Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[CH2:28](O)[CH3:29]>>[CH2:28]([O:9][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[C:13]([C:19]([F:22])([F:20])[F:21])[CH:12]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:29]
Reactant: CCO
Reactant: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(CC1CCCC1)c1ccc(SC)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionic acid (1.29 g, 3.89 mmol) in ethanol (25 mL) was treated slowly with concentrated sulfuric acid (0.01 mL). The resulting reaction mixture was heated under reflux for 48 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. The residue was dissolved in ethyl acetate (35 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×15 mL), water (1×15 mL), and a saturated aqueous sodium chloride solution (3×20 mL). The organic layer was then dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionic acid ethyl ester (1.39 g, 94.8%) as yellow oil: EI-HRMS m/e calcd for C18H23F3O2S (M+) 360.1370, found 360.1370.
Reaction SMILES: NC1C=CC(C2C=C(C)C=CC=2S(C2C=CC(C)=CC=2C2C=CC(N)=C([N+]([O-])=O)C=2)=O)=CC=1[N+]([O-])=O.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([S:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]3[C:56]([N+:57]([O-])=O)=[C:55]([NH2:60])[CH:54]=[CH:53][C:52]=3[S:61]([C:63]3[CH:68]=[CH:67][C:66]([NH2:69])=[C:65]([N+:70]([O-])=O)[C:64]=3[C:73]3[CH:78]=[CH:77][C:76]([S:79][C:80]4[CH:85]=[CH:84][C:83]([Cl:86])=[C:82]([N+:87]([O-])=O)[CH:81]=4)=[CH:75][CH:74]=3)=[O:62])=[CH:47][CH:46]=2)=[CH:40][C:39]=1[N+:90]([O-])=O>>[Cl:86][C:83]1[CH:84]=[CH:85][C:80]([S:79][C:76]2[CH:75]=[CH:74][C:73]([C:64]3[C:65]([NH2:70])=[C:66]([NH2:69])[CH:67]=[CH:68][C:63]=3[S:61]([C:52]3[CH:53]=[CH:54][C:55]([NH2:60])=[C:56]([NH2:57])[C:51]=3[C:48]3[CH:49]=[CH:50][C:45]([S:44][C:41]4[CH:42]=[CH:43][C:38]([Cl:37])=[C:39]([NH2:90])[CH:40]=4)=[CH:46][CH:47]=3)=[O:62])=[CH:78][CH:77]=2)=[CH:81][C:82]=1[NH2:87]
Reactant: Nc1ccc(S(=O)c2ccc(N)c([N+](=O)[O-])c2-c2ccc(Sc3ccc(Cl)c([N+](=O)[O-])c3)cc2)c(-c2ccc(Sc3ccc(Cl)c([N+](=O)[O-])c3)cc2)c1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Product: Nc1cc(Sc2ccc(-c3c(S(=O)c4ccc(N)c(N)c4-c4ccc(Sc5ccc(Cl)c(N)c5)cc4)ccc(N)c3N)cc2)ccc1Cl

Procedure:
Following the procedure described in Example 2 but using as a starting material instead of (4-amino-3-nitro-phenyl)-4-methylphenyl sulfoxide a corresponding amount of [4-(4-chloro-3-nitrophenylthio)-phenyl]-4-amino-3-nitrophenyl sulfoxide, the title compound is obtained.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:36])([F:35])[C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:36])([F:19])[F:35])[CH:22]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: O=C(O)c1ncoc1-c1cccc(C(F)(F)F)c1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(C(F)(F)F)c3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([O:15][CH3:16])([O:13][CH3:14])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][C:19]=1[C:33]1[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=1>>[CH3:14][O:13][C:11]([C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:21]3[CH:22]=[CH:23][C:18]([F:17])=[C:19]([C:33]4[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:20]=3)=[CH:3][N:4]=[C:5]2[N:10]=1)([O:15][CH3:16])[CH3:12]
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Reactant: COC(C)(OC)c1ccn2c(Br)cnc2n1
Product: COC(C)(OC)c1ccn2c(-c3ccc(F)c(-c4ccccc4C#N)c3)cnc2n1
Yield: 100.2 %

Procedure:
3-Bromo-7-(1,1-dimethoxyethyl)imidazo[1,2-α]pyrimidine (860 mg, 3 mmol) was coupled with 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (1.45 g, 4.5 mmol) as described in Example 1 to give crude 5′-[7-(1,1-dimethoxyethyl)imidazo[1,2-α]pyrimidin-3-yl]-2′-fluorobiphenyl-2-carbonitrile (1.21 g).
Reaction SMILES: COC(C1C=CC(C(O)=O)=NC=1)=O.C(N)C1C=CC=CC=1.[CH2:22]([NH:29][C:30]([C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38]C)=[O:37])=[CH:34][N:33]=1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:29][C:30]([C:32]1[CH:41]=[CH:40][C:35]([C:36]([OH:38])=[O:37])=[CH:34][N:33]=1)=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc(C(=O)NCc2ccccc2)nc1
Agent: COC(=O)c1ccc(C(=O)O)nc1
Solvent: NCc1ccccc1
Product: O=C(O)c1ccc(C(=O)NCc2ccccc2)nc1

Procedure:
250 mg of 5-(methoxycarbonyl)picolinic acid was coupled to benzylamine via Procedure G. Crude methyl 6-(benzylcarbamoyl)nicotinate was hydrolyzed via Procedure M to yield 300 mg of 6-(benzylcarbamoyl)nicotinic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-(benzylcarbamoyl)nicotinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N2-benzyl-N5-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-2,5-dicarboxamide. MS (Q1) 443.1 (M)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:14])[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[OH:17]O.N>C(O)C.ClCCl>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:14])[N:5]=[CH:4][C:3]=1[C:15]([NH2:16])=[O:17]
Reactant: Cc1cccc(C)c1-n1ncc(C#N)c1N
Reactant: OO
Agent: N
Solvent: CCO
Solvent: ClCCl
Product: Cc1cccc(C)c1-n1ncc(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 g (9.4 mmol) of 5-amino-1-(2,6-dimethylphenyl)-1H-pyrazole-4-carbonitrile (Example 1A) are dissolved in 25 ml of ethanol, and a mixture of 20 ml of 30% strength hydrogen peroxide and 40 ml of 25% strength ammonia is added. The solution is stirred at room temperature overnight and then concentrated to about 15 ml in a rotary evaporator. The oily emulsion resulting thereby is taken up in dichloromethane. It is washed several times with water and saturated sodium thiosulphate solution. Drying over magnesium sulphate is followed by removal of the solvent in vacuo. The residue is purified by preparative HPLC (YMC Gel ODS-AQ S 5/15 μm; eluent A: water, eluent B: acetonitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95% B). 0.88 g (40% of theory) of the product is obtained as colourless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.CN(C)CCN(C)C.C([Li])CCC.[I:26]CI>O.C(OCC)C>[CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[C:7]([I:26])[CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: ICI
Reactant: CC1(C)CCOc2ccccc21
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC1(C)CCOc2c(I)cccc21
Temperature: -78 °C
Reaction time: 2 h

Procedure:
2.00 g (12.3 mmol) of 4,4-dimethylchroman and 30 ml of ethyl ether are introduced into a three-necked flask under argon. 2.4 ml (15.9 mmol) of tetramethylethylenediamine (TMEDA) are added dropwise, the mixture is cooled to -78° C. and 5.9 ml (14.8 mmol) of n-butyllithium (2.5M in hexane) are added dropwise. The temperature is allowed to return to -20° C. over two hours and then to room temperature and the mixture is stirred for 12 hours. 1.3 ml (16.0 mmol) of diiodomethane and 15 ml of ethyl ether are introduced into another three-necked flask under argon. Cooling is carried out to 0° C. and the preceding solution, cooled beforehand to -78° C., is introduced, then the reaction mixture is allowed to return to room temperature and stirred for 12 hours. The reaction mixture is poured into water and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with heptane. After evaporating the solvents, 1.30 g (37%) of the expected compound are collected in the form of a pale-yellow oil.
Reaction SMILES: C([N:3]1[CH2:21][CH2:20][C@@:10]23[C:11]4[CH:12]=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][C:16]=4[CH2:17][C@@H:4]1[C@:5]2([O:24][CH3:25])[C@@H:6]([CH3:23])[CH2:7][C:8](=[O:22])[CH2:9]3)#N.C([O-])([O-])=O.[Na+].[Na+].NC(N)=O.C(O)C.[ClH:39]>O.C(OCC)C>[ClH:39].[CH3:19][O:18][C:13]1[CH:14]=[CH:15][C:16]2[CH2:17][C@H:4]3[NH:3][CH2:21][CH2:20][C@@:10]4([C:11]=2[CH:12]=1)[C@@:5]3([O:24][CH3:25])[C@@H:6]([CH3:23])[CH2:7][C:8](=[O:22])[CH2:9]4
Reactant: COc1ccc2c(c1)[C@]13CCN(C#N)[C@H](C2)[C@]1(OC)[C@@H](C)CC(=O)C3
Agent: Cl
Agent: NC(N)=O
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@]1(OC)[C@@H](C)CC(=O)C3

Procedure:
A solution of 17-cyano-3,14-dimethoxy-8β-methyl morphinan-6-one (36) (3.6 g, 0.011 mol) in 100 ml of 4 N HCl was heated at 80°-90° C. in an oil bath for 16 hours. The reaction mixture was cooled, diluted with 150 ml of H2O and made basic with Na2CO3. The aqueous solution was extracted with four portions of chloroform, dried over Na2SO4 and concentrated under reduced pressure to give 3.8 g of crude product. The NMR spectrum of this crude material indicated the presence of the intermediate urea, and the crude material was therefore dissolved in 150 ml of 4 N HCl and heated at reflux for 10 additional hours. Similar workup as described above yielded 0.4 g of crude product which was taken up in diethyl ether, and treated with ethanol to give a precipitate. Collection of the precipitate by suction filtration gave 1.38 g (36% theory) of the title compound as a tan solid which was used in the next step without further purification.
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[CH:34][N:35]=2)[N:32]=1.C(N(C(C)C)C(C)C)C>C(O)CCC>[C:20]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([N:33]=[CH:34][N:35]=4)[N:32]=3)[CH2:11][CH2:10]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: NCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: Clc1ccc2ncnn2n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(C(OC2CCN(CCCCNc3ccc4ncnn4n3)CC2)c2ccccc2)cc1
Yield: 9.1 %

Procedure:
4-(Diphenylmethoxy)-1-piperidinebutanamine (1.83 g) and 6-chloro[1,2,4]triazolo[1,5-b]pyridazine (557 mg) were dissolved in 1-butanol (30 ml), followed by addition of N-ethyldiisopropylamine (931 mg). The mixture was refluxed under heating for 14 hours. After being cooled, the mixture was concentrated under reduced pressure, followed by addition of ice-water and extraction with ethyl acetate. The extract was washed with an aqueous sodium chloride saturated solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography and eluted with a mixture of ethyl acetate, methanol and triethylamine (45:5:1). Fractions containing the objective compound were collected and concentrated. The resulting crystals were collected, washed with ethyl ether and dried to yield the title compound (149 mg).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:16]3[S:20][C:19]([N:21]4[CH2:26][CH2:25][CH:24]([C:27]([O:29]CC)=[O:28])[CH2:23][CH2:22]4)=[N:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)[N:4]=1.[OH-].[Li+]>O1CCCC1.CO.CC1CCCO1>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:16]3[S:20][C:19]([N:21]4[CH2:26][CH2:25][CH:24]([C:27]([OH:29])=[O:28])[CH2:23][CH2:22]4)=[N:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)[N:4]=1
Reactant: CCOC(=O)C1CCN(c2ncc(-c3cccc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC1CCCO1
Product: O=C(O)C1CCN(c2ncc(-c3cccc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Temperature: 90 °C

Procedure:
To a solution of ethyl 1-[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-4-carboxylate (22 mg, 0.046 mmol) in tetrahydrofuran (0.5 mL) and methanol (0.5 mL) was added 1M aqueous lithium hydroxide (0.5 mL, 0.5 mmol) and the mixture was heated to 90° C. for 90 minutes. The mixture was cooled to room temperature, diluted with 2-methyltetrahydrofuran (30 mL), and, washed with 1 N aqueous hydrochloric acid (30 mL) and brine (30 mL). The aqueous layers were further extracted with 2-methyltetrahydrofuran (30 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to provide 1-[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-4-carboxylic acid as a white solid. MS APCI: [M+H]+ m/z 450.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH3:12])[C:6](=[O:13])[C:5]2([CH3:15])[CH3:14].[CH3:16][N:17]1[C:21]([C:22]#[N:23])=[CH:20][CH:19]=[C:18]1B(O)O.[F-].[K+]>O1CCOCC1.CCOC(C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:11][C:9]1[CH:10]=[C:2]([C:18]2[N:17]([CH3:16])[C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[CH:3]=[C:4]2[C:8]=1[N:7]([CH3:12])[C:6](=[O:13])[C:5]2([CH3:15])[CH3:14]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: CN1C(=O)C(C)(C)c2cc(Br)cc(F)c21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN1C(=O)C(C)(C)c2cc(-c3ccc(C#N)n3C)cc(F)c21
Temperature: 45 °C
Reaction time: 6 h
Yield: 28 %

Procedure:
5-Bromo-7-fluoro-1,3,3-trimethyl-1,3-dihydro-2H-indol-2-one (0.10 g, 0.36 mmol), 1-methyl-5-cyano-2-pyrroleboronic acid (95 mg, 0.63 mmol), KF (69 mg, 1.19 mmol) were suspended in 1 mL of dioxane. Pd2(dba)3 monochloroform adduct (3.1 mg, 0.003 mmol) and Pd(P(t-Bu)3)2 (4.6 mg, 0.009 mmol) were added and the mixture was stirred vigorously at 45° C. for 6 h. The mixture was diluted with 100 mL of EtOAc and filtered through a plug of silica gel and concentrated. Purification by flash chromatography (2% acetone/hexane) afforded the title compound (30 mg, 28%) as a tan solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].C([O:17][C:18](=O)[C:19]([F:22])([F:21])[F:20])C>C(O)C>[F:20][C:19]([F:22])([F:21])[C:18]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[O:17]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCCCCCCCCCCCCO
Solvent: CCO
Product: O=C(NCCCCCCCCCCCCO)C(F)(F)F
Yield: 98.2 %

Procedure:
An ethanol solution (100 ml) of 12-aminododecanol (4.81 g, 23.9 mmol) and trifluoroacetic acid ethyl ester (6.79 g, 47.8 mmol) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give 12-trifluoroacetamidododecanol (1) (6.98 g, q.) as a colorless syrup.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:3]=1.S(=O)(=O)(O)O.[OH-].[NH4+].[CH2:19](O)[CH3:20]>>[CH2:19]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1)[CH3:20]
Reactant: O=C(O)Cc1cccnc1
Reactant: CCO
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: CCOC(=O)Cc1cccnc1
Temperature: 25 °C

Procedure:
To a solution of 3-pyridylacetic acid hydrochloride (40 g, 230.41 mmol) in ethanol (90 mL) was added sulfuric acid (73 g, 744.3 mmole, 98%) under N2. The reaction mixture was refluxed for 4 h, then cooled to rt. Ammonium hydroxide (250 mL, 25%) was added and extracted with DCM (500 mL) twice, dried over sodium sulfate, concentrated to afford the title product (33 g),
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([NH2:17])=[O:16])=[C:6]2[C:11]=1[O:10][CH2:9][CH:8]([N+:12]([O-])=O)[CH2:7]2.C(O)C>O1CCCC1.[Ni]>[NH2:12][CH:8]1[CH2:7][C:6]2=[C:5]([C:15]([NH2:17])=[O:16])[CH:4]=[CH:3][C:2]([F:1])=[C:11]2[O:10][CH2:9]1
Reactant: NC(=O)c1ccc(F)c2c1CC([N+](=O)[O-])CO2
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: NC(=O)c1ccc(F)c2c1CC(N)CO2
Reaction time: 48 h
Yield: 99 %

Procedure:
8-Fluoro-3-nitro-3,4-dihydro-2H-1-benzopyran-5-carboxamide (9.0 g, 37.5 mmol), dissolved in tetrahydrofuran (100 mL) and absolute ethanol (400 mL), was subjected to atmospheric hydrogenation conditions using Raney nickel (W-2, 9 g) at room temperature. The reaction was complete after 48 hours, at which time the catalyst was filtered off, washed with hot ethanol and the combined solvents were removed in vacuo to give 7.8 g (99% yield) of an off-white solid. A portion was recrystallized from ethyl acetate to give white crystals as the title compound (mp 187-188° C). EIMS (70 eV) m/z (relative intensity) 210 (6, M+), 194 (30), 193 (100), 192 (20), 178 (12).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[C:26]([C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>>[CH3:25][O:24][C:22]([C:4]1[N:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:34](=[O:35])[C:33]1[CH:37]=[CH:38][C:30]([C:26]([CH3:28])([CH3:27])[CH3:29])=[CH:31][CH:32]=1)=[CH:10][CH:9]=[C:8]([O:14][CH3:15])[CH:7]=2)=[O:23]
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(OC)cc2n1-c1ccccc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: COC(=O)c1c(CNC(=O)c2ccc(C(C)(C)C)cc2)c(=O)c2ccc(OC)cc2n1-c1ccccc1

Procedure:
3-[(4-tert-Butyl-benzoylamino)-methyl]-7-methoxy-4-oxo-1-phenyl-1,4-dihydro-quino-line-2-carboxylic acid methyl ester was prepared starting from intermediate K and 4-tert-butyl-benzoyl chloride. MS calcd. for C30H30N2O5 [(M+H)+] 499.2, obsd. 499.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH2:48]([C:51]1[CH:52]=[C:53]2[C:58](=[CH:59][C:60]=1[Cl:61])[NH:57][C:56](=[O:62])[C:55]([C:63]1[CH:68]=[C:67]([CH3:69])[CH:66]=[C:65]([CH3:70])[CH:64]=1)=[C:54]2O)[CH:49]=[CH2:50]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:54]1[C:53]2[C:58](=[CH:59][C:60]([Cl:61])=[C:51]([CH2:48][CH:49]=[CH2:50])[CH:52]=2)[NH:57][C:56](=[O:62])[C:55]=1[C:63]1[CH:68]=[C:67]([CH3:69])[CH:66]=[C:65]([CH3:70])[CH:64]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCO
Reactant: C=CCc1cc2c(O)c(-c3cc(C)cc(C)c3)c(=O)[nH]c2cc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=CCc1cc2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c(-c3cc(C)cc(C)c3)c(=O)[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.5 %

Procedure:
To a solution of 6-allyl-7-chloro-3-(3,5-dimethylphenyl)-4-hydroxy-1H-quinolin-2-one (960 mg in 30 mL of tetrahydrofuran) at 0° C. was added 615 mg of 2-(2-hydroxyethyl)-piperidine-1-carboxylic acid tert-butyl ester and 1.04 g of triphenylphosphine followed by 0.56 mL of diethyl azodicarboxylate and the mixture warmed to room temperature. After 20 hours, the solvents were removed in vacuo and the residue purified by flash chromatography on silica gel (hexane:ethyl acetate, 85:15; then 80:20; then 90:10) to give 1.19 g of the title compound.
Reaction SMILES: CNC(=O)C1C=CC(N2CCC(=O)N(C3C=CC(C#N)=C(C(F)(F)F)C=3)C2=O)=CC=1.[C:31]([O:35][CH2:36][CH3:37])(=[O:34])[CH:32]=[CH2:33].C1CCN2C(=NCCC2)CC1.[NH2:49][C:50]1[CH:59]=[CH:58][C:53]([C:54]([NH:56][CH3:57])=[O:55])=[C:52]([F:60])[CH:51]=1>CS(C)=O>[CH3:57][NH:56][C:54]([C:53]1[CH:58]=[CH:59][C:50]([NH:49][CH2:33][CH2:32][C:31]([O:35][CH2:36][CH3:37])=[O:34])=[CH:51][C:52]=1[F:60])=[O:55]
Reactant: CNC(=O)c1ccc(N)cc1F
Reactant: C=CC(=O)OCC
Agent: CNC(=O)c1ccc(N2CCC(=O)N(c3ccc(C#N)c(C(F)(F)F)c3)C2=O)cc1
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CCNc1ccc(C(=O)NC)c(F)c1
Reaction time: 24 h

Procedure:
Synthesis of N-methyl-4-{[3-(trifluoromethyl)-4-cyanophenyl]-2,4-dioxo-tetrahydropyrimidin-1(2H)-yl}benzamide 1.3.2(1), (X═O, R1=CH3). Ethyl acrylate (8 g, 80 mmol) and DBU (0.81 g, 5.4 mmol) were added to a solution of 4-amino-N-methyl-2-fluorobenzamide (9 g, 53.6 mmol) in DMSO (90 ml) and stirring was continued for 24 h at 70° C. (LCMS control). The reaction mixture was subjected to lyophilization, the residue was recrystallized from aqueous alcohol. It gave ethyl N-[4-(methylcarbamoyl)-3-fluorophenyl]-β-alaninate 5. LCMS (M+H)+ 269. 1H NMR (DMSO-d6, 400 MHz) δ 7.57 (br. s, 1H), 7.48 (t, J=8.8 Hz, 1H), 6.47 (br. s, 1H), 6.42 (d, J=8.8 Hz, 1H), 6.33 (d, J=14.8 Hz, 1H), 4.07 (q, J=7.2 Hz, 2H), 3.32 (br. m, 2H), 2.73 (d, J=4.4 Hz, 3H), 2.55 (t, J=6.4 Hz, 2H), 1.18 (t, J=7.2 Hz, 3H). The solution of 4-isocyanato-2-(trifluoromethyl)benzonitrile (425 mg, 1.87 mmol) 3.1 and ethyl N-[4-(methylcarbamoyl)-3-fluorophenyl]-β-alaninate (500 mg, 1.87 mmol) 5 (R1=CH3) in CH2Cl2 (10 ml) was stirred for 5 h. The reaction mixture was evaporated in vacuo, and the product was isolated by colomn chromatography on SiO2 (eluent—n-hexane:AcOEt:Et3N=1:1:0.03). It gave ethyl N-[4-(methylcabamoyl)-3-fluorophenyl]-N-{[3-(trifluoromethyl)-4-cyanophenyl]-carbamoyl}-β-alaninate 6(1) (R1=CH3, X═O). LCMS (M+H)+ 481. HCl (2.5 ml) was added to the solution of ethyl N-[4-(methylcabamoyl)-3-fluorophenyl]-N-{[3-(trifluoromethyl)-4-cyanophenyl]-carbamoyl}-β-alaninate (500 mg, 1.04 mmol) 6(1) in AcOH (5 ml) and the resultant mixture was stirred for 15 h. The reaction mixture was poured into water, the product was extracted with EtOAc. Organic layer was dried over Na2SO4, evaporated in vacuo and by means of colomn chromatography on SiO2 (eluent—n-hexane:AcOEt=1:1) N-methyl-4-{[3-(trifluoromethyl)-4-cyanophenyl]-2,4-dioxo-tetrahydropyrimidin-1(2H)-yl}benzamide 1.3.2, (X═O, R1=CH3) was isolated; Ki1.3.2(1)=85.6 nM, LCMS (M+H)+ 435. 1H NMR (DMSO-d6, 400 MHz): δ 8.29 (d, J=7.6 Hz, 1H), 8.23 (br. m, 1H), 8.11 (s, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.67 (t, J=8.4 Hz, 1H), 7.39 (d, J=12.4 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 4.02 (t, J=6.4 Hz, 2H), 3.03 (t, J=6.4 Hz, 2H), 2.77 (d, J=4.4 Hz, 3H).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH:7]2[CH2:9][CH:5]([C:6]2([CH3:11])[CH3:10])[CH:4]1[CH3:12])=O.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)=O>[N:13]1([CH2:1][CH:3]2[CH2:8][CH:7]3[CH2:9][CH:5]([C:6]3([CH3:11])[CH3:10])[CH:4]2[CH3:12])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC1C(C=O)CC2CC1C2(C)C
Reactant: C1CCNC1
Solvent: O=CO
Product: CC1C(CN2CCCC2)CC2CC1C2(C)C
Yield: 73 %

Procedure:
33 g of (+)-3-formylpinane, 14 g of pyrrolidine and 70 g of formic acid are heated under reflux for 12 hours. Excess formic acid is then distilled off and the residue is boiled with 150 g of 25% strength aqueous potassium hydroxide solution. The amine separates out as the upper phase and is separated off and purified by fractional distillation. 31.8 g of (+)-3-pyrrolidinomethylpinane boiling at from 125° to 127° C/5 mm Hg are obtained.