Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2>>[NH:21]1[C:22]2[C:18](=[CH:17][C:16]([NH:15][C:12](=[O:13])[CH2:11][C:1]34[CH2:10][CH:5]5[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]5)[CH2:2]3)[CH2:8]4)=[CH:24][CH:23]=2)[CH:19]=[CH:20]1
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccc2[nH]ccc2c1
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1ccc2[nH]ccc2c1
Yield: 45.4 %

Procedure:
Prepared according to the method of Example 1b) from 1-adamantaneacetyl chloride (0.076 g) and 5-aminoindole (0.05 g) to give the title compound as a white solid (0.05 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.Cl.[OH-].[Na+].[Cl-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][NH2:9])[CH:3]=1
Reactant: N#Cc1cc(Br)ccn1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NCc1cc(Br)ccn1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 18.70 g 4-bromopyridine-2-carbonitrile [62150-45-2] in 200 ml of tetrahydrofuran is admixed under argon dropwise with 500 ml of 1M borane-tetrahydrofuran complex solution. The reaction solution is subsequently left to stand at room temperature for 16 hours. The reaction solution is cooled to 0° C., admixed dropwise with 500 ml of 2M HCl and heated to reflux for 30 minutes. The reaction solution is cooled to room temperature, basified with 2M NaOH, saturated with sodium chloride and extracted with tetrahydrofuran (3×300 ml). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60 F).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH:15]=O)=O)=[CH:9][CH:8]=1.[BH4-].[Na+]>CO.O1CCCC1>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:15][NH:4][CH2:1][CH2:2][NH:3]2)=[CH:9][CH:8]=1
Reactant: COc1ccc(C(=O)C=O)cc1
Reactant: NCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C2CNCCN2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 45.3 %

Procedure:
Methanol (5 ml) solution of ethylenediamine (3.74 g, 62.29 mmol) was added to the ice-cooled solution of 4-methoxyphenylglyoxal (8.30 g, 45.5 mmol) in methanol (100 ml) and tetrahydrofuran (50 ml) and stirred for 10 min. After cooling to 0° C., sodium tetrahydroborate (6.14 g, 162.2 mmol) and additional methanol (50 ml) was added and stirred overnight. After removal of the solvent, aqueous sodium hydroxide was added and was extracted with dichloromethane three times and washed with brine and dried over sodium sulfate. After removal of the solvent, purification of the residue by silica gel column chromatography (eluent; dichloromethane/ethanol/diethylamine=20/2/1) gave 2-(4-methoxypheny)-piperazine (3.96 g, 45%).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH3:15])=[C:9]([N+:16]([O-])=O)[CH:8]=1)=[O:5].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:31]([N:38]1[C:42](=[O:43])[C:41](=[C:44]2[N:48]([CH3:49])[C:47]3[CH:50]=[C:51]([O:54][CH2:55][CH2:56][Cl:57])[CH:52]=[CH:53][C:46]=3[S:45]2)[S:40][CH2+:39]1SC)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:38]1[C:42](=[O:43])[C:41](=[C:44]2[N:48]([CH3:49])[C:47]3[CH:50]=[C:51]([O:54][CH2:55][CH2:56][Cl:57])[CH:52]=[CH:53][C:46]=3[S:45]2)[S:40][C:39]1=[N:16][C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][N:2]([CH3:19])[CH3:1])[CH:12]=[CH:11][C:10]=1[NH:13][CH2:14][CH3:15])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CS[CH2+]1SC(=C2Sc3ccc(OCCCl)cc3N2C)C(=O)N1Cc1ccccc1
Reactant: CCNc1ccc(NC(=O)CN(C)C)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccc(OCCCl)cc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 2-dimethylamino-4′-ethylamino-3′-nitroacetanilide was hydrogenated and then condensed with 3-benzyl-5-[5-(2-chloroethoxy)-3-methylbenzothiazol-2-ylidene]-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. MS(ESI): 651 (MH+).
Reaction SMILES: BrC1C=CC=CC=1O[CH2:9][CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24].BrC/C=C/C(OCC)=O>>[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24][CH2:9][CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C=CCOc1ccccc1Br
Reactant: Sc1ccccc1Br
Agent: CCOC(=O)/C=C/CBr
Product: CCOC(=O)C=CCSc1ccccc1Br

Procedure:
The title compound was prepared (26.1 g, 82%) in a manner analogous to the preparation of ethyl 4-(2-bromophenyloxy)but-2-enoate (Example 5) by the reaction of 2-bromothiophenol with ethyl 4-bromocrotonate.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#N)=[CH:18][CH:17]=1.C(O)=[O:25]>[Ni]>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:25])=[CH:18][CH:17]=1
Reactant: O=CO
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C#N)cc1
Agent: [Ni]
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)cc1
Yield: 78.5 %

Procedure:
A mixture of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzonitrile (6.5 g), Raney nickel alloy (6.5 g) and 70% formic acid (100 ml) was heated under reflux for 2 hours. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The remaining oily material was chromatographed on a column of silica gel, and from the fractions eluted with chloroform-hexane (1:1, V/V), there were obtained crystlas (5.2 g, 78.5%) of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde. Recrystallization from ether-hexane yielded colorless needles, m.p. 82°-84° C. Elemental analysis for C19H17NO3 ; Calcd.: C, 74.25; H, 5.57; N, 4.56. Found: C, 74.47; H, 5.53; N, 4.34.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].Cl.Cl[CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.[Cl-].[NH4+]>CCCCCC.C1COCC1.CN1C(=O)N(C)CCC1>[N:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH2:23][C:14]([CH3:16])([CH3:15])[C:13]([O:18][CH2:19][CH3:20])=[O:17])[CH:25]=1
Reactant: CCOC(=O)C(C)C
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Cc1cccnc1
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
1.5M Butyllithium in hexane (20 ml) was added dropwise, under argon, to a stirred, cooled (-20° C.) solution of diisopropylamine (4.2 ml) in THF (50 ml). After 10 minutes the mixture was cooled to -70° C. and ethyl isobutyrate (3.99 ml) was added dropwise keeping the temperature <-60° C. Stirring was continued for 20 minutes after completion of the addition then DMPU (15 ml) was added followed by solid 3-chloromethylpyridine hydrochloride (2.0 g). After stirring for 30 minutes at -70° C., the mixture was allowed to warm to 4° C. and was then added to saturated ammonium chloride solution (200 ml). The mixture obtained was extracted with ether (3×100 ml). The combined extracts were washed with brine (50 ml), dried (MgSO4) and evaporated. The residue was purified by flash chromatrography using ether as eluant to give ethyl 3-(3-pyridyl)-2,2-dimethylpropionate (A) as a clear oil (2.12 g); NMR (CDCl3): 1.20 (6H, s), 1.23 (3H, t J=7 Hz), 2.87 (2H, s), 4.12 (2H, q J=7 Hz). 7.20 (1H, J=7, 5 Hz), 7.46 (1H, dt J=7, 1 Hz), 8.40 (1H, d J=1.5 Hz), 8.47 (1H, dd J=5, 1.5 Hz).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]4[CH2:27][CH2:26][CH2:25][C:12]=4[N:13]=[C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C@@:17]4([CH3:24])[C:21](O)=[O:22])[N:15]=3)[CH:5]=2)[CH2:3][CH2:2]1.[F:28][C:29]1[N:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]4[CH2:27][CH2:26][CH2:25][C:12]=4[N:13]=[C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C@@:17]4([CH3:24])[C:21]([NH:35][C:32]4[CH:33]=[N:34][C:29]([F:28])=[CH:30][CH:31]=4)=[O:22])[N:15]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc(F)nc1
Reactant: C[C@@]1(C(=O)O)CCCN1c1nc2c(c(Nc3cc(C4CC4)[nH]n3)n1)CCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@@]1(C(=O)Nc2ccc(F)nc2)CCCN1c1nc2c(c(Nc3cc(C4CC4)[nH]n3)n1)CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 3.6 %

Procedure:
To a solution of (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylpyrrolidine-2-carboxylic acid (1.1 g, 2.99 mmol) in DMF (12 mL) was added 6-fluoropyridin-3-amine (1.7 g, 15.18 mmol), diisopropylethylamine (0.578 g, 4.48 mmol) and HBTU (1.13 g, 2.99 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layer was washed with water (9×200 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave a crude product which was purified by reverse phase HPLC to afford 50 mg of (S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide. 1H NMR (400 MHz, CD3OD, TFA salt) δ (ppm): 0.70-0.80 (m, 2H), 0.89-0.99 (m, 2H), 1.77-1.83 (m, 1H), 1.80 (s, 3H), 2.16-2.30 (m, 5H), 2.38-2.43 (m, 1H), 2.77-2.83 (m, 2H), 2.98-3.05 (m, 2H), 3.78-3.82 (m, 1H), 3.88-3.98 (m, 1H), 6.02 (s, 1H), 6.99 (d, 1H), 7.82-7.90 (m, 1H), 8.18 (s, 1H). The other enantiomer was prepared using the (R) chiral starting material.
Reaction SMILES: [NH3:1].[OH:2][C:3]([CH3:19])([CH3:18])[C:4]([C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12](OC)=[O:13])=[CH:8][CH:7]=1)=[O:5]>O1CCOCC1>[OH:2][C:3]([CH3:19])([CH3:18])[C:4]([C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12]([NH2:1])=[O:13])=[CH:8][CH:7]=1)=[O:5]
Reactant: COC(=O)COc1ccc(C(=O)C(C)(C)O)cc1
Reactant: N
Solvent: C1COCCO1
Product: CC(C)(O)C(=O)c1ccc(OCC(N)=O)cc1
Reaction time: 2 h

Procedure:
75.0 g of 25% strength ammonia are added dropwise with stirring to 25.2 g (0.1 mol) of methyl 4-(2-hydroxy-2-methylpropionyl)phenoxyacetate (obtained by esterifying compound IIg using methanol) in 50 ml of dioxane.After being stirred for 2 hours, the mixture is evaporated to solidification. The crude product is recrystallized from hot water, 22.1 gof compound IIt of melting point 139° C. being obtained.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(OC([N:18]1[C:22]([NH2:23])=[CH:21][C:20]([CH2:24][CH2:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)=[N:19]1)=O)(C)(C)C.[F:36][CH:37]1[CH2:42][CH2:41][CH2:40][N:39]([CH2:43][C:44]2[CH:53]=[CH:52][C:47]([C:48](OC)=[O:49])=[CH:46][CH:45]=2)[CH2:38]1.C(=O)([O-])[O-]>C1COCC1.CC#N>[CH3:33][O:32][C:30]1[CH:31]=[C:26]([CH2:25][CH2:24][C:20]2[NH:19][N:18]=[C:22]([NH:23][C:48](=[O:49])[C:47]3[CH:46]=[CH:45][C:44]([CH2:43][N:39]4[CH2:40][CH2:41][CH2:42][CH:37]([F:36])[CH2:38]4)=[CH:53][CH:52]=3)[CH:21]=2)[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=1
Reactant: COC(=O)c1ccc(CN2CCCC(F)C2)cc1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(CN4CCCC(F)C4)cc3)n[nH]2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.9 %

Procedure:
A solution of NaHMDS in THF (1 M, 0.86 ml, 0.86 mmol, 1.5 eq) was added dropwise at ambient temperature to a mixture of tert-butyl-5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate (200 mg, 0.58 mmol, 1 eq) and methyl 4-[(3-fluoro-1-piperidyl)methyl]benzoate (174 mg, 0.69 mmol, 1.2 eq) in THF (1 ml). The reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was then concentrated and the crude product was purified by reverse-phase prep. HPLC (acidic) using a gradient of acetonitrile in water containing 0.1% TFA. The clean fractions were taken and evaporated. The residue was dissolved in 3:1 DCM:MeCN mixture (4 ml) and MP-carbonate (2.74 mmol/g, 1 g, 2.74 mmol) was added. The mixture was stirred for 4 h, filtered and the filtrate evaporated to afford the title compound as a pale yellow gum (43 mg, 16% yield); 1H NMR (399.902 MHz, DMSO) δ□ 1.46-1.34 (2H, m), 1.82-1.61 (2H, m), 2.36-2.28 (2H, m), 2.66-2.56 (2H, m), 2.81 (4H, s), 3.50 (2H, s), 3.65 (6H, s), 4.66-4.47 (1H, m), 6.26-6.24 (1H, m), 6.35 (2H, d), 6.40 (1H, s), 7.32 (2H, d), 7.88 (2H, d), 10.51 (1H, br.s), 12.07 (1H, br.s). MS: m/z 467 (MH+)
Reaction SMILES: [OH:1][C@H:2]1[C@@H:9]2[N:5]([C:6](=[O:23])[N:7]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=3)[C:8]2=[O:10])[CH2:4][CH2:3]1.I[CH3:25]>C(#N)C.[Ag-]=O>[CH3:25][O:1][C@H:2]1[C@@H:9]2[N:5]([C:6](=[O:23])[N:7]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=3)[C:8]2=[O:10])[CH2:4][CH2:3]1
Reactant: CI
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2ccccc12
Agent: O=[Ag-]
Solvent: CC#N
Product: CO[C@@H]1CCN2C(=O)N(c3ccc(C#N)c4ccccc34)C(=O)[C@H]12
Temperature: 85 °C
Yield: 68.7 %

Procedure:
To a solution of compound 6C (100 mg, 0.326 mmol) in acetonitrile (2 mL), at RT, was added iodomethane (86 μL, 1.38 mmol), followed by silver(I) oxide (42 mg, 0.18 mmol). The mixture was refluxed at 85° C. for 16 hours. After cooling to RT, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by using a preparative HPLC (gradient, 20 to 90% of MeOH/H2O containing 0.1% of CF3CO2H over 10 minutes) to yield the title compound (racemate) (72 mg, 69% yield) as an off-white solid. mp. 185-186° C. HPLC: 99% at 2.45 min (retention time) (YMC S5 ODS column 4.6×50 mm; 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nM), MS (ES): m/z 322 [M+1]+.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[CH3:7][C:8]([Si:11]([CH3:20])([CH3:19])[O:12][C@H:13]1[CH2:17][CH2:16][NH:15][C:14]1=[O:18])([CH3:10])[CH3:9].C(Br)C#C.O>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:10][C:8]([Si:11]([CH3:20])([CH3:19])[O:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH2:3][C:2]#[CH:1])[C:14]1=[O:18])([CH3:7])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCNC1=O
Reactant: CC(C)(C)[O-]
Agent: C#CCBr
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCN1CC[C@H](O[Si](C)(C)C(C)(C)C)C1=O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of 11.5 g of potassium tert-butoxide in 300 ml of dimethylformamide was cooled to -20° C. An 18 g portion of (S)-3-[[(1,1-dimethylethyl)dimethylsilyl]-oxy]-2-pyrrolidinone was added and the mixture stirred at -20° C. for 30 minutes. A 12 ml portion of 80% propargyl bromide in toluene was added and the reaction was allowed to warm to room temperature and was stirred for 1 hour. Water was added and the mixture was extracted with 5×100 ml of ether and 3×100 ml of dichloromethane. The extracts were combined, backwashed with water, dried and concentrated in vacuo, giving 15.8 g of (S)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-(2-propynyl)-2-pyrrolidinone [α]D26° =-44° (dichloromethane); mp 35°-36° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[NH:8][C:7]([C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]([C:26]3[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][C:31]([O:35][CH3:36])=[C:30]([O:37][CH3:38])[C:29]=4[O:39][CH3:40])=O)[CH2:20][CH2:19]1)=O)=[CH:6]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:36][O:35][C:31]1[CH:32]=[C:33]2[C:28](=[C:29]([O:39][CH3:40])[C:30]=1[O:37][CH3:38])[NH:27][C:26]([CH2:24][N:21]1[CH2:20][CH2:19][N:18]([CH2:16][C:7]3[NH:8][C:9]4[C:5]([CH:6]=3)=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[C:10]=4[O:14][CH3:15])[CH2:23][CH2:22]1)=[CH:34]2
Reactant: COc1cc2cc(C(=O)N3CCN(C(=O)c4cc5cc(OC)c(OC)c(OC)c5[nH]4)CC3)[nH]c2c(OC)c1OC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2cc(CN3CCN(Cc4cc5cc(OC)c(OC)c(OC)c5[nH]4)CC3)[nH]c2c(OC)c1OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
N,N′-Bis(5,6,7-trimethoxyindole-2-carbonyl)-piperazine (148 mg) was dissolved in THF (5 mL), and lithium aluminum hydride (10 mg) was gradually added to the solution under ice cooling. The mixture was warmed to room temperature and stirred for 6 hours, and sodium sulfate decahydrate was added thereto. After filtration, the filtrate was concentrated under reduced pressure and purified by column chromatography on silica gel (chloroform:methanol=20:1) to obtain the title compound as a free base.
Reaction SMILES: Cl/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)[CH2:6][CH3:7].C(N)CCC.[C:21]([C:25]#[CH:26])([CH3:24])([CH3:23])[CH3:22]>[Cu]I.O1CCCC1>[CH3:22][C:21]([CH3:24])([CH3:23])[C:25]#[C:26]/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)[CH2:6][CH3:7]
Reactant: C#CC(C)(C)C
Reactant: CCN(C/C=C/Cl)Cc1cccc(O)c1
Agent: [Cu]I
Solvent: CCCCN
Solvent: C1CCOC1
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77 %

Procedure:
To 30 ml of tetrahydrofuran were added 4.51 g (20 mmol) of (E)-N-(3-chloro-2-propenyl)-N-ethyl-3-hydroxybenzylamine, 190.5 mg (1 mmol) of copper (I) iodide and 324 mg (0.28 mmoi) of tetrakis (triphenyiphospnine)palladium, and further, 3.95 ml (40 mmol) of n-butyiamine and 2.94 ml (24 mmol) of tert-butylacetylene under ice cooling. The mixture was stirred for 20 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel chromatography (n-hexane→n-hexane/ethyl acetate =7/3). The desired fractions were put together and concentrated under reduced pressure to oil. The oil was cooled to crystallize and the crystals were suspended in cooled n-hexane. The crystals were collected by filtration and then dried to obtain 4.20 g (yield: 77%) of the above identified compound as slightly yellow crystalline powder.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:29])=[C:9]([C:11]2[N:16]=[C:15]3[N:17]([CH3:28])[S:18](=[O:27])(=[O:26])[N:19]([CH2:20][CH:21]4[CH2:23][C:22]4([F:25])[F:24])[C:14]3=[CH:13][CH:12]=2)[CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1.CCOC(C)=O>[F:25][C:22]1([F:24])[CH2:23][CH:21]1[CH2:20][N:19]1[C:14]2[C:15](=[N:16][C:11]([C:9]3[CH:10]=[C:5]([CH2:4][NH2:1])[CH:6]=[CH:7][C:8]=3[CH3:29])=[CH:12][CH:13]=2)[N:17]([CH3:28])[S:18]1(=[O:26])=[O:27]
Reactant: Cc1ccc(CN=[N+]=[N-])cc1-c1ccc2c(n1)N(C)S(=O)(=O)N2CC1CC1(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(CN)cc1-c1ccc2c(n1)N(C)S(=O)(=O)N2CC1CC1(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-[5-(azidomethyl)-2-methylphenyl]-1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide (44-1) (480 mg, 1.1 mmol, 1.0 eq) in THF (6.7 mL) was added triphenylphosphine (600 mg, 2.3 mmol, 2.0 eq) followed by water (0.31 mL, 17.1 mmol, 15 eq). The reaction mixture stirred at ambient temperature overnight and was then diluted with EtOAc (100 mL), washed with sodium bicarbonate (4×10 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (24 g SiO2, 20-100% EtOAc in hexanes) to afford 1-(3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-4-methylphenyl)methanamine (44-2). HRMS m/z (M+H) 395.1348 found, 395.1348 required.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[F:23]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:20]3[CH:19]=[CH:18][C:17]([F:16])=[C:22]([F:23])[CH:21]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: OB(O)c1ccc(F)c(F)c1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccc(F)c(F)c1

Procedure:
The title compound, MS: m/e=330.4 (M+H+), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1 H-imidazol-4-ylethynyl)-pyridine and 3,4-difluorobenzene boronic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[BH3-]C#N.[Na+]>CO.C(O)(=O)C.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCc1ccc(CN2CCOCC2)cc1
Reaction time: 1 h

Procedure:
(4-Formyl-benzyl)-carbamic acid tert-butyl ester Compound 15a (555 mg, 2.37 mmol, prepared as described in Far A R, Cho Y L, Rang A, Rudkewich D M, Rebek J, Tetrahedron, 2002, 58(4), 741-756) was added to a solution of morpholine (207 μL, 2.37 mmol) in MeOH (5 mL) and acetic acid (0.20 mL). The mixture was stirred for 1 hr and then 95% NaBH3CN (198 mg, 3.0 mmol) was added. The reaction was diluted after 2 hr with saturated NaHCO3 and extracted with EtOAc to provide (4-morpholin-4-ylmethyl-benzyl)-carbamic acid tert-butyl ester Compound 15b (230 mg), isolated by flash chromatography as a white solid. MS 307 (MH+). Compound 15b (230 mg, 0.752 mmol) was deprotected with 20% TFA in DCM (10 mL) to provide 4-morpholin-4-ylmethyl-benzylamine Compound 15c (63 mg) upon work-up. MS 207 (MH+).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[N:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][N:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C(Cl)(Cl)Cl.ClC(OCC)=O.[NH3:29]>C(N(CC)CC)C>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[N:15]=[CH:14][C:13]([C:16]([NH2:29])=[O:18])=[CH:12][N:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](c2ncc(C(=O)O)cn2)CC1
Reactant: N
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC[C@H]1CC[C@H](c2ncc(C(N)=O)cn2)CC1
Temperature: 2 °C
Reaction time: 0.25 h

Procedure:
A solution of 13.85 g of trans-2-(4-propylcyclohexyl)-5-pyrimidinecarboxylic acid, 260 ml of chloroform and 7.8 ml of triethylamine is cooled to 2° C. and treated with 5.32 ml of ethyl chloroformate. The mixture is stirred at 2° C. for 15 minutes and then a strong stream of ammonia gas is conducted in for 10 minutes (while cooling with an ice-bath). The resulting suspension is stirred at 20° C. for a further 1 hour and then evaporated in vacuo. The solid residue is stirred up with 210 ml of water for 45 minutes and then filtered off under suction and dried. There are obtained 9.6 g of crude trans-2-(4-propylcyclohexyl)-5-pyrimidinecarboxamide (m.p. 234°-235° C.) which can be purified by sublimation at 175° C./0.05 mmHg; m.p. 249.3°-250.5° C.