Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[O:28])[N:22]=1>C1(C)C=CC=CC=1.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>[CH:27]([C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[N:22]=1)=[O:28]
Reactant: OB(O)c1cccc2ccccc12
Reactant: O=Cc1cccc(Br)n1
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: [Na+]
Solvent: Cc1ccccc1
Product: O=Cc1cccc(-c2cccc3ccccc23)n1
Temperature: 70 °C
Yield: 87 %

Procedure:
Inside of a dry box, naphthylboronic acid (9.12 g, 53.0 mmol) and Na2CO3 (11.64 g, 110 mmol) are dissolved in 290 mL of degassed 4:1 H2O/MeOH. This solution is added to a solution of 8 g (43 mmol) of 2-bromo-6-formylpyridine and 810 mg (0.7 mmol) of Pd(PPh3)4 in 290 mL of degassed toluene. The charged reactor is removed from the dry box, while under a blanket of N2 and is connected to the house N2 line. The biphasic solution is vigorously stirred and heated to 70° C. for 4 h. On cooling to RT, the organic phase is separated. The aqueous layer is washed with 3×75 mL of Et2O. The combined organic extracts are washed with 3×100 mL of H2O and 1×100 mL of brine and dried over Na2SO4. After removing the volatiles in vacuo, the resultant light yellow oil is purified via trituration with hexanes. The isolated material is recrystallized from a hot hexane solution and ultimately yielded 8.75 g, 87% yield. mp 65-66° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: BrCCCCBr
Product: N#Cc1ccc2c(ccn2CCCCBr)c1

Procedure:
The procedure is as for Example 39 using as substrate 1H-indole-5-carbonitrile and 1,4-dibromobutane.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16](F)=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH2:24]([OH:26])[CH3:25]>>[CH2:24]([O:26][C:16]1[CH:15]=[C:14]2[C:19]([C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[CH:2])[CH:4]=3)=[N:11][CH:12]=[N:13]2)=[CH:18][C:17]=1[N+:20]([O-:22])=[O:21])[CH3:25]
Reactant: C#Cc1cccc(Nc2ncnc3cc(F)c([N+](=O)[O-])cc23)c1
Reactant: CCO
Product: C#Cc1cccc(Nc2ncnc3cc(OCC)c([N+](=O)[O-])cc23)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 93.4 %

Procedure:
Na (1.4 g, 0.060 mol) was carefully dissolved in 80 ml of anhydrous ethanol to form a clear solution, then N-(3-ethynylphenyl)-7-fluoro-6-nitroquinazolin-4-amine (8 g, 0.025 mol) was added and stirred for 4 hours at 80° C. The solution was concentrated under reduced pressure to remove excess ethanol, and 50 ml H2O was added. The resulting solid precipitate was filtered and dried under vacuum to get 7-ethoxy-N-(3-ethynylphenyl)-6-nitroquinazolin-4-amine as yellow solid 8.1 g (93.4% yield).
Reaction SMILES: O.NN.[C:4]([C:8]1[CH:35]=[CH:34][C:11]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=4)=[CH:19][CH:20]=3)[C:15]([C:29](=O)[C:30]([OH:32])=[O:31])=[CH:14]2)=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5].C[O-].[Na+]>COCCO>[C:4]([C:8]1[CH:35]=[CH:34][C:11]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=4)=[CH:19][CH:20]=3)[C:15]([CH2:29][C:30]([OH:32])=[O:31])=[CH:14]2)=[CH:10][CH:9]=1)([CH3:7])([CH3:5])[CH3:6]
Reactant: Cc1cccc(-c2ccc3c(c2)c(C(=O)C(=O)O)cn3Cc2ccc(C(C)(C)C)cc2)c1
Agent: C[O-]
Agent: NN
Agent: [Na+]
Solvent: O
Solvent: COCCO
Product: Cc1cccc(-c2ccc3c(c2)c(CC(=O)O)cn3Cc2ccc(C(C)(C)C)cc2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
Hydrazine monohydrate (0.56 mL, 11.75 mmol) was added to a stirring solution of 2-[1-[4-(tert-Butyl)benzyl]-5-(3-methylphenyl)-1H-indol-3-yl]-2-oxoacetic acid (WAY-201417, 1.0 g, 2.35 mmol) in 2-methoxyethanol (10 mL). After the mixture was heated to 60° C. Sodium methoxide (1.34 g, 23.5 mmol) was added portionwise to the mixture. The reaction mixture was then slowly heated to 150° C., and concentrated. The mixture was kept stirring at 150° C. for 1 hour. The reaction mixture was cooled and poured onto ice water (100 mL). The aqueous mixture was extracted with methylene chloride and acidified with concentrated hydrocloric acid at 0° C. The organic extracts were washed with water and brine. Evaporation of the solvent and purification by flash column chromatography (5% methanol in methylene chloride) afforded an orange solid (0.452 g), m.p. 91-92° C. Mass spectrum [+ESI, (M+H)+] m/z 412. 1H NMR (400 MHz, DMSO-d6) δ 12.00 (br s, 1H), 7.75 (s, 1H), 7.51 (d, 1H, J=8.55 Hz), 7.45 (s, 1H), 7.42-7.37 (m, 3H), 7.32-7.29 (m, 3H), 7.15 (d, 2H, J=8.25 Hz), 7.19 (d, 1H, J=7.48 Hz), 5.34 (s, 2H), 3.70 (s, 2H), 2.37 (s, 3H), and 1.22 ppm (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([N:22]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[S:23]([CH3:26])(=[O:25])=[O:24])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([CH2:11][CH3:12])[C:9]#[CH:10])=[CH:4][CH:3]=1.[Li]CCCC.[C:40](Cl)(=[O:43])[O:41][CH3:42]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:13]2[C:21]3[C:16](=[C:17]([N:22]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[S:23]([CH3:26])(=[O:25])=[O:24])[CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([CH2:11][CH3:12])[C:9]#[C:10][C:40]([O:41][CH3:42])=[O:43])=[CH:4][CH:3]=1
Reactant: COC(=O)Cl
Reactant: C#CC(CC)(c1ccc(Cl)cc1)n1ccc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(C#CC(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Reaction time: 0.5 h

Procedure:
To a solution of compound N-(1-(3-(4-chlorophenyl)pent-1-yn-3-yl)-1H-indol-4-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)methanesulfonamide (2.9 g, 5.6 mmol, enantiomer A), as described in Example 55 Step A, in dry THF (10 mL) was added BuLi (4.5 mL, 11.2 mmol, 2.5 M in hexane) at −78° C. After stirring for 30 min, methyl carbonchloridate (0.88 mL, 6.2 mmol) was added to the mixture at −78° C. The resulting mixture was stirred for another 2 h and then quenched with saturated NH4Cl (10 mL), extracted with ethyl acetate, washed with brine (50 mL), dried over sodium sulfate, then filtered. After removing the organic solvent, the residue was purified by column chromatography (EA/PE=1:10) to obtain the title compound. LC/MS m/z=597.0 [M+Na]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)=[O:19])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:34][C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:36]>CN(C=O)C>[CH:27]1[C:28]2[C:23](=[CH:22][C:21]([NH:20][C:18](=[O:19])[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([O:1][CH2:34][C:35](=[O:36])[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:3][CH:4]=3)[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[CH:30][CH:29]=2)[CH:24]=[CH:25][N:26]=1
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(O)cc1
Reactant: O=C(CBr)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(OCC(=O)c2ccccc2)cc1
Temperature: -35 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl 2-(4-hydroxyphenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E249) in DMF cooled to −35° C. was added NaH and the solution was stirred at −35° C. for 30 min. Then, 2-bromoacetophenone was added and the solution was warmed and stirred at 0° C. for 2 h. The solution was poured into NaHCO3(sat)/EtOAc and further extracted with EtOAc. The combined organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 3% MeOH/CH2Cl2) gave tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(4-(2-oxo-2-phenylethoxy)phenyl)propylcarbamate (E275).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:7][N:8]1[C:13](=O)[NH:12][C:11]([CH2:15][CH3:16])=[N:10][S:9]1(=[O:18])=[O:17].P(Cl)(Cl)([Cl:21])=O>ClCCCl>[Cl:21][C:13]1[N:8]([CH3:7])[S:9](=[O:18])(=[O:17])[N:10]=[C:11]([CH2:15][CH3:16])[N:12]=1
Reactant: CCC1=NS(=O)(=O)N(C)C(=O)N1
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCC1=NS(=O)(=O)N(C)C(Cl)=N1

Procedure:
110 parts of phosphorus pentachloride were added to a stirred mixture of 86 parts of 2-methyl-5-ethyl-2H-1,2,4,6-thiatriazine-3-one-1,1-dioxide, 100 parts of 1,2-dichloroethane and 112 parts of phosphorus oxychloride at room temperature. The reaction mixture was then stirred under reflux for 12 hours. After concentration, 94 parts (100% of theory) of 3-chloro-2-methyl-5-ethyl-2H-1,2,4,6-thiatriazine-1,1-dioxide of nD25 =1.5331 were obtained. (NMR (60 MHz, CDCl3): CH3 -N 3.7δ). The very pure product (nD25 =1.5337) boils at 123°-125° C./0.2 mbar (Compound No. 3).
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[C:47](Cl)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.O>N1C=CC=CC=1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:54])[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.200 g, 0.33 mmol) in pyridine (2 mL) was added benzoyl chloride (0.046 mL, 0.40 mmol). The reaction was stirred at room temperature for 15 h. Water (10 mL) was added and the solid collected by suction filtration. The solid was dried in a vacuum oven for 3 h. The residue was dissolved in 4 N hydrochloric acid in 1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. After neutralization with aqueous sodium bicarbonate, the reaction mixture was extracted with ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and evaporated. Addition of dichloromethane (10 mL) to the residue gave a solid which was isolated by filtration. (0.069 g, 55% yield): 1H NMR (DMSO-d6) δ 14.10 (br s, 1H), 13.44 (br s, 1H), 10.50 (s, 1H), 8.74 (s, 1H), 8.48 (s, 1H), 8.03 (td, 4H), 7.74 (m, 2H), 7.58 (m, 4H); ES-MS (m/z) 381 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH2:11]Cl)=[C:9]([CH3:13])[C:6]([O:7][CH3:8])=[C:5]([CH3:14])[C:4]=1[CH3:15].[Mg].[CH2:17](Br)[C:18]#[CH:19]>C1COCC1.CCOCC.[I-].[Na+]>[CH2:11]([C:10]1[C:3]([O:2][CH3:1])=[C:4]([CH3:15])[C:5]([CH3:14])=[C:6]([O:7][CH3:8])[C:9]=1[CH3:13])[CH2:19][C:18]#[CH:17]
Reactant: C#CCBr
Reactant: COc1c(C)c(C)c(OC)c(CCl)c1C
Agent: [I-]
Agent: [Mg]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CCCc1c(C)c(OC)c(C)c(C)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
A solution of chloromethyltrimethylhydroquinone dimethyl ether (7.5 g; 32 mmol) in THF (20 ml) was treated dropwise at 0° with a freshly Prepared solution of a Grignard reagent Prepared from 1.9 g of magnesium shavings and 4.91 ml (65 mmol) of propargyl bromide. After the addition of solid sodium iodide (0.42 g) the mixture was warmed to room temperature and stirred overnight. Thereafter, the reaction mixture was diluted with ether and washed with 2N hydrochloric acid. The ethereal solution was deacidified with bicarbonate, dried and freed from solvent. Distillation (0.04 mbar; 140° C.) of the residue gave 7.16 g of 1-(3-butynyl)-3,6-dimethoxy-2,4,5-trimethylbenzene; melting point: 54° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:22][C:11]2[CH2:12][CH2:13][C:14]3[CH:15]=[N:16][C:17]([S:20][CH3:21])=[N:18][C:19]=3[C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1.CC(C)=O>[C:1]([O:5][C:6]([C:8]1[S:22][C:11]2=[CH:12][CH:13]=[C:14]3[C:19]([N:18]=[C:17]([S:20][CH3:21])[N:16]=[CH:15]3)=[C:10]2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2c(n1)-c1cc(C(=O)OC(C)(C)C)sc1CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: CSc1ncc2ccc3sc(C(=O)OC(C)(C)C)cc3c2n1
Temperature: 25 °C
Yield: 72.7 %

Procedure:
2-Methylsulfanyl-5,6-dihydro-thieno[2,3-h]quinazoline-8-carboxylic acid tert-butyl ester (9.0 g, 26.91 mmol) and DDQ (12.22 g, 53.82 mmol) were suspended/dissolved in dry dioxane (100 mL) and heated at reflux for 1 hour. Further DDQ (12.22 g, 53.82 mmol) was added and the resulting suspension was heated at reflux for 1.5 hours. After cooling to room temperature the mixture was concentrated under reduced pressure and then partitioned between EtOAc and saturated Na2CO3. The aqueous layer was further extracted with EtOAc (3×200 mL) and the combined organics were washed with saturated Na2CO3 (2×250 mL) and brine (1×200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The deep brown gum obtained was redissolved in hot acetone, silica (˜60 mL) was added and the resultant suspension was concentrated under reduced pressure. The solid obtained was subjected to column chromatography (gradient elution, 20-30% acetone in hexanes, ˜600 mL silica) giving a light brown solid (6.50 g, 73% yield).). MS (ES+) 333. δH (CDCl3) 1.7 (9H, s), 2.8 (3H, s), 7.8 (1H, d), 7.9 (1H, d), 8.8 (1H, s), 9.2 (1H, s)
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([N:11]=[C:12]=[O:13])=[N:8][C:7]=2[CH:14]=1.[Br:17][CH2:18][CH2:19][NH:20][CH2:21][CH:22]=[O:23]>C1C=CC=CC=1>[Br:17][CH2:18][CH2:19][N:20]([CH2:21][CH:22]=[O:23])[C:12]([NH:11][C:9]1[S:10][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:14][C:7]=2[N:8]=1)=[O:13]
Reactant: O=CCNCCBr
Reactant: O=C=Nc1nc2cc(C(F)(F)F)ccc2s1
Solvent: c1ccccc1
Product: O=CCN(CCBr)C(=O)Nc1nc2cc(C(F)(F)F)ccc2s1
Reaction time: 1 h

Procedure:
5-Trifluoromethylbenzothiazol-2-yl isocyanate dimer (0.1 mole), the dimethyl acetal of 2-β-bromoethylaminoacetaldehyde (0.2 mole) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at ambient temperatures for a period of about one hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent to yield the desired product the dimethyl acetal of 2-[1-β-bromoethyl-3-(5-trifluoromethylbenzothiazol-2-yl)-ureido]acetaldehyde as the residue.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[Cl:8][C:9]1[N:13]2[C:14]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:38])=[C:24]([CH:37]=3)[C:25]([N:27]3[CH2:33][CH2:32][CH2:31][N:30]([CH2:34][CH2:35][NH3+:36])[CH2:29][CH2:28]3)=[O:26])=[CH:15][NH:16][C:17](=[O:18])[C:12]2=[CH:11][C:10]=1[Cl:39].[CH3:40][C:41](OC(C)=O)=[O:42]>N1C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[C:41]([NH:36][CH2:35][CH2:34][NH+:30]1[CH2:31][CH2:32][CH2:33][N:27]([C:25](=[O:26])[C:24]2[CH:37]=[C:20]([CH2:19][C:14]3[N:13]4[C:9]([Cl:8])=[C:10]([Cl:39])[CH:11]=[C:12]4[C:17](=[O:18])[NH:16][CH:15]=3)[CH:21]=[CH:22][C:23]=2[F:38])[CH2:28][CH2:29]1)(=[O:42])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: [NH3+]CCN1CCCN(C(=O)c2cc(Cc3c[nH]c(=O)c4cc(Cl)c(Cl)n34)ccc2F)CC1
Agent: O=C([O-])C(F)(F)F
Solvent: c1ccncc1
Product: CC(=O)NCC[NH+]1CCCN(C(=O)c2cc(Cc3c[nH]c(=O)c4cc(Cl)c(Cl)n34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 20, T1 in pyridine (0.15 M) was added Ac2O (1 eq) and the resulting mixture stirred overnight at RT. The solvent was evaporated under reduced pressure and the residue was purified at the prep RP-HPLC using H2O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18 column), the desired fractions were lyophilized to afford the titled compound as yellow powder. 1H NMR (300 MHz, DMSO-d6) δ: 10.97 (1H, d, J=5.6 Hz), 9.51 (1H, br. S), 8.22-8.16 (1H, m), 7.37-7.26 (3H, m), 7.20 (1H, s), 6.66-6.61 (1H, m), 4.42 (2H, s), 4.10 (1H, m), 3.63-3.14 (11H, m), 2.11 (1H, m), 1.95-1.88 (4H, m). MS (ES) C24H26Cl2FN5O3 required: 521, found: 522 (M+H)+.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C)C(=O)C>[CH3:29][N:15]([CH2:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([CH2:7][O:6][CH2:5]/[CH:4]=[CH:3]/[CH2:2][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:9][CH2:10]1)[S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: CN(C[C@H]1CC[C@H](COC/C=C/CBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: C1CCNC1
Solvent: CC(=O)N(C)C
Product: CN(C[C@H]1CC[C@H](COC/C=C/CN2CCCC2)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with pyrrolidine in N,N-dimethylacetamide at room temperature to yield trans-N-methyl-N-[4-(4-pyrrolidin-1-yl-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfonamide as light yellow solid, MS: 489 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl[C:23]([O:25][CH:26]1[CH:33]2[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:35][CH:27]1[CH2:28]3)[CH2:32]2)=[O:24]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:10][CH2:11][N:12]([C:23]([O:25][CH:26]3[CH:27]4[CH2:35][CH:31]5[CH2:30][CH:29]([CH2:34][CH:33]3[CH2:32]5)[CH2:28]4)=[O:24])[CH2:13][CH2:14]1)[CH2:8][CH:7]2[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CC1CC2(CCNCC2)c2c(Br)cccc21
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Solvent: ClCCl
Product: CCOC(=O)CC1CC2(CCN(C(=O)OC3C4CC5CC(C4)CC3C5)CC2)c2c(Br)cccc21
Reaction time: 1 h
Yield: 39.2 %

Procedure:
A 100-mL flask was charged with (±)-ethyl 2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate (457 mg, 1.3 mmol) dissolved in dry CH2Cl2 (10 mL). TEA (394 mg, 3.9 mmol) was added at 0° C. and stirred for 1 h. 2-adamantyl chloroformate (301 mg, 1.4 mmol) was added and the mixture was stirred overnight. The mixture was concentrated to give a residue was purified by column chromatography to give (±)-(2-adamantyl) 7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (270 mg, 39%). The enantiomers were separated by chiral HPLC to give isomer 1 (100 mg, 14%) and isomer 2 (100 mg, 14%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CC(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:20]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)c1cn(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(Cl)cc2)n1

Procedure:
A mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, step 1) (12.1 g, 39.2 mmol), sodium bicarbonate (6.58 g, 78.3 mmol), and 90% ethyl bromopyruvate (16.9 g) in 480 ml of 2-propanol was stirred at reflux overnight. After cooling, the mixture was concentrated. The residue was partitioned between dichloromethane and water and the aqueous layer further extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. Trituration of the residue with ethyl acetate gave the title compound as a pale beige, crystalline solid (6.61 g): mp (DSC) 218° C. Anal. Calc'd. for C19H17ClN2O4S (MW 404.87): C, 56.37; H, 4.23; N, 6.92. Found: C, 56.28;.H, 4.13; N, 6.80.
Reaction SMILES: O.[NH2:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1.[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14])([O-:10])=[O:9]>O>[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1)=[O:14])([O-:10])=[O:9]
Reactant: Nc1nnn[nH]1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: O
Product: O=C(Nc1nnn[nH]1)c1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of 10.3 g of 5-aminotetrazole monohydrate in 300 ml of tetahydrofuran and 15 ml of water was added 9.3 g of 2-nitrobenzoyl chloride. The solution was allowed to stand for 30 minutes before it was diluted with 200 ml of water and stored in a refrigerator for 72 hours. The solid which formed was separated by filtration to give 2-nitro-N-(1H-tetrazol-5-yl)benzamide melting at about 272°-273° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22])(=[O:11])=[O:10].[CH2:23](O)[CH2:24][CH2:25][OH:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]12[O:26][CH2:25][CH2:24][CH2:23][O:22]1)(=[O:11])=[O:10]
Reactant: OCCCO
Reactant: COC[C@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COC[C@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C(=O)N2
Temperature: 25 °C
Yield: 27 %

Procedure:
To a rapidly and efficiently stirred mixture of 5-{[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonyl}-1H-indole-2,3-dione (4.21 g, 13.0 mmol) in benzene (300 mL), was added 1,3-propanediol (3.81 mL, 52 mmol, 4 eq) and p-toluenesulfonic acid (0.989 g, 5.2 mmol, 0.4 mole % ) and the reaction was refluxed with a Dean Stark Trap for 4.5 hours under a dry N2 atmosphere. After cooling to room temperature the reaction was washed with sat. aq. NaHCO3 (3×), water (3×), brine (3×), dried over MgSO4, and concentrated. The crude product was purified on Biotage KP silica gel eluting with 50/50 Pet ether/EtOAc to give the title compound as a white solid (1.34 g, 27% yield). NMR (400 MHz, DMSO-d6): consistent; MS: (API-ES−) m/z 381 [M−H]. MS: (API+ES+) m/z 383 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])=[N:6][CH:7]=1.Br[C:26]1C=NC=CC=1C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[CH3:26])=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])=[N:6][CH:7]=1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccc(F)cn2)n1
Reactant: Cc1ccncc1Br
Product: Cc1ccc(Nc2cnccc2C)c(C(=O)Nc2ccc(F)cn2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-pyridin-2-yl)-amide (example 8) in accordance with the general method of example 5, step 6 using 3-Bromo-4-methylpyridine instead of 3-Bromopyridine to yield the final compound as a light yellow crystalline solid, MS (ISP): m/e=338.3 (M+H+).