Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:17][CH:16]=3)=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[K].CC(C)([O-])C.[CH2:34](Br)[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].C(OCC)(=O)C>CS(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCBr
Reactant: CCCCCCCc1ccc(-c2cnc(-c3ccc(O)c(F)c3)nc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCCCCc1ccc(-c2cnc(-c3ccc(OCCCCCC)c(F)c3)nc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
0.5 g of 2-(3-fluoro-4-hydroxyphenyl)-5-(4-heptylphenyl)pyrimidine and 0.185 g of potassium-tertbutoxide were dissolved in 20 ml of dimethyl sulfoxide. The resulting solution was stirred at room temperature for 30 minutes and then 0.295 of n-hexyl bromide was added dropwise thereto. After the completion of the addition, the mixture was stirred at room temperature for six hours. Then 100 ml of ethyl acetate and 100 ml of water were added to the reaction mixture and the organic layer was repeatedly washed with water until the pH value of the aqueous layer became neutral. Subsequently the organic layer was separated and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (developing solvent: toluene) and then recrystallized from ethanol. Thus 0.467 g of 2-(3-fluoro-4-hexyloxyphenyl)-5-(4-heptylphenyl)pyrimidine was obtained. Yield: 74%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][C:9]=1[NH:25][C:26](=[O:38])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][C:9]2[NH:25][C:26](=[O:38])[CH2:27][C:28]([C:30]3[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=3)[C:36]#[N:37])=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(C#N)c2)cc1C#Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1C#Cc1ccccc1)NC(=O)CC(c1cccc(C#N)c1)=N2

Procedure:
The title compound was prepared from {2-[3-(3-cyano-phenyl)-3-oxo-propionyl-amino]-5-dimethylamino-4-phenylethynyl-phenyl}-carbamic acid tert.-butyl ester (Example M4) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an orange solid (65 mg).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@@H:5]([C:13]([NH:15][CH2:16][C:17](=[O:20])[CH2:18][CH3:19])=O)[O:4]1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:11])([CH3:12])[O:10][C@@H:6]2[C@@H:5]([C:13]2[O:20][C:17]([CH2:18][CH3:19])=[CH:16][N:15]=2)[O:4]1
Reactant: CCC(=O)CNC(=O)[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@H]21
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1cnc([C@H]2O[C@@H](OC)[C@@H]3OC(C)(C)O[C@@H]32)o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 119.7 %

Procedure:
To a solution of (3aR,4S,6R,6aR)-6-methoxy-2,2-dimethyl-N-(2-oxobutyl)tetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide (740 mg) in dry toluene (10 ml), under nitrogen was added phosphorous oxychloride (1.44 ml) and the mixture was heated under reflux for 3.5 h. The reaction mixture was cooled to 0° C., quenched with saturated aqueous sodium bicarbonate (30 mls), stirred vigorously for 30 min and extracted with ethyl acetate (4×50 ml); the organic layers were combined, washed with brine (30 ml), dried (MgSO4) and concentrated in vacuo to give a crude product, which was purified by flash column chromatography on silica gel, eluting with a mixture of 5:1 to 7:2 cyclohexane:ethyl acetate, to give the title compound as a yellow oil (0.83 g).
Reaction SMILES: [H-].[Na+].C1COCC1.C(OCC)(=O)CC(OCC)=O.[CH3:19][C:20]1([CH3:49])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]2[CH:25]=[C:24]([CH:32]=[CH:33][C:34]([O:36][C:37]3[CH:38]=[C:39]([CH:46]=[CH:47][CH:48]=3)[C:40]([O:42]CC=C)=[O:41])=[O:35])[CH:23]=[CH:22][C:21]1=2>O>[CH3:19][C:20]1([CH3:49])[CH2:29][CH2:28][C:27]([CH3:30])([CH3:31])[C:26]2[CH:25]=[C:24]([CH:32]=[CH:33][C:34]([O:36][C:37]3[CH:38]=[C:39]([CH:46]=[CH:47][CH:48]=3)[C:40]([OH:42])=[O:41])=[O:35])[CH:23]=[CH:22][C:21]1=2
Reactant: C=CCOC(=O)c1cccc(OC(=O)C=Cc2ccc3c(c2)C(C)(C)CCC3(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(C=CC(=O)Oc3cccc(C(=O)O)c3)ccc21

Procedure:
210 mg (6.8 mmol) of sodium hydride (80% in oil) and 15 ml of THF are introduced into a round-bottomed flask under a stream of nitrogen. 1 ml (6.8 mmol) of diethyl malonate is then added dropwise and the mixture is stirred until the evolution of gas has ceased. This solution is introduced dropwise into a mixture of 2.6 g (6.2 mmol) of allyl 3-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acryloyloxy]-benzoate, 50 ml of THF and 400 mg of tetrakis-(triphenylphosphine)palladium(0) and the mixture is stirred at room temperature for three hours. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of ethyl ether and hexane (50/50). After evaporating the solvents, 1.5 g (64%) of 3-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acryloyloxy]-benzoic acid, with a melting point of 134-5° C., are collected.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1)([CH3:10])[C:7]([OH:9])=[O:8].[CH:24]1C=CC=C[CH:25]=1>C(N(CC)CC)C>[CH3:10][C:6]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[CH:14][CH:13]=1)([CH3:5])[C:7]([O:9][CH2:24][CH3:25])=[O:8]
Reactant: c1ccccc1
Reactant: CC(C)(Oc1ccc(C2CCOCC2)cc1)C(=O)O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C)(C)Oc1ccc(C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.2 ml of thionyl chloride were added at 15° C to a mixture of 7 g of 2-methyl-2-[p-(4-tetrahydropyranyl)-phenoxy]-propanoic acid, 70 ml of benzene and 3.5 ml of triethylamine and the mixture was stirred for 2 hours at room temperature and was then filtered. The filtrate was slowly added to 250 ml of 5.4N hydrochloric acid in ethanol and the mixture was stirred for 12 hours at room temperature and was then concentrated to dryness. The residue was added to 100 ml of ether and the solution was washed with a saturated sodium bicarbonate solution and then with water. The solution was dried and evaporated to dryness and the oily residue was distilled under reduced pressure to obtain 6.5 g of ethyl 2-methyl-2-[p-(4-tetrahydropyranyl)-phenoxy]-propanoate with a boiling point of 138°-140° C at 0.1 mm Hg.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:22]([OH:24])=O)[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O:29][C:30](=[O:46])[NH:31][CH2:32][CH2:33][CH2:34][C@H:35]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36][NH2:37])([CH3:28])([CH3:27])[CH3:26].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:15]([O:14][C:12](=[O:13])[NH:11][C@@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:22]([NH:37][CH2:36][C@@H:35]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34][CH2:33][CH2:32][NH:31][C:30]([O:29][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:46])=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(N[C@@H](COCc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CN)NC(=O)OC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)[C@H](COCc1ccccc1)NC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Preparation takes place in analogy to Example 79A from 150 mg (0.46 mmol) of O-benzyl-N-[(benzyloxy)carbonyl]-L-serine and 188 mg (0.59 mmol) of tert-butyl{(4S)-5-amino-4-[(tert-butoxycarbonyl)amino]pentyl}carbamate (Example 86A) in 6 ml of dimethylformamide with the addition of 114 mg (0.57 mmol) of EDC and 18 mg (0.13 mmol) of HOBt. The product is purified by preparative RP-HPLC (mobile phase water/acetonitrile gradient: 90:10→5:95).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N+:4]([O-:17])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cc(Br)cc(Br)c1

Procedure:
3,5-Dibromopyridine 2.37 g is dissolved in methylene chloride 25 ml and thereto is added m-chloroperbenzoic acid 2.96 g at room temperature under stirring. After stirring for 5 hours at room temperature, additional m-chloroperbenzoic acid 246 mg is added thereto and the mixture is stirred. After 15 hours the solvent is removed in vacuo and the residue is purified by silica gel chromatography (solvent; n-hexane:ethyl acetate=1:1) to give 3,5-dibromopyridine N-oxide as colorless crystals, 2.26 g. mp 140-142° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][C:3]=1[CH3:18].CI.[CH3:21]C(C)([O-])C.[K+].O>[Cl-].[Na+].O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([O:17][CH3:21])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][C:3]=1[CH3:18]
Reactant: CC(C)(C)[O-]
Reactant: Cc1cc2c(cc1Br)C(=O)C1(CCC(O)CC1)C2
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COC1CCC2(CC1)Cc1cc(C)c(Br)cc1C2=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
6′-Bromo-4-hydroxy-5′-methylspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (Intermediate 3, 1.72 g, 5.57 mmol) was dissolved in 2-Me THF (13 mL) under an inert atmosphere and the solution was cooled to 0° C. Methyl iodide (0.453 mL, 7.24 mmol) was added followed by portionwise addition of potassium tert-butoxide (0.875 g, 7.80 mmol). The resulting mixture was stirred at r.t. for 1 h. Potassium tert-butoxide (0.250 g, 2.23 mmol) was added and stirring continued. After another 30 min, potassium tert-butoxide (0.094 g, 0.84 mmol) was added and stirring continued. After a total of 4 h, full conversion was obtained and water (6 mL) and brine (3 mL) were added. The phases were separated and the organic layer was treated with charcoal and diatomaceous earth and then filtered through a plug of diatomaceous earth. The plug was rinsed with EtOAc and the organics were concentrated to yield 1.3 g (77% yield) of the title compound as a mixture of isomers with the methoxy group in either equatorial position (major) or axial position (minor). This mixture was used in the next step without further purification: MS (ES+) m/z 323, 325 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[CH2:12]([O:14]C1N=CC(N)=CC=1)[CH3:13]>CC(C)=O>[CH2:12]([O:14][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1)[CH3:13]
Reactant: CCOc1ccc(N)cn1
Reactant: CC(C)Nc1ccc(Cl)nc1
Solvent: CC(C)=O
Product: CCOc1ccc(NC(C)C)cn1

Procedure:
Following the procedure described for Preparation 2(A), 6-ethoxy-pyridin-3-ylamine (10 g, 72.4 mmol) was reacted with acetone (4.8 mL) to provide 11.18 g of (6-ethoxy-pyridin-3-yl)-isopropyl-amine. 1H NMR (CD3OD) δ 7.48 (d, 1H), 7.11 (dd, 1H), 6.61 (d, 1H), 4.14 (q, 2H), 3.48 (m, 1H), 1.32 (t, 3H), 1.14 (d, 6H); MS 181.3 (M+1).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[N:8]=[N:9][C:10]2[C:15]([C:16]=1[NH2:17])=[CH:14][CH:13]=[CH:12][C:11]=2Br)=[O:6])[CH:2]=[CH2:3].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1B(O)O>>[CH2:1]([NH:4][C:5]([C:7]1[N:8]=[N:9][C:10]2[C:15]([C:16]=1[NH2:17])=[CH:14][CH:13]=[CH:12][C:11]=2[C:25]1[CH:26]=[C:21]([O:20][CH3:19])[CH:22]=[CH:23][C:24]=1[O:27][CH3:28])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1ccc(OC)c(B(O)O)c1
Product: C=CCNC(=O)c1nnc2c(-c3cc(OC)ccc3OC)cccc2c1N

Procedure:
The title compound was prepared from 4-amino-8-bromo-cinnoline-3-carboxylic acid allylamide (273 mg, 0.89 mmol) and 2,5-dimethoxyphenyl boronic acid (201.1 mg, 1.11 mmol) according to Method A to afford an off-white solid (105 mg, 32%). 1H NMR (300.132 MHz, CDCl3) δ 8.64 (bs, 1H), 7.87 (d, J=7.3 Hz, 1H), 7.77-7.69 (m, 2H), 6.96 (t, J=2.8 Hz, 1H), 6.96 (s, 1H), 6.93 (d, J=1.8 Hz, 1H), 6.00-5.88 (m, 1H), 5.29 (dq, J=17.2, 1.6 Hz, 1H), 5.17 (dq, J=10.2, 1.4 Hz, 1H), 4.12 (tt, J=5.7, 1.6 Hz, 2H), 3.79 (s, 3H), 3.64 (s, 3H). MS APCI, m/z=365 (M+H). HPLC 1.76 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][Cl:28].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[ClH:28].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])[C:12]3[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3cc(F)ccc3NC(=O)[C@@H]2O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3cc(F)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Yield: 74.8 %

Procedure:
A mixture of 4 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-fluoro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 1.99 g of 2-(dimethylamino)ethyl chloride hydrochloride, 4.3 g of potassium carbonate and 50 ml of acetone is refluxed for 18 hours. After the reaction is completed, insoluble materials are removed by filtration and washed with hot acetone. The filtrate and the washings are combined and then evaporated to remove solvent. The residue is converted to its hydrochloride and recrystallized from a mixture of isopropanol, ethanol and ether. 4 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-fluoro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride are obtained.
Reaction SMILES: C(O[CH2:5][C:6]1[N:7]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[C:8]2[C:13]([C:14]=1[C:15](=[O:19])[C:16]([OH:18])=[O:17])=[CH:12][C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1)=[CH:10][CH:9]=2)(=O)C.[OH-].[K+]>C1COCC1.CO>[C:34]([C:31]1[CH:30]=[CH:29][C:28]([CH2:27][N:7]2[C:8]3[C:13](=[CH:12][C:11]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=4)=[CH:10][CH:9]=3)[C:14]3[C:15](=[O:19])[C:16](=[O:18])[O:17][CH2:5][C:6]2=3)=[CH:33][CH:32]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(=O)OCc1c(C(=O)C(=O)O)c2cc(-c3cccc(C)c3)ccc2n1Cc1ccc(C(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc(-c2ccc3c(c2)c2c(n3Cc3ccc(C(C)(C)C)cc3)COC(=O)C2=O)c1

Procedure:
A solution of [2-[(acetyloxy)methyl]-1-(4-tert-butylbenzyl)-5-(3-methylphenyl)-1H-indol-3-yl](oxo)acetic acid (0.27 g, 0.63 mmol) and aqueous potassium hydroxide (1.0 N, 1.1 mL, 1.1 mmol) in THF:MeOH (1:1, 6.6 mL) was stirred at room temperature for 4 h. The reaction mixture was evaporated to dryness. The residue was washed with water and hexane to give an oil. This oil was partitioned between methylene chloride (80 mL) and 15% aqueous HCl (15 mL) with stirring. The organic layer was separated, washed with water and evaporated to afford the title compound as an off-white solid, mp: 196-197° C. Mass spectrum (ESI, [M+H]+) m/z 438. 1HNMR (400 MHz, DMSO-d6): δ 8.21 (s, 1H), 7.75 (d, 2H, J =8.55 Hz), 7.66 (dd, 1H, J=8.70 and 1.52 Hz), 7.50 (s, 1H), 7.47 (d, 1H, J=8.71 Hz), 7.38-7.35 (m, 3H), 7.20-7.17 (m, 3H), 5.92 (s, 2H), 5.50 (s, 2H), and 2.39 ppm (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][N:13]3[C:19]([C:20](=[O:27])[N:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:22])=[CH:18][C:17]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)=[C:14]32)=[CH:9][C:8]=1[O:33][CH3:34])C.[OH-].[K+].Cl>C(O)C.O>[C:23]([N:21]([CH3:22])[C:20]([C:19]1[N:13]2[CH2:12][CH2:11][C:10]3[C:15]([C:14]2=[C:17]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)[CH:18]=1)=[CH:16][C:7]([O:6][CH2:5][C:4]([OH:35])=[O:3])=[C:8]([O:33][CH3:34])[CH:9]=3)=[O:27])([CH3:25])([CH3:26])[CH3:24]
Reactant: CCOC(=O)COc1cc2c(cc1OC)CCn1c(C(=O)N(C)C(C)(C)C)cc(-c3cccs3)c1-2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc2c(cc1OCC(=O)O)-c1c(-c3cccs3)cc(C(=O)N(C)C(C)(C)C)n1CC2
Temperature: 78 °C
Reaction time: 1 h

Procedure:
A mixture of the product of example 63 (150 mg) and solid KOH (51 mg) in ethanol (5 ml) and water (5 ml) was stirred at 78° C. for 1 h. At room temperature, the reaction mixture was acidified with an aqueous HCl solution (1.0 M) until pH=1-2 and extracted with dichloromethane. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: [CH2:1]([P:3]([O-:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2].C([Li])CCC.B(F)(F)F.[CH3:19][CH2:20][O:21]CC.C1OC1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.CCCCCC>[CH2:1]([P:3]([CH2:19][CH2:20][OH:21])(=[O:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCCCOP([O-])CC
Reactant: CCOCC
Agent: FB(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CO1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCCOP(=O)(CC)CCO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.1 %

Procedure:
4.5 g (30 mmol) of butyl ethylphosphonite (prepared as in Example 3) are dissolved in 30 ml of toluene and admixed at −78° C. with 12 ml (30 mmol) of a 2.5 molar solution of butyllithium in hexane. After 15 minutes of stirring, 5.68 g (40 mmol) of boron trifluoride etherate are added and ethylene oxide is passed in and the mixture is subsequently reacted for a further two hours. Thereafter, aqueous ammonium chloride solution is added and the mixture is warmed to room temperature. That is subsequently concentrated in vacuo, the residue is taken up in diethyl ether, insoluble salts are filtered off and the mixture is again concentrated. Chromatographic purification leaves 4.2 g (73% of theory) of butyl ethyl(2-hydroxyethyl)phosphinate being obtained as oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[C:13](C1NC=CN=1)(C1NC=CN=1)=[O:14]>C1COCC1>[O:14]=[C:13]1[NH:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[O:12]1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: COC(=O)c1ccc(N)c(O)c1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2[nH]c(=O)oc2c1
Yield: 56 %

Procedure:
To a solution of methyl 4-amino-3-hydroxybenzoate (Intermediate 75, 1.06 g, 6.34 mmol) in THF (13.5 mL) was added carbonyl diimidazole (1.88 g, 11.6 mmol) and the reaction mixture was heated to reflux temperature for 1 day. After that time, the solvent was removed and the residue was partitioned between CH2Cl2 and 1N aqueous HCl solution. The organic phase was washed with 1N aqueous HCl solution (2×) and water, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to provide the title compound as white solid (870 mg of a 79% purity, 56% yield). The crude was used in the next step without any further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:10][CH:9]=1)[NH2:6].[CH3:24][O:25][CH2:26][CH2:27][C:28]1([C:33](O)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:12][CH:13]=1)[NH:6][C:33]([C:28]1([CH2:27][CH2:26][O:25][CH3:24])[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:34]
Reactant: COCCC1(C(=O)O)CCCC1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cc(Cl)cn(C)c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCC1(C(=O)N[C@@H](Cc2ccc(-c3cc(Cl)cn(C)c3=O)cc2)C(=O)OC)CCCC1
Yield: 59.4 %

Procedure:
A solution of 4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride (47.4 mg, 0.25 mmol), 1-(2-methoxyethyl)cyclopentane carboxylic acid (47 mg, 0.28 mmol), DIEA (175 μL, 1.0 mmol) and HBTU (133 mg, 0.35 mmol) in DMF (3 mL) was stirred at room temperature for 4 hr. The mixture was concentrated, the residue was dissolved in ethyl acetate (15 mL), was washed with 0.5 N HCl (1×5 mL), sat. NaHCO3 (1×5 mL), brine (1×5 mL) and was dried (MgSO4). The residue obtained upon evaporation was chromatographed on 25 g of silica gel, eluting with ethyl acetate to give 4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (70.5 mg, 59%). LR-Electrospray: m/z positive ion, 943 (2M+Na), 483 (M+Na), 478, (M+NH4), 461 (M+H); negative ion 919 (2M−H), 521, 459 (M−H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[C:5]([C:11]#[N:12])=[C:4](F)[C:3]=1[F:14].[Br-:15].[Na+]>O>[Br:15][C:4]1[C:3]([F:14])=[C:2]([F:1])[C:7]([C:8]#[N:9])=[C:6]([F:10])[C:5]=1[C:11]#[N:12]
Reactant: [Br-]
Reactant: N#Cc1c(F)c(F)c(F)c(C#N)c1F
Agent: [Na+]
Solvent: O
Product: N#Cc1c(F)c(F)c(Br)c(C#N)c1F
Temperature: 120 °C
Yield: 55 %

Procedure:
In a 3 liter reaction vessel, were added 200 g (1.00 mol) of tetrafluoroisophthalonitrile, 1 liter of N-dimethylformamide (DMF) and 102.7 g (1.00 mol) of sodium bromide (NaBr). This mixture was heated at 120° C. for 1 hour. Separately, 3 liter of water was poured to a 5 liter of beaker, and to which was poured the resulting reaction solution. After suction filtration, the residue was washed with water and hexane, and then dried in vacuo to offer 198.2 g of a white solid. The solid was purified by means of solid distillation to give 142.8 g (0.55 mol) of 4-bromo-2,5,6-trifluoroisophthalonitrile as a white solid (yield: 55%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])([F:12])[CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=O)[CH2:6]1.Cl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31]N)=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]([S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])([CH:5]1[CH2:10][CH2:9][C:8]2[C:29]3[C:28](=[CH:27][CH:26]=[C:25]([Cl:24])[CH:30]=3)[NH:31][C:7]=2[CH2:6]1)[F:12]
Reactant: COC(=O)C(F)(C1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C(F)(C1CCc2c([nH]c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Temperature: 40 °C
Yield: 68.8 %

Procedure:
To 1.70 g (5.2 mmol) (RS,SR)-benzenesulfonyl-fluoro-(3-oxo-cyclohexyl)-acetic acid methyl ester in glacial acetic acid (20 mL), 1.05 g (5.72 mmol, 1.1 eq) of (4-chloro-phenyl)-hydrazine hydrochloride were added and the reaction mixture was stirred at 40° C. over night. An aqueous solution of NaHCO3 was added until pH=7 was reached, and the mixture was extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. A column chromatography on silica gel with heptane/EtOAc 2:1 followed by a trituration from Et2O yielded 1.56 g (70%) of (RS,SR)-benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-fluoro-acetic acid methyl ester as a white solid, MS: 436 (MH+).