Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH2:15])=[CH:5][C:4]=1[O:16][CH3:17].[CH2:18]1[O:29][C:28]2[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][C:20]=2[O:19]1>C(Cl)Cl.C(N(CC)CC)C>[CH3:17][O:16][C:4]1[CH:5]=[C:6]([C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]3[O:29][CH2:18][O:19][C:20]=3[CH:21]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: COc1ccc([C@@H]2CCCC[C@@H]2N)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc([C@H]2CCCC[C@H]2NC(=O)c2ccc3c(c2)OCO3)cc1OC
Reaction time: 8 h
Yield: 95.1 %

Procedure:
4.0 g of (−)-cis-1,2-dimethoxy-4-(2-aminocyclohexyl)benzene (compound B2) are dissolved in 100 ml of methylene chloride and 5.0 ml of triethylamine. A solution of 3.8 g of 3,4-methylenedioxybenzoyl chloride in 50 ml of methylene chloride is added dropwise at RT and the mixture is extracted with 100 ml each of water, 2N hydrochloric acid, satd. sodium hydrogencarbonate solution and water again after stirring overnight. The organic phase is dried using sodium sulfate and concentrated. 6.2 g of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[H-].[Na+].[Cl:12][C:13]1[CH:14]=[C:15]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:16]=[CH:17][C:18]=1F.Cl>O1CCCC1.ClCCl.CN(C)C=O>[Cl:12][C:13]1[CH:14]=[C:15]([S:20]([NH2:23])(=[O:21])=[O:22])[CH:16]=[CH:17][C:18]=1[O:9][CH2:8][C:2]1([F:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: NS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: OCC1(F)CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(OCC2(F)CCOCC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of EXAMPLE 296C (0.175 g) in tetrahydrofuran (5 ml) was added sodium hydride (0.209 g) and the reaction stirred at room temperature for 15 minutes. 3-Chloro-4-fluorobenzenesulfonamide (0.273 g) was added and the reaction stirred for 3 hours. To the thick suspension was added tetrahydrofuran (2 ml) and N,N-dimethylformamide (3 ml). The reaction was stirred for 3 hours at 60° C. then poured into dichloromethane (50 ml) and 1N aqueous HCl (50 ml). The organic layer was washed with brine (35 ml) dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (Reveleris 40 g) eluting with a gradient of 10-100% ethyl acetate/hexanes over 30 minutes (flow=40 ml/minute) gave the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].Br[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[C:17]12([C:27](O)=[O:28])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2>>[CH3:1][C:2]1[N:3]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)/[C:4](=[N:8]/[C:27]([C:17]23[CH2:26][CH:21]4[CH2:20][CH:19]([CH2:25][CH:23]([CH2:22]4)[CH2:24]2)[CH2:18]3)=[O:28])/[S:5][C:6]=1[CH3:7]
Reactant: Cc1nc(N)sc1C
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: BrCc1cccnc1
Product: Cc1s/c(=N\C(=O)C23CC4CC(CC(C4)C2)C3)n(Cc2cccnc2)c1C

Procedure:
4,5-dimethythiazol-2-ylamine, 3-bromomethylpyridine and 1-adamantane carboxylic acid were processed according to the method of Example 47 to afford the title compound. 1H NMR (CDCl3, 500 MHz) δ ppm 1.49-1.71 (m, 6 H) 1.74 (d, J=2.50 Hz, 6 H) 1.85-2.02 (m, 3 H) 2.19 (d, J=11.54 Hz, 6 H) 5.44 (s, 2 H) 7.29 (t, J=7.33 Hz, 2 H) 7.69-7.85 (m, 1 H) 8.49 (d, J=4.68 Hz, 1 H); MS (ESI) m/z 382 (M+H)+
Reaction SMILES: [CH3:1][N:2]([CH:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])[CH3:3].[CH2:19]([Mg][Cl:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[ClH:27].[CH2:19]([C:6]1([OH:11])[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]1[CH:4]([N:2]([CH3:1])[CH3:3])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccccc1C(C1CCCCC1=O)N(C)C
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(C1CCCCC1(O)Cc1ccccc1)N(C)C
Product: Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 29.6 %

Procedure:
2.0 g (7.5 mmole) of the 2-(dimethylamino-o-tolylmethyl) cyclohexanone prepared according to Example 66 were dissolved in 15 ml of tetrahydrofuran, added dropwise while cooling in an ice bath to 6.1 ml (12.2 mmole) of benzylmagnesium chloride (2 M solution in tetrahydrofuran), and stirred for 15 hours at RT. The reaction mixture was worked up by adding 158 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 15 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 3.39 g of crude base (98.5% of theory) were obtained, from which 0.83 g of 1-benzyl-2-(dimethylamino-o-tolylmethyl)cyclo-hexanol, hydrochloride (21.8% of theory) having a melting point of 180-183° C. was obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH2:19][CH2:20][Cl:21].O>CN(C)C=O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH2:19][CH2:20][Cl:21])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 81 %

Procedure:
To a solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.54 g) in N,N-dimethylformamide (20 mL) was added cesium carbonate (4.89 g) under ice-cooling, and the mixture was stirred under ice-cooling for 20 min. 1-Bromo-3-chloropropane (1.89 g) was added and the mixture was stirred under ice-cooling for 1 hr and at room temperature for 32 hrs. The reaction mixture was poured into water (40 mL), and the mixture was extracted with ethyl acetate (60 mL×2). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→50:50) to give the title compound (1.87 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:7][N:6]=[CH:5][N:4]=1.[CH2:8]([O:10][CH2:11]Cl)[CH3:9]>C1(C)C=CC=CC=1>[CH2:8]([O:10][CH2:11][N:6]1[CH:5]=[N:4][C:3]([S:2][CH3:1])=[N:7]1)[CH3:9]
Reactant: CCOCCl
Reactant: CSc1ncn[nH]1
Solvent: Cc1ccccc1
Product: CCOCn1cnc(SC)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.4 %

Procedure:
A suspension of 5-methylthio-1,2,4-triazole (6.19, 53 mmol) and chloromethyl ethyl ether (2.5 ml, 26 mmol) in toluene (40 ml) was stirred at room temperature for 24 hours. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was chromatographed on silica by elution with ethyl acetate/diethylamine (95:5) to yield the title compound (1.1 g, 27%), as a colourless oil, which was characterised by
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:8]=[C:9]([O:15][CH3:16])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1.C1(S([CH:26]2[CH2:30][CH2:29][CH:28]([O:31][CH3:32])[O:27]2)(=O)=O)C=CC=CC=1>C1COCC1.[Zn+2].[Br-].[Br-]>[CH3:16][O:15][C:9]1[CH:8]=[C:7]([CH:26]2[CH2:30][CH2:29][CH:28]([O:31][CH3:32])[O:27]2)[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: COC1CCC(S(=O)(=O)c2ccccc2)O1
Reactant: COc1ccc(Br)cc1OC
Agent: [Br-]
Agent: [Mg]
Agent: [Zn+2]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COc1ccc(C2CCC(OC)O2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
Magnesium (2.18 g, 0.091M) was placed in a 3-necked flask containing dry THF (10 ml) and 1,2-dibromoethane (0.2 ml). A solution of 4-bromoveratrole (18.0 g, 0.086M) in THF (50 ml) was added dropwise, with warming to initiate reaction. The resulting solution was heated at reflux for 0.75 h then cooled to room temperature and cannulated into a 1M solution of ZnBr2 in THF (50 ml, 0.05M) and stirred for 0.5 h at room temperature. A solution of 2-benzenesulphonyl-5-methoxytetrahydrofuran (10.0 g, 0.041M) in THF (50 ml) was added dropwise to the pale yellow suspension and the mixture allowed to stir at room temperature for 20 h. Reaction was quenched by addition of 1N HCl (50 ml), and extracted with ether (2×100 ml). The organics were combined washed with water (50 ml) dried over anhydrous sodium sulphate, filtered and evaporated. Column chromatography (flash silica gel; 3:2 hexane/ethyl acetate) gave 2-(3,4-dimethoxyphenyl)-5-methoxytetrahydrofuran (8.0 g, 82%) as a yellow oil (rf 0.28).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:3]=1.[CH2:19]([OH:21])[CH3:20].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:21][CH2:19][CH3:20])[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:3]=1
Reactant: CCO
Reactant: Cc1ccc(-c2nc(N)nc(S(C)=O)c2C#N)o1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CCOc1nc(N)nc(-c2ccc(C)o2)c1C#N

Procedure:
From 2-amino-4-methanesulfinyl-6-(5-methyl-furan-2-yl)-pyrimidine-5-carbonitrile, ethanol and DBU in DME. ES-MS m/e (%): 245 (M+H+, 100), 217 ([M+H—CH2═CH2]+, 80).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH2:44])=[CH:41][CH:40]=1>CC(N(C)C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:44][CH2:43][C:42]2[CH:45]=[CH:46][C:39]([CH3:38])=[CH:40][CH:41]=2)=[O:15])[CH:3]=1
Reactant: Cc1ccc(CN)cc1
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Product: CCOc1nc(C(=O)NCc2ccc(C)cc2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a 20 mL scintillation vial, 4-amino-5-cyano-6-ethoxy-pyridine-2-carboxylic acid (19 mg, 0.09 mmol) was dissolved in DMA (0.7 mL). Then TBTU (30 mg, 0.09 mmol) dissolved in DMA (0.7 mL) was added, followed by the addition of 4-methylbenzylamine (12 mg, 0.11 mmol, 1.2 eq.) in DMA (0.6 mL). Then TEA (9.37 mg, 0.09 mmol) dissolved in DMA (0.7 mL) was added. The reaction mixture was shaken at room temperature for 24 hours. The crude mixture was purified using reverse phase HPLC (TFA). 1H NMR (500 MHz, DMSO-D6/D2O) 1.23-1.36 (m, 3H) 2.20-2.34 (m, 3H) 4.37-4.55 (m, 4H) 7.04-7.22 (m, 4H) 8.97-9.10 (m, 1H). MS (ESI) positive ion 311 (M+H)+; negative ion 309 (M−H)−.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([C:26](O)=[O:27])[N:16]([CH3:25])[C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1>>[C:1]([NH:5][C:26]([C:15]1[N:16]([CH3:25])[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[C:13]([C:10]2[CH:9]=[CH:8][C:7]([CH3:6])=[CH:12][CH:11]=2)[N:14]=1)=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: Cc1ccc(-c2nc(C(=O)O)n(C)c2-c2ccc(C)cc2)cc1
Product: Cc1ccc(-c2nc(C(=O)NC(C)(C)C)n(C)c2-c2ccc(C)cc2)cc1

Procedure:
Using essentially the same procedure as Example 9, Step B, but using t-butylamine (0.022 mL), 4,5-di-(4-methylphenyl)-1-methylimidazole-2-carboxylic acid (25 mg, 0.08 mmol) from Example 9, Step A was converted to the title compound. HPLC/MS: 362 (M+1); Rt=3.92 min.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1.[H-].[Na+].I[CH2:31][CH2:32][CH3:33]>CN(C)C=O>[CH2:31]([N:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1)[CH2:32][CH3:33]
Reactant: CCCI
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1ccc(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)n1
Yield: 29.2 %

Procedure:
In the manner of Example 25, employing [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.98 g), 60% sodium hydride in oil (0.30 g), dimethylformamide (25 ml), and 1-iodopropane (0.60 g), the title compound (0.32 g) was obtained as a crystalline solid, m.p. 159-161° C.
Reaction SMILES: [NH2:1][NH2:2].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](Cl)=[O:12])=[CH:6][CH:5]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:1][NH2:2])=[O:12])=[CH:6][CH:5]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NNC(=O)Cc1ccc(F)cc1
Reaction time: 0.75 h
Yield: 125.3 %

Procedure:
To a solution of hydrazine (0.46 mL, 14.49 mmol, 2.5 equiv) in CH2Cl2 (29 mL) was added slowly over 30 sec 2-(4-fluorophenyl)acetyl chloride (0.79 mL, 5.79 mmol, 1.0 equiv). Slight warming of the mixture and white precipitate were observed. After stirring 45 min, the mixture was poured into a saturated aqueous solution of NaHCO3, layered with CH2Cl2 forming a thick emulsion. This emulsion was filtered through a medium glass frit to give a biphasic homogenous solution. This was extracted with CH2Cl2 (×3). The combined CH2Cl2 extracts were dried (Na2SO4) and then concentrated in vacuo to provide the title compound (1.22 g, 124% yield) as a white solid. Source of extra mass is unclear as product is of high purity. Extra mass may reflect a measuring error of the acid chloride. 1H NMR (400 MHz, CDCl3) δ ppm 7.19-7.24 (m, 2H), 6.99-7.07 (m, 2H), 6.60 (s, 1H), 3.85 (d, J=2.01 Hz, 2H), 3.52 (s, 2H); LCMS (ES+, (M+H)+) m/z 169.22.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Br)[N:8]=1)([CH3:5])=[O:4].[NH2:14][C:15]1[S:16][C:17]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][C:24]=2[F:33])=[CH:18][C:19]=1[C:20]([NH2:22])=[O:21]>>[CH3:1][O:2][P:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:14][C:15]2[S:16][C:17]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:30])[CH3:31])=[CH:25][C:24]=3[F:33])=[CH:18][C:19]=2[C:20]([NH2:22])=[O:21])[N:8]=1)([CH3:5])=[O:4]
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: COP(C)(=O)Cc1cccc(Br)n1
Product: COP(C)(=O)Cc1cccc(Nc2sc(-c3ccc(C(C)(C)O)cc3F)cc2C(N)=O)n1

Procedure:
The title compound was synthesized from methyl[(6-bromopyridin-2-yl)methyl]methylphosphinate (90 mg, 0.34 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (100 mg, 0.34 mmol) according to the general procedure in Example 1.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]C)=O.[NH2:19][C:20]1[C:21](=[O:29])[C:22]([O:27][CH3:28])=[CH:23][CH:24]=[CH:25][CH:26]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:14])[C:3]=1[C:15]([NH:19][C:20]1[C:21](=[O:29])[C:22]([O:27][CH3:28])=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:17]
Reactant: COc1ccccc(N)c1=O
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: COc1ccccc(NC(=O)C2=C(O)c3ccccc3S(=O)(=O)N2C)c1=O
Reaction time: 8 h
Yield: 34.1 %

Procedure:
A solution of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (1.5 g) and 2-amino-7-methoxy-2,4,6-cycloheptatrien-1-one (0.8 g) in xylene (25 ml) is refluxed for 6.5 hours. The reaction mixture is then allowed to stand at room temperature overnight. The crystals that have separated out are collected by filtration and recrystallized from dimethylformamide to give 4-hydroxy-2-methyl-N-(7-methoxy-1-oxo-2,4,6-cycloheptatrien-2-yl)-2H-1,2 -benzothiazine-3-carboxamide 1,1-dioxide (0.7 g), m.p. 243°-247° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH2:11][NH:12]C(C(F)(F)F)=O)=[C:9](F)[C:8](F)=[C:7]([CH3:21])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:22][C:23]1[C:31]([CH2:32][NH:33]C(C(F)(F)F)=O)=[C:30](F)[C:29](F)=[C:28]([Cl:42])[C:24]=1[C:25]([OH:27])=[O:26].CSC1C2C(=CC(Br)=CC=2Br)NC=1SC>Cl>[NH2:12][CH2:11][C:10]1[C:2]([Cl:1])=[C:3]([C:7]([CH3:21])=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5].[NH2:33][CH2:32][C:31]1[C:23]([CH3:22])=[C:24]([C:28]([Cl:42])=[CH:29][CH:30]=1)[C:25]([OH:27])=[O:26]
Reactant: Cc1c(F)c(F)c(CNC(=O)C(F)(F)F)c(Cl)c1C(=O)O
Reactant: Cc1c(CNC(=O)C(F)(F)F)c(F)c(F)c(Cl)c1C(=O)O
Agent: CSc1[nH]c2cc(Br)cc(Br)c2c1SC
Agent: Cl
Product: Cc1c(CN)ccc(Cl)c1C(=O)O
Product: Cc1ccc(CN)c(Cl)c1C(=O)O

Procedure:
Prepared analogously to 44a with 2-chloro-6-methyl-difluoro-3-(trifluormethylcarbonylamino)methyl-benzoic acid/2-methyl-6-chloro-difluoro-3-(trifluormethylcarbonylamino)methyl-benzoic acid (5.62 g 19 mmol) in 6 M aq. HCl solution. Yield: 4.37 g; (97%; mixture of regioisomers); MS: [M−H]−=198; HPLC: Rt=0.189 min (Method MC-6)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[C:7]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8]2.[CH2:19]=O.[BH4-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14]2)=[C:7]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8]2
Reactant: COc1ccc(C2CCCNC2)c2c1NC(=O)C2
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C2CCCN(C)C2)c2c1NC(=O)C2
Temperature: 5 °C

Procedure:
4.5 g of the product of Example 1 were dissolved in 100 ml of methanol with stirring under an inert atmosphere and after cooling to about 5° C., 3.4 ml of 40% formic aldehyde were added dropwise. After stirring for 1 hour, 1.8 g of 95% sodium borohydride were added in small fractions and the mixture was stirred for 1 hour. The temperature was allowed to return to ambient and after diluting with iced water, extracting with methylene chloride, drying and evaporating to dryness under reduced pressure, filtering, washing with ether and drying, 4 g of 1,3-dihydro-7-methoxy-4-(1-methyl-3-piperidinyl)-2H-indol-2-one were obtained in the form of a base melting at ≈170° C.
Reaction SMILES: [CH3:1][C:2]([O-:5])(C)[CH3:3].[K+].[F:7][C:8]1C=[CH:14][CH:13]=[CH:12][C:9]=1C#N.C[C:17]#[N:18].Cl>C(Cl)Cl.O.CCOCC>[F:7][C:8]1[CH:9]=[CH:12][CH:13]=[CH:14][C:1]=1[C:2](=[O:5])[CH2:3][C:17]#[N:18]
Reactant: CC#N
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1ccccc1F
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: N#CCC(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.1 %

Procedure:
To a flask charged with KOtBu (4 g, 36 mmol) and ether (100 mL, dry) was added dropwise a mixture of 2-fluorobenzonitrile (2.1 g, 17.5 mmol) and MeCN (0.738 g, 18 mmol) at 0° C. After addition the mixture was stirred at RT. for 2 days. Water was added and the reaction and extracted with ether (3×100 mL). The organic layers were combined, washed with brine and dried (Na2SO4). The solvent was evaporated under reduced pressure to afford a yellow oil, which was dissolved in CH2Cl2 and the solution was acidified with 3M HCl. After stirring the solution at RT for 2 hours, the solution was extracted with dichloromethane (3×200 mL). The organic layers were combined, washed with brine and dried (Na2SO4). After filtration, the filtrate was concentrated in vacuo to give 3-(2-fluoro-phenyl)-3-oxo-propionitrile (2 g, 70% yield) as a yellow solid.
Reaction SMILES: [C:1]1(=[O:10])[C:5]2=[CH:6][S:7][CH:8]=[C:4]2[C:3](=[O:9])O1.[NH2:11][CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19].C1N=CN(C(N2C=NC=C2)=O)C=1>C1COCC1.CN(C1C=CN=CC=1)C>[O:19]=[C:13]1[CH:12]([N:11]2[C:3](=[O:9])[C:4]3=[CH:8][S:7][CH:6]=[C:5]3[C:1]2=[O:10])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: NC1CCC(=O)NC1=O
Reactant: O=C1OC(=O)c2cscc21
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cscc3C2=O)C(=O)N1
Yield: 79.5 %

Procedure:
1.54 g thieno(3,4-c)furan-1,3-dione was dissolved in 20 mL of anhydrous THF, and 12.8 g of 3-aminopiperidine-2,6-dione was added. The reaction mixture was allowed to react at room temperature for 4 h. Then, 2 g of CDI and a catalytic quantity of DMAP were added, and the reaction mixture was allowed to reflux for 6 h until a large amount of white solid precipitated. The solid was cooled and filtered to yield 2.1 g of the title product.
Reaction SMILES: C(N(CC)CC)C.Cl.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.[CH2:24]([CH2:26][NH2:27])[OH:25]>ClCCl>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:27][CH2:26][CH2:24][OH:25])=[O:20])=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(-c2ccccn2)cc1
Reactant: NCCO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCO)c1ccc(-c2ccccn2)cc1
Reaction time: 0.5 h

Procedure:
Triethylamine (0.14 ml) was added to a suspension of 4-pyridine-2-ylbenzoylchloride hydrochloride (254 mg) in dichloromethane (2 ml). To the mixture a solution of ethanolamine (0.060 ml) in dichloromethane (3 ml) was added. This mixture was stirred for 30 minutes. At the end of this time the reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed with aqueous sodium chloride and dried over anhydrous magnesium sulfate and concentrated to afford crystals. The crystals were washed with isopropyl ether to afford the title compound (111 mg).
Reaction SMILES: C([CH:4]1[C:9]2[N:10]=[C:11](Cl)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[C:8]=2[CH2:7][CH2:6][N:5]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])C=C.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1>>[NH2:43][C:40]1[N:41]=[CH:42][C:37]([C:11]2[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[C:8]3[CH2:7][CH2:6][N:5]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:4][C:9]=3[N:10]=2)=[CH:38][N:39]=1
Reactant: C=CCC1c2nc(Cl)nc(N3CCOC[C@@H]3C)c2CCN1C(=O)OC(C)(C)C
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: C[C@H]1COCCN1c1nc(-c2cnc(N)nc2)nc2c1CCN(C(=O)OC(C)(C)C)C2

Procedure:
Compound fh was prepared according to the procedure described in Example 2 step 2 by reacting tert-butyl 8-allyl-2-chloro-4-((S)-3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine. LC-MS: m/z=+428 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1B(O)O>>[CH:18]1([N:13]2[C:12]([C:32]3[S:31][CH:35]=[CH:34][CH:33]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1cccs1
Product: c1csc(-c2c3c(nn2C2CCCC2)CCNCC3)c1
Yield: 65.5 %

Procedure:
The title compound (83 mg) was prepared according to Example 180 using 200 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 282 mg of 2-thiopheneboronic acid. MS (ESI): exact mass calculated for C16H21N3S, 287.15. found, m/z 288.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.70-7.68 (m, 1H), 7.24-7.22 (m, 1H), 7.15-7.14 (m, 1H), 4.64 (m, 1H), 3.41-3.39 (m, 2H), 3.16-3.15 (m, 2H), 2.85-2.83 (m, 2H), 2.01-1.88 (m, 6H), 1.64-1.60 (m, 2H).
Reaction SMILES: N#N.[I:3][C:4]1[CH:8]=[CH:7][NH:6][N:5]=1.[CH3:9][C:10](O)([CH3:12])[CH3:11].S(=O)(=O)(O)O>>[C:10]([N:6]1[CH:7]=[CH:8][C:4]([I:3])=[N:5]1)([CH3:12])([CH3:11])[CH3:9]
Reactant: Ic1cc[nH]n1
Reactant: CC(C)(C)O
Agent: N#N
Agent: O=S(=O)(O)O
Product: CC(C)(C)n1ccc(I)n1
Temperature: 100 °C

Procedure:
To a round-bottomed flask equipped with a stifling bar and a N2 tee, 3-iodo-1H-pyrazole (2.00 g, 10 mmol), 2-methylpropan-2-ol (7.64 g, 103 mmol), and concentrated sulfuric acid (1.08 g, 11 mmol) were added. The resulting mixture was heated at 100° C. for 3 hrs.