Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[CH2:12](O)[CH2:13][OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:14][CH2:13][CH2:12][O:6]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)cc1Br
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(C2OCCO2)cc1Br
Yield: 92.6 %

Procedure:
A solution of 53.0 g of 3-bromo-4-methoxy benzaldehyde, 18.4 g of ethylene glycol, and 4.24 g of p-toluene sulfonic acid/1 hydrate in benzene was refluxed for 5 hours while taking water out of the system. After the mixture was cooled, the reaction solution was poured into a saturated aqueous solution of NaHCO3, liquid separation was performed, and the aqueous layer was extracted with benzene. The combined organic layer was washed with saturated brine and dried over MgSO4, then, the drying agent was separated by filtration and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (Chromatorex NH; mobile phase: EtOAc/n-hexane=1/9; v/v) to obtain 59.1 g of the title compound (colorless oil) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[N:12]=[C:13](Br)[C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[CH:16]=1.C(OCC)(=O)C>CN(C=O)C>[Br:10][C:11]1[N:12]=[C:13]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[CH:16]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Brc1cn2ccnc2c(Br)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Nc2nc(Br)cn3ccnc23)cc1
Temperature: 140 °C

Procedure:
A mixture of 4-aminobenzonitrile (220 mg; 1.89 mmol) and 6,8-dibromo-imidazo[1,2-a]pyrazine (500 mg; 1.81 mmol) is slurried in DMF (1 mL) and heated to 140° C. for 20 minutes. The reaction is allowed to cool, and when the bath reaches 75° C., ethyl acetate (40 mL) is added and the slurry is stirred to break up large solid lumps into fine powder. The powdered 4-(6-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzonitrile is filtered, washed with diethyl ether (2×50 mL) and dried under vacuum to a fine orange/tan solid (600 mg).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])[CH3:10].[C:17]([CH2:19][C@@H:20]([OH:27])[CH2:21][C:22](OCC)=[O:23])#[N:18].Cl>O1CCCC1>[C:17]([CH2:19][C@@H:20]([OH:27])[CH2:21][C:22](=[O:23])[CH2:10][C:9]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])#[N:18]
Reactant: CCOC(=O)C[C@H](O)CC#N
Reactant: CC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)C[C@H](O)CC#N
Reaction time: 0.83 h

Procedure:
To a stirred -50° C. solution of lithium diisopropylamide (100 kg of 2 M) in tetrahydrofuranheptane was added tertiary-butyl acetate (30 kg, 255 mol) followed by a rinse of 3 kg of tetrahydrofuran, and the mixture was stirred to -45° C. to -5° C. for 50 minutes. (R)-4-cyano-3-hydroxybutyric acid, ethyl ester (Step A) (10 kg, 64 mol) as a solution in 30 kg of tetrahydrofuran was then added to the previous mixture. The reaction mixture was stirred for 30 minutes at -5° C. to -30° C., and transferred to 240 L of 0° C. 2.8N aqueous hydrochloric acid solution. The aqueous layer was extracted with 50 kg of ethyl acetate, the aqueous layer was separated and reextracted with 36 kg of ethyl acetate, the extracts are combined, and concentrated in vacuo to afford crude (5R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxo-hexanoate which was not isolated. A small sample was purified by column chromatography on flash silica gel eluting with 1:1 hexane:ethyl acetate.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([CH:22]=[O:23])=[CH:20][CH:21]=3)[O:13][N:12]=2)=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(-c2noc(-c3ccc(CO)cc3)n2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)Cc1ccc(-c2noc(-c3ccc(C=O)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.8 %

Procedure:
A solution of {4-[3-(4-isobutylphenyl)-1,2,4-oxadiazol-5-yl]phenyl}methanol (1.30 g, 4.21 mmol) and dichloromethane (20 mL) was added to a solution of Dess-Martin periodinane (2.25 g, 5.30 mmol) and dichloromethane (20 mL) and stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethene, washed with 1 N NaOH (2×) and brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (0.333 g, 26% yield) as a white solid.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH:14][CH2:15][C@@H:16]1[NH:21][C:20](=[O:22])[CH2:19][CH2:18][CH2:17]1.C1C=CC=CC=1>CN(C=O)C.CCOC(C)=O>[Si:6]([O:14][CH2:15][C@@H:16]1[NH:21][C:20](=[O:22])[CH2:19][CH2:18][CH2:17]1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCC[C@H](CO)N1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCCC(=O)N1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.7 %

Procedure:
Imidazole (773 mg, 11.4 mmol) and tert-butyldimethylsilyl chloride (787 mg, 5.22 mmol) were added sequentially to a solution of (R)-6-hydroxymethyl-piperidin-2-one (prepared from D-□-aminoadipic acid according to Huang, et al., Synth. Commun. 1989, 19, 3485-3496, 613 mg, 4.75 mmol) in DMF (8 mL) at 0° C. The reaction mixture was allowed to warm to rt and was stirred at rt for 20 h. Benzene and EtOAc (3:7, 200 mL) was added and the solution was washed with brine (3×50 mL). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→3% MeOH/CH2Cl2, gradient) afforded 1.13 g (98%) of (R)-6-(tert-butyldimethylsilanyloxymethyl)-piperidin-2-one as a white solid.
Reaction SMILES: C(OC(=O)[N:7]([CH:17]1[CH2:19][CH:18]1[C:20]1[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][N:21]=1)[C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[I:15])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:26][C:25]1[C:20]([CH:18]2[CH2:19][CH:17]2[NH:7][C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[I:15])=[N:21][CH:22]=[C:23]([Cl:27])[CH:24]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)c1ccccc1I)C1CC1c1ncc(Cl)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CC1c1ncc(Cl)cc1Cl)c1ccccc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
0.800 g of tert-butyl[2-(3,5-dichloropyridin-2-yl)cyclopropyl](2-iodobenzoyl)carbamate (0.00075 mol) are dissolved in 7 ml of dichloromethane. 0.70 ml of trifluoroacetic acid are added to the reaction mixture which is left stirring at room temperature overnight. The reaction mixture is quenched with 15 ml of an aqueous solution of saturated sodium bicarbonate. After separation, the aqueous phase is extracted with dichloromethane (10 ml). The combined organic phases are dried over magnesium sulfate, filtered, concentrated to dryness and purified on silica to yield to 245 mg of N-[2-(3,5-dichloropyridin-2-yl)cyclopropyl]-2-iodobenzamide (65%).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]>>[C:7]([C:11]1[CH:16]=[CH:15][C:14]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CCCC(=O)Cl
Reactant: CC(C)(C)c1ccccc1
Product: CCCC(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The procedure of Example 3 was followed for the reaction of 53g (0.5 mole) of butyryl chloride with 67g (0.5 mole) of tert-butyl benzene. Obtained after high vacuum concentration was 94g of a clear liquid. A VPC analysis indicated a pure product. Ir (film) 3.5 (s), 5.9 (s) microns; nmr (CDCl3) 7.65 (4H, center doublet of doublets), 2.9 (2H, t), 1.75 (2H, sextet), 1.3 (9H, s), 0.95 (3H, t) ppm.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:23]=[CH:22][C:10]2[S:11](=[O:21])[C:12]([C:18]([NH2:20])=[O:19])=[C:13](OC(C)C)[C:9]=2[CH:8]=1>C(#N)C>[CH3:5][O:6][C:7]1[CH:23]=[CH:22][C:10]2[S:11](=[O:21])[C:12]([C:18]([NH2:20])=[O:19])=[C:13]([NH:4][CH:1]([CH3:3])[CH3:2])[C:9]=2[CH:8]=1
Reactant: COc1ccc2c(c1)C(OC(C)C)=C(C(N)=O)S2=O
Reactant: CC(C)N
Solvent: CC#N
Product: COc1ccc2c(c1)C(NC(C)C)=C(C(N)=O)S2=O
Reaction time: 16 h
Yield: 64 %

Procedure:
Isopropyl amine (379 μL, 4.45 mmol) is added to a room temperature solution of 5-methoxy-(3-(1-methylethoxy))benzo[b]thiophene-2-carboxamide-1-oxide (250 mg, 0.89 mmol) in 25 mL of acetonitrile. Stirring is continued for 16 hours. The reaction mixture is concentrated and recrystallized from acetonitrile to provide 5-methoxy-3-[(1-methylethyl)amino]benzo[b]thiophene-2-carboxamide-1-oxide in 64% yield; mp=193.5°-194.5° C.
Reaction SMILES: [OH-].[Na+].C(O)C.C([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:19]=[C:18]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:17]=2)=[CH:12][CH:11]=1)(=O)C>O>[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[C:18]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:19]=[C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:21]=2)=[CH:12][CH:11]=1
Reactant: CC(=O)Nc1ccc(-c2cc(-c3ccccc3)nc(-c3ccccc3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2cc(-c3ccccc3)nc(-c3ccccc3)c2)cc1
Yield: 88.2 %

Procedure:
1.50 g of sodium hydroxide, 100 ml of ethanol and 10 ml of water were added to 1.50 g of 4-(4-acetamidophenyl)-2,6-diphenylpyridine obtained on the basis of Reference Example 2 as a reference, and the mixture was refluxed for 46 hours. After cooling, 100 ml of water was added thereto, and the resulting product was recovered therefrom by filtration. By recrystallization from ethanol, 1.17 g of the captioned compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]2)[CH2:7][CH2:6]1.FC(F)(F)C(O)=O.[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([C:42](O)=[O:43])=[CH:34][CH:33]=1>>[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C@H:13]2[CH2:14][CH2:15][C@H:16]([NH:19][C:42]([C:35]3[C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:32]=[CH:33][CH:34]=3)=[O:43])[CH2:17][CH2:18]2)[CH2:7][CH2:6]1
Reactant: NC1CCC(CCN2CCC(Oc3ccc(F)cc3F)CC2)CC1
Reactant: O=C(O)c1ccnc2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(Oc3ccc(F)cc3F)CC2)CC1)c1ccnc2ccccc12

Procedure:
According to the procedure described in Example 22.5, the title compound was synthesized from Trans(4-{2-[4-(2,4-Difluoro-phenoxy)-piperidin-1-yl]-ethyl}-cyclohexylamine; trifluoro-acetic acid salt and quinoline-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[C:9]([N:10]=1)=[C:8]([NH:11][C@H:12](C)[CH2:13][OH:14])[N:7]=[C:6]([S:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[F:25])[N:5]=2.C(CN)O>>[NH2:1][C:2]1[NH:3][C:4]2[C:9]([N:10]=1)=[C:8]([NH:11][CH2:12][CH2:13][OH:14])[N:7]=[C:6]([S:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[F:25])[N:5]=2
Reactant: C[C@H](CO)Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(N)nc12
Solvent: NCCO
Product: Nc1nc2c(NCCO)nc(SCc3cccc(F)c3F)nc2[nH]1

Procedure:
The titled compound was prepared from the product of example 9, step (b) (3 g) and ethanolamine (9 ml) using the method of example 9, step (c).
Reaction SMILES: C[O-].[Na+].CO.[C:6]([O:12][CH3:13])(=[O:11])[C:7]([O:9]C)=O.[CH3:14][C:15]([CH3:17])=[O:16]>O>[O:9]=[C:7]([CH2:14][C:15](=[O:16])[CH3:17])[C:6]([O:12][CH3:13])=[O:11]
Reactant: CC(C)=O
Reactant: COC(=O)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(=O)CC(C)=O
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a 500 mL flask, 25% sodium methoxide of methanol solution (43.20 g, 0.200 mol), methanol (200 mL) were added, the mixture of dimethyl oxalate (23.60 g, 0.200 mol) and acetone (11.60 g, 0.200 mol) were added dropwise at ice-salt bath. The reaction mixture was stirred for 8 hours at 0˜5° C. The reaction mixture was poured into 200 mL water and extracted with ethyl acetate (150 mL) to remove organic impurity. The aqueous solution was acidified with concentrated hydrochloric acid to pH of 2˜3 and extracted with ethyl acetate (3×200 mL). The organic layer was washed with water (150 mL), and saturated brine (150 mL), dried over anhydrous magnesium sulfate and concentrated to give the product (25.9 g) as yellow oil in 90% yield. 1H NMR (300 MHz, CDCl3): 6.396 (s, 1H, enol isomer), 3.906 (s, 3H), 2.279 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:35][CH2:36][CH2:37][O:38][C:39]4[N:44]=[CH:43][C:42]([Cl:45])=[CH:41][N:40]=4)=[N:12][N:13]([CH3:34])[C:14]=3[N:15](S(C3C=CC=CC=3)(=O)=O)[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1.[Na]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:35][CH2:36][CH2:37][O:38][C:39]4[N:44]=[CH:43][C:42]([Cl:45])=[CH:41][N:40]=4)=[N:12][N:13]([CH3:34])[C:14]=3[NH:15][S:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cn1nc(OCCOc2ncc(Cl)cn2)c(-c2ccc3c(c2)OCO3)c1N(S(=O)(=O)c1ccccc1)S(=O)(=O)c1ccccc1
Agent: [Na]
Solvent: CO
Product: Cn1nc(OCCOc2ncc(Cl)cn2)c(-c2ccc3c(c2)OCO3)c1NS(=O)(=O)c1ccccc1
Yield: 54.8 %

Procedure:
To a solution of N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-yl)-N-(phenylsulfonyl)benzene sulfonamide (Example 47) (60 mg) in methanol (4 ml), at room temperature, was added an aqueous solution of sodium hydroxyde (1M, 510□l). After three hours the reaction was quenched by the addition of an aqueous saturated solution of ammonium chloride (5 ml) and extracted with ethyl acetate (3×5 ml). The combined organic fractions were washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The yellow residue was purified by preparative TLC (silica) eluted with dichloromethane:methanol (95:5) yielding the title compound as a colourless oil (26 mg).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[CH2:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:15]([NH:23][C:24]1[CH:36]=[C:35](Br)[CH:34]=[CH:33][C:25]=1[C:26]([O:28]C(C)(C)C)=[O:27])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:15]([NH:23][C:24]1[CH:36]=[C:35](/[CH:2]=[CH:1]/[CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH:34]=[CH:33][C:25]=1[C:26]([OH:28])=[O:27])(=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Reactant: C=CC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(Nc1cc(/C=C/C2CCCCC2)ccc1C(=O)O)c1ccccc1
Temperature: 110 °C
Reaction time: 48 h

Procedure:
0.037 mL of vinylcyclohexane, 87 mg of cesium carbonate, 13 mg of tetrabutylammonium bromide and 21 mg of polymer supported di(acetato)dicyclohexylphosphino palladium(11) were added to 1.0 mL of toluene solution containing 50 mg of tert-butyl 2-(benzamido)-4-bromobenzoate at room temperature and stirred at 110° C. for 48 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added. The organic layer was separated, and the solvent was evaporated under reduced pressure after washed with 10% citric acid aqueous solution. 5 mL of trifluoroacetic acid; was added to the obtained residue and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the obtained residue was purified with reversed-phase silica gel column chromatography [eluent; 55-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to obtain 2.9 mg of 2-(benzamido)-4-((E)-2-cyclohexylvinyl)benzoic acid as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]([O:13]CC)=O.[C-:16]#[N:17].[Na+].CN>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]([NH:17][CH3:16])=[O:13]
Reactant: CCOC(=O)CCc1c(Cl)cccc1Br
Reactant: [C-]#N
Agent: CN
Agent: [Na+]
Product: CNC(=O)CCc1c(Cl)cccc1Br

Procedure:
Ethyl 3-(2-bromo-6-chlorophenyl)propanoate (Example 1f), 5.0 g, 17.1 mmol) and sodium cyanide (0.168 g, 3.43 mmol) were stirred in methanamine (8 M in ethanol, 30 mL, 240 mmol) at rt overnight. The solvent was evaporated, the residue was taken up in ethyl acetate and the mixture was washed with saturated aqueous sodium carbonate and brine. The organic phase was separated and the solvent was removed by rotary evaporation. The crude product was added to a silica gel column and was eluted with 0-100% ethyl acetate in heptane. The collected fractions were combined and the solvent was removed by rotary evaporation to give the title product. Yield 2.98 g, 63%. 1H NMR (500 MHz, CDCl3) δ ppm 2.40-2.47 (m, 2H) 2.85 (d, 3H) 3.28-3.35 (m, 2H) 5.44 (br. s., 1H) 7.02 (t, 1H) 7.33 (dd, Hz, 1H) 7.47 (dd, Hz, 1H). MS m/z 277.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:32]=[CH:31][N:30]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[N:29]=4)=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7][C:6]1=[O:13].Br[C:41]1(CCOCC)C(=O)NC(=O)NC1=O>>[CH2:1]([O:2][CH2:3][CH2:4][C:5]1([O:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:32]=[CH:31][N:30]([C:33]5[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=5)[N:29]=4)=[CH:24][CH:23]=3)=[CH:19][CH:20]=2)[C:6](=[O:13])[NH:7][C:8](=[O:12])[NH:9][C:10]1=[O:11])[CH3:41]
Reactant: COCCC1(Oc2ccc(Oc3ccc(-c4ccn(-c5ccc(F)cc5)n4)cc3)cc2)C(=O)NC(=O)NC1=O
Reactant: CCOCCC1(Br)C(=O)NC(=O)NC1=O
Product: CCOCCC1(Oc2ccc(Oc3ccc(-c4ccn(-c5ccc(F)cc5)n4)cc3)cc2)C(=O)NC(=O)NC1=O

Procedure:
By the same procedure as Example 1, Part C, 4-{4-[1-(4-Fluoro-phenyl)-1H-pyrazol-3-yl]-phenoxy}-phenol (from Example 67, Part D) and 5-bromo-5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-trione (from Preparation 3A) were converted to the title compound. MS m/z: ESI+545.3 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43](OC)=[O:44])[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH:27]=1.CCN(C(C)C)C(C)C.[CH3:63][O:64][CH2:65][CH2:66][NH2:67]>CN(C=O)C>[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43]([NH:67][CH2:66][CH2:65][O:64][CH3:63])=[O:44])[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[CH:27]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Reactant: COCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
HATU (0.052 g, 0.138 mmol) was added into a mixture of methyl 4-(4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.050 g, 0.125 mmol) and Hünig's base (22 μL, 0.125 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. 2-Methoxyethylamine (54.3 μL, 0.625 mmol) was added and the coolant removed. The reaction mixture was stirred at ambient temperature overnight. The product was purified by reverse phase preparative HPLC to yield white solid (0.029 g, 50%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:22][CH2:21][CH2:20][C:8]32[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]3)[CH:2]=1.[ClH:23]>ClCCl.Cl>[ClH:23].[ClH:23].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:8]3([CH2:9][CH2:10][NH:11][CH2:12]3)[CH2:20][CH2:21][CH2:22]2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCN2c2cccnc2)C1
Agent: Cl
Solvent: ClCCl
Product: c1cncc(N2CCCC23CCNC3)c1
Yield: 72 %

Procedure:
A solution of tert-butyl 6-(3-pyridyl)-2,6-diazaspiro[4.4]nonane-2-carboxylate (100 mg, 0.330 mmol) in dichloromethane (5 mL) was rapidly stirred with 1 mL of 12 M hydrochloric acid at ambient temperature for 1 h, during which time the biphasic mixture became monophasic. The dichloromethane was evaporated, and the residue was dissolved in water (3 mL) and made strongly basic (pH 9) with potassium carbonate. The mixture was saturated with sodium chloride and extracted with chloroform (4×10 mL). The extracts were dried (K2CO3) and concentrated, first by rotary evaporation and then by high vacuum treatment. The viscous brown oil which resulted was 98% pure by GCMS and weighed 50 mg (73%). A sample of this free base (40 mg, 020 mmol)was dissolved in 10 drops of 12 M hydrochloric acid. The water was azeotropically removed by repeated treatment with small volumes of ethanol (˜5 mL) and rotary evaporation. The resulting solid was recrystallized from hot isopropanol to give 40 mg (72%) of fine tan crystals (mp 170-175° C.).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@:10]12[CH2:15][C@@H:14]1[CH2:13][O:12][C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@:10]12[CH2:15][C@@H:14]1[CH2:13][O:12][CH2:11]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC[C@H]2C[C@@]12COCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClC(Cl)Cl
Product: c1ccc(COC[C@]23COC[C@H]2C3)cc1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
The conditions in Sakai, N., et al. Synthesis, 2008 3533-3536 was used for this step. To a stirred mixture of (1R,5S)-1-((benzyloxy)methyl)-3-oxa-bicyclo[3.1.0]hexan-2-one (3b, 50 mmol) and InBr3 (1.0 mmol) in chloroform (200 mL) was added triethylsilane (200 mmol). The mixture was then heated and stirred at 65° C. for 16 h, then cooled to room temperature. The reaction was concentrated. The residue was purified by column (0-10 ethyl acetate in hexane) to give a colorless liquid as pure (1S,5S)-1-((benzyloxy)methyl)-3-oxa-bicyclo[3.1.0]hexane (3c). MS (ESI) m/z=205 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:24])[CH2:11][CH2:12][C:13](C2C=CC([N+]([O-])=O)=CC=2)=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+].O>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([OH:24])[CH2:11][CH2:12][CH2:13][OH:14])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(CCC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(C(O)CCCO)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 127.3 %

Procedure:
To a solution of the product from Example 1A (1.0 g, 3.05 mmol) in anhydrous THF (30 ml) at 0° C. was added sodium borohydride (0.357 g, 9.44 mmol). The resulting mixture was stirred at 50° C. overnight. The cooled mixture was poured into water, extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated in vacuo. The resulting solid was triturated with dichloromethane to give a tan solid that was collected by filtration and dried to give the title compound (0.82 gm, 81% yield).