Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BrH:1].[OH:2][C:3]1[C:19]([OH:20])=[CH:18][C:6]2[CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>CO>[BrH:1].[C:12]1([CH:7]2[C:6]3=[CH:18][C:19](=[O:20])[C:3](=[O:2])[CH:4]=[C:5]3[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1cc2c(cc1O)C(c1ccccc1)CNCC2
Agent: Br
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Product: O=C1C=C2CCNCC(c3ccccc3)C2=CC1=O
Yield: 97 %

Procedure:
To a suspension of 7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (34 g, 0.101 mole, U.S. Pat. No. 3,393,192) in methanol (275 ml) was added a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (25.2 g, 0.111 mole) in methanol (125 ml). The addition was carried out rapidly with stirring at 0° under an argon atmosphere. After stirring at 0° for 1 hour the reaction mixture was filtered and the orange precipitate was washed with cold methanol (75 ml), ethyl acetate (100 ml) and then diethyl ether (100 ml). After drying at room temperature under vacuum, 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dione hydrobromide (32.8 g, 0.98 mole, 97%) was obtained, mp 164°-165° (dec.).
Reaction SMILES: [BH4-].[Na+].[CH:3]1([NH:9][C:10]2[C:15]([C:16]3[CH2:20][C:19]([CH2:25][C:26](OC)=[O:27])([C:21](OC)=[O:22])[O:18][N:17]=3)=[CH:14][N:13]=[C:12]3[N:30]([CH2:33][CH3:34])[N:31]=[CH:32][C:11]=23)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>O1CCCC1.CO>[CH:3]1([NH:9][C:10]2[C:15]([C:16]3[CH2:20][C:19]([CH2:25][CH2:26][OH:27])([CH2:21][OH:22])[O:18][N:17]=3)=[CH:14][N:13]=[C:12]3[N:30]([CH2:33][CH3:34])[N:31]=[CH:32][C:11]=23)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCn1ncc2c(NC3CCCCC3)c(C3=NOC(CC(=O)OC)(C(=O)OC)C3)cnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC(CO)(CCO)C3)cnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium borohydride (14 mg, 0.00036 mole) was added to methyl 3-[4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-5-(2-methoxy-2-oxoethyl)-4,5-dihydroisoxazole-5-carboxylate (80 mg, 0.00018 mole) (example 10) in tetrahydrofuran (5 ml). Methanol (2 drops) was added and the reaction mixture was stirred at room temperature overnight. It was quenched with saturated ammonium chloride solution, diluted with ethyl acetate and extracted with brine. The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo. The crude product was purified by column chromatography.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C@H:8]2[CH2:15][C@@:14]3([C:16]([O:18]C)=[O:17])[C@H:10]([CH2:11][CH2:12][CH2:13]3)[CH2:9]2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1[N:3]([C@H:8]2[CH2:15][C@@:14]3([C:16]([OH:18])=[O:17])[C@H:10]([CH2:11][CH2:12][CH2:13]3)[CH2:9]2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: COC(=O)[C@@]12CCC[C@@H]1C[C@@H](n1c(C)ccc1C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(C)n1[C@@H]1C[C@H]2CCC[C@@]2(C(=O)O)C1
Temperature: 65 °C

Procedure:
To a solution of Example 1D (5.3 g, 20.3 mmol) in methanol (33 mL) and water (15 mL) was added a aqueous solution of sodium hydroxide (3.2 g, 80 mmol in 4 mL of water) and the mixture was heated at 65° C. for 16 hours. The mixture was cooled to room temperature, acidified to pH=4 with 4N hydrochloric acid. The solid was filtered to afford Example 1E which was used in next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24]([OH:26])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[C:28]1([C:38](=[NH:40])[NH2:39])[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH2:29]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:24]3[O:26][N:40]=[C:38]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=4)[N:39]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1
Reactant: N=C(N)C1(O)C=CC=C(C(F)(F)F)C1
Product: CCc1ccc(C2CC(c3nc(-c4cccc(C(F)(F)F)c4)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1

Procedure:
80 mg (0.22 mmol) of 5-(4-ethylphenyl)-1-[(4-hydroxypiperidin-1-yl)carbonyl]piperidine-3-carboxylic acid (Example 59A) and 68 mg (0.33 mmol) of 1-hydroxy-3-(trifluoromethyl)benzenecarboximidamide were reacted according to the General Method 2. Yield: 75 mg (64% of theory)
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15]C(=O)OC(C)(C)C)[CH:10]=2)=[CH:6][CH:5]=[C:4]([NH:23][C:24]([NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:25])[N:3]=1>C(O)(C(F)(F)F)=O>[NH2:15][C:11]1[CH:10]=[C:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([NH:23][C:24]([NH:26][C:27](=[O:32])[C:28]([CH3:30])([CH3:29])[CH3:31])=[O:25])=[N:3][C:2]=2[CH3:1])[CH:14]=[CH:13][N:12]=1
Reactant: Cc1nc(NC(=O)NC(=O)C(C)(C)C)ccc1Oc1ccnc(NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(NC(=O)NC(=O)C(C)(C)C)ccc1Oc1ccnc(N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A mixture of tert-butyl (4-((2-methyl-6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)carbamate (0.370 g, 0.834 mmol in TFA (5 mL) was stirred at RT for 0.5 h and concentrated to dryness to afford N-((5-((2-aminopyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)pivalamide (280 mg, 98%). MS (ESI) m/z: 344.2 (M+H+).
Reaction SMILES: CN1CCOCC1.[O:8]=[C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][CH:23]([C:25]([OH:27])=O)[O:22][C:21]3=[O:28])=[CH:16][CH:15]=2)[NH:10]1.[NH:29]1[CH2:34][CH2:33][CH:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[O:8]=[C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:24][CH:23]([C:25]([N:29]4[CH2:34][CH2:33][CH:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]4)=[O:27])[O:22][C:21]3=[O:28])=[CH:18][CH:19]=2)[NH:10]1
Reactant: O=C(O)C1CN(c2ccc(-c3noc(=O)[nH]3)cc2)C(=O)O1
Reactant: CC(C)(C)OC(=O)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1CCN(C(=O)C2CN(c3ccc(-c4noc(=O)[nH]4)cc3)C(=O)O2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3.03 g of N-methylmorpholine are added to a solution of 2.91 g of 3-[4-(5-oxo-1,2,4-oxadiazolin-3-yl)phenyl]-2-oxo-5-oxazolidinecarboxylic acid [obtainable according to Example 3], 2.77 g of tert-butyl piperidine-4-carboxylate, 2.02 g of 1-hydroxybenzotriazole and 2.86 g of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in 20 ml of DMF, and the mixture is stirred at room temperature for 5 h. 200 ml of water are subsequently added dropwise with intensive stirring, the crystalline precipitate formed is separated off and taken up in 90 ml of dichloromethane, and the mixture is dried over Na2SO4. The solution is concentrated in vacuo, and the resulting oil is triturated with diethyl ether to give tert-butyl 1-{3-[4-(5-oxo-1,2,4-oxadiazolin-3-yl)phenyl]-2-oxo-5-oxazolidinylcarbonyl}piperidine-4carboxylate, m.p. 171°-175°.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH:14]([OH:15])[C:7]2=[N:6][C:5]=1[CH3:16].Cl.[F:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:24][O:25][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].C(#N)C>[CH3:16][C:5]1[N:6]=[C:7]2[N:8]([CH2:11][CH2:12][CH2:13][CH:14]2[OH:15])[C:9](=[O:10])[C:4]=1[CH2:3][CH2:2][N:29]1[CH2:28][CH2:27][CH:26]([C:23]2[C:22]3[CH:32]=[CH:33][C:19]([F:18])=[CH:20][C:21]=3[O:25][N:24]=2)[CH2:31][CH2:30]1
Reactant: Cc1nc2n(c(=O)c1CCCl)CCCC2O
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2O
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 77.4 %

Procedure:
300 ml of acetonitrile was charged followed by 20.0 g of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]-pyrimidin-4-one and 21.0 g of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride at room temperature. The reaction mass was stirred for 5 minutes and 20.0 g of potassium carbonate and 0.7 g of potassium iodide were charged. Further, 0.2 g of butylated hydroxytoluene was charged and the temperature was raised to 65±2° C. The reaction mass was maintained at 65±2° C. for 25 hours. After reaction completion, the reaction mass was slowly cooled to room temperature. The solids were filtered, washed with 50 ml of acetonitrile and then dissolved in 800 ml of methylene chloride at room temperature. The contents were heated to 30-35° C., maintained for 10 minutes at 30-35° C., filtered and washed with 20 ml of methylene chloride. The clear filtrate was distilled completely under vacuum below 35° C. and replaced with 50 ml of acetone. Further, 300 ml of acetone was charged, heated to 45° C. and stirred for 30 minutes. The reaction mass was cooled to room temperature and stirred for 1 hour. The product was filtered, washed with 20 ml of acetone and dried under vacuum at 50-55° C. to yield paliperidone (27 g, yield: 135% w/w, efficiency: 76.6%, keto impurity by HPLC: 0.03%, total impurity level by HPLC: 1.0%)
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>CO.O>[NH2:1][C:2]1[C:3]([CH3:12])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cnc(C)c(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ncc(C(=O)O)cc1N
Temperature: 25 °C

Procedure:
Into a round-bottom flask, was placed a solution of methyl 5-amino-6-methylnicotinate (5.00 g, 30.1 mmol, 1.00 equiv) and sodium hydroxide (20 g) in MeOH/H2O (80/200 mL). The resulting solution was heated at reflux overnight. After cooling to ambient temperature, the methanol was removed under reduced pressure. The pH of the remaining aqueous phase was adjusted to 4 with aqueous hydrogen chloride (2 M). The resulting mixture was then concentrated under reduced pressure to yield 5.00 g (crude) of the title compound as a yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:7][C:8]([CH3:34])([C:10]12[CH2:19][C:14]3([O:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[CH2:15][CH:16]([CH2:18][C:12]([O:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])([CH2:13]3)[CH2:11]1)[CH2:17]2)[OH:9].C(N(CC)CC)C.C1COCC1>O>[C:1]([O:9][C:8]([C:10]12[CH2:19][C:14]3([O:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[CH2:15][CH:16]([CH2:18][C:12]([O:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])([CH2:13]3)[CH2:11]1)[CH2:17]2)([CH3:34])[CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: COCCOCOC12CC3CC(OCOCCOC)(C1)CC(C(C)(C)O)(C3)C2
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC(C)(C)C12CC3CC(OCOCCOC)(CC(OCOCCOC)(C3)C1)C2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A total of 30 mmole of methacrylic chloride was added dropwise to a mixture of 20 mmole of the above-prepared α,α-dimethyl-3,5-bis(2-methoxyethoxymethoxy)-1-adamantanemethanol, 40 mmole of triethylamine, and 80 ml of THF, over about 30 minutes. The resulting mixture was stirred at room temperature for 6 hours after the completion of addition. Water was added to the reaction mixture, and the resulting mixture was then extracted with ethyl acetate, the organic layer was concentrated, and the concentrate was subjected to column chromatography on a silica gel to yield 1-(1-methacryloyloxy-1-methylethyl)-3,5-bis(2-methoxyethoxymethoxy)adamantane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][C:21](OC)=[O:22])=[C:10]1[C:25]([O:27][CH3:28])=[O:26].[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][C:21]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:22])=[C:10]1[C:25]([O:27][CH3:28])=[O:26]
Reactant: C1CNCCN1
Reactant: COC(=O)CC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(C)N1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1=C(C)NC(CC(=O)N2CCNCC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of dimethyl 4-(2,6-dichlorophenyl)-2-methoxycarbonylmethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate(13.9 g, 30 mmol) , piperazine(39.2 g, 460 mmol), and dimethylformamide(30 ml) was heated to 100° C. (becomes a solution) and stirred for 1.5 h (longer reaction times result in decomposition). The reaction mixture was cooled briefly, poured into water(800 ml), and extracted with ethyl acetate. The extract was washed thoroughly with water, dried over sodium sulfate, and concentrated to give 12.2 g (84%) of an orange color oil, suitable for use in succeeding steps. It can be purified by column chromatography on silica gel using dichloromethane/methanol: 2/1 as eluent.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=1)[CH2:15][NH2:16].C(N(CC)CC)C>>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=1)[CH2:15][NH:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NCc1cc(F)cc(F)c1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1NCc1cc(F)cc(F)c1
Yield: 100.9 %

Procedure:
Reaction of 2-fluoronitrobenzene (3 g, 21 mmole), 3,5-difluorobenzylamine, (3 g, 21 mmole) and triethylamine (2.6 g, 26.2 mmole) substantially as described in 1C above produced 5.6 g (100%) of title compound as orange crystals: mp 104°-105°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.S(Cl)(Cl)(=O)=O.[CH3:18]O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:18])=[O:11])=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)/C=C/c1ccc(Br)cc1
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)/C=C/c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of (2E)-3-(4-bromophenyl)prop-2-enoic acid (4.5 g, 0.020 mol) in MeOH (20 mL), sulfuryl dichloride (2.7 g, 0.023 mol) was added dropwise at 0° C. The resulting solution was heated to reflux for 1 h. The reaction mixture was allowed to cool to rt and concentrated to dryness under reduced pressure to yield a residue, which was subjected to flash column chromatography on silica gel (5-10% EtOAc/petroleum ether) to afford compound 66c as a colorless oil. Mass Spectrum (GCMS, ESI pos.): Calcd. for C10H9BrO2: 241.1 (M). found: 241.0.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[O:7]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C(Cl)(Cl)Cl.[Ti]>[C:5]([CH:17]([OH:18])[C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([O:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:15]=1)#[N:6]
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: C[Si](C)(C)C#N
Agent: [Ti]
Agent: Cl
Solvent: ClC(Cl)Cl
Product: N#CC(O)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
To a solution of L-(+)-diisopropyl tartarate (1.030 mg, 4.4 mmol) in absolute chloroform (40 ml), tetaraisopropyl titanate (1.136 mg, 4 mmol) was dropwise added and stirred at room temperature for 30 minutes. After evaporating volatile components off in the same manner as in Example 1, absolute chloroform (40 ml) was added to the residue and stirred at room temperature to obtain a homogeneous solution. To the resulting solution, trimethylsilyl cyanide (436 mg, 4.4 mmol) and then 3-phenoxybenzaldehyde (793 mg, 4 mmol) were added and stirred at room temperature for 14 hours. Thereafter, 1N hydrochloric acid (40 ml) was added and stirred at room temperature for 30 minutes. Then, the reaction mixture was extracted with dichloromethane and dried over sodium sulfate followed by evaporation of the solvent to give an oily product. The product was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate) to obtain α-cyano-3-phenoxybenzyl alcohol (580 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]2)=[N:7][CH:8]=1)#[N:2].[ClH:23]>O1CCOCC1>[ClH:23].[NH:12]1[CH2:13][CH2:14][CH2:15][CH:10]([NH:9][C:6]2[N:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2ccc(C#N)cn2)C1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(NC2CCCNC2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.24 g (3.4 mmol) of tert-butyl 3-[(5-cyanopyridin-2-yl)amino]piperidine-1-carboxylate (Example 60A) are dissolved in 4.3 ml of a solution of hydrochloric acid in dioxane (4M) and stirred at RT for 3 h. After the reaction is complete, the solvent is completely removed. 1.74 g (90% of theory) of the product are obtained as a solid.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.CN(C)C=O.F[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28]>O>[N+:27]([C:18]1[CH:19]=[C:20]([C:23]([F:24])([F:25])[F:26])[CH:21]=[CH:22][C:17]=1[N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: c1ccc2c(c1)CCNC2
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.9 %

Procedure:
1,2,3,4-tetrahydroisoquinoline (909 μl, 7.26 mmol, commercially available product) was added at 0° C. to an N,N-dimethylformamide (DMF; 4 ml) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (506 g, 2.42 mmol, commercially available product). The resulting mixture was warmed to room temperature and stirred for 3.5 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 g, hexane/ethyl acetate=10/1). Thus, 1,2,3,4-tetrahydro-2-[2-nitro-4-(trifluoromethyl)phenyl]isoquinoline (779 mg, 99.9%) was yielded as an orange-colored solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N+:11]([O-])=[CH:10][CH:9]=2)=[C:4]([O:15][CH3:16])[CH:3]=1.C(OC(=O)C)(=[O:19])C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:19])[CH:9]=2)=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(Cl)ccc1-c1cc[n+]([O-])cc1
Product: COc1cc(Cl)ccc1-c1cc[nH]c(=O)c1
Temperature: 25 °C
Yield: 91 %

Procedure:
4-(4-Chloro-2-methoxyphenyl)pyridine 1-oxide (673 mg, 2.86 mmol) and acetic anhydride (10 mL) were heated at reflux for 3 h. The mixture was concentrated under reduced pressure, and a 1:1 solution of H2O/MeOH (20 mL) was added. The reaction mixture was heated to reflux for 1 h, cooled to 25° C. and concentrated under reduced pressure. The resulting residue was dissolved in hot 2-propanol (3 mL), triturated with Et2O, sonicated for 30 min then placed in the freezer. The solid was filtered off providing the title compound (550 mg, 91%) as a tan solid: 1H NMR (500 MHz, DMSO-d6) δ 11.54 (s, 1H), 7.35-7.33 (m, 2H), 7.01 (s, 1H), 7.08 (d, J=6.6 Hz, 1H), 6.36 (s, 1H), 6.28 (s, 1H), 3.82 (s, 3H); ESI MS m/z 235 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=[O:12])[O:6][CH2:5]2.[Br:13]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:13][CH:5]1[C:4]2[C:8](=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=2)[C:7](=[O:12])[O:6]1
Reactant: O=C1OCc2cc(Cl)c(Cl)cc21
Reactant: NC(=O)CCC(=O)NBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C1OC(Br)c2cc(Cl)c(Cl)cc21
Yield: 99.1 %

Procedure:
A suspension of 5,6-Dichloro-3H-isobenzofuran-1-one (1.45 g), N-bromosuccinamide (1.27 g) and catalytic benzoyl peroxide in chloroform (30 mL) was heated to reflux for 1 hour. After cooling, the reaction mixture was washed with water, brine, dried (magnesium sulfate), filtered and concentrated to give the sub-title compound as a white solid (1.82 g, 91%). 1H NMR (400 MHz, CDCl3) δ 7.36 (1H, s), 7.77 (1H, s), 8.03 (1H, s) ppm.
Reaction SMILES: [O:1]=[CH:2][CH2:3][C@@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5].Cl.[C:11](=O)([O-])O.[Na+]>CO>[O:1]([CH3:11])[C@H:2]1[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[CH2:3]1
Reactant: O=CC[C@H](O)[C@H](O)CO
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CO[C@@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 1.1 liters of methanol, 52 g of 2-deoxy-D-erythro-pentose was dissolved, and 3.8 ml of 1M hydrochloric acid solution in methanol was added at room temperature, followed by stirring the resulting solution at room temperature for 1 hour. To the reaction mixture, 1 g of sodium hydrogen carbonate was added and the resultant was concentrated after confirming that the solution was weakly basic. To the residue, 100 ml of toluene and 100 ml of pyridine were added to dissolve the residue and the resultant was concentrated. This operation was repeated totally twice to completely remove methanol. The thus obtained crude methyl 2-deoxy-α-D-erythro-pentofuranoside was used in the subsequent step without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=[O:6].[CH3:23][C:24]1[CH:25]=[CH:26][C:27]([Sn](CCCC)(CCCC)CCCC)=[N:28][CH:29]=1>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.C1(C)C=CC=CC=1>[CH3:23][C:24]1[CH:25]=[CH:26][C:27]([C:2]2[CH:3]=[C:4]([CH:16]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:18]=2)[C:5]([NH:7][CH2:8][C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[O:6])=[N:28][CH:29]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Reactant: Cc1ccc(CNC(=O)c2cc(Br)cc(S(C)(=O)=O)c2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(S(C)(=O)=O)c2)nc1

Procedure:
A mixture of 3-bromo-N-((6-methylpyridin-3-yl)methyl)-5-(methylsulfonyl)benzamide (71 mg, 0.18 mmol), 5-methyl-2-(tributylstannyl)pyridine (91 mg, 0.23 mmol), tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.0093 mmol) and toluene (2.0 mL) under argon was subjected to microwave irradiation at 120° C. for 2 hours. The mixture was cooled to allow the product to precipitate. The solvent was discarded and the precipitated solids were rinsed with hexane and then purified by preparative HPLC (100×21.2 mm C18 column, 30-70% CH3CN/water[10 mM Et2NH]) to afford a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]=[C:10]([C:15](=O)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11]([O:13][CH3:14])=[O:12].[NH2:25][C:26]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:27][C:28]([O:30][CH3:31])=[O:29]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:15]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:25][C:26]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:32]1[C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)C(=Cc1c(Cl)cccc1Cl)C(=O)CCc1ccccc1
Reactant: COC(=O)C=C(N)CC(=O)OC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)CC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CCc2ccccc2)N1
Temperature: 120 °C

Procedure:
A mixture of methyl 2-(2,6-dichlorophenylmethylidene)-3-oxo-5-phenylpentanoate (the crude product from the preceding experiment) and dimethyl 2-amino-1-propene-1,3-dicarboxylate (8.4 g, 48.5 mmol) was heated without solvent at 120° C. for 18 h. TLC showed a strong fluorescent spot at Rf=0.3 (dichloromethane/ethyl acetate: 24/1). This whole was chromatographed on silica gel (1.5 kg ) to yield 3.93 g of product. The slightly less pure product (2 g) was also obtained. 1H NMR (CDCl3) δ 7.23 (m, 7H), 6.99 (t, J=8.6 Hz, 1H), 6.93 (br. s, 1H), 5.98 (s, 1H), 3.70 (s, 3H), 3.68 (ABq, J=17Hz, 2H), 3.58 (s, 3H), 3.52 (s, 3H), 2.91 (m, 4H).