Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:33]=[C:34]([CH3:39])[N:35]=[C:36]([CH3:38])[CH:37]=4)[CH:27]=3)[CH2:23][C:22](=[O:40])[NH:21][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(N(C)CC(C)C)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)CC(C)C)c(Cl)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from [4-chloro-2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(isobutyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example M305) (0.43 g, 0.74 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (282 mg, 82%).
Reaction SMILES: [CH2:1]([CH2:5][C:6](=O)[CH3:7])[C:2]([CH3:4])=O.C([CH:12]([NH2:15])[CH2:13][NH2:14])(=O)C.[CH2:16]([OH:18])[CH3:17]>>[CH3:4][C:2]1[N:15]([CH2:12][CH2:13][NH:14][C:16](=[O:18])[CH3:17])[C:6]([CH3:7])=[CH:5][CH:1]=1
Reactant: CC(=O)CCC(C)=O
Reactant: CCO
Reactant: CC(=O)C(N)CN
Product: CC(=O)NCCn1c(C)ccc1C

Procedure:
171.2 g (1.5 mol) of acetonylacetone and 153.2 g (1.5 mol) of 1-acetylethylenediamine are heated under reflux in 1.8 l of ethanol for 3 h. The reaction mixture is concentrated, and the residue is recrystallized from toluene. Yield: 259.3 g (96% of theory), Melting point: 106°-107° C. Elemental analysis: C10H16N2O (180.25) calculated: C 66.6 H 8.9 N 15.5 0 8.9 found: C 66.8 H 8.8 N 15.6 0 8.9
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:49]([N+:53]1[N:57]=[C:56]([CH3:58])[S:55][C:54]=1[CH3:59])[CH2:50][CH2:51][CH3:52]>>[CH2:49]([N:53]1[N:57]=[C:56]([CH3:58])[S:55]/[C:54]/1=[CH:59]\[C:7]([C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:1])([F:14])[F:13])[CH:5]=1)=[O:9])[CH2:50][CH2:51][CH3:52]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-(trifluoromethoxy)benzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.90 (t, 3H) 1.27-1.42 (m, 2 H) 1.69-1.80 (m, 2 H) 2.49 (s, 3 H) 4.27 (t, 2 H) 6.78 (s, 1 H) 7.43-7.53 (m, 1 H) 7.58-7.65 (m, 1 H) 7.92 (s, 1 H) 8.03-8.11 (m, 1 H); MS (ESI) m/z 359 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([NH:9][C:10](=[O:27])[CH2:11][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[S:15][CH:16]=2)=[N:6][CH:5]=1)([CH3:3])[CH3:2].C=O.O.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl>[CH:1]([C:4]1[S:8][C:7]([NH:9][C:10](=[O:27])[CH2:11][C:12]2[N:13]=[C:14]([N:17]([CH3:31])[CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)[S:15][CH:16]=2)=[N:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)c1cnc(NC(=O)Cc2csc(NCCN3CCN(C)CC3)n2)s1
Agent: C=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)c1cnc(NC(=O)Cc2csc(N(C)CCN3CCN(C)CC3)n2)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
N-(5-isopropyl-1,3-thiazol-2-yl)-2-(2-{[2-(4-methyl-1piperazinyl)ethyl]amino}-1,3-thiazol-4-yl)acetamide (1 g, 2.45 mmol) and 40% formaldehyde in water (0.17 ml, 2.45 mmol) were mixed in CHCl3 (10 ml) and then treated with sodium triacetoxyborohydride (0.727 g, 3.43 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 5 hours. The reaction mixture was quenched by adding aqueous saturated sodium bicarbonate and the product was extracted with CHCl3. The organic layer was washed with brine, dried and evaporated. The title compound was obtained after chromatographic purification in 75% yield.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:20])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:21][C:22]1[N:27]=[C:26](Cl)[C:25]([Cl:29])=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:21][C:22]1[N:27]=[C:26]([NH:2][C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:20])[C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[CH:6]=[CH:7][CH:8]=2)[C:25]([Cl:29])=[CH:24][N:23]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Nc1cccc(NC(=O)c2cccc([N+](=O)[O-])c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Nc2nc(Cl)ncc2Cl)c1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 131.9 %

Procedure:
To a solution of N-(3-aminophenyl)-3-nitrobenzamide hydrochloride (0.200 g, 0.681 mmol) and 2,4,5-trichloropyrimidine (0.071 mL, 0.619 mmol) in DMF (1.6 mL) was added potassium carbonate (0.30 g, 2.2 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with sat'd NH4Cl and water. EtOAc was added and the layers separated. The aqueous layer was extracted with EtOAc twice. The combined organics were washed with water, dried, filtered and concentrated to give the desired product as a light brown powder (330 mg). LCMS for C17H11Cl2N5O3 (M+H)+: m/z=403.9, 405.9, 407.9. 1H NMR (400 MHz, CD3OD): δ 8.82 (t, J=2.0 Hz, 1H), 8.45 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 8.34 (ddd, J=7.6, 2.0, 1.2 Hz, 1H), 8.24 (s, 1H), 7.97 (br, 2H), 7.76 (t, J=8.0 Hz, 1H), 7.56 (m, 1H), 7.43 (ddd, J=8.0, 2.0, 1.2, 1H).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)[C:2]#[CH:3].C(NC(C)C)(C)C.I[C:19]1[CH:24]=[CH:23][C:22](/[C:25](/[C:42]2[CH:47]=[CH:46][C:45]([S:48][CH3:49])=[CH:44][CH:43]=2)=[CH:26]\[CH2:27][O:28][C:29]2[CH:40]=[CH:39][C:32]([O:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:31]([CH3:41])[CH:30]=2)=[CH:21][CH:20]=1>O1CCCC1.C(N(CC)CC)C.[Cu]I.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>[OH:10][CH:7]1[CH2:8][CH2:9][N:4]([CH2:1][C:2]#[C:3][C:19]2[CH:20]=[CH:21][C:22](/[C:25](/[C:42]3[CH:47]=[CH:46][C:45]([S:48][CH3:49])=[CH:44][CH:43]=3)=[CH:26]\[CH2:27][O:28][C:29]3[CH:40]=[CH:39][C:32]([O:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:31]([CH3:41])[CH:30]=3)=[CH:23][CH:24]=2)[CH2:5][CH2:6]1
Reactant: C#CCN1CCC(O)CC1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(SC)cc2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCC(O)CC3)cc2)c2ccc(SC)cc2)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-Propargylpiperidin-4-ol (0.401 g, 2.88 mmol) and diisopropylamine (1.6 mL, 11.73 mmol) were added to a solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-[4-(methylsulfanyl)phenyl]allyloxy]-2-methylphenoxy]acetate (1.40 g, 2.5 mmol; prepared as described in example 40) in tetrahydrofuran (12 mL) and triethylamine (12 mL). The mixture was degassed and copper(I) iodide (49.0 mg, 0.256 mmol) and tetrakis(triphenylphosphine)palladium (148 g, 0.128 mmol) were added. The reaction mixture was stirred at ambient temperature for 20 h and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, chloroform/methanol 97:3) yielding methyl (E)-[4-[3-[4-[3-(4-hydroxypiperidin-1-yl)propynyl]phenyl]-3-[4-(methylsulfanyl)phenyl]-allyloxy]-2-methylphenoxy]acetate as yellow oil.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].[CH2:16]([NH2:19])[CH2:17][NH2:18]>C(O)C>[N+:1]([C:4]1[C:9]([CH:10]=[C:16]([NH2:19])[C:17](=[CH:10][C:9]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([O:14][CH3:15])=[C:7]([O:12][CH3:13])[CH:8]=2)[NH2:18])=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: NCCN
Solvent: CCO
Product: COc1cc(C=C(N)C(N)=Cc2cc(OC)c(OC)cc2[N+](=O)[O-])c([N+](=O)[O-])cc1OC
Yield: 84 %

Procedure:
A heated suspension of 6-nitroveratraldehyde (168.8 g, 0.8 moles) and 1200 ml of ethanol was treated with ethylenediamine (24 g, 0.4 moles) and 200 ml of ethanol. The mixture was nearly in solution when a solid precipitated. Ethanol (500 ml) was added. The suspension was refluxed for 1.5 hrs. The resulting solid was filtered and washed with ethanol to yield 150 g (84%) of the product.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15]([CH3:17])=[C:14]([CH3:18])[N:13]=[C:12]([N:19](CC=C)CC=C)[C:11]=2[NH:10][C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C>O>[CH2:1]([N:8]1[C:16]2[C:15]([CH3:17])=[C:14]([CH3:18])[N:13]=[C:12]([NH2:19])[C:11]=2[NH:10][C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCN(CC=C)c1nc(C)c(C)c2c1[nH]c(=O)n2Cc1ccccc1
Solvent: O
Solvent: CC#N
Product: Cc1nc(N)c2[nH]c(=O)n(Cc3ccccc3)c2c1C
Temperature: 25 °C
Yield: 28.7 %

Procedure:
1-Benzyl-4-diallylamino-6,7-dimethyl-1,3-dihydro-imidazo[4,5-c]pyridin-2-one (358 mg, 1 mmol) was taken up in water (10 mL) and acetonitrile (25 mL) and RhCl(PPh3)3 (286 mg, 0.3 mmol) was added in one portion and the mixture then heated at reflux for 16 h. The mixture was allowed to cool to room temperature, and then concentrated in vacuo, and the residue purified by column chromatography on silica gel using a gradient of 95:5→85:15 DCM:MeOH to afford the title compound as a pale brown solid (77 mg, 29%).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.C(N(CC)C(C)C)(C)C.[CH:26]1([C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>ClCCl>[CH:26]1([C:32]2[CH:33]=[CH:34][C:35]([C:36]([N:5]3[CH2:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:2]([CH3:1])[C:3]4[CH:16]=[CH:15][CH:14]=[CH:13][C:4]3=4)=[O:37])=[CH:39][CH:40]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: O=C(Cl)c1ccc(C2CCCCC2)cc1
Reactant: CN1c2ccccc2CNc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1c2ccccc2CN(C(=O)c2ccc(C3CCCCC3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
A solution of 10,11-dihydro-5-methyl-dibenzo[b,e][1,4]diazepine of Step C (0.42 g) in dichloromethane (10 mL) containing N,N-diisopropylethyl amine (0.29 g) was treated with 4-cyclohexylbenzoyl chloride (0.50 g). After stirring overnight at room temperature, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate, then dried over anhydrous sodium sulfate. The solution was filtered through a short column of Magnesol® which was eluted with several additional volumes of dichloromethane. Evaporation of all volatiles gave a glassy residue which was triturated with anhydrous diethyl ether to provide the title compound as an off-white crystalline solid (0.66 g), m.p. 111–112° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][C:11]1[C:15]([C:16]([O:18]C)=O)=[CH:14][S:13][CH:12]=1)=[O:9].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[C:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1.NC1C(C(OC)=O)=CSC=1.BrCCCCCN=C=O>C1(C)C=CC=CC=1>[F:40][C:37]1[CH:38]=[CH:39][C:34]([C:27]([C:24]2[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=2)=[C:28]2[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]3[C:16](=[O:18])[C:15]4=[CH:14][S:13][CH:12]=[C:11]4[NH:10][C:8]3=[O:9])[CH2:30][CH2:29]2)=[CH:35][CH:36]=1
Reactant: COC(=O)c1cscc1NC(=O)NCCCCCBr
Reactant: Fc1ccc(C(=C2CCNCC2)c2ccc(F)cc2)cc1
Agent: COC(=O)c1cscc1N
Agent: O=C=NCCCCCBr
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cscc2c(=O)n1CCCCCN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 98 %

Procedure:
The title compound was prepared by the procedure of Example 10 using N-(5-bromopentyl)-N'-(4-carbomethoxythien-3-yl)urea (9.01 g, 26 mmol) and 4-[bis(4-fluorophenyl)methylene]piperidine (14.76 g, 52 mmol). The urea was prepared by reacting methyl 4-aminothiophene-3-carboxylate with one equivalent of 5-bromopentylisocyanate in toluene at room temperature for four hours to produce the urea as a tan solid (98% yield). This material was recrystallized from CH2Cl2 /ether/hexane to afford the urea as a white solid, mp 92°-93.5° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:7][C:6](=[O:12])[CH:5]=[CH:4][C:3]1=2.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(=O)([O-])[O-].[Ag+2].C1(C)C=CC=CC=1>[O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]=[C:6]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: BrCc1ccccc1
Reactant: O=C1CCCc2[nH]c(=O)ccc21
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C1CCCc2nc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 89 %

Procedure:
A suspension of 5,6,7,8-tetrahydro-5-oxo-2(1H)-quinolinone (33.0 g), silver carbonate (35.0 g), benzyl bromide (44.4 g), and toluene (400 ml) was stirred at room temperature for 72 hrs. The mixture was filtered and the filtrate was concentrated. Trituration of the residue with petroleum ether gave 45.6 g (83%) of product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH2:17]S(C)(=O)=O)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:22][C:23]([F:41])([F:40])[C:24]1[CH:25]=[C:26]([CH2:34][S:35]([NH:38][CH3:39])(=[O:37])=[O:36])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:41][C:23]([F:22])([F:40])[C:24]1[CH:25]=[C:26]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:34][S:35]([N:38]([CH2:17][C:10]1[CH:11]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=1)[CH3:39])(=[O:36])=[O:37]
Reactant: CNS(=O)(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)c1cc(CS(C)(=O)=O)nn1-c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(CN(C)S(=O)(=O)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)nn1-c1ncccc1Cl
Temperature: 50 °C
Reaction time: 12 h

Procedure:
5.00 g (14.4 mmol) of methyl 1-(3-chloropyridin-2-yl)-3-[(methylsulphonyl)methyl]-1H-pyrazole-5-carboxylate were dissolved in 50 ml of acetonitrile, and 4.64 g (14.4 mmol) of 1-[3,5-bis(trifluoromethyl)phenyl]-N-methylmethanesulphonamide were added a little at a time at room temperature. Then 2.40 g (17.35 mmol) of potassium carbonate were added to the reaction solution, and the mixture was stirred at 50° C. for 12 hours. After cooling to room temperature, the reaction solution was freed from the solvent under reduced pressure. 250 ml of water were added to the residue, and the mixture was extracted with ethyl acetate (3×100 ml). The combined organic phases were dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was purified by chromatography. (logP: 3.83; MH+: 571; 1H-NMR (400 MHz, DMSO, δ, ppm): 2.79 (s, 3H), 3.74 (s, 3H), 4.43 (s, 2H), 4.80 (s, 2H), 7.06 (s, 1H), 7.70 (dd, 1H), 8.12 (s, 2H), 8.15 (s, 1H), 8.26 (d, 1H), 8.57 (d, 1H).
Reaction SMILES: [C:1]1([C@@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12](=[O:17])[CH2:13][C:14](=O)[CH3:15].[CH3:18][O:19][C:20](=[O:23])[C:21]#[CH:22]>CO>[CH3:18][O:19][C:20](=[O:23])[CH:21]=[CH:22][C:13](=[C:14]([NH:9][C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])[CH3:15])[C:12]([O:11][CH3:10])=[O:17]
Reactant: C#CC(=O)OC
Reactant: C[C@H](N)c1ccccc1
Reactant: COC(=O)CC(C)=O
Solvent: CO
Product: COC(=O)C=CC(C(=O)OC)=C(C)N[C@@H](C)c1ccccc1
Temperature: 25 °C
Yield: 63.8 %

Procedure:
A mixture of (S)-1-phenyl-ethylamine (3 g, 24.8 mmol) and 3-oxo-butyric acid methyl ester (3.2 mL, 29.7 mmol) in MeOH (100 mL) was refluxed for 2 h. Propynoic acid methyl ester (3.3 mL, 37.1 mmol) was added, and the resulting mixture was refluxed for 2 days. After cooling to r.t., the solvent was evaporated, and the crude solid was recrystallized from MeOH to give 4.8 g of the title compound as a pale orange solid. MS: (+) m/z 326.29 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:16])=[C:4]([C:13]([OH:15])=[O:14])[C:5]([I:12])=[C:6]([C:9]([OH:11])=[O:10])[C:7]=1[I:8].[OH2:17]>CC(N(C)C)=O>[C:13]([CH2:4][CH2:5][CH2:6][C:9]([NH:1][C:2]1[C:7]([I:8])=[C:6]([C:9]([OH:11])=[O:10])[C:5]([I:12])=[C:4]([C:13]([OH:15])=[O:14])[C:3]=1[I:16])=[O:10])([OH:14])=[O:17]
Reactant: O
Reactant: Nc1c(I)c(C(=O)O)c(I)c(C(=O)O)c1I
Solvent: CC(=O)N(C)C
Product: O=C(O)CCCC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)O)c1I
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To an ice cool stirred solution of 5-amino-2,4,6-triiodo-1,3-benzenedicarboxylic acid, diacid chloride (2.7 g, 4.6 mmol) in 3 mL of dimethylacetamide was added methyl (4-chloroformyl)butyrate (1.5 g, 9.0 mmol). The solution was stirred for 18 hours at room temperature. The reaction mixture ws poured into 25 mL of water and extracted with 3×15 mL of ethyl acetate. The combined organic phase was extracted with 2×10 mL of water, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the desired product as a residue. The crude product was crystallized from CH3CN to yield 1.35 g of the title A compound, i.e., the isophthalyl chloride. The product was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][NH2:16].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:16][CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1C=O
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCC1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.8 %

Procedure:
To a suspension of 2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.68 g) in methanol (30 mL) at room temperature was added a solution of methylamine (831 mg) in methanol (3 mL). The reaction mixture was stirred at room temperature for 72 h and then sodium borohydride (760 mg) and molecular sieves were added. After stirring at room temperature for 2 h, the reaction mixture was filtered and the filtrate reduced in vacuo. The residue was redissolved in dichloromethane (30 mL) and washed with saturated sodium bicarbonate solution (30 mL). The combined organics were washed with brine (30 mL), dried (MgSO4) and reduced in vacuo to give 2-methylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a pale yellow oil (2.56 g).
Reaction SMILES: [CH:1]1(/[C:4](=[N:15]/[O:16][CH3:17])/[CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[C:18]([CH:20]([C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)[CH2:21][C:22]([O:24]C)=[O:23])#[N:19]>>[C:18]([CH:20]([C:26]1[CH:31]=[CH:30][C:29]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5]/[C:4](/[CH:1]3[CH2:3][CH2:2]3)=[N:15]\[O:16][CH3:17])=[CH:8][CH:9]=2)=[CH:28][CH:27]=1)[CH2:21][C:22]([OH:24])=[O:23])#[N:19]
Reactant: CO/N=C(\COc1ccc(CO)cc1)C1CC1
Reactant: COC(=O)CC(C#N)c1ccc(O)cc1
Product: CO/N=C(\COc1ccc(COc2ccc(C(C#N)CC(=O)O)cc2)cc1)C1CC1
Yield: 56.32 %

Procedure:
Compound 105 was synthesized from (4-{[(2Z)-2-cyclopropyl-2-(methoxyimino)ethyl]oxy}phenyl)methanol (0.5 g, 2.12 mmol) and methyl 3-cyano-3-(4-hydroxyphenyl)propanoate (0.44 g, 2.12 mmol) by following the procedure described in scheme 5 (0.008 g, yield: 56.32%); Purity: 84.26%.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:9]1[CH2:14][NH:13][C:12](=[O:15])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23]C(C)([O-])C.[K+].CI.[Na+].[Cl-]>O1CCCC1.C(OCC)(=O)C>[CH2:16]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]1[CH2:14][N:13]([CH3:23])[C:12](=[O:15])[CH2:11][CH2:10]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CN1
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CI
Product: CN1C[C@@H](N(Cc2ccccc2)Cc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
500 mg (S)-5-dibenzylamino-piperidin-2-one are suspended in 15 ml of tetrahydrofuran. While cooling with the ice bath 175 mg potassium-tert-butoxide are added. The reaction mixture is then stirred for 30 minutes at ambient temperature. While cooling with the ice bath 95 μl methyliodide are added. The reaction mixture is then stirred for 48 hours at ambient temperature and then combined with a saturated NaCl solution and ethyl acetate. The organic phase is dried and evaporated to dryness. 450 mg of the product are obtained as an oil. Analytical HPLC-MS (method D): RT=−1.07 min.
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=1)[OH:4].C1(=O)[NH:22]C(=O)C2=CC=CC=C12.[K]>CN(C)C=O.O>[NH2:22][CH2:2][CH:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=1)[OH:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OC(CBr)C1=CC2(CCCC2)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: NCC(O)C1=CC2(CCCC2)c2ccccc21

Procedure:
Crude 2-bromo-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol (7.3 g; prepared as described in Example 3) in dimethylformamide (100 g) is stirred at 40° C. for 4 hours with potassium phthalimide (5.0 g), then diluted with water and extracted three times with chloroform. The combined extracts are dried and evaporated to dryness. The crude 2-phthalimido-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol is added to ethanol (100 ml) containing hydrazine hydrate (1.5 g). The reaction mixture is stirred under reflux for 4 hours, concentrated hydrochloric acid (2 ml) is added, and the mixture is heated for 15 minutes. The solution is cooled, filtered from the solid precipitate and concentrated to a small volume. The concentrate is made alkaline with 2 N sodium hydroxide solution and repeatedly extracted with diethyl ether. Evaporation of the ether and crystallization of the residual product from cyclohexane gives 2-amino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol, m.p. 76°-78° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][CH2:6][CH:5]([CH2:8][NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:4][O:3]1.Cl[C:17]1[N:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.O.[NH2:28][NH2:29]>>[CH:10]1([N:9]([CH2:8][CH:5]2[CH2:4][O:3][C:2]([CH3:15])([CH3:1])[O:7][CH2:6]2)[S:23]([C:20]2[CH:21]=[N:22][C:17]([NH:28][NH2:29])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NN
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CC1(C)OCC(CNC2CCCC2)CO1
Solvent: O
Product: CC1(C)OCC(CN(C2CCCC2)S(=O)(=O)c2ccc(NN)nc2)CO1

Procedure:
The compound is prepared according to processes 14.1 and 5.2, starting with N-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]cyclopentanamine, 6-chloropyridine-3-sulfonyl chloride and hydrazine hydrate.