Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[CH:5]=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2cccc(C)c12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc2cccc(CBr)c12
Temperature: 25 °C

Procedure:
1,8-Dimethyl-naphthalene (1.30 g, 8.32 mmol) was dissolved in dry carbon tetrachloride (80 mL). To the reaction mixture was added N-bromosuccinimide (1.39 g, 7.82 mmol), dibenzoyl peroxide (6 mg, catalyst) and the reaction mixture was refluxing for 6 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature, a precipitate formed on cooling and the precipitate was separated by filtration. The filtrate was evaporated in vacuo to yield the title compound as a solid which was used in further steps without additional purification.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([N:15]2[C@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][O:17][C:16]2=[O:26])=[O:14])=[CH:7][CH:6]=1>C1COCC1.CSC>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([C@H:11]([CH3:1])[CH2:12][C:13]([N:15]2[C@H:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][O:17][C:16]2=[O:26])=[O:14])=[CH:9][CH:10]=1
Reactant: C[Mg]Br
Reactant: O=C(/C=C/c1ccc(Br)cc1)N1C(=O)OC[C@H]1c1ccccc1
Solvent: CSC
Solvent: C1CCOC1
Product: C[C@H](CC(=O)N1C(=O)OC[C@H]1c1ccccc1)c1ccc(Br)cc1
Temperature: -20 °C
Reaction time: 12 h

Procedure:
To a stirred solution of copper(II) bromide dimethylsulfide complex (8.78 g, 42.7 mmol) in THF (60 mL) and dimethylsulfide (30 mL) was added methylmagnesium bromide (12.7 mL, 3.0M in diethyl ether, 38.1 mmol) at −40° C. The resultant mixture was stirred at −40° C. for 30 min, then warmed to −20° C. The product from Step A (3.53 g, 9.48 mmol) in THF (30 mL) was added to the above reaction mixture over 1 h at −20° C. The resultant mixture was stirred at −20° C. for 2 h, then slowly warmed to room temperature and stirred at room temperature for 12 h. The reaction was quenched by slow addition of saturated aqueous ammonium chloride solution. The organic phase was separated and the aqueous phase was extracted with two portions of ethyl acetate. The combined organic layers were washed with brine and concentrated in vacuo. Purification by flash chromatography (silica gel, 83:17 hexanes/ethyl acetate) afforded the desired product.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:8]2[C:13]([C:14]=1[O:15]C)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][CH3:33])=[C:28]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:27]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][CH3:33])=[C:28]([S:34]([CH2:37][C:3]([C:5]2[N:6]=[C:7]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[C:8]3[C:13]([C:14]=2[OH:15])=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:4])(=[O:35])=[O:36])[CH:27]=1
Reactant: CNc1ccc(Cl)cc1S(C)(=O)=O
Reactant: COC(=O)c1nc(Cc2ccc(F)cc2)c2ccccc2c1OC
Product: CNc1ccc(Cl)cc1S(=O)(=O)CC(=O)c1nc(Cc2ccc(F)cc2)c2ccccc2c1O

Procedure:
2-(5-Chloro-2-methylamino-benzenesulfonyl)-1-[1-(4-fluoro-benzyl)-4-hydroxy-isoquinolin-3-yl]-ethanone (36a) was prepared from 1-(4-fluoro-benzyl)-4-methoxy-isoquinoline-3-carboxylic acid methyl ester and (4-chloro-2-methanesulfonyl-phenyl)-methyl-amine as described in steps 1-4 of Example 8.
Reaction SMILES: S(Cl)([Cl:3])=O.N1C=CC=CC=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18](O)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH:18]([Cl:3])[C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)=[CH:21][CH:22]=1
Reactant: O=S(Cl)Cl
Reactant: OC(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Clc1ccc(CC(Cl)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of of thionyl chloride in toluene is cooled to 0° C., and a catalytic amount of pyridine is added. A solution of 1,2-di(4-chlorophenyl)ethan-1-ol in toluene is then added drop wise. Upon completion addition of addition, the reaction mixture is allowed to warm to ambient temperature where it stirs for about 30 minutes. The reaction mixture is washed with water, dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding the subject compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:23]=[C:22]([OH:24])[C:21]([F:25])=[CH:20][C:11]=1[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13].[CH2:26](OC(OCC(C)(C)C)N(C)C)C(C)(C)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2[C:11](=[CH:20][C:21]([F:25])=[C:22]([OH:24])[N:23]=2)[C:12](=[O:13])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:26]1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(O)nc1Nc1ccc(F)cc1F
Reactant: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(O)c(F)cc2c1=O
Yield: 75.4 %

Procedure:
In 4 ml of toluene was suspended 200 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinoyl]acetate, and 200 mg of N,N-dimethylformamide dineopentylacetal was added thereto, after which the resulting mixture was subjected to reaction at room temperature for 4 hours. The crystals thus deposited were collected by filtration, and to the crystals were added 5 ml of ethanol and 5 ml of water, after which the pH thereof was adjusted to 1.0 with 2N hydrochloric acid. Thereafter, the crystals thus deposited were collected by filtration to obtain 155 mg (yield 75.4%) of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-hydroxy-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 244°-248° C. The physical properties of this compound were identical with those of the compound obtained in Example 40.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([CH:14]([OH:16])[CH3:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=2)[CH2:3][CH2:2]1.C[N+]1([O-])CCOCC1.C(#N)C>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14](=[O:16])[CH3:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=2)[CH2:3][CH2:2]1
Reactant: CCOc1ccc(Cc2nc3cc(C(C)O)ccc3n2CC2CC2)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CCOc1ccc(Cc2nc3cc(C(C)=O)ccc3n2CC2CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.4 %

Procedure:
To a mixture 1-[1-(cyclopropylmethyl)-2-(4-ethoxybenzyl)-1H-benzimidazol-5-yl]ethanol (1.35 g, 3.86 mmol), N-methylmorpholine-N-oxide (0.497 g, 4.24 mmol) and 4 Å molecular sieves (2.0 g) in CH2Cl2 (10 mL) was added tetrapropylammonium perruthenate (0.068 g, 0.193 mmol) and the resulting mixture was stirred at room temperature for 90 minutes. N-methylmorpholine-N-oxide (0.124 g, 1.06 mmol) and acetonitrile (1 mL) were added and the mixture was stirred at room temperature overnight. The solvent was concentrated in vacuo and the crude product was purified by silica gel column chromatography (30% EtOAc/hexanes to 60% EtOAc/hexanes) to provide the title compound (0.880 g, 65%) as a white solid. 1H NMR (CDCl3): δ 8.34 (s, 1H), 7.94 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 2H), 6.91 (dd, J=6.4 Hz, J=2.0 Hz, 2H), 4.29 (s, 2H), 3.98 (q, J=7.2 Hz, 2H) 3.41 (d, J=6.8 Hz, 2H), 2.67 (s, 3H), 1.38 (t, J=7.0 Hz, 3H), 1.07–1.00 (m, 1H), 0.55–0.51 (m, 2H), 0.29–0.26 (m, 2H). 13C NMR (CDCl3): δ 198.71, 159.01, 156.43, 143.29, 140.01, 132.68, 130.44, 128.67, 123.50, 121.95, 115.83, 110.73, 64.38, 49.23, 34.63, 27.63, 15.76, 11.99, 5.20. MS (ESI) (M+H)+=349. Anal. Calcd for C22H24N2O2+0.1H2O: C, 75.44, H, 6.96; N, 8.00. Found: C, 75.48; H, 7.13; N, 8.01.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.Cl.[OH:13][CH:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[NH2:8][C:6]1[CH:7]=[C:2]([N:16]2[CH2:17][CH2:18][CH2:19][CH:14]([OH:13])[CH2:15]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: OC1CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(N2CCCC(O)C2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 18 h
Yield: 53.6 %

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (1.3 g, 7.0 mmol), 3-hydroxypiperidine hydrochloride (3.0 g, 20 mmol), and K2CO3 (3.0 g, 22 mmol) in DMF (10 mL) was stirred at 120° C. for 18 h. The reaction mixture was cooled to room temperature, poured into water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography (silica gel, 4×7.5 cm, eluted with 50:50 CHCl3/EtOAc) to yield the product as an orange solid (0.89 g, 54%).
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO[CH2:16][N:17]([CH2:25][Si](C)(C)C)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl.FC(F)(F)C(O)=O>[CH2:12]([O:11][C:1]([C@H:2]1[C@H:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:25][N:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:16]1)=[O:10])[CH3:13]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 48 %

Procedure:
To a mixture of ethyl trans-cinnamate (2 g, 11.4 mmol) and N-(methoxymethyl)(phenyl)-N-((trimethylsilyl)methyl)methanamine (2.37 mL) in dichloromethane (18 mL) was added 3 drops of trifluoroacetic acid and the mixture was stirred at 40° C. for 45 min. Then another 0.56 mL of N-(methoxymethyl)(phenyl)-N-((trimethylsilyl) methyl)methanamine and 1 drop of trifluoroacetic acid were added and the mixture was stirred at 40° C. for another 45 min. Then another 0.26 mL of N-(methoxymethyl)(phenyl)-N-((trimethylsilyl)methyl)methanamine and 1 drop of trifluoroacetic acid were added and the mixture was stirred at 40° C. for overnight. After cooling down to room temperature, the mixture was concentrated under vacuum and purified by Flash Chromatography with from 8% ethyl acetate/92% hexane to 10% ethyl acetate/90% hexane over 20 min. to give the title compound as a clear colorless sticky oil (1.69 g, 48% yield). 1H NMR (400 MHz, CDCl3) δ 1.20 (3H, t, J=6.4, 9.6 Hz), 2.86 (1H, m), 3.00 (1H, t, J=9.6 Hz), 3.04–3.07 (2H, m), 3.65–3.68 (3H, m), 4.09–4.13 (2H, m), 7.19–7.37 (10H, m). HPLC purity (retention time): 93% (1.30 min, method C). MS: 310.30 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1)#[N:2].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].CN(C1C=CC=CN=1)C>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#Cc1ccc(CCO)cc1
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5 g of 2-(4-cyanophenyl)ethanol are introduced into 50 ml of dimethylformamide 2.54 g of imidazole, 5,63 g of tert-butyldimethylsilyl chloride and a spatula tip-ful of dimethylaminopyridine are added. The reaction medium is left for 2 hours at room temperature and is then added to an ice-water mixture. The mixture is extracted with ethyl acetate and the extracts dried over anhydrous sodium sulphate. The product is purified by chromatography on a column of silica gel, using a mixture of cyclohexane and ethyl acetate (10:1 v/v) as eluent, to give 1-cyano-4-(tert-butyldimethylsilyloxyethyl)benzene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1.[H][H]>C(O)(=O)C.Cl(O)(=O)(=O)=O.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1
Reactant: O=C(O)/C=C/C(=O)c1ccc(-c2ccccc2F)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: O=C(O)CCCc1ccc(-c2ccccc2F)cc1

Procedure:
13.7 gm (0.05 mol) of 4-(2'-fluoro-4-biphenylyl)-4-oxo-crotonic acid in 100 ml of glacial acetic acid and 2 ml of perchloric acid were hydrogenated in the presence of 4 gm of 5% palladium/barium sulfate at room temperature and at atmospheric pressure; the reaction was finished after absorption of 3 mols of hydrogen. After filtering, the mixture was evaporated in vacuo, the residue distributed between water and ethyl acetate and the ethyl acetate phase was evaporated. The residue was crystallized from cyclohexane. Yield: 11.1 gm (61.4% of theory); m.p. 65°-66° C. Melting point of the cyclohexylamine salt: 130°-132° C. Melting point of the sodium salt: 139°-141° C. Melting point of the isobutylamine salt: 92°-93° C. (from ethyl acetate).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[C:15]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:16][C:17]4[C:22]([C:23]=3[C:24]([OH:26])=O)=[CH:21][CH:20]=[C:19]([O:27][CH3:28])[C:18]=4[Br:29])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:67]1([C@@H:73]([NH2:76])[CH2:74][CH3:75])[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>>[C:67]1([C@@H:73]([NH:76][C:24]([C:23]2[C:22]3[C:17](=[C:18]([Br:29])[C:19]([O:27][CH3:28])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:14]=2[CH2:13][N:10]2[CH2:11][CH2:12][CH:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:8][CH2:9]2)=[O:26])[CH2:74][CH3:75])[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: COc1ccc2c(C(=O)O)c(CN3CCC(N4CCCCC4)CC3)c(-c3ccccc3)nc2c1Br
Reactant: CC[C@H](N)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CC[C@H](NC(=O)c1c(CN2CCC(N3CCCCC3)CC2)c(-c2ccccc2)nc2c(Br)c(OC)ccc12)c1ccccc1
Yield: 16.5 %

Procedure:
Prepared as described in Example 2 from 2 g (3.7 mmol) of 3-[1,4′]bipiperidinyl-1′-ylmethyl-8-bromo-7-methoxy-2-phenyl-quinoline-4-carboxylic acid (compound of Description 29), 1.55 ml (11.1 mmol) of triethylamine (TEA) 1.82 g (4.8 mmol) of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexa-fluorophosphate (HBTU) and 0.75 g (5.5 mmol) of (S)-1-phenyl-propylamine The crude material was purified by flash column chromatography on 230-400 mesh silica gel, utilising a mixture of EtOAc/MeOH 95:5 containing 0.05% NH4OH (28%) affording 0.4 g of title compound. After trituration with iPr2O, 0.3 g of the title compound were recovered as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].[CH2:10]([CH:12]([C:18](OCC)=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:11]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:18]([CH:12]([CH2:10][CH3:11])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:19])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: CCOC(=O)C(CC)C(=O)OCC
Reactant: Nc1cc(F)cc(F)c1
Product: CCOC(=O)C(CC)C(=O)Nc1cc(F)cc(F)c1

Procedure:
Prepared according to Procedure A using 3,5-difluoroaniline (5.60 g, 43.4 mmol) and diethyl 2-ethylmalonate to give ethyl 2-(3,5-difluorophenylcarbamoyl)butanoate. Mass Spectrum (ESI) m/e=272.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([N:9]([CH3:11])[CH3:10])[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[Cl:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Cl:19][CH2:20][CH2:21][CH2:22][C:23]([N:5]1[CH2:6][CH2:7][C@H:8]([N:9]([CH3:10])[CH3:11])[C@H:3]([O:2][CH3:1])[CH2:4]1)=[O:24]
Reactant: O=C(Cl)CCCCl
Reactant: CO[C@@H]1CNCC[C@@H]1N(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO[C@@H]1CN(C(=O)CCCCl)CC[C@@H]1N(C)C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred and cooled (ice/bath) mixture of 7.9 parts of cis-3-methoxy-N,N-dimethyl-4-piperidinamine, 7 parts of N,N-diethylethanamine, 195 parts of dichloromethane were added dropwise 6.16 parts of 4-chlorobutanoyl chloride (temperature <5° C.). Upon completion, stirring was continued for 30 minutes. The organic layer was washed twice with a saturated sodium chloride solution, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 13.7 parts (100%) of cis-1-(4-chloro-1- oxobutyl)-3-methoxy-N,N-dimethyl-4-piperidinamine (int. 29).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14](Cl)[N:13]=[C:12]([Cl:17])[N:11]=2)=[CH:5][CH:4]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:17][C:12]1[N:11]=[C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:15]=[C:14]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:13]=1
Reactant: COc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Reactant: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(Nc2nc(Cl)nc(Nc3ccccc3)n2)cc1
Reaction time: 24 h
Yield: 57 %

Procedure:
To a solution of 2-(4-methoxyphenyl)amino-4,6-dichloro-1,3,5-triazine (57 mg, 0.21 mmoles) in acetonitrile (0.5 ml) was added a solution of aniline (0.021 ml, 0.23 mmoles) and diisopropylethylamine (0.05 ml, 0.29 mmoles) in acetonitrile (0.5 ml). After stirring for 24 hours, the mixture was concentrated under vacuum and the residue was dissolved in ethyl acetate (10 ml). The solution was washed with a solution composed of saturated aqueous sodium chloride solution and 1 M hydrochloric acid (1: 1, 2×10 ml), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with 10% ethyl acetate-hexane to provide CT-31942 (38 mg, 57% yield). 1H NMR (d6-DMSO) δ 10.00–10.22 (m, 2 H), 7.26–7.82 (m, 6 H), 7.01–7.10 (m, 1 H), 6.91 (d, J=9 Hz, 2 H), 3.74 (s, 3 H).
Reaction SMILES: [C:1]([NH2:12])(=O)[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.S(Cl)(Cl)=O>C(OCC)(=O)C>[C:1](#[N:12])[C:2]1[CH:3]=[C:4]([OH:5])[C:6]([OH:7])=[C:8]([OH:9])[CH:10]=1
Reactant: NC(=O)c1cc(O)c(O)c(O)c1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: N#Cc1cc(O)c(O)c(O)c1
Temperature: 90 °C
Yield: 86 %

Procedure:
A reaction mixture containing 23.5 g. of gallamide, 180 ml. of ethyl acetate and 35 ml. of thionylchloride was refluxed for about 18 hours. The volatile contents were removed by evaporation in vacuo and the resulting residue dissolved in 215 ml. of water. This aqueous solution was heated to about 90° C. until the evolution of gas had ceased. The aqueous solution was filtered through charcoal and the water removed from the filtrate by evaporation. 18 g. of gallonitrile were obtained melting at about 219° C. with decomposition (86% yield). Other nitriles useful as starting materials can be prepared similarly.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:24]I>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:24])[C:6]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccc(Br)cc3c2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2c(c3cc(Br)ccc31)CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 8-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (0.53 g, 1.5 mmol) in DMF (6 mL) was added NaH (60% weight dispersion in mineral oil, 91 mg, 2.3 mmol) and CH3I (0.14 mL, 2.3 mmol). The reaction mixture was stirred at room temperature until the reaction was complete. Then the reaction was quenched with H2O and extracted with CH2Cl2. The organic layer was washed with H2O and 5% LiCl, dried with Na2SO4, filtered and concentrated to give tert-butyl 8-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate, which was used directly without purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[C:14]3=[N:15][C:16]([Sn](C)(C)C)=[CH:17][N:18]=[C:13]3[NH:12][CH2:11][C:10]2=[O:23])[CH2:3][CH2:2]1.C(OC([N:31]1[C:35]2=[N:36][CH:37]=[CH:38][C:39](Br)=[C:34]2[CH:33]=[CH:32]1)=O)(C)(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O1CCOCC1>[NH:31]1[C:35]2=[N:36][CH:37]=[CH:38][C:39]([C:16]3[N:15]=[C:14]4[N:9]([CH2:8][CH2:7][CH:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[C:10](=[O:23])[CH2:11][NH:12][C:13]4=[N:18][CH:17]=3)=[C:34]2[CH:33]=[CH:32]1
Reactant: CC(C)(C)OC(=O)n1ccc2c(Br)ccnc21
Reactant: C[Sn](C)(C)c1cnc2c(n1)N(CCC1CCOCC1)C(=O)CN2
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C1CNc2ncc(-c3ccnc4[nH]ccc34)nc2N1CCC1CCOCC1
Temperature: 95 °C
Reaction time: 3.5 h
Yield: 35 %

Procedure:
A mixture of 1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (See Example 15.C) (1 equiv), 4-bromo-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (1 equiv), tris(dibezylideneacetone) palladium (0.13 equiv), tri-o-tolylphosphine (0.25 equiv) and triethylamine (2.8 equiv) in anhydrous dioxane was purged, degassed for 2 min and stirred at 95° C. under nitrogen for 3-4 h. Upon completion of the reaction as indicated by TLC, the volatiles were removed under reduced pressure and the residue was purified by column chromatography to give the desired product in 35% yield. MS (ESI) m/z 479.7 [M+1]+. tert-Butyl 4-(7-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was stirred in methanolic hydrochloride solution at room temperature. Upon completion of the reaction as indicated by TLC, the solvent was removed under reduced pressure and the residue was purified on silica gel to give the title compound in 63% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 11.72 (s, 1H), 8.38 (s, 1H), 8.25 (d, J=4.8 Hz, 1H), 7.79 (s, 1H), 7.53-7.51 (m, 2H), 6.97 (q, J=1.6 Hz, 1H), 4.23 (s, 2H), 4.14 (t, J=7.6 Hz, 2H), 3.81 (dd, J1=2.4 Hz, J2=11.2 Hz, 2H), 3.25 (d, J=10.8 Hz, 2H), 1.67 (d, J=13.2 Hz, 2H), 1.61 (m, 3H), 1.22 (m, 2H); MS(ESI): m/z 379.2 [M+1]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[CH3:9][N:10]1[C:19]2[NH:18][C:17]3[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:16]=3[N:15]([C:25]([C:27]3[CH:43]=[CH:42][C:30]([CH2:31][NH:32][C:33](=[O:41])[CH2:34][CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)=[C:29]([F:44])[CH:28]=3)=[O:26])[CH2:14][C:13]=2[CH:12]=[N:11]1>CN(C=O)C.C(N(CC)CC)C>[CH3:9][N:10]1[C:19]2[NH:18][C:17]3[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:16]=3[N:15]([C:25]([C:27]3[CH:43]=[CH:42][C:30]([CH2:31][NH:32][C:33](=[O:41])[CH2:34][CH:35]4[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:37][CH2:36]4)=[C:29]([F:44])[CH:28]=3)=[O:26])[CH2:14][C:13]=2[CH:12]=[N:11]1
Reactant: CCCCCCBr
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CNC(=O)CC2CCNCC2)c(F)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCN1CCC(CC(=O)NCc2ccc(C(=O)N3Cc4cnn(C)c4Nc4cc(C)ccc43)cc2F)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1-bromohexane (0.83 mg, 0.005 mmol) in DMF (0.05 ml) was added to a solution of N-[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-2-piperidin-4-yl-acetamide hydrochloride (Compound number 1110) (2.82 mg, 0.005 mmol) in DMF (0.05 ml) and triethyl-amine (0.0021 ml). The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=575.7