Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[H-].[Na+].C(OC([N:19]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[C:35]3[C:30](=[N:31][CH:32]=[CH:33][C:34]=3[CH2:36][CH2:37][CH3:38])[N:29]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:28]=2Cl)=[O:26])[CH2:21][CH2:20]1)=O)(C)(C)C>CN1C(=O)CCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][C:28]1[N:29]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:30]2=[N:31][CH:32]=[CH:33][C:34]([CH2:36][CH2:37][CH3:38])=[C:35]2[C:27]=1[C:25]([N:22]1[CH2:23][CH2:24][NH:19][CH2:20][CH2:21]1)=[O:26]
Reactant: CCCc1ccnc2c1c(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c(Cl)n2-c1ccccc1
Reactant: Cc1cccc(C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCCc1ccnc2c1c(C(=O)N1CCNCC1)c(Oc1c(C)cccc1C)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 35.1 %

Procedure:
To a solution of 2,6-dimethylphenol (152 mg, 1.24 mmol) in NMP (3 ml) was added sodium hydride (50 mg, 1.24 mmol, 60% dispersion in mineral oil), and the suspension was stirred at room temperature under an argon atmosphere for 20 min. After addition of 100 mg (207 μmol) of the compound of step 7, the reaction mixture was stirred for 2 h at 140° C. After cooling, the reaction mixture was quenched with water and extracted with EA. The organic phases were concentrated and the remaining residue was dissolved in DCM (12 ml) and TFA (3 ml) and stirred at room temperature for 2 h. The solvents were evaporated and the resulting solid was purified by preparative HPLC. The fractions containing the title compound were combined and lyophilized overnight. The obtained solid was dissolved in a small quantity of MOH, mixed with hydrochloric acid (0.1 M) and lyophilized overnight to give 34 mg of the title compound in the form of the [2-(2,6-dimethyl-phenoxy)-1-phenyl-4-propyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperazin-1-yl-methanone dihydrochloride.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[CH:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14])[CH3:3].C(N(CC)CC)C.[CH3:25][O:26][C:27]([S:29]Cl)=[O:28]>C1C=CC=CC=1>[CH3:25][O:26][C:27]([S:29][C:5]([C:6](=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14])=[CH:4][N:2]([CH3:3])[CH3:1])=[O:28]
Reactant: COC(=O)SCl
Reactant: CN(C)C=CC(=O)c1ccccc1C(F)(F)F
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)SC(=CN(C)C)C(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
4.2 g of 1-(N,N-dimethylamino)-2-(2-trifluoromethylbenzoyl)ethene and 2.6 g of triethylamine were added to 50 ml of benzene. 2.4 g of methoxycarbonylsulfenyl chloride dissolved in 10 ml of benzene was added dropwise to the solution obtained above under cooling in an ice-bath. After completion of the addition, the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled away under reduced pressure. After adding an aqueous solution of sodium hydrogencarbonate, the mixture was extracted with ether. Thus 5.0 g of 1-methoxycarbonylthio-1-(2-trifluoromethylbenzoyl)-2-(N,N-dimethylamino)ethene was obtained (Compound 209).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)=[O:25])=[CH:19][CH:18]=1)=[O:16])[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15]([C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)=[O:25])=[CH:21][CH:22]=1)=[O:16]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Temperature: 100 °C
Yield: 83 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added N-[4-(hydrazinocarbonyl)phenyl][1,1′-biphenyl]-4-carboxamide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 243 mg of the title compound (83%) as a yellow powder in 95.7% purity by HPLC (Rt: 5.34, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>>[F:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(F)c1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: O=c1[nH]c2nccc(Nc3cccc(F)c3)c2c2ccccc12
Yield: 65.5 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 3-fluoroaniline (96 mg, 0.87 mmol) to provide 190 (86 mg, 65% yield) as a white solid. LC-MS (M+H=306, obsd.=306).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:16]=[C:15]3[NH:40][C:41](=[O:61])[C:42]2[CH:47]=[CH:46][C:45]([C:48]([N:50]3[CH2:55][CH2:54][CH:53]([N:56]4[CH2:60][CH2:59][CH2:58][CH2:57]4)[CH2:52][CH2:51]3)=[O:49])=[CH:44][CH:43]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.CO>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[NH:40][C:41](=[O:61])[C:42]2[CH:43]=[CH:44][C:45]([C:48]([N:50]3[CH2:55][CH2:54][CH:53]([N:56]4[CH2:60][CH2:59][CH2:58][CH2:57]4)[CH2:52][CH2:51]3)=[O:49])=[CH:46][CH:47]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(S(=O)(=O)c3cc(F)cc(F)c3)cc12)c1ccc(C(=O)N2CCC(N3CCCC3)CC2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(Nc1n[nH]c2ccc(S(=O)(=O)c3cc(F)cc(F)c3)cc12)c1ccc(C(=O)N2CCC(N3CCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The crude N-[5-(3,5-difluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-yl]-4-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-benzamide was treated with 15 mL of 1,4-dioxane and with 4M hydrochloric acid in 1,4-dioxane (4 mL). The mixture was stirred at room temperature for 2 days then treated with methanol (15 mL) and stirred for additional 3 hours. The solvents were removed under reduced pressure and the residue taken up with ethyl acetate, washed with 10% aqueous ammonium hydroxide, dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography over silica gel eluting with dichloromethane/methanol/7N NH3 in methanol 100:7:1 affording 185 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>COCCOC>[C:2]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1cccc(-c2ccccc2)c1
Yield: 68.7 %

Procedure:
A solution of benzoic acid N′-[3-(3-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (100 mg, 0.26 mmol) in DME (5 ml)/2M Na2CO3 (450 μL, 0.90 mmol) was treated with phenylboronic acid (47 mg, 0.39 mmol) and Pd[PPh3]4 (30 mg, 0.026 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a solid (69 mg, 70%). LC-MS m/e 387.19 (M+H+)
Reaction SMILES: [C:1]([O:5]CC)(=[O:4])[CH:2]=O.C([NH:10][C:11]([CH2:22][C:23]([CH3:25])=[CH2:24])(C(OCC)=O)[C:12]([O:14]CC)=[O:13])=O.O>C(Cl)Cl>[NH2:10][CH:11]([CH2:22][C:23](=[CH2:24])[CH2:25][CH2:2][C:1]([OH:5])=[O:4])[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)C=O
Reactant: C=C(C)CC(NC=O)(C(=O)OCC)C(=O)OCC
Solvent: O
Solvent: ClCCl
Product: C=C(CCC(=O)O)CC(N)C(=O)O
Temperature: -20 °C
Reaction time: 1 h
Yield: 228.4 %

Procedure:
A solution of 26.5 g of ethyl glyoxylate in 180 ml of methylene chloride was added dropwise over 10 minutes to a solution of 84 g of ferric chloride in 180 ml of methylene chloride and after stirring for one hour, the mixture was cooled to -20° C. A solution of 34 g of the product of Step A in 180 ml of methylene chloride was added dropwise over 20 minutes and the mixture was stirred for one hour at -20° C. and then was poured into 300 ml of iced water. The mixture was extracted with methylene chloride and the organic phase was washed with 2N hydrochloric acid, then with aqueous sodium chloride, dried and evaporated to dryness under reduced pressure to obtain 56.5 g of the expected product melting at 68° C. after purification by chromatography on silica and elution with a 6-4 ethyl acetate-cyclohexane mixture.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.CS(C)=O.C([O-])([O-])=O.[K+].[K+]>O>[OH:6][C@@H:3]1[CH2:4][CH2:5][N:1]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:2]1
Reactant: O[C@@H]1CCNC1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(N2CC[C@@H](O)C2)cc1
Yield: 99.9 %

Procedure:
Dissolve (R)-pyrrolidin-3-ol (0.08 mL, 1.00 mmol) and 4-fluorobenzonitrile (121 mg, 1.00 mmol) into 1 mL of DMSO. Add K2CO3 (276 mg, 2.00 mmol) and heat the mixture at 120° C. for 16 h. LC-MS analysis indicates the desired intermediate. Add 10 mL of H2O. Filter the precipitate and dry in a Buchner funnel for 1 h to give 188 mg of 4-((R)-3-hydroxy-pyrrolidin-1-yl)-benzonitrile.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C1C=CC=CC=1>[Pd].C1COCC1.CO>[C:24]1([C:9]2([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:16][CH2:17][NH:8]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(CN2CCc3ccccc3C2(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc(C2(c3ccccc3)NCCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.6 %

Procedure:
10% Pd-supported carbon (900 mg) was added to a solution of 2-benzyl-1,1-diphenyl-1,2,3,4-tetrahydroisoquinoline (1.81 g) in a 2:1 THF-MeOH mixture (30 mL). The mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. Further, 10% Pd-supported carbon (900 mg) was added to the mixture, followed by stirring for 8 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 1,1-diphenyl-1,2,3,4-tetrahydroisoquinoline (339 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:23](=[O:30])[NH:24][C:25]2([CH3:29])[CH2:28][CH2:27][CH2:26]2)[CH2:8][CH2:7][N:6]([CH:9]2[CH2:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>C(Cl)Cl>[OH:37][C:31]([C:33]([F:36])([F:35])[F:34])=[O:32].[NH:12]1[CH2:13][CH2:14][CH2:15][CH:9]([N:6]2[CH2:7][CH2:8][C:3]([O:2][CH3:1])([C:23]([NH:24][C:25]3([CH3:29])[CH2:26][CH2:27][CH2:28]3)=[O:30])[CH2:4][CH2:5]2)[CH2:10][CH2:11]1
Reactant: COC1(C(=O)NC2(C)CCC2)CCN(C2CCCN(C(=O)OC(C)(C)C)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC1(C(=O)NC2(C)CCC2)CCN(C2CCCNCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-butyl 4-{4-methoxy-4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}azepane-1-carboxylate (0.25 g, 0.06 mmol) was dissolved in DCM (4 mL) and TFA (1 mL) was added. The reaction mixture was stirred at rt overnight under nitrogen, then the solvents were removed in vacuo, to give 1-(azepan-4-yl)-4-methoxy-N-(1-methylcyclobutyl)piperidine-4-carboxamide TFA salt (0.26 g), Intermediate 7, as a dark yellow oil which was used directly without further purification.
Reaction SMILES: [I:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:17][CH2:18][OH:19]>CN(C=O)C>[I:1][C:2]1[C:7]([O:8][CH2:17][CH2:18][OH:19])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1ccc(O)c(I)n1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCCO)c(I)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
To a stirred mixture of 2-iodo-6-methylpyridin-3-ol (530 g, 2.25 mol), Cs2CO3 (876 g, 2.7 mol) and DMF (2.5 L) was added 2-bromo-ethanol (560 g, 4.51 mol) dropwise at 0° C. The mixture was stirred at 90° C. overnight. The reaction was cooled and the solvent was removed in vacuo. The residue was diluted with water (2 L) and the aqueous solution was extracted with CH2Cl2 (3×350 mL). The combined organic layers were washed with brine (2×150 mL), dried over anhydrous Na2SO4 and concentrated to afford 2-(2-iodo-6-methylpyridin-3-yloxy)ethanol (630 g) as a brown solid which was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH3:9])([CH3:8])[C:5]([NH2:7])=[O:6])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:21]([O:23][C:24]([CH3:26])=[CH2:25])=[O:22]>C1COCC1>[CH2:1]([O:3][C:4]([CH3:9])([CH3:8])[C:5]([NH:7][C:21](=[O:22])[O:23][C:24]([CH3:26])=[CH2:25])=[O:6])[CH3:2]
Reactant: C=C(C)OC(=O)Cl
Reactant: CCOC(C)(C)C(N)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)OC(=O)NC(=O)C(C)(C)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 110.7 %

Procedure:
A −78° C. solution of 2-ethoxy-2-methylpropanamide (1.1 g, 8.39 mmol) in THF (37 mL), under Ar, was treated with LiHMDS (1 M in THF, 11 mL, 11 mmol) stirred for 0.5 h, treated with a solution of isopropenyl chloroformate (1.46 g, 12.10 mmol) in THF (2 mL), stirred for 15 minutes at −78° C. then slowly warmed to RT as the cooling bath expired. The mixture was treated with satd. NH4Cl, extracted with DCM (4×) and the combined organics were dried over MgSO4 and concentrated to dryness to afford prop-1-en-2-yl (2-ethoxy-2-methylpropanoyl)carbamate (2.0 g, 84%) as an orange oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=O)=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][N:3]=1.C(OP([CH2:23][C:24]([O:26]CC)=[O:25])(OCC)=O)C.[H-].[Na+].Cl>CN(C)C=O>[CH3:1][C:2]1[C:6](/[CH:7]=[CH:23]/[C:24]([OH:26])=[O:25])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][N:3]=1
Reactant: Cc1noc(-c2ccccc2)c1C=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccccc2)c1/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.5 %

Procedure:
To a mixture of 3-methyl-5-phenylisoxazole-4-carbaldehyde (4.94 g), ethyl diethylphosphonoacetate (6.53 g) and N,N-dimethylformamide (70 ml) was added sodium hydride (60%, oil, 1.13 g) at 0° C., and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and a yellow oil was obtained from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio). A mixture of the obtained yellow oil, 2N hydrochloric acid (50 ml) and acetic acid (50 ml) was refluxed for 3 hr. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were filtrated to give (E)-3-(3-methyl-5-phenyl-4-isoxazolyl)propenoic acid (4.02 g, yield 93%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 173–174° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][NH:12][C@H:11]([C:14]([OH:16])=[O:15])[CH2:10]2)=[CH:5][CH:4]=1.O.[OH-].[Na+].[N+:22]([C:25]1[CH:35]=[CH:34][C:28]([CH2:29][O:30][C:31](Cl)=[O:32])=[CH:27][CH:26]=1)([O-:24])=[O:23]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:31]([O:30][CH2:29][C:28]3[CH:27]=[CH:26][C:25]([N+:22]([O-:24])=[O:23])=[CH:35][CH:34]=3)=[O:32])[C@H:11]([C:14]([OH:16])=[O:15])[CH2:10]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(CS[C@@H]2CN[C@H](C(=O)O)C2)cc1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Yield: 77.5 %

Procedure:
A suspension of 1.87 g of (2S,4S)-4-(4-methoxybenzylthio)-2-pyrrolidinecarboxylic acid [prepared as described in step (i) above] in 80 ml of a 1:1 by volume mixture of tetrahydrofuran and water was transformed to a homogeneous solution by adding 7 ml of a 1N aqueous solution of sodium hydroxide. The solution was ice-cooled and stirred, and, little by little, a solution of 1510 mg of 4-nitrobenzyloxycarbonyl chloride in 10 ml of tetrahydrofuran and 7 ml of a 1N aqueous solution of sodium hydroxide were simultaneously added dropwise. The resulting mixture was stirred at the same temperature for 10 minutes. At the end of this time, the reaction mixture was freed from tetrahydrofuran by distillation under reduced pressure, and its pH was adjusted to a value of between 2 and 3 by the addition of 1N aqueous hydrochloric acid. The crystals which precipitated were collected by filtration, washed well with water and subjected to air-drying. The crystals were further washed with a small amount of diethyl ether and dried, to give 2.42 g of the title compound, melting at 96°-98° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:22]2[C:26](=[O:27])[NH:25][N:24]=[CH:23]2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.C([O-])([O-])=O.[K+].[K+].Br[CH:35]([CH2:37][CH3:38])[CH3:36]>CS(C)=O.O>[CH:35]([N:25]1[C:26](=[O:27])[N:22]([C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH2:9][CH2:10][N:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=4)[CH2:12][CH2:13]3)=[C:2]([F:1])[CH:3]=2)[CH:23]=[N:24]1)([CH2:37][CH3:38])[CH3:36]
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3F)CC2)cc1
Reactant: CCC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCC(C)n1ncn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)c(F)c2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a suspension of triazolone 7 (0.11 g, 0.3 mmol) in dimethylsulfoxide (4 mL) was added K2CO3 (0.08 g, 0.6 mmol). The resulting mixture was stirred at room temperature for 1 h. After the addition of 2-bromo butane (0.05 mL, 0.45 mmol), the temperature increased to 80° C. for overnight. After cooling to room temperature, the reaction mixture was diluted with water and extracted with dichlormethane. The combined organic layer was dried over Na2SO4, filtered, and concentrated to yield the crude product, which was purified by column chromatography to obtain triazolone 8 (0.11 g, 87%). 1H NMR (400 MHz, CDCl3, δH): 7.64 (s, 1H), 7.37 (dd, J=13.0, 2.2 Hz, 1H), 7.26-7.24 (m, 1H), 7.04 (t, J=8.8 Hz, 1H), 6.99-6.97 (m, 2H), 6.88-6.84 (m, 2H), 4.31-4.26 (m, 1H), 3.77 (s, 3H), 3.26 (bs, 8H), 1.86-1.81 (m, 1H), 1.73-1.71 (m, 1H), 1.38 (d, J=6.8 Hz, 3H), 0.89 (t, J=7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3, δC): 154.6, 154.2, 151.6, 139.4, 133.3, 128.4, 119.4, 118.7, 118.0, 114.5, 111.0, 110.8, 55.6, 52.8, 51.0, 50.5, 28.4, 19.3, 10.8.
Reaction SMILES: [CH3:1][N+:2]([CH3:4])=[CH2:3].[I-].[CH3:6][C:7]1([CH3:23])[C:11]([CH3:13])([CH3:12])[O:10][B:9]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH:18]=[CH:17]3)[O:8]1>CC#N.CC(O)=O>[CH3:3][N:2]([CH3:4])[CH2:1][C:17]1[C:16]2[C:20](=[CH:21][CH:22]=[C:14]([B:9]3[O:10][C:11]([CH3:13])([CH3:12])[C:7]([CH3:23])([CH3:6])[O:8]3)[CH:15]=2)[NH:19][CH:18]=1
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN(C)Cc1c[nH]c2ccc(B3OC(C)(C)C(C)(C)O3)cc12
Reaction time: 2 h
Yield: 48.7 %

Procedure:
To a suspension of Eschenmoser's salt (0.91 g, 4.9 mmol) in CH3CN (3 mL) and HOAc (1.5 mL) at rt was added a solution of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (1.0 g, 4.1 mmol) in CH3CN (3 mL) dropwise over about 10 min. After about 2 hours, the reaction was quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2 (3×15 mL). The combined organic layers were washed with brine, dried over Na2SO4, decanted, and concentrated to give crude N,N-Dimethyl-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl]methanamine (0.60 g, 50%); RP-HPLC (Table 1, Method g) Rt 1.39 min; 1H NMR (d6-DMSO, 400 MHz) δ11.26 (br s, 1H), 8.07 (s, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.37 (m, 2H), 3.92 (s, 2H), 2.40 (s, 6H), 1.31 (s, 12H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][C:10]([OH:14])=[CH:9]2)([O-:3])=[O:2].[F:15][C:16]([F:24])([F:23])[CH2:17]OS(C)(=O)=O>>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][C:10]([O:14][CH2:17][C:16]([F:24])([F:23])[F:15])=[CH:9]2)([O-:3])=[O:2]
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: O=[N+]([O-])c1cccc2cc(O)cnc12
Product: O=[N+]([O-])c1cccc2cc(OCC(F)(F)F)cnc12
Yield: 18 %

Procedure:
In a manner analogous to that described in Example 30 a) the alkylation of the 8-nitro-quinolin-3-ol (CAS25369-37-3) with methanesulfonic acid 2,2,2-trifluoro-ethyl ester yielded the title compound as a yellow solid (yield 18%); (calculated) C11H7F3N2O3 [272.2]; (found) [M+H]+=273.
Reaction SMILES: [S:1]([C:5]1[CH:14]=[CH:13][C:12]([NH:15][N:16]=[C:17]([C:20]([CH3:22])=[O:21])[C:18]#[N:19])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)(O)(=[O:3])=[O:2].[K].P(Cl)(Cl)([Cl:26])=O>CN1CCCC1=O>[Cl:26][S:1]([C:5]1[CH:14]=[CH:13][C:12]([NH:15][N:16]=[C:17]([C:20]([CH3:22])=[O:21])[C:18]#[N:19])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)(=[O:3])=[O:2]
Reactant: CC(=O)C(C#N)=NNc1ccc(S(=O)(=O)O)c2cccnc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [K]
Solvent: CN1CCCC1=O
Product: CC(=O)C(C#N)=NNc1ccc(S(=O)(=O)Cl)c2cccnc12
Reaction time: 1 h

Procedure:
To a 250 ml round-bottom flask fitted with calcium sulfate drying tube was added 4.5 g (0.0126 m) of 2-(5-sulfo-8-quinolylhydrazono)acetoacetonitrile, potassium salt and 45 ml phosphorus oxychloride. The resultant slurry was chilled to <5° C. and 4.5 ml N-methylpyrrolidinone was slowly added. After stirring 1 hour. at 0°-5° C., the slurry was stirred overnight at room temperature followed by quenching in 500 ml ice water. The resultant yellow solid was collected, air dried and recrystallized from 100 ml acetonitrile. Yield 3.0 g yellow needles (70 percent).