Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][C:3]([C:9]1[NH:26][C:12]3=[N:13][CH:14]=[CH:15][C:16]([C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=4[O:24][CH3:25])=[C:11]3[CH:10]=1)=[CH:2]2.[CH3:27][S:28](Cl)(=[O:30])=[O:29].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[F:23][C:21]1[CH:20]=[CH:19][C:18]([O:24][CH3:25])=[C:17]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[NH:26][C:9]([C:3]4[CH2:4][CH:5]5[N:8]([S:28]([CH3:27])(=[O:30])=[O:29])[CH:1]([CH2:7][CH2:6]5)[CH:2]=4)=[CH:10][C:11]=23)[CH:22]=1
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CC4CCC(C3)N4)cc12
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CC4CCC(C3)N4S(C)(=O)=O)cc12
Reaction time: 3 h

Procedure:
To a solution of Example 223C (80.0 mg, 0.189 mmol) in N,N-dimethylformamide (2 mL) was added methanesulfonyl chloride (0.030 mL, 0.379 mmol) and triethylamine (0.158 mL, 1.137 mmol) and the mixture was stirred for 3 hours. The mixture was treated with brine and aqueous sodium bicarbonate and extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate, filtered, concentrated, and purified on silica gel using an ISCO Companion eluting with heptanes/ethyl acetate (1:9 to 0:10) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 1.63-1.74 (m, 1H), 1.91-2.14 (m, 2H), 2.15-2.27 (m, 1H), 2.92-3.00 (m, 4H), 3.74 (s, 3H), 4.32-4.40 (m, 1H), 4.44 (t, J=5.8 Hz, 1H), 6.22 (s, 1H), 6.79 (d, J=6.0 Hz, 1H), 7.03 (d, J=4.9 Hz, 1H), 7.15-7.31 (m, 3H), 8.20 (d, J=4.9 Hz, 1H), 11.73-11.86 (m, 1H). MS (ESI+) m/z 428.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClC(Cl)C.C(O)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:27]2[CH2:28][CH2:29][N:24]([C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[CH2:25][CH2:26]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A mixture of piperazine-1-carboxylic acid benzyl ester (6.6 g, 29.96 mmol) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester in dichloroethane (150 mL) containing two drops of acetic acid was stirred at RT for 1 h and then sodium triacetoxyborohydride (19.05 g, 89.89 mmol) was added in portions. The reaction mixture was stirred at RT overnight, water (150 mL) was added, and the reaction mixture was stirred at RT for 2 h. The reaction mixture was extracted with DCM (4×30 mL). Combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (20-30% EtOAc/petroleum ether) to provide the title intermediate (9 g, 74% yield) as a colorless oil. (m/z): [M+H]+ calcd for C22H33N3O4 404.25, found 404.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([OH:14])[CH:7]=1)[CH3:2].[Cl:16][C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([CH:24]=1)[CH:22]=[O:23]>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:20]2[CH:19]=[CH:18][C:17]([Cl:16])=[CH:24][C:21]=2[CH:22]=[O:23])[CH:7]=1)[CH3:2]
Reactant: O=Cc1cc(Cl)ccc1F
Reactant: CCOC(=O)Cc1ccc(OC)c(O)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 4, using the following starting materials: (3-hydroxy-4-methoxy-phenyl)-acetic acid ethyl ester and 5-chloro-2-fluorobenzaldehyde.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[C:18]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])(=[O:20])[CH3:19]>>[C:18]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH:4]=[C:5]2[C:16]3[C:8](=[CH:9][CH:10]=[C:11]4[C:15]=3[S:14][CH:13]=[N:12]4)[NH:7][C:6]2=[O:17])=[CH:27][CH:26]=1)(=[O:24])=[O:23])(=[O:20])[CH3:19]
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Reactant: CC(=O)NS(=O)(=O)c1ccc(N)cc1
Product: CC(=O)NS(=O)(=O)c1ccc(NC=C2C(=O)Nc3ccc4ncsc4c32)cc1
Yield: 26 %

Procedure:
The title compound was prepared in 26% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and N-acetyl-4-aminobenzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ 12.0 (s, 1H), 11.2 (d, 1H), 10.9 (s, 1H), 8.1 (d, 1H), 7.9 (m, 3H), 7.6 (d, 2H), 7.1 (d, 1H), 2.0 (s, 3H); ESI-MS m/z 413 (M−H)−.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=O)=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[N:1]1([CH:6]([C:10]2[CH:11]=[CH:12][C:13]([C:14]#[N:16])=[CH:17][CH:18]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCC(c1ccc(C(N)=O)cc1)n1ccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CCCC(c1ccc(C#N)cc1)n1ccnc1
Temperature: 5 °C
Reaction time: 20 h
Yield: 70.5 %

Procedure:
4.9 g of the amide of example 3 is dissolved in 50 ml of dioxane and 3.23 ml of pyridine and mixed with 3.16 ml of trifluoroacetic acid anhydride under ice cooled at 5° C. internal temperature. After 20 hours of stirring at room temperature it is added to half-saturated potassium carbonate solution, extracted with ether and the ether phase is dried and concentrated by evaporation. After distillation on a bulb tube at 200°-215° C./0.05 mbar, 3.2 g of 4-[1-(1-imidazolyl)-butyl]-benzonitrile is obtained, which, after crystallization from ether, melts at 63°-71° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:29])([F:28])[CH:20]([OH:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].CN(C1C=CC=CN=1)C.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:27][CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:19]([F:18])([F:28])[F:29])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCC(O)C(F)(F)F
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCC(OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Temperature: 0 °C
Yield: 61.2 %

Procedure:
To a solution of 4-benzyloxybenzoic acid chloride (4.3 g) in methylene chloride (50 ml) was slowly added under ice cooling a solution of optically active 1,1,1-trifluoro-2-octanol (2.9 g), dimethylaminopyridine (0.6 g) and triethylamine (1.7 g) in methylene chloride (50 ml). The mixture was left to stand until it reached room temperature and allowed to react overnight. The mixture was poured in ice water and extracted with methylene chloride. The extracted layer was washed with dilute aqueous hydrochloric acid solution, water, 1N aqueous sodium carbonate solution and water, in this order, and dried over anhydrous magesium sulfate. After the solution was distilled to remove the solvent, the crude product obtained was purified by silica-gel column chromatography and recrystallized from ethanol to obtain the titled compound (3.8 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:7][CH2:8]Cl)=[CH:2]1.[NH2:10][C:11]1[S:12][C:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18][C:19]=2[N:20]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(C)C>C(Cl)(Cl)Cl>[NH2:10][C:11]1[S:12][C:13]2[CH2:14][CH2:15][N:16]([CH2:8][CH:7]=[CH:6][C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[CH2:17][CH2:18][C:19]=2[N:20]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: ClCC=Cc1ccsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: Nc1nc2c(s1)CCN(CC=Cc1ccsc1)CC2
Yield: 8 %

Procedure:
Prepared from 3-(3-thienyl)allyl chloride and 1 equivalent of 2-amino-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine in chloroform in the presence of I equivalent of potassium carbonate. Yield: 8% of theory, Melting point: 128°-132° C. (isopropanol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)[CH:5]=[CH:4][N:3]=1.[CH3:19][N:20]1[CH:28]=[C:27]2[C:22]([CH:23]=[C:24]([NH2:29])[CH:25]=[CH:26]2)=[N:21]1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:29][C:24]2[CH:25]=[CH:26][C:27]3[C:22]([CH:23]=2)=[N:21][N:20]([CH3:19])[CH:28]=3)=[O:14])[CH:5]=[CH:4][N:3]=1
Reactant: Cn1cc2ccc(N)cc2n1
Reactant: O=C(O)c1ccccc1NCc1ccnc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(Br)c3)cc2n1
Yield: 95.8 %

Procedure:
0.500 g (1.6 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid, 0.471 g (3.2 mmol) of 2-methyl-2H-indazol-6-ylamine, 0.4 ml (3.68 mmol) of N-methylmorpholine and 0.729 g (1.92 mmol) of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU) in 25 ml of dimethylformamide are stirred for 16 hours at room temperature. The dimethylformamide is drawn off in an oil pump vacuum. The remaining residue is drawn off in saturated sodium bicarbonate solution. It is extracted three times with ethyl acetate, and the combined organic phases are dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with a gradient that consists of hexane:acetone=100:0 to 50:50 as an eluant. 0.669 g (96% of theory) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benzamide is obtained in the form of a beige foam.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:36]=[C:37]([Cl:39])[CH:38]=1)[O:27][C:28]1[O:32][C:31]([C:33](Cl)=[O:34])=[CH:30][CH:29]=1>C1COCC1>[Cl:23][C:24]1[CH:25]=[C:26]([CH:36]=[C:37]([Cl:39])[CH:38]=1)[O:27][C:28]1[O:32][C:31]([C:33]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:12]=3)[CH2:7][CH2:6]2)=[O:34])=[CH:30][CH:29]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(Cl)c1ccc(Oc2cc(Cl)cc(Cl)c2)o1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)c3ccc(Oc4cc(Cl)cc(Cl)c4)o3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 5-(3,5-dichlorophenoxy)-2-furoyl chloride: ESMS m/e: 558.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:11]([O-])=O)[CH:8]=2)[C:3]1=[O:14].[Sn](Cl)(Cl)(Cl)Cl>CCO.O>[NH2:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3](=[O:14])[N:2]([CH3:1])[CH2:10]2
Reactant: CN1Cc2cc([N+](=O)[O-])ccc2C1=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: CN1Cc2cc(N)ccc2C1=O
Temperature: 79 °C
Reaction time: 2 h

Procedure:
The 2-methyl-5-nitroisoindolin-1-one (50 mg, 0.26 mmol) was dissolved in EtOH (1.3 ml) with heating, and tin chloride (117 mg, 0.52 mmol) added. The solution was stirred at 79° C. for 2 hours. The mixture was cooled to RT, diluted with 4:1 water:saturated sodium bicarbonate (aq, 100 ml), extracted with EtOAc (3×100 ml), the organics combined, washed with brine, dried over Na2SO4, filtered and the volatiles removed in vacuum. The product was purified by chromatography on SiO2 eluting with 5% MeOH:DCM+1% TEA to give the titled compound.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:41]1[S:45][N:44]=[CH:43][N:42]=1)[S:7]([C:10]1[C:39]([F:40])=[CH:38][C:13]2[N:14]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3([OH:37])[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]3)[CH3:19])[C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].C(Cl)Cl.C(O)(C(F)(F)F)=O>CO>[F:40][C:39]1[C:10]([S:7]([NH:6][C:41]2[S:45][N:44]=[CH:43][N:42]=2)(=[O:8])=[O:9])=[CH:11][C:12]2[O:16][C:15](=[O:17])[N:14]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3([OH:37])[CH2:27][NH:28][CH2:29]3)[CH3:19])[C:13]=2[CH:38]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)n([C@H](C)c4ccccc4C4(O)CN(C(=O)OC(C)(C)C)C4)c3cc2F)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: C[C@H](c1ccccc1C1(O)CNC1)n1c(=O)oc2cc(S(=O)(=O)Nc3ncns3)c(F)cc21
Reaction time: 0.25 h

Procedure:
In a 1 dram vial, added (R)-tert-butyl 3-(2-(1-(6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-5-fluoro-2-oxobenzo[d]oxazol-3(2H)-yl)ethyl)phenyl)-3-hydroxyazetidine-1-carboxylate (32-3, 60 mg, 0.081 mmol) to DCM (647 μl) and TFA (162 μl). After 15 min, diluted with 1 mL MeOH, filtered through Celite, purified by reverse-phase HPLC (20 min run, 5-60% 0.1% TFA/CH3CN:0.1% TFA/H2O) to give 32-4 as a white solid. 1H NMR δ (ppm) (CH3OH-d4): 8.21 (1H, s), 7.83 (1H, d, J=7.64 Hz), 7.71 (1H, d, J=5.61 Hz), 7.54-7.41 (2H, m), 7.27 (1H, d, J=7.61 Hz), 7.00 (1H, d, J=10.04 Hz), 5.52 (1H, dt, J=13.86, 6.77 Hz), 4.42 (2H, dd, J=10.60, 3.89 Hz), 4.14 (2H, dd, J=10.77, 3.87 Hz), 1.95 (3H, d, J=6.97 Hz). HRMS C20H19FN505S2 [M+H] calc: 492.0806, obs: 492.0796.
Reaction SMILES: CC(C)(C)C(Cl)=O.C(N(CC)CC)C.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26](=[O:33])[NH:25][N:24]=2)=[CH:18][C:17]=1[NH:34][C:35](=[O:42])[NH:36][CH:37]([CH3:41])[C:38](O)=[O:39]>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26](=[O:33])[NH:25][N:24]=2)=[CH:18][C:17]=1[N:34]1[C:38](=[O:39])[CH:37]([CH3:41])[NH:36][C:35]1=[O:42]
Reactant: CC(NC(=O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)C(=O)O
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: CC1NC(=O)N(c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)C1=O

Procedure:
To a premixed solution of trimethyl acetyl chloride (240 mg, 2.0 mmol) and triethylamine (0.35 ml, 2.5 mmol) was added 2-{3-[2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-phenyl]-urido}-propionic acid (45)(0.76 g, 2.0 mmol). The reaction was stirred at room temperature for 4 days at room temperature with slow progression to the desired product. The reaction mixture was then concentrated in vacuo and the crude material was submitted for preparative HPLC (40 mg isolated, 95% purity, RT (mins): 4.35)
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:17][C:16]3[C:15](=[O:18])[N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:13](=[O:25])[N:12]([CH2:26][C:27]4[O:31][N:30]=[C:29]([CH2:32][O:33][CH3:34])[N:28]=4)[C:11]=3[CH:10]=2)=[C:5]([O:35][CH3:36])[CH:4]=1.[CH2:37]([O:39][C:40]1[C:49]([O:50][CH3:51])=[CH:48][C:47]2[C:46]([C:52]3[CH:53]=[C:54]([CH:58]=[CH:59][CH:60]=3)[C:55](O)=[O:56])=[N:45][C@@H:44]3[CH2:61][CH2:62][S:63][CH2:64][C@@H:43]3[C:42]=2[CH:41]=1)[CH3:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:37]([O:39][C:40]1[C:49]([O:50][CH3:51])=[CH:48][C:47]2[C:46]([C:52]3[CH:53]=[C:54]([C:55]([N:22]4[CH2:23][CH2:24][CH:19]([N:14]5[C:15](=[O:18])[C:16]6[S:17][C:9]([C:6]7[CH:7]=[CH:8][C:3]([F:2])=[CH:4][C:5]=7[O:35][CH3:36])=[CH:10][C:11]=6[N:12]([CH2:26][C:27]6[O:31][N:30]=[C:29]([CH2:32][O:33][CH3:34])[N:28]=6)[C:13]5=[O:25])[CH2:20][CH2:21]4)=[O:56])[CH:58]=[CH:59][CH:60]=3)=[N:45][C@@H:44]3[CH2:61][CH2:62][S:63][CH2:64][C@@H:43]3[C:42]=2[CH:41]=1)[CH3:38]
Reactant: COCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc(F)cc4OC)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)O)c1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccc(F)cc6OC)cc5n(Cc5nc(COC)no5)c4=O)CC3)c1)=N[C@@H]1CCSC[C@H]21

Procedure:
6-(4-fluoro-2-methoxyphenyl)-1-{[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]methyl}-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (415 mg; compound B84) is reacted with 3-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (408 mg; compound C8) and HBTU (322 mg) in DCM (10 ml) in the presence of DIPEA (498 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: Cyclohexane/EtOAc, 100/0 to 0/100 (v/v)] and by preparative HPLC as a solid.
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.CS(Cl)(=O)=O.[CH2:13]([N:17]1[C:21]([CH2:22]O)=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:19]=[C:18]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:14][CH2:15][CH3:16]>C(#N)C.[C-]#N.C([N+](CC)(CC)CC)C>[CH2:13]([N:17]1[C:21]([CH2:22][C:1]#[N:3])=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:19]=[C:18]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCN(CC)CC
Reactant: CCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1CO
Agent: CC[N+](CC)(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Solvent: CC#N
Product: CCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1CC#N
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Triethylamine (1.0 ml, 7.18 mmol) and methanesulfonyl chloride (0.37 ml, 4.89 mmol) are added to a stirred solution of (3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-methanol (1.0 g, 3.26 mmol)(185) in anhydrous acetonitrile (30 mL) at 0° C. After proceeding for 1 hour the reaction is concentrated at 60° C. to remove all solvent and excess MsCl. Cold acetonitrile is added to precipitate triethylammonium chloride, which is then removed by filtration. The remaining solution of mesylate product is reduced to a 30 ml volume; tetraethylammonium cyanide (1.53 g, 9.79 mmol) is added to the solution, and the reaction is heated at 60° C. overnight. Solvent is removed in vacuo and the crude product dissolved in ethyl acetate (100 mL). The organic layer is washed with saturated sodium bicarbonate (2×100 mL), brine (1×100 mL) and dried over magnesium sulfate. The sample is filtered, concentrated and purified by flash chromatography on SiO2 using an eluent of 2:3 acetate:hexane to afford (3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-acetonitrile (187) as a light orange oil.
Reaction SMILES: O.[CH:2]([C:4]1[CH:13]=[N+:12]([O-:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]=1[O-:15])=[O:3].[CH2:16]([CH2:18][NH2:19])O>CO.C(N(CC)CC)C>[O:3]1[CH2:16][CH2:18][NH:19][CH:2]1[C:4]1[CH:13]=[N+:12]([O-:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]=1[O-:15]
Reactant: O=Cc1c[n+]([O-])c2ccccc2[n+]1[O-]
Reactant: NCCO
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: [O-][n+]1cc(C2NCCO2)[n+]([O-])c2ccccc21
Temperature: 25 °C

Procedure:
2-Formylquinoxaline-1,4-dioxide hydrate 4 g (0.02 mole) was dissolved at 60°-65° C. in 30 ml methanol containing 2-4 drops of triethylamine. The solution was agitated and 1.5 g (0.0246 mole) of ethanolamine was added. The heat source was removed and the mixture was then allowed to cool slowly to room temperature with stirring. There was obtained a precipitate of 2-(2-oxazolidinyl)quinoxaline-1,4-dioxide (hereinafter designated P-2244 for convenience). The precipitate was filtered, rinsed with a small amount of methanol, then dried. The resulting product had a melting point of 153°-154° C. and analyzed as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.O1CCCC1.CO.C(=O)([O-])O.[Na+]>[Zn].C(O)(=O)C>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13][CH2:12]2)=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2Cl)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2Cl)CC1
Reaction time: 1 h

Procedure:
To a solution of the product of Example 18A (1.5 g, 4.4 mmol) in 1:1 tetrahydrofuran/methanol (80 mL) at ambient temperature was slowly added zinc power (1.43 g, 22 mmol) and acetic acid (5 mL). The mixture was stirred for 1 hour, and saturated aqueous sodium hydrogen carbonate solution was added. The mixture was stirred for 1 hour and filtered, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 5/1 petroleum ether/ethyl acetate to give title compound. MS: 312 (M+H+).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:30][CH2:31][CH3:32])[C:6]([C:8]2[N:12]3[CH:13]=[C:14]([Cl:25])[N:15]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=4[CH3:24])[C:11]3=[N:10][C:9]=2[C:26]([F:29])([F:28])[F:27])=O)[CH2:3][CH2:2]1.COCCO[AlH2-]OCCOC.[Na+].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[Cl:25][C:14]1[N:15]([C:16]2[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])[C:11]2[N:12]([CH:13]=1)[C:8]([CH2:6][N:5]([CH2:4][CH:1]1[CH2:2][CH2:3]1)[CH2:30][CH2:31][CH3:32])=[C:9]([C:26]([F:27])([F:28])[F:29])[N:10]=2
Reactant: CCCN(CC1CC1)C(=O)c1c(C(F)(F)F)nc2n(-c3c(C)cc(C)cc3C)c(Cl)cn12
Agent: COCCO[AlH2-]OCCOC
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCN(Cc1c(C(F)(F)F)nc2n(-c3c(C)cc(C)cc3C)c(Cl)cn12)CC1CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylic acid cyclopropylmethyl-propyl-amide (27.2 mg, 0.058 mmol) in toluene (3 mL) was added a 65% solution of Red-Al in toluene (0.10 mL, 0.320 mmol). The reaction mixture was stirred at room temperature for 14 h. A solution of Rochelle's salt (2.0 mL) was added carefully at 0° C. and the mixture was vigorously stirred for 30 min. The crude product was extracted with ethyl acetate. The combined organic extracts were dried with Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by a reverse-phase preparative HPLC. Yield—12.8 mg (39%). LC/MS: tR=1.77 min., MS: [M+H]=453.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[O:13][C:14]([CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:15][N:16]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>[Pt].CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[O:13][C:14]([CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:15][N:16]=2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(-c2nnc(CN3CCCC3)o2)ccc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: COc1cc(-c2nnc(CN3CCCC3)o2)ccc1N
Reaction time: 8 h
Yield: 25.1 %

Procedure:
A mixture of 2-[3-(methyloxy)-4-nitrophenyl]-5-(1-pyrrolidinylmethyl)-1,3,4-oxadiazole (1.13 g, 3.70 mmol) and platinum on carbon (sulfided) in EtOAc (25 mL) was stirred under H2 (1 atm.) overnight. The mixture was filtered through Celite® and concentrated. Purification by flash chromatography provided the title compound of step B (0.26 g, 0.93 mmol, 25%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.62-1.71 (m, 4H), 2.48-2.57 (m, 4H), 3.76-3.85 (m, 5H), 5.51 (br. s., 2H), 6.64-6.71 (m, 1H), 7.25 (d, J=1.8 Hz, 1H), 7.29 (dt, J=8.1, 2.4 Hz, 1H).