Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([NH:16][C@H:17]([C:19]([OH:21])=[O:20])[CH3:18])[CH2:7][C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Na+].[Na+]>[H][H].C(O)C.O>[CH2:1]([O:3][C:4]([C@@H:6]([NH:16][C@H:17]([C:19]([OH:21])=[O:20])[CH3:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)N[C@@H](C)C(=O)O
Reactant: [H][H]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)O
Temperature: 20 °C
Yield: 67.6 %

Procedure:
N-(1-ethoxycarbonyl-3-oxo-3-phenylpropyl)-L-alanine [(1S/1R)=9.0] (10.0 g, 34 mmoles) was added to 105 ml of 7% (w/w) water-containing ethanol containing 1.9 N sulfuric acid. Thereto 50% (w/w) water-containing 5% Pd--C (5.0 g) was added and the catalytic reduction was carried out in hydrogen atmosphere (atmospheric pressure) under the conditions of an inner temperature of about 20° C. and an agitation power of a range from 0.5 to 1 kW/m3 (amount of sulfuric acid based on substrate: 6 equivalents). Supply of hydrogen was stopped at the time when hydrogen is absorbed in 90% and somewhat more of the required amount. And then, the atmosphere was rapidly replaced with nitrogen to stop the reaction. Pd--C was rapidly removed by filtration and the Pd--C cake was conscientiously washed with 10 ml of 7% (w/w) water-containing ethanol and 5 ml of water. After 30 ml of water was added to the resulting filtrate, the filtrate was neutralized (pH 4.5) by slowly adding dropwise an aqueous 30% (w/w) sodium hydroxide solution. The filtrate was concentrated at the inner temperature of a range from 40° to 60° C. under reduced pressure, and then concentrated under reduced pressure with appropriately adding water to obtain slurry with replacing with water. The content of ethanol in the slurry was 3% (w/w), the content of sodium sulfate was 9% (w/w) and the pH was 5.0. After cooling to an inner temperature of 20° C., the crystal was filtered and washed with water in a 2-fold amount of the cake. The resulting crystal was vacuum-dried (30 mmHg to 0.1 mmHg) at a range from 40° to 60° C. to obtain N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine (6.3 g, 23 mmoles). The yield was 75%. HPLC purity: 99.3% (w/w), the content of N-(1(R)-ethoxycarbonyl-3-phenylpropyl)-L-alanine: not detected, the content of N-(1-ethoxycarbonyl-3-cyclohexylpropyl)-L-alanine: 0.1% (w/w), the content of N-(1-carboxy-3-phenylpropyl)-L-alanine: less than 0.1% (w/w), residue on ignition: 0.1% 35 (w/w).
Reaction SMILES: [OH:1][C:2]([CH:5]1[CH2:10][NH:9][CH2:8][C:7]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[O:6]1)([CH3:4])[CH3:3].C([O-])(O)=O.[Na+].FC(F)(F)S(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O>C(O)C>[OH:1][C:2]([CH:5]1[O:6][C:7]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:8][N:9]([CH2:40][C:41]([F:44])([F:43])[F:42])[CH2:10]1)([CH3:4])[CH3:3]
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CNCC(C(C)(C)O)O3)ccc1OC(C)C
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(CC(F)(F)F)CC(C(C)(C)O)O3)ccc1OC(C)C
Temperature: 80 °C
Yield: 52.9 %

Procedure:
(2-(2-Hydroxypropan-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)(4-isopropoxy-3-methylphenyl)methanone (25 mg, 0.06 mmol) was dissolved in dry ethanol (300 μL) and NaHCO3 (50 mg, 0.60 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (20 μL, 0.13 mmol) were added and the reaction mixture was heated at 80° C. for 16 hours. The reaction mixture was filtered, concentrated in vacuo and purified by silica gel column chromatography using 0-100% EtOAc/hexanes as eluent to give [10-(1-hydroxy-1-methyl-ethyl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (15 mg, 53%) as a colorless oil. ESI-MS m/z calc. 472.5. found 473.5 (M+1)+; Retention time: 1.93 minutes (3 min run).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:30])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](CCCC(OC(C)C)=O)=[CH:15][C:14]=2[O:28][CH3:29])[N:10]=1.CN(C)C=O.[C:36]([O:44][CH:45]([CH3:47])[CH3:46])(=[O:43])[C:37]([O:39]C(C)C)=O.[H-].[Na+].[C:50]1(C)[CH:55]=CC=C[CH:51]=1>C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:30])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:51][CH2:50][CH2:55][CH:37]([OH:39])[C:36]([O:44][CH:45]([CH3:46])[CH3:47])=[O:43])=[CH:15][C:14]=2[O:28][CH3:29])[N:10]=1
Reactant: CC(C)OC(=O)C(=O)OC(C)C
Reactant: COc1cc(CCCC(=O)OC(C)C)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(CCCC(O)C(=O)OC(C)C)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
A solution of isopropyl 4-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]butanoate (100 g) in toluene (30 ml)-N,N-dimethylformamide (DMF) (30 ml) was added dropwise, at 100° C., to a mixture of diisopropyl oxalate (84.3 g), sodium hydride (60% oil, 11.6 g) and toluene (300 ml)-N,N-dimethylformamide (DMF) (30 ml). The mixture was stirred for one hour at the same temperature, which was distributed into ice-water-2N HCl and ethyl acetate. The ethyl acetate layer separated was washed with water, dried (MgSO4) and then concentrated. The concentrate was dissolved in dimethyl sulfoxide (DMSO) (400 ml)-water (40 ml), to which was added sodium chloride (14.1 g). The mixture was stirred for 10 hours at 120° C. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and then concentrated. The concentrate was dissolved in tetrahydrofuran (100 ml)-isopropanol (200 ml), to which was added portionwise sodium borohydride (NaBH4) (1.83 g) under ice-cooling. The reaction mixture was stirred for 90 minutes at 0° C., which was poured into ice-water and acidified with 2N HCl, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and then concentrated. The residue was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-hexane (1:2), was obtained isopropyl (±)-5-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]-2-hydroxypentanoate (35.1 g, 33%), which was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.75-76° C.
Reaction SMILES: C(O[C:4]([S:6][Cl:7])=[O:5])C.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]([OH:26])([CH:23]([SH:25])[CH3:24])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1.[CH2:27](O)[CH3:28]>>[ClH:7].[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]([OH:26])([CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[CH:23]([SH:25]([CH2:27][CH3:28])[C:4](=[S:6])[OH:5])[CH3:24]
Reactant: CC(S)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CCOC(=O)SCl
Reactant: CCO
Product: CC[SH](C(O)=S)C(C)C(O)(Cn1cncn1)c1ccc(F)cc1F
Product: Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Ethoxycarbonylsulfenyl chloride (0.12 g) was dissolved in ethanol (2 ml). To the solution was added portionwise at room temperature (2RS,3RS)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol (0.22 g). The reaction mixture was stirred for 5 minutes at room temperature, then the solvent was distilled off under reduced pressure. To the residue was added diethyl ether to give ethyl [(2RS,3RS)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butyl]dithiocarbonate hydrochloride (Compound 21:0.25 g) as a colorless powder.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]3C(=O)C4=CC=CC=C4C3=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[C:1]1([CH:7]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:11][CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Yield: 68.2 %

Procedure:
3.70 g of potassium phthalimide was dissolved in 20 ml of N,N-dimethylformamide; 5.4 ml of 1,5-dibromopentane was added, followed by stirring at room temperature for 15 hours. Ice water was added to the reaction mixture, followed by extraction with ethyl acetate; the extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (4:1). The desired fraction was collected to yield 4.68 g of N-(5-bromopentyl)phthalimide as an oily substance. 4.68 g of N-(5-bromopentyl)phthalimide and 4.25 g of 4-(diphenylmethoxy)piperidine were dissolved in 30 ml of N,N-dimethylformamide; 2.42 g of potassium carbonate was added, followed by stirring at room temperature for 15 hours. Ice water was added to the reaction mixture, followed by extraction with ethyl acetate; the extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate-triethylamine (50:50:1). The desired fraction was collected to yield 6.67 g of N-[5-[4-(diphenylmethoxy)piperidino]pentyl]phthalimide as an oily substance. 6.6 g of N-[5-[4-(diphenylmethoxy)piperidino]pentyl]phthalimide was dissolved in 30 ml of ethanol; 0.694 ml of hydrazine monohydrate was added, followed by thermal refluxing for 3 hours. After cooling, the mixture was concentrated under reduced pressure; ethyl acetate was added to the residue; the crystal precipitated was collected, dissolved in 15 ml of a 1N aqueous solution of sodium hydroxide and 20 ml of water and extracted with ethyl acetate; the extract was washed with saline, dried over sodium sulfate and concentrated under reduced pressure; the crystal obtained was collected to yield 3.29 g of the title compound.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]#[N:15])[CH2:9]1)C1C=CC=CC=1.N1C=CC=CC=1.Cl[C:35]([O:37][CH3:38])=[O:36]>C(Cl)Cl>[C:14]([C:13]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:10]1[CH2:11][CH2:12][N:8]([C:35]([O:37][CH3:38])=[O:36])[CH2:9]1)#[N:15]
Reactant: COC(=O)Cl
Reactant: N#CC(c1ccccc1)(c1ccccc1)C1CCN(Cc2ccccc2)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)N1CCC(C(C#N)(c2ccccc2)c2ccccc2)C1
Reaction time: 5 h
Yield: 68.7 %

Procedure:
To a solution of 36.5 g (0.10 mole) of α-(1-benzyl-3-pyrrolidinyl)-α,α-diphenylacetonitrile and 8.7 g (0.11 mole) of pyridine in methylene chloride was added dropwise at 25° C., 10.4 g (0.11 mole) of methyl chloroformate. The solution was refluxed for 16 hr. To the refluxing solution was added 26.1 g (0.33 mole) of pyridine and 31.2 g (0.33 mole) additional methyl chloroformate. Heating at reflux was continued for 5 hr. The mixture was cooled and washed four times with water. The methylene chloride layer was dried and concentrated in vacuo. The residual oil was crystallized twice from a mix of petroleum ether (30°-60°) and isopropanol to give 22 g (68%) of title product, m.p. 133°-135° C.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[O:20][C:21]([C:24](Cl)=[O:25])=[CH:22][CH:23]=2)=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1>[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[O:20][C:21]([C:24](=[O:25])[NH:2][CH3:1])=[CH:22][CH:23]=2)=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN
Reactant: O=C(Cl)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.97 ml (5.94 mmol) of a 2M solution of methylamine in THF were initially charged in 20 ml of THF, and a solution of 0.8 g (2.4 mmol) of 1-benzyl-3-(5-chlorocarbonyl-2-furyl)indazole in 10 ml of THF was added dropwise at RT. After 1 h, the mixture was poured into ice-water and the oil that separated off was extracted with ethyl acetate. The organic phase was washed with 1N hydrochloric acid, dried and concentrated using a rotary evaporator. The crude product was recrystallized from isopropanol. This gave 0.44 g (55%) of the title compound. m.p.: 182-183° C.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:17][CH2:16]1)=[O:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[OH:54][C:55]1[CH:63]=[CH:62][C:58]([C:59](O)=[O:60])=[CH:57][N:56]=1>CN(C=O)C.O>[OH:54][C:55]1[CH:63]=[CH:62][C:58]([C:59]([NH:11][CH2:12][C:13](=[O:14])[N:15]2[CH2:16][CH2:17][N:18]([C:21](=[O:32])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([F:31])([F:29])[F:30])[CH2:19][CH2:20]2)=[O:60])=[CH:57][N:56]=1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(O)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(O)nc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 24.9 %

Procedure:
DIPEA (418 mg, 0.56 mL, 3.2 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (303.4 mg, 0.86 mmol) in DMF (4 mL). HOBT (106 mg, 0.79 mmol) and EDCI (344 mg, 1.7 mmol) were then added at room temperature. After 2 minutes, 6-hydroxy nicotinic acid (100 mg, 0.71 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by preparative HPLC to afford 77 mg (24.6% yield) of 6-hydroxy-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-nicotinamide. LCMS Purity: 95.26%. 1H NMR (DMSO-d6): δ 12 (s, 1H), 8.4 (s, 1H), 7.9-7.74 (m, 3H), 7.72-7.62 (m, 1H), 7.6-7.5 (m, 1H), 4.2-4.0 (d, 2H), 3.9-3.52 (m, 5H), 3.24-3.0 (m, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[NH:38]1C2C(=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)[CH:40]=[CH:39]1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:18][CH2:19][N:14]([C:13]4[N:12]=[CH:11][N:10]=[C:9]([NH2:37])[C:8]=4[C:5]4[CH:4]=[C:3]5[C:2](=[CH:7][CH:6]=4)[NH:38][CH:39]=[CH:40]5)[CH2:15][CH2:16]3)[N:21]([CH3:36])[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:34])([F:35])[F:33]
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc3[nH]ccc3c2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using (1H-indol-5-yl)boronic acid pinacol ester instead of 4-fluorophenylboronic acid. LC-MS: (M+1=536, obsd.=536).
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[C:10]([NH2:16])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:6]=2[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:35])=[CH:20][N:19]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[Na]>O.CC(O)C>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:16][C:10]2[C:7]3[CH2:8][CH2:9][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]=3[C:13]([O:14][CH3:15])=[CH:12][CH:11]=2)=[N:19][CH:20]=1
Reactant: CCN1CCc2c(N)ccc(OC)c2CC1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: [Na]
Solvent: O
Solvent: CC(C)O
Product: CCN1CCc2c(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc(OC)c2CC1
Temperature: 120 °C

Procedure:
3-Ethyl-9-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-ylamine (50.01 mg, 0.2270 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (67.4 mg, 0.227 mmol) and 10-camphorsulfonic acid (79.1 mg, 0.340 mmol) were charged to 2 ml IPA in a microwave tube. The reaction was heated to at 120° C. for 40 minutes. Pour reaction into water (50 ml) and saturated sodium bicarb (90 ml) and extract 3 times with 25 ml portions of methylene chloride. Dry combined organic over magnesium sulfate, filter and evaporate to a brown oil (102 mg). The crude reaction was purified on silica gel (12 g Isco column) using a gradient of 0-10% methanol in methylene chloride and then isocratic 20% methanol in methylene chloride to yield 2-[5-Chloro-2-(3-ethyl-9-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a beige foam. 1H-NMR (CDCl3) δ 11.10 (br s, 1H), 8.42 (br s, 1H), 8.02 (s, 1H), 7.40 (d, J=7.6 Hz, 1H), 7.15 (d, J=8.6 Hz, 1H), 6.95 (m, 1H), 6.77 (d, J=8.6 Hz, 1H), 6.43 (s, 1H), 3.89 (s, 3H), 3.12 (br s, 1H), 3.03 (d, J=4.8 Hz, 3H), 2.93 (br s, 1H), 2.60-2.41 (m, 6H), 1.00 (m, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7]#[CH:8])[CH2:3][CH2:4][OH:5].[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(N(CC)CC)C.Cl>O1CCCC1>[CH3:9][S:10]([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][C:7]#[CH:8])(=[O:12])=[O:11]
Reactant: C#CCC(C)CCO
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCC(C)CCOS(C)(=O)=O
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of 2.9 g of 3-methyl-5-hexyn-1-ol and 3.0 g of methanesulfonyl chloride in 50 ml of tetrahydrofuran was added dropwise 4 ml of triethylamine at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. To the reaction mixture was 10% hydrochloric acid and the extracted with ethyl acetate. The organic layer was washed sequentially with 10% hydrochloric acid and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.88 g of 3-methyl-5-hexynyl methanesulfonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[H-].[Na+].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>CN(C=O)C>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][O:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[CH:7]=[O:8])[CH3:19]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1cc(Br)ccc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Br)cc1C=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
This compound was prepared according to a literature procedure (Yoo et al., Bioorg. Med. Chem. 5:445, 1997). 5-Bromo-2-hydroxybenzaldehyde (10.0 g, 49.7 mmol) was dissolved in 90 mL anhyd. DMF and the mixture was cooled to 0° C. NaH (60% dispersion in mineral oil, 2.38 g, 59.6 mmol) was added in portions and the reaction was stirred at 0° C. for 1 hour. Ethyl bromoacetate (9.95 g, 59.6 mmol) was then added dropwise over 10 minutes and the reaction was stirred at rt overnight (18 hours). After this time, 30 mL of 1 N HCl was added to adjust the pH to acidity, and the reaction mixture was transferred to a separatory funnel and extracted with EtOAc (3×60 mL). The combined organics rinsed with water (2×40 mL), dried over MgSO4, filtered, and concentrated in vacuo to provide a thick oil. Purification by flash chromatography (10% EtOAc/hexanes) provided the product as a clear oil (14.0 g, 98%). 1H-NMR (CD2Cl2, δ): 1.29 (t, 3H), 4.26 (q, 2H), 4.78 (s, 2H), 6.83 (d, 1H), 7.65 (dd, 1H), 7.94 (s, 1H), 10.47 (s, 1H); LRMS (GC/MS/EI) 286 [M]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]([CH:15]=[CH2:16])=[CH:13][CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:24][C:25]1[CH:30]=[C:29](I)[CH:28]=[CH:27][C:26]=1[N:32]1[S:36](=[O:38])(=[O:37])[N:35]([CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:34](=[O:45])[CH2:33]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:17]([O:24][C:25]1[CH:30]=[C:29](/[CH:16]=[CH:15]/[C:14]2[N:10]([CH2:9][O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:11]=[CH:12][CH:13]=2)[CH:28]=[CH:27][C:26]=1[N:32]1[S:36](=[O:37])(=[O:38])[N:35]([CH2:39][CH2:40][Si:41]([CH3:43])([CH3:42])[CH3:44])[C:34](=[O:45])[CH2:33]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: C=Cc1ccnn1COCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/c3ccnn3COCc3ccccc3)cc2OCc2ccccc2)S1(=O)=O
Temperature: 110 °C

Procedure:
A mixture of 1-benzyloxymethyl-5-vinyl-1H-pyrazole (385 mg, 1.80 mmol), 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (500 mg, 0.90 mmol), Pd(OAc)2 (13 mg, 0.06 mmol), P(o-tolyl)3 (43 mg, 0.14 mmol) and triethylamine (0.21 mL, 1.5 mmol) in MeCN is heated at 110° C. for 30 min in a microwave apparatus. The reaction mixture is concentrated and chromatographed using a gradient of 15-30% EtOAc/hexanes to afford the title compound as a yellow oil: (M+1)+=631.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH:19]=[N:20]O)[CH:12]=[CH:11]1.C(N(CC)CC)C>C1COCC1>[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[C:19]#[N:20])[CH:12]=[CH:11]1
Reactant: ON=Cc1cccc2cc[nH]c12
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1cccc2cc[nH]c12
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 97.3 %

Procedure:
2-chloro-1-methylpyridinium iodide (1.930 g) was added to a solution of 1H-indole-7-carbaldehyde oxime (D1) (1.1 g) in dry THF (80 mL) at RT. After stirring for 10 min, triethylamine (3.35 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at RT for 2 hours, then was heated to 50° C. and stirred at 50° C. for 2.5 hours. The solvent was evaporated. The residue was dissolved in EtOAc (100 mL) and water (100 mL) was added. The organic fraction was separated, washed with aqueous HCl (0.5 M, 50 mL). The organic fraction was dried over anhydrous magnesium sulfate. The dried solution was concentrated to afford 1H-indole-7-carbonitrile (D2) as a white solid (0.95 g). δH (DMSO-d6, 400 MHz): 6.64 (1H, m), 7.16 (1H, t), 7.56 (1H, m), 7.68 (1H, d), 7.93 (1H, d), 12.02 (1H, br s). MS (ES): C9H6N2 requires 142; found 141.0 (M−H+).