Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)SC)[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1>NC(CC)C>[CH:18]([NH:17][C:14]([NH:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=1)=[C:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[C:12]#[N:13])([CH2:19][CH3:20])[CH3:23]
Reactant: CSC(Nc1cc(Cl)cc(Cl)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCC(C)N
Product: CCC(C)NC(Nc1cc(Cl)cc(Cl)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Yield: 138 %

Procedure:
2-(4-Chloro-phenylsulfonyl)-3-(3,5-dichlorophenylamino)-3-methylsulfanyl-2-propenenitrile (0.50 g, 1.2 mmol) was stirred in 2-aminobutane (1 ml) for 17 h at 100° C. under nitrogen in a sealed flask. Work-up as described in EXAMPLE 17, 2) without chromatography gave 0.38 g (69%) of the title compound. Mp 150-152 ° C. 1H NMR (200 MHz, CDCl3): δ=0.85 (t, 3H), 1.06 (d, 3H), 1.48 (p, 2H), 3.25 (m, 1H), 6.90 (d, 2H), 7.20 (t, 1H), 7.47 (d, 2H), 7.78 (d, 2H); EI SP/MS: 457 (M+), 459 (M+2), 461 (M+4).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([I:21])=[CH:15][CH:14]=3)=[S:9])=[CH:4][CH:3]=1.[C:24]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OCC)=O)=NC(OCC)=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([I:21])[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[S:9])=[CH:22][CH:23]=1
Reactant: Oc1c(C(=S)NCc2ccc(Cl)cc2)cnc2ccc(I)cc12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cc(C(=S)NCc2ccc(Cl)cc2)c(=O)c2cc(I)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarbothioamide (0.20 g) from Preparation No. 43 and triphenylphosphine (0.15 g) in freshly distilled tetrahydrofuran (5 mL) is added MeOH (0.027 mL) followed by diethyl azodicarboxylate. After an initial exotherm, the reaction is stirred at room temperature for 3 h. To drive the reaction to completion, additional triphenylphosphine (0.030 g), methanol (0.010 mL), and diethyl azodicarboxylate (0.020 mL) are added. The reaction is stirred at room temperature overnight. The reaction is concentrated in vacuo. The residue is dissolved in CH2Cl2 and adsorbed onto silica. Purification by chromatography (eluent CH2Cl2 (1 L), 1% MeOH:CH2Cl2 (1 L)) affords N-(4-chlorobenzyl)-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbothioamide (0.065 g) as a yellow solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[C:8]([CH3:21])=[N:9][N:10]2[C:15](O)=[C:14]([CH2:17][CH2:18]O)[C:13]([CH3:20])=[N:12][C:11]=12.C[N:23](C)[C:24]1[CH:29]=[CH:28]C=[CH:26][CH:25]=1>C(OCC)(=O)C>[Br:6][C:7]1[C:8]([CH3:21])=[N:9][N:10]2[C:15]3[N:23]([CH:24]([CH2:29][CH3:28])[CH2:25][CH3:26])[CH2:18][CH2:17][C:14]=3[C:13]([CH3:20])=[N:12][C:11]=12
Reactant: Cc1nc2c(Br)c(C)nn2c(O)c1CCO
Reactant: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCC(CC)N1CCc2c(C)nc3c(Br)c(C)nn3c21
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
Phosphorus oxychloride (3.3 mL) was added to a solution of 3-bromo-6-(2-hydroxyethyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-ol (1.0 mg, 3.50 mmol) in N,N-dimethyaniline (5 mL), followed by stirring at 120° C. for 20 minutes. After cooling to room temperature, the mixture was added dropwise slowly into ice-water under vigorously stirring. Then, the mixture was stirred for two hours while raising a temperature gradually to room temperature, followed by diluting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. 3-Aminopentane (10 mL) was added to a solution of the residue in acetonitrile (30 mL), followed by heating under reflux for three hours. The mixture was diluted with ethylacetate, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The resulting crystals were collected by filtration, to give the title compound (700 mg) as white crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=1.Cl[C:16]([F:21])([F:20])C([O-])=O.[Na+]>CN(C)C=O>[Cl:7][C:8]1[C:13]([O:14][CH:16]([F:21])[F:20])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Oc1cccnc1Cl
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)Oc1cccnc1Cl
Temperature: 100 °C
Reaction time: 1 h

Procedure:
This reaction was carried out 3 times. A mixture of potassium carbonate (282 g, 2.04 mol) and N,N-dimethylformamide (750 mL) was heated to 100° C. and slowly treated, in a drop-wise manner over 1 hour, with a solution of 2-chloropyridin-3-ol (66.7 g, 515 mmol) and sodium chloro(difluoro)acetate (200 g, 1.31 mol) in N,N-dimethylformamide (750 mL). After completion of the addition, the reaction mixture was stirred at 100° C. for 1 hour, then cooled to 25° C. and partitioned between water (10 L) and tert-butyl methyl ether (5 L). The aqueous layer was extracted with ethyl acetate (4×2.5 L), and the combined organic layers were washed with saturated aqueous sodium chloride solution (6×2.5 L), dried over sodium sulfate, filtered, and concentrated in vacuo. The combined crude products from the three reactions were purified via distillation at reduced pressure (30-40° C., 1-5 mm Hg) to provide the product as a colorless oil. Yield: 192 g, 1.07 mol, 69%. LCMS m/z 180.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.26-8.30 (m, 1H), 7.60 (br d, J=8.2 Hz, 1H), 7.28 (br dd, J=8.0, 4.8 Hz, 1H), 6.60 (t, JHF=72.5 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](=O)[CH2:6][C:7]#[N:8])[CH3:2].Cl.[CH:11]([NH:14][NH2:15])([CH3:13])[CH3:12].Cl>C(O)C>[CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[C:7]([NH2:8])[N:14]([CH:11]([CH3:13])[CH3:12])[N:15]=1)[CH3:2]
Reactant: CC(C)NN
Reactant: CCOCC(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CCOCc1cc(N)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
To a 25 mL round bottom was added 4-(ethyloxy)-3-oxobutanenitrile (550 mg, 4.33 mmol), isopropyl hydrazine hydrochloride (478 mg, 4.33 mmol), and HCl (2.163 mL, 4.33 mmol) in Ethanol (10 mL). The reaction mixture was stirred at the room temperature overnight. The reaction mixture was then evaporated, and partitioned between 20 mL of ethyl acetate and 20 mL of 1 M Na2CO3. The organic layer was washed with brine, filtered and evaporated. 3-[(Ethyloxy)methyl]-1-(1-methylethyl)-1H-pyrazol-5-amine (520 mg, 2.84 mmol, 65.6% yield) was isolated as yellow oil. The product was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) ppm 1.09 (t, J=7.07 Hz, 3 H) 1.26 (d, J=6.57 Hz, 6 H) 3.40 (q, J=6.91 Hz, 2 H) 4.16 (s, 2 H) 4.32 (quin, J=6.57 Hz, 1 H) 5.06 (s, 2 H) 5.22 (s, 1 H)
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:27])[CH:13]([OH:26])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:8]=2)[O:3]1.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.N1C=CC=CC=1>ClCCl>[CH3:1][C:2]1([CH3:28])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:27])[CH:13]([O:26][S:35]([C:32]3[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=3)(=[O:37])=[O:36])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:8]=2)[O:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(C(O)C(=O)c2ccc3c(c2)C=CC(C)(C)O3)cc(OC)c1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(OS(=O)(=O)c2ccc(C)cc2)C(=O)c2ccc3c(c2)C=CC(C)(C)O3)cc(OC)c1OC
Temperature: 25 °C

Procedure:
To a stirred solution of 1-(2,2-dimethyl-2H-chromen-6-yl)-2-hydroxy-2-(3,4,5-trimethoxy-phenyl)-ethanone (28 mg, 0.073 mmol) in dichloromethane (1.5 mL) is added p-toluenesulfonyl chloride (15.3 mg, 0.080 mmol) and pyridine (6.47 μL, 0.080 mmol). The reaction mixture continues to stir at room temperature. The crude material is purified using silica gel chromatography.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[C:11]([C:17]([OH:19])=[O:18])[CH:10]=3)[CH3:2].CS(C)=O.[CH:24]1([CH2:30][NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.O>C(O)(=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:31][CH2:30][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[C:11]([C:17]([OH:19])=[O:18])[CH:10]=3)[CH3:2]
Reactant: NCC1CCCCC1
Reactant: CCn1ncc2c(Cl)c3ccc(C(=O)O)cc3nc21
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCn1ncc2c(NCC3CCCCC3)c3ccc(C(=O)O)cc3nc21

Procedure:
A mixture of 1-ethyl-4-chloro-7-carboxy-1H-pyrazolo[3,4-b]quinoline (0.9 g, 3.3 mmol), DMSO (9 ml) and cyclohexanemethyl amine (0.86 ml, 6.6 mmol) was heated at 120°-130° C. for 6 hours. The reaction mixture was poured into water, acidified with acetic acid and the solid which formed was collected by filtration, dissolved in 5% NaOH and extracted with CH2Cl2 (2×50 ml). The aqueous layer was acidified with acetic acid and the solid which formed was collected by filtration and washed with water. The solid was purified by column chromatography on silica gel eluting with 30% methanol/10% acetic acid/60% CH2Cl2 to afford 1-ethyl-7-carboxy-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, as a yellow solid.
Reaction SMILES: C(O[C:6]([C:8]1[C:9]([OH:24])=[C:10]2[C:22]([CH3:23])=[N:21][S:20][C:11]2=[C:12]([C:14]#[C:15][Si](C)(C)C)[N:13]=1)=[O:7])CCC.[NH2:25][CH2:26][C:27]([OH:29])=[O:28]>>[C:14]([C:12]1[N:13]=[C:8]([C:6]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:7])[C:9]([OH:24])=[C:10]2[C:22]([CH3:23])=[N:21][S:20][C:11]=12)#[CH:15]
Reactant: CCCCOC(=O)c1nc(C#C[Si](C)(C)C)c2snc(C)c2c1O
Reactant: NCC(=O)O
Product: C#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(C)nsc12

Procedure:
The title compound was synthesized in analogy Example 1 from 4-hydroxy-3-methyl-7-trimethylsilanylethynyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester and glycine: MS (m/z) 290.1 (M−1).
Reaction SMILES: C1C[O:37][C:3]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([CH2:4][CH2:5][C@H:6]2[C@H:10]([O:11]C3CCCCO3)[CH2:9][C:8](=[O:18])[C@@H:7]2[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O-:29])=[O:28])O1.C(O)(=O)C.[CH2:43]1[CH2:47]OC[CH2:44]1>O>[OH:11][C@@H:10]1[CH2:9][C:8](=[O:18])[C@H:7]([CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH:43]([CH3:47])[CH3:44])=[O:28])[C@H:6]1[CH2:5][CH2:4][C:3](=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCC1(CC[C@H]2[C@H](OC3CCCCO3)CC(=O)[C@@H]2C/C=C\CCCCCC(=O)[O-])OCCO1
Reactant: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCC(=O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCCCC(=O)OC(C)C
Reaction time: 3 h

Procedure:
The compound (45) (0.311 g) was dissolved in a mixed solvent (5 ml) consisting of acetic acid, THF and water (2:1:1) and kept at 50° C. for 3 hours. The resultant mixture was worked up with the conventional procedure and the residue was subjected to silicagel column chromatography to give the titled compound (46). Yield: 0.156 g (66%). Compound (46) [Q1 =Q2 =H, Rb-Rc=hexyl, P3 =isopropyl]NMR(CDCl3)δ: 0.86 (t,3H,J=6.5 Hz), 1.20 (d,6H,J=6 Hz), 1.23-2.75 (m,33H), 4.20 (m,1H), 4.99 (Hept,1H,J=6 Hz), 5.15-5.50 (m,2H)
Reaction SMILES: O=[CH:2][CH:3]=[CH:4][C:5]1[CH:27]=[CH:26][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:10])=[CH:7][CH:6]=1.[CH:28]1([O:33][C:34]2[CH:35]=[C:36]([CH:38]=[CH:39][C:40]=2[O:41][CH3:42])[NH2:37])[CH2:32][CH2:31][CH2:30][CH2:29]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1>[CH:28]1([O:33][C:34]2[CH:35]=[C:36]([NH:37][CH2:2][CH:3]=[CH:4][C:5]3[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:10])=[CH:26][CH:27]=3)[CH:38]=[CH:39][C:40]=2[O:41][CH3:42])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: COc1ccc(N)cc1OC1CCCC1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=CC=O)cc1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(NCC=Cc2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)cc1OC1CCCC1
Reaction time: 0.17 h

Procedure:
To a stirred solution at room temperature of compound XVI (210 mg, 0.57 mmol), 3-cyclopentyloxy-4-methoxy-aniline (125 mg, 0.60 mmol) or ArNH2 (1.05–1.2 equiv.) in anhydrous THF (7 ml) under nitrogen were added dibutyltin dichloride (3.5 mg, 0.01 mmol). After 10 min, phenylsilane (78 μl, 0.63 mmol) was added dropwise. After 3 days, the reaction mixture was concentrated and directly purified by flash chromatography on silica gel (AcOEt/hexane:30/70→50/50) to afford the title compound XVIIa as a yellow sticky oil.
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][O:9][C:10](=[O:33])[C@@H:11]([O:30][CH2:31][CH3:32])[C@@H:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][C:15]=1[CH2:28][CH3:29])O>FC(F)(F)C(O)=O>[CH3:8][O:9][C:10](=[O:33])[C@@H:11]([O:30][CH2:31][CH3:32])[CH2:12][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][C:15]=1[CH2:28][CH3:29]
Reactant: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(OCc2ccccc2)cc1CC
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1CC)C(=O)OC
Yield: 55 %

Procedure:
Triethylsilane (3.2 ml, 20 mmol) was added to a vigorously stirred, ice-cooled solution of (2S,3R)-3-(4-benzyloxy-2-ethyl-phenyl)-2-ethoxy-3-hydroxy-propionic acid methyl ester (720 mg, 2 mmol) in trifluoroacetic acid (10 ml) under an argon atmosphere. The mixture was stirred at 0° C. for 30 min and for additional 2 h at ambient temperature. The solution was poured onto crashed ice and extracted with ethyl acetate. The organic layer was washed two times with water and neutralized with saturated aqueous sodium bicarbonate solution. The ethyl acetate layer was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give a colorless oil which was purified by column chromatography (silica gel, cyclohexane/AcOEt) to yield 390 mg (1.1 mmol, 57%) of the title compound as colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)N.ClC1C=C(Cl)C=C(Cl)C=1.[F-:19]>>[F:1][C:2]1[CH:3]=[C:4]([F:19])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: [F-]
Agent: Clc1cc(Cl)cc(Cl)c1
Product: Fc1cc(F)cc(F)c1

Procedure:
In a further embodiment, the present invention relates to a method for the two step preparation of 3,5-difluoroaniline from 1,3,5-trichlorobenzene. First, an amount of 1,3,5-trichlorobenzene is reacted with a fluoride-containing compound to obtain 1,3,5-trifluorobenzene. Second, the 1,3,5-trifluorobenzene is reacted with aqueous ammonia and a metal oxide or metal hydroxide to obtain the product 3,5-difluoroaniline.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[K+].[K+].[CH2:49]([O:51][C:52]([C:54]1[S:55][C:56]([C:59]2[CH:64]=[CH:63][N:62]=[C:61](Cl)[N:60]=2)=[CH:57][CH:58]=1)=[O:53])[CH3:50].[NH2:66][C:67]1[CH:68]=[N:69][CH:70]=[CH:71][CH:72]=1>O1CCOCC1.CCOC(C)=O.O.CC(O)=O.CC(O)=O.[Pd]>[CH2:49]([O:51][C:52]([C:54]1[S:55][C:56]([C:59]2[CH:64]=[CH:63][N:62]=[C:61]([NH:66][C:67]3[CH:68]=[N:69][CH:70]=[CH:71][CH:72]=3)[N:60]=2)=[CH:57][CH:58]=1)=[O:53])[CH3:50]
Reactant: CCOC(=O)c1ccc(-c2ccnc(Cl)n2)s1
Reactant: Nc1cccnc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccnc(Nc3cccnc3)n2)s1
Temperature: 100 °C
Yield: 62.4 %

Procedure:
Palladium II acetate (8.3 mg, 0.1 mmol) and xantphos 42.8 mg, 0.2 mmol) were precombined in 4 mL dry dioxane under nitrogen gas. Potassium carbonate (1.03 g, 7.46 mmol) was added followed by a solution of 5-(2-Chloro-pyrimidin-4-yl)-thiophene-2-carboxylic acid ethyl ester (100 mg, 0.373 mmol) and 3-aminopyridine (42 mg, 0.447 mmol) in 3 mL dioxane. The reaction was heated in a capped vial at 100° C. for 20 h. The cooled reaction mixture was diluted with EtOAc and water and the layers were separated. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was redissolved in ethyl ether and treated with 2 M HCl in ether to generate a precipitate which was collected by filtration to afford 76 mg (56.3%) of the title compound. The crude material was used in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([C:17](O)=[O:18])[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7].[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([C:17]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:18])[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(C(=O)O)(c2ccc(Cl)cc2)CC1
Reactant: C1CCNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(C(=O)N2CCCC2)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 4 mL vial was added 50 mg of 1-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-4-(4-chloro-phenyl)-piperidine-4-carboxylic acid (0.11 mmol, 1.0 equiv), 11 μL of pyrrolidine (0.13 mmol, 1.2 equiv), 60 μL TEA (0.43 mmol, 4.00 equiv), 71 mg BOP (0.16 mmol, 1.5 equiv), and 500 μL NMP. The mixture was stirred overnight at room temperature and the crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-phenyl)-4-(pyrrolidine-1-carbonyl)-piperidin-1-yl]-ethanone:.MS (ES) M+H expected=517.4, found=517.1.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C:9]1[CH:18]=[C:17]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29]([NH:31][CH:32]4[CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH:33]4[C:44]([O:46][CH3:47])=[O:45])=[O:30])=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1>C(Cl)Cl>[CH3:8][C:9]1[CH:18]=[C:17]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29]([NH:31][CH:32]4[CH2:36][NH:35][CH2:34][CH:33]4[C:44]([O:46][CH3:47])=[O:45])=[O:30])=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CC1NC(=O)c1ccc2c(ccn2Cc2cc(C)nc3ccccc23)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CNCC1NC(=O)c1ccc2c(ccn2Cc2cc(C)nc3ccccc23)c1
Reaction time: 2 h
Yield: 186.4 %

Procedure:
TFA (2mL) was added to a solution of the coupled product (0.11 g, 0.2 mmol) from step (501c) in methylene chloride (3 mL) at room temperature. The reaction was complete after stirring for 2 h and was concentrated to give methyl 4-[({1-[(2-methyl-4-quinolinyl)methyl]-1H-indol-5-yl}carbonyl)amino]-3-pyrrolidinecarboxylate (0.165 g, 100%) as an oil, MS (M+2H)++=222.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[O:8].COC(=O)C(Br)CCBr.[CH3:18][NH:19][C:20](=[O:26])[CH:21]([Br:25])[CH2:22][CH2:23]Br>>[Br:25][CH:21]1[CH2:22][CH2:23][N:19]([CH3:18])[C:20]1=[O:26].[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[O:8]
Reactant: CNC(=O)C(Br)CCBr
Agent: CN1CCC(O)C1=O
Agent: COC(=O)C(Br)CCBr
Product: CN1CCC(Br)C1=O

Procedure:
There is also provided by this invention a method for preparation of 3-hydroxy-N-methylpyrrolidone which comprises conversion of delta-butyrolactone to methyl-2,4-dibromobutyrate, conversion of the methyl-2,4-dibromobutyrate to N-methyl-2,4-dibromobutyramide, ring closure of the N-methyl-2,4-dibromobutyramide to form 3-bromo-N-methyl-2-pyrrolidone, and conversion of the 3-bromo-N-methyl-2-pyrrolidone to 3-hydroxy-N-methyl-2-pyrrolidone by reaction with alkali metal carbonate.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[C:11]([N+:19]([O-])=O)[CH:12]=[CH:13][CH:14]=3)[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.N.[NH4+].[Cl-]>O>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[C:11]([NH2:19])[CH:12]=[CH:13][CH:14]=3)[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2cccc([N+](=O)[O-])c21
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Nc1cccc2c1C(=O)c1cccc(N)c1C2=O
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
45 g of 1,5-dinitroanthraquinone (97 %) are heated to 200° C in 100 ml of water in a 0.7 liter steel autoclave. 300 ml of a cold, 25% strength aqueous ammonia solution, which contains 10% of NH4Cl, are pumped into this mixture over a period of 30 minutes. Thereafter, the temperature is kept constant for another 5 1/2 hours, the pressure thereby rising to 60 bar. The product is left to cool without outside help, the pressure released and the product filtered off with suction. The entire filtrate, 350 ml, is faintly yellow in color, E47010 cm = 6.0. After washing and drying there are obtained 34.8 g of 93.0 % pure 1,5-diaminoanthraquinone (92.7 % of theory). The product still contains 4.5 % (4.0 % of theory) of 1-amino-5-nitroanthraquinone.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH3:27][O:28][CH2:29][C:30](Cl)=[O:31]>>[CH3:27][O:28][CH2:29][C:30]([NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][N:12]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]4)[CH2:17][CH2:16]2)[CH:21]=1)=[O:31]
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: COCC(=O)Cl
Product: COCC(=O)Nc1cccc(CCN2CCN(c3cccc4nc(C)ccc34)CC2)c1
Yield: 62 %

Procedure:
The title compound was prepared in 62% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and (methyloxy)acetyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([O:13]C)[C:5]=1[CH:15]=[O:16].B(Cl)(Cl)Cl>ClCCl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([OH:13])[C:5]=1[CH:15]=[O:16]
Reactant: COC(=O)c1c(C)c(OC)cc(OC)c1C=O
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1c(C)c(OC)cc(O)c1C=O
Temperature: 20 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
To a suspension of 95.3 g of 2-formyl-3,5-dimethoxy-6-methylbenzoic acid methyl ester in 250 ml of dichloromethane were added 800 ml of a 1M solution of boron trichloride in dichlormethane over 40 min at a temperature of 5°-10° C. The mixture was allowed to warm to 20° C. within 30 min and stirring was continued at room temperature for 4 h. The clear solution was cooled to 5° C. and then poured into a mixture of 1.5 l of ice-water and 0.5 l of dichloromethane. The layers were separated and the aqueous phase was back-extracted with 0.4 l of dichloromethane. The organic layers were washed with water, dried over sodium sulfate and evaporated in vacuo. Crystallization of the residual material from ethyl acetate/hexane provided 77.3 g of 2-formyl-3-hydroxy-5-methoxy-6-methylbenzoic acid methyl ester as colorless crystals of m.p. 118°-119° C.