Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([C:34](O)=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+].[Cl-].[NH4+]>O1CCCC1.O>[CH3:32][N:16]1[C:15](=[O:33])[C:14]([C:13]2[N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[N:10]=[CH:11][C:12]=2[CH2:34][OH:35])=[C:19]([CH3:20])[N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)[C:17]1=[O:31]
Reactant: Cc1c(-c2c(C(=O)O)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1c(-c2c(CO)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1

Procedure:
To a solution of 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carboxylic acid (prepared in Example 132) (100 mg) and N-methylmorpholine (66 μL) in tetrahydrofuran (2 ml) was added at 0° C. isobutyl chloroformate (79 μl). After thirty minutes, to the reaction mixture was added sodium borohydride (26.4 mg) and the resulting mixture was stirred for three and a half hours. Thereto was added sodium borohydride (55.6 mg) and the mixture was stirred for another thirty minutes and thereto were added water and saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over sodium sulfate, and then concentrated on evaporator instrument. The residue was purified by silica gel column chromatography to afford the intended 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-(hydroxymethyl)-1H-pyrazol-1-yl)benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[S:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2[Cl:35])=[N:26][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:22][C:23]3[S:24][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=4[Cl:35])=[N:26][N:27]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: Clc1cccc(-c2nnc(CBr)s2)c1Cl
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Product: O=c1n(Cc2nnc(-c3cccc(Cl)c3Cl)s2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
Analogously to the preparation of Example 18, 36 mg (0.12 mmol) of the compound from Example 5A were reacted with 38 mg (0.12 mmol) of the compound from Example 87A. This gave 33 mg (48% of theory) of the target compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:25](O)=[O:26])[CH2:9]2)=[O:7])[CH2:3]1.O[N:29]=[C:30]([NH2:32])[CH3:31]>>[OH:1][CH:2]1[CH2:3][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:18][CH:19]=3)[CH2:11][CH:10]([C:25]3[O:26][N:32]=[C:30]([CH3:31])[N:29]=3)[CH2:9]2)=[O:7])[CH2:5]1
Reactant: CC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Product: Cc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CC(O)C3)C2)n1

Procedure:
185 mg (about 0.400 mmol) of the compound from Example 110A and 55 mg (0.600 mmol) of N′-hydroxyethanimidamide were reacted according to the General Method 2. Yield: 16 mg (9% of theory)
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.Br[C:31]1[CH:32]=[C:33]([CH2:37][C:38]([NH:40][CH3:41])=[O:39])[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:13]=[CH:14][C:15]([C:35]2[CH:36]=[CH:31][CH:32]=[C:33]([CH2:37][C:38]([NH:40][CH3:41])=[O:39])[CH:34]=2)=[CH:16][CH:17]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Reactant: CNC(=O)Cc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CNC(=O)Cc1cccc(-c2ccc(O[C@@H](C)[C@H](O)CCc3cccnc3)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
A solution of (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxy]benzeneboronic acid (0.20 g, Example 11), 2-(3-bromophenyl)-N-methyl -acetamide (0.21 g, Example 12a)), 2M aqueous sodium carbonate (0.57 ml) and tetrakis(triphenylphosphine)palladium (0) (0.1 g) in toluene (5 ml) and ethanol (2 ml) was heated at 100° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) was added to a solution of the residue in methanol (5 ml). The suspension was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the residue partitioned between ether and water. The aqueous layer was neutralised and extracted with dichloromethane (2×50 ml). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give the title compound as an oil (0.15 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:14][NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C1(C)C=CC=CC=1.O1CCOCC1>CCO>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[N:14][N:15]2[CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCN1CCCCC1
Reactant: c1ccc(COc2ccc3c(C4CCCC4)n[nH]c3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(COc2ccc3c(C4CCCC4)nn(CCN4CCCCC4)c3c2)cc1
Temperature: 25 °C
Yield: 8 %

Procedure:
6-benzyloxy-3-cyclopentyl-1H-indazole was heated for 1 hour with NaOH (1.64 g, 41 mmol) and 1-(2-chloroethyl)piperidine in EtOH (60 ml) at 40° C. The reaction was followed by TLC (toluene/dioxane: 7/3), and when completed, the mixture was cooled to room temperature. The mixture was quenched by NH4Cl, extracted with AcOEt, dried over Na2SO4, filtered and concentrated under vacuum. Purification by flash chromatography (toluene/1,4-dioxane 7/3) gave the expected product (600 mg, 8% as solid).
Reaction SMILES: [OH-].[K+].CC1[O:21][C:9]2[C:10]([O:19][CH3:20])=[C:11]3[O:18][CH:17]=[CH:16][C:12]3=[C:13]([O:14][CH3:15])[C:8]=2[C:6](=[O:7])[CH:5]=1.Cl>O>[CH3:5][C:6]([C:8]1[C:9]([OH:21])=[C:10]([O:19][CH3:20])[C:11]2[O:18][CH:17]=[CH:16][C:12]=2[C:13]=1[O:14][CH3:15])=[O:7]
Reactant: COc1c2occc2c(OC)c2c(=O)cc(C)oc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1c(C(C)=O)c(O)c(OC)c2occc12
Temperature: 25 °C
Yield: 92.2 %

Procedure:
To a stirred solution of potassium hydroxide (193.2 g) in 1.5 l of water, heated to 75° C., is added 300 g of khellin (formula XXI) in 50 g portions over a period of 30 minutes. When khellin addition is complete, the resulting mixture is then heated to reflux for 2 hr and thereafter cooled to ambient temperature. Concentrated hydrochloric acid (300 ml) is then added to the cooled solution and the resulting precipitate is collected by filtration and dried at ambient temperature in a vacuum for 18 hr. The resulting crude yellow solid is then recrystallized from one liter of methanol, yielding 251 g of pure title product. Melting point is 99°-100° C. Silica gel TLC Rf is 0.60 in hexane and ethyl acetate (1:1). Infrared absorptions are observed at 3160, 3140, 2700, 1695, 1680, 1620, 1590, 1550, 1300, 1265, 1150, 1075, and 1060 cm-1. NMR absorptions are observed at 7.52, 6.91, 4.15, 4.05, 2.72, and 13.06δ (deuterochloroform solvent). The mass spectrum exhibits peaks at 236, 221, 206, 203, 191, 175, 163, and 119. Carbon:hydrogen ratio is 60.65:5.15.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:9][P:10]=[O:11].C1C(C(OOC(C)(C)C)=O)=CC=CC=1.O>CC(O)C.CCCCCCC>[CH2:1]([PH:10](=[O:9])[OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=CCCCCCC
Reactant: O=PO
Agent: CC(C)(C)OOC(=O)c1ccccc1
Solvent: CCCCCCC
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCC[PH](=O)O
Yield: 98.5 %

Procedure:
In a round bottom flask, 1 L (715 g, 6.38 mols) of 1-octene and 1.3 L (12.76 mols) of hypophosphorus acid (50% aqueous solution), 50 mL of tert-butyl perbenzoate, as initiator, and 1.7 L of 2-propanol as solvent are stirred at 80° C. for 7 h. The completed reaction mixture is combined with 2.0 L of water and 2.0 L of n-heptane. The mixture is separated and the organic phase is further washed with 1 L water. The water layer is further washed with 1 L of heptane and all the heptane layers are combined. This mixture is treated with 1 kg of anhydrous sodium sulfate and the solvent is evaporated to obtain 1.12 kg of crude n-octyl phosphinic acid with 85% purity (31P NMR).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=O)[CH3:12])=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:8][CH2:9][N:10]=[C:11]2[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(=O)NCCc1ccc(Cl)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1=NCCc2ccc(Cl)cc21

Procedure:
In close analogy to the procedure described above, N-[2-(4-chloro-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@@H:4]([C@H:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1.[ClH:23].C=O.C(OCC)C>CO.O.CCO.CCCCCC>[ClH:23].[CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[C@@H:4]1[C@@H:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:22][CH2:1][NH:2][CH2:3]1
Reactant: CNC[C@H](c1ccc2ccccc2c1)[C@H](O)c1ccccc1
Agent: C=O
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: O
Product: c1ccc([C@H]2OCNC[C@@H]2c2ccc3ccccc3c2)cc1
Temperature: 65 °C

Procedure:
To a stirred solution of PRC200.HCl (100 mg, 0.361 mmol) dissolved in 2 mL of MeOH was added 36% aq. formaldehyde solution (0.5 mL). This solution was heated at 65° C. overnight. After rotary evaporation of the volatiles, the product was leached with diethyl ether and hexane. The crude product could be purified by converting it to a hydrochloride salt, then crystallization from a solvent mixture prepared by dissolving 5 mL of MeOH, 20 mL of diethyl ether, and 17 mL of hexane. Yield 99 mg, 95%. 1H NMR (CD3OD) δ 7.82-7.69 (m, 4H), 7.63 (s, 1H), 7.48-7.39 (m, 2H), 7.23 (d, J=8.1 Hz, 1H), 7.15 (s, 4H), 5.29 (d, J=9.1 Hz, 1H), 5.09 (d, J=10.3 Hz, 1H), 5.02 (d, J=9.2 Hz, 1H), 3.87 (dd, J=12.2, 12.2 Hz, 1H), 3.75 (dd, J=13.0, 4.1 Hz, 1H), 3.71 (dd, J=4.1 Hz, 1H), 3.57-3.45 (m, 1H); MS: m/z (ESI) 290.11 (M+1)+; [α]D20 +125 (c 0.22, 9:1 EtOH:H2O).
Reaction SMILES: [C:1]([CH:5]([CH:8]=O)[CH:6]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:10][NH:11][C:12](=[O:17])[CH2:13][N+:14]([O-:16])=[O:15].N1CCCC1>C(O)C>[C:1]([C:5]1[CH:6]=[C:13]([N+:14]([O-:16])=[O:15])[C:12](=[O:17])[N:11]([CH3:10])[CH:8]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)C[N+](=O)[O-]
Reactant: CC(C)(C)C(C=O)C=O
Solvent: C1CCNC1
Solvent: CCO
Product: Cn1cc(C(C)(C)C)cc([N+](=O)[O-])c1=O
Yield: 29.5 %

Procedure:
To a solution of 2-tert-butyl-malonaldehyde (385 mg, 3.00 mmol) and the above amide (355 mg, 3.00 mmol) dissolved in ethanol (6.0 mL) was added pyrrolidine (63 microL, 0.750 mmol). The mixture was heated at reflux for 18 h and concentrated in vacuo. Purification by silica-gel chromatography (75% ethyl acetate in hexanes) provided 5-tert-butyl-1-methyl-3-nitro-1H-pyridin-2-one (186 mg, 30%) as an orange solid.
Reaction SMILES: [CH3:1][CH:2]([S:4]([C:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:3].Br[C:17]1[N:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.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.COCCOC>[CH3:1][CH:2]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:17]2[N:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:3]
Reactant: Oc1ccc(Br)nc1
Reactant: CC(C)S(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)S(=O)(=O)c1ccc(-c2ccc(O)cn2)cc1
Yield: 29.5 %

Procedure:
6-{4-[(1-Methylethyl)sulfonyl]phenyl}-3-pyridinol (0.47 g, 29%) was prepared as a tan solid from {4-[(1-methylethyl)sulfonyl]phenyl}boronic acid (1.97 g, 8.62 mmol), 6-bromo-3-pyridinol (1 g, 5.75 mmol), Pd(PPh3)2Cl2 (200 mg, 0.28 mmol), 2M Na2CO3 (5 mL) and DME (5 mL) in a manner similar to Example 21, Step 3. The material was purified by chromatography on a silica gel column eluted with 0 to 5% MeOH/CH2Cl2. 1H NMR (400 MHz, CDCl3): δ 8.36 (d, 1H, J=2.9 Hz), 8.06 (d, 2H, J=8.6 Hz), 7.93 (d, 2H, J=8.6 Hz), 7.68 (d, 1H, J=8.8 Hz), 7.30 (dd, 1H, Ja=8.8 Hz, Jb=2.9 Hz), 3.32-3.16 (m, 1H), 1.30 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 276 (M−H).
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:34]=[C:35]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[CH:36]=[CH:37][CH:38]=2)[CH2:29][CH2:28]1>>[C:17]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]([NH:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH:30]([C:33]3[CH:34]=[C:35]([NH:39][C:40]([CH:42]4[CH2:44][CH2:43]4)=[O:41])[CH:36]=[CH:37][CH:38]=3)[CH2:29][CH2:28]2)=[O:9])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Product: O=C(Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)c1)C1CC1

Procedure:
Example 114 was prepared from triphenylacetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described in Scheme 10: ESMS m/e: 572.3 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[Cl-].[Na+]>CN(C)C=O>[C:22]1([CH:15]([S:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: ClC(Cn1ccnc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.4 %

Procedure:
1.5 g of methyl 4-mercaptobenzoate was dissolved in 8 ml of dry dimethylformamide, and the resulting solution was added to 388 mg of a 55% w/w suspension of sodium hydride in mineral oil, whilst ice-cooling, and then the mixture was stirred at room temperature for 30 minutes. A solution of 1.5 g of 1-(2-chloro-2-phenylethyl)imidazole dissolved in 8 ml of dry dimethylformamide was added to the thus obtained solution, and the mixture was then heated at 65° to 70° C. for 6 hours. At the end of this time, the reaction mixture was poured into a saturated aqueous solution of sodium chloride, and the resulting solution was extracted with diethyl ether. The extract was washed with water and dried over anhydrous potassium carbonate, and then the solvent was removed by distillation. The residue was purified by column chromatography through silica gel (eluent: ethyl acetate:triethylamine=40:1 by volume) to obtain 747 mg of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][S:6][CH2:7][CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:3].[P:16]([O-:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]>>[CH2:18]([O:17][P:16]([O:20][CH2:21][CH3:22])([C:9]([OH:15])([CH2:8][CH2:7][S:6][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:23])[CH3:19]
Reactant: CCOC(=O)C(=O)CCSCCN(C)C
Reactant: CCOP([O-])OCC
Product: CCOC(=O)C(O)(CCSCCN(C)C)P(=O)(OCC)OCC
Reaction time: 96 h

Procedure:
A mixture of 2.33 g (0.01 mole) of ethyl 4-(2-(N,N-dimethylamino)ethylthio)-2-oxobutanoate in 6.9 g (0.05 mole) of diethyl phosphite was stirred at 20°-30° for 4 days. The excess diethyl phosphite is removed under vacuum on a rotary evaporator, and the crude product is purified by flash chromatography on silica gel using chlorofomi/ethanol as eluant.
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[N:9]([CH3:17])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3](=[O:6])[CH:4]=[CH2:5].[C:18]1([NH:24][C:25]2[CH:30]=[CH:29][C:28](Br)=[CH:27][N:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][N:2]([CH2:7][C:8]1[N:9]([CH3:17])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3](=[O:6])/[CH:4]=[CH:5]/[C:28]1[CH:27]=[N:26][C:25]([NH:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:30][CH:29]=1
Reactant: Brc1ccc(Nc2ccccc2)nc1
Reactant: C=CC(=O)N(C)Cc1cc2ccccc2n1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(Nc2ccccc2)nc1
Temperature: 25 °C
Yield: 69 %

Procedure:
N-Methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (from Example 76 (a)) was taken up in propionitrile (50 mL). To this solution was added with stirring 2-phenylamino-5-bromopyridine (1.3 g, 5.2 mmole), DIEA (1.8 mL, 10 mmole), Pd(OAc)2 (112 mg, 0.5 mmole) and P(o-tol)3 (304 mg, 1.0 mmole). The reaction was purged with argon then stirred at reflux for 16 h. After cooling to room temperature the reaction was concentrated to dryness under vacuum. Flash chromatography on silica gel (5% methanol/CHCl3) followed by a second flash column on silica gel (50-70% EtOAc/CHCl3) left a residue that was triturated with EtOAc/petroleum ether. Filtration and drying under vacuum gave the title compound (1.42 g, 69%) as an off-white powder: MS (ES) m/e 396.20 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[C@H:5]([OH:9])[C:6]([OH:8])=O.Cl.[NH2:15][C@H:16]([C:20]([NH:22][N:23]1[C:29](=[O:30])[CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:27]2[CH:41]=[CH:42][CH:43]=[CH:44][C:26]=2[C:25]2[CH2:45][CH2:46][CH:47]=[CH:48][C:24]1=2)=[O:21])[CH:17]([CH3:19])[CH3:18]>>[F:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([F:1])[CH:12]=1)[C@H:5]([OH:9])[C:6]([NH:15][C@H:16]([C:20]([NH:22][N:23]1[C:29](=[O:30])[CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:27]2[CH:41]=[CH:42][CH:43]=[CH:44][C:26]=2[C:25]2[CH:45]=[CH:46][CH:47]=[CH:48][C:24]1=2)=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:8]
Reactant: CC(C)[C@H](N)C(=O)NN1C(=O)C(CCCCc2ccccc2)c2ccccc2C2=C1C=CCC2
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
Agent: Cl
Product: CC(C)[C@H](NC(=O)[C@@H](O)c1cc(F)cc(F)c1)C(=O)NN1C(=O)C(CCCCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-valinyl)amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-U), the title compound was prepared. The product was purified by chromatography (silica, 1-2% MeOH/CHCl3).
Reaction SMILES: [O:1]([CH2:9][C@H:10]1[C@H:18]2[N:13]([C:14]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:19][C:15]=3[O:16][CH2:17]2)[C:12](=[O:30])[O:11]1)[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.CO>C1COCC1>[OH:1][CH2:9][C@H:10]1[C@H:18]2[N:13]([C:14]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:19][C:15]=3[O:16][CH2:17]2)[C:12](=[O:30])[O:11]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1COCCN1c1ccc2c(c1)OC[C@H]1[C@H](CO)OC(=O)N21
Temperature: 0 °C
Yield: 70.8 %

Procedure:
Compound (3R,3aS)-3-((t-butyldimethylsiloxy)methyl)-7-(3-oxomorpholin-4-yl)-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-1 (3H)-one (3.6 g, 8.295 mmol) prepared as above in (a) was dissolved in 50 ml of THF, cooled to 0° C., to which was slowly added tetra-n-butylammonium fluoride (1M, 10 ml). The resulting mixture was raised to room temperature and reacted for 2 h. TLC (DCM/MeOH=10/1) was employed to monitor the reaction. After the reaction completed, THF was evaporated. The resulting mixture was washed with ethyl acetate/n-hexane=1/1 under stirring, filtered under reduced pressure, and dried to afford 1.88 g of white solid, yield 70.86%.
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.[K].[CH3:20][O:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([N:33]3[CH2:38][CH2:37][CH:36]([OH:39])[CH2:35][CH2:34]3)=[CH:30][CH:31]=2)[N:26]([CH3:40])[CH:25]=1)=[O:23].Br[CH2:42][C:43]1[C:44]([C:51]2[C:56]([Cl:57])=[CH:55][CH:54]=[CH:53][C:52]=2[Cl:58])=[N:45][O:46][C:47]=1[CH:48]1[CH2:50][CH2:49]1.[NH4+].[Cl-]>C(O)(C)(C)C.O1CCCC1>[CH3:20][O:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([N:33]3[CH2:38][CH2:37][CH:36]([O:39][CH2:42][C:43]4[C:44]([C:51]5[C:52]([Cl:58])=[CH:53][CH:54]=[CH:55][C:56]=5[Cl:57])=[N:45][O:46][C:47]=4[CH:48]4[CH2:50][CH2:49]4)[CH2:35][CH2:34]3)=[CH:30][CH:31]=2)[N:26]([CH3:40])[CH:25]=1)=[O:23]
Reactant: Clc1cccc(Cl)c1-c1noc(C2CC2)c1CBr
Reactant: COC(=O)c1cn(C)c2cc(N3CCC(O)CC3)ccc12
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [K]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: COC(=O)c1cn(C)c2cc(N3CCC(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)CC3)ccc12
Reaction time: 0.25 h
Yield: 34 %

Procedure:
Tetrahydrofuran (4 mL) is added at room temperature to a mixture of 18-crown-6 (306 mg, 1.14 mmole), tert-butyl alcohol, potassium derivative (134 mg, 1.14 mmole) and 6-(4-hydroxy-piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic acid methyl ester (300 mg, 1.040 mmole). The mixture is stirred for 15 minutes and then 4-bromomethyl-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole (361 mg, 1.04 mmole) is added. After 1.5 h, a saturated solution of NH4Cl is added and extracted with ethyl acetate. The organic layers are combined, dried over anhydrous sodium sulfate, filtered and the solvent is removed under reduced pressure. The residue is purified via flash chromatography (12 g silica) eluting with a gradient of hexane:ethyl acetate from 20% to 100% to provide the title compound (196 mg, 34%) as a white solid. ES/MS m/z 554.0 (M+1)