Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([C:12]([OH:14])=[O:13])[CH2:7]1.[CH3:15]O>>[NH2:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([C:12]([O:14][CH3:15])=[O:13])[CH2:7]1
Reactant: CO
Reactant: N[C@@H]1CCC[C@H](C(=O)O)C1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CCC[C@@H](N)C1
Yield: 90.9 %

Procedure:
Thionyl chloride (0.6 ml) was added to solution of cis-3-amino-cyclohexanecarboxlic acid (bought from AMRI, USA, cat.-no.: A00342, 0.50 g, 2.80 mmol) in MeOH (20 ml) at 0° C. and stirred at reflux for 12 h. The volatiles were evaporated in vacuo and the resulting residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The separated organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuo to afford 400 mg (90.9%) of cis-methyl 3-aminocyclohexanecarboxylate as colorless liquid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:13]=[CH:12][C:11]2[N:10]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=3)[C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:7][C:6]=2[C:5]1=[O:28]>C(Cl)(Cl)Cl.C(#N)C.[O-2].[O-2].[Mn+4]>[OH:1][CH2:2][CH2:3][N:4]1[CH:13]=[CH:12][C:11]2[N:10]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][CH:15]=3)[C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:7][C:6]=2[C:5]1=[O:28]
Reactant: O=c1c2cc(-c3ccccc3)c(-c3ccc(CO)cc3)nc2ccn1CCO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(-c2nc3ccn(CCO)c(=O)c3cc2-c2ccccc2)cc1
Temperature: 70 °C

Procedure:
A solution of 6-(2-hydroxyethyl)-2-[4-(hydroxymethyl)phenyl]-3-phenyl-1,6-naphthyridin-5(6H)-one (35 mg, 0.094 mmol) in a mixture of chloroform (3 mL) and acetonitrile (3 mL) containing a suspension of activated manganese dioxide (230 mg, 2.6 mmol) was warmed at 70° C. for 1.5 hours. This suspension was filtered, rinsed with chloroform and the solvents evaporated. This residue was triturated with diethyl ether and some pure title compound was isolated by filtration. The mother liquors were subjected to column chromatography on silica gel and upon elution with 50-100% ethyl acetate/hexane and then 0.25-0.75% methanol/ethyl acetate additional product was obtained. 1H-NMR (500 MHz, CDCl3): δ 10.02 (1H, s), 8.74 (1H, s), 7.80 (2H, d, J=8 Hz), 7.62 (2H, d, J=8 Hz), 7.44 (1H, d, J=7.6 Hz), 7.27-7.31 (4H, m), 7.20-7.22 (2H, m), 6.89 (1H, d, J=7.5 Hz), 4.25 (2H, t, J=4.8 Hz), 4.04 (2H, br s), 2.56 (1H, br s).
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][C:9]1=[O:15].[C:16](C#N)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl.[Cl-].[Zn+2].[Cl-]>[C:16]([CH:10]1[C:11](=[O:14])[CH2:12][CH2:13][NH:8][C:9]1=[O:15])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#CC(=O)c1ccccc1
Reactant: O=C1CCNC(=O)C1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCNC(=O)C1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23 %

Procedure:
Dry triethylamine (1.33 g) was added at 0°-5° C. to a stirred suspension of piperidine-2,4-dione (1.13 g), anhydrous zinc chloride (1.64 g) and benzoyl cyanide (1.31 g) in dry dichloromethane (50 ml) and the mixture stirred at ambient temperature for 18 hours. The mixture was washed successively with 2N hydrochloric acid (2×30 ml) and water (3×30 ml) dried over magnesium sulphate and evaporated under reduced pressure to give a pale yellow solid which was recrystallised from acetonitrile (0.5 ml) to give 3-benzoylpiperidine-2,4-dione (0.5 g), mp 164°-165° C., as a cream crystalline solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]=[C:18]1[C:23]2=[CH:24][NH:25][C:26]([CH:27]=O)=[C:22]2[CH2:21][CH2:20][O:19]1>>[O:16]=[C:11]1[C:10](=[CH:27][C:26]2[NH:25][CH:24]=[C:23]3[C:18](=[O:17])[O:19][CH2:20][CH2:21][C:22]=23)[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=2)[NH:12]1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Product: O=C1Nc2ccc(-c3ccccc3)cc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
5-Phenyl-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:21][CH2:20][C:5]2[N:6]([CH2:14][C:15](OCC)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:22]([NH2:25])([CH3:24])[CH3:23]>>[CH3:1][N:2]1[CH2:21][CH2:20][C:5]2[N:6]([CH2:14][C:15]([NH:25][CH:22]([CH3:24])[CH3:23])=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CCOC(=O)Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: CC(C)N
Product: Cc1ccc2c(c1)c1c(n2CC(=O)NC(C)C)CCN(C)C1
Temperature: 120 °C

Procedure:
A mixture of ethyl 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetate (100 mg) and isopropylamine (1 ml) was heated at 120° C. for 15 h to obtain 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-N-isopropylacetamide after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][N:15](CC2C=CC=CC=2)[CH2:14][CH2:13]1)(=[O:4])=[O:3].CO.Cl>[Pd].CCOC(C)=O>[CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Nc1ccccc1N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccccc1N1CCNCC1

Procedure:
To a round-bottomed flask equipped with stirring was added (methylsulfonyl){2-[4-benzylpiperazinyl]phenyl}amine (42 g, 120 mmol), MeOH, 10% Pd/C (Aldrich)(25 g), and HCO2NH4 (38 g, 610 mmol). After heating at reflux for 2 h, the mixture was filtered through Celite® and washed with CH2Cl2. The combined organic layers were washed with NaHCO3 and concentrated in vacuo to afford a light yellow solid. This was treated with a soln of EtOAc and HCl to afford the salt of the desired compound as the hydrochloride salt (20 g). MS (ESI, pos. Ion) m/z: 256 (M+H); MS (ESI, neg. Ion) m/z: 254 (M−H). Calc'd for C11H17N3O2S: 255.10.
Reaction SMILES: C(C1C=CC(OCC2ON=C(CC3C=C(C=CC=3)[C:19]([OH:21])=[O:20])N=2)=C(C)C=1O)(=O)C.[Cl:29][C:30]1[C:31]([OH:54])=[C:32]([C:51](=[O:53])[CH3:52])[CH:33]=[CH:34][C:35]=1[O:36][CH2:37][C:38]1[O:42][N:41]=[C:40]([CH2:43][C:44]2[CH:49]=[CH:48][C:47](I)=[CH:46][CH:45]=2)[N:39]=1>>[C:51]([C:32]1[CH:33]=[CH:34][C:35]([O:36][CH2:37][C:38]2[O:42][N:41]=[C:40]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([C:19]([OH:21])=[O:20])=[CH:46][CH:45]=3)[N:39]=2)=[C:30]([Cl:29])[C:31]=1[OH:54])(=[O:53])[CH3:52]
Reactant: CC(=O)c1ccc(OCc2nc(Cc3cccc(C(=O)O)c3)no2)c(C)c1O
Reactant: CC(=O)c1ccc(OCc2nc(Cc3ccc(I)cc3)no2)c(Cl)c1O
Product: CC(=O)c1ccc(OCc2nc(Cc3ccc(C(=O)O)cc3)no2)c(Cl)c1O

Procedure:
The title compound is prepared essentially as described for 3-[5-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-[1,2,4]oxadiazol-3-ylmethyl]-benzoic acid of Example 140, employing 1-{3-chloro-2-hydroxy-4-[3-(4-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-phenyl}-ethanone. 1H NMR (DMSO-d6) δ 13.05 (s, 1H), 12.86 (s, 1H), 7.92 (d, 1H), 7.85 (m, 2H), 7.38 (d, 2H), 6.84 (d, 1H), 5.72 (s, 2H), 4.18 (s, 2H), 2.59 (s, 3H). LC-MS (m/e): 401 (M−1).
Reaction SMILES: C(O[C:6]([N:8](C)[C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[N:15](C(OC(C)(C)C)=O)[CH3:16])=O)(C)(C)C.[ClH:25]>C(O)C>[ClH:25].[CH3:6][NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][CH3:16]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCCC[C@@H]1N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CN[C@H]1CCCC[C@H]1NC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
cis-N1,N2-Bis(tert-butoxycarbonyl)-N1,N2-dimethyl-1,2-cyclohexanediamine (2.15 g) was dissolved in a saturated ethanol solution of hydrochloric acid, and the solution was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and solids were collected by filtration to obtain the title compound (1.19 g) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH3:28][C:29]([CH3:31])=O>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][O:16][CH2:17][CH:18]3[CH2:19][CH2:20][N:21]([CH:29]([CH3:31])[CH3:28])[CH2:22][CH2:23]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: CCCCC(COCC1CCNCC1)NC(=O)c1ccc2c(Cl)c[nH]c2c1
Product: CCCCC(COCC1CCN(C(C)C)CC1)NC(=O)c1ccc2c(Cl)c[nH]c2c1

Procedure:
Using alkylation method A, 3-chloro-N-[1-butyl-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (0.18 mmol) and acetone (1 mL, 14 mmol) afforded, after SCX purification, 60 mg (70%) of the title compound.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.[CH3:14]I>O1CCCC1>[CH3:14][O:3][CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=1
Reactant: OCCSCc1ccncc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCSCc1ccncc1
Reaction time: 0.08 h

Procedure:
Sodium hydride (170 mg., 7.1 mmoles, from 340 mg. of 50% dispersion in oil washed, under nitrogen, with hexane) was slurried in 5 ml. of dry tetrahydrofuran. A solution of 4-(2-hydroxyethylthiomethyl)pyridine (1.0 g., 5.9 mmoles) in 10 ml. ws added dropwise over 5 minutes and the mixture stirred for 5 minutes. Finally, methyl iodide (260 mg., 0.1 ml., 5.9 mmoles) in 2 ml. of tetrahydrofuran was added and the mixture stirred overnight. The reaction mixture was clarified by filtration and evaporated to an oil (approximately 1.3 g.) which was chromatographed on silica gel with chloroform as eluent. Pure fractions of product were combined and concentrated to yield 4-(2-methoxyethylthiomethyl)pyridine [210 mg. of oil; m/e 183; pnmr/CDCl3 /TMS/τ: 7.4 (t, 2H), 6.7 (s, 3H), 6.5 (t, 2H), 6.3 (s, 2H), 2.7 (d, 2H), 1.4 (d, 2H)].
Reaction SMILES: C([O:5][CH2:6][CH:7]([CH2:12][CH3:13])[CH2:8][CH2:9][CH2:10][CH3:11])(=O)C=C.C(=O)([O-])[O-:15].[Cs+].[Cs+]>C(#N)C>[CH3:11][CH2:10][CH2:9][CH2:8][CH:7]([C:6]([OH:5])=[O:15])[CH2:12][CH3:13]
Reactant: O=C([O-])[O-]
Reactant: C=CC(=O)OCC(CC)CCCC
Agent: [Cs+]
Solvent: CC#N
Product: CCCCC(CC)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 399.2 %

Procedure:
A mixture of TMIT (1.0 g, 6.33 mmol), 2-ethylhexyl acrylate (1.16 g, 6.33 mmol) and cesium carbonate (1.0 g, 3.3 mmol) in acetonitrile (15 mL) was stirred at room temperature for 24 h. The reaction mixture was filtered to separate solid cesium carbonate and solvent was evaporated from the filtrate to obtain the product as a colorless oil (1.9 g, 88 %). IR: 3325, 2961, 1732, 1595, 1480 cm31 1; 1H NMR (CDCl3, 500 MHz): δ3.96 (overlapping d, 2 H), 3.83 (t, 1.72 H), 3.22 (t, 0.28 H), 2.82 (t, 1.72 H), 2.71 (t, 0.28 H), 1.91 (bs, 1H), 1.42 (s, 6 H), 1.40 (s, 6H), 1.35-1.20 (m, 8 H), 0.85 (overlapping t, 6 H) ppm; 13C NMR (CDCl3, 125 MHz): δ205.8, 173.6, 171.9, 171.3, 130.2, 128.5, 88.7, 82.9, 70.35, 69.6, 67.2, 66.9, 66.8, 40.6, 38.6, 33.9, 31.4, 30.26, 30.21, 28.79, 28.71, 28.23, 25.8, 23.64, 22.83, 13.9, 10.9 ppm.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl.Cl>CO>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: CC(C)N1CCN(c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
1-Isopropyl-4-(4-nitro-phenyl)-piperazine (8.3 g, 33.2 mmol) is dissolved in MeOH (120 mL) and tin (II) dichloride dihydrate (37.4 g, 0.165 mol) is added. The mixture is cooled using a water bath and conc. HCl is added (36 mL). The reaction is stirred at room temperature overnight. After removing the methanol, the resultant solution is basified using conc. NaOH (pH 11). The water phase is extracted with diethyl ether (3×) and the organic layers combined, dried over MgSO4, filtered, concentrated in vacuo to afford the title compound (6.4 g, 88%).
Reaction SMILES: [C:1]([C:3]1[N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2)#[N:2].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[C:1]([C:3]1[N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][Br:20])=[CH:7][CH:6]=2)#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(c1)cc(C#N)n2C(=O)OC(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1c(C#N)cc2cc(CBr)ccc21
Yield: 78 %

Procedure:
To a stirred solution of 334 mg of tert-butyl 2-cyano-5-methyl-1H-indole-1-carboxylate (1.3 mmol) in carbon tetrachloride (5 mL) was added 232 mg of N-bromosuccinimide (1.3 mmol) and 11 mg of AIBN (0.065 mmol). The mixture was refluxed for 1 h, then cooled and concentrated, and the residues were purified by chromatography on silica gel using hexane-ethyl acetate 20:1 to give 340 mg of tert-butyl 2-cyano-5-bromomethyl-1H-indole-1-carboxylate. 1H NMR (600 MHz, CDCl3): δ 8.22 (d, 1H, J=8.8 Hz), 7.64 (s, 1H), 7.53 (d, 1H, J=8.8 Hz), 7.31 (s, 1H), 4.60 (s, 2H), 1.73, (s, 9H). 13C NMR (150 MHz, CDCl3): δC 147.64, 136.27, 133.92, 129.34, 127.45, 122.33, 121.15, 116.46, 113.02, 109.75, 87.14, 33.23, 28.01.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:9]=[C:8]([C:10]2[S:11][C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14](=[O:16])[N:15]=2)[CH:7]=[CH:6][CH:5]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)(Cl)Cl>[CH2:1]([S:3]([C:4]1[N:9]=[C:8]([C:10]2[S:11][C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14](=[O:16])[N:15]=2)[CH:7]=[CH:6][CH:5]=1)=[O:29])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: ClC(Cl)Cl
Product: CCS(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
2-[6-(Ethylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-one (0.10 g, 0.33 mmol) was dissolved in chloroform (50 ml). A solution of 3-chloroperbenzoic acid (ca. 77%, 0.075 g, 0.33 mmol) in chloroform (10 ml) was added dropwise to the mixture, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated and the residue was recrystallized from ethanol to give the titled compound (0.050 g, 47%) as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[CH:12][NH:11][C:8]=3[N:9]=[CH:10][C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[N:3]=1.[H-].[Na+].[CH3:26][CH:27]([Si:29](Cl)([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])[CH3:28]>C1COCC1>[CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[CH:12][N:11]([Si:29]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:28])[CH3:26])[C:8]=3[N:9]=[CH:10][C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:21])[CH3:22])=[CH:16][CH:15]=2)[N:3]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Cc1nc(-c2ccc(C(C)(C)O)cc2)c2cnc3[nH]ccc3n12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(C)(C)O)cc2)c2cnc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)n12
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 96.5 %

Procedure:
To a solution of 2-(4-(1-methyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenyl)propan-2-ol (1.03 g, 3.36 mmol; Example #N.1.50) in THF (32 ml) at about −20° C. was added NaH (0.148 g, 3.70 mmol). The mixture was allowed to stir at about −20° C. for about 20 min. TIPSCl (0.790 ml, 3.70 mmol) was added and the resulting solution was allowed to stir at about −20° C. for about 1 h. The mixture was treated with 15 mL of an ice cold saturated aqueous NaCl solution and the resulting mixture was partitioned between EtOAc (100 mL) and water (50 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×25 mL). The combined organic phases were washed with saturated aqueous NaCl solution (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give 2-(4-(1-methyl-6-(triisopropylsilyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenyl)propan-2-ol (1.5 g, 96%). LC/MS (Table 2, Method h) Rt=2.28 min; MS m/z 463 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[N:7]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:6]=1)=[O:4].O.O[Li].O.Cl>C1COCC1>[N+:14]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[N:6]=[C:5]2[C:3]([OH:4])=[O:2])([O-:16])=[O:15]
Reactant: COC(=O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc([N+](=O)[O-])cc12
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-nitro-1-trityl-1H-indazole-3-carboxylic acid methyl ester 19AP (12.95 g, 27.96 mmol) in THF (270 ml) and H2O (135 ml) was added LiOH.H2O (2.34 g, 55.92 mmol) at room temperature. After stirring for overnight at room temperature, it was cooled to 0° C. and acidified with slow addition of 1N HCl (55.9 ml, 55.92 mmol). Reaction mixture was concentrated under reduced pressure. Solid was collected by filtration and washed with water to give desired 5-nitro-1-trityl-1H-indazole-3-carboxylic acid 20AP (12.06 g, 96%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:38](=[O:37])[CH2:39][OH:40])[CH2:32][CH2:33]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f14) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:18])=O>>[CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([Cl:18])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(C2CCCCC2)cc1

Procedure:
To 4-cyclohexylbenzoic acid (2 g) is added thionyl chloride (20 ml), and the mixture is refluxed for two hours. The mixture is evaporated to remove the thionyl chloride to give 4-cyclohexylbenzoyl chloride. To a solution of 5-ethoxycarbonylmethyl-7-chloro-2,3,4,5-tetrahydro-1H-benzazepine (2.2 g) in dichloromethane (50 ml) is added pyridine (3.3 g), and to the mixture is added with stirring the above obtained 4-cyclohexylbenzoyl chloride under ice-cooling, and the mixture is stirred at room temperature overnight. To the reaction solution is added water, and the mixture is extracted with dichloromethane. The extract is washed with diluted hydrochloric acid, and washed with water, and dried over magnesium sulfate. The mixture is evaporated to remove the solvent, and the residue is purified by silica gel column chromatography (solvent; dichloromethane) to give 5-ethoxycarbonylmethyl-7-chloro-1-(4-cyclohexylbenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (4 g) as colorless oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])[CH:6]=1)=[O:4].CO.C(=O)([O-])[O-].[Na+].[Na+]>O>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]([NH:15][CH2:14][CH2:13][CH2:12][N:7]1[C:8](=[O:11])[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6]1)=[O:17]
Reactant: COC(=O)c1ccc(=O)n(CCCNC(=O)c2ccccn2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(=O)n(CCCNC(=O)c2ccccn2)c1

Procedure:
1,6-dihydro-1-[3-(2-pyridinylcarbonylamino)propyl]-6-oxo-3-pyridinecarboxylic acid methyl ester (0.260 g, 0.83 retool) was hydrolysed in a mixture consisting of methanol (1.0 ml), water (1.0 ml), and 15% aqueous sodium carbonate (2.0 ml) at 60° for 1.5 hours. The solution was filtered and acidified (to pH 5.5 with acetic acid). The precipitated product was recovered by filtration, washed with water, and dried, MP: 180°-182° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=O)=[N:8]1.[OH:20][C:21]1[CH:30]=[CH:29][C:24]2[C:25](=[O:28])[CH2:26][O:27][C:23]=2[C:22]=1[CH2:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1.N1CCCCC1>CO>[OH:20][C:21]1[CH:30]=[CH:29][C:24]2[C:25](=[O:28])/[C:26](=[CH:16]/[C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:19])([CH3:18])[CH3:1])[N:8]=3)/[O:27][C:23]=2[C:22]=1[CH2:31][N:32]1[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH2:37]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: C[Si](C)(C)CCOCn1nc(C=O)c2ccccc21
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2nn(COCC[Si](C)(C)C)c4ccccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 53.9 %

Procedure:
A solution of the positional isomer (2) of N-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-3-carboxaldehyde (0.354 g, 1.28 mmol) obtained in Step 1 in methanol (5 mL) was added with tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.446 g, 1.28 mmol) and piperidine (0.0109 g, 0.128 mmol), and the mixture was stirred at 60° C. for 5 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (Z)-4-({6-hydroxy-3-oxo-2-[(N-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.419 g, 53%).
Reaction SMILES: [CH:1]([N:4]([CH3:27])[C:5]1[C:6]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[CH:1]([N:4]([CH3:27])[C:5]1[C:6]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc(OC)cc3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2nc3ccc(C(=O)O)cc3nc2N(C)C(C)C)cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(isopropyl(methyl)amino)-2-(4-methoxyphenyl)quinoxaline-6-carboxylate (40 mg, 0.11 mmol, 1.00 equiv) in methanol (10 mL). Then a solution of sodium hydroxide (21.9 mg, 0.55 mmol, 5.00 equiv) in water (1 mL) was added. The resulting solution was stirred for 5 hrs at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The reaction was then quenched by the addition of 20 mL of water. The pH value of the aqueous solution was adjusted to 4-5 with aq. 1N hydrogen chloride. The resulting solids were collected by filtration. This resulted in 25 mg (65%) of 3-(isopropyl(methyl)amino)-2-(4-methoxyphenyl)quinoxaline-6-carboxylic acid as a yellow solid.