Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:7]1[C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccccc1CNc1cccnc1Cl
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COc1ccccc1CNc1cccnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
To a 22 L three neck round bottom flask equipped with a mechanical stirrer, thermometer, addition funnel, and nitrogen inlet, were added 3.84 L of tetrahydrofuran, 91.6 grams (0.17 moles) of bis(diphenylphosphino)ethanenickel (II) chloride, and 96 grams (0.39 moles) of 2-chloro-3-(2-methoxybenzylamino)pyridine. The orange slurry was stirred at 25° C. for about 30 minutes. Phenylmagnesium bromide (3M in ether, 231.6 mL, 0.69 moles) was added over a 4 hour period and the resulting black slurry was stirred for 22 hours at 25° C. During this time, the reaction was monitored by thin layer chromatography assay, and a total of 86 mL (0.26 moles) of additional phenylmagnesium bromide solution was added to the system. The reaction mixture was cooled to 10° C. and the reaction was quenched with 3.84 L of 20% aqueous HCl over 30 minutes. Ethyl acetate (3.84 L) was added and the reaction mixture was stirred an additional 10 minutes. The layers were separated and the organic layer was washed with 4 L of 25% aqueous HCl . The pH of the aqueous layer was adjusted from 0.98 to 11.6 with 1.6 L of 50% aqueous sodium hydroxide. Diatomaceous earth (Celite®) (1 kg) and 7 L of ethyl acetate were added. The mixture was stirred for 15 minutes, filtered through diatomaceous earth (Celite®) and the cake was washed with about 1 L of ethyl acetate. The layers were separated, the aqueous layer washed twice with 2 L of ethyl acetate, and the organic layers were combined and dried with sodium sulfate. The drying agent was removed by filtration, the cake was washed with ethyl acetate, and the filtrate was vacuum concentrated to about 2 L volume. This solution was treated with 510 g of silica gel for 30 minutes at 20-25° C., filtered, and the silica gel was washed twice with 2 L of ethyl acetate. The filtrate was vacuum concentrated to a yellow slurry and displaced with 1 L of isopropanol to a final volume of about 275 mL. The slurry was granulated at 0-5° C. for 30 minutes, filtered, washed with cold isopropanol, and dried giving 83.8 g (74.8%) of crude material (Mp 122°-125° C). A portion (48.3 g) of this material was purified by chromatography to give 38.6 g of the title compound as a yellow solid. Mp 124°-128° C. Spectral data for this compound are identical to the data reported in step 1 of Example 4.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]([O:18]C2C=CC=CC=2)=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH:39][C:40](=[O:55])[C:41]1[CH:46]=[CH:45][C:44]([CH2:47][NH:48][CH2:49][CH2:50][CH2:51][N:52]([CH3:54])[CH3:53])=[CH:43][CH:42]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:15][C:16](=[O:18])[N:48]([CH2:47][C:44]2[CH:45]=[CH:46][C:41]([C:40]([NH:39][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[NH:32][C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:31])=[O:55])=[CH:42][CH:43]=2)[CH2:49][CH2:50][CH2:51][N:52]([CH3:53])[CH3:54])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cccc(OCc2ccccc2)c1)Oc1ccccc1
Reactant: CN(C)CCCNCc1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Solvent: O
Solvent: CS(C)=O
Product: CN(C)CCCN(Cc1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1)C(=O)Nc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 15 %

Procedure:
1-Benzyloxy-3-(phenoxycarbonylamino)benzene (Reference Compound No. 5-1, 3.7 g, 12 mmol) was added to a solution of the mixture containing N-(2-t-butoxycarbonylaminophenyl)-4-(3-dimethylaminopropylaminomethyl)benzamide (Reference Compound No. 4-5, 10 g, 24 mmol) in DMSO (30 mL), and then the reaction mixture was stirred at room temperature for 15 hours. Water (300 mL) was added thereto, the whole was extracted with ethyl acetate (250 mL) twice, and then the organic layer was washed with brine (250 mL) twice. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 1.1 g of the title reference compound as a white amorphous product. (Yield 15%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15].[Br:16]N1C(=O)CCC1=O>CC#N>[Br:16][C:6]1[CH:5]=[C:4]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[CH3:9]
Reactant: COCCCOc1ccc(C)cc1OC
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COCCCOc1cc(Br)c(C)cc1OC
Reaction time: 2 h

Procedure:
To a solution of 2-methoxy-1-(3-methoxy-propoxy)-4-methyl-benzene (2.00 g, 9.51 mmol) in MeCN (30 mL) is added N-bromosuccinimide (1.96 g, 10.5 mmol) at room temperature. Stirring is continued for 2 hrs, followed by evaporation of the solvent. The title compound is obtained after flash chromatography on silica gel (hexane/AcOEt 6:1) as an oil. MS: 289.0/291.0 [M]+. tR (HPLC, Nucleosil C18HD column, 20-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 5.04 min. 1H-NMR (CDCl3): δ 2.13 (m, 2H), 2.36 (s, 3H), 3.39 (s, 3H), 3.58 (m, 2H), 3.87 (s, 3H), 4.12 (m, 2H), 6.77 (s,1H), 7.08 (s, 1H) ppm.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH2:11])=[O:10].CCN(CC)CC.[C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])#[CH:20]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:22][Si:21]([C:19]#[C:20][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH2:11])=[O:10])([CH3:24])[CH3:23]
Reactant: NC(=O)Cc1ccccc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccccc1CC(N)=O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(2-iodophenyl)acetamide (I6) (12.91 g, 49.52 mmol), Et3N (26 mL), ethynyltrimethylsilane (9.08 mL, 64.3 mmol), PdCl2(PPh3)2 (0.347 g, 0.495 mmol) and CuI (0.188 g, 0.989 mmol) in DMF (44 mL) was stirred under a nitrogen atmosphere at 50° C. for 3 hours. The volatiles were removed in vacuo and the resulting residue partitioned between EtOAc (100 mL) and water. The aqueous phase was extracted with EtOAc (3×50 mL), then the combined organic extracts were washed with water (3×70 mL), brine, dried (MgSO4), filtered and evaporated in vacuo to give the title compound I7 as a brown solid (11.4 g, 99%); 1H NMR (300 MHz, d6-DMSO) δ 7.40 (d, J=7.5 Hz, 1H), 7.20-7.36 (m, 4H), 6.94 (brs, 1H), 3.58 (s, 2H), 0.24 (s, 9H). LCMS-B: rt 6.884 min; m/z 232 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[N:34]1[CH:39]=[C:38]([CH2:40][NH2:41])[CH:37]=[N:36][CH:35]=1>>[F:1][C:2]([F:32])([F:33])[C:3]1[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([NH:41][CH2:40][C:38]4[CH:39]=[N:34][CH:35]=[N:36][CH:37]=4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: NCc1cncnc1
Product: O=C1N=C(NCc2cncnc2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(pyrimidin-5-ylmethyl)-amino]-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and C-pyrimidin-5-yl-methylamine following General Procedure B.
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:25])[C:7]1[CH:12]=[C:11]([N:13]2[CH:17]=[N:16][N:15]=[N:14]2)[CH:10]=[C:9]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)[CH:8]=1>O.C1COCC1>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([C:9]2[CH:8]=[C:7]([CH:12]=[C:11]([N:13]3[CH:17]=[N:16][N:15]=[N:14]3)[CH:10]=2)[C:6]([OH:25])=[O:5])=[N:19][CH:20]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)cc(-n2cnnn2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(=O)O)cc(-n3cnnn3)c2)nc1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A solution of LiOH hydrate (82 mg, 1.94 mmol) in H2O (7 mL) was added dropwise to a suspension of 3-(5-methyl-pyridin-2-yl)-5-tetrazol-1-yl-benzoic acid methyl ester (440 mg, 1.49 mmol) in THF (4 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred until the reaction solution turned into clear. Solvent was removed under vacuum and the resulting aqueous solution was acidified by 10% HCl to pH=6-7. The resulting precipitate was collected and dried to afford 3-(5-Methyl-pyridin-2-yl)-5-tetrazol-1-yl-benzoic acid as a yellow solid (390 mg, 93%). MS (M+H)=282.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl.[N:32]1([CH2:39][C:40]2[CH:48]=[CH:47][C:43]([C:44](O)=O)=[CH:42][CH:41]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[N:32]1([CH2:39][C:40]2[CH:48]=[CH:47][C:43]([CH2:44][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[C@@H:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[CH:42][CH:41]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(O)c1ccc(CN2CCCCCC2)cc1
Agent: Cl
Product: COc1cc(NCCCc2ccc(CN3CCCCCC3)cc2)c([C@@H]2CCc3cc(O)ccc3C2)cc1OC
Yield: 72.2 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (416 mg) and 4-azepan-1-ylmethylbenzoic acid hydrochloride (328 mg) according to an analogous synthetic method to the above-mentioned Preparation Example 86 and Example 337,the title compound (386 mg) was obtained.
Reaction SMILES: [NH2:1][C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](N4N=NC(CC)=N4)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1.[ClH:45].[C:46]1([CH:52]([C:94]2[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70]([NH:72][CH2:73][C:74]4[CH:79]=[CH:78]C=[CH:76][N:75]=4)=[O:71])[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:80]2[CH2:84][C@H:83]([N:85]3[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]3)[C@@H:82]([OH:92])[C@H:81]2[OH:93])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.N1C=CC(CN)=NC=1>>[ClH:45].[C:94]1([CH:52]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70]([NH:72][CH2:73][C:74]4[CH:79]=[CH:78][N:1]=[CH:76][N:75]=4)=[O:71])[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:80]2[CH2:84][C@H:83]([N:85]3[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]3)[C@@H:82]([OH:92])[C@H:81]2[OH:93])[CH:95]=[CH:96][CH:97]=[CH:98][CH:99]=1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Agent: NCc1ccncn1
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccncn6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from ((1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 48) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113) by replacing 2-aminomethyl pyridine with C-pyrimidin-4-yl-methylamine. MS (ES+) m/e 731.46 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[CH2:11][OH:12].O.[Sn](Cl)Cl.[OH-].[Na+]>CCOC(C)=O>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:11][OH:12])[CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(CO)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(Cl)c(CO)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 93.2 %

Procedure:
To a solution of (2-chloro-5-nitrophenyl)methanol (5.00 g, 26.7 mmol) in EtOAc (100 mL) was added water (2.41 mL, 134 mmol) followed by tin(II) chloride (12.7 g, 67.0 mmol). The solution was stirred at RT for 21 h, then additional tin(II) chloride (5.06 g, 26.7 mmol) was added, and the mixture heated at 50° C. for 2 h, and then at 70° C. for 3 h. The cooled mixture was slowly basified with 1N sodium hydroxide solution (˜300 mL). The suspension was filtered through Celite, washing with EtOAc. The aqueous layer was extracted with EtOAc (3×100 mL), then the combined organics washed with brine, dried over MgSO4, and concentrated in vacuo to give the title compound (3.92 g, 93%). LCMS (Method 3): Rt 0.98 min, m/z 158 [MH+].
Reaction SMILES: [CH2:1]([O:5][C:6](Cl)=[O:7])[CH:2]([CH3:4])[CH3:3].CCN(CC)CC.FC(F)(F)C([O-])=O.C([O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH2:47][CH2:46][NH2+:45][CH2:44][CH2:43]3)=[CH:38][CH:37]=2)=[O:35])=[CH:29][CH:28]=1)(=O)C.C(O)C(N)(CO)CO>C1COCC1>[OH:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH2:47][CH2:46][N:45]([C:6]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:7])[CH2:44][CH2:43]3)=[CH:38][CH:37]=2)=[O:35])=[CH:29][CH:28]=1
Reactant: CC(C)COC(=O)Cl
Reactant: CC(=O)Oc1ccc(NC(=O)c2ccc(N3CC[NH2+]CC3)cc2)cc1
Agent: NC(CO)(CO)CO
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)COC(=O)N1CCN(c2ccc(C(=O)Nc3ccc(O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
2 eq of isobutyl-chloroformate and 3.5 eq of Et3N were added to a solution of 4-[4-({[4-(acetyloxy)phenyl]amino}carbonyl)phenyl]piperazin-1-ium trifluoroacetate in dry THF (0.05 M) and the solution was allowed to stir at RT for 3 h under N2. PS-trisamine resin (excess) was added and the reaction mixture was stirred for 16 h. The resin and a white precipitate were filtered off. Excess aqueous NaOH (1 M) was added to the organic solution and the reaction mixture was stirred for 2 h. The organic solvent was removed in vacuo and aqueous HCl (1 M) was added until precipitation of a white solid that was filtered off, washed and dried in vacuo to afford the title compound (90%).
Reaction SMILES: [F-].[CH2:2]([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:41]=[C:40]([C:42]([NH:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([O:52][Si](C(C)(C)C)(C)C)[CH:47]=2)=[O:43])[CH:39]=[C:38]([CH3:60])[C:21]=1[C:22]([NH:24][C@H:25]([C:35]([OH:37])=[O:36])[CH2:26][NH:27][C:28]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)=[O:29])=[O:23]>O1CCCC1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:41]=[C:40]([C:42]([NH:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([OH:52])[CH:47]=2)=[O:43])[CH:39]=[C:38]([CH3:60])[C:21]=1[C:22]([NH:24][C@H:25]([C:35]([O:37][CH3:2])=[O:36])[CH2:26][NH:27][C:28]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)=[O:29])=[O:23]
Reactant: Cc1cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc(Cl)c1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.5 %

Procedure:
Tetra-n-butylammonium fluoride (1 M in tetrahydrofuran; 3.4 mL, 3.4 mmol) was added to a solution of N-[2-chloro-4-[[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]methyl]amino]carbonyl]-6-methylbenzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine (2.0 g, 3.1 mmol) in tetrahydrofuran (10 mL). The solution was stirred at room temperature for 20 min, then diluted with ethyl acetate and washed with water and then brine. The solution was dried (MgSO4), filtered, evaporated, concentrated, evaporated, dried overnight under high vacuum and then crystallized from methanol to give N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]-6-methylbenzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine, methyl ester (1.06 g) as a solid. The mother liquors were concentrated and chromatographed (70% ethyl acetate/hexanes then methanol/ethyl acetate/hexanes10:133:57) to give a further portion of the product (0.16 g). The overall yield was1.22 g (74%).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:13][C:14]1[C:15]([CH3:21])=[N:16][N:17]([CH3:20])[C:18]=1[CH3:19].N1C=CC=CC=1.CCOCC>C(Cl)Cl>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:13][C:14]2[C:15]([CH3:21])=[N:16][N:17]([CH3:20])[C:18]=2[CH3:19])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: Cc1nn(C)c(C)c1N
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1nn(C)c(C)c1NS(=O)(=O)c1ccc(CBr)cc1
Yield: 55 %

Procedure:
4-Bromomethylbenzene sulfonyl chloride (3.72 g, 13.8 mmol) was added portionwise to a solution of 4-amino-1,3,5-trimethyl-1H-pyrazole (1.73 g, 13.8 mmol) and pyridine (1.5 ml) in DCM (100 ml) at rt. Concentration in vacuo gave a solid which was collected by vacuum filtration and washed with water (2×25 ml) then Et2O (100 ml) to give the title compound as a white solid (2.71 g, 7.59 mmol, 55%). δH (D-6 DMSO, 300K) 9.13 (1H, s), 7.64-7.55 (4H, m), 4.77 (2H, s), 3.55 (3H, s), 1.80 (3H, s), 1.54 (3H, s). m/z (ES+, 70V) 358.1 (MH+).
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH3:45])=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:41][CH2:42][N:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH3:45])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([OH:24])[CH:20]=[CH:21][C:22]=2[CH2:23]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: COCCCN(C)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)CCCOC)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 20.7 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 2-chloro-N-(3-methoxypropyl)-N-methylacetamide (9.8 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (3.5 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:31])[C:21]1[CH:26]=[CH:25][C:24](F)=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1.[CH3:32][NH:33][CH3:34].O>C(#N)C>[CH3:32][N:33]([CH3:34])[C:24]1[CH:25]=[CH:26][C:21]([C:20]([NH:19][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([C:8]([F:17])([C:13]([F:14])([F:16])[F:15])[C:9]([F:12])([F:10])[F:11])=[CH:5][C:4]=2[CH3:18])=[O:31])=[CH:22][C:23]=1[N+:28]([O-:30])=[O:29]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CNC
Solvent: CC#N
Solvent: O
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(N(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-4-fluoro-3-nitrobenzamide (5.0 g, 11 mmol) (prepared according to WO 05/073165) in acetonitrile (100 ml) was added a solution of N,N-dimethylamine in water (40% by weight) (3.55 ml, 28 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes. Then the reaction mixture was concentrated and the residue purified by chromatography over silica gel (eluent: ethyl acetate) to give 4-dimethylamino-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-3-nitrobenzamide (5.3 g, 100% yield).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)=[CH:6][C:5]=1[C:27]([F:30])([F:29])[F:28].[OH-].[K+].Cl>O1CCCC1.CO.O>[Cl:26][C:21]1[CH:20]=[C:19]([C:13]2([C:15]([F:17])([F:16])[F:18])[O:12][N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:31])=[O:2])=[C:5]([C:27]([F:30])([F:28])[F:29])[CH:6]=3)[CH2:14]2)[CH:24]=[C:23]([Cl:25])[CH:22]=1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-trifluoromethyl-benzoic acid methyl ester (Example I13) (4.3 g) in tetrahydrofuran (3 ml) and methanol (3 ml) was added a solution of potassium hydroxide (1.0 g) in water (4.0 ml). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was acidified by addition of hydrochloric acid (2M) (200 ml) and the mixture extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was re-crystallized from dichloromethane and heptane to give 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-trifluoromethyl-benzoic acid (3.58 g) as a white powder. 1H-NMR (CDCl3, 400 MHz): 8.08-7.45 (m, 6H), 4.14 (d, 1H), 3.76 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14](Cl)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)Cl)CC1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)N2CCOCC2)CC1
Reaction time: 8 h

Procedure:
To a solution of 4-chlorosulfonyl-piperidine-1-carboxylic acid tert-butyl ester (295 mg) in dichloromethane stirring at 0° C. was added triethylamine (96 μL) and morpholine (55 μL). The reaction mixture was stirred overnight then quenched with water and extracted into dichloromethane. The combined organics were washed with brine and dried (MgSO4). The solvent was removed in vacuo to yield 4-(morpholine-4-sulfonyl)-piperidine-1-carboxylic acid tert-butyl ester (120 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1>C(O)C.C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 120 °C

Procedure:
A mixture of 34.5 g of N-(3-bromophenyl)-6-nitro-4-quinazolinamine and 16.8 g of iron powder in 150 ml of ethanol and 150 ml of glacial acetic acid was heated in an oil bath at 120° C. for 2 hours. After filtration of the solid, solid sodium carbonate was added to the filtrate giving a solid. This was filtered, and the solid was extracted with methanol. The extracts were treated with charcoal and evaporated to a solid. After washing the solid with ether 27.5 g of N-(3-bromophenyl)-4,6-quinazolindiamine was obtained: mass spectrum (m/e): 315.