Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9](/[C:11](=[CH:19]\[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)/C(OC(C)(C)C)=O)=[O:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>NC(N)=S.C1(C)C=CC=CC=1>[CH3:8][C:6]1[CH:7]=[C:2]2[C:3]([C:9](=[O:10])[CH2:11][C@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:1]2)=[CH:4][CH:5]=1
Reactant: Cc1ccc(C(=O)/C(=C\c2ccccc2)C(=O)OC(C)(C)C)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NC(N)=S
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)O[C@@H](c1ccccc1)CC2=O
Yield: 97.9 %

Procedure:
Prepared according to general procedure using (E)-tert-butyl 2-(2-hydroxy-4-methylphenylcarbonyl)-3-phenylprop-2-enoate (51 mg, 0.15 mmol), thiourea catalyst III (10 mg, 0.020 mmol) in 1.5 mL toluene for 6 d at −25° C. and p-toluenesulfonic acid (15 mg, 0.08 mmol) for 9 h. Purification via column chromatography with 10% EtOAc/hexanes afforded 35 mg (97%) of 14 as a white solid in 90% ee. [α]D: +54.8 (EtOH, c=0.52). Analytical data for 14: IR (film) 1688.6, 1616.6, 1295.2, 1242.3 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J=8.4 Hz, 1H), 7.49-7.38 (m, 5H), 6.89-6.87 (m, 2H), 5.46 (dd, J=13.3, 2.7 Hz, 1H), 3.06 (dd, J=16.9, 13.3 Hz, 1H), 2.87 (dd, J=16.9, 2.7 Hz, 1H) 2.34 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 192.0, 161.8, 148.0, 139.1, 129.1, 129.0, 127.2, 126.4, 123.2, 118.9, 118.4, 79.8, 44.9, 22.2; LRMS (electrospray): Exact mass calcd for C16H14O2 [M]+, 238.10. Found [M+1], 239.1.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[CH3:20][C:17]1[N:16]([CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=2)[C:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)=[CH:19][CH:18]=1
Reactant: CCCCCc1ccc(CCCn2c(C)ccc2-c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCc1ccc(CCCn2c(C)ccc2-c2ccc(O)cc2)cc1
Yield: 54 %

Procedure:
To a solution of 2-(4-benzyloxyphenyl)-5-methyl-1-(4-pentylphenylpropyl)-1H-pyrrole (2.99 g, 6.6 mmol) in ethanol (60 ml) was added 10% palladium carbon (300 mg) and the mixture was stirred under hydrogen atmosphere. The insoluble matter was filtered out and the filtrate was concentrated to give the object compound as an oily substance. 1.28 g, (yield 54% )
Reaction SMILES: [C:1]([CH:4](C(C([O-])=O)O)O)([O-])=[O:2].[CH:11]1([CH2:14][N:15]2[CH2:33][CH2:32][C@:22]34[C:23]5[C:24]6[O:31][C@H:21]3[C@H:20]([N:34]([CH3:45])[C:35](=[O:44])[CH:36]=[CH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:19][CH2:18][C@@:17]4([OH:46])[C@H:16]2[CH2:29][C:28]=5[CH:27]=[CH:26][C:25]=6[OH:30])[CH2:13][CH2:12]1>>[CH:11]1([CH2:14][N:15]2[CH2:33][CH2:32][C@:22]34[C:23]5[C:24]6[O:31][C@H:21]3[C@H:20]([N:34]([CH3:45])[C:35](=[O:44])[CH:36]=[CH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:19][CH2:18][C@@:17]4([O:46][C:1](=[O:2])[CH3:4])[C@H:16]2[CH2:29][C:28]=5[CH:27]=[CH:26][C:25]=6[OH:30])[CH2:12][CH2:13]1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Reactant: CN(C(=O)C=Cc1ccccc1)[C@@H]1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Product: CC(=O)O[C@@]12CC[C@@H](N(C)C(=O)C=Cc3ccccc3)[C@@H]3Oc4c(O)ccc5c4[C@@]31CCN(CC1CC1)[C@@H]2C5

Procedure:
tartrate 144 (yield: 48%) was obtained by following the procedure of example 133 but using 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-(N-methylcinnamamido)morphinan (free base of 99) instead of 17-cyclopropylmethyl-4,5α-epoxy-3,14β-dihydroxy-6α-(N-methyl-3,4-dichlorophenylacetamido) morphinan (free base of 1).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[O:43]1CC[C@@H:45](O)[CH2:44]1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([C@H:14]3[CH2:45][CH2:44][O:43][CH2:15]3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O[C@@H]1CCOC1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn([C@H]3CCOC3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (R)-tetrahydrofuran-3-ol and isolated as colorless gum. MS(m/e): 353.3 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[C:28]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)([OH:30])=[O:29].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.Cl[Pd]Cl.[Fe+2]>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:34]3[CH:35]=[CH:36][C:31]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:3][CH:4]=2)[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)=[C:21]([F:27])[CH:22]=1
Reactant: Cc1cc(/C(CC(c2ccc(Br)cc2)c2ccc(Cl)cc2F)=N/O)ccn1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(/C(CC(c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccc(Cl)cc2F)=N/O)ccn1

Procedure:
In analogy to example 74, step 6, (E)-3-(4-bromo-phenyl)-3-(4-chloro-2-fluoro-phenyl)-1-(2-methyl-pyridin-4-yl)-propan-1-one oxime (example 147, step 5) was reacted with 4-carboxyphenylboronic acid in the presence of dichloro(1,1′-bis(diphenylphosphino) ferrocene)palladium(II) dichloromethane adduct in a mixture of 1,4-dioxane, water and 2 M aqueous sodium carbonate solution to give the title compound as an off-white solid, MS (ESI+): m/z=489.3 [M+H]+.
Reaction SMILES: [Cl-].[Na+].[S:3]1[CH:7]=[CH:6][N:5]=[C:4]1[SH:8].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19](S(C)(=O)=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([S:8][C:4]2[S:3][CH:7]=[CH:6][N:5]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Sc1nccs1
Reactant: CC(C)(C)OC(=O)N1CCC(S(C)(=O)=O)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Sc2nccs2)CC1
Temperature: 25 °C
Yield: 30.5 %

Procedure:
To sodium chloride (60% wt. suspension in mineral oil, 108 mg) in dry DMF (5 ml) was added 1,3-thiazole-2-thiol (315 mg) at 0° C. After 30 minutes added 4-methanesulfonyl-piperidine-carboxylic acid tert-butyl ester (500 mg) as a solution in DMF (2 ml) and the reaction mixture was warmed up to room temperature overnight, then heated at 50° C. for 3 hours. Aqueous work-up and purification on silica yielded 4-(thiazol-2-ylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester (174 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH3:9][O-:10].[Na+]>CS(C)=O>[CH3:9][O:10][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccnc(N)c1
Temperature: 150 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
To a solution of 4-chloropyridin-2-amine (3 g, 23.2 mmol) in DMSO (60 mL) was added sodium methoxide (12.6 g, 232 mmol) and the mixture was then stirred at 150° C. for 3 hours then poured into ice-water. The product was extracted with EtOAc (2×100 mL), and the combined organic layers were washed with water (50 mL) and brine (50 mL), dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography using a solvent system of 50% petroleum ether/EtOAc to give 4-methoxypyridin-2-amine (460 mg, 16%) as a yellow solid MS ESI calcd for C6H8N2O [M+H]+ 125, found 125.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[N:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[C:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:17]=2)=[N:13][CH:14]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36](=O)[O:37]C2C=CC=CC=2)[N:30]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:8][C:9]1[CH:10]=[N:11][C:12]([O:15][C:16]2[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=2)[CH:22]=[C:23]2[CH2:28][CH2:27][N:26]([C:36]([NH:35][C:31]3[N:30]=[N:29][CH:34]=[CH:33][CH:32]=3)=[O:37])[CH2:25][CH2:24]2)=[N:13][CH:14]=1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Reactant: Brc1cnc(Oc2cccc(C=C3CCNCC3)c2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnn1)N1CCC(=Cc2cccc(Oc3ncc(Br)cn3)c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.3 %

Procedure:
5-Bromo-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyrimidine trifluoroacetate (0.315 mmol, from Step 5), in acetonitrile (1.5 mL) was treated with phenyl pyridazin-3-ylcarbamate (75 mg, 0.35 mmol) and diisopropylethylamine (0.192 mL, 1.10 mmol) and stirred at ambient temperature for 72 h. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel (0-10% ethanol (containing 11% aq NH4OH):dichloromethane) to afford the title compound (0.099 g, 67% yield) as a white foam. MS (APCI) M=466.0; 1H NMR (400 MHz, CDCl3) δ ppm 2.50 (t, J=5.56 Hz, 2H) 2.63 (t, J=5.65 Hz, 2H) 3.59-3.67 (m, 2H) 3.73 (t, J=4.39 Hz, 2H) 6.44 (s, 1H) 7.02-7.09 (m, 2H) 7.12 (d, J=7.60 Hz, 1H) 7.41 (t, J=7.90 Hz, 1H) 7.49 (dd, J=9.06, 4.58 Hz, 1H) 8.41-8.50 (m, 1H) 8.59 (s, 2H) 8.78 (br. s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:20])([CH3:19])[CH2:5][N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.O1CCOCC1.[ClH:28]>C(O)(C)C>[ClH:28].[ClH:28].[CH3:19][C:4]([CH3:20])([CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[C:3]([O:2][CH3:1])=[O:21]
Reactant: COC(=O)C(C)(C)CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: COC(=O)C(C)(C)CN1CCNCC1
Temperature: 55 °C
Yield: 58.8 %

Procedure:
To a solution of tert-butyl 4-(3-methoxy-2,2-dimethyl-3-oxopropyl)piperazine-1-carboxylate (58.0 g, 193.08 mmoles) in isopropyl alcohol (150 mL) add a 4M dioxane solution of hydrogen chloride ((4 equiv); 193.08 mL, 772.31 mmoles) over 15 minutes, observing gas evolution and a fine precipitate. Heat at 55° C. for 3 h to give a white precipitate. Cool to 10° C. and collect the white solid by filtration, wash with further isopropyl alcohol (30 mL), then EtOAc. Dry in a vacuum oven at 45° C. for 1 h to give methyl 2,2-dimethyl-3-(piperazin-1-yl)propanoate dihydrochloride (31 g, 59% yield). MS (m/z): =201.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[H-].[Li+].Cl[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([O:17][CH2:16][N:7]1[C:6]2[CH:12]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCOCc1ccccc1
Reactant: O=C1COc2ccc(Br)cc2N1
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C1COc2ccc(Br)cc2N1COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.7 %

Procedure:
In N,N-dimethylformamide (4 ml) was dissolved 6-bromo-2H-1,4-benzoxazin-3(4H)-one (200 mg, 0.88 mmol). The solution was cooled in an ice bath, the reaction vessel was charged with nitrogen gas, lithium hydride (purity 90%, 11.7 mg, 1.32 mmol) was then added thereto and the mixture was stirred at room temperature for 10 minutes. Thereafter, benzyl chloromethyl ether (0.20 ml, 1.44 mmol) was added dropwise to the reaction solution at the same temperature and the mixture was stirred at the same temperature for 1.5 hours. Thereafter, lithium hydride (purity 90%, 2.3 mg, 0.26 mmol) and benzyl chloromethyl ether (0.04 ml, 0.29 mmol) were added while continuing stirring, whereby the reaction was quenched. The reaction solution was diluted with dichloromethane, washed with water (×4), dried over anhydrous magnesium sulfate and filtered, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to yield 278 mg (91%) of the title compound in the form of a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](Cl)=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[F:21])=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccnc2Cl)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCN(c2cccnc2-c2ccccc2F)CC1
Temperature: 100 °C
Yield: 91 %

Procedure:
Dissolve 4-(2-chloropyridin-3-yl)-piperazine-1-carboxylic acid t-butyl ester (0.9 g, 3.0 mmol) in a mixture of 5 mL 1,2 dimethoxyethane and 4 mL water. Add 2-fluorophenylboronic acid (0.51 g, 3.64 mmol) followed by tetrakis(triphenylphosphine) palladium(0) (0.35 g, 0.30 mmol), and potassium carbonate (1.13 g, 8.2 mmol). Heat the reaction mixture at 100° C. for 22 hr. Cool to room temperature, concentrate and partition the residue between ethyl acetate and water. Extract water layer with ethyl acetate. Wash combined organic layers with brine. Dry organic extracts (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 10:90 to 30:70 ethyl acetate:hexanes), to give 4-[2-(2-Fluoro-phenyl)-pyridin-3-yl]-piperazine-1-carboxylic acid t-butyl ester (91%). MS (ES): m/z=358 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:41][CH2:42][CH2:43][N:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]2([CH2:54][CH2:53]2)[C:45]1=[O:55]>CC(=O)CC>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:41][CH2:42][CH2:43][N:44]3[C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:46]4([CH2:54][CH2:53]4)[C:45]3=[O:55])[CH2:10][CH2:11]2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22]
Reactant: O=C1N(CCCCl)c2ccccc2C12CC2
Reactant: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccccc2)C2(CCNCC2)C1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccccc2)C2(CCN(CCCN3C(=O)C4(CC4)c4ccccc43)CC2)C1=O
Temperature: 78 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
To a solution of tert-butyl 2-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.2 g, 0.47 mmol), sodium iodide (0.021 g, 0.14 mmol) and potassium carbonate (0.097 g, 0.7 mmol) in 2-butanone (5 mL), was added 1′-(3-chloropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one (0.112 g, 0.47 mmol). After stirring at 78° C. for 2 hours, the reaction mixture was filtered and isolated by Biotage flash chromatography (1-10% methanol/dichloromethane) to obtain the title compound (0.18 g, 62%); 1H NMR (DMSO-d6): δ 1.51 (t, 4H, J=7.2 Hz), 1.57 (s, 9H), 1.67 (d, 2H, J=12.4 Hz), 1.79 (t, 2H, J=6.8 Hz), 2.36 (t, 2H, J=6.8 Hz), 2.54-2.74 (m, 6H), 3.81 (t, 2H, J=7.2 Hz), 4.62 (s, 2H), 4.84 (s, 2H), 6.76 (t, 1H, J=7.2 Hz), 6.84 (d, 2H, J=8 Hz), 6.96-7.02 (m, 2H), 7.17-7.27 (m, 5H), 7.41 (t, 1H, J=6.8 Hz), 7.57 (t, 1H, J=7.6 Hz), 7.83 (dd, 1H, J=8 and 1.2 Hz); MS for C38H44N4O4 m/z 621.12 (M+H)+.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[CH3:24][NH:25][CH3:26]>[OH-].[Na+].Cl>[CH3:24][N:25]([CH3:26])[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Reactant: CNC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCOc1ccccc1-c1nc2nc(N(C)C)ncc2c(=O)[nH]1

Procedure:
7-Methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.60 g) was treated with a solution of dimethylamine in industrial methylated spirit (33%; 20 ml) in a pressure vessel for 18 hours at 90° C. The cooled reaction mixture was evaporated under reduced pressure to yield a solid which was dissolved in aqueous sodium hydroxide. The filtered aqueous solution was neutralized with a few drops of concentrated hydrochloric acid to yield a pale yellow solid which was recrystallized from 2-propanol to yield the title compound, 0.33 g, m.p. 177.5-178.5° C.
Reaction SMILES: [C:1]([CH:4]1[C:8]([CH3:10])([CH3:9])[CH2:7][C:6](=[O:11])[CH:5]1[CH3:12])([OH:3])=[O:2].S(Cl)(Cl)=O.S(Cl)(Cl)(=O)=O.[CH3:22]O>>[CH3:22][O:2][C:1]([C:4]1[C:8]([CH3:9])([CH3:10])[CH2:7][C:6](=[O:11])[C:5]=1[CH3:12])=[O:3]
Reactant: CC1C(=O)CC(C)(C)C1C(=O)O
Reactant: CO
Solvent: O=S(=O)(Cl)Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)C1=C(C)C(=O)CC1(C)C

Procedure:
1-Carboxy-3-oxo-2,5,5-trimethyl-cyclopentane is first dehydrogenated and halogenated and subsequently esterified by treatment with thionyl chloride/sulphuryl chloride followed by the addition of methanol. The 1-methoxycarbonyl-3-oxo-2,5,5-trimethyl-cyclopent-1-ene obtained is then reduced with the aid of a reducing agent (e.g. sodium borohydride) firstly to 1-methoxycarbonyl-3-hydroxy-2,5,5-trimethyl-cyclopent-1-ene and subsequently with the aid of diisobutyl aluminum hydride to 1-hydroxymethyl-3-hydroxy-2,5,5-trimethyl-cyclopent-1-ene.
Reaction SMILES: [CH2:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][NH:2]1.[Cl:11][C:12]1[CH:13]=[C:14]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:35][CH3:36])=[C:27]([O:30][CH2:31][CH2:32][CH2:33]Cl)[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH:15]=[CH:16][C:17]=1[F:18].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:35][CH3:36])=[C:27]([O:30][CH2:31][CH2:32][CH2:33][N:2]4[CH2:3][CH2:4][CH:5]5[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]5)[CH2:1]4)[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCCl
Reactant: C1CCC2CNCCC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCC2CCCCC2C1
Temperature: 80 °C
Yield: 48.7 %

Procedure:
A mixture of decahydroisoquinoline (200 mg, 1.44 mmol, 1 eq), N-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (570 mg, 1.44 mmol, 1 eq) and K2CO3 (238 mg, 1.70 mmol, 1.2 eq) in DMF (15 mL) was heated at 80° C. overnight and cooled to room temperature. To this, 100 mL of CH2Cl2 was added, the mixture was washed with brine (20 mL×3) and water (20 mL×2). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo and the residue was chromatographed with a silica gel column (20:1 (v/v) CH2Cl2/MeOH) to afford the title compound as a yellow solid (350 mg, 49.00%), HPLC: 90.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 499.2 (M+1); 1H NMR (CDCl3, 400 MHz) δ: 1.27-1.59 (12H, m), 1.80-1.82 (2H, m), 2.07-2.33 (2H, m), 2.40-2.51 (2H, m), 3.22-3.26 (2H, m), 4.22-4.24 (2H, m), 7.14-7.16 (1H, m), 7.23 (1H, s), 7.47 (1H, s), 7.65-7.69 (1H, m), 8.00-8.02 (1H, m), 8.64 (1H, s) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([Cl:26])=[CH:5][C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[C:7]=2[CH:25]=1.Cl>C(O)C>[ClH:26].[CH3:1][O:2][C:3]1[C:4]([Cl:26])=[CH:5][C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[C:7]=2[CH:25]=1
Reactant: COc1cc2c(cc1Cl)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCO
Product: COc1cc2c(cc1Cl)[nH]c(=O)n2C1CCNCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1,1-Dimethylethyl 4-(6-methoxy-5-chloro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinecarboxylate (D49) (35 mg) was dissolved in ethanol (1 ml) and HCl (4M in 1,4-dioxane, 1 ml) was added at room temperature. The mixture was stirred at room temperature for 4 h then evaporated to give the title compound, 30 mg.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([Cl:12])=[C:4]([O:13][CH2:14][C:15]#[CH:16])[N:3]=1.C1OCCOCCOCCOCCOCCOC1.[F-:35].[K+].S1(CCCC1)(=O)=O>C(OC)(C)(C)C>[Cl:12][C:5]1[C:4]([O:13][CH2:14][C:15]#[CH:16])=[N:3][C:2]([F:35])=[C:7]([C:8]([F:11])([F:10])[F:9])[CH:6]=1
Reactant: [F-]
Reactant: C#CCOc1nc(Cl)c(C(F)(F)F)cc1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: O=S1(=O)CCCC1
Product: C#CCOc1nc(F)c(C(F)(F)F)cc1Cl
Reaction time: 5 h

Procedure:
47.3 g (0.175 mol) of 2,5-dichloro-6-propargyloxy-3-trifluoromethylpyridine, 0.5 g (1.89 mmol) of 18-crown-6 and 15.2 g (0.263 mol) of potassium fluoride were added to 150 ml of sulfolane and the mixture was stirred for 5 hours at 150°-155° C. After cooling, the reaction mixture was stirred with methyl tert-butyl ether and separated from the inorganic precipitate. The filtrate was extracted four times using water, dried and concentrated. The residue together with methylene chloride was filtered with suction through a silica gel frit and concentrated, giving 31.4 g (71% of theory) of the title compound of ηD24 =1.4732 (Table III, No. 3.036).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[H-].C([Al+]CC(C)C)C(C)C.ClCCl.C([O:22][C:23](=O)[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[NH:39][C:33]3[N:34]=[CH:35][N:36]=[C:37]([Cl:38])[C:32]=3[CH:31]=2)=[CH:26][CH:25]=1)C>C1COCC1.O1CCOCC1>[Cl:38][C:37]1[C:32]2[CH:31]=[C:30]([C:27]3[CH:26]=[CH:25][C:24]([CH2:23][OH:22])=[CH:29][CH:28]=3)[NH:39][C:33]=2[N:34]=[CH:35][N:36]=1
Reactant: CCOC(=O)c1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Al+3]
Agent: [H-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCc1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1

Procedure:
The following Examples are synthesized using an analogous procedure as described in Example 1. However, a modified protocol is applied for the preparation of the intermediates: Instead of reducing the ethyl-ester with lithium aluminum hydride in THF (as described in step 1.2), the 4-hydroxymethyl derivatives are prepared by reduction with diisobutyl-aluminium hydride in a 1:1 mixture of dichloromethane and dioxane at ambient temperature (Examples 67-72 and 76-78). For preparing the intermediates of Examples 73-75, reduction of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acid ethyl ester with diisobutyl-aluminium hydride in THF at ambient temperature yields [4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenyl]-methanol (see step 108.3). Substitution of the chlorine by 2-methoxy-5-aminophenol as described in step 1.1 then gives 5-[6-(4-hydroxymethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-2-methoxy-phenol.