Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[NH:28][CH:29]=[CH:30][N:31]=2)=[CH:23][CH:22]=1)#[N:20]>>[CH2:14]([C@H:6]1[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]2[N:3]=[C:2]([N:28]3[CH:29]=[CH:30][N:31]=[C:27]3[C:24]3[CH:23]=[CH:22][C:21]([C:19]#[N:20])=[CH:26][CH:25]=3)[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7]1=[O:13])[CH3:15]
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C(C)C
Reactant: N#Cc1ccc(-c2ncc[nH]2)cc1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3-c3ccc(C#N)cc3)nc2N1C(C)C

Procedure:
The title compound was prepared similarly to the methods described in Example 26, with Intermediate C instead of Intermediate B and with 2-(4-cyanophenyl)-1H-imidazole instead of 2-phenyl-1H-imidazole. LCMS: 402.2 m/z (M+H)+; ret. Time: 6.26 min (Analytical Method C).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][NH:15][CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[CH:10]=[CH:11][CH:12]=1.Cl[CH2:26][C:27]([NH2:29])=[O:28].C(N(CC)CC)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][N:15]([CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[CH2:26][C:27]([NH2:29])=[O:28])[CH:10]=[CH:11][CH:12]=1
Reactant: NC(=O)CCl
Reactant: Fc1cccc(COc2cccc(CCNCc3ccco3)c2)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)CN(CCc1cccc(OCc2cccc(F)c2)c1)Cc1ccco1
Yield: 99.3 %

Procedure:
A solution of 1.8 g (5.53 mmol) of [2-[3-(3-fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amine, 0.57 g (6.08 mmol) of 2-chloro-acetamide and 0.92 ml (6.62 mmol) of triethylamine in 5 ml of dry dimethylformamide was heated at 120° C. for 2 hours with microwaves. Solvent was removed under vacuum, water was added and the product was extracted with ethyl acetate. The crude reaction mixture was purified by flash chromatography (dichloromethane/methanol 95:5 v:v). 2.1 g (99% yield) of a yellow oil were isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][C@H:19]1[CH2:21][O:20]1.[NH:22]1[CH2:25][CH2:24][CH2:23]1>CN(C=O)C>[N:22]1([CH2:21][C@@H:19]([OH:20])[CH2:18][O:17][C:4]2[CH:5]=[CH:6][C:7]3[C:8]4[N:9]([CH2:14][CH2:15][N:16]=4)[C:10]([NH2:13])=[N:11][C:12]=3[C:3]=2[O:2][CH3:1])[CH2:25][CH2:24][CH2:23]1
Reactant: COc1c(OC[C@H]2CO2)ccc2c1N=C(N)N1CCN=C21
Reactant: C1CNC1
Solvent: CN(C)C=O
Product: COc1c(OC[C@H](O)CN2CCC2)ccc2c1N=C(N)N1CCN=C21
Yield: 114.9 %

Procedure:
A solution of 7-Methoxy-8-[(2R)-oxiran-2-ylmethoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Intermediate F, 0.35 g, 1.21 mmol) and azetidine (0.82 mL, 12.1 mmol, 10 equiv.) in DMF (10 mL) was heated in a microwave reactor for 45 min. at 140° C. The resulting mixture was concentrated under reduced pressure and purified using MPLC to give N-(8-{[(2R)-3-(azetidin-1-yl)-2-hydroxypropyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)amine (0.48 g, 115%): HPLC ret. time 0.67 min.; mass spectrum m/z 346 ((M+1)+, 100%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15]>>[OH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15]
Reactant: O=C1CCCCN1
Reactant: OCCCCCCCl
Product: O=C1CCCCN1CCCCCCO

Procedure:
In like manner, 6-chloro-1-hexanol is reacted with 2-piperidone to produce 1-(6-hydroxy-1-hexyl)-2-piperidone. The latter is reacted with methanesulfonyl chloride in methylene chloride in the presence of one equivalent of triethylamine to yield 1-(6-methanesulfonyloxy-1-hexyl)-2-piperidone.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](Cl)=[N:19][OH:20])=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCCC1>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=3)[O:20][N:19]=2)=[CH:15][CH:16]=1
Reactant: ON=C(Cl)Cc1ccc(Br)cc1
Reactant: C#Cc1cccnc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(Br)cc2)no1
Temperature: 25 °C
Reaction time: 15 h
Yield: 23.6 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 3-ethynyl-pyridin-2-ylamine (50 mg, 0.423 mmol) described in Manufacturing Example 1-2-3 and 4-bromophenyl acetohydroximoyl chloride (168 mg, 0.677 mmol) described in Manufacturing Example 207-1-3 was added triethylamine (147 μL, 1.06 mmol), which was stirred for 15 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:4 to 1:2) to obtain the title compound (33 mg, 24%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-])[CH:6]=[CH:7][CH:8]=1.COS(OC)(=O)=O.[C-:27]#[N:28].[Na+]>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]2[N:12]=[C:13]([C:27]#[N:28])[CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: [C-]#N
Reactant: [O-][n+]1ccccc1C=Cc1cccc(C(F)(F)F)c1
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Product: N#Cc1cccc(C=Cc2cccc(C(F)(F)F)c2)n1

Procedure:
Following the general method described in example 2b, 2-[2-(3-trifluoromethyl-phenyl)-vinyl]-pyridine 1-oxide was reacted first with dimethylsulfate and then with NaCN. After extraction and chromatography (SiO2 with CH2Cl2/MeOH=97/3) the title compound was obtained as a yellow oil and directly used in the next step.
Reaction SMILES: [Br:1]CCCC1CCCCN1C(OCC1C=CC=CC=1)=O.O[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:29][CH2:28]1>>[Br:1][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:29][CH2:28]1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCCBr
Reactant: O=C(OCc1ccccc1)N1CCC(CCCCCO)CC1
Product: O=C(OCc1ccccc1)N1CCC(CCCCCBr)CC1

Procedure:
Prepared similarly to Intermediate 10 from phenylmethyl 4-(5-hydroxypentyl)-1-piperidinecarboxylate (for a preparation, see Chem. Pharm. Bull., 1986, 34(9), 3747-3761)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:10](=[O:23])[N:11]([CH3:22])[C:12]3([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]3)[C:13]=2[OH:14])=[C:4]([Cl:24])[CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(COC)OC.O>[Cl:24][C:4]1[CH:3]=[C:2]([C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9]1[C:10](=[O:23])[N:11]([CH3:22])[C:12]2([CH2:19][CH2:18][N:17]([O:20][CH3:21])[CH2:16][CH2:15]2)[C:13]=1[OH:14]
Reactant: CON1CCC2(CC1)C(O)=C(c1c(C)cc(Br)cc1Cl)C(=O)N2C
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CON1CCC2(CC1)C(O)=C(c1c(C)cc(-c3ccc(Cl)cc3)cc1Cl)C(=O)N2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-(4-bromo-2-chloro-6-methyl-phenyl)-4-hydroxy-8-methoxy-1-methyl-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound P2.34) (150 mg, 0.361 mmol) in dimethoxyethane (10 ml) under argon atmosphere was added tetrakis(triphenyl-phosphine)palladium(0) (25 mg, 0.022 mmol) and the mixture stirred at room temperature for 15 minutes. After further addition of water (2 ml), 4-chlorophenylboronic acid (68 mg, 0.435 mmol) and sodium carbonate (153 mg, 1.444 mmol), the mixture was heated at 80° C. for 10 hours. The reaction mixture was acidified at room temperature to pH 4 with 1N hydrochloric acid and extracted with ethyl acetate (4×15 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with diethyl ether, stirred at room temperature, filtered and dried. Yield: 114 mg of 3-(3,4′-dichloro-5-methyl-biphenyl-4-yl)-4-hydroxy-8-methoxy-1-methyl-1,8-diaza-spiro[4.5]dec-3-en-2-one as a pale brown solid, mp 236° C. (dec).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:7]([CH3:9])([CH3:8])[O:6][C:5](OC2C=CC([N+]([O-])=O)=CC=2)=[N:4][S:3]1(=[O:21])=[O:20].[NH2:23][C@H:24]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])[CH2:25][C:26]([O:28][CH3:29])=[O:27]>ClCCl.C(N(CC)C(C)C)(C)C>[CH3:29][O:28][C:26](=[O:27])[CH2:25][C@@H:24]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])[NH:23][C:5]1[O:6][C:7]([CH3:8])([CH3:9])[C:2]([CH3:1])([CH3:22])[S:3](=[O:20])(=[O:21])[N:4]=1
Reactant: CC1(C)OC(Oc2ccc([N+](=O)[O-])cc2)=NS(=O)(=O)C1(C)C
Reactant: COC(=O)C[C@H](N)c1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@H](NC1=NS(=O)(=O)C(C)(C)C(C)(C)O1)c1ccccc1Cl
Yield: 77.9 %

Procedure:
200 mg of 5,5,6,6-tetramethyl-2-(4-nitrophenoxy)-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 130 mg of methyl(S)-3-amino-3-(2-chlorophenyl)propionate were dissolved in 5 ml of dichloromethane and 0.52 ml of N,N-diisopropylethylamine, and the mixture was stirred at room temperature for 16 hours. Subsequently, the reaction solution was diluted with 20 ml of dichloromethane and washed repeatedly with 20 ml of 25% aqueous ammonia solution, until the organic phase was colorless. The organic phase was dried over Na2SO4 and concentrated by rotary evaporation. This gave the product (191 mg) with a molecular weight of 402.9 g/mol (C17H23ClN2O5S); MS (ESI): m/e=403 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=1
Reactant: COC(=O)COc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)COc1ccc(N)cc1
Yield: 97.6 %

Procedure:
A solution of 30.8 g of methyl 4-nitrophenoxyacetate [prepared as described in step (a) above] in 500 ml of methanol was shaken in an atmosphere of hydrogen and in the presence of 5.0 g of 10% w/w palladium-on-charcoal for 6 hours. At the end of this time, the reaction mixture was filtered and the filtrate was concentrated by evaporation under reduced pressure, to give 25.8 g of the title compound having an Rf value=0.79 (on thin layer chromatography on silica gel; developing solvent: ethyl acetate).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][C:9]([C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:14])=[C:10]([CH3:12])[N:11]=2)[C:3]1=[O:24].C(=O)([O-])[O-].[K+].[K+].[CH:31]1([CH2:34][CH2:35][NH2:36])[CH2:33][CH2:32]1>O1CCCC1.O>[CH:31]1([CH2:34][CH2:35][NH:36][CH:2]2[CH2:6][CH2:5][N:4]([C:7]3[S:8][C:9]([C:13]([NH:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)=[O:14])=[C:10]([CH3:12])[N:11]=3)[C:3]2=[O:24])[CH2:33][CH2:32]1
Reactant: NCCC1CC1
Reactant: Cc1nc(N2CCC(Br)C2=O)sc1C(=O)NCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(N2CCC(NCCC3CC3)C2=O)sc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 60 %

Procedure:
To a solution of 2-(3-bromo-2-oxopyrrolidin-1-yl)-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide (0.050 g, 0.12 mmol) in a mixture of tetrahydrofuran and water (1/0.1, v/v) was added potassium carbonate (0.034 g, 0.24 mmol) and 2-cyclopropylethanamine (0.012 g, 0.15 mmol). The reaction mixture was stirred at ambient temperature for 17 hours and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexanes (3/1)) to afford the title compound as a white solid (0.030 g, 60%): mp 151-152° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.32-7.22 (m, 2H), 7.05-6.96 (m, 2H), 6.01 (t, J=5.6 Hz, 1H), 4.51 (d, J=5.6 Hz, 2H), 4.27-4.17 (m, 1H), 3.93-3.81 (m, 1H), 3.76-3.66 (m, 1H), 2.88-2.67 (m, 2H), 2.61 (s, 3H), 2.58-2.44 (m, 1H), 2.10-1.91 (m, 1H), 1.52-1.29 (m, 2H), 0.75-0.59 (m, 1H), 0.49-0.37 (m, 2H), 0.08-0.01 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 173.6, 162.3, 162.2, 155.2, 152.9, 133.7, 129.6, 118.6, 115.6, 59.5, 47.9, 44.9, 43.4, 35.0, 26.9, 17.3, 8.8, 4.4, 4.2; MS (ES+) m/z 417.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7]O.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:15][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(CCO)cc1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCBr)cc1OC

Procedure:
Part A. A solution of 3,4-dimethoxyphenethyl alcohol (7.30 g, 40.1 mmol) and carbon tetrabromide (17.3 g, 52.1 mmol) in methylene chloride (100 mL)was cooled to 0° C., and a solution of triphenylphosphine (13.7 g, 52.1 mmol) in methylene chloride (50 mL) was added dropwise with stirring.After 20 hours, the reaction mixture was evaporated, and separated by flashchromatography (1:9 ethyl acetate-hexane) to afford the product, 1-(2-bromoethyl)-3,4-dimethoxybenzene, as a waxy solid, mp 72°-73° C. (9.48 g, 38.7 mmol, 96%). 1H NMR (CDCl3): δ 6.82 (1H, d, J=8.1 Hz); 6.75 (1H, dd, J=8.1, 1.8 Hz); 6.73 (1H, d, J=1.8 Hz); 3.88 (3H, s); 3.87 (3H, s); 3.55 (2H, t, J=7.7 Hz); 3.11 (2H, t, J=7.7 Hz). Mass spectrum (NH3 -CI/DDIP): m/z 264 (93%); 262 (100%); 245 (9%); 165 (6%).
Reaction SMILES: [OH:1][C:2]1[C:3]([NH:12][C:13](=[O:15])[CH3:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.I[CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:17]([O:1][C:2]1[C:3]([NH:12][C:13](=[O:15])[CH3:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:18][CH3:19]
Reactant: CCCI
Reactant: CC(=O)Nc1cc2ccccc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1cc2ccccc2cc1NC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
N-(3-Hydroxynaphthalen-2-yl)acetamide (4.87 g, 24.2 mmol) was suspended in acetonitrile (50 ml). A 1-iodopropane (4.52 g, 26.6 mmol) acetonitrile solution (40 ml) and potassium carbonate (4.35 g, 31.5 mmol) were added thereto, and the resulting mixture was stirred for 3 hours while heating under reflux. The mixture was then cooled to room temperature and concentrated to dryness under reduced pressure. Water was added to the residue, followed by extraction using dichloromethane. The thus-obtained organic layer was concentrated to dryness under reduced pressure, and the residue was then purified using silica gel column chromatography (dichloromethane:ethyl acetate=20:1). The purified product was concentrated to dryness under reduced pressure, giving a white powder of N-(3-propoxynaphthalen-2-yl)acetamide (5.64 g, yield: 96%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:48])[CH2:30][CH2:31][NH:32][C:33]([CH2:35][N:36]([S:44]([CH3:47])(=[O:46])=[O:45])[C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1)=[O:34]>>[CH3:28][N:29]([CH3:48])[CH2:30][CH2:31][NH:32][C:33]([CH2:35][N:36]([C:37]1[CH:42]=[CH:41][C:40]([NH:43]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:39][CH:38]=1)[S:44]([CH3:47])(=[O:46])=[O:45])=[O:34]
Reactant: CN(C)CCNC(=O)CN(c1ccc(N)cc1)S(C)(=O)=O
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(N(CC(=O)NCCN(C)C)S(C)(=O)=O)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and N-[(2-dimethylamino-ethylamino)-carbonylmethyl]-N-methylsulphonyl-p-phenylenediamine
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[O:23]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: BrCCCCCCOc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCOc2ccccc2)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-phenoxyhexyl bromide (1.56 g) were reacted and treated in the same manner as in Example 168 to give 0.78 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-phenoxyhexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: Br[C:2]1[C:3]([C:12]#[N:13])=[N:4][N:5]([CH2:8][CH2:9][CH2:10][CH3:11])[C:6]=1[CH3:7].Cl.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[C:3]([C:12]#[N:13])=[N:4][N:5]([CH2:8][CH2:9][CH2:10][CH3:11])[C:6]=1[CH3:7]
Reactant: Nc1ccccc1B(O)O
Reactant: CCCCn1nc(C#N)c(Br)c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCCn1nc(C#N)c(-c2ccccc2N)c1C
Yield: 124.6 %

Procedure:
A modification of the method described in Part G of Examples 1-4 was used to couple 4-bromo-1-butyl-5-methyl-1H-pyrazole-3-carbonitrile (2.42 g, 10.0 mmol) and 2-aminophenylboronic acid hydrochloride (2.43 g, 14.0 mmol). Palladium (II) acetate was added as a 5 mg/mL solution in toluene (1.3 mL). The reaction was heated under nitrogen for 17 hours and combined with the product mixture from another run before being subjected to the work-up procedure. The crude product was purified by chromatography on a HORIZON HPFC system (40+M cartridge, eluting with chloroform:CMA in a gradient from 100:0 to 80:20) to provide 3.17 g of 4-(2-aminophenyl)-1-butyl-5-methyl-1H-pyrazole-3-carbonitrile as an orange oil. A small amount (0.21 g) of 2-butyl-1-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine was also obtained as a beige powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]([C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:24]=1[OH:25])[C:19](Cl)=[O:20])([CH3:15])([CH3:14])[CH3:13]>COCCOC>[C:26]([C:23]1[CH:22]=[C:18]([CH:17]=[C:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:24]=1[OH:25])[C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)=[O:20])([CH3:29])([CH3:28])[CH3:27]
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Solvent: COCCOC
Product: CC(C)(C)c1cc(C(=O)Nc2ccc(CC(=O)O)cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 11.6 %

Procedure:
A suspension of 9.2g (0.061 mole) of p-aminophenylacetic acid in 150 ml of 1,2-dimethoxyethane was added to a suspension of 8.0g (0.0298 mole) of 3,5-di-t-butyl-4-hydroxybenzoyl chloride in 100 ml of 1,2-dimethoxyethane, and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was then filtered. The filtrate was thereafter diluted with water and chilled. The resulting precipitate was collected and recrystallized from a mixture of ethanol and water to give 1.32 g of yellow crystalline 4-(3,5-di-t-butyl-4-hydroxybenzamido)phenylacetic acid, m.p. 253°-254° C. Analysis: Calculated for C22H29NO4 : %C, 72.0; %H, 7.6; %N, 3.6; Found: %C, 72.0; %H, 7.7; %N, 3.4.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[C:5]=2[CH:4]=[N:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][NH:6][C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2c1CCCN2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1ncc2c1CCCN2
Reaction time: 18 h
Yield: 69.1 %

Procedure:
To a stirred solution of tert-butyl 1-methyl-6,7-dihydro-1H-pyrazolo[4,3-b]pyridine-4(5H)-carboxylate (55 mg, 232 μmol) in CH2Cl2 (4 mL) was added TFA (740 mg, 500 μL, 6.49 mmol). After 18 h, the reaction mixture was concentrated in vacuo and the residue obtained purified by chromatography (40 g column, 50 m silica-gel from Analogix, 0 to 5% 9:1 methanol:ammonium hydroxide in CH2Cl2, 20 min) to give 1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (22 mg, 69%). 1H NMR (CHLOROFORM-d) δ: 7.05 (s, 1H), 3.70 (s, 3H), 3.08-3.21 (m, 2H), 2.88 (br. s., 1H), 2.64 (t, J=6.4 Hz, 2H), 1.84-2.01 (m, 2H). MS (EI/CI) m/z: 138.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:12]([OH:18])[C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].B(O)(O)[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>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.O.O1CCOCC1>[OH:18][CH:12]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)[C:10]1[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=[C:2]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:11]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(Br)cc(C(O)c2nccs2)c1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccc(C)cc2)cc(C(O)c2nccs2)c1
Temperature: 95 °C

Procedure:
To a mixture of methyl 3-bromo-5-(hydroxy(thiazol-2-yl)methyl)benzoate (320 mg, 0.98 mmol), p-tolylboronic acid (0.16 g, 1.2 mmol), potassium carbonate (0.20 g, 1.5 mmol), 1,4-dioxane (5 mL), and water (0.5 mL, 0.03 mol) under argon was added tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.052 mmol). The reaction mixture was heated at 95° C. for 8 h. After cooling, the mixture was treated with water (15 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were dried (MgSO4) and concentrated. The residue was purified by flash chromatography to afford the title compound.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13]([C:16]3[Se:17][CH:18]=[CH:19][CH:20]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Li][CH2:22]CCC.CI.[Cl-].[NH4+].N>C(OCC)C>[CH3:22][C:18]1[Se:17][C:16]([CH:13]2[CH2:14][CH2:15][CH:10]([CH:7]3[CH2:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:8]3)[CH2:11][CH2:12]2)=[CH:20][CH:19]=1
Reactant: [Li]CCCC
Reactant: CCCC1CCC(C2CCC(c3ccc[se]3)CC2)CC1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CCOCC
Product: CCCC1CCC(C2CCC(c3ccc(C)[se]3)CC2)CC1
Temperature: -60 °C
Reaction time: 8.5 h

Procedure:
2.0 g (5.9 mmol) of 2-(4′-propylbicyclohexyl-4-yl)selenophene are initially introduced in 20 ml of diethyl ether, and 5.0 ml (8.0 mmol, 15% soln. in hexane) of n-BuLi are metered in rapidly. The mixture is heated under reflux for 25 min and subsequently cooled to −60° C. 1.5 ml (24.1 mmol) of methyl iodide are added, and the batch is stirred for 8.5 h with slow thawing to RT. Sat. ammonium chloride soln. and conc. ammonia soln. are added successively, and the mixture is stirred vigorously for a few minutes. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with water, 2 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography (SiO2, n-heptane n-heptane:EtOAc=95:5). The further purification is carried out by recrystallisation from IPA/n-heptane (10:1) and from acetone. 2-Methyl-5-(4′-propylbicyclohexyl-4-yl)selenophene is obtained as a colourless solid (m.p. 26° C.).