Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[N:7]=[C:6]([NH:10][C:11]([N:13]3[C:21]4[C:16](=[CH:17][C:18]([O:22][C:23]5[CH:28]=[CH:27][N:26]=[C:25]([CH2:29][N:30](C)[C:31](=O)OC(C)(C)C)[CH:24]=5)=[CH:19][CH:20]=4)[CH:15]=[CH:14]3)=[O:12])[CH:5]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([C:4]2[N:8]([CH3:9])[N:7]=[C:6]([NH:10][C:11]([N:13]3[C:21]4[C:16](=[CH:17][C:18]([O:22][C:23]5[CH:28]=[CH:27][N:26]=[C:25]([CH2:29][NH:30][CH3:31])[CH:24]=5)=[CH:19][CH:20]=4)[CH:15]=[CH:14]3)=[O:12])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CN(Cc1cc(Oc2ccc3c(ccn3C(=O)Nc3cc(C4CC4)n(C)n3)c2)ccn1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cc(C4CC4)n(C)n3)c2)ccn1
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (4-(1-(5-cyclopropyl-1-methyl-1H-pyrazol-3-ylcarbamoyl)-1H-indol-5-yloxy)pyridin-2-yl)methyl(methyl)carbamate (0.124 g, 0.240 mmol) in DCM (5 ml) is added TFA (2 ml, 0.240 mmol). The reaction is stirred for approximately 30 minutes and then concentrated in vacuo to near dryness. The residue is dissolved in DCM, diluted with water and neutralized via the addition of saturated aqueous NaHCO3. The resulting layers are then separated and the aqueous layer is extracted twice with DCM. The organic layers are combined dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue is purified via FCC (0-15% MeOH/DCM) to provide the title compound. MS (ESI) m/z 417.2 (M+1). 1HNMR (400 MHz, DMSO-d6) δ ppm 0.64-0.70 (m, 2H) 0.96-1.02 (m, 2H) 1.87-1.96 (m, 1H) 2.27 (s, 3H) 3.71 (s, 2H) 3.80 (s, 3H) 6.16 (d, J=0.51 Hz, 1H) 6.73 (dd, J=3.79, 0.51 Hz, 1H) 6.80 (dd, J=5.56, 2.53 Hz, 1H) 6.93 (d, J=2.02 Hz, 1H) 7.09 (dd, J=8.97, 2.40 Hz, 1H) 7.42 (d, J=2.27 Hz, 1H) 8.17 (d, J=3.54 Hz, 1H) 8.33 (d, J=8.84 Hz, 1H) 8.36 (d, J=5.81 Hz, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1[CH2:5][C:6]1[NH:7][C:8](=[O:21])[N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[N:10]=1.[C:22]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][CH:37]=1)(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][N:7]2[C:6]([CH2:5][CH:3]3[CH2:4][CH:2]3[CH3:1])=[N:10][N:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]([F:20])([F:19])[F:18])[C:8]2=[O:21])=[CH:38][CH:37]=1)(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC1CC1Cc1nn(-c2ccccc2C(F)(F)F)c(=O)[nH]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Product: CC1CC1Cc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1

Procedure:
The title compound was prepared from 2,4-dihydro-5-[(2-methylcylopropyl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Step E) and [2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl bromide (from Example 12, Step D) according to the procedure of Example 13, Step A. The crude material was purified by flash chromatography over silica gel (gradient elution using 0.3-1.0% MeOH/CH2Cl2) to give a 64% yield of the desired material as a cream-colored solid, homogeneous by TLC in 2% MeOH/CH2Cl2 ; mass spectrum (FAB) m/e 599 (M+1)+ ; mp 128°-130° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[O:21][CH3:22])[N:17]=[CH:16][N:15]=[C:14]3Cl)[CH2:3][CH2:2]1.[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][C:26]=1[Cl:32].Cl>CO>[Cl:32][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:25]=1[F:24])[NH:29][C:14]1[C:13]2[C:18](=[CH:19][C:20]([O:21][CH3:22])=[C:11]([O:10][CH2:9][CH2:8][CH2:7][N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:12]=2)[N:17]=[CH:16][N:15]=1
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCN1CCOCC1
Agent: Cl
Solvent: CO
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCOCC1
Temperature: 17.5 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
Methanol (1200 ml) and 6-(3-morpholino propoxy)-7-methoxy-4-chloro quinazoline (200 gm) were stirred for 15 minutes at 25-30° C., then a solution of 4-fluoro-3-chloroaniline in methanol (213 gm in 400 ml) was charged and refluxed for 6 hours. The reaction mass was cooled to 15-20° C., hydrochloric acid (40 ml) was added drop wise, and stirred at 5-10° C. for 30 minutes. The solid obtained was filtered and washed with chilled methanol (150 ml). The solid was dissolved in a mixture of toluene (30 volume) and methanol (5 volume), the reaction mass was concentrated to half the volume and cooled to 5-10° C. The solid obtained was filtered, washed with toluene (200 ml) and dried at 45-50° C. to yield the title compound (183 gm, 70% yield).
Reaction SMILES: CC1OC(=O)O[C:3]=1[CH2:8][O:9][C:10](=[O:29])[C@H:11]([OH:28])[CH2:12][C@H:13]([NH2:27])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.OC1C=C(C(O)=O)ON=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:8]([O:9][C:10](=[O:29])[C@H:11]([OH:28])[CH2:12][C@H:13]([NH2:27])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)[CH3:3]
Reactant: Cc1oc(=O)oc1COC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: O=C(O)c1cc(O)no1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reaction time: 0.03 h
Yield: 42.5 %

Procedure:
(2R,4R)-4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester (100 mg, 0.3 mmol, 1.0 eq.) and 3-hydroxyisoxazole-5-carboxylic acid (50.5 mg, 391 μmol, 1.5 eq.) were combined in DMF (5 mL) and the resulting mixture was stirred for 2 minutes. DIPEA was added and the resulting mixture was stirred for 1 hour. The material was dried under vacuum then purified using reverse phase chromatography to yield the title compound (40 mg, 98% purity). MS m/z [M+H]+ calc'd for C26H24N2O9, 509.15. found 509.4.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:6][NH:5][C:4]1=[O:7])[CH3:2].[C:8]([O-:11])(=[O:10])[CH3:9].[Na+].C(O)(=O)C.C(OO)(=O)C>C(OCC)(=O)C.O.O.O.[Os](Cl)(Cl)Cl.O>[C:8]([O:11][CH:6]1[NH:5][C:4](=[O:7])[CH:3]1[CH2:1][CH3:2])(=[O:10])[CH3:9]
Reactant: CCC1CNC1=O
Reactant: CC(=O)[O-]
Agent: Cl[Os](Cl)Cl
Agent: CC(=O)OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCC1C(=O)NC1OC(C)=O
Yield: 99.3 %

Procedure:
To a solution prepared by mixing 500 mg (5 mmole) of 3-ethylazetidin-2-one, 415 mg (5 mmole) of anhydrous sodium acetate, 5 ml of acetic acid, and 30 mg (abut 2 mole % based on the amount of 3-ethylazetidin-2-one) of osmium trichloride trihydrate was added dropwise, with stirring , 2.8 g (11 mmole) of a 30% peracetic acid solution in ethyl acetate at room temperature over a period of 2 hours or more. The reaction mixture was further stirred at room temperature for 4 hours, subsequently poured into 80 ml of water, and then extracted thrice with 100 ml of hexane. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation under reduced pressure. The residue was separated and purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1 by volume). Thus, 780 mg of 4-acetoxy-3-ethylazetidin-2-one was obtained. The percent yield was 78%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([NH:7][C:8]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2)=[O:6])[CH3:2].C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:21])[C:5]([NH:7][C:8]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH2:12][NH:13]2)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])ccc2ncccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])ccc2c1C=CCN2
Reaction time: 4 h
Yield: 78 %

Procedure:
A solution of the product from Example 85 (5 g, 17.5 mmol) in 80 mL acetic acid was treated with sodium cyanoborohydride (2.2 g, 35 mmol) portionwise under an argon atmosphere and stirred for 4 hours. Water (100 mL) was added to the reaction mixture, and the resulting solid was collected by filtration and dried (3.9 g, 78% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.CS(Cl)(=O)=O.O[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH:23]=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CCOC(C)=O>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH:23]=[O:24]
Reactant: COc1ccc(C=O)cc1O
Reactant: CN(C)CCO
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C=O)cc1OCCN(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.1 %

Procedure:
To a solution of 2-(dimethylamino)ethanol (5.0 g, 56.0 mmol) and triethylamine (8.5 g, 84.0 mmol) in anhydrous DCM (50 mL) was added methanesulfonyl chloride (7.1 g, 62.0 mmol) at 0° C. under N2. The mixture was stirred at 0° C. for 1 hour. The solvent was removed in vacuo (6.0 g, yield 65%), and the crude was taken up in CH3CN (100 mL). 3-hydroxy-4-methoxybenzaldehyde (5.5 g, 36.0 mmol) and potassium carbonate (13.8 g, 100.0 mol) was added and reaction was refluxed under N2 overnight. An aqueous/EtOAc workup was followed, and crude was purified by silica gel column chromatography (PE:EtOAc=3:1) to give product (2.5 g, yield 31%) as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH2:17]([N:24]1[C:32]2[C:27](=[CH:28][C:29](/[C:33](/[CH3:38])=[CH:34]/[C:35](O)=[O:36])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:24]1[C:32]2[C:27](=[CH:28][C:29](/[C:33](/[CH3:38])=[CH:34]/[C:35]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:36])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2Cc2ccccc2)c1
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2Cc2ccccc2)c1

Procedure:
131 mg of compound 26 was obtained in a similar manner to those described in the Examples 1 and 2 using 223 mg of ethyl 4-(2-aminophenoxy)butyrate and 291 mg of 3-(1-benzylindol-5-yl)isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][C:8](O)=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:15]>C(OCC)(=O)C.O>[Cl:15][C:8]1[N:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncc2ccc(Cl)cc2n1
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1ccc2cnc(Cl)nc2c1
Temperature: 110 °C

Procedure:
In a 250 mL three neck round bottom flask, 7-chloroquinazolin-2-ol (19 g, 105.55 mmol) was suspended in freshly distilled POCl3 (190 mL) at rt. The resulting suspension was heated to 110° C. for 4 h. On completion of reaction, the reaction mixture was cooled to rt and concentrated under reduced pressure. The residue obtained was diluted with ethyl acetate (200 mL) and cold water (200 mL). The organic layer was separated and the aqueous phase was re-extracted with ethyl acetate (500 mL×2). The combined EtOAc extract was washed with brine and concentrated under reduced pressure. The residue (pale brown) obtained was purified by silica gel (60-120 mesh) column chromatography and gradient elution with 12-20% ethyl acetate-hexanes gave 2,7-dichloroquinazoline as a pale yellow solid. Yield: 7 g (33.5%). LCMS (ESI, m/z): 199 (M+1)+.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[OH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:16][CH2:15]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N2CCC(O)CC2)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 15.8 %

Procedure:
To a 20 ml N,N-dimethylformamide solution of 1.0 g (5.95 mmol) of ethyl 4-fluorobenzoate, 662 mg (6.54 mmol) of 4-hydroxypiperidine and 1.23 g (8.92 mmol) of potassium carbonate were added, and the mixture was stirred for 24 hours at 120° C. The reaction mixture was returned to room temperature, and the solvent was distilled off under reduced pressure. Then, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Then, the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue, and precipitated crystals were collected to obtain 234 mg (16%) of the captioned compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH:27]2[CH2:30][C:29](C(O)=O)([C:31]([OH:33])=[O:32])[CH2:28]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.CS(C)=O>O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2)[CH2:26][C@@H:27]1[CH2:30][C@H:29]([C:31]([OH:33])=[O:32])[CH2:28]1
Reactant: O=C(O)C1(C(=O)O)CC(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)[C@H]1C[C@@H](Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1
Temperature: 160 °C
Reaction time: 4 h

Procedure:
3-((3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)-methyl)cyclobutane-1,1-dicarboxylic acid (0.360 g, 0.716 mmol) treated with 4 mL DMSO, fitted with a water cooled reflux condenser, and heated to 160° C. After 4 h, the reaction mixture was cooled to rt. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with water once, satd NaCl once and the organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a light yellow solid, as an approximately 2:1 mixture of isomers. Separation by SFC (Gradient with Chiralpak IC (21×250 mm, 5 micron), pure methanol with CO2 70 mL/min) gave (cis)-3-(3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)benzyl)cyclobutanecarboxylic acid as a white solid. MS (ESI) m/z: calculated: 458.2; Observed: 459.1 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)[S:11][CH:12]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[CH3:42][N:43]([CH2:50][C@H:51]1[CH2:56][CH2:55][C@H:54]([NH2:57])[CH2:53][CH2:52]1)[CH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10](/[CH:13]=[CH:14]/[C:15]([NH:57][C@H:54]3[CH2:53][CH2:52][C@H:51]([CH2:50][N:43]([CH3:42])[CH:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)[CH2:56][CH2:55]3)=[O:17])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CN(C[C@H]1CC[C@H](N)CC1)C1CCOCC1
Reactant: Cc1ccc(-c2csc(/C=C/C(=O)O)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(-c2csc(/C=C/C(=O)N[C@H]3CC[C@H](CN(C)C4CCOCC4)CC3)c2)cc1
Reaction time: 2 h

Procedure:
Into a suspension of (E)-3-[4-(4-methylphenyl)-thiophen-2-yl]acrylic acid (150 mg) and 1-hydroxybenzotriazole (124 mg) in acetonitrile (10 ml) was added at room temperature 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (177 mg), and the resulting mixture was stirred for 2 hours. Into the reaction mixture was added a solution of trans-4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexylamine dihydrochloride (276 mg), 1,8-diazabicyclo[5,4,0]-7-undecene (281 mg) and triethylamine (0.17 ml) in acetonitrile (15 ml), and the resulting mixture was stirred for 16 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After the resulting organic layer was concentrated under reduced pressure to remove the solvent, the residue was subjected to purification using column chromatography (ethanol/ethyl acetate 1:2) and to recrystallization (ethanol) to obtain (trans, E)-3-[4-(4-methylphenyl)thiophen-2-yl]-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexyl]acrylamide (compound 72) (191 mg) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:4]=1[CH2:5][N:6]([C:30]1[S:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[C:28]([F:29])=[CH:27][C:13]2[N:14]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3I)[CH3:19])[C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].[O:41]=[C:42]1[CH2:45][N:44]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:43]1>C1COCC1.CS(C)=O>[CH3:1][O:2][C:3]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:4]=1[CH2:5][N:6]([C:30]1[S:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[C:28]([F:29])=[CH:27][C:13]2[N:14]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:42]3([OH:41])[CH2:43][N:44]([C:46]([O:48][C:49]([CH3:51])([CH3:50])[CH3:52])=[O:47])[CH2:45]3)[CH3:19])[C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)n([C@H](C)c4ccccc4I)c3cc2F)c(OC)c1
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)n([C@H](C)c4ccccc4C4(O)CN(C(=O)OC(C)(C)C)C4)c3cc2F)c(OC)c1
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
In an oven-dried 25 mL RB flask, added (R)—N-(2,4-dimethoxybenzyl)-5-fluoro-3-(1-(2-iodophenyl)ethyl)-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (32-1, 400 mg, 0.574 mmol) to THF (2154 μl) and cooled to −40° C. Was a suspension. Added isopropylmagnesium chloride-lithium chloride complex (1325 μl, 1.723 mmol) dropwise, stirred at −40° C. for 20 min—became a dark orange solution. Following this duration, added tert-butyl 3-oxoazetidine-1-carboxylate (32-2, 295 mg, 1.723 mmol) in THF (718 μl) dropwise via syringe. Solution turned yellow in color. After 60 min at −40° C., partitioned between 10 mL saturated NH4Cl+15 mL EtOAc, separated layers. Back-extracted aqueous with 2×10 mL EtOAc. Dried combined organics over Na2SO4, filtered, concentrated to give a yellow oil. Dissolved in 2 mL DMSO, purified by reverse-phase HPLC (C18 column, 10-90% (0.1% TFA/CH3CN:0.1% TFA/H2O) to give 32-3 as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[N:8]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1.[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][N:23]=1>>[CH:16]1([N:8]2[C:6]3[N:7]=[C:2]([NH:21][C:22]4[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][N:23]=4)[N:3]=[CH:4][C:5]=3[CH:10]=[C:9]2[C:11](=[O:12])[N:13]([CH3:15])[CH3:14])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: COC(=O)c1ccc(Nc2ncc3cc(C(=O)N(C)C)n(C4CCCC4)c3n2)nc1
Yield: 95.1 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (5.0 g, 17 mmol) was combined with methyl 6-aminonicotinate (2.86 g, 1.10 eq) which gave methyl 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinate (6.6 g) in 94% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.33 (s, 1H), 8.89 (s, 1H), 8.83 (d, J=2.1 Hz, 1H), 8.44 (d, J=8.9 Hz, 1H), 8.22 (dd, J=8.9, 2.2 Hz, 1H), 6.67 (s, 1H), 4.77 (m, 1H), 3.86 (s, 3H), 3.06 (s, 6H), 2.42 (m, 2H), 2.00 (m, 4H), 1.68 (m, 2H); MS m/z 409.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.CS(C)=O.C1C=CC=CC=1.[F-:22].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:22]
Reactant: [F-]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reaction time: 2 h
Yield: 63.4 %

Procedure:
50 g of 3,4-dichloro-nitro benzene were added to a mixture of 120 ml of dimethylsulfoxide, 80 ml of benzene and 35 g of potassium fluoride and the mixture was stirred at 180°-185° C. for two hours. The water vapor was entrained and the distillate was extracted with isopropyl ether. The combined organic phases were dried and distilled at 40° C. under a pressure of 3 to 4 mm Hg. The residue was rectified at a pressure of 15 mm Hg to obtain 29 g of 3-chloro-4-fluoro-nitrobenzene melting at 41° to 43° C.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH:12]=[O:13].[BH4-].[Na+].O.C(OCC)(=O)C>CO>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:10])([F:9])[F:11])[C:3]=1[CH2:12][OH:13]
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1nc(C(F)(F)F)c(CO)c1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
A solution of 10.0 g (47.0 mmoles) of 5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 100 ml of methanol was cooled to 0° C. Thereto was gradually added 2.1 g (56.5 mmoles) of sodium borohydride. The mixture was stirred at room temperature for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein, to obtain 8.3 g (yield: 82.2%) of (5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:28])[C:9]([C:11]1[S:27][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24](O)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[NH:29]([CH3:31])[CH3:30].Cl.N1C=CC=CC=1.ClC1C=CC=CC=1N(C)C(C1SC2C3C=CC(C(Cl)=O)=CC=3OCCC=2C=1)=O>O=S(Cl)Cl.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:28])[C:9]([C:11]1[S:27][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]([N:29]([CH3:31])[CH3:30])=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: CNC
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(C(=O)O)cc1OCC2)c1ccccc1Cl
Agent: CN(C(=O)c1cc2c(s1)-c1ccc(C(=O)Cl)cc1OCC2)c1ccccc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 330.7 %

Procedure:
Alternatively, a solution of 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid (100 mg, 0.24 mmol) in 2 mL of SOCl2 was heated at 80° C. for 2 h. After removal of the solvent, the residue was co-evaporated with toluene to give the crude acid chloride 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carbonyl chloride. To a solution of (CH3)2NH HCl salt (118 mg, 1.412 mmol) and pyridine (0.2 mL) in 5 mL of THF was slowly added 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carbonyl chloride (417 mg, 0.966 mmol) in 20 mL of THF. The mixture was stirred at room temperature overnight, concentrated in vacuo, dissolved in ethyl acetate, washed with water and brine, dried over Na2SO4, and concentrated to give 101 (350 mg, yield: 82%). 1H NMR (CDCl3, 400 MHz): δ 6.67-7.59 (m, 8H), 4.16 (t, J=4.8 Hz, 2H), 3.33 (s, 1H), 2.95-2.97 (m, 8H). MS (ESI): 441.1