Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([O:19][CH3:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17]Br)=[CH:9][CH:8]=1)C.C([C:29]1[CH:34]=[C:33]([OH:35])[CH:32]=[CH:31][C:30]=1[C:36]([C:38]1C=CC(O)=CC=1CC1C=CC=CC=1)=[O:37])C1C=CC=CC=1>>[CH3:20][O:19][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][O:35][C:33]2[CH:34]=[CH:29][C:30]([C:36](=[O:37])[CH2:38][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:31][CH:32]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:21]
Reactant: O=C(c1ccc(O)cc1Cc1ccccc1)c1ccc(O)cc1Cc1ccccc1
Reactant: CCOC(=O)C(Cc1ccc(C#CCCCBr)cc1)OC
Product: CO[C@@H](Cc1ccc(C#CCCCOc2ccc(C(=O)Cc3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from 3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 24, Step A and benzyl-4-hydroxyphenylketone in a manner analogous to that described for Example 24, Step B. MS(ES) for C29H25O5[M−H]−:455.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([OH:21])=O)[C:4]=12.[Br:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][N:28]([C:19](=[O:21])[C:18]([C:17]1[C:4]3[C:5](=[C:6]([N:9]4[CH:13]=[N:12][C:11]([CH3:14])=[N:10]4)[N:7]=[CH:8][C:3]=3[O:2][CH3:1])[NH:15][CH:16]=1)=[O:22])[CH2:29]2
Reactant: Brc1cccc2c1CCNC2
Reactant: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)O)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)N3CCc4c(Br)cccc4C3)c12
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A 20 mL vial was charged with 2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (0.1 g, 0.332 mmol), 5-bromo-1,2,3,4-tetrahydroisoquinoline (0.083 g, 0.332 mmol), o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.133 g, 0.415 mmol), Hunig's Base (0.580 mL, 3.32 mmol), and DMF (3 mL). The vial was sealed and stirred at rt. After stirring the mixture for 70.5 h, the reaction was quenched with water. The solids that formed were collected by filtration. The mother liquor was concentrated under reduced pressure, and a second batch of solids was collected by recrystallizing from MeOH and water. The expected product, 1-(5-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (0.145 g, 0.293 mmol, 88% yield), was isolated as an off-white solid. LC/MS: m/z 495 (M+H)+, 497.02 (M+3H)+1.935 min (method 1). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.42 (s, 1H) 9.22-9.27 (m, 1H) 8.18-8.31 (m, 1H) 7.84 (s, 1H) 7.09-7.59 (m, 3H) 4.59-4.87 (m, 2H) 3.67-3.95 (m, 5H) 2.73-2.96 (m, 2H) 2.47-2.52 (m, 3H).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]([OH:18])[CH3:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[N:37]([C:38]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:36]=[N:35][N:34]=2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([C:5]1[N:14]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:37]([C:38]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:36]=[N:35][N:34]=3)=[CH:25][CH:26]=2)[C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:16]([OH:18])[CH3:17])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(C(C)O)ccc2[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCc1nc2ccc(C(C)O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
A suspension of 2.50 g of 2-butyl-6-(1-hydroxyethyl)-4(1H)-quinazolinone, 6.79 g of 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-1-(triphenylmethyl)-1H-tetrazole and 4.20 g of anhydrous potassium carbonate in 225 ml of dry acetone is heated at reflux for 16 hours. The reaction mixture is allowed to cool to room temperature, filtered and the filtrate evaporated in vacuo. The residue is purified by high pressure liquid chromatography on silica gel by eluting with 1:2 ethyl acetate-hexanes to afford 4.25 g of the desired product as a white solid, FAB M+H 723.
Reaction SMILES: [CH2:1]([O:8][N:9]=[CH:10][C:11]1([C:19]([OH:21])=[O:20])[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C.Cl.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:8][NH:9][CH2:10][C:11]1([C:19]([OH:21])=[O:20])[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CCC(C=NOCc2ccccc2)(C(=O)O)CC1
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CC1(C)CCC(CNOCc2ccccc2)(C(=O)O)CC1
Temperature: 0 °C

Procedure:
A solution of 1-(benzyloxyimino-methyl)-4,4-dimethyl-cyclohexanecarboxylic acid (1.47 g, 5.11 mmol) in methanol (100 mL) at 0° C. under a nitrogen atmosphere was added a trace amount of methyl orange. A solution of saturated methanolic HCl was added until a persistent red color was observed. Sodium cyanoborohydride (0.42 g, 6.68 mmol) was added portionwise alternately with methanolic HCl to maintain the red color. The reaction mixture was maintained at 0° C. for an additional 2 h and the volatiles were removed in vacuo. The product was used without further purification. MH+292.
Reaction SMILES: N([O-])=O.[Na+].S(=O)(=O)(O)O.N[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([C:21]([OH:23])=[O:22])[CH:15]=[CH:14]2.O.[ClH:25]>C(O)(=O)C.[Cu]Cl>[Cl:25][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([C:21]([OH:23])=[O:22])[CH:15]=[CH:14]2
Reactant: Cl
Reactant: Nc1ccc2cc(C(=O)O)ccc2c1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc2cc(Cl)ccc2c1
Temperature: 70 °C

Procedure:
Sodium nitrite (811 mg, 11.8 mmol) is added over a period of 15 minutes to concentrated sulfuric acid (10 mL) while stirring. The mixture is heated to 70° C. for 15 minutes. After cooling to room temperature, a solution of 6-amino-2-naphthoic acid (2 g, 10.7 mmol) in acetic acid (10 mL) is added dropwise at such a rate that the temperature is kept below 40° C. After stirring at 40° C. for an additional 30 minutes, the reaction mixture is poured into an ice-cooled solution of copper(I) chloride (2.54 g, 25.6 mmol) in concentrated HCl (30 mL). After stirring at 80° C. for 30 minutes, water (80 mL) is added. The precipitate is collected and purified by flash chromatography on silica gel (5% methanol in dichloromethane) to give 6-chloro-2-naphthoic acid as a brown solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][OH:13]>>[OH:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: O=C1CCNCC1
Reactant: OCCCCCl
Product: O=C1CCN(CCCCO)CC1

Procedure:
1-(4-Hydroxybutyl)-4-piperidone is prepared from 4-piperidone and 4-chloro-1-butanol essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][CH2:5][OH:6].CN(C)C=[N:10][S:11]([C:14]1[CH:19]=[CH:18][C:17](F)=[C:16]([F:21])[CH:15]=1)(=[O:13])=[O:12]>CN(C=O)C>[OH:6][CH2:5][CH2:4][S:3][C:17]1[CH:18]=[CH:19][C:14]([S:11]([NH2:10])(=[O:13])=[O:12])=[CH:15][C:16]=1[F:21]
Reactant: OCCS
Reactant: CN(C)C=NS(=O)(=O)c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(SCCO)c(F)c1
Temperature: 80 °C

Procedure:
Sodium hydride (1.11 g, 50% oil dispersion, 0.023 mol) was washed with petroleum ether then suspended in freshly degassed DMF (50 ml). 2-Mercaptoethanol (1.8 g, 0.023 mol) was added dropwise under nitrogen. When gas evolution ceased, N,N-Dimethyl-N'-(3,4-difluorobenzenesulfonyl)formamidine (5 g, 0.02 mol) was added and the mixture was heated in an oil bath about 2 hours (80° C.). DMF was removed in vacuo and the residue was treated with 100 ml of 10% NaOH. After an additional hour of stirring the solution was acidified with concentrated HCl and extracted with ethylacetate (2×100 ml), and dried over anhydrous magnesium sulfate. Removal of solvent left 3 g of a white solid which when recrystallized from butyl chloride had m.p.=109°-111° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[Cl:20][C:21]1[CH:26]=[C:25](F)[C:24]([CH3:28])=[CH:23][C:22]=1[N+:29]([O-:31])=[O:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:25]4[CH:26]=[C:21]([Cl:20])[C:22]([N+:29]([O-:31])=[O:30])=[CH:23][C:24]=4[CH3:28])=[C:11]3[CH:10]=[N:9]2)=[CH:18][CH:19]=1
Reactant: COc1ccc(Cn2ncc3c(O)ccnc32)cc1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ncc3c(Oc4cc(Cl)c([N+](=O)[O-])cc4C)ccnc32)cc1
Temperature: 95 °C
Yield: 9 %

Procedure:
A stirred mixture of 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (255 g, 999 mmol, prepared using the procedure described in Example 1, Step B), 1-chloro-5-fluoro-4-methyl-2-nitrobenzene (94.7 g, 499 mmol), cesium carbonate (325 g, 1.0 mol) and DMF (2 L) was heated to 95° C. for 6 hours. The reaction was cooled to ambient temperature and partitioned between EtOAc and water. The phases were filtered and then separated. The aqueous phase was re-extracted with EtOAc. The combined organic phases were washed with water, brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude was purified by Biotage Flash 75 L chromatographic system, eluting with 5% EtOAc/hexanes (12 L), 10% EtOAc/hexanes (6 L), 20% EtOAc/hexanes (6 L), then 30% EtOAc/hexanes (6 L). The product was obtained as a viscous oil (42 g, 9%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]3[NH:18][CH:19]=[CH:20][C:13]=23)[C:9]([CH:21]=[O:22])=[N:8]1.[OH-].[K+].Cl.[CH3:26]O>>[CH3:26][O:22][CH:21]1[C:20]2[C:13]3[C:14]([NH:18][CH:19]=2)=[N:15][CH:16]=[CH:17][C:12]=3[C:10]2[C:9]1=[N:8][N:7]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH:11]=2
Reactant: O=Cc1nn(C2CCCCO2)cc1-c1ccnc2[nH]ccc12
Reactant: CO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: COC1c2nn(C3CCCCO3)cc2-c2ccnc3[nH]cc1c23
Temperature: 25 °C
Reaction time: 42 h

Procedure:
To a stirred solution of 1-(oxan-2-yl)-4-{1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazole-3-carbaldehyde (1.88 g, 6.35 mmol) in MeOH (280 mL, a concentration of 0.023 mol/L), was added KOH (3.56 g, 27.68 mmol). The reaction mixture was stirred at room temperature for 42 hours. When TLC showed completion of reaction, the pH was adjusted to 7 by addition of HCl (4 M in MeOH).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:9]=[C:8]([CH2:10][Br:18])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)c(Br)c1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)cc1Br
Temperature: 25 °C
Yield: 83.6 %

Procedure:
A mixture of 2-bromo-4-methylbenzonitrile (13.3 g, 81.4 mmol), NBS (14.4 g, 84.4 mmol) and BPO (0.20 g) in CCl4 (150 mL) was heated for 4 h at reflux. The reaction mixture was cooled to room temperature and filtered. Then the solid was washed with CCl4 (20 mL×2) and the combined filtrates were washed successively with saturated sodium bicarbonate (50 mL), water (2×100 mL) and sodium thiosulfate (50 mL). The organic phase was dried over NaSO4 and concentrated in vacuum afforded the titled compound, 2-bromo-4-(bromomethyl)benzonitrile (18.7 g, 100%).
Reaction SMILES: [C:1]([N:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[S:8][CH2:7][CH2:6]1)(=[O:4])[CH:2]=[CH2:3].S(Cl)([Cl:19])(=O)=O.O>C(Cl)Cl>[C:1]([N:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[S:8][CH:7]([Cl:19])[CH2:6]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: O=S(=O)(Cl)Cl
Reactant: C=CC(=O)N1CCSc2ccccc2C1
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)N1Cc2ccccc2SC(Cl)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
4-Acryloyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (10 g) was dissolved in methylene chloride (150 ml) and sulfuryl chloride (9.3 g) was added thereto under ice cooling and agitated at 0° C. for 1 hour. To the reaction mixture water was added and extracted with chloroform. The chloroform phase was washed with a saturated saline solution and dried on sodium sulfate and thereafter the solvent was distilled out under reduced pressure. Residue was purified by silica gel column chromatography (Wako Gel C-200, 200 g) and eluted with a mixed solvent of n-hexane (70 parts)+ethyl acetate (30 parts) to give 4-acryloyl-2-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (10.5 g).
Reaction SMILES: [OH-:1].[K+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH2:13]Br>C(O)/C=C/C>[CH2:9]([O:1][CH2:13][C:5]1[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=1[Br:3])/[CH:4]=[CH:5]/[CH3:6]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1cccc(Br)c1CBr
Agent: C/C=C/CO
Agent: [K+]
Product: C/C=C/COCc1c(Br)cccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of KOH (0.57 g, 0.099 mol) in (2E)-but-2-en-1-ol (100 mL) was added 1-bromo-2-(bromomethyl)-3-nitrobenzene (10 g, 0.033 mol), and the mixture was stirred at r.t for 30 min. Then the mixture was washed with water (200 mL*4), extracted with EtOAc, dried over Na2SO4, concentrated in vacuo. The residue was purified via chromatography (petrol ether) to give 2-bromo-6-nitrobenzyl (2E)-but-2-en-1-yl ether. 1H-NMR (400 MHz, CDCl3) δ 7.76 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.25˜7.30 (m, 1H), 5.68˜5.77 (m, 1H), 5.51˜5.58 (m, 1H), 4.82 (s, 2H), 1.69 (d, J=6.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14](O)=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:17][NH:18][CH3:19]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][N:18]([CH3:19])[CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCCC1
Reactant: CNC
Product: CN(C)CC1(c2ccc(F)cc2)CCCCC1
Yield: 9 %

Procedure:
The title compound was synthesized from 1-(4-fluorophenyl)cyclohexane-carboxylic acid and dimethyl amine using General Procedure G, followed by General Procedure E in 9% yield as a solid. LCMS Rt=7.22 min, m/z=236 (M+1). 1H NMR (CDCl3, δ): 7.32 (dd, J=5.5, 8.9 Hz, 2H), 6.99 (t, J=8.8 Hz, 2H), 2.30 (s, 2H), 2.1 (m, 2H), 1.97, (s, 6H), 1.7-1.3 (m, 8H. 13C NMR (CDCl3, δ, mult): 162.0(0), 159.6(0), 141.7(0), 128.8(1), 128.7(1), 114.7(1), 114.5(1), 72.9(2), 56.5(0), 48.4(3), 34.3(2), 26.6(2), 22.1(2).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:6]=2[N:5]=[C:4]1[CH3:14])[CH3:2].[CH2:15]1[CH2:22][O:21][S:18](=[O:20])(=[O:19])[CH2:17][CH2:16]1>>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:6]=2[N:5]([CH2:22][CH2:15][CH2:16][CH2:17][S:18]([OH:21])(=[O:20])=[O:19])[CH:4]1[CH3:14])[CH3:2]
Reactant: O=S1(=O)CCCCO1
Reactant: CCn1c(C)nc2cc(C#N)ccc21
Product: CCN1c2ccc(C#N)cc2N(CCCCS(=O)(=O)O)C1C
Yield: 72 %

Procedure:
18.6 g (0.1 mole) of compound V and an equimolar amount of 1,4-butanesultone were heated at 140° C for 4 h, then washed with acetone and dried. Melting point: over 260° C. Yield: 72% (23 g).
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:8][O:7][CH2:6][C:5]([NH2:9])=[N:4][C@@:3]21[C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=1)[O:12][CH:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10]2.[C:27]([C:29]1[CH:30]=[CH:31][C:32]([C:35](O)=[O:36])=[N:33][CH:34]=1)#[N:28]>>[NH2:9][C:5]1[CH2:6][O:7][CH2:8][C:2]([F:1])([F:26])[C@@:3]2([C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:35](=[O:36])[C:32]4[CH:31]=[CH:30][C:29]([C:27]#[N:28])=[CH:34][N:33]=4)[CH:17]=3)[O:12][CH:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10]2)[N:4]=1
Reactant: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(N)cc32)C(F)(F)COC1
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: N#Cc1ccc(C(=O)Nc2ccc3c(c2)[C@@]2(CC(c4ccccc4)O3)N=C(N)COCC2(F)F)nc1

Procedure:
The condensation of (2RS,4R)-6′,6′-difluoro-2-phenyl-6′,7′-dihydro-2′H-spiro[chroman-4,5′-[1,4]oxazepine]-3′,6-diamine (intermediate C4.3) and 5-cyanopicolinic acid yielded the title compound as an off-white solid. MS (ISP): m/z=490.2 [M+H]+. In a manner analogous to that described in Example 19, the following compounds were obtained:
Reaction SMILES: [CH3:1][N:2]1[CH2:16][CH2:15][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH2:13][OH:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:17]([C:19]1[CH:20]=[CH:21][C:22]([CH2:25][OH:26])=[N:23][CH:24]=1)=[CH2:18].[OH-].[K+]>CN1C(=O)CCC1>[OH:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:18][CH2:17][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][OH:26])=[N:23][CH:24]=3)[C:5]3[CH2:15][CH2:16][N:2]([CH3:1])[CH2:3][C:4]=3[C:12]=2[CH:11]=1
Reactant: C=Cc1ccc(CO)nc1
Reactant: CN1CCc2[nH]c3ccc(CO)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(CO)ccc3n2CCc2ccc(CO)nc2)C1

Procedure:
The title compound is prepared from a mixture of (2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indol-8-yl)methanol, (5-vinylpyridin-2-yl)methanol and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH3:1]CCCC.C([Li])(C)(C)C.[CH2:11]([CH:13]1[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[S:23][C:24]([CH:26]=O)=[CH:25][C:15]=2[N:14]1[S:28]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:11]([CH:13]1[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[S:23][C:24]([CH:26]=[CH2:1])=[CH:25][C:15]=2[N:14]1[S:28]([C:31]1[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=1)(=[O:29])=[O:30])[CH3:12]
Reactant: CCCCC
Reactant: CCC1c2ccccc2-c2sc(C=O)cc2N1S(=O)(=O)c1ccc(OC)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C=Cc1cc2c(s1)-c1ccccc1C(CC)N2S(=O)(=O)c1ccc(OC)cc1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
A suspension of methyltriphenylphosphonium bromide (2.30 g, 6.44 mmol) in dry tetrahydrofuran (16 mL) was treated dropwise with a pentane solution of t-butyllithium (1.0 M, 3.9 mL, 3.9 mmol) at 0° C. during several min. After the addition was complete, the suspension was warmed to 23° C. and after a further 10 min, a solution of 5-ethyl-4-[(4-methoxyphenyl)sulfonyl]-4,5-dihydrothieno[3,2-c]isoquinoline-2-carbaldehyde (1.33 g, 3.22 mmol) in dry tetrahydrofuran (16 mL+8 mL wash) was added. After a further 15 min, the reaction was quenched with water (160 mL) and extracted with ethyl acetate (160 mL). The extract was washed with brine (160 mL), dried (Na2SO4), and concentrated in vacuo to give the crude product as an orange solid (2.46 g). Flash chromatography on silica gel (24 g) eluting 25-, and then 50% methylene chloride-hexane gave the title compound (1.20 g, 90%, m.p. 131-33° C.) as a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([C:5]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:4].N1C=CC=CC=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>ClCCl.S([O-])([O-])(=O)=O.[Cu+2]>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:1][CH2:2][C@H:3]([C:5]2([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6]2)[CH3:4])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: C[C@H](CO)C1(O)CCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](C)C2(O)CCCC2)cc1
Reaction time: 48 h
Yield: 169.5 %

Procedure:
A mixture of 3a (1.79 g, 12.4 mmol), pyridine (5 mL), and p-toluenesulfonyl chloride (4.26 g, 22.3 mmol) in dichloromethane (40 mL) was stirred below 10° C. for 2 days. The reaction mixture was poured into copper (II) sulfate solution and extracted with diethyl ether. The combined organic layers were washed with copper (II) sulfate solution, water, sodium bicarbonate solution and brine, and dried over sodium sulfate. Filtration and concentration gave 6.27 g of an oily material, which was purified by column chromatography (silica gel 60 g, ethyl acetate in n-hexane, 5-33%) to give 3.74 g (quantitative) of 4a as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([N:19]3[CH2:23][CH2:22][CH2:21][CH:20]3[CH2:24][CH2:25][CH2:26][CH2:27][O:28]C3CCCCO3)=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CO>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([N:19]3[CH2:23][CH2:22][CH2:21][CH:20]3[CH2:24][CH2:25][CH2:26][CH2:27][OH:28])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ncc(N3CCCC3CCCCOC3CCCCO3)nc2-c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCCCCC1CCCN1c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 107.8 %

Procedure:
To a solution of 1.25 g of (±)-1-[1-(5,6-diphenylpyrazin-2-yl)pyrrolidin-2-yl]-4-(2-tetrahydropyranyloxy)butane in 13 ml of methanol, 0.52 g of p-toluenesulfonic acid monohydrate was added, followed by stirring at room temperature for 3 hours. The reaction solution was alkalified by adding an aqueous saturated sodium hydrogen carbonate solution, and then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to obtain 1.10 g of the desired compound as a pale yellow oily substance.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[F:12].CC1(C)COB(B2OCC(C)(C)CO2)OC1.C([O-])(=O)C.[K+].[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:47]2[C:52](Cl)=[N:51][CH:50]=[CH:49][N:48]=2)[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.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:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:47]2[C:52]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=3[F:12])=[N:51][CH:50]=[CH:49][N:48]=2)[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Reactant: Fc1c(Br)cccc1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2-c2cccc(C(F)(F)F)c2F)CC1
Temperature: 80 °C
Yield: 17.6 %

Procedure:
Combine 1-bromo-2-fluoro-3-trifluoromethylbenzene (0.424 g, 1.77 mmol), 5,5,5′,5′-tetramethyl-[2,2′]bi[1,3,2]dioxaborinanyl] (0.458 g, 2.03 mmol), 1,1′-bis(diphenylphosphino)ferrocene dichloropalladium (0.0632 g, 0.0774 mmol), and potassium acetate (0.499 g, 5.08 mmol) in DMF (10 mL), and purge with nitrogen for 0.5 hr. Heat for 2 hr. at 80° C. and cool to room temperature. Add 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (0.406 g, 1.36 mmol), sodium carbonate (4.0 mL of a 2M solution in water,) and bis(diphenylphosphino)ferrocene dichloropalladium (0.052 g, 0.0638 mmol). Heat the reaction at 80° C. for 20 hr. Purify by silica gel chromatography, eluting with 5:95 to 40:60 ethyl acetate:hexanes to give the 3′-(2-fluoro-3-trifluoromethyl-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (0.102 g, 18%).