Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:41])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:22]=[C:23]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=4)[C:24]4[N:29]=[CH:28][S:27][C:25]=4[N:26]=3)[CH:16]=2)=[CH:9][CH:8]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:40][O:39][C:33]1[CH:32]=[C:31]([NH:30][C:23]2[C:24]3[N:29]=[CH:28][S:27][C:25]=3[N:26]=[C:21]([C:17]3[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=3)[C:14]([NH:13][C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:42])=[O:5])=[CH:8][CH:9]=3)=[O:41])[N:22]=2)[CH:36]=[CH:35][C:34]=1[O:37][CH3:38]
Reactant: COc1ccc(Nc2nc(-c3cccc(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)c3)nc3scnc23)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Nc2nc(-c3cccc(C(=O)Nc4ccc(C(=O)O)cc4)c3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
tert-Butyl-4-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzamido)benzoate (45 mg, 0.077 mmol) in 10 mL of DCM was treated with TFA (2 mL) dropwise. The resulting yellow solution was stirred at ambient temperature overnight. The excess of solvent was removed under reduced pressure, the residue was triturated with n-hexane decanted, and dried to give 4-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzamido)benzoic acid (27 mg, 66.4%). 1H NMR (300 MHz, DMSO): δ 12.80 (brs, 1H), 10.76 (s, 1H), 10.19 (s, 1H), 9.41 (s, 1H), 8.96 (s, 1H), 8.62 (d, 1H, J=7.8 Hz), 8.09 (d, 1H, J=7.8 Hz), 7.97 (s, 4H), 7.84 (s, 1H), 7.71 (t, 1H, J=7.7 Hz), 7.54 (dd, 1H, J1=8.7 Hz, J2=2.1 Hz), 6.99 (d, 1H, J=8.7 Hz), 3.81 (s, 3H), 3.74 (s, 3H). LC-MS: 528 [M+H]+, tR=1.54 min. HPLC: 96.02% at 214 nm, 95.94% at 254 nm, tR=6.62 min.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:21]=[CH:22][CH:23]=1)[CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[NH:11][C:10]1=[O:20])=[O:4].[OH-].[Na+].O>CO>[C:3]([C:5]1[CH:6]=[C:7]([CH:21]=[CH:22][CH:23]=1)[CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[NH:11][C:10]1=[O:20])([OH:4])=[O:2]
Reactant: COC(=O)c1cccc(Cn2c(=O)[nH]c(=O)c3ccccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(Cn2c(=O)[nH]c(=O)c3ccccc32)c1
Yield: 77.9 %

Procedure:
1-(3-methoxycarbonylbenzyl)quinazoline-2,4(1H,3H)-dione (1.6 g, 5.2 mmol), NaOH (0.31 g, 7.7 mmol), water (40 mL) and methanol (40 mL) were added into a 250 mL three-mouth flask. The mixture was refluxed and reacted for 3 hours. The methanol was removed via evaporation under reduced pressure after the reaction was finished. The mixture was adjusted to pH=2-3 by 3N HCl, forming many precipitates. The mixture was filtered and the solid was washed by water and methonal. The solids were dried to give the title compound as white solid (1.2 g, 78% yield). 1H NMR (300 M, DMSO-d6): 13.09 (brs, 1H), 11.77 (s, 1H), 8.01 (dd, J=7.7 and 1.4 Hz, 1H), 7.84-7.80 (m, 2H), 7.66-7.61 (m, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.44 (t, J=7.7 Hz, 1H), 7.27-7.21 (m, 2H), 5.36 (s, 2H). MS: m/z 297.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[NH:12][C:13](=O)[C:8]=2[C:7]([CH3:22])=[N:6]1)[CH2:2][CH2:3][CH3:4].C(Cl)(Cl)[Cl:24]>P(Cl)(Cl)(Cl)=O>[CH2:1]([N:5]1[C:9]2=[N:10][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])=[N:12][C:13]([Cl:24])=[C:8]2[C:7]([CH3:22])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nc(C)c2c(=O)[nH]c(-c3ccccc3F)nc21
Reactant: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCn1nc(C)c2c(Cl)nc(-c3ccccc3F)nc21
Temperature: 0 °C
Yield: 55 %

Procedure:
1-Butyl-6-(2-fluoro-phenyl)-3-methyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (1.23 g, 4.1 mmole) was dissolved in phosphorous oxychloride (15 ml) and heated to reflux overnight. Removed excess phosphorous oxychloride under vacuum, treated residue with ice water, extracted product into ethyl acetate, washed with water, sat'd sodium chloride, dried over sodium sulfate (anh.) and removed solvent to give crude product. Chromatographed product on silica gel eluting with chloroform to give 723 mg purified product (yield: 55%).
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[Cl:22].[Cl:23][C:24]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=[CH:26][C:25]=1[N:39]1[C:48](=[O:49])[C:47]2[C:42](=[C:43]([F:50])[CH:44]=[CH:45][CH:46]=2)[N:41]([CH3:51])[C:40]1=[O:52].CCO.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Cl:22][C:3]1[CH:4]=[C:5]([C:19]([NH2:21])=[O:20])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([N:39]2[C:48](=[O:49])[C:47]4[C:42](=[C:43]([F:50])[CH:44]=[CH:45][CH:46]=4)[N:41]([CH3:51])[C:40]2=[O:52])[C:24]=1[Cl:23])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3
Reactant: Cn1c(=O)n(-c2cccc(B3OC(C)(C)C(C)(C)O3)c2Cl)c(=O)c2cccc(F)c21
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cn1c(=O)n(-c2cccc(-c3c(Cl)cc(C(N)=O)c4[nH]c5cc(C(C)(C)O)ccc5c34)c2Cl)c(=O)c2cccc(F)c21
Temperature: 90 °C
Yield: 12.5 %

Procedure:
A mixture of 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 3] (30 mg, 0.079 mmol), 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dione [Intermediate 41] (40.6 mg, 0.094 mmol), EtOH (1 mL), toluene (1 mL) and 2 M aqueous Na2CO3 (0.13 mL, 0.26 mmol) was bubbled with nitrogen for 5 min. The mixture was treated with tetrakis(triphenylphosphine)palladium (7.3 mg, 6.29 μmol), and the reaction vessel was sealed and heated at 90° C. for 16 h. The cooled mixture was partitioned between EtOAc and water, and the organic phase was dried and concentrated. The residue was purified by column chromatography on silica gel (12 g), eluting with MeOH-DCM containing 1% TEA (gradient from 0-5%). The resulting material was further purified using preparative HPLC (PHENOMENEX® Axia C18 30×100 mm), eluting with MeCN-water containing 0.1% TFA (gradient from 20-100%, 10 min, 30 mL/min) The appropriate fractions were treated with saturated aqueous NaHCO3 and concentrated. The residue was partitioned between EtOAc and water, and the organic phase was washed with brine, dried and concentrated to provide 3-chloro-4-(2-chloro-3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) as a white solid (6 mg, 11% yield). Mass spectrum m/z 587 (M+H—H2O)+. 1H NMR (400 MHz, chloroform-d) δ 10.46 (s, 1H), 7.74 (s, 1H), 7.68 (s, 1H), 7.66-7.61 (m, 1H), 7.59-7.54 (m, 1H), 7.51-7.46 (m, 2H), 7.27-7.17 (m, 2H), 7.06-6.88 (m, 1H), 3.88 (dd, J=11.6, 8.0 Hz, 3H), 1.64 (s, 6H). 19F NMR (400 MHz, chloroform-d) δ −121.34.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29]>CN1CCCC1=O.O>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NC(CO)CO
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(CO)CO)c2c1
Temperature: 160 °C
Reaction time: 16 h
Yield: 15 %

Procedure:
A solution of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (200.0 mg, 0.54 mmol, prepared in analogy to the one in Example 2-1) and 2-aminopropane-1,3-diol (420.0 mg, 4.6 mmol) in 1-methyl-2-pyrrolidinone (1.0 mL) was stirred at 160° C. for 16 hours. After being cooled to room temperature and diluted with water (50 mL), the resulting mixture was extracted with ethyl acetate (100 mL), washed with brine (50 mL×2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford 34.6 mg of the product as a white solid (yield was 15%). MS obsd. (ESI+) [(M+H)+] 428, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (dd, J=7.83, 1.01 Hz, 1 H), 7.86 (d, J=7.07 Hz, 1 H), 7.71-7.58 (m, 2 H), 7.51-7.40 (m, 2 H), 7.36-7.24 (m, 1 H), 6.16 (s, 1 H), 5.16 (s, 2 H), 4.79-4.59 (m, 1 H), 4.54 (brs, 1 H), 3.81 (s, 5 H), 3.69-3.50 (m, 2 H), 2.42 (s, 3 H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][O:7][C@@H:8]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[F:29])[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1)(=[O:3])[CH3:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:28][C:24]1[C:23]([F:29])=[C:22]([C@@H:8]([C@@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[O:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)NCCO[C@@H](c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCCO[C@@H](c1cccc(Cl)c1F)[C@@H]1CCCNC1
Temperature: 25 °C
Yield: 10.2 %

Procedure:
(R)-tert-butyl 3-((R)-(2-acetamidoethoxy)(3-chloro-2-fluorophenyl)methyl)piperidine-1-carboxylate (95 mg, 1.88 mmol) was dissolved in 20% v/v TFA/CH2Cl2 (8 mL) at 0° C., the mixture was allowed to warm to rt for 1 h and then concentrated in vacuo to give N-(2-((R)-(3-chloro-2-fluorophenyl)((R)piperidin-3-yl)methoxy)ethyl)acetamide (63 mg, 87%), which was used without further purification. MS (E/Z): 329 (M+)
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1.O>CC(C)=O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:13][S:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][CH2:2][CH2:3]3)(=[O:11])=[O:12])=[O:25])=[CH:19][CH:18]=1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCC2
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1ccc2c(c1)CCC2
Yield: 87.4 %

Procedure:
To a mixture of 93.2 g of indane-5-sulfonamide in 300 ml of acetone were added 490 ml of 1 N sodium hydroxide. A solution of 79.36 g of 4-chlorophenylisocyanate in 250 ml of acetone was added to the reaction mixture with stirring. After stirring at room temperature for about 18 hours, the reaction mixture was filtered and 490 ml of 1 N hydrochloric acid were added to the filtrate, thereby providing a fine white precipitate. One liter of water was added, and the solid was recovered by filtration to provide 144.86 g of the desired title product. m.p. 169-172° C.
Reaction SMILES: C(O[CH:5]([C:28]1[CH:29]=[CH:30][C:31]2[N:35]=[C:34]3[S:36][CH2:37][CH2:38][CH2:39][N:33]3[C:32]=2[CH:40]=1)[C:6]1(Br)[C:12](=[O:13])[N:11]2[C@@H:7]1[S:8][CH:9]=[C:10]2[C:14]([O:16]CC1C=CC([N+]([O-])=O)=CC=1)=[O:15])(=O)C.[H][H]>C1COCC1.P([O-])([O-])([O-])=O>[S:36]1[C:34]2=[N:35][C:31]3[CH:30]=[CH:29][C:28](/[CH:5]=[C:6]4\[C@@H:7]5[N:11]([C:12]\4=[O:13])[C:10]([C:14]([OH:16])=[O:15])=[CH:9][S:8]5)=[CH:40][C:32]=3[N:33]2[CH2:39][CH2:38][CH2:37]1
Reactant: [H][H]
Reactant: CC(=O)OC(c1ccc2nc3n(c2c1)CCCS3)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: O=C(O)C1=CS[C@@H]2/C(=C\c3ccc4nc5n(c4c3)CCCS5)C(=O)N12
Yield: 18.4 %

Procedure:
4-nitrobenzyl (5R)-6-[(acetyloxy)(3,4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazol-7-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (700 mg, 1.1 mmol) was suspended in 20 ml THF and 20 ml pH=6.5 aqueous phosphate buffer. The mixture was then subjected to 45 psi hydrogen for two hours. Then it was filtered through a pad of celite and concentrated in vacuo to remove most of the THF. The solution was then cooled to zero degree and basified to pH=8 with 1 N sodium hydroxide. Then it was purified via reverse phase HPLC using 1 liter of water followed by 5%-25% acetonitrile and water. Water was then removed through concentrate in vacuo and 75 mg of product (Yield 18%) was collected. MP: >250° C.; H-NMR(D2O): δ 7.08(m, 6H), 3.70(m, 2H), 4.05(m, 2H), 3.13(m, 2H), 2.22(m, 2H); MS: 372.1(M+H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10]NC=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[Se].[CH2:34]([N:41]=[C:42]=[Se:43])[C:35]1C=CC=CC=1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:35][CH2:34][N:41]=[C:42]=[Se:43])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CNCCCCc1ccccc1
Reactant: [Se]=C=NCc1ccccc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Se]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [Se]=C=NCCCCCCc1ccccc1
Yield: 95 %

Procedure:
A mixture of phenylbutyl formamide (g, 1.5 mmol), triethylamine (6.4 mmol), 4 Å molecular sieves (g), triphosgene (0.8 mmol), and selenium powder (3.0 mmol) in CH2Cl2 was refluxed and worked up as mentioned for 2a. The crude residue thus obtained was purified by silica gel column chromatography (EtOAc/hexanes 2:98) to give 0.96 g (95%) of 2d as an oil. 1H NMR (CDCl3) δ 1.37-1.43 (m, 2H), 1.45-1.51 (m, 2H), 1.67 (dt, 2H, J=15.2 and 7.6 Hz), 1.75 (dt, 2H, J=14.9 and 6.7 Hz), 2.64 (t, 2H, J=7.6 Hz), 3.60 (t, 21-1, J=6.7 Hz), 7.19-7.25 (m, 3H), 7.32-7.40 (m, 2H); HRMS (EI) calcd for C13H17NSe, 267.0521. found, 267.0529.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([N:10]([CH3:20])[C:11]1([C:18]#[N:19])[CH2:14][N:13]([C:15]([O-:17])=[O:16])[CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.OO>C(O)C>[NH2:19][C:18]([C:11]1([N:10]([CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:20])[CH2:14][N:13]([C:15]([O:17][C:4]([CH3:9])([CH3:5])[CH3:3])=[O:16])[CH2:12]1)=[O:1]
Reactant: CN(Cc1ccccc1)C1(C#N)CN(C(=O)[O-])C1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: CN(Cc1ccccc1)C1(C(N)=O)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 165.3 %

Procedure:
A 1M solution of sodium hydroxide (12.5 ml, 12.5 mmol) at 0° C. was added dropwise to a solution of 3-[benzyl(methyl)amino]-3-cyanoazetidine-1-carboxylate (800 mg, 2.66 mmol) in ethanol (25 ml). Hydrogen peroxide 30% wt (1 ml) was then added and the reaction mixture was allowed to stir at room temperature overnight. After removal of solvent under reduced pressure, the remaining aqueous layer was extracted with ethyl acetate (×2) and the combined organic layers washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl 3-(aminocarbonyl)-3-[benzyl(methyl)amino]azetidine-1-carboxylate (702 mg, 87%) as a white solid, used without any further purification in the next step; 1H NMR Spectrum: (CDCl3) 1.45 (s, 9H), 2.27 (s, 3H), 3.61 (s, 2H), 4.07 (d, 2H), 4.22 (brd, 2H), 5.51 (brs, 1H), 6.70 (brs, 1H), 7.26-7.36 (m, 5H); Mass Spectrum: (M+H)+ 320.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C@@H:25]([C:39]([OH:41])=O)[CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=3)=[O:23])[CH2:18][CH2:17]2)[CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[NH:10]1.[CH3:46][N:47]1[CH2:52][CH2:51][CH:50]([N:53]2[CH2:58][CH2:57][NH:56][C@H:55]([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:54]2)[CH2:49][CH2:48]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[NH2:37][C:30]1[C:31]([C:33]([F:36])([F:35])[F:34])=[CH:32][C:27]([CH2:26][C@@H:25]([O:24][C:22]([N:19]2[CH2:20][CH2:21][CH:16]([N:15]3[CH2:14][CH2:13][C:12]4[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=4[NH:10][C:9]3=[O:8])[CH2:17][CH2:18]2)=[O:23])[C:39]([N:56]2[CH2:57][CH2:58][N:53]([CH:50]3[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]3)[CH2:54][C@H:55]2[C:59]([O:61][CH2:62][CH3:63])=[O:60])=[O:41])=[CH:28][C:29]=1[Cl:38]
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Reactant: CCOC(=O)[C@@H]1CN(C2CCN(C)CC2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CN(C2CCN(C)CC2)CCN1C(=O)[C@@H](Cc1cc(Cl)c(N)c(C(F)(F)F)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.30 mL (2.16 mmol) triethylamine were added to a mixture of 700 mg (1.26 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1f), 430 mg (1.41 mmol) ethyl(S)-4-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylate (Example A11b) and 450 mg (1.40 mmol) TBTU in 7 mL DMF and the reaction mixture was stirred for 18 h at RT. It was evaporated down i. vac., the residue was stirred with saturated NaHCO3 solution, extracted exhaustively with EtOAc and the combined organic phases were dried over Na2SO4. After elimination of the desiccant and solvent the residue was purified by HPLC; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][CH:3]=1.O.[NH2:13][NH2:14].O>C(O)C>[I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:13][NH2:14])=[O:7])=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC(=O)c1ccc(I)cc1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(I)cc1
Temperature: 25 °C

Procedure:
To Methyl 4-iodobenzoate (30.0 g, 114 mmol) in ethanol (180.0 ml) was added hydrazine hydrate (30.0 g, 599 mmol). The reaction mixture was reflux for 22.5 hours. Heating was stopped and then water (300.0 ml) was added. After cooling down to room temperature, white solid was appeared. The white product solid was collected by filtration. The product was washed with water and dried under vacuum. Final white pure product was obtained in 26.0 g (86.7%). 1H NMR (400 MHz, DMSO-d6, δ): 9.84 (s, 1H, NH), 7.82 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 4.50 (s, 2H, NH2).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13])=O.[NH2:14][C:15]([NH2:17])=[S:16]>C(O)C>[C:6]1([CH3:13])[CH:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:14]=[C:15]([NH2:17])[S:16][CH:2]=1
Reactant: NC(N)=S
Reactant: Cc1cc(C)c(C(=O)CBr)c(C)c1
Solvent: CCO
Product: Cc1cc(C)c(-c2csc(N)n2)c(C)c1
Yield: 107 %

Procedure:
2-Bromo-1-mesitylethanone (2.43 g, 10.1 mmol) and thiourea (0.810 g, 10.6 mmol) were dissolved in 95% ethanol (20 mL). The reaction mixture was heated at reflux for 2.0 h. The solution was concentrated under reduced pressure, and the residue was recrystallized from 2-propanol to give the desired 4-mesitylthiazol-2-amine (2.36 g) as white solids: 1H NMR (500 MHz, CD3OD) δ 7.00 (s, 2 H), 6.67 (s, 1 H), 2.31 (s, 3 H), 2.19 (s, 6 H).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:27]1([NH:33][NH2:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:24])([F:23])[F:25])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NNc1ccccc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OCC(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OCC(F)(F)F)cc2)nc1-c1ccnn1-c1ccccc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-1H-pyridazin-4-one (A-32) and phenylhydrazine according to the method described for example 43. MS: M=413.1 (M+H)+
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>N1C=CC=CC=1>[C:1]1([S:7]([NH:12][CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(N)c1cccc([N+](=O)[O-])c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)CC(NS(=O)(=O)c1ccccc1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.8 %

Procedure:
8.1 g of phenylsulphonyl chloride were added at 0° C. to a solution of 10 g of (1b) in 100 ml of pyridine. After a reaction time of 15 min, 6.3 ml of triethylamine were added and the mixture was stirred at room temperature. After 5 h, it was concentrated, treated with 1 N HCl, extracted with dichloromethane, dried over MgSO4 and concentrated. Chromatographic purification (dichloromethane/methanol=5:1) yielded 11.4 g of a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([OH:17])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.Cl.[CH3:59][NH:60][O:61][CH3:62]>C(Cl)Cl>[CH3:62][O:61][N:60]([CH3:59])[C:15]([CH:11]1[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1)=[O:17]
Reactant: CC(C)(C)OC(=O)NC1CCCC(C(=O)O)C1
Reactant: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CCCC(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.4 %

Procedure:
To a cold (0° C.) solution of 3-[(tert-butoxycarbonyl)amino]-cyclohexanecarboxylic acid (5.00 g, 20.6 mmol) in CH2Cl2 (50 mL) including triethylamine (3.1 mL, 22.2 mmol) were added benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexa-fluorophosphate (10.7 g, 20.6 mmol), N,O-dimethylhydroxyamine hydrochloride (2.21 g, 20.6 mmol) and Et3N (3.2 mL, 23.0 mmol) successively. The resulting mixture was allowed to warm to room temperature, and the stirring was continued for 18 hrs. The reaction mixture was diluted with CH2Cl2 and washed with 1N HCl, saturated aqueous NaHCO3 solution, and brine, successively. The organic phase was dried over Na2SO4, filtered, and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=1:1) to give tert-butyl 3-{[methoxy(methyl)amino]carbonyl}cyclohexylcarbamate as a colorless oil (5.39 g, yield; 92%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH:10]([CH2:18][F:19])[CH2:9]2)=[CH:6][C:5]([C:20]#[N:21])=[CH:4][C:3]=1[NH:22]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH:10]([CH2:18][F:19])[CH2:9]2)[C:2]=1[Cl:1])[C:20]#[N:21]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCN(C3COC3)C(CF)C2)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(N)c(Cl)c(N2CCN(C3COC3)C(CF)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
(+/−) Tert-butyl (2-chloro-5-cyano-3-(3-(fluoromethyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)carbamate (Peak 2) (315 mg, 0.741 mmol) was taken up in DCM (4 mL) and TFA (1.142 mL, 14.83 mmol) was added. The reaction was stirred at rt for 1 h. The solvent was removed in vacuo and the material was taken up in MeOH and loaded onto an SCX column (5 g, benzenesulfonic acid sorbent). The column was rinsed with MeOH, then 7N NH3/MeOH to release the product. The solvent was removed in vacuo to give (+/−) 3-amino-4-chloro-5-(3-(fluoromethyl)-4-(oxetan-3-yl)piperazin-1-yl)benzonitrile (234 mg) as a yellow foam.