Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([O:13]CC)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:18]1=[O:36].C(O)(=O)C.C1CCCCC=1>C1(C)C=CC=CC=1.[Pd]>[C:11]([CH:10]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[C:18]1=[O:36])[CH2:9][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([OH:13])=[O:12]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CCc2ccccc21
Reactant: CCOC(=O)C=CC(=O)c1ccccc1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)O)CCc2ccccc21
Temperature: 80 °C
Reaction time: 18 h
Yield: 58.8 %

Procedure:
Ethyl 3-benzoylacrylate (13a) (55.6 g, 272 mmoles) is dropped into a solution of (3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one (11) (66.2 g, 228 mmoles) in 200 ml of toluene, at room temperature in 1 h. The resulting mixture is left under stirring for 18 h, then added with 10% Pd—C (26 g, 22 mmoles) and hydrogenated at 3 atm for 18 h at room temperature. After completion of the reaction the catalyst is filtered off through Celite, 50 ml of acetic acid are added and the solvent mixture is evaporated to kettle temperature of 110–120° C. The residue is taken up in 200 ml of toluene, 50 ml of acetic acid then cyclohexene (50 ml) and 10% Pd—C (26 g, 22 mmoles) are added. The reaction mixture is heated to 80° C. for 18 h, after that the catalyst is filtered off through Celite and solvents are evaporated off. The residue is taken up with isopropanol (500 ml) and the resulting precipitate is filtered, washed with 20 ml of isopropanol and dried to give 3-[[1-(carboxy)-3-phenyl-propyl]amino]-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one (15) (60.7 g, yield: 54%).
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[CH3:8][C:9](=[N:11][OH:12])[CH3:10]>>[CH3:8][C:9](=[N:11][O:12][CH2:2][C:3]([OH:5])=[O:4])[CH3:10]
Reactant: O=C(O)CBr
Reactant: CC(C)=NO
Agent: [Na+]
Agent: [OH-]
Product: CC(C)=NOCC(=O)O
Temperature: 25 °C

Procedure:
To bromoacetic acid (500 g, 3.60 mol) and ice (400 g) was added dropwise 40% sodium hydroxide (375 g, 3.75 mol) at below 20° C. Acetone oxime (239 g, 3.27 mol) was added. At below 20° C., 40% sodium hydroxide (375 g, 3.27 mol) was added dropwise. The reaction mixture was allowed to warm to room temperature overnight and extracted with 500 ml of ether. The aqueous phase was acidified to pH 2 and extracted with ether (3×500 ml). The combined organic layers were dried over MgSO4, filtered, and concentrated to dryness. Hexane (250 ml) was added to the residue and the precipitate was collected to give the title compound.
Reaction SMILES: [Br:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6](Br)[C:3]=1[C:4]#[N:5].[NH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]=1[C:4]#[N:5]
Reactant: NCCCc1ccccc1
Reactant: N#Cc1c(Br)ccnc1Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCCCc2ccccc2)ccnc1Br
Yield: 65.4 %

Procedure:
Prepared according to the methods above using 2,4-dibromonicotinonitrile (100 mg, 0.382 mmol), 3-aminopropylbenzene (0.058 mL, 0.401 mmol) and Hunig's Base (0.080 mL, 0.458 mmol) in DMF (1.5 mL) to give the desired product as a white solid (79 mg). LC/MS (316/318, [M−H]−/[M+H]+); 1H NMR (400 MHz, CHLOROFORM-d) δ 8.02 (dd, J=6.0, 0.5 Hz, 1H), 7.37-7.30 (m, 2H), 7.28-7.15 (m, 3H), 6.42 (d, J=6.0 Hz, 1H), 5.26 (br. s., 1H), 3.28 (td, J=7.0, 5.8 Hz, 2H), 2.75 (t, J=7.4 Hz, 2H), 2.03 (quin, J=7.3 Hz, 2H).
Reaction SMILES: [NH:1]([CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O:28][C:29]([NH:31][CH2:32][C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C>CN(C)C=O.O>[C:24]([O:28][C:29](=[O:30])[NH:31][CH2:32][C:33](=[O:34])[N:1]([CH2:8][C:9](=[O:10])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: O=C(CNc1ccccc1)Nc1ccc(-c2ccncc2)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)N(CC(=O)Nc1ccc(-c2ccncc2)cc1)c1ccccc1
Reaction time: 24 h
Yield: 48.1 %

Procedure:
To a mixture of 2-anilino-N-[4-(4-pyridinyl)phenyl]acetamide (50.0 mg) and [(tert-butoxycarbonyl)amino]acetic acid (86.6 mg) in N,N-dimethylformamide (1.0 mL) were added diisopropylethylamine (0.189 mL) and N-[(dimethylamino) (3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminium hexafluorophosphate (207 mg) at ambient temperature and the mixture was stirred at the same temperature for 24 hours. Water (3.0 mL) was added to the mixture and the resulting mixture was extracted with ethyl acetate (6.0 mL). The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (10% methanol in chloroform) to afford tert-butyl{2-oxo-2-[(2-oxo-2-{[4-(4-pyridinyl)phenyl]amino}ethyl)(phenyl)amino]ethyl}carbamate (36.5 mg) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:17]1[CH:18]=[N:19][C:20]([O:23]C)=[CH:21][CH:22]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].Cl.CCOC(C)=O.O>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:17]1[CH:22]=[CH:21][C:20](=[O:23])[NH:19][CH:18]=1)([OH:16])[C:12]([F:14])([F:15])[F:13]
Reactant: COc1ccc(C(C)C(O)(c2ccc(OC)nc2)C(F)(F)F)c(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C(C)C(O)(c2ccc(=O)[nH]c2)C(F)(F)F)c(Cl)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
To a solution of 3-(2-chloro-4-methoxy-phenyl)-1,1,1-trifluoro-2-(6-methoxy-pyridin-3-yl)-butan-2-ol (Example 193, 212 mg) in dioxane (8.5 ml) was added concentrated aqueous HCl (0.934 ml). The mixture was stirred at 100° C. for 1 h. After cooling to room temperature, EtOAc and water were added and the mixture was extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated to dryness to give the title compound (207 mg) as a colorless solid. MS (m/e, ISP neg. ion)=360.0 [M−H+].
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]([OH:13])=O.Cl.[NH:15]1[CH2:18][CH:17]([C:19]2[C:24]([Cl:25])=[N:23][CH:22]=[CH:21][N:20]=2)[CH2:16]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C.O>[Cl:25][C:24]1[C:19]([CH:17]2[CH2:18][N:15]([C:11]([C:3]3[N:2]([CH3:1])[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[N:4]=3)=[O:13])[CH2:16]2)=[N:20][CH:21]=[CH:22][N:23]=1
Reactant: Clc1nccnc1C1CNC1
Reactant: Cn1c(C(=O)O)nc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cn1c(C(=O)N2CC(c3nccnc3Cl)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.5 %

Procedure:
A mixture of 1-methyl-1H-benzoimidazole-2-carboxylic acid (82) (176 mg, 1.0 mmol), 2-Azetidin-3-yl-3-chloro-pyrazine hydrochloride (8) (169 mg, 1.0 mmol), HOBt (151 mg, 1.2 mmol), EDCI (231 mg, 1.2 mmol) and N-methyl-morpholine (NMM) (300 mg, 3.0 mmol) in DMF (5 mL) was stirred at RT for 24 h. The mixture was diluted with water (20 mL), and filtered. The filter cake was washed with water and dried in vacuo to provide [3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-(1-methyl-1H-benzoimidazol-2-yl)-methanone (83) (300 mg, yield 90%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH:34](=[C:41]1/[CH2:42][N:43]([C:48]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:44][CH2:45][CH:46]/1O)/[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[C:67]([OH:70])(=[S:69])[CH3:68]>O1CCCC1.C1(C)C=CC=CC=1>[C:67]([S:69][CH:46]1[CH2:45][CH2:44][N:43]([C:48]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:42]/[C:41]/1=[CH:34]\[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:70])[CH3:68]
Reactant: CC(O)=S
Reactant: OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)SC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of triphenylphosphine (6.39 g) in tetrahydrofuran (100 ml) was added a solution of diisopropyl azodicarboxylate in toluene (13.11 ml) under ice-cooling, and the resulting mixture was stirred at the same temperature for 1 hour. Subsequently, to the reaction mixture was added dropwise a solution of (E)-3-benzylidene-1-(triphenylmethyl)piperidin-4-ol (5.26 g) and thioacetic acid (1.74 ml) in tetrahydrofuran (50 ml) at the same temperature, and the resulting mixture was furthermore stirred at room temperature for 2.5 hours. The reaction mixture was evaporated in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (2:23) as the eluent to afford (E)-4-(acetylsulfanyl)-3-benzylidene-1-(triphenylmethyl)piperidine (containing impurities) as a pale yellow amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[I:20]I.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[C:13]3[C:19]([I:20])=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cnc3[nH]ccc3c2)cc1OC
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cnc3[nH]cc(I)c3c2)cc1OC
Temperature: -40 °C

Procedure:
5-(3,4-Dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine, 82, (0.270 g, 0.00106 mol) was dissolved in Tetrahydrofuran (8.5 mL, 0.10 mol) under an atmosphere of Nitrogen. The solution was stirred at −40° C. and Iodine (0.269 g, 0.00106 mol) dissolved in 2.5 mL of Tetrahydrofuran was added. The chilled reaction mixture was stirred for 2 h and was then quenched with the addition of Sodium thiosulfate, pentahydrate (0.13 g, 0.00053 mol) in water (1M). The reaction mixture was partitioned between water (20 mL and ethyl acetate (30 mL). The two layers were seperated, and the aquous layer was extracted with ethyl acetate. The organic layers were washed with water and brine, dried with sodium sulfate, then concentrated under reduced pressure. The dark colored crude residue was carried onto the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:10]=3[CH:9]=2)[C:5]([Cl:20])=[CH:4][N:3]=1.[CH:21]1([NH2:24])[CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C.Cl.C(N(CC)CCCN=C=NCC)C.ON1C2C=CC=CC=2N=N1>ClCCl.O>[CH:21]1([NH:24][C:17]([C:16]2[C:10]3[CH:9]=[C:8]([C:6]4[C:5]([Cl:20])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=4)[S:12][C:11]=3[CH:13]=[CH:14][CH:15]=2)=[O:19])[CH2:23][CH2:22]1
Reactant: NC1CC1
Reactant: O=C(O)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Agent: CCN=C=NCCCN(CC)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Reaction time: 0.33 h
Yield: 99.8 %

Procedure:
A suspension of 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid (5.00 g, 15.4 mmol) in dichloromethane (100 mL) is treated at room temperature with cyclopropylamine (1.20 mL, 17.3 mmol) in the presence of N,N-diisopropylethylamine (3.00 mL, 17.2 mmol), 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.34 g, 17.4 mmol), and 1-hydroxybenzotriazole (2.33 g, 17.2 mmol) for 20 hours. Water (20 mL) is then added, and after stirring for 20 minutes, the mixture is filtered, and dried. The obtained solid is suspended in dichloromethane (50 mL), stirred for 2 hours, filtered, and dried to provide the title compound (5.60 g, 99%).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([N:14]=[C:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:17][C:18]1[NH:22][N:21]=[C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH:19]=1.Cl>C(OCC)(=O)C>[C:8]1([NH:14][C:15]([N:22]2[C:18]([CH3:17])=[CH:19][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:31])([F:32])[F:33])=[N:21]2)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1cc(Oc2ccccc2C(F)(F)F)n[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(Oc2ccccc2C(F)(F)F)nn1C(=O)Nc1ccccc1
Reaction time: 6 h
Yield: 89.9 %

Procedure:
Triethylamine (0.19 g, 1.4 mmol) and phenyl isocyanate (0.17 g, 1.4 mmol) were added to a solution of 5-methyl-3-(2-trifluoromethylphenyloxy)pyrazole (0.30 g, 1.2 mmol) in ethyl acetate (5 ml) at 0° C., and the mixture was allowed to have room temperature gradually and stirred for 6 hours. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×2). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/15), to give an orange solid of N-phenyl-5-methyl-3-(2-trifluoromethylphenyloxy)pyrazole-1-carboxamide (0.39 g, yield: 87.5%). mp: 87-89° C., 1H-NMR (CDCl3, TMS, ppm): δ 2.65 (d, J=0.7 Hz, 3H), 5.78 (d, J=0.7 Hz, 1H), 7.14 (ddd, J=1.2, 2.3 and 7.3 Hz, 1H), 7.28-7.38 (m, 4H), 7.51-7.60 (m, 3H), 7.69-7.73 (m, 1H), 8.90 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[Cl:9].[NH:10]1[C:18]2[C:13](=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[Cl:9][C:3]1[CH:4]=[C:5]([N:10]2[C:18]3[C:13](=[C:14]([CH2:19][N:20]4[CH2:25][CH2:24][CH:23]([C:26]5[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:29]=[CH:30][CH:31]=5)[CH2:22][CH2:21]4)[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Clc1ccc(I)cc1Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3ccc(Cl)c(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1,2-dichloro-4-iodobenzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 520.0 (M+H)+.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1
Reactant: CCOC(=O)c1cnn2ccc(O)nc12
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnn2ccc(Cl)nc12
Yield: 97.6 %

Procedure:
Ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (22.7 g, 110 mmol) was suspended in phosphoryl trichloride (100 mL) and heated to reflux. After heating for 2 hours, the reaction mixture was cooled and concentrated to remove excess POCl3. The residue was diluted in DCM (100 mL) and slowly added to a flask containing ice water. The mixture was separated and the aqueous layer was extracted with DCM (2×200 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to afford ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate as a pale-yellow solid (24.2 g, 97.6% yield). MS (apci) m/z=225.9 (M+H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([N+:18]([O-:20])=[O:19])=[CH:7][C:8]2[CH:13]3[O:14][CH:12]3[C:11]([CH3:16])([CH3:15])[O:10][C:9]=2[CH:17]=1)(=[O:3])[CH3:2].[NH3:21]>C(O)C>[C:1]([NH:4][C:5]1[C:6]([N+:18]([O-:20])=[O:19])=[CH:7][C:8]2[C@@H:13]([NH2:21])[C@H:12]([OH:14])[C:11]([CH3:16])([CH3:15])[O:10][C:9]=2[CH:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])C1OC1C(C)(C)O2
Reactant: N
Solvent: CCO
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])[C@@H](N)[C@H](O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 21 h

Procedure:
7-Acetamido-3,4-epoxy-3,4-dihydro-2,2-dimethyl-6-nitro-2H-benzo[b]pyran (0.76 g, prepared as in European Pat. No. 28,449) was dissolved in dry ethanol and saturated with dry ammonia, and stirred at room temperature for 21 hr. Evaporation gave a crude mixture which was purified on the chromatotron (using pentane-ethyl acetate in a gradient elution), to give the title compound (280 mg).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[K+].[Br-:8].C[Si](C#C[C:15]1[CH:16]=[CH:17][C:18]2[N:24]3[CH:25]=[N:26][C:27]([C:28](OCC)=[O:29])=[C:23]3[CH2:22][N:21]=[C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3F)[C:19]=2[CH:40]=1)(C)C>>[Br:8][C:15]1[CH:16]=[CH:17][C:18]2[N:24]3[CH:25]=[N:26][C:27]([C:28]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[O:29])=[C:23]3[CH2:22][N:21]=[C:20]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:19]=2[CH:40]=1
Reactant: OCC(F)(F)F
Reactant: [Br-]
Reactant: CCOC(=O)c1ncn2c1CN=C(c1ccccc1F)c1cc(C#C[Si](C)(C)C)ccc1-2
Agent: [K+]
Product: O=C(OCC(F)(F)F)c1ncn2c1CN=C(c1ccccc1)c1cc(Br)ccc1-2

Procedure:
A white solid (69.1%) from acid 27 and 2,2,2-trifluoroethanol: mp 202-204° C.; IR (KBr) 3114, 1711, 1608, 1495, 1368, 1288, 1158 cm−1; 1H NMR (300 MHz, CDCl3) δ 4.10 (d, 1H, J=12.6 Hz), 4.68 (m, 1H), 4.85 (m, 1H), 6.02 (d, 1H, J=12.6 Hz), 7.41-7.54 (m, 6H), 7.62 (d, 1H, J=2.1 Hz), 7.83 (dd, 1H, J=2.1 Hz, 8.4 Hz), 7.97 (s, 1H); MS (EI) m/e (rel intensity) 463 (M+, 14), 465 (14).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][S:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1.CS[C:15](=[N:20][CH3:21])[S:16]([O-:19])(=[O:18])=[O:17]>C(#N)C.CO>[CH3:21][NH:20][C:15]([S:16]([OH:19])(=[O:18])=[O:17])=[N:12][CH2:11][CH2:10][S:9][CH2:8][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CN=C(SC)S(=O)(=O)[O-]
Reactant: NCCSCc1ncccc1Cl
Solvent: CO
Solvent: CC#N
Product: CNC(=NCCSCc1ncccc1Cl)S(=O)(=O)O
Reaction time: 0.5 h

Procedure:
A solution of 2-(3-chloropyrid-2-ylmethylthio)ethylamine (2.03 g) in dry acetonitrile (150 ml) was added dropwise, with stirring, to a solution of 1-methylthio-1-methyliminomethanesulphonate (1.69 g) in dry acetonitrile (150 ml) at 50°. The mixture was stirred at 60° for 30 minutes and then allowed to cool. The mixture was stripped to dryness, dissolved in methanol and absorbed onto silica gel. Chromatography on a column of silica gel produced a viscous oil which was collected by eluting the column with a chloroform/methanol mixture and evaporating off the solvent. The viscous oil analysed by micro-analysis and nuclear magnetic resonance spectroscopy to the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C)C=O>[CH:21]1([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH:11]([F:12])[F:13])[CH:5]=[O:6])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC(F)F)c(OC2CCCC2)c1
Temperature: 50 °C

Procedure:
To a mixture of 3-hydroxy-4-difluoromethoxybenzaldehyde (2.9 g,.15 mmol) and powdered potassium carbonate (3.2 g, 23 mmol) in dimethylformamide (15 mL) under an argon atmosphere was added bromocyclopentane (2.5 mL, 23 mmol) and the mixture was stirred and heated at 50° C. for 1 h and at 80°-85° C. for 1.5 h. The mixture was allowed to cool and was partitioned between ethyl acetate and water. The organic extract was washed three times with water, was dried (sodium sulfate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with 20-30% ether/hexanes, provided a yellow soild (3.5 g, 89%).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:8]=2[C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].Cl.C(N(CCCC)CCCC)CCC>>[CH2:1]([C:5]1[O:6][C:7]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:8]=2[C:9]=1[C:10](=[O:19])[C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: CCCCN(CCCC)CCCC
Product: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.50 g (4.25 mmol) of 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran (Ia) were dissolved in 4.71 g (21.2 mmol) of tri-n-butylamine-hydrochloride at 150° C. After 16 h LC-MS analysis indicated the complete consumption of the starting material and the reaction mixture was cooled to room temperature. After addition of 20 ml of water and 50 ml MTBE the phases were separated, the organic layer was washed once with 25 ml of 1M HCl and 20 ml of water, dried over MgSO4 and evaporated. Flash chromatography gave the title compound which crystallized to yield 1.10 g (76%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[CH2:40]([O:42][C:43]1[CH:44]=[C:45]([CH:63]=[CH:64][CH:65]=1)[CH2:46][N:47]1[C:51]([CH3:52])=[C:50](B2OC(C)(C)C(C)(C)O2)[C:49]([CH3:62])=[N:48]1)[CH3:41].C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[CH2:40]([O:42][C:43]1[CH:44]=[C:45]([CH:63]=[CH:64][CH:65]=1)[CH2:46][N:47]1[C:51]([CH3:52])=[C:50]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[C:49]([CH3:62])=[N:48]1)[CH3:41]
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Reactant: CCOc1cccc(Cn2nc(C)c(B3OC(C)(C)C(C)(C)O3)c2C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOc1cccc(Cn2nc(C)c(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(-c5ccc(N6CCN(C(=O)OC(C)(C)C)CC6)cc5)cc34)c2C)c1
Yield: 97.3 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (intermediate 41) (125 mg, 0.189 mmol) was coupled with 1-(3-ethoxybenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 46) (81.13 mg, 0.227 mmol) in sodium carbonate (60.1 mg, 0.567 mmol), Pd(PPh3)2Cl2 (6.6 mg, 0.0095 mmol), toluene/ethanol/water (3/5/1 ml) to give 140 mg of titled compound. MS: m/z=761.0 (M+1).