Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)([O-])=[O:2].C=O.CO.[H][H]>[Pd].O1CCCC1>[OH:2][N:1]=[CH:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(C=C[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Agent: C=O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(CC=NO)cc1
Yield: 20.7 %

Procedure:
A mixture of methyl 4-(2-nitrovinyl)benzoate (18.6 g, 90 mmol), paraformaldehyde (3.2 g, 108 mmol) and 10% Pd/C (0.9 g) in the mixture of methanol (220 mL) and tetrahydrofuran (220 mL) was stirred at room temperature over 1 atm of hydrogen for 3 h. Then the mixture was filtered and evaporated, purified by column chromatography (silica gel, petroleum ether/ethyl acetate 15:1 to 8:1) to obtain methyl 4-(2-(hydroxyimino)ethyl)benzoate (3.6 g, yield 21%) as yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.55-3.56 (d, J=6.0 Hz, 0.5H), 3.69-3.71 (d, J=5.2 Hz, 1.5H), 3.84 (s, 3H), 6.84-6.87 (t, J=5.6 Hz, 0.75H), 7.45-7.47 (t, J=6.2 Hz, 0.25H), 7.37-7.41 (m, 2H), 7.90-7.91 (m, 2H), 10.68 (s, 0.25H), 11.14 (s, 0.75H); LC-MS (ESI) m/z: 194 (M+1)+.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][CH:10]=[C:9]3[CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:25]O)[CH2:20][CH2:19]2)[CH:5]=1.C([N:36](CC)CC)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.N>CO.C1COCC1>[N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][CH:10]=[C:9]3[CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:25][NH2:36])[CH2:20][CH2:19]2)[CH:5]=1
Reactant: OCC(c1ccc(F)cc1)N1CCN(CCCc2c[nH]c3ccc(-n4cnnc4)cc23)CC1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: NCC(c1ccc(F)cc1)N1CCN(CCCc2c[nH]c3ccc(-n4cnnc4)cc23)CC1
Yield: 53.6 %

Procedure:
In the same way as that described in Example 6 using 1-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]-4-[1-(4-fluorophenyl)-2-hydroxyethyl]piperazine (113 mg, 0.25 mmol), triethylamine (70 μL, 0.50 mmol), methanesulphonyl chloride (39 μL, 0.50 mmol) and THF (5 mL). The crude mesylate was converted to the amine in the same manner as that used in Example 6, using ammonia (2.5 mL of a 2M solution in MeOH, 5.0 mmol). The amine (60 mg, 53%) was isolated as a pale yellow foam. 1H NMR (250 MHz, CDCl3) δ1.89-2.01 (2H, m), 2.27-2.85 (14H, m), 4.10 (1H, dd, J=10.1 and 3.8 Hz), 7.00 (2H, dd, JHA-HB =8.7 Hz and JHA-F =8.7 Hz), 7.13-7.16 (2H, m), 7.34 (2H, dd, JHB-HA =8.7 Hz and JHB-F =5.5 Hz), 7.47 (1H, d, J=8.6 Hz), 7.57 (1H, d, J=1.9 Hz), 8.37 (1H, br s), 8.47 (2H, s). MS (ES+) (448, M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:14]=[CH:15][C:16]([NH2:20])=[N:17][C:18]=1[CH3:19].C([O-])(=O)C.[K+]>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:14]=[CH:15][C:16]([NH2:20])=[N:17][C:18]=2[CH3:19])=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1nc(N)ccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(N)nc2C)cc1

Procedure:
(4-methoxyphenyl)boronic acid (1 g, 6.58 mmol), 5-bromo-6-methylpyridin-2-amine (1.23 g, 6.58 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (537 mg, 0.658 mmol), potassium acetate (1.29 g, 13.16 mmol) and 1,4-dioxane (5 mL) were placed in a sealed tube and the mixture was subjected to microwave irradiation at 140° C. for 30 minutes. The resulting crude mixture was purified by flash column chromatography on SiO2 (Biotage 40+M cartridge, ethyl acetate) to afford 5-(4-methoxyphenyl)-6-methylpyridin-2-amine as a purple solid. LCMS calc.=214.11; found=215.17 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]=1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:5])[CH3:2].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[Cl:35]>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:31]3[CH:32]=[CH:33][C:34]([Cl:35])=[C:29]([F:28])[CH:30]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:7]=1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccccc1
Reactant: OB(O)c1ccc(Cl)c(F)c1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(Cl)c(F)c3)ccc2n1-c1ccccc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-phenylindole-3-carboxylic acid ethyl ester (140 mg, 0.38 mmol, see step (b) Example 3) and 3-fluoro-4-chlorophenylboronic acid (133 mg, 0.76 mmol). Yield 103 mg (54%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[F:9])=[N:3][CH:4]=1
Reactant: OB(O)c1ccccc1F
Reactant: Brc1ccc(Br)nc1
Product: Fc1ccccc1-c1ccc(Br)cn1
Yield: 50 %

Procedure:
Obtained (0.534 g, yield 50%) following the procedure described in Intermediate 27, starting with 2,5-dibromopyridine (4.22 mmol, 1.0 g), 2-fluorophenylboronic acid (4.22 mmol, 2.42 g).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)O)[CH2:5]1)(=[O:3])[CH3:2].C(OC(=O)C)(=O)C>[C].[Pd].CO>[C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCC(C(O)(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCCC(C(c2ccccc2)c2ccccc2)C1
Temperature: 140 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
To 1-acetyl-3-(diphenylhydroxymethyl)piperidine (500 mg), acetic anhydride (2 ml) was added and the mixture was stirred at 140° C. for 16 hours. After concentration of the reaction solution, 10 ml of methanol and 30 mg of 10% palladium-carbon were added, followed by stirring the mixture under hydrogen atmosphere for 17 hours. Palladium was removed by filtration through Celite and the filtrate was concentrated to obtain 250 mg of 1-acetyl-3-(diphenylmethyl)piperidine. Yield: 52%.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].[C:11](#[N:14])[CH:12]=[CH2:13]>CO>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:13][CH2:12][C:11]#[N:14])[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: C=CC#N
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: CO
Product: CS(=O)(=O)N1CCN(CCC#N)CC1
Yield: 83.1 %

Procedure:
To 1-(methylsulfonyl)piperazine (1 g, 6.09 mmol) in MeOH (11 mL) at 0° C. is added acrylonitrile (0.402 mL, 6.09 mmol). The reaction mixture is concentrated in vacuo and the resulting residue diluted with 5 mL of water and extracted with EtOAc (3×25 mL). The combined organic layers are dried (MgSO4) and concentrated in vacuo. The residue is purified over silica (2% MeOH in CH2Cl2) to afford 1.1 g (99% yield) of the desired compound. 1H NMR (CDCl3, 300 MHz) δ2.56 (t, J=6.9 Hz, 2H), 2.66 (t, J=4.8 Hz, 4H), 2.76 (t, J=6.9 Hz, 2H), 2.81 (s, 3H), 3.30 (t, J=4.8 Hz, 4H). MS (ESI, pos. ion) m/z: 218 (M+1).
Reaction SMILES: [N:1]1([CH2:7][C@@H:8]2[CH2:12][CH2:11][N:10]([C@H](C3C=CC=CC=3)C)[C@@H:9]2[C:21]([NH2:23])=[O:22])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>[Pd].O>[N:1]1([CH2:7][C@@H:8]2[CH2:12][CH2:11][NH:10][C@@H:9]2[C:21]([NH2:23])=[O:22])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C[C@@H](c1ccccc1)N1CC[C@@H](CN2CCOCC2)[C@H]1C(N)=O
Agent: [Pd]
Solvent: O
Product: NC(=O)[C@H]1NCC[C@H]1CN1CCOCC1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 1.8 but (2S,3S)-3-morpholin-4-ylmethyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid amide (Step 7.2) was used instead of (2S,3R)-3-methyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid amide. Moreover, 10% Pd on charcoal, wet with 50% H2O (Aldrich 330108) was used instead of the dry catalyst.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[C:26]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:25][N:24]=[N:23]3)[CH:17]=1)[C:10]([CH3:35])([CH3:34])[CH2:9]2)=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH2:27]([C:26]1[N:22]([C:18]2[CH:17]=[C:16]([CH:11]3[C:10]([CH3:35])([CH3:34])[CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:21]=[CH:20][CH:19]=2)[N:23]=[N:24][N:25]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-n3nnnc3Cc3ccccc3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(-n2nnnc2Cc2ccccc2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
To a stirred mixture solution of 2-[3-(5-benzyl-tetrazol-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.4 g, 3.0 mmol) in methanol (10.0 mL) and tetrahydrofuran (10.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(5-benzyl-tetrazol-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (1.2 g, 90%) as a white solid: LC/MS m/e calcd for C26H25N5O2 (M+H)+: 440.52, observed: 440.2.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]3[CH:26]=[CH:25][C:15]([CH2:16][NH:17]C(OC(C)(C)C)=O)=[CH:14][CH:13]=3)[CH:7]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([CH2:4][NH:5][C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]3[CH:13]=[CH:14][C:15]([CH2:16][NH2:17])=[CH:25][CH:26]=3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2cc(NCC3CC3)ncn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(-c2cc(NCC3CC3)ncn2)cc1
Yield: 99.9 %

Procedure:
Dissolve 4-[6-(cyclopropylmethyl-amino)-pyrimidin-4-yl]-N-(tert-butoxycarbonyl)-benzylamine (450 mg, 1.2 mmol) in DCM (5 mL). Add trifluoroacetic acid (3 mL) and stir under nitrogen for 3 h. Concentrate in vacuo and purify the crude mixture by SCX chromatography (5 g) to obtain the title compound (305 mg, 93%) suitable for use without additional purification. MS (ES+) m/z: 255 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]2[CH2:25][OH:26])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH:13]2[CH2:25][O:26][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC2(CCN(Cc3ccccc3)C2)C1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC2(CCN(Cc3ccccc3)C2)C1COS(C)(=O)=O
Temperature: 0 °C

Procedure:
A solution of 10 mmol of tert-butyl 2-benzyl-6-hydroxymethyl-2,7-diazaspiro[4.5]decane-7-carboxylate in 30 ml of dichloromethane is admixed at 0° C. with 15 mmol of triethylamine, followed by 11 mmol of methanesulphonyl chloride. The reaction mixture is stirred at 0° C. for an hour and then at room temperature for an hour. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The combined organic extracts are washed with brine, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([O:9]CC)=[O:8])=[C:4]([CH3:12])[C:3]=1[C:13]([O:15]CC)=O.[C:18]([CH2:20][CH2:21][NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)#[N:19]>>[CH2:25]([O:24][C:23]([NH:22][CH2:21][CH2:20][C:18]1[NH:19][C:13](=[O:15])[C:3]2[C:4]([CH3:12])=[C:5]([C:7]([OH:9])=[O:8])[S:6][C:2]=2[N:1]=1)=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1sc(N)c(C(=O)OCC)c1C
Reactant: N#CCCNC(=O)OCc1ccccc1
Product: Cc1c(C(=O)O)sc2nc(CCNC(=O)OCc3ccccc3)[nH]c(=O)c12

Procedure:
Using diethyl 5-amino-3-methylthiophene-2,4-dicarboxylate and benzyl N-(2-cyanoethyl)carbamate, the ring-closing reaction was carried out similarly to Production Example 1. Successively the hydrolysis was carried out similarly to Example 1, to provide 2-(2-benzyloxycarbonylaminoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].S([O-])([O-])(=O)=O.[Ba+2].N1C2C(=CC=CC=2)C=CC=1.[S].[H][H].Cl>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[C:10]([C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]=[O:5]
Reactant: Cc1c(C(=O)Cl)cccc1C(=O)c1ccc(Cl)cc1
Reactant: [H][H]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: Cc1ccccc1C
Solvent: c1ccc2ncccc2c1
Product: Cc1c(C=O)cccc1C(=O)c1ccc(Cl)cc1
Temperature: 130 °C
Reaction time: 0.75 h
Yield: 62.7 %

Procedure:
A mixture of 43.92 g of 2-methyl-3-(4-chlorobenzoyl)benzoyl chloride [prepared by process of French Patent No. 2,085,638], 450 ml of xylene, 4.5 g of barium sulfate containing 10% palladium and 0.4 ml of a solution prepared by refluxing 6 g of quinoline and 1 g of sulfur for 5 hours and diluting the product with 70 ml of xylene after cooling was stirred for 45 minutes at 130° C. while passing hydrogen therethrough. The mixture was stirred at 130° C. until hydrochloric acid evolution ceased and was then allowed to cool to 30° C. while passing an inert gas therethrough. The catalyst was removed by filtration and the solvent was evaporated from the filtrate. The oily residue was taken up in isopropyl ether and after adding sodium bisulfite thereto, the mixture was stirred for 18 hours. The precipitated bisulfite was removed by vacuum filtration, was washed and then was decomposed by stirring for 21/2 hours under an inert gas in the presence of ether and dilute sulfuric acid. The ether was decanted and the aqueous phase was extracted again with ether. The combined ether phases were washed with water, dried and the ether was evaporated under reduced pressure. The residue was crystallized from isopropyl ether to obtain 24.3 g of 2-methyl-3-(4-chlorobenzoyl)-benzaldehyde melting at 68° C.
Reaction SMILES: [C:1]([NH:4][C:5]([NH2:7])=[S:6])(=[NH:3])[NH2:2].Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O>CC(C)=O>[C:12]1([C:10]2[N:7]=[C:5]([NH:4][C:1]([NH2:2])=[NH:3])[S:6][CH:9]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: N=C(N)NC(N)=S
Solvent: CC(C)=O
Product: N=C(N)Nc1nc(-c2ccccc2)cs1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
A mixture of amidinothiourea (2.0 g, 16.9 mmol), 2-bromoacetophenone (3.4 g, 16.9 mmol) was heated at reflux in acetone (12 mL) for 4 h. The mixture was cooled to room temperature and removed half of the solvent. The precipitate was filtered, washed with acetone, and dried to give N-(4-phenyl-1,3-thiazol-2-yl)guanidine (3.2 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([SH:10])[C:3]=1[C:4]#[N:5].[OH:11][C:12]1[CH:19]=CC=C[C:13]=1C#N>>[NH2:5][C:4]1[C:3]2[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=2[S:10][C:13]=1[C:12](=[O:11])[CH3:19]
Reactant: N#Cc1c(S)cccc1Cl
Reactant: N#Cc1ccccc1O
Product: CC(=O)c1sc2cccc(Cl)c2c1N

Procedure:
The procedure was similar to step S1A, while the starting material was 2-chloro-6-mercapto-benzonitrile (2A) in stead of 2-hydroxy-benzonitrile.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[Cl:39])[C:5]([N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]([C:32]3([CH3:35])[CH2:34][CH2:33]3)=[O:31])[CH2:26][CH2:25]2)=[O:23])[CH2:10]1)[CH3:8])=[O:6].[CH2:40]([Zn]CC)[CH3:41]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:39][C:38]1[CH:37]=[CH:36][C:4]([C:5]([N:7]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH2:12][N:11]([C:22]([CH:24]3[CH2:29][CH2:28][N:27]([C:30]([C:32]4([CH3:35])[CH2:34][CH2:33]4)=[O:31])[CH2:26][CH2:25]3)=[O:23])[CH2:10]2)[CH3:8])=[O:6])=[CH:3][C:2]=1[CH2:40][CH3:41]
Reactant: CC[Zn]CC
Reactant: CN(C(=O)c1ccc(Cl)c(Br)c1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1cc(C(=O)N(C)C2CN(C(=O)C3CCN(C(=O)C4(C)CC4)CC3)CC2c2ccc(Cl)c(Cl)c2)ccc1Cl
Temperature: 65 °C
Reaction time: 5 h
Yield: 80.5 %

Procedure:
To a solution of 3-bromo-4-chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-benzamide (50 mg; 0.076 mmol) in THF (0.5 mL) was added under an argon atmosphere tetrakis(triphenylphosphine)palladium (0) (5 mg; 0.04 mmol) and diethylzinc (1 M in hexane, 762 μL; 0.762 mmol). The resulting solution was stirred for 5 h at 65° C. before it was diluted with ethyl acetatec (30 mL) and washed with aqueous sodium carbonate (saturated, 20 mL), water (20 mL) and aqueous sodium carbonate. (saturated, 20 mL). The aqueous phases were extracted with ethyl acetate (30 mL) and dried over sodium sulfate. Purification by chromatography (SiO2, ethyl acetate:methanol=100:0 to 90:10) afforded the title compound (37 mg, 47%) as a light brown foam. MS m/e: 604.2 [M]+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH:8]=[N:9][OH:10])=[N:4][CH:5]=[CH:6][CH:7]=1.ClN1C(=O)CCC1=O.[CH2:19]([O:21][C:22](=[O:26])[C:23]#[C:24][CH3:25])[CH3:20].C(N(CC)CC)C>CN(C)C=O.C(OCC)C.C(OCC)(=O)C.O>[CH2:19]([O:21][C:22]([C:23]1[C:8]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[N:9][O:10][C:24]=1[CH3:25])=[O:26])[CH3:20]
Reactant: ON=Cc1ncccc1F
Reactant: CC#CC(=O)OCC
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1c(-c2ncccc2F)noc1C
Yield: 11.5 %

Procedure:
Dissolve 3-fluoropyridine-2-carboxaldehyde oxime (2.55 g, 0.018 mol) in N,N-dimethylformamide (20 mL). Add N-chlorosuccinimide (2.71 g, 0.02 mol) in small portions and stir for 6 h at ambient temperature. Pour into water and extracte with ethyl acetate. Wash the combined extracts with water and dry over sodium sulfate. Concentrate in vacuo to give crude product. Use without further purification. MS(FD): M+ 174.0, 175.9 m/z. Combine this material with ethyl-2-butynoate (5.30 mL, 0.046 mol) in diethyl ether (200 mL) under a nitrogen atmosphere. Add triethylamine (3.29 mL, 0.024 mol) in a dropwise manner and stir over a weekend at ambient temperature. Quench the mixture with water and extract with ethyl acetate. Dry the combined extracts over sodium sulfate and concentrate. Elute over silica gel with methanol/dichloromethane to give the desired isoxazole (0.52 g, 11%). ES(ES): (M+1)+ 251.0, 252.0 m/z.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[C:11]1[CH:12]=[N:13][CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1.[CH3:19][C@@H:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([C@H:20]([NH:27][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]([C:11]3[CH:12]=[N:13][CH:14]=[C:15]([O:17][CH3:18])[CH:16]=3)[CH:5]=2)[CH3:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: COc1cncc(-c2cc(C=O)ccc2OC)c1
Product: COc1cncc(-c2cc(CN[C@H](C)c3ccccc3)ccc2OC)c1

Procedure:
The title compound (0.8 g, white solid as HCl salt) was prepared from 4-methoxy-3-(5-methoxy(3-pyridyl))benzaldehyde (0.71 g) and (R)-α-methylbenzylamine (0.371 mL) analogously to Example 66, step 3.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH:12]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:34]I>O1CCCC1>[CH2:3]([O:10][CH2:11][CH:12]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1)[O:13][CH3:34])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: OC(COCCCCCCCCCCCCC1CCCCC1)COCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(COCCCCCCCCCCCCC1CCCCC1)COCc1ccccc1

Procedure:
In 70 ml of tetrahydrofuran is suspended 0.86 g of sodium hydride, to which a solution of 10.2 g of 1-benzyl-3-(12-cyclohexyldodecyl)glycerine in 50 ml of tetrahydrofuran is added dropwise at room temperature with stirring. After 40 minutes stirring at room temperature, 5.11 g of methyl iodide is added and the mixture is further stirred for 2 hours. The solvent is then distilled off under reduced pressure and the residue is extracted with hexane. The extract layer is washed with water, dried and concentrated to obtain crude 1-benzyl-2-methyl-3-(12cyclohexyldodecyl)glycerine which in turn is dissolved in a mixed solvent consisting of 100 ml of ethanol and 30 ml of acetic acid. The solution is shaked in the presence of 10% palladium-carbon under hydrogen streams. The catalyst is removed by filtration and the filtrate is concentrated to obtain 9.6 g of the captioned compound as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:14])=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.CO[CH2:17][N:18]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][Si](C)(C)C.C(O)(C(F)(F)F)=O.CCN(CC)CC>C(Cl)Cl>[CH3:13][O:12][C:10]([CH:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([CH3:14])[CH2:17][N:18]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:19]1)=[O:11]
Reactant: COC(=O)/C=C(\C)c1ccc(Cl)cc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1CN(Cc2ccccc2)CC1(C)c1ccc(Cl)cc1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
A mixture of 11.7 g (55 5 mmol) (E)-methyl 3-(4-chlorophenyl)but-2-enoate (Organic Letters 2008, 2131-2134), 16.5 g (69 4 mmol) N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine and 0.63 g (5.5 mmol) TFA in 30 mL DCM was stirred at 0-5° C. for 1 h and then at room temperature over night. The mixture was neutralised with NEt3 and evaporated. The residue was taken up on isolute and purified by column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane. After evaporation of the product containing fractions 9.6 g (50%) of the title compounds was isolated as colorless oil. MS m/e: 344.1 [M+H]+.