Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)[CH2:9]2)[CH2:4][CH2:3]1.C(O)C.[H][H]>[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[CH2:9]2)[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: CN1CCN(C2CCCN(c3ccc([N+](=O)[O-])cc3)C2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCN(C2CCCN(c3ccc(N)cc3)C2)CC1
Yield: 76.1 %

Procedure:
1-Methyl-4-[1-(4-nitro-phenyl)-piperidin-3-yl]-piperazine (1.40 g, 4.60 mmol) was dissolved in Ethanol (36.1 mL, 618 mmol) and the solution was carefully added to 10% Palladium on Carbon (0.515 g, 38.6 mmol) under nitrogen. The mixture was then placed on a Parr hydrogenation apparatus and was allowed to shake at 55 psi until uptake of hydrogen ceased. The catalyst was then filtered to afford 0.960 g of 4-[3-(4-Methyl-piperazin-1-yl)-piperidin-1-yl]-phenylamine without further purification. (M+H)=275.7. 1H NMR (400 MHz, DMSO, d6) δ 6.67 (d, 2H, J=8.56 Hz), 6.47 (d, 2H, J=8.51 Hz), 4.54 (s, 2H), 3.39 (m, 2H), 3.20 (m, 1H), 2.62 (m, 4H), 2.33 (m, 6H), 2.12 (s, 3H), 1.85 (m, 1H), 1.74 (m, 1H), 1.52 (m, 1H), 1.18 (m, 1H).
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[S:3]Cl.C(N(CC)CC)C.[NH:14]1[CH2:20][C:18](=[O:19])[NH:17][C:15]1=[O:16]>C(OCC)(=O)C>[Cl:1][C:2]([Cl:6])([Cl:5])[S:3][N:14]1[CH2:20][C:18](=[O:19])[N:17]([S:3][C:2]([Cl:6])([Cl:5])[Cl:1])[C:15]1=[O:16]
Reactant: O=C1CNC(=O)N1
Reactant: ClSC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1CN(SC(Cl)(Cl)Cl)C(=O)N1SC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.5 %

Procedure:
At about 0° C., 37.2 g (0.2 mole) of trichloromethylsulfenyl chloride and subsequently 20.2 g (0.2 mole) of triethylamine are dripped, while stirring thoroughly, into a suspension of 10 g (0.1 mole) of hydantoin in 150 ml of anhydrous ethyl acetate. After stirring for 90 minutes at room temperature, the precipitated triethylamine hydrochloride is filtered off and washed with 100 ml of ethyl acetate. The filtrate is concentrated and the residue is crystallized by trituration with n-pentane. There is obtained 36.1 g (90.5% of theory) of 1,3-bis-(trichloromethylthio)-hydantoin; m.p.: 142° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:6]([N+:12]([O-:14])=[O:13])=[N:7][CH:8]=[C:9](Br)[CH:10]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:6]([N+:12]([O-:14])=[O:13])=[N:7][CH:8]=[C:9]([N:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)[CH:10]=1
Reactant: CN1CCNCC1
Reactant: COC(=O)Cc1cc(Br)cnc1[N+](=O)[O-]
Product: COC(=O)Cc1cc(N2CCN(C)CC2)cnc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of (5-Bromo-2-nitro-pyridin-3-yl)-acetic acid methyl ester (472 mg, 1.72 mmol) and N-methylpiperazine (344 mg, 3.44 mmol) is heated for 18 h under an argon atmosphere. TLC analysis indicated complete consumption of starting material. The reaction mixture is cooled to RT, diluted with water and adjusted to pH 8-9 with a saturated aq. NaHCO3 solution. The aqueous phase is extracted three times with methylene chloride and the combined organic layers are washed with brine, dried over Na2SO4, and concentrated at reduced pressure. The crude product is purified by FCC (methylene chloride/MeOH 95:5 to 90:10) to afford the title compound as a yellow solid. 1H NMR (d6-DMSO 400 MHz): δ 2.01 (s, 3H), 2.22-2.26 (m, 4H), 3.24-3.28 (m, 4H), 3.40 (s, 3H), 3.81 (s, 2H), 7.26 (d, J=2 Hz, 1H), 7.97 (d, J=2 Hz, 1H). ES+−MS: 295.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH:11]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([CH3:13])[CH3:12]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([CH:11]([CH3:13])[CH3:12])=[CH:15][CH:16]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=C(O)c1cccc(Cl)n1
Product: CC(C)c1ccc(NC(=O)c2cccc(Cl)n2)cc1

Procedure:
The intended compound was produced according to the method of Example 92 but using 6-chloropyridine-2-carboxylic acid and 4-isopropylaniline as the starting materials.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10](F)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.O>CS(C)=O>[C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([N:25]2[CH2:26][CH2:27][CH:22]([NH2:21])[CH2:23][CH2:24]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CCNCC1
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1ccc(N2CCC(N)CC2)cc1
Temperature: 120 °C
Reaction time: 17 h

Procedure:
4-fluorobenzoic acid tert-butyl ester (19.6 g, 100 mmol) was dissolved in dimethyl sulfoxide (hereinafter referred to as DMSO) (50 ml), and potassium carbonate (20.7 g, 150 mmol) and 4-aminopiperidine (11.0 g, 110 mmol) were added thereto, followed by stirring at 120° C. for 17 hours. After the reaction mixture was cooled to room temperature, water was added to the mixture, and the precipitate was collected by filtration, thereby obtaining 4-(4-aminopiperidin-1-yl)-benzoic acid tert-butyl ester (23.3 g, 84%) as a milky-white solid.
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)#[N:32]>>[C:31]([C:33]1[CH:38]=[CH:37][C:36]([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)=[CH:35][CH:34]=1)#[N:32]
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)N1CCOC=C1c1ccc(C#N)cc1
Yield: 58 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and 4-cyanophenylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as an off-white solid (58% yield); 1H-NMR (d6-DMSO) 1.09 (9H, s), 3.68 (2H, t), 4.13 (2H, t), 6.68 (1H, s), 7.37 (2H, d), 7.74 (2H, d); 13C-NMR (CDCl3) 27.7, 41.5, 66.8, 125.1, 131.8, 134.4; MS ES(+) 287.0 (M++1). IR λmax=2227, 1699 cm−1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].CCO[CH2:12][CH3:13]>C(Cl)Cl>[N:1]1[CH:2]=[CH:3][CH:4]=[CH:5][C:12]=1[CH:13]=[N:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: CCOCC
Reactant: Nc1ccccc1O
Solvent: ClCCl
Product: Oc1ccccc1N=Cc1ccccn1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
2-Aminophenol (1.09 g, 10 mmol) was dissolved in ether (20 mL) and DCM (5 mL). 2-pyridinecaroxaldehyde (0.95 mL, 10 mmol) was added to the above solution. The reaction mixture was stirred at room temperature for 17 h; precipitate was formed. The light yellow solid (1.52 g, 77%) was filtered and dried. 1H (CDCl3) δ 8.85 (s, 1H), 8.72 (d, J=3 Hz, 1H), 8.21 (d, J=9 Hz, 1H), 7.84 (t, J=7.5 Hz, 1H), 7.39 (t, J=7.5 Hz, 1H), 7.31 (bs, 1H), 7.25 (t, J=9 Hz, 1H), 7.04 (d, J=6 Hz, 1H), 6.94 (t, J=7.5 Hz, 1H), MS (M+H) 199.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1.[Li]CCCC.CN([CH:18]=[O:19])C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: Clc1cc(Cl)cc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c(Cl)cc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
2,4,6-Trichlorobenzaldehyde was prepared according to the procedure outlined in Synthesis 2008, 279. To a solution of 1,3,5-trichlorobenzene (10.0 g, 55.1 mmol) in THF (200 ml) at −78° C. was slowly added n-BuLi (1.6 M in hexanes, 34.4 ml, 55.1 mmol) over 20 min. The reaction mixture was stirred at −78° C. for 30 min then DMF (7.5 ml, 96.4 mmol) was added dropwise. The reaction was stirred at −78° C. for an additional 1.5 h then quenched with 3 N HCl (200 ml) and warmed to room temperature. The mixture was extracted with EtOAc. The organic layer was washed with sat NaHCO3 and brine then dried over MgSO4 and concentrated to afford 10.7 g (93%) of 2,4,6-trichlorobenzaldehyde as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[N:3]=1.[CH3:16][O:17][C:18]([C:20]1([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19]>C(O)(C)C>[CH3:16][O:17][C:18]([C:20]1([C:25]2[CH:26]=[CH:27][C:28]([NH:31][C:2]3[C:7]4[CH2:8][CH2:9][CH2:10][C:6]=4[N:5]=[C:4]([CH:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)[N:3]=3)=[CH:29][CH:30]=2)[CH2:21][CH2:22][CH2:23][CH2:24]1)=[O:19]
Reactant: COC(=O)C1(c2ccc(N)cc2)CCCC1
Reactant: Clc1nc(C2CCCC2)nc2c1CCC2
Solvent: CC(C)O
Product: COC(=O)C1(c2ccc(Nc3nc(C4CCCC4)nc4c3CCC4)cc2)CCCC1
Yield: 92.6 %

Procedure:
A mixture of 4-chloro-2-cyclopentyl-6,7-dihydro-5H-cyclopentapyrimidine (4.2 g, 18.91 mmol) and 1-(4-amino-phenyl)-cyclopentanecarboxylic acid methyl ester (4.2 g, 19.1 mmol) in anhydrous isopropanol (50 mL) was heated at reflux in a nitrogen atmosphere for 8 to 18 hours. Thereafter, volatiles were evaporated under reduced pressure. The mixture was triturated with ether and filtered. The solid was dissolved in ethyl acetate and washed with 5% sodium bicarbonate and brine. The organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a light yellow powder (7.1 g, 93.4% yield).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH3:37][O:38][C:39](=[O:46])[C@@H:40]([CH2:42][CH2:43][S:44][CH3:45])[NH2:41]>C(Cl)Cl>[CH3:7][C:4]([CH3:5])([O:3][C:1]([NH:8][C@H:9]([C:18]([NH:41][C@@H:40]([C:39]([O:38][CH3:37])=[O:46])[CH2:42][CH2:43][S:44][CH3:45])=[O:20])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)=[O:2])[CH3:6]
Reactant: COC(=O)[C@H](N)CCSC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H](CCSC)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 18 h
Yield: 98.1 %

Procedure:
To Boc-tyrosine (16.9 g, 60 mmol) in 150 ml of methylene chloride (CH2Cl2) cooled to 0° C. under an argon (Ar) atmosphere were added 6.6 ml (60 mmol) of N-methylmorpholine (NMM). After cooling this vigorously stirred solution to -78° C., 7.9 ml (60 mmol) of isobutylchloroformate (IBCF) were added to this reaction. The mixture was allowed to warm to 20° C. before it was again cooled to -78° and another 7.9 ml (60 mmol) of NMM were added. (D)Methionine methyl ester hydrochloride (12.0 g, 60 mmol) was then added to the reaction in a single portion. The mixture was allowed to warm to room temperature and stir for an additional 18 hours (h). After filtering the reaction through diatomaceous earth, the filtrate was washed 3×100 ml 0.5N potassium bisulfate (KHSO4). The combined aqueous washed was extracted with CH2Cl2 (100 ml). The combined organic extracts were washed with 100 ml of brine, dried over sodium sulfate (Na2SO4) and stripped of all solvent under reduced pressure to produce the title product (25.1 g) as a light yellow glass. The material was used in subsequent reactions without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:5][C:3]=1[NH2:4].CC(C)=O.C([O-])([O-])=O.[K+].[K+].[C:28](Cl)(=[O:37])[CH:29]=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:5][C:3]=1[NH:4][C:28](=[O:37])[CH:29]=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1cc(OCCN2CCCCC2)ccc1Cl
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(C=Cc1ccccc1)Nc1cc(OCCN2CCCCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
2-chloro-5-(2-piperidinoethoxy)aniline (500 mg, 1.9 mmol, 1 eq.) was placed in mixture of acetone (653 μL) and water (852 μL) in the presence of K2CO3(541 m g, 3.9 mmol, 2 eq.). Cinnamoyl chloride (326 mg, 1.9 mmol, 1 eq.) was then added at 0° C. The reaction mixture was allowed to warm-up to room temperature, stirred for 2 hours and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford N-(2-chloro-5-(2-(piperidin-1-yl)ethoxy)phenyl)cinnamamide (521 mg, 69%).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=1)[C:7]([NH:9][NH:10]C(OC(C)(C)C)=O)=[O:8]>C(OCC)(=O)C>[ClH:2].[Cl:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[CH:19]=[CH:20][C:21]([N:24]([CH3:26])[CH3:25])=[CH:22][CH:23]=1)[C:7]([NH:9][NH2:10])=[O:8]
Reactant: CN(C)c1ccc(C(CCCCl)C(=O)NNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(C(CCCCl)C(=O)NN)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4 N hydrochloric acid in ethyl acetate (2.64 mL) was added to tert-butyl N′-[5-chloro-2-(4-dimethylaminophenyl)pentanoyl]hydrazinecarboxylate (106.9 mg), and the reaction solution was stirred at room temperature for four hours. The reaction solution was concentrated under reduced pressure to obtain 5-chloro-2-(4-dimethylaminophenyl)pentanoic acid hydrazide hydrochloride. A solution of ethyl (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate hydrochloride (77.6 mg) and triethylamine (0.16 mL) in ethanol (1.25 mL) was added to a solution of the resulting 5-chloro-2-(4-dimethylaminophenyl)pentanoic acid hydrazide hydrochloride and triethylamine (0.291 mL) in ethanol (1.25 mL), and the reaction solution was stirred at 80° C. in a nitrogen atmosphere for 22 hours. The reaction solution was cooled to room temperature, and then the solvent was evaporated from the reaction solution under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the resulting residue, and the organic layer was separated. The resulting organic layer washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=1:1->ethyl acetate->ethyl acetate:methanol=9:1) and further purified by silica gel column chromatography (elution solvent: ethyl acetate->ethyl acetate:methanol=9:1) to obtain 26.6 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([NH:18][C:17](=[O:19])[C:16]3[CH:20]=[C:21](/[CH:24]=[CH:25]/[C:26]([NH:28][O:29]C4CCCCO4)=[O:27])[CH:22]=[CH:23][C:15]=3[O:14]2)[CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[O:19]=[C:17]1[C:16]2[CH:20]=[C:21](/[CH:24]=[CH:25]/[C:26]([NH:28][OH:29])=[O:27])[CH:22]=[CH:23][C:15]=2[O:14][C:10]2([CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[NH:18]1
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)NC(=O)c1cc(/C=C/C(=O)NOC3CCCCO3)ccc1O2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(/C=C/c1ccc2c(c1)C(=O)NC1(CCCNC1)O2)NO
Yield: 68.6 %

Procedure:
A solution of (±)-(E)-3-{1′-tert-butoxycarbonyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (360 mg, 0.74 mmol) in DCM (14 ml) was treated with 4 M HCl in dioxane (1.9 ml) as described in Example 30, STEP C to give (±)-(E)-3-{3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-hydroxy-acrylamide (154 mg, hydrochloride salt) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[C:6]=1[F:23])[CH3:2].Br[C:26]1[CH:27]=[N:28][CH:29]=[C:30]([CH3:32])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:26]3[CH:27]=[N:28][CH:29]=[C:30]([CH3:32])[CH:31]=3)[C:13]=2[CH3:22])[C:6]=1[F:23])[CH3:2]
Reactant: Cc1cncc(Br)c1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1F
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cncc(C)c3)c3cc(Cl)ccc23)c1F

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-2-fluoro-benzoic acid ethyl ester and 3-bromo-5-methylpyridine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18].C(N(CC)CC)C>CN(C=O)C>[CH2:9]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:18]=[CH:17][C:16]([O:20][CH3:21])=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=CC(=O)OC
Reactant: Brc1ccccc1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccccc1OCc1ccccc1
Temperature: 120 °C
Yield: 55.1 %

Procedure:
A mixture of 2-bromo-O-benzyl phenol (J. Med. Chem. (1992) 35:3483) (2.17 g; 8.25 mmol), methyl acrylate (0.83 g; 9.9 mmol), dichloropalladium(II)bis(triphenylphosphine) (150 mg) and triethylamine (2.51 g; 24.7 mmol) in 10 mL of DMF was heated in a sealed tube to 120° C. for 16 hrs. After cooling, the tube's contents were partitioned between ethyl acetate and water. Removal of the organic solvent and purification on silica gel (20% ethyl acetate/hexane) afforded 1.22 g (55%) of methyl 2-benzoxycinnamate, 1H NMR (CDCl3): δ 3.78 (s, 3H); 5.15 (s, 2H); 6.54 (d, 1H, J=16.2); 6.95 (m, 2); 7.33-7.41 (m, 6H); 7.52 (d, 1H, J=7.7).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([I:10])=[CH:8][N:7]=[C:6]2[NH:11][CH:12]=[CH:13][C:5]=12.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[Cl:3][C:4]1[C:9]([I:10])=[CH:8][N:7]=[C:6]2[N:11]([S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[CH:12]=[CH:13][C:5]=12
Reactant: Clc1c(I)cnc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1ccc2c(Cl)c(I)cnc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.9 %

Procedure:
NaH (0.960 g, 24.0 mmol, 60% dispersion in mineral oil) at 0° C. was added to 4-chloro-5-iodo-1H-pyrrolo[2,3-b]pyridine (5.57 g, 20.0 mmol) in dimethylformamide (“DMF”; 40 mL) and stirred at 0° C. for 20 minutes. Benzenesulfonyl chloride (2.82 mL, 22.0 mmol) was added, and the reaction was stirred at room temperature for 2 hours. Water (200 mL) was added and stirred for 10 minutes. The solid formed was collected by filtration, washed with ether, and dried to give 4-chloro-5-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (8.20 g, 98% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][S:5][CH:6]=1.O.O.O.[C:14]([O-])(=[O:16])C.[Na+].C(O)=O>O>[CH:14]([NH:1][C:2]1[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][S:5][CH:6]=1)=[O:16]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1cscc1N
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: COC(=O)c1cscc1NC=O

Procedure:
A stirred solution of methyl 4-amino-3-thenoate (4 g), sodium acetate trihydrate (2.8 g) and formic acid (27 ml) was heated at 95° C. for 1 hour. On cooling the solution was poured into water, and the solution filtered to give the title product as a solid.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[CH:6][N:7]=1)[CH3:2].Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][N:4]1[CH:5]=[CH:6][N:7]=[C:3]1[CH2:1][CH3:2])[CH3:14]
Reactant: CCOC(=O)CBr
Reactant: CCc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)Cn1ccnc1CC
Yield: 30.4 %

Procedure:
2-Ethyl-imidazole (10.0 g, 104 mmol) was dissolved in acetone (80 mL) and then ethyl bromoacetate (17.4 g, 104 mmol) and potassium carbonate (2.6 g, 18.7 mmol) was added and the resulting mixture was heated under reflux for 12 h. After filtration and evaporation the residue was extracted with water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated to afford the title compound as a light yellow solid (5.76 g, 30%). MS: m/e=183.1 [M+H]+.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=[O:6].[CH2:14]([O:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27]O)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1.OS(O)(=O)=O>[C:5]([C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[CH2:2][C:1]([O:13][CH2:27][CH2:26][CH2:25][NH:24][C:22]([O:21][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:23])=[O:12])([OH:7])=[O:6]
Reactant: O=C(NCCCO)OCc1ccccc1
Reactant: O=C(O)Cc1ccccc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: O=C(Cc1ccccc1C(=O)O)OCCCNC(=O)OCc1ccccc1
Yield: 88.9 %

Procedure:
Homophthalic acid (18 g, 0.1 mole) and 3-(benzyloxycarbonylamino)-1-propanol (41 g, 0.2 mole) were heated in 150 ml of benzene at 120°-130° C. for 2 hrs in the presence of a few drops of conc. H2SO4. Benzene was evaporated, and 200 ml of ethylacetate was added. The organic solution was washed with 4% NaHCO3 twice (150 ml×2). The aqueous layer which contained the monoester salt was acidified with 5N HCl and extracted with ethylacetate. 33 g of 3-(benzyloxycarbonylamino)propyl 2-carboxyphenylacetate (yield, 89%) was obtained after the solvent was evaporated. Hydrogenation of this monoester (1.86 g, 5 mmole) was performed in methanol containing 0.3 ml of acetic acid and 10% palladium on carbon to give 1 g of 3-aminopropyl 2-carboxphenylacetate.HAc (yield, 67%). This compound was identified by its NMR spectrum and TLC (Butanol:acetic acid:pyridine:water=4:1:1:2). 2 g of 3-aminopropyl 2-carboxyphenylacetate.HAc (3 mmole) was heated with 1.6 g of PCl5 (7.5 mmole) in 50 ml of anhydrous THF at 70°-80° for 2 hrs, a white precipitate formed. This white solid was purified by column chromatography (methylene chloride:methanol=5:1) and crystalline from MeOH-ether to give 0.2 g of 3-(3-aminopropoxy)isocoumarin.HCl (yield, 26%), m.p. 173°-174° C.; mass spectrum, m/e=220 (M + -Cl). Anal. Calc. for C12H14N1O3Cl1 : C, 56.37; H, 5.52; N, 5.48; Cl, 13.87. Found: C, 56.15; H, 5.49; N, 5.44; Cl 13.95.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C@H:13]([C:21]([OH:23])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[OH-].[Na+]>[CH2:5]([O:4][C:2]([NH:12][CH:13]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]([OH:23])=[O:22])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NC(Cc1ccccc1)C(=O)O)OCc1ccccc1
Reaction time: 1 h

Procedure:
82 mmol (13.9 g) of benzyl chloroformate and 20 ml of 4M aqueous sodium hydroxide are added over a period of 30 minutes to a solution, cooled to 0° C., of 80 mmol (13.2 g) of phenylalanine in 20 ml of 4M aqueous sodium hydroxide. The solution returns to room temperature during a period of 1 hour. The reaction mixture is extracted with ether. The aqueous phase is rendered acidic to pH=2 with a dilute hydrochloric acid solution. The precipitate that forms is filtered off and washed to yield the expected compound.