Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([O:13]C=O)[CH2:9]1)([CH3:4])[CH3:3].C(=O)([O-])O.[K+]>CO.O.C(OCC)(=O)C>[CH3:4][C:2]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OC=O)C1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
A solution of (1S-trans)-[3-(formyloxy)cyclopentyl]carbamic acid 1,1-dimethylethyl ester (0.081 g, 0.35 mmol) in methanol (3 ml) was treated with a slurry of potassium hydrogen carbonate (0.707 g, 7.06 mmol) in water (1.5 ml) and stirred at room temperature for 2 h. The mixture was then diluted with water (20 ml) and ethyl acetate (20 ml) and the aqueous phase was extracted with ethyl acetate (2×20 ml). The combined organic phase was dried (MgSO4) and evaporated to leave a solid which was purified by column chromatography on flash silica eluting with 30-40% ethyl acetate in cyclohexane to give the title compound (0.037 g) from diisopropyl ether m.p. 83°-85° C., [α]D 0.0° (CHCl3 c=0.55%).
Reaction SMILES: Cl.[CH3:2][C:3]([NH2:16])([CH3:15])[CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1.[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1F.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1[NH:16][C:3]([CH3:2])([CH3:15])[CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CC(C)(N)Cc1ccc2ccccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(Cc1ccc2ccccc2c1)Nc1ccc([N+](=O)[O-])cc1Cl
Temperature: 140 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
A mixture of 2-methyl-1-(naphthalen-2-yl)propan-2-amine hydrochloride (5.9 g, 25.0 mmol), 3-chloro-4-fluoro-1-nitrobenzene (5.27 g, 30.0 mmol) and K2CO3 (6.9 g, 50.0 mmol) in DMSO (50 mL) was stirred at 140° C. overnight. The mixture was cooled to rt and poured into 150 mL of water. The mixture was then extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/DCM (V/V)=10:1) to give the title compound as yellow foam (3.78 g, 43%).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH2:17][NH:18][C:19]4[CH:20]=[C:21]5[C:25](=[CH:26][CH:27]=4)[C:24](=[O:28])[N:23]([C@@H:29]([CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])[C:30]([O:32]CC)=[O:31])[CH2:22]5)[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.Cl>[OH-].[Na+]>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH2:17][NH:18][C:19]4[CH:20]=[C:21]5[C:25](=[CH:26][CH:27]=4)[C:24](=[O:28])[N:23]([C@@H:29]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])[C:30]([OH:32])=[O:31])[CH2:22]5)[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOC(=O)CC[C@@H](C(=O)OCC)N1Cc2cc(NCc3ccc4ccc5nc(C)[nH]c(=O)c5c4c3)ccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2ccc3ccc(CNc4ccc5c(c4)CN([C@@H](CCC(=O)O)C(=O)O)C5=O)cc3c2c(=O)[nH]1
Yield: 99 %

Procedure:
A solution of diethyl (S)-2-(5-(((1,2-dihydro-3-methyl-1-oxo-benzo[f]quinazolin-9-yl)methyl)amino)-1-oxo-2-isoindolinyl)glutarate (3.20 g, 5.75 mmol) in 0.2 N NaOH (140 ml) was stirred under nitrogen for 3 hours at room temperature. The solution was then slowly adjusted to pH 3 with 1 N HCl and the resulting suspension allowed to stir briefly. The white solid was filtered under nitrogen, washed with water, and dried under high vacuum to give (S)-2-(5-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-1-oxo-2-isoindolinyl)glutaric acid (2.85 g). 1H NMR (DMSO-d6/D2O, 300 MHz) δ: 1.86-2.34 (m, 4H, gluCH2CH2), 2.44 (s, 3H, CH3), 4.25 (very strongly coupled AB pair, 2H, gluNCH2Ar), 4.58 (s, 2H, C9—CH2), 4.67-4.75 (m, 1H, gluCH), 6.69-6.77 (m, 2H, Ar), 7.37 (d, J=8 Hz, 1H, Ar), 7.59 (d, J=9 Hz, 1H, Ar), 7.64 (dd, J=8, 2 Hz, 1H, Ar), 8.01 (d, J=8 Hz, 1H, Ar), 8.22 (d, J=9 Hz, 1H, Ar), 9.85 (s, 1H, Ar). Anal. Calculated for C27H24N4O6.1.6H2O: C, 61.27; H, 5.18; N, 10.58. Found: C, 61.29; H, 5.18; N, 10.57.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([Li])[CH2:10][CH2:11][CH3:12].C(NC(C)C)(C)C.[CH3:21][O:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][CH2:27][C:28]2=[O:33].ICCCC.C(=O)(O)[O-].[Na+]>C(COC)OC>[CH2:9]([CH:27]1[CH2:26][CH2:25][C:24]2[C:29](=[CH:30][CH:31]=[CH:32][C:23]=2[O:22][CH3:21])[C:28]1=[O:33])[CH2:10][CH2:11][CH3:12]
Reactant: [Li]CCCC
Reactant: COc1cccc2c1CCCC2=O
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: COCCOC
Solvent: CCCCI
Product: CCCCC1CCc2c(OC)cccc2C1=O
Temperature: 34 °C

Procedure:
To a solution of lithium diisopropylamide prepared from n-butyllithium (4.0 ml, 1.56M solution in n-hexane) and diisopropylamine (0.88 ml) in freshly distillated dimethoxyethane (20 ml) was added dropwise a solution of 3,4-dihydro-5-methoxy-1(2H)-naphthalenone (881 mg) in dimethoxyethane (5 ml) at -20° C. under N2 gas atmosphere. The mixture was stirred at -20°~0° C. for half an hour and then warmed to 34° C. rapidly. To the mixture was added iodobutane (1.8 ml) in one portion. The mixture was refluxed for 50 minutes, allowed to cool to ambient temperature and poured into aqueous saturated sodium bicarbonate solution (50 ml). The separated oil was extracted with ethyl acetate. The organic layer was washed with dilute aqueous hydrochloric acid, aqueous sodium bicarbonate solution, and brine succeedingly. The solvent was dried and evaporated in vacuo. The residue was purified by column chromatography on silica gel (elution by chloroform/n-hexane, 1/10-1/3) to give 2-butyl-3,4-dihydro-5-methoxy-1 (2H)-naphthalenone (309 mg) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([Br:12])[C:9]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.CC(C)=O.ClC(OCC(C)C)=O.[CH:29]1([CH2:32][N:33]2[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34]2)[CH2:31][CH2:30]1>O.C(N(CC)CC)C>[CH:29]1([CH2:32][N:33]2[CH2:37][CH2:36][CH:35]([NH:38][C:5](=[O:7])[C:4]3[CH:8]=[C:9]([S:13]([CH3:16])(=[O:15])=[O:14])[C:10]([Br:12])=[CH:11][C:3]=3[O:2][CH3:1])[CH2:34]2)[CH2:31][CH2:30]1
Reactant: NC1CCN(CC2CC2)C1
Reactant: COc1cc(Br)c(S(C)(=O)=O)cc1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(Br)c(S(C)(=O)=O)cc1C(=O)NC1CCN(CC2CC2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
9.3 g of 2-methoxy-4-bromo-5-methylsulphonyl benzoic acid (0.030 mole), 70 ml of acetone, 10 ml of water and 4.2 ml of triethylamine of density 0.72 (0.030 mole) are placed in a 250 ml flask fitted with an agitator, a thermometer and a dropping funnel. A solution is obtained and cooled to about 0° C. 4.2 g of isobutyl chloroformate (0.030 mole) is added drop by drop, the reaction medium is agitated for 30 minutes with the temperature between 0° and +5° C., then 4.7 g of 1-cyclopropylmethyl-3-aminopyrrolidine (0.033 mole) is poured in drop by drop. The reaction is continued for 2 hours at room temperature then 50 ml of water and 5 ml of soda lye are added. The acetone is evaporated under vacuum and the oil, which is insoluble in water, is extracted twice, each time with 50 ml of methylene chloride. The organic solution is dried over magnesium sulphate and filtered, and the filtrate is evaporated under vacuum. The viscous residue is dissolved hot in 90 ml of isopropanol. The solution is acidified with 7 ml of 6N hydrochloric ethanol. The hydrochloride is crystallised in the refrigerator, then the crystals are filtered, washed with a little isopropanol and dried in an oven at 50° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH:22][C:23](=[O:39])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[O:37][N:36]=[C:35]([CH3:38])[CH:34]=2)[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:14]1([C:12]2[C:11]([C:18]([F:21])([F:19])[F:20])=[CH:10][C:9]3[NH:22][C:23](=[O:39])[CH2:24][C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]5[O:37][N:36]=[C:35]([CH3:38])[CH:34]=5)[CH:28]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N4CCC4)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(N5CCC5)c(C(F)(F)F)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (5-azetidin-1-yl-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example M53) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (94 mg).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][OH:10].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18]Br)[N:13]=1>C1COCC1.O.C(Cl)Cl>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:10][CH2:9][CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][O:3]2)[N:13]=1
Reactant: BrCc1cccc(Br)n1
Reactant: OCC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Brc1cccc(COCC2CCCCO2)n1
Temperature: 25 °C

Procedure:
To a suspension of NaH (63.8 mg, 1.59 mmol) in THF (4 mL) at 0° C. under argon was added tetrahydro-2H-pyran-2-ylmethanol (92.5 mg, 0.80 mmol). The mixture was maintained at 0° C. for 20 minutes, at which time 2-bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (200 mg, 0.80 mmol) was added. The reaction allowed to warm to room temperature and then heated to 55° C. overnight. The reaction was then cooled to ambient temperature and quenched by the addition of water. The quenched reaction mixture was diluted with water (10 mL) and DCM (10 mL) and shaken. The suspensions were passed through disposable phase separators and the DCM eluent was captured and evaporated to dryness to afford the title compound which was used without further purification.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[F:20][C:21]1[CH:26]=[C:25](B(O)O)[CH:24]=[CH:23][N:22]=1>>[F:20][C:21]1[CH:26]=[C:25]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[C:7]([CH3:17])[C:6]=3[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=2)[CH:24]=[CH:23][N:22]=1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Reactant: OB(O)c1ccnc(F)c1
Product: Cc1c2n(c3c(-c4ccnc(F)c4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, white solid (59 mg, 71%), MS (ISP) m/z=335.5 [(M+H)+], mp 264° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 2-fluoro-pyridin-4-ylboronic acid (45.8 mg, 0.325 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH2:14][CH2:15][NH:16][CH3:17].C(=O)([O-])[O-].[Na+].[Na+].O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:13]([CH3:12])[CH2:14][CH2:15][NH:16][CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CNCCNC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CNCCN(C)S(=O)(=O)c1ccc(F)cc1

Procedure:
A solution of 4-fluorobenzenesulphonyl chloride (6.0 g) in chloroform (30 ml) was added dropwise to a well-stirred solution of N,N'-dimethyl-ethylenediamine (25 g) in chloroform (300 ml) at room temperature. After 2 hours the chloroform solution was vigorously shaken with aqueous sodium carbonate solution, separated, dried (MgSO4) and evaporated under reduced pressure to give an oil. The oil was treated with chloroform (60 ml) and water (100 ml). The two solvents were mixed thoroughly and were then separated. The chloroform layer was dried (MgSO4) and evaporated under reduced pressure to give an oil. Final traces of N,N'-dimethyl-ethylenediamine were removed by heating the oil under low vacuum to give 4-fluoro-N-methyl-N-[2-(methylamino)ethyl]benzenesulphonamide.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][C:7]=1[CH:15]=[O:16].[CH3:18][N:19]1[CH2:24]CNC[CH2:20]1.CNC>>[CH3:18][N:19]1[CH2:24][CH2:1][N:2]([CH2:3][CH2:4][CH2:5][C:6]2[C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[NH:8][C:7]=2[CH:15]=[O:16])[CH2:17][CH2:20]1
Reactant: CN1CCNCC1
Reactant: CN(C)CCCc1c(C=O)[nH]c2c1CCCC2
Agent: CNC
Product: CN1CCN(CCCc2c(C=O)[nH]c3c2CCCC3)CC1

Procedure:
3-[3-(4-Methylpiperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde was prepared following the procedure described for 3-(3-dimethylamino-propyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde as described for Example 1 above but substituting 1-methylpiperazine in step 2 above for dimethylamine.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([NH:33][C@H:34]([C:38]([NH:40][C:41]3[CH:49]=[CH:48][CH:47]=[C:46]([CH3:50])[C:42]=3[C:43](O)=[O:44])=[O:39])[CH:35]([CH3:37])[CH3:36])=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([NH:33][C@H:34]([C:38]3[O:39][C:43](=[O:44])[C:42]4[C:46]([CH3:50])=[CH:47][CH:48]=[CH:49][C:41]=4[N:40]=3)[CH:35]([CH3:36])[CH3:37])=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc(NC(=O)[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(C)C)c1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: Cc1cccc2nc([C@@H](NC(=O)OCC3c4ccccc4-c4ccccc43)C(C)C)oc(=O)c12
Reaction time: 3 h
Yield: 87.4 %

Procedure:
263 mg of N,N'-dicyclohexylcarbodiimide was added under ice-cooling to a solution of 401 mg of 2-{[N-(9-fluorenylmethoxycarbonyl)-L-valyl]amino}-6-methylbenzoic acid in 5 ml of N,N-dimethylformamide. After stirring for 3 hours, dicyclohexyl urea precipitated was filtered off and the filtrate was condensed. The residue was purified by a silica gel column chromatography (eluting solution: hexane-ethyl acetate) to afford 337 mg of 2-{1(S)-[(9-fluorenylmethoxycarbonyl)amino]-2-methylpropyl}-5-methyl-4H-3,1-benzoxazin-4-one, as a white foam. The physicochemical data are shown in Table 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].F[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18].CC(C)([O-])C.[K+].O>CN(C=O)C>[F:16][C:14]1[CH:13]=[CH:12][C:11]([N+:17]([O-:19])=[O:18])=[C:10]([CH:15]=1)[NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Nc1cccc(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(F)cc1Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-fluoroaniline (1.813 mL, 18.86 mmol) and 2,4-difluoro-1-nitrobenzene (1.723 mL, 15.71 mmol) in DMF (26.2 mL) was added potassium tert-butoxide (3.53 g, 31.4 mmol) under argon gas. The solution was stirred overnight at rt poured into water and extracted with DCM. The combined organic extracts were purified by column chromatography on a silica gel column using 5 to 10% gradient of EtOAc in hexane as eluent to give an orange solid that was triturated in EtOAc:hexane (1:1) and filtered to give 5-fluoro-N-(3-fluorophenyl)-2-nitroaniline as an orange solid: LC-MS (ESI), m/z 251.1 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].C1(=O)O[CH2:14][CH2:13][O:12]1.O.O.[F-].[K+]>CN(C)C=O>[CH3:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:14][CH2:13][OH:12])=[CH:6][CH:5]=1)=[CH2:3]
Reactant: C=C(C)c1ccc(O)cc1
Reactant: O=C1OCCO1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)c1ccc(OCCO)cc1
Temperature: 150 °C
Yield: 69 %

Procedure:
A mixture of 20 g p-isopropenylphenol, 1.1 equivalents ethylene carbonate, 0.02 equivalent potassium fluoride dihydrate, and 200 ml N,N-dimethylformamide (DMF) was heated at about 150° C. for about 1.5 hours. After removal of DMF under reduced pressure, the crude product was distilled. 2-(4-(1-Methylethenyl)phenoxy)ethanol, bp 143° C./7 torr, was obtained as a white solid in 69% yield.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]([O:14][CH3:15])[O:4]1>CCOC(C)=O.[Rh]>[CH3:1][O:2][CH:3]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH:5]([O:14][CH3:15])[O:4]1
Reactant: COC1C=C(c2ccccc2)C(OC)O1
Agent: [Rh]
Solvent: CCOC(C)=O
Product: COC1CC(c2ccccc2)C(OC)O1
Reaction time: 24 h
Yield: 97.9 %

Procedure:
A mixture of 2,5-dihydro-2,5-dimethoxy-3-phenylfuran (590 mg, 2.86 mmol) and 10% Rh/Al2O3 (110 mg) in EtOAc (10 mL) was stirred under H2 atmosphere for 24 hours. The catalyst was filtered onto Celite and rinsed with EtOAc. The filtrate was concentrated in vacuo to afford 583 mg(98%) of 2,5-dimethoxy-3-phenyl-tetrahydrofuran as a colorless oil which was typically used without further purification. 1H NMR: δ 7.40-7.18 (m, 5H), 5.30-4.80 (m, 2H), 3.70-3.40 (m, 6H), 2.78-2.43 (m, 1.2H), 2.34 (ddd, 0.75H, J=5.6, 12.7, 18.3Hz), 2.17 (dd, 0.1H, J=8.4, 12.8 Hz). Anal. Calcd for C12H16O3.0.2 H2O: C, 68.03; H, 7.80. Found: C, 68.11; H, 7.60.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[N:12]#[C:13]Br>C(OCC)C>[NH:1]([C:2]1[CH:3]=[C:4]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:6][CH:7]=1)[C:13]#[N:12]
Reactant: N#CBr
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CCOCC
Product: N#CNc1cccc(C(F)(F)F)c1

Procedure:
A mixture of 3-aminobenzotrifluoride (15.0 g, 93.1 mmol), cyanogen bromide (12.2 g, 129 mmol) and diethyl ether was stirred at reflux for 40 h. The crude mixture was purified by chromatography using silica gel and a mixture of petroleum ether and dichloromethane as eluent (1:1). The product was isolated as the free base. Yield 5.2 g, 25%.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]([S:23]([C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=1)(=[O:25])=[O:24])[C:10]1[CH:22]=[CH:21][C:13]2[S:14][C:15]([C:17](OC)=[O:18])=[CH:16][C:12]=2[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:34]>>[C:1]([O:5][C:6](=[O:7])[CH2:8][N:9]([C:10]1[CH:22]=[CH:21][C:13]2[S:14][C:15]([C:17](=[O:18])[NH2:34])=[CH:16][C:12]=2[CH:11]=1)[S:23]([C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=1)(=[O:25])=[O:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc2cc(N(CC(=O)OC(C)(C)C)S(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc2s1
Reactant: N
Product: CC(C)(C)OC(=O)CN(c1ccc2sc(C(N)=O)cc2c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
250 mg methyl 5-[tert-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)-amino]-benzo[b]thiophen-2-carboxylate are dissolved in 30 ml ammonia-saturated methanol and stirred for 24 hours at ambient temperature. Then the solution is heated to 80° C. in a pressurised vessel for 8 hours. Then the solvent is eliminated in vacuo and the residue is extracted from diisopropylether. The product thus obtained is chromatographed on silica gel with cyclohexane/ethyl acetate (9:1 to 1:4).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]3[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=3[C:12]3[CH2:13][N:14]([C@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]4[OH:25])[C:15](=[O:18])[C:16]=3[CH:17]=2)=[CH:4][CH:3]=1.[CH3:30][Zn]C.ClCCl>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:25][C@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@@H:19]1[N:14]1[CH2:13][C:12]2[C:11]3[CH:26]=[CH:27][CH:28]=[CH:29][C:10]=3[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([CH3:30])=[CH:3][CH:4]=3)=[CH:17][C:16]=2[C:15]1=[O:18]
Reactant: C[Zn]C
Reactant: O=C1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2CN1[C@H]1CCCC[C@@H]1O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(Cc2cc3c(c4ccccc24)CN([C@H]2CCCC[C@@H]2O)C3=O)cn1
Temperature: 50 °C

Procedure:
To a solution of 5-[(6-chloropyridin-3-yl)methyl]-2-[(1S,2S)-2-hydroxycyclohexyl]-1,2-dihydro-3H-benzo[e]isoindol-3-one (0.040 g, 0.098 mmol) in 3 mL of tetrahydrofuran under an atmosphere of nitrogen was added dimethylzinc (1.2 M in tetrahydrofuran, 0.16 mL, 0.20 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II), 1:1 complex with dichloromethane (7.2 mg, 0.0098 mmol). The mixture was heated at 50° C. for 3 hr and then cooled to ambient temperature. Additional dimethyl zinc (1.2 M in tetrahydrofuran, 0.16 mL, 0.20 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II), 1:1 complex with dichloromethane (7.2 mg, 0.0098 mmol) were added and the mixture was heated at 50° C. for an additional 12 hr. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 387.4 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.92-7.84 (m, 3H), 7.69 (s, 1H), 7.65-7.61 (m, 2H), 7.41 (d, J=8.1 Hz, 1H), 4.87-4.73 (m, 2H), 4.53 (s, 2H), 4.23-4.16 (m, 1H), 3.81-3.75 (m, 1H), 2.77 (s, 3H), 2.23-2.20 (m, 1H), 2.02-1.99 (m, 1H), 1.87-1.84 (m, 2H), 1.84-1.64 (m, 1H), 1.55-1.33 (m, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH:8]=[C:7]2[C:18]#[N:19].C([N:23](CC)C(C)C)(C)C.Cl.NO>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH:8]=[C:7]2[C:18]([NH2:23])=[NH:19]
Reactant: CCN(C(C)C)C(C)C
Reactant: N#Cc1cn(CC2CCOCC2)c2c(Cl)cccc12
Agent: Cl
Agent: NO
Solvent: CCO
Product: N=C(N)c1cn(CC2CCOCC2)c2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.6 %

Procedure:
To a suspension of 7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carbonitrile (12.9 g, 46.9 mmol) in ethanol (280 ml) and N,N-diisopropylethylamine (16.7 ml, 96.0 mmol) was added hydroxylamine hydrochloride (6.8 g, 121.4 mmol). The reaction mixture was warmed to reflux and stirred for 6 h before cooling to room temperature and the solvent removed in vacuo. The solid was dissolved in dichloromethane, washed with water and brine, dried over sodium sulfate and the solvent removed in vacuo. The resulting solid was crystallised from diethyl ether to yield 7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carboxamidine (13.1 g, 42.5 mmol) as an off white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:51][CH2:52][CH2:53][O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[F:62])(=O)=O)=CC=1>>[F:62][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=1[CH2:55][O:54][CH2:53][CH2:52][CH2:51][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O)cc3)cc21
Reactant: Cc1ccc(S(=O)(=O)OCCCOCc2ccccc2F)cc1
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOCc4ccccc4F)cc3)cc21

Procedure:
Analogously to Method I, 0.250 g of benzyl 4-(4-hydroxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 259b) and 0.185 g of 3-(2-fluorobenzyloxy)propyl toluene-4-sulphonate are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.27 (1:1 EtOAc-heptane); Rt=6.04.