Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]2[NH:9][C:10](=[O:17])[CH:11]=[C:12]([C:13]([F:16])([F:15])[F:14])[C:7]=2[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:5]1.Br[CH2:25][C:26]([O:28]CC)=[O:27].O>CN(C=O)C>[CH3:3][N:4]1[C:8]2=[N:9][C:10]([O:17][CH2:25][C:26]([OH:28])=[O:27])=[CH:11][C:12]([C:13]([F:14])([F:16])[F:15])=[C:7]2[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:5]1
Reactant: CCOC(=O)CBr
Reactant: Cn1cc(-c2ccccc2)c2c(C(F)(F)F)cc(=O)[nH]c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2ccccc2)c2c(C(F)(F)F)cc(OCC(=O)O)nc21
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
NaH (23 mg, 0.56 mmol) was added to a stirred solution of 1-methyl-3-phenyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6(7H)-one (41 mg, 0.14 mmol) in DMF (4 ml) and the resulting mixture was stirred for 30 min. Then ethyl bromoacetate (47 mg, 6.50 mmol) was added and the mixture was stirred for additional 1 h. To the mixture water (0.5 ml) was added and stirred for 2 h. The reaction mixture was concentrated. 1N aqueous HCL was added to the mixture and the solution was extracted with diethyl ether. The organic layer was washed with water and brine, filtered and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure. The crude product was purified by flash column chromatography (80% EtOAc in hexane) to yield the title compound (29 mg, 59%) [1H-NMR (CDCl3, 300 MHz) δ 7.45-7.30 (m, 5H), 7.05 (s, 1H), 7.00 (s, 1H), 5.03 (s, 2H), 3.81 (s, 3H); LCMS RtE=1.94 min; [M+H]+=351.0]
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([NH:14][CH:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)(=[O:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:17]2[CH2:18][CH2:19][CH:15]([NH:14][C:11](=[O:13])[CH3:12])[CH2:16]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(=O)NC1CCNC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)NC1CCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 100 °C
Yield: 100.3 %

Procedure:
After dissolving 56.4 g of 1-fluoro-4-nitrobenzene (0.4 mol) and 51.2 g of 3-acetamido-pyrrolidine (0.4 mol) in 400 ml of NMP, 66.4 g of potassium carbonate (0.48 mol) are added under a nitrogen atmosphere and the mixture is heated at 100° C. for 18 hours. The reaction medium is allowed to cool and is then poured into 2 l of water. The yellow precipitate formed is filtered off, washed with water and then dried in a vacuum oven over P2O5. 100 g (100%) of N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide (1) are thus obtained in the form of a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[F:20])[NH2:16]>>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1ccc(F)c(Cl)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-chloro-4-fluoroaniline to yield 2-[(3-chloro-4-fluorophenyl)amino]phenylacetic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[OH:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C@@H:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].CCCCCC.C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)C>[C:1]([O:5][C:6]([N:7]([CH3:8])[CH2:9][C@@H:10]([O:11][C:23](=[O:24])[C@@H:22]([O:21][CH3:20])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CC(O)c1ccc(F)cc1)C(=O)OC(C)(C)C
Reactant: CO[C@H](C(=O)O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CO[C@H](C(=O)O[C@H](CN(C)C(=O)OC(C)(C)C)c1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of [2-(4-fluorophenyl)-2-hydroxyethyl]methyl-carbamic acid t-butyl ester (the compound of Preparation Example 32) (8.46 g) and (S)-(+)-α-methoxyphenyl acetic acid (5.74 g) in dichloromethane (60 mL) was added 4-dimethylaminopyridine (0.19 g) and N,N-dicyclohexylcarbodiimide (7.7 g) on an ice bath. The solution was stirred for 3.5 hours while being slowly warmed to room temperature. When the reaction solution was developed with silica gel TLC (hexane/ethyl acetate=4:1), two products could be identified. After diluting with diethyl ether, the insoluble matter was removed by Celite filtration. The residue that was obtained upon removing the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), the (S, S) isomer (the compound that demonstrates a high Rf value in TLC) (3.60g) was obtained from the low polarity elution portion. The NMR suggested that it was a mixture of rotamers. The three-dimensional structure was determined from the NMR data by applying the Mosher method.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]=1[CH:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:25][CH:24]=1)[OH:22]>Cl.C1COCC1.O>[CH3:20][O:19][C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]3[C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[CH2:2][O:22][CH:21]([C:23]4[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][N:32]5[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]5)=[CH:27][CH:28]=4)[C:10]3=2)[CH:15]=1
Reactant: COc1ccc2c(C(O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3CO)ccc2c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c3c(ccc2c1)-c1ccccc1COC3c1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
Add several drops of HCl (5M) to a stirred solution of crude [2-(2-hydroxymethyl-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanol in THF (5 mL) and water (0.5 mL). Stir at r.t. for 24 h. Quench with aq. NaHCO3 and dilute with CH2Cl2. Wash the organic phase with water and brine, dry over MgSO4, filter and concentrate. Purify the crude product by flash chromatography (0-5% (2M NH3/MeOH) in CH2Cl2) to yield 1-{2-[4-(8-methoxy-11,13-dihydro-12-oxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-11-yl)-phenoxy]-ethyl}-piperidine (105 mg, 64%).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]([OH:19])(=[O:18])[C:12]([CH2:14][C:15]([OH:17])=[O:16])=[CH2:13].O.[OH-].[Na+]>OS(O)(=O)=O>[N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][C:2]=1[S:1][CH2:13][CH:12]([C:11]([OH:19])=[O:18])[CH2:14][C:15]([OH:17])=[O:16]
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Sc1nc2ccccc2[nH]1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CC(CSc1nc2ccccc2[nH]1)C(=O)O

Procedure:
47.4 g of 2-mercaptobenzimidazole are reacted in the same manner as in Example 10 with 40.7 g of itaconic acid in 150 ml of 70% H2SO4 at 40°-43°. After dilution with water, sodium hydroxide solution is added until pH 4 is reached, the product being precipitated as the dihydrate. Anhydrous 3-(benzimidazol-2-ylthio)-propane-1,2-dicarboxylic acid, melting at 165°-168°, is obtained from the dihydrate by recrystallisation.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:17](O)[CH3:18]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:16])[CH2:11][CH2:12][C:13]([O:15][CH2:17][CH3:18])=[O:14])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCO
Reactant: CC(CCC(=O)O)c1ccc([N+](=O)[O-])cc1
Product: CCOC(=O)CCC(C)c1ccc([N+](=O)[O-])cc1
Yield: 97 %

Procedure:
A mixture of 110 g of 4-(4-nitrophenyl)valeric acid, 660 ml of absolute ethanol and 10 ml of concentrated sulfuric was heated under reflux overnight. The ethanol was evaporated in vacuo and the residue was partitioned between ether and water. The ether extract was washed with 5% sodium bicarbonate, with water, dried over anhydrous sodium sulfate, filtered and evaporated to give 119 g (97%) of product. The product has bp 127°-128° C. (1.5 mm).
Reaction SMILES: Cl.[F:2][C:3]1[C:11]2[O:10][CH:9]([C:12]3([OH:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C1C(=O)N([Br:26])C(=O)C1>CO.C(Cl)Cl>[Br:26][C:5]1[CH:4]=[C:3]([F:2])[C:11]2[O:10][CH:9]([C:12]3([OH:18])[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[CH2:8][C:7]=2[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OC1(C2Cc3cccc(F)c3O2)CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: OC1(C2Cc3cc(Br)cc(F)c3O2)CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.3 %

Procedure:
To a solution of 4-(7-fluoro-2,3-dihydrobenzofuran-2-yl)piperidin-4-ol hydrochloride (380 mg, 1.388 mmol) in MeOH (11.1 mL) at 0° C. was added NBS (235 mg, 1.319 mmol) in one portion. Upon completion of addition, the reaction mixture was stirred at room temperature for 3 hours, and then quenched with aqueous Na2H2S2O5 (10%, 5 mL). The solvent was removed under reduced pressure to yield a residue. The residue was diluted with CH2Cl2 (5 mL), washed with aqueous NaOH (1 N, 3 mL) and brine (3 mL). The organic layer was separated, dried (K2CO3), filtered, and concentrated to afford Compound 1G as a white solid (0.168 g, 38% yield). LC/MS (m/z)=317 (M+H)+.
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].[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:21]Br>C(O)C>[CH2:10]([O:9][C:7](=[O:8])[C:6]([NH:5][C:2](=[O:4])[CH3:3])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:21][C:20]1[CH:23]=[CH:24][C:25]([Cl:26])=[C:18]([Cl:17])[CH:19]=1)[CH3:11]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: Clc1ccc(CBr)cc1Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(Cl)c(Cl)c1)(NC(C)=O)C(=O)OCC
Reaction time: 0.5 h

Procedure:
Sodium pellets were dissolved in ethanol (200 ml). Diethyl acetamidomalonate (6.53 g) was added and the solution stirred for 30 minutes. 3,4-Dichlorobenzyl bromide (10.0 g), was added and the solution refluxed for 3.5 hours. The solution was filtered whilst hot and allowed to cool before water (200 ml) was added. On standing at 4° C. for 12 hours the title compound precipitated as colourless crystals which were removed by filtration and dried under vacuum (9.27 g). 1H NMR (360 MHz, CDCl3) δ7.32 (1H, d, J=8 Hz), 7.10 (1H, d, J=2 Hz), 6.85 (1H, dd, J=8, 2 Hz), 6.55 (1H, s), 4.28 (2H, m), 3.62 (2H, s), 2.05 (3H, s), 1.3 (3H, t, J=7 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:12])=[C:6]([CH:11]=1)[CH2:7][NH:8][CH2:9][CH3:10].C(N(CC)C(C)C)(C)C.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1.O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:12])=[C:6]([CH:11]=1)[CH2:7][N:8]([CH2:9][CH3:10])[C:25]([CH:22]1[CH2:24][CH2:23]1)=[O:26]
Reactant: CCNCc1cc(Br)ccc1I
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1cc(Br)ccc1I)C(=O)C1CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(5-Bromo-2-iodo-benzyl)-ethyl-amine (5.0 g, 14.7 mmol) was dissolved in dichloromethane (75 mL) along with N,N-diisopropylethylamine (5.12 mL, 29.4 mmol). The solution was cooled to 0° C. and cyclopropanecarbonyl chloride (1.41 mL, 15.4 mmol) was added. The reaction was monitored by analytical LCMS and after 15 minutes water was added and the layers were separated. The organic layer was dried with magnesium sulfate then filtered and concentrated to afford the title compound, which was used without further purification.
Reaction SMILES: [CH:1]([C:4]1[C:9]2[C:10](=[O:33])[N:11]([CH2:15][O:16][C:17]3[N:21]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[N:20]=[C:19]([C:29]([F:32])([F:31])[F:30])[CH:18]=3)[S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[C:6]([OH:34])[CH:5]=1)([CH3:3])[CH3:2].[C:35]1([CH2:41][O:42][C:43](=[O:48])[CH2:44][CH2:45][CH2:46]O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CCOC(/N=N/C(OCC)=O)=O.P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[CH:1]([C:4]1[C:9]2[C:10](=[O:33])[N:11]([CH2:15][O:16][C:17]3[N:21]([C:22]4[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=4)[N:20]=[C:19]([C:29]([F:30])([F:31])[F:32])[CH:18]=3)[S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[C:6]([O:34][CH2:46][CH2:45][CH2:44][C:43]([O:42][CH2:41][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:48])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=C(CCCO)OCc1ccccc1
Reactant: CC(C)c1cc(O)cc2c1C(=O)N(COc1cc(C(F)(F)F)nn1-c1ccc(Cl)cc1)S2(=O)=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1cc(OCCCC(=O)OCc2ccccc2)cc2c1C(=O)N(COc1cc(C(F)(F)F)nn1-c1ccc(Cl)cc1)S2(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
A mixture of 4-isopropyl-6-hydroxy-2-[1-(4-chlorophenyl)-3-trifluoromethylpyrazol-5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (9.95 g; 19.3 mmol), 4-hydroxybutanoic acid phenylmethyl ester (4.49 g;23.16 mmol), DEAD (4.03 g; 23.16 mmol) was dissolved in 193 ml of THF at 0° C. and then (Ph)3P (6.068 g; 23.16 mmol) was added at 0° C. The above mixture was stirred overnight at room temperature, concentrated in vacuo, and the residue was purified by column chromatography (2×, silica gel; 12-50% ethyl acetate/hexane; methylene chloride/hexane, 1/4-30/1) to afford 4.55 g (34%) of 4-isopropyl-6-[3-(phenylmethyloxycarbonyl)propoxy]-2-[1-(4-chlorophenyl)-3-trifluoromethylpyrazol-5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =4-Cl--Ph; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-O(CH2)3CO2 CH2Ph) as a solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([OH:10])=[N:5][C:6]([OH:9])=[CH:7][CH:8]=1)#[N:2].[CH3:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16]>>[C:1]([C:3]1[C:4]([OH:10])=[N:5][C:6]([O:9][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[C:12]([CH3:11])[CH:13]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: N#Cc1ccc(O)nc1O
Product: Cc1cccc(C(=O)Oc2ccc(C#N)c(O)n2)c1
Yield: 57.9 %

Procedure:
The general procedure of Example 81 was followed using 2.00 g of 3-cyano-2,6-dihydroxypyridine and 2.27 g of 3-methylbenzoyl chloride, thereby producing 2.16 g of the title compound in a yield of 58%.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([N:17]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]#[N:38])=[CH:27][CH:26]=2)[C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn]([N:52]=[N+:53]=[N-:54])(CCCC)CCCC)CCC>CC1C=CC=CC=1C>[CH2:1]([O:8][C:9]([C:11]1([N:17]([C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:54][N:53]=[N:52][N:38]=3)=[CH:29][CH:30]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)C1(C(=O)OCc2ccccc2)CCCCC1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C1(C(=O)OCc2ccccc2)CCCCC1

Procedure:
A mixture of 3.3 g (6.5 mmol) of N-(1-benzyloxycarbonylcyclohexyl)-N-(2'-cyanobiphenyl-4-ylmethyl)-N-pentanoyl-amine, 4.1 g (12.3 mmol) of tributyltin azide and 30 ml of o-xylene is heated to reflux for 44 hours. Working-up of the mixture in a manner analogous to that described in Example 23 yields the N-(1-benzyloxycarbonylcyclohexyl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine in the form of light-brown crystals melting between 189° and 190° (from ethyl acetate/diethyl ether).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[N+:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=1)([O-:35])=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:8][C:9]=1[N:10]([C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])[CH:20]1[CH2:25][CH2:24][CH:23]([O:26][C:40](=[O:41])[C:39]2[CH:38]=[CH:37][C:36]([N+:33]([O-:35])=[O:34])=[CH:44][CH:43]=2)[CH2:22][CH2:21]1)=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(OC(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 53.5 %

Procedure:
3-[(4-Hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (62 mg, 0.136 mmol) was dissolved in benzene (0.7 ml) and then p-nitrobenzoic acid (27 mg, 0.163 mmol) and triphenylphosphine (43 mg, 0.163 mmol) were added. The resulting solution was cooled in an ice bath and diethyl azodicarboxylate (26 ul, 0.163 mmol) was added. After stirring at room temperature for 22 hours, the solvents were removed and the residue was purified by preparative chromatography (30% EtOAc/Hexane) to obtain 44 mg (54%) of 3-{(4-Methyl-cyclohexanecarbonyl)-[4-(4-nitro-benzoyloxy)-cyclohexyl]-amino}-5-phenyl-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[C@@H:9]12[NH:16][C@@H:13]([CH2:14][CH2:15]1)[CH2:12][N:11]([C:17]1[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=3)[N:22]=1)[CH2:10]2>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:16]2[C@H:9]3[CH2:15][CH2:14][C@@H:13]2[CH2:12][N:11]([C:17]2[CH:18]=[CH:19][C:20]4[N:21]([C:23]([C:26]([F:29])([F:27])[F:28])=[N:24][N:25]=4)[N:22]=2)[CH2:10]3)[CH:2]=1
Reactant: O=Cc1cccnc1
Reactant: FC(F)(F)c1nnc2ccc(N3C[C@H]4CC[C@@H](C3)N4)nn12
Product: FC(F)(F)c1nnc2ccc(N3C[C@H]4CC[C@@H](C3)N4Cc3cccnc3)nn12
Yield: 68 %

Procedure:
A mixture of pyridine-3-carboxaldehyde and 6-[(1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 5 to give 6-[(1R,5S)-8-(pyridin-3-ylmethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine in 68% yield.
Reaction SMILES: [F:1][C:2]1([F:40])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][C:25]=4[F:26])[N:22]([CH2:27][C@@H:28]4[CH2:32][O:31]C(C)(C)[O:29]4)[C:21]([C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])=[CH:20]5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.O.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO>[F:40][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][C:25]=4[F:26])[N:22]([CH2:27][C@@H:28]([OH:29])[CH2:32][OH:31])[C:21]([C:35]([CH3:38])([CH3:39])[CH2:36][OH:37])=[CH:20]5)=[O:15])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: CC1(C)OC[C@@H](Cn2c(C(C)(C)CO)cc3cc(NC(=O)C4(c5ccc6c(c5)OC(F)(F)O6)CC4)c(F)cc32)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)(CO)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)c(F)cc2n1C[C@@H](O)CO
Temperature: 80 °C

Procedure:
(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (3.0 g, 5.4 mmol) was dissolved in methanol (52 mL). Water (5.2 mL) was added followed by p-TsOH.H2O (204 mg, 1.1 mmol). The reaction was heated at 80° C. for 45 minutes. The solution was concentrated and then partitioned between ethyl acetate and saturated NaHCO3 solution. The ethyl acetate layer was dried over MgSO4 and concentrated. The residue was purified by column chromatography (50-100% ethyl acetate-hexanes) to yield the product as a cream colored foamy solid. (1.3 g, 47%, ee >98% by SFC). ESI-MS m/z calc. 520.5, found 521.7 (M+1)+. Retention time 1.69 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.53 (s, 1H), 7.42-7.38 (m, 2H), 7.33-7.30 (m, 2H), 6.22 (s, 1H), 5.01 (d, J=5.2 Hz, 1H), 4.90 (t, J=5.5 Hz, 1H), 4.75 (t, J=5.8 Hz, 1H), 4.40 (dd, J=2.6, 15.1 Hz, 1H), 4.10 (dd, J=8.7, 15.1 Hz, 1H), 3.90 (s, 1H), 3.65-3.54 (m, 2H), 3.48-3.33 (m, 2H), 1.48-1.45 (m, 2H), 1.35 (s, 3H), 1.32 (s, 3H) and 1.14-1.11 (m, 2H) ppm.
Reaction SMILES: [CH:1]([C@@H:4]1[NH:9][CH2:8][CH2:7][N:6]([C:10]2[C:11]3[C:18]([CH3:19])=[CH:17][NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:5]1)([CH3:3])[CH3:2].[Br:20][C:21]1[CH:22]=[C:23]([NH:27][C:28](=[N:36][C:37]#[N:38])OC2C=CC=CC=2)[CH:24]=[CH:25][CH:26]=1>C(O)(C)C>[Br:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]([N:9]2[CH2:8][CH2:7][N:6]([C:10]3[C:11]4[C:18]([CH3:19])=[CH:17][NH:16][C:12]=4[N:13]=[CH:14][N:15]=3)[CH2:5][C@@H:4]2[CH:1]([CH3:3])[CH3:2])=[N:36][C:37]#[N:38])[CH:24]=[CH:25][CH:26]=1
Reactant: N#CN=C(Nc1cccc(Br)c1)Oc1ccccc1
Reactant: Cc1c[nH]c2ncnc(N3CCN[C@@H](C(C)C)C3)c12
Solvent: CC(C)O
Product: Cc1c[nH]c2ncnc(N3CCN(C(=NC#N)Nc4cccc(Br)c4)[C@@H](C(C)C)C3)c12
Temperature: 120 °C
Yield: 7 %

Procedure:
The piperazine from step A was combined with phenyl N-3-bromophenyl-N′-cyanocarbamimidate, from example 5, step A, (40 mg, 1.2 mmol) in isopropanol in a sealed tube. The reaction was heated to 120° C., monitored by LC/MS until no starting material remained, and then concentrated under vacuum. The residue was purified by prep HPLC (Sunfire C18 5u 30×100 mm, 10% to 100% B, gradient time=13 min, flow rate=45 ml/min, wavelength=220 nm, solvent A=10 mM aq. Ammonium acetate, solvent B=acetonitrile) to give (S)—N-(3-bromophenyl)-N′-cyano-2-isopropyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboximidamide (2.2 mg, 7%) as a white solid.
Reaction SMILES: [OH-].[NH4+:2].[I:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1>CCOCC>[I:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:2])=[O:9])=[CH:6][CH:5]=1
Reactant: [NH4+]
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: [OH-]
Solvent: CCOCC
Product: NC(=O)c1ccc(I)cc1

Procedure:
A total of 20 ml of 15 M ammonium hydroxide was reacted with a solution of 5.4 g p-iodobenzoyl chloride in 25 ml of ether. The crude product was recovered as described in Example 3 and recrystallized from ethanol to yield 3.5 g of p-iodobenzamide as white crystals, m.p. 221°-223°, Rf 0.46.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([O:13]C)=O)(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[CH2:18]([N:4]1[C:5]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:11]([OH:13])=[CH:2][C:1]1=[O:3])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cnccc1NC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1cc(O)c2cnccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26426.9 %

Procedure:
A mixture of methyl 4-(acetylamino)pyridine-3-carboxylate (70 g, 0.36 mol) and sodium hydride (50 g, 1.25 mol, 60% in mineral oil) in anhydrous tetrahydrofuran (800 mL) was stirred at room temperature for 30 minutes. To the above mixture was added bromomethylbenzene (60 g, 0.36 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured onto crashed ice (600 mL), concentrated in vacuo, and washed with ethyl acetate (400 mL). The aqueous layer was neutralized by addition of 3 N aqueous solution of hydrochloric acid to pH 7. The formed solid was collected by filtration and dried in vacuo to afford 24 g of 1-benzyl-4-hydroxy-1,6-naphthyridin-2(1H)-one as a pale yellow solid.