Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:36][CH2:37][CH2:38][CH2:39][N:40]1[C:52]2[C:51]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[N:45]=[C:44]([NH2:53])[C:43]=2[N:42]=[C:41]1[CH2:54][CH2:55][CH2:56][CH3:57]>CN1CCCC1=O>[NH2:53][C:44]1[C:43]2[N:42]=[C:41]([CH2:54][CH2:55][CH2:56][CH3:57])[N:40]([CH2:39][CH2:38][CH2:37][NH:36][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])[C:52]=2[C:51]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[N:45]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: O=C(O)c1cc2ccccc2cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)c1cc2ccccc2cn1
Reaction time: 0.29 h
Yield: 75.4 %

Procedure:
Isoquinoline-3-carboxylic acid (1.05 g, 6.05 mmol) was stirred in 1-methyl-2-pyrrolidinone (50 mL). 1-Hydroxybenzotriazole (885 mg, 6.55 mmol) was added in a single portion. This solution was stirred for 15-20 minutes and then cooled in an ice bath. 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.26 g, 6.55 mmol) was added in small portions over a period of 10 minutes. The solution was stirred for 1 hour and then added dropwise to a solution of 1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine-(1.50 g, 5.04 mmol) in 1-methyl-2-pyrrolidinone (100 mL). After 3 hours the reaction mixture was poured into distilled water (800 mL). A solid precipitated. This material was stirred for 5 hours, isolated by filtration and then air dried over the weekend. The solid was taken up in chloroform (100 mL) and then purified by column chromatography (silica gel eluting sequentially with chloroform (1 L), 1% methanol in chloroform (1 L) and 5% methanol in chloroform (1 L)). The purified material was slurried with hot acetonitrile, cooled, isolated by filtration and then dried in a vacuum oven to provide 1.72 g of N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]isoquinoline-3-carboxamide as a solid, m.p. 203.8-205.3° C. Analysis: Calculated for C27H28N6O: % C, 71.66; % H, 6.24; % N, 18.57; Found: % C, 71.63; % H, 6.17; % N, 18.57.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:22]=[CH:21][C:14]3[N:15]([CH3:20])[C:16](=O)[CH2:17][S:18][C:13]=3[CH:12]=2)[CH2:6]1)=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>O1CCOCC1>[CH3:1][O:2][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:22]=[CH:21][C:14]3[N:15]([CH3:20])[C:16](=[S:32])[CH2:17][S:18][C:13]=3[CH:12]=2)[CH2:6]1)=[O:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)[C@H]1CN(c2ccc3c(c2)SCC(=O)N3C)C(=O)O1
Solvent: C1COCCO1
Product: COC(=O)[C@H]1CN(c2ccc3c(c2)SCC(=S)N3C)C(=O)O1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
To a stirred suspension of the (5R)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazin-7-yl)-2-oxo-5-oxazolidinecarboxylic acid methyl ester (EXAMPLE 62, Step 5, 1.26 g, 3.907 mmol) in dry dioxane (25 mL) is added Lawesson's reagent (2.37 g, 5.861 mmol). This reaction mixture is heated at 70–80° C. for 1.5–2 h at which time the reaction is cooled to room temperature and concentrated under reduced pressure. The residue is washed with EtOAc (15 mL×3), sonicated and filtered to give the title compound as a yellow solid (1.18 g, 89%), MS (m/z): 339.5 [M+H]+.
Reaction SMILES: O1C2C=CC=C(C=O)C=2OCC1.O1C2C=CC=C(C=N)C=2OCC1.C[Mg]Br.[O:28]1[C:33]2[CH:34]=[CH:35][CH:36]=[C:37]([CH:38]([NH2:40])[CH3:39])[C:32]=2[O:31][CH2:30][CH2:29]1.FC(F)(F)C(O)=O.[CH3:48][NH:49][C:50]([C:52]1[CH:57]=[C:56]([O:58][C:59]2[CH:70]=[CH:69][C:62]3[N:63]=[C:64](S(C)=O)[O:65][C:61]=3[CH:60]=2)[CH:55]=[CH:54][N:53]=1)=[O:51]>>[CH3:48][NH:49][C:50]([C:52]1[CH:57]=[C:56]([O:58][C:59]2[CH:70]=[CH:69][C:62]3[N:63]=[C:64]([NH:40][CH:38]([C:37]4[C:32]5[O:31][CH2:30][CH2:29][O:28][C:33]=5[CH:34]=[CH:35][CH:36]=4)[CH3:39])[O:65][C:61]=3[CH:60]=2)[CH:55]=[CH:54][N:53]=1)=[O:51]
Reactant: CC(N)c1cccc2c1OCCO2
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)oc3c2)ccn1
Agent: C[Mg]Br
Agent: N=Cc1cccc2c1OCCO2
Agent: O=Cc1cccc2c1OCCO2
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc(Oc2ccc3nc(NC(C)c4cccc5c4OCCO5)oc3c2)ccn1

Procedure:
An amine linked to a resin is reacted with 2,3-dihydro-benzo[1,4]dioxine-5-carbaldehyde, thus giving C-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-methyleneamine. C-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-methyleneamine is derivatized with alkylation at the imino site, such as with methyl magnesium bromide. Other alkylating agents can be used according to the desired molecule. The resulting 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethylamine is cleaved from the resin. An example of a resin-cleaving agent is trifluoroacetic acid (TFA). The resulting 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethylamine can be used for synthesis of a compound of the embodiments. For instance, 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethylamine can be used to react with 4-(2-methanesulfinyl-benzooxazol-6-yloxy)-pyridine-2-carboxylic acid methylamide to form 4-{2-[1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethylamino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic acid methylamide.
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[OH:3].CCN(CC)CC.[Si:13](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[Si:13]([O:3][CH:2]([CH3:4])[C:1]#[N:5])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(O)C#N
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C#N)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Into a flask containing DL-lactonitrile (36.3 mmol, 2.8 g) in DCM (25 ml), Et3N (54.7 mmol, 8.1 ml) and tert-butyldiphenylsilyl chloride (36.3 mmol, 10 g) were added. The resulting solution was stirred at RT for 24 h. The reaction mixture was quenched with H2O and extracted with DCM. The organic layer was washed with brine, dried, filtered and evaporated. The crude product was purified by flash-chromatography. Yield 4.52 g. 1H-NMR (400 MHz; CDCl3): δ 1.10 (s, 9H), 1.50 (d, 3H), 4.43 (q, 1H), 7.39-7.51 (m, 6H), 7.65 (d, 2H), 7.71 (d, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[C:29]1([C:35]#[CH:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.[Al]>CN(C=O)C.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.[Cu]I>[CH3:28][N:25]1[CH2:24][CH2:23][N:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15]/[CH:14]=[C:5]3\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]4[C:4]\3=[CH:3][C:2]([C:36]#[C:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:11][CH:10]=4)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1
Reactant: CN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Al]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(C#Cc5ccccc5)cc43)cc2)CC1
Temperature: 70 °C
Yield: 53.6 %

Procedure:
A mixture of (4Z)-6-bromo-4-({[4-(4-methylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione (0.10 g, 0.23 mmol), 0.03 mL (0.27 mmol) of phenylacetylene, 0.04 g (0.046 mmol) of dichlorobis(triphenylphosphine)-palladium(II), 0.0043 g (0.023 mmol) of CuI, and 0.12 mL (1.14 mmol) of triethylamine in 2 mL of N,N′-dimethylformamide is added to a 10 mL round bottom flask, sealed with a rubber septum, de-aired and backfilled with nitrogen gas 3 times, and wrapped around with aluminum foil. The reaction mixture is stirred vigorously at 70° C. in an oil bath under nitrogen. Mass spectroscopy suggested the completion of reaction after 45 min. The reaction mixture is filtered through celite, and subsequently evaporated under high-pressure vacuum to brown solid. The solid is dissolved in warm chloroform and ran through a pad of florisil, which is rinsed with 200 mL of warm chloroform. The collected organic portion is evaporated under vacuum to give 0.057 g (54.3% yield) of brown solid: mp 169-170° C.; MS (ESI) m/z 463.1 (M+H)+1
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30](O)=[O:31])[CH:28]=2)[CH:23]=[CH:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:30]([C:27]1[CH:28]=[C:29]2[C:24]([CH:23]=[CH:22][NH:21]2)=[CH:25][CH:26]=1)=[O:31]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1NC(=O)c1ccc2cc[nH]c2c1

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 1H-indole-6-carboxylic acid. MS: 417.5 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([N+]([O-])=O)=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1.[ClH:13]>>[Br:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1
Reactant: Cl
Reactant: Cc1cc([N+](=O)[O-])c(Br)c[n+]1[O-]
Product: Cc1cc(Cl)c(Br)c[n+]1[O-]
Temperature: 25 °C

Procedure:
5-Bromo-2-methyl-4-nitropyridine oxide (7.0 g, 30 mmol) was refluxed in conc. HCl (80 mL) for 16 hrs. The mixture was allowed to cool to rt, partially concentrated and then neutralized by NaOH (10N) to pH 7. The crude was partitioned between CHCl3 and water. The organic solution was separated, dried and concentrated to yield 5-bromo-4-chloro-2-methylpyridine oxide as a white solid (6.71 g). MS [M+H]+: 223.7; tR=1.91 min. (method 1).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:33]=[C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[N:26][N:27]([CH2:29][C:30]([OH:32])=O)[CH:28]=5)[N:18]4[N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:64]([NH2:69])[C:65]([CH3:68])([CH3:67])[CH3:66]>CN(C)C=O>[CH3:66][C:65]([CH3:68])([CH3:67])[CH2:64][NH:69][C:30](=[O:32])[CH2:29][N:27]1[CH:28]=[C:24]([C:23]2[N:18]3[N:17]=[C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)=[CH:10][CH:11]=4)[N:33]=[C:19]3[CH:20]=[CH:21][CH:22]=2)[CH:25]=[N:26]1
Reactant: CC(C)(C)CN
Reactant: O=C(O)Cn1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)CNC(=O)Cn1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (4-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-pyrazol-1-yl)-acetic acid (0.60 g, 0.128 mmol) in dimethylformamide (1 ml) was added EDCI (50 mg, 0.256 mmol), diisopropylethylamine (112 μl, 0.640 mmol), HOBT (35 mg, 0.256 mmol) and finally neopentylamine (30 μl, 0.256 mmol). The mixture was stirred for 18 hours at room temperature, then filtered and concentrated in vacuo. The title compound was purified by preparatory HPLC to yield the desired product. LCMS method: 2, RT: 2.51 min, MI: 517 [M+1]; 1H NMR (300 MHz, DMSO) 9.40 (s, 1H), 8.85 (s, 1H), 8.42 (s, 1H), 8.16 (s, 2H), 7.61 (d, 2H), 7.54 (d, 1H), 7.40 (dd, 2H), 6.92 (d, 2H), 4.98 (s, 2H), 4.02 (t, 2H), 2.93 (d, 2H), 2.87 (t, 2H), 2.63 (s, 4H), 1.69 (s, 4H), 0.83 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24]([OH:26])=O.Cl.[F:28][C:29]1[CH:34]=[CH:33][C:32]2[C:35]3([CH2:41][O:42][C:31]=2[CH:30]=1)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24]([N:38]1[CH2:39][CH2:40][C:35]2([C:32]3[CH:33]=[CH:34][C:29]([F:28])=[CH:30][C:31]=3[O:42][CH2:41]2)[CH2:36][CH2:37]1)=[O:26]
Reactant: Fc1ccc2c(c1)OCC21CCNCC1
Reactant: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)O)cnc12
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc12
Yield: 99.6 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-(2-chloro-5-methylphenylamino)-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.130 g, 0.347 mmol) obtained in Example 66, step 2 and 6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]hydrochloride (0.079 g, 0.382 mmol), the title compound (0.195 g, 100%) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:14][CH2:15][CH2:16][CH3:17])=[N:8][C:9](SC)=[N:10][CH:11]=1)=[O:5])[CH3:2].C([N:21](CC)C(C)C)(C)C.N.O>CN1CCCC1=O.ClC1C=CC=C(C(OO)=O)C=1>[NH2:21][C:9]1[N:8]=[C:7]([NH:14][CH2:15][CH2:16][CH3:17])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][N:10]=1
Reactant: CCCNc1nc(SC)ncc1C(=O)OCC
Reactant: CCN(C(C)C)C(C)C
Agent: N
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCNc1nc(N)ncc1C(=O)OCC
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-(methylthio)-4-(propylamino)pyrimidine-5-carboxylic acid ethyl ester (A1, 11.7 g) in N-methylpyrrolidone (90 mL), meta-chloroperbenzoic acid (70 to 75% wt, 20.8 g) was added under ice cooling, and the mixture was stirred at room temperature for 40 minutes. To the reaction mixture, N,N-diisopropylethylamine (23.9 mL) and 10% aqueous ammonia (60.0 mL) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into water (400 mL). The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain ethyl 2-amino-4-(propylamino)pyrimidine-5-carboxylate (C3, 8.0 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=[O:12].S(Cl)(Cl)=O.[CH3:18]O>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([O:13][CH3:18])=[O:12]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2ccccc2n1
Temperature: 0 °C

Procedure:
To an ice-cooled solution of quinoline-2-carboxylic acid 3.1 (10 g, 0.0578 mol) in 100 mL of absolute methanol was added dropwise thionyl chloride (20 g, 0.173 mol). After the addition was completed, the mixture was heated to reflux for 2 h. The solvent was then evaporated to dryness under reduced pressure and treated with 100 mL of 10% aqueous solution of K2CO3. The mixture was extracted with ethyl acetate; combined organic extracts were dried over sodium sulfate and evaporated to dryness to afford of methyl quinoline-2-carboxylate. Yield: 10.1 g (93%).
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:11]([CH:13]1[O:15][CH2:14]1)Br>CN(C=O)C.O>[O:15]1[CH2:14][CH:13]1[CH2:11][O:8][CH2:7][C:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCC1CO1
Reactant: OCC1=CC=CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C1=CCCC(COCC2CO2)=C1
Reaction time: 0.17 h
Yield: 76.4 %

Procedure:
(Compound No. 229) 1,3-Cyclohexadiene-1-methanol (2 g, 0.0182 mol) synthesized in Example 21 was dissolved in DMF (10 ml) and 60% sodium hydride (775 mg, 0.0194 mol) was added at 0° C. The mixture was stirred for 10 minutes and a solution of epibromohydrin (3 g, 0.022 mol) in DMF (3 ml) was added dropwise. The mixture was stirred at room temperature for 1 hour and at 40° C. for 1 hour and the reaction mixture was poured in water, extracted with ethyl acetate and the combined ethyl acetate layer was washed with water, dried over sodium sulfate and the solvent was distilled off. The residue was separated and purified by silica gel column chromatography (silica gel 60 g, ethyl acetate:hexane=1:10) to obtain 1-(2,3-epoxypropoxymethyl)-cyclohexa-1,3-diene (2.31 g, 76%). This compound has the following NMR spectrum.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.C(N(CC)CC)C.[Br:18][CH:19]([CH3:23])[C:20](Br)=[O:21].C(=O)([O-])O.[Na+]>O1CCCC1>[Br:18][CH:19]([CH3:23])[C:20]([NH:6][C:5]1[C:7]([CH3:9])=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[CH3:10])=[O:21]
Reactant: Cc1cc(Br)cc(C)c1N
Reactant: CC(Br)C(=O)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1NC(=O)C(C)Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of 4-bromo-2,6-dimethylaniline (100.0 g) in tetrahydrofuran (400 mL) was added triethylamine (60.7 g) and 2-bromopropionyl bromide (129.5 g) under ice-cooling. The mixture was stirred at room temperature for 1 hour and cooled in an ice-cooling bath. To the reaction mixture was added a sodium hydrogencarbonate aqueous solution and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with water and diethyl ether, and dried to give 2-bromo-N-(4-bromo-2,6-dimethylphenyl)propionamide (151.2 g).
Reaction SMILES: [N:1]1([S:11]([C:14]2[N:15]=[N:16][CH:17]=[CH:18][CH:19]=2)(=[O:13])=[O:12])[C:10]2[CH:5]([CH2:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.FS(C1N=N[C:27]([O:30]C)=CC=1)(=O)=O.N1C2C(=CC=CC=2)CCC1>>[CH3:27][O:30][C:17]1[N:16]=[N:15][C:14]([S:11]([N:1]2[C:10]3[CH:5]([CH2:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)(=[O:13])=[O:12])=[CH:19][CH:18]=1
Reactant: COc1ccc(S(=O)(=O)F)nn1
Reactant: O=S(=O)(c1cccnn1)N1CCCC2CC=CC=C21
Agent: c1ccc2c(c1)CCCN2
Product: COc1ccc(S(=O)(=O)N2CCCC3CC=CC=C32)nn1
Temperature: 140 °C
Yield: 73 %

Procedure:
3-Methoxy-6-(tetrahydroquinoline-1-sulfonyl-pyridazine. A mixture of 3-fluorosulfonyl-6-methoxypyridazine (2 mmol, 384 mg) and tetrahydroquinoline (4 mmol, 532 mg) was heated at 140° C. for two hours. The reaction mixture was cooled, extracted with EtOAc (20 mL), and the EtOAc extract was dried, filtered and evaporated to obtain 3-methoxy-6-(tetrahydroquinoline-1-sulfonyl)-pyridazine (73%, 451 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([C:8]([N:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C([O-])(=O)C.[Pd]>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]([C:8]([N:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2-c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Product: Nc1ccc(C(=O)N2CCc3ccccc3-c3ccccc32)cc1
Yield: 94.9 %

Procedure:
A solution of 0.15 g of 5-(4-nitrobenzoyl)-6,7-dihydro-5H-dibenz[b,d]azepine in 20 μl of ethanolethyl acetate and 10 mg of 10% palladium-on-carbon is hydrogenated under 35 pounds per square inch of hydrogen for 8 hr. The mixture is filtered through diatomaceous earth and the filtrate evaporated to give 0.13 g of product as a light yellow solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[N+:16]([O-])([OH:18])=[O:17]>O>[N+:16]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:5]=[N:4][C:3]([S:2][CH3:1])=[CH:15][C:14]2=1)([O-:18])=[O:17]
Reactant: CSc1cc2c(cn1)[nH]c1ccccc12
Reactant: O=[N+]([O-])O
Solvent: O
Product: CSc1cc2c(cn1)[nH]c1ccc([N+](=O)[O-])cc12

Procedure:
970 mg of 3-methylthio-β-carboline are stirred for 4 hours at room temperature with 60 ml of 65% nitric acid. After introduction of the preparation into water, it is suctioned off and dried. 950 mg of 6-nitro-3-methylthio-β-carboline with a >250° C. melting point are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCCc1ccccc1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCCc2ccccc2)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.3 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (60 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and 2-bromoethylbenzene (0.10 ml, 0.73 mmol) in order. The mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (117 mg, yield 63%).
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](Cl)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[NH2:18][C:19]1[CH:27]=[CH:26][C:25]2[N:24]([CH2:28][CH2:29][OH:30])[C:23]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:22][C:21]=2[C:20]=1[C:35]#[N:36].C(N(CC)CC)C>ClCCl>[C:31]([C:23]1[N:24]([CH2:28][CH2:29][OH:30])[C:25]2[C:21]([CH:22]=1)=[C:20]([C:35]#[N:36])[C:19]([NH:18][C:14]([C:11]1([C:9]3[CH:8]=[CH:7][C:5]4[O:6][C:2]([F:17])([F:1])[O:3][C:4]=4[CH:10]=3)[CH2:13][CH2:12]1)=[O:15])=[CH:27][CH:26]=2)([CH3:34])([CH3:32])[CH3:33]
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: CC(C)(C)c1cc2c(C#N)c(N)ccc2n1CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1cc2c(C#N)c(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2n1CCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (196 mg, 0.75 mmol) was added to a solution of 5-amino-2-tert-butyl-1-(2-hydroxyethyl)-1H -indole-4-carbonitrile (150 mg, 0.58 mmol) and triethylamine (242 μL, 1.74 mmol) in dichloromethane (2 mL). The reaction was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and extracted with 1N HCl solution (×2), saturated NaHCO3 solution (×2), brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in DMSO and purified by reverse-phase HPLC to yield the product, N-(2-tert-butyl-4-cyano -1-(2-hydroxyethyl)-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 481.2, found 482.5 (M+1)+. Retention time 1.99 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.51 (s, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.33 (d, J=1.6 Hz, 1H), 7.08 (d, J=8.8 Hz, 1H), 6.28 (s, 1H), 5.05 (t, J=5.6 Hz, 1H), 4.42 (t, J=6.8 Hz, 2H), 3.70-3.65 (m, 2H), 1.51-1.48 (m, 2H), 1.44 (s, 9H), 1.19-1.16 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:26][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: NC1CCCCC1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccccc2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NC2CCCCC2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-methanesulfonyl-6-phenyl-pyrimidine-5-carbonitrile and cyclohexylamine in DME. ES-MS m/e (%): 294 (M+H+, 100).