Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[O:10]([C@H:18]([CH2:21][CH3:22])[CH:19]=O)[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].[OH2:23]>C(OC(C)C)(C)C>[O:10]([C@H:18]([CH3:19])[CH2:21][CH:22]([C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1)[OH:23])[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC[C@H](C=O)O[Si](C)(C)C(C)(C)C
Reactant: O
Reactant: Clc1cnc(Cl)c(Br)c1
Solvent: CC(C)OC(C)C
Product: C[C@H](CC(O)c1cc(Cl)cnc1Cl)O[Si](C)(C)C(C)(C)C
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a cooled (-70° C.) solution of n-butylithium (129.3 mL of 1.18M hexanes solution, 0.153 mol) in isopropyl ether was added a solution of 3-bromo-2,5-dichloropyridine (36.45 g, 0,161 mol) in isopropyl ether (225 mL) over a period of 30 minutes. The resulting white suspension was then treated with a solution of 3 (R) -t-butyldimethylsiloxybutyraldehyde (34.14 g, 0,169 tool) in isopropyl ether (106 mL) and allowed to stir for an additional 30 minutes at -70° C. followed by warming to room temperature. After the addition of 480 mL of water, the biphasic mixture was separated and the organic layer was extracted with isopropyl ether (2×200 mL). The combined organic layers were washed once with water, heated with decolorizing carbon [G-60 DARCO (trademark)] filtered through diatomateous earth [Celite (trademark)] and condensed on a rotary evaporator. The resulting hazy yellow liquid was heated at 80° C. under high vacuum overnight to yield the desired product (mixture of diastereomers) as an amber oil (40.52 g, 72%): Rf 0.36 (25% Et2O in hexanes); 1H NMR (60 MHz, CDCl3)δ 0.1 (s, 6H), 0.82 (s, 9H) , 1.18 (m, 3H) , 1.72 (m, 2H) , 4.16 (m, 1H) , 4.42 (m, 1H) , 5.10 (m, 1H) , 7.92 (d, 1H, J=2.6 Hz) , 8.13 (d, 1H, J=2.6 Hz) .
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1C(C2C=CC=CC=2)=CS[C:25]=1C(OC)=O.C(OCC)(OCC)OCC.C1(N)CCCCCCC1>C(O)(=O)C>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH2:2][CH2:25][CH2:24][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: NC1CCCCCCC1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3)c2ncn1C1CCCCCCC1
Yield: 57 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), cyclooctylamine (0.113 ml, 0.81 mmol), and acetic acid (0.1 ml) were used to give 82.9 mg (0.24 mmol, 57% yield) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:3])[NH2:2].O1CCOCC1.C(=O)(O)[O-].[Na+].[C:27](=O)([O:33]C(C)(C)C)[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]>O>[C:29]([O:28][C:27]([N:13]1[CH2:14][CH2:15][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:1](=[O:3])[NH2:2])[CH2:11][CH2:12]1)=[O:33])([CH3:32])([CH3:31])[CH3:30]
Reactant: NC(=O)c1ccccc1N1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
1-(2-Carbamoylphenyl)piperazine (300 mg, 1.5 mmol) was dissolved in water (2 ml) and 1,4-dioxane (2 ml) The resulting solution was mixed with sodium bicarbonate (250 mg, 2.9 mmol) and di-t-butyl carbonate (480 mg, 2.2 mmol), and then stirred at a room temperature for 4 hours. The reaction solution was mixed with water (20 ml), and the reaction product was extracted with chloroform (80 ml) and washed with water and saturated brine. Then the solvent was evaporated under a reduced pressure to obtain colorless crystals. Thereafter, the crystals were washed with hexane and then dried to obtain 430 mg of the title compound (1.4 mmol, 96% in yield).
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].O.[OH-].[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH:7][NH:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:16]
Reactant: CC(C)(C)NN
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)NNC(=O)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a suspension of t-butyl hydrazine hydrochloride (6.2 g, 0.05 mole), water (30 mL) and toluene (60 mL) at 0° C. to 5° C. was added 50% sodium hydroxide (4.0 g,0.05 mol). To the above reaction mixture was then added, separately and simultaneously, 50% sodium hydroxide (4.0 g,0.05 mol) and 3-chlorobenzoyl chloride (8.8 g, 0.05 mol) from two dropping funnels. After addition was completed, the reaction mixture was stirred at 0° C. for 30 minutes and room temperature for 30 minutes. The resultant precipitate was collected by suction-filtration and washed with water (100 mL) and dried in air to give 9.0 g (79% yield) of 1-(3-chlorobenzoyl)-2-t-butyl hydrazine as a white solid. mp 116°-118° C.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[NH2:7][C:8]1[N:13]=[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[N:22]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:21]([CH3:37])([CH3:36])[CH2:20]2)[N:11]=[C:10]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH:43]2[CH2:48][C:47]([CH3:50])([CH3:49])[N:46]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:45]([CH3:61])([CH3:60])[CH2:44]2)[N:9]=1>>[CH2:28]([O:27][N:22]1[C:23]([CH3:26])([CH3:25])[CH2:24][CH:19]([CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:12]2[N:11]=[C:10]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH:43]3[CH2:44][C:45]([CH3:60])([CH3:61])[N:46]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:47]([CH3:49])([CH3:50])[CH2:48]3)[N:9]=[C:8]([N:7]=[C:2]=[O:3])[N:13]=2)[CH2:20][C:21]1([CH3:36])[CH3:37])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(N)nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C
Product: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(N=C=O)nc(NCCCCC3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of oxalyl chloride with the compound prepared in Example 21.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[NH2:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[N:29][NH:30]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>C(O)CCC.C(OC(=O)C)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][C:24]2[CH:32]=[C:31]3[C:27]([CH:28]=[N:29][NH:30]3)=[CH:26][CH:25]=2)[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(Cl)nc(Cl)nc32)cc1
Reactant: Nc1ccc2cn[nH]c2c1
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(C)c3c(Nc4ccc5cn[nH]c5c4)nc(Cl)nc32)cc1
Temperature: 90 °C
Yield: 39.7 %

Procedure:
To a solution of 2,4-dichloro-5-methyl-7-tosyl-pyrrolo[2,3-d]pyrimidine (0.36 g, 1 mmol) in n-butyl alcohol (3 mL) was added 6-aminoindazole (0.27 g, 2 mmol) and DIPEA (0.27 mL, 1.5 mmol) at room temperature. After heating at 90° C. for 4 h, the mixture was diluted with ethylacetate and the organic layer was sequentially washed with 1N HCl, saturated NaHCO3, and brine. The organic extract was then dried over Na2SO4 and concentrated to give a crude residue, which was purified by flash column (Hex/EtOAc=1:1) to give 2-Chloro-N-(1H-indazol-6-yl)-5-methyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.18 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:20][N:19]([CH2:21][CH3:22])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:23]([O:26][CH2:27][C:28]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:31]([F:43])=[CH:30][C:29]=1[N:44]1[CH2:55][CH2:54][C:53]2[C:52]3[CH2:51][C:50]([CH3:57])([CH3:56])[CH2:49][C:48]=3[S:47][C:46]=2[C:45]1=[O:58])(=[O:25])[CH3:24]>>[C:23]([O:26][CH2:27][C:28]1[C:33]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([CH:17]4[CH2:20][N:19]([CH2:21][CH3:22])[CH2:18]4)=[CH:13][N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)=[CH:32][C:31]([F:43])=[CH:30][C:29]=1[N:44]1[CH2:55][CH2:54][C:53]2[C:52]3[CH2:51][C:50]([CH3:57])([CH3:56])[CH2:49][C:48]=3[S:47][C:46]=2[C:45]1=[O:58])(=[O:25])[CH3:24]
Reactant: CCN1CC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Product: CCN1CC(c2ccc(Nc3cc(-c4cc(F)cc(N5CCc6c(sc7c6CC(C)(C)C7)C5=O)c4COC(C)=O)cn(C)c3=O)nc2)C1
Yield: 37 %

Procedure:
Following Example 136a, starting with 5-bromo-3-(5-(1-ethylazetidin-3-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one 250a and (2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.02,6]dodeca-1(8),2(6)-dien-10-yl}-4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 247b, compound 257a was obtained in 37% yield.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH2:3][CH3:4].[C:6]([OH:17])(=[O:16])[C:7]1[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:9]([OH:11])=[O:10]>CO>[CH3:1][NH+:2]([CH3:5])[CH2:3][CH3:4].[C:6]([O-:17])(=[O:16])[C:7]1[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:9]([O-:11])=[O:10]
Reactant: CCN(C)C
Reactant: O=C(O)c1ccccc1C(=O)O
Solvent: CO
Product: CC[NH+](C)C
Product: O=C([O-])c1ccccc1C(=O)[O-]
Yield: 98 %

Procedure:
Further, dimethylethylamine (0.1 mol) was added into a methanol solution of phthalic acid (0.1 mol) to obtain a dimethylethylammonium• phthalate solution. Then, said solution was distilled while being heated at 110° C. under reduced pressure of 1.0 KPa or lower to remove methanol, thereby obtaining dimethylethylammonium• phthalate. The yield was 98%.
Reaction SMILES: FC(F)(F)[C:3]([NH:5][C:6]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[N:7]=1)=[O:4].C(O)=O.ClC1C=C(N2CC(C)C(NC=O)=N2)C=CC=1Cl>O>[F:23][C:20]1[CH:19]=[CH:18][C:17]([N:8]2[CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][C:6]([NH:5][CH:3]=[O:4])=[N:7]2)=[CH:22][CH:21]=1
Reactant: O=C(NC1=NN(c2ccc(F)cc2)C(c2ccccc2)C1)C(F)(F)F
Agent: CC1CN(c2ccc(Cl)c(Cl)c2)N=C1NC=O
Solvent: O
Solvent: O=CO
Product: O=CNC1=NN(c2ccc(F)cc2)C(c2ccccc2)C1
Reaction time: 2 h

Procedure:
A mixture of 5.0 g. of 3-amino-1-(p-fluorophenyl)-5-phenyl-2-pyrazoline (prepared as described in Example 43) and 85.0 ml. of a mixture of formic acid and acetic anhydride (Example 15) is allowed to remain at room temperature for 2 hours. The solvent is evaporated in vacuo to give an oil. Water is added to separate a solid. The solid is dissolved in dichloromethane and is columnized and recrystallized twice as described in Example 26 (A) to give 3.55 g. of the desired product as colorless crystals, m.p. 158.5°-160.5° C.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[N:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26].C1COCC1.[Li][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1>CCOCC.O>[C:1]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[N:22]=[C:21]([CH:23]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[NH:29][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NCc1ccc2ccccc2c1-c1cccc(C=O)n1
Reactant: [Li]c1ccccc1
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)NCc1ccc2ccccc2c1-c1cccc(C(NC(C)(C)C)c2ccccc2)n1
Temperature: -80 °C
Reaction time: 8 h

Procedure:
A mixture of 4.10 g (12.9 mmol) of 6-{2-[(tert-butylamino)methyl]-1-naphthyl}pyridine-2-carbaldehyde, 2.83 g (38.7 mmol) of tert-butylamine, 90 g of molecular sieves (4A), and 80 ml of THF was stirred overnight. After decantation of the molecular sieves (they were additionally washed by 2×50 ml of THF), the resulting combined solution was additionally centrifuged to remove slight precipitate. The obtained solution was evaporated to dryness. A solution of the residue in 80 ml of THF was cooled to −80° C., and 50.0 ml (37.5 mmol) of 0.75 M of PhLi in ether was added. The resulting mixture was stirred for 1 h at room temperature. Further on, 20 ml of water was added. The organic layer was separated, and the aqueous layer was extracted with 2×40 ml of ether. The combined organic extract was washed by 20 ml of water, dried over K2CO3, and then evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um; ethyl acetate-triethylamine=20:1, vol.). Yield 2.84 g (49%) of white solid of a ca. 1 to 1 mixture of two diastereomers. Anal. calc. for C31H37N3: C, 82.44; H, 8.26; N, 9.30. Found: C, 82.59; H, 8.35; N, 9.19. For 1H NMR (in CDCl3) see FIG. 2—Top spectrum.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[NH:32][CH3:33])=[O:26])[CH3:23].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[N:32]([C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)[CH3:33])=[O:26])[CH3:23]
Reactant: CCOC(=O)C1CCCC1NC
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCC1N(C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.1665 g, 0.5 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL). 2-Methylamino-cyclopentanecarboxylic acid ethyl ester (0.0856 g, 0.5 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.1003 g, 0.525 mmol). Then N-methylmorpholine (115 μL, 1.05 mmol) was added. The mixture was stirred at 25° C. for 5 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product, 2-{[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-methyl-amino}-cyclopentanecarboxylic acid ethyl ester, as a yellow oil. LC-MS (ESI) calcd for C19H26N4O7S2 486.12, found 487.2 [M+H+].
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH:41]([CH3:43])[CH3:42])[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14][C@H:13]1[C:28]([NH:30][C@H:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH2:32]1)=[O:29])=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:9]([CH:41]([CH3:43])[CH3:42])[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14][C@H:13]1[C:28]([NH:30][C@H:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH2:32]1)=[O:29])=[O:11]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](N)C(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21

Procedure:
Compound 4 (15.50 g, 26.2 mmol) is BOC-deprotected using TFA (97 mL, 1.31 mol) in CH2Cl2 (500 mL) under the same conditions as for step 2. After workup, the desired free amine 5 is obtained as an off-white foam (12.57 g, 97% yield): 1H NMR δ (CDCl3) 7.28-7.42 (m, 5H), 7.03-7.19 (m, 4H), 6.07-6.35 (br m, 1H), 5.09-5.27 (br m, 3 H), 3.68-4.81 (br m, 3H), 2.66-3.53 (br m, 6H), 1.45-2.04 (br m, 8H), 0.74-1.00 (br m, 1H); LCMS (APCl+) 493.7 (MH+, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[Cl:15][C:16]1[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=[CH:23][C:17]=1[CH:18]=[CH:19][C:20](O)=O>>[Cl:15][C:16]1[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=[CH:23][C:17]=1/[CH:18]=[CH:19]/[C:20]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: COc1ccc(C=CC(=O)O)c(Cl)c1OC
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(OC)c3Cl)nc2n(CC)c1=O
Yield: 53.6 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.00 g (10.1 mmol) of 5,6-diamino-1,3-diethyluracil and 2.94 g (12.1 mmol) of 2-chloro-3,4-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from 2-propanol/water to give 2.19 g (yield 54%) of Compound 112 as pale yellow needles.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=O)=[CH:5][CH:4]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[C:26]=1[NH2:32]>>[F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:31]=[C:27]3[CH2:28][CH2:29][CH2:30][NH:25][C:26]3=[N:32][C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: O=C(C(=O)c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Reactant: Nc1cccnc1N
Product: FC(F)(F)c1ccc(-c2nc3c(nc2-c2ccc(C(F)(F)F)cc2)NCCC3)cc1

Procedure:
The title compound was prepared from 1,2-bis(4-(trifluoromethyl)phenyl)ethane-1,2-dione (this may be prepared according to the procedure of Bioorganic & Medicinal Chemistry Letters (2007), 17(21), 5825-5830) and pyridine-2,3-diamine analogously to Intermediate E;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:14][CH2:15][C@@H:16]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[CH2:17]([C@H:16]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:15][NH:14][C:11](=[O:13])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:10])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NC[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 15 h
Yield: 99 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-D-alanine (595 mg, 3.14 mmol) in DMF (20 mL) was added benzyl [(1S)-2-amino-1-benzylethyl]carbamate (Tet. Lett. 2005, 46(41), 7069) (968 mg, 3.30 mmol), HBTU (1.43 g, 3.77 mmol) and triethylamine (1.8 ml, 12.6 mmol) at room temperature. After stirring the reaction mixture for 15 hours, water (20 mL) was added to the mixture. The mixture was extracted with ethyl acetate/heptane 5/1 (2×20 mL) and the combined extracts were washed with 1N citric acid (20 mL), saturated aqueous sodium bicarbonate (20 mL) and brine (20 mL). The organic layer was dried over sodium sulfate, and concentrated under reduced pressure to afford the title compound as a white solid in 99% yield, 1.42 g. 1H NMR (400 MHz, CDCl3) : 1.24 (d, 3H), 1.43 (s, 9H), 2.59-2.86 (m, 4H), 3.13-3.25 (m, 2H), 3.34-3.44 (m, 1H), 3.89-4.05 (m, 2H), 4.90-5.05 (m, 2H), 7.11-7.36 (m, 10H).
Reaction SMILES: [CH:1]1([CH2:7]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Mg].[B:10](OC)(OC)OC.OS(O)(=O)=O.[OH:22][C:23]([C:26]([OH:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C(OCC)C.CO>[CH:1]1([CH2:7][B:10]2[O:29][C:26]([CH3:28])([CH3:27])[C:23]([CH3:25])([CH3:24])[O:22]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COB(OC)OC
Reactant: CC(C)(O)C(C)(C)O
Reactant: BrCC1CCCCC1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CO
Solvent: CCOCC
Product: CC1(C)OB(CC2CCCCC2)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
62.9 ml of cyclohexylmethyl bromide are slowly added dropwise to 12.0 g of magnesium and 200 ml of diethyl ether. After the magnesium has dissolved, the solution of the Grignard compound is added dropwise to a solution of 50.3 ml of trimethyl borate in 100 ml of diethyl ether which has been precooled to -78° C. in such a way that the temperature does not rise above -55° C., and the mixture is then stirred at R.T. for 2 h. Then, while cooling in ice, 113 ml of 40% strength H2SO4 are added in such a way that the internal temperature does not rise above 25° C. 53.2 g of pinacol in 100 ml of diethyl ether are now poured in, and the diethyl ether together with the biproduct methanol are removed in a rotary evaporator. The pH is then adjusted with NaHCO3 to 8, the mixture is extracted 3 times with 200 ml of MTB, the organic phase is dried over Na2SO4, the solvent is removed in vacuo, and the residue is distilled under high vacuum. 49.7 g of the title compound are obtained as a colorless oil. ##EQU5##
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:18]([CH2:19][CH:20]([OH:22])[CH3:21])[N:17]=[CH:16][N:15]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:25][C:26]([OH:43])([CH3:42])[CH2:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1>>[OH:22][CH:20]([CH3:21])[CH2:19][N:18]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:31]5[CH:30]=[N:29][N:28]([CH2:27][C:26]([CH3:42])([OH:43])[CH3:25])[CH:32]=5)[CH:24]=[CH:23][C:5]=4[C:6]=3[N:7]=2)=[N:15][CH:16]=[N:17]1
Reactant: CC(O)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(O)Cn1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CC(C)(C)O)c3)ccc1-2

Procedure:
Following the procedure for 114, 1-[5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-[1,2,4]triazol-1-yl]-propan-2-ol was reacted with 2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol to give 459. MS (ESI+) 467.1. 1H NMR (400 MHz, DMSO) δ 8.35 (d, J=8.3, 1H), 8.17 (s, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.43 (dd, J=8.3, 1.8, 1H), 7.30 (d, J=1.7, 1H), 4.95 (d, J=5.3, 1H), 4.82 (dd, J=13.3, 7.5, 1H), 4.76-4.66 (m, 2H), 4.46-4.32 (m, 2H), 4.28-4.14 (m, 1H), 4.03 (s, 2H), 3.44 (t, J=5.0, 2H), 1.16 (d, J=6.3, 3H), 1.10 (s, 6H)
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2.[CH3:18]I>CN(C)P(=O)(N(C)C)N(C)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:18])[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2
Reactant: CI
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1cc2cc(Cl)ccc2n1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 83.7 %

Procedure:
8.7 gm (0.2 mol) of a 55% dispersion of sodium hydride in oil were added over a period of 15 minutes at a temperature of 0° C. and in a nitrogen atmosphere to a solution of 40.0 gm (0.18 mol) of ethyl 5-chloro-indole-2-carboxylate in 150 ml of hexamethyl-phosphoric acid triamide. After stirring the resulting mixture for 2.5 hours at room temperature, 35.5 gm (0.25mol) of methyl iodide were added dropwise, while cooling. After stirring overnight, 1200 ml of ice water were added to the mixture, while externally cooling on an ice bath. The aqueous mixture was then extracted 5 times with 150 ml of ether each. The combined ether extracts were washed with water 5 times, dried over magnesium sulfate, and evaporated in vacuo. The raw product was then recrystallized from petroleum ether, yielding 35.8 gm (85% of theory) of ethyl 5-chloro-1-methyl-indole-2-carboxylate. M.p.: 81.5°-82° C.