Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[C:6]([NH:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])([CH3:9])([CH3:8])[CH3:7].[B:20](OC)([O:23]C)[O:21]C.[Cl-].[NH4+]>C1COCC1>[B:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[S:11]([NH:10][C:6]([CH3:9])([CH3:7])[CH3:8])(=[O:13])=[O:12])([OH:23])[OH:21]
Reactant: COB(OC)OC
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Temperature: 22 °C
Reaction time: 1 h

Procedure:
27 ml of n-butyllithium (15% solution in n-hexane) are added dropwise at −5° C. to a solution of 4.29 g of N-tert-butylbenzenesulfonamide in 25 ml of THF under argon. The mixture is stirred at 22° C. for 1 h, re-cooled to −5° C., and 2.8 g of trimethyl borate are slowly added dropwise. The mixture is stirred at 22° C. for 3 h, before 100 ml of aqueous ammonium chloride solution is added dropwise. The phases are separated, and the aqueous phase is extracted a further twice with MTB ether. The combined organic phases are dried over magnesium sulfate. Filtered and evaporated to dryness in vacuo.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]1([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:12][CH2:11][CH2:10][CH:9]([C:13](OCC)=[O:14])[CH2:8]1.C(Cl)Cl.CO>C1COCC1.[OH-].[Na+].O>[OH:14][CH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][N:7]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH2:8]1
Reactant: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCCC(CO)C1
Temperature: -10 °C

Procedure:
A 250-mL 3-necked round-bottomed flask was charged with a solution of LiAlH4 (2.96 g, 77.83 mmol, 2.00 equiv) in THF (150 mL). To this solution was added 1-benzyl 3-ethyl piperidine-1,3-dicarboxylate (11.4 g, 39.16 mmol, 1.00 equiv) in THF (50 mL) drop wise with stirring at −10° C. The resulting mixture was allowed to stir about 1 hour at −10° C. The progress was monitored by TLC (DCM: MeOH=10:1). The resulting solution was diluted with 10 mL of NaOH/H2O. The solids were filtered out. The resulting mixture was concentrated on a rotary evaporator to afford benzyl 3-(hydroxymethyl)piperidine-1-carboxylate as pale yellow oil in (8.94 g, (92%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C.[CH:24]1([CH2:27][NH2:28])[CH2:26][CH2:25]1>C(O)C>[CH:24]1([CH2:27][NH:28][C:2]2[N:10]=[C:9]([F:11])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:12]([CH3:14])[CH3:13])[CH2:26][CH2:25]1
Reactant: NCC1CC1
Reactant: CC(C)n1cnc2c(Cl)nc(F)nc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)n1cnc2c(NCC3CC3)nc(F)nc21
Yield: 83.1 %

Procedure:
6-Chloro-2-fluoro-9-isopropyl-9H-purine (0.3 g, 1.4 mmol), diisopropylethylamine (0.2 g, 1.55 mmol) and cyclopropylmethylamine (0.24 g, 2.7 mmol) were stirred together in ethanol (30 ml) at room temperature for 6 h. Volatiles were removed and the residue taken up in ethyl acetate, washed with water (50 ml), brine (50 ml), dried (MgSO4) and concentrated. The crude was purified by silica gel flash column chromatography (ethyl acetate:hexane 3:2) to give the pure product (290 mg, 83%) as a colorless gum. δH (CDCl3, 500 MHz) 0.29-0.27 (2 H, m, CHHCHH of Cp), 0.56-0.54 (2H, m, CHHCHH of Cp), 1.13 (1 H, s, br, CH of Cp), 1.58 (6 H, d, J 7.5, CH[CH3]2), 3.44 (2 H, s, br, NHCH2Cp) 2.97 (1 H, s, br, CH of Cp), 4.74-4.72 (1 H, m, CHMe2), 6.22 (1 H, s, br, NH), 7.76 (1 H, s, ArH); δC (CDCl3, 500 MHz) 160.09 (C), 156.14 (C), 147.4 (C), 137.38 (CH), 118.26 (C), 47.14 (CH), 45.78 (CH2), 22.46 (2×CH3), 10.06 (CH), 3.5 (2×CH2)
Reaction SMILES: [C:1]12([C:11]3[CH:22]=[CH:21][C:14]([O:15][CH2:16][CH2:17][C:18](O)=[O:19])=[C:13]([CH3:23])[CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[C:1]12([C:11]3[CH:22]=[CH:21][C:14]([O:15][CH2:16][CH2:17][C:18]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:19])=[C:13]([CH3:23])[CH:12]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: C1COCCN1
Reactant: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1OCCC(=O)O
Product: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1OCCC(=O)N1CCOCC1
Yield: 91.1 %

Procedure:
The title compound was prepared from 3-(4-(adamantan-1-yl)-2-methylphenoxy)propanoic acid (0.2 g, 0.63 mmol) and morpholine (0.055 g, 0.63 mmol) according to the example 1, which was given 3-(4-(adamantan-1-yl)-2-methylphenoxy)-1-morpholinopropan-1-one as a white solid (0.22 g, 90.5% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH:27]=[N:26][NH:25][C:24]1=[O:28]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:25]1[C:24](=[O:28])[N:23]([C:17]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=2[F:15])[CH:27]=[N:26]1)[CH3:13]
Reactant: O=c1[nH]ncn1-c1ccc(F)cc1F
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1ncn(-c2ccc(F)cc2F)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 58.3 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.36 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.07 g of 4-(2,4-difluorophenyl)-3(2H,4H)-1,2,4-triazolone, 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-(2,4-difluorophenyl)-3(2H, 4H)-1,2,4-triazolone (1.20 g) was obtained as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21]Br)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>CN(C)C=O>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Cn2cccn2)CC1
Temperature: 50 °C
Reaction time: 0.42 h
Yield: 55.8 %

Procedure:
To a solution of pyrazole (68 mgs) in anhydrous dimethylformamide was added sodium hydride (44 mgs). The reaction mixture was stirred at 50° C. for 25 minutes. 4-Bromomethyl-piperidine-1-carboxylic acid tert-butyl ester (280 mgs) in anhydrous dimethylformamide was added. The reaction mixture was stirred at 70° C. under argon for 2.5 hours. The reaction mixture was quenched with water (1 ml) and the solvents were removed in vacuo. The crude residue was partitioned between dichloromethane and water, dried (MgSO4) and the solvents removed in vacuo to give a crude product. This was purified using flash chromatography to yield 4-Pyrazol-1-ylmethyl-piperidine-1-carboxylic acid tert-butyl ester (148 mg).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH2:9].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:11](=[O:13])[CH3:12]
Reactant: Cc1ccccc1CCN
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCCc1ccccc1C
Yield: 88 %

Procedure:
In close analogy to the procedure described above, 2-o-tolyl-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22][C:23]5[CH:28]=CC=C[CH:24]=5)=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.O1C2C=CC(C3(C(NC4C=CC(Br)=CN=4)=O)CC3)=CC=2OC1.[Br-].C([Zn+])C(C)C>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([CH3:28])[CH3:24])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Nc1ccc(Cc2ccccc2)cn1)C1(c2ccc3c(c2)OCO3)CC1
Agent: CC(C)C[Zn+]
Agent: O=C(Nc1ccc(Br)cn1)C1(c2ccc3c(c2)OCO3)CC1
Agent: [Br-]
Product: CC(C)Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-isobutylpyridin-2-yl)cyclopropanecarboxamide was synthesized using the procedure of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-benzylpyridin-2-yl)cyclopropanecarboxamide by reacting 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-bromopyridin-2-yl)cyclopropanecarboxamide with isobutylzinc(II) bromide.
Reaction SMILES: CO.[CH:3]1([O:8][C:9]2[CH:10]=[C:11]([C:17](=[O:19])[CH3:18])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:7][CH2:6][CH2:5][CH2:4]1.[Br-:20].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C1C=CC=CC=1)(C)C.C[N+](C1C=CC=CC=1)(C)C.C(=O)([O-])O.[Na+]>O>[Br:20][CH2:18][C:17]([C:11]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7]2)[CH:10]=1)=[O:19]
Reactant: [Br-]
Reactant: COc1ccc(C(C)=O)cc1OC1CCCC1
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)CBr)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 41.7 %

Procedure:
To 200 ml of methanol solution containing 11.6 g (49.5 mmol) of 1-(3-cyclopentoxy-4-methoxyphenyl)ethanone (see Bioorg. Med. Chem. Lett. 2003, 13, 2355) was added 20.47 g (54.5 mmol) of trimethylphenylammonium tribromide at room temperature, and the mixture was stirred at room temperature for 40 minutes. After completion of the reaction, water was added to the reaction mixture, and the mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate and then extracted with chloroform. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To the obtained concentrate was added 50 ml of a mixed solvent (diisopropyl ether/hexane=1/2 (V/V)), and precipitated solid was collected by filtration. The obtained solid was washed with diisopropyl ether, and dried under reduced pressure to obtain 6.47 g of the title compound as a white solid. (Yield: 41%)
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]([CH3:16])[CH2:12][C:13]([OH:15])=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][CH:18](O)[CH2:19][CH3:20].C1(C)C=CC=CC=1.OS(O)(=O)=O>O>[CH:18]([O:14][C:13](=[O:15])[CH2:12][CH:11]([NH:10][S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:9])=[O:8])[CH3:16])([CH2:19][CH3:20])[CH3:17]
Reactant: CCC(C)O
Reactant: CC(CC(=O)O)NS(=O)(=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(C)OC(=O)CC(C)NS(=O)(=O)c1ccccc1

Procedure:
The mixture of 2.0 gr DL-N benzensulfonyl-3 aminobutyric acid (I), 1.0 gr 2-butanol, 30 ml toluene and 0.04 gr H2SO4 (conc) was heated under reflux for ca 6 hr. The water formed in the reaction was separated by azeotropic distillation. The cooled reaction mixture was washed twice with bicarbonate 2%, and dried over magnesium sulfate. Distillation of the solvent and alcohol yield 1.8 gr procuct, confirmed by spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].Cl.[NH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]1.CCN(CC)CC.Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (5 g, 22.6 mmol) in DMF (35 mL) were added trans-4-aminocyclohexanol hydrochloride (3.8 g, 24.8 mmol) and Et3N (3.5 mL, 24.8 mmol) at 0° C. The reaction mixture was warmed up to room temperature and stirred overnight. After adding 1N HCl (40 mL) and water, the resulting white precipitates were collected by suction filtration. The collected solid was thoroughly washed with water. White powers collected were dissolved in EtOH (200 mL) then aqueous 30% NaOH (25 mL) was added. The reaction mixture was refluxed overnight. EtOH was removed in vacuo. The precipitates were filtered and washed with water. Recrystallization from methanol afforded 9.5 g (42%) of the title compound as a white solid. Mp: 239.5-241.1° C. NMR (DMSO-d6): δ 8.79 (s, 1H), 8.06 (d, J=2 Hz, 1H), 7.55-7.47 (m, 2H), 6.20 (d, J 8 Hz, 1H), 4.54 (d, J=4 Hz, 1H), 3.45-3.34 (m, 2H), 1.86-1.75 (m, 4H), 1.28-1.11 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9](N)=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[NH:20][C:19]2[C:14](=[N:15][CH:16]=[N:17][CH:18]=2)[N:13]=1.[CH2:21]([OH:23])[CH3:22]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([O:23][CH2:21][CH3:22])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[NH:20][C:19]2[C:14](=[N:15][CH:16]=[N:17][CH:18]=2)[N:13]=1
Reactant: COc1cc(C(N)=O)ccc1-c1nc2ncncc2[nH]1
Reactant: CCO
Product: CCOC(=O)c1ccc(-c2nc3ncncc3[nH]2)c(OC)c1

Procedure:
A quantity of 0.42 gm of 8-(2'-methoxy-4'-chlorocarbonyl-phenyl)-purine hydrochloride (see Example 43) was refluxed in 30 ml of ethanol for 45 minutes. The solvent was evaporated off, and the residue was purified over a silica gel column [eluant: methylene chloride/ethanol (50:1 to 19:1)].
Reaction SMILES: C(NC1CCCCC1)(C)C.C([Li])CCC.CCCCCC.[C:22](#[N:26])[CH:23]([CH3:25])[CH3:24].[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[CH3:24][C:23]([CH3:25])([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]#[N:26]
Reactant: CC(C)C#N
Reactant: ClCc1ccccc1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C#N)Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 69.4 %

Procedure:
A solution of N-isopropylcyclohexyl amine (2.8 g, 19.72 mmol) in anhydrous tetrahydrofuran (25 mL) at −78° C. was treated with 1.6 M n-butyl lithium in hexane (12.23 mL, 19.72 mmol) drop-wise over 15 minutes. The reaction solution was stirred for 10 min at −78° C. The solution turned yellow from colorless. Isobutyronitrile (1.36 g, 19.72 mmol) was added to the reaction solution, and the reaction mixture was stirred for a further 10 min at −78° C. This solution was syringed into a solution of benzyl chloride (2.62 g, 20.71 mmol) in anhydrous tetrahydrofuran at −78° C. under a nitrogen atmosphere. The reddish/brown reaction was solution stirred for 1 h at −78° C. The dry ice/acetone bath was then removed, and the solution stirred at room temperature for 5 h. The reaction solution was quenched with saturated aqueous ammonium chloride solution (10 mL). Ethyl acetate (25 mL) was added to the quenched reaction solution. The layers were partitioned and the aqueous layer was extracted with ethyl acetate (150 mL). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure to yield 3.18 g of crude material. The crude material was partitioned between 2 N hydrochloric acid solution and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated to give 2.18 g (69%) 2,2-dimethyl-3-phenylpropanenitrile. 1H NMR (DMSO-d6, 400 MHz) δ 7.369-7.333 (m, 2H), 7.309-7.270 (m, 3H), 2.832 (s, 2H), 1.294 (s, 6H). This compound was used in subsequent reaction with out further analysis.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[C:6]=1[NH2:23])=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].[F:30][C:31]1[CH:36]=[C:35]([Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:34]=[CH:33][C:32]=1OS(C(F)(F)F)(=O)=O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]([C:5]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[C:6]=1[NH:23][C:32]1[CH:33]=[CH:34][C:35]([Si:37]([CH3:39])([CH3:38])[CH3:40])=[CH:36][C:31]=1[F:30])=[O:4]
Reactant: COC(=O)c1c(N)c2cnccc2n1Cc1ccc(OC)cc1
Reactant: C[Si](C)(C)c1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1c(Nc2ccc([Si](C)(C)C)cc2F)c2cnccc2n1Cc1ccc(OC)cc1
Temperature: 105 °C
Yield: 88 %

Procedure:
3-Amino-1-(4-methoxy-benzyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester (200 mg, 0.64 mmol) was dissolved in toluene (6 mL), to which Cs2CO3 (417 mg, 1.28 mmol) and trifluoro-methanesulfonic acid 2-fluoro-4-trimethylsilanyl-phenyl ester (263 mg, 0.83 mmol) were added and the mixture degassed with nitrogen before addition of Pd2dba3 (29 mg, 0.032 mmol) and Xantphos (37 mg, 0.064 mmol). The mixture was heated at 105° C. for 18 hours, allowed to cool to ambient temperature then partitioned between EtOAc (50 mL) and water (30 mL). The organic layer was isolated, dried (Na2SO4), filtered and evaporated to give a black oil. The oil was purified by flash column chromatography on silica (Si-PPC, cyclohexane:EtOAc, gradient 90:10 to 40:60) to provide the title compound as a pale brown solid (269 mg, 88%). LCMS (method B): RT=2.81 min, M+H+=478.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=2[O:37][CH3:38])[C:23]2[S:27][N:26]=[CH:25][N:24]=2)(=[O:21])=[O:20])=[CH:15][C:14]=1[N+:39]([O-])=O.C1COCC1.C(O)(=O)C>C(Cl)Cl.CO.[Fe]>[NH2:39][C:14]1[CH:15]=[C:16]([S:19]([N:22]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=2[O:37][CH3:38])[C:23]2[S:27][N:26]=[CH:25][N:24]=2)(=[O:21])=[O:20])[CH:17]=[CH:18][C:13]=1[NH:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:7][C:2]=1[Cl:1]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Nc3ccc(C(F)(F)F)cc3Cl)c([N+](=O)[O-])c2)c(OC)c1
Agent: [Fe]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Nc3ccc(C(F)(F)F)cc3Cl)c(N)c2)c(OC)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A vial was charged with INTERMEDIATE T (0.250 g, 0.397 mmol), iron (0.222 g, 3.97 mmol), THF (0.25 mL), and acetic acid (0.25 mL). The vial was sealed and stirred at 70° C. for one hour. The mixture was diluted with DCM and MeOH, then filtered through a pad of Celite® (diatomaceous earth) and concentrated. The material was purified via silica gel chromatography (40 g, gradient elution 0 to 50% EtOAc:Heptane) to afford 3-amino-4-((2-chloro-4-(trifluoromethyl)phenyl)amino)-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (INTERMEDIATE U) as an off-white solid. m/z (ESI) 621.8 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:18]=[CH:17][CH:16]=[CH:15][CH2:14][N:13]2[C:19]([OH:21])=[O:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].Cl>O.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:18]=[CH:17][C:16]([C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])=[CH:15][CH2:14][N:13]2[C:19]([OH:21])=[O:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)N2C=CC=CCN2C(=O)O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)N2C=CC(C(=O)OCc3ccccc3)=CCN2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 1-[(4-methoxyphenyl)sulfonyl]-diazepine-2-carboxylic acid (0.570 g, 1.33 mmol) is dissolved in water (5 mL) and p-dioxane (10 mL). Triethyl amine (0.74 mL, 5.32 mmol) and benzyl chloroformate (0.228 mL, 1.59 mmol) are next added. The reaction mixture is stirred overnight at room temperature, and then the solution is acidified with 1N HCl to pH˜1 and poured into water and extracted with methylene chloride. The organic extracts are dried (Na2SO4) and concentrated down to an oil. The oil is purified by HPLC with a reverse phase column using 70% (95% water, 5% acetonitrile, 0.1% formic acid) and 30% (80% acetonitrile, 20% water) as the eluent.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=CC=1OC(C)C.[CH2:54]([C:56]1[S:67][C:59]2=[N:60][C:61]([CH:65]=O)=[CH:62][C:63](=[O:64])[N:58]2[N:57]=1)[CH3:55].C(N1C(C)=C(C=O)C(C)=N1)C>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:65][C:61]3[N:60]=[C:59]4[S:67][C:56]([CH2:54][CH3:55])=[N:57][N:58]4[C:63](=[O:64])[CH:62]=3)[C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1nn2c(=O)cc(C=O)nc2s1
Reactant: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Agent: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: CCn1nc(C)c(C=O)c1C
Product: CCc1nn2c(=O)cc(CC3=C(O)CC(CCc4ccc(C(C)(C)C#N)c(F)c4)(C4CCCC4)OC3=O)nc2s1

Procedure:
The title compound was prepared on a 0.5-mmol scale analogously to example B(19): except using 2-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-methyl-propionitrile from step 3 of example A(84) in place of 6-[2-(3-chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione and 2-ethyl-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-7-carbaldehyde from step 2 below in place of 1-ethyl-3,5-dimethyl-1H-pyrazole-4-carbaldehyde. Yield: 10 mg (4%). 1H NMR (300 MHz, DMSO-d6): δ 1.29 (t, 3H), 1.35-1.7 (s, m overlap, 14H), 1.99 (m, 2H), 2.38 (m, 1H), 2.63 (m, overlap, 3H), 2.75 (d, 1H), 3.03 (q, 2H), 3.48 (ABq, 2H), 6.06 (s, 1H), 7.10 (m, overlap, 2H), 7.35 (m, 1H), 10.98 (s, 1H). LC-MS (APCI) calcd for C30H33FN2O4S: 564.22, found (M+H+): 565.2 m/z.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)Cl.[C:13]1([CH:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:20][CH2:21][CH2:22][NH2:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C:3]([CH:4]([NH:23][CH2:22][CH2:21][NH:20][CH:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:12]
Reactant: NCCNC(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(Cl)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C(NCCNC(c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
A solution of 9.2 g of α-chlorophenylacetic acid methyl ester, dissolved in 10 ml of acetonitrile, is added dropwise in the course of 10 minutes, while stirring, to a mixture of 11.3 g of N-diphenylmethyl-ethylenediamine, 5.05 g of triethylamine and 70 ml of acetonitrile. The mixture is then heated under reflux for 18 hours. It is then concentrated to dryness by evaporation under reduced pressure, triturated with 100 ml of 10% sodium hydroxide solution and extracted twice by shaking with 100 ml of diethyl ether each time. The ether phases are combined, washed three times with 30 ml of saturated sodium chloride solution each time, dried over magnesium sulphate and concentrated by evaporation. The residue obtained after concentration by evaporation is shaken with 10% (by weight) sodium hydroxide solution and diethyl ether in order to remove any excess triethylamine. The ether phases are further treated as indicated above. Finally, drying is effected at approximately 0.15 mbar. N-(α-methoxycarbonylbenzyl)-N'-diphenylmethyl-ethylenediamine is obtained which is converted into the diacetate for characterisation. For that purpose, 14.8 g of base are dissolved in 15 ml of diethyl ether and 15 ml of hexane, and glacial acetic acid is added dropwise while stirring and cooling. The precipitate is filtered with suction, recrystallised from approximately 360 ml of diethyl ether and 90 ml of hexane and dried under reduced pressure (under 0.2 mbar). The N-(α-methoxycarbonylbenzyl)-N'-diphenylmethyl-ethylenediamine acetate melts at 78°-81° C. Pure N-(α-methoxycarbonylbenzyl)-N'-diphenylmethyl-ethylenediamine can be freed from this by treatment with 10% sodium hydroxide solution, extraction by shaking with diethyl ether, drying over magnesium sulphate and evaporating off the solvent.