Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[NH:14][C:13]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:12]1.[C:21]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[CH:40]=[CH:39][C:38]([CH2:41]Br)=[CH:37][CH:36]=1)(=[O:28])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:41][C:38]2[CH:39]=[CH:40][C:35]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[S:26](=[O:28])(=[O:27])[NH:25][C:21]([CH3:22])([CH3:24])[CH3:23])=[CH:36][CH:37]=2)[C:13]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:12]1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Br)c(=O)[nH]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Br)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Yield: 92 %

Procedure:
The alkylation of 2-(2-bromo-5-nitrophenyl)-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step A) with [2'-(N-t-butylsulfamoyl)-biphenyl-4-yl]methyl bromide (from Example 12, Step D) was carried out according to the procedure of Example 13, Step A, to give a 92% yield of the title compound as a yellow solid, mp 126°-128° C.; homogeneous by TLC in 98:2 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 642, 644 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[CH3:13][C:14]([S@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15].O>C1COCC1>[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([C:8](=[N:19][S@@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])[CH3:9])[CH:7]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cc(Br)c(F)cc1F
Solvent: O
Solvent: C1CCOC1
Product: CC(=N[S@](=O)C(C)(C)C)c1cc(Br)c(F)cc1F
Temperature: 70 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
To a solution of 1-(5-bromo-2,4-difluoro-phenyl)-ethanone (19 g, 64.7 mmoles, 1 equiv.) and (R)-2-methyl-propane-2-sulfinic acid amide (10.2 g, 84.1 mmoles, 0.76 equiv) in THF (0.3 M, 215 mL) is added Ti(OEt)4 (29.5 g, 129 mmoles, 2.0 equiv) in a single portion at ambient temperature. The reaction is heated to 70° C. and allowed to stir 18 h. The reaction is cooled to ambient temperature, and poured into water. The resulting suspension is filtered through a pad of diatomaceous earth and washed with ethyl acetate. The filtrate is collected and extracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by silica gel chromatography, eluting with a linear gradient of hexane to hexane:ethyl acetate (3:1) over 20 minutes to give the title compound (81% yield): MS (m/z): 338, 340 (M+1).
Reaction SMILES: [C:1]1([CH:7]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:8]([O:10]CC)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:18]>O1CCOCC1>[ClH:18].[C:1]1([CH:7]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:8]([OH:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(c1ccccc1)N1CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)C(c1ccccc1)N1CCCC1
Yield: 77.8 %

Procedure:
Ethyl 2-phenyl-2-(pyrrolidin-1-yl)acetate (0.31 g, 1.33 mmol) was dissolved in dioxane (11 ml) and 37% HCl (1.09 ml, 13.3 mmol) was added dropwise. The mixture was stirred at reflux overnight. Then 37% HCl (1.09 ml, 13.3 mmol) was added again and the reaction was refluxed for additional 24 hours. The solvent was evaporated, the residue was triturated with acetonitrile (10 ml) and the suspension was filtered on a buckner funnel. The solid was recovered to obtain 2-phenyl-2-(pyrrolidin-1-yl)acetic acid hydrochloride (0.25 g, 79% yield) as a white solid.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH3:34])[C:23](O)=[O:24]>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:12]=[CH:13][C:14]([CH2:17][CH3:18])=[CH:15][N:16]=3)[CH2:7][CH2:6]2)[C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]([N:29]3[CH:33]=[CH:32][N:31]=[C:30]3[CH3:34])=[C:20]([F:19])[CH:21]=2)[CH2:2][CH2:3]1
Reactant: Cc1nccn1-c1ccc(C(=O)O)cc1F
Reactant: CCc1cnc(N2CCC(NC3CC3)CC2)nc1
Product: CCc1cnc(N2CCC(N(C(=O)c3ccc(-n4ccnc4C)c(F)c3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from cyclopropyl-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-amine and 3-fluoro-4-(2-methyl-imidazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 90. LC (method 19): tR=3.81 min; Mass spectrum (ESI+): m/z=449 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[N:20]=[C:21]([CH2:24][OH:25])[S:22][CH:23]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.I[CH2:32][CH3:33]>>[CH2:32]([O:25][CH2:24][C:21]1[S:22][CH:23]=[C:19]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]([CH3:26])[C:11]2[N:27]([CH3:30])[C:28](=[O:29])[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:9][C:10]3=2)[N:20]=1)[CH3:33]
Reactant: CCI
Reactant: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3cc(-c4csc(CO)n4)ccc3n(C)c21
Product: CCOCc1nc(-c2ccc3c(c2)c2cc(-c4ccc(F)cc4)c(=O)n(C)c2n3C)cs1

Procedure:
The process is carried out as in Example 10 above, using 3-(4-fluorophenyl)-6-(2-hydroxymethylthiazol-4-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one, compound from Example 63 and iodoethane.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.[CH3:10][CH:11]([CH3:15])[C:12](=O)[CH3:13]>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:8]=[C:12]([CH3:13])[C:11]2([CH3:15])[CH3:10]
Reactant: NNc1ccc(Br)cc1
Reactant: CC(=O)C(C)C
Product: CC1=Nc2ccc(Br)cc2C1(C)C
Temperature: 25 °C
Yield: 87.6 %

Procedure:
To a 500 mL flask were added p-bromophenylhydrazine 1 (50.3 g, 0.27 mol) glacial acetic acid (300 mL) and 3-methylbutanone (40 mL, 0.37 mol). The mixture was heated at reflux for 4 h and then cooled to rt. The volatile components were removed in vacuo and the residue was partitioned between petroleum ether (350 mL) and water (100 mL). The aqueous phase was washed again with petroleum ether (2×100 mL). The combined organic solutions were dried (MgSO4) and filtered and the solvent was evaporated in vacuo to afford 5-bromo-2,3,3-trimethyl-3H-indole 2 (56.3 g, 87%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]2[C:23]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:22][CH:21]=[CH:20][N:19]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1.CCN(C(C)C)C(C)C>CN(C)C=O.O>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]2[C:23]([N:24]3[CH2:29][CH2:28][N:27]([CH2:32][C:33]4[CH:42]=[CH:41][C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:34]=4)[CH2:26][CH2:25]3)=[N:22][CH:21]=[CH:20][N:19]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=S(=O)(Nc1nccnc1N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(Nc1nccnc1N1CCN(Cc2ccc3ccccc3n2)CC1)c1ccc(Oc2ccccc2)cc1
Yield: 76 %

Procedure:
To a solution of 4-phenoxy-N-(3-piperazin-1-ylpyrazin-2-yl)benzenesulfonamide (411 mg, 1.0 mmol, 1 eq) in dimethylformamide (10 mL) was added 2-(chloromethyl)quinoline hydrochloride (214 mg, 1 mmol, 1 eq) and DIPEA (322 mg, 2.5 mmol, 2.5 eq). The reaction mixture was heated to 50 degrees over 1 hour. The reaction was cooled, diluted with 30 mL of water and extracted with diethyl ether. The organic layer was dried over MgSO4, evaporated and purified by flash chromatography on silica gel eluting with AcOEt and cyclohexane to give pure 4-phenoxy-N-{3-[4-(quinolin-2-ylmethyl)piperazin-1-yl]pyrazin-2-yl}benzenesulfonamide as a yellow solid (419 mg, 0.76 mmol, yield: 76%, 97% HPLC purity).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].C(N(C(C)C)CC)(C)C.I.[NH2:26][C:27]1[C:28]([C:35]([NH:37][C:38](=[NH:41])SC)=[O:36])=[N:29][C:30]([Cl:34])=[C:31]([NH2:33])[N:32]=1>C(O)C>[NH2:26][C:27]1[C:28]([C:35]([N:37]=[C:38]([NH2:41])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:36])=[N:29][C:30]([Cl:34])=[C:31]([NH2:33])[N:32]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: NCCCCCCCCCCCC(=O)O
Agent: I
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: NC(=NC(=O)c1nc(Cl)c(N)nc1N)NCCCCCCCCCCCC(=O)O
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A solution of 12-aminododecanoic acid (1) (0.096 g, 0.45 mmol) and diisopropylethylamine (0.39 mL, 2.23 mmol) in absolute ethanol (5 mL) was stirred at 70° C. for 30 min. 1-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (191 mg, 0.49 mmol) was added in one portion and heating at 70° C. was continued for a further 16 hours. After this time, the reaction was cooled to room and the resulting yellow precipitate collected by filtration and washed with ethanol (2×2 mL). Further purification by Biotage silica gel column chromatography using a gradient of 3% to 20% of 10% concentrated aqueous ammonium hydroxide in methanol to dichloromethane afforded acid 2 (96 mg, 50%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 1.25 (m, 14H), 1.50 (m, 4H), 2.18 (t, 2H), 3.15 (t, 2H), 6.92 (m, 3H). m/z (ESI) 428 [C18H30ClN7O3+H]+. mp 194-196° C.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH:26]#[C:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[C:26]([C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])#[C:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: C#CCCCC
Reactant: CCCCNc1nc2c(N)nc(I)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: CCCCC#Cc1nc(N)c2nc(NCCCC)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1

Procedure:
The reaction was performed with 2-iodo-8-butylaminoadenosine (10, 200 mg, 0.43 mmol) and 1-hexyn (2.08 mmol). The mixture was purified by column chromatography (5% MeOH in CH2Cl2). Yield 111 mg (0.26 mmol, 62%), mp 182–184÷C; 1H NMR (DMSO-d6) δ 6.95 (t, 1H, J=5.49 Hz, NH), 6.55 (bs, 2H, NH2), 5.87 (d, 1H, J=7.90 Hz, H-1′), 5.77–5.72 (m, 1H, OH-2′), 5.26 (d, 1H, J=6.52 Hz, OH-5′), 5.15 (d, 1H, J=4.12 Hz, OH-3′), 4.54 (q, 1H, J=5.84 Hz, H-2′), 4.09–4.04 (m, 1H, H-3′), 3.95–3.93 (m, 1H, H-4′), 3.64–3.59 (m, 2H, H-5′), 3.09 (m, 2H, NHCH2), 2.36 (m, 2H, ≡CCH2), 1.51–1.30 (m, 8H, 2×CH2CH2), 0.89 (t, 6H, J=,7.55 Hz, 2×CH3); MS m/z 419 (M+H)+; Anal. (C20H30N6O4) C, H, N.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[F:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([N:61]=[C:62]=[O:63])[CH:56]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:62]([NH:61][C:57]2[CH:58]=[CH:59][CH:60]=[C:55]([F:54])[CH:56]=2)=[O:63])[CH2:48]1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C=Nc1cccc(F)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCN(C(=O)Nc2cccc(F)c2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 80 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 1-fluoro-3-isocyanatobenzene as the starting materials in 80% yield. LCMS for C30H29ClFN8O2 (M+H)+: m/z=587.0.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[C:12]([C:20]([S:23]([CH3:26])(=[O:25])=[O:24])([CH3:22])[CH3:21])[CH:13]=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[CH:15]3)[CH:5]=1.[Li+].[OH-].Cl>C1COCC1>[CH3:26][S:23]([C:20]([C:12]1[CH:13]=[C:14]2[C:19](=[C:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:27])=[O:2])[CH:11]=1)[N:18]=[CH:17][CH:16]=[CH:15]2)([CH3:22])[CH3:21])(=[O:25])=[O:24]
Reactant: COC(=O)c1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(c1cc(-c2cccc(C(=O)O)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a solution of 3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-benzoic acid methyl ester from Step 1 (1.0 eq.) in THF (0.2M) was added aqueous LiOH (1.0M; 3.0 eq.). The mixture was stirred for 5 h at 60° C., neutralized to pH=5 using aqueous HCl (1M) and extracted with CH2Cl2 (4×). The combined organic extracts were dried over MgSO4, filtered and concentrated. Stirring in Hex:Et2O (1:1) afforded the title compound after filtration.
Reaction SMILES: [F:1][C:2]1([F:35])[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[CH:34]=[CH:33][C:10]2[N:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:31])OC(C)(C)C)[CH3:23])=[CH:16][C:15]=3[F:32])[O:13][C:9]=2[CH:8]=1.Cl.[C:37](OCC)(=O)C>C(OCC)(=O)C>[F:35][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[CH:34]=[CH:33][C:10]2[N:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:31])[CH3:37])[CH3:23])=[CH:16][C:15]=3[F:32])[O:13][C:9]=2[CH:8]=1
Reactant: C[C@@H](COc1cnc(-c2nc3ccc(OCC4CC4(F)F)cc3o2)c(F)c1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1cnc(-c2nc3ccc(OCC4CC4(F)F)cc3o2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl {(1S)-2-[(6-{6-[(2,2-difluorocyclopropyl)methoxy]-1,3-benzoxazol-2-yl}-5-fluoropyridin-3-yl)oxy]-1-methylethyl}carbamate (690 mg), 4 M hydrogen chloride/ethyl acetate (10 mL), and ethyl acetate (10 mL) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was mixed with pyridine (10 mL) and acetic anhydride (5 mL). The mixture was stirred at room temperature overnight. 1 M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallization (ethyl acetate) to give the title compound (496 mg) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][O:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[N:3]=1.CC1N(CCOC[Si](C)(C)C)N=CC=1.[Li]CCCC.[CH2:34]([Sn:38](Cl)([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH3:37]>C1COCC1>[CH3:1][C:2]1[CH:6]=[C:5]([Sn:38]([CH2:39][CH2:40][CH2:41][CH3:42])([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:34][CH2:35][CH2:36][CH3:37])[N:4]([CH2:7][CH2:8][O:9][CH2:10][Si:11]([CH3:13])([CH3:12])[CH3:14])[N:3]=1
Reactant: Cc1ccn(CCOC[Si](C)(C)C)n1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: Cc1ccnn1CCOC[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C)nn1CCOC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a solution containing a 1:1 mixture of 3-methyl-1-(2-trimethylsilanylmethoxy-ethyl)-1H-pyrazole and 5-methyl-1-(2-trimethylsilanylmethoxy-ethyl)-1H-pyrazole (1.5 g, 7.06 mmol) in THF (20 mL) at −78° C. was added dropwise n-BuLi (1.6M in hexanes, 4.4 mL, 1 equiv) while keeping the temperature below −70° C. The mixture was then stirred 30 min at −78° C. prior to the addition of tributyltin chloride (1.9 mL, 1 equiv) (the temperature was maintained below −70° C.). The mixture was stirred at −78° C. for 30 min and for 2 h at r.t. Hexanes was added to the mixture and the insoluble material was removed by filtration. Concentration of the solution in vacuo gave a colorless syrup. The crude product was purified by flash chromatography (hexanes to EtOAc/hexanes (20/80)) to provide 3-methyl-5-tributylstannanyl-1-(2-trimethylsilanylmethoxy-ethyl)-1H-pyrazole (847 mg, 24%) as a colorless syrup. (TLC rf 0.33 in EtOAc/hexanes 5:95).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:19]=[C:20]1[C:25]2[S:26][CH:27]=[C:28]([S:29](Cl)(=[O:31])=[O:30])[C:24]=2[CH2:23][CH2:22][CH2:21]1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]([CH3:11])[S:29]([C:28]2[C:24]3[CH2:23][CH2:22][CH2:21][C:20](=[O:19])[C:25]=3[S:26][CH:27]=2)(=[O:30])=[O:31])=[CH:6][CH:7]=1
Reactant: O=C1CCCc2c(S(=O)(=O)Cl)csc21
Reactant: CNCCc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(CCc1ccc(F)cc1)S(=O)(=O)c1csc2c1CCCC2=O
Reaction time: 0.5 h

Procedure:
To a solution of [2-(4-fluorophenyl)-ethyl]-methyl-amine (the compound of Preparation Example 14) (520 mg) and triethylamine (474 μL) in tetrahydrofuran was added a solution of 7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonyl chloride (the compound of Preparation Example 7) (800 mg) in tetrahydrofuran. The solution was stirred on an ice bath for 30 minutes, and at room temperature for 30 minutes. The residue resulting from the removal of the solvent by evaporation was purified by NH silica gel column chromatography (hexane/ethyl acetate), and the title compound (834 mg) was obtained as a colorless candy-like substance.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:21])[CH2:5][CH:6]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[C:7]=1[C:8](O)=[O:9].[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[C:26]2[CH3:32].C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[CH3:1][C:2]1[NH:3][C:4](=[O:21])[CH2:5][CH:6]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[C:7]=1[C:8]([NH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[C:26]2[CH3:32])=[O:9]
Reactant: Cc1n[nH]c2ccc(N)cc12
Reactant: CC1=C(C(=O)O)C(c2ccc3ccccc3c2)CC(=O)N1
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(C)c3c2)C(c2ccc3ccccc3c2)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.5 %

Procedure:
The product of Example 1, Step 2 (50 mg, 0.178 mmol, 1.00 equiv), 5-amino-3-methylindazole (26 mg, 0.178 mmol, 1.0 equiv), and EDC (41 mg, 0.213 mmol, 1.20 equiv) were suspended in 0.5 mL DMF. Et3N (0.030 mL, 0.213 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (20-100% EtOAc in Hexanes) to provide 15 mg (21%) of the title compound as an off white solid. MS (ES+) m/e 411 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9](O)=[O:10])=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([Cl:16])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C(=O)Cl)c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 97.4 %

Procedure:
2-(4-Chlorophenyl)-2-methylpropanoic acid (3.85 g, 19.4 mmol) in toluene (5 mL) was treated with thionyl chloride (5.00 g, 3.1 mL) and heated at 80° C. for 2 hours. The cooled solution was concentrated under reduced pressure to provide a yellow oil containing a crystalline residue. The mixture was dissolved in hexane, filtered and the filtrate concentrated to provide the compound as a pale yellow oil (4.10 g, 98%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)=[CH:8][C:7]=1[N+:22]([O-])=O)C>C(O)(=O)C.[Pd]>[NH2:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][C:9]1[CH:8]=[C:7]2[C:6]([CH2:5][C:4](=[O:3])[NH:22]2)=[CH:11][CH:10]=1
Reactant: CCOC(=O)Cc1ccc(Oc2cccc([N+](=O)[O-])c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1cccc(Oc2ccc3c(c2)NC(=O)C3)c1
Reaction time: 8 h
Yield: 35.7 %

Procedure:
To a solution of [2-nitro-4-(3-nitro-phenoxy)-phenyl]-acetic acid ethyl ester (496 mg, 1.4 mmol) in acetic acid (5 mL) is added 10% Pd/C (48 mg). The mixture is stirred under hydrogen (balloon) overnight. The catalyst is filtered off and the solvent is evaporated to dryness. The crude product is purified by column chromatography (EtOAc/Hexane=9:1) to give 120 mg of the desired product (yield 50%). LC/MS: 242.2 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(=O)([O-])[O-].[Na+].[Na+].[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31](Cl)=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.Cl>O1CCCC1.O>[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O

Procedure:
To a mixture consisting of 19.4 g. of L-leucine, 15.7 g. of sodium carbonate, and 500 ml. of water, cooled to 0° C., is added a solution of 19.1 g. of 9-fluorenylmethylchloroformate in 200 ml. of tetrahydrofuran, and the resulting mixture is stirred at 0° C. for one hour and at room temperature for 15 hours. The mixtue is then acidified with 3 N hydrochloric acid and concentrated to remove the solvent. The residue is extracted with ethyl acetate, and the extract is washed with 100 ml. of 10% hydrochloric acid and with 100 ml. of water, dried, and evaporated to dryness to give a residue of N-9-fluorenylmethoxycarbonyl-L-leucine, which is slurried with n-hexane, isolated, and dried; m.p. 76°-79° C.; [α]D25 -28.7° (1.01% in methanol). To a mixture consisting of 15.2 g. of this intermediate product, 37 g. of pentachlorophenol, and 300 ml. of N,N-dimethylformamide, cooled to 5° C., is added 9.8 g. of dicyclohexylcarbodiimide, and the resulting mixture is kept at 4° C. for 2 days. It is then filtered, and the filtrate is evaporated to dryness to give a residue of N-9-fluoroenylmethoxycarbonyl-L-leucine pentachlorophenyl ester, which is triturated with n-hexane, isolated and dried; m.p. 119°-121° C.; [α]D25 -35.4° (1.00% in methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:19])=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.CO.[OH-].[K+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH3:19])=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1oc(-c2ccc(Cl)cc2)nc1CC(=O)O
Yield: 83.4 %

Procedure:
2.0 g of ethyl 2-[2-(4-chlorophenyl)-5-methyl-4-oxazolyl]acetate, 15 ml of methanol, 5 ml of water and 0.8 g of potassium hydroxide are treated in the same manner as described in Example 8. 1.50 g of 2-[2-(4-chlorophenyl)-5-methyl-4-oxazolyl]acetic acid are thereby obtained. Yield: 83.3%.