Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)([O-])=O.[H][H]>[Ni].O1CCCC1>[C:18]1([CH2:17][N:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:5]3[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:12][CH2:13]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1NC1CCN(Cc2ccccc2)CC1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccccc1NC1CCN(Cc2ccccc2)CC1

Procedure:
A solution of 31 parts of N-(2-nitrophenyl)-1-(phenylmethyl)-4-piperidinamine in 160 parts of tetrahydrofuran is hydrogenated at normal pressure and at a temperature of 40° C, with 20 parts of Raney nickel catalyst. After the calculated amount of hydrogen is taken up (3 moles) hydrogenation is stopped. The catalyst is filtered off and from the filtrate the solvent is evaporated. The solid residue is washed with 160 parts of 2,2'-oxybispropane, to yield 22 parts of N-[1-(phenylmethyl)-4-piperidinyl]-1,2-benzenediamine; mp. 112°-113° C. On concentrating the filtrate to about one quarter of its volume a second crop of 2.5 parts of N-[1-(phenylmethyl)-4-piperidinyl]-1,2-benzenediamine is obtained; mp. 108°-109° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:38]3[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=3)[C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=3)[N:8]=2)[CH2:3]1.[ClH:45].[C:46]([Cl:54])(=[O:53])[C:47]1[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=1>C1COCC1.CN1C(=O)CCC1>[ClH:54].[ClH:45].[OH:44][C:41]1[CH:42]=[CH:43][C:38]([CH:30]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[CH2:29][NH:28][C:9]2[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:46](=[O:53])[C:47]4[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=4)[CH2:3]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@@H:16]2[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C@@H:18]([OH:26])[C@H:17]2[OH:27])=[CH:39][CH:40]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccc(O)cc4)c4ccc(O)cc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccc(O)cc4)c4ccc(O)cc4)nc(N4CC[C@@H](NC(=O)c5ccncc5)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture comprising N-((1S,2R,3S,4R)-4-{2-((R)-3-amino-pyrrolidin-1-yl)-6-[2,2-bis-(4-hydroxy-phenyl)-ethylamino]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide (Example 22 step 4) (20 mg, 33 μmol) in THF (0.5 ml) and NMP (0.5 ml) is treated with TEA (13 mg, 0.13 mmol) followed by isonicotinoyl chloride hydrochloride (16 mg, 83 μmol). After stirring at room temperature for 2 hours, the solvent is removed in vacuo and purification by C-18 reverse phase column chromatography eluting with acetonitrile:water:HCl (0.1%) (gradient of 0 to 100% acetonitrile) yields the title compound. (MH+ 708.4)
Reaction SMILES: C(Cl)(=O)C.[NH2:5][CH2:6][C:7]1[CH:35]=[CH:34][C:10]([CH2:11][NH:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([N:24]3[CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([F:33])[CH:30]=4)[CH2:25]3)=[O:23])=[CH:17][CH:16]=2)=[O:14])=[CH:9][CH:8]=1.NC1C=C2C(=CC=1)CN(C(N[C:49]1[CH:54]=[CH:53][C:52]([C:55](=[O:60])NCCC)=[CH:51][CH:50]=1)=O)C2>>[C:55]([NH:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][NH:12][C:13]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]([N:24]3[CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([F:33])[CH:30]=4)[CH2:25]3)=[O:23])=[CH:19][CH:20]=2)=[O:14])=[CH:34][CH:35]=1)(=[O:60])[C:52]1[CH:53]=[CH:54][CH:49]=[CH:50][CH:51]=1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Reactant: NCc1ccc(CNC(=O)c2ccc(NC(=O)N3Cc4ccc(F)cc4C3)cc2)cc1
Solvent: CC(=O)Cl
Product: O=C(NCc1ccc(CNC(=O)c2ccc(NC(=O)N3Cc4ccc(F)cc4C3)cc2)cc1)c1ccccc1

Procedure:
The title compound was prepared as described in Example 278, substituting benzoyl chloride for acetyl chloride and N-(4-{[4-(aminomethyl)benzyl]carbamoyl}phenyl)-5-fluoro-1,3-dihydro-2H-isoindole-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.01 (t, J=6.0 Hz, 1H), 8.83 (t, J=5.9 Hz, 1H), 8.60 (s, 1H), 7.85-7.91 (m, 2H), 7.78-7.83 (m, 2H), 7.63-7.68 (m, 2H), 7.36-7.56 (m, 4H), 7.27 (s, 4H), 7.21-7.26 (m, 1H), 7.10-7.19 (m, 1H), 4.72-4.81 (m, 4H), 4.40-4.48 (m, 4H); MS (ESI(+)) m/e 523 (M+H)+.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@H:10]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28](=[O:45])[CH2:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1)[CH3:26]>>[CH2:25]([O:27][C:28](=[O:45])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:20]2[CH:21]=[CH:22][C:17]([C:16]3[O:15][N:14]=[C:13]([CH3:24])[C:12]=3[C@H:10]([OH:11])[CH2:9][S:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:18][CH:19]=2)=[CH:32][CH:31]=1)[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1[C@H](O)CSCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3[C@H](O)CSCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using (S)-2-benzylsulfanyl-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanol and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:17])[C:13]([NH:15][NH2:16])=[O:14])[CH3:2].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:17])[C:13]([NH:15][N:16]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:14])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN=Cc1ccccc1
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a 100 mL volume three-necked flask with Dean-Stark, 9.38 g of 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetohydrazide ((12-1)-(11)-39), 32 ml of toluene and 4.51 g of benzaldehyde were added under a nitrogen atmosphere, and the mixture was subjected to azeotropic dehydration under 100 mmHg at 50° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give 12.51 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-(phenylmethylidene)hydrazine ((40-a)-(14)-6).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@@H:13]([CH2:15][F:16])[CH2:12][CH2:11][N:10]2C(OCC2C=CC=CC=2)=O)[CH:5]=[CH:6][C:7]=1[F:8].[H][H]>[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@@H:13]([CH2:15][F:16])[CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N1CC[C@H](CF)C[C@@H]1c1ccc(F)c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: FC[C@H]1CCN[C@@H](c2ccc(F)c(F)c2)C1
Yield: 74 %

Procedure:
A mixture of (±)-phenylmethyl (2R,4S)-2-(3,4-difluorophenyl)-4-(fluoromethyl)piperidine-1-carboxylate (85 mg, 0.23 mmol), 10% palladium on carbon (85 mg) and ethyl acetate (5 mL) in a 100 mL flask was stirred under 1 atmosphere of hydrogen at room temperature for three days. The mixture was filtered and the filtrate concentrated and dried to give (±)-(2R,4S)-2-(3,4-difluorophenyl)-4-(fluoromethyl)piperidine (39 mg, 73% yield), MS (EI) for C12H14F3N: 230 (MH+).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[N:18]([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:17]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)=[N:16][C:15]=2[N:14]([CH3:35])[C:13]1=[O:36])(C(C)(C)C)(C)C.Cl>C(O)C.O>[Cl:34][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=1)[O:27][C:17]1[N:18]([CH2:22][CH2:23][CH:24]([CH3:25])[CH3:26])[C:19]2[C:20](=[O:21])[N:12]([CH2:11][CH2:10][CH2:9][OH:8])[C:13](=[O:36])[N:14]([CH3:35])[C:15]=2[N:16]=1
Reactant: CC(C)CCn1c(Oc2cccc(Cl)c2)nc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)CCn1c(Oc2cccc(Cl)c2)nc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
Step 2 1-(3-((tert-Butyldimethylsilyl)oxy)propyl-8-(3-chlorophenoxy)-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione (0.55 g, 1.03 mmol) was dissolved in ethanol (10 mL) and 6N HCl (2 mL) was added and the reaction was stirred at room temperature for 1 h. The reaction was diluted with water (100 mL) and extracted with DCM (3×75 mL). The combined extracted were dried with magnesium sulfate, filtered and evaporated under reduced pressure to leave a golden oil. The oil was purified using a 24 g silica gel flash column eluted with 50% ethyl acetate/hexanes to give 8-(3-chlorophenoxy)-1-(3-hydroxypropyl)-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione (0.21 g, 49% yield) as a white solid. LCMS retention time=3.859 min and 98% purity, LCMS MH+=421. 1H NMR (CDCl3) δ 7.35-7.38 (m, 2H), 7.24-7.28 (m, 1H), 7.18-7.25 (m, 1H), 4.27 (t, 2H, J=8 Hz), 4.20 (t, 2H, J=8 Hz), 3.52-3.58 (m, 3H), 3.47 (s, 3H), 1.86-1.94 (m, 2H), 1.70-1.78 (m, 2H), 1.59-1.69 (m, 1H), 0.98 (d, 6H, J=8 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([CH3:14])([CH3:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[CH3:21]I.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:21])[C:10](=[O:12])[C:9]([CH3:13])([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)[C:6]=2[N:20]=1
Reactant: CI
Reactant: CC1(C)CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21

Procedure:
Reaction of 2-chloro-9-cyclopentyl-7,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one with MeI and NaH in DMF gave 2-chloro-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[N:2]=1.[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][N:16]=[C:17]=[S:18]>>[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][NH:16][C:17]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:3]1[N:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[S:18]
Reactant: NCCNCc1cccnn1
Reactant: CN(C)CCN=C=S
Product: CN(C)CCNC(=S)NCCNCc1cccnn1

Procedure:
Reacting N-(3-pyridazinylmethyl)ethylenediamine with 2-dimethylaminoethyl isothiocyanate by the procedure of Example 40 gives the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:11](=[O:13])[CH2:10][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:8][C:7]=2[NH:6][CH:5]=1.[CH3:20]I>CN(C)C=O>[CH3:20][N:6]1[C:7]2[CH2:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][C:11](=[O:13])[C:12]=2[C:4]([CH3:3])=[CH:5]1
Reactant: Cc1c[nH]c2c1C(=O)CC(c1ccccc1)C2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(C)c2c1C(=O)CC(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a suspension of 60% sodium hydride (0.085 g, washed with hexane thrice) in dimethylformamide (10 ml) was added 3-methyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.4 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added a solution of methyl iodide (0.28 g) in dimethylformamide (1 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to give colorless crystals of 1,3-dimethyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.37 g).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C1COCC1.CCCCCCC.[F:21][C:22]1[CH:23]=[CH:24][C:25]([O:30][CH3:31])=[C:26]([CH:29]=1)[CH:27]=[O:28].[CH3:32][N:33]([CH3:36])[CH:34]=[S:35]>C1COCC1>[F:21][C:22]1[CH:23]=[CH:24][C:25]([O:30][CH3:31])=[C:26]([CH:27]([OH:28])[C:34](=[S:35])[N:33]([CH3:36])[CH3:32])[CH:29]=1
Reactant: COc1ccc(F)cc1C=O
Reactant: CN(C)C=S
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(O)C(=S)N(C)C
Temperature: -78 °C
Yield: 28000.7 %

Procedure:
To a solution of lithium diisopropylamide, 2M in THF/n-heptane (210 mL, 583 mmol) was added THF (100 mL) and the solution cooled to −78° C. under nitrogen. This was then added dropwise over 1 h to a solution of the 5-fluoro-2-methoxybenzaldehyde (50 g, 0.32 mmol) and N,N-dimethylthioformamide (34.7 g, 389 mmol) in dry THF (200 mL). This was warmed to −5° C. and quenched with water (400 mL). The solution was filtered and washed with diethyl ether, the aqueous layer was extracted with ether (1 L). The combined organic layers were washed with water (500 mL), dried (MgSO4) and the solvent removed in vacuo to give a crystalline suspension in oil. This was triturated in ether and filtered to give a crystalline solid (21.8 g, 28%); δH (300 MHz, CDCl3) 7.16-6.81 (3H, m, ArH), 5.81-5.75 (1H, m, CHOH), 5.31-5.22 (1H, m, OH), 4.89 (3H, s, OCH3), 3.50 (3H, s, N(CH3)2) and 3.08 (3H, s, N(CH3)2).
Reaction SMILES: [N:1]1([C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=2[O:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Br[CH2:32][CH2:33][CH2:34][OH:35]>C(#N)C>[OH:35][CH2:34][CH2:33][CH2:32][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=2[O:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][CH2:5]1
Reactant: OCCCBr
Reactant: CCOC(=O)CCCOc1ccccc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CCCOc1ccccc1N1CCN(CCCO)CC1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a stirred solution of ethyl 4-(2-(piperazin-1-yl)phenoxy)butanoate 25 (0.48 g, 0.0016 mol) in 60 mL acetonitrile was added DIEA (0.56 mL, 0.0032 mol) followed by 3-bromo-1-propanol 26 (0.14 mL, 0.0016 mol) and the resulting mixture was stirred at 60° C. for 6 h. The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was concentrated and the residue was diluted with DCM (50 mL). The reaction mixture was washed with water (50 mL×2), dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography using 0-100% gradient of hexane and ethyl acetate to give the pure ethyl 4-(2-(4-(3-hydroxypropyl)piperazin-1-yl)phenoxy)butanoate 27. Brown oil, 0.39 g (63%). 1H NMR (400 MHz, CDCl3): δ 1.21 (t, J=7.2 Hz, 3H); 2.00 (quintet, J=7.2 Hz, 2H); 2.13 (quintet, J=7.2 Hz, 2H); 2.51 (t, J=7.2 Hz, 2H); 3.08 (broad s, 8H); 3.54 (t, J=6.4 Hz, 2H); 4.02 (t, J=6.4 Hz, 2H); 4.11 (q, J=7.2 Hz, 2H); 4.13-4.18 (m, 2H); 6.83-7.25 (m, 4H). MS (ESI): m/z=351.50 (M+H+).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH2:18][N:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20]2)=[C:5]([C:14]([O:16]C)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].O.CO.[OH-].[Na+:34]>O1CCCC1.O.CO>[Na+:34].[C:1]([C:3]1[C:4]([CH2:18][N:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20]2)=[C:5]([C:14]([O-:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: COC(=O)c1sc(N2CCOCC2)c(C#N)c1Cn1cnc2ccccc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: N#Cc1c(N2CCOCC2)sc(C(=O)[O-])c1Cn1cnc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.2 %

Procedure:
Methyl 4-cyano-5-(morpholin-4-yl)-3-[(4-oxoquinazolin-3(4H)-yl)methyl]thiophene-2-carboxylate (0.139 g, 0.339 mmol) was dissolved in Tetrahydrofuran (15.0 mL), Water (2.0 mL) and Methanol (5.0 mL). 1.00 M of Sodium hydroxide in Water (1.0 mL, 1.0 mmol) was added and the homogeneous solution was stirred at room temperature for 24 hours. The solution was concentrated in rotavapor to give a white crude solid, dissolved in H2O/MeOH (1/10, ˜20 mL) and concentrated in rotavapor until a white suspension (˜2 mL volume). The suspension was filtered to collect the solid, dried in lypholizer to give a white solid product (0.132 g, yield 92.2%). LC/MS: (FA) ES+ 397; ES− 395. 1H NMR (400 MHz, d4-methanol) δ 8.37 (s, 1H), 8.22 (d, J=8.03 Hz, 1H), 7.78-7.82 (m, 1H), 7.65 (d, J=7.28 Hz, 1H), 7.51-7.55 (m, 1H), 5.99 (s, 2H), 3.78-3.81 (m, 4H), 3.47-3.50 (m, 4H).
Reaction SMILES: C([O-])(O)=O.[Na+].Br[C:7]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][C:8]=1[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:34]3[C:35]4[CH:36]=[C:22]([C:23](=[O:38])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:37])[CH2:33]3)[CH:21]=[CH:20][C:19]=4[C:18]=2[CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:13][CH:12]=1.[Cl:51][C:52]1[CH:57]=[CH:56][C:55](B(O)O)=[CH:54][CH:53]=1>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([C:7]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][C:8]=2[CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:34]4[C:35]5[CH:36]=[C:22]([C:23](=[O:38])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:37])[CH2:33]4)[CH:21]=[CH:20][C:19]=5[C:18]=3[CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[CH:13][CH:12]=2)=[CH:54][CH:53]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COc1ccc(Br)c(COc2ccc(-c3c(C4CCCCC4)c4ccc5cc4n3CC(=O)NCCCCCCNC5=O)cc2)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2ccc(Cl)cc2)c(COc2ccc(-c3c(C4CCCCC4)c4ccc5cc4n3CC(=O)NCCCCCCNC5=O)cc2)c1
Temperature: 73 °C

Procedure:
A saturated solution of NaHCO3 (1 mL) was added to a solution of 9 (20 mg, 0.029 mmol), 4-chlorobenzeneboronic acid (11 mg, 0.068 mmol) and bis(triphenyl-phosphine)palladium (II) chloride (4 mg, 0.0063 mmol) in dimethoxyethane (DME; 6 mL). The resulting solution was heated at 73° C. for 8 h. Then, the reaction mixture was successively cooled down to room temperature, partitioned between water and ethyl acetate, dried (Na2SO4) and evaporated. Purification by column chromatography (CH2Cl2/methanol, 97:3) afforded the target product contaminated with impurities. The product was further purified by trituration in methanol, then filtered off to give the target product 10: m/z=704 (M+H)+. NMR (DMSO-d6): δ (ppm) 1.23-1.33 (m, 6H), 1.42-1.53 (m, 8H), 1.67-1.77 (m, 2H), 1.87-2.02 (m, 2H), 2.80 (m, 1H, CH cyclohexyl), 3.15 (m, 4H, 2×CH2NHCO), 3.83 (s, 3H, OCH3), 4.44 (s, 2H, CH2CONH), 5.00 (s, 2H, CH2O), 7.04-7.09 (m, 3H), 7.23 (d, J=2.6 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.40-7.47 (m, 7H), 7.76 (d, J=8.4 Hz, 1H), 7.93 (s, 1H), 8.30 (broad s, 1H, NH), 8.51 (broad s, 1H, NH).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([CH:26]=3)[CH2:14][CH2:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][C:17]=3[NH2:25].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[S:34]1[CH:38]=[N:37][N:36]=[C:35]1[N:39]1[CH2:44][CH2:43][CH:42]([CH2:45][C:46](O)=[O:47])[CH2:41][CH2:40]1>>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([CH:26]=3)[CH2:14][CH2:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][C:17]=3[NH:25][C:46](=[O:47])[CH2:45][CH:42]1[CH2:43][CH2:44][N:39]([C:35]2[S:34][CH:38]=[N:37][N:36]=2)[CH2:40][CH2:41]1
Reactant: O=C(O)CC1CCN(c2nncs2)CC1
Reactant: Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(c2nncs2)CC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 27 %

Procedure:
The desired compound was prepared according to the procedure of Example A169, step B using 6-chloro2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine dihydrochloride and [1-(1,3,4-thiadiazol-2-yl)piperidin-4-yl]acetic acid trifluoroacetate as starting materials in 27% yield. LCMS for C27H28ClN8OS (M+H)+: m/z=547.2.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](OCC)(=[O:20])[CH2:16][C:17]([CH3:19])=[O:18]>C(O)C>[C:15]([O:14][CH:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:20])[CH2:16][C:17]([CH3:19])=[O:18]
Reactant: CCOC(=O)CC(C)=O
Reactant: OC(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CC(=O)CC(=O)OC(c1ccccc1)c1ccccc1
Yield: 39.1 %

Procedure:
Benzhydrol (20 g, 0.1087 mole) and ethyl acetoacetate (13 g, 0.1 mole) were heated together to 170° and the ethanol so formed removed by distillation. Fractional distillation at 1.0 mm Hg yielded 10.5 g, 39% of benzhydryl acetoacetate as a colourless liquid which later solidified, melting point 44°-54°.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][C:10]1=[O:15].[O-]P([O-])([O-])=O.[K+].[K+].[K+].N[C@@H]1CCCC[C@H]1N>O1CCOCC1.[Cu]I>[N:9]1([CH:3]2[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]2)[CH2:14][CH2:13][O:12][CH2:11][C:10]1=[O:15]
Reactant: O=C1COCCN1
Reactant: Brc1ccncc1
Agent: [Cu]I
Agent: Cl
Agent: N[C@@H]1CCCC[C@H]1N
Solvent: C1COCCO1
Product: O=C1COCCN1C1CCNCC1
Temperature: 110 °C
Yield: 11.5 %

Procedure:
A mixture of 4-bromopyridine hydrochloride (778 mg, 4.00 mmol), 3-morpholinone (404 mg, 4.00 mmol), K3PO4 (1.70 g, 8.00 mmol) and 1,2-trans-diaminocyclohexane (200 uL, 1.60 mmol) in dioxane (10 mL) was degassed with Ar before being charged with CuI (152 mg, 0.80 mmol). The mixture in a sealed tube was heated at 110° C. overnight. The mixture was applied to a silica gel column, which was then eluted with 2-5% MeOH in CH2Cl2 to give the desired product (85 mg). MS 179.5 (M+H)
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:13])=[C:4]([C:8]([F:12])=[C:9]([F:11])[CH:10]=1)[C:5](O)=[O:6].B>C1COCC1>[NH2:1][C:2]1[C:3]([F:13])=[C:4]([CH2:5][OH:6])[C:8]([F:12])=[C:9]([F:11])[CH:10]=1
Reactant: Nc1cc(F)c(F)c(C(=O)O)c1F
Agent: B
Solvent: C1CCOC1
Product: Nc1cc(F)c(F)c(CO)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.3 %

Procedure:
A solution of 3-Amino-2,5,6-trifluoro benzoic acid (500 mg, 2.6 mmol) in THF (4 mL) was cooled to 0° C. (ice bath). Borane (2.5 eq., 1M in THF) was added dropwise over 20 min. The reaction was allowed to warm slowly to rt and stirred at rt for 18 h. The reaction was quenched by addition of saturated NH4Cl (aq) and extracted with EtOAc. The organic phase was washed with H2O then brine, dried (Na2SO4), filtered and concentrated in vacuo to give (3-amino-2,5,6-trifluorophenyl)methanol as a pale brown solid (425 mg, 92%)