Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:32])[C@@H:9]([CH3:31])[C:10]([NH:12][C@@H:13]([CH:28]([CH3:30])[CH3:29])[C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C@H:17]1[C:25]([OH:27])=O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[F:57][C:58]1[CH:64]=[CH:63][C:62]([CH3:65])=[CH:61][C:59]=1[NH2:60].OS([O-])(=O)=O.[K+]>C(Cl)Cl>[F:57][C:58]1[CH:64]=[CH:63][C:62]([CH3:65])=[CH:61][C:59]=1[NH:60][C:25]([C@H:17]1[N:16]([C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([N:8]([CH3:32])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH3:31])[CH:28]([CH3:30])[CH3:29])[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18]1)=[O:27]
Reactant: Cc1ccc(F)c(N)c1
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1C(=O)O
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(F)c(NC(=O)[C@@H]2Cc3cccnc3N2C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C)c1
Reaction time: 0.08 h
Yield: 79.4 %

Procedure:
To a solution of (S)-1-((S)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-3-methylbutanoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Intermediate 8) (50 mg, 111 μmol, Eq: 1.00) and diisopropylethylamine (58.4 μL, 334 μmol, Eq: 3) in DCM (1.5 mL) was added diphenylphosphinic chloride (58.0 mg, 46.7 μL, 245 μmol, Eq: 2.2). After stirring for 5 min, 2-fluoro-5-methylaniline (21 mg, 167 μmol, Eq: 1.5) was added and the resulting solution was stirred at rt for 2 days. The reaction mixture was poured into 0.1 M aqueous KHSO4 (20 mL) and extracted with EtOAc. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 40% EtOAc in hexanes) to give tert-butyl (S)-1-((S)-1-((S)-2-(2-fluoro-5-methylphenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate as a colorless oil (49 mg), m/z=556 (M+H).
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11](Cl)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CS(C)=O>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CNCCN1
Reactant: CC(C)(C)c1nc2cc(Cl)c([N+](=O)[O-])cc2s1
Solvent: CS(C)=O
Product: CC(C)(C)c1nc2cc(N3CCNCC3)c([N+](=O)[O-])cc2s1
Temperature: 0 °C

Procedure:
A solution of 13.5 g of 2-tert-butyl-5-chloro-6-nitrobenzothiazole described in Example 5, and 40 g of anhydrous piperazine in 100 ml of dimethylsulphoxide is heated at 140° for 2 hours, cooled and poured into ice-water. The yellow solid is filtered, washed with water and dried at 80° to yield 2-tert-butyl-6-nitro-5-[piperazin-1-yl]benzothiazole, melting at 144°-146°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O:24][C:25](=[O:33])[CH2:26][CH:27]([NH2:32])[CH:28]([OH:31])[CH2:29][F:30])([CH3:23])([CH3:22])[CH3:21].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C1COCC1>[C:20]([O:24][C:25](=[O:33])[CH2:26][CH:27]([NH:32][C:17]([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:19])[CH:28]([OH:31])[CH2:29][F:30])([CH3:23])([CH3:21])[CH3:22]
Reactant: O=C(O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CC(N)C(O)CF
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)CC(NC(=O)C1CCCCN1C(=O)OCc1ccccc1)C(O)CF
Temperature: 25 °C
Yield: 89 %

Procedure:
A stirred mixture of (S)-1-(benzyloxy carbonyl)-2-piperidinecarboxylic acid (4.82 g, 18.31 mmol), 3-amino-5-fluoro-4-hydroxy-pentanoic acid tert-butyl ester (3.99 g, 19.25 mmol), HOBt (2.72 g, 20.13 mmol), DMAP (2.57 g, 21.04 mmol) and anhydrous THF (60 ml) was cooled to 0° C. before EDC (3.86 g, 20.13 mmol) was added. The mixture was allowed to warm to room temperature over 16 hrs before being concentrated under reduced pressure. The residue was purified by flash chromatography (60% ethyl acetate in hexane) to afford the sub-title compound as a white foam (7.3754 g, 72%): 1H NMR (400 MHz, CDCl3) δ 1.31-1.80 (14H, m), 2.20-2.38 (1H, m), 2.49-3.07 (3H, m), 3.11-3.70 (1H, m), 3.80-4.58 (4H, m), 4.70-5.28 (1H, m), 6.58-7.05 (1H, m), 7.23-7.48 (5H, m).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(C(F)(F)F)cc2)CC1
Yield: 47 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 4-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (47%).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:26])=[CH:23][CH:24]=[C:13]3[CH2:12]2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40].C(N(CC)C(C)C)(C)C.[CH2:52]1[O:54][C@@H:53]1[CH2:55][OH:56]>CO>[CH3:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25]([N:27]4[CH2:28][CH2:29][N:30]([CH2:52][C@H:53]([OH:54])[CH2:55][OH:56])[CH2:31][CH2:32]4)=[O:26])=[CH:23][CH:24]=[C:13]3[CH2:12]2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:40])([F:42])[F:41]
Reactant: OC[C@@H]1CO1
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)N4CCNCC4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N4CCN(C[C@H](O)CO)CC4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Temperature: 60 °C

Procedure:
To a solution of 10,11-dihydro-10-[[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl]-3-(1-piperazinylcarbonyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine hydrochloride salt of Step B (0.50 g, 0.84 mmol) and N,N-diisopropylethyl amine (0.16 mL, 0.92 mmol) in methanol (5 mL) was added (R )-(+)-glycidol (0.10 mL, 1.50 mmol). The reaction mixture was heated to 60° C. for 4 hours then cooled and concentrated in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a white foam. Purification by flash chromatography on silica gel using a solvent system of 5% methanol in chloroform provided the title product, which was redissolved in dichloromethane and evaporated to dryness in vacuo to a white foam (0.38 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:17]=1.P(Cl)(Cl)Cl>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][C:15]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[C:16]([C:18]([CH3:20])([CH3:21])[CH3:19])[N:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: CC(C)(C)C(=O)c1sc(N)nc1C(C)(C)C
Solvent: ClP(Cl)Cl
Solvent: Clc1ccccc1
Product: CC(C)(C)C(=O)c1sc(NC(=O)c2cc(Cl)ccc2O)nc1C(C)(C)C
Temperature: 25 °C
Yield: 48.5 %

Procedure:
A mixture of 5-chlorosalicylic acid (143.6 mg, 0.83 mmol), 2-amino-4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazole (200.0 mg, 0.83 mmol), phosphorus trichloride (40 μL, 0.46 mmol) and chlorobenzene (4 mL) was refluxed for 3 hours. After the reaction mixture was cooled to room temperature, the residue obtained by concentration of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=3:1) to give the title compound(159.1 mg, 48.4%) as a white powder.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)[CH3:16])=[CH:9][CH:8]=1.C(N(CC)CC)C>O1CCCC1>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]([CH2:14][CH2:13][C:10]3[CH:9]=[CH:8][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:12][CH:11]=3)[CH3:16])[CH2:18][CH2:19]2)=[CH:28][CH:27]=1)#[N:30]
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCc1ccc(N)cc1)C1CCN(c2ccc(C#N)cc2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(CCc1ccc(NS(C)(=O)=O)cc1)C1CCN(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
0.34 g (3 mmol) of methanesulfonyl chloride dissolved in tetrahydrofuran was added dropwise at 0° C. to 1.0 g (3 mmol) of the product from Example 3 and 0.6 g (6 mmol) of triethylamine in 100 ml of anhydrous tetrahydrofuran. The mixture was stirred at room temperature for 16 h and then the solvent was removed under reduced pressure. The residue was partitioned between aqueous sodium bicarbonate solution and methylene chloride, and the organic phase was dried and concentrated under reduced pressure. The resulting oil was purified by chromatography (eluent: methylene chloride/methanol 10:1). 0.73 g of 1-(4-cyanophenyl)-4-(2-(4-methanesulfonylaminophenyl)-N-methylethylamino) piperidine was obtained. 1H NMR (d -DMSO) δ=1.3-1.5 (2H); 1.7 (2H); 2.1 (3H); 2.5-2.7 (4H); 2.7-3.0 (5H); 3.3 (1H); 3.9 (2H); 6.9 (2H); 7.0-7.2 (4H); 7.5 (2H) and 9.6 (1H) ppm.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:22])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:5]2[N:6]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:7]=1.[C:23](Cl)(=[O:25])[CH3:24].ClCC(NC1N=C2C(C3C=CC=C(C(F)(F)F)C=3)=C(C)C(C3N(C4C=CC(C#N)=CC=4)N=CC=3)=CN2N=1)=O>>[Br:1][C:2]1[C:3]([CH3:22])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:5]2[N:6]([N:8]=[C:9]([NH:11][C:23](=[O:25])[CH3:24])[N:10]=2)[CH:7]=1
Reactant: CC(=O)Cl
Reactant: Cc1c(Br)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Agent: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CCl)nc2c1-c1cccc(C(F)(F)F)c1
Product: CC(=O)Nc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(Br)cn2n1

Procedure:
The title compound was prepared from 6-bromo-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (Int. 2, 6.7 g, 18.06 mmol) and acetyl chloride (2.83 mL, 39.7 mmol) using a similar method to that employed for Intermediate 17 (5.65 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH:12]=[CH2:13].CC(C)([O-])C.[K+].C(OCC)(=O)C>C(O)(C)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:13][C:12]([C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][C:6]=2[CH:9]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=Cc1cc(Br)ccc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)C1=Cc2cc(Br)ccc2OC1
Temperature: 25 °C

Procedure:
To a solution of 5-bromosalicylaldehyde (10.0 g) and tert-butyl acrylate (17.5 ml) in tert-butanol (100 ml) was added potassium tert-butoxide (1.67 g) at room temperature, and the mixture was refluxed for 66 hours and cooled to room temperature. To the mixture was added ethyl acetate, and the mixture was washed with water, 1N sodium hydroxide and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:19) to give tert-butyl 6-bromo-2H-1-benzopyran-3-carboxylate (10.86 g) as pale yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:19])[CH:7]1[CH:12]([C:13]2=[O:18])[CH2:11][CH:10]=[CH:9][CH2:8]1)([O-])=[O:2].C(N)CCC>C1(C)C=CC=CC=1>[OH:2][NH:1][C:4]1[C:5]2[C:6](=[O:19])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:18])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)C2CC=CCC12
Solvent: Cc1ccccc1
Solvent: CCCCN
Product: O=C1c2ccccc2C(=O)c2c(NO)cccc21
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 5.0 parts of 5-nitro-1,4,4a,9a-tetrahydroanthraquinone with 80 parts of toluene and 1.0 part of n-butylamine was stirred at 70°C for 2 hours. The mixture was then distilled under a reduced pressure of 100 mm Hg to remove toluene, washed with 50 parts of methanol and dried under reduced pressure to obtain 4.4 parts of 1-hydroxylaminoanthraquinone.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[C:8]1[CH:9]=[N:10][CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1.C(N(CC)CC)C>C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:15][O:14][C:12]1[CH:11]=[N:10][CH:9]=[C:8]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:13]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1cncc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cncc(C#C[Si](C)(C)C)c1
Temperature: 25 °C

Procedure:
Add (trimethylsilyl)acetylene (1.3 mL, 9.45 mmol) and bis(triphenylphosphine)palladium (II) dichloride (0.102 g, 0.15 mmol) to a mixture of 3-bromo-5-methoxypyridine from PREPARATION 9 (1.366 g, 7.26 mmol), copper (I) iodide (0.055 g, 0.29 mmol) and triethylamine (4.1 mL, 29.04 mmol) in ethyl acetate (7.5 mL) in a sealed tube. Stir the resultant reaction mixture at 75° C. for 20 h and cool to room temperature. Dilute the reaction mixture with ethyl acetate and filter through a pad of diatomaceous earth. Wash with ethyl acetate and concentrate the filtrate to give the title compound as a solid which is used without further purification (1.48 g, 100%).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[CH:19]=[CH:20]C=2O)=[O:15])=[C:9]([F:31])[CH:8]=1.Cl>O1CCCC1.N1C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:14](=[O:15])[C:16]3[CH:17]=[C:18]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=4[F:30])[CH:19]=[CH:20][C:5]=3[O:4][C:2]2=[O:3])=[C:9]([F:31])[CH:8]=1
Reactant: COC(=O)Cl
Reactant: O=C(Nc1ccc(Cl)cc1F)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=c1oc2ccc(-c3ccc(F)cc3F)cc2c(=O)n1-c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 10 h
Yield: 11 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 1 (1.5 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 2.5 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 13.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:35])[C:32]([CH3:34])=[CH2:33]>C1COCC1>[CH3:34][C:32](=[CH2:33])[C:31]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1)=[O:35]
Reactant: C=C(C)C(=O)Cl
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(N)c3)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=C(C)C(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Reaction time: 1 h

Procedure:
To a solution of ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (50 mg, 0.18 mmol) and DIPEA (93 μL, 0.53 mmol) in THF (1.8 mL) at room temperature was added methacryloyl chloride (27.8 mg, 0.266 mmol) and the solution stirred for 1 hour. The reaction was quenched with ethanol (0.1 mL). The desired product was purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. The combined fractions with the desired product were concentrated until only the water layer remained. The water layer was neutralized with 2M aqueous potassium bicarbonate and the mixture was extracted with ethyl acetate (×5). The combined organic fractions were dried over sodium sulfate, filtered and concentrated under reduced pressure to give ethyl 4-{3-[(2-methylacryloyl)amino]phenyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C19H19N4O3 [M+H]+: 351, found 351. 1H NMR (600 MHz, DMSO-D6) δ 13.0 (s, 1H), 9.91 (s, 1H), 8.91 (s, 1H), 8.30 (s, 1H), 8.05 (s, 1H), 7.84 (d, 1H, J=7.04 Hz), 7.40 (t, 1H, J=7.63 Hz), 7.32 (d, 1H, J=7.04 Hz), 5.82 (s, 1H), 5.53 (s, 1H), 3.86 (q, 2H, J=7.04 Hz), 1.95 (s, 3H), 0.85 (t, 3H, J=7.04 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10])=[O:4].C(O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:1]([O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10])=[O:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccccc1
Reactant: COC(=O)C1CCCC1=O
Product: O=C1CCCC1C(=O)OCc1ccccc1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
A mixture of 50 g. of methyl-2-oxocylopentanecarboxylate and 50 g. of redistilled benzyl alcohol was heated at 160° C. under a stream of nitrogen in a 500 ml. flask for 20 hours. Methanol distilled off as it was formed. The reaction mixture was subsequently cooled and the mixture distilled on the kugelrohr apparatus. The benzyl alcohol was removed by heating to 120° C. at 2 mm and the benzyl ester collected at 130° C. Yield was 45 g. (59%).
Reaction SMILES: [PH2:1](=[O:3])[OH:2].[CH2:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH2:4]([P:1]([OH:2])[OH:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=[PH2]O
Reactant: C=CCCCCCC
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCP(O)O
Yield: 87.5 %

Procedure:
99 g (0.75 mol) of phosphinic acid, 86 g (0.76 mol) of octene, 34 mg of tris(dibenzylideneacetone)dipalladium and 48 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene in 750 g of tetrahydrofuran are reacted at about 70° C. for 9 hours, passed through a column charged with Deloxan® THP II for purification and freed of solvent in a rotary evaporator. The residue is admixed with 500 g of completely ion-free water and stirred, and then filtered, the filtrate is extracted with ethyl acetate. This is followed by removal of solvent in a rotary evaporator to obtain 117 g (84% of theory) of octylphosphonous acid.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.Br[CH:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:37]1[C:41](=[O:42])[C:40]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:39]2[C:38]1=[O:47])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)CC)C>C(#N)C>[CH2:27]([O:26][C:24]([C@H:23]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:37]1[C:38](=[O:47])[C:39]2=[CH:46][CH:45]=[CH:44][CH:43]=[C:40]2[C:41]1=[O:42])=[O:25])[CH3:28]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSc2ccccc21
Reactant: CCOC(=O)C(Br)CCCCCCCCN1C(=O)c2ccccc2C1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](CCCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 80 °C
Yield: 25 %

Procedure:
In 100 ml of acetonitrile are dissolved 1.7 g of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 2.4 g of ethyl 2-bromo-10-phthalimidodecanoate, and 0.75 g of triethylamine is added to the solution. The mixture is heated at 80° C. for 3 days, concentrated under reduced pressure, diluted with 100 ml of water and extracted with 150 ml of ethyl acetate. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily substance is separated and purified by silicagel column chromatography (hexane:ethyl acetate=3:1 - 2:1) to give from the first fraction 0.9 g of tert-butyl 3(R)-[1(R)-ethoxycarbonyl-9-phthalimidononyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oil.
Reaction SMILES: CO[C:3]1([CH2:10][CH2:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][C:17]([O:22]C)([O:20]C)OC)[CH:7]=[CH:6][CH:5]([O:8]C)O1.O.P([O-])(O)(O)=[O:26].[Na+].O1CCOCC1.S(=O)(=O)(O)O>P([O-])([O-])(O)=O.[Na+].[Na+].O>[OH:26][CH:7]1[CH2:6][C:5](=[O:8])[C:10]([CH2:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][C:17]([OH:20])=[O:22])=[CH:3]1
Reactant: COC1C=CC(CCC#CCCCC(OC)(OC)OC)(OC)O1
Reactant: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCCC#CCC1=CC(O)CC1=O
Temperature: 50 °C
Yield: 112.5 %

Procedure:
A stirred mixture of 7.1 g of 2,5-dihydro-2,5-di- methoxy-2-(8,8,8-trimethoxy-3-octynyl)furan, 2.76 g of sodium dihydrogen phosphate monohydrate, 140 mg of disodium hydrogen phosphate, 60 ml of dioxane and 40 ml of water was boiled under reflux for 19 hours, then cooled to 50° C. and treated dropwise with 4.1 ml of concentrated sulfuric acid. The resulting solution was boiled under reflux for 12 hours, cooled and partitioned with ether and brine. The ether layer was separated, washed with brine, dried and concentrated, giving 5.0 g of crude 7-(4-hydroxycyclopent-2-en-1-on-2-yl)-5-heptynoic acid. This crude product was dissolved in 40 ml of pyridine and the stirred solution treated at 0° to 10° C. with 10.5 ml of hexamethyldisilizane followed by 6.3 ml of chlorotrimethylsilane. The resulting mixture was stirred at 25° C. for 3 hours and then concentrated to dryness at 30° C. The residue was extracted with hexane, the extract filtered through diatomaceous earth and concentrated. The residue was distilled at 0.11 mm on a Kugelrohr at 155°-170° C., giving 1.66 g of the desired compound as an oil.