Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]([C:10]3[CH:11]=[C:12]([CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=4)[CH:18]=3)[C:13](O)=[O:14])=[CH:8][CH:7]=[N:6]2)[CH2:3][CH2:2]1.[CH3:26][C:27]1[N:28]=[CH:29][C:30]([CH2:33][NH2:34])=[N:31][CH:32]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>ClCCl>[CH:1]1([CH2:4][N:5]2[C:9]([C:10]3[CH:11]=[C:12]([CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=4)[CH:18]=3)[C:13]([NH:34][CH2:33][C:30]3[CH:29]=[N:28][C:27]([CH3:26])=[CH:32][N:31]=3)=[O:14])=[CH:8][CH:7]=[N:6]2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3ccnn3CC3CC3)c2)nc1
Reactant: Cc1cnc(CN)cn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)cn3)cc(-c3ccnn3CC3CC3)c2)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.7 %

Procedure:
3-(2-Cyclopropylmethyl-2H-pyrazol-3-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid (0.120 g, 0.36 mmol), C-(5-methyl-pyrazin-2-yl)-methylamine (0.044 g, 0.36 mmol), EDCI (0.103 g, 0.54 mmol), HOBt (0.073 g, 0.54 mmol), and NMM (0.183 g, 1.80 mmol) were added to 7 mL of dichloromethane. The reaction mixture was stirred for 48 hours at room temperature, then concentrated under reduced pressure. The residue was purified via flash chromatography (5:1 EtOAc/hexanes) to give 0.14 g of 3-(2-cyclopropylmethyl-2H-pyrazol-3-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide, MS (M+H)=439.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([N:12]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[O:11].[CH3:28][N:29](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:28]([C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([N:12]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[O:11])#[N:29]
Reactant: COC(CN(C(=O)CCOCCc1cccc(Br)c1)C1CCCCC1)OC
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(CN(C(=O)CCOCCc1cccc(C#N)c1)C1CCCCC1)OC
Temperature: 130 °C
Reaction time: 1 h

Procedure:
To 3-(3-bromophenethoxy)-N-cyclohexyl-N-(2,2-dimethoxyethyl)propanamide (4 g) [Preparation 3] in DMF (30 mL) was added zinc cyanide (1.59 g) and Pd(Ph3P)4 (0.52 g). The reaction flask was flushed with nitrogen then heated to 130° C. with stirring under nitrogen for 1 h. The reaction was worked up by the addition of ethyl acetate, which was washed three times with water, twice with brine, dried over sodium sulphate, filtered and the solvent removed to afford crude product as a yellow oil/gum. Further purification on silica eluting with 10-40% ethyl acetate/isohexane afforded the sub-titled compound as a pale yellow oil (3.44 g). MS [M+H-MeOH]+=357 (MultiMode+)
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:8]([CH3:21])[CH:7]=1.[CH3:23]I>CN(C)C=O>[CH3:3][O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH3:23])=[C:8]([CH3:21])[CH:7]=1
Reactant: CI
Reactant: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(C)C(=O)OC(C)(C)C)c(C)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Add in portions of 60% sodium hydride dispersion in oil (472 mg, 11.81 mmol) to 4-(tert-butoxycarbonylamino-methyl)-3-methyl-benzoic acid methyl ester (3.0 g, 10.74 mmol) in anhydrous dimethylformamide (50 mL) at 0° C. under argon gas. After complete addition, stir the reaction mixture for 15 min at 0° C. Add methyl iodide (735 μL, 11.8 mmol) to the reaction mixture. Allow the reaction mixture to warm-up to room temperature and stir overnight. Quench the reaction mixture with saturated aqueous ammonium chloride and extract with ethyl acetate (3×). Combine the organic layers, wash with brine, dry over sodium sulfate, and concentrate. Purify the residue by chromatography (silica gel) eluting with 25% ethyl acetate/hexane to give the title compound. MS (m/z): 316 (M+23).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[O:3]1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1.O>CN(C=O)C>[Si:14]([O:1][CH:2]1[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[O:3]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: OC1CC[C@@H](c2ccc(F)cc2)O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CC[C@@H](c2ccc(F)cc2)O1
Reaction time: 8 h
Yield: 96.4 %

Procedure:
(5S)-2-Hydroxy-5-(4-fluorophenyl) tetrahydrofuran (211, 620 mg, 3.5 mmol), t-butyldimethylsilyl chloride (700 mg, 5.25 mmol) and imidazole (595 mg, 8.75 mmol) were dissolved in 2 mL of dry DMF. The resulting solution was stirred under dry argon overnight, poured into 200 mL of water, and extracted with a 2:1-mixture of ethyl acetate and hexane (3×100 mL). The combined organic extracts were washed with water (4×200 mL) and brine (100 mL), dried over sodium sulfate and the solvent was removed in vacuo to yield 1 g (96%) of (5S)-2-(t-Butyldimethylsilyloxy)-5-(4-fluorophenyl) tetrahydrofuran (212, mixture of cis and trains isomers) as a colorless oil, which did not need further purification. 1H-NMR (CDCl3) δ 7.40-7.50(2H, m, minor isomer), 7.25-7.35 (2H, m, major isomer), 7.00-7.10 (2H, m, both major and minor isomers), 5.71-5.75 (1H, m, major isomer), 5.59-5.62 (1H, m, minor isomer), 5.12-5.20 (1H, m, major isomer), 4.90-4.98 (1H, m, minor isomer), 2.40-2.55 (1H, m, both major and minor isomers), 2.05-2.17 (1H, m, both major and minor isomers), 1.87-2.00 (1H, m, both major and minor isomers), 1.67-1.70 (1H, m, both major and minor isomers), 0.92 (s, 9H, both major and minor isomers), 0.16 (s, 6H, both major and minor isomers).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([I:19])[S:18][C:11]=12)[NH2:5].[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:32](=[O:33])[C:31]([C:34](O)=[O:35])=[CH:30][CH:29]=[N:28]2)=[CH:23][CH:22]=1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:34]([C:31]2[C:32](=[O:33])[N:27]([C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)[N:28]=[CH:29][CH:30]=2)=[O:35])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([I:19])[S:18][C:11]=12
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A round-bottomed flask was charged with 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A, 1.00 g, 2.59 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (0.728 g, 3.11 mmol, example 104, step C), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.596 g, 3.11 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (0.420 g, 3.11 mmol), N-ethyl-N-isopropylpropan-2-amine (0.669 g, 5.178 mmol) and DMF (50 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (200 mL) and H2O (200 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×200 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (1.34 g, 85.8%). LRMS (APCI pos): >99% purity, 254 nm, m/e 603 (M+1). 1H NMR (400 MHz, CDCl3) δ 11.85 (s, 1H), 8.43 (m, 2H), 8.24 (d, 1H), 7.96 (dd, 1H), 7.77 (s, 1H), 7.60 (m, 2H), 7.40 (m, 1H), 7.21-7.28 (m, 3H), 6.48 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[O:6][CH2:7][CH2:8][N:9]1[CH2:17][CH2:16][CH:15]2[NH:18][CH:11]([CH2:12][CH2:13][CH2:14]2)[C:10]1=[O:19].CCN(C(C)C)C(C)C.[O:34]=[C:35]1[NH:39][C:38]2[CH:40]=[CH:41][C:42]([S:44](Cl)(=[O:46])=[O:45])=[CH:43][C:37]=2[S:36]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[O:6][CH2:7][CH2:8][N:9]1[CH2:17][CH2:16][CH:15]2[N:18]([S:44]([C:42]3[CH:41]=[CH:40][C:38]4[NH:39][C:35](=[O:34])[S:36][C:37]=4[CH:43]=3)(=[O:46])=[O:45])[CH:11]([CH2:12][CH2:13][CH2:14]2)[C:10]1=[O:19]
Reactant: O=c1[nH]c2ccc(S(=O)(=O)Cl)cc2s1
Reactant: COc1ccc(OCCN2CCC3CCCC(N3)C2=O)cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(OCCN2CCC3CCCC(C2=O)N3S(=O)(=O)c2ccc3[nH]c(=O)sc3c2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(2-(3,4-Dimethoxyphenoxy)ethyl)-3,10-diazabicyclo[4.3.1]decan-2-one (15 mg, 0.05 mmol) in 3 ml DCM was treated with DIPEA (12 mg, 0.09 mmol) and stirred for 30 min at room temperature followed by addition of 2-oxo-2,3-dihydrobenzo[d]thiazole-6-sulfonyl chloride (22 mg, 0.09 mmol). After stirring overnight at room temperature, the reaction was quenched with saturated NH4Cl solution (5 ml), extracted with DCM (4×10 ml). The organic layers were dried over MgSO4 and concentrated in vacuo. The mixture was purified with Preparative-HPLC in 55-65% buffer B in 16 mins.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:3]1.[Cl:13][C:14]1[CH:23]=[C:22]([C:24](Cl)=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1>C(Cl)(Cl)Cl>[CH:7]1([N:4]2[CH2:5][CH2:6][CH:2]([NH:1][C:24]([C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:14]([Cl:13])[CH:23]=3)=[O:25])[CH2:3]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: NC1CCN(C2CCCCC2)C1
Reactant: O=C(Cl)c1cc(Cl)nc2ccccc12
Solvent: ClC(Cl)Cl
Product: O=C(NC1CCN(C2CCCCC2)C1)c1cc(Cl)nc2ccccc12

Procedure:
To 3.16 gm. (0.0195mole) of 3-amino-1-cyclohexylpyrrolidine in 50 ml. of chloroform was added dropwise a solution of 3.5 gm. (0.015 mole) of 2-chloro-4-quinolinecarbonyl chloride in 50 ml. of chloroform. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate containing 10% isopropyl ether and dilute hydrochloric acid. The separated acid layer was made basic with dilute sodium hydroxide solution and extracted with chloroform. The chloroform solution was dried over sodium sulfate, concentrated and the residue recrystallized twice from isopropyl ether-ethyl acetate. The product (0.7 gm.; 13%) melted at 127°-219° C.
Reaction SMILES: Br[CH:2]([CH:6]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=2)[CH:9]=1)[CH3:7])[C:3](Br)=[O:4].[C:20]([NH2:28])(=[S:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:19][O:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:6]([C:2]1[S:27][C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:28][C:3]=1[OH:4])[CH3:7])[CH:17]=[CH:16]2
Reactant: NC(=S)c1ccccc1
Reactant: COc1ccc2cc(C(C)C(Br)C(=O)Br)ccc2c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1ccc2cc(C(C)c3sc(-c4ccccc4)nc3O)ccc2c1
Temperature: 100 °C
Yield: 35.4 %

Procedure:
To a solution of 2-bromo-3-(6-methoxy-2-naphthyl) butyrylbromide (386 mg, 1 mmol) in toluene (20 mL) was added thiobenzamide (137 mg, 1 mmol) and pyridine (0.16 mL, 2 mmol) in toluene (60 mL) at 23° C. The reaction mixture was heated at 100° C. for 4 hours and then cooled and the solvent removed in vacuo. Recrystallization of the residue from ethanol/ether provided the desired product (128 mg). mp 224°-226° C., 1H NMR (60 MHz, DMSO-d6) 1.30 (3H, d, J=7 Hz), 3.82 (3H, s), 3.92 (1H, g, J=7 Hz), 7.1-8.0 (11H, m), 10.55 (1H, s); Mass Spectrum: 361 (M+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH:9]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:16][CH2:15]3)=O)[CH2:8][CH2:7][C:5]=2[N:6]=1.[BH4-].[Na+].B(F)(F)F.CCOCC>O1CCCC1>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:17]1[CH2:18][CH2:19][N:14]([CH2:12][CH2:11][CH:9]2[CH2:8][CH2:7][C:5]3[N:6]=[C:2]([NH2:1])[S:3][C:4]=3[CH2:10]2)[CH2:15][CH2:16]1
Reactant: Nc1nc2c(s1)CC(CC(=O)N1CCN(c3ccccn3)CC1)CC2
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Nc1nc2c(s1)CC(CCN1CCN(c3ccccn3)CC1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a solution of (+)-1-[(2-amino-4,5,6,7-tetrahydro-6-benzothiazolyl)acetyl]-4-(2-pyridyl)piperazine (2.70 g) (Example M) in 250 ml of tetrahydrofuran is added sodium borohydride (1.07 g) under nitrogen. This suspension is cooled in an ice bath and boron trifluoride etherate (4.6 ml) added dropwise. The mixture is stirred at room temperature for one hour and the solvent removed in vacuo. The residue is dissolved in 250 ml of a 10% solution of hydrochloric acid and stirred for two hours. The solution is made basic with ammonium hydroxide and extracted with chloroform (2×200 ml). The combined chloroform extracts are dried (magnesium sulfate), filtered, and concentrated. The residue is purified by MPLC (silica; 5% methanol, 95% chloroform) to give 1.74 g of (+)-4,5,6,7-tetrahydro-6-[2-[4-(2-pyridinyl)-1-piperazinyl]ethyl]-2-benzothiazolamine, containing one-fourth of a molecule of water, as a colorless solid; mp 176°-190° C.; [α]D =+52.2° (c=1.02; 0.1 N hydrochloric acid solution).
Reaction SMILES: CN(C1C=CC=CC=1)/[CH:3]=[CH:4]/[CH:5]=[CH:6]/[CH:7]=[O:8].[CH2:15]([N:19]([CH2:26][CH2:27][CH2:28][CH3:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:16][CH2:17][CH3:18].P(Cl)(Cl)(Cl)=O>C1COCC1>[CH2:15]([N:19]([CH2:26][CH2:27][CH2:28][CH3:29])[C:20]1[CH:25]=[CH:24][C:23](/[CH:3]=[CH:4]/[CH:5]=[CH:6]/[CH:7]=[O:8])=[CH:22][CH:21]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CN(/C=C/C=C/C=O)c1ccccc1
Reactant: CCCCN(CCCC)c1ccccc1
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCN(CCCC)c1ccc(/C=C/C=C/C=O)cc1
Temperature: 50 °C
Reaction time: 0.58 h
Yield: 13 %

Procedure:
To a solution of the vinylogous amide 2 (1.135 g, 6.06 mmol) and dibutylaniline (1.43 g) in dry THF (6 ml) at −20° C. was added a solution of phosphorus oxychloride (1.08 g, 1.17 eq.) and dibutylaniline (1.03 g, 1.98 eq. for the sum) in THF (3.6 ml) dropwise at such a rate as to keep the mixture between −10° C. and −20° C. Following the addition, the mixture was stirred at room temperature for 2 hours and at 50° C. for 35 minutes. To the reaction mixture (a dark blue-green oil) was added petroleum ether (25 ml) and the mixture was triturated; the ether was separated and discarded. Methanol (4 ml) was then added and the mixture was neutralized with 2N NaOH. Silicagel was then added, the suspension was diluted with ethyl acetate and methanol and dried to a solid on the rotovap. The crude product was purified by MPLC using hexanes-ethyl acetate 5-30% gradient to give the desired aldehyde as an intense yellow oil (225 mg, 13%). MS (EI): 285 (M+, 45%); 242 (100%); 200 (85%); 128 (30%); 118 (40%). H-NMR (CDCl3): 0.95 (t, J=12 Hz, 6H); 1.35 (m, 4H); 1.45 (m, 4H); 3.8 (t, J=9 Hz, 4H); 6.4, (d, J=17 Hz, 1 H); 6.5-6.8 (m, 3H); 7.1 (d, J=15 Hz,1 H); 7.5 (d, J=17 Hz,1 H); 7.8 (d, J=11 Hzm 2H); 9.8 (s,1 H).
Reaction SMILES: [C:1]([C:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:7]([CH3:26])[NH:6][C:5]=1OCOCC[Cl:32])(=[O:3])[CH3:2].[I-].[Na+].Cl.[C:36]1([C:42]2([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(OCC)C>[ClH:32].[C:1]([C:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])=[C:7]([CH3:26])[NH:6][C:5]=1[CH2:22][O:21][CH2:19][CH2:8][N:45]1[CH2:44][CH2:43][C:42]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:47][CH2:46]1)(=[O:3])[CH3:2]
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: CC(=O)C1=C(OCOCCCl)NC(C)=C(C(=O)OC(C)(C)C)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)C1=C(COCCN2CCC(c3ccccc3)(c3ccccc3)CC2)NC(C)=C(C(=O)OC(C)(C)C)C1c1cccc([N+](=O)[O-])c1

Procedure:
8.5 g (19 mmol) 3-acetyl-5-tert-butoxycarbonyl-2-(2-chloro-1-ethoxy)methoxy-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-pyridine are reacted first with 5.6 g (38 mmol) sodium iodide, as described for starting compound B, and then with 10.3 g (36 mmol) 4,4-diphenylpiperidine hydrochloride. Working up is carried out as described for starting compound B. The crude product is chromatographed with toluene/acetone=9/1. The product thus obtained is taken up in 50 ml diethyl ether. The title compound is precipitated by addition of ethereal hydrochloric acid. Yield: 11 g (84%). M.p. 175°-177° C. (diethyl ether).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:15])[C:12]([OH:14])=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.CCN(C(C)C)C(C)C.[CH2:32]([N:34]=[C:35]=[O:36])[CH3:33]>C(Cl)Cl>[CH2:32]([NH:34][C:35](=[O:36])[O:14][C:12]1[C:11]([CH3:15])=[C:10]2[N:9]([CH:13]=1)[N:8]=[CH:7][N:6]=[C:5]2[O:4][C:3]1[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:2]=1[F:1])[CH3:33]
Reactant: CCN=C=O
Reactant: Cc1c(O)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Oc1cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
To a mixture of 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ol (25 mg, 0.082 mmol, Compound F of Example 1), DIEA (0.017 mL, 0.1 mmol) in CH2Cl2 (5 mL) was added ethyl isocyanate (0.078 mL, 0.1 mL) and stirred at room temperature for 2 h. The reaction was quenched with water (5 mL). The organic layer was separated, dried and concentrated in vacuo. The mixture was purified by flash chromatography (1-5% Methanol/CH2Cl2) to give the title compound (12.5 mg, 32%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][CH:8]2[CH2:13][CH2:12][N:11](C(OC3C=CC=CC=3)=O)[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[ClH:23]>>[ClH:23].[ClH:23].[N:1]1[CH:6]=[CH:5][C:4]([S:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:3][CH:2]=1
Reactant: O=C(Oc1ccccc1)N1CCC(Sc2ccncc2)CC1
Agent: Cl
Product: c1cc(SC2CCNCC2)ccn1

Procedure:
A solution of phenyl 4-[(4-pyridyl)thio]-1-piperidine-carboxylate (5.0 g) in conc. hydrochloric acid (50 ml) was refluxed for 7 hours and concentrated to dryness in vacuo. The crystalline residue was washed with isopropanol and recrystallized from methanol to give 4-[(4-pyridyl)thio]piperidine dihydrochloride (2.85 g).
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[CH:8]1C=CC=CC=1.CO.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[CH2:25][CH:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)[CH3:27]>CC(O)=O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[CH2:25][CH:26]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:8])=[O:33])=[CH:35][CH:36]=1)[CH3:27]
Reactant: c1ccccc1
Reactant: COc1ccc(Br)c(CC(C)c2ccc(C(=O)O)cc2)c1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(C(C)Cc2cc(OC)ccc2Br)cc1

Procedure:
(Trimethylsilyl)diazomethane (2.0M hexanes, 4.8 mL) was added dropwise to a benzene/MeOH solution (7/3, 50 mL) containing the intermediate from Step A (2.8 g, 8.0 mmol). After 20 minutes AcOH was added dropwise to quench the excess reagent. The solution was concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (500 MHz, CDCl3): δ 7.98 (d, J=8.2 Hz, 2H); 7.43 (d, J=8.2 Hz, 1H); 7.29 (d, J=8.2 Hz, 2H); 6.63 (dd, J=3.0, 8.7 Hz, 1H); 6.50 (d, J=3.0 Hz, 1H); 3.93 (s, 3H); 3.68 (s, 3H); 3.26-3.19 (m, 1H); 2.96 (d, J=7.0 Hz, 2H); 1.34 (d, J=6.9 Hz, 3H). LCMS1 4.14 min. (M-31)=331
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[C-:20]#[N:21].[Na+].[Na+].[I-]>C(#N)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]3[C:4]=2[CH2:3][C:20]#[N:21])=[CH:14][CH:15]=1
Reactant: [C-]#N
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: N#CCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
30.0 g of molecular sieves were activated under vacuum, at 100° C., for 1 h. 5.00 g of 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride (15.94 mmol, 1 eq), 9.38 g of NaCN (191.3 mmol, 12 eq), 428 mg of Bu4NCN (1.59 mmol, 0.1 eq), 9.56 g of NaI (63.77 mmol, 4 eq) and 150 mL of ACN were added. The mixture were stirred at RT, O/N. Sieves were filtered and washed with EtOAc. The filtrate was washed twice with NaHCO3, dried on MgSO4, filtered and concentrated to give 4.95 g of crude. It was purified by silica gel chromatography (MeOH/CH2Cl2, 0 to 5%) and gave two batches: batch #01 (very pure)=3.90 g, batch #02 (some impurities) was purified on activated carbon to give 0.90 g. Total yield=82%. m/e+=268 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:5])[O-:4].[CH3:6][N+:7]([CH3:16])([CH3:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[C:3](=[O:2])([O-:5])[OH:4].[CH3:6][N+:7]([CH3:16])([CH3:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)[O-]
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: O
Product: O=C([O-])O
Reaction time: 3 h

Procedure:
112.5 g of trimethylbenzylammonium monomethylcarbonate and 55.0 g of water were introduced in the same reactor as used in Preparation Example 1 and heated with stirring. After the temperature in the reactor reached 120° C., the reaction was continued for 3 hours at 120° C. Trimethylbenzylammonium hydrogencarbonate was obtained in a yield of 95.7 mol %.
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]([Cl:15])([Cl:14])[CH:5]=[CH:6][C:7]([O:9]CCCC)=[O:8].Cl>O.C1COCC1>[Cl:3][C:4]([Cl:15])([Cl:14])[CH:5]=[CH:6][C:7]([OH:9])=[O:8]
Reactant: CCCCOC(=O)C=CC(Cl)(Cl)Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C=CC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
17.82 g of LiOH in 20 ml of water are added to a solution containing 3 g of butyl 4,4,4-trichloro-but-2-enoate (0.0128 moles) in 300 ml of THF. The mixture is stirred for 1 hour at room temperature. It is then brought to neutral pH with the addition of HCl 1N, extracted with ethyl acetate and anhydrified on Na2SO4. The solid obtained after evaporation of the solvent at reduced pressure and washing with petroleum ether weighs 2.1 g (87% yield).