Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([NH2:8])(=N)[CH2:3][C:4]([NH2:6])=[NH:5].N12CCCN=C1CCCCC2.[O:20]1CCCC1.[F:25][C:26]([F:33])([F:32])[C:27](OCC)=O>O>[NH2:6][C:4]1[N:5]=[C:27]([C:26]([F:33])([F:32])[F:25])[N:8]=[C:2]([OH:20])[CH:3]=1
Reactant: N=C(N)CC(=N)N
Reactant: CCOC(=O)C(F)(F)F
Reactant: C1CCOC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Nc1cc(O)nc(C(F)(F)F)n1
Temperature: 25 °C

Procedure:
Under stirring at room temperature, malonamidine hydrochloride (406 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (870 ml) were added to tetrahydrofuran (2 L), and ethyl trifluoroacetate (1040 ml) was added dropwise. After stirring under heating at a bath temperature of 65° C. for 17.5 hr, water (200 ml) was added, and the reaction mixture was concentrated. Water (1 L) was added to the concentrated residue, concentrated hydrochloric acid (485 ml) was added dropwise with stirring at room temperature and the mixture was stirred for 1 hr. After cooling the inside temperature to 0° C. or below, the precipitated crystals were collected by filtration, washed twice with water (600 ml), and dried to give the title compound (251 g).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=O)[C@@H](CC)[N:5]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:4]=2[N:3]=1.[NH2:20][NH2:21].[CH2:22]1[CH2:26]O[CH2:24][CH2:23]1.C(OCC)(=O)C>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]3[CH:7]=[N:20][N:21]=[C:24]3[C@@H:23]([CH2:22][CH3:26])[N:5]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:4]=2[N:3]=1
Reactant: CC[C@@H]1C(=O)Nc2cnc(Cl)nc2N1C1CCCC1
Reactant: NN
Reactant: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC[C@@H]1c2nncn2-c2cnc(Cl)nc2N1C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
(R)-2-Chloro-8-cyclopentyl-7-ethyl-7,8-dihydropteridin-6(5H)-one (100 mg, 0.357 mmol) in phosphorus oxychloride (3.0 ml) was stirred at 110° C. for 3 hours then concentrated under reduced pressure. The residue was dissolved in anhydrous dichloromethane and added dropwise to 1.0 M hydrazine in THF (3.6 ml, 3.57 mmol). The mixture was stirred at RT overnight, taken into ethyl acetate and washed with aqueous sodium hydrogen carbonate, dried over magnesium sulphate and concentrated. The residue of crude hydrazide was dissolved in trimethyl orthoformate (2.0 ml) and stirred at 110° C. for 90 min. The mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel eluting with ethyl acetate to give (R)-7-chloro-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine (68 mg, 63%) as a pale brown solid; 1H NMR (DMSO D6) 0.75 (3H, t), 1.50-1.64 (2H, m), 1.80-2.08 (8H, m), 4.22-4.33 (1H, m), 5.28-5.35 (1H, m), 8.68 (1H, s), 9.35 (1H, s); MS (ES+) 305.
Reaction SMILES: [NH-][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[C:11]([OH:13])=[O:12].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>>[C:5]1(=[O:7])[O:13][C:11](=[O:12])[C:3]2=[CH:2][CH:10]=[CH:9][CH:8]=[C:4]12
Reactant: [NH-]c1cccc(C(=O)O)c1C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2ccccc21
Temperature: 80 °C

Procedure:
13.8 g (0.04 mol) of this amidylphthalic acid are mixed with 1.4 g of anhydrous sodium acetate and 25 ml of acetic anhydride and the mixture is heated to 80°C for 30 minutes, whilst stirring. The resulting reaction solution is evaporated to dryness, the residue is extracted with 60 ml of hot benzene and the benzene solution is filtered using animal charcoal. After evaporating the benzene, the residue is dried for 24 hours at 60°C/0.05 mm Hg. 9.95 g (80% of theory) of crystalline 3-(bicyclo[1.2.2]hept-5-ene-2,3-dicarboxylic acid imidyl)-phthalic anhydride are obtained; melting point 178°-180°C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:12]=1[NH2:13]>CO.O>[CH3:10][C:11]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:12]=1[NH:13][C:2]1[N:7]=[C:6]([NH:13][C:12]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:11]=2[CH3:10])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: O
Solvent: CO
Product: Cc1ccc([N+](=O)[O-])cc1Nc1ncc(F)c(Nc2cc([N+](=O)[O-])ccc2C)n1
Temperature: 70 °C

Procedure:
2,4-Dichloro-5-fluoropyrimidine (33 mg, 0.2 mmol) was dissolved in a mixture of MeOH (1 ml) and H2O (0.1 ml). 2-Methyl-5-nitroaniline (122 mg, 0.8 mmol) was added and the mixture was refluxed for 2 days (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-Acetone, 9:1) to give N2,N4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6+CD3OD): δ 8.31 (d, 1H, J=2.3 Hz), 8.20 (d, 1H, J=2.3 Hz), 8.06 (d, 1H, J=3.5 Hz), 7.91 (dd, 1H, J=2.3, 8.2 Hz), 7.65 (dd, 1H, J=2.9, 8.8 Hz), 7.41 (m, 1H), 7.28 (d, 1H, J=8.2 Hz), 2.28 (s, 3H), 2.24 (s, 3H); LCMS purity: 87.4%; MS (m/e): 399.20 (M+, 100).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9](Cl)[N:8]=2)[CH2:3][CH2:2]1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(O)(C)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: Fc1cccc2c(N3CCSCC3)nc(Cl)cc12
Reactant: C1CNCCN1
Solvent: CC(C)O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Fc1cccc2c(N3CCSCC3)nc(N3CCNCC3)cc12
Yield: 90 %

Procedure:
1-Thiomorpholino-3-piperazino-5-fluoro-isoquinoline was prepared analogous to Example 3 from 1-thiomorpholino-3-chloro-5-fluoro-isoquinoline by heating for 30 hours with piperazine in diphenyl ether at 200°C. M.p. 213°-215°C (from isopropanol); yield: 90% of theory.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].Cl.[OH:30][CH:31]1[CH2:34][NH:33][CH2:32]1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([N:33]1[CH2:34][CH:31]([OH:30])[CH2:32]1)=[O:21]
Reactant: OC1CNC1
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Agent: Cl
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)N2CC(O)C2)c(=O)n(C)c1=O
Yield: 52 %

Procedure:
The title compound was synthesized from compound 2A and 3-hydroxyazetidine hydrochloride in 52% yield following a similar procedure described in the synthesis of Example 5. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.83 (s, 1 H) 7.65 (d, J=9.85 Hz, 1 H) 7.52 (d, J=9.60 Hz, 1 H) 6.90-6.99 (m, 1 H) 5.64 (d, J=5.31 Hz, 1 H) 4.25-4.34 (m, 1 H) 3.96-4.04 (m, 1 H) 3.69-3.75 (m, 1 H) 3.39-3.47 (m, 1 H) 3.35 (s, 3 H) 3.17-3.23 (m, 1 H) 3.16 (s, 3 H). [M+H] calc'd for C16H16FIN4O4, 475; found, 475.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]CC)=O.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20].CC[O:23][CH2:24][CH3:25]>CO>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:25][C:24]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])=[O:23]
Reactant: CCOCC
Reactant: NCCCCCCN
Reactant: CCOC(=O)CN1CCCC1=O
Solvent: CO
Product: O=C(CN1CCCC1=O)NCCCCCCNC(=O)CN1CCCC1=O
Reaction time: 19 h

Procedure:
10 g (0.06 mol) of ethyl 2-oxo-1-pyrrolidineacetate and 3.4 g (0.03 mol) of 1,6-diaminohexane are dissolved in 5 ml of absolute methanol and the solution is boiled for 19 hours, moisture being excluded. Ether is added to the solution and the precipitate which separates out is filtered off. The product is purified by chromatography on silica gel from methanol:water (100:25).
Reaction SMILES: CC1C=CC(S([O-])(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH3+:26])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:28]([O-:31])([O-:30])=O.[K+].[K+].[O:34]=[C:35]1[O:40][C:39](=[O:41])[CH2:38][N:37]([CH2:42]CC(O)=O)[CH2:36]1.O>CN(C=O)C>[CH2:12]([O:19][C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:39](=[O:41])[CH2:38][N:37]([CH2:36][C:35]([OH:40])=[O:34])[CH2:42][C:28]([OH:31])=[O:30])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [NH3+]CCCCCC(=O)OCc1ccccc1
Reactant: O=C(O)CCN1CC(=O)OC(=O)C1
Reactant: O=C([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CN(CC(=O)O)CC(=O)NCCCCCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 6-(benzyloxy)-6-oxohexan-1-aminium 4-methylbenzenesulfonate (2.0 g, 5.08 mmol) in DMF (10 mL) at 0° C. was added K2CO3 (738 mg, 5.34 mmol). After stirring at 0° C. for 2 hr, the supernant of the reaction mixture was added to a solution of 3-(2,6-dioxomorpholin-4-yl)propanoic acid (1.10 g, 6.35 mmol) in DMF (10 mL) at 0° C. After stirring at 0° C. for 30 min, the reaction mixture was allowed to stir at rt for 1 hr and then cooled down to 0° C. followed by the addition of water (10 mL). The resulting mixture was concentrated and the residue was suspended in water (10 mL). After stirring at 0° C. for 16 hr, the solid was collected through filtration and dried to yield the title compound. 1H NMR (CD3OD) δ 7.36-7.30 (m, 5H), 5.11 (s, 2H), 3.56 (s, 4H), 3.43 (s, 2H), 3.23 (t, J=6.7, 2H), 2.39 (t, J=7.3, 2H), 1.68-1.62 (m, 2H), 1.57-1.51 (m, 2H), 1.40-1.35 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][C:6](=[O:8])[CH:5]=[CH:4][CH2:3]1.[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1)([O-:12])=[O:11].C(C1C(O[SiH](C)C)=C(Br)C(OC)=CC=1CC1C(=O)C=CCC1(C)C)(C)(C)C>>[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17][CH:7]2[C:6](=[O:8])[CH:5]=[CH:4][CH2:3][C:2]2([CH3:9])[CH3:1])=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC1(C)CC=CC(=O)C1
Agent: COc1cc(CC2C(=O)C=CCC2(C)C)c(C(C)(C)C)c(O[SiH](C)C)c1Br
Product: CC1(C)CC=CC(=O)C1Cc1ccc([N+](=O)[O-])cc1

Procedure:
This compound was prepared from 5,5-dimethylcyclohex-2-en-1-one (11) (0.600 g, 4.83 mmol) and p-nitrobenzyl bromide (1.581 g, 7.32 mmol) in the manner previously described for the synthesis of enone 13, affording 627 mg (50%), of the nitro-enone as a pale yellow oil. 1H NMR (400MHz, CDCl3) δ1.02 and 1.18 (2s, 2×3H, geminal-CH3 's), 2.83 and 3.10 (d of ABq, 2H, benzylic-CH2), 6.00 (ddd, 1H, 2-H), 6.81 (ddd, 1H, 3-H), 7.38 and 8.10 ppm (ABq, 2×2H, Ar--H).
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[C:15]([F:26])[CH:14]=1.[CH3:27][S:28]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:40]=1[NH:39][CH:38]=[CH:37]2)(=[O:30])=[O:29]>ClCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:37]2[C:36]3[C:40](=[C:32]([CH2:31][S:28]([CH3:27])(=[O:30])=[O:29])[CH:33]=[CH:34][CH:35]=3)[NH:39][CH:38]=2)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[C:15]([F:26])[CH:14]=1
Reactant: CS(=O)(=O)Cc1cccc2cc[nH]c12
Reactant: N#CC1CC1C(O)c1ccc(Cl)cc1F
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Cc1cccc2c(C(c3ccc(Cl)cc3F)C3CC3C#N)c[nH]c12

Procedure:
1.76 g (7.98 mmol) of indium(III) chloride and 0.92 ml (12.0 mmol) of trifluoroacetic acid were added to 1.50 g (6.65 mmol) of the compound from Example 165A and 1.67 g (7.98 mmol) of the compound from Example 86A under argon in 69 ml of dichloromethane, and the mixture was heated under reflux for three days. It was concentrated and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) and another isocratic RP18 separation with acetonitrile/water 1:1 to result in 283 mg (10% of theory) of diastereomer 1 and 145 mg (5% of theory) of diastereomer 2 of the title compound.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:22])([CH3:21])[CH:8]1[CH2:12][N:11]([CH:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10](=[O:20])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:23][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[C:1]([SiH2:5][O:6][C:7]([CH3:22])([CH3:21])[CH:8]1[CH2:12][N:11]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[C:10](=[O:20])[CH:9]1[CH3:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1CC(=O)N(C2CCCCCC2)C1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1C(=O)N(C2CCCCCC2)CC1C(C)(C)O[SiH2]C(C)(C)C
Reaction time: 2 h

Procedure:
A solution of Example 1B (1.09 g, 3.07 mmoles) in tetrahydrofuran (3.5 mL) was added drop wise to a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (3.7 mL, 3.7 mmoles) at room temperature and stirred for two hours at that temperature. A solution of methyl iodide (0.54 g, 3.83 mmoles) in tetrahydrofuran (1 mL) was added drop wise to the reaction mixture at room temperature and stirred for another two hours. The reaction was quenched with 10% NH4Cl (25 mL) and extracted with ethyl acetate. The organic layer was washed with brine (25 mL), dried with MgSO4, filtered, and solvent evaporated in vacuo. The crude product was purified by flash column chromatography (hexanes:ethyl acetate 95:5 to 60:40) to provide the title compound.
Reaction SMILES: [C:1](OC(=O)C)(=O)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[OH:14][C:15]1[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:16]=1[C:22](=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1.O>CN(C=O)C>[OH:21][C:19]1[CH:20]=[C:15]2[C:16]([C:22](=[O:32])[C:23]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[C:1]([CH3:2])[O:14]2)=[CH:17][CH:18]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CC(=O)c2ccc(O)cc2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2c(C)oc3cc(O)ccc3c2=O)cc1
Temperature: 115 °C

Procedure:
Acetic anhydride (3 ml, 30 mmol) was added to a suspension of potassium carbonate (4.0 g, 29 mmol) and 1-(2,4-dihydroxy-phenyl)-2-(4-methoxy-phenyl)-ethanone (1.95 g, 7.5 mmol) in DMF (10 ml), and the resulting suspension heated at 115° C. for ˜90 mins. The mixture was allowed to cool and poured into water (200 ml), to give an off-white precipitate. The solids were removed by filtration and washed with water (100 ml) and diethyl ether (2×40 ml), to give 7-hydroxy-3-(4-methoxy-phenyl)-2-methyl-chromen-4-one as an off-white powder, dried in vacuo, (1.65 g)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.I[CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH:13]([CH3:15])[CH3:14])[CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc([N+](=O)[O-])c(OC(C)C)c1
Yield: 64 %

Procedure:
A mixture of 23 g (150 mmol) of 5-methyl-2-nitrophenol 28.1 g (1.1 x 150 mmol) of 2-iodopropane and 22.8 g (1.1 x 150 mmol) of anhydrous potassium carbonate in 150 ml of acetonitrile is stirred and refluxed for 18 hours overnight. The solids were removed, the solvent evaporated and the residue is taken up in diethyl ether and the solution washed with 50 ml of 2N potassium hydroxide (2X), brine, dried (magnesium sulfate), and evaporated to an oil. Distillation gives 18.6 g (64%) of 5-methyl-1-(1-methylethoxy)-2-nitrobenzene; bp 98°-100° C. at 0.5 mm.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([NH:21]C(=O)OC(C)(C)C)[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1>C(Cl)Cl>[CH3:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=1)[NH2:21]
Reactant: CSCc1cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cc(N)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 97.4 %

Procedure:
TFA (2.5 ml) was added to a stirred solution of tert-butyl {3-[(methylsulfanyl)methyl]-5-(tri-fluoromethyl)phenyl}carbamate (502 mg; 1.56 mmol) in DCM (5 mL) at 0° C. The ice bath was removed and the mixture was stirred for 45 min at RT. The batch was concentrated and saturated aqueous sodium bicarbonate solution was added. The batch was extracted with ethyl acetate (2×). The combined organic phases were dried (sodium sulfate), filtered and concentrated to give the crude product (336 mg), that was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9](Cl)(=[O:18])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C(C)=CC=CC=1C.BrC1C=C(NC(=O)/C=C/C2C=CC=CC=2)C=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:9](=[O:18])/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: O=C(/C=C/c1ccccc1)Nc1cccc(Br)c1
Solvent: Cc1cccc(C)n1
Product: O=C(/C=C/c1ccccc1)Nc1cccc(F)c1

Procedure:
The compound was prepared from 3-fluoroaniline (5.8 mL, 60 mmol) and cinnamoylchloride (10 g, 60 mmol) in the presence of 2,6-lutidine (10.5 mL, 90 mmol) as described for Intermediate 18 to give a colorless solid, 13.9 g (96%), mp 110° C.
Reaction SMILES: BrC1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=O.C(Cl)(=O)C(Cl)=O.[NH4+:23].[OH-].[CH2:25]([Cl:27])Cl>>[Cl:27][C:25]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH2:23])=[O:16]
Reactant: [NH4+]
Reactant: COc1ccc2ncc(C(=O)O)c(Br)c2c1
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Product: COc1ccc2ncc(C(N)=O)c(Cl)c2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of dried 4-bromo-6-(methyloxy)-3-quinolinecarboxylic acid (1.4 g, 5 mmol) in CH2Cl2 (20 mL) at 0° C. was added oxalyl chloride (2M in CH2Cl2, 5.0 mL, 10 mmol). After 1 h, an aliquot was quenched with NH4OH and LCMS indicated desired product was formed. Excess NH4OH (2 mL) was slowly added to the reaction solution, maintained at 0° C. (very exothermic), and the reaction was stirred an additional 2 h. The product was isolated via filtration to give 1.0 g (83%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:8](=[O:18])[CH2:7]2)(=[O:3])[CH3:2].[CH2:19](O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:2][C:1]1([C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[N:9]([CH2:13][C:14]([F:15])([F:16])[F:17])[C:8](=[O:18])[CH2:7]3)[O:21][CH2:20][CH2:19][O:3]1
Reactant: OCCO
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2CC(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC1(c2ccc3c(c2)CC(=O)N3CC(F)(F)F)OCCO1

Procedure:
A solution of 5-acetyl-1-(2,2,2-trifluoro-ethyl)-1,3-dihydro-indol-2-one (1.04 g, 4.0 mmol), ethylene glycol (1.37 mL, 24 mmol) and p-toluenesulfonic acid (10 mg) in benzene (25 mL) was heated to reflux for 4 hours in a flask fitted with a Dean-Stark trap. The solution was diluted with ethyl acetate, washed with saturated sodium bicarbonate, water and brine, dried over magnesium sulfate and concentrated in vacuo to an oil which solidified upon standing (1.19 g, 98%, mp 87-89° C.).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=1[CH3:23]>CN1CCCC1=O>[CH3:23][C:14]1[CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[CH:17]=[C:18]([CH3:19])[C:13]=1[O:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1
Reactant: COc1ccc(O)cc1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of sodium hydride (NaH; 60% dispersion in mineral oil; 64.11 g, 1.603 mol) in 350 mL of N-methylpyrrolidone (NMP) is cooled to 0° C. and treated with a solution of 4-methoxyphenol (208.4 g, 1.679 mol) over 30 min. The mixture is warmed to room temperature (RT) and after 30 min, 4-chloro-3,5-dimethylnitrobenzene (283.2 g, 1.526 mol; prepared by the method described by Yokoyama et. al. in EP580550) is added in one portion and the reaction is heated at 120° C. for 2 h. The reaction is cooled to room temperature (RT) and quenched with water (1500 mL). The suspension is cooled to 0° C., stirred for 30 min, then filtered and the filtercake is washed with water and dried in vacuo. The crude product, ethyl acetate (EtOAc; 2100 mL) and charcoal (42.6 g) were heated to reflux and the solids were removed by filtration through celite while hot. The filtrate is concentrated under reduced pressure to ca. 800 mL and the resulting suspension is cooled to 0° C. and stirred for 30 min. The product is collected by vacuum filtration, washed with cold EtOAc and dried in vacuo to afford 3,5-dimethyl-4-(4′-methoxyphenoxy)nitrobenzene: NMR (CDCl3) 2.22 (s, 6H), 3.78 (s, 3H), 6.68 (d, 2H, J=8.7), 6.82 (d, 2H, J=8.7), 8.02 (s, 2H).
Reaction SMILES: C([O:5][C:6](=[O:24])[CH2:7][C:8]1[C:9]([CH3:23])=[N:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=2)[C:12]=1[CH3:13])(C)(C)C.[Cl:25][C:26]1[CH:27]=[CH:28][C:29](I)=[C:30]([NH2:32])[CH:31]=1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN1CCCC1=O>[Cl:25][C:26]1[CH:31]=[C:30]2[C:29]([CH:22]=[C:21]([C:18]3[CH:17]=[CH:16][C:15]([CH2:14][N:11]4[C:12]([CH3:13])=[C:8]([CH2:7][C:6]([OH:5])=[O:24])[C:9]([CH3:23])=[N:10]4)=[CH:20][CH:19]=3)[NH:32]2)=[CH:28][CH:27]=1
Reactant: C#Cc1ccc(Cn2nc(C)c(CC(=O)OC(C)(C)C)c2C)cc1
Reactant: Nc1cc(Cl)ccc1I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1nn(Cc2ccc(-c3cc4ccc(Cl)cc4[nH]3)cc2)c(C)c1CC(=O)O
Temperature: 50 °C
Reaction time: 18 h
Yield: 37.9 %

Procedure:
To a stirred solution of 1-(4-ethynylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl-acetic acid tert.-butyl ester (4.4 g) and 5-chloro-2-iodophenylamine (3.4 g) in tetrahydrofuran (100 ml) at room temperature is added diisopropylethylamine (5.8 ml). The reaction is degassed and put under argon. Copper(I)iodide (260 mg) and bis(triphenylphosphine)palladiumdichloride (475 mg) are added. After 18 h, the reaction mixture is absorbed onto Extrelut and purified by flash chromatography (7:3 isocratic-cyclohexane:ethyl acetate) to yield a solid (4.3 g; HPLC retention time 1.66 min (Method J)). The solid (4.2 g) is dissolved in N-methyl-2-pyrrolidone (25 ml) and the solution degassed and put under argon. Potassium tert-butoxide (4.1 g) is added and the reaction is then heated to 50° C. After 15 h, further potassium tert-butoxide (1.0 g) is added. After 15 h the reaction temperature is increased to 75° C. After 3 h, the reaction mixture is allowed to cool to room temperature and a copious amount of water is added. The reaction mixture is extracted twice with ethyl acetate and the aqueous phase is acidified to pH 3 with 1M aqueous hydrochloric acid. The resultant precipitate is filtered off and triturated with hot acetonitrile to yield (1-[4-(6-Chloro-1H-indol-2-yl)-benzyl]-3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid (2.0 g; [M+H]=394; HPLC retention time 1.51 min (Method E)).