Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:25][CH2:24][N:23]([C:26]5[CH:31]=[CH:30][N:29]=[C:28](Cl)[N:27]=5)[CH2:22][CH2:21]4)[C:15](=[O:33])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:34]=1.[CH2:35]([CH2:37][NH2:38])[OH:36]>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:21][CH2:22][N:23]([C:26]5[CH:31]=[CH:30][N:29]=[C:28]([NH:38][CH2:37][CH2:35][OH:36])[N:27]=5)[CH2:24][CH2:25]4)[C:15](=[O:33])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:34]=1
Reactant: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1CC1CCN(c2ccnc(Cl)n2)CC1
Reactant: NCCO
Solvent: CCO
Product: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1CC1CCN(c2ccnc(NCCO)n2)CC1

Procedure:
To a solution of 4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-1-[1-(2-chloro-pyrimidin-4-yl)-piperidin-4-ylmethyl]-piperazin-2-one (0.40 g, 0.74 mmol) in EtOH is added ethanolamine (0.089 mL, 1.5 mmol). The solution is heated to reflux for 18 h and evaporated to dryness. The residue is chromatographed eluting successively with 1%, 2% and 4% MeOH in CH2Cl2. Fractions containing only product are combined and the solvent evaporated. Trituration with ether afforded the title compound as a yellow solid: MS (ESI): m/z 565 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[CH:7]=[CH:8][C:9](O)=[O:10])=[O:4].[BH4-].[Na+].O>CCOCC>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1/[CH:7]=[CH:8]/[CH2:9][OH:10])=[O:4]
Reactant: COC(=O)c1ccccc1C=CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1ccccc1/C=C/CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Methoxycarbonylcinnamic acid, m.p. 176° C., was prepared by the method described in Example 2(a) and converted to the acid chloride, m.p. 75°-80° C., by the method described in Example 2(b). A solution of this acid chloride (15.5 g) in ether (250 ml) was added to a stirred suspension of sodium borohydride on alumina (60 g - prepared by addition of a solution of 1 part of sodium borohydride in 2 parts of water to 10 parts of alumina, with cooling, followed by drying under vacuum) in ether (360 ml). The mixture was stirred for 2 hours at room temperature and filtered. The filtrate was washed with 10% sodium carbonate solution, then with saturated sodium chloride solution, dried and evaporated to yield the title compound as a colourless oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:14][CH2:13][N:12]=[C:11]2[NH2:15])=[CH:5][CH:4]=1.[N:16](=[C:18]([C:24]#[N:25])[C:19](OCC)=[O:20])[OH:17]>>[NH2:25][C:24]1[N:15]=[C:11]2[N:10]([CH2:9][C:6]3[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=3)[CH2:14][CH2:13][N:12]2[C:19](=[O:20])[C:18]=1[N:16]=[O:17]
Reactant: NC1=NCCN1Cc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C#N)=NO
Agent: Cl
Product: Nc1nc2n(c(=O)c1N=O)CCN2Cc1ccc(Cl)cc1

Procedure:
The product of Procedure 91 was condensed with ethyl oximinocyanoacetate according to the method described in Procedure 1. The crude product, 1.6 g., from 2.9 g. of the product of Procedure 91, was a blue solid, m.p. 273°-275° d, recrystallized from dimethylformamide, m.p. 290°-291° d.
Reaction SMILES: [CH:1]1([N:4]2[C:8](=[O:9])[N:7]([CH2:10][C:11]3[C:12]([Cl:21])=[C:13]([CH:17]=[CH:18][C:19]=3[Cl:20])[C:14](O)=[O:15])[N:6]=[N:5]2)[CH2:3][CH2:2]1.S(Cl)([Cl:24])=O>CN(C=O)C.ClCCCl>[CH:1]1([N:4]2[C:8](=[O:9])[N:7]([CH2:10][C:11]3[C:12]([Cl:21])=[C:13]([CH:17]=[CH:18][C:19]=3[Cl:20])[C:14]([Cl:24])=[O:15])[N:6]=[N:5]2)[CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Cl)c(Cn2nnn(C3CC3)c2=O)c1Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cl)c(Cn2nnn(C3CC3)c2=O)c1Cl
Yield: 102.4 %

Procedure:
3-[(4Cyclopropyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)methyl]-2,4-dichlorobenzoic acid (5.05 g) and thionyl chloride (5.48 g) were added to 1,2-dichloroethane (60 ml) and the mixture, after adding several drops of DMF, was refluxed upon heating. After cooling, the solvent was distilled off to obtain crude 3-[(4-cyclopropyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)methyl]-2,4-dichlorobenzoyl chloride (5.46 g).
Reaction SMILES: C(OC(N1CCC(C([O:20][C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)CC)CC1)=O)C1C=CC=CC=1.[H-].[Na+].[CH2:46]([O:48][C:49](=[O:58])[C:50](Br)([CH3:56])[C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH3:47]>CN(C=O)C>[CH2:46]([O:48][C:49](=[O:58])[C:50]([O:20][C:21]1[CH:43]=[CH:42][C:24]2[C:25]3[N:29]([CH2:30][CH2:31][O:32][C:23]=2[CH:22]=1)[CH:28]=[C:27]([C:33]1[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=1)[N:26]=3)([CH3:56])[C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH3:47]
Reactant: CCOC(=O)C(C)(Br)C(=O)OCC
Reactant: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.9 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (100 mg, 0.307 mmol) in DMF (2 mL) was added sodium hydride (12.3 mg, 60% in oil, 0.307 mmol). The mixture was stirred at RT (room temperature) for 15 min, then 2-bromo-2-methylmalonic acid diethyl ester (88 μL, 0.461 mmol) was added. The reaction mixture was stirred at RT for 45 min, and then partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-8% MeOH in DCM) affording the title compound as a colourless gum (148 mg, 97%). LCMS (Method B): RT 3.46 min [M+H]+ 498.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH:17]([CH3:29])[C@H:18]([C:26]([NH2:28])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CN1CCOCC1>O1CCCC1>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([N:17]([CH3:29])[C@H:18]([C:26]([NH2:28])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CN[C@@H](Cc1ccccc1)C(N)=O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)[C@@H](Cc1ccccc1)C(N)=O
Yield: 48 %

Procedure:
Condensation of Boc-Leu-OH (liberated from 5.0 g. of the monohydrate by heating at 45° C. under vacuum) and H-MePhe-NH2 and H-MepheNH2 (mixture of isomers) hydrobromide salt (4.92 g.) and N-methylmorpholine (two 2.31 g. portions) in tetrahydrofuran (50 ml.) for 45 min. at 25° C. and then overnight at room temperature, isolation of the crude product (5.94 g.) by ethyl acetate extraction, and purification by HPLC on silica gel gave Boc-Leu-MePhe-NH2 and Boc-Leu-Mephe-NH2 (mixture of isomers) as a colorless foam (3.8 g., 48% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[Br:15][C@@H:16]1[CH2:18][C@H:17]1[C:19](Cl)=[O:20]>O1CCCC1>[Br:15][C@@H:16]1[CH2:18][C@H:17]1[C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:20]
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Reactant: O=C(Cl)[C@@H]1C[C@H]1Br
Solvent: C1CCOC1
Product: O=C1CCC(c2ccc(NC(=O)[C@@H]3C[C@H]3Br)cc2)=NN1
Yield: 58 %

Procedure:
4.0 g (21.1 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone of trans-2-bromocyclopropanecarboxylic acid chloride, 4.3 g (23.4 millimoles) and 100 ml of absolute tetrahydrofuran are kept for 20 hours at room temperature and then refluxed for 6 hours. The product is filtered off at 10° C., washed with water and recrystallized from dimethylformamide/water. 4.1 g (58% of theory) of trans-6-[p-(2-bromocyclopropylcarbonylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone are obtained as colorless crystals, of melting point 260°-261° C. (with decomposition).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:22]=[N:23][C:24]([Cl:27])=[CH:25][CH:26]=3)=[N:19][CH:20]=2)[N:12]([S:28]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)(=[O:30])=[O:29])[CH:11]=1)C)(C)(C)C.C(OCC)(=O)C.Cl>C(O)C>[Cl:27][C:24]1[N:23]=[CH:22][C:21]([C:18]2[CH:17]=[CH:16][C:15]([C:13]3[N:12]([S:28]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)(=[O:30])=[O:29])[CH:11]=[C:10]([CH2:9][NH:7][CH3:6])[CH:14]=3)=[CH:20][N:19]=2)=[CH:26][CH:25]=1
Reactant: CN(Cc1cc(-c2ccc(-c3ccc(Cl)nc3)nc2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cc(-c2ccc(-c3ccc(Cl)nc3)nc2)n(S(=O)(=O)c2cccnc2)c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl{[5-(6′-chloro-2,3′-bipyridin-5-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (100 mg) was dissolved in ethanol (8 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added and the mixture was stirred at 70° C. for 30 min. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol=99:1→19:1) to give a free salt of the title compound. The obtained free salt was dissolved in ethyl acetate (8 mL), a solution of fumaric acid (116 mg) in methanol (2 mL) was added, and the obtained crystals were collected by filtration to give the title compound as colorless crystals (yield 61 mg, 66%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[OH:8].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:28][CH2:29][CH2:30][CH2:31][NH:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][CH2:38][CH2:39][CH2:40][NH2:41]>COCCOC.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:41][CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30][CH2:29][NH2:28])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Reactant: NCCCNCCCCNCCCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: COCCOC
Product: NCCCNCCCCNCCCNC(=O)Cc1ccc(O)c(F)c1
Reaction time: 48 h

Procedure:
According to the General Procedure using 3-fluoro-4-hydroxyphenylacetic acid (85 mg, 0.50 mMol), dicyclohexylcarbodiimide (106 mg, 0.31 mMol), and spermine (512 mg, 2.53 mMol) in DME/DMF (4 ml, 3:1), activation during 2 h and coupling over 48 h. The product was eluted over silica gel with dichloromethane/methanol/0.880 ammonia solution (4:2:1). The desired amide was in fractions 12-19 and was homogeneous when monitored by tlc on silica (CH2Cl2 /MeOH/NH4OH, 4:2:1), Rf =0.19, (39 mg, 22%), lyophilisation gave 30 mg of a colourless, viscous oil whose spectroscopic data include: pmr (90 MHz, 2H2O) 1.6-2.2 (m, 8H, 4×CH2 --CH2), 2.85-3.2 (m, 10H, 5×CH2 --N), 3.4 (t, J=7, 2H, CON2H--CH2 --CH2), 3.6 (s, 2H, Ar--CH2 --CO), 6.8-7.1 (m, 2H, 2×ArH 5,6), and 7.1 (d, 3 J H--F=11, H, ArH 2)ppm.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=1.[Cl:17][CH:18]([CH3:22])[C:19](Cl)=[O:20]>ClCCl>[Cl:17][CH:18]([CH3:22])[C:19]([NH:8][C:9]1[CH:14]=[N:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)=[O:20]
Reactant: CC(Cl)C(=O)Cl
Reactant: N#Cc1ccc(N)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Cl)C(=O)Nc1ccc(C#N)nc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Triethylamine (0.635 g, 6.3 mmol) was added to a suspension of 5-amino-2-cyano-pyridine (0.500 g, 4.2 mmol) in dry dichloromethane (10 mL) under stirring at 0° C. To this, 2-chloropropionyl chloride (0.800 g, 6.3 mmol) was added dropwise and the reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for 3 hours. Reaction mixture was diluted with dichloromethane (50 mL) and was washed with saturated sodium bicarbonate solution (50 mL) and water (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product obtained was purified using column chromatography (silica gel, 30% ethyl acetate in petroleum ether as an eluent), and further crystallized from ethyl acetate and petroleum ether to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[CH:21]1[CH2:25][CH2:24][N:23]([CH3:26])[C:22]1=[O:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:26][N:23]1[CH2:24][CH2:25][C@H:21]([O:1][C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[C:22]1=[O:27]
Reactant: CN1CCC(Br)C1=O
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)cc(O[C@H]2CCN(C)C2=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 3-hydroxy-5-phenylmethoxy-benzoate (CAS no. 54915-31-0) (10.3 g, 40 mmol) and 3-bromo-1-methyl-pyrrolidin-2-one (Intermediate 4) (8.54 g, 48 mmol) were dissolved in DMF, treated with potassium carbonate (12.1 g, 88 mmol) and stirred at room temperature for 16 hours and then at 50° C. for 3 hours. The DMF was evaporated under reduced pressure and the residue partitioned between ethyl acetate (100 mL) and water (30 mL). The organic layer was separated, washed with brine (30 mL), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with 0-100% ethyl acetate in hexane to give the racemic product (8.7 g). The desired product was separated from its enantiomer by chiral HPLC using Merck 50 mm 20 μm Chiralpak AS—No ASV00SC JG001 and ASV000SC BD004 columns in series, eluting with 30% ethylacetate in isohexane at a flow rate of 60 mL/min, using 9 separate injections of 70 mL of a 14 mg/ml solution of the racemate in ethanol (32 mL) and isohexane (38 mL) to afford the product (3.6 g, 41%) which eluted before its enantiomer. 1H NMR δ (300 MHz, CDCl3) 2.06-2.20 (m, 1H), 2.51-2.63 (m, 1H), 2.94 (s, 3H), 3.31-3.54 (m, 2H), 3.89 (s, 3H), 4.87 (t, 1H), 5.08 (s, 2H), 6.90 (t, 1H), 7.27-7.46 (m, 7H).
Reaction SMILES: C(C1N(C)C2C=C(N3C=CC(OCC4C=C([F:26])SC=4)=CC3=O)C=CC=2N=1)C.[CH2:28]([C:30]1[N:34]([CH3:35])[C:33]2[CH:36]=[C:37]([N:40]3[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]4[CH:52]=[CH:51][S:50][CH:49]=4)=[CH:42][C:41]3=[O:53])[CH:38]=[CH:39][C:32]=2[N:31]=1)[CH3:29]>>[CH2:28]([C:30]1[N:34]([CH3:35])[C:33]2[CH:36]=[C:37]([N:40]3[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]4[CH:52]=[CH:51][S:50][C:49]=4[F:26])=[CH:42][C:41]3=[O:53])[CH:38]=[CH:39][C:32]=2[N:31]=1)[CH3:29]
Reactant: CCc1nc2ccc(-n3ccc(OCc4csc(F)c4)cc3=O)cc2n1C
Reactant: CCc1nc2ccc(-n3ccc(OCc4ccsc4)cc3=O)cc2n1C
Product: CCc1nc2ccc(-n3ccc(OCc4ccsc4F)cc3=O)cc2n1C

Procedure:
A mixture of the title compound, 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-((5-fluoro-3-thienyl)methoxy)pyridin-2(1H)-one and 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-(3-thienylmethoxy)pyridin-2(1H)-one obtained in step B in example 231 was subjected to HPLC separation (C18, mobile phase: H2O/CH3CN (0.1% TFA included)). The desired fraction was neutralized with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo to give the title compound (1.8 mg) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](/[N:11]=[C:12](/[NH:32][C:33](=[O:42])[CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)\[NH:13][CH2:14][CH2:15][CH2:16][C@H:17]2[C:20](=[O:21])[NH:19][C@@H:18]2[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:43]1([N:49]=[C:50]=[O:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]1([CH2:7][CH2:8][C:9](/[N:11]=[C:12](/[NH:32][C:33](=[O:42])[CH2:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)\[NH:13][CH2:14][CH2:15][CH2:16][C@H:17]2[C:20](=[O:21])[N:19]([C:50](=[O:51])[NH:49][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@@H:18]2[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCc1ccccc1)/N=C(\NCCC[C@H]1C(=O)N[C@@H]1C(=O)OCc1ccccc1)NC(=O)CCc1ccccc1
Reactant: O=C=Nc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)/N=C(\NCCC[C@H]1C(=O)N(C(=O)Nc2ccccc2)[C@@H]1C(=O)OCc1ccccc1)NC(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 149 (50 mg, 1.0 eq.) in DCM (2 mL) was added phenylisocyanate (29 μL, 3.0 eq.), triethylamine (12 μL, 1 eq.) and DMAP (1 mg). The reaction was stirred for 18 hours at room temperature and then diluted with dichloromethane and washed with 1N HCl and water. The organic layer was then concentrated in vacuo and purified via silica gel chromatography eluting with 15% EtOAc in hexanes to give 150 (10 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:25])[N:5]([C:12]1([F:24])[CH2:17][CH:16]([O:18]C(=O)C)[C:15](=[O:22])[NH:14][C:13]1=[O:23])[C:6]2=[O:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:25])[N:5]([C:12]1([F:24])[CH2:17][CH:16]([OH:18])[C:15](=[O:22])[NH:14][C:13]1=[O:23])[C:6]2=[O:11]
Reactant: CC(=O)OC1CC(F)(N2C(=O)c3cccc(N)c3C2=O)C(=O)NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: Nc1cccc2c1C(=O)N(C1(F)CC(O)C(=O)NC1=O)C2=O

Procedure:
A solution of 3-(4-amino-1,3-dioxoisoindolin-2-yl)-3-fluoro-2,6-dioxo-5-acetoxy-piperidine (1 g, 2.9 mmol) and p-toluenesulfonic acid (0.28 g, 1.5 mmol) in methanol (10 mL) is heated at reflux for 5 h. The solvent is removed in vacuo to give 4-amino-2-(3-fluoro-5-hydroxy-2,6-dioxopiperid-3-yl)isoindoline-1,3-dione which is further purified by column chromatography.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[OH-].[Na+].[CH2:12]([O:15][C:16](Cl)=[O:17])[CH:13]=[CH2:14]>C(Cl)Cl>[CH2:12]([O:15][C:16]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:17])[CH:13]=[CH2:14]
Reactant: O=C(O)C1CCNCC1
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C=CCOC(=O)N1CCC(C(=O)O)CC1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
To a solution of 4-piperidincarboxylic acid (25 g) in dry DCM (30 ml) a solution of NaOH 2N (207 ml) was added. The reaction mixture was then cooled to 0-5° and a solution of allylchloroformate (22 ml) in DCM (1 ml) was added over 40 min. The reaction was stirred at 0-5° C. for 2 h, then NaOH 2N (40 ml) was added and the organic phase was separated. The aqueous phase was washed with DCM, then acidified with H2SO4 conc. (10 ml) to pH2 and extracted with EA. The organic layer was washed with brine, dried and the solvent removed in vacuo to give the title compound as a colourless oil (39.5 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])[C:5]([N+:23]([O-:25])=[O:24])=[CH:4][N:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:36])[CH3:35])=[CH:29][CH:28]=1.Cl.C(OCC)C>CC(O)C>[ClH:1].[C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:6]1[C:5]([N+:23]([O-:25])=[O:24])=[CH:4][N:3]=[C:2]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([NH:33][C:34](=[O:36])[CH3:35])=[CH:31][CH:32]=2)[N:7]=1)(=[O:16])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: O=C(c1ccccc1)c1ccccc1Nc1nc(Cl)ncc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: CC(=O)Nc1ccc(Nc2ncc([N+](=O)[O-])c(Nc3ccccc3C(=O)c3ccccc3)n2)cc1
Temperature: 90 °C
Yield: 13.4 %

Procedure:
To a mixture of {2-[(2-chloro-5-nitropyrimidin-4-yl)amino]phenyl}(phenyl)-methanone (63 mg, 0.178 mmol) and N-(4-aminophenyl)acetamide (28 mg, 0.185 mmol) in 2-propanol (2 mL) was added 1N HCl in diethyl ether (50 uL, 0.05 mmol). The reaction mixture was heated at 90° C. for approx. 18 hours. After the reaction was cooled to room temperature cold diethyl ether was added to precipitate out the product. The precipitate was filtered and washed with cold diethyl ether, then dried under vacuum to give N-[4-({4-[(2-benzoylphenyl)amino]-5-nitropyrimidin-2-yl}amino)phenyl]acetamide hydrochloride (12 mg, 13%) as a tan solid. 1H NMR (DMSO-d6/D2O): δ 8.98 (s, 1H), 8.12 (m, 1H), 7.69-7.43 (m, 12 H), 2.05 (s, 3 H). MS m/z 468 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[C:11](Cl)(=[O:13])[CH3:12]>ClC(Cl)C>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:11](=[O:13])[CH3:12])(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: CC(=O)c1ccccc1N
Solvent: CC(Cl)Cl
Product: CC(=O)Nc1ccccc1C(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice cold slurry of the 1-(2-amino-phenyl)-ethanone (2 g, 14.79 mmol) in dichloroethane (10 mL), acetyl chloride (1.22 g, 16.2 mmol) was added slowly. The reaction mixture was warmed to room temperature and stirred for 2 h. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (2×25 mL). The combined organic layers were washed with an aq. solution of 5% NaHCO3 followed by water and brine, then dried over anhydrous sodium sulphate and concentrated to dryness. The obtained residue was purified by column chromatography using 2% ethyl acetate in hexane to obtain the title compound as off-white solid which directly used for the next reaction.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[C:4]=1[C:5](Cl)=[O:6].[CH3:20][C:21]([N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)([CH3:30])[CH:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl.C(N(CC)CC)C>[CH3:30][C:21]([N:31]1[CH2:32][CH2:33][CH2:34][CH2:35]1)([CH3:20])[CH:22]([NH:29][C:5](=[O:6])[C:4]1[C:8]([C:16]([F:19])([F:18])[F:17])=[CH:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:3]=1[S:2][CH3:1])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CSc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)Cl
Reactant: CC(C)(C(N)c1ccccc1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC(c1ccccc1)C(C)(C)N1CCCC1
Reaction time: 8 h
Yield: 85 %

Procedure:
A solution of 2-(methylthio)-4,6-bis(trifluoromethyl)benzoyl chloride D55 (60 mg; 0.19 mmol) in dry DCM (1 ml) was treated with (+)-[2-methyl-1-phenyl-2-(1-pyrrolidinyl)propyl]amine D6 (60 mg, 0.27 mmol) followed by triethylamine (5drops) and left overnight at room temperature. The volatile components were removed under reduced pressure and the residue chromatographed on silica gel. Elution with 0-80% ethyl acetate in pentane gave the title product as an oil (80 mg, 85%). 1H NMR (CDCl3) δ: 0.94 (3H, s), 1.00 (3H, s), 1.69 (4H, overlapping m), 2.54 (3H, s), 2.62 (2H, m), 2.72 (2H, m), 4.78 (1H, s), 7.25-7.45 (6H, overlapping m), 7.68 (1H, s), 7.72 (1H, s). Mass Spectrum (Electrospray LC/MS): Found 505 (MH+) C24H26F6N2OS requires 504. Ret time 2.24 min.