Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:38])[C:13]3[CH:18]=[CH:17][C:16]([N:19]([CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])C(=O)C(F)(F)F)=[CH:15][C:14]=3[O:36][CH3:37])[CH2:10][CH2:9][CH2:8][CH:7]([CH2:39][C:40]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)=[O:41])[C:6]=2[CH:49]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:38])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])=[CH:15][C:14]=3[O:36][CH3:37])[CH2:10][CH2:9][CH2:8][CH:7]([CH2:39][C:40]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)=[O:41])[C:6]=2[CH:49]=1
Reactant: COc1cc(N(CCOc2ccccc2C)C(=O)C(F)(F)F)ccc1C(=O)N1CCCC(CC(=O)N2CCN(C)CC2)c2cc(Cl)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cc(NCCOc2ccccc2C)ccc1C(=O)N1CCCC(CC(=O)N2CCN(C)CC2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 30.9 %

Procedure:
To a solution of 7-chloro-5-[(4-methyl-1-piperazinyl)carbonylmethyl]-1-[2-methoxy-4-{N-[2-(2-methylphenoxy)ethyl]-N-trifluoroacetylamino}benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.45 g) in methanol (20 ml) is added a solution of potassium carbonate (0.11 g) in water (5 ml), and the mixture is stirred at room temperature for 12 hours. The mixture is evaporated to remove the solvent, and thereto is added water. The mixture is extracted with ethyl acetate, and the extract is dried, evaporated to remove the solvent. The resulting residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=80:1→50:1→30:1), and recrystallized from acetone/n-hexane to give 7-chloro-5-[(4-methyl-1-piperazinyl)carbonylmethyl]-1-{2-methoxy-4-[2-(2-methylphenoxy)ethylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.12 g) as white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[NH:8][C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[H-].[Na+].BrC[CH2:20][CH2:21][O:22][CH3:23]>CN(C=O)C>[CH3:23][O:22][CH2:21][CH2:20][N:8]1[C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:15]=[CH:14][C:7]1=2
Reactant: COCCCBr
Reactant: O=C1CCCc2cc([N+](=O)[O-])ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCN1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Reaction time: 0.25 h

Procedure:
To a solution of 7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one solid (566.6 mg, 2.75 mmol) in DMF (5 mL) was added NaH (200 mg, 60% dispersion in mineral oil, 5.0 mmol). After stirring for 15 min, 1-bromo-3-methoxy-propane (764 mg, 5.5 mmol) was added and the mixture stirred at room temperature for 1 hour prior to quenching with 10% aqueous NH4Cl solution. Solvent was removed by rotary evaporation and the residue extracted into EtOAc, washed with water (2×), brine and dried by passing through a plug of MgSO4. The resulting filtrate was evaporated onto Florisil and purified by chromatography (silica gel, DCM→15% EtOAc/DCM gradient). The appropriate fractions were combined and evaporated to afford 1-(2-methoxy-ethyl)-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as an oil that was carried onto the next step.
Reaction SMILES: [C:1]1([CH:7](O)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=[O:19].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:1]1([CH2:7][C:8](=[O:19])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)=O
Reactant: OC(CCc1ccccc1)c1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A solution of racemic 1,3-diphenyl-1-propanol (1.26 g; 5.94 mmol) was dissolved in 10 mL of acetone, and Jones reagent was added until persistence of the orange color. After stirring for 30 min, the reaction was quenched by adding 2 mL of 2-propanol. The solvent was decanted away from the precipitated solids, which were washed with ethyl acetate. The combined organic fractions were washed with 2×20 mL of water, dried and concentrated. The crude product was filtered through a plug of silica gel, eluting with 25% ethyl acetate/hexane, to obtain 1.07 g (86%) of 1,3-diphenylpropanone as a white crystalline solid, 1H NMR (360 Mhz; CDCl3): d 3.09 (t, 2H, J=8.1); 3.33 (t, 2H, J8.1); 7.29 (m, 5H); 7.49 (m, 3H); 7.98 (m, 2H).
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.CN(C)CCN(C)CCN(C)C.CN(C)[CH:37]=[O:38]>C1COCC1>[Si:5]([O:8][CH2:9][CH2:10][C:11]1[C:12]([F:17])=[C:13]([CH:14]=[CH:15][CH:16]=1)[CH:37]=[O:38])([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:6])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccccc1F
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1cccc(C=O)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
tert-Butyl(2-fluorophenethoxy)dimethylsilane (example 78, step a) (5.00 g) was added over 5 minutes to a stirred solution of sec-butyllithium (1.4 molar solution in cyclohexane, 14.0 mL) and N1-(2-(dimethylamino)ethyl)-N1,N2,N2-trimethylethane-1,2-diamine (4.10 mL) in THF (25 mL) cooled to −78° C. After 2 h, N,N-dimethylformamide (10.06 g) was added, the reaction mixture was stirred at −78° C. for 1 h, and then the cooling bath was removed. After a further 0.5 h, the reaction was quenched with water. Ethyl acetate (300 mL) was added and the reaction mixture washed with water (3×150 mL), 2M HCl (2×50 mL), water (2×50 mL), brine then dried over sodium sulphate, filtered and evaporated in vacuo to give the subtitled compound as an oil. Yield 5.3 g.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:7][CH2:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2)=[O:6].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:31][CH2:32][N:33]([CH3:35])[CH3:34].Cl>O>[Cl:22][C:3]1[C:2]([NH:1][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])=[CH:21][CH:20]=[CH:19][C:4]=1[C:5]([NH:7][CH2:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2)=[O:6]
Reactant: CN(C)CCCl
Reactant: Nc1cccc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN(C)CCNc1cccc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1Cl
Temperature: 138 °C

Procedure:
A mixture of the amino compound from Example 54 (0.10 g), potassium carbonate (0.087 g) and N-(2-chloroethyldimethylamine hydrochloride was stirred and heated at 138° C. for 72 hr. The residue was dissolved in water and the product extracted into ethyl acetate. The organic extract was washed with brine, dried over sodium sulphate (Na2SO4) and concentrated to give an oil which was purified by Supercritical Fluid Chromatography eluting with CO2/methanol/0.1% diethylamine to give an oil. Addition of excess ethereal hydrogen chloride solution gave a solid which was triturated under an ether/ethanol/dichloromethane mixture to give a colourless powder (0.04 g).
Reaction SMILES: [C:1](=[O:18])(ON1C(=O)CCC1=O)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:19][N:20]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=1)[C:1](=[O:18])[O:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CNCc1cccc([N+](=O)[O-])c1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(Cc1cccc([N+](=O)[O-])c1)C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 97.1 %

Procedure:
Benzyl 2,5-dioxopyrrolidin-1-yl carbonate (1.65 g, 6.6 mmol) was added to a solution of N-methyl-1-(3-nitrophenyl)methanamine (1 g, 6 mmol) in CH2Cl2 (24 mL) and DIEA (2.7 mL, 15 mmol) and the reaction mixture was stirred for 1 h. The mixture was diluted with CH2Cl2 (100 mL), washed with NH4Cl, NaHCO3, brine, dried over Na2SO4 and concentrated in vacuo to yield 60A (1.75 g, 99%) as a white solid. MS (ESI) m/z 301.03 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH3:9][C@@H:10]1[N:15]([CH3:16])[CH2:14][CH2:13][N:12]([CH2:17][CH2:18][OH:19])[CH2:11]1.[OH-].[K+]>CS(C)=O.O>[CH3:9][C@@H:10]1[N:15]([CH3:16])[CH2:14][CH2:13][N:12]([CH2:17][CH2:18][O:19][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH2:11]1
Reactant: C[C@H]1CN(CCO)CCN1C
Reactant: Nc1cc(Cl)ccn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H]1CN(CCOc2ccnc(N)c2)CCN1C
Temperature: 95 °C
Yield: 49.7 %

Procedure:
4-Chloropyridin-2-amine (0.500 g, 3.89 mmol), (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol (1.23 g, 7.78 mmol), and crushed potassium hydroxide (0.546 g, 9.72 mmol) were combined in 8 mL of DMSO in a pressure tube and heated to 95° C. for 16 hours. The mixture was then diluted with water (100 mL), extracted 2 times with EtOAc, extracts washed with brine, dried and concentrated under reduced pressure. Column chromatography (5% MeOH/DCM) afforded 0.484 g (50%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1Br)[CH3:2].C([Li])CCC.CN(C)[CH:22]=[O:23].O>C(OCC)C>[CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:22]=[O:23])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(OCC)c1ccccc1Br
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CCOC(OCC)c1ccccc1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10.4 g of 2-bromobenzaldehyde diethyl acetal in 200 ml of dry diethyl ether at −65° C. was added 27.5 ml of a 1.6 M solution of butyllithium in hexanes. The solution was stirred at this temperature for 30 min. then slowly warmed to −40° C. when 3.4 ml of dimethylformamide was added dropwise. The reaction was warmed to room temperature then 100 ml of water was added and the organic layer was separated. The aqueous layer was extracted with two 100 ml portions of ether and the combined organic extracts were dried over sodium sulfate and evaporated to give 8.5 g of 2-formylbenzaldehyde diethylacetal as an oil; 1H-NMR (200 MHz, CDCl3) d 5.06 (CHOEt).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[F:18][CH:19]([F:36])[O:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>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>[F:18][CH:19]([F:36])[O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:3]=[N:4][C:5]([NH:8][C:9]3[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=3)=[N:6][CH:7]=2)=[CH:23][CH:22]=1
Reactant: O=C(O)c1ccc(Nc2ncc(Br)cn2)cc1
Reactant: CC1(C)OB(c2ccc(OC(F)F)cc2)OC1(C)C
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+]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1
Temperature: 90 °C

Procedure:
To 4-(5-bromopyrimidin-2-ylamino)benzoic acid 53 (0.25 mmol) in 1,4-dioxane (2.0 mL) is added 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7 (0.28 mmol), 1.8M K2CO3 (0.5 mmol) and Pd(PPh3)4 (0.017 mmol). The reaction is evacuated and backfilled with nitrogen twice then heated at 90° C. for 8 h. The reaction mixture is diluted with water (10 mL) neutralized with 2M HCl and extracted with DCM (3×20 mL). Purification by preparative HPLC (ACN gradient 20-70%) affords 4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)benzoic acid 54 as white solid. MS (m/z) (M+1)+: 358.2.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](Cl)=[O:6].[CH3:12][NH2:13].C1COCC1>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:13][CH3:12])=[O:6]
Reactant: Cc1ccc(C(=O)Cl)cc1I
Reactant: CN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)c1ccc(C)c(I)c1
Reaction time: 8 h
Yield: 95 %

Procedure:
To a cooled (0° C.) solution of 3-iodo-4-methylbenzoyl chloride (2.80 g; 10.0 mmol) in DCM (10 mL) was slowly added a 2 M solution of methylamine in THF (11 mL, 2.2 eq.). Upon completion of the addition, the ice bath was removed and the mixture was stirred overnight. All volatiles were removed in vacuo and the residue was treated with aq. NaHCO3 (25 mL) and subsequently extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over MgSO4 and evaporated. The target compound 3-iodo-N,4-dimethylbenzamide (2.62 g, 95% yield) was used without further purification.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][OH:9].Br[CH2:17][CH2:18][O:19]C1CCCCO1.[OH-].[K+].O>CS(C)=O>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][O:9][CH2:17][CH2:18][OH:19]
Reactant: BrCCOC1CCCCO1
Reactant: OCCc1ccccc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: OCCOCCc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of the alcohol prepared above (8.5 g, 43 mmol), 2-bromoethyltetrahydro-2-pyranylether (17.9 g, 86 mmol) and potassium hydroxide (9.6 g, 171 mmol) in dimethylsulfoxide (100 ml) was stirred at ambient temperature for 72 h. An extra batch of 2-bromoethyltetrahydro-2-pyranylether (3.6 g, 17 mmol) was added and the mixture stirred for 48 h at ambient temperature. Water (350 ml) was added and the mixture was extracted with diethylether (2×250 ml). The organic phases were combined, washed with water (100 ml), dried (MgSO4) and concentrated in vacuo. The residue was submitted to column chromatography on silica gel (400 ml) using heptane and ethyl acetate (3:2) as eluent to give 6.6 g of 2-(2-(biphenyl-2-yl)ethoxy)ethanol as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]2)=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[C:7]([CH3:13])[C:6]=2[CH:14]=1.Cl.[F:26][C:27]1([F:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[Cl:1][C:2]1[C:3]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]2)=[CH:4][C:5]2[O:9][C:8]([C:10]([N:30]3[CH2:31][CH2:32][C:27]([F:33])([F:26])[CH2:28][CH2:29]3)=[O:12])=[C:7]([CH3:13])[C:6]=2[CH:14]=1
Reactant: FC1(F)CCNCC1
Reactant: Cc1c(C(=O)O)oc2cc(OC3CCN(C(C)C)CC3)c(Cl)cc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)N2CCC(F)(F)CC2)oc2cc(OC3CCN(C(C)C)CC3)c(Cl)cc12
Yield: 99.1 %

Procedure:
In a flask were mixed together the above prepared 5-chloro-6-(1-isopropyl-piperidin-4-yloxy)-3-methyl-benzofuran-2-carboxylic acid (0.200 g, 0.406 mmol, corrected for purity), 4,4-difluoropiperidine hydrochloride (0.077 g, 1.2 eq.), (benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium hexafluorophosphate (0.216 g, 1.2 eq.) and 2.4 eq. of N-ethyldiisopropylamine (0.166 mL) in 4 mL of abs. THF and stirred over night at ambient temperature. Pouring onto crashed ice/AcOEt/NH4Cl-solution, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, NEt3/AcOEt=2/98) yielded 0.183 g of the title compound as white solid.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].C(N(CC)CC)C.[Mg+2].[Cl-].[Cl-].[CH3:21][C:22]1[CH:30]=[CH:29][C:25](C(Cl)=O)=[CH:24][CH:23]=1>C(#N)C>[CH3:21][C:22]1[CH:30]=[CH:29][C:25]([C:3]([CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[O:5])=[CH:24][CH:23]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred suspension of potassium ethyl malonate (1.62 g, 9.51 mmol, 2.1 eq) in acetonitrile (14 mL) at 10° C. under nitrogen was added triethylamine (1.8 mL) followed by MgCl2 (1.1 g, 11.3 mmol, 2.5 eq). The mixture was allowed to stir at room temperature for 2.5 hours. The mixture was cooled to 0° C. and 4-methylbenzoyl chloride (700 mg, 4.53 mmol, 1 eq) was added dropwise over 15 minutes followed by addition of triethylamine (0.3 mL). The mixture was allowed to warm to room temperature and was stirred overnight. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and cooled to 10° C. The solution was washed (cautiously) with 4N aqueous HCl. The aqueous layer was back extracted with ethyl acetate. The organic extracts were combined, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was dissolved in aqueous 2N NaOH and extracted 3× with diethyl ether. The ether extracts were combined, washed with water, then brine, dried over anhydrous Na2SO4, filtered and concentrated. The title compound was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1([F:20])[O:19][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][NH:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]#[C:30][CH3:31]>CN(C)C=O.C(OCC)(=O)C>[CH2:28]([N:4]1[CH2:3][C:2]([F:1])([F:20])[O:19][C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]2)[CH2:5]1)[C:29]#[C:30][CH3:31]
Reactant: CC#CCBr
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(F)(F)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCN1CC(F)(F)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 45 °C
Yield: 65.4 %

Procedure:
To a mixture of crude tert-butyl 10,10-difluoro-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (65.0 mg, 0.222 mmol) and K2CO3 (61.5 mg, 0.445 mmol) in N,N-dimethylformamide (1.0 mL) was added 1-bromobut-2-yne (29.2 μL, 0.334 mmol) and the reaction heated at 45° C. for 48 h. The reaction was diluted with ethyl acetate and filtered. The filtrate was dried over Na2SO4, filtered and concentrated. Silica gel chromatography (4 g silica, 1-100% ethyl acetate/hexane) provided tert-butyl 8-but-2-ynyl-10,10-difluoro-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (50.0 mg, 65%) as a colorless oil. ESI-MS m/z calc. 344.2. Found 345.3 (M+1)+; Retention time: 1.91 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 3.80 (br s, 2H), 3.35 (q, J=2.2 Hz, 2H), 3.23 (t, J=12.1 Hz, 2H), 2.80 (t, J=8.5 Hz, 2H), 2.48 (s, 2H), 2.02 (d, J=13.2 Hz, 2H), 1.84 (t, J=2.3 Hz, 3H), 1.54-1.48 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:5]2=[N:6][CH:7]=1.CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC.[NH2:46][C:47]1[N:52]=[C:51](Cl)[N:50]=[C:49]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[C:48]=1[N+:59]([O-:61])=[O:60]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:46][C:47]1[N:52]=[C:51]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[CH:2][CH:3]=3)[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[N:9]=2)[N:50]=[C:49]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[C:48]=1[N+:59]([O-:61])=[O:60]
Reactant: Fc1cnc2c(c1)c(I)nn2Cc1ccccc1F
Reactant: CCOC(=O)c1nc(Cl)nc(N)c1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[Sn](CCCC)CCCC
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Under argon, 3.85 g (10.91 mmol) of the compound from example 24A were initially charged in dioxane (100 ml) and the reaction mixture was purged with argon. Subsequently, 8.27 ml (16.36 mmol) of hexabutylditin and 2.96 g (12.00 mmol) of ethyl 6-amino-2-chloro-5-nitropyrimidine-4-carboxylate (prepared according to J. Chem. Res. 1989, 2086-2097) were added. Thereafter, 3.83 g (5.45 mmol) of bis(triphenylphosphine)palladium(II) chloride were added and the reaction mixture was stirred at 100° C. overnight. Thereafter, the mixture was cooled to RT and filtered through Celite, and the residue was washed with methanol. The filtrate was concentrated, and the residue was extracted by stirring with ethyl acetate and filtered off. The filtrate was concentrated and the residue was purified by means of prep. HPLC (eluent: acetonitrile/water with 0.1% formic acid gradient). This gave 1.36 g (71% purity, 14% of theory) of crude product, which was converted without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([CH3:34])=[CH:28]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([CH3:34])=[CH:28]2
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCN1CCCCC1
Temperature: 85 °C
Yield: 54.8 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (100 mg, 0.29 mmol), 5-hydroxy-2-methylindole (53 mg, 0.36 mmol), (prepared as described for the starting material in Example 48), and potassium carbonate (62 mg, 0.44 mmol) in DMF (2 ml) was heated at 85° C. for 3 hours, followed by heating at 95° C. for 2 hours. After cooling, ice/water (15 ml) was added and the precipitate was collected by filtration and dried under vacuum. The solid was purified by column chromatography eluting with methylene chloride/methanol (95/5) followed by methylene chloride/methanol/3M ammonia in methanol (95/3/2) to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-piperidinopropoxy)quinazoline (71 mg, 54%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([C:14]([S:17]([CH3:20])(=[O:19])=[O:18])([CH3:16])[CH3:15])[N:11]=[C:10]([C:21]2[S:25][C:24]([NH2:26])=[N:23][CH:22]=2)[N:9]=1.Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29].C(=O)([O-])O.[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([C:14]([S:17]([CH3:20])(=[O:19])=[O:18])([CH3:15])[CH3:16])[N:11]=[C:10]([C:21]2[S:25][C:24]([NH:26][C:28](=[O:29])[O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:23][CH:22]=2)[N:9]=1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=O)nc(-c2cnc(N)s2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=O)nc(-c2cnc(NC(=O)Oc3ccccc3)s2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
A mixture of 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-(2-methylsulfonylpropan-2-yl)pyrimidin-2-yl]-1,3-thiazol-2-amine (1.05 g, 2.6 mmol), phenyl chloroformate (618 mg, 3.9 mmol) and sodium hydrogen carbonate (311 mg, 3.9 mmol) in dioxane (10 mL) was stirred at RT for 2 hours then diluted with ethyl acetate and washed with water (150 mL) and brine (100 mL). The organics were dried over magnesium sulphate and concentrated in vacuo. The residue was recrystallised from diethyl ether and hexane to give the desired product as a beige solid (1 g).