Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH3:16])([CH3:15])[C:4]=2[CH:3]=1.[C:17]1(C)C=CC=C[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[CH:17]([C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH3:16])([CH3:15])[C:4]=2[CH:3]=1)=[CH2:18]
Reactant: CC1(C)c2ccccc2-c2ccc(I)cc21
Reactant: Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C=Cc1ccc2c(c1)C(C)(C)c1ccccc1-2
Temperature: 80 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
8.19 g (25.6 mmole) of 2-iodo-(9,9-Dimethyl)-fluorene, 5.18 g (28.1 mmole) of dibutyl vinylborate, 0.26 g of Pd(PPh3)4, 60 ml of toluene, 30 ml of ethanol, and 60 ml of a 2M sodium carbonate aqueous solution were fed into a 300-ml round-bottomed flask, and the whole was stirred at 80° C. for 8 hours in a stream of nitrogen. After the completion of the reaction, the reaction liquid was extracted with toluene. The organic layer was washed with water and dried with magnesium sulfate, followed by evaporation to dryness under reduced pressure. The resultant was purified by means of silica gel column chromatography (eluent: hexane/ethyl acetate=10/1) to yield 3.5 g of 2-vinyl-(9,9-Dimethyl)-fluorene (62.1% yield). 1.05 g (4.77 mmole) of the obtained 2-vinyl-(9,9-Dimethyl)-fluorene and 10 ml of THF were fed into a 100-ml round-bottomed flask, and the whole was cooled to −5° C. in a stream of nitrogen. 6.21 ml of a 0.5M 9-BBN solution were slowly added dropwise to the resultant, and the whole was stirred at 0° C. for 2 hours. After that, 4.8 ml of a 3N aqueous solution of NaOH, 130 mg of PdCl2(dppf), and 956 mg (2.144 mmol) of 2,2′-diodo-(9,9-Dimethyl)-fluorene were added to the resultant, and the whole was stirred at 60° C. for 7 hours. After the completion of the reaction, the reaction liquid was extracted with toluene. The organic layer was washed with water and dried with magnesium sulfate, followed by evaporation to dryness under reduced pressure. Then, the resultant was recrystallized with toluene/hexane. After the obtained crystal had been removed by filtration, the remainder was purified by means of mother liquor silica gel column chromatography (eluent: hexane/ethyl acetate=5/1→1/1), recrystallized with toluene, dried in a vacuum, and subjected to sublimation purification to yield 272 mg of Compound 21 (20% yield).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:20].[N:21]1([CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:3](=[CH:2][NH:37][C:34]4[CH:35]=[CH:36][C:31]([O:30][CH2:29][CH2:28][CH2:27][N:21]5[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]5)=[CH:32][CH:33]=4)[C:4](=[O:20])[NH:5]3)=[CH:10][CH:9]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccc(OCCCN2CCCCC2)cc1
Reactant: COc1cccc(-c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: C1CCOC1
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3=CNc2ccc(OCCCN3CCCCC3)cc2)c1
Temperature: 25 °C

Procedure:
The named compound is prepared by refluxing 0.020 gms E & Z 3-hydroxymethylene-6-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (see example 268) with 0.0375 gms 4-(3-piperidin-1-yl-propoxy)-phenylamine (used in the preparation of Example 218) in tetrahydrofuran (0.33 mL) for 36 h. Following cooling to room temperature, solvent evaporation in vacuo, trituration with isopropanol and filtration the reaction yields the named compound as a solid in the amount of 16.8 mg.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:21]([S:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1)[CH2:22][CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)CCSc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)CCSc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 26 %

Procedure:
A mixture of methyl thiosalicylate (1.21 g, 7.2 mmol), 2-cyano-6-isopentylthiopyridine (1.48 g, 7.2 mmol), triethylamine (1.5 ml, 10.8 mmol) and toluene (30 ml) was refluxed for 48 hrs. The reaction mixture was concentrated under reduced pressure to give the precipitated crystals, which were recrystallized from ethyl acetate-hexane to give the titled compound (0.64 g, 26%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][C@@H:33]([C@H:45]([CH3:53])[CH2:46][CH:47]([CH3:52])[CH2:48][CH2:49][CH:50]=[CH2:51])[C:34]([N:36]1[CH2:40][C@H:39]([OH:41])[CH2:38][C@H:37]1[C:42](O)=[O:43])=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.[NH2:55][C@:56]1([C:61]([NH:63][S:64]([C:67]2([CH2:70][F:71])[CH2:69][CH2:68]2)(=[O:66])=[O:65])=[O:62])[CH2:58][C@H:57]1[CH:59]=[CH2:60].C(N(CC)CC)C>C(Cl)Cl>[C:25]([O:29][C:30](=[O:31])[NH:32][C@@H:33]([C@H:45]([CH3:53])[CH2:46][CH:47]([CH3:52])[CH2:48][CH2:49][CH:50]=[CH2:51])[C:34]([N:36]1[CH2:40][C@H:39]([OH:41])[CH2:38][C@H:37]1[C:42](=[O:43])[NH:55][C@:56]1([C:61](=[O:62])[NH:63][S:64]([C:67]2([CH2:70][F:71])[CH2:69][CH2:68]2)(=[O:66])=[O:65])[CH2:58][C@H:57]1[CH:59]=[CH2:60])=[O:35])([CH3:28])([CH3:27])[CH3:26]
Reactant: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1(CF)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2(CF)CC2)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
HATU (11.61 g, 30.5 mmol) was added to a DCM (220 mL) solution of (2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (10.50 g, 25.5 mmol), (1R,2S)-1-amino-N-((1-(fluoromethyl)cyclopropyl)sulfonyl)-2-vinylcyclopropanecarboxamide HCl (8.37 g, 28 mmol), triethylamine (14.19 mL, 102 mmol). The reaction mixture was stirred at RT for overnight. The reaction was washed with 1N HCl (3×) and then with brine and evaporated on rotovap. The crude material was purified by silica gel chromatography using 20-40% Acetone in hexanes. The product fractions were collected and the solvent removed under vacuum to give the desired product tert-butyl((2S,3R)-1-((2S,4R)-2-(((1R,2S)-1-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate (15 g, 90% yield). MS: MS m/z 657.3 (M++1).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([N:18]3[CH2:22][CH2:21][N:20]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][C:28]=4[CH3:29])[C:19]3=[O:30])[S:17][C:11]=2[CH2:10]1)=O)(C)(C)C>CO.C(Cl)Cl>[ClH:1].[CH3:29][C:28]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[N:20]1[CH2:21][CH2:22][N:18]([C:16]2[S:17][C:11]3[CH2:10][NH:9][CH2:14][CH2:13][C:12]=3[CH:15]=2)[C:19]1=[O:30]
Reactant: Cc1ccncc1N1CCN(c2cc3c(s2)CN(C(=O)OC(C)(C)C)CC3)C1=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1ccncc1N1CCN(c2cc3c(s2)CNCC3)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
6N HCl (5 mL) was added dropwise to stirred solution of 2-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acid tert-butyl ester (70 mg, 0.16887 mmol) in methanol (2 mL) at 0° C. The reaction mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC (5% MeOH in DCM). The solvent was distilled from the reaction mixture under reduced pressure, followed by the addition of diethyl-ether. The precipitate was washed with ether and dried under reduced pressure to afford 36 mg of the product (61% yield).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:10]1[CH2:14][CH2:13][C@H:12]([CH2:15][NH2:16])[CH2:11]1)(=O)[CH3:8].C(O)C>C1COCC1>[CH2:7]([N:10]1[CH2:14][CH2:13][C@H:12]([CH2:15][NH2:16])[CH2:11]1)[CH3:8]
Reactant: CC(=O)N1CC[C@H](CN)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCN1CC[C@H](CN)C1
Yield: 66.5 %

Procedure:
Lithium aluminium hydride was added to a stirred solution of ((R)-1-acetylpyrrolidin-3-ylmethyl)amine (Intermediate 164, 1.5 g) in THF (50 mL) and the resulting mixture was stirred and heated at reflux for 2 hours. After cooling, ethanol was slowly added and the mixture was concentrated under vacuum. The residue was diluted with DCM and the solid was filtered off. The filtrate was evaporated to dryness to give ((R)-1-ethylpyrrolidin-3-ylmethyl)amine (0.9 g) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][C:7]=1[CH3:11])=[O:5])[CH3:2].Br[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:7]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc[nH]c1C
Reactant: BrCC1CCCCC1
Product: CCOC(=O)c1ccn(CC2CCCCC2)c1C

Procedure:
Prepared from 2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester, example 96(a), and (bromomethyl)cyclohexane under conditions analogous to experimental example 96(b). 1H NMR (200 MHz, CDCl3) δ 6.50 (1H, d, J=3.2 Hz), 6.43 (1H, d, J=3.2 Hz), 4.23 (2H, q, J=7.0 Hz), 3.62 (2H, d, J=6.6 Hz), 2.50 (3H, s), 1.78-0.88 (11H, m), and 1.33 (3H, t, J=7.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.Cl.CN(C)CCCN=C=NCC.[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[C:6]([CH2:8][C:9]([NH:48][S:45]([CH3:44])(=[O:47])=[O:46])=[O:11])[CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CC(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.9 %

Procedure:
To a solution of (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acetic acid (0.70 g, 1.44 mmol) was added 4-dimethylaminopyridine (0.26 g, 2.16 mmol), (3-(dimethylamino)propyl)ethyl carbodiimide hydrochloride (0.42 g, 2.16 mmol), methanesulfonamide (0.15 g, 1.58 mmol) and triethylamine (0.40 mL, 2.88 mmol). The reaction was stirred at ambient temperature for 18 hours. The reaction mixture was then diluted with dichloromethane and washed with 1 M aqueous hydrochloric acid. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel to give the title compound (0.34 g, LRMS: 526.2).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.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>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: Brc1nccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1-c1nccc2ccccc12
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of 1-bromoisoquinoline (2.06 g, 10 mmol), prepared as described in European Journal of Organic Chemistry 2002, 4181-4184, 2-methoxyphenylboronic acid (2.79 g, 10 mmol), Pd(PPh3)4 (5% mol), K2CO3 (5 g) in DMF/water (3/1) is stirred at 50° C. for 12 hours. The reaction mixture is then pored on water (150 mL). The aqueous phase is extracted with ethyl acetate (3×100 mL). The combined organic layers are washed with water (3×200 mL). The organic phase is dried over magnesium sulfate and evaporated under vacuum to afford the title compound.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([NH:22][CH3:23])=[N:19][C:18]=3[CH3:24])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([N:22]([CH3:23])[S:33]([CH3:32])(=[O:35])=[O:34])=[N:19][C:18]=3[CH3:24])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(NC)nc3C)c(C)nc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nn2c(-c3sc(N(C)S(C)(=O)=O)nc3C)c(C)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
60 mg of N-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-methylamine (0.17 mmol) and 86 mg of triethylamine (0.85 mmol) are dissolved in 3.0 ml of CH2Cl2 and 23 mg of methanesulfonyl chloride (0.2 mmol) is added. The vial is capped with a Teflon® lined cap and shaken at room temperature for 2 h. The reaction mixture is concentrated and applied to silica-gel chromatography (Hexane:AcOEt=2:1) to give 53.8 mg of the title compound. Yield 75%. mass spectrum (m/e): 422 (M+1); 1H-NMR (CDCl3): 6.96 (s, 1H), 3.60 (s, 3H), 3.34 (m, 1H), 3.19 (s, 3H), 2.56 (s, 3H), 2.48 (s, 3H), 2.29 (s, 3H), 1.86 (m, 4H), 0.90 (t, 6H, J=7.4 Hz).
Reaction SMILES: [NH2:1][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1.[C:16](=O)(O)[O-:17].[Na+]>C(O)=O>[CH:16]([NH:1][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1)=[O:17]
Reactant: O=C([O-])O
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(N)S1
Agent: [Na+]
Solvent: O=CO
Product: Cn1c([N+](=O)[O-])cnc1C1=CNN(NC=O)S1

Procedure:
The above compound is prepared by refluxing 8 gm. of 2-(2-amino-5-thiadiazolyl)-1-methyl-5-nitroimidazole in 30 ml. of 98% formic acid for 10 hours, cooling, and adding the mixture to saturated sodium bicarbonate solution, and the solid collected. The compound melts at 225° to 227° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:21][O:22][C:23](=[O:44])[C@H:24]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:43])[C:35]2[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:42])=[CH:29][CH:28]=1)[NH2:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O>[CH3:21][O:22][C:23](=[O:44])[C@H:24]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([NH:33][C:34]([C:35]2[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:42])=[O:43])=[CH:31][CH:32]=1)[NH:25][C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])=[CH:10][C:2]=1[Cl:1])=[O:6]
Reactant: O=C(Nc1cccc(O)c1)c1ccc(C(=O)O)c(Cl)c1
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[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: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1ccc(C(=O)Nc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 40.3 %

Procedure:
In an argon atmosphere, to a stirred solution of 2-chloro-4-[[(3-hydroxyphenyl)amino]carbonyl]benzoic acid (45 mg; 0.1472 mmol), 4-(2,6-dichlorobenzoylamino)-L-phenylalanine methyl ester (60 mg; 0.1488 mmol) and HBTU (59 mg; 0.16 mmol) in dimethylformamide (3 mL) was added DIPEA (0.102 mL; 0.585 mmol). The reaction mixture was stirred for 17 hr at room temperature, then was concentrated to dryness in vacuo and the residue was partitioned between dichloromethane (25 mL) and 0.5 N HCl (10 mL). The organic layer was washed with water and the aqueous layers were backwashed in turn with dichloromethane. The combined dichloromethane extracts were dried (Na2SO4) and evaporated to give 80 mg of crude material that was crystallized from methanol-ethyl acetate to provide 38 mg of N-[[2-chloro-4-[[(3-hydroxyphenyl)amino]carbonyl]phenyl]carbonyl]-4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester. mp 230-232° C. FAB HRMS: (C32H26Cl3N3O6) Obs. Mass 654.0952 Calcd. Mass 654.0965 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[O:20][N:19]=[C:18]([CH3:21])[C:17]=1[CH3:22]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[C:17]=2[CH3:22])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1noc(N)c1C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1noc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.3 %

Procedure:
4-Tert-butylbenzenesulfonyl chloride (498 mg, 2.14 mmol) and 4-(dimethyl)aminopyridine (5 mg) were added to a solution of 5-amino-3,4-dimethylisoxazole (200 mg, 1.78 mmol) in dry pyridine (2.0 ml). The reaction mixture was stirred at room temperature for 4 h. Pyridine was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with 1N HCl (2×25 ml), brine (25 ml) and dried over anhydrous magnesium sulfate. Evaporation of the solvents left an oily residue which, after purification by column chromatography over silica gel (1% methanol in chloroform as eluent), yielded 320 mg (58%) of an off-white solid. Further purification was achieved by recrystallization from ethyl acetate/hexanes, to yield the pure product as a white solid, m.p. 151°-154° C.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[S:5][C:6]2[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:7]=2[N:8]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[CH2:22]Cl.O>CN(C)C=O>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[CH2:22][O:13][C:11]1[CH:10]=[CH:9][C:7]2[N:8]=[C:4]([NH2:3])[S:5][C:6]=2[CH:12]=1
Reactant: Nc1nc2ccc(O)cc2s1
Reactant: Fc1cccc(Cl)c1CCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc2ccc(OCc3c(F)cccc3Cl)cc2s1
Reaction time: 1 h
Yield: 18.2 %

Procedure:
add 337 mg of anhydrous potassium hydroxide to a solution of 1 g of 2-amino-1,3-benzothiazol-6-ol in 5 cm3 of N,N-dimethylformamide. After stirring for one hour at a temperature close to 20° C., a solution of 1.08 g of 1-chloro-2-(chloromethyl)-3-fluorobenzene in 2 cm3 of N,N-dimethylformamide is added dropwise. Stir the resultant mixture for about twenty hours at about 20° C. The reaction mixture is poured into 30 cm3 of water, and extracted three times with 50 cm3 of dichloromethane. The organic phases are combined and washed three times with 50 cm3 of a 0.1N aqueous solution of sodium hydroxide, then dried over magnesium sulphate, filtered and concentrated under reduced pressure (0.2 kPa). The residue is taken up in 10 cm3 of a dichloromethane/methanol mixture (98/2 by volume), drained and then washed twice with 5 cm3 of the same mixture, stove-dried under reduced pressure (0.2 kPa) and at a temperature close to 35° C. We obtain 339 mg of 6-[(2-chloro-6-fluorobenzyl)oxy]-1,3-benzothiazol-2-amine in the form of a white solid, which has the following characteristics:
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][C:10]=2[Cl:12])[NH:5][C@@H:4]([C:14]([O:16]C)=[O:15])[CH2:3]1.C(N(CC)CC)C.[C:25]1(=[O:35])[O:30][C:28](=[O:29])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12>O1CCCC1.CN(C)C1C=CN=CC=1>[C:28]([C:27]1[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=1[C:25]([NH:1][C@@H:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][C:10]=2[Cl:12])[NH:5][C@@H:4]([C:14]([OH:16])=[O:15])[CH2:3]1)=[O:35])([OH:30])=[O:29]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COC(=O)[C@H]1C[C@H](N)c2c(Cl)cc(Cl)cc2N1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1C(=O)N[C@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21
Yield: 68.7 %

Procedure:
To a suspension of trans-4-amino-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline (0.5 g, 1.6 mmol) in anhydrous tetrahydrofuran (50 ml) under an atmosphere of nitrogen was added dry triethylamine (0.49 ml, 3.5 mmol) and the mixture stirred until dissolution was complete. To this solution was added phthalic anhydride (0.28 g, 1.9 mmol) and 4-dimethylaminopyridine (5 mg) and the reaction mixture was stirred at room temperature for 3 hours. The mixture was then evaporated to dryness in vacuo and the residue was partitioned between ethyl acetate (100 ml) and water (200 ml). The organic layer was separated and washed successively with dilute hydrochloric acid (2×50 ml, 1M), water (1×50 ml) and brine (1×50 ml), then dried (MgSO4) and evaporated to give a solid which was recrystallised from ethyl acetate/hexane to give the title compound as colourless crystals (0.45 g), m.p. 241°-243° C.; δ (360 MHz, DMSO) 1.71 (1H, ddd, J=13.0, 12.5 and 4.1 Hz, CHACHBHCCHD), 2.45 (1H, dm, J=13.0 Hz, CHACHBHCCHD), 3.74 (3H, dd, J=12.6 and 4.1 Hz, CHACHBHCCHD), 5.19 (1H, m, CHACHBHCCHD), 6.68 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.82 (1H, s, ArNH), 6.84 (1H, d, J=2.0 Hz, 6-H or 8-H), 7.54 (4H, m, ArH), 8.64 (1H, d, J=7.0 Hz, CHDNHCOCH2), 12.86 (1H, bs, CO2H); m/e (FAB+) 423 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[N:6][CH:7]=1.S(Cl)(Cl)=O.N1C=CC=C[CH:17]=1>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:17])=[O:10])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)Cc1cncc(Br)c1
Reactant: c1ccncc1
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
2-(5-bromopyridin-3-yl)acetic acid (5.00 g, 23.14 mmol) in methanol (55 mL) at 0° C. was added thionyl chloride (2.196 mL, 30.1 mmol) slowly, pyridine (2.434 mL, 30.1 mmol) was added slowly after and the reaction was stirred at room temperature overnight. Solvent was removed in vacuo and the residue was diluted with water and extracted with ethyl acetate, the organics was washed with brine, dried over magnesium sulfate, filtered and concentrated. Biotage purification (35% EtOAc/Hex) gave title compound (4.73 g, 20.6 mmol, 89% yield). 1H-NMR (CDCl3, 500 MHz) δ 8.63 (d, J=2.14 Hz, 1H), 8.47 (d, J=1.83 Hz, 1H), 7.84 (dd, J=2.14, 1.83 Hz, 1H), 3.76 (s, 3H), 3.65 (s, 2H). Mass spec.: 230.9 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[N:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]([CH3:31])[NH:26][CH2:25][CH2:24]3)=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[C:21]([C:18]5[CH:19]=[N:20][C:15]([F:14])=[CH:16][CH:17]=5)[CH:22]=4)[CH:27]3[CH3:31])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cc(-c3ccc(F)nc3)ccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2ccc(-c3ccc(F)nc3)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(6-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.