Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([S:7](Cl)(=[O:9])=[O:8])[N:4]=[CH:3]1.[CH3:11][NH2:12].O>C(Cl)Cl.C1COCC1>[CH3:11][NH:12][S:7]([C:5]1[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=1)(=[O:9])=[O:8]
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNS(=O)(=O)c1cn(C)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (1-methyl-1H-imidazol-4-yl)sulfonyl chloride (3.14 g, 17.4 mmol) in methylene chloride was added a solution of methylamine (26 mL of a 2M solution in THF, 52 mmol). The resulting mixture was stirred at room temperature for 16 hr. Water (25 mL) was added and the mixture was extracted with methylene chloride (2×100 mL). The combined organic extracts were washed with water (10 mL) and dried (MgSO4). The solvent was evaporated in vacuo to afford the title compound.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C@@H:12]1[C:18](=[O:19])[N:17]2[C@H:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:22][CH2:23][N:16]2[C:15](=[O:31])[CH2:14][CH2:13]1.NN>C(O)C>[NH2:3][C@@H:12]1[C:18](=[O:19])[N:17]2[C@H:20]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:21][CH2:22][CH2:23][N:16]2[C:15](=[O:31])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](N3C(=O)c4ccccc4C3=O)C(=O)N12
Agent: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](N)C(=O)N12
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
In a 200 mL round-bottomed flask, (1S,9S)-tert-butyl 9-(1,3-dioxoisoindolin-2-yl)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate (5 g, 11.7 mmol) was combined with ethanol (50 ml) to give a colorless suspension. Hydrazine (825 mg, 808 μl, 25.7 mmol) was added and stirred at room temperature for 2 hr. The crude reaction mixture was concentrated in vacuo and evaporated with toluene. 2M aqueous acetic acid (50 ml) was added and stirred at room temperature overnight. The precipitate was filtered and the filtrate was basified with sodium carbonate solution. It was extracted with CH2Cl2 (2×150 ml). The combined organic layer was dried with MgSO4 and concentrated in vacuo to afford (1S,9S)-tert-butyl 9-amino-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate as a sticky white solid (3.4 g, 97.8%). ESI-LRMS m/e calcd for C14H23N3O4 [M+] 297. found 298 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[CH:6]=[C:5]2[CH:24]=[O:25].[CH:26]1([NH:29][C:30](=[O:48])[C:31]2[CH:36]=[C:35](B3OC(C)(C)C(C)(C)O3)[C:34]([CH3:46])=[C:33]([F:47])[CH:32]=2)[CH2:28][CH2:27]1>>[CH:26]1([NH:29][C:30](=[O:48])[C:31]2[CH:36]=[C:35]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8](=[O:12])[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:16][CH:15]=3)[CH:6]=[C:5]4[CH:24]=[O:25])[C:34]([CH3:46])=[C:33]([F:47])[CH:32]=2)[CH2:27][CH2:28]1
Reactant: CS(=O)(=O)c1ccc(Cn2cc(C=O)c3cc(Br)ccc3c2=O)cc1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(S(C)(=O)=O)cc3)cc(C=O)c2c1

Procedure:
The sub-title compound was prepared by the method of Example 60 step iii) using product of Example 103 step ii) and N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1C=CC=CC=1.C/C(/C(C)=O)=N\O.C1(C)C=CC(C=O)=CC=1>>[I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[O:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: CC(=O)/C(C)=N/O
Agent: Cc1ccc(C=O)cc1
Product: Cc1ccc(-c2nc(CI)c(C)o2)cc1

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and p-tolualdehyde gave 4-iodomethyl-5-methyl-2-p-tolyloxazole.
Reaction SMILES: [CH3:1][C:2]1[N:25]([CH3:26])[C:5]2[CH:6]=[C:7]([C:20]([O:22]CC)=[O:21])[C:8]3[CH2:9][CH2:10][CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:12][C:13]=3[C:4]=2[N:3]=1.Cl>O1CCOCC1.[OH-].[Na+]>[CH3:1][C:2]1[N:25]([CH3:26])[C:5]2[CH:6]=[C:7]([C:20]([OH:22])=[O:21])[C:8]3[CH2:9][CH2:10][CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:12][C:13]=3[C:4]=2[N:3]=1
Reactant: CCOC(=O)c1cc2c(nc(C)n2C)c2c1CCC(c1ccccc1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc2c3c(c(C(=O)O)cc2n1C)CCC(c1ccccc1)N3
Temperature: 100 °C
Yield: 88.8 %

Procedure:
A suspension of 12 g (3.4 mmol) ethyl 2,3-dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-h]quinoline-5-carboxylate in 20 ml dioxane and 12 ml 2N aqueous sodium hydroxide was heated to 100° C. until no starting material was left. The mixture was cooled down and neutralized with 2N hydrochloric acid. The precipitate was collected, washed with water and dried. The crude product was recrystallized from ethanol to yield 0.97 g (88%) of the title compound as a colourless solid. m.p. 325-326° C.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15]#[N:16])=[N:6]1.C[O-].[Na+].C(O)(=O)C.[Cl-].[NH4+:29]>CO>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15](=[NH:29])[NH2:16])=[N:6]1
Reactant: [NH4+]
Reactant: Cc1ncc2c(C#N)nn(Cc3ccccc3F)c2n1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ncc2c(C(=N)N)nn(Cc3ccccc3F)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, 994 mg (purity 81%, approx. 3.01 mmol) of 1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile were dissolved in 15 ml of absolute methanol. 209 mg (3.72 mmol) of sodium methoxide were added and the mixture was stirred at RT for 1 h. Subsequently, 31 mg (0.56 mmol) of sodium methoxide were added and the mixture was stirred at RT for 15 min. 871 mg (14.50 mmol) of acetic acid and 489 mg (4.46 mmol) of ammonium chloride were added and the mixture was stirred at 45° C. for 45 min. The reaction mixture was concentrated, the residue was stirred with 1N sodium hydroxide solution, and the precipitate was filtered off with suction and dried under high vacuum. 918 mg (purity 91%, 97% of theory) of the target compound were obtained.
Reaction SMILES: C(SC1C=C(O)C(=O)NC=1)C1C=CC=CC=1.C[O:18][C:19]1[C:24]([O:25]C)=[CH:23][C:22]([S:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])=[CH:21][N:20]=1>>[OH:25][C:24]1[C:19](=[O:18])[NH:20][CH:21]=[C:22]([S:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH:23]=1
Reactant: COc1cc(SCc2ccccc2C)cnc1OC
Agent: O=c1[nH]cc(SCc2ccccc2)cc1O
Product: Cc1ccccc1CSc1c[nH]c(=O)c(O)c1

Procedure:
Prepared as described for 5-(benzylsulfanyl)-3-hydroxypyridin-2(1H)-one (Example 1) from 2,3-dimethoxy-5-[(2-methylbenzyl)sulfanyl]pyridine (Intermediate 12).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7](O)[C:8]3[C:13]([O:14][C:4]2=[CH:3][CH:2]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[CH3:16][NH:17][C:18]([NH:20][CH3:21])=[O:19].C1(C)C=CC=CC=1>C(O)(=O)C>[CH3:16][N:17]([CH:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[O:14][C:4]2[C:5]1=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:18]([NH:20][CH3:21])=[O:19]
Reactant: OC1c2ccccc2Oc2ccccc21
Reactant: CNC(=O)NC
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CNC(=O)N(C)C1c2ccccc2Oc2ccccc21

Procedure:
A mixture of xanthydrol (2 g.), N,N'-dimethylurea (1 g.), toluene (15 ml.) and acetic acid (0.6 ml.) was refluxed for 20 minutes, evaporated to dryness, the residue was washed with water and dried. It was recrystallised from benzene and the crystals dried at 90°C./2mm. to give N,N'-dimethyl-N-9-xanthenylurea, m.p. 169°-170°C.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].CC1(C)C(C)(C)OB([C:19]2[CH:20]=[CH:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[N:23][CH:24]=2)O1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=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]>[F:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[N:23][CH:24]=2)[CH:9]=1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=Cc1ccc(F)cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(-c2cc(F)ccc2C=O)cn1
Temperature: 25 °C

Procedure:
2-bromo-4-fluorobenzaldehyde (800 mg, 3.9 mmol), methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate (1.2 g, 4.7 mmol), Pd(dppf)Cl2 (433 mg, 0.6 mmol), and K2CO3 (1.1 g, 7.9 mmol) were dissolved in 1,4-dioxane (40 mL) and water (10 mL) and the resulting mixture was heated to 65° C. After 1.5 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: C([NH:5][S:6]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[N:21](COCC[Si](C)(C)C)[CH:22]=[C:23]([C:25]#[N:26])[N:24]=2)=[O:19])=[C:13]([C:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]=2)[CH:12]=1)(=[O:8])=[O:7])(C)(C)C.CCO.C1(OC)C=CC=CC=1.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53]>C(Cl)Cl>[F:55][C:54]([F:57])([F:56])[C:52]([OH:58])=[O:53].[C:35]1([C:13]2[CH:12]=[C:11]([CH2:10][CH2:9][S:6](=[O:7])(=[O:8])[NH2:5])[CH:16]=[CH:15][C:14]=2[NH:17][C:18]([C:20]2[NH:21][CH:22]=[C:23]([C:25]#[N:26])[N:24]=2)=[O:19])[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]=1
Reactant: CC(C)(C)NS(=O)(=O)CCc1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(CCS(N)(=O)=O)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 11 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [4-(2-tert-butylsulfamoyl-ethyl)-2-cyclohex-1-enyl-phenyl]-amide (as the prepared in previous step, 275 mg, 0.470 mmol) in DCM (5 mL), EtOH (140 μL), anisole (51 μL) and TFA (1.5 mL) were added. The resulting solution was stirred at RT for 6 h. An additional 0.35 mL of TFA was added and the resulting mixture was stirred at RT overnight. The reaction mixture was concentrated and the residue was subjected to RP-HPLC eluting with 20% to 100% CH3CN in 0.1% TFA/H2O over 20 min on a C18 column to afford the title compound (26.6 mg, 11%). 1H-NMR (DMSO-d6; 400 MHz): δ 9.72 (s, 1H), 8.31 (s, 1H), 7.85 (d, 1H, J=8.4 Hz), 7.17 (d, 1H, J=8.4 Hz), 7.10 (s, 1H), 6.82 (s, 2H), 5.72 (br s, 1H), 3.23 (m, 2H), 2.92 (m, 2H), 2.1-2.29 (m, 4H), 1.62-1.75 (m, 4H); Mass spectrum (ESI, m/z): Calcd. for C19H21N5O3S, 400.1 (M+H), found 400.1.
Reaction SMILES: [CH2:1]1[CH2:29][O:28][C:3]2([C:20]3[C:19](=[O:21])[C:18]4[C:9](=[C:10]([OH:24])[C:11]5[CH2:12][CH2:13][CH:14]([OH:23])[CH2:15][C:16]=5[C:17]=4[OH:22])[C:8](=[O:25])[C:7]=3[CH:6]=[CH:5][CH:4]2[CH2:26][CH3:27])[O:2]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:42]Br>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl.O>[Br:42][CH:12]1[CH2:13][CH:14]([OH:23])[CH2:15][C:16]2[C:17]([OH:22])=[C:18]3[C:9]([C:8](=[O:25])[C:7]4[CH:6]=[CH:5][CH:4]([CH2:26][CH3:27])[C:3]5([O:2][CH2:1][CH2:29][O:28]5)[C:20]=4[C:19]3=[O:21])=[C:10]([OH:24])[C:11]1=2
Reactant: BrBr
Reactant: CCC1C=CC2=C(C(=O)c3c(O)c4c(c(O)c3C2=O)CCC(O)C4)C12OCCO2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC1C=CC2=C(C(=O)c3c(O)c4c(c(O)c3C2=O)C(Br)CC(O)C4)C12OCCO2
Reaction time: 1 h

Procedure:
9-(1,1-Ethylenedioxy)ethyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (10.0 g) was dissolved in a mixture of chloroform (395 ml), carbon tetrachloride (980 ml) and water (890 ml) while heating, azobisisobutyronitrile (2.0 g) and bromine (8.0 g) were added thereto in order, and the resultant mixture was stirred under reflux for 1.5 hours. The reaction mixture was stirred in an ice bath for 1 hour, and the precipitated red orange crystals were collected by filtration, washed with water and dried under reduced pressure to give the crude product of 7-bromo-9-(1,1-ethylenedioxy)ethyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione. M.P., 196°-235° C.; IR (Nujol) ν cm-1 : 3550, 1625, 1590. This product was used as such in the following step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[C:16](C1NC=CN=1)(C1NC=CN=1)=[O:17]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:16](=[O:17])[O:15][C:9]3([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[C:3]=2[CH:4]=1
Reactant: Nc1ccc(Br)cc1C1(O)CCCCC1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Product: O=C1Nc2ccc(Br)cc2C2(CCCCC2)O1

Procedure:
Prepared from 1-(2-amino-5-bromo-phenyl) cyclohexanol and carbonyl diimidazole according to the procedure of Example 2. Off-white solid: mp 208-210° C. 1H-NMR (DMSO-d6) δ10.26 (s, 1H), 7.45 (d, 1H, J=2.2 Hz), 7.39 (dd, 1H, J=8.2, 2.2 Hz), 6.81 (d, 1H, J=8.3 Hz), 1.90-1.97 (m, 2H), 1.80-1.85 (m, 5H), 1.25-1.35 (m, 1H); MS (APC1) m/z 296 ([M+H]+, 68%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][CH2:17][C:18]1([CH2:23][OH:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[OH:24][CH2:23][C:18]1([CH2:17][NH:16][C:8]([C:5]2[CH:4]=[C:3]([O:11][CH2:12][CH:13]3[CH2:15][CH2:14]3)[C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NCC1(CO)CCCC1
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Product: O=C(NCC1(CO)CCCC1)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 12d, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and 1-(aminomethyl)-cyclopentanemethanol (CAN 2239-31-8) as starting materials and isolated (35 mg, quant.) as colorless oil; LC-MS (UV peak area, m/z) 100%, 339.1470 (MH+).
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=[O:4])=[O:3].O[CH2:11][CH2:12][CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]2[C:24](=[O:38])[NH:25][C:26](=[O:37])[C:27]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N+:34]([O-:36])=[O:35])=[CH:15]1.N1C=CC=CC=1>ClCCl>[CH3:1][S:2]([O:5][CH2:11][CH2:12][CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]2[C:24](=[O:38])[NH:25][C:26](=[O:37])[C:27]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N+:34]([O-:36])=[O:35])=[CH:15]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: O=C1NC(=O)C(c2cn(CCCO)c3ccccc23)=C1c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCCn1cc(C2=C(c3ccccc3[N+](=O)[O-])C(=O)NC2=O)c2ccccc21
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
93 mg of methanesulphonic anhydride were added to a solution of 0.46 mmol of the product of Example 55 in 25 ml of dichloromethane. 0.5 ml of pyridine was added and the mixture was stirred for 0.5 hour, then washed with water, dried and concentrated. Chromatography of the residue on silica gel with 10% methanol in dichloromethane gave 160 mg of 3-[1-[3-(methylsulphonyloxy)propyl]-3-indolyl]-4-(2-nitrophenyl)-1H-pyrrole-2,5-dione, m.p. 177°-178° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][C@H:10]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:8]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([CH2:9][C@H:10]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc([N+](=O)[O-])cn2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(N)cn2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (s)-tert-butyl 2-((4-nitro-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (3.2 g, 10.2 mmol) in methanol (100 mL) was added Pd/C (600 mg). The mixture was stirred under 1 atm H2 at room temperature overnight, and then filtrated through a pad of celite. The filtrate was concentrated to afford (S)-tert-butyl 2-((4-amino-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate. MS (ES+) C13H22N4O3 requires: 282, found: 283 [M+H]+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:28]([F:31])([F:30])[F:29])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:32][NH2:33]>>[CH3:32][NH:33][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[C:19]([C:28]([F:31])([F:30])[F:29])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]=2[O:14]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C(F)(F)F)cc(-c4ccccc4)c3O2)cc1
Product: CNCC1Cc2cc(C(F)(F)F)cc(-c3ccccc3)c2O1

Procedure:
The title compound was prepared (0.031 g, 67%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-phenyl-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.060 g, 0.13 mmol) and methylamine (0.12 g, 3.9 mmol). mp 189-190° C.
Reaction SMILES: [CH2:1]([N:8]1[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[CH:10][C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+].Cl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClCCl>[CH2:1]([N:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][C:9]1=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(O)cc(=O)n1Cc1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(OCc2ccccc2)cc(=O)n1Cc1ccccc1

Procedure:
1-benzyl-4-hydroxy-6-methylpyridin-2(1H)-one (10 mmol, 2.15 g), dichloromethane (100 mL), benzylbromide (11 mmol, 1.88 g), sodium hydroxide (2.5 N, 20 mmol, 8 mL), and benzyltriethylammonium chloride (0.5 g) were vigorously stirred at room temperature for 16 h. Hydrochloric acid (1 N) was added until the mixture produced an acidic reaction to pH paper. The mixture was then extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The product was obtained by flash chromatography eluting with ethyl acetate:hexanes (1:2). The appropriate fractions were concentrated to a clear oil. (1.3 g, 43%): 1H NMR (DMSO-d6/300 MHz) δ: 7.4-7.1 (m, 10H), 6.0 5.9 (m, 2H), 5.2 (s, 2H), 5.1 (s, 2H), 2.2 (s, 3H). ESHRMS m/z 306.147 (M+H, C20H19NO2 requires 306.149).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:5]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])[CH3:8])=[O:6].[N:31]1([S:35](C2C=C(C=C(C(F)(F)F)C=2)C(O)=O)(=[O:37])=[O:36])[CH2:34][CH2:33][CH2:32]1>>[N:31]1([S:35]([C:2]2[CH:3]=[C:4]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=2)[C:5]([N:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[O:22][CH3:23])[CH3:8])=[O:6])(=[O:37])=[O:36])[CH2:34][CH2:33][CH2:32]1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCC2)c1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCC2)c1

Procedure:
The title compound was prepared in analogy to example 90, from 4-(4-fluoro-2-methoxyphenyl)-N-methylpyridin-3-amine (example 129, intermediate) and 3-(azetidine-1-sulfonyl)-5-trifluoromethyl-benzoic acid after a reaction time of 16.5 hours. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (ISCO) system eluting with EtOAc (isocratic). Colorless foam (43%). MS (ESI): m/z=524.13 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C@H:16]([C:20]([OH:22])=O)[CH:17]([CH3:19])[CH3:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH:2]=[C:3]=[CH2:4].[OH:23][N:24]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.NO>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH:16]([CH:17]([CH3:19])[CH3:18])[C:20]([NH:24][OH:23])=[O:22])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH:2]=[C:3]=[CH2:4]
Reactant: C=C=CCOc1ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C=C=CCOc1ccc(S(=O)(=O)NC(C(=O)NO)C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
To a solution of product from Example 12 (210 mg, 0.65 mmol) in dimethylformamide (6 ml) was added 1-hydroxybenzotriazol (105 mg, 0.78 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodimide hydrochloride (173 mg, 0.90 mmol), and N-methylmorpholine (0.106 mmol, 0.97 mmol) and the resulting mixture was stirred for 1 hour at room temperature. A 50% aqueous solution of hydroxylamine (0.119 ml, 1.94 mmol) was added and the mixture was stirred for 15 hours at room temperature. The reaction mixture was concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water, saturated sodium bicarbonate, saturated sodium chloride and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo gave 100 mg (45%) of the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]2[CH2:19][C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[O:17][N:16]=2)[CH:14]=1)[C:5]([O:7]C(C)(C)C)=[O:6].Cl>O1CCOCC1.Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]2[CH2:19][C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[O:17][N:16]=2)[CH:14]=1)[C:5]([OH:7])=[O:6]
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(C2=NO[C@H](c3ccccn3)C2)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cc(Br)cc(C2=NO[C@H](c3ccccn3)C2)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-bromo-5-[(5S)-5-(2-pyridinyl)-4,5-dihydro-3-isoxazolyl]benzoate (0.530 g, 1.31 mmol) in dioxane (6.5 mL) was added hydrogen chloride (4M in dioxane, 1.3 mL, 5.26 mmol). The reaction mixture was stirred at 50° C. for 2 h. Two drops of concentrated hydrogen chloride (12.1 N) were added. The reaction mixture was stirred at 50° C. for 2 d. The mixture was concentrated to dryness to give the hydrochloride salt of the title compound which was used directly in Step B (0.476 g). MS 346.9 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.OCC1C=CNN=1.[Na].[CH2:16]([OH:19])[CH2:17][OH:18]>>[OH:18][CH2:17][CH2:16][O:19][CH2:2][C:3]1[CH:7]=[CH:6][NH:5][N:4]=1
Reactant: OCCO
Reactant: ClCc1cc[nH]n1
Agent: OCc1cc[nH]n1
Agent: [Na]
Product: OCCOCc1cc[nH]n1

Procedure:
3-Chloromethylpyrazole, prepared by reacting 3-hydroxymethylpyrazole witth thionyl chloride, is reacted with the sodium salt of ethylene glycol to give 3-(2-hydroxyethoxymethyl)pyrazole. Treatment of 3-(2-hydroxyethoxymethyl)pyrazole with thionyl chloride gives 3-(2-chloroethoxymethyl)pyrazole.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].Cl.Cl.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[CH2:24][NH2:25])[CH:17]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:25][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[C:18]3[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: NCc1ccccc1-c1cccnc1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]nc(Cl)c2cc(NCc3ccccc3-c3cccnc3)ccc12

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.58 mmol), 2-pyridin-3-yl-benzylamine dihydrochloride (165 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (108 mg, 0.17 mmol) and NaOt-Bu (251 mg, 2.61 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2-pyridin-3-yl-benzylamino)-2H-phthalazin-1-one: 51 mg (24.2%): m/z (M+H)=363. 1H-NMR (DMSO-d6) δ: 12.32 (s, 1H), 8.65 (d, 1H), 8.58 (dd, 1H), 7.88 (m, 2H), 7.61 (m, 1H), 7.46 (m, 4H), 7.34 (m, 1H), 7.06 (dd, 1H), 6.55 (s, 1H), 4.30 (d, 2H).