Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH:20]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])[N:23]=[C:22]([C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])[CH2:21]3)[CH:19]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[ClH:40]>C(OCC)(=O)C>[ClH:40].[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[N:24]1[CH:20]([C:18]2[CH:19]=[C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)[CH:15]=[N:16][CH:17]=2)[CH2:21][C:22]([C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])=[N:23]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cncc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cncc(C3=CCNCC3)c2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-[3-(1-BOC-1,2,3,6-tetrahydropyridin-4-yl)-pyridin-5-yl]-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (330.0 mg, 0.6 mmol) prepared in Example 164 was added to a saturated solution of hydrochloric acid in ethyl acetate (2.0 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give 310.0 mg of the titled compound as a brown liquid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6](O)=[O:7])=[C:4]([F:12])[CH:3]=1.O[N:14]1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.N>>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6]([NH2:14])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)c1c(F)cc(Br)cc1F
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: N
Product: NC(=O)c1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a solution of 4-bromo-2,6-difluoro-benzoic acid (2.77 g, 11.7 mmol) and 1-hydroxybenzotriazole (1.74 g, 12.8 mmol) is added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (2.46 g, 12.9 mmol) and the solution is stirred at room temperature for 2 hours. After cooling at 0° C. is added aq. NH3 (1.74 mL) and the reaction mixture is stirred for an additional 20 hours. The solvent is evaporated in vacuo and the residue partitioned between diethyl ether and water. The aqueous phase is extracted several times with Et2O, the organic layers are then combined, washed with 1M HCl, sat. NaHCO3, dried over MgSO4, filtered and concentrated in vacuo to afford the benzamide as a white solid (2.56 g, 93%).
Reaction SMILES: [C:1]([O:10][C:11](OCCCC)(OCCCC)[CH:12]([O:16][CH2:17][CH3:18])OCC)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=[O:7].[C:29]([O:37][C:38](OCCCC)(OCCCC)[CH:39](OCC)[O:40][CH2:41][CH3:42])(=O)[CH2:30][CH2:31][CH2:32]C([O-])=O>>[CH3:32][CH2:31][CH2:30][CH2:29][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:8][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:10][CH2:11][CH2:12][O:16][CH2:17][CH2:18][O:7][CH2:6][CH2:5][CH2:4][CH3:3])=[O:9])=[O:7]
Reactant: CCCCOC(OCCCC)(OC(=O)CCCCC(=O)[O-])C(OCC)OCC
Reactant: CCCCOC(OCCCC)(OC(=O)CCCC(=O)[O-])C(OCC)OCC
Product: CCCCOCCOCCOC(=O)CCCCC(=O)OCCOCCOCCCC

Procedure:
a mixture of 30 mole % dibutoxydiethoxyethyl adipate and 70 mole % dibutoxydiethoxyethyl glutarate purchased from Morton Thioko, Inc. under the tradename "TP-759 Plasticizer".
Reaction SMILES: [C:1](=[O:20])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1>CN(C=O)C>[CH3:30][C:31]1[CH:32]=[CH:33][C:34]([N:37]2[CH2:42][CH2:41][N:40]([C:1]([O:2][CH:3]3[CH2:4][CH2:5][N:6]([CH3:9])[CH2:7][CH2:8]3)=[O:20])[CH2:39][CH2:38]2)=[CH:35][CH:36]=1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: CN1CCC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(C(=O)OC3CCN(C)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution of 1-methylpiperidin-4-yl 4-nitrophenyl carbonate (1.81 g, 6.44 mmol) and DIPEA (0.76 mL, 4.4 mmol) in DMF (20 mL) was added 4-(4-methylphenyl)piperazine (1.53 g, 6.14 mmol). The reaction mixture was stirred at room temperature for 3 hours, the reaction mixture was then concentrated in vacuo. The resulting residue was dissolved in EtOAc (250 mL) and washed with 1M aq Na2CO3 (5×150 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 90:10 mixture of DCM:MeOH) to give 1-methyl-piperidin-4-yl 4-(4-methylphenyl)piperazine-1-carboxylate (1.54 g, 79%) as a cream solid.
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([CH2:25][C:26]([O:28]C)=[O:27])=[CH:20][C:19]=3[Cl:30])=[CH:14][CH:13]=2)[C:9]([CH3:31])=[N:8][C:7]=1[CH3:32])(=[O:5])[NH2:4].Cl>C(O)(C)(C)C>[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([CH2:25][C:26]([OH:28])=[O:27])=[CH:20][C:19]=3[Cl:30])=[CH:16][CH:17]=2)[C:9]([CH3:31])=[N:8][C:7]=1[CH3:32])(=[O:5])[NH2:4]
Reactant: COC(=O)Cc1cc(Cl)c(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1nc(C)c(-c2ccc(-c3cc(Cl)c(CC(=O)O)cc3Cl)cc2)nc1C(N)=O
Temperature: 55 °C
Reaction time: 0.75 h
Yield: 55.6 %

Procedure:
Powdered potassium hydroxide (56.1 mg, 1.00 mmol) was added in one portion to methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,5-dichlorobiphenyl-4-yl)acetate (Intermediate 4-1; 148 mg, 0.33 mmol) in tert-butanol (10 mL) at 55° C. The resulting solution was stirred at 55° C. for 45 minutes, 2M HCl (2 mL) was added and the mixture was evaporated to remove the organic solvent. The suspension was collected by filtration, washed with water (50 mL) and air dried to afford crude product as a pale yellow solid, which contained a minor impurity. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,5-dichlorobiphenyl-4-yl)acetic acid (79 mg, 55.2%) as a white solid.
Reaction SMILES: C1(COC(=O)[NH:10][C:11]2[S:12][C:13](=[O:29])[C:14]3[N:19]=[CH:18][N:17]([C@@H:20]4[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]4[OH:22])[C:15]=3[N:16]=2)C=CC=CC=1>CN(C=O)C.[Pd]>[C@@H:20]1([N:17]2[C:15]3[N:16]=[C:11]([NH2:10])[S:12][C:13](=[O:29])[C:14]=3[N:19]=[CH:18]2)[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]1[OH:22]
Reactant: O=C(Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)s1)OCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)s1
Reaction time: 6 h

Procedure:
A solution of [3,7-dihydro-7-oxo-3-(β-D-ribofuranosyl)imidazo[4,5-d][1,3]thiazin-5-yl]carbamic acid phenylmethyl ester (170 mg, 0.39 mmol) in dry DMF (10 mL) was hydrogenated in the presence of 10% palladium on charcoal (200 mg) at room temperature and 50 psig for 6 h. Additional catalyst (200 mg) was added and hydrogenation continued for another 16 h. Catalyst was removed by filtration and was washed with DMF (10 mL) and ethanol (10 mL). The washing and filtrate were combined and concentrated under reduced pressure. The residue was dissolved in CH3OH and mixed with silica gel (3 g) and evaporated again to dryness. This silica gel sample was loaded on top of a silica gel column (30 g) packed in CHCl3 --CH3OH mixture, 4:1, v/v, and eluted with the same solvent, collecting 30-mL fractions. Fractions 7 to 12 were combined and concentrated, and pumped under reduced pressure to give pure 1-thiaguanosine: 90 mg (53%). 1-Thiaguanosine was crystallized from water-ethanol mixture to give needles: mp 212°-215° C. (dec); IR (KBr) 3415, 3385, 3300, 3190, 3105, 1695, 1662, 1635, and 1530 cm-1 ; HRMS [(+) FAB] m/z found 301.0597 [calcd for C10H13N4O5S, 301.0607 (M+H+)]; NMR (Me2SO-d6) δ3.53 (m, 1), 3.60 (m, 1), 3.86 (q, 1, J=4 Hz), 4.09 (m, 1), 4.38 (m, 1), 5.03 (t, 1, J=5 Hz), 5.20 (m, 1), 5.48 (d, 1, J=5 Hz), 5.80 (d, 1, J=6 Hz), 8.11 (s, 1), 8.34 (s, 2); UV max (95% C2H5OH) 207 nm (ε26750), 218 (sh, 24375), 264 (8000), 274 (5750), 323 (6725); (0.1N HCl) 210 nm (ε19000 ), 266 (8450), 277 (sh, 6400), 325 (6600); (pH 7 and pH 11) 209 nm (ε18400), 220 (sh, 18200), 264 (7600), 275 (sh, 5200), 325 (6450).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@H:9]([CH2:13]S(OC)(=O)=O)[C@H:8]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH2:7][CH2:6]2.C([N:46]1[CH:50]=[C:49]([CH3:51])[N:48]=[CH:47]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@H:9]([CH2:13][N:48]1[C:49]([CH3:51])=[CH:50][N:46]=[CH:47]1)[C@H:8]([C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc([C@@H]2CCc3cc(OC)ccc3[C@@H]2CS(=O)(=O)OC)cc1
Reactant: Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CC#N
Product: COc1ccc([C@@H]2CCc3cc(OC)ccc3[C@@H]2Cn2cncc2C)cc1

Procedure:
A mixture of methyl (1R*,2R*)-1,2,3,4-tetrahydro-6-methoxy-2-(4-methoxyphenyl)-1-naphthylmethanesulphonate (0.2 g) and 1-trityl-4-methylimidazole (0.172 g) in acetonitrile (10 ml) was stirred and heated under reflux for 72 h. The acetonitrile was evaporated under reduced pressure, and the residue was dissolved in 90% by volume aqueous acetic acid (20 ml). This acetic acid solution was heated under reflux for 24 h, and then evaporated to dryness under reduced pressure, and the residue was dissolved in a mixture of ethylacetate (25 ml) and water (25 ml). The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate (40 ml). The combined ethyl acetate solutions were dried and evaporated to dryness, and the residue was purified by flash column chromatography on silica (K60), using methanol/dichloromethane, 2:98 by volume, then methanol/dichloromethane, 5:95 by volume, as the eluting solvent, to give (1R*,2R*)-1,2,3,4-tetrahydro-6-methoxy-2-(4-methoxyphenyl)-1-(5-methylimidazol-1 -ylmethyl)naphthalene as a colourless gum. Nmr in CDCl3 : δ 7.25(2H, d); 6.95(3H, m); 6.7(2H, m); 6.5(1H, dd); 5.95(1H, d); 3.85(3H, s); 3.8(3H, s); 3.65(2H, m); 3.3(1H, m); 3.05(3H, m); 2.15(2H, m); 1.65 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:14]=[CH:13][C:12]([CH:15]3[O:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]3)=[CH:11][C:10]=2[CH3:28])=[N:6][CH:7]=1.FC(F)(F)C(O)=O.CCOC(C)=O.C1COCC1>C(#N)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[C:10]([CH3:28])=[CH:11][C:12]([CH:15]3[O:20][CH2:19][CH2:18][NH:17][CH2:16]3)=[CH:13][N:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(C2CN(C(=O)OC(C)(C)C)CCO2)cnc1Nc1ccc(Br)cn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C2CNCCO2)cnc1Nc1ccc(Br)cn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 54.4 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(6-(5-bromopyridin-2-ylamino)-5-methylpyridin-3-yl)morpholine-4-carboxylate (26 mg) in acetonitrile (1.5 ml) and water (4.5 ml) was added trifluoroacetic acid (45 μl). The reaction mixture was then capped and the mixture was shaken at 80° C. for 3 h. The reaction mixture was then cooled to room temperature and poured into EtOAc/THF (1:1) and washed with 1 M aq. NaOH. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis; gradient: heptane/EtOAc/MeOH) to afford (RS)—N-(5-bromopyridin-2-yl)-3-methyl-5-(morpholin-2-yl)pyridin-2-amine (11 mg, 54%) as a colourless amorphous solid. MS (ISP): 351.1 ([{81Br}M+H]+), 349.1 ([{79Br}M+H]+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1)=O.Cl.[CH:20]1([NH:26][C:27]([C:29]2([F:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:20]1([NH:26][C:27]([C:29]2([F:35])[CH2:34][CH2:33][N:32]([CH2:1][C:3]3[CH:4]=[C:5]([NH:9][C:10](=[O:18])[C:11]4[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13][CH:12]=4)[CH:6]=[CH:7][CH:8]=3)[CH2:31][CH2:30]2)=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: O=C(NC1CCCCC1)C1(F)CCNCC1
Reactant: Cc1cncc(C(=O)Nc2cccc(C=O)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cncc(C(=O)Nc2cccc(CN3CCC(F)(C(=O)NC4CCCCC4)CC3)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of N-(3-formyl-phenyl)-5-methyl-nicotinamide L-1 (60 mg, 0.25 mmol) and 4-fluoro-piperidine-4-carboxylic acid cyclohexylamide hydrochloride (66 mg, 0.25 mmol) in DCM (3 mL) is treated with DIPEA (0.128 mL, 0.75 mmol). Sodium triacetoxyborohydride (132 mg, 0.62 mmol) is added at once and the mixture is stirred at RT for 18 h. The mixture is diluted with DCM (5 mL) and washed twice with aq. sat. NaHCO3 (5 mL). The organic phase is dried over MgSO4 and evaporated. The residue is dissolved in acetonitrile and purified by prep HPLC E, delivering the title compound as a colorless powder, LC-MS A: tR=0.62 min; [M+H]+=453.4. 1H-NMR (CDCl3): δ 1-1.4 (m, 5H), 1.6-1.8 (m, 6H), 1.9-2.1 (m, 2H), 2.2-2.4 (m, 4H), 3.45 (s, 3H), 2.7-2.8 (m, 2H), 3.7-3.8 (m, 1H), 6.28 (t, J=6.5, 1H), 7.15 (d, J=8, 1H), 7.35 (t, J=8, 1H), 7.55 (s, 1H), 7.73 (d, J=8, 1H), 8.05 (s, 1H), 8.12 (s, 1H), 8.61 (s, 1H), 8.93 (s, 1H).
Reaction SMILES: Br[C:2]1[N:21]=[C:5]2[C:6]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:7][CH:8]=[C:9]([C:10]([OH:13])([CH3:12])[CH3:11])[N:4]2[N:3]=1.[CH3:22][C:23]1[N:28]=[CH:27][N:26]=[C:25]([N:29]2[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]2)[CH:24]=1.[O-]C1C=CC=CC=1.[Na+].C(Cl)(Cl)Cl.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:35][CH:32]4[CH2:33][CH2:34][N:29]([C:25]5[CH:24]=[C:23]([CH3:22])[N:28]=[CH:27][N:26]=5)[CH2:30][CH2:31]4)[N:21]=3)[C:9]([C:10]([OH:13])([CH3:12])[CH3:11])=[CH:8][CH:7]=2)=[CH:15][CH:16]=1
Reactant: Cc1cc(N2CCC(N)CC2)ncn1
Reactant: CC(C)(O)c1ccc(-c2ccc(Cl)cc2)c2nc(Br)nn12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Cc1cc(N2CCC(Nc3nc4c(-c5ccc(Cl)cc5)ccc(C(C)(C)O)n4n3)CC2)ncn1
Temperature: 160 °C
Reaction time: 0.08 h

Procedure:
A solution of 2-[2-bromo-8-(4-chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-propan-2-ol (42 mg, 0.11 mmol), 1-(6-methyl-pyrimidin-4-yl)-piperidin-4-ylamine (18 mg, 0.1 mmol) and sodium phenoxide (17 mg, 0.15 mmol) in dry 1,4-dioxane (6 mL) in a sealed tube was purged with argon for 10 minutes. Pd2(dba)3.CHCl3 (8 mg, 0.012 mmol) and xanthphos (2 mg) were added to the solution and degassing continued for another 5 minutes before the reaction mixture was heated to 160° C. for 15 hours. The reaction mixture was cooled to room temperature and water (10 mL) was added. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using dichloromethane/methanol as eluent. The title compound was obtained as a white solid (7 mg, 13%). MS ESI (m/e): 478.0 [(M+H)+].
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][NH:12][C:13]([C:15]2[S:25][C:24]3[N:26]4[C:17](=[CH:18][N:19]=[C:20]4[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)=[O:14])[CH2:5][CH2:4]1.C(N(CC)CC)C.Br[CH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(O)C>[C:38]1([CH2:37][CH2:36][CH2:35][N:3]2[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][NH:12][C:13]([C:15]3[S:25][C:24]4[N:26]5[C:17](=[CH:18][N:19]=[C:20]5[CH:21]=[CH:22][CH:23]=4)[CH:16]=3)=[O:14])[CH2:5][CH2:4]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: BrCCCc1ccccc1
Reactant: O=C(NCCCC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NCCCC1CCN(CCCc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1

Procedure:
To a solution of 1.0 g (2.41 mM) of N-[3-(4-piperidyl)propan-1-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.7 ml (12.2 mM) of triethylamine in ethanol (10 ml) was added 0.45 ml (2.96 mM) of 1-bromo-3-phenylpropane at room temperature and the mixture was refluxed under nitrogen for 20 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over MgSO4, and purified by column chromatography (methanol/ethyl acetate 30-50-100%) to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1[CH3:30])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2Br)=[CH:12][CH:11]=1.[CH3:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=1[NH2:39].C(O[Na])(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1[CH3:30])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:39][C:33]3[CH:34]=[CH:35][C:36]([CH3:38])=[CH:37][C:32]=3[CH3:31])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(N)c(C)c1
Reactant: Cc1ccc(N(c2ccc(-c3ccccc3Br)cc2)c2ccc(C)cc2C)c(C)c1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Product: Cc1ccc(Nc2ccc(-c3ccc(N(c4ccc(C)cc4C)c4ccc(C)cc4C)cc3)cc2)c(C)c1
Temperature: 25 °C

Procedure:
Into a 1 liter three-necked reaction vessel fitted with a cooling tube and a mechanical stirrer, 91.3 g (0.2 mol) of bis(2,4-dimethylphenyl)[4-(bromophenyl)phenyl]amine, 36.3 g (0.3 mol) of 2,4-dimethylphenylamine, 2.24 g (0.01 mol) of palladium acetate, 11.1 g (0.02 mol) of bis(diphenylphosphino)ferrocene, 26.9 g (0.28 mol) of tert-butoxysodium and 500 mL of xylene were introduced to effect reflux for 3 hours in a nitrogen gas atmosphere and with heating in an oil bath. After the reaction was completed, the reaction mixture was left to cool to room temperature, followed by extraction with toluene/water, then washing with hydrochloric acid water, and thereafter distillation of the organic layer under reduced pressure and purification with a silica gel column (developer solvent: hexane/toluene=1:1) to give the desired bis(2,4-dimethylphenyl)(4-{4-[(2,4-dimethylphenyl)amino]phenyl}phenyl)amine. The compound obtained was in a yield of 83.4 g corresponding to 84%. The compound obtained was measured with the same elementary analyzer as the above.
Reaction SMILES: [CH:1]([C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:11]3[CH2:26][CH2:25][CH2:24][C:12]=3[N:13]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[C:21](O)=[O:22])[N:15]=2)[CH:5]=1)([CH3:3])[CH3:2].Cl.CN.[CH3:30][N:31](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH:1]([C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:11]3[CH2:26][CH2:25][CH2:24][C:12]=3[N:13]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[C:21]([NH:31][CH3:30])=[O:22])[N:15]=2)[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(Nc2nc(N3CCCC3C(=O)O)nc3c2CCC3)n[nH]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)C1CCCN1c1nc2c(c(Nc3cc(C(C)C)[nH]n3)n1)CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.4 %

Procedure:
To a solution of 1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylic acid (300 mg, 0.842 mmol) in DMF (5 mL) was added methylamine hydrochloride (284 mg, 4.207 mmol), HATU (320 mg, 0.842 mmol), diisopropylethylamine (163 mg, 1.263 mmol). The reaction mixture was stirred at RT for 16 h. The progress of reaction was monitored by LCMS. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×30 mL). The organic layer was washed with water (8×40 mL) and dried over anhydrous sodium sulfate. Removal of solvent under vacuum gave a crude product which was purified by reverse HPLC to obtain pure 1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide (20 mg) as racemate. The enantiomers were separated by chiral HPLC to afford (R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide (5 mg). 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 1.30 (d, 6H), 1.95-2.25 (m, 6H), 2.68 (s, 3H), 2.74 (t, 2H), 2.78 (t, 2H), 2.93-3.03 (m, 1H), 3.59 (brs, 1H), 3.80 (brs, 1H), 4.54 (d, 1H), 6.40 (brs, 1H). The other enantiomer was made using the chiral (R) starting material.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:4][CH2:3]1.C1C(=O)N([Br:24])C(=O)C1>CC#N.CO.C(OCC)(=O)C>[Br:24][C:13]1[CH:14]=[C:15]2[C:5]3([CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[C:8](=[O:16])[NH:9][C:10]2=[CH:11][CH:12]=1
Reactant: CN1CCC2(CC1)C(=O)Nc1ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CO
Product: CN1CCC2(CC1)C(=O)Nc1ccc(Br)cc12
Yield: 48.9 %

Procedure:
A solution of 1′-(methyl)spiro[indole-3,4′-piperidin]-2(1H)-one (6.3 g, 29.1 mmol) in CH3CN (100 ml) and MeOH (5 ml) was cooled to −5° C. and NBS (7.8 g, 44 mmol) was slowly added with stirring. The reaction mixture was stirred for 3.5 h at 0° C. Solvent was removed by vacuo. The residue was purified by silica gel chromatography (2-20% MeOH/CH2Cl2) to give 6 g as a solid. The solid compound was dissolved in ethyl acetate (600 ml) and washed with saturated aqueous NaHCO3 solution, dried (Na2SO4). Evaporation of the solvent in vacuo gave 4.2 g (47%) of 11. 1HNMR (CD3OD, 400 MHz) δ 7.51 (d, J=1.8 Hz, 1H), 7.35 (dd, J=1.9 and 8.2 Hz, 1H), 6.81 (d, J=8.2 Hz, 1H), 2.93 (m, 2H), 2.67 (m, 2H), 2.41 (s, 3H), 1.86 (m, 4H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][C:25]1[O:24][CH2:23][CH:22]([C:31]3[N:32]=[C:33]([NH2:36])[S:34][CH:35]=3)[CH2:21][C:20]2=1>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][C:25]1[O:24][CH2:23][CH:22]([C:31]3[N:32]=[C:33]([NH:36][C:12]([C:9]4[CH:10]=[CH:11][C:5]5[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)=[O:14])[S:34][CH:35]=3)[CH2:21][C:20]2=1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: COc1ccc2ncc3c(c2c1)CC(c1csc(N)n1)CO3
Product: COc1ccc2ncc3c(c2c1)CC(c1csc(NC(=O)c2ccc4c(c2)NC(=O)CS4)n1)CO3

Procedure:
The titled compound is prepared as a white lyophilizated powder following Scheme 1 and in analogy to Example 1 using 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid and 4-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-thiazol-2-ylamine as starting materials.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9](OCC)=[O:10])[CH:5]=[CH:4][CH:3]=1.[Li+].[BH4-].O.Cl>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1cccc(Cl)n1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
To a solution of ethyl (6-chloro-2-pyridinyl)acetate (Example 469, 5.00 g, 25 mmol) in THF (50 mL) was added LiBH4 (13.0 mL, 25.0 mmol, 2M solution in THF) at 0° C. The mixture was stirred at rt for 18 h, then water was slowly added [strong gaseous evolution] followed by HCl (10 mL, 1N aqueous solution). The mixture was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered and then concentrated under reduced pressure. The residue was purified using a short pad of silica gel (4:1 hexanes/EtOAc) to give the product (3.00 g, 76%) as a light-yellow oil which solidified upon standing. 1H NMR (400 MHz, CDCl3) δ 2.97 (t, 2H), 3.98 (t, 2H), 7.10 (dd, 2H), 7.54 (t, 1H).