Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=O)=[N:13][CH:14]=1>C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[Br:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:15]=[N:7]/[S@@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])=[N:13][CH:14]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1ccc(Br)cn1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 21 h
Yield: 97.1 %

Procedure:
To a solution of (R)-(+)-2-methyl-2-propanesulfinamide (2.60 g, 21.5 mmol) in 100 mL of CH2Cl2 at room temperature was added CuSO4 (7.53 g, 47.2 mmol) and 5-bromo-pyridine-2-carbaldehyde (4.39 g, 23.6 mmol). The reaction mixture was stirred at room temperature for 21 h and then filtered through Diatomaceous earth, washing with CH2Cl2. The filtrates were concentrated to give a pale brown oil that was purified by flash chromatography on silica gel, eluting with 10-25% EtOAc in hexanes, to afford 6.04 g (97%) of (R)-2-methyl-propane-2-sulfinic acid 1-(5-bromo-pyridin-2-yl)-meth-(E)-ylideneamide as a pale yellow solid.
Reaction SMILES: C([NH:8]C1C=C(C=C(S(Cl)(=O)=O)C=1C1C=CC=CC=1)C(O)=O)C1C=CC=CC=1.Cl[S:29]([C:32]1[C:33]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[C:34]([N+:41]([O-:43])=[O:42])[CH:35]=[C:36]([CH:40]=1)[C:37]([OH:39])=[O:38])(=[O:31])=[O:30]>>[N+:41]([C:34]1[CH:35]=[C:36]([CH:40]=[C:32]([S:29](=[O:31])(=[O:30])[NH2:8])[C:33]=1[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:37]([OH:39])=[O:38])([O-:43])=[O:42]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(-c2ccccc2)c(S(=O)(=O)Cl)c1
Reactant: O=C(O)c1cc(NCc2ccccc2)c(-c2ccccc2)c(S(=O)(=O)Cl)c1
Product: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1-c1ccccc1

Procedure:
By replacing in Example 1, step G, 3-benzylamino-5-chlorosulfonyl-4-phenylbenzoic acid with 5-chlorosulfonyl-3-nitro-4-phenylbenzoic acid, and following the procedure described, 3-nitro-4-phenyl-5-sulfamylbenzoic acid is obtained as a hydrate with a melting point of 119°-121° C.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([C:14]#[N:15])[N:10](CC=C)[C:9]=2[C:8](=[O:19])[N:7]([CH3:20])[C:6]1=[O:21])[CH2:2][CH2:3][CH3:4]>C1COCC1.CS(C)=O.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>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([C:14]#[N:15])[NH:10][C:9]=2[C:8](=[O:19])[N:7]([CH3:20])[C:6]1=[O:21])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(C#N)nc2c1c(=O)n(C)c(=O)n2CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCCCn1c(=O)n(C)c(=O)c2[nH]c(C#N)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.6 %

Procedure:
A solution of 3-butyl-1-methyl-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purine-8-carbonitrile (230 mg, 0.80 mmol) in anhydrous THF (5 ml) and anhydrous DMSO (0.5 ml) was treated with Pd(PPh3)4 (185 mg, 0.16 mmol). The mixture was degassed under gentle vacuum, morpholine (698 uL) added, and left to stir at rt under nitrogen for 2 hours. The yellow solution was partitioned between 2M HCl(aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The residue was taken up in MeOH and passed down and amino-propyl SPE (5 g), eluting with MeOH followed by 5% AcOH then 10%, 20% and 30% AcOH/MeOH mixtures. The product fractions were combined and concentrated to afford a pale yellow solid (116 mg). This was washed with MeOH and the title compound a white solid was collected by filtration and dried under vacuum (55 mg, 28%). NMR; δH (400 MHz, d6-DMSO) 0.90 (t, 3H, J=7.5 Hz), 1.25-1.35 (m, 2H), 1.59-1.68 (m, 2H), 3.24 (s, 3H), 3.96 (t, 2H, J=7 Hz), NH not observed to δH 15; m/z 248.2[MH+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:16])=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=1.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:29]([O:28][C:26](=[O:27])[CH2:25][O:16][C:7]1[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:23])=[CH:9][C:8]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)c1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(-c2ccccc2)c(OCC(=O)OC(C)(C)C)c(-c2ccccc2)c1
Temperature: 70 °C
Yield: 96.2 %

Procedure:
To the phenol from Step 2 (3.50 g, 11.5 mmol) in acetonitrile (40 mL) was added tert-butyl bromoacetate (3.39 mL, 23 mmol) and K2CO3 (1.93 g, 12.65 mmol). The mixture was heated for 2 h at 70° C. then cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate/H2O. The organic phase was dried (MgSO4) and concentrated to give crude product. The compound was purified by passing it through a short filter column (SiO2) using hexane as the elutant. Concentration afforded 4.63 g (96%) of product as a clear oil. 1H NMR (DMSO-d6) δ 7.86 (s, 2H), 7.60-7.40 (m, 10H), 3.85 (2s, 5H), 1.19 (s, 9H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][CH2:7][CH2:8][NH:9][C@:10]12[CH2:44][CH2:43][C@@H:42]([C:45]([CH3:47])=[CH2:46])[C@@H:11]1[C@@H:12]1[C@@:25]([CH3:28])([CH2:26][CH2:27]2)[C@@:24]2([CH3:29])[C@@H:15]([C@:16]3([CH3:41])[C@@H:21]([CH2:22][CH2:23]2)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]2[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=2)=[CH:18][CH2:17]3)[CH2:14][CH2:13]1)([OH:3])=O.[CH3:48][N:49](C)[C:50](=O)C=C>>[CH3:48][N:49]([CH3:50])[C:1](=[O:3])[CH2:4][CH2:5][NH:6][CH2:7][CH2:8][NH:9][C@:10]12[CH2:44][CH2:43][C@@H:42]([C:45]([CH3:47])=[CH2:46])[C@@H:11]1[C@@H:12]1[C@@:25]([CH3:28])([CH2:26][CH2:27]2)[C@@:24]2([CH3:29])[C@@H:15]([C@:16]3([CH3:41])[C@@H:21]([CH2:22][CH2:23]2)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]2[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=2)=[CH:18][CH2:17]3)[CH2:14][CH2:13]1
Reactant: C=CC(=O)N(C)C
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNCCC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCNCCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(2-carboxyethylamino)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using N,N-dimethylacrylamide as the Michael aceptor reagent in the first step. The product was isolated as a white solid (9 mg, 50%). LCMS: m/e 672.47 (M+H)+, 2.33 min (method 2). 1H NMR (500 MHz, Acetic acid d4) δ ppm 8.04 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 5.37 (d, J=4.6 Hz, 1H), 4.88 (s, 1H), 4.76 (s, 1H), 3.86-3.59 (m, 4H), 3.51-3.37 (m, 2H), 3.07 (s, 3H), 2.99 (s, 3H), 2.95 (t, J=5.6 Hz, 2H), 2.90-2.76 (m, 1H), 2.37-1.22 (m, 22H), 1.78 (s, 3H), 1.20 (s, 3H), 1.14 (s, 3H), 1.09 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: Clc1ccc(I)cc1
Product: Clc1ccc(-n2ccc3ccc(Cl)cc32)cc1

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and 1-chloro-4-iodobenzene: ESMS m/e: 262.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[CH:32][CH:31]=2)=[C:4]([C:8]2[N:13]=[C:12]([N:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]3)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl[C:52]([O:54][CH3:55])=[O:53]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH2:26]([O:25][C:23]([C:17]1[CH:16]=[N:15][N:14]([C:12]2[N:13]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=3[O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([CH:36]4[CH2:41][CH2:40][N:39]([C:52]([O:54][CH3:55])=[O:53])[CH2:38][CH2:37]4)=[CH:34][CH:35]=3)[CH:9]=[CH:10][CH:11]=2)[C:18]=1[C:19]([F:21])([F:22])[F:20])=[O:24])[CH3:27]
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cccc(F)c3OCc3ccc(C4CCNCC4)cc3)n2)c1C(F)(F)F
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn(-c2cccc(-c3cccc(F)c3OCc3ccc(C4CCN(C(=O)OC)CC4)cc3)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound from Example 5 Step C (194 mg, 0.34 mmol) in DCM (2 mL) were added diisopropyl ethyl amine (0.60 mL, 3.41 mmol) and methyl chloroformate (0.08 mL, 1.02 mmol). The reaction mixture was stirred for 1 h at ambient temperature, then was diluted with sat. aq. NaHCO3 and extracted with DCM. The organic phase was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The product was used in the subsequent step without further purification: LCMS m/z 626.9 [M+H]+.
Reaction SMILES: N[C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[BrH:13].N([O-])=O.[Na+]>O>[Br:13][C@@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)[C@H](N)c1ccccc1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)[C@@H](Br)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 40.5 %

Procedure:
(R)-methyl 2-amino-2-phenylacetate (5 g, 24.8 mmol, 1 equiv) was dissolved in a mixture of 48% hydrogen bromide (13 ml, 198 mmol, 8 equiv) and water (19 ml). An aqueous solution of sodium nitrite (5.48 g, 79.36 mmol, 3.2 equiv) was added slowly and the mixture stirred at 0° C. for 1.5 h. The reaction was degassed in vacuo and extracted with ether. The organic layer was further washed with water and brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified using the Biotage flash chromatography system (SNAP 100 g cartridge, Rf=0.5, gradient—10% ethyl acetate/hexanes) to afford the (S)-methyl 2-bromo-2-phenylacetate as a light yellow oil (2.3 g, 40% yield); 1H NMR (400 MHz, DMSO-d6): δ 3.72 (s, 3H); 5.95 (s, 1H); 7.36-7.42 (m, 3H); 7.53 (d, 2H, J=1.2 Hz); 7.56 (d, 1H, J=2 Hz). MS for C9H9BrO2 m/z 229.98 (M+H)+.
Reaction SMILES: [N:1]1([C:5]2[N:10]=[CH:9][C:8]([C:11]3([OH:18])[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[NH:19]1[CH2:23][CH2:22][C@@H:21]([NH:24][C:25]([CH2:27][NH:28][C:29](=[O:40])[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)=[O:26])[CH2:20]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[N:1]1([C:5]2[N:10]=[CH:9][C:8]([C:11]3([OH:18])[CH2:16][CH2:15][CH:14]([N:19]4[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:26])[CH2:27][NH:28][C:29](=[O:40])[C:30]5[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:39])[F:38])[CH:31]=5)[CH2:20]4)[CH2:13][CH2:12]3)=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(O)(c2ccc(N3CCC3)nc2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCC(O)(c3ccc(N4CCC4)nc3)CC2)C1
Reaction time: 16 h

Procedure:
To a solution of 4-(6-azetidin-1-ylpyridin-3-yl)-4-hydroxycyclohexanone (115 mg, 0.467 mmol) and N-((R)-pyrrolidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (140.4 mg, 0.445 mmol) in dry CH2Cl2 (19 mL) was added Na(OAc)3BH (198 mg, 0.934 mmol) in one portion under N2 at rt. The reaction mixture was stirred under N2 overnight (16 h) and treated with Na2CO3 (aq), extrated with CH2Cl2×3, dried, filtered and concentrated to give a crude, which was purified by column chromatography (20:80:0.5 MeOH(EtOAc/NH4OH) to provide 60 mg (25%) of desired isomer product (top spot on TLC) as a white solid. MS (M+H+)=546.1. 1H NMR (CD3OD) δ 8.24 (m, 2H), 8.17 (m, 2H), 7.88 (m, 2H), 7.74 (m, 2H), 6.56 (d, 1H), 4.36 (m, 2H), 4.27 (m, 3H), 4.06 (m, 3H), 3.86 (m, 1H), 3.48 (m, 2H), 3.20 (m, 1H), 2.69 (m, 1H), 2.60 (m, 2H), 2.35-2.30 (m, 4H), 2.20-1.97 (m, 4H), 1.73 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][N:4]=[C:5]([NH2:20])[NH:6][C:7]1[N:12]=[C:11]([S:13][CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])[CH:10]=[CH:9][CH:8]=1.C([N:25](CC)CC)C.C(OC(Cl)=O)C(C)C.N>CN(C=O)C.CCO>[F:1][C:2]([F:22])([F:21])[CH2:3][N:4]=[C:5]([NH2:20])[NH:6][C:7]1[N:12]=[C:11]([S:13][CH2:14][CH2:15][CH2:16][C:17]([NH2:25])=[O:18])[CH:10]=[CH:9][CH:8]=1
Reactant: CCN(CC)CC
Reactant: NC(=NCC(F)(F)F)Nc1cccc(SCCCC(=O)O)n1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CCO
Solvent: CN(C)C=O
Product: NC(=O)CCCSc1cccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-[6-(2-[2,2,2-trifluoroethyl]guanidino)pyrid-2-ylthio]butyric acid (84 mg.) and triethylamine (0.2 ml.) in DMF (5 ml.) was stirred at 0° while isobutylchloroformate (68 mg.) was added. The solution was kept at 0° for 0.5 hours, treated with a saturated solution of ammonia in EtOH (1 ml.) and then stirred at room temperature for 18 hours. The solution was evaporated to dryness and the residue partitioned between N aqueous HCl and EtOAc. The aqueous phase was basified with 10 N aqueous NaOH and extracted with EtOAc, and the extract was dried and evaporated to dryness to give 4-[6-(2-[2,2,2-trifluoroethyl]guanidino)pyrid-2-ylthio]butyramide (60 mg.) which was crystallised as the hydrogen maleate salt from acetone, m.p. 138°-141°.
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:9][CH2:8][CH2:7][S:6]1)([O-:3])=[O:2].ClC1C=C(Cl)C=C(Cl)C=1[O:19][C:20](=O)[CH:21]([CH3:34])[C:22](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:23].C(OC(=O)C)C>C1(C)C(C)=CC=CC=1>[OH:23][C:22]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]2[S:6][CH2:7][CH2:8][N:9]2[C:20](=[O:19])[C:21]=1[CH3:34]
Reactant: CC(C(=O)Oc1c(Cl)cc(Cl)cc1Cl)C(=O)Oc1c(Cl)cc(Cl)cc1Cl
Reactant: O=[N+]([O-])C=C1NCCS1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: Cc1c(O)c([N+](=O)[O-])c2n(c1=O)CCS2
Reaction time: 8 h
Yield: 46.4 %

Procedure:
2-Nitromethylene-thiazolidine (7.3 g, 50 mmol) and 2-methyl-malonic acid bis-(2,4,6-trichloro-phenyl) ester (23.8 g, 50 mmol) in xylene (80 mL) was taken in a reaction flask and the flask was heated to reflux for 3 hours. The reaction mixture was monitored by TLC (100% ethylacetate). The reaction mixture was cooled, concentrated and partitioned between DCM and water. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated. The crude product was kept at 0° C. for overnight. The solid formed was collected and washed with hexane and ether to afford 5.3 g of the product (46% yield).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])[CH:8]=[C:7]([O:25][CH2:26][CH3:27])[CH:6]=1)C.[H-].[Li+].[Al+3].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:26]([O:25][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[O:16][C:17]=2[CH3:18])[CH:8]=1)[CH2:4][OH:3])[CH3:27]
Reactant: CCOC(=O)c1cc(OCC)cc(OCc2nc(-c3ccccc3)oc2C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(CO)cc(OCc2nc(-c3ccccc3)oc2C)c1
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To a solution of ethyl-3-ethoxy-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzoate (5.40 g) in tetrahydrofuran (80 ml) was gradually added aluminum lithium hydride (540 mg) at 0° C. and the mixture was stirred for 1 hr. Sodium sulfate 10 hydrate (4.60 g) was added to the reaction mixture and the mixture was further stirred for 30 min. The insoluble materials were filtered off, and the filtrate was concentrated. The obtained crystals were recrystallized from ethyl acetate-isopropyl ether to give 3-ethoxy-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl alcohol (4.44 g, 92%) as colorless needle-shaped crystals. melting point: 103–104° C.
Reaction SMILES: C([Li])CCC.[CH2:6]([C:8]1[CH:18]=[C:11]2[C:12]([O:16][CH3:17])=[CH:13][CH:14]=[CH:15][N:10]2[N:9]=1)[CH3:7].[Br:19]CCBr.[Cl-].[NH4+]>O1CCCC1>[Br:19][C:15]1[N:10]2[N:9]=[C:8]([CH2:6][CH3:7])[CH:18]=[C:11]2[C:12]([O:16][CH3:17])=[CH:13][CH:14]=1
Reactant: BrCCBr
Reactant: CCc1cc2c(OC)cccn2n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1cc2c(OC)ccc(Br)n2n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (1.31 mL) was slowly added dropwise to a solution of 2-ethyl-4-methoxypyrazolo[1,5-a]pyridine (303 mg) in tetrahydrofuran (15 mL) at −78° C. After stirring the mixture at −78° C. for 1 hour, 1,2-dibromoethane (0.18 mL) was added and stirring was continued for 1 hour. Saturated aqueous ammonium chloride was added, extraction was performed with ethyl acetate, the extract was washed with brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (20 g), and the title compound (282 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:21])[N:11]([CH3:20])[C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][C:14]=2[Cl:15])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.CN(C=O)C.O.ClCCl>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[C:10](=[O:21])[N:11]([CH3:20])[C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][C:14]=2[Cl:15])=[CH:3][C:2]=1[NH:1][S:23]([CH3:22])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(C(F)(F)F)cc(Cl)c(-c2ccc(Cl)c(N)c2)c1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(Cl)c(-c2ccc(Cl)c(NS(C)(=O)=O)c2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To 20 ml of dichloromethane, 0.4 g (1.19 mmol) of 3-(3-amino-4-chlorophenyl)-4-chloro-1-methyl-6-trifluoromethyl-2(1H)-pyridone and 0.3 g (2.62 mmol) of methylsulfonyl chloride were dissolved, and 0.3 g (2.96 mmol) of triethylamine was added thereto under cooling with ice, followed by stirring at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted with dichloromethane. The organic layer was washed with water and a 10% citric acid aqueous solution and dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure, and the obtained crude crystals were dissolved in a mixed solvent comprising 15 ml of ethanol and 5 ml of DMF, and 3 ml of an aqueous sodium hydroxide solution [0.05 g (1.25 mmol) of sodium hydroxide] was added, followed by stirring at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into water and weakly acidified with citric acid and then extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 0.47 g (yield: 95%) of the desired product. Melting point: 161-163° C. 1H-NMR (400 MHz, CDCl3) δ value: 3.02(3H,s), 3.75(3H,s), 6.60(1H,s), 6.92(1H,s), 7.06(1H,dd), 7.26(1H,s), 7.47(1H,d), 7.59(1H,d)ppm.
Reaction SMILES: Br[C:2]1[S:13][C:12]2[N:11]=[C:10]([CH3:14])[C:9]3[N:5]([C:6]([CH2:16][CH2:17][CH3:18])=[N:7][C:8]=3[CH3:15])[C:4]=2[N:3]=1.[CH3:19][O-:20].[Na+]>CO>[CH3:19][O:20][C:2]1[S:13][C:12]2[N:11]=[C:10]([CH3:14])[C:9]3[N:5]([C:6]([CH2:16][CH2:17][CH3:18])=[N:7][C:8]=3[CH3:15])[C:4]=2[N:3]=1
Reactant: C[O-]
Reactant: CCCc1nc(C)c2c(C)nc3sc(Br)nc3n12
Agent: [Na+]
Solvent: CO
Product: CCCc1nc(C)c2c(C)nc3sc(OC)nc3n12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2-Bromo-5,6-dimethyl-8-propyl-3-thia-1,4,7,8a-tetraaza-as-indacene was dissolved in 5 mL of methanol and sodium methoxide (4.98 mg, 0.092 mmol) was added. The resulting mixture was stirred at 60° C. for 1 h. LC-MS showed complete consumption of 2-bromo-5,6-dimethyl-8-propyl-3-thia-1,4,7,8a-tetraaza-as-indacene. After removal of the solvent under reduced pressure, 5 mL of water and 10 mL of EA were added. The organic layer was concentrated, crude product was purified by prep-HPLC to give 4 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#N.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.Cl.C1C[O:32]CC1>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:32]
Reactant: N#Cc1ccc(O)cc1Br
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=Cc1ccc(O)cc1Br
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-4-hydroxy-benzonitrile (Intermediate 7, 2000 mg, 10.1 mmol) in DCM (50 mL) and THF (10 mL), at 0° C., diisobutylaluminum hydride 1M in toluene (20.2 ml, 20.2 mmol) was slowly added (10 min) and the reaction mixture was stirred at the same temperature for 1 hour. Then 40 ml of HCl 2M were added and the reaction mixture was warmed at 40° C. for 30 minutes. After cooling ethyl acetate (100 ml) was added and two phases were separated. The organic layer was washed with brine (3×100 ml) dried over sodium sulphate and concentrated under vacuum to give the title compound (1950 mg) which was used in the next step without further purification.
Reaction SMILES: [C:1]([N:9]1[CH2:19][CH2:18][C:12]2[N:13]=[N:14][C:15](S)=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][NH:21][NH2:22]>>[C:1]([N:9]1[CH2:19][CH2:18][C:12]2[N:13]=[N:14][C:15]([N:21]([CH3:20])[NH2:22])=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCc2nnc(S)cc2C1
Reactant: CNN
Product: CN(N)c1cc2c(nn1)CCN(C(=O)c1ccccc1)C2

Procedure:
A solution of 3.4 g of 6-benzoyl-5,6,7,8-tetrahydro-3-mercaptopyrido[4,3-c]pyridazine in 40 cc of methylhydrazine is stirred at a bath temperature of 110° for 11/2 hours. The oil obtained after concentrating the mixture in a vacuum is taken up in absolute ethanol, and the calculated amount of gentisic acid is added. After standing for some time the crystalline bisgentisinate of the title compound is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][CH:3]=1.Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:11]=2)=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1ccc(F)cc1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(Nc2ccc(F)cc2)n1

Procedure:
The reaction described in Preparation 42 was repeated, but using 12 g of p-fluorophenylthiourea, 14.8 g of ethyl bromopyruvate, and 120 ml of ethanol, giving the title compound as pale yellow prisms.