Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=O)[CH2:3]1.[OH:12][C:13]1[CH:14]=[C:15]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=O)[CH:16]=[CH:17][C:18]=1[CH3:19].Cl.[CH2:29]1COCC1>CCOC(C)=O.[Zn].Cl[Ti](Cl)(Cl)Cl>[CH2:19]([C:18]1[CH:17]=[CH:16][C:15]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]2[CH2:3][C:2]([CH3:11])([CH3:1])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5]2)=[CH:14][C:13]=1[OH:12])[CH3:29]
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: C1CCOC1
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Product: CCc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of Zn powder (2.0 g, 36.0 mmol) and THF (50 mL) under N2 was added TiCl4 (6.0 g, 18.0 mmol). The resulting yellow suspension was refluxed for 1 h. A solution of 3,3,5,5-tetramethylcyclohexanone (1.6 g, 10.7 mmol) and compound 40 (1.00 g, 3.6 mmol) in THF (50 mL) was added dropwise to the refluxing reaction over 15 min. After 2 h, the reaction was cooled to RT and then poured into 150 mL 50% aqueous HCl and stirred for 30 min. The mixture was then diluted with EtOAc (150 mL) and the phase separated. The aqueous phase was washed with 2×100 mL EtOAc and the combined organics washed with brine (150 mL). The organics were then dried over MgSO4, filtered, and the solvents removed in vacuuo. The crude material was purified by column chromatography on silica gel (150 g) with 20% EtOAc to give a the desired product contaminated with 3% of 3,3,5,5-tetramethylcyclohexanone. The desired product was recrystallized from hexanes to give 1.8 g (48%) of 41 as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 0.89 (s, 6H), 0.93 (s, 6H), 1.25 (s, 2H), 1.75 (s, 2H), 1.90 (s, 2H), 2.13 (s, 3H), 6.57-6.89 (m, 3H), 7.01-7.30 (m, 5H), 9.15 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:3]=1.C(N(CC)CC)C.CN(C=O)C.Cl.[CH3:32][NH:33][O:34][CH3:35]>C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:33]([O:34][CH3:35])[CH3:32])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:3]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(F)cc1Nc1ccccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(F)cc1Nc1ccccc1F
Reaction time: 1 h
Yield: 85.2 %

Procedure:
In a 500 mL round bottom flask, 4-fluoro-2-(2-fluoro-phenylamino)-benzoic acid (6.0 g, 24.1 mmol), O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluorophosphate (HBTU) (18.5 g, 48 mmol) and triethylamine (20 mL, 144 mmol) were added to DMF (80.0 mL). The reaction mixture was stirred for 1 hr. at room temperature, then N,O-dimethylhydroxylamine hydrochloride (4.7 g, 48 mmol) was added. The mixture was stirred for 2 hr. The reaction mixture was poured into 300 mL of ethyl acetate and washed with saturated ammonium chloride (2×150 mL), water (2×200 mL) and brine (1×200 mL). The organic layer was evaporated and purified by flash chromatography using 30% ethyl acetate-hexanes to give 4-fluoro-2-(2-fluoro-phenylamino)-N-methoxy-N-methyl-benzamide (6.0 g, 85.3%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[C:6]([CH3:15])=[CH:7][N:8]([C@H:11]([CH2:13][CH3:14])[CH3:12])[C:9]=2[CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:35][N:36]([CH:38]=O)[CH3:37].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:35][N:36]([CH2:38][C:2]1[CH:10]=[C:9]([C:2]2[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]3[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])=[O:17])[C:5]3[C:6]([CH3:15])=[CH:7][N:8]([C@@H:11]([CH3:12])[CH2:13][CH3:14])[C:9]=3[CH:10]=2)[CH:5]=[CH:4][CH:3]=1)[CH3:37]
Reactant: CC[C@H](C)n1cc(C)c2c(C(=O)NCc3c(C)cc(C)[nH]c3=O)cc(Br)cc21
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CC[C@H](C)n1cc(C)c2c(C(=O)NCc3c(C)cc(C)[nH]c3=O)cc(-c3cccc(CN(C)C)c3)cc21

Procedure:
(S)-6-bromo-1-(sec-butyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-1H-indole-4-carboxamide (100 mg, 0.23 mmol), N,N-dimethyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine, HCl (100 mg, 0.34 mmol) and Palladium Tetrakis (26 mg, 0.023 mmol) in DMF/water (3 ml:1 ml) were stirred for 10 min under nitrogen. Cesium carbonate (220 mg, 0.68 mmol) was added and the insoluble mixture was irradiated (microwave) at 150° C. for 15 min. The contents were evaporated, dissolved in DCM/MeOH (1:1), and pre-absorbed on silica gel and purified using silica gel chromatography (eluent: DCM/MeOH/NH4OH, gradient 0 to 80:20:2 in DCM). The isolated product was first treated with EtOAc along with some hexanes. The product was then dissolved in MeOH and purified by reverse-phase HPLC (30×100 Varian Polaris C18 column, eluent: 10-80% gradient of MeCN in water with 0.1% TFA). The product fractions were combined, most of the solvent was evaporated, and a sat. solution of NaHCO3 was added. Solids that crashed out were filtered, air-dried for 15 min, and dried in vacuum-oven overnight. The solid product was collected as 87 mg (75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.38 (br. s., 1H), 8.23 (t, J=4.67 Hz, 1H), 7.77 (d, J=1.01 Hz, 1H), 7.60-7.64 (m, 2H), 7.40 (t, J=7.58 Hz, 1H), 7.30 (s, 1H), 7.20-7.26 (m, 2H), 5.87 (s, 1H), 4.59-4.68 (m, 1H), 4.36 (s, 1H), 4.35 (s, 1H), 3.46 (s, 2H), 2.24 (s, 3H), 2.18 (s, 9H), 2.11 (s, 3H), 1.76-1.88 (m, 2H), 1.41 (d, J=6.57 Hz, 3H), 0.74 (t, J=7.33 Hz, 3H); LCMS: 499.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(C(C)C)CC)(C)C.[CH3:28][Si:29]([CH3:36])([CH3:35])[CH2:30][CH2:31][O:32][CH2:33]Cl.O>ClCCl>[Cl:1][C:2]1[C:3]([N:12]([CH2:33][O:32][CH2:31][CH2:30][Si:29]([CH3:36])([CH3:35])[CH3:28])[S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCCS(=O)(=O)Nc1nc2ccccc2nc1Cl
Reactant: C[Si](C)(C)CCOCCl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)N(COCC[Si](C)(C)C)c1nc2ccccc2nc1Cl
Temperature: 25 °C
Yield: 94.4 %

Procedure:
Compound A1 (1.22 g, 4.28 mmol) obtained in Reference Example 1 was dissolved in dichloromethane (12.0 mL). Diisopropylethylamine (1.5 mL, 8.6 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (1.10 mL, 6.40 mmol) were added and the mixture was stirred at room temperature for minutes. Water was added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to give Compound A5 (1.68 g, 94% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[C:13]([F:19])=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9]/[C:10](/[C:12]2[C:13]([F:19])=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)=[N:28]\[OH:29])=[CH:4][CH:3]=1
Reactant: Cc1cnc(F)c(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cnc(F)c(/C(CC(c2ccc(Br)cc2)c2ccccc2C)=N/O)c1

Procedure:
In analogy to example 74, step 7, from 3-(4-bromo-phenyl)-1-(2-fluoro-5-methyl-pyridin-3-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a colorless oil, MS (ESI+): m/z=427.0814 ([M+H]+, 1Br).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]([N:13]([CH3:43])[C@@H:14]1[CH2:21][N:20]2[C:22]3[CH:23]=[C:24]([C:35]([O:37][CH3:38])=[O:36])[CH:25]=[CH:26][C:27]=3[C:28]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[C:19]2[C:18]2[CH:39]=[CH:40][CH:41]=[CH:42][C:17]=2[O:16][CH2:15]1)=[O:12])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][C:11]([N:13]([CH3:43])[C@@H:14]1[CH2:21][N:20]2[C:22]3[CH:23]=[C:24]([C:35]([O:37][CH3:38])=[O:36])[CH:25]=[CH:26][C:27]=3[C:28]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[C:19]2[C:18]2[CH:39]=[CH:40][CH:41]=[CH:42][C:17]=2[O:16][CH2:15]1)=[O:12]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)C(=O)CCNC(=O)OC(C)(C)C)COc1ccccc1-3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)C(=O)CCN)COc1ccccc1-3

Procedure:
A solution of methyl(7R)-7-[[N-(tert-butoxycarbonyl)-β-alanyl](methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.15 M) in DCM was treated with TFA (10 eq.) and the resulting mixture was stirred for 4h at RT before removing all volatiles in vacuo. The residue was partitioned between EtOAc and sat aq NaHCO3 and the layers separated. The combined organics were washed with brine, before being dried (Na2SO4), filtered and concentrated in vacuo. The product was used directly in the next step without further purification. (ES+) m/z 490 (M+H)+.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.S(Cl)([Cl:23])=O>ClC(Cl)Cl>[Cl:23][CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1c2ccccc2nc(-c2ccccc2)n1CCO
Solvent: ClC(Cl)Cl
Product: O=c1c2ccccc2nc(-c2ccccc2)n1CCCl
Reaction time: 2 h

Procedure:
To a stirred mixture of 15 parts of 3-(2-hydroxyethyl)-2-phenyl-4(3H)-quinazolineone and 375 parts of trichloromethane are added dropwise 24 parts of thionyl chloride at room temperature. Upon completion, stirring is continued for 2 hours at reflux. The reaction mixture is evaporated. Water is added to the residue and the whole is neutralized with a sodium hydrogen carbonate solution. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and petroleumether. The product is filtered off and dried, yielding 11.6 parts of 3-(2-chloroethyl)-2-phenyl-4(3H)-quinazolinone.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][C@H:11]([SiH:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[C:22]([F:28])[CH:21]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:29][C@H:30](O)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:1]([C@H:8]1[CH2:13][CH2:12][C@H:11]([Si@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]3[CH:25]=[C:24]([F:26])[C:23]([O:27][C@H:30]([CH3:29])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[C:22]([F:28])[CH:21]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC[C@H](C)O
Reactant: CCCCCCC[C@H]1CC[C@H]([SiH]2CCC(c3cc(F)c(O)c(F)c3)CC2)CC1
Product: CCCCCCC[C@@H](C)Oc1c(F)cc([C@H]2CC[Si@H]([C@H]3CC[C@H](CCCCCCC)CC3)CC2)cc1F

Procedure:
The general procedure of Example 1 was repeated using 4-(4-(trans-4-n-heptylcyclohexyl)-4-silacyclohexyl)-2,6-difluorophenol and (S)-2-nonanol, thereby obtaining the intended compound.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.S(Br)([Br:31])=O.[CH2:33](O)[CH3:34]>>[BrH:31].[CH2:33]([O:13][C:11](=[O:12])[C@H:10]([CH3:14])[CH2:9][C@H:8]([NH2:15])[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:2][CH:3]=1)[CH3:34].[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: CCO
Reactant: O=S(Br)Br
Agent: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Product: Br
Product: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
10 g (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (3-a, R1=BOC, R2=R3=H) are added to ethanol (100 ml). The mixture is heated to 65° C. 3 ml of thionyl bromide is then added over 0.5 hour. The mixture is then stirred for a further 1 hour. The ethanol is removed and heptane added. Further azeotropic distillations are performed using heptane to remove any residual ethanol. The solvent is removed in vacuo to afford (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrobromide (3-a, R1=R2=H, R3=Et). 1H NMR (DMSO): 1.11 (6 H), 1.61 (1H), 1.87 (1H), 2.73 (1H), 2.84 (1H), 3.04 (1H), 3.42 (1H), 4.01 (2H), 7.36 (3H), 7.47 (2H), 7.65 (4H), 8.03 (3H). m/z (ES+) 312 ([MH]+, 100%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([NH:21][CH2:22][CH2:23][OH:24])[N:18]=[C:17]([O:25][CH3:26])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:26][O:25][C:17]1[N:16]=[C:15]([NH:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[N:20]=[C:19]([NH:21][CH2:22][CH2:23][OH:24])[N:18]=1
Reactant: COc1nc(NCCO)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1COCCO1
Product: COc1nc(NCCO)nc(NC2CCNCC2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
To a stirred solution of 4-[4-(2-hydroxy-ethylamino)-6-methoxy-[1,3,5]triazin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 2.7 mmol, 1.0 equiv) in ethanol (30 mL) was added 4 M HCl in dioxane (3.40 mL, 13.6 mmol, 5.0 equiv) drop by drop. The reaction mixture was subsequently stirred at rt for 72 h and at 80° C. for 2 h. It was then cooled down to rt, poured into ice water and the pH was adjusted to 9-10 by addition of a sat. solution of potassium carbonate. The solution was extracted six times with a mixture of dichloromethane/isopropanol (4:1). The combined organic layers were concentrated by evaporation under reduced pressure to yield 0.60 g (83%) of the title compound as light yellow oil. MS (ISP): 269.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C(C)(C)C)=[C:4]([C:15]2(O)[CH2:20][CH2:19][N:18]([CH2:21]/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[CH2:17][CH2:16]2)[CH:3]=1.O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:15]2[CH2:20][CH2:19][N:18]([CH2:21]/[CH:22]=[CH:23]/[C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[CH2:17][CH:16]=2)[CH:3]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C1(O)CCN(C/C=C/c2ccc(Cl)cc2)CC1
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Cl)cc1C1=CCN(C/C=C/c2ccc(Cl)cc2)CC1

Procedure:
A suspension of N-(4-chloro-2-{1-[(E)-3-(4-chloro-phenyl)-allyl]-4-hydroxy-piperidin-4-yl}-phenyl)-2,2-dimethyl-propionamide (1.00 g) in 3NH2SO4 (7.5 ml) and DMSO (3 ml) was heated to reflux temperature for 48 hours. Then, water was added and the mixture extracted three times with CH2Cl2, the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography (CH2Cl2:MeOH 95:5) to afford 4-chloro-2-{1-[(E)-3-(4-chloro-phenyl)-allyl]-1,2,3,6-tetrahydro-pyridin-4-yl}-phenylamine (0.205 g; viscous oil; Retention Time HPLC 2.15 min; MS (ES+) 359 (M+H+) and 4-(2-amino-5-chloro-phenyl)-1-[(E)-3-(4-chloro-phenyl)-allyl]-piperidin-4-ol (0.182 g; M.p. 168-170° C.; Retention Timc HPLC 1.95 min; MS (ES+) 377 (M+H+).
Reaction SMILES: C(N[C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][C:7]=1[N+:19]([O-:21])=[O:20])(CC)C.C(C1C=CC([OH:32])=CC=1)(C)(C)C.[N+]([O-])(O)=O>C(O)(=O)C>[N+:19]([C:7]1[CH:8]=[C:9]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]=1[OH:32])([O-:21])=[O:20]
Reactant: CCC(C)Nc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: CC(C)(C)c1ccc(O)cc1
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: CC(C)(C)c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1

Procedure:
The synthesis of N-sec-butyl-4-tert-butyl-2,6-dinitroaniline is generally described in a number of U.S. Pat. Nos. including, for example, 3,672,866; 3,927,127 and 3,991,116 all to Damiano. The process described in U.S. Pat. Nos. 3,672,866 and 3,991,116 begins with a starting material, 4-tert-butylphenol. The 4-tert-butylphenol is subjected to nitration utilizing nitric acid in acetic acid solution to produce 2,6-dinitro-4-tert-butylphenol. The 2,6-dinitro-4-tert-butylphenol is then chlorinated to produce 2,6-dinitro-4-tert-butylchlorobenzene. This 2,6-dinitro-4-tert-butylchlorobenzene is then converted into N-sec-butyl-4-tert-butyl-2,6-dinitroaniline by amination with sec-butylamine.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH2:6]=O>>[CH3:6][NH:1][CH2:2][C:3]([OH:5])=[O:4].[CH2:6]=[N:1][CH2:2][C:3]([OH:5])=[O:4]
Reactant: NCC(=O)O
Reactant: C=O
Product: C=NCC(=O)O
Product: CNCC(=O)O

Procedure:
Ehrat, U.S. Pat. No. 4,237,065, describes a process in which glycine is condensed with formaldehyde in the presence of a tertiary base to produce N-methyl glycine or N-methylene glycine, and the latter is in turn reacted with phosphorous acid to produce glyphosate.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[N:20]([S:23]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:21]=[CH:22][C:15]=23)=[C:5]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[N:6]=1.[CH3:33][NH:34][CH3:35].[O:36]1[CH2:40]CCC1>>[CH3:33][N:34]([CH3:35])[C:40]([NH:11][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([CH3:1])[S:3][C:4]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[N:20]([S:23]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:21]=[CH:22][C:15]=23)=[CH:13][CH:12]=1)=[O:36]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4sc(C)nc4-c4ccc(N)cc4)ccnc32)cc1
Reactant: CNC
Reactant: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4sc(C)nc4-c4ccc(NC(=O)N(C)C)cc4)ccnc32)cc1

Procedure:
Following the procedure in Example 5a with 4-(2-methyl-5-{1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1,3-thiazol-4-yl)aniline and 2M dimethylamine in tetrahydrofuran provided the title compound. ESMS [M+H]+: 532.2
Reaction SMILES: [Cl-:1].[NH2:2][C:3]1[CH:8]=[CH:7][N+:6]([CH2:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([S:20](=[O:30])(=[O:29])[N:21]([CH3:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[CH:16][C:15]=2[NH:31][CH3:32])=O)=[CH:5][CH:4]=1>C(#N)C.S(Cl)(Cl)=O.C(OCC)C>[Cl-:1].[NH2:2][C:3]1[CH:8]=[CH:7][N+:6]([CH2:9][CH2:10][C:11]2[N:31]([CH3:32])[C:15]3[CH:16]=[CH:17][C:18]([S:20](=[O:30])(=[O:29])[N:21]([CH3:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][C:14]=3[N:13]=2)=[CH:5][CH:4]=1
Reactant: CNc1ccc(S(=O)(=O)N(C)c2ccccc2)cc1NC(=O)CC[n+]1ccc(N)cc1
Agent: [Cl-]
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: CN(c1ccccc1)S(=O)(=O)c1ccc2c(c1)nc(CC[n+]1ccc(N)cc1)n2C
Reaction time: 24 h

Procedure:
To a suspension of 4-amino-1-(3-(5-(N-methyl-N-phenylsulfamoyl)-2-(methylamino)phenylamino)-3-oxopropyl)pyridinium chloride (0.2 g, 0.00042 mol) in acetonitrile (8 ml), thionyl chloride (0.2 ml) was added. After boiling the reaction mixture for 10 min, it was left to stand at room temperature for 24 h and then diluted with diethyl ether (8 ml). The precipitate formed was collected by filtration and crystallized from a 10:1 mixture of acetonitrile with dehydrated ethanol. The yield of 4-amino-1-(2-(1-methyl-5-(N-methyl-N-phenylsulfamoyl)-1H-benzo[d]imidazol-2-yl)ethyl)pyridinium chloride was 0.055 g (26%).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[C:5]([CH3:8])=[N:4][CH:3]=1.C([Mg]Br)C.CON(C)[C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>ClCCl.O>[CH3:7][N:6]1[C:2]([C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:23])=[CH:3][N:4]=[C:5]1[CH3:8]
Reactant: Cc1ncc(Br)n1C
Reactant: CON(C)C(=O)c1ccccc1
Agent: CC[Mg]Br
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: Cc1ncc(C(=O)c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a solution of 5-bromo-1,2-dimethyl-1H-imidazole (10.0 g, 57.1 mmol) in dichloromethane (50 mL) was added dropwise ethylmagnesium bromide (3 M in Et2O, 19.0 mL, 57.0 mmol). After stirring at room temperature for 30 min, the reaction mixture was cooled down to 0° C. with an ice-brine bath and N-Methoxy-N-methyl-benzamide (8.70 mL, 57.1 mmol) was added dropwise. The mixture was stirred for 7.5 h at room temperature. The mixture was worked-up by addition of water (100 mL), then acidified with aq. HCl (1 M) until pH=7. After extraction with dichloromethane (2×75 mL), the organic layers were washed with water (2×100 mL) then dried over MgSO4 and concentrated in vacuo. Purification of the residue on silica gel afforded (1,2-dimethyl-1H-imidazol-5-yl)(phenyl)methanone [8.41 g, yield 44%; HPLC/MS: m/z=201 (M+H); log P(HCOOH)=0.56].
Reaction SMILES: O=O.[K+].[C:4]1([O:14][CH2:15][CH2:16][CH2:17][CH2:18]Cl)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.C1OCCOCCOCCOCCOCC[O:22]C1.O>CS(C)=O>[C:4]1([O:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:22])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: ClCCCCOc1cccc2ccccc12
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: O=O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: OCCCCOc1cccc2ccccc12

Procedure:
Potassium superoxide (0.71 g) was added to a solution of 4-(1-naphthyloxy)butyl chloride (2.0 g) and 18-Crown-6 (0.5 g) in dimethylsulfoxide (10 ml). After 8 hors the mixture was added to water and the solution was extracted with ether. The ethereal solution was dried and evaporated and the residue chromatographed on silica gel, eluting with 2:1 hexane ether, to yield the title compound as an oil.
Reaction SMILES: [OH-].[Na+].I[C:4]1[C:9]([OH:10])=[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:7]=[C:6]([I:17])[N:5]=1.[CH3:18]I.O>CN(C)C=O.C(OCC)(=O)C>[I:17][C:6]1[CH:7]=[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:9]([O:10][CH3:18])=[CH:4][N:5]=1
Reactant: CI
Reactant: COCCCCc1cc(I)nc(I)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COCCCCc1cc(I)ncc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 60 mmol NaOH in 50 ml N,N-dimethyl formamide is progressively added 50 mmol 2,6-diiodo-4-(4-methoxy-butyl)-pyridin-3-ol. The reaction mixture is stirred for 30 minutes and then cooled to 0° C. 60 mmol methyl iodide are added and the mixture is stirred for 15 minutes at room temperature. Water and ethyl acetate are added to the mixture, the layers are separated and the aqueous layer is extracted with ethyl acetate (3×). The combined organic layers are dried over sodium sulphate, filtered and concentrated. The title compound is obtained from the residue by means of flash chromatography (SiO2 60 F) and identified based on its Rf value.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:4][N:3]=1.[C:19]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])#[CH:20].CS(C)=O>C(Cl)Cl>[C:19]([C:21]1[CH:22]=[C:23]([NH:24][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:10]=[N:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:5]=[CH:4][N:3]=2)[CH:25]=[CH:26][CH:27]=1)#[CH:20]
Reactant: C#Cc1cccc(N)c1
Reactant: Clc1nccc(Nc2cnc3ccccc3c2)n1
Solvent: CS(C)=O
Solvent: ClCCl
Product: C#Cc1cccc(Nc2nccc(Nc3cnc4ccccc4c3)n2)c1
Temperature: 100 °C

Procedure:
A mixture of (2-chloro-pyrimidin-4-yl)-quinolin-3-yl-amine (70 mg 0.272 mmol) and 3-ethynylaniline (33 mg, 0.282 mmol) was suspended in a sealed tube with 0.3 mL of DMSO. The resulting mixture was heated at 100° C. for 2 h, cooled to RT, diluted with CH2Cl2. The precipitate was collected by suction filtration then dried under vacuum to give the desired product as an off-white solid. M+H—338; Calc'd for C21H15N5: 337.13.