Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([OH:19])[CH:5]=2.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.O[CH2:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]1>>[Br:1][C:2]1[C:3](=[O:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([F:17])[CH:16]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[CH2:45][CH2:44]1)[CH:5]=2
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Reactant: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Reaction time: 2 h
Yield: 48 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-hydroxy-1H-inden-1-one obtained in Step 5 of Example 36 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, t-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate instead of 4-(2-hydroxyethyl)morpholine, being stirred for 2 h, and being purified by silica gel column chromatography (EtOAc/CH2Cl2=1:1) to obtain the title compound (48%).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[N:3]1[C:7](=[O:8])[CH:6]([CH3:9])[S:5][C:4]1=[N:10][OH:11].[CH3:13][N:14]=[C:15]=[O:16]>CC(C)=O.C(N(CC)CC)C>[CH3:12][N:2]([CH3:1])[N:3]1[C:7](=[O:8])[CH:6]([CH3:9])[S:5][C:4]1=[N:10][O:11][C:15](=[O:16])[NH:14][CH3:13]
Reactant: CC1SC(=NO)N(N(C)C)C1=O
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CNC(=O)ON=C1SC(C)C(=O)N1N(C)C
Reaction time: 24 h
Yield: 325.6 %

Procedure:
A solution of 1.18 g of 3-dimethylamino-5-methyl-2-oximino-4-thiazolidinone in 50 ml acetone, 1.0 g methylisocyanate and 2 drops of triethylamine was placed in a pressure bottle and left standing at room temperature. After 20 hours additional 0.75 ml of methylisocyanate and 2 drops of triethylamine were added and left standing for 24 hours. Concentration yielded 5.0 g of crude product. Crystallized from methylene chloride and isopropyl ether, m.p. 110°-113°C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][CH3:7])[CH2:3][OH:4].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1.CO>C1COCC1>[OH:4][CH2:3][C@@H:2]([NH:1][C:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1)=[O:18])[CH2:5][CH2:6][CH3:7]
Reactant: CCC[C@H](N)CO
Reactant: COc1ccc(N=C=O)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CCC[C@@H](CO)NC(=O)Nc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 105.3 %

Procedure:
A solution of (2S)-2-aminopentan-1-ol (500 mg) in THF (6 mL) was cooled in a dry ice-acetone bath under nitrogen atmosphere, and a solution of 4-methoxyphenyl isocyanate (657 mg) in THF (4 mL) was added dropwise thereto. After the mixture was stirred for 17 hr while gradually warming to room temperature, methanol was added thereto, and the solvent was distilled off under reduced pressure to afford 1-[(2S)-1-hydroxypentan-2-yl]-3-(4-methoxyphenyl)urea (1.17 g).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:35][CH2:36][CH2:37][CH2:38][OH:39])(=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[C:40]1([CH2:46][CH2:47][CH2:48][C:49](O)=[O:50])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:16]([O:35][CH2:36][CH2:37][CH2:38][O:39][C:49](=[O:50])[CH2:48][CH2:47][CH2:46][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: O=C(O)CCCc1ccccc1
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCOC(=O)CCCc1ccccc1

Procedure:
A solution of 1,3-dicyclohexylcarbodiimide (710 mg, 3.45 mmol) and 4-(N,N-dimethylamino)pyridine (475 mg, 3.9 mmol) in methylene chloride (10 ml) was added to a solution of 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (1 g, 3 mmol) and 4-phenylbutanoic acid (520 mg, 3.15 mmol) in methylene chloride (15 ml). The resultant mixture was stirred at room temperature under nitrogen until it was complete as indicated by tlc. The mixture was filtered, concentrated and purified by flash chromatography to yield 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-(4-phenylbutanoyloxy)propane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[CH:6]=[C:5]2[CH3:13].[NH4+].[OH-].CCCCCC.C(Cl)[Cl:23]>O=P(Cl)(Cl)Cl.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:23])[CH:6]=[C:5]2[CH3:13]
Reactant: Cc1cc(=O)[nH]c2ccc(Br)cc12
Reactant: ClCCl
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: CCO
Product: Cc1cc(Cl)nc2ccc(Br)cc12
Temperature: 0 °C

Procedure:
A 0.46 g, (0.0019 mole) sample of 6-bromo-4-methyl-2-(1H)-quinolinone was dissolved in 3.0 ml POCl3 under N2 with stirring and heated to reflux for 2 hours. The solution solidified into a purple gum; 2.0 ml of extra POCl3 was added to dissolve the solid. The solution was then slowly poured onto a vigorously stirred slurry of 8 ml concentrated NH4OH and approximately 75 g of ice. An immediate pink crystalline solid formed. The slurry was transferred to a separatory funnel and extracted with five 30 ml portions of CH2Cl2. The extracts were washed with two 40 ml portions of water and dried over MgSO4. The solvent was removed under vacuum, leaving a rusty red crystalline solid, 0.48 g (97%). The product was taken up in hot absolute ethanol, Norite A decolourising carbon added, and filtered through Celite to yield a yellow liquid. Slow cooling of the ethanolic solution gave very fine, pink crystals, m.p. 139.1°-139.80° C. TLC showed Rf 0.25 on silica with 1:1 hexane:CH2Cl2 eluent. Anal. Calcd. for C10H7BrClN: C, 46.82; H, 2.75; N, 5.46; Br, 31.15; Cl, 13.82. Found: C, 46.97; H, 2.79; N, 5.42; Br, 31.08; Cl, 13.79.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH3:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[CH2:23][CH2:24][NH2:25]>>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:25][CH2:24][CH2:23][C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[CH3:20])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: Cc1ccccc1CCN
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Product: Cc1ccccc1CCNCc1ccc(Oc2ccc(C(N)=O)nc2)c(F)c1
Yield: 64.4 %

Procedure:
Using a method similar to Example 405, using 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.0294 g, 0.113 mmol) and 2-methylphenethylamine (0.017 g, 0.124 mmol) gives the title compound (0.0276 g, 65.2%): TOF MS ES+ 380.2 (M+H)+, HRMS calcd for C22H23N3O2F 380.1774 (M+H)+, found 380.1741, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 30-99% over 19 min], tR=8.2 min, 100% purity.
Reaction SMILES: [CH3:1][C:2]([NH:16]C=O)([CH3:15])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].Cl.CO>>[NH2:16][C:2]([CH3:15])([CH3:1])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14]
Reactant: CC(C)(CCn1c(=O)[nH]c2ccccc21)NC=O
Agent: Cl
Solvent: CO
Product: CC(C)(N)CCn1c(=O)[nH]c2ccccc21
Temperature: 25 °C
Reaction time: 50 h

Procedure:
A mixture of N-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)propyl]formamide (1.1 g) and hydrogen chloride-methanol (80-90% methanol, 18 mL) was stirred at rt for 50 h. The mixture was concentrated in vacuo and the residue was basified by aq. potassium carbonate and the mixture was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to give 0.81 g (3.7 mmol, 73% for 3 steps) of the title compound.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].N[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[SH:13]>C(O)C>[S:13]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:4]=[C:3]1[CH2:2][C:1]1[S:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:5]=1
Reactant: Nc1ccccc1S
Reactant: N#CCC#N
Solvent: CCO
Product: c1ccc2sc(Cc3nc4ccccc4s3)nc2c1
Reaction time: 8 h
Yield: 82 %

Procedure:
To produce the above compound, in a two-neck 100 ml round bottom flask with a condenser and a stir bar, malononitrile (2.64 g, 40 mmol) was dissolved in absolute ethanol (40 ml). 2-amino thiophenol (10 g, 80 mmol) was slowly added to this solution under stirring. Under a nitrogen blanket, the reaction mixture was heated and refluxed for six hours. After cooling, the flask was refrigerated overnight. Pale green crystals of bis(2-benzothiazolyl) methane that formed were recovered following vacuum filtration, washing with hexane and drying (yield: 82%). 2.82 g (10 mmol) of the bis(2-benzothiazolyl) methane was dissolved in chloroform (50 ml) in an erlenmeyer flask. Hydrobromic acid (10 mmol) in glacial acetic acid was added dropwise with gentle stirring. A canary yellow precipitate formed within minutes, causing thickening of the reaction mixture. Stirring was continued for one hour at room temperature. A fine yellow powder was recovered, following filtration and washing with ether. The yield was quantitative and the bis(2-benzothiazolyl) methane monohydrobromide product was sufficiently pure to be used in the next step.
Reaction SMILES: [O:1]=[C:2]([N:12]1[CH2:15][CH:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH2:13]1)/[CH:3]=[CH:4]/[C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[N:9][CH:10]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].C([O-])(O)=O.[Na+]>C1COCC1>[O:1]=[C:2]([N:12]1[CH2:13][CH:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[CH2:15]1)/[CH:3]=[CH:4]/[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:24](=[O:26])[CH3:25])=[N:9][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(/C=C/C(=O)N2CC(OCc3ccncc3)C2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(/C=C/C(=O)N2CC(OCc3ccncc3)C2)cn1
Temperature: 60 °C
Reaction time: 40 h
Yield: 13.1 %

Procedure:
To a solution of 5-{(1E)-3-oxo-3-[3-(pyridin-4-ylmethoxy)azetidin-1-yl]prop-1-en-1-yl}pyridin-2-amine (16 mg, 0.05 mmol) and acetic anhydride (6 μL, 0.06 mmol) in THF (2.4 mL) was added NaHCO3 (5.5 mg, 0.065 mmol). The reaction mixture was warmed at 60° C. and stirred for 40 h. LCMS showed that some starting material was remaining. Another portion of acetic anhydride (6 μL) and NaHCO3 (5.5 mg) were added and the mixture was stirred at 60° C. for 24 h. These additions were repeated twice over 48 h. The mixture was then concentrated, partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed wih brine, dried over sodium sulfate, filtered and concentrated under vacuum to give an oil. The crude was purified on preparative TLC (eluent: 90/10 DCM/MeOH) to give the title compound (2.3 mg, 12%) as a pale yellow solid.
Reaction SMILES: [O:1]=[C:2]([CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[C:3]([OH:5])=[O:4].[CH3:14]N(C)P(=O)(N(C)C)N(C)C>>[O:1]=[C:2]([C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[C:3]([OH:5])=[O:4]
Reactant: CC(C(=O)C(=O)O)c1ccccc1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C(=O)C(=O)O)c1ccccc1
Yield: 2 %

Procedure:
Example 9 was repeated except that 6 ml of hexamethylphosphoric triamide was used instead of t-butyl alcohol as the solvent. A mixture of 2-oxo-3-phenylbutanoic acid (46 %) and 2-oxo-3-methyl-3-phenylbutanoic acid (2 %) was obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[CH:11](=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14]>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:11]([OH:16])[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: c1ccoc1
Reactant: CC(C)CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)CC(O)c1ccco1
Temperature: 25 °C
Yield: 49 %

Procedure:
Furan was added dropwise to a stirred solution of n-butyllithium (2.5M in hexanes, 58.8 ml, 147 mmol) in dry THF (200 ml) at -20° C. under argon. The mixture was allowed to warm to room temperature and was then heated at reflux for 4 h. The mixture was cooled to -30° C. and isovaleraldehyde (12.8 g, 147 mmol) was added dropwise. The mixture was allowed to warm to room temperature and was then heated at reflux for 16 h. The reaction mixture was allowed to cool to room temperature, poured onto crushed ice, extracted with ether and the combined organic extracts dried over anhydrous potassium carbonate, filtered and concentrated to give a dark yellow oil. Distillation under reduced pressure gave 1-(2-furyl)-3-methylbutanol (11.0 g, 49%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:26](=[O:27])[CH2:25][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[CH2:7]1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(Cc1ccc(F)cc1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 23.1 %

Procedure:
Example 4 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.055 g) and (4-fluorophenyl)acetic acid (0.031 g) to give thetitle compound (0.019 g).
Reaction SMILES: [Si]([O:8][C@@H:9]([CH3:36])[C@@H:10]([NH:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29]([Cl:35])[CH:28]=1)[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[N:14][N:15]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:35][C:29]1[CH:28]=[C:27]([NH:26][C@@H:10]([C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)=[N:14][N:15]=2)[C@@H:9]([OH:8])[CH3:36])[CH:34]=[CH:33][C:30]=1[C:31]#[N:32]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(Cl)c1)c1nnc(-c2ccc(S(C)(=O)=O)cc2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1)c1nnc(-c2ccc(S(C)(=O)=O)cc2)o1

Procedure:
To a pre-cooled (−50° C.) solution of 4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-(methylsulfonyl)phenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-chlorobenzonitrile (2.55 g, 4.66 mmol) in THF (600 mL) was added TBAF (4.66 mL, 4.66 mmol, 1 M solution in THF) dropwise over 10 min. Upon complete addition, the reaction mixture was concentrated under reduced pressure. The resulting residue was taken up in EtOAc (100 mL) and washed with H2O (80 mL). The biphasic mixture was separated and the aqueous layer extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (1×70 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography over silica gel (60% EtOAc in hexanes then 100% EtOAc) to provide the title compound as an off-white solid. The resulting solid was diluted with CH2Cl2 (45 mL) and hexanes (90 mL) was added. Upon concentration of the suspension a white solid was provided (0.5 g, 24%). 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.26 (d, J=8.8 Hz, 2H), 8.17 (d, J=9 Hz, 2H), 7.57 (d, J=9 Hz, 1H), 7.14 (s, 1H), 6.98 (d, J=8 Hz, 1H), 6.61 (d, J=9 Hz, 1H), 5.17-5.15 (m, 1H), 4.63-5.53 (m, 2H), 3.2 (s, 3H), and 1.39 (d, J=7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:33])[N:10]1[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[NH:40][S:41]([CH3:44])(=[O:43])=[O:42].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:57][S:58]([NH2:61])(=[O:60])=[O:59].C1CCN2C(=NCCC2)CC1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][O:22][CH2:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:26]([C:27](=[O:28])[NH:61][S:58]([CH3:57])(=[O:60])=[O:59])[CH:25]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:33])[N:10]1[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[NH:40][S:41]([CH3:44])(=[O:43])=[O:42]
Reactant: CS(N)(=O)=O
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2cccc(C(=O)O)c2)C1c1ccc(Cl)cc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)NC(=O)c1cccc(CONC(=O)C2c3ccccc3C(=O)N(C3CCCCC3NS(C)(=O)=O)C2c2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
To a solution of 330 mg of 3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}benzoic acid in 5 ml of DMF was added 122 mg of CDI, followed by stirring at room temperature for 30 minutes. To the reaction solution were added 71 mg of methane sulfonamide and 0.11 ml of DBU, followed by stirring at room temperature for 3 hours. To the reaction solution was added ethyl acetate, followed by washing with 1 M hydrochloric acid and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain a crude purified product. This was recrystallized with acetonitrile-water to obtain 273 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-N-({3-[(methylsulfonyl)carbamoyl]benzyl}oxy)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:36])[CH:11]([CH2:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])C1C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)C>[OH:8][NH:9][C:10](=[O:36])[CH:11]([CH2:24][S:25]([C:28]1[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)(=[O:27])=[O:26])[CH2:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: COc1ccc(S(=O)(=O)CC(CS(=O)(=O)c2ccc(OC)cc2)C(=O)NOCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)CC(CS(=O)(=O)c2ccc(OC)cc2)C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of N-benzyloxy-2-(4-methoxybenzenesulfonylmethyl)-3-(4-methoxybenzenesulfonyl)-propionamide (5.0 g, 9.4 mmol), Pearlman's catalyst (0.9 g), and ethyl alcohol (50 mL) is agitated under hydrogen (20 psig) at room temperature overnight. The reaction mixture is filtered through celite and the soluble solids dissolved with methyl alcohol followed by chloroform/methyl alcohol (9:1). The combined filtrates are concentrated in vacuo to yield N-hydroxy-2-(4-methoxybenzenesulfonylmethyl)-3-(4-methoxybenzenesulfonyl)-propionamide as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[NH2:17][C@@H:18]([CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)[C:19]([N:21]([CH3:23])[CH3:22])=[O:20].C(O)(=O)C.[O-]S([O-])(=O)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O1CCCC1>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH:17][C@@H:18]([CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)[C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: CN(C)C(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C)C(=O)[C@H](Cc1c[nH]c2ccccc12)NC1CCC(c2ccccc2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-(dimethylamino)-4-phenylcyclohexanone (1.1 g, 5.41 mmol) was dissolved in a mixture of 1,2-dichloroethane (30 ml) and tetrahydrofuran (40 ml) in argon, mixed with (S)-2-amino-3-(1H-indol-3-yl)-N,N-dimethylpropanamide (1 g, 4.3 mmol), acetic acid (0.31 ml, 5.41 mmol) and Na2SO4 (2.7 g). The mixture was stirred for 15 min at RT and then mixed with sodium triacetoxyboron hydride (1.65 g, 7.57 mmol) and stirred for 48 hours. For work up of the batch the mixture was mixed with saturated NaHCO3 solution (60 ml) and stirred for 15 min. The aqueous phase was extracted with dichloromethane (2×40 ml). The combined organic phases were concentrated to low volume after drying and a light brown oil was obtained. The chromatographic separation of the substance mixture on silica gel 60 (100 g) was conducted with ethyl acetate/methanol (1:1).
Reaction SMILES: O[N:2]=[C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:12]2)=[CH:7][CH:6]=1)[CH3:4]>[Ni].CO.[OH-].[NH4+]>[CH3:18][O:17][C:15]([N:11]1[CH2:10][CH2:9][C:8]2[C:13](=[CH:14][C:5]([CH:3]([NH2:2])[CH3:4])=[CH:6][CH:7]=2)[CH2:12]1)=[O:16]
Reactant: COC(=O)N1CCc2ccc(C(C)=NO)cc2C1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)N1CCc2ccc(C(C)N)cc2C1
Yield: 70 %

Procedure:
A suspension of 1,2,3,4-tetrahydro-7-[1-(hydroxyimino)ethyl]-isoquinoline-2-carboxylic acid, methyl ester, Preparation 9 (9.9 g, 40 mmol) and Raney nickel (1 mL) in methanol (50 mL) and ammonium hydroxide (15 mL) was hydrogenated (H2, 50 psi) for 3 days. The reaction mixture was then filtered and the resultant filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica using a gradient system of solvents: ethyl acetate (100%) to ammonium hydroxide/methanol (30%). The product was obtained as an oil (6.55 g, 70%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH3:16])[CH2:14][N:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:12]3)=[C:8]([C:21]([NH2:23])=[O:22])[CH:7]=[N:6][N:5]2[CH:24]=1.[CH3:25][NH:26][C:27](=[O:43])[C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[CH3:16][C@H:15]1[CH2:14][N:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:12][C@H:11]1[NH:10][C:9]1[C:4]2[N:5]([CH:24]=[C:2]([C:31]3[CH:30]=[N:29][C:28]([C:27](=[O:43])[NH:26][CH3:25])=[CH:33][CH:32]=3)[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:21]([NH2:23])=[O:22]
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@H]1CN(S(C)(=O)=O)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Product: CNC(=O)c1ccc(-c2cc3c(N[C@@H]4CN(S(C)(=O)=O)C[C@@H]4C)c(C(N)=O)cnn3c2)cn1

Procedure:
The title compound was prepared from 6-bromo-4-((3S,4S)-4-methyl-1-(methylsulfonyl)pyrrolidin-3-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide using the method previously described in Step 2 of Example 191 and by replacing 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane with N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide. LCMS (method H) retention time=1.09 min. (MH+472.2). 1H NMR (500 MHz, DMSO-d6, appeared as rotomers) δ 11.19 (d, J=7.9 Hz, 1H), 9.11 (d, J=2.0 Hz, 1H), 8.70 (q, J=4.5 Hz, 1H), 8.51 (d, J=1.5 Hz, 1H), 8.41 (dd, J=8.2, 2.2 Hz, 1H), 8.31 (s, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.87 (br. s., 1H), 7.48 (d, J=1.5 Hz, 1H), 7.23 (br. s., 1H), 5.04-4.92 (m, 1H), 3.86-3.63 (m, 2H), 3.38 (d, J=1.5 Hz, 1H), 3.03 (t, J=9.9 Hz, 1H), 2.89 (s, 3H), 2.84 (d, J=5.0 Hz, 3H), 2.72-2.64 (m, 1H), 1.09 (d, J=6.9 Hz, 3H).