Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:18]=1)N.[CH3:19][N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1>>[CH3:19][N:20]1[CH2:25][CH2:24][C:23]2[NH:2][C:4]3[C:18]([C:22]=2[CH2:21]1)=[C:8]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][S:11][C:7]1=[CH:6][CH:5]=3
Reactant: CN1CCC(=O)CC1
Reactant: NNc1ccc2scc(-c3ccccc3)c2c1
Agent: Cl
Product: CN1CCc2[nH]c3ccc4scc(-c5ccccc5)c4c3c2C1

Procedure:
The compound is formed analogously to that described in Example 5, from 14 g of 5-hydrazino-3-phenylbenzothiophene hydrochloride and 6.2 g of 1-methyl-4-piperidone. Melting point: >250° C. (decomposition)
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[CH:7]([C:10]#[N:11])[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH2:13]1CCN2C(=NCCC2)CC1.IC.O>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:12])[C:7]([C:10]#[N:11])([CH3:13])[CH2:8][CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCC(C#N)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CCC(C)(C#N)C(=O)OC(C)(C)C
Temperature: 40 °C

Procedure:
To a solution of 2-cyano-butyric acid tert-butyl ester (810 mg, 4.79 mmoL) and DBU (1.4 mL, 9.58 mmol) in DMF (5 mL) was added iodomethane (1.2 mL, 19.20 mmol) dropwise at 0° C. The resulting mixture was heated to 40° C. for 24 hours. After cooling to room temperature, H2O (50 mL) and EtOAc (50 mL) were added. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% EtOAc/hexanes) to give the title compound in 650 mg. 1H NMR (CDCl3, 200 MHz): δ=2.05-1.6 (m, 2H), 1.53 (s, 3H), 1.50 (s, 9H), 1.07 (t, 3H, J=7.3 Hz).
Reaction SMILES: Br[C:2]1[C:3]([F:25])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:24]=1.[C:26]([C@:28]1([OH:35])[CH2:32][CH2:31][N:30]([CH3:33])[C:29]1=[O:34])#[CH:27]>>[F:25][C:3]1[C:2]([C:27]#[C:26][C@:28]2([OH:35])[CH2:32][CH2:31][N:30]([CH3:33])[C:29]2=[O:34])=[CH:24][C:6]2[C:7]3[N:8]([C:12]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1nc2n(c1CN1CCCC1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#C[C@]1(O)CCN(C)C1=O
Product: CN1CC[C@@](O)(C#Cc2cc3c(cc2F)OCCn2c-3nc(C(N)=O)c2CN2CCCC2)C1=O
Yield: 3.3 %

Procedure:
10-bromo-9-fluoro-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford 3 mg (3.3%) of 9-fluoro-10-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-3-(pyrrolidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide. M+1=468.2.
Reaction SMILES: [ClH:1].Cl.[N+:3]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].Br[CH:20]([CH3:36])[C:21]([C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:34][CH3:35])[C:29]=2[Cl:33])[CH:24]=1)=[O:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:33].[ClH:1].[N+:3]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH:20]([C:21]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[C:28]([O:34][CH3:35])[C:29]=4[Cl:33])[CH:24]=3)=[O:22])[CH3:36])[CH2:13][CH2:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc(CN2CCNCC2)cc1
Reactant: COc1ccc2cc(C(=O)C(C)Br)ccc2c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2cc(C(=O)C(C)N3CCN(Cc4ccc([N+](=O)[O-])cc4)CC3)ccc2c1Cl
Yield: 108.2 %

Procedure:
A mixture of N-(4-nitrobenzyl)piperazine dihydrochloride (2.94 g, 10 mmol), 2-bromo-1-(5-chloro-6-methoxynaphthalen-2-yl)propan-1-one (3.93 g, 12 mmol) and K2CO3 (4.83 g, 35 mmol) in 50 ml of DMF was treated according to general preparation 2 to give 3.51 g of compound (IV-32), yield 65%. M+ 467.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[N:13]2[CH:14]=[C:15]([I:17])[CH:16]=[C:12]2[C:11](=[O:18])[NH:10][CH2:9]1)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>C(#N)C.CN(C=O)C>[N:19]([CH2:6][CH2:7][CH:8]1[N:13]2[CH:14]=[C:15]([I:17])[CH:16]=[C:12]2[C:11](=[O:18])[NH:10][CH2:9]1)=[N+:20]=[N-:21]
Reactant: CS(=O)(=O)OCCC1CNC(=O)c2cc(I)cn21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: [N-]=[N+]=NCCC1CNC(=O)c2cc(I)cn21
Yield: 76.9 %

Procedure:
2-(7-iodo-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)ethyl methanesulfonate (0.150 g, 0.39 mmol) was reacted with sodium azide (0.076 g, 1.17 mmol) in ACN/DMF (4 ml, 1:1 ratio) for 4 hours at 80° C. under N2. The solvents were removed under vacuum, the residue was partitioned between water and DCM. The organic phase was dried (Na2SO4), filtered and evaporated, yielding the title compound as a white solid (0.097 g, 0.30 mmol, 75%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH:9][CH:10]=[O:11])=[C:4]([Cl:12])[N:3]=1.[NH2:13][CH2:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C:22]2=[O:26])[CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>CC(O)C>[NH2:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]([NH:9][CH:10]=[O:11])=[C:6]([NH:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([N:21]3[CH2:25][CH2:24][CH2:23][C:22]3=[O:26])[N:20]=2)[N:7]=1
Reactant: NCc1cccc(N2CCCC2=O)n1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Nc1nc(Cl)c(NC=O)c(NCc2cccc(N3CCCC3=O)n2)n1
Yield: 54.1 %

Procedure:
A mixture of N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide (3.61 g, 17.43 mmol) and 1-(6-aminomethylpyridin-2-yl)pyrrolidin-2-one (containing triphenylphosphine oxide) (10.00 g, ca. 50 mmol) and triethylamine (4.86 mL, 34.86 mmol) in propan-2-ol (100 mL) was heated at reflux for 18 h, cooled and the resulting precipitate filtered to give the title compound (3.41 g) as an off-white solid; NMR δH (400 MHz, d6-DMSO) 9.21 (1H, s), 8.20 (1H, d, J 1 Hz), 8.12 (1H, d, J 8.5 Hz), 7.73 (1H, t, J 7.5 Hz), 7.38 (1H, t, J 6 Hz), 7.02 (1H, d, J 7.5 Hz), 6.45 (2H, br s), 4.53 (2H, d, J 6.0 Hz), 4.00-3.95 (2H, m), 2.57 (2H, t, J 8.0 Hz) and 2.08-2.00 (2H, m).
Reaction SMILES: [Li]CCCC.CCCCCC.CC1(C)CCCC(C)(C)N1.[C:22]1(=[O:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.Cl[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37]>C1COCC1>[CH3:37][O:36][C:31]1[CH:32]=[C:33]([CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C:22]2=[O:28])[CH:34]=[CH:35][CH:30]=1
Reactant: O=C1CCCCC1
Reactant: COc1ccccc1Cl
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(C2CCCCC2=O)c1
Reaction time: 0.17 h

Procedure:
To 1.6 M n-BuLi in hexane (12.5 mL, 20 mmol) at 0° C. was added a solution of 2,2,6,6-tetramethyl piperidine (3.4 mL, 20 mmol) in anhydrous THF (40 mL) over 5 min. Cyclohexanone (2.1 mL, 20 mmol) was added dropwise. After stirring the reaction mixture for 10 min, a further portion of 1.6M n-BuLi in hexane (12.5 mL, 20 mmol) was added, the mixture stirred for 10 min, and 2-chloroanisole (2.5 mL, 20 mmol) was added. After stirring for 30 min under Ar, the reaction mixture was quenched with H2O (300 mL) and extracted with EtOAc (150 mL). The organic layer was separated, washed with 2N HCl (100 mL), H2O (200 mL) and brine, then dried (MgSO4). Filtration and concentration gave the title compound after SiO2 chromatography (CHCl3:MeOH, 200:1).
Reaction SMILES: NC1C=CC(F)=CC=1C(NC)=O.[F:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][CH3:21])=[O:19])=[C:16]([N+:24]([O-])=O)[CH:15]=1>>[NH2:24][C:16]1[CH:15]=[C:14]([F:13])[CH:23]=[CH:22][C:17]=1[C:18]([NH:20][CH3:21])=[O:19]
Reactant: CNC(=O)c1ccc(F)cc1[N+](=O)[O-]
Agent: CNC(=O)c1cc(F)ccc1N
Product: CNC(=O)c1ccc(F)cc1N

Procedure:
The title compound was prepared using the procedure from Compound 102A with 4-Fluoro-N-methyl-2-nitrobenzamide (Compound 103B). MS (ES+): m/z 169.07 [MH+] (TOF, polar).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[C@H:4]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[NH:5][C:6](=[O:35])[C@H:7]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[NH:8][C:9](=[O:27])[C@H:10]([CH2:23][C:24](=[O:26])[NH2:25])[NH:11][C:12](=[O:22])[CH2:13][NH:14]C(OC(C)(C)C)=O.C(N1CCOCC1)C.ClC1C(O[C:60](=[S:82])[CH2:61][CH2:62][C:63]([C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)=C(Cl)C(Cl)=C(Cl)C=1Cl>FC(F)(F)C(O)=O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:43])[C@H:4]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[NH:5][C:6](=[O:35])[C@H:7]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[NH:8][C:9](=[O:27])[C@H:10]([CH2:23][C:24](=[O:26])[NH2:25])[NH:11][C:12](=[O:22])[CH2:13][NH:14][C:60](=[S:82])[CH2:61][CH2:62][C:63]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C:76]1[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=1
Reactant: S=C(CCC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)OC(C)(C)C
Agent: CCN1CCOCC1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=S)CCC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A solution of t-butoxycarbonyl-glycyl-asparaginyl-phenylalanyl-phenylalanine methyl ester (0.525 g, 0.879 mmole, described in Example 4) in trifluoroacetic acid (10 ml) is stirred at 0° C. for 90 minutes and evaporated. The residue is dissolved in methanol (1 ml) and diethyl ether (100 ml) is added. The precipitate is collected and dried. A solution of the precipitate, N-ethylmorpholine (0.11 ml, 0.85 mmole) and 3-tritylthiopropionic acid pentachlorophenyl ester (0.556 g, 0.935 mmole) in dimethylformamide (25 ml) is stirred at 0° C. for 1 hour and at 25° C. for 20 hours and evaporated. The residue is triturated with methanol and the precipitate is dried to give the title compound as a powder, mp 234°-236.5° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=O.Cl.[NH2:30][OH:31].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:31][NH:30][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:2]
Reactant: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(OC)c(OC)c3)CC2)s1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(S(=O)(=O)N2CCN(c3ncc(C(=O)NO)s3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound (12b) (125 mg, 0.292 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (202 mg, 2.92 mmol) and a freshly prepared solution of sodium methoxide in methanol (100 mg, 4.35 mmol of sodium dissolved in 1 mL of methanol) under N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethylacetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethyl acetate (5 mL) and the combined organic layers were dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 13b as a solid. HPLC: 86.09% (Rt=12.51 min).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][F:12])[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=3[CH3:21])[C:6]=2[CH:5]=[C:4]([NH2:22])[CH:3]=1.[OH-].[Na+].Br[CH2:26][CH2:27][O:28][CH2:29][CH2:30]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][F:12])[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=3[CH3:21])[C:6]=2[CH:5]=[C:4]([N:22]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:3]=1
Reactant: Cc1c(Cl)cccc1Cn1c(CF)nc2c(Br)cc(N)cc21
Reactant: BrCCOCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Product: Cc1c(Cl)cccc1Cn1c(CF)nc2c(Br)cc(N3CCOCC3)cc21
Temperature: 110 °C
Yield: 26.4 %

Procedure:
Into a 100 ml round bottomed flask with 4-bromo-1-(3-chloro-2-methylbenzyl)-2-(fluoromethyl)-1H-benzo[d]imidazol-6-amine (2.49 g, 6.51 mmol), tetrabutylammonium iodide (0.120 g, 0.325 mmol) was added 6N sodium hydroxide (16.27 ml, 98 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (1.623 ml, 13.01 mmol), Reaction was heated to 110° C. for 2 h then cooled to room temperature and the mixture was extracted with EtOAc, washed with Brine and concentrated. The residue was purified by reversed phase eluted with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (35-65%) over 12 minutes. The expected compound was collected and evaporated to yield a colorless oil 4-(4-bromo-1-(3-chloro-2-methylbenzyl)-2-(fluoromethyl)-1H-benzo[d]imidazol-6-yl)morpholine (777 mg, 1.716 mmol, 26.4% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.50 (s, 3H) 3.12-3.18 (m, 4H) 3.78-3.86 (m, 4H) 5.55-5.71 (m, 4H) 6.37 (d, J=8.08 Hz, 1H) 6.84 (d, J=2.02 Hz, 1H) 7.06 (t, J=8.08 Hz, 1H) 7.36 (d, J=8.08 Hz, 1H) 7.39 (d, 1H); LC/MS: MS (ES+) m/e 453 [M+H]+.
Reaction SMILES: C1([C@@H]([NH:9][C@H:10]2[C:14]3([CH2:16][CH2:15]3)[CH2:13][NH:12][CH2:11]2)C)C=CC=CC=1.C(O)C.[ClH:20].[H][H]>[OH-].[Pd+2].[OH-].O>[ClH:20].[ClH:20].[NH2:9][C@H:10]1[C:14]2([CH2:16][CH2:15]2)[CH2:13][NH:12][CH2:11]1
Reactant: [H][H]
Reactant: C[C@H](N[C@@H]1CNCC12CC2)c1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N[C@@H]1CNCC12CC2
Yield: 82 %

Procedure:
An autoclave was charged with 79 mg of (S)-7-[(S)-1-phenylethyl]amino-5-azaspiro[2.4]heptane, 37 mg of 20% palladium hydroxide, 2 ml of ethanol, 1 ml of water and 0.5 ml of concentrated hydrochloric acid, and the contents were stirred overnight at room temperature in an atmosphere of hydrogen (40 kgf/cm2). After completion of the reaction, the catalyst was removed by filtration and the resulting filtrate was concentrated under a reduced pressure to obtain 72 mg (82%) of the title compound in the form of colorless crystals. The thus obtained crystal compound was recrystallized from ethanol and diethyl ether and used as a sample for analyses.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]([C:13]1[S:17][C:16]([CH3:18])=[N:15][C:14]=1[CH3:19])(=[O:12])[CH3:11]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]([C:13]2[S:17][C:16]([CH3:18])=[N:15][C:14]=2[CH3:19])([OH:12])[CH3:11])=[CH:3][CH:4]=1
Reactant: CC(=O)c1sc(C)nc1C
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(C(C)(O)c2sc(C)nc2C)cc1

Procedure:
Following the general method of Example 3 but starting with 4-bromoanisole and 5-acetyl-2,4-dimethylthiazole, the title compound was prepared. M.p. 114-115.5° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:12][CH:13]([CH3:15])[CH3:14])[C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[CH:7]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.CS(C)=O.C[CH2:52][O:53][C:54](C)=[O:55].O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:52][O:53][C:54]([C:2]1[N:3]=[C:4]([NH:12][CH:13]([CH3:15])[CH3:14])[C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[CH:7]=1)=[O:55]
Reactant: CC(C)Nc1nc(Br)cn2c(=O)[nH]nc12
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)c1cn2c(=O)[nH]nc2c(NC(C)C)n1
Temperature: 75 °C
Reaction time: 14 h

Procedure:
A solution of 521 mg of the product of Step E, 313 mg of 1,3-bis-(diphenylphosphino)propane, 212 mg of palladium(II) acetate and 13.8 g of TEA in a 10:1 mixture of MeOH/DMSO (209 mL) was agitated under a carbon monoxide atmosphere (45 psi) at 75° C. After 14 h, the reaction was cooled to ambient temperature and portioned between EtOAc/water. The resulting mixture was filtered through a pad of diatomaceous earth and the solids washed with EtOAc. The layers were separated and the aqueous was extracted with EtOAc. The combined organic extracts were washed with sat. sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated to provide 8-isopropylamino-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-6-carboxylic acid methyl ester as an oil. MS (M+H+)=252.3.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH:11]([CH3:15])[C:12]([OH:14])=O.[NH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH:11]([CH3:15])[C:12]([N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1)=[O:14]
Reactant: CC(Sc1nc2ccccc2s1)C(=O)O
Reactant: c1ccc2c(c1)CCCN2
Product: CC(Sc1nc2ccccc2s1)C(=O)N1CCCc2ccccc21
Yield: 34 %

Procedure:
The title compound was synthesized according to General Procedure B using 2-(benzo[d]thiazol-2-ylthio)propanoic acid and 1,2,3,4-tetrahydroquinoline to yield 47 as a yellow oil (34%): MS m/z: 355 (M+H)+. Anal. Calcd. For, C19H18N2OS2: C, 64.38; H, 5.12; N, 7.90; S, 18.09. Found: C, 64.38; H, 5.26; N, 7.97; S, 18.08.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]2=1.[CH:23]1[C:31]2[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[O:28][C:27]=2[C:26](B(O)O)=[CH:25][CH:24]=1>>[CH:23]1[C:31]2[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[O:28][C:27]=2[CH:26]=[C:25]([C:2]2[CH:3]=[C:4]([CH:20]([CH3:21])[CH3:22])[CH:5]=[C:6]3[C:10]=2[NH:9][C:8]2[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]3=2)[CH:24]=1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(Br)cc(C(C)C)cc21
Product: CCC1(CCO)OCCc2c1[nH]c1c(-c3ccc4c(c3)oc3ccccc34)cc(C(C)C)cc21

Procedure:
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 4-dibenzofuranboronic acid in step 1.F.
Reaction SMILES: C([NH:5][S:6]([C:9]1[O: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]([Cl:29])=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.B(Cl)(Cl)Cl>C(Cl)Cl>[Cl:29][C:17]1[C:18]([NH:20][C:21]2[CH:25]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[NH:23][N:22]=2)=[N:19][C:14]([C:11]2[O:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=2)=[N:15][CH:16]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)o1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)o1
Reaction time: 2 h
Yield: 52.5 %

Procedure:
To a solution of compound N-tert-butyl-5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)furan-2-sulfonamide (45 mg, 0.10 mmol, 1.0 equiv.) in CH2Cl2 (5 mL) was added BCl3 (1.0 mL, 1.0 mmol, 10.0 equiv.) at room temperature. The mixture was stirred for 2 hours, then, concentrated. The residue was recrystallized with methanol and isopropylether to give the title compound 5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)furan-2-sulfonamide (Compound 240) (20 mg, 53%). LC-MS (m/z)=380.9 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.73-0.81 (m, 2H), 0.91-1.00 (m, 2H), 1.91-1.97 (m, 1H), 6.50 (s, 1H), 7.12 (d, J=3.2 Hz, 1H), 7.21 (d, J=2.8 Hz, 1H), 7.93 (s, 2H), 8.48 (s, 1H), 9.44 (s, 1H), 12.28 (s, 1H).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:13][S:12][C:11](=[N:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[N:10]2[CH3:22])=[CH:5][C:4]=1[S:24](=[O:29])(=[O:28])[N:25]([CH3:27])[CH3:26].O>CO.C(N(CC)CC)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:22])[C:11](=[N:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[S:12][CH:13]=2)=[CH:5][C:4]=1[S:24](=[O:29])(=[O:28])[N:25]([CH3:26])[CH3:27]
Reactant: CN1C(=Nc2ccccc2Cl)SCC1(O)c1ccc(Cl)c(S(=O)(=O)N(C)C)c1
Agent: Br
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)S(=O)(=O)c1cc(-c2csc(=Nc3ccccc3Cl)n2C)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10.8 g of 4-(4-chloro-3-dimethylsulfamoylphenyl)-2-(2-chlorophenyl-imino)-3-methylthiazolidin-4-ol hydrobromide are heated at the boil in a mixture of 100 ml of methanol and 10 ml of triethylamine for 30 minutes and the reaction mixture is then poured into an equal volume of water. The resulting mixture is stirred for about 2 hours at room temperature and the crystals are filtered off and recrystallized from ethanol. Melting point 153°-156° C.
Reaction SMILES: CS(O)(=O)=O.[CH2:6]([C:9]([CH2:20][CH2:21][CH3:22])(C(OCC)=O)[C:10]([O:12]CC)=[O:11])[CH2:7][CH3:8].C(O)C>O>[C:10]([OH:12])(=[O:11])[CH:9]([CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH3:8]
Reactant: CCCC(CCC)(C(=O)OCC)C(=O)OCC
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CCO
Product: CCCC(CCC)C(=O)O
Reaction time: 1.5 h
Yield: 123.9 %

Procedure:
A mixture of 38.6 ml of 70% methanesulfonic acid and 352.2 g of diethyl dipropylmalonate was heated to 135°-145° C. in a flask equipped with a distillation column packed with Raschig rings. After 1.5 hour, ethanol began to reflux in the distillation head. Ethanol was distilled as it formed and the pot temperature was maintained at 120°-145° C. by periodic addition of water to the pot. After 5 hours, additional ester (133 g) was added to the pot and the distillation of ethanol was continued. After 24 hours, the distillation of ethanol had ceased. The mixture then was cooled and treated with 50 ml of water. The layers were separated and the organic layer was washed with 100 ml of 5% sodium chloride solution to afford 257.6 g (90% yield) of valproic acid as a light brown liquid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[C:8]2[CH2:7][C:6](Br)([CH:17]([CH3:19])[CH3:18])[C:5](=[O:21])[C:4]=2[C:3]=1[CH3:22].[Br-].[Li+]>CN(C)C=O>[CH3:1][C:2]1[C:10]2[O:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[C:8]2[CH2:7][C:6](=[C:17]([CH3:18])[CH3:19])[C:5](=[O:21])[C:4]=2[C:3]=1[CH3:22]
Reactant: Cc1c2c(c3cc(C(=O)O)oc3c1C)CC(Br)(C(C)C)C2=O
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)=C1Cc2c(c(C)c(C)c3oc(C(=O)O)cc23)C1=O
Temperature: 0 °C

Procedure:
A solution of 4,5-dimethyl-6-oxo-7,8-dihydro-7-bromo-7-isopropyl-6H-indeno[5,4-b]furan-2-carboxylic acid (0.01 mole) and lithium bromide (0.02 mole) in dimethylformamide (100 ml.) is heated in an inert atmosphere (nitrogen) at 95°C. for 2.0 hours; poured into ice water (300 ml.) to afford 4,5-dimethyl-6-oxo-7,8-dihydro-7-isopropylidene-6H-indeno[5,4-b]furan-2-carboxylic acid.