Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)=O)[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[NH2:31][CH:32]1[CH2:36][CH2:35][N:34]([CH3:37])[C:33]1=[O:38].C[O-].[Na+]>CC(N(C)C)=O.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:31][CH:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Reactant: CN1CCC(N)C1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)N(C)C
Product: CN1CCC(Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1=O
Temperature: 140 °C

Procedure:
A solution of 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 15a, (0.060 g, 0.129 mmol) in DMA (0.5 mL) was treated with 3-amino-1-methylpyrrolidin-2-one (0.030 g, 0.258 mmol) and the reaction was heated at 140° C. for 20 minutes. The reaction mixture was cooled to room temperature and then treated with 0.5 mL of 25% NaOMe in MeOH and heated at 50° C. for 15 min. The mixture was then partitioned between aqueous saturated Na2CO3 solution and EtOAc. The aqueous layer was extracted with EtOAc twice more and the combined organic phases were concentrated in vacuo. The crude material was purified by preparative HPLC. The isolated product was filtered through basic resin to remove residual TFA and provide the desired product.
Reaction SMILES: [Br-:1].[K+].N[CH:4]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:5]([OH:7])=[O:6]>Br>[CH2:16]([O:15][C:13]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][C@H:4]([Br:1])[C:5]([OH:7])=[O:6])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [Br-]
Reactant: NC(CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: Br
Agent: [K+]
Product: O=C(NCCCC[C@H](Br)C(=O)O)OCc1ccccc1
Temperature: 0 °C

Procedure:
(S-2-Amino-6-{[(benzyloxy)carbonyl]amino}hexanoic acid, 20.0 g (0.14 mole), and potassium bromide, 28.9 g (0.24 mole), were dissolved in 80 mL of ˜6N aqueous HBr, previously chilled to 0° C. A stream of nitrogen was bubbled through the solution and the mixture was chilled to −10° C. by means of a cold bath. Sodium nitrite, 5.9 g (0.86 mole) was added in portions over 30 min with stirring, while maintaining the temperature of the reaction from −13° C. to −10° C. After 6 hours stirring at −10° C., the mixture was extracted with ethyl ether, 4×50 mL and the resulting solution dried with magnesium sulfate. The mixture was filtered to remove the drying agent and evaporated to give an orange oil. The oil was purified by flash chromatography, chloroform-hexanes to give a clear and colorless oil. The yield was 20.0 g, i.e., 81%, based on starting 2-amino-6-{[(benzyl-oxy)carbonyl]-amino}hexanoic acid. NMR is consistent with structure. (Nicolaides et al.)
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])=[O:13].C(=O)([O-])O.[Na+].[Cl:26][CH2:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C(OCC)(=O)C>[Cl:26][CH2:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([N:18]2[CH2:19][CH2:20][N:15]([S:12]([C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:2]=3)(=[O:14])=[O:13])[CH2:16][CH2:17]2)=[O:33])=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: O=S(=O)(c1ccc2ccccc2c1)N1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(c1ccc(CCl)cc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To a mixture of 1-(2-naphthalenesulfonyl)piperazine hydrochloride (5.0 g) in ethyl acetate (60 ml) and an aqueous solution of 10% sodium hydrogen carbonate (40 ml) was added 4-chloromethylbenzoylchloride (3.02 g), and the solution was stirred at room temperature for 30 minutes. The organic layer was separated, washed with water and saturated sodium chloride, dried and concentrated. The residue was washed with diisopropylether and dried under reduced pressure to give the title compound (4.945 g, 78%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH2:9]Cl)[CH2:3][CH2:2]1.[C-:18]#[N:19].[Na+]>CN(C)C=O>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH2:9][C:18]#[N:19])[CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH2:3][CH2:2]1
Reactant: FC(F)Oc1ccc(CCl)cc1OCC1CC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
To 3-cyclopropylmethoxy-4-difluoromethoxybenzyl chloride (26 g) in dimethylformamide (150 mL) under an argon atmosphere was added sodium cyanide (9.7 g, 198 mmol). The resulting mixture was stirred at room temperature and heated gently for 2 h, then cooled and concentrated. The mixture was partitioned between basic brine and ether and extracted twice. The organic extract was washed with brine and was dried (sodium sulfate). The solvent was removed in vacuo to provide an orange-brown oil (24 g), which was used without purification.
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[C:5]([NH2:8])[C:4](Cl)=[N:3][CH:2]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>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>[NH2:8][C:5]1[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:3][CH:2]=[CH:1][C:6]=1[Cl:7]
Reactant: Nc1c(Cl)ccnc1Cl
Reactant: OB(O)c1ccccc1
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: [K+]
Product: Nc1c(Cl)ccnc1-c1ccccc1

Procedure:
3-Amino-2-4-dichloropyridine d (0.7047 g, 4.32 mmol), phenylboronic acid (0.5177 g, 4.24 mmol), K2CO3 (0.8023 g, 5.80 mmol), and Pd(PPh3)4 (0.0702 g, 0.0607 mmol) were combined. The sample was evacuated and purged with nitrogen three times. Dry DMF (2 mL) and deoxygenated H2O (0.4 mL) were added. The sample was microwaved at 130° C. for 40 minutes. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3×50 mL). The EtOAc extracts was dried over MgSO4 and filtered. The crude material was adsorbed onto silica gel and purified by flash chromatography (40 g SiO2, 0-30% EtOAc in hexanes) to give 3-amino-4-chloro-2-phenylpyridine e (0.435 g, 2.12 mmol, 49%).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][CH2:14][CH:13]([CH3:17])[CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:3]=1.C(N(CC)CC)C.[CH3:35][C:36]1([CH3:43])[C:40]([CH3:42])([CH3:41])[O:39][BH:38][O:37]1>O1CCOCC1.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]>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([S:18]([N:4]2[C:5]3[N:6]=[CH:7][N:8]=[C:9]([N:11]4[CH2:16][CH2:15][CH2:14][CH:13]([CH3:17])[CH2:12]4)[C:10]=3[C:2]([B:38]3[O:39][C:40]([CH3:42])([CH3:41])[C:36]([CH3:43])([CH3:35])[O:37]3)=[CH:3]2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: CC1(C)OBOC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(N4CCCC(C)C4)ncnc32)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3c(N4CCCC(C)C4)ncnc32)cc1
Temperature: 95 °C

Procedure:
5-Bromo-7-[(4-methylphenyl)sulfonyl]-4-(3-methylpiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (racemic version of C15, see Example 7) (1.44 g, 3.20 mmol) was added to a solution of triethylamine (1.3 g, 13 mmol) in 1,4-dioxane (15 mL). 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (1.64 g, 12.8 mmol) was then slowly added, and the mixture was degassed by bubbling nitrogen through it for 5 minutes. 2-Dicyclohexylphosphino-2′,6′-triisopropylbiphenyl (XPhos, 137 mg, 0.287 mmol) and tris(dibenzylideneacetone)dipalladium(0) (146 mg, 0.160 mmol) were then introduced, and the reaction mixture was heated at 95° C. for 18 hours. After cooling, the mixture was filtered through cotton and the filtrate was concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 75% ethyl acetate in heptane) afforded the product as a solid. Yield: 1.25 g, 2.52 mmol, 79%. 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 8.10 (br d, J=8.4 Hz, 2H), 7.95 (s, 1H), 7.30 (brd, J=8.6 Hz, 2H), 4.28 (brd, J=13 Hz, 1H), 4.18-4.24 (m, 1H), 2.99 (ddd, J=13, 11, 4 Hz, 1H), 2.70 (dd, J=12.9, 10.9 Hz, 1H), 2.40 (s, 3H), 1.77-1.85 (m, 1H), 1.56-1.70 (m, 4H), 1.35 (s, 12H), 0.88 (d, J=6.6 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N:18]([CH2:25][CH3:26])[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-])=O.[H][H]>C1C=CC=CC=1.C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N:18]([CH2:25][CH3:26])[CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: CCN(c1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-])C1CCCCC1
Reactant: [H][H]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCN(c1ccc(C(=O)c2ccccc2)cc1N)C1CCCCC1

Procedure:
7.1 g. of 3-nitro-4-(N-ethyl-N-cyclohexylamino)-benzophenone are dissolved in a 1:1 mixture of benzene and ethyl acetate, and 0.7 g. of palladiumized carbon are added to the mixture. The mixture is hydrogenated at room temperature and 3 atm. hydrogen pressure until the uptake of the calculated amount of hydrogen (this requires about one hour). Thereafter the catalyst is removed by filtration, and the filtrate is evaporated to dryness under reduced pressure. 6.35 g. of crude product are obtained. After recrystallization from isopropanol, 5.8 g. of pure 3-amino-4-(N-ethyl-N-cyclohexylamino)-benzophenone, melting at 106.5°-107.5° C are obtained.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]12[C:19]([CH3:21])([CH3:20])[CH:16]([CH2:17][CH2:18]1)[CH2:15][C:14](=[O:22])[O:13]2.O>C1(C)C=CC=CC=1>[CH3:11][C:12]12[C:19]([CH3:21])([CH3:20])[CH:16]([CH2:17][CH2:18]1)[CH2:15][CH:14]([OH:22])[O:13]2
Reactant: CC12CCC(CC(=O)O1)C2(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC12CCC(CC(O)O1)C2(C)C
Temperature: -60 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
25 ml of a solution of 1.1M of diisobutylaluminum hydride in toluene was added at -60° C. over 90 minutes to a solution of 5 g of 1,8,8-trimethyl-2-oxa-bicyclo [3,2,1] octane-3-one [process of Ronald et al, J.A.C.S., Vol. 81 (1959), p. 925] in 20 ml of toluene and the mixture was stirred for 2 hours at -60° C. Water was added dropwise while the temperature was allowed to rise to 20° C. and the mixture was then stirred at 20° C. for 2 hours. The mixture was filtered to remove lithium salts and the filter was washed with methylene chloride. The decanted aqueous phase of the filtrate was extracted with methylene chloride. The organic phase was dried and evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 1--1 benzene-ethyl acetate mixture yielded 3.5 g of 1,8,8-trimethyl-2-oxa-bicyclo [3,2,1] octan-3-ol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](I)[CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([NH:7][CH3:8])=[O:6])[CH:9]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1
Reactant: CNC(=O)c1cc(Br)cc(I)c1
Reactant: OB(O)c1ccccc1
Product: CNC(=O)c1cc(Br)cc(-c2ccccc2)c1

Procedure:
In a manner similar to that of Example 1(e), by reacting 4.9 g (14 mmol) of 3-bromo-5-iodo-N-methyl-benzamide and 1.93 g (15.8 mmol) of phenylboronic acid, and after purification by chromatography on a column of silica eluted with a heptane/ethyl acetate mixture(8/2), 2.1 g (50%) of the expected product are obtained in the form of a white solid with a melting point of 132° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:11][CH2:12]N(CC)CC.ClC(OCC)=O.CCO>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(Br)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-bromopicolinic acid from Step 1 (92 g, 0.455 mol) and Et3N (69 g, 0.68 mol) in THF (1.1 L) at 0° C. there was slowly added ethyl chloroformate (61.6 g, 0.57 mol). The resulting suspension was stirred at 0° C. for 15 min., EtOH (250 mL) was added, and the mixture was stirred at r.t. overnight. After filtration, the filtrate was evaporated down, the residue was taken up in ET2O (1 L) and filtered again. The filtrate on evaporation of the solvents afforded the title compound as an oil which was immediately used as such.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([F:19])[CH:18]=1)[N:15]=[CH:14][C:13]([C:20]([O:22]CC)=O)=[C:12]2[OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>C(Cl)(Cl)Cl.CO>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([F:19])[CH:18]=1)[N:15]=[CH:14][C:13]([C:20]([NH:32][CH2:31][C:30]1[CH:33]=[CH:34][C:27]([Cl:26])=[CH:28][CH:29]=1)=[O:22])=[C:12]2[OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(F)cc(SCc3ccccc3)cc2c1O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(SCc3ccccc3)cc2c1O
Yield: 95 %

Procedure:
A solution of 3.93 g of of ethyl 6-(benzylsulfanyl)-8-fluoro-4-hydroxy-3-quinolinecarboxylate in 8.8 g of 4-chlorobenzylamine is heated at 165° C. under argon for 16 h, then cooled and diluted with CHCl3 and MeOH. The solution is washed with dil. HCl, dried (Na2SO4), and concentrated under reduced pressure to a yellow solid. Flash chromatography on silica using 3-6% MeOH in CH2Cl2 affords 4.73 g (95%) of 6-(benzylsulfanyl)-N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-3-quinolinecarboxamide as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]([CH3:27])[C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>O1CCOCC1>[CH2:1]([N:8]([CH3:27])[C:9]1[C:14]2[N:15]=[C:16]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)c1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Reactant: C1CNCCN1
Solvent: C1COCCO1
Product: CN(Cc1ccccc1)c1ncnc2c(N3CCS(=O)CC3)nc(N3CCNCC3)nc12

Procedure:
8.1 gm (0.002 mol) of 8-(N-benzyl-methylamino)-2-chloro-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 158°-160° C.) were refluxed for 30 minutes with 6.9 gm (0.08 mol) of anhydrous piperazine in 150 ml of dioxane. The solvent was then distilled off, and the residue was taken up in about 600 ml of water. After standing for a short time, the reaction product was suction-filtered off, washed with water and dried at about 60° C.
Reaction SMILES: C(N[C:5]1[CH:6]=[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Br:17])=[CH:9][CH:10]=1)(=O)C.Br[C:24]1C=CC(C)=CC=1C(OCC)=O>>[Br:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6][C:5]([CH3:24])=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1cc(NC(C)=O)ccc1-c1ccccc1Br
Reactant: CCOC(=O)c1cc(C)ccc1Br
Product: CCOC(=O)c1cc(C)ccc1-c1ccccc1Br

Procedure:
Prepared in a similar way to ethyl 4-(acetylamino)-2′-bromo-2-biphenylcarboxylate but using ethyl 2-bromo-5-methylbenzoate instead of ethyl 5-(acetylamino)-2-bromobenzoate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:15][CH3:16])[C:9]=1[O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[O:6].C1COCC1.[C:22]1([Mg]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[OH:6])[CH:7]=[C:8]([O:15][CH3:16])[C:9]=1[O:10][CH2:11][CH2:12][O:13][CH3:14]
Reactant: Br[Mg]c1ccccc1
Reactant: COCCOc1c(Br)cc(C=O)cc1OC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCCOc1c(Br)cc(C(O)c2ccccc2)cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 1l round bottomed flask with a stirring bar and an argon inlet was added 3-bromo-4-(2-methoxyethoxy)-5-methoxybenzaldehyde (12.00 g, 41.50 mmol) and dry THF (150 mL). This solution was cooled in an ice bath and phenylmagnesiumbromide in diethyl ether (16.6 mL of a 3.0 M solution, 49.81 mmol) was added with a syringe. The resulting solution was stirred for 1 h at 0° C. The reaction was quenched with aqueous NH4Cl solution. The mixture was diluted with EtOAc and the layers were separated. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. This material was chromatographed on 400g of silica gel using 30/70 EtOAc-hexane as eluant. There was obtained 1-(3-bromo-4-(2-methoxyethoxy)-5-methoxyphenyl)-1-phenylmethanol as an oil. 1H NMR (CDCl3): δ2.29 (d, j=4Hz, 1H); 3.44 (s, 3H); 3.74 (t, j=4 Hz, 2H); 3.82 (s, 3H); 4.13 (t, j=4 Hz, 2H); 5.75 (d, j=4Hz, 1H); 6.88 (s, 1H); 7.12 (s, 1H); 7.35 (m, 5H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[CH:9]2)=[O:4].[F:15][C:16]1[CH:28]=[CH:27][C:19]([CH2:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1>C(OCC)C>[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][CH:21]2[CH2:22][CH2:23][N:24]([CH2:2][C:3]([NH:5][C:6]3[CH:7]=[C:8]4[C:12](=[CH:13][CH:14]=3)[NH:11][N:10]=[CH:9]4)=[O:4])[CH2:25][CH2:26]2)=[CH:27][CH:28]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: O=C(CCl)Nc1ccc2[nH]ncc2c1
Solvent: CCOCC
Product: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)Nc1ccc2[nH]ncc2c1

Procedure:
The title compound is prepared from 2-chloro-N-(1H-indazol-5-yl)-acetamide (Example 147a) and 4-(4-fluoro-benzyl)-piperidine according to the method described in Example 142b. Melting Point: 149-152° C. (diethylether)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:42]=[CH:41][CH:40]=[CH:39][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]2[O:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][CH2:34][C:35]([O:37]C)=[O:36])=[CH:13][CH:12]=1.Cl>O1CCOCC1.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:42]=[CH:41][CH:40]=[CH:39][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]2[O:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:15][CH:16]=1
Reactant: COC(=O)CCc1ccccc1OCCOC1CNCCC1c1ccc(OCCCOCc2ccccc2OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccccc1COCCCOc1ccc(C2CCNCC2OCCOc2ccccc2CCC(=O)O)cc1
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
A mixture of 0.057 g of methyl 3-{2-[2-(4-{4-[3-(2-Methoxybenzyloxy)propoxy]phenyl}piperidin-3-yloxy)ethoxy]phenyl}propionate (Example 52) in 1 ml of dioxane and 0.2 ml of 2N NaOH is stirred at 80° C. over 40 minutes. The reaction mixture is cooled to room temperature and made neutral with 0.5N HCl. The mixture is subsequently extracted with ethyl acetate (3×). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The crude title compound is obtained as a yellow solid from the residue. Rt=4.26.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.[CH:9]([O:11][CH2:12][CH3:13])=[CH2:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[CH2:9]([O:11][CH:12]([O:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)[CH3:13])[CH3:10]
Reactant: OCc1c[nH]cn1
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(C)OCc1c[nH]cn1
Reaction time: 2 h

Procedure:
To a flask containing 4 gms 4-hydroxymethyl imidazole hydrochloride in 30 ml dimethylformamide add 3.1 ml vinylethyl ether and 50 mg paratoluene sulfonic acid. Stir for 11/2 hours until the reaction is complete. Extract from saturated K2CO3 /NaCl with ethylacetate to obtain 1-ethoxy-1-(imidazol-4-yl)methoxy ethane.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[N:8][C:6]=2[N:7]=1.[NH:19]1[CH2:22][CH:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:19]3[CH2:22][CH:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH2:20]3)=[N:8][C:6]=2[N:7]=1
Reactant: O=Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: C1CN(C2CNC2)CCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Clc1nc(N2CCOCC2)c2sc(CN3CC(N4CCOCC4)C3)nc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.6 %

Procedure:
A mixture of 5-chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidine-2-carbaldehyde (250 mg, 0.88 mmol), 4-azetidin-3-yl-morpholine (150 mg, 1.05 mmol) and 4 Å molecular sieves (1.0 g) in 1,2-dichloroethane (15 mL) was stirred at RT under nitrogen atmosphere for 1.5 h. Sodium triacetoxyborohydride (280 mg, 1.32 mmol) was added and the resulting reaction mixture was stirred at RT for 16 h. The solvent was reduced in vacuo and the residue was loaded on an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with DCM/MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM. The resulting residue was further purified by column chromatography (Si—PCC, MeOH:DCM: 0:100 to 6:94 by volume). The solvents were reduced in vacuo to afford the title compound as a yellow solid (165 mg, 46%). LCMS (Method A): RT 2.31 min, [M+H]+ 411. 1H NMR (400 MHz, CDCl3): δ 4.11 (2 H, s), 3.95 (4 H, t, J=4.85 Hz), 3.83 (4 H, t, J=4.84 Hz), 3.74-3.67 (6 H, m), 3.22 (2 H, t, J=6.84 Hz), 3.12-3.11 (1 H, m), 2.34 (4 H, s)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[F:11][C:7]1[C:3]2[C:4](=[O:6])[O:5][C:13](=[O:15])[NH:1][C:2]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cccc(F)c1C(=O)O
Solvent: C1CCOC1
Product: O=c1[nH]c2cccc(F)c2c(=O)o1
Temperature: 50 °C
Reaction time: 12 h
Yield: 175.5 %

Procedure:
To a solution of 2-amino-6-fluorobenzoic acid (8.0 g, 51.6 mmol) in THF (110 mL) was added triphosgene (7.6 g, 25.8 mmol). The resulting suspension was stirred at 50° C. for 12 h. The reaction mixture was cooled to RT and filtered to give 8.2 g of the title compound as a pink solid (87%). 1H NMR (DMSO-d6, 500 MHz) δ=6.95 (d, J=8.5 Hz, 1H), 7.02-7.05 (m, 1H), 7.69-7.72 (m, 1H), 11.85 (brs, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([SH:8])=[CH:6][CH:7]=1.Cl.Cl[CH2:11][C:12]1[N:13]([CH2:17][CH2:18][CH3:19])[CH:14]=[N:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[N:3]=[N:4][C:5]([S:8][CH2:11][C:12]2[N:13]([CH2:17][CH2:18][CH3:19])[CH:14]=[N:15][CH:16]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(S)nn1
Reactant: CCCn1cncc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1cncc1CSc1ccc(N)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
3-amino-6-mercaptopyridazine (0.5 g), 4-chloromethyl-3-propylimidazole hydrochloride (0.62 g) and potassium carbonate (2.0 g) were added to N,N-dimethylformamide (10 ml), and the mixture was stirred overnight at room temperature. The solvent was distilled off, the residue was purified by basic silica gel column chromatography (elution solvent: methanol/ethyl acetate), to give 3-amino-6-[(3-propylimidazol-4-yl)methylthio]pyridazine (0.52 g) as yellow crystals.