Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:23]2[CH2:22][CH2:21][CH2:20][CH:19]([C:24](O)=[O:25])[C:18]=2[C:17]2[C:12]1=[C:13]([Cl:29])[CH:14]=[CH:15][C:16]=2[O:27][CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:33])=O>ClCCl.CN(C=O)C>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:23]2[CH2:22][CH2:21][CH2:20][CH:19]([C:24]([Cl:33])=[O:25])[C:18]=2[C:17]2[C:12]1=[C:13]([Cl:29])[CH:14]=[CH:15][C:16]=2[O:27][CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cl)c2c1c1c(n2CCOCc2ccccc2)CCCC1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Cl)c2c1c1c(n2CCOCc2ccccc2)CCCC1C(=O)Cl
Temperature: 20 °C
Reaction time: 2 h

Procedure:
9-(2-Benzyloxy-ethyl)-8-chloro-5-methoxy-2,3,4,9,-tetrahydro-1H-carbazole-4-carboxylic acid (7) (1.5 g, 3.7 mmol) was dissolved in dichloromethane (50 mL) and oxalyl chloride (700 mg, 5.5 mmol, 470 μL) and DMF (1 drop) were added and the reaction stirred at 20° C. for 2 h. There was a moderate evolution of gas for about 30 min as the reaction proceeded. The reaction was then concentrated in vacuo to give 9-(2-Benzyloxy-ethyl)-8-chloro-5-methoxy-2,3,4,9,-tetrahydro-1H-carbazole-4-carbonyl chloride (8) as a gum which was used into the next step without purification. The structure was confirmed by 13C NMR (75 MHz; CDCl3): δC 20.8, 22.1, 26.4, 44.2, 51.8, 55.1, 70.7, 73.3, 100.7, 106.0, 108.6, 119.5, 123.4, 127.3, 127.7, 128.3, 131.9, 138.0, 138.2, 152.0. and 176.3.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)(C)(C)C.[NH2:25][C:26]1[C:31]([CH:32]=O)=[CH:30][N:29]=[CH:28][CH:27]=1.[OH-].[Na+]>C(O)C>[C:16]1([C:15]2[C:14]([C:11]3[CH:10]=[CH:9][C:8]([CH2:7][OH:6])=[CH:13][CH:12]=3)=[N:25][C:26]3[C:31]([CH:32]=2)=[CH:30][N:29]=[CH:28][CH:27]=3)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)Cc2ccccc2)cc1
Reactant: Nc1ccncc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCc1ccc(-c2nc3ccncc3cc2-c2ccccc2)cc1
Temperature: 70 °C

Procedure:
To a partial suspension of 1-[4-({[t-butyl-(dimethyl)silyl]oxy}methyl)phenyl]-2-phenylethanone (1.36 gm, 4.0 mmol) and 4-aminonicotinaldehyde (prepared as described in J. Org. Chem. 48, 3401 (1983)) (540 mg, 4.42 mmol) in absolute ethanol (10 mL) was added dropwise 5N NaOH (3 mL, 15 mmol). This mixture was heated at 70° C. for three hours. The solvent was evaporated in vacuo and the residue was partitioned between methylene chloride and aqueous sodium carbonate. The organic layer was dried (Na2SO4), the solution filtered, and the solvent evaporated. This residue was triturated with a small amount of ethyl acetate as the product crystallized out. The mother liquors were chromatographed on silica gel eluting with 0-2% methanol/ethyl acetate (sat'd with ammonia) to give additional product. 1H-NMR (500 MHz, CDCl3): δ 9.32 (1H, s), 8.77 (1H, d, J=5.9 Hz), 8.29 (1H, s), 7.99 (1H, d, J=6.1 Hz), 7.46 (2H, d, J=8 Hz), 7.28-7.33 (5H, m), 7.24-7.26 (2H, m), 4.71 (2H, s),
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1([F:35])[CH2:31][O:30][CH:29]([C:32]([OH:34])=O)[CH2:28][CH2:27]1.CCN(C(C)C)C(C)C.O[N:46]=[C:47]([C:49]1[CH:50]=[CH:51][C:52]([CH3:67])=[C:53]([NH:55][C:56]([C:58]2[N:62]3[CH:63]=[CH:64][CH:65]=[CH:66][C:61]3=[N:60][CH:59]=2)=[O:57])[CH:54]=1)[NH2:48]>CN(C=O)C>[F:35][C:26]1([F:25])[CH2:31][O:30][CH:29]([C:32]2[O:34][N:46]=[C:47]([C:49]3[CH:50]=[CH:51][C:52]([CH3:67])=[C:53]([NH:55][C:56]([C:58]4[N:62]5[CH:63]=[CH:64][CH:65]=[CH:66][C:61]5=[N:60][CH:59]=4)=[O:57])[CH:54]=3)[N:48]=2)[CH2:28][CH2:27]1
Reactant: O=C(O)C1CCC(F)(F)CO1
Reactant: Cc1ccc(C(N)=NO)cc1NC(=O)c1cnc2ccccn12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2noc(C3CCC(F)(F)CO3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
HATU (0.134 g, 0.355 mmol) was added in one portion to a stirred solution of 5,5-difluorotetrahydro-2H-pyran-2-carboxylic acid (17) (53 mg, 0.31 mmol) and DIEA (60 L, 0.355 mmol) in dry DMF (3 mL). After 10 minutes, N-(5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (9) (0.1 g, 0.323 mmol) was added in one portion and continued to stir for another 30 minutes, then heated at 110° C. for 30 minutes. The reaction was filtered and purified by preparative reverse phase HPLC to afford N-(5-(5-(5,5-difluorotetrahydro-2H-pyran-2-yl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F10) as a white solid. 1H NMR (400 MHz, d4-MeOH) δ 9.73 (d, J=7.2 Hz, 1H), 8.74 (s, 1H), 8.17 (m, 1H), 7.98-7.95 (m, 3H), 7.52-7.50 (m, 2H), 5.06 (dd, J=8.4, 2.8 Hz, 1H), 4.07-4.00 (m, 1H), 3.91-3.81 (m, 1H), 2.44 (s, 3H), 2.40-2.21 (m, 4H). MS m/z 440.1 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=[O:13].[OH:23][CH2:24][CH2:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[OH:23][CH2:24][CH2:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=1)=[O:13]
Reactant: C#CCOc1ccc(N)c(C(=O)c2ccc(C(C)C)cc2)c1
Reactant: O=Cc1ccccc1OCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C#CCOc1ccc(NCc2ccccc2OCCO)c(C(=O)c2ccc(C(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 100 mg (0.341 mmol) (2-amino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone in 1.5 ml CH2Cl2 is added 61 mg (0.36 mmol) 2-(2-hydroxyethoxy)benzaldehyde and 84 mg (0.38 mmol) sodium triacetoxyborohydride. The mixture is stirred at r.t. for two days, diluted with water and extracted with CH2Cl2. Purification of the crude product by chromatography (ethyl acetate/hexanes 1:1) affords a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O[C:14]1C=C(O)C=CC=1C(O)=O.CI.C(=O)([O-])[O-].[K+].[K+]>S1(CCCC1)(=O)=O>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C(O)c1ccc(O)cc1O
Reactant: COC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O=S1(=O)CCCC1
Product: COC(=O)c1ccc(OC)cc1O
Reaction time: 8 h

Procedure:
Methyl 2,4-dihydroxybenzoate (prepared from 2,4-dihydroxybenzoic acid by the general method of Brunner (Monatsh. 1913, 34, 916) (12 g) was treated with methyl iodide (12.2 g) and anhydrous potassium carbonate (4.95 g) in dry sulpholane (140 ml) at 60°-70° C. After 8 hours, further methyl iodide (12.2 g) was added and heating was continued for 14 hours. The excess of methyl iodide was evaporated and the mixture was poured into a mixture of ice and water (1 liter) and the mixture was acidified with aqueous acetic acid (2N). The separated solid was filtered off and washed with water to give methyl 2-hydroxy-4-methoxybenzoate (10.8 g), m.p. 47°-50° C. [a sample of which, purified by chromatography on silica gel (eluting with chloroform), had the melting point 49°-51° C⟧ The said crude methyl 2-hydroxy-4-methoxybenzoate (2.0 g) was heated with benzyl chloride (1.88 g) and anhydrous potassium carbonate (0.76 g) in dry sulpholane (15 ml) at 100° C. for 16 hours and was then poured into a mixture of ice and water (300 ml). The mixture was extracted with diethyl ether and the extract was washed with several portions of aqueous sodium hydroxide solution (0.5N) at 0° C., and was then dried and evaporated to give crude methyl 2-benzyloxy-4-methoxybenzoate (2.5 g) in the form of an oil. This material was heated at reflux with a mixture of aqueous sodium hydroxide solution (2N; 100 ml) and ethanol (20 ml) for 3 hours. The mixture was then treated with water (100 ml) and then cooled and extracted with diethyl ether (2 × 50 ml). The aqueous layer was cooled to 10° C. and acidified to pH 2 by treatment with concentrated hydrochloric acid to give 2-benzyloxy-4-methoxybenzoic acid (1.6 g), m.p. 99°-101° C.
Reaction SMILES: C[S-:2].[Na+].Cl[C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.Cl>CN(C)P(N(C)C)(N(C)C)=O>[C:14]1([S:11]([C:8]2[CH:7]=[CH:6][C:5]([SH:2])=[CH:10][CH:9]=2)(=[O:13])=[O:12])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(Cl)cc1
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=S(=O)(c1ccccc1)c1ccc(S)cc1
Temperature: 100 °C
Yield: 301 %

Procedure:
1.25 g of sodium thiomethylate are added under a nitrogen atmosphere to a solution of 15 g (0.0593 mol) of 1-chloro-4-(phenylsulfonyl)benzene in 150 ml of hexamethylphosphoramide. The mixture obtained is heated for 4 hours at 100° C. and then cooled and hydrolyzed in an ice/water mixture. The reaction medium obtained is extracted with ethyl acetate and the aqueous phase obtained is then poured into a 4 N solution of hydrochloric acid at 0° C. The product formed precipitates. After filtration, washing with water until the pH of the washings is neutral, and drying, 13.44 g (yield: 90.5%) of the expected product are obtained. M.p.=117° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].OC1C=C(C=CC=1)C(=O)C=CC1C=CC2OCOC=2C=1>>[OH:21][C:17]1[CH:16]=[C:15]([C:13](=[O:14])[CH2:12][CH2:11][C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:10][O:2][C:3]=3[CH:4]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(CCC(=O)c2cccc(O)c2)cc1OC
Agent: O=C(C=Cc1ccc2c(c1)OCO2)c1cccc(O)c1
Product: O=C(CCc1ccc2c(c1)OCO2)c1cccc(O)c1
Yield: 41 %

Procedure:
Prepared in a similar manner as (7) from 3'-Hydroxy-3,4-methylenedioxy chalcone (6). Crystallization of crude material from EtOAc/hexanes afforded 4.10 g (41%) of white solids: 1H NMR (CDCl3, 300 MHz) 9.73 (s, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.34-7.29 (m, 2H), 7.02 (dd, J=8.0 Hz, 1H), 6.88 (m, 1H), 6.80 (d, J=7.9 Hz, 1H), 6.71 (d, J=7.9 Hz, 1H), 5.96 (s, 2H), 3.26 (t, J=7.6 Hz, 2H), 2.84 (t, J=7.5 Hz, 2H); 13C NMR (CDCl3, 75 MHz) 199.4 158.0, 147.5, 145.7, 138.4, 135.4, 130.1, 121.5, 120.5, 119.3, 114.4, 109.2, 108.4, 101.0, 40.2, 29.7.
Reaction SMILES: CO[CH2:3][N:4]([CH2:11][CH2:12][CH3:13])[CH2:5][CH2:6][Si](C)(C)C.[Br:14][C:15]1[CH:16]=[N:17][C:18]([CH:21]=C)=[N:19][CH:20]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:14][C:15]1[CH:16]=[N:17][C:18]([CH:21]2[CH2:6][CH2:5][N:4]([CH2:11][CH2:12][CH3:13])[CH2:3]2)=[N:19][CH:20]=1
Reactant: CCCN(CC[Si](C)(C)C)COC
Reactant: C=Cc1ncc(Br)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN1CCC(c2ncc(Br)cn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.3 %

Procedure:
Methoxymethyl-propyl-trimethylsilanylethyl-amine (14.13 g, 74.61 mmol) in CH2Cl2 (4 ml) was added dropwise to a 0° C. cooled solution of 5-bromo-2-vinyl-pyrimidine (2 g, 10.80 mmol) and TFA (210 μl, 2.72 mmol) in CH2Cl2 (45 ml) over a period of 20 min. The reaction mixture was then stirred at room temperature for 2 h. The crude material was diluted with CH2Cl2, washed with saturated aqueous NaHCO3 and the organic layer was dried over Na2SO4 and evaporated. The residue was chromatographied on silica gel (CH2Cl2:methanol, 97:3) to afford the title compound (1.03 g, 34%) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH3:20])[CH:18]=3)[NH:13][C:12]=2[CH3:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:24]([O:26][C:27](=[O:30])[CH2:28]Br)[CH3:25]>C(O)C>[CH2:24]([O:26][C:27](=[O:30])[CH2:28][N:13]1[C:14]2[C:19](=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])=[C:12]1[CH3:21])[CH3:25]
Reactant: Cc1ccc2[nH]c(C)c(S(=O)(=O)c3ccc(Cl)cc3)c2c1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cn1c(C)c(S(=O)(=O)c2ccc(Cl)cc2)c2cc(C)ccc21
Reaction time: 0.5 h

Procedure:
The product of step (b) (1.27 g) was dissolved in THE (20 ml) at ° C. and NaH (0.115 g, 60% dispersion in oil) was added and stirred for 30 min. Ethylbromoacetate (0.66 ml) was then added and stirred for 1 h at room temperature. Ethanol was added to quench the reaction, the solvent was removed and the product washed with water and extracted with EtOAc. Purification by Flash column chromatography (30% EtOAc/hexane as eluent) gave the sub-title compound (0.716 g).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[N:45]=[C:44]([C:46]([NH:48][CH2:49][CH3:50])=[O:47])[CH:43]=[CH:42][CH:41]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:49]([NH:48][C:46]([C:44]1[CH:43]=[CH:42][CH:41]=[C:40]([C:33]2[CH:32]=[CH:31][C:30]([C:2]([OH:1])([C:6]3[N:7]=[CH:8][N:9]([C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:10]=3)[CH:3]([CH3:5])[CH3:4])=[CH:35][CH:34]=2)[N:45]=1)=[O:47])[CH3:50]
Reactant: CCNC(=O)c1cccc(Br)n1
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCNC(=O)c1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)n1
Yield: 59.5 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (3.10 g), 6-bromo-N-ethyl-2-pyridinecarboxamide (1.20 g) and tetrakis(triphenylphosphine)palladium(0) (0.170 g), the title compound (1.89 g) was obtained as colorless powder crystals.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[O:20]=[C:18]1[C:17]2[C:16](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15](=[O:25])[N:19]1[CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(N2C(=O)c3ccccc3C2=O)C1
Yield: 28.4 %

Procedure:
tert-Butyl 3-hydroxypiperidine-1-carboxylate (4.38 g) (21.76 mmol), phthalimide (4.82 g, 32.76 mmol), and triphenylphosphine (8.62 g, 32.86 mmol) were added to tetrahydrofuran (60 ml), 40% diethyl azodicarboxylate-toluene solution (15 ml) was slowly added at room temperature with stirring, and the mixture was stirred at the same temperature overnight. The reaction mixture was concentrated under reduced pressure, diluted with diethyl ether, and the precipitated colorless solid was filtered off. The mother liquor was concentrated under reduced pressure and the obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (2.04 g, yield 28%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[C:5]([C:6]#[N:7])=[C:4]([Cl:11])[CH:3]=1.[C:12](Cl)(Cl)=[S:13].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:11][C:4]1[CH:3]=[C:2]([N:1]=[C:12]=[S:13])[CH:9]=[C:8]([Cl:10])[C:5]=1[C:6]#[N:7]
Reactant: S=C(Cl)Cl
Reactant: N#Cc1c(Cl)cc(N)cc1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: N#Cc1c(Cl)cc(N=C=S)cc1Cl
Yield: 71.3 %

Procedure:
A suspension of 4-amino-2,6-dichlorobenzonitrile (500 mg, 2.67 mmol, Eq: 1.00), thiophosgene (1.35 g, 900 μl, 11.7 mmol, Eq: 4.39), triethylamine (875 mg, 1.2 ml, 8.64 mmol, Eq: 3.23) in benzene (30 ml) was heated at reflux overnight. The brown reaction mixture was concentrated and chromatographed (80 g Analogix, 0 to 5% ethyl acetate/hexane) to give 436 mg (71%) of desired product as a light brown solid.
Reaction SMILES: [C:1]([CH:4]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][O:25][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])=[CH:20][CH:19]=1)[CH2:5][NH:6][C:7]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])=[O:8])([OH:3])=O.C(Cl)CCl.[NH2:40][C:41]1[CH:42]=[C:43]2[C:48](=[CH:49][CH:50]=1)[CH:47]=[N:46][CH:45]=[CH:44]2>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[O:12]=[C:11]1[C:10]2[C:9](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=[O:8])[N:6]1[CH2:5][CH:4]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][O:25][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:27]([CH3:28])[CH3:29])[CH:30]([CH3:32])[CH3:31])=[CH:22][CH:23]=1)[C:1]([NH:40][C:41]1[CH:42]=[C:43]2[C:48](=[CH:49][CH:50]=1)[CH:47]=[N:46][CH:45]=[CH:44]2)=[O:3]
Reactant: CC(C)[Si](OCc1ccc(C(CNC(=O)c2ccccc2C(=O)O)C(=O)O)cc1)(C(C)C)C(C)C
Reactant: Nc1ccc2cnccc2c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)[Si](OCc1ccc(C(CN2C(=O)c3ccccc3C2=O)C(=O)Nc2ccc3cnccc3c2)cc1)(C(C)C)C(C)C
Reaction time: 8 h

Procedure:
To 2-(2-carboxy-2-(4-((triisopropylsilyloxy)methyl)phenyl)ethylcarbamoyl)benzoic acid (E135) in pyridine was added EDC, DMAP and 6-aminoisoquinoline and the solution was flushed with N2, capped, and stirred overnight. The mixture was poured into EtOAc/NaHCO3(sat) and the aqueous layer was further extracted with EtOAc. The organics were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 5% MeOH/CH2Cl2) gave pure 3-(1,3-dioxoisoindolin-2-yl)-N-(isoquinolin-6-yl)-2-(4-((triisopropylsilyloxy)methyl)phenyl)propanamide (E136).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(N)cc2)c1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(NC(=O)c3ccccc3)cc2)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.1 %

Procedure:
To a solution of [4-(4-amino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (115 mg, 0.34 mmol) and benzoyl chloride (52.64 mg, 0.37 mmol) were mixed together in dichloromethane (5 mL) under nitrogen and then diisopropylethylamine (0.12 mL, 0.67 mmol) was added to afford clear solution. The resulting solution was stirred for 4 hours at room temperature and then concentrated. Ethyl acetate (20 mL) was added and the mixture was washed with water (20 mL) and brine solution (20 mL) and then dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum gave a crude residue which was purified using an ISCO (12 g) column, eluting with 5-35% ethyl acetate in hexanes, to afford [4-(4-benzoylamino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (133 mg, 88.8%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.46 (s, 1 H), 7.93-8.03 (m, 5 H), 7.88 (s, 1 H), 7.51-7.68 (m, 3 H), 7.48 (dd, J=8.6, 1.8 Hz, 1 H), 7.23 (d, J=8.5 Hz, 2 H), 7.18 (d, J=1.8 Hz, 1 H), 3.97 (s, 2 H), 3.66 (s, 3 H), 2.10 (s, 3 H). HRMS calcd. for C27H23ClNO3 [(M+H)+] 444.1361, obsd. 444.1361.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[CH:29][CH:28]=[CH:27]2>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[C:31]=2[N:30]=[CH:29][CH:28]=[CH:27]3)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: Nc1cccc2cccnc12
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(Nc1cccc2cccnc12)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and 8-amino quinoline (74 mg, 0.51 mmol). The title compound was obtained as a yellow solid (20 mg, 10% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.83 (1H, m), 9.01 (3H, m), 8.83 (1H, m), 8.47 (1H, m), 8.28 (1H, m), 7.82 (1H, m), 7.66 (2H, m), 1.25 (1H, m). MS m/z: 477.23, 479.23 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)=[CH:4][CH:3]=1.[NH2:18][CH:19]1[CH:26]2[CH2:27][C:22]3([OH:29])[CH2:23][CH:24]([CH2:28][CH:20]1[CH2:21]3)[CH2:25]2>>[Br:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH:18][CH:19]2[CH:20]3[CH2:28][CH:24]4[CH2:23][C:22]([OH:29])([CH2:27][CH:26]2[CH2:25]4)[CH2:21]3)=[O:14])=[CH:4][CH:3]=1
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Reactant: O=C(O)c1cccc(Oc2ccc(Br)nc2)c1
Product: O=C(NC1C2CC3CC1CC(O)(C3)C2)c1cccc(Oc2ccc(Br)nc2)c1

Procedure:
Prepared from 3-(6-bromo-pyridin-3-yloxy)-benzoic acid and 4-amino-1-hydroxyadamantane. LC-MS (m/z): 444 (M+1).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:20]([CH3:21])=[CH:19][C:18]([NH2:22])=[CH:17][C:16]=1[Br:23])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:24]([S-:26])#[N:25].[K+].BrBr>CC(O)=O.C1COCC1>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:20]([CH3:21])=[CH:19][C:18]2[N:22]=[C:24]([NH2:25])[S:26][C:17]=2[C:16]=1[Br:23])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: N#C[S-]
Reactant: Cc1cc(N)cc(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc2nc(N)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of S)-2-(2-bromo-6-methyl-4-nitrophenyl)-2-tert-butoxyethyl pivalate (9 g, 21.63 mmol) in EtOH (50 ml) and EtOAc (50 ml) was added Pt/C (1.5 g), attached with a balloon of H2. More Pt/C (500 mg) was added after 3 h. Then the reaction mixture was stirred at rt for another 2 h. The reaction mixture was filtered over celite, concentrated down to give product (S)-2-(4-amino-2-bromo-6-methylphenyl)-2-tert-butoxyethyl pivalate (65G) and went to next step without purification. To a solution of (S)-2-(4-amino-2-bromo-6-methylphenyl)-2-tert-butoxyethyl pivalate (65G) (21.63 mmol) in HOAc/THF (80 ml, 1:1) was added KSCN at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h. Then Br2 was added slowly, reacted at 0° C. The reaction was quenched by adding sat. NaHSO3, extracted by EtOAc, dried over MgSO4, purified by silica gel column, eluting by 0-40% EtOAc in Hexanes to give 65H (2.3 g, 24% over 2 steps).