Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH2:27][CH2:28][CH2:29]Cl)[O:24][CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][O:20]2)=[CH:15][CH:14]=1.O>CN(C)C=O>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([CH2:27][CH2:28][CH2:29][O:3][C:4]3[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=3)[C:7]#[N:8])[O:20][CH2:21][C:22]([CH3:25])([CH3:26])[CH2:23][O:24]2)=[CH:17][CH:18]=1
Reactant: N#Cc1cccc(O)c1
Reactant: CC1(C)COC(CCCCl)(c2ccc(Br)cc2)OC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)COC(CCCOc2cccc(C#N)c2)(c2ccc(Br)cc2)OC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
236 mg (5.9 mmol) of sodium hydride (oily, 60%) was stirred in dimethylformamide. 691 mg (5.8 mmol) of 3-hydroxybenzonitrile was added thereto under cooling with ice. After stirring at room temperature for 30 minutes, a solution of 2 g (5.75 mmol) of 2-(4-bromophenyl)-2-(3-chloropropyl)-5,5-dimethyl-1,3-dioxane in dimethylformamide was added to the reaction mixture, and they were stirred at 100° C. overnight. Water was added to the mixture. After the extraction with ethyl acetate, the organic layer was washed with 1 N aqueous sodium hydroxide solution and saturated aqueous common salt solution and dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the crude title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9]([Cl:10])=[C:8]([C:11]#[N:12])[CH:7]=[N:6][N:5]2[CH:13]=1.[OH:14]S(O)(=O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([Cl:10])=[C:8]([C:11]([NH2:12])=[O:14])[CH:7]=[N:6][N:5]2[CH:13]=1
Reactant: N#Cc1cnn2cc(Br)cc2c1Cl
Reactant: O=S(=O)(O)O
Product: NC(=O)c1cnn2cc(Br)cc2c1Cl
Temperature: 55 °C
Yield: 89 %

Procedure:
To a 50 mL round bottom flask was added 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carbonitrile (12 g, 0.046 mol) and concentrated H2SO4 (60 mL). The reaction mixture was heated at 55° C. for 2 hours then cooled to room temperature and slowly diluted with ice water to precipitate the product which was collected by vacuum filtration, rinsed with water and dried to yield 11.2 g (89%) of the title compound as a yellow solid. HPLC (condition P): retention time=7.780 min. LCMS (condition C): m/z 274.0, 276.0−ve. 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.32 (2H, s), 8.05 (1H, s), 7.90 (1H, s), 7.01 (1H, s).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:9][CH:10]([O:25][CH2:26][CH3:27])[CH2:11][O:12][C:13]1[C:22]([CH3:23])=[CH:21][C:16]([C:17](OC)=[O:18])=[C:15]([CH3:24])[CH:14]=1)[CH3:8].C(O)C>C1COCC1>[CH2:26]([O:25][CH:10]([O:9][CH2:7][CH3:8])[CH2:11][O:12][C:13]1[C:22]([CH3:23])=[CH:21][C:16]([CH2:17][OH:18])=[C:15]([CH3:24])[CH:14]=1)[CH3:27]
Reactant: CCOC(COc1cc(C)c(C(=O)OC)cc1C)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(COc1cc(C)c(CO)cc1C)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium aluminium hydride solution (1M in THF, 1.17 mL) was added dropwise to a solution of methyl 4-(2,2-diethoxyethoxy)-2,5-dimethylbenzoate (example 18, step c) (0.231 g) in THF (20 mL) at 0° C. The resulting mixture was allowed to warm to RT and stirred for 1 h. Ethanol (0.5 mL) was cautiously added and the reaction concentrated. The residue was partitioned between 1M NaOH (50 mL) and ethyl acetate (100 mL). The aqueous was separated and extracted with ethyl acetate (2×50 mL). The combined organics were washed with brine (50 mL), dried over magnesium sulphate, filtered and evaporated to give the subtitled compound as a clear oil. Yield 0.20 g.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[N+:28]([C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)([O-:30])=[O:29]>>[S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[C:22]([O:24][C:34]3[CH:35]=[CH:36][C:31]([N+:28]([O-:30])=[O:29])=[CH:32][CH:33]=3)=[O:23])=[CH:18][CH:19]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCOC(Cc1ccc(OCCN2CCSc3ccccc32)cc1)C(=O)O
Product: CCOC(Cc1ccc(OCCN2CCSc3ccccc32)cc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Yield: 38 %

Procedure:
The title compound (0.15 g, 38%) was prepared as a yellow liquid from 3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.3 g, 0.77 mmol) obtained in example 29 and 4-nitrophenol by an analogous procedure to that described in example 32.
Reaction SMILES: [C@@H:1]12[CH2:10][CH2:9][CH2:8][NH:7][C@H:6]1[CH2:5][CH2:4][CH2:3][NH:2]2.[CH2:11]=O>[Pd]>[CH3:11][N:2]1[CH2:3][CH2:4][CH2:5][C@H:6]2[C@H:1]1[CH2:10][CH2:9][CH2:8][NH:7]2
Reactant: C=O
Reactant: C1CN[C@@H]2CCCN[C@H]2C1
Agent: [Pd]
Product: CN1CCC[C@@H]2NCCC[C@H]21
Reaction time: 10 h

Procedure:
A mixture of trans-2,7-diazabicyclo[4.4.0]decane (1.4 g, 10 mmoles), 37% aqueous formaldehyde solution (0.6 ml, 8 mmoles) and 0.5 g of palladium on charcoal (10%) was hydrogenated for 10 hours at 60° C. under a pressure of 3 to 4 bar. Hydrogenation under the conditions given above was continued after adding a further 0.3 ml of the 37% aqueous formaldehyde solution, the reaction mixture was then concentrated and digested with petrolether. The petrolether solution was concentrated under reduced pressure and the oily residue (1.2 g) was used for further reactions without further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=O)[CH2:12][C:13]#[N:14].[CH2:16]([NH:23][NH2:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]1[C:13]([NH2:14])=[CH:12][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[N:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NNCc1ccccc1
Reactant: N#CCC(=O)c1ccc2ccccc2c1
Product: Nc1cc(-c2ccc3ccccc3c2)nn1Cc1ccccc1

Procedure:
900 mg of 2-benzyl-5-(2-naphthyl)-2H-pyrazol-3-ylamine obtained from 3-(naphthalen-2-yl)-3-oxopropionitrile and benzyl hydrazine in the similar method as described in Production example 30 was subjected to the similar reaction as described in Production example 31, to afford 770 mg of the title compound as a pale yellow powder.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)([O:12][CH2:13][CH3:14])[PH2:10]=[O:11])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].O.O.Cl[Sn]Cl>CCO>[CH2:1]([O:3][P:4]([C:9]([C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=1)([O:12][CH2:13][CH3:14])[PH2:10]=[O:11])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOC([PH2]=O)(c1ccc([N+](=O)[O-])cc1)P(=O)(OCC)OCC
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CCOC([PH2]=O)(c1ccc(N)cc1)P(=O)(OCC)OCC
Temperature: 70 °C
Reaction time: 0.73 h
Yield: 76.2 %

Procedure:
A mixture of [(4-nitro-phenyl)-ethoxy-phosphinoylmethyl]-phosphonic acid diethyl ester (940 mg, 2.57 mmol) and SnCl2.2H2O (2.9 g, 12.9 mmol) in EtOH (˜10 mL) was stirred at 70° C. for 44 min and then concentrated at ambient temperature. The residue was taken up in CH2Cl2 and washed with half saturated aq NaHCO3 (40 mL), H2O (40 mL) and brine (40 mL). The aqueous washes were reextracted once with CH2Cl2, and the combined extracts were dried over K2CO3 and concentrated. The crude material was purified by flash chromatography on silica gel. Elution with 20:1 CHCl3—MeOH followed by 15:1 CHCl3—MeOH afforded 657 mg of product.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[CH2:15]([O:17][C:18](=[C:27]=[O:28])[CH2:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:16].C(N(CC)CC)C>O1CCCC1>[C:21]1([N:20]([CH2:19][C:18](=[C:27]=[O:28])[O:17][CH2:15][CH3:16])[C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([NH:2][CH3:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=C=O)CNc1ccccc1
Reactant: CNc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=C=O)CN(C(=O)c1ccc(NC)c([N+](=O)[O-])c1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 24.7 g (0.115 mol) of 4-methylamino-3-nitro-benzoic acid chloride and 22.3 g (0.115 mol) of N-(2-ethoxy-carbonylethyl)-aniline in 300 ml of tetrahydrofuran, 13.1 g (0.13 mol) of triethylamine were added dropwise in 15 minutes, with stirring, at room temperature. After 2 hours stirring the solvent was distilled off in a water-jet vacuum and the residue was mixed with 700 ml of water with stirring. The mixture was extracted 3 times with 200 ml of dichloromethane, the organic extract was washed twice with 200 ml of 2N hydrochloric acid and twice with 300 ml of water and dried over sodium sulphate. The solvent was then distilled off and the oily product thus obtained was purified by column chromatography (1 kg silica gel; eluant: petroleum ether/ethyl acetate=2:1). Yield: 35.0 g (82% of theory), Rf value: 0.28 (silica gel; dichloromethane/ethanol=50:1)
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[C:47]1([CH2:53][CH2:54][OH:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[Cl:17][C:18]1[C:19]([O:55][CH2:54][CH2:53][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCCc1ccccc1
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCCc2ccccc2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with 2-phenylethanol, the title compound was obtained as a colorless solid (0.06 g, 15%): 1H NMR (300 MHz, DMSO-d6) δ 11.76 (s, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.37-7.21 (m, 6H), 4.36 (t, J=6.8 Hz, 2H), 3.09 (t, J=6.8 Hz, 2H), 2.87 (s, 6H); MS (ES−) m/z 399.1, 401.1 (M−1).
Reaction SMILES: FC(F)(F)C(O)=O.[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)=[N:15][CH:16]=1)([O-:10])=[O:9]>ClCCl>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:15][CH:16]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(OC2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (5 eq) was added to a solution of tert-butyl 4-(5-nitropyridin-2-yloxy)piperidine-1-carboxylate (1 eq) in dichloromethane, stirring at room temperature for 1 hour. The solvent was then evaporated, the residue brought to pH=10 with sat. aq. Na2CO3 solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and evaporated to afford the product as a light yellow crystalline solid. LC/MS (m/z): 224.3 (MH+), Rt 1.64 minutes
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([OH:24])=O)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[NH2:25][CH2:26][C:27]1([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1>>[F:1][C:2]1[C:3]([C:22]([NH:25][CH2:26][C:27]2([C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:31][CH2:32]2)=[O:24])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2cccnc2)CC1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5cccnc5)CCN(C(=O)OC(C)(C)C)CC4)c3F)s2)c1

Procedure:
Following the amide bond forming procedure given in example 37, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (intermediate B in example 1) and tert-butyl 4-(aminomethyl)-4-(pyridin-3-yl)piperidine-1-carboxylate (amine intermediate “M”) were reacted to give the title compound. LC/MS (M+H)+: 636. Ret. time: 1.53 min. (Condition G); analytical HPLC Ret. time: 6.11 min (Condition H).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]([N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH2:39][CH2:40][OH:41])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O[C:43]1[C:44]([I:53])=[N:45][CH:46]=[C:47]([CH:52]=1)[C:48]([O:50][CH3:51])=[O:49].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>O>[I:53][C:44]1[C:43]([O:41][CH2:40][CH2:39][C:35]2[N:34]([C:15]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:38]=[CH:37][N:36]=2)=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:46][N:45]=1
Reactant: COC(=O)c1cnc(I)c(O)c1
Reactant: OCCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cnc(I)c(OCCc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reaction time: 3 h
Yield: 43.6 %

Procedure:
Diisopropyl azodicarboxylate (1160 uL, 5.90 mmol) was added dropwise to a mixture of 2-(1-trityl-1H-imidazol-2-yl)ethanol (1900 mg, 5.4 mmol), methyl 5-hydroxy-6-iodonicotinate (1570 mg, 5.63 mmol) and Triphenylphosphine (1550 mg, 5.90 mmol) in Tetrahydrofuran (45.0 mL, 555 mmol) at 00 C. After stirring for 3 hours the mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over MgSO4 and concentrated in vacuum. The residue was purified on 40 g silica column eluting with 50% ethyl acetate in DCM to give 1.45 g (44%) of methyl 6-iodo-5-(2-(1-trityl-1H-imidazol-2-yl)ethoxy)nicotinate. MS (ESI+): 616.0. 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J=1.9, 1H), 7.40-7.28 (m, 10H), 7.20-7.16 (m, 6H), 6.99 (d, J=1.5, 1H), 6.81 (d, J=1.5, 1H), 3.98-3.91 (m, 5H), 2.46 (t, J=7.3, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[N:9]=2)=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[Br:17][C:11]1[CH:12]=[CH:13][C:8]([NH:7][CH2:6][C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:9][C:10]=1[F:14]
Reactant: Fc1cccc(NCc2ccc(Cl)cc2)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: Fc1nc(NCc2ccc(Cl)cc2)ccc1Br
Reaction time: 2 h

Procedure:
To (4-chloro-benzyl)-(6-fluoro-pyridin-2-yl)-amine (536, 1.03 g, 4.35 mmol) in acetonitrile (30.0 mL), under an atmosphere of nitrogen, N-bromosuccinimide (0.820 g, 4.61 mol) was added slowly. After 2 hours, the reaction was poured into a solution of sodium thiosulfate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and crystallized with ethyl acetate and hexane to give a white solid (537, 1.10 g, 80.1%).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:16][C:17]1[C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:20][S:19][CH:18]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH2:33]([Sn:37](Cl)([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH3:36]>C1COCC1>[CH2:42]([Sn:37]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:38][CH2:39][CH2:40][CH3:41])[C:18]1[S:19][CH:20]=[C:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:17]=1[O:16][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCCCCCOc1cscc1OCCCCCCCCCC
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1csc([Sn](CCCC)(CCCC)CCCC)c1OCCCCCCCCCC
Temperature: -40 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
n-Butyllithium (1.8 mL, 4.5 mmol, 2.5 M solution in hexane) was added dropwise at -78° C. to a solution of 3,4-didecyloxythiophene (1.86 g, 4.69 mmol) in anhydrous THF (200 mL) under nitrogen. The solution was stirred for 1 h and warmed to -40° C. Tributylstannyl chloride (1.47 g, 4.52 mmol) was added and the entire solution was finally allowed to warm to room temperature. At room temperature the mixture was filtered using Celite and the solvent was stripped. The organo-tin compound was vacuum dried to give 2-(tributylstannyl)-3,4-didecyloxythiophene, obtained as a light yellow liquid, yield=99%. MS(EI) m/z (rel int): 629 [(M)+ --C4H9, 22%], 396 [(M+ --C12H27Sn), 8.5%], 256 [(M+ --C22H47Sn), 3%] and 116 [(M+ --C32H67Sn), 43%].
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([O:29][C:30]3[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=3)[C:23]=1[F:39])=[O:19])=[CH:12]2.[CH3:40][C:41]([O:44][C:45]([NH:47][CH2:48][C:49](O)=[O:50])=[O:46])([CH3:43])[CH3:42].CCN(C(C)C)C(C)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:18]([C:13]2[NH:14][C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([NH:8][C:49](=[O:50])[CH2:48][NH:47][C:45](=[O:46])[O:44][C:41]([CH3:40])([CH3:42])[CH3:43])=[CH:17][CH:16]=3)=[O:19])=[C:23]([F:39])[C:24]=1[O:29][C:30]1[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Yield: 480.4 %

Procedure:
5-amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.060 g, 0.0103 mmol) was treated with N-{[(1,1-dimethylethyl)oxy]carbonyl}glycine (0.018 g, 0.103 mmol), DIPEA (0.090 mL, 0.514 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.079 g, 0.309 mmol) in a similar manner as described herein to afford crude 1,1-dimethylethyl {2-[(2-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-indol-5-yl)amino]-2-oxoethyl}carbamate (0.031 g) as an off-white solid. This material was treated with trifluoroacetic acid (0.30 mL, 3.89 mmol) in dichloromethane (1 mL) for 1 h. The solvent was evaporated to give the title compound (0.011 g, 40%) as a white solid. 1H NMR (400 Hz, DMSO-d6): δ ppm 11.60 (s, 1H), 10.23 (s, 1H), 8.97 (s, 1H), 8.04 (m, 3H), 7.91 (s, 1H), 7.77 (s, 1H), 7.40-7.54 (m, 2H), 7.29-7.40 (m, 2 H), 7.17-7.27 (m, 1H), 7.10 (s, 1H), 4.60 (s, 2H), 3.72 (s, 2H). MS: m/z 526 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:10]1[CH:33]=[CH:32][CH:31]=[CH:30][C:11]=1[O:12][C@@H:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C@@H:14]1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:35].O>CN(C)C=O>[CH2:3]([C:10]1[CH:33]=[CH:32][CH:31]=[CH:30][C:11]=1[O:12][C@@H:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C@@H:14]1[N:22]([CH3:35])[C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Oc1ccccc1Cc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@H]1Cc2ccccc2[C@H]1Oc1ccccc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92.5 %

Procedure:
To a suspension of sodium hydride (80% disp. in oil, 43 mg, 1.4 mmol) in dry N,N-dimethylformamide (2 ml) under nitrogen was added dropwise a solution of (±)cis-1-(2-benzylphenoxy)-2-tert-butoxycarbonylaminoindane (492 mg, 1.2 mmol) in dimethylformamide (5 ml). After stirring the mixture for 45 minutes at room temperature, iodomethane (88 μl, 1.4 mmol) was added dropwise and stirring continued for a further 45 minutes. The reaction mixture was then poured into a large excess of water and extracted with diethyl ether (3×30 ml). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The residue was subjected to column chromatography on silica gel eluting with 10% diethyl ether in hexanes to afford the title compound as a colourless oil (477 mg).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][C:3]=1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])=[O:14].ClS([N:28]=[C:29]=[O:30])(=O)=O.O>ClCCl>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[NH:15][C:13]([C:3]1[O:4][C:5]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=2[C:2]=1[NH:1][C:29]([NH2:28])=[O:30])=[O:14]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COc1ccc2c(N)c(C(=O)Nc3ccc(Cl)cc3Cl)oc2c1
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(NC(N)=O)c(C(=O)Nc3ccc(Cl)cc3Cl)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
3-Amino-N-(2,4-dichlorophenyl)-6-methoxybenzofuran-2-carboxamide ¼ hydrate (0.9 g) obtained in Example 1 was dissolved in dichloromethane (10 ml) and chlorosulfonyl isocyanate (0.4 g) was added under ice-cooling. The mixture was further stirred at room temperature for 1 hr. Then water was added and the precipitated crystals were recrystallized from water-containing dimethylformamide to give the title compound (0.3 g). melting point: >260° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[C:8]([C:14]([OH:16])=O)[C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[NH2:17]C(N)=O>O>[O:1]1[C:6]2=[CH:7][C:8]3[C:14](=[O:16])[NH:17][C:11](=[O:12])[C:9]=3[CH:10]=[C:5]2[O:4][CH:3]=[CH:2]1
Reactant: O=C(O)c1cc2c(cc1C(=O)O)OCCO2
Reactant: NC(N)=O
Solvent: O
Product: O=c1[nH]c(=O)c2cc3occoc3cc12
Yield: 88.3 %

Procedure:
A mixture of 1,4-benzodioxan-6,7-dicarboxylic acid (100 mg) and urea (54 mg) was heated to 160° for 2 h. When cool, the mixture was diluted with water and the resulting solid collected by filtration and washed with water and dried to afford the title compound (80 mg). M.p. 277°-280°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:11]1.CC(C)([O-])C.[K+].Br[CH2:33][CH:34]1[CH2:37][CH2:36][CH2:35]1.C(Cl)(Cl)Cl>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:33][CH:34]2[CH2:37][CH2:36][CH2:35]2)[C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:11]1
Reactant: BrCC1CCC1
Reactant: O=C(Nc1ccn(Cc2c(O)cccc2Cl)n1)c1c(F)cccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: O=C(Nc1ccn(Cc2c(Cl)cccc2OCC2CCC2)n1)c1c(F)cccc1F
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of N-{1-[(2-chloro-6-hydroxyphenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide (for a preparation see Intermediate 11)(0.047 g, 0.13 mmol) in dry DMSO (0.6 ml) in a reactivial was added potassium t-butoxide (0.0145 g, 0.13 mmol). The mixture was stirred for 20 min and then (bromomethyl)cyclobutane (0.023 g, 0.15 mmol, Aldrich) added. The mixture was stirred and heated at 60° C. for 24 h. The cooled reaction mixture was added to chloroform (about 20 ml) and this solution filtered through a hydrophobic frit and evaporated in vacuo. The residue was purified on MDAP (Method B) to give the title compound as a white solid (0.038 g); LCMS: (System 4) MH+=432, tRET=3.36 min.