Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[C:6]([Si:8]([CH3:11])([CH3:10])[CH3:9])#[CH:7].[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15]>C1COCC1>[CH3:9][Si:8]([CH3:11])([CH3:10])[C:6]#[C:7][Sn:16]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: C#C[Si](C)(C)C
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Temperature: 0 °C
Reaction time: 18 h
Yield: 99.3 %

Procedure:
n-BuLi (1.6 M, 24.4 mL, 39 mmol) was added dropwise to a solution of ethynyltrimethylsilane (4.0 g, 41 mmol) in THF (40 mL) at −78° C. and gradually warmed to 0° C. over 30 min. The reaction mixture was cooled to −78° C. again and tributyltin chloride (11.4 mL, 39 mmol) in THF (30 mL) was added dropwise to the resultant mixture. The reaction mixture was stirred for 18 h at room temperature and quenched with water (20 mL). The mixture was extracted with diethyl ether (2×100 mL) and the combined organic extracts were washed with brine (50 mL). The organic phase was dried and concentrated to give yellow oil (15.0 g, 95%), which was used directly in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 1.67-1.45 (m, 6H), 1.45-1.20 (m, 6H), 0.98 (t, 6H, J=8.4 Hz), 0.90 (t, 9H, J=7.2 Hz), 0.16 (s, 9H).
Reaction SMILES: [CH2:1]=[CH:2][CH3:3].[O:4]=[O:5].C[C:7]1[C:12]2[CH2:13][O:14][C:15](=[O:16])[C:11]=2C(O[C@@H]2O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]2O)=C(C/C=C(/CCC(O)=O)\C)C=1OC>C(O)(=O)C.O>[C:15]([O:14][CH2:13][CH:12]=[CH2:7])(=[O:16])[CH3:11].[CH2:1]=[CH:2][CH3:3].[O:4]=[O:5]
Reactant: COc1c(C)c2c(c(O[C@@H]3O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]3O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Agent: O=O
Solvent: O
Solvent: CC(=O)O
Solvent: C=CC
Product: C=CCOC(C)=O

Procedure:
After uniformly diluting 10.5 ml of each of the catalysts A-F obtained in Examples 1-4 and Comparative Examples 1 and 2 with 31.5 ml of silica carrier, each one was packed into a reaction tube (SUS316 L, inner diameter: 25 mm). Gas with a gas composition of propylene:oxygen:acetic acid:water in a volume ratio of 29:6:7.1:19:38.9 was introduced at a space velocity of 2070 h−1 with a reaction temperature of 135° C. and a reaction pressure of 0.8 MPaG (gauge pressure), for reaction to obtain allyl acetate from propylene, oxygen and acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:18]([NH2:20])[CH3:19])[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[NH:24][CH:25]=[N:26]2.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:18]([NH:20][C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][NH:26]4)[CH3:19])[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1cc2ccc(F)cc2nc1-c1cccnc1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2ccc(F)cc2nc1-c1cccnc1

Procedure:
Prepared according to Procedure H using (1S)-1-(7-fluoro-2-(pyridin-3-yl)-quinolin-3-yl)ethanamine (0.067 g, 0.236 mmol), 6-chloropurine (0.044 g, 0.283 mmol, 1.2 eq) and DIEA (0.48 mmol, 2.0 eq) in n-butanol (3 mL). N—((S)-1-(7-fluoro-2-(pyridin-3-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine [PI3Kδ IC50=23 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.99 (s, 1 H), 8.57-8.65 (m, 2 H), 8.33 (d, J=7.83 Hz, 1 H), 8.16 (s, 1 H), 8.08 (s, 1 H), 7.85-7.96 (m, 2 H), 1.62 (d, 3 H), Mass Spectrum (ESI) m/e=402 (M+1).
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:20][F:21])([CH3:19])[C:4](=[O:18])[CH:5](Br)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][CH2:2][C:3]([CH2:20][F:21])([CH3:19])[C:4](=[O:18])[CH:5]([N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1
Reactant: CC(CF)(CF)C(=O)C(Br)Oc1cccc(C(F)(F)F)c1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(CF)(CF)C(=O)C(Oc1cccc(C(F)(F)F)c1)n1ccnc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 48.6 %

Procedure:
135 g (0.36 mole) of 3,3-bisfluoromethyl-1-bromo-1-(3-trifluoromethyl-phenoxy)-butan-2-one in 400 ml of acetone were added dropwise to 24.5 g (0.36 mole) of imidazole and 55.3 g (0.4 mole) of potassium carbonate in 400 ml of acetone. The mixture was stirred at 50° C. for 6 hours and was then concentrated by distilling off the solvent under a waterpump vacuum. The oily residue was taken up in 800 ml of methylene chloride, the mixture was washed twice with 2,000 ml of water each time, the organic phase was stirred with active charcoal, filtered and dried over sodium sulphate and the solvent was distilled off. The oily residue was distilled under a high vacuum. 63.4 g (48.8% of theory) of 3,3-bisfluoromethyl-1-(imidazol-1-yl)-1-(3-trifluoromethyl-phenoxy)-butan-2-one of boiling point 169°-73° C./0.1 mm Hg were obtained.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]([N:25]2[CH:29]=[N:28][N:27]=[C:26]2[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[Cl:20])[N:16]=[C:15]([O:21][CH3:22])[C:14]([O:23][CH3:24])=[N:13]2>ClC(Cl)(Cl)C>[Cl:9][C:10]1[C:11]([N:25]2[C:29]([Br:1])=[N:28][N:27]=[C:26]2[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[Cl:20])[N:16]=[C:15]([O:21][CH3:22])[C:14]([O:23][CH3:24])=[N:13]2
Reactant: COc1nc2cc(Cl)c(Cl)c(-n3cnnc3-c3cccnc3)c2nc1OC
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(Cl)(Cl)Cl
Product: COc1nc2cc(Cl)c(Cl)c(-n3c(Br)nnc3-c3cccnc3)c2nc1OC
Yield: 72.2 %

Procedure:
N-Bromosuccinimide (58 mg, 0.33 mmol) was added to a stirred suspension of 6,7-dichloro-2,3-dimethoxy-5-[3-(3-pyridyl)-4H-1,2,4-triazol-4-yl]quinoxaline (Preparation 98, 102 mg, 0.25 mmol) in 1,1,1-trichloroethane (6 mL) at room temperature under nitrogen and the mixture was heated under reflux for 18 hours. The mixture was concentrated under reduced pressure and the residue purified by flash chromatography on silica gel, by gradient elution using hexane:ethyl acetate (7:3 changing to 1:1, by volume) to give the title compound (87 mg, 71%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:35])([C:29]2[N:30]([CH3:34])[CH:31]=[N:32][CH:33]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH3:28])[CH:21]=2)=[CH:4][CH:3]=1.Br[CH2:37][CH:38]1[CH2:40][CH2:39]1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:35])([C:29]2[N:30]([CH3:34])[CH:31]=[N:32][CH:33]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH2:37][CH:38]2[CH2:40][CH2:39]2)[C:14](=[O:19])[CH:13]=[C:12]3[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH3:28])[CH:21]=2)=[CH:4][CH:3]=1
Reactant: BrCC1CC1
Reactant: CCOc1cccc(-c2cc(=O)[nH]c3ccc(C(O)(c4ccc(Cl)nc4)c4cncn4C)cc23)c1
Product: CCOc1cccc(-c2cc(=O)n(CC3CC3)c3ccc(C(O)(c4ccc(Cl)nc4)c4cncn4C)cc23)c1
Yield: 7.2 %

Procedure:
The same procedure described in example 8, 6-[(6-chloro-pyridin-3-yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethoxy-phenyl)-1H-quinolin-2-one (50 mg, 0.103 mmol) and (bromomethyl)cyclopropane (0.020 ml, 0.206 mmol) generated the title compound as a white solid (4 mg, 7% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH2:12][C:11](=[O:14])[N:10]([CH:15]([CH2:18][CH2:19][CH:20]=[O:21])[CH:16]=[O:17])[C@@H:9]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:9]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[N:10]([CH:15]([CH2:18][CH2:19][CH2:20][OH:21])[CH2:16][OH:17])[C:11](=[O:14])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCC(C=O)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1C(CO)CCCO
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)pentanedial (Example 107, Step A) (492 mg, 1.176 mmol) in MeOH (11 mL) was added sodium borohydride (89 mg, 2.352 mmol) at room temperature. Evolution of gas was observed. The reaction mixture was stirred at room temperature for 15 min and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 50 to 100% EtOAc in hexanes and then 10% MeOH in DCM) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[OH:21])[C:8]=2[Cl:13])[N:3]=1.Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[O:21][CH2:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)[C:8]=2[Cl:13])[N:3]=1
Reactant: ClCc1ccccn1
Reactant: Nc1nc(N)c2c(Cl)c(-c3cc(Cl)ccc3O)ccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(N)c2c(Cl)c(-c3cc(Cl)ccc3OCc3ccccn3)ccc2n1
Reaction time: 2 h
Yield: 72.8 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 0.5 gram (0.002 mole) of 2,4-diamino-5-chloro-6-(5-chloro-2-hydroxyphenyl)quinazoline, 0.3 gram (0.002 mole) of pyridin-2-ylmethyl chloride hydrochloride, and 0.5 gram (0.004 mole) of potassium carbonate in 5 mL of N,N-dimethylformamide was heated at 60° C. for about 24 hours. After this time, the reaction mixture was concentrated under reduced pressure to a residue. The residue was taken up in 100 mL of water and was stirred for about 2 hours. The resultant solid was collected by filtration, yielding 0.6 gram of 2,4-diamino-5-chloro-6-[5-chloro-2-(pyridin-2-ylmethoxy)phenyl]quinazoline. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[OH-:9].[Na+]>>[C:1]([NH2:2])(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: [OH-]
Reactant: N#Cc1ccncc1
Agent: [Na+]
Product: NC(=O)c1ccncc1

Procedure:
As to preparative methods for these compounds, cyanopyridines have frequently been hydrolyzed in batch and continuous processes with catalytic to stoichiometric excesses of a base. A majority of the methods reported have been batch processes. For example, 4-cyanopyridine in the presence of sodium hydroxide at a molar ratio of 1:(0.03-0.075) and at 120°-170° C. is reported to give isonicotinamide. See U.S.S.R. SU 1,553,531 (1990); CA:113:78174f (1990). Similarly, 2-cyanopyridine is reported to react with sodium hydroxide at a molar ratio of 1:(0.03-0.20) and at temperatures ranging from 100°-130° C. to give 2-picolinamide. See U.S.S.R. SU 1,553,530 (1990); CA:113:78173e (1990). With a molar ratio of 4-cyanopyridine:sodium hydroxide of 1:(1.5-1.75) and a hydrolysis temperature of 50°-80° C., the reported hydrolysis product was isonicotinic acid. See U.S.S.R. SU 1,288,183; CA:106:176187n (1987). The hydrolysis of 3-cyanopyridine with excess ammonia at 107°-109° C. for 12 hours was reported to give mixtures of nicotinamide and niacin. See J. Am Chem. Soc. 65, at pages 2256-7 (1943). In still another variation, the hydrolysis of 3-cyanopyridine has been reported with a polymeric base, Dowex 1X4 (in the hydroxide form), to yield nicotinamide. See Dutch Patent Application No. 7706612-A; CA:90:186814e. U.S. Pat. No. 4,314,064 describes the continuous hydrolysis of 3-cyanopyridine with 0.3 to 3.0 moles of an alkali metal hydroxide for each 100 moles of cyanopyridine at pressures of between 3 to 20 bars and with heating or cooling to maintain the prescribed reaction temperature. Similarly, 3-cyanopyridine is reported to react in a continuous process with aqueous ammonia at a molar ratio of 1:0.5 and a contact time of 40-50 minutes at 200°-260° C. to give nicotinamide. See Journal of Applied Chemistry of the USSR (English Translation: 45:2716-2718 (1972).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][CH:39]([CH2:42][NH:43]C(=O)OC(C)(C)C)[CH2:38][CH2:37]2)=[CH:4][N:3]=1.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>ClCCl>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][CH2:35][N:36]2[CH2:37][CH2:38][CH:39]([CH2:42][NH2:43])[CH2:40][CH2:41]2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(/C=C/CCN4CCC(CNC(=O)OC(C)(C)C)CC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COc1cc(-c2csc3c(/C=C/CCN4CCC(CN)CC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reaction time: 8 h
Yield: 30 %

Procedure:
Tert-butyl (1-{(3E)-4-[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)thieno[3,2-c]pyridin-7-yl]but-3-enyl}piperidin-4-yl)methylcarbamate (0.08 g, 0.112 mmol) was reacted according to General Procedure H. Dichloromethane and MP-carbonate resin were added and shaken overnight. The resin was filtered and the solvent evaporated under reduced pressure to give 0.02 g (29%) of the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 9.51 (s, 1H), 8.01–7.99 (d, 1H), 7.92 (s, 1H), 7.71–7.69 (d, 1H), 7.60–7.57 (m, 2H), 7.35–7.31 (m, 2H), 7.19 (m, 1H), 7.15 (m, 1H), 7.13–7.07 (m, 1H), 6.59–6.55 (d, 1H), 6.27–6.23 (m, 1H), 5.58 (brs, 2H), 4.04 (s, 3H), 3.91 (s, 3H), 2.94–2.91 (m, 3H), 2.44 (m, 6H), 1.92–1.87 (t, 2H), 1.69–1.66 (d, 1H), 1.23 (m, 1H), 1.16–1.11 (m, 2H); LCMS (conditions a) Rt 2.37 min (100%), M+ 595.4.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[C:18](Cl)(=O)/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[N+:15]([C:13]1[CH:12]=[CH:11][C:3]2[N:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=3)[C:18](/[CH:19]=[CH:20]/[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:1][C:2]=2[CH:14]=1)([O-:17])=[O:16]
Reactant: O=C(Cl)/C=C/c1ccccc1
Reactant: Nc1cc([N+](=O)[O-])ccc1Nc1ccccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: O=[N+]([O-])c1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1

Procedure:
The titled compound was prepared from 2-(2-amino-4-nitroanilino)pyridine (Runti, C. Ann. Chim. (Rome), 1956, 46, 406) and (E)-cinnamoyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). MW: 342.36; mp: 200.5-201.5° C.; 1H NMR (CDCl3) δ: 8.82 (1H, ddd, J=4.8, 1.8, 0.7 Hz), 8.72 (1H, d, J=2.2 Hz), 8.20 (1H, dd, J=8.8, 2.2 Hz), 8.81 (1H, d, J=16.0 Hz), 8.66 (1H, ddd, J=8.1, 7.7, 1.8 Hz), 7.58-7.47 (5H, m), 7.45-7.32 (3H, m), 7.07 d, J=16.0 Hz).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:11][CH:10]=[CH:9][CH2:8][N:7]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]2=[O:20])[CH2:3][CH2:2]1>CCO.[Pd]>[CH:1]1([CH2:4][N:5]2[CH2:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:12][C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[C:6]2=[O:20])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CN1CC=CCN(CC2CC2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1CCCCN(CC2CC2)C1=O
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl [3-(cyclopropylmethyl)-2-oxo-2,3,4,7-tetrahydro-1H-1,3-diazepin-1-yl]acetate (250 mg, 0.89 mmol) in EtOH (10 mL) was added 10% Pd/C (9.5 mg) and the reaction stirred vigorously under hydrogen (ca. 1 atm). After 90 min, the catalyst was filtered off and the filtrate was concentrated to yield the title compound as a pale brown solid. MS: m/z=283 (M+1).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[NH:40][C:41](=[O:43])[CH3:42])[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[NH:40][C:41](=[O:43])[CH3:42])=[O:9])[NH:23][C:24]=2[C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(-c2nc(Sc3ccccc3NC(C)=O)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccccc3NC(C)=O)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is dropped to a solution of 4.46 g of 4,5-bis(4-methoxyphenyl)-2-(2-acetoamidophenylthio)imidazole in 100 ml of dichloromethane. The mixture is stirred for 3 hours at room temperature, the solution washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane, thus obtaining 3.96 g of 4,5-bis(4-methoxyphenyl)-2-(2-acetamidophenylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1.C(OC([NH:30][C:31]1[S:35][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[F:42])=[N:33][C:32]=1[C:43](O)=[O:44])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:30][C:31]1[S:35][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[F:42])=[N:33][C:32]=1[C:43]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1)=[O:44]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1NCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3F)sc2N)c1NCC1CCNCC1
Yield: 10 %

Procedure:
Following the procedures as described in Example 113, tert-butyl 4-((4-amino-1-methyl-1H-pyrazol-5-ylamino)methyl)piperidine-1-carboxylate and 5-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)thiazole-4-carboxylic acid, and HATU were reacted to give 104 as a white solid (5.4 mg, 10%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.06 (s, 1H), 8.32 (dd, J=15.5, 6.0, 2H), 7.52-7.24 (m, 6H), 4.95 (t, J=6.7, 1H), 3.61 (s, 4H), 2.96 (t, J=22.0, 3H), 2.82 (t, J=6.5, 2H), 1.77 (d, J=12.5, 2H), 1.58 (s, 1H), 1.25-1.04 (m, 2H). ESIMS m/z=430.1 (M+1)
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[C:29]3[N:28]=[CH:27][N:26]=[C:24]([NH2:25])[C:23]=3[N:22]=[CH:21]2)[C@H:17]([OH:30])[C@@H:16]1O)([O:4]P(OP(O)(O)=O)(O)=O)(=[O:3])[OH:2].P(OC[C@H]1O[C@@H](N2C3N=C(N)NC(=O)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.P(O)(O)(O)=O.O=C(CN(C(=N)N)C)O.O=C(CN(C(=N)N)C)O.CC(CN1C(=O)N(C)C(=O)C2NC=NC1=2)C>C(O)C(N)(CO)CO>[CH:27]1[N:26]=[C:24]([NH2:25])[C:23]2[N:22]=[CH:21][N:20]([C@@H:18]3[O:19][C@@H:15]4[CH2:14][O:13][P:1]([OH:2])([O:3][C@H:16]4[C@H:17]3[OH:30])=[O:4])[C:29]=2[N:28]=1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: CC(C)Cn1c(=O)n(C)c(=O)c2[nH]cnc21
Agent: CN(CC(=O)O)C(=N)N
Agent: NC(CO)(CO)CO
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@@H]2COP(=O)(O)O[C@H]2[C@H]1O
Reaction time: 0.25 h

Procedure:
Membranes are incubated in 25 mM Tris (pH 7.6), 0.2% BSA, 2.6 mM Mg, 0.8 mM ATP, 0.1 mM GTP, 5 mM creatine phosphate, 50 U/ml creatine kinase, 0.2 mM IBMX at 32° C. Prospective ligands are added and incubation is continued for another 15 minutes. The amount of cAMP produced is assayed using an fluorescent immunoassay method.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][C:9]([N+:13]([O-])=O)=[CH:8][CH:7]=3)[CH2:3][CH2:2]1>CO.[Ni]>[CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][C:9]([NH2:13])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc2[nH]c(C3CC3)cc2c1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc2[nH]c(C3CC3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
To a solution of 2-cyclopropyl-5-nitro-1H-indole (1.3 g, 6.4 mmol) in MeOH (30 mL) was added Raney Nickel (0.3 g) under nitrogen atmosphere. The mixture was stirred under hydrogen atmosphere (1 atm) at room temperature overnight. The catalyst was filtered through a Celite pad and the filtrate was evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=5/1) to give 2-cyclopropyl-1H-indol-5-amine (510 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 6.89 (d, J=8.4 Hz, 1H), 6.50 (d, J=1.6 Hz, 1H), 6.33 (dd, J=2.0, 8.4 Hz, 1H), 5.76 (s, 1H), 4.33 (brs, 2H), 1.91-1.87 (m, 1H), 0.90-0.85 (m, 2H), 0.70-0.66 (m, 2H); MS (ESI) m/e (M+H+) 173.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH3:19])[C:9]1[CH:14]=[N:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[N:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ncc(NC(=O)OC(C)(C)C)cn1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ncc(N(C)C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.1 %

Procedure:
A solution of methyl 5-((tert-butoxycarbonyl)amino)pyrimidine-2-carboxylate (1.31 g, 5.16 mmol) in DMF (13 mL) was treated with cesium carbonate (2.19 g, 6.71 mmol) followed by iodomethane (0.64 mL, 10.32 mmol). The resulting suspension was stirred at ambient temperature for 5 h. The suspension was diluted with DCM (50 mL), filtered, concentrated, and purified by flash chromatography on silica gel eluting with a gradient of 0 to 40% EtOAc in DCM to give methyl 5-((tert-butoxycarbonyl)(methyl)amino)pyrimidine-2-carboxylate (1.16 g, 84% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.91 (s, 2H), 4.07 (s, 3H), 3.38 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[N:9]([CH2:10][C@H:11]2[CH2:16][N:15]([S:17]([C:20]3[S:21][C:22]([N+:25]([O-])=O)=[CH:23][CH:24]=3)(=[O:19])=[O:18])[CH2:14][CH2:13][N:12]2[C:28]2[N:33]=[CH:32][C:31]([C:34]([OH:43])([C:39]([F:42])([F:41])[F:40])[C:35]([F:38])([F:37])[F:36])=[CH:30][N:29]=2)[CH2:8][CH2:7][NH:6][C:5]1=[O:44])[CH3:3].C([O-])(O)=O.[Na+]>C(O)(=O)C.[Fe]>[NH2:25][C:22]1[S:21][C:20]([S:17]([N:15]2[CH2:14][CH2:13][N:12]([C:28]3[N:29]=[CH:30][C:31]([C:34]([OH:43])([C:35]([F:36])([F:38])[F:37])[C:39]([F:40])([F:41])[F:42])=[CH:32][N:33]=3)[C@@H:11]([CH2:10][N:9]3[CH2:8][CH2:7][NH:6][C:5](=[O:44])[CH:4]3[CH:2]([CH3:3])[CH3:1])[CH2:16]2)(=[O:18])=[O:19])=[CH:24][CH:23]=1
Reactant: CC(C)C1C(=O)NCCN1C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)C1C(=O)NCCN1C[C@H]1CN(S(=O)(=O)c2ccc(N)s2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
3-(1-methylethyl)-4-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-2-piperazinone (228 mg, 0.337 mmol) and iron filings (94 mg, 1.69 mmol, Sigma-Aldrich, St. Louis, Mo.) were combined in acetic acid (7.18 mL). The reaction mixture was stirred at 50° C. for 1.5 h. The mixture was allowed to cool to room temperature and saturated aqueous NaHCO3 was slowly added. After partitioning with EtOAc, the aqueous phase was extracted with EtOAc (×3). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give a light brown oil. The crude product was purified by silica gel chromatography (25 to 75% EtOAc in hexanes gradient) to give a mixture of diastereomers which were separated via preparative SFC (Chrialpak® ASH (21×250 mm, 5 μm)), eluting with liquid CO2 in 30% methanol with 20 mM NH3, at a flow rate of 65 mL/min (40° C.), to give two products in >95% diastereomeric excess and >98% purity: