Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH2:22][CH3:23])[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([O:18][C:19](=O)[CH3:20])=[CH:12][CH:11]=3)(=O)[CH3:2].[ClH:24].[N:25]1(CC[Cl:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C[O-].[Na+]>ClC1C=CC=CC=1>[ClH:33].[ClH:24].[CH2:22]([N:9]1[C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:1][CH2:2][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([O:18][CH2:19][CH2:20][N:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)[CH:14]=2)[CH3:23]
Reactant: CCn1c2ccc(OC(C)=O)cc2c2cc(OC(C)=O)ccc21
Reactant: ClCCN1CCCCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Clc1ccccc1
Product: CCn1c2ccc(OCCN3CCCCC3)cc2c2cc(OCCN3CCCCC3)ccc21

Procedure:
A mixture of 15.5 g (0.05 mole) of N-ethyl-3,6-carbazolediol diacetate, 18.4 g (0.1 mole) of 2-piperidinoethylchloride hydrochloride, 10.8 g (0.2 mole) of sodium methoxide and 400 ml of chlorobenzene is refluxed for 24 hours. Upon cooling, the reaction mixture is filtered, and the filtrate is washed with several portions of water, dried over anhydrous magnesium sulfate, diluted with ether and acidified with ethereal HCl. The resulting precipitate is collected and recrystallized from methanol-ethyl acetate to give N-ethyl-3,6-bis(2-piperidinoethoxy)carbazole dihydrochloride, M.P. 248°-250°C.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([O:19][CH3:20])[CH:11]=2)[CH2:6][CH2:5]1>CCOC(C)=O.[Pd]>[F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([O:19][CH3:20])[CH:11]=2)[CH2:6][CH2:5]1
Reactant: COc1cc(C2=CCN(CCF)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(C2CCN(CCF)CC2)ccc1N
Reaction time: 72 h
Yield: 100 %

Procedure:
To 1-(2-fluoroethyl)-4-[3-(methyloxy)-4-nitrophenyl]-1,2,3,6-tetrahydropyridine (0.90 g, 3.2 mmol) in EtOAc (20 mL) was added Pd (10%) on carbon (100 mg). The reaction was evacuated then refilled with 10 psi H2 gas. The reaction was stirred for 3 days. The reaction was evacuated and the atmosphere replaced with N2. The solution was filtered to remove Pd/carbon and rotovaped down to give the title compound of step C as a red crystalline solid (800 mg, 3.2 mmol, 100% yield). 1H NMR (400 MHz, CDCl3) δ 6.69 (s, 1H), 6.66-6.64 (m, 2H), 4.70 (dd, J=5.1, 4.8 Hz, 1H), 4.58 (dd, J=5.1, 4.81 Hz, 1H), 3.83 (s, 3H), 3.69 (brs, 2H), 3.17-3.05 (m, 2H), 2.84-2.72 (m, 2H), 2.48-2.36 (m, 1H), 2.27-2.14 (m, 2H), 1.92-1.79 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7]([N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.[Na+].[I-:17].NCCN.N>O.[Cu]I.O1CCOCC1>[I:17][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7]([N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1
Reactant: Brc1ccc2[nH]c(N3CCCC3)nc2c1
Reactant: [I-]
Agent: [Cu]I
Agent: N
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: NCCN
Product: Ic1ccc2[nH]c(N3CCCC3)nc2c1
Temperature: 110 °C
Reaction time: 14 h

Procedure:
0.48 g (1.8 mmol) of 5-bromo-2-pyrrolidin-1-yl-1H-benzimidazole and 34 mg (0.18 mmol) of CuI are placed in a round flask. The reaction vessel is flushed with argon. Then 0.54 g (3.6 mmol) of NaI, 32 mg (0.36 mmol) of dimethylenediamine, and 3 mL of 1,4-dioxane are added under argon. The reaction mixture is stirred for 14 hours at 110° C. Subsequently, the cooled reaction mixture is combined with concentrated ammonia solution, diluted with water, and the precipitate formed is filtered off. The solid is stirred with methanol and again filtered. Yield: 0.3 g (53% of theoretical); C11H12IN3 (M=313.13); calc.: molpeak (M+H)+: 314; found: molpeak (M)+: 314.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]([OH:20])=[O:19])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]>C(OCC)(=O)C.[Pd]>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](c2ccc(C=CC(=O)O)cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC[C@H]1CC[C@H](c2ccc(CCC(=O)O)cc2)CC1

Procedure:
A solution of 12.6 g of 3-[4-(trans-4-propylcyclohexyl)-phenyl]-propenoic acid (obtained by condensation of 4-(trans-4-propylcyclohexyl)-benzaldehyde with malonic acid in pyridine) in 120 ml of ethyl acetate is hydrogenated at room temperature and atmospheric pressure, using 4 g of Pd/C (5% Pd) as catalyst. The catalyst is filtered off, and the filtrate is evaporated. Colorless crystals are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:24][N:25]=[C:26]=[O:27]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:18]2[CH2:23][CH2:22][N:21]([C:26]([NH:25][CH3:24])=[O:27])[CH2:20][CH2:19]2)[N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:26]([NH:25][CH3:24])=[O:27])=[CH:6][CH:7]=1
Reactant: Fc1ccc(C(NCCc2ccccc2)C2CCNCC2)cc1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)N1CCC(C(c2ccc(F)cc2)N(CCc2ccccc2)C(=O)NC)CC1
Yield: 79.1 %

Procedure:
A solution of 2.25 g (0.0072 mol) of α-(4-fluorophenyl)-N-(2-phenylethyl)-4-piperidinemethanamine and 2.50 g (0.044 mol) of methyl isocyanate in 200 mL of methylene chloride was stirred at room temperature overnight. The solvent was removed in vacuo to give a solid. This was triturated with anhydrous ether, and the solid was collected to give 2.43 g (79.1%) of white solid, mp 186°-188° C.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:8]=[CH:9][C:10]2[NH:16][C:15]3[N:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=[CH:20][C:14]=3[CH2:13][N:12]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:11]=2[CH:39]=1)([CH3:6])[C:3](O)=[O:4].[CH:40]([NH2:43])([CH3:42])[CH3:41]>>[CH:40]([NH:43][C:3](=[O:4])[C:2]([CH3:6])([C:7]1[CH:8]=[CH:9][C:10]2[NH:16][C:15]3[N:17]=[C:18]([C:21]([F:23])([F:22])[F:24])[CH:19]=[CH:20][C:14]=3[CH2:13][N:12]([S:25]([C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]([F:38])([F:36])[F:37])=[CH:32][CH:33]=3)(=[O:26])=[O:27])[C:11]=2[CH:39]=1)[CH3:1])([CH3:42])[CH3:41]
Reactant: CC(C)(C(=O)O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2
Reactant: CC(C)N
Product: CC(C)NC(=O)C(C)(C)c1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2

Procedure:
The title compound was prepared from 2-methyl-2-[6-{[4-(trifluoromethoxy)phenyl]sulfonyl}-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl]propanoic acid (Example 382) and isopropylamine using the procedure described in Example 516 to afford the title compound; Mass Spectrum: m/e=617 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:29]([C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[CH2:37][NH:36][CH2:35]2)([O-:31])=[O:30].FC(F)(F)C([O-])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11]([N:36]1[CH2:35][C:34]2[C:38](=[CH:39][CH:40]=[C:32]([N+:29]([O-:31])=[O:30])[CH:33]=2)[CH2:37]1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNC2
Reactant: CC(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(=O)N2Cc3ccc([N+](=O)[O-])cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
A solution of 2,4-bis-benzyloxy-5-isopropyl-benzoic acid (505 mg; 1.3 mmol) (Preparation B5), 5-nitroisoindoline, trifluoroacetate (360 mg; 1 equiv.), EDAC (300 mg; 1.2 equiv.), HOBt (210 mg; 1.2 equiv.) and NEt3 (270 μl; 1.5 equiv.) in DMF (10 ml) was stirred at room temperature overnight then evaporated in vacuo. The residue was partitioned between EtOAc and 2M HCl, the EtOAc layer was separated, washed with saturated NaHCO3, dried (MgSO4) and evaporated. Purification by flash column chromatography (1:4 then 1:2 then 1:1 EtOAc/P.E. as eluant) gave 460 mg of (2,4-bis-benzyloxy-5-isopropyl-phenyl)-(5-nitro-1,3-dihydro-isoindol-2-yl) methanone. MS: [M+H]+ 523.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:23])[CH2:5][S:6][C:7]=1[CH:8]1[CH:13]=[CH:12][N:11](C(OCC(Cl)(Cl)Cl)=O)[N:10]=[C:9]1[CH3:22].[S]>>[CH3:1][C:2]1[NH:3][C:4](=[O:23])[CH2:5][S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[N:10][C:9]=1[CH3:22]
Reactant: CC1=NN(C(=O)OCC(Cl)(Cl)Cl)C=CC1C1=C(C)NC(=O)CS1
Agent: [S]
Product: CC1=C(c2ccnnc2C)SCC(=O)N1
Yield: 36 %

Procedure:
A mixture of 5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-3-methyl-1,4-dihydro-4-pyridazinyl]-2H-1,4-thiazin-3(4H)-one (0.4 g) and sulfur sublimed (0.2 g) was treated in the same manner as described in Example 3 (ii) to give the titled compound (0.08 g, yield 36%) as white crystals. Chloroform-methanol (=20:1) was used as a developing eluant.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]CC.[Na+].[CH:12]12[O:18][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]2>C(O)C>[C:1]1([S:7][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[OH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: C1CCC2OC2C1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O[C@@H]1CCCC[C@H]1Sc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Thiophenol (2.14 g, 0.0194 mole) was added to freshly prepared sodium ethoxide (sodium, 0.45 g) in ethanol (30 ml). After several minutes, cyclohexene oxide was added, and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated with a gentle flow of nitrogen gas. The residue was dissolved in diethyl ether (75 ml) and washed with in hydrochloric acid (19 ml). The diethyl ether was washed three times with 50 ml of 5% sodium carbonate, once with 0.5N hydrochloric acid (50 ml) and once with brine (25 ml), dried over anhydrous magnesium sulphate, filtered and concentrated with a rotary evaporator to give the product as an oil. The structure was supported by NMR and infrared spectroscopy.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].NC(N)=[S:32].NCCNCCNCCNCCN>C1COCC1.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][SH:32])[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: NC(N)=S
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Agent: NCCNCCNCCNCCN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCS)c1CCC(=O)OCC
Yield: 81.1 %

Procedure:
To a solution of 4-[3-(6-Bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (5g, 10.60 mmol) in THF (100 mL), thiourea (0.889 g, 11.68 mmol) was added and heated to reflux overnight. According to HPLC analysis, the starting material was completely consumed. Tetraethylenepentamine (4.02 g, 2.7 mL, 21.23 mmol) was added and the reaction mixture was heated to reflux overnight. At this time, the reaction mixture was diluted with EtOAc (500 mL), washed with 3N HCl (100 mL), water brine and dried over Na2SO4. The solvent was removed in vacuo to afford an oil. FCC (2% EtOAc/Hex) provided an oil (3.65 g, yield 81%). 1H NMR (CDCl3): □ 7.09 (t, 1H), 6.75 (d, 1H), 6.69 (d, 1H), 4.18-4.08 (m, 4H), 3.99 (t, 2H), 2.95 (t, 2H), 2.64-2.46 (m, 8H), 2.13 (m, 2H), 1.67-1.39 (m, 8H), 1.27 (m, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH:17]([C:19]1[NH:23][C:22]([CH3:24])=[C:21]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:20]=1[CH3:30])=O>>[CH3:24][C:22]1[NH:23][C:19]([CH:17]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[NH:11][C:10]2=[O:16])=[C:20]([CH3:30])[C:21]=1[CH2:25][CH2:26][C:27]([OH:29])=[O:28]
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)c(C)c1CCC(=O)O

Procedure:
4-Pyridin-4-yl-1,3-dihydro-indol-2-one was condensed with 3-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid to give the title compound.
Reaction SMILES: C(OC1C=C(C(C)(C)O)C=C(C(C)(C)O)C=1)C1C=CC=CC=1.C([O:30][C:31]1[CH:32]=[C:33]([C:47]([CH2:53][CH2:54][CH2:55][CH3:56])([CH2:49][CH2:50][CH2:51][CH3:52])O)[CH:34]=[C:35]([C:37]([CH2:43][CH2:44][CH2:45][CH3:46])([CH2:39][CH2:40][CH2:41][CH3:42])O)[CH:36]=1)C1C=CC=CC=1>>[CH2:39]([CH:37]([C:35]1[CH:36]=[C:31]([OH:30])[CH:32]=[C:33]([CH:47]([CH2:49][CH2:50][CH2:51][CH3:52])[CH2:53][CH2:54][CH2:55][CH3:56])[CH:34]=1)[CH2:43][CH2:44][CH2:45][CH3:46])[CH2:40][CH2:41][CH3:42]
Reactant: CCCCC(O)(CCCC)c1cc(OCc2ccccc2)cc(C(O)(CCCC)CCCC)c1
Agent: CC(C)(O)c1cc(OCc2ccccc2)cc(C(C)(C)O)c1
Product: CCCCC(CCCC)c1cc(O)cc(C(CCCC)CCCC)c1

Procedure:
The procedure (including reaction and treatment) of Example 2 was repeated, except that 5-benzyloxy-α,α,α′,α′-tetramethyl-1,3-benzenedimethanol was replaced by 5-benzyloxy-α,α,a′,a′-tetrabutyl-1,3-benzenedimethanol, to thereby yield the above-described target as colorless needles. IR(film)cm−1: 3355, 2957, 2927, 1616, 1597. 1H-NMR(CDCl3)δ: 0.81(12H,t,J=7.3 Hz), 1.05-1.33(16H,m), 1.43-1.63(8H,m), 2.37(2H,t,J=9.1,5.1 Hz), 4.52(1H,s), 6.42(2H,s), 6.47 (1H,s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([N+:17]([O-])=O)[CH:11]=2)[CH:3]=1>[Ni].C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH2:17])[CH:11]=2)[CH:3]=1
Reactant: Cc1ccnc(NC(=O)c2ccc(N)c([N+](=O)[O-])c2)c1
Agent: [Ni]
Solvent: C1CCOC1
Product: Cc1ccnc(NC(=O)c2ccc(N)c(N)c2)c1

Procedure:
Prepared analogously to example 14b from the product obtained in 116b by hydrogenation using Raney nickel in THF at 3.5 bar.
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH3:31])[C:12]=1[C:13](=[O:30])[NH:14][C:15]1[CH:20]=[CH:19][N:18]2[CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:23]=[C:17]2[CH:16]=1)=[O:7])C>C(O)C>[CH3:31][N:11]1[C:12]([C:13](=[O:30])[NH:14][C:15]2[CH:20]=[CH:19][N:18]3[CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:23]=[C:17]3[CH:16]=2)=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[N:10]1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2cc(-c3ccccc3)nc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2cc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
KOH (1.67 g, 26 mmol) was added to a solution of 1-methyl-5-(2-phenyl-imidazo[1,2-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid ethyl ester (Example 10, 6.65 g, 17 mmol) in ethanol (150 ml) and the mixture was heated to reflux (4 h). The solvent was evaporated and water and ethanol (as little as needed to avoid sticky precipitate) was added. HCl (conc., 12 ml) was added, the white suspension was stirred for 30 min (r.t.) and filtered. The precipitated title compound (7.19 g, 99%) was isolated and dried under vacuum. MS (m/e)=362.2 [M+H+].
Reaction SMILES: [O-]S(S([O-])=O)=O.[Na+].[Na+].[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([F:26])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1COCC1.CCO>O>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([F:26])[CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
A solution of Na2S2O4 (34.8 g, 200 mmol) in H2O (200 mL) was added to a mixture of 4-(benzyloxy)-2-fluoro-1-nitrobenzene (16.0 g, 64.7 mmol), THF (150 mL), and EtOH (150 mL), and the mixture was stirred for 30 min at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane/AcOEt (1/1) to give the title compound (5.84 g, 42% yield) as a light brown oil: 1H NMR (300 MHz, CDCl3): δ ppm 3.42 (2H, brs), 4.97 (2H, s), 6.60 (1H, ddd, J=1.1, 2.6, 8.7 Hz), 6.67-6.74 (2H, m), 7.28-7.43 (5H, m).
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]1([C:11]#[C:12][C:13]2[CH:14]=[C:15]([CH:19]=[O:20])[CH:16]=[N:17][CH:18]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OCC)(=O)C>[C:5]1([C:11]#[C:12][C:13]2[CH:14]=[C:15]([CH2:19][OH:20])[CH:16]=[N:17][CH:18]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=Cc1cncc(C#Cc2ccccc2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Product: OCc1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add sodium cyanoborohydride (0.31 g, 4.98 mmol) to a solution of 5-phenylethynyl-pyridine-3-carbaldehyde, (prepared as described in EXAMPLE 5), (0.86 g, 4.15 mmol) and stir at room temperature for 2 h. Dilute with ethyl acetate, wash with an aqueous saturated solution of bicarbonate, dry (magnesium sulfate), filter and concentrate. Purify by silica gel chromatography, eluting with 0:100 to 50:50 ethyl acetate:hexanes, to give the title compound as a colorless oil which solidifies on standing (0.465 g, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1
Reactant: Clc1ccncc1
Reactant: COc1ccc(C=O)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CO
Product: COc1ccc(Cc2cnccc2Cl)cc1

Procedure:
4-Chloropyridine is treated sequentially with LDA (1.1 molar equivalents) and 4-methoxybenzaldehyde (1 molar equivalent). The resulting carbinol is isolated and deoxygenated with triethylsilane (10 molar equivalents) and 50% trifluoroacetic acid in methylene chloride to provide the title compound.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16](/[CH:20]=[CH:21]/[C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][C:26]([Cl:32])=[CH:27][CH:28]=4)[N:23]=3)[CH:15]=2)=[CH:6][CH:5]=1)#[N:2].[CH3:33]I.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClCCl.O>[C:1]([CH:3]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16](/[CH:20]=[CH:21]/[C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][C:26]([Cl:32])=[CH:27][CH:28]=4)[N:23]=3)[CH:15]=2)=[CH:6][CH:5]=1)[CH3:33])#[N:2]
Reactant: N#CCc1ccc2ccn(Cc3cccc(/C=C/c4ccc5ccc(Cl)cc5n4)c3)c2c1
Reactant: CI
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C#N)c1ccc2ccn(Cc3cccc(/C=C/c4ccc5ccc(Cl)cc5n4)c3)c2c1

Procedure:
A solution of 6-(cyanomethyl)-1-[3-{2(E)-(7-chloroquinolin-2-yl)ethenyl}benzyl]indole (Example 29b) (180 mg, 0.41 mmol), methyl iodide (77 μl, 1.24 mmol) and benzyl-triethyl-ammonium chloride (94 mg, 0.41 mmol) in dichloromethane (3 ml) was stirred with a solution of sodium hydroxide (1.5 g) in water (1.5 ml) heating under reflux for 2 hours. The mixture was diluted with dichloromethane and water and the aqueous layer was extracted with further dichloromethane. The combined solvent layer was dried and evaporated and the residue was chromatographed on silica in ethyl acetate-hexane (1:3). The resulting crude product was further purified by RP-HPLC on a C18 column (eluting with 85 methanol:15 water:0.1 acetic acid) followed by crystallisation from methanol-water.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([C:39](O)=[O:40])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([C:39]([N:14]2[CH2:13][C@H:12]([N:10]([C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:25])[CH3:11])[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15]2)=[O:40])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound rac-4-{(3S,4R)-3-(3,4-dichloro-phenyl)-4-[(4-fluoro-phenoxycarbonyl)-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using piperidine-1,4-dicarboxylic acid mono-tert-butyl ester instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as a yellow foam. MS m/e: 593.1 [M]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6]([Cl:15])[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:3]=1.[K].[C:23]1([CH2:29][CH2:30][S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CS(C)=O.O>[Cl:15][C:6]1[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:3]=[C:2]([NH:34][S:31]([CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:32])=[O:33])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1
Reactant: NS(=O)(=O)CCc1ccccc1
Reactant: Cc1ccc(-c2c(Cl)nc(-c3ccncc3)nc2Cl)cc1
Agent: [K]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccc(-c2c(Cl)nc(-c3ccncc3)nc2NS(=O)(=O)CCc2ccccc2)cc1
Yield: 21.8 %

Procedure:
A solution of 4,6-dichloro-2-(4-pyridyl)-5-(p-tolyl)-pyrimidine (1.5 g), 2-phenyl-ethanesulfonic acid amide potassium salt (1.44 g, Referential Example 1e) and Hunig's base (1 ml) in DMSO (20 ml) was stirred at rt for 24 h before it was diluted with water (150 ml) and extracted twice with diethyl ether. The aqueous layer was acidified with acetic acid. The precipitate was collected, and further purified by column chromatography on silica gel eluting with hexane:EA 1:1 to give 2-phenyl-ethanesulfonic acid (6-chloro-2-pyridin-4-yl-5-p-tolyl-pyrimidin-4-yl)-amide (480 mg) as a foam. LC-MS: tR=5.08 min, [M+1]+=465.13, [M−1]−=462.96.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[Cl-].COCP(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:35][C:36]([F:46])([F:45])[C:37]1[CH:44]=[CH:43]C(C=O)=[CH:39][CH:38]=1>O>[F:35][C:36]([F:46])([F:45])[C:37]1[CH:44]=[CH:43][C:2]([CH:1]=[CH:5][O:4][CH3:3])=[CH:39][CH:38]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: COC[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: O
Product: COC=Cc1ccc(C(F)(F)F)cc1
Reaction time: 3 h
Yield: 33.6 %

Procedure:
THF (1 l) was added to methoxymethyltriphenylphosphine chloride (128 g, 370 mmol), followed by adding to the mixture, potassium-t-butoxide (41.5 g, 370 mmol) at 0° C., stirring the mixture at the same temperature for 3 hours, dropwise adding to the reaction solution, a 500 ml THF solution of commercially available 4-trifluoromethylbenzaldehyde (50.0 g, 287 mmol), stirring the mixture at the same temperature for one hour, stirring it at room temperature for 3 hours, adding water (1.5 l) to the reaction solution, extracting the resulting product with ethyl acetate, washing the organic layer successively with a saturated aqueous solution of sodium bicarbonate and water, drying over magnesium sulfate, distilling off the solvent, purifying the resulting yellow solution according to column chromatography treatment using heptane/ethyl acetate (3:2) as a developing solvent, on silica gel, and distilling the purified substance under reduced pressure by means of Vigoureux tube, to obtain 1-trifluoromethyl-4-(2-methoxyvinyl)benzene (19.5 g, 96.5 mmol) (b.p. 93.5° C. under 9 Torr). Yield: 33.6%.