Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([I:12])[NH:8][C:7]=1[CH3:13])=[O:5])[CH3:2].[CH3:14]OS(C1C=CC(C)=CC=1)(=O)=O.CC(C)([O-])C.[Na+]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([I:12])[N:8]([CH3:14])[C:7]=1[CH3:13])=[O:5])[CH3:2]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)c1c(C)[nH]c(I)c1C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)c(I)n(C)c1C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
5-Iodo-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6d (4.1 g, 13.99 mmol) was dissolved in 80 mL of tetrahydrofuran followed by addition of 4-methyl-benzenesulfonic acid methyl ester (2.73 g, 14.69 mmol) and sodium tert-butoxide (2.02 g, 20.99 mmol). Upon completion of the addition, the reaction mixture was stirred for 0.5 hours and monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure to obtain the title compound 5-iodo-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6e (3.8 g, yield 88.6%) as a grey solid.
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].Br[CH:18]([CH2:24][C:25]([NH2:27])=[O:26])[C:19](OCC)=[O:20]>C(O)C>[C:2]([NH:5][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:24]1[CH2:18][C:19](=[O:20])[NH:27][C:25]1=[O:26])(=[O:4])[CH3:3]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCOC(=O)C(Br)CC(N)=O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(NC(C)=O)(C(=O)OCC)C1CC(=O)NC1=O

Procedure:
In 100 ml of ethanol was dissolved 3.4 g of sodium, and following addition of 32 g of diethyl acetylaminomalonate, the mixture was refluxed for 2 hours. To the reaction mixture was added dropwise a solution of 16.5 g of ethyl 2-bromosuccinamate in ethanol (40 ml) and under stirring the mixture was refluxed for 30 minutes. This reaction mixture was concentrated under reduced pressure, followed by addition of ethyl acetate and water, and stirred. The aqueous layer was separated and the ethyl acetate layer was extracted with water. These aqueous extracts were combined, washed with ethyl acetate, adjusted to pH 1.5 with conc. hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the residue was added ethyl ether and the mixture was allowed to stand in a refrigerator, whereupon crystals separated out. Yield 7.3 g.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]2[CH2:15][N:14]([CH3:16])[CH2:13]2)[CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([C:34](=[O:46])[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=2)[CH2:29][CH2:28]3)O1.O1CCOCC1.C([O-])(O)=O.[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][N:14]1[CH2:15][CH:12]([N:4]2[C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH2:11])[C:10]=3[C:2]([C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[N:30]([C:34](=[O:46])[CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:43])[F:44])[CH:37]=3)[CH2:29][CH2:28]4)=[CH:3]2)[CH2:13]1
Reactant: CC1(C)OB(c2ccc3c(c2)CCN3C(=O)Cc2cccc(C(F)(F)F)c2)OC1(C)C
Reactant: CN1CC(n2cc(Br)c3c(N)ncnc32)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CC(n2cc(-c3ccc4c(c3)CCN4C(=O)Cc3cccc(C(F)(F)F)c3)c3c(N)ncnc32)C1
Temperature: 100 °C
Yield: 13.2 %

Procedure:
To 5-bromo-7-(1-methyl-3-azetidinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (64 mg, 0.227 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indole (137 mg, 0.318 mmol) were added 1,4-Dioxane (2 mL) and saturated NaHCO3 (1 mL) in a 5 ml sealable vessel. The mixture was then bubbled with N2 gas for 5 minutes and Pd(Ph3P)4 (26.2 mg, 0.023 mmol) was added and the vessel was capped. The reaction was then heated at 100° C. overnight. The reaction was then diluted with water (2 ml) then extracted with EtOAc (3×3 ml). The organics were then combined and washed with brine, dried over MgSO4, filtered and concentrated. The crude product was then dissolved in 3 mL of DMSO and purified by HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 20% ACN/H2O, 0.1% TFA to 45% ACN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. To the water left behind was added saturated NaHCO3 and then the mixture was extracted with EtOAc (3×15 mL). The organics were combined and washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated. Then the product was transferred to a 40 mL vial with MeCN then water was added and the solution was freeze-dried to give 7-(1-methyl-3-azetidinyl)-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (15 mg, 0.030 mmol, 13.06% yield) as a white solid. LC/MS (ES) m/z=507.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 8.14 (d, J=8.08 Hz, 1H), 7.69 (s, 1H), 7.57-7.67 (m, 4H), 7.38 (s, 1H), 7.27 (d, J=8.08 Hz, 1H), 6.16 (br. s., 2H), 5.41 (quin, J=7.20 Hz, 1H), 4.28 (t, J=8.34 Hz, 2H), 4.06-4.13 (m, 2H), 4.04 (s, 2H), 3.90-3.99 (m, 2H), 3.24-3.29 (m, 2H), 2.65 (br. s., 3H).
Reaction SMILES: C([O:3][C:4]([CH:6]([NH:15][CH:16]1[C:22](=[O:23])[N:21]([CH2:24][C:25]([O:27]CC)=[O:26])[CH:20]2[CH2:30][CH:31]=[CH:32][CH:33]=[C:19]2[S:18][CH2:17]1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])C.[OH-].[Na+]>>[C:4]([CH:6]([NH:15][CH:16]1[C:22](=[O:23])[N:21]([CH2:24][C:25]([OH:27])=[O:26])[CH:20]2[CH2:30][CH:31]=[CH:32][CH:33]=[C:19]2[S:18][CH2:17]1)[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)OCC)CSC2=CC=CCC21
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)O)CSC2=CC=CCC21

Procedure:
The diethyl ester product from part (f) is treated with sodium hydroxide according to the procedure of Example 1(h) to yield (±)-dihydro-3-[(1-carboxy-3-phenylpropyl)amino]-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5]2([CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]2)[O:4][CH2:3]1.[ClH:18]>O1CCOCC1>[ClH:18].[O:4]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7]2)[CH2:6][CH:2]([OH:1])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(O)CO2)C1
Agent: Cl
Solvent: C1COCCO1
Product: OC1COC2(CCNC2)C1
Yield: 58 %

Procedure:
A mixture of tert-butyl 3-hydroxy-1-oxa-7-azaspiro[4.4]nonane-7-carboxylate (CAN 1331825-50-3, 33 mg, 136 μmol) and a 4 M solution of HCl in dioxane (339 μL, 1.36 mmol) in dioxane (0.3 mL) was stirred at ambient temperature for 3 h to give the title compound (14 mg, 58%) as light brown oil which was sufficiently pure to be used in the next step; MS (EI): m/e=144.2 [(M-Cl)H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)=[O:19])=[O:10])=[N:6][CH:7]=1.[BH4-].[Na+]>CN(C=O)C.[Co](Cl)Cl>[NH2:27][CH2:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:19])=[CH:25][CH:24]=1
Reactant: N#Cc1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)cc1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NCc1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)cc1
Reaction time: 2.5 h
Yield: 32.3 %

Procedure:
A mixture of N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}(4-cyanophenyl)carboxamide (1 g, 2.6 mmol, 1.0 equiv.), cobalt chloride (0.5 g, 3.85 mmol, 1.5 equiv.) and sodium borohydride (0.295 g, 7.8 mmol, 3.0 equiv.) in DMF (20 mL) was stirred at 0° C. to rt for 2.5 hr. The reaction was quenched with ice cubes, diluted with ethyl acetate (100 mL) and filtered through celite. The filtrate was washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, evaporated and HPLC (C18 reversed phase) eluting with 0.1% TFA in H2O/CH3CN gave [4-(aminomethyl)phenyl]-N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}carboxamide (320 mg, 30%). MS found for C20H17ClN4O2 (M+H)+: 381.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.Cl.[CH3:33][NH:34][CH3:35]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH2:28][N:34]([CH3:35])[CH3:33])=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: CNC
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Agent: Cl
Product: CN(C)Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and dimethylamine hydrochloride (39.5 mg; 0.48 mmol) to give Example 131 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.62 (2H, dd, J=4.5, 1.7 Hz), 7.84 (2H, d, J=8.1 Hz), 7.78 (1H, td, J=7.6, 1.7 Hz), 7.63-7.56 (1H, m), 7.48 (2H, dd, J=4.5, 1.7 Hz), 7.42-7.35 (4H, m), 3.38 (2H, s), 2.08 (6H, s). LC/MS (Method C): 442 (M+H)+. HPLC (Method E) Rt 2.14 min (Purity: 94.2%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4](C(OC(C)(C)C)=O)[CH:3]=1.C(N(CC)CC)C.CC1(C)C(C)(C)OBO1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:41]1[CH:50]=[CH:49][N:48]=[C:47]2[C:42]=1[CH:43]=[CH:44][C:45]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[N:46]2>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O.O1CCOCC1>[C:51]1([C:45]2[CH:44]=[CH:43][C:42]3[C:47](=[N:48][CH:49]=[CH:50][C:41]=3[C:2]3[C:10]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[NH:4][CH:3]=3)[N:46]=2)[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: Clc1ccnc2nc(-c3ccccc3)ccc12
Reactant: CC(C)(C)OC(=O)n1cc(I)c2cccnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)OBOC1(C)C
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: COCCOC
Product: c1ccc(-c2ccc3c(-c4c[nH]c5ncccc45)ccnc3n2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A Schlenk tube is filled successively under nitrogen with 189 mg (0.55 mmol) of tert-butyl 3-iodopyrrolo[2,3-b]pyridine-1-carboxylate, 9.5 mg (8.2 μmol) of tetrakis(triphenylphosphine)palladium, 2.3 ml of dioxane, 0.23 ml (1.6 mmol) of triethylamine and 80 μml (0.55 mmol) of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The reaction mixture is stirred at 80° C. for 3 hours under nitrogen. The reaction mixture is cooled to room temperature; 1 ml of water, 175 mg (2.1 mmol) of sodium carbonate, 22 mg (19 μmol) of tetrakis(triphenylphosphine)palladium, 132 mg (0.55 mmol) of 5-chloro-2-phenyl-1,8-naphthyridine and 4.6 ml of 1,2-dimethoxyethane are added under a nitrogen atmosphere. The reaction mixture is stirred at 100° C. for 20 hours. The reaction mixture is cooled to room temperature and evaporated in vacuo. The residue is chromatographed on a silica-gel column with methanol/dichloromethane as eluent: 2-phenyl-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1,8-naphthyridine (“A5”) as yellowish crystals; MS (ESI): 322 [M+H]+;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9].CCCCCC.C([Li])CCC.[CH2:21]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1.O>[CH2:21]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34]([OH:37])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][CH3:9])[CH2:33][CH2:32]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CSc1ccccc1Br
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccccc1C1(O)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 6 °C
Reaction time: 0.5 h
Yield: 15.1 %

Procedure:
A solution of 2-bromothioanisole (1.05 g) in 20 mL of anhydrous tetrahydrofuran was cooled to -78° C. and treated with 2 mL of 2.5M hexane solution of n-butyl lithium. After the addition was complete the reaction mixture was stirred for 30 minutes and then treated with a solution of N-benzyloxycarbonyl-4-oxopiperidine (1.17 g) in 1 mL of tetrahydrofuran. After stirring at -78° C. for 30 minutes the reaction mixture was allowed to warm to 6° C. and treated with 10 mL of water. Upon extracting with ethyl acetate, drying and evaporation, the organic layer afforded the crude product. This material was purified by chromatography; elution with 6:4 hexane:ethyl acetate afforded the named material (0.27 g); MS: 358; NMR: 1.9-2.1 (b, 4), 2.5 (s, 3), 3.4 (b, 2), 4.1b (b, 2), 5.1 (s, 2), 7.1-7.5 (m, 9).
Reaction SMILES: [OH-:1].[Na+:2].Cl[C:4]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:5]=1[CH:6]=[C:7]1[S:11]C(=S)N[C:8]1=[O:13]>O>[Cl:18][C:14]1[C:5]2[CH:6]=[C:7]([C:8]([O-:1])=[O:13])[S:11][C:4]=2[CH:17]=[CH:16][CH:15]=1.[Na+:2]
Reactant: O=C1NC(=S)SC1=Cc1c(Cl)cccc1Cl
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C([O-])c1cc2c(Cl)cccc2s1
Temperature: 25 °C

Procedure:
After sodium hydroxide (4.55 g) was dissolved in water (50 ml), 2,6-dichlorobenzylidenerhodanine (10.00 g) was added. The mixture was stirred under reflux for 5 hours, and then cooled to room temperature. The precipitated crystals were collected by filtration and washed with cold water to obtain sodium 4-chlorobenzo[b]thiophen-2-carboxylate.
Reaction SMILES: [CH2:1]([N:3]1C([N+]([O-])=O)=CN=C1C=CC1C=CC=CC=1)C.NN1[NH:24][CH:23]=[C:22]([C:25]2[N:26]([CH2:33][CH2:34][CH3:35])[C:27]([N+:30]([O-:32])=[O:31])=[CH:28][N:29]=2)[S:21]1>>[NH2:3][C:1]1[S:21][C:22]([C:25]2[N:26]([CH2:33][CH2:34][CH3:35])[C:27]([N+:30]([O-:32])=[O:31])=[CH:28][N:29]=2)=[CH:23][N:24]=1
Reactant: CCCn1c([N+](=O)[O-])cnc1C1=CNN(N)S1
Reactant: CCn1c([N+](=O)[O-])cnc1C=Cc1ccccc1
Product: CCCn1c([N+](=O)[O-])cnc1-c1cnc(N)s1

Procedure:
The procedure of Example 23, with the substitution of β-(1-propyl-5-nitro-2-imidazolyl)styrene for β-(1-ethyl-5-nitro-2-imidazolyl)styrene in the first step is utilized to prepare 2-(2-amino-5-thiadiazolyl)-1-propyl-5-nitroimidazole, melting at 234.5°-236° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([OH:14])[CH:11]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22]([O:25][CH:26]=[CH2:27])(=[O:24])[CH3:23].C(Cl)(Cl)Cl>COC(C)(C)C>[CH2:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([OH:14])[CH:11]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([O:8][C@@H:9]1[CH2:13][C@H:26]([O:25][C:22](=[O:24])[CH3:23])[CH:27]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=COC(C)=O
Agent: O[C@@H]1C=C[C@H](OCc2ccccc2)C1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CC(=O)O[C@@H]1C=C[C@H](OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 70 %

Procedure:
Cis-4-benzyloxy-cyclopent-2-enol (500 mg, prepared in example 16) is dissolved in tert-butyl methyl ether (8.6 mL, anhydrous). To the solution is added triethylamine (0.7 eq), pancreatin (3 wt eq, available from Sigma Chemical Company), and vinyl acetate (5 eq). The reaction is allowed to stir for 7 hours at room temperature. The reaction is then filtered through diatomaceous earth and the filtrate is concentrated under vacuum. The products are separated by chromatography on silica gel (20% ethyl acetate/hexane) to provide (-)-cis-4-benzyloxy-cyclopent-2-enol (A) (147 mg, 29% yield) [α]20D --12°, (c=1.09, chloroform), and (-)-acetic acid cis-4-benzyloxy-cyclopent-2-enyl ester (B) (427 mg, 70% yield),[α]20D =-5.2°, (c=0.97, chloroform), 1 H NMR (CDCl3) δ 7.3 (m, 5 H), 6.13 (d, 1 H, J=5 Hz), 5.99 (d, 1 H, J=5 Hz), 5.5 (m, 1 H), 4.59 (d, 1 H, J=11.8 Hz), 4.54 (d, 1 H, J=11.8 Hz), 4.5 (m, 1 H), 2.78 (d appt, 1 H, J=7.2, 14.3 Hz), 2.05 (s, 3 H) , 1.76 (d appt, 1 H, J=4.4, 14.3 Hz); 13C NMR (CDCl3) δ 171.1, 138.5, 136.4, 133.1, 128.7, 128, 127.9, 81.4, 77.1, 71.2, 37.8, 21.4.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.I.[NH2:13][C:14]([S:16][CH3:17])=[NH:15].C(N(CC)CC)C>C(Cl)(Cl)Cl.N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([C:8]([NH:15][C:14](=[NH:13])[S:16][CH3:17])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1
Reactant: O=C(Cl)c1cc(Cl)cnc1Cl
Reactant: CSC(=N)N
Agent: I
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CSC(=N)NC(=O)c1cc(Cl)cnc1Cl
Temperature: 25 °C
Yield: 56.5 %

Procedure:
Under an atmosphere of nitrogen, and at a temperature of 0° C., a solution of 2,5-dichloropyridine-3-carbonyl chloride [175277-81-3] (4.82 g, 23 mmol) in CHCl3 (7 ml) was slowly added to a solution of methyl aminomethanimidothioate hydroiodide [4338-95-8] (5.00 g, 23 mmol) and triethylamine (6.36 ml, 46 mmol) in pyridine (7 ml). The reaction mixture was stirred at r.t. over the weekend, was taken up in ethyl acetate and washed (water). After drying (Na2SO4) and evaporation of the solvent, the residue was purified (column chromatography, silica gel, CH2Cl2/MeOH) to give 1-(2,5-dichloro-pyridine-3-carbonyl)-2-methyl-isothiourea (3.50 g, 13 mmol; 58%). MS: m/e=262.0 [M+H+]); 1H NMR (d6-DMSO): δ 2.44 (s, 3H), 8.27 (d, 1H), 8.55 (d, 1H), 9.15 (bs, 1H), 9.55 (bs, 1H).
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][N:7]=1.[O:8]=[C:9]([C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[F:24])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(N(CC)CC)C>[O:8]=[C:9]([C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[F:24])[C:10](=[C:3]1[CH2:4][CH2:5][CH2:6][NH:7]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)cc1F
Reactant: COC1=NCCC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)c1cc(F)c(F)cc1F)=C1CCCN1
Temperature: 60 °C
Reaction time: 96 h

Procedure:
5-Methoxy-3,4-dihydro-2H-pyrrole and triethylamine were added to ethyl 3-oxo-3-(2,4,5-trifluorophenyl)propanoate, for stirring at 60° C. for 4 days, to obtain ethyl 3-oxo-2-pyrrolidin-2-ylidene-3-(2,4,5-trifluorophenyl)propanoate.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[Cl:19][C:16]([F:17])([F:18])[O:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:3][CH:4]=2)=[CH:14][CH:13]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Reactant: C1COCCN1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CCOCC2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and morpholine to afford a white powder. HPLC (Condition 4) tR=5.62 min, UPLC-MS (Condition 3) tR=1.03 min, m/z=450 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.14 (d, J=1.17 Hz, 4H) 3.55-3.68 (m, 4H) 6.71 (br. s, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.87 (d, J=8.99 Hz, 3H) 8.34 (br. s, 1H) 8.75 (s, 1H) 10.41 (br. s, 1H) 13.04 (br. s, 1H).
Reaction SMILES: [ClH:1].CCOCC.C(OC(=O)[NH:13][CH2:14][CH2:15][CH2:16][C:17](=[O:38])[NH:18][CH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][N:23]([CH:30]1[CH2:35][CH2:34][C:33](=[O:36])[NH:32][C:31]1=[O:37])[C:24]2=[O:29])(C)(C)C>CN(C=O)C.C(Cl)Cl>[ClH:1].[NH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH:18][CH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][N:23]([CH:30]1[CH2:35][CH2:34][C:33](=[O:36])[NH:32][C:31]1=[O:37])[C:24]2=[O:29])=[O:38]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: ClCCl
Product: NCCCC(=O)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 168 h
Yield: 87 %

Procedure:
2N HCl/ether (4 mL) was added to a stirred solution of (3-{[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-carbamoyl}-propyl)-carbamic acid t-butyl ester (1 g, 2.2 mmol) in DMF (20 mL). The mixture was stirred at room temperature for 7 days. The mixture was diluted with CH2Cl2 (20 mL) and filtered to give 4-amino-N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-butyramide hydrochloride (0.8 g, 87%) as a white solid: mp 268-270° C.; 1H NMR (DMSO-d6) δ 1.74-1.86 (m, 2H, CH2), 2.00-2.04 (m, 1H), 2.24-2.79 (m, 6H), 2.86-2.98 (m, 1H), 4.32-4.39 (m, 3H), 4.49 (d, J=17.5 Hz, 1H), 5.10-5.18 (dd, J=5.0 and 12.5 Hz, 1H, CH), 7.49-7.64 (m, 3H, Ar), 8.01 (b, 3H, NH3), 8.61 (t, J=5.0 Hz, 1H, NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.59, 23.10, 31.18, 31.87, 38.40, 38.98, 46.20, 51.57, 121.64, 128.28, 130.64, 131.63, 134.61, 140.09, 168.03, 170.99, 171.37, 172.85; Anal. calcd. for C18H23N4O4Cl: C, 54.75; H, 5.87; N, 14.19; Cl, 8.98. Found: C, 54.50; H, 5.81; N, 13.90; Cl, 8.92.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)(O)[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+]>S(Cl)(Cl)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)\[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(F)ccc3n2CC(C)(O)c2ccncc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: C/C(=C\n1c2c(c3cc(F)ccc31)CN(C)CC2)c1ccncc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
1-(8-Fluoro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(pyridin-4-yl)propan-2-ol (1 g, 2.9 mmol) was dissolved in thionyl chloride (10 mL) and the solution was stirred for 2 h. Excess thionyl chloride was removed under reduced pressure and the residue was dissolved in N-methyl-2-pyrrolidone (6 mL) and the solution was stirred for 5 min. at RT. Powdered KOH (1.7 g, 31 mmol) was added and the reaction mixture was heated at 100° C. for 2 h. The reaction mixture was cooled to RT, diluted with ice water and extracted with EtOAc. The organic layer washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 5% MeOH-DCM. 1HNMR (CD3OD, HCl salt) δ (ppm): 8.85 (d, 2H), 8.40 (d, 2H), 7.80 (s, 1H), 7.30 (m, 2H), 7.05 (m, 1H), 4.75 (d, 1H), 4.40 (d, 1H), 3.90 (m, 1H), 3.60 (m, 1H), 3.30 (m, 2H), 3.18 (s, 3H), 2.20 (s, 3H).