Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:25])(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[CH3:26]O.S(=O)(=O)(O)O>CCOCC>[C:1]([O:25][CH3:26])(=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CO
Reactant: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)OC
Reaction time: 1 h
Yield: 74 %

Procedure:
10,12-Tricosadiynoic acid (3.0 g, 0.0084 mol), methanol (15 ml) and concentrated sulfuric acid (0.8 ml) were heated to reflux and stirred for 1 hour. The cooled mixture was taken up in ether (40 ml) and washed with 10% NaHCO3 (20 ml) and water (20 ml), and the organic phase was dried (MgSO4). Evaporation of the solvent gave 2.68 g (74%) of the title compound. 1H NMR (60 MHz, CDCl3): δ 0.98 (m, 3H, CH3CH2), 1.28. (m, 28H, CH2), 2.25 (m, 6H, CH2), 3.70 (s, 3H, CH3O).
Reaction SMILES: [CH3:1][C@@H:2]1[N:6]2[C:7](=[O:21])[C:8]3[N:9]([CH:11]=[C:12]([C:18]([OH:20])=O)[C:13](=[O:17])[C:14]=3[O:15][CH3:16])[CH2:10][C@H:5]2[O:4][CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:34][C:35]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38]>COCCOC>[F:34][C:35]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:36]=1[CH2:37][NH:38][C:18]([C:12]1[C:13](=[O:17])[C:14]([O:15][CH3:16])=[C:8]2[C:7](=[O:21])[N:6]3[C@@H:2]([CH3:1])[CH2:3][O:4][C@@H:5]3[CH2:10][N:9]2[CH:11]=1)=[O:20]
Reactant: COc1c2n(cc(C(=O)O)c1=O)C[C@H]1OC[C@H](C)N1C2=O
Reactant: NCc1ccc(F)cc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: COCCOC
Product: COc1c2n(cc(C(=O)NCc3ccc(F)cc3F)c1=O)C[C@H]1OC[C@H](C)N1C2=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
(3S,11aR)-3-Methyl-6-(methyloxy)-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (3.00 g) and 1,1′-carbonyldiimidazole (CDI) (2.15 g) were slurried in 1,2-dimethoxyethane (DME) (30 mL). The mixture was heated to 80° C. for 1 h. The resulting solution was cooled to 20° C., then treated with 2,4-difluorobenzylamine (1.45 mL). After stirring for 1 h, the mixture was quenched with water (30 mL) and DME was removed under reduced pressure. The product was collected by filtration and dried in a vacuum oven overnight at 50° C. The product was obtained as a solid.
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[C:16]4[C:21]=3[CH:20]=[C:19]([OH:22])[CH:18]=[CH:17]4)=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>CN(C)C=O>[C:1]1([C:7]2[NH:11][C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[C:16]4[C:21]=3[CH:20]=[C:19]([O:22][C:36](=[O:37])[NH:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:18]=[CH:17]4)=[C:9]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=Nc1ccccc1
Reactant: Oc1ccc2cccc(-c3[nH]c(-c4ccccc4)nc3-c3ccncc3)c2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)Oc1ccc2cccc(-c3[nH]c(-c4ccccc4)nc3-c3ccncc3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.4 %

Procedure:
A mixture of 8-(2-phenyl-5-pyridin-4-yl-3H-imidazol-4-yl)-naphthalen-2-ol (31 mg, 0.085 mmol), phenyl isocyanate (11 mg, 0.094 mmol) and triethylamine (17.8 μL, 12.9 mg, 0.128 mmol) in N,N-dimethylformamide (1.5 mL) is stirred for 2 hours at room temperature. Preparative LCMS afforded phenyl-carbamic acid 8-(2-phenyl-5-pyridin-4-yl-3H-imidazol-4-yl)-naphthalen-2-yl ester (17 mg, 41% yield); 1H NMR 400 Hz (CD3OD) δ 7.01 (m, 2H), 7.25 (m, 4H), 7.39 (m, 5H), 7.45 (dd, J=2.28, 8.86 Hz, 1H), 7.53 (m, 3H), 7.72 (dd, J=7.14, 8.23 Hz, 1H), 7.83 (d, J=6.02 Hz, 1H), 7.90 (d, J=6.99 Hz, 2H), 8.10 (m, 3H), 8.19 (d, J=8.29 Hz, 1H), 8.43 (d, J=7.00 Hz, 2H); MS m/z (M+H+) 483.20.
Reaction SMILES: [F:1][C:2]([F:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]3=[N:15][S:16](=[O:20])(=[O:19])[CH2:17][CH2:18][N:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>C1COCC1.CO.[Pt](=O)=O>[F:27][C:2]([F:1])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]3=[N:15][S:16](=[O:20])(=[O:19])[CH2:17][CH2:18][N:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(C(F)(F)c4ccccc4)cc3)C2=N1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: O=S1(=O)CCN2CCCC(c3ccc(C(F)(F)c4ccccc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38 %

Procedure:
Platinum(IV) oxide (14 mg) was added to a solution of 9-{4-[difluoro(phenyl)methyl]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (49 mg) in THF (dry) (10 mL) and MeOH (10 mL). The mixture was stirred at room temperature under hydrogen for 4 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (18.8 mg) as colorless crystals.
Reaction SMILES: O1CCOC[CH2:2]1.[OH-].[Li+].[CH:9]1([C:14]([N:16]2[CH2:21][CH:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH2:19][CH:18]([C:30]([O:32]CC)=[O:31])[CH2:17]2)=[O:15])[CH2:13]CC[CH2:10]1>O>[CH3:13][C:9]([CH3:2])([CH3:10])[C:14]([N:16]1[CH2:21][CH:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:19][CH:18]([C:30]([OH:32])=[O:31])[CH2:17]1)=[O:15]
Reactant: C1COCCO1
Reactant: CCOC(=O)C1CC(c2ccc(OC)cc2)CN(C(=O)C2CCCC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C2CC(C(=O)O)CN(C(=O)C(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
55 ml of dioxane, 28 ml of water and 0.77 g (32.2 mmol) of lithium hydroxide were added to 2.8 g (14.3 mmol) of ethyl 1-(cyclopentylcarbonyl)-5-[4-(methoxy)phenyl]piperidine-3-carboxylate. The mixture was stirred overnight at RT. For work-up, the dioxane was removed under reduced pressure, water was added and the reaction mixture was acidified using aqueous 1 N hydrochloric acid solution. The mixture was extracted with dichloromethane. The organic phase was dried with sodium sulphate and concentrated under reduced pressure. Yield: 2.44 g (95% of theory)
Reaction SMILES: [C:1]([NH:5][C@H:6]1[CH2:10][CH2:9][C@@H:8]([C:11]([OH:13])=O)[CH2:7]1)(=[O:4])[CH2:2][CH3:3].ClC(N(C)C)=C(C)C.[CH3:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:34]([CH3:35])[C:33]3[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=3[N:31]=2)=[CH:26][CH:25]=1.N1C(C)=CC(C)=CC=1C>C1COCC1.C(Cl)Cl>[CH3:22][N:23]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:34]([CH3:35])[C:33]3[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=3[N:31]=2)=[CH:26][CH:25]=1)[C:11]([C@@H:8]1[CH2:9][CH2:10][C@H:6]([NH:5][C:1](=[O:4])[CH2:2][CH3:3])[CH2:7]1)=[O:13]
Reactant: CNc1ccc(-c2nc3ccccc3n2C)cc1
Reactant: CCC(=O)N[C@H]1CC[C@@H](C(=O)O)C1
Agent: CC(C)=C(Cl)N(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: CCC(=O)N[C@H]1CC[C@@H](C(=O)N(C)c2ccc(-c3nc4ccccc4n3C)cc2)C1

Procedure:
100.0 mg (0.54 mmol) (1R,3S)-3-Propionylamino-cyclopentanecarboxylic acid (educt IV.1) and 78.6 μL (0.59 mmol) 1-chloro-N,N,2-trimethyl-propenylamine are stirred in 5 mL dry THF at RT for 1 hour. Then this mixture is given to a mixture of 128.1 mg (0.54 mmol) N-methyl-N-[4-(1-methyl-1H-benzoimidazol-2-yl)-phenyl]-amine (educt III.1.a) and 107.0 μL (0.81 mmol) 2,4,6-collidine in DCM at RT. The mixture is stirred over night. The solvent is evaporated. The residue is taken up with water and extracted with DCM. The organic phase is dried and the solvent is evaporated. The residue is triturated with diethyl ether, filtered off and dried.
Reaction SMILES: [CH3:1][CH:2]([CH2:10][CH:11]=[CH2:12])[CH:3]([OH:9])[CH2:4][C:5]([O:7]C)=[O:6]>[OH-].[K+].CO>[CH3:1][CH:2]([CH2:10][CH:11]=[CH2:12])[CH:3]([OH:9])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: C=CCC(C)C(O)CC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=CCC(C)C(O)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4-methyl-3-hydroxyhept-6-enoate (5.72 g, 33.2 mmol) was dissolved in a 2 N solution of potassium hydroxide in methanol (50 mL), and the solution was stirred overnight at room temperature. From the reaction solution, the solvent was distilled off under reduced pressure. To the residue, a 1 N aqueous sodium hydroxide solution was then added, followed by extraction with diethyl ether. The aqueous layer was made acidic by the addition of concentrated hydrochloric acid under ice cooling, followed by extraction with diethyl ether again. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the compound of interest as a yellow oil substance (2.21 g, 42%, mixtures of diastereomers).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]N=1.[CH3:8][CH2:9][CH2:10]CCCCCCCN.C(=O)([O-])[O-:20].[Cs+].[Cs+]>C1COCC1>[Br:1][C:2]1[C:9]([CH3:8])=[C:10]([OH:20])[C:5]([CH3:4])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCCCCCCCCCN
Reactant: Brc1ccccn1
Agent: [Cs+]
Solvent: C1CCOC1
Product: Cc1ccc(Br)c(C)c1O

Procedure:
For example, bromo pyridine (Apollo) 11.6 is treated with amine 10.7 in the presence of cesium carbonate in THF or alternative solvent at reflux to give the amine 11.7. The amine is then converted to the sulfonyl chloride 11.9 through the intermediate chloride 11.8 as described in Scheme 10. Using the above procedures, but employing, in place of the amino alkyl phosphonate 10.7, different alkyl phosphonates 10.6, and in place of the pyridine 11.6 different halo pyridines 11.1, the corresponding products 6.3 are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH:15]([P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[CH2:16]>CN(C)C=O.C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:19]([O:18][P:17]([O:21][CH2:22][CH3:23])(/[CH:15]=[CH:16]/[C:2]1[CH:3]=[C:4]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1)=[O:24])[CH3:20]
Reactant: CCOC(=O)CNc1cccc(Br)c1
Reactant: C=CP(=O)(OCC)OCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1cccc(/C=C/P(=O)(OCC)OCC)c1
Temperature: 95 °C
Reaction time: 20 h
Yield: 60.5 %

Procedure:
A solution of ethyl N-(3-bromophenyl)glycinate (Example B) (4 g, 15.5 mmol), diethyl vinylphosphonate (4.92 g, 30 mmol), and bis(triphenylphosphine) palladium (II) chloride (1 g) in dimethylformamide (15 ml) and triethyamine (5 ml) is immersed in an oil bath (95° C.) and stirred for 20 hours. After cooling the dimethylformamide is removed in vacuo and the oily brown residue is dissolved in a saturated solution of sodium chloride and extracted with chloroform. The chloroform layer is dried over magnesium sulfate, filtered and evaporated to give a residue (3.2 g). Purification is accomplished by silica gel chromatography (ethyl acetate as eluant, a single fluorescent spot on tlc, Rf=0.5 (ethyl acetate)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[CH:14][C:13]=1[CH3:26].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][C:13]=1[CH3:26]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CC(=O)O)ccc1NC(=O)Nc1c(Cl)cccc1Cl
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a stirred solution of tert-butyl 4-[N′-(2,6-dichlorophenyl)ureido]-3-methylphenylacetate (2.58 g, 6.30 mmol) in CH2Cl2 (50 ml) was added TFA (20 ml) at room temperature. After 2 h stirring, the mixture was concentrated in vacuo. The residue was triturated by the addition of water, to give 4-[N′-(2,6-dichlorophenyl)ureido]-3-methylphenylacetic acid (2.12 g, 95%) as a colorless powder. mp 274–283° C. (dec.); 1H-NMR (DMSO-d6) δ 2.24 (s, 3H), 3.46 (s, 2H), 7.00 (d, J=8.6 Hz, 1H), 7.06 (s, 1H), 7.30 (t, J=7.8 Hz, 1H), 7.52 (d, J=8.3 Hz, 2H1), 7.65 (d, J=8.2 Hz, 1H), 8.12 (s, 1H), 8.50 (s, 1H), 12.22 (br, 1H); MS (ESI) m/z 353 (M++1), 355 (M++3), 357 (M++5).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)=[CH:16][C:15]=2[CH2:26][NH:27][CH2:28][CH3:29])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)=[CH:16][C:15]=2[CH2:26][N:27]([C:34]([CH:31]2[CH2:33][CH2:32]2)=[O:35])[CH2:28][CH3:29])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Cl)C1CC1
Reactant: CCNCc1cc(-c2cnn(C)c2)ccc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3cnn(C)c3)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: [2′-ethylaminomethyl-6-methoxy-4′-(1-methyl-1H-pyrazol-4-yl)-biphenyl-3-yl]-acetic acid ethyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([N:29]3C(=O)C4=CC=CC=C4C3=O)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].C([Sn]([N:53]=[N+:54]=[N-:55])(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:55]=[N:54][N:53]=3)=[CH:14][CH:15]=2)[C:7]2[CH:24]=[C:25]([NH2:29])[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCCc1nc2c(C)cc(N3C(=O)c4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: Cc1ccccc1
Product: CCCc1nc2c(C)cc(N)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
4.75 g (12.5 mMol) of 4'-[(2-n-propyl-4-methyl-6-phthalimido-1H-benzimidazol-1-yl)-methyl]-2-cyanobiphenyl are dissolved in 200 ml of absolute toluene and combined with 20.8 g (62.5 mMol) of tributyl tin azide. The reaction mixture is refluxed for 5 days with stirring. Then the solvent is distilled off, the residue is taken up in saline solution and extracted 3 times with 100 ml of ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down. The residue is chromatographed on silica gel (particle size: 0.032-0.063 mm) using as eluant first methylene chloride and then methylene chloride/ethanol (50:1, 25:1 and 9:1). The uniform fractions are combined and evaporated down. The residue is triturated with ether/petroleum ether (1:1) and suction filtered.
Reaction SMILES: [NH2:1][C:2]([CH3:23])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([C:19]([F:22])([F:21])[F:20])[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[C:8]2=[N:7]1)[C:3]#[N:4].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[S:31])=[CH:28][CH:27]=1>>[F:18][C:15]([F:16])([F:17])[C:14]1[C:8]2[C:9](=[N:10][N:6]([CH2:5][C:2]([NH:1][C:30](=[S:31])[C:29]3[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:35])[F:36])=[CH:34][CH:33]=3)([C:3]#[N:4])[CH3:23])[N:7]=2)[CH:11]=[C:12]([C:19]([F:21])([F:20])[F:22])[CH:13]=1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1nc2cc(C(F)(F)F)cc(C(F)(F)F)c2n1
Product: CC(C#N)(Cn1nc2cc(C(F)(F)F)cc(C(F)(F)F)c2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(4,6-bis(trifluoromethyl)-2H-benzotriazol-2-yl)-2-methylpropionitrile, described in Example 23, and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (0.40 g, 83%). Rf=0.7 (1:1 EA/heptane). MS (ES): M/Z [M+H]=542. 1H NMR: (400 MHz, DMSO-d6): 1.79 (s, 3H), 5.62 (dd, J=60.6, 13.3 Hz, 2H), 7.76-7.97 (m, 4H), 8.13 (s, 1H), 8.92 (s, 1H) and 8.97 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −61.62 (s, 3F), −61.04 (s, 3F) and −42.10 (s, 3F).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][CH2:6][C:5](=[C:8]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:31])[CH2:7][CH2:6][C:5](=[C:8]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=C(c2ccc(O)cc2)c2ccc(/C=C/C(=O)OC(C)(C)C)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCC(=C(c2ccc(O)cc2)c2ccc(/C=C/C(=O)O)cc2)CC1
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a stirred solution of 1,1-dimethylethyl (2E)-3-{4-[(4,4-dimethylcyclohexylidene)(4-hydroxyphenyl)methyl]phenyl}-2-propenoate (21) (0.24 g, 0.57 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (4 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 1 h and concentrated in vacuo to give an oil. The oil was dissolved in CH2Cl2 and the solvent was removed in vacuo to give a solid which was dried under vacuum at 90° C. to give 0.170 g (82%) of compound 22 as a pale tan solid. 1H NMR (400 MHz, DMSO-d6): δ 0.93 (s, 6H), 1.31 (m, 4H), 2.16 (m, 4H), 6.44 (d, J=15.9 Hz, 1H), 6.65 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.3 Hz, 2H), 7.05 (d, J=7.9 Hz, 2H), 7.52 (d, J=15.9 Hz, 1H), 7.57 (d, J=8.1 Hz, 2H), 9.32 (s, 1H), 12.33 (br s, 1H). The compound was silated prior to EI analysis. HRMS (EI) Calcd for C30H42O3Si2: 506.2673 (M+). Found: 506.2669.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl-].FC(F)(F)C(O)=O.[NH2:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41]([C:46]([NH:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[C:52]([O:57][C:58]3[CH:63]=[C:62]([C:64]#[N:65])[CH:61]=[C:60]([Cl:66])[CH:59]=3)[C:51]=1[F:67])=[O:47])=[CH:40]2.[CH3:68][C:69]([O:72][C:73]([N:75]1[CH2:80][CH2:79][CH:78]([C:81](O)=[O:82])[CH2:77][CH2:76]1)=[O:74])([CH3:71])[CH3:70].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][NH:48][C:46]([C:41]2[NH:42][C:43]3[C:39]([CH:40]=2)=[CH:38][C:37]([NH:36][C:81]([CH:78]2[CH2:79][CH2:80][N:75]([C:73]([O:72][C:69]([CH3:71])([CH3:70])[CH3:68])=[O:74])[CH2:76][CH2:77]2)=[O:82])=[CH:45][CH:44]=3)=[O:47])=[C:51]([F:67])[C:52]=1[O:57][C:58]1[CH:63]=[C:62]([C:64]#[N:65])[CH:61]=[C:60]([Cl:66])[CH:59]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc3[nH]c(C(=O)NCc4ccc(Cl)c(Oc5cc(Cl)cc(C#N)c5)c4F)cc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
BOP chloride (0.079 g, 0.309 mmol) was added to a solution of 5-amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.060 g, 0.103 mmol), 1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinecarboxylic acid (0.0236 g, 0.103 mmol) and diisopropylethylamine (0.090 mL, 0.514 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography with hexane:ethyl acetate to give the title compound (0.029 g, 41%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.50 (br. s., 1H), 9.72 (br. s., 1H), 8.95 (br. s., 1H), 7.95 (s, 1H), 7.78 (s, 1H), 7.41-7.52 (m, 2H), 7.36 (t, 1H), 7.25-7.32 (m, 1H), 7.21 (d, 1H), 7.06 (br. s., 1H), 4.52 (d, 2H), 3.85-4.17 (m, 2H), 2.58-2.94 (m, 2 H), 1.63-1.85 (m, 2H), 1.41-1.53 (m, 2H), 1.36 (s, 9H). ES MS: m/z 680 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]3[C:29]4[CH2:30][NH:31][C:32](=[O:33])[C:28]=4[CH:27]=[CH:26]N=3)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.Cl[C:35]1C2CNC(=O)C=2C=CN=1.BrC1C=CC=C2C=1CNC2=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]3[CH:35]=[CH:26][CH:27]=[C:28]4[C:29]=3[CH2:30][NH:31][C:32]4=[O:33])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:7]=1
Reactant: O=C1NCc2c1ccnc2-c1cc(-c2cc(Cl)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1
Reactant: O=C1NCc2c1ccnc2Cl
Agent: O=C1NCc2c(Br)cccc21
Product: O=C1NCc2c1cccc2-c1cc(-c2cc(Cl)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1

Procedure:
The synthesis of the title compound is performed starting from 100 mg (0.24 mmol) of the product from step 3 of the compound from example 10 in a manner analogous to step 4 of the synthesis of the compound from example 10. Instead of the compound from example 22A, 4-bromo-2,3-dihydroisoindole-1-on (61 mg, 0.29 mmol) is used. This produces 28 mg (24% of theoretical yield, 94% purity) of the title compound.
Reaction SMILES: [N:1]1([CH:6]([CH3:10])[CH2:7][CH2:8]O)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:13])=O>C(Cl)Cl>[ClH:13].[Cl:13][CH2:8][CH2:7][CH:6]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CC(CCO)N1CCCC1
Solvent: ClCCl
Product: CC(CCCl)N1CCCC1
Product: Cl
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
3-Pyrrolidin-1-yl-butan-1-ol (1.0 g, 7 mmol) was dissolved in DCM (20 ml). The reaction was cooled to 0-5° C. and thionyl chloride (1.65 g, 14 mmol) was added slowly. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was concentrated in vacuo and azeotroped with DCM (20 ml) to give the title compound (1.4 g, 100%) as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:14](=[O:15])[CH:13]([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([O:25][CH2:26][CH:27]=[CH2:28])=[C:20]([Cl:29])[CH:19]=2)[CH2:12][CH2:11][CH2:10][N:9]1[S:31]([CH3:34])(=[O:33])=[O:32])([CH3:4])([CH3:3])[CH3:2].C(N1[C:49](=[O:50])CCC(NC(C2C3C(=CC=CC=3)C=CN=2)=O)C(=O)N1CC(O)=O)C1C=CC=CC=1>>[CH2:26]([O:25][C:21]1[C:20]([Cl:29])=[CH:19][C:18]([C:17]([NH:16][CH:13]2[C:14](=[O:15])[N:8]([CH2:7][C:6]([OH:35])=[O:5])[N:9]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:10][CH2:11][CH2:12]2)=[O:30])=[CH:23][C:22]=1[Cl:24])[CH:27]=[CH2:28].[C:1]([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:14](=[O:15])[CH:13]([N:16]2[C:17](=[O:30])[C:18]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:49]2=[O:50])[CH2:12][CH2:11][CH2:10][N:9]1[S:31]([CH3:34])(=[O:33])=[O:32])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(O)CN1C(=O)C(NC(=O)c2nccc3ccccc23)CCC(=O)N1Cc1ccccc1
Reactant: C=CCOc1c(Cl)cc(C(=O)NC2CCCN(S(C)(=O)=O)N(CC(=O)OC(C)(C)C)C2=O)cc1Cl
Product: C=CCOc1c(Cl)cc(C(=O)NC2CCCN(S(C)(=O)=O)N(CC(=O)O)C2=O)cc1Cl
Product: CC(C)(C)OC(=O)CN1C(=O)C(N2C(=O)c3ccccc3C2=O)CCCN1S(C)(=O)=O
Yield: 100 %

Procedure:
[6-(4-Allyloxy-3,5-dichloro-benzoylamino)-2-methanesulfonyl-7-oxo-[1,2]diazepan-1-yl]-acetic acid (25) was prepared from [6-(4-allyloxy-3,5-dichloro-benzoylamino)-2-methanesulfonyl-7-oxo-[1,2]diazepan-1-yl]-acetic acid tert-butyl ester (24) by the method used to prepare 8a to afford 173 mg (100% yield) of the title compound. 1H-NMR (500 MHz, CDCl3) δ 1.74-1.77 (m, 1H), 1.91-1.93 (m, 1H), 2.22-2.25 (m, 2H), 3.19 (s, 3H), 3.39-3.44 (m, 1H), 4.24-4.28 (m, 2H), 4.61-4.63 (m, 2H), 4.71-4.75 (d, 1H), 5.12-5.15 (m, 1H), 5.28-5.31 (m, 1H), 5.40-5.44 (m, 1H), 6.10-6.16 (m, 1H), 7.31-7.33 (d, 1H), 7.79 (s, 2H). Analytical HPLC: 5.70 min. LC-MS (ES+): m/e=494, 496 (M+H+).