Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[CH:15][C:14]3[C:17]([I:20])=[N:18][NH:19][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.CS(O)(=O)=O.C(N(CC)CC)C>O1CCCC1.C(Cl)Cl>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]2[N:16]=[CH:15][C:14]3[C:17]([I:20])=[N:18][N:19]([CH:22]4[CH2:23][CH2:24][CH2:25][CH2:26][O:21]4)[C:13]=3[CH:12]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: C1=COCCC1
Reactant: COc1cc(OC)cc(-c2cc3[nH]nc(I)c3cn2)c1
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(OC)cc(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 90.9 %

Procedure:
A mixture of 6-(3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine (0.50 g, 1.3 mmol), dihydropyran (360 μL, 3.9 mmol), and methanesulfonic acid (17 μL, 0.26 mmol) in tetrahydrofuran (3 mL) and methylene chloride (7.5 mL) was stirred at 80° C. for 2 days. After cooling, to the mixture was added some triethylamine, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.55 g). LCMS (M+H)+=466.0.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:9])[CH3:8].[C:10]([NH:20][CH2:21][C:22](O)=[O:23])([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:14]1([CH2:13][O:12][C:10](=[O:11])[NH:20][CH2:21][C:22]([NH:1][N:2]2[CH:6]=[CH:5][CH:4]=[C:3]2[C:7](=[O:9])[CH3:8])=[O:23])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(=O)c1cccn1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=O)c1cccn1NC(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.8 %

Procedure:
To a stirred solution consisting of 1-(1-amino-1H-pyrrol-2-yl)ethanone (3.88 g) and carbobenzyloxyglycine (6.54 g) in dry DCM (115 ml) was added DCC (6.77 g) at 0° C. under nitrogen. The reaction mixture was allowed to stir at room temperature for 18 hours. The precipitated DCU was removed by filtration and washed with ethyl acetate. The combined filtrates were concentrated to give the crude product. Purification via flash column chromatography (silica gel, 10% EtOAc/hexane) afforded 6.98g of the product as a solid, m.p. 109°-111° C.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C@H:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([N:28]3[CH:32]=[N:31][N:30]=[CH:29]3)[CH2:23]2)(=[O:20])=[O:19])=[C:14]([CH2:33][CH3:34])[CH:13]=1.[N-:35]=[N+:36]=[N-:37].[Na+]>C(O)(=O)C>[CH2:33]([C:14]1[CH:13]=[C:12]([N:11]2[CH:1]=[N:37][N:36]=[N:35]2)[CH:17]=[CH:16][C:15]=1[S:18]([NH:21][C@H:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([N:28]2[CH:29]=[N:30][N:31]=[CH:32]2)[CH2:23]1)(=[O:20])=[O:19])[CH3:34]
Reactant: CCc1cc(N)ccc1S(=O)(=O)N[C@H]1CCC[C@@H](n2cnnc2)C1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1cc(-n2cnnn2)ccc1S(=O)(=O)N[C@H]1CCC[C@@H](n2cnnc2)C1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
Triethyl orthoformate (70.0 μL, 0.420 mmol) was added to a mixture of 4a (33.0 mg, 0.094 mmol) and sodium azide (20.0 mg, 0.308 mmol) in acetic acid (1.00 mL), and the resulting mixture was heated to 90° C. After 15 h, the reaction mixture was cooled to rt, quenched with satd. aq. NaHCO3 and extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (gradient elution, 0-15% MeOH/DCM as eluent) to afford the title compound, 5a. m/z (ES) 403 (MH)+; IC50=815 nM
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH:11]=[C:10]([CH3:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:23]([NH:27][S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([NH:27][S:28]([C:31]1[CH:36]=[C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=4)[CH:11]=[C:10]([CH3:22])[N:9]=3)[CH:3]=2)[CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
3′-[4-(3,4-Dichloro-phenyl)-6-methyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-(3,4-dichloro-phenyl)-6-methyl-pyrimidine (example E.62) (0.39 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as a light brown solid (0.54 g), which was subsequently deprotected.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)([CH3:16])[CH3:15])=[CH:10][CH:9]=1.[N:24]#[C:25]Br.CC(C)=O.C(N(CC)CC)C>O>[O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[C:8]1[CH:9]=[CH:10][C:11]([C:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:25]#[N:24])=[CH:21][CH:22]=2)([CH3:16])[CH3:15])=[CH:12][CH:13]=1
Reactant: N#CBr
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(N2C(=O)C=CC2=O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(c1ccc(OC#N)cc1)c1ccc(N2C(=O)C=CC2=O)cc1
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 91.4 %

Procedure:
A 21.70 gram portion of 4-(1-(4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)phenyl)-1-methylethyl)phenol (0.1037 mole), 11.53 grams of cyanogen bromide (0.1089 mole) and 250 milliliters of acetone were added to a reactor and maintained under a nitrogen atmosphere with stirring. The stirred solution was cooled to -5° C. then 10.55 grams of triethylamine (0.1043 mole) was added to the reactor over a eight minute (480 s) period and so as to maintain the reaction temperature at -5° to -3° C. After completion of the triethylamine addition, the reactor was maintained at -5° to -3° C. for an additional 37 minutes (2220 s), followed by addition of the reactor contents to 1500 milliliters of deionized water. After 5 minutes (300 s), the water and product mixture was multiply extracted with three 100 milliliter volumes of methylene chloride. The combined methylene chloride extract was washed with 500 milliliters of 0.05 percent aqueous hydrochloric acid followed by washing with 500 milliliters of deionized water then drying over anhydrous sodium sulfate. The dry methylene chloride extract was filtered and solvent removed by rotary evaporation under vacuum for 30 minutes (1800 s) at 90° C. 4-(1-(4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)phenyl)-1-methylethyl)phenyl cyanate (22.2 grams) was recovered in 91.4 percent yield as a light amber colored oil. Infrared spectrophotometric analysis of a film sample of the product confirmed the product structure (disappearance of phenolic hydroxyl absorbance, appearance of cyanate absorbance at 2242 and 2271 cm-1, maintenance of malemide carbonyl absorbance at 1722 cm-1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[CH3:31][C:32]1[N:33]=[C:34]([C:37]([NH:39][NH2:40])=O)[S:35][CH:36]=1>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:37]([C:34]3[S:35][CH:36]=[C:32]([CH3:31])[N:33]=3)=[N:39][N:40]=[C:14]2[CH2:13]1)=[O:11]
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Reactant: Cc1csc(C(=O)NN)n1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1csc(-c2nnc3n2CCN(C(=O)c2ccc(Cl)c(F)c2Cl)C3)n1
Temperature: 25 °C

Procedure:
A mixture of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37) (170 mg, 0.585 mmol) in dry dichloromethane (DCM) (1.463 ml) was stirred at room temperature under an atmosphere of argon. Triethyloxonium tetrafluoroborate (122 mg, 0.644 mmol) was added and the resulting mixture was stirred for 2½ hours. After this time, 4-methyl-1,3-thiazole-2-carbohydrazide (I121)(115 mg, 0.732 mmol) was added and the solution was stirred for a further 18 hours at room temperature. The solution was concentrated under reduced pressure and then redissolved in 1-butanol (1.463 ml) and the resulting solution was heated at reflux for 4 hours. The solution was cooled to room temperature, diluted with DCM (approx. 50 ml) and washed with water (2× approx. 20 ml). The organics were dried over MgSO4, filtered and concentrated under reduced pressure to give a yellow coloured oil. The residue was purified using MDAP and dried under vacuum for 4 days to give the desired product in 42 mg.
Reaction SMILES: C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:30][C:31]1[CH:46]=[CH:45][C:34]([O:35][C:36]2[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][C:37]=2[F:44])=[C:33]([F:47])[CH:32]=1.[N:48]1[CH:53]=[C:52]([C:54]([NH:56][C:57]2([C:60](O)=[O:61])[CH2:59][CH2:58]2)=[O:55])[CH:51]=[N:50][CH:49]=1>O1CCCC1>[ClH:30].[Cl:30][C:31]1[CH:46]=[CH:45][C:34]([O:35][C:36]2[CH:43]=[CH:42][C:39]([CH2:40][NH:41][C:60]([C:57]3([NH:56][C:54]([C:52]4[CH:51]=[N:50][CH:49]=[N:48][CH:53]=4)=[O:55])[CH2:59][CH2:58]3)=[O:61])=[CH:38][C:37]=2[F:44])=[C:33]([F:47])[CH:32]=1
Reactant: O=C(NC1(C(=O)O)CC1)c1cncnc1
Reactant: NCc1ccc(Oc2ccc(Cl)cc2F)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cl
Product: O=C(NC1(C(=O)NCc2ccc(Oc3ccc(Cl)cc3F)c(F)c2)CC1)c1cncnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
0.5 mL (3.6 mmol) of triethylamine, 0.433 g (1.35 mmol) of TBTU and 325.5 mg (1.2 mmol) of 4-(4-chloro-2-fluoro-phenoxy)-3-fluoro-benzylamine were added to a solution of 250 mg (1.2 mmol) of 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b) in 15 mL tetrahydrofuran and the mixture was stirred overnight at ambient temperature. Then the mixture was evaporated to dryness and the crude product thus obtained was purified by chromatography. The purified product was dissolved in approx. 4 mL ethyl acetate and the dropwise addition of ethereal hydrochloric acid solution caused the hydrochloride to precipitate out, which was then filtered off and dried.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]2[C:5]=1[CH:6]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:8]2.I[CH3:20]>CN(C=O)C>[Cl:3][C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]2[C:5]=1[CH:6]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:8]2[CH3:20]
Reactant: CCOC(=O)c1cc2c(Cl)cc(Cl)cc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)cc(Cl)cc2n1C
Temperature: 0 °C
Reaction time: 0.04 h
Yield: 97.4 %

Procedure:
NaH (60% dispersion in mineral oil, 0.24 g, 6 mmole) was washed with hexanes, then was suspended in anhydrous DMF (16 mL). The mixture was cooled to 0° C., and ethyl 4,6-dichloroindole-2-carboxylate (1.03 g, 4 mmole) was added. After 2-3 min, iodomethane (1.3 mL, 20 mmole) was added, and the mixture was warmed to RT. The mixture became thick, and stirring became difficult for several minutes. After 0.5 hr, the reaction was cooled to 0° C. and quenched with 10% NH4Cl (2 mL). The mixture was concentrated to dryness, and the residue was partitioned between Et2O (50 mL) and H2O (10 mL). The layers were separated and the organic layer was washed with H2O (5 mL), dried (MgSO4), and filtered, and the filter pad was washed with a little CH2Cl2. Concentration afforded the title compound (1.06 g, 97%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 7.34 (s, 1H), 7.30 (s, 1H), 7.17 (d, J=1.5 Hz, 1H), 4.39 (q, J=7.1 Hz, 2H), 4.05 (s, 3H), 1.42 (t, J=7.1 Hz, 3H); MS (ES) m/e 272 and 274 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.CCN(CC)CC.[CH3:20][C@H:21]1[CH2:26][O:25][CH2:24][CH2:23][NH:22]1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][C@@H:21]2[CH3:20])[C:5]2[CH2:11][S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: C[C@H]1COCCN1
Reactant: Clc1nc(Cl)c2c(n1)CCSC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1CSCC2
Yield: 58.3 %

Procedure:
To a solution of 2,4-dichloro-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine (200 mg, 0.9 mmol), and Et3N (182 mg, 1.8 mmol) in DMF (3 mL) at 0° C. was added 3-(S)-methylmorpholine (100 mg, 0.99 mmol). The resultant mixture was stirred at rt overnight. The solvent was removed under vacuum to give a residue which was partitioned between water and ethyl acetate. The organic layer was washed with brine dried and concentrated to give the product which was purified by preparative TLC (petroleum ether/ethyl acetate=2/1) to produce (S)-2-chloro-4-(3-methylmorpholino)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine (150 mg, 58%).
Reaction SMILES: [NH2:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4](F)[CH:3]=1.[F:17][CH:18]([F:21])[CH2:19][OH:20].[H-].[Na+].C1COCC1>CN(C=O)C>[NH2:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([O:20][CH2:19][CH:18]([F:21])[F:17])[CH:3]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1F
Reactant: OCC(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1OCC(F)F

Procedure:
The sub-title compound was prepared in accordance with Example 59 (f) using ethyl 4-amino-2-fluoro-5-nitrobenzoate (4.80 g; 21.0 mmol), 2,2-difluoroethanol (1.73 g; 21.0 mmol), sodium hydride (0.841 g; 60%; 21.0 mmol), THF (100 mL) and DMF (50 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([NH:11][C:12]1[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:15]=[CH:14][C:13]=1[F:24])[CH3:10].C(OC([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][C@@H:33]1[C:38](O)=[O:39])=O)(C)(C)C.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>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([NH:11][C:12]1[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:38]([C@H:33]3[CH2:34][CH2:35][CH2:36][CH2:37][NH:32]3)=[O:39])[CH2:20][CH2:19]2)[CH:15]=[CH:14][C:13]=1[F:24])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Reactant: C[C@@H](Nc1cc(N2CCNCC2)ccc1F)c1ccc(Cl)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1cc(N2CCN(C(=O)[C@H]3CCCCN3)CC2)ccc1F)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
To a stirred solution of the (R)—N-(1-(2,4-dichlorophenyl)ethyl)-2-fluoro-5-(piperazin-1-yl)aniline (0.085 g, 0.23 mmol) and (R)-1-(t-butoxycarbonyl)piperidine-2-carboxylic acid (0.053 g, 0.23 mmol) in DMF (1.5 mL) was added HATU (0.11 g, 0.28 mmol) and iPr2NEt (0.075 g, 0.58 mmol). The reaction mixture was stirred at room temperature for 2 h, and quenched with deionzied water. The aqueous layer was extracted with diethyl ether (2×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 10-70% ethyl acetate in hexanes) to afford the desired product (0.080 g, 0.14 mmol, 65%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>O>[C:23]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=1)(=[O:25])[CH3:24]
Reactant: COC(=O)C(C)(C)c1ccc(CN)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C(C)(C)c1ccc(CNC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-(4-aminomethylphenyl)-2-methylpropionate (29.4 g) and triethylamine (23.8 ml) indichloroethane (300 ml) was added dropwise acetyl chloride (11.1 ml) at 5° C. over 30 min. The mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water and the organic layer was separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (developing solvent; ethyl acetate:hexane=3:1, ethyl acetate) to give the title compound (23.47 g) as a pale-yellow oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl>CO.[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15](=[O:20])[C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:10][CH2:9]1
Reactant: CC(C)(C)C(=O)OC1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)C(=O)OC1CCNCC1

Procedure:
A solution of piperidine 51 (35.99 g, 130.7 mmol) in methanol is hydrogenated with Pd/C in the presence of one equivalent of HCl (104.5 ml, 130.7 mmol, 1.25M in MeOH). After filtration and evaporation, the crude is taken up in ether and washed with 1N-NaOH and brine. Drying, evaporation and distillation (0.08 mbar, 75-90 C) gave a colourless oil. Yield: 17.98 g (74%).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][NH:24]C(OC(C)(C)C)=O)=[O:22])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>ClCCl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][NH2:24])=[O:22])=[CH:16][CH:17]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(COc2ccc(CCNC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc(COc2ccc(CCNC(=O)NN)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of tert-butyl 2-{[2-(4-{[2-(acetylamino)-1,3-thiazol-4-yl]methoxy}phenyl)ethyl]carbamoyl}hydrazinecarboxylate (305.0 mg, 0.667 mmol) in anhydrous dichloromethane (20 ml) was added trifluoroacetic acid (2.48 ml, 33.4 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hr,and concentrated under reduced pressure. Dichloromethane (20 ml) was added to the residue and the mixture was concentrated again under reduced pressure. This operation was repeated 3 times to remove trifluoroacetic acid azeotropically. Ethyl acetate (30 ml) was added to the residue and the mixture was stirred. The precipitate was collected by filtration, washed 5 times with ethyl acetate and 5 times with diethyl ether, and dried under reduced pressure to give the title compound (253.4 mg, 0.547 mmol, yield 81.9%) as a white solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]1([CH:25]=[CH:26][CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[CH2:50]([Cl:52])[Cl:51]>C(O)(=O)C>[NH3:1].[CH2:50]([Cl:52])[Cl:51].[C:19]1([CH:25]=[CH:26][CH2:27][N:28]2[CH2:29][CH2:30][N:31]([CH2:15][C:14]3[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:12][CH:13]=3)[CH2:32][CH2:33]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(OCCCN2CCCCC2)cc1
Reactant: C(=Cc1ccccc1)CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C(=Cc1ccccc1)CN1CCN(Cc2ccc(OCCCN3CCCCC3)cc2)CC1
Product: N
Reaction time: 16 h

Procedure:
A solution of the product of Example 9 (215 mg), 1-(3-phenyl-allyl)-piperazine (176 mg), and acetic acid (0.06 mL) in DCM (3 mL) was treated with sodium triacetoxyborohydride (290 mg). After 16 h, the resulting mixture was treated with 10% sodium hydroxide (5 mL) and extracted with DCM (3×10 mL). The combined organic phases were dried (sodium sulfate) and evaporated. Chromatography of the residue (1–5% 2 M methanolic ammonia/DCM) gave the title compound as a colorless oil (303 mg). 1H NMR (400 MHz, CDCl3): 7.36 (m, 2H), 7.30 (m, 2H), 7.24–7.18 (m, 3H), 6.83 (d, J=8.6 Hz, 2H), 6.51 (d, J=15.9 Hz, 1H), 6.31–6.23 (m, 1H), 3.98 (t, J=6.3 Hz, 2H), 3.45 (s, 2H), 3.15 (m, 2H), 2.60–2.32 (m, 12H), 1.67 (br, 1H), 1.62–1.56 (m, 4H), 1.47–1.40 (m, 2H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:11]=2)[CH:4]=1.C1([O:29][C:30](=O)[NH:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)C=CC=CC=1.NC1C=NC=CC=1.C(N(CC)CC)C>C(#N)C>[CH3:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH:16]=[C:17]2[CH2:22][CH2:21][N:20]([C:30]([NH:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[O:29])[CH2:19][CH2:18]2)[CH:4]=1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: Cc1ccnc(Oc2cccc(C=C3CCNCC3)c2)c1
Agent: Cl
Agent: Nc1cccnc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccnc(Oc2cccc(C=C3CCN(C(=O)Nc4cccnc4)CC3)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Methyl-2-(3-piperidin-4-ylidenemethyl-phenoxy)-pyridine hydrochloride (530 mg, 1.5 mmol, from Step 5), pyridin-3-yl-carbamic acid phenyl ester (402 mg, 1.88 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 3-aminopyridine) and triethylamine (0.836 mL, 6.0 mmol) were combined in acetonitrile (10 mL) and stirred at room temperature. After 16 hours, the reaction was concentrated forming a residue and the residue was partitioned between EtOAc and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-5%, (8:1 EtOH:conc. NH4OH):DCM) to afford the desired product (429 mg) as a foamy white solid. MS (APCI 10V) AP+ 401.4, 281.2 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.35 (s, 3H) 2.45 (td, J=5.82, 0.99 Hz, 2H) 2.57 (td, J=5.81, 1.11 Hz, 2H) 3.51-3.57 (m, 2H) 3.61-3.67 (m, 2H) 6.44 (s, 1H) 6.73-6.80 (m, 1H) 6.90-6.95 (m, 2H) 6.97 (dt, J=5.18, 0.61 Hz, 1H) 7.08 (d, J=8.02 Hz, 1H) 7.30-7.42 (m, 2H) 7.91 (ddd, J=8.38, 2.58, 1.45 Hz, 1H) 7.98 (d, J=5.24 Hz, 1H) 8.16 (dd, J=4.81, 1.40 Hz, 1H) 8.58 (d, J=2.51 Hz, 1H)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2.C(OC([N:20]1[CH2:25][CH2:24][C:23]2([CH2:30][CH2:29][CH:28](O)[CH2:27][CH2:26]2)[CH2:22][CH2:21]1)=O)(C)(C)C>>[CH2:22]1[C:23]2([CH2:30][CH2:29][CH:28]([O:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[O:8][C:7](=[O:12])[CH:6]=[CH:5]4)[CH2:27][CH2:26]2)[CH2:24][CH2:25][NH:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(O)CC2)CC1
Reactant: O=c1ccc2cc(O)ccc2o1
Product: O=c1ccc2cc(OC3CCC4(CCNCC4)CC3)ccc2o1

Procedure:
Was prepared according to method A from 6-hydroxycoumarin and 9-hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester. Mp. 192.9-193.6° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N1(C2CCCCCCCC2)CCCCCCCC1>[Br:15][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]#[N:14])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2sccc2C#N)cc1
Agent: C1CCCCC(N2CCCCCCCC2)CCC1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccsc1-c1ccc(CBr)cc1
Yield: 67.1 %

Procedure:
A mixture of 2-(4-methylphenyl)-3-cyanothiophene (1.5 g, 7.5 mmol), N-bromosuccinimide (1.34 g, 7.5 mmol), and azabicyclononane (20 mg) in carbon tetrachloride was irradiated with UV light for one hour. The reaction mixture was cooled, and the solid filtered off. The filtrate was concentrated, and the residue purified by flash chromatography, eluting with 5% ethyl acetate/hexane, to yield 2-(4-bromomethylphenyl)-3-cyanothiophene 1.4 g, m.p. 68-75 (slightly impure, used as such).