Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:12]=1.ClC1C=CC=CC=1C1N(C2CCCCO2)N=NN=1.[CH3:37][O:38][CH:39]([O:48][CH3:49])[C:40]1[CH:45]=[CH:44][C:43]([Mg]Br)=[CH:42][CH:41]=1.Cl.ClC1C=CC=CC=1C1NN=NN=1.N1C(C2C=CC=CC=2C2C=CC(C=O)=CC=2)=NN=N1.CO>O1CCCC1>[CH3:49][O:48][CH:39]([O:38][CH3:37])[C:40]1[CH:41]=[CH:42][C:43]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[N:9]=[N:10][N:11]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[N:12]=2)=[CH:44][CH:45]=1
Reactant: Clc1ccccc1-c1nnn(C2CCCCO2)n1
Reactant: COC(OC)c1ccc([Mg]Br)cc1
Agent: Cl
Agent: Clc1ccccc1-c1nnn[nH]1
Agent: Clc1ccccc1-c1nnnn1C1CCCCO1
Solvent: C1CCOC1
Solvent: CO
Product: COC(OC)c1ccc(-c2ccccc2-c2nnn(C3CCCCO3)n2)cc1
Temperature: 15 °C

Procedure:
A mixture of 5-(2-chlorophenyl)-2-(tetrahydropyran-2-yl)-2H-tetrazole and 5-(2-chlorophenyl) 1-(tetrahydropyran-2-yl)-1H-tetrazole (94% content; 4.22 g; 15.0 mmol; same batch as used in Example 7) is dissolved in anhydrous tetrahydrofuran (2.8 mL) under an inert atmosphere. The vigorously stirred resulting suspension is cooled to about 15° C. and a 0.96 M 4-(dimethoxymethyl)phenylmagnesium bromide solution (18 mL; 17.3 mmol; same batch as used in Example 7) is added over one hour while keeping the temperature below 25° C. by external cooling. The brown reaction mixture is agitated at room temperature for 22 hours. After that, HPLC analysis is done on a sample which is, as usual, hydrolyzed with dilute aqueous hydrochloric acid. The analysis shows mainly unconverted starting material (detected as 5-(2-chlorophenyl)-1H-tetrazole) and less than 0.25 area % of C—C-coupling product (detected as 2′-(1H-tetrazol-5-yl)biphenyl-4-carbaldehyde). Finally, when methanol (1.2 mL; 30 mmol) is added to the mixture, an unusually strong exotherm is observed which indicates that most of the 4-(dimethoxymethyl)phenylmagnesium bromide is still present after a total reaction time of 23 hours.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([OH:17])=[C:12]([Cl:18])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][C:27]=1[O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN(C)C=O>O>[C:1]([O:9][C:10]1[CH:11]=[C:12]([Cl:18])[C:13]([O:17][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([F:25])=[C:27]([O:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:28]=2)=[C:14]([Cl:16])[CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Reactant: O=C(Oc1cc(Cl)c(O)c(Cl)c1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Oc1cc(Cl)c(OCc2ccc(F)c(Oc3ccccc3)c2)c(Cl)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.2 %

Procedure:
A reaction vessel was charged with 1.54 g of 3,5-dichloro-4-hydroxyphenyl benzoate, 0.83 g of potassium carbonate, 1.53 g of 4-fluoro-3-phenoxybenzyl bromide, and 10 ml of N,N-dimethylformamide, followed by stirring at room temperature for 5 hours. The reaction mixture was poured into water, and extracted twice with 50 m of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 2.32 g of 3,5-dichloro-4-(4-fluoro-3-phenoxybenzyloxy)phenyl benzoate (88% yield).
Reaction SMILES: [Cl:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[Cl:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:21][CH:22]=2)=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(Cl)Cc1ccc(CCOc2ccc(O)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(Cl)Cc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1
Temperature: -20 °C
Yield: 95.4 %

Procedure:
Methyl 2-chloro-3-{4-[2-(4-hydroxyphenoxy)ethyl]phenyl}propanoate (334 mg, 1.0 mmol) and triethylamine (303 mg, 3.0 mmol) was dissolved in 20 ml dichlormethane and cooled to −20° C. under nitrogen atmosphere. Methanesulfonyl chloride (114 mg, 1.0 mmol) was added dropwise. The mixture was allowed to reach room temperature. After 2 hours dichlormethane was added, the mixture was washed (water, brine), dried (Na2SO4) and evaporated under reduced pressure to yield 394 mg pure product (yield 96%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.C[O:13][C:14](=[O:22])[CH:15]([CH3:21])[CH2:16][C:17]([O:19]C)=[O:18].[OH-].[Na+]>C1(C)C=CC=CC=1.CO>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:16]([CH:15]([CH3:21])[C:14]([OH:22])=[O:13])[C:17]([OH:19])=[O:18])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COC(=O)CC(C)C(=O)OC
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C(=O)O)C(=Cc1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.3 %

Procedure:
After careful addition of absolute methanol (0.1 mL) to a suspension of sodium hydride (60% in mineral oil, 16 g, 0.40 mol) in anhydrous toluene (200 mL), a solution of 4-chloro-benzaldehyde (28 g, 0.20 mol) and 2-methyl-succinic acid dimethyl ester (48 g, 0.30 mol) in anhydrous toluene (100 mL) was added dropwise at room temperature under a stream of nitrogen. After being stirred at room temperature for 2 hours, the resulting mixture was diluted by adding 2 N sodium hydroxide (200 mL) dropwise, then heated to 80° C., and stirred at the same temperature for 2 hours. After being cooled to room temperature naturally, the aqueous layer was separated, washed with ethyl acetate (100 mL×3), then acidified with 2 N hydrochloric acid to pH 2, and extracted with ethyl acetate (150 mL×3). The combined organic layers were dried over sodium sulfate, and concentrated in vacuo. The residue was precipitated from ethyl acetate/petroleum ether (10:1) to give 2-(4-chloro-benzylidene)-3-methyl-succinic acid (13.4 g, 26%) as a yellow solid.
Reaction SMILES: [CH:1]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1I)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27](=[O:42])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][C:37]#[C:38][CH2:39][CH2:40][OH:41])=[CH:30][CH:29]=1.[Li+].[Cl-]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[CH3:25][O:26][C:27](=[O:42])[C:28]1[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH2:36][C:37]2[C:16]3[C:15](=[CH:20][CH:19]=[C:18]([N+:21]([O-:23])=[O:22])[CH:17]=3)[N:14]([CH:1]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:38]=2[CH2:39][CH2:40][OH:41])=[CH:32][CH:33]=1
Reactant: O=[N+]([O-])c1ccc(NC(c2ccccc2)c2ccccc2)c(I)c1
Reactant: COC(=O)c1ccc(OCCC#CCCO)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCc2c(CCO)n(C(c3ccccc3)c3ccccc3)c3ccc([N+](=O)[O-])cc23)cc1
Temperature: 100 °C
Yield: 71 %

Procedure:
Benzhydryl-(4-nitro-2-iodo-phenyl)-amine (1 eq.), 4-(6-hydroxy-hex-3-ynyloxy)-benzoic acid methyl ester (1.5 eq.), LiCl (1 eq.) KOAc (5 eq.) and palladium (II) acetate (0.04 eq.) were added to a roundbottom containing 10 mL of DMF that had been degassed with argon. The reaction heated to 100° C. 7.5 hours. It was then cooled, diluted with ethyl acetate, washed with water and brine, dried over Na2SO4 and concentrated to give a brown solid. Purification by flash chromatography gave two products, 4-{2-[1-benzhydryl-5-nitro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester and the desired, 4-{2-[1-benzhydryl-5-nitro-3-(2-hydroxy-ethyl)-1H-indol-2-yl]-ethoxy}-benzoic acid methyl ester in an overall yield of 71%. The products were not seperable by flash chromatography and were both carried on to the next step. 1H NMR (400 MHz, CDCl3) □ ppm 1.66 (t, J=5.56 Hz, 1H), 1.80 (t, J=5.18 Hz, 1H), 3.14 (m, 4H), 3.35 (m, 4H), 3.81 (m, 2H), 3.87 (m, J=1.52 Hz, 6H), 3.97 (q, J=6.32 Hz, 2H), 4.10 (t, J=6.82 Hz, 2H), 4.31 (t, J=6.19 Hz, 2H), 6.58 (d, J=4.04 Hz, 1H), 6.60 (d, J=4.04 Hz, 1H), 6.67 (d, J=9.10 Hz, 2H), 6.89 (d, J=8.84 Hz, 2H), 7.10 (m, 9H), 7.20 (s, 1H), 7.32 (m, 12H), 7.75 (m, 2H), 7.90 (d, J=8.84 Hz, 2H), 7.95 (d, J=9.09 Hz, 2H), 8.52 (d, J=2.27 Hz, 1H), 8.59 (d, J=2.27 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.C(N=C=NCCCN(C)C)C.[CH3:25][S:26]([NH2:29])(=[O:28])=[O:27]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:29][S:26]([CH3:25])(=[O:28])=[O:27])=[O:8]
Reactant: O=C(O)c1cc(Cl)c(F)cc1F
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
5-chloro-2,4-difluorobenzoic acid (0.291 g, 1.511 mmol), N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.438 g, 2.285 mmol) and 4-dimethylaminopyridine (0.420 g, 3.438 mmol) were suspended in DCM (5 mL). Methanesulfonamide (0.222 g, 2.334 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with DCM (10 mL) and washed with aqueous HCl solution (2 M, 2×15 mL). The organic layer was dried with a phase separating cartridge and concentrated in vacuo to yield the title compound as a white solid (0.388 g):
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].ClC1C=CC(O[CH2:22][C:23]#[N:24])=CC=1.CC([O-])(C)C.[K+].Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([C:12]([F:13])([F:14])[F:15])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[C:7]([CH2:22][C:23]#[N:24])[CH:8]=1
Reactant: N#CCOc1ccc(Cl)cc1
Reactant: COc1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(CC#N)c([N+](=O)[O-])cc1C(F)(F)F
Temperature: -10 °C
Yield: 77.7 %

Procedure:
A mixture of 1-methoxy-4-nitro 2-trifluoromethylbenzene (D26) (93 g, 0.421 mol) and 4-chlorophenoxyacetonitrile (77.55 g, 0.463 mol) in dry DMF (500 ml) was added dropwise over 0.75 h to a stirred solution of KOtBu (103.85 g, 0.927 mol) in dry DMF (400 ml) at -10° C. After complete addition the resulting purple solution was maintained at -10° C. for 1 h then poured into a mixture of ice/water (1.5 1) and 5 M aqueous HCl (1.5 l). The resulting mixture was extracted with dichloromethane (3×1 l). The combined extracts were washed with water (3 l), dried (Na2SO4) and evaporated under reduced pressure. The residue was chromatographed on silica using 10-40% ethyl acetate/petroleum ether as eluant to give the crude product which was recrystallised from ethyl acetate/petroleum ether to afford the title compound (85.13 g, 78%) as a white solid. Mp 103-104° C.
Reaction SMILES: Cl.[NH:2]1[N:6]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH:5]2[CH2:4][CH2:3]1.[N:14]#[C:15][NH2:16]>CCCCCO>[N:2]1([C:15](=[NH:14])[NH2:16])[N:6]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH:5]2[CH2:4][CH2:3]1
Reactant: N#CN
Reactant: c1ccc2c(c1)CN1NCCC21
Agent: Cl
Solvent: CCCCCO
Product: N=C(N)N1CCC2c3ccccc3CN21
Reaction time: 2 h

Procedure:
3.92 g (0.02 mol) of 2,3,3a,8-tetrahydro-1H-pyrazolo[5,1-a]isoindole hydrochloride and 0.95 g of cyanamide in 20 ml of n-amyl alcohol are heated to boiling for 2 hours. After distilling out the solvent, the residue is taken up in boiling ethanol, active charcoal is added, and, after filtration, the filtrate is evaporated in vacuo. After recrystallisation from isopropanol/ethyl acetate, 2.4 g of the hydrochloride of 2,3,3a,8-tetrahydro-1H-pyrazolo[5,1-a]isoindole-1-carboximidamide are obtained. Melting point 233°-234° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:17]=[C:18]([C:22]3[CH:23]=[C:24]([CH:32]([CH3:34])[CH3:33])[CH:25]=[C:26]4[C:31]=3[N:30]=[CH:29][CH:28]=[CH:27]4)[CH:19]=[CH:20][CH:21]=2)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C1C=C(C([O-])=[O:42])C(C(O[O-])=O)=CC=1.[Mg+2]>C(Cl)Cl.CO.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[CH3:33][CH:32]([C:24]1[CH:25]=[C:26]2[CH:27]=[CH:28][CH:29]=[N:30][C:31]2=[C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:9][C:10]3[CH:11]=[CH:12][N+:13]([O-:42])=[CH:14][CH:15]=3)[CH:17]=2)[CH:23]=1)[CH3:34]
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: CC(C)c1cc(-c2cccc(C(Cc3ccncc3)c3ccc(Cl)cc3)c2)c2ncccc2c1
Agent: O=C([O-])O
Agent: [Mg+2]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)c1cc(-c2cccc(C(Cc3cc[n+]([O-])cc3)c3ccc(Cl)cc3)c2)c2ncccc2c1
Reaction time: 18 h

Procedure:
To a solution of Example 60 (100 mg, 0.22 mmol) in CH2Cl2/MeOH (1:1, 6 mL) was added MMPP (320 mg, 0.65 mmol). After 18 h, the resulting reaction mixture was diluted with a sodium bicarbonate solution and ethyl acetate. The organic extracts were washed (H2O, brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with ethanol/ethyl acetate, 10:90 to 25:75) provided the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][C:44]([OH:46])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:47][NH2:48]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][C:44](=[O:46])[NH:48][CH3:47])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCC(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: CN
Product: CNC(=O)CC[C@@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1C(=O)OCc1ccccc1

Procedure:
Similar to example 6a, 80.0 mg of (2R,4R,5R)-2-(2-carboxy-ethyl)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1 carboxylic acid benzyl ester are reacted with methylamine to afford the title compound as a yellow oil. Rf=0.35 (dichlormethane-methanol 9:1); Rt=4.69.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=1)[C:5]([OH:7])=O.[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1)([O-:26])=[O:25]>>[Br:23][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Br:1])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=1)[C:5]([C:31]1[CH:32]=[C:27]([N+:24]([O-:26])=[O:25])[CH:28]=[CH:29][C:30]=1[S:33]([NH2:36])(=[O:34])=[O:35])=[O:7]
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(Oc2c(Br)cc(C(=O)O)cc2Br)cc1C(C)C
Product: CC(C)c1cc(Oc2c(Br)cc(C(=O)c3cc([N+](=O)[O-])ccc3S(N)(=O)=O)cc2Br)ccc1O
Yield: 37.2 %

Procedure:
3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (, 0.035 mmol) was coupled with 4-nitrophenylsulfonamid (0.175 mmol) using the method described in Example 58. Purification on HPLC of the residue gave 8 mg (37%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[S:17][CH:16]=[N:15][C:14]=1[CH3:18])=[O:12].C(N(CC)CC)C.N1C=CC=NC1=O>ClCCl.CCO>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[S:17][CH:16]=[N:15][C:14]=2[CH3:18])=[O:12])[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: Cc1ncsc1C(=O)CBr
Agent: O=c1nccc[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ncsc1C(=O)Cn1cc(Cl)cnc1=O
Temperature: 25 °C

Procedure:
A suspension of 5-chloropyrimidin-2-one (392 mg) and 5-bromoacetyl-4-methylthiazole (660 mg) in dry dichloromethane was treated with triethylamine (0.42 ml) and the resulting pale yellow solution was stirred at room temperature. After 1.25 h a precipitate had formed and the mixture was cooled in an ice-bath. The solid was collected, washed with cold dichloromethane and dried (346 mg). A second crop was obtained by concentration of the mother liquors (255 mg). The combined solids were recrystallised from acetone and then dichloromethane to give white crystals, the title pyrimidinone (186 mg) m.p. 212°-215° C. λmax (EtOH) 250.5 nm (E1cm1% 403), 266.5 nm (E1cm1% 401), 334 nm (E1cm1% 65). High performance liquid chromatography (reverse phase column, acetonitrilewater, 1:3) showed only one major component. N.M.R. (DMSO d6): 0.68 (2'-H), 1.28, 1.54 (two doublets, J 4 Hz) (4,6-H), 4.69 (--CH2 --), 7.21 τ (4' -CH3).
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([OH:18])=[C:9](C=O)[C:8]1=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(Br)CCCCC.CC1C=CC=C2NC(=O)OC(=O)C=12>>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([OH:18])=[CH:9][C:8]1=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCn1c(=O)c(C=O)c(O)c2cc(C)ccc21
Agent: Cc1cccc2[nH]c(=O)oc(=O)c12
Solvent: CCCCCCBr
Product: CCCCCCn1c(=O)cc(O)c2cc(C)ccc21

Procedure:
The 1-hexyl-3-formyl-4-hydroxy-6-methyl-2(1H)-quinolinone was obtained by following Steps (2) to (4) of Preparation A wherein hexyl bromide was reacted with 6-methyl-isatoic anhydride to produce 1-hexyl-4-hydroxy-6-methyl-2(1H)-quinolinone. Then the 1-hexyl-4-hydroxy-6-methyl-2(1H)-quinolinone was converted to 1-hexyl-3-formyl-4-hydroxy-6-methyl-2(1H)-quinolinone following the procedure of Preparation B.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH2:18])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([NH2:18])=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2c(c1)CCNC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-Amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.345 g, 1.39 mmol) was treated with Trifluoroacetic Acid (0.418 mL, 5.42 mmol) in Methylene chloride (3.00 mL). Partial conversion after 3 h, added additional 1 ml TFA and allowed to stir at rt for 16 h. Complete conversion to more polar peak on LCMS. Reaction mixture was concentrated to an orange film which was used without purification in the next reaction.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:13][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
15.0 g (0.1 mol) 4-phenylbutanol and 39.8 g (0.12 mol) carbontetrabromide were dissolved in 500 ml dry dichloromethane and cooled to 0° C., 36.7 g (0.14 mol) triphenylphosphine was then added and the mixture stirred 1.5 hours under argon at 0° C. then evaporated in vacuo. The resulting mixture was stirred in ether-hexane (1:1) and filtered to remove insoluble material. The filtrate was then passed through a pad of silica gel and concentrated to give a pale yellow liquid 21.3 g.
Reaction SMILES: C(OC([N:8]1[C@@H:16]2[C@@H:11]([CH2:12][N:13]([CH2:17][C:18]3[S:26][C:25]4[C:24]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[N:23][C:22]([C:33]5[CH:41]=[C:40]([F:42])[CH:39]=[C:38]6[C:34]=5[CH:35]=[CH:36][NH:37]6)=[N:21][C:20]=4[CH:19]=3)[CH2:14][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:42][C:40]1[CH:39]=[C:38]2[C:34]([CH:35]=[CH:36][NH:37]2)=[C:33]([C:22]2[N:23]=[C:24]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[C:25]3[S:26][C:18]([CH2:17][N:13]4[CH2:14][CH2:15][C@@H:16]5[NH:8][CH2:9][CH2:10][C@@H:11]5[CH2:12]4)=[CH:19][C:20]=3[N:21]=2)[CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CN(Cc3cc4nc(-c5cc(F)cc6[nH]ccc56)nc(N5CCOCC5)c4s3)CC[C@@H]21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(-c2nc(N3CCOCC3)c3sc(CN4CC[C@@H]5NCC[C@@H]5C4)cc3n2)c2cc[nH]c2c1

Procedure:
Prepared by BOC-deprotection of (3aR,7aS)-5-[2-(6-fluoro-1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-octahydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester using TFA:DCM (1:6). The title compound was obtained as a beige solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:18]=[C:19](Br)[C:12]2=[N:11][C:10]=1[C:27]1[S:28][C:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[CH:30][N:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:40]([N:43]1[CH2:47][CH2:46][NH:45][C:44]1=[O:48])([CH3:42])[CH3:41].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+].N#N>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].O>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:18]=[C:19]([N:45]3[CH2:46][CH2:47][N:43]([CH:40]([CH3:42])[CH3:41])[C:44]3=[O:48])[C:12]2=[N:11][C:10]=1[C:27]1[S:28][C:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[CH:30][N:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(OCc2ccccc2)c(-c2ncc(Cc3ccc(F)cc3)s2)nc2c(Br)cc(N3CCOCC3)cn12
Reactant: CC(C)N1CCNC1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: N#N
Solvent: O
Solvent: C1COCCO1
Product: CC(C)N1CCN(c2cc(N3CCOCC3)cn3c(=O)c(OCc4ccccc4)c(-c4ncc(Cc5ccc(F)cc5)s4)nc23)C1=O
Yield: 80.6 %

Procedure:
3-Benzyloxy-9-bromo-2-[5-(4-fluoro-benzyl)-thiazol-2-yl]-7-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-one (product of example 218, 110 mg, 0.18 mmol), 1-isopropyl-imidazolidin-2-one (30 mg, 0.22 mmol), Pd2(dba)3 (15 mg, 0.02 mmol), Xantphos (15 mg, 0.2 mmol), Cs2CO3 (58.5 mg, 0.18 mmol) were mixed in anhydrous dioxane (5 ml). The mixture was heated at 90° C. under the atmosphere of N2 for 4 h, after which water was added and then extracted with ethyl acetate. The extracts were combined, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography to give the desired product (95 mg, yield 81%).