Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9](Cl)[N:8]=2)[CH2:3][CH2:2]1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.O>C1(OC2C=CC=CC=2)C=CC=CC=1>[S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: COc1cccc2c(N3CCSCC3)nc(Cl)cc12
Reactant: C1CNCCN1
Solvent: O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cccc2c(N3CCSCC3)nc(N3CCNCC3)cc12
Yield: 41 %

Procedure:
1-Thiomorpholino-3-piperazino-5-methoxy-isoquinoline was prepared analogous to Example 3 from 1-thiomorpholino-3-chloro-5-methoxy-isoquinoline by heating for 50 hours with piperazine at 190°C in diphenyl ether. M.p. of the hemisulfate: 282°-284°C (decomp., from water). Yield: 41% of theory.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:51])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]([CH:36]4[CH2:38][CH2:37]4)[CH2:22][C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=4[O:30][C@H:31]([CH2:33][CH:34]=C)[CH3:32])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:39])[C:12]=2[C@H:40]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:7][CH2:6]1)[CH:2]=C.[BH4-].[Na+]>C(Cl)Cl.O>[C:47]([O:46][C@@H:40]([C:12]1[C:13]([CH3:39])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:7][CH2:6][C:5]([CH3:51])([O:4][CH2:1][CH2:2][CH2:34][CH2:33][C@H:31]([CH3:32])[O:30][C:24]2[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=2[CH2:22][N:21]([CH:36]2[CH2:37][CH2:38]2)[CH2:20]3)[CH2:10][CH2:9]1)[C:41]([O:43][CH2:44][CH3:45])=[O:42])([CH3:50])([CH3:49])[CH3:48]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CN(Cc4ccc(C)cc4O[C@@H](C)CC=C)C4CC4)nn23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(C)ccc1CN(C1CC1)C3
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
A mixture of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((cyclopropyl(4-methyl-2-((S)-pent-4-en-2-yloxy)benzyl)amino)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (90 mg, 0.128 mmol) and Grubb's II catalyst (10.89 mg, 0.013 mmol) in DCM (80 mL) was refluxed for 2 h. It was then concentrated and the residue was dissolved in MeOH (2 mL). NaBH4 (4.85 mg, 0.128 mmol) was added and the reaction was stirred at rt for 1 h. It was then diluted with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 25% EtOac/hexane to obtain ethyl (2S)-2-(tert-butoxy)-2-[(20S)-11-cyclopropyl-4,16,20,26-tetramethyl-19,25-dioxa-1,5,7,8,11-pentaazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13(18),14,16-heptaen-3-yl]acetate (90 mg, 0.107 mmol, 83% yield) as a white solid. LCMS (M+1)=676.4.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)[C:3](=O)[CH3:4].[NH2:15][C:16]([NH2:18])=[S:17]>C(O)C>[CH3:4][C:3]1[N:15]=[C:16]([NH2:18])[S:17][C:2]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1
Reactant: NC(N)=S
Reactant: CC(=O)C(Br)c1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: Cc1nc(N)sc1-c1cccc([N+](=O)[O-])c1
Temperature: 70 °C

Procedure:
A stirred solution of 1-Bromo-1-(3-nitro-phenyl)-propan-2-one (98a) (2.4 g, 9.3 mmol) in ethanol (20 ml) at room temperature is treated with thiourea (0.71 g, 9.3 mmol). The reaction mixture is heated to 70° C. for 10 minutes. The resulting precipitate is removed by filtration and dried under vacuum to give the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[C:5]2=O.[NH2:13][C:14]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:15]=1[NH:16]C.Br.O>C(O)(=O)C>[CH3:22][C:20]1[CH:21]=[C:14]2[C:15](=[CH:18][CH:19]=1)[N:16]=[C:6]1[NH:7][C:8]3[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=3[C:5]1=[N:13]2
Reactant: CNc1ccc(C)cc1N
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc2nc3[nH]c4ccc(Br)cc4c3nc2c1
Reaction time: 2 h

Procedure:
A solution of 2.26 g 5-bromoisatin (0.01 mole) and 1.36 g 2-amino N-methyl-p-toluidine (0.01 mole) in 15 ml acetic acid is boiled with reflux for 45 minutes. Finally hydrogen bromide is introduced and the mixture is boiled for further 2 hours. After cooling it is poured into water. The dried reaction product is recrystallized from acetic acid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[NH2:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]=[N:12]2)=[C:8](Cl)[N:7]=1>O.CS(C)=O>[NH2:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]=[N:12]2)=[C:8]([N:1]=[N+:2]=[N-:3])[N:7]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=Nc1nc(N)nc2nc[nH]c12
Yield: 89.3 %

Procedure:
A solution of sodium azide (14.08 g, 0.216 mol) in water (35 mL) was added to a solution of 2-amino-6-chloropurine (28.27 g, 0.166 mol) in dimethyl sulfoxide (DMSO, 280 mL). The mixture was heated at 100°-110° C. for 24 h, then the resulting suspension was cooled and poured into 1.3 L of water. The precipitate was collected by filtration, washed with water and dried to afford 26.11 g of 2-amino-6-azidopurine, mp>260° C.; IR (KBr) 3313, 3146, 1678, 1641, 1551 cm-1 ; 1H NMR (DMSO-d6, 360 MHz) δ8.18 (s, 1H), 8.25 (bs, 2H), 13 (vbs, 1H); 13C NMR (DMSO-d6, 90 MHz), 110.8, 138.7, 143.4, 145.7 , 146.1 ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[Se:4][NH:3]1.[OH:12]O>CO>[CH3:1][C:2]1([CH3:11])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[Se:4](=[O:12])[NH:3]1
Reactant: CC1(C)N[Se]c2ccccc21
Reactant: OO
Solvent: CO
Product: CC1(C)N[Se](=O)c2ccccc21
Reaction time: 0.25 h
Yield: 55 %

Procedure:
The derivative 3,3-dimethyl-benzisoselenazoline BXT-51056 (212 mg; 1 mmole) was dissolved at room temperature in methanol (5 ml) with stirring. After addition of 5% hydrogen peroxide (600 μl; 1.05 mmole), stirring was continued for 15 min. The solvent was evaporated off under reduced pressure. The residue was taken up in 25 ml of dichloromethane and washed with 3×3 ml of a saturated NaCl solution, dried over Na2SO4 then filtered. After evaporation of the solvent under reduced pressure, the desired product was obtained in the form of yellowish crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH2:31][C:32](O)=[O:33])[CH:25]=1>>[OH:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][NH:14][C:10]2[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[CH:7]=[CH:6][CH:5]=3)[CH:13]=[CH:12][N:11]=2)=[CH:22][CH:21]=1
Reactant: O=C(O)CCc1cccnc1
Reactant: Nc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Product: O=C(CCc1cccnc1)Nc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 24 was coupled to 3-Pyridin-3-yl-propionic acid following procedure K. LC-MS showed the product had the expected M+H+ of 440. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 9.1 (s, 1H), 8.5 (d, 1H) 8.3 (d, 1H) 7.7 (m, 3H), 7.4 (t, 1H), 7.3 (t, 1H), 7.2 (d, 1H), 7.1 (d, 1H), 7.0 (d, 2H), 6.7 (d, 2H), δ 3.5 (t, 2H), 2.9 (t, 2H), 2.8 (t, 2H), δ 2.7 (t, 2H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]([CH2:29][CH3:30])[C:6]3[C:11]([N:12]=2)=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][C@@H:14]2[CH3:19])[N:9]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)[N:7]=3)[CH2:3][CH2:2]1.C1COCC1>CO.[Pd]>[CH:1]1([C:4]2[N:5]([CH2:29][CH3:30])[C:6]3[C:11]([N:12]=2)=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][C@@H:14]2[CH3:19])[N:9]=[C:8]([C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=2)[N:7]=3)[CH2:2][CH2:3]1
Reactant: CCn1c(C2CC2)nc2c(N3CCOC[C@@H]3C)nc(-c3ccc([N+](=O)[O-])cc3)nc21
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCn1c(C2CC2)nc2c(N3CCOC[C@@H]3C)nc(-c3ccc(N)cc3)nc21
Yield: 73.9 %

Procedure:
A solution of (S)-4-(8-cyclopropyl-9-ethyl-2-(4-nitrophenyl)-9H-purin-6-yl)-3-methylmorpholine (76.0 mg, 0.186 mmol) dissolved in anhydrous methanol (3.0 mL) and anhydrous THF (4.6 mL) was subjected to a continuous flow hydrogenated apparatus (H-Cube: 10% Pd/C cartridge, 1.0 mL/min flow). The crude was concentrated in vacuo and purified by column chromotagraphy (Si-PPC, gradient 20 to 100% ethyl acetate in heptane) to give the desired product as a white solid (52.0 mg, 73.8%). 1H NMR (CDCl3, 500 MHz) δ ppm 8.28 (d, J=8.5 Hz, 2H), 6.73 (d, J=8.6 Hz, 2H), 5.47 (broad s, 1H), 5.17 (broad s, 1H), 4.40 (broad s, 2H), 4.03 (dd, J=11.3 Hz, 3.3 Hz, 1H), 3.89 to 3.77 (m, 2H), 3.68 (td, J=12.0 Hz, 2.8 Hz, 1H), 3.50 (t, J=11.7 Hz, 1H), 2.02 to 1.91 (m, 1H), 1.48 (t, J=7.2 Hz, 3H), 1.39 (d, J=6.8 Hz, 3H), 1.33 to 1.22 (m, 2H), 1.20 to 1.10 (m, 2H), 1.06 (dd, J=8.0 Hz, 3.1 Hz, 2H); LC-MS m/z (method A)=379.3 [M+H]+, RT=1.96 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH:5]([N+:27]([O-])=O)[CH:6]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[NH:12][CH:11]=1)[CH2:7][O:8][CH3:9])[CH3:2]>C(O)C.[Ni]>[CH2:1]([O:3][C:4](=[O:30])[CH:5]([NH2:27])[CH:6]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[NH:12][CH:11]=1)[CH2:7][O:8][CH3:9])[CH3:2]
Reactant: CCOC(=O)C(C(COC)c1c[nH]c2cccc(Cc3ccccc3Cl)c12)[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)C(N)C(COC)c1c[nH]c2cccc(Cc3ccccc3Cl)c12
Yield: 92.6 %

Procedure:
6.1 g (0.014 mol) of 3-[4-(2-chlorobenzyl)-indol-3-yl]-4-methoxy-2-nitrobutyric acid ethyl ester is hydrogenated in 125 ml of ethanol with 6 g of Raney nickel at standard pressure and room temperature. After 41/2 hours the hydrogen absorption is completed. The Raney nickel is filtered off, the filtrate is concentrated by evaporation and a crude product of 5.2 g of 2-amino-3-[4-(2-chlorobenzyl)-indol-3-yl]-4-methoxybutyric acid ethyl ester is obtained, that is used without further purification in the next stage.
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[C:16]2[CH:25]=[C:24]([CH:26]=[O:27])[NH:23][C:17]=2[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=1.[CH3:33][Mg]Br.Cl>O1CCCC1>[F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:12])=[O:13])=[CH:7][C:6]=1[C:15]1[C:16]2[CH:25]=[C:24]([CH:26]([OH:27])[CH3:33])[NH:23][C:17]=2[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=1
Reactant: C[Mg]Br
Reactant: Cn1cc(-c2cc(S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)c2cc(C=O)[nH]c2c1=O
Agent: Cl
Solvent: C1CCOC1
Product: CC(O)c1cc2c(-c3cc(S(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c(=O)c2[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.4 %

Procedure:
To a solution of Example 278a (0.20 g, 0.44 mmol) in tetrahydrofuran (6 mL) at 0° C. was added methylmagnesium bromide (1.0 M in tetrahydrofuran, 0.873 mL, 0.873 mmol). The reaction mixture was stirred at 0° C. for one hour, and then 1M aqueous HCl (2 mL) was added. The reaction mixture was concentrated and partitioned between saturated aqueous sodium chloride (10 mL) and ethyl acetate (2×30 mL). The combined organic phase was washed with saturated aqueous sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin layer chromatography (silica gel, dichloromethane/methanol, 15/1) to provide the title compound (51 mg, 24% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.83 (s, 1H), 7.96 (d, J=2.4 Hz, 1H), 7.86 (dd, J=2.4, 6.4 Hz, 1H), 7.55-7.50 (m, 1H), 7.42-7.36 (m, 2H), 7.20-7.15 (m, 1H), 6.97 (d, J=8.8 Hz, 1H), 6.15 (d, J=2 Hz, 1H), 5.13 (d, J=5.2 Hz, 1H), 4.80-4.77 (m, 1H), 3.57 (s, 3H), 3.25 (s, 3H), 1.38 (d, J=6.4 Hz, 3H). MS (ESI+) m/z 475.1 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][P:4]([O:7][CH2:8][CH2:9][C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16]C(C)(C)C)=[O:15])=[CH:12][CH:11]=1)([CH3:6])=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][P:4]([O:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:21][CH:22]=1)([CH3:6])=[O:5])[CH3:2]
Reactant: CCOP(C)(=O)OCCc1ccc(C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOP(C)(=O)OCCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-(2-{[ethoxy(methyl)phosphoryl]oxy}ethyl)benzoate (108 mg, 0.33 mmol) in DCM (0.66 mL) was added TFA (0.60 mL, 7.8 mmol). After stirring at room temperature for 30 minutes, the solution was concentrated in vacuo to give the title compound as a colorless oil. 1H NMR (CDCl3, 600 MHz) δ 7.85 (d, J=8.2 Hz, 2H), 7.37 (d, J=8.2 Hz, 2H), 4.10-4.16 (m, 2H), 3.80-3.88 (m, 2H), 2.95 (t, J=6.4 Hz, 2H), 1.32 (d, J=17.3 Hz, 3H), 1.13 (t, J=7.1 Hz, 3H). MS cal'd 272 (MH+), exp 272 (MH+).
Reaction SMILES: [CH:1]([NH:14][C:15]1[C:20]([Cl:21])=[C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]3[C:37](=[O:38])[C:36]([C:39]4[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=4)=[CH:35][NH:34][CH:33]=3)=[O:31])=[CH:25][C:24]=2[F:46])[CH:18]=[CH:17][N:16]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[N:53]1([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:58][CH2:57][CH:56]([C:59]([O:61][CH2:62]Cl)=[O:60])[CH2:55][CH2:54]1>CN(C=O)C.C(Cl)Cl>[N:53]1([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:54][CH2:55][CH:56]([C:59]([O:61][CH2:62][N:34]2[CH:35]=[C:36]([C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)[C:37](=[O:38])[C:32]([C:30](=[O:31])[NH:29][C:26]3[CH:27]=[CH:28][C:23]([O:22][C:19]4[CH:18]=[CH:17][N:16]=[C:15]([NH:14][CH:1]([C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)[C:20]=4[Cl:21])=[C:24]([F:46])[CH:25]=3)=[CH:33]2)=[O:60])[CH2:57][CH2:58]1
Reactant: O=C(Nc1ccc(Oc2ccnc(NC(c3ccccc3)c3ccccc3)c2Cl)c(F)c1)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)OCCl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)OCn2cc(C(=O)Nc3ccc(Oc4ccnc(NC(c5ccccc5)c5ccccc5)c4Cl)c(F)c3)c(=O)c(-c3ccc(F)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
A mixture of N-(4-(2-(benzhydrylamino)-3-chloropyridin-4-yloxy)-3-fluorophenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (120 mg, 0.189 mmol), K2CO3 (104 mg, 0.756 mmol) and 1-tert-butyl 4-chloromethyl piperidine-1,4-dicarboxylate (157 mg, 0.567 mmol) in DMF (2 mL) was stirred at rt for 3 h. The reaction mixture was then diluted with DCM and the solid that formed was filtered off. The residue was washed with sat. aq. KH2PO4 solution. The organic layer was dried over MgSO4 and the desired product was purified by flash column chromatography (SiO2, eluting with a DCM/EtOAc gradient) to give the desired compound (145 mg) as a white solid. MS (ESI+) m/z 876 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:22]=[CH:21][C:7]([NH:8][C:9]2[NH:10][C:11](=[O:20])[C:12]([C:15]([O:17]CC)=[O:16])=[CH:13][N:14]=2)=[CH:6][CH:5]=1)[CH3:2].[OH-].[Na+].O>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:22]=[CH:21][C:7]([NH:8][C:9]2[NH:10][C:11](=[O:20])[C:12]([C:15]([OH:17])=[O:16])=[CH:13][N:14]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc(Nc2ccc(OCC)cc2)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCOc1ccc(Nc2ncc(C(=O)O)c(=O)[nH]2)cc1
Reaction time: 1 h
Yield: 55.1 %

Procedure:
Ethyl 1,6-dihydro-2-(4-ethoxyanilino)-6-oxo-5-pyrimidinecarboxylate (10 g) and sodium hydroxide (3 g) are added to water (50 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (50 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80° C. under reduced pressure to give 1,6-dihydro-2-(4-ethoxyanilino)-6-oxo-5-pyrimidinecarboxylic acid (5 g). M.p. 250°-252° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][CH3:20])=[CH:15][C:14](Br)=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(NCC)C.[CH3:27][N:28]([CH3:32])[CH2:29][C:30]#[CH:31]>[Cl-].[Cl-].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Pd+2].CN1CCCC1=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][CH3:20])=[CH:15][C:14]([C:31]#[C:30][CH2:29][N:28]([CH3:32])[CH3:27])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(Br)cc3c2c1CC
Reactant: C#CCN(C)C
Agent: [Pd+2]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: CCNCC
Product: CCOC(=O)c1ncc2[nH]c3ccc(C#CCN(C)C)cc3c2c1CC
Yield: 48.7 %

Procedure:
347 mg of 6-bromo-4-ethyl-beta-carboline-3-carboxylic-acid-ethylester, 32 mg of palladium-bis-(tri-o-tolylphosphine)-dichloride, 32 mg of cuprous iodide, 5 ml of diethylamine, 5 ml of N-methyl-2-pyrrolidone and 250 mg of 3-dimethylamino-1-propine are heated anhydrously and under nitrogen for 7.5 h at 80°-90° C. After concentration in an oil pump vacuum, the residue is chromatographed on 30 g of silica gel with methylene-chloride/methanol (10/2) as the eluant. The correspondingly consolidated fractions are separated by preparative film chromatography and 170 mg of 6-(3-dimethylamino-1-propinyl)-4-ethyl-beta-carboline-3-carboxylic-acid-ethylester is obtained in the form of an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]([O:10]C)=O.[NH2:12][NH2:13]>C(O)C>[NH2:12][NH:13][C:8](=[O:10])[CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][NH:1]1
Reactant: NN
Reactant: COC(=O)CC1CCCCN1
Solvent: CCO
Product: NNC(=O)CC1CCCCN1

Procedure:
To a solution of methyl 2-piperidylacetate (1.082 mL, 5.84 mmol) in 1 mL of anhydrous ethanol was added anhydrous hydrazine (0.283 mL, 5.84 mmol). The solution was heated to reflux temperature overnight. The solvent was then removed under reduced pressure and the product was isolated as a gummy white solid in a quantitative yield and was used without further purification: ES-MS (m/z) 158 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[CH:9]=[C:8](C(O)=O)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1>CO.[Cu]>[Br:1][C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2c(Br)cccc2s1
Agent: [Cu]
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: Brc1cccc2sccc12
Temperature: 105 °C
Reaction time: 0.17 h
Yield: 38.2 %

Procedure:
Copper powder (49.8 g) is added to a stirred mixture of 4-bromo-benzo[b]thiophene-2-carboxylic acid (995.5 g, 3.87 mol) and quinoline (1.99 L) and the resultant mixture is heated to and maintained at 15 to 195° C. for 5 h. The mixture is allowed to cool to room temperature and the reaction is quenched by the addition of a mixture of ice (5.81 Kg) and concentrated hydrochloric acid (2.48 L). TBME (9 L) is added and the mixture is stirred vigorously for 10 min and filtered. The clarified layers are separated and the aqueous layer is extracted with TBME (1.0 L). The combined extracts are washed with hydrochloric acid (1 M, 2×5.00 L) and water (4.0 L), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude product (640 g) as a brown oil which solidifies on standing overnight. The residue is slurried in methanol (500 mL, 0.5 vol) at −10 to 0° C. for 1.5 h, the observed solid material is collected by filtration and pulled dry on the filter. The methanolic mother liquors are concentrated by rotary evaporation. The residue is combined with the isolated solid material, slurried in TBME (2.0 L) and the collected solids are washed with TBME (660 L). The combined liquors and washes are washed with hydrochloric acid (1 M, 660 mL), saturated aqueous sodium hydrogen carbonate. (2×1.0 L) and water (4.0 L), dried over magnesium sulfate, filtered and concentrated by rotary evaporation at 40° C. to afford the crude product. The residue is slurried in methanol (1.10 L) at −10 to 0° C. for 1 h. The observed solid is collected by filtration and dried under vacuum at 20° C. to afford 4-bromo-benzo[b]thiophene as an off-white solid (315 g, 37%). 1H NMR (CDCl3): δ 7.81 (d, 1H, J=8.0 Hz), 7.57-7.48 (m, 3H), 7.21 (t, 1H, J=7.7 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH2:11][CH:12](C)C=C)(=[O:10])=[O:9])[CH:3]=1.C([Li])CCC.CI.B.[O:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.OO>O1CCCC1.O>[CH3:25][CH:26]([CH:11]([S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)(=[O:9])=[O:10])[CH3:12])[CH2:27][CH2:28][OH:24]
Reactant: C1CCOC1
Reactant: C=CC(C)CS(=O)(=O)c1cccc(C)c1
Agent: B
Agent: OO
Agent: [Li]CCCC
Solvent: O
Solvent: CI
Product: Cc1cccc(S(=O)(=O)C(C)C(C)CCO)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1-Methyl-3-(2-methylbut-3-ene-1-sulphonyl)benzene (444 mg, 1.96 mmol) was dissolved in tetrahydrofuran (5 ml) and cooled to −78° C. n-Butyllithium (1.6M in hexanes, 1.96 mmol) was added. The reaction was treated with methyl iodide (130 μL, 2.16 mmol) and allowed to warm to room temperature. The mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were dried (MgSO4) and concentrated in vacuo to give a 1:1 mixture of dimethyl diastereoisomers containing approximately 28% monomethyl starting material. This crude mixture (265 mg, 1.12 mmol) was dissolved in tetrahydrofuran (3 ml) at 0° C. and treated with borane-tetrahydrofuran complex (1.0M in tetrahydrofuran, 4.5 ml, 4.5 mmol) then allowed to warm to room temperature and stirred for 6 hours. The reaction was treated cautiously with pre-mixed hydrogen peroxide 35% w/w (5 ml) and water (5 ml) and stirred for 18 hours. The reaction mixture was extracted with ethyl acetate and the combined organic layers were concentrated in vacuo to give a clear oil which was purified by preparative thin layer chromatography, eluting with 25% ethyl acetate/i-hexane to give a 1:1 mixture of diastereoisomers that was used in the next step.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2]2.Br[C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:23][C:22]1[C:17]([N:8]2[CH:5]3[CH2:6][CH2:7][CH:1]2[CH2:2][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]3)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: Clc1cccnc1Br
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2CCC(C1)N2c1ncccc1Cl
Temperature: 120 °C
Reaction time: 48 h

Procedure:
tert-Butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (454 mg, 2.36 mmol) and 2-bromo-3-chloropyridine (418 mg, 1.97 mmol) were combined in dry N,N-dimethylformamide (10 mL) and treated with potassium carbonate (408 mg, 2.95 mmol). After stirring at 120° C. for 48 hours, the mixture was allowed to cool to room temperature, diluted with ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (4:1, hexanes:ethyl acetate) to provide the title compound. MS (ESI) m/z: 324 (M+H)+; 1H NMR (CDCl3) δ 1.47 (s, 9H), 1.77 (m, 2H), 1.93 (m, 2H), 3.22 (d, 1H), 3.31 (d, 1H), 3.76 (d, 1H), 3.90 (d, 1H), 4.53 (d, 2H), 6.76 (dd, 1H), 7.56 (dd, 1H), 8.09 (dd, 1H).