Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:16])/[CH:11]=[CH:12]/OCC.C1C(=O)N(Br)C(=O)C1.[NH2:25][C:26]([NH2:28])=[S:27].[OH-].[NH4+]>O1CCOCC1.O>[NH2:28][C:26]1[S:27][C:11]([C:10]([NH:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[O:16])=[CH:12][N:25]=1
Reactant: CCO/C=C/C(=O)Nc1c(C)cccc1Cl
Reactant: NC(N)=S
Agent: O=C1CCC(=O)N1Br
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(Cl)c1NC(=O)c1cnc(N)s1
Temperature: 21 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
To a mixture of compound 5B (5.00 g, 20.86 mmol) in 1,4-dioxane (27 mL) and water (27 mL) was added NBS (4.08 g, 22.9 mmol) at −10 to 0° C. The slurry was warmed and stirred at 20-22° C. for 3 h. Thiourea (1.60 g, 21 mmol) was added and the mixture heated to 80° C. After 2 h, the resulting solution was cooled to 20-22° and conc. ammonium hydroxide (4.2 mL) was added dropwise. The resulting slurry was concentrated under vacuum to about half volume and cooled to 0-5° C. The solid was collected by vacuum filtration, washed with cold water (10 mL), and dried to give 5.3 g (94.9% yield) of 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ δ 2.19 (s, 3H), 7.09-7.29 (m, 2H, J=7.5), 7.29-7.43 (d, 1H, J=7.5), 7.61 (s, 2H), 7.85 (s, 1H), 9.63 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ: 18.18, 120.63, 126.84, 127.90, 128.86, 132.41, 133.63, 138.76, 142.88, 159.45, 172.02.
Reaction SMILES: [NH:1]([CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[Br:31][CH2:32][C:33](Br)=[O:34].O>C(Cl)(Cl)(Cl)Cl>[CH2:17]([O:16][C:14]([CH2:13][N:1]([CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])[C:33](=[O:34])[CH2:32][Br:31])=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Br)CBr
Reactant: O=C(CNCC(=O)OCc1ccccc1)OCc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CN(CC(=O)OCc1ccccc1)C(=O)CBr)OCc1ccccc1
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A solution of dibenzyl iminodiacetate (9.7 g, 0.031 mol) and triethylamine (4.05 g, 0.04 mol) in 30 ml of carbon tetrachloride was added dropwise to a solution of bromoacetyl bromide (8.88 g, 0.044 mol) in 20 ml of carbon tetrachloride at 0° C and stirring was continued for 30 min. After addition of water, the organic layer was washed with saturated-NaHCO3 solution and saturated-brine, dried with MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography [silica gel, hexane:EtOAc (3:1)]and yielded 12.66 g (94%) of Compound 1; NMR (CDCl3): δ 3.86 (s,2H), 4.25 (s,2H), 5.15 (s,2H), 5.19 (s,2H), 7.3-7.5 (m, 10H).
Reaction SMILES: [F:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][OH:4].N1C=CC=CC=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:4][CH2:3][CH:2]([F:1])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCC(F)CO
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCC(F)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
In a vessel sufficiently replaced with nitrogen, 0.40 g (3.0 mmol) of (-)-2-fluoroheptanol and 1.00 g (13 mmol) of dry pyridine were placed and stirred for 30 min. under cooling on an ice bath. Into the solution, 0.69 g (3.6 mmol) of p-toluenesulfonyl chloride was added, and the mixture was stirred for 5 hours. After the reaction, 10 ml of 1N-HCl was added, and the resultant mixture was subjected to two times of extraction with 10 ml of methylene chloride. The extract liquid was washed once with 10 ml of distilled water and dried with an appropriate amount of anhydrous sodium sulfate, followed by distilling-off of the solvent to obtain 0.59 g (2.0 mmol) of (+)-2-fluoroheptyl p-toluenesulfonate.
Reaction SMILES: [N:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:14])=O.[S:15]([O-:18])([OH:17])=[O:16].[Na+].[OH-].[Na+]>O>[NH2:1][C:3]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[C:6]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:5][C:4]=1[OH:14]
Reactant: O=Nc1c(O)ccc2cc(Br)ccc12
Reactant: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(O)cc(S(=O)(=O)O)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.8 %

Procedure:
84.8 g (0.337 mol) of crude 1-nitroso-6-bromo-β-naphthol were stirred into a solution of 97.5 g (0.939 mol) of sodium hydrogen sulfite and 4.0 g (0.1 mol) of sodium hydroxide solution in 376 ml of water at room temperature. The suspension was made up to 1350 ml with water and stirred for 24 hours at room temperature. Then 6.8 g (8% of the amount taken) of the solution residue were separated off by filtration. Then acidification was carried out with 119.4 g (1.17 mol) of 96%-strength sulfuric acid at no more than 30° C. and the product was crystallized out for 48 hours at room temperature. After filtration by suction and drying, 92.0 g (86%) of 1-amino-2-hydroxy-6-bromo-4-naphthalene sulfonic acid were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[C:9](Cl)(=[O:11])[CH3:10]>O1CCOCC1>[NH2:8][C:4]1[N:3]=[C:2]([NH:1][C:9](=[O:11])[CH3:10])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)Cl
Reactant: Nc1cccc(N)n1
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(N)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
Dissolve 2,6-diaminopyridine (9.822 g, 90 mmol) in dioxane (100 mL) and cool to 0° C. Add acetyl chloride (2.355 g, 2.1 mL, 30 mmol) slowly and stir for 1 hr. at 0° C. Remove the ice bath and stir at room temperature overnight. Quench the reaction mixture with saturated NaHCO3 solution, extract with ethylacetate three times. Combine the organic layers, dry over Na2SO4, filter, and concentrate to give a solid. Chromatography on silica gel, eluting with a gradient of 60–70% ethylacetate in hexanes affords the title intermediate (3.45 g, 76%): mass spectrum (ion spray): mz/z=152.1 (M+1); 1H NMR (CDCl3, ppm): 7.49 (m, 3H), 6.28 (d, 1H), 4.31 (s, br, 2H), 2.19 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10](O)[CH3:11])=[CH:6][C:5]=1[N+:13]([O-:15])=[O:14].CCN(S(F)(F)[F:23])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([F:23])[CH3:11])=[CH:6][C:5]=1[N+:13]([O-:15])=[O:14]
Reactant: COC(=O)c1ccc(C(C)O)cc1[N+](=O)[O-]
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(C(C)F)cc1[N+](=O)[O-]
Temperature: -50 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
To a solution of 4-(1-hydroxy-ethyl)-2-nitro-benzoic acid methyl ester (1.09 g, 4.84 mmol) in DCM (15 mL) cooled at −50° C. was added dropwise a solution of DAST (0.734 mL, 5.32 mmol) in DCM (2 mL). The reaction was stirred at −50° C. for 2 h. Sat. aq NaHCO3 was added to reaction mixture and the solution was stirred at r.t. for 1 h. The aqueous phase was extracted with DCM (3×) and the combined organic phases were dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, hexanes to EtOAc/hexanes (4:6)) to give 4-(1-fluoro-ethyl)-2-nitro-benzoic acid methyl ester (0.60 g, 2.64 mmol, 56%). 1H-NMR (CDCl3, 300 MHz) 7.85 (s, 1H); 7.75 (d, J=7.9 Hz, 1H); 7.7.61 (d, J=7.3 Hz, 1H); 5.60-5.82 (qd, J=6.45, 47.2 Hz, 1H); 3.92 (s, 3H); 1.70 (dd, J=6.4, 23.7 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([CH:17](C)[C:18]([OH:20])=[O:19])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.OC1C=CC(CC(O)=O)=CC=1N.FC1C=CC(C(Cl)=O)=CC=1.P(=O)(O)(O)O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1ccc2oc(-c3ccc(F)cc3)nc2c1
Agent: Nc1cc(CC(=O)O)ccc1O
Agent: O=C(Cl)c1ccc(F)cc1
Agent: O=P(O)(O)O
Product: O=C(O)Cc1ccc2oc(-c3ccc(F)cc3)nc2c1

Procedure:
A process for preparing 2(4-fluorophenyl)α-methyl-5-benzoxazole acetic acid starting from 4-hydroxy-3-amino-phenylacetic acid, which is firstly reacted with 4-fluorobenzoyl chloride, and the product obtained is reacted with phosphoric acid; the 2(4-fluorophenyl)5-benzoxazole acetic acid obtained in this manner is esterified with ethyl alcohol, and the ester is treated with diethyloxalate; the ethyl 2(4-fluorophenyl)5-benzoxazole oxalacetate obtained is reacted with formaldehyde and potassium carbonate to obtain ethyl 2(4-fluorophenyl)5-benzoxazole acrylate, which is hydrolysed to obtain the corresponding acid, from which the 2(4-fluorophenyl)α-methyl-5-benzoxazole acetic acid is obtained by hydrogenation.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.CN1CCCC1=O.[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[C:21](F)[CH:20]=1.CC([O-])(C)C.[K+]>CCCCCCC>[Br:18][C:19]1[CH:26]=[C:25]2[C:22]([CH:23]=[N:10][N:9]2[C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)=[CH:21][CH:20]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=Cc1ccc(Br)cc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCCCCCC
Product: Fc1ccc(-n2ncc3ccc(Br)cc32)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 53.4 %

Procedure:
A flask was charged with (4-fluorophenyl)hydrazine hydrochloride (25.0 g, 154 mmol), 1-methyl-2-pyrrolidinone (500 mL) and 4-bromo-2-fluorobenzaldehyde (31.2 g, 154 mmol). The mixture was stirred at rt for about 14 h then potassium 2-methylpropan-2-olate (18.98 g, 169 mmol) was added. The mixture was stirred for about 1 h then a second portion of potassium 2-methylpropan-2-olate (17.25 g, 154 mmol) was added. The mixture was stirred for about 15 min then warmed in an oil bath heated to about 160° C. for about 24 h. The mixture was cooled to rt then about 250 mL solvent was removed under reduced pressure. The mixture was diluted with about 750 mL water then allowed to stand overnight. The supernatant was decanted and the resulting residue was stirred with EtOAc (350 mL) for about 1 h. The solids were collected by filtration. The filtrate was concentrated then stirred in a mixture of DCM (350 mL), water (250 mL) and 6 N HCl (25 mL) for about 3 h. The layers were separated then the organic layer was dried over MgSO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified on silica gel (330 g) using a gradient of 0-10% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure to give a solid which was treated with heptane (100 mL) and stirred overnight at room rt. The solids were collected by filtration and washed with heptane (25 mL). The solids from the initial EtOAc trituration and the material from the column and heptane trituration were combined to yield 6-bromo-1-(4-fluorophenyl)-1H-indazole (1, R1=4-fluorophenyl) (23.94 g, 54%); LC/MS, method 3, Rt=2.83 min, MS m/z 291, 293 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.41 (s, 1H), 7.97 (s, 1H), 7.88-7.79 (m, 3H), 7.46-7.42 (m, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[N:5]=[C:4]([NH2:17])[CH:3]=1.[NH2:18][C@@H:19]([CH2:21][OH:22])[CH3:20].[Cl-].[NH4+]>C(N(CC)CC)C>[NH2:17][C:4]1[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[N:7]=[C:2]([NH:18][C@H:19]([CH3:20])[CH2:21][OH:22])[CH:3]=1
Reactant: C[C@@H](N)CO
Reactant: Nc1cc(Cl)nc(SCc2ccccc2F)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Product: C[C@H](CO)Nc1cc(N)nc(SCc2ccccc2F)n1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
A solution of the product from example 4, step (b) (15 g), triethylamine (15 ml) and D-alaninol (10 g) was heated at 160° C. for 18 h. The reaction mixture was allowed to cool to room temperature and poured into aqueous ammonium chloride (11). The resultant white precipitate was purified by silica gel chromatography, eluting first with 1:1 DCM:ethyl acetate and then 3:1 DCM:methanol, giving the subtitled product as a yellow foam (10.7 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11](=[O:20])[CH:10]2[CH2:21][CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[OH:24])[CH:6]=[CH:7][CH:8]=1.[OH:32][CH:33]([CH:55]([OH:62])[CH:56]([OH:61])[CH:57]([OH:60])[CH2:58][OH:59])[C:34](=[O:54])[CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH:42][C:43]([CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][C:51](O)=[O:52])=[O:44].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[F:19][C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:11](=[O:20])[CH:10]([CH2:21][CH2:22][CH:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[OH:24])[CH:9]2[C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH2:2][NH:1][C:51](=[O:52])[CH2:50][O:49][CH2:48][CH2:47][O:46][CH2:45][C:43](=[O:44])[NH:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][C:34](=[O:54])[CH:33]([OH:32])[CH:55]([OH:62])[CH:56]([OH:61])[CH:57]([OH:60])[CH2:58][OH:59])=[CH:18][CH:17]=1
Reactant: NCc1cccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)c1
Reactant: O=C(O)COCCOCC(=O)NCCOCCOCC(=O)C(O)C(O)C(O)C(O)CO
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: O=C(COCCOCC(=O)NCc1cccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)c1)NCCOCCOCC(=O)C(O)C(O)C(O)C(O)CO

Procedure:
31 is prepared similarly to 18 starting from 68 mg of 4-(3-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (15), 76 mg of [2-({2-[2-(3,4,5,6,7-pentahydroxy-2-oxoheptyloxy)ethoxy]ethylcarbamoyl}methoxy)-ethoxy]acetic acid (27), 62 μl of diisopropylcarbodiimide and 44 mg of hydroxybenzotriazole in 2 ml of dimethylformamide. This gives 31: C43H55F2N3O14 (875.93) MS (ESI) 876 (M+H)
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20](OC(C)(C)C)=[O:21])[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[Cl:41][CH2:42]C(Cl)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:41][CH2:42][C:20]([N:17]1[CH2:16][CH2:15][N:14]([CH2:13][C@:2]2([CH3:1])[O:6][C:5]3=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]3[CH2:3]2)[CH2:19][CH2:18]1)=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Reactant: O=C(Cl)CCl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(CN2CCN(C(=O)CCl)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.6 %

Procedure:
A mixture of tert-butyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-piperazine-1-carboxylate prepared in Example 393 (1.5 g, 4.1 mmol) and trifluoroacetic acid (20 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (20 ml), and the solution was added triethylamine (3 ml) and 4-dimethylaminopyridine (100 mg, 0.82 mmol) in this order. To the mixture, a solution of chloroacetyl chloride (0.49 ml, 6.2 mmol) in methylene chloride (2 ml) was added slowly with cooling on ice-bath followed by stirring at room temperature overnight. The reaction mixture was washed with water twice, a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford (S)-2-chloro-1-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]ethanone (600 mg, yield 43%) as a light brown powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[C:43]([O:44][CH3:45])=[CH:42][C:26]2[CH2:27][CH2:28][N:29]([CH2:32][C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[O:34])[CH2:30][CH2:31][C:25]=2[CH:24]=1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:22][C:23]2[C:43]([O:44][CH3:45])=[CH:42][C:26]3[CH2:27][CH2:28][N:29]([CH2:32][C:33]([N:35]4[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]4)=[O:34])[CH2:30][CH2:31][C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N1CCN(C)CC1)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)CCN(CC(=O)N1CCN(C)CC1)CC2
Yield: 36 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1-(4-methyl-piperazin-1-yl)-ethanone. Product was isolated as a white foam (40 mg, 36%). mp: ˜140° C. (glass 100), MS (ESI+): 643.5 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.35 (s, 1H), 8.54 (d, J=8 Hz, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.90 (d, J=8 HZ, 1H), 7.58 (t, 1H), 7.52 (s, 1H), 7.25 (m, 1H), 6.67 (s, 1H), 3.89 (s, 3H), 3.72 (m, 2H), 3.68 (m, 2H), 3.30 (s, 2H), 2.88 (m, 2H), 2.76 (s, 8H), 2.70 (m, 2H), 2.66 (m, 2H), 2.46 (m, 2H), 2.42 (m, 2H), 2.34 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=2)=[C:13]([CH3:25])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][NH2:28].CC(C)=O.C(Cl)Cl>CCO>[CH2:1]([O:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[C:22]([NH:28][CH3:27])[N:21]=[CH:20][N:19]=2)=[C:13]([CH3:25])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: Cc1cc(NC(=O)OCc2ccccc2)ccc1Oc1cc(Cl)ncn1
Solvent: CC(C)=O
Solvent: CCO
Solvent: ClCCl
Product: CNc1cc(Oc2ccc(NC(=O)OCc3ccccc3)cc2C)ncn1

Procedure:
The title compound is prepared from [4-(6-chloro-pyrimidin-4-yloxy)-3-methyl-phenyl]-carbamic acid benzyl ester by aminomethylation (30% CH3NH2 in EtOH, 60 min, rt): M+H=363.9; Rf (acetone/CH2Cl2=3:7): 0.26.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18]Cl.[Na+].[Cl-]>CN(C)C=O>[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18][O:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1
Reactant: Oc1ccc2ncsc2c1
Reactant: COCCOCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCOc1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1 g of 6-hydroxybenzothiazole in dimethyl-formamide was dropped into a solution of 0.4 g of 60% sodium hydride in 3 ml of dimethylformamide at 0° C. After the mixture was stirred at room temperature for 1 hour, 0.75 ml of (2-methoxyethoxy)methylchloride was added dropwise into the mixture and the mixture was stirred for another 1 hour. NaCl was added to the reaction mixture and the mixture was extracted with ether. The extracts were dried over sodium sulfate and concentrated, and then the residue was purified by column-chromatography (hexane : ethyl acetate=5:1) to give 0.6 g of 6-[(2-methoxyethoxy)-methoxy]benzothiazole. 1 1H-NMR(CDCl3): 3.38(s,3H), 3.58(m,2H), 3.87(m,2H), 7.22(dd,J=8.8,2.4 Hz,1H), 7.66(d,J=2.4 Hz,1H), 8.82(d,J=8.8 Hz,1H), 8.86(s,1H) IR(neat) cm-1 : 2927, 1674, 1475, 1230, 1103, 999 MS(EI) m/z: 239(M+), 89, 59
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH3:23][CH:24]([N:26]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]2[S:37][C:36]([C:38](OCC)=[O:39])=[CH:35][CH:34]=2)[CH2:28][CH2:27]1)[CH3:25].CO>C1(C)C=CC=CC=1>[CH3:14][O:13][C:11]1[CH:10]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH:22][C:38]([C:36]3[S:37][C:33]([N:29]4[CH2:30][CH2:31][CH2:32][N:26]([CH:24]([CH3:25])[CH3:23])[CH2:27][CH2:28]4)=[CH:34][CH:35]=3)=[O:39])[NH:20][N:21]=2)[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=1
Reactant: CCOC(=O)c1ccc(N2CCCN(C(C)C)CC2)s1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCCN(C(C)C)CC4)s3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 41.2 %

Procedure:
Trimethylaluminium (0.751 ml, 1.50 mmol) was added dropwise to a stirred suspension of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (148 mg, 0.60 mmol) and ethyl 5-(4-propan-2-yl-1,4-diazepan-1-yl)thiophene-2-carboxylate (178 mg, 0.60 mmol) in toluene (3.002 ml) at 25° C. The resulting solution was stirred at 60° C. for 18 h. The cooled reaction mixture was added to methanol (50 mL) and treated with HCL (2M aqueous solution, to pH7 or below) and purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure material. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (123 mg, 41%) as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)=[O:7].[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][CH:26]([C:22]3[CH:21]=[C:20]([NH:19][C:17](=[O:18])[CH:16]([CH3:15])[CH3:32])[CH:25]=[CH:24][CH:23]=3)[CH2:27][CH2:28]2)[CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1cccc(Cl)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme E using 5-chloro-1-(3-chlorophenyl)-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 441.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](/[C:8](=[C:11](/OC)\[CH3:12])/[C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](/[C:8](=[C:11](/[NH:21][CH2:17][CH2:18][CH2:19][CH3:20])\[CH3:12])/[C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1
Reactant: CO/C(C)=C(\C#N)C(=O)c1ccc(F)cc1
Reactant: CCCCN
Product: CCCCN/C(C)=C(\C#N)C(=O)c1ccc(F)cc1

Procedure:
A sample of 2.5 g. of 2-(p-fluorobenzoyl)-3-methoxycrotononitrile is dissolved in 10 ml. of n-butylamine. The solution is sealed in a stainless steel bomb and heated on a steam bath overnight. The bomb is then opened and the solvent evaporated under reduced pressure. A greenish oil is obtained which is distilled on a Kugelrohr apparatus at 200° C./0.1 mm. to obtain the yellow oily product.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1>[Rh]>[CH2:1]1[CH:11]2[CH:12]3[CH:7]([CH2:8][CH2:9][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1
Reactant: c1cc2c3c(cccc3c1)CC2
Agent: [Rh]
Product: C1CC2CCCC3CCC(C1)C23
Reaction time: 0.67 h
Yield: 100 %

Procedure:
Acenaphthene was hydrogenated by the same procedure as in Example 4 except that the catalyst was replaced by a 0.5% Rh/Al2O3 catalyst and reaction was effected at 125° C. for 40 minutes. Perhydroacenaphthene was produced in a yield of 100%, containing 3.4% of No. 1 isomer, 4.7% of No. 2 isomer, and 4.1% of No. 3 isomer, indicating a selectivity of No. 4 isomer of 89.7%.