Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=CC(C(NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=NC=2)=O)=CC=1)(C)(C)C.[CH2:37]([O:41][C:42]1[CH:76]=[CH:75][C:45]([C:46]([NH:48][C:49]2[CH:54]=[CH:53][C:52]([C:55]3[CH:63]=[C:62]4[C:58]([CH2:59][N:60]([C@@H:65]([CH:70]([CH3:72])[CH3:71])[C:66]([O:68]C)=[O:67])[C:61]4=[O:64])=[CH:57][CH:56]=3)=[C:51]([O:73][CH3:74])[CH:50]=2)=[O:47])=[CH:44][CH:43]=1)[CH2:38][CH2:39][CH3:40]>>[CH2:37]([O:41][C:42]1[CH:76]=[CH:75][C:45]([C:46]([NH:48][C:49]2[CH:54]=[CH:53][C:52]([C:55]3[CH:63]=[C:62]4[C:58]([CH2:59][N:60]([C@@H:65]([CH:70]([CH3:71])[CH3:72])[C:66]([OH:68])=[O:67])[C:61]4=[O:64])=[CH:57][CH:56]=3)=[C:51]([O:73][CH3:74])[CH:50]=2)=[O:47])=[CH:44][CH:43]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCOc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)c(OC)c2)cc1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Product: CCCCOc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)c(OC)c2)cc1
Yield: 72 %

Procedure:
The compound of example 460 was prepared analogous to the compound of example 404 by hydrolysis of the compound of example 459.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+].[CH2:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][C:19]1=O>CO>[ClH:1].[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][CH:24]1[CH2:25][CH2:26][C:27]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:23]1)[CH3:3]
Reactant: CCOC(=O)CN
Reactant: O=C1CCc2ccccc2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CO
Product: CCOC(=O)CNC1CCc2ccccc2C1
Temperature: 0 °C
Yield: 67.7 %

Procedure:
In a solution of 20 g of 1,2,3,4-tetrahydro-2-naphthalenone in 200 ml of methanol, there is dissolved 23 g of glycine ethyl ester hydrochloride, and 9.0 g of sodium cyanoborohydride is added portionwise with ice cooling and stirring. After stirring at room temperature for 2 hours, the reaction mixture is poured into 500 ml of ice water, and the whole mixture is make alkaline with sodium hydrogen carbonate and extracted with 500 ml of ethyl acetate. The extract is washed with water and dried, the ethyl acetate is distilled off under reduced pressure, 10 ml of 20% ethanolic hydrochloric acid and 200 ml of ethyl ether are added to the residue, and the mixture is allowed to stand at room temperature. The crystalline precipitate is collected by filtration and dried to give 25 g of N-(1,2,3,4-tetrahydronaphthalen-2-yl)glycine ethyl ester hydrochloride as colorless needles melting at 198°-200° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][CH:9]=[CH:8][CH:7]1O)=[O:5])[CH3:2].S(Cl)([Cl:21])=O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][CH:9]=[CH:8][CH:7]1[Cl:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccccc2)CCC=CC1O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccccc2)CCC=CC1Cl

Procedure:
15 g of 1-phenyl-2-hydroxy-cyclohex-3-ene-1-carboxylic-acid-ethyl-ester and 15 cc. of thionyl chloride and 1 cc. of dimethylformamide are heated under reflux for 10 minutes. Then direct distillation is done. 12.2 g of 1-phenyl-2-chloro-cyclohex-3-ene-1-carboxylic-acid-ethyl-ester of the boiling point 0.1/122°-5° C are obtained. By reacting with 12 g of β-phenylethyl amine in 100 cc. of DMSO for 2 hrs. at 100° C, processing as described above, 6.0 g of hydrochloride m.p. 179°-82° C are obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])([CH2:6]3)[CH2:4]1)[CH2:10]2.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[C:16]([O:15][C:14](=[O:20])[NH:13][C:5]12[CH2:11][CH:9]3[CH2:8][CH:7]([CH2:12][C:3]([CH:2]=[O:1])([CH2:10]3)[CH2:4]1)[CH2:6]2)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NC12CC3CC(CC(CO)(C3)C1)C2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC12CC3CC(CC(C=O)(C3)C1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a stirred solution of tert-butyl 3-(hydroxymethyl)-1-adamantylcarbamate (1.2 g, 4.3 mmol) in DCM (50 mL) was added PCC (1.4 g, 6.5 mmol) in portions under N2 atmosphere. After stirring at room temperature for two hours. the mixture was filtered through a pad of silica gel and the filtrate was concentrated under reduced pressure to give 1.1 g (92%) of the title compound, tert-butyl-3-formyl-1-adamantylcarbamate, as a brown oil, which was used in the next step without further purification. ESI-MS m/z: 224 (M-55)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].B(F)(F)F>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:10]([C:19](=[O:21])[CH3:20])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(-c2cc3cccc(Cl)n3n2)cc1
Agent: FB(F)F
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nn3c(Cl)cccc3c2C(C)=O)cc1
Temperature: 25 °C
Yield: 65.2 %

Procedure:
To a solution of 7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine (18.7 g, 72.4 mmol) in toluene (300 mL) at room temperature was added acetic anhydride (8.2 mL, 86.9 mmol). Boron trifluoride diethyletherate (10.1 mL, 79.6 mmol) was then added dropwise and the resulting solution was heated at reflux for 4 hours. The reaction mixture was cooled to room temperature and quenched by the dropwise addition of saturated aqueous sodium bicarbonate. The reaction was extracted with ethyl acetate, and the ethyl acetate phase washed with brine, dried (magnesium sulfate), filtered and concentrated. The residue was purified by recrystallization from ethyl acetate-hexanes to give 1-[7-(chloro)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (14.2 g, 65%) as reddish needles. 1H NMR (CDCl3): δ 8.37 (dd, 1H), 7.49 (dd, 2H), 7.39 (dd, 1H), 7.10 (dd, 1H), 6.98 (dd, 2H), 3.84 (s, 3H), 2.13 (s, 3H); MS m/z 301 (M+1).
Reaction SMILES: [NH2:1][O:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[Cl:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([Cl:26])[C:17]=1[N:27]1[C:31]([C:32](Cl)=[O:33])=[C:30]([C:35]#[N:36])[CH:29]=[N:28]1>C(OCC)C.O1CCCC1.C(OCC)(=O)C>[CH3:7][O:6][C:4]([CH2:3][O:2][NH:1][C:32]([C:31]1[N:27]([C:17]2[C:18]([Cl:26])=[CH:19][C:20]([C:22]([F:24])([F:25])[F:23])=[CH:21][C:16]=2[Cl:15])[N:28]=[CH:29][C:30]=1[C:35]#[N:36])=[O:33])=[O:5]
Reactant: N#Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C(=O)Cl
Reactant: COC(=O)CON
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CONC(=O)c1c(C#N)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 2.08 h

Procedure:
A solution of 2.31 g (0.022 mole) of methyl aminooxyacetate and 2.53 g (0.025 mole) of triethylamine in 70 mL of diethyl ether was cooled to -5° to 0° C. While this temperature was maintained, a solution of 7.4 g (0.020 mole) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-4-cyano-1H-5-pyrazolylcarboxylic acid chloride in 105 mL of tetrahydrofuran was added to the cooled solution during a 20 minute period. Upon completion of addition, the cooling bath was removed, and the resulting slurry was stirred at ambient temperature for 125 minutes. The slurry was filtered, and the filtrate was evaporated under reduced pressure, leaving a residue. This residue was dissolved in ethyl acetate, and this solution was washed twice with an aqueous solution of sodium chloride. The solution was then dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated from the filtrate under reduced pressure, leaving a tacky solid residue weighing 8.54 g. This solid was triturated with petroleum ether for a period of approximately 17 hours. The resulting N-methoxycarbonylmethoxy-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-cyano-1H-5-pyrazolylcarboxamide, weighing 7.5 g, was recovered by filtration. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][OH:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(OCC)(=O)C>[CH3:22][S:23]([O:14][CH2:13][CH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=1)(=[O:25])=[O:24]
Reactant: CCCCc1ccc(CCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCc1ccc(CCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 3-(4-butylphenyl)propanol (2.86 g, 14.9 mmol) and triethylamine (1.51 g, 14.9 mmol) in ethyl acetate (30 ml) was added methanesulfonyl chloride (1.70 g, 14.9 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with water and saturated brine, dried over magnesium sulfate anhydride and concentrated under reduced pressure to give the object compound as an oily substance. 4.02 g (yield: 100%)
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+]([O-])=O)[N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:19][C:20]1[N:21]=[C:22]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]3[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: O=[N+]([O-])c1cccc(Cl)n1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cccc(Cl)n3)cc(C)c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (0.1 g, 0.4 mmol, 1 eq.) and 2-chloro-6-nitropyridine (158 mg, 1 mmol, 2.5 eq.) in 5 ml DMF was added cesium carbonate (392 mg, 1.2 mmol, 3 eq.). The reaction was stirred at room temperature for three hours. It was then quenched by water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel (DCM/methanol=39:1 to 19:1) to give desired product as light yellow oil. MS (ESI) m/z=362 [M+H]+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[N:12]([C:25]([CH2:28][CH3:29])=[CH:26][CH:27]=3)[N:13]=[C:14]([CH2:23][OH:24])[C:15]=2[CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])[CH:7]=[N:8][CH:9]=1.Br.Br[CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[N:12]([C:25]([CH2:28][CH3:29])=[CH:26][CH:27]=3)[N:13]=[C:14]([CH2:23][O:24][CH2:32][C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[C:15]=2[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:7]=[N:8][CH:9]=1
Reactant: CCOC(=O)CCc1c(CO)nn2c(CC)ccc2c1-c1cncc(Br)c1
Reactant: BrCc1cccnc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1ccc2c(-c3cncc(Br)c3)c(CCC(=O)O)c(COCc3cccnc3)nn12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a suspension of 60% NaH (74 mg) in DMF (3 mL) was added ethyl 3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate (200 mg) under ice-water cooling, and the mixture was stirred at 0° C. for 0.5 hour. To this was added 3-(bromomethyl)pyridine hydrobromide (234 mg) under ice-water cooling, and the mixture was stirred at ambient temperature for 2 hours. The mixture was partitioned between AcOEt and water. The aqueous layer was separated, acidified to pH 3-4 with HCl and extracted with AcOEt. The organic layer was washed with water and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of CHCl3 and MeOH (100:1-20:1) to give 3-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoic acid as a yellow powder (110 mg).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:6]=1C=O)[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:26]>C(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:6]=1[OH:26])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(OCc2ccccc2)ccc1C=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C=CCOc1cc(OCc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.4 %

Procedure:
To a solution of 53.6 g (0.20 mole) of 2-allyloxy-4-(benzyloxy)benzaldehyde in 500 mL of methylene chloride was added a solution of 90 g (˜0.3 mole) of 57-86% m-chloroperoxybenzoic acid in 500 mL of methylene chloride. The mixture was stirred at room temperature for 3 days. It was then diluted to 2 L with methylene chloride and washed four times with 500 mL portions of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuum to a brown oil. This was redissolved in 1 L of methanol, 110 g of basic alumina added and the mixture stirred at room temperature for 15 hours. The alumina was removed by filtration and the filtrate concentrated to 50 g of a yellow solid. The crude solid was column chromatographed on silica gel with hexane/methylene chloride as eluant to give 33 g of the title compound as a white solid, m.p. 62° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([CH2:11][CH:12](O)[CH3:13])=[CH:9][N:8]([C@@H:15]3[O:30][C@H:29]([CH2:31][O:32][CH2:33][C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=4[Cl:41])[C@@H:18]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[C@@:16]3([CH3:42])[OH:17])[C:4]=2[N:5]=[CH:6][N:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:62]1(=[O:72])[NH:66][C:65](=[O:67])[C:64]2=[CH:68][CH:69]=[CH:70][CH:71]=[C:63]12.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O.C(Cl)Cl>[Cl:1][C:2]1[C:3]2[C:10]([CH2:11][CH:12]([N:66]3[C:62](=[O:72])[C:63]4=[CH:71][CH:70]=[CH:69][CH:68]=[C:64]4[C:65]3=[O:67])[CH3:13])=[CH:9][N:8]([C@@H:15]3[O:30][C@H:29]([CH2:31][O:32][CH2:33][C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=4[Cl:41])[C@@H:18]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[C@@:16]3([CH3:42])[OH:17])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(O)Cc1cn([C@@H]2O[C@H](COCc3ccc(Cl)cc3Cl)[C@@H](OCc3ccc(Cl)cc3Cl)[C@@]2(C)O)c2ncnc(Cl)c12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(Cc1cn([C@@H]2O[C@H](COCc3ccc(Cl)cc3Cl)[C@@H](OCc3ccc(Cl)cc3Cl)[C@@]2(C)O)c2ncnc(Cl)c12)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a solution of compound 4.3 (1.28 g, 1.89 mmol) in THF (70 mL) were added triphenylphosphine (648 mg, 2.47 mmol) and phthalimide (364.0 mg, 2.47 mmol) followed by DEAD (440 μL, 2.53 mmol), and the solution was stirred for overnight at room temperature. The reaction mixture was diluted by adding 100 mL of CH2Cl2 and water (100 mL) and the aqueous layers extracted three times with CH2Cl2, dried over Na2SO4, filtered and evaporated. The residue obtained was purified by flash column chromatography using 20-30% EtOAc in hexanes as eluent to give the desired compound 4.4 (1.5 g, 100%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CC(C)OC(=O)CBr
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)OC(=O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (3.6 g) obtained in Example 2 was suspended in dimethyl sulfoxide (200 ml), and to the suspension was added potassium carbonate (2.5 g), and the mixture was stirred at room temperature for 30 minutes. i-propyl bromoacetate (1.4 ml) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water (300 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: methylene chloride containing 3% methanol), and the crude product was washed with ether and a small amount of methanol in succession, and recovered by filtration to obtain the title compound (2.6 g, 59%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]2=[N:7][S:8][N:9]=[C:5]2[CH:4]=1.C(=O)([O-])[O-:13].[Ca+2]>O1CCOCC1.O>[OH:13][CH2:2][C:3]1[CH:11]=[CH:10][C:6]2=[N:7][S:8][N:9]=[C:5]2[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccc2nsnc2c1
Agent: [Ca+2]
Solvent: O
Solvent: C1COCCO1
Product: OCc1ccc2nsnc2c1
Yield: 76.4 %

Procedure:
5-Bromomethylbenzo-2,1,3-thiadiazole (4.8 g) and calcium carbonate (10 g) were heated at reflux in 1:1 dioxane/water (120 mL) for 3 hours. The solvents were evaporated and the residue was partitioned between 2N hydrochloric acid and methylene 6 3 chloride. The organic layers were dried (magnesium sulfate), evaporated and chromatographed on silica gel eluting with 1:1 ethyl acetate/hexane to provide 2.66 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH2:17])[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].Cl[S:19]([C:22]1[CH:31]=[C:30]2[C:25]([CH2:26][CH2:27][N:28]([C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH2:29]2)=[CH:24][CH:23]=1)(=[O:21])=[O:20].N1C=CC=CC=1.O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([NH:17][S:19]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][N:28]([C:32](=[O:37])[C:33]([F:36])([F:34])[F:35])[CH2:29]3)=[CH:24][CH:23]=2)(=[O:20])=[O:21])[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(N)CCN(c2ccncc2)CC1
Reactant: O=C(N1CCc2ccc(S(=O)(=O)Cl)cc2C1)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)C1(NS(=O)(=O)c2ccc3c(c2)CN(C(=O)C(F)(F)F)CC3)CCN(c2ccncc2)CC1

Procedure:
To a solution of 4-amino-1-(pyridin-4-yl)piperidine-4-carboxylic acid methyl ester (330 mg) in chloroform (5 ml) were added 7-chlorosulfonyl-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline (Journal of Medicinal Chemistry, vol. 23, No.8, p. 837 (1980)) (500 mg) and pyridine (0.23 ml), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, water was added, and the mixture was extracted with chloroform and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (627 mg).
Reaction SMILES: O.[OH-].[Li+].[F:4][CH:5]([F:20])[C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([CH2:16][N:17]([CH3:19])[CH3:18])[CH:15]=1)[C:9]([O:11]C)=[O:10].Cl>O.O1CCCC1>[F:4][CH:5]([F:20])[C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([CH2:16][N:17]([CH3:18])[CH3:19])[CH:15]=1)[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1cc(CN(C)C)cc(C(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)Cc1cc(C(=O)O)cc(C(F)F)c1
Reaction time: 3.5 h
Yield: 100.7 %

Procedure:
Lithium hydroxide, monohydrate (65.2 mg, 1.55 mmol) in water (0.7 mL) was added to a solution of methyl 3-(difluoromethyl)-5-[(dimethylamino)methyl]benzoate (45 mg, 0.13 mmol, from Step C) in tetrahydrofuran (2 mL). Upon stirring for 3.5 hours, the mixture was treated with 1N HCl to adjust the pH to 7, then THF was removed by rotary evaporation. Acetonitrile was added to make a 1:1 ACN:water mixture, the mixture was filtered, and the filtrate was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) to afford product as a white solid (0.030 g, 100%). 1H NMR (300 MHz, DMSO-d6): δ 7.95 (s, 2H), 7.50 (s, 1H), 7.05 (t, 1H), 3.44 (s, 2H), 2.15 (s, 6H); LCMS (M+H)+: 230.1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]2[C:8](=[O:10])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=3)[NH:11][C:6]=2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Nc1ccc(F)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=c1c2cc(F)ccc2[nH]c2c([N+](=O)[O-])ccc(Cl)c12
Yield: 87.1 %

Procedure:
A mixture of 6-chloro-2-[(4-fluorophenyl)amino]-3-nitrobenzoic acid (12.39 g, 0.04 mol), chloroform (100 ml), and POCl3 (60 ml, 0.64 mol) was stirred at reflux for 8 h. Solvents were removed under reduced pressure. To the residue was added 200 ml of a mixture of 1,4-dioxane and water (8:1), and the mixture was acidified with concentrated hydrochloric acid and stirred at reflux for 2 h. Water was added (200 ml) and the precipitate was collected by filtration and crystallized from N,N-dimethylformamide—water to give 10.2 g (87%) of 1b as orange needles: mp 287-291° C. Anal. (C13H6N2O3ClF) C, H, N.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([F:15])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[CH:64]1[C:76]2[NH:75][C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[C:68]=2[C:67]([C:77]2[CH:78]=[CH:79][C:80]([C:83]#[N:84])=[N:81][CH:82]=2)=[CH:66][CH:65]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:83]([C:80]1[N:81]=[CH:82][C:77]([C:67]2[C:68]3[C:69]4[C:74](=[CH:73][CH:72]=[CH:71][CH:70]=4)[N:75]([C:2]4[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([F:15])[CH:3]=4)[C:76]=3[CH:64]=[CH:65][CH:66]=2)=[CH:78][CH:79]=1)#[N:84]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1F
Reactant: N#Cc1ccc(-c2cccc3[nH]c4ccccc4c23)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1F
Temperature: 25 °C
Yield: 68 %

Procedure:
0.63 g of 2-methylpropan-2-yl 4-bromo-2-fluorobenzoate, 1.88 g of caesium carbonate, 0.11 g of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) and 0.03 g of palladium acetate are successively added, under argon, to a solution of 0.41 g of 5-(9H-carbazol-4-yl)pyridine-2-carbonitrile, obtained in stage 1 of Example 28, in 20 ml of dioxane. The reaction mixture is refluxed for 4 and a half hours, cooled to ambient temperature, filtered through celite and concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a mixture of cyclohexane and ethyl acetate (90/10 by volume), so as to give 0.48 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-fluorobenzoate in the form of a light brown oil, the characteristics of which are the following:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[C:27]([S:32](Cl)(=[O:34])=[O:33])[CH:26]=[CH:25]2>C(Cl)Cl>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:32]([C:27]2[CH:26]=[CH:25][C:24]3[C:29](=[CH:30][CH:31]=[C:22]([Cl:21])[CH:23]=3)[CH:28]=2)(=[O:33])=[O:34])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1

Procedure:
To a stirring solution of N-Boc-piperazine (400 mg, 2.1 mmol) and triethylamine (1 mL, 7 mmol) in methylene chloride (5 mL) was added 6-chloro-2-naphthalenesulfonyl chloride (500 mg, 1.9 mmol). After 2 h the solution was washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed on a (Biotage) silica column, eluting with ethyl acetate:hexanes (2:8), to give 300 mg (38%).