Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[SH:7].[C:8]([C:12]1[N:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][Cl:27])[CH2:20][CH2:19]2)[CH:15]=[C:14]([C:28]([F:31])([F:30])[F:29])[N:13]=1)([CH3:11])([CH3:10])[CH3:9]>>[ClH:27].[C:8]([C:12]1[N:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][S:7][C:3]3[N:2]([CH3:1])[CH:6]=[N:5][N:4]=3)[CH2:20][CH2:19]2)[CH:15]=[C:14]([C:28]([F:29])([F:30])[F:31])[N:13]=1)([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1nc(N2CCN(CCCCl)CC2)cc(C(F)(F)F)n1
Reactant: Cn1cnnc1S
Product: Cl
Product: Cn1cnnc1SCCCN1CCN(c2cc(C(F)(F)F)nc(C(C)(C)C)n2)CC1
Yield: 50.3 %

Procedure:
1 g of 4-methyl-4H-[1,2,4]triazole-3-thiol (8.7 mmol) were reacted with 3.2 g of 2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-trifluoromethyl-pyrimidine (8.7 mmol to yield 2.1 g of the title compound as a solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([NH2:10])=[N:7][C:6]=1[CH:11]=O)=O.O.[NH2:14][NH2:15].C(O)(=O)C>C(O)C>[NH2:10][C:8]1[S:9][C:5]2[C:3](=[O:2])[NH:15][N:14]=[CH:11][C:6]=2[N:7]=1
Reactant: COC(=O)c1sc(N)nc1C=O
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1nc2cn[nH]c(=O)c2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the compound (1.20 g) obtained in Step 4 in ethanol (120 ml) was added hydrazine monohydrate (374 μl), and the mixture was heated under reflux for 24 hr. Since the reaction was not completed, acetic acid (1.0 ml) was added, and the mixture was further heated under reflux for 20 hr. The reaction mixture was concentrated under reduced pressure to an amount of 5 ml, a small amount of ethanol was added, and the mixture was stirred at room temperature for 30 min. The precipitated solid was collected by filtration, washed with a small amount of ethanol, and dried to give the title compound (822 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH2:5][CH2:6][CH2:7][C:8](=[O:13])[C:9]=2[C:10]=1[CH2:11][CH3:12].[O:14]1[CH2:19][CH2:18][N:17]([CH2:20]N2CCOCC2)[CH2:16][CH2:15]1>>[CH3:12][CH2:11][C:10]1[C:9]2[C:8]([CH:7]([CH2:20][N:17]3[CH2:18][CH2:19][O:14][CH2:15][CH2:16]3)[CH2:6][CH2:5][C:4]=2[NH:3][C:2]=1[CH3:1])=[O:13]
Reactant: CCc1c(C)[nH]c2c1C(=O)CCC2
Reactant: C1CN(CN2CCOCC2)CCO1
Product: CCc1c(C)[nH]c2c1C(=O)C(CN1CCOCC1)CC2

Procedure:
In yet a further embodiment, the invention provides a method of manufacturing molindone through a 5-step process, wherein in the 1st step 2,3-pentanedione is reacted with hydroxylamine hydrochloride to produce 2,3-pentanedione-2-oxime (SUMO-1); in the 2nd step 2,3-pentanedione-2-oxime and 1,3-cyclohexanedione are reacted to produce 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole (SUMO-2); in the 3rd step 2-methyl-3-ethyl-4-oxo-4,5,6,7-tetrahydroindole reacts with bismorpholinomethane to produce molindone (SUMO-3); in the 4th step molindone is converted into a molindone salt; and in the 5th step the molindone salt is purified/recrystallized, and, optionally, various polymorphic forms of molindone salt are prepared.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]([C:15](=[O:29])[C@@H:16]([NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:17]([CH3:19])[CH3:18])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)[CH3:2].[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1.CCOC(C)=O.Cl>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:31](=[O:33])[CH3:32])[CH:9]=1)[C:15](=[O:29])[C@@H:16]([NH:20][C:21](=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH:17]([CH3:19])[CH3:18])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CN(Cc1cccc(N)c1)C(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(Cc1cccc(NC(C)=O)c1)C(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a solution of 735 (435.0 mg, 1.06 mmol) in pyridine (3.0 ml) was added acetic anhydride (50 μL, 1.59 mmol) and the reaction allowed to stir overnight. The reaction was diluted with EtOAc and 1N HCl. The layers were separated and the organic phase washed with brine, dried over MgSO4, filtered and concentrated to dryness to provide 480 mg of 742. ##STR121##
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.[O:22]=[S:23]1(=[O:29])[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:17])[CH3:18])[C:13]([NH:28][CH:25]3[CH2:26][CH2:27][S:23](=[O:29])(=[O:22])[CH2:24]3)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: NC1CCS(=O)(=O)C1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)[C@H](C(=O)NC1CCS(=O)(=O)C1)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Yield: 24.5 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol). DMF (0.5 mL), 1,1-dioxidotetrahydrothien-3-ylamine (10.4 mg, 0.077), HOBt (11.83 mg, 0.077 mmol), EDC (14.81 mg, 0.077 mmol) and N,N-dimethylpyridin-4-amine (9.44 mg, 0.077 mmol) were added and the solution was stirred at 25° C. for 4 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%). The fractions were collected and lyophilized to afford the title compound as a white solid (5.1 mg, 24.3%). 1H NMR (400 MHz, CD3OD) δ 0.93 (dd, J=6.57, 1.26 Hz, 3 H) 1.05 (dd, J=6.32, 3.79 Hz, 3 H) 2.06-2.28 (m, 1 H) 2.40-2.59 (m, 2 H) 2.98 (td, J=12.57, 7.45 Hz, 1 H) 3.04-3.18 (m, 1 H) 3.21-3.29 (m, 1 H) 3.35-3.53 (m, 1 H) 4.51-4.66 (m, 1 H) 4.95-5.12 (m, 2 H) 5.40 (dd, J=19.20, 13.39 Hz, 1 H) 7.83-7.89 (m, 1 H) 8.17 (dd, J=3.28, 1.52 Hz, 1 H). [M+H] calc'd for C18H21FN4O4S, 409; found, 409.3.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][OH:5].[CH3:8][S:9](Cl)(=[O:11])=[O:10]>>[CH3:8][S:9]([O:5][CH2:4][CH2:3][C:2]([F:7])([F:6])[F:1])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC(F)(F)F
Product: CS(=O)(=O)OCCC(F)(F)F

Procedure:
3,3,3-Trifluoropropyl methanesulfonate was prepared by reaction of 3,3,3-trifluoropropanol with methanesulfonyl chloride by an analogous procedure to that used for Example 52 step 1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:16][CH2:15][N:14]([C:17](=[O:27])/[CH:18]=[CH:19]/[CH2:20][N:21]([CH:23]4[CH2:26][CH2:25][CH2:24]4)[CH3:22])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:16][CH2:15][N:14]([C:17](=[O:27])/[CH:18]=[CH:19]/[CH2:20][N:21]([CH:23]4[CH2:26][CH2:25][CH2:24]4)[CH3:22])[CH2:13]3)[N:9]=[C:10]([C:32]3[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=3)[C:3]=12
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CN(C/C=C/C(=O)N1CC[C@@H](n2nc(I)c3c(N)ncnc32)C1)C1CCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: COCCOC
Product: CN(C/C=C/C(=O)N1CC[C@@H](n2nc(-c3ccc(Cl)cc3)c3c(N)ncnc32)C1)C1CCC1
Temperature: 80 °C

Procedure:
A mixture of (R,E)-1-(3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl) pyrrolidin-1-yl)-4-(cyclobutyl(methyl)amino)but-2-en-1-one (22) (400 mg, 0.832 mmol), 4-chlorophenylboronic acid (156 mg, 1 mmol), K3PO4.3H2O (664 mg, 2.5 mmol) and Pd(dppf)2Cl2 (34 mg, 0.04 mmol) in DME/H2O (8 mL/2 mL) was purged with N2 (3×) and then heated to 80° C. overnight. After cooling down to rt, the reaction mixture was concentrated and the residue was purified by prep. HPLC (15%-95% acetonitrile/H2O (0.2% NH3H2O)) to provided (R,E)-1-(3-(4-amino-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin 1-yl)pyrrolidin-1-yl)-4-(cyclobutyl(methyl)amino)but-2-en-1-one (23) as a white solid. (20 mg, 5%), LC-MS (ESI): m/z (M+1) 466.1. 1H NMR (400 MHz, DMSO) δ 8.25 (s, 1H), 7.64 (m, 2H), 7.56 (m, 2H), 6.60 (m, 1H), 6.36 (dd, J=29.6, 15.6 Hz, 1H), 5.44 (m, 1H), 3.85 (m, 4H), 2.96 (dd, J=20.5, 6.3 Hz, 2H), 2.78 (m, 1H), 2.40 (m, 2H), 1.96 (m, 5H), 1.73 (m, J2H), 1.56 (m, 2H).
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18].CS(C)=O>CC(C)=O>[C:5]([NH:3][C:2]([NH:14][C:13]1[CH:15]=[CH:16][C:10]([CH3:9])=[C:11]([N+:17]([O-:19])=[O:18])[CH:12]=1)=[S:1])(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: CS(C)=O
Product: CC(=O)NC(=S)Nc1ccc(C)c([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of ammonium thiocyanate (1.05 g, 13.85 mmol) in acetone (21 mL) was added dropwise acetyl chloride (0.90 mL 12.70 mmol). The reaction mixture was stirred at 40° C. for 30 min. Then, a solution of 4-methyl-3-nitroaniline (1.76 g, 11.54 mmol) in acetone (7 mL) was added and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was poured into ice-water and the precipitate was filtered, washed with more water and cyclohexane to give compound IV-c as brown solid in 50% yield. (300 MHz, DMSO) δ 12.45 (s, 1H), 11.53 (s, 1H), 8.38 (d, J=2.0 Hz, 1H), 7.69 (dd, J=8.3, 2.0 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H), 2.44 (s, 3H), 2.09 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:66][O:67][CH2:68][CH2:69][CH2:70][NH2:71]>CC(N(C)C)=O.C(#N)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:34]=[CH:33][C:29]([C:30]([NH:71][CH2:70][CH2:69][CH2:68][O:67][CH3:66])=[O:31])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COCCCN
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(C(=O)O)cc2)cc(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: COCCCNC(=O)c1ccc(S(=O)(=O)Nc2nc3ccccc3nc2Nc2cc(OC)cc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]benzoic acid (100 mg; 0.21 mmol; 1 eq.), EDC-HCl (51.87 mg; 0.27 mmol; 1.3 eq.) and HOBT (36.56 mg; 0.27 mmol; 1.3 eq.) were taken up in DMA (5 ml) then DIEA(106.88 μl; 0.62 mmol; 3 eq.) and 3-methoxypropylamine (21.23 μl; 0.21 mmol; 1 eq.) were added. The solution was stirred at rt for 3 h. The DMA was evaporated and the residue was taken up in DCM. The organic phase was washed with a saturated solution of NaHCO3 then a saturated solution of NH4Cl and brine. It was dried over MgSO4 and concentrated to near dryness. The residue obtained was taken up in ACN and refluxed. After cooling at 4° C., the precipitate was filtered off then washed with ACN to afford 76 mg(66%) of the title compound as a parent. Treatment of the parent (74 mg; 0.13 mmol; 1 eq.) with an aqueous solution of potassium hydroxide (268.30 μl; 0.5 M; 0.13 mmol; 1 eq.) affords 76 mg (96%) of the title compound as a yellow powder. 1H NMR (DMSO-d6) δ 8.77 (s, 1H), 8.49-8.45 (m, 1H), 8.08 (d, J=8.3 Hz, 2H), 7.80 (d, J=8.3 Hz, 2H), 7.41-7.38 (m, 1H), 7.31 (d, J=2.3 Hz, 2H), 7.27-7.24 (m, 1H), 7.17-7.08 (m, 2H), 6.13-6.12 (m, 1H), 3.77 (s, 6H), 3.35-3.31 (m, 2H), 3.28-3.22 (m, 2H), 3.20 (s, 3H), 1.75-1.66 (m, 2H). HPLC (max plot) 97%; Rt 4.17 min. LC/MS: (ES+): 552.4, (ES−): 550.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.[CH3:15][NH:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=1)=[O:18].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=[C:2]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:17]([NH:16][CH3:15])=[O:18])=[CH:25][CH:24]=2)[N:7]=1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CNC(=O)Nc1ccc(-c2nc(Cl)nc(N3CCOCC3)n2)cc1
Yield: 34 %

Procedure:
A mixture of compound 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (10 g, 42.7 mmol), Pd (PPh3)4 (2.46 g, 2.1 mmol), 1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea. (11.7 g, 42.4 mmol) and 1 N Na2CO3 (168 mL, 168 mmol) in degassed 1,2-dimethoxyethane (400 mL) was heated to 65° C. for 8 hours under N2 atmosphere. The reaction mixture filtered, diluted with water, extracted with ethyl acetate and washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Crude product was purified by silica gel (100-200 mesh) column chromatography using 20-60% ethyl acetate in pet-ether as an eluent. To give 1-(4-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-methylurea (5.0 g, 34% yield).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+].O>C(O)C>[OH:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[N:17][OH:18]
Reactant: O=Cc1ccc(-c2ccccc2)cc1O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=Cc1ccc(-c2ccccc2)cc1O
Temperature: 80 °C
Reaction time: 3 h
Yield: 75.4 %

Procedure:
2-Hydroxy-4-phenylbenzaldehyde (3.7 g), hydroxylamine hydrochloride (1.4 g), sodium acetate (3.1 g) and water (10 mL) were suspended in ethanol (50 mL), and the mixture was stirred at 80° C. for 3 hours. To the reaction mixture was added water (50 mL), and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give the title compound (3.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][N:21]=[N:20][CH:19]=2)[C:13]=1[C:24]#[N:25])[C:5](O)=[O:6].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:48][CH2:49][C:50]1[C:51](=[O:58])[NH:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>O.ClCCl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][N:21]=[N:20][CH:19]=2)[C:13]=1[C:24]#[N:25])[C:5]([NH:48][CH2:49][C:50]1[C:51](=[O:58])[NH:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56])=[O:6]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: N#Cc1c(Oc2ccc(C(=O)O)cc2Cl)cccc1-c1ccnnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3cccc(-c4ccnnc4)c3C#N)c(Cl)c2)c(=O)[nH]1
Temperature: 25 °C
Yield: 72 %

Procedure:
A mixture of 3-chloro-4-(2-cyano-3-(pyridazin-4-yl)phenoxy)benzoic acid (70 mg, 0.2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (60 mg, 0.3 mmol) and N-hydroxybenzotriazole (45 mg, 0.3 mmol), triethylamine (0.1 mL) and dichloromethane (5 mL) were stirred at 25° C. for half an hour and then 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (30 mg, 0.2 mmol) was added. The mixture was stirred at 25° C. for 12 hours. To the mixture, water (10 mL) was added and the mixture was extracted with dichloromethane (10 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 3-chloro-4-(2-cyano-3-(pyridazin-4-yl)phenoxy)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzamide as a white solid (70 mg, 70%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[CH2:10].CO.[OH-].[Na+]>O.C(O)(=O)C>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:9][CH2:10][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([OH:1])[CH:3]=1
Reactant: Nc1cccc(O)c1
Reactant: C=Cc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Oc1cccc(NCCc2ccccn2)c1
Yield: 79.9 %

Procedure:
With stirring a mixture of 44.0 g of 3-hydroxyaniline, 60.0 g of 2-vinylpyridine, 140.0 ml of methyl alcohol and 5.0 ml of glacial acetic acid was maintained at reflux temperature for approximately twenty-four hours. The methyl alcohol was removed by distillation and a mixture of water and toluene was added to the resultant residue. Three layers resulted. Sufficient 5 percent aqueous sodium hydroxide was added to adjust the water layer to approximately pH 7. The bottom oil layer was separated, and dried under reduced pressure to obtain a gummy solid which was triturated with hexane to obtain 69.0 g of N-[2-(2-pyridyl)ethyl]-3-hydroxyaniline(Formula V: R4 =R9 =H; R10 =OH), a pale tan solid which after being exposed to air turned into a taffy-like solid. The nuclear magnetic resonance spectrum was concordant with the assigned structure. The water layer was discarded. The toluene layer was washed first with water and then with saturated sodium chloride solution and evaporated to dryness under reduced pressure. The residue was recrystallized from a mixture of ispropanol and hexane to obtain 3.9 g of N-[2-(2-pyridyl)ethyl]-3-hydroxyaniline, a white solid which melted at 118°-120° C. A significant infrared maximum appeared at 1195 cm-1 (N--C;s). The nuclear magnetic resonance spectrum was consistent with the assigned structure.
Reaction SMILES: N#N.[CH2:3]([O:10][C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20](O)=[O:21])[CH2:16][CH2:15]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(C)C.[BH4-].[Na+]>C1COCC1.CO>[CH2:3]([O:10][C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([CH2:20][OH:21])[CH2:16][CH2:15]1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CSC
Solvent: CO
Solvent: C1CCOC1
Product: O=C(N[C@H]1CC[C@H](CO)CC1)OCc1ccccc1
Temperature: 0 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of trans-4-benzyloxycarbonylaminocyclohexanecarboxylic acid (417 mg, 1.50 mmol) in THF (15 mL) was added BH3.Me2S complex (2.0 M in THF, 1.5 mL, 3.00 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h30. More BH3.Me2S complex (2.0 M in THF, 1.0 mL, 2.00 mmol) was added at 0° C. followed by NaBH4 (12 mg, 0.30 mmol). The reaction mixture was warmed to rt and stirred at this temperature until completion of the reaction. MeOH was carefully added to quench the reaction, the volatiles were removed under reduced pressure and the residue co-evaporated with MeOH (2×). Purification by FC (hept-EA, 1:0->3:2) gave pure trans-4-benzyloxycarbonylaminocyclohexane-methanol as a white solid. TLC:rf (1:2 hept-EA)=0.35. LC-MS-conditions 01: tR=0.82 min; [M+H]+=264.05.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15](O)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N.N.C[N:25]([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[C:15]([C:14]1[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=1[CH:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)(=[O:16])[NH2:25]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2C(=O)O)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2C(N)=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
A stirred solution of 2-[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]benzoic acid a1-3 (5.5 g, 19 mmol, 1 eq) in dichloromethane (150 ml) is saturated, at 0° C., with gaseous ammonia NH3 for 1 hour. BOP reagent (8.82 g, 19.9 mmol, 1.05 eq) is added portionwise to this solution. The reaction mixture is warmed to room temperature and stirred overnight. The reaction mixture is filtered off and the solid washed with dichloromethane (100 ml). The organic layer is evaporated under vacuum and the residue obtained is purified by chromatography over silicagel (eluent: CH2Cl2/MeOH 98.5/1.5) to give 5.4 g of tert-butyl 3-(2-carbamoylphenyl)pyrrolidine-1-carboxylate a1-4.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)=[N:6]2)[CH2:2][CH2:3]1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Reactant: C1CCNC1
Product: COc1ccc(-c2cc(CN3CCCC3)c(=O)n(CC3CC3)n2)cc1F
Yield: 75.9 %

Procedure:
Following the procedure of Example 1(10), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and pyrrolidine were reacted to yield the title compound as a yellow oil (yield: 75.9%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([Cl:8])=[O:7])[N:3]=[N:2]1.[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[C:12]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:11]=1>>[ClH:8].[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[C:12]([N:24]2[CH2:29][CH2:28][N:27]([C:6]([C:4]3[N:3]=[N:2][S:1][CH:5]=3)=[O:7])[CH2:26][CH2:25]2)[N:11]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: O=C(Cl)c1csnn1
Product: COc1cc2nc(N3CCN(C(=O)c4csnn4)CC3)nc(N)c2cc1OC
Product: Cl

Procedure:
The title compound was prepared by reacting 1,2,3-thiadiazole-4-carbonyl chloride (D. L. Pain and R. Slack, J. Chem. Soc., 5166 (1965)) and 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline according to the procedure of Example 1. After crystallization from aqueous ethanol, the title compound melted at 270° C. (dec.).
Reaction SMILES: C([O:9][CH2:10][C:11]1[O:15][N:14]=[C:13]([CH3:16])[C:12]=1[C:17]1[C:26]2[O:25][CH2:24][CH:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[N:22]3[C:33](=[O:35])[NH:34][C:20]([C:21]=23)=[CH:19][CH:18]=1)(=O)C1C=CC=CC=1.[OH-].[Li+].O>O1CCCC1.CO>[OH:9][CH2:10][C:11]1[O:15][N:14]=[C:13]([CH3:16])[C:12]=1[C:17]1[C:26]2[O:25][CH2:24][CH:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[N:22]3[C:33](=[O:35])[NH:34][C:20]([C:21]=23)=[CH:19][CH:18]=1
Reactant: Cc1noc(COC(=O)c2ccccc2)c1-c1ccc2[nH]c(=O)n3c2c1OCC3c1ccccn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(CO)c1-c1ccc2[nH]c(=O)n3c2c1OCC3c1ccccn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68.6 %

Procedure:
A solution of [3-methyl-4-(2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-7-yl)isoxazol-5-yl]methyl benzoate (15.0 mg, 0.0320 mmol) in tetrahydrofuran (1.0 mL) and methanol (1.0 mL) was treated with 2.0 M lithium hydroxide in water (0.10 mL, 0.20 mmol) and stirred at room temperature for 20 min. The reaction mixture was quenched with 6 N hydrogen chloride in water (to pH ˜2) and then concentrated. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) gave the desired product (8 mg, 69%) as a racemic mixture. 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, J=4.8 Hz, 1H), 7.77 (ddd, J=7.7, 7.7, 1.7 Hz, 1H), 7.31 (dd, J=7.4, 4.9 Hz, 1H), 7.09 (d, J=7.9 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 5.51 (s, 1H), 4.77 (dd, J=11.4, 1.8 Hz, 1H), 4.42 (dd, J=11.4, 3.1 Hz, 1H), 4.36 (s, 2H), 3.15 (s, 1H), 2.06 (s, 3H); LCMS calculated for C19H17N4O4 (M+H)+: m/z=365.1. found: 365.1.