Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:6]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([NH:31][CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[CH:24]=2)[N:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:45](Cl)(=[O:47])[CH3:46].O>C(Cl)(Cl)Cl>[C:45]([N:31]([CH:32]1[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]1)[C:25]1[CH:24]=[C:23]([N:6]2[C:7]3=[N:8][CH:9]=[CH:10][C:11]([C:13]4[CH:14]=[N:15][C:16]5[C:21]([CH:22]=4)=[CH:20][CH:19]=[CH:18][CH:17]=5)=[C:12]3[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5]2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28])(=[O:47])[CH3:46]
Reactant: CC(C)c1nn(-c2ccc(C#N)c(NC3CCNCC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)N(c1cc(-n2nc(C(C)C)c3c(-c4cnc5ccccc5c4)ccnc32)ccc1C#N)C1CCNCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68 %

Procedure:
Compound (77a) (0.050 g) and triethylamine (0.017 mL) were dissolved in chloroform (1.0 mL), and acetyl chloride (0.017 mL) was added to the resulting mixture, followed by stirring at room temperature for 15 hr. The reaction solution was distributed between chloroform and water. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled away to obtain 2-(acetylpiperidin-4-ylamino)-4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile, which was used in the subsequent reaction without being purified. According to Example 1(7), compound (77) (the second stage yield: 68%) was prepared as a white solid using 2-(acetylpiperidin-4-ylamino)-4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile instead of compound (1f).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C:14]#[CH:15])[C:7]=12.[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH:13]=[C:14]=[CH2:15])[C:7]=12)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCc1ccccc1
Reactant: C#CCn1c(C)c(C)c2cnnc(Cl)c21
Product: C=C=Cn1c(C)c(C)c2cnnc(OCc3ccccc3)c21
Yield: 37.6 %

Procedure:
The title compound was prepared as pale brown crystals in 37.6% yield in a similar procedure to that described in Example 44 by using 7-chloro-2,3-dimethyl-1-(2-propynyl)pyrrolo[2,3-d]pyridazine and benzyl alcohol.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH2:13][CH2:14][CH:15]=[C:16]([CH3:23])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[C:5](=[O:12])[CH2:6][C:7](OCC)=O.Br[CH2:25][C:26](C)=[CH:27][CH2:28][CH2:29][C:30]([CH3:37])=[CH:31][CH2:32][O:33]C(=O)C>CCOCC>[CH3:37][C:30]([CH2:29][CH2:28][CH:27]=[C:26]([CH3:25])[CH2:7][CH2:6][C:5](=[O:12])[CH:4]([CH3:3])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:23])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:21])[CH3:22])=[CH:31][CH2:32][OH:33]
Reactant: CCOC(=O)CC(=O)C(C)CCC=C(C)CCC=C(C)C
Reactant: CC(=O)OCC=C(C)CCC=C(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)=CCCC(C)=CCCC(C)C(=O)CCC(C)=CCCC(C)=CCO
Temperature: 0 °C
Yield: 96.2 %

Procedure:
To a suspension of sodium hydride (2.64 g) in ether (70 ml), a solution of ethyl 3,7,11-trimethyl-6,10-dodecadien-2-one-1-carboxylate (14.7 g) in ether (15 ml) is dropwise added, and then a solution of 1-bromo-8-acetoxy-2,6-dimethyl-2,6-octadiene (15 g) in ether (15 ml) is dropwise added thereto while cooling with ice. The reaction mixture is poured into ice water. The ether layer is washed with water, dried and evaporated. The residue (24.8 g) is added to a solution of potassium hydroxide (8.4 g) in ethanol (150 ml), and the resultant mixture is poured into water, followed by washing with petroleum ether, acidifying with 5% aqueous solution of sulfuric acid and extracting with ether. The ether layer is washed with water, dried and evaporated. The resulting product (23.5 g) is purified by chromatography on silica gel (235 g) using benzene to give 3,7,11,15,19-pentamethyl-2,6,14,18-eicosatetraen-10-on-1-ol (18 g). IR: 3400, 1000 cm-1 (OH): 1705 cm-1 (C=O); 1668 cm-1 (C=C). NMR (carbon tetrachloride): δ 1.04 (d), 1.59 (s), 1.66 (s), 2.01 (m), 2.7 (m), 4.1 (m), 5.05 (m).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]([NH2:16])=[O:15])[CH:5]=[CH:4][CH:3]=1.[I:17]N1C(=O)CCC1=O>CN(C)C=O.ClCCl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[I:17][C:11]1[S:10][C:9]([NH:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)=[C:13]([C:14]([NH2:16])=[O:15])[CH:12]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cccc(Nc2sccc2C(N)=O)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cccc(Nc2sc(I)cc2C(N)=O)n1

Procedure:
To a solution of 2-[(6-methylpyridin-2-yl)amino]thiophene-3-carboxamide (2.8 g, 12.0 mmol) in dimethylformamide (40 mL) and dichloromethane (80 mL) was added slowly N-iodosuccinimide (1.060 g, 4.71 mmol). After twenty minutes, the reaction mixture was diluted with ethyl acetate (400 mL), hexanes (40 mL), and saturated aqueous sodium bicarbonate (100 mL) and filtered through a Buchner funnel. The layers of the filtrate were separated, and the organic layer was washed with water (3×100 mL, filtering before separated layers as above) and a 5:1 mixture of brine:saturated aqueous sodium thiosulfate (120 mL). The resulting organic layer was dried over sodium sulfate, filtered through a pad of Celite, and concentrated. The resulting solid was triturated with a mixture of dichloromethane, ethyl acetate, methanol, and dichloromethane to afford the title compound as a purple powder.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=O.C(Cl)(=O)C(Cl)=O.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH3:9][O:8][C:1](=[O:7])/[CH:2]=[CH:3]/[C:4]([N:26]1[CH2:25][CH2:24][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:28][CH2:27]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)/C=C/C(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)/C=C/C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 20.8 %

Procedure:
Mono methyl fumarate (650 mg, 5.0 mmol) was takes up in 10 mL of CH2Cl2 and oxalyl chloride (420 μl, 5.0 mmol) was added. After a few drops of DMF was added, the reaction mixture was stirred at room temperature until all gas evolution had ceased (1 h). This freshly prepared solution of acid chloride was then added dropwise at 0° C. to a solution containing Boc-piperazine (930 mg) and triethylamine (1.0 mL, 7.5 mmol) in 20 mL of CH2Cl2. The resulting reaction mixture was stirred at room temperature for 1 h and washed with brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (CH2Cl2) afforded 310 mg of (E)-tert-butyl 4-(4-methoxy-4-oxobut-2-enoyl)piperazine-1-carboxylate (21% yield).
Reaction SMILES: Cl.Cl.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][N:21]4[CH:25]=[CH:24][N:23]=[N:22]4)[O:17][C:16]3=[O:26])=[CH:11][C:10]=2[F:27])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:35][CH2:36][C:37](Cl)=[O:38]>ClCCl>[Cl:35][CH2:36][C:37]([N:6]1[CH2:5][CH2:4][N:3]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][N:21]4[CH:25]=[CH:24][N:23]=[N:22]4)[O:17][C:16]3=[O:26])=[CH:11][C:10]=2[F:27])[CH2:8][CH2:7]1)=[O:38]
Reactant: O=C(Cl)CCl
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(N2CCNCC2)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)CC1
Reaction time: 0.25 h
Yield: 67.7 %

Procedure:
(5R)-3-(4-(piperazin-1-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one dihydrochloride (4.19 g, 10 mM) was suspended in dry dichloromethane (100 ml) under nitrogen and treated with triethylamine (3.03 g, 30 mM) to give a solution. After cooling to 4°, chloroacetyl chloride (1.14 g, 10 mM) was added and the mixture stirred for 15 minutes. The volume was reduced to 20 ml, and the solution chromatographed on silica, eluting with dichloromethane (30 ml). Relevant fractions were combined, washed with water (50 ml) and dried (magnesium sulfate). Evaporation gave the desired product (2.86 g).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[CH:13]1([CH:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[Cl:25])O)[CH2:15][CH2:14]1.ClC1C=CC(C(C2CC2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[Cl:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[CH:16]([CH:13]1[CH2:14][CH2:15]1)[C:9]1[C:8]2[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=2)[NH:11][CH:10]=1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: OC(c1ccc(F)cc1Cl)C1CC1
Agent: CSCc1cccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Product: CSCc1cccc2c(C(c3ccc(F)cc3Cl)C3CC3)c[nH]c12

Procedure:
The title compound was prepared starting from 500 mg (2.82 mmol) of the compound from Example 8A and 566 mg (2.82 mmol) of the compound from Example 155A in analogy to the synthesis of the compound from Example 227. 394 mg (39% of theory) of the target compound were obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:20][OH:21])[CH:8]=[C:9]([O:16][CH2:17][O:18][CH3:19])[C:10]=1[CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14].C(N(CC)CC)C.[Cl-].[S:30]([O-])(=[O:33])(=[O:32])[CH3:31]>C(Cl)Cl>[CH3:19][O:18][CH2:17][O:16][C:9]1[CH:8]=[C:7]([CH:6]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:10]=1[CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH2:20][O:21][S:30]([CH3:31])(=[O:33])=[O:32]
Reactant: COCOc1cc(CO)cc(OCOC)c1CC=C(C)C
Reactant: CS(=O)(=O)[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOc1cc(COS(C)(=O)=O)cc(OCOC)c1CC=C(C)C
Temperature: 0 °C

Procedure:
[3,5-Bis-methoxymethoxy-4-(3-methyl-but-2-enyl)-phenyl]-methanol (2.0 g, 6.75 mmol) was dissolved in CH2Cl2 and placed in an ice bath. Triethylamine (1.2 ml, 8.92 mmol) was added and stirred until the reaction solution was at 0° C., followed by the dropwise addition of mesylate chloride (900 ul, 8.92 mmol). After stirring in the ice bath for 1 hour, the reaction was quenched with water, extracted with EtOAc, washed with brine, dried with MgSO4, filtered and evaporated yielding methanesulfonic acid 3,5-bis-methoxymethoxy-4-(3-methyl-but-2-enyl)-benzyl ester as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ (ppm): 6.82 (s, 2H), 5.20 (t, 1H), 5.16 (s, 4H), 4.13 (s, 2H), 3.48 (s, 6H), 3.39 (d, 2H) 2.96 (s, 3H), 1.78 (s, 3H), 1.65 (s, 3H). MS (ESI) m/z: 375 (M+H)+, 397 (M+Na)+.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([CH2:15][C@@:16]([OH:45])([C:41]([F:44])([F:43])[F:42])[CH2:17][C:18]([C:21]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:22]=3[C:23]([NH:25][C@H]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)C)=[O:24])([CH3:20])[CH3:19])[NH:12][C:9]2=[CH:10][N:11]=1)(=[O:5])=[O:4])[CH3:2].C1(OC)C=CC=CC=1.OP(O)(O)=O.CO>CCC(C)=O.O>[C:31]1([O:34][CH3:35])[CH:32]=[CH:33][CH:28]=[CH:29][CH:30]=1.[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([CH2:15][C@@:16]([OH:45])([C:41]([F:42])([F:43])[F:44])[CH2:17][C:18]([C:21]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:22]=3[C:23]([NH2:25])=[O:24])([CH3:20])[CH3:19])[NH:12][C:9]2=[CH:10][N:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cc2cc(C[C@](O)(CC(C)(C)c3ccc(F)cc3C(=O)N[C@@H](C)c3ccc(OC)cc3)C(F)(F)F)[nH]c2cn1
Agent: O=P(O)(O)O
Solvent: COc1ccccc1
Solvent: O
Solvent: CCC(C)=O
Product: CCS(=O)(=O)c1cc2cc(C[C@](O)(CC(C)(C)c3ccc(F)cc3C(N)=O)C(F)(F)F)[nH]c2cn1
Reaction time: 1 h
Yield: 92.1 %

Procedure:
2-((R)-4-((5-(ethylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)-5,5,5-trifluoro-4-hydroxy-2-methylpentan-2-yl)-5-fluoro-N—((S)-1-(4-methoxyphenyl)ethyl)benzamide (50.0 g, 93.5 wt. %) and 200 mL of anisole are charged to a reactor and agitation at ˜150 rpm initiated to obtain an off-white slurry. 100 mL of 85% aqueous H3PO4 was added and the reaction mixture heated to 100° C.±5° C. After 1.0 hour, the reaction was checked by HPLC after preparing a sample by adding a ˜0.1 mL reaction mixture aliquot to 10 mL of MeOH. If the area % of 2-((R)-4-((5-(ethylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)-5,5,5-trifluoro-4-hydroxy-2-methylpentan-2-yl)-5-fluoro-N—((S)-1-(4-methoxyphenyl)ethyl)benzamide is <0.5%, proceed; if it is not, age another 30 minutes at 100° C.±5° C. and repeat the HPLC check. The reaction mixture was cooled to 65° C.-70° C. and 200.0 mL of water was added while maintaining the reaction mixture at 65° C.-70° C. A rough slurry was obtained and 150 mL of MEK was added while maintaining the reaction mixture at 65° C.-70° C. The reaction mixture became a smooth slurry, which was held at 65° C.-70° C. for 30 minutes, then ramped to 20° C.-25° C. over no less than 3 hours. The reaction mixture was then held at 20° C.-25° C. for 3 to 4 hours. The solid was filtered, washed with 150 mL of water and then 150 mL of a mixture of MEK/heptane (1:2 v/v), and transferred to a vacuum oven and dried at 65° C.-70° C. with a nitrogen sweep until KF<0.5%. (R)-2-(4-((5-(Ethylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)-5,5,5-trifluoro-4-hydroxy-2-methylpentan-2-yl)-5-fluorobenzamide anisole solvate was obtained as a white-yellow solid (44.1 g, 92.1% yield, HPLC: 98.0 area % (220 nm)).
Reaction SMILES: [CH3:1][N:2]1[C:8](=O)[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:4]2[CH2:3]1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:31]2)=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:8](=[S:31])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:4]2[CH2:3]1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncn2c1CN(C)C(=S)c1ccccc1-2

Procedure:
670 mg (2.3 mmol) of ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate and 497 mg (1.23 mmol) of 2,4-bis(p-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulphide are heated to boiling under reflux for 2.5 hours in 5 ml of absolute toluene. The mixture is chromatographed on silica gel with ethyl acetate and there is obtained ethyl 5,6-dihydro-5-methyl-6-thioxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 164°-165° C.
Reaction SMILES: [F:1][C:2]([F:19])([CH:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(OCC)(=O)C.O.COCCN(S(F)(F)[F:37])CCOC>C(Cl)Cl>[F:1][C:2]([F:19])([CH:8]([F:37])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CCOC(=O)C(F)(F)C(O)c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(F)(F)C(F)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 2,2-difluoro-3-hydroxy-3-(3-nitrophenyl)propanoate (C29, 1.02 g) in methylene chloride (22 mL), bis(2-methoxyethyl)aminosulfur trifluoride (1.6 mL) was added under ice cooling, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture, ethyl acetate and water were added. The organic layer was separated, washed successively with 1.0 mol/L aqueous hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain ethyl 2,2,3-trifluoro-3-(3-nitrophenyl)propanoate (C30, 1.19 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.CON(C)[C:32]([C@@H:34]1[CH2:39][CH2:38][CH2:37][N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35]1)=[O:33]>C1COCC1>[CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=1[C:32]([C@@H:34]1[CH2:39][CH2:38][CH2:37][N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35]1)=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc(F)c(OCc2ccccc2)c(Br)c1
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cc(F)cc(F)c2OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
To a solution of 2-(benzyloxy)-1-bromo-3,5-difluorobenzene (13.7 g, 46 mmol) in anhydrous THF (100 mL) at −78° C. under nitrogen was added dropwise a solution of 2.5 M n-BuLi in hexane (18.4 mL, 46 mmol). After stirring for 1 hr at −78° C., a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (10.43 g, 38.3 mmol) in anhydrous THF (40 mL) was added dropwise. After addition, the reaction mixture was allowed to warm to rt and stirred for 2 h. The mixture was quenched with saturated NH4Cl solution (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with AcOEt/hexane (1:20→1:10) to provide (R)-tert-butyl 3-(2-(benzyloxy)-3,5-difluorobenzoyl)piperidine-1-carboxylate (6.4 g, 32%) as a light yellow oil.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[CH2:14]([O:17][CH3:18])[C:15]#[CH:16].CCCCCC>COCCOC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[C:16]#[C:15][CH2:14][O:17][CH3:18]
Reactant: C#CCOC
Reactant: Brc1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: COCCOC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCC#Cc1nccs1
Temperature: 55 °C
Yield: 13.6 %

Procedure:
2-Bromo-1,3-thiazole (2.0 g, 12 mmol) and CuI (456 mg, 2.4 mmol) were combined in DME (30 mL) and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamine (8.6 mL, 60 mmol) and PdCl2(PPh3)2 (842 mg, 1.2 mmol) were added and methyl propargyl ether (1.00 g, 14.4 mmol) was added dropwise. The reaction was stirred at 55° C. under a condenser. After stirring at 55° C. for 16 h, GC/MS analysis indicated that the reaction was complete. The mixture was filtered through Celite.™., and the filter pad was washed thoroughly with ethyl acetate. The combined filtrates were concentrated in vacuo and the residue was dissolved in ethyl acetate (300 mL), washed with water (300 mL), brine (300 mL), dried over Na2SO4 filtered, and concentrated in vacuo. The residue was purified by column chromatography eluting with hexane, 99:1, 97:3, then 96:4 hexane:ethyl acetate to afford methyl 3-(1,3-thiazol-2-yl)-2-pr-opynyl ether (250 mg, 13% yield) as a yellow oil. 1H NMR (CDCl3, 300 MHz) Δ7.78 (d, J=3.0 Hz, 1H), 7.37 (d, J=3.0 Hz, 1H), 4.37 (s, 2H), 3.47 (s, 3H). MS (ESI) 154.1 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11](NC(C3CC3)=O)[CH:10]=2)[C:5](=[O:21])[N:4]2[C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29](F)C=3)(C)[NH:23][C:24](=[O:25])[C:3]=12.I[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>CN(C)C=O.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][N:14]=2)[C:5](=[O:21])[N:4]2[C:22]3([CH2:29][CH2:30][CH2:31][CH2:32][CH2:27]3)[N:23]([C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[C:24](=[O:25])[C:3]=12
Reactant: Ic1cccnc1
Reactant: CC1(c2cccc(F)c2)NC(=O)c2c(Cl)cc(Nc3cc(NC(=O)C4CC4)ncn3)c(=O)n21
Agent: [Cu]I
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=C1c2c(Cl)cc(Nc3ccncn3)c(=O)n2C2(CCCCC2)N1c1cccnc1
Temperature: 130 °C

Procedure:
To a solution of 8′-chloro-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (1, 450 mg, 1.3 mmol) and 3-iodopyridine (800 mg, 3.9 mmol) in dimethylformamide (10 mL) in a vial, cesium carbonate (550 mg, 1.6 mmol) was added and the mixture was degassed with argon for 15 min. To this mixture 1,10,-phenanthroline (37 mg, 0.2 mmol), copper(I) iodide (12 mg, 0.05 mmol), XantPhos (26 mg, 0.065 mmol) were added and the reaction was heated the mixture at 130° C. for 26 h. TLC showed consumption of starting material, the reaction mixture was filtered over celite bed and washed with 5% methanol in dichloromethane followed by concentration of the filtrate. Obtained solid was purified by Combi-Flash chromatography on neutral alumina using 3% methanol/dichloromethane as a eluent, appropriate fractions were concentrated under reduced pressure to afford 8′-chloro-2′-(pyridin-3-yl)-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (Cpd. No. 136) as yellow solid. Yield: 0.025 g, 4.6%; MS (ESI) m/z 423.12 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 8.61 (d, J=2.0 Hz, 1H), 8.58 (s, 1H), 8.49 (d, J=4.8 Hz, 1H), 8.33 (d, J=6.0 Hz, 1H), 8.03 (s, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.47 (dd, J=4.4, 8.8 Hz, 1H), 6.65 (d, J=6.0 Hz, 1H), 2.85-2.79 (m, 2H), 1.74-1.53 (m, 6H), 1.17-1.14 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CO.C(O)(=O)C.[Br:19]Br>>[Br:19][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[CH3:1])[N:9]=[CH:8][NH:7][C:6]2=[O:12]
Reactant: BrBr
Reactant: Cc1ccc2c(=O)[nH]cnc2c1
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc2nc[nH]c(=O)c2cc1Br
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.3 %

Procedure:
7-methylquinazolin-4(3H)-one (14.56 g, 91 mmol) was added to methanol (70 ml, 91 mmol) and glacial acetic acid (70 ml, 1212 mmol). The mixture was stirred at RT for 5 min followed by the slow addition of bromine (9.3 mL, 182 mmol). The reaction was stirred at RT for 3 h. Volatiles were evaporated under reduced pressure and the resulting crude residue washed with aqueous sodium thiosulfate to remove excess bromine and HBr, then oven dried to give 6-bromo-7-methylquinazolin-4(3H)-one (18.35 g, 84% yield) as light yellow amorphous solid. MS (ESI, pos. ion) m/z: 239 [M+H]+
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].[Br:12][C:13]1[N:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[S:21](Cl)(=[O:23])=[O:22])=[CH:15][CH:14]=1>>[Br:12][C:13]1[N:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[S:21]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH2:11])(=[O:9])=[O:10])(=[O:23])=[O:22])=[CH:15][CH:14]=1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Br)nc1
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)/C=C/c1ccc(Br)nc1
Yield: 69 %

Procedure:
The title compound was synthesized as described for Example 178 in 69% yield, starting from 2-aminobenzenesulfonamide and (E)-2-(6-bromopyridin-3-yl)ethenesulfonyl chloride. Purification by column chromatography, using ammonium hydroxide/methanol/chloroform (1:10:89) as the eluent.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([N+]([O-])=O)[CH:11]=1>C(O)C>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[C:14]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH3:8])[CH:15]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: Cc1ccccc1N
Solvent: CCO
Product: Cc1ccccc1Nc1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
81 ml of o-toluidine was added to a solution of 10 g of 1-chloro-3,4-dinitrobenzene in 50 ml of ethanol, and it was refluxed for 72 hours. It was concentrated by evaporation in a vacuum, the residue was taken up in ethyl acetate and 2N aqueous hydrochloric acid. The organic phase was extracted three more times with 2N aqueous hydrochloric acid, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by chromatography on silica gel.