Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:28][CH3:29].Cl>C(#N)C>[CH2:28]([N:18]1[CH2:19][CH2:20][CH:15]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:9])=[O:10])[C:2]=2[F:1])[CH2:16][CH2:17]1)[CH3:29]
Reactant: CCI
Reactant: O=S(=O)(c1cccc(C2CCNCC2)c1F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(c2cccc(S(=O)(=O)C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 4-{2-fluoro-3-[(trifluoromethyl)sulfonyl]phenyl}-piperidine (0.11 g, 0.35 mmol), acetonitrile (4 ml), potassium carbonate (0.063 g, 0.7 mmol) and 1-iodoethane (0.055 g, 0.35 mmol). Yield: 0.068 g (57%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 189-191° C. MS m/z (relative intensity, 70 eV) 339 (M+, 8), 325 (15), 324 (bp), 205 (6), 191 (15).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([CH3:14])([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])[CH3:3].C(N(C(C)C)C(C)C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:46]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[O:54][C:55]1[N:60]=[CH:59][C:58]([NH2:61])=[CH:57][CH:56]=1)[CH3:47]>CN(C)C=O>[CH2:46]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[O:54][C:55]1[N:60]=[CH:59][C:58]([NH:61][C:11](=[O:13])[C:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:10])[CH3:14])=[CH:57][CH:56]=1)[CH3:47]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: CCc1ccccc1Oc1ccc(N)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1ccccc1Oc1ccc(NC(=O)C(C)(C)NC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21.7 %

Procedure:
In a 8 mL vial N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-methylalanine (208 mg, 1.022 mmol) was dissolved in N,N-dimethylformamide (4 mL) to give a colourless solution. N-ethyl-N-(1-methylethyl)-2-propanamine (0.223 mL, 1.277 mmol) and N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylidene]-N-methylmethanaminium tetrafluoroborate (328 mg, 1.022 mmol) were added. The reaction mixture was stirred at room temperature for 15 min. 6-[(2-ethylphenyl)oxy]-3-pyridinamine (Intermediate 46, 228 mg) was added and the reaction mixture was warmed to 60° C. After 24 hours, additional 150 mg of N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylidene]-N-methylmethanaminium tetrafluoroborate were added. After additional 8 hours, the solvent was evaporated under vacuum using the Genevac affording a dark brown oil which was purified by silica gel chromatography (Biotage system, 25 g SNAP column) with as eluent a gradient Cyclohexane/EtOAc from 3:1 to 1:1 in 10 CV, then 1:1 for 5 CV. The collected fractions afforded the title compound as a pale orange solid (88.6 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1.C([O-])(O)=O.[Na+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C(OCC)(=O)C.O>[CH2:20]([O:19][C:17]([NH:2][C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C1(N)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1(NC(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
A suspension of ethyl 1-aminocyclopropanecarboxylate hydrochloride (9.5 g, 57.3 mmol) in 450 mL of ethyl acetate was cooled to 0° C., a solution of NaHCO3 (39.5 g, 470.3 mmol) in 325 mL of water was added slowly. Then benzyl chloroformate (13.3 g, 78.2 mmol) was added drop-wise. The cold bath was removed and the mixture was stirred at room temperature for 16 hours. The organic phase was washed with 1N HCl (100 mL), saturated NaHCO3 solution (100 mL), brine (100 mL), and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated to give a white solid. The solid was purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of ethyl acetate and petroleum ether (1:3, v/v) to give ethyl 1-(benzyloxycarbonylamino)cyclopropanecarboxylate (13.7 g, 91%) as a white solid. MS: (M+H)+=286.1; 1H NMR (300 MHz, CDCl3): δ 7.37-7.32 (m, 5H), 5.13 (s, 2H), 4.70 (s, 1H), 4.13 (brs, 2H), 1.59-1.53 (m, 2H), 1.23-1.19 (m, 5H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[C:26]([F:29])([F:28])[F:27])[C:20]([OH:22])=O>CCCCCCC.CCOC(C)=O>[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[C:26]([F:29])([F:28])[F:27])[C:20]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:22]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(O)c1ccc(C(F)(F)F)c(F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1ccc(C(F)(F)F)c(F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-fluoro-4-(trifluoromethyl)benzoic acid (CAS RN 115754-21-7) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light brown solid (20%). MS (ESI): m/z=389.13 [M+H]+.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([NH2:28])=[O:27].CO>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([N:24]5[CH2:31][CH2:30][CH2:29][C@H:25]5[C:26]([NH2:28])=[O:27])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Solvent: ClCCl
Solvent: CO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCC[C@H]3C(N)=O)cc1OCC2
Yield: 44 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and L-prolinamide, were reacted and the crude product subjected to flash chromatography (SiO2, gradient 0 to 8% methanol in DCM) then recrystallisation from methanol to give 338 as a white solid (115 mg, 44%). LCMS: RT=2.48 min, [M+H]+409. 1H NMR 400 MHz (DMSO-d6) δ: 9.06 (1 H, s), 7.88 (1 H, s), 7.83 (1 H, s), 7.33 (1 H, br), 6.92 (1 H, br), 5.97-5.96 (1 H, m), 5.94 (1 H, s), 4.53-4.45 (4 H, m), 4.30 (1 H, d, J=8.51 Hz), 3.59 (1 H, s), 3.37 (1 H, d, J=9.93 Hz), 2.18 (1 H, m), 1.95 (3 H, m), 1.47 (6 H, dd, J=6.59, 3.43 Hz)
Reaction SMILES: [O:1]=[C:2]1[CH2:3][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][CH:7]=[CH:8]1.C[Si]([N:20]=[N+:21]=[N-:22])(C)C>C(#N)C>[N:20]([CH:7]1[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C:2](=[O:1])[CH2:8]1)=[N+:21]=[N-:22]
Reactant: CC(C)(C)OC(=O)N1CCC=CC(=O)C1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])CC(=O)C1
Temperature: 60 °C
Yield: 91.5 %

Procedure:
To as solution of (Z)-tert-butyl 3-oxo-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (2.0 g, 9.5 mmol) in acetonitrile (3 mL), was added trimethylsilyl azide (3.76 mL, 28.4 mmol) followed by AMBERLITE® IRA 900F resin (loading: 2-3 mmolg-1, 2.4 g) and the resulting mixture was heated at 60° C. behind a blast shield for 16 hr. After cooling to room temperature, the solution was filtered washing the resin with acetonitrile and the filtrate was concentrated under reduced pressure (temperature of bath<40° C.) to give tert-butyl 5-azido-3-oxoazepane-1-carboxylate as a yellow liquid (2.21 g). To a solution of the azide (2.2 g, 8.70 mmol) in THF/water (1/1, 40 mL), was added portionwise NaBH4 (0.82 mg, 21.8 mmol) and the mixture was stirred at room temperature for 2 hr. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-60% EtOAc/isohexane) gave tert-butyl 5-azido-3-hydroxyazepane-1-carboxylate as an oil (2.01 g). To a solution of this oil (2.0 g, 7.8 mmol) in MeOH (20 mL), was added HCl (4 M in 1,4-dioxane, 43 mL, 173 mmol) and the solution was stirred at room temperature for 16 hr. The solvents were removed under reduced pressure and the crude residue was dissolved in MeOH and passed through an SCX column, washing with MeOH and eluting with 7 N ammonia in MeOH to give 5-azidoazepan-3-ol as a yellow oil. To this oil in dry DMSO (20 mL) was added potassium fluoride (1.68 g, 28.9 mmol) and 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (1.17 g, 7.2 mmol) and the mixture heated at 65° C. for 16 hr. The mixture was diluted with water (300 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (3×20 mL), separated, dried over MgSO4 and the solvents removed under reduced pressure. Purification via silica gel column chromatography (0-30% EtOAc/isohexane) gave 5-azido-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-3-ol as a viscous yellow oil (1.9 g, 72% over four steps). 1H NMR (400 MHz, CDCl3) δ 8.06 and 8.02 (2s, 1H), 4.15-3.97 (m, 2H), 3.95-3.83 (m, 4H), 3.58-3.46 (m, 1H), 3.39-3.16 (m, 3H), 2.29-1.91 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=[O:13])[C:10]=1[Cl:11])[N:7](C(OC(C)(C)C)=O)[CH:6]=[CH:5]2.O.C(=O)([O-])[O-].[K+].[K+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=[O:13])[C:10]=1[Cl:11])[NH:7][CH:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)n1ccc2cc(Br)c(Cl)c(C(=O)O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(O)c1c(Cl)c(Br)cc2cc[nH]c12
Temperature: 70 °C
Reaction time: 5.5 h
Yield: 100.1 %

Procedure:
To a mixture of 5-bromo-1-(tert-butoxycarbonyl)-6-chloro-1H-indole-7-carboxylic acid (0.3 g), water (2.0 mL), and methanol (6.0 mL) was added potassium carbonate (0.6 g) at room temperature. The reaction mixture was stirred at 70° C. for 5.5 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and water were added thereto, followed by acidification with 1 M hydrochloric acid. Then, a liquid-separation operation was carried out, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to obtain 5-bromo-6-chloro-1H-indole-7-carboxylic acid (0.22 g).
Reaction SMILES: [C:1]1([CH3:32])[CH:6]=[CH:5][C:4]([N:7]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:30]C)[CH:26]=3)[CH:21]=2)[C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18]C)[CH:14]=3)[CH:9]=2)=[CH:3][CH:2]=1.B(Br)(Br)Br>C(Cl)Cl>[C:1]1([CH3:32])[CH:2]=[CH:3][C:4]([N:7]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([OH:30])[CH:26]=3)[CH:21]=2)[C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[CH:9]=2)=[CH:5][CH:6]=1
Reactant: COc1ccc2cc(N(c3ccc(C)cc3)c3ccc4cc(OC)ccc4c3)ccc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(N(c2ccc3cc(O)ccc3c2)c2ccc3cc(O)ccc3c2)cc1
Temperature: 25 °C

Procedure:
In a reaction vessel equipped with an agitator, thermometer and a cooling pipe, 2.1 g of p-tolyl-bis(6-methoxy-2-naphthyl)amine and 50 mL of methylene chloride were placed. While the vessel was being cooled with ice, 12 mL of a 1M methylene chloride solution of boron tribromide was delivered by drops into the vessel, and the mixture was reacted at the same temperature for one hour. The temperature was raised to a room temperature and further reacted for one hour. Then, the reacted solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and separated, and it was then dried with magnesium sulfate and subjected to vacuum concentration. Thus, the objective product was obtained with the yield of 2.38 g.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1CCCC1>CO>[N+:11]([C:3]1[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[S:6][C:2]=1/[CH:1]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O-:13])=[O:12]
Reactant: O=Cc1ccccc1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)s1
Solvent: CO
Solvent: C1CCNC1
Product: COC(=O)c1cc([N+](=O)[O-])c(/C=C/c2ccccc2)s1
Yield: 67 %

Procedure:
A solution (0.33 M) of methyl 5-methyl-4-nitrothiophene-2-carboxylate in MeOH, was treated with benzaldehyde (1.5 eq.). The reaction mixture was heated to reflux and when it became a clear solution a catalytic amount of pyrrolidine (0.01 eq.) was added. After 18 h at reflux additional pyrrolidine (0.01 eq.) was added. The reaction was heated to reflux for 40 h. After cooling down, evaporation of the solvent gave a residue that was purified by flash chromatography on silica gel (1:9 AcOEt/petroleum ether) to afford the title compound (67%) as a solid.
Reaction SMILES: [C:1]1([S:7]([N:10]=[C:11]2[CH:16]=[CH:15][C:14](=[N:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:13]=[CH:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:31])=[O:30].[Na]>>[C:1]1([S:7]([NH:10][C:11]2[C:12](=[N:10][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:13]=[C:14]([NH:17][S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:20])=[O:19])[C:15](=[N:28][S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:16]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(N=C1C=CC(=NS(=O)(=O)c2ccccc2)C=C1)c1ccccc1
Reactant: O=S(=O)(NCl)c1ccccc1
Agent: [Na]
Product: O=S(=O)(N=C1C=C(NS(=O)(=O)c2ccccc2)C(=NS(=O)(=O)c2ccccc2)C=C1NS(=O)(=O)c1ccccc1)c1ccccc1

Procedure:
N,N′-Bis[phenylsulfonyl]-1,4-benzoquinone diimine is sulfanylamidated by sodium N-chlorobenzenesulfonamide to form 2,5-bis(phenylsulfonylamino)-N,N′-bis(phenylsulfonyl)-1,4-benzoquinone diimine. Similarly, amidation of N,N′-bis[phenylsulfonyl]-1,4-benzoquinone diimine with N-chloroamides gives the corresponding sulfonyl benzoquinone diimine derivatives in one step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:23]([O:25][CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:24])[CH:20]=2)[N:15]([CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][C:36]([Cl:42])=[CH:37][CH:38]=3)[N:33]=2)[CH:14]=1)[C:6](O)=[O:7].[CH3:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[S:50]([NH2:53])(=[O:52])=[O:51].Cl.CN(C)CCCN=C=NCC.CC(O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:23]([O:25][CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:24])[CH:20]=2)[N:15]([CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][C:36]([Cl:42])=[CH:37][CH:38]=3)[N:33]=2)[CH:14]=1)[C:6]([NH:53][S:50]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=1[CH3:43])(=[O:52])=[O:51])=[O:7]
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(Cc2ccc3ccc(Cl)cc3n2)c2ccc(NC(=O)OC3CCCC3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cn(Cc2ccc3ccc(Cl)cc3n2)c2ccc(NC(=O)OC3CCCC3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a solution the acid from Step 4 (159 mg) and 2-methylbenzenesulfonamide (70 mg) in CH2Cl2 (3 ml) was added successively 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (78 mg) and DMAP (50 mg). After stirring at r.t. overnight, HOAc (200 μl) was added and the mixture was concentrated. Chromatography of the residue using EtOAc/hexane (2:3) containing 1% HOAc afforded 172 mg of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]=[C:7]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])[C:8]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:9]=2[N:10]=1.[CH:31]1[CH:36]=[CH:35][C:34]([O:37][C:38](OC2C=CC=CC=2)=[N:39][C:40]#[N:41])=[CH:33][CH:32]=1>C(O)(C)C>[C:40]([NH:39][C:38](=[N:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]=[C:7]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])[C:8]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:9]=2[N:10]=1)[O:37][C:34]1[CH:35]=[CH:36][CH:31]=[CH:32][CH:33]=1)#[N:41]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: NCCNc1nc(-c2ccc(F)cc2F)c2ccc(=O)n(-c3ccccc3F)c2n1
Solvent: CC(C)O
Product: N#CNC(=NCCNc1nc(-c2ccc(F)cc2F)c2ccc(=O)n(-c3ccccc3F)c2n1)Oc1ccccc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[(2-aminoethyl)amino]-4-(2,4-difluorophenyl)-8-(2-fluorophenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (28 mg, 0.070 mmol) in isopropanol (2 mL) was added diphenyl cyanocarbonimidate (17 mg, 0.070 mmol). The mixture was stirred for about 30 min at about 20° C. LC/MS showed a new peak corresponding to the desired product and no starting material in the solution. LC-MS m/z 556 (M+H)+, 3.24 min (ret time).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=O)=[CH:9][N:10]=2)[CH:7]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(O)(=O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: O=Cc1cnc2ccc(Br)cn12
Reactant: C1COCCN1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Brc1ccc2ncc(CN3CCOCC3)n2c1
Yield: 42.4 %

Procedure:
Reflux a solution of 6-bromo-imidazo[1,2-a]pyridine-3-carbaldehyde (J. Med. Chem. 1970, 13(6), 1048-51; 0.45 g, 1.99 mmol), morpholine (1.7 g, 19.9 mmol), and acetic acid (0.12 mL, 1.99 mmol) in toluene (200 mL) for 3 h. Concentrate to dryness and re-dissolve in methanol (100 mL). Add sodium borohydride (0.226 g, 5.99 mmol) in portions and stir for 30 min. Concentrate to ˜25 mL, dilute with saturated aqueous sodium bicarbonate, extract into ethyl acetate, combine and concentrate. Flash chromatography gives the titled compound (0.25 g, 42%). MS ES+ m/e 295.8, 297.8 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 7.54 (d, J=10 Hz, 1H), 7.51 (s, 1H), 7.35 (d, J=10 Hz, 1H), 3.81 (s, 2H), 3.52 (t, J=4 Hz, 1H), 2.35 (t,J=4 Hz, 4H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.I[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 30 °C

Procedure:
Anhydrous K2CO3 (416g, 3 mol) was added to a mixture of 4-bromo-4′-hydroxybiphenyl (300 g, 1.2 mol), 1-iodopentane (234 ml, 1.79 mol) and 2-butanbne (600 ml). The reaction mixture was refluxed for 44 h until TLC (85:15 hexanes/EtOAc) showed complete consumption of the bromo alcohol. The mixture was cooled to about 30° C., diluted with CH2C12 (600 ml) and then filtered. The filtrate was washed twice with H2O and twice with a saturated aqueous NaCl solution, dried over anhydrous Na2SO4, filtered and then dried at reduced pressure to provide a solid. This solid was isolated by filtration, washed repeatedly with a total of 2 L of ice-cold heptane to remove all traces of iodopentane and then dried overnight under high vacuum. Yield: 340 g (88%) of a white powder.
Reaction SMILES: FC[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:11][NH2:12]>C(O)CO>[NH:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:3]=[N:12]1
Reactant: NN
Reactant: O=C(CF)c1ccccc1
Solvent: OCCO
Product: c1ccc2[nH]ncc2c1

Procedure:
100 g of fluoro-acetophenone in 400 mL of ethylene glycol was stirred at room temperature with hydrazine (0.624 mol, 20 g) for 4 h after which the reaction mixture was heated to 150 C for 48 h. TLC analysis indicated complete reaction. Partitioned the reaction mixture into dichloromethane and brine. Dried organic phase over sodium sulphate and evaporated to a solid. Re-crystallized from hexane/dicholomethane gave indazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])NC2SC(SCC(O)=O)=CN=2)[CH:5]=[CH:6][CH:7]=1.C([O:34][C:35](=[O:46])[C:36]([S:39][C:40]1[S:44][C:43]([NH2:45])=[N:42][CH:41]=1)([CH3:38])[CH3:37])C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:12](=[O:24])[NH:45][C:43]2[S:44][C:40]([S:39][C:36]([CH3:37])([CH3:38])[C:35]([OH:34])=[O:46])=[CH:41][N:42]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Product: CC(C)(Sc1cnc(NC(=O)N(CCCc2cccc(Cl)c2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:14]([CH3:18])([CH3:17])[C:15]#[N:16])[CH:6]=[C:7]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:8]=1.N1C=CC=CC=1.S(Cl)([Cl:27])=O>ClCCl>[Cl:27][CH2:2][C:3]1[CH:4]=[C:5]([C:14]([CH3:18])([CH3:17])[C:15]#[N:16])[CH:6]=[C:7]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C#N)c1cc(CO)cc(C(C)(C)C#N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C#N)c1cc(CCl)cc(C(C)(C)C#N)c1
Reaction time: 2 h

Procedure:
A solution of 2,2'-(5-hydroxymethyl-1,3-phenylene)di-(2-methylpropiononitrile), (3.8 g) and pyridine (1.58 g) in dichloromethane (10 ml) was stirred, and cooled in an ice bath, while thionyl chloride (3 g) was added over 10 minutes. The solution was kept at room temperature for 2 h and then heated under reflux for 1 h and evaporated to dryness under reduced pressure The residue was partitioned between water and ethyl acetate and the organic phase was separated, dried and evaporated to dryness under reduced pressure to give 2,2'-(5-chloromethyl-1,3-phenylene)di(2-methylpropiononitrile), which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[CH2:19][CH2:20][O:21][C:22]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)=[CH:25][C:23]=3[CH:24]=2)=[O:17])=[CH:11][CH:10]=1)=[O:8].CI.[CH:38](N(C(C)C)CC)(C)C>ClCCl>[CH3:38][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]2[CH2:19][CH2:20][O:21][C:22]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=4)=[CH:25][C:23]=3[CH:24]=2)=[O:17])=[CH:13][CH:14]=1)=[O:8]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(=O)C4CCCCN4)cc2)CCO3)cc1
Solvent: CI
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(=O)C4CCCCN4C)cc2)CCO3)cc1
Temperature: 25 °C

Procedure:
In dichloromethane (35ml) was dissolved N-(4(piperidin-2-ylcarbonyl)-phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.3g), and to the solution were added methyl iodide (0.08ml) and diisopropyl-ethylamine (0.17ml). The mixture was stirred at room temperature over night. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give N-(4-(1-methylpiperidin-2-ylcarbonyl)-phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 157) (0.17g) as colorless crystals.