Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][C:5]2[N:6]([CH2:10][CH3:11])[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1.[Br:15][CH2:16][CH2:17][N:18]1[C:22](=[O:23])[CH2:21][CH2:20][C:19]1=[O:24].C1(OC)C=CC=CC=1>C(OCC)(=O)C>[Br-:15].[Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][C:5]2[N+:6]([CH2:10][CH3:11])=[C:7]([CH3:9])[N:8]([CH2:16][CH2:17][N:18]3[C:22](=[O:23])[CH2:21][CH2:20][C:19]3=[O:24])[C:4]=2[CH:3]=1
Reactant: CCn1c(C)nc2cc(Cl)c(Cl)cc21
Reactant: O=C1CCC(=O)N1CCBr
Solvent: CCOC(C)=O
Solvent: COc1ccccc1
Product: CC[n+]1c(C)n(CCN2C(=O)CCC2=O)c2cc(Cl)c(Cl)cc21
Product: [Br-]
Temperature: 130 °C

Procedure:
11.5 g of 5,6-dichloro-1-ethyl-2-methylbenzoimidazole and 20.6 g of N-(2-bromoethyl)succinimide were put into a 200-ml three-necked flask equipped with a stirrer and a reflux condenser and heated for 2 hours on an oil bath which has been heated to a temperature of 130° C. 10 ml of anisole was added to the mixture. The admixture was then allowed to stand for cooling. 50 ml of ethyl acetate was added to the admixture. The admixture was then refluxed for 30 minutes. After being allowed to cool to room temperature, the resulting crystal was filtered off, washed with acetone, and then dried at a temperature of 50° C. for 5 hours. Yield: 18.7 g (86%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:19][NH:20][C:21]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[C:25]([OH:33])[CH:24]=3)=[O:22])[CH3:18])[C:12]=2[OH:34])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>C1COCC1.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:19][NH:20][C:21]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[C:25]([OH:33])[CH:24]=3)=[O:22])[CH3:18])[C:12]=2[OH:34])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=NNC(=O)c1ccc(C(=O)O)c(O)c1)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Temperature: 50 °C
Reaction time: 14 h
Yield: 76.8 %

Procedure:
To methyl 4-[(2-{1-[5-(4-tert-butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]-2-hydroxybenzoate (0.438 mmol, 203.3 mg), methanol (20 mL) was added, and 1 M aqueous sodium hydroxide (2.2 mmol, 2.2 mL) was added. After 5 hours of stirring at 50° C., 14 hours of stirring at room temperature and 4 hours of stirring at 50° C., 1 M hydrochloric acid (2.2 mmol, 2.2 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump to give the crude desired product as a yellow solid (175.0 mg). It was further dissolved in THF (35 mL) and stirred at room temperature for 2 days. The insolubles were filtered off, and the filtrate was concentrated and dried by means of a vacuum pump. After addition of chloroform, the precipitated solid was recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (151.6 mg, yield 77%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][CH:5]=[C:4]([C:8]2[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=2[CH3:17])[CH:3]=1.[C:18]1([S:24]([NH2:27])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[CH3:17][C:9]1[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=1[C:4]1[CH:3]=[C:2]([NH:27][S:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:26])=[O:25])[N:7]=[N:6][CH:5]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CC(=O)Nc1nc(C)c(-c2cnnc(Cl)c2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1nc(C)c(-c2cnnc(NS(=O)(=O)c3ccccc3)c2)s1
Temperature: 200 °C
Yield: 9.2 %

Procedure:
A mixture of N-[5-(6-chloropyridazin-4-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (55 mg), benzenesulphonamide (49 mg), caesium carbonate (101 mg), cuprous iodide (30 mg) and DMA (1.5 mL) was heated in a microwave reactor to 200° C. under an argon atmosphere for 3 hours. The resultant mixture was evaporated and the residue was purified by preparative HPLC on reversed phase silica using a solvent gradient of 10% to 100% acetonitrile in water (containing 1% acetic acid) as eluent. The material so obtained was triturated under diethyl ether. There was thus obtained the title compound as a solid (7.3 mg); 1H NMR Spectrum: (DMSOd6+CD3CO2D) 2.20 (s, 3H), 2.43 (s, 3H), 7.51-7.64 (m, 3H), 7.75 (s, 1H), 7.89 (d, 2H), 8.51 (s, 1H); Mass Spectrum: M+H+ 390.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Cl[C:17]1[N:18]=[CH:19][C:20]([C:23]([O:25][CH3:26])=[O:24])=[N:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][N:8]([C:17]2[N:18]=[CH:19][C:20]([C:23]([O:25][CH3:26])=[O:24])=[N:21][CH:22]=2)[CH2:9][CH2:10]1
Reactant: Fc1ccc(Br)c(OC2CCNCC2)c1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cnc(N2CCC(Oc3cc(F)ccc3Br)CC2)cn1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(2-bromo-5-fluorophenoxy)piperidine from Step 2 (1.90 g, 6.95 mmol), methyl 5-chloropyrazine-2-carboxylate (1.00 g, 5.79 mmol) and potassium carbonate (1.60 g, 11.59 mmol) in dioxane (30 mL) was heated at 100° C. After a period of 2 h, the reaction mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The solvent was separated, dried over sodium sulfate and evaporated. The title compound was purified by flash chromatography (50% ethyl acetate in hexane) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:76][CH2:77][CH2:78][O:79][CH2:80][CH2:81][O:82][CH2:83][CH2:84][O:85][CH2:86][CH2:87][NH2:88]>O1CCCC1>[NH2:88][CH2:87][CH2:86][O:85][CH2:84][CH2:83][O:82][CH2:81][CH2:80][O:79][CH2:78][CH2:77][NH:76][C:35]([C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)=[O:37]
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: NCCOCCOCCOCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(C(=O)NCCOCCOCCOCCN)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 20 mL round-bottomed flask, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 100 mg, 162 μmol), HBTU (61.5 mg, 162 μmol) and Hunig's base (105 mg, 142 μL, 811 μmol) were combined with dry tetrahydrofuran (2 mL) to give an off-white suspension at room temperature. It was stirred at room temperature for 30 min. 1,11-Diamino-3,6,9-trioxaundecane (15.6 mg, 15.2 μL, 81.1 μmol) was added. After stirring at room temperature overnight, the reaction mixture was absorbed on small amount of silica gel, loaded on a 24 g pre-packed silica gel column and eluted with ethyl acetate to give (2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-{2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-ethylcarbamoyl)-2-methoxy-phenyl]-amide, dimer as white solid (148 mg, 66% yield). LCMS (ES+) m/z calcd. for C70H74Cl4F4N8O9 [(M+H)+]: 1387. found: 1387.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](O)([Sn:10]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[C:1]([N:4]1[CH2:5][CH:6]=[C:7]([Sn:10]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)C1(O)CCN(C(C)=O)CC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC[Sn](CCCC)(CCCC)C1=CCN(C(C)=O)CC1
Temperature: 0 °C
Reaction time: 60 h

Procedure:
1-Acetyl-4-hydroxy-4-tributylstannyl-piperidine, 20 (16.4 g, 38 mmol) and triethylamine (15.0 ml, 108 mmol) were dissolved in methylene chloride (250 ml) and the solution cooled to 0° C. Methanesulfonylchloride (6.0 ml, 50 mmol) in methylene chloride (50 ml) was added dropwise to the cooled solution and the mixture was allowed to warm to room temperature and stir for 60 hours. The reaction solution was washed with NaCl solution, dried (MgSO4), filtered, and evaporated to give a red oil which was purified by flash column chromatography on silica gel, eluting with 3% ethanol in CH2Cl2. After combining the appropriate fractions and evaporating the solvent, the title compound, 21, was obtained (7.5 g).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:24][Si]([N-][Si](C)(C)C)(C)C.[Li+].[OH:34][C:35]([C:68]1[S:69][CH:70]=[CH:71][CH:72]=1)([C:63]1[S:64][CH:65]=[CH:66][CH:67]=1)[C:36]([O:38][C@H:39]1[CH2:44][CH2:43][C@H:42]([N:45]([CH2:47][CH2:48][C:49]([NH:51][C:52]2[CH:57]=[C:56]([O:58][CH3:59])[C:55](C=O)=[CH:54][C:53]=2[Cl:62])=[O:50])[CH3:46])[CH2:41][CH2:40]1)=[O:37].[Cl-].[NH4+]>>[OH:34][C:35]([C:68]1[S:69][CH:70]=[CH:71][CH:72]=1)([C:63]1[S:64][CH:65]=[CH:66][CH:67]=1)[C:36]([O:38][C@H:39]1[CH2:40][CH2:41][C@H:42]([N:45]([CH2:47][CH2:48][C:49]([NH:51][C:52]2[CH:57]=[C:56]([O:58][CH3:59])[C:55](/[CH:24]=[CH:4]/[O:3][CH3:2])=[CH:54][C:53]=2[Cl:62])=[O:50])[CH3:46])[CH2:43][CH2:44]1)=[O:37]
Reactant: COc1cc(NC(=O)CCN(C)[C@H]2CC[C@H](OC(=O)C(O)(c3cccs3)c3cccs3)CC2)c(Cl)cc1C=O
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Product: CO/C=C/c1cc(Cl)c(NC(=O)CCN(C)[C@H]2CC[C@H](OC(=O)C(O)(c3cccs3)c3cccs3)CC2)cc1OC
Reaction time: 0.5 h

Procedure:
To a suspension of (methoxymethyl) triphenylphosphonium chloride (0.83 g, 2.43 mmol) in anhydride tetrahydrofuran (4.3 mL) was added dropwise a solution of lithium bis(trimethylsilyl) amide 1M (2.43 mL, 2.43 mmol) at 0° C. under nitrogen atmosphere. The mixture was stirred for 30 minutes, then a solution of trans-4-((3-(2-chloro-4-formyl-5-methoxyphenylamino)-3-oxopropyl)(methyl)amino)cyclohexyl hydroxy(di-2-thienyl)acetate (intermediate 43; 0.41 g, 0.69 mmol) in anhydride tetrahydrofuran (2.1 mL) was added dropwise into the mixture. The reaction was stirred for 30 minutes at 0° C. and for 1.5 hours at room temperature. The crude was added into a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water, brine, dried and the solvent was removed under reduced pressure giving an orange solid. This crude was purified by column chromatography with silica gel, eluting with methylene chloride/isopropanol (93:7) to give the title compound as a white solid (56%).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.[CH3:17][CH:18]([C@H:20]1[CH2:24][O:23][C:22](=[O:25])[NH:21]1)[CH3:19].[Li]CCCC>C(Cl)Cl.CN(C=O)C.C1COCC1>[CH:18]([C@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:6](=[O:8])[CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:10])[F:9])([CH3:19])[CH3:17]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: O=C(O)CCCC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)[C@H]1COC(=O)N1C(=O)CCCC(F)(F)F
Temperature: 0 °C

Procedure:
To a stirred solution of 5,5,5-trifluoropentanoic acid (5.04 g, 32.3 mmol) in DCM (50 mL) and DMF (3 drops) was added oxalyl chloride (3.4 mL, 38.8 mmol) dropwise over 5 min. The solution was stirred until all bubbling subsided. The reaction mixture was concentrated under reduced pressure to give a pale yellow oil. To a separate flask, charged with a solution of (4S)-4-(propan-2-yl)-1,3-oxazolidin-2-one (4.18 g, 32.4 mmol) in THF (100 mL) at −78° C. was added n-BuLi (13.0 mL, 32.5 mmol, 2.5M in hexane) dropwise via syringe over 5 min. After stirring for 10 min, the above acid chloride, dissolved in THF (20 mL), was added via cannula over 15 min. The reaction mixture was warmed to 0° C. and was allowed to warm to room temperature as the bath warmed and stirred overnight. To the reaction mixture was then added saturated NH4Cl, and it was then extracted with EtOAc (2×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (hexanes/EtOAc) to provide Intermediate S-1G (7.39 g, 86%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 4.44 (1H, dt, J=8.31, 3.53 Hz), 4.30 (1H, t, J=8.69 Hz), 4.23 (1H, dd, J=9.06, 3.02 Hz), 2.98-3.08 (2H, m), 2.32-2.44 (1H, m, J=13.91, 7.02, 7.02, 4.03 Hz), 2.13-2.25 (2H, m), 1.88-2.00 (2H, m), 0.93 (3H, d, J=7.05 Hz), 0.88 (3H, d, J=6.80 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH3:2].C(N(CC)C(C)C)(C)C.Cl.[NH2:27][CH2:28][C:29]1([C:35]2[CH:40]=[CH:39][C:38]([S:41]([NH:44][C:45]3[S:46][C:47]([CH:50]([CH3:52])[CH3:51])=[N:48][N:49]=3)(=[O:43])=[O:42])=[CH:37][CH:36]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([NH:27][CH2:28][C:29]1([C:35]2[CH:36]=[CH:37][C:38]([S:41](=[O:43])(=[O:42])[NH:44][C:45]3[S:46][C:47]([CH:50]([CH3:52])[CH3:51])=[N:48][N:49]=3)=[CH:39][CH:40]=2)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)=[O:8])[CH3:2]
Reactant: CCOc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: CC(C)c1nnc(NS(=O)(=O)c2ccc(C3(CN)CCCCC3)cc2)s1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(C(F)(F)F)ccc1C(=O)NCC1(c2ccc(S(=O)(=O)Nc3nnc(C(C)C)s3)cc2)CCCCC1
Yield: 94.6 %

Procedure:
55 mg of 2-ethoxy-4-trifluoromethyl-benzoic acid (example 1g), 85 mg Totu and 100 mg N,N-diisopropylethylamine were dissolved in cold dimethylformamide. After 30 minutes 100 mg of 4-(1-aminomethyl-cyclohexyl)-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-benzenesulfonamide hydrochloride were added and the mixture stirred over night. After evaporation of the solvent the residue was purified by chromatography on silica gel with the eluents dichloromethane:methanol=98:2 to obtain 134 mg of an oily product.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.[NH2:8][CH2:9][CH2:10][N:11]1[CH2:16][C@H:15]([CH3:17])[O:14][C@H:13]([CH3:18])[CH2:12]1.[S-:19][C:20]#[N:21].[K+].II>>[C:2]([C:3]1[S:19][C:20](=[NH:21])[N:8]([CH2:9][CH2:10][N:11]2[CH2:16][C@@H:15]([CH3:17])[O:14][C@@H:13]([CH3:18])[CH2:12]2)[CH:4]=1)([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(C)(C)CC=O
Reactant: N#C[S-]
Reactant: C[C@@H]1CN(CCN)C[C@H](C)O1
Agent: II
Agent: [K+]
Product: C[C@@H]1CN(CCn2cc(C(C)(C)C)sc2=N)C[C@H](C)O1

Procedure:
Commercially available 3,3-dimethylbutanal (Aldrich), 4-(2-aminoethyl)-cis-2,6-dimethylmorpholine (Oakwood), potassium thiocyanate (Aldrich) and iodine (EMD chemicals) were processed using the method described in Example 315A to afford the title compound. MS (ESI+) m/z 298 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][Cl:12])[CH:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[Br:16]Br.C(=O)(O)[O-].[Na+]>CCOCC>[Br:16][CH2:14][C:13]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH2:10][CH2:11][Cl:12])=[CH:7][C:2]=1[CH3:1])=[O:15]
Reactant: CC(=O)c1ccc(OCCCCl)cc1C
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: Cc1cc(OCCCCl)ccc1C(=O)CBr
Reaction time: 17 h

Procedure:
A solution of the product of Step A (9.33 g) in ether (42 mL) was treated with bromine (2.1 mL) and the mixture stirred for approximately 17 hours. The mixture was slowly poured into saturated sodium bicarbonate solution (100 mL) and then the organic layer was separated. The aqueous layer was washed with a fresh portion of ether (100 mL). The combined organic layers were washed with a fresh portion of water (100 mL), dried over magnesium sulfate, filtered and evaporated to give the title compound (11 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.[N-:20]=[N+:21]=[N-:22].[Na+].O1CCOCC1.[Si](Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[NH:22][N:21]=[N:20][N:8]=2)=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(C(N)=O)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Cc1ccc(-c2nnn[nH]2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.27 g, 1.0 mmol) and sodium azide (0.20 g, 3.1 mmol) were added to dioxane (5.2 mL, 1.0 mmol) before silicon tetrachloride (0.12 mL, 1.0 mmol) was added. The reaction mixture was heated to 85° C. for 7 h when two spots were observed by tlc. The reaction mixture was stirred at 60° C. overnight. The reaction mixture was diluted with 50 mL chloroform, partitioned with brine (saturated, aqueous), washed 2 times with 50 mL of chloroform, separated, dried over sodium sulfate, and concentrated in vacuo to give the title compound. MS (ES+): 287 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1>CN(C=O)C>[O:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH:22]1[O:21][CH2:20][CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCOC2CCCCO2)cc1
Temperature: 100 °C
Yield: 105.4 %

Procedure:
A mixture containing 40 g of methyl 4-hydroxybenzoate and 90.84 g of K2CO3 in 400 ml of DMF is heated to 100° C. and 71.47 g of 2-(2-bromoethoxy)tetrahydro-2H-pyran are added slowly, with continued heating for 8 hours. The inorganic material is filtered off and rinsed with DMF. The filtrate is evaporated under vacuum and then taken up in DCM, washed 3 times with water, dried over MgSO4 and then evaporated. 77.66 g of the expected compound are obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[N:16][O:17][CH:18]=2)=[CH:10][CH:11]=1)=[O:5])C.COC(C1C=NC(OCC2C(C3C=CC(Cl)=CC=3)=NOC=2)=CN=1)=O>>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:15]1[C:14]([CH2:13][O:12][C:9]2[N:8]=[N:7][C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=2)=[CH:18][O:17][N:16]=1
Reactant: CCOC(=O)c1ccc(OCc2conc2-c2ccccn2)nn1
Agent: COC(=O)c1cnc(OCc2conc2-c2ccc(Cl)cc2)cn1
Product: O=C(O)c1ccc(OCc2conc2-c2ccccn2)nn1
Yield: 86 %

Procedure:
As described for example 112a, 6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethyl ester (693 mg, 2.12 mmol) was converted, instead of 5-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-pyrazine-2-carboxylic acid methyl ester, to the title compound (544 mg, 86%) which was obtained as a grey solid. MS: m/e=297.5 [M−H]−.
Reaction SMILES: [OH-].[K+].[C:3]([O-])([O-:5])=[O:4].[K+].[K+].Br[C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1C(O)=O.[NH2:19][CH2:20][C:21]([OH:23])=[O:22]>O>[C:10]1([N:19]([C:3]([OH:5])=[O:4])[CH2:20][C:21]([OH:23])=[O:22])[CH:11]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C([O-])[O-]
Reactant: NCC(=O)O
Reactant: O=C(O)c1ccccc1Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CN(C(=O)O)c1ccccc1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
To a solution of KOH (25 g, 440 mmol) and K2CO3 (25 g, 180 mmol) in H2O (400 mL) was added 2-bromobenzoic acid, (38.2 g, 190 mmol), followed by glycine (25 g, 330 mmol) and CuBr (540 mg, 3.76 mmol). This mixture was heated at reflux for 4 h. After cooling to room temperature, the mixture was filtered over a fritted funnel to remove traces of Cu and the filtrate was acidified to pH 3 with concentrated HCl. The precipitate was collected and dried to obtain 32.44 g (88%) of the title compound, mp 225.9-226.2° C. (decomp., white foam); 1H NMR (DMSO-d6) δ 12.4 (br, 1H), 8.06 (br, 1H), 7.80 (m, 1H), 7.35 (m, 1H), 6.60 (m, 2H), 3.99 (s, 2H); 13C NMR (DMSO-d6) δ 171.8, 169.7, 150.0, 134.4, 131.7, 114.7, 111.5, 110.6, 44.4; MS (EI, m/z) 195 (M+).
Reaction SMILES: [F:1][C:2]1[C:3](NN)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:10]([N:12](CC)CC)C.CO[C:19](=[O:51])[N:20]=[C:21](SC)[C:22]([C:36]1[CH:46]=[C:45]([O:47][CH3:48])[C:39]2[O:40][CH2:41][CH2:42][CH2:43][O:44][C:38]=2[CH:37]=1)=[N:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:34]=[C:33]([CH3:35])[O:32][N:31]=2)=[CH:26][CH:25]=1>CN(C=O)C>[F:1][C:2]1[C:3]([CH:10]2[C:19](=[O:51])[NH:20][C:21]([CH:22]([C:36]3[CH:46]=[C:45]([O:47][CH3:48])[C:39]4[O:40][CH2:41][CH2:42][CH2:43][O:44][C:38]=4[CH:37]=3)[NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]4[N:34]=[C:33]([CH3:35])[O:32][N:31]=4)=[CH:28][CH:29]=3)=[N:12]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1)OCCCO2
Reactant: NNc1ncccc1F
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)C2=NC(c3ncccc3F)C(=O)N2)cc2c1OCCCO2
Temperature: 85 °C
Reaction time: 8 h

Procedure:
After adding 28 mg of (3-fluoropyridin-2-yl)hydrazine and 50 μl of triethylamine to a solution of 119 mg of {2-(9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 2-(3-fluoropyridin-2-yl)-5-{(9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2,4-dihydro-[1,1,4]triazol-3-one.
Reaction SMILES: C[C:2](P(OC)(O)=O)([C:4]([O-:6])=[O:5])[CH3:3].[H-].[Na+].[CH2:14]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([Cl:30])[CH:28]=2)[C:23]([S:31][C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)C=O)=[C:22]1[CH3:40])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:41]1COCC1>CCOC(C)=O>[CH3:41][O:6][C:4](=[O:5])/[CH:2]=[CH:3]/[C:34]1[CH:37]=[CH:38][CH:39]=[C:32]([S:31][C:23]2[C:24]3[C:29](=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:21]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:22]=2[CH3:40])[CH:33]=1
Reactant: C1CCOC1
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Reactant: Cc1c(Sc2cccc(C=O)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/c1cccc(Sc2c(C)n(Cc3ccccc3)c3cc(Cl)ccc23)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Trimethylphosphonoacetate (248 μL, 1.72 mmol) was dissolved in THF (10 mL) and the reaction was cooled to 0° C. then sodium hydride (60% dispersion in mineral oil, 0.042 g, 1.77 mmol) was added and the reaction stirred for 10 minutes. 3-(1-Benzyl-6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzaldehyde (0.225 g, 0.57 mmol) as a THF solution was added and the reaction was allowed to warm to room temperature. After 30 minutes, the reaction was diluted with EtOAc then quenched with aq. HCl (5 mL, 1M). Standard workup procedure afforded the title compound.