Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([C:12]1[CH:13]=[C:14]([C:16]([Cl:21])=[CH:17][C:18]=1[O:19][CH3:20])[NH2:15])=[O:11].C(N(CC)[C:25](Cl)=[S:26])C.ClC1C=CC=CC=1.O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([C:12]1[CH:13]=[C:14]([N:15]=[C:25]=[S:26])[C:16]([Cl:21])=[CH:17][C:18]=1[O:19][CH3:20])=[O:11]
Reactant: COc1cc(Cl)c(N)cc1C(=O)Nc1c(C)cccc1C
Reactant: CCN(CC)C(=S)Cl
Solvent: Clc1ccccc1
Solvent: O
Solvent: ClCCl
Product: COc1cc(Cl)c(N=C=S)cc1C(=O)Nc1c(C)cccc1C
Yield: 46 %

Procedure:
A mixture of 3-[N-(2,6-dimethylphenyl)carbamoyl]-4-methoxy-6-chloroaniline (650 mg), diethylthiocarbamoyl chloride (360 mg) and chlorobenzene (6 ml) is refluxed for 30 minutes. The reaction mixture is mixed with water and shaken with methylene chloride. The organic layer is washed with water, dried over Glauber's salt and concentrated to remove the solvent. The residue is chromatographed on a column of silica gel, which is eluted with methylene chloride. The eluted fractions are collected and the solvent is evaporated. The residue is recrystallized from ethyl acetate to give 3-[N-(2,6-dimethylphenyl)carbamoyl]-4-methoxy-6-chlorophenyl isothiocyanate (340 mg) as crystals melting at 191°-192.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([C:23]2[CH:24]=[N:25][NH:26][CH:27]=2)=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=1.[H-].[Na+].[CH3:30]I.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([C:23]2[CH:24]=[N:25][N:26]([CH3:30])[CH:27]=2)=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3-c3cn[nH]c3)c2cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cnn(C)c3)c2cc1OC
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
6,7-Dimethoxy-4-[6-methyl-2-(1H-pyrazol-4-yl)-pyridin-3-yloxy]-quinoline (compound 434) (30 mg) was suspended in N,N-dimethylformamide (1 ml), 60% sodium hydride (9.9 mg) was added to the suspension, and the mixture was then stirred for 30 min. Methyl iodide (18 mg) was added to the reaction solution, and the mixture was stirred for one hr. Water was added to the reaction solution to stop the reaction, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using hexane-acetone to give the title compound (23 mg, yield 73%).
Reaction SMILES: Cl[Si:2]([Cl:5])([CH3:4])[CH3:3].[C:6]1([Li])[C:18]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1>CCCCCC>[Cl:5][Si:2]([CH3:3])([CH3:4])[CH:17]1[C:18]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[C:11]2[C:16]1=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: [Li]c1cccc2c1Cc1ccccc1-2
Reactant: C[Si](C)(Cl)Cl
Solvent: CCCCCC
Product: C[Si](C)(Cl)C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
Into a 3000 ml flask, under nitrogen, was placed a solution of dichlorodimethyl silane (80.2 ml, 0.64 mol.) in 1000 ml of dry hexane, and the solution was Dre-cooled to −78° C. A suspension of fluorenyllithium (53.13 g, 0.32 mol.) in 2000 ml of hexane was slowly added via a cannula and the reaction mixture was stirred for an additional one hour at this temperature. The resulting mixture was gradually allowed to warm to room temperature and stirred for another 16 hours. The reaction mixture was then filtered under nitrogen, through a Celite plug (250 ml). The filtrate was concentrated and kept at −20° C. overnight. The resulting light-green crystals were recrystallised from hexane at −20° C. to afford 75.09 g (90.68 % yield) of chlorodimethyl-(9-fluorenyl)silane.
Reaction SMILES: [O:1]1[CH2:5][CH:4]=[CH:3][CH:2]1[C:6]1[C:7]([F:12])=[N:8][CH:9]=[CH:10][CH:11]=1>CO.[Pd]>[F:12][C:7]1[C:6]([CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: Fc1ncccc1C1C=CCO1
Agent: [Pd]
Solvent: CO
Product: Fc1ncccc1C1CCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A round-bottom flask containing 3-(2,5-dihydrofuran-2-yl)-2-fluoropyridine (170 mg, 1 mmol) and 10% Pd/C in methanol (3.1 mL) is evacuated under vacuum and filled with hydrogen with the aid of a balloon. The reaction is stirred overnight at room temperature and filtered over celite. The solvent is evaporated in vacuo to give 148 mg of 2-fluoro-3-(tetrahydrofuran-2-yl)pyridine. MS (m/z): 168 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH3:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)Oc1sc3c(c1C(=O)N2)CCCC3
Reactant: CN1CCNCC1
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c(c1)Oc1sc3c(c1C(N1CCN(C)CC1)=N2)CCCC3

Procedure:
In the same manner as in Example 80 and using 1,2,3,4-tetrahydro-8-methyl-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 1,2,3,4-tetrahydro-8-methyl-12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzoxazepine is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]([CH3:19])([CH3:18])[C:14]([O:16]C)=[O:15])=[CH:8][CH:7]=2.[Li+].[OH-].CO.Cl>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]([CH3:19])([CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=2
Reactant: COC(=O)C(C)(C)c1ccc2ncc(OC)cc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cnc2ccc(C(C)(C)C(=O)O)cc2c1

Procedure:
A solution of methyl 2-(3-methoxyquinolin-6-yl)-2-methylpropanoate (400 mg, 1543 μmol), LiOH (1928 μl, 7713 μmol) [4M], MeOH (2 mL), and THF (2 mL) was stirred at 50° C. overnight. LCMS suggests full conversion. Solution cooled, acidified to pH 1 with 5M HCl, and precipitate collected by filtration. White cake washed with water (2 mL) and EtOH (1 mL). Product air dried for 3 h and isolated as a white solid. MS (ESI pos. ion) m/z: 246 (MH+). Calc'd exact mass for C14H15NO3: 245.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].O.[NH2:17][NH2:18].[BH4-].[Na+].O>CO>[CH:1]([C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH2:13][CH:12]([NH:17][NH2:18])[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1noc(C2CCC(=O)CC2)n1
Reactant: NN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)c1noc(C2CCC(NN)CC2)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
A mixture of 4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexanone (Intermediate 11; 600 mg, 2.9 mmol) and hydrazine hydrate (160 mg, 3.2 mmol) in methanol (2 mL) was heated at reflux for 3 h. The reaction mixture was cooled to 0° C. and sodium borohydride (220 mg, 5.8 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 4 h and then at room temperature overnight. Water was added and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried (sodium sulfate), filtered, and evaporated to give [4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-hydrazine (280 mg, 43%) which was used directly in the next step without further purification. Mass spectrum M+=224.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][CH2:11][C@H:12]1[CH2:14][O:13]1)[CH3:9].[CH3:15][O:16][C:17](=[O:21])[CH2:18][CH:19]=[CH2:20]>>[O:13]1[CH2:14][C@@H:12]1[CH2:11][O:10][C@@H:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1/[CH:20]=[CH:19]/[CH2:18][C:17]([O:16][CH3:15])=[O:21])[CH3:9]
Reactant: C=CCC(=O)OC
Reactant: C[C@@H](OC[C@H]1CO1)c1ccccc1Br
Product: COC(=O)C/C=C/c1ccccc1[C@@H](C)OC[C@H]1CO1
Yield: 65 %

Procedure:
By using (2R)-2-{[(1R)-1-(2-bromo phenyl)ethoxy]methyl}oxirane (257 mg, 1.00 mmol) described in WO 2004/094362 and methylbut-3-enoate, the reaction was carried out in the same manner as the method described in Example 3 (3c) to give the title compound as a yellow oily substance (yield 65%).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>N1C=CC=CC=1.CC1C=CC(C)=CC=1>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([C:9]2[S:21][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[N:8]=2)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: O=C(Nc1cnccc1O)c1ccc([N+](=O)[O-])cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccc(C)cc1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(-c2nc3cnccc3s2)cc1
Temperature: 140 °C
Reaction time: 18 h
Yield: 58.3 %

Procedure:
A mixture of N-(4-hydroxypyridin-3-yl)-4-nitrobenzamide (5.18 g, 0.02 mol) and P2S5 (8.90 g, 0.04 mol) in pyridine (25 mL) and p-xylene (100 mL) was stirred at 140° C. for 18 h. The solvent was removed under vacuo while hot and the residue was purified by recrystallization from EtOH to afford 2-(4-nitrophenyl)thiazolo[4,5-c]pyridine as a yellow solid (3.00 g, yield: 59%). MS (ESI), calcd for C12H7N3O2S (m/z): 257, found: 258 [M+1]+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C@@H:5]([C@H:7]([C@H:9]([C@@H:11]([CH2:13][OH:14])[OH:12])[OH:10])[OH:8])[OH:6])[CH3:2].N([O-])=O.[Na+].[C:19](Cl)(=[O:22])[CH:20]=[CH2:21].[OH-].[K+]>O.C(Cl)Cl>[C:19]([N:3]([CH2:1][CH3:2])[CH2:4][C@@H:5]([C@H:7]([C@H:9]([C@@H:11]([CH2:13][OH:14])[OH:12])[OH:10])[OH:8])[OH:6])(=[O:22])[CH:20]=[CH2:21]
Reactant: C=CC(=O)Cl
Reactant: CCNC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)N(CC)C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Yield: 72 %

Procedure:
The N-ethyl-1-amino-1-deoxy-D-galacitol (63 g) is mixed with about 300 ml of water and 1 g of sodium nitrite. Then 100-150 ml of methylene chloride are added, and the solution is cooled in an ice bath. Acryloyl chloride (10% molar excess over the amine) is mixed with the same volume of methylene chloride. Potassium hydroxide, equal to twice the molar amount of acryloyl chloride, is dissolved in water and cooled. To the well stirred two-phase reaction mixture, portions of acryloyl chloride and KOH solutions were added in such a way that the pH remained between 7.5-9.5 (as checked frequently by a narrow range pH paper). After the last additions of acryloyl chloride and KOH solutions, the reaction mixture was further stirred for about one hour (the pH was periodically checked and corrected, if necessary). The two phases were allowed to separate in a separating funnel and the lower organic phase was discarded. The aqueous phase was treated with charcoal and filtered. The filtrate was treated with a combination of ion exchangers either in solution or by passing the filtrate through columns packed with ion exchangers. Thus, to the stirred solution, portions of Amberlite IR-120,H+ and IRA-68 (free base) were added (pH being kept neutral or slightly acid) until the silver reaction for chloride was negative. The resin was then removed, the filtrate treated with activated charcoal and the solution poured into crystallization dishes. Alternatively, the monomer solution was passed through 600 ml of IR-120 and 600 ml of IRA-68, preferentially packed in more than two columns. The solution passed always first through the cationic ion exchanger. A small quantity (several hundred mg) of p-methoxy phenol or sodium nitrite (polymerization inhibitors) were added to the monomer solution. The water evaporated within 1-2 weeks. The monomer appeared as a white solid. The yield was 72%. The monomer was recrystallized from ethanol-acetone, m.p. 80°-84° C. (polymerization).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21](O)=[O:22].[CH:24]([N:37]1[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH:24]([N:37]1[CH2:42][CH2:41][CH:40]([NH:43][C:21](=[O:22])[CH2:20][N:3]2[CH2:4][CH2:5][CH2:6][C:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:2]2=[O:1])[CH2:39][CH2:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: NC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)NC1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
The title compound was prepared as described in Example 28B, reacting 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E) with 1-benzhydrylpiperidin-4-amine (Example 48A). 1H NMR (300 MHz, CDCl3) δ ppm 7.14-7.43 (m, 20H), 6.58 (d, J=8.1 Hz, 1H), 4.24 (s, 1H), 4.01 (s, 2H), 3.72-3.84 (m, 1H), 3.53 (t, J=6.4 Hz, 2H), 2.70-2.77 (m, 2H), 2.58-2.63 (m, 2H), 1.97-2.08 (m, 2H), 1.76-1.91 (m, 5H), 1.41-1.50 (m, 1H); MS (ESI+) m/z 558 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH2:8][C@@H:9]3[C@@H:14]([CH2:15][C:6]=2[S:5][C:4]=1[N:32](C)[C:33](=O)OC(C)(C)C)[N:13]([CH3:16])[CH2:12][C@H:11]([C:17]([N:19]([C:23](=[O:31])[NH:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[CH2:20][CH2:21][CH3:22])=[O:18])[CH2:10]3)#[N:2].C(OCC)(=O)C.[ClH:47]>C(OCC)(=O)C>[ClH:47].[ClH:47].[C:1]([C:3]1[C:7]2[CH2:8][C@@H:9]3[C@@H:14]([CH2:15][C:6]=2[S:5][C:4]=1[NH:32][CH3:33])[N:13]([CH3:16])[CH2:12][C@H:11]([C:17]([N:19]([CH2:20][CH2:21][CH3:22])[C:23]([NH:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[O:31])=[O:18])[CH2:10]3)#[N:2]
Reactant: CCCN(C(=O)NCCCN(C)C)C(=O)[C@@H]1C[C@@H]2Cc3c(sc(N(C)C(=O)OC(C)(C)C)c3C#N)C[C@H]2N(C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCN(C(=O)NCCCN(C)C)C(=O)[C@@H]1C[C@@H]2Cc3c(sc(NC)c3C#N)C[C@H]2N(C)C1
Temperature: 25 °C

Procedure:
To a mixture of tert-butyl N-[(4aR*,6R*,8aR*)-3-cyano-6-[({[3-(dimethylamino)propyl]carbamoyl}(propyl)amino)carbonyl]-8-methyl-4H,4aH,5H,6H,7H,8H,8a H,9H-thieno[3,2-g]quinolin-2-yl]-N-methylcarbamate (118 mg) and ethyl acetate (10 mL) was added a 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) while stirring at room temperature, and the mixture was stirred at the same temperature for 11 hours. To the reaction mixture were added a 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) while stirring at room temperature, and then stirred at the same temperature for 14 hours. The solid was collected by filtration to give the title compound (compound 3-2) (45 mg). The structure was illustrated in Table 11.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11].Br[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCOCC.C(OCC)(=O)C>C(#N)C.CO.C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:5]2[N:6]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11]
Reactant: Cc1c(Cl)[nH]c2ncccc12
Reactant: BrCCc1ccccc1
Solvent: CC#N
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c2cccn(CCc3ccccc3)c-2nc1Cl

Procedure:
A solution of 0.1 g (0.6 mmol) 2-chloro-3-methylpyrrolo-[2,3-b]pyridine and 0.14 g (0.78 mmol) (2-bromoethyl)-benzene in 10 ml acetonitril was refluxed 72 h. The solvent was evaporated. The solid that formed was treated with ether and ethyl acetate and isolated by filtration. Chromatography on silica gel eluting with methylene chloride and methanol (10:1) gave the desired product. (0.03 g 18% ).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH2:17][CH2:18][CH3:19])(=[O:3])[CH3:2].[H-].[Na+].[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[N:6]([CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[Cl:22])[C:5]=1[CH2:17][CH2:18][CH3:19])(=[O:3])[CH3:2]
Reactant: Clc1ccccc1CBr
Reactant: CCCc1[nH]c2cc(C(=O)OC)ccc2c1C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(C(C)=O)c2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 3-acetyl-2-propylindole-6-carboxylate (74 mg) in dimethylformamide (1.4 m ) was added sodium hydride (60%, 15.4 mg). The mixture was stirred at 20° C. for 30 minutes, then 2-chlorobenzyl bromide (0.045 ml) was added. After stirred for 1 hour, the mixture was diluted with ethyl acetate and washed with water and brine. The organic chase was dried over sodium sulfate and evaporated in vacuo to give methyl 3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate (125 mg) as solid.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=3)[CH:17]=2)[CH2:13][CH3:14])[CH2:9]1)=O)(C)(C)C.[NH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1>>[NH:8]1[CH2:9][CH:10]([N:12]([CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:29][CH2:30][CH2:31][C:32]4[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=4)[N:23]=3)[CH:19]=[CH:20][CH:21]=2)[CH2:13][CH3:14])[CH2:11]1
Reactant: CCN(Cc1cccc(-c2ccnc(Cl)n2)c1)C1CN(C(=O)OC(C)(C)C)C1
Reactant: NCCc1ccc(O)cc1
Product: CCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1)C1CNC1

Procedure:
Intermediate 105 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 405. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.69 (s, 1H), 8.40 (d, 1H), 8.34 (s, 1H), 7.96 (d, 1H), 7.72 (t, 1H), 7.68 (d, 1H), 7.11 (d, 2H), 6.67 (d, 2H), 4.56 (m, 5H), 3.78 (m, 4H), 3.21 (q, 2H), 2.93 (t, 2H), 1.39 (t, 3H).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8].CS(Cl)(=O)=O.[CH2:22]([N:24](CC)CC)C>C(OCC)(=O)C>[C:22]([CH2:2][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:24]
Reactant: COC(=O)c1ccc(CO)cc1C(=O)OC
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CC#N)cc1C(=O)OC

Procedure:
1.30 g of dimethyl 4-hydroxymethylphthalate was dissolved in 15 ml of ethyl acetate, and 0.58 ml of methanesulfonyl chloride and 1.55 ml of triethylamine were added under cooling with ice with stirring, followed by stirring at room temperature overnight. Insoluble matters were filtered off, and then, the solvent was distilled off under reduced pressure. The residue was dissolved in 13 ml of dimethylformamide, and then, 0.54 g of sodium cyanide was added, followed by stirring at room temperature for 3 hours. The reaction solution was extracted by an addition of ethyl ether and water, and the organic layer was post-treated in accordance with a usual method. Then, the product was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 0.78 g of the above identified compound as a colorless oily substance.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[O:18][CH2:17][C@:13]2([C:19]3[CH:24]=[C:23]([Br:25])[C:22]([F:26])=[CH:21][C:20]=3[F:27])[NH:14][O:15][CH2:16][C@@H:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Sm+3].[I-].[I-].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.ClCCl>[NH2:14][C@@:13]1([C:19]2[CH:24]=[C:23]([Br:25])[C:22]([F:26])=[CH:21][C:20]=2[F:27])[CH2:17][O:18][C@@H:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11][C@H:12]1[CH2:16][OH:15]
Reactant: Fc1cc(F)c([C@]23CO[C@@H](COCc4ccccc4)C[C@H]2CON3)cc1Br
Agent: O=S([O-])([O-])=S
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: N[C@@]1(c2cc(Br)c(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To C6 (1.0 g, 2.27 mmol) in tetrahydrofuran (1 mL) cooled to 0° C. was added a tetrahydrofuran solution of samarium iodide (0.1 M, 90.8 mL, 9.08 mmol) in a drop-wise manner. The resulting solution was allowed to stir at room temperature for 90 minutes. A saturated aqueous solution of sodium thiosulfate pentahydrate (1 L) was added to the reaction, followed by extraction with ethyl acetate (3×250 mL). The combined organics were washed with brine (1×500 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford a clear oily residue. The residue was dissolved in dichloromethane (5 mL) and filtered through a silica gel plug (approx 100 g) with dichloromethane (3×100 mL). The combined filtrates were concentrated in vacuo to afford the product as a clear oily residue, which was used directly in the next step. Yield: 947 mg, 2.14 mmol, 94%. LCMS m/z 443.1 [M+H+], Br isotopic pattern. 1H NMR (400 MHz, CD3OD), characteristic peaks: δ 8.00 (t, J=8.1 Hz, 1H), 7.24-7.38 (m, 5H), 7.10 (dd, J=12.1, 8.4 Hz, 1H), 4.58 (s, 2H), 4.03 (dd, J=11.2, 2.2 Hz, 1H), 3.72-3.80 (m, 1H), 3.56-3.64 (m, 2H), 3.44 (d, J=11.3 Hz, 1H), 3.34, (d, J=5.1 Hz, 1H), 2.46-2.53 (m, 1H), 1.68-1.80 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5](OC)=[O:6].O.[NH2:14][NH2:15]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([NH:14][NH2:15])=[O:6]
Reactant: NN
Reactant: COC(=O)c1cc(O)cc(Br)c1
Solvent: CC#N
Solvent: O
Product: NNC(=O)c1cc(O)cc(Br)c1
Yield: 80 %

Procedure:
Methyl 3-bromo-5-hydroxybenzoate (1 g, 4.33 mmol) was treated with hydrazine hydrate (1 ml, 20.5 mmol) and acetonitrile (5 ml) as a solvent according the method described in Preparation 226a to obtain 0.8 g (64% yield) of the title compound that was used in the next synthetic step without further purification. Purity 80%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([O:6][C:7](=[O:20])[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=1[N+:17]([O-])=O)[CH3:5].[H][H]>[Pd].CO>[CH3:1][O:2][CH2:3][CH:4]([O:6][C:7](=[O:20])[C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[NH2:17])[CH3:5]
Reactant: COCC(C)OC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COCC(C)OC(=O)c1ccc(N)cc1N
Yield: 93.9 %

Procedure:
A 500 ml Parr Shaker was charged with 75.6 g of (1-methoxy-2-propyl)-2,4-dinitrobenzoate, 200 ml methanol, and 1.5 g of a 5% palladium on carbon/50% water catalyst. The mixture was hydrogenated at 50 psi hydrogen pressure while maintaining the temperature below 50° C. Hydrogen uptake ceased after 4 hrs. The mixture was cooled, filtered, and the methanol removed under reduced pressure to give 56 g of (1-methoxy-2-propyl)-2,4-diaminobenzoate, a brown viscous liquid.
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:37][CH2:38][C:39]1[CH:46]=[CH:45][C:42](C#N)=[C:41](F)[CH:40]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][C@H:2]1[C:3]([NH:37][CH2:38][C:39]1[CH:46]=[CH:45][CH:42]=[CH:41][CH:40]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Reactant: N#Cc1ccc(CN)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
To an ice cooled solution of Boc-Aze-OH (0.194 g, 0.96 mmol) in 5 mL of DMF was added TBTU (0.50 g, 9.6 mmol). After 30 min another solution, comprising 4-aminomethyl-2-fluorobenzonitrile (0.17 g, 0.81 mmol; see step (v) above) and diisopropylethyl amine (0.326 g, 2.53 mmol) in 7 mL of DMF was added. The resulting solution was stirred overnight at room temperature. The solvent was evaporated and the product was purified by preparative RPLC using CH3CN:0.1M NH4OAc (50:50). Freeze-drying gave 0.237 g (74%) of the desired sub-title compound.