Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16]C2C=CC=CC=2)[C@@H:13]([O:23][CH2:24]C2C=CC=CC=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]4[O:48][CH2:47][CH2:46][C:45]=4[CH:49]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1([CH2:52][OH:53])CO)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:55](F)(F)[C:56](O)=O>ClCCl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:13]([O:23][CH2:24][C:56]2[CH:55]=[CH:52][CH:10]=[CH:9][CH:14]=2)[C@:12]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]5[O:48][CH2:47][CH2:46][C:45]=5[CH:49]=4)[CH:34]=3)[O:11][C@@:10]1([CH2:52][OH:53])[CH2:32][O:31]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc4c(c3)CCO4)c2)OC(CO)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: ClCCl
Product: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc5c(c4)CCO5)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Reaction time: 1.5 h
Yield: 100.9 %

Procedure:
[(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 5k (1.2 g, 1.63 mmol) was dissolved in 25 mL dichloromethane, followed by dropwise addition of trifluoroacetic acid (0.5 mL, 6.52 mmol). The reaction mixture was stirred for 1.5 hours. Thereafter, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system D to obtain the title compound [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 5m (580 mg, white solid), yield: 50.4%. MS m/z (ESI): 722.3 [M+18]; 1H NMR (400 MHz, CD3OD): δ 7.48-7.39 (m, 3H), 7.35-7.23 (m, 10H), 7.21-7.11 (m, 3H), 6.97 (s, 1H), 6.90 (d, 1H), 6.84 (d, 2H), 6.57 (d, 1H), 4.83 (d, 4H), 4.44 (t, 2H), 4.23 (m, 2H), 4.07-4.00 (m, 3H), 3.95 (dd, 1H), 3.87 (d, 1H), 3.79 (d, 1H), 3.73-3.69 (m, 2H), 3.56 (d, 1H), 3.01 (t, 2H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].OS(O)(=O)=O.[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([F:21])[C:19]=1[F:20])[C:14]([OH:16])=[O:15]>>[N+:1]([C:17]1[C:18]([F:21])=[C:19]([F:20])[C:11]([F:10])=[CH:12][C:13]=1[C:14]([OH:16])=[O:15])([O-:4])=[O:2]
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(F)c(F)c(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
5.0 mL of conc. HNO3 at 0° C. was slowly treated with 10.0 mL of conc. H2SO4, then 3.52 g (20.0 mmol) of 3,4,5-trifluoro-benzoic acid. The reaction mixture was warmed up to room temperature and stirred overnight. The mixture was poured into a beaker containing ice. The resulting solid was collected by filtration, washed with cold water and dried to produce 3.4 g (16.0 mmol, 80%) of 2-nitro-3,4,5-trifluoro-benzoic acid. LCMS: 222 (M+1)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)=[CH:20][C:19]=2[C:34]2[N:35]([CH3:40])[N:36]=[CH:37][C:38]=2[Cl:39])[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[Cl:39][C:38]1[CH:37]=[N:36][N:35]([CH3:40])[C:34]=1[C:19]1[CH:20]=[C:21]([NH:24][C:25](=[O:33])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[CH:22]=[CH:23][C:18]=1[O:17][CH2:16][CH2:15][NH:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(F)c2)ccc1OCCNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(F)c2)ccc1OCCNC1CCNCC1
Yield: 72.9 %

Procedure:
A solution of 4-{2-[2-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(3-fluoro-benzoylamino)-phenoxy]-ethylamino}-piperidine-1-carboxylic acid tert-butyl ester (0.035 g, 0.061 mmol) in 4 M HCl in dioxane (2.2 mL) was shaken on a rotary stirrer for 3 hours. The reaction was concentrated and purified by RP-HPLC. Lyophilization afforded a TFA salt as a pale solid (0.021 g, 48%). LCMS m/z (%)=472 (M+H, 35Cl, 100), 474 (M+H, 37Cl, 40). 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 7.96 (dd, J=2.6, 9.0 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.77 (m, 1H), 7.73 (d, J=2.6 Hz, 1H), 7.68 (s, 1H), 7.64-7.57 (m, 1H) 7.47 (dt, J=2.6, 8.8 Hz, 1H), 7.30 (d, J=9.1 Hz, 1H), 4.37-4.22 (m, 2H), 3.69 (s, 3H), 3.42-3.28 (m, 4H), 3.22-3.10 (m, 1H), 2.86-2.70 (m, 2H), 2.05 (d, J=12.1 Hz, 2H), 1.65-1.50 (m, 2H).
Reaction SMILES: C([O:8][C:9](=[O:17])[CH2:10][N:11]1[CH:15]=[N:14][C:13]([CH3:16])=[N:12]1)C1C=CC=CC=1>CCO>[CH3:16][C:13]1[N:14]=[CH:15][N:11]([CH2:10][C:9]([OH:17])=[O:8])[N:12]=1
Reactant: Cc1ncn(CC(=O)OCc2ccccc2)n1
Solvent: CCO
Product: Cc1ncn(CC(=O)O)n1

Procedure:
This compound was prepared using a method analogous to that of Example 14 step 14.2, (3-methyl-[1,2,4]triazol-1-yl)acetic acid benzyl ester (described in Precursor for Example 212 step 212.1) replacing intermediate 14.1 and using EtOH instead of MeOH/AcOH. LC-MS (B): tR=0.18 min; [M+H]+: 142.22.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:15]2([OH:19])[CH2:18][O:17][CH2:16]2)[N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=1.C1C(=O)N([I:27])C(=O)C1>C(#N)C>[I:27][C:6]1[N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:13])([CH3:14])[CH3:12])[C:4]([C:15]2([OH:19])[CH2:18][O:17][CH2:16]2)=[N:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cn(COCC[Si](C)(C)C)c(C2(O)COC2)n1
Solvent: CC#N
Product: Cc1nc(C2(O)COC2)n(COCC[Si](C)(C)C)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-(4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)oxetan-3-ol (compound 192.2, 200 mg, 0.70 mmol) in ACN (10 mL). NIS (237.7 mg, 1.06 mmol) was added to the reaction. The reaction mixture was stirred overnight at room temperature, then concentrated under reduced pressure. The reaction mixture was diluted with 40 mL of EtOAc. The organic layer was washed with 3×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (2:3) as eluent to furnish 100 mg (35%) of the title compound as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:3]=1.[NH2:14][C:15]1[C:16](=[O:25])[C:17](=[O:24])[C:18]=1OCCCC.O>N1C=CC=CC=1>[NH2:14][C:15]1[C:16](=[O:25])[C:17](=[O:24])[C:18]=1[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:3]=1
Reactant: CCCCOc1c(N)c(=O)c1=O
Reactant: Nc1cccc(-c2ccncc2)n1
Solvent: c1ccncc1
Solvent: O
Product: Nc1c(Nc2cccc(-c3ccncc3)n2)c(=O)c1=O
Reaction time: 1 h
Yield: 13.8 %

Procedure:
A stirred solution of 2-amino-6-(4-pyridyl)pyridine (0.34 g) and 3-amino-4-n-butoxy-3-cyclobutene-1,2-dione (0.34 g) in pyridine (2 ml) is heated under reflux for 8 hours. The cool mixture is treated with water (15 ml) and the mixture stirred for 1 hour. The solid is filtered, washed with water, ethanol and ether, charcoaled and recrystallised from dimethylformamide to give 73 mg of the title compound, mp >340° C.
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][C:8](S(C)(=O)=O)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH3:15]>C(O)C>[NH2:15][C:8]1[S:9][C:10]2[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)c1nc2cccc(F)c2s1
Reactant: N
Solvent: CCO
Product: Nc1nc2cccc(F)c2s1
Temperature: 160 °C

Procedure:
A mixture of 7-fluoro-2-methylsulfonyl-1,3-benzothiazole (500 mg, 2.16 mmol) in 10 mL ethanol and 20% ethanolic ammonia (20 mL) was heated at 160° C. in a sealed tube for 12 h. It was cooled to RT, ethanol was removed under reduced pressure, and the brownish residue was purified by column chromatography (5% to 10% methanol in methylene chloride) to afford the title compound. 1H-NMR (CDCl3, 300 MHz): δ=7.35 (d, J=7.5 Hz, 1H), 7.33-7.37 (m, 1H), 6.93-6.84 (m, 1H), 5.30 (brs, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[S:11][CH3:12].C([BH3-])#N.[Na+]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[S:11][CH3:12]
Reactant: CSc1cc2cc[nH]c2cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CSc1cc2c(cc1Cl)NCC2
Yield: 98.8 %

Procedure:
6-Chloro-5-methylthioindole (D47) (0.72 g, 3.65 mmol) was treated with sodium cyanoborohydride as in the method of Description 10 to give the title compound (0.72 g, 98%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]Cl)=[C:6]([CH3:10])[CH:5]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[OH:15].C(N(CC)CC)C.[SH2:23]>O1CCCC1>[CH3:1][C:2]1[C:7]([CH2:8][SH:23])=[C:6]([CH3:10])[CH:5]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[OH:15]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CCl
Reactant: S
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)(C)C)c(O)c(C)c1CS

Procedure:
This material was synthesized according to the procedure of Song (Song, J. U.S. Pat. No. 3,810,929) using 2,4-dimethyl-3-chloromethyl-6-t-butylphenol (160.8 g, 0.71 m), triethylamine (80 g), tetrahydrofuran (200 ml) and excess hydrogen sulfide. This afforded upon work-up a slightly yellow odorous oil.
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([F:18])=[CH:16][N:15]([CH2:19][CH2:20][C@@:21]([CH3:31])([S:27]([CH3:30])(=[O:29])=[O:28])[C:22]([O:24]CC)=[O:23])[C:14](=[O:32])[CH:13]=2)=[CH:8][CH:7]=1)[CH3:4].Cl>O1CCCC1.O>[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([F:18])=[CH:16][N:15]([CH2:19][CH2:20][C@@:21]([CH3:31])([S:27]([CH3:30])(=[O:28])=[O:29])[C:22]([OH:24])=[O:23])[C:14](=[O:32])[CH:13]=2)=[CH:8][CH:7]=1)[CH3:4]
Reactant: CCOC(=O)[C@@](C)(CCn1cc(F)c(-c2ccc(OCC)cc2)cc1=O)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(-c2cc(=O)n(CC[C@](C)(C(=O)O)S(C)(=O)=O)cc2F)cc1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
Lithium hydroxide (108 mg, 4.37 mmol) was added to a solution of ethyl (2R)-4-[4-(4-ethoxyphenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoate (320 mg, 0.728 mmol) in tetrahydrofuran:water (1:1, 20 mL) and the reaction was allowed to stir at rt until complete. The reaction mixture was acidified with 4 M aq HCl and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated to afford the title compound as a solid (220 mg, 73%). MS (LCMS) m/z 412.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26-1.40 (m, 3 H) 1.54 (s, 3 H) 2.07-2.26 (m, 1 H) 2.43 (d, J=6.24 Hz, 1 H) 3.14 (s, 3 H) 3.83-4.15 (m, 4 H) 6.42 (d, J=7.81 Hz, 1 H) 6.93-7.07 (m, 2 H) 7.50 (dd, J=8.68, 1.85 Hz, 2 H) 7.97 (d, J=6.83 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:11](=O)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][CH2:23][CH2:24][OH:25].CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH2:1]([O:8][CH2:9][C@H:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:11]([NH:22][CH2:23][CH2:24][OH:25])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: NCCO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(NCCO)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
A solution of (3S)-4-benzyloxy-3-tert-butoxycarbonylamino-2-butanone (4.3 g) in dry MeOH (20 ml) was added to a solution of 2-aminoethanol (2.0 g) and AcOH (1.8 g) in dry MeOH (20 ml). NaBH3CN (1.4 g) was added and the mixture was stirred at ambient temperature overnight. The mixture was concentrated in vacuo and the residue was partitioned between AcOEt and aqueous NaHCO3 solution. The organic layer was washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution. The organic layer was mixed with 1N HCl (50 ml) and the mixture was stirred vigorously for 1 hour. The organic layer was separated, washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution, dried over MgSO4 and concentrated in vacuo to give 4.1 g of (2R, 3RS)-O-benzyl-2-tert-butoxycarbonylamino-3-(2-hydroxyethylamino)butanol as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:24]3[CH2:27][CH2:26][CH2:25]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:11]=3)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([N+]([O-])=O)=C[CH:39]=1)=[O:36].CC(C1CC1)O>ClC(Cl)C>[CH:43]1([CH:38]([O:37][C:35](=[O:36])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]([CH:24]4[CH2:27][CH2:26][CH2:25]4)[C:10]4[C:15]([C:16]=3[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:11]=4)=[CH:6][CH:7]=2)[CH3:39])[CH2:42][CH2:41]1
Reactant: COCCOc1ccc2c(C#N)c(-c3ccc(N)cc3)n(C3CCC3)c2c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CC(O)C1CC1
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: COCCOc1ccc2c(C#N)c(-c3ccc(NC(=O)OC(C)C4CC4)cc3)n(C3CCC3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-aminophenyl)-1-cyclobutyl-6-(2-methoxy-ethoxy)-1H-indole-3-carbonitrile (76.0 mg, 0.21 mmol), pyridine (36.5 mg, 0.46 mmol) in 10 mL of 1,1 dichloroethane is added 4-nitrophenyl chloroformate (93.2 mg, 0.46 mmol). The resulting mixture is stirred at room temperature for 2 h. Then α-methylcyclopropane methanol (54.3 mg, 0.63 mmol) is added. The reaction mixture is heated to 70° C. for 5 h. After cooling, the reaction is partitioned between ethyl acetate (10 mL) and saturated K2CO3 (10 mL). The organic phase is washed with additional saturated K2CO3 (2×10 mL), water, and saturated NaCl. The colorless solution is dried over MgSO4, filtered and evaporated. The remaining solid is washed with diethyl ether to yield the title compound, of [4-(3-cyano-1-cyclobutyl-6-(2-methoxyethoxy)-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (compound 1423) as a white solid.
Reaction SMILES: S1[CH:5]=[CH:4][C:3]([S:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)=C1.[N+:16]([C:19]1C=CC(S)=C[CH:20]=1)([O-])=O.BrC1C=CSC=1.[OH-].[K+]>CN(C=O)C.[Cu]=O>[N:16]1[CH:19]=[CH:20][CH:5]=[CH:4][C:3]=1[S:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: O=[N+]([O-])c1ccc(Sc2ccsc2)cc1
Agent: O=[Cu]
Agent: Brc1ccsc1
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(Sc2ccccn2)cc1
Temperature: 130 °C
Reaction time: 42 h
Yield: 34 %

Procedure:
4-(3-Thienylthio)-1-nitrobenzene: To a solution of 4-nitrothiophenol (80% pure; 1.2 g, 6.1 mmol), 3-bromothiophene (1.0 g, 6.1 mmol) and copper(II) oxide (0.5 g, 3.7 mmol) in anhydrous DMF (20 mL) was added KOH (0.3 g, 6.1 mmol), and the resulting mixture was heated at 130° C. with stirring for 42 h and then allowed to cool to room temp. The reaction mixture was then poured into a mixture of ice and a 6N HCl solution (200 mL) and the resulting aqueous mixture was extracted with EtOAc (3×100 mL). The combined organic layers were sequentially washed with a 1M NaOH solution (2×100 mL) and a saturated NaCl solution (2×100 mL), dried (MgSO4), and concentrated in vacuo. The residual oil was purified by MPLC (silica gel; gradient from 10% EtOAc/90% hexane to 5% EtOAc/95% hexane) to afford of the desired product (0.5 g, 34%). GC-MS m/z 237 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[N:13]=2)=[N:6][CH:7]=1.CO.[ClH:36]>C(Cl)Cl.O1CCOCC1>[ClH:36].[ClH:36].[Br:1][C:2]1[CH:3]=[C:4]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:13]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: Brc1cnc(Nc2nc(C3CCNCC3)cs2)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate was dissolved in 1:1 CH2Cl2:methanol and 4N HCl in dioxane was added and stirred at room temperature for 1 hour. The solvents were removed to afford the title compound. 1H NMR (d6-DMSO) δ 10.98 (bs, 1H), 8.90 (bs, 1H), 8.70 (bs, 1H), 8.23 (d, 1H), 7.45 (m, 2H), 7.40 (d, 1H), 7.22 (m, 1H), 7.12 (m, 2H), 6.76 (s, 1H), 3.31 (m, 2H), 2.98 (m, 2H), 2.89 (m, 1H), 2.10 (m, 2H), 1.79 (m, 2H). Mass spectrum (apci) m/z=431.2, 433.2 (M+H-2HCl).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.Cl.CN.[CH:12]([N:15](C(C)C)CC)(C)C>C(#N)C>[Br:8][C:5]1[CH:4]=[N:3][C:2]([NH:15][CH3:12])=[N:7][CH:6]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1ncc(Br)cn1
Agent: CN
Agent: Cl
Solvent: CC#N
Product: CNc1ncc(Br)cn1

Procedure:
A mixture of 2-chloro-5-bromopyrimidine (2.5 g, 13 mmol), methylamine hydrochloride (7.9 g, 116 mmol), and diisopropylethylamine (18 mL, 103 mmol) in 43 mL acetonitrile was heated in a sealed vessel for 16 h. The reaction was partitioned between EtOAc and water. The organic layer was washed once with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 5-bromo-N-methylpyrimidin-2-amine. MS m/z=188 [M+H]+. Calc'd for C5H6BrN3: 187.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:8])[CH3:7].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC>CCO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([CH2:9][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)([CH3:8])[CH3:7]
Reactant: CCCCNC(C)(C)Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCNC(C)(C)CC1CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
Compound D-3-8 (50.0 g, 127 mmol) is combined with palladium (II) acetate (5.0 g), dppp (5.0 g) and Et3N (25.7 g, 254 mmol) in EtOH (1.0 L). The mixture is then stirred at 80° C. overnight under an atmosphere of CO at a pressure of 4 MPa. The mixture is cooled to room temperature and the solids are removed by filtration. The filtrate is concentrated under reduced pressure and the residue is purified by flash silica gel chromatography (using 20:1 petroleum ether:EtOAc) to provide compound D-3-9 (25.0 g, 62% yield).
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=O)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>O1CCCC1>[N:1]1([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[S:32])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCN1S(=O)(=O)c1ccc(N2CCCCCC2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(N2CCCCCC2)cc1)N1CCCC1=S

Procedure:
A mixture comprising 12.53 g of 1-[4-(1-hexahydroazepinyl)benzenesulphonyl]-2-pyrrolidinone, prepared as in Example 18 of the European Patent published under No. 0,033,578, and 7.5 g of Lawesson reagent (or 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulphide) in 250 cm3 of tetrahydrofuran is heated to reflux for 48 hours. The mixture is allowed to return to room temperature and is evaporated to dryness, and the residue is chromatographed on silica (eluant: benzene). 7.3 g of product are recovered. M.p. 173°-175° C. After crystallization in a chloroform/n-hexane mixture, 6 g of expected pure product are obtained. M.p. 176°-178° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH3:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:26]([CH3:25])[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CNS(C)(=O)=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N(C)S(C)(=O)=O)cc3F)CC2)c(C)c1
Yield: 89.5 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (624 mg) described in Preparation Example 114 and N-methylmethanesulfonamide (349 mg) and by the reaction and treatment in the same manner as in Example 4, the title compound (599 mg) was obtained.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11](=[O:16])[CH:12](Br)[CH2:13]Br)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(C)(C)C.O>[C:1]1([N:7]2[C:12](=[CH2:13])[C:11](=[O:16])[NH:10][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NC(=O)C(Br)CBr)Nc1ccccc1
Solvent: CC(C)(C)O
Solvent: O
Product: C=C1C(=O)NC(=O)N1c1ccccc1

Procedure:
20.0 g of the N-phenyl-N'-(2,3-dibromopropionyl)-urea prepared in accordance with Example 1(b) are suspended in 200 ml of tert.-butanol, 23 g of potassium tert.-butylate (90%) are introduced into the resulting suspension and the mixture is heated under reflux for 1 hour. The solvent is then distilled off under normal pressure and the residue is heated in vacuo for 20 minutes to 120° C. The white crystalline powder obtained is dissolved in 400 ml of water at 60° C. and the solution is filtered and adjusted to pH 1 with dilute hydrochloric acid. The precipitated imidazolidine derivative is filtered off, washed and dried. Yield: 9.0g m.p: 168° - 170° C. (from methanol)
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:17])[CH2:6]1)C.Cl.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH2:30])=[NH:29])=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][C:28]2[N:30]=[CH:4][C:5]3[CH2:6][C:7](=[O:17])[NH:8][C:9]4[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=4[C:11]=3[N:29]=2)=[CH:25][CH:26]=1
Reactant: COc1ccc(CC(=N)N)cc1
Reactant: CN(C)C=C1CC(=O)Nc2ccccc2C1=O
Agent: Cl
Product: COc1ccc(Cc2ncc3c(n2)-c2ccccc2NC(=O)C3)cc1
Yield: 31 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and 2-(4-methoxyphenyl)-acetamidine hydrochloride. Yield: 31%. White solid, m/z (ISP) 332 (MH).
Reaction SMILES: [C:1]1([C:11]23[CH2:16][CH:15]2[CH:14]([OH:17])[CH2:13][CH2:12]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.O>[C:1]1([C:11]23[CH2:16][CH:15]2[C:14](=[O:17])[CH2:13][CH2:12]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OC1CCC2(c3cccc4ccccc34)CC12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C1CCC2(c3cccc4ccccc34)CC12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 5-naphthalen-1-yl-bicyclo[3.1.0]hexan-2-ol (1.00 g, 4.46 mmol) in dichloromethane (40 mL) was added pyridine (0.50 mL, 6.24 mmol, 1.4 eq.) followed by Dess-Martin periodinane (2.27 g, 5.35 mmol, 1.2 eq.) and the reaction mixture was warmed to room temperature and stirred for 3 h. To the reaction mixture was added 3 drops of water and the reaction mixture was left to stir for a further 0.5 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (100 mL) followed by saturated aqueous sodium sulphite (100 mL) and extracted with dichloromethane (3×200 mL). The combined organic layers were dried over magnesium sulphate and concentrated in vacuo to afford the desired compound as a yellow oil. The crude material was purified by flash chromatography (SiO2, ethyl acetate:petroleum ether 40-60; 30%:70%) to afford the desired compound as a yellow oil (0.71 g, 72%). 1H NMR (400 MHz, CDCl3) δ ppm 1.59-1.61 (1H, m, CH), 1.68-1.70 (2H, m, CH2), 2.21-2.23 (1H, m, CH), 2.24-2.40 (3H, m, CH and CH2), 7.44-7.54 (4H, m, ArH), 7.79 (1H, d, J 8.0 Hz, ArH), 7.88 (1H, d, J 8.0 Hz, ArH), 8.17 (1H, d, J 8.0 Hz, ArH).