Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].B(O)(O)[C:16]1[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([C:2]2[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1Br
Reactant: Cc1ccc(B(O)O)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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 100 °C

Procedure:
To a 350 mL high-pressure vial was added tert-butyl 2-bromobenzoate (5.142 g, 20.0 mmol), p-tolylboronic acid (4.08 g, 30.0 mmol), Pd(PPh3)4 (3.47 g, 3.0 mmol), potassium carbonate (8.29 g, 60.0 mmol) and dioxane with water (4:1, 200 mL). The mixture was degassed for 5 min and sealed. The mixture was heated at 100° C. for 40 min wherein analytical HPLC analysis indicated the completion of the reaction. The mixture was filtered through Celite and MeOH was used to wash the Celite pad. The solvent was removed and the crude was purified by flash chromatography (AcOEt/Hexane 0→30%) to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[N:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])SC)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34]([C:37]3[CH:41]=[C:40]([C:42]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[NH:43])[S:39][C:38]=3[S:52][CH3:53])(=[O:36])=[O:35])[CH:29]=2)=[C:23]([NH:54][C:55](=[O:72])[NH:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][O:62][C:63]2[CH:71]=[CH:70][C:66]([C:67]([OH:69])=[O:68])=[CH:65][CH:64]=2)[CH:22]=1>CC(O)=O.CO>[C:48]([O:47][C:45]([NH:44][C:42](=[NH:43])[C:40]1[S:39][C:38]([S:52][CH3:53])=[C:37]([S:34]([C:30]2[CH:29]=[C:28]([C:24]3[C:25]([CH3:27])=[CH:26][C:21]([NH:20][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[N:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[CH:22][C:23]=3[NH:54][C:55](=[O:72])[NH:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][O:62][C:63]3[CH:64]=[CH:65][C:66]([C:67]([OH:69])=[O:68])=[CH:70][CH:71]=3)[CH:33]=[CH:32][CH:31]=2)(=[O:35])=[O:36])[CH:41]=1)=[O:46])([CH3:51])([CH3:49])[CH3:50]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(N)cc2NC(=O)NCCCCCOc2ccc(C(=O)O)cc2)c1
Solvent: CO
Solvent: CC(=O)O
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2NC(=O)NCCCCCOc2ccc(C(=O)O)cc2)c1
Yield: 22.9 %

Procedure:
1,3-bis(tert-Butoxycarbonyl)-2-methyl-2-thiopseudourea (433 mg, 1.49 mmol) was added to a solution of 4-[5-(3-{4-amino-3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-ureido)-pentyloxy]-benzoic acid (233 mg, 0.298 mmol, Example 283: step e) in 5% AcOH/MeOH (10 mL) over 2 days at 35° C. The solvents were removed in vacuo and the residue was purified by flash chromatography (1–6% MeOH/methylene chloride) to afford the title compound as a yellow solid (70 mg, 23%). ESI-MS (m/z): Calcd. for C48H61N7O12S3: 1024.4 (M+1); found: 1024.0.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH:4]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH3:29])=[CH:8][C:7]=1[CH3:30].[Li+].[OH-]>>[CH2:32]([O:31][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH3:29])=[CH:8][C:7]=1[CH3:30])[C:3]([OH:36])=[O:2])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCOC(Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCCCOC(Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-2-butoxy-3-{2-methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-propionic acid methyl ester was treated with 1 N LiOH to obtain [rac]-2-butoxy-3-{2-methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-propionic acid as yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[N:23]1([CH2:29][CH2:30][OH:31])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[OH:31][CH2:30][CH2:29][N:23]1[CH2:28][CH2:27][N:26]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:19])[CH2:25][CH2:24]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: OCCN1CCNCC1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCN(CCO)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 2-(piperazin-1-yl)ethanol (1.2 equiv) to give 160 (20.9 mg, M+1 426.1)
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[OH-].[K+].[C:14](Cl)(=[O:18])[CH:15]([CH3:17])[CH3:16]>ClCCl>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH:4][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)C(=O)Cl
Reactant: COc1cc(N)c(Br)cc1C
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cc(NC(=O)C(C)C)c(Br)cc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.3 %

Procedure:
To a biphasic mixture of 2-bromo-5-methoxy-4-methyl-aniline (5.6 g, 25.96 mmol), 10% KOH (27 mL) and dichloromethane (30 mL), was added dropwise isobutyryl chloride (3 mL, 28.55 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 48 hrs. The layers were separated. The aqueous layer was further extracted with dichloromethane and the combined organics washed successively with water and brine, dried over MgSO4, filtered and evaporated to give 7.38 g of N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide (99% yield). 1H NMR (300 MHz; CDCl3): 1.29 (d, J=6.9 Hz, 6 H), 2.14 (s, 3 H), 2.59 (m, 1 H), 3.84 (s, 3 H), 7.24 (s, 1 H), 7.66 (br s, 1 H), 8.07 (s, 1 H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].Cl[C:20]1[N:25]=[C:24]([NH2:26])[CH:23]=[CH:22][N:21]=1.O>CC(N(C)C)=O>[NH2:26][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:15])([F:16])[F:1])=[CH:8][CH:9]=2)[N:25]=1
Reactant: Nc1ccnc(Cl)n1
Reactant: O=C(NCc1ccc(CO)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1ccnc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)n1
Temperature: 90 °C

Procedure:
760 mg (3.25 mmol) 2,2,2-Trifluoro-N-(4-hydroxymethyl-benzyl)-acetamide is dissolved in 3 mL dry dimethylacetamide under argon atmosphere, and 273 mg (8.15 mmol) NaH is added over 5 min. 211 mg (1.63 mmol) 2-Chloropyrimidin-4-amine is then added and the solution stirred at 90° C. over night. 1 mL Water is added carefully to quench all excess NaH, and the mixture poured into 50 ml of 0.5 N HCl. The crude product is extracted with ethyl acetate, the combined organic phases washed with brine and dried over MgSO4. After evaporation of the solvent, the product is purified by flash column chromatography (gradient ethyl acetate:cyclohexane from 1:1 to 3:1). Yield: 350 mg (52%). ESI-MS m/z 327 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]([CH3:17])=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:15]([CH3:17])[CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)=O
Product: CC(C)N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Prepared from acetone and piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]([NH:21][NH2:22])=[O:20])[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[Cl:25][CH2:26][C:27](OC)(OC)OC>>[Cl:25][CH2:26][C:27]1[O:20][C:19]([C:16]2[CH:17]=[CH:18][C:13]3[O:12][CH:11]=[C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:23])([F:1])[F:24])[CH:5]=4)[C:14]=3[CH:15]=2)=[N:21][N:22]=1
Reactant: COC(CCl)(OC)OC
Reactant: NNC(=O)c1ccc2occ(-c3cccc(OC(F)(F)F)c3)c2c1
Product: FC(F)(F)Oc1cccc(-c2coc3ccc(-c4nnc(CCl)o4)cc23)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
A mixture of 3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-carbohydrazide (3.00 g, 8.92 mmol) and 2-chloro-1,1,1-trimethoxyethane (4.70 mL, 24.4 mmol) was stirred at 80° C. for 3 hr. The reaction mixture was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) and recrystallized from hexane/ethyl acetate to give the title compound (2.39 g, yield 68%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH:9]=[C:8]2[C:16]([F:19])([F:18])[F:17].[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>C1COCC1>[CH2:24]([NH:26][C:27]([NH:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH:9]=[C:8]2[C:16]([F:19])([F:17])[F:18])=[O:28])[CH3:25]
Reactant: CCN=C=O
Reactant: Nc1ccccc1Cc1ccc2[nH]c(=O)cc(C(F)(F)F)c2c1
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccccc1Cc1ccc2[nH]c(=O)cc(C(F)(F)F)c2c1
Temperature: 20 °C
Reaction time: 36 h
Yield: 62.2 %

Procedure:
A stirred THF (5 mL) solution of 6-(2-aminobenzyl)-4-trifluoromethyl-1H-quinolin-2-one (Preparation #2, 50 mg, 157 μmol) was treated dropwise with a solution of EtNCO (78 μL, 985 μmol) in anhydrous THF (1 mL) at 0° C. The reaction mixture was allowed to warm to 20° C., before being stirred for 36 h. The precipitate formed was collected, washed with THF, & dried to give the title compound (38 mg, 62%): δH ((CD3)2SO)=1.00 (t, 3H), 3.05 (q, 2H), 4.00 (s, 2H), 6.30 (t, 1H), 6.90–6.95 (m, 2H), 7.05 (d, 1H), 7.15 (t, 1H), 7.35 (d, 1H), 7.40 (d, 1H), 7.55 (s, 1H), 7.70–7.80 (m, 2H); m/z (ES+)=390.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:14][C:15]=2[CH3:16])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=2.[NH3:23]>>[CH:17]1([C:13]2[N:4]3[C:5]4[C:10]([N:11]=[C:2]([NH2:23])[C:3]3=[C:15]([CH3:16])[N:14]=2)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=4)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1nc(C2CCCCC2)n2c1c(Cl)nc1ccc(F)cc12
Reactant: N
Product: Cc1nc(C2CCCCC2)n2c1c(N)nc1ccc(F)cc12

Procedure:
640 mg 4-Chloro-1-cyclohexyl-8-fluoro-3-methyl-imidazo(1,5-a)quinoxaline (2 mmol) and 30 ml 32% aqueous ammonia were heated 7 hours at 130-135° C. After cooling the product was filtered off, washed with water, dried and chromatographed on silica gel with 2% MeOH/CH2Cl2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[C:10]([CH3:21])([CH3:20])[CH2:9][N:8]([C:22](=[O:30])[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH:7]=1)=[O:5])[CH3:2].[H][H]>C(O)(=O)C.O=[Pt]=O>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:11]=2[C:10]([CH3:21])([CH3:20])[CH2:9][N:8]([C:22](=[O:30])[C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1ccccc21
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1c2CCCC1

Procedure:
A solution of 3-(4-fluoro-benzoyl)-1,1-dimethyl-1,2,3,6-tetrahydro-azepino[4,5-b]indole-5-carboxylic acid ethyl ester (1.03 g) in 40 mL of glacial acetic acid containing 370 mg of Adams catalyst was subjected to hydrogenation under atmospheric pressure of hydrogen for 20 hours at room temperature. (Boekelheide, V. and Liu, C-T, J. Am. Chem. Soc. 1952, 74, 4920-4922). The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The crude product was purified first by column chromatography on silica gel eluting with hexane/DCM and then by preparative normal phase HPLC eluting with hexane/DCM. The title compound was obtained as yellow solid (64 mg). 1H-NMR(CDCl3):δ 10.18 (1H, s), 7.64-7.59 (2H, m), 7.41 (1H, s), 7.13-7.07 (2H, m), 4.18 (2H, q), 3.95 (2H, brs), 2.68-2.61 (4H, m), 1.78 (4H, m), 1.39 (6H, s), 1.18 (3H, t); MS (ES): 411 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[NH:18][CH:19]=[C:20]([C:22]#[N:23])[N:21]=3)=[O:16])=[CH:12][CH:11]=[C:10]([C:24]3(O)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)=[CH:4][CH2:3]1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH3:1][C:2]1([CH3:31])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[NH:18][CH:19]=[C:20]([C:22]#[N:23])[N:21]=3)=[O:16])=[CH:12][CH:11]=[C:10]([C:24]3([N:36]4[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]4)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2nc(C3(O)CCOCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: CN1CCNCC1
Product: CN1CCN(C2(c3ccc(NC(=O)c4nc(C#N)c[nH]4)c(C4=CCC(C)(C)CC4)n3)CCOCC2)CC1

Procedure:
The title compound is prepared from 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-6-(4-hydroxy-tetrahydro-pyran-4-yl)-pyridin-3-yl]-amide (as prepared in the previous step) and N-methylpiperazine according to the procedure in Example 4.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:11](OC(OCC)OCC)C>>[N:1]1[C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:6])[O:5][CH:11]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: CCOC(OCC)OCC
Product: O=c1ocnc2ccccc12
Temperature: 25 °C

Procedure:
A mixture of 2-aminobenzoic acid (1 g, 7.29 mmol) and triethylorthoformate (3 mL) was refluxed overnight. The reaction mixture was cooled to room temperature and triturated with 10 mL of hexane. The resulting solid was filtered and further washed with hexane to yield 1.1 g of the expected benzo[d][1,3]oxazin-4-one.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12].[S:17](N)(N)(=[O:19])=[O:18]>COCCOCCOC>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]1[CH2:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[NH:1][S:17]1(=[O:19])=[O:18]
Reactant: Nc1ccccc1CNc1ccccc1F
Reactant: NS(N)(=O)=O
Solvent: COCCOCCOC
Product: O=S1(=O)Nc2ccccc2CN1c1ccccc1F
Yield: 53.9 %

Procedure:
A solution of N-(2-aminobenzyl)-2-fluoroaniline (4.3 g, 20 mmol) in diglyme (50 mL) was treated with sulfamide (2.5 g, 26 mmol) and heated to reflux for 0.5 h. The reaction mixture was evaporated and the oily residue purified by flash chromatography (SiO2, 10-100% ethyl acetate/hexanes) to provide 3-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (3.0 g) as a tan solid:
Reaction SMILES: [C:1](=[S:4])([S-:3])[NH2:2].[NH4+].Br[CH2:7][CH2:8][C:9]([F:13])=[C:10]([F:12])[F:11]>C(O)C>[C:1](=[S:3])([S:4][CH2:7][CH2:8][C:9]([F:13])=[C:10]([F:12])[F:11])[NH2:2]
Reactant: NC(=S)[S-]
Reactant: FC(F)=C(F)CCBr
Agent: [NH4+]
Solvent: CCO
Product: NC(=S)SCCC(F)=C(F)F
Temperature: 40 °C
Reaction time: 3 h

Procedure:
2.8 g (25 mmol) of ammonium dithiocarbamate in 40 ml of ethanol are admixed dropwise with 5.32 g (26.3 mmol; purity 93.2%) of 4-bromo-1,1,2-trifluoro-1-butene, stirred at 40° C. for 3 h, another 2.8 g of ammonium dithiocarbamate is added after 1 h, and everything is left to stand at room temperature for 8 h. The filtrate is filtered off with suction and concentrated by evaporation under reduced pressure, the residue taken up in dichloromethane and washed once with water, and the organic phase dried over sodium sulphate. After concentration by evaporation under reduced pressure, 4.3 g (63% of theory; purity by GC/MS: 74 area %) of a semicrystalline residue are obtained.
Reaction SMILES: [Mg].[CH3:2]I.[C:4]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11]([Cl:16])[CH:10]=[N:9]1)([CH3:7])([CH3:6])[CH3:5].Cl>O1CCCC1.C1(C)C=CC=CC=1>[C:4]([N:8]1[C:13](=[O:14])[C:12]([CH3:2])=[C:11]([Cl:16])[CH:10]=[N:9]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Reactant: CI
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Temperature: 0 °C

Procedure:
To a solution of 6.0 g (0.25 mol) of magnesium in 50 ml of dry tetrahydrofuran was added dropwise under stream of nitrogen 35.5 g (0.25 mol) of methyl iodide to prepare a Grignard reagent. After dropwise addition of the methyl iodide, 1000 ml of dry toluene was added thereto. The resulting solution was heated at 60° to 70° C. and additional methyl iodide was added thereto until the magnesium completely disappeared. The Grignard reagent was cooled to room temperature and then added dropwise over 20 minutes with a solution of 22.1 g (0.1 mol) of 2-t-butyl-4,5-dichloro-3(2H)-pyridazinone in 200 ml of dry toluene. After dropwise addition, the resulting mixture was subjected to reaction at room temperature for 1.5 hours. The reaction liquid was poured into a solution of 100 ml of concentrated hydrochloric acid in 900 ml of ice water to effect extraction. The resulting organic layer was washed with 500 ml of a 10% sodium hydroxide solution and then with 500 ml of water, and then dried over anhydrous sodium sulfate. Solvent was distilled off therefrom under reduced pressure to give 17.2 g of a crude product. The crude product was subjected to distillation (boiling point: 60° to 62° C./0.22 mmHg) and then to column chromatography [on silica gel; eluting with hexane-acetone (15:1)] for separation and purification to obtain 4.5 g of 2-t-butyl-5-chloro-4-methyl-3(2H)-pyridazinone.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[C:16]([F:21])=[N:17][CH:18]=[CH:19][CH:20]=2)[N:12]([S:22]([C:25]2[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=2)(=[O:24])=[O:23])[CH:11]=1)C)(C)(C)C.C(OCC)(=O)C.Cl>C(O)C>[F:21][C:16]1[C:15]([C:13]2[N:12]([S:22]([C:25]3[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=3)(=[O:23])=[O:24])[CH:11]=[C:10]([CH2:9][NH:7][CH3:6])[CH:14]=2)=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2cccnc2F)cn1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccc(C)nc2)c1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl({5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (86 mg) in ethanol (2 mL) was added a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) at room temperature. The mixture was stirred for 2 hr, and concentrated under reduced pressure. The residue was basified with a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a free salt of the title compound as a pale-yellow oil. The obtained free salt was dissolved in ethyl acetate (2 mL) and added to a solution (2 mL) of fumaric acid (11.3 mg) in ethanol, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 14 mg, 18%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=O.[CH3:12][NH:13][NH2:14]>C(O)C>[CH3:12][NH:13]/[N:14]=[CH:4]/[C:3]1[C:2]([F:1])=[CH:9][C:8]([F:10])=[CH:7][C:6]=1[F:11]
Reactant: CNN
Reactant: O=Cc1c(F)cc(F)cc1F
Solvent: CCO
Product: CN/N=C/c1c(F)cc(F)cc1F

Procedure:
A solution of 2,4,6-trifluorobenzaldehyde (3 g, 18.74 mmol) and methyl hydrazine (40% in water, 2.6 mL, 18.74 mmol) in 20 mL of anhydrous ethanol was stirred at rt for 1 h. Solvent was evaporated to give the crude title compound as a white solid which was used in the next step without purification (3.95 g, 100%). LCMS (method B): [MH]+=189, tR=2.16 min.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][C:8]([Si:11]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:12][C@@H:13](C)[CH2:14]C(O)=O)([CH3:10])[CH3:9].CN(C=O)C>C(Cl)Cl>[CH3:7][C:8]([Si:11]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[O:12][C@@H:13]([CH3:14])[CH2:1][C:2]([Cl:4])=[O:3])([CH3:9])[CH3:10]
Reactant: C[C@@H](CC(=O)O)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](CC(=O)Cl)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C

Procedure:
Oxalyl chloride (4.1 mL, 48 mmol; conc. 1.5 g/mL) was added dropwise to a stirred solution of intermediate D2 (11 g, 32 mmol) and DMF (1 mL) in DCM (300 mL) at r.t. for 90 min. The reaction mixture was evaporated under reduced pressure and co-evaporated with toluene (×3) to give the crude intermediate D3 as a yellow oil. This material was used in the next step of the reaction sequence without any further purification.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH3:28])[C:14](=[O:27])[C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[C:3]1=[O:29].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH:21]1([C:18]2[CH:19]=[CH:20][C:15]([C:14]([N:13]([CH3:28])[C:10]3[CH:11]=[CH:12][C:7]([N:4]4[CH2:5][CH2:6][CH:2]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[C:3]4=[O:29])=[CH:8][CH:9]=3)=[O:27])=[CH:16][CH:17]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1COCCN1
Reactant: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(Br)C2=O)cc1
Product: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(N3CCOCC3)C2=O)cc1

Procedure:
N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with morpholine by method L. This resulted in the product with the molecular weight 461.61 (C28H35N3O3); MS (ESI): 462 (M+H+).
Reaction SMILES: O.[NH2:2][NH2:3].[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1>CO>[N:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[N:2][NH2:3])=[CH:12][CH:11]=1
Reactant: NN
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Solvent: CO
Solvent: O
Product: NN=Cc1ccc(-c2ccccn2)cc1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a mixture of 80% hydrazine hydrate (1.64 g, 26.2 mmol) and methanol (5.0 ml) was dropwise added a solution of 4-(pyridin-2-yl)benzaldehyde (1.5 g, 8.2 mmol) in methanol (5.0 ml) at 25° C. over 10 minutes. After the dropwise addition, the mixture was stirred for 30 minutes. Methanol and excess hydrazine hydrate were evaporated under reduced pressure. The residue was crystallized and 4-(pyridin-2-yl)benzaldehyde hydrazone was obtained as crude crystals at a yield of 1.6 g (yield: 100%). The percentage of the area of 4-(pyridin-2-yl)benzaldehyde hydrazone in the crude crystals as determined by liquid chromatography was 94.3%. crude crystals melting point: 65.7-67.8° C. IR(KBr)cm−1: 3700-3000, 1636, 1590, 1468, 1432, 1394, 1150, 1114, 924, 840, 778, 742, 726. 1H-NMR(CDCl3) δ: 5.60(s,2H), 7.22(m,1H), 7.65(d,2H), 7.74(m,2H), 7.78(s,1H), 8.00(d,2H), 8.69(d,1H)