Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH:21](Cl)[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=O)=[CH:15][CH:14]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=S)c1ccc(Br)cc1
Reactant: COc1ccc(C(=O)C(Cl)c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-c2nc(-c3ccc(Br)cc3)sc2-c2ccc(OC)cc2)cc1
Temperature: 100 °C
Yield: 57 %

Procedure:
Fifty ml. of dioxane was used to dissolve 7.43 g. (0.034 mole) of 4-bromothiobenzamide with heating to about 60° C. Then 10.0 g. (0.034 mole) of 4,4'-dimethoxydesyl chloride in 50 ml. of dioxane was added and the mixture was heated to 100° C. for two hours. The mixture was cooled and acidified with 1 N hydrochloric acid. Most of the dioxane was removed in vacuo and the solid formed was filtered. The solid was purified by silica gel chromatography (400 g.), using benzene as the eluting agent. The product had a melting point of about 155°-157° C. and weighed 8.83 g. (57% yield). The mass spectrum showed the expected molecular ions at m/e=451 and 453.
Reaction SMILES: [C:1](=[S:3])=S.[OH-].[K+].C(O)C.[F:9][C:10]1[CH:38]=[CH:37][C:13]([O:14][C:15]2[C:23]3[N:22]=C(C4C=CC=CN=4)[NH:20][C:19]=3[CH:18]=[C:17]([O:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH:16]=2)=[CH:12][CH:11]=1>C(OCC)(=O)C>[F:9][C:10]1[CH:38]=[CH:37][C:13]([O:14][C:15]2[C:23]3[N:22]=[C:1]([SH:3])[NH:20][C:19]=3[CH:18]=[C:17]([O:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH:16]=2)=[CH:12][CH:11]=1
Reactant: S=C=S
Reactant: Fc1ccc(Oc2cc(Oc3cccnc3)cc3[nH]c(-c4ccccn4)nc23)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Fc1ccc(Oc2cc(Oc3cccnc3)cc3[nH]c(S)nc23)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
0.06 ml of carbon disulfide and 54 mg of potassium hydroxide were added to an ethanol (2.0 ml) solution of 273 mg of 3-(4-fluoro-phenoxy)-5-(pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 68, and the reaction liquid was stirred overnight at 80° C. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:31]>CN(C=O)C.C(OCC)C>[CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][O:27][CH3:31])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(CO)cc2)cccc1[N+](=O)[O-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCc1ccc(CN(Cc2ccccc2)c2cccc([N+](=O)[O-])c2C)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The product from Example 38A (0.1 g, 0.276 mmoles) in DMF (0.7 mL) was treated with sodium hydride (0.012 g, 0.3 mmoles, 60% dispersion). After 10 minutes, the reaction mixture was treated with iodomethane (0.02 mL, 0.36 mmoles) and then stirred overnight at room temperature. The mixture was diluted with diethyl ether (100 mL), washed with saturated ammonium chloride (50 mL) and water (50 mL) twice, washed with brine (50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound which was used in the next step without further purification.
Reaction SMILES: C1COC([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:19]=[N:20][N:21]3[C:26]([OH:27])=[N:25][CH:24]=[N:23][C:22]=23)(C2C=CC=CC=2)O1.Cl.[OH2:29].CO>CC(C)=O>[C:18]([C:16]1[CH:17]=[CH:12][C:13]([C:18]2[CH:19]=[N:20][N:21]3[C:26]([OH:27])=[N:25][CH:24]=[N:23][C:22]=23)=[CH:14][CH:15]=1)(=[O:29])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:12]=1
Reactant: O
Reactant: Oc1ncnc2c(-c3ccccc3C3(c4ccccc4)OCCO3)cnn12
Agent: Cl
Solvent: CO
Solvent: CC(C)=O
Product: O=C(c1ccccc1)c1ccc(-c2cnn3c(O)ncnc23)cc1
Reaction time: 2 h

Procedure:
A mixture of 8-(4-α,α-ethylenedioxybenzylphenyl)-4-hydroxypyrazolo[1,5-a]-1,3,5-triazine (0.20 g), conc. hydrochloric acid (0.5 ml), water (1 ml), methanol (4 ml) and acetone (1 ml) is stirred at 45°-60° C. for 2 hours. After cooling, the resulting precipitate is separated by filtration, washed with water and dried to give the title compound (0.15 g).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]([C@H:15]3[CH2:22][CH2:21][C:18]4([CH2:20][CH2:19]4)[CH2:17][C@@H:16]3[C:23]([OH:25])=O)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.NO.F[P-](F)(F)(F)(F)F.[N:36]1([O:45][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:45][NH:36][C:23]([C@@H:16]1[C@@H:15]([C:13]([N:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)=[O:14])[CH2:22][CH2:21][C:18]2([CH2:19][CH2:20]2)[CH2:17]1)=[O:25]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)[C@H]1CC2(CC[C@@H]1C(=O)N1CCN(c3ccccc3)CC1)CC2
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NO)[C@H]1CC2(CC[C@@H]1C(=O)N1CCN(c3ccccc3)CC1)CC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.6 %

Procedure:
The product from step 9 (36 mg, 0.105 mmole), and hydroxylamine hydrochloride (22 mg, 0.315 mmole) were dissolved in DMF (0.70 ml). To the solution, BOP (49 mg, 0.11 mmole) was added with stirring at r.t. for 10 min. DIEA (61 mg, 0.47 mmole) was added. The mixture was stirred at r.t. for 2 hours. The product was purified with preparative HPLC providing 22 mg of (5S,6S)—N-hydroxy-6-((4-phenylpiperazin-1-yl)carbonyl)spiro(2.5)octane-5-carboxamide. Yield: 44%. MS: M/Z 358.2 (M+H)+; 380.2 (M+Na)+; 737.2 (2M+Na)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@@H:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[C@@H:11]([NH2:13])[CH3:12])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.Cl[C:32]1[CH:37]=[CH:36][C:35]([C:38](=O)[C:39]([CH3:42])([OH:41])[CH3:40])=[CH:34][CH:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@@H:10]([C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[C:20]#[N:21])[C@@H:11]([NH:13][CH:38]([C:35]2[CH:36]=[CH:37][CH:32]=[CH:33][CH:34]=2)[C:39]([OH:41])([CH3:42])[CH3:40])[CH3:12])=[CH:5][CH:4]=1
Reactant: CC(C)(O)C(=O)c1ccc(Cl)cc1
Reactant: C[C@H](N)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(c1ccccc1)C(C)(C)O)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Reaction time: 0.08 h

Procedure:
To a solution of 100 mg (0.31 mmol) of 3-(4-chlorophenyl)-2(S)-(3-cyanophenyl)-1(S)-methyl-propylamine hydrochloride in 2 mL of CH2Cl2, 54 μL (0.31 mmol) of diisopropylethylamine and 62 mg (0.31 mmol) of 1-(4-chlorophenyl)-2-methyl-2-hydroxy-propan-1-one were added. After 5 min, 99 mg (0.47 mmol) of sodium triacetoxyborohydride was added and stirred for 3 hr. The reaction was quenched with water and the layers were separated. The organic layer was dried and concentrated. The residue was purified on a prep TLC plate using 30% EtOAc/hexane as an eluant to isolate two products. The higher Rf band gave 3-(1(S)-(4-chlorobenzyl)-2(S)-((2-hydroxy-2-methyl-1-phenylpropyl)amino)propyl)benzonitrile (diastereomer A) and the lower Rf band gave 3-(1(S)-4-chlorobenzyl)-2(S)-((2-hydroxy-2-methyl-1-phenylpropyl)amino)propyl)benzonitrile (diastereomer B). Diastereomer A, LC-MS: m/e=467 (M+1), 469 (M+3) (3.28 min). Diastereomer B, LC-MS: m/e=467 (M+1), 469 (M+3) (3.28 min).
Reaction SMILES: [NH:1]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@H:2]([C:7]([NH:9][C@H:10]([C:19]([NH:21][C@H:22]([C:27](O)=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:55][C@H:56]([C:58]([CH2:60][Cl:61])=[O:59])[CH3:57]>C1COCC1>[NH:1]([C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])[C@H:2]([C:7]([NH:9][C@H:10]([C:19]([NH:21][C@H:22]([C:27]([NH:55][C@H:56]([C:58]([CH2:60][Cl:61])=[O:59])[CH3:57])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)O
Reactant: C[C@H](N)C(=O)CCl
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)CCl
Temperature: -20 °C
Reaction time: 3 h

Procedure:
Boc-Ala-CH2Cl (2 g) in 5 equiv of HCl in dioxane was stirred at room temp for 1 h. After removal of solvent, the residue was triturated with diethyl ether to give crude H-Ala-CH2Cl (1.41 g). The Z-Leu-Asp(OtBu)-Leu-OH (2.68 g) and N-methylmorpholine (0.54 mL) were dissolved in THF (25 mL), the cooled to -20° C. Isobutyl chloroformate (0.64 mL) was added to generate the mixed anhydride, which was transferred to the H-Ala-CH2Cl (1.41 g in 10 mL of DMF) solution at -20° C. The resulting mixture was allowed to come to room temp and reaction was completed in 3 h. The salt was removed by filtration. The filtrate was concentrated, redissolved in ethyl acetate (100 mL). The solution was washed with 0.2N HCl, 5% NaHCO3, sat. NaCl; dried over Na2SO4, filtered, and concentrated to yield crude solid of 3.19 g. The crude Z-Leu-Asp(OtBu)-Leu-Ala-CH2Cl was purified by Sephadex LH20 column chromatography.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:11][N:10]=[N:9][N:8]=2)[CH:2]=1.[OH-].[Na+].[CH3:14]I>C(O)C>[CH3:14][N:9]1[N:10]=[N:11][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:8]1
Reactant: c1cncc(-c2nnn[nH]2)c1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nnc(-c2cccnc2)n1
Yield: 29.4 %

Procedure:
5-(3-pyridyl)-tetrazole (11) (J. M. McManus and R. M. Herbst, J. Am. Chem. Soc., 24 (1959) 1462-64) (10 g, 0.068 mol), sodium hydroxide (2.73 g, 0.068 mol), and methyl iodide (14.5 g, 0.1 mol) in ethanol (100 ml) was stirred at 40° C. overnight. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in dichloromethane (100 ml), and the solution was washed three times with water (100 ml). The organic phase was dried over magnesium sulphate and evaporated yielding 3.21 g (0.020 mol, 30%) of 12 with M.P. 108°-110° C. According to the 1H NMR spectrum the product contained less than 10% of the 1-isomer.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O.Cl>C(O)(C)(C)C>[Cl:11][C:10]1[C:3]2[C:2]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: Clc1c[nH]c2ncnc(Cl)c12
Reactant: C1CCNCC1
Agent: Cl
Solvent: O
Solvent: CC(C)(C)O
Product: Clc1c[nH]c2ncnc(N3CCCCC3)c12
Temperature: 25 °C
Yield: 63.4 %

Procedure:
The product from Method R (57 mg, 0.3 mmol) was suspended in 3.0 mL of tert-butanol and to this solution was added piperidine (90 μL, 0.9 mmol) and the resulting system heated at reflux for 1 h. The reaction mixture was cooled to room temperature and water was added (4.0 mL). The solution was adjusted to pH 1 with 1 N HCl and then washed with ether. The aqueous layer was removed and adjusted to pH 12 with 2 N NaOH. The solution was then extracted 2×15 mL with dichloromethane and the combined organics washed with water then brine and dried over MgSO4. Evaporation of solvent afforded 45 mg of a yellow solid that was purified by silica-gel chromatography (3:1 ethyl acetate/hexanes) to yield 23 mg (32%) of the title compound as a light yellow solid. Mp 170-172° C. 1H NMR (400 MHz, CDCl3) δ: 1.67 -1.74 (m, 6H), 3.65-3.67 (m, 4H), 7.10 (s, 1H), 8.31 (s, 1H). LRMS: 237 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])=[CH:4][CH:3]=1.C=O.S(=O)(=O)(O)O.[CH2:24](O)C>O>[F:1][C:2]1[CH:16]=[C:15]2[C:5](=[CH:4][CH:3]=1)[NH:6][C:7]1[CH2:24][NH:11][C@H:10]([C:12]([OH:14])=[O:13])[CH2:9][C:8]2=1
Reactant: CCO
Reactant: N[C@@H](Cc1c[nH]c2ccc(F)cc12)C(=O)O
Agent: C=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)[C@@H]1Cc2c([nH]c3ccc(F)cc23)CN1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
A mixture of 111 mg of 5-fluoro-L-tryptophan, 50 mg of 35% formalin, 0.8 ml of 0.1N sulfuric acid, 0.4 ml of ethanol and 0.3 ml of water is stirred at room temperature for 24 hours. The precipitates are collected by filtration, washed with water and ethanol and then dried. 80 mg of (3S)-6-fluoro-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid are obtained as white powder. Yield: 69%
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].Br[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: C=CCCCCCCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Product: O=[N+]([O-])c1ccc(CCCCCCCCc2ccccc2)cc1
Yield: 64.4 %

Procedure:
General procedure M was used to convert 5.31 mmol of 15a and 5.84 mmol of 1-bromo-4-nitrobenzene to 3.42 mmol (71%) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][C@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]3)=[N:19][CH:20]=1)=[N:11][C:10](Cl)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([Cl:52])[C:38]=1[OH:53]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][C@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]3)=[N:19][CH:20]=1)=[N:11][C:10]([C:41]1[CH:40]=[C:39]([Cl:52])[C:38]([OH:53])=[C:37]([Cl:36])[CH:42]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 44.9 %

Procedure:
Following general procedure II, (S)-tert-butyl (1-{5-[(3-acetyl-6-chloro-1,5-naphthyridin-4-yl)-amino]pyridin-2-yl}piperidin-3-yl)carbamate (98 mg, 0.20 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (85 mg, 0.30 mmol) to afford the product (56 mg) which was carried forward without any purification: ESI MS m/z 625 [M+H]+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[Cl:6][C:7]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:8]=1[C:9](=[O:12])[CH2:10][Cl:11].[Cl-].[NH4+].Cl>CCOCC>[Cl:11][CH2:10][C:9]([C:8]1[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:7]=1[Cl:6])([OH:12])[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: [Li]CCCC
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCC(O)(CCl)c1ccc(Cl)cc1Cl

Procedure:
Into a 500 ml four-necked flask equipped with a thermometer, a condenser, a mechanical stirrer, an addition funnel, and a nitrogen inlet tube are placed 102 ml (0.2 m, 1.97 M solution in hexane) of n-butyllithium. This solution is cooled to -60° with an acetone-dry ice bath. 2,4-Dichlorphenacyl chloride (44.7 g, 0.2 m) dissolved in 250 ml of ether is then added dropwise. The temperature is maintained below -55° throughout the reaction. After the addition, the reaction is allowed to warm gradually to -10° and then poured into a mixture containing 250 ml of saturated ammonium chloride and 250 ml of 10% hydrochloric acid solution. The layers are separated and the aqueous layer is extracted with 100 ml of ether. The combined ether extracts are washed with 10% hydrochloric acid, saturated sodium chloride solution, and dried over MgSO4. Solvent is evaporated to give 52 g of a pale yellow oil. Vacuum distillation (100°-120°/0.2 mm) affords 44 g of pure product.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][NH:10][C:11](=[O:28])[NH:12][CH2:13][C:14]2[CH:19]=[C:18]([CH:20]=[CH2:21])[C:17]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[C:16]([F:27])[CH:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11](=[O:28])[NH:12][CH2:13][C:14]2[CH:15]=[C:16]([F:27])[C:17]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])=[C:18]([CH2:20][CH3:21])[CH:19]=2)=[CH:29][CH:30]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1cc(CNC(=O)NCc2ccc(C(C)(C)C)cc2)cc(F)c1NS(C)(=O)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCc1cc(CNC(=O)NCc2ccc(C(C)(C)C)cc2)cc(F)c1NS(C)(=O)=O
Reaction time: 1 h
Yield: 90.7 %

Procedure:
N-{4-[3-(4-t-butyl-benzyl)-ureidomethyl]-2-fluoro-6-vinyl-phenyl}methanesulfonamide (15.6 mg, 0.04 mmol) was dissolved in methanol. To the solution was added Pd/C (10 wt. %) and air in the flask was displaced with hydrogen gas. The reaction solution was stirred for 1 hour. After confirming the completion of the reaction with TLC, Pd/C was filtered off through celite. The methanol was removed under reduced pressure and column-chromatographed (n-hexane/ethyl acetate ˜1/1) to yield a white solid (15.8 mg, 100.0%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>O>[C:13]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cccc(C(=O)O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cccc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.7 %

Procedure:
To a solution of 1.37 g of 3-aminobenzoic acid and 0.4 g of sodium hydroxide in 50 ml of water, 1.41 g of benzoyl chloride and a solution containing 0.4 g of sodium hydroxide in 5 ml of water were simultaneously added dropwise, in an ice bath, and the mixture was stirred at room temperature for 6 hours. The reaction solution was adjusted to pH 1 by addition of 1N hydrochloric acid, and thus obtained solid was collected by filtration to give 1.92 g (yield 80%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48][C:49]#[N:50])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48][CH2:49][NH2:50])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCC#N)CCC3)cc1
Solvent: C1CCOC1
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCCN)CCC3)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
To a well stirred solution of 0.130 g (0.190 mmol) of (3R,4R)-3-[1-(3-cyano-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester in 0.5 ml of absolute THF was added dropwise 1 ml of a 1M solution of borane-THF complex in THF. After stirring for 3 h at 70° C., the reaction was allowed to warm to room temperature, poured into 50 ml of an ice/water mixture and extracted three times with 50 ml of ethyl acetate. The combined organic phases were washed twice with 20 ml of water, evaporated under reduced pressure and dried in a high vacuum. The thus-obtained crude product was purified by chromatography on silica gel using a 140:10:1 v/v/v mixture of dichloromethane/methanol/28% ammonium hydroxide solution as the eluent to yield 0.090 g (0.131 mmol, 68.9% of theory) of (3R,4R)-3-[1-(4-amino-butyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 688 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:20][C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][CH2:26][NH:27]2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][CH2:26][N:27]2[C:2]2[C:3]3[CH:10]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=4)[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:23][CH:22]=1
Reactant: Clc1ccc2c(c1)NCC2
Reactant: O=[N+]([O-])c1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Product: O=[N+]([O-])c1ccc(-c2cc3c(N4CCc5ccc(Cl)cc54)ncnc3[nH]2)cc1

Procedure:
This product is prepared in a manner analogous to that described in Example 6 from 4-chloro-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine and 6-chloro-2,3-dihydroindole (1.1 equivalents).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[CH3:13][O:14]C1C=CC=CC=1C(OC)=O>>[CH3:13][O:14][C:5]1[CH:4]=[CH:3][CH:8]=[CH:7][C:6]=1[C:9]([NH2:12])([CH3:10])[CH3:11]
Reactant: COC(=O)c1ccccc1OC
Reactant: COc1ccc(C(C)(C)N)cc1
Product: COc1ccccc1C(C)(C)N
Yield: 81 %

Procedure:
Following a procedure similar to that described in Preparation 10a, but using methyl 2-methoxybenzoate as a starting material, in a relative amount similar to that used in that Preparation, the title compound was obtained in a yield of 81%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=2)[CH:4]=[CH:3]1.Cl[C:18](=[O:23])[C:19]([O:21][CH3:22])=[O:20]>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[CH:9]=2)[C:4]([C:18](=[O:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:3]1
Reactant: Cn1ccc2ccc(N3CCOCC3)cc21
Reactant: COC(=O)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)C(=O)c1cn(C)c2cc(N3CCOCC3)ccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 110.3 %

Procedure:
1-Methyl-6-morpholin-4-yl-1H-indole (3.89 g, 18 mmol) was dissolved in CH2Cl2 (18 mL) and cooled at 0° C. Methyl chlorooxoacetate (2.4 mL, 26 mmol) was added to give a dark solution. Stirring was continued for 2 h at 0° C. and more methyl chlorooxoacetate (0.40 mL, 4.3 mmol) was added. After a further 2 h, the solvent was evaporated. The resulting solid was taken up in ether, filtered and washed well with ether to give crude methyl (1-methyl-6-morpholin-4-yl-1H-indol-3-yl)glyoxylate (6 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:11][O:12][CH2:13][C@H:14]([NH2:16])[CH3:15]>>[NH2:1][C:2]1[CH:9]=[C:8]([NH:16][C@H:14]([CH3:15])[CH2:13][O:12][CH3:11])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: COC[C@@H](C)N
Product: COC[C@@H](C)Nc1cc(N)ncc1C#N

Procedure:
From intermediate 21 and (R)-1-methoxy-2-propylamine, reacted in an analogous manner to the preparation of intermediate 112. (UPLC-MS 7) tR 0.42; ESI-MS 207.1 [M+H]+.