Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[CH3:17])=[CH:10][C:9]=1[OH:25].Cl[CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([CH3:34])[CH2:29]1.C(O)(C(F)(F)F)=O>C(#N)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[CH3:17])=[CH:10][C:9]=1[O:25][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([CH3:34])[CH2:29]1
Reactant: CN1CCCC(CCl)C1
Reactant: C[C@@H](NCc1ccc(Cl)c(O)c1)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: C[C@@H](NCc1ccc(Cl)c(OCC2CCCN(C)C2)c1)c1cccc(Cl)c1
Temperature: 85 °C
Reaction time: 14 h
Yield: 78.6 %

Procedure:
A small vial was charged with 2 mL of acetonitrile, cesium carbonate (50 mg, 0.15 mmol), (R)-2-chloro-5-((1-(3-chlorophenyl)ethylamino)methyl)phenol 83 (30 mg, 0.10 mmol), and 3-(chloromethyl)-1-methylpiperidine (16 mg, 0.11 mmol). The vial was placed in a reaction block and it was heated to 85° C. and stirred for 14 h. The vial was allowed to cool to room temperature and the solution was filtered through a syringe filter into a well of a 24 well plate. This plate was concentrated down in a Genevac vacuum instrument. The plate was by preparatory HPLC. The desired fractions were combined and lyophilized. The final product, (1R)—N-(4-chloro-3-((1-methylpiperidin-3-yl)methoxy)benzyl)-1-(3-chlorophenyl)ethanamine 84 (32 mg, 75% yield) was isolated as a white solid of the TFA salt. 1H NMR (400 MHz, d4-methanol) δ ppm 1.44-1.56 (m, 1H) 1.72 (m, 2H) 1.99 (m, 1H) 2.07 (m, 1H) 2.40 (m, 1H) 2.91-3.00 (m, 4H) 3.55 (m, 1H) 3.67-3.74 (m, 1H) 3.93-4.01 (m, 2H) 4.10 (dd, J=9.00, 4.11 Hz, 1H) 4.18 (d, J=13.11 Hz, 1H) 4.48 (q, J=6.85 Hz, 1H) 5.50 (s, 1H) 7.00 (d, J=8.22, 1H) 7.15 (s, 1H) 7.43-7.52 (m, 3H) 7.57 (s, 1H). Mass spectrum: calculated for C22H28C12N2O 407.4. found 408.4 (M++1).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([CH2:27][CH:28]([NH:38][OH:39])[CH2:29][CH2:30][C:31]3[N:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=3)(=[O:26])=[O:25])[CH2:20][CH2:19]2)=[N:16][CH:17]=1>O1CCCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:19][CH2:20][N:21]([S:24]([CH2:27][CH:28]([N:38]([OH:39])[CH:5]=[O:7])[CH2:29][CH2:30][C:31]3[N:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=3)(=[O:25])=[O:26])[CH2:22][CH2:23]2)=[N:16][CH:17]=1
Reactant: O=S(=O)(CC(CCc1ncc(F)cn1)NO)N1CCN(c2ccc(Cl)cn2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O=CO
Product: O=CN(O)C(CCc1ncc(F)cn1)CS(=O)(=O)N1CCN(c2ccc(Cl)cn2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Acetic anhydride (0.51 ml) was added directly to formic acid (2.0 ml) which had been cooled to 0° C. and then added a solution of 2-[4-[4-(5-chloropyridin-2-yl)piperazino]sulfonyl-3-(hydroxyamino)butyl]-5-fluoropyrimidine (0.485 g) in tetrahydrofuran (11 ml). The solution was stirred at room temperature for 3 hours and then evaporated in vacuo, the resulting residue was azeotroped with toluene and then it was dissolved in methanol and heated to 40° C. for 30 minutes. The solution was evaporated to dryness and then added diethylether and stirred at room temperature for 10 minutes, solid filtered, dried in vacuo to give N-[1-([4-(5-chloropyridin-2-yl)piperazino]sulfonylmethyl)-3-(5-fluoropyrimidin-2-yl)propyl]-N-hydroxyformamide, (0218 g), mp 154–155° C.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH2:16])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:23][C:19]=1[C:20](O)=[O:21].S(Cl)(Cl)=O.CCN(C(C)C)C(C)C>C1COCC1>[C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH:16][C:20](=[O:21])[C:19]3[CH:23]=[C:24]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:31])([CH3:32])[CH3:33])[CH:25]=[CH:26][C:18]=3[Cl:17])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Reactant: CC(C)(C)Nc1ncnc2c(N)cccc12
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Nc1ncnc2c(NC(=O)c3cc(CNC(=O)C(C)(C)C)ccc3Cl)cccc12
Yield: 79 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(tert-butyl)quinazoline-4,8-diamine (Intermediate-55, 50 mg, 0.23 mmol), 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-5, 93 mg, 0.34 mmol), thionyl chloride (1 mL), and DIPEA (119 mg, 0.92 mmol) in THF (2 mL) to afford 85 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.11 (s, 1H), 8.69-8.67 (d, J=7.4 Hz, 1H), 8.49 (s, 1H), 8.16-8.13 (m, 2H), 7.58-7.38 (m, 5H), 4.31-4.29 (d, J=5.6 Hz, 2H), 1.55 (s, 9H), 1.12 (s, 9H); MS (m/z): 468.42 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:25]=[C:26]1[O:30][C:28](=[O:29])[CH2:27]1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:28]([O:11][CH2:10][CH2:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:29])[CH2:27][C:26]([CH3:25])=[O:30]
Reactant: C=C1CC(=O)O1
Reactant: OCCCC(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OCCCC(c1ccccc1)c1ccccc1
Temperature: 80 °C

Procedure:
825 mg (3.65 mmol) of 4,4-diphenylbutane-1-ol, 0.1 ml (0.72 mmol) of triethylamine and 0.40 ml (5.19 mmol) of diketene were stirred in 30 ml of toluene under heating at 80° C. for 4 hours. After the addition of saturated aqueous sodium hydrogencarbonate solution at room temperature followed by the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[NH:31]1[CH2:35][CH2:34][CH:33]([C:36]([OH:38])=[O:37])[CH2:32]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:31]5[CH2:35][CH2:34][CH:33]([C:36]([OH:38])=[O:37])[CH2:32]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:30])[F:29])[CH:3]=1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: O=C(O)C1CCNC1
Product: O=C1N=C(N2CCC(C(=O)O)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-pyrrolidine-3-carboxylic acid was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and pyrrolidine-3-carboxylic acid following General Procedure B.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:7]([NH:9][C@H:10]([C:23]1[N:24]=[C:25]([CH2:28][CH3:29])[S:26][CH:27]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18]S(=O)(=O)O)=[CH:14][CH:13]=1)=[O:8])=[O:4].[NH4+].[OH-:38].C[OH:40]>[Pd]>[CH2:28]([C:25]1[S:26][CH:27]=[C:23]([C@@H:10]([NH:9][C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:40])=[O:38])=[CH:14][CH:13]=2)[N:24]=1)[CH3:29]
Reactant: CCc1nc([C@H](Cc2ccc(NS(=O)(=O)O)cc2)NC(=O)[C@H](Cc2ccccc2)NC(=O)OC)cs1
Reactant: CO
Reactant: [OH-]
Agent: [Pd]
Agent: [NH4+]
Product: CCc1nc([C@H](Cc2ccc([N+](=O)[O-])cc2)NC(=O)[C@H](Cc2ccccc2)NC(=O)OC)cs1
Reaction time: 18 h

Procedure:
Preparation of 4-((S)-2-(S)-2-(methoxycarbonylamino)-3-phenylpropanamido)-2-(2-ethylthiazol-4-yl)ethyl)phenylsulfamic acid ammonium salt (13): tert-Butyl (S)-1-(S)-2-(4-nitrophenyl)-1-(2-ethylthiazole-4-yl)ethylamino-1-oxo-3-phenylpropan-2-ylcarbamate, 12, (0.300 g) is dissolved in MeOH (4 mL). A catalytic amount of Pd/C (10% w/w) is added and the mixture is stirred under a hydrogen atmosphere 18 hours. The reaction mixture is filtered through a bed of CELITE™ and the solvent is removed under reduced pressure. The crude product is dissolved in pyridine (12 mL) and treated with SO3-pyridine (223 mg, 1.40 mmol). The reaction is stirred at room temperature for 5 minutes after which a 7% solution of NH4OH (12 mL) is added. The mixture is then concentrated and the resulting residue is purified by reverse phase chromatography to afford 25 mg of the desired product as the ammonium salt. 1H NMR (300 MHz, MeOH-d4) δ 7.14-7.24 (m, 6H), 6.97-7.0 (m, 4H), 6.62 (s, 1H), 5.10-5.30 (m, 1H), 4.36 (t, J=7.2 Hz, 1H), 3.63 (s, 3H), 3.14 (dd, J=13.5 and 6.3 Hz, 1H), 2.93-3.07 (m, 5H), 2.81 (dd, J=13.5 and 6.3 HZ, 1H), 1.39 (t, J=7.8 Hz, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[F:14][C:15]([Si](C)(C)C)([F:17])[F:16]>O1CCCC1.CN(C)C=O>[F:14][C:15]([F:17])([F:16])[CH:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[OH:7]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: OC(c1ccsc1)C(F)(F)F
Yield: 53 %

Procedure:
According to Reference Example 8-2, by use of thiophene-3-carbaldehyde (300 mg, 2.67 mmol) dissolved in tetrahydrofuran (4.5 mL) and N,N-dimethylformamide (1.5 mL), potassium carbonate (74 mg, 0.53 mmol) and (trifluoromethyl)trimethylsilane (0.772 mL, 5.34 mmol), the mixture was stirred and reacted at room temperature for 16 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=100/1) was performed to give 2,2,2-trifluoro-1-(thiophen-3-yl)ethanol (Compound DO) (258 mg, yield: 53%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[CH2:9][CH2:10][OH:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:9][CH2:10][OH:11])[CH:3]=1
Reactant: OCCCl
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1cccnc1

Procedure:
The yield of the title compound according to D1, starting from 3-hydroxypyridine, 2-chloroethanol and K2CO3 in DMF was 19%. The title compound has also been prepared according to EP 0 286 242 A2 starting from methyl [(3-pyridinyl)oxy]acetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:33])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2SC)=[CH:17][C:16]=1[C:29]([F:32])([F:31])[F:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[O:35][S:36]([O-:38])=O.[K+].[C:40](#N)C>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:33])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=2[S:36]([CH3:40])(=[O:38])=[O:35])=[CH:17][C:16]=1[C:29]([F:30])([F:31])[F:32])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC#N
Reactant: CSc1ccccc1-c1ccc(NC(=O)C2CCCN2C(=O)OC(C)(C)C)c(C(F)(F)F)c1
Reactant: O=S([O-])OO
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 96 h

Procedure:
2-(2′-Methylsulfanyl-3-trifluoromethyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.8 g, 3.7 mmol) was dissolved in 20 mL acetonitrile, and added oxone (4.6 g, 6.8 mmol) in one portion and stirred at ambient temperature 4 days and then concentrated. Redissolved in 100 mL EtOAc and 100 mL sat. NaHCO3, separated layers, washed organics with brine, dried with MgSO4, filtered and concentrated. Purified on a silica gel column eluted with 20% EtOAc in hexanes. Combined and concentrated pure fractions to yield title compound. (1.05 g, 55%) APCI (AP−): 511.1 (M−H)−.
Reaction SMILES: [CH3:1][O:2][P:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[CH:8]2.[I:21]I.[OH-].[K+]>CN(C)C=O>[CH3:1][O:2][P:3]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[I:21]
Reactant: II
Reactant: COP(=O)(Oc1ccc2[nH]ncc2c1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COP(=O)(Oc1ccc2[nH]nc(I)c2c1)c1ccccc1
Yield: 71.1 %

Procedure:
Phenylphosphonic acid 3-iodo-1H-indazol-5-yl ester methyl ester is prepared according to procedure A using 76 mg of phenylphosphonic acid 1H-indazol-5-yl ester methyl ester, 134 mg of iodine and 30.6 mg of potassium hydroxide ground before hand in 3 ml of dimethylformamide. The crude is purified by flash chromatography on silica with a particle size of 15-35 μm. Eluent: ethyl acetate/cyclohexane 1:1 to obtain 77.6 mg of phenyl-phosphonic acid 3-iodo-1H-indazol-5-yl ester methyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH:18]([CH3:20])[CH3:19]>CN(C=O)C>[CH3:19][CH:18]([O:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8])[CH3:20]
Reactant: CC(C)Br
Reactant: COC(=O)c1[nH]ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1[nH]ccc1OC(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.4 %

Procedure:
Methyl 3-hydroxy-1H-pyrrole-2-carboxylate (2.0 g, 0.014 moles) is dissolved in DMF (15 mL) under nitrogen. Potassium carbonate (2.8 g, 0.020 moles) is added followed by 2-bromopropane (5 mL, 0.05 moles) and the mixture is stirred at room temperature for 18 hours, then at 50° C. for 3 hours, then stirred into ice water (400 mL). The mixture is extracted with CH2Cl2 (3x) and the combined extracts are washed with brine (2x) and dried over MgSO4. Removal of the solvent under reduced pressure leaves the crude product as a crystalline residue. Recrystallization from ether gave the pure product (1.6 g); mp 77°-79° C.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[CH2:6]([CH:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:7].BrCC.Cl>C1COCC1.O>[CH2:6]([C:8]1([CH2:1][CH3:2])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:15]2[C:20]1=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:7]
Reactant: [Li]CCCC
Reactant: CCC1c2ccccc2-c2ccccc21
Agent: Cl
Solvent: CCBr
Solvent: O
Solvent: C1CCOC1
Product: CCC1(CC)c2ccccc2-c2ccccc21
Temperature: -75 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
A solution of n-butyllithium (77.34 cm3, 0.1934 mol, 2.5 M in hexane) was added slowly to a solution of 9-ethylfluorene (25.00 g, 0.1289 mol) in THF (250 cm3) at −70° C. The solution was stirred for 1 hour at −75 ° C. and 1-bromoethane (17.59 cm3, 0.1934 mol) was added slowly. The solution was allowed to warm to room temperature and then stirred overnight. Dilute hydrochloric acid (200 cm3, 20%) was added to the reaction mixture and stirred for a further 10 minutes. Water (250 cm3) was added and the product extracted into diethyl ether (3×300 cm3). The combined organic extracts were dried (MgSO4) and the solvent removed on a rotary evaporator. The resulting oil was cooled to room temperature and recrystallised with ethanol to yield white crystals (19.50 g, 68%, m.pt. 60-62° C.).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:19][CH2:18]1>>[ClH:1].[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:2]3[N:3]=[N:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)[CH2:26][CH2:25]2)[CH2:19][CH2:18]1
Reactant: CN1CCC(CN2CCNCC2)CC1
Reactant: N#Cc1ccc(-c2ccc(Cl)nn2)cc1
Product: CN1CCC(CN2CCN(c3ccc(-c4ccc(C#N)cc4)nn3)CC2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 3-chloro-6-(4-cyanophenyl)pyridazine and (1-methylpiperidin-4-ylmethyl)piperazine.
Reaction SMILES: [CH2:1]1[C:5]2[CH2:6][NH:7][CH2:8][C:4]=2[CH2:3][N:2]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].Br[C:17]1[S:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:21]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:25]([O:24][C:22]([C:19]1[S:18][C:17]([N:7]2[CH2:6][C:5]3[CH2:1][N:2]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C:4]=3[CH2:8]2)=[N:21][CH:20]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)c1cnc(Br)s1
Reactant: CC(C)(C)OC(=O)N1CC2=C(CNC2)C1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(N2CC3=C(CN(C(=O)OC(C)(C)C)C3)C2)s1
Yield: 64.3 %

Procedure:
tert-Butyl 3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-2-carboxylate (1.2 g, 5.7 mmol), ethyl 2-bromothiazole-5-carboxylate (1.69 g, 7.17 mmol) and triethylamine (1.09 ml, 7.84 mmol) were stirred at 100° C. in 70 ml of DMF for 7 h. The residue was filtered off, the filtrate was concentrated and the remaining residue was extracted with ethyl acetate. 1.34 g of crude product were obtained, which were reacted without further purification (M+H+: 366.14).
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8]Br)=[CH:5][CH:4]=1.[CH2:12](Br)[CH:13]=[CH2:14]>CCOCC>[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][CH2:14][CH:13]=[CH2:12])=[CH:5][CH:4]=1
Reactant: C=CCBr
Reactant: Clc1ccc(CCBr)cc1
Agent: [Mg]
Solvent: CCOCC
Product: C=CCCCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To a flame-dried flask containing 7.75 g of magnesium turnings under ether was added 4-chlorophenethyl bromide (70 g) in anhydrous ether (250 mL) at such a rate as to maintain a gentle reflux. When the addition was complete, the mixture was heated under reflux for an additional hour and then treated dropwise over one hour with allyl bromide (27.6 mL, 38.6 g) in ether (75 mL) maintaining a gentle reflux. The resulting mixture was stirred overnight at room temperature and then poured onto 600 mL of ice-cold dilute sulfuric acid. The product was extracted with ethyl acetate and the combined extracts were washed with dilute aqueous potassium carbonate, dried (MgSO4) and evaporated. The resulting brown oil was distilled under reduced pressure to give 43 g of 5-(4-chlorophenyl)pent-1-ene, b.p. 74°-80° (2 mmHg) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[C:3]=1[C:10]#[N:11].ClC1C=C(C=CC=1)C(OO)=[O:17]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N+:5]([O-:17])=[C:4]([CH3:9])[C:3]=1[C:10]#[N:11]
Reactant: Cc1cc(Cl)c(C#N)c(C)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(Cl)c(C#N)c(C)[n+]1[O-]
Reaction time: 8 h

Procedure:
50 g (0.3 mol) of 4-chloro-3-cyano-2,6-dimethylpyridine were dissolved in 1 L of dichloromethane and, at room temperature, 130 g (0.6 mol) of 80% pure m-chloroperoxybenzoic acid were added in portions, and the mixture was stirred overnight and the precipitated m-chlorobenzoic acid was filtered off. Water was added to the filtrate, the pH was adjusted to 12 with solid potassium hydroxide, and the two phases were shaken together to extract. The dichloromethane phase was separated off, dried over sodium sulfate, filtered and evaporated. 4-Chloro-3-cyano-2,6dimethylpyridine 1-oxide was obtained as a solid compound which sintered at 140° C. Yield: 49.3 g (90% of theory).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:4]=[CH:3]1.[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.O>CN(C=O)C>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:5]1[N:4]=[CH:3][N:2]([C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)Cc1c[nH]cn1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
A solution of 2.78 g (19.80 mmol) of the compound from example 1c, 5.52 g (19.80 mmol) of triphenylmethyl chloride and 2.00 g (19.80 mmol) of triethylamine in 5 ml of DMF was stirred at RT overnight, then poured into 200 ml of water and stirred at RT for one hour. The precipitate which separated out was filtered off with suction. The filtrate was extracted three times with EA. The combined organic phases were dried over Na2SO4, filtered and concentrated. The yellow oil resulting from this and the precipitate were combined and chromatographed on silica gel. 4.2 g of the desired compound resulted.
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[CH2:4][C:3](=[O:8])[CH2:2]1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[CH3:18])[CH:13]=O.[NH2:19]/[C:20](/[CH3:26])=[CH:21]\[C:22]([O:24][CH3:25])=[O:23]>CO>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]2[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([CH3:26])[NH:19][C:5]3[CH2:6][O:1][CH2:2][C:3](=[O:8])[C:4]2=3)[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: COC(=O)/C=C(/C)N
Reactant: O=C1COCC(=O)C1
Reactant: Cc1ccc(C=O)cc1Br
Solvent: CO
Product: COC(=O)C1=C(C)NC2=C(C(=O)COC2)C1c1ccc(C)c(Br)c1
Temperature: 25 °C

Procedure:
The product from Example 11B (0.34 g, 3.0 mmol), 3-bromo-4-methylbenzaldehyde (Pearson.; Org. Synth. Coll. Vol. V, 1973, 117) (0.60 g, 3.0 mmol) and methyl 3-aminocrotonate (0.35 g, 3.0 mmol) in methanol (8 mL) were heated at 80° C. in a sealed tube for 60 hours. After cooling to ambient temperature, the mixture was filtered and the filter cake washed with methanol and dried to provide the title compound (0.63 g).
Reaction SMILES: [Br-].C([P+](CCCC)(CCCC)[CH:7]1[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=2[C:9](=[O:16])[O:8]1)CCC.[CH3:25][O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]=O)[CH:29]=1.C(N(CC)CC)C>ClCCl>[O:16]=[C:9]1[C:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:7](=[CH:34][C:30]2[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=2)[C:27]([O:26][CH3:25])=[O:36])[O:8]1
Reactant: CCCC[P+](CCCC)(CCCC)C1OC(=O)C2=C1CCCC2
Reactant: COC(=O)c1cccc(C=O)c1
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(C=C2OC(=O)C3=C2CCCC3)c1

Procedure:
A solution of EXAMPLE 1B (25.8 g, 61.5 mmol), methyl-3-formylbenzoate (10.01 g, 61.0 mmol), and triethylamine (8.7 mL, 62.4 mmol) in dichloromethane (125 mL) was stirred at room temperature for 16 hours, and concentrated. The residue was stirred with a mixture of ethyl acetate and water. The precipitated solid was filtered, washed with water, and dried to provide the title compound. MS (DCI/NH3) m/z 285 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:4]([O:6]CC)=[O:5].[OH-].[Na+:18]>CO.O>[NH2:2][C@H:3]([CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:4]([O-:6])=[O:5].[Na+:18]
Reactant: CCOC(=O)[C@H](N)CCC1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N[C@H](CCC1CCCCC1)C(=O)[O-]
Reaction time: 1 h

Procedure:
Ethyl (2R)-2-amino-4-cyclohexylbutanoate hydrochloride (4.00 g, 18.75 mmol) was dissolved in MeOH/Water (10/5 ml). Sodium hydroxide (1.50 g, 37.50 mmol) was added. The reaction mixture was stirred for 1 h and concentrated to give the title compound as a colourless solid (containing 100 mol % of sodium chloride). 1H NMR [(CD3)2SO), 400 MHz] δ0.83-0.97 (m, 2H), 1.10-1.33 (m, 6H), 1.48-1.78 (m, 7H), 3.15 (dd, 1H).