Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C)C>Cl>[N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccccc1NCCCN1CCCCC1
Agent: Cl
Solvent: CC(C)O
Product: Nc1ccccc1NCCCN1CCCCC1

Procedure:
The balance of the 2-[3-(1-piperidinyl)propylamino]nitrobenzene was reduced to the corresponding N-substituted o-phenylenediamine by means of stannous chloride in concentrated hydrochloric acid as described in Example 1 for the corresponding 4-methylpiperazino compound. The product, N-[3-(1-piperidinyl)propyl]-o-phenylenediamine, was isolated as the hydrochloride salt by crystallization frm isopropanol, m.p. 208°-210° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].S(=O)(=O)(O)O.[CH3:18]O>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH3:18])=[O:11]
Reactant: CO
Reactant: O=C(O)Cc1cc(O)ccc1O
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cc(O)ccc1O

Procedure:
2,5-Dihydroxyphenylacetic acid is refluxed in methanol in the presence of sulfuric acid, to give methyl 2-(2,5-dihydroxyphenyl)acetate.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([OH:14])[CH2:11][C:12]#[N:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CO[CH:18](OC)[CH2:19][NH2:20]>CCOCC>[CH2:1]([O:8][CH2:9][C@@H:10]([OH:14])[CH2:11][C:12]1[NH:13][CH:18]=[CH:19][N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC[C@H](O)COCc1ccccc1
Reactant: COC(CN)OC
Agent: Cl
Solvent: CCOCC
Product: O[C@H](COCc1ccccc1)Cc1ncc[nH]1
Yield: 28.1 %

Procedure:
Using (3S)-4-(benzyloxy)-3-hydroxybutyronitrile (6.51 g), a 5.12 N solution of hydrogen chloride in ether (7.0 ml), and aminoacetaldehyde dimethyl acetal (3.58 g), the same reaction as Reference Example 6 was carried out to yield the titled compound (2.22 g) as a light-brown oily substance.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH:3]=[CH2:4].C([Li])CCC.[CH2:29]([N:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[CH2:29]([N:36]1[CH2:41][CH2:40][C:39](=[CH:2][CH2:3][CH3:4])[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: C=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC=C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
In a stream of argon, 2.9 g (7.5 mmol) of allyltriphenylphosphonium bromide was suspended in 10 ml of anhydrous tetrahydrofurane, and thereto 4.3 ml of butyllithium a was added dropwise under cooling with ice. After stirring the mixture at room temperature for 30 minutes, thereto was added dropwise a solution of 1 g (5.3 mmol) of 1-benzyl-4-piperidone in anhydrous tetrahydrofurane under cooling with ice and the obtained mixture was stirred at room temperature for 15 hours. The reaction solution was filtrated, and ethyl acetate and water were added to the filtrate, and the organic phase was taken out. The organic phase was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the resulting oily matter was subjected to a column chromatography using 40 g of silica gel and eluted with ethyl acetate-hexane (1:1 to 1:3) to obtain 200 mg of 1-benzyl-4-propylidenepiperidine.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:12])[NH:4][N:5]=[C:6]([O:9][CH2:10][CH3:11])[C:7]=1Cl.[CH2:13]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:21][NH2:22])[CH2:14][CH2:15][CH3:16].O1CCOCC1>O>[Cl:1][C:2]1[C:3](=[O:12])[NH:4][N:5]=[C:6]([O:9][CH2:10][CH3:11])[C:7]=1[NH:22][CH2:21][C:20]1[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:18]([O:17][CH2:13][CH2:14][CH2:15][CH3:16])[CH:19]=1
Reactant: CCOc1n[nH]c(=O)c(Cl)c1Cl
Reactant: CCCCOc1cc(CN)ccc1OC
Solvent: O
Solvent: C1COCCO1
Product: CCCCOc1cc(CNc2c(OCC)n[nH]c(=O)c2Cl)ccc1OC
Reaction time: 15 h

Procedure:
A mixture comprising 7.32 g of 4,5-dichIoro-6-ethoxy-3(2H)pyridazinone prepared in Reference Example 2, 21.95 g of 3-n-butoxy-4-methoxybenzylamine, 60 ml of 1,4-dioxane and 60 ml of water, was refluxed under stirring for 15 hours. Then, most 1,4-dioxane was distilled off under reduced pressure, and dilute hydrochloric acid was added for acidification. Then, chloroform was added thereto, and the mixture was vigorously shaked. The precipitated crystals were separated by filtration, and the chloroform layer of the filtrate was subjected to liquid separation and washed with water and dried over sodium sulfate. Then, the solvent was distilled off to obtain a light yellow oily substance. The product was crystallized from n-propanol-di-i-propyl ether (1:9 v/v), to obtain 10.48 g of the above identified compound having a melting point of from 117° to 118° C. as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(O)(=O)C.[H][H]>[Rh].C(O)C>[CH2:9]([O:8][C:6]([C@H:5]1[CH2:11][CH2:12][C@@H:2]([OH:1])[CH2:3][CH2:4]1)=[O:7])[CH3:10]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@@H](O)CC1

Procedure:
A mixture of 10 g of ethyl 4-hydroxybenzoate, 5 mL of acetic acid, 0.8 g of 5% rhodium on alumina, and 200 mL of ethanol was shaken under 55 psi of hydrogen for 48 h, filtered and concentrated under reduced pressure. The residue was taken up in 200 mL of toluene and again concentrated under reduced pressure to remove acetic acid. Drying under vacuum overnight gave 11 g of product, which was predominantly cis (83:17 cis: trans by HPLC), as a colorless oil: MS (m+1)=173.2; 1H NMR (400 MHz, CDCl3) 4.1 (dd, 2H), 3.9 (m, cis isomer, 0.85H), 3.6 (m, trans isomer, 0.15H), 2.4 and 2.2 (m, 1H), 2.0 (m, 2H), 1.62 (m, 6H), 1.2 (t, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]1[CH2:14][N:13](C(OCC2C=CC=CC=2)=O)[CH2:12]1.[H][H]>CO.[Pd]>[NH:13]1[CH2:14][CH:11]([C:3]2[N:2]([CH3:1])[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[N:4]=2)[CH2:12]1
Reactant: [H][H]
Reactant: Cn1c(C2CN(C(=O)OCc3ccccc3)C2)nc2ccccc21
Agent: [Pd]
Solvent: CO
Product: Cn1c(C2CNC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.6 %

Procedure:
A solution of 1-3 (3.32 g, 10.33 mmol) in MeOH (52 mL) was subjected to 2 cycles of the evacuation/backfilling with nitrogen and then treated with 10% Pd/C (1.1 g). The evacuation/backfilling with nitrogen procedure was repeated two times and then the nitrogen atmosphere was exchanged for a hydrogen atmosphere by evacuation/backfilling with a balloon of hydrogen. After stirring for 3 hours under hydrogen at ambient temperature, the reaction mixture was filtered through celite, and washed with additional MeOH (20 mL). The filtrate was concentrated to yield Intermediate 1 as brown solid (2.1 g, 100%). MS: m/z=188.2 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([O:8]C)=[O:7])#[N:2].O.[OH-].[Li+]>O1CCCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(OC)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)O)cc1C#N
Reaction time: 1 h
Yield: 92.6 %

Procedure:
Methyl 3-cyano-4-methoxybenzoate (879 mg) was dissolved in tetrahydrofuran (8 mL) and water (4 mL), and lithium hydroxide monohydrate (772 mg) was added to the solution, and then the mixture was stirred at mom temperature for 1 hour. The organic solvent was distilled off under reduced pressure and acidified with 2N hydrochloric acid, and then the precipitated crystal was collected by filtration to obtain the title compound (754 mg) as a colorless crystal.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[F:12][C:13]1([F:27])[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:15]([CH2:25]O)[CH2:14]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:25][C@@H:15]3[CH2:14][C:13]([F:27])([F:12])[CH2:17][N:16]3[C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[N:3]=[C:2]([I:1])[C:10]=12
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1CO
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1Cn1nc(I)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
Under nitrogen, to a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.61 g, 10.00 mmol, 1.00 equiv), tert-butyl (2S)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.37 g, 9.99 mmol, 1.00 equiv) and TPP (4 g, 15.2 mmol, 1.50 equiv) in THF was DIAD (3.00 g, 15.0 mmol, 1.50 equiv) at 0° C. in 30 min. The resulting solution was stirred overnight at room temperature. The mixture was then concentrated under vacuum and the residue was applied onto a silica gel column with dichloromethane/ethyl acetate (3/1) to give 1 g of tert-butyl (2S)-2-([4-amino-3-iodo-1H-pyrazolo[3,4-d]-pyrimidin-1-yl]methyl)-4,4-difluoropyrrolidine-1-carboxylate as reddish oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23](Cl)=[O:24])[CH:19]=[CH:20][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:23](=[O:24])[CH2:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN)cc1OC
Reactant: COc1cccc(CC(=O)Cl)c1
Product: COc1cccc(CC(=O)NCCc2ccc(OC)c(OC)c2)c1

Procedure:
prepared by reaction of 3,4-dimethoxyphenylethylamine with 3-methoxyphenyl acetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].CCN=C=NCCCN(C)C.[CH3:34][N:35]([CH3:40])[S:36]([NH2:39])(=[O:38])=[O:37].OS([O-])(=O)=O.[K+]>ClCCl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:39][S:36]([N:35]([CH3:40])[CH3:34])(=[O:38])=[O:37])=[O:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20]
Reactant: CN(C)S(N)(=O)=O
Reactant: O=C(O)c1ccc(COc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CN(C)S(=O)(=O)NC(=O)c1ccc(COc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
To a solution of 4-{[4-chloro-3-(trifluoromethyl)phenoxy]methyl}benzoic acid (Preparation 16, 237 mg, 0.72 mmol) in dichloromethane (8 mL) was added EDCI (344 mg, 1.79 mmol) followed by addition of N,N-dimethylsulfamide (222 mg, 1.79 Calculation isn't correct mmol). The reaction was left to stir at room temperature for 3 hours. A solution of KHSO4 (10 mL) was added and the mixture separated using a phase separation cartridge. The organics were dried in vacuo to yield a white solid as the title compound (285 mg, 97%).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:38])[N:24]([CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[CH:25]([CH3:27])[CH3:26])[CH:20]=[C:19]([Cl:39])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.ClCCl.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>ClCCl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[Cl:39][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[CH:25]([CH3:26])[CH3:27])=[O:38]
Reactant: CC(C)N(CCCNC(=O)C(C)(C)C)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(CCCNC(=O)C(C)(C)C)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of [2-(3-chloro-5-{[3-(2,2-dimethyl-propionylamino)-propyl]-isopropyl-carbamoyl}-phenoxy)-ethyl]-pyridine-4-yl-carbamic acid tert-butyl ester in dichloromethane (1 ml) was treated with dichloromethane:trifluoroacetic acid (1:1 v/v) (1 ml), stirred for 3 h at room temperature and concentrated under reduced pressure. The residue was subjected to preparative hplc to give the title compound (0.039 g) as an oil.
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9]([N:11]1[C@@H:15]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C@H:14]([C:23]([O:25]CC)=[O:24])[O:13][C:12]1([CH3:29])[CH3:28])=[O:10])([CH3:7])([CH3:6])[CH3:5]>O.C(O)C>[C:4]([O:8][C:9]([N:11]1[C@@H:15]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C@H:14]([C:23]([OH:25])=[O:24])[O:13][C:12]1([CH3:29])[CH3:28])=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CCOC(=O)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1c1ccc(C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc([C@H]2[C@H](C(=O)O)OC(C)(C)N2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.3 %

Procedure:
A solution of 0.19 g of lithium hydroxide hydrate in 3 cm3 of distilled water is added at a temperature in the region of 25° C. to a solution of 0.54 g of ethyl (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-(4-methylphenyl)-5-oxazolidinecarboxylate in 10 cm3 of ethanol. The reaction medium is stirred for 20 minutes at a temperature in the region of 25° C. and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. The residue obtained is dissolved in 3.5 cm3 of distilled water and then extracted with 2 times 1 cm3 of diisopropyl ether. The aqueous phase is then acidified to a pH in the region of 1 with 5 cm3 of 1N aqueous hydrochloric acid solution and thereafter extracted with 3 times 4 cm3 of dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. 0.43 g of (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-(4-methylphenyl)-5-oxazolidinecarboxylic acid is thereby obtained in the form of an orange-colored oil.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[C:13]([CH:15]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[Cl:38])[C:16](=[O:30])[CH:17]([S:19][C:20]1[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28])[CH3:18])#[N:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:8][C:7]1[C:2]([O:26][C:24]2[CH:23]=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[C:20]([S:19][CH:17]([CH3:18])[C:16](=[O:30])[CH:15]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[Cl:38])[C:13]#[N:14])[CH:25]=2)=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: CC(Sc1cc(O)ccc1[N+](=O)[O-])C(=O)C(C#N)c1ccc(Cl)cc1Cl
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(Sc1cc(Oc2ncc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)C(C#N)c1ccc(Cl)cc1Cl
Temperature: 80 °C
Yield: 55 %

Procedure:
2,3-Dichloro-5-trifluoromethylpyridine (1.08 g), 2.05 g of 1-cyano-1-(2,4-dichlorophenyl)-3-(5-hydroxy-2-nitrophenylthio)-2-butanone and 2.07 g of potassium carbonate were refluxed in 50 ml of acetonitrile under heat at 80° C. for 3 hours. The reaction liquid was filtered, and the filtrate was concentrated. A 10% hydrochloric acid aqueous solution was added to the residue, and the mixture was extracted with chloroform, followed by concentrating the extract. The residue was purified by silica gel chromatography to obtain 1.62 g of compound No. 148 which was a pale yellow viscous substance. The yield was 55.0%. The results of analysis of compound No. 148 are shown in Table 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:28](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]2)[CH3:28])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cc(Br)cc(N(C)[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c1C
Temperature: 80 °C

Procedure:
To a stirred solution of trans-methyl 5-bromo-3-((4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-2-methylbenzoate (3 g, 6.81 mmol) in acetonitrile (40 mL), cesium carbonate (4.4 g, 13.62 mmol) and methyl iodide (4.83 g, 34.05 mmol) were added; the resulting reaction mixture was heated at 80° C. for 7 h. Upon completion, the reaction mixture was cooled to room temperature and filtered, the residue was washed with ethyl acetate and filtrate was concentrated to afford desired crude compound which then purified by column chromatography giving the desired compound (1.3 g, 43%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)=[C:14]([O:31][CH3:32])[CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCCl>[CH3:32][O:31][C:14]1[CH:13]=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:17]=[CH:16][C:15]=1[CH:18]1[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]1
Reactant: COc1cc(NC(=O)OCc2ccccc2)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COc1cc(NC(=O)OCc2ccccc2)ccc1C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
A mixture of tert-butyl 4-(4-{[(benzyloxy)carbonyl]amino}-2-methoxyphenyl)piperidine-1-carboxylate (Preparation Example 454) (4.92 g), trifluoroacetic acid (10 mL) and 1,2-dichloroethane (50 mL) was stirred at room temperature for 1 hour. The reaction solvent was concentrated under reduced pressure, and after addition of saturated aqueous sodium hydrogen carbonate, the residue was extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was solidified by addition of diethyl ether to give benzyl (3-methoxy-4-piperidin-4-ylphenyl)carbamate (3.24 g) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([Cl:28])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][N:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[CH:27]=[C:26]([Cl:28])[S:25][C:15]=2[N:16]=1
Reactant: Clc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3cnccn3)nc3sc(Cl)cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3-nitrobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=O)=[CH:4][C:3]=1[CH3:16].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[S:26])=[CH:4][C:3]=1[CH3:16]
Reactant: Cc1cc(C(=O)NC[Si](C)(C)C)ccc1Br
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(C(=S)NC[Si](C)(C)C)ccc1Br
Temperature: 25 °C
Yield: 123.7 %

Procedure:
To a suspension of 4-bromo-3-methyl-N-trimethylsilanylmethyl-benzamide (32.75 g, 109.1 mmol) in toluene (250 mL) was added Lawesson's reagent (31.32 g, 77.44 mmol) at room temperature. The mixture was heated at reflux for 1 h and cooled to ambient temperature. After adsorption of the reaction mixture on silica gel, the solvents were distilled off in vacuum. The residue was purified by flash chromatography on silica gel to give the title compound (30.3 g, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](O)([CH3:10])[CH3:9])[CH:5]=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O>ClCCl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]([CH3:10])=[CH2:9])[CH:3]=1
Reactant: CC(C)(O)c1cncc(Br)c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C(C)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-(5-bromo-pyridin-3-yl)-propan-2-ol, prepared as described in Example 16a (200 mg, 0.93 mmol) in dichloromethane (8 mL) at 0° C. was added diisopropylethylamine (0.63 mL 3.7 mmol) followed by methanesulfonyl chloride (0.14 mL, 1.85 mmol). After 5 minutes the reaction was place at room temperature and stirred for an additional half hour. The reaction was quenched with saturated aqueous sodium bicarbonate, diluted with brine and ethyl acetate and the layers were separated. The aqueous layer was extracted two additional times with ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane, 0 to 50%) to furnish 3-bromo-5-isopropenyl-pyridine; MS: (ES+) m/z 198.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[CH:21]=[CH:20][C:11]3[NH:12][C:13]([NH:15][C:16](=[O:19])[O:17][CH3:18])=[N:14][C:10]=3[CH:9]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26].[NH4+].[OH-]>CO.O>[F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6](=[N:25][OH:26])[C:8]2[CH:21]=[CH:20][C:11]3[NH:12][C:13]([NH:15][C:16](=[O:19])[O:17][CH3:18])=[N:14][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: COC(=O)Nc1nc2cc(C(=O)c3ccc(F)cc3)ccc2[nH]1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)Nc1nc2cc(C(=NO)c3ccc(F)cc3)ccc2[nH]1
Temperature: 25 °C

Procedure:
Methyl [5-(4-fluorobenzoyl)-1H-benzimidazol-2-yl]carbamate, (581.6 g, 1.86 mole) (Janssen Pharmaceutica, U.S. Pat. No. 3,657,267, Apr. 18, 1972) was suspended in MeOH (15 L) in which hydroxylamine hydrochloride (508.1 g, 7.32 mole) was dissolved. The mixture was heated at reflux (80 hrs) until a clear solution was obtained and the starting material was no longer detected at TLC. After cooling to room temperature, the mixture was filtered to remove undissolved material, and the solvent was removed under reduced pressure to give a solid residue. This material was suspended in H2O (5 L) and adjusted to pH 12 with conc. NH4OH. The title product that was obtained as a precipitate was collected by filtration, washed with H2O, then dried under reduced pressure at 70° C. for 16 hrs. Yield: 620.8 g. TLC Rf=0.4-0.6 (2nd spot), 0.0 (base line material). Mp:>315° C.; 3405, 1725, 1660-1640, 1600, 835, 760 cm-1, 1H NMR (DMSO-d6): δ 3.78 (s, 3 H, OCH3), 6.70-8.00 (m, 7 H, Ar--H), 11.20 (bs, 1 H, NH), 11.90 (bs, 1 H, OH).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-])=O>C(Cl)Cl.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2cccnc2)cc1
Agent: [Pd]
Solvent: ClCCl
Product: Nc1ccc(-c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.2 %

Procedure:
In a flame-dried r.b. flask equipped with a magnetic stirring bar was dissolved 3-(4-nitrophenyl)pyridine (131 mg, 0.655 mmol) and 10% Pd on C (10 mg) in anhydrous CH2Cl2 (3 mL) was added. The flask was repeatedly evacuated and filled with N2 to remove any residual O2, and then H2 gas was introduced. The solution was stirred at rt for 18 h, filtered though a Celite™ plug and concentrated in vacuo to give the desired amine (105 mg, 95%) as an off-white solid. Data for 3-(4-aminophenyl)pyridine: Rf =0.17 (silica gel, methanol/CHCl3, 5/95); 1H NMR (400 MHz, acetone-d6) 8.77 (d, J=2.3, 1 H), 8.42 (dd, J=6.4, 1.6, 1 H), 7.88 (m, 1 H), 7.41 (d, J=8.5, 2 H), 7.33 (m, 1 H), 6.78 (d, J=8.5, 2 H), 4.86 (br s, 2 H).