Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7](SC)=[N:6]2.CC1N=C(C2C=CC=CC=2)N2C=1C=NC(S(C)(=O)=[O:30])=N2.Cl.[CH:40]1([NH2:46])[CH2:45][CH2:44]C[CH2:42][CH2:41]1.C(N(CC)CC)C>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:46][CH:40]1[CH2:45][CH2:44][O:30][CH2:42][CH2:41]1)=[N:6]2
Reactant: CSc1ncc2c(C)nc(-c3ccccc3)n2n1
Reactant: Cc1nc(-c2ccccc2)n2nc(S(C)(=O)=O)ncc12
Reactant: NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc(-c2ccccc2)n2nc(NC3CCOCC3)ncc12
Reaction time: 0.5 h

Procedure:
Applying the displacement procedure, using 5-methyl-2-(methylthio)-7-phenylimidazo[5,1-f][1,2,4]triazine (Intermediate 72) (45 mg, 0.16 mmol), cyclohexylamine hydrochloride (21.5 mg, 0.16 mmol) and ethanol (2.5 mL) except that after 1 h, the mixture was treated with triethylamine (0.022 mL, 0.16 mmol), and heating continued for 0.5 h, to afford 5-methyl-7-phenyl-N-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-2-amine (15 mg) as a yellow solid. MS m/z 310 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][CH:8](C(=O)C)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+].[Cl-].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]#N>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]2[C:24]3[C:23](=[N:22][CH:27]=[CH:26][CH:25]=3)[NH:28][C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(Cc1ccc(OC)cc1)C(C)=O
Reactant: N#[N+]c1ccccn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2ncccc2c1-c1ccc(OC)cc1
Temperature: 25 °C

Procedure:
To a solution of ethyl 2-(4-methoxybenzyl)-3-oxobutyrate in EtOAc stirred at ice bath temperature under an argon atmosphere is added an aquious solution of NaOH. This is immediately followed by the addition of an aqueous solution of pyrid-2-yldiazonium chloride [prepared from 2-aminopyridine in 6 N HCl and NaNO2 ]. The mixture is partitioned between EtOAc and H2O. The aqueous layer is washed with EtOAc. The combined organic extracts are washed with saturated aqueous NaCl solution, dried (Na2SO4) and the solvent is removed in vacuo. The residue is dissolved in EtOH and the solution is saturated with HCl gas. This is refluxed then cooled to room temperature and partitioned EtOAc and saturated aqueous NaHCO3 solution. The aqueous layer is washed with EtOAc. The combined organic extract is washed with H2O then saturated aqueous NaCl solution, dried (Na2SO4) and the solvent is removed in vacuo. The residue is purified by chromatography to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.C1C(=O)N([Br:19])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>FC(F)(F)C1C=CC=CC=1>[Br:19][CH2:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: Cc1cc(F)cc([N+](=O)[O-])c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: FC(F)(F)c1ccccc1
Product: O=[N+]([O-])c1cc(F)cc(CBr)c1
Temperature: 105 °C
Yield: 6.3 %

Procedure:
A solution of 3-fluoro-5-nitrotoluene (1.0 g, 6.45 mmol) in trifluorotoluene (15 ml) was treated with NBS (1.721 g, 9.67 mmol) and AIBN (0.212 g, 1.289 mmol) and heated at 105° C. overnight. The mixture was cooled to RT, the solids removed via filtration and the filtrate concentrated to dryness to afford 1-(bromomethyl)-3-fluoro-5-nitrobenzene (95 mg, 63% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([NH:14][C:15]2[C:16](=[O:34])[N:17]([C:21]3[CH:22]=[C:23]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:24]([NH:26][CH:27]3[CH2:29][CH2:28]3)=[O:25])[CH:18]=[CH:19][N:20]=2)[CH2:13][CH2:12]1.[CH3:35][NH2:36]>C(O)C>[CH:27]1([NH:26][C:24](=[O:25])[C:23]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:21]([N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:11]4([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:36][CH3:35])[CH2:13][CH2:12]4)[C:16]3=[O:34])[CH:22]=2)[CH2:29][CH2:28]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CC2)c1=O
Reactant: CN
Solvent: CCO
Product: CNCCOc1ccccc1C1(Nc2nccn(-c3cc(C(=O)NC4CC4)ccc3C)c2=O)CC1
Temperature: 100 °C

Procedure:
To 3-(3-(1-(2-(2-Chloroethoxy)phenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide (Example 167e, 100 mg) in a 10 mL microwave vial was added methylamine (2 mL of a 33% solution in ethanol). This was sealed and heated within a CEM Discover microwave for 30 min at 100° C. The volatiles were removed in vacuo and the residue taken up in methanol and purified by preparative HPLC (ACE column, 0.1% TFA:acetonitrile eluent) afforded the title compound. This was dissolved in acetonitrile and filtered through SCX resin eluting with acetonitrile and methanol (discarded) followed by 7N NH3 in methanol. The basic fractions were collected and the volatiles were removed in vacuo. Trituration with diethyl ether afforded the title product as a white solid (46 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[C:5]([N:7]([CH3:24])[C@H:8]([C:21]([OH:23])=O)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:20][N:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:6].Cl.[CH3:30][O:31][C:32](=[O:45])[C@H:33]([CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)[NH2:34].OC1C2N=NNC=2C=CC=1.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:30][O:31][C:32](=[O:45])[C@H:33]([CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)[NH:34][C:21](=[O:23])[C@@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:20][N:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[N:7]([C:5](=[O:6])[C:4]1[CH:3]=[C:2]([CH3:1])[CH:27]=[C:26]([CH3:28])[CH:25]=1)[CH3:24]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: Cc1cc(C)cc(C(=O)N(C)[C@@H](Cc2ccc(-c3ccno3)cc2)C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](Cc1ccc(-c2ccno2)cc1)N(C)C(=O)c1cc(C)cc(C)c1

Procedure:
At 0° C., N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)-phenyl]-alanine (445 mg) is stirred in N,N-dimethylformamide (24 ml) together with (L)-tryptophane methyl ester hydrochloride (400 mg), hydroxybenztriazol (330 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.32 ml) for 1 hour and at ambient temperature over night. After extraction with ethyl acetate and 10% aqueous citric acid the organic phase is washed with 4% aqueous sodium bicarbonate, and with brine, dried and evaporated. Flash chromatography on silica gel (hexane/ethyl acetate 2:1) gives the product as a mixture of diastereoisomers. Separation by medium pressure chromatography on a silica gel column, using ether/dichloromethane (1:1) as solvent gives both [N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)-phenyl]-(D)-alanyl]-(L)-tryptophane methyl ester. NMR (CDCl3, 400 MHz) δ [ppm] 8.60 (s), 8.30 (m), 7.70 (m), 7.55 (m), 7.30 (m), 7.10 (m), 6.90 (m), 6.50 (m), 5.85 (s), 5,43 (m), 4.90 (m), 4.33 (m), 3.75 (s), 3.70 (s), 3.35 (m), 3.15 (m), 2.85 (s), 2.57 (s), 2.35 (s), 2.20 (s), 1.93 (s), 1.85 (s).
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([F:17])[CH2:15]Br)=[CH:10][CH:9]=1>CCCCC>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])=[CH2:15])=[CH:10][CH:9]=1
Reactant: FC(CBr)c1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCC
Product: C=C(F)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
796 mg (7.09 mmol) of potassium tert-butoxide were added in several portions to a solution, cooled to 0° C., of 1.0 g (3.55 mmol) of 1-bromo-4-(2-bromo-1-fluoroethyl)benzene in 10 ml of pentane. The resulting suspension was stirred at 0° C. for 30 min and then at RT for 1 h. The solid was filtered off, and the filtrate was washed with saturated ammonium chloride solution, dried over magnesium sulphate and carefully concentrated under reduced pressure. This gave 0.61 g (85.6% of theory) of the title compound.
Reaction SMILES: [OH:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].N1C=CN=C1.[C:12]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])([CH3:14])[CH3:13].CN(C1C=CC=CN=1)C>O.CN(C)C=O>[C:12]([Si:16]([CH3:18])([CH3:17])[O:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4])([CH3:15])([CH3:14])[CH3:13]
Reactant: C#CC(C)(C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C#CC(C)(C)O[Si](C)(C)C(C)(C)C
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To the stirred mixture of 25 g (0.29M) of 3-hydroxy-3-methylbutyne, 50 ml of anhydrous N,N-dimethyl-formamide and 44.5 g (0.65M) imidazole cooled in an ice-bath was added 50 g (0.33M) tert.butyldimethylsilyl chloride. Stirring in the ice-bath was continued for 15 minutes and then at room termperature overnight. After addition of 250 mg of dimethylaminopyridine, the reaction mixture was heated at 70° C. for two hours and then poured into one liter of cold water. It was then extracted with 5×150 ml of ether. The organic extract was washed with brine, dried over MgSO4 and evaporated to dryness. The crude product was purified by vacuum distillation yielding 3-(tert.butyldimethylsilyl)oxy-3-methyl-butyne.
Reaction SMILES: [O:1]=[C:2]([C:14]1[O:18][C:17](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[NH3:24]>CCOCC>[O:1]=[C:2]([C:14]1[O:18][C:17](/[CH:19]=[CH:20]/[C:21]([O-:23])=[O:22])=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[NH4+:24]
Reactant: N
Reactant: CCCCCCCCCCCC(=O)c1ccc(/C=C/C(=O)O)o1
Solvent: CCOCC
Product: CCCCCCCCCCCC(=O)c1ccc(/C=C/C(=O)[O-])o1
Product: [NH4+]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5.0 g (0.0156 mole) of (E)-3-[5-(1-oxododecyl)-2-furanyl]-2-propenoic acid and 200 ml of anhydrous ether is stirred at room temperature. The above mixture is saturated with ammonia gas and allowed to stand at room temperature overnight. The solid precipitate is separated by filtration and washed with ether to give ammonium (E)-3-[5-(1-oxododecyl)-2-furanyl]-2-propenoate.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH:4]=[CH2:5].[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1)[CH3:16].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(OCC)C>[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([O:13][C:12]([C@H:9]2[CH2:8][CH2:7][C@H:6]([CH2:1][CH2:2][CH2:3][CH:4]=[CH2:5])[CH2:11][CH2:10]2)=[O:14])=[CH:20][CH:19]=1)[CH3:16]
Reactant: CCOc1ccc(O)cc1
Reactant: C=CCCC[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCCC[C@H]1CC[C@H](C(=O)Oc2ccc(OCC)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 520 mg of trans-4-(4-pentenyl)cyclohexanecarboxylic acid, 439.4 mg of p-ethoxyphenol, 765.5 mg of dicyclohexylcarbodiimide and 45 mg of 4-(dimethylamino)pyridine were dissolved in 80 ml of methylene chloride and the solution was stirred at room temperature for 20 hours. Subsequently, the reaction mixture was diluted with diethyl ether, the precipitated urea was filtered off and the filtrate was concentrated. The residue was taken up in hexane and the solution was washed with dilute hydrochloric acid, sodium hydrogen carbonate solution and water. The aqueous phases were back-extracted twice with hexane. The organic phases were dried over magnesium sulphate and evaporated. Low-pressure chromatography of the resulting residue on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gave 0.7 g (83%) of trans-4-(4-pentenyl)cyclohexanecarboxylic acid p-ethoxyphenyl ester. After recrystallization from 3 ml of methanol there were finally obtained 455 mg of product in the form of colourless crystals; m.p. (C--N) 32.7° C., cl.p. (N--I) 57.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[S:12](Cl)([CH3:15])(=[O:14])=[O:13].C(N(CC)C(C)C)C>C(Cl)Cl>[CH3:15][S:12]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(N)cc1
Agent: CCN(CC)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(NS(C)(=O)=O)cc1
Reaction time: 8 h

Procedure:
1.13 g (7.48 mmol) of methyl 4-aminobenzoate was dissolved in 20 mL of anhydrous DCM and 1.97 g (17.19 mmol) of mesyl chloride was added at 4 deg C., followed by the 2.22 g (17.19 mmol) of the diethylisopropylamine. Reaction was carried out overnight at room temperature resulting methyl 4-[(methylsulfonyl)amino]benzoate, which was used in the next step without additional purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:9][C:10]=1[CH2:11][Br:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(-c2ccccc2)sc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(-c2ccccc2)sc1CBr
Temperature: 25 °C
Yield: 108.9 %

Procedure:
A mixture of 5-methyl-2-phenyl-thiazole-4-carboxylic acid ethyl ester (7.76 g, 0.03 mol), N-bromosuccinimide (5.87 g, 0.03 mol) and benzoyl peroxide (761 mg, 3.30 mmol) in carbon tetrachloride (130 mL) was refluxed for 16 h before it was cooled to room temperature and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow oil (10.66 g); MS: (+) m/z 325.93, 328.00 (M+1, 79Br/81Br).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([NH:12][S:13]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH3:24])=[C:18]([CH3:25])[C:17]=1[CH3:26])(=[O:15])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[I:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:27])[CH:4]([N:12]([CH2:33][C:32]1[CH:35]=[CH:36][C:29]([I:28])=[CH:30][CH:31]=1)[S:13]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH3:24])=[C:18]([CH3:25])[C:17]=1[CH3:26])(=[O:15])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrCc1ccc(I)cc1
Reactant: COC(=O)C(Cc1ccccc1)NS(=O)(=O)c1c(C)cc(OC)c(C)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccccc1)N(Cc1ccc(I)cc1)S(=O)(=O)c1c(C)cc(OC)c(C)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.8 %

Procedure:
To a solution of 2-(4-Methoxy-2,3,6-trimethyl-benzenesulfonylamino)-3-phenyl-propionic acid methyl ester (50 mg, 0.129 mmol) in anhydrous DMF (1 mL), 4-iodobenzyl bromide (46 mg, 0.154 mmol) and cesium carbonate (50 mg, 0.154 mmol) were added and the reaction mixture was stirred at room temperature under a N2 atmosphere for 12 h. The reaction mixture was partitioned between water and ether. The ether layer was separated, dried (Na2SO4), concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:3) as eluent to obtain 2-[(4-Iodo-benzyl)-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-amino]-3-phenyl-propionic acid methyl ester (68 mg, 90%) as a foam. 1H NMR (CDCl3, 400 MHz): δ7.48 (d, 2H), 7.21 (m, 3H), 7.09 (d, 2H), 6.91(d, 2H), 6.45 (s, 1H), 4.60 (m, 3H), 3.81 (s, 3H), 3.38 (s, 3H), 3.17 (dd, 1H), 2.81 (dd, 1H), 2.63, 2.44, 2.14 (3s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+].[OH2:18]>CO.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(CCN2CCCCC2)c1
Reactant: O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OC(CN1CCCCC1)c1cccc(F)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of 1-(3-fluoro-phenyl)-2-piperidin-1-yl-ethan Intermediate (64.1) (1.50 g; 6.78 mmol; 1.00 eq.) in MeOH (15 mL) was added sodium borohydride (0.38 g; 10.17 mmol; 1.50 eq.) and 1 mL of water and 1 drop of 10% NaOH. Then the mixture was stirred at 50° C. for 5 hours. The reaction mixture was partitioned between CHCl3 and water. The organic layer was separated, dried over MgSO4 and concentrated. The residue was purified through flash chromatography on silica gel to yield 1-(3-fluoro-phenyl)-2-piperidin-1-yl-ethanol. LC-MS: 224 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(C(=O)c2ccccc2)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(Cc2ccccc2)c1
Yield: 95.6 %

Procedure:
3-benzoyl-benzoic acid methyl ester (653 mg, 2.72 mmol) was stirred in trifluoroacetic acid (3 mL) with triethylsilane (1.3 mL, 8.15 mmol) at room temperature for 22 h. The reaction mixture was diluted with ethyl acetate and washed with an aqueous NaHCO3 solution. The organic layer was dried over MgSO4, filtered and concentrated. The resultant oil was subjected to column chromatography (25 hexanes: 1 ethyl acetate) to provide 3-benzyl-benzoic acid methyl ester (589 mg, 2.6 mmol) as an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[NH:10][C:9]=2[C:8]([OH:22])=[CH:7][CH:6]=1)=[O:4].O[Li].O>C1COCC1.CO.O>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:11]1[NH:10][C:9]2[C:8]([OH:22])=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=2[N:12]=1
Reactant: COC(=O)c1ccc(O)c2[nH]c(-c3ccc(F)cc3F)nc12
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(F)cc3F)nc12
Temperature: 25 °C
Yield: 89.4 %

Procedure:
Wang resin-supported 2-(2,4-difluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester (570 mg, 0.47 mmol) obtained in step 5 was dissolved in THF, LiOH.H2O (99 mg, 2.35 mmol) in MeOH—H2O was added thereto and the resulting mixture was refluxed for 5 hours. The resulting solution was cooled to room temperature and filtered. The filtrate was washed with MeOH and CH2Cl2, and dried to obtain the title compound (551 mg, 0.42 mmol) in a yield of 90%.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[NH2:15])[CH2:3]1.N1C=CC=CC=1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl.O>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[NH:15][S:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:35])=[O:34])[CH2:3]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1ccccc1N)N2
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc2c(c1)C(C)(C)CC(c1ccccc1NS(=O)(=O)c1ccccc1)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4,4,6-trimethyl-1,2,3,4-tetrahydroquinolin-2-yl)aniline (150 mg, 0.56 mmol) and pyridine (0.5 mL) in dichloromethane (2 mL) was added benzenesulfonyl chloride (72 μL) at ice-bath under nitrogen. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Sodium sulfate, removed the solvent under reduced pressure, the residue was purified by HPLC to give N-[2-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzensulfonamide LC/MS m/e obsd. (ESI+) [(M+H)+] 407.3.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[C:7]1[C:12](=S)[NH:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[S:8]1.Cl.[NH2:19][OH:20].C(N(CC)CC)C>C(O)C>[OH:20][N:19]=[C:12]1[NH:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[S:8][C:7]1=[CH:6][C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: S=C1Nc2ccccc2SC1=Cc1ccc[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: ON=C1Nc2ccccc2SC1=Cc1ccc[nH]1

Procedure:
A mixture of 2-[(pyrrol-2-yl)methylene]-2H-1,4-benzothiazine-3(4H)-thione (1.70 g, 6.6 mmol) (Example 270), hydroxylamine hydrochloride (1.38 g, 20.0 mmol) and triethylamine (2.18 g, 20.0 mmol) in dry ethanol (50 ml) was refluxed for 24 h with stirring. The solvent was removed in vacuo and the residue was purified by silica gel chromatography using (9:1) hexane:ethanol as the mobile phase.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:24]C(=O)OC(C)(C)C)([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=2)[CH2:4][O:3]1>FC(F)(F)C(O)=O.C(Cl)Cl.CO>[NH2:24][C:5]([CH2:8][NH:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:14][CH:15]=1)([CH2:6][OH:7])[CH2:4][OH:3]
Reactant: CCCCCCCCc1ccc(NCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCc1ccc(NCC(N)(CO)CO)cc1
Yield: 82.2 %

Procedure:
A solution of a product of Step A (0.32 g; 0.71 mmol) in 60% trifluoroacetic acid in CH2Cl2 (4 ml) was stirred for 15 min at room temperature then diluted to 6 ml with methanol (MeOH). The resulting mixture was evaporated to dryness under reduced pressure and the residue dried in vacuo for 1 h. This was purified by flash column chromatography (FCC) (SiO2; CH2Cl2 saturated with NH4OH:MeOH 95:5), to give pure title compound (0.18 g; 82%), as colourless solid. 1H-NMR (CDCl3) 0.86 (tr, 2H, J=6.96 Hz); 1.25 (m, 10H); 1.52 (m, 2H); 2.1-2.51 (broad m, 4H); 2.47 (tr, 2H, J=7.9 Hz); 3.1 (s, 2H); 3.55 (m, 4H); 4.05 (broad s, 1H); 6.6 (d, 2H, J=8.34 Hz); 6.96 (d, 2H, J=8.34 Hz).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)(=O)C>C(O)(C)C>[C:22]1([C:9]2[C:8]([N:5]3[CH2:6][CH2:7][CH:2]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:3][CH2:4]3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=3)[N:10]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(=O)CC3)nc2c1
Reactant: Nc1ccccc1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(Nc4ccccc4)CC3)nc2c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 3-(4-oxopiperidin-1-yl)-2-phenylquinoxaline-6-carboxylate (329.7 mg, 0.91 mmol, 1.00 equiv) in isopropanol (12 mL). Then aniline (255.2 mg, 2.74 mmol, 3.00 equiv) and acetic acid (221.8 mg, 3.70 mmol, 4.00 equiv) was added dropwise with stiffing. The resulting solution was stirred for 1 h at 60° C. in an oil bath. To the above NaHB(OAc)3 (968.1 mg, 4.57 mmol, 4.57 equiv) was added at 0° C. The resulting solution was stirred for an additional 3 h at room temperature. The reaction was then quenched by the addition of water. The resulting aqueous solution was extracted with 6×20 mL of dichloromethane. The organic layers were combined and dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM/MeOH (30:1). This resulted in 297.4 mg (74%) of methyl 2-phenyl-3-(4-(phenylamino)piperidin-1-yl)quinoxaline-6-carboxylate as a yellow solid.