Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: IC.[C:3]1([C@@:9]2([CH2:21][NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH2:11][C@H:10]2[CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:32](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:32][N:22]([CH2:21][C@:9]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:11][C@H:10]1[CH2:12][O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24]
Reactant: O=S(=O)(NC[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CN(C[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
Iodomethane (2.12 g, 14.9 mmol, 4 eq) was added portionwise to N-[((1R,2R)-1-phenyl-2-{[(phenylmethyl)oxy]methyl}cyclopropyl)methyl]benzenesulfonamide (1.71 g, 3.74 mmol, 1 eq), accessed via the method of preparation 5B, in 7 mL DMF with potassium carbonate (1.03 g, 7.48 mmol, 2 eq) over 6 h at 80° C. Following addition, the reaction mixture was stirred 16 h at 80° C. The reaction mixture was diluted with EtOAc, washed successively with saturated aqueous NaHCO3, water (4×) and brine, dried over MgSO4, filtered and concentrated to give a brown oil. The crude material was purified by flash chromatography (SiO2, eluted successively with hexanes and EtOAc/hexanes (1:4)) to give the title product (1.57 g, 100%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.58-7.21 (m, 15H), 4.26 (ABq, J=26.5, 11.7 Hz, 2H), 3.50 (d, J=14.0 Hz, 1H), 3.23-3.20 (m, 1H), 2.94-2.89 (m, 2H), 2.54 (s, 3H), 1.39 (m, 1H), 1.10 (m, 1H), 0.92 (m, 1H). ES-LCMS m/z 444.3 (M+Na).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)=O>COCCOC>[CH3:23][O:22][C:20]([C:19]1[CH:24]=[CH:25][C:16]([CH:14]=[CH:3][C:1]#[N:2])=[CH:17][CH:18]=1)=[O:21]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc(C=CC#N)cc1

Procedure:
To a stirred solution of diethyl cyanomethylphosphonate (96 ml) in 1,2-dimethoxyethane (375 ml) was added sodium hydride (60%: 22g) portionwise below 5° C. and the stirring was continued at 0° C. for half an hour and then at ambient temperature for half an hour. The reaction mixture was recooled to 0° C. and a solution of methyl p-formylbenzoate (75 g) in 1,2-dimethoxyethane (375 ml) was added to the reaction mixture below 6° C. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and diluted with ethyl acetate. The organic layer was washed with water and aqueous saturated sodium bicarbonate and dried over magnesium sulfate and filtered. The solvent was removed in vacuo and the solid product was recrystallized from ethanol to give 4-methoxycarbonylcinnamonitrile (52.12 g) as a white needle.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([CH:7]=1)[O:8][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Oc1cc(Br)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(Oc2cc(Br)ccc2Cl)nc1
Temperature: 110 °C
Yield: 102 %

Procedure:
To a solution of 5-bromo-2-chlorophenol (1.5 g, 7.23 mmol) in DMF (6 mL) was added potassium carbonate (2.5 g, 18.07 mmol) at RT followed by 2-chloro-5-(trifluoromethyl)pyridine (1.3 g, 7.23 mmol) and the mixture was refluxed at 110° C. for 12 h. The reaction mixture was quenched with water and extracted with ethyl acetate three times. The total organic extract was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (2.6 g, 100%). 1H NMR (500 MHz, CDCl3): δ 8.38 (s, 1H), 7.95 (d, J=6.5 Hz, 1H), 7.65 (s, 1H), 7.47 (d, J=2 Hz, 1H), 7.12 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][NH:6][C:7](=[O:20])[NH:8][C:9]1[S:10][C:11]([F:19])=[C:12]([CH2:14][N:15](OC)[CH3:16])[N:13]=1>C(O)(=O)C.O.[Zn]>[F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][NH:6][C:7](=[O:20])[NH:8][C:9]1[S:10][C:11]([F:19])=[C:12]([CH2:14][NH:15][CH3:16])[N:13]=1
Reactant: CON(C)Cc1nc(NC(=O)NCc2cccc(F)c2)sc1F
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CNCc1nc(NC(=O)NCc2cccc(F)c2)sc1F
Reaction time: 1.5 h
Yield: 66.7 %

Procedure:
A solution of 2-(3-(3-fluorobenzyl)ureido)-4-(N-methoxy-N-methyl-aminomethyl)-5-fluorothiazole (2.05 g, 6 mmol) in glacial acetic acid (30 mL) was treated with micronized zinc dust (12 g) and stirred at 60 C for 1-2 hours. The mixture was diluted with water (30 mL) and filtered on Celite. The filter cake was washed with 1:1 HOAc:water (3×20 mL) and the combined filtrate were brought to pH 10 with ammonium hydroxide (−82 mL). The resulting mixture was stirred in ice and the crude product was collected by filtration and washed with water (4 mL). The crude product was further purified by silica gel chromatography (5:94:1 MeOH:DCM:NH4OH) to afford Intermediate 40 as a white solid (1.25 g, 67% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][N:5]([S:27](=[O:37])(=[O:36])[NH:28]C(OC(C)(C)C)=O)[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:12][C:11](=[O:24])[C:10]([O:25][CH3:26])=[CH:9]2>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3](=[O:38])[CH2:4][N:5]([S:27](=[O:37])(=[O:36])[NH2:28])[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:12][C:11](=[O:24])[C:10]([O:25][CH3:26])=[CH:9]2
Reactant: COC(=O)CN(c1cc2cc(OC)c(=O)oc2cc1OCc1ccccc1)S(=O)(=O)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CN(c1cc2cc(OC)c(=O)oc2cc1OCc1ccccc1)S(N)(=O)=O

Procedure:
A solution of N-(t-butoxycarbonylsulfamoyl)-N-(7-benzyloxy-3-methoxy-2-oxo-2H-chromen-6-yl)glycine methyl ester (0.550 g, 1 mmol) in 40 mL of CH2Cl2/TFA (3:1) is stirred for 40 min at ambient temperature. The solvent is removed under reduced pressure. Methylene chloride is added to the residue and the solvent removed under reduced pressure (4×). The residue is purified by flash chromatography using CH2Cl2/EtOAc (4:1) to afford N-sulfamoyl-N-(7-benzyloxy-3-methoxy-2-oxo-2H-chromen-6-yl)glycine methyl ester as a white solid: mp=178-179° C.; 1H NMR (DMSO-d6) δ 7.74 (s, 1H), 7.52-7.32 (m, 5H), 7.29 (s, 1H), 7.13 (s, 1H), 5.22 (s, 2H), 4.30 (s, 2H), 3.80 (s, 3H), 3.58 (s, 3H); (M−H)−=447.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C@@H:11]2[O:16][CH2:15][C@@H:14]3[CH2:17][NH:18][CH2:19][CH2:20][N:13]3[CH2:12]2)=[CH:4][CH:3]=1.[NH2:21][C:22]1[N:27]=[CH:26][C:25]([C:28]([F:33])([F:32])[C:29](O)=[O:30])=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CO>[NH2:21][C:22]1[N:23]=[CH:24][C:25]([C:28]([F:33])([F:32])[C:29]([N:18]2[CH2:19][CH2:20][N:13]3[C@H:14]([CH2:15][O:16][C@@H:11]([C:5]4[C:6]([CH3:10])=[C:7]([C:2]([F:1])=[CH:3][CH:4]=4)[C:8]#[N:9])[CH2:12]3)[CH2:17]2)=[O:30])=[CH:26][N:27]=1
Reactant: Cc1c([C@H]2CN3CCNC[C@H]3CO2)ccc(F)c1C#N
Reactant: Nc1ncc(C(F)(F)C(=O)O)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1c([C@H]2CN3CCN(C(=O)C(F)(F)c4cnc(N)nc4)C[C@H]3CO2)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-fluoro-2-methyl-3-((3S,9aS)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl)benzonitrile (60 mg, 0.218 mmol) and 2-(2-aminopyrimidin-5-yl)-2,2-difluoroacetic acid (60.3 mg, 0.218 mmol) in anhydrous DMF (2724 μL) was added DIEA (133 μL, 0.763 mmol) followed by HATU (149 mg, 0.392 mmol). The mixture was stirred at RT overnight. The reaction mixture was diluted with methanol and purified on mass-directed preparative HPLC, Polar method (Column: Sunfire Prep C18, OBD 5 um, 30×100 mm). LC/MS: [(M+1)]+=447.08; 1H NMR (500 MHz, DMSO-d6) δ 8.36 (s, 2H), 8.11-8.17 (m, 1H), 7.30-7.39 (m, 3H), 4.83-4.92 (m, 1H), 4.07-4.27 (m, 1H), 3.43-3.76 (m, 2H), 3.00-3.37 (m, 4H), 2.72-2.96 (m, 2H), 2.58-2.68 (m, 1H), 2.16-2.55 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20]CC)=O)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:23][NH2:24].ClCCl.CO>O1CCCC1>[Br:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][CH2:17][C:18]([NH:24][CH3:23])=[O:20])=[O:15])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(Br)nc2)CC1
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)N1CCN(c2ccc(Br)nc2)CC1

Procedure:
The procedure described in Example 1 (step 1.4.) is used. Starting with 2.35 g (6.32 mmol) of 2-(ethyloxy)-2-oxoethyl 4-(6-bromo-3-pyridyl)-1-piperazinecarboxylate, obtained in step 7.4. of Example 7, and 15.80 ml (31.61 mmol) of a solution of methylamine (2M) in tetrahydrofuran, and after chromatography on silica gel, eluting with a 98/2 and then 97/3 mixture of dichloromethane and methanol, 1.779 g of product are obtained in the form of a white solid.
Reaction SMILES: CC1C2C(=CC=CC=2)C(N)=CC=1.[CH2:13]([C:15]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[C:21]2[C:16]=1[CH2:17][CH2:18][CH2:19][CH2:20]2)[CH3:14]>>[CH2:13]([C:15]1[C:16]2[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=2[C:22]([NH2:25])=[CH:23][CH:24]=1)[CH3:14]
Reactant: CCc1ccc([N+](=O)[O-])c2c1CCCC2
Agent: Cc1ccc(N)c2ccccc12
Product: CCc1ccc(N)c2c1CCCC2

Procedure:
The procedure was essentially identical to the route for 4-Methyl-naphthalen-1-ylamine as described above, however, started with a solution of 5-ethyl-8-nitro-1,2,3,4-tetrahydro-naphthalene (795 mg, 3.95 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Si:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22]O)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>O1CCCC1>[Si:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][O:10][C:3]1[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6])([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:12])[CH3:13]
Reactant: O=Cc1cccc(Cl)c1O
Reactant: CC(C)(C)[Si](C)(C)OCCCCO
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCOc1c(Cl)cccc1C=O
Reaction time: 0.33 h
Yield: 24.8 %

Procedure:
To 3-chloro-2-hydroxybenzaldehyde (313 mg, 2 mmol) in tetrahydrofuran (4 mL) was added 4-(tert-butyldimethylsilyloxy)butan-1-ol (409 mg, 2 mmol), triphenylphosphine (524 mg, 2 mmol), and (E)-di-tert-butyl diazene-1,2-dicarboxylate (460 mg, 2 mmol). The mixture was stirred for 20 minutes and was purified by silica gel column chromatography eluting with hexanes and ethyl acetate (4:1) to afford the titled compound (170 mg; 25%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][Si:7]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[C:2]=[O:3].[CH3:17][N:18]([CH3:23])[CH2:19][CH2:20][CH2:21][NH2:22]>>[CH3:17][N:18]([CH3:23])[CH2:19][CH2:20][CH2:21][NH:22][C:2]([NH:1][CH2:4][CH2:5][CH2:6][Si:7]([O:14][CH2:15][CH3:16])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])=[O:3]
Reactant: CN(C)CCCN
Reactant: CCO[Si](CCCN=C=O)(OCC)OCC
Product: CCO[Si](CCCNC(=O)NCCCN(C)C)(OCC)OCC

Procedure:
To a stirred solution of 3-isocyanatopropyltriethoxysilane (74 g; 0.31 mole) was slowly added 30 g (0.30 mole) of N,N-dimethyl-1,3-propanediamine. There was a significant exotherm. The product was purified by strip distillation at 205° C. (0.1 torr). NMR (CDCl3) 0.40-0.9 (m; 2H), 1.22 (t; 9H), 1.4-1.9 (m; 4H), 2.21 (s; 6H), 2.33 (t; 2H), 2.9-3.4 (m; 4H), 3.81 (q; 6H), 5.8 (b, 2H) ppm. IR (neat film) 3340, 2980, 2940, 1635, 1575, 1105, 1080, 960, 780 cm-1.
Reaction SMILES: [CH2:1]([Zn]CC)C.[Br:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[O:14][CH:15]=[CH2:16].ICI>ClC(Cl)C>[Br:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[O:14][CH:15]1[CH2:1][CH2:16]1
Reactant: C=COc1ccc(F)cc1Br
Reactant: CC[Zn]CC
Solvent: CC(Cl)Cl
Solvent: ICI
Product: Fc1ccc(OC2CC2)c(Br)c1
Reaction time: 72 h
Yield: 8.7 %

Procedure:
Diethyl zinc (1M in toluene, 23 ml, 23 mmol) was added under nitrogen with stirring to a solution of 2-bromo-4-fluoro-1-vinyloxy-benzene (Preparation 88, 1.0 g, 4.61 mmol) in dichloroethane (45 ml) at −10° C. (ice-salt-MeOH), taking care to maintain the temperature below 0° C. Diiodomethane (6.17 g, 23 mmol) in dichloroethane (10 ml) was then added via a syringe to the reaction mixture over 5 minutes ensuring that the reaction mixture remained at a temperature below +5° C. (internal temp). The reaction mixture was stirred at this temperature for twenty minutes and then allowed to attain room temperature and stirring was continued for 72 hours. The reaction was quenched with cold saturated ammonium chloride (aqueous solution) (5 ml) then the lower organic phase was removed, whilst the aqueous was extracted with a further dichloromethane (20 ml). The combined organic layers were dried over anhydrous Na2SO4 (s), filtered and evaporated in vacuo. Purification by column chromatography on silica gel eluting with tert-butyldimethyl ether:heptane 1:99 to 1:19 afforded almost pure title compound (93 mg, 9%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1.C(N(CC)CC)C.[Cl:26][CH2:27][C:28](Cl)=[O:29]>C1C=CC=CC=1>[F:18][C:2]([F:1])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:28](=[O:29])[CH2:27][Cl:26])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1
Reactant: O=C(Cl)CCl
Reactant: CN1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN1CCC(OC(=O)CCl)N(c2nnc(C(F)(F)F)s2)C1=O

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol- 2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Chloroacetyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-trifluoromethyl- 1,3,4-thiadiazol-2-yl)-3-methyl-6-chloroacetyloxy- 2(1H)-pyrimidinone as the residue.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>>[C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](=[O:10])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: Oc1ccccc1
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
In a 3-necked flask with thermometer and reflux condenser, a mixture of 9.4 g (0.10 mol) of phenol and 15.7 g (0.10 mol) of phenyl chloroformate was heated to 100° C. in the presence of 0.94 g (10 wt. % with reference to phenol) of a powdered aluminium oxide 507-C-I (neutral) from CAMAG. After 5 h reaction time, a phenol conversion of 38% to give diphenyl carbonate was found. Carbonate selectivity was >99%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[CH3:11][C:12]1[N:13]([C:27]2[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=2)[C:14]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1>CCOCC.C1COCC1.[Cl-].[Zn+2].[Cl-].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>[CH3:11][C:12]1[N:13]([C:27]2[CH:32]=[CH:31][C:30]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[CH:29][CH:28]=2)[C:14]([C:17]2[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[CH:15][CH:16]=1
Reactant: c1cscn1
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(-c2nccs2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 13.2 %

Procedure:
To a stirred solution of thiazole (0.072 g, 0.85 mmol) in anhydrous ether (2 mL) was added n-BuLi (0.58 mL, 1.61 M solution in hexane, 0.94 mmol) at −78° C. under nitrogen, the mixture was stirred for 30 minutes at −78° C., and then zinc chloride (2.55 mL, 1.0 M solution in ether, 2.55 mmol) was added at −78° C., the mixture was stirred for 30 minutes at −78° C. The reaction mixture was warmed to 0° C., and added the solution of 2-methyl 5-[4-(methylsulfonyl)phenyl]-1-(4-bromophenyl)-1H-pyrrole (0.3 g, 0.77 mmol) in THF (5 mL), tetrakis(triphenylphosphine)palladium (0) (0.088 g, 0.08 mmol). The reaction mixture was heated at reflux temperature for 19 hours, and cooled down to room temperature. The reaction mixture was filtered through celite, the filtrate was poured into water and the whole was extracted with ethyl acetate (20 mL×3). The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with hexane/ethyl acetate (2/1). The resulting solid was recrystallized from CH2Cl2/hexane to give the title compound (0.040 g, 13.2% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:12])[CH2:9][CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:9][CH2:10][O:11][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCN(C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.4 %

Procedure:
In THF (100 ml) was dissolved N-(tert-butoxycarbonyl)-2-(methylamino)ethanol (3.03 g, 17.3 mmol). To the resulting solution was added methyl 4-hydroxybenzoate (2.77 g, 18.2 mmol) and under stirring at 0° C. in a nitrogen gas stream, triphenylphosphine (6.35 g, 24.2 mmol) and DIAD (3.5 ml, 24.5 mmol) were added. The resulting mixture was stirred further at room temperature for 18 hours. From the reaction mixture, the solvent was distilled off under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane-ethyl acetate (4:1, v/v) eluate fractions, methyl 4-(2-(N-(tert-butoxycarbonyl)-N-methylamino)ethoxy)benzoate (4.09 g, 76%) was obtained as a yellow oil. The resulting compound (933 mg, 3.01 mmol) was dissolved in methylene chloride (3 ml). To the resulting solution was added trifluoroacetic acid (1 ml) under stirring at 0° C. The reaction mixture was stirred further at room temperature for 2 hours. From the reaction mixture, the solvent was distilled off under reduced pressure. The residue was neutralized with a saturated aqueous solution of sodium bicarbonate, followed by extraction with a chloroform-methanol mixture (5:1, v/v). The extract was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent, whereby methyl 4-(2-(N-methylamino)ethoxy)benzoate (618 mg, 98%) was obtained as a yellow oil.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C@@H:21]([O:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH3:22])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C@H:11]2[CH2:12][NH:8][CH2:9][C@@H:10]2[C@@H:21]([O:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH3:22])=[CH:14][C:15]=1[F:20]
Reactant: C[C@H](Oc1ccc(C#N)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(F)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Oc1ccc(C#N)cn1)[C@H]1CNC[C@@H]1c1ccc(Cl)c(F)c1
Temperature: 100 °C
Yield: 75.4 %

Procedure:
To a solution of 6-{(S)-1-[(3R,4S)-1-benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile—100 mg (0.23 mmol) dissolved in toluene (2 mL) were added 98 mg (0.69 mmol) of 1-chloroethyl chloroformate and 89 mg (0.69 mmol) of Hunig's base. The reaction mixture was heated at 100° C. for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (10 mL). The reaction mixture was heated at 85° C. for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 60 mg (76%) of the title compound as a light yellow oil. ES-MS m/e: 346.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1Br.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:9][C:5]1[CH:4]=[C:3]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:6]=1[CH3:8]
Reactant: Cc1cc(Br)c(Br)cc1C
Reactant: Nc1ccccc1
Product: Cc1cc(Nc2ccccc2)c(Nc2ccccc2)cc1C
Yield: 92.9 %

Procedure:
The synthesis is carried out in accordance with the general procedure in accordance with Example 2 from 63.3 g (240 mmol) of 1,2-dibromo-4,5-dimethylbenzene and 46 ml (505 mmol) of aniline. The precipitated solid is recrystallised from toluene/acetonitrile (5:1), and the residue is washed with MeOH, giving 65 g (223 mmol) of a crystalline solid. The overall yield is 93%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]=[C:4]([CH3:13])[C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.CN(C=O)C>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[CH3:12])[N:5]=[C:4]([CH3:13])[C:3]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1c(C)nc2cccc(C)c2c1Cl
Reactant: COc1ccc(CN)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc2cccc(C)c2c1NCc1ccc(OC)cc1
Yield: 78.8 %

Procedure:
A solution of ethyl 4-chloro-2,5-dimethylquinoline-3-carboxylate (Example 12b, 0.518 g, 1.96 mmol) and (4-methoxyphenyl)methanamine (1.15 mL, 8.86 mmol) in toluene (10 mL) and DMF (5 mL) were stirred at 115° C. under nitrogen for 12 hrs. The solvent was removed under vacuum, and the residue was purified by chromatography on silica gel (0% to 50% EtOAc in hexanes) to give the title compound as an oil (563 mg, 79%). 1H NMR (400 MHz, DMSO-d6) δ 1.24 (t, J=7.6 Hz, 3H), 2.45 (s, 3H), 2.78 (s, 3H), 3.73 (s, 3H), 4.2-4.3 (m, 4H), 6.27 (t, J=6.0 Hz, 1H), 6.88 (d, J=8.4 Hz, 2H), 7.19 (m, 3H), 7.48 (m, 1H), 7.58 (d, J=8.4 Hz, 1H). MS 365 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][S:23](=[O:26])[CH2:22][CH2:21]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[N:7]=1.[NH2:27][CH2:28][CH:29]([OH:31])[CH3:30]>>[OH:31][CH:29]([CH3:30])[CH2:28][NH:27][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][S:23](=[O:26])[CH2:22][CH2:21]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[N:7]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(NCc4cccnc4)ncnc23)CC1
Reactant: CC(O)CN
Product: CC(O)CNc1nc(N2CCS(=O)CC2)c2ncnc(NCc3cccnc3)c2n1

Procedure:
This compound was prepared analogous to Example 2 from 2-chloro-4-(1-oxido-thiomorpholino)-8-(3-picolyl-amino)pyrimido[5,4-d]pyrimidine (melting point: 227°-229° C.) and 1-amino-2-propanol.