Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].BrBr.[NH2:13][C:14]([NH2:16])=[S:15]>C(O)(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:13]=[C:14]([NH2:16])[S:15][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: NC(N)=S
Reactant: CC(=O)N1CCC(=O)CC1
Agent: BrBr
Solvent: CC(=O)O
Product: CC(=O)N1CCc2nc(N)sc2C1
Reaction time: 4 h
Yield: 10.2 %

Procedure:
N-Acetyl4-piperidone (7.05 g, 0.05 mol) in acetic acid (35 mL) was treated dropwise with bromine (8.0 g, 0.05 mol) in acetic acid (10 mL) at room temperature. After 4 h, the formed precipitate was collected on a filter, washed with diethyl ether and air-dried. This crude intermediate (3.01 g) was dissolved in ethanol (20 mL) and after the addition of thiourea (0.76 g, 10.0 mmol)the reaction mixture was refixed for 4 h. The solvent was removed in vacuo. Water (20 mL) was added and the pH was adjusted to 9. Extraction with DCM, drying (sodium sulfate) and removal of the organic phase gave 1.1 g of a crude product. Modification by flash chromatography on silica gel gave 202 mg (10%) of 5-acetyl4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-ylamine. This compound was sulfonylated with 3-chloro-2-methylbenzene sulfonyl chloride (234 mg, 1.02 mmol) in pyridine according to METHOD A. After workup, the final product was crystallised from methanol to afford 75 mg (%) of white crystals: 1H NMR (DMSO-d6, 70° C.) δ 2.05 (s, 3H), 2.66 (s, 3H), 3.09 (m, 2H), 3.69 (m, 2H), 4.38 (m 2H), 7.37 (t, 1H), 7.64 (d, 1H), 7.91 (d, 1H), 12.53 (br s, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]([CH3:13])[CH2:9][C:10](O)=[O:11])=O)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].O.[NH2:20][NH2:21]>C(O)(=O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]2[CH:8]([CH3:13])[CH2:9][C:10](=[O:11])[NH:20][N:21]=2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17]
Reactant: NN
Reactant: CC(CC(=O)O)C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: O
Solvent: CC(=O)O
Product: CC1CC(=O)NN=C1c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
920 g of 3-(4-chloro-3-nitrobenzoyl)-butyric acid are added to a mixture of 6.8 1 of acetic acid and 499 g of hydrazine hydrate, and the mixture is stirred for 2 hours at 95°-100°. It is poured into ice water, and filtration gives 6-(4-chloro-3-nitrophenyl)-5-methyl-2,3,4,5-tetrahydropyridazin-3-one, m.p. 186°-188°.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][S:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH:3]=1.[OH:26]O>>[Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][S:18]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[O:26])[CH:3]=1
Reactant: OO
Reactant: Cc1ccc(SCCCCOc2cc(Cl)c3c(c2)COC(=O)N3)cc1
Product: Cc1ccc(S(=O)CCCCOc2cc(Cl)c3c(c2)COC(=O)N3)cc1

Procedure:
Prepared analogously to Example 2 from 8-chloro-6-[4-(4-methyl-phenylmercapto)-butoxy]-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.[C:16]([O:20][C:21]([NH:23][C@H:24]([C:27](O)=[O:28])[CH2:25][Cl:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:27](=[O:28])[C@H:24]([CH2:25][Cl:26])[NH:23][C:21]([O:20][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:22])[CH3:3]
Reactant: CCOC(=O)CN
Reactant: CC(C)(C)OC(=O)N[C@@H](CCl)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CNC(=O)[C@H](CCl)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.2 %

Procedure:
To a solution of 0.28 g (2 mmol) of glycine ethyl ester hydrochloride and 0.28 mL (2 mmol) of triethylamine in 10 mL of chloroform, 0.52 g (2 mmol) of N-(tert-butoxycarbonyl)-3-chloro-L-alanine in 6 mL of chloroform and 0.42 g (2 mmol) of dicyclohexylcarbodiimide were added at 0° C. The reaction mixture was stirred for 16 hours at room temperature. The resultant precipitate was removed by filtration and the filtrate was washed successively with 0.5N hydrochloric acid, water and 3% aqueous sodium bicarbonate, then was dried over anhydrous sodium sulfate. Removal of the solvent left a crystalline residue which was recrystallized from a mixture of ethyl acetate and n-hexane to give 0.415 g (60%) of the pure product melting at 71.5-72.0° C. The identity of the product, which has the structural formula ##STR73## was confirmed by IR and NMR analyses.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:21])[CH:17]=3)[CH:12]=2)(=[O:10])=[O:9])[CH2:4][C:3]1=[O:22].[N:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]2)=[CH:25][CH:24]=1>C(O)C>[Cl:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([S:8]([N:5]1[CH2:6][CH2:7][N:2]([N:1]=[C:32]3[CH2:31][CH2:30][N:29]([C:26]4[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=4)[CH2:34][CH2:33]3)[C:3](=[O:22])[CH2:4]1)(=[O:9])=[O:10])[CH:20]=[CH:19]2
Reactant: NN1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O
Reactant: O=C1CCN(c2ccncc2)CC1
Solvent: CCO
Product: O=C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1N=C1CCN(c2ccncc2)CC1

Procedure:
1-(tert-Butoxycarbonylamino)-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (575 mg) was combined with methanol (4 ml) and a 4N solution of hydrochloric-acid in ethyl acetate (4 ml) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated and the residue obtained was combined with aqueous sodium bicarbonate, extracted with dichloromethane, dried and concentrated to obtain 1-amino-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone as a colorless solid. A solution of the resultant 1-amino-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone and 1-(4-pyridyl)-4-piperidone (237 mg) in ethanol (30 ml) was dehydrated using a Soxlet extractor packed with molecular sieves 4A while refluxing for 24 hours. The reaction mixture was concentrated and the residue was purified by a column chromatography (dichloromethane: 10% aqueous ammonia-containing methanol=20:1) and crystallized from ether to obtain the title compound (265 mg) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=O)[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[C:3]=1[NH:13][C:14]([CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=O.P(Cl)(Cl)(Cl)(Cl)[Cl:22]>P(Cl)(Cl)(Cl)=O>[CH:16]1([C:14]2[NH:13][C:3]3[C:4](=[O:12])[N:5]([CH2:9][CH2:10][CH3:11])[C:6]([Cl:22])=[N:7][C:2]=3[N:1]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCCn1c(=O)[nH]c(N)c(NC(=O)C2CCCC2)c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCn1c(Cl)nc2nc(C3CCCC3)[nH]c2c1=O

Procedure:
To a suspension of cyclopentanecarboxylic acid (6-amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide (0.40 g, crude) obtained from step 1 in phosphorus oxychloride (25 ml) was added phosphorus pentachloride (0.10 g) and the resulting reaction mixture was refluxed overnight. Phosphorus oxychloride was evaporated under reduced pressure. The residue was slowly quenched with water. Ethyl acetate was added and the organic layer was separated and washed thoroughly with water followed by brine. The ethyl acetate layer was dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by preparative TLC using dichloromethane, methanol (9:1) as the solvent system to give 0.075 g (19% over two steps) of the product as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:17][C:18]1[CH:19]=[N:20][C:21]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34][CH3:35])[CH:29]=2)=[C:22]([CH:26]=1)[C:23](O)=[O:24].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:18]1[CH:19]=[N:20][C:21]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34][CH3:35])[CH:29]=2)=[C:22]([CH:26]=1)[C:23]([NH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([CH2:8][OH:9])[CH2:4][CH2:3]1)=[O:24]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Reactant: N[C@H]1CC[C@@H](CO)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](CO)CC2)c1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
(cis-4-Amino-cyclohexyl)-methanol (73 mg, 0.56 mmol) and triethylamine (225 μl, 1.61 mmol) were dissolved in dimethylformamide (225 μl) and a solution of 5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (150 mg, 0.54 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (113 mg, 0.59 mmol) and 1-hydroxybenzotriazole (80 mg, 0.59 mmol) in dimethylformamide (5 ml) was added. The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between 0.5N HCl (10 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (2×10 ml). The combined organic phases were washed with brine (10 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:concentrated aqueous ammonia (98.7:1.3:0.13, by volume). The product was triturated with ethyl acetate (3 ml) to give 5-fluoro-N-(cis-4-hydroxymethyl-cyclohexyl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide (111 mg) as a white solid.
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([C:10]2[S:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:16][C:17]1[O:21][N:20]=[C:19]([CH3:22])[C:18]=1[Br:23]>>[Br:23][C:18]1[C:19]([CH3:22])=[N:20][O:21][C:17]=1[NH:16][S:2]([C:5]1[S:6][C:7]([C:10]2[S:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: Cc1noc(N)c1Br
Reactant: Cc1ccc(-c2ccc(S(=O)(=O)Cl)s2)s1
Product: Cc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)s2)s1
Yield: 90.4 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(5-methyl-2-thienyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 2-chlorosulfonyl-5-(5-methyl-2-thienyl)thiophene (200 mg, 0.72 mmol) with 5-amino-4-bromo-3-methylisoxazole (127 mg, 0.72 mmol) yielded 273 mg (90%) of the crude sulfonamide. After passing through a small plug of silica gel, a portion of the product was further purified by preparative HPLC to give the pure sulfonamide as a white powder, m.p. 161-162° C.
Reaction SMILES: Cl.Cl.[CH:3]([N:6]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([CH3:5])[CH3:4].[CH3:13][C:14]1([CH3:30])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[O:15]1>>[CH:3]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:25]([C:24]2[CH:23]=[CH:22][C:21]([B:16]3[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:30])([CH3:13])[O:15]3)=[CH:29][CH:28]=2)=[O:26])[CH2:8][CH2:7]1)([CH3:5])[CH3:4]
Reactant: CC(C)N1CCCNCC1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Agent: Cl
Product: CC(C)N1CCCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1

Procedure:
The tile compound (D12) was prepared in a similar manner to Description 7 from 1-(isopropyl)-hexahydro-1H-1,4-diazepine (free base of D2) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and isolated as a brown oil. LCMS electrospray (+ve) 373 (MH+).
Reaction SMILES: C(O)(=O)C1C=CC=CC=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[C:15]([OH:17])=O.C([O:29][C:30](=[O:57])[CH2:31][N:32]([C:42](=[O:56])[C@@H:43]([NH:47]C(=O)C1C=CC=CC=1)[CH:44]([CH3:46])[CH3:45])[CH:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]1)(C)(C)C>>[CH3:24][O:23][C:19]1[CH:18]=[C:14]([CH:13]=[C:12]([O:11][CH3:10])[C:20]=1[O:21][CH3:22])[C:15]([NH:47][C@@H:43]([CH:44]([CH3:46])[CH3:45])[C:42]([N:32]([CH2:31][C:30]([OH:57])=[O:29])[CH:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]1)=[O:56])=[O:17]
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Agent: O=C(O)c1ccccc1
Product: COc1cc(C(=O)N[C@H](C(=O)N(CC(=O)O)C2Cc3ccccc3C2)C(C)C)cc(OC)c1OC

Procedure:
Compound 730 was prepared by a method similar to the method used to prepare compound 724, except benzoic acid is replaced with 3,4,5-trimethoxybenzoic acid in the preparation of 723. ##STR109##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6][C:5]2=1.[H-].[Na+].[Cl:22][C:23]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:24]=1[CH2:25]Cl>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:25][C:24]1[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:23]=1[Cl:22])[C:10]1[CH:9]=[N:8][C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6][C:5]2=1
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(N)cc12
Reactant: ClCc1cc(Cl)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c3cc(N)ccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Yield: 53.8 %

Procedure:
A mixture of ethyl 6-amino-9H-β-carboline-3-carboxylate (100 mg, 0.39 mmol), NaH (0.58 mmol, 24 mg of 60 wt. % suspension in mineral oil) and 2,5-dichlorobenzyl chloride (115 mg, 0.59 mmol) in DMF (2 mL), was treated according to Method A. Purification of the crude product by column chromatography on silica with hexane/ethyl acetate (7:3) as eluent furnished the desired product (87 mg, 54% yield) as a yellow solid. 1H NMR (DMSO-d6) δ8.96 (s, 1H), 8.74 (s,1H), 7.60 (d,J=8.6 Hz, 1H), 7.48 (d, 1H), 7.41 (dd, J=8.4 Hz, 2.1Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 7.01 (d,J=8.6 Hz, 1H), 6.51 (d, J=1.8 Hz, 1H), 5.80 (s, 2H), 5.10 (br s, 1H), 4.37 (q,J=7.0 Hz, 2H), 1.37 (t, J=7.0 Hz, 3H); MS (APCI; (M+H)+) m/z 414.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](=[O:6])[CH3:5].O.C(=O)([O-])[O-].[K+].[K+].[C:20](Cl)(=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(OCC)(=O)C>[C:20]([NH:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](=[O:6])[CH3:5])(=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC(=O)C(N)c1ccccc1
Reactant: CCCCCC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCC(=O)NC(C(C)=O)c1ccccc1

Procedure:
To a mixture of 1-amino-1-phenyl-2-propanone hydrochloride (5.55 g), water (40 ml), ethyl acetate (75 ml) and potassium carbonate (4.55 g) was added dropwise hexanoyl chloride (4.42 g) under ice-cooling and stirring. The mixture was further stirred for an hour with ice-cooling. The ethyl acetate layer was separated, washed with water, diluted hydrochloric acid and water in that order, and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was recrystallized from isopropyl ether to give crystals of 1-hexanoylamino-1-phenyl-2-propanone, yield 5.80 g (78.2%), m.p. 77°-78° C.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][S:11][C:10](=[O:13])[N:9]1[C:14](=[O:28])[CH2:15][CH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=[N:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[C@H]2N(C[C@H]3[C@@H]4CCCCN4C[C@@H]2C3)CC1.[F:46][C:47]1[CH:48]=[C:49]([C:54]2[CH:59]=[CH:58][C:57]([CH2:60][CH2:61][CH:62]=[O:63])=[CH:56][CH:55]=2)[CH:50]=[C:51]([F:53])[CH:52]=1>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C@H:8]1[CH2:12][S:11][C:10](=[O:13])[N:9]1[C:14]([C@@H:15]([C@@H:62]([OH:63])[CH2:61][CH2:60][C:57]1[CH:58]=[CH:59][C:54]([C:49]2[CH:48]=[C:47]([F:46])[CH:52]=[C:51]([F:53])[CH:50]=2)=[CH:55][CH:56]=1)[CH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=[N:18]1)=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCn1nnc2ccccc2c1=O)N1C(=O)SC[C@@H]1Cc1ccccc1
Reactant: O=CCCc1ccc(-c2cc(F)cc(F)c2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C1CCN2C[C@@H]3C[C@@H](CN4CCCC[C@@H]34)[C@H]2C1
Solvent: ClCCl
Product: O=C1SC[C@H](Cc2ccccc2)N1C(=O)[C@H](Cn1nnc2ccccc2c1=O)[C@@H](O)CCc1ccc(-c2cc(F)cc(F)c2)cc1
Temperature: 0 °C
Reaction time: 0.21 h

Procedure:
In a flame-dried flask, 3-{3-[(4S)-4-benzyl-2-oxo-1,3-thiazolidin-3-yl]-3-oxopropyl}-1,2,3-benzotriazin-4(3H)-one (0.25 g) was taken up in dichloromethane (10 mL) and cooled to 0° C. Titanium tetrachloride (0.76 mL, 1 M solution) was added drop-wise and the reaction mixture was stirred for 10 to 15 minutes. (−)-Sparteine (0.36 mL) was added slowly to the reaction mixture and stirred at 0° C. for 20 minutes. A solution of the compound obtained from step e above (0.187 g) in dichloromethane (10 mL) was added slowly and stirring was continued at 0° C. After 3 hours, the reaction was quenched with the drop-wise addition of saturated ammonium chloride solution, and dichloromethane was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product thus obtained was purified by silica gel flash column chromatography using 30% ethyl acetate in hexane as eluant to afford the title compound (0.24 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[N:5]([CH2:17][C:16]1[CH:19]=[CH:20][C:13]([N+:10]([O-:12])=[O:11])=[CH:14][CH:15]=1)[CH2:17][C:16]1[CH:19]=[CH:20][C:13]([N+:10]([O-:12])=[O:11])=[CH:14][CH:15]=1
Reactant: Nc1ccc(F)c(F)c1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: O=[N+]([O-])c1ccc(CN(Cc2ccc([N+](=O)[O-])cc2)c2ccc(F)c(F)c2)cc1

Procedure:
3,4-Difluoroaniline and 4-nitrobenzyl bromide were processed using the method described in Example 32A to afford the title compound. LC/MS Rt 2.15 m/z 400 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](Cl)=[O:12])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].N1C=CC=CC=1>C(Cl)Cl>[CH3:18][O:17][N:16]([CH3:15])[C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[N:4]2)=[O:12]
Reactant: O=C(Cl)c1ccc2nccnc2c1
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of intermediate from step B (484 mg, 2.51 mmol) in 17 mL anhydrous methylene chloride cooled to 0° C. was added N,O-dimethylhydroxylamine hydrochloride (368 mg, 3.77 mmol) followed by pyridine (0.61 mL, 7.54 mmol). The reaction was warmed to room temperature and stirred overnight after which it was quenched with water. The aqueous layer was extracted with methylene chloride (2×) and the combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography using 40% EtOAc/Hexanes to give the product as a colorless oil. 1H NMR (CDCl3, 500 MHz): 3.45 (d, J=2.5 Hz, 3H), 3.59 (d, J=2.5 Hz, 3H), 8.05 (m, 1H), 8.15 (dd, J=8.7, 3.2 Hz, 1H), 8.46 (d, J=1.8 Hz, 1H), 8.91 (d, J=2.5, 2H). LC-MS: 1.11 min. (M+H)=111.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][C:22]#[N:23])[C@@H:17]([O:24][CH3:25])[CH2:16]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:25][O:24][C@H:17]1[CH2:16][C@@H:15]([NH:14][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH:11]=[CH:12][S:13][C:3]=23)[CH2:20][CH2:19][C@@H:18]1[CH2:21][C:22]#[N:23]
Reactant: CO[C@H]1C[C@@H](N)CC[C@@H]1CC#N
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H]1C[C@@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC[C@@H]1CC#N
Temperature: 90 °C
Yield: 76.1 %

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (381 mg, 1.78 mmol), [(1R,2S,4S)-4-amino-2-methoxycyclohexyl]acetonitrile (racemic) (310 mg, 1.8 mmol) and N,N-diisopropylethylamine (1.2 mL, 7.1 mmol) in isopropyl alcohol (4.2 mL) was heated at 90° C. for 2 h. The crude was concentrated and purified with flash chromatography to give the desired product (469 mg, 76%). LCMS calculated for C15H19N4O3S (M+H)+: m/z=347.1. Found: 347.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([OH:15])[CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C:13](=[O:15])[CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC(=O)CN(C(=O)OCc2ccccc2)C1
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of (3S,5R)-benzyl 3-(tert-butoxycarbonylamino)-5-hydroxypiperidine-1-carboxylate (1 eq) in 10 mL dichloromethane was added Dess-Martin periodinane (1.2 eq) at room temperature. The reaction mixture was stirred at that temperature overnight. The mixture was diluted with ethyl acetate, washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:2) to yield (S)-benzyl 3-(tert-butoxycarbonylamino)-5-oxopiperidine-1-carboxylate (81%). LC/MS (m/z): 249.1 (MH+-100), Rt: 0.83 min. HPLC: Rt: 3.26 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5])[CH3:2].[CH3:26][CH:27]([CH3:41])[CH2:28][C:29](=O)[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>ClCCl>[CH2:1]([O:3][C:4]([CH:6]=[C:29]([CH2:28][CH:27]([CH3:41])[CH3:26])[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[O:5])[CH3:2]
Reactant: CC(C)CC(=O)C(=O)OCc1ccccc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C=C(CC(C)C)C(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 91.1 %

Procedure:
Ethoxycarbonylmethylenetriphenylphosphorane (53.8 g., 0.155 mol.) was dissolved in dry dichloromethane (400 mls.) and the resulting solution was cooled to 0° C. To the cooled solution was added a solution of benzyl 4-methyl-2-oxopentanoate (34.0 g., 0.155 mol.) in dry dichloromethane (100 mls.) over a period of 25 minutes and the reaction mixture was then heated under reflux for 1 hour. The solvent was removed from the reaction mixture by evaporation in vacuo to yield an off-white solid. The solid was extracted with hexane (3×200 mls.) and the solvent was removed from the combined hexane extracts to yield a crude product as a yellow oil. The crude product was purified by distillation (0.6 mm Hg), to yield E and Z benzyl 3-(ethoxycarbonyl)-2-(2-methylpropyl)propenoate (41.0 g.) being collected at 137°-142° C.
Reaction SMILES: [F:1][C:2]1[O:6][C:5]2[CH:7]=[C:8]([CH3:18])[C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[CH:10][C:4]=2[CH:3]=1.[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:21]=1[C:22](Cl)=[O:23].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:21]=1[C:22]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[C:8]([CH3:18])=[CH:7][C:5]3[O:6][C:2]([F:1])=[CH:3][C:4]=3[CH:10]=2)=[CH:16][N:15]=1)=[O:23]
Reactant: Cc1cc2oc(F)cc2cc1-c1ccc(N)nc1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc2oc(F)cc2cc1-c1ccc(NC(=O)c2c(F)cccc2F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
To a solution of 5-(2-fluoro-6-methylbenzo[b]furan-5-yl)-2-pyridylamine (231) (23 mg, 0.095 mmol) in 3 ml DCM was added 2,6-difluorobenzoyl chloride (36 μl, 3 eq) followed by addition of DIEA (149 μl). The resulting solution was stirred overnight at r.t. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 3 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (200 μl) at r.t. for 2 h before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished (2,6-difluorophenyl)-N-[5-(2-fluoro-6-methylbenzo[b]furan-5-yl)(2-pyridyl)]carboxamide (223) (24.9 mg, yield: 68.6%, purity>95%) as white solid.