Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH3:32])[C:20]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH3:31])[CH:23]=3)=[O:21])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]#[N:11].[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][N:19]([CH3:32])[C:20]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH3:31])[CH:23]=3)=[O:21])=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[NH:35][N:34]=[N:33][N:11]=1
Reactant: CN(Cc1ccc(-c2ccc(OCC#N)c(Br)c2)cc1)C(=O)c1cn(C)c2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1ccc(-c2ccc(OCc3nnn[nH]3)c(Br)c2)cc1)C(=O)c1cn(C)c2ccccc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 73.4 %

Procedure:
A mixture of N-{[3′-bromo-4′-(cyanomethoxy)-1,1′-biphenyl-4-yl]methyl}-N,1-dimethyl-1H-indole-3-carboxamide (2.0 g, 4.1 mmol), prepared in the previous step, sodium azide (0.80 g, 12.3 mmol) and ammonium chloride (0.66 g, 12.3 mmol) in 42 mL of DMF was stirred under nitrogen at 100° C. for 4 h. By TLC a small amount of starting material remained. An additional 0.80 g (12.3 mmol) of sodium azide and 0.66 g (12.3 mmol) of ammonium chloride were added and the reaction stirred at 100° C. for 3 h. After cooling to room temperature the reaction was diluted with 65 mL of water, made basic by the addition of 1 N NaOH and extracted three times with ethyl acetate. The aqueous layer was acidified with 1 N HCl. An oil separated which eventually solidified. The solid was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (1.6 g, 73%) as a tan solid, mp 239° C. Elemental Analysis for C26H23BrN6O2Calc'd: C, 58.77; H, 4.36; N, 15.81. Found: C, 57.73; H, 4.40; N, 15.52
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH:10]([CH3:15])[C:11]2=[O:14])=[CH:7][C:6]=1[O:16][CH3:17])([CH3:4])([CH3:3])[CH3:2].ClCCl.[Br:21]Br.[O-]S([O-])=O.[Na+].[Na+]>[N+](CC)(CC)(CC)CC.[I-].O>[Br:21][C:7]1[C:6]([O:16][CH3:17])=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[CH:13]=[C:12]2[C:8]=1[CH2:9][CH:10]([CH3:15])[C:11]2=[O:14]
Reactant: BrBr
Reactant: COc1cc2c(cc1C(C)(C)C)C(=O)C(C)C2
Agent: CC[N+](CC)(CC)CC
Agent: O=S([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: ClCCl
Product: COc1c(C(C)(C)C)cc2c(c1Br)CC(C)C2=O
Temperature: 5 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a mixture of 60.0 g (0.258 mol) of 6-tert-butyl-5-methoxy-2-methylindan-1-one, 130 g of NaOAc(H2O)3, 1.5 g of Et4NI, 220 ml of dichloromethane, and 450 ml of water cooled to 5° C. 45.0 g (0.282 mol) of bromine was added for ca. 5 min by vigorous stirring. This mixture was stirred for 1 h at 5° C., and then a solution of 60.0 g of NaOAc(H2O)3 in 200 ml of water was added. To the resulting mixture 23.5 (0.147 mmol) of bromine was added at 5° C. The resulting solution was stirred for 30 min and then Na2SO3 was added by small portions to remove an excess of bromine. The CH2Cl2-layer was separated from the top aqueous one and the latter was extracted with 2×300 ml of dichloromethane. The combined organic extract was dried over K2CO3, passed through a short layer of silica gel 60 (40-63 um) and then evaporated to dryness. The residue was dried in vacuum to give 79.9 g (99%) of the title compound which was further used without an additional purification.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:18][C:19]([CH3:30])=[CH:20]B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.O>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.C(OCC)(=O)C>[CH3:20][C:19]([CH3:30])=[CH:18][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Reactant: CC(C)=CB1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)=Cc1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a mixture of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (121.6 mg, 0.4177 mmol, 2-methyl-1-propenylboronic acid pinacol ester (129 uL, 0.629 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (15.9 mg, 0.0224 mmol), and potassium carbonate (150.5 mg, 1.089 mmol) was added 1,4-dioxane (2 mL, 20 mmol) and water (0.2 mL, 10 mmol). The reaction mixture was stirred at 90° C. for 3 hours. The reaction mixture was then poured into ethyl acetate, which was washed with two portions water, dried with brine and MgSO4, filtered, and evaporated in vacuo to yield 144.5 mg of crude product. 44 mg of this crude material was purified via reverse phase HPLC and lyophilized to yield 28.2 mg N-(7-(2-methylprop-1-enyl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=4.919, M+H=267.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.10 (s, 1H), 8.41 (s, 1H), 7.86 (s, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.57 (dd, J=8.6, 1.4 Hz, 1H), 6.41 (s, 1H), 2.12-1.99 (m, 1H), 1.93 (d, J=7.7 Hz, 6H), 0.83 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14]([O:20]C4C=CC=CC=4)=[N:15][CH:16]=[N:17]3)=[CH:12][C:11]=2[O:27][CH3:28])[CH:5]=[C:4]([O:29]C)[N:3]=1.N>Cl>[Cl:1][C:2]1[NH:3][C:4](=[O:29])[CH:5]=[C:6]([CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:20])[NH:15][CH:16]=[N:17]3)=[CH:12][C:11]=2[O:27][CH3:28])[CH:7]=1
Reactant: COc1cc(COc2cc3ncnc(Oc4ccccc4)c3cc2OC)cc(Cl)n1
Agent: Cl
Agent: N
Product: COc1cc2c(=O)[nH]cnc2cc1OCc1cc(Cl)[nH]c(=O)c1
Yield: 59.9 %

Procedure:
A mixture of 7-((2-chloro-6-methoxy-4-pyridyl)methoxy)-6-methoxy-4-phenoxyquinazoline (400 mg, 0.95 mmol) and 2M hydrochloric acid (20 ml ) was heated at reflux for 3 hours. The mixture was allowed to cool and adjusted to pH6-7 with aqueous ammonia solution. The resulting precipitate was collected by filtration washed with water and dried to give crude 7-((6-chloro-2-oxo-1,2-dihydropyrid-4-yl)methoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (190 mg, 60%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([CH2:10][CH2:11][C@@H:12]1[C:17](=[O:18])[NH:16][C:15]2[CH:19]=[C:20]([CH2:23][C@H:24]([NH:30][C:31]([O:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:32])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:21]=[CH:22][C:14]=2[O:13]1)(O)=[O:8].S(O)(O)(=O)=O.[NH2:44][C:45]1[NH:46][CH:47]=[CH:48][N:49]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:38][C:35]([CH3:36])([CH3:37])[CH2:34][O:33][C:31]([NH:30][C@@H:24]([CH2:23][C:20]1[CH:21]=[CH:22][C:14]2[O:13][C@H:12]([CH2:11][CH2:10][C:7](=[O:8])[NH:44][C:45]3[NH:46][CH:47]=[CH:48][N:49]=3)[C:17](=[O:18])[NH:16][C:15]=2[CH:19]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:32]
Reactant: CCOC(=O)[C@H](Cc1ccc2c(c1)NC(=O)[C@@H](CCC(=O)O)O2)NC(=O)OCC(C)(C)C
Reactant: Nc1ncc[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc2c(c1)NC(=O)[C@@H](CCC(=O)Nc1ncc[nH]1)O2)NC(=O)OCC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.6 g of potassium carbonate are added to a solution of 10 g of 9, 4.4 g of 2-aminoimidazole sulfate, 9.26 g of TBTU and 0.9 g of HOBt in 100 ml of absolute DMF, and the mixture is stirred at 700 under nitrogen for 16 hours. The mixture is cooled to room temperature, poured into 750 ml of cold water, the precipitate is separated off, washed with cold water and dried. The crude product is treated with hot acetonitrile and filtered off after cooling. The residue is recrystallised from ethanol, giving 10.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([CH2:24]O)[CH:19]=4)[CH:13]=3)[CH2:9][C:8](=[O:26])[NH:7][C:6]=2[CH:27]=1.S(Cl)(Cl)=O.[Cl-].[CH:34]1([NH2:37])[CH2:36][CH2:35]1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][NH:37][CH:34]5[CH2:36][CH2:35]5)[CH:19]=4)[CH:13]=3)[CH2:9][C:8](=[O:26])[NH:7][C:6]=2[CH:27]=1
Reactant: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2
Reactant: NC1CC1
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccnc(CNC4CC4)c3)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-methyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 282) (196 mg, 0.50 mmol) by reaction with thionylchloride in CH2Cl2 and subsequent treatment of the corresponding crude chloride with cyclopropylamine in DMF according to the general procedure of example 288. Obtained as a light brown (96 mg, 45%).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.Cl.Cl[CH2:15][CH2:16][NH2:17].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:15][CH2:16][NH2:17]
Reactant: NCCCl
Reactant: Brc1cccc2[nH]ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: CC#N
Solvent: O
Product: NCCn1ccc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38.8 %

Procedure:
Tetrabutylammonium hydrogen sulfate (41.0 mg, 0.121 mmol) and sodium hydroxide (210 mg, 5.25 mmol) were added to a solution of 4-bromo-1H-indole (0.30 ml, 2.39 mmol) in acetonitrile (0.80 mL), and the mixture was stirred at room temperature for 20 minutes. Subsequently, 2-chloroethylamine hydrochloride (334 mg, 2.88 mmol) was added and the mixture was heated with stirring at 100° C. for seven hours. After cooling, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and saturated brine and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane-methanol) to give 2-(4-bromo-indol-1-yl)-ethylamine (222 mg, 39%).
Reaction SMILES: C(OC(=O)C(C)CC=C)C.CC(C[AlH]CC(C)C)C.CC(CC=C)C=O.C(N)C=C.[CH2:31]([N:34]=[CH:35][CH:36]([CH3:40])[CH2:37][CH:38]=[CH2:39])[CH:32]=[CH2:33].[BH4-].[Na+]>C(Cl)Cl.CO>[CH2:31]([NH:34][CH2:35][CH:36]([CH3:40])[CH2:37][CH:38]=[CH2:39])[CH:32]=[CH2:33]
Reactant: C=CCN=CC(C)CC=C
Agent: C=CCC(C)C(=O)OCC
Agent: C=CCC(C)C=O
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: ClCCl
Solvent: C=CCN
Product: C=CCNCC(C)CC=C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a solution of 2-methyl-pent-4-enoic acid ethyl ester (7.1 g, 50 mmol) was added dropwise a solution of DIBAL (1.0 M in hexanes, 75 ml) at −78 C. over 1.0 h. After the addition, the reaction mixture was stirred at −78 C. for another hour. The reaction was quenched with saturated NH4Cl (10 ml) and 4% HCl, then was extracted with EtOAc (3×100 ml). The combined organic extracts were dried with MgSO4, filtered, concentrated by rotary evaporation and the crude reaction product was used in the next reaction without further purification. 2-Methyl-4-pentenal (3.3 g, 33.7 mmol) was dissolved in CH2Cl2 (100 ml). To this solution allylamine (2.9 g, 50.5 mmol) was added. Molecular sieves (5 g) were used to absorb water generated during the reaction. The mixture was stirred at room temperature over night. The reaction mixture was concentrated by rotary evaporation and the crude product was used in the next reaction without further purification. Allyl-(2-methyl-pent-4-enylidene)-amine (3.2 g, 23.4 mmol) was diluted in 50 ml MeOH. To the solution NaBH4 (1.0 g, 26.3 mmol) was added at 0° C. After addition the mixture was stirred at RT for 5 h. The reaction mixture was concentrated and the residue was partitioned between EtOAc/20% aq. NaOH. The organic layer was dried over Na2SO4, fitered and concentrated by rotary evaporation to give allyl-(2-methyl-pent-4-enyl)-amine (1.5 g 48% yield): 1H-NMR (400 Hz, CDCl3): d=5.93–5.68 (m, 2H), 5.18–4.92(m, 4H), 3.21 (d, 2H), 2.60–2.40(m, 2H), 1.97–1.65(m, 2H), 0.92(d, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]([O-:10])=O)[O:6][CH2:5][CH2:4][N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Li+].Cl.C([NH+](CC)CC)C.N1C2C(=NC=CC=2)N(O)N=1.[F:36][C:37]1[CH:38]=[C:39]([NH2:56])[CH:40]=[CH:41][C:42]=1[O:43][C:44]1[C:53]2[C:48](=[CH:49][C:50]([O:54][CH3:55])=[CH:51][CH:52]=2)[N:47]=[CH:46][CH:45]=1>>[F:36][C:37]1[CH:38]=[C:39]([NH:56][C:8]([CH:7]2[O:6][CH2:5][CH2:4][N:3]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:2]2=[O:1])=[O:10])[CH:40]=[CH:41][C:42]=1[O:43][C:44]1[C:53]2[C:48](=[CH:49][C:50]([O:54][CH3:55])=[CH:51][CH:52]=2)[N:47]=[CH:46][CH:45]=1
Reactant: COc1ccc2c(Oc3ccc(N)cc3F)ccnc2c1
Reactant: O=C([O-])C1OCCN(c2ccccc2)C1=O
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: On1nnc2cccnc21
Product: COc1ccc2c(Oc3ccc(NC(=O)C4OCCN(c5ccccc5)C4=O)cc3F)ccnc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 15.2 %

Procedure:
A dry, 10 mL schlenk-type flask was charged with a stirbar, lithium 3-oxo-4-phenylmorpholine-2-carboxylate (0.096 g, 0.42 mmol), triethylammonium hydrochloride (0.058 g, 0.42 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.072 g, 0.53 mmol), and evacuated. The flask was back-filled with nitrogen and treated with 2 mL dry THF and 1 mL dry NMP. To the stirring solution was added Si-DCC (0.55 g, 0.53 mmol) followed by 3-fluoro-4-(7-methoxyquinolin-4-yloxy)benzenamine (0.100 g, 0.35 mmol). The reaction was stirred for 3 d at RT, and then 60° C. for 24 h. The slurry was filtered through a 0.22 nm frit, and the THF removed. The crude was purified by HPLC (Waters Spherisorb S5 column (PN PSS830195, 20×250 mm, 60 Å pore, 5 nm particle size)) to afford the title compound (0.026 g, 15.2% yield) 1H NMR (400 MHz, Chloroform-d) 3.74 (ddd, J=12.32, 3.72, 3.52 Hz, 1H), 3.95-4.03 (m, 4H), 4.23 (dt, J=12.42, 3.91 Hz, 1H), 4.27-4.38 (m, 1H), 5.06 (s, 1H), 6.37 (dd, J=5.23, 1.12 Hz, 1H), 7.20 (t, J=8.56 Hz, 1H), 7.24 (dd, J=9.15, 2.49 Hz, 1H), 7.27 (ddd, J=8.83, 2.47, 1.12 Hz, 1H), 7.32-7.41 (m, 3H), 7.43 (d, J=2.45 Hz, 1H), 7.46-7.51 (m, 2H), 7.81 (dd, J=12.03, 2.35 Hz, 1H), 8.26 (d, J=9.19 Hz, 1H), 8.59 (d, J=5.18 Hz, 1H), 9.66 (br. s., 1H). MS (ESI pos. ion) m/z=488, calc'd for C27H22FN3O5 487.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:5]=1.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[N:31]=[C:30]([C:38](O)=O)[N:29]=2)[CH:21]=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25])[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:28]2[CH:33]=[C:32]([C:34]([F:36])([F:37])[F:35])[N:31]=[C:30]([C:38]3[O:1][N:2]=[C:3]([C:4]4[CH:5]=[C:6]([S:10]([NH2:11])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=4)[N:14]=3)[N:29]=2)[CH:21]=[CH:22][C:23]=1[C:24]([F:25])([F:26])[F:27])[CH3:16]
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Reactant: CCOc1cc(-c2cc(C(F)(F)F)nc(C(=O)O)n2)ccc1C(F)(F)F
Product: CCOc1cc(-c2cc(C(F)(F)F)nc(-c3nc(-c4cccc(S(N)(=O)=O)c4)no3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (0.16 g, 0.75 mmol) and 4-(3-ethoxy-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.4) (0.19 g, 0.5 mmol) according to the general procedure V. Obtained as a white solid (0.05 g, 18%). MS (ISP) 560.0 [(M+H)+]; mp 227° C.
Reaction SMILES: Cl[C:2]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:13]=[CH:12][C:11]=2[NH:22][C:23]([C:25]2[CH:26]=[C:27]([CH:39]=[CH:40][CH:41]=2)[CH2:28][S:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:24])[CH:5]=1)=[O:3].[O:42]1[CH2:47][CH2:46][N:45]([C:48]2[CH:53]=[CH:52][C:51]([CH2:54][NH2:55])=[CH:50][CH:49]=2)[CH2:44][CH2:43]1.CCN(C(C)C)C(C)C.CN>O1CCCC1.O>[O:42]1[CH2:43][CH2:44][N:45]([C:48]2[CH:49]=[CH:50][C:51]([CH2:54][NH:55][C:2]([C:4]3[CH:9]=[CH:8][N:7]=[C:6]([C:10]4[CH:15]=[C:14]([N:16]5[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]5)[CH:13]=[CH:12][C:11]=4[NH:22][C:23]([C:25]4[CH:26]=[C:27]([CH:39]=[CH:40][CH:41]=4)[CH2:28][S:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:24])[CH:5]=3)=[O:3])=[CH:52][CH:53]=2)[CH2:46][CH2:47]1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)Cl)ccn2)c1
Reactant: NCc1ccc(N2CCOCC2)cc1
Agent: CN
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3ccc(N4CCOCC4)cc3)ccn2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 133.3 %

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 3-(3-(2-(4-(chlorocarbonyl)pyridin-2-yl)-4-(piperidin-1-yl)phenylcarbamoyl)-benzylthio)-propanoate (120 mg, 0.20 mmol, 1.00 equiv) in tetrahydrofuran (10 mL), (4-morpholinophenyl)methanamine (68 mg, 0.35 mmol, 1.50 equiv), and DIPEA (32 mg, 0.25 mmol, 3.00 equiv). The resulting solution was stirred for 4 h at room temperature. An additional 68 mg of 4-morpholinophenyl)methanamine was added. The resulting solution was stirred for an additional 2 h at room temperature. The resulting solution was diluted with 10 mL of H2O. The resulting solution was extracted with 3×50 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 200 mg of crude product as a yellow oil.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([CH2:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].NC1[CH:26]=[CH:25][C:24]([N:27]2[CH2:31][CH2:30][C@@H:29]([N:32]([CH2:34][CH2:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH3:33])[CH2:28]2)=[CH:23][CH:22]=1>>[CH:17]1([CH2:16][CH2:15][C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([C:14]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:31][CH2:30][C@@H:29]([N:32]([CH2:34][CH2:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH3:33])[CH2:28]5)=[CH:23][CH:22]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)[CH2:18][CH2:19]1
Reactant: CN(CCS(C)(=O)=O)[C@@H]1CCN(c2ccc(N)cc2)C1
Reactant: COC(=O)c1sc(CCC2CC2)cc1N=CN(C)C
Product: CN(CCS(C)(=O)=O)[C@@H]1CCN(c2ccc(-n3cnc4cc(CCC5CC5)sc4c3=O)cc2)C1

Procedure:
5-(2-Cyclopropylethyl)-3-(dimethylaminomethyleneamino)thiophene-2-carboxylic acid methyl ester was reacted with [(R)-1-(4-aminophenyl)pyrrolidin-3-yl]-(2-methanesulfonylethyl)methylamine by method A1. The product with the molecular weight of 500.57 (C25H32N4O3S2) was obtained in this way; MS (ESI): 501 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:27]5[O:26][CH2:25][CH2:24][C:23]=5[CH:22]=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:29][CH2:30][NH:31][CH3:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:27]5[O:26][CH2:25][CH2:24][C:23]=5[CH:22]=[CH:21][CH:20]=4)[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:29][CH2:30][NH:31][CH3:32])=[CH:4][CH:3]=1
Reactant: CNCCCl
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2cccc3c2OCC3)CC1
Product: CNCCn1cc(C(=O)N2CCC(c3cccc4c3OCC4)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) (2-chloro-ethyl)-methyl-amine gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[O:18][C:14]=4[CH:13]=3)[C:7]=2[CH:24]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32].CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]5[OH:32])[O:18][C:14]=4[CH:13]=3)[C:7]=2[CH:24]=1
Reactant: COc1ccc2ncn(Cc3ccc4nc(S(C)=O)oc4c3)c2c1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc2ncn(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)oc4c3)c2c1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 29 %

Procedure:
A mixture of 6-((6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methyl sulfinyl)benzo[d]oxazole (595 mg, 1.74 mmol), (1R,2R)-2-aminocyclohexanol (301 mg, 2.6 mmol) and DIEA (449 mg, 3.48 mmol) in DMA (12 mL) was stirred at 120° C. for 1.5 h. The reaction mixture was cooled to rt, poured into water (30 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to give (1R,2R)-2-((6-((6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol as a white solid (198 mg, 29.0%). 1H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.80 (d, J=6.9 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.36 (s, 1H), 7.14 (s, 3H), 6.80 (dd, J=2.4, 9.0 Hz, 1H), 5.42 (s, 2H), 4.68 (d, J=3.3 Hz, 1H), 3.76 (s, 3H), 3.33 (br s, 2H), 1.89 (br s, 2H), 1.62 (br s, 2H), 1.22 (br s, 4H). LCMS (ESI) m/z 393 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][S:16][CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][S:16]([CH3:17])=[O:35])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCCCC(C)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Product: CC(CCCS(C)=O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The 2-[1-[(4-chlorophenyl)sulfonyl]-2-methyl-5-(methylthio)pentyl]-1,4-difluorobenzene (Isomer 43-B) (175 mg, 0.418 mmol) obtained in Example 43 was dissolved in methylene chloride (10 ml). Under ice cooling, 3-chloroperbenzoic acid (87 mg, 0.50 mmol) was added. The resulting mixture was stirred at room temperature for 14 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was purified silica gel chromatography (methylene chloride:methanol=40:1) to yield a white solid. The resulting solid was washed with diethyl ether, whereby the title compound (118 mg, 65%) was obtained as a white powder.
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH3:15])=[C:13]2[C:5]([CH2:6][CH2:7][C:8]3([O:12]2)[CH2:11][CH2:10][CH2:9]3)=[CH:4][C:3]=1[OH:16].[CH3:17][C:18](=[CH:20][CH2:21][CH2:22]/[C:23](=[CH:25]/[CH2:26]O)/[CH3:24])[CH3:19].O>O1CCOCC1>[CH3:24][C:23]([CH2:22][CH2:21][CH:20]=[C:18]([CH3:19])[CH3:17])=[CH:25][CH2:26][C:4]1[C:3]([OH:16])=[C:2]([CH3:1])[C:14]([CH3:15])=[C:13]2[C:5]=1[CH2:6][CH2:7][C:8]1([O:12]2)[CH2:9][CH2:10][CH2:11]1
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: Cc1c(O)cc2c(c1C)OC1(CCC1)CC2
Solvent: C1COCCO1
Solvent: O
Product: CC(C)=CCCC(C)=CCc1c(O)c(C)c(C)c2c1CCC1(CCC1)O2
Reaction time: 8 h

Procedure:
To a solution of 7,8-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol (0.5 g) in 20 mL of dioxane under argon, was added borontrifluoride-diethyl etherate (0.72 mL) followed by geraniol (0.4 mL) and the reaction was stirred overnight. After addition of water, the solution was extracted with EtOAc, washed with brine, dried over Na2SO4, and evaporated. The residue was purified on a silica column eluting with 1:8 EtOAc/hexane to give 5-(3,7-dimethylocta-2,6-dienyl)-7,8-dimethylspiro[chroman-2,1′-cyclobutan]-6-ol (104 mg ) as an amber oil. 1H-NMR (300 MHz, CDCl3) δ=1.65-1.99 (m, 10H), 2.01-2.28 (m, 17H), 2.74-2.79 (t, 2H), 3.35-3.37 (d, H), 4.78 (s, 1H), 5.10-5.12 (t, 1H), 5.17-5.21 (t, 1H) ppm. 13C-NMR (75 MHz, CDCl3) δ=11.93, 12.15, 12.61, 16.21, 17.80, 20.47, 25.55, 25.80, 26.45, 29.58, 34.05, 39.74, 76.23, 117.15, 121.87, 121.97, 122.48, 123.62, 123.89, 132.02, 138.03, 145.52, 145.89 ppm. MS (m/z)=354 (M+H+).