Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([N+:26]([O-])=O)[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C>[NH2:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]([C:29]#[N:30])=[C:16]2[NH:15][C:4]1[CH:5]=[CH:6][C:7]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:2]([Cl:1])[CH:3]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(Sc2ccccc2)c(Cl)c1
Solvent: CCO
Product: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(Sc2ccccc2)c(Cl)c1
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A mixture of 6.753 g (15.6 mmol) 4-[(3-chloro-4thiophenoxyphenyl)amino]-6-nitro-3-quinolinecarbonitrile, 250 ml ethanol, and 17.66 g (78.0 mmol) SnCl2 dihydrate was heated to reflux under N2. Removed heat at 2 hours, added large volume of ice water, and made basic with sodium bicarbonate. Stirred for 2 hours and with mixture still basic, extracted with chloroform. Stirred organic layer with Darco, dried with sodium sulfate, filtered, stripped solvent and dried in vacuo, giving 5.996 g of yellow-brown solid: mass spectrum (electrospray m/e): M+H=403.1, 405.1.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N:10]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11]2)=[N:7][C:8]=1[OH:9])=O.N1CCCCC1.C(O)(=O)C.[CH3:34][C:35]1[N:36]=[C:37]([CH3:50])[C:38]2[N:39]([CH:41]=[C:42]([CH2:44][C:45](OCC)=[O:46])[N:43]=2)[CH:40]=1>CCO>[CH3:34][C:35]1[N:36]=[C:37]([CH3:50])[C:38]2[N:39]([CH:41]=[C:42]([C:44]3[C:45](=[O:46])[O:9][C:8]4=[N:7][C:6]([N:10]5[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11]5)=[CH:5][CH:4]=[C:3]4[CH:1]=3)[N:43]=2)[CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(C=O)c(O)n2)CC1
Reactant: CCOC(=O)Cc1cn2cc(C)nc(C)c2n1
Solvent: CCO
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: Cc1cn2cc(-c3cc4ccc(N5CCCN(C(=O)OC(C)(C)C)CC5)nc4oc3=O)nc2c(C)n1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-(5-formyl-6-hydroxypyridin-2-yl)-1,4-diazepane-1-carboxylate (225 mg, 0.7 mmol) in 3 mL of EtOH were treated with piperidine (119.2 mg, 1.4 mmol), acetic acid (252 mg, 4.2 mmol) and ethyl 2-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)acetate (196 mg, 0.84 mmol) at room temperature. The reaction mixture was stirred in microwave reactor at 150° C. for 2 hours. The mixture was concentrated, quenched with a saturated NaHCO3 solution and extracted with dichloromethane three times. The combined organic layers were combined and concentrated. The residue was purified on silica gel to provide tert-butyl 4-(3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-oxo-2H-pyrano[2,3-b]pyridin-7-yl)-1,4-diazepane-1-carboxylate after concentration. MS m/z 491 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:19])[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)#[CH:21]>>[OH:19][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:21]#[C:20][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:3]=1)[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(Br)c1
Reactant: C#Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCC(O)c1cccc(C#Cc2ccccc2)c1

Procedure:
Sonogashira reaction of 39 with ethynylbenzene gave tert-butyl 3-hydroxy-3-(3-(phenylethynyl)phenyl)propylcarbamate as brown oil. Yield (0.911 g, 85%): 1H NMR (400 MHz, CDCl3) δ 7.51-7.55 (m, 3H), 7.42-7.44 (m, 1H), 7.30-7.37 (m, 5H), 4.87 (bs, 1H), 4.74-4.76 (m, 1H), 3.46-3.51 (m, 1H), 3.41 (bs, 1H), 3.13-3.19 (m, 1H), 1.79-1.88 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: CN(C)C1CCCCC1NC(=O)OCC1C=CC=CC=1.[CH3:21][N:22]([CH3:39])[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[C:29]([O:31]CC1C=CC=CC=1)=[O:30]>>[CH3:21][N:22]([CH3:39])[C@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[C:29]([OH:31])=[O:30]
Reactant: CN(C)C1CCCCC1C(=O)OCc1ccccc1
Agent: CN(C)C1CCCCC1NC(=O)OCc1ccccc1
Product: CN(C)[C@H]1CCCC[C@H]1C(=O)O

Procedure:
A mixture of the amino acid prepared in Part C (31.2 g., 0.15 mole), diphenyl phosphoryl azide (41.3 g.; 0.15 mole), and triethylamine (30.4 g., 0.30 mole) in 750 ml. benzene was refluxed with stirring for 1 hour. Benzyl alcohol (48.7 g., 0.45 mole) was added and the mixture refluxed overnight. The mixture was extracted with 10% HCl. The extract was washed with ether, made basic with 40% KOH, and extracted with ether. The organic layer was washed with water and saturated NaCl solution, dried, and evaporated. The residual oil was distilled to give 8.5 g. (20% yield) mixture of carbamate and benzyl ester, b.p. 130°-50°/0.1 mm. The nmr (CDCl3) was consistent with a mixture of benzyl N-(2-dimethylaminocyclohexyl)carbamate and benzyl 2-dimethylaminocyclohexanecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[NH:6]2.[Br:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([C:23]2[O:24][C:25]([CH2:28]Cl)=[N:26][N:27]=2)[CH:22]=1>>[Br:16][C:17]1[CH:22]=[C:21]([C:23]2[O:24][C:25]([CH2:28][N:6]3[C:7]4[C:3](=[C:2]([Cl:1])[C:10]([C:11]#[N:12])=[CH:9][CH:8]=4)[CH:4]=[C:5]3[CH2:13][CH2:14][CH3:15])=[N:26][N:27]=2)[CH:20]=[N:19][CH:18]=1
Reactant: CCCc1cc2c(Cl)c(C#N)ccc2[nH]1
Reactant: ClCc1nnc(-c2cncc(Br)c2)o1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1nnc(-c2cncc(Br)c2)o1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-propyl-1H-indole-5-carbonitrile and 3-bromo-5-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyridine: 1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J=1.3 Hz, 1H), 8.94 (d, J=2.0 Hz, 1H), 8.46 (s, 1H), 7.97 (s, 1 H), 7.81 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 5.96 (s, 2H), 2.95-2.87 (m, 2H), 1.75-1.48 (m, 2H), 0.93 (t, J=7.3 Hz, 3H); MS (ES) m/z 457 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][C:10]2[C:15]([CH:16]([CH3:18])[CH3:17])=[CH:14][C:13]([OH:19])=[C:12]([I:20])[CH:11]=2)=[CH:4][N:3]=1.Br[CH2:22][CH2:23][O:24][Si:25]([C:28](C)(C)C)([CH3:27])[CH3:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[I:20][C:12]1[C:13]([O:19][CH2:22][CH2:23][O:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[CH:14][C:15]([CH:16]([CH3:18])[CH3:17])=[C:10]([CH:11]=1)[O:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)c1cc(O)c(I)cc1Oc1cnc(N)nc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1cc(OCCO[Si](C)(C)C)c(I)cc1Oc1cnc(N)nc1N
Temperature: 50 °C
Yield: 97 %

Procedure:
A mixture of 4-(2,4-Diamino-pyrimidin-5-yloxy)-2-iodo-5-isopropyl-phenol (0.3 g, 0.78 mmol), (2-bromoethoxy)-tert-butyl-dimethyl silane (0.28 g, 1.17 mmol), and K2CO3 (0.22 g, 1.56 mmol) in anhydrous DMF (5 ml) was heated at 50° C. for 16 hrs. Solvent was removed in vacuo. The residue was partitioned between methylene chloride and water. The combined organic extracts was washed with water, dried over Na2SO4, filtered and concentrated. Flash chromatography on silica(3% MeOH in methylene chloride with 0.1% NH4OH) gave 5-[5-Iodo-2-isopropyl-4-(2-trimethylsilanyloxy-ethoxy)-phenoxy]-pyrimidine-2,4-diamine (0.38 g, 90% ) as a solid.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:12]([C:14]1[S:15][C:16]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:17]=3[CH:18]=1)=[O:13])[CH2:4]2.C(N(CC)CC)C.[C:31]([Cl:39])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[ClH:39].[N:3]12[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]1)[C@@H:5]([NH:11][C:12]([C:14]1[S:15][C:16]3[CH:22]=[CH:21][C:20]([NH:23][C:31](=[O:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:19][C:17]=3[CH:18]=1)=[O:13])[CH2:4]2
Reactant: Nc1ccc2sc(C(=O)N[C@H]3CN4CCC3CC4)cc2c1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2sc(C(=O)N[C@H]3CN4CCC3CC4)cc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
30 mg (0.08 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-amino-1-benzothiophene-2-carboxamide dihydrochloride are dissolved in 1 ml of DMF, and 33.5 μl (0.24 mmol) of triethylamine are added. At 0° C., 16.9 mg (0.12 mmol) of benzoyl chloride are added. After 3 h of stirring at RT, the reaction mixture is separated by preparative HPLC. The product fraction is concentrated under reduced pressure and codistilled with 4M HCl in dioxane. 9 mg (25.4% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]([N:22]([CH2:30][CH2:31][C:32]3[CH:37]=[C:36]([O:38][CH3:39])[C:35]([NH2:40])=[CH:34][C:33]=3[Cl:41])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:42]([C:44]1[N:45]=[CH:46][C:47]([NH:50][C:51](=O)[O:52]C2C=CC=CC=2)=[N:48][CH:49]=1)#[N:43]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]([N:22]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:30][CH2:31][C:32]3[CH:37]=[C:36]([O:38][CH3:39])[C:35]([NH:40][C:51]([NH:50][C:47]4[CH:46]=[N:45][C:44]([C:42]#[N:43])=[CH:49][N:48]=4)=[O:52])=[CH:34][C:33]=3[Cl:41])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1cnc(NC(=O)Oc2ccccc2)cn1
Reactant: COc1cc(CCN(C(=O)OC(C)(C)C)[C@@H](C)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)c(Cl)cc1N
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CCN(C(=O)OC(C)(C)C)[C@@H](C)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)c(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Temperature: 25 °C
Yield: 57.3 %

Procedure:
A stirred solution of 4-[4-((S)-1-{[2-(4-amino-2-chloro-5-methoxy-phenyl)-ethyl]-tert-butoxycarbonyl-amino}ethyl)-phenyl]piperazine-1-carboxylic acid tert-butyl ester (0.28 g, 0.475 mmol) and phenyl 5-cyanopyrazin-2-ylcarbamate (0.091 g, 0.38 mmol) in DMF (18 mL) was heated to 100° C. for 1 hour. The mixture was allowed to cool to room temperature, diluted with water (50 mL) and extracted with EtOAc (2×40 mL). The combined organic extracts were washed with water (3×40 mL), brine (40 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified with column chromatography on neutral silica gel using 25% EtOAc in hexane to give the title compound (0.16 g, 46%).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])O)=[C:16]([F:30])[CH:15]=1.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1.FC(F)(F)C(O)=O>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])[C:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH:10]=2)=[C:16]([F:30])[CH:15]=1
Reactant: OC(c1ccc(F)cc1F)c1ccc(Cl)cc1F
Reactant: CSCc1cccc2cc[nH]c12
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3)c[nH]c12
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc2c(C(c3ccc(F)cc3F)c3ccc(Cl)cc3F)c[nH]c12
Temperature: 80 °C
Reaction time: 48 h

Procedure:
The title compound was prepared starting from 750 mg (4.23 mmol) of the compound from Example 8A and 1.15 g (4.23 mmol) of the compound from Example 181A in analogy to the synthesis of the compound from Example 278. A difference was that stirring at 80° C. for two days was followed by addition of 0.33 ml (4.23 mmol) of trifluoroacetic acid and stirring for an additional 16 h. 65 mg (75% purity, 3% of theory) of the target compound were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[Cl:16])\[CH3:7])[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[Cl:16])\[CH2:7][Br:18])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)/C=C(\C)Oc1cc(Cl)ccc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1cc(Cl)ccc1Cl
Yield: 42.4 %

Procedure:
To a stirred mixture of (E)-3-(2,5-dichloro-phenoxy)-but-2-enoic acid ethyl ester (3.25 g, 0.012 mol) in carbon tetrachloride (20 mL) under a nitrogen atmosphere was added N-bromosuccinimide (3.20 g, 0.018 mol) and benzoyl peroxide (290 mg, 0.001 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(2,5-dichloro-phenoxy)-but-2-enoic acid ethyl ester (1.80 g, 43%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][N:9]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:6]2=[N:7][CH:8]=1.[Cl:30][C:31]1[CH:36]=[C:35](I)[CH:34]=[C:33]([Cl:38])[N:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.CCO.O.O.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>[Cl:30][C:31]1[CH:36]=[C:35]([C:11]2[C:5]3[C:6](=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]([S:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)(=[O:23])=[O:22])[CH:10]=2)[CH:34]=[C:33]([Cl:38])[N:32]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: COc1cnc2c(c1)c(B1OC(C)(C)C(C)(C)O1)cn2S(=O)(=O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: COc1cnc2c(c1)c(-c1cc(Cl)nc(Cl)c1)cn2S(=O)(=O)c1ccccc1
Temperature: 80 °C
Yield: 56 %

Procedure:
A suspension of Example 149c (0.150 g, 0.362 mmol), 2,6-dichloro-4-iodopyridine (0.099 g, 0.362 mmol), dichlorobis(triphenylphosphine)palladium(II) (10.17 mg, 0.014 mmol) and 1M sodium carbonate (0.290 mL, 0.290 mmol) in dimethoxyethane/EtOH/water (7:2:3, 2.5 mL) was degassed and heated at 80° C. overnight. After cooling, the suspension was diluted with water and extracted with EtOAc (2×). The suspension in the aq. layer was filtered, washed with water, and dried to give 88.0 mg of the title compound
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[O:16])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH:17]([OH:20])([CH3:19])[CH3:18]>O1CCCC1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([O:20][CH:17]([CH3:19])[CH3:18])=[O:16])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(N=C=O)ccc1Cl
Reactant: CC(C)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)Nc1ccc(Cl)c(C(=O)OC(C)C)c1
Reaction time: 8 h

Procedure:
NMR (CDCl3): 1.39 (6H,d), 5.26 (1H,m), 6.98-7.52 (3H,m). 1-Methylethyl 2-chloro-5-isocyanatobenzoate (3 g, 0.013 mole) in tetrahydrofuran (5 ml) was added to isopropyl alcohol (5 ml) in tetrahydrofuran (5 ml). A few drops of triethylamine were added and the reaction mixture left at ambient temperature overnight. Removal of the solvent and crystallization from isopropyl alcohol gave the title compound, m.p. 108°-109° C. (2.7 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].[H-].[Na+].[Cl:16][C:17]1[N:18]=[C:19](Cl)[C:20]2[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:21]=2[N:22]=1>CN(C=O)C>[Cl:16][C:17]1[N:18]=[C:19]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[C:20]2[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:21]=2[N:22]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)nc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nc2c1ccn2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42 %

Procedure:
To a solution of 1-amino-2-(isopropylsulphonyl)benzene (199 mg, 1 mmol) in 2 mL of DMF was added NaH (60% in oil, 44 mg, 1.1 mmol) in one portion at 0° C. After the reaction mixture was stirred for 20 min, 2,4-dichloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (317 mg, 1 mmol) was added at 0° C. The reaction mixture was then warmed up to room temperature and stirred for additional 2 h. The reaction was quenched with water. Extraction with EtOAc followed by silica gel column chromatography (20% EtOAc in heptane) gave the desired product (202 mg, 42% yield). MS/ES+: m/z=481.
Reaction SMILES: C([CH:4]1[C:16]2[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH2:7][CH2:6][NH:5]1)(=O)C.Cl>[OH-].[Na+].CO.O.C(OCC)C>[CH2:17]([N:15]1[C:16]2[CH2:4][NH:5][CH2:6][CH2:7][C:8]=2[C:9]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)C1NCCc2c1n(Cc1ccccc1)c1ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: c1ccc(Cn2c3c(c4ccccc42)CCNC3)cc1

Procedure:
A portion of the Orude -acetyl 9-benzyl-1,2,3,4-tetrahydro-β-carboline (1.7 g) was heated at reflux for 4.5 hours in 2 N NaOH (50 mL) in methanol:water 2:3, v/v). The methanol was removed by evaporation under vacuum, and the crude 9-benzyl-1,2,3,4-tetrahydro-β-carboline free base was extracted into chloroform. This extract was dried over anhydrous MgSO4, filtered, and the filtrate evaporated under vacuum. The hydrochloride salt was prepared by passing dry HCl through a solution of the crude free base in diethyl ether. The resulting precipitate was filtered and recrystallized from acetonitrile to yield pure 9-benzyl-1,2,3,4-tetrahydro-β-carboline.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:25]=[C:26]([C:31]([O:33]C)=[O:32])[C:27]=1[N+:28]([O-:30])=[O:29])[O:8][CH2:9][C:10]([N:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:11])([O:3]C)=[O:2].[OH-].[Na+].Cl>C(O)C>[C:31]([C:26]1[CH:25]=[C:7]([CH:6]=[C:5]([C:1]([OH:3])=[O:2])[C:27]=1[N+:28]([O-:30])=[O:29])[O:8][CH2:9][C:10]([N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:11])([OH:33])=[O:32]
Reactant: CCCCCCN(CCCCCC)C(=O)COc1cc(C(=O)OC)c([N+](=O)[O-])c(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCN(CCCCCC)C(=O)COc1cc(C(=O)O)c([N+](=O)[O-])c(C(=O)O)c1

Procedure:
A solution of crude (3,5-dicarbomethoxy-4-nitrophenoxy)-N,N-dihexylacetamide in ethanol is treated with aqueous sodium hydroxide (3 equivalents) at room temperature for 15 min. After this time the reaction is poured into cold dilute hydrochloric acid. The diacid product which precipitates is collected and washed well with water; m.p. 180°-184° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>O1CCCC1>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:12])=[O:13])=[CH:9][CH:10]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.56 g of a 50 % oil dispersion, 33.0 mmol) is suspended in tetrahydrofuran (85 mL). To this is added a solution of N-[4-methoxybenzenesulfonyl]-benzylamine (9.0 g, 32.5 mmol) also in tetrahydrofuran (85 mL), and the reaction is stirred for 30 minutes at room temperature. Then ethyl bromoacetate (5.40 mL, 48.8 mmol) is added, and the reaction is stirred overnight at room temperature. The reaction is quenched with a small amount of water, and all the solvent is removed. The crude mixture is partitioned between ethyl acetate and water, the aqueous phase is extracted several times with ethyl acetate, the combined organic layers are dried (Na2SO4), and the solvent is evaporated. The product is purified by silica gel chromatography (30% ethyl acetate/hexane) to give ethyl 2-[[4-methoxybenzenesulfonyl](benzyl)amino]acetate.
Reaction SMILES: [NH2:1][C@@H:2]([CH:15]([CH3:17])[CH3:16])[C:3]([NH:5][C@@H:6]([CH3:14])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4].[C:18]1(=[O:33])[N:22]([C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[C:21](=[O:32])[CH:20]=[CH:19]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[O:32]=[C:21]1[CH:20]=[CH:19][C:18](=[O:33])[N:22]1[C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:1][C@@H:2]([CH:15]([CH3:17])[CH3:16])[C:3]([NH:5][C@@H:6]([CH3:14])[C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])=[O:4])=[O:28])=[CH:25][CH:24]=1
Reactant: CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(N2C(=O)C=CC2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1ccc(N2C(=O)C=CC2=O)cc1)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.2 %

Procedure:
To a mixture of the 97 (100 mg, 0.41 mmol) and 4-maleimidobenzoic acid (101) (98 mg, 0.45 mmol) was added dichloromethane (5 mL), followed by TBTU (157 mg, 0.49 mmol) and DIPEA (212 uL, 1.23 mmol). The mixture was stirred at an ambient temperature for 16 h and then purified on a 2 mm radial chromatotron plate eluting with 50% ethyl acetate in hexanes to give 95 mg (51%) of 100: 1H-NMR (400 MHz, CDCl3) δ 7.85 (d, J=6.6 Hz, 2H), 7.42 (d, J=6.6 Hz, 2H), 6.81 (s, 2H), 6.38 (bs, 1H), 4.43 (m, 2H), 2.14 (sept, J=6.6 Hz, 1H), 1.41 (s, 9H), 1.31 (d, J=7.0 Hz, 3H), 0.98 (m, 6H); MS (ES−) m/z 441.90 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:12].[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[CH3:21])[NH2:17].[B][B][B][B][B][B][B][B][B][B]>CO>[Br:13][C:14]1[CH:15]=[C:16]([NH:17][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:12])[CH:4]=2)[CH2:9][CH3:10])[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: Cc1ccc(N)cc1Br
Reactant: CCC(=O)c1ccc(Cl)c(C)c1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: CCC(Nc1ccc(C)c(Br)c1)c1ccc(Cl)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of INT 5 (3.00 g, 16.4 mmol) and 3-bromo-4-methylaniline (3.06 g, 16.4 mmol) in MeOH (164 mL) was added decaborane (1.00 g, 8.2 mmol). The reaction mixture was stirred at room temperature overnight. More decaborane (0.50 g, 4.1 mmol) was added. The mixture was stirred at 60° C. for 2 hours. The mixture was concentrated. The residue was purified by chromatography on silica gel (heptane/EtOAc) to afford INT 8.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]2[N:18]=[C:17]3[N:19]([CH2:22][C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[N:29]=[CH:28][CH:27]=[CH:26]5)[N:20]=[N:21][C:16]3=[CH:15][CH:14]=2)[CH:10]=[CH:9][C:3]=1[C:4]([NH:6]CC)=[O:5].ClC1C=CC=C(C(OO)=[O:41])C=1>ClCCl.O>[C:4]([C:3]1[CH:9]=[CH:10][C:11]([C:13]2[N:18]=[C:17]3[N:19]([CH2:22][C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[N+:29]([O-:41])=[CH:28][CH:27]=[CH:26]5)[N:20]=[N:21][C:16]3=[CH:15][CH:14]=2)=[CH:12][C:2]=1[Cl:1])(=[O:5])[NH2:6]
Reactant: CCNC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5c(ccc[n+]5[O-])c4)c3n2)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of example 119 (0.060 g, 0.135 mmol) in dichloromethane (1 ml), 3-chloroperbenzoic acid (0.46 g, 0.270 mmol) was added and stirred at RT for 12 h. The mixture was diluted with water, extracted with dichloromethane, the organic layer dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol:dichloromethane as the eluent to afford the title compound as a grey solid. (0.016 g, 26%). M.P.: 212-215° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.71 (d, J=8.8 Hz, 1H), 8.68 (d, J=9.1 Hz, 1H), 8.56 (m, 2H), 8.30 (d, J=1.5 Hz, 1H), 8.24 (m, 2H), 8.12 (s, 1H), 7.93 (d, J=8.6 Hz, 1H), 7.86 (dd, J=9.1, 1.8 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.48 (dd, J=8.4, 6.0 Hz, 1H), 6.20 (s, 2H), 3.28 (m, 2H), 1.14 (t, J=7.3 Hz, 3H).