Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](N)[CH:9]=2)[CH:4]=[N:3]1.N([O-])=[O:13].[Na+].O.C([O-])(O)=O.[Na+]>O.OS(O)(=O)=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:13])[CH:9]=2)[CH:4]=[N:3]1
Reactant: O=N[O-]
Reactant: Cn1ncc2ccc(N)cc21
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cn1ncc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-methyl-1H-indazol-6-amine (300 mg, 2.04 mmol) in H2O/H2SO4=1:1 (5 ml) was added NaNO2 (141 mg, 2.04 mmol) at 0° C. The mixture was then stirred for 2 h at 25° C. before being added to water (0.5 ml) and stirred for a further 2 h at 120° C. Once the reaction was complete by TLC, the mixture was treated with NaHCO3 until pH=7. The mixture was then extracted with ethyl acetate (2×10 ml) and the organic layer washed with brine (20 ml), dried over Na2SO4 and concentrated to give 1-methyl-1H-indazol-6-ol as a red solid which was used in the next step without further purification (300 mg, 99.0%). LCMS (m/z):149.1 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][NH:4][C:5]1[N:10]=[C:9](Cl)[CH:8]=[C:7]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:6]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][NH:4][C:5]1[N:10]=[C:9]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:8]=[C:7]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:6]=1
Reactant: C1CNCCN1
Reactant: CC(C)(C)CNc1nc(Cl)cc(N2CCCC2)n1
Product: CC(C)(C)CNc1nc(N2CCCC2)cc(N2CCNCC2)n1
Yield: 76 %

Procedure:
(2,2-Dimethylpropylamino)-4-chloro-6-pyrrolidinopyrimidine is reacted with piperazine as described in Example 5 to obtain the title compound in a yield of 76%, m.p.:118°-120° C.
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:11]([OH:15])(=[O:14])[CH2:12][CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:11]([O:15][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:14])[CH2:12][CH3:13]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CCC(=O)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)COC(=O)CC

Procedure:
A solution of 71 ml of ethyl 4-chloro-3-oxobutyrate in 165 ml of toluene is added to a boiling solution of 73 ml of propionic acid and 132 ml of triethylamine in 833 ml of toluene in the course of 30 minutes. The mixture is boiled under reflux for 90 minutes and then cooled, the triethylamine hydrochloride which has precipitated out is filtered off with suction and extracted twice with 300 ml of water each time and the solvent is distilled off in vacuo. The residue is subjected to fractional distillation under a high vacuum.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([C:19]([OH:22])([CH3:21])C)([CH3:18])[CH2:13]1.[CH2:23](OC(C1(CC)CCCN(CC2OC3C=CC=CC=3OC2)C1)=O)C.C[Mg]Br>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([C:19](=[O:22])[CH3:21])([CH2:18][CH3:23])[CH2:13]1
Reactant: CC(C)(O)C1(C)CCCN(CC2COc3ccccc3O2)C1
Reactant: CCOC(=O)C1(CC)CCCN(CC2COc3ccccc3O2)C1
Agent: C[Mg]Br
Product: CCC1(C(C)=O)CCCN(CC2COc3ccccc3O2)C1

Procedure:
The procedure described for 2-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]propan-2-ol was repeated except that 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidine-3-carboxylic acid ethyl ester was used as starting material and only one instead of three equivalents of methyl magnesium bromide was used.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.FC(F)(F)C([N:19]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:20]1[CH:35]=[CH:34][C:23]([C:24](ON2C(=O)CCC2=O)=[O:25])=[CH:22][CH:21]=1)=O.[OH-].[Na+]>O.C(O)C>[CH2:36]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4])=[O:25])=[CH:34][CH:35]=1)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]
Reactant: CCCCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)ON2C(=O)CCC2=O)cc1
Reactant: CC(C)(N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NC(C)(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a stirred solution of 103 mg. of 2-aminoisobutyric acid and 4.5 ml. of triethylamine in 1.5 ml. of water is added a solution of 550 mg. of N-[N-trifluoroacetyl-4-(hexadecylamino)benzoyloxy]succinimide in 4.5 ml. of ethanol. The mixture is stirred for 23 hours at room temperature, treated with 2 ml. of 2N sodium hydroxide solution, and then acidified. The mixture is diluted with water and then filtered. Recrystallization from ether-hexane affords the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[C:17]1[CH2:20][O:19][CH2:18]1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])C1C=CC=CC=1.C(OC(OC)=O)(OC)=O.[H][H]>C(OCC)(=O)C.C(Cl)Cl.[Pd]>[CH3:1][O:8][C:9]([NH:11][CH:12]([CH:17]1[CH2:20][O:19][CH2:18]1)[C:13]([O:15][CH3:16])=[O:14])=[O:10]
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)=C1COC1
Reactant: [H][H]
Agent: [Pd]
Agent: COC(=O)OC(=O)OC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)NC(C(=O)OC)C1COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114 %

Procedure:
A solution of methyl 2-(benzyloxycarbonylamino)-2-(oxetan-3-ylidene)acetate (intermediate LS28; Source: Moldes et al, Il Farmaco, 2001, 56, 609 and Wuitschik et al, Ang. Chem. Int. Ed. Engl, 2006, 45, 7736; 200 mg, 0.721 mmol) in ethyl acetate (7 mL) and CH2Cl2 (4.00 mL) was degassed by bubbling nitrogen for 10 min. Dimethyl dicarbonate (0.116 mL, 1.082 mmol) and Pd/C (20 mg, 0.019 mmol) were then added, the reaction mixture was fitted with a hydrogen balloon and allowed to stir at ambient temperature overnight. The reaction mixture was filtered through diatomaceous earth (Celite®) and concentrated. The residue was purified via Biotage (load with dichloromethane on 25 samplet; elute on 25S column with dichloromethane for 3CV then 0 to 5% methanol/dichloromethane over 250 mL then hold at 5% methanol/dichloromethane for 250 mL; 9 mL fractions). Fractions containing the desired product were concentrated to provide 167 mg methyl 2-(methoxycarbonylamino)-2-(oxetan-3-yl)acetate as a colorless oil which solidified on standing. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 3.29-3.40 (m, 1H) 3.70 (s, 3H) 3.74 (s, 3H) 4.55 (t, J=6.41 Hz, 1H) 4.58-4.68 (m, 2H) 4.67-4.78 (m, 2H) 5.31 (br s, 1H). MS: Anal. Calcd. for [M+H]+ C8H13NO5: 204.1; found 204.0. To methyl 2-(methoxycarbonylamino)-2-(oxetan-3-yl)acetate (50 mg, 0.246 mmol) in THF (2 mL) and Water (0.5 mL) was added lithium hydroxide monohydrate (10.33 mg, 0.246 mmol). The resultant solution was allowed to stir overnite at ambient temperature then concentrated to dryness to provide intermediate LS29 as a colorless powder. 1H NMR (500 MHz, CH3OD) δ ppm 3.38-3.50 (m, 1H) 3.67 (s, 3H) 4.28 (d, J=7.63 Hz, 1H) 4.57-4.79 (m, 4H).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:16]=[N:15][CH:14]=[C:13]([Cl:17])[N:12]=1.Cl.[F:19][C:20]1[CH:21]=[CH:22][C:23]([C@@H:26]([NH2:28])[CH3:27])=[N:24][CH:25]=1>CN1CCCC1=O>[Cl:17][C:13]1[N:12]=[C:11]([NH:28][C@H:26]([C:23]2[CH:22]=[CH:21][C:20]([F:19])=[CH:25][N:24]=2)[CH3:27])[CH:16]=[N:15][CH:14]=1
Reactant: Clc1cncc(Cl)n1
Reactant: C[C@H](N)c1ccc(F)cn1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1cncc(Cl)n1)c1ccc(F)cn1
Temperature: 180 °C
Yield: 58465.3 %

Procedure:
N,N′-Diisopropylethylamine (2.50 mL, 14.35 mmol) was added dropwise to a solution of 2,6-dichloropyrazine (525 mg, 3.52 mmol) and (S)-1-(5-fluoropyridin-2-yl)ethanamine hydrochloride (prepared as described in WO2006/123113, 750 mg, 3.52 mmol) in 1-methylpyrrolidin-2-one (4 mL) and the resulting mixture was stirred and heated for 6 hours at 180° C. in a microwave oven. After cooling to ambient temperature, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (7:3 hexanes/ethyl acetate) to give the title compound (520 g, 57%) as a brown oil.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5]NC(=N)N.N[C@H:14](C(O)=O)CCC(=O)O>>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH:4]([CH3:14])[CH3:5]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
Tyr 0.93 (1); Glu 1.22 (1); Arg 1.08 (1)
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][CH:20]=3)[CH:12]=2)[C@@H:9]([O:27]C(=O)C)[C@H:8]([CH2:31][O:32]C(=O)C)[C@@H:7]([O:36]C(=O)C)[C@@H:6]1[O:40]C(=O)C)(=O)C.[OH-].[Na+].Cl>CO>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:10]2[C@@H:9]([OH:27])[C@H:8]([CH2:31][OH:32])[C@@H:7]([OH:36])[C@H:6]([OH:40])[C@H:5]2[OH:4])=[CH:12][C:13]=1[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][CH:24]=1
Reactant: CCc1ccc(Cc2cc([C@H]3[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)[C@@H]3OC(C)=O)ccc2Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1ccc(Cc2cc([C@H]3[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)[C@@H]3O)ccc2Cl)cc1
Yield: 90 %

Procedure:
To a stirred solution of (1S,2R,3R,4S,5R,6R)-4-(acetoxymethyl)-6-(4-chloro-3-(4-ethylbenzyl)phenyl)cyclohexane-1,2,3,5-tetrayl tetraacetate (98 g, >99%, 0.158 mol, 1 eq) in methanol (1 L) was added sodium hydroxide (powder, 12.6 g, 0.315 mol, 2 eq) and the mixture was refluxed overnight. The mixture was acidified to pH 6 with 1 N hydrochloric acid and the volatiles were removed under reduced pressure. The residues were dissolved in ethyl acetate (3 L), washed with water (1 L), then with brine (1 L), dried over sodium sulfate, filtered and concentrated to give a white foam. The foam was recrystallized in refluxing ethanol/water (v/v=1:3, 20 mL/g (crude)) twice to give a white solid (58 g, purity of 99.3%, yield 90%).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[CH2:11]([C@@H:13]1[NH:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)[CH3:12]>>[NH2:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[N:18]1[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:14][C@@H:13]1[CH2:11][CH3:12]
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CC[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Product: CC[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1c(N)cnn1C

Procedure:
Following the procedure for Intermediate 10 starting from 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 and (S)-tert-butyl 3-ethylpiperazine-1-carboxylate gave (S)-tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-3-ethylpiperazine-1-carboxylate as an orange gum (110 mg, 65% over two steps). LCMS (ES+) m/z 310 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH3:10])([CH2:7]O)[C:3]([O:5][CH3:6])=[O:4].S(Cl)([Cl:13])=O.N1C=CC=CC=1>>[CH3:1][C:2]([CH2:9][CH3:10])([CH2:7][Cl:13])[C:3]([O:5][CH3:6])=[O:4]
Reactant: CCC(C)(CO)C(=O)OC
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCC(C)(CCl)C(=O)OC
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
The methyl 2-methyl-2-ethyl-3-hydroxypropionate was added at below 20° C. to 178.6 g (1.5 mol) of thionyl chloride, and the mixture was stirred at 50° C. for a further 30 min. Excess thionyl chloride was then distilled off at 100 mbar, 0.5 g (0.006 mol) of pyridine was added to the residue, and the mixture was heated at from 130° to 135° C. for 45 min. Fractional distillation gave 114.4 g of methyl 2-methyl-2-ethyl-3-chloropropionate having a boiling point of 101°-104° C./8 mbar, corresponding to a 93.2% yield, based on methyl 2-methyl-2-ethyl-3-hydroxypropionate. The overall yield was 69.5%, based on 2-methyl-2-ethyl-3-hydroxypropanal.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][C:8]([CH3:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:27]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:30]4[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=4)[C:26]#[N:27])[CH:14]=3)[O:9][C:8]([CH3:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(C)(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(C)(c3ccccc3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Yield: 35.6 %

Procedure:
Pd(PPh3)2Cl2 (14 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′,2-dimethyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (45 mg, 0.113 mmol) in 1,4-dioxane (2 mL), Cs2CO3 (2 N, 0.45 mL) and 4-cyanophenylboronic acid (33 mg, 0.226 mmol). The mixture was refluxed under Ar in a microwave reactor for 2 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative HPLC twice to give pure 3-(2′-amino-1′,2-dimethyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (17 mg, 36%). 1H-NMR (CDCl3): 1.78 (s, 3H), 1.97 (s, 3H), 2.60 (d, 1H), 2.85 (d, 1H), 6.84 & 6.93 (s, 1H), 7.23 (m, 2H), 7.31 (m, 4H), 7.48 (m, 2H), 7.52 (m, 2H), 7.62 (m, 1H), 7.67 (m, 1H), 11.51 (brs, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][N:19]([CH3:21])[C:18](=[O:22])[N:17]([CH3:23])[CH2:16]2)=[CH:11][C:10]=1Br.[C:25]1(B(O)O)[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1>>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][N:19]([CH3:21])[C:18](=[O:22])[N:17]([CH3:23])[CH2:16]2)=[CH:11][C:10]=1[C:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1
Reactant: CN1CC(c2ccc(N)c(Br)c2)CN(C)C1=O
Reactant: OB(O)C1=CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: CN1CC(c2ccc(N)c(C3=CCCCC3)c2)CN(C)C1=O
Yield: 38 %

Procedure:
5-(4-Amino-3-bromo-phenyl)-1,3-dimethyl-tetrahydro-pyrimidin-2-one trifluoroacetic acid salt (as prepared in the previous step, 92 mg, 0.30 mmol) was reacted with cyclohex-1-enyl boronic acid (48.7 mg, 0.375 mmol) according to the Suzuki coupling procedure of Example 4, step (e) and purified on silica (2% MeOH-EtOAc) to afford the title compound (35 mg, 38%): Mass spectrum (ESI, m/z): Calcd. for C18H25N3O, 300.2 (M+H). found 300.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([NH2:15])[N:3]=1.[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C@@H:18]([CH2:26][OH:27])[NH:17]1.C(N(CC)CC)C>CN1CCCC1=O.CO>[NH2:15][C:4]1[N:3]=[C:2]([N:17]2[C@H:18]([CH2:26][OH:27])[CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16]2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=1
Reactant: OC[C@@H]1Cc2ccccc2CN1
Reactant: CN1CCN(c2cc(Cl)nc(N)n2)CC1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: CO
Product: CN1CCN(c2cc(N3Cc4ccccc4C[C@H]3CO)nc(N)n2)CC1
Temperature: 120 °C

Procedure:
A mixture of 4-chloro-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (20 mg, 87.8 mmol), (3 S)-1,2,3,4-tetrahydroisoquinolin-3-ylmethanol (21.5 mg, 132 mmol, Aldrich, Cat. 494186) and triethylamine (0.5 mL, 4 mmol) in N-methylpyrrolidinone (1 mL) was heated at 120° C. overnight. The reaction mixture was diluted in MeOH, and purified by RP-HPLC (pH=10) to afford the desired compound. LCMS (M+H)+: m/z=355.3.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[S:19].[C:20]1([CH3:29])[CH:25]=[CH:24][CH:23]=[C:22]([N:26]=[C:27]=[O:28])[CH:21]=1>O1CCCC1>[CH3:29][C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3]2=[S:19])=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=S
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NC2N=C(c3ccccc3)c3ccccc3NC2=S)c1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
1,3-Dihydro-3-amino-5-phenyl-2H-1,4-benzodiazepin-2-thione (400 mg, 1.5 mmole) and m-tolylisocyanate (194 μL, 1.5 mmole) were combined in 40 mL of dry tetrahydrofuran at 0° C. The reaction mixture was warmed to room temperature over a 1 hour period and diluted with 20 mL of tetrahydrofuran. The reaction mixture was filtered and concentrated under reduced pressure. The residual material was chromatographed on silica gel (96:4:0.4 chloroform-methanol-concentrated ammonium hydroxide) to give 480 mg of the title compound analytically pure after trituration with ether/petroleum ether:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH2:17][CH2:18][CH3:19].[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[CH2:16]([O:15][C@H:3]1[C@@H:2]([NH:1][C:28]([C:23]2[NH:24][C:25]([CH2:26][CH3:27])=[C:21]([Cl:20])[N:22]=2)=[O:29])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4]1)[CH2:17][CH2:18][CH3:19]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 117.1 %

Procedure:
The same operation as in Example (106d) was performed using tert-butyl cis(±)-4-amino-3-butoxypiperidine-1-carboxylate obtained in Example (119d) (1.26 g, 4.6 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 1.03 g, 5 mmol), WSC hydrochloride (2.88 g, 15 mmol), HOBt (1.01 g, 7.5 mmol), DMA (15 mL) and dichloromethane (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 2.31 g of the title compound as a colorless solid (100%).
Reaction SMILES: [F:1][CH:2]([F:20])[C:3]1[N:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:19])=[CH:11][CH:10]=2)[C:5]([SH:8])=[N:6][N:7]=1.C([O-])([O-])=O.[K+].[K+].C[CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](=[O:41])(=[O:40])[NH2:39])=[CH:34][C:33]=1[CH3:42])=[O:30].O>CN(C=O)C>[F:20][CH:2]([F:1])[C:3]1[N:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:19])=[CH:11][CH:10]=2)[C:5]([S:8][CH2:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([S:38](=[O:41])(=[O:40])[NH2:39])=[CH:34][C:33]=2[CH3:42])=[O:30])=[N:6][N:7]=1
Reactant: CCC(=O)Nc1ccc(S(N)(=O)=O)cc1C
Reactant: Cc1ccc(-n2c(S)nnc2C(F)F)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(S(N)(=O)=O)ccc1NC(=O)CSc1nnc(C(F)F)n1-c1ccc(C)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
In a solution of 5-difluoromethyl-4-(4-methyl-naphthalen-1-yl)-4H-[1,2,4]triazole-3-thiol (53 mg, 0.18 mmol), K2CO3 (27.0 mg, 0.20 mmol) in DMF (1.5 mL) was added 2-methyl-N-(2-methyl-4-sulfamoyl-phenyl)-acetamide (47 mg, 0.18 mmol). The reaction mixture was stirred at room temperature for 16 h. Upon the completion of the reaction, H2O (4.0 mL) was added to the reaction and stirred until precipitation occurred and filtered off product (77.0 mg, 83% yield). 1H NMR (DMSO, 300 MHz) δ 9.84 (broad s, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.70-7.53 (m, 7H), 7.18 (t, J=51.5 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 4.26 (s, 2H), 2.82 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[C:26]([O:32]C)=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=2)[N:4]=1)[CH3:2].Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.O>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[C:26]([OH:32])=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2ccc(C)nc2OC)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1nn(Cc2ccc(C)nc2O)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 80 °C
Yield: 102.3 %

Procedure:
A mixture of N-(3-ethyl-1-((2-methoxy-6-methylpyridin-3-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (50 mg, 0.11 mmol) and HCl (2 mL, 4M in dioxane) was heated at 80° C. in a sealed vial for 4 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and water (5 mL). Saturated NaHCO3 aqueous solution was added to adjust pH=7. The solution was concentrated under reduced pressure to a solid residue. The residue was dissolved in DCM/MeOH and filtered to remove inorganic impurities. The solution was concentrated under reduced pressure to give the product (48 mg).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O.[OH-].[Na+]>CO>[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1/[CH:15]=[CH:2]/[C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(C(=O)O)s1
Reactant: O=Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(C(=O)/C=C/c2ccccc2Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
Commercially available 5-acetylthiophene-2-carboxylic acid (1.0 g, 5.9 mmol) and commercially available 2-chlorobenzaldehyde (670 uL, 5.9 mmol) were dissolved in 30 mL of methanol. The solution was cooled in an ice bath and solid sodium hydroxide (940 mg, 23.5 mmol) was added. The cold bath was removed and the reaction was stirred for 2 hours at room temperature. The reaction was then heated at 50° C. for another 2 hours. Concentrated HCl was added to lower the pH to 3. The reaction was filtered, washed with water and air dried to give 1.5 g of product. MS (EI) for C14H9ClO3S: 292 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20]O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:22][NH:23][CH3:24]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][N:23]([CH3:24])[CH3:22])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: OCCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: CN(C)CCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 19.1, 4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol and Dimethylamine were converted to yield {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-dimethyl-amine as light brown semisolid, MS: 385 (MH+, 1Br).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:21](B(CC)CC)[CH3:22]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCCC1>[CH2:21]([C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8])[CH3:22]
Reactant: COC(=O)CCc1ccc(O)c(Br)c1
Reactant: CCB(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCc1cc(CCC(=O)OC)ccc1O
Temperature: 65 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed methyl 3-(3-bromo-4-hydroxyphenyl)propanoate (220 mg, 0.85 mmol, 1.00 equiv), Pd(dppf)Cl2 (25.76 mg, 0.04 mmol, 0.04 equiv), Cs2CO3 (616.4 mg), tetrahydrofuran (5 mL), triethylborane (1.26 mL). The resulting solution was stirred overnight at 65° C. in an oil bath. The reaction was then quenched by the addition of 5 mL of water. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 20 mL of EA. The resulting mixture was washed with 3×10 mL of H2O. The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (10:90). This resulted in 300 mg (170%) of methyl 3-(3-ethyl-4-hydroxyphenyl)propanoate as colorless oil.