Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1C=CC=C[CH:3]=1.[O:12]1C(COC)[CH2:13]1>>[CH3:13][O:12][CH2:3][CH:2]1[O:11][CH2:10][CH2:9][NH:8][CH2:1]1
Reactant: OCCNCc1ccccc1
Reactant: COCC1CO1
Product: COCC1CNCCO1
Temperature: 50 °C
Reaction time: 16 h
Yield: 98.3 %

Procedure:
N-Benzylethanolamine (459 g) is mixed with 1,2-epoxy-3-methoxypropane (422 g) and the mixture is stirred at 50° C. for 16 hours and thereafter the excess 1,2-epoxy-3-methoxypropane is distilled off under reduced pressure. The residue is dissolved in 1,4-dioxane (3 liters) and thereto are added powdery potassium hydroxide (692.5 g) and tris(3,6-dioxaheptyl)amine (11.4 g). To the mixture is added dropwise with stirring a solution of p-toluenesulfonyl chloride (809.4 g) in 1,4-dioxane (2 liters) over a period of 1.5 hour, during which the temperature of the reaction mixture raises and the solvent is refluxed. After the dropwise addition, the mixture is stirred for 2 hours, and the undissolved materials are filtered off and washed with ethyl acetate. The filtrate and the washing liquid are combined and distilled under reduced pressure to remove the solvent. To the residue are added water (600 ml) and conc. hydrochloric acid (300 ml) to make acidic. The aqueous layer is washed with ethyl acetate, made strongly basic by adding sodium hydroxide (160 g) under ice cooling and extracted with ethyl acetate. The ethyl acetate layer is washed with saturated saline solution, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The obtained residue is distilled under reduced pressure to give the title compound (391.3 g) as colorless liquid.
Reaction SMILES: [C:1](Cl)(=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[CH2:27]([OH:31])[CH2:28][CH2:29][OH:30].C(N(CC)CC)C>C(Cl)Cl>[OH:30][CH2:29][CH2:28][CH2:27][O:31][C:1](=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCCCC(=O)Cl
Reactant: OCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC/C=C\CCCCCCCCCCCCCC(=O)OCCCO
Temperature: 0 °C

Procedure:
A solution of z-15-tetracosenoyl chloride, prepared according to Description 1, (0.129 mol, 49.7 g) in methylene chloride (500 mL) was added dropwise (over a period of 2.5-3 h) to a mixture of propane-1,3-diol (0.780 mol, 58.9 g) and triethylamine (0.323 mol, 32.6 g) in methylene chloride (1200 mL) at 0° C. under nitrogen. The mixture was left stirring in the ice bath for another 2 h, until TLC (80:18:2 petroleum ether-ethyl ether-acetic acid) showed that the by-product of the reaction started to form (Rf product: 0.16; by-product: 0.63). The solution was washed with 2M sulphuric acid (2×150 mL), saturated sodium bicarbonate (3×300 mL) and saturated sodium chloride (2×300 mL). It was finally dried over anhydrous sodium sulphate, concentrated and purified by flash chromatography on silica gel (7:3 petroleum ether-ethyl ether) to yield 1-hydroxy-3-(z-15-tetracosenoyloxy)propane as a white solid.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH:26]4[CH2:28][CH2:27]4)[NH:23][N:22]=3)[C:17]([CH2:29][O:30][Si](C(C)(C)C)(C)C)=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[C:1]([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH:26]4[CH2:28][CH2:27]4)[NH:23][N:22]=3)[C:17]([CH2:29][OH:30])=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(CO[Si](C)(C)C(C)(C)C)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(CO)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Yield: 82671.5 %

Procedure:
A solution of N-tert-butyl-5-(5-((tert-butyldimethylsilyloxy)methyl)-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-sulfonamide (120 mg, 0.24 mmol, 1.0 equiv.) and TBAF (0.3 ml, 0.29 mmol, 1.2 equiv.) in THF (5 mL) was stirred for 0.5 h at 23° C. Water was added and the reaction was extracted with EtOAc (3×50 ml). The combined organic phases were washed (brine), dried (Na2SO4), filtered and concentrated to afford N-tert-butyl-5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(hydroxymethyl)pyrimidin-2-yl) thiophene-2-sulfonamide (Compound 163) (89.0 g, 86.34%) as white solid. LC-MS (m/z)=449.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.75 (m, 2H), 0.96-0.98 (m, 2H), 1.20 (s, 9H), 1.93 (m, 1H), 4.56 (d, 4.4 Hz, 2H), 5.62 (s, 1H), 6.52 (s, 1H), 7.59 (d, J=3.6 Hz, 1H), 7.76 (d, J=3.6 Hz, 1H), 7.86 (s, 1H), 8.23 (s, 1H), 8.96 (s, 1H), 12.18 (s, 1H)
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:24][OH:25].C([O-])(O)=O.[Na+]>>[CH:1]1[C:13]2[CH:12]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:24][OH:25])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C(CC1c2ccccc2-c2ccccc21)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: ON=C(CC1c2ccccc2-c2ccccc21)c1ccncc1

Procedure:
In analogy to example 1, step 2, from 2-(9H-fluoren-9-yl)-1-pyridin-4-yl-ethanone and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (1:1) as a white foam, MS (ESI+): m/z=301.3 ([M+H]+).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:17])[C:6]1[CH:11]=[C:10](Cl)[C:9]([N:13]([CH2:15][CH3:16])[CH3:14])=[N:8][CH:7]=1)([CH3:3])[CH3:2].[CH3:18]N1C(=O)CCC1.C[Mg]Br>C1COCC1.CC(=O)OCC>[CH:1]([O:4][C:5](=[O:17])[C:6]1[CH:11]=[C:10]([CH3:18])[C:9]([N:13]([CH2:15][CH3:16])[CH3:14])=[N:8][CH:7]=1)([CH3:3])[CH3:2]
Reactant: CN1CCCC1=O
Reactant: CCN(C)c1ncc(C(=O)OC(C)C)cc1Cl
Agent: C[Mg]Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(C)c1ncc(C(=O)OC(C)C)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.1 %

Procedure:
A solution of 5-chloro-6-(ethyl-methyl-amino)-nicotinic acid isopropyl ester (5.18 g, 20.1 mmol), NMP (3.0 g, 30.2 mmol) and Fe(acac)3 (498 mg, 1.41 mmol) in THF (150 mL) is put under argon before a methylmagnesium bromide (3.0 g, 25.2 mmol, solution in diethyl ether) is added dropwise. The dark red-brown solution turns yellow, then dark brown again. The mixture is stirred at rt for 2 h before another portion of methylmagnesium bromide (1.44 g, 12.1 mmol) is added. The dark mixture is stirred at rt for 16 h. Another portion of NMP (3.0 g, 30.2 mmol), Fe(acac)3 (498 mg, 1.41 mmol) and methylmagnesium bromide (1.44 g, 12.1 mmol) is added and stirring is continued at rt for one more hour. The reaction mixture is diluted with EA (200 mL) and carefully quenched with ice-water (100 mL). The suspension is basified by adding 1 N aq. NaOH solution (10 mL) and filtered over a small pad of Hyflo and silica gel. The org. phase of the filtrate is separated and collected and the aq. phase is extracted with DCM (3×100 mL). The org. extracts are combined, dried over MgSO4, filtered and concentrated. The crude product is purified by prep. MPLC on silica gel eluting with a gradient of EA in heptane to give 6-(ethyl-methyl-amino)-5-methyl-nicotinic acid isopropyl ester (2.19 g) as a beige oil; LC-MS: tR=0.76 min, [M+1]+=237.20.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:16][C:17]1[NH:18][C:19]2[C:24]([C:25]=1[CH:26]=O)=[CH:23][CH:22]=[CH:21][CH:20]=2>>[CH3:16][C:17]1[NH:18][C:19]2[C:24]([C:25]=1/[CH:26]=[CH:14]/[C:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: Cc1[nH]c2ccccc2c1C=O
Product: COc1cc(C(=O)/C=C/c2c(C)[nH]c3ccccc23)cc(OC)c1OC
Yield: 60.7 %

Procedure:
Substantially the same procedure as in Example 1 was repeated using 3',4',5'-trimethoxyacetophenone (2.10 g) and 2-methylindole-3-carboxaldehyde (1.59 g) except that the obtained crude crystals were recrystallized from ethanol, to give Compound 12 (2.13 g).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:20])[C:5]([CH3:19])=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].C(OC([NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[NH2:29][CH:30]1[CH2:34][CH2:33][N:32]([C:3]2[C:2]([Cl:1])=[C:11]3[C:6]([C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9][N:10]3[CH:12]3[CH2:14][CH2:13]3)=[C:5]([CH3:19])[C:4]=2[F:20])[CH2:31]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: Cc1c(F)c(F)c(Cl)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(F)c(N2CCC(N)C2)c(Cl)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
A mixture of 0.50 g (1.60 mmol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.36 g (1.93 mmol) of 3-(t-butoxycarbonyl)aminopyrrolidine, 0.48 g (4.75 mmol) of triethylamine, and 20 ml of acetonitrile was refluxed for four hours, then stirred at room temperature overnight. The solution was concentrated and the residue was triturated with ether:hexane (1:1) and filtered. The solid was washed with water and hexane. The crude product was suspended in 15 ml of dichloromethane and 1.5 ml of trifluoroacetic acid and was stirred at room temperature for four hours. The solution was concentrated to a gold solid which was suspended in water, made basic (pH 11) with 10% sodium hydroxide, and filtered. The solution was then neutralized (pH 7.10), and the precipitate was filtered and washed with water to give 0.29 g of the title compound, mp 124°-126° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].CO[C:12](=[NH:20])[CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:12](=[NH:20])[CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]
Reactant: NCc1ccccc1Br
Reactant: CCOC(OCC)C(=N)OC
Product: CCOC(OCC)C(=N)NCc1ccccc1Br

Procedure:
Starting from 2-bromobenzylamine (20.00 g; commercial) and 2,2-diethoxy-ethanimidic acid methyl ester (24.46 g; 85% pure) and proceeding in analogy to Procedure A, the title compound was obtained as a yellow oil (39.31 g).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.ClC1C=CC([C@@H](CNC(C)C)[C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[C:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][N:31]=[C:30]4[NH:40][N:41]=[C:42]([O:43][CH3:44])[C:29]=34)[CH2:24][CH2:23]2)=[O:21])=CC=1.[C:50]([O:54][C:55]([NH:57][C@H:58]([CH2:62][C:63]1[CH:68]=[CH:67][C:66]([Cl:69])=[CH:65][CH:64]=1)C(O)=O)=[O:56])([CH3:53])([CH3:52])[CH3:51].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:69][C:66]1[CH:65]=[CH:64][C:63]([CH2:62][C@@H:58]([NH:57][C:55](=[O:56])[O:54][C:50]([CH3:52])([CH3:51])[CH3:53])[C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[C:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][N:31]=[C:30]4[NH:40][N:41]=[C:42]([O:43][CH3:44])[C:29]=34)[CH2:24][CH2:23]2)=[O:21])=[CH:68][CH:67]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: COc1n[nH]c2ncc(-c3ccccc3)c(N3CCN(C(=O)[C@H](CNC(C)C)c4ccc(Cl)cc4)CC3)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1n[nH]c2ncc(-c3ccccc3)c(N3CCN(C(=O)[C@@H](Cc4ccc(Cl)cc4)NC(=O)OC(C)(C)C)CC3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DIEA (0.0558 mL, 0.320 mmol) was added to 3-methoxy-5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.034 g, 0.080 mmol, see Example 9), (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (0.024 g, 0.080 mmol) and TBTU (0.0308 g, 0.0961 mmol) in DCM (1 mL) and stirred at room temperature for 1 hour. The reaction was then concentrated to dryness. The resulting residue was dissolved in THF/MeOH (2 mL, 1:1), and an aqueous LiOH solution (1 mL, 2M) was added. It was stirred for 20 minutes, and then ether (20 mL) was added. The organic layer was separated, washed with brine (10 mL), and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by chromatography (hexane:ethyl acetate, 1:1) to give (R)-tert-butyl 3-(4-chlorophenyl)-1-(4-(3-methoxy-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The mixture was stirred at room temperature for 2 hours and then concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (R)-2-amino-3-(4-chlorophenyl)-1-(4-(3-methoxy-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)propan-1-one (0.036 g, 79%). MS APCI (+) m/z 491.3 detected.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][CH2:4][C@H:3]([NH2:12])[CH2:2]1.CC1C=CC(S(O[CH2:24][C@H:25]([CH3:36])[CH2:26][S:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])(=O)=O)=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:35][O:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[S:27][CH2:26][C@@H:25]([CH3:36])[CH2:24][NH:12][C@H:3]1[CH2:4][S:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:1][CH2:2]1
Reactant: N[C@@H]1COc2ccccc2SC1
Reactant: COc1ccccc1SC[C@@H](C)COS(=O)(=O)c1ccc(C)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccccc1SC[C@@H](C)CN[C@@H]1COc2ccccc2SC1
Temperature: 105 °C
Reaction time: 24 h

Procedure:
6.5 g (35.9 mmol) of (R)-3,4-dihydro-2H-1,5-benzoxathiepin-3-amine and 11 g (30 mmol) of (S)-3-(2-methoxyphenyl-sulfanyl)-2-methylpropyl 4-methylbenzenesulfonate in 33 ml of toluene are introduced into a three-necked flask under an inert atmosphere. 6 g (60 mmol) of triethylamine are added and then the reaction mixture is heated with stirring at 105° C. for 24 hours. After returning to ambient temperature, 33 ml of toluene are added. The organic phase is washed twice with 66 ml of demineralised water and is then decolourised by stirring for one hour in the presence of 2 g of Black CXV. After concentrating under reduced pressure, driving-off with 33 ml of ethanol 100 is carried out. The title product is obtained in the form of a yellow oil (8.85 g; 79%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][S:5][C:6]=1[C:7]([NH2:9])=[O:8].[N:16]([O-])=O.[Na+]>C(O)(=O)C.Cl.O>[C:10]1([C:3]2[C:2]3[N:1]=[N:16][NH:9][C:7](=[O:8])[C:6]=3[S:5][N:4]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=N[O-]
Reactant: NC(=O)c1snc(-c2ccccc2)c1N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]nnc2c(-c3ccccc3)nsc12
Reaction time: 8 h
Yield: 71.3 %

Procedure:
219 mg of 4-amino-3-phenyl-5-isothiazolecarboxamide in 7.2 ml of glacial acetic acid and 4 ml of concentrated hydrochloric acid were stirred at 0° C. during the addition of a solution of 80 mg of sodium nitrite in 1.2 ml of water. The mixture was held at below room temperature overnight and the precipitated product was filtered off and recrystallized from methanol to give 164 mg of 7-phenylisothiazolo[4,5-d]-1,2,3-triazin-4(3H)-one. A sample recrystallized from aqueous methanol melted at 179°-180° C. (dec.).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([N:27]([CH3:35])C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[N:36]1[CH:41]=[C:40](B(O)O)[CH:39]=[N:38][CH:37]=1>>[CH3:35][NH:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:40]3[CH:41]=[N:36][CH:37]=[N:38][CH:39]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cncnc1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Product: CN[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncnc2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (5)-tert-butyl (1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (Stage 102.1) and pyrimidin-5-ylboronic acid. LC-MS (Condition 6) tR=0.89 min, m/z=459.0 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[NH:9][C:8]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]([CH3:21])[CH2:16][C:17](=[O:20])[NH:18][N:19]=3)=[CH:13][C:7]=2[N:6]=1.[CH:22]([OH:25])([CH3:24])C>>[C:22]([NH:9][C:5]([NH:1][CH2:2][CH2:3][CH2:4][C:5]1[NH:9][C:8]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]([CH3:21])[CH2:16][C:17](=[O:20])[NH:18][N:19]=3)=[CH:13][C:7]=2[N:6]=1)=[N:6][CH3:7])(=[O:25])[C:24]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:8]=1
Reactant: CC1CC(=O)NN=C1c1ccc2[nH]c(CCCN)nc2c1
Reactant: CC(C)O
Product: CN=C(NCCCc1nc2cc(C3=NNC(=O)CC3C)ccc2[nH]1)NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 41 %

Procedure:
0.44 g (1.54 mmol) of 6-[2-(3-aminopropyl)-1H-benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone and 0.43 g (1.71 mmol) of N1 -benzyl-N2 -cyano-0-phenyl-isourea are boiled under reflux in 20 ml of isopropanol for 4 hours. The solid obtained after cooling of the solution to room temperature is suction filtered and recrystallized from methanol. 0.28 g (41%) of colorless crystals melting at 270° C. are obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:14]=[CH:13][C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=1.[C:15]1([CH3:27])[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:15]1([CH3:27])[CH:16]=[CH:17][C:18]([CH:21]2[CH2:22][CH2:23][N:24]([CH2:2][CH2:3][C:4]3[CH:14]=[CH:13][C:7]4[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=4[CH:5]=3)[CH2:25][CH2:26]2)=[CH:19][CH:20]=1
Reactant: O=C1COc2ccc(CCCl)cc2N1
Reactant: Cc1ccc(C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C2CCN(CCc3ccc4c(c3)NC(=O)CO4)CC2)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a 20 mL screw cap vial was added 123 (100 mg, 0.472 mmol), 4-p-tolylpiperidine (83 mg, 0.472 mmol), K2CO3 (131 mg, 0.945 mmol) in DMF (2 mL). The reaction was stirred at 80° C. for 4 h. The reaction was filtered and the crude material was purified by prep HPLC-MS using a 25-95% MeCN in water gradient. The appropriate fractions were collected and concentrated in vacuo to give the title compound as a white solid: 1H NMR (DMSO-d6, 400 MHz): δ=10.79 (br. s., 1H), 9.27 (br. s., 1H), 7.14 (br. s., 4H), 6.94 (br. s., 1H), 6.80-6.87 (m, 1H), 6.78 (br. s., 1H), 4.56 (br. s., 2H), 3.65 (br. s., 2H), 3.27 (br. s., 2H), 3.08 (br. s., 2H), 2.94 (br. s., 2H), 2.78 (br. s., 1H), 2.28 (br. s., 3H), 2.00 (br. s., 2H), 1.82 ppm (br. s., 2H). ESI-MS: m/z 351.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[N:5]([C:12]1([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:22](Cl)(=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26].CO>C1COCC1>[CH3:20][C:12]1([N:5]2[C:4](=[O:21])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19]
Reactant: CC1(N2C(=O)c3cccc(N)c3C2=O)CCC(=O)NC1=O
Reactant: CCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCCCC(=O)Nc1cccc2c1C(=O)N(C1(C)CCC(=O)NC1=O)C2=O
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
To a suspension of 4-amino-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione (0.10 g, 0.35 mmol) in THF (15 ml) was added valeryl chloride (0.08 g, 0.70 mmol). The mixture was heated to reflux for 18 h. The reaction mixture was allowed to cool and to the solution was added methanol (2 ml). The reaction mixture was stirred for an additional 15 minutes followed by solvent evaporation in vacuo. The resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.11 g (81%) of product as an off-white solid: mp 190-192° C.; 1H NMR (DMSO-d6) 11.04 (s, 1H), 9.65 (s, 1H), 8.50 (d, J=8.4 Hz, 1H), 7.79 (t, J=7.8 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 2.74-2.44 (m, 5H), 2.10-2.03 (m, 1H), 1.90 (s, 3H), 1.66-1.54 (m, 2H), 1.42-1.27 (m, 2H), 0.91 (t, J=7.3 Hz, 3H); 13C NMR (DMSO-d6) 172.13, 172.03, 168.75, 167.36, 136.42, 135.91, 131.20, 125.68, 117.71, 116.29, 58.81, 36.25, 29.07, 28.54, 26.83, 21.65, 20.98, 13.64; Anal. Calcd. For C19H21N3O5: C, 61.39; H, 5.70; N, 11.30. Found: C, 61.03; H, 5.51; N, 11.13+0.02H2O.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([CH3:13])=[C:11]([S:14](=[O:20])(=[O:19])[NH:15][CH:16]3[CH2:18][CH2:17]3)[CH:10]=[C:9]2[C:21]([O:23]CC)=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-]>CO.O>[CH:1]1([CH2:7][N:8]2[C:12]([CH3:13])=[C:11]([S:14](=[O:20])(=[O:19])[NH:15][CH:16]3[CH2:17][CH2:18]3)[CH:10]=[C:9]2[C:21]([OH:23])=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc(S(=O)(=O)NC2CC2)c(C)n1CC1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(S(=O)(=O)NC2CC2)cc(C(=O)O)n1CC1CCCCC1
Temperature: 50 °C
Yield: 80.1 %

Procedure:
To a solution of compound 3a (8.0 g, 22.0 mmol) in MeOH (200 mL) was added a solution of LiOH (4.2 g, 100 mmol) in water (50 mL) and the solution was warmed to 50° C. overnight, cooled to rt and concentrated. The residue was diluted with water and acidified to pH˜4 with 4N aq. HCl and the solution was extracted with EA twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA=2/1) to give compound 3b (6.0 g, 80%) as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33]/[CH:34]=[C:35](\[C:39]2[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=2)/[C:36]([OH:38])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:47][C:48]1[S:49][CH:50]=[CH:51][N:52]=1>C(Cl)Cl>[S:49]1[CH:50]=[CH:51][N:52]=[C:48]1[NH:47][C:36](=[O:38])/[C:35](/[C:39]1[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=1)=[CH:34]/[CH2:33][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: O=C(O)/C(=C/CC1CCCC1)c1ccc(F)c(F)c1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)/C(=C/CC1CCCC1)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
A solution of triphenylphosphine (1.05 g, 4 mmol) in methylene chloride (15 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (712 mg, 4 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of (E)-4-cyclopentyl-2-(3,4-difluoro-phenyl)-but-2-enoic acid (0.63 g, 2.36 mmol) in methylene chloride (4 mL). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (0.59 g, 5.9 mmol), and the resulting suspension was stirred at 25° C. over the weekend. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (100 mL) and a 1N aqueous hydrochloric acid solution (100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×50 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (2×50 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 8/1 hexanes/ethyl acetate) afforded (E)-4-cyclopentyl-2-(3,4-difluoro-phenyl)-but-2-enoic acid thiazol-2-ylamide (435 mg, 53%) as an amorphous solid: EI-HRMS m/e calcd for C18H18F2N2OS (M+) 348.1108, found 348.1103.