Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:26][CH:27]=[CH2:28])[CH:9]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19]CCCC)=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:26][CH:27]=[CH2:28])[C@@H:9]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:24][CH:25]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: C=CCC(c1ccc(Cl)cc1)C(CCC)c1ccc(C(=O)OCCCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=CC[C@@H](c1ccc(Cl)cc1)[C@H](CCC)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A THF/MeOH/water (8 ml/8 ml/3 ml) solution containing the intermediate from Step F (790 mg, 1.98 mmol) and lithium hydroxide monohydrate (406 mg, 9.90 mmol) was stirred overnight at room temperature. The solution was concentrated and the nonvolatile portion was partitioned between aqueous 2N hydrochloric acid and EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated to give the title compound. 1H NMR (500 MHz, DMSO-d6): δ 7.90 (d, J=8.2 Hz, 2H); 7.39 (d, J=8.5 Hz, 2H); 7.36 (d, J=8.5 Hz, 2H); 7.26 (d, J=8.4 Hz, 2H); 5.36-5.26 (m, 1H); 4.71-4.60 (m, 2H); 2.94-2.84 (m, 2H); 2.13-2.07 (m, 1H); 1.95-1.87 (m, 1H); 1.42-1.34 (m, 1H); 1.19-1.11 (m, 1H); 0.85-0.77 (m, 2H); 0.60 (t, J=7.3 Hz, 3H). LC3 2.57 min (M+H) 343
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]2[NH:19][N:18]=[N:17][N:16]=2)[C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.CCN(CC)CC.[C:27](Cl)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl.CCOCC>[C:28]1([C:27]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:16]2[C:15]([C:4]3[C:5]([C:8]4[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=4)=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[N:19][N:18]=[N:17]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(-c2ccc(Cl)cc2-c2nnn[nH]2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(-c2ccc(Cl)cc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 100 %

Procedure:
A solution of N-Triphenylmethyl-5-(4'-methyl-4-nitrobiphen-2-yl)tetrazole (0.115 g, 0.224 mmol) in MeOH/DMF (2 mL/12 mL) was submitted to hydrogenation at 40 psi H2 with 10% Pd on carbon (50 mg) at room temperature for 1 hour. The reaction was filtered through celite and the filtrate was concentrated in vacuo. The triphenyl methyl group had been lost during the hydrogenation. The crude 4-amino compound was dissolved in glacial acetic acid (3 mL) and added slowly to a cooled (0° C.) solution of NaNO2 (28.8 mg, 0.417 mmol) in conc. sulfuric acid (1 mL). The diazonium solution was stirred well for 2 hours then slowly added to a cooled (0° C.) solution of CuCl (0.449 g; 20 equiv) in conc. HCl. This mixture was stirred for 30 minutes and then poured over H2O and extracted with Et2O/EtOAc. The combined organic extracts were washed with H2O and brine, dried over MgSO4 and concentrated in vacuo. The product was purified by flash chromatography on a silica column eluting with Hex/EtOAc/HOAc (80:20;1) to afford 27 mg (45% for 2 steps) of 5-(4-chloro-4'-methyl-biphen-2-yl)tetrazole. The free tetrazole was dissolved in CH2Cl2 (3.5 mL) and NEt3 (0.035 mL, 2.5 equiv) and Ph3CCl (27 mg, 1.0 equiv) were added. After 30 minutes the reaction was diluted with Et2O washed with 10% citric acid, 1N NaOH and brine. The organic was dried over anhydrous MgSO4 and concentrated in vacuo to afford 51.2 mg (100%) of crude N-triphenylmethyl-5-(4-chloro-4'-methyl-biphen-2-yl)tetrazole. 1H NMR (300 MHz, CDCl3) δ2.26 (s, 3H), 6.91 (d, 6H), 6.94 (ABq, 4H), 7.20-7.25 (comp, 7H), 7.43 (dd, 1H), 7.99 (dd, 1H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:21][CH2:20][C:11]3[NH:12][C:13]4[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=4[C:10]=3[CH2:9]2)=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][N:24]=1.[OH-].[K+]>CN1C(=O)CCC1>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:21][CH2:20][C:11]3[N:12]([CH2:30][CH2:29][C:26]4[CH:25]=[N:24][C:23]([CH3:22])=[CH:28][CH:27]=4)[C:13]4[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=4[C:10]=3[CH2:9]2)=[CH:6][CH:7]=1
Reactant: C=Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(c1ccc(I)cc1)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(c2ccc(I)cc2)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2-(4-iodophenyl)-8-methyl-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[C:14]1([C:20]2[CH:28]=[C:27]3[C:23]([CH2:24][C:25](=[O:29])[NH:26]3)=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1CCCCC1.C(O)C>[CH3:13][C:7]1[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:10][NH:9][C:8]=1[CH:11]=[C:24]1[C:23]2[C:27](=[CH:28][C:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:21][CH:22]=2)[NH:26][C:25]1=[O:29]
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2cc(-c3ccccc3)ccc21
Yield: 78.5 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90.5 mg), 105 mg 6-phenyl-2-oxindole and 2 drops piperidine in 2 mL of ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 146 mg (78%) of the title compound as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[CH3:16][CH:17]1[NH:21][C:20](=O)[CH2:19][CH2:18]1.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:20]3[CH2:19][CH2:18][CH:17]([CH3:16])[N:21]=3)[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)Nc1ccccc1O2
Reactant: CC1CCC(=O)N1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1CCC(N2c3ccccc3Oc3ccc(Cl)cc32)=N1

Procedure:
Reaction of 2-chlorophenoxazine, 5-methyl-2-pyrrolidinone and phosphorus oxychloride according to the procedure of Example 1 provides the free base 2-CHLORO-10-(5-METHYL-1-PYRROLIN-2-YL)PHENOXAZINE as a distillable oil, b.p. 150°-170° C. at 0.1 mm Hg. Conversion of the free base to the hydrochloride salt affords 2-CHLORO-10-(5-METHYL-1-PYRROLIN-2-YL)PHENOXAZINE HYDROCHLORIDE, m.p. 213.5°-215.5° C., as a crystalline solid in a 34% overall yield by refluxing with benzene.
Reaction SMILES: [CH3:1][N:2]([CH:7]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[S:22][C:21]3[C:16](=[N:17][CH:18]=[CH:19][C:20]=3Cl)[CH:15]=2)=[O:13])[CH2:8]1)[S:3]([CH3:6])(=[O:5])=[O:4].[CH3:24][C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([NH2:34])=[CH:29][CH:28]=2>>[CH3:1][N:2]([CH:7]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[S:22][C:21]3[C:16](=[N:17][CH:18]=[CH:19][C:20]=3[NH:34][C:30]3[CH:31]=[C:32]4[C:27](=[CH:28][CH:29]=3)[NH:26][C:25]([CH3:24])=[CH:33]4)[CH:15]=2)=[O:13])[CH2:8]1)[S:3]([CH3:6])(=[O:5])=[O:4]
Reactant: CN(C1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1)S(C)(=O)=O
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CCC(N(C)S(C)(=O)=O)C5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from (+/−)-methanesulfonic acid methyl-{1-[7-chloro-thieno[3,2-b]pyridine-2-carbonyl]-pyrrolidin-3-yl}-amide and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 484 (MH+); HPLC Rf: 3.69 min.; HPLC purity 91%.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:41][CH2:42][CH3:43])[C@@H:5]([N:7]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1[N:39]=[CH:38][CH:37]=[CH:36]2)[C:8](=[O:29])[C@@H:9]([NH:11]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[CH3:10])[CH3:6])[CH3:2].N1CCCCC1.CC(=O)OCC.CO>C(Cl)Cl>[NH2:11][C@@H:9]([CH3:10])[C:8]([N:7]([C@@H:5]([CH3:6])[CH:4]([O:41][CH2:42][CH3:43])[O:3][CH2:1][CH3:2])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1[N:39]=[CH:38][CH:37]=[CH:36]2)=[O:29]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCNCC1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.2 %

Procedure:
(9H-Fluoren-9-yl)methyl (S)-1-(((S)-1,1-diethoxypropan-2-yl)(quinolin-8-ylmethyl)amino)-1-oxopropan-2-ylcarbamate (Compound III-11) 15.7 g (27 mmol) and piperidine 22.7 g (270 mmol) were added in DCM (90 ml). The mixture was stirred for 1.5 h at room temperature. The mixture was diluted with DCM (200 ml) and washed with water (150 ml×3). The solution was concentrated in vacuo. The residue was purified by column chromatography on silica gel with PE:EA=50:1 to DCM:MeOH=10:1 to give the title compound 7.1 g, (yield 73%).
Reaction SMILES: Cl[C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.CS(C)=O.[CH2:15]([SH:17])[CH3:16].CC([O-])(C)C.[K+]>C1COCC1>[Cl:8][C:5]1[N:4]=[C:3]([C:9]#[N:10])[C:2]([S:17][CH2:15][CH3:16])=[CH:7][CH:6]=1
Reactant: CCS
Reactant: N#Cc1nc(Cl)ccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCSc1ccc(Cl)nc1C#N
Temperature: 20 °C
Reaction time: 40 h
Yield: 31 %

Procedure:
In a reaction flask with condenser, mechanical stirrer, thermometer and dropping funnel were placed 53.4 g of 3,6-dichloro-2-pyridinecarbonitrile and 300 ml of DMSO. The mixture was chilled to about 10°-15° C. and then 19.8 g of ethanethiol was added. While maintaining the temperature at <20° C., 34.8 g of t-BuOK in 300 ml of THF was added in small portions. After the addition was complete, the reaction mixture was warmed to 20° C. and stirred for about 40 hrs. The reaction mixture was then poured onto about 2 kilograms (kg) of ice, stirred and filtered leaving a solid residue. The residue was washed with water, dissolved in CH2Cl2, dried over MgSO4, concentrated and diluted with hexane to give 19.0 g of 6-chloro-3-ethylthio-2-pyridinecarbonitrile. The filtrate was concentrated and separated on a Water's Prep LC 500 instrument using 15% ethyl acetate in hexane to give another 10.1 g of the same isomer. Total yield of 6-chloro-3-ethylthio-2-pyridinecarbonitrile was 29.1 g (46.5%), m.p. 79°-81° C. Further separation on the Prep LC 500 instrument gave a small amount of 3-chloro-6-ethylthio-2-pyridinecarbonitrile (m.p. 46°-48° C.) and 3,6-bis-ethylthio-2-pyridinecarbonitrile (m.p. 63°-64° C.).
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH2:20])[CH:17]([CH3:19])[CH3:18].NC(N)=O.[N-]=C=O>CCCCC>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14]([NH:20][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N=NC1(N=C=O)CCCCC1
Reactant: CC(C)CN
Agent: NC(N)=O
Agent: [N-]=C=O
Solvent: CCCCC
Product: CC(C)CNC(=O)NC1(N=NC(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 7.4 grams (0.0353 moles) of 1-t-butylazo-1-isocyanatocyclohexane stirred with a magnetic stirrer in a 50 ml erlenmeyer flask was added 2.59 grams (0.0353 moles) of isobutylamine. The reaction mixture became viscous, was diluted with pentane and stirred for 3 hours at room temperature. The pentane was stripped from the reaction mixture leaving a yellow solid weighing 9.7 grams (97% crude yield). The product melted at 90°-92° C. The infrared spectrum of the product contained a very strong urea type carbonyl around 1625 cm-1 and a broad NH band at 3330 cm-1. The isocyanate band at 2225 cm-1 was absent.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:35])[CH3:34])[NH:28][C:27](=[O:36])[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:35])[CH3:34])[NH:28][C:27](=[O:36])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: CC(=O)Nc1cc2c(cc1F)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Product: CC(=O)Nc1cc2c(cc1F)C(=Cc1[nH]c3c(c1C)C(=O)N(CCN1CCOCC1)CC3)C(=O)N2
Yield: 39.3 %

Procedure:
The title compound was prepared under the same conditions as described in Example 15 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-acetamide as starting materials to give N-{5-fluoro-3-[3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-acetamide (35 mg, 39.3%) as a light brown solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=3)[CH:4]([CH2:5][C:6]2=[O:17])[CH2:3]1.[CH3:18][C:19]([CH3:24])([CH2:22]O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>CCOCC>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([C:7]23[C:6]4([O:21][CH2:20][C:19]([CH3:24])([CH3:22])[CH2:18][O:17]4)[CH2:5][CH:4]2[CH2:3][N:2]([CH3:1])[CH2:8]3)[CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(CO)CO
Reactant: COc1cccc(C23CN(C)CC2CC3=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1cccc(C23CN(C)CC2CC32OCC(C)(C)CO2)c1

Procedure:
A mixture of 1.18 g. of 3-methyl-5-(m-methoxyphenyl)-3-azabicyclo[3.2.0]heptan-6-one, 0.78 g. of 2,2-dimethyl-1,3-propanediol and 1.05 g. of p-toluenesulfonic acid in 25 ml. of toluene was heated at reflux under a Dean-Stark trap for 29 hours. The mixture was cooled, diluted with ether, washed with 10% sodium hydroxide, and then with water giving a brown oil. This oil was distilled in a Kugelrohr apparatus at 175° C. and 0.10 mm., giving the desired product as a colorless oil.
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[NH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.O=O.CN(C1C=CC2N=C3C(=CC(C=C3)=[N+](C)C)SC=2C=1)C>C(Cl)Cl>[CH:1]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[CH:1](=[O:4])[CH2:2][CH3:3]
Reactant: C1COCCN1
Agent: CN(C)c1ccc2nc3ccc(=[N+](C)C)cc-3sc2c1
Agent: O=O
Solvent: CCC=O
Solvent: ClCCl
Product: O=CN1CCOCC1

Procedure:
Mixture of propionaldehyde (VII, 2.73 mmole) and morpholine (5.76 mmole) in methylene chloride was irradiated for 90 min with oxygen bubbling in the presence of methylene blue. N-formylmorpholine was obtained in 103% yield on the basis of (VII), as expected. Further, mixture of propionaldehyde (2.73 mmole) and morpholine (11.52 mmole) gave N-formylmorpholine in 145% yield. When n-octylaldehyde (VIII) was used, the yield of N-formylmorpholine went up to 272% by irradiation for 240 min. (Table III.) Also the reaction of mixture of (VIII) and piperidine affords the same results. For example, N-formylpiperidine was obtained in 282% yield for 1.29 mmole of (VIII) and 20.5 mmole of (V). Also, N-formylpiperidine was obtained in 281% yield for the mole ratio of piperidine (V) to n-octylaldehyde (VIII) being 9 for 280 min.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[OH:1]
Reactant: CO
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1O
Temperature: 25 °C

Procedure:
To a MeOH solution (200 ml) of 2-hydroxy-4-nitro-benzoic acid (18 g) was added concentrated sulfuric acid. The resulting mixture was heated to reflux for 24 h. After it was cooled to rt, volatile was removed in vacuo. The residue was then partitioned between water and EtOAc. The EtOAc layer was washed with water (2×), NaHCO3 (sat.), NaCl (sat.), dried over Na2SO4 and concentrated. The crude product was purified on a silica gel column with 20% EtOAc in hexane to give 14.5 g of 2-hydroxy-4-nitro-benzoic acid methyl ester as a solid (M+: 197).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH2:12])=[CH:2]1.CS(C)=[O:15].[ClH:17]>>[ClH:17].[NH2:12][CH2:11][CH2:10][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:15]
Reactant: CS(C)=O
Reactant: NCCc1c[nH]c2ccccc12
Agent: Cl
Product: NCCC1C(=O)Nc2ccccc21
Temperature: 50 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
To a solution of 2-(1H-indol-3-yl)ethanamine (6.00 g, 37.50 mmol) in DMSO (8.0 mL, 112.50 mmol) was added concentrated hydrochloric acid (9.5 mL, 112.50 mmol) slowly. The resulting reaction mixture was stirred at 50° C. in a sealed tube for 16 h. After cooling to room temperature, the reaction mixture was filtered. The resulting cake was stirred in EtOH (15 mL). The mixture was filtered and dried to give the desired title compound as a brown solid (5.00 g, 23.64 mmol, 63% yield). MS (ESI) m/z 177.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[NH:5][C:4]=2[CH2:3]1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[CH3:35]>CN(C=O)C.[Cu]I>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:34]([CH3:35])=[CH:33][N:5]2[C:6]3[C:11](=[CH:10][C:9]([CH3:15])=[CH:8][CH:7]=3)[C:12]3[CH2:13][CH2:14][N:2]([CH3:1])[CH2:3][C:4]2=3)=[CH:37][CH:38]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)C3
Reactant: CC(=CBr)c1ccc(Cl)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CC(=Cn1c2c(c3cc(C)ccc31)CCN(C)C2)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.9 %

Procedure:
2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (72 mg, 0.362 mmol) was dissolved in DMF (5 mL). To this solution was added CuI (6 mg, 0.0362 mmol), L-proline (8 mg, 0.072 mmol), and K3PO4 (154 mg, 0.724 mmol). The reaction mixture was stirred for 10 min at room temperature followed by addition of 1-(1-bromoprop-1-en-2-yl)-4-chlorobenzene (100 mg, 0.434 mmol). The reaction mixture was heated at 80° C. overnight. Solvent was evaporated under reduced pressure, the residue was diluted with brine and extracted with ethyl acetate. Organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to obtain 85 mg of 9-(2-(4-chlorophenyl)prop-1-enyl)-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. 1H NMR (CDCl3) FREE BASE 7.48 (d, 1H), 7.39 (d, 1H), 7.29 (s, 1H), 7.18-7.10 (m, 1H), 7.09-7.0 (m, 2H), 6.93 (d, 1H), 6.86 (s, 1H), 3.78-3.68 (m, 2H), 3.43-3.35 (m, 1H), 3.16-2.70 (m, 3H), 2.64 (s, 3H), 2.47 (s, 3H), 1.99 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:4]=2[S:5](=[O:8])(=[O:7])[CH:6]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.ClS(Cl)(=O)=O>ClCCl>[Cl:13][C:10]1[CH:11]=[CH:12][C:3]2[C:2]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:6][S:5](=[O:8])(=[O:7])[C:4]=2[CH:9]=1
Reactant: C1CNCCN1
Reactant: O=S1(=O)C=C(Cl)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: O=S1(=O)C=C(N2CCNCC2)c2ccc(Cl)cc21
Reaction time: 1 h
Yield: 66.5 %

Procedure:
A mixture of 3,6-dichlorobenzo[b]thiophene-1,1-dioxide (16.00 g, 0.0681 mol), piperazine (20.52 g, 0.238 mol) and dichloromethane (300 ml) was heated to reflux. After 1 hour, TLC analysis showed the dichlorosulfone (Rf =0.47, 30% ethyl acetate in hexanes, silica gel) to be consumed. The cloudy mixture was washed with 0.25 N NaOH (400 ml), H2O (300 ml), brine (250 ml), dried (Na2SO4), and the solvent removed under reduced pressure. The residue was chromatographed on silica gel, eluting with 50% methanol in dichloromethane, to afford 12.90 g (66.5%) of a yellow solid. A 1.60 g sample was recrystallized from dichloromethane/ether yielding 0.480 g of light yellow crystals: m.p. 154° C. dec.
Reaction SMILES: [OH-].[Na+].Cl.Cl.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][S:12][C:13](=N)N.BrC[CH2:18][CH2:19][Cl:20]>O>[Cl:20][CH2:19][CH2:18][CH2:13][S:12][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=1
Reactant: N=C(N)SCc1ccccn1
Reactant: ClCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClCCCSCc1ccccn1
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 86.7 %

Procedure:
A solution of sodium hydroxide pellets (151 g) in distilled water (342 cc) is added, in the course of 5 minutes, at a temperature which does not exceed 10° C., to a solution, originally at 5° C., of 2-(pyrid-2-ylmethyl)-isothiourea dihydrochloride (453 g) in distilled water (840 cc). After heating the reaction mixture for 20 minutes at a temperature of about 70° C., and then cooling to 3° C., a solution of sodium hydroxide pellets (92.5 g) in distilled water (210 cc) is added dropwise in the course of 3 minutes. After stirring the reaction mixture for 5 minutes at 10° C., 1-bromo-3-chloropropane (303 g) is added. Stirring is then continued for 20 hours at a temperature of about 20° C. The reaction mixture is then extracted four times with methylene chloride (1100 cc in total). The combined organic extracts are washed three times with distilled water (600 cc in total) and then dried over anhydrous sodium sulphate. After filtering, the resulting solution is poured onto neutral silica gel (380 g) contained in a column of diameter 6 cm, and the column is then washed with methylene chloride (2700 cc). A first fraction of effluent (600 cc) is discarded and a second fraction (3200 cc) is then collected and concentrated to dryness under reduced pressure (20 mm Hg) at 20° C. Pyrid-2-ylmethyl 3-chloropropyl sulphide (330 g) is thus obtained in the form of a yellow liquid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]([CH3:14])([CH3:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[NH3:15]>C(O)C>[CH3:13][C:6]([NH:5][C:3](=[O:4])[CH2:2][NH2:15])([CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N
Reactant: CC(C)(NC(=O)CCl)c1ccccc1
Solvent: CCO
Product: CC(C)(NC(=O)CN)c1ccccc1
Reaction time: 144 h

Procedure:
A solution of 2-chloro-N-(α,α-dimethylbenzyl)-acetamide (11.5 g; 0.054 mole) in ethanol (300 ml) was cooled to 0°C. The solution was saturated with ammonia (5 hours). Stirring was continued at room temperature for about 6 days. The solvent was removed under vacuum. The oily residue was taken up in 2N HCl and filtered. The filtrate was made alkaline by the addition of 2N NaOH. The alkaline phase was extracted three times with ether. The organic layer was dried over, anhydrous Na2SO4 and the solvent was evaporated. The N1 -(α,α-dimethylbenzyl)glycineamide was obtained as a light brown oil. Yield: 6.5 g (62.5 %).
Reaction SMILES: C([O:8][C:9](=[O:43])[C@@H:10]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]2[CH2:22][C:21](=[O:23])[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[S:19]2(=[O:34])=[O:33])[CH:13]=1)C1C=CC=CC=1.CCO.[H][H]>CCOC(C)=O.[Pd]>[C:39]([O:38][C:36]([NH:35][C@@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]2[CH2:22][C:21](=[O:23])[N:20]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[S:19]2(=[O:33])=[O:34])[CH:13]=1)[C:9]([OH:43])=[O:8])=[O:37])([CH3:40])([CH3:42])[CH3:41]
Reactant: [H][H]
Reactant: COc1ccc(CN2C(=O)CN(c3cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc4ccccc4)c3)S2(=O)=O)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)CN(c3cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c3)S2(=O)=O)cc1

Procedure:
The title D compound, (S)-2-t-butoxycarbonylamino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid benzyl ester (187 mg, 0.307 mmol) is dissolved in a 1:1 mixture of EtOAc:EtOH (50 mL) in a 200 mL Parr bottle. 10% Palladium on carbon (52 mg) is added as a solid and the reaction mixture is hydrogenated on a Parr Shaker Apparatus at 47 psi of hydrogen for 1.33 h. The reaction mixture is filtered through celite and concentrated in vacuo to give (S)-2-t-butoxycarbonylamino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid as a white foam: [M−1]−=518.1.