Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]([OH:15])[CH2:12][NH:11][CH2:10][CH2:9]2)[C:5]([O:16][CH3:17])=[CH:4][CH:3]=1.C(=O)(OC(C)(C)C)[O:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]([OH:15])[CH2:12][N:11]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[CH2:10][CH2:9]2)[C:5]([O:16][CH3:17])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)nc1N1CCNCC(O)C1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(Br)nc1N1CCN(C(=O)OC(C)(C)C)CC(O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
A mixture of 1-(6-bromo-3-methoxy-2-pyridyl)-1,4-diazepan-6-ol (0.9968 mmol; 301.2 mg), tert-butoxycarbonyl tert-butyl carbonate (1.495 mmol; 326.3 mg), and sodium bicarbonate (9.968 mmol; 837.4 mg) in dichloromethane (20 Ml) was stirred at room temperature overnight. The mixture was concentrated, and the residue was purified on silica eluted with 0 to 40% EtOAc in DCM to afford tert-butyl 4-(6-bromo-3-methoxy-2-pyridyl)-6-hydroxy-1,4-diazepane-1-carboxylate (262.5 mg, 65%).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@:14]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([OH:15])[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][C:33](=[O:41])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[O:11]C1OCC=C)(=[O:3])[CH3:2].N1(C2CCCCCCC2)CCC[CH2:46][CH2:45][CH2:44]N1.[CH3:58][OH:59]>>[CH2:46]([C:58]1([O:11][C@H:12]([CH2:31][O:32][C:33](=[O:41])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@:14]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([OH:15])[C@H:5]1[NH:4][C:1](=[O:3])[CH3:2])[OH:59])[CH:45]=[CH2:44]
Reactant: C1CCCC(N2CCCCCCN2)CCC1
Reactant: C=CCOC1O[C@H](COC(=O)CCCCCCC)[C@@H](OCc2ccccc2)[C@@](O)(Cc2ccccc2)[C@H]1NC(C)=O
Reactant: CO
Product: C=CCC1(O)O[C@H](COC(=O)CCCCCCC)[C@@H](OCc2ccccc2)[C@@](O)(Cc2ccccc2)[C@H]1NC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8 g of (f), 1.2 g of diazabicyclooctane (DABCO) and 3 g of tris triphenylphosphine rhodium chloride (Rh(PPh3)3Cl) in 400 ml of an aqueous methanol solution (90% v/v) were heated under reflux for 4 hours. After filtering through paper and concentrating, it was taken up in 250 ml of chloroform, washed with 5% (m/v) citric acid then with water. After drying and evaporating off the solvents, the crude mixture was taken up in 150 ml of an aqueous acetone solution (90%, m/v). 3 g of HgCl2 was added and it was stirred at ambient temperature for 60 minutes.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:2].[Br:17][C:18]1[CH:19]=[CH:20][C:21](F)=[C:22]([CH:25]=1)[CH:23]=[O:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH2:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[C:22]([CH:23]=[O:24])[CH:25]=1
Reactant: CCOCCNCCCC(=O)OC(C)(C)C
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCN(CCCC(=O)OC(C)(C)C)c1ccc(Br)cc1C=O
Temperature: 90 °C
Reaction time: 60 h
Yield: 25.6 %

Procedure:
In DMF (43.9 ml) was dissolved tert-butyl 4-[(2-ethoxyethyl)amino]butyrate (5.5 g). To the solution was added 5-bromo-2-fluorobenzaldehyde (4.4 g), followed by addition of potassium carbonate (3.6 g). The mixture was stirred at 90° C. for 60 hours and cooled to room temperature. The reaction solution was added to water, the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=6/1→5/1) to give tert-butyl 4-(4-bromo(2-ethoxyethyl)-2-formylanilino]butyrate (2.3 g).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([S:11](Cl)(=[O:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CCCCCC>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([S:11]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)(=[O:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: C1CCNCC1
Reactant: Cc1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1nc2ccc(S(=O)(=O)N3CCCCC3)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
A solution of Compound 2 (2.5 g, 10 mmol) in chloroform (15 ml) was added drop wise to a solution of piperidine (1.7 g, 20.0 mmol) in chloroform (10 ml). The combined mixture was stirred at room temperature for 1 hour. The reaction mixture was then washed with water (2×, 50 ml) and brine (1×, 50 ml). The organic layer was dried with sodium sulfate and evaporated. The sticky white solid thus obtained was dissolved in ca. 5 ml of hot ethyl acetate and this solution was then slowly added to 40 ml hexane. The white solid that precipitated was collected, washed with hexane and dried to yield 2.2 g (74%) of Compound 3, Rf=0.28 (30% ethyl acetate in hexane). The structure of Compound 3 is given below:
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:37])[CH3:36])[C:30]=1[N:38]=[C:39]=[O:40])([CH3:28])[CH3:27]>>[CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:36])[CH3:37])[C:30]=1[NH:38][C:39](=[O:40])[N:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:25])[CH3:1])=[CH:8][CH:7]=1)[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=1)([CH3:27])[CH3:28]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCCc1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: CCCCCCCCc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 13.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(4-dimethylaminophenyl)methyl](4-octylphenyl)amine (1.1 g) and 2,6-diisopropylphenyl isocyanate (0.71 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]-N-(4-octylphenyl)urea (0.23 g) was obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[NH:15]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:25]I>CN(C=O)C>[CH2:3]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:15]2[CH3:25])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2n1C

Procedure:
To a stirred suspension of sodium hydride (0.27 g, 60% dispersion in mineral oil) in DMF (50 mL) under nitrogen at room temperature was added ethyl 4-benzyloxyindole-2-carboxylate (1.59 g). Methyl iodide (0.5 mL) was added 10 min later. After 2 h excess sodium hydride was quenched with acetic acid (0.4 mL) and the solvent evaporated under reduced pressure. The residue was taken into EtOAc, washed with water and brine, dried over MgSO4, and evaporated to dryness to give an oil which was triturated with hexane to precipitate 1.45 g of the title compound. M.P. 89–90.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[C:10]([S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>C1COCC1.O>[Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[C:10]([S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCS(=O)(=O)c1ccc(C(=O)OC)c(Cl)c1OCC(=O)N1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1OCC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.500 g of methyl 2-chloro-3-(pyrrolidinocarbonylmethoxy)-4-ethylsulfonylbenzoate were dissolved in 20 ml of THF and 20 ml of water, 0.056 g of NaOH was added and the mixture was stirred at RT for 12 hours. The mixture was admixed with 6 N HCl and extracted with CH2Cl2. Drying of the organic phase over Na2SO4 gave 2-chloro-3-(pyrrolidinocarbonylmethoxy)-4-ethylsulfonylbenzoic acid as a viscous colorless oil.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13].N([O-])=O.[Na+].[ClH:21]>O.[Cu]Cl>[Cl:21][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cccc2c(N)cccc12
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cccc2c(Cl)cccc12
Temperature: 25 °C

Procedure:
While stirring ethyl 5-amino-1-naphthoate (1.358 g, 6.309 mmol) in conc. hydrochloric acid (10 ml), a solution of sodium nitrite (0.52 g, 7.57 mmol) in water (1 ml) was added dropwise under ice-cooling and the mixture was stirred at said temperature for 0.5 hr. To the reaction solution was added a solution of copper(I) chloride (0.34 g, 3.47 mmol) in conc. hydrochloric acid (2 ml) under ice-cooling, and the mixture. was stirred at 100° C. for 0.5 hr. After cooling to room temperature, the reaction solution was diluted with water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=15/1) to give the objective substance.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)[CH3:15]>C(O)CCC>[CH3:15][C:14]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6]2[NH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1
Reactant: CC(=O)c1ccccc1
Reactant: NCCc1c[nH]c2ccccc12
Agent: Cl
Solvent: CCCCO
Product: CC1(c2ccccc2)NCCc2c1[nH]c1ccccc21
Yield: 56.4 %

Procedure:
1-Methyl-1-phenyl-1,3,4,9-tetrahydrobeta-carboline was prepared by the addition of tryptamine-HCl (500 mg, 2.54 mmol), 1-butanol (12 mL), and acetophenone (1.5 mL, 13 mmol) to a 25 mL flask attached with Dean-Stark Trap. Azeotropic removal of a butanol/H2O mixture was conducted during a vigorous reflux period of 4 hours. The concentrated solution was allowed to stir near reflux for an additional 14 hours. The solution was concentrated under reduced pressure. The residue was taken up into EtOAc (70 mL), washed with sat. NaHCO3 (40 mL×3), washed with H2O (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was chromatographed (SiO2 100% DCM to 5% MeOH) to provide 376 mg of 1-methyl-1-phenyl-1,3,4,9-tetrahydrobeta-carboline; 1H NMR (CDCl3) δ 7.74 (1H, br s), 7.54 (1H, d), 7.23-7.32 (6H, m), 7.09-7.21 (2H, m), 3.13 (1H, m), 2.71-2.94 (3H, m), 1.84 (3H, s); 13C NMR (CDCl3) δ 146, 138, 136, 128, 127, 127, 126, 122, 119, 118, 110, 110, 57, 40, 28, 23; TLC (SiO2, 10:1 DCM/MeOH) Rf=0.3; MS (ESI): 263 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[CH:4][CH:3]=1.[CH:10]([Mg]Cl)([CH3:12])[CH3:11].[Cl-].[NH4+].C([O:19]CC)C>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[O:19])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: CC(C)[Mg]Cl
Reactant: N#Cc1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Bromobenzonitrile (10 g) was dissolved in anhydrous diethyl ether (125 ml) and 2M isopropyl magnesium chloride in diethyl ether (30.24 ml) was added dropwise with stirring. The resulting solution was then heated to reflux for 18 hours. The reaction mixture was allowed to cool to ambient temperature and a saturated aqueous solution of ammonium chloride was added slowly with stirring. Stirring was continued for a further 2 hours. The organic phase was separated and the aqueous layer was extracted with diethyl ether (3×100 ml). The combined organic phases were washed with water (50 ml), then brine (50 ml), dried (MgSO4) and evaporated to give 1-bromo-4-(2-methylpropanoyl)benzene (11.6 g); 1H NMR (CDCl3): 1.15 (d, 6H), 3.1 (septet, 1H), 7.5-7.6 (m, 4H); mass spectrum (Cl+) 226 (M.)+.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[NH:12][CH2:11][C:10]=2[CH:20]=1)(=[O:5])=[O:4].[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23].Cl>N1C=CC=CC=1>[CH3:1][N:2]([CH3:21])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[N:12]([C:29](=[O:30])[C:28]3[CH:27]=[CH:26][C:25]([N+:22]([O-:24])=[O:23])=[CH:33][CH:32]=3)[CH2:11][C:10]=2[CH:20]=1)(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CNc1ccccc1O2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1O2
Reaction time: 7 h
Yield: 82 %

Procedure:
A mixture of 0.9 g of 10,11-dihydro-N,N-dimethyldibenz[b,f] [1,4]oxazepine-2-sulfonamide and 0.55 g of 4-nitrobenzoyl chloride in 3 ml of pyridine is stirred for 7 hours. To the mixture is added 20 ml of 2N hydrochloric acid and the mixture is extracted with ethyl acetate. The extract is washed with 5 ml of 2N HCl and three times with 5 ml of 2N Na2CO3. The extract is dried (MgSO4) and filtered through a thin pad of hydrous magnesium silicate. The pad is washed with ethyl acetate and the filtrate concentrated to give 1.1 g of a yellow solid. Crystallization from dichloromethane-diisopropylether gives 0.62 g of crystals, m.p. 177°-178° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)OC(C)(C)C)=[CH:4][C:3]=1[C@:16]1([CH3:27])[C:21]([F:23])([F:22])[CH2:20][C@@:19]([F:25])([CH3:24])[C:18](=[S:26])[NH:17]1.C(O)(C(F)(F)F)=O>ClCCl.C1(C)C=CC=CC=1>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@@:16]2([CH3:27])[NH:17][C:18](=[S:26])[C@:19]([F:25])([CH3:24])[CH2:20][C:21]2([F:23])[F:22])[CH:4]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)c([C@@]2(C)NC(=S)[C@@](C)(F)CC2(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C[C@]1(F)CC(F)(F)[C@@](C)(c2cc(N)ccc2F)NC1=S
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 63.2 %

Procedure:
tert-butyl (4-fluoro-3-((2R,5S)-3,3,5-trifluoro-2,5-dimethyl-6-thioxopiperidin-2-yl)phenyl)carbamate (1.15 g, 2.83 mmol) was dissolved in dichloromethane (13 ml). The solution was cooled to 0° C. and TFA (6.5 ml, 84 mmol) was added. The solution was stirred at 0° C. for 1 h 20 min. The reaction was diluted with toluene (25 mL) and concentrated to approx 10 mL under reduced pressure. The residue was diluted with ethyl acetate (50 mL) and washed with saturated aqueous NaHCO3 (25 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure to afford (3S,6R)-6-(5-amino-2-fluorophenyl)-3,5,5-trifluoro-3,6-dimethylpiperidine-2-thione (548 mg (70% purity), 63.2% yield). The crude product was used in the next reaction step without further purification. LC-MS (m/z) 307.2 (MH+) tR=0.49 minutes (Method B) 1H NMR (600 MHz, CDCl3) δ 7.93 (bs, 1H), 6.93-6.88 (m, 1H), 6.66-6.61 (m, 1H), 6.59-6.55 (m, 1H), 2.62-2.57 (m, 2H), 1.90 (s, 3H), 1.86 (d, J=22.4 Hz, 3H) [α]D20=−211° (589 nm, c=0.1 g/100 mL, MeOH
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[S:14][C:13]3[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][C:7]=3[C:6]=2[CH:15]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[CH:30])=[N:27][CH:28]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[C:30][C:2]3[CH:3]=[CH:4][C:5]4[S:14][C:13]5[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][C:7]=5[C:6]=4[CH:15]=3)=[N:27][CH:28]=2)=[CH:21][CH:22]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Ic1ccc2sc3c(c2c1)CCNCC3
Product: Clc1ccc(-c2ccc(C#Cc3ccc4sc5c(c4c3)CCNCC5)nc2)cc1

Procedure:
Prepared according to general working method I from 3-iodo-6,7,8,9-tetrahydro-5H-10-thia-7-aza-benzo[a]azulene (770 mg, 2.34 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (500 mg, 2.34 mmol).
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[C:9]=1[CH2:8][CH2:7][NH:6][C:5]2=[O:10].[I:11][CH:12]([CH3:14])[CH3:13]>CN(C=O)C>[I-:11].[CH:12]([N+:2]1[CH:1]=[C:9]2[N:4]([C:5](=[O:10])[NH:6][CH2:7][CH2:8]2)[CH:3]=1)([CH3:14])[CH3:13]
Reactant: CC(C)I
Reactant: O=C1NCCc2cncn21
Solvent: CN(C)C=O
Product: CC(C)[n+]1cc2n(c1)C(=O)NCC2
Product: [I-]
Temperature: 25 °C

Procedure:
To a suspension of 7,8-dihydroimidazo[1,5-c]pyrimidin-5(6H)-one, obtained in step I as describe above (28.18 g; 205.5 mmol; 1 eq), in DMF (140.9 ml), is added 2-iodopropane (61.5 ml; 616.4 mmol; 3 eq). The reaction is stirred at RT, until a red suspension is obtained. The reaction mixture is concentrated and acetonitrile (200 ml) is added. The resulting precipitate is filtered, washed with acetonitrile (2×50 ml) and dried under vacuum, affording the title compound that is used in the next step without further purification (45.95 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([F:9])=[C:4](Cl)[N:3]=1.C(N(CC)CC)C.[CH3:18][C:19]1([OH:24])[CH2:23][CH2:22][NH:21][CH2:20]1>C1COCC1.CO>[Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:22][CH2:23][C:19]([CH3:18])([OH:24])[CH2:20]2)[C:5]([F:9])=[C:6]([Cl:8])[N:7]=1
Reactant: Fc1c(Cl)nc(Cl)nc1Cl
Reactant: CC1(O)CCNC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: CC1(O)CCN(c2nc(Cl)nc(Cl)c2F)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.4 %

Procedure:
To a solution of 2,4,6-trichloro-5-fluoropyrimidine (0.476 g, 2.36 mmol) and triethylamine (0.36 mL, 2.60 mmol) in THF was added 3-methyl-3-pyrrolidinol (0.239 g, 2.36 mmol) in THF and MeOH (2 mL). The reaction was stirred at room temperature for 2.5 hours, and then the solvent was removed in vacuo. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organics were dried (Na2SO4) and evaporated to provide 1-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-3-methyl-3-pyrrolidinol as an orange solid (0.486 g, 77%). LCMS: (M+H)+=266.1.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.O.[NH2:11][NH2:12]>C(O)C>[CH3:1][C:2]1[N:7]=[C:6]([C:8](=[N:11][NH2:12])[NH2:9])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C#N)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1cccc(C(N)=NN)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
11.97 g (101.4 mmol) 6-methylpyridine-2-carbonitrile are dissolved in 25 mL ethanol. After addition of 36.3 mL (304.05 mmol) hydrazine hydrate (w=30%) the reaction mixture is stirred for 24 hours at room temperature. The precipitated product (K1=1.45 g) has been filtered off and the filtrate is evaporated to ⅓ of its volume. After dilution with water the reaction mixture is extracted three times with ethyl acetate. The combined organic extracts are washed with brine and dried (Na2SO4). The solvent has been removed yielding a K2 (11.11 g) of the desired product. The overall yield is 78.9%.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:53][OH:54])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:62][S:63](Cl)(=[O:65])=[O:64]>O1CCCC1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:53][O:54][S:63]([CH3:62])(=[O:65])=[O:64])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(CO)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCc1nc2ccc(COS(C)(=O)=O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 0.250 g of 2-butyl-6-(hydroxymethyl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone and 0.246 ml of triethylamine in 5.0 ml of tetrahydrofuran is cooled to -78° C. and 0.137 ml of methanesulfonyl chloride added. The reaction mixture is allowed to warm to room temperature and continue stirring for 18 hours. The reaction mixture is partitioned between chloroform and water. The organic layer is washed with aqueous 5% HCl, water and saturated aqueous sodium bicarbonate then dried with magnesium suflate and evaporated to afford 0.278 g of the desired product. FAB MASS SPEC 787 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]3)[C:11]([C:28]([F:31])([F:30])[F:29])=[CH:10][N:9]=2)[CH:4]=[N:3]1>CN(C=O)C.CCOC(C)=O.CCN(CC)CC.[Pd]>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]3)[C:11]([C:28]([F:29])([F:31])[F:30])=[CH:10][N:9]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3C3(C(N)=O)CC3)n2)cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3C3(C(N)=O)CC3)n2)cn1
Reaction time: 16 h
Yield: 74 %

Procedure:
A mixture of 1-(2-((2-((1-methyl-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)phenyl)cyclopropanecarboxamide A75 (0.120 g, 0.281 mmol) and 10% Pd/C (0.135 g) in DMF (3 mL), EtOAc (5 mL) and Et3N (0.5 mL) was stirred under a hydrogen atmosphere for 16 hours. The mixture was filtered through Celite and concentrated under reduced pressure before purification by silica gel column chromatography (0-15% MeOH in EtOAc). The product was triturated with Et2O and the resulting precipitate was collected to give the title compound 65 (0.090 g, 74%). LCMS-D: rt 3.316 min; m/z 431.2 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:18])[CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2].[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28](O)=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1>>[CH2:1]([CH:3]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:18])[CH:13]([NH:17][C:28](=[O:29])[CH2:27][C:22]2[CH:21]=[C:20]([F:19])[CH:25]=[C:24]([F:26])[CH:23]=2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CCCC(N)C(=O)Nc1cn(C(CC)CC)cn1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(CC)CC)cn1

Procedure:
2-Amino-pentanoic acid [1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide was coupled with (3,5-Difluoro-phenyl)-acetic acid to provide the title compound: C13 NMR (100 MHz, CDCl3) 10.7, 10.8, 13.9, 18.9, 28.8, 36.1, 43.0, 53.0, 62.9, 102.5, 102.7, 103.3, 104.5, 112.3, 112.4, 112.5, 112.6, 132.9, 138.0, 138.9, 161.9, 164.3, 164.5, 169.2, 169.5; MS 407.23 m/z (M+1).