Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.[Cl:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][C:6]=1[Cl:12].[O:13]=[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]([N:24]([CH3:28])[C:25](=[O:27])[CH3:26])[CH2:16][CH2:15]1.S(=O)(=O)(O)O>C(OCC)C.O1CCCC1>[Cl:12][C:6]1[CH:7]=[C:8]([C:14]2([OH:13])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]([N:24]([CH3:28])[C:25](=[O:27])[CH3:26])[CH2:16][CH2:15]2)[CH:9]=[CH:10][C:5]=1[Cl:4]
Reactant: Clc1ccc(I)cc1Cl
Reactant: CC(=O)N(C)C1CCC(=O)c2ccccc21
Agent: II
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)N(C)C1CCC(O)(c2ccc(Cl)c(Cl)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.5 %

Procedure:
Magnesium turnings (2.04 g) and a crystal of iodine were stirred in dry diethyl ether (24 ml) as a solution of 1,2-dichloro-4-iodobenzene (23.17 g) in dry diethyl ether (60 ml) was added over 15 minutes. The mixture was stirred for 15 minutes and refluxed for a further 15 minutes to complete formation of the Grignard reagent. The mixture was cooled to room temperature and a solution of N-(1,2,3,4-tetrahydro-4-keto-1-naphthyl)-N-methylacetamide (12.3 g) in dry tetrahydrofuran (134 ml ) was added over 5 mutes. The mixture was stirred for 4 hours at room temperature, heated under reflux for 30 minutes, cooled and treated with 4N aqueous sulphuric acid (30 ml). The lower aqueous phase was separated and discarded, dichloromethane was added, and the solution was washed with water (2×25 ml). The organic layer was evaporated under vacuum to give a mixture of racemic cis-(1R*, 4S*)- and trans-(1R*, 4R*)-isomers (ratio 87:13 respectively by nmr spectroscopy techniques) as a light brown gum (24.5 g) which was stirred with diethyl ether (150 ml) for 1 hour, then filtered, to give the title compound as cream crystals (10.2 g, 49.5%), m.p. 146°-148° C.; Rf 0.41 (silica; chloroform, methanol; 95:5). Found: C,62.96; H,5.24; N,4.00 C19H19Cl2NO2 requires C,62.65; H,5.26; N 3.85%. GLC assay on a 2.1 m×4 mm 3% OV-17 column, temperature programmed from 100° to 275° C. at 10° C./minute, showed the product to be 96% pure (retention time 41.5 minutes) containing 3% recovered ketone.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](=[O:7])[CH2:5]Cl.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](=[O:7])[CH2:5][C:14]1[NH:13][CH:17]=[CH:16][N:15]=1
Reactant: c1c[nH]cn1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: O=C(Cc1ncc[nH]1)c1ccc(Cl)cc1Cl

Procedure:
2,4-Dichlorophenacyl chloride (1.42 g, 6.4 mmol) and imidazole (1.18 g, 16 mmol) were heated in toluene (40 ml) at 75° C. for 2.25 hours. The mixture was concentrated to dryness in vacuo. The residue was dissolved in dichloromethane and washed with 5% aqueous potassium carbonate solution and water, dried and concentrated in vacuo. The crude product was purified by passage over a pad of silica gel, eluting with 5% methanol in dichloromethane to give 1-(2,4-dichlorophenyl)-2-imidazolylethan-1-one as an orange oil.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]=[O:16]>C(O)CCC>[C:1]1([C@H:7]([N:9]([CH2:10][Si:11]([CH3:13])([CH3:12])[CH3:14])[CH2:15][O:16][CH2:6][CH2:1][CH2:2][CH3:3])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](NC[Si](C)(C)C)c1ccccc1
Reactant: C=O
Solvent: CCCCO
Product: CCCCOCN(C[Si](C)(C)C)[C@H](C)c1ccccc1

Procedure:
The title compound was prepared from (R)-(+)-N-1-phenylethyl-N-trimethylsilylmethylamine by reaction with n-butanol and aqueous formaldehyde following the procedure of Example 2 to give the crude acetal (85% pure) as a colourless oil (34.2 g, 84%). The nmr spectrum was identical to the above (S)-isomer.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:10]=[C:11]([N:18]3CCC=C[CH2:20][CH2:19]3)[C:12]3[S:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[C:4]([F:25])[CH:3]=1.C[N+]1([O-])CC[O:30]CC1.[CH2:34]1[CH2:38][O:37][CH2:36][CH2:35]1.O.Cl.CCOC(C)=O>C1COCC1.[Os](=O)(=O)(=O)=O.C(O)(C)(C)C.O>[ClH:1].[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:10]=[C:11]([N:18]3[CH2:38][CH2:34][CH:35]([OH:30])[CH:36]([OH:37])[CH2:20][CH2:19]3)[C:12]3[S:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[C:4]([F:25])[CH:3]=1
Reactant: C1CCOC1
Reactant: Fc1cc(-c2nc(N3CCC=CCC3)c3sccc3n2)c(F)cc1Cl
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: OC1CCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3ccsc23)CCC1O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 582 mg of 2-(4-chloro-2,5-difluorophenyl)-4-(2,3,6,7-tetrahydro-1H-azepine-1-yl)thieno[3,2-d]pyrimidine, 235 mg of N-methylmorpholine-N-oxide, 1.30 ml of 2.5 w % osmium tetroxide-tert-butanol solution and 10 ml of THF-water (4:1) was stirred for 20 hours at room temperature. After 50 ml of water was added to the reaction mixture and extracted with EtOAc, the resultant washed with a saturated saline solution. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. the obtained residue was purified by silica gel column chromatography (chloroform-MeOH) to give a foam-like substance. After the obtained foam-like substance was dissolved in 20 ml of THF and 2 ml of 4M HCl-EtOAc solution was added, it was concentrated under reduced pressure to give a solid. This solid was recrystallized from EtOH-ether to give 618 mg of (4RS,5SR)-1-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]azepane-4,5-diol hydrochloride.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cl:19][Si:20]([Cl:26])([Cl:25])[CH2:21][SiH:22]([Cl:24])[Cl:23]>>[Cl:19][Si:20]([Cl:26])([Cl:25])[CH2:21][Si:22]([Cl:24])([Cl:23])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C=CCCCCCCCCCCCCCCCC
Reactant: Cl[SiH](Cl)C[Si](Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCCCC[Si](Cl)(Cl)C[Si](Cl)(Cl)Cl

Procedure:
The 1,1,1,3,3-pentachloro-1,3-disilapropane may be reacted directly with an olefin by a hydrosilylation reaction or may be esterified to the corresponding pentaalkoxysilane derivative and then reacted with an olefin by a hydrosilylation reaction to yield the final desired product. As a simple example, octadecene may be reacted with 1,1,1,3,3-pentachloro-1,3-disilapropane (II) to form 1,1,1,3,3-pentachloro-1,3-disilaheneicosane. This compound may then be esterified with an alcohol to form, for example, 1,1,1,3,3-pentamethoxy-1,3-disilaheneicosane (from esterification with methanol) or reduced to form 1,3-disilaheneicosane. In some cases it is advantageous to form the esterified product, for example, 1,1,1,3,3-pentaethoxy-1,3-disilapropane, first, followed by hydrosilylation as the second step. This is especially important if the olefin reacts with chlorosilanes but does not react with alkoxy silanes. For example, the epoxy group of allylglycidyl ether reacts with chlorosilanes but is unreactive with alkoxy silanes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:18](=[S:37])[NH:19]C(OCC3C4C=CC=CC=4C4C3=CC=CC=4)=O)[CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].N1CCCCC1.O>CN(C=O)C>[NH2:19][C:18]([NH:17][CH2:16][CH:13]1[CH2:14][CH2:15][N:10]([CH2:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:11][CH2:12]1)=[S:37]
Reactant: O=C(NC(=S)NCC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: NC(=S)NCC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving N-{[({1-[(3,4-dichlorophenyl)methyl](4-piperidyl)}methyl)amino]thioxomethyl}(fluoren-9-ylmethoxy)carboxamide (553 mg, 1 mmol) in DMF (4 ml), piperidine (0.989 ml, 10 mmol) was added and the mixture was stirred at room temperature overnight. Upon completion of the reaction, water (20 ml) was added and extraction was performed with ethyl acetate (20 ml×3 times). The extracted organic layer was washed with water (100 ml×2 times) and then with saturated brine, dried over anhydrous sodium sulfate, and then filtered and concentrated. Purification was performed by silica gel column chromatography (ethyl acetate/methanol=1/0→4/1) to obtain amino[({1-[(3,4-dichlorophenyl)methyl](4-piperidyl)}methyl)amino]methane-1-thione. The compound was identified by LC-MS.
Reaction SMILES: O=[C:2]1[CH2:10][C@@H:9]2[C@@H:4]([CH2:5][CH:6]=[CH:7][CH2:8]2)[CH2:3]1.C(O)C.Cl.[OH:15][NH2:16].[OH-].[Na+]>O>[OH:15][N:16]=[C:2]1[CH2:10][C@@H:9]2[C@@H:4]([CH2:5][CH:6]=[CH:7][CH2:8]2)[CH2:3]1
Reactant: O=C1C[C@H]2CC=CC[C@H]2C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=C1C[C@H]2CC=CC[C@H]2C1
Reaction time: 1 h

Procedure:
To a mixed solution of 8-oxo-cis-bicyclo[4,3,0]nona-3-ene (10 g), ethyl alcohol (100 ml), water (20 ml) and hydroxyamine hydrochloride (20 g), was added sodium hydroxide (37 g) at room temperature. After being stirred for one hour, the reaction mixture was poured into water. The crystals were gathered by filtration and washed with water. After drying, there was obtained 8-hydroxyimino-cis-bicyclo[4,3,0]nona-3-ene.
Reaction SMILES: Br[CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[F:12])[CH2:3][CH3:4].C[Si]([C:17]#[N:18])(C)C>>[F:12][C:6]1[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:5]=1[CH:2]([CH2:3][CH3:4])[C:17]#[N:18]
Reactant: C[Si](C)(C)C#N
Reactant: CCC(Br)c1cccc(F)c1F
Product: CCC(C#N)c1cccc(F)c1F

Procedure:
rac-2-(2,3-Difluoro-phenyl)-butyronitrile was prepared from rac-1-(1-bromo-propyl)-2,3-difluoro-benzene and trimethylsilyl cyanide in analogy to Example 23 c): colourless oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4]C=[C:2]1C(O)=O.[O-:9]CC.[Na+].S1C=CC=C1CC(O)=O.ClC[Si:24]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]>COCCOCCOC>[C:5]([S:1][CH2:2][Si:24]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])(=[O:9])[CH3:4]
Reactant: CC[O-]
Reactant: O=C(O)c1cccs1
Reactant: CCO[Si](CCl)(OCC)OCC
Agent: O=C(O)Cc1cccs1
Agent: [Na+]
Solvent: COCCOCCOC
Product: CCO[Si](CSC(C)=O)(OCC)OCC
Temperature: 8 °C
Yield: 55 %

Procedure:
This example illustrates the preparation of a thiocarboxylate alkoxysilane from a salt of a thiolcarboxylic acid using a nonprotic solvent. 88 grams of powdered sodium ethoxide and 600 ml diglyme were charged into a one-liter, three-neck round bottomed flask equipped with magnetic stir bar, temperature probe/controller, heating mantle, addition funnel, condenser, N2 inlet, and ice water bath. The solution was cooled to 8° C., and 105 grams of thiolacetic acid was added slowly via the addition funnel, keeping the temperature below 60° C. The solution was allowed to cool to 35° C., and 250 grams of chloromethyltriethoxysilane was added via the addition funnel. After addition was complete, the solution was heated to 70° C., where a brief exotherm to 120° C. was observed. The solution was heated at 70° C. for an additional three hours. A white solid formed which was filtered first through a 0.1 μm pressure filter and then a 0.01 μm filter to give a clear, black solution. The solvent was removed under reduced pressure, and the remaining liquid vacuum distilled to yield 163 grams of a clear and colorless liquid, a 55 percent yield.
Reaction SMILES: [CH2:1]([C:8]1[N:12]([CH:13]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:14]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[C:11]2[CH:29]=[C:30]([Cl:34])[C:31]([F:33])=[CH:32][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([CH:41]=[O:42])CCCCC1.[CH3:43][O:44]C1C=CC(C=O)=CC=1.ClC1C=C(CC(O)=O)C=CC=1.COC(C(O)=O)C1C=CC=CC=1>>[Cl:34][C:30]1[C:31]([F:33])=[CH:32][C:10]2[N:9]=[C:8]([CH:1]([O:44][CH3:43])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:12]([CH:13]([C:23]3[CH:28]=[CH:27][C:26]([O:42][CH3:41])=[CH:25][CH:24]=3)[C:14]([NH:16][CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)=[O:15])[C:11]=2[CH:29]=1
Reactant: COc1ccc(C=O)cc1
Reactant: O=C(NC1CCCCC1)C(C1CCCCC1)n1c(Cc2ccccc2)nc2cc(F)c(Cl)cc21
Reactant: O=CC1CCCCC1
Agent: COC(C(=O)O)c1ccccc1
Agent: O=C(O)Cc1cccc(Cl)c1
Product: COc1ccc(C(C(=O)NC2CCCCC2)n2c(C(OC)c3ccccc3)nc3cc(F)c(Cl)cc32)cc1

Procedure:
The title compound was prepared in analogy to Example 1, replacing (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester with (2-amino-4-chloro-5-fluoro-phenyl)-carbamic acid tert-butyl ester (([CAS RN 579474-50-3]), Example 47), cyclohexanecarbaldehyde with anisaldehyde ([CAS RN 123-11-5]) and (3-chloro-phenyl)-acetic acid with DL-α-methoxyphenylacetic acid ([CAS RN 7021-09-2]). MS (ISP): 536.3 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([S:4]([Cl:7])(=[O:6])=[O:5])[CH3:3].[NH2:8][CH2:9][C@@H:10]([C@@H:12]([NH:34]C(=O)OC(C)(C)C)[CH2:13][C@H:14]([CH2:18][NH:19][C:20](=[O:33])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:15]([CH3:17])[CH3:16])[OH:11].C(N(CC)CC)C>ClCCl>[ClH:7].[NH2:34][C@H:12]([C@@H:10]([OH:11])[CH2:9][NH:8][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])[CH2:13][C@@H:14]([CH:15]([CH3:17])[CH3:16])[CH2:18][NH:19][C:20](=[O:33])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32]
Reactant: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN)C(C)C
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@H](N)[C@@H](O)CNS(=O)(=O)C(C)C)C(C)C
Product: Cl
Reaction time: 6 h

Procedure:
0.007 ml of propane-2-sulphonyl chloride is added at 0° C. to a solution of 0.0255 g of tert-butyl (1(S)-(2-amino-1(S)-hydroxyethyl)-3(S)-{[2-(3-methoxypropoxy)benzoylamino]methyl}-4-methylpentyl)carbamate (Example 2b) and 0.007 ml of triethylamine in 1 ml of dichloromethane. After 6 hours, the reaction mixture is concentrated by evaporation—the N-Boc intermediate is identified from the residue by means of flash chromatography (SiO2 60F) on the basis of the Rf value. This is dissolved in 0.82 ml of 4N HCl/dioxane—after 4 hours, the reaction mixture is concentrated by evaporation, and the residue is dissolved in 0.5 ml of tert-butanol, frozen in liquid nitrogen and lyophilized under high vacuum overnight. The title compound is identified from the residue on the basis of the Rf value.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][S:13][C:7]2=[N:6][C:5]=1[CH3:14].[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(OCC)(=O)C>ClCCl.C(N(CC)CC)C>[CH3:14][C:5]1[N:6]=[C:7]2[S:13][CH2:12][CH2:11][N:8]2[C:9](=[O:10])[C:4]=1[CH2:3][CH2:2][O:1][S:16]([CH3:15])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc2n(c(=O)c1CCO)CCS2
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2n(c(=O)c1CCOS(C)(=O)=O)CCS2

Procedure:
After dissolving 6-(2-hydroxy-ethyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyrimidin-5-one (CAS 86487-53-8) (225 mg) in dichloromethane (10 ml), triethylamine (0.44 ml) was added, and then methanesulfonyl chloride (0.20 ml) was added dropwise while stirring on ice. After stirring for 10 minutes, ethyl acetate was added to the reaction mixture and the resulting mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (264 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[CH:15]([CH3:17])[CH3:16]>>[CH:15]([C:9]1[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)([CH3:17])[CH3:16]
Reactant: Cc1ccc(C(C)C)c(Br)c1
Reactant: C1CNCCN1
Product: Cc1ccc(C(C)C)c(N2CCNCC2)c1

Procedure:
The title compound was prepared in a manner similar to Preparation 1A except that piperazine was coupled to 1-bromo-5-methyl-2-isopropyl-benzene.
Reaction SMILES: [N+:1]([O-])([O-])=O.[Na+].[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18])#[C:7][CH2:8][CH2:9][CH2:10][CH3:11].[OH2:19]>Cl>[CH2:8]([C:7]1[N:1]=[N:18][C:13]2[C:12]([C:6]=1[OH:19])=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH3:11]
Reactant: O=[N+]([O-])[O-]
Reactant: CCCCC#Cc1ccccc1N
Reactant: O
Agent: Cl
Agent: [Na+]
Product: CCCCc1nnc2ccccc2c1O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 2 g of sodium nitrate in 60 ml of water was added at 0° C. to a suspension at 0° C. of 3.2 g of the product of Step A in 100 ml of concentrated hydrochloric acid. The mixture was stirred for 90 minutes at 0° C., then for one hour at 100° C. The reaction medium was poured into 100 ml of ice-cooled water, followed by separating and washing with ice-cooled water. The moist product was taken up in 100 ml of water and alkalized with concentrated ammonium hydroxide. After separating, the residue was washed with water and dried at 70° C. under reduced pressure to obtain 1.47 g of the expected product melting at 180° C.
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].[CH2:22]([O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[N:36]=[CH:35][N:34]=[C:33]2Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[N:36]=[CH:35][N:34]=[C:33]2[N:18]1[CH2:19][CH2:20][CH:15]([N:5]2[C:6](=[O:14])[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=3)[N:3]([CH3:2])[C:4]2=[O:21])[CH2:16][CH2:17]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Clc1ncnc2cc(OCc3ccccc3)c(OCc3ccccc3)cc12
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Agent: Br
Product: Cc1ccc2c(c1)c(=O)n(C1CCN(c3ncnc4cc(OCc5ccccc5)c(OCc5ccccc5)cc34)CC1)c(=O)n2C
Yield: 54 %

Procedure:
The procedure similar to that described in Example 61 was repeated, except that 836.0 mg (2.36 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazoline hydrobromide (Compound v) obtained in Example 41 was used and 6,7-dibenzyloxy-4-chloroquinazoline was used in place of 4-chloro-6,7-dimethoxyquinazoline. As a result, 786.3 mg (yield: 54%) of Compound 88 was obtained as white crystals.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[CH:19][CH:18]=1)[C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C>C(O)(C(F)(F)F)=O>[NH2:8][CH:9]([CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[CH:21][CH:22]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(CCOc1ccc(N2CCN(c3ccncc3)CC2)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(N)CCOc1ccc(N2CCN(c3ccncc3)CC2)cc1
Yield: 74.1 %

Procedure:
The compound of Example 140 (0.96 g) in TFA (10 ml) was kept at room temperature for 2 hours. The solution was evaporated and the residue dissolved in water (15 ml) and the solution basified with sodium carbonate. The mixture was extracted three times with dichloromethane. Evaporation of the combined extracts gave the title compound (0.56 g); m.p. 125°-127° C.; NMR(d6DMSO) δ 8.2(2H,d), 6.92(6H,m), 4.0(2H,m), 3.64(3H,s), 3.46(4H,t), 3.15(4H,t), 2.04(2H,m), 1.84(1H, m); m/e 371(M+H)+. Calculated for C20H26N4 O3. 0.75 H2O: C, 62.5; H, 7.17; N, 14.6. Found: C, 62.8; H, 6.8; N, 14.3%.
Reaction SMILES: [OH:1][C@H:2]([CH3:20])[C@@H:3]([CH2:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:4]([OH:6])=O.[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][NH2:28].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][NH:28][C:4](=[O:6])[C@H:3]([CH2:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C@H:2]([OH:1])[CH3:20]
Reactant: NOC1CCCCO1
Reactant: C[C@@H](O)[C@@H](CC1CCC(c2ccccc2)CC1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@@H](O)[C@@H](CC1CCC(c2ccccc2)CC1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 133.6 %

Procedure:
A mixture of (2R,3R)-3-hydroxy-2-(4-phenylcyclohexylmethyl)butanoic acid (3.43 g, 0.012 mol), 2-tetrahydropyranyloxyamine (1.64 g, 0.014 mol), BOP (5.75 g, 0.013 mol), HOBt (1.76 g, 0.13 mol) and NMM (2.63 g, 0.026 mol) in DMF (30 mL) is stirred at 25° C. for 18 h. The mixture is concentrated in vacuo and the residue is taken up in EtOAc. The mixture is washed with ice-cold 0.1 M HCl, saturated aqueous sodium bicarbonate, and saturated aquesous sodium chloride. The organic phase is dried over sodium sulfate and concentrated in vacuo to give 6.02 g of a white solid. Chromatography on silica gel using EtOAc as eluent gives 4.05 g (90%) of (2R,3R)-3-hydroxy-2-(4-phenylcyclohe,(ylmethyl)butanoic acid 2-tetrahydropyranyloxyamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][N:3]=1.[O:10]=[C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].CC(O)=O.N1CCCCC1>C1C=CC=CC=1.C([O-])(O)=O.[Na+]>[C:11](/[C:12](=[CH:6]/[C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:9][CH:8]=1)/[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCOC(=O)/C(=C\c1ccc(Cl)nc1)C(=O)c1ccccc1
Yield: 90.5 %

Procedure:
A mixture of 6-chloronicotinaldehyde (1 g), ethyl 3-oxo-3-phenylpropanoate (1.36 g), AcOH (0.04 ml), piperidine (0.028 ml) in benzene (15 ml) was refluxed for 1.5 hours. After cooling, the reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a mixture of EtOAc and n-hexane (1:2) to give ethyl (2Z)-2-benzoyl-3-(6-chloro-3-pyridyl)acrylate (2.018 g) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]([CH3:17])[C:13](SC)=[N:12]3)[CH2:10][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:27].[I-]>N.CCO>[NH2:27][C:13]1[N:14]([CH3:17])[C:15](=[O:16])[C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[CH2:10]2)[N:12]=1
Reactant: [NH4+]
Reactant: CSC1=NC2(CC(c3ccccc3F)Oc3ccc(Br)cc32)C(=O)N1C
Agent: N
Agent: [I-]
Solvent: CCO
Product: CN1C(=O)C2(CC(c3ccccc3F)Oc3ccc(Br)cc32)N=C1N
Yield: 70.3 %

Procedure:
A solution of 6-bromo-2-(2-fluorophenyl)-1′-methyl-2′-(methylthio)spiro-[chroman-4,4′-imidazol]-5′(1′H)-one (80 mg, 0.183 mmol) and NH4I (53.21 mg, 0.367 mmol) in NH3/EtOH (2 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 3 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-2-(2-fluorophenyl)-1′-methylspiro-[chroman-4,4′-imidazol]-5′(1′H)-one (52 mg, 70%). 1H-NMR (MeOD): 2.15 (d, 1H), 2.25 (d, 1H), 3.20 (s, 3H), 6.15 (d, 1H), 6.78 (d, 1H), 6.99 (t, 1H), 7.05 (s, 1H), 7.15 (t, 1H), 7.25 (d, 2H), 7.50 (t, 1H).