Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([CH3:23])[C:10]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.C1(N(C)C2CCCCC2)CCCCC1.N#N.[CH:40]([O:42]CCCC)=[CH2:41].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1>[C:40]([C:2]1[N:6]2[CH2:7][CH2:8][N:9]([CH3:23])[C:10]3([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]3)[C:5]2=[CH:4][CH:3]=1)(=[O:42])[CH3:41]
Reactant: CN1CCn2c(Br)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Reactant: C=COCCCC
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Agent: N#N
Solvent: C1COCCO1
Product: CC(=O)c1ccc2n1CCN(C)C21CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 37.1 %

Procedure:
A solution of tert-butyl 6-bromo-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (2 g, 5.2 mmol) and N-cyclohexyl-N-methyl-cyclohexanamine (1.67 mL, 7.81 mmol) in 1,4-dioxane (8.0 mL) was purged with N2 for 5 minutes. 1-Vinyloxybutane (7.04 mL, 52.04 mmol), Pd(dba)3 (1.078 g, 1.04 mmol) and tri tert-butylphosphane (642.0 μL, 2.60 mmol) were added and the reaction was heated at 80° C. for 5 hours in a pressure vessel. The reaction was filtered through a plug of celite using ethyl acetate. The solvent was evaporated under reduced pressure. The crude product was purified by silica gel chromatography utilizing a gradient of 1-100% ethyl acetate in hexane to yield tert-butyl 6-acetyl-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (672.1 mg, 1.93 mmol, 37%) as a yellow solid. 1H NMR (400 MHz, DMSO) δ 7.04 (d, J=4.1 Hz, 1H), 6.12 (d, J=4.2 Hz, 1H), 4.17 (t, J=6.0 Hz, 2H), 3.83-3.68 (m, 2H), 3.21 (t, J=6.0 Hz, 2H), 3.17-2.91 (m, 2H), 2.31 (s, 3H), 2.24 (s, 3H), 2.07-1.97 (m, 2H), 1.72-1.59 (m, 2H), 1.41 (s, 9H). ESI-MS m/z calc. 347.2, found 348.5 (M+1)+; Retention time: 0.95 minutes (3 minute run).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:5][NH2:6])=[S:4].[CH:7]1([C:12](O)=O)[CH2:11][CH2:10][CH2:9][CH2:8]1>O>[NH2:1][N:2]1[C:12]([CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[N:6][N:5]=[C:3]1[SH:4]
Reactant: O=C(O)C1CCCC1
Reactant: NNC(=S)NN
Solvent: O
Product: Nn1c(S)nnc1C1CCCC1
Temperature: 165 °C

Procedure:
34.29 g (323 mmol) of finely mortared thiocarbohydrazide are suspended in 38.5 ml (355.3 mmol) of cyclopentanecarboxylic acid and the suspension is heated at 165° C. for 20 min. During this, the water produced in the reaction is distilled off until a yellowish condensate appears. After cooling down, 250 ml of dichloromethane/methanol 95:5 are added to the suspension and the precipitate is filtered off. The filtrate is concentrated and subject to column filtration on silica gel (dichloromethane/methanol 98:2). After drying under high vacuum, the product is obtained as a colorless solid.
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>ClCCl>[F:1][C:2]1([F:10])[CH2:7][CH2:6][CH:5]([CH2:8][O:9][S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:4][CH2:3]1
Reactant: OCC1CCC(F)(F)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CCC(F)(F)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 184A (8.5 g, 57 mmol) in dichloromethane (100 mL) were added triethylamine (Aldrich, 25 mL, 180 mmol) and tosyl chloride (Aldrich, 11.4 g, 60 mmol). The reaction mixture was stirred at room temperature for 16 hours and washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in hexanes) to afford the title compound. 1H NMR (300 MHz, chloroform-d) δ ppm 1.17-1.42 (m, 2 H) 1.57-1.69 (m, 1 H), 1.70-1.91 (m, 4 H), 1.93-2.18 (m, 2 H), 2.46 (s, 3 H), 3.86 (d, J=6.4 Hz, 2 H), 7.35 (d, J=8.5 Hz, 2 H), 7.78 (d, J=8.1 Hz, 2 H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][NH:7][C:8]#[N:9].Br[CH2:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CC(=O)CC>[C:13]([C:12]1[O:17][C:8](=[NH:9])[N:7]([CH2:6][C@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[CH:11]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: N#CNC[C@H]1CCCO1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CC(C)(C)c1cn(C[C@H]2CCCO2)c(=N)o1

Procedure:
A mixture of Example 32A (2.35 g, 18.63 mmol), 1-bromo-3,3-dimethylbutan-2-one (2.52 mL, 18.63 mmol) and potassium carbonate (2.57 g, 18.63 mmol) in 2-butanone (75 mL) was heated to 80° C. overnight. The mixture was poured into water, and extracted with ethyl acetate (2×). The combined organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure to afford the title compound. MS (ESI) m/z 225 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([CH:16]=[CH2:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[CH3:18][C:19]1[CH:23]=[C:22]([CH2:24][C:25](Cl)=[O:26])[O:21][N:20]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:18][C:19]1[CH:23]=[C:22]([C:24]2[C:25](=[O:26])[NH:1][C:2]3[C:3]([C:4]=2[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:12][C:13]([CH:16]=[CH2:17])=[CH:14][CH:15]=3)[O:21][N:20]=1
Reactant: C=Cc1ccc(N)c(C(=O)c2ccccc2)c1
Reactant: Cc1cc(CC(=O)Cl)on1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1ccc2[nH]c(=O)c(-c3cc(C)no3)c(-c3ccccc3)c2c1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
A mixture of 2-amino-5-vinylbenzophenone (c) (0.1 g, 0.45 mmol), (3-methyl-isoxazol-5-yl)-acetyl chloride (0.9 mmol) [from example 4], triethylamine (0.20 mL) and DCM (10 mL) was heated to reflux overnight. After the mixture was cooled to room temperature and concentrated, the residue was purified by flash chromatography on silica gel (5% methanol in DCM) to give 3-(3-methyl-isoxazol-5-yl)-4-phenyl-6-vinyl-1H-quinolin-2-one (d) (0.12 g, 81%). 1H NMR (300 MHz, CDCl3) 8 12.68 (s, 1H), 7.74-7.65 (m, 1H), 7.52-7.41 (m, 4H), 7.30-7.13 (m, 3H), 6.58 (dd, J=11, 19.6 Hz, 1H), 6.45 (s, 1H), 5.62 (d, J=19.6 Hz, 1H), 5.18 (d, J=11 Hz,1H), 2.27 (s, 3H). MS: 329.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11]3[C:14]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[CH:15][C:16]4[NH:17][C:18]([CH3:21])=[N:19][C:20]=4[C:10]=3[O:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:30][C:31]1[CH:35]=[CH:34][O:33][N:32]=1>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11]3[C:14]([C:22]([N:24]([CH3:25])[CH3:26])=[O:23])=[CH:15][C:16]4[N:17]=[C:18]([CH3:21])[N:19]([CH2:30][C:31]5[CH:35]=[CH:34][O:33][N:32]=5)[C:20]=4[C:10]=3[O:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nc2c3c(c(C(=O)N(C)C)cc2[nH]1)CCC(c1ccc(F)cc1)O3
Reactant: BrCc1ccon1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(C(=O)N(C)C)c3c(c2n1Cc1ccon1)OC(c1ccc(F)cc1)CC3
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a solution of 8-(4-fluorophenyl)-N,N,2-trimethyl-3,6,7,8-tetrahydrochromeno[7,8-d]imidazole-5-carboxamide (50.0 mg, 0.141 mmol, Step 8 of Example 8) in N,N-dimethylformamide (1.4 mL), was added sodium hydride (6.7 mg, 0.17 mmol) at 0° C. and the mixture was stirred at 0° C. for 30 minutes. Then a solution of 3-(bromomethyl)isoxazole in N,N-dimethylformamide (1.0 mL, Step 1) was added to the mixture at 0° C. The mixture was allowed to warm to room temperature, stirred for 4 hours and left at the same temperature overnight. The reaction was quenched by saturated ammonium chloride aqueous solution. The mixture was extracted twice with ethyl acetate. The combined organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative TLC eluting with hexane/ethyl acetate (1:1, twice), then dichloromethane/methanol (20:1, twice) to afford the title compound as a pale yellow solid (23.5 mg, 38%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[N:12][O:13][CH2:14][CH2:15][OH:16].O[C:18]1[CH:50]=[CH:49][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[N:25]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]2=[O:48])=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[N:12][O:13][CH2:14][CH2:15][O:16][C:18]1[CH:50]=[CH:49][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[N:25]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]2=[O:48])=[CH:20][CH:19]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCON=Cc1ccc2ccccc2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1SC(Cc2ccc(OCCON=Cc3ccc4ccccc4c3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 69.8 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 430 mg of 2-(2-naphthylmethyleneaminooxy)ethanol (prepared as described in Preparation 7), 716 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 525 mg of triphenylphosphine and 348 mg of diethyl azodicarboxylate, 712 mg of the title compound were obtained as a foam-like solid.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@@H:13]3[CH2:15][C@H:14]3[CH2:16][OH:17])=[CH:10][CH:11]=2)[N:6]([CH3:18])[C:5]1=[O:19].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([O:17][CH2:16][C@@H:14]1[CH2:15][C@H:13]1[C:9]1[N:8]=[C:7]2[N:6]([CH3:18])[C:5](=[O:19])[N:4]([CH2:3][C:2]([CH3:21])([CH3:20])[CH3:1])[C:12]2=[CH:11][CH:10]=1)(=[O:32])=[O:31]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc([C@@H]3C[C@H]3CO)nc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc([C@@H]3C[C@H]3COS(C)(=O)=O)nc21
Temperature: -10 °C
Reaction time: 0.02 h

Procedure:
1-(2,2-Dimethylpropyl)-5-[(1R,2R)-2-(hydroxymethyl)cyclopropyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (31-4, 53.2 mg, 0.18 mmol, 1.0 equiv) was added to anhydrous DCM (1.8 mL) and cooled to −10° C. Triethylamine (108 μL, 0.77 mmol, 4.2 equiv) and methanesulfonyl chloride (32 μL, 0.40 mmol, 2.2 equiv) were added sequentially and the resulting reaction mixture was stirred for 1 min. Following this duration, TLC showed complete consumption of 31-4. The reaction mixture was partitioned between ethyl acetate (5 mL) and saturated NaHCO3 (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give a clear, yellow oil. The crude product was carried forward without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@H:4]([NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:5][C:6]1[C:7]([CH2:16][O:17]C(=O)C)=[C:8]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][N:10]=[CH:9]2.COC(=O)[C@H](NC(OCC1C=CC=CC=1)=O)CC1C=CC(NC(OC(C)(C)C)=O)=C(C)C=1CO>>[CH3:1][O:2][C:3](=[O:32])[C@H:4]([NH:21][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[CH2:5][C:6]1[C:7]([CH2:16][OH:17])=[C:8]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][N:10]=[CH:9]2
Reactant: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1COC(C)=O)NC(=O)OCc1ccccc1
Agent: COC(=O)[C@@H](Cc1ccc(NC(=O)OC(C)(C)C)c(C)c1CO)NC(=O)OCc1ccccc1
Product: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1CO)NC(=O)OCc1ccccc1
Yield: 95 %

Procedure:
3-(4-Acetoxymethyl-7-chloro-1H-indazol-5-yl)-2-(R)-benzyloxycarbonylamino-propionic acid methyl ester (290 mg, 0.63 mmol) was converted into the desired product in a manner analogous to the preparation of 2-(R)-benzyloxycarbonylamino-3-(4-tert-butoxycarbonylamino-2-hydroxymethyl-3-methyl-phenyl)-propionic acid methyl ester. Crude product was obtained as an orange solid in 95% yield. Material was carried forward without firther purification. 1H NMR (300 MHz, CDCl3): δ=8.15 (s, 1H); 7.27 (m, 5H); 7.14 (s, 1H); 6.10 (m, 1H); 5.01 (d, J=4.8, 2H); 4.95 (s, 2H); 4.75 (m, 1H); 3.79 (s, 3H); 3.34 (m, 1H); 3.09 (m, 1H). MS m/e (M+H)+=418.0.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].[F:8][C:9]([F:21])([F:20])[S:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>C1COCC1>[OH:5][CH2:4][CH2:3][C:2]([NH:1][C:18]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([S:10][C:9]([F:20])([F:8])[F:21])=[CH:12][CH:13]=1)=[O:19])([CH3:7])[CH3:6]
Reactant: CC(C)(N)CCO
Reactant: O=C=Nc1ccc(SC(F)(F)F)cc1
Solvent: C1CCOC1
Product: CC(C)(CCO)NC(=O)Nc1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of 3-amino-3-methyl-butan-1-ol (941 mg, 9.12 mmol) in 10 mL THF was added 4-(trifluoromethylthio)phenylisocyanate (2.0 g, 9.12 mmol). The reaction was stirred at ambient temperature for 16 h. The solution was concentrated and subjected to a hot filtration with CH2Cl2 to give solid 1-(4-hydroxy-2-methylbutan-2-yl)-3-{4-[(trifluoromethyl)sulfanyl]phenyl}urea (95%). LCMS [M+H]+=323.1.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH3:5][C:6]1([CH3:18])[CH2:11][CH:10]([N:12]2[CH2:16][CH2:15][NH:14][C:13]2=[O:17])[CH2:9][CH2:8][O:7]1.N1C=CC=CC=1>C(Cl)Cl>[CH3:5][C:6]1([CH3:18])[CH2:11][CH:10]([N:12]2[CH2:16][CH2:15][N:14]([C:1]([Cl:4])=[O:2])[C:13]2=[O:17])[CH2:9][CH2:8][O:7]1
Reactant: CC1(C)CC(N2CCNC2=O)CCO1
Reactant: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(N2CCN(C(=O)Cl)C2=O)CCO1
Temperature: 25 °C
Yield: 100 %

Procedure:
A 0° C. solution of phosgene (20% in toluene, 0.361 mL, 0.676 mmol) in DCM (2 mL), under Ar, was treated slowly drop-wise with a solution of 1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)imidazolidin-2-one (0.067 g, 0.338 mmol) and pyridine (0.055 mL, 0.676 mmol) in DCM (1 mL). The mixture was warmed to RT and concentrated to dryness to afford 3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-oxoimidazolidine-1-carbonyl chloride as a yellow solid which was carried on to the next step assuming 100% yield (88 mg).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([F:24])[CH:23]=1)[C:7]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=1)([OH:12])[C:8]([O:10][CH3:11])=[O:9].[C@@:25]12(O)[N:32](C)[C@@H:29]([CH2:30][CH2:31]1)[CH2:28][CH:27]=[CH:26]2>C1(C)C=CC=CC=1>[F:3][C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([F:24])[CH:23]=1)[C:7]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=1)([OH:12])[C:8]([O:10][C@@:11]12[N:32]([CH3:25])[C@@H:29]([CH2:30][CH2:31]1)[CH2:28][CH:27]=[CH:26]2)=[O:9]
Reactant: CN1[C@@H]2CC=C[C@@]1(O)CC2
Reactant: COC(=O)C(O)(c1cc(F)cc(F)c1)c1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1[C@@H]2CC=C[C@@]1(OC(=O)C(O)(c1cc(F)cc(F)c1)c1cc(F)cc(F)c1)CC2

Procedure:
1.53 g (0.0636 mol) of NaH are placed in 30 ml of toluene, a solution of 14 g (0.0446 mol) of 3j and 8.85 g (0.0636 mol) of tropenol in 80 ml of toluene is added dropwise at 10° C. and 860 mbar. The alcohol produced during the reaction is distilled off while at the same time toluene is added dropwise. After 3 hours, the mixture is cooled and extracted, with dichloromethane and water. The combined organic phases were dried over MgSO4 and evaporated to dryness. The residue was stirred with petroleum ether/ethyl acetate 95:5. Yield: 11.21 g of light beige crystals (60% of theory); melting point: 168° C.-170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15](O)[CH:14]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O=P(Cl)(Cl)[Cl:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([Cl:26])[CH:14]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(Nc2nc(O)cc(-c3ccccc3)n2)cc1Cl
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(Nc2nc(Cl)cc(-c3ccccc3)n2)cc1Cl

Procedure:
Chlorination of 2-(3-chloro-4-methoxy-phenylamino)-6-phenyl-pyrimidin-4-ol (1.5 g, 4.1 mmol) with POCl3 (10 mL) as explained above, afforded (3-chloro-4-methoxy-phenyl)-(4-chloro-6-phenyl-pyrimidin-2-yl)-amine.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=O)=[C:8]([F:15])[CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[NH2:30][C:31]1[C:39]([NH2:40])=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([NH2:35])=[O:34]>N1C=CC=CC=1.CN(C)C=O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:14]=[CH:13][C:9]([C:10]2[NH:40][C:39]3[CH:38]=[CH:37][CH:36]=[C:32]([C:33]([NH2:35])=[O:34])[C:31]=3[N:30]=2)=[C:8]([F:15])[CH:7]=1
Reactant: O=C(O)c1ccc(C2OCCO2)cc1F
Reactant: NC(=O)c1cccc(N)c1N
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: NC(=O)c1cccc2[nH]c(-c3ccc(C4OCCO4)cc3F)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
A solution of EXAMPLE 20D (1.5 g, 7.1 mmol) in pyridine (5 mL) and N,N-dimethylformamide (20 mL) was treated with 1,1′-carbonyldiimidazole (1.4 g, 8.5 mmol) at 40° C. for 30 minutes. 2,3-Diaminobenzamide dihydrochloride (synthesized as described in U.S. Pat. No. 6,737,421, column 11, EXAMPLE 2, step (e), 1.58 g, 7.1 mmol) was added and the mixture stirred at ambient temperature overnight. Solvents were removed and the residue suspended in 10 mL of acetic acid. The mixture was stirred at 80° C. overnight, cooled, and concentrated and the residue was purified by flash chromatography using ethyl acetate to give the title compound (500 mg, 22%). MS (DCI/NH3) m/z 329 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[S:6][CH:7]=[CH:8][C:2]1=2.C([Li])CCC.[Cl:14]C(Cl)(Cl)C(Cl)(Cl)Cl.[Cl-].[NH4+]>O1CCCC1>[Cl:14][C:5]1[S:1][C:2]2[CH:8]=[CH:7][S:6][C:3]=2[CH:4]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: c1cc2sccc2s1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Clc1cc2sccc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
A solution of thieno[3,2-b]thiophene (see Fuller, L.; Iddon, B.; Smith, K. A. J. Chem. Soc. Perkin Trans 1 1997, 3465-3470) (1.27 g) in tetrahydrofuran (30 ml) was cooled to −78° C. under argon atmosphere, and thereto was added dropwise n-butyl lithium (1.59 M hexane solution, 5.70 ml). The mixture was stirred at 0° C. for 30 minutes, and cooled again to −78° C. Added thereto was a solution of hexachloroethane (2.14 g) in tetrahydrofuran (5 ml). The mixture was stirred at the same temperature for one hour, and warmed to 0° C. Added thereto was a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane) to give 2-Chlorothieno[3,2-b]thiophene (1.19 g) as a solid.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:29](=[O:30])[CH2:28][C@H:27]6[NH:31][C@H:24]([CH2:25][CH2:26]6)[CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:37]=O>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:29](=[O:30])[CH2:28][C@H:27]6[N:31]([CH3:37])[C@H:24]([CH2:25][CH2:26]6)[CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@H]5CC[C@@H](CC4=O)N5)cn3)nc2n1C1CCCC1
Reactant: C=O
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@H]5CC[C@@H](CC4=O)N5C)cn3)nc2n1C1CCCC1
Yield: 97.3 %

Procedure:
Following general reductive alkylation method 1, 7-cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (90 mg, 0.184 mmol) was combined with formaldehyde (37% solution in water, 0.041 ml, 1.474 mmol) which after silica gel chromatography gave 7-cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (90 mg) in 97% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.69 (s, 1H), 8.81 (s, 1H), 8.31 (d, J=9.09 Hz, 1H), 8.12 (d, J=2.53 Hz, 1H), 7.58 (dd, J=9.09, 2.53 Hz, 1H), 6.63 (s, 1H), 4.76 (m, 1H), 4.16 (d, J=14.65 Hz, 1H), 3.35 (m, 1H), 3.28 (m, 1H), 3.20 (t, J=6.57 Hz, 1H), 3.06 (br. s., 6H), 2.99 (m, 1H), 2.46 (m, 2H), 2.34 (s, 3H), 2.06 (m, 6H), 1.81 (m, 2H), 1.67 (m, 3H). MS m/z 503.6 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]([CH3:13])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[N:6]=[C:5]1[CH3:12].[NH2:14][C@@H:15]([CH3:32])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[C:28]([F:30])[C:25]([C:26]#[N:27])=[C:24]([Cl:31])[CH:23]=2)=[N:18]1.CN(C=O)C>C(Cl)Cl>[Cl:31][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C@@H:15]([NH:14][C:9]([C:7]3[N:6]=[C:5]([CH3:12])[N:4]([CH2:3][C@H:2]([OH:1])[CH3:13])[CH:8]=3)=[O:11])[CH3:32])[N:18]=2)[CH:29]=[C:28]([F:30])[C:25]=1[C:26]#[N:27]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: Cc1nc(C(=O)O)cn1C[C@@H](C)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)cn1C[C@@H](C)O
Yield: 45.3 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from (R)-1-(2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxylic acid (1.059 mmol, 195 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.882 mmol, 246 mg) and using dry DMF (2 ml) as the solvent. After the reaction was finished, DCM was added and the reaction mixture was concentrated. The crude product was purified by flash chromatography and preparative HPLC, respectively. 177.8 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.00-1.10 (m, 6H), 2.34 (s, 3H), 3.69-3.90 (m, 3H), 4.22-4.48 (m, 3H), 4.91 (d, 1H), 7.02 (d, 1H), 7.47 (s, 1H), 7.86 (d, 1H), 7.91-7.96 (m, 1H), 8.00 (s, 1H), 8.06 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[C:14]1([CH:22]=C(O)[CH:19]=[C:17]([OH:18])[CH:16]=1)[OH:15]>>[OH:15][C:14]1[C:22]2[C:5](=[O:7])[C:4]3[C:3](=[C:11]([O:12][CH3:13])[CH:10]=[CH:9][CH:8]=3)[O:2][C:1]=2[CH:19]=[C:17]([OH:18])[CH:16]=1
Reactant: Oc1cc(O)cc(O)c1
Reactant: COc1cccc(C(=O)O)c1OC
Product: COc1cccc2c(=O)c3c(O)cc(O)cc3oc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 94.5 %

Procedure:
2,3-dimethoxybenzoic acid (0.91 g, 5 mmol), phloroglucinol (0.95 g, 7.5 mmol), ZnCl□ (4.69 g, 30 mmol) and POCl□ (20 mL) were charged to a dry round-bottom flask, followed by stirring at 80° C. for 4 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and was very slowly added to 500 mL of ice water. When the reaction liquid was poured in ice water, ice was added portionwise to prevent overheating. The resulting precipitate was allowed to stand at 4° C. overnight, combined, washed with water and ether, and then dried under reduced pressure to give the title compound (1.22 g, 94.8%) as a reddish brown solid.
Reaction SMILES: [CH2:1]([C:3]1([C:8]2[S:12][C:11]([CH2:13][OH:14])=[CH:10][CH:9]=2)[O:7][CH2:6][CH2:5][O:4]1)[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].[Cl-].[NH4+]>ClCCl>[CH3:22][S:23]([O:14][CH2:13][C:11]1[S:12][C:8]([C:3]2([CH2:1][CH3:2])[O:4][CH2:5][CH2:6][O:7]2)=[CH:9][CH:10]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CCC1(c2ccc(CO)s2)OCCO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1(c2ccc(COS(C)(=O)=O)s2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
9.25 g (43.2 mmol) of [5-(2-ethyl-[1,3]dioxolan-2-yl)-2-thienyl]methanol are dissolved in 500 mL of dichloromethane and cooled to 0° C. 9.0 mL (64.7 mmol) of triethylamine are added, followed by 3.5 mL of methylsulphonyl chloride (45.3 mmol). After stirring for 1 hour, the reaction medium is treated with ammonium chloride solution and extracted with dichloromethane. The organic phases are combined, dried and concentrated under reduced pressure. A brown oil is obtained (m=9.28 g; Y=75%).