Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][NH2:10])[CH2:4]1.NCC1CCC(CN)CC1.NCC1CC2CC1CC2CN.NCC1CC2CC1C(CN)C2>>[C:5]1([CH2:9][NH2:10])[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH2:1])[CH:4]=1
Reactant: NCC1CCCC(CN)C1
Agent: NCC1CC2CC(CN)C1C2
Agent: NCC1CC2CC1CC2CN
Agent: NCC1CCC(CN)CC1
Product: NCc1cccc(CN)c1

Procedure:
5 to 50 mol % of one or more diamines selected from 1,3-bis-(aminomethyl)-cyclohexane; 1,4-bis-(aminomethyl)-cyclohexane; 2,5-bis-(aminomethyl)-bicyclo-[2,2,1]-heptane; 2,6-bis(aminomethyl)-bicyclo-[2,2,1]-heptane; bis-(4-aminocyclohexyl) derivative of an alkane having from 1 to 6 carbon atoms; and m-xylylenediamine, provided that up to 50 mol % of the m-xylylenediamine may be substituted by p-xylylene diamine,
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]=1[F:14].Cl[C:20]1[CH:30]=[C:24]2[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][C:20]2[CH:30]=[C:24]3[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]3[C:22](=[O:31])[N:21]=2)=[CH:8][C:7]=1[F:14]
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccc(F)c(Cl)c2)c(F)c1
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(F)c(Cl)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (4-(3-chloro-4-fluorophenoxy)-3-fluorophenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[C:5]([NH2:6])=[C:4]([CH2:11][CH3:12])[CH:3]=1.[C:13](Cl)(Cl)=[S:14]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH3:12])[C:5]([N:6]=[C:13]=[S:14])=[C:7]([CH2:9][CH3:10])[CH:8]=1
Reactant: S=C(Cl)Cl
Reactant: CCc1cc(C)cc(CC)c1N
Product: CCc1cc(C)cc(CC)c1N=C=S

Procedure:
Using the same process, 4-methyl-2,6-diethylaniline and thiophosgene give 4-methyl-2,6-diethyl-phenyl isothiocyanate, boiling point 113°-116° C./1.2 mm Hg.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:31])[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[C:10]2[CH:9]=[C:8]([CH:16]=[CH:17][C:18]([NH:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=3)=[O:19])[CH:7]=[CH:6][C:5]1=2.I[CH3:33].O>CN(C=O)C>[CH3:33][N:20]([C:18](=[O:19])[CH:17]=[CH:16][C:8]1[CH:7]=[CH:6][C:5]2[C:4]([CH3:31])([CH3:3])[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[C:10]=2[CH:9]=1)[C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=1
Reactant: CI
Reactant: COC(=O)c1ccc(NC(=O)C=Cc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(C)C(=O)C=Cc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
300 mg (10 mmol) of sodium hydride (80% in oil) and 30 ml of DMF are introduced into a three-necked flask under a stream of nitrogen. A solution of 1.8 g (4.8 mmol) of methyl 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) acryloylamino]benzoate (prepared in Example 2 (a)) in 50 ml of DMF is added dropwise and the mixture is stirred until the evolution of gas has ceased. 750 μl (12 mmol) of iodomethane are then added and the mixture is stirred at room temperature for four hours. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The solid obtained is triturated from hexane, filtered off and dried. 1.6 g (83%) of the expected methyl ester, with a melting point of 167-8° C., are collected.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:18][C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[C:21](Cl)[N:20]=1>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[C:6]([S:11][C:21]3[N:20]=[C:19]([NH2:18])[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Sc1cccc2cnccc12
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(Sc2cccc3cnccc23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
According to the method in Example 10, a mixture of 5-isoquinolinethiol 300 mg (1.9 mmol), DMF 10 ml, potassium carbonate 520 mg (3.7 mmol) and 2-amino-6-chloro-3-nitropyridine 300 mg (1.9 mmol) was stirred at room temperature for 30 minutes, and 6-(5-isoquinolylsulfanyl)-3-nitro-2-pyridylamine 460 mg (86.7%) was obtained.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21]CC)=[O:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.O>C(O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]2[CH2:14][CH2:15][CH:16]([C:19]([OH:21])=[O:20])[CH2:17][CH2:18]2)(=[O:12])=[O:11])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Reaction time: 1 h
Yield: 94.8 %

Procedure:
Sodium hydroxide solution (100 ml at 40% w/v) was added to a stirred suspension of the above ester (78.0 g) in ethanol (200 ml)/water (100 ml). Water (100 ml) was added and the reaction mixture heated to reflux and reflux maintained for 30 minutes. The reaction mixture was cooled and the crystalline sodium salt was collected. This sodium salt was suspended in water (350 ml) and glacial acetic acid added to adjust the pH of the solution to 5. The mixture was stirred for 1 hour and the colourless solid collected, washed with water and dried to give, as a colourless solid, 1-(4-bromophenylsulphonyl)piperidine-4-carboxylic acid (68.4 g): m.p. 225-227° C.; microanalysis, found: C, 41.0; H, 3.7; N, 3.9%; C12H14BrNO4S requires: C, 41.4; H, 4.1; N 4.0%; NMR: 1.41-1.63(m, 2H), 1.73-1.93(m, 2H), 2.11-2.30(m, 1H), 2.44(t, 2H); 3.28-3.60(m, 2H), 7.62(d, 2H) 7.89(d, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][C:20]2[N:21]=[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]3[CH:28]=2)[CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH2:15][C:14]1[CH:13]=[CH:12][C:11]([CH2:18][CH2:19][C:20]2[N:21]=[C:22]3[CH2:27][CH2:26][CH2:25][CH2:24][N:23]3[CH:28]=2)=[CH:10][C:9]=1[OH:8]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(C=Cc2cn3ccccc3n2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CCc2cn3c(n2)CCCC3)cc1O
Yield: 68.6 %

Procedure:
A solution of 2-[2-(3-benzyloxy-4-nitrophenyl)vinyl]imidazo[1,2-a]pyridine (40 g) in ethanol (600 ml) was hydrogenated over 10% palladium on carbon (10 g) at 4 to 6 atmospheric pressure of hydrogen gas for 4 hours at 40° to 70° C. The catalyst was removed by filtration an the filtrate was evaporated in vacuo to give a crystalline residue, which was washed with diethyl ether and dried to give 2-[2-(4-amino-3-hydroxyphenyl)ethyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (19.0 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13](I)=[C:12]([Cl:23])[CH:11]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.[F-].[Cs+].CCOC(C)=O>COCCOC.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.O>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([C:30]2[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=2)=[C:12]([Cl:23])[CH:11]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(Cl)c(I)c(OCC(F)(F)F)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(CC(C)C)c1cc(Cl)c(-c2ccc(C(F)(F)F)cc2)c(OCC(F)(F)F)c1
Yield: 51.3 %

Procedure:
A mixture of ethyl-2-(3-chloro-4-iodo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.5, 1.04 mmol), 4-trifluoromethylphenylboronic acid (0.96 g, 2.09 mmol), CsF (0.395 g, 2.6 mmol) and Pd (PPh3)4 (0.121 g, 0.104 mmol) in 50 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 25 mL of EtOAc and 25 mL of water were added. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to yellow oil. The oil was purified by column chromatography over silica gel (hexane/EtOAc, 95:5) to give ethyl-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoate (0.265 g), as a colorless oil.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:7][SiH:8]([Cl:10])[Cl:9]>[Pt]>[CH:1]1([Si:8]([CH3:7])([Cl:10])[Cl:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1=CCCCC1
Reactant: C[SiH](Cl)Cl
Agent: [Pt]
Product: C[Si](Cl)(Cl)C1CCCCC1
Reaction time: 70 h
Yield: 91 %

Procedure:
Into a glass-made flask of 100 ml capacity equipped with a reflux condenser and stirrer were introduced 0.25 mole of cyclohexene, 0.25 mole of methyl dichlorosilane and 0.11 g of the same platinum catalyst as used in Example 1 and the flask containing the mixture was put under direct sun light at room temperature. A reaction took place in the mixture and continued without loss of the catalyst activity. The reaction was almost complete after 70 hours of exposure to sun light. Distillation of the thus obtained reaction mixture gave cyclohexyl methyl dichlorosilane in a yield of 91%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24].[CH2:25]([N:27]([CH2:38][CH3:39])[CH2:28][CH2:29][O:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)[CH3:26]>ClCCl.CO.C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:35][C:34]3[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH2:28][N:27]([CH2:38][CH3:39])[CH2:25][CH3:26])=[CH:37][CH:36]=3)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: CN1C(=O)N(c2ccc(Cl)cc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(c2ccc(Cl)cc2Cl)C3)cc1
Temperature: 180 °C
Yield: 7.5 %

Procedure:
A mixture of 200 mg (0.52 mmol) of 3-(2,4-dichlorophenyl)-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 300 mg (1.4 mmol) of 4-[2-(diethylamino)ethoxy]aniline was heated at 180° C. for 30 minutes and then cooled. The residue was subjected to column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined and evaporated and the residue was evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give 20 mg (8%) of 3-(2,4-dichlorophenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as an orange colored solid of melting point 172° C.
Reaction SMILES: [C-:1]#[CH:2].[Li+].C(N)CN.Br[C:9]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2.O>CN(P(N(C)C)(N(C)C)=O)C.CCOCC>[C:1]([C:9]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)#[CH:2]
Reactant: BrC1(c2ccccc2)c2ccccc2-c2ccccc21
Reactant: [C-]#C
Agent: [Li+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: C#CC1(c2ccccc2)c2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
Lithium acetylenide-ethylenediamine (10 mmol) is added to a dry flask under argon, diluted with 5 mL of HMPA, and cooled to between 0 and 5° C. with stirring. A solution of 8 mmol of 9-bromo-9-phenylfluorene dissolved in 4 mL of HMPA is added slowly to the reaction flask. The reaction mixture is warmed to room temperature and, after 2 h, 25 mL of water is slowly added. The mixture is taken up in 100 mL of ether and washed with 20mL of H2O, 20 mL of brine, dried (Na2SO4) and concentrated. The product is purified by chromatography over SiO2 using EtOAc/hexanes (2/98) as eluent. (Smith, W. N.; Beumel, O. F., Preparation of Alkynes with Dialkynes by reaction of monohalo- and dihaloalkanes with lithium acetylenide-ethylenediamine complex., Synthesis, 1974, 441-442.)
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][C:8]([CH2:10][CH:3]1[CH2:4][CH2:5]2)=O.[CH2:11]([N:13]([CH2:31][CH3:32])[C:14]([C:16]1[CH:17]=[CH:18][C:19]2[C:20](=O)[C:21]3[C:26]([O:27][C:28]=2[CH:29]=1)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:15])[CH3:12]>>[CH2:31]([N:13]([CH2:11][CH3:12])[C:14]([C:16]1[CH:17]=[CH:18][C:19]2[C:20](=[C:8]3[CH2:10][CH:3]4[N:2]([CH3:1])[CH:6]([CH2:5][CH2:4]4)[CH2:7]3)[C:21]3[C:26]([O:27][C:28]=2[CH:29]=1)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:15])[CH3:32]
Reactant: CCN(CC)C(=O)c1ccc2c(=O)c3ccccc3oc2c1
Reactant: CN1C2CCC1CC(=O)C2
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2C

Procedure:
Following Procedure 7 and substituting tropinone for N-carbethoxynortropinone, compound 6a was converted to the title compound. MS m/z=403.2 (M+1); 1H NMR 300 MHz (CDCl3) δ 1.2 (br s, 6H), 1.9 (m, 2H), 2.5 (s, 3H), 2.8 (m, 2H), 3.1 (m, 2H), 3.3 (m, 2H), 3.4 (br s, 2H), 3.6 (m, 4H), 7.0-7.3 (m, 7H).
Reaction SMILES: Br[C:2]1[C:6]([CH3:8])([CH3:7])[O:5]/[C:4](=[C:9]2/[C:10](=[O:19])[NH:11][C:12]3[C:17]/2=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)/[CH:3]=1.[F:20][C:21]1[N:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[F:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:19])/[C:9]/2=[C:4]1/[O:5][C:6]([CH3:8])([CH3:7])[C:2]([C:24]2[CH:25]=[N:26][C:21]([F:20])=[CH:22][CH:23]=2)=[CH:3]/1
Reactant: OB(O)c1ccc(F)nc1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3ccc(F)cc32)C=C1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)O/C(=C2/C(=O)Nc3ccc(F)cc32)C=C1c1ccc(F)nc1
Temperature: 65 °C
Yield: 47 %

Procedure:
to a mixture or 3-[4-bromo-5,5-dimethyl-5H-furan-(2E)-ylidene]-5-fluoro-1,3-dihydro-indol-2-one (3.24 g, 10.0 mmol), 6-fluoropyridin-3-ylboronic acid (1.8 g, 12 mmol) in THF (150 mL), was added a solution of potassium carbonate (13.8 g, 100 mmol) in water (20 mL). The resulting mixture was deoxygenated by bubbling nitrogen through the reaction mixture for 3 minutes and palladium(0) tetrakis(triphenylphosphine) (578 mg, 5 mol %) was then added. The reaction mixture was heated at 65° C. for 18 hours. The reaction was cooled to room temperature and ethyl acetate (500 mL) added. The organic phase was washed with water (100 mL×2), dried over sodium sulfate, and evaporated to give the crude product, which was purified first by silica gel column chromatography (5% CH3OH/CH2Cl2 elution) and then by titration with ethyl acetate. The resulting product was isolated by filtration and dried under vacuum to provide 5-fluoro-3-[4-(6-fluoro-pyridin-3-yl)-5,5-dimethyl-5H-furan-(2E)-ylidene]-1,3-dihydro-indol-2-one as a yellow solid (1.6 g, yield 48%).
Reaction SMILES: C1C=C(C(O)=[O:8])C(C(OO)=O)=CC=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[C:19]2[CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:30][CH2:29]1.[OH-].[Na+]>CCOCC.CO>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N+:22]([O-:8])=[CH:21][CH:20]=[C:19]2[CH2:26][CH2:27][CH:28]1[CH2:29][CH2:30][N:31]([C:34](=[O:41])[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:32][CH2:33]1
Reactant: COc1ccc2nccc(CCC3CCN(C(=O)c4ccccc4)CC3)c2c1
Reactant: O=C(O)c1ccccc1C(=O)OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: COc1ccc2c(c1)c(CCC1CCN(C(=O)c3ccccc3)CC1)cc[n+]2[O-]
Temperature: 10 °C
Reaction time: 4 h

Procedure:
269 ml of a 0.09M solution of monoperphthalic acid in ether (prepared according VOGEL--Textbook of Practical Organic Chemistry, 1978, 307) are added rapidly to a solution of 7.9 g of 6-methoxy-4-[2-(1-benzoyl-4-piperidyl)-ethyl]-quinoline in 45 ml of methanol, stirred and cooled to 10° C. After four hours at the ambient temperature, a further 20 ml of the same monoperphthalic acid solution are added, and the stirring is then maintained for 15 hours. The reaction mixture is then made alkaline with 100 ml of a 0.7N aqueous solution of sodium hydroxide. The organic phase, separated, is again washed with 100 ml of a 0.5N solution of sodium hydroxide, dried, then concentrated. The residue obtained, after recrystallization from cyclohexane, gives 5.1 g of 6-methoxy-4-[2-(1-benzoyl-4-piperidyl)-ethyl]quinoline-N-oxide melting at 138° C.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][C:9](=[O:21])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[F:20])[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].I[CH:25]([CH3:27])[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:21])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:25]([CH3:27])[CH3:26])=[CH:15][C:14]=2[F:20])[O:11][CH3:12])=[CH:22][CH:23]=1)#[N:2]
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(O)cc1F
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(OC(C)C)cc1F

Procedure:
In analogy to example 16.4, (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-4-hydroxy-phenyl)-2-methoxy-acetamide was alkylated with 2-iodopropane and cesium carbonate in DMF to give (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-4-isopropoxy-phenyl)-2-methoxy-acetamide. Light yellow oil. MS 357.2 ([M+H]+)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([CH3:16])[S:15][C:8]=2[C:7]=1[OH:17])=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)CCC>>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]2[N:13]=[C:14]([CH3:16])[S:15][C:8]=2[C:7]=1[OH:17])=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: CCOC(=O)c1nc(Br)c2nc(C)sc2c1O
Product: CCOC(=O)c1nc(-c2ccccc2)c2nc(C)sc2c1O

Procedure:
The title compound was prepared from 4-Bromo-7-hydroxy-2-methyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester and tributylphenyl tin under conditions analogous to the experimental procedure found in example 169(a). MS (ESI+): m/z 315.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C@:5]1([NH:15][S:16]([C:19]2[S:23][C:22]([NH2:24])=[N:21][CH:20]=2)(=[O:18])=[O:17])[CH2:7][C@:6]1([CH3:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[Br:25][CH2:26][C:27]([CH2:29]Br)=O>C(OCC)(=O)C>[CH3:1][O:2][C:3]([C@:5]1([NH:15][S:16]([C:19]2[S:23][C:22]3=[N:24][C:27]([CH2:26][Br:25])=[CH:29][N:21]3[CH:20]=2)(=[O:18])=[O:17])[CH2:7][C@:6]1([CH3:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: O=C(CBr)CBr
Reactant: COC(=O)[C@]1(NS(=O)(=O)c2cnc(N)s2)C[C@]1(C)c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@]1(NS(=O)(=O)c2cn3cc(CBr)nc3s2)C[C@]1(C)c1ccccc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 24.2 %

Procedure:
To a solution of (1S,2R)-1-(2-amino-thiazol-5-sulfonylamino)-2-methyl-2-phenyl-cyclopropanecarboxylic acid methyl ester (0.21 g, 0.58 mmol) in ethyl acetate (6.4 mL) was added 1,3-dibromoacetone (0.18 mL, 0.87 mmol), and the mixture was stirred at 60° C. for 18 hours. After cooling to room temperature, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and dried over sodium sulfate. After filtration and evaporation, the obtained residue was separated and purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (68 mg, yield 24%) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([CH3:12])[N:6]=[C:5]2[Sn](CCCC)(CCCC)CCCC.[C:26]([CH:28]1[CH2:33][CH2:32][N:31]([C:34](=[O:60])[C@H:35]([NH:39][C:40]([C:42]2[C:50]3[C:45](=[N:46][CH:47]=[C:48](Br)[N:49]=3)[N:44]([CH2:52][O:53][CH2:54][CH2:55][Si:56]([CH3:59])([CH3:58])[CH3:57])[CH:43]=2)=[O:41])[CH:36]2[CH2:38][CH2:37]2)[CH2:30][CH2:29]1)#[N:27]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:26]([CH:28]1[CH2:33][CH2:32][N:31]([C:34](=[O:60])[C@H:35]([NH:39][C:40]([C:42]2[C:50]3[C:45](=[N:46][CH:47]=[C:48]([C:5]4[C:4]5[C:8](=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=5)[N:7]([CH3:12])[N:6]=4)[N:49]=3)[N:44]([CH2:52][O:53][CH2:54][CH2:55][Si:56]([CH3:58])([CH3:57])[CH3:59])[CH:43]=2)=[O:41])[CH:36]2[CH2:37][CH2:38]2)[CH2:30][CH2:29]1)#[N:27]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(Cl)c(Cl)cc12
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(Br)cnc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)cn3COCC[Si](C)(C)C)c2cc(Cl)c(Cl)cc21
Temperature: 90 °C
Yield: 86.7 %

Procedure:
To a solution of 5,6-dichloro-1-methyl-3-tributylstannyl-1H-indazole (crude from Step 5, 218 mg, 0.44 mmol) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (125 mg, 0.22 mmol) in DMF (2 mL) were added Pd(PPh3)4 (12.9 mg, 0.011 mmol) and copper(I) iodide (8 mg, 0.044 mmol). The yellow reaction mixture was heated at 90° C. for 1.5 h then cooled to room temperature, quenched with water and extracted with EtOAc (2×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The crude residue was purified by silica gel chromatography with 50% to 100% EtOAc/hexanes to isolate 130 mg (86%) of 2-(5,6-dichloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a pale yellow foamy solid.
Reaction SMILES: C([O:3][P:4]([CH2:9][O:10][C@@H:11]([CH2:24][OH:25])[CH2:12][O:13][N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][CH:17]=[N:18][C:19]=2[NH2:23])([O:6]CC)=[O:5])C.C[Si](Br)(C)C>ClCCl>[OH:25][CH2:24][C@H:11]([O:10][CH2:9][P:4]([OH:5])([OH:6])=[O:3])[CH2:12][O:13][N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][CH:17]=[N:18][C:19]=2[NH2:23]
Reactant: CCOP(=O)(CO[C@@H](CO)COn1cnc2c(N)ncnc21)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: Nc1ncnc2c1ncn2OC[C@H](CO)OCP(=O)(O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.3 %

Procedure:
To a solution of (S)-9-[2-(diethoxyphosphorylmethoxy)-3-hydroxypropoxy]adenine (0.09 g, 0.24 mmol) in dry dichloromethane (3 ml) was added trimethylsilyl bromide (0.31 ml, 2.4 mmol) and the solution stirred at ambient temperature for 4 hours. The solvent was removed under reduced pressure and the residue co-evaporated with acetone/water 1:1 (x3). Crystallisation of the residue from water/acetone gave the title compound as a white solid (0.06 g, 78%), mp. 93°-198° C.