Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCOCC1.Cl.[NH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].[CH2:15]([O:22][C:23]([NH:25][C@:26]([CH:33]([CH2:35][CH3:36])[CH3:34])([CH2:30][CH:31]=[CH2:32])[C:27](O)=[O:28])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[CH2:15]([O:22][C:23]([NH:25][C@:26]([CH:33]([CH2:35][CH3:36])[CH3:34])([CH2:30][CH:31]=[CH2:32])[C:27]([NH:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:28])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)CN
Reactant: C=CC[C@@](NC(=O)OCc1ccccc1)(C(=O)O)C(C)CC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C=CC[C@@](NC(=O)OCc1ccccc1)(C(=O)NCC(=O)OC)C(C)CC
Reaction time: 16 h
Yield: 99.4 %

Procedure:
Step L (1): NMM (9.8 mL, 89.1 mmol) was added to a mixture of methyl 2-aminoacetate hydrochloride (3.95 g, 31.4 mmol), (2S)-2-(benzyloxycarbonyl-amino)-2-sec-butylpent-4-enoic acid (8.0 g, 26.2 mmol) [prepared as described in WO 2004/013098] HATU (12 g, 31.4 mmol in DCM (300 mL) at room temperature. The mixture was stirred for 16 h. Poured the reaction mixture into 150 mL H2O. Extracted with DCM (3×250 mL). Washed combined organic extracts with brine, dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give methyl 2-((2S)-2-(benzyloxycarbonylamino)-2-sec-butylpent-4-enamido)acetate 9.8 g (99% yield) as a yellow-oily residue: ESI (M+H)+=377.43. 1H NMR (300 MHz, CDCl3) δ ppm 0.93-1.08 (m, 6H) 1.49-1.56 (m, 3H) 2.74-2.89 (m, 2H) 3.68 (s, 3H) 4.10-3.96 (m, 2H) 5.00-5.22 (m, 4H) 5.85-5.94 (m, 1H) 7.33-7.40 (m, 5H).
Reaction SMILES: [CH2:1]([O:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][C:24](O)=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(Cl)(=O)C([Cl:32])=O>CN(C)C=O.C(Cl)Cl>[CH2:1]([O:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][C:24]([Cl:32])=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 100.6 %

Procedure:
A mixture of 13.2 g of [4-(hexadecyloxy)phenoxy]acetic acid, 6.4 g of oxalyl chloride, 225 ml of methylene chloride and 5 drops of N,N-dimethylformamide is stirred at ambient temperature for 17 hours. The solvent is evaporated to a residue which is dissolved in ether and filtered through diatomaceous earth. The filtrate is evaporated to give 13.9 g of the desired product as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])[C:4]=2[N:3]=1.[C:28]([O:32][C:33]([N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[CH2:44]Cl)=[O:34])([CH3:31])([CH3:30])[CH3:29].[I-].[K+].C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>CC#N>[C:28]([O:32][C:33]([N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[CH2:44][N:12]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])[CH:5]1[C:4]2[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1ccc2c(n1)C(NCCCCN1C(=O)c3ccccc3C1=O)CCC2
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(n1)C(N(CCCCN1C(=O)c3ccccc3C1=O)Cc1nc3ccccc3n1C(=O)OC(C)(C)C)CCC2
Temperature: 60 °C
Reaction time: 17 h
Yield: 66.4 %

Procedure:
To a solution of 2-[4-(2-methyl-5,6,7,8-tetrahydroquinolin-8-ylamino)-butyl]-isoindole-1,3-dione (210 mg, 0.578 mmol) in CH3CN (12 mL) was added 2-chloromethyl-benzoimidazole-1-carboxylic acid tert-butyl ester (200 mg, 0.751 mmol), potassium iodide (14 mg), and diisopropylethylamine (0.201 ml, 1.16 mmol). The reaction mixture was stirred at 60° C. for 17 hours. Saturated sodium bicarbonate (15 mL) was added and the mixture was extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. Purification of the crude material by column chromatography on silica gel (1:10 EtOAc:hexanes then EtOAc then 1:10 MeOH:EtOAc) provided the product as a clear oil (228 mg, 66%): 1H NMR (CDCl3): δ 1.23-1.31 (m, 2H), 1.46-1.58 (m, 2H), 1.63-1.73 (m, 1H), 1.68 (s, 9H), 1.73-1.85 (m, 1H), 1.89-1.98 (m, 1H), 2.10-2.18 (m, 1H), 2.40 (s, 3H), 2.60-2.83 (m, 5H), 3.50 (t, 2H, J=7.2 Hz), 4.20 (dd, 1H, J=9.6, 6.0 Hz), 4.50 (d, 1H, J=15.6 Hz), 4.72 (d, 1H, J=15.6 Hz), 6.79 (d, 1H, J=7.5 Hz), 7.14 (d, 1H, J=7.5 Hz), 7.19-7.24 (m, 2H), 7.63-7.69 (m, 3H), 7.74-7.81 (m, 3H).
Reaction SMILES: Cl[C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:7].O=C1C(C(O)=O)=CC(C2C=CN=CC=2)=NN1.C(Cl)(=O)C(Cl)=O.ClC1C=CC(CN)=CC=1>C(N(CC)CC)C.CN(C)C=O.ClCCl>[Cl:25][C:23]1[CH:24]=[CH:2][C:3]([CH2:4][NH:5][C:6]([C:8]2[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH:13]=2)=[O:7])=[CH:21][CH:22]=1
Reactant: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccncc2)n[nH]c1=O
Agent: NCc1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1cc(-c2ccncc2)n[nH]c1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cc(-c2ccncc2)n[nH]c1=O

Procedure:
Working as in example 2 for the preparation of N-(2,4-dichlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide, but starting with 0.3 g of 3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxylic acid, 10 cm3 of dichloromethane, 0.02 cm3 of dimethylformamide, 0.12 cm3 of oxalyl chloride, 0.19 cm3 of 4-chlorobenzylamine and 0.19 cm3 of triethylamine, 0.2 g of N-(4-chlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide was obtained in the form of a cream-colored solid melting at 250° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([OH:31])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:45]([O:47][C:48]([C:50]1(Br)[CH2:53][CH2:52][CH2:51]1)=[O:49])[CH3:46]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][C:50]3([C:48]([O:47][CH2:45][CH3:46])=[O:49])[CH2:53][CH2:52][CH2:51]3)[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Reactant: CCOC(=O)C1(Br)CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)n(-c3ccccc3)n2)CC1
Temperature: 100 °C

Procedure:
To a solution of 1.5 g of 4-{(S)-4-tert-Butoxycarbonyl-2-[(5-hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 20 ml of DMF, 1.8 g of cesium carbonate and 1.2 g of 1-Bromo-cyclobutanecarboxylic acid ethyl ester was added and heated to 100° C. for 2 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate (3×150 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 860 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][NH2:25])=[S:23])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:26](O)(=O)C.C(=N)N.O(C(C)C)C(C)C>C(O)CCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:26]=[N:25][N:24]=[C:22]4[SH:23])=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCN(c3ccc(NC(=S)NN)cc3)CC2)cc1
Reactant: CC(=O)O
Agent: N=CN
Solvent: CC(C)OC(C)C
Solvent: CCCCO
Product: COc1ccc(N2CCN(c3ccc(-n4cnnc4S)cc3)CC2)cc1

Procedure:
A mixture of 23 parts of N-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}hydrazinecarbothioamide, 23 parts of methanimidamide acetate and 80 parts of 1-butanol is stirred and refluxed for 1 hour. The reaction mixture is cooled and poured onto water. 2,2'-oxybispropane is added. The precipitated product is filtered off, washed with water and with methanol and crystallized from 1-butanol, yielding 17.7 parts of 4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-4H-1,2,4-triazole-3-thiol; mp. 231.9° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([Br:11])=[C:9]([Br:12])[N:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:7]=1[CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:5])C.CCC([O-])(C)C.[K+].[Cl-].[NH4+].C(O)(C(F)(F)[F:48])=O>C1(C)C=CC=CC=1>[CH2:27]([O:26][C:24]([C:23]1[C:4]([OH:5])=[C:6]2[C:10]([Br:11])=[C:9]([Br:12])[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:48])[CH:15]=3)[C:7]2=[CH:21][N:22]=1)=[O:25])[CH3:28]
Reactant: CCOC(=O)CN(Cc1c(C(=O)OCC)c(Br)c(Br)n1Cc1ccc(F)cc1)C(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Agent: CCC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice/water bath cooled crude 4,5-dibromo-2-[(tert-butoxycarbonyl-ethoxycarbonylmethyl-amino)-methyl]-1-(4-fluoro-benzyl)-1H-pyrrole-3-carboxylic acid ethyl ester (29.49 g) in toluene (100 mL) was added a 25% (weight) concentration of potassium tert-pentoxide in toluene (67.04 mL) during a course of ˜5 min; after that, the reaction was stirred for 1 h in the cold bath and then poured to a stirring mixture of ice/water and ammonium chloride, organic phase was separated and washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated to give the cyclized intermediate. The intermediate was then dissolved in 50 mL toluene and 50 mL TFA and stirred at room temperature for 1 h, then concentrated, the residue was partitioned between toluene and water; the organic phase was washed once with saturated sodium hydrogen carbonate, saturated sodium chloride solution respectively, then dried over anhydrous sodium sulfate, filtered, and air bubbled through the filtrate for a period of overnight. The precipitates were collected as the first crop of the title product (8.161 g). The filtrate was concentrated and purified with column directly to give the second crop of the title product (4.98 g). The title compound, ESI MS (m/z): 489 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1/[CH:10]=[C:11](\[SH:15])/[C:12]([OH:14])=[O:13].II.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].CCOCC>C(COC)OC>[F:1][C:2]1[C:3]2[CH:10]=[C:11]([C:12]([OH:14])=[O:13])[S:15][C:4]=2[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(F)c(/C=C(\S)C(=O)O)c1
Agent: II
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: COc1ccc(F)c2cc(C(=O)O)sc12
Temperature: 160 °C
Yield: 58.5 %

Procedure:
(2Z)-3-(2-Fluoro-5-methoxyphenyl)-2-mercapto-2-propenoic acid (1.00 g, 4.38 mmol) was added in one portion to a solution of iodine (1.66 g, 6.56 mmol) in dimethoxyethane (10 mL). This was heated in the microwave with 300 W at 160° C. for 10 mins. After this time the reaction was allowed to cool to room temperature and poured onto saturated sodium metabisulphite (200 mL) and ether (400 mL). Ether layer was separated and product extracted with aqueous sodium hydroxide (2 N, 2×100 mL). This was then acidified to pH 2 with aqueous hydrochloric acid (2 N, 250 mL), and product extracted with ether (2×150 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give a white solid (580 mg, 30%); δH (300 MHz, CD3OD) 8.00 (1H, s, Ar), 7.30-7.19 (1H, m, Ar), 7.10-7.00 (1H, m, Ar), 3.95.(3H, s, OCH3).
Reaction SMILES: [C:1](Cl)(=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:12](=[CH2:14])=[N-:13]>C(O)(=O)C>[N+:12](=[CH:14][C:1](=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[N-:13]
Reactant: C=[N+]=[N-]
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CC(=O)O
Product: [N-]=[N+]=CC(=O)CCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of hydrocinnamoyl chloride (10.00 grams; 100 mL dry diethyl ether) was carefully added to freshly prepared etherial diazomethane (85.6 grams Diazald; 100 mL dry ethyl ether) at 0° C. The reaction was held at 0° C. until outgassing subsided (15 minutes), then raised to room temperature (15 minutes). Acetic acid (5.0 mL) was added and the reaction partitioned (pH4 pthalate buffer and methyl tert-butyl ether). The organic was washed with water, dried over MgSO4 and filtered to provide, upon evaporation, an oil containing the title compound. The crude product was used with no further purification or delay.
Reaction SMILES: Cl.[C:2]([CH2:5][CH2:6][CH2:7][CH:8]1[C:20]2[NH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH2:11][CH2:10][N:9]1[CH2:21][CH3:22])([OH:4])=[O:3].C(=O)(O)[O-].[Na+].[CH2:28](O)[CH3:29]>>[CH2:28]([O:3][C:2]([CH2:5][CH2:6][CH2:7][CH:8]1[C:20]2[NH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH2:11][CH2:10][N:9]1[CH2:21][CH3:22])=[O:4])[CH3:29]
Reactant: CCO
Reactant: CCN1CCc2c([nH]c3ccccc23)C1CCCC(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)CCCC1c2[nH]c3ccccc3c2CCN1CC
Yield: 85 %

Procedure:
15 ml of ethanol and 3 ml of 10% ethanolic hydrogen chloride were added to 2.86 g of 1,2,3,4-tetrahydro-1-(3-carboxypropyl)-2-ethyl-β-carboline, and the mixture was refluxed for 2 hours. After the reaction was completed, the mixture was evaporated under reduced pressure to remove solvent. The residue thus obtained was alkalified with an aqueous saturated sodium bicarbonate solution and then extracted with ethyl acetate. The extract was washed with water, dried and evaporated to remove solvent. 2.67 g of 1,2,3,4-tetrahydro-1-(3-ethoxycarbonylpropyl)-2-ethyl-β-carboline were obtained. Yield: 85.0%.
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:14][CH3:15])=[N:7]2.[Li]C(C)(C)C.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1>C1COCC1.CCCCC>[CH3:13][O:12][C:11]1[C:2]([CH:27]([C:26]2[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[OH:28])=[C:3]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([S:14][CH3:15])[CH:5]=[CH:4]2
Reactant: COc1ccc(C=O)cc1
Reactant: COc1ccc2nc(SC)ccc2c1Br
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2c(OC)ccc3nc(SC)ccc23)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35 %

Procedure:
A solution of 280 mg (1 mmole) of 5-bromo-6-methoxy-2-methylsulfanyl-quinoline in 4 mL THF was cooled to −78° C. and treated with 1.5 mL of 1.5 M t-BuLi in pentane. After stirring for 1.5 hours, 1.5 eq of p-methoxybenzaldehyde was added and the reaction allowed to warm to room temperature. After partitioning between EtOAc and water the product was purified by chromatography on silica gel (1:3 EtOAc/hexane) to afford (6-methoxy-2-methylsulfanyl-quinolin-5-yl)-(4-methoxy-phenyl)methanol (120 mg, 35%).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[H-].[Li+].[CH2:13](Cl)[O:14][CH3:15].[NH4+].[Cl-]>CN(C=O)C>[CH3:13][O:14][CH2:15][O:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COCCl
Reactant: O=C(CO)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COCOCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
To a cooled (0° C.) solution of 2-hydroxyacetophenone (1.0 g, 7.3 mmol) in DMF (50 mL) was added lithium hydride (74 mg, 95%, 8.8 mmol). After stirring for 30 minutes, MOM-Cl (0.73 mL, 9.5 mmol) was added slowly via syringe and the mixture was allowed to warm slowly to room temperature and was stirred for 16 hours. The reaction mixture was treated with saturated NH4Cl (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organics were washed with water (6×50 mL) and brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The brown residue was chromatographed (9:1 to 4:1 hexanes/ethyl acetate) to provide the product as a colorless oil (0.60 g, 45%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([F:10])=[C:4](Cl)[N:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>C(#N)C>[C:12]([NH:16][C:4]1[N:3]=[C:2]([Cl:1])[C:7]([C:8]#[N:9])=[CH:6][C:5]=1[F:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: CC(C)(C)N
Solvent: CC#N
Product: CC(C)(C)Nc1nc(Cl)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of 7.6 g of 2,6-dichloro-3-cyano-5-fluoropyridine in 40 ml acetonitrile was added 8.8 g of t-butylamine, and the mixture was stirred overnight at room temperature. The solvent was distilled off the reaction solution. The residue was separated by adding methylene chloride and water. The organic layer was dried over magnesium sulfate, and the solvent was distilled off to obtain 6 g of the title compound as a pale yellow powder.
Reaction SMILES: [CH2:1]([CH:3]([CH2:20][CH3:21])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[C:9]([F:19])[CH:8]=1)=[O:5])[CH3:2].[C:22]([O:26][C:27](N1CCN(C2C=CC(N)=CC=2F)CC1)=[O:28])([CH3:25])([CH3:24])[CH3:23].CCN(CC)CC>C(Cl)Cl>[C:22]([O:26][C:27]([N:16]1[CH2:15][CH2:14][N:13]([C:10]2[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[CH:3]([CH2:1][CH3:2])[CH2:20][CH3:21])=[CH:8][C:9]=2[F:19])[CH2:18][CH2:17]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCC(CC)C(=O)Nc1ccc(N2CCNCC2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2F)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)C(=O)Nc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Reaction time: 18 h

Procedure:
2-Ethyl-N-(3-fluoro-4-piperazin-1-yl-phenyl)-butyramide. To a solution of 4-(4-amino-2-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (2.0 g, 8.9 mmol) and Et3N (1.4 mL, 10.0 mmol) in DCM (60 mL) was added 1-ethylbutyryl chloride (1.4 mL, 10.0 mol). The mixture was stirred for 18 h, quenched with 1 N NaHCO3 (50 mL), and extracted with DCM (3×50 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the residue (SiO2; EtOAc/hexanes) gave 4-[4-(2-ethyl-butyrylamino)-2-fluoro-phenyl]-piperazine-1-carboxylic acid tert-butyl ester. A mixture of this intermediate in MeOH (25 mL) and 2 N HCl in Et2O (10 mL) was stirred for 18 h. The solution was concentrated to give 2-ethyl-N-(3-fluoro-4-piperazin-1-yl-phenyl)-butyramide hydrochloride. This salt was treated with 1 N NaOH (10 mL) and extracted with EtOAc (40 mL). The organic layer was dried and concentrated to give the title compound as the free base (1.5 g, 58%). MS (ESI): mass calcd. for C16H24FN3O, 293.19. m/z found, 294.4 [M+H]+. 1H NMR (CDCl3): 7.25-7.23 (m, 1H), 7.17 (s, 1H), 6.58-6.55 (m, 1H), 3.08-3.00 (m, 8H), 2.02-1.99 (m, 1H), 1.80-1.50 (m, 4H), 1.00-0.95 (m, 6H).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH2:20][S:21]([NH2:24])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)[CH2:6][CH2:5]C[CH2:3][CH2:2]1.Cl[C:26]1N=CN=C(NC2C=C(CS(N)(=O)=O)C=CC=2)[N:27]=1.CN1CCNCC1>>[CH3:26][N:27]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH2:20][S:21]([NH2:24])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)[CH2:2][CH2:3]1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCCCC3)n2)c1
Agent: CN1CCNCC1
Product: CN1CCN(c2ncnc(Nc3cccc(CS(N)(=O)=O)c3)n2)CC1

Procedure:
B12 was prepared following the procedure reported for B1 using A1 and N-methylpiperazine. MS (ES) C15H21N7O3S requires: 363. found: 364 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[N:7]1[CH:12]=[C:11](B(O)O)[CH:10]=[N:9][CH:8]=1.Br[C:17]1[CH:30]=[CH:29][C:28]2[O:27][C:26]3[C:21](=[CH:22][C:23]([O:31][CH3:32])=[CH:24][CH:25]=3)[C:20]3([CH:36]([CH3:37])[O:35][C:34]([NH2:38])=[N:33]3)[C:19]=2[CH:18]=1.COCCOC>CCOC(C)=O.O>[CH3:32][O:31][C:23]1[CH:24]=[CH:25][C:26]2[O:27][C:28]3[C:19](=[CH:18][C:17]([C:11]4[CH:12]=[N:7][CH:8]=[N:9][CH:10]=4)=[CH:30][CH:29]=3)[C@:20]3([C@H:36]([CH3:37])[O:35][C:34]([NH2:38])=[N:33]3)[C:21]=2[CH:22]=1
Reactant: OB(O)c1cncnc1
Reactant: COc1ccc2c(c1)C1(N=C(N)OC1C)c1cc(Br)ccc1O2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)[C@]1(N=C(N)O[C@H]1C)c1cc(-c3cncnc3)ccc1O2
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To a mixture of sodium carbonate (0.636 g, 6.00 mmol), palladium tetrakistriphenylphosphine (0.185 g, 0.160 mmol), pyrimidin-5-ylboronic acid (0.322 g, 2.60 mmol) and 2′-bromo-7′-methoxy-5-methyl-5H-spiro[oxazole-4,9′-xanthen]-2-amine (0.750 g, 1.999 mmol) in a resealable pressure tube, was added DME (6 mL) and water (2 mL) at RT. The tube was sealed and heated to 85° C. After 2 hrs, the mixture was cooled to RT, diluted with EtOAc, and washed with brine. The organic fraction was dried with sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography using 2-8% MeOH in CH2Cl2 with 1% NH4OH to afford a mixture of diastereomers as an off-white foam. MH+=375.2@1.54 min. Purification of the resulting racemic product mixture using Chiralpack AD-H (2×15 cm) 30% MeOH/CO2, 100 bar, 70 ml/min afforded:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2CC3[C:13]([C:2]=12)=[CH:12][CH:11]=[CH:10][CH:9]=3.[CH3:14][C:15]([CH3:18])([O-])[CH3:16].[K+].IC.O>O1CCCC1>[CH3:14][C:15]1([CH3:18])[C:3]2[C:2](=[N:1][CH:6]=[CH:5][CH:4]=2)[C:13]2[C:16]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: c1ccc2c(c1)Cc1cccnc1-2
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C)c2ccccc2-c2ncccc21
Temperature: -10 °C
Reaction time: 6 h

Procedure:
13.5 g (80.7 mmol) of 5H-indeno[1,2-b]pyridine was dissolved in 120 ml dry tetrahydrofuran, and 22.7 g (202 mmol) of potassium tert-butoxide was added to the solution at −10° C. The reaction mixture was maintained at −10° C. for 1 hour. Then the iodomethane 28.7 g (202 mmol) was added dropwise; the solution was then warmed slowly to room temperature and stirred for 6 h. After the reaction completion, water was added to the mixture to terminate the reaction. The reaction mixture was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was evaporated in vacuo, and the residue was crystallized with toluene to give the 5,5-dimethyl-5H-indeno[1,2-b]pyridine, 13.5 g (86%)
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([N:21]=[C:22]=[O:23])[CH2:19][CH3:20]>>[CH2:18]([NH:21][C:22](=[O:23])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10]2)[CH2:19][CH3:20]
Reactant: CCCN=C=O
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Product: CCCNC(=O)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (15.0 mg, 66.6 μmol) using the same procedure employed for Example 2 (2), but with n-propylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (12.3 mg, 60%) having the following characteristics.