Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH2:13][CH2:12][C:11]1([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH3:22])(C)(=O)=[O:2].[C-:31]#[N:32].[K+:33].[Cl-].[Na+]>CS(C)=O>[CH3:21][O:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6][C:31]#[N:32])[C:11]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)([CH3:22])[CH2:12][CH2:13]2.[OH-:2].[K+:33]
Reactant: [C-]#N
Reactant: COc1ccc(C2(C)CCc3cc(OC)ccc3C2CCCCOS(C)(=O)=O)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(C2(C)CCc3cc(OC)ccc3C2CCCCC#N)cc1
Product: [OH-]
Temperature: 90 °C
Reaction time: 5 h
Yield: 1114.2 %

Procedure:
A mixture of (1RS,2RS)-1,2,3,4-tetrahydro-1-(4-mesyloxybutyl)-6-methoxy-2-p-methoxyphenyl-2-methylnaphthalene (Example 1, 1.73 g.), potassium cyanide (0.4 g.) and dimethylsulphoxide (13 ml.) was stirred for 5 hours at 90° C. under an atmosphere of argon and then poured into saturated aqueous sodium chloride solution, and the mixture was extracted with ethyl acetate. The extract was dried and evaporated to dryness and a solution of the 5-[(1RS,2RS)-6-methoxy-2-p-methoxyphenyl-2-methyl-1,2,3,4-tetrahydronaphth-1-yl]valeronitrile thus obtained as residue (2.5 g.) and powdered potassium hydroxide (2.5 g.) in a mixture of ethane-1,2-diol (25 ml.) and water (2.5 ml.) was heated at 180° C. for 31/2 hours and then added to a mixture of ice and water. The mixture was washed with diethyl ether and the aqueous phase was acidified with aqueous 3N-hydrochloric acid and extracted with diethyl ether. The extract was dried and evaporated to dryness and a mixture of the 5-[(1RS,2RS)-6-methoxy-2-p-methoxyphenyl-2-methyl-1,2,3,4-tetrahydronaphth-1-yl]valeric acid thus obtained as residue (0.457 g.), oxalyl chloride (0.15 ml.), dimethyl formamide (1.01 ml.) and methylene chloride (20 ml.) was stirred at laboratory temperature for 2 hours and then evaporated to dryness. A solution of the residue thus obtained in methylene chloride (10 ml.) was added to a stirred solution of 3-hexylthiopropionohydrazide (0.242 g.) and triethylamine (0.15 ml.) in methylene chloride (15 ml.) and the mixture was kept at laboratory temperature for 1 hour. The reaction mixture was washed with water, dried and evaporated to dryness and the residue was purified by chromatography on a silica gel column using a 1:1 v/v mixture of toluene and ethyl acetate as eluent. There was thus obtained as an oil N1 -{b 5-[(1RS,2RS)-6-methoxy-2-p-methoxyphenyl-2-methyl-1,2,3,4-tetrahydronaphth-1-yl]valeryl}-N2 -(3-hexylthiopropionyl)hydrazine.
Reaction SMILES: [I:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>BrCC1C=CC=CC=1>[CH2:18]([O:11][C:3]1[C:2]([I:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][N:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccccc1
Reactant: O=[N+]([O-])c1cnc(O)c(I)c1
Agent: BrCc1ccccc1
Product: O=[N+]([O-])c1cnc(OCc2ccccc2)c(I)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
To a solution of 3-iodo-5-nitropyridin-2-ol (0.011 mol, 3 g) in 30 ml of toluene, 2.5 ml of (bromomethyl)benzene and 5.1 g of Ag2CO3 was added. The mixture was stirred at 70° C. for 6 h. The crude was filtered through Celite and washed with ethyl acetate. The solvent was evaporated affording 3.6 g (yield 90%) of the expected product.
Reaction SMILES: C[Li].[N:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[CH:4]=1.[C:11]1(C)C=CC=CC=1>CCOCC>[CH3:11][C:4]1[C:5]([CH3:10])=[CH:6][C:7]([CH3:9])=[CH:8][N:3]=1.[N:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[CH3:11]
Reactant: Cc1cncc(C)c1
Reactant: Cc1ccccc1
Agent: [Li]C
Solvent: CCOCC
Product: Cc1cnc(C)c(C)c1
Reaction time: 4 h

Procedure:
To 500 ml of a 5% solution of methyl lithium in ether were added dropwise at room temperature under argon 1200 ml of ether, subsequently 35.6 g of 3,5-lutidine (3,5-dimethylpyridine) and finally 400 ml of toluene. The ether was distilled off completely, whereupon the solution was stirred at 100° for 4 hours. Ice was then added portionwise thereto while cooling with methanol/ice until the evolution of heat no longer occurred. The toluene phase was separated from rhe precipitated solid and was extracted wirh 66 ml of semi-concentrated hydrochloric acid. The separated aqueous phase was adjusted to a pH of about 10 with 3N sodium hydroxide solution while cooling and extracted twice with 300 ml of ether. The ether extracts were dried over sodium sulfate and evaporated. The residue was distilled in vacuo at 20 mm/ 72-74° ; there was obtained 2,3,5-collidine 2,3,5-trimethylpyridine) which had a 99.15% purity in accordance with gas chromatography.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[CH3:15][S-:16].[Na+]>CS(C)=O.O>[CH3:15][S:16][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2[C:6](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]1=[O:14]
Reactant: C[S-]
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CSCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of N-(2-bromoethyl)phthalimide (500 mg) in DMSO (8 mL) was added sodium thiomethoxide (152 mg) and the reaction stirred at room temperature for 16 h. Then with water (2 mL) was added and the mixture stirred at room temperature for 10 min. The reaction was diluted with water (20 mL) and extracted into ethyl acetate (2×20 mL). The combined organics were washed with aqueous brine solution (2×20 mL), dried (MgSO4) and reduced in vacuo to give 2-(2-methylsulfanyl-ethyl)-isoindole-1,3-dione as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>O>[CH2:19]([O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[N:1]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCc1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCCCCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 95 °C
Reaction time: 19 h
Yield: 90 %

Procedure:
Twenty-five grams (151.3 mmol) of (L)-phenylalanine and 66.67 g (482.4 mmol) of potassium carbonate were dissolved in 100 ml of water, and 57.51 g (454.3 mmol) of benzyl chloride were added thereto. The mixture was heat-stirred at 95° C. for 19 hours. After the reaction mixture was cooled to room temperature, 67 ml of n-heptane and 50 ml of water were added thereto. The organic layer was washed twice with 50 ml of a mixture of methanol and water at a volume ratio of 1:2 and was then dried over anhydrous sodium sulfate. The dried substance was filtered and concentrated to give 61.64 g (90%, 121.8 mmol) of the above-mentioned compound (Ia) in a yield of 84.7%.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]3[N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([CH2:27][N:28]3[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][CH2:30][C:29]3([CH3:37])[CH3:36])[CH:12]=2)=[CH:7][CH:6]=1.[C:38]([N:45]([CH2:47][CH:48]=O)[CH3:46])([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(OCC)(=O)C.O>[C:41]([O:40][C:38](=[O:39])[N:45]([CH2:47][CH2:48][N:31]1[CH2:30][C:29]([CH3:37])([CH3:36])[N:28]([CH2:27][C:13]2[CH:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][CH:9]=3)[N:16]=[C:15]3[N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[N:18]=[C:19]([CH3:20])[C:14]=23)[CH2:33][C:32]1([CH3:35])[CH3:34])[CH3:46])([CH3:44])([CH3:43])[CH3:42]
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Reactant: COCOc1ccc(-c2cc(CN3CC(C)(C)NCC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COCOc1ccc(-c2cc(CN3CC(C)(C)N(CCN(C)C(=O)OC(C)(C)C)CC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1
Yield: 404.2 %

Procedure:
To a solution of 290 mg of 6-(4-methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-4-(2,2,5,5-tetramethyl-piperazin-1-ylmethyl)-1H-pyrazolo[3,4-b]pyridine and 1040 mg N-Boc-(methylamino)acetaldehyde in 5 ml dichloromethane was added 250 mg of sodium triacetoxyborohydride. After 1 h at rt the reaction was diluted with ethyl acetate and water. The phases were separated. The aqueous phase was extracted with ethyl acetate twice. The combined organic phases were dried over sodium sulphate, filtrated and concentrated in vacuo. 1535 mg of a crude product of the title compound were obtained, which was used without purification in the next step.
Reaction SMILES: CC1C=CC([N:8]2C3C(C(C)C)=[C:14]([OH:17])[CH:15]=CC=3C([N+]([O-])=O)=[C:9]2/[CH:24]=[CH:25]/[N:26](C)C)=CC=1.[NH:29]([C:31]1[N:36]([CH3:37])[C:35](=[O:38])[N:34]([CH3:39])[C:33](=[O:40])[CH:32]=1)[NH2:30].[OH2:41].NN>>[NH:29]([C:31]1[N:36]([CH3:37])[C:35](=[O:38])[N:34]([CH3:39])[C:33](=[O:40])[CH:32]=1)[NH2:30].[C:33]([O:40][C:14](=[O:17])[CH3:15])(=[O:41])[CH3:32].[NH:26]1[CH:25]=[CH:24][CH:9]=[N:8]1
Reactant: O
Reactant: Cc1ccc(-n2c(/C=C/N(C)C)c([N+](=O)[O-])c3ccc(O)c(C(C)C)c32)cc1
Agent: Cn1c(NN)cc(=O)n(C)c1=O
Agent: NN
Product: CC(=O)OC(C)=O
Product: c1cn[nH]c1

Procedure:
An approach for the synthesis of compounds of the general formula (Id-1) where R1, R2, U and V are as defined herein above is depicted in Scheme 8. The synthesis starts from known 6-hydrazino-1,3-dimethyluracil (30) which is readily prepared by the displacement of halogen of 6-chloro-1,3-dialkyuracil of the formula (20) with hydrazine hydrate according to the known procedure. The cyclisation of compound of the formula (30) with acetic anhydride gave pyrazole of the formula (31). The deacetylation followed by selective N-alkylation of pyrazole (31) with dimethyl sulfate afforded compounds of the formula (33) (Pfleiderer, W. et al., Justus Liebigs Ann Chem. 1958, 615, 42-47). The reaction of compound of formula (33) with dimethyl carbonate in presence of a strong base (e.g. NaH) under reflux conditions gives ester of the formula (34). Hydrolysis of ester (34) with aqueous acid afforded the desired pyrazolo[3,4-d] pyrimidinedione acetic acid of the formula (35). The coupling of compound of formula (35) with respective amines of formula (18) by using a standard amide coupling method gives compounds of general formula (Id-1).
Reaction SMILES: O.C([O-])(=O)C.[Na+].[Cl:7][C:8]1[C:9]([OH:18])=[C:10]([CH:12]=[C:13]([Cl:17])[C:14]=1[CH2:15][CH3:16])[NH2:11].[CH3:19][C:20]([C:24]1[CH:36]=[C:35]([C:37]([CH3:41])([CH3:40])[CH2:38][CH3:39])[CH:34]=[CH:33][C:25]=1[O:26][CH:27]([CH2:31][CH3:32])[C:28](Cl)=[O:29])([CH3:23])[CH2:21][CH3:22]>CCCCCCC.C1(C)C=CC=CC=1>[CH3:23][C:20]([C:24]1[CH:36]=[C:35]([C:37]([CH3:40])([CH3:41])[CH2:38][CH3:39])[CH:34]=[CH:33][C:25]=1[O:26][CH:27]([CH2:31][CH3:32])[C:28]([NH:11][C:10]1[CH:12]=[C:13]([Cl:17])[C:14]([CH2:15][CH3:16])=[C:8]([Cl:7])[C:9]=1[OH:18])=[O:29])([CH3:19])[CH2:21][CH3:22]
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Cl
Reactant: CCc1c(Cl)cc(N)c(O)c1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCCCC
Product: CCc1c(Cl)cc(NC(=O)C(CC)Oc2ccc(C(C)(C)CC)cc2C(C)(C)CC)c(O)c1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a 4-neck flask with a gas inlet, condenser, thermometer, and addition funnel, 50 mL of deionized water and 31 g of sodium acetate was added and stirring was continued until the solid dissolved. At this point, 57 g of heptane, 20 g of toluene, and 30 g (0.146 moles) of 3,5-dichloro-4-ethyl-2-hydroxyaniline was added and the 2-phase mixture was warmed to 60° C. A solution of 53.2 g of 2-[2,4-bis(1,1-dimethylpropyl)phenoxy]butyryl chloride (0.157 moles, 8% excess) in 53 g of heptane was then added at 60° C.-65° C. The reaction was held for 2 hr at 60° C. -65° C., upon which time the area percent product by HPLC was 92% on a solvent-free basis. The two-phase mixture was heated to 75° C.-80° C. and held for 15 minutes. The agitator was stopped and the lower layer was decanted. The product solution was washed twice with 42 g of deionized water, cooled to 70° C. and seeded. The product slurry was cooled to 0° C.-5° C., and the product was collected by filtration, washed with cold heptane, and dried to give 66.9 g (90% yield), with an assay of 99.5% (wt.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.O>O1CCCC1>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[OH:16])=[CH:13][CH:12]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: O=Cc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
4-Chlorophenylmagnesium bromide (12.97 ml, 1M solution in diethyl ether) was added slowly to a solution of 4-bromobenzaldehyde (2.0 g, 10.81 mmol) in tetrahydrofuran (25 ml) at 0° C., under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature and was stirred for 17 hours. Water (3 ml) was then added and the solvent was removed under reduced pressure. The residue was then partitioned between ethyl acetate and 1N HCl solution. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The crude product was then purified by column chromatography (SiO2), eluting with ethyl acetate/petroleum ether (1:9), to yield the title compound (2.30 g). LC/MS: (PS-B3) Rt 3.49 [M−H]+297.
Reaction SMILES: C([O:5][C:6](=[O:40])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:32]2[N:37]=[CH:36][C:35]([CH2:38][CH3:39])=[CH:34][N:33]=2)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[N:30][CH:29]=[CH:28][N:27]=3)=[CH:22][CH:21]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O.[Cl:48]CCl>>[ClH:48].[CH2:38]([C:35]1[CH:36]=[N:37][C:32]([N:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[N:30][CH:29]=[CH:28][N:27]=3)=[CH:24][CH:25]=2)[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:40])=[O:5])[S:12][CH:13]=2)=[N:33][CH:34]=1)[CH3:39]
Reactant: ClCCl
Reactant: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(-c3cnccn3)cc2)nc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)O)n2)Cc2ccc(-c3cnccn3)cc2)nc1
Product: Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-[(4-{2-[(5-Ethylpyrimidin-2-yl)(4-pyrazin-2-ylbenzyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (180 mg) obtained in Example 403-1 was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; dichloromethane:methanol=10:1). The obtained compound was dissolved in diethyl ether (5 mL), hydrochloric acid-ethyl acetate (4 mol/L, 1 mL) was added, and the mixture was stirred at room temperature for 1 hr. The precipitated solid was collected by filtration to give the title compound (140 mg) as a white solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[C:16]([O:17][CH3:18])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.[C:19]1(=[O:25])[O:24][C:22](=[O:23])[CH2:21][CH2:20]1.O>C(Cl)Cl>[CH3:18][O:17][C:16]1[CH:15]=[C:14]2[C:9](=[CH:8][C:7]=1[O:6][CH3:5])[CH:10]=[C:11]([C:19](=[O:25])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:12]=[CH:13]2
Reactant: O=C1CCC(=O)O1
Reactant: COc1cc2ccccc2cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1cc2ccc(C(=O)CCC(=O)O)cc2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aluminium chloride (9.5 g) was added to a solution of 2,3-dimethoxynaphthalene (10 g) and succinic anhydride 7.1 g in methylene chloride (140 ml). The mixture was stirred at room temperature overnight and then treated with water and filtered. The resulting solid was taken into 1 M sodium hydroxide, washed once with methylene chloride, acidified and filtered. Yield: 8.3 g, melting point 215-229° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=1[Cl:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:23]Br.O>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([Cl:16])=[CH:11][C:12]([NH2:13])=[C:14]([Br:23])[CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)c(Cl)c1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Nc1cc(Cl)c(OCc2ccccc2)cc1Br
Temperature: -15 °C
Reaction time: 1.25 h
Yield: 125.3 %

Procedure:
To a suspension of 4-benzyloxy-3-chloroaniline (674 mg) and potassium carbonate (1.14 g) in dichloromethane (32 mL) was added dropwise a solution of bromine (1.25 g) in dichloromethane (16 mL) at −15° C. in one hour, and the mixture was stirred at −15° C. for 75 minutes. Water was added to the reaction mixture and this resulting mixture was stirred vigorously for additional 10 minutes. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (1.13 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH:29]=[CH2:30])[C@H:9]([NH:17][S:18](/C=C/C2C=CC=CC=2)(=O)=O)[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)Cl>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl.ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH:29]=[CH:30][S:18][NH:17][C@@H:9]2[C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=C[C@H](c1cccc(Cl)c1)[C@H](NS(=O)(=O)/C=C/c1ccccc1)c1ccc(Cl)cc1
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: Clc1ccc([C@H]2NSC=C[C@@H]2c2cccc(Cl)c2)cc1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
To a degassed solution of 7.29 g (15.90 mmol) of (E)-N-((1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-enyl)-2-phenylethenesulfonamide (Example 117, Step A) in a 1:1 mixture of DCM (350 mL) and DCE (350 mL) was added Grubbs First Generation (1.20 g, 1.434 mmol). The resulting solution was stirred at 70° C. for 20 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure. Purification by flash chromatography on silica gel (0 to 2% MeOH in DCM gradient) provided the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3([CH2:20][CH2:19]3)[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:23][C:24]1[CH:40]=[CH:39][C:27]([C:28]([NH:30][CH2:31][C:32]([CH3:38])([CH3:37])[CH2:33][N:34]([CH3:36])[CH3:35])=[O:29])=[CH:26][C:25]=1[O:41][CH3:42].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C.CO.O>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:20][CH2:19]3)[C:7](=[O:21])[N:6]([CH3:22])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:40]=[CH:39][C:27]([C:28]([NH:30][CH2:31][C:32]([CH3:37])([CH3:38])[CH2:33][N:34]([CH3:35])[CH3:36])=[O:29])=[CH:26][C:25]=4[O:41][CH3:42])=[N:12][C:11]2=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cc(C(=O)NCC(C)(C)CN(C)C)ccc1N
Reactant: CN1C(=O)C2(CC2)CN(C2CCCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CC(C)CC(C)O
Solvent: O
Product: COc1cc(C(=O)NCC(C)(C)CN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC1(CC1)C(=O)N2C
Temperature: 160 °C
Yield: 54.5 %

Procedure:
2′-chloro-9′-cyclohexyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 270; 86 mg, 0.27 mmol) and 4-amino-N-(3-dimethylamino-2,2-dimethyl-propyl)-3-methoxy-benzamide (Intermediate 22; 75 mg, 0.27 mmol) were taken up in 4-methyl-2-pentanol (3 mL) and p-toluenesulphonic acid monohydrate (102 mg, 0.54 mmol) added. The reaction mixture was heated at 160° C. for 1 hour by microwave irradiation. After cooling, the reaction mixture was diluted with methanol (5 mL) and water (5 mL) and the resultant solution loaded onto an SCX-3 (5 g) cartridge. The cartridge was washed with methanol (40 mL) and then eluted with 2M ammonia in methanol (25 mL). Evaporation of the ammoniacal solution gave an opaque cream coloured film which was purified by base modified reverse phase preparative HPLC to yield the title compound as a white foam (83 mg, 55%)
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].Br[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2>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.CN(C=O)C.CCN(CC)CC>[OH:7][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2
Reactant: C#CCCCCO
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCCCO)c21

Procedure:
Using general Method D above, 5-hexyn-1-ol (56 mg, 0.57 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (110 mg, 0.38 mmol) (Starting Material 1 supra) using (Ph3P)2PdCl2 (13 mg) (Aldrich) and Cul (7 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 14 h to yield (Z)-1,3-dihydro-4-(6-hydroxy-1-hexynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one.
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:12]=[C:11]([S:13][CH3:14])[N:10]=[CH:9][N:8]=1.[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>C1COCC1>[CH3:14][S:13][C:11]1[CH:12]=[C:7]([Sn:19]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH2:16][CH2:17][CH3:18])[N:8]=[CH:9][N:10]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CSc1cc(I)ncn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(SC)ncn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of isopropylmagnesium chloride (2M in THF solution, 5 mL, 10 mmol) was added slowly to a solution of 4-iodo-6-methylsulfanyl-pyrimidine (2.53 g, 10 mol) in THF (50 mL) at −78° C. After 10 min, tri-n-butyltin chloride (2.75 mL, 10 mmol) was added, and the mixture was stirred and allowed to warm to rt overnight. The crude product was purified by silica gel flash chromatography (0 to 10% ethyl acetate in hexanes eluant) to afford the title compound.
Reaction SMILES: [N:1]1([C:5]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].Cl.[NH2:24][OH:25]>CO.O>[N:1]1([C:5]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:10][CH2:9][C:8](=[N:24][OH:25])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CCC(c2ccccc2)(N2CCC2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ON=C1CCC(c2ccccc2)(N2CCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(azetidin-1-yl)-4-phenylcyclohexanone (8.4 g) in methanol (84 ml), water (84 ml) and sodium hydrogen carbonate (10.08 g) was stirred for 5 min at room temperature, then hydroxylamine hydrochloride (6.95 g) was added in portions and the mixture was stirred for 8 hours at RT. A further 0.4 equiv. of sodium hydrogen carbonate and hydroxylamine hydrochloride were then added, and stirring was carried out for 16 h at room temperature. Then the reaction mixture was concentrated under reduced pressure, the organic phase was separated off and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to yield the desired crude product. Yield: 6 g (67% crude)