Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][Cl:23].O>CN(C=O)C>[Cl:23][CH2:22][CH2:21][CH2:20][NH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5]
Reactant: ClCCCBr
Reactant: CN(C)C(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)c1ccccc1NCCCCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-amino-N,N-dimethylbenzamide (1.15 g, 6,97 mmol), prepared as in Example 22, potassium carbonate (1.44 g, 10.46 mmol) and 1-bromo-3-chloro-propane (0.7 mL, 7 mmol) in 10 mL of DMF was stirred at room temperature for 16 hours and then at 70° C. for an additional 4 hours. The mixture was poured into water and extracted with ethyl acetate (3×20 mL). The combined extract was washed with brine, dried (MgSO4) and concentrated to give 2-(3-chloropropyl)amino-N,N-dimethylbenzamide as a crude mixture.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:15][CH2:14]/[C:13](=[CH:16]\[CH:17]=[CH:18]\[C:19]([O:21]CC)=[O:20])/[CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C1COCC1.CO.[OH-].[Li+]>O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:15][CH2:14]/[C:13](=[CH:16]\[CH:17]=[CH:18]\[C:19]([OH:21])=[O:20])/[CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)/C=C/C=C1\CCN(Cc2ccc3c(c2)OCO3)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)/C=C/C=C1\CCN(Cc2ccc3c(c2)OCO3)C1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
A solution of ester 275 (0.15 g, 0.485 mmol) in 2:1 THF:MeOH (6 mL) was treated with a solution of lithium hydroxide (59 mg, 1.41 mmol) in H2O (3 mL) and stirred for 18 h. The reaction mixture was quenched with 1N HCl (2.0 mL), concentrated, diluted with H2O, cooled to −78° C. and lyophilized to provide title compound 276 (quantitative, in a mixture with LiCl).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1.[CH3:19][C:20]([CH3:25])=[CH:21][C:22](Cl)=[O:23].Cl>CN(C)C1C=CN=CC=1.O.C(Cl)Cl.C(N(CC)CC)C>[CH2:13]([N:12]([CH2:16][CH:17]=[CH2:18])[C:4]1[N:3]=[C:2]([NH:1][C:22](=[O:23])[CH:21]=[C:20]([CH3:25])[CH3:19])[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=1)[CH:14]=[CH2:15]
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Reactant: CC(C)=CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)c1nc(NC(=O)C=C(C)C)n2oc(=O)nc2n1
Temperature: 5 °C

Procedure:
15 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one are suspended in 300 ml. of methylene chloride, 30 ml. of triethylamine and 0.9 g. of 4-dimethylaminopyridine. 10.66 g. of 3,3-dimethylacrylyl chloride in 100 ml. of methylene chloride are added dropwise while stirring and cooling to about 5° C. The mixture is then stirred at 0° C. for 1 hour, treated with water and adjusted to pH 4 with 3-N hydrochloric acid. The two phases are separated and the aqueous phase is extracted with methylene chloride. The combined organic extracts are dried over magnesium sulfate and evaporated under reduced pressure. The residue is recrystallized from methylene chloride/diethyl ether, there being obtained pure N-{5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-7-yl}-3-methylcrotonamide having a melting point of 165°-166° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][C:12]1C=CC(S(O)(=O)=O)=CC=1.[CH2:22]([OH:24])[CH3:23]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH:7]([O:24][CH2:22][CH3:23])[O:8][CH2:11][CH3:12])[CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=Cc1cc(Br)ccc1I
Reactant: CCO
Product: CCOC(OCC)c1cc(Br)ccc1I

Procedure:
A mixture of 5-bromo-2-iodobenzaldehyde (14.9) (1.0 g, 3.2 mmol) and PTSA (0.1 g) in ethanol was stirred under reflux for 18 hrs and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated NaHCO3, dried over anhydrous Na2SO4 and concentrated to give 4-bromo-2-(diethoxymethyl)-1-iodobenzene (14.10) that was directly used in next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:24])(=[O:25])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([NH:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:11])[CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Reactant: NCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)NCc2ccccc2)c1
Reaction time: 3 h

Procedure:
To the mixture of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (500 mg, 1.4 mmol) and benzyl amine (0.5 ml, 4.5 mmol) in DMF (5 ml), added PyBOP (730 mg, 1.4 mmol) then triethyl amine (0.4 ml, 3 mmol). Stirring was kept for 3 hours. Diluted with EtOAc, washed with 1N HCl, water and brine. Dried over anhydrous sodium sulfate. Concentrated, the residue was dissolved in DMSO and purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). The title compound was obtained as white powder. MS calcd for (C22H22BN3O5S): 451.14. MS found (ESI negative): (M−H)−=450.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.78 (s, 1H), 9.15 (br, 1H), 8.38 (t, J=6 Hz, 1H), 7.37 (d, J=1.2 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.30-7.10 (m, 6H), 7.01 (dd, J=8.4 Hz, 1H), 6.43 (d, J=2 Hz, 1H), 6.30 (dd, J=8.4 Hz, 1H), 4.80 (s, 2H), 4.25 (d, J=5.6 Hz, 1H), 3.79 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1.CCCCC>[C:13]1([S:19]([N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([Br:1])=[C:3]3[CH:10]=[CH:9]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1ccnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Yield: 72.5 %

Procedure:
4-bromo-1H-pyrrolo[2,3-b]pyridine (1 g, 1 Eq.) was dissolved in dry THF and cooled in an ice-bath. NaH (60% dispersion in mineral oil, 305 mg, 1.2 Eq.) was added portionwise. The resultant mixture was stirred at 0° C. for 45 minutes and benzene sulfonyl chloride (1.076 g, 1.2 Eq.) was added slowly dropwise. The resultant mixture was stirred at 0° C. for a further 75 minutes and then the solvent was removed in vacuo. The residue was partitioned in EtOAc/sat. NH4Cl and extracted with EtOAc (3×50 mL). The combined organics were washed with sat. aq. Na2CO3 (1×20 mL), brine (1×20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification was achieved using column chromatography (20% EtOAc/80% hexanes), followed by recrystallization from EtOAc/hexanes. The product was filtered and then washed with pentane obtaining the title compound as a white powder (1.24 g, 73% yield); 1H NMR (DMSO D6) 6.8 (1H, d), 7.6-7.66 (3H, m), 7.72-7.76 (1H, m), 8.0 (1H, d), 8.1 (2H, m), 8.24-8.26 (1H, m); LC/MS M+1; (obs.) 339.1; LC/MS M−1 (obs.) 337.1.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[C:6]([NH:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2].[CH3:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[C:27]([CH3:29])[CH:28]=1>>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13]([N:33]2[CH2:34][CH2:35][N:30]([C:25]3[CH:26]=[C:27]([CH3:29])[CH:28]=[C:23]([CH3:22])[CH:24]=3)[CH2:31][CH2:32]2)=[O:21])[C:6]([NH:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2]
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(NC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3cc(C)cc(C)c3)CC2)c(NC)nc1C
Yield: 56 %

Procedure:
Phenyl N-(5-ethyl-6-methyl-2-methylaminopyridin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: C(O)(=O)[C@H](C1C=CC=CC=1)O.[NH2:12][C@@H:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=2)[CH2:15][C@H:14]1[OH:25].[OH-].[Na+].[C:28]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][C:31]([C:34](Cl)=[O:35])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[N+:22]([C:19]1[CH:20]=[C:21]2[C:16]([CH2:15][CH:14]([OH:25])[C@@H:13]2[NH:12][C:34]([C:31]2[CH:32]=[CH:33][C:28]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:29][CH:30]=2)=[O:35])=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: N[C@@H]1c2cc([N+](=O)[O-])ccc2C[C@H]1O
Agent: O=C(O)[C@@H](O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(N[C@@H]1c2cc([N+](=O)[O-])ccc2CC1O)c1ccc(-c2ccccc2)cc1
Reaction time: 1 h
Yield: 106.8 %

Procedure:
Add 1(R)-amino-2(R)-hydroxy-6-nitroindane (S)-mandelate (0.64 kg, 1.85 mol) to a mixture of toluene (9.6 L) and aqueous 1 N NaOH (4.8 L, 4.8 mol, 2.6 equiv). After 1 h, add 4-biphenylcarbonyl chloride (0.44 kg, 2.0 mol, 1.1 equiv) in portions over 20-30 min. After 22 hours, filter the solids under vacuum and rinse sequentially with 0.5 L of toluene, 2 L of water, and 2 L of toluene. Dry the cake to afford 0.74 kg of biphenyl-4-carboxylic acid (R)-(6-nitro-2-hydroxyindan-1-yl)amide. Add 38.2 L of ethyl acetate to 1.914 kg of biphenyl-4-carboxylic acid (R)-(6-nitro-2(R)-hydroxyindan-1-yl)amide prepared in a similar manner. Stir the slurry for 18 h, collect the solid by filtration, dry to afford 1.76 kg of biphenyl-4-carboxylic acid (R)-(6-nitro-2(R)-hydroxyindan-1-yl)amide as a white solid.
Reaction SMILES: [NH2:1][C@:2]([CH3:14])([CH2:5][CH2:6][C:7]1[N:8]([CH2:12][CH3:13])[CH:9]=[CH:10][CH:11]=1)[CH2:3][OH:4].[C:15](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:16].C(N(CC)CC)C.O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:14][C@@:2]1([CH2:5][CH2:6][C:7]2[N:8]([CH2:12][CH3:13])[CH:9]=[CH:10][CH:11]=2)[CH2:3][O:4][C:15](=[O:16])[NH:1]1
Reactant: CCn1cccc1CC[C@@](C)(N)CO
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCn1cccc1CC[C@]1(C)COC(=O)N1
Yield: 50.6 %

Procedure:
Subsequently, to a suspension of (2R)-2-amino-2-methyl-4-(1-ethylpyrrol-2-yl)butan-1-ol ½ D-(−)tartrate (55.5 mg, 0.16 mmol) in dichloromethane (1.6 ml) were added successively di-t-butyl dicarbonate (0.17 g, 0.78 mmol), triethylamine (0.22 ml, 1.58 mmol) and 4-dimethylaminopyridine (3.0 mg, 0.025 mmol) with stirring, and the resulting mixture was stirred at room temperature for 20minutes. After stirring, water was added to the reaction mixture, and the resulting mixture was concentrated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethylacetate (1:1) as the eluent to afford (4R)-4-methyl-4-[2-(1-ethylpyrrol-2-yl)ethyl]-1,3-oxazolidin-2-one (18.0 mg, yield: 58%).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1)(=[O:5])=[O:4].S(Cl)([Cl:18])=O>>[CH3:1][N:2]([CH3:15])[S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:18])=[O:11])=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: CN(C)S(=O)(=O)c1ccc(C(=O)Cl)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 4-dimethylsulfamoylbenzoic acid (688 mg) and thionyl chloride (5 mL) was stirred at 90° C. overnight. The reaction mixture was concentrated to give 4-dimethylsulfamoylbenzoyl chloride (495 mg) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[C:13]4[CH2:20][CH2:19][CH2:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[CH:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][CH2:23]1>O1CCCC1.C(O)C.C(O)(=O)C.[Pt]=O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[C:13]4[CH2:20][CH2:19][CH2:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:8][CH:9]=2)[CH2:4][CH:3]1[CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:24][CH2:23]1
Reactant: O=C1C(=CC2CCN(Cc3ccccc3)CC2)Cc2cc(Nc3ncnc4c3CCC4)ccc21
Agent: O=[Pt]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1c2ccc(Nc3ncnc4c3CCC4)cc2CC1CC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
0.53 g of platinum oxide was added to 1.35 g of 4-[1-oxo-2-(1-benzylpiperidin-4-yl)methyleneindan-5-yl]amino-5,6-dihydro-7H-cyclopenta[d]pyrimidine dissolved in a mixed solution of 60 ml of tetrahydrofuran, 60 ml of ethanol and 1 ml of acetic acid, and the mixture was stirred under a hydrogen stream at room temperature for 8 hours. After the catalyst was removed by filtration, the filtrate was condensed. The obtained residue was applied to silica gel column chromatography to obtain 1.31 g of the title compound as pale yellow powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[C:5]([O:13][C:14]([F:17])([F:16])[F:15])[CH:4]=1)#[N:2].Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>C(O)(C)C>[OH:20][NH:19][C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[C:5]([O:13][C:14]([F:15])([F:17])[F:16])[CH:4]=1)=[NH:2]
Reactant: CC(=O)Nc1ccc(C#N)cc1OC(F)(F)F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Product: CC(=O)Nc1ccc(C(=N)NO)cc1OC(F)(F)F

Procedure:
The mixture consisting of 610 mg of N-(4-cyano-2-trifluoromethoxyphenyl)-acetamide, 15 ml of isopropanol, 255 mg of hydroxylamine hydrochloride and 410 mg of sodium acetate was heated to reflux for 5 hours. After cooling, the insoluble fraction was filtered off, and the filtrate is concentrated and taken up in a little isopropanol, the product was precipitated, filtered off with suction and dried by adding water until the first cloudiness and subsequent stirring.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([S:12][CH2:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25]O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][O:1][C:2]1[CH:11]=[C:10]([S:12][CH2:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCSc1ccc(C(=O)OC)c(O)c1
Reactant: CC(C)(C)OC(=O)NCCCO
Product: CCSc1ccc(C(=O)OC)c(OCCCNC(=O)OC(C)(C)C)c1
Yield: 85 %

Procedure:
Using a procedure analogous to Example 21-C, methyl 2-hydroxy-4-(ethylthio)-benzoate and 3-t-butoxycarbonylaminopropanol gave the title compound as a solid (10.41 g, 85%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH:6]([CH2:10][CH3:11])[C:7](Br)=[O:8].[CH3:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][C:14]1=[O:22]>C(=S)=S>[Br:5][CH:6]([CH2:10][CH3:11])[C:7]([C:19]1[CH:20]=[CH:21][C:16]2[S:15][C:14](=[O:22])[N:13]([CH3:12])[C:17]=2[CH:18]=1)=[O:8]
Reactant: Cn1c(=O)sc2ccccc21
Reactant: CCC(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(Br)C(=O)c1ccc2sc(=O)n(C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
A mixture of aluminum chloride (120 g) and 2-bromobutyryl bromide (48 g) in carbon disulfide (120 ml) was stirred for 30 minutes at ambient temperature. To the resultant mixture was added 3-methyl-2-benzothiazolinone (23 g) and the mixture was stirred for an hour at ambient temperature. The solvent was removed by evaporation at 60°-70° C. and stirred for an hour under the same condition. The reaction mixture was poured into ice-water (360 g) and extracted with chloroform (100 ml×2). The extract was washed with water and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was subjected to column chromatography on silica gel (300 g) by eluting with benzene. The fractions containing the desired compound were combined and the solvent was removed by distillation to give 5-(2-bromobutyryl)-3-methyl-2-benzothiazolinone (27.18 g).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH2:20][CH2:21][CH3:22])[N:13]=2)[CH:3]=1.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]>CN1C(=O)CCC1.C(OCC)(=O)C>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH2:20][CH2:21][CH3:22])[N:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: CCCc1nc(Nc2cc(Cl)nnc2C(N)=O)ccc1OC
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCCc1nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)ccc1OC
Temperature: 140 °C
Reaction time: 7 h
Yield: 30.9 %

Procedure:
To a solution of 6-chloro-4-(5-methoxy-6-propylpyridin-2-ylamino)pyridazine-3-carboxamide (200 mg, 622 μmol) in NMP (2.07 mL) was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (133 mg, 622 μmol) and the mixture heated at 140° C. for 20 h. A second portion of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (133 mg, 622 μmol) was added and the mixture stirred for a further 7 h. A final portion of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (133 mg, 622 μmol) was added and the mixture heated for 16 h, then cooled, diluted with ethyl acetate, and washed with brine (4×). The organic layer was collected, concentrated in vacuo, and the residue obtained was purified by chromatography (silica, 1 to 5% methanol in dichloromethane) to give tert-butyl (1S,2R)-2-(6-carbamoyl-5-(5-methoxy-6-propylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (96 mg, 192 μmol, 31%) as a light brown solid. MS (EI/CI) m/z: 500.2 [M+H].
Reaction SMILES: C(OC([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[C:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)=O)C.[OH-].[Na+].Cl>CCO.C1COCC1>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[C:27]2[CH2:28][C:29]([CH3:36])([CH3:35])[CH2:30][C:31]([CH3:34])([CH3:33])[CH2:32]2)[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)C#Cc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(OC(=O)OCC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(C#CC(=O)O)cc2)CC(C)(C)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
To a solution of ethyl 3-{4-[(4-{[(ethyloxy)carbonyl]oxy}phenyl)(3,3,5,5-tetramethyl cyclohexylidene)methyl]phenyl}-2-propynoate (148) (88 mg, 0.18 mmol) in a mixture of EtOH (4 mL) and THF (4 mL) was added an aqueous solution of 1 N NaOH (5 mL). The mixture was stirred at 60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 1 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract washed with water, brine and dried over Na2SO4. Upon concentration and trituration with hot 1:1 hexanes/ether (contained 1% of methanol), (35 mg (50%) of compound 149 was obtained as white solid. mp 172-174° C. (dec.). 1H NMR (400 MHz, DMSO-d6): δ 0.86 (s, 6H), 0.87 (s, 6H), 1.24 (s, 2H), 1.85 (s, 2H), 1.91 (s, 2H), 6.66 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.1 Hz, 2H), 7.52 (d, J=8.1 Hz, 2H), 9.31 (s, 1H), 13.73 (s, 1H). HRMS (EI) Calcd for C32H44O3Si2: 532.2829 (M+); Found: 532.1591.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1OS([C:15]([F:18])([F:17])[F:16])(=O)=O.C1(P(C2CCCCC2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]2[C:37](OC(C)C)=[CH:36][CH:35]=[CH:34][C:33]=2OC(C)C)CCCCC1.[C:52]([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:16][C:15]([F:18])([F:17])[C@@H:26]1[CH2:31][C@H:30]1[C:29]1[CH:28]=[CH:27][C:32]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:52]=1
Reactant: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(Oc1ccc2ccccc2c1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)[C@@H]1C[C@H]1c1ccc2ccccc2c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 388.6 %

Procedure:
In an open vial with pressure-release top, a stirred mixture of 2-naphthyltrifluoromethanesulfonate (Aldrich, St. Louis, Mo.) (69 mg, 0.25 mmol), palladium(II) acetate (5.5 mg, 0.025 mmol), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (23 mg, 0.05 mmol), K2CO3 (138 mg, 1.0 mmol) and trans-2-(trifluoromethyl)cyclopropylboronic acid MIDA ester (99 mg, 0.38 mmol) in toluene (2.5 mL) and H2O (0.5 mL) was de-gassed with N2 for 15 minutes, then the reaction mixture placed under nitrogen, sealed and heated to 100° C. and stirred for 6 hours. After allowing to cool, the reaction mixture was diluted with H2O (15 mL) and EtOAc (20 mL), filtered through Celite and the filter cake washed with EtOAc (2×20 mL). The filtrate was partitioned and the aqueous layer extracted with EtOAc (2×15 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under vacuum to leave a crude residue. The residue was purified by preparative thin-layer chromatography (2 prep TLC plates used) using EtOAc/hexane (1:99) as eluent to give the product (45.9 mg, 78%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH:12][CH2:13][C@H:14]([OH:21])[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=O)=[CH:4][CH:3]=1.[B].CSC.CO.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][NH:12][CH2:13][C@@H:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[OH:21])=[CH:6][CH:7]=1
Reactant: O=C(CCc1ccc(Br)cc1)NC[C@H](O)c1cccnc1
Agent: Cl
Agent: [B]
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: O[C@@H](CNCCCc1ccc(Br)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a suspension of 3-(4-bromophenyl)-N-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]propanamide (3.42 g) in tetrahydrofuran (58 ml) was added 2.0M dimethyl sulfide—borane (1:1) in tetrahydrofuran (16.1 ml) dropwise at 0-5° C. over 45 minutes. After cooling to room temperature, to the reaction mixture were added methanol (2.99 ml) and 37% hydrochloric acid (4.8 ml) at 4° C. (ice bath). The mixture was stirred at 80° C. for 1 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and to the residue was added water (100 ml). The pH was adjusted to 10 with 24% aqueous sodium hydroxide solution at 4° C. and the mixture was extracted with ethyl acetate (200 ml). The organic layer was washed with water and brine and dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave (1R)-2-[[3-(4-bromophenyl)propyl]-amino]-1-(3-pyridyl)ethanol (3.22 g) as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH:11][C:12](=[O:22])[CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH:20]=[O:21])[CH2:16][CH2:15]2)=[C:6]([Cl:23])[CH:5]=1)([O-])=O.S1C=CC=C1.[NH4+].[OH-]>CO.[Pt].C(Cl)Cl>[NH2:1][C:4]1[CH:5]=[C:6]([Cl:23])[C:7]([NH:11][C:12](=[O:22])[CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH:20]=[O:21])[CH2:16][CH2:15]2)=[C:8]([Cl:10])[CH:9]=1
Reactant: O=CN1CCN(CC(=O)Nc2c(Cl)cc([N+](=O)[O-])cc2Cl)CC1
Agent: [Pt]
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccsc1
Solvent: CO
Solvent: ClCCl
Product: Nc1cc(Cl)c(NC(=O)CN2CCN(C=O)CC2)c(Cl)c1
Yield: 31.7 %

Procedure:
A mixture of N-(4-nitro-2,6-dichlorophenyl)-4-formyl-1-piperazineacetamide (1.79 g crude) was suspended in methanol (50 mL) containing 4% methanolic thiophene (0.5 mL) and 5% platinum on charcoal catalyst (900 mg). This was hydrogenated using a Parr apparatus for 30 minutes at 50° C. and 26 psi. After filtration and the removal of solvent in vacuo, the filtrate yielded 1.38 g of crude residue. This was subjected to flash chromatography on deactivated silica gel (from a slurry of 300 g of silica gel in methylene chloride containing 3.4 mL of conc. NH4OH). The product was eluted with CH2Cl2 :MeOH:NH4OH 98.8:1.0:0.2 yielding 590 mg of III an off-white solid. This was triturated in methylene chloride-ether to yield a white solid (520 mg, 39% yield).: m.p.>220° C. (dec.).