Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([CH2:59][CH3:60])=[CH:55][CH:54]=2)=[CH:4][C:5]([C@@:9]2([CH2:48][CH2:49][CH2:50][OH:51])[C@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:11]([CH2:39][O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:10]2)=[C:6](O)[CH:7]=1.N1C=CC=CC=1.CS(OS(C)(=O)=O)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CN(C=O)C>[CH2:16]([O:15][C@@H:14]1[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@H:12]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C@@H:11]([CH2:39][O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:10][C@@:9]21[CH2:48][CH2:49][CH2:50][O:51][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([CH2:52][C:53]3[CH:58]=[CH:57][C:56]([CH2:59][CH3:60])=[CH:55][CH:54]=3)=[CH:4][C:5]2=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCc1ccc(Cc2cc([C@]3(CCCO)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)cc2Cl)cc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCc1ccc(Cc2cc3c(cc2Cl)OCCC[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
To a solution of 35 (115 mg, 0.139 mmol) and pyridine (100 μL) in DCM (1 mL) was added methanesulfonic anhydride (44 mg, 0.25 mmol, 1.8 equiv). The resulting mixture was stirred at ambient temperature for 1 hour. LC/MS analysis indicated complete conversion of 35 to mono mesic ester 36. The reaction mixture was partitioned between 10% sodium bicarbonate and DCM, after which the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to obtain a residue which was heated in DMF (3 mL) containing potassium carbonate (100 mg) at 90° C. for 0.5 hours. The resulting mixture was extracted with DCM, after which the organic layer was separated, dried (Na2SO4), filtered, and evaporated. Preparatory TLC of the residue eluting with 12% ethyl acetate in petroleum ether gave 37 (62 mg, 55% yield). 1H NMR (300 MHz, CDCl3) δ 7.54 (s, 1H), 7.16-7.28 (m, 21H), 7.08-7.11 (m, 2H), 6.98 (m, 4H), 6.97 (s, 1H), 4.81 (d, J=11.1 Hz, 1H), 4.77 (d, J=10.8 Hz, 1H), 4.73 (d, J=10.8 Hz, 1H), 4.47-4.60 (m, 3H), 4.35 (d, J=10.5 Hz, 1H), 4.16-4.24 (m, 1H), 3.70-4.02 (m, 11H), 2.60-2.71 (m, 1H), 2.54 (q, J=7.5 Hz, 2H), 2.02-2.13 (m, 1H), 1.81-1.93 (m, 2H), 1.16 (t, J=7.5 Hz, 3H). LC/MS m/z 832 (M+Na), 810 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)=[O:11])#[N:2].[CH2:24]([NH:26][CH3:27])[CH3:25].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][NH:9][C:10](=[O:11])[C:12]1[CH:13]=[CH:14][C:15]([C:16](=[O:18])[N:26]([CH3:27])[CH2:24][CH3:25])=[CH:19][CH:20]=1)#[N:2]
Reactant: CCNC
Reactant: N#Cc1cccc(OCCNC(=O)c2ccc(C(=O)O)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCN(C)C(=O)c1ccc(C(=O)NCCOc2cccc(C#N)c2)cc1

Procedure:
258 mg (0.83 mmol) of 4-[N-[2-(3-cyanophenoxy)ethyl]carbamoyl]benzoic acid, 53 mg (0.9 mmol) of N-ethyl-N-methylamine, 129 mg (0.83 mmol) of 1-hydroxybenzotriazole (hydrous, 87%) and 159 mg (0.83 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were stirred in 10 ml of dichloro ee at room temperature overnight. The resultant mixture was diluted with 1 N hydrochloric acid. After the extraction with dichloromethane, the organic layer was washed with 1 N aqueous sodium hydroxide solution and then with saturated aqueous NaCl solution and dried over anhydrous magnesium-sulfate. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([N:15]([CH2:17][C:18]1([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:16])[N:7]=[C:6]2[NH2:30].Cl[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>CN1CCCC1=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([N:15]([CH3:16])[CH2:17][C:18]1([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:20][N:21]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[CH2:22][CH2:23]1)[N:7]=[C:6]2[NH2:30]
Reactant: Clc1ccccn1
Reactant: COc1cc2nc(N(C)CC3(c4ccccc4)CCNCC3)nc(N)c2cc1OC
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc2nc(N(C)CC3(c4ccccc4)CCN(c4ccccn4)CC3)nc(N)c2cc1OC

Procedure:
A solution of 6,7-dimethoxy-N2-(4-phenyl-piperidin-4-ylmethyl)-N2-methyl-quinazoline-2,4-diamine 11 (250 mg) and 2-chloropyridine in N-methylpyrrolidone (5 m) was stirred at 130° C. under nitrogen for 48 hours. The cooled reaction mixture was diluted with water and extracted with chloroform. The extract was chromatographed on silica gel to yield 6,7-dimethoxy-N2-methyl-N2-(4-phenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylmethyl)-quinazoline-2,4-diamine 22, MS: 485 ([M+H]+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:10]([NH2:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21](=O)[CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(OCC)(=O)C.O.C(O)(=O)C>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[C@H:10]([NH:20][CH2:21][CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC=O
Reactant: NC1CN(Cc2ccccc2)CC1c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
A mixture of 38 g (141 mmol) rac-(3S,4R)-1-Benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-ylamine, 7.12 g (162 mmol) acetaldehyde, 12.1 mL acetic acid and 44.7 g (211 mmol) sodium triacetoxyborohydride in 400 mL THF was stirred for 3 h at 0° C. and then warmed to room temperature. Water, Na2CO3 aq. and ethyl acetate was added. The organic layer was washed with brine, dried with Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica eluting with a gradient formed from ethyl acetate, heptane and NEt3. The product containing fractions were evaporated to yield 18.5 g (44%) of the title compound as brown oil. MS m/e: 299.4 [M+H]+.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][C:9]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].Cl.[CH3:21]OC(OC)(C)C>CO.C(Cl)Cl>[CH3:21][O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:9]1[NH:10][C:11]2[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=2[N:8]=1
Reactant: Cn1c(=O)c2[nH]c(CCCC(=O)O)nc2n(C)c1=O
Reactant: COC(C)(C)OC
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCCc1nc2c([nH]1)c(=O)n(C)c(=O)n2C

Procedure:
10 g of theophylline-8-butyric acid are suspended in 50 ml of methanol. For one hour HCl-gas is fed into the suspension. While further feeding HCl-gas into the suspension, heating for one hour under reflux is effected. The feed of HCl-gas is interrupted, and 13.5 ml of 2,2-dimethoxypropane are added to the suspension. Afterwards, for a further 20 minutes HCl-gas is fed into the suspension. After standing over night at room temperature, the suspension is brought to dryness in vacuo. The residue is dissolved in 300 ml of methylenechloride. After having extracted the methylenechloride phase twice with 100 ml of saturated aqueous soda solution and twice with 100 ml of water, it is dried over annealed sodium sulfate and brought to dryness in vacuo. The residue is recrystallized from methanol. In this way 5.15 g (48.4 percent of the theoretically-calculated amount) of the title compound of melting point 200° to 204° C. are obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:13]([O:15][CH3:16])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=1)(=O)=O.[Li+].[Cl-].[CH2:21]([Sn](CCCC)(CCCC)C=C)[CH2:22]CC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:21]([C:7]1[C:8]([C:13]([O:15][CH3:16])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=1)=[CH2:22]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ncccc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1cccnc1C(=O)OC
Temperature: 100 °C

Procedure:
To a solution of methyl 3-(trifluoromethylsulfonyloxy)picolinate (i.e., Cap-174, step a) (570 mg, 2.0 mmol), an intermediate in the preparation of Cap-174, in DMF (20 mL) was added LiCl (254 mg, 6.0 mmol), tributyl(vinyl)stannane (761 mg, 2.4 mmol) and bis(triphenylphosphine)palladium dichloride (42 mg, 0.06 mmol). The mixture was heated at 100° C. for 4 h before the solvent was removed in vacuo. The residue was taken up in acetonitrile (50 mL) and hexanes (50 mL) and the resulting mixture was washed twice with hexanes. The acetonitrile layer was then separated, filtered through CELITE®, and evaporated. Purification of the residue by flash chromatography on a Horizon instrument (gradient elution with 25% ethyl acetate in hexanes to 65% ethyl acetate in hexanes) afforded methyl 3-vinylpicolinate (i.e., Cap-175, step a) (130 mg, 40%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ ppm 8.60 (1H, dd, J=4.6, 1.7 Hz), 7.94 (1H, d, J=7.7 Hz), 7.33-7.51 (2H, m), 5.72 (1H, d, J=17.2 Hz), 5.47 (1H, d, J=11.0 Hz), 3.99 (3H, s). Rt=1.29 min (Cond.-MD1); LC/MS: Anal. Calcd. for [M+H]+ C9H10NO2: 164.07. Found: 164.06.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=1.Cl[C:20]1N=C2C(N=CN2CC)=C(Cl)N=1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:20])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1ncn2C
Reactant: CCn1cnc2c(Cl)nc(Cl)nc21
Product: CCn1cnc2c(N3CCOC[C@@H]3C)nc(Cl)nc21

Procedure:
The compound (f-4) was prepared in an analogous fashion to (S)-4-(2-chloro-9-methyl-9H-purin-6-yl)-3-methylmorpholine, using 2,6-dichloro-9-ethyl-9H-purine as the starting material. 1H NMR (CDCl3, 400 MHz) δ ppm 7.71 (s, 1H), 5.41 (broad s, 1H), 5.00 (broad s, 1H), 4.19 (q, J=7.4 Hz, 2H), 4.00 (dd, J=7.8, 3.6 Hz, 1H), 3.76 (m, 2H), 3.61 (td, J=11.6, 2.6 Hz, 1H), 3.48 (broad s, 1H), 1.48 (t, J=7.2 Hz, 3H), 1.41 (d, J=6.8 Hz, 3H); LCMS m/z (method A)=284 [M+H]+, RT=2.06 min.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[N+:15]([O-])([O-:17])=[O:16].[NH4+].[OH-].[NH4+]>>[N+:15]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][CH2:1][NH2:9])=[CH:4][CH:5]=1)([O-:17])=[O:16]
Reactant: NCCc1ccccc1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: NCCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
24.2 g. (0.20 mol) Phenethylamine are carefully mixed in an ice-bath with 125 ml. concentrated sulphuric acid. After stirring for 1 hour, 16.8 g. (0.21 mol) ammonium nitrate in 125 ml. concentrated sulphuric acid are carefully added dropwise thereto at 0° to 5° C. After a further hour, the reaction mixture is poured on to 1.5 liters of ice and the pH adjusted to 9 with a concentrated aqueous solution of ammonium hydroxide. The aqueous phase is extracted several times with diethyl ether, the combined organic phases are dried over anhydrous magnesium sulphate, evaporated to dryness and the residue is distilled. There are obtained 14.5 g. (44% of theory) of a colourless oil; b.p. 110°-115° C./0.01 Torr. 1H-NMR (60 MHz, CDCl3, ppm): δ=2.99 (q, 2H, J=2.0 Hz, CH2); 3.05 (t, 2H, J=2.0 Hz, CH2).
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].C([O-])(O)=[O:16].[Na+]>O>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[O:16])=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: O=C([O-])O
Reactant: COc1ccc(C(Br)Br)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: COc1ccc(C=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 85 %

Procedure:
A mixture of 1-(dibromomethyl)-4-methoxy-2-nitrobenzene (42 g, 0.23 mol) and NaHCO3 (3 Eq) in water (400 mL) is refluxed for 22 h. The reaction mixture is cooled to room temperature and the product is extracted with EtOAc (2×150 mL). The organic layer is washed with a solution of 1.5N HCl (2×100 mL), water (2×100 mL) and brine then dried over Na2SO4. The solvent is removed under reduced pressure to afford 20 g (85%) of the title compound as a brown solid. 1H NMR (DMSO-d6, 400 MHz) δ 10.03 (s, 1H), 7.93-7.95 (m, 1H), 7.61 (s, 1H), 7.40-7.41 (m, 1H), 3.93 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:13]2[S:12][C:11](=[O:14])[NH:10][C:9]=2[C:8]([OH:15])=[CH:7][CH:6]=1)=[O:4].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O>[N:16]([CH2:2][C:3]([C:5]1[C:13]2[S:12][C:11](=[O:14])[NH:10][C:9]=2[C:8]([OH:15])=[CH:7][CH:6]=1)=[O:4])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CCl)c1ccc(O)c2[nH]c(=O)sc12
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(=O)c1ccc(O)c2[nH]c(=O)sc12
Reaction time: 0.17 h

Procedure:
7-(2-Chloro-acetyl)-4-hydroxy-3H-benzothiazol-2-one (example 1, step a) (331 g) was dissolved in N,N-dimethylformamide (1800 mL) and stirred in an ice bath for 10 minutes. Sodium azide (88.3 g) was added portionwise over 15 minutes. The reaction was stirred for 72 hours and then the reaction mixture was divided into 3 equal portions and each quenched separately into ice and water (2.5 L). The solid was filtered off and washed with water (1 L) and re-suspended in acetonitrile (1.5 L). The solvent was evaporated and a further portion of acetonitrile (1 L) added and solvent evaporated again to dry the product. Diethyl ether (1.5 L) was added and the mixture stirred to achieve an homogeneous suspension. The solid was collected and dried in vacuo at 35° C. for 24 hours to give the subtitled compound. Yield 285 g.
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].N1C=CN=C1.[CH3:17][Si:18](Cl)([CH3:20])[CH3:19].O>CN(C)C=O>[C:1]([C:3]1([O:11][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2]
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C#CC1(O[Si](C)(C)C)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.2 %

Procedure:
3-Ethynyl-3-hydroxyquinuclidine (1.5 g) and imidazole (1.7 g) were stirred in dimethyl formamide (25 ml). Trimethylsilylchloride (1.35 g) was added slowly to the solution and the mixture was stirred at ambient temperature for 20 hours. The reaction mixture was poured into water (150 ml) and the aqueous phase extracted with ethyl acetate (2×100 ml). The ethyl acetate extracts were combined, washed with water (2×100 ml), brine (100 ml), dried (MgSO4) and evaporated to give 3-ethynyl-3-trimethylsilyloxyquinuclidine as an oil (1.8 g), NMR: 0.15 (9H, s), 1.2-1.38 (1H, m), 1.42-1.6 (1H, m), 1.65-1.9 (3H, m), 2.55-2.7 (4H, m), 2.76 (1H, d), 3.02 (1H, d), 3.55 (1H, s), m/z 224 (M+H).
Reaction SMILES: O[C:2](C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:25]=[C:26]3[CH2:37][CH2:36][NH:35][CH2:34][C:27]3=[N:28][C:29]=2[NH:30][CH:31]([CH3:33])[CH3:32])[CH2:20][CH2:19]1)[C:12]#[N:13].C=O.CCN(C(C)C)C(C)C.[Na]>CO>[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:19][CH2:20][N:21]([C:24]2[N:25]=[C:26]3[CH2:37][CH2:36][N:35]([CH3:2])[CH2:34][C:27]3=[N:28][C:29]=2[NH:30][CH:31]([CH3:33])[CH3:32])[CH2:22][CH2:23]1)[C:12]#[N:13]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CCNC2
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: [Na]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CCN(C)C2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90 %

Procedure:
A solution of 3-fluoro-4-((1-(3-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)oxy)benzonitrile TFA salt (12.8 mg, 0.024 mmol) and formaldehyde (2.2 mg, 0.027 mmol) in MeOH (244 μL) at room temperature was treated with DIPEA (8.5 μL, 0.049 mmol) and sodium triacetoxyhydroborate (10.3 mg, 0.049 mmol). The reaction mixture was stirred for 45 min at room temperature. The crude reaction mixture was purified directly by HPLC Method B, with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column was used, using a 30% to 55% ACN gradient to give the title compound (about 90% purity), as a TFA salt, as a pale yellow solid. (6.0 mg, 46%). 1H NMR (400 MHz, methanol-d4) δ ppm 1.24 (d, J=6.6 Hz, 6H), 1.98 (m, 2H), 2.19 (m, 2H), 3.08 (m, 7H), 3.38 (m, 3H), 3.76 (br s, 1H), 4.16 (m, 1H), 4.29 (m, 2H), 4.79 (m, 1H), 7.34 (m, 1H), 7.53 (m, 2H); ESI-MS m/z [M+H]+ 425.5.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@@H:13]([NH:25][C:26]([C:28]1[S:29][C:30]([CH2:39][CH3:40])=[C:31]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=2)[CH:32]=1)=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22].NN>O1CCCC1.CO>[NH2:3][CH2:12][C@@H:13]([NH:25][C:26]([C:28]1[S:29][C:30]([CH2:39][CH3:40])=[C:31]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=2)[CH:32]=1)=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22]
Reactant: CCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: CCc1sc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)cc1-c1ccnn1C
Reaction time: 12 h
Yield: 57.1 %

Procedure:
To a solution of N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (486 mg, 0.86 mmol) in tetrahydrofuran (2.144 ml) and methanol (2.14 ml) at 25° C. was added hydrazine (0.269 ml, 8.58 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded and purified via column chromatography (silica, 5% MeOH in DCM (1% NH4OH)). The free base was then converted to the HCl salt by adding excess 4M HCl in dioxane (500 ul) to the residue in MeOH (2 ml) affording N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (250 mg, 0.491 mmol, 57.2% yield)-2HCl as a white solid: LCMS (ES) m/z=437 (M+H)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (d, J=8.84 Hz, 1H) 8.08 (br. s., 3H) 7.93 (s, 1H) 7.69 (d, J=7.83 Hz, 1H) 7.51-7.61 (m, 3H) 7.39-7.46 (m, 1H) 6.34 (d, J=2.02 Hz, 1H) 4.48 (br. s., 1H) 3.77 (s, 3H) 2.99-3.11 (m, 4H) 2.74 (q, J=7.49 Hz, 2H) 1.16 (t, J=7.45 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([C:25]5[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=5)=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccc(-c3cccnc3)cc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cc(-c3cccnc3)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-pyridin-3-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: CS[C:3]1[S:4][CH2:5][C:6](=[O:8])[N:7]=1.[CH2:9]([NH:12][CH3:13])[CH:10]=[CH2:11]>>[CH2:9]([N:12]([CH3:13])[C:3]1[S:4][CH2:5][C:6](=[O:8])[N:7]=1)[CH:10]=[CH2:11]
Reactant: C=CCNC
Reactant: CSC1=NC(=O)CS1
Product: C=CCN(C)C1=NC(=O)CS1

Procedure:
2-(Allyl-methyl-amino)-thiazol-4-one was prepared from 2-methylsulfanyl-thiazol-4-one and allyl-methyl-amine following General Procedure E.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[C:11]([O:15][C:16]([C:18]1[CH:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C=O)C>[C:11]([O:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)=[CH:20][N:19]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Nc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccc(N)cc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
A mixture of 4-aminophenol (2.6 g, 24 mmol) and NaH (1.1 g, 28 mmol) in dry DMF (50 ml) was stirred at RT for 30 min. 4-Chloro-pyridine-2-carboxylic acid t-butyl ester (5.0 g, 24 mmol) was added and the resulting mixture was stirred in a sealed tube at 80° C. for 12 h. The reaction mixture was concentrated in vacuo and was purified on silica gel to give 5-(4-amino-phenoxy)-pyridine-2-carboxylic acid t-butyl ester as a yellow solid (2.4 g, 35% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.48 (d, J=5.7 Hz, 1H), 7.33 (d, J=1.8 Hz, 1H), 7.03 (m, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 5.18 (s, 2H), 1.50 (s, 9H); MS (ESI) m/z: 287.2 (M+H+).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[OH:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:15][C:16]1[CH:17]=[C:18]([CH:28]([NH:30][C:31]([C:33]2[N:34]=[C:35](Cl)[O:36][CH:37]=2)=[O:32])[CH3:29])[CH:19]=[C:20]([F:27])[C:21]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24].C([O-])([O-])=O.[K+].[K+]>>[F:27][C:20]1[CH:19]=[C:18]([CH:28]([NH:30][C:31]([C:33]2[N:34]=[C:35]([O:14][C:8]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=3[CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[O:36][CH:37]=2)=[O:32])[CH3:29])[CH:17]=[C:16]([F:15])[C:21]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: Cc1ccc(C2CCCCC2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(C2CCCCC2)c(Oc2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)c1
Yield: 68.1 %

Procedure:
2-Cyclohexyl-5-methylphenol (28 mg, 0.15 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (40 mg, 0.11 mmol) was reacted using K2CO3 (50 mg, 0.36 mmol) as described above to give the title compound (40 mg, 71%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][NH2:22])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:23](OC)(=[O:28])[CH2:24][C:25]([CH3:27])=O>CCO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:21]4[C:23](=[O:28])[CH2:24][C:25]([CH3:27])=[N:22]4)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC(C)=O
Reactant: NNc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Solvent: CCO
Solvent: CC(=O)O
Product: CC1=NN(c2cc(-c3ccnc(Nc4cccc(Cl)c4)n3)ccn2)C(=O)C1
Yield: 92.4 %

Procedure:
A mixture of (3-Chloro-phenyl)-[4-(2-hydrazino-pyridin-4-yl)-pyrimidin-2-yl]-amine (3.14 g, 0.010 mol) and Methyl acetoacetate (1.28 g, 0.010 mol) in EtOH (30 ml) and Acetic acid (30 ml) is stirred at reflux for one hour. At room temperature the resulting precipitate is filtered with suction to yield the title compound,(3.50 g, 92%) m.p. 149–150° C.