Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1(C)O[C:6](=[O:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([CH3:15])[O:3]1.C=[N:18][C:19]([CH3:31])([CH3:30])[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>C1(C)C(C)=CC=CC=1>[CH3:31][C:19]([N:18]1[C:6](=[O:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([CH3:15])[O:3][CH2:2]1)([CH3:30])[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]
Reactant: C=NC(C)(C)C(=O)OCc1ccccc1
Reactant: CC1=C(c2ccccc2)C(=O)OC(C)(C)O1
Solvent: Cc1ccccc1C
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)OCc2ccccc2)CO1
Yield: 90.2 %

Procedure:
To a mixture of 2,2,6-trimethyl-5-phenyl-4H-1,3-dioxin-4-one (13.97 g) and benzyl 2-(N-methylenamino)-2-methylpropionate (13.8 g) was added 130 ml of xylene, and the mixture was refluxed for 2 h. The solvent was evaporated and the residue was purified by chromatography on a silica gel column to get the captioned compound (21.1 g).
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[Cl:22][C:23]1[CH:24]=[C:25]([F:33])[CH:26]=[C:27]2[C:31]=1[C:30](=[O:32])[CH2:29][CH2:28]2>CO>[Cl:22][C:23]1[CH:24]=[C:25]([F:33])[CH:26]=[C:27]2[C:31]=1[C:30](=[O:32])[CH:29]([F:21])[CH2:28]2
Reactant: O=C1CCc2cc(F)cc(Cl)c21
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: F[B-](F)(F)F
Solvent: CO
Product: O=C1c2c(Cl)cc(F)cc2CC1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Selectfluor™ (2.49 g, 7.02 mmol) was added to a solution of 7-chloro-5-fluoro-1-indanone (CAS No. 1260008-48-7, 1.08 g, 5.85 mmol) in MeOH (30 mL) at room temperature. The mixture was refluxed for 2 hours. After cooling to room temperature, the resulting mixture was evaporated to remove the solvent under reduced pressure. To the residue was added DCM and the insoluble matter was filtered off. The filtrate was concentrated in vacuo. The residue was dissolved in MeCN (20 mL) and 5 N HCl (10 mL) and the solution was stirred at room temperature for 1 hour. After concentration of the solution in vacuo, the residue was partitioned between AcOEt and H2O. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to afford the title compound (1.13 g, 5.58 mmol).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][N:6]=1)(=[O:3])[CH3:2].C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16]>N1C=CC=CC=1.C(O)C>[C:1]([NH:4][C:5]1[N:6]=[CH:7][C:8](/[CH:11]=[CH:14]/[C:15]([OH:17])=[O:16])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C=O)cn1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=O)Nc1ccc(/C=C/C(=O)O)cn1
Yield: 81.9 %

Procedure:
A mixture of 2-acetylamino-5-formylpyridine (241 mg) and malonic acid (168 mg) in pyridine (0.12 ml) and ethanol (0.36 ml) was refluxed for 2 hours. After cooling the mixture, the precipitate was collected by filtration, and washed ethyl acetate to give (E)-3-(6-acetylamino-3-pyridyl)acrylic acid (248 mg) as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][C:3]=1[CH3:11].Cl[CH2:13][C:14](=O)[CH3:15]>C(O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][CH:13]=[C:14]([CH3:15])[N:8]=2)=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(N)=S)ccc1Br
Reactant: CC(=O)CCl
Solvent: CCO
Product: Cc1csc(-c2ccc(Br)c(C)c2)n1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
4-Bromo-3-methylthiobenzamide (D38, 0.87 g, 0.0038 mole) was dissolved in ethanol (60 ml) and treated with chloroacetone (0.39 ml, 0.0049 mole). The reaction mixture was heated under reflux for 5 h, then more chloroacetone (0.39 ml, 0.0049 mole) was added and the mixture heated under reflux for a further 3 h. After cooling to room temperature, the solvent was removed in vacuo to leave the title compound as a pale oil (1.00 g, 98%).
Reaction SMILES: [C:1]([CH:3]1[C:7](=O)[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[N:2].[C:16]1([C:22]2[N:27]=[CH:26][C:25]([C:28]3[CH:29]=[N:30][NH:31][C:32]=3[NH2:33])=[CH:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[NH2:2][C:1]1[N:31]2[N:30]=[CH:29][C:28]([C:25]3[CH:26]=[N:27][C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:23][CH:24]=3)=[C:32]2[N:33]=[C:7]2[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][C:3]=12
Reactant: Nc1[nH]ncc1-c1ccc(-c2ccccc2)nc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C(C#N)C1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1Cc2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N)c2C1
Temperature: 115 °C

Procedure:
A mixture of tert-butyl 3-cyano-4-oxopyrrolidine-1-carboxylate (60.3 mg, 0.28 mmoL) and 4-(6-phenylpyridin-3-yl)-1H-pyrazol-5-amine (67.8 mg, 0.28 mmoL) in toluene (5 mL) was heated at 115° C. overnight. Concentration afforded crude tert-butyl 8-amino-3-(6-phenylpyridin-3-yl)-5H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate, which was converted to 3-(6-phenylpyridin-3-yl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyrimidin-8-amine by the treatment of 20% TFA/CH2Cl2 at room temperature: LCMS tR=0.38 Min (5 min run, UV254nm), Mass calculated for, M+328.1, observed LC/MS m/z 329.2 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.C(OP(C#N)(OCC)=O)C.CCN(C(C)C)C(C)C.[CH:37]1([CH2:40][C@H:41]([NH2:48])[C:42]2[N:46]=[C:45]([CH3:47])[O:44][N:43]=2)[CH2:39][CH2:38]1>COCCOC>[CH:37]1([CH2:40][C@H:41]([NH:48][C:15]([C:7]2[CH:6]=[N:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[C:42]2[N:46]=[C:45]([CH3:47])[O:44][N:43]=2)[CH2:39][CH2:38]1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: Cc1nc([C@@H](N)CC2CC2)no1
Agent: CCOP(=O)(C#N)OCC
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc([C@H](CC2CC2)NC(=O)c2cnc(C3CC3)c(OCC3CC3)n2)no1
Temperature: 100 °C
Yield: 12.1 %

Procedure:
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.43 mmol) was suspended in DME (3 mL). Diethoxy-phosphorylformonitrile (226.0 mg, 0.80 mmol), DIEA (0.63 mL, 4.2 mmol) and (S)-2-cyclopropyl-1-(5-methyl-[1, 2, 4]oxadiazol-3-yl)-ethylamine (Example 20e, 82.2 mg, 0.64 mmol) were added and the reaction mixture was heated at 100° C. for 10 min under microwave condition. The mixture was extracted with ethyl acetate and water; the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC (Xterra-RP18, 10 μ, 19×250 mm/acetonitrile/10 mM ammonium acetate in water) to give the desired product (20 mg, 11.72%) as white solid; LC-MS (UV peak area, ESI) 96.20%, 384.2 (M+H).
Reaction SMILES: [CH2:1]1N2CN3CN(C2)C[N:2]1[CH2:9]3.Cl.S(=O)(=O)(O)O.C(O)(=O)C(O)=O.[C:23]1(C)[CH:28]=C[C:26]([S:29](O)(=O)=O)=[CH:25][CH:24]=1.CS(O)(=O)=O.[OH-].[Na+]>C1COCC1.C1(C)C=CC=CC=1.C(O)=O>[S:29]1[C:23]2[CH2:28][CH2:9][NH:2][CH2:1][C:24]=2[CH:25]=[CH:26]1
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CS(=O)(=O)O
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: O=CO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: c1cc2c(s1)CCNC2

Procedure:
The formimine (2) is shaken with a dilute solution of an aqueous acid (such as hydrochloric acid or sulfuric acid) or a solution of formamine (2) dissolved in an organic solvent such as THF or toluene, preferably THF, is shaken with an organic acid (such as formic acid, oxalic acid, paratoluene sulfonic acid or methane sulfonic acid; preferably methane sulfonic acid) for 3 to 10 hours, preferably about 6 hours. The mixture is then basified (e.g., with NaOH) and extracted, e.g., with methylene chloride (or another solvent). The extracts are washed and concentrated in vacuo to give 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (a 80-90% yield of the compound of Formula 3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=O)[C:5]=1[NH2:25]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:25]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)[NH:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:26]
Reactant: COC(=O)c1cccc(NC(=O)c2ccc(-c3ccccc3)cc2)c1N
Solvent: CC(=O)O
Product: COC(=O)c1cccc2[nH]c(-c3ccc(-c4ccccc4)cc3)nc12
Temperature: 130 °C

Procedure:
2-Amino-3-[(biphenyl-4-carbonyl)-amino]-benzoic acid methyl ester (300 mg, 0.86 mmol) was dissolved in glacial acetic acid (20 mL) and heated to 130° C. until the reaction was completed which was monitored by TLC (2 to 3 h). After the reaction is completed the solvent was removed and solid residue was purified over silica gel using chloroform and methanol as an eluent to get the required example 79.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[H-].[Na+].[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CO>C1COCC1.O>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1noc(N)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1noc(NS(=O)(=O)c2ccccc2)c1Br
Temperature: 2.5 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-amino-4-bromo-3-methylisoxazole (354 mg, 2.0 mmol) in dry THF (1 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 188 mg, 4.4 mmol) in dry THF (1 ml) at 0° C. After stirring at 0-5° C. for 10 min., the reaction was warmed to room temperature for 10 min. to complete the reaction. The reaction mixture was re-cooled to 0° C. and benzenesulfonyl chloride (0.283 ml, 2.2 mmol) was added slowly. Stirring was continued for 20 min. at 0-5° C. Excess sodium hydride was decomposed by the addition of methanol (0.4 ml) followed by water (0.5 ml). The solvent was removed under reduced pressure. The residue was dissolved in water (20 ml), basified to pH 8-9 by the addition of sodium hydroxide and extracted with ethyl acetate (2×10 ml) to remove the neutral impurities. The aqueous layer was acidified with concentrate HCl (pH 2-3) and extracted with ethyl acetate (3×10 ml) The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide. The pure material was obtained by recrystallization using hexanes/ethyl acetate (0.59 g, 93% yield), m.p. 142-144° C.
Reaction SMILES: [OH-].[Li+].[CH2:3]([C:5]1[N:6]=[C:7]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH:30]([CH3:35])[C:31]([O:33]C)=[O:32])[CH:25]=[CH:24]4)=[N:14][CH:15]=2)[S:8][CH:9]=1)[CH3:4].CO.O>C1COCC1>[CH2:3]([C:5]1[N:6]=[C:7]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH:30]([CH3:35])[C:31]([OH:33])=[O:32])[CH:25]=[CH:24]4)=[N:14][CH:15]=2)[S:8][CH:9]=1)[CH3:4]
Reactant: CCc1csc(-c2ccc(OCCCOc3ccc4c(ccn4C(C)C(=O)OC)c3)nc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCc1csc(-c2ccc(OCCCOc3ccc4c(ccn4C(C)C(=O)O)c3)nc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.3 %

Procedure:
Lithium hydroxide (0.05 g, 2.15 mmol) was added to a solution of methyl 2-[5-(3-{[5-(4-ethyl-1,3-thiazol-2-yl)-2-pyridinyl]oxy}propoxy)-1H-indol-1-yl]propanoate (Example 69, 0.1 g, 0.21 mmol) in a mixture of THF (2 mL), methanol (2 mL), and water (1 mL). The reaction mixture was stirred at rt for 18 h and then concentrated under reduced pressure. The residue was diluted with water and acidified with 5% H3PO4. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered, and concentrated to give the title compound as a solid (0.079 g, 82%). 1H NMR (400 MHz, CD2Cl2) δ 8.45 (dd, 1H), 7.94 (dd, 1H), 7.08-6.62 (m, 6H), 6.22 (d, 1H), 4.94 (qt, 1H), 4.37 (t, 2H), 4.00 (t, 2H), 2.66 (qt, 2H), 2.31-2.07 (m, 2H), 1.60 (d, 3H), 1.15 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([NH:24]C(=O)C)=[CH:20][CH:19]=3)[C:16](=[O:28])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>Cl>[NH2:24][C:21]1[CH:20]=[CH:19][C:18]([N:17]2[C:16](=[O:28])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=[C:8]2[C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:23][CH:22]=1
Reactant: CC(=O)Nc1ccc(-n2c(-c3ccc(C)nc3)nc3ccccc3c2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(-c2nc3ccccc3c(=O)n2-c2ccc(N)cc2)cn1
Yield: 101.5 %

Procedure:
N-(4-(2-(6-methylpyridin-3-yl)-4-oxoquinazolin-3(4H)-yl)phenyl)acetamide (0.130 g, 0.33 mmol) was refluxed in 2 N HCl for 1 hour. The mixture was cooled to room temperature and basified with 1 N NaOH, and extracted with CH2Cl2. The organics were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo, to afford 3-(4-aminophenyl)-2-(6-methylpyridin-3-yl)quinazolin-4(3H)-one (0.110 g, quantitative).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.FC(F)(F)C(O)=[O:14].S(=O)(=O)(O)O>O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([NH2:7])=[O:14])=[C:4]([F:10])[CH:3]=1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: O=C(O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: NC(=O)c1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 6 h
Yield: 87.7 %

Procedure:
A solution of 4-bromo-2-fluorobenzonitrile (1.00 g, 5.00 mmol), trifluoroacetic acid (3.5 mL, 45 mmol), and sulfuric acid (3.5 mL, 66 mmol) was stirred at ambient temperature for 4 hours, at 30° C. for 15 hours, and at 50° C. for 6 hours. After cooling to 0° C., water (20 mL) was added, and the resulting suspension was stirred at 0° C. for 1.5 hours. The solids were collected by vacuum filtration, rinsed with excess water, and dried to afford 4-bromo-2-fluorobenzamide (0.956 g, 88%) as an off-white solid which was carried on without further purification.
Reaction SMILES: CC1(C)O[C:6](=[O:8])[C:5](=[CH:9][NH:10][C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)C(=O)O1.C1(OC2C=CC=CC=2)C=CC=CC=1>CC(OC)(C)C>[S:13]1[C:12]2[C:11](=[N:10][CH:9]=[CH:5][C:6]=2[OH:8])[CH:15]=[CH:14]1
Reactant: CC1(C)OC(=O)C(=CNc2ccsc2)C(=O)O1
Solvent: COC(C)(C)C
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Oc1ccnc2ccsc12
Temperature: 25 °C
Reaction time: 0.62 h

Procedure:
A 200-mL rb flask was charged with 2,2-dimethyl-5-((thiophen-3-ylamino)methylene)-1,3-dioxane-4,6-dione (6.73 g, 26.6 mmol) and diphenyl ether (25 mL) and heated to about 200 deg C. for about 30-45 min and the mixture was allowed to cool to rt overnight. The mixture was scraped down with a spatula and diluted with MTBE. The mixture was filtered through paper and washed with MTBE. The brown solid was air dried to yield thieno[3,2-b]pyridin-7-ol.
Reaction SMILES: COC(=O)[C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[N:11]([CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=O)[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13].CC(C)([O-])C.[K+].Cl.[Cl-].[Li+]>C1COCC1.[Cl-].[Na+].O>[CH:15]([O:14][C:12]([N:11]1[CH2:18][CH2:19][CH2:20][C:21](=[O:23])[C:4]2[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]1=2)=[O:13])([CH3:16])[CH3:17]
Reactant: CCOC(=O)CCCN(C(=O)OC(C)C)c1cccc(C)c1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc2c1C(=O)CCCN2C(=O)OC(C)C
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 27.4 %

Procedure:
Add a solution of 2-[(3-Ethoxycarbonyl-propyl)-isopropoxycarbonyl-amino]-6-methyl-benzoic acid methyl ester (4.60 g, 12.6 mmol) in THF (197 mL) to a solution of potassium tert-butoxide (25.2 mL, 25.2 mmol, 1 M in THF) in THF (175 mL) at room temperature under an atmosphere of nitrogen. After 30 min, pour the mixture into ice/water. Treat aqueous phase with 1M HCl to pH neutral and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Dissolve the former crude in DMSO (101 mL) and add water (8 drops) followed by addition of lithium chloride (1.32 g, 31.5 mmol) and heat the resulting solution at 160° C. for 45 minutes. Cool the mixture to room temperature and pour into brine. Extract the mixture with ethyl acetate. Dry the organic layers over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (903 mg, 27% over two steps): MS (ES+): 262 (M+H).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[Br:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:28])=[C:23](B(O)O)[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[Br:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:28])=[C:23]([Pb+3:17])[CH:24]=1
Reactant: OB(O)c1cc(Br)ccc1Cl
Reactant: [Pb+4]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc(Br)cc1[Pb+3]
Temperature: 40 °C
Yield: 82.3 %

Procedure:
To a mixture of lead tetraacetate (1.46 g, 3.3 mmol) and mercuric diacetate (42 mg, 0.13 mmol), thoroughly flushed with nitrogen, is added anhydrous chloroform (2.5 ml) is introduced and the reaction mixture is stirred and heated to 40° C. 5-Bromo-2-chlorophenylboronic acid (0.62 g, 2.6 mmol) is added in one portion, and the reaction mixture is stirred at 40° C. for 4 hours. After cooling to room temperature potassium carbonate (0.18 g) is added, the mixture stirred vigorously for 5 minutes and then filtered. The filtrate is concentrated in vacuo to give 5-bromo-2-chlorophenyllead triacetate (1.23 g), used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:56]1([CH2:61][C@@H:62]2[CH2:67][CH2:66][CH2:65][NH:64][CH2:63]2)[CH2:60][CH2:59][CH2:58][CH2:57]1>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](=[O:32])[N:64]2[CH2:65][CH2:66][CH2:67][C@@H:62]([CH2:61][N:56]3[CH2:57][CH2:58][CH2:59][CH2:60]3)[CH2:63]2)[C:25]=1[CH3:34])(=[O:12])=[O:11]
Reactant: C1CNC[C@H](CN2CCCC2)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)N1CCC[C@@H](CN2CCCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
A mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (156 mg, 0.3 mmol), HOBt (80 mg) and EDAC (110 mg) in DMF (4 mL) was added TEA (3 drops). After stirring at rt for 2 hours, to the mixture was added (R)-3-pyrrolidin-1-ylmethyl-piperidine (250 mg). After stirring at rt for overnight, the reaction was concentrated and dissolved in ethyl acetate. It was then washed with water and sodium bicarbonate, dried and concentrated. The residue was purified on a silica gel column to give 172 mg of the titled compound. MS m/z 667 [M−1].
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][C@@H:40]([CH3:44])[C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:41](=[O:42])[C@@H:40]([OH:39])[CH3:44])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)cc1F
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f46) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([NH:11][CH2:12][CH2:13][C:14]2[O:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)=[CH:17][CH:18]=2)=[O:10])[NH:6][N:5]=1)(=O)[CH3:2].[NH2:27][CH2:28][CH2:29][OH:30].[BH4-].[Na+].Cl>C1(C)C=CC=CC=1.O.C1COCC1>[Cl:26][C:21]1[CH:20]=[C:19]([C:16]2[O:15][C:14]([CH2:13][CH2:12][NH:11][C:9]([C:7]3[NH:6][N:5]=[C:4]([CH:1]([NH:27][CH2:28][CH2:29][OH:30])[CH3:2])[CH:8]=3)=[O:10])=[CH:18][CH:17]=2)[CH:24]=[CH:23][C:22]=1[Cl:25]
Reactant: NCCO
Reactant: CC(=O)c1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)[nH]n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(NCCO)c1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)[nH]n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 25.6 %

Procedure:
3-Acetyl-N-(2-(5-(3,4-dichlorophenyl)furan-2-yl)ethyl)-1H-pyrazole-5-carboxamide (78 mg; 0.20 mmol) and 2-aminoethanol (10 mg; 0.17 mmol) were dissolved in 5 ml of dry toluene and 5 ml of dry THF and stirred for 6.5 h at 75° C. under nitrogen atmosphere and then overnight at RT. Sodium tetrahydroborate (18.8 mg; 0.50 mmol) was added, stirred for 3 days at RT and then 4.5 h at 75° C. 10 mg of sodium tetrahydroborate was added and the mixture was heated for 5 h at 50° C. to complete the reaction. 0.1 ml of water was added at 0° C. and pH adjusted to 1 with 1 M HCl. Solution was evaporated to dryness, 15 ml of DCM was added and the mixture was washed with 10 ml of water. pH was adjusted to 12 with 1 M NaOH and 15 ml of DCM was added. After Na2SO4 drying the compound was purified by chromatography (CombiFlash, Silica column, 2.5-10% MeOH/DCM) to obtain 19 mg (26%) of the title compound. 1H-NMR (400 MHz; d1-CDCl3): δ 1.43 (d, 3H), 2.55-2.70 (m, 1H), 2.74-2.85 (m, 1H), 2.97 (t, 2H), 3.60-3.76 (m, 4H), 4.02-4.12 (m, 1H), 6.16 (d, 1H), 6.53 (d, 1H), 6.65 (s, 1H), 7.33-7.41 (m, 3H), 7.67 (d, 1H).
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][N:12]=[N:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]([NH:24][NH2:25])=[S:23])[CH2:18][CH2:17]1>C(O)C.C(Cl)Cl>[CH3:15][N:16]1[CH2:17][CH2:18][N:19]([C:22](=[S:23])[NH:24][N:25]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9]2[CH:14]=[CH:13][N:12]=[N:11][CH:10]=2)[CH2:20][CH2:21]1
Reactant: O=C(c1ccccc1)c1ccnnc1
Reactant: CN1CCN(C(=S)NN)CC1
Solvent: ClCCl
Solvent: CCO
Product: CN1CCN(C(=S)NN=C(c2ccccc2)c2ccnnc2)CC1
Temperature: 65 °C
Yield: 42.6 %

Procedure:
A mixture of phenyl-pyridazin-4-yl-methanone (12; Synthon A, 2.3 g, 12.4 mmol) and 4-Methylpiperazine-1-carbothioic acid hydrazide (6; Synthon B, 2.82 g, 16.18 mmol) in ethanol (7.5 mL) was heated to 65° C. for 5 h under N2 in a 50 mL pyrex tube equipped with a screw cap. The mixture remained heterogeneous during the heating and a brown suspension resulted at the end of the reaction. The mixture was diluted with CH2Cl2 (7.5 mL) and was chromatographed on silica gel that was eluted with MeOH/CH2Cl2 (2.5-5%) to give 1.8 g of a yellow foamy solid 1A (99.3% pure by HPLC); m.p. 141-143° C. (m.p. of a crystalline sample 143-145). TLC (CH2Cl2/MeOH/NH4OH: 95/5/0.5): Rf=0.6, product is visibly yellow, UV and Dragendorff stain active. MS (ESI+): [M+H]+=340.93. HRMS: m/z calcd. for C17H21N6S ([M+H]+): 341.15429. found: 341.15501. 1H NMR (300 MHz, CDCl3), δ ppm: 2.38 (s, 3H), 2.61 (t, 4H, J=5.0 Hz), 4.12 (t, 4H, J=5.0 Hz), 7.29 (m, 3H), 7.63 (m, 3H), 8.64 (s, 1H), 9.14 (dd, 1H, J=5.7 Hz, J′=1.5 Hz), 9.44 (dd, 1H, J=2.4 Hz, J′=1.5 Hz). 13C NMR (75.4 MHz, CDCl3), δ ppm: 45.75, 51.64, 54.75, 123.30, 128.29, 128.39, 130.40, 131.10, 134.86, 143.94, 148.31, 151.31, 181.49.