Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[Si]([O:34][CH2:35][CH2:36][N:37]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[N:38]1)(C(C)(C)C)(C)C.C(=O)(O)[O-].[Na+].O1CCOCC1>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>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:40]4[CH:39]=[N:38][N:37]([CH2:36][CH2:35][OH:34])[CH:41]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: CC1(C)OB(c2cnn(CCO[Si](C)(C)C(C)(C)C)c2)OC1(C)C
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1Cc2ccc(-c3cnn(CCO)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10 mg, 0.029 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. After cooling it was concentrated. The residue was treated with methanol. The solid was filtered off. The filtrate was concentrated. The resulting residue was dissolved in 1.5 ml of 1% HCl ethanol solution, and stirred at r.t. overnight. Then it was purified with RP-HPLC (pH=10) to afford the desired product (4.6 mg). LCMS (M+H)+: m/z=449.3.
Reaction SMILES: [NH:1]([C:6]([O:8]C(C)(C)C)=O)[CH2:2][C:3]([OH:5])=[O:4].[NH:13]1[C:17](=[O:18])[CH2:16][CH2:15][C@H:14]1C(O)=O>>[NH:13]1[C:17](=[O:18])[CH2:16][CH2:15][C@H:14]1[C:6]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:8]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Product: O=C(O)CNC(=O)[C@@H]1CCC(=O)N1

Procedure:
2 mmoles of Boc-Gly-Rx were used as starting material, and 0.90 g of pGlu were added according to the usual principles for solid peptide synthesis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][C@@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C@@H:7]1[N:15](C)[C:16](OC(C)(C)C)=O.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][C@@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C@@H:7]1[NH:15][CH3:16]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1Cc2ccccc2[C@H]1Cc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H]1Cc2ccccc2[C@H]1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
To a solution of (±) cis-1-(3,4-dichlorobenzyl)-2-(N-methyl-N-tert-butoxycarbonyl-amino)indane (1.016 g, 2.5 mmol) in dichloromethane (20 ml) at 0° C. was added trifluoroacetic acid (4 ml) dropwise. The solution was then stirred at room temperature for 2 h, poured into saturated aqueous NaHCO3 (150 ml) and extracted with dichloromethane (3×30 ml). The combined organic phases were dried over sodium sulfate, and concentrated in vacuo. The residue was subjected to column chromatography on silica eluting with 5% ethanol in chloroform to afford the title compound as a colourless oil (585 mg) which was converted to the HCl salt and crystallised to afford a white solid. m.p.>245° C. dec. (from ethanol-diethyl ether).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)=[O:12])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:21].[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(O)(=O)C>[CH3:1][C:2]1([CH3:22])[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:23]([CH3:24])=[O:25])=[CH:18][CH:19]=3)=[O:12])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:21]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)C(=O)Nc2cc(C(=O)Nc3ccc(N)cc3)ccc21
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(NC(=O)c2ccc3c(c2)NC(=O)C3(C)C)cc1

Procedure:
0.83 g. (2.4 mmol) 2,3-Dihydro-3,3-dimethyl-N-(4-aminophenyl)-2-oxo-(1H)-indole-6- carboxamide (from Example 29) was stirred in 5 ml. 2N acetic acid and ml. (53.4 mmol) acetic anhydride for 3 hours at 40° C. The solvent was removed under vacuum and the residue purified by column chromatography (silica gel; isohexane:ethyl acetate:methanol 5:4:0.5 v/v/v) to give 0.6 g. (63% of theory) of the title compound; m.p. 294-295° C.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9]1>O>[Cl:3][CH2:6][CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9]1
Reactant: O=c1c2ccccc2ncn1CCO
Reactant: O=S(Cl)Cl
Solvent: O
Product: O=c1c2ccccc2ncn1CCCl
Temperature: 85 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
This thionyl chloride (1,095 mL, 15 mmol) was added to 3-(2-hydroxyethyl)quinazoline-4(3H)-one (2.0 g, 10.52 mmol) in a reactor, forming a white suspension that heated spontaneously to 85° C. The reaction medium was kept at this temperature under agitation for thirty minutes, after which it was left to cool to about 40° C. Next, 50 mL of water was added, forming a pinkish suspension, which was kept under agitation for two hours. The product was then vacuum filtered and washed with three portions of 10 mL of an ethanol/water mixture (50% v/v), yielding 3-(2-chloroethyl)quinazoline-4(3H)-one as a pale white solid (1.8 g, 8.63 mmol, yield=82%).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([C@H:15]3[C@@H:19]([CH2:20]O)[O:18][C:17]([CH3:23])([CH3:22])[O:16]3)=[O:14])[CH:10]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[NH:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:54]>C(Cl)Cl>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([C@H:15]3[C@@H:19]([CH2:20][Br:54])[O:18][C:17]([CH3:23])([CH3:22])[O:16]3)=[O:14])[CH:10]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[NH:3]1
Reactant: BrC(Br)(Br)Br
Reactant: CC1(C)O[C@H](CO)[C@H](C(=O)Nc2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(C)O[C@H](CBr)[C@H](C(=O)Nc2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 176.3 %

Procedure:
The (4R,5R)-5-hydroxymethyl-2,2-dimethyl-[1,3]dioxolan-4-carboxylic acid [1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]amide (1.5 g, 3.24 mmol) obtained in step A was dissolved in an anhydrous methylene chloride solution (30 ml). Thereafter, triphenylphosphine (2.21 g, 8.43 mmol) and carbon tetrabromide (2.80 g, 8.43 mmol) were added to the solution, and the obtained mixture was stirred at a room temperature for 3 hours. Thereafter, the solvent was distilled away. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=50:1), so as to obtain (4R,5S)-5-bromomethyl-2,2-dimethyl-[1,3]dioxolan-4-carboxylic acid [1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]amide (3.0 g).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][NH:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:26][CH:25]=5)[S:23][C:16]=34)=[C:10]([F:36])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:37][O:38][CH2:39][CH2:40][O:41][CH2:42][C:43](Cl)=[O:44]>C1COCC1.CCOC(C)=O>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH2:32][CH2:33][O:34][CH3:35])[C:43](=[O:44])[CH2:42][O:41][CH2:40][CH2:39][O:38][CH3:37])=[CH:26][CH:25]=5)[S:23][C:16]=34)=[C:10]([F:36])[CH:9]=2)[CH2:2][CH2:3]1
Reactant: COCCOCC(=O)Cl
Reactant: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCOCC(=O)N(CCOC)Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a suspension of 113 (120 mg, 0.237 mmol) in THF (3 mL) was added 2-(2-methoxyethoxy)acetyl chloride (54.2 mg, 0.355 mmol) and TEA (71.9 mg, 0.711 mmol) and the reaction mixture was stirred overnight at RT. The reaction mixture was diluted with EtOAc then washed with saturated ammonium chloride solution. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated. The resultant solid was triturated with Et2O to give title compound 115 (113 mg, 77% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.72 (s, 1H), 8.50 (d, J=5.48, 1H), 8.05 (s, 1H, rotamer), 7.90 (m, 2H, rotamer), 7.75 (m, 1H), 7.20 (m, 3H), 7.19 (m, 1H), 6.59 (m, 2H), 4.61 (s, 1H, rotamer), 4.31 (s, 2H, rotamer), 3.61 (m, 2H), 3.49 (m, 6H), 3.23 (m, 7H), 2.55 (m, 1H), 0.64 (m, 2H), 0.43 (m, 2H). MS (m/z)=623.66 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[C:9]([CH3:19])=[C:10]([CH2:14][CH2:15][CH2:16][CH:17]=O)[CH:11]=[CH:12][CH:13]=2)=O)=[CH:4][CH:3]=1.[C:22]([CH:27]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:24]CC)=[O:23]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:8]2[C:9]([CH3:19])=[C:10]([CH2:14][CH2:15][CH2:16][CH:17]=[CH:27][C:22]([OH:24])=[O:23])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1c(CCCC=O)cccc1C(=O)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: Cc1c(CCCC=CC(=O)O)cccc1Cc1ccc(Cl)cc1
Reaction time: 17 h
Yield: 41 %

Procedure:
A mixture of 4.5 g of the said butyraldehyde and 5.48 g of carbethoxy methylene triphenyl phosphorane in 100 ml of toluene was refluxed under an inert atmosphere with stirring for 17 hours and the toluene was then evaporated. The residue was saponified with 30 ml of 2 N sodium hydroxide and 50 ml of methanol at 75°-80° C. and the methanol was then removed. Water was added to the mixture which was then washed with ether containing 20% of methylene chloride, was treated with activated carbon and filtered. The filtrate was acidified with concentrated hydrochloric acid and was extracted with ether. The ether extracts were treated with activated carbon, filtered and evaporated to dryness. The residue was chromatographed over silica and eluted with a 95:5 methylene chloride-methanol mixture. The product was crystallized from isopropyl ether to obtain 2.015 g of 6-[3'-(4-chlorobenzyl)-2'-methylphenyl]-hex-2-enoic acid melting at 115° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH:20]1[CH2:23][N:22]([C:24]([N:26]2[CH2:32][CH2:31][CH2:30][N:29]([CH:33]3[CH2:36][CH2:35][CH2:34]3)[CH2:28][CH2:27]2)=[O:25])[CH2:21]1)(=O)=O>CN(C=O)C.ClCCl>[CH:33]1([N:29]2[CH2:30][CH2:31][CH2:32][N:26]([C:24]([N:22]3[CH2:23][CH:20]([O:1][C:2]4[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=4)[CH2:21]3)=[O:25])[CH2:27][CH2:28]2)[CH2:34][CH2:35][CH2:36]1
Reactant: CS(=O)(=O)OC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Reactant: Cc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(OC2CN(C(=O)N3CCCN(C4CCC4)CC3)C2)cn1
Temperature: 90 °C
Reaction time: 72 h
Yield: 35 %

Procedure:
3-Hydroxy-6-methylpyridine (24 mg, 0.22 mmol) and K2CO3 (33 mg, 0.24 mmol) were stirred in DMF (1 ml) for 30 minutes and 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-yl methanesulfonate (66 mg, 0.20) was added. The reaction was stirred at 90° C. for 3 days and then diluted with dichloromethane (30 ml) and washed with saturated NaHCO3 (3×15 ml), dried (MgSO4), filtered and concentrated at reduced pressure. The residue was purified by FCC (DCM/MeOH/NH3 with gradient, 98:2:1 to 90:10:1) to give the title product as off-white solid (24 mg, 35%).
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]#[N:29])=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[C:13](=[O:30])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:31])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:36]=[N+:37]=[N-:38])(C)C>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]4[NH:38][N:37]=[N:36][N:29]=4)=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[C:13](=[O:30])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:31])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C)cc2c(=O)n1Cc1ccc(-c2cccnc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCCCc1nc2ccc(C)cc2c(=O)n1Cc1ccc(-c2cccnc2-c2nnn[nH]2)cc1
Temperature: 25 °C

Procedure:
A solution of the product of step C (1.0 eq.) is added trimethylstannylazide (3 eq.) in toluene (3 mL) and heated to reflux for 36 h. The mixture is cooled to rt, concentrated and then can be purified by flash chromatography on SiO2 to give the titled compound.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:7]=[N:6]1)[CH2:2][C:3]#[CH:4].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[CH:7]=[N:6][N:5]([CH2:1][CH2:2][C:3]#[C:4][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=3)[CH:9]=2)=[CH:15][CH:14]=1
Reactant: c1ccncc1
Reactant: C#CCCn1cc(-c2ccc(F)cc2)cn1
Product: Fc1ccc(-c2cnn(CCC#Cc3ccccn3)c2)cc1

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 50 mg (0.23 mmol) of 1-but-3-ynyl-4-(4-fluoro-phenyl)-1H-pyrazole. Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) and SCX column (DCM, DCM/MeOH 95:5, DCM/MeOH/NH4OH 94:5:1) to yield 2 mg (7 mmol, 3%) of 244-(4-(4-fluorophenyl)-1H-pyrazol-1-yl)but-1-ynyl)pyridine as a yellow solid.
Reaction SMILES: [Br-].[CH:2]1([C:8]2([CH2:13][CH2:14][P+:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:34]1(C2(CC[Br:47])OCCO2)CCCCC1>>[Br-:47].[C:7]1([CH2:2][C:8]2([CH2:13][CH2:14][P+:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[O:9][CH2:10][CH2:11][O:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:34]=1
Reactant: BrCCC1(C2CCCCC2)OCCO1
Reactant: c1ccc([P+](CCC2(C3CCCCC3)OCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: c1ccc(CC2(CC[P+](c3ccccc3)(c3ccccc3)c3ccccc3)OCCO2)cc1

Procedure:
[2-(2-cyclohexyl-1,3-dioxolane-2-yl)ethyl]triphenylphosphonium bromide from 2-cyclohexyl-2-(2-bromoethyl)-1,3-dioxolane (ex. 27): Liq., IR (microcell) ν cm-1 : 2920-2850, 1440-1110;
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Br:13]Br.ClCCl>C(Cl)(Cl)Cl>[Br:13][C:6]1[CH:5]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: BrBr
Reactant: Oc1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Oc1ccc(OC(F)(F)F)cc1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (0° ) solution of 4-trifluoromethoxyphenol (35.6 g, 0.2 mol) in chloroform (280 ml) was added dropwise a solution of bromine (32 g, 0.2 mol) in chloroform (50 ml). The solution was stirred at 0° C. for 1 h. and at room temperature for 2 h. Dichloromethane (200 ml) and waster (400 ml) ware added and the organic phase was washed further with water (400 ml), brine (200 ml) and dried (MgSO4). The solvent was removed and the residue was purified by distillation at reduced pressure to give the title compound. 1H NMR (250 MHz, CDCl3) δ7.38 (1H, d, J 2.1 Hz), 7.13 (1H, dd, J 9.1, 2.1 Hz), 7.03 (1H, d, J 9.1 Hz), and 5.53 (1H, s).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][Cl:15])=[CH:7][N:6]=1)=[O:4].Cl>>[Cl:15][CH2:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCCCCl)cn1
Agent: Cl
Product: O=C(O)c1ccc(OCCCCl)cn1

Procedure:
A mixture of 9.0 g of 5-(3-chloropropoxy)-2-pyridinecarboxylic acid methyl ester and 100 ml of 6 N-hydrochloric acid is heated on a steam bath for 30 minutes. After that, the solution is cooled and evaporated to a residue. To the residue is added water and the resulting suspension is adjusted to pH 5 with saturated aqueous solution of sodium bicarbonate. The precipitated product is collected, dissolved in ethyl acetate and filtered. The filtrate is evaporated to a small volume. To the concentrate is added hexane to yield 5-(3-chloropropoxy)-2-pyridinecarboxylic acid melting at 120°-121°.
Reaction SMILES: [Cl:1][C:2]1[N:3]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([F:12])[C:6]=1[C:7](OCC)=[O:8].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:4]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:5]([F:12])[C:6]=1[CH2:7][OH:8]
Reactant: CCOC(=O)c1c(F)c(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1c(Cl)c(CO)c(F)c1-c1ccccc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
A solution (20 mL) of ethyl 2-chloro-4-fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (250 mg) in tetrahydrofuran was cooled to −70° C., and a 1.5 mol/L solution (6 mL) of diisobutylaluminum hydride in toluene was added dropwise by small portions. The mixture was further stirred at −70° C. for 1 hr, 1 mol/L hydrochloric acid (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3→1:1) to give the title compound as a colorless oil (yield 210 mg, 94%).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([C:26]5[CH2:31][CH2:30][N:29]([S:32]([CH2:35][CH2:36][N:37]6C(=O)C7C(=CC=CC=7)C6=O)(=[O:34])=[O:33])[CH2:28][CH:27]=5)[CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].NN>C(Cl)Cl.CO>[CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([C:26]5[CH2:31][CH2:30][N:29]([S:32]([CH2:35][CH2:36][NH2:37])(=[O:34])=[O:33])[CH2:28][CH:27]=5)[CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(S(=O)(=O)CCN6C(=O)c7ccccc7C6=O)CC5)cc4s3)CC2)nc1
Agent: NN
Solvent: CO
Solvent: ClCCl
Product: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(S(=O)(=O)CCN)CC5)cc4s3)CC2)nc1
Temperature: 40 °C
Yield: 76.7 %

Procedure:
To a suspension of 2-(2-(4-(2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)ethyl)isoindoline-1,3-dione (0.184 g, 0.274 mmol) in DCM (9.1 mL) and MeOH (9.1 mL) was added hydrazine (0.21 ml, 6.58 mmol). The mixture was heated in 40° C. oil bath overnight. The reaction became homogenous. The solvent was removed under reduced pressure. The residue was triturated in MeOH (6 mL) to afford desired product as a white solid (114 mg, 77% yield). 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 2H), 7.64 (dd, J=6.8, 5.2 Hz, 2H), 7.40 (dd, J=8.5, 1.8 Hz, 1H), 6.08 (s, 1H), 5.49-5.37 (m, 1H), 4.28-4.11 (m, 2H), 4.05 (d, J=2.8 Hz, 2H), 3.77-3.65 (m, 2H), 3.61 (t, J=5.7 Hz, 2H), 3.48-3.36 (m, 6H), 2.70 (s, 2H), 2.42 (t, J=7.5 Hz, 2H), 2.25-2.13 (m, 2H), 2.03-1.89 (m, 2H), 1.59 (dd, J=14.9, 7.4 Hz, 2H), 0.95 (t, J=7.4 Hz, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]3[CH2:24][C:23]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.CO>C1COCC1.[Pd]>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]3[CH2:24][C:23]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccncc2C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc(C2CCNCC2)cc1)N1Cc2ccncc2C1
Temperature: 25 °C
Reaction time: 38 h

Procedure:
N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide (2.0 g, 6.24 mmol) in 80 mL of 1:1 THF:methanol was added to 5% Pd on carbon (wet) (0.500 g) in a 250 mL SS pressure bottle and the mixture was stirred for 38 hours at 30 atm and 25° C. The mixture was filtered through a nylon membrane, concentrated and suspended in ether. Filtration with ether washes provided the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[S:9](=[O:12])(=[O:11])[N:8]=[CH:7][NH:6][C:5]=2[S:4][CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:13][N:6]1[C:5]2[S:4][CH:3]=[C:2]([CH3:1])[C:10]=2[S:9](=[O:12])(=[O:11])[N:8]=[CH:7]1
Reactant: O=C([O-])[O-]
Reactant: Cc1csc2c1S(=O)(=O)N=CN2
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: Cc1csc2c1S(=O)(=O)N=CN2C
Temperature: 65 °C

Procedure:
150 mg of the compound obtained in Step A above are suspended in 5 ml of acetonitrile. 300 mg of potassium carbonate and 0.15 ml of iodomethane are added thereto. The reaction mixture is heated at 65° C. for 30 minutes, with stirring. After evaporation of the solvents under reduced pressure, the residue is taken up in 5 ml of water and then collected by filtration, washed with water and dried.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: COCCCCCCCS(=O)(=O)c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCCCCCCS(=O)(=O)c1ccc(C(=O)O)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 98.3 %

Procedure:
A mixture of 7-methoxyheptyl-[4-(methoxycarbonyl)phenyl]sulfone (0.85 g) and 1N-aqueous sodium hydroxide (5 ml) in a mixture of ethanol (20 ml) and tetrahydrofuran (10 ml) was stirred at 80° C. for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The solution was adjusted to pH 1.0 using diluted hydrochloric acid. The precipitates were collected by filtration, washed with water and dried in vacuo to give 7-methoxyheptyl-(4-carboxyphenyl)sulfone (0.8 g) white solid.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.[C:25]1([NH:31]N)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([N:31]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: NNc1ccccc1
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Yield: 10 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-3) and phenylhydrazine according to the method described for Example 1 in 10% yield. MS: M=383.4 (M+H)+