Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][CH2:19][OH:20])[CH2:13][CH2:12]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:7]([CH3:8])[CH2:9][CH2:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([CH2:17][CH2:18][CH2:19][O:20][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:15][CH2:16]1)=[O:21])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(CC[C@H]1CC[C@H](CCCO)CC1)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CC[C@H]1CC[C@H](CCCOS(C)(=O)=O)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3.35 g (11.20 mmol) trans-{2-[4-(3-hydroxy-propyl)-cyclohexyl]-ethyl}-methyl-carbamic acid tert-butyl ester and 1.54 ml (13.4 mmol) of methanesulfonyl chloride in 35 ml dichloromethane was added under ice-cooling within 5 minutes a solution of 1.87 ml (13.4 mmol) triethylamine in 5 ml of dichloromethane. The reaction mixture was then stirred for 1 hour at room temperature. It was subsequently partitioned between ether, water and 1N hydrogen chloride solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure giving 4.06 g (96.1%) almost pure trans-methanesulfonic acid 3-{4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexyl}-propyl ester as colorless viscous oil, MS: 395 (MNH4+).
Reaction SMILES: [NH:1]([C:8]1[C:13](I)=[CH:12][N:11]=[C:10]([Cl:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([CH2:22][CH2:23][C:24]#[CH:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:1]([C:8]1[C:13]([C:25]#[C:24][CH2:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][N:11]=[C:10]([Cl:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncc(I)c(Nc2ccccc2)n1
Reactant: C#CCCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Clc1ncc(C#CCCc2ccccc2)c(Nc2ccccc2)n1
Reaction time: 20 h
Yield: 74.9 %

Procedure:
A solution of 4-anilino-2-chloro-5-iodopyrimidine (Method 59; 662 mg, 2.0 mmol), 4-phenyl-1-butyne (260 mg, 2.0 mmol) and triethylamine (0.56 ml, 4.0 mmol) in THF (20 ml) was purged with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (25 mg) and cuprous iodide (12.5 mg) were added and the mixture was stirred for 20 hours. Insoluble material was removed by filtration and washed with diethyl ether (50 ml). The filtrate and washings were combined and concentrated, and the residue was purified by bond elute chromatography, eluting with 25% ethyl acetate in isohexane, to give the product (0.5 g). NMR (CDCl3): 2.85 (m, 2H), 2.95 (m, 2H), 7.05 (m, 2H), 7.1-7.4 (m, 7H), 7.45 (dd, 2H), 8.2 (s, 1H); MS (MH+): 334, 336.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[C:9]([NH:15][C:16](=[O:18])[CH3:17])[CH:10]=[CH:11][C:12]=2[Cl:14])[C:7](=[O:19])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:20]([NH:23]C1C=CC=C2C=1C(=O)CCC2)(=[O:22])[CH3:21]>>[C:1]([N:4]1[C:13]2[C:8](=[C:9]([NH:15][C:16](=[O:18])[CH3:17])[CH:10]=[CH:11][C:12]=2[Cl:14])[C:7](=[O:19])[CH:6]([NH:23][C:20](=[O:22])[CH3:21])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1C(=O)CCC2
Reactant: CC(=O)Nc1ccc(Cl)c2c1C(=O)CCN2C(C)=O
Product: CC(=O)Nc1ccc(Cl)c2c1C(=O)C(NC(C)=O)CN2C(C)=O

Procedure:
The reaction was carried out in the same manner as in Example 1-(2), except that 1.4 gm of the compound prepared in (1) above was used instead of 8-acetylamino-1-tetralone of Example 1-(2). The reaction mixture obtained by the post-treatment was further reacted in the same manner as in Example 1-(3) and post-treated to produce 0.62 gm of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:33]([N:35](CC)[CH2:36]C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CNC>C(Cl)Cl>[CH3:32][O:31][C:29](=[O:30])[CH2:28][CH2:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:10](=[O:12])[N:35]([CH3:36])[CH3:33])=[CH:15][CH:16]=2)=[CH:26][CH:25]=1
Reactant: CCN(CC)CC
Reactant: COC(=O)CCc1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCc1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)N(C)C)cc2)cc1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
The hydrogenated compound 4 (8.0 g, 18.0 mmol) was dissolved in CH2Cl2 and stirred at room temperature under an atmosphere of argon. Triethylamine (3.02 mL, 21.6 mmol) and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 8.78 g, 20.0 mmol) were added and the reaction mixture was stirred for 15 min. Dimethylamine (2.0 M solution in THF, 45.2 mL, 90.0 mmol) was added and the resulting solution was stirred at room temperature for about 2-3 h. The solvent was removed under reduced pressure and the resulting oil was taken up in EtOAc (200 mL). The organic layer was extracted with 0.5 N NaOH (1×30 mL), water (2×100 mL) and brine (1×100 mL). Drying and concentration of the organic layer gave the desired amide 5 (8.4 g, ˜98%). 1H NMR (400 MHz, DMSO-d6): 7.24 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.4 Hz, 1H), 6.89 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 4.23 (m, 1H), 3.58 (s, 3H), 2.91 (s, 3H), 2.70-2.86 (m, 7H), 2.62 (t, J=7.6 Hz, 2H), 1.31 (s, 9H).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[N:4]=1.[CH3:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([OH:35])[CH2:28][N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:21][C:19]=2[N:20]=1.C(N(C(C)C)CC)(C)C>CCO>[F:14][C:10]1[CH:9]=[C:8]([C:5]2[N:4]=[C:3]([CH2:2][N:32]3[CH2:33][CH2:34][N:29]([CH2:28][CH:27]([OH:35])[CH2:26][O:25][C:22]4[CH:23]=[CH:24][C:18]5[S:17][C:16]([CH3:15])=[N:20][C:19]=5[CH:21]=4)[CH2:30][CH2:31]3)[O:7][N:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Fc1cccc(-c2noc(CCl)n2)c1
Reactant: Cc1nc2cc(OCC(O)CN3CCNCC3)ccc2s1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(OCC(O)CN3CCN(Cc4nc(-c5cccc(F)c5)no4)CC3)ccc2s1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To 5-(chloromethyl)-3-(3-fluorophenyl)-1,2,4-oxadiazole (300 mg, 1.41 mmol) and 1-(2-methylbenzothiazol-5-yloxy)-3-piperazine-1-yl-propan-2-ol, a compound of formula (6) (291 mg, 0.94 mmol) in EtOH (20 mL, anhydrous) was added diisopropylethylamine (0.329 m, 1.89 mmol), and the reaction was shaken on a J-Kem™ block overnight at 90° C. Upon cooling to room temperature, the solution was concentrated to an oil and purified on an Isco™ Combi Flash Si 10X, using Redi Sep columns (10 g), eluting with ethyl acetate, then gradient to 4:1 ethyl acetate/methanol, to yield 3-(4-{[3-(3-fluorophenyl)(1,2,4-oxadiazol-5-yl)]methyl}piperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol, a compound of Formula I, (136 mg, 30%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7](=[O:12])[NH:6][C:5]=2[CH:4]=[N:3]1.N[C:14]1C(C)=NN(C)C=1C(N)=O>>[CH3:1][N:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7](=[O:12])[NH:6][C:5]=2[C:4]([CH3:14])=[N:3]1
Reactant: Cc1nn(C)c(C(N)=O)c1N
Reactant: Cn1ncc2[nH]c(=O)[nH]c(=O)c21
Product: Cc1nn(C)c2c(=O)[nH]c(=O)[nH]c12

Procedure:
This compound was prepared in an analogous fashion to 1-methyl-1H-pyrazolo[4,3-d]pyrimidine-5,7(4H,6H)-dione, using 4-amino-1,3-dimethyl-1H-pyrazole-5-carb oxamide as the starting material. 1H NMR ((DMSO-d6, 400 MHz) δ ppm 11.02 (s, 2H), 3.97 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][C:23]([CH3:26])=[N:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36].N1C=CC=CC=1>O1CCCC1>[F:27][C:3]1[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][C:23]([CH3:26])=[N:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)=[O:10])=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[F:28])(=[O:37])=[O:36]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: Cc1ncc(-c2cnc3[nH]cc(C(=O)c4c(F)ccc(N)c4F)c3c2)cn1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ncc(-c2cnc3[nH]cc(C(=O)c4c(F)ccc(NS(=O)(=O)c5ccccc5F)c4F)c3c2)cn1
Temperature: 60 °C
Yield: 41.2 %

Procedure:
To (3-amino-2,6-difluoro-phenyl)-[5-(2-methyl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone (50, 0.220 g, 0.602 mmol) in 4.01 mL of tetrahydrofuran, 2-fluoro-benzenesulfonyl chloride (20, 0.352 g, 1.807 mmol) and pyridine (0.146 mL, 1.807 mmol) are added and the reaction is heated at 60° C. overnight. The reaction is partitioned between brine/water and ethyl acetate/tetrahydrofuran. The organic layer is separated and the solvent is removed under vacuum. The resulting residue is purified by silica gel column chromatography eluting with 0-10% methanol in dichloromethane, then triturated with ethyl acetate/heptane to provide the desired compound as a light tan solid (P-1520, 0.130 g, 0.248 mmol, 41.2% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH2:36]([C:43]1([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:46]3[CH2:45][CH2:44][C:43]([CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(Cc2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Cc4ccccc4)(C(N)=O)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-benzyl-piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: S([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[CH:8][CH:7]=1)(O)(=O)=O.[C:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1)(=[O:16])[CH3:15].C(N(CC)CC)C>C(O)C>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]([CH3:13])[S:24]([C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:14](=[O:16])[CH3:15])=[CH:23][CH:22]=2)(=[O:26])=[O:25])=[CH:10][CH:11]=1
Reactant: CNc1ccc(OS(=O)(=O)O)cc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(S(=O)(=O)N(C)c2ccc(O)cc2)cc1

Procedure:
4-Methylaminophenol sulfate and equivalent 4-acetamidobenzenesulfonyl chloride and double equivalent triethylamine were reacted in ethanol at room temperature for 4 hours. After the solvent was removed in vacuo, the residue was extracted with diethyl ether. The ether layer was washed successively with 2 N hydrochloric acid, saturated aqueous NaHCO3 solution and water, then dried over anhydrous Na2SO4 The solvent was removed and the residue was recrystallized from ethanol to give N-(4-hydroxyphenyl)-N-methyl-4-acetamidobenzenesulfonamide, mp 202-203° C.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[C:14]([OH:27])(=O)[CH2:15][CH2:16][CH2:17][S:18][S:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24]>C(C(C)=O)C(C)C>[C:23]([O:25][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH2:6])(=[O:24])[CH2:22][CH2:21][CH2:20][S:19][S:18][CH2:17][CH2:16][CH2:15][C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH2:6])=[O:27]
Reactant: O=C(O)CCCSSCCCC(=O)O
Reactant: NCCCCCCO
Agent: CS(=O)(=O)O
Solvent: CC(=O)CC(C)C
Product: NCCCCCCOC(=O)CCCSSCCCC(=O)OCCCCCCN
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
5.1 g of methanesulfonic acid (manufactured by Wako Pure Chemical Industries, Ltd.) was added dropwise, under an atmosphere of nitrogen and at 70° C., to 5.9 g of 6-amino-1-hexanol. After stirring for 10 minutes, 6.0 g of 4,4′-dithiodibutyric acid (manufactured by Tokyo Chemical Industry Co., Ltd.) was added, and the resulting mixture was heated to 120° C. and then stirred at 110° C. for 4 hours. Following completion of the reaction, the reaction mixture was cooled to room temperature and then added gradually to 50 mL of methyl isobutyl ketone (manufactured by Wako Pure Chemical Industries, Ltd.). After stirring for 2 hours, the precipitated crystals were collected by filtration and washed with acetone, yielding the methanesulfonate salt of di(6-aminohexyl) 4,4′-dithiodibutyrate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]([NH:38]C(=O)OC(C)(C)C)=[C:12]([C:14](=[O:37])[NH:15][C:16]2[CH:17]=[N:18][N:19]([CH3:36])[C:20]=2[N:21]2[CH2:27][CH2:26][CH:25]([NH:28]C(=O)C(F)(F)F)[CH:24]([F:35])[CH2:23][CH2:22]2)[N:13]=1.Cl.O1CCOCC1>CO>[NH2:38][C:11]1[S:10][C:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])=[N:13][C:12]=1[C:14]([NH:15][C:16]1[CH:17]=[N:18][N:19]([CH3:36])[C:20]=1[N:21]1[CH2:22][CH2:23][CH:24]([F:35])[CH:25]([NH2:28])[CH2:26][CH2:27]1)=[O:37]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCC(N)C(F)CC1
Temperature: 60 °C

Procedure:
tert-Butyl 2-(2,6-difluorophenyl)-4-(5-(4-fluoro-5-(2,2,2-trifluoroacetamido)azepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate was suspended in MeOH (20 mL) in a pressure vessel and to this was added a solution of HCl in 1,4-dioxane (4 M, 20 mL, 80.0 mmol). The vessel was sealed and the mixture heated at 60° C. for 16 hr. The solvent was removed under reduced pressure and the residue was purified via silica gel column chromatography (0-10% 7 N ammonia in MeOH/DCM) to yield 5-amino-N-(5-(4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide as a pale brown solid (653 mg, 70% over two steps). The 4-amino and the 5-fluoro groups are cis. 1H NMR (400 M Hz, CDCl3) δ 8.63 (s, 1H), 7.84 (s, 1H), 7.37-7.29 (m, 1H), 7.03 (t, J=8.7 Hz, 2H), 6.13 (s, 2H), 4.48 (dtd, J=47.9, 8.6, 3.6 Hz, 1H), 3.72 (s, 3H), 3.37-3.15 (m, 5H), 2.23-1.92 (m, 3H), 1.75-1.67 (m, 1H). Alkyl NH2 not observed. LCMS (ES+) m/z 466 (M+1). Chiral separation of the racemic mixture by SFC gave 147 as a single enantiomer. 1H NMR (400 MHz, DMSO) δ 9.04 (s, 1H), 7.59 (s, 1H), 7.56-7.43 (m, 3H), 7.26 (dd, J=14.5, 5.9 Hz, 2H), 4.82 (dd, J=47.0, 7.4 Hz, 1H), 3.63 (s, 3H), 3.29-3.15 (m, 4H), 3.08-2.91 (m, 2H), 2.24-2.06 (m, 1H), 1.91-1.76 (m, 2H), 1.74-1.59 (m, 1H). MS (ESI) m/z: 466.1 [M+H+].
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]=[C:5]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[O:9][C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[CH2:6]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:24](Cl)(=[O:26])[CH3:25]>ClCCl>[C:24]([C:19]1[C:7]2[CH2:6][C:5](=[CH:4][CH2:3][CH2:2][Br:1])[C:15]3[C:10]([O:9][C:8]=2[CH:16]=[CH:17][CH:18]=1)=[N:11][CH:12]=[CH:13][CH:14]=3)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: BrCCC=C1Cc2ccccc2Oc2ncccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cccc2c1CC(=CCCBr)c1cccnc1O2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of example 53, step 1 (7.2 g) in dichloromethane (70 ml) was added aluminum chloride (9.1 g) and acetyl chloride (3.2 ml), and the mixture stirred at 0° C. for 10 minutes. The reaction mixture was poured into ice. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The Residue was purified by silica gel chromatography, eluting with ethyl acetate-hexane (1:2) to give 7-acetyl-5-(3-bromopropylidene)-5,11-dihydro[1]benzoxepino[2,3-b]pyridine (7.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([CH2:19]Cl)=[CH:7]2.[N-:21]=[N+]=[N-].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([CH2:19][NH2:21])=[CH:7]2
Reactant: ClCc1cc2cccc(Cl)c2nc1Oc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: NCc1cc2cccc(Cl)c2nc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 8-chloro-3-(chloromethyl)-2-phenoxyquinoline (1 eq) in DMSO (0.25 M) was added NaN3 (3 eq) at rt and the mixture was stirred for 4 h at rt. The mixture was diluted with water, extracted with EtOAc (2 times) and the combined organic layers were washed with water (2 times), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in MeOH and treated with 10% Pd—C (5 wt %) and the mixture was then stirred under H2 balloon over night. The mixture was filtered through a Celite™ pad followed by removal of solvents to give (8-chloro-2-phenoxyquinolin-3-yl)methanamine.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7]([C:9]3[CH2:13][C:12]4([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[O:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7]([C:9]3[CH2:13][C:12]4([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[O:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: Brc1ccc2[nH]c(C3=NOC4(CCCCC4)C3)nc2c1
Reactant: OB(O)c1ccccc1Cl
Product: Clc1ccccc1-c1ccc2[nH]c(C3=NOC4(CCCCC4)C3)nc2c1

Procedure:
The title compound was prepared from 3-(5-bromo-1H-benzimidazol-2-yl)-1-oxa-2-aza-spiro[4.5]dec-2-ene (as prepared in the previous step) and 2-chloro-benzene-boronic acid according to the procedure described in Example 1, step D. 1H-NMR (400 MHz, d4-MeOH) δ: 7.46-7.76 (m, 3H), 7.29-7.42 (m, 4H), 3.27 (s, 2H), 1.69-1.87 (m, 6H), 1.46-1.62 (m, 4H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:7]2[C:8](=[O:19])[N:9]([CH2:16][CH2:17][CH3:18])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[NH:5][N:4]=1.[H-].[Na+].[C:22](Cl)(=[O:25])[O:23][CH3:24]>CN(C=O)C>[CH3:24][O:23][C:22]([N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]([CH2:16][CH2:17][CH3:18])[C:8](=[O:19])[C:7]=2[C:3]([NH:2][CH3:1])=[N:4]1)=[O:25]
Reactant: COC(=O)Cl
Reactant: CCCn1c(=O)c2c(NC)n[nH]c2c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(NC)nn(C(=O)OC)c2c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
In 70 ml of DMF was suspended 1.69 g (6.6 mmol) of Compound 1, and 0.33 g (8.3 mmol) of 60% sodium hydride was added and dissolved therein. To the mixture was added 0.80 ml (10 mmol) of methyl chlorocarbonate, followed by stirring at room temperature for 1 hour. The reaction mixture was dried under reduced pressure, and the residue was partitioned between chloroform and water. The chloroform layer was dried under reduced pressure, passed through a silica gel column, and eluted with chloroform. The main fraction collected was dried under reduced pressure and recrystallized from water-containing ethanol to obtain 1.03 g (50%) of the titled compound as a colorless crystal.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[NH:12][C:11](=[O:19])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH2:37])[CH:35]=3)[NH:30][N:29]=2)=[CH:23][CH:22]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH:37][C:15]([C:14]4[CH:9]([C:4]5[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=5)[NH:10][C:11](=[O:19])[NH:12][C:13]=4[CH3:18])=[O:17])[CH:35]=3)[NH:30][N:29]=2)=[CH:25][CH:26]=1
Reactant: CC1=C(C(=O)O)C(c2ccc(F)c(F)c2)NC(=O)N1
Reactant: Nc1ccc2[nH]nc(Nc3ccc(F)cc3)c2c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Nc4ccc(F)cc4)c3c2)C(c2ccc(F)c(F)c2)NC(=O)N1

Procedure:
The titled compound was prepared following the procedure of Example 175 using 4-(3,4-Difluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, N3-(4-fluoro-phenyl)-1H-indazole-3,5-diamine, PyBroP and diisopropylethylamine in methylene chloride. MS (ESI) m/z=493 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:4]=1[NH2:5].[Cl:13][CH2:14][CH:15]([CH3:19])[C:16](Cl)=[O:17]>C1C=CC=CC=1.O>[Cl:13][CH2:14][CH:15]([CH3:19])[C:16]([NH:5][C:4]1[CH:6]=[C:7]([C:10](=[O:12])[CH3:11])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1])=[O:17]
Reactant: COc1ccc(C(C)=O)cc1N
Reactant: CC(CCl)C(=O)Cl
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(C(C)=O)cc1NC(=O)C(C)CCl
Reaction time: 2 h
Yield: 77 %

Procedure:
24.8 g of 2-methoxy 5-acetyl aniline [obtained according to Oelschager Arzneimit. Forschung 8 532-539 (1958)] dissolved in 150 ml benzene are added with 10.6 g of 3-chloro isobutyric acid chloride in 40 ml benzene. The mixture is kept at room temperature for 2 hours under stirring then diluted with 250 ml water. The benzenic phase is separated. The aqueous phase is extracted twice with benzene. The benzenic solutions are united, washed with 2N hydrochloric acid and then with water, dried on sodium sulphate, filtered and evaporated to dryness. The residue is recrystallised from isopropyl ether from which 15.5 g or pure compound are recovered (yield = 77%) -1-(β-chloroα-methyl propionylamino) 2-methoxy 5-acetylbenzene melts at 92-97°.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([O:8][CH2:9][CH:10]([F:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7])=[CH:4][CH:3]=1.N1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[CH2:21]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:1][C:2]2[CH:19]=[CH:18][C:5]([C:6]([O:8][CH2:9][CH:10]([F:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7])=[CH:4][CH:3]=2)=[O:7])=[CH:18][CH:19]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:13][CH2:12][CH2:11][CH:10]=[CH2:9]
Reactant: CCCCCCC(F)COC(=O)c1ccc(O)cc1
Reactant: c1ccncc1
Solvent: Cc1ccccc1
Product: C=CCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)OCC(F)CCCCCC)cc2)cc1
Reaction time: 15 h
Yield: 167.8 %

Procedure:
To 3.0 g of 4-(9-decenyloxy)benzoic acid prepared in the same manner as in 9.(2) in Example 9 added was toluene, and the mixture was cooled in an ice bath. 2.0 g of thionyl chloride was added dropwise to the mixture. Subsequently, reaction was carried out for 3 hours at 80° C. After conclusion of the reaction, the product was concentrated to obtain an acid chloride compound. While, 1.7 g of 2-fluorooctyl 4-hydroxybenzoate and 0.9 g of pyridine were dissolved in toluene, and the resulting solution was cooled in an ice bath. Added dropwise thereto was a toluene solution of the above-described acid chloride compound. Reaction was then carried out for 15 hours at room temperature. After conclusion of the reaction, the product was washed with water and dried over magnesium sulfate, and the solvent was then distilled out from the dried product under reduced pressure. The residue was purified by column chromatography to obtain 2.8 g of the objective ester compound. (Yield: 85%)