Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][CH:8]=[C:7]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:6]=2.C(N(CC)CC)C.[CH3:40][O:41][CH2:42][CH2:43][C:44](Cl)=O>ClCCl>[CH2:26]([O:25][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:44]([CH2:43][CH2:42][O:41][CH3:40])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Reactant: COCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
Under a nitrogen atmosphere, a solution of tert-butyl {4-[3-amino-7-(benzyloxy)quinolin-4-ylamino]butyl}carbamate (28.62 g, 65.5 mmol) in dichloromethane (1 L) was cooled to ˜0° C.; triethylamine (10.0 mL, 72.1 mmol) was added. Methoxypropionyl chloride (8.57 mL, 78.6 mmol) was added dropwise, and the reaction was stirred at ambient temperature for two hours. The volatiles were removed under reduced pressure, and the residue was dissolved in ethanol (840 mL). Triethylamine (33 mL) was added, and the reaction was heated at reflux overnight and allowed to cool to ambient temperature. The volatiles were removed under reduced pressure to provide 30.77 g of tert-butyl {4-[7-benzyloxy-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate as a brown oil, which was used without purification.
Reaction SMILES: C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[CH3:20][N:21]([CH3:23])[NH2:22].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH:34]([C:44]2[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=2[F:51])[C:35]2[N:40]=[CH:39][C:38]([C:41](O)=[O:42])=[CH:37][CH:36]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1>CN(C)C1C=CN=CC=1.ClCCl.CO>[CH3:20][N:21]([CH3:23])[NH:22][C:41](=[O:42])[C:38]1[CH:37]=[CH:36][C:35]([CH:34]([S:31]([C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=2)(=[O:32])=[O:33])[C:44]2[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=2[F:51])=[N:40][CH:39]=1
Reactant: CN(C)N
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)NC(=O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 68 %

Procedure:
Triethylamine (32 μl, 0.23 mmol), 4-dimethylaminopyridine (12 mg, 0.095 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23 mmol) and 1,1-dimethylhydrazine (21 μl, 0.23 minol) were added to the [6-[(4-chlorophenylsulfonyl) (2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (80 mg, 0.19 mmol), which had been obtained in Example 338, in dichloromethane (5 ml). The resulting mixture was stirred at room temperature for 7 hours. The reaction mixture was diluted with dichloromethane, followed by successive washing with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column and a fraction obtained from the elution portion with dichloromethane:methanol =50:1 was concentrated under reduced pressure, whereby the title compound (60 mg, 0.13 mmol, 68%) was obtained as a colorless amorphous substance.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]([F:14])([F:13])[CH:11]=[O:12].Cl>CCOCC.C([Li])CCC>[F:9][C:10]([F:14])([F:13])[CH:11]([OH:12])[C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: O=CC(F)(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC(C#Cc1ccccc1)C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
In a solution of phenylacetylene (4.08 g, 40 mmol) in dry ether (30 ml), n-butyllithium (27 ml, 1.5 M in hexane) was slowly added at -78° C. Trifluoroacetaldehyde (3.7 g, 38 mmol) was introduced in the above mixture under bubbling and the mixture was then agitated 2 hours at -78° C. After the temperature of reaction mixture was elevated to room temperature, the whole solution was poured into aqueous 2% HCl solution. Extraction was made for the oily layer using diethyl ether. The extracts were dried on magnesium sulfate and solvent was removed. Distillation gave 1,1,1-trifluoro-4-phenyl-3-butyne-2-ol (b.p.: 82° C./1.8 mmHg) at a yield of 74%. The above product gave the following analytical data:
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[C:5]([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH:4]=1)#N.C(O)=[O:24]>[Ni]>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[O:14][C:5]1[CH:4]=[C:3]([CH:1]=[O:24])[CH:13]=[CH:12][C:6]=1[NH:7][S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)Nc1ccc(C#N)cc1Oc1ccc(F)cc1F
Reactant: O=CO
Agent: [Ni]
Product: CS(=O)(=O)Nc1ccc(C=O)cc1Oc1ccc(F)cc1F

Procedure:
A mixture of 4'-cyano-2'-(2,4-difluorophenoxy)methanesulfonanilide (1.5 g) and Raney's Nickel (1.5 g) in 75% formic acid (40 ml) was refluxed for 2 hours. The mixture was filtered and the filtrate was concentrated to dryness. The residue was recrystallized from ethanol to give pale yellow needles of 2'-(2,4-difluorophenoxy)-4'-formylmethanesulfonanilide (1.4 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]([NH2:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:17]=1[C:18](Cl)=O.FC1C=CC=C(F)C=1C1OC(=O)C2C=C([N+]([O-])=O)C=CC=2N=1.Cl>C(N(CC)CC)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]=[C:18]([C:17]3[C:16]([F:15])=[CH:24][CH:23]=[CH:22][C:21]=3[F:25])[O:11][C:10](=[O:12])[C:9]=2[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(N)c(C(=O)O)c1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: Cl
Agent: O=c1oc(-c2c(F)cccc2F)nc2ccc([N+](=O)[O-])cc12
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc2nc(-c3c(F)cccc3F)oc(=O)c2c1
Yield: 94 %

Procedure:
5-Acetamidoanthranilic acid (0.64g) and 2,6-difluorobenzoyl chloride (1.3 g) were reacted in triethyl amine/toluene (1/1) (20 mL) like described for compound (9), reaction time 1 h. Ethyl acetate (50 mL) and HCl-solution (1 mL 4N in 50 mL water) were added resulting in the formation of a precipitate.The mixture was filtered and the residue dissolved in THF followed by evaporation to dryness, subsequent dissolution in hot dioxane followed by precipitation with hexane resulted in colourless crystals of 6-acetamido-(2,6-difluoro-phenyl)-benzo[d][1,3]oxazin-4-one (0.98 g), mp.246 C, MS m/e.: 316 M+.
Reaction SMILES: Cl.CO.[CH3:4][O:5][C:6](=[O:22])[C:7]([N+:19]([O-])=O)=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[NH:11][CH:10]=1>CCOCC>[ClH:18].[CH3:4][O:5][C:6](=[O:22])[C:7]([NH2:19])=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[NH:11][CH:10]=1
Reactant: COC(=O)C(=Cc1c[nH]c2cc(Cl)ccc12)[N+](=O)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C(N)=Cc1c[nH]c2cc(Cl)ccc12
Reaction time: 1.5 h
Yield: 180.1 %

Procedure:
A 3-l. three-necked flask, equipped with a thermometer and a mechanical stirrer was charged with 316 g (1.4 moles) of stannous chloride dihydrate and a solution of 111 g (3 moles) of dry hydrogen chloride gas in 1 l. of methyl alcohol. The colorless solution was stirred and cooled to -30° in a dry ice-acetone bath. 112.3 g (0.40 moles) of alpha-nitro-6-chloro-3-indoleacrylic acid methylester was added in 4 equal portions over 1 hour, maintaining the temperature between -25 and -20°. After the addition was complete, the temperature was allowed to rise to -10° and stirring at this temperature was continued for 90 minutes. Then 500 ml. of ether was added to the yellow suspension, followed by addition of 500 ml of 12N hydrochloric acid (concentrated), the temperature was kept below 5°. The mixture was then filtered through a Buchner funnel. The filter cake was washed with 1000 ml of methyl alcohol-9N aqueous hydrochloric acid 1:1, precooled to -20°, and 400 ml of ether. The tan product was dried at 40°/0.1 mmHg for 8 hours and then at 20°/0.1 mmHg to constant weight to yield 103.4 g (90%) of crude product, m.p. 191° (dec.).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]([CH2:12]O)=[CH:10][C:9]2[CH:14]=[CH:15][S:16][C:8]=2[S:7]1(=[O:18])=[O:17].C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]([CH2:12][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[CH:10][C:9]2[CH:14]=[CH:15][S:16][C:8]=2[S:7]1(=[O:18])=[O:17]
Reactant: COCCCN1C(CO)=Cc2ccsc2S1(=O)=O
Reactant: C1COCCN1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCCN1C(CN2CCOCC2)=Cc2ccsc2S1(=O)=O
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of the product from Step C (1.30 g, 4.50 mmol) and triethylamine (1.36 g, 13.5 mmol) in anhydrous THF (30 mL) at ambient temperature was added methanesulfonic anhydride (1.18 g, 6.75 mmol). After stirring for 30 min, morpholine (5 mL) was added; this mixture was stirred at ambient temperature for 18 h and then heated at reflux for 1 h. The volatiles were evaporated and a saturated aqueous solution of sodium bicarbonate (100 mL) was added. The mixture was extracted with ethyl acetate (2×100 mL) and the combined extracts were dried (MgSO4) and evaporated to give a viscous oil which was purified by column chromatography (silica, 30 to 50% ethyl acetate/hexane) to give a viscous oil (1.51 g, 94%).
Reaction SMILES: [NH2:1][C@H:2]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].C[B:24]1[O:29]B(C)OB(C)O1.[C:32]1(C)C=CC=CC=1>>[CH:17]1([C@@H:2]2[C:3]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[O:4][B:24]([O:29][CH3:32])[NH:1]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: N[C@H](C1CCCCC1)C(O)(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1
Reactant: CB1OB(C)OB(C)O1
Product: COB1N[C@H](C2CCCCC2)C(c2ccccc2)(c2ccccc2)O1
Reaction time: 0.5 h

Procedure:
A solution of (R)-2-amino-2-cyclohexyl-1,1-diphenylethanol, (2.95 g, 10 mmole) in toluene (34 mL) was distilled to remove (10 mL) of solvent. Additional toluene (17 mL) was added and a further 17 mL of solvent was distilled out. An additional 58 mL of toluene was added and a further 17 mL of solvent was distilled out. A further 17 mL of toluene was added followed by the addition of trimethylboroxine (0.93 mL, 6.68 mmole) at room temperature. The reaction mixture was kept at room temperature for 30 minutes and concentrated to a volume of 10 mL. Toluene (17 mL) was again added and a further 17 mL of distillate was distilled out. Additional toluene (17 mL) was added and the distillation was continued at atmospheric pressure until no more distillate was removed. Dry tetrahydrofuran was added to the residue to give a stock solution of the product (R)-4-cyclohexyl-5,5-diphenyl-2-methoxy-1,3,2-oxazaborolidine (3.2 g) in tetrahydrofuran (30 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:27])[N:13]([C:15]3[N:20]=[C:19]([N:21]4[CH2:26][CH2:25][S:24][CH2:23][CH2:22]4)[CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[OH2:28].C(=O)(O)[O-:30].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:27])[N:13]([C:15]3[N:20]=[C:19]([N:21]4[CH2:22][CH2:23][S:24](=[O:30])(=[O:28])[CH2:25][CH2:26]4)[CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cccc(N2CCSCC2)n1
Reactant: O
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cccc(N2CCS(=O)(=O)CC2)n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
4-{6-[4-(3-Chloro-phenylethynyl)-2-methyl-imidazol-1-yl]-pyridin-2-yl}-thiomorpholine (250 mg, 0.63 mmol) was dissolved in 6 mL of methanol and Oxone monopersulfate triple salt (389 mg, 0.63 mmol) was added. The reaction mixture was stirred at room temperature for 4 days. Then additional Oxone monopersulfate triple salt (78 mg, 1.3 mmol) was added to drive the reaction to completion. The reaction mixture was treated with 50 mL water. The pH was adjusted to 9 by addition of sat. sodium bicarbonate solution, and the reaction mixture was extracted three times with methylene chloride (50 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude material was purified by flash chromatography (heptane/ethyl acetate 1:4) and the desired product was obtained as a white solid (97 mg, 36%), MS: m/e=427.4, 429.4 (M+H+).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[S:26]([Cl:29])(=[O:28])=[O:27])[CH:19]=[N:18][CH:17]=1>C(Cl)Cl>[ClH:29].[ClH:29].[Br:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[S:26]([N:1]2[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)(=[O:27])=[O:28])[CH:19]=[N:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1cccc2cncc(Br)c12
Reactant: C1CNCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cl
Product: O=S(=O)(c1cccc2cncc(Br)c12)N1CCCNCC1
Temperature: 25 °C

Procedure:
To a solution of 1.5 g of homopiperazine in methylene chloride were added triethylamine and 4-bromo-5-chlorosulfonylisoquinoline, and the mixture was stirred at room temperature and after-treated. The crude product was purified by silica gel column chromatography (chloroform/methanol=10/1) and further treated as in Example 1 to provide 0.55 g of the objective compound (white crystals).
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[C:11]3[C:7]([C:8]([CH2:19][C:20]4[N:25]=[C:24]([C:26](OCC5C=CC=CC=5)=[O:27])[CH:23]=[CH:22][CH:21]=4)=[C:9]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[NH:10]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[NH3:36]>CO>[CH:1]1([C:4]2[CH:12]=[C:11]3[C:7]([C:8]([CH2:19][C:20]4[N:25]=[C:24]([C:26]([NH2:36])=[O:27])[CH:23]=[CH:22][CH:21]=4)=[C:9]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[NH:10]3)=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: O=C(OCc1ccccc1)c1cccc(Cc2c(-c3ccccc3)[nH]c3cc(C4CC4)ccc23)n1
Reactant: N
Solvent: CO
Product: NC(=O)c1cccc(Cc2c(-c3ccccc3)[nH]c3cc(C4CC4)ccc23)n1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Benzyl 6-(6-cyclopropyl-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxylate (200 mg) was dissolved in a solution of ammonia in methanol (about 7 mol/L, 3.3 mL). This solution was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (138 mg). 1H-NMR (CDCl3) δ ppm: 0.69-0.77 (2H, m), 0.92-1.02 (2H, m), 1.97-2.06 (1H, m), 4.42 (2H, s), 5.38-5.59 (1H, br), 6.86 (1H, dd, J=1.4, 8.2 Hz), 7.11-7.15 (1H, m), 7.24-7.29 (1H, m), 7.32-7.48 (4H, m), 7.51-7.58 (2H, m), 7.63-7.71 (1H, m), 7.76-7.96 (1H, br), 7.97-8.03 (1H, m), 8.08 (1H, br).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([C:11]([OH:13])=[O:12])=[C:4]([CH3:14])[N:3]=1.N1C=C(C(O)=O)C=C(C(O)=O)[CH:16]=1>>[CH3:16][O:12][C:11]([C:5]1[C:4]([CH3:14])=[N:3][C:2]([CH3:1])=[C:7]([CH:6]=1)[C:8]([OH:10])=[O:9])=[O:13]
Reactant: O=C(O)c1cncc(C(=O)O)c1
Reactant: Cc1nc(C)c(C(=O)O)cc1C(=O)O
Product: COC(=O)c1cc(C(=O)O)c(C)nc1C

Procedure:
5-(methoxycarbonyl)-2,6-dimethylnicotinic acid was synthesized from 2,6-dimethylpyridine-3,5-dicarboxylic acid following the general procedure as described for the pyridine-3,5-dicarboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=3)[C:10]([C:18]([N:20]([CH3:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.O1C=CN=C1C(O)(C#C)C.[N:38]1[CH:43]=[CH:42][CH:41]=[N:40][C:39]=1[C:44]([OH:48])([C:46]#[CH:47])[CH3:45]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:47]#[C:46][C:44]([OH:48])([C:39]4[N:40]=[CH:41][CH:42]=[CH:43][N:38]=4)[CH3:45])[CH:15]=3)[C:10]([C:18]([N:20]([CH3:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: C#CC(C)(O)c1ncccn1
Reactant: CN(C(=O)c1nn(-c2ccnc(N)n2)c2cc(I)ccc12)c1ccccn1
Agent: C#CC(C)(O)c1ncco1
Product: CN(C(=O)c1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3ncccn3)ccc12)c1ccccn1

Procedure:
The title compound was prepared according to the procedure described in Example 70-b, by substituting 4-{6-iodo-3-[(morpholin-4-yl)carbonyl]-1H-indazol-1-yl}pyrimidin-2-amine with 1-(2-aminopyrimidin-4-yl)-6-iodo-N-methyl-N-(pyridin-2-yl)indazole-3-carboxamide and 2-(1,3-oxazol-2-yl)but-3-yn-2-ol with 2-(pyrimidin-2-yl)but-3-yn-2-ol in Step 2: 1H NMR (500 MHz, DMSO) delta 1.91 (3H, s), 3.54 (3H, s), 6.25 (1H, s), 6.28 (1H, d, J=5.5 Hz), 7.10 (2H, s), 7.25 (1H, dd, J=6.9, 5.1 Hz), 7.37 (1H, dd, J=8.4, 1.0 Hz), 7.41 (1H, d, J=8.1 Hz), 7.50 (1H, t, J=4.9 Hz), 7.80 (1H, td, J=7.8, 1.8 Hz), 8.00 (1H, d, J=8.4 Hz), 8.19 (1H, d, J=5.4 Hz), 8.32 (1H, d, J=3.4 Hz), 8.80 (1H, s), 8.86-8.96 (2H, m); LC-MS: m/z=+492.15 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3](=S)[NH:4][C:5]1[CH:9]=[N:8][N:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[N:6]=1.[NH3:17]>>[CH3:1][N:2]=[C:3]([NH2:17])[NH:4][C:5]1[CH:9]=[N:8][N:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[N:6]=1
Reactant: N
Reactant: CNC(=S)Nc1cnn(CCCCC#N)n1
Product: CN=C(N)Nc1cnn(CCCCC#N)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5-[4-(3-methylthioureido)1,2,3-triazol-2-yl]valeronitrile in methanolic ammonia (6M; 15 ml.) was treated with mercuric oxide (1.1 g.) and tne mLxture stirred for 3 hours at room temperature. The resulting suspension was filtered through diatomaceous earth and the filtrate evaporated to give 5-[4-(2-methylguanidino)-1,2,3-triazol-2-yl]valeronitrile as a yellow oil.
Reaction SMILES: CC([N:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:41])[CH2:16][C@@H:17]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:21]2[CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[CH:34][C:20]=2[N:19]2[C:37]([CH3:40])=[N:38][N:39]=[C:18]12)C(=O)[O-])(C)C.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[NH2:5][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:41])[CH2:16][C@@H:17]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:21]2[CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[CH:34][C:20]=2[N:19]2[C:37]([CH3:40])=[N:38][N:39]=[C:18]12
Reactant: COc1ccc2c(c1)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)NCCCCCN(C(=O)[O-])C(C)(C)C)c1nnc(C)n1-2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)NCCCCCN)c1nnc(C)n1-2
Reaction time: 3 h

Procedure:
To a solution of 1,1-dimethylethyl[5-({[(4S)-6-(4-chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetyl}amino)pentyl]carbamate (for a preparation see Reference compound I) (0.2 g, 0.34 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (0.053 ml, 0.68 mmol) dropwise at 0° C. The reaction mixture was stirred for 3 h from 0° C. to room temperature. The reaction mixture was concentrated to dryness to afford the title compound as a hygroscopic yellow oil (200 mg)
Reaction SMILES: CN(C(ON1N=N[C:11]2[CH:12]=[CH:13]C=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:34]1[CH2:39][CH2:38][O:37][CH2:36][CH:35]1[C:40]1[C:48]2[S:47][C:46]([NH2:49])=[N:45][C:44]=2[C:43]([O:50][CH3:51])=[CH:42][CH:41]=1.C(Cl)(Cl)Cl.[CH2:56]1[CH2:60][O:59][CH2:58][CH2:57]1>>[CH:56]1([CH2:57][C:58]([NH:49][C:46]2[S:47][C:48]3[C:40]([CH:35]4[CH2:36][O:37][CH2:38][CH2:39][O:34]4)=[CH:41][CH:42]=[C:43]([O:50][CH3:51])[C:44]=3[N:45]=2)=[O:59])[CH2:60][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CCOC1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)CC3CCCCC3)nc12

Procedure:
From cyclohexylacetic add, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+19.3° (c=1.02, CHCl3), ES-MS m/e (%): 391 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.O.C(Cl)(Cl)Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][CH2:20][O:21][S:28]([C:25]4[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=4)(=[O:30])=[O:29])=[CH:15][CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: OCCCOc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCOc2ccc(-c3cn4cc(Br)ccc4n3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
177 mg (corresponding to 0.5 mmol) of 6-bromo-2-[4′-(3″-hydroxypropoxy)phenyl]imidazo[1,2-a]pyridine was dissolved in 10 mL of pyridine, and 197 mg (corresponding to 1.0 mmol) of p-toluenesulfonylchloride was added under an ice bath. After the reaction solution was stirred at room temperature for 16 hours, it was poured into water and extracted three times with chloroform. The combined chloroform layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by recycle preparative HPLC(HPLC apparatus: LC-908 (under trade name: manufactured by Japan Analytical Industry Co., Ltd.); column: two JAIGEL 2H (under trade name; manufactured by Japan Analytical Industry Co., Ltd.) connected together; mobile phase: chloroform), to obtain 87 mg (corresponding to 0.17 mmol) of 6-bromo-2-[4′-(3″-p-toluenesulfonyloxypropoxy)phenyl]imidazo[1,2-a]pyridine (FIG. 1-2, Step 4).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:24](=[O:30])[NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:15]=1)[C:24]([NH:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:30]
Reactant: CC(C)(C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reaction time: 0.33 h
Yield: 91.3 %

Procedure:
A solution of (S)-[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-carbamic acid tert-butyl ester (6.0 g, 14.1 mmol, Example 1, Step A) in CH2Cl2 (28 mL) was treated with trifluoroacetic acid (28 mL). The resulting solution was stirred for 20 minutes and then concentrated. The residue was diluted with EtOAc (300 mL), washed with saturated bicarbonate solution (2×300 mL) and brine (300 mL), dried over Na2SO4, and concentrated to give 4.2 g (91%) of (S)-2-Amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.