Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.[C:20]([O:24][C:25]([N:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[CH2:32]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:26])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[C:20]([O:24][C:25]([N:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[CH2:32][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:4]2[S:3][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=2)=[CH:18][CH:17]=1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccc(Cc2nc3ccccc3s2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
To a 25 mL vial which contained a suspension of NaH (60% in mineral oil, 60 mg, 1.5 mmol) in DMF (10 mL) was added the product from step 1 (241 mg, 1 mmol) at 0° C. The mixture was allowed to warm to rt and stir at rt for 30 min then cooled to 0° C. To this reaction mixture was added (R)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (355 mg, 1 mmol) at 0° C. The resulting mixture was allowed warm to rt and stir at rt for 30 min and then was heated to 95° C. and stirred at 95° C. for 16 h. After cooling to rt, the mixture was poured onto 200 mL ice-water solution and this solution was allowed to stir at 0° C. for 30 min. The solid which formed was filtered out, dried through air to afford the title product (320 mg, 70%); 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.81-2.11 (m, 4H), 3.32-3.47 (m, 2H), 3.70-4.20 (m, 3H), 4.37 (s, 2H), 6.84-6.97 (m, 4H), 7.33 (t, J=7.6, 1H), 7.45 (t, J=7.6, 1H), 7.78 (d, J=8.0, 1H), 7.98 (d, J=8.4, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH2:17][CH3:18])[C:15]([C:19]#[N:20])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=O)[O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>>[CH3:1][C:2]1([CH3:22])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH2:17][CH3:18])[C:15]([C:19]#[N:20])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[S:32])[O:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Product: CCn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=S)N2

Procedure:
The title compound was prepared according to the procedure for Example 16 from 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-ethyl-1H-pyrrole-2-carbonitrile and Lawesson's reagent. The product was obtained in the form of white needles: mp 212-213° C.; 1H-NMR (DMSO-d6) δ 1.25 (t, 3H, J=7 Hz), 1.68 (s, 6H), 4.07 (q, J=7 Hz, 2H), 6.32 (d, J=3.9 Hz, 1H), 7.07 (d, J=3.9 Hz, 1H), 7.15 (d, J=9 Hz, 1H), 7.42 (m, 2H), 12.33 (s, 1H); MS (ESI) m/z 310 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[CH:3]=1.[CH2:21]([O:23][C:24](=[O:29])[CH2:25][C:26](Cl)=[O:27])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:29])[CH2:25][C:26]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=1[C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:18])([F:19])[F:20])=[O:27])[CH3:22]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: Nc1ccc(Cl)cc1C#Cc1ccccc1C(F)(F)F
Product: CCOC(=O)CC(=O)Nc1ccc(Cl)cc1C#Cc1ccccc1C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 29 step A from 4-chloro-2-((2-(trifluoromethyl)phenyl)ethynyl)aniline (200 mg, 0.68 mmol) and chlorocarbonyl-acetic acid ethyl ester (128 μl, 1.01 mmol). Off white solid (213 mg, 77%). MS (ESI): 410 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][C@@H:14]([CH3:18])[C:15](O)=[O:16])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:19][C:20]1[S:21][C:22]2[CH:28]=[C:27]([O:29][C:30]([F:33])([F:32])[F:31])[CH:26]=[CH:25][C:23]=2[N:24]=1.[CH3:34][NH:35][CH3:36].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>>[CH3:34][N:35]([CH3:36])[C:15]([C@@H:14]([NH:13][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:19][C:20]3[S:21][C:22]4[CH:28]=[C:27]([O:29][C:30]([F:31])([F:33])[F:32])[CH:26]=[CH:25][C:23]=4[N:24]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])[CH3:18])=[O:16]
Reactant: C[C@H](NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C)C(=O)O
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C)C(=O)N(C)C
Temperature: 0 °C

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ((S)-1-dimethylcarbamoyl-ethyl)-amide (46 mg) was prepared by following General Procedure F using (S)-2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-propionic acid (48 mg), dimethyl amine (0.3 ml, 1.0 M solution in THF), HBTU (38 mg), and DIEA (0.1 ml), with a minor modification of General Procedure F where DIEA was slowly added to the reaction mixture at last while stirring at 0° C. LC/MS: m/z 508. 1H NMR (DMSO-d6, 400 MHz): δ 8.39 (d, 1H), 7.98 (s, 1H), 7.95 (s, 1H), 7.76 (m, 1H), 7.66 (m, 1H), 7.45 (br, 1H), 7.30 (m, 1H), 7.22 (d, 1H), 4.93 (p, 1H), 3.62 (s, 3H), 2.87 (d, 6H), and 1.31 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=3)[CH:14]=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:31][Mg]Cl.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:16]3[CH:17]=[C:18]([F:23])[CH:19]=[C:20]([F:22])[CH:21]=3)[CH:14]([OH:15])[CH3:31])[CH2:10]2)=[CH:29][CH:28]=1
Reactant: O=CC(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Reactant: C[Mg]Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 805 mg (1.81 mmol) of {1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(3,5-difluorophenyl)acetaldehyde in 20 mL of THF was added slowly a solution of 1.33 mL (4.0 mmol) of methylmagnesium chloride (3.0M solution in THF) at −78° C. and stirred for 1 h. The reaction mixture was warmed to 0° C. for 1 h and 3 g of sodium sulfate decahydrate was added to quench the reaction, followed by stirring for 1 h at rt. The quenched reaction mixture was filtered and the organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/acetone=8:1 to afford {1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-1-(3,5-difluorophenyl)propan-2-ol as a white solid. Mass Spectrum m/e=460 (M+1 35Cl, 35Cl) and 462 (M+1 35Cl, 37Cl).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)C.[Li+].[OH-].Cl>C1COCC1>[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:15]=[CH:16][C:11]([C:9]2[O:10][C:6]([CH2:5][C:4]([OH:23])=[O:3])=[CH:7][CH:8]=2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)Cc1ccc(-c2ccc(-c3ccccc3)cc2)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(-c2ccc(-c3ccccc3)cc2)o1
Yield: 99.8 %

Procedure:
To a solution of 2-(2-biphenyl-4-yl-furan-5-yl)-acetic acid ethyl ester (0.465 g, 1.44 mmol) in THF (10 mL) at 0° C. was added 2M aqueous LiOH (2 mL). The mixture was allowed to warm over 4 hours to ambient temperature and then poured into 0.5M aqueous HCl (50 mL). The resultant pale orange precipitate was filtered off, rinsed with water, and dried under vacuum over P2O5 to provide 400 mg (100%) of 2-(2-biphenyl-4-yl-furan-5-yl)-acetic acid as a light orange solid, mp 196-210° C., used without further purification. 1H NMR (acetone-d6): δ 7.78 (d, 2H, J=8.1 Hz), 7.72-7.67 (m, 4H), 7.46 (t, 2H, J=7.4 Hz), 7.35 (t, 1H, J=7.4 Hz), 6.84 (d, 1H, J=3.3 Hz), 6.41 (d, 1H, J=3.3 Hz), 3.81 (s, 2H). Anal. Calculated for C18H14O3: C, 77.68; H, 5.07. Found: C, 77.44; H, 5.16.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=[O:19])[C:10]=2[NH:20][C:21]([NH:23][C:24]2[CH:29]=[C:28]([CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:27]=[CH:26][C:25]=2[C:37]([CH3:40])([CH3:39])[CH3:38])=[O:22])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].I[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>CN(C=O)C.O>[CH2:50]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][N:14]=2)[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[C:10]([NH:20][C:21]([NH:23][C:24]2[CH:29]=[C:28]([CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:27]=[CH:26][C:25]=2[C:37]([CH3:40])([CH3:39])[CH3:38])=[O:22])[C:11]1=[O:19])[CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCCI
Reactant: COc1cccc(-c2c(NC(=O)Nc3cc(CN4CCOCC4)ccc3C(C)(C)C)c(=O)[nH]c3ncccc23)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCn1c(=O)c(NC(=O)Nc2cc(CN3CCOCC3)ccc2C(C)(C)C)c(-c2cccc(OC)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a solution of N-[4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-[2-tert-butyl-5-(morpholinomethyl)phenyl]urea (300 mg, 0.55 mmol) in DMF (10 ml) are added successively potassium carbonate (91.8 mg, 0.66 mmol), potassium iodide (18.4 mg, 0.11 mmol) and 1-iodohexane (117 mg, 0.55 mmol), and the mixture is stirred at room temperature for one hour, and stirred at 40-50° C. for 4 hours. The reaction solution is poured into water, and the mixture is extracted with ethyl acetate. The extract is washed with water and a saturated brine, and dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (chloroform→3% methanol/chloroform) to give the title compound (290 mg, 0.47 mmol) as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14](I)=[CH:13][N:12]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:19]1([C:22]([NH2:24])=[O:23])[CH2:21][CH2:20]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O.[Cu]I>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([NH:24][C:22]([CH:19]3[CH2:21][CH2:20]3)=[O:23])=[CH:13][N:12]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(=O)C1CC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(I)cn2)CC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(NC(=O)C3CC3)cn2)CC1
Temperature: 110 °C
Yield: 55.1 %

Procedure:
A mixture of 0.20 g (0.56 mmol) of [1-(5-iodo-pyridin-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester, 22 mg (0.12 mmol) of CuI, 0.035 mL (0.22 mmol) of 1,2-trans-di(methylamino)cychlohexane, 0.090 mg (1.1 mmol) of cyclopropanecarboxamide, and 0.24 mg (1.1 mmol) of K3PO4 in 1 mL of 1,4-dioxane was heated under an N2 atmosphere for overnight at 110° C. The mixture was cooled, diluted with 10 mL of EtOAc, and washed with aq. NH4Cl/NH4OH (pH 8), then with aq. NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was triturated with acetonitrile to provide 98 mg (56%) of {1-[5-(cyclopropanecarbonyl-amino)-pyridin-2-yl]-cyclopropyl}-carbamic acid tert-butyl ester as an off-white powder.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[N:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=2)=[O:12])=[C:6]([O:24][CH3:25])[CH:5]=1.O.[OH-].[Li+]>CO>[CH3:25][O:24][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][N:15]=1)=[O:12])[C:3]([OH:26])=[O:2]
Reactant: COC(=O)c1ccc(NC(=O)Nc2cnc(C(F)(F)F)cn2)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)ccc1NC(=O)Nc1cnc(C(F)(F)F)cn1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-methoxy-4-[3-(5-trifluoromethyl-pyrazin-2-yl)-ureido]-benzoic acid methyl ester (213 mg, 0.575 mmol) in 5.75 mL 3:1 MeOH:H20 at room temperature under nitrogen was added lithium hydroxide monohydrate (240 mg, 5.8 mmol) and the reaction warmed to 65° C. After reaching temperature, the suspension gradually became a bright yellow solution. After about 4 hours a precipitate formed but the reaction was continued overnight. After cooling to RT, MeOH was removed by rotovap and the aqueous suspension neutralized to pH=5 with concentrated HCl. As pH=5 was approached, the suspension turned from yellow to white. The suspension was then filtered through paper on a ceramic funnel. When most of the H20 was removed the residue was dryed under high vacuum in a dessicator overnight (133 mg, 55%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH:7]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:18]=C([CH:23]=[CH:24][CH:25]=2)C(O)=O)[CH2:12][CH2:11]1)([CH3:9])[CH3:8]>CN(C=O)C.C(Cl)Cl>[CH:7]([N:10]1[CH2:11][CH2:12][CH:13]([O:16][C:17]2[CH:18]=[C:1]([CH:23]=[CH:24][CH:25]=2)[C:2]([Cl:4])=[O:3])[CH2:14][CH2:15]1)([CH3:9])[CH3:8]
Reactant: CC(C)N1CCC(Oc2cccc(C(=O)O)c2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)N1CCC(Oc2cccc(C(=O)Cl)c2)CC1

Procedure:
Oxalyl chloride (0.34 ml) was added to a stirred mixture of 3-(N-isopropylpiperidin-4-yloxy)benzoic acid (0.782 g), DMF (2 drops) and methylene chloride (20 ml) which had been cooled in an ice bath. The resultant mixture was stirred at ambient temperature for 4 hours. The mixture was evaporated and the 3-(N-isopropylpiperidin-4-yloxy)benzoyl chloride so obtained was dissolved in methylene chloride (20 ml).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([Cl:11])[C:6]([CH2:9][NH2:10])=[N:7][CH:8]=1.[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12>C1(C)C=CC=CC=1>[Br:2][C:3]1[CH:4]=[C:5]([Cl:11])[C:6]([CH2:9][N:10]2[C:15](=[O:16])[C:14]3[C:13](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:12]2=[O:17])=[N:7][CH:8]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCc1ncc(Br)cc1Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1Cc1ncc(Br)cc1Cl
Yield: 50.8 %

Procedure:
To a stirred solution of (5-bromo-3-chloropyridin-2-yl)methanamine hydrochloride (0.3 g, 1.4 mmol) in toluene (40 mL) was added TEA (0.41 g, 4.08 mmol) and phthalic anhydride (0.24 g, 1.63 mmol), and the reaction mixture was heated at reflux for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with EtOAc. The combined EtOAc layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (20-30% EtOAc in hexane) to afford the title compound as a white solid (0.25 g, 65%): 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.45 (s, 1H), 7.88 (m, 2H), 7.74 (m, 2H), 4.56 (m, 2H); ESIMS m/z 349 ([M−H]−); IR (thin film) 3307, 1665, 1114, 813 cm−1.
Reaction SMILES: [Cl:1]Cl.[C:3]1(=[O:13])[NH:7][C:6](=[O:8])[C:5]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:4]12.[K]>>[Cl:1][N:7]1[C:3](=[O:13])[C:4]2=[CH:12][CH:11]=[CH:10][CH:9]=[C:5]2[C:6]1=[O:8]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCl
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1Cl
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 91 %

Procedure:
Chlorine gas was bubbled into one liter of methylene chloride maintained at 0° C. The chlorine was added for about 10 minutes and until saturation was achieved. To the resulting chlorine-saturated methylene chloride were added 50 grams (270 mmoles) of potassium phthalimide as a solid and in one portion. The resulting mixture was allowed to warm gradually to 20° C., and additional chlorine was introduced as a gas during two separate periods to ensure the presence of an excess of chlorine. The mixture then was stirred vigorously at 20° C. for 60-90 minutes. The resulting precipitated potassium chloride was removed by filtration, and the filtrate was evaporated in vacuo to dryness. The residual white solid was suspended in 150 ml. of water for a few minutes, filtered, and washed with 100 ml. of water. The solid was vacuum dried overnight to obtain 44.5 grams (91% yield) of N-chlorophthalimide.
Reaction SMILES: [C:1]([CH:9]([C:15](=O)[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[NH2:18][NH2:19].C(=O)([O-])O.[Na+]>C(O)C>[CH3:16][C:15]1[NH:19][N:18]=[C:1]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C(C)=O)C(=O)c1ccncc1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccncc2)n[nH]c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a solution of ethyl 2-isonicotinoyl-3-oxobutanoate (8.0 g) in ethanol (80 mL) was added hydrazine (1.7 g), and the mixture was stirred at room temperature for 1 hr, and poured into saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.4 g).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH2:6]([O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH3:7].C(N(CC)CC)C>ClCCl>[CH2:6]([O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:1](=[O:4])[CH:2]=[CH2:3])=[CH:12][CH:11]=1)[CH3:7]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)Nc1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.1 %

Procedure:
To a solution of acryloyl chloride (1.08 mL, 13.32 mmol) in dry dichloromethane (10 mL) was slowly added dropwise, via addition funnel, a solution of 4-aminobenzoic acid ethyl ester (2.0 g, 12.11 mmol) and triethylamine (1.86 mL, 13.32 mmol) in dry dichloromethane (5 mL) over about 30 minutes. The reaction was stirred at room temperature for 16 hours. The solution was then partitioned between dichloromethane and water in a separatory funnel. The organic layer was washed with 2 N HCl, dried with sodium sulfate, and concentrated in vacuo to dryness. The resulting residue was triturated with hexane, and vacuum filtered to yield 2.02 g (76%) of 4-acryloylaminobenzoic acid ethyl ester as a solid.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([C:13]1[S:17][C:16]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[CH:15][CH:14]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CN(C)[CH:25]=[O:26]>>[CH:25]([C:20]1[S:19][C:18]([C:16]2[S:17][C:13]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:14][CH:15]=2)=[CH:22][CH:21]=1)=[O:26]
Reactant: CCCCCCCc1ccc(-c2cccs2)s1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCc1ccc(-c2ccc(C=O)s2)s1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Dimethyl formamide (DMF) (8 ml) was stirred at 0° C. for 10 minutes, POCl3 (1 ml) was added and then stirred for 1 hours. 5-Heptyl-2,2'-bithiophene (0.5 g) dissolved in dimethyl formamide (5 ml) was added and stirred at room temperature for half an hour at room temperature, then the temperature was raised to 60° C. and was further stirred for 4 hours. The reaction solution was then extracted with dichloromethane, neutralized with sodium acetate, washed with water to neutrality, dried, concentrated and separated by silica gel chromatography eluted with ethyl acetate/n-hexane (1/15). Light yellowish oily product (0.86 g, 86%) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=2[O:19]1>>[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH:23][C:2]3[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]4[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=4)[N:3]=3)=[CH:21][C:20]=2[O:19]1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Nc1ccc2c(c1)OCO2
Product: FC(F)(F)c1cc(Nc2ccc3c(c2)OCO3)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3,4-methylenedioxyaniline (53 mg, 0.386 mmol) similar to Example 58 and isolated as a light brown solid (37 mg, 53%). 1H NMR (CDCl3): 9.63 (dd, J=0.9, 1.8 Hz, 1H), 8.73-8.68 (m, 2H), 7.43-7.39 (m, 1H), 6.93 (s, 1H), 6.88 (d, J=8.1 Hz, 2H), 6.83 (dd, J=1.8, 8.1 Hz, 1H), 6.77 (s, 1H), 6.06 (s, 2H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@@H:21]([NH:23]C(=O)OC(C)(C)C)[CH3:22])=[CH:17][CH:16]=2)[CH:10]=3)[CH2:3][CH2:2]1.[ClH:33].C(OCC)(=O)C>C(OCC)C>[ClH:33].[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@@H:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=2)[CH:10]=3)[CH2:3][CH2:2]1
Reactant: C[C@@H](COc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C[C@H](N)COc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl [(1S)-2-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}-1-methylethyl]carbamate (310 mg) and 4M hydrogen chloride/ethyl acetate (5 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added diethyl ether, and the resultant precipitate was collected by filtration, and washed with ethyl acetate to give (2S)-1-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}propan-2-amine hydrochloride (255 mg). A mixture of (2S)-1-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]phenoxy}propan-2-amine hydrochloride (84 mg), methyl isocyanate (38.5 mg), triethylamine (68 mg) and THF (1 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate, and the mixture was washed with water. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as colorless crystals (51.9 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[S:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:43])=[O:42])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C#N)cc4c3)S(=O)(=O)c3ccccc3)cc2)CC1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, benzenesulfonyl chloride.