Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH:16]([C:18]3[CH:19]=[C:20]([N:27]([CH3:29])[CH3:28])[CH:21]=[C:22]4[C:26]=3[NH:25][N:24]=[CH:23]4)[CH3:17])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:30]([BH3-])#N.[Na+].C=O>C(#N)C.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH:16]([C:18]3[CH:19]=[C:20]([N:27]([CH3:28])[CH3:29])[CH:21]=[C:22]4[C:26]=3[NH:25][N:24]=[CH:23]4)[CH3:17])[CH2:13][CH2:12][N:11]([CH3:30])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(OCC1(c2ccc(F)cc2)CCNCC1)c1cc(N(C)C)cc2cn[nH]c12
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(N(C)C)cc2cn[nH]c12
Reaction time: 2 h

Procedure:
To a suspension of (±)-7-(1-((4-(4-fluorophenyl)piperidin-4-yl)methoxy)ethyl)-N,N-dimethyl-1H-indazol-5-amine (101 mg, 0.255 mmol) and sodium cyanoborohydride (80 mg, 1.27 mmol) in acetonitrile (6 mL) at 0° C. was added formalin (0.053 mL). The reaction was treated with 5 drops of acetic acid and the ice bath was removed, stirring continued for 2 h. The reaction was concentrated and purified by preparative HPLC to give 78.5 mg (75%). 1H-NMR (CDCl3, 500 MHz) δ 8.17 (s, 1H), 7.90 (s, 1H), 7.38 (s, 1H), 7.23 (m, 3H), 7.10 (m, 2H), 4.66 (q, J=5.0 Hz, 1H), 3.50-3.57 (m, 2H), 3.39 (d, J=10 Hz, 1H), 3.27 (s, 6H), 3.18 (d, J=10 Hz, 1H), 2.74 (s, 3H), 2.50-2.73 (m, 4H), 2.35-2.45 (m,2H), 1.51 (d, J=5.0 Hz, 3H); Mass spec.: 411.45 (MH)+.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.[N:29]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:35][C:32]1[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=1)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Reactant: O=Cc1ccncc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cnc2c(c1)CCCC2N(Cc1ccncc1)Cc1nc2ccccc2[nH]1
Reaction time: 18 h
Yield: 70.2 %

Procedure:
Following General Procedure B: To a solution of (1-tert-butoxycarbonyl-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine (120 mg, 0.32 mmol) and 4-pyridinecarboxaldehyde (30 μL, 0.32 mmol) in CH2Cl2 (5 mL) was added sodium triacetoxyborohydride (136 mg, 0.64 mmol) and the reaction stirred for 18 h. The resulting crude material was taken up in neat TFA (1 mL) and stirred 3 h. Saturated aqueous sodium bicarbonate (5 mL) was added, and the resulting mixture was extracted with CH2Cl2 (3×10 mL) then the combined organic extracts were dried (MgSO4), and concentrated in vacuo. Purification of the crude material by radial chromatography (1 mm plate, 50:1:1 CH2Cl2-MeOH—NH4OH) afforded the title compound (83 mg, 70%) as a white solid. 1H NMR (CDCl3) δ 1.68-1.72 (m, 1H), 1.97-2.06 (m, 2H), 2.26-2.30 (m, 1H), 2.74-2.77 (m, 1H), 2.80-2.86 (m, 1H), 3.77 (s, 2H), 3.92 (d, 1H, J=16 Hz), 4.09 (dd, 1H, J=9.7 Hz), 4.17 (d, 1H, J=16 Hz), 7.18-7.22 (m, 3H), 7.36 (d, 2H, J=6 Hz), 7.44 (dd, 1H, J=7.1 Hz), 7.52 (br d, 1H, J=7 Hz), 7.66 (br d, 1H, J=7 Hz), 8.46 (dd, 2H, J=5.2 Hz), 8.70 (dd, 1H, J=5.1 Hz); 13C NMR (CDCl3) δ 21.2, 23.8, 29.0, 49.1, 53.0, 60.5, 110.9, 118.8, 121.4, 121.9, 122.5, 123.3, 133.7, 134.7, 137.4, 144.2, 146.9, 148.7, 149.8, 155.4, 156.9. ES-MS m/z 370 (M+H). Anal. Calcd. for C23H23N5.0.2H2O.0.2CH2Cl2: C, 71.44; H, 6.15; N, 17.95. Found: C, 71.63; H, 6.30; N, 17.77.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([S:13][CH2:14][C:15](OC)=[O:16])=[N:6][CH:5]=1>C(O)(=O)C.[Fe]>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[N:6][C:7]2[S:13][CH2:14][C:15](=[O:16])[NH:10][C:8]=2[CH:9]=1)=[O:19]
Reactant: COC(=O)CSc1ncc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)c1cnc2c(c1)NC(=O)CS2
Temperature: 60 °C
Yield: 108.5 %

Procedure:
The ester (a) (1.0 g) in acetic acid (50 ml) was treated with iron powder (10 g) and the mixture was stirred and heated at 60° C. for 1 hour, cooled and filtered. The filtrate was evaporated, treated with sodium bicarbonate solution and extracted with warm chloroform. It was dried over sodium sulfate and evaporated to give a white solid (0.85 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1.[N+:14]([CH3:17])([O-:16])=[O:15].CN(C)C(=N)N(C)C>C(OCC)C.Cl>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH:5]([C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[CH:10][CH:11]=1)[CH2:17][N+:14]([O-:16])=[O:15]
Reactant: COC(=O)C=Cc1ccc(C)cc1
Reactant: C[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CCOCC
Product: COC(=O)CC(C[N+](=O)[O-])c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture to 300 g of p-methylcinnamic acid methyl ester, 500 g of nitromethane and 39 g of tetramethylguanidine is allowed to stir at room temperature for 72 hours. The solution is diluted with diethyl ether and (1 liter, 1 N) aqueous hydrochloric acid solution added. The organic layer is separated, dried over anhydrous magnesium sulfate, and evaporated to give 4-nitro-3-(4-methylphenyl) butanoic acid methyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:19]([OH:21])=[O:20])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22](O)[CH:23]=[CH2:24].C(Cl)CCl.C(OCC)(=O)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:24]([O:20][C:19](=[O:21])[C@@H:9]([CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:23]=[CH2:22]
Reactant: C=CCO
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCOC(=O)[C@@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
N-(t-Butoxycarbonyl)-O-benzyl-D-serine (600 mg; 2.03 mmol) was dissolved in dry methylene chloride (5 ml), allyl alcohol (152 μl; 2.23 mmol) and DMAP (25 mg; 0.20 mmol) added and finally EDC (428.5 mg; 2.24 mmol) added to the acid. The reaction mixture was stirred at room temperature for 2.5 h and the resulting homogeneous solution quenched with water and extracted with methylene chloride. The methylene chloride layer was washed with 5% aqueous citric acid then 10% aqueous sodium carbonate solution. The methylene chloride layer was dried over anhydrous magnesium sulfate powder, filtered and evaporated under reduced pressure to give an oil. Chromatography of the oil using ethyl acetate and hexanes 1:2 v/v afforded the product (408 mg; 60%) as a pale yellow gum. FAB-MS:- Calculated for C36H33N5 335.1; found 336.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[N:6]2[CH2:9][CH2:10][CH2:11][CH2:12][C:5]2=[N:4][C:3]=1[C:13]([O:15]C)=O.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>CO>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:13]([C:3]2[N:4]=[C:5]3[CH2:12][CH2:11][CH2:10][CH2:9][N:6]3[C:7](=[O:8])[C:2]=2[OH:1])=[O:15])=[CH:20][CH:19]=1
Reactant: COC(=O)c1nc2n(c(=O)c1O)CCCC2
Reactant: NCc1ccc(F)cc1
Solvent: CO
Product: O=C(NCc1ccc(F)cc1)c1nc2n(c(=O)c1O)CCCC2
Temperature: 65 °C

Procedure:
A solution of methyl 3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate obtained in Step 3b or Step 5a and 4-fluoro-benzylamine (2 eq.) in methanol was stirred and heated to 65° C. for 22 h. The solvent was removed under reduced pressure and the title product was obtained by preparative RP-HPLC, using water (0.1% TFA) and acetonitrile (0.1% TFA) as eluents (column: C18). The pooled product fractions were lyophilized to afford the title compound as a fluffy white material.
Reaction SMILES: [Na].[CH3:2][Si](C)(C)N[Si](C)(C)C.[C:11]([O:15][C:16]([N:18]1[C@@H:22]([CH2:23][C:24]2([CH:27]=O)[CH2:26][CH2:25]2)[CH2:21][O:20][C:19]1([CH3:30])[CH3:29])=[O:17])([CH3:14])([CH3:13])[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:11]([O:15][C:16]([N:18]1[C@@H:22]([CH2:23][C:24]2([CH:27]=[CH2:2])[CH2:25][CH2:26]2)[CH2:21][O:20][C:19]1([CH3:30])[CH3:29])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2(C=O)CC2)COC1(C)C
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na]
Solvent: C1CCOC1
Product: C=CC1(C[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
27.05 g of sodium-hexamethyldisilazane are added in portions to a suspension of 52.7 g of methyltriphenylphosphonium bromide in 470 ml of tetrahydrofuran in the course of 10 min. 20.9 g of 3-tert-butoxycarbonyl-2,2-dimethyl-4(S)-[(1-formylcyclopropyl)methyl]-1,3-oxazolidine are added dropwise to this mixture at 5° C. in the course of 10 min, and after warming to room temperature, the mixture is stirred for 1 h. The mixture is poured onto ice-water and the aqueous phase is extracted with methylene chloride. The title compound is purified by means of FC over 900 g of silica gel (mobile phase G): Rf (G)=0.56.
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:5]=1)=[C:2]=[S:3].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2([C:28]#[N:29])[CH2:27][CH2:26][CH2:25]2)=[CH:19][CH:18]=1>CN(C=O)C>[NH:29]=[C:28]1[C:24]2([CH2:27][CH2:26][CH2:25]2)[N:23]([C:20]2[CH:19]=[CH:18][C:17]([CH3:16])=[CH:22][CH:21]=2)[C:2](=[S:3])[N:1]1[C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:13])([F:15])[F:14])[CH:5]=1
Reactant: Cc1ccc(NC2(C#N)CCC2)cc1
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=N)C23CCC3)cc1
Reaction time: 4 h
Yield: 52 %

Procedure:
To a solution of 1a (2.28 g, 10 mmol) in dry DMF (3 ml) was added progressively, over 20 hours, a solution of 7a (1.764 g, 9 mmol) in dry DMF (3 ml) at room temperature. The medium was stirred for an additional 4 h. After DMF being evaporated, the residue was chromatographed (dichloromethane/acetone, 95:5) to afford 4-(8-imino-6-thioxo-5-(4-methylphenyl)-5,7-diazaspiro[3.4]oct-7-yl)-2-trifluoromethylbenzonitrile, 7b (1.937 g, 4.68 mmol, 52%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.C[Al](C)C.C([O:15][C:16]([C:18]1[N:19]=[C:20]([CH3:31])[S:21][C:22]=1[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.O>[C:27]([O:26][C:24](=[O:25])[NH:23][C:22]1[S:21][C:20]([CH3:31])=[N:19][C:18]=1[C:16](=[O:15])[NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: Cc1cc(N)ccn1
Reactant: CCOC(=O)c1nc(C)sc1NC(=O)OC(C)(C)C
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(NC(=O)c2nc(C)sc2NC(=O)OC(C)(C)C)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A solution of 2-methyl-pyridin-4-ylamine (0.623 g, 5.77 mmol) in 20 ml dry dioxane was treated at 0° C. with trimethylaluminium (2M in hexane, 2.88 ml, 5.77 mmol). The mixture was stirred at room temperature for 1 h. 5-tert-Butoxycarbonylamino-2-methyl-thiazole-4-carboxylic acid ethyl ester (0.55 g, 1.92 mmol) was added and the reaction mixture was refluxed for 4 h. 1 ml water and 2 g sodium sulfate were sequentially added and filtered. The filtrate was evaporated and the residue purified by flash chromatography on silica gel with heptane/ethyl acetate 100:0→0:100 to yield [2-methyl-4-(2-methyl-pyridin-4-ylcarbamoyl)-thiazol-5-yl]-carbamic acid tert-butyl ester (0.555 g, 83%) as a light yellow solid, MS (ISP): m/e=349.5 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[C:7](/[CH2:17][CH3:18])=[CH:8]/[CH2:9][CH2:10][C:11]([CH2:15][CH3:16])([OH:14])[CH2:12][CH3:13])[S:5][CH:6]=1.CN(C1C=CC=CN=1)C.C(N(CC)CC)C.FC(F)(F)S(O[Si:41]([CH2:46][CH3:47])([CH2:44][CH3:45])[CH2:42][CH3:43])(=O)=O>ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4](/[C:7](/[CH2:17][CH3:18])=[CH:8]/[CH2:9][CH2:10][C:11]([CH2:15][CH3:16])([CH2:12][CH3:13])[O:14][Si:41]([CH2:46][CH3:47])([CH2:44][CH3:45])[CH2:42][CH3:43])[S:5][CH:6]=1
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Reactant: CC/C(=C\CCC(O)(CC)CC)c1cc(Br)cs1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC/C(=C\CCC(CC)(CC)O[Si](CC)(CC)CC)c1cc(Br)cs1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
11.8 g (35.6 mmol) of (E)-7-(4-bromo-2-thienyl)-3-ethylnon-6-en-3-ol are dissolved in 150 mL of dichloromethane. 130 mg (1.1 mmol) of dimethylaminopyridine and 14.9 mL (107 mmol) of triethylamine are added. The reaction medium is cooled to 0° C. and 12.1 mL (53.4 mmol) of triethylsilyl trifluoromethanesulphonate are added dropwise. The medium is warmed to room temperature and stirred for 15 minutes, after which it is poured into 150 mL of water and extracted with dichloromethane. After chromatography on silica gel (eluent: heptane), the desired product is obtained in the form of a colourless oil (m=15 g; Y=100%).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8]C2C=CC(Cl)=C(NC(=O)C3C=CC=CC=3F)C=2)=[O:7])=[CH:4][N:3]=1.CC1CNCC(C)N1>>[C:6]([NH2:8])(=[O:7])[C:5]1[CH:26]=[CH:27][CH:2]=[N:3][CH:4]=1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2F)c1)c1ccc(Cl)nc1
Agent: CC1CNCC(C)N1
Product: NC(=O)c1cccnc1

Procedure:
6-chloro-N-(4-chloro-3-(2-fluorobenzamido)phenyl)nicotinamide (0.177 mmol) was used in general procedure 3 with 2,6-dimethylpiperazine (0.70 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(2-fluorobenzamido)phenyl))-6-(3S,5R)-3-5-dimethylpiperazine-1-yl)nicotinamide. MS (Q1) 482.1 (M)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C(Cl)(Cl)(Cl)[Cl:12]>>[Cl:12][C:8]1[N:6]2[N:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Clc1ccc2nccn2n1
Reactant: ClC(Cl)(Cl)Cl
Product: Clc1ccc2ncc(Cl)n2n1

Procedure:
6-Chloroimidazo[1,2-b]pyridazine (7.68 g) was added to 150 ml of carbon tetrachloride, to which 7.0 g of N-chlorossuccinimide were added and refluxed for 2 hours. After cooling, the precipitated crystals were filtered off. The filtrate was washed in turn with 1N-sodium hydroxide aqueous solution, 1N-hydrochloric acid and water, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was washed with diethyl ether to obtain 7.13 g of 3.6-dichloroimidazo[1,2-b]pyridazine.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[I:11].Cl.[CH3:13]O>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:13])=[O:7])=[CH:4][C:3]=1[I:11]
Reactant: CO
Reactant: O=C(O)c1ccc(O)c(I)c1
Agent: Cl
Product: COC(=O)c1ccc(O)c(I)c1
Temperature: 65 °C
Yield: 36.3 %

Procedure:
4-Hydroxy-3-iodobenzoic acid (59.6 g, 226 mmol) is combined with 3N HCl/MeOH (276 mL, 678 mmol) and heated to 65° C. for 24 h, then concentrated to dryness. The residue is diluted with water, neutralized to pH 7 with 3N NaOH and the resulting solid collected via filtration. The crude material is adsorbed onto silica gel and chromatographed over 1 kg of silica gel with 50% EtOAc/hexane. Fractions containing product are combined and concentrated to a solid (47.2 g). The material is recrystallized from EtOAc to afford 22.8 g (36%) of methyl 4-hydroxy-3-iodobenzoate as a white solid. HRMS (FAB) calcd for C8H7IO3+H: 278.9520, found 278.9534 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[Li]CCCC.CN([CH:20]=[O:21])C>CCOCC>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH:20]=[O:21])[CH:7]=1
Reactant: FC(F)(F)c1ccnc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1cc(C(F)(F)F)ccn1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To 2-bromo-4-(trifluoromethyl)pyridine (700 mg, 3.1 mmol) in ether (30 ml) at −78° C., BuLi (1.6M in hexanes, 2.13 ml) was added. After 40 min, DMF (340 mg) was added and the reaction mixture was stirred at −78° C. for a further 45 minutes and the reaction mixture was allowed to come to rt over a period of 1 h. Then the reaction mixture was quenched with solid ammonium chloride and partitioned between water and ether. Organic layers were dried and evaporated to provide 4-(trifluoromethyl)picolinaldehyde as a crude residue which was carried to the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17](Br)[CH:16]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2].[C:29]1([C:35]#[CH:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:16]=[C:17]([C:36]#[C:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:18]=[C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:20]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2]
Reactant: C#Cc1ccccc1
Reactant: CCOC(=O)COc1ccc(SCc2cc(Br)cc(OCC(C)C)c2)cc1C
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(SCc2cc(C#Cc3ccccc3)cc(OCC(C)C)c2)cc1C

Procedure:
The title product was prepared from [4-(3-Bromo-5-isobutoxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (300 mg; 0.64 mmol) and phenylacetylen (262 mg; 2.6 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 130 mg (45%). HPLC-MS: m/z: 489.1 (M+H)+; Rt: 3.01 min
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1)[CH3:2].[OH-].[K+].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1>CN1CCCC1=O.O>[CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([CH3:19])=[CH:25][CH:24]=3)[C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: C=Cc1ccc(C)nc1
Reactant: CCc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.4 %

Procedure:
To a solution of 8-Ethyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.107 g, 0.5 mmol) in N-methyl 2-pyrolidone (2 mL) was added powdered potassium hydroxide (0.224 g, 4.0 mmol) and allowed to stir for 10 min at RT. 2-methyl-5-vinyl pyridine (0.065 g, 0.55 mmol) was added and stirred for further 24 h. at 120 deg C., After completion of TLC, Reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (8% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide the desired compound as brown oil (0.034 g, 20% yield). 8-Ethyl-2-methyl-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.034 g, 0.102 mmol) was dissolved in THF (0.5 mL). A solution of oxalic acid dihydrate (0.013 g, 0.102 mol) in THF (0.5 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.015 g, 32% yield).
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[N:8]([CH3:11])[C:7](=[O:12])[N:6]([CH3:13])[C:5]1=[O:14])(=O)[CH3:2].[CH2:15]([O:17][NH2:18])[CH3:16]>C(O)C>[CH2:15]([O:17][NH:18][C:1](=[C:4]1[C:9](=[O:10])[N:8]([CH3:11])[C:7](=[O:12])[N:6]([CH3:13])[C:5]1=[O:14])[CH3:2])[CH3:16]
Reactant: CC(=O)C1C(=O)N(C)C(=O)N(C)C1=O
Reactant: CCON
Solvent: CCO
Product: CCONC(C)=C1C(=O)N(C)C(=O)N(C)C1=O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
1.5 g of 5-acetyl-1,3-dimethylbarbituric acid was dissolved in 50 ml of ethanol and 1.5 ml of ethoxyamine was added to it. After the resulting solution was stirred at 40° C during 2 hours, it was allowed to stand at a room temperature. The separated white plates were filtered and recrystallized from ethanol, and thereby 1.4 g of the desired compound was obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]([C:12]1[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=1)[C:7]1[NH:8][CH:9]=[CH:10][N:11]=1)[CH3:3].O.[NH2:23][NH2:24]>C(O)C>[CH3:1][N:2]([CH2:4][CH2:5][CH:6]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([NH:23][NH2:24])=[O:17])=[CH:14][CH:13]=1)[C:7]1[NH:8][CH:9]=[CH:10][N:11]=1)[CH3:3]
Reactant: COC(=O)c1ccc(C(CCN(C)C)c2ncc[nH]2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CN(C)CCC(c1ccc(C(=O)NN)cc1)c1ncc[nH]1

Procedure:
A solution of 4-[3-(N,N-dimethylamino)-1-(imidazol-2-yl)propyl]benzoic acid, methyl ester (3.0 g) and hydrazine hydrate (12.5 ml) in ethanol (50 ml) was boiled under reflux for 1 day. Removal of the solvent gave a white solid which was recrystallised from isopropanol-ether to give the title compound, m.p. 168°-170° (2.46 g).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH:14]3[CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]1([CH2:31][CH:32]=O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([BH3-])#N.[Na+]>CO.CC(O)=O>[C:25]1([CH2:31][CH2:32][N:16]2[CH2:17][CH:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:14]([CH2:13][N:10]3[CH2:9][CH2:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:12][CH2:11]3)[CH2:15]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=CCc1ccccc1
Reactant: c1ccc(C2CCN(CC3CNCC3c3ccccc3)CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(CCN2CC(CN3CCC(c4ccccc4)CC3)C(c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.1 %

Procedure:
A mixture of 50 mg (0.16 mmol) 3-(SR)-((4-phenyl)piperidin-1-yl)methyl-4-(SR)-phenylpyrrolidine (from Example 30, Step A) and 37 mg (0.31 mmol) of phenylacetaldehyde and 100 mg 4 A powdered molecular sieves in 3 mL of MeOH was treated with 18 mg (0.28 mmol) of sodium cyanoborohydride and 2 drops of HOAc and stirred at rt for 18 h. The mixture was filtered onto a pad of Celite; the pad and flask were rinsed well with MeOH (25 mL). The filtrate was concentrated in vacuo and the residue was partitioned between 25 mL of EtOAc and 15 mL of sat'd NaHCO3 and the layers were separated. The organic layer was dried over MgSO4 and concentrated in vacuo. Flash chromatography on 15 g of silica gel using 2:1 v/v hexanes/EtOAc afforded 32 mg (48%) of the title compound as an oil. 1H NMR (500 MHz, CDCl3): δ1.66-2.04 (6H), 2.42-3.13 (15H), 7.20-7.37 (15H). Mass Spectrum (NH3 -CI): 427 (M+1).
Reaction SMILES: [CH2:1]([CH2:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](=O)([O-])[O-].[K+].[K+].[Cl:16]C[C:18]1[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[CH:22][C:23]=1[CH2:24]Cl.Cl>CC(C)=O.O>[Cl-:16].[CH2:1]([CH:8]1[C:18]2[C:23](=[CH:22][C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)[CH2:24][NH+:9]1[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(CCl)c(CCl)cc1OC
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc2c(cc1OC)C(Cc1ccccc1)[NH+](C)C2
Product: [Cl-]
Reaction time: 18 h

Procedure:
1.33 g (11 mmol) of N-benzylmethylamine and 2.07 g (15 mmol) of potassium carbonate were suspended in 24 ml of acetone, and 2.35 g (10 mmol) of 4,5-bis(chloromethyl)veratrol was added thereto at room temperature. The mixture was stirred for 18 hours. After cooling, the precipitate was collected by filtration, washed with 10 ml of acetone and dried in air to obtain 5.03 g (purity: 53%) of a white powder of the above identified compound containing inorganic substance. This powder was dissolved in 20 ml of water. Then, the solution was adjusted to pH 2.8 with 2N hydrochloric acid and subjected to HP-20 (50 ml). Elution was conducted with water, and a fraction containing the desired product was collected. The solvent was distilled off, and 10 ml of acetone was added to the oily residue. The mixture was left to stand overnight. The precipitated crystals were collected by filtration and washed with 10 ml of acetone to obtain 720 mg of the above identified compound as colorless needle crystals.