Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]Cl.[F:3][C:4]([F:14])([F:13])[O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:8]1[CH:7]=[C:6]([O:5][C:4]([F:13])([F:14])[F:3])[CH:11]=[CH:10][C:9]=1[OH:12]
Reactant: ClCl
Reactant: Oc1ccc(OC(F)(F)F)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc(OC(F)(F)F)cc1Cl
Reaction time: 1 h

Procedure:
Gaseous chlorine was slowly introduced to a stirred solution of 35.6 g of 4-trifluoromethoxyphenol in 100 ml carbon tetrachloride. The reaction temperature was kept at 20° to 30° C. by outer cooling. After saturaring with chlorine, the reaction mixture was stirred at 20° to 30° C. for 1 hour, cooled, washed with water, dried over anhydrous sodium sulfate, and evaporated to give a pale yellow residue. The residue was distilled under reduced pressure to give 29.8 g of 2-chloro-4-trifluoromethoxyphenol which boiled at 67°-70° C./18 mmHg.
Reaction SMILES: [Cl:1]C1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[N:19][CH:18]=[CH:17]2.CO.Cl>ClCCl.C(OCC)C>[ClH:1].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[N+:19]([O-:9])[CH:18]=[CH:17]2
Reactant: COc1ccc2cnccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc2c[n+]([O-])ccc2c1
Reaction time: 3 h

Procedure:
At room temperature 133 g of m-chloroperbenzoic acid (purity 75%) was added in portions to a stirred solution of 6-methoxy-isoquinoline [Hendrickson, J. B.; Rodriguez, C.; J. Org. Chem. 1983, 48, 3344-3346; 79.8 g; 500 mmol] in 1.2 L of dichloromethane. Stirring was continued for 3 hours and subsequently methanol (1 L) was added. The bulk was reduced to 700 mL after which 800 mL of a saturated solution of hydrogen chloride in diethyl ether was added. Dilution with 1.5 L of diethyl ether resulted in precipitation of yellow crystals, which were separated by filtration, washed with chilled diethyl ether and dried in vacuo. Yield: 85 g (80%); white solid; m.p. 189-191° C.; (+)-FAB-MS: 176 (MH+-HCl).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=2[C:15]([F:18])([F:17])[F:16])[CH2:3][CH2:2]1.[NH2:19][OH:20]>C(O)C>[OH:20][N:19]=[C:11]([NH2:12])[C:10]1[CH:13]=[CH:14][C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[C:8]([C:15]([F:18])([F:17])[F:16])[CH:9]=1
Reactant: N#Cc1ccc(N2CCOCC2)c(C(F)(F)F)c1
Reactant: NO
Solvent: CCO
Product: NC(=NO)c1ccc(N2CCOCC2)c(C(F)(F)F)c1
Temperature: 65 °C
Yield: 95.5 %

Procedure:
To a solution of 4-morpholino-3-(trifluoromethyl)benzonitrile (17.3 g, 67.3 mmol) in ethanol (400 mL) was added a 50% aqueous solution of hydroxylamine (4.9 mL, 74.1 mmol) dropwise. The mixture was heated at about 65° C. for 24 hours. The mixture was cooled to ambient temperature and the solid was removed by filtration. The fitrate was partitioned between ethyl acetate (1.8 L) and water (1.5 L). The organic layer was washed with water (1.0 L) and brine (1.0 L) and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo to give N′-hydroxy-4-morpholino-3-(trifluoromethyl)benzimidamide (18.6 g, 91%) as a mixture of syn/anti isomers. LCMS (Table 1, Method b) Rt=1.85 min, m/z 290.15 (M+H)+; 1H NMR (DMSO-d6, 400 MHz) 9.75 (s, 1H), 8.09-8.16 (m, 1H), 7.89-7.96 (m, 1H), 7.52-7.58 (m, 1H), 3.66-3.72 (m, 4H), 2.83-2.93 (m, 4H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:48][C:49]1[S:50][CH:51]=[CH:52][N:53]=1>C(Cl)Cl>[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([NH:48][C:49]2[S:50][CH:51]=[CH:52][N:53]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
A solution of triphenylphosphine (3.35 g, 12.79 mmol) in methylene chloride (19 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (2.28 g, 12.79 mmol) in small portions. The reaction mixture was stirred at 0° C. for 30 min, and during this time period, the color of the reaction mixture changed from light yellow to a darker yellow then to a purple color. The cooled purple reaction mixture was then treated with the (2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid (2.23 g, 7.52 mmol). The resulting reaction mixture was then allowed to warm to 25° C. over 45 min, at which time, the reaction mixture was then treated with 2-aminothiazole (1.88 g, 18.81 mmol). The resulting reaction mixture was stirred at 25° C. for 12 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The remaining black residue was diluted with ethyl acetate (300 mL) and then washed well with a 10% aqueous hydrochloric acid solution (2×100 mL), a 5% aqueous sodium bicarbonate solution (3×100 mL), and a saturated aqueous sodium chloride solution (1×200 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 9/1, 3/1, and then 11/9 hexanes/ethyl acetate) afforded (2R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide (2.10 g, 74%) as a white foam: mp 78–80° C. (foam to gel); [α]23589=−70.4° (c=0.027, chloroform); EI-HRMS m/e calcd for C18H22N2O3S2 (M+) 378.1072, found 378.1081.
Reaction SMILES: O.[C:2]([O:5][CH2:6][CH:7]([N+:32]([O-])=[O:33])[C:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@:22]([OH:27])([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C:17]4(OCC[O:28]4)[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH:9]=1)(=[O:4])[CH3:3].[Cl-].[Na+]>CC(C)=O.[Cr](Cl)(Cl)=O.[Cl-].[Cr+2].[Cl-].[Zn]>[C:2]([O:5][CH2:6][C:7](=[N:32][OH:33])[C:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@:22]([OH:27])([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH:9]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)OCC(C1=CC[C@H]2[C@@H]3CC=C4CC5(CC[C@]4(C)[C@@]3(O)CC[C@]12C)OCCO5)[N+](=O)[O-]
Agent: O=[Cr](Cl)Cl
Agent: [Cr+2]
Agent: [Cl-]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)OCC(=NO)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(O)CC[C@]12C
Reaction time: 0.01 h

Procedure:
A filtered aqueous solution of chromous chloride, prepared from chromium (II) chloride (26.1 g), water (121.8 ml) concentrated hydrochloric acid (52.2 ml) and zinc powder (15.7 g) according to the method of J. R. Hanson and T. D. Organ; J. Chem. Soc.(C) 1970, 1182, was added under nitrogen to a stirred solution of 21-acetoxy-3,3-ethylenedioxy-20-nitropregna-5,16-dien-9α-ol (8.70 g as a mixture of 2 diastereomers) in acetone (1.3 1). After stirring for 45 seconds the reaction mixture was poured into an aqueous sodium chloride solution. The resulting layers were separated after which the aqueous layer was washed twice with diethyl ether (400 ml). The combined organic layers were washed once with aqueous sodium chloride solution (450 ml), dried and evaporated under reduced pressure to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][C:19]([Br:25])=[CH:20][CH:21]=3)[CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:26](=O)[CH2:27][CH3:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][C:19]([Br:25])=[CH:20][CH:21]=3)[CH2:16]2)[CH2:26][CH2:27][CH3:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC=O
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CCc3ccc(Br)cc3C2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCN(C1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.7 %

Procedure:
To a solution of 4-(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (610 mg, 1.5 mmol) and propionaldehyde (0.1 mL, 1.5 mmol) in dichloroethane (20 mL) under a nitrogen atmosphere was added sodium triacetoxyborohydride (795 mg, 3.75 mmol) in a single portion. The reaction was stirred at room temperature for 24 h then concentrated in vacuo. The residue was partitioned between EtOAc (75 mL) and 5% aq. KOH (50 mL). The aqueous phase was extracted twice more with EtOAc (2×30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated onto silica (10 g). This was placed on top of a flash column and eluted with 20% hexanes in acetone. The fractions containing product were pooled and concentrated to afford 4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (587 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:19][C:20]2[CH:24]=[C:23]([O:25][CH:26]([CH3:28])[CH3:27])[NH:22][N:21]=2)=[N:4][C:5]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)[CH3:11])=[N:6][C:7]=1Cl.[OH-].[NH4+:30]>C(O)CCC>[Cl:1][C:2]1[C:3]([NH:19][C:20]2[CH:24]=[C:23]([O:25][CH:26]([CH3:28])[CH3:27])[NH:22][N:21]=2)=[N:4][C:5]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)[CH3:11])=[N:6][C:7]=1[NH2:30]
Reactant: [NH4+]
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)nc(Cl)c2Cl)n[nH]1
Agent: [OH-]
Solvent: CCCCO
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)nc(N)c2Cl)n[nH]1
Temperature: 165 °C
Yield: 23.6 %

Procedure:
(S)-5,6-Dichloro-N2-(1-(5-fluoropyridin-2-yl)ethyl)-N4-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (Example 30, 0.100 g, 0.469 mmol) was mixed with n-butanol (1.75 ml) and ammonium hydroxide (1.75 ml, 28.2 mmol) in an Argonaut Endeaver reactor. This was sealed and heated to 165° C. for 48 hours. The solvent was removed under reduced pressure and the resulted residue was purified by reverse phase Biotage chromatography to give the title compound as a brownish solid (0.045 g, 24%). 1H NMR (400 MHz) δ 11.92 (s, 1H), 9.03 (s, 1H), 8.49 (s, 1H), 7.66 (m, 1H), 7.52 (s, 1H), 7.46 (m, 1H), 6.32 (s, 2H), 5.38 (s, 1H), 5.05 (s, 1H), 4.65 (m, 1H), 1.43 (d, J=7.2 Hz, 3H), 1.26 (d, J=6.0 Hz, 6H). MS: Calcd.: 406. Found: [M+H]+ 407.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[F:10].C([Li])CCC.[CH3:16][C:17]1[C:21]([C:22]2[CH:23]=[C:24]([C:41]([C:43]3[CH:48]=[N:47][CH:46]=[CH:45][N:44]=3)=[O:42])[C:25]3[N:29]=[C:28]([O:30]CC)[N:27](C(OC(C)(C)C)=O)[C:26]=3[CH:40]=2)=[C:20]([CH3:49])[O:19][N:18]=1.Cl>C(OCC)C.C(O)C>[CH3:16][C:17]1[C:21]([C:22]2[CH:23]=[C:24]([C:41]([OH:42])([C:43]3[CH:48]=[N:47][CH:46]=[CH:45][N:44]=3)[C:2]3[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=3[F:10])[C:25]3[NH:29][C:28](=[O:30])[NH:27][C:26]=3[CH:40]=2)=[C:20]([CH3:49])[O:19][N:18]=1
Reactant: Fc1cc(F)c(Br)c(F)c1
Reactant: CCOc1nc2c(C(=O)c3cnccn3)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCO
Product: Cc1noc(C)c1-c1cc(C(O)(c2cnccn2)c2c(F)cc(F)cc2F)c2[nH]c(=O)[nH]c2c1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
To 1-bromo-2,4,6-trifluorobenzene (0.01 ml, 0.12 mmol) in diethyl ether (0.5 mL) at −78° C. was added n-butyllithium (0.13 mL, 0.14 mmol, 1.6 M in hexanes). After 30 tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(pyrazine-2-carbonyl)-1H-benzo[d]imidazole-1-carboxylate (36.6 mg, 0.08 mmol) in diethyl ether (1 mL) was added drop-wise to the reaction. After 90 minutes, the reaction was warmed, quenched with saturated NH4Cl(aq) (10 mL), extracted with ethyl acetate (3×10 mL), dried over Na2SO4, and concentrated in vacuo. To the crude residue in ethanol (1.5 mL) was added hydrochloric acid (0.20 mL, 0.79 mmol, 4 M in 1,4-dioxane) and the mixture was heated to 70° C. in a microwave reactor for 45 minutes. Purification by reverse-phase HPLC (35-50% acetonitrile/water with 0.01% trifluoroacetic acid, Gemini C18 5μ) afforded 6-(3,5-dimethylisoxazol-4-yl)-4-(hydroxy(pyrazin-2-yl)(2,4,6-trifluorophenyl)methyl)-1H-benzo[d]imidazol-2(3H)-one as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([CH3:13])[O:12][C:8]=2[CH:7]=1)=[O:4].[C:18]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.O>[F:17][C:2]([F:1])([F:16])[C:3]([N:5]([CH3:18])[C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([CH3:13])[O:12][C:8]=2[CH:7]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: Cc1nc2ccc(NC(=O)C(F)(F)F)cc2o1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1nc2ccc(N(C)C(=O)C(F)(F)F)cc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.4 %

Procedure:
A solution of 2,2,2-trifluoro-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (15.0 g, 61.2 mmol) in DMF (100 mL) was treated with K2CO3 (8.448 g, 61.2 mmol) and the reaction mixture was stirred at rt for 1 h, then cooled to 0° C. Iodomethane (3.9 mL, 64.2 mmol) was added dropwise and stirring continued at rt overnight. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The organics were washed with brine, dried over Na2SO4 and concentrated to obtain crude 2,2,2-trifluoro-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (16.5 g), (MS: ESI +ve, 259.26 [M+H]).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][S:16][C:10]=2[CH2:9]1)=O)(C)(C)C.[ClH:17]>CO>[ClH:17].[S:16]1[C:10]2[CH2:9][NH:8][CH2:13][CH2:12][C:11]=2[CH:14]=[CH:15]1
Reactant: CC(C)(C)OC(=O)N1CCc2ccsc2C1
Agent: Cl
Solvent: CO
Product: c1cc2c(s1)CNCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.427 g (5.962 mmol) of 6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine in 5 ml of methanol, 3 ml of concentrated hydrochloric acid was added, followed by stirring at room temperature for 1 hour. The solvent was distilled off under reduced pressure to yield the desired product.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH3:3].[BH4-].[Na+].[CH2:8]([N:10]([CH2:21][CH3:22])[C:11]([O:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[NH2:20])=[O:12])[CH3:9].[OH-].[Na+]>C1C=CC=CC=1>[CH2:21]([N:10]([CH2:8][CH3:9])[C:11]([O:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[NH:20][CH2:1][CH2:2][CH3:3])=[O:12])[CH3:22]
Reactant: CCC(=O)O
Reactant: CCN(CC)C(=O)Oc1cnccc1N
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CCCNc1ccncc1OC(=O)N(CC)CC
Temperature: 80 °C

Procedure:
A solution of propionic acid (58.5 ml) in 100 ml of benzene was treated with NaBH4 (9.6 g added portionwise). After the frothing subsided, 4-amino-3-pyridinol N,N-diethylcarbamate (5.30 g) was added and the mixture was heated at 80° C. for 2 hours. The reaction mixture was poured into a dilute NaOH solution and the aqueous phase was extracted with ethyl acetate (3×). The combined organics were washed with water and dried (saturated NaCl, MgSO4). The desired amine was purified via flash chromatography to give 3.2 g of solid, m.p. 60°-70° C. This product was combined with a crop obtained from another run and recrystallized from hexane to give analytically pure material, m.p. 75°-78° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=O)[CH2:4][C:3]1([CH3:12])[CH3:11].Cl.[NH2:14][OH:15]>>[CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[N:14][OH:15])[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: CN1C(C)(C)CC(=O)CC1(C)C
Reactant: NO
Agent: Cl
Product: CN1C(C)(C)CC(=NO)CC1(C)C

Procedure:
1,2,2,6,6-Pentamethyl-piperidin-4-one oxime was prepared from 1,2,2,6,6-pentamethyl-piperidin-4-one and hydroxylamine hydrochloride using conditions of General Method 1. 1H NMR (250 MHz, CHLOROFORM-d) δ 2.52 (2H, s), 2.28 (3H, s), 2.21 (2H, s), 1.12 (6H, s), 1.11 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:34]=[CH:33][C:15]3[N:16]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:18][C:14]=3[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:37][O:38][C:39](=[O:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]Br>O>[CH3:37][O:38][C:39](=[O:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[C:12]1[CH:34]=[CH:33][C:15]2[N:16]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:18][C:14]=2[CH:13]=1
Reactant: COc1ccc(-n2c(-c3ccccc3)nc3cc(NS(=O)(=O)c4ccc(Cl)cc4)ccc32)cc1
Reactant: COC(=O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)CCCCCN(c1ccc2c(c1)nc(-c1ccccc1)n2-c1ccc(OC)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
75 mg of 4-chloro-N-[1-(4-methoxyphenyl)-2-phenyl-1H-benzimidazol-5-yl]benzenesulfonamide was suspended in 0.5 ml of N,N-dimethylfonmamide, mixed with 6 mg of sodium hydride and stirred for 30 minutes at 20° C. 44 mg of 6-bromohexanoic acid methyl ester was added, allowed to stir for 15 hours, mixed with water, extracted three times with ethyl acetate, the extracts were dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([F:8])=[N:6][CH:7]=1.C(O)C.Cl>[Fe].O>[I:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([F:8])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(I)cnc1F
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(I)cnc1F
Temperature: 80 °C
Yield: 53.2 %

Procedure:
5-Iodo-3-nitro-2-fluoropyridine (1.739 g, 6.49 mmol), ethanol (13 mL), water (2 mL), and concentrated HCl (0.20 mL) were added to a 25 mL round bottom flask and allowed to stir. Iron (3.6 g, 64.4 mmol) was added in portions to the reaction followed by heating at 80° C. for 30 min. The iron was then removed and washed with ethanol over a fritted filter while the ethanol washings were concentrated under reduced pressure. The residue was purified by flash chromatography using 1:2 hexane:ethyl acetate as eluent to give 5-Iodo-2-fluoro-3-aminopyridine as a colorless solid (53%, 0.821 g).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27])=[CH:14][CH:13]=1.O>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:2][OH:3])=[O:27])=[CH:14][CH:13]=1
Reactant: NO
Reactant: COc1ccc(CCCCCCCCC(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CCCCCCCCC(=O)NO)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a cold stirring suspension of 1 gm hydroxylamine hydrochloride and 1.3 gm sodium carbonate in 25 ml CH2Cl2 was added dropwise 1.58 gms 9(4-methoxyphenyl)nonanoyl chloride over a period of 15 min. The mixture was then stirred in the cold for a further 45 min, then 1.5 ml H2O was added, the mixture was allowed to warm up to room temperature, and stirring was continued for 72 hrs. The precipitated solid was filtered, washed with water, and crystallized twice from CH2Cl2 to give A. The filtrate from the reaction mixture was evaporated in vacuo to give a granular solid which was also crystallized twice from CH2Cl2 to give B. A and B were shown to be the same by spectral comparison. Total yield (A+B)=1.58 gm (51%) m.p. 96°-98° C. Elemental analysis: calculated C 67.90, H 8.90, N 4.95. Found C 67.96, H 9.08, N 4.95 (calculated for 0.2 moles H2O).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]([NH2:11])=[O:10])[C:6]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[N:5][C:4]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-])=O)[CH:28]=1)[CH3:2].[Cl-].[NH4+].C(=O)([O-])O.[Na+]>C(O)C.O.[Zn]>[NH2:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[O:26][C:4]1[N:5]=[C:6]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[C:7]([C:9]([NH2:11])=[O:10])=[N:8][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(C3CCN(C)CC3)cc2)nc1Oc1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCc1nc(C(N)=O)c(Nc2ccc(C3CCN(C)CC3)cc2)nc1Oc1cccc(N)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 54.4 %

Procedure:
A mixture of 6-ethyl-3-{[4-(1-methylpiperidin-4-yl)phenyl]amino}-5-(3-nitrophenoxy)pyrazine-2-carboxamide (500 mg) in ethanol (10 mL) and water (10 mL) were heated to 80° C., and zinc powder (686 mg) and ammonium chloride (561 mg) were added thereto, followed by stirring at 80° C. for 3 hours. The reaction mixture was left to be cooled, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-100:10:1) to obtain 5-(3-aminophenoxy)-6-ethyl-3-{[4-(1-methylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide (255 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28]Br)=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][S:31]([O-:33])=[O:32].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(CBr)cc3)c2CC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(CS(C)(=O)=O)cc3)c2CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the crude 3-tert-butoxycarbonyl-6-(4-bromomethyl-benzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine in anhydrous DMF (1 mL) under nitrogen, add with string sodium methanesulfinate (400 mg, 3.9 mmol), and continue stirring for 30 min at ambient temperature followed by 2 h at 40° C. Add water, extract three times with EtOAc, wash with brine, dry over anhydrous MgSO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (3:1) to give a clear oil that solidifies on standing to a white solid (118 mg, 61%).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([NH2:8])=[N:6][C:5]2[CH:9]=[C:10]([CH2:13][CH2:14][N:15]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)C(OC(C)(C)C)=O)[CH:11]=[CH:12][C:4]=2[O:3]1.[ClH:31]>O1CCOCC1>[ClH:30].[ClH:31].[CH3:1][CH:2]1[C:7]([NH2:8])=[N:6][C:5]2[CH:9]=[C:10]([CH2:13][CH2:14][NH:15][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CC1Oc2ccc(CCN(Cc3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2N=C1N
Agent: Cl
Solvent: C1COCCO1
Product: CC1Oc2ccc(CCNCc3cccc(Cl)c3)cc2N=C1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
203.9 mg (0.474 mmol) of 2-methyl-3-amino-6-[2-(3-chlorobenzyl-tert-butyloxycarbonylamino)-ethyl]-2H-1,4-benzoxazine is mixed with 7 ml of an HCl in dioxane solution (4M) and stirred for three hours at room temperature. The precipitated product is suctioned off, and washed with toluene and with dichloromethane. After drying on the oil pump, 163.3 mg (85.5%) of the desired product is obtained as dihydrochloride.