Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=2)[N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH:42]1([C:48](Cl)=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>ClCCl.CN(C1C=CN=CC=1)C>[CH:42]1([C:48]([NH:1][C:2]2[CH:3]=[C:4]([C@@H:8]([N:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=3)[CH:5]=[CH:6][CH:7]=2)=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(N)c2)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(NC(=O)C3CCCCC3)c2)N2CCNCC2)cc1
Reaction time: 5 h

Procedure:
To a room temperature solution of INTERMEDIATE 5a (250 mg; 0.54 mmol) in dichloromethane (5 mL) were added triethylamine (0.15 mL; 1.08 mmol), DMAP (cat.) and cyclohexane carbonyl chloride (86 μL; 0.64 mmol). The reaction mixture was stirred for 5 hours then more triethylamine (0.08 mL; 0.58 mmol) and DMAP (cat.) were added. The reaction mixture was stirred overnight then more cyclohexane carbonyl chloride (28 μL; 0.21 mmol) was added. The reaction mixture stirred for 5 hours then was washed with two portions of saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Column chromatography eluting with 2% methanol in dichloromethane gave the desired product.
Reaction SMILES: BrC1SC([N+]([O-])=O)=C(C(N)=O)C=1.[OH:13][CH:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:26][C:25]([N+:27]([O-])=O)=[C:24]([C:30]([NH2:32])=[O:31])[CH:23]=2)=[CH:18][CH:17]=1)[CH3:15]>>[NH2:27][C:25]1[S:26][C:22]([C:19]2[CH:20]=[CH:21][C:16]([CH:14]([OH:13])[CH3:15])=[CH:17][CH:18]=2)=[CH:23][C:24]=1[C:30]([NH2:32])=[O:31]
Reactant: CC(O)c1ccc(-c2cc(C(N)=O)c([N+](=O)[O-])s2)cc1
Agent: NC(=O)c1cc(Br)sc1[N+](=O)[O-]
Product: CC(O)c1ccc(-c2cc(C(N)=O)c(N)s2)cc1

Procedure:
The title compound was prepared according to the general procedure in Intermediate 10 Step 6 using 5-[4-(1-hydroxyethyl)phenyl]-2-nitrothiophene-3-carboxamide (198 mg, 0.68 mmol) as the starting material.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:20][C:21]1[C:25]([S:26](Cl)(=[O:28])=[O:27])=[C:24]([CH3:30])[O:23][N:22]=1>C1(C)C=CC=CC=1.N1C=CC=CC=1>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=2)=[CH:3][C:2]=1[NH:1][S:26]([C:25]1[C:21]([CH3:20])=[N:22][O:23][C:24]=1[CH3:30])(=[O:28])=[O:27]
Reactant: Nc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1noc(C)c1S(=O)(=O)Nc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Yield: 50.1 %

Procedure:
A solution of 2.5 g of 2-(3-amino-4-chlorophenyl)-3-chloro-5-trifluoromethylpyridine and 2.3 g of 3,5-dimethylisoxazole-4-sulfonyl chloride in a mixture of 100 ml of toluene and 100 ml of pyridine was refluxed for 16 hours. The mixture was concentrated and the residue was taken up in 50 ml of ethyl acetate. The solution was washed with 50 ml each of 10% strength hydrochloric acid and 10% strength aqueous sodium bicarbonate solution and was dried over sodium sulfate and concentrated. Chromatography on silica gel with cyclohexane/ethyl acetate (6:1) resulted in 1.9 g of colorless crystals; melting point: 161°-162° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.CN(CCN(CCN(C)C)C)C.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([C:40](=[O:45])N(OC)C)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C1COCC1.C(OCC)(=O)C>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([C:40](=[O:45])[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:8][CH3:9])[C:2]=2[F:1])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccccc1F
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1F
Reaction time: 0.22 h
Yield: 125.2 %

Procedure:
To a stirred solution of 2-fluoroanisole (6.00 g, 47.6 mmol) and anhydrous THF (125 mL) at −78° C. under nitrogen was added butyllithium (35 mL of a 1.6 M solution in hexanes, 56.0 mmol). After stirring for 13 min, N,N,N′,N′,N″-Pentamethyldiethylenetriamine (12.9 mL, 61.8 mmol) was added dropwise and the reaction stirred at −78° C. After 168 min, a solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (16.8 g, 61.7 mmol) in anhydrous THF (40 mL) was added dropwise over 25 min. The reaction was stirred at −78° C. for 35 min and at room temperature for 65 min. The reaction was diluted with ethyl acetate (400 mL) and washed with cold 0.5 N aqueous HCl (2×200 mL), 5% aqueous potassium carbonate (200 mL), water (200 mL), and brine (200 mL) successively. The organic phase was dried over magnesium sulfate, filtered, and the solvent removed to give 20.1 g of a yellow oil. The product was chromatographed on silica gel (350 g), using a step gradient elution of 20% ethyl acetate/heptane to 30% ethyl acetate/heptane, to afford 12.0 g (75%) of the desired product as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.[C:26]([C:29]12[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][C:31]([CH2:39][OH:40])([CH2:32]3)[CH2:30]1)[CH2:36]2)(O)=[O:27]>CN(C=O)C>[OH:40][CH2:39][C:31]12[CH2:37][CH:35]3[CH2:34][CH:33]([CH2:38][C:29]([C:26](=[O:27])[N:2]([CH3:3])[CH3:1])([CH2:36]3)[CH2:30]1)[CH2:32]2
Reactant: CNC
Reactant: O=C(O)C12CC3CC(CC(CO)(C3)C1)C2
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Product: CN(C)C(=O)C12CC3CC(CC(CO)(C3)C1)C2
Temperature: 100 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1-carboxy-3-hydroxymethyladamantane obtained by the method of Example 73 was dissolved in 10 ml of DMF. To the mixture, 15 mmole of N,N′-carbodiimidazol in the form of powder was added in one portion. After stirring for 1 hour at the room temperature, 15 mmole of dimethylamine and 15 mmole of diazabicycloundecene were added. The mixture was heated to 100° C. and stirred f or 8 hours. As a result, the conversion of 1-carboxy-3-hydroxymethyladamantane was 99%, and 1-hydroxymethyl-3-(N,N-dimethylcarbamoyl)adamantane (yield 95%) was formed.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[Cl:12])[N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[Cl:12][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[F:13])=[N:3]2
Reactant: Clc1ccc2c(Cl)ccnc2n1
Reactant: OB(O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Fc1ccccc1-c1ccc2c(Cl)ccnc2n1
Temperature: 80 °C
Yield: 91.6 %

Procedure:
A stirred mixture of 2,5-dichloro-[1,8]naphthyridine (Barlin, G. B.; Tan, W.-L. Aust. J. Chem. 1984, 37, 1065) (0.1029 g, 0.513 mmol) and 2-fluorobenzeneboronic acid (72.4 mg, 0.517 mmol) in 2 N aqueous sodium carbonate (0.620 mL, 1.24 mmol) and ethylene glycol dimethyl ether (3 mL) was degassed by bubbling nitrogen through for 15 min. Tetrakis-(triphenylphosphine)palladium(0) (29.9 mg, 0.0259 mmol) was added and the mixture was degassed for a further 10 min, then heated at 80° C. for 16 h under nitrogen. The mixture was partitioned between water (20 mL) and dichloromethane (20 mL). The aqueous layer was further extracted with dichloromethane (2×20 mL), and the combined organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 15% EtOAc/CH2Cl2, to afford 0.1216 g (91%) of the title compound as an off-white solid. δH (360 MHz, CDCl3) 7.22 (1H, dd, J 11.8 and 8.2), 7.34 (1H, td, J 7.7, 0.7), 7.49 (1H, tdd, J 7.4, 5.3, and 2.1), 7.58 (1H, d, J 4.7), 8.18 (1H, dd, J 8.8, 2.5), 8.39 (1H, td, J 7.7, 1.8), 8.66 (1H, d, J 8.8), 9.03 (1H, d, J 4.8).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Br[C:40]1[CH:41]=[C:42]([O:50][CH3:51])[C:43]([O:48][CH3:49])=[C:44]([CH:47]=1)[CH:45]=[O:46]>O1CCOCC1.O.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>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18]([C:40]4[CH:41]=[C:42]([O:50][CH3:51])[C:43]([O:48][CH3:49])=[C:44]([CH:45]=[O:46])[CH:47]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: COc1cc(Br)cc(C=O)c1OC
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
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: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(C=O)c(OC)c(OC)c4)cc23)CC1
Temperature: 120 °C
Yield: 59.1 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (500 mg, 1.09 mmol) in dioxane (9.0 mL) and H2O (3.0 mL) was added sodium carbonate (690 mg, 6.51 mmol), and 5-bromo-2,3-bis(methyloxy)benzaldehyde (7.95 mg, 3.25 mmol). The reaction mixture was flushed under Argon for 10 min before addition of tetrakis(triphenylphosphine)palladium (0) (63 mg, 0.054 mmol). The reaction was then heated in a microwave at 120° C. for 30 min. All solvent was then concentrated and an aqueous wash was performed with EtOAc and H2O. The desired compound then precipitated and was filtered to give 322 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-formyl-4,5-bis(methyloxy)phenyl]-1H-indole-7-carboxamide (59%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15](F)=[N:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:20]([CH3:23])=[N:21][O:22][C:11]=3[CH2:10][N:9]=2)=[CH:4][CH:3]=1.[OH-:24].[Na+].[Cl-].[NH4+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15](=[O:24])[NH:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:20]([CH3:23])=[N:21][O:22][C:11]=3[CH2:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: Cc1noc2c1-c1ccnc(F)c1C(c1ccc(Cl)cc1)=NC2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1noc2c1-c1cc[nH]c(=O)c1C(c1ccc(Cl)cc1)=NC2
Temperature: 110 °C
Yield: 87.1 %

Procedure:
To a solution of 6-(4-chlorophenyl)-7-fluoro-1-methyl-4H-isoxazolo[4,5-e]pyrido[3,4-c]azepine from Example 19 (0.244 g, 0.744 mmol) in 1,4-dioxane (5 mL) was added an aqueous solution of sodium hydroxide (1M) (5.00 mL, 5.00 mmol) at room temperature. The reaction was heated to 110° C. for 90 min, then cooled to room temperature before a saturated solution of ammonium chloride was added. The product was extracted with CH2Cl2 (repeated 4 times), and the organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness under vacuum. The product was purified twice by flash chromatography (hexane/EtOAc 8:2 to 1:9) to give 6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7(8H)-one as a white solid (0.211 g). 1H NMR (400 MHz, DMSO-d6) δ 11.92 (br.s., 1H), 7.66 (d, J=6.64 Hz, 1H), 7.38 (d, J=8.00 Hz, 2H), 7.33 (d, J=8.47 Hz, 2H), 6.60 (d, J=6.87 Hz, 1H), 5.19 (d, J=13.05 Hz, 1H), 4.07 (d, J=13.05 Hz, 1H), 2.50 (s, 3H); LC/MS m/z 326 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[O:15]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[O:15]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=2)=[O:27])=[CH:29][CH:30]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)CCc1ccc(N)cc1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1ccc(NC(=O)c2ccc(Oc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.5 %

Procedure:
To a solution of ethyl 4-aminobenzenepropanoate (0.70 g, 3.6 mmol) in N,N-dimethylformamide (25 mL) were added 4-phenoxybenzoic acid (0.85 g, 4.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.76 g, 4.0 mmol) and 1-hydroxybenzotriazole monohydrate (0.61 g, 4.0 mmol), and the mixture was stirred at room temperature for 16 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2:1) to give the title compound (0.96 g, yield 68%) as a white powder.
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]#[C:14][C:15]1[C:16]2[N:17]([N:21]=[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[N:23]=2)[CH:18]=[CH:19][CH:20]=1)[S:3]([CH3:6])(=[O:5])=[O:4].C(OCC)(=O)C>[Pd].CO>[CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][C:15]1[C:16]2[N:17]([N:21]=[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[N:23]=2)[CH:18]=[CH:19][CH:20]=1)[S:3]([CH3:6])(=[O:4])=[O:5]
Reactant: CN1CCN(c2ccc(Nc3nc4c(C#Cc5ccccc5N(C)S(C)(=O)=O)cccn4n3)cc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(Nc3nc4c(CCc5ccccc5N(C)S(C)(=O)=O)cccn4n3)cc2)CC1
Reaction time: 1 h

Procedure:
To a Paar bottle was added N-methyl-N-(2-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylethynyl}-phenyl)-methanesulfonamide (50.0 mg, 0.0970 mmol), 10% palladium on carbon (50% wet) (25.0 mg, 0.0117 mmol) and 2:1 ethyl acetate:methanol (10 mL). The mixture was degassed and charged with hydrogen (38 psi). The mixture was shaken on a Paar apparatus for 1 hour. The mixture was degassed and kept under an atmosphere of Nitrogen. The mixture was filtered through a plug of diatomaceous earth and rinsed with dichloromethane. The filtrate was evaporated. N-Methyl-N-[2-(2-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-ethyl)-phenyl]-methanesulfonamide was isolated as a pale yellow foam (0.037 g, 73%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.31 (s, 1H), 8.58 (d, J=6.6 Hz, 1H), 7.55 (d, J=7.8 Hz, 2H), 7.48-7.44 (m, 1H), 7.35-7.26 (m, 3H), 7.23 (d, J=7.0 Hz, 1H), 6.92-6.84 (m, 3H), 3.23-3.00 (m, 14H), 2.48-2.43 (m, 4H), 2.22 (s, 3H). MS=520 (MH)+.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[F:13][C:14]1[CH:15]=[C:16]([NH:21][CH:22]([C:24]2[CH:25]=[C:26]([C:41](O)=[O:42])[CH:27]=[C:28]3[C:33]=2[O:32][C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:30][C:29]3=[O:40])[CH3:23])[CH:17]=[C:18]([F:20])[CH:19]=1.[Si:44]([O:61][CH2:62][CH2:63][NH:64][CH3:65])([C:57]([CH3:60])([CH3:59])[CH3:58])([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.OC1C=CC=C[N+]=1[O-]>C(Cl)Cl>[Si:44]([O:61][CH2:62][CH2:63][N:64]([CH3:65])[C:41]([C:26]1[CH:27]=[C:28]2[C:33](=[C:24]([CH:22]([NH:21][C:16]3[CH:17]=[C:18]([F:20])[CH:19]=[C:14]([F:13])[CH:15]=3)[CH3:23])[CH:25]=1)[O:32][C:31]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[CH:30][C:29]2=[O:40])=[O:42])([C:57]([CH3:59])([CH3:60])[CH3:58])([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: CNCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [O-][n+]1ccccc1O
Solvent: ClCCl
Product: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)N(C)CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (135 mg, 0.71 mmol) was added in one portion to 8-(1-(3,5-difluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (200 mg, 0.35 mmol, enantiomer 1; [α]D20°: +115°), 2-(tert-butyldiphenylsilyloxy)-N-methylethanamine (221 mg, 0.71 mmol) and 2-hydroxy-pyridine N-oxide (78 mg, 0.71 mmol) dissolved in DCM (2 mL) under argon. The resulting solution was stirred at RT overnight. The solution was evaporated to dryness, water was added and product was extracted with DCM. The organic phase was washed with brine and dried over magnesium sulfate, the solvent was evaporated to afford N-(2-(tert-butyldiphenylsilyloxy)ethyl)-8-(1-(3,5-difluorophenylamino)ethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (94%) as a white solid. Mass Spectrum: M+H+ 726.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:13][C:14]2[C:19]([F:20])=[CH:18][C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[C:16]([F:34])[CH:15]=2)=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1Cl)(=[O:3])[NH2:2].O.[NH2:36][NH2:37]>O1CCOCC1>[C:1]([C:4]1[C:5]([NH:13][C:14]2[C:19]([F:20])=[CH:18][C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[C:16]([F:34])[CH:15]=2)=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1[NH:36][NH2:37])(=[O:3])[NH2:2]
Reactant: CSc1nc(Cl)c(C(N)=O)c(Nc2cc(F)c(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)n1
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: CSc1nc(NN)c(C(N)=O)c(Nc2cc(F)c(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the product of Example 15D (3.53 mg, 0.69 mmol) in 1,4-dioxane (5 mL) was added hydrazine hydrate (0.3 mL). After stirring at ambient temperature for 4 hours, the mixture was concentrated. The residue was washed with hexane and dried under vacuum to give the crude title compound, which was used in the next step without further purification (281 mg, 80%). MS: 511 (M+H+).
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]([F:30])([F:29])[C:7]1[CH:8]=[C:9]([NH:13][C:14]([N:16]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]3[CH:23]=[C:24]([O:27]C)[CH:25]=[CH:26][C:17]2=3)=[O:15])[CH:10]=[CH:11][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>C(Cl)Cl.C(=O)=O.CC(C)=O>[F:29][C:6]([F:5])([F:30])[C:7]1[CH:8]=[C:9]([NH:13][C:14]([N:16]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]3[CH:23]=[C:24]([OH:27])[CH:25]=[CH:26][C:17]2=3)=[O:15])[CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccc2c(c1)CCCCN2C(=O)Nc1cccc(C(F)(F)F)c1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)N1CCCCc2cc(O)ccc21
Temperature: -42.5 °C
Reaction time: 1.5 h

Procedure:
A solution of 10 ml BBr3 in 40 ml CH2Cl2 is cooled in dry ice and acetone. Then 2.43 g (6.67 mMol) of 7-methoxy-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide in 20 ml CH2Cl2 are added dropwise. The mixture is warmed up (−45 to −40° C.) and then stirred at this temperature for 1.5 h. The solution is poured into a mixture of 300 g ice, 150 ml sat. Na2CO3 solution and 200 ml EtOAc, the aqueous phase separated off and extracted twice with EtOAc. The organic layers are washed with water (2×) and brine, dried (Na2SO4) and concentrated. Crystallization from hexane gives the title compound: m.p.: 172-173° C.; MS: [M+1]+=351; Anal.: C,H,N,F.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C:7]([CH3:11])([CH3:10])[C:8]#[N:9])=[CH:4][CH:3]=1.N[C:15]([CH3:19])([CH3:18])[CH2:16][OH:17].N>[Zn].C([O-])(=O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C:7]([C:8]2[O:17][CH2:16][C:15]([CH3:19])([CH3:18])[N:9]=2)([CH3:10])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C#N)Oc1ccc(Cl)cc1
Reactant: CC(C)(N)CO
Agent: CC(=O)[O-]
Agent: N
Agent: [Zn]
Solvent: ClC(Cl)Cl
Product: CC1(C)COC(C(C)(C)Oc2ccc(Cl)cc2)=N1
Reaction time: 48 h
Yield: 88 %

Procedure:
19.57 g (0.1 moles) of 2-(p-chlorophenoxy)-2-methyl-propionitrile are reacted under stirring for 34 hours with 17.83 g (0.2 moles) of 2-amino-2-methyl-1-propanol in the presence of 0.66 g (0.003 moles) of zinc-acetate catalyst at a temperature of 140°-150° C. The reaction takes place under an intensive development of ammonia gas. When the gas development is finished, the mixture is cooled, dissolved in 300 ml of chloroform and the solution washed with water to neutral reaction. After drying the solution over anhydrous magnesium sulphate, it is evaporated to dryness. The green-yellow colored oil (26.5 g) is subjected to fractional distillation in vacuo. The main fraction is a product 2-[(p-chlorophenoxy)-isopropyl]-4,4-dimethyl-2-oxazoline of 23.6 g (yield 88%), m.p.: 98°-100° C./0.02 mmHg. The distilled product crystallizes after standing for 48 hours, m.p.: 59°-61° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:17][CH2:16][NH:15][CH2:14]1)=[O:12])[CH3:9].[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]=[C:41]=[O:42]>ClCCl>[CH2:8]([O:10][C:11]([C:13]1([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[CH:22][CH:21]=2)[CH2:17][CH2:16][N:15]([C:41](=[O:42])[NH:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[Cl:33])[CH2:14]1)=[O:12])[CH3:9]
Reactant: O=C=Nc1ccccc1Cl
Reactant: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCN(C(=O)Nc2ccccc2Cl)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
Triethylamine (0.23 mL, 1.67 mmol) was added to a stirred solution of 3-(4′-fluoro-biphenyl-4-yloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (see Preparation 65) (185 mg, 0.54 mmol) in dichloromethane (10 mL) and the resulting mixture cooled to 0° C. 2-Chloro phenyl isocyanate (0.065 mL, 0.54 mmol) was added and the reaction mixture stirred at room temperature for 16 hours. The mixture was partitioned between water (25 mL) and dichloromethane (25 mL). The organic layer was separated, washed brine (25 mL), dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 25% ethyl acetate in hexane to afford the title compound as a colourless liquid (245 mg, 91%).
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:11]=[C:12]2[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:16][C:13]2=[N:14][CH:15]=1>>[CH2:1]([N:16]1[C:13]2=[N:14][CH:15]=[C:10]([F:9])[CH:11]=[C:12]2[CH:18]=[C:17]1[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2cc(F)cnc2[nH]1
Reactant: OCc1ccccc1
Product: CCOC(=O)c1cc2cc(F)cnc2n1Cc1ccccc1

Procedure:
The ethyl 1-benzyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate was prepared according to a method similar to that described in Example 4.1, from benzyl alcohol and the ethyl 5-fluoro-1H-pyrrolo[2,3-b]pyridine-2--carboxylate prepared in the preceding step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[Cl:24][C:25]1[CH:26]=[C:27]([SH:33])[CH:28]=[C:29]([Cl:32])[C:30]=1[Cl:31]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[N:11][C:12]([S:33][C:27]3[CH:28]=[C:29]([Cl:32])[C:30]([Cl:31])=[C:25]([Cl:24])[CH:26]=3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Reactant: Sc1cc(Cl)c(Cl)c(Cl)c1
Product: COc1ccc(-c2cc(Sc3cc(Cl)c(Cl)c(Cl)c3)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (200 mg, 0.613 mmol) and 3,4,5-trichlorothiophenol [Ger. Offen. DE 2515699 19751023 (Dow Chemical Co., U.S.A.)] were reacted as starting materials at 100° C. for 72 hours and post-treatment was then conducted, whereby the title compound was obtained as a colorless amorphous solid (125.3 mg, 40.6%)