Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C@@H:7]1[NH:11][C@H:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8]1)([CH3:4])[CH3:3].CN(C1C=CC=CN=1)C.CN1CCOCC1.O.[C:33]([O:37][C:38]([NH:40][C@H:41]([C:46](O)=[O:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:39])([CH3:36])([CH3:35])[CH3:34].Cl.CN(C)CCCN=C=NCC>ClCCl>[C:33]([O:37][C:38]([NH:40][C@H:41]([C:46]([N:11]1[C@@H:7]([C:6]#[C:5][Si:2]([CH3:3])([CH3:4])[CH3:1])[CH2:8][CH2:9][C@H:10]1[C:12]([O:14][CH3:15])=[O:13])=[O:47])[CH2:42][CH:43]([CH3:44])[CH3:45])=[O:39])([CH3:35])([CH3:36])[CH3:34]
Reactant: COC(=O)[C@@H]1CC[C@H](C#C[Si](C)(C)C)N1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: COC(=O)[C@@H]1CC[C@H](C#C[Si](C)(C)C)N1C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl (5R)-5-((trimethylsilyl)ethynyl)-L-prolinate (1.6 grams, 7.48 mmol), dimethylaminopyridine (913 mg, 7.48 mmol), N-methylmorpholine (1.23 mL, 11.22 mmol), and N-(tert-butoxycabonyl)-L-leucine monohydrate (2.24 g, 8.98 mmol) in dichloromethane (30 mL) at room temperature was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.72 g, 8.98 mmol). The resulting mixture was stirred 16 hours at room temperature, and partitioned between ethyl acetate (200 mL) and 1 MHO (200 mL). The aqueous layer was further extracted with ethyl acetate (200 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated. The residue was chromatographed with a Biotage 40 M cartridge with 40% ethyl acetate/hexane provide the titled compound. MS (DCI/NH3) m/e 439 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:22])[CH2:4][C@@H:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[CH2:8][CH2:7][C@H:6]1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[C:23]([O:27][C:28](SC1C=C(C)C=C(C)N=1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(CC)CC)C.O>CO>[C:23]([O:27][C:28]([NH:1][CH2:2][CH:3]([OH:22])[CH2:4][C@@H:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[CH2:8][CH2:7][C@H:6]1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCCCCCCCO[C@@H]1CCC(C)(C)C[C@H]1CC(O)CN
Reactant: Cc1cc(C)nc(SC(=O)OC(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CCCCCCCCO[C@@H]1CCC(C)(C)C[C@H]1CC(O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
A mixture of 3-amino-1-[(1S*,2R*)-5,5-dimethyl-2-octyloxycyclohexyl]-2-propanol (50 mg), S-t-butyloxycarbonyl-4,6-dimethyl-2-mercaptopyridine (46 mg) and triethylamine (20 ml) in methanol (1.5 ml) was stirred at room temperature for 2 hrs. Water was added to a reaction mixture and the mixture was partitioned between water and ether. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification of the residue by silica gel chromatography (using n-hexane:ethylacetate=5:1 as an eluent) gave 3-[(tert-butoxycarbonyl)amino]-1-[(1S*,2R*)-5,5-dimethyl-2-octyloxycyclohexyl]-2-propanol (55 mg, y. 83%); EI-MS: m/z 395 (M+ -H2O).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][CH3:3].ClCC(OC(=O)CCl)=O.[CH3:15][C:16]1[O:17]C=[CH:19][CH:20]=1>C1(C)C=CC=CC=1>[C:16]([C:15]1[O:5][CH:1]=[CH:2][CH:3]=1)(=[O:17])[CH2:20][CH3:19]
Reactant: Cc1ccco1
Reactant: CCC(=O)O
Agent: O=C(CCl)OC(=O)CCl
Solvent: Cc1ccccc1
Product: CCC(=O)c1ccco1
Temperature: 50 °C
Reaction time: 7 h
Yield: 47.7 %

Procedure:
In 50 ml of toluene were dissolved 3.7 g (0.05 mole) of propionic acid and 10.26 g (0.06 mole) of monochloroacetic anhydride. To the resulting solution were added 5.36 g (0.065 mole) of 2-methylfuran and 0.71 g of boron trifluoride-diethyl ether complex and the resulting mixture was then stirred at 50° C. for 7 hours. After completion of the reaction, the reaction solution was cooled and washed successively with 5% aqueous sodium carbonate solution and water. The organic layer was concentrated under reduced pressure and the resulting concentrated residue was then purified by silica gel-filled column chromatography to obtain 2.96 g of 2-propionylfuran.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:15])[CH2:13][O:12][C:11]([NH2:14])=[N:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1>CCO.CCCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:15])[CH2:13][O:12][C:11]([NH2:14])=[N:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC1(c2cc(F)cc(Cl)c2)COC(N)=N1
Solvent: CCO
Solvent: CCCCCCC
Product: C[C@]1(c2cc(F)cc(Cl)c2)COC(N)=N1

Procedure:
(RS)-4-(3-Chloro-5-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine was sepa-rated by chiral HPLC (Chiralpak AD, EtOH/heptane 15:850) to give (S)-4-(3-chloro-5-fluoro-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine. (+)-Enantiomer. White solid.
Reaction SMILES: CO[CH:3](OC)[CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].O>ClC1C=CC=CC=1>[CH3:12][C:7]1[C:6]2[S:5][CH:4]=[CH:3][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COC(CSc1ccccc1C)OC
Solvent: Clc1ccccc1
Solvent: O
Product: Cc1cccc2ccsc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.6 %

Procedure:
To a heated (130° C.) solution of polyphosphoric acid (59 g) in chlorobenzene (500 ml) is added a solution of 1-[(2,2-dimethoxyethyl)thio]-2-methyl-benzene (23.4 g, 110 mmol) in chlorobenzene (125 ml) slowly over several hours and when addition is complete the reaction mixture is heated for a further 8 hours. The reaction mixture is cooled to ambient temperature and stirred for an additional 24 hours. Water is added, the layers are separated, and the aqueous layer is extracted with dichloromethane. The combined organic extracts are dried over anhydrous MgSO4, filtered, and concentrated. The crude material thus obtained is purified via flash chromatography on silica gel eluting with 100% pentane then 100% hexanes to afford 7-methyl-benzo[b]thiophene (12.65 g, 69%). 1H NMR (CDCl3): δ=7.71 (1H, d), 7.45 (1H, d), 7.39 (1H, d), 7.33 (1H, dd), 7.17 (1H, d), 2.61 (3H, s).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].C(OC([O-])=O)([O-])=O.[K+].[K+].[I-].[K+].[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[S:30]([O:33][C:34]1[C:39]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([CH2:47]Cl)=[CH:43][C:42]=2[O:49][CH3:50])=[C:38]([CH3:51])[N:37]=[C:36]([NH2:52])[N:35]=1)(=[O:32])=[O:31]>C(#N)C>[NH2:52][C:36]1[N:35]=[C:34]([O:33][S:30]([C:23]2[C:22]([CH3:21])=[CH:27][C:26]([CH3:28])=[CH:25][C:24]=2[CH3:29])(=[O:31])=[O:32])[C:39]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([CH2:47][N:3]([CH2:1][CH3:2])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:43][C:42]=2[O:49][CH3:50])=[C:38]([CH3:51])[N:37]=1
Reactant: CCNCC(=O)OCC
Reactant: COc1cc(CCl)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Agent: O=C([O-])OC(=O)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN(CC)Cc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
The product from step (vi) (390 mg) was added to the mixture of potassium dicarbonate (410 mg), potassium iodide (49 mg) and the crude product from step (v) in acetonitrile (5 mL). After the mixture was stirred at 70° C. for 4 h, the reaction mixture was cooled to RT, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography to afford the sub-title compound (490 mg) as a colourless amorphous solid; 1H NMR (300 MHz, CDCl3); 6.91 (2H, s), 6.87 (1H, s), 6.72 (2H, s), 4.65 (2H, br s), 4.14 (2H, q), 3.82-3.79 (5H, m), 3.70 (2H, s), 3.28 (2H, s), 2.67 (2H, q), 2.56 (6H, s), 2.28 (3H, s), 2.23 (3H, s), 1.25 (3H, t), 1.07 (3H, t).
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH3:26])[CH:20]=3)[CH2:13][CH2:12]2)=[N:3]1.[CH3:27][C:28]([CH3:33])=[CH:29][C:30](Cl)=[O:31]>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:30](=[O:31])[CH:29]=[C:28]([CH3:33])[CH3:27])=[C:21]([CH3:26])[CH:20]=3)[CH2:15][CH2:16]2)=[N:3]1
Reactant: CC(C)=CC(=O)Cl
Reactant: Cc1cc(CCN2CCN(c3nsc4ccccc34)CC2)ccc1N
Agent: Cl
Product: CC(C)=CC(=O)Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1C
Yield: 74.1 %

Procedure:
Starting with 4-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-2-methyl-phenylamine hydrochloride (0.60 g, 1.702 mmol) and 3,3-dimethyl-acryloyl chloride (0.189 mL, 1.702 mmol) and following the procedure outlined in Example 512, 3-methyl-but-2-enoic acid{4-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-2-methyl-phenyl]amide (0.553 g, 1.261 mmol) was obtained. Yield=75%. 100% purity at 254 nM; LCMS (APCI): 435.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.00 (d, J=8.42 Hz, 2H), 7.50 (t, J=7.47 Hz, 1H), 7.38 (t, J=7.47 Hz, 1H), 7.26 (d, J=7.47 Hz, 1H), 7.02 (s, 1H), 6.97 (d, J=7.47 Hz, 1H), 5.90 (s, 1H), 3.44–3.36 (m, 4H), 3.30 (s, H2O), 2.71–2.58 (m, 6H), 2.57–2.49 (m, 2H), 2.45 (p, DMSO), 2.11 (s, 3H), 2.07 (s, 3H), 1.80 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:15][S:32]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[Cl:25])(=[O:34])=[O:33])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: Oc1cccc(OCc2ccccc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(Oc1cccc(OCc2ccccc2)c1)c1ccccc1Cl
Yield: 95.2 %

Procedure:
3-Benzyloxyphenol (2.97 g, 15 mmol), as prepared in the preceding step, in methylene chloride (50 mL) was treated with diisopropylethylamine (2 mL) and 2-chlorobenzenesulfonyl chloride (3.27 g, 15.5 mmol) at 0° C. for 2 h and at room temperature for 2 h. The reaction mixture was diluted with 200 mL of methylene chloride, washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (1:1 hexane:methylene chloride) to give the title compound as a colorless liquid (5.35 g, 95%). 1H-NMR (300 Mz, CDCl3) δ 4.97 (s, 2 H), 6.71 (dd, 1 H, J=1.1, 4.1 Hz), 6.78 (t, 1 H, J=2.3 Hz), 6.85 (dd, 1 H, J=1.1, 4.1 Hz), 7.17 (t, 1 H, J=8.3 Hz), 7.37 (m, 5 H), 7.58 (m, 2 H), and 7.91 (dd, 1 H, J=1.1, 4.1 Hz).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC(C)([O-])C.[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[C:41]5[S:40](=[O:43])(=[O:42])[N:39]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:38][C:37]=5[CH:36]=[CH:35][CH:34]=4)=[CH:29][CH:28]=3)=[O:25])=[CH:22][C:21]([C:51]([F:54])([F:53])[F:52])=[N:20]2)=[CH:15][C:14]=1[C:55]#[N:56]>CN(C=O)C>[C:2](=[N:4][O:5][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]([C:24]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([C:33]4[C:41]5[S:40](=[O:43])(=[O:42])[N:39]([C:44]([O:46][C:47]([CH3:50])([CH3:48])[CH3:49])=[O:45])[CH2:38][C:37]=5[CH:36]=[CH:35][CH:34]=4)=[CH:31][CH:32]=3)=[O:25])=[CH:22][C:21]([C:51]([F:52])([F:53])[F:54])=[N:20]2)=[CH:15][C:14]=1[C:55]#[N:56])([CH3:3])[CH3:1]
Reactant: CC(C)=NO
Reactant: CC(C)(C)OC(=O)N1Cc2cccc(-c3ccc(NC(=O)c4cc(C(F)(F)F)nn4-c4ccc(F)c(C#N)c4)cc3)c2S1(=O)=O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)=NOc1ccc(-n2nc(C(F)(F)F)cc2C(=O)Nc2ccc(-c3cccc4c3S(=O)(=O)N(C(=O)OC(C)(C)C)C4)cc2)cc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
To a solution of acetone oxime (74 mg, 1.0 mmol) in DMF (6 mL) was added sodium t-butoxide (1 M in THF, 1.0 mL). The mixture was stirred at room temperature for half hour followed by addition of a solution of 1,1-dimethylethyl 7-[4-[[[1-[4-fluoro-3-cyanophenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl]amino]phenyl]-1,2-benzisothiazole-2(3H)-carboxylate 1,1-dioxide (0.22 g, 0.34 mmol) prepared according to Example 15 in DMF (4 mL). The reaction was stirred at room temperature for 5 hours. The reaction mixture was then partitioned between ethyl acetate and HCl (5%), washed with HCl (5%), four times with water, brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography (30% ethyl acetate/hexane) gave 100 mg of 1,1-dimethylethyl 7-[4-[[[1-[4-isopropylideneaminooxy-3-cyanophenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl]amino]phenyl]-1,2-benzisothiazole-2(3H)-carboxylate 1,1-dioxide. The intermediate (100 mg, 0.14 mmol) was dissolved in ethanol (4 mL) and to the solution was added HCl (20%, 4 mL). The reaction mixture was stirred at 80° C. for three hours. The reaction mixture was cooled to room temperature. The white precipitate was filtered to give the product that was purified by HPLC utilizing gradient elution with a mixture of water: acetonitrile with 0.05% of trifluoroacetic acid on a reverse phase C18(60 angstrom) column to give the title compound (37 mg, 19%). LRMS (ES+) 577.1 (M+Na)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4]2=[C:13]3[C:18](=[N:19][C:3]=12)[CH:17]=[CH:16][CH:15]=[CH:14]3.[C:20]([O:24][C:25](=[O:36])[NH:26][CH2:27][CH2:28][CH2:29][N:30]([CH2:32][CH2:33][CH2:34][NH2:35])[CH3:31])([CH3:23])([CH3:22])[CH3:21]>C(OCCO)C>[C:20]([O:24][C:25](=[O:36])[NH:26][CH2:27][CH2:28][CH2:29][N:30]([CH3:31])[CH2:32][CH2:33][CH2:34][NH:35][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4]2=[C:13]3[C:18](=[N:19][C:3]=12)[CH:17]=[CH:16][CH:15]=[CH:14]3)([CH3:23])([CH3:22])[CH3:21]
Reactant: CN(CCCN)CCCNC(=O)OC(C)(C)C
Reactant: Cn1c2c3ccccc3nc-2c(Cl)c2ccccc21
Solvent: CCOCCO
Product: CN(CCCNC(=O)OC(C)(C)C)CCCNc1c2nc3ccccc3c-2n(C)c2ccccc12
Temperature: 120 °C
Yield: 490 %

Procedure:
A solution of 11-chloro-5-methyl-5H-indolo[3,2-b]quinoline (cf. Bierer et al., J. Med. Chem. 1998, vol. 41, pp. 2754) (61 mg, 0.23 mmol) and [[3-[(3-amino-propyl)methylamino]propyl]carbamic acid tert-butyl ester previously prepared (Spicer at el., Bioorg. Med. Chem. 2002, vol. 10, p. 19) (84_l, 0.34 mmol) in 2-ethoxyethanol (10 ml) was heated at 120° C. for 10 min. Removal of the solvent and purification by chromatography on alumina (CHCl3: MeOH 2%) yielded [3-[methyl-[3-(5-methyl-5H-indolo[3,2-b]quinolin-11-yl-amino)propyl]-amino]propyl]carbamic acid tert-butyl ester (49 mg, 490%) as a foam. 1H NMR [CDCl3—, ppm]: 8.16 (d, J=8.5 Hz, 1H), 7.81 (m, 4H), 7.55-7.48 (m, 2H), 7.21 (m, 1H), 4.51 (s, 3H, NCH3), 4.27 (m, 2H, CH2NO), 3.12 (m, 2H, CH2NHBOC), 2.76 (m, 2H, CH2N(CH3)), 2.63 (m, 2H, CH2N(CH3)), 2.39 (s, 3H, N(CH3)), 2.34 (m, 2H, CH2CN(CH3)), 1.73 (m, 2H, CH2CN(CH3)), 1.37 (s, 9H, C(CH3)3).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(Cl)(=O)C(Cl)=O.[N:19]1[O:23][N:22]=[C:21]2[CH:24]=[C:25]([CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[CH:26]=[CH:27][C:20]=12.C(N(C(C)C)CC)(C)C>C1COCC1.CN(C=O)C.ClCCl>[N:19]1[O:23][N:22]=[C:21]2[CH:24]=[C:25]([CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][N:33]([C:10]([C:6]4[CH:5]=[C:4]5[C:9](=[CH:8][CH:7]=4)[NH:1][CH:2]=[CH:3]5)=[O:12])[CH2:34][CH2:35]3)[CH:26]=[CH:27][C:20]=12
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: c1cc2nonc2cc1CCN1CCNCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2[nH]ccc2c1)N1CCN(CCc2ccc3nonc3c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Indole-5-carboxylic acid (57 mg, 0.35 mmol) was dissolved in THF (2 ml) and DMF (1 drop), then oxalyl chloride (37 μl, 54 mg, 0.42 mmol) was added. The mixture was stirred at room temperature for 3 hours, the solvent was evaporated under reduced pressure and the residue was dissolved in DMF (2 ml) and added to a stirred solution of 1-[2-(benzofurazan-5-yl)ethyl]piperazine (81 mg, 0.35 mmol) and diisopropylethylamine (91 μl, 68 mg, 0.52 mmol) in dichloromethane (1 ml). The mixture was stirred at room temperature for 24 hours, then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2 /CH3OH/NH3 ; 96:4:0.4 and crystallized from ethyl acetate/CHCl3 /hexane to give the piperazine as yellow microcrystals (16 mg, 12%), mp 180°-183° C.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10](C3C=NC=C(C(F)(F)F)C=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1.N1(CCN2C=C([C:48]3[CH:53]=[CH:52][N:51]=[C:50]([Cl:54])[CH:49]=3)N=C2C2CCNCC2)CCC1>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:48]3[CH:53]=[CH:52][N:51]=[C:50]([Cl:54])[CH:49]=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCc1c(N)ncnc1N1CCC(c2nc(-c3cncc(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Reactant: Clc1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccn1
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccnc(Cl)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine of using 4-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-2-chloropyridine instead of 3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyridine hydrochloride salt. LC-MS: (M+1=467, obsd.=467).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][C:10]([C:13]#[CH:14])=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1COCC1>[CH2:25]([O:24][C:22](=[O:23])[C:14]#[C:13][C:10]1[S:9][C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:15])=[N:12][CH:11]=1)[CH3:26]
Reactant: CCOC(=O)Cl
Reactant: C#Cc1cnc(NC(=O)OC(C)(C)C)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C#Cc1cnc(NC(=O)OC(C)(C)C)s1
Temperature: -78 °C
Yield: 88.3 %

Procedure:
(5-Ethynyl-thiazol-2-yl)-carbamic acid tert-butyl ester (1.2 g, 5.350 mMol) was dissolved in THF (25 ml) in inert atmosphere and stirred at −78° C., nBuLi (7.4 ml, 1.6 M solution in hexane, 11.848 mMol) was added drop wise. After complete addition the reaction was stirred for 0.5 hr. followed by addition of ethyl chloroformate (0.775 g, 7.141 mMol) at −78° C. Reaction was allowed to come to 0° C. and quenched with water (50 ml) and extracted with ethyl acetate (25 ml×3). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to get (2-tert-butoxycarbonylamino-thiazol-5-yl)-propynoic acid ethyl ester (1.4 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([NH2:7])[NH:4][N:3]=1.[C:8]12([CH2:18][S:19](O)(=O)=O)C(C)(C)[CH:12]([CH2:13][CH2:14]1)[CH2:11][C:9]2=O>C1(C)C=CC=CC=1>[S:19]1[CH:18]=[CH:8][CH:9]=[C:11]1[C:12]1[N:3]2[N:4]=[C:5]([NH2:7])[N:6]=[C:2]2[N:1]=[CH:14][CH:13]=1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: Nc1n[nH]c(N)n1
Solvent: Cc1ccccc1
Product: Nc1nc2nccc(-c3cccs3)n2n1
Temperature: 100 °C
Yield: 66.2 %

Procedure:
The obtained 3-dimethylamino-1-thiophen-2-ylpropenone (10.78 g) was dissolved in toluene (160 ml). Thereafter, 3,5-diamino-1,2,4-triazole (14.15 g) was added to the solution, and the obtained mixture was stirred at 100° C. After 10-camphorsulfonic acid (13.82 g) was added thereto, the mixture was heated to reflux for 1.5 hours. The reaction solution was cooled to a room temperature, and the supernatant was then eliminated (decant). The residue was washed by successive suspension in an aqueous 5% sodium carbonate-10% ethanol solution, a 10% ethanol solution, ethanol, and methylene chloride. The resultant was then dried under a reduced pressure to obtain the captioned compound (8.55 g).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])[N:6]=1.O.O.O.C([O-])(=O)C.[Na+]>[Pd].C(O)C>[F:12][C:9]([F:10])([F:11])[C:8]([NH:7][C:5]1[N:6]=[CH:2][S:3][CH:4]=1)=[O:13]
Reactant: O=C(Nc1csc(Br)n1)C(F)(F)F
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(Nc1cscn1)C(F)(F)F
Yield: 70 %

Procedure:
A mixture of 50 g. (0.182 mole) of 2-bromo-4-trifluoroacetamidothiazole 36.5 g. (0.268 mole) of sodium acetate, trihydrate and 16.6 g. of 10% palladium on carbon in 1.5 l. of absolute ethanol is hydrogenated at one atmosphere over 18 hours at room temperature. The catalyst is filtered off and washed well with ethanol. The filtrate is evaporated to dryness and the residue extracted several times with warm methylene chloride. The combined extracts are evaporated to dryness and the residue crystallized from carbon tetrachloride (activated carbon treatment) to give 25 g (70%) of heavy white crystals m.p. 138°-9°C. Recrystallization of the second crop obtained from the mother liquor raises the yield to 28.5 g. (80%). The product can also be satisfactorily recrystallized from ethanol/water mixtures.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14].[C:18]([OH:21])(=[S:20])[CH3:19].CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:17])[C:4]1[C:5]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][S:20][C:18](=[O:21])[CH3:19]
Reactant: CC(O)=S
Reactant: C=Cc1cccc(CC(=O)OC)c1C(=O)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COC(=O)Cc1cccc(CCSC(C)=O)c1C(=O)OC
Temperature: 25 °C
Yield: 31.9 %

Procedure:
Nitrogen was bubbled through a solution of 2-methoxycarbonylmethyl-6-vinyl-benzoic acid methyl ester (1.31 g, 5.60 mmol), thioacetic acid (4.00 mL, 56.0 mmol), and AIBN (0.184 g, 1.10 mmol) in benzene (30 mL) for 3 h at rt to remove oxygen. The mixture was heated at reflux for 3 h. The solution was allowed to cool to rt and saturated aqueous NaHCO3 (100 mL) was added. The mixture was extracted with EtOAc (100 mL) and the organic layer was washed with H2O (100 mL) and brine (100 mL), then dried over MgSO4 and concentrated in vacuo. Flash chromatography on SiO2 (10% EtOAc/hexanes) provided 2-(2-acetylsulfanyl-ethyl)-6-methoxycarbonylmethyl-benzoic acid methyl ester as a yellow solid (0.555 g, 33%): 1H NMR (CDCl3): δ2.40 (s, 3H), 2.94-2.99 (m, 2H), 3.13-3.18 (m, 2H), 3.75 (s, 3H), 3.78 (s, 2H), 3.99 (s, 3H), 7.25 (d, J=7.6 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7](=O)[C:8]3([CH2:11][NH:12][C:4]=2[CH:3]=1)[CH2:10][CH2:9]3.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>O1CCCC1>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7](=[S:25])[C:8]3([CH2:11][NH:12][C:4]=2[CH:3]=1)[CH2:10][CH2:9]3
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1Nc2ccc(Br)cc2NCC12CC2
Solvent: C1CCOC1
Product: S=C1Nc2ccc(Br)cc2NCC12CC2
Yield: 44.1 %

Procedure:
A solution of 7-bromo-4,5-dihydrospiro[benzo[b][1,4]diazepine-3,1′-cyclopropan]-2(1H)-one (267 mg, 1.0 mmol) and Lawesson's reagent (606 mg, 1.5 mmol) in tetrahydrofuran (15 mL) was heated to 80° C., and maintained at the same temperature for 1 hours. The mixture was concentrated. To the residue was added water (50 mL), extracted with ethyl acetate (50 mL). The organic phase was washed with water (50 mL*2), dried by sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=6:1) to afford 7-bromo-4,5-dihydrospiro[benzo[b][1,4]diazepine-3,1′-cyclopropane]-2(1H)-thione (125 mg, 44%).