Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C1C=CC=CC=1.N1CCCCC1.C(O)(=O)C>[CH:8](=[C:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)CC(C)=O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: O
Product: CC(=O)C(=Cc1ccccc1)C(C)=O
Temperature: 25 °C
Yield: 95.3 %

Procedure:
2,4-Pentanedione (2, 4.10 ml, 39.2 mmol) and benzaldehyde (1b, 4.06 ml, 40.0 mmol) were stirred in benzene (10 ml). Piperdine (3 drops) and glacial acetic acid (6 drops) were added and the mixture refluxed with a Dean-Stark water trap for 3 hr. The resulting mixture was cooled to room temperature, extracted into ethyl ether, washed with hydrochloric acid (1 N), saturated sodium bicarbonate, hydrochloric acid (1 N) and twice with water. The organic layer was dried over magnesium sulfate, filtered and evaporated to afford an oil. The crude oil was distilled bulb to bulb to give 7.03 g (95%) of a yellow oil; [expected mp 165-167° C.]; 1H NMR: δ 2.24 (s, 3H), 2.38 (s, 3H), 7.35 (s, 5H), 7.45 (s, 1H); 13C NMR: δ 26.5, 31.6, 128.9, 129.6, 130.5, 132.8, 139.6, 142.7, 196.2, 205.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][NH2:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(O[C:22](=[NH:24])[CH3:23])C.CCN(CC)CC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:24][C:22]([CH3:23])=[N:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nnc(C2CCN(C(=O)OC(C)(C)C)CC2)[nH]1
Temperature: 100 °C
Yield: 10.5 %

Procedure:
4-Hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester (1.19 g, 5 mmol) was mixed with ethylacetimidate hydrochloride (0.91 g, 7 mmol) in DMF (5 ml) and Et3N (2 ml, 15 mmol) was added. The reaction was stirred for 1 h after which time the DMF was evaporated, the residue redissolved in AcOH and 0.5 g of ammonium acetate added and the reaction heated to 100° C. for a further 3 h. The reaction was then concentrated, redissolved in CH2Cl2, washed with NaHCO3, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (CH2Cl2:MeOH 1:0-9:1) to afford the title product (0.14 g, 10%) as a colourless gum. MS: 267.4 (MH+)
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9](C=O)[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.COC1C=C2C(N=CC(SCCN3CCC(N)CC3)=N2)=CC=1.C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCCl.CO>[O:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[NH:7][C:2](=[O:1])[CH2:3]1
Reactant: O=Cc1ccc2c(c1)NC(=O)CO2
Agent: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C1COc2ccccc2N1
Temperature: 25 °C
Reaction time: 15 h
Yield: 167.6 %

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde (354 mg, 2.00 mmol, 1.0 eq) is added at room temperature to a stirred solution of 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (0.65 g, 2.00 mmol, 1.0 eq) in 1,2-dichloroethane (4 mL) and methanol (1 mL), followed by acetic acid (0.11 mL, 2.00 mmol, 1.0 eq) and sodium cyanoborohydride (160 mg, 2.6 mmol, 1.4 eq). After 15 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×20 mL) and a saturated sodium hydrogen carbonate aqueous solution (20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 6-({1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amino)-methyl)-4H-benzo[1,4]oxazin-3-one as a white solid (500 mg, 52% yield).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([NH2:11])[CH2:9][NH2:10]>C(O)C.O=[Pt]=O>[CH:1]1([NH:10][CH2:9][CH2:8][NH2:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCN
Reactant: O=C1CCCCC1
Agent: O=[Pt]=O
Solvent: CCO
Product: NCCNC1CCCCC1
Reaction time: 1 h

Procedure:
Cyclohexanone (50 g) and ethylene diamine (60 g) were mixed in ethanol (50 ml) at room temperature and allowed to stand for one hour. Meanwhile Adams catalyst (1 g) in ethanol (20 ml) was pre-reduced on a Parr apparatus at 60 p.s.i. under hydrogen for one hour. The imine solution was added to the hydrogenation flask and reduced at 60 p.s.i. for 18 hours. The catalyst was removed by filtration and the ethanol removed under vacuum. N-Cyclohexyl ethylene diamine was obtained on distillation of the crude product collecting the fraction boiling between 110°-120° C. at 20 ram.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH2:24][CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[CH:15]=[CH:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:10])[CH2:4][CH2:3]1.[ClH:33]>O1CCOCC1>[ClH:33].[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([O:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH:15]=[CH:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:10])[CH2:6][CH2:7]1
Reactant: CN1CCC(OC(=O)Nc2cc(CCC(=O)OC(C)(C)C)ccc2-c2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCC(OC(=O)Nc2cc(CCC(=O)O)ccc2-c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To tert-butyl 3-[3-({[(1-methylpiperidin-4-yl)oxy]carbonyl}amino)-4-phenylphenyl]propionate (5.08 g, 11.6 mmol) was added a 4M solution of hydrochloric acid in dioxane (70 mL) and the mixture was stirred at 70° C. for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 3-[3-({[(1-methylpiperidin-4-yl)oxy]carbonyl}amino)-4-phenylphenyl]propionate hydrochloride (5.49 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[I:9]N1C(=O)CCC1=O>C(O)(=O)C>[Br:8][C:6]1[CH:7]=[C:2]([NH2:1])[C:3]([I:9])=[N:4][CH:5]=1
Reactant: Nc1cncc(Br)c1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: Nc1cc(Br)cnc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
3-Amino-5-bromopyridine (13.8 g, 79.8 mmol) was dissolved in acetic acid (440 mL) and placed under a nitrogen atmosphere. N-Iodosuccinimide (16.15 g, 71.8 mmol) was charged to the reaction which was stirred at room temperature overnight. The reaction was concentrated and the residue partitioned between EtOAc (200 mL) and saturated aqueous sodium hydrogen carbonate (200 mL). The layers were separated and the organic phase was washed with saturated aqueous sodium hydrogen carbonate (200 mL). The aqueous phase was extracted with EtOAc (3×200 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated. Chromatography (silica; 1.4 Kg packed in 70% DCM:30% heptane, eluting with 70-100% DCM in heptane) gave the title compound (11.5 g). 1H NMR (270 MHz, CDCl3): 7.83 (1H, m), 7.04 (1H, m), 4.33 (2H, br s).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].C(N(CC)CC)C.[C:19]([NH:21][C:22](Cl)=[N:23][CH3:24])#[N:20]>CO>[C:19]([N:21]=[C:22]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:3]1[N:4]=[CH:5][NH:6][C:2]=1[CH3:1])[NH:23][CH3:24])#[N:20]
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CN=C(Cl)NC#N
Solvent: CO
Solvent: CCN(CC)CC
Product: CNC(=NC#N)NCCSCc1nc[nH]c1C
Reaction time: 7.5 h
Yield: 22.4 %

Procedure:
To a stirred solution of 2-(5-methylimidazol-4-ylmethylthio)ethylamine (1.0 g) and triethylamine (0.71 g) in methanol (20 ml) was added N-cyano-N'-methylchloroformamidine (0.82 g) and stirred for 7.5 hrs. at 50°-55° C. After evaporation, the residue was subjected to chromatography on SiO2 [eluant: CHCl3 -MeOH (10:1)]. The resulting crude product was added to water (3 ml) and extracted repeatedly with ethyl acetate. Ethyl acetate extracts were dried over anhydrous MgSO4 and concentrated under a reduced pressure to small volume. The resulting crystals were collected by filtration and washed with ethyl acetate to give N"-cyano-N-methyl-N'-[2-(5-methylimidazol-4-ylmethylthio)ethyl]guanidine (0.33 g). Yield 22.4%, m.p. 134°-137° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([C:19](O)([CH3:21])[CH3:20])=[CH:15][N:14]3[CH:23]=2)=[O:10])=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:21])=[CH2:20])=[CH:15][N:14]3[CH:23]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)(O)c1ccc2nc(C(=O)Nc3ccc(F)cc3)cn2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: C=C(C)c1ccc2nc(C(=O)Nc3ccc(F)cc3)cn2c1
Yield: 65.6 %

Procedure:
A solution of 110 mg of N-(4-fluorophenyl)-6-(1-hydroxy-1-methylethyl)imidazo[1,2-a]pyridine-2-carboxamide and 3.3 mg of para-toluenesulfonic acid in 5 ml of xylene is heated at reflux for 6 hours and then evaporated to dryness under reduced pressure. The residue is taken up in 200 ml of dichloromethane and 20 ml of water. The organic phase is dried and concentrated, and the residue is purified by chromatography on silica, elution being carried out with a mixture of dichloromethane and ethyl acetate (95/5). The fractions comprising the expected product are combined and concentrated to dryness. The residue is triturated and washed with ethyl ether, filtered off and dried to give 68 mg of N-(4-fluorophenyl)-6-isopropenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a beige solid.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[C:16]([C:26]([O:28]CC)=O)[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:34][CH:33]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[C:16]([C:26]([N:41]3[CH2:42][CH2:43][CH:38]([C:35]4[CH:34]=[CH:33][C:32]([F:31])=[CH:37][CH:36]=4)[CH2:39][CH2:40]3)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC(C)(C)C)cnn2c1Nc1ccccc1Cl
Product: CC(C)(C)NS(=O)(=O)c1cnn2c(Nc3ccccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 46.9 %

Procedure:
Using ethyl 3-(N-tert-butylsulfamoyl)-7-(2-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (4.25 g, 8.82 mmol) obtained in Example 6 step 3 and 4-(4-fluorophenyl)piperidine (1.87 g, 10.46 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (2.42 g, 59%) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH3:13][C@H:14]1[CH2:19][NH:18][CH2:17][CH2:16][N:15]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:13][C@H:14]1[CH2:19][N:18]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:17][CH2:16][N:15]1[C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C[C@H]1CN(Cc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-nitrobenzaldehyde (15.1 g, 0.1 mol), 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate hydrochloride (21.3 g, 0.09 mol), triethylamine (15 ml, 0.108 mol) and sodium tri(acetoxy)borohydride (42.4 g, 0.2 mol) in 1,2-DCE (500 ml) was stirred at room temperature overnight. Saturated aqueous NaHCO3 solution (200 ml) was added and the mixture stirred for 20-30 minutes. The phases were separated and the aqueous phase was washed with DCM. The combined organics were washed with brine, dried and concentrated. Column chromatography eluting with 0-20% EtOAc/hexane gave the title compound as a yellow oil which crystallized on standing (25.61 g). δH (CDCl3, 400 MHz) 8.19 (2H, d), 7.53 (2H, d), 4.21 (1H, br.s), 3.83 (1H, d), 3.62 (1H, d), 3.50 (1H, d), 3.13 (1H, td), 2.74 (1H, m), 2.54 (1H, m), 2.20 (1H, dd), 2.08 (1H, m), 1.46 (9H, s), 1.25 (3H, d).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([Cl:16])[N:7]=1)C.[NH3:18].CO>>[Cl:16][C:8]1[N:7]=[C:6]([CH2:5][C:4]([NH2:18])=[O:3])[C:15]2[C:10]([CH:9]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: CCOC(=O)Cc1nc(Cl)cc2ccccc12
Reactant: N
Solvent: CO
Product: NC(=O)Cc1nc(Cl)cc2ccccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(3-chloro-isoquinolin-1-yl)-acetic acid ethyl ester (2.5 g, 10 mmol) is dissolved in 4N NH3/MeOH (50 ml). The solution is transferred into an autoclave and kept at 120° C. for 48 hours. After cooling to RT the solvent is removed and the resulting crude product is purified on silica gel using methylene chloride (100%)→methylene chloride/methanol (95/5) as eluent, affording 2-(3-chloro-isoquinolin-1-yl)-acetamide as a pale yellow solid.
Reaction SMILES: O[N:2]=[C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:4]([CH3:12])[C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:12][C:4]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:2][O:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=O)C(C)C(=NO)c1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1onc(-c2ccccc2)c1C
Temperature: 25 °C
Yield: 102 %

Procedure:
Ethyl 4-(hydroxyimino)-3-methyl-2-oxo-4-phenylbutanoate (13.2 g, 53.0 mmol) and concentrated sulfuric acid (10 mL) were added to 150 mL of absolute ethanol and the mixture was refluxed for 20 hours. After the mixture cooled to room temperature, saturated sodium bicarbonate solution was added to neutralize the mixture. The product was extracted with EtOAc and the combined organic layers were dried over MgSO4 and concentrated to give 12.5 g of the title compound. MS: (+) m/z 232.46 (M+1).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:24][CH2:23][C:18]2(OCC[O:19]2)[CH2:17][CH2:16]1.Cl>CO>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:16][CH2:17][C:18](=[O:19])[CH2:23][CH2:24]1
Reactant: COCOc1ccc(C2CCC3(CC2)OCCO3)c(OCOC)c1
Agent: Cl
Solvent: CO
Product: O=C1CCC(c2ccc(O)cc2O)CC1
Yield: 67.1 %

Procedure:
A round bottomed flask equipped with magnetic stirrer was loaded 8-[2,4-bis(methoxymethoxy)phenyl]-1,4-dioxaspiro[4.5]decane (1.30 g, 3.9 mmol) and methanol (15 ml). To the resulting stirred solution was added aqueous HCl (15 ml, 1M) in one portion. After stirring for one hr at room temperature the acid was quenched by adding saturated aqueous sodium bicarbonate solution (10 ml). After stirring vigorously for 10 min, the reaction mixture was transferred to a separating funnel and the phases separated and the aqueous phase was extracted with ethyl acetate (3×20 ml). The combined organic phases were washed with brine and the solvent evaporated. To the slightly wet crude product was added methanol (30 ml) and acidic ion exchange resin (4 g). The resulting mixture was heated under reflux, with stirring, for 5 hr. Filtering through a plug of Celite, washing with ethyl acetate, followed by removal of solvent in vacuo afforded an orange oil. Purification by flash column chromatography, (SiO2, ethyl acetate/petroleum ether, 1:1, v/v) furnished the title compound as a white powder (0.54 g, 68%). m/z (ES−) 411 (2M−1); δH(CD3OD) 1.94 (2H, ddd), 2.16-2.23 (2H, m), 2.41 (2H, dt), 2.62 (1H, t), 2.63 (1H, t), 6.24 (1H, dd), 6.31 (1H, d), 6.92 (1H, d).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[F:39])[CH:34]=O.O>C1COCC1.CCCCCCC>[CH3:2][O:3][CH2:4][CH2:34][C:33]1[CH:36]=[CH:37][C:38]([F:39])=[C:31]([F:30])[CH:32]=1
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COCCc1ccc(F)c(F)c1
Temperature: -30 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
Into a 2 liter three-necked flask equipped with a stirrer, a thermometer, a dropping funnel and a nitrogen gas tube, 133.7 g (390 mmol) of methoxymethyltriphenyl phosphonium chloride were charged in a nitrogen atmosphere and dried, and 450 ml of THF were added. The mixture was cooled to −30° C., 43.76 g (390 mmol) of potassium-t-butoxide were added and the mixture was stirred for 1 hr. To the mixture, a solution of 42.63 g (300 mmol) of 3,4-difluorobenzaldehyde in 150 ml of THF was added dropwise over a period of one and a half hours. The mixture was stirred as such over night and raised to room temperature. Water and heptane were added, the precipitate was filtered through Celite, and an organic layer and an aqueous layer were separated. The aqueous layer was extracted with heptane, an extract combined with the organic layer was washed with water, and the organic layer was dried over anhydrous magnesium sulfate. A solvent was distilled away from the solution, and the solution was condensed. The concentrate was purified by column chromatography (elution solvent: mixed solvent of toluene and heptane), the eluate was further purified by vacuum distillation to obtain 46.70 g of the title compound (91%, bp 98-100° C./15 Torr., cis:trans=1:1) as oily product.
Reaction SMILES: C([O:3][C:4](=[O:14])[C:5]([C:7]1[S:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)=[O:6])C>[OH-].[K+].CO.O>[CH3:13][O:12][C:9]1[S:8][C:7]([C:5](=[O:6])[C:4]([OH:14])=[O:3])=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(=O)c1ccc(OC)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)C(=O)O)s1

Procedure:
The latter ester (25 g) is stirred in 500 ml of 5% aqueous KOH in methanol (250 ml H2O, 250 ml CH3OH, 25 g KOH) at room temperature for about 2 hr. The mixture is diluted with water and extracted several times with ether to remove all neutral material. The aqueous fraction is cooled with crushed ice, acidified with 10% HCl and extracted with ether. The ether extract is washed with water and brine, dried (MgSO4) and concentrated to give 5-methoxy-2-thiopheneglyoxylic acid (3; X1 = CH3O, X2 and X3 = H and R10 = H); γmaxCHCl3 3000, 1630, 1625, 1530 cm -1.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:24]1(B(O)O)[CH2:26][CH2:25]1.F[B-](F)(F)F.C1([PH+](C2CCCCC2)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH:24]1([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:26][CH2:25]1
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)Nc1cnccc1I
Agent: [Pd+2]
Agent: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cnccc1C1CC1
Temperature: 100 °C
Yield: 86.7 %

Procedure:
A pressure tube purged with nitrogen was charged with tert-butyl 4-iodopyridin-3-ylcarbamate (1.0 g, 3.12 mmol), potassium phosphate (2.393 g, 10.93 mmol), toluene (16 mL) and H2O (0.800 mL). The mixture was sparged with nitrogen for 20 minutes. Then cyclopropylboronic acid (0.349 g, 4.06 mmol), tricyclohexylphosphonium tetrafluoroborate (0.116 g, 0.312 mmol), and palladium(II) acetate (0.035 g, 0.156 mmol) were added, and the mixture was sparged with nitrogen for 15 minutes. The tube was closed with a pressure release valve top, and the mixture was heated at 100° C. for 20 hours. TLC (SiO2, 50% ethyl acetate/CH2Cl2) showed no starting material and a lower. Rf product. LCMS showed no starting material, and a large product peak, m/z 235. The reaction was cooled to room temperature, and the residue was taken up in ethyl acetate (100 mL), and washed with H2O (50 mL). The aqueous phase was re-extracted with ethyl acetate (50 mL), and the combined organic extracts were washed with brine (25 mL), dried over anhydrous MgSO4, filtered, and concentrated by rotary evaporation. The crude material was purified by SiO2 flash chromatography (2.5 cm×15 cm) eluting with CH2Cl2 to 6:4 ethyl acetate/CH2Cl2 to afford the product as a colorless viscous oil (634 mg).
Reaction SMILES: BrC1N=C(C(C2C3C(Cl)=NC=[N:14][C:13]=3[N:12](C(C)C)C=2)=O)C=CC=1.[NH2:23][C:24]1[C:25]2[C:32]([C:33]([C:35]3C=N[CH:38]=[C:39](N)[CH:40]=3)=[O:34])=[CH:31][N:30]([CH:42]([CH3:44])[CH3:43])[C:26]=2[N:27]=[CH:28][N:29]=1>>[NH2:23][C:24]1[C:25]2[C:32]([C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[C:13]([NH2:14])[N:12]=3)=[O:34])=[CH:31][N:30]([CH:42]([CH3:43])[CH3:44])[C:26]=2[N:27]=[CH:28][N:29]=1
Reactant: CC(C)n1cc(C(=O)c2cccc(Br)n2)c2c(Cl)ncnc21
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2c(N)ncnc21
Product: CC(C)n1cc(C(=O)c2cccc(N)n2)c2c(N)ncnc21
Yield: 85 %

Procedure:
The title compound (5.30 g, 85%) was prepared from (6-Bromo-pyridin-2-yl)-(4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (8.0 g, 21.3 mmol) by procedures analogous to those described for the preparation of (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(5-amino-pyridin-3-yl)-methanone. MS: 297.1 (MH+); HPLC Rf: 370 min. (HPLC method 4); HPLC purity: 100%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11](N1C=CN=C1)(N1C=CN=C1)=[S:12].C(N(CC)CC)C.Cl>CCCCCCC.C(Cl)Cl>[N:1]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[C:11]=[S:12]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1ccc(N=C=S)cc1
Yield: 95 %

Procedure:
4-Aminobenzoic acid (5.00 g, 36.5 mmol) was added to a methylene chloride solution (51 mL) of thiocarbonyldiimidazole (8.45 g, 47.4 mmol) and triethylamine (5.6 mL, 40.2 mmol) at an internal temperature of at most 5° C., followed by stirring under cooling with ice for one hour. The mixture was dropped to a separately prepared mixed solution of concentrated hydrochloric acid (12.2 mL, 140.5 mmol) and n-heptane (51 mL) so that the internal temperature became from 25° C. to 30° C., whereupon a pale yellow suspension was obtained. This was stirred under cooling with ice for 3 hours, and the solid was collected by filtration and washed with water (50 mL) to obtain a pale yellow crude product. The obtained crude product was subjected to an operation of washing with water (50 mL) with stirring and collection by filtration twice, followed by drying under reduced pressure to obtain 4-isothiocyanatobenzoic acid as a pale yellow solid (6.23 g, yield: 95%, HPLC purity: 100.0%).
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=1>CC(C)=O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]2[N:14]([C:2]([CH3:11])=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:12]=2)[CH:15]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC(Br)C(=O)c1ccccc1
Solvent: CC(C)=O
Product: Cc1c(-c2ccccc2)nc2ccc(Br)cn12
Yield: 24.5 %

Procedure:
In a 100 ml round-bottomed flask, 865 mg of 2-amino-5-bromopyridine are dissolved in 25 ml of acetone, then 1.06 g of 2-bromo-1-phenyl-1-propanone are added and the mixture is heated at the reflux of the solvent for 57 hours. The reaction mixture is allowed to cool and then the precipitate is recovered by filtration, washed with diethyl ether and dried under reduced pressure. 350 mg of compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][N:10]=[C:11]3[CH:16]=[CH:15][C:14]([CH:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[OH:18])=[CH:13][C:12]=23)[CH:5]=[CH:6][CH:7]=1>O1CCOCC1.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][N:10]=[C:11]3[CH:16]=[CH:15][C:14]([C:17]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)=[O:18])=[CH:13][C:12]=23)[CH:5]=[CH:6][CH:7]=1
Reactant: OC(c1ccc(F)cc1)c1ccc2noc(-c3cccc(Cl)c3)c2c1
Agent: O=[Mn]=O
Solvent: C1COCCO1
Product: O=C(c1ccc(F)cc1)c1ccc2noc(-c3cccc(Cl)c3)c2c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of intermediate 1 (0.0514 mol) and MnO2 (18 g) in 1,4-dioxane (200 ml) was stirred at 80° C. for 3 hours, then cooled to room temperature and filtered over celite. The solvent was evaporated till dryness. The product was used without further purification, yielding (quant.) of [3-(3-chlorophenyl)-2,1-benzisoxazol-5-yl](4-fluorophenyl)-methanone (intermediate 2), mp. 165° C.