Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[Cl:5][C:6]1[C:7](I)=[C:8]([OH:13])[CH:9]=[C:10]([Cl:12])[CH:11]=1>N1C=CC=CC=1>[Cl:5][C:6]1[C:7]2[CH:3]=[C:2]([CH2:1][OH:4])[O:13][C:8]=2[CH:9]=[C:10]([Cl:12])[CH:11]=1
Reactant: Oc1cc(Cl)cc(Cl)c1I
Reactant: C#CCO
Solvent: c1ccncc1
Product: OCc1cc2c(Cl)cc(Cl)cc2o1
Yield: 56.4 %

Procedure:
Propargyl alcohol (0.12 ml; 1.96 mmol) was added drop wise to a refluxing mixture of the product of Step D (0.55 g; 1.96 mmol) and Cu2O (0.2 g; 1.4 mmol) in anhydrous pyridine (4 ml) under N2. After refluxing for 1 h, the solvent was removed under reduced pressure and the residue was treated with EtOAc (15 ml). The insoluble material was filtered off and the filtrate was washed with 10% citric acid, H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2; CH2Cl2) to give the title compound (0.24 g; 56%) as colourless solid. 1H-NMR (CDCl3) 1.91 (tr, 1H, J=6.3 Hz); 4.75 (d, 1H, J=6.3 Hz); 6.72 (s, 1H); 7.23 (s, 1H); 7.37 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[OH:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1>C1COCC1.CCN(CC)CC>[OH:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:2][C:3]#[N:4])[CH2:8][CH2:7]1
Reactant: OC1CCNCC1
Reactant: N#CCBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CCN1CCC(O)CC1
Temperature: 47.5 °C
Yield: 56858.5 %

Procedure:
BrCH2CN (28.55 g, 0.238 mmol) was added dropwise to a solution of 4-hydroxypiperidine (24.98 g, 0.216 mol) and Et3N (33.18 mL, 0.238 mmol) in dry THF (100 mL) under N2, maintaining the temperature between 45-50° C. After addition of BrCH2CN, the solution was refluxed for 30 min., before allowing the solution to cool down to room temperature. The title-compound was afforded as a straw-coloured oil (18.97 g, 63%) after purification by flash chromatography using ether/CH3OH (19:1) as eluent. dH (250 MHz; CDCl3); 1.65 (m, 2H, 1×CH2CH2CH and 1×CHCH2CH2), 1.75 (s, 1H, OH), 1.95 (m, 2H, 1×CH2CH2CH, 1×CHCH2CH2), 2.45 (m, 2H, 1×NCH2CH2 and 1×NCH2CH2), 2.78 (m, 2H, 1×NCH2CH2 and 1×NCH2CH2), 3.55 (s, 2H, NCH2CN) and 3.75 (m, 1H, CH2CHOH); δC (62.9 MHz; CDCl3); 33.96, 46.09, 49.73, 66.58 and 114.71 (CN); IR υmax/cm−1; 3375(broad), 2230, 1420, 1330, 1150 and 1060; FAB MS, m/z(M+H)+ 141.
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[CH:23]=[CH:22][C:12]2[O:13][C:14]3[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][C:15]=3[O:16][C:11]=2[CH:10]=1.N1C=CC=CC=1.[C:30]([OH:33])(=O)[CH3:31].C1C[O:37][CH2:36][CH2:35]1>>[C:36]([NH:8][C:9]1[CH:23]=[CH:22][C:12]2[O:13][C:14]3[C:20]([NH:21][C:30](=[O:33])[CH3:31])=[CH:19][CH:18]=[CH:17][C:15]=3[O:16][C:11]=2[CH:10]=1)(=[O:37])[CH3:35]
Reactant: Nc1ccc2c(c1)Oc1cccc(N)c1O2
Reactant: CC(=O)O
Reactant: C1CCOC1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc2c(c1)Oc1cccc(NC(C)=O)c1O2
Temperature: 25 °C
Yield: 82 %

Procedure:
To a mixture of 900 ml of toluene and 900 ml of THF were added 50.0 g (0.233 mole) of 2,6-diaminodibenzodioxin and 55.3 g (0.699 mole) of pyridine and 59.5 g (0.583 mole) of anhydrous acetic acid was added in drops to the mixture over a period of 10 minutes with stirring at room temperature. After the dropwise addition was over, the mixture was stirred overnight and a precipitate was recovered by filtration. The precipitate was submitted to reslurrying with toluene (250 ml×2) and then dried under reduced pressure to give 57.0 g (0.191 mole) of N,N′-diacetyl-2,6-diaminodibenzodioxin in an 82.0% yield. The product showed a purity of 99.3 area % (HPLC, 254 nm).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:15]=[N:14][CH:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12.[CH3:19][CH:20]([N:22]1[C:26]([C:27]([NH:29][C:30]2[C:31]3[C:35]([CH:36]=[C:37](B4OC(C)(C)CC(C)(C)O4)[CH:38]=2)=[N:34][N:33](C2CCCCO2)[CH:32]=3)=[O:28])=[CH:25][CH:24]=[N:23]1)[CH3:21].O>O1CCOCC1>[CH3:21][CH:20]([N:22]1[C:26]([C:27]([NH:29][C:30]2[CH:38]=[C:37]([C:10]3[CH:15]=[N:14][CH:13]=[C:12]4[NH:16][CH:17]=[CH:18][C:11]=34)[CH:36]=[C:35]3[C:31]=2[CH:32]=[N:33][NH:34]3)=[O:28])=[CH:25][CH:24]=[N:23]1)[CH3:19]
Reactant: CC(C)n1nccc1C(=O)Nc1cc(B2OC(C)(C)CC(C)(C)O2)cc2nn(C3CCCCO3)cc12
Reactant: Brc1cncc2[nH]ccc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1nccc1C(=O)Nc1cc(-c2cncc3[nH]ccc23)cc2[nH]ncc12
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A microwave vial was charged with Solvias catalyst (7 mg), tripotassium phosphate (84 mg) and 4-bromo-1H-pyrrolo[2,3-c]pyridine (from prep such as in US2005/0090529, 29 mg). 1-(1-methylethyl)-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1H-pyrazole-5-carboxamide (65 mg) in 1,4-dioxane (0.5 ml) was added, followed by water (0.1 ml) and the reaction was heated under microwave irradiation for a total of 30 min at 120° C. The reaction was washed through a silica cartridge preconditioned with methanol, with methanol. The solvent was removed under a stream of nitrogen, then washed with DCM and water. The resultant solution was evaporated under a stream of nitrogen. The residue was dissolved in DMSO:methanol (1 ml, 1:1, v/v) and purified by MDAP (method A). Appropriate fractions were dried under a stream of nitrogen. The residue was dissolved in methanol, 2M HCl (aq) (3 drops) was added and the solution was left to stand for 60 min. The solvent was removed under a stream of nitrogen and the residue was dissolved in methanol, washed with methanol through an aminopropyl cartridge preconditioned with methanol and dried under a stream of nitrogen to give title compound, 5 mg.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[NH2:23]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:3]3[C:10]4[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Reactant: CCOC(=O)N1Cc2sc3ncnc(Cl)c3c2C1
Product: CCOC(=O)N1Cc2sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c3c2C1

Procedure:
In analogy to Example 22A, ethyl 4-chloro-5,7-dihydro-6H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidine-6-carboxylate from Example 21A (100 mg, 0.35 mmol) and 3-chloro-4-(pyridin-2-ylmethoxy)aniline from Example 6A (87 mg, 0.37 mmol) were reacted to the title compound to give 158 mg of a crude product (72% purity, 67% yield), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[O:3].[CH3:14][Li]>C(OCC)C>[OH:3][C:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)([CH3:14])[CH3:1]
Reactant: [Li]C
Reactant: CC(=O)c1cccc2ccccc12
Solvent: CCOCC
Product: CC(C)(O)c1cccc2ccccc12

Procedure:
A 10 ml (65.8 mmole) quantity of 1-acetonaphthone was dissolved in 150 ml of diethyl ether in a 500 ml, two neck, round bottom flask equipped with a pressure equalizing dropping finnel and fitted with a rubber septum and a protected reflux condenser. A 138 ml (98 mmole) quantity of 1.4 M methyllithium in ether (Aldrich) was transferred to the fiumel by use of a cannula and nitrogen pressure. This was slowly added to the stirred ketone over a 20 minute period. A light green color indicated an excess of methyllithium. This was refluxed for an additional hour and the reaction was carefully quenched with water. The ether layer was made acidic using HCl, neutralized with NaHCO3, dried using MgSO4, and filtered. After the solvent was removed, the crude product was recrystallized from benzene, filtered and washed with cold pentane to yield white, fibrous crystals (>98%), m.p. 81-86° C. 1H NMR (acetone-d6): (=9.01 (m, 1 H, aromatic), 7.95 (m, 1 H, aromatic), 7.82 (d, J=10.6, 1 H, aromatic), 7.68 (d, J=10.3, 1 H, aromatic), 7.50 (m, 3 H, aromatic), 4.30 (s, 1 H, --OH), 1.84 (s, 6 H, --CH3).
Reaction SMILES: S(Cl)(Cl)=O.CC1C=CC=CC=1OCC(O)=O.CC1C=CC=CC=1OCC(Cl)=O.[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][C:40]=1[O:41][CH3:42])[N:37]=[CH:36][N:35]=[C:34]2[O:43][C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=1.[CH3:51][C:52]1[CH:64]=[CH:63][CH:62]=[CH:61][C:53]=1[O:54][CH2:55][C:56]([N:58]=[C:59]=[S:60])=[O:57]>C1(C)C=CC=CC=1.C(O)C>[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][C:40]=1[O:41][CH3:42])[N:37]=[CH:36][N:35]=[C:34]2[O:43][C:44]1[CH:50]=[CH:49][C:47]([NH:48][C:59]([NH:58][C:56](=[O:57])[CH2:55][O:54][C:53]2[CH:61]=[CH:62][CH:63]=[CH:64][C:52]=2[CH3:51])=[S:60])=[CH:46][CH:45]=1
Reactant: Cc1ccccc1OCC(=O)N=C=S
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: Cc1ccccc1OCC(=O)Cl
Agent: Cc1ccccc1OCC(=O)O
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)COc4ccccc4C)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2-(2-methylphenoxy)acetic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2-(2-methylphenoxy)ethanoyl isothiocyanate was prepared using the resultant 2-(2-methylphenoxy)ethanoyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-(2-methylphenoxy)ethanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (37 mg, yield 44%).
Reaction SMILES: [Li+].[OH-].[CH3:3][C:4]([O:7][C:8]([NH:10][C@@H:11]([CH2:18][CH3:19])/[CH:12]=[CH:13]/[C:14]([O:16]C)=[O:15])=[O:9])([CH3:6])[CH3:5].O>C1COCC1.CO>[CH3:6][C:4]([O:7][C:8]([NH:10][C@@H:11]([CH2:18][CH3:19])/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[O:9])([CH3:3])[CH3:5]
Reactant: CC[C@@H](/C=C/C(=O)OC)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H](/C=C/C(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.7 %

Procedure:
LiOH (2.95 g, 123 mmol) was added to a solution of methyl (2E,4S)-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-hexenoate (6 g, 24.66 mmol) in THF (50 mL), MeOH (10.00 mL), and water (50.0 mL). The reaction was stirred overnight at RT. After 18.5 h, the reaction mixture was concentrated under reduced pressure to remove the THF and MeOH. Water (40 mL) was added, and aqueous mixture was adjusted to pH=3 with 6 M aq. HCl, as measured by pH paper. EtOAc (80 mL) was added, the layers were separated, and the aqueous layer was extracted with EtOAc (2×40 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure, and dried under high vacuum, giving 6.09 g of the title compound. LC-MS m/z 230 (M+H)+, 0.77 min (ret time).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(Cn2cnc3ccccc32)cc1
Temperature: 5 °C

Procedure:
To a flask were added 2 g benzimidazole, 3.5 g potassium carbonate, 20 ml N,N-dimethylformamide and the mixture was stirred under nitrogen. 3.2 g Benzyl chloride were added and the mixture was heated to 5° C. for 16 hrs. The reaction was quenched with 40 ml water and 7 ml 3M hydrochloric acid and cooled to 5 C. The product was filtered and washed with water. The product was recrystallized by dissolving in 10 ml 2-propanol at reflux, hot filtered and 30 ml hexane were added. After cooling to 5 C, the product was filtered, washed with hexane and dried giving 1.6 g.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][N:5]=1.[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([F:21])=[CH:14][C:13]=1F>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:13]2[CH:14]=[C:15]([F:21])[C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=2[F:11])[CH:7]=[CH:6][N:5]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: Oc1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Temperature: 25 °C
Yield: 65.9 %

Procedure:
Anhydrous N,N-dimethylformamide (150 mL) was added to 60% NaH in mineral oil (2.72 g, 67.9 mmol) under an atmosphere of argon. The mixture was cooled in an ice bath and stirred. To this suspension was added, portion-wise, a solution of 2-chloropyridin-4-ol (8 g, 61.8 mmol) in DMF (30.0 mL). The reaction mixture was stirred cold for 5 minutes and the cooling bath was removed. The reaction mixture was warmed to RT and stirred for 20 minutes. 1,2,4-trifluoro-5-nitrobenzene (13.12 g, 74.1 mmol) was added and the reaction mixture heated at 90° C. for 3 hours. The reaction mixture was cooled to RT. The mixture was concentrated to dryness. EtOH (50 mL) and MeOH (20 mL) were added and the sample was stirred with gentle warming and then cooled to RT. The yellow solid was collected by filtration, and rinsed with EtOH (50 mL) and hexanes (20 mL). The solid was dried under vacuum overnight to provide 2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine as a yellow solid (11.68 g, 63% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.48 (dd, J=10.2, 7.0 Hz, 1H), 8.41 (d, J=5.6 Hz, 1H), 7.90 (dd, J=11.6, 6.7 Hz, 1H), 7.41 (d, J=2.1 Hz, 1H), 7.26 (dd, J=5.6, 2.4 Hz, 1H); MS (ESI): m/z 287.0 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[CH3:12][O-].[Na+].[Cl-]>CO.CN(C=O)C>[CH3:12][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: Oc1cccc2cnccc12
Reactant: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cccc2cnccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of 5-hydroxyisoquinoline (10 g, 69 mmol) in MeOH (100 ml) was added a solution of sodium methoxide in methanol (30% by weight, 13.8 ml, 72.4 mmol) followed by phenyltrimethylanmmonium chloride (12.4 g, 72.4 mmol). The reaction mixture was stirred at room temperature for 2 h, after which time it was filtered and the filtrate evaporated under reduced pressure to afford an oil which was dissolved in DMF (50 ml). The reaction mixture was refluxed for 2 h after which time the reaction mixture was evaporated under reduced pressure. The resulting oil was partitioned between CH2Cl2 and 1N aqueous NaOH, the organic layer was washed twice with 1N aqueous NaOH, dried over MgSO4 and evaporated under reduced pressure. The crude product was purified on silica gel eluting with EtOAc/hexane (1/1, v/v) to afford the subtitle compound as a yellow oil (6.11 g, 56%). 1H NMR (CDCl3) δ: 4.05 (3H, s), 7.00 (1H, d), 7.55 (2H, m), 8.02 (1H, d), 8.55 (1H, d), 9.22 (1H, s).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([S:19]([N:22]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23][C:24]([OH:26])=[O:25])(=[O:21])=[O:20])=[CH:16][CH:17]=2)[C:12]([NH:34][C:35]([NH2:37])=[NH:36])=[N:11][CH:10]=1.[H-].[Na+].[C:40](OC(=O)CN(S(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)CC1C=CC=CC=1)([CH3:43])([CH3:42])[CH3:41].O>COCCOC>[C:40]([O:25][C:24](=[O:26])[CH2:23][N:22]([S:19]([C:15]1[CH:14]=[C:13]2[C:18]([C:9]([Cl:8])=[CH:10][N:11]=[C:12]2[NH:34][C:35]([NH2:37])=[NH:36])=[CH:17][CH:16]=1)(=[O:20])=[O:21])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:43])([CH3:42])[CH3:41]
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N(CC(=O)O)Cc3ccccc3)cc12
Reactant: CC(C)(C)OC(=O)CN(Cc1ccccc1)S(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)CN(Cc1ccccc1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 60 °C
Yield: 72.8 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-benzylglycine trifluoroacetate ##STR19## Guanidine hydrochloride (180 mg, 1.88 mmol) was added in one portion to a suspension of NaH (45 mg, 80% dispersion by wt in mineral oil, 1.5 mmol) in DME (11 mL) and the mixture was heated at 60° C. under N2 for 30 min. N-[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]-N-benzylglycine t-butyl ester (225 mg, 0.467 mmol) was added and the mixture heated at 90° C. for 18 h. The cooled mixture was poured into water, extracted with EtOAc (×3) and the combined organic phase was then washed with water, dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880NH3 (97:3:0.3) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-benzylglycine t-butyl ester (172 mg, 0.34 mmol) as a yellow foam.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:39]=[CH:38][C:27]2[N:28]([CH2:34][CH2:35][O:36][CH3:37])[C:29](=[O:33])[CH2:30][CH2:31][CH2:32][C:26]=2[CH:25]=1>>[CH3:37][O:36][CH2:35][CH2:34][N:28]1[C:29](=[O:33])[CH2:30][CH2:31][CH2:32][C:26]2[CH:25]=[C:24]([NH:23][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=4[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=3)[CH:39]=[CH:38][C:27]1=2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Reactant: COCCN1C(=O)CCCc2cc(N)ccc21
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3CCOC)ncc1C(F)(F)F

Procedure:
The title compound was prepared from 2-(2-chloro-5-trifluoromethyl-pyrimidin-4-ylamino)-N-methyl-benzamide and 7-amino-1-(2-methoxyethyl)-1,3,4,5-tetrahydrobenzo[b]azepin-2-one in an analogous manner to Example 195 (microwave: 120° C., 90 minutes) to afford a white solid (29 mg, 47%). Mp: 73-6° C. LCMS (m/e) 529 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 10.90 (s, 1H), 8.44 (d, J=9 Hz, 1H), 8.39 (s, 1H), 7.50-7.40 (m, 4H), 7.24 (m, 1H), 7.15 (m, 2H), 6.20 (br s, 1H), 4.00 (br m, 2H) 3.57 (t, 2H, J=5 Hz), 3.32 (s, 3H), 3.04 (d, J=5 Hz, 3H), 2.67 (br m, 2H), 2.31 (t, J=5 Hz, 2H), 2.13 (br m, 2H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1>CN(C)C=O>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][O:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)=[CH:13][CH:12]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(COc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To prewashed NaH (3X 20 ml hexane) (2.52 g active NaH, 105 mmol) in dimethylformamide (DMF) (50 ml) is added 3-hydroxypyridine (10.0 g, 105 mmol) in DMF (50 ml) with cooling over 0.5 hour. The reaction mixture is stirred at RT for 1 hour and is then cooled to 15°. To this is rapidly added 4-chlorobenzyl chloride (16.25 g, 99.8 mmol) in 5 ml of DMF. The reaction is allowed to warm to RT, and is then poured into ice and extracted with chloroform (3X). The chloroform layers are combined, washed with water and with brine, dried over calcium sulfate and rotoevaporated. The crude product is poured into ice and extracted with ether (3X). The combined ether layers are washed with water and with brine, and dried over calcium sulfate to give 3-(4-chlorobenzyloxy)pyridine.
Reaction SMILES: CC(C)([O-])C.[K+].N[CH:8]=[CH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12].CO[CH:18](OC)[CH2:19][C:20]#[N:21].Cl>C(COC)OC>[F:12][C:11]([F:14])([F:13])[C:10](=[O:15])[CH:9]=[CH:8][CH:18]=[CH:19][C:20]#[N:21]
Reactant: COC(CC#N)OC
Reactant: NC=CC(=O)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: COCCOC
Product: N#CC=CC=CC(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
In a three-necked flask, 61.6 g (0.55 mol) of potassium tert-butoxide were introduced into 250 ml of dimethoxyethane under N2 and the solution was cooled to 0° C. 4-Amino-1,1,1-trifluoro-3-buten-2-one, 69.5 g (0.5 mol), was added dropwise at this temperature in the course of 30 min and then 60.3 g (0.525 mol) of 3,3-dimethoxypropionitrile were added dropwise. The mixture was then stirred at 30° C. for 3-4 h. The reaction mixture was added to ice and acidified to pH 3-4 using HCl. The precipitate was filtered off and washed with water.
Reaction SMILES: [CH3:1][N:2]([CH2:16][CH2:17][OH:18])[C:3](=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH3:19][C:20]([CH3:25])([CH3:24])[C:21](Cl)=[O:22]>>[CH3:1][N:2]([CH2:16][CH2:17][O:18][C:21](=[O:22])[C:20]([CH3:25])([CH3:24])[CH3:19])[C:3](=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCCCCCCCCCCC(=O)N(C)CCO
Product: CCCCCCCCCCCC(=O)N(C)CCOC(=O)C(C)(C)C

Procedure:
N-methyl-N-(trimethylacetoxyethyl)lauramide was prepared by the procedure of example 1 from 26 gms. (0.1 mole) of N-methyl-N-(2-hydroxyethyl)lauramide and 12 gms. (0.1 mole) trimethylacetyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[CH3:14][O:15][C:16](=[O:42])[C:17]([O:20][C:21]1[CH:22]=[C:23]([CH:39]=[CH:40][CH:41]=1)[CH2:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([C:34](O)=[O:35])=[CH:31][CH:32]=2)[C:27]([CH3:37])=[C:26]1[CH3:38])([CH3:19])[CH3:18]>>[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH:13][C:34]([C:30]2[CH:29]=[C:28]3[C:33](=[CH:32][CH:31]=2)[N:25]([CH2:24][C:23]2[CH:22]=[C:21]([CH:41]=[CH:40][CH:39]=2)[O:20][C:17]([CH3:18])([CH3:19])[C:16]([O:15][CH3:14])=[O:42])[C:26]([CH3:38])=[C:27]3[CH3:37])=[O:35])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: COC(=O)C(C)(C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Agent: Cl
Product: COC(=O)C(C)(C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the 1-(3-((1-methoxy-2-methyl-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:17]([C:18]#[N:19])=[CH:16][O:15][CH:14]3[C:20]4[C:24](=[CH:25][CH:26]=[C:13]23)[N:23]=[CH:22][CH:21]=4)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].IC.[C:29](=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:17]([C:18]#[N:19])=[CH:16][O:15][C:14]3[C:20]4[CH:21]=[CH:22][N:23]([CH3:29])[C:24]=4[CH:25]=[CH:26][C:13]2=3)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C2C(C#N)=COC3C4=CC=NC4=CC=C32)cc(Br)c1OC
Agent: [Cs+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1cc(C2C(C#N)=COc3c2ccc2c3ccn2C)cc(Br)c1OC
Temperature: 25 °C
Yield: 96.7 %

Procedure:
A mixture of 4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-indolo[4,5-b]pyran (51 mg, 0.124 mmol), iodomethane (23 μL, 0.370 mmol) and cesium carbonate (120 mg, 0.368 mmol) in acetone (2 mL) was stirred at room temperature in a sealed tube. After stirring at room temperature for 2.5 days, the reaction was diluted with EtOAc (20 mL). The insoluble material was filtered, and washed with EtOAc (30 mL). The EtOAc solution were combined, washed with brine (2×5 mL), dried over MgSO4, and evaporated to yield an off-white solid. The crude product was purified by column chromatography (silica gel, EtOAc:hexanes, 1:1) to yield 51 mg (97%) of an off-white solid. 1H NMR (CDCl3): 7.43 (d, J=0.6 Hz, 1H), 7.07 (d, J=3.3 Hz, 1H), 7.05 (dd, J=0.6, 8.4 Hz, 1H), 6.95 (d, J=2.1 Hz, 1H), 6.76 (d, J=2.4 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 6.58 (dd, J=0.6, 3.3 Hz, 1H), 4.81 (s, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H).