Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1CCCO[CH:2]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([F:21])[F:20])=[CH:15][CH:16]=2)[C:11]([C:22]2[N:23]=[C:24]3[C:30]([C:31]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][N:28]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:25]3=[N:26][CH:27]=2)=[N:10]1.Cl.C(=O)([O-])O.[Na+]>C1COCC1>[C:34]([NH:33][C:31]([C:30]1[C:24]2[C:25](=[N:26][CH:27]=[C:22]([C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[C:14]([O:18][CH:19]([F:21])[F:20])[CH:13]=4)[N:9]([CH2:8][CH2:7][CH:2]=[O:1])[N:10]=3)[N:23]=2)[N:28]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH:29]=1)=[O:32])([CH3:36])([CH3:35])[CH3:37]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCC4OCCCO4)c4ccc(OC(F)F)cc34)nc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCC=O)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.7 %

Procedure:
2-(1-(2-(1,3-Dioxan-2-yl)ethyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (130 mg, 202 μmol) was dissolved in THF (3 mL), and HCl 3N (672 μL, 2.02 mmol0.00) was added. After stirring the mixture at 25° C. overnight, TLC and LCMS showed about 10% conversion. Added 0.5 mL of concentrated HCl and reaction heated to 50° C. for 48 h more. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane (5×30 mL). The obtained organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel chromatography (n-hexane-ethyl acetate 0 to 100% over 30 min to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-oxopropyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (34 mg, 58.0 μmol, 28.7%). MS (M+H)+=587; 1H NMR (CDCl3) δ: 9.97 (s, 1H), 9.20 (s, 1H), 8.42 (s, 1H), 8.30 (d, J=2.3 Hz, 1H), 8.08 (s, 1H), 7.63 (d, J=9.1 Hz, 1H), 7.39 (dd, J=9.1, 2.3 Hz, 1H), 6.54 (t, J=74.4 Hz, 1H), 5.75 (s, 2H), 5.34 (s, 1H), 4.82 (t, J=6.2 Hz, 2H), 3.55-3.65 (m, 2H), 3.33 (t, J=6.4 Hz, 2H), 1.64 (s, 9H), 0.90-1.05 (m, 2H), 0.05-0.07 (m, 1H), 0.00 (s, 9H). Unreacted starting material (31 mg, 24%) as also obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:14]([C:15]#[C:16][Si](C)(C)C)=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F-].[K+]>CO>[C:15]([C:14]1[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[N:11][NH:12][CH:13]=1)#[CH:16]
Reactant: C[Si](C)(C)C#Cc1c[nH]nc1-c1cccc([N+](=O)[O-])c1
Agent: [F-]
Agent: [K+]
Solvent: CO
Product: C#Cc1c[nH]nc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
300 mg (1.05 mmol) of 3-(3-nitrophenyl)-4-[(trimethylsilyl)ethynyl]-1H-pyrazole were suspended in 60 ml of methanol and 120 mg (2.1 mmol) of potassium fluoride were added and the mixture stirred at room temperature overnight. After this time the solvent was removed under reduced pressure and the residue taken up with dichloromethane and washed with water. The organic layer was then dried over sodium sulphate and evaporated. The crude was finally purified by flash-chromatography on a silica gel column (CH2C12-CH3COCH3 9/1), giving 150 mg (67%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[CH:34]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1

Procedure:
The title compound was prepared from [2-amino-4-(4-fluoro-phenylethynyl)-phenyl]-carbamic acid tert-butyl ester {CAS-No. [335255-58-0]} (245 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K3) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous light brown substance (325 mg, 79%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([CH3:24])([S:20]([CH3:23])(=[O:22])=[O:21])[C:17](O)=[O:18])=[CH:10][CH:9]=1.CN(C=O)C.[Si]([O:34][NH2:35])(C)(C)C>C(Cl)Cl>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([CH3:24])([S:20]([CH3:23])(=[O:22])=[O:21])[C:17]([NH:35][OH:34])=[O:18])=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)ON
Reactant: CC(CCc1ccc(Br)cc1)(C(=O)O)S(C)(=O)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(CCc1ccc(Br)cc1)(C(=O)NO)S(C)(=O)=O
Yield: 96.8 %

Procedure:
Oxalyl chloride (4.50 mL, 50 mmol) was added to a solution of 4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoic acid (II) (14.69 g, 43.82 mmol) in DCM (300 mL) under nitrogen at ambient temperature, followed by DMF (340 ul). The reaction was stirred until effervescence ceased and then was allowed to stir for 1 hour. O-TMS-hydroxylamine (16.0 mL, 130 mmol) was added via syringe and the suspension was stirred for 1 hour. The reaction was quenched with methanol (60 mL), stirred for 1 hour and concentrated in vacuo to afford a yellow-white solid. The solid was triturated in DCM (200 mL) overnight. The solid was collected by filtration, washed with 1:1 DCM:heptane (2×100 mL), and dried under vacuum to afford the title compound as a white solid (14.85 g, 96.76%). LC-MS m/z 350.0 (M+1). 1H NMR (500 MHz, METHANOL-d4) δ ppm 1.64 (s, 3H) 2.00-2.10 (m, 1H) 2.44-2.58 (m, 2H) 2.61-2.77 (m, 1H) 3.04 (s, 3H) 7.18 (d, J=8.29 Hz, 2H) 7.44 (d, J=8.29 Hz, 2H).
Reaction SMILES: Br.C[O:3][C:4]1[C:5]2[CH:18]=[C:17]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:16]=[CH:15][C:6]=2[CH2:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=1>O>[O:3]=[C:4]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[CH2:7][C:6]2[CH:15]=[CH:16][C:17]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:5]1=2
Reactant: COC(=O)Cc1ccc2c(c1)C(OC)=Cc1ccccc1C2
Agent: Br
Solvent: O
Product: COC(=O)Cc1ccc2c(c1)C(=O)Cc1ccccc1C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
Six milliliters of 47% hydrobromic acid was added to 0.51 g of methyl 11-methoxy-5H-dibenzo[a,d]cycloheptene-2-acetate obtained in Example 12, and the mixture was stirred at room temperature for 2 hours. After the reaction, water was added to the reaction mixture, and the mixture was extracted with ether. The ethereal layer was washed with a saturated aqueous solution of sodium chloride, and the ether was distilled off. Recrystallization of the residue from n-hexane afforded 0.43 g of methyl 10,11-dihydro-11-oxo-5H-dibenzo[a,d]cycloheptene-2-acetate as colorless needle-like crystals having a melting point of 111° to 112° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][CH2:9][C:10]3([CH2:12][CH2:11]3)[C:6]=2[C:5]([O:13][C:14]2[N:19]=[CH:18][C:17]([NH:20][C:21]([C@H:23]([NH:26]C(=O)OC(C)(C)C)[CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:26][C@H:23]([CH2:24][CH3:25])[C:21]([NH:20][C:17]1[CH:18]=[N:19][C:14]([O:13][C:5]2[C:6]3[C:10]4([CH2:9][O:8][C:7]=3[C:2]([CH3:1])=[CH:3][CH:4]=2)[CH2:12][CH2:11]4)=[CH:15][CH:16]=1)=[O:22]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2ccc(C)c3c2C2(CC2)CO3)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](N)C(=O)Nc1ccc(Oc2ccc(C)c3c2C2(CC2)CO3)nc1
Reaction time: 3 h
Yield: 95.7 %

Procedure:
To a solution of tert-butyl N-[(1R)-1-[[6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-3-pyridyl]carbamoyl]propyl]carbamate (Intermediate 159, 55 mg) in dry DCM (3 ml) at 0° C. TFA (1 ml) was slowly added and the reaction mixture was stirred for 3 hours at the same temperature. The solvent and the excess of TFA were removed under reduced pressure and the residue was diluted with DCM (10 ml) and an aqueous saturated solution NaHCO3 was added while the pH was allowed to reach ˜8. Two phases were separated and the organic layer was dried (Na2SO4), filtered and evaporated affording the title compound (41 mg) as white solid.
Reaction SMILES: [CH:1]1([N:7]=[C:8](Cl)[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClS(O)(=O)=O.[CH3:22][N:23]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]1[CH2:29][C:30]([O:32][CH3:33])=[O:31].[Cl:34]([OH:38])(=[O:37])(=[O:36])=[O:35]>>[Cl:34]([OH:38])(=[O:37])(=[O:36])=[O:35].[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:8](=[N:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:27]2[N:23]([CH3:22])[C:24]([CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:25][C:26]=2[CH3:28])=[CH:10][CH:11]=1
Reactant: COC(=O)Cc1cc(C)cn1C
Reactant: ClC(=NC1CCCCC1)c1ccc(Cl)cc1
Agent: O=S(=O)(O)Cl
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)Cc1cc(C)c(C(=NC2CCCCC2)c2ccc(Cl)cc2)n1C

Procedure:
The title compound was prepared as in Example X from N-cyclohexyl 4-chlorobenzimidoyl chloride (7.4 g, 29 mmole), chlorosulfonic acid (0.34 g, 3 mmole), methyl 1,4-dimethyl-1H-pyrrole-2-acetate (4.82 g, 28.86 mmole), and 70% perchloric acid (4.6 g, 32 mmole) to yield 1.97 g (14%) of a lime green solid, m.p. 196°-202° C. (dec).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.F[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C(OCC)(=O)C>[O:12]=[C:10]1[NH:9][C:8](=[O:13])[CH:7]([CH2:6][C:5]2[CH:14]=[CH:15][C:2]([O:1][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=3)=[CH:3][CH:4]=2)[S:11]1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Temperature: 100 °C
Yield: 65.6 %

Procedure:
To a solution of 52 (5.35 g, 24 mmol) in DMF (150 mL) was added 4-fluorobenzaldehyde (3.00 g, 24 mmol) and Cs2CO3 (20 g, 62 mmol) and the mixture was heated to 100° C. for 2 h. The mixture was poured over vigorously stirring 10% citric acid (200 mL) and ethyl acetate (200 mL). The organic layer was washed with water (300 mL), brine (300 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was triturated in hexanes-ethyl acetate (2:1) to yield a white solid (5.15 g, 65%). 1H NMR: (400 MHz, DMSO-d6): δ 12.07 (bs, 1H), 9.92 (s, 1H), 7.92 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H) 4.94 (dd, J=8.4 and 4.4 Hz, 1H), 3.41 (dd, J=14.4 and 4.4 Hz, 1H), 3.17 (dd, J=14.4 and 9.2 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[NH2:11][CH2:12][CH:13]([OH:36])[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH:21]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C>CO>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH:21]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH:13]([OH:36])[CH2:12][NH:11][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[NH:4][CH:5]=[N:6]4)[CH2:16][CH2:17]2)=[CH:23][CH:24]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NCC(O)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Solvent: CCN(CC)CC
Solvent: CO
Product: OC(CNc1ncnc2nc[nH]c12)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A mixture of 6-chloropurine (0.728 g, 4.7 mmol), 1-amino-3-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]-2-propanol (1.73 g, 4.77 mmol) and triethylamine (1.36 mL, 9.5 mmol) in MeOH (20 mL) was heated to reflux for 7 days and the solvent was removed in vacuo. The residue was dissolved in CHC3 and the extracted with aqueous sodium bicarbonate (2×100 mL); the organic phase was dried over sodium sulfate and evaporated to give a solid which was purified by flash chromatography on silica gel with 5% MeOH in CHCl3. The product was a colorless solid which was triturated with ether, 1.5 g (70%), mp 140°-170° C.; IR (KBr) 3000 cm-1 ; 300 MHz 1H NMR (CDCl3); δ 8.17 (s, 1H), 8.11 (s, 1H), 7.5-7.0 (m, 8H), 4.90 (br s, 1H), 4.34 (s, 1H), 3.87 (br s, 1H), 3.7-2.0 (m, 12H); MS 480 (MH+)
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:39])[NH:18][C:19]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>Br.C(O)(=O)C>[CH2:32]([O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:23]1[N:22]=[CH:21][N:20]=[C:19]([NH:18][C:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)=[O:39])[CH:24]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(Nc1cc(-c2ccccc2OCc2ccccc2)ncn1)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: Br
Solvent: CC(=O)O
Product: O=C(Nc1cc(-c2ccccc2OCc2ccccc2)ncn1)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 7.2 %

Procedure:
4-[6-(2-Benzyloxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XVI) (0.5 g, 1 mmol) was dissolved in 33% HBr in acetic acid (3 ml) and stirred at room temperature for 45 minutes. A yellow solid precipitated out; the reaction mixture was quenched at 0° C. with aqueous sodium hydroxide solution and extracted with ethyl acetate (3×10 ml). The organic phases were separated, combined, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative HPLC (C-18, AcN:H2O with 0.05% TFA) and lyophilized to afford piperidine-4-carboxylic acid [6-(2-benzyloxy-phenyl)-pyrimidin-4-yl]-amide (compound #9A) (0.028 g, 7%) as a white solid.
Reaction SMILES: [K].[CH3:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].Cl[CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15]>CN(C)C=O>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:6]=1)(=[O:4])[CH3:2]
Reactant: COC(=O)C(C)Cl
Reactant: CC(=O)c1ccc(O)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ccc(C(C)=O)cc1
Temperature: 87.5 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
To a solution of the potassium salt of 4-hydroxyacetophenone (25.0 g, 0.14 mol) in dimethylformamide (DMF) (100 mL) is added methyl 2-chloropropanoate (24.5 g, 0.20 mol) over 30 minutes and stirred at 85-90° C. for 3 hours under nitrogen. The reaction is filtered to remove KCl and the filtrate is concentrated under reduced pressure to remove DMF and the product analyzed by GLC. The product is dissolved in ethyl acetate (300 mL) and extracted with 2N NaOH (2×100 mL) and water (100 mL). The organic phase is dried and concentrated to give pure methyl 2-(4-acetylphenoxy)propanoate (25 g) (yield 64%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][N:22]=1.C([Sn](CCCC)(CCCC)[CH:33]=[CH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)CCC>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:33](/[C:21]1[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][N:22]=1)=[CH:34]\[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCCC[Sn](C=Cc1ccccc1)(CCCC)CCCC
Reactant: Nc1ccnc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Nc1ccnc(/C=C/c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
Under inert atmosphere (Ar) a mixture of palladium-(II)-acetate (0.117 mg, 0.5 mmol) and triphenylphosphine (0.248 g, 0.9 mmol) in DMF (13 ml) was stirred for 30 min at rt. 2-Bromo-pyridin-4-ylamine (0.90 g, 5.2 mmol) (H. J. den Hertog, C. R. Kolder and W. P. Combe, Rec. Trav. Chim., 1951, 70, 591) was added followed by tributyl-styryl-stannane (3.93 g, 10 mmol). After heating at 130° C. for 15 min the solvent was evaporated and the residue partitioned between AcOEt and 3N HCl. The aqueous phase was neutralized with 6N NaOH and extracted with AcOEt. The organic phase was dried with Na2SO4, concentrated and chromatographed (SiO2 with CH2Cl2/CH3OH/NH4OH=140/10/1) to give the title compound (0.40 g, 39%) as a colorless solid. Mp. 164-165° C. (AcOEt), MS: 196 (M+).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][CH:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH2:29][O:30][CH3:31])=[CH:25][CH:26]=2)[O:21][CH2:20][C:19]1([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:35][CH:34]=1)[CH3:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(OCC)(=O)C>CO.O1CCCC1.[Pd]>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH2:29][O:30][CH3:31])=[CH:25][CH:26]=2)[O:21][CH2:20][C:19]1([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:35][CH:34]=1)[CH3:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2C#CCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 8884.4 %

Procedure:
To a solution of 4-[9-(t-butyldimethylsilyloxy)-1-nonynyl]-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman (150 g, 2.51 mmol) in methanol (100 ml) and tetrahydrofuran (10 ml) was added 10% Pd—C (570 mg), which was then stirred at room temperature under hydrogen (atmospheric pressure) for 1 day. Ethyl acetate was added to the reaction solution, which was then filtered, extracted several times with ethyl acetate, and concentrated under reduced pressure to give the title compound (134 g, yield 89%, 3RS/4RS:3RS/4SR=6:1) as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2].[NH:21]1[CH2:25][CH2:24][CH:23]([CH2:26][NH2:27])[CH2:22]1>C(#N)C.C(OCC)C>[NH2:27][CH2:26][CH:23]1[CH2:24][CH2:25][N:21]([C:10]2[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4][N:3]3[CH2:1][CH3:2])=[C:8]([F:16])[C:9]=2[F:15])[CH2:22]1
Reactant: CCn1cc(C(=O)O)c(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: NCC1CCNC1
Solvent: CCOCC
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2c(F)c(F)c(N3CCC(CN)C3)c(F)c21
Temperature: 45 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
To 1.0 g (3.5 mmol) of 1-ethyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 20 ml of acetonitrile was added 1.05 g (6.9 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene and 0.35 g (3.5 mmol) of 3-pyrrolidinemethanamine and the mixture was stirred at 45° C. for 18 hours, then refluxed one hour. The mixture was cooled, diluted with 50 ml of diethyl ether, and filtered. The solids were washed with ethanol and then diethyl ether to give 1.04 g (82%) of the title compound, mp>170° C. (decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].CC(N(C)C)=O.C([O-])(=O)C.S(Cl)([Cl:32])=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:32])=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-:19])=[O:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c([N+](=O)[O-])cccc2c1=O
Reactant: O=S(Cl)Cl
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of 8-Nitro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (10 g, 38.14 mmol) in 100 ml of thionyl chloride in a 250 ml round bottom flask was added a catalytic amount of 200 ul of dimethyl acetamide. The mixture was heated and refluxed for 2 hrs with stirring. The reaction was monitered by TLC (n-hexanelethyl acetate=3/1). After completing and cooling to room temperature, thiony chloride was removed under vacuum and 100 ml of water was added. The residue was extracted three times with 100 ml of ethyl acetate each time and the organic layer was dried over magnesium sulfate and filtrated. The residue was purified by column chromatography (hexan/ethyl acetate=3/1) to give 8-nitro-4-chloro-quinoline-3-carboxylic acid ethyl ester (9.5 g, 33.85 mmol, 89%)
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[S:15][N:14]=3)[C:10]([CH2:25][CH2:26][CH3:27])=[N:9]2)=CC=1.COC1C=CC(CN2C(CCC)=C(C3N=C(NC4C=CC=CN=4)SN=3)C=N2)=CC=1>C(O)(C(F)(F)F)=O.ClC(Cl)C>[CH2:25]([C:10]1[C:11]([C:13]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[S:15][N:14]=2)=[CH:12][NH:8][N:9]=1)[CH2:26][CH3:27]
Reactant: CCCc1nn(Cc2ccc(OC)cc2)cc1-c1nsc(Nc2ccccn2)n1
Agent: CCCc1c(-c2nsc(Nc3ccccn3)n2)cnn1Cc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: CCCc1n[nH]cc1-c1nsc(Nc2ccccn2)n1
Yield: 62 %

Procedure:
According to Scheme 1 Step 4: A solution of a mixture of 3-(1-(4-methoxybenzyl)-3-propyl-1H-pyrazol-4-yl)-N-(pyridin-2-yl)-1,2,4-thiadiazol-5-amine and of 3-(1-(4-methoxybenzyl)-5-propyl-1H-pyrazol-4-yl)-N-(pyridin-2-yl)-1,2,4-thiadiazol-5-amine (0.39 mmol, 160 mg) in TFA (2 mL) and dichloroethane (2 mL) was stirred under reflux for 12 hours. After evaporation of the solvent, DCM was added and the organic phase was washed with a saturated solution of NH4OH and brine. Then the organic phase was dried over Na2SO4, was filtered and was concentrated under reduced pressure. The resulting crude product was purified by flash chromatography over silica gel using DCM/MeOH (95:5) as eluent to yield 3-(3-propyl-1H-pyrazol-4-yl)-N-(pyridin-2-yl)-1,2,4-thiadiazol-5-amine (0.24 mmol, 70 mg, 62%) as a white solid.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27]COC)[C:22]=2[O:31][CH3:32])=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13]([CH3:35])=[CH:14][C:15]([CH3:34])([CH3:33])[NH:16]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>O1CCOCC1>[C:1]([O:9][CH2:10][C:11]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[C:22]=2[O:31][CH3:32])=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13]([CH3:35])=[CH:14][C:15]([CH3:34])([CH3:33])[NH:16]2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1cccc(-c2ccc3c(c2COC(=O)c2ccccc2)C(C)=CC(C)(C)N3)c1OC
Agent: Cl
Solvent: C1COCCO1
Product: COc1c(O)cccc1-c1ccc2c(c1COC(=O)c1ccccc1)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 6.8 %

Procedure:
5-Benzoyloxymethyl-6-(2-methoxy-3-methoxymethoxylphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound 1-28, 228 mg, 0.481 mmol) was dissolved in 1,4-dioxane (4 mL), and 4N HCl/1,4-dioxane (1 mL) was added thereto, and then the reaction mixture was stirred at room temperature for 45 minutes. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (14.0 mg) as a colorless solid. (Yield 7%)