Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:11][C:12]1[C:13]([O:19][CH3:20])=[N:14][C:15](F)=[CH:16][CH:17]=1>C1COCC1.O>[CH2:1]([O:8][C:15]1[N:14]=[C:13]([O:19][CH3:20])[C:12]([F:11])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1nc(F)ccc1F
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(OCc2ccccc2)ccc1F
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
step 2—To a solution of benzyl alcohol (1.12 g, 10.3 mmol) in THF was added NaH (0.413 g, 10.3 mmol, 60% mineral oil dispersion) and stirred for 30 min. To this solution was added 140 (1.5 g, 10.3 mmol) and the resulting solution was irradiated in the microwave synthesizer at 100° C. for 1 h. The reaction was cooled, diluted with H2O, extracted with EtOAc (2×50 mL). The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by SiO2 chromatography to afford 1 g (41%) of 6-benzyloxy-3-fluoro-2-methoxy-pyridine (142).
Reaction SMILES: [ClH:1].[OH:2][C@H:3]([CH2:18][O:19][CH2:20][CH2:21][CH:22](CC)[CH2:23][CH2:24][CH3:25])[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[ClH:28].OC(COC1C=CC(C(C)(C)C)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.O[C@H](COC1C=CC=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[C:21]([Cl:1])=[CH:22][CH:23]=[CH:24][C:25]=1[Cl:28])[CH2:4][NH:5][C:6]([CH3:16])([CH3:17])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: CCCC(CC)CCOC[C@@H](O)CNC(C)(C)Cc1ccc(OC)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: COc1ccc(CC(C)(C)NC[C@H](O)COc2ccccc2)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2c(Cl)cccc2Cl)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 382 (M−15, 1), 279 (11), 279 (9), 277 (64), 275 (100), 163 (11), 163 (5), 161 (6), 121 (33), 114 (12).
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][NH:7][S:8](/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][C:16]2[N:17]=[CH:18][N:19](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:20]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(O)C.[NH3:45]>C1COCC1>[NH2:45][CH:12]([CH2:13][CH2:14][CH2:15][C:16]1[N:17]=[CH:18][NH:19][CH:20]=1)[CH2:11][S:8]([NH:7][CH2:6][C:5]1[CH:40]=[CH:41][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: N
Reactant: O=S(=O)(/C=C/CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NCc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: NC(CCCc1c[nH]cn1)CS(=O)(=O)NCc1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
A mixture of (E)-N-(4-chlorobenzyl)-5-(1-(triphenylmethyl)imidazol-4-yl)-1-pent-1-enesulfonamide (Example 5, step e) (290 mg, 0.50 mmol), ethanol saturated with ammonia (10 ml) and THF (10 ml) was sealed in a Teflon-lined pressure vessel and heated at 120° C. overnight. The solution was allowed to cool and the solvent evaporated. The residue was purified by flash column chromatography (silica, 1:10:90 ammonia(880)/methanol/dichloromethane) to give the title compound was obtained as a white solid (123 mg, 79%): 1H NMR (300 MHz, d6-DMSO) 7.92(1H, br s), 7.61(1H, d), 7.41(4H, m), 6.58(1H, d), 4.54(1H, m), 4.21(2H, s), 3.65(1H, dd), 3.50(1H, dd), 3.29(2H, s), 2.67(2H, m), 2.65(2H, t), 2.10(1H, m), 1.95(1H, m), 1.81(1H, m), 1.66(1H, m). Found: C, 50.17; H, 5.99; N, 15.48%; C15H21ClN4O2S requires: C, 50.48; H, 5.93; N, 15.70%.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[C:26](Cl)=[N:25][CH:24]=[CH:23][N:22]=1>C(#N)C>[Cl:20][C:21]1[C:26]([N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)=[N:25][CH:24]=[CH:23][N:22]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Temperature: 100 °C
Reaction time: 40 h
Yield: 99.6 %

Procedure:
The title compound was prepared according to the procedure described in WO 00/76984. A mixture of N-Boc-piperazine (11.47 g, 61.5 mmol), K2CO3 (8.5 g, 61 mmol) and 2,3-dichloropyrazine (9.20 g, 61.7 mmol) in acetonitrile (100 mL) was stirred at 100° C. for 40 h. The reaction mixture was concentrated, dissolved in toluene, washed with water, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel using toluene/EtOAc (7:3) as eluent to give 18.3 g (100%) of the title product. HRMS m/z calcd for C13H19N4O2 (M)+298.1197, found 298.1206.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:12]([NH2:14])[CH3:13].[Br:15][C:16]1[N:21]=[C:20](NCC2C=C3C(=CC=2)N=CC=C3)[C:19]([NH2:34])=[N:18][CH:17]=1>>[Br:15][C:16]1[N:21]=[C:20]([NH:14][CH:12]([C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][C:2]=2[F:1])[N:9]=[CH:8][CH:7]=[CH:6]3)[CH3:13])[C:19]([NH2:34])=[N:18][CH:17]=1
Reactant: CC(N)c1cc2cccnc2cc1F
Reactant: Nc1ncc(Br)nc1NCc1ccc2ncccc2c1
Product: CC(Nc1nc(Br)cnc1N)c1cc2cccnc2cc1F

Procedure:
The title compound was prepared as a white solid from 1-(7-fluoroquinolin-6-yl)ethanamine in analogy to the synthesis of compound 52.1. LCMS (method B): [MH]+=364, tR=2.38 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]CC=C)[C:12]=3[C:13]=2[CH3:14])=[O:8])=[CH:5][CH:4]=1.Cl[C:26]1[CH:31]=CC=C[C:27]=1Cl>>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([CH2:31][CH:26]=[CH2:27])=[C:15]([OH:19])[C:12]=3[C:13]=2[CH3:14])=[O:8])=[CH:5][CH:4]=1
Reactant: Clc1ccccc1Cl
Reactant: C=CCOc1cccc2oc(C(=O)c3ccc(OC)cc3)c(C)c12
Product: C=CCc1ccc2oc(C(=O)c3ccc(OC)cc3)c(C)c2c1O
Yield: 93 %

Procedure:
A solution of 2-(p-methoxybenzoyl)-3-methyl-4-allyloxybenzofuran (0.7 gm; 2.2 mmoles) in orthodichlorobenzene (3 mL) was refluxed under nitrogen for a period of 4 hours. The mixture was cooled to rom temperature and purified by chromatography on silica gel using 15% ethylacetate in hexane as eluent to yield 650 mg (93%) of 2-(p-methoxybenzoyl)-3-methyl-4-hydroxy-5-allylbenzofuran, mp. 48°-50° C.
Reaction SMILES: N#N.[F:3][C:4]([F:18])([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[N:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[N:10]1.[NH4+].[Cl-]>CCO.O.[Fe]>[F:18][C:4]([F:3])([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[N:13]=[C:12]([NH2:14])[CH:11]=[N:10]1
Reactant: CC(F)(F)CCCCn1ncc([N+](=O)[O-])n1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC(F)(F)CCCCn1ncc(N)n1
Temperature: 85 °C
Reaction time: 0.33 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 2-(5,5-difluoro-hexyl)-4-nitro-2H-[1,2,3]triazole (71 mg, 0.30 mmol), iron powder (51 mg, 0.91 mmol) and NH4Cl (82 mg, 1.52 mmol) in a mixture of EtOH (1.0 mL) and water (0.5 mL) was stirred at 85° C. for 20 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (10 mL) was added followed by water (10 mL). The aq. layer was extracted with CH2Cl2 (2×10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.79 min; [M+H]+=205.54.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[F:7][C:8]([F:33])([F:32])[C:9]([NH:11][C@H:12]1[CH2:31][CH2:30][N:15]2[C:16]3[CH:29]=[CH:28]C=[CH:26][C:17]=3[N:18]([CH3:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C@@H:14]2[CH2:13]1)=[O:10]>CN(C=O)C>[F:33][C:8]([F:7])([F:32])[C:9]([NH:11][C@H:12]1[CH2:31][CH2:30][N:15]2[C:16]3[CH:29]=[CH:28][C:2]([CH:1]=[O:5])=[CH:26][C:17]=3[N:18]([CH3:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C@@H:14]2[CH2:13]1)=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN1c2ccccc2[C@@H]2C[C@@H](NC(=O)C(F)(F)F)CCN2c2ccccc21
Solvent: CN(C)C=O
Product: CN1c2ccccc2[C@@H]2C[C@@H](NC(=O)C(F)(F)F)CCN2c2ccc(C=O)cc21
Temperature: 80 °C
Reaction time: 0.42 h

Procedure:
Oxalyl chloride (436 μL, 5 mmol) was carefully added dropwise, with stirring, to DMF (0.5 ml) at 0° C. then held for 25 minutes. A solution of cis-2,2,2-trifluoro-N-(1,2,3,4,10,14b-hexahydro-10-methyldibenzo[b,f]pyrido[1,2-d][1,4]diazepin-2-yl)acetamide (9: R2=COCF3) (400 mg, 1.07 mmol) in DMF (2 ml) was added dropwise to the resulting suspension and the reaction mixture heated to 80° C. and held for 1.5 hours. The reaction was cooled to ambient temperature and quenched by dropwise addition of NaHCO3 solution in H2O. The product was extracted into EtOAc, dried (Na2SO4) and concentrated under reduced pressure. Then the crude product was purified by column chromatography on silica to afford cis-2,2,2-trifluoro-N-(8-formyl-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[b,f]pyrido[1,2-d][1,4]diazepin-2-yl)acetamide (9: R2=COCF3; R8=CHO) (130 mg, 30%). Data: (m/z)=404 (M+H)+. [Column chromatography also afforded cis-2,2,2-trifluoro-N-(6-formyl-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[b,f]pyrido[1,2-d][1,4]diazepin-2-yl)acetamide (9: R2=COCF3; R6=CHO) (45 mg, 10%). Data: (m/z)=404 (M+H)+.]
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[S:16][CH:17]=[C:18]([C:20]([O-:22])=O)[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na+].[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(OCC)(=O)C>[C:24]([NH:28][C:20]([C:18]1[N:19]=[C:15]([CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13][CH2:12]2)[S:16][CH:17]=1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2nc(C(=O)[O-])cs2)CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1csc(CN2CCN(C(=O)OC(C)(C)C)CC2)n1
Yield: 53.4 %

Procedure:
To a solution of sodium 2-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-thiazole-4-carboxylate (3.596 g, 10.29 mmol), tert butylamine (0.753 g, 10.29 mmol, 1.082 mL) and triethylamine (3.12 g, 30.9 mmol, 4.29 mL) in dichloromethane (50 mL) was added 1-propanephosphonic acid cyclic anhydride (13.10 g, 20.58 mmol, 12.25 mL, 50% solution in ethyl acetate. The reaction was concentrated under reduced pressure and the residue was taken up in ethyl acetate, washed with sodium bicarbonate (×3) and brine. The organic phase was concentrated under reduced pressure to afford the title compound (2.10 g). MS (ESI) m/z 283.5 [M+H]+
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]=[N+]=[N-])=[N+:2]=[N-:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>Cl.CCOCC>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH2:15])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCOCCOCCOCCN=[N+]=[N-]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: [N-]=[N+]=NCCOCCOCCOCCN
Reaction time: 24 h
Yield: 75.5 %

Procedure:
To a mechanically, vigorously stirred suspension of 1,11-diazido-3,6,9-trioxaundecane (20.8 g, 0.085 mol) in 5% hydrochloric acid (200 ml) was added a solution of triphenylphosphine (19.9 g, 0.073 mol) in ether (150 ml) over 3 hrs at room temperature. The reaction mixture was stirred for additional 24 hrs. The phases were separated and the aqueous phase was extracted with dichloromethane (3×40 ml). The aqueous phase was cooled in an ice/water bath and pH was adjusted to ca 12 by addition of KOH. The product was extracted into dichloromethane (5×50 ml). Combined organic phases were dried (MgSO4). Filtration and evaporation gave 14.0 g (88%) of yellow oil. Analysis by MALDI-TOF mass spectroscopy (matrix: α-cyano-4-hydroxycinnamic acid) gave a M+H peak at 219 as expected. Further characterisation using 1H (500 MHz) and 13C (125 MHz) NMR spectroscopy verified the structure.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[N:11]([CH2:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:10][C:9](=[O:19])[NH:8][C:5]2=[N:6][CH:7]=1.C[Sn](C)(C)[C:22]1[CH:23]=[CH:24][C:25]([C:28]([OH:31])([CH3:30])[CH3:29])=[N:26][CH:27]=1.ClCCl>CN(C)C=O>[OH:31][C:28]([C:25]1[N:26]=[CH:27][C:22]([C:2]2[N:3]=[C:4]3[N:11]([CH2:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[CH2:10][C:9](=[O:19])[NH:8][C:5]3=[N:6][CH:7]=2)=[CH:23][CH:24]=1)([CH3:30])[CH3:29]
Reactant: CC(C)(O)c1ccc([Sn](C)(C)C)cn1
Reactant: O=C1CN(CC2CCOCC2)c2nc(Br)cnc2N1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(O)c1ccc(-c2cnc3c(n2)N(CC2CCOCC2)CC(=O)N3)cn1
Temperature: 125 °C
Yield: 35.7 %

Procedure:
6-Bromo-4-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (35.98 g, 110 mmol), 2-(5-(trimethylstannyl)pyridin-2-yl)propan-2-ol (See Example 5.E) (33.0 g, 110 mmol) and [1,1′-bis(diphenyl-phosphino)ferrocene]dichloro-palladium(II) complex with dichloromethane (1:1) (8.05 g, 11.00 mmol) were combined in a sealed tube and suspended in N,N-dimethylformamide (288 mL). The reaction was then heated to 125° C. for 2 h. The reaction was cooled slightly and poured while still warm onto a silica gel column and purified using an Biotage SP1 (0-100% (5% methanol in ethyl acetate) in hexanes). The desired fractions were combined and organic volatiles removed under reduced pressure. The residue was triturated with 20% ethyl acetate in hexanes followed by several washes with denatured ethanol. The slightly yellow solid was dried under reduced pressure to afford the desired compound (15.08 g, 39.3 mmol, 35.8% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.32 (s, 1H), 9.07 (d, J=1.56 Hz, 1H), 8.29 (dd, J=8.59, 2.34 Hz, 1H), 8.05 (s, 1H), 7.72 (d, J=8.20 Hz, 1H), 5.26 (s, 1H), 4.21 (s, 2H), 3.83 (d, J=2.73 Hz, 2H), 3.51 (d, J=7.42 Hz, 2H), 3.27 (t, J=11.32 Hz, 2H), 2.09 (br. s., 1H), 1.61 (d, J=11.3 Hz, 2H), 1.46 (s, 6H), 1.24-1.38 (m, 2H); MS (ESI) m/z 384.2 [M+1]+; mp 268-269° C.
Reaction SMILES: BrC1C2N3CCN(C)C(=O)C3=[C:10]([O:11][CH2:12][C:13]3C=CC=CC=3)[C:6]=2C(=O)N(CC2C=CC(F)=C(Cl)C=2)N=1.C([Sn](CCCC)(CCCC)C(OCC)=C)CCC.[O:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:58]([O:53][CH:54]=[CH:55][O:56][CH:6]=[CH:10][O:11][CH2:12][CH3:13])[CH3:57]
Reactant: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(Br)c32)C1=O
Reactant: C1COCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Product: CCOC=COC=COCC
Temperature: 100 °C

Procedure:
A mixture of 4-bromo-10-(benzyloxy)-2-(3-chloro-4-fluorobenzyl)-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (1.00 g, 1.83 mmol), tributyl(1-ethoxyvinyl)tin (0.73 g, 2.01 mmol), and trans-dichlorobis(triphenylphosphine)palladium (II) (64 mg, 92 μmol) in dioxane (10 mL) was purged with nitrogen for 15 minutes. The reaction mixture was heated in a sealed tube at 100° C. overnight. The product mixture was filtered through a pad of Celite, and the filtrate concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 1:1 mixture of ethyl acetate in chloroform. Collecting and concentration of appropriate fractions provided the intermediate ethoxyvinyl ether as off white solid. A solution of the ethoxyvinyl ether (0.70 g, 1.30 mmol) in acetone at room temperature was treated with hydrochloric acid (2 mL, 1 M) and stirred at the same temperature for 30 minutes. The resultant solution was concentrated under vacuum to provide the title ketone.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:16][CH3:17])=[CH:5][C:6]2[S:11](=[O:13])(=[O:12])[NH:10][C:9](=[O:14])[NH:8][C:7]=2[CH:15]=1.[H-].[Na+].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35]Cl)[CH2:30][CH2:29]1.O>CN(C)C=O>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][N:10]2[C:9](=[O:14])[NH:8][C:7]3[CH:15]=[C:3]([O:2][CH3:1])[C:4]([O:16][CH3:17])=[CH:5][C:6]=3[S:11]2(=[O:13])=[O:12])[CH2:32][CH2:33]1
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Reactant: COc1cc2c(cc1OC)S(=O)(=O)NC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1OC)S(=O)(=O)N(CCN1CCN(c3ccccc3OC)CC1)C(=O)N2
Temperature: 80 °C
Reaction time: 5 h
Yield: 36 %

Procedure:
One gram and a half of 6,7-dimethoxy-3,4-dihydro-1,2,4-benzothiadiazine-3-one 1,1-dioxide was dissolved in 10 ml of dimethylformamide. After adding 280 mg of sodium hydride in 50% oil, the mixture was heated to 80° C. Then, a solution of 1.5 g of 2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl chloride in 5 ml of dimethylformamide was added dropwise to the resultant reaction liquid. After the addition was finished, the stirring was continued for 5 hours while heating at 80° C. to react. The resultant reaction mixture was poured into water to precipitate crystals. The produced crystals were filtered off followed by recrystallizing from methanol to obtain 1.0 g of the titled compound (yield: 36%).
Reaction SMILES: [CH2:1]([N:3]([CH:14]1[CH2:23][CH2:22][C:17]2(OCC[O:18]2)[CH2:16][CH2:15]1)[C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].Cl>C(#N)C>[CH2:1]([N:3]([CH:14]1[CH2:23][CH2:22][C:17](=[O:18])[CH2:16][CH2:15]1)[C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCN(C(=O)OCc1ccccc1)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC#N
Product: CCN(C(=O)OCc1ccccc1)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzyl ethyl(1,4-dioxaspiro[4.5]decan-8-yl)carbamate (350 mg, 1.1 mmol) was dissolved in acetonitrile, treated with 6N HCl, and stirred at room temperature for 18 h. reaction mixture was concentrated in vacuo, treated with saturated NaHCO3 to pH 6. The solvents were removed under vacuum and the residue treated with saturated NaCl (2 mL) and extracted with 4:1 EtOAc/iPrOH (×4). The organic fractions were combined, filtered and evaporated to give the title compound.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[S:5][C:6]([CH3:11])=[CH:7][C:8]=1[C:9]#[N:10].F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].O>C(#N)C>[N+:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:3][C:4]1[S:5][C:6]([CH3:11])=[CH:7][C:8]=1[C:9]#[N:10])([O-:21])=[O:20]
Reactant: Cc1cc(C#N)c(N)s1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Cc1cc(C#N)c(Nc2ccccc2[N+](=O)[O-])s1
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
Potassium hydroxide (101.4 g) in acetonitrile (150 ml) is taken under nitrogen and cooled to 0-5° C. A solution of 2-amino-5-methylthiophene-3-carbonitrile (100 g) and o-fluoronitrobenzene (122.6 g) in acetonitrile (550 ml) is added. The reaction is then stirred for 3 hours and chilled water is added. The solid thus obtained is filtered off and air-dried. The solid is crystallized from water-methanol mixture and the crystallized solid is dried under vacuum at 40-45° C. to obtain the title compound (140 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH2:30][NH:31][CH2:32]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH2:30][N:31]([C:7]1[C:2]([F:1])=[C:3]3[C:4]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:18]3[CH:13]=[CH:14][C:15]([F:21])=[CH:16][C:17]=3[F:19])=[CH:5][C:6]=1[F:8])[CH2:32]2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Reactant: COc1cccc2c1CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cccc2c1CN(c1c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4F)c3c1F)C2
Yield: 30.9 %

Procedure:
178 mg of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 90 mg of 4-methoxyisoindoline, 137 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 75 mg of the target compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:34]2[CH2:33][CH2:32][N:31]([C:25]3[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=3)[CH2:36][CH2:35]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc(C)c(C)nc3OC)CC2)c1
Yield: 85 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([NH:9][C:10]2[C:11]3[CH2:38][CH2:37][CH2:36][C:12]=3[N:13]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[C:21]([NH:23][C@H:24]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)=[O:22])[N:15]=2)[NH:6][N:5]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([C:4]1[CH:8]=[C:7]([NH:9][C:10]2[C:11]3[CH2:38][CH2:37][CH2:36][C:12]=3[N:13]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[C:21]([NH:23][C@H:24]3[CH2:28][CH2:27][NH:26][CH2:25]3)=[O:22])[N:15]=2)[NH:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(Nc2nc(N3CCCC3C(=O)N[C@H]3CCN(C(=O)OC(C)(C)C)C3)nc3c2CCC3)[nH]n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1cc(Nc2nc(N3CCC[C@@H]3C(=O)N[C@H]3CCNC3)nc3c2CCC3)[nH]n1
Yield: 7.4 %

Procedure:
To a stirred solution of (3S)-tert-butyl 3-(1-(4-(3-isopropyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamido)pyrrolidine-1-carboxylate (350 mg, 0.667 mmol) in DCM (3.5 mL) was added TFA (0.15 ml, 2.003 mmol) dropwise under nitrogen atmosphere at 0° C. The resultant mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure. The crude obtained was purified by reverse phase HPLC. The stereoisomers obtained were separated by chiral HPLC to afford 21 mg of (R)-1-(4-(3-isopropyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N—((S)-pyrrolidin-3-yl)pyrrolidine-2-carboxamide. 1H NMR (400 MHz, CDCl3) δ (ppm) 1.30 (d, 6H), 1.94-2.15 (m, 6H), 2.60-2.77 (m, 4H), 2.79-3.10 (m, 6H), 3.58-3.66 (m, 1H), 3.70-3.80 (m, 1H), 4.05-4.13 (m, 1H), 4.58 (dd, 1H), 6.38 (s, 1H), 6.79 (s, 1H). The other diastereomers were prepared using appropriate chiral starting materials.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][C:9]([C:11]2([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12]2)=[O:10])=[CH:5][C:4]=1[N:20]=[C:21]=S.[NH2:25][C:26]1[C:27]([NH:47][CH3:48])=[CH:28][C:29]([O:42][CH2:43][CH:44]([F:46])[F:45])=[C:30]([CH:41]=1)[C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([Br:40])=[CH:36][CH:35]=1)=[O:32].CC(C)N=C=NC(C)C>CN(C=O)C>[Br:40][C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:31]([C:30]2[C:29]([O:42][CH2:43][CH:44]([F:45])[F:46])=[CH:28][C:27]3[N:47]([CH3:48])[C:21]([NH:20][C:4]4[CH:5]=[C:6]([CH2:7][NH:8][C:9]([C:11]5([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12]5)=[O:10])[CH:18]=[CH:19][C:3]=4[C:2]([F:24])([F:23])[F:1])=[N:25][C:26]=3[CH:41]=2)=[O:32])=[CH:35][CH:36]=1
Reactant: O=C(NCc1ccc(C(F)(F)F)c(N=C=S)c1)C1(C(F)(F)F)CC1
Reactant: CNc1cc(OCC(F)F)c(C(=O)Nc2ccc(Br)cc2)cc1N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2C(F)(F)F)nc2cc(C(=O)Nc3ccc(Br)cc3)c(OCC(F)F)cc21

Procedure:
The title compound was prepared in accordance with the procedure in Example 72, step (a) using N-(4-trifluoromethyl-3-isothiocyanato-benzyl)-1-(trifluoromethyl)cyclopropane carboxamide (184 mg; 0.50 mmol), 5-amino-N-(4-bromophenyl)-2-(2,2-difluoroethoxy)-4-(methylamino)benzamide (200 mg; 0.50 mmol), DIC (63 mg; 0.50 mmol) and DMF (4 mL). Yield: 59 mg (16%). 400 MHz 1H-NMR (DMSO-d6, ppm) 10.62 (0.57H, s, major tautomer) 10.09-9.96 (1H, m) 8.47-8.41 (0.38H, m, minor tautomer) 8.36-8.28 (1H, m) 7.72-7.61 (3H, m) 7.58-7.47 (3H, m) 7.36-7.28 (1H, m) 7.12-6.84 (2H, m) 6.67-6.35 (1H, m) 4.58-4.45 (2H, m) 4.34-4.25 (2H, m) 3.64 (0.96H, s, minor tautomer) 3.41 (1.93H, s, major tautomer) 1.31-1.17 (4H, m). MS m/z: 734, 736 [M+H]+.