Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([O:22][CH3:23])=[CH:4][C:5]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH:7]=1.[N+:24]([O-])([OH:26])=[O:25]>C(Cl)Cl>[OH:1][C:2]1[C:7]([N+:24]([O-:26])=[O:25])=[C:6]([C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[C:5]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[CH:4][C:3]=1[O:22][CH3:23]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(-c2noc(C)n2)c(C(=O)c2ccccc2)cc1O
Solvent: ClCCl
Product: COc1cc(-c2noc(C)n2)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1O
Reaction time: 0.33 h

Procedure:
To a mixture of [5-hydroxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]phenylmethanone (reference example 21-1) (383 mg) and methylene chloride (10 mL) was added fuming nitric acid (68 μL) at room temperature, and the mixture was stirred for 20 minutes. The separated organic layer was washed with water, a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The residue was triturated with hexane:methylene chloride=4:1 to give the title compound (377 mg).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:11]([C:13]2[N:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:15]3[C:20]([C:21]=2[NH2:22])=[CH:19][CH:18]=[C:17]([Cl:23])[CH:16]=3)=[O:12])[O:9][CH:10]=1)(=[O:3])[CH3:2].[C:29](Cl)(=[O:34])[CH2:30][CH:31]([CH3:33])[CH3:32]>>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:11]([C:13]2[N:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:15]3[C:20]([C:21]=2[NH:22][C:29](=[O:34])[CH2:30][CH:31]([CH3:33])[CH3:32])=[CH:19][CH:18]=[C:17]([Cl:23])[CH:16]=3)=[O:12])[O:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2cc(COC(C)=O)co2)c(N)c2ccc(Cl)cc21
Reactant: CC(C)CC(=O)Cl
Product: CCOC(=O)n1c(C(=O)c2cc(COC(C)=O)co2)c(NC(=O)CC(C)C)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) employing 2-(4-acetoxymethyl-2-furoyl)-3-amino-6-chloro-1-(ethoxycarbonyl)indole (step 2) and isovaleryl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH:11]=[CH:12][CH:13]=2)[C:8]([N+:23]([O-:25])=[O:24])=[CH:7]1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([CH2:15][C:16]([OH:18])=[O:17])[CH:11]=[CH:12][CH:13]=2)[C:8]([N+:23]([O-:25])=[O:24])=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1cc([N+](=O)[O-])c2c(CC(=O)OC(C)(C)C)cccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cn1cc([N+](=O)[O-])c2c(CC(=O)O)cccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl [1-(2-ethoxy-2-oxoethyl)-3-nitro-1H-indol-4-yl]acetate from Step E (300 mg, 0.828 mmol) in CH2Cl2 (1 mL) was added TFA (0.63 mL, 8.28 mmol). The mixture was stirred at ambient temperature for 1 h then concentrated in vacuo to give the title compound. MS: m/z=307 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](Cl)=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:21]1([CH2:26][CH2:27][CH2:28][NH2:29])[CH:25]=[CH:24][N:23]=[CH:22]1.C(N(CC)CC)C.CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([NH:29][CH2:28][CH2:27][CH2:26][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NCCCn1ccnc1
Reactant: O=C(Cl)c1ccccc1NS(=O)(=O)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NCCCn1ccnc1)c1ccccc1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(4-Chlorobenzenesulphonamido)benzoyl chloride (3.40 g) was added in portions to a stirred mixture of 3-imidazol-1-ylpropylamine (1.29 g), triethylamine (1.04 g) and dimethylformamide (25 ml) at room temperature. The temperature of the mixture rose to 33° C.; the mixture was then stirred at room temperature for 4 hours before pouring into water (500 ml). The aqueous solution was decanted from the crude product which had precipitated as a gum. This gummy material was dissolved in dichloromethane (50 ml), the solution was dried over magnesium sulphate and the solution was evaporated. The crude product was recrystallised from ethyl acetate to give 2-(4-chlorobenzenesulphonamido)-N-(3-imidazol-1-ylpropyl)benzamide, in the form of a white solid, m.p. 175°-177° C. (yield: 2.1 g).
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[CH2:6][C@H:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH:3]=1.C(C1CC(=O)C(C)=CC1)=CC(=C)C.C[O-].[Na+].O.[H][H].C#N>>[CH3:1][C:2]1[C:7](=[O:8])[CH2:6][CH:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH:3]=1
Reactant: C=C(C)[C@@H]1CC=C(C)C(=O)C1
Reactant: [H][H]
Agent: C#N
Agent: C=C(C)C=CC1CC=C(C)C(=O)C1
Agent: C[O-]
Solvent: O
Product: C=C(C)C1CC=C(C)C(=O)C1
Reaction time: 1 h

Procedure:
1379.4 g (9 mol) of R-(−)-carvone (5-isoprenyl-2-methylcyclohex-2-enone) with a purity of 98% (5-isoprenyl-2-methylcyclohex-2-enone) were heated in a 4000 ml glass flask to approx. 150° C. with stirring. At 144° C., 18.4 g of 30% sodium methoxide in water (0.1 mol) were added and then a mixture of 1287.9 g (8.4 mol) of 98% R-(−)-carvone (5-isoprenyl-2-methylcyclohex-2-enone) and 330.5 g (12.15 mol) of hydrogen cyamide (HCN) was added dropwise at 136-148° C. with stirring within 8 h. The postreaction time was approx. one hour. Subsequently, the HCN conversion was checked, and was 99.5%. The entire raw output weighed 3014 g and had a dark red color. The raw output was distilled through a Vigreux column. The first fraction recovered was unconverted carvone (approx. 900 g), and, after a mixed fraction (147.5 g), 1809.8 g of carvonenitrile were obtained with a purity of 98-99% (gas chromatography).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[Na].Cl.Cl[CH2:9][C:10]1[C:15]([O:16][CH2:17][CH3:18])=[CH:14][CH:13]=[CH:12][N:11]=1>C(O)C>[NH2:2][CH2:3][CH2:4][S:5][CH2:9][C:10]1[C:15]([O:16][CH2:17][CH3:18])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CCOc1cccnc1CCl
Reactant: NCCS
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOc1cccnc1CSCCN
Reaction time: 8 h
Yield: 89.5 %

Procedure:
Cysteamine hydrochloride (2.76 g) was added to a stirred mixture of sodium (1.576 g) in ethanol (75 cc) at 12°, 2-Chloromethyl-3-ethoxypyridine hydrochloride (4.60 g) in ethanol (70 cc) was added over 30 minutes to this mixture stirred at 10°-12°. The mixture was left to stand overnight, filtered and the filtrate was evaporated to dryness. The residue was dissolved in water, acidified to pH 4 with hydrochloric acid and extracted with chloroform (discarded). The aqueous phase was adjusted to pH 12 with aqueous sodium hydroxide and was extracted with chloroform. The chloroform extracts were evaporated to give 2-(2-aminoethylthiomethyl)-3-ethoxypyridine (4.2 g) as an oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][CH:18]=2)[CH2:14][C:13]1([F:16])[F:15])=O)C.O.[OH-].[Na+]>CCOCC>[CH2:24]([O:23][C:20]1[CH:19]=[CH:18][C:17]([C:12]2([CH2:10][OH:9])[CH2:14][C:13]2([F:15])[F:16])=[CH:22][CH:21]=1)[CH3:25]
Reactant: CCOC(=O)C1(c2ccc(OCC)cc2)CC1(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCOc1ccc(C2(CO)CC2(F)F)cc1
Yield: 92 %

Procedure:
To 1.0 g of lithium aluminium hydride in 120 ml of dry ether, at room temperature is added dropwise 5.4 g (0.02 moles) of ethyl-1-(4-ethoxyphenyl)-2,2-difluorocyclopropane-1-carboxylate in 20 ml of ether. The reaction mixture is stirred for 1 hr after which 1.0 ml of water 1.0 ml of 15% NaOH, followed by 3.0 ml of water are added. The solid precipitate is filtered off, washed with ether and the combined filtrates dried and concentrated under reduced pressure to yield (4.2 g) a colourless oil; nD 1.5129.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[Br:27]Br.C(O)(=O)C>C(Cl)(Cl)Cl>[Br:27][CH:10]([C:11](=[O:16])[C:12]([CH3:14])([CH3:13])[CH3:15])[CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)C(CC(=O)C(C)(C)C)c2ccc(Cl)cc2Cl)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)C(c2ccc(Cl)cc2Cl)C(Br)C(=O)C(C)(C)C)cc1

Procedure:
The bromination of 1-(2,4-dichlorophenyl)-1-p-toluenesulfonyl-4,4-dimethylpentan-3-one was carried out in the same manner as that of Example 3 but using 25 g of 1-(2,4-dichlorophenyl)-1-p-toluenesulfonyl-4,4-dimethyl-3-one, 9.2 g of bromine, 200 ml of acetic acid and 300 ml of chloroform, and 29 g of 2-bromo-1-(2,4-dichlorophenyl)-4,4-dimethyl-1-p-toluenesulfonylpentan-3-one was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:34]([NH:33][C:30]2[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=2)=[O:35])=[CH:25][CH:24]=1)#[N:18]
Reactant: COCCOc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Reactant: O=C=Nc1ccc(F)cc1
Solvent: Cc1ccccc1
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1C#N
Yield: 95.7 %

Procedure:
4-(4-Aminophenoxy)-7-(2-methoxyethoxy)-6-cyanoquinoline (109 mg, 0.325 mmol) was dissolved in toluene (5 ml) while heating, and then 4-fluorophenyl isocyanate (0.057 ml, 0.488 mmol) was added and the mixture was heated to reflux for 1 hour. After cooling, the precipitated crystals were filtered out, washed with ethyl acetate and dried under reduced pressure to obtain the title compound (148 mg, 0.311 mmol, 96.4%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10][CH2:11]2)[CH:16]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccccc1N1CCN(Cc2cccc(-c3ccccc3)c2)CC1

Procedure:
47 mg of the target compound (0.13 mmol, 23.8%) was obtained using 1-(2-methoxyphenyl)piperazine (209 mg, 1.09 mmol), biphenyl-3-carbaldehyde (100 mg, 0.55 mmol) and NaBH(OAc)3 (355 mg, 1.65 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[C:4]([NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17](Cl)(=[O:19])=[O:18])=[CH:9][CH:8]=1)=[O:5].[N:26]([CH:29]([CH3:31])C)=[C:27]=[O:28]>C(N(CC)CC)C>[C:27]([N:26]1[CH2:29][CH2:31][CH:4]([NH:6][S:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:24][CH:23]=[CH:22][C:21]=3[F:25])=[CH:8][CH:9]=2)(=[O:19])=[O:18])[CH2:3][CH2:2]1)(=[O:28])[CH2:8][CH2:7][CH3:16]
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)c2ccccc12)c1c(F)cccc1F
Reactant: CC(C)N=C=O
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3c(F)cccc3F)c3ccccc23)CC1

Procedure:
The title compound was prepared following the general proedure in Sheme 5, beginning with 4-(2,6-difluoro-benzoylamino)-naphthalene-1-sulfonyl chloride, and substituting butyryl chloride and triethylamine for 2-isocyanato-propane. 1H NMR (300 MHz, DMSO) δ 11.12 (s, 1H), 8.71 (m, 1H), 8.26 (m, 2H), 8.13 (d, 1H), 7.98 (d, 1H), 7.75 (m, 2H), 7.62 (m, 1H), 7.31 (t, 2H), 4.01 (d, 1H), 3.60 (d, 1H), 2.93 (t, 1H), 2.59 (m, 2H), 2.15 (t, 2H), 1.45 (m, 2H), 1.43 (q, 2H), 1.17 (m, 2H), 0.81 (t, 3H); LC/MS m/z 514 (M−H)−, 516 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].[OH-].[Na+].O.O.[C:16]([O-])(=O)C.[Zn+2:20].[C:21]([O-:24])(=[O:23])[CH3:22].[Na]>O>[CH3:16][C:10]1[CH:9]=[C:8]([OH:11])[CH:7]=[CH:6][C:5]=1[C:3]([O-:2])=[O:4].[CH3:5][C:6]1[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:22]=1[C:21]([O-:24])=[O:23].[Zn+2:20]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: Cc1cc(O)ccc1C(=O)[O-]

Procedure:
To a suspension of 17.5 parts (0.115 mole) of methyl p-hydroxybenzoate in 40 grams of water that had been cooled to 0°-10° C. was slowly added a 50% aqueous sodium hydroxide solution until the pH of the resulting solution was 12. A solution of 12.6 parts (0.06 mole) of zinc acetate dihydrate in 200 parts of water was added to the sodium salt solution. The white precipitate that formed was separated by filtration, washed with cold water, and dried. There was obtained 19.2 parts of zinc bis(methyl p-hydroxybenzoate).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH:1]1([O:6][C:19]([C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:16][CH:17]=2)=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCC1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Solvent: c1ccncc1
Product: O=C(OC1CCCC1)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C

Procedure:
Cyclopentanol (2.58g.; 0.03 m) was dissolved in pyridine (50 ml), 4-benzyloxybenzoyl chloride (6.76g; 0.03 m) was added and the mixture was boiled under reflux 6 hours. The resulting mixture was added to ice-water, extracted with ether, the organic extract washed with 2×100 ml. of 2N hydrochloric acid, 2×100 ml. saturated sodium bicarbonate solution and 1×100 ml. of water, dried (MgSO4) and evaporated. The ester was purified by elution from a column of silica in toluene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:20]([CH3:21])=[N:19][C:12]3[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:4][C:3]=1[NH2:22].[CH3:23][O:24][CH2:25][CH2:26][NH2:27].O>CN(C=O)C>[NH2:22][C:3]1[C:2]([F:1])=[CH:7][C:6]([CH3:8])=[C:5]([C:9]2[C:20]([CH3:21])=[N:19][C:12]3[N:13]=[C:14]([NH:27][CH2:26][CH2:25][O:24][CH3:23])[N:15]=[CH:16][C:11]=3[CH:10]=2)[CH:4]=1
Reactant: COCCN
Reactant: CSc1ncc2cc(-c3cc(N)c(F)cc3C)c(C)nc2n1
Solvent: CN(C)C=O
Solvent: O
Product: COCCNc1ncc2cc(-c3cc(N)c(F)cc3C)c(C)nc2n1
Temperature: 100 °C
Yield: 85.4 %

Procedure:
Treat a solution of 2-fluoro-4-methyl-5-(7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl)benzenamine (0.300 g, 0.954 mmol) in DMF (1 mL) with 2-methoxyethanamine (0.430 g, 5.73 mmol) in a screw-capped vial and heat at 100° C. for 20 h. Cool the mixture to RT, treat with H2O and extract with EtOAc (2×). Wash the combined organics with brine, dry over Na2SO4 and concentrate to dryness to afford the title compound as a dark semi-solid (278 mg, 85% yield). MS (m/z): 342.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])/[C:4](/[NH:18][C:19](=[O:21])[CH3:20])=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]=[CH2:14])=[CH:8][C:7]=1[SiH:15]([CH3:17])[CH3:16]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[C@@H:4]([NH:18][C:19](=[O:21])[CH3:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]=[CH2:14])=[CH:8][C:7]=1[SiH:15]([CH3:16])[CH3:17]
Reactant: C=CCc1ccc(/C=C(\NC(C)=O)C(=O)OC)c([SiH](C)C)c1
Solvent: ClCCl
Product: C=CCc1ccc(C[C@H](NC(C)=O)C(=O)OC)c([SiH](C)C)c1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a round bottomed flask containing (2Z)-methyl-2-acetamido-3-(4-allyldimethylsilylphenyl)prop-2-enoate (1 Scheme 5, 3.2 g, 10 mmol) in deoxygenated CH2Cl2 (40 mL) was added [(COD)Rh(S,S)-Et-DuPHOS]OTf(7 mg). After eight vacuum/H2 cycles, the reaction was stirred for 23 h at room temperature under H2 (1 atm). Once the reaction was finished, the solution was passed through a short plug of silica to remove the catalyst to afford a colorless oil (3.2 g. 100%); 1H NMR (300 MHz, CDCl3) δ 0.25 (s, 6 H), 1.72 (dd, J=8.10 Hz, 2 H), 1.98 (s, 3 H), 3.10 (m, 2 H), 3.72 (s, 3 H), 4.81 (d, J=1.2 Hz, 1 H), 4.83-4.92 (2 H), 5.76 (m, 1 H), 5.94 (bd, J=7.80 Hz, NH, 1 H), 7.06 (d, J=7.20 Hz, 2 H), 7.42 (d, J=7.20 Hz, 2 H); 13C NMR (75 MHz, CDCl3) −3.2, 23.3, 23.9, 37.9, 52.6, 53.3, 113.7, 128.9, 134.1, 134.8, 136.9, 137.5, 170.1, 172.5; HRMS (EI) calcd for C17H25NO3Si 319.1600, found 319.1602.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]2[C:6](=[O:31])[N:7]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][C:19]=3[F:30])[CH2:8][C:9]=2[C:10]([OH:17])=[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12)[CH3:2].Cl[C:33]([F:38])([F:37])C([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[F:37][CH:33]([F:38])[O:17][C:10]1[C:9]2[CH2:8][N:7]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][C:19]=3[F:30])[C:6](=[O:31])[C:5]=2[C:4]([O:3][CH2:1][CH3:2])=[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=12
Reactant: O=C([O-])C(F)(F)Cl
Reactant: CCOC(=O)Cc1ccc(N2Cc3c(c(OCC)c4ccccc4c3O)C2=O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(N2Cc3c(c(OCC)c4ccccc4c3OC(F)F)C2=O)c(F)c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 22.4 %

Procedure:
To a solution of ethyl {4-[9-(ethyloxy)-4-hydroxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-3-fluorophenyl}acetate (2.40 g, 5.67 mmols) in DMF (30 ml) was added sodium chlorodifluoroacetate (1.72 g, 11.34 mmol) and sodium carbonate (1.20 g, 11.34 mmol). The mixture was heated to 100° C. for 3 hours. Further sodium chlorodifluoroacetate (1.72 g, 11.34 mmol) was added, heating continued for 1.5 hours, and the same amount added again and heating continued for 30 minutes. The mixture was cooled to room temperature and partitioned between ethyl acetate ×2 and water. The combined organics were washed with water ×3 and brine. This was dried over magnesium sulphate, filtered and evaporated to a brown oil. This was purified by chromatography on silica gel, eluting with ethyl acetate (5-40%) in hexane to give the title compound as a yellow solid (0.60 g, 1.27 mmol).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[C:4]([Cl:11])[N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([NH2:21])[CH3:20])=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[Cl:11][C:4]1[CH:5]=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=[C:2]([NH:21][C@H:19]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[CH3:20])[N:3]=1
Reactant: CC(=O)c1cc(Cl)nc(Cl)c1
Reactant: C[C@H](N)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(Cl)nc(N[C@@H](C)c2ccc(F)cc2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
535 mg of 1-(2,6-dichloropyridin-4-yl)ethanone (Steps 1 and 2 of Example 29), 391 mg of (S)-(−)-1-(4-fluorophenyl)ethylamine, 262 mg of (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 1.28 g of cesium carbonate and 63 mg of palladium acetate were added in turn to 10 ml of degassed toluene, and the mixture was stirred at 100° C. for 3 hours under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 132 mg of the objective compound as pale yellow powder.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][C:18]2[N:21]([CH2:31][CH:32]([OH:48])[CH2:33][N:34]3[CH2:39][CH2:38][N:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[C:46]#[N:47])[CH2:36][CH2:35]3)[N:22]=[C:23]([C:24]3[CH:29]=[CH:28][C:27]([I:30])=[CH:26][CH:25]=3)[C:17]=2[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[OH:48][CH:32]([CH2:31][N:21]1[C:18]2[CH2:19][CH2:20][NH:15][CH2:16][C:17]=2[C:23]([C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][CH:25]=2)=[N:22]1)[CH2:33][N:34]1[CH2:35][CH2:36][N:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[C:46]#[N:47])[CH2:38][CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccc(I)cc3)nn2CC(O)CN2CCN(c3ccccc3C#N)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1N1CCN(CC(O)Cn2nc(-c3ccc(I)cc3)c3c2CCNC3)CC1
Reaction time: 2 h
Yield: 100.1 %

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of 1-{3-[4-(2-cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3-(4-iodo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.402 g, 0.601 mmol) in CH2Cl2 (3 mL) and the reaction mixture was stirred for 2 h. The mixture was concentrated, then diluted with EtOAc. The organic layer was washed with aqueous NaHCO3 and brine, dried (Na2SO4), and concentrated to afford the amine (0.342 g, 100%) as a yellowish foam. TLC (silica, 10% acetone/CH2Cl2): Rf=0.14. MS (electrospray): m/z 569.2 (569.1, calculated for C26H29IN6O, [M+H]+). 1H NMR (400 MHz, CDCl3:CD3OD(6:1)): 7.73 (d, J=8.6 Hz, 2H), 7.56 (dd, J=7.6, 1.8 Hz, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.25 (d, J=8.6 Hz, 2H), 7.09 (t, J=7.6 Hz, 1H), 7.02 (dd, J=8.4 Hz, 1H), 4.43-4.36 (m, 1H), 4.31 (s, 2H), 4.21 (dd, J=14.1, 4.5 Hz, 1H), 4.11 (dd, J=14.5, 6.3 Hz, 1H), 3.54-3.49 (m, 2H), 3.40-3.24 (m, 8H), 3.18-3.06 (m, 3H), 3.03-2.95 (m, 3H).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([C:31]#[N:32])=[N:14][C:15]=2[NH:19][CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.N.[H][H]>C(O)C.[Pd]>[NH3:10].[NH2:32][CH2:31][C:13]1[N:12]=[C:11]2[C:16]([N:17]=[CH:18][N:10]2[C@H:3]2[C@H:2]([OH:1])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4]2)=[C:15]([NH:19][CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)[N:14]=1
Reactant: [H][H]
Reactant: N#Cc1nc(NCc2cccc3ccccc23)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Agent: [Pd]
Agent: N
Solvent: CCO
Product: NCc1nc(NCc2cccc3ccccc23)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 42 h
Yield: 47.4 %

Procedure:
A solution of 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(1-naphthylmethyl)amino]-9H-purine-2-carbonitrile (0.75 g, 1.74 mmol) (Preparation 14) in ethanol (30 ml) was saturated with ammonia gas, treated with 5% w/w palladium on charcoal (0.50 g), pressurised to 1034 kPa (150 psi) with hydrogen in a sealed vessel and stirred at room temperature for 42 hours. TLC analysis indicated that some starting material still remained and therefore further 5% w/w palladium on charcoal (0.30 g) and ethanol (10 ml) saturated with ammonia gas were added. The mixture was re-pressurised to 1034 kPa (150 psi) with hydrogen in a sealed vessel and stirred at room temperature for 24 hours. The mixture was filtered through a pad of Arbocel (trade mark) and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:0.88 ammonia (90:10:0.5 by volume) gradually changing to dichloromethane:methanol:0.88 ammonia (85:15:0.75 by volume) to afford the title compound (0.18 g).