Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[S:4][CH:5]=[C:6]([CH2:8][OH:9])[N:7]=1.Br[C:12]1[CH:17]=[CH:16][N:15]([C:18]2[CH:19]=[CH:20][C:21]3[N:25]=[C:24]([CH2:26][CH3:27])[N:23]([CH3:28])[C:22]=3[CH:29]=2)[C:14](=[O:30])[CH:13]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[F:1][CH:2]([F:10])[C:3]1[S:4][CH:5]=[C:6]([CH2:8][O:9][C:12]2[CH:17]=[CH:16][N:15]([C:18]3[CH:19]=[CH:20][C:21]4[N:25]=[C:24]([CH2:26][CH3:27])[N:23]([CH3:28])[C:22]=4[CH:29]=3)[C:14](=[O:30])[CH:13]=2)[N:7]=1
Reactant: CCc1nc2ccc(-n3ccc(Br)cc3=O)cc2n1C
Reactant: OCc1csc(C(F)F)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCc1nc2ccc(-n3ccc(OCc4csc(C(F)F)n4)cc3=O)cc2n1C
Temperature: 100 °C
Yield: 30.5 %

Procedure:
To a suspension of (2-(difluoromethyl)thiazol-4-yl)methanol (39 mg) and 4-bromo-1-(2-ethyl-1-methyl-1H-benzo[d]imidazol-6-yl)pyridin-2(1H)-one (52.3 mg) in toluene (1 ml) was added potassium tert-butoxide (35.3 mg) at 100° C. The mixture was stirred at 100° C. under dry atmosphere (CaCl2 tube) for 30 min. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by recrystallization from EtOH-water to give the title compound (20.0 mg) as an off-white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].[CH3:12][O:13][C:14](=[O:38])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([C:30](=[O:37])[C:31]#[C:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2I)[CH:16]=1>>[CH3:12][O:13][C:14](=[O:38])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:31](=[C:32](\[C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)/[C:33]([CH3:36])([CH3:35])[CH3:34])/[C:30]2=[O:37])[CH:16]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cccc(CN(C(=O)C#CC(C)(C)C)c2ccccc2I)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(/c3ccc(C#N)cc3)C(C)(C)C)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 84 starting from 4-cyano-phenylboronic acid (commercially available) and 3-{[(4,4-dimethyl-pent-2-ynoyl)-(2-iodo-phenyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (400 MHz, DMSO-d6) δppm 1.35 (s, 9H) 3.84 (s, 3H) 5.07 (s, 2H) 5.19 (d, J=7.83 Hz, 1H) 6.56 (t, J=7.71 Hz, 1H) 6.88 (d, J=7.83 Hz, 1H) 7.06 (t, J=7.71 Hz, 1H) 7.42 (d, J=8.08 Hz, 2H) 7.50 (t, J=7.71 Hz, 1H) 7.59 (d, J=7.58 Hz, 1H) 7.87 (d, J=7.58 Hz, 1H) 7.95-8.05 (m, 3H).
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([O:27][C:28](=[O:44])[CH2:29][CH2:30][NH:31][C:32]([C:34]1[N:35]=[C:36]2[CH:41]=[CH:40][C:39](Cl)=[N:38][N:37]2[CH:43]=1)=[O:33])[CH3:26].C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH2:25]([O:27][C:28](=[O:44])[CH2:29][CH2:30][NH:31][C:32]([C:34]1[N:35]=[C:36]2[CH:41]=[CH:40][C:39]([NH:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)=[N:38][N:37]2[CH:43]=1)=[O:33])[CH3:26]
Reactant: CCOC(=O)CCNC(=O)c1cn2nc(Cl)ccc2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 95 °C
Reaction time: 24 h
Yield: 29.7 %

Procedure:
0.649 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 0.594 g of N-(6-chloroimidazo[1,2-b]pyridazine-2-carbonyl)-β-alanine ethyl ester were dissolved in 7 ml of 1-methyl-2-pyrrolidone; 0.345 ml of N-ethyldiisopropylamine was added, followed by stirring in an oil bath (90-100° C.) for 24 hours. After cooling, ice water was added, followed by extraction with ethyl acetate; the extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (370:30:4). The desired fraction was collected and recrystallized from ethyl ether to yield 0.347 g of the title compound.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@H:10]([NH:15][C:16](=[O:38])[CH2:17][N:18]1[CH:22]=[C:21]([CH2:23][O:24][C:25]2[CH:37]=[CH:36][C:28]3[N:29]=[C:30]([S:32](=[O:35])(=[O:34])[NH2:33])[S:31][C:27]=3[CH:26]=2)[N:20]=[N:19]1)[C:11]([O:13]C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH2:1]([S:8][CH2:9][C@H:10]([NH:15][C:16](=[O:38])[CH2:17][N:18]1[CH:22]=[C:21]([CH2:23][O:24][C:25]2[CH:37]=[CH:36][C:28]3[N:29]=[C:30]([S:32](=[O:34])(=[O:35])[NH2:33])[S:31][C:27]=3[CH:26]=2)[N:20]=[N:19]1)[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CSCc1ccccc1)NC(=O)Cn1cc(COc2ccc3nc(S(N)(=O)=O)sc3c2)nn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1nc2ccc(OCc3cn(CC(=O)N[C@@H](CSCc4ccccc4)C(=O)O)nn3)cc2s1
Temperature: 25 °C

Procedure:
Compound 141 (5.0 mg, 0.0087 mmol, 1 equiv) in a THF/H2O mixture (1:1, 1 mL) was treated with LiOH (0.4 mg, 0.010 mmol, 1.2 equiv) and irradiated in a Biotage Emrys Optimizer microwave reactor (250 W) at 100° C. for 10 min. After cooling the contents of the tube to room temperature, the solvent was removed and the crude product was purified by HPLC. Yield: 3 mg, 63%.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[NH:15]1[CH2:20][CH2:19][C:18]2([CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:29])[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:15]3[CH2:16][CH2:17][C:18]4([CH2:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C:21]4=[O:29])[CH2:19][CH2:20]3)=[CH:7][CH:6]=2)[O:12][N:11]=1
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Reactant: O=C1c2ccccc2CC12CCNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1noc(-c2ccc(N3CCC4(CC3)Cc3ccccc3C4=O)nn2)n1

Procedure:
The object product (173 mg, 76%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (124 mg) obtained in Example 43(2), spiro[indene-2,4′-piperidin]-1(3H)-one hydrochloride (150 mg) and potassium carbonate (174 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)=[C:7]([NH2:9])[CH:8]=1.Br[C:23]1[CH:37]=[CH:36][C:26]([O:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)=[C:7]([NH:9][C:23]2[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[CH:36][CH:37]=2)[CH:8]=1
Reactant: COc1ccc(C2=Cc3ccc(OC)cc3CC2)c(N)c1
Reactant: Brc1ccc(OCCN2CCCCC2)cc1
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1Nc1ccc(OCCN3CCCCC3)cc1)=C2
Yield: 85.1 %

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-3,4-dihydronaphthalen-2-yl)phenylamine (150 mg) and 1-[2-(4-bromophenoxy)ethyl]piperidine (155 mg) according to an analogous synthetic method to Example 116, the title compound (220 mg) was obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]4[CH:26]=[CH:27][N:28]=[C:24]4[CH:23]=[C:22]([C:29]4[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=4)[N:21]=3)=[CH:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>C(Cl)Cl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[CH3:34][N:32]1[CH:33]=[C:29]([C:22]2[N:21]=[C:20]([C:17]3[CH:18]=[CH:19][N:15]([C:4]4([CH2:3][C:1]#[N:2])[CH2:7][NH:6][CH2:5]4)[CH:16]=3)[N:25]3[CH:26]=[CH:27][N:28]=[C:24]3[CH:23]=2)[CH:30]=[N:31]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3ccn(C4(CC#N)CN(C(=O)OC(C)(C)C)C4)c3)n2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(-c2cc3nccn3c(-c3ccn(C4(CC#N)CNC4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 3-(cyanomethyl)-3-(3-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrrol-1-yl)azetidine-1-carboxylate (Preparation O, 79.0 mg, 0.172 mmol) in dry DCM (1.5 mL) was added trifluoroacetic acid (2 mL) and the mixture stirred at ambient temperature for 3 hours. The mixture was concentrated and the residual gel was treated with EtOAc and sonicated until a white suspension. The EtOAc was decanted, the residual solid was washed with EtOAc and dried in vacuum to afford the title compound (trifluoroacetate salt, 100 mg, 99% yield) as an ivory white solid. MS (apci) m/z=359.2.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>ClCCl.O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][O:13]3)[CH:8]=2)[N:3]=1
Reactant: Oc1ccc2nc(Cl)ccc2c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Clc1ccc2cc(OC3CCCCO3)ccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloroquinolin-6-ol (36 g, 0.20 mol) was dissolved in dichloromethane (500 ml) and tetrahydrofuran (500 ml). 3,4-dihydro-2H-pyran (74 ml, 0.81 mol) and p-toluenesulfonic acid (0.49 g, 0.005 mol) were added to the mixture in ice cooling water bath, followed by stirring at room temperature overnight. A 10% sodium hydroxide aqueous solution was added to the reaction mixture, followed by extraction with dichloromethane. The result was dried over potassium carbonate and subjected to filtration, and then the filtrate was concentrated under reduced pressure. The crude crystal thus obtained was recrystallized from ethanol to afford the title compound as a colorless granular compound (47 g, yield 89%).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][N:8]([CH2:24][CH2:25][O:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:9]1[C:10]([N+:21]([O-:23])=[O:22])=[CH:11][C:12]([N+:18]([O-:20])=[O:19])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)(=[O:4])=[O:3].[NH2:31][CH2:32][CH2:33][OH:34].Cl>O=S(Cl)Cl.CN(C=O)C>[CH3:1][S:2]([O:5][CH2:6][CH2:7][N:8]([CH2:24][CH2:25][O:26][S:27]([CH3:30])(=[O:28])=[O:29])[C:9]1[CH:17]=[C:13]([C:14]([NH:31][CH2:32][CH2:33][OH:34])=[O:16])[C:12]([N+:18]([O-:20])=[O:19])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)OCCN(CCOS(C)(=O)=O)c1cc(C(=O)O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: NCCO
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CS(=O)(=O)OCCN(CCOS(C)(=O)=O)c1cc(C(=O)NCCO)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 82.2 %

Procedure:
A suspension of 8 (3.20 g, 6.79 mmol) in SOCl2 (60 mL) containing DMF (2 drops) was heated under reflux for 1 h. Evaporation of the solvent under reduced pressure, followed by azeotroping in with benzene gave the crude acid chloride, which was dissolved in dry Me2CO (80 mL) and treated at 0° C. with 2-aminoethanol (1.24 g, 20.3 mmol). After stirring at 0° C. for 5 min, the mixture was acidified to pH 2-3 with 0.2 N HCl, concentrated to half volume, and then solid NaBr was added. The mixture was extracted with EtOAc (2×) and the combined extracts were washed with saturated NaBr solution, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with EtOAc/MeOH (15:1) to give 2-(5-{[(2-hydroxyethyl)amino]carbonyl} {2-[(methylsulfonyl)oxy]ethyl}-2,4-dinitroanilino)ethyl methanesulfonate (9a) (2.87 g, 82%) as a gum that was used directly.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:33]=[CH:32][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)=[O:20])=[C:17]([O:34][CH3:35])[CH:16]=2)[N:10]=1.[C:36]([Cu])#[N:37]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:36]#[N:37])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:33]=[CH:32][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)=[O:20])=[C:17]([O:34][CH3:35])[CH:16]=2)[N:10]=1
Reactant: N#C[Cu]
Reactant: COc1cc(-n2nc(-c3c(Cl)cccc3I)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)(F)F)c1
Solvent: CN(C)C=O
Product: COc1cc(-n2nc(-c3c(Cl)cccc3C#N)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 13.8 %

Procedure:
To a solution of 4-(3-(2-chloro-6-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxy-N-(3-(trifluoromethyl)phenyl)benzamide (Intermediate-34, 0.130 g, 0.211 mmol) in DMF (5 mL) was added CuCN (0.020 g, 0.232 mmol) and reaction mixture was heated at 80° C. for 4-5 h. The reaction mass was quenched with aq. KMnO4 solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.015 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.95 (s, 3H), 7.44 (d, J=7.8 Hz, 1H), 7.59 (t, J=8.4 Hz, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.80-7.86 (m, 3H), 7.95 (d, J=8.7 Hz, 1H), 8.06-8.12 (m, 2H), 8.25 (s, 1H), 10.38 (s, 1H), 13.00 (br s, 1H); MS (m/z): 512.14 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:11](I)=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([CH3:24])[O:23][CH2:22][CH2:21][O:20]4)=[CH:15][CH:14]=3)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:5]2=[N:6][C:7]=1[CH3:8].[Li][CH2:34][CH2:35]CC.CI>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]2[C:11]([CH2:34][CH3:35])=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([CH3:24])[O:23][CH2:22][CH2:21][O:20]4)=[CH:15][CH:14]=3)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:5]2=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc2c(nc1Br)c(I)c(-c1ccc(C3(C)OCCO3)cc1)n2COCC[Si](C)(C)C
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CCc1c(-c2ccc(C3(C)OCCO3)cc2)n(COCC[Si](C)(C)C)c2nc(C)c(Br)nc12
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 63.5 %

Procedure:
2-Bromo-7-iodo-3-methyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (12.7 g, 20.2 mmol) in THF (200 mL) was cooled to about −75° C. then n-BuLi (1.5 M, 14.8 mL, 22.2 mmol) was added while maintaining the internal temperature of the mixture between −70 and −75° C. The mixture was stirred for about 20 min then the mixture was treated with MeI (6.51 mL, 81 mmol). The cooling bath was removed and replaced with a warm water bath. The temperature of the mixture was raised to about 20° C. over about 10 min. The mixture was stirred at about 20° C. for about 30 min then saturated aqueous NH4Cl (10 mL) was added. The mixture was stirred for about 15 min then concentrated under reduced pressure. The material was partitioned between Et2O (200 mL) and water (100 mL). The organic layer was isolated and the aqueous layer was extracted with Et2O (50 mL). The combined organics were washed with water (50 mL) then brine (50 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The material was purified with an 80 g silica column and eluted with 85:15 heptane/Et2O to give 2-bromo-7-ethyl-3-methyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (6.83 g, 64%): LC/MS (Table 2, Method g) Rt=2.17 min; MS m/z 532 (M+H)+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[CH2:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH:22]1[C:30]([O:32][CH3:33])=[O:31].[CH3:34][C:35]([CH3:37])=[O:36]>C1COCC1>[OH:36][C:35]([C:22]1([C:30]([O:32][CH3:33])=[O:31])[CH2:21][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)([CH3:37])[CH3:34]
Reactant: CC(C)=O
Reactant: COC(=O)C1Cc2ccccc2C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(C(C)(C)O)Cc2ccccc2C1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To a dried THF solution of lithiumdiisopropylamide prepared from 107.3 ml (0.149 mole) of n-butyllithium and 15.81 g (0.156 mole) of diisopropylamine, was added dropwise at -50° C. a solution of 25.0 g (0.142 mole) of methyl indane-2-carboxylate in 50 ml of dried THF over a period of 10 minutes. To the resulting mixture, which had been stirred for 30 minutes at -50° C., was added dropwise over a period of 10 minutes a solution of 9.88 g (0.17 mole) of dried acetone in 10 ml of dried THF. After the addition, stirring was continued for further 10 minutes. The reaction mixture was poured into ice water and extracted with ether. The aqueous layer was extracted twice with ether. The ether layers were combined, washed successively with 3% aqueous hydrochloric acid solution, saturated aqueous hydrogen-carbonate solution, and saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the intended product as a oily substance.
Reaction SMILES: [C:1]([C:4]1[C:23]([CH3:24])=[CH:22][C:7]2[NH:8][C:9]([S:11][CH2:12][C:13]3[C:18]4[O:19][CH2:20][O:21][C:17]=4[CH:16]=[CH:15][N:14]=3)=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:33])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(=O)([O-])O.[Na+]>[C:1]([C:4]1[C:23]([CH3:24])=[CH:22][C:7]2[NH:8][C:9]([S:11]([CH2:12][C:13]3[C:18]4[O:19][CH2:20][O:21][C:17]=4[CH:16]=[CH:15][N:14]=3)=[O:33])=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2nc(SCc3nccc4c3OCO4)[nH]c2cc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)c1cc2nc(S(=O)Cc3nccc4c3OCO4)[nH]c2cc1C
Temperature: 25 °C

Procedure:
5-Acetyl-6-methyl-2-[[(3,4-methylenedioxy-2pyridinyl)methyl]thio]-1H-benzimidazole (140 mg, 0,41 mmol) was dissolved in methylene chloride (20 ml) and sodium hydrogen carbonate (5 ml,1M). The mixture was stirred at ambient temperature and MCPBA (100 mg, 0.41 mmol, 70%) dissolved in methylene chloride (10 ml) was added portionwise. After 10 min sodium thiosulphate (100 mg) was added whereupon the phases were separated. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica (CH2Cl2 /MeOH/NH3, 97.5: 2.5: sat.) Yield: 90 mg (61%) of the title compound. Mp: 178°-180° C. (dec., uncorr.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]#[N:40])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:17]([NH:19][C:20]3[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=3C(OCC)=O)=[O:18])[C:10](=[O:38])[CH:9]=2)[CH:7]=1.[C:41](=[O:44])([O-])[O-:42].[Cs+].[Cs+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]#[N:40])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:28]([C:41]([OH:42])=[O:44])=[CH:27][CH:21]=3)=[O:18])[C:10](=[O:38])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccccc1NC(=O)C(CC1CCOCC1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: COc1cn(C(CC2CCOCC2)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
1.07 g (1.89 mmol) of ethyl ({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-4-yl)propanoyl}amino)benzoate (racemate) in 24 ml of methanol/water (4/1) were reacted with 1.24 g (3.79 mmol) of caesium carbonate according to General Method 4. Yield: 1.24 g (purity 73%, 88% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[CH2:38]([P:47](=[O:54])([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:38]/[P:47](=[O:54])([O:48][CH2:49][CH3:50])[O:51][CH2:52][CH3:53])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 67.7 %

Procedure:
To a mixture of 3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (0.50 g), tetraethyl methylenediphosphonate (0.32 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.05 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-[3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate as colorless crystals (0.43 g, yield 68%) from a fraction eluted with ethyl acetate-hexane (3:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 92-93° C.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C@:9]23[CH2:16][C@H:15]([NH2:17])[CH2:14][N:13]2[C:12](=[O:18])[N:11]([C:19]2[CH:24]=[C:23]([Cl:25])[N:22]=[C:21]([Cl:26])[CH:20]=2)[C:10]3=[O:27])=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+].CO[C:39]1O[C:41](OC)=[CH:42][CH:43]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C.CCOC(C)=O>[F:31][C:2]([F:30])([F:1])[O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C@:9]23[CH2:16][C@H:15]([N:17]4[CH:39]=[CH:43][CH:42]=[CH:41]4)[CH2:14][N:13]2[C:12](=[O:18])[N:11]([C:19]2[CH:24]=[C:23]([Cl:25])[N:22]=[C:21]([Cl:26])[CH:20]=2)[C:10]3=[O:27])=[CH:6][CH:5]=1
Reactant: COc1ccc(OC)o1
Reactant: N[C@@H]1CN2C(=O)N(c3cc(Cl)nc(Cl)c3)C(=O)[C@@]2(Cc2ccc(OC(F)(F)F)cc2)C1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1N(c2cc(Cl)nc(Cl)c2)C(=O)[C@@]2(Cc3ccc(OC(F)(F)F)cc3)C[C@H](n3cccc3)CN12

Procedure:
To a solution of the compound from Example 63 (0.25 g) in acetic acid (5 mL) was added sodium acetate (0.26 g) and 2,5-dimethoxyfuran (0.14 mL). After 20 minutes at reflux, the reaction was cooled, diluted with EtOAc, neutralized with solid NaHCO3. The organic solution was collected, washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered, concentrated and purified by chromatography (silica gel; 95:5 CH2Cl2/methanol, Chromatotron) to afford the titled compound (0.145 g): MS (m/z) 525 [MH+]. mp 129.5° C.