Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:23]=[CH:22][C:12]([C:13]([C:15]3[CH:20]=[CH:19][C:18](F)=[CH:17][CH:16]=3)=[O:14])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:13]([C:12]2[CH:22]=[CH:23][C:9]([C:8]#[C:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:10][CH:11]=2)=[O:14])=[CH:27][CH:26]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(C#Cc2ccccc2)cc1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1ccc(Oc2ccccc2C(=O)c2ccc(C#Cc3ccccc3)cc2)cc1

Procedure:
The phenylethynyl group has two important advantages over the ethynyl group. These are stability towards conditions of aromatic nucleophilic displacement reactions and stability at moderate temperatures (i.e. 150°-250° C.). For example, when 4-phenylethynyl-4'-fluorobenzophenone was treated with a slight excess of 3 or 4-aminophenol in the presence of an alkali metal base such as potassium carbonate in a polar aprotic solvent such as N,N-dimethylacetamide (DMAc) at 143° C., 3 or 4-aminophenoxy-4'-phenylethynylbenzophenone was afforded in nearly quantitative yield. However, several attempts to make the 3-aminophenoxy-4'-ethynylbenzophenone from the 4-ethynyl-4'-fluorobenzophenone under similar reaction conditions afforded a mixture of products. In addition, imide model compounds of the phenylethynyl endcapper react at a moderate to fast rate in air at 300° to 350° C. whereas analogous model compounds containing the ethynyl group react at a moderate to fast rate in air at 200° to 250° C. Phenylethynyl containing imide model compounds are reasonably stable at 200° C. (see Example 6) whereasthynyl containing imide model compounds react at 200° C.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]([CH3:14])[CH:11]([OH:15])[C:10]([CH3:18])([CH2:16][CH3:17])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[CH3:18][C:10]1([CH2:16][CH3:17])[CH:11]([OH:15])[CH:12]([CH3:14])[CH2:13][NH:8][CH2:9]1
Reactant: [H][H]
Reactant: CCC1(C)CN(Cc2ccccc2)CC(C)C1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1(C)CNCC(C)C1O

Procedure:
A mixture of 1-benzyl-3,5-dimethyl-3-ethyl-4-hydroxypiperidine (2.9 g, 11.74 mmole) and 20% palladium hydroxide (0.5 g) in methanol (20 ml) was stirred in hydrogen atmosphere (1 atm.) for 8 hr at 35° C. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 3,5-dimethyl-3-ethyl-4-hydroxypiperidine as oil. Yield 1.7 g (93%), C9H19NO, m/z 158 (M+1).
Reaction SMILES: C(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C1(O)C=CC=CC=1.C1(O)C=CC=CC=1.C(OC1C=CC=CC=1)=O.C(OC1C=CC=CC=1)=O.[CH:49]1[C:54]([CH2:55][C:56]2[CH:61]=[CH:60][C:59]([N:62]=C=O)=[CH:58][CH:57]=2)=[CH:53][CH:52]=[C:51]([N:65]=C=O)[CH:50]=1.C(OC1C=CC=CC=1)(=O)N>C(O)=O>[CH2:55]([C:56]1[CH:61]=[CH:60][C:59]([NH2:62])=[CH:58][CH:57]=1)[C:54]1[CH:53]=[CH:52][C:51]([NH2:65])=[CH:50][CH:49]=1
Reactant: O=C=Nc1ccc(Cc2ccc(N=C=O)cc2)cc1
Agent: NC(=O)Oc1ccccc1
Agent: O=C(Oc1ccccc1)Oc1ccccc1
Agent: O=COc1ccccc1
Solvent: Oc1ccccc1
Solvent: O=CO
Product: Nc1ccc(Cc2ccc(N)cc2)cc1
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
The di-formamide of 4,4′-methylene-dianiline is prepared by the reaction of the diamine with 2.1 molar equivalents of formic acid, and removing the water byproduct by azeotropic distillation with toluene. Using the same apparatus as Example 1, but without the addition funnel, diphenyl carbonate (48.45 grams, 0.226 mole) and 4,4′-MDA-di-formamide (6.92 grams, 0.0272 mole), containing 0.21 grams of phenol, is heated to reflux at 38 mmHg. Reaction and phenol/phenyl formate distillation commences at a pot temperature of 155° C., and ceases 30 minutes later at a pot temperature of 195° C., 17 mmHg. IS/GC analysis of the condensate (10.55 grams) shows only phenyl formate, phenol and a trace of DPC. The pot material (43.97 grams) contains 3.02 grams of 4,4′-diphenylmethane diisocyanate (MDI) and 3.21 grams of MDI as the mono-phenol carbamate, a recovery of 0.0249 mole equivalents of MDI, equal to a 91.6% yield, based on di-formamide charged.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][NH:17][CH:18]1[CH:23]2[CH2:24][CH2:25][CH:19]1[CH2:20][N:21]([CH2:26][CH2:27][CH2:28][NH:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1)[CH2:22]2.[CH3:38][CH:39]([CH3:44])[CH2:40][C:41](O)=[O:42].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[C:34]([C:33]1[CH:32]=[CH:31][C:30]([NH:29][CH2:28][CH2:27][CH2:26][N:21]2[CH2:22][CH:23]3[CH:18]([N:17]([CH3:16])[C:41](=[O:42])[CH2:40][CH:39]([CH3:44])[CH3:38])[CH:19]([CH2:25][CH2:24]3)[CH2:20]2)=[CH:37][CH:36]=1)#[N:35]
Reactant: CC(C)CC(=O)O
Reactant: CNC1C2CCC1CN(CCCNc1ccc(C#N)cc1)C2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)CC(=O)N(C)C1C2CCC1CN(CCCNc1ccc(C#N)cc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
1,3-Dicyclohexylcarbodiimide on N-methylpolystyrene (0.67 g of 2.39 mmol/g, 1.74 mmol) was added to a solution of 4-({3-[8-(methylamino)-3-azabicyclo[3.2.1]oct-3-yl]propyl}amino)benzonitrile (Peparation G; 74.6 mg, 0.25 mmol) in DMF (3.0 mL). A solution of 3-methylbutyric acid (105.0 mg, 1.02 mmol) in DCM (1.0 mL) was added, and the mixture was stirred overnight at rt, followed by a further 72 h at 50° C. Polystyrene isocyanate (150 mg) and DCM (1.5 mL) were added, and this mixture was stirred for 1.5 h. K2CO3 (75 mg) was added and the mixture stirred for an additional 5 h. The solvents were evaporated and DCM (3 mL) was added to the resulting residue. This mixture was added to an ion-exchange solid-phase extraction plug (CBA). The plug was washed with DCM:MeCN (4:1; 10 mL). The product was then eluted with DCM:MeOH:TEA (90:5:5; 7.5 mL) to give 75 mg (70.9%) of the title compound.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=[O:2].[NH2:13][CH:14]1[C:20](=[O:21])[N:19]([CH2:22][C:23]([N:25](C(C)C)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[C:18]2[CH:35]=[CH:36][CH:37]=[CH:38][C:17]=2[C:16](C2C=CC=CC=2)=[N:15]1.Cl.[N:46]1[NH:47][N:48]=[N:49][C:50]=1[C:51]1[CH:52]=C(N)C=[CH:55][CH:56]=1>C1COCC1>[CH:26]([CH:22]([N:19]1[C:18]2[CH:17]=[CH:38][CH:37]=[CH:36][C:35]=2[C:16]([C:17]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:18]=2)=[N:15][CH:14]([NH:13][C:1]([NH:8][C:12]2[CH:11]=[CH:55][CH:56]=[C:51]([C:50]3[NH:46][N:47]=[N:48][N:49]=3)[CH:52]=2)=[O:2])[C:20]1=[O:21])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24])([CH3:31])[CH3:27]
Reactant: Nc1cccc(-c2nn[nH]n2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)N(C(=O)CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)C(C(=O)Nc1ccccc1)N1C(=O)C(NC(=O)Nc2cccc(-c3nnn[nH]3)c2)N=C(c2ccccc2)c2ccccc21

Procedure:
According to Process B, a mixture of of 1,1'-carbonyldiimidazole (28.6 mg, 0.176 mmol) and 2-(3-Amino-2-oxo-5-phenyl-2,3-dihydro-benzo[e][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl-acetamide (75.0 mg, 0.176 mmol), prepared as in Intermediate 13, in anhydrous THF (5 mL) is stirred at ambient temperature under a nitrogen atmosphere for approximately 30 min. and then heated to reflux. After refluxing for 2 hrs, 3-(2H-tetrazol-5-yl)-phenylamine hydrochloride (36.5 mg, 0.185 mmol), prepared as in Intermediate 17, is added in one portion and the reaction is held at reflux for an additional 5 hrs and then concentrated in vacuo to a residue. The residue is purified by reversed-phase HPLC on a C-18 column with a gradient elution of 30-68% acetonitrile in aqueous trifluoroacetic acid (0.1% v/v) over 30 min. at 100 mL/min. Fractions containing the product are combined, frozen, and lyophilized to provide the title compound as a white lyophile (37 mg, 0.060 mmol). 1H NMR (300 MHz, d6-DMSO) δ=1.04 (d, 6H); 4.21 (d, J=16.4 Hz, 1H); 4.31 (d, J=17.1 Hz, 1H); 4.79-6.86 (m, 1H); 5.35-5.36 (m, 1H); 7.32-7.78 (m, 19H); 8.26 (b, 1H); 9.38 (b, 1H); MS (ESI): [M+H]+ =614.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:19])[CH:17]=[CH2:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1([CH2:23][NH2:24])[CH2:22][CH2:21]1>C(#N)C>[CH2:1]([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:19])[CH2:17][CH2:18][N:24]([CH2:18][CH2:17][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:19])[CH2:23][CH:20]1[CH2:22][CH2:21]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Reactant: NCC1CC1
Solvent: CC#N
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)CCN(CCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1)CC1CC1
Reaction time: 16 h
Yield: 43.9 %

Procedure:
A solution of 444 mg (1.71 mmol) (R)-1-acryloyl-pyrrolidine-2-carboxylic acid benzyl ester and 74 ml (0.85 mmol) cyclopropylmethylamine in 5 ml acetonitrile was stirred for 1 h at room temperature, then for 16 h at 80° C. Concentration in vacuo and flash chromatography (gradient: 0-100% MeOH in EtOAc) afforded 220 mg (44%) of the title compound as a yellow oil. MS m/e (%): 590 (M+H+, 100).
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[CH3:7]I.[C:9](O)([C:11]([F:14])([F:13])[F:12])=O>CCO>[CH3:1][N:2]1[C:9]([C:11]([F:14])([F:13])[F:12])=[N:5][N:4]=[C:3]1[S:6][CH3:7]
Reactant: CNC(=S)NN
Reactant: O=C(O)C(F)(F)F
Reactant: CI
Solvent: CCO
Product: CSc1nnc(C(F)(F)F)n1C

Procedure:
4-Methylthiosemicarbazid (10.0 g, 95.09 mmol) in TFA (46.7 ml) was heated to reflux o.n. Excess TFA was removed via evaporation. The residue was dissolved in aq. 1M NaOH (100 ml), followed by dropwise addition of CH3I (4.47 ml, 71.17 mmol) in EtOH (22 ml). The resulting mixture was stirred o.n. Partial evaporation of the solvent induced crystallization. After dilution with H2O the solid was collected via filtration and gave after drying the title compound (5.2 g, 28%). MS (M++1) 198
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[N:13]([C:17]3[CH:18]=[C:19]([C:23]4[O:27][C:26](=[O:28])[N:25]([CH3:29])[N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:12][C@H:11]3[N:7]([CH2:8][CH2:9][CH2:10]3)[C:6]=2[N:5]=[C:4]([S:30][CH3:31])[N:3]=1.[CH:32]1([NH2:35])[CH2:34][CH2:33]1>C1COCC1>[CH:32]1([NH:35][C:2]2[C:15]3[C:14](=[O:16])[N:13]([C:17]4[CH:18]=[C:19]([C:23]5[O:27][C:26](=[O:28])[N:25]([CH3:29])[N:24]=5)[CH:20]=[CH:21][CH:22]=4)[CH2:12][C@H:11]4[N:7]([CH2:8][CH2:9][CH2:10]4)[C:6]=3[N:5]=[C:4]([S:30][CH3:31])[N:3]=2)[CH2:34][CH2:33]1
Reactant: NC1CC1
Reactant: CSc1nc(Cl)c2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn(C)c(=O)o3)c1)C2=O
Solvent: C1CCOC1
Product: CSc1nc(NC2CC2)c2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn(C)c(=O)o3)c1)C2=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
(S)-5-[3-(7-Chloro-9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-3-methyl-1,3,4-oxadiazol-2(3H)-one (30.0 mg, 0.0654 mmol) obtained in Step 8 of Example 156 was dissolved in THF (3 mL), and the mixture was stirred at room temperature for 17 hours after adding cyclopropylamine (0.023 mL, 0.327 mmol). The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give (S)-5-[3-(7-cyclopropylamino-9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-3-methyl-1,3,4-oxadiazol-2 (3H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:12][CH2:13][C:14]1[N:18]([C:19]2[S:20][C:21]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:22][C:23]=2[C:24](=[O:32])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:17]([CH3:38])=[N:16][N:15]=1>>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:24]([C:23]1[CH:22]=[C:21]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[S:20][C:19]=1[N:18]1[C:17]([CH3:38])=[N:16][N:15]=[C:14]1[CH2:13][NH:12][C:10]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:11])=[O:32]
Reactant: COC(=O)Cc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Reactant: COc1cccc(N=C=O)c1
Product: COC(=O)Cc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)Nc2cccc(OC)c2)s1

Procedure:
3-Methoxyphenyl isocyanate and methyl (2-(3-aminomethyl-5-methyl[1,2,4]triazol-4-yl)-3-(2-chlorobenzoyl)thiophen-5-yl)acetate are reacted to give methyl (3-(2-chlorobenzoyl)-2-(3-(3-(3-methoxyphenyl)ureidomethyl)-5-methyl[1,2,4]triazol-4-yl)thiophen-5-yl)acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[NH:7]C(=O)O[C:10](=[O:11])[C:5]=2[CH:4]=1.[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>CN(C=O)C>[NH2:7][C:6]1[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:10]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([Br:15])=[CH:17][CH:18]=1)=[O:11]
Reactant: Nc1ccc(Br)cc1
Reactant: COc1ccc2[nH]c(=O)oc(=O)c2c1
Solvent: CN(C)C=O
Product: COc1ccc(N)c(C(=O)Nc2ccc(Br)cc2)c1

Procedure:
A solution of 6-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione (0.800 g, 4.10 mmol) and 4-bromoaniline (0.750 g, 4.30 mmol) in anhydrous DMF (10 mL) was stirred at 115° C. for 16 hours under nitrogen. DMF was removed and the residue was mixed with water (100 mL) and ethyl acetate (150 mL). The organic phase was separated, backwashed with brine (50 mL), and concentrated. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate=1:1) to give 2-amino-N-(4-bromo-phenyl)-5-methoxy-benzamide. Yield: 0.240 g (18%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:6][C:7]([CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][CH2:10]1)=[O:8]>>[CH3:15][C:13]1([CH3:16])[CH2:12][CH2:11][CH2:10][CH:9]([C:7]([OH:8])([CH2:2][CH2:3][CH2:4][CH3:5])[CH3:6])[CH2:14]1
Reactant: CC(=O)C1CCCC(C)(C)C1
Reactant: CCCCBr
Product: CCCCC(C)(O)C1CCCC(C)(C)C1

Procedure:
The protocol of example 1 is carried out again with 1-bromobutane replacing bromoethane and herbac replacing dehydroherbac.
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]1[CH2:18][C:17](=[O:19])[NH:16][C:14]1=[O:15])=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:20](=O)(SC)OC(OC(=O)C(C)(C)C)C>>[C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]1[CH2:18][C:17](=[O:19])[NH:16][C:14]1=[O:15])=[O:11])[CH3:8])(=[O:5])[C:2]([CH3:20])([CH3:4])[CH3:3]
Reactant: CSC(=O)OC(C)OC(=O)C(C)(C)C
Reactant: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Product: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)(C)C

Procedure:
Following the procedures for synthesizing [(1-isobutanoyloxyethoxy)carbonyloxy]succinimide (17) and replacing compound (2) with compound (5) affords [(1-pivaloyloxyethoxy)carbonyloxy]succinimide (19).
Reaction SMILES: S(=O)(=O)(O)[O-].[K+].[K+].C(OC([C:13]1[C:17](=[O:18])[O:16][CH2:15][C:14]=1[O-])=O)C.[Cl:20][C:21]1[N:26]=[CH:25][C:24]([CH2:27][NH:28][CH2:29][CH:30]([F:32])[F:31])=[CH:23][CH:22]=1.O>C(#N)CCC.ClCCl>[Cl:20][C:21]1[N:26]=[CH:25][C:24]([CH2:27][N:28]([CH2:29][CH:30]([F:32])[F:31])[C:14]2[CH2:15][O:16][C:17](=[O:18])[CH:13]=2)=[CH:23][CH:22]=1
Reactant: FC(F)CNCc1ccc(Cl)nc1
Reactant: CCOC(=O)C1=C([O-])COC1=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CCCC#N
Product: O=C1C=C(N(Cc2ccc(Cl)nc2)CC(F)F)CO1
Temperature: 92.5 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
At room temperature, 11.5 g of potassium bisulphate are added to a suspension of 10.4 g of 4-(ethoxycarbonyl)-5-oxo-2,5-dihydrofuran-3-olate potassium salt and 7.5 g of N-[(6-chloropyridin-3-yl)methyl)-2,2-difluoroethylamine in 68 ml of butyronitrile. The mixture is stirred at a temperature of from 90 to 95° C. for 3 hours. The mixture is then cooled to room temperature, 120 ml of water and 120 ml of dichloromethane are added, the organic phase is separated off and the aqueous phase is extracted twice with in each case 120 ml of methylene chloride. The combined organic phases are concentrated to dryness. This gives 11.4 g of amorphous 4-[[(6-chloropyridin-3-yl)methyl](2,2-difluoroethyl)amino]furan-2(5H)-one in a purity of 84% (this corresponds to a yield of 92%).
Reaction SMILES: [I:1][CH2:2][C:3]([NH2:5])=[O:4].[O:6]1[CH:10]2[O:11][CH2:12][CH2:13][N:9]2[CH2:8][CH2:7]1>CO>[I-:1].[NH2:5][C:3](=[O:4])[CH2:2][N+:9]12[CH2:13][CH2:12][O:11][CH:10]1[O:6][CH2:7][CH2:8]2
Reactant: NC(=O)CI
Reactant: C1CN2CCOC2O1
Solvent: CO
Product: NC(=O)C[N+]12CCOC1OCC2
Product: [I-]
Yield: 68 %

Procedure:
A solution of 1.850 g (10 mmol) iodoacetamide and 1.152 g (10 mmol) tetrahydro[1,3]oxazolo[2,3-b][1,3]oxazole in 20 ml of methanol was refluxed for 1 hour. The solvent was then removed under reduced pressure and the residue was allowed to crystallize overnight. The precipitate was filtered off, washed twice with dichloromethane and dried. 2.041 g (68.0%) of white crystalline product was obtained.
Reaction SMILES: N1C=CC=CC=1.[I:7]Cl.[CH3:9][CH2:10][C@@:11]1([OH:38])[C:16](=[O:17])[O:15][CH2:14][C:13]2[C:18]([N:20]3[C:24](=[CH:25][C:12]1=2)[C:23]1[N:26]=[C:27]2[C:32](=[CH:33][C:22]=1[CH2:21]3)[C:31]([CH2:34][CH:35]=[CH2:36])=[C:30]([OH:37])[CH:29]=[CH:28]2)=[O:19]>C(Cl)(Cl)Cl.[N+]([O-])([O-])=O.[Ag+]>[CH2:10]([C@:11]1([OH:38])[C:12]2[CH:25]=[C:24]3[N:20]([CH2:21][C:22]4[C:23]3=[N:26][C:27]3[C:32]([CH:33]=4)=[C:31]4[CH2:34][CH:35]([CH2:36][I:7])[O:37][C:30]4=[CH:29][CH:28]=3)[C:18](=[O:19])[C:13]=2[CH2:14][O:15][C:16]1=[O:17])[CH3:9]
Reactant: C=CCc1c(O)ccc2nc3c(cc12)Cn1c-3cc2c(c1=O)COC(=O)[C@]2(O)CC
Reactant: ClI
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c4c(ccc3nc2-1)OC(CI)C4
Reaction time: 0.25 h

Procedure:
Silver nitrate (6.8 g, 0.040 mol) in dry, freshly distilled chloroform (50 mL) and dry pyridine (20 mL) was treated, dropwise, with stirring with a solution of iodine monochloride (6.48 g, 0.0400 mol) in dry chloroform (40 mL) over a two min period. After stirring for 15 min, the mixture was centrifuged; the supernatent was then added to a solution of (S)-9-allyl-10-hydroxycamptothecin (3.92 g, 0.00960 mol) in dry chloroform (15 mL) giving a deep amber solution which was stirred overnight at ambient temperature. The solution was concentrated to a small volume and then partitioned between methylene chloride and water. After separation of the layers, the aqueous phase was re-extracted with methylene chloride. The combined organic layer was washed successsively with ice cold 5% aq. HCl, dilute sodium thiosulfate solution, and finally with water. The solution was dried (sodium sulfate) and evaporated to a golden-brown residue which was triturated with a small amount of cold methanol to afford the title compound as a light brown solid. (2.25 g, 44%). 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=4.3 Hz, 1H), 8.07 (d, J=9.2 Hz, 1H), 7.61 (s, 1H), 7.40 (dd, J=7.1 Hz and J=2.0 Hz, 1H), 5.73 (d, J=16.3 Hz, 1H), 5.29 (d, J=16.3 Hz, 1H), 5.26 (s, 2H), 5.20-5.10 (m, 1H), 3.83-3.81 (m, 1H), 3.72-3.70 (m, 1H), 3.57-3.54 (m, 1H), 3.49-3.46 (m, 1H), 3.39-3.38 (m, 1H), 1.92-1.84 (m, 2H), 1.03 (t, J=7.3 Hz, 3H). Anal.: (C23H19IN2O5.1/2H2O) calcd.: C, 51.22; H, 3.74; N, 5.19 found: C, 51.03; H, 3.56; N, 4.87.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15]N)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:18]=O.[C:20]([BH3-])#[N:21].[Na+]>CO.C(O)(=O)C.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:21]([CH3:20])[CH3:18])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: C=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)CC[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
To a suspension of tert-butyl[trans-4-(2-aminoethyl)cyclohexyl]carbamate (970 mg, 4.0 mmol) and paraformaldehyde (360 mg, 12 mmol) in methanol (40 mL) was added sodium cyanoborohydride (750 mg, 12 mmol) and acetic acid (1 drop). The resultant suspension was stirred at room temperature for 16 h, diluted with a saturated NaHCO3 solution and extracted with a mixture of CHCl3/isopropanol (3:1). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, methanol/dichloromethane) to afford the desired product (340 mg, 31%) as a white solid. ESI MS m/z 271 [C15H30N2O2+H]+
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[N:36]1([S:33]([C:29]2[CH:28]=[C:27]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)=[N:8][C:7]=34)[CH:32]=[CH:31][CH:30]=2)(=[O:34])=[O:35])[CH2:37][CH2:38][O:39][CH2:40][CH2:41]1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(c1cccc(Br)c1)N1CCOCC1
Product: O=S(=O)(c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1)N1CCOCC1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 4-(3-bromo-benzenesulfonyl)-morpholine (example B.31) (275 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (490 mg, 84%). MS (ISP) 581.2 [(M+H)+]; mp 203-204° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:3][CH:2]=1.[OH:13][N:14]=C(C1C=CC=CN=1)C(OCC)=O>>[OH:13][N:14]=[C:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)Cc1ccncc1
Reactant: CCOC(=O)C(=NO)c1ccccn1
Product: CCOC(=O)C(=NO)c1ccncc1
Yield: 82 %

Procedure:
The oxime was prepared in 82% yield from ethyl pyridine-4-acetate using a procedure similar to that described above under Examples 321-324 for the preparation of ethyl hydroxyimino-pyridine-2-acetate.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Cl)[C:5]=1[NH:12][C:13](=[O:29])[CH2:14][CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH3:3])[CH3:2].[O:30]1CCC[CH2:31]1.O>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:31][OH:30])[C:5]=1[NH:12][C:13](=[O:29])[CH2:14][CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(C)c1cccc(CCl)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)c1cccc(CCO)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 60 °C
Reaction time: 7 h
Yield: 66 %

Procedure:
4.24 g (25 mmol) of silver nitrate were added to a solution of 10.14 g (25.0 mmol) N-(2-isopropyl-6-chloromethylphenyl)-2-(9H-xanthen-9-yl)acetamide [prepared as described in step (iv) above] in a mixture of 500 ml of acetone, 100 ml of tetrahydrofuran and 200 ml of water, and the resulting mixture was stirred for 7 hours at 60° C. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the concentrate was diluted with ethyl acetate. The diluted mixture was washed with water and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 3:1 by volume mixture of methylene chloride and ethyl acetate as the eluent, to give 6.41 g (yield 66%) of the title compound as crystals.