Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[CH:6]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:50]([C:52]([OH:84])([CH2:82][CH3:83])[CH:53]=[CH:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]([CH2:79][CH3:80])([C:64]2[CH:69]=[CH:68][C:67](B3OC(C)(C)C(C)(C)O3)=[CH:66][CH:65]=2)[CH2:62][CH3:63])=[CH:57][C:56]=1[CH3:81])[CH3:51].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[C:7]([C:67]2[CH:66]=[CH:65][C:64]([C:61]([CH2:79][CH3:80])([C:58]3[CH:59]=[CH:60][C:55](/[CH:54]=[CH:53]/[C:52]([CH2:82][CH3:83])([OH:84])[CH2:50][CH3:51])=[C:56]([CH3:81])[CH:57]=3)[CH2:62][CH3:63])=[CH:69][CH:68]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCC(O)(C=Cc1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1C)CC
Reactant: COC(=O)Cc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3cccc(CC(=O)OC)c3)cc2)cc1C)CC
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 81.3 %

Procedure:
(3-Bromo-phenyl)acetic acid methyl ester (Tetrahedron Letters 44 (2003) 331-334; 26 mg, 0.114 mmol), palladium acetate (1.8 mg, 0.008 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (6.2 mg, 0.015 mmol), potassium phosphate (48 mg, 0.228 mmol) and water (0.2 mL) were added to a solution of 3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example 39-(5); 36.3 mg, 0.076 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for 2.5 hours. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the target compound as a colorless oil (30.8 mg, 81%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[O:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16](O)=[O:17])[CH2:11][CH2:10]1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[O:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH:2][C@@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5])=[O:17])[CH2:11][CH2:10]1
Reactant: O=C(O)CN1CCOCC1
Reactant: COC(=O)[C@H](C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](C)NC(=O)CN1CCOCC1
Reaction time: 0.25 h

Procedure:
To (S)-methyl 2-aminopropanoate HCl salt (5.0 g, 35.8 mmol) in DMF (30 mL) at 0° C. was added morpholinoacetic acid (5.19 g, 35.8 mmol), HOBt (7.74 g, 57.3 mmol), HBTU (21.7 g, 57.3 mmol), followed by DIEA (24.9 mL, 0.143 mol). The mixture was allowed to stir for 15 min at which time it was quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated to provide (S)-methyl 2-(2-morpholinoacetamido)propanoate (quant. yield) as a colorless solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[C:10]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]2[CH3:35])[C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([O:27][CH3:28])[CH:19]=3)=[N:14][C:12]=2[N:13]=1.[CH3:36][N:37](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C(N(CC)CC)C>C1COCC1>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[C:10]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]2[CH3:35])[C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:37][CH3:36])=[O:23])=[C:20]([O:27][CH3:28])[CH:19]=3)=[N:14][C:12]=2[N:13]=1
Reactant: COc1cc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)ccc1C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)c1ccc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-benzoic acid (1 equiv) was dissolved in THF (0.1 M) and HBTU (1.5 equiv) was added. Methylamine in THF (15 equiv) was added dropwise followed by triethylamine (1.5 equiv) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and CH2Cl2. The aqueous phase was extracted with CH2Cl2. Combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by preparative HPLC to give the desired product.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:12]1[CH:17]=[CH:16][C:15]([S:18]([F:23])([F:22])([F:21])([F:20])[F:19])=[CH:14][CH:13]=1>O.[Ru](=O)=O>[F:19][S:18]([F:20])([F:21])([F:22])([F:23])[C:15]1[CH:14]=[CH:13][C:12]([C@H:6]2[O:7][C@@H:3]([CH2:1][OH:2])[CH2:4][CH2:5]2)=[CH:17][CH:16]=1
Reactant: FS(F)(F)(F)(F)c1ccc(Br)cc1
Reactant: O=Cc1ccc(B(O)O)o1
Agent: O=[Ru]=O
Solvent: O
Product: OC[C@H]1CC[C@@H](c2ccc(S(F)(F)(F)(F)F)cc2)O1

Procedure:
The requisite {cis-5-[4-(pentafluoro-λ6-sulfanyl)phenyl]tetrahydrofuran-2-yl}methanol was prepared via Suzuki reaction of (5-formylfuran-2-yl)boronic acid with 1-bromo-4-(pentafluoro-λ6-sulfanyl)benzene, followed by hydrogenation in the presence of ruthenium(IV) oxide hydrate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH2:21]>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[N:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: N#Cc1cnc2ncc([N+](=O)[O-])cc2c1Cl
Reactant: Nc1ccc(F)c(Cl)c1
Product: N#Cc1cnc2ncc([N+](=O)[O-])cc2c1Nc1ccc(F)c(Cl)c1
Yield: 95.8 %

Procedure:
By using the method of Example 21, 2.5 g (10.66 mmol) of 4-chloro-6-nitro-[1.8]naphthyridine-3-carbonitrile and 1.55 g (10.66 mmol) of 3-chloro-4-fluoro-aniline was converted to 3.51 g of the title compound, a yellow solid, as its hydrochloride salt: mass spectrum (electrospray, m/e): M+H 344.1.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([Cl:30])=[C:17]([S:19]([NH:22][Si](C(C)(C)C)(C)C)(=[O:21])=[O:20])[CH:18]=3)=[O:12])=[CH:8][CH:9]=2)[N:4]([Si](C(C)(C)C)(C)C)[CH:3]=1.[CH3:38][C:39]1[CH:44]=[C:43](B(O)O)[CH:42]=[CH:41][N:40]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(COC)OC.O>[Cl:30][C:16]1[CH:15]=[CH:14][C:13]([C:11]([C:7]2[CH:6]=[C:5]3[C:10]([C:2]([C:43]4[CH:42]=[CH:41][N:40]=[C:39]([CH3:38])[CH:44]=4)=[CH:3][NH:4]3)=[CH:9][CH:8]=2)=[O:12])=[CH:18][C:17]=1[S:19]([NH2:22])(=[O:20])=[O:21]
Reactant: Cc1cc(B(O)O)ccn1
Reactant: CC(C)(C)[Si](C)(C)NS(=O)(=O)c1cc(C(=O)c2ccc3c(Br)cn([Si](C)(C)C(C)(C)C)c3c2)ccc1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2c[nH]c3cc(C(=O)c4ccc(Cl)c(S(N)(=O)=O)c4)ccc23)ccn1
Temperature: 130 °C

Procedure:
To a mixture of 0.1 g of 5-[3-bromo-1-(tert-butyl-dimethyl-silyl)-1H-indole-6-carbonyl]-2-chloro-N-(tert-butyl-dimethyl-silyl)-benzenesulfonamide, 0.095 g of crude (2-methyl-4-pyridinyl)-boronic acid and 0.025 g of 1,1′-bis(diphenylphosphino)-ferrocenedichloropalladium(II)-dichloromethane complex in dimethoxyethane (3.6 mL) is added 0.099 g of tri-potassium phosphate in water (1.2 mL). The solution is heated to 130° C. for 5 minutes (microwave irradiation). The reaction mixture is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated to 0.071 g of crude product. Purification via flash chromatography on silica gel (95:5:0.5 methylene chloride/methanol/ammonium hydroxide) afforded 2-chloro-5-[3-(2-methyl-pyridin-4-yl)-1H-indole-6-carbonyl]-benzenesulfonamide as a tan powder. MS (m/z): 424 (M−1); Rf 0.06 (95:5:0.5 methylene chloride/methanol/ammonium hydroxide).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][NH2:18])[C@H:13]([OH:19])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C@H:13]([OH:19])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccccn1
Reactant: NC[C@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1O
Product: O=C(OCc1ccccc1)N1CC[C@H](CNc2ccccn2)[C@H](O)C1
Temperature: 120 °C

Procedure:
A mixture of (cis)-4-aminomethyl-3-hydroxy-piperidine-1-carboxylic acid benzyl ester (0.1 g, 378 mmol) and 2-fluoropyridine (0.25 mL) was heated to 120° C. for 24 h. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent evaporated to give a (cis)-3-hydroxy-4-(pyridin-2-ylaminomethyl)-piperidine-1-carboxylic acid benzyl ester crude product, which was purified by flash column chromatography (50% EtOAc hexane to 5% MeOH EtOAc). M.S (M+1): 342
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8]CC2C=CC(OC)=CC=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])F.BrC1C=C(C(F)F)[C:26](Cl)=[N:27]C=1>>[NH2:8][C:5]1[CH:4]=[C:3]([CH:18]([F:20])[F:21])[C:2]([C:26]#[N:27])=[N:7][CH:6]=1
Reactant: FC(F)c1cc(Br)cnc1Cl
Reactant: COc1ccc(CNc2cnc(Cl)c(C(F)(F)F)c2)cc1
Product: N#Cc1ncc(N)cc1C(F)F

Procedure:
The title compound was synthesized as described in Intermediate 1 (Steps 3-5) using 5-bromo-2-chloro-3-(difluoromethyl)pyridine as the starting material. 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, 1H), 7.28-7.01 (m, 2H), 6.80 (s, 2H). LCMS [M+H]+ 170.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.I[CH2:10][CH3:11]>>[CH2:10]([N:1]1[CH2:6][CH:5]=[C:4]([CH2:7][OH:8])[CH2:3][CH2:2]1)[CH3:11]
Reactant: CCI
Reactant: OCc1ccncc1
Product: CCN1CC=C(CO)CC1

Procedure:
The title compound was prepared from 4-pyridylcarbinol and iodoethane following a similar procedure to that described for the 1-methyl analogue in J. Med. Chem., 1988, 31, 545(92%).
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:10])([CH3:9])[S:4]1)[OH:2].[CH:11]1([N:15]=[C:16]=[O:17])[CH2:14][CH2:13][CH2:12]1>>[CH:11]1([NH:15][C:16]([O:2][N:1]=[C:3]2[N:7]=[C:6]([CH3:8])[C:5]([CH3:10])([CH3:9])[S:4]2)=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: O=C=NC1CCC1
Reactant: CC1=NC(=NO)SC1(C)C
Product: CC1=NC(=NOC(=O)NC2CCC2)SC1(C)C

Procedure:
2-oxo-4,5,5-trimethyl-3-thiazoline-oxime was reacted with cyclobutyl isocyanate as described in Example 4 to yield 2-oxo-4,5,5-trimethyl-3-thiazoline-O-(cyclobutylcarbamoyl)-oxime, m.p. 94°-96° C.
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O:15]C(OCC)CCO)C.C(OC(OCC)C(O)CO)C>>[Br:1][C:2]1[C:7]2[O:8][CH2:9][CH:10]([OH:15])[CH2:11][NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2c1OCCCN2
Reactant: CCOC(CCO)OCC
Agent: CCOC(OCC)C(O)CO
Product: OC1CNc2cccc(Br)c2OC1

Procedure:
9-Bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ol was prepared using a procedure analogous to 9-bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine except that 3,3-diethoxypropan-1-ol was replaced by 3,3-diethoxypropane-1,2-diol. LCMS, [M+H]+=246.1. 1H NMR (400 MHz, CDCl3) δ 7.11 (dd, J=7.7, 1.8 Hz, 1H), 6.81-6.69 (m, 2H), 4.37 (ddd, J=12.3, 3.7, 1.3 Hz, 1H), 3.99 (br. s., 1H), 3.93 (dd, J=12.3, 2.2 Hz, 1H), 3.57 (br. s., 1H), 3.40 (dd, J=13.0, 4.0 Hz, 1H), 3.22 (dd, J=13.0, 2.4 Hz, 1H), 3.01 (br. s., 1H).
Reaction SMILES: [C:1]([N:11](C)[C@H:12]([C:16]([NH:18][C@H:19]([C:32]([NH2:34])=[O:33])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])(OCC1C=CC=CC=1)=O.[H][H]>[OH-].[OH-].[Pd+2].CO>[NH:11]([CH3:1])[C@H:12]([C:16]([NH:18][C@H:19]([C:32]([NH2:34])=[O:33])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:29])([CH3:31])[CH3:30])[CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)[C@@H](C(=O)N[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN[C@H](C(=O)N[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)C(C)C
Yield: 87.1 %

Procedure:
A mixture of the thus obtained Z-N-Me-Val-Tyr(3-tBu)-NH2 (1.7 g), 20% palladium hydroxide/carbon (0.15 g) and methanol (30 ml) was stirred at room temperature in a hydrogen atmosphere for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: methylene chloride:methanol=10:1), giving the titled compound (1.07 g, 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][N:16]([CH3:34])[C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=2)[CH2:21][CH2:20]1)=[O:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S([O-])(O)=O.[Na+]>O.CC(N(C)C)=O>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:32]([C:29]1[CH:28]=[CH:27][C:26]([O:25][CH:22]3[CH2:23][CH2:24][N:19]([C:17]([N:16]([CH3:15])[CH3:34])=[O:18])[CH2:20][CH2:21]3)=[CH:31][CH:30]=1)=[N:1]2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CN(C)C(=O)N1CCC(Oc2ccc(C=O)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OC4CCN(C(=O)N(C)C)CC4)cc3)nc2c1
Temperature: 115 °C
Reaction time: 17 h

Procedure:
To a 100 mL round-bottom flask was added 2-amino-4,6-dimethoxybenzamide (196 mg, 1.00 mmol), 4-(4-formylphenoxy)-piperidine-1-carboxylic acid dimethylamide (300 mg, 1.10 mmol), p-toluenesulfonic acid monohydrate (21 mg, 0.10 mmol), sodium hydrogensulfite (216 mg, 1.20 mmol) and dimethylacetamide (5 mL). The mixture was stirred at 115° C. under N2 for 17 hours and cooled to room temperature. Water (20 mL) was added and stirred for 0.5 hours. The precipitate was filtered off, washed with water, and air dried. The crude product was purified by column chromatography (SiO2, neat ethyl acetate, then ethyl acetate/methanol=19:1, then CH2Cl2/methanol=19:1) to afford the title compound as a white solid. Yield: 110 mg (24%). MP 248-249° C. 1H NMR (400 MHz, DMSO-d6): δ 11.91 (s, 1H), 8.15 (d, J=8.8 Hz, 2H), 7.10 (d, J=8.8 Hz, 2H), 6.72 (s, 1H), 6.51 (s, 1H), 4.71-4.69 (m, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.44-3.39 (m, 2H), 3.06-2.99 (m, 2H), 2.74 (s, 6H), 2.00-1.96 (m, 2H), 1.64-1.59 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[NH:12][C@@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[F:25][C:26]1[CH:59]=[CH:58][C:29]([C:30](/[N:32]=[C:33]2/N([C@H]3CC[C@@H](C(=O)NC(C)C)CC3)C3C=C(S(C)(=O)=O)N=CC=3N/2)=[O:31])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([C:30](/[N:32]=[C:33]2\[NH:1][C:2]3[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=3[N:12]\2[C@H:13]2[CH2:14][CH2:15][C@@H:16]([C:19](=[O:20])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:17][CH2:18]2)=[O:31])=[CH:58][CH:59]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3cnc(S(C)(=O)=O)cc32)CC1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(S(C)(=O)=O)ccc2N)CC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(S(C)(=O)=O)cc32)CC1

Procedure:
The title compound was prepared from cis-4-(2-amino-5-(methylsulfonyl) phenylamino)-N-isopropylcyclohexanecarboxamide using a method analogous to that used in the preparation of (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(methylsulfonyl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide, as an off-white solid (0.111 g, 75% yield). MS, m/z (C25H29FN4O4S): calcd, 500.59. found 501.2 [M+H]. 1H NMR (400 MHz, DMSO-d6) d ppm 1.09 (d, J=6.55 Hz, 6H) 1.62-1.81 (m, 4H) 2.14 (m, J=13.10 Hz, 2H) 2.51-2.57 (m, 2H) 2.75-2.91 (m, 2H) 3.28 (s, 3H) 3.99-4.10 (m, 1H) 4.72-4.88 (m, 1H) 7.22-7.29 (m, 2H) 7.64 (d, J=7.73 Hz, 1H) 7.68-7.79 (m, 2H) 8.23-8.27 (m, 1H) 8.32-8.40 (m, 2H) 13.04 (br. s, 1H). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (d, J=6.55 Hz, 6H) 1.62-1.81 (m, 4H) 2.09-2.19 (m, 2H) 2.51-2.57 (m, 2H) 2.75-2.91 (m, 2H) 3.28 (s, 3H) 4.05 (sxt, J=6.94 Hz, 1H) 4.72-4.88 (m, 1H) 7.25 (s, 2H) 7.64 (d, J=7.73 Hz, 1H) 7.68-7.79 (m, 2H) 8.23-8.27 (m, 1H) 8.32-8.40 (m, 2H) 13.04 (br. s, 1H).
Reaction SMILES: CC1N(CCC2CCNCC2)C=CN=1.[C:15]([Cl:34])(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]CCCCCC>>[C:15]([Cl:34])(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: Cc1nccn1CCC1CCNCC1
Product: CCCCCCCCCCCC(=O)Cl

Procedure:
Following essentially the last step of the procedure for preparing the compound of Example 1, and using in place of stearoyl chloride, an approximately equivalent amount of dodecanoyl chloride, a solid was obtained.
Reaction SMILES: O.[O:2]=[CH:3][C:4]([Cl:7])([Cl:6])[Cl:5].[CH2:8]([OH:13])[CH2:9][CH2:10][CH2:11][CH3:12]>C1C=CC=CC=1>[CH2:8]([O:2][CH:3]([O:13][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:4]([Cl:7])([Cl:6])[Cl:5])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: CCCCCO
Solvent: c1ccccc1
Solvent: O
Product: CCCCCOC(OCCCCC)C(Cl)(Cl)Cl

Procedure:
A mixture of 5 g of chloral-hydrate, 10 ml of amyl-alcohol, 0.1 g of 4-methyl-sulphonic acid and 50 ml of benzene is kept at reflux temperature and the formed water is separated by means of a Dean-Stark apparatus. After a reaction time of 9 hours the benzene is washed with a sodium hydrogen carbonate solution and water, dried on magnesium sulfate, then it is vacuum-distilled.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][C:25]([O:27]C)=[O:26])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:29](=[O:31])[NH2:30].[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][C:25]([OH:27])=[O:26])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:29](=[O:31])[NH2:30]
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
A suspension of the {9-[(2,6-difluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (85 mg, 0.2 mM) and 0.22 mL (0.22 mM) of 1 N NaOH in 5 mL of ethanol was stirred for 18 hours at 25° C. A small volume of diethyl ether/hexanes was added, then cooled in the refrigerator. The resultant white precipitate was collected by filtration, washed with a small amount of EtOH/diethyl ether/hexanes, then dried in vacuo to afford 82 mg (95%) of the {9-[(2,6-difluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a white powder. 1H NMR (DMSO-d6) δ7.6 (d, 1H, J=8 Hz), 7.55 (br s, 1H), 7.45-7.3 (m, 3H), 7.25 (t, 1H, J=8 Hz), 7.1-7.0 (m, 4H), 6.5 (d, 1H, J=8 Hz), 5.65 (s, 2H), and 4.3 (s, 2H). IR (KBr, cm−1) 3470, 3360, 1658, and 1606. MS (ES) m/e 409, 411, 433.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](C1C2N=NNC=2C=CC=1)=[O:4].[CH2:16]([CH:19]1[CH2:24][CH2:23][CH:22]([CH:25]2[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][OH:33])[CH2:27][CH2:26]2)[CH2:21][CH2:20]1)[CH2:17][CH3:18]>C1COCC1>[CH2:16]([CH:19]1[CH2:24][CH2:23][CH:22]([CH:25]2[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][O:33][C:3](=[O:4])[C:2]([F:15])([F:14])[F:1])[CH2:27][CH2:26]2)[CH2:21][CH2:20]1)[CH2:17][CH3:18]
Reactant: CCCC1CCC(C2CCC(CCO)CC2)CC1
Reactant: O=C(c1cccc2[nH]nnc12)C(F)(F)F
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCC(CCOC(=O)C(F)(F)F)CC2)CC1

Procedure:
Trifluoroacetylbenzotriazole in an amount of 7.0 g (33 mmol) was dissolved in 70 ml of THF, 5.0 g (20 mmol) of 2-(4-(4-propylcyclohexyl)cyclohexyl)ethanol was added thereto, they were refluxed for 1 hour, and then the solvent was distilled off. After the residue was purified by column chromatography on silica gel (eluent: heptane/ethyl acetate=5/1), the solvent was distilled off, and the residue was subjected twice to recrystallization by using heptane to give 2.9 g (8.3 mmol) of trifluoroacetic acid 2-(4-(4-propylcyclohexyl)cyclohexyl)-ethyl ester. Yield of this compound based on 2-(4-(4-propylcyclohexyl)cyclohexyl)ethanol was 42%.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8][OH:9])=[CH:5][CH:4]=1.ClN1C(=O)CCC1=O.[CH:21]([P:23](=[O:28])([O:26][CH3:27])[O:24][CH3:25])=[CH2:22].C(N(CC)CC)C>>[CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]2[CH2:22][CH:21]([P:23](=[O:28])([O:26][CH3:27])[O:24][CH3:25])[O:9][N:8]=2)=[CH:5][CH:4]=1
Reactant: C=CP(=O)(OC)OC
Reactant: CN(C)c1ccc(C=NO)cc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Product: COP(=O)(OC)C1CC(c2ccc(N(C)C)cc2)=NO1
Yield: 46.7 %

Procedure:
In analogy to Example 1, 40 g (0.24 mol) of 4-dimethylaminobenzaldoxime, 36.17 g (0.27 mol) of N-chlorosuccinimide, 32.7 g (0.24 mol) of dimethyl vinylphosphonate and 52.3 ml (0.376 mol) of triethylamine are reacted. The resulting oily crude product is purified by chromatography on silica gel and recrystallization from tert.butyl methyl ether. 33.4 g of the isoxazoline of melting point 123° C. (decomposition) are obtained.
Reaction SMILES: Cl[C:2]1[S:10][C:9]2[C:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])=[N:7][C:6]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:5][C:4]=2[CH:3]=1.[CH3:26][NH:27][CH3:28].O>CC(N(C)C)=O>[CH3:26][N:27]([CH3:28])[C:2]1[S:10][C:9]2[C:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])=[N:7][C:6]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:5][C:4]=2[CH:3]=1
Reactant: O=C(c1cccs1)c1nc(NCc2cccnc2)nc2cc(Cl)sc12
Reactant: CNC
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C)c1cc2nc(NCc3cccnc3)nc(C(=O)c3cccs3)c2s1
Temperature: 170 °C
Reaction time: 0.25 h
Yield: 42 %

Procedure:
A stirred solution of Example 5 (0.02 g, 0.052 mmol) in dimethylacetamide (1.5 ml) was treated with dimethylamine (2.0M in THF, 0.52 mmol). The solution was heated to 170° C. for 30 min in a microwave reactor. The cooled solution was poured onto stirred iced water (20 ml). After 15 min stirring, an orange solid was filtered. Recrystallisation from hot ethyl acetate gave the title compound in 42% yield, >95% purity. LC-MS m/z=396.0 [M+H]+; RT=2.97; LC-MS method 1. 1H NMR: δH (400 MHz, D6-DMSO) 3.13 (6H, s), 4.68 (2H, bd), 5.91 (1H, s), 7.26-8.61 (8H, m).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:4](=[O:18])[CH:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+].S(OC)(O[CH3:31])(=O)=O.C([N+](CC)(CC)CC)C1C=CC=CC=1>O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[CH3:1][N:2]1[C:6]([NH:7][CH3:31])=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:9]=2)[C:4](=[O:18])[CH:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN1C(N)=C(c2cccc(C(F)(F)F)c2)C(=O)C1c1ccccc1
Reactant: COS(=O)(=O)OC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CNC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2)N1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In this example, 4.1 g of 1-methyl-2-phenyl-3-oxo-4-(3-trifluoromethylphenyl)-5-amino-4-pyrroline, was added to 100 ml of methylene chloride containing 1.0 g of sodium hydroxide, dissolved in 4.0 ml of water, and 0.28 g of benzyltriethylammonium chloride at room temperature. Dimethyl sulfate (1.17 ml) dissolved in 20 ml of methylene chloride was admixed dropwise to the aforementioned mixture at room temperature. After the addition was complete, another 0.28 g of benzyltriethylammonium was added and the mixture was stirred at room temperature for 18 hours. At the end of this time, a white precipitate was collected from the mixture by filtration. This solid was stirred with 50 ml of 1N aqueous hydrochloric acid for two hours after which it was collected with suction filtration and washed with aqueous sodium bicarbonate solution followed by water. The solid was dried affording 1.0 g of the title compound as a white powder.