Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][C:31]([C:37]#[N:38])=[CH:32][CH:33]=4)[CH:28]=3)[C:22](=[O:25])[CH2:23]Br)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][NH:40][CH3:41]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][C:31]([C:37]#[N:38])=[CH:32][CH:33]=4)[CH:28]=3)[C:22](=[O:25])[CH2:23][N:40]([CH3:41])[CH3:39])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C#N)cc4c3)C(=O)CBr)cc2)CC1
Reactant: CNC
Solvent: CO
Product: CN(C)CC(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
N-[4-[(1-t-Butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]-2-bromoacetamide obtained in Reference Example 27 (237 mg) was dissolved in 1 ml of methanol, 10 ml of 40% dimethylamine aqueous solution was added to the solution, and the mixture was stirred at 60° C. for 12 hours. The reaction solution was evaporated and chloroform was added to the resulting residue. The mixture was washed with water and brine in that order, dried over anhydrous sodium sulfate and then evaporated to give 247 mg of N-[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]-2-dimethylaminoacetamide.
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:10][CH:9]=1)[C:5](Cl)=[O:6])([CH3:3])[CH3:2].[C:18]([CH:20]([OH:34])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)#[N:19].N1C=CC=CC=1>CCOCC>[CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:10][CH:9]=1)[C:5]([O:34][CH:20]([C:18]#[N:19])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:22]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)C(C(=O)Cl)c1ccc(OC(F)F)cc1
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)c1ccc(OC(F)F)cc1
Reaction time: 8 h

Procedure:
A solution of α-isopropyl-4-difluoromethoxyphenylacetyl chloride (4.58 mmol) in ether (5 ml) is added to an ether (20 ml) solution of α-cyano-m-phenoxybenzyl alcohol (4.58 mmol) and pyridine (0.5 ml). The mixture is stirred overnight and filtered. The filtrate and the washings are evaporated and the residual oil is purified on 5×20 cm silica gel plates using 1:1 methylenechloride-hexane as eluent. The band in the silica gel plate is extracted with ether and evaporated to give the desired ester as an oil.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:6][S:7]([NH2:10])(=[O:9])=[O:8].Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([N:22]=[CH:23][N:24]=2)[N:21]=1.Cl>CN(C)C=O.O>[CH2:11]([C:5]([CH2:13][CH3:14])([CH2:6][S:7](=[O:8])(=[O:9])[NH2:10])[CH2:4][O:3][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([N:22]=[CH:23][N:24]=2)[N:21]=1)[CH3:12]
Reactant: Clc1ccc2ncnn2n1
Reactant: CCC(CC)(CO)CS(N)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)(COc1ccc2ncnn2n1)CS(N)(=O)=O
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
In 20 ml of dimethylformamide was suspended 0.64 g of 60% sodium hydride in oil, followed by addition of 1.56 g of 3-hydroxy-2,2-diethyl-1-propanesulfonamide and the mixture was stirred under reduced pressure at room temperatue for 30 minutes. Then, 1.24 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine was added and the mixture was further stirred at room temperature for 1.5 hours. Following addition of 100 ml of iced water, the reaction mixture was adjusted to pH 6 with 1N-hydrochloric acid and the resulting crystals were collected by filtration and washed with 20 ml of water and 20 ml of ethyl ether. The washed crystals were recrystallized from hot ethanol to provide 1.57 g of the title compound. m.p. 194°-197° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:13]([OH:18])(=[O:17])[C:14]([OH:16])=[O:15]>C1COCC1>[C:13]([OH:18])(=[O:17])[C:14]([OH:16])=[O:15].[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH2:10][CH2:11][NH2:12])([O-:3])=[O:2]
Reactant: N#CCc1cccc([N+](=O)[O-])c1
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Product: NCCc1cccc([N+](=O)[O-])c1

Procedure:
3-Nitrophenyl acetonitrile (6.486 g, 0.04 mol) was refluxed with borane-THF complex (40 mL, 0.04 mole) in anhydrous THF (80 mL) for 45 min under argon. The reaction mixture was quenched with methanol and concentrated. 3-Nitrophenylethyl amine was crystallized from the reaction mixture by adding oxalic acid (10 g, 0.08 mol). Yield 4.36 g, 85%.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:19]([NH2:24])[C:20]([CH3:23])([CH3:22])[CH3:21].[OH-].[Na+]>C(O)CCC>[NH2:1][C:2]1[N:10]=[C:9]([NH:24][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: CC(C)(C)CN
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: CC(C)(C)CNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 100 °C
Yield: 73.6 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (100 mg, 0.385 mmol) and neo-pentylamine (336 mg, 3.85 mmol) suspended in 1-butanol (10 ml) were heated at 100° C. for 10 hours in autoclave. The reaction mixture was condensed in vacuo. To the residue was added 1N aqueous sodium hydroxide and the solution was extracted with chloroform. The organic layer was dried on sodium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (88 mg, yield 74%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6]C)=[O:5].C(N(CC)CC)C.[CH3:15][NH:16][C:17]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([O:28][C:29]3[CH:34]=[CH:33][N:32]=[C:31]([N:35](C(OC4C=CC=CC=4)=O)[C:36](=O)[O:37]C4C=CC=CC=4)[CH:30]=3)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1)=[O:18].O>CN(C)C=O.C(OCC)(=O)C.O1CCCC1>[CH3:15][NH:16][C:17]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([O:28][C:29]3[CH:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]([NH:2][CH2:3][C:4]([OH:6])=[O:5])=[O:37])[CH:30]=3)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1)=[O:18]
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)c3)ccc21
Reactant: COC(=O)CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)NCC(=O)O)c3)ccc21
Temperature: 25 °C
Reaction time: 22 h
Yield: 79.2 %

Procedure:
Methyl aminoacetate hydrochloride (300 mg, 2.3 mmol) was dissolved in N,N-dimethylformamide (4 ml), and then triethylamine (1 ml) was added. Phenyl N-(4-(1-(methylamino)carbonyl-1H-indol-5-yloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (250 mg, 0.48 mmol) synthesized in Production example 5-2 was added thereto. The reaction mixture was stirred at room temperature for 22 hours. After water was added to the reaction mixture, extraction was performed with a solvent mixture of ethyl acetate-tetrahydrofuran. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300, ethyl acetate). The obtained pale yellow oil was dissolved in a solvent mixture of tetrahydrofuran (2 ml)-methanol (1 ml), then 4N aqueous solution of lithium hydroxide (0.48 ml) was added, and the reaction mixture was stirred at room temperature for 1 hour. After that, 1N hydrochloric acid (2 ml) was added, and this was subjected to extraction with ethyl acetate-tetrahydrofuran. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield the title compound (145 mg, 0.38 mmol, 79%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[OH:22][C:23]1[C:32]([N:33]([CH3:35])[CH3:34])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([C:18]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:32]([N:33]([CH3:35])[CH3:34])[C:23]=4[OH:22])[CH2:28]3)=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(-c2cccc(F)c2)nc2ccccc12
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Agent: Cl
Product: CN(C)c1ccc2c(c1O)CCN(C(=O)c1nc(-c3cccc(F)c3)nc3ccccc13)C2
Yield: 11 %

Procedure:
Reaction of 2-(3-fluorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 45 (11% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 2.66 and 3.15 (2d, 6H), 2.85 and 3.07 (2t, 2H), 3.58 and 4.21 (2t, 2H), 4.49 and 5.09 (2s, 2H), 6.34 and 6.82 (2d, 1H), 6.97 and 7.15 (2d, 1H), 7.19-8.06 (m, 6H), 8.13-8.18 (m, 1H), 8.34-8.47 (m, 2H); MS (ESI) m/z 443 ([M+H]+).
Reaction SMILES: O.O.[Sn](Cl)Cl.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:19][N:18]=[C:17]([C:20]([F:23])([F:22])[F:21])[N:16]=2)=[CH:11][CH:10]=1)([O-])=O.C(=O)(O)[O-].[Na+]>C(O)C>[F:23][C:20]([F:21])([F:22])[C:17]1[N:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([NH2:6])=[CH:14][CH:13]=2)[NH:19][N:18]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc(C(F)(F)F)n[nH]2)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2nc(C(F)(F)F)n[nH]2)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
8.9 g (39.7 mmol, 4 eq.) of tin(II) chloride dihydrate were added to a solution of 2.7 g (9.9 mmol) of 5-(4-nitrophenyl)-3-(trifluoromethyl)-1H-1,2,4-triazole in 110 ml of ethanol, and the mixture was stirred at 70° C. for 1 h. The reaction mixture was poured into ice-water, and sodium bicarbonate was added carefully until a pH of 8 had been reached. The mixture was filtered through a filter layer and the residue was washed with ethyl acetate. After phase separation, the aqueous phase was washed twice with ethyl acetate. The combined organic phases were washed with aqueous sodium chloride solution, dried (magnesium sulphate), filtered and concentrated under reduced pressure. Yield: 1.9 g (79% of theory)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:12]=[CH:13][C:14]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[C:15]([CH:18]=1)[CH:16]=[O:17].[CH3:28][Mg]Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:12]=[CH:13][C:14]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[C:15]([CH:16]([OH:17])[CH3:28])[CH:18]=1
Reactant: C[Mg]Cl
Reactant: O=Cc1cc(/C=C/c2ccc(F)cc2F)ccc1S(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Product: CC(O)c1cc(/C=C/c2ccc(F)cc2F)ccc1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A solution of 5-[(E)-2-(2,4-difluorophenyl)vinyl]-2-(phenylsulfonyl)benzaldehyde (prepared from Example 58 according to the method of Example 50 Step 1, 74 mg, 0.193 mmol) in tetrahydrofuran (2 mL) was cooled to −78° C. under nitrogen. Methylmagnesium chloride (3.0M in tetrahydrofuran, 0.15 mL, 0.424 mmol) was added and the reaction stirred for 30 minutes then quenched with 1N HCl (5 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 30% ethyl acetate/isohexane to obtain the title compound as a white solid (56 mg, 72%). δH (360 MHz, d6 DMSO): 8.02 (1H, d, J=8.3 Hz), 7.95–7.59 (8H, m), 7.39 (2H, s), 7.33–7.27 (1H, m), 7.14 (1H, td, J=2.1, 8.5 Hz), 5.37 (2H, t, J=5.4 Hz), 1.07 (3H, d, J=5.9 Hz).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8]([C:10]1[NH:11][C:12]2[C:17]([C:18]=1[S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])=[CH:16][C:15]([Cl:28])=[CH:14][CH:13]=2)=[O:9].B(Br)(Br)Br.CCCCCC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8]([C:10]1[NH:11][C:12]2[C:17]([C:18]=1[S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:20])=[O:21])=[CH:16][C:15]([Cl:28])=[CH:14][CH:13]=2)=[O:9]
Reactant: COc1cccc(CNC(=O)c2[nH]c3ccc(Cl)cc3c2S(=O)(=O)c2ccccc2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(NCc1cccc(O)c1)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Reaction time: 16 h

Procedure:
To a saturated solution of N-(3-methoxybenzyl) 3-phenylsulfonyl-5-chloroindole-2-carboxamide (1.37 g, 3.0 mmol) in dry methylene chloride (140 mL) under an inert atmosphere was added boron tribromide in hexane (1M, 10 mL, 10 mmol). After stirring for 12-20 hours, the reaction was neutralized by addition of aq. NaHCO3. After two hours, the solution was made weakly acidic by addition of dilute HC1. The precipitated product was collected by filtration and then the aqueous filtrate extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered, and the solvent evaporated. The residue was triturated with diethyl ether to give additional product. The solids were combined and crystallized from hot methanol/ethyl acetate to give analytically pure product, mp 73.5°-274.5° C.
Reaction SMILES: [C:1]([C:5]1[N:6]([C:20]([OH:22])=[O:21])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([Br:14])=[C:9]([C:15]([F:18])([F:17])[F:16])[C:8]=2[CH3:19])([CH3:4])([CH3:3])[CH3:2].BrN1C(=[O:29])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[N:6]([C:20]([OH:22])=[O:21])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([Br:14])=[C:9]([C:15]([F:17])([F:18])[F:16])[C:8]=2[CH:19]=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C(F)(F)F)c(Br)cc2cc(C(C)(C)C)n(C(=O)O)c12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc2cc(Br)c(C(F)(F)F)c(C=O)c2n1C(=O)O
Temperature: 90 °C
Reaction time: 18 h
Yield: 20.9 %

Procedure:
To a mixture of tert-butyl 5-bromo-7-methyl-6-(trifluoromethyl)-1H-indole-1-carboxylic acid (1.2 g) and carbon tetrachloride (20 mL) were added N-bromosuccinimide (0.70 g) and 2,2′-azobis(2-methylpropionitrile) (20 mg) at room temperature. The reaction mixture was stirred at 90° C. for 18 hours. The reaction mixture was left to be cooled to room temperature and filtered through Celite to remove the insoluble materials. The filtrate was evaporated under reduced pressure, and to the residue was added acetonitrile (20 mL), followed by addition of 4-methyl morpholine-4-oxide (0.50 g) under ice-cooling. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was evaporated under reduced pressure, ethyl acetate and water were added thereto, and a liquid-separation operation was carried out. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-90:10) to obtain tert-butyl 5-bromo-7-formyl-6-(trifluoromethyl)-1H-indole-1-carboxylic acid (0.26 g).
Reaction SMILES: [C:1]1([NH:7][C@H:8]([C:10]([OH:12])=[O:11])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:13](OCCCC)=[O:14]>COCCOC>[N:13]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C@H:8]([C:10]([OH:12])=[O:11])[CH3:9])=[O:14]
Reactant: CCCCON=O
Reactant: C[C@H](Nc1ccccc1)C(=O)O
Solvent: COCCOC
Product: C[C@@H](C(=O)O)N(N=O)c1ccccc1
Reaction time: 2.5 h

Procedure:
N-Phenylalanine (825 mg) in 1,2-dimethoxyethane (20 ml) was treated with n-butyl nitrite (0.64 ml) and the mixture was stirred for 2.5 h and then the solvent was removed to leave crude N-nitroso-N-phenylalanine. This was dissolved in dichloromethane (10 ml), cooled in an ice-bath and treated with trifluoroacetic anhydride (1.06 ml). The mixture was stirred for 1 h and then the solvents were removed, toluene was added and removed using a rotary evaporator. The residue was chromatographed on silica gel eluting with ethanol/chloroform mixtures to give the sydnone (1 g), νmax (CH2Cl2) 1803(sh), 1763(sh), 1734, 1485, 1243, and 1065 cm-1 ; δ (CDCl3) 2.16 (3H,s), 7.51-7.73 (5H, m); Found m/z 176.0590; C9H8N2O2 requires 176.0586. The sydnone in xylene (8 ml) was treated with ethynyltributylstannane and the mixture was heated under reflux for 8 h. After standing for 16 h at room temperature the mixture was diluted with hexane(15 ml) and loaded onto silica gel and eluted with hexane (100 ml) followed by hexane/ethyl acetate mixtures to give 5-methyl-2-phenyl-3-(tri-n-butylstannyl)pyrazole (602 mg), δ (CDCl3) 0.87-1.76 (27H, m), 2.35 (3H, s), 6.25 (1H, s), 7.26-7.47 (5H, m); Found m/z 448.1900. C22H36N2Sn requires 448.1900.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:16])[N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:4][N:3]=1.[CH3:17]I.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:17])[C:7](=[O:16])[N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:4][N:3]=1
Reactant: CCC(CC)n1c(=O)[nH]c2cnc(Cl)nc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CC)n1c(=O)n(C)c2cnc(Cl)nc21
Reaction time: 1.5 h
Yield: 99.6 %

Procedure:
To a solution of 2-chloro-9-(1-ethyl-propyl)-7,9-dihydro-purin-8-one (100 mg, 0.41 mmol) in anhydrous DMF (2 mL) is added methyl iodide (21 uL, 0.41 mmol) and NaH (50% dispersion in mineral oil, 22 mg, 0.46 mmol). The reaction is stirred for 1.5 h. The reaction mixture is quenched with ice water and extracted with EtOAc. The extracts are dried over Na2SO4 and concentrated in vacuo to give 104 mg of 2-chloro-9-(1-ethyl-propyl)-7-methyl-7,9-dihydro-purin-8-one. The crude product is used as is.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[C:18](Br)=[CH:19][N:20]=[CH:21]3)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[C:18]([C:27]#[N:28])=[CH:19][N:20]=[CH:21]3)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2cccc3cncc(Br)c23)CC1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2cccc3cncc(C#N)c23)CC1
Temperature: 120 °C
Reaction time: 19 h

Procedure:
A suspension of Intermediate 121 (113.7 mg), zinc cyanide (19.4 mg, Wako Pure Chemical Industries), tris(dibenzylideneacetone)dipalladium(0) (24.0 mg) and 1,1′-bis(diphenylphosphino)ferrocene (35.3 mg, Tokyo Kasei Kogyo) in DMF (2 ml) was stirred at 120° C. for 19 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (34.9 mg).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.CCOC(C)=O>O1CCOCC1>[NH2:1][C@H:2]([C:7]([N:9]1[CH2:23][CH2:22][CH2:21][C@H:10]1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 5 h

Procedure:
To a flask containing Boc-Leu-Pro-OBn (113.8 g, 272 mmol) a solution of hydrogen chloride in dioxane (209 ml, 5.3 N) was added and the stirring was continued for 5 h or until total conversion by TLC (disappearance of starting material; Rf=0.47 (hex-EtOAc 2:1, silica). The solution was concentrated under reduced pressure and the resulting oil was chased with CHCl3 (3×50 ml), CHCl3-MTBE (30 ml-50 ml), MTBE (50 ml) and hex (50 ml). The residue was dried under vacuum (16 h) to remove residual HCl, to give the title compound as a white solid. A5 (96.4 g, 100%) was used directly without further purification in the next step. [α]D22−85.21 (c=1, CHCl3).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[C:19]([Cl:25])[CH:18]=1.I[CH2:28][CH:29]1[CH2:33][CH2:32][C:31]2([O:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:30]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:26])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[C:19]([Cl:25])[CH:18]=1)[CH2:28][CH:29]1[CH2:33][CH2:32][C:31]2([O:34][CH2:35][CH2:36][CH2:37][O:38]2)[CH2:30]1
Reactant: COC(=O)Cc1ccc(SC)c(Cl)c1
Reactant: ICC1CCC2(C1)OCCCO2
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCC2(C1)OCCCO2)c1ccc(SC)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 56.2 %

Procedure:
A solution of diisopropylamine (1.9 mL, 13.64 mmol) in dry tetrahydrofuran (19.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (6.5 mL) cooled to −78° C. under nitrogen was treated with a 2.5M solution of n-butyllithium in hexanes (5.5 mL, 13.64 mmol). The reaction mixture was stirred at −78° C. for 45 min and then treated dropwise with a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (prepared as in Example 4, 2.42 g, 10.49 mmol) in dry tetrahydrofuran (19.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (6.5 mL). The reaction mixture turned bright yellow. The reaction mixture was allowed to stir at −78° C. for 15 min, then at 0° C. for an additional 30 min, and then re-cooled to −78° C. At this point, a solution of 2-iodomethyl-6,10-dioxa-spiro[4.5]decane (prepared as in Example 43, 3.85 g, 13.64 mmol) in dry tetrahydrofuran (10 ML) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3 mL) was added dropwise. The reaction mixture stirred at −78° C. for 30 min and was then allowed to warm to 25° C., where it was stirred for 24 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was diluted with ethyl acetate (200 mL), and the organic layer was washed with a saturated aqueous lithium chloride solution (2×200 mL), water (200 mL), and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 25% ethyl acetate/hexanes) afforded the 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(6,10-dioxa-spiro[4.5]dec-2-yl)-propionic acid methyl ester (2.27 g, 56%) as a yellow oil: EI-HRMS m/e calcd for C19H25ClO4S (M)+ 384.1162. found 384.1181.
Reaction SMILES: [N+:1]([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)([O-])=O.C([O-])=O.[NH4+]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:1][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
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Under argon, 15 g (60.84 mmol) of ethyl 5-nitro-1H-indole-2-carboxylate are initially charged in 750 ml of ethyl acetate and 750 ml of ethanol. 15.82 g (15.82 mmol) of ammonium formate and 1.50 g of palladium on activated carbon (10%) are added. The mixture is stirred at 90° C. for 30 minutes and then cooled and filtered off through Celite, which is washed with ethyl acetate. The solvent is removed under reduced pressure and the residue is dissolved in chloroform and washed twice with water. The organic phase is dried with sodium sulphate, filtered and concentrated under reduced pressure using a rotary evaporator.