Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[O:2].S(=O)(=O)(O)O.[C:8]1(C)[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1>>[C:10]1([CH3:14])[C:11]([CH3:1])=[CH:12][CH:13]=[CH:8][CH:9]=1.[CH2:1]=[O:2]
Reactant: Cc1cccc(C)c1
Agent: C=O
Agent: O=S(=O)(O)O
Product: Cc1ccccc1C
Reaction time: 7 h

Procedure:
A reactor was charged with 106 g of m-xylene, 129 g of a 37% aqueous solution of formaldehyde (formalin) and 98% by weight sulfuric acid, and the reaction was started at 95° C. with stirring. The reaction was performed for 7 hours, and the temperature finally rose to 104° C. After the end of the reaction, the aqueous phase at the bottom (sulfuric acid phase) was separated, and the resulting oil phase was steam-distilled at 100° C. at atmospheric pressure. 107 g of a xylene/formaldehyde resin was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:40][CH2:41][OH:42]>CCO.O>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:40][CH2:41][OH:42])[CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: O=C(NC(COCC1CCNCC1)c1ccccc1Cl)c1ccc2c(Cl)c[nH]c2c1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(NC(COCC1CCN(CCO)CC1)c1ccccc1Cl)c1ccc2c(Cl)c[nH]c2c1
Yield: 31.7 %

Procedure:
To a solution of 3-chloro-N-[1-(2-chlorophenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (200 mg, 0.45 mmol) in 5 mL of EtOH was added potassium carbonate (247 mg, 1.8 mmol), potassium iodide (224 mg, 1.4 mmol) and 2-chloroethanol (0.09 mL, 1.4 mmol). The reaction was allowed to stir at room temperature overnight after which time water was added and the resulting precipitate was isolated by filtration. Purification of the filtrate (SiO2: 10:0.5 EtOAc:isopropylamine) provided 70 mg (32%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C=O)C.CC[N:19]([CH:23]([CH3:25])[CH3:24])C(C)C.C1(N)CC1>O>[NH2:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH:23]1[CH2:25][CH2:24]1)=[O:6]
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1c(I)cccc1C(=O)O
Agent: NC1CC1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(I)cccc1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
To 2-amino-3-iodo-benzoic acid (200 mg, 0.76 mmol) in DMF (1 mL) TBTU (244.15 mg, 0.76 mmol) and DIPEA (245.69 μL, 1.52 mmol) are added and stirred at r.t. for 7 min. Cyclopropylamine (52.69 μL, 0.76 mmol) is added and stirred at r.t. overnight. The reaction mixture is diluted with water and the precipitate is filtered off and dried.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1.C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:40].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([Cl:40])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3c(Cl)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a solution of 25 (0.84 g, 1.90 mmol) in CHCl3 (9 mL) was added triethylamine (0.50 mL, 3.59 mmol) and POCl3 (1.60 mL, 17.1 mmol). After heating at reflux for 16 h, the reaction mixture was cooled to room temperature and poured onto ice and sat. aq. NaHCO3 (150 mL). The resulting mixture was extracted with CH2Cl2 (3×75 mL) and the combined organic layers dried (MgSO4). Concentration followed by flash chromatography (9:1/CH2Cl2:EtOAc) afforded 708 mg (87%) of product as a white solid, m.p. 101-103° C. 1H NMR (400 MHz, CDCl3) δ 6.10 (d, J=2.8 Hz, 1H), 6.01 (dd, J=5.6, 3.2 Hz, 1H), 5.92 (t, J=6.0 Hz, 1H), 5.42 (s, 2), 4.97 (dd, J=11.6, 3.6 Hz, 1H), 4.32 (m, 1), 4.21 (dd, J=12.0, 5.2 Hz, 1H), 2.12 (s, 6H), 2.06 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Br[CH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>>[C:16]1([CH2:15][N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=3)[N:3]=[CH:2]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Reactant: BrCc1cccc2ccccc12
Product: N#Cc1ccnc(-c2cn(Cc3cccc4ccccc34)cn2)c1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 4) and 1-(bromomethyl)naphthalene according to the procedure for the preparation of Example 43, part A using room temp. [M+H] Calc'd for C20H14N4, 311. Found, 311.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f30) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[C:12]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:17]=3[N:18]=2)[C:11]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:10][C:9]=1[C:31]1[O:32][C:33]2[CH:39]=[CH:38][C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:36][C:34]=2[N:35]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:44]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:44][CH2:23][C:19]1[C:17]2[N:18]=[C:14]([C:12]3[CH:13]=[C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:9]([C:31]4[O:32][C:33]5[CH:39]=[CH:38][C:37]([C:40]([CH3:41])([CH3:43])[CH3:42])=[CH:36][C:34]=5[N:35]=4)=[CH:10][C:11]=3[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[O:15][C:16]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCOc1cc(-c2nc3c(C)cccc3o2)c(OCCCCCC)cc1-c1nc2cc(C(C)(C)C)ccc2o1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCOc1cc(-c2nc3c(CBr)cccc3o2)c(OCCCCCC)cc1-c1nc2cc(C(C)(C)C)ccc2o1
Temperature: 0 °C

Procedure:
A mixture of 2-(2,5-bis(hexyloxy)-4-(4-methylbenzo[d]oxazol-2-yl)phenyl)-5-(tert-butyl)benzo[d]oxazol (3.7 g, 6.35 mmol), N-bromosuccinimide (NBS) (1.13 g, 6.35 mmol), and AIBN (0.1 g, 0.6 mmol) in CCl4 (40 mL) was heated to reflux for 15 h under dry argon atmosphere. The reaction mixture was cooled to 0° C. and the precipitate was removed by filtration while maintaining the temperature at 0° C. After the solvent was evaporated, 4-(bromomethyl)-2-(4-(5-(tert-butyl)benzo[d]oxazol-2-yl)-2,5-bis(hexyloxy)phenyl)benzo[d]oxazole was obtained as an oil, which was used for next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=2[CH:15]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C@@H:24]2[C@@H:29]3[CH2:30][C@@H:26]([CH:27]=[CH:28]3)[C@@H:25]2[C:31]([NH2:33])=[O:32])[C:20]([Cl:34])=[CH:19][N:18]=1>>[Cl:34][C:20]1[C:21]([NH:23][C@@H:24]2[C@@H:29]3[CH2:30][C@@H:26]([CH:27]=[CH:28]3)[C@@H:25]2[C:31]([NH2:33])=[O:32])=[N:22][C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=3[CH:15]=2)=[N:18][CH:19]=1
Reactant: CC1(C)CCC(=O)Nc2cc(N)ccc21
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: CC1(C)CCC(=O)Nc2cc(Nc3ncc(Cl)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)ccc21

Procedure:
Title compound was prepared from 8-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide in a manner analogous to Example 1221d. (120° C., 30 min). Product was isolated as a white foam (82 mg, 49%), HPLC purity 90%, LCMS 467.24 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.52 (bs, 1H), 9.08 (bs, 1H), 7.88 (bs, 1H), 7.80 (s, 1H), 7.72 (s, 1H), 7.32 (s, 1H), 6.95 bs, 1H), 6.67 (bs, 1H), 6.31-6.28 (m, 1H), 6.18-6.16 (m, 1H), 4.26 (t, J=7.6 Hz, 1H), 3.05 (s, 1H), 2.94 (s, 1H), 2.65 (d, J=8.0 Hz, 1H), 2.56-2.50 (m, 1H), 2.47-2.36 (m, 1H), 2.17-2.10 (m, 3H), 1.54 (d, J=8.8 Hz, 1H), 1.42 (s, 6H).
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH2:11])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:12][C:13]1[C:14]([CH:20]=O)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:12][C:13]1[C:14]([CH2:20][NH:11][CH:9]2[C:10]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7][CH2:8]2)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1
Reactant: NC1CCCc2cccnc21
Reactant: Cc1cnc(C=O)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CNC2CCCc3cccnc32)c(C)c1

Procedure:
Using General Procedure B: Reaction of 5,6,7,8-Tetrahydro-quinolin-8-ylamine and 3,5-dimethyl-pyridine-2-carboxaldehyde with NaBH(OAc)3 in CH2Cl2 gave (3,5-Dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine as a colorless oil.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1>CS(C)=O.CCOC(C)=O>[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:2]2[C:7]([C:8]3[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH:9]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:26][CH:25]=1
Reactant: Nc1ccc(O)cc1
Reactant: CC(=O)N1CC=C(c2cccnc2F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(=O)N1CC=C(c2cccnc2Oc2ccc(N)cc2)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A solution of 1-(4-(2-fluoropyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone (1.68 g, 7.63 mmol) in dimethylsulfoxide (25 mL) under argon was added cesium carbonate (2.73 g, 8.39 mmol), followed by 4-aminophenol (0.874 g, 8.01 mmol). The reaction was stirred at 80° C. for 18 h. The cooled reaction mixture was diluted with EtOAc and washed with water; the aqueous layer was back-extracted with EtOAc (1×). The organic layers were combined, dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (20% to 50% EtOAc/Hexanes) afforded 1-(4-(2-(4-aminophenoxy)-pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone as a tan solid. MS (ESI, pos. ion) m/z: 310.0 (M+1).
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:18][C:19]([F:43])([F:42])[C:20](=O)[CH2:21][C:22]([C:24]1[CH:40]=[CH:39][C:27]([O:28][CH2:29][CH2:30][NH:31]C(=O)OC(C)(C)C)=[CH:26][CH:25]=1)=O>>[ClH:1].[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[C:22]([C:24]3[CH:40]=[CH:39][C:27]([O:28][CH2:29][CH2:30][NH2:31])=[CH:26][CH:25]=3)=[CH:21][C:20]([C:19]([F:18])([F:42])[F:43])=[N:17]2)=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Agent: Cl
Product: NCCOc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(OCc3ccccc3)cc2)cc1
Yield: 87.5 %

Procedure:
The title compound (12.9 g, 87.5%) was prepared from 1-[4-(benzyloxy)phenyl]hydrazine hydrochloride obtained by Example 79-1 and tert-butyl 2-[4-(4,4,4-trifluoro-3-oxobutanoyl)phenoxy]ethylcarbamate obtained by Example 78-2 in a similar manner to that of Example 78-3.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:3]1.CCN(CC)CC.[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32](Cl)=[O:33]>C(Cl)Cl>[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([NH:1][C@H:2]1[C@H:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][N:4]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:3]1)=[O:33]
Reactant: O=C(Cl)CCCCBr
Reactant: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1NC(=O)CCCCBr
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.9 %

Procedure:
To a solution of trans-1-tert-butyl 4-ethyl 3-aminopiperidine-1,4-dicarboxylate 7 (2.5 g, 9.2 mmol, 1.0 equiv) in CH2Cl2 (50 mL), Et3N (2.5 mL, 18.4 mmol, 2.0 equiv) was added at rt. After the reaction solution was stirred at rt for 10 min, 5-bromovaleryl chloride (1.9 g, 9.6 mmol, 1.05 eq) was added. The reaction solution was stirred at rt for 2 h. The mixture was quenched with H2O (20 mL) and extracted with CH2Cl2 (50 mL×3). The organic layer was collected, concentrated in vacuo, and the residue was purified by column chromatography (silica, petroleum ether/EtOAc=1:1) to give (trans)-1-tert-butyl 4-ethyl 3-(5-bromopentanamido)piperidine-1,4-dicarboxylate 8 as yellow oil (3.2 g, yield: 80%). ESI-MS (M+H-56)+: 379.0. 1H NMR (400 MHz, CDCl3) δ: 5.99 (d, 1H), 4.39-4.38 (m, 1H), 4.15 (q, 2H), 3.79-3.74 (m, 1H), 3.66-3.60 (m, 1H), 3.41 (t, 2H), 3.30-3.26 (m, 1H), 3.21-3.14 (m, 1H), 2.78-2.74 (m, 1H), 2.19 (t, 2H), 1.99-1.85 (m, 3H), 1.80-1.72 (m, 3H), 1.45 (s, 9H), 1.27 (t, 3H).
Reaction SMILES: [NH2:1][C:2](=[N:20][N+:21]([O-:23])=[O:22])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:10])[NH2:8].[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(O)(=O)C>[C:24]([NH:8][C@@H:7]([C:9]([NH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1)=[O:10])[CH2:6][CH2:5][CH2:4][NH:3][C:2]([NH2:1])=[N:20][N+:21]([O-:23])=[O:22])(=[O:26])[CH3:25]
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](N)C(=O)NCc1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)NCc1ccc(O)cc1
Temperature: 50 °C

Procedure:
0.3 g (0.925 mMol) of (R)-N5 -[amino(nitroimino)methyl]-N-[(4-hydroxyphenyl)methyl]-ornithinamide were dissolved in 3 ml of glacial acetic acid and after the addition of 3 ml (0.032 Mol) of acetic anhydride the mixture was heated to a reaction temperature of 50° C. for 30 minutes. The product remaining after the volatile components had evaporated off was further processed without purification.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][N:8]=[C:9]1[C:13](=O)[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[O:10]1)(=[O:3])[CH3:2].Cl.[CH3:20][O:21][NH2:22].O>CN1CCCC1=O>[C:1]([O:4][CH2:5][CH2:6][O:7][N:8]=[C:9]1[C:13](=[N:22][O:21][CH3:20])[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[O:10]1)(=[O:3])[CH3:2]
Reactant: CON
Reactant: CC(=O)OCCON=C1Oc2ccccc2C1=O
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: CON=C1C(=NOCCOC(C)=O)Oc2ccccc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
10 g (0.04 mol) of 2-(3-oxo-3H-benzofuran-2-ylideneaminooxy)-ethyl acetate (XIV-1) and 4.18 g (0.05 mol) of O-methylhydroxylamine hydrochloride are dissolved in 40 ml of N-methyl-2-pyrrolidinone and stirred at 80° C. for 1 hour. The reaction mixture is poured into water and the resulting mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. 10.6 g of crude 2-(3-methoxyimino-3H-benzofuran-2-ylideneaminooxy)-ethyl acetate (XIII-1) are obtained, which are chromatographed over silica gel using a mixture of tert-butyl methyl ether and petroleum ether (1:1). 6.9 g (59.1% of theory) of 2-(3-methoxyimino-3H-benzofuran-2-ylideneaminooxy)ethyl acetate (XIII-1) having a content of 82.15% of stereoisomer A and 13.38% of stereoisomer B are obtained.
Reaction SMILES: Cl[C:2]1[S:6][C:5]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[Cl:12].C([Li])CCC.Cl>CCOCC.CCCCCC>[Cl:12][C:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[S:6][CH:2]=1
Reactant: Cc1cccc2c(Cl)c(Cl)sc12
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1cccc2c(Cl)csc12

Procedure:
10 g of 2,3-Dichloro-7-methylbenzo[b]thiophene are dissolved in 200 ml ether and 28.8 ml of a 1.6M solution of butyllithium in hexane added dropwise at 0°. After one hour the mixture is poured into dilute aqueous HCl, the organic phase separated, washed, dried and concentrated on a rotary evaporator. The raw title product thus obtained is reacted directed further (B.p.=60°-62°/0.13 Pascal. 3-Chloro-4-methylbenzo[b]thiophene may be prepared analogously.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][NH:14][CH2:15][C@H:10]3[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][C:6]=2[CH:20]=1.Br[CH2:22][CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][N:14]([CH2:22][CH2:23][N:24]4[C:28](=[O:29])[C:27]5=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]5[C:25]4=[O:34])[CH2:15][C@H:10]3[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][C:6]=2[CH:20]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Clc1ccc2c(c1)Cc1ccccc1[C@@H]1CNCCN21
Product: O=C1c2ccccc2C(=O)N1CCN1CCN2c3ccc(Cl)cc3Cc3ccccc3[C@@H]2C1
Yield: 47 %

Procedure:
Following a procedure similar to that described in Preparation 14(a), but using (14bR)-8-chloro-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine and N-(2-bromoethyl)phthalimide, the title compound was obtained in a yield of 47%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH:34]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:32])[N:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[CH3:24])[CH:17]=2)O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+].O>C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:42])[CH:34]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:32])[N:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[CH3:24])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C(=O)c1cccc(C(O)(c2cccc(O[Si](C)(C)C(C)(C)C)c2)C2CCN(C(=O)OC(C)(C)C)CC2)c1)c1cccc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CN(C(=O)c1cccc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)c1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
A mixture of 4-([3-(tert-butyldimethylsilanyloxy)phenyl]{3-[N-(3-fluorophenyl)-N-methyl-carbamoyl]phenyl}hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (3.59 g) and p-toluenesulfonic acid monohydrate (3.5 g) in benzene (200 mL) was refluxed overnight in a round bottom flask equipped with Dean-Stark trap. The reaction solution was cooled to room temperature. Saturated Na2CO3 solution (50 mL) was added to the solution, followed by the addition of 100 mL of H2O. The resulting mixture was extracted by EtOAc (300 mL). It was observed that solids were floating between the two layers. Consequently, 75 ml of 0.5 M NaOH solution was added to the mixture. After being stirred for 30 minutes, the mixture became clear. The organic layer and water layer were separated. The water layer was extracted by EtOAc (100 mL×1). The combined organic layer was washed by water (75 mL×2) and brine (75 mL×1), dried by Na2SO4 and concentrated to give 4-([3-(tert-butyl-dimethylsilanyloxy)phenyl]{3-[N-(3-fluorophenyl)-N-methylcarbamoyl]phenyl}-methylene)piperidine-1-carboxylic acid tert-butyl ester (2.83 g; crude). TLC and 1H NMR of the crude product indicated a mixture of compounds, apparently including the desired dehydration product with the loss of N-Boc and/or O-TBDMS protecting groups. The crude product was carried to next step without purification.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=4)[N:16]=[CH:17]3)[N:21]=2)=[CH:35][CH:34]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.8 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{1-[6-(4-chloro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.34 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (3 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as an off-white solid (0.24 g, 34%). MS (ISN) 478.0 [(M−H)−]; mp 225° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([Cl:13])=[C:10]([Cl:12])[Cl:11].[Br:14]N1C(=O)CCC1=O>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:14])=[CH:4][C:3]=1[C:9]([Cl:13])=[C:10]([Cl:11])[Cl:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)c(C(Cl)=C(Cl)Cl)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: ClC(Cl)=C(Cl)c1cc(CBr)ccc1Cl
Yield: 99.4 %

Procedure:
A solution of 4-chloro-3-(trichlorovinyl)toluene (13.77 g) and dibenzoyl peroxide (1.0 g) in 500 ml of benzene was heated at reflux. N-Bromosuccinimide (11.6 g) was added in portions and the resulting mixture stirred at reflux for 1.5 hours (negative KI test). The reaction mixture was concentrated under reduced pressure. The residue was partially dissolved in 300 ml of petroleum ether and the insoluble succinimide removed by filtration. The filtrate was concentrated to give 17.9 g of the benzyl bromide.