Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([Br:5])(C)C.Cl[C:7]1[C:12]2[S:13][C:14]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])=[N:15][C:11]=2[C:10]([F:24])=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)CC>[Br:5][C:7]1[C:12]2[S:13][C:14]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])=[N:15][C:11]=2[C:10]([F:24])=[CH:9][N:8]=1
Reactant: Fc1cnc(Cl)c2sc(-c3c(Cl)cccc3Cl)nc12
Reactant: C[Si](C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC#N
Product: Fc1cnc(Br)c2sc(-c3c(Cl)cccc3Cl)nc12
Temperature: 85 °C
Yield: 103.2 %

Procedure:
Trimethylsilyl bromide (1.2 mL, 9.0 mmol) was added to a solution of 4-chloro-2-(2,6-dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridine (1.0 g, 3.0 mmol) in propionitrile (30 mL) at room temperature under argon. The reaction mixture was heated at 85° C. in a sealed vial for 16 hours. The resultant mixture was poured in an ice-cooled saturated solution of potassium carbonate. The product was extracted with DCM (×2) and the combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as an off-white solid (1.17 g, quantitative). LCMS (Method E): RT=4.32 min, m/z: 379 [M+H+].
Reaction SMILES: [OH-].[Na+].C([N:6]1[C:14]2[C:9](=[CH:10][C:11]([N:15](C(=O)C)[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:12][CH:13]=2)[C:8](=[C:28]([O:35][CH2:36][CH3:37])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:7]1=[O:38])(=O)C>ClCCl.C(O)C>[CH2:36]([O:35][C:28](=[C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:17])=[O:18])[CH:10]=2)[NH:6][C:7]1=[O:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:37]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc(N(C(C)=O)S(=O)(=O)c3ccccc3)cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=C1C(=O)Nc2ccc(NS(=O)(=O)c3ccccc3)cc21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
8 ml of 4 N sodium hydroxide solution are added to a solution of 4.0 g (8 mmol) of 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-(N-acetyl-N-phenylsulphonyl-amino)-2-indolinone (Example 1e) in a mixture of 20 ml of dichloromethane and 20 ml of ethanol and the resulting mixture is stirred for 20 minutes at ambient temperature. It is then evaporated down to about. 10 ml and 150 ml of water are added. The pH is adjusted to 8–9 with 1 N hydrochloric acid. The precipitate formed is suction filtered, washed with water, isopropanol and ether, then dried in vacuo.
Reaction SMILES: CO[CH:3](OC)[CH2:4][C:5]([CH3:11])=[C:6]([C:9]#[N:10])[C:7]#[N:8].C(C(C#N)=C(C)C=C[O:20]C)#N.S(=O)(=O)(O)O>>[C:7]([C:6]1[C:9](=[O:20])[NH:10][CH:3]=[CH:4][C:5]=1[CH3:11])#[N:8]
Reactant: COC=CC(C)=C(C#N)C#N
Reactant: COC(CC(C)=C(C#N)C#N)OC
Agent: O=S(=O)(O)O
Product: Cc1cc[nH]c(=O)c1C#N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68 %

Procedure:
69.35 g of the mixture of 4,4-dicyano-3-methyl-3-butenal-dimethylacetal and 1,1-dicyano-4-methoxy-2-methyl-1,3-butadiene obtained in Step (a) was slowly added to 113 g of concentrated sulfuric acid over a period of 3 hours so that the temperature would not exceed 30° C. After stirring at room temperature for 20 minutes, the temperature was increased to 50° C., and stirring was carried out at the same temperature for 2 hours. After the reaction mixture was left to stand to cool, it was slowly poured into water ice (500 ml), the obtained crystals were collected by filtration and the crystals were washed with 100 ml of water. The crystals were air-dried for 1 week and further dried at 70° C. under reduced pressure for 8 hours to obtain 34.2 g (two step yield: 68%) of crude crystals of 3-cyano-4-methylpyridone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11](N3CCC4C=CNC=4C3C)=[O:12])[CH:10]=2)[CH:7]=1.[Cl:23][C:24]1[O:25][C:26]2[CH2:31][CH2:30][NH:29][CH:28]([CH3:32])[C:27]=2[N:33]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:29]3[CH2:30][CH2:31][C:26]4[O:25][C:24]([Cl:23])=[N:33][C:27]=4[CH:28]3[CH3:32])=[O:12])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2oc(Cl)nc21
Reactant: CC1c2[nH]ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Product: CC1c2nc(Cl)oc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-methyl-1,4,5,7-tetrahydro-pyrrolo[2,3-c]pyridin-6-yl)-methanone is reacted with 2-chloro-4-methyl-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine to provide the title compound.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[CH3:9][N:10]1[C:14]([C:15]2[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[S:18][CH:19]=2)=[C:13]([CH3:24])[CH:12]=[N:11]1>O1CCCC1>[Cl:8][C:12]1[C:13]([CH3:24])=[C:14]([C:15]2[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[S:18][CH:19]=2)[N:10]([CH3:9])[N:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cc(-c2c(C)cnn2C)cs1
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2c(C)c(Cl)nn2C)cs1
Temperature: 100 °C
Yield: 91 %

Procedure:
NCS (1.78 g, 13.09 mmol) was added in portions to a 125 mL sealed tube reactor containing methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2.07 g, 8.76 mmol) in Tetrahydrofuran (THF) (40 ml) at room temperature. The mixture was heated to 100° C. for 1 hour. Upon completion the product was partitioned between CHCl3 and H2O, the organic layer dried with Na2SO4, solvents removed by vacuum distillation affording the title compound (2.18 g, 7.97 mmol, 91%) which was used without further purification: LC-MS (ES) m/z=271 (M+H)+.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:20]1[CH2:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(OCC)(=O)C.O>[N:20]1([CH:16]2[CH2:17][N:14]([CH:1]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:15]2)[CH2:23][CH2:22][CH2:21]1
Reactant: C1CNC1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: c1ccc(C(c2ccccc2)N2CC(N3CCC3)C2)cc1
Temperature: 25 °C
Yield: 73.1 %

Procedure:
To a solution of 1-benzhydrylazetidin-3-one (750 mg) in dichloromethane (12 ml) was added azetidine hydrochloride (326 mg), followed by stirring at room temperature. Sodium triacetoxy borohydride (1.01 g) was added thereto, followed by stirring at room temperature for 25 hr. To the reaction mixture were added sodium carbonate (until bubbling stopped), water (50 ml) and ethyl acetate (100 ml). The organic layer was separated. This was washed with brine, and dried over anhydrous sodium sulfate. The organic layer after drying was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:1, 1:2, then ethyl acetate) to provide the titled compound as a pale yellow solid (643 mg, 73.1%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[F:10][C:11]([F:24])([F:23])[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[NH2:22].[OH-].[Na+]>>[N+:1]([C:14]1[C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=[C:12]([C:11]([F:10])([F:23])[F:24])[C:13]=1[NH2:22])([O-:4])=[O:2]
Reactant: Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1c(C(F)(F)F)ccc(C(F)(F)F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Nitric acid (7 mL) was added to sulfuric acid (10 mL) cautiously at 0° C. 2,5-Bis(trifluoromethyl)benzenamine (2 g, 8.7 mmol) was added in small portions at 0° C. over 20 minutes and the resulting slurry was stirred at 0° C. to room temperature for 3 hours. The mixture was poured into ice water (100 mL) and basified with sodium hydroxide solution, and extracted with EtOAc (80 mL×3). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, filtered and concentrated to give a crude product of 2-nitro-3,6-bis(trifluoromethyl)benzenamine (containing isomers) which was used in the next step without further purification (2.3 g). MS (ESI): m/z 275 [M+H]+
Reaction SMILES: Cl[C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([Cl:11])[N:3]=1.[OH-].[Na+].[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([Cl:11])[N:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCc1ccccc1
Reactant: Clc1cc2nc[nH]c2c(Cl)n1
Agent: [Na+]
Agent: [OH-]
Product: Clc1cc2nc[nH]c2c(OCc2ccccc2)n1
Temperature: 150 °C

Procedure:
To a solution of 4,6-dichloro-3H-imidazo[4,5-c]pyridine (2.00 g, 10.6 mmol) in BnOH (23 mL) was added powdered NaOH (1.28 g, 31.9 mmol) and the reaction was heated to 150° C. overnight. The benzyl alcohol was removed by vacuum distillation, and the residue was suspended in water (15 mL) and AcOH (3 mL) was added to bring the pH to ˜7. The aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined organics were dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (1:1 hex EtOAc-->EtOAc/10% MeOH) to afford 4-(benzyloxy)-6-chloro-3H-imidazo[4,5-c]pyridine 2.24.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)[N:3]=1.CN1CC(=O)OB([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)OC(=O)C1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)[N:3]=[C:2]([C:34]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[CH:7]=1
Reactant: CC(C)Oc1ccc(-c2cc(Cl)cc(Cl)n2)cc1
Reactant: CN1CC(=O)OB(c2cccnc2)OC(=O)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Product: CC(C)Oc1ccc(-c2cc(Cl)cc(-c3ccncc3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To a 2 dram vial equipped with a stir bar was added 2,4-dichloro-6-(4-isopropoxyphenyl)pyridine (60 mg, 0.21 mmol), 6-methyl-2-(3-pyridinyl)-1,3,6,2-dioxazaborocane-4,8-dione (“4-pyridyl MIDA boronate”, 50 mg, 0.21 mmol), Pd(dppf)Cl2 (8.0 mg, 10 μmol) and K3PO4 (337 mg, 1.59 mmol). The vial was capped with a septum screw-cap and then placed under N2 atmosphere. To the vial was added degassed THF (5 mL) and degassed water (1 mL). The vial was placed in a 60° C. heating block with stirring for 3 hours. The reaction mixture was cooled to room temperature and the aqueous phase was decanted. The organic solution was concentrated under a stream of N2 and the resulting solid residue was subjected to silica gel chromatography (hexanes:EtOAc) to afford 4-chloro-6-(4-isopropoxyphenyl)-2,4′-bipyridine as a white solid (45 mg, 65%). 1H-NMR (400 MHz, CDCl3) δ 8.84-8.81 (m, 2H), 8.16-8.11 (m, 2H), 8.00-7.97 (m, 3H), 7.04-6.99 (m, 2H), 4.69 (spt, J=6.0 Hz, 1H), 1.40 (d, J=6.0 Hz, 6H); MS: MS m/z 326.2 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH2:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26][C:27]2[C:28](=[O:35])[N:29]=[C:30](SC)[NH:31][CH:32]=2)=[CH:22][N:21]=1>C(O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:30]3[NH:31][CH:32]=[C:27]([CH2:26][C:23]4[CH:22]=[N:21][C:20]([O:19][CH3:18])=[N:25][CH:24]=4)[C:28](=[O:35])[N:29]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: NCCc1ccc(Oc2ccc(F)cc2)cc1
Reactant: COc1ncc(Cc2c[nH]c(SC)nc2=O)cn1
Solvent: CCO
Product: COc1ncc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(F)cc4)cc3)nc2=O)cn1
Temperature: 125 °C
Reaction time: 16 h
Yield: 83.3 %

Procedure:
2-[4-(4-fluoro-phenoxy)-phenyl]ethylamine (0.216 mmol, 1 eq) and 5-(2-methoxy-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (0.108 mmol, 0.5 eq) were dissolved in dry ethanol (300 μL) and stirred at 125° C. for 16 hours. Solvent was evaporated and crude product was purified by Waters Mass Direct Autopurification system giving 2-{2-[4-(4-fluoro-phenoxy)phenyl]-ethylamino}-5-(2-methoxy-pyrimidin-5-ylmethyl)-1H-pyrimidin-4-one (0.090 mmol; yield: 18%, HPLC-MS/UV: [M+H]=448.34; rt: 10.25 min; purity: 94%). 1H NMR (300 MHz; CDCl3) δ/ppm 2.88 (t, J=7.17, 2H), 3.51 (s, 2H), 3.55-3.67 (m, 2H), 3.95 (s, 3H), 5.11 (br.s., 1H), 6.87-7.05 (m, 5H), 7.14-7.21 (m, 2H), 7.23-7.30 (m, 1H), 7.65 (s, 1H), 8.39 (s, 1H)
Reaction SMILES: [N:1]([O-])=O.[Na+].[I:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9].O.O.[Sn](Cl)Cl>O.Cl>[I:5][C:6]1[CH:7]=[C:8]([NH:9][NH2:1])[CH:10]=[CH:11][CH:12]=1
Reactant: O=N[O-]
Reactant: Nc1cccc(I)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cccc(I)c1
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
A solution of sodium nitrite (13.2 g, 186 mmol) in water (65 mL) was added over 90 minutes to a cooled (˜0 degrees) mixture of 3-iodo-aniline (40.71 g, 182 mmol) in concentrated hydrochloric acid (80 mL), taking care to ensure that the temperature remained below 0 degrees). The mixture was stirred for 30 min and then filtered. To the filtrate was added dropwise a solution of tin(II) chloride dihydrate (142 g, 0.63 mol) in water, and then the mixture was stirred for 30 minutes with the temperature maintained below 0 degrees. The reaction mixture was placed in the refrigerator overnight and then filtered. The residue was washed with brine, then 1:1 petroleum ether/ether (750 mL) and then with 2:1 petroleum ether/ether (375 mL) and the washings were discarded. The remaining residue was dissolved in 5 M NaOH and ether, and the aqueous layer was extracted with ether. The combined ether layers were washed with water and brine, dried (sodium sulfate), filtered, and evaporated to give 3-iodo-phenylhydrazine (25.3 g, 53%) as a dark red viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[OH:12].[C:13](Cl)(=[O:17])[C:14]([CH3:16])=[CH2:15].C(=O)([O-])[O-].[Na+].[Na+].Cl>COC1C=CC(O)=CC=1.CO.O.N1C=CC=CC=1>[OH:12][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:8]=1[CH:9]=[CH:10][CH:11]=[C:2]2[NH:1][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: Nc1cccc2c(O)cccc12
Reactant: C=C(C)C(=O)Cl
Agent: COc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: c1ccncc1
Solvent: O
Product: C=C(C)C(=O)Nc1cccc2c(O)cccc12
Temperature: -10 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
Into a mixture comprising 227 g of 5-amino-α-naphthol, 1 g of hydroquinone monomethyl ether and 2 liters of pyridine was dropwise added with stirring 110 g of methacrylic acid chloride cooled to -10° C. by the use of a coolant. After completion of the addition, the mixture was stirred at 0°-3° C. for 2 hours, followed by stirring at 25° C. for 2 hours. Thereafter, the reaction liquid was poured into 20 liters of water to form a precipitate which was then filtered, water-washed and then dried to obtain solids. The solids were added to 2 liters of a 1:1 mixture of methanol and a 5% sodium carbonate solution, and after stirring at 40° C. the mixture was poured into 4 liters of a 5% hydrochloric acid to form a large amount of precipitate. The precipitate was filtered by suction and then recrystallized from ethanol to obtain 210 g of N-(5-hydroxy-α-naphthyl)methacrylamide, m.p. 223°-224° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH:19]([C:21]1[NH:22][C:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C:28]=2[C:29]=1[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=O>N1CCCCC1.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[C:16]3[C:12]([C:13](=[CH:19][C:21]4[NH:22][C:23]5[CH2:24][CH2:25][CH2:26][CH2:27][C:28]=5[C:29]=4[CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c3c(c2CCC(=O)O)CCCC3)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
A mixture of 103 mg 6-(3-methoxyphenyl)-2-oxindole, 95 mg 3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid and piperidine (3 drops) in ethanol (2 mL) was heated in sealed tube to 90° C. and held there overnight. The reaction mixture was concentrated and acidified with 6 N hydrochloric acid. The precipitate that formed was collected by filtration and washed with water and hexane to give 156 mg of 3-{2-[6-(3-methoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-4,5,6,7-tetrahydro-1H-indol-3-yl}-propionic acid as a brown solid (82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@@H:13]([C:18]([OH:20])=[O:19])[CH2:14][C:15](=[O:17])[NH2:16])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:21](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O.[Cl-].[NH4+]>[CH3:21][O:19][C:18](=[O:20])[C@@H:13]([CH2:14][C:15](=[O:17])[NH2:16])[NH:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(S(=O)(=O)N[C@H](CC(N)=O)C(=O)O)cc1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Agent: [NH4+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](CC(N)=O)NS(=O)(=O)c1ccc(OC)cc1
Reaction time: 8 h

Procedure:
N-[4-methoxybenzenesulfonyl]-(D)-asparagine (10.1 g, 33.3 mmol) is dissolved in dimethylformamide (167.0 mL). Cesium carbonate (5.43 g, 16.66 mmol) is added, followed by the addition of methyl iodide (2.22 mL, 33.3 mmol), and the reaction is stirred overnight. The reaction is then diluted with saturated ammonium chloride (366.0 mL), and extracted well with ethyl acetate. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is recrystallized from toluene to provide N-[4-methoxybenzenesulfonyl]-(D)-asparagine methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.C1C(=O)N([Br:16])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][Br:16])[CH:3]=1
Reactant: Cc1cc(Br)ccn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc(Br)ccn1
Temperature: 100 °C
Yield: 36 %

Procedure:
A mixture of 4-bromo-2-methylpyridine (2.0 g, 11.63 mmol), NBS (2.69 g, 15.11 mmol), and diphenylperoxyanhydride (0.282 g, 1.163 mmol) in carbon tetrachloride (50 mL) was heated to 100° C. overnight. Cooled to RT, diluted with saturated NaHCO3, and extracted with ethyl acetate (3×). The combined organic extracts were washed with saturated NaCl (2×), dried over Na2SO4, filtered, and concentrated. The residue was purified via silica gel chromatography (ISCO, 120 g silica, 60 mL/min, 0-80% EtOAc/Hexanes over 45 min) to afford 4-bromo-2-(bromomethyl)pyridine (1.05 g, 36%). MS (m/z) 251.9.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[F:18][C:19]([F:23])([F:22])[CH2:20][NH2:21].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([NH:21][CH2:20][C:19]([F:23])([F:22])[F:18])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Reactant: NCC(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: O=C1c2cc(Br)ccc2CC12CCC(NCC(F)(F)F)CC2
Temperature: 25 °C
Yield: 16.8 %

Procedure:
In a 25 mL round bottom flask was placed 6′-bromospiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione (501 mg, 1.716 mmol) and it was dissolved in dichloroethane (5.7 mL). To this solution was added the trifluoro ethylamine (162 μL, 2.059 mmol), AcOH (124 μL, 2.059 mmol), and NaBH(OAc)3 (582 mg, 2.746 mmol) at last. The reaction was stirred at room temperature. When the reaction was completed it was quenched with saturated NaHCO3 (aq) (20 mL) and diluted with ethyl acetate (20 mL). The phases were separated and the aqueous phase was back-extracted with ethyl acetate twice (5 mL/each). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduce pressure. The crude material was purified by flash chromatography (ISCO, 40 g SiO2 cartridge, ethyl acetate/hexanes as the eluents). At the end, two isomers were obtained and their corresponding fractions were combined separately and concentrated under reduce pressure yielding 6′-bromo-4-(2,2,2-trifluoroethylamino)spiro[cyclohexane-1,2′-inden]-1′(3′H)-one (axial, 97b) (420 mg, 1.120 mmol) and 6′-bromo-4-(2,2,2-trifluoroethylamino)spiro[cyclohexane-1,2′-inden]-1′(3′H)-one (equatorial, 98b) (108 mg, 0.288 mmol) (82% yield). Compound 97b: M+H=375.9, 1H NMR=(CDCl3, 400 MHz) δ 7.85 (d, J=1.6 Hz, 1H), 7.67 (dd, J=8.0, 1.6 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 3.21 (q, J=9.2 Hz, 2H), 2.93 (s, 2H), 2.90 (m, 1H), 2.01-1.94 (m, 2H), 1.87-1.81 (m, 2H), 1.75-1.68 (m, 2H), 1.38-1.29 (m, 2H). Compound 98b: M+H=375.8, 1H NMR=(CDCl3, 400 MHz) δ 7.86 (d, J=1.6 Hz, 1H), 7.68 (dd, J=8.0, 1.6 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 3.24 (q, J=9.6 Hz, 2H), 2.95 (s, 2H), 2.68 (m, 1H), 2.03-1.97 (m, 2H), 1.81-1.74 (ddd, J=14.0, 14.0, 3.6 Hz, 2H), 1.46 (m, 2H), 1.31-1.21 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[N:17]=3)[OH:15])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:23]=[CH:24][CH:25]=[N:26][C:5]1=2.[Si:27](N(C)C(=O)C(F)(F)F)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>C(#N)C>[Br:22][C:18]1[N:17]=[C:16]([CH:14]([O:15][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[C:11]2[CH:12]=[CH:13][C:8]3[S:7][C:6]4[N:23]=[CH:24][CH:25]=[N:26][C:5]=4[N:4]([CH2:3][O:2][CH3:1])[C:9]=3[CH:10]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CN(C(=O)C(F)(F)F)[Si](C)(C)C(C)(C)C
Reactant: COCN1c2cc(C(O)c3cccc(Br)n3)ccc2Sc2nccnc21
Solvent: CC#N
Product: COCN1c2cc(C(O[Si](C)(C)C(C)(C)C)c3cccc(Br)n3)ccc2Sc2nccnc21
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 1.05 g of (10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)-(6-bromopyridin-2-yl)methanol in 15 ml of acetonitrile was added in a nitrogen atmosphere 3.2 ml of N-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide and the resulting mixture was stirred at room temperature for 22 hours. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 0.72 g of the title compound as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([CH:7]=[C:8]([C:16](=O)[CH3:17])[C:9]([O:11][CH2:12][CH2:13][C:14]#[N:15])=[O:10])=[C:5]([O:21][CH3:22])[CH:4]=1)#[N:2].[NH2:23][C:24]1[C:29]([CH3:30])=[CH:28][NH:27][C:26](=[O:31])[CH:25]=1>CC(O)C>[C:1]([C:3]1[CH:20]=[CH:19][C:6]([CH:7]2[C:25]3[C:26](=[O:31])[NH:27][CH:28]=[C:29]([CH3:30])[C:24]=3[NH:23][C:16]([CH3:17])=[C:8]2[C:9]([O:11][CH2:12][CH2:13][C:14]#[N:15])=[O:10])=[C:5]([O:21][CH3:22])[CH:4]=1)#[N:2]
Reactant: Cc1c[nH]c(=O)cc1N
Reactant: COc1cc(C#N)ccc1C=C(C(C)=O)C(=O)OCCC#N
Solvent: CC(C)O
Product: COc1cc(C#N)ccc1C1C(C(=O)OCCC#N)=C(C)Nc2c(C)c[nH]c(=O)c21
Reaction time: 8 h

Procedure:
2.69 g (9.00 mmol) of the compound from Example 24A are introduced into 45 ml of 2-propanol, mixed with 1.17 g (9.00 mmol) of 4-amino-5-methylpyridin-2(1H)-one [Bisagni, E., Hung, N. C., Synthesis, 765-766 (1984)] and then stirred at the reflux temperature overnight. After cooling, the precipitate is filtered off, washed with diethyl ether and dried under high vacuum. 2.22 g (61% of theory) of the title compound are obtained.