Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C:18]([CH:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])[CH:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)=[O:4].Cl.[NH2:34][OH:35].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([CH:11]1[CH2:16][CH2:15][C:14](=[N:34][OH:35])[CH2:13][CH2:12]1)[C:18]([CH:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])=[O:4]
Reactant: NO
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(=NO)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
3-[(4-Methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (67 mg, 0.148 mmol) was dissolved in methanol (1.5 ml) and hydroxylamine hydrochloride salt (62 mg, 0.888 mmol) was added. After stirring for 2 hours at room temperature and 2 hours at reflux, the pH of the solution was adjusted to 8-9 by addition of a 10% sodium hydroxide solution. The resulting solution was then refluxed for 30 minutes and cooled to room temperature. It was then quenched with water (5 ml) and extracted with ethyl acetate (3×5 ml). The combined ethyl acetate layer was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (0% to 60% EtOAc/Hex) to obtain 49 mg (71%) of 3-[(4-Hydroxyimino-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[CH:30][CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[CH:30][CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-propyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].Cl[Sn]Cl.O.[CH3:15][CH2:16][O:17]C(C)=O>ClCCCl>[C:16]([C:6]1[C:2]([Cl:1])=[C:3]([C:7]([O:9][CH3:10])=[O:8])[NH:4][CH:5]=1)(=[O:17])[CH3:15]
Reactant: COC(=O)c1[nH]ccc1Cl
Reactant: CCOC(C)=O
Agent: Cl[Sn]Cl
Solvent: ClCCCl
Solvent: O
Product: COC(=O)c1[nH]cc(C(C)=O)c1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 26 %

Procedure:
A solution of methyl 3-chloro-1H-pyrrole-2-carboxylate (0.100 g, 0.627 mmol) in DCE (3 mL) was added to a suspension of SnCl2 (0.238 g, 1.25 mmol) and methyl 3-chloro-1H-pyrrole-2-carboxylate (0.100 g, 0.627 mmol) in DCE (3 mL) at 0° C. The reaction was stirred for 10 min. at 0° C. then warmed to room temp over 2 hours. The reaction mixture was poured into water and EtOAc. The organic layer was separated, washed with 1N sodium hydroxide, dried over MgSO4, filtered and evaporated to a residue. Purification was accomplished on silica with EtOAc and hexanes to afford the title compound (0.034 g, 26%) as a solid, along with methyl 4-acetyl-3-chloro-1H-pyrrole-2-carboxylate (0.047 g, 37%) as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 10.19 (br. s., 1H), 7.34-7.84 (m, 1H), 3.90 (s, 3H), 2.52 (s, 3 H). LCMS: m/z 200.0 (M−1).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:19]=1
Reactant: COC(=O)Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(CC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
n-BuLi (1.60M in hexanes, 35.6 mL, 56.9 mmol) was added to a 0° C. solution of diisopropylamine (8.35 mL, 59.6 mmol) in THF (200 mL). The mixture was allowed to stir at 0° C. for 30 minutes, and was then cooled to −78° C. A solution of methyl 2-(4-chlorophenyl)acetate (10.0 g, 54.2 mmol) in THF (10 mL) was added to the −78° C. LDA solution by syringe, which was then stirred for 45 minutes. Neat tert-butyl bromoacetate (9.60 mL, 65.0 mmol) was added by syringe, and the reaction was stirred for 15 minutes at −78° C. The bath was removed, and the reaction was allowed to warm to room temperature. After stirring an additional 5 hours, the reaction mixture was quenched with saturated NH4Cl solution, and the solvent(s) were removed in vacuo. The oily mixture was extracted with ethyl acetate, and the organics were combined. The organic portion was dried over MgSO4, filtered, and concentrated in vacuo. The crude oil was purified on silica gel (95:5 hexanes:EtOAc) to afford the 4-tert-butyl 1-methyl 2-(4-chlorophenyl)succinate as a pale yellow oil (14.3 g, 88%). 1H NMR (CDCl3, 400 MHz) δ 7.29 (d, J=7.2 Hz, 2H), 7.22 (d, J=7.2 Hz, 2H), 4.00 (dd, J=9.6, 5.6 Hz, 1H), 3.67 (s, 3H), 3.07 (dd, J=16.4, 9.6 Hz, 1H), 2.58 (dd, J=16.8, 6.0 Hz, 1H), 1.40 (m, 3H).
Reaction SMILES: [P:1]([O:10]CCCl)([O:6]CCCl)[O:2]CCCl.[CH3:14][N:15]1[C:19](=[O:20])[N:18]([CH3:21])[CH2:17]P1(=O)OCCCl>C(O)(=O)C.O>[CH3:17][N:18]([CH2:21][P:1](=[O:2])([OH:6])[OH:10])[C:19]([NH:15][CH3:14])=[O:20]
Reactant: ClCCOP(OCCCl)OCCCl
Reactant: CN1CP(=O)(OCCCl)N(C)C1=O
Solvent: O
Solvent: CC(=O)O
Product: CNC(=O)N(C)CP(=O)(O)O

Procedure:
This phosphonic acid is prepared in a similar manner using tris(2-chloroethyl) phosphite as the phosphorus ester reactant. The crude intermediate 1,4-dimethyl-2-(2-chloroethoxy)-1,4,2-diazaphospholidin-5-one-2-oxide (31P nmr -24.9 ppm) is hydrolyzed without isolation from the reaction mixture to give the acid: mp 171°-172° dec. (acetic acid-water).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13])(=[O:3])[CH3:2].O[CH2:15][C:16]1[O:20][C:19]([CH:21]=[O:22])=[CH:18][CH:17]=1.N1CCCCC1>C(O)C>[OH:22][CH2:21][C:19]1[O:20][C:16]([CH:15]=[C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]([C:1](=[O:3])[CH3:2])[C:5]2=[O:13])=[CH:17][CH:18]=1
Reactant: O=Cc1ccc(CO)o1
Reactant: CC(=O)N1C(=O)Cc2ccccc21
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(=O)N1C(=O)C(=Cc2ccc(CO)o2)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
N-acetyloxindole (1 equivalent), 5-hydroxymethyl-2-furaldehyde (0.5 equivalent) and piperidine (0.2 equivalent) were dissolved in ethanol such that 1 mL of ethanol was used per 1 μmol of the total amount of the compounds, and the resulting mixture was stirred at room temperature for 12 hours. After completion of the reaction, the resulting precipitate was collected by filtration, washed with cooled ethanol several times and dried, whereby 3-((5-(hydroxymethyl)furan-2-yl) methylene)-N-acetyl-2-oxoindoline was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:21]=[CH:20][C:14]([C:15](=[NH:19])OCC)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[CH3:28][O:29][CH2:30][CH2:31][CH2:32][NH2:33]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:12]=[CH:13][C:14]([C:15](=[NH:19])[NH:33][CH2:32][CH2:31][CH2:30][O:29][CH3:28])=[CH:20][CH:21]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: COCCCN
Reactant: CCOC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Solvent: CO
Product: COCCCNC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml of a 0.075 M methanol solution, 0.15 mmol) was treated with 3-methoxypropan-1-amine (23 μl, 0.23 mmol) via procedure W to afford 68 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(3-methoxypropyl)carbamimidoyl)-benzamide.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH3:13][C:14](=O)[CH2:15][CH2:16][C:17](=O)[CH3:18].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:18][C:17]1[N:1]([C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]3)=[CH:4][CH:3]=2)[C:14]([CH3:13])=[CH:15][CH:16]=1
Reactant: Nc1ccc2c(c1)NC(=O)CC2
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc2c(c1)NC(=O)CC2
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
A mixture of 7-amino-3,4-dihydroquinolin-2(1H)-one (3.0 g, 18.50 mmol), hexane-2,5-dione (3.0 g, 25.9 mmol) and 4-methylbenzenesulfonic acid (3.2 g, 18.50 mmol) in toluene (40 mL) was stirred at 100° C. for 30 min. The reaction mixture was cooled to ambient temperature, concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (eluting with 10% EtOAc in petroleum ether) to give 7-(2,5-dimethyl-pyrrol-1-yl)-3,4-dihydro-1H-quinolin-2-one (3.0 g, 67%). 1H NMR (CDCl3, 400 MHz): δ 8.72 (brs, 1H), 7.23 (d, J=8.0 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.67 (s, 1H), 5.89 (s, 2H), 3.02 (t, J=8.0 Hz, 2H), 2.68 (m, 2H), 2.03 (s, 6H).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:6][C:5]=2[N:19]=1.[NH2:20][CH2:21][CH2:22][C:23]1[N:27]=[CH:26][NH:25][CH:24]=1>>[Cl:10][C:9]1[C:4]2[S:3][C:2]([NH:20][CH2:21][CH2:22][C:23]3[N:27]=[CH:26][NH:25][CH:24]=3)=[N:19][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: Clc1nc(SCc2ccccc2)nc2nc(Br)sc12
Reactant: NCCc1c[nH]cn1
Product: Clc1nc(SCc2ccccc2)nc2nc(NCCc3c[nH]cn3)sc12

Procedure:
Prepared according to the method of Example 231 using the product of Example 219 and histamine.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:11])[NH:5][CH2:6][CH2:7][CH2:8][C:9]#[N:10]>C1(C)C=CC=CC=1>[ClH:1].[CH3:2][O:3][C:4]([N:5]1[CH2:6][CH2:7][CH2:8][C:9]1=[NH:10])=[O:11]
Reactant: COC(=O)NCCCC#N
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)N1CCCC1=N
Yield: 96.9 %

Procedure:
77 g hydrogen chloride are introduced, with slight cooling, into 155 g (1.04 mole) N-(cyanopropyl)-carbamic acid methylester in 200 ml toluene at 20° C. During this procedure the product precipitates after only a short time. It is worked up as normal. 180 g of product are obtained. This corresponds to a yield of 93%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:8][O:9][C:5]=2[CH:4]=1.[Br:18]Br>ClCCl>[Br:18][C:8]1[O:9][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:17]=[CH:16][C:6]=2[C:7]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrBr
Reactant: COc1ccc2c(-c3ccccc3)coc2c1
Solvent: ClCCl
Product: COc1ccc2c(-c3ccccc3)c(Br)oc2c1

Procedure:
To a solution of 25 g (0.112 mole) of 6-methoxy-3 -phenylbenzofuran in 400 ml of dichloromethane is added over 1 hour dropwise with stirring 17.9 g (0.112 mole) of bromine in 20 ml of dichloromethane. The solution is washed with 200 ml of 10% aqueous sodium acetate, dried and evaporated to provide 2-bromo-6-methoxy-3-phenylbenzofuran as a dark oil.
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=2)[CH:9]=1)([CH3:7])[CH3:6])C.[OH-].[Li+]>C(O)C.O1CCCC1>[CH3:26][O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]#[C:14][C:10]2[CH:9]=[C:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:27])=[O:3])[CH:13]=[CH:12][CH:11]=2)=[CH:21][CH:20]=1)=[O:24]
Reactant: CCOC(=O)C(C)(C)c1cccc(C#Cc2ccc(CC(=O)OC)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)Cc1ccc(C#Cc2cccc(C(C)(C)C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
A solution of 2-[3-(4-methoxycarbonylmethyl-phenylethynyl)-phenyl]-2-methyl-propionic acid ethyl ester (Intermediate 133, 0.12 g, 0.33 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was treated with 2M lithium hydroxide (1 mL, 2 mmol) and the resulting reaction mixture was stirred at ambient temperature for 1 h. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as an oil (0.11 g, 95%).
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:14][CH:9]3[S:10][CH:11]([S:13][CH:7]([S:8]3)[CH2:6]1)[CH2:12]2)=O.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C>CCCCCC>[OH:2][CH2:3][C:5]12[CH2:12][CH:11]3[S:10][CH:9]([S:8][CH:7]([S:13]3)[CH2:6]1)[CH2:14]2
Reactant: COC(=O)C12CC3SC(C1)SC(C2)S3
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: OCC12CC3SC(C1)SC(C2)S3
Temperature: 0 °C
Yield: 99 %

Procedure:
A flame-dried, 25 mL round-bottomed flask equipped with a Teflon-coated magnetic bar and a septum with an argon inlet was charged with 270 mg (1.10 mmol) of 2,4,9-Trithia-tricyclo[3.3.1.13,7]decane-7-carboxylic acid methyl ester and 5 mL of dry toluene. Cooled by an ice bath, the solution was charged with 1.60 mL of 1.5 M (2.3 mmol) diisobutyl aluminum hydride in hexane. The solution was stirred at 0° C. until the complete consumption of the starting material was observed (monitored by TLC). The solution was quenched by 2 mL of methanol and allowed to warm to the ambient temperature. The filtration through a celite filter cake gave 240 mg (97%) of 7-hydroxymethyl-2,4,9-trithiaadamantane.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[CH3:2].[OH-:22].[Na+]>S(=O)(=O)(O)O.O>[CH2:20]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6](=[O:22])[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[CH3:21]
Reactant: [OH-]
Reactant: CCN(CC)CC#CCCCc1ccc(OC)c(OC)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCN(CC)CCC(=O)CCCc1ccc(OC)c(OC)c1

Procedure:
Add mercuric sulphate (0.45 g) to a stirred solution of 1-diethylamino-6-(3,4-dimethoxyphenyl)hex-2-yne (8.5 g) in concentrated sulphuric acid (2.5 cc) and water (25 cc) and maintain the solution at 75° for 90 minutes. Make the cooled solution basic with 10% aqueous sodium hydroxide and filter to remove mercuric oxide. Extract the product with ether and wash and dry the ethereal solution. Evaporate the solvent to obtain 1-diethylamino-6-(3,4-dimethoxyphenyl)hexan-3-one as an oily residue.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C1(C)C=CC=CC=1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:21]([NH:20][C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([C:27]4[CH:26]=[N:25][N:24]([CH3:23])[CH:28]=4)=[CH:3][C:4]3=[N:10][CH:9]=2)[CH:12]=1)=[O:19])[CH3:22]
Reactant: CCNC(=O)Nc1cccc(-c2cnc3cc(Cl)ccn23)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1cccc(-c2cnc3cc(-c4cnn(C)c4)ccn23)c1

Procedure:
A solution of 1-[3-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-ethyl urea (200 mg, 0.636 mmol, 1 equivalent, made using procedure F1a), 1-methylpyrazole-4-boronic acid pinacol ester (commercially available, 265 mg, 1.272 mmol, 2 equivalents), potassium carbonate (527 mg, 3.816 mmol, 6 equivalents), and bis(tri-t-butylphosphine)palladium(0) (16 mg, 0.032 mmol, 0.05 equivalents) in ethanol (10 ml), toluene (10 ml) and water (10 ml) was heated at 70° C. for 24 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated brine solution, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography (Biotage SP4, 25S, flow rate 25 ml/min, gradient 0% to 20% methanol in ethyl acetate) to give 1-ethyl-3-{3-[7-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-urea as a white solid (35 mg). MS: [M+H]+ 361.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[C@H:17]([CH3:18])[CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:14]([CH3:26])[CH2:13]2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35]>CC#N>[CH3:26][C@H:14]1[CH2:13][N:12]([CH2:11][C:4]2[C:5]3[O:9][CH:8]=[CH:7][C:6]=3[CH:10]=[C:2]([NH:1][S:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH3:27])(=[O:36])=[O:35])[CH:3]=2)[C@H:17]([CH3:18])[CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1Cc1cc(N)cc2ccoc12
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: CC#N
Product: Cc1ccccc1S(=O)(=O)Nc1cc(CN2C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]2C)c2occc2c1

Procedure:
The title product was prepared according to the procedure of Example 121, Step 4, starting from tert-butyl trans-4-[(5-amino-1-benzofuran-7-yl)methyl]-2,5-dimethylpiperazine-1-carboxylate (obtained in Example 121, Step 3) and 2-methylbenzenesulfonyl chloride (0.039 g, 0.2 mmol). Yield: 0.022 g (43%). HPLC 95% RT=1.99 min (System A; 10-97% MeCN over 3 min), 93% RT=1.85 min (System B; 10-97% MeCN over 3 min). MS (ESI+) m/z 514.2 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:23][CH2:22][CH2:21][C@H:15]1[C:16](OCC)=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([N:14]1[CH2:23][CH2:22][CH2:21][CH:15]1[CH2:16][OH:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)[C@@H]1CCCN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCCN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Into a 5,000 ml 3-necked roundbottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of lithium aluminum hydride (54.0 g, 1.42 mol) in tetrahydrofuran (3,500 ml) at 0° C. This was followed by the dropwise addition of a solution of ethyl 1-benzylprolinate (330 g, 1.42 mol) in tetrahydrofuran (500 ml), maintaining an internal temperature of 0° C. (2 hours total addition time). The resulting solution was allowed to stir for 2 hours while the temperature was maintained at 0° C. The reaction mixture was then quenched by the addition of water. The solution was filtered, and the filtration residue was washed once with 500 ml of tetrahydrofuran. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. The residue was dissolved in 3,000 ml of ethyl acetate, dried over sodium sulfate, filtered and concentrated to afford 1-benzylpyrrolidin-2-yl)methanol, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4].[C:12]1([C:18]2[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:11]=[CH:22][C:21]2[CH:24]=[CH:25][C:18]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:19][CH:20]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4]
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1cc(Cl)cn1N
Solvent: CO
Product: COC(=O)c1cc(Cl)cn1N=Cc1ccc(-c2ccccc2)cc1

Procedure:
Prepared according to the imine formation condition used in Example 18 step b) from 1-amino-4-chloro-1H-pyrrole-2-carboxylic acid methyl ester and 4-phenyl benzaldehyde in refluxing methanol for 12 h. 1H NMR (CDCl3, δ in ppm): 8.43 (s, 1H), 7.91 (d, 2H, J=8.4 Hz), 7.68 (d, 2H, J=8.4 Hz), 7.66-7.16 (m, 5H), 7.20 (d, 1H, J=2.2 Hz), 6.90 (d, 1H, J=1.8 Hz), 3.84 (s, 3H).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[C:11]1([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[O:2]1[C:6]2[CH2:7][N:8]([C:20](=[O:21])[CH2:19][CH2:18][CH2:17][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1
Reactant: O=C(O)CCCc1ccccc1
Reactant: c1cc2c(o1)CNCC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CCCc1ccccc1)N1CCc2ccoc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.18 g (1.1 mmol) of 4-phenylbutyric acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel chromatography (hexane/ethyl acetate=10/1 to 5/1) to yield the desired product.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[F:39][C:40]1[CH:41]=[CH:42][C:43]([O:49][CH3:50])=[C:44](B(O)O)[CH:45]=1>>[NH2:30][C:29]1[S:28][C:27]([C:42]2[CH:41]=[C:40]([F:39])[CH:45]=[CH:44][C:43]=2[O:49][CH3:50])=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH2:8])[CH2:11][CH2:12]1)=[O:24]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Product: COc1ccc(F)cc1-c1nc(C(=O)Nc2cnn(C)c2N2CCC(CN)CC2)c(N)s1
Yield: 26 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 5-fluoro-2-methoxyphenyl boronic acid gave 390 as a pale brown solid (24 mg, 26% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 9.12 (s, 1H), 8.19 (d, J=10.0 Hz, 1H), 7.36 (d, J=2.1 Hz, 1H), 7.28 (d, J=7.1 Hz, 1H), 7.26-7.22 (m, 2H), 3.99 (s, 3H), 3.67 (s, 3H), 3.16-3.00 (m, 4H), 2.47 (d, J=5.6 Hz, 2H), 1.78 (d, J=11.5 Hz, 2H), 1.30-1.17 (m, 3H). LCMS (ES+) m/z 460 (M+1)
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[C:17]([F:30])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:32]1[N:37]=[N:36][C:35]([NH2:38])=[CH:34][CH:33]=1>>[NH2:38][C:35]1[N:36]=[N:37][C:32]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:9]([S:6]([NH:5][C:1]([CH3:2])([CH3:3])[CH3:4])(=[O:8])=[O:7])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:16][C:17]=2[F:30])=[CH:33][CH:34]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2ccc(N)nn2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 444 using N-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide and 6-chloropyridazin-3-amine. MS (ESI): mass calcd. for C20H21FN4O2S, 400.14; m/z found, 401.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.26-8.22 (m, 1H), 8.16-8.13 (m, 1H), 7.91-7.85 (m, 1H), 7.69-7.64 (m, 1H), 7.63-7.56 (m, 2H), 7.44-7.37 (m, 3H), 1.09 (s, 9H).