Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:37])([CH3:36])[C@@:8](C)(/[CH:20]=[CH:21]/[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][C:26]([C@H:32]([OH:34])[CH3:33])=[CH:27][CH:28]=2)[CH:23]=1)[C:9](N1[C@H](C(C)C)COC1=O)=O)([CH3:4])([CH3:3])[CH3:2].[OH:38]O.O.[OH-].[Li+].[O:43]1[CH2:47]CCC1.O>>[C:1]([SiH2:5][O:6][C:7]([CH3:36])([CH3:37])[C@@:8]([CH3:9])(/[CH:20]=[CH:21]/[C:22]1[CH:23]=[CH:24][C:29]2[C:30](=[CH:25][C:26]([C@H:32]([OH:34])[CH3:33])=[CH:27][CH:28]=2)[CH:31]=1)[C:47]([OH:43])=[O:38])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[C@@H]1COC(=O)N1C(=O)[C@](C)(/C=C/c1ccc2ccc([C@@H](C)O)cc2c1)C(C)(C)O[SiH2]C(C)(C)C
Reactant: OO
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: C[C@@H](O)c1ccc2ccc(/C=C/[C@@](C)(C(=O)O)C(C)(C)O[SiH2]C(C)(C)C)cc2c1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 84 %

Procedure:
A cooled (0° C.) solution of (R)-3-{(E)-(R)-2-(tert-butyl-dimethyl-silanyloxymethyl)-4-[7-((R)-1-hydroxy-ethyl)-naphthalen-2-yl]-2-methyl-but-3-enoyl}-4-isopropyl-oxazolidin-2-one (116.7 mg, 0.222 mmol) in tetrahydrofuran/water (12 mL, 5:1) was subsequently treated with hydrogen peroxide (30% aqueous, 120 μL, 1.110 mmol) and lithium hydroxide monohydrate (18.6 mg, 0.444 mmol). After stirring at 0° C. for 3.5 h, the reaction mixture was treated with hydrogen peroxide (30% aqueous, 120 μL, 1.110 mmol) and lithium hydroxide monohydrate (18.6 mg, 0.444 mmol). After stirring at 0° C. for 2.5 h the reaction was quenched with solid sodium metabisulfite (850 mg). After stirring at room temperature for 45 mins the mixture was acidified with hydrochloric acid (1 M, 20 mL). The aqueous layer was extracted with dichloromethane (2×). The combined organics were filtered through a phase separator and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 25 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 3:2 to afford the title compound (77.1 mg, 84%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 0.15 (s, 6H), 0.94 (s, 9H), 1.47 (s, 3H), 1.60 (d, J=6.5 Hz, 3H), 3.79, 3.92 (ABq, JAB=9.6 Hz, 2H), 5.08 (q, J=6.5 Hz, 1H), 6.43 (d, J=16.5 Hz, 1H), 6.72 (d, J=16.5 Hz, 1H), 7.06-7.22 (m, 2H), 7.40-7.60 (m, 2H), 7.70-7.84 (m, 2H). LCMS (m/z) 415.2 [M+H], Tr=3.40 min.
Reaction SMILES: N[C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[O:7])=[C:4]([OH:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]#[CH:29].C[N:32](C=O)C>C1(C)C=CC=CC=1>[NH2:32][C:3]1[C:4]([O:20][CH2:27][C:28]#[CH:29])=[C:5]([CH:17]=[C:18]([Cl:19])[CH:2]=1)[C:6]([NH:8][CH:9]1[CH:14]2[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]2)[CH2:10]1)=[O:7]
Reactant: CN(C)C=O
Reactant: Nc1cc(O)c(C(=O)NC2CN3CCC2CC3)cc1Cl
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C#CCOc1c(N)cc(Cl)cc1C(=O)NC1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
A mixture of 4-amino-N-(1-azabicyclo[2.2.2]-oct-3-yl)-5-chloro-2-hydroxybenzamide (590 mg), potassium carbonate (2.8 g), propargyl bromide (9.3 g of an 80% solution of propargyl bromide in toluene) in DMF (10 mL) was stirred at room temperature for 1 hour. The solid was filtered off, and the filtrate diluted with ether. The resulting precipitate was collected and washed with ether. This solid was dissolved in a small amount of a mixture of acetonitrile, methanol and ammonium hydroxide in the ratio of 100:15:0.5, and flash chromatographed over silica gel eluting with the same solvent system. The appropriate fractions were combined and concentrated. The resulting solid was dried under vacuum to yield the title compound (0.115 g; 17%), m.p. >170° C. decomp.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][C:3]1=[O:13].B.[Na].Cl.[CH3:18]O>CO>[CH3:18][O:13][CH:3]1[C:2]([CH3:14])([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4]1
Reactant: CC1(C)C(=O)NC(=O)c2ccccc21
Reactant: CO
Agent: B
Agent: Cl
Agent: [Na]
Product: COC1NC(=O)c2ccccc2C1(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound (2.0 g) obtained in step (c) just above was dissolved in methanol (100 ml). Sodium boron hydride (1.7 g) was added to the solution. The mixture was stirred at room temperature for 3 hr. Hydrochloric acid-methanol (50 ml) was added to the reaction solution, and the mixture was stirred at room temperature for one hr. The reaction solution was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 3-methoxy-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one (1.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.CO[CH:13](OC)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH:15]=1>>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]2[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]=3[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]4[N:22]=[CH:23][CH:24]=[CH:25][N:26]=4)[CH:15]=3)[C:3]=2[C:4](=[O:10])[CH2:5]1
Reactant: COC(OC)c1cccc(Oc2ncccn2)c1
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc(Oc2ncccn2)c1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 3-(2-pyrimidinyloxy)-benzaldehyde dimethyl acetal in an analogous manner to that described in Example 1 gave 3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9-[3-(2-pyrimidinyloxy)-phenyl]-1,8(2H,5H)-acridinedione. Crystallization from dimethylformamide/water gave a pale yellow crystalline solid of melting point 220-221° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16].[BH4-].[Na+].Cl>COCCOC.O1CCCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[CH:13]=[C:14]([CH2:15][OH:16])[CH:17]=[CH:18][CH:19]=1
Reactant: Cc1ccc2ccccc2c1-c1cccc(C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: Cc1ccc2ccccc2c1-c1cccc(CO)c1
Reaction time: 3 h
Yield: 81.4 %

Procedure:
3-(2-Methyl-1-naphthyl)benzaldehyde (2.39 g, 9.70 mmol) was dissolved in a mixture of 1,2-dimethoxyethane (10 mL) and tetrahydrofuran (10 mL), and sodium borohydride (0.189 g, 5.00 mmol) was added under ice-cooling. The mixture was stirred at the same temperature for 3 hr. Dilute hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-30% ethyl acetate/hexane) to give the title compound (1.96 g, yield 81%) as a colorless viscous oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=[C:5]([O:20][CH3:21])[CH:4]=1.[C-:22]#[N:23].[K+].C1OCCOCCOCCOCCOCCOC1.O>CN(C)C=O>[CH3:21][O:20][C:5]1[CH:4]=[C:3]([CH2:2][C:22]#[N:23])[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=1
Reactant: [C-]#N
Reactant: COc1ccc(-c2cc3cc(OC)cc(CBr)c3o2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3cc(OC)cc(CC#N)c3o2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a solution of benzyl bromide 17 (0.640 g, 1.843 mmole) in 100 mL dimethylformamide was added pulverized potassium cyanide (0.186 g, 2.76 mmole) and 18-crown-6 ether (0.786 g, 2.965 mmole). After stirring at 80° C. for 2 hours, the reaction mixture was cooled and poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 9:1) to afford 0.529 g (98%) of acetonitrile 18 as a white solid: Mp=149–150° C.; 1H NMR (DMSO-d6) δ 7.87 (d, 2 H, J=8.8 Hz), 7.26 (s, 1 H), 7.12 (d, 1 H, J=2,4 Hz), ), 7.10 (d, 2 H, J=8.7 Hz), 6.88 (d, 1 H, J=2.4 Hz), 4.42 (s, 2 H), 3.82 (s, 3 H), 3.81 (s, 3 H); MS 294 (M+H)+
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[CH:13]=[CH:14][C:15]([OH:17])=[O:16])[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[H][H]>CO.[Pd]>[N:1]1([CH:6]([C:10]2[CH:11]=[C:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:18]=[CH:19][CH:20]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCC(c1cccc(C=CC(=O)O)c1)n1ccnc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCC(c1cccc(CCC(=O)O)c1)n1ccnc1
Reaction time: 2 h
Yield: 96.5 %

Procedure:
1.08 g of 3-[1-(1-imidazolyl)-butyl]-cinnamic acid (example 42) is dissolved in 20 ml of methanol and mixed with 100 mg of palladium on carbon (10%) and hydrogenated at normal pressure. After 2 hours, the reaction mixture does not take up any more hydrogen. Then the catalyst is filtered off on kieselguhr and the filtrate is concentrated by evaporation in a vacuum. 1.05 g of 3-[3-[1-(1-imidazolyl)-butyl]-phenyl]propionic acid is obtained
Reaction SMILES: N#N.[C:3]([O:7][C:8](=[O:20])[NH:9][C@H:10]([C:12]1[CH:17]=[C:16]([CH3:18])[C:15](Br)=[CH:14][N:13]=1)[CH3:11])([CH3:6])([CH3:5])[CH3:4].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[CH:25][N:24]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O>[C:3]([O:7][C:8](=[O:20])[NH:9][C@H:10]([C:12]1[N:13]=[CH:14][C:15]([C:27]2[CH:26]=[CH:25][N:24]=[C:23]([C:22]([F:33])([F:32])[F:21])[CH:28]=2)=[C:16]([CH3:18])[CH:17]=1)[CH3:11])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1cc([C@H](C)NC(=O)OC(C)(C)C)ncc1Br
Reactant: OB(O)c1ccnc(C(F)(F)F)c1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc([C@H](C)NC(=O)OC(C)(C)C)ncc1-c1ccnc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 82.6 %

Procedure:
N2 was bubbled through a solution of (S)-tert-butyl(1-(5-bromo-4-methylpyridin-2-yl)ethyl)carbamate (200 mg, 0.635 mmol), (2-(trifluoromethyl)pyridin-4-yl)boronic acid (145 mg, 0.761 mmol) and Na2CO3 (2.0 M, 635 μl, 1.269 mmol) in dioxane for 5 min. Cl2Pd(dppf) (CH2Cl2 adduct) (51.8 mg, 0.063 mmol) was added. The reaction mixture was stirred at 90° C. for 16 hr. The mixture was diluted with EtOAc, washed with water, brine, dried over Na2SO4, filtered, concentrated and purified through flash column chromatography (0-100% EtOAc/Heptane) to give 200 mg (S)-tert-butyl(1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)carbamate as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.83 (d, J=4.9 Hz, 1H), 8.36 (s, 1H), 7.66 (s, 1H), 7.51-7.42 (m, 1H), 7.21 (s, 1H), 5.60 (d, J=7.7 Hz, 1H), 4.87 (p, J=6.9 Hz, 1H), 2.30 (s, 3H), 1.48 (d, J=6.9 Hz, 3H), 1.45 (s, 9H). MS m/z 382.3 (M+H).
Reaction SMILES: [C:1]([NH:9][CH:10]([C:16](=[O:18])[CH3:17])[CH2:11][C:12]([O:14][CH3:15])=[O:13])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH3:17][C:16]1[O:18][C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9][C:10]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CC(NC(=O)c1ccccc1)C(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)Cc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.7 %

Procedure:
To β-methyl N-benzoyl-L-aspartate (compound [3]; 229.9 g) obtained in Example 1 were successively added toluene (1.2 L), acetic anhydride (346 mL), N-methylmorpholine (4.7 mL) and 4-dimethylaminopyridine (1.04 g) and the mixture was stirred at internal temperature of 55–0° C. for 4 hr to give a solution of methyl 3-benzoylamino-4-oxopentanoate (compound [4]) in toluene. Without isolating compound [4], p-toluenesulfonic acid monohydrate (31.8 g) was added to this solution of methyl 3-benzoylamino-4-oxopentanoate (compound [4]) in toluene. The mixture was stirred at 85–90° C. for 5 hr and cooled to room temperature. To the reaction mixture was added, with stirring, an aqueous solution of sodium carbonate (75.6 g) in water (303 mL), and the mixture was adjusted to pH 7–7.5. After standing still, the aqueous layer was removed and the organic layer was concentrated to give the title compound (compound [5]; 206.7 g, yield 97.7%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38]>>[CH:18]1([N:13]2[C:12]([C:35]3[CH:34]=[CH:33][C:32]([F:31])=[C:37]([F:38])[CH:36]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: Fc1ccc(-c2c3c(nn2C2CCCC2)CCNCC3)cc1F
Yield: 47.9 %

Procedure:
The title compound (70 mg) was prepared according to Example 180 using 209 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 218 mg of 3,4-difluorophenylboronic acid. MS (ESI): exact mass calculated for C18H21F2N3, 317.17; found, m/z 318.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.50-7.45 (m, 1H), 7.36-7.32 (m, 1H), 7.18-7.17 (m, 1H), 4.49 (m, 1H), 3.43-3.41 (m, 2H), 3.21-3.19 (m, 2H), 2.80-2.78 (m, 2H), 2.15-1.87 (m, 6H), 1.66-1.61 (m, 2H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][CH2:11][CH:12]([CH3:16])C(O)=O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([N:19]([CH2:22]C)CC)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:31])=CC=1.C1(C)C=CC=CC=1>C(Cl)(Cl)Cl.CO>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:11][CH:12]([CH3:16])[NH:19][C:22]3=[O:31])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Reactant: CC(CNc1ccc2ncsc2c1)C(=O)O
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC1CN(c2ccc3ncsc3c2)C(=O)N1
Yield: 70.8 %

Procedure:
3-(Benzothiazol-6-ylamino)-2-methyl-propionic acid (I-167a: 500 mg, 2.118 mmol) was refluxed with triethylamine (1 mL, 6.989 mmol), DPPA (1.75 g, 6.35 mmol) and toluene (10 mL) at 120° C. in a sealed tube to afford the crude product. The reaction was monitored by TLC (5% methanol in chloroform). Purification by column chromatography on silica gel (2% methanol in chloroform) afforded 350 mg of the product (71.42% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:19]=[CH:18][C:11]([O:12][CH2:13][CH:14]([OH:17])[CH2:15][NH2:16])=[CH:10][CH:9]=1.[CH3:20][C:21]1[CH:32]=[CH:31][C:24]([C:25]([CH2:27][C:28](=O)[CH3:29])=[O:26])=[CH:23][N:22]=1.C(O)C>C(O)=O>[CH3:20][C:21]1[CH:32]=[CH:31][C:24]([C:25]([CH:27]=[C:28]([NH:16][CH2:15][CH:14]([OH:17])[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:19][CH:18]=2)[CH3:29])=[O:26])=[CH:23][N:22]=1
Reactant: COCCCCOc1ccc(OCC(O)CN)cc1
Reactant: CC(=O)CC(=O)c1ccc(C)nc1
Solvent: CCO
Solvent: O=CO
Product: COCCCCOc1ccc(OCC(O)CNC(C)=CC(=O)c2ccc(C)nc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89 %

Procedure:
54.0 g of 1-(p-[4-methoxybutoxy]-phenoxy)-3-aminopropan-2-ol ##STR76## 37.3 g of 6-methylnicotinoyl-acetone ##STR77## 400 ml of ethanol and 0.1 ml of formic acid are heated to 50° for 1 hour and stirred at room temperature for a further 20 hours. Filtration gives 61.3 g of 1-(2-[6-methylnicotinoyl]-1-methylvinylamino)-3-(p-[4-methoxybutoxy]-phenoxy)-propan-2-ol ##STR78## Melting point: 143°-145°. A further 15.0 g of the same substance can be obtained from the filtrate. Yield: 89% of theory.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([N:25]=[C:26]=[S:27])(=O)C1C=CC=CC=1.CO.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:26]([NH2:25])=[S:27])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cccc(NC(N)=S)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3 g (13.5 mmol) (3-amino-benzyl)-carbamic acid tert-butyl ester (WO 9740028 A1) and 1.81 ml (13.5 mmol) benzoyl isothiocyanate in 60 ml THF was stirred at room temperature for 1 h and afterwards evaporated under reduced pressure. 80 ml MeOH and 5.6 g (40.5 mmol) potassium carbonate in 80 ml water were added and the mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layers were washed with saturated NaHCO3 solution and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica eluting with a gradient of hexane/ethyl acetate to yield after evaporation of the product fractions 3.56 g (94%) of the title compound as yellow amorphous solid.
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][NH:9][CH2:10][CH2:11][C@@H:12]([CH3:24])[O:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1.COC(=O)C.[Cl:46]C1C(C(F)(F)F)=CC=CC=1C=O.Cl.CCOCC>CCOCC>[ClH:46].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:9]([CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:10][CH2:11][C@@H:12]([CH3:24])[O:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)=[CH:35][CH:34]=1
Reactant: COc1ccc(C=O)cc1
Reactant: C[C@H](CCNCC(c1ccccc1)c1ccccc1)Oc1cccc(CC(=O)O)c1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Agent: Cl
Solvent: COC(C)=O
Solvent: CCOCC
Product: COc1ccc(CN(CC[C@@H](C)Oc2cccc(CC(=O)O)c2)CC(c2ccccc2)c2ccccc2)cc1

Procedure:
Following the procedure of Example 7(d) except (R)-2-(3-{3-[(2,2-diphenylethyl)amino]-1-methyl-propoxy}-phenyl)acetic acid and 4-methoxybenzaldehyde were used instead of (R)-2-(3-{3-(2,2-diphenylethyl)amino]-3-methyl-propoxy}phenyl)acetic acid methyl ester and 2-chloro-3-trifluoromethylbenzaldehyde in step (d) the corresponding carboxylic acid was obtained. The crude product was purified by preparative HPLC (TMC CombiPrep PDS, 75×30 mm, 25 mL/min, acetonitrile: H2O, UV detection at 254 nm) to afford the free base. The resulting amine/carboxylic acid was dissolved in Et2O (diethylether) and acidified with 1.0 M HCl/Et2O. The reaction mixture was concentrated in vacuo and dried under reduced pressure to give the title compound as a white solid, 78 mg (80%). MS (ESI) 524.6 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:15]=2[O:24][CH3:25])=[C:4]([CH3:26])[N:3]=1.[CH2:27](O)[CH2:28][OH:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:27][CH2:28][OH:29])=[O:22])=[CH:16][C:15]=2[O:24][CH3:25])=[C:4]([CH3:26])[N:3]=1
Reactant: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1OC
Reactant: OCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)OCCO)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from step (vi) (100 mg), ethane-1,2-diol (0.031 ml) and Hunig's Base (0.146 ml) were combined in DMF (5 mL) and HATU (106 mg) was added and stirred at rt for 1 h. The reaction mixture was purified by RPHPLC to give the title compound as a solid, 6 mg.
Reaction SMILES: C([C:11]1[S:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[CH:12]=1)#CCCCCCCCC.[CH2:20]([Li])[CH2:21][CH2:22][CH3:23].CN(C)[CH:27]=[O:28]>CCOCC>[C:20]([C:18]1[CH:17]=[CH:16][C:14]2[S:15][C:11]([CH:27]=[O:28])=[CH:12][C:13]=2[CH:19]=1)#[C:21][CH2:22][CH2:23][CH2:11][CH2:12][CH2:13][CH2:14][CH2:16][CH3:17]
Reactant: CN(C)C=O
Reactant: [Li]CCCC
Reactant: CCCCCCCCC#Cc1cc2ccccc2s1
Solvent: CCOCC
Product: CCCCCCCCC#Cc1ccc2sc(C=O)cc2c1
Temperature: 25 °C
Yield: 52 %

Procedure:
To a solution of 5° (1-decynyl)benzo[b]thiophene (20.0 g) in dry ether (150 ml), under nitrogen, was added n-butyllithium (2.5M in hexanes) (32.6 ml) dropwise, with stirring at room temperature. The solution was stirred at room temperature, under nitrogen, for 2.5 hrs and then cooled to -60° C. A solution of dry dimethylformamide (5.95 g) in dry ether (15 ml) was added dropwise, and the reaction mixture was allow to warm to room temperature. The reaction mixture was quenched with ammonium chloride solution and the layers separated. The aqueous phase was extracted with ether, the organic extracts combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was flash chromatographed (silica: 3-4%, ethyl acetate:heptane). The appropriate fractions were collected and evaporated. The residue was recrystallized from heptane to give 11.5 g (52.0%) of product, mp 45°-47° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:17]3[C:12]([C:13]([NH2:18])=[N:14][CH:15]=[N:16]3)=[C:11]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:35]1(=O)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH2:28]([N:24]1[CH:23]=[C:22]2[C:26]([CH:27]=[C:19]([C:11]3[CH:10]=[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][CH:35]5[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)[CH:4]=4)[N:17]4[C:12]=3[C:13]([NH2:18])=[N:14][CH:15]=[N:16]4)[CH:20]=[CH:21]2)=[N:25]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Reactant: O=C1CCCCCC1
Product: Nc1ncnn2c(-c3cccc(CNC4CCCCCC4)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 56 %

Procedure:
Using a procedure similar to that of Example 111 with 7-(3-aminomethyl-phenyl)-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and cycloheptanone as starting materials, 136 mg (56%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.00 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.70 (s, 2 H), 2.50 (m, 1 H), 1.80-1.30 (m, 12 H); ES-MS m/z 5542.21 [M+H]+, HPLC RT (min) 2.58.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1.O.O.[Sn](Cl)Cl>C(O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2F)cc1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
Add together 4-(2-fluoro-phenoxy)-nitrobenzene (3.18 g, 13.6 mmol) and Tin(II) chloride dihydrate (12.89 g, 5 Eq.) in absolute ethanol (20 mL) and heat to reflux while stirring under a nitrogen atmosphere for 3 hours. Cool to room temperature and dilute with ethyl acetate (50 mL). Wash this organic layer once with water, dry over potassium carbonate, filter, and concentrate under reduced vacuum to give 2.90 g as a dark oil. Purify the material by silica gel chromatography (Prep. 2000) eluting with methylene chloride to provide 1.74 g of the title compound as a tan solid. Mass spectrum (m/e): 204.2 (M*+1): (Bruker 300) 1H NMR (CDCl3) δ 7.08-7.15 (2H, m), 6.95-7.02 (3H, m), 6.81-6.92 (4H, m), 6.63-6.67 (2H, d).