Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([BH-](CC)CC)C.[Li+].C(N(CC)[C:12]1[N:17]=[C:16]([NH:18][C:19]([NH:21][C:22]2[N:23]=[C:24]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[S:25][CH:26]=2)=[O:20])[C:15](C)=[CH:14][CH:13]=1)C.[CH3:36][CH2:37][N:38]([CH:42](C)C)[CH:39](C)[CH3:40]>C1COCC1>[CH2:37]([N:38]([CH2:42][C:12]1[N:17]=[C:16]([NH:18][C:19]([NH:21][C:22]2[N:23]=[C:24]([CH:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)[S:25][CH:26]=2)=[O:20])[CH:15]=[CH:14][CH:13]=1)[CH2:39][CH3:40])[CH3:36]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCN(CC)c1ccc(C)c(NC(=O)Nc2csc(-c3ccncc3)n2)n1
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)Cc1cccc(NC(=O)Nc2csc(C3CCNCC3)n2)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Lithium triethylborohydride (0.84 mL, 0.84 mmol, 1.0 M in THF) was added to a solution of 1-(6-diethylamino-methyl-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)urea (100 mg, 0.24 mmol, Example 117) and DIEA (63 μL, 0.36 mmol) in THF (5 mL) and the resulting mixture was stirred 6 h at RT. The reaction was quenched via dropwise addition of MeOH and concentrated in vacuo. Purification by preparative HPLC (5–60% CH3CN/H2O) gave a white solid. MS m/z: 389.2 (M+H). Calc'd for C19H28N6OS-388.53.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:16])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)=[N:6][C:7]=1[CH3:8].[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](Cl)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C1C=CN=CC=1.CS(C)=O>[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([O:16][C:4]3[C:5]([C:9]4[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=4)=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccc(-c2nc(C)c(C)cc2O)nc1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1OCc1ccccc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
5,6,5′-Trimethyl-[2,2′]bipyridin-3-ol (300 mg), 7-benzyloxy-4-chloro-6-methoxyquinoline (1.26 g), 4-dimethylaminopyridine (513 mg), and cesium carbonate (1.37 g) were suspended in dimethyl sulfoxide (6 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (504 mg, yield 75%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.C(O)(C(F)(F)F)=O.[CH3:20][O:21][C:22](=[O:47])[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH:29][C:30]1[CH:46]=[CH:45][C:33]([C:34]([NH:36][NH:37]C(OC(C)(C)C)=O)=[O:35])=[CH:32][CH:31]=1)=[O:28]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:37][NH:36][C:34]([C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][C:22]([O:21][CH3:20])=[O:47])=[CH:46][CH:45]=1)=[O:35]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: COC(=O)CCCCC(=O)Nc1ccc(C(=O)NNC(=O)OC(C)(C)C)cc1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCCCC(=O)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 82 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid in the presence of 5% TFA was added tert-butyl 2-{4-[(6-methoxy-6-oxohexanoyl)amino]benzoyl)hydrazinecarboxylate. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 70° C. for 15 hrs gave 496 mg of the title compound (82%) as a yellow solid in 99.5% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: NC1C=C(C)C=CC=1[C:4](O)=[O:5].[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])=[O:21].[NH2:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1>>[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])=[O:21].[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]([C:14]1[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=1[NH:12][C:4]([NH:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1)=[O:5])=[O:21]
Reactant: Cc1ccc(C(=O)O)c(N)c1
Reactant: Nc1nccs1
Agent: COc1ccccc1C(=O)c1ccc(C)cc1N
Product: COc1ccccc1C(=O)c1ccc(C)cc1NC(=O)Nc1nccs1
Yield: 70 %

Procedure:
(2-Amino-4-methyl-phenyl)-(2-methoxy-phenyl)-methanone (723 g, 30%) was prepared from 2-amino-4-methyl-benzoic acid (1.51 g, 10 mmol) following the general procedure S. 1-[2-(2-methoxy-benzoyl)-5-methyl-phenyl]-3-thiazol-2-yl-urea (129 mg, 70%) was prepared from (2-amino-4-methyl-phenyl)-(2-methoxy-phenyl)-methanone (121 mg, 0.5 mmol) and 2-aminothiazole (0.060 g, 0.6 mmol) following the general procedure D.
Reaction SMILES: C(OC([N:8]([C:26]1[CH:38]=[CH:37][C:29]([C:30](N2C=CN=C2)=[O:31])=[CH:28][CH:27]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][Br:25])=O)(C)(C)C.[OH-].[Na+].[NH2:41][CH2:42][CH:43]([OH:46])[CH2:44][OH:45]>C(Cl)(Cl)Cl>[Br:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:41][CH2:42][CH:43]([OH:46])[CH2:44][OH:45])=[O:31])=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N(CCCCCCCCCCCCCCCCBr)c1ccc(C(=O)n2ccnc2)cc1
Reactant: NCC(O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C(NCC(O)CO)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a mixture containing 4.3 g. of 1-{4-[N-(t-butyloxycarbonyl)-N-(16-bromohexadecyl)amino]benzoyl}imidazole, 50 ml. of chloroform, and 50 ml. of 5 N sodium hydroxide is added 1.1 g. of 3-amino-1,2-propanediol. The solution is vigorously stirred for 24 hours, the layers are separated, and the chloroform solution is washed once with 50 ml. of 1 N sodium hydroxide. The solid is evaporated and the residue is heated for 30 minutes at 40° C. and 50 ml. of anhydrous trifluoroacetic acid. The solvent is again evaporated and the oil is crystallized from acetone to yield the product as a light yellow crystalline solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][S:16]([OH:19])(=O)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O>CN(C)C=O.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][S:16]([Cl:23])(=[O:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=S(=O)(O)Cc1ccccc1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=S(=O)(Cl)Cc1ccccc1OCc1ccccc1
Reaction time: 3 h
Yield: 77.5 %

Procedure:
Tetrahydrofuran (10 ml), (2-Benzyloxy-phenyl)-methanesulfonic acid (138 mg), and N,N-dimethylformamide (2 drops) was cooled to −78° C. and oxalyl chloride (315 mg) was added slowly. The reaction mixture was stirred for 3 h from −78° C. to 0° C. The reaction mixture was clarified by filtration. The filtrate was washed with iced-water and heptane, and dried to give (2-benzyloxy-phenyl)-methanesulfonyl chloride (114 mg, 77%). 1H NMR (400 MHz, CDCl3): δ 5.06 (s, 2 H) 5.15 (s, 2 H) 7.04 (m, 2 H) 7.42 (m, 7 H).
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]\[NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[C@H:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: Nc1ccccc1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: COC[C@H]1OC(=O)/C(=C/Nc2ccccc2)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@]4(C)[C@@H](O)CC[C@@H]34)[C@]21C
Temperature: 25 °C
Yield: 42.8 %

Procedure:
To a solution of 50 mg (0.116 mmol) 17-hydroxywortmannin in 1 mL CH2Cl2 is added 26.2 mL (0.287 mmol) aniline. The reaction mixture is stirred at room temperature for 1 week and then concentrated in vacuo. The residue is dissolved in EtOAc and triturated with hexane to give a yellow powder. The yellow powder is purified by silica gel chromatography, (hexane/EtOAc) to give an oil. The oil is triturated with hexane to give 26 mg (42.8%) product as an orange powder. HRMS (ESI) m/z calcd for C29H33NO8 523.22074, found: 524.22692 (M+H)+1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]1[CH2:15][C@@H:14]([C:16]([OH:18])=O)[C@H:13]([CH2:19][O:20][CH3:21])[CH2:12]1)(=[O:10])=[O:9].[NH2:22][CH2:23][C:24]#[N:25]>>[C:23]([CH2:24][NH:25][C:16]([C@@H:14]1[CH2:15][CH:11]([S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:9])=[O:10])[CH2:12][C@H:13]1[CH2:19][O:20][CH3:21])=[O:18])#[N:22]
Reactant: N#CCN
Reactant: COC[C@@H]1CC(S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)O
Product: COC[C@@H]1CC(S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)NCC#N

Procedure:
The title compound was synthesized in analogy to Example 68/69, Step 11, from (1R,2R)-4-(2-Chloro-benzenesulfonyl)-2-methoxymethyl-cyclopentanecarboxylic acid (epimeric mixture) and aminoacetonitrile to afford the desired product as a light yellow foam. MS (EI): 371.0 (M+H)+.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH2:8]1[CH2:13]CC[CH2:10][CH2:9]1.O>CC(CC)=O>[CH2:8]([C:9]1([CH3:10])[N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][O:4]1)[CH3:13]
Reactant: C1CCCCC1
Reactant: OCCNCCO
Solvent: CCC(C)=O
Solvent: O
Product: CCC1(C)OCCN1CCO
Yield: 78 %

Procedure:
A mixture of 315 g (3 mols) of diethanolamine, 432 g (6 moles) of methylethylketone, and 100 ml of cyclohexane is stirred and heated to reflux using a Dean-Stark trap to separate the water formed. The mixture is stirred and refluxed for a total of 311/2 hours during which 54 ml of aqueous layer, 85% water and 15% methylethylketone by NMR, is collected (85% of the theoretical amount of water of reaction). The mixture is then concentrated and the residue distilled to give 373 g (78% yield) of product, b.p. 85°-88° C./2.5-3.0 mm Hg.
Reaction SMILES: Cl[C:2]([N:4]1[CH2:7][CH:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[CH2:5]1)=[O:3].[CH3:16][NH2:17]>O1CCCC1.O>[Cl:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH:6]1[CH2:7][N:4]([C:2]([NH:17][CH3:16])=[O:3])[CH2:5]1
Reactant: O=C(Cl)N1CC(Oc2cccc(Cl)c2)C1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1CC(Oc2cccc(Cl)c2)C1
Reaction time: 16 h
Yield: 39.1 %

Procedure:
A solution of 1-chlorocarbonyl-3-(3-chlorophenoxy) azetidine (0.01275 mole) in 20 ml of tetrahydrofuran was treated with 4 ml (0.05 mole) of 40% aqueous methylamine and stirred for 16 hr. The reaction mixture was diluted with water until an oil began to separate, then extracted with 3×50 ml of benzene. The combined extracts were dried over magnesium sulfate and concentrated to a solid which was recrystallized from benzene/ligoin to yield 1.2 g (40.0%) of fine white crystals, m.p. 140°-141° C.
Reaction SMILES: C([C:5]1N=C(N2CCC(F)(F)C2)[C:8]2[C:9](=[N:11][N:12](CC)[N:13]=2)[N:10]=1)(C)(C)C.[C:23]([NH:27][C:28]1[N:29]=[C:30]([N:37]2[CH2:41][CH2:40][C@H:39]([OH:42])[CH2:38]2)[C:31]2[N:36]=[N:35][NH:34][C:32]=2[N:33]=1)([CH3:26])([CH3:25])[CH3:24].ClCC1N(C)N=NN=1>>[C:23]([NH:27][C:28]1[N:29]=[C:30]([N:37]2[CH2:41][CH2:40][C@H:39]([OH:42])[CH2:38]2)[C:31]2[C:32](=[N:34][N:35]([CH2:8][C:9]3[N:10]([CH3:5])[N:13]=[N:12][N:11]=3)[N:36]=2)[N:33]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: CC(C)(C)Nc1nc(N2CC[C@H](O)C2)c2nn[nH]c2n1
Agent: Cn1nnnc1CCl
Product: Cn1nnnc1Cn1nc2nc(NC(C)(C)C)nc(N3CC[C@H](O)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from (S)-1-(5-tert-Butylamino-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-ol and 5-(chloromethyl)-1-methyl-1H-tetrazole. MS (m/e): 374.3 (MH+).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][N:12](C(OC(C)(C)C)=O)[C@H:11]([CH2:21][O:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=2[N+:33]([O-:35])=[O:34])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C@H:9]1[CH2:13][NH:12][C@H:11]([CH2:21][O:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=2[N+:33]([O-:35])=[O:34])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@@H](OCc3ccccc3)CN2C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(OC[C@@H]2C[C@@H](OCc3ccccc3)CN2)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 94.5 %

Procedure:
To a stirred solution of methyl (2S, 4R)4-[4-benzyloxy-1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy-3-nitrobenzoate (681 mg, 1.4 mmol) in CH2Cl2 (2 mL) was added TFA (2 mL), and the resulting mixture was stirred for 2 hr. After the reaction mixture was concentrated, the residue was made basic by the addition of sat. NaHCO3 and extracted with CHCl3. The extract was washed with H2O, dried over MgSO4, and evaporated to give 511 mg (95%) methyl (2S,4R)-4-[4-benzyloxy-2-pyrrolidinyl]methoxy-3-nitrobenzoate as a yellow oil.
Reaction SMILES: [Br:1]Br.C(Cl)(Cl)(Cl)Cl.[OH:8][CH2:9][C:10]1[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Ca+2]>C(Cl)Cl>[Br:1][C:12]1[CH:13]=[CH:14][C:15]([OH:16])=[C:10]([CH:11]=1)[CH2:9][OH:8]
Reactant: OCc1ccccc1O
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: OCc1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
At 0°-5° C., 11.5 ml. of bromine in 100 ml. of carbon tetrachloride was added dropwise to a suspension of 24.8 g. of saligenin and 24 g. of calcium carbonate in a solvent mixture of 200 ml. of carbon tetrachloride and 220 ml. of methylene chloride. The reaction mixture was stirred for 24 hours at room temperature, then filtered, and the precipitate was washed with carbon tetrachloride. The CCl4 /CH2Cl2 phase was discarded. The solid substance was taken up in ethyl acetate/water, and the organic phase was separated, dried over magnesium sulfate, and evaporated to dryness. The residue was recrystallized from methylene chloride, thus obtaining colorless crystal flakes (24 g.). Melting point: 107°-109° C. (methylene chloride).
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[S:10][C:11]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[ClH:21]>C(#N)C.C(Cl)Cl.[Cu](Cl)Cl>[Cl:21][C:9]1[S:10][C:11]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2s1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
Combine tert-butyl nitrite, (35 mL, 292 mmol, technical 90%) and copper (II) chloride (31.7 g, 236 mmol) in acetonitrile (400 mL) and warm to 65° C. under nitrogen for 1 hour. Slowly add 2-amino-6-nitrobenzthiazole (41.7 g, 214 mmol) over 15 min. Continue to stir at 65° C. for 30 min. Cool to room temperature, dilute with CH2Cl2, and add 0.1 N HCl to precipitate the product. Filter and dry in a vacuum oven overnight to afford 2-chloro-6-nitrobenzthiazole (35.1 g, 77%). 1H NMR (400 MHz, DMSO-d6): δ 9.18 (d, 1H, J=2.2 Hz), 8.37 (dd, 1H, J=9.0, 2.4 Hz), 8.18 (d, 1H, J=8.8 Hz).
Reaction SMILES: [NH2:1][C@H:2]([CH2:13][O:14][CH3:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[C:16](OC(=O)C)(=[O:18])[CH3:17]>ClCCl.C(OCC)(=O)C>[CH3:17][C:16]([NH:1][C@@H:2]([C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])[CH2:13][O:14][CH3:15])=[O:18]
Reactant: COC[C@@H](N)C(=O)NCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.6 %

Procedure:
To a cold solution (−2° C.) of 1.94 g of Intermediate 6, in 40 mL of dichloromethane was added dropwise 2.12 g of acetic anhydride maintaining the temperature below 5° C. The reaction mixture was stirred at room temperature for 3 hours and the organic phase was washed with water (2×20 mL), sodium bicarbonate solution (2×20 mL), brine and dried over sodium sulfate. The solvent was removed under vacuum and a white solid was obtained. The product was dissolved in 20 mL of ethyl acetate at reflux temperature and cooled slowly to 0° C. The solid was collected by filtration and dried yielding 1.6 g of lacosamide as a white solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=1)[NH2:4].[F:18][C:19]([F:28])([F:27])[C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)N>>[OH:1][N:2]=[C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=1)[NH:4][C:25]1[CH:24]=[CH:22][CH:21]=[C:20]([C:19]([F:28])([F:27])[F:18])[CH:26]=1
Reactant: CS(=O)(=O)NCCNc1nonc1C(N)=NO
Reactant: Nc1cccc(C(F)(F)F)c1
Product: CS(=O)(=O)NCCNc1nonc1C(=NO)Nc1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared according to the procedure of Example 17, step E, using N′-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide and 3-trifluoromethylaniline [Aldrich, product # A41801] as the starting materials. LCMS for C13H16F3N6O4S (M+H)+: m/z=409.1. 1H NMR (500 MHz, DMSO-d6): δ 11.63 (s, 1H), 9.08 (s, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.21 (m, 2H), 7.10 (s, 1H), 6.99 (d, J=8.1 Hz, 1H), 6.28 (t, J=5.4 Hz, 1H), 3.36 (q, J=5.8 Hz, 2H), 3.17 (q, J=5.8 Hz, 2H), 2.91 (s, 3H).
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].CB(O)O.ClCCl.[CH:14]([O:17][C:18]([N:20]1[C:26]2[C:27]3[CH2:28][CH2:29][CH2:30][C:31]=3[C:32](Br)=[CH:33][C:25]=2[C@@H:24]([NH:35][CH2:36][C:37]2[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[C:39]([C:47]([F:50])([F:49])[F:48])[CH:38]=2)[CH2:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])[CH3:15]>O1CCOCC1>[CH:14]([O:17][C:18]([N:20]1[C:26]2[C:27]3[CH2:28][CH2:29][CH2:30][C:31]=3[C:32]([CH3:1])=[CH:33][C:25]=2[C@@H:24]([NH:35][CH2:36][C:37]2[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[C:39]([C:47]([F:50])([F:49])[F:48])[CH:38]=2)[CH2:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])[CH3:15]
Reactant: O=C([O-])[O-]
Reactant: CC(C)OC(=O)N1CCC[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(Br)c3c(c21)CCC3
Agent: CB(O)O
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc2c(c3c1CCC3)N(C(=O)OC(C)C)CCC[C@@H]2NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
Add cesium carbonate (383 mg, 2.52 mmol), methyl boronic acid (76 mg, 1.26 mmol) and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (69 mg, 0.084 mmol) to a solution of (S)-6-(3,5-bis-trifluoromethyl-benzylamino)-4-bromo-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylic acid isopropyl ester (500 mg, 0.84 mmol) in dioxane (7 mL). Stir the mixture under nitrogen at 110° C. for 2 h. Cool down the mixture to room temperature and filter over Celite® washing with dichloromethane. Evaporate the solvent and purify the crude by chromatography, eluting with hexane/ethyl acetate (90/10) to afford the title compound (355 mg, 0.67 mmol, 80%). MS (ES+): 529 (M+H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19](O)=[O:20])[CH2:17][C:6]=2[CH:5]=1.Cl.[O:31]=[C:32]1[N:41]([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33]1.ClC1C2NN=CC=2C2CN(CC(C)(C)C)C(=O)[C@H](CC(=O)N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)CC=2C=1>>[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19](=[O:20])[N:45]3[CH2:44][CH2:43][CH:42]([N:41]4[CH2:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[NH:33][C:32]4=[O:31])[CH2:47][CH2:46]3)[CH2:17][C:6]=2[CH:5]=1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Agent: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: Cl
Product: O=C(C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Yield: 27 %

Procedure:
(S)-2-(4-Chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid dihydrochloride (90 mg, 0.23 mmol) and 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine hydrochloride (75 mg, 0.28 mmol) were reacted following a procedure analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as white solid in 27% yield. MS m/e (M+H)+=598.2. 1H NMR (500 MHz, DMSO-D6): δ=13.47 (s, 1H), 9.19 (s, 1H), 8.31 (s, 2H), 8.23 (s, 1H), 7.22 (s, 1H), 7.12 (s, 3H), 6.99 (m, 1H), 6.84 (m, 2H), 6.77 (s, 1H), 5.40 (d, J=15.26, 1H), 4.65 (m, 3H), 4.54 (d, J=10.38, 1H), 4.40 (m, 1H), 4.30 (s, 1H), 4.22 (s, 1H), 4.09 (m, 1H), 3.99 (m, 1H), 3.14 (m, 2H), 3.03 (m, 1H), 2.93 (m, 1H), 2.60 (m, 1H), 1.78 (m, 1H), 1.58 (m, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(CC)CC.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[F:25]>CCOC(C)=O>[F:25][C:17]1[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:16]=1[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Yield: 97.9 %

Procedure:
To a solution of 1-methylpiperazine (6.91 g, 69 mmol) and Et3N (6.98 g, 69 mmol) in EtOAc (60 mL) was added 1,2-difluoro-4-nitrobenzene (10.02 g, 63 mmol) dropwise with stirring and the mixture was stirred at rt overnight. The reaction mixture was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a yellow solid (14.75 g, 98%).