Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.[C:13]1([C:19]([CH3:25])=[CH:20][CH2:21][C:22]([OH:24])=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(I)(C)C>C1COCC1.CCCCCC.O>[CH:1]([CH:21]([CH:20]=[C:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:25])[C:22]([OH:24])=[O:23])([CH3:3])[CH3:2]
Reactant: CC(C)NC(C)C
Reactant: CC(=CCC(=O)O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(=CC(C(=O)O)C(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 3.2 ml (23 mmole) diisopropylamine in 15 ml THF at 0° under nitrogen is added 14.4 ml (23 mmole) 1.6 M n-butyllithium. The reaction is warmed to RT over 2 hr and cooled to 0°, and 2.0 g (11.4 mmole) 4-phenyl-3-pentenoic acid in several ml of THF is added. After 1.5 hr at about 10°, 1.16 ml (11.6 mmole) isopropyl iodide is added and the reaction stirred about 60 hours. The reaction is poured into water and hexane. The aqueous phase is acidified and extracted with ether. The ether extracts are washed to neutrality, dried over calcium sulfate and solvent removed under vacuum to give 2-isopropyl-4-phenyl-3-pentenoic acid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[C:10]1[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][C:11]=1[CH2:18][N:19]([CH2:30][C:31]1[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][N:32]=1)[CH:20]1[C:29]2[N:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:23][CH2:22][CH2:21]1.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1>[NH2:17][CH2:16][C:14]1[CH:13]=[CH:12][C:11]([CH2:18][N:19]([CH2:30][C:31]2[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:20]2[C:29]3[N:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH2:23][CH2:22][CH2:21]2)=[C:10]([CH2:9][OH:8])[CH:15]=1
Reactant: COC(=O)c1cc(C#N)ccc1CN(Cc1ncccc1C)C1CCCc2cccnc21
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cccnc1CN(Cc1ccc(CN)cc1CO)C1CCCc2cccnc21
Yield: 37 %

Procedure:
To a cold (0° C.) mixture of LiAlH4 (187 mg, 4.93 mmol) in dry THF (5 mL) was added 5-cyano-2-{[(3-methyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoic acid methyl ester (245 mg, 0.57 mmol) as a solution in THF (6 mL). The resultant mixture was stirred at room temperature for 5 hours then cooled in an ice water bath. The mixture was treated with saturated aqueous sodium-potassium tartrate (11 mL) and diluted with THF (11 mL). The phases were separated and the aqueous phase was extracted with THF (2×11 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) followed by radial chromatography on silica gel (1 mm plate, 75:1:1 CH2Cl2-MeOH—NH4OH) gave COMPOUND 405 (85 mg, 34%) as a white solid. 1H NMR (CDCl3) δ 1.46-1.64 (m, 4H), 1.91-1.98 (m, 1H), 2.06-2.19 (m, 5H), 2.51-2.59 (m, 1H), 2.68-2.77 (m, 1H), 3.62 (d, 2H, J=12.3 Hz), 3.72-3.76 (m, 3H), 3.84 (dd, 1H, J=7.5, 7.8 Hz), 4.06-4.15 (m, 2H), 4.30 (d, 1H, J=11.4 Hz), 6.92-7.07 (m, 3H), 7.15-7.29 (m, 3H), 7.35 (d, 1H, J=7.5 Hz), 8.27-8.31 (m, 2H); 13C NMR (CDCl3) δ 17.32, 19.78, 20.72, 28.66, 45.11, 53.06, 53.62, 56.48, 61.63, 120.59, 121.46, 124.93, 129.32, 130.07, 133.01, 133.58, 134.44, 135.60, 137.18, 141.23, 142.21, 144.76, 145.58, 155.32, 155.89; ES-MS m/z 403 (M+H). Anal. Calcd. for C25H30N4O.1.0CH3OH: C, 71.86; H, 7.89; N, 12.89. Found: C, 71.78; H, 7.59; N, 12.59.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH:12](C)[N:13]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:23])[CH:4]=1.C(OC(O)C(F)(F)F)C>>[F:25][C:2]([F:1])([F:24])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][N:13]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:23])[CH:4]=1
Reactant: CC1CCc2cc3[nH]c(=O)cc(C(F)(F)F)c3cc2N1CC(F)(F)F
Agent: CCOC(O)C(F)(F)F
Product: O=c1cc(C(F)(F)F)c2cc3c(cc2[nH]1)CCCN3CC(F)(F)F

Procedure:
This compound was prepared in a similar fashion as that described in Example 84 from Compound 192 (Structure 33 of Scheme VI, where R1═H, n=1) and trifluoroacetaldehyde ethyl hemiacetal. 1H NMR (400 MHz, CDCl3) 11.32 (br. s, 1H), 7.11 (s, 1H), 7.02 (s, 1H), 6.99 (s, 1H), 3.88 (q, 2H, J=8.9), 3.47 (t, 2H, J=5.6), 2.93 (t, 2H, J=6.3), 2.03 (m, 2H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[CH:15]=[CH:14][C:13]=2[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=2)=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[O-:33][C:34]#[N:35].[Na+]>C(O)(=O)C.O>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:12]3[C:13](=[CH:14][CH:15]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[CH:17]=3)[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)[C:34](=[O:33])[N:35]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: N#C[O-]
Reactant: C#CCOc1ccc(NCc2cccc([N+](=O)[O-])c2)c(C(=O)c2ccc(C(C)C)cc2)c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
A red solution of 34 g (79.4 mmol) of the benzophenone prepared in step A in 200 ml acetic acid is treated with 6.2 g (95 mmol) sodium cyanate under vigorous stirring which is continued overnight. The mixture is diluted with water and extracted with ethyl acetate. Concentration after washing with bicarbonate solution yields several crops of product. While the initial batches are yellow and pure, the subsequent ones are orange and have to be purified by flash chromatography. Combined yield: 25.9 g (72%). m.p. 167-168° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][C:30]=1[CH3:38].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:32]2[CH:33]=[CH:34][C:29]([F:28])=[C:30]([CH3:38])[CH:31]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(B(O)O)ccc1F
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCCc1nc(C)n(-c2ccc(F)c(C)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), (4-fluoro-3-methylphenyl)boronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.11 g, 85%).
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]2=[N:6][C:7]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[N:4]2[N:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([C:2]2[CH:14]=[CH:13][C:5]3=[N:6][C:7]4[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=4[N:4]3[N:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Clc1ccc2nc3c(n2n1)CCCC3
Reactant: C1CCNC1
Product: c1cc2nc3c(n2nc1N1CCCC1)CCCC3
Temperature: 0 °C

Procedure:
A mixture was prepared from 5.0 g of 2-chloro-6,7,8,9-tetrahydropyridazino[1,6-a]benzimidazole and 30 ml of pyrrolidine and this was stirred and heated at reflux for 18 hours. The reaction mixture was then poured into 200 ml of ice water. A solid formed and this was separated by filtration and recrystallized from a mixture of ethanol and water to give 2-(1-pyrrolidinyl)-6,7,8,9-tetrahydropyridazino[1,6-a]benzimidazole melting at about 161° C. This compound has the following structure formula ##STR2##
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25](O)=[O:26].[CH3:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]2([NH2:42])[CH2:41][CH2:40]2)[N:34]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([C:25](=[O:26])[NH:42][C:39]2([C:35]3[N:34]=[C:33]([CH3:32])[CH:38]=[CH:37][N:36]=3)[CH2:40][CH2:41]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Reactant: Cc1ccnc(C2(N)CC2)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5nccc(C)n5)CC4)ccc3C)c(F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.04 g, 0.095 mmol, 1 eq), 1-(4-methylpyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.064 g, 0.12 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.029 g, 0.28 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.024 g (46%). 1H NMR (400 MHz, CDCl3): δ 8.63 (d, J=6.0 Hz, 1H), 8.39 (bs, 1H), 7.99-7.95 (m, 2H), 7.82 (dd, J=2.0, 8.0 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.41-7.36 (m, 2H), 7.34 (d, J=5.6 Hz, 1H), 7.21-7.15 (m, 3H), 6.39 (bs, 1H), 3.03 (d, J=4.8 Hz, 3H), 2.71 (s, 3H), 2.24 (s, 3H), 2.06-2.03 (m, 2H), 1.74-1.71 (m, 2H). 19F NMR (376.47 MHz, CDCl3) δ −75.92 (TFA), −109.79, −119.33. LCMS: (ES+) m/z=553.2 (M+H)+
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([O:16][CH2:17][CH3:18])[CH:15]=1)[O:12][C:11]([CH3:20])([CH3:19])[CH:10]=[C:9]2[C:21]([OH:24])([CH3:23])[CH3:22].O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[CH2:17]([O:16][C:14]1[CH:15]=[C:6]([CH:2]=[O:1])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([CH3:20])([CH3:19])[CH:10]=[C:9]2[C:21]([OH:24])([CH3:23])[CH3:22])[CH3:18]
Reactant: CCOc1cc(C2OCCO2)cc2c1OC(C)(C)C=C2C(C)(C)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: O
Product: CCOc1cc(C=O)cc2c1OC(C)(C)C=C2C(C)(C)O
Reaction time: 0.25 h

Procedure:
The above prepared 2-(6-[1,3]dioxolan-2-yl-8-ethoxy-2,2-dimethyl-2H-chromen-4-yl)-propan-2-ol was dissolved in 6 ml of methanol and 3 ml of water and treated with 54 mg of pyridinium p-toluenesulfonate. After 15 min. at room temperature, the reaction mixture was poured onto crushed ice/AcOEt, the organic layer washed with water, dried over magnesium sulfate and evaporated to dryness. Flash chromatography (SiO2 with n-hexane/AcOEt=7/3) yielded 194 mg of the title compound as colourless oil.
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][O:5][C@@H:6]([CH2:16][CH2:17][CH:18]=C)[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CSC.C(N(CC)CC)C>ClCCl>[CH2:9]([O:8][CH2:7][C@@H:6]([O:5][CH3:4])[CH2:16][CH2:17][CH:18]=[O:1])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=[O+][O-]
Reactant: C=CCC[C@@H](COCc1ccccc1)OC
Solvent: ClCCl
Solvent: CSC
Solvent: CCN(CC)CC
Product: CO[C@@H](CCC=O)COCc1ccccc1
Temperature: 25 °C

Procedure:
A stream of ozone was dispersed into a cold (initial T=−78° C.) stirred solution of ({[(2S)-2-methoxyhex-5-en-1-yl]oxy}methyl)benzene (40 g, 182 mmol) in dichloromethane (1800 mL) until a blue color persisted. The solution was purged with nitrogen until a clear, colorless solution was obtained. Dimethyl sulfide (67.2 mL, 908 mmol) and triethylamine (76 mL, 545 mmol) were added. The stirred mixture was allowed to warm to room temperature over 60 minutes. (A test for peroxide with wet starch-iodide paper was negative.) The mixture was concentrated under reduced pressure to provide the crude title product which was used in the next step without purification.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][N:7]=1)(=O)C.[OH-].[Na+]>CO.O>[F:14][C:12]([F:13])([F:15])[C:10]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:5][OH:4])[CH:11]=1
Reactant: CC(=O)OCc1cc(C(F)(F)F)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OCc1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of [4-(trifluoromethyl)pyridin-2-yl]methyl acetate (1.0 g, 3.2 mmol) in methanol (10 mL) was added a 1.0 M solution of sodium hydroxide in water (10 mL). After being stirred at room temperature overnight, the solution was diluted with 20 mL of water and extracted with EtOAc twice. The combined organic layers were dried (MgSO4) and concentrated under vacuum. Chromatography on silica gel eluting with hexanes/EtOAc (1:1) afforded the title compound (0.34 g) as a clear oil. MS (M+H) 178.1.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])=[CH:22][CH:21]=2)[C:7]2[N:8]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:38]=[N+:39]=[N-:40])(C)C>>[CH2:1]([C:5]1[N:6]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:40][N:39]=[N:38][N:33]=3)=[CH:24][CH:25]=2)[C:7]2[N:8]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn2cc(-c3ccccc3)nc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Product: CCCCc1nn2cc(-c3ccccc3)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 44 %

Procedure:
Reaction of 2-butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]-5-phenyl-3H-imidazo[1,2-b][1,2,4]triazole (from Step B and C) with trimethyltin azide according to the procedure of Example 1, Step G, gave a 44% yield of the title compound as a light tan solid, mp >160° C. (gradual); homogeneous by TLC in 90:10:0.1 CH2Cl2 -MeOH-AcOH.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH3:10])=[N:4][CH:3]=1.[Br:11][C:12]1[S:16][C:15]([S:17](Cl)(=[O:19])=[O:18])=[CH:14][CH:13]=1>>[Br:11][C:12]1[S:16][C:15]([S:17]([NH:8][C:6]2[C:5]([O:9][CH3:10])=[N:4][CH:3]=[C:2]([Cl:1])[N:7]=2)(=[O:19])=[O:18])=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: COc1ncc(Cl)nc1N
Product: COc1ncc(Cl)nc1NS(=O)(=O)c1ccc(Br)s1

Procedure:
Prepared by the method of Example 1 from 6-chloro-3-methoxy-2-pyrazinamine and 5-bromothiophenesulphonyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.CN(C)[CH:29]=[O:30].[Cl-].[NH4+]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:29]=[O:30])[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(Br)c2)C1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=O)c2)C1
Reaction time: 0.25 h
Yield: 43 %

Procedure:
The solution of 1.3 g (3.6 mmol) (R)-2-(3-bromo-benzyl)-morpholine-4-carboxylic acid tert-butyl ester in 80 mL diethyl ether was cooled down to −100° C. and treated dropwise with 2.6 mL (3.9 mmol; 1.5M solution in n-pentane) tert-butyllithium. After 15 min. 0.31 mL (4.0 mmol) N,N-dimethylformamide were added and the reaction stirred for another 1.5 h. The solution was poured on 10% aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel with n-hexane:ethyl acetate (2:1 v/v) as eluant to give the desired compound as colorless oil (43%).
Reaction SMILES: CS(C)=O.[CH2:5]([OH:7])[CH3:6].[H-].[Na+].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:49])[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[N:32][C:33]([NH2:48])=[C:34]([O:36][CH:37]([C:39]4[C:44]([Cl:45])=[CH:43][CH:42]=[C:41](F)[C:40]=4[Cl:47])[CH3:38])[CH:35]=3)=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:49])[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[N:32][C:33]([NH2:48])=[C:34]([O:36][CH:37]([C:39]4[C:44]([Cl:45])=[CH:43][CH:42]=[C:41]([O:7][CH2:5][CH3:6])[C:40]=4[Cl:47])[CH3:38])[CH:35]=3)=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCO
Reactant: CC(Oc1cc(-c2ccc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1ccc(Cl)c(C(C)Oc2cc(-c3ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cnc2N)c1Cl
Temperature: 40 °C

Procedure:
To 4 mL of DMSO was added 0.124 ml ethanol followed by 32 mg NaH. After stirring for 30 minutes 250 mg of 250 mg 4-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester was added and the reaction was heated to 40° C. After three hours the reaction was cooled and poured into water to precipitate. After neutralization to pH 6, 200 mg of a tan solid was isolated, 77%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=O>C(O)C.N1CCCCC1>[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[NH:12][C:11]1=[O:17]
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 51.4 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (61 mg, 51%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].O[C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27].CO>C(Cl)Cl>[CH2:29]([O:28][C:26](=[O:27])[C:25]([O:23][C:21]1[N:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=1)[N:18]=3)([CH3:32])[CH3:31])[CH3:30]
Reactant: CCOC(=O)C(C)(C)O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)C(C)(C)Oc1cc2c(cn1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Yield: 40 %

Procedure:
Following the procedures of Example 426, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and ethyl 2-hydroxyisobutyrate were reacted and the crude product was subjected to flash chromatography (SiO2, gradient 0-5% methanol in DCM) to give 2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-2-methyl-propionic acid ethyl ester as a yellow oil (103 mg, 40%). LCMS: RT=3.52 min, [M+H]+=427
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[N:39]=[N:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[N:39]=[N:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nn1
Product: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)nn1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (239 mg, 0.75 mmol) and 3-[3-(6-methoxy-pyridazin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K7) (246 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (317 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][C:12]1=[O:17])[CH2:5]2.CC(O)=O.[O:22]=[C:23]1[C:27]2[CH:28]=[CH:29][C:30]([CH2:32][CH:33]=O)=[CH:31][C:26]=2[CH2:25][O:24]1.[BH3-]C#N.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([N:11]1[CH2:16][CH2:15][N:14]([CH2:33][CH2:32][C:30]3[CH:29]=[CH:28][C:27]4[C:23](=[O:22])[O:24][CH2:25][C:26]=4[CH:31]=3)[CH2:13][C:12]1=[O:17])[CH2:5]2
Reactant: O=C1CNCCN1C1Cc2ccc(Br)cc2C1
Reactant: O=CCc1ccc2c(c1)COC2=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: O=C1OCc2cc(CCN3CCN(C4Cc5ccc(Br)cc5C4)C(=O)C3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of product from Step C (0.39 mmol) in 20 mL of DCM/MeOH (3/1, v/v) was added HOAc (47 mg, 0.78 mmol), (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (68 mg, 0.39 mmol) and NaBH3CN (49 mg, 0.78 mmol), and the mixture was stirred at RT for 2 hours. The reaction was diluted with DCM, washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to give the title product.
Reaction SMILES: [C:1]([Si:5]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[CH:12][CH:11]=1)[OH:9])([CH3:4])([CH3:3])[CH3:2].[CH3:38][O:39][C:40](=[O:59])[C@@H:41]([NH:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:42][C:43]1[CH:48]=[CH:47][C:46](O)=[C:45]([Br:50])[CH:44]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH3:38][O:39][C:40](=[O:59])[C@@H:41]([NH:51][C:52]([O:54][C:55]([CH3:57])([CH3:56])[CH3:58])=[O:53])[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:9][CH:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)=[CH:14][CH:15]=2)[CH2:7][O:6][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:45]([Br:50])[CH:44]=1
Reactant: CC(C)(C)[Si](OCC(O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc(O)c(Br)c1)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)c(Br)c1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-(tert-Butyl-diphenyl-silanyloxy)-1-[4-(3,4-dichloro-benzyloxy)-phenyl]-ethanol (11.0 g), (S)-3-(3-bromo-4-hydroxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester (7.46 g), and triphenylphosphine (7.87 g) were dissolved in 75.0 mL of anhydrous DCM and the mixture cooled to 0° C. DIAD (5.85 mL) was added drop wise to the reaction mixture. After 1 h, the cooling bath was removed and the reaction stirred overnight. Concentration gave a dark orange oil which was purified by silica gel chromatography (ethyl acetate/hexanes) to obtain the desired product. LCMS: 910.