Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[CH:11][CH3:12])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CC=C1CCc2ccc(Br)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC1CCc2ccc(Br)cc21
Yield: 89.2 %

Procedure:
6-Bromo-1-ethylidene-indan 41a (3.07 g, 13.7 mmol) was dissolved in 80 mL of ethyl acetate followed by addition of palladium on carbon (0.61 g) at room temperature. The mixture was hydrogenated for 5 hours in a hydrogenator under 3 atm. of hydrogen. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered to remove palladium on carbon and the filter cake was washed with ethyl acetate (10 mL×3). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound 6-bromo-1-ethyl-indan 41b (2.75 g, 88.7%) as a light yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21].C(NC(C)C)(C)C>C1COCC1.[Cu]I.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].C(Cl)Cl>[CH3:8][N:6]1[CH:7]=[C:2]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])[CH:3]=[C:4]([O:10][CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]1=[O:9]
Reactant: Cn1cc(Br)cc(OCOCC[Si](C)(C)C)c1=O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cn1cc(C#C[Si](C)(C)C)cc(OCOCC[Si](C)(C)C)c1=O

Procedure:
To a solution of 5-bromo-1-methyl-3-{[2-(trimethylsilyl)ethoxy]methoxy}pyridin-2(1H)-one (2.92 g, 8.74 mmol) in 20 mL THF was added trimethylsilylacetylene (1.72 g, 17.47 mmol), copper (I) iodide (166 mg, 0.874 mmol), diisopropylamine (1.25 mL, 8.74 mmol), and PdCl2(dppf)-DCM adduct (713 mg, 0.874 mmol). This mixture was microwaved in a sealed vial at 145° C. for 10 minutes. After cooling, the mixture was filtered to remove solids, evaporated, and purified by flash chromatography (50 g silica gel, 0-40% ethyl acetate in hexane) to afford 1-methyl-3-{[2-(trimethylsilyl)ethoxy]methoxy}-5-[(trimethylsilyl)ethynyl]pyridin-2(1H)-one as a dark, viscous oil (2 g, 65% yield). LCMS [M+H]+=352.6
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:21])[C:18]=1[O:19]C)[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][CH2:8]1)=[O:6].[Cl-].[Li+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:21])[C:18]=1[OH:19])[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][CH2:8]1)=[O:6]
Reactant: COc1c(Cl)cc(C(=O)N2CSc3ccccc32)cc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(c1cc(Cl)c(O)c(Cl)c1)N1CSc2ccccc21
Temperature: 120 °C
Reaction time: 16 h
Yield: 74.4 %

Procedure:
3-(3,5-dichloro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole (300 mg) was dissolved in N,N-dimethylformamide (6 mL), and lithium chloride (374 mg) was added to the solution, and then the mixture was stirred at 120° C. for 16 hours. To the reaction solution, 1N hydrochloric acid was added, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from n-hexane-ethyl acetate to obtain the title compound (214 mg) as a brown crystal.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[NH2:21][C:22]1[N:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][OH:36])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:21][C:22]3[N:27]=[CH:26][C:25]([N:28]4[CH2:29][CH2:30][CH:31]([CH2:34][CH2:35][OH:36])[CH2:32][CH2:33]4)=[CH:24][CH:23]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: Nc1ccc(N2CCC(CCO)CC2)cn1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCC(CCO)CC4)cn3)nc2n1C1CCCC1
Yield: 49.3 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.34 mmol) and 2-(6′-amino-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-ethanol (90 mg, 0.38 mmol) to give 7-cyclopentyl-2-[4-(2-hydroxy-ethyl)-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (80 mg, 93%). MS(ESI) m/z 478.3 (M+H)+
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:5]=1)(=[S:3])[NH2:2].Cl[CH:15]([C:21](=[O:28])C1C=CC=CC=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].S(=O)(=O)(O)O>CC(O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].C(OC(=O)C)(=O)C>[C:11]([NH:10][C:6]1[CH:5]=[C:4]([C:1]2[S:3][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:21]([OH:28])[N:2]=2)[CH:9]=[CH:8][N:7]=1)(=[O:13])[CH3:12]
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1
Reactant: CC(=O)Nc1cc(C(N)=S)ccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1sc(-c2ccnc(NC(C)=O)c2)nc1O
Temperature: 90 °C
Yield: 31 %

Procedure:
To a suspension of N-(4-carbamothioylpyridin-2-yl)acetamide (15 g, 77 mmol) produced in the same manner as in Example 1-B (ii) in 2-propanol (136 mL) was added ethyl 2-chloro-3-oxo-3-phenylpropanoate, and the mixture was stirred with heating at 90° C. for 12 hr. Tetrabutylammonium bromide (1.2 g, 3.9 mmol) was added to the reaction solution, and the mixture was further stirred with heating at the same temperature for 10 hr. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (200 mL), and saturated aqueous sodium bicarbonate solution (200 mL) was added. The resulting solid was collected by filtration, and washed with water (200 mL), ethanol (100 mL) and diethyl ether (100 mL×2). The obtained crude product was suspended in acetic anhydride (150 mL), concentrated sulfuric acid (0.05 mL) was added, and the mixture was heated under reflux at 120° C. for 2 hr. The reaction mixture was cooled to room temperature, and acetic anhydride was evaporated under reduced pressure. The residue was suspended in methanol (50 mL), and after stirring, methanol was evaporated under reduced pressure. The obtained residue was suspended in tetrahydrofuran (300 mL), 25% aqueous ammonia solution (150 mL) was added, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added methanol (100 mL), and the mixture was further stirred at room temperature for 30 min. The resulting solid was collected by filtration, and washed with water (100 mL) and diethyl ether (100 mL) to give the title compound (7.4 g, 31%) as a yellow solid. The combined filtrate and washing solution was concentrated under reduced pressure, the resulting yellow solid was collected by filtration, and washed with water (500 mL), ethanol (100 mL) and diethyl ether (200 mL) to give a second crop (2.9 g, 12%) of the title compound as a yellow solid.
Reaction SMILES: C(OC(N1CC2C([CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[N:20]=[C:21]([Cl:32])[N:22]=[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[C:24]=4[N:25]=3)[CH2:13]2)C1)=O)(C)(C)C.[C:33]([O:37][C:38]([N:40]1[CH2:44][CH2:43][C:42]2([CH2:49]CNC[CH2:45]2)[CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38]([N:40]1[CH2:44][CH2:43][C:42]2([CH2:49][CH2:13][N:12]([CH2:16][C:17]3[S:18][C:19]4[N:20]=[C:21]([Cl:32])[N:22]=[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[C:24]=4[N:25]=3)[CH2:11][CH2:45]2)[CH2:41]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4c(N5CCOCC5)nc(Cl)nc4s3)CC2C1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Product: CC(C)(C)OC(=O)N1CCC2(CCN(Cc3nc4c(N5CCOCC5)nc(Cl)nc4s3)CC2)C1

Procedure:
Prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 2,8-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a white solid (81 mg, 80%).
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][C:11](=[O:16])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C=O)CCCCC1>>[CH:1]1([O:7][N:8]2[C:13]([CH3:14])([CH3:15])[CH2:12][C:11](=[O:16])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1OC1CCCCC1
Agent: O=CC1CCCCC1
Product: CC1(C)CC(=O)CC(C)(C)N1OC1CC=CCC1

Procedure:
1-Cyclohexyloxy-2,2,6,6-tetramethyl-piperidin-4-one, compound B, can be prepared in analogy using Cyclohexanecarboxaldehyde
Reaction SMILES: Cl.[CH:2]1([NH:8][NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(Cl)Cl.C1(NN)CCCCC1.[C:21](OCC)(=[O:26])[CH2:22][C:23]([CH3:25])=O>O.CC(OC)(C)C.C(O)(=O)C>[CH:2]1([N:8]2[C:21](=[O:26])[CH:22]=[C:23]([CH3:25])[NH:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NNC1CCCCC1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: Cc1cc(=O)n(C2CCCCC2)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Cyclohexylhydrazine hydrochloride (700 g, 4643 mmol) was added to a stirred solution of DCM (3000 ml) and ice cold 2M NaOH solution (1778 mL, 3556 mmol) and this was stirred for 10 minutes at RT. The phases were separated and the aqueous layer was washed with DCM (4×2000 ml). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give a yellow solid. The solid cyclohexylhydrazine (406 g, 3556 mmol) was dissolved in water (1300 mL) and acetic acid (1300 mL) and treated with ethyl acetoacetate (450 mL, 3556 mmol). The reaction mixture was heated to 85° C. and stirred for 1 hour. The resulting mixture was concentrated to dryness under reduced pressure and the residue was dissolved in DCM (3000 ml) and water (1000 ml). The mixture was neutralized with 2M potassium carbonate to pH>9, the resulting phases were separated and the organic extract was washed with brine (1×2 L). The first aqueous layer was saturated with sodium chloride and both aqueous phases washed with DCM (4×2 L). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a beige solid. The crude product was ground to a powder, TBME (2000 ml) was added and the mixture was stirred at 50° C. for 1 hour, followed by 1 hour at room temperature. The resulting solid was collected by filtration, washed with TBME (4×500 ml) and dried under vacuum at 45° C. for 16 hours to yield the title compound as off-white crystals.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][NH:9][CH:10]([CH2:34][CH3:35])[CH2:11][CH2:12][C:13]([N:15]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:25][CH:24]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH:1]1([CH2:7][CH2:8][NH:9][CH:10]([CH2:34][CH3:35])[CH2:11][CH2:12][CH2:13][N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]2[CH:24]=[CH:25][C:26]([NH:29][S:30]([CH3:33])(=[O:31])=[O:32])=[CH:27][CH:28]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(CCC(=O)N(Cc1ccccc1)c1ccc(NS(C)(=O)=O)cc1)NCCC1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCC(CCCN(Cc1ccccc1)c1ccc(NS(C)(=O)=O)cc1)NCCC1CCCCC1

Procedure:
In a manner similar to Example 1 react 4-[[2-(cyclohexyl)ethyl]amino]-N-[4-[(methylsulfonyl)amino]phenyl]-N-(phenylmethyl)hexanamide with lithium aluminum hydride to obtain the title compound.
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[C:11]([CH:19]2[CH2:24][CH2:23][N:22](C)[CH2:21][CH2:20]2)=[N:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>ClCCl>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[C:11]([CH:19]2[CH2:24][CH2:23][N:22]([C:27]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])[CH2:21][CH2:20]2)=[N:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1CCC(c2nn(C(=O)c3ccccc3)c3cc(F)ccc23)CC1
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCC(c2nn(C(=O)c3ccccc3)c3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.9 %

Procedure:
To a solution of 1-benzoyl-6-fluoro-3-(1-methyl-4-piperidinyl)-1H-indazole (2.0 g, 5.93 mmol) in dichloromethane (100 ml) was added phenyl chloroformate (3.9 ml, 29.65 mmol) at room temperature. The reaction mixture was stirred at room temperature for 24 hours, refluxed for an additional 0.5 hours and subsequently concentrated. The remaining residue was dissolved into dichloromethane and washed with 10% HCl (aq.). The organic phase was dried (MgSO4), filtered, and concentrated to give an oil which was purified via flash column chromatography (silica gel, 20% DCM/EtOAc). Concentration of the product-containing fractions gave an oil which solidified on standing. The white solid was washed with EtOAc, leaving 0.47 g of the desired product, m.p. 137°-139° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN1CCOCC1.Cl.[NH2:43][CH2:44][C:45]([O:47]C(C)(C)C)=[O:46].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:43][CH2:44][C:45]([OH:47])=[O:46])=[O:31])=[CH:33][CH:34]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(Cl)cc3)C(=O)N2c2ccc(Cl)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(Cl)cc3)C(=O)N2c2ccc(Cl)cc2)cc1
Reaction time: 0.17 h

Procedure:
[4-((2R,3R)-1-(4-Chlorophenyl)-3-{[2-(4-chlorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetic acid, 302.1 mg, 0.585 mmol) was dissolved in DCM (6 ml). N-Methylmorpholine (190 μl, 1.728 mmol) and tert-butyl glycinate hydrochloride (133.4 mg, 0.80 mmol) were added. After 10 minutes, TBTU (224.3 mg, 0.67 mmol) was added and the reaction mixture was stirred for 60 h. The intermediate tert-butylester of the title compound was confirmed. M/z: 626.88 (M−H). DCM (10 ml) and water (15 ml) were added and the mixture was acidified to pH of 3 using KHSO4 (2M). The organic phase was washed with water (2×15 ml). The combined aqueous phases were extracted with DCM (10 ml), dried over Na2SO4, filtered and concentrated. A solution of the residue (500 mg) in DCM (10 ml) and TFA (4 ml) was stirred overnight. The solvent was removed under reduced pressure. Toluene was added and evaporated to assist the removal of TFA. The residue was purified with preparative HPLC on a C8 column. A gradient from 20 to 50% MeCN in 0.1M ammonium acetate buffer was used as eluent. After lyophilisation, the title compound was obtained as a white solid (166.9 mg, 50%). H-NMR (400 MHz, DMS-d6): 3.51 (d, 2H), 4.33 (d, 1H), 4.34 (s, 1H), 4.36 (s, 1H), 4.47 (s, 2H), 5.17 (d, 1H), 6.96 (d, 2H), 7.16-7.21 (m, 2H), 7.35 (d, 4H), 7.54-7.59 (m, 2H), 7.83-7.90 (brs, 1H), 7.91-7.95 (m, 2H). M/z: 571.04 (M−H) and 572.88 (M+H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:29]=[CH:28][C:11]([C:12]([NH:14][CH2:15][CH2:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH:21]=[C:20]4[C:26]#[N:27])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[C:30]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:14][CH2:15][CH2:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH:21]=[C:20]4[C:26]#[N:27])=[O:13])=[CH:28][CH:29]=2)[CH2:6][CH2:7]1)(=[O:32])[CH3:31]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(N4CCC(N)CC4)cc3)cc12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NC1CCN(c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
40 mg (0.09 mmol) of 4-(4-amino-piperidin-1-yl)-N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-benzamide. (reference Example 1aav). was dissolved in 2 ml of pyridine, 22 mg (0.22 mmol) of acetic anhydride was added and stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness. MS (CI) 430 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[F:10][C:11]([F:16])([F:15])[C:12](O)=O>C(Cl)Cl>[Br:8][C:7]1[C:2]2[N:1]=[C:12]([C:11]([F:16])([F:15])[F:10])[O:9][C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1c(O)cccc1Br
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1nc2c(Br)cccc2o1
Temperature: 120 °C
Yield: 15.9 %

Procedure:
A solution of 2-amino-3-bromophenol (480 mg, 2.6 mmol), polyphosphoric ester (PPE, 3.4 g) and trifluoroacetic acid (0.88 mL, 11.5 mmol) was heated to 100° C. under a nitrogen atmosphere overnight. A reflux condenser was added as was fresh PPE and the reaction heated to 120° C. for 8 hr. The reaction was cooled and diluted with methylene chloride. The solvent was removed by rotoevaporation. The residue was dissolved in fresh methylene chloride and successively washed with 2N sodium hydroxide solution and saturated salt solution. After drying over anhydrous magnesium sulfate and filtering, the solvent was removed by rotoevaporation. The residue was purified by flash column chromatography in silica gel eluted with 15% acetone in hexanes to yield the title compound (110 mg, 16% yield).
Reaction SMILES: CS(O[CH2:6][C:7]1[O:11][N:10]=[C:9]([CH3:12])[C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=O)=O.CN(C=O)C.[N-:33]=[N+:34]=[N-:35].[Na+]>O>[N:33]([CH2:6][C:7]1[O:11][N:10]=[C:9]([CH3:12])[C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[O:27])=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1noc(COS(C)(=O)=O)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(CN=[N+]=[N-])c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a round bottomed flask was added crude (4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)methyl methanesulfonate (30.8 mg, 0.076 mmol), DMF (2 mL), and sodium azide (4.93 mg, 0.076 mmol). The reaction was stirred at room temperature for 2 h before diluting with water and extracting with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated to afford crude (2-(5-(azidomethyl)-3-methylisoxazol-4-yl)phenyl) (4-chlorophenyl)methanone.
Reaction SMILES: N([C:4]1[C:5]2[C:10]([N:11]=[C:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2)=C=S.CC(N)[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3OC[C@@](O)(C)[C@H]([NH:43]C)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](N)CC1.CC(NC)[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3OC[C@@](O)(C)[C@H](NC)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](N)CC1.C[C@@]1(O)[C@H](NC)[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](CN)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC1.OS(O)(=O)=O.O.OS(O)(=O)=O>CO>[NH2:43][C:6]1[C:5]2[C:10](=[N:11][C:12]3[C:17]([CH:4]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:8][CH:7]=1
Reactant: S=C=Nc1c2ccccc2nc2ccccc12
Reactant: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](C(C)N)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Agent: CNC(C)[C@@H]1CC[C@@H](N)[C@@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3OC[C@](C)(O)[C@H](NC)[C@H]3O)[C@H](N)C[C@@H]2N)O1
Agent: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](CN)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: Nc1cccc2nc3ccccc3cc12
Reaction time: 0.5 h
Yield: 910.6 %

Procedure:
9-Isothiocyanatoacridin (100 mg) was dissolved in MeOH (5 mL), and added to the solution of gentamicin sulfate (250 mg) in 5 mL MeOH and some drops of water, followed by the solution of BaO (100 mg) in 5 mL MeOH. The suspension was stirred 30 min, neutralized with 3% H2SO4 in MeOH, filtered, evaporated to dryness and the residue was washed carefully with dichloromethane. Obtained 297 mg of yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[I:12]N1C(=O)CCC1=O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:12])=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: O=C1CCC(=O)N1I
Product: Nc1ccc(I)cc1S(N)(=O)=O

Procedure:
Commercially available 2-aminobenzenesulfonamide can be treated with N-iodosuccinimide (NIS) to afford 2-amino-5-iodo-benzenesulfonamide. Acylation with a malonyl halide monoester, such as ethyl 3-chloro-3-oxo-propionate, or with a dialkyl malonate, such as diethyl malonate, affords the corresponding amide, which can simultaneously be cyclized to the thiadiazine-dioxide and hydrolyzed to the desired acid intermediate (or a salt thereof, e.g., sodium salt).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[NH2:21]>CCOC(C)=O.C1CCCCC1>[CH3:28][O:27][C:23]1[CH:22]=[C:20]([NH:21][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])[N:3]=2)[CH:19]=[C:18]([O:17][CH3:16])[C:24]=1[O:25][CH3:26]
Reactant: Clc1cncc(Oc2ccccc2Cl)n1
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(Oc3ccccc3Cl)n2)cc(OC)c1OC
Yield: 71 %

Procedure:
Using Method EE with 2-chloro-6-(2-chlorophenyloxy)-pyrazine (200 mg, 0.83 mmol) and 3,4,5-trimethoxyaniline (183 mg, 1.00 mmol), and purification by column chromatography (AcOEt:cyclohexane, 1:1), the title compound was obtained (227 mg). Yield: 71%. 1H NMR (250 MHz, DMSO-d6) δ 3.43 (s, 6H, [CH3O]3+5), 3.54 (s, 3H, [CH3O]4), 6.68 (s, 2H, Harom2′+6′), 7.26-7.30 (m, 1H, Harom 4), 7.37-7.40 (m, 2H, Harom 5+6), 7.59 (d, 1H, Harom 3, J=7.8 Hz), 7.82 (s, 1H, HPz 5), 7.95 (s, 1H, HPz 3), 9.56 (s, 1H, NH). m/z: 388.1 [(M+H)+, calcd for C19H18ClN3O4 387.1].
Reaction SMILES: [F:1][C:2]([F:38])([CH2:34][CH2:35][CH2:36][CH3:37])[C:3](=[O:33])[CH2:4][CH2:5][C@H:6]1[C@H:10]([OH:11])[CH2:9][C:8](=[O:12])[C@@H:7]1[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC(C1C=CC=CC=1)=O)=[O:22]>C(O)(=O)C.[Zn]>[F:1][C:2]([F:38])([CH2:34][CH2:35][CH2:36][CH3:37])[C:3](=[O:33])[CH2:4][CH2:5][C@H:6]1[C@H:10]([OH:11])[CH2:9][C:8](=[O:12])[C@@H:7]1[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: CCCCC(F)(F)C(=O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCCCC(=O)OCC(=O)c1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCCC(F)(F)C(=O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCCCC(=O)O
Reaction time: 2.5 h
Yield: 83.5 %

Procedure:
The compound (16-b)(0.272 g) was dissolved in acetic acid (10 ml). Zinc (3.5 g) was added little by little at room temperature, and the mixture was agitated for 2.5 hours. The crude product obtained by the conventional treatment of the reaction mixture was purified on silica gel column to give the titled compound (17-a) [yield:0.177 g(81%)].