Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:64][CH2:65][CH:66]1[CH2:68][CH2:67]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:66]1([CH2:65][NH:64][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[CH:7][C:8]([CH3:12])=[N:9]3)=[CH:4][CH:3]=2)[CH2:68][CH2:67]1
Reactant: Cc1cc(N2CCCC2)c2ccc(I)cc2n1
Reactant: NCC1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCCC2)c2ccc(NCC3CC3)cc2n1
Yield: 30 %

Procedure:
A suspension of 1.01 g (3 mmol) of 7-iodo-2-methyl-4-pyrrolidin-1-yl-quinoline, 0.186 g (0.3 mmol) rac BINAP, 33.7 mg (0.15 mmol) of palladium(II)acetate and 0.87 g (9 mmol) of sodium tert-butylate in toluene (25 ml) was treated at RT with 0.427 g (6 mmol) of aminomethyl cyclopropane and then heated to reflux under an argon atmosphere for 20 h. The reaction mixture was then filterd by suction over fiberglass filter paper and the filtrate was partitioned between EtOAc and water. The layers were separated, the organic layer dried over sodium sulphate and concentrated in vacuo. The residue was applied to silica gel column with CH2Cl2/MeOH/NH4OH (15:1:0.2) as eluent. Combination of the purified fractions and concentration in vacuo gave 253 mg (30%) of the desired cyclopropylmethyl-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yl)-amine as light yellow foam. ISP mass spectrum, m/e: 282.2 (M+1 calculated for C18H23N3O: 282).
Reaction SMILES: [CH3:1][Si:2]([CH2:5][CH2:6][O:7][CH2:8]Cl)([CH3:4])[CH3:3].[OH:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.CCN(CC)CC.CCOCC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][Si:2]([CH2:5][CH2:6][O:7][CH2:8][O:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)([CH3:4])[CH3:3]
Reactant: N#Cc1ccc(O)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[Si](C)(C)CCOCOc1ccc(C#N)cc1
Temperature: 25 °C
Yield: 45.2 %

Procedure:
To a solution of 1.63 ml (9.23 mmol) of SEM-Cl in 10 ml of dry DCM were added 1.00 g (8.39 mmol) of 4-hydroxy benzonitrile, 103 mg (0.84 mmol) of DMAP and 2.34 ml (16.8 mmol) of Et3N, stirring at RT under N2. After stirring overnight, 10 ml of ether were added and the solids filtered off. The filtrate was evaporated and the product purified by flash chromatography (20% ethyl acetate in petrol), obtaining 945 mg (3.79 mmol, 48%) of a colourless oil.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[C:17]([C:18]2[NH:19][C:20](=[O:33])[C:21]3[C:22](=[C:24]([CH2:31][CH3:32])[N:25]([CH2:27][CH2:28][O:29][CH3:30])[N:26]=3)[N:23]=2)=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][N:9]=1)[CH2:4][CH2:5][CH3:6].Cl>O1CCOCC1>[CH2:3]([O:7][C:8]1[C:17]([C:18]2[NH:19][C:20](=[O:33])[C:21]3[C:22](=[C:24]([CH2:31][CH3:32])[N:25]([CH2:27][CH2:28][O:29][CH3:30])[N:26]=3)[N:23]=2)=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOc1ncc(C(=O)OC)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCOc1ncc(C(=O)O)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Reaction time: 14 h

Procedure:
Sodium hydroxide (0.52 mL of 2N) was added to a solution of methyl 6-butoxy-5-[3-ethyl-2-(2-methoxyethyl)-7-oxo-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-5-yl]nicotinate (Example 2) (226 mg, 0.53 mmol) in dioxane. The solution was stirred for 14 h. The pH was adjusted to pH 2-3 with hydrochloric acid (1N) and the mixture concentrated to dryness. Hot ethanol was added to the solid and the slurry filtered. The ethanol solution was concentrated and the resulting solid was washed with dichloromethane resulting in the title compound (156 mg, 72%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:13]([CH2:21][C:22](=[O:26])[C:23]([CH3:25])=[CH2:24])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])C=C)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.CC1C=C(C)C=C(C)C=1N1CCN(C2C(C)=CC(C)=CC=2C)C1=[Ru](Cl)(Cl)=CC1C=CC=CC=1OC(C)C>[Si:1]([O:8][CH2:9][C@@H:10]1[CH:25]=[C:23]([CH3:24])[C:22](=[O:26])[CH2:21][N:13]1[C:14]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:20])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)C(=C)C)C(=O)OC(C)(C)C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: Cc1ccccc1
Product: CC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC1=O
Temperature: 65 °C
Yield: 87.3 %

Procedure:
A solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)but-3-en-2-yl(3-methyl-2-oxobut-3-enyl)carbamate (Intermediate 6, 26.18 g, 68.25 mmol) in toluene (600 mL) was purged with nitrogen for 15 minutes. (1,3-Bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium (0.987 g, 1.57 mmol) was then added. The reaction mixture was heated at 65° C. for 1.5 hours. The reaction mixture was concentrated onto silica gel. Silica gel chromatography (0%-15% ethyl acetate/hexanes) afforded the desired product (21.18 g, 87%) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.[CH:9](O)=O.C=O>>[CH3:9][N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4]1
Reactant: O=CO
Reactant: OCC1CCCNC1
Agent: C=O
Product: CN1CCCC(CO)C1
Yield: 76.1 %

Procedure:
A! At 0° C., 3-hydroxymethyl-piperidine (20 g, 173 mmoles) was slowly added to formic acid (63 ml, 1.66 moles) then a 40% solution of formaldehyde was added (62.4 ml, 833 mmoles). The mixture was refluxed for 5 hours, then the solvent was evaporated and the residue taken up in little water, brought to basic pH with 32% sodium hydroxide and extracted with ethyl ether. The organic phase was anhydrified over sodium sulfate and evaporated. The resultant crude was purified by distillation and provided 17 g (yield: 76%) of N-methyl-3-hydroxymethylpiperidine (b.p.--85°-86° C./1 mmHg).
Reaction SMILES: [CH3:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOCC>[CH3:1][C:2]1([CH:8]=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: CC1(CO)CCOCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(C=O)CCOCC1
Reaction time: 1.17 h
Yield: 68.5 %

Procedure:
To a solution of (4-methyl-tetrahydro-pyran-4-yl)-methanol (1.5 g, 11.5 mmol) in CH2Cl2 was added a suspension of Dess-Martin periodinane (5.8 g, 14 mmol) in CH2Cl2 (30 mL). After 70 min, the heterogenous mixture was diluted with Et2O (100 mL), stirred for 10 min, treated with 1 N HaOH (10 mL), and stirred for another 10 min. The mixture was filtered, and the filtrate was concentrated. The residue was purified by chromatography (Et2O/CH2Cl2) to give the title compound (1.01 g, 68%) as a colorless volatile oil. The spectral data matched that reported in PCT Intl. Pat. Appl. Publ. No. WO 2006/001752.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](C(O)=O)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(=O)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)C(C(=O)O)c1ccc(Br)cc1
Agent: O=C=O
Product: O=C(O)Cc1ccc(Br)cc1
Yield: 1099.1 %

Procedure:
2-(4-Bromophenyl)malonic acid (36 g, 11 mmol) was heated at 165° C. until evolution of CO2. the production was crystallized from petrol ether to give 2-(4-bromophenyl)acetic acid (26 g, 87%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]=[CH:10][C:11]([C:13]1[N:14]=[C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:36])[CH2:25][N:26]3[C:30]([CH3:31])=[CH:29][C:28]([C:32]([F:35])([F:34])[F:33])=[N:27]3)[CH2:20][CH2:19]2)[S:16][CH:17]=1)=[O:12].[Cl-].[NH4+]>C(O)C.[Zn]>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH2:9][CH2:10][C:11]([C:13]1[N:14]=[C:15]([CH:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:36])[CH2:25][N:26]3[C:30]([CH3:31])=[CH:29][C:28]([C:32]([F:34])([F:35])[F:33])=[N:27]3)[CH2:22][CH2:23]2)[S:16][CH:17]=1)=[O:12]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)C=Cc3c(F)cccc3F)cs2)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)CCc3c(F)cccc3F)cs2)CC1
Reaction time: 8 h

Procedure:
A mixture of 3-(2,6-difluorophenyl)-1-[2-[1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolyl]-2-propen-1-one (i.e. the product of Example 2, Step A) (0.25 g, 0.48 mmol), zinc dust (0.25 g, 3.8 mmol) and saturated ammonium chloride (0.25 mL) in ethanol (5 mL) was stirred overnight, concentrated to dryness, treated with dichloromethane and filtered. The filtrate was concentrated and purified via silica gel chromatography (hexanes: ethyl acetate gradient) to provide 0.025 g of 3-(2,6-difluorophenyl)-1-[2-[1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolyl]-1-propanone.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:26])([F:25])[C:12]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:13]=1[C:14]([OH:16])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:49]=[C:50]([N:67]1[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]1)[CH2:51][NH:52][C:53]([C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:57][CH:56]=1)=[O:54]>CN(C=O)C.O>[F:25][C:11]([F:10])([F:26])[C:12]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:13]=1[C:14]([N:70]1[CH2:69][CH2:68][N:67]([C:50](=[O:49])[CH2:51][NH:52][C:53]([C:55]2[CH:60]=[CH:59][C:58]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[CH:57][CH:56]=2)=[O:54])[CH2:72][CH2:71]1)=[O:16]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(C(F)(F)F)ccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.2 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 2,5-bis-trifluoromethyl-benzoic acid (66.5 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 50% EtOAc in hexane as eluent) to afford 75 mg (51.6% yield) of biphenyl-4-carboxylicacid {2-[4-(2,5-bis-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 95.51%, 1H NMR: (DMSO) δ 8.65 (t, 1H), 8.1 (t, 3H), 8.0 (d, 2H), 7.83-7.7 (q, 4H), 7.5 (t, 2H), 7.42 (t, 1H), 4.2 (d, 2H), 3.8-3.42 (d, 6H), 3.2 (m, 2H).
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH:13]1([CH:17]=[O:18])[CH2:16][CH2:15][CH2:14]1>>[CH:13]1([CH:17]([OH:18])[C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: O=CC1CCC1
Reactant: CCOC(=O)c1ccc(I)cc1
Product: CCOC(=O)c1ccc(C(O)C2CCC2)cc1

Procedure:
The title compound was prepared by a method analogous to that described for Intermediate (16), using ethyl 4-iodobenzoate and cyclobutanecarbaldehyde. 1H NMR (400 MHz, CDCl3, δ): 7.93 (d, J=8.0 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H), 4.58 (d, J=8.0 Hz, 1H), 4.29 (q, J=6.8 Hz, 2H), 2.50-2.58 (m, 1H), 1.70-2.02 (m, 6H), 1.34 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[NH:16][C:17]1[C:18]2[CH:25]=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1)=[O:10])C1C=CC=CC=1.[Br:26][C:27]1[CH:35]=[CH:34][C:30]([CH2:31]CN)=[CH:29][CH:28]=1>>[Br:26][C:27]1[CH:35]=[CH:34][C:30]([CH2:31][CH2:1][NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[NH:16][C:17]2[C:18]3[CH:25]=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)=[O:10])=[CH:29][CH:28]=1
Reactant: NCCc1ccc(Br)cc1
Reactant: O=C(NCc1ccccc1)c1sccc1Nc1ncnc2[nH]ccc12
Product: O=C(NCCc1ccc(Br)cc1)c1sccc1Nc1ncnc2[nH]ccc12
Yield: 20 %

Procedure:
The title compound was prepared in an analogous manner as 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid benzylamide using 4-bromophenethylamine instead of benzylamine and obtained in 20% yield (HPLC: 60%, RT: 6.81 min). 1H NMR (DMSO-d6) 11.98 (br s, 1H), 11.37 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.38 (s, 1H), 8.32 (t, J=5.5 Hz, 1H), 7.75 (d, J=5.1 Hz, 1H), 7.50-7.47 (m, 2H), 7.37 (dd, J=3.3, 2.2 Hz, 1H), 7.25-7.21 (m, 2H), 6.45 (dd, J=3.6, 1.8 Hz, 1H), 3.54-3.47 (m, 2H), 2.85 (t, J=7.0 Hz, 2H); MS (m/z) 442 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:13]2[N:9]([C:10]([CH2:15][CH2:16][CH3:17])=[N:11][C:12]=2[CH3:14])[C:8]2[N:7]=[CH:6][S:5][C:4]=2[N:3]=1.[Br:18]Br>C(Cl)(Cl)Cl>[Br:18][C:6]1[S:5][C:4]2[N:3]=[C:2]([CH3:1])[C:13]3[N:9]([C:10]([CH2:15][CH2:16][CH3:17])=[N:11][C:12]=3[CH3:14])[C:8]=2[N:7]=1
Reactant: CCCc1nc(C)c2c(C)nc3scnc3n12
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCCc1nc(C)c2c(C)nc3sc(Br)nc3n12
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a solution of 5,6-dimethyl-8-propyl-3-thia-1,4,7,8a-tetraaza-as-indacene from example 1 (40 mg, 0.16 mmol) in CHCl3 (10 mL) was added Br2 (78 mg, 0.5 mmol), then the solution was stirred at room temperature overnight to give a brown solution. LC-MS showed 30% of the title compound and 35% of 5,6-dimethyl-8-propyl-3-thia-1,4,7,8a-tetraaza-as-indacene. The reaction mixture was diluted with sat. NaHSO3 solution. The aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were dried with Na2SO4, filtered and concentrated.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.CC([O-])(C)C.[K+].C1COCC1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.O>[CH2:21]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc2[nH]nnc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(Cn2nnc3ccccc32)cc1
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
To a solution of benzotriazole (1.2 g, 10.1 mmol) in DMF (40 mL) at r.t. was added a solution of 1M KOtBu in THF (11 mL, 11 mmol). After stirring for 30 min., benzyl bromide (2.0 g, 11.6 mmol) was added. The mixture was further stirred for 1 h, diluted with H2O, and extracted with EtOAc. The EtOAc extract was washed with H2O (3×), dried (MgSO4) and concentrated. The residue was stirred with hexane containing small amount of Et2O to give 1.2 g (57%) of the title compound as a white powder.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:34]=[C:33]([CH2:35][CH3:36])[C:18]([O:19][S:20]([C:23]5[S:27][CH:26]=[C:25]([C:28]([OH:30])=[O:29])[C:24]=5[O:31]C)(=[O:22])=[O:21])=[C:17]([CH2:37][CH3:38])[CH:16]=4)[C:4]=2[C:3]=1[CH3:39])[CH:12]=[CH:11][CH:10]=[CH:9]3.B(Br)(Br)Br.C(Cl)Cl.C(=O)=O.CC(C)=O>C(Cl)Cl>[CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:16]=[C:17]([CH2:37][CH3:38])[C:18]([O:19][S:20]([C:23]5[S:27][CH:26]=[C:25]([C:28]([OH:30])=[O:29])[C:24]=5[OH:31])(=[O:21])=[O:22])=[C:33]([CH2:35][CH3:36])[CH:34]=4)[C:4]=2[C:3]=1[CH3:39])[CH:12]=[CH:11][CH:10]=[CH:9]3
Reactant: CCc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(CC)c1OS(=O)(=O)c1scc(C(=O)O)c1OC
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(CC)c1OS(=O)(=O)c1scc(C(=O)O)c1O
Reaction time: 1.5 h
Yield: 82.2 %

Procedure:
At -78° C., to a stirred solution of 5-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxysulfonyl]-4-methoxy-thiophene-3-carboxylic acid (0.374 g, 0.644 mmol) in CH2Cl2 (3.74 mL) was added 1M boron tribromide/CH2Cl2 (2.00 mL). After the addition was complete, the dry ice/acetone bath was replaced with an ice water bath and the reaction was stirred for 1.5 h. The reaction was carefully quenched into crushed ice, diluted with H2O and extracted with EtOAc. The combined organic extracts were dried (MgSO4) and concentrated. The crude product was purified on Biotage KP-Sil eluting with 40% EtOAc/hexane to give 0.300 g (82%) of the title compound as an off white solid. 1H NMR (DMSO-d6) δ 1.09 (t, 6 H), 1.59 (s, 3 H), 2.41 (s, 3 H), 2.62-2.73 (m, 4 H), 7.16 (s, 2 H), 7.38-7.47 (m, 3 H), 7.98 (d, 1 H), 8.49 (s, 1 H), 8.68 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:10]([Si:12]([C:17]#[CH:18])([CH2:15][CH3:16])[CH2:13][CH3:14])[CH3:11].[Cl-].[Li+].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:11]=[C:10]([Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][CH3:14])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C#C[Si](CC)(CC)CC
Reactant: Nc1ncc(Cl)cc1I
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)c1cc2cc(Cl)cnc2[nH]1
Temperature: 90 °C
Yield: 43.9 %

Procedure:
A mixture of 40 (9.5 g, 37.3 mmol) was dissolved in 320 mL of DMF and triethylsilylacetylene (20 mL, 112 mmol), Pd2Cl2 (dppf)2 (1.52 g, 1.9 mmol), lithium chloride (1.58 g, 37.3 mmol) and 2M Na2CO3 (7.9 mL, 74.7 mL) were added and the mixture was stirred and refluxed at 90° C. for 15 h under nitrogen. Diluted with ethyl acetate-ether mixture (1:1) and the organic phase washed with water and brine then dried (Na2SO4) and concentrated in vacuo. The residue was subjected to flash chromatography (20% EtOAc/80% hexanes) to give 4.37 g (44%) of the desired product 41. 1H NMR (500 MHz, CDCl3) 9.4 (bs, 1H), 8.2 (s, 1H), 7.9 (s, 1H), 6.6 (s, 1H), 0.9 (t, 9H), 0.75 (q, 6H).
Reaction SMILES: [F-].[Cs+].[CH2:3]([C:7]1[N:8]([CH2:41][CH2:42][CH3:43])[C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25](=[O:40])(=[O:39])[N:26]([CH2:35][CH2:36][O:37][CH3:38])COCC[Si](C)(C)C)=[CH:21][CH:20]=3)[N:13]=2)=[CH:10][N:11]=1)[CH2:4][CH:5]=[CH2:6]>CN(C=O)C.O>[CH2:3]([C:7]1[N:8]([CH2:41][CH2:42][CH3:43])[C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([S:25](=[O:40])(=[O:39])[NH:26][CH2:35][CH2:36][O:37][CH3:38])=[CH:23][CH:24]=3)[N:13]=2)=[CH:10][N:11]=1)[CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)N(CCOC)COCC[Si](C)(C)C)cc3)n2)n1CCC
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOC)cc3)n2)n1CCC

Procedure:
A mixture of caesium fluoride (180 mg, 1.2 mmole), and 4-(2-(but-3-enyl)-1-propylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)-N-(2-trimethylsilylethoxymethyl)sulphamoyl]anilino}pyrimidine (Method 100; 100 mg, 0.17 mmol), in DMF (3 ml), was heated at 140° C. under nitrogen for 24 hours. The mixture was diluted with water and extracted with EtOAc. The extracts were washed with water and brine, dried, and the solvent evaporated. The residue was purified by chromatography on silica gel eluting with EtOAc to give the title compound. (8 mg, 10%). NMR: 0.7 (t, 3H), 1.52 (q, 2H), 2.80 (t, 2H), 2.85-2.89 (m, 2H), 3.19 (s, 3H), 3.18-3.22 (m, 2H), 3.30 (t, 2H), 4.52 (t, 2H), 4.98 (d, 1H), 5.10 (dd, 1H), 5.95-5.89 (m, 1H), 7.20 (d, 1H), 7.44 (t, 1H), 7.70 (s, 3H), 7.74 (d, 2H), 7.89 (d, 2H), 8.45 (d, 1H), 9.80 (s, 1H); m/z: 471.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].N1C=CC=CC=1.[C:21](Cl)(Cl)=[O:22].C1(C)C=CC=CC=1>ClCCl>[N:6]([C@@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([O:3][CH3:2])=[O:14])=[C:21]=[O:22]
Reactant: O=C(Cl)Cl
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)[C@H](Cc1ccccc1)N=C=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A well-stirred cold mixture (0° C.) of phenylalanine methyl ester hydrochloride (200 mg), anhydrous dichloromethane (3 ml), and anhydrous pyridine (295 μl, 4 eq.) was stirred for 15 min. A 2M phosgene solution in toluene (455 μl, 0.98 eq.) was added over 30 sec. followed by stirring for 2 h at 0° C. The reaction mixture was poured into dichloromethane washed with cold IN hydrochloric acid then ice water. Each aqueous layer was back extracted once with dichloromethane. The combined organic layer was washed once with brine, dried over anhydrous magnesium sulfate and concentrated. Distillation under vacuum afforded methyl (S)-2-isocyanato-3-phenylpropanoate (125 mg).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[CH:7]=1)CCC.[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([C:6]1[CH:7]=[C:8]([O:16][CH3:17])[C:9]([O:14][CH3:15])=[C:10]([O:12][CH3:13])[CH:11]=1)=[O:32]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(OC)c(OC)c(OC)c1
Reactant: O=C(Cl)CCCCBr
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)CCCCBr)cc(OC)c1OC

Procedure:
A solution of 8.5 g of the compound obtained in Step A, 3.2 ml of 5-bromopentanoyl chloride, 0.3 g of Pd2(dba)3 and 250 ml of toluene is refluxed for 6 hours, and then cooled and evaporated in vacuo. The residue is purified by chromatography over silica gel eluted with dichloromethane, enabling the expected product to be isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([OH:20])=O)[N:9]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH3:34][NH:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)(Cl)Cl>[CH3:34][N:35]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:18]([C:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:20]
Reactant: CNCc1ccccc1
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2Cl)n1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(Cc1ccccc1)C(=O)c1cc2ccccc2c(-c2ccccc2Cl)n1
Yield: 64.8 %

Procedure:
Operations are carried out as for Example 7, starting from 2.83 g of 1-(2-chloro phenyl) isoquinoline 3-carboxylic acid, 1.15 g of triethylamine, 1.24 g of ethyl chloroformate and 1.56 g of N-methyl benzylamine in 100 ml of chloroform. 2.5 g of N-methyl N-phenylmethyl 1-(2-chloro phenyl) isoquinoline 3-carboxamide, melting at 128° C., are obtained.