Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([F:24])([F:23])[F:22])[N:3]=1.[OH:25][CH2:26][C@H:27]1[O:32][CH2:31][CH2:30][N:29]([C:33]2[S:34][CH2:35][C:36](=[O:38])[N:37]=2)[CH2:28]1>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[C:35]3[S:34][C:33]([N:29]4[CH2:30][CH2:31][O:32][CH:27]([CH2:26][OH:25])[CH2:28]4)=[N:37][C:36]3=[O:38])[CH:9]=2)[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([F:22])([F:23])[F:24])[N:3]=1
Reactant: O=Cc1ccc2c(c1)c(Cl)nn2Cc1ccc(Cl)cc1C(F)(F)F
Reactant: O=C1CSC(N2CCO[C@H](CO)C2)=N1
Product: O=C1N=C(N2CCOC(CO)C2)SC1=Cc1ccc2c(c1)c(Cl)nn2Cc1ccc(Cl)cc1C(F)(F)F

Procedure:
5-[3-Chloro-1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(2-hydroxymethyl-morpholin-4-yl)-thiazol-4-one was prepared from 3-Chloro-1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and 2-(2-(S)—Hydroxymethyl-morpholin-4-yl)-thiazol-4-one following general procedure D.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:15])=[C:7]([CH:14]=1)[C:8]([O:10]C(C)C)=[O:9])=[CH2:2].I[C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[OH:15][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[CH:2][C:17]2[CH:18]=[CH:19][C:20]([S:23]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[CH:14][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=S(=O)(Nc1ccccn1)c1ccc(I)cc1
Reactant: C=Cc1ccc(O)c(C(=O)OC(C)C)c1
Product: O=C(O)c1cc(C=Cc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O
Yield: 40 %

Procedure:
Isopropyl 5-ethenyl-2-hydroxybenzoate was reacted with 4-iodo-N-(2-pyridinyl)benzenesulfonamide similarly to the procedure of Example 5c. After the reaction, the solvent was evaporated, toluene was added and the suspension filtered and washed with toluene. After drying on the filter and washing with water the material was hydrolyzed and precipitated similarly to the procedure of Example 3c. Yield 40%
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][OH:17].[Na]>O>[C:1]([O:17][CH2:16][CH2:15][N:14]([CH3:18])[CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCO
Reactant: O=C(Cl)c1ccccc1
Agent: [Na]
Solvent: ClCCl
Solvent: O
Product: CN(C)CCOC(=O)c1ccccc1
Reaction time: 3.25 h
Yield: 61.6 %

Procedure:
A solution of 70.29 grams (0.50 mol) of benzoyl chloride in 500 milliters of methylene chloride was added to a solution of 44.57 grams (0.50 mol) of 2-dimethylaminoethanol, 20.0 grams (0.50 mol) of sodium hydroxideand 500 milliters of water over 15 minutes with rapid stirring. Stirring was continued for 3.25 hours after which the organic layer was separated, washed with water, dried over MgSO4 and concentrated. Distillation of the residue gave 59.5 grams of product; bp=102°-108° C./0.50 min.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[NH2:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([NH:24][C:23]1[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:21]([O:20][CH3:19])[CH:22]=1)=[O:15]
Reactant: O=C(O)c1cccc(-c2nc3ncccc3o2)c1
Reactant: COc1cc(N)cc(OC)c1OC
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: CCOC(C)=O
Product: COc1cc(NC(=O)c2cccc(-c3nc4ncccc4o3)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
For amide formation, 3-(oxazolo[4,5-b]pyridin-2-yl)benzoic acid (30 mg, 0.125 mmol) was dissolved in 2 mL of DMF along with 3,4,5-trimethoxyaniline (23 mg, 1 eq) and 71 mg of HATU (1.5 eq). After 45 microliters of DIEA (2 eq) were added, the reaction mixture was stirred at room temperature for 18 hrs. It was then diluted with ethyl acetate and washed with water and concentrated. The resulting residue was purified by chromatography using a 9:1 mixture of CH2Cl2 to MeOH to afford 3-(oxazolo[4,5-b]pyridin-2-yl)-N-(3,4,5-trimethoxyphenyl)benzamide. (MS, M++H=406).
Reaction SMILES: [CH2:1]([P+:3]([CH2:8]O)([CH2:6]O)[CH2:4]O)O.[Cl-:10].[CH3:11][N:12]([CH3:16])[C:13]([NH2:15])=[O:14]>C1(C)C=CC=CC=1>[Cl-:10].[CH3:11][N:12]([CH3:16])[C:13](=[O:14])[NH:15][CH2:8][P+:3]([CH2:1][NH:15][C:13]([N:12]([CH3:16])[CH3:11])=[O:14])([CH2:4][NH:15][C:13]([N:12]([CH3:16])[CH3:11])=[O:14])[CH2:6][NH:15][C:13]([N:12]([CH3:16])[CH3:11])=[O:14]
Reactant: OC[P+](CO)(CO)CO
Reactant: CN(C)C(N)=O
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CN(C)C(=O)NC[P+](CNC(=O)N(C)C)(CNC(=O)N(C)C)CNC(=O)N(C)C
Yield: 99.7 %

Procedure:
Reaction of THPC (9.53 g, 0.05 mol) with 1,1-dimethylurea (17.62 g, 0.2 mol) in toluene (75 ml), following Example 1, gave 23.47 g (99.7%) of tetrakis(3,3-dimethylureidomethyl)phosphonium chloride (I, R=H, R'=R"=CH3, X=Cl) as a colorless, hygroscopic resin.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:18].[OH-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([Cl:18])[C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccsc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(Cl)c1ccsc1
Reaction time: 0.17 h
Yield: 55.8 %

Procedure:
To a solution of 12.2 g of 2-t-butoxycarbonylamino-1-(3-thienyl)ethanol [prepared as described in step (a) above] in 100 ml of absolute methylene chloride was added a solution of 10.4 g of phosphorus pentachloride in 200 ml of absolute methylene chloride at 0° to -5° C. After the addition, the reaction mixture was stirred for 10 minutes. To the reaction mixture was added a 4N aqueous solution of sodium hydroxide, and the mixture was stirred for 5 minutes. The methylene chloride layer was separated, washed with large amount of water and dried over anhydrous magnesium sulfate, and the solvent was evaporated off. The residue was subjected to silica gel column chromatography using a 1:4 by volume mixture of ethyl acetate and cyclohexane as eluent, to yield 7.3 g of the title compound melting at 63°-65° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:27][CH:26]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([N:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[CH:30]=3)[CH2:25]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[OH-].[Na+].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:27][CH:26]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([N:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[CH:30]=3)[CH2:25]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Oc4cccc(N5CCNCC5)c4)C3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Oc4cccc(N5CCNCC5)c4)C3)CC2)cc1
Temperature: 60 °C
Yield: 77.5 %

Procedure:
To a solution of methyl 4-(1-(5-chloro-2-(3-(3-(piperazin-1-yl)phenoxy)azetidin-1-yl)nicotinamido)cyclopropyl)benzoate (D156) (105 mg, 0.186 mmol) in a mixture 1-4-dioxane/water (3 ml/1 ml), 1N NaOH (0.28 ml) was added. The reaction mixture was heated to 60° C. overnight. After cooling at room temperature, the reaction mixture was acidified with 1N HCl (pH=1) and the solvents were evaporated in vacuo. The residue was loaded on Porapak RXN RP cartridge (5 g) eluting with water+0.1% acetic acid/acetonitrile+0.1% acetic acid from 90/10 to 0/100. Collected fractions after solvente evaporation afforded the title compound (E21) (79 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH2:18]2)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1.[C:40]([C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][C:43]=1[F:51])#[N:41].[F-].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[C:40]([C:42]1[CH:47]=[CH:46][C:45]([C:2]2[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[CH2:28][CH2:27]4)[CH2:18]3)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=2)=[CH:44][C:43]=1[F:51])#[N:41]
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccc(C#N)c(F)c2)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 49.3 %

Procedure:
To 300.0 mg (0.49 mmol) tert-butyl 4-{3-[(3R)-3-{[1-(5-bromopyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 8c) in 12 ml toluene were added 11.4 mg (0.01 mmol) tetrakis(triphenylphosphine)palladium(0), 97.4 mg (0.59 mmol) (4-cyano-3-fluoro-phenyl)boronic acid in 3.0 ml ethanol and 57.2 mg (0.98 mmol) potassium fluoride in 3.0 ml water. The mixture was stirred at 100° C. for 10 hours and at 60° C. for 20 hours, diluted with water and extracted with ethyl acetate and sodium hydrogen carbonate solution. The organic phase was dried over sodium sulfate and concentrated in vacuum. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-95/5-90/10) gave 157 mg (44%) tert-butyl 4-{3-[(3R)-3-({1-[5-(4-cyano-3-fluorophenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:18]([OH:20])=O)[CH2:13][O:14][CH:15]([CH3:17])[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:22]1CCOCC1.C(OC(Cl)=O)C(C)C.N>O1CCCC1>[NH2:22][C:18](=[O:20])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][O:14][CH:15]([CH3:17])[CH3:16]
Reactant: CN1CCOCC1
Reactant: CC(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)OC[C@H](NC(=O)OCc1ccccc1)C(N)=O
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
N-[(benzyloxy)carbonyl]-O-isopropyl-L-serine (0.346 g, 1.23 mmol) was dissolved in tetrahydrofuran (5 ml) and the resulting solution was cooled to −10° C. N-methyl morpholine (0.189 g, 1.84 mmol) was added, followed by isobutylchloroformate (0.21 g, 1.48 mmol) over a period of 5 minutes. The reaction mixture was stirred for 10 minutes at −10° C. and aqueous ammonia (approximately 500 μl) was added in one portion and the reaction mixture was allowed to warm to room temperature. The resulting suspension was concentrated and extracted with EtOAc (2×20 ml). The combined extracts were washed with water (5 ml), 10% w/v aqueous solution of potassium hydrogensulfate, saturated aqueous sodium bicarbonate (5 ml) and water (5 ml). The organics were dried over magnesium sulfate filtered and concentrated to give benzyl [(1S)-2-amino-1-(isopropoxymethyl)-2-oxoethyl]carbamate as a white solid, (0.340 g, 100%); 1H NMR Spectrum: (CDCl3) 1.15 (m, 6H), 3.66 (m, 1H), 3.86 (m, 2H), 4.28 (m, 1H), 5.13 (s, 2H), 5.43 (br s, 1H), 5.72 (br s, 1H), 6.54 (br s, 1H), 7.35 (m, 5H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:35](OSC1C=CC=CC=1[N+]([O-])=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1C=C(SSC2N=CC=CC=2)N=CC=1>C(Cl)Cl>[CH2:35]([O:14][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1SOCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: ClCCl
Product: O=C(CNC(=O)OCc1ccccc1)OCc1ccccc1

Procedure:
A mixture of 2.09 g. of N-benzyloxycarbonylglycine, 2.62 g. of triphenyl phosphine, 2.61 g. of 2-nitrobenzenesulfenic acid benzyl ester, 2.20 g. of 2,2'-dipyridyl disulfide and 50 ml. of methylene chloride is stirred at room temperature for 3 hours. The reaction mixture is washed successively with water, saturated aqueous sodium bicarbonate, water, 0.1 N hydrochloric acid and water and then dried over anhydrous sodium sulfate. The solvent is distilled off. The residue is dissolved in methylene chloride. The solution is subjected to column chromatography using silica gel and eluted with methylene chloride. Distillation of the solvent from the eluate gives 2.51 g. of the desired product melting at 72°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3[CH:21]=[N:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=3[N:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:36]=[CH:37][C:38]([CH3:42])=[C:39]([OH:41])[CH:40]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3[CH:21]=[N:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=3[N:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2[O:41][C:39]2[CH:40]=[C:35]([F:34])[CH:36]=[CH:37][C:38]=2[CH3:42])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(F)cc1O
Reactant: COc1cc2c(cn1)c(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c(Cl)n2-c1ccccc1
Product: COc1cc2c(cn1)c(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c(Oc1cc(F)ccc1C)n2-c1ccccc1

Procedure:
The title compound was prepared analogously as described in example 1, step 6, from the compound of example 32, step 6, (100 mg, 212 μmol) and 5-fluoro-2-methylphenol.
Reaction SMILES: [OH-].[K+].C(OC(=O)[NH:7][C:8]1[C:13]([C:14]#[C:15][Si](C)(C)C)=[CH:12][CH:11]=[CH:10][C:9]=1[O:20][C:21]([F:24])([F:23])[F:22])C>C(O)(C)(C)C>[F:22][C:21]([F:24])([F:23])[O:20][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[NH:7][CH:15]=[CH:14]2
Reactant: CCOC(=O)Nc1c(C#C[Si](C)(C)C)cccc1OC(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: FC(F)(F)Oc1cccc2cc[nH]c12
Reaction time: 2 h
Yield: 103.3 %

Procedure:
Potassium hydroxide (17.9 g, 321 mmol) was boiled for 2 h in t-butanol (500 mL). (2-Trifluoromethoxy-6-trimethylsilanylethynyl-phenyl)-carbamic acid ethyl ester (52.8 g, 153 mmol) dissolved in t-butanol (500 mL) was added and boiling was continued for 2 h. The solvent was removed in vacuo and the residue was partitioned between diethyl ether and water. The organic phases were washed with brine, pooled and dried with MgSO4. Evaporation of the solvent yielded 31.8 g of brownish oil, which was purified by chromatography on silica gel with hexane/ethylacetate (9:1). This yielded the title compound, (30.2 g, 98%) as a yellow oil. (EI-MS: m/e=201.0 (M+)).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:21]=[CH:20][C:12]([CH2:13][N:14]2[CH2:19][CH:18]=[CH:17][CH2:16][CH2:15]2)=[CH:11][CH:10]=1.[Cl:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(Cl)Cl>[ClH:22].[CH2:26]([O:25][C:23]([O:8][C:9]1[CH:21]=[CH:20][C:12]([CH2:13][N:14]2[CH2:15][CH:16]=[CH:17][CH2:18][CH2:19]2)=[CH:11][CH:10]=1)=[O:24])[CH3:27]
Reactant: Oc1ccc(CN2CC=CCC2)cc1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1ccc(CN2CC=CCC2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.2 %

Procedure:
Triethylamine (1.2 g.) was added with stirring to a solution of 1-(4-hydroxybenzyl)-1,2,3,6-tetrahydropyridine (1.9 g.) in methylene chloride (30 ml.) at 0° C. Ethyl chloroformate (1.2 g.) was then added dropwise and the mixture stirred at 25° C. for 16 hours and then evaporated. Water (30 ml.) was added to the residue and the mixture was extracted with ether (2×30 ml.). The combined extracts were dried (MgSO4) and evaporated. The residue was dissolved in acetone (20 ml.) and acidified with ethereal hydrogen chloride to give 1-[4-(ethoxycarbonyloxy)benzyl]-1,2,3,6-tetrahydropyridine hydrochloride (1.5 g.) m.p. 168°-172° C. (after recrystallisation from ethanol-ethyl acetate).
Reaction SMILES: [C:1]1([CH:13]2[CH2:18][CH2:17][C:16](=[C:19]([CH3:22])[C:20]#[N:21])[CH2:15][CH2:14]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2.C1(C2CCC(=CC#N)CC2)N=NN2C=1C1C=CNC=1N=C2>>[C:1]1([C@@H:13]2[CH2:14][CH2:15][C@H:16]([CH:19]([CH3:22])[C:20]#[N:21])[CH2:17][CH2:18]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2.[C:1]1([C@H:13]2[CH2:14][CH2:15][C@H:16]([CH:19]([CH3:22])[C:20]#[N:21])[CH2:17][CH2:18]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2
Reactant: CC(C#N)=C1CCC(c2nnn3cnc4[nH]ccc4c23)CC1
Agent: N#CC=C1CCC(c2nnn3cnc4[nH]ccc4c23)CC1
Product: CC(C#N)[C@H]1CC[C@@H](c2nnn3cnc4[nH]ccc4c23)CC1
Product: CC(C#N)[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1

Procedure:
The reactions in Synthetic Examplea 435 were carried out in substantially the same manners except that 2-[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexylidene]propanenitrile obtained in Synthetic Examplea 437 was used instead of 2-[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexylidene]acetonitrile to give 2-[cis-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]propanenitrile (Synthetic Examplea 439a; colorless solid, 0.750 mg, yield 7%) in a less polar fraction and 2-[trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]propanenitrile (Synthetic Examplea 439b; colorless solid, 2.00 mg, yield 19%) in a more polar fraction.
Reaction SMILES: Cl.C([O:9][C:10](=[O:28])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:27])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])C1C=CC=CC=1.ON1[C:34]2[CH:35]=[CH:36][CH:37]=C[C:33]=2[N:32]=N1.CN(C)CCCN=C=NCC.C(OCC)(=[O:52])C>CN(C)C=O>[NH:32]1[CH2:33][CH2:34][CH2:35][C@H:36]1[C:37]([NH:24][C@H:23]([C:22]([N:18]1[CH2:19][CH2:20][CH2:21][C@H:17]1[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:10]([OH:9])=[O:28])=[O:27])=[O:26])[CH3:25])=[O:52]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: CCOC(C)=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 2 h

Procedure:
L-alanyl-L-prolyl-L-proline benzylester hydrochloride (2.46 g, 6 m mole), benzyloxcarbonyl-L-proline (1.65 g, 6.6 m mole) and 1-hydroxybenzotriazole (0.9 g, 6.6 m mole) were dissolved in dimethylformamide (6 ml) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.2 ml, 6.6 m mole) was added thereto at -15° C. The mixture was stirred for 16 hours at room temperature and to the reaction solution, ethyl actate was added. The solution was washed with 1N hydrochloric acid, 5% aqueous sodium bicarbonate and water in order. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The thus obtained oily residue was dissolved in methanol-water (4:1, 25 ml and hydrogen gas was passed through the solution in the presence of palladium carbon as a catalyst for 2 hours. The catalyst was separated by filtration and the solvent was distilled off under reduced pressure. The thus obtained residue was recrystallized with methanol-ether to give L-prolyl-L-alanyl-L-prolyl-L-proline (1.48 g).
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:7]([NH:14][CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCc1ccccc1
Reactant: C[Si](C)(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C[Si](C)(C)CNCc1ccccc1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
A mixture of chloromethyltrimethylsilane (325 g, 370 ml, 2.65 mole) and benzylamine (835 g, 850 ml, 7.78 mole) was heated at 120° C. (oil bath temperature) for 2 h. A white solid began appearing after only 10 minutes and a viscous mixture eventually resulted. The reaction mixture was allowed to cool, then basified with potassium carbonate solution and extracted twice with ether. The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave a yellow oil, which was purified by distillation. The excess benzylamine was removed in the first fractions (b.p. 47°-62° C. at 2 mmHg). The title compound (D11) was obtained as a colourless oil (380 g, 74%) b.p. 75°-80° C. at 2 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]2[C:7]([C:15]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[O:16])=[C:8]([C:10]3[CH:11]=[N:12][NH:13][CH:14]=3)[O:9][C:5]=2[CH:4]=1.ClCCl.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.O=O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]2[C:7]([C:15]([C:17]3[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=3)=[O:16])=[C:8]([C:10]3[CH:14]=[N:13][N:12]([C:39]4[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[CH:37][CH:38]=4)[CH:11]=3)[O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c(-c3cn[nH]c3)oc2c1
Agent: O=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-n2cc(-c3oc4cc(OC)ccc4c3C(=O)c3cc(OC)c(OC)c(OC)c3)cn2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 14.4 %

Procedure:
To an 8 mL screw cap glass vial was added [6-methoxy-2-(1H-pyrazol-4-yl)-benzofuran-3-yl]-(3,4,5-trimethoxyphenyl)-methanone (11 mg, 0.027 mmol), 3 Å molecular sieves, dichloromethane (0.5 mL), cupric acetate (10 mg, 0.054 mmol), 4-methoxy-phenyl boronic acid (9 mg, 0.059 mmol) and pyridine (15 μL, excess) and the capped vial was shaken at room temperature for two days with occasional removal of the cap to expose the mixture to atmospheric oxygen. After this time the reaction mixture was filtered through celite and the filtrate was concentrated and purified by silica-gel flash chromatography (eluent=hexane:ethyl acetate, 3:1) to afford the product as a yellow solid (2 mg, 15% yield). 1H-NMR (CDCl3) δ 8.56 (s, 1H), 8.17 (s, 1H), 7.60 (d, J=8.9 Hz, 2H), 7.15 (s, 2H), 7.14 (d, J=8.7 Hz, 1H), 7.07 (d, J=2.0 Hz, 1H), 6.96 (d, J=8.9 Hz, 2H), 6.81 (dd, J=8.7, 2.0 Hz, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 3.84 (s, 3H), 3.78 (s, 6H).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][C:10]1=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[CH2:17]CCO>>[C:1]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:17][C:10]1=[O:15])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COCCN1C(=O)c1ccccc1
Reactant: NCCCO
Product: O=C1CCOCCN1C(=O)c1ccccc1

Procedure:
Synthesized as for N-benzoyl-3-oxomorpholine (Example I) using 3-aminopropanol (Aldrich) in place of 2-aminoethanol.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2.[CH2:14]([O:16][CH:17]([O:22][CH2:23][CH3:24])[CH2:18][N:19]=[C:20]=[S:21])[CH3:15]>C(O)C>[CH2:23]([O:22][CH:17]([O:16][CH2:14][CH3:15])[CH2:18][NH:19][C:20]([NH:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2)=[S:21])[CH3:24]
Reactant: CCOC(CN=C=S)OCC
Reactant: Cc1ccc2c(N)c(F)ccc2n1
Solvent: CCO
Product: CCOC(CNC(=S)Nc1c(F)ccc2nc(C)ccc12)OCC

Procedure:
To 17.85 g (0.1013 mole) of 5-amino-6-fluoro-2-methylquinoline was added 19.5 g (0.1114 mole) of 2,2-diethoxyethylisothiocyanate and the mixture was heated at 80°-90° C. for 1.5 hours. The residue was slurried in ethanol, separated by filtration, washed with ethanol and then recrystallized from ethanol to provide N-(2,2-diethoxyethyl)-N'-(6-fluoro-2-methylquinolin-5-yl)thiourea, m.p. 189°-191° C. Analysis: Calculated for C17H22FN3O2S: %C, 58.1; %H, 6.3; %N, 12.1; Found: %C, 58.3; %H, 6.5; %N, 11.9.