Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[CH2:4][CH2:5]CN=C=NCC.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]([C:38]3[C:46]4[C:41](=[CH:42][C:43]([C:47]([OH:49])=[O:48])=[CH:44][CH:45]=4)[N:40]([CH3:50])[CH:39]=3)[C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=3[O:36][CH3:37])(=[O:28])=[O:27])=[O:24])=[CH:21][C:16]=2[O:15][CH2:14]1.CN(CCO)C>C(Cl)Cl.CN(C=O)C>[CH3:2][N:3]([CH3:12])[CH2:4][CH2:5][O:48][C:47]([C:43]1[CH:42]=[C:41]2[C:46]([C:38]([CH:22]([C:20]3[CH:19]=[CH:18][C:17]4[O:13][CH2:14][O:15][C:16]=4[CH:21]=3)[C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=3[O:36][CH3:37])(=[O:27])=[O:28])=[O:24])=[CH:39][N:40]2[CH3:50])=[CH:45][CH:44]=1)=[O:49]
Reactant: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(C(=O)O)ccc12
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)CCO
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(C(=O)OCCN(C)C)ccc12

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (128 mg, 0.67 mmol) was added to a stirred solution of 3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-6-indolecarboxylic acid (the product of Example 17, 300 mg, 0.56 mmol), N,N-dimethylaminopyridine (75 mg, 0.61 mmol) and dimethylaminoethanol (0.17 ml, 1.67 mmol) in a mixture of CH2Cl2 (9 ml) and DMF (0.5 ml) at room temperature under a nitrogen atmosphere. After 12 h a fine white precipitate had formed. The product was removed by filtration and washed with cold methanol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH2:15][N+:16]([O-])=O)[CH2:11][N+:12]([O-])=O)[CH:5]=1)([O-])=O.[H][H]>CO.[Pt](=O)=O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]([CH2:15][NH2:16])[CH2:11][NH2:12])[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])CC(C[N+](=O)[O-])c1cccc([N+](=O)[O-])c1
Agent: O=[Pt]=O
Solvent: CO
Product: NCC(CN)c1cccc(N)c1

Procedure:
A mixture of 1-nitro-3-[2-nitro-1-(nitromethyl)ethyl]benzene (115 mg, 0.45 mmol) and 58 mg platinum (IV) oxide in 6 mL MeOH contained in a pressure tube was reacted under 65 PSI hydrogen. After 16 hours the mixture was filtered and rinsed with MeOH. The MeOH solution of product was stored under N2 in the freezer and used as is for the next reaction [upon evaporation of MeOH solvent 69.9 mg (94%) of the title compound was obtained as a light yellow oil]. 1H NMR (CD3OD) δ: 7.06-7.13 (m, 1H), 6.55-6.65 (m, 3H), 2.83-2.91 (m, 2H), 2.72-2.81 (m, 2H), 2.57-2.68 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1C=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=C[NH:38]C(=O)C=1)C1C=CC=CC=1.BrCC(C1C=CC(CO)=CC=1)=O>>[CH2:1]([O:8][C:9]1[N:38]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Reactant: O=c1cc(OCc2ccccc2)nc[nH]1
Agent: O=C(CBr)c1ccc(CO)cc1
Product: O=C(Cn1cnc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1

Procedure:
6-Benzyloxy-3-[2-(4-hydroxymethyl-phenyl)-2-oxo-ethyl]-3H-pyrimidin-4-one is prepared following preparation 15b from 1.50 g (7.42 mmol) 6-benzyloxy-3H-pyrimidin-4-one and 1.87 g (8.16 mmol) 2-bromo-1-(4-hydroxymethyl-phenyl)-ethanone (preparation 15a).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:10]=[C:9]([NH2:11])[CH:8]=[CH:7][N:6]=1.CC1(C)C(C)(C)OB([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:31]=[N:32][C:33]([NH2:36])=[N:34][CH:35]=3)=[N:28][CH:29]=2)O1>>[NH2:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([O:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[N:34][C:33]([NH2:36])=[N:32][CH:31]=3)=[N:28][CH:29]=2)[N:10]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)nc2)OC1(C)C
Reactant: Nc1ccnc(Oc2ccccc2Br)n1
Product: Nc1ccnc(Oc2ccccc2-c2ccc(-c3cnc(N)nc3)nc2)n1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-(2-bromophenoxy)pyrimidin-4-amine and 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine. MS (ESI): mass calcd. for C19H15N7O, 357.13; m/z found, 358.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.86 (s, 2H), 8.64 (dd, J=2.3, 0.8, 1H), 7.95 (dd, J=8.3, 2.3, 1H), 7.78-7.72 (m, 2H), 7.53-7.45 (m, 2H), 7.38 (m, 1H), 7.23 (dd, J=8.1, 1.2, 1H), 6.11 (d, J=5.9, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Br[CH2:13][C:14]([C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1)=[O:15]>>[CH3:1][O:2][C:3]1[C:4]2[CH:13]=[C:14]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[O:15][C:5]=2[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(O)cc(OC)c1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Product: COc1cc(OC)c2cc(-c3ccc(C#N)cc3)oc2c1
Yield: 24 %

Procedure:
This compound was prepared using Method A from 3,5-dimethoxyphenol and 4-(2-bromoacetyl)benzonitrile: Yield 24% following procedure A.2; m.p. 220-221° C.; IR 3042, 2955, 2223, 1600, 1507, 1217, 1145, 1104 cm−1; 1H-NMR (500 MHz, δ ppm, CDCl3) 7.84 (d, J=8.2 Hz, 2H), 7.67 (d, J=8.3 Hz, 2H), 7.18 (s, 1H), 6.68 (s, 1H), 6.34 (s, 1H), 3.92 (s, 3H), 3.87 (s, 3H); 13C-NMR (126 MHz, δ ppm, CDCl3) 160.5, 157.4, 154.2, 151.6, 134.9, 132.8, 124.5, 119.1, 113.4, 110.8, 102.4, 94.9, 88.4, 56.1, 55.9.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH:14]([S:15][CH2:16][C:17]([OH:26])(C)[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:13]([OH:27])[CH2:12][C:11]1=[O:28])([OH:3])=[O:2].[BH4-].[Na+].Cl>CO.O>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH:14]([S:15][CH2:16][CH:17]([OH:26])[C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[CH:13]([OH:27])[CH2:12][C:11]1=[O:28])([OH:3])=[O:2]
Reactant: Cc1ccc(C(C)(O)CSC2C(O)CC(=O)C2CCCCCCC(=O)O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(O)CSC2C(O)CC(=O)C2CCCCCCC(=O)O)cc1
Temperature: 0 °C

Procedure:
2 g of 2-(6-carboxyhexyl)-3-(2-hydroxy-2-methyl-2-p-tolylethylthio)-4-hydroxy-cyclopentanone is dissolved in 50 ml methanol, two drops of water are added and with cooling by ice and agitating 1.5 g NaBH4 is added during 2 hours. After addition of 50 ml ice-water the mixture is acidified with aqueous HCl and extracted three times with respectively 50 ml portions of dimethylether. The combined organic phases are washed three times with a saturated aqueous NaCl-solution, dried over Na2SO4, filtered and evaporated. After chromatographic purification of the residue (silica gel/chloroform : methanol = 9 : 1) 2-(6-carboxyhexyl-3-(2-hydroxy-2-methyl-2-p-tolylethylthio)-1,4-cyclopentanediol is obtained as an oil,
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6](O)[C:7]2[S:12][CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:3])[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:18]>C(Cl)(Cl)Cl>[Cl:18][C:6]1[C:7]2[S:12][CH:11]=[CH:10][C:8]=2[N:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)c1nc(O)c2sccc2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)c1nc(Cl)c2sccc2n1
Yield: 99 %

Procedure:
A suspension of 2-isopropylthieno[3,2-d]pyrimidine-4-ol (1.66 g, 8.56 mmol) in POCl3 (30 mL) was refluxed for 1 h, cooled, diluted with chloroform (100 mL) and poured into a mixture of ice and NH4OH (150 mL). The organic phase was separated, washed with saturated NaHCO3 (20 mL), water and brine, dried (MgSO4) and concentrated in vacuo to give the title compound (2.01 g, 99%) as a pale yellow solid: IR νmax (Nujol)/cm−1 3065, 2960, 2926, 2855, 1561, 1513, 1457, 803; NMR δH (400 MHz, CDCl3) 1.40 (6H, d J 6.5 Hz), 3.38 (1H, heptet, J 6.5 Hz), 7.60 (1H, d J 5.0 Hz), 8.05 (1H, d, J 5.0 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)=[N:6][CH:7]=1.[BH4-].[Na+]>C1COCC1.CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[N:6][CH:7]=1
Reactant: Cc1ccc(NC(=O)c2ccccc2[N+](=O)[O-])nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2ccccc2N)nc1
Yield: 94.8 %

Procedure:
To a stirring solution of N-(5-methylpyridin-2-yl)-2-nitrobenzamide (1.5 g, 5.8 mmol) and Ni(OAc)2.4H2O (2.9 g, 11.7 mmol) in THF (20 mL) and methanol (40 mL) at 0° C. was added, in small portions, sodium borohydride (0.88 g, 23.2 mmol). After complete addition and an additional 5 min, the solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (200 mL) and 50% conc NH4OH (206 mL). The organic phase was separated and washed again with 50% conc NH4OH, followed by brine, then dried with MgSO4, filtered and concentrated in vacuo to give 1.25 g (95%) of a light yellow solid.
Reaction SMILES: [OH-].[Li+].[NH2:3][C:4]1[N:5]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([CH:28]3[CH2:30][CH2:29]3)=[CH:20][CH:19]=2)[C:6]([S:9][C:10]([CH3:17])([CH3:16])[C:11]([O:13]CC)=[O:12])=[N:7][N:8]=1.Cl>C1COCC1.CO>[NH2:3][C:4]1[N:5]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([CH:28]3[CH2:30][CH2:29]3)=[CH:20][CH:19]=2)[C:6]([S:9][C:10]([CH3:17])([CH3:16])[C:11]([OH:13])=[O:12])=[N:7][N:8]=1
Reactant: CCOC(=O)C(C)(C)Sc1nnc(N)n1-c1ccc(C2CC2)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(Sc1nnc(N)n1-c1ccc(C2CC2)c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.3 %

Procedure:
Lithium hydroxide solution (1M aqueous, 0.757 mL, 0.757 mmol) was added to a solution of ethyl 2-(5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate (100 mg, 0.252 mmol) in THF (2 mL) and methanol (1 mL) and the mixture stirred at room temperature for 20 h. The crude reaction mixture was acidified with HCl (1N, 1 mL) and sonicated to break up the solids, which were then isolated by filtration to give 2-(5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoic acid as a white solid (69 mg, 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:13][C:14]1[S:15][CH:16]=[N:17][N:18]=1.[BH4-].[Na+].C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1.CC1CCCO1.O.CO>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:13][C:14]1[S:15][CH:16]=[N:17][N:18]=1
Reactant: Nc1nncs1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CC1CCCO1
Solvent: CO
Product: COc1ccc(CNc2nncs2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
2,4-Dimethoxybenzaldehyde (771.37 g, 4.64 moles) was added to a suspension of 2-amino-1,3,4-thiadiazole (391.2 g, 3.87 moles) in xylene (5.87 L) and heated to reflux. Dean-Stark apparatus was used to remove the water and the reaction was stirred overnight. After cooling to room temperature, the reaction was further cooled to 5° C. and diluted with 2-methyltetrahydrofuran (2.93 L). Sodium tetrahydroborate (73.17 g, 1.93 moles) was added as a single portion. Methanol (782.8 mL) was then added slowly over 30 minutes, maintaining the temperature below 15° C. After a further 30 minutes water (1 L) was added followed by saturated aqueous sodium hydrogencarbonate solution (1 L) and the mixture stirred at room temperature overnight. The biphasic mixture was diluted with 2-methyltetrahydrofuran and heated to 43° C. to aid dissolution. The layers were separated and the organic layer washed with water (3 L) before concentrating in vacuo. The resulting solid was slurried in heptanes (2.5 L), homogenised, filtered, washed with tert-butylmethyl ether and dried to afford 715 g of the title compound.
Reaction SMILES: [N:1]1([C:7]2[S:8][C:9]3[C:10](=O)[NH:11][CH2:12][CH2:13][C:14]=3[N:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1.C(Cl)Cl.O>C1COCC1>[N:1]1([C:7]2[S:8][C:9]3[C:10](=[S:26])[NH:11][CH2:12][CH2:13][C:14]=3[N:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1NCCc2nc(N3CCOCC3)sc21
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: S=C1NCCc2nc(N3CCOCC3)sc21
Yield: 59.4 %

Procedure:
To a stirred solution of Example 3 (0.139 g, 0.58 mmol) in THF (10 mL) was added Lawesson's reagent (2.36 g, 5.8 mmol). The suspension was stirred for 1 week. DCM (10 mL) and water (10 mL) were added. The aqueous fraction was extracted with DCM (3×15 mL). The combined organic fractions were washed with water (3×20 mL), dried (MgSO4), filtered and the solvent evaporated in vacuo. The oily residue was purified by column chromatography (SiO2, 1:1 EtOAc/hexanes). Fractions containing the title compound were concentrated and the residue washed with Et2O to give the title compound (0.088 g, 51%) as a yellow solid. δH (DMSO-d6) 9.38 (1H, s), 3.69 (4H, t, J 4.8 Hz), 3.51 (4H, t, J 4.8 Hz), 3.44-3.48 (2H, m), 2.74 (2H, t, J 7.6 Hz). LCMS (ES+), 256.0 (M+H)+, RT 2.60 minutes (Method 5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[N:25](S(C2C=CC(C)=CC=2)(=O)=O)[C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][OH:24])=[C:17]2[CH:16]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[NH:25][C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][OH:24])=[C:17]2[CH:16]=1
Reactant: COc1cc2c(-c3cc4c(CO)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4c(CO)ccnc4[nH]3)cn(C)c2cc1OC
Yield: 65.6 %

Procedure:
[2-(5,6-Dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-yl]methanol is prepared as described in Example 179a starting with 0.08 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-yl]methanol instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 0.55 cm3 of 5N potassium hydroxide. 0.036 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-yl]methanol is obtained, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:29][C:30]([CH:32]2[CH2:34][CH2:33]2)=[O:31])=[C:6]2[C:10]=1[CH2:9][N:8]([CH:11]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=1)[CH2:12][C:13](=[O:16])[NH:14][OH:15])[C:7]2=[O:28].[C:35](OC(=O)C)(=[O:37])[CH3:36]>CC#N>[C:35]([O:15][NH:14][C:13]([CH2:12][C@@H:11]([N:8]1[C:7](=[O:28])[C:6]2[C:10](=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[NH:29][C:30]([CH:32]2[CH2:33][CH2:34]2)=[O:31])[CH2:9]1)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=1)=[O:16])(=[O:37])[CH3:36]
Reactant: CCOc1cc(C(CC(=O)NO)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reactant: CC(=O)OC(C)=O
Solvent: CC#N
Product: CCOc1cc([C@@H](CC(=O)NOC(C)=O)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 8 h
Yield: 0.8 %

Procedure:
To the solution of cyclopropanecarboxylic acid {7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (0.45 g, 92 mmol) in CH3CN (50 ml) was added acetic anhydride (0.1 ml, 92 mmol) at room temperature. The mixture was stirred overnight. The solvent was removed in vacuo and the resulted solid was stirred with ether (10 ml) for 2 hrs. The suspension was filtered and the solid was dried in oven to give (1R)-cyclopropanecarboxylic acid {2-[2-acetoxycarbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (0.4 g, 80%): mp 139–141° C.; 1HNMR (CDCl3): δ 0.85–0.92 (m, 2H, c-CH2), 1.05–1.11 (m, 2H, c-CH2), 1.43 (t, J=7.5 Hz, 3H, OCH2CH3), 1.62–1.68 (m, 1H, c-CH), 2.12 (s, 3H, CH3), 3.02 (dd, J=5, 16 Hz, 1H, CHH), 3.50 (dd, J=5, 16 Hz, 1H, CHH), 3.85 (s, 3H, OCH3), 4.08 (q, J=7.5 Hz, 2H, OCH2CH3), 4.12 (d, J=17 Hz, 1H, CHH), 4.38 (d, J=17 Hz, 1H, CHH), 5.61–5.65 (m, 1H, CHN), 6.81–6.94 (m, 3H, Ar), 7.31 (d, J=10 Hz, 1H, Ar), 8.38 (d, J=10 Hz, 1H, Ar), 10.41 (s, 1H); 13C NMR (CDCl3): δ 9.0, 9.1, 15.3, 16.7, 18.7, 36.8, 48.2, 54.4, 56.5, 65.2, 112.2, 112.8, 119.7, 119.8, 120.2, 122.4, 131.1, 133.5, 137.2, 139.8, 149.3, 150.1, 167.0, 169.0, 170.0, 173.5; Anal. Calcd. for C26H28ClN3O7: C, 58.92; H, 5.33; N, 7.93. Found: C, 58.58; H, 5.00; N, 7.76.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:14]=[CH:13][C:12]2[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]=2[N:6]=1)[CH2:3][OH:4].CO[C:18](OC)([CH3:20])[CH3:19].[C@@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(C)=O>[CH3:19][C:18]1([CH3:20])[O:1][CH:2]([C:5]2[CH:14]=[CH:13][C:12]3[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]=3[N:6]=2)[CH2:3][O:4]1
Reactant: O=C1CCCc2nc(C(O)CO)ccc21
Reactant: COC(C)(C)OC
Agent: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)=O
Product: CC1(C)OCC(c2ccc3c(n2)CCCC3=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
A mixture of 2-(1,2-dihydroxyethyl)-7,8-dihydroquinolin-5(6H)-one (Preparation 54D, 0.226 g, 1.09 mmol), 2,2-dimethoxypropane (0.402 mL, 3.27 mmol), and (1R)-(−)-camphorsulfonic acid (0.051 g, 0.22 mmol) in acetone (6 mL) was stirred at room temperature overnight. The reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate and concentrated under reduced pressure. The aqueous residue was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate and brine. The organic layer was collected, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated and purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane (50%) to afford 2-(2,2-dimethyl-1,3-dioxolan-4-yl)-7,8-dihydroquinolin-5(6H)-one (0.182 g, 0.736 mmol, 68% yield) as a clear, colorless oil. The product had an HPLC ret. time=1.75 min. (condition A); LC/MS M+1=247.9.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)=[O:13])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30]>C(O)C>[CH3:30][C:29]([NH:33][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)=[O:13])=[CH:8][CH:7]=1)([CH3:32])[CH3:31]
Reactant: CC(C)(C)N
Reactant: O=C(c1ccc(OCCCCl)cc1)c1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)NCCCOc1ccc(C(=O)c2cccc3[nH]ccc23)cc1
Temperature: 140 °C

Procedure:
A mixture of 7.75 8 of the product of Step E, 6.83 g of potassium carbonate, 25.8 ml of tertbutylamine and 150 ml of ethanol was heated at 140° C. for 48 hours in an autoclave. After filtering, the filtrate was brought to dryness under reduced pressure and the 11.7 g of residue were chromatographed on silica (eluant: ethyl acetate-triethylamine (95-5)) to obtain 6.32 g of the desired product.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[N:11]#[C:12]Br.C(N(CC)CC)C>C(Cl)Cl>[O:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:1][CH:2]=[CH2:3])=[CH:5][CH:6]=1)[C:12]#[N:11]
Reactant: C=CCc1ccc(O)cc1
Reactant: N#CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCc1ccc(OC#N)cc1
Yield: 65.7 %

Procedure:
To a solution of 2.142 g (15.96 mmol) of 4-(2-propenyl)phenol (prepared as in Example 1) in 15 mL of methylene chloride was added 2.351 g (22.19 mmol) of cyanogen bromide (Aldrich). The mixture was cooled in an ice-salt bath and 3 mL (22 mmol) of triethylamine was added dropwise with stirring. The mixture was stirred for an additional 15 minutes. The solvent was removed under vacuum and the mixture was transferred to a separatory funnel with 25 mL of water and 75 mL of petroleum ether (30-60° C. boiling range). The aqueous and organic layers were separated. The organic layer was washed with three 50 mL portions 6 N hydrochloric and one 50 mL portion of saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under vacuum to yield 1.668 g (66%) of crude 1-cyanato-4-(2-propenyl)benzene. The product was distilled to yield 1.307 g (51%) of 1-cyanato-4-(2-propenyl)benzene. The structure of the product was verified by IR and NMR spectroscopy. The product can be further purified by passing the product through a silica gel column using 1% toluene in petroleum ether as the solvent system.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1.CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.[Cu](I)I>[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:16]2[C:17]3[C:12](=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:19][CH:18]=3)[CH2:13][CH2:14][C:15]2=[O:20])=[CH:24][CH:23]=1
Reactant: Fc1ccc(I)cc1
Reactant: O=C1CCc2cc(OCCCN3CCCC3)ccc2N1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C1CCc2cc(OCCCN3CCCC3)ccc2N1c1ccc(F)cc1
Temperature: 105 °C
Reaction time: 60 h
Yield: 37.2 %

Procedure:
A suspension of 6-[3-(pyrrolidin-1-yl)propoxy]-3,4-dihydroquinolin-2(1H)-one prepared in Example 10-(2) (0.20 g), 1-fluoro-4-iodobenzene (0.24 g), rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (0.10 g), copper iodide (0.035 g) and cesium carbonate (0.48 g) in toluene (1.0 mL) was stirred at 105° C. for 60 hours. The reaction mixture was cooled to room temperature, diluted with chloroform and filtered to remove insoluble materials. The filtrate was concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: hexane/ethyl acetate=1/1), and the resulting solid was subjected to recrystallization from a mixture of diisopropyl ether and ethyl acetate to give the titled compound (0.10 g, 37%) as a colorless solid.
Reaction SMILES: C([CH:3]([C:11]1[C:16]([O:17][CH2:18][CH2:19][CH3:20])=[CH:15][CH:14]=[CH:13][N:12]=1)[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)#N.C(=O)([O-])[O-:22].[K+].[K+].O>CS(C)=O.O>[F:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([C:11]2[C:16]([O:17][CH2:18][CH2:19][CH3:20])=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:22])=[CH:5][CH:6]=1
Reactant: CCCOc1cccnc1C(C#N)c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCOc1cccnc1C(=O)c1ccc(F)cc1
Yield: 85.8 %

Procedure:
Under oxygen atmosphere, a mixed solution of 2-(α-cyano-4-fluorobenzyl)-3-propoxypyridine (5.42 g) and potassium carbonate (3.07 g) in DMSO-water (200-40 ml) was stirred at room temperature for 20 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:3→1:2), to give 2-(4-fluorobenzoyl)-3-propoxypyridine (4.46 g) as pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[CH:13][C:12]([O:15][C:16]2[CH:25]=[C:24](F)[CH:23]=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])=[CH:11][C:10]=1[F:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.ClCCl>CS(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[CH:13][C:12]([O:15][C:16]2[CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:23]=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])=[CH:11][C:10]=1[F:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(F)cc1Oc1cnc(NC(=O)OC(C)(C)C)c(F)c1
Reactant: C1CNCCN1
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N2CCNCC2)cc1Oc1cnc(NC(=O)OC(C)(C)C)c(F)c1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Methyl 2-(6-(tert-butoxycarbonylamino)-5-fluoropyridin-3-yloxy)-4-fluorobenzoate (0.170 g) and piperazine (0.154 g) were dissolved in dimethylsulfoxide (2 mL) and heated to 85° C. After 1 hour, the reaction was cooled, poured into dichloromethane (75 mL), and washed with water (30 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated to give the title compound.