a pale yellow oil; LC-MS: tR=0.68 min, [M+1]+=208.22; 1H NMR (D6-DMSO): δ 0.91 (d, J=6.8 Hz, 6H), 2.06-2.17 (m, 1H), 2.29 (s, 3H), 2.61 (d, J=7.0 Hz, 2H), 5.85 (s br, 2H), 7.76 (s, 1H), 8.60 (s, 1H), 9.68 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[N:11][N:10]=2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[C:32]1[CH:33]=[N:34][CH:35]=[N:36][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[N:34]1[CH:33]=[C:32]([O:20][C:17]2[CH:18]=[CH:19][C:14]([C:12]3[O:13][C:9]([NH:8][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:10][N:11]=3)=[CH:15][CH:16]=2)[CH:37]=[N:36][CH:35]=1
Reactant: Brc1cncnc1
Reactant: Oc1ccc(-c2nnc(Nc3ccc(Cl)cc3)o2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: Clc1ccc(Nc2nnc(-c3ccc(Oc4cncnc4)cc3)o2)cc1
Temperature: 80 °C
Yield: 33.7 %

Procedure:
4-{5-[(4-chlorophenyl)amino]-1,3,4-oxadiazol-2-yl}phenol (144.0 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (100.0 mg, 0.5 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 5-bromopyrimidine (79.5 mg, 0.5 mmol) was added, followed by anhydrous K2CO3 (34.5 mg, 0.25 mmol). Then the vial was capped and microwaved at 200° C. for 15 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated NaHCO3. EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and filtered. Solvent was removed in vacuo to give the title product as a beige solid (61.6 mg).
Reaction SMILES: [CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[N:14](C(OC(C)(C)C)=O)[C:13]=1[C:29]([O:31][CH3:32])=[O:30])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].FC(F)(F)C(O)=O.C(OCC)(=O)C>C(Cl)Cl>[CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[NH:14][C:13]=1[C:29]([O:31][CH3:32])=[O:30])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: COC(=O)c1c(NCCC(=O)c2ccccc2)c2ccc(Cl)cc2n1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1[nH]c2cc(Cl)ccc2c1NCCC(=O)c1ccccc1

Procedure:
Dissolve 3-[(phenacyl)methylamino]-2-carbmethoxy-6-chloro-1-(tert-butyloxycarbonyl)-indole from above in methylene chloride (3 mL). Add trifluoracetic acid (1mL) and stir for 2 hours. Dilute into ethyl acetate and rinse with saturated sodium bicarbonate. Dry the organic phase over magnesium sulfate, filter and concentrate in vacuo to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:7]=O)=[CH:5][N:6]=1.[CH2:9]([NH2:11])[CH3:10]>C1COCC1>[CH2:9]([NH:11][CH2:7][C:4]1[S:3][C:2]([CH3:1])=[N:6][CH:5]=1)[CH3:10]
Reactant: Cc1ncc(C=O)s1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1cnc(C)s1

Procedure:
prepared by reaction of 2-methyl-thiazole-5-carbaldehyde (Khanna I. K. et al J. Med. Chem. 2000, 43, 16, 3168-3185) with 2M ethylamine in THF.
Reaction SMILES: [NH2:1][C@H:2]([CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[NH:27][C:26]2=[O:36])[CH2:21][CH2:20]1.C1C[O:40][CH2:39]C1>>[O:36]=[C:26]1[N:25]([CH:22]2[CH2:21][CH2:20][N:19]([C:39]([NH:1][C@H:2]([CH2:8][C:9]3[CH:18]=[CH:17][C:16]4[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=4[CH:10]=3)[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:40])[CH2:24][CH2:23]2)[CH2:31][CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[NH:27]1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: CCOC(=O)[C@H](N)Cc1ccc2c(c1)CCCC2
Reactant: C1CCOC1
Product: CCOC(=O)[C@@H](Cc1ccc2c(c1)CCCC2)NC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 0 °C

Procedure:
A mixture of 20 mL THF, 1.65 g (6.7 mmol) ethyl (R)-2-amino-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propionate and 1.25 g (7.6 mmol) CDT was stirred for 1 h in the ice bath and for 1 h at RT. Then 1.70 g (6.9 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one was added and the mixture was refluxed for 3 h. The reaction mixture was evaporated down under reduced pressure, the residue combined with 15% K2CO3 solution, the precipitate was suction filtered and dried.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH:4]([NH:11][C:12]([O:14]C)=O)[CH2:5][CH2:6][C:7]([F:10])([F:9])[F:8].[Li+].[OH-:18].[CH3:19]O>>[F:10][C:7]([F:8])([F:9])[CH2:6][CH2:5][C:4]([N:11]=[C:12]=[O:14])([O:18][CH3:19])[C:3]([OH:2])=[O:16]
Reactant: [OH-]
Reactant: COC(=O)NC(CCC(F)(F)F)C(=O)OC
Reactant: CO
Agent: [Li+]
Product: COC(CCC(F)(F)F)(N=C=O)C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 5,5,5-Trifluoro-2-methoxycarbonylamino-pentanoic acid methyl ester (194 mg, 0.80 mmol) in methanol (3 mL) was added an aqueous LiOH solution (1M, 2 mL, 2 mmol). The resulting solution was stirred at room temperature for 45 minutes and then washed with ethyl acetate. The ethyl acetate washing was discarded and the aqueous layer was acidified with concentrated HCl. The acidified aqueous layer was extracted twice with ethyl acetate. The combined organics were washed with brine, dried (MgSO4), and concentrated to give clean 5,5,5-Trifluoro-2-methoxy-carbonylamino-pentanoic acid. To a solution of the pentanoic acid in dimethylformamide (2 mL) was added HATU (300 mg, 0.79 mmol). After stirring for 5 minutes, a solution of 2-{5-[4′-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (412 mg, 0.79 mmol) in dimethylformamide (1.9 mL) was added to the reaction, followed immediately by diisopropylethylamine (275 μL, 1.58 mmol). The reaction was stirred for 1 hour at room temperature then diluted with ethyl acetate. The organic layer was washed with water and brine, dried (MgSO4), concentrated and purified by flash chromatography to yield 2-[5-(4′-{2-[1-(5,5,5-trifluoro-2-methoxycarbonylamino-pentanoyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (340 mg, 59%). LCMS-ESI+: calculated for C38H44F3N7O5: 735.34; observed [M+1]+: 736.05.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[C:3]=1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1.O>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[CH:7][CH:8]=2)[C:3]=1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)Nc1c(Br)ccc2ccc(O)cc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1c(Br)ccc2ccc(O[Si](C)(C)C(C)(C)C)cc12
Reaction time: 18 h

Procedure:
2-Bromo-1-(tert-butoxycarbonylamino)-7-hydroxynaphthalene, as described above in Step F, (4.80 g, 14.19 mmol), tert-butyldimethylsilyl chloride (2.8 g, 18.45 mmol) and imidazole (2.2 g, 32.64 mmol) were dissolved in DMF (25 mL) and stirred for 18 hours. The mixture was poured into H2O and extracted with Et2O (2×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with CH2Cl2—50% hexanes, to yield the above-titled compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:14]=3[C:15]#[N:16])[CH2:7][CH:6]3[CH2:22][O:23][CH2:24][CH2:25][N:5]3[C:4]=2[N:3]=1.S(=O)(=O)(O)[OH:27]>CCOC(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:14]=3[C:15]([NH2:16])=[O:27])[CH2:7][CH:6]3[CH2:22][O:23][CH2:24][CH2:25][N:5]3[C:4]=2[N:3]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(C#N)c(CN2CC3COCCN3c3nc(Cl)ncc32)c1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(N)=O)c(CN2CC3COCCN3c3nc(Cl)ncc32)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 20 mL round-bottomed flask charged with 2-((2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)-4-methylbenzonitrile (PREPARATION x83, 52 mg, 0.146 mmol) was added sulfuric acid (1.6 mL, 29.2 mmol). The resulting yellow solution was stirred overnight at room temperature and was subsequently diluted with EtOAc and washed with saturated NaHCO3 to adjust the pH to −8. The combined organic layers were dried over MgSO4, filtered, and concentrated to give an orange solid, which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.88-3.02 (m, 5H), 3.09-3.18 (m, 3H), 3.19-3.28 (m, 2H), 3.41-3.51 (m, 3H), 3.59-3.71 (m, 2H), 3.80-3.91 (m, 3H), 3.91-4.00 (m, 2H), 4.19-4.29 (m, 3H), 4.30-4.58 (m, 2H), 7.16-7.29 (m, 10H), 7.37-7.45 (m, 2H), 7.73-7.82 (m, 2H); ESI-MS m/z [M+H]+ calc'd for C18H20ClN5O2, 374.1. found 374.2.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[F:18][C:19]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:20]=1[CH2:21][C:22]1[O:26][N:25]=[C:24]([C:27](O)=[O:28])[CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][N:15]([C:27]([C:24]2[CH:23]=[C:22]([CH2:21][C:20]3[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:19]=3[F:18])[O:26][N:25]=2)=[O:28])[CH2:14][CH2:13]1
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Reactant: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(Cc2cc(F)ccc2F)on1)N1CCC(c2c[nH]c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.4 %

Procedure:
The mixture of 5-chloro-3-(piperidin-4-yl)-1H-indole hydrochloride (0.070 g; 0.258 mmol), 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid (0.062 g; 0.258 mmol), HATU (N,N,N′N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate) (0.098 g: 0.258 mmol) and N,N-diisopropylethylamine (0.113 mL; 0.634 mmol) in DMF (3 mL) was stirred for 72 hours at room temperature and was concentrated under reduced pressure. The residue was dissolved in dichloromethane and the organic layer was washed with water and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent: 0 to 10% of ethyl acetate in dichloromethane) to give 0.0428 g (36%) of (4-(5-chloro-1H-indol-3-yl)piperidin-1-yl)(5-(2,5-difluorobenzyl)isoxazol-3-yl)methanone as a white solid.
Reaction SMILES: [N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][C:6](O)=[O:7])=[N+:2]=[N-:3].CO.Cl>C1COCC1>[N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][CH2:6][OH:7])=[N+:2]=[N-:3]
Reactant: CC(C)(CC(=O)O)N=[N+]=[N-]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(CCO)N=[N+]=[N-]
Reaction time: 16 h

Procedure:
Borane dimethylsulfide complex (2 M, 15 mL, 30 mmol) was added over 20 min to 3-azido-3-methylbutanoic acid (4.25 g, 30 mmol) in THF (15 mL) at room temperature. The reaction was stirred for 16 h. The reaction mixture was cooled in an ice bath and methanol (50 mL) was added dropwise to the solution over 15 min. Then 4 M HCl in dioxanes (7.5 mL, 30 mmol) was added to the reaction mixture and stirred for 30 min. The reaction mixture was concentrated on a rotovap to a colorless liquid (3.33 g, 91%). This material was used without further purification. 1H NMR (CDCl3, 400 MHz): δ 1.35 (s, 6H), 1.74-1.78 (t, J=6.4, 2H), 3.75-3.80 (t, J=6.4, 2H). LRMS (ESI+) for C5H11N3O (129.1); Found: did not ionize.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.O.C([O-])([O-])=O.[Na+].[Na+].[CH3:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][N:18]=1>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:7]1[C:2]([C:20]2[CH:19]=[N:18][C:17]([CH3:16])=[CH:22][CH:21]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: Clc1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2ncccc2Cl)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
To a solution of 0.5 g (3.6 mmol) 2,3-dichloropyridine in 20 mL 1,2-dimethoxyethane and 20 mL distilled water were added 2.2 g (21.1 mmol) Na2CO3, 0.41 g (3.0 mmol) 2-methylpyridine-5-boronic acid and 50 mg Pd(PPh3)4, followed by stirring for 18 hours in a heat flux condition. After being cooled to room temperature, the solution was 50% concentrated in a vacuum condition. The aqueous layer was washed with ethyl acetate. Thereafter, the organic layer was dried over magnesium sulfate and vacuum concentrated. The concentrate was separated using column chromatography (developing solvent: ethyl acetate/hexane=1/10) to produce 0.56 g of 3-chloro-2-(6-methylpyridin-3-yl)pyridine (yield 80%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH:12]([CH2:23][OH:24])[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].O>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH2:1]([N:8]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH:12]([CH2:23][O:24][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1OCCN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1OCCN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Yield: 90.3 %

Procedure:
A solution of [(6RS,7SR)-4-benzyl-6-(3,4-dichlorophenyl)-1,4-oxazepan-7-yl]methanol (1.63 g), triethylamine (0.741 mL), tert-butyldimethylsilyl chloride (738 mg) and 4-dimethylaminopyridine (catalytic amount) in DMF (10 ml) was stirred at room temperature for 2 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.93 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:3]=1.C(N(CC)CC)C.[N:38]1([S:44](Cl)(=[O:46])=[O:45])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>ClCCl>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH:20][S:44]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)(=[O:46])=[O:45])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][CH:22]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(N)c3)n2)n1
Reactant: O=S(=O)(Cl)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(NS(=O)(=O)N4CCOCC4)c3)n2)n1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 12.6 %

Procedure:
To a stirred solution of 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-phenylamine (example 327) (0.200 g, 0.5 mmol) and triethyl amine (0.21 mL, 1.5 mmol) in dichloromethane (5 mL) was added commercially available morpholine-4-sulfonyl chloride (0.101 mg, 0.55 mmol) and the mixture was stirred at 23° C. for 30 min. Diluted with DCM, washed with sat. NaHCO3-sol. and water, dried the organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product which was purified by silica gel column chromatography with heptane/EtOAc, followed by trituration with heptane/diethyl ether to give the title compound as an off-white solid (0.035 g, 13%). MS (ISP) 555.2 [(M+H)+]; mp 191° C.
Reaction SMILES: [O:1]([CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl>CN(C=O)C>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(OCc2nc3ccccc3[nH]2)cc1
Reactant: COc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(Cn2c(COc3ccccc3)nc3ccccc32)c1
Temperature: 100 °C
Yield: 91.8 %

Procedure:
A 50 mL flask fitted with a stir-bar and a septum with an Ar inlet was charged with 2-(phenoxymethyl)-1 H-benzimidazole (61) (1.00 g, 4.46 mmol), K2CO3 (1.23 g, 8.92 mmol), and DMF (12 mL). 3-Methoxybenzyl chloride (769 mg, 4.91 mmol) was added, and the suspension was heated in a 100° C. bath for 2 hr. The mixture was cooled, and the solids were filtered off and rinsed with EtOAc (50 mL). The filtrate was then washed with sat'd NH4Cl (2×30 mL), H2O (2×30 mL), and brine (20 mL), filtered through phase separation paper, and concentrated in vacuo to a yellow oil. Upon standing the oil crystallized, and was subsequently collected with hexanes:EtOAc 30:1 (15 mL). Upon drying, 1.41 g of Compound #11 were obtained as an off-white crystalline solid (92%). 1H NMR (300 MHz, CDCl3): δ 7.84 (m, 1H), 7.36-7.25 (m, 5H), 7.21 (t, 1H), 6.82 (dd, 1H), 6.68 (d, 1H), 6.62 (m, 1H), 5.52 (s, 2H), 5.36 (s, 2H), 3.64 (s, 3H) ppm. HPLC analysis (5:10:85 H2O:A1:MeOH) showed a purity of greater than 99% with a retention time of 4.8 min.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=S.Cl.[Cl:7][CH:8]([C:14]([CH3:16])=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[S]>C(O)C.O>[ClH:7].[NH2:5][C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:14]([CH3:16])[NH:1][N:2]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NNC(N)=S
Agent: Cl
Agent: [S]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(N)n[nH]c1C
Temperature: 0 °C
Yield: 55.9 %

Procedure:
A stirred mixture of 9.1 g (0.1 mole) of 3-thiosemicarbazide and 1 mL of concentrated hydrochloride acid in 150 mL of absolute ethanol was cooled to 0° C. in an ice bath and 16.5 g (0.1 mole) of ethyl 2-chloroacetoacetate was added dropwise. The thiosemicarbazide dissolved as the reaction mixture was allowed to slowly come to ambient temperature, it then became yellow and a new precipitate formed. The reaction mixture was heated at reflux for 3 hr. All the material had not dissolved so the reaction mixture was diluted with water and made acidic with 3N hydrochloric acid to dissolve all the solids but sulfur. After filtering, the filtrate was concentrated in vacuo leaving an orange-red oil which slowly crystallized when acetone was added to give 11.5 g of orange powder, mp 186°-188° C., with decomposition.