Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[C:30][P:31](=[O:36])([OH:35])[O:32][CH2:33][CH3:34])=[CH:25][CH:24]=1.[Cl:37][CH2:38][CH2:39][CH2:40][C:41]#[CH:42]>[Au].ClC(Cl)C>[CH2:33]([O:32][P:31]1(=[O:35])[CH:30]=[C:29]([C:26]2[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][CH:27]=2)[CH:42]=[C:41]([CH2:40][CH2:39][CH2:38][Cl:37])[O:36]1)[CH3:34]
Reactant: CCOP(=O)(O)C#Cc1ccc(Cl)cc1
Reactant: C#CCCCCl
Agent: [Au]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC(Cl)Cl
Product: CCOP1(=O)C=C(c2ccc(Cl)cc2)C=C(CCCCl)O1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49 %

Procedure:
A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tert-butylphosphine] (11.3 mg, 0.015 mmol) was put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl hydrogen (4-chlorophenyl)ethynylphosphonate (73.4 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and finally, 5-chloropent-1-yne (61.5 mg, 0.6 mmol) was put thereinto. Then, when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain 2-ethoxy-4-p-chlorophenyl-6-(3-chloropropyl)-1,2-oxaphosphorin 2-oxide (51.0 mg, 49%) which is a title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[C:6]([O:10][C:11]([N:13]1[CH:18]([C@@H:19]([OH:33])[C@@H:20]([NH:29][C:30](=[O:32])[CH3:31])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)[CH2:17][O:16][C@@H:15]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C@@H:14]1[CH3:40])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:6]([O:10][C:11]([N:13]1[C@@H:18]([C@@H:19]([OH:33])[C@@H:20]([NH:29][C:30](=[O:32])[CH3:31])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:2][CH2:3][CH2:4][CH3:5])[CH:23]=2)[CH2:17][O:16][C@@H:15]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C@@H:14]1[CH3:40])=[O:12])([CH3:8])([CH3:9])[CH3:7]
Reactant: CCCCBr
Reactant: CC(=O)N[C@@H](Cc1cccc(O)c1)[C@H](O)C1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOc1cccc(C[C@H](NC(C)=O)[C@H](O)[C@H]2CO[C@@H](OCC(C)(C)C)[C@H](C)N2C(=O)OC(C)(C)C)c1
Temperature: 60 °C
Yield: 102.5 %

Procedure:
Add 1-bromobutane (6 μL, 55.6 μmol) to a solution of 5-[2-(S)-acetylamino-1-(S)-hydroxy-3-(3-hydroxyphenyl)-propyl]-2-(R)-(2,2-dimethylpropoxy)-3-(S)-methylmorpholine-4-carboxylic acid tert-butyl ester (25 mg, 50.5 μmol) and cesium carbonate (33 mg, 1.01 mmol) in N,N-dimethylformamide (250 μL). Heat to 60° C. for 3 hours. Dilute with ethyl acetate, wash with water, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 20:80 to 85:15 ethyl acetate:dichloromethane) to give the title compound (28.5 mg, 80%).
Reaction SMILES: CC(C)CN[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15].[C:17](=[S:19])=[S:18].C(O)C>[OH-].[Na+]>[S:18]1[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=[C:17]1[SH:19]
Reactant: CC(C)CNc1c(N)cnc2ccccc12
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Sc1nc2cnc3ccccc3c2s1

Procedure:
N4-(2-methylpropyl)quinoline-3,4-diamine (5.4 g, 25 mmol) was combined with carbon disulfide (9 mL, 150 mmol) and ethanol (55 mL) and then heated at reflux on a steam bath for 2 hours. The resulting precipitate was isolated by filtration, washed with ethanol and then air dried to provide 4.4 g of crude product. A portion (1 g) was dissolved in hot dilute sodium hydroxide and then reprecipitated with acetic acid. The precipitate was isolated by filtration while still hot, washed with hexane and then air dried to provide thiazolo[4,5-c]quinoline-2-thiol as a solid, m.p. 282–284° C. Analysis: Calculated for C10H6N2S2: % C, 55.02; % H, 2.77; % N, 12.83: Found: % C, 54.96; % H, 2.69; % N, 12.74.
Reaction SMILES: [C:1]1([C:7]([NH:20][CH:21]2[C:41](=[O:42])[N:23]3[CH:24]([C:29](Cl)=[N:30][CH2:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[NH3:46]>C(Cl)(Cl)Cl>[C:1]1([C:7]([NH:20][CH:21]2[C:41](=[O:42])[N:23]3[CH:24]([C:29](=[N:30][CH2:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[NH2:46])[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: COc1ccc(CN=C(Cl)C2N3C(=O)C(NC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]3SC2(C)C)cc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1ccc(CN=C(N)C2N3C(=O)C(NC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]3SC2(C)C)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of 13.1 g. (22 mmoles) of 6-(triphenylmethylamino)-2,2-dimethyl-3-{chloro-[N-(4-methoxybenzyl)imino]methyl}penam in 45 ml. of ethanol-free chloroform, a 1.33 N ammonia solution in chloroform is added all at once. The resulting mixture is stirred 5 minutes at 0° C. and then for 45 minutes at 25° C. The mixture is then filtered, and the filtrate rotoevaporated to an amber oil. Addition of ether (100 ml.) affords a precipitate which is filtered and then taken up in 150 ml. chloroform. The chloroform solution is washed first with 100 ml. 0.5N NaOH; and then with three 150 ml. portions of water. It is then dried over anhydrous sodium sulfate and rotoevaporated to afford the title compound as an orange foam. Rotoevaporation of the filtrate obtained after the ether precipitation procedure affords more of the title compound, as an orange foam. Total yield= 12.05 g. (95%). 1H--NHR (CDCl3 ) ppm (δ) 1.33 (3H, s, 2--CH3); 1.60 (3H, s, 2--CH3); 3.81 (3H, s, --OCH3); 4.17-4.68 (3H, m; 3-, 5- and 6-H); 4.24 (2H, s, --CH2 --), 4H, AB with Ha within 7.2-7.68 multiplet; Hb centered at 6.89, J= 9 HZ. (CH3O--C6H4 --), 7.2-7.68 (15H, m, C6H5). Infrared (CH2Cl2) λmax (μ) 5.62 (s, strong); 5.75-5.83 (broad s, strong); 5.97 (broad s, strong).
Reaction SMILES: Cl[C:2]1[CH2:6][C@@H:5]([C@H:7]([N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])[C:8]([O:10]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:9])[O:4][N:3]=1.[BrH:35]>[N+](C)([O-])=O>[Br:35][C:2]1[CH2:6][C@@H:5]([C@H:7]([N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])[C:8]([OH:10])=[O:9])[O:4][N:3]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)[C@H]([C@@H]1CC(Cl)=NO1)N1C(=O)c2ccccc2C1=O
Reactant: Br
Solvent: C[N+](=O)[O-]
Product: O=C(O)[C@H]([C@@H]1CC(Br)=NO1)N1C(=O)c2ccccc2C1=O
Reaction time: 1 h

Procedure:
To 185 mg (0.4 mmole) of the (αS,5S)-chloro-4,5-dihydro-α-phthalimido-5-isoxazole acetic acid, benzhydryl ester in 3 ml of dry nitromethane in an ice bath under nitrogen is bubbled dry hydrogen bromide for five minutes. The bath is removed and the solution stirred for one hour. After concentrating the solution is vacuo the residue is chromatographed on CC-4 silica gel (30 g) with 30%) ethyl concentrating the solution in vacuo the residue is chromatographed on CC-4 silica gel (30 g) with 30%) ethyl acetate/hexane to yield 115 mg of a white foam. This foam is recrystallized from 4/1 hexane/ethanol to yield 3-bromo-4,5-dihydro-α-phthalimido-5-isoxazole acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][C:15](=[O:17])[CH:14]=[CH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H][H].Cl.C(OCC)(=O)C>C(O)C.C(OCC)(=O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:12][CH2:13][CH2:14][C:15](=[O:17])[CH2:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: [H][H]
Reactant: COc1ccc(C2CC=CC(=O)C2)cc1OC
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(C2CCCC(=O)C2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
5-(3,4-Dimethoxyphenyl)-2-cyclohexen-1-one (6.76 g) was dissolved in ethanol (100 ml), and 10% palladium-carbon (684 mg) was added thereto. After substituting the reaction vessel with hydrogen gas, hydrogen addition was effected for 30 minutes at normal pressure and room temperature. After the reaction, the catalyst was filtered off and the solvent was distilled off under reduced pressure to produce an oily substance which was dissolved in ethyl acetate (50 ml), and then 4 N HCl-ethyl acetate solution (2 ml) was added and the mixture was stirred at room temperature for 20 minutes. The solvent was distilled off under reduced pressure to produce crude crystals which were then washed with n-hexane to give 6.72 g of 3-(3,4-dimethoxyphenyl)cyclohexanone (98.5%).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][C:9]1[NH:14][C:13](=[O:15])[NH:12][C:11](=[O:16])[C:10]=1[Cl:17])SC)#[N:2].[CH3:18][NH2:19]>C(O)C>[C:1]([NH:3][C:4]([NH:19][CH3:18])=[N:7][CH2:8][C:9]1[NH:14][C:13](=[O:15])[NH:12][C:11](=[O:16])[C:10]=1[Cl:17])#[N:2]
Reactant: CN
Reactant: CSC(=NCc1[nH]c(=O)[nH]c(=O)c1Cl)NC#N
Solvent: CCO
Product: CNC(=NCc1[nH]c(=O)[nH]c(=O)c1Cl)NC#N
Temperature: 50 °C
Yield: 96 %

Procedure:
Next, 150 mg of the N-cyano-N'-(5-chlorouracil-6-ylmethyl)-S-methylisothiourea were suspended in ethanol (3 ml), followed by the addition of 2 ml of a 30% solution of methylamine in ethanol. The resulting mixture was heated at 50° C. for 3.5 hours under stirring. After an insoluble matter was filtered off, the filtrate was allowed to cool back to room temperature. A precipitate from the filtrate was collected by filtration, whereby 12 mg of the title compound were obtained (yield: 96%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:20]1([C:25]2[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O>[CH3:19][C:13]1([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([N:20]5[CH2:21][CH2:22][CH2:23][CH2:24]5)[CH:26]=4)[N:3]=3)[NH:8][CH:9]=2)=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCC1
Reactant: OB(O)c1cccc(N2CCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C(=O)c2c[nH]c3ncc(-c4cccc(N5CCCC5)c4)nc23)CCCCC1
Yield: 62.1 %

Procedure:
A microwave tube was charged with (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone (95 mg, 0.29 mmol), 3-pyrrolidino phenylboronic acid (62 mg, 0.32 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(ll) (19 mg, 0.02 mmol), and freshly grounded K2CO3 (102 mg, 0.74 mmol). Dioxane (3 ml) and water (0.7 ml) were added, and the reaction mixture was microwaved at 150° C. for 30 minutes. The reaction mixture was partitioned between EtOAc/water. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a dark brown solid. The residue was purified by silica gel chromatography using 10-50% EtOAc in hexanes as eluant to provide 70 mg (61%) of (1-methyl-cyclohexyl)-[2-(3-pyrrolidin-1-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone as a yellow solid. MP 243-245.4° C., M+H=389.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:24][O:25][C:26]1(OC)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][O:19][C:26]3([O:25][CH3:24])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: COC1(OC)CCCCC1
Reactant: Cc1cc(C)cc(Sc2c(C(C)C)nc(C)n2COCCO)c1
Product: COC1(OCCOCn2c(C)nc(C(C)C)c2Sc2cc(C)cc(C)c2)CCCCC1
Yield: 62.7 %

Procedure:
The compound 1 (33.4 mg, 0.1 mmol) was converted to the acetal with 1,1-dimethoxycyclohexane (144 mg, 1.00 mmol) in the same manner as the example 1 to give the compound 3 (28 mg, 60 %). Rf 0.57 (Al2O3 60, Type E, 2:1 hexane -EtOAc).
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:19]2[NH:27][C:26]3[CH2:25][CH2:24][NH:23][C:22](=[O:28])[C:21]=3[CH:20]=2)[N:3]=1.[CH3:29][C:30](OC(C)=O)=[O:31].C(Cl)Cl.C([O-])(O)=O.[Na+]>CO.C(Cl)Cl>[C:30]([N:15]1[CH2:16][CH2:17][CH2:18][C@@H:13]([NH:12][C:11]2[C:2]([CH3:1])=[N:3][C:4]3[C:9]([N:10]=2)=[C:8]([C:19]2[NH:27][C:26]4[CH2:25][CH2:24][NH:23][C:22](=[O:28])[C:21]=4[CH:20]=2)[CH:7]=[CH:6][CH:5]=3)[CH2:14]1)(=[O:31])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@@H]1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCC[C@@H](Nc2nc3c(-c4cc5c([nH]4)CCNC5=O)cccc3nc2C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
Prepared according to Example 50, using TEA (39.9 μl, 0.287 mmol), 2-(2-methyl-3-((3R)-3-piperidinylamino)-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (Ex. 75, 90 mg, 0.239 mmol), Ac2O (45.1 μl, 0.478 mmol), and DCM (2.4 mL) and stirring at 25° C. for 1 h. Isolation of the free base from the mixture by addition of saturated aq. NaHCO3 and extraction with 10% MeOH/DCM, followed by drying of the organic extract over Na2SO4, filtration, and concentration under reduced pressure afforded 2-(3-(((3R)-1-acetyl-3-piperidinyl)amino)-2-methyl-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (34 mg, 30%). 1H NMR (DMSO-d6) δ: 7.85-7.91 (m, 1H), 7.77-7.83 (m, 1H), 7.54-7.63 (m, 2H), 7.30-7.40 (m, 2H), 7.05-7.11 (m, 1H), 4.45-4.55 (m, 1H), 4.27-4.39 (m, 1H), 4.13-4.27 (m, 1H), 3.96-4.10 (m, 1H), 3.86-3.95 (m, 1H), 3.76-3.86 (m, 1H), 3.39-3.46 (m, 3H), 2.87-2.97 (m, 1H), 2.07 (s, 3H), 1.59 (s, 3H), 1.10-1.22 (m, 3H). m/z (ESI, +ve) 419.1 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][N:16]=[C:15]2[CH:22]=[CH:23][S:24][C:14]=12.C(N(CC)CC)C>C(O)(C)C>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:13]3[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][N:16]=[C:15]4[CH:22]=[CH:23][S:24][C:14]=34)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: NC1CCC2(CC1)OCCO2
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc2ccsc2c1NC1CCC2(CC1)OCCO2
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 1,4-dioxaspiro[4.5]decan-8-amine (from J&W PharmLab, 0.40 g, 2.5 mmol), 7-chloro-6-nitrothieno[3,2-b]pyridine (0.29 g, 1.4 mmol) and triethylamine (0.38 mL, 2.7 mmol) in isopropyl alcohol (4.4 mL) was stirred at 90° C. for 2 h. The mixture was concentrated to give the desired product to be used in the next step directly. LCMS calculated for C15H18N3O4S (M+H)+: m/z=336.1. Found: 336.0.
Reaction SMILES: [C:1]([CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:12]=1)[C:5](OCC)=[O:6])(=O)[CH3:2].O.[NH2:26][NH2:27]>C(O)C>[CH:20]1([O:19][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=2[O:17][CH3:18])[CH2:10][C:4]2[C:5](=[O:6])[N:26]=[N:27][C:1]=2[CH3:2])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(OC2CCCC2)c1)C(C)=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(CC2=C(C)N=NC2=O)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 65.6 %

Procedure:
To a stirred solution of ethyl 2-acetyl-3-(3-cyclopentyloxy-4-methoxyphenyl)-propanoate (585 mg, 1.74 mmol) in absolute ethanol (10 ml) at 0° C. was added hydrazine monohydrate (87 mg, 1.74 mmol) in one portion. The resulting solution was stirred at 0° C. for 45 minutes and then refluxed at 80° C. for 3 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo and purified by flash chromatography (SiO2 ; methylene chloride/ethanol/ammonia (4:1:0.1)) to afford the title compound as a white solid (343 mg). m.p. 186-187° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)=[O:2].Br[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([F:20])[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([F:20])[CH:14]=1)=[O:2]
Reactant: Nc1ccc(Br)cc1F
Reactant: O=Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccc(-c2ccccc2C=O)cc1F

Procedure:
4-(2′-N,N-Dimethylaminomethylphenyl)-2-fluoroaniline: To a solution of 2-formylphenylboronic acid (5 g, 33 mmol) in THF (80 mL) was added 4-bromo-2-fluoroaniline (4.2 g, 22 mmol) and sodium carbonate (2 M, 80 mL) and then was bubbled with nitrogen for 10 min. After Pd(PPh3)4 (1.54 g, 1.33 mmol) was added, the resulting mixture was refluxed under nitrogen for 4 h. The THF layer was separated and filtered through a pad of silica gel. The pad was washed with THF to give an 80 mL solution of 4(2′-formylphenyl)-2-fluoroaniline in THF. To the filtrate (15 mL from total 80 mL) was added Me2NH.HCl (0.68 g, 8.3 mmol) and the resulting mixture was refluxed for 2 h. The mixture was cooled to rt and MeOH (5 mL) was added followed by NaBH4 (0.32 g, 8.3 mmoL). After being stirred at 50° C. for 1 hour, the mixture was cooled to rt and quenched with 1 N HCl to pH 1. The aqueous layer was separated, neutralized with 50% NaOH to pH 12, and extracted with EtOAc. The EtOAc layer was dried over MgSO4, concentrated, and purified by SiO2 chromatography eluted with EtOAc to give 54a (0.89 g, 88% yield); [M+H]+=245.2; 1H NMR (CDCl3) δ 7.49 (dd, J=8.8 Hz, J=1.8 Hz, 1H), 7.31-7.21 (m, 3H), 7.14 (dd, J=12.1 Hz, J=1.8 Hz, 1H), 6.97 (dd, J=8.1 Hz, J=1.5 Hz, 1H), 6.80 (t, J=8.8 Hz, 1H), 3.76 (bs, 2H), 3.34 (s, 2H), 2.17 (s, 6H); 19F NMR (CDCl3) δ-136.19. This material was converted to the bis-HCl salt by dissolving a sample in a minimum volume of methanol and adding 2.2 equivalents of 1.0 M HCl in diethyl ether followed by removal of the solvent under reduced pressure.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][C@@H:29]1[CH3:34]>>[CH3:34][C@@H:29]1[N:28]([CH3:27])[CH2:33][CH2:32][N:31]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:30]1
Reactant: C[C@H]1CNCCN1C
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCN(C)[C@@H](C)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1,2-dimethylpiperazine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (br. s., 3H) 2.36 (s, 3H) 2.60 (s, 3H) 2.90 (br. s., 1H) 3.04 (br. s., 1H) 3.26 (br. s., 2H) 3.41-3.57 (m, 1H) 3.73 (d, J=17.68 Hz, 1H) 4.29 (br. s., 1H) 7.59 (dd, J=8.08, 1.52 Hz, 1H) 7.66 (s, 1H) 7.72 (d, J=8.08 Hz, 1H) 8.03 (dd, J=8.59, 2.02 Hz, 1H) 8.10 (s, 1H) 8.35 (d, J=7.83 Hz, 1H) 8.51 (d, J=1.52 Hz, 1H) 12.09 (br. s., 1H); ESI-MS m/z [M+H]+ 417.3.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[NH:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:2]1.[Na].Cl.Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C=O)C.C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[NH:14][C:13](=[O:15])[N:12]([CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:11]2=[O:16])=[CH:2]1
Reactant: O=C1NC(=O)C(c2c[nH]c3ccccc23)N1
Reactant: ClCCCN1CCCCC1
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C1NC(c2c[nH]c3ccccc23)C(=O)N1CCCN1CCCCC1
Reaction time: 18 h

Procedure:
5-(Indol-3-yl)hydantoin (8.6 g, 0.04 mole) in 200 ml of DMF was added to a solution of sodium (1.84 g, 0.08 mole) in 150 ml of anhydrous C2H5OH. N-(3-Chloropropyl)piperidine hydrochloride (7.9 g, 0.04 mole) was added and the mixture was heated to reflux with stirring for 18 hours, filtered and concentrated in vacuo to dryness. The concentrate was crystallized from aqueous methanol and twice recrystallized from aqueous DMF, yield 1.7 g, mp 233°-4° C.
Reaction SMILES: C(=N[OH:9])C1C=CC=CC=1.CN(C=O)C.[H-].[Na+].O1CCOCC1.[C:23]([C:25]([C:28]1[C:33]([C:34]#[C:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32][CH:31]=[CH:30][N:29]=1)([CH3:27])[CH3:26])#[N:24]>>[OH:9][C:34]1[C:33]2[CH:32]=[CH:31][CH:30]=[N:29][C:28]=2[C:25]([CH3:27])([CH3:26])[C:23](=[NH:24])[C:35]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: ON=Cc1ccccc1
Reactant: CCOC(=O)C#Cc1cccnc1C(C)(C)C#N
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(O)c2cccnc2C(C)(C)C1=N
Reaction time: 0.5 h

Procedure:
A solution of benzaldehyde oxime (0.6 g, 5 mmol) in dry DMF (10 mL, 129 mmol) was added to a stirred suspension of 60% NaH (0.2 g, 5 mmol) in dry 1,4-dioxane (10 mL, 117 mmol) under a nitrogen atmosphere at room temperature. After 0.5 hours, a solution of the ethyl 3-(2-(2-cyanopropan-2-yl)pyridin-3-yl)propiolate (0.98 g, 4 mmol) in dry DMF (10 mL, 129 mmol) was added, and the solution was stirred for 30 minutes. The solvent was removed under vacuum, and water was added to the residue. The product was extracted with EtOAc. The organic layer was washed with water (3×) and then with saturated NH4Cl and brine (3× each) and dried over MgSO4. The resulting mixture was concentrated in vacuo to give a light-yellow crystalline solid/yellow oil. The yellow residue was washed with hexane providing the product as a yellow solid which was filtered off (0.65 g, 62%). MS (m/z)=261 (M+H)+. Calculated for C14H16N2O3 260.3.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)([CH3:21])[CH3:20]>>[CH:19]([C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[CH:11]=2)=[CH:24][CH:23]=1)([CH3:21])[CH3:20]
Reactant: O=C(O)c1cccc(S(=O)(=O)c2ccccc2)c1
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(NC(=O)c2cccc(S(=O)(=O)c3ccccc3)c2)cc1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(phenylsulfonyl)benzoic acid and 4-isopropylaniline as the starting materials.