Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:18][CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:19])[CH:14]=3)[N:9]([CH3:20])[C:8]=2[CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:19][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:20])[C:8]1[CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:18][CH2:17][C:16]2=1
Reactant: CCOC(=O)C1CCc2c(n(C)c3ccc(Cl)cc23)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c2c(c3cc(Cl)ccc31)CCC(C(=O)O)C2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 4.6 g. of 6-chloro-9-methyl-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid ethyl ester, 25 ml. of ethanol and 25 ml. of 3N sodium hydroxide was refluxed and stirred for 6 hours. Upon cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in water (300 ml.) and filtered. The filter cake was washed with water (4 × 50 ml.) and dried, yielding 4.2 g. of product, m.p. 259°-260° . Upon recrystallization from ethyl acetate, 4.0. g. of 6-chloro-9-methyl-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid was obtained, m.p. 259°-260°.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:8]([CH2:9][CH:10](O)[CH3:11])[N:7]=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][N:2]1[CH:10]([CH3:11])[CH2:9][N:8]2[N:7]=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=[C:4]2[CH2:3]1
Reactant: CNCc1cc([N+](=O)[O-])nn1CC(C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1Cn2nc([N+](=O)[O-])cc2CN1C
Temperature: 0 °C
Reaction time: 5 h
Yield: 80.3 %

Procedure:
To a mixture of 250c (1.129 g, 5.27 mmol) and triphenylphosphine (4.14 g, 15.8 mmol) in anhydrous THF (40 mL) cooled at 0° C. was added the solution of di-isopropyl azodicarboxylate (DIAD) (3.19 g, 15.8 mmol) in THF (15 mL) over a period of 30 minutes while maintaining the internal temperature below 5° C. The reaction mixture was warmed to 30° C. and stirred at this temperature for 5 h. The mixture was then quenched with water (50 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (3×80 mL). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80:1 to 30:1) to afford 250d (0.83 g, 80%) as yellow solid. MS-ESI: [M+H]+ 197.2
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.O[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1
Reactant: Oc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccn2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-hydroxypyridine (2.0 g), tert-butyl 4-hydroxy-1-piperidinecarboxylate (5.3 g) and triphenylphosphine (8.3 g) in tetrahydrofuran (63 ml) was slowly added diethyl azodicarboxylate (5.5 g) at 8° C., and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo to give the crude product of the title compound and the crude product was purified by chromatography on silica gel.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([CH2:9][C:10]([OH:12])=O)[C:4]=1[CH3:13])=[O:2].[CH2:14]([N:16]([CH2:19][CH2:20][NH2:21])[CH2:17][CH3:18])[CH3:15]>>[CH2:14]([N:16]([CH2:17][CH3:18])[CH2:19][CH2:20][NH:21][C:10](=[O:12])[CH2:9][C:5]1[C:4]([CH3:13])=[C:3]([CH:1]=[O:2])[NH:7][C:6]=1[CH3:8])[CH3:15]
Reactant: CCN(CC)CCN
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)O
Product: CCN(CC)CCNC(=O)Cc1c(C)[nH]c(C=O)c1C

Procedure:
(5-Formyl-2,4-dimethyl-1H-pyrrol-3-yl)-acetic acid was reacted with diethylaminoethylamine using General Amidation Procedure 1 to give N-(2-diethylamino-ethyl)-2-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-acetamide. MS m/z 280 [M+1].
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH2:26][CH:27]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:28]([OH:30])=[O:29].C[O-].[Na+].CO.Cl>O>[C:35]([O:34][C:32]([NH:31][C@@H:27]([CH2:26][NH:25][C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4])[C:28]([OH:30])=[O:29])=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)NC(CN)C(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Temperature: 95 °C
Yield: 71 %

Procedure:
A 20-mL scintillation vial was charged with 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.31 mmol), 3-amino-2-tert-butoxycarbonylamino-propionic acid (319 mg, 1.56 mmol) (Bachem) and 0.5 M NaOMe/MeOH solution (2.5 mL, 1.25 mmol). The vial was close capped and heated in a 90-100° C. oil bath for 2 days. Reaction mixture was diluted with water (70 mL), acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried in vacuo to provide the title compound 108 mg (0.22 mmol) in 71% yield. LC-MS ESI−: 491.16 (M−1)−.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7](=[O:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[CH2:48](Br)[C:49]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:50]>>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:7](=[O:10])[N:8]([CH2:48][C:49]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:50])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCc1nn(CC(=O)c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 81 %

Procedure:
The alkylation of 5-n-butyl-2,4-dihydro-4-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]-3H- 1,2,4-triazol-3-one (from Example 2, Step D) with phenacyl bromide was carried out as described in Example 3, Step A, except that only 3 equivalents of the alkylating agent was used. After work-up, the residue was flash chromatographed over silica gel (25 mL for 0.162 mmole, gradient elution using 0.5-2.0% MeOH/CH2Cl2) to give the desired compound as a white foam in 81% yield, homogeneous by TLC in 2% MeOH/CH2Cl2, mass spectrum (FAB) 736 (M+1)+.
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].BrBr.[Cl:7][C:8]1[NH:9][C:10]([CH3:15])=[CH:11][C:12]=1[C:13]#[N:14].O>CO>[Cl:7][C:8]1[NH:9][C:10]([CH3:15])=[C:11]([S:1][C:2]#[N:3])[C:12]=1[C:13]#[N:14]
Reactant: Cc1cc(C#N)c(Cl)[nH]1
Reactant: N#C[S-]
Agent: BrBr
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1[nH]c(Cl)c(C#N)c1SC#N
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium thiocyanate (7.5 g) in 50 ml of methanol was cooled to −76° C. Bromine in 30 ml of cold methanol was added dropwise over 12 min. A slurry of 2-chloro-3-cyano-5-methylpyrrole in 30 ml of cold methanol was added at once. After stirring 30 min at −78° C., the mixture was poured into H2O and stirred overnight, then filtered, washed with water and hexane, and air dried to afford 6.57 g of an off-white solid, m.p. 171° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[C:4]([CH3:12])[N:3]=1.[C:13]([O:17][C:18](=[O:29])[NH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)([CH3:16])([CH3:15])[CH3:14]>C(N(CC)C(C)C)(C)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:28][C:25]2[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][NH:19][C:18](=[O:29])[O:17][C:13]([CH3:15])([CH3:14])[CH3:16])=[CH:27][CH:26]=2)[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2ccc(CCNC(=O)OC(C)(C)C)cc2)c([N+](=O)[O-])c(Cl)n1
Yield: 15.8 %

Procedure:
A mixture of 2,4-dichloro-6-methyl-3-nitro-pyridine (Chorvat, Robert J. et al., J. Med. Chem., 1999, 42, 833., 7.5 g, 36.2 mmol), [2-(4-amino-phenyl)-ethyl]-carbamic acid tert-butyl ester (Stark, Peter A. et al., J. Med. Chem., 1992, 35, 4264., 1.14 g, 4.83 mmol) in N,N-diisopropylethylamine (50 ml) was heated at reflux temperature for 16 h. After cooling, the mixture was concentrated. The residue was diluted with dichloromethane (200 ml) and washed with saturated aqueous NaHCO3 solution (50 ml×2). The organic layer was dried (MgSO4), and concentrated. Purification by flash column chromatography eluting with hexane/ethyl acetate (1:1) to afford 310 mg (16%) of the title compound as orange solids.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:17]=[N:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=NN=1>C1(C)C=CC=CC=1>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:1][C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[Cl:9])=[N:17][N:18]=1
Reactant: C=Cc1ccccc1
Reactant: Clc1ccccc1-c1nnc(-c2ccccc2Cl)nn1
Solvent: Cc1ccccc1
Product: Clc1ccccc1C1=NN=C(c2ccccc2Cl)C(c2ccccc2)C1

Procedure:
To styrene (2.34 ml) was added 3,6-bis(2-chlorophenyl)-1,2,4,5-tetrazine (2.6 g) in toluene (20 ml). The mixture was heated to reflux for 3 hours, and was then cooled. The solid which separated was filtered off and dried to yield 2.6 g of the desired product, mp 151°-153° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.I[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)=[CH:20][CH:21]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: COc1ccc(I)cc1
Product: COc1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C)c2)cc1
Yield: 15 %

Procedure:
As described for Example 2b, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (100 mg, 0.44 mmol) using 4-iodoanisole instead of iodobenzene was converted to the title compound (22 mg, 15%) which was obtained as a yellow gum. MS: m/e=332.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:32]=[C:31]([F:33])[C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]3[N:21]=[C:20]([NH:22][C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[C:19]([O:29][CH3:30])=[CH:18][N:17]=3)=[N:8]2)=[C:4]([F:34])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:40]([O:42][CH2:43][CH3:44])=[CH2:41])CCC.CN1CCCC1=O>C1(C)C=CC=CC=1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:43]([O:42][C:40]([C:2]1[CH:3]=[C:4]([F:34])[C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]3[N:21]=[C:20]([NH:22][C:23]4[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=4)[C:19]([O:29][CH3:30])=[CH:18][N:17]=3)=[N:8]2)=[C:31]([F:33])[CH:32]=1)=[CH2:41])[CH3:44]
Reactant: COc1cnc(-c2nn(Cc3c(F)cc(Br)cc3F)c3ccccc23)nc1Nc1ccncc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: C=C(OCC)c1cc(F)c(Cn2nc(-c3ncc(OC)c(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
100 mg of 2-[1-(4-bromo-2,6-difluorobenzyl)-1H-indazol-3-yl]-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine (2-12-1, 0.191 mmol, 1 eq.) was suspended in dry toluol. 1.34 mg of dichloropalladium-triphenylphosphane (1:2) (0.002 mmol, 0.01 eq.) and 71 μl of tributyl(1-ethoxyethenyl)stannane (0.21 mmol, 1.2 eq.) were added. The mixture was stirred for 5 hours at 100° C. bath temperature and for 18 hours at 120° C. bath temperature. 5 mg of dichloropalladium-triphenylphosphane (1:2) (0.007 mmol, 0.035 eq.) and 140 μl of tributyl(1-ethoxyethenyl)stannane (0.42 mmol, 2.4 eq.) and 1 ml of 1-methylpyrrolidin-2-one were added. The solution was stirred for 3 days at 100° C. bath temperature. 5 mg of dichloropalladium-triphenylphosphane (1:2) (0.007 mmol, 0.035 eq.) and 140 μl of tributyl(1-ethoxyethenyl)stannane (0.42 mmol, 2.4 eq.) were added and stirred at 100° C. again for 22 hours. The reaction mixture was concentrated in vacuo and purified by flash chromatography to yield 119 mg (0.2 mmol, 107%) of the analytically pure target compound.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[C:15](OCC)(=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].[Na]>C(O)C>[CH2:19]([O:18][C:16](=[O:17])/[C:15](/[OH:21])=[CH:11]/[C:10](=[O:12])[C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=1)[CH3:20]
Reactant: CC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)/C(O)=C/C(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
A solution of 1-(4-trifluoromethoxy-phenyl)-ethanone (5 g, 24 mmol) and diethyl oxalate (3.25 ml, 24 mmol) in ethanol (5 ml) was added within 20 min to an ice cooled solution of metallic sodium (552 mg, 24 mmol) in ethanol (15 ml) under an argon atmosphere. The cooling bath was removed and the reaction stirred 30 min after reaching ambient temperature. After standing 14 h, the precipitated yellow solid was filtered. The solid was partitioned between 1 M HCl/ice water 1/1 and tert butyl methyl ether. The aqueous layer was extracted two times with tert butyl methyl ether, the combined extracts were washed with brine/ice water 1/1 and dried over sodium sulfate. Evaporation of the solid gave 7.2 g (23.8 mmol, 99%) of the title compound as orange crystals.
Reaction SMILES: C([NH:4][C:5]1[C:6]([N+:14]([O-:16])=[O:15])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=O)C.S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>>[NH2:4][C:5]1[C:6]([N+:14]([O-:16])=[O:15])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O:10][CH2:22][CH3:23])=[O:9]
Reactant: CCO
Reactant: CC(=O)Nc1cccc(C(=O)O)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cccc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A mixture of 20.2 g of 3-acetylamino-2-nitrobenzoic acid, 11.4 g of 97% sulfuric acid and 300 ml of ethanol was stirred for 23 hours while being heat-refluxed. One-hundred milliliters of ethanol were distilled off under reduced pressure, and the residue was cooled to room temperature. Subsequently, the reaction solution was poured into 200 ml of ice water containing 19.5 g of sodium hydrogencarbonate. The crystals precipitated were separated through filtration, and were washed with water. Further, these crystals were dispersed in 30 ml of a mixed solution of ethyl acetate and hexane at a ratio of 1:2. The crystals were separated through filtration, washed with hexane, and then dried to give 18.0 g of ethyl 3-amino-2-nitrobenzoate.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]([C:39]#[N:40])([NH:12][C:13](=[O:38])[CH:14]([NH:22][C:23]([CH:25]2[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]2)=[O:24])[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>Cl.O1CCOCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9]([C:39]#[N:40])([NH:12][C:13](=[O:38])[CH:14]([NH:22][C:23]([CH:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]2)=[O:24])[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)N1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC(=O)C2CCNCC2)CC1

Procedure:
The ester from (a) was dissolved in 10 mL of 4 N HCl in 1,4-dioxane at 0° C. for 1 hour. The solution was concentrated in vacuo and the salt neutralized by sodium bicarbonate solution and the product extracted with CH2Cl2. After concentration of the organic extract, the crude product was purified by reverse-phase HPLC to yield the desired product; MS, m/z 462=M+1.
Reaction SMILES: [K].[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.OC1C([C:24]([OH:26])=[O:25])=CC2C(C=1)=CC=CC=2>>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:24]([OH:26])=[O:25])[CH:7]=[CH:6]2
Reactant: Oc1ccc2ccccc2c1
Reactant: O=C(O)c1cc2ccccc2cc1O
Agent: [K]
Product: O=C(O)c1ccc2cc(O)ccc2c1

Procedure:
In the carboxylation of the potassium salt of 2-hydroxynaphthalene, the initial product form is 3-hydroxy-2-naphthoic acid which subsequently rearranges in situ to form 6-hydroxy-2-naphthoic acid. It has been found that the conditions which favor the formation of 3-hydroxy-2-naphthoic acid in the Kolbe-Schmitt reaction hinder the rearrangement reaction.
Reaction SMILES: [N:1]1([C:6]([NH2:8])=[NH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:9][C:10]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:11]=1[CH:12]=[C:13]([C:16]#[N:17])[C:14]#[N:15]>>[NH2:17][CH2:16][C:13]1[C:14]([NH2:15])=[N:7][C:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:8][C:12]=1[C:11]1[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:10]=1[Cl:9]
Reactant: N=C(N)N1CCCC1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: NCc1c(N)nc(N2CCCC2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=337.8 (M+), was prepared from pyrrolidine-1-carboxamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][N:8]([C:12](=[O:18])[CH2:13][O:14]C(=O)C)[CH2:7][C:6]=2[S:5][C:4]=1[NH:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21])#[N:2].[OH-].[Na+]>>[C:1]([C:3]1[C:11]2[CH2:10][CH2:9][N:8]([C:12](=[O:18])[CH2:13][OH:14])[CH2:7][C:6]=2[S:5][C:4]=1[NH:19][C:20](=[O:21])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)#[N:2]
Reactant: CC(=O)OCC(=O)N1CCc2c(sc(NC(=O)c3ccccc3)c2C#N)C1
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1c(NC(=O)c2ccccc2)sc2c1CCN(C(=O)CO)C2

Procedure:
Acetic acid 2{3-cyano-2-[(1-phenyl-methanoyl)-amino]-4,7-dihydro-5H-thieno[2,3-c]pyridin-6-yl}-2-oxo-ethyl ester is stirred on 1N NaOH over night at room temperature. Workup as described in general procedure A3 gives the desired product.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:34])([F:33])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[N:10]=[C:9]([NH:19][C:20](=[O:32])[N:21]([CH3:31])[C:22]2[S:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)[N:8]=1.[CH3:35]I>C1COCC1>[CH3:35][N:19]([C:9]1[N:8]=[C:7]([O:6][CH2:5][C:4]([F:3])([F:33])[F:34])[CH:12]=[C:11]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[N:10]=1)[C:20](=[O:32])[N:21]([CH3:31])[C:22]1[S:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=1
Reactant: CN(C(=O)Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1)c1ccc(C(F)(F)F)s1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)N(C)c1ccc(C(F)(F)F)s1)c1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (18 mg, 0.36 mmol) in anhydrous THF (3 mL) was added a solution of the 3-(4,6-bis(2,2,2-trifluoro ethoxy)pyrimidin-2-yl)-1-methyl-1-(5-(trifluoromethyl)thiophen-2-yl)urea (2) (150 mg, 0.30 mmol). The reaction was stirred for 10 minutes after which time gas evolution had subsided. To the reaction was added methyl iodide (51.2 mg, 0.36 mmol). The reaction was stirred at ambient temperature for 2 h. The reaction was quenched with H2O (5 mL) and extracted with t-butyl ethyl ether (3×5 mL). The organics were combined and extracted with an equal amount of H2O. The organics were dried (MgSO4), filtered and concentrated to afford crude product. The crude material was purified by silica gel chromatography (5% EtOAc in pet ether) to afford 3-methyl-3-(4,6-bis(2,2,2-trifluoro ethoxy)pyrimidin-2-yl)-1-methyl-1-(5-(trifluoromethyl)thiophen-2-yl)urea (6) as an off white solid (31 mg, 20%), mp 113-114° C.; 1H NMR (400 MHz, Acetone-d6) δ 7.35-7.24 (m, 1H), 6.73 (d, J=4.2 Hz, 1H), 5.88 (s, 1H), 4.76 (q, J=8.7 Hz, 4H), 3.35 (s, 3H), 3.28 (s, 3H); ESIMS m/z 513 ([M+H]+).
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([NH2:13])=[CH:5][CH:4]=[C:3]3[CH2:2]1.C(N(CC)CC)C.[C:21]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>C1(C)C=CC=CC=1>[CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([NH:13][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:26][CH:27]=2)=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: Nc1ccc2c3c(cccc13)CC2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(CNc2ccc3c4c(cccc24)CC3)cc1
Temperature: 4 °C

Procedure:
A mixture of 5-acenaphthylamine (1.0 g, 6 mmol) and triethylamine (0.76 g, 7.5 mmol) in toluene (50 mL) was stirred at 4° C., and 4-tert-butylbenzyl-bromide (1.36 g, 6 mmol) was added in slowly. The reaction mixture was stirred at 23° C. for 15 hours and precipitates formed. The precipitates (triethylamine.HBr) were filtered out; the filtrate was concentrated to dryness. Then the crude reaction mixture was purified by column chromatography (SiO2, hexane/CH2Cl2=5/1). N-(5-acenaphthyl)-4-tert-butylbenzylamine (1.67 g, an oil) was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][NH:1][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:7]
Reactant: CCOC(=O)CN
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)c1ccccc1
Yield: 83.6 %

Procedure:
To a suspension of ethyl 2-amino-acetate (1.0 g, 7.16 mmol) in anhydrous CH2Cl2 (5 ml) was added TEA (1.82 g, 17.96 mmol). The reaction mixture was cooled in an ice bath, and a solution of benzoyl chloride (1.0 g, 7.17 mmol) in CH2Cl2 (2 ml) was added dropwise. After addition was completed, stirring was continued at RT for two more hours. The reaction mixture was washed with water, dried with MgSO4, filtered, and concentrated. Column chromatography (silica, 30% EtOAc in hexanes) gave benzoylaminoacetic acid ethyl ester (intermediate XXa, 1.24 g) as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:19]([CH:16]2[CH2:18][CH2:17]2)=[O:20])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cccc(I)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc(I)c1)C1CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74 %

Procedure:
1.53 g of 3-iodoaniline and 2.78 ml of triethylamine are dissolved in 25 ml of methylene chloride and treated dropwise at room temperature with a solution of 1.6 ml of cyclopropane carbonyl chloride in 10 ml of methylene chloride. The mixture is stirred at room temperature for a further 5 hrs., evaporated and poured into 50 ml of water. The mixture is made slightly acid with dil. hydrochloric acid and extracted three times with ethyl acetate. The residue is recrystallized from toluene. 1.47 g of cyclopropanecarboxylic acid (3-iodo-phenyl)-amide are isolated as a colourless solid. Yield: 74%. M.p.=133°.