Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:28])([CH3:27])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]3[CH2:22][C:21]([CH3:24])([CH3:23])[NH:20][C:19]([CH3:26])([CH3:25])[CH2:18]3)[N:11]=2)=[CH:7][CH:6]=1>CO.[Pd]>[NH2:1][C:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]3[CH2:22][C:21]([CH3:24])([CH3:23])[NH:20][C:19]([CH3:26])([CH3:25])[CH2:18]3)[N:11]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(N)C#Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1
Agent: [Pd]
Solvent: CO
Product: CC(C)(N)CCc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1

Procedure:
{4-[5-(3-Amino-3-methyl-but-1-ynyl)-thiophen-2-yl]-pyrimidin-2-yl}-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (Example 5, 100 mg, 0.252 mmol) in MeOH (100 ml) was hydrogenated over Pd/C (10%, 50 mg) at 1 atm for 2 hours. The reaction mixture was filtered, evaporated to dryness and purified via chromatography on silicagel (DCM/MeOH/ammonia: 95/5/1 to 90/10/1) to give the title compound as colorless solid, which crystallized from ether.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[CH:7]1[O:15][CH:6]21)#[N:2].[CH:16]1([SH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[C@@H:7]([OH:15])[C@@H:6]2[S:22][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: SC1CCCCC1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](SC2CCCCC2)[C@@H]1O

Procedure:
A mixture of 1.5 g of 6-cyano-2,2-dimethyl-3,4-epoxychroman, 1.2 g of cyclohexylmercaptan and 0.3 g of a 35% methanolic solution of benzyltrimethylammonium hydroxide in 10 ml of tetrahydrofuran is refluxed for 8 hours.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[N:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23].Cl>C(#N)C.C(O)C.C(O)(C)C>[ClH:2].[Cl:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:10][CH2:11][N:12]([CH2:23][CH:22]=[CH2:21])[CH2:13][CH2:14]2)[CH:6]=[N:5][CH:4]=1
Reactant: Clc1cncc(N2CCNCC2)n1
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Solvent: CC(C)O
Product: C=CCN1CCN(c2cncc(Cl)n2)CC1

Procedure:
A stirred suspension of 6-chloro-2-(1-piperazinyl)-pyrazine hydrochloride (2.35 g, 10.0 mmol) and 2.8 g potassium carbonate in 25 ml of acetonitrile at 50° C. is treated with 0.9 ml (10.4 mmol) allylbromide. After 4 hours at 50° C. the mixture is concentrated under vacuum and the residue partitioned between water and chloroform. The chloroform extract is chromatographed on silica gel. Elution with 1% methanol-chloroform gives fractions containing 0.4 g (15%) title salt, mp 233.5°-234° C. by treatment with hydrogen chloride in ethanol-isopropanol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:22]1([C:28]2[N:29]([CH2:33][CH2:34][CH2:35][NH2:36])[CH:30]=[CH:31][N:32]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[C:22]1([C:28]2[N:29]([CH2:33][CH2:34][CH2:35][NH:36][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[O:9])[CH:30]=[CH:31][N:32]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NCCCn1ccnc1-c1ccccc1
Reactant: O=C(O)c1ccccn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(NCCCn1ccnc1-c1ccccc1)c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 124.8 %

Procedure:
A mixture of 1.85 g of picolinic acid and 2.43 g of 1,1'-carbonyldiimidazole in 60 ml of tetrahydrofuran was stirred at room temperature for 2 hours. Then 3.0 g of 2-phenyl-1H-imidazole-1-propanamine was added and the procedure as described in Example 33 was continued to obtain 5.7 g of a viscous oil. The oil was treated by preparative high pressure liquid chromatography using a PrepPAK®-500 Silica column (Waters Associates, Millipore) and ethyl acetate as eluent. Fractions were collected and fractions 5 and 6 were concentrated, treated with ether, and dried and gave 3.8 g of the compound of the Example as an oil.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]4[OH:33])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[CH2:32][CH2:31][N:30]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:29][C@@H:28]4[OH:33])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CCNC[C@H]1O
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)[C@@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-N-[(3R*,4S*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f11) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11](=O)[CH2:12][C:13]([O:15]CC)=O)[CH2:7][CH2:6]1)=[O:4].[NH2:19][C:20]1[CH:24]=[CH:23][NH:22][N:21]=1>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:12]=[C:13]([OH:15])[N:21]3[N:22]=[CH:23][CH:24]=[C:20]3[N:19]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)CC(=O)C1CCC(C(=O)OC)CC1
Solvent: ClCCl
Product: COC(=O)C1CCC(c2cc(O)n3nccc3n2)CC1
Temperature: 100 °C

Procedure:
4-(2-Ethoxycarbonyl-acetyl)-cyclohexanecarboxylic acid methyl ester (8.5 g) and 3-amino-1H-pyrazole (26.5 mmol, 2.2 g) were mixed and heated neat at 100° C. for 16 hours. The resulting residue is dissolved in dichloromethane (100 mL) and concentrated in vacuo to remove water formed during cyclization. This solid is taken forward without further purification. LC-MS: 403 [M+H].
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[NH:15]1[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOC(C)=O>[OH:20][C@H:17]1[CH2:18][CH2:19][N:15]([C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:16]1
Reactant: O[C@H]1CCNC1
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(N2CC[C@H](O)C2)cc1
Temperature: 130 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
To a solution of tert-butyl 4-fluorobenzoate (1 g, 5.1 mmol) and (S) -pyrrolidin-3-ol (462 mg, 5.3 mmol) in DMSO (10 mL) was added powdered potassium carbonate (705 mg, 5.1 mmol). The mixture was stirred at 130° C. for 4 h and allowed to cool down to room temperature. The mixture was diluted with EtOAc (300 mL) and the solution was washed with water (2×100 mL), dried over Na2SO4, filtered and concentrated to provide title compound 157 (1.23 g, 88% yield) that was used in the next step without further purification. LRMS (ESI): (calc) 263.15 (found) 264.1 (MH+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:15]1[C:16]([CH3:33])=[N:17][N:18]2[C:23]3[N:24]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH2:25][CH2:26][C:22]=3[C:21]([CH3:32])=[N:20][C:19]=12.O>N1C=CC=CC=1>[CH3:1][S:2]([N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]=[C:7]1[C:15]1[C:16]([CH3:33])=[N:17][N:18]2[C:23]3[N:24]([CH:27]([CH2:28][CH3:29])[CH2:30][CH3:31])[CH2:25][CH2:26][C:22]=3[C:21]([CH3:32])=[N:20][C:19]=12)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(CC)N1CCc2c(C)nc3c(-c4nc5ccccc5[nH]4)c(C)nn3c21
Solvent: c1ccncc1
Solvent: O
Product: CCC(CC)N1CCc2c(C)nc3c(-c4nc5ccccc5n4S(C)(=O)=O)c(C)nn3c21
Reaction time: 1 h
Yield: 81.6 %

Procedure:
Methanesulfonyl chloride (12 mL, 0.16 mmol) was added to a soltution of 3-(1H-benzo[d]imidazol-2-yl)-8-(1-ethylpropyl)-2,5-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (50 mg, 0.13 mmol) in pyridine (0.5 mL) at room temperature and the mixture was stirred for one hour. Water was added thereto, and the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane), to give the title compound (48 mg) as pale yellow crystals.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[F:12].CCN(C(C)C)C(C)C.[CH3:22][C@H:23]1[CH2:28][NH:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C>[F:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[CH2:2][N:27]1[CH2:26][CH2:25][N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@@H:23]([CH3:22])[CH2:28]1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(CBr)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(Cc2ccc([N+](=O)[O-])cc2F)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A mixture of 2-fluoro-4-nitrotoluene (1.55 g, 10 mmol), N-bromosuccinimide (1.96 g, 11 mmol) and benzoyl peroxide (0.121 g, 0.5 mmol) in CCl4 (60 mL) was irradiated with a 500 W lamp overnight. The reaction mixture was filtered, concentrated and eluted through a silica column with EtOAc/pentane to give a crude product mixture (2.34 g) which was used in step 2. Step 2: A mixture of crude 4-(bromomethyl)-3-fluoro-1-nitrobenzene (2.11 g) from step 1, Hunig's base (1.9 mL, 10.913 mmol) and 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (2 g, 10 mmol) in DMF (15 mL) was stirred at room temperature for 40 minutes. The reaction mixture was concentrated, re-dissolved in DCM and washed with water (×2) and brine, then dried and concentrated. The crude product was purified by column chromatography. Elution with EtOAc/pentane yielded the title compound as a yellow gum which crystallised on standing (2.11 g). δH (CDCl3, 400 MHz) 8.03 (1H, dd), 7.91 (1H, dd), 7.70 (1H, m), 4.22 (1H, br.s), 3.84 (1H, d), 3.61 (2H, m), 3.12 (1H, td), 2.74 (1H, m), 2.57 (1H, m), 2.27 (1H, dd), 2.11 (1H, m), 1.46 (9H, s), 1.25 (3H, d). MS (ES): MH+ 354.1. Description 66
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@@H:17]([NH2:19])[CH3:18])=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=2)[CH:4]=[CH:3]1.[Cl:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[C:23]([S:30][CH3:31])[N:22]=1.CCN(CC)CC>C1COCC1.C(OCC)(=O)C>[Cl:20][C:21]1[C:26]([C:27]#[N:28])=[C:25]([NH:19][C@H:17]([C:7]2[N:6]=[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:10]3=[CH:9][C:8]=2[N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH3:18])[N:24]=[C:23]([S:30][CH3:31])[N:22]=1
Reactant: CSc1nc(Cl)c(C#N)c(Cl)n1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCOCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1nc(Cl)c(C#N)c(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
(S)-1-(1-Methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (200 mg, 0.768 mmol) was dissolved in THF (5 mL) along with 4,6-dichloro-2-(methylthio)pyrimidine-5-carbonitrile (169 mg, 0.768 mmol) and Et3N (0.118 mL, 0.845 mmol) to give an orange suspension. The reaction mixture was stirred at room temperature for 2 h, then diluted with ethyl acetate and washed saturated aq NH4Cl (3×15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was then loaded onto an ISCO® silica gel cartridge (12 g) and eluted using an EtOAc/Hexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a white solid (200 mg, 59%). ESI-MS m/z [M+H]+ calc'd for C20H22ClN7OS, 443.95; found 444.3.
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44](O)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.[CH3:50][C:51]1[N:52]=[CH:53][C:54]([CH2:57][NH2:58])=[N:55][CH:56]=1>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([NH:58][CH2:57][C:54]4[CH:53]=[N:52][C:51]([CH3:50])=[CH:56][N:55]=4)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:48][CH:49]=1
Reactant: Cc1cnc(CN)cn1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1cnc(CNC(=O)c2sc(N3CCN(Cc4ccc(F)cc4)C3=O)nc2C)cn1
Yield: 38 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with (5-methylpyrazin-2-yl)methanamine, the title compound was obtained as a colorless solid in 38% yield: mp 191-193° C.; 1H NMR (300 MHz, CDCl3) δ 8.52 (s, 1H), 8.40 (s, 1H), 7.30-7.27 (m, 2H), 7.07-7.02 (m, 2H), 6.76 (br s, 1H), 4.70 (d, J=3.0 Hz, 2H), 4.47 (s, 2H), 4.09 (t, J=9.0 Hz, 2H), 3.46 (t, J=9.0 Hz, 2H), 2.63 (s, 3H), 2.57 (s, 3H); MS (ES+) m/z 441.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:29])[C:13](=[N:26][C:27]#[N:28])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([C:24]#[N:25])([CH3:23])[CH3:22])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.[B:30]1(B2OC(C)(C)C(C)(C)O2)[O:34]C(C)(C)C(C)(C)[O:31]1.C([O-])(=O)C.[K+].C(Cl)Cl>O1CCOCC1.C(OCC)(=O)C>[C:27]([N:26]=[C:13]1[N:12]([CH3:29])[C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:2]([B:30]([OH:34])[OH:31])=[CH:3][C:4]=3[C:5]=2[N:14]1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:24]#[N:25])([CH3:22])[CH3:23])=[CH:17][CH:16]=1)#[N:28]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Cn1c(=NC#N)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(Br)ccc3ncc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1c(=NC#N)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(B(O)O)ccc3ncc21

Procedure:
N-(8-bromo-1-(4-(2-cyanopropan-2-yl)phenyl)-3-methyl-1H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (2.463 mmol), bis(pinacolato)diboron (1.347 mmol), potassium acetate (2.246 mmol) and (1,1-bis(diphenylphosphino)ferrocene)-dichloropalladium (II) complex with DCM (50 mg) was dissolved in dioxane under argon atmosphere. The reaction mixture was refluxed for 8 h. The reaction mixture was cooled, diluted with ethyl acetate (15 mL) and filtered. The filtrate was concentrated. The crude product was purified (silica gel column ethyl acetate/petroleum ether) to obtain the title compound. 1HNMR (300 MHz, DMSO-d6): δ 9.17 (s, 1H), 8.05 (m, 4H), 7.86 (m, 6H), 7.26 (s, 1H), 3.88 (s, 3H), 1.78 (s, 6H); MS (m/z): 411(M+1)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]CC)=[O:19])=[CH:13][CH:12]=2)[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.[OH-].[Na+]>C(O)C.O>[CH3:1][C:2]1[N:3]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:15][CH:16]=2)[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1
Reactant: CCOC(=O)Cc1ccc(-n2c(C)nc3cnccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc2cnccc2n1-c1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.3 %

Procedure:
A solution of ethyl 4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenylacetate (750 mg, 2.54 mmol) and sodium hydroxide 160 mg, 4.0 mmol) in a mixture of ethanol (5 ml) and water (5 ml) was stirred at room temperature for 16 hours and evaporated. The residue was taken up in water, acidified with 2M hydrochloric acid to pH 4-5 and extracted into 1-butanol. The combined 1-butanol extracts were evaporated and the residue triturated with diethyl ether. The resulting solid was collected, washed with hexane and dried to give the title compound (267 mg, 39%) as a buff solid, m.p. 226°-230° C., which was characterised by its 1H-NMR spectrum. 1H-NMR (d6 -DMSO) δ=8.86(1H,s), 8.23(1H,d,J=8 Hz), 7.48(4H,s), 7.15(1H,d,J=8 Hz), 3.70(2H,s), 2.42(3H,s).
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=2[O:7][CH:6]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]1=[O:21])#[N:2].Cl.N[C:24]1[C:29]([F:30])=[C:28]([F:31])[CH:27]=[C:26]([F:32])[C:25]=1[SH:33]>C(O)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]2[O:7][CH:6]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5](=[O:21])[N:4]([CH2:3][C:1]3[S:33][C:25]4[C:26]([F:32])=[CH:27][C:28]([F:31])=[C:29]([F:30])[C:24]=4[N:2]=3)[C:9]=2[CH:10]=1
Reactant: Nc1c(F)c(F)cc(F)c1S
Reactant: CCOC(=O)CC1Oc2ccc(F)cc2N(CC#N)C1=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC1Oc2ccc(F)cc2N(Cc2nc3c(F)c(F)cc(F)c3s2)C1=O

Procedure:
Ethyl 2-(4-cyanomethyl-6-fluoro-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-2-yl]acetate (500 mg) and 2-amino-3,4,6-trifluorothiophenol hydrochloride (388 mg) were added to anhydrous ethanol (5 ml), and the mixture was refluxed under heating under an argon atmosphere. Fifteen hours later, the solvent was distilled away and water was added to the residue, which was followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was. distilled away.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)[CH2:9]1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:33][O:32][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][CH2:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][CH:10]2[CH2:11][CH2:12][CH2:13][N:8]([CH3:6])[CH2:9]2)[CH:31]=[CH:30][CH:29]=1
Reactant: COc1cccc(CCCCc2ccccc2OCC2CCCN(C(=O)OC(C)(C)C)C2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(CCCCc2ccccc2OCC2CCCN(C)C2)c1
Yield: 96 %

Procedure:
A solution of 2.70 g of 1-t-butoxycarbonyl-3-{2-[4-(3-methoxyphenyl)butyl]phenoxymethyl}piperidine [prepared as described in Example 82(a)] in 25 ml of tetrahydrofuran was added dropwise to a mixture of 0.450 g of lithium aluminum hydride in 30 ml of tetrahydrofuran, whilst ice-cooling and stirring, and the mixture was stirred at room temperature for 30 minutes and then stirred whilst heating under reflux for 2 hours. At the end of this time, the reaction mixture was cooled, and sodium sulfate decahydrate was added to the mixture to decompose excess lithium aluminium hydride. Insoluble materials were removed by filtration, and the filtrate was concentrated by distillation under reduced pressure. The resulting oil was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 2.10 g (yield 96%) of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[CH3:23])[N:19]3[C:24]([C@@H:27]5[CH2:31][CH2:30][CH2:29][C@@H:28]5[O:32][Si](C(C)(C)C)(C)C)=[N:25][CH:26]=[C:18]3[C:17](=[O:40])[NH:16]4)=[O:12])[C:5]2=[N:6][CH:7]=1.Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[CH3:23])[N:19]3[C:24]([C@@H:27]5[CH2:31][CH2:30][CH2:29][C@@H:28]5[OH:32])=[N:25][CH:26]=[C:18]3[C:17](=[O:40])[NH:16]4)=[O:12])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1cc2c(cc1C(=O)N1CCc3cc(Br)cnc31)[nH]c(=O)c1cnc([C@@H]3CCC[C@@H]3O[Si](C)(C)C(C)(C)C)n12
Agent: Cl
Solvent: CO
Product: Cc1cc2c(cc1C(=O)N1CCc3cc(Br)cnc31)[nH]c(=O)c1cnc([C@@H]3CCC[C@@H]3O)n12
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.4 %

Procedure:
To a mixture of 369 mg of 7-[(5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)carbonyl]-1-(cis-2-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl)-8-methylimidazo[1,5-a]quinoxalin-4(5H)-one and 3.70 mL of methanol was added 0.15 mL of concentrated hydrochloric acid, followed by stirring at room temperature for 3 days. The solvent was evaporated under reduced pressure, then the residue was dissolved in water, and a saturated aqueous sodium hydrogen carbonate solution was added thereto to adjust the pH to about 8. The mixture was extracted with chloroform, the organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0-95/5) and triturated with methanol to obtain 221 mg of 7-[(5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)carbonyl]-1-(cis-2-hydroxycyclopentyl)-8-methylimidazo[1,5-a]quinoxalin-4(5H)-one as a colorless solid.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][O:18][C:19]1[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=[CH:23][C:20]=1[CH:21]=O>C1COCC1>[CH3:17][O:18][C:19]1[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=[CH:23][C:20]=1[CH:21]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1ccc(C=O)c(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1ccc(OC)c(OC)c1OC
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 245 mg) was suspended in THF (1 mL) under an argon atmosphere, to the suspension ethyl diethylphosphonoacetate (1.11 mL) was added dropwise under ice cooling, and the mixture was stirred for 30 minutes. After 2,3,4-trimethoxybenzaldehyde (1.0 g) was then added to the mixture, the reaction mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure. The residue was dissolved in chloroform, and the solution was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:19]([O:20][CH3:21])=[N:18][NH:17][C:14]3=[N:15][CH:16]=2)=[O:9])=[C:6]([F:22])[C:5]([NH:23][S:24]([CH2:27][CH2:28][CH2:29][O:30]C2C=CC(OC)=CC=2)(=[O:26])=[O:25])=[CH:4][CH:3]=1>CC#N>[Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:19]([O:20][CH3:21])=[N:18][NH:17][C:14]3=[N:15][CH:16]=2)=[O:9])=[C:6]([F:22])[C:5]([NH:23][S:24]([CH2:27][CH2:28][CH2:29][OH:30])(=[O:26])=[O:25])=[CH:4][CH:3]=1
Reactant: COc1ccc(OCCCS(=O)(=O)Nc2ccc(Cl)c(C(=O)Nc3cnc4[nH]nc(OC)c4c3)c2F)cc1
Solvent: CC#N
Product: COc1n[nH]c2ncc(NC(=O)c3c(Cl)ccc(NS(=O)(=O)CCCO)c3F)cc12
Temperature: 25 °C
Yield: 83.7 %

Procedure:
A 100 mL, round-bottomed flask was charged with 6-chloro-2-fluoro-N-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(3-(4-methoxyphenoxy) propylsulfonamido)benzamide (30.0 mg, 0.053 mmol), Ce(NH4)2(NO2)6 (72.9 mg, 0.13 mmol) and CH3CN (0.5 mL) The reaction mixture was stirred at room temperature until LC-MS showed that the starting material had been consumed (overnight). Then the reaction mixture was partitioned between EtOAc (200 mL) and water (100 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (3×100 mL) The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (EtOAc/hexane from 1/2 to 1/0, v/v) to afford impure 6-chloro-2-fluoro-3-(3-hydroxypropylsulfonamido)-N-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide (20.3 mg). Further purification by preparation HPLC afforded pure product (2.1 mg, 8.6%). LRMS (APCI pos): >95% purity, 254 nm, m/e 458.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 8.59 (d, 1H), 8.50 (d, 1H), 7.65 (m, 1H), 7.36 (d, 1H), 4.01 (s, 3H), 3.65 (t, 2H), 3.25 (t, 2H), 2.03 (m, 2H).