Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]2[N:14]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[O:26]C)[C:15](=[O:18])[NH:16][N:17]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.N1C=CC=CC=1.O>C(OCC)(=O)C>[Cl:25][C:23]1[CH:22]=[CH:21][C:20]([OH:26])=[C:19]([N:14]2[C:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:28])([F:1])[F:29])[CH:4]=3)=[N:17][NH:16][C:15]2=[O:18])[CH:24]=1
Reactant: COc1ccc(Cl)cc1-n1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n[nH]c1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: O=c1[nH]nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1-c1cc(Cl)ccc1O
Temperature: 225 °C
Yield: 95.7 %

Procedure:
5-[3,5-Bis(trifluoromethyl)phenyl]-4-(5-chloro-2-methoxy phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1.6 g, 3.6 mmol) was admixed with pyridine hydrochloride (6.7 g, 58 mmol) and heated at 225° C. for 1 h. After being cooled, the solid was covered with ethyl acetate (25 ml) and water (15 ml) and subjected to ultrasonication (bath) for several minutes in order to break the solid free from the glass wall. The organic suspension was diluted with ethyl acetate (100 ml) washed with water (25 ml), saturated sodium carbonate solution (25 ml), and brine. Concentration gave a solid 1.46 g (95%) which was recrystallized from acetonitrile. mp 275°-278° C. IR(KBr, ν=cm-1) 3166,1681, 1314, 1275, 1180, 1140; 1H NMR (300 MHz, DMSO6) δ6.92 (1H, d, J=8.8 Hz), 7.38 (1H, dd, J=8.8 Hz, 2.6 Hz), 7.58 (1H, d, J=2 Hz), 7.91 (2H, s), 8.17 (1H, s), 10.45 (1H, s), 10.45 (1H, s), 12.44 (1H, s); MS(DCl)m/z: 424(MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([S:9](=[O:12])(=[O:11])[NH2:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:13][CH2:14][C:15](Cl)=[O:16]>>[Cl:13][CH2:14][C:15]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([S:9](=[O:12])(=[O:11])[NH2:10])=[CH:8][C:2]=1[CH3:1])=[O:16]
Reactant: Cc1cc(S(N)(=O)=O)ccc1N
Reactant: O=C(Cl)CCl
Product: Cc1cc(S(N)(=O)=O)ccc1NC(=O)CCl

Procedure:
2-methyl-4-sulphamoylaniline (18,6 g) and α-chloroacetyl chloride (30g) were refluxed together 30 min. and the mixture worked up as in Example 2(a) to yield 11 g, m.p. 193°-194°
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C@H:5]([NH:12][C:13]([C:15]1[N:16]=[C:17]([C:33]#[N:34])[C:18]2[C:23]([C:24]=1[OH:25])=[CH:22][CH:21]=[C:20]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:19]=2)=[O:14])[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.O1CCCC1.[OH-].[Na+]>CO>[C:33]([C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[C:20]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:19]=2)[C:24]([OH:25])=[C:15]([C:13]([NH:12][C@H:5]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:4][C:3]([OH:35])=[O:2])=[O:14])[N:16]=1)#[N:34]
Reactant: COC(=O)C[C@H](NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1nc(C(=O)N[C@@H](CC(=O)O)c2cccnc2)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
3-(S)-[(1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-3-pyridin-3-yl-propionic acid methyl ester (25 mg, 0.0533 mmol) was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL.) Sodium hydroxide solution (2 mL, 2M) was added and the reaction was permitted to stir overnight at room temperature. After 18 hours, the pH was adjusted to 4 and reaction lyophilized. The crude product was purified by HPLC to provide the title compound in 68% yield. LC-MS ESI+: 455 (M+1)+; ESI−: 453 (M−1)−.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6]([C:8]1[C@H:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:10]([C:16]([OH:18])=[O:17])=[C:11]([CH3:15])[NH:12][C:13]=1[CH3:14])=[O:7])#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH3:34][O:35][CH2:36]Cl>CN(C)C=O.C(OCC)(=O)C>[C:1]([CH2:3][CH2:4][O:5][C:6]([C:8]1[C@H:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:10]([C:16]([O:18][CH2:34][O:35][CH3:36])=[O:17])=[C:11]([CH3:15])[NH:12][C:13]=1[CH3:14])=[O:7])#[N:2]
Reactant: CC1=C(C(=O)O)[C@@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OCCC#N)=C(C)N1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCC#N)[C@@H]1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 10 mg of (4R)-5-(2-cyanoethoxycarbonyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid in 0.5 ml of N,N-dimethylformamide were added 4.3 mg of potassium carbonate, and then 8 μl of chloromethyl methyl ether. The mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with 5 ml of ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and with water, and dried over anhydrous Glauber's salt (sodium sulfate), followed by distilling off the solvent under reduced pressure the residue was purified using preparative TLC to obtain 3.6 mg of the objective compound.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:20](=O)[CH2:21][CH2:22][C:23]([OH:25])=O)[CH:17]=3)[CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:28][NH2:29]>C(O)(=O)C>[C:1]1([S:7]([NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:20]4[CH2:21][CH2:22][C:23](=[O:25])[NH:28][N:29]=4)[CH:17]=3)[CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCC(c2ccc3c(c2)CC(NS(=O)(=O)c2ccccc2)C3)=NN1

Procedure:
3.0 g (8 mmol) of 4-(2-benzenesulphonamido-indan-5-yl)-4-oxobutyric acid and 0.53 g (10.4 mmol) of 99% hydrazine hydrate in 12 ml of glacial acetic acid are boiled for 3 hours. The mixture is evaporated in vacuo, water is added to the residue, which is neutralised with sodium carbonate solution, and the reaction product is filtered off with suction and recrystallised from n-propanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][S:10][CH:9]1[C:13](=O)[NH:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:34]4[N:35]=[C:36]([CH:39]5[CH2:45][C:42]6([CH2:44][CH2:43]6)[CH2:41][N:40]5[C:46](=[O:56])[CH:47]([NH:51][C:52]([O:54][CH3:55])=[O:53])[CH:48]([CH3:50])[CH3:49])[NH:37][CH:38]=4)[CH:30]=3)[CH:25]=2)=[CH:20][CH:19]=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:62]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][S:10][CH:9]1[C:13]1[NH:62][C:16]([C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:34]5[N:35]=[C:36]([CH:39]6[CH2:45][C:42]7([CH2:43][CH2:44]7)[CH2:41][N:40]6[C:46](=[O:56])[CH:47]([NH:51][C:52]([O:54][CH3:55])=[O:53])[CH:48]([CH3:50])[CH3:49])[NH:37][CH:38]=5)[CH:30]=4)[CH:25]=3)=[CH:22][CH:23]=2)=[CH:15][N:14]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: [NH4+]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1nc(-c2ccc3cc(-c4ccc(C(=O)CNC(=O)C5SCCN5C(=O)OC(C)(C)C)cc4)ccc3c2)c[nH]1)C(C)C
Agent: CC(=O)[O-]
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1nc(-c2ccc3cc(-c4ccc(-c5cnc(C6SCCN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)c[nH]1)C(C)C
Temperature: 135 °C
Reaction time: 0.75 h
Yield: 44.3 %

Procedure:
2-{2-[4-(6-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-1H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-2-oxo-ethylcarbamoyl}-thiazolidine-3-carboxylic acid tert-butyl ester (350 mg, 0.44 mmol) was dissolved in m-xylenes (3.0 mL) and heated at 135° C. Solid ammonium acetate (400 mg, 9.07 mmol) was added and the reaction was stirred at 135° C. After 45 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude reaction product was partitioned between chloroform and water. The organic layer was collected and dried over sodium sulfate. Filtration and evaporation of solvents gave the crude product. The crude material was purified via silica gel chromatography (eluent: EtOAc/hexanes) to yield the product (151.3 mg, 0.195 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[C:11](=[O:42])[CH:12]([CH:15]([OH:41])[C:16]3[N:17]=[CH:18][N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:20]=3[CH3:21])[CH2:13][CH2:14][C:6]1=[C:5]2[CH3:43]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[C:11](=[O:42])[CH:12]([CH:15]([OH:41])[C:16]3[N:17]=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:13][CH2:14][C:6]1=[C:5]2[CH3:43]
Reactant: Cc1c2n(c3ccc(Cl)cc13)C(=O)C(C(O)c1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Solvent: CC(=O)O
Solvent: O
Product: Cc1[nH]cnc1C(O)C1CCc2c(C)c3cc(Cl)ccc3n2C1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 12.6 %

Procedure:
A solution of the mixture of two diastereoisomers of 2-chloro-8,9-dihydro-7-[(hydroxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-10-methylpyrido[1,2-a]indol-6(7H)-one (0.50 g) in acetic acid-water (5:2, 7 ml) was stirred at 60° C. for 2 hours. After evaporation of the solvent, the residue was partitioned between water and chloroform and neutralized with an aqueous sodium hydroxide, to give precipitates. The organic layer and the precipitates were combined and chromatographed on silica gel eluted by chloroform-methanol (0-10% V/V), to give two isomers of 2-chloro-8,9-dihydro-10-methyl-7[(hydroxy)(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (0.037 g), respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][C:3]=1[CH2:12][NH:13][C:14]([O:16][CH3:17])=[O:15].[H-].C([Al+]CC(C)C)C(C)C.Cl.O>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH2:12][NH:13][C:14](=[O:15])[O:16][CH3:17]
Reactant: COC(=O)NCc1cc(C(=O)OC)ccc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)NCc1cc(CO)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
10.3 g of methyl 4-chloro-3-(methoxycarbonylaminomethyl)benzoate was dissolved in 80 ml of anhydrous tetrahydrofuran, 100 ml of diisobutylaluminum hydride (0.95 M hexane solution) was dropwise added thereto in an atmosphere of nitrogen at from −50° C. to −30° C., and after completion of the dropwise addition, the mixture was stirred at room temperature for 16 hours. After completion of the reaction, diluted hydrochloric acid was dropwise added to the reaction mixture at 0° C., water was added thereto, extraction with ethyl acetate was carried out, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Wakogel C-200, eluent: hexane/ethyl acetate=1/1) to obtain 6.5 .g of methyl N-(2-chloro-5-hydroxymethylbenzyl)carbamate as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(-c2ccccc2)nc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cnc(-c2ccccc2)nc1
Temperature: 25 °C

Procedure:
A suspension of 5-methyl-2-phenyl-pyrimidine (3.0 g, 17.6 mmol), N-bromosuccinimide (2.0 g, 11.2 mmol) and a,a'-azobis(isobutyronitrile) (0.10 g, 0.61 mmol) in dry carbon tetrachloride (150 mL) is refluxed for 0.5 hours. After cooling to room temperature, the mixture is filtered and the filtrate is concentrated in vacuo, giving 5-bromomethyl-2-phenyl-pyrimidine as an orange oil.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21]([CH2:24][CH2:25][OH:26])[C:20]([CH3:28])([CH3:27])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21]([CH2:24][CH:25]=[O:26])[C:20]([CH3:28])([CH3:27])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC=C(CCO)C(C)(C)C1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC=C(CC=O)C(C)(C)C1
Reaction time: 0.17 h
Yield: 41.6 %

Procedure:
A solution of dimethylsulfoxide (1.1 mL, 15 mmol) in dichloromethane (5ml) was added to a cooled (−78° C.) solution of oxalyl chloride (0.67 mL, 7.5 mmol) in dichloromethane (50 mL) under an atmosphere of argon, and stirred for 10 minutes. Then a solution of 4-(2-hydroxyethyl)-3,3-dimethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (0.96 g, 3.7 mmol) in dichloromethane (5 mL) was added thereto and stirred for 15 minutes at −78° C. and subsequently for 45 minutes at −40° C. Then triethylamine (3.7 mL, 26.4 mmol) was added thereto and stirred for 30 minutes at room temperature. After the reaction was completed, saturated aqueous ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was washed with water three times and dried over anhydrous magnesium sulfate. After drying, it was filtered and the filtrate was concentrated under a reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent, hexane:ethyl acetate=10:1 to 7:1) to obtain 0.39 g (yield 41.1%) of 3,3-dimethyl-4-(2-oxoethyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (VII-152). Its physical property is shown below.
Reaction SMILES: C(O)=O.[S:4](Cl)([N:7]=C=O)(=[O:6])=[O:5].[CH3:11][N:12]([CH3:35])[C:13]([C:15]1[N:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:18]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:17]([OH:33])[C:16]=1[OH:34])=[O:14]>CN1C(=O)CCC1>[CH3:35][N:12]([CH3:11])[C:13]([C:15]1[N:19]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:18]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:17]([OH:33])[C:16]=1[O:34][S:4](=[O:5])(=[O:6])[NH2:7])=[O:14]
Reactant: CCOC(=O)c1c(O)c(O)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN1CCCC1=O
Solvent: O=CO
Product: CCOC(=O)c1c(O)c(OS(N)(=O)=O)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Temperature: 25 °C
Yield: 12.3 %

Procedure:
Formic acid (165 μL, 4.31 mmol) was added dropwise to neat sulfurisocyanatidic chloride (374 μL, 4.31 mmol) at 0° C. with stirring. The reaction mixture allowed to warm to RT and stirred for 2 h, after which a solution of ethyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (UL1-012) (0.5 g, 1.44 mmol) in NMP (3 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min and allowed to warm to RT and stirred for a further 2 h. The reaction mixture was partitioned with brine (30 mL) and EtOAc (25 mL), the aqueous layer was extracted with EtOAc (2×25 mL) the combined organics were dried (MgSO4), filtered and solvents removed in vacuo to give a yellow oil. The compound was purified by preparative HPLC (C-18 column, 21.2 mm i.d.×100 mm, 5 micron particle size, gradient 5-95% MeCN in 0.1% aqueous formic acid over 16 min) to afford ethyl 5-(dimethylcarbamoyl)-3-hydroxy-1-(4-methoxyphenyl)-4-(sulfamoyloxy)-1H-pyrrole-2-carboxylate (UL1-068) (76 mg, 12%) as a white solid: m/z 428 (M+H)+ (ES+); 426 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 8.87 (s, 1H), 7.92 (s, 2H), 7.16-7.08 (m, 2H), 6.96-6.88 (m, 2H), 4.03 (q, J=7.1 Hz, 2H), 3.79 (s, 3H), 2.75 (s, 3H), 2.67 (s, 3H), 1.02 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:16]3[N:17]=[C:18]([N:21]4[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]4)[S:19][CH:20]=3)[CH:13]=[CH:14][CH:15]=2)[N:4]=1.[Cl-].[NH4+].C([N:37](C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:16]3[N:17]=[C:18]([N:21]4[CH2:22][CH2:23][CH:24]([C:27]([NH2:37])=[O:28])[CH2:25][CH2:26]4)[S:19][CH:20]=3)[CH:13]=[CH:14][CH:15]=2)[N:4]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)C1CCN(c2nc(-c3cccc(Nc4nccc(C(F)(F)F)n4)c3)cs2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)C1CCN(c2nc(-c3cccc(Nc4nccc(C(F)(F)F)n4)c3)cs2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.5 %

Procedure:
To a solution of 1-[4-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-4-carboxylic acid (36 mg, 0.08 mmol) in N,N-dimethylformamide (0.8 mL) was added ammonium chloride (13 mg, 0.24 mmol), diisopropylethylamine (56 L, 0.32 mmol), and (1H-benzotriazol-1-yloxy)(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (83 mg, 0.16 mmol). The mixture was stirred for 60 minutes at room temperature. The mixture was diluted with ethyl acetate (30 mL), and washed with 1:1 saturated sodium bicarbonate:brine (30 mL), and 1:1 water:brine (30 mL). The aqueous fractions were further extracted with ethyl acetate (30 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC to provide 8 mg (0.018 mmol, 22% yield) of 1-[4-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-4-carboxamide as a white solid. MS APCI: [M+H]+ m/z 449.1. 1H NMR (400 MHz, DMSO) δ 10.26 (s, 1H), 8.84 (d, J=4.8 Hz, 1H), 8.01 (s, 1H), 7.55-7.51 (m, 2H), 7.35-7.29 (m, 3H), 7.16 (d, J=7.6 Hz, 1H), 6.84 (s, 1H), 3.93 (m, 2H), 3.09 (m, 2H), 2.37 (m, 1H), 1.97-1.70 (m, 2H), 1.62 (m, 2H). rhSyk=++.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:11][C:12]1[C:13]([CH3:19])=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1.C([O:22][C:23]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)=O)C>O1CCCC1>[C:34]([O:33][C:31]([N:28]1[CH2:29][CH2:30][CH:25]([C:23](=[O:22])[CH2:19][C:13]2[C:12]([Br:11])=[CH:17][N:16]=[C:15]([Cl:18])[CH:14]=2)[CH2:26][CH2:27]1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1cc(Cl)ncc1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Cc2cc(Cl)ncc2Br)CC1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
Lithium bis(trimethylsilyl)amide (1.0 mol/L in tetrahydrofuran; 11.00 mL) is added dropwise to 5-bromo-2-chloro-4-picoline (0.95 g) dissolved in tetrahydrofuran (15 mL) at −40° C. under argon atmosphere. The mixture is stirred for 2 h at −35 to −45° C. prior to addition of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (1.33 g) dissolved in tetrahydrofuran (15 mL). The reaction mixture is allowed to warm to room temperature over a period of 1 h. Ice-cold water is added and the mixture is extracted with ethyl acetate. The combined extracts are washed with brine, dried (MgSO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 75:25→60:40) to give the title compound. Mass spectrum (ESI+): m/z=417/419/421 (Cl+Br) [M+H]+.
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]1([CH2:37][S:38](Cl)(=[O:40])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>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][S:38]([CH2:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:40])=[O:39])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)Cc4ccccc4)ccc3N2)c(O)c2cccnc21
Temperature: 120 °C
Yield: 24.1 %

Procedure:
A solution of the product of Example 205 (21.5 g, 0.05 mmol) in pyridine (1 mL) was treated with α-toluenesulfonyl chloride (38 mg, 0.2 mmol), heated in a microwave reactor at 120° C. for 120 minutes, cooled to 25C and concentrated under reduced pressure. The residue was triturated with water (1 ml), filtered, and washed with hexane:ethyl acetate (1:1). The crude product was chromatographed on silica gel, eluting with dichloromethane:methanol (399:1) to give the title compound (7 mg, 24%). 1H NMR (300 MHz, DMSO-d6) δ 0.99 (d, J=6.62 Hz, 6 H) 1.58 (m, 2 H) 1.69 (m, 1 H) 4.49 (m, 2 H) 4.59 (s, 2 H) 7.32 (m, 5 H) 7.51 (m, 2 H) 7.57 (d, J=2.21 Hz, 1 H) 7.71 (d, J=8.82 Hz, 1 H) 8.57 (dd, J=8.09, 1.84 Hz, 1 H) 8.90 (dd, J=4.78, 1.84 Hz, 1 H) 10.38 (s, 1 H) 14.08 (s, 1 H) 15.14 (s, 1 H) (ESI−) m/z 580 (M−H)−
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[N:9]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCNCC1
Reactant: Clc1ccc(Cl)nn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(c2ccc(Cl)nn2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 7.5 parts of 3,6-dichloropyridazine in 75 parts of N,N-dimethylformamide was added dropwise a solution of 8 parts of ethyl 1-piperazinecarboxylate and 5.6 parts of N,N-diethylethanamine in 25 parts of N,N-dimethylformamide. Upon completion, the whole was stirred overnight at a temperature of about 50° C. After cooling, the reaction mixture was poured onto water and the product was extracted with trichloromethane. The organic layer was dried, filtered and evaporated. The residue was crystallized from 2-propanol, yielding 3.6 parts of ethyl 4-(6-chloro-3-pyridazinyl)-1-piperazinecarboxylate; mp. 123.8° C. (compound 208).
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:15][CH3:16])[CH:10]([OH:14])[C:11]([OH:13])=O)=O)(C)(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CN1CCOCC1>>[CH2:31]([NH:38][C:11](=[O:13])[C@@H:10]([OH:14])[CH:9]([NH2:8])[CH2:15][CH3:16])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)C(=O)O
Reactant: NCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CCC(N)[C@H](O)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-tert-Butoxycarbonylamino-2-hydroxy-pentanoic acid (300 mg, 1.29 mmol) was combined with EDC (400 mg, 2.1 mmol) and HOBt (400 mg, 2.6 mmol). A solution of benzylamine (0.22 mL) and 4-methylmorpholine (0.5 mL) in dichloromethyl (4 mL) was added in one portion. The mixture was stirred at ambient temperature for 2 hours. After dilution with ethyl acetate (150 mL), the solution was washed with 1N aqueous HCl, water, saturated aqueous NaHCO3 solution and brine. The resultant mixture was dried with magnesium sulfate and evaporated under vacuum to yield (S)-3-amino-2-hydroxy-pentanoic acid benzylamide (380 mg) as a white solid.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[Cl:18])=[C:7](Cl)[N:6]=[CH:5][N:4]=1>C(O)C>[Cl:2][C:3]1[N:4]=[CH:5][N:6]=[C:7]([NH2:1])[C:8]=1[O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[Cl:18]
Reactant: N
Reactant: COc1ccc(Cl)c(Oc2c(Cl)ncnc2Cl)c1
Solvent: CCO
Product: COc1ccc(Cl)c(Oc2c(N)ncnc2Cl)c1
Temperature: -78 °C
Reaction time: 50 h

Procedure:
About 500 ml of NH3 were conducted at -78° C. into a solution of 9.9 g of 4,6-dichloro-5-(2-chloro-5-methoxy-phenoxy)-pyrimidine from Example 1e) in 400 ml of ethanol. Thereafter, the reaction mixture was stirred at -78° C. for 15 hours and at room temperature for 50 hours and finally evaporated. The residue was partitioned between ethyl acetate and water and the organic phase was worked-up. 8.53 g of 6-chloro-5-(2-chloro-5-methoxy-phenoxy)-pyrimidin-4-ylamine were thus obtained as yellow crystals. MS: 285 (M).