Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:8]3[NH:12][C:11]([C:13]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)=[C:14]4[CH:42]=[CH:41][C:16](=[C:17]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[C:18]5[CH:34]=[CH:33][C:20](=[C:21]([C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=6)[C:22]6[CH:23]=[CH:24][C:25]=2[N:26]=6)[N:19]=5)[NH:15]4)=[CH:10][CH:9]=3)=[CH:5][CH:6]=1.O.C([O-])(=O)C.[Cu+2:54].C([O-])(=O)C.C(Cl)Cl>C(Cl)(Cl)Cl.CO>[C:43]1([C:13]2[C:11]3[NH:12][C:8](=[CH:9][CH:10]=3)[C:7]([C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)=[C:25]3[N:26]=[C:22]([CH:23]=[CH:24]3)[C:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:20]3[NH:19][C:18]([CH:34]=[CH:33]3)=[C:17]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:16]3=[N:15][C:14]=2[CH:42]=[CH:41]3)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[Cu+2:54]
Reactant: C1=Cc2nc1c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc([nH]3)c(-c3ccccc3)c3ccc([nH]3)c2-c2ccccc2)C=C1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: C1=Cc2nc1c(-c1ccccc1)c1ccc([nH]1)c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc([nH]3)c2-c2ccccc2)C=C1

Procedure:
Tetraphenylporphyrin (II) (16.80 g., 27.3 mmol) is dissolved in 2000 ml of chloroform under reflux. Copper (II) acetate monohydrate (5.45 g., 27.3 mmol) is dissolved in 600 ml of methanol, and added dropwise to the methylene chloride solution in about 15 minutes. After the addition is over, the solution is refluxed for 30 minutes and cooled. The completion of the reaction is checked by UV-VIS spectrophotometry. The product IIa is isolated by evaporation of the solvents.
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].[ClH:5].Cl.[C:7]1([CH2:13][O:14][CH2:15][CH:16]([N:20]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27][N:26]([CH:32]([CH2:36][O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]([OH:35])=[O:34])[CH2:25][CH2:24][N:23]([CH:45]([CH2:49][O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:46]([OH:48])=[O:47])[CH2:22][CH2:21]2)[C:17]([OH:19])=[O:18])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[K+].Cl>O>[ClH:5].[ClH:5].[OH:4][CH:2]([CH3:3])[CH2:1][N:29]1[CH2:30][CH2:31][N:20]([CH:16]([CH2:15][O:14][CH2:13][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:17]([OH:19])=[O:18])[CH2:21][CH2:22][N:23]([CH:45]([CH2:49][O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:46]([OH:48])=[O:47])[CH2:24][CH2:25][N:26]([CH:32]([CH2:36][O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]([OH:35])=[O:34])[CH2:27][CH2:28]1
Reactant: CC1CO1
Reactant: O=C(O)C(COCc1ccccc1)N1CCNCCN(C(COCc2ccccc2)C(=O)O)CCN(C(COCc2ccccc2)C(=O)O)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(O)CN1CCN(C(COCc2ccccc2)C(=O)O)CCN(C(COCc2ccccc2)C(=O)O)CCN(C(COCc2ccccc2)C(=O)O)CC1
Reaction time: 0.25 h
Yield: 185 %

Procedure:
4.7 g (0.08 mol) of propylene oxide were added drop by drop, in 15 minutes, to a solution of α,α′,α″-tris[(phenylmethoxy)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid bis hydrochloride (obtained as described in WO 89/05802, Example 2) (31.2 g; 0.04 mol) in 2N KOH (160 mL; 0.32 mol). After 18 hours at room temperature (20° C.), the reaction mixture was diluted with H2O (250 mL). The solution was acidified with 37% HCl (60 mL), to obtain a precipitate which, after 18 hours, was filtered, washed with 2N HCl (50 mL) and dried (P2O5—NaOH; 50° C.; 2 kPa) to obtain the desired compound (31.7 g dry; 0.037 mol). Yield: 92%.
Reaction SMILES: [OH:1][C:2]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=1)([C:4]1[CH:5]=[N:6][N:7]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:12]=[C:11]([CH3:26])[CH:10]=2)[CH:8]=1)[CH3:3].O.[OH-].[Li+].C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[OH:1][C:2]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1)([C:4]1[CH:5]=[N:6][N:7]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=[CH:18][N:17]=3)[CH:12]=[C:11]([CH3:26])[CH:10]=2)[CH:8]=1)[CH3:3]
Reactant: COC(=O)c1ccc(C(C)(O)c2cnn(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)c2)cc1
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-n2cc(C(C)(O)c3ccc(C(=O)O)cc3)cn2)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 4-{1-hydroxy-1-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-4-yl]ethyl}benzoate (isomer 1, early eluting) (100 mg, 0.2 mmol) and lithium hydroxide monohydrate (26 mg, 0.6 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was stirred at 60° C. for 3 hours. After being cooled to 0° C., the mixture was adjusted to pH 7 with aqueous sodium bicarbonate solution. Then the mixture was extracted with ethyl acetate and washed by brine. The organic layer was concentrated and the residue was purified by reverse phase chromatography to afford 4-{1-hydroxy-1-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-4-yl]ethyl}benzoic acid (Example 19.7). MS ESI calc'd. for C24H21F3N5O3 [M+H]+ 484. found 484. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 9.66 (s, 1H), 8.99 (s, 1H), 8.93 (s, 1H), 8.69-8.71 (m, 2H), 8.42-8.44 (m, 3H), 8.24 (s, 1H), 8.10-8.11 (m, 2H), 6.67 (s, 1H), 3.16 (s, 3H), 2.64 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.[F:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[N:24][N:25]2[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[I:35])=[CH:21][C:20]=1[S:36](Cl)(=[O:38])=[O:37]>C1COCC1>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:11][N:10]=[CH:9][N:8]=1)[S:36]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:19]=1[F:18])[N:25]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[I:35])[N:24]=[CH:23]2)(=[O:37])=[O:38]
Reactant: O=S(=O)(Cl)c1cc2cnn(Cc3ccccc3I)c2cc1F
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3cnn(Cc4ccccc4I)c3cc2F)c(OC)c1
Reaction time: 0.5 h

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (0.61 g, 2.44 mmol, 1.1 equiv) in THF (5.55 mL) at −78° C. was added LIHMDS (2.441 mL, 2.44 mmol, 1.1 equiv) and stirred for 0.5 h followed by the slow addition of 6-fluoro-1-(2-iodobenzyl)-1H-indazole-5-sulfonyl chloride (2-2, 1.0 g, 2.22 mmol, 1.0 equiv) in THF (1.85 mL) and stirred overnight as the system approached ambient temperature. The reaction was quenched with ammonium chloride and extracted with EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated and the residue was purified by normal phase chromatography (0→40% EtOAc in hexanes). ESI+ MS [M+H]+ C25H21FIN5O4S2: 666.1 found, 666.5 required.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:26][O:27][CH2:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1>C(Cl)Cl>[CH3:26][O:27][CH2:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC[C@@H]1CCCN1
Reactant: COC(=O)c1cc(C)cc(CO)c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC[C@@H]1CCCN1Cc1cc(C)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold, stirred solution of methyl 3-(hydroxymethyl)-5-methylbenzoate (200 mg, 1.1 mmol) in methylene chloride (2.2 mL) is added triethylamine (0.304 mL, 2.2 mmol) followed by methanesulfonyl chloride (0.116 mL, 1.5 mmol). The reaction mixture is stirred for 15 min and filtered. (S)-(+)-2-(Methoxymethyl)pyrrolidine (380 mg, 3.3 mmol) is added to the filtrate, and the reaction mixture is stirred at room temperature for 5 h. The reaction mixture is diluted with methylene chloride (10 mL), washed with 1 N hydrochloric acid, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 15% ethyl acetate/hexanes) provides the title compound. 1H NMR (300 MHz, CDCl3) δ 7.77 (s, 1H), 7.73 (s, 1H), 7.37 (s, 1H), 4.12 (d, J=17 Hz, 1H), 3.90 (s, 3H), 3.85 (m, 2H), 3.51 (m, 2H), 3.44 (m, 2H), 3.15 (s, 1H), 2.38 (s, 3H), 1.94 (m, 3H), 1.72 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]#[N:10])=[CH:4][NH:5][C:6](=[O:8])[CH:7]=1.Br[CH:12]([CH3:16])[C:13]([OH:15])=[O:14]>>[Br:1][C:2]1[C:3]([C:9]#[N:10])=[CH:4][N:5]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[C:6](=[O:8])[CH:7]=1
Reactant: CC(Br)C(=O)O
Reactant: N#Cc1c[nH]c(=O)cc1Br
Product: CC(C(=O)O)n1cc(C#N)c(Br)cc1=O

Procedure:
1.0 g (purity 77%, 3.87 mmol) of 4-bromo-6-oxo-1,6-dihydropyridin-3-carbonitrile and 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted according to General Method 4A at 35-45° C. After aqueous work-up, the crude product was triturated with cyclohexane/dichloromethane, and the solid was filtered off and dried under high vacuum. Yield: 648 mg (purity 66%, 41% of theory)
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.[CH2:13]([N:15]=[C:16]=NCCCN(C)C)C.[C:24]([O:28][C:29]([N:31]1[CH2:38][C@H:37]([OH:39])[CH2:36][C@H:32]1[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].CNC>O1CCCC1>[CH3:13][N:15]([CH3:16])[C:33]([C@@H:32]1[CH2:36][C@@H:37]([OH:39])[CH2:38][N:31]1[C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])=[O:34]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
24.9 g of 1-hydroxybenzotriazole monohydrate and 24.9 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added under ice cooling to a 250 mL tetrahydrofuran solution of 25.1 g of (4R)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline and stirred for 15 minutes. 10.7 g of a 50% dimethylamine aqueous solution was added dropwise over a period of 10 minutes to the reaction mixture, and the reaction mixture was stirred for 15 hours at room temperature. The solvent was distilled off under reduced pressure, after which 100 mL of a saturated sodium hydrogencarbonate aqueous solution was added and extraction was performed with chloroform (50 mL×2). The extract was dried with anhydrous sodium sulfate, the drying agent was filtered off, and the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60N, mobile phase: chloroform/methanol=20/1 to 9/1; v/v) to obtain 26.2 g of the titled compound (colorless solid).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31]>>[CH2:25]([O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]([NH:16][CH2:15][C:13]1[N:14]=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([O:1][CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH:3]=2)[O:11][CH:12]=1)=[O:27])[CH3:26]
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC)c(O)c2)n1
Reactant: CCC(Br)CC
Product: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC)c(OC(CC)CC)c2)n1

Procedure:
Using the compound obtained in Example 2 and 3-bromopentane, white powdery 2-ethoxy-N-{2-[3-(1-ethylpropoxy)-4-methoxyphenyl]oxazol-4-ylmethyl}benzamide was obtained following the procedure of Example 3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:10]1=[O:15]
Reactant: O=C1CCCCC1c1cc(Cl)cc(Cl)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C1C(Br)CCCC1c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 110.9 %

Procedure:
2-(3,5-Dichloro-phenyl)-cyclohexanone (50 mg, 0.21 mmol) was dissolved in chloroform (1 mL). To this solution bromine (34.5 mg, 0.22 mmol) in chloroform (0.5 mL) was added drop wise at room temperature. The reaction was stirred for 1½ hours at room temperature. The solvent was removed under reduced pressure to yield the crude title compound (75 mg) which was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].O>N1C=CC=CC=1>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][C:31](=[O:33])[CH3:32])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccnc3n(CCC(C)C)c1=O)N2
Temperature: 100 °C
Yield: 71.6 %

Procedure:
To the product of Example 205 (0.020 g, 0.047 mmol) in pyridine (0.5 mL) was added acetic anhydride (0.057 g, 0.0053 mL, 0.056 mmol). The reaction mixture was heated in a microwave reactor at 100° C. for 30 minutes. The reaction was poured into 30 mL of water. The solid was collected by filtration to give the title compound (15.8 mg, 72%). 1H NMR (300 MHz, DMSO-d6) δ 0.98 (d, J=6.62 Hz, 6 H) 1.57 (m, 2 H) 1.70 (m, 1 H) 2.10 (s, 3 H) 4.48 (m, 2 H) 7.48 (dd, J=8.09, 4.78 Hz, 1 H) 7.66 (d, J=8.82 Hz, 1 H) 7.78 (m, 1 H) 8.30 (d, J=1.84 Hz, 1 H) 8.55 (dd, J=7.72, 1.84 Hz, 1 H) 8.87 (dd, J=4.60, 1.65 Hz, 1 H) 10.39 (s, 1 H) 14.21 (br s, 1 H). MS (ESI−) m/z 468 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: COC(=O)COCCCl
Solvent: CCN(CC)CC
Product: COC(=O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1

Procedure:
10 gr. of (0.035 mole) of 1-[(4-chlorophenyl)phenylmethyl]piperazine, 8.06 gr. (0.0525 mole) of methyl 2-chloroethoxyacetate and 50 ml. of triethylamine were introduced into a pressure vessel and treated in a similar way as described in example 1. 12.5 gr. of methyl [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetate is obtained as reddish oil (88.7% yield).
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:23]#[N:24])[C:10]([CH3:22])=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=4[F:21])[C:12]=3F)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:32][N:33]([CH3:39])[C@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1.C(=O)([O-])O.[Na+]>CS(C)=O.C(OCC)(=O)C>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:23]#[N:24])[C:10]([CH3:22])=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=4[F:21])[C:12]=3[N:36]3[CH2:37][CH2:38][C@H:34]([N:33]([CH3:39])[CH3:32])[CH2:35]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(-c2cccc(F)c2F)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2cccc(F)c2F)c(N2CC[C@H](N(C)C)C2)c2oc(C3CC3)nc2c1C#N
Temperature: 90 °C
Reaction time: 23 h
Yield: 85.4 %

Procedure:
2-Cyclopropyl-6-(2,3-difluorophenyl)-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-177) (109 mg, 0.33 mmol) was dissolved in dimethyl sulfoxide (3 ml), then at room temperature, triethylamine (70 μl, 0.50 mmol) and (3S)-3-(dimethylamino)pyrrolidine (55 μl, 0.43 mmol) were added. The solution was stirred under nitrogen atmosphere at 90° C. for 23 hours. After cooling to room temperature, the reaction liquid was fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, then the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=92:8) to obtain a roughly-purified product (119 mg, 85%) as a white solid. This was recrystallized from diisopropyl ether to obtain the entitled compound (71 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]2[CH:14]=[C:15]([CH3:17])[N:16]=[C:4]2[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25]>C(COC)OC.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]>[CH3:17][C:15]1[N:16]=[C:4]2[N:3]=[C:2]([C:29]3[CH:30]=[CH:31][C:26]([CH:24]=[O:25])=[CH:27][CH:28]=3)[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][N:5]2[CH:14]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Cc1cn2cc(-c3ccccc3)c(Cl)nc2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Cc1cn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
2.3 g (9.4 mmol) 7-Chloro-2-methyl 6-phenyl-imidazo[1,2-a]pyrimidine is given in 32 mL dimethoxyethane (not completely dissolved). 18.5 mL Na2CO3 solution (10%) and 1.56 g (10.4 mmol) 4-formylphenylboronic acid are added. After addition of 0.35 g (0.43 mmol) 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) the reaction mixture is purged 3× with argon and heated to 90° C. After 18 h stirring at 90° C. complete dissolution has taken place. The reaction mixture is cooled down and treated with 100 mL water and 150 mL dichloromethane. After vigorous stirring at rt for one hour the organic phase is separated, washed twice with water (100 mL each) and dried (Na2SO4). After removal of the solvent the crude product is purified via chromatography (Isolute, dichloromethane/methanol). 1.82 g (61.5%) of the pure compound and 0.82 g (27.7%) of the product containing traces of the starting material have been obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:38])(=[N:27][C:28](=[O:37])[NH:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)=[O:26])=[CH:21][CH:20]=1>>[C:33]1([CH3:36])[CH:32]=[CH:31][C:30]([NH:29][C:28]([N:27]=[S:25]([C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:2]3[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)=[CH:4][N:3]=3)=[CH:24][CH:23]=2)([CH3:38])=[O:26])=[O:37])=[CH:35][CH:34]=1
Reactant: Cc1ccc(NC(=O)N=S(C)(=O)c2ccc(N)cc2)cc1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Product: Cc1ccc(NC(=O)N=S(C)(=O)c2ccc(Nc3ncc(-c4cccs4)c(N[C@H](C)CO)n3)cc2)cc1
Yield: 21 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (39.1 mg, 0.15 mmol) with (RS)—S-(4-aminophenyl)-N-(p-tolylcarbamoyl)-S-methylsulphoximide (40 mg, 0.13 mmol) according to procedure 5c, the desired product is obtained in 21% yield (15 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: [OH:1][C@H:2]([C@@H:10]([NH:32]C(=O)OC(C)(C)C)[CH2:11][C@H:12]([CH2:16][NH:17][C:18](=[O:31])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH:13]([CH3:15])[CH3:14])[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[ClH:40]>>[ClH:40].[ClH:40].[NH2:32][C@H:10]([C@@H:2]([OH:1])[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH2:11][C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:16][NH:17][C:18](=[O:31])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30]
Reactant: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN1CCCCC1)C(C)C
Agent: Cl
Product: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@H](N)[C@@H](O)CN1CCCCC1)C(C)C

Procedure:
The solution of 0.024 g of tert-butyl (1(S)-(1(S)-hydroxy-2-piperidin-1-ylethyl)-3(S)-{[2-(3-methoxypropoxy)benzoylamino]methyl}-4-methylpentyl)carbamate in 1 ml of 4M HCl (in dioxane) is stirred at 0° C. over 3 hours and subsequently concentrated by evaporation to dryness—the residue is dissolved in 1 ml of tert-butanol, frozen and lyophilized under high vacuum. The title compound is obtained as a white powder. Rf=0.09 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=2.95 (gradient I).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][C:11]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[O:10][CH2:9][C:8]2=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:21]=[N:22][C:23]([C:26]2[S:30][N:29]=[C:28]([CH3:31])[N:27]=2)=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:31][C:28]1[N:27]=[C:26]([C:23]2[N:22]=[N:21][C:20]([N:15]3[CH2:14][CH2:13][C:11]4([O:10][CH2:9][C:8](=[O:18])[N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH2:12]4)[CH2:17][CH2:16]3)=[CH:25][CH:24]=2)[S:30][N:29]=1
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Reactant: O=C1COC2(CCNCC2)CN1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nsc(-c2ccc(N3CCC4(CC3)CN(c3ccccc3)C(=O)CO4)nn2)n1

Procedure:
The object product (147 mg, 49%) was obtained in the same manner as in Example 1 and using 4-phenyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one (230 mg), 3-chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (150 mg) and potassium carbonate (140 mg).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:13]([C:24]([O:26][CH3:27])=[O:25])[C:12]2=[O:28])=[CH:2]1.[CH:29]1(CO)[CH2:31][CH2:30]1>CN(C)C(=O)C.[Zn]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[C:13]([C:24]([O:26][CH2:27][CH:29]3[CH2:31][CH2:30]3)=[O:25])[C:12]2=[O:28])=[CH:2]1
Reactant: COC(=O)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Reactant: OCC1CC1
Agent: [Zn]
Solvent: CC(=O)N(C)C
Product: O=C(OCC1CC1)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 19.1 %

Procedure:
Under a nitrogen atmosphere, a solution of the compound (0.038 g, 0.10 mmol) of Example 51, cyclopropyl carbinol (0.10 mL, 1.3 mmol) and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.0019 g, 0.0020 mmol) in N,N-dimethylacetamide (0.9 mL) was stirred with the microwave synthesizer (Biotage Initiator™) at 150° C. for 30 min. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.0080 g, y. 19%).
Reaction SMILES: [CH3:1][CH:2]([C@@H:4]1[NH:9][CH2:8][CH2:7][N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([O:19][CH3:20])[CH:11]=2)[CH2:5]1)[CH3:3].[CH:21]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH2:22]>O1CCOCC1>[CH3:3][CH:2]([C@H:4]1[CH2:5][N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([O:19][CH3:20])[CH:11]=2)[CH2:7][CH2:8][N:9]1[CH2:22][CH2:21][S:23]([CH3:26])(=[O:25])=[O:24])[CH3:1]
Reactant: C=CS(C)(=O)=O
Reactant: COc1cc(N2CCN[C@@H](C(C)C)C2)ccc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: COc1cc(N2CCN(CCS(C)(=O)=O)[C@@H](C(C)C)C2)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 78.3 %

Procedure:
(3S)-3-(1-Methylethyl)-1-[3-(methyloxy)-4-nitrophenyl]piperazine (0.355 g, 1.27 mmol) was dissolved in 15 mL of dioxane with stirring. Methyl vinyl sulfone (0.34 mL, 3.88 mmol) was added via syringe. The reaction was heated to 60° C. for 2.5 days. Additional methyl vinyl sulfone (0.68 mL, 7.76 mmol) was added, and the heat was increased to 90° C. The reaction was maintained at that temperature for one week. The reaction was cooled to rt and concentrated onto silica gel. Purification by flash chromatography afforded the title compound of step G (0.383 g, 0.994 mmol, 78%). 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J=9.5 Hz, 1H), 6.53 (dd, J=9.5, 2.4 Hz, 1H), 6.40 (d, J=2.4 Hz, 1H), 3.86 (s, 3H), 3.77 (d, J=12.5 Hz, 1H), 3.66 (br. s., J=12.5 Hz, 1H), 3.28-3.39 (m, 1H), 3.13-3.24 (m, 1H), 3.00-3.13 (m, 2H), 2.88-3.00 (m, 5H), 2.77-2.88 (m, 1H), 2.39-2.51 (m, 1H), 2.17-2.26 (m, 1H), 1.93-2.07 (m, 1H), 0.96 (d, J=6.8 Hz, 3H), 0.85 (d, J=6.8 Hz, 3H).