Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH:19]=[O:20])=[C:17]2[C:12]([C:13](=[O:32])[C:14]([CH3:31])=[C:15]([CH:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:23][CH2:22]3)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1([Mg]Br)[CH2:35][CH2:34]1.Cl.O>O1CCCC1>[CH2:1]([O:8][C:9]1[C:18]([CH:19]([CH:33]2[CH2:35][CH2:34]2)[OH:20])=[C:17]2[C:12]([C:13](=[O:32])[C:14]([CH3:31])=[C:15]([CH:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:23][CH2:22]3)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br[Mg]C1CC1
Reactant: CCC(=O)N1CCC(c2oc3c(C=O)c(OCc4ccccc4)ccc3c(=O)c2C)CC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)N1CCC(c2oc3c(C(O)C4CC4)c(OCc4ccccc4)ccc3c(=O)c2C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of 7-(benzyloxy)-3-methyl-4-oxo-2-(1-propanoylpiperidin-4-yl)-4H-chromene-8-carbaldehyde (200 mg, 0.46 mmol) obtained in Example 34-2 in tetrahydrofuran (6 mL), a 1 N solution of cyclopropyl magnesium bromide in tetrahydrofuran (1.5 mL, 1.50 mmol) was added dropwise at −30° C., and the mixture was gradually heated to 0° C. over 45 minutes and then stirred at 0° C. for 2 hours. A 1 N aqueous hydrochloric acid solution (5 mL) was added dropwise to the reaction solution, and then water was added to the mixture, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=60/40→0/100) to obtain 159 mg of the title compound (yield: 68%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([CH3:15])=[CH:13][N:14]=1)=[O:8].[H-].[Na+].Cl[CH2:22][C:23]1[O:24][CH:25]=[CH:26][CH:27]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[C:7](/[N:9]=[C:10]1\[S:11][C:12]([CH3:15])=[CH:13][N:14]\1[CH2:22][C:23]1[O:24][CH:25]=[CH:26][CH:27]=1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C)s1
Reactant: ClCc1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C)cn1Cc1ccco1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To a solution of Example 340A (0.15 g, 0.53 mmol) in 5 mL DMF was added sodium hydride (0.016 g, 0.67 mmol, 95%). After the solution was allowed to stir at ambient temperature for 30 min, 2-(chloromethyl)furan (0.08 g, 0.67 mmol) was added. The reaction was held at ambient temperature overnight and then quenched with water. The crude was extracted with ethyl acetate and the organics washed with water, then dried over MgSO4, filtered, and concentrated. Flash chromatography over silica gel (50% ethyl acetate/hexane) gave 0.075 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.26 (d, J=1.36 Hz, 3H) 3.80 (s, 3H) 5.18 (s, 2H) 6.54 (s, 1H) 7.12 (d, J=8.81 Hz, 1H) 7.29 (d, J=1.36 Hz, 1H) 7.46 (dd, J=8.81, 2.71 Hz, 1H) 7.64 (t, J=1.70 Hz, 1H) 7.67-7.76 (m, 2H). m/z 363.0 (M+H)+.
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([NH2:13])=[CH:8][C:7]=1[OH:14].[CH2:16](Br)[CH:17]=[CH2:18].O>CN(C)C=O>[NH2:13][C:9]1[C:10]([Cl:12])=[CH:11][C:6]([C:5]([OH:4])=[O:15])=[C:7]([O:14][CH:16]=[CH:17][CH3:18])[CH:8]=1
Reactant: C=CCBr
Reactant: COC(=O)c1cc(Cl)c(N)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC=COc1cc(N)c(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
A suspension of 60% sodium hydride/oil dispersion (1.52 g, 0.038 mole) in anhydrous dimethylformamide (50 ml) under nitrogen was treated in portions with 4-amino-5-chloro-2-hydroxybenzoic acid methyl ester (6.05 g, 0.030 mole), stirred at room temperature for 30 minutes, and treated with allyl bromide (4.60 g, 0.038 mole). The mixture was stirred at 95°±5° C. for one hour, cooled to room temperature, and added to water (250 ml). The solid was removed by filtration and saved, and the filtrate was extracted with ether (2×100 ml). The concentrated ethereal extracts were combined with the filtered solid, taken up in 20% aqueous ethanol (100 ml), treated with potassium hydroxide (10 g), and refluxed for 45 minutes. The ethanol was removed in vacuo and the aqueous solution was extracted with ether (50 ml) and petroleum ether (30°-60°, 50 ml), cooled (0° C.), and acidified to pH 4 with concentrated hydrochloric acid (17 ml). The suspension was filtered and solid was air dried, dissolved in methylene chloride (150 ml) containing a little methanol, dried (sodium sulfate), and concentrated in vacuo. Trituration from cold ether/petroleum ethers (30°-60°) and recrystallization from ethyl acetate/hexane (2 crops) afforded 4.25 g (62.2%) of the title compound as a pale tan solid; mp 136°-137° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:33][CH2:34][C:35]2([CH3:39])[CH2:38][O:37][CH2:36]2)=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1.COB([C:45]#[C:46][Si:47]([CH3:50])([CH3:49])[CH3:48])OC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.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>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C:9]3([CH:8]([C:6]4[CH:7]=[C:2]([C:45]#[C:46][Si:47]([CH3:48])([CH3:49])[CH3:50])[CH:3]=[CH:4][C:5]=4[O:33][CH2:34][C:35]4([CH3:39])[CH2:38][O:37][CH2:36]4)[CH2:13][C:12](=[O:14])[NH:11][CH:10]3[C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:30]2=[CH:29][CH:28]=1
Reactant: Cc1ccc(Cl)cc1C1NC(=O)CC(c2cc(Br)ccc2OCC2(C)COC2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COB(C#C[Si](C)(C)C)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1C1NC(=O)CC(c2cc(C#C[Si](C)(C)C)ccc2OCC2(C)COC2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 80 °C

Procedure:
To a mixture of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(3-methyl-oxetan-3-ylmethoxy)-phenyl]-6-chloro-2′-(5-chloro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg, 0.08 mmol), trimethylsilylacetylene boronic acid dimethyl ester (0.7 M, 0.7 mL, 0.49 mmol) and K3PO4 (100 mg, 0.48 mmol) in THF was added Pd(PPh3)4 (15 mg) under argon. The reaction mixture was heated at 80° C. for 20 h, purified by prep-HPLC to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([CH2:18][NH2:19])=[CH:7]2.Cl[C:21]1[C:22]2[CH:29]=[CH:28][NH:27][C:23]=2[N:24]=[CH:25][N:26]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([CH2:18][NH:19][C:21]1[C:22]3[CH:29]=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)=[CH:7]2
Reactant: NCc1cc2cccc(Cl)c2nc1-c1ccccc1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Clc1cccc2cc(CNc3ncnc4[nH]ccc34)c(-c3ccccc3)nc12

Procedure:
Prepared according to Procedure H using (8-chloro-2-phenylquinolin-3-yl)methanamine (0.050 g, 0.186 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.034 g, 0.22 mmol, 1.2 eq) and DIEA (0.38 mmol, 2.0 eq) in n-butanol (3 mL). N-((8-chloro-2-phenylquinolin-3-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine [PI3Kδ IC50=270 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.65-8.76 (m, 1H), 8.53 (s, 1H), 8.11-8.20 (m, 4H), 8.07 (d, J=1.96 Hz, 1H), 7.91-8.00 (m, 2H), 7.86 (s, 1H), 7.51-7.58 (m, 2H), 4.73-4.85 (m, 2H), Mass Spectrum (ESI) m/e=386 (M+1).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]([CH3:23])[CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:35]([O:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1)[CH3:36].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[CH2:35]([O:37][C:38]1[CH:43]=[C:42]([C:19]([C:11]2[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[CH:20][CH:21]([CH3:22])[CH3:23])[CH:41]=[CH:40][CH:39]=1)[CH3:36]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOc1cccc(C(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)c1
Yield: 81.6 %

Procedure:
A suspension of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (prepared as in Example 130, 3.0 g, 6.04 mmol), 3-ethoxy-phenylboronic acid (2.51 g, 15.1 mmol), bis(triphenylphosphine)palladium(II) dichloride (420 mg, 0.60 mmol) in 1,4-dioxane (30 mL) and an aqueous sodium carbonate solution (2N, 15.4 mL) was heated in a microwave at 100° C. for 2 h under nitrogen. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with a saturated aqueous sodium bicarbonate solution (2×40 mL). The organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (40 g, 11% ethyl acetate/petroleum ether) afforded 2-(1-(3-ethoxy-phenyl)-3-methyl-but-1-enyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (2.2 g, 81%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ ppm 8.49 (d, 1H, J=4.5 Hz), 7.87 (d, 1H, J=8.4 Hz), 7.67 (d, 2H, J=4.8 Hz), 7.41 (t, 1H, J=7.5 Hz), 7.27-7.10 (m, 4H), 6.79 ((t, 2H, J=6.3 Hz), 6.52 (s, 1H), 6.14 (d, 1H, J=6.6 Hz), 3.94-3.85 (m, 2H), 2.71-2.64 (m, 1H), 1.33 (t, 3H, J=7.2 Hz), 1.14 (t, 6H, J=7.5 Hz).
Reaction SMILES: O.C([O-])=O.[NH4+].C([N:13]1[C:17]([CH2:18][CH2:19][CH2:20][CH:21]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][N:15]=[CH:14]1)C1C=CC=CC=1>C(O)C.[Pd]>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:20][CH2:19][CH2:18][C:17]2[N:13]=[CH:14][NH:15][CH:16]=2)=[CH:29][CH:30]=1
Reactant: Fc1ccc(C(CCCc2cncn2Cc2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Fc1ccc(C(CCCc2c[nH]cn2)c2ccccc2)cc1

Procedure:
A concentrated water solution of ammoniumformate (0,98 g, 15,6 mmol) is added dropwise to the boiling mixture of 1-benzyl-5-[4-(4-fluorophenyl)-4-phenylbutyl]-1H-imidazole (1,5 g, 3,9 mmol) and 10% Pd/C (0,156 g) in 16 ml of 50% ethanol. The mixture is refluxed for 2 hours. The catalyst is filtrated off and the solvent is evaporated. 2M NaOH is added and the product is extracted into ethyl acetate. The ethyl acetate phase is dried and evaporated to dryness to give the product. Yield 1,02 g. Melting point of the hydrochloride salt (from ethyl acetate) is 175°-182° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CCc1cc2c(NCc3ccc(F)cc3)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc(F)cc3)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-ethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-ethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[S:18][C:17]3[N:19]=[CH:20][CH:21]=[N:22][C:16]=3[N:15]([CH2:23][O:24][CH3:25])[C:14]=2[CH:26]=1.C(OCC)C>ClCCl>[CH3:25][O:24][CH2:23][N:15]1[C:14]2[CH:26]=[C:10]([CH2:9][NH:8][C:5](=[O:7])[CH3:6])[CH:11]=[CH:12][C:13]=2[S:18][C:17]2[N:19]=[CH:20][CH:21]=[N:22][C:16]1=2
Reactant: CC(=O)OC(C)=O
Reactant: COCN1c2cc(CN)ccc2Sc2nccnc21
Solvent: CCOCC
Solvent: ClCCl
Product: COCN1c2cc(CNC(C)=O)ccc2Sc2nccnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1 ml of acetic anhydride was added to 5 ml of a solution of 350 mg of 8-aminomethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine in dichloromethane and the resulting mixture was stirred at room temperature for 2 hours. After adding diethyl ether, the precipitate thus formed was taken up by filtration to thereby give 350 mg of the title compound as yellow crystals.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:10][C:11]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([N+]([O-])=O)[CH:15]=1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][CH2:3][NH:2][C:16]1[CH:15]=[C:14]([O:13][C:12]2[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:31])[F:32])=[CH:29][C:11]=2[Cl:10])[CH:19]=[CH:18][C:17]=1[N+:20]([O-:22])=[O:21])[CH3:9]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CCOC(=O)CCNc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of ethyl 3-aminopropionate hydrochloride (10.29 gm, 0.067 mol), 4-(2-chloro-4-(trifluoromethyl)phenoxy)-1,2-dinitrobenzene (5.96 gm, 0.016 mol) and 150 ml of dry dioxane there was added 9.12 gm (0.066 mol) of anhydrous potassium carbonate. The mixture was stirred at room temperature for about 48 hours. The resultant bright-yellow suspension was poured into water and extracted with ether. The etheral solution was then washed with saturated sodium chloride and dried over anhydrous magnesium sulfate. Filtration and evaporation of the filtrate gave an orange oil which, when mixed with methanol yielded orange crystals which were isolated by filtration and dried to give the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:21]3[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=3[N:19]=2)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CN(C)C=O>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:22]2[C:21]3[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=3[N:19]=[C:18]2[NH:17][CH:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][NH:8][C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:12][CH2:13]2)=[CH:25][CH:26]=1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2c(NC3CCN(CCNc4ncccn4)CC3)nc3ccccc32)cc1
Temperature: 70 °C
Yield: 34 %

Procedure:
A mixture of 1.14 parts of 2-chloropyrimidine, 3.7 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine, 1.06 parts of sodium carbonate, 0.1 parts of potassium iodide and 135 parts of N,N-dimethylformamide was stirred and heated overnight at 70° C. The reaction mixture was poured onto water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume), saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 1.5 parts (34%) of 1-[(4-fluorophenyl)-methyl]-N-[1-[2-[(2-pyrimidinyl)amino]ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 168.4° C. (compound 1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23].C(O)(=O)C(O)=O>CO.C(#N)C>[CH2:23]([N:11]1[CH2:12][CH2:13][C:9]([C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=2)([OH:14])[CH2:10]1)[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: C=CCN1CCC(O)(c2cc(F)cc(F)c2)C1

Procedure:
Preparation according to Example 51: Enantiomer E1 of 3-(3,5-difluorophenyl)-pyrrolidin-3-ol (0.18 g, 0.92 mmol), acetonitrile (6 mL), potassium carbonate (0.25 g, 1.84 mmol) and allyl bromide (0.077 mL, 0.92 mmol). Flash chromatography on silica gel (ethyl acetate/methanol, 10:1). Yield: 0.1 g. [α]D=+22.4° (methanol). The amine was converted to the oxalic acid salt and recrystallized from methanol/diisopropyl ether: M.p. 104-105° C.; MS m/z (relative intensity, 70 eV) 239 (M+, 40), 83 (bp), 198 (84), 82 (13), 14 (33), 127 (31).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[C:9]([Cl:11])[N:8]=[C:7](Cl)[C:6]=2[N:13]=1.[CH2:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:17][CH2:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15]2)[C:5]2[N:10]=[C:9]([Cl:11])[N:8]=[C:7]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15]3)[C:6]=2[N:13]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Clc1nc(Cl)c2nc(Cl)nc(Cl)c2n1
Solvent: C1CCOC1
Product: Clc1nc(N2CCc3ccccc3C2)c2nc(Cl)nc(N3CCc4ccccc4C3)c2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 7 %

Procedure:
To a solution of 2,4,6,8-tetrachloropyrimidopyrimidine (0.54 g, 8.0 mmol) in THF (50 ml) was added a solution of 1,2,3,4-tetrahydroisoquinoline (1.0 ml) in THF (15 ml) dropwise over 10 minutes. The mixture was stirred for 12 hours at 25° C., the resultant solid was removed by filtration. The filtrate was evaporated under reduced pressure to afford a brown solid. Chromatography on silica gel, employing petrol:EtOAc (8:2) as eluent, afforded the title compound as a pale brown powder (0.27 g, 7%).
Reaction SMILES: C([O:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20](=[O:30])[CH2:21][O:22]CC2C=CC=CC=2)=[CH:15][CH:14]=1)=[O:11])C1C=CC=CC=1>CO.[Pd]>[OH:22][CH2:21][C:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[CH2:9][OH:8])=[CH:18][CH:17]=1)=[O:30]
Reactant: O=C(COCc1ccccc1)Nc1ccc(OC(=O)COCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: O=C(CO)Nc1ccc(OC(=O)CO)cc1
Reaction time: 10 h

Procedure:
Benzyloxyacetic acid-4-(2-benzyloxyacetylamino)phenyl ester 74 was dissolved in methanol (50 ml) in a pressure vessel, palladium on carbon (5%, 4 grams) added and the mixture stirred under a hydrogen atm. (4 Kg) for 10 hrs. Catalyst was removed by filtration and methanol distilled off under vacuum. Crude 75 was purified by column chromatography on silica gel using benzene:ethyl acetate (8:2) as eluant.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:30][CH:19]3[CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[N:10]=[CH:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.Cl.CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:30][CH:19]3[CH2:20][NH:21][CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[N:10]=[CH:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cn1cnc(Nc2ncc(Cl)c(NC3CC4CN(C(=O)OC(C)(C)C)CC4C3)n2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1cnc(Nc2ncc(Cl)c(NC3CC4CNCC4C3)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a solution of tert-butyl 5-((5-chloro-2-((1-methyl-1H-imidazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (398.3 mg, 0.92 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (10 mL, 40 mmol). The reaction mixture was stirred at rt for 1 h and concentrated in vacuo. The residue was dissolved in water (30 mL) and adjusted to pH=10 with a saturated Na2CO3 aqueous solution, then extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) to give the title compound as a beige solid (0.29 mg, 95%).
Reaction SMILES: [F:1][C:2]1([F:31])[CH2:3][CH2:4][N:5]([C:17]([C:19]2[S:23][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:21][C:20]=2[CH3:30])=[O:18])[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2/[C:8]/1=[CH:9]/[C:10](O)=[O:11].Cl.C(N=C=NCCCN(C)C)C.ON1C(=O)CCC1=O.[BH4-].[Na+].Cl>ClCCl.O1CCCC1.C(OCC)(=O)C>[F:31][C:2]1([F:1])[CH2:3][CH2:4][N:5]([C:17]([C:19]2[S:23][C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[N:21][C:20]=2[CH3:30])=[O:18])[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2/[C:8]/1=[CH:9]/[CH2:10][OH:11]
Reactant: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)O)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\CO)c2ccccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 20 %

Procedure:
To a solution of 1.19 g of (Z)-2-[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetic acid in 100 ml of dichloromethane were added 623 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride and 374 mg of N-hydroxysuccinimide, and the mixture was stirred at room temperature for 14 hours. The reaction solution was washed with water and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent was dissolved in 40 ml of tetrahydrofuran, and 112 mg of sodium borohydride was added with ice cooling, followed by stirring at 0° C. for 24 hours. To the reaction solution were added ethyl acetate and 0.5N hydrochloric acid to undergo liquid separation, the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of NaCl, followed by drying over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent was purified by silica gel column chromatography (eluting with ethyl acetate-n-hexane) to give 230 mg of (Z)-2-[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]ethanol as a colorless amorphous solid.