Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH:11]([CH2:14][OH:15])[CH2:12][OH:13])=[CH:6][CH:5]=1.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>O1CCCC1>[CH3:25][C:24]1[CH:26]=[CH:27][C:21]([S:18]([O:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([Br:3])=[CH:17][CH:16]=2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: OCC(CO)CCOc1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCC(CO)CCOc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
To a suspension of NaH (0.11 g, 4.58 mmol) in anhydrous tetrahydrofuran (10 mL) was added a solution of 2-(2-(4-bromophenoxy)ethyl)propane-1,3-diol (0.63 g, 2.29 mmol) in anhydrous tetrahydrofuran (10 mL) dropwise. The reaction mixture was stirred at room temperature for 30 minutes. Then, tosyl chloride (0.44 g, 2.3 mmol) was added in portions. The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was carefully quenched with water and extracted with ethyl acetate (4×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (0-35% ethyl acetate/petroleum ether) to afford the title compound (0.45 g, 46%) as white solid. 1H NMR (400 MHz, CDCl3) ppm 7.80 (d, 2H), 7.40-7.30 (m, 4H), 6.71 (d, 2H), 4.21-4.09 (m, 2H), 4.00-3.90 (m, 2H), 3.74-3.62 (m, 2H), 2.45 (s, 3H), 2.14 (m, 1H), 1.89-1.74 (m, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:2]1.[C:15]([O:19][C:20](=O)[O:21]C(C)(C)C)([CH3:18])([CH3:17])[CH3:16]>CN(C1C=CN=CC=1)C.C(#N)C.C(OCC)(=O)C>[C:15]([O:19][C:20]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:2]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1c[nH]c2ccccc12
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2ccccc12
Yield: 105.9 %

Procedure:
A solution of 3.15 g of ethyl indole-3-carboxylate, 4.36 g of di-tert-butylcarbonate and 0.02 g of 4-DMAP in 30 ml of acetonitrile is stirred at room temperature for 15 min. The reaction mixture is then diluted with 200 ml of ethyl acetate. The organic phase is washed with dilute hydrochloric acid, water and saturated sodium chloride solution in succession, dried over sodium sulfate and concentrated. Purification by means of FC over 80 g of silica gel with a 15:1 mixture of hexane and ethyl acetate as the mobile phase gives 5.1 g of the title compound: Rf (G)=0.41.
Reaction SMILES: [C:1]([N:4]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@H:5]([C:10]([OH:12])=[O:11])[C@@H:6]([CH2:8][F:9])[OH:7])([OH:3])=[O:2].[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1.C(O)(=O)C>CN(C=O)C.ClCCl.C1COCC1.CO>[C:1]([N:4]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@H:5]([C:10]([OH:12])=[O:11])[C@@H:6]([CH2:8][F:9])[O:7][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])([OH:3])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(O)[C@H]([C@H](O)CF)N(OCc1ccccc1)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)O[C@H](CF)[C@@H](C(=O)O)N(OCc1ccccc1)C(=O)O
Temperature: 80 °C
Reaction time: 4 h
Yield: 82.6 %

Procedure:
To a stirred solution of N-carboxybenzyloxy-(2S,3S)-4-fluorothreonine 102 (0.060 g, 0.22 mmol) in DMF (3 ml) was added tert-butyldimethylsilyl chloride (0.073 g, 0.49 mmol) and imidazole (0.033 g, 0.49 mmol). The solution was gently heated at 80° C. for 18 hours. After allowing the solution to cool to room temperature, the solution was diluted with dichloromethane (15 ml) and washed with 1N HCl solution (3×10 ml). The organic layer was dried (MgSO4) and the solvent was removed in vacuo to give a yellow oil. The residue was redissolved in a 1:1 THF/methanol solution (4 ml) and upon stirring 50% aqueous acetic acid (2 ml) was added. After stirring the solution vigorously for 4 hours the solvent was removed in vacuo to give a yellow oil. Trace amounts of acetic acid were removed by treatment of the residue in ethyl acetate (5 ml) with saturated sodium hydrogen carbonate solution (10 ml). The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford N-carboxybenzyloxy-O-tert-butyldimethylsilyl-(2S,3S)-4-fluorothreonine 103 as a pale yellow oil (0.073 g, 86% yield); 1H (400 MHz, CDCl3) 9.50 (1H, bs, OH, exchange with CH3OD), 7.60-7.20 (5H, m, Ph), 6.25, 5.75 and 5.45 (1H, 3×d, J 9.1, NH, exchange with CH3OD), 5.20-5.10 (2H, m, CH2Ph), 4.75-4.20 (4H, H-2, H-3, 4-CH2), 1.00-0.80 (9H, 2×s, SiC(CH3)3), 0.15-0.00 (6H, m, Si(CH3)2); 19F (376 MHz, CDCl3) −224.82 and −225.39 (2×dtJ 47, 4 due to rotamers).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@H:15]2[CH2:19][CH2:18][C@@H:17]([NH:20][C:21]([C@:23]34[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:24]3[C@@H:25]3[C@@:38]([CH3:41])([CH2:39][CH2:40]4)[C@@:37]4([CH3:42])[C@@H:28]([C@:29]5([CH3:46])[C@@H:34]([CH2:35][CH2:36]4)[C:33]([CH3:44])([CH3:43])[C@@H:32]([OH:45])[CH2:31][CH2:30]5)[CH2:27][CH2:26]3)=[O:22])[CH2:16]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CN=C(N)C=1C.[CH3:62][C:63]1([CH3:71])[CH2:68][C:67](=[O:69])[O:66][C:65](=[O:70])[CH2:64]1>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@H:15]2[CH2:19][CH2:18][C@@H:17]([NH:20][C:21]([C@:23]34[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:24]3[C@@H:25]3[C@@:38]([CH3:41])([CH2:39][CH2:40]4)[C@@:37]4([CH3:42])[C@@H:28]([C@:29]5([CH3:46])[C@@H:34]([CH2:35][CH2:36]4)[C:33]([CH3:44])([CH3:43])[C@@H:32]([O:45][C:67](=[O:69])[CH2:68][C:63]([CH3:71])([CH3:62])[CH2:64][C:65]([OH:70])=[O:66])[CH2:31][CH2:30]5)[CH2:27][CH2:26]3)=[O:22])[CH2:16]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCC(Cc5ccccc5)CC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1(C)CC(=O)OC(=O)C1
Agent: Cc1ccnc(N)c1C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCC(Cc5ccccc5)CC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)CC(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-N-((1R,3S)-3-((4-benzylpiperidin-1-yl)methyl)cyclopentyl)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamide (Example 32, 0.5 g, 0.80 mmol) in pyridine (5 ml), dimethyl amino pyridine (0.2 g, 1.6 mmol) was added, followed by 4,4-dimethyldihydro-2H-pyran-2,6(3H)-dione (0.82 ml) was added. The contents were refluxed for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl, water followed by brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.25 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.80-0.95 (m, 17H); 1.14-1.67 (m, 23H); 1.82-2.02 (m, 15H); 2.23-3.50 (m, 15H); 4.21-4.45 (m, 2H); 4.57 (s, 1H); 4.72 (s, 1H); 6.28-6.30 (m, 1H); 7.11-7.13 (m, 2H); 7.14-7.22 (m, 1H); 7.24-7.29 (m, 2H); ES Mass: 841 (100%), [M+1].
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CC(C)=O>[CH2:20]([O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])[CH:19]=[CH2:18]
Reactant: O=[N+]([O-])c1cccc(O)c1Cl
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc([N+](=O)[O-])c1Cl
Reaction time: 0.08 h

Procedure:
To a solution of 2-chloro-3-nitrophenol (1.5 g, 8.64 mmol) in acetone was added potassium carbonate (1.194 g, 8.64 mmol). After 5 minutes, allyl bromide (0.823 ml, 9.51 mmol) was added and the solution was heated to reflux overnight. The reaction mixture was cooled, filtered, and concentrated. Chromatography was performed with an Analogix 280 with an SF 40-80 column, 0% to 10% ethyl acetate/hexane gradient over 30 minutes to provide the title compound. MS (DCI+) m/z 231.1 (M+NH4)+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][N:16]([C:18](=[O:37])[C@H:19]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[NH:20][C:21]([O:23][CH2:24][C:25]([CH3:30])([CH3:29])[CH2:26][CH:27]=[CH2:28])=[O:22])[C@H:15]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:14]2)=[CH:4][C:3]=1[O:43][CH3:44].[CH2:45](C([Sn])=C(CCCC)CCCC)[CH2:46]CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:31]1([C@H:19]([NH:20][C:21]([O:23][CH2:24][C:25]([CH3:30])([CH3:29])[CH2:26][CH:27]=[CH2:28])=[O:22])[C:18]([N:16]2[CH2:17][C@H:13]([O:12][C:9]3[C:10]4[C:5](=[CH:4][C:3]([O:43][CH3:44])=[C:2]([CH:45]=[CH2:46])[CH:11]=4)[CH:6]=[CH:7][N:8]=3)[CH2:14][C@H:15]2[C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C=CCC(C)(C)COC(=O)N[C@H](C(=O)N1C[C@H](Oc2nccc3cc(OC)c(Br)cc23)C[C@H]1C(=O)OCC)C1CCCCC1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCC(C)(C)COC(=O)N[C@H](C(=O)N1C[C@H](Oc2nccc3cc(OC)c(C=C)cc23)C[C@H]1C(=O)OCC)C1CCCCC1
Temperature: 105 °C
Yield: 87.3 %

Procedure:
A solution of the product from Step 5 (1.02 g, 1.51 mmol) in PhMe (30 mL) was degassed for 30 minutes by bubbling nitrogen. Tri-n-butylvinyltin (533 μL, 1.81 mmol) and tetrakis(triphenylphosphine)palladium (175 mg, 0.151 mmol) were added, and the reaction mixture was heated to 105° C. for 3 hours, then cooled to RT for 18 hours. The volatiles were evaporated, and the residue was purified by chromatography on silica (20-50% EtOAc/hexane) to afford the title compound (820 mg) as a foam. LRMS ESI+ (M+H)+622.5.
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([NH:41][C:42](=[O:54])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20]([OH:22])=O)=O)C3C(=CC=CC=3)C=2C=CC=1.[NH2:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67]([O:69]C(C)(C)C)=[O:68]>>[NH2:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([NH:41][C:42](=[O:54])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20](=[O:22])[NH:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67]([OH:69])=[O:68]
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCN
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(=O)CCCCCCCCCCC
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCC(=O)O)NC(=O)CCCCCCCCCCC

Procedure:
The title product was prepared from (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(((R)-2-dodecanamido-3-(dodecyloxy)propyl)thio)propanoic acid (1 eq, from example 26, step 8) and tert-butyl 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoate (1.2 eq) by following the procedure described for example 32, step 1-3. 1H NMR (DMSO-d6): δ 8.06 (t, 1H), 7.78 (d, 1H), 5.05 (br s, 2H), 3.90-3.98 (m, 1H), 3.58 (t, 2H), 3.19-3.50 (m, 15H), 2.77 (dd, 2H), 2.62 (dd, 2H), 2.39 (t, 2H), 2.05 (t, 2H), 1.42-1.48 (m, 4H), 1.21-1.29 (m, 36H), 0.85 (t, 6H). LRMS [M+H]=748.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1ccc(F)cc1
Yield: 88 %

Procedure:
Prepared according to the procedure described for Example 121 using 4-fluorobenzenesulfonyl chloride (2.14 g, 10 mmol) and 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g, 10.0 mmol) to afford the product (3.522 g); m.p. 209-211° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:20]2[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[S:23][C:19]=2[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[S:23][C:22]([C:24]([F:25])([F:27])[F:26])=[CH:21][C:20]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2sc(C(F)(F)F)cc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cc(C(F)(F)F)sc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4-methyl-2-trifluoromethyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.[NH2:15][NH2:16]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:13])[NH:15][N:16]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccc(Br)cc1
Reactant: NN
Solvent: CCO
Product: O=C1CCC(c2ccc(Br)cc2)=NN1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
A solution of 4-(4-bromo-phenyl)-4-oxo-butyric acid (Aldrich, 25.0 g, 97.3 mmol) in EtOH (100 mL) was treated with aqueous hydrazine (Aldrich, 55%, 9.1 mL, 100 mmol) at 80° C. for 2 h. The mixture was cooled to room temperature and the precipitate was collected by filtration and dried under vacuum to provide the title compound (24 g, 97% yield). 1H NMR (300 MHz, CDCl3) δ 2.35-2.76 (m, 2H), 2.80-3.11 (m, 2H), 7.45-7.77 (m, 4H), 8.55 (s, 1H); MS (DCl/NH3) m/z 253 (M+H)+, 255 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[CH3:28])[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:42]=[CH:41][C:40]([S:43]([NH2:46])(=[O:45])=[O:44])=[CH:39][CH:38]=2)O1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([C:37]3[CH:42]=[CH:41][C:40]([S:43]([NH2:46])(=[O:45])=[O:44])=[CH:39][CH:38]=3)=[CH:7][CH:6]=2)[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[C:22]([CH3:28])[CH:23]=1
Reactant: Cc1cc(F)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Product: Cc1cc(F)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
The title compound was prepared in analogy to example 166, from (−)-5-{3-(4-bromo-phenyl)-3-(4-fluoro-2-methyl-phenyl)-1-[(E)-hydroxyimino]-propyl}-1-methyl-1H-pyridin-2-one (example 404) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (CAS RN 214360-51-7). The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of dichloromethane:methanol (100:0 to 90:10). Light brown solid. MS (ESI+): m/z=520.2 ([M+H]+).
Reaction SMILES: [CH:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=O)([CH2:3][CH3:4])[CH3:2].Cl.[CH3:20][S:21]([C:24]1[S:28][C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:26][CH:25]=1)(=[O:23])=[O:22]>>[CH:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([N:32]1[CH2:33][CH2:34][N:29]([C:27]2[S:28][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:25][N:26]=2)[CH2:30][CH2:31]1)=[O:10])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: CS(=O)(=O)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CCC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(S(C)(=O)=O)s2)CC1
Yield: 44 %

Procedure:
Prepared in analogy to example 1 (b) from rac-2-sec-butoxy-5-methanesulfonyl-benzoic acid (Example A10) and 1-(5-methanesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 21(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as an off-white crystalline solid (yield 44%). MS (m/e): 502.1 (M+H+, 99%), 519.3 (M+NH4+, 100%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1.[OH:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH2:22]>C(O)(C)C>[ClH:2].[OH:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:22][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: Cc1ccc(N)cc1O
Reactant: COCCOc1ccc2c(Cl)ncnc2c1
Agent: Cl
Solvent: CC(C)O
Product: COCCOc1ccc2c(Nc3ccc(C)c(O)c3)ncnc2c1
Yield: 73.9 %

Procedure:
A mixture of 4-chloro-7-(2-methoxyethoxy)quinazoline hydrochloride (450 mg, 1.6 mmol), (prepared as described for the starting material in Example 1), and 3-hydroxy4-methylaniline (280 mg, 2.27 mmol) in isopropanol (20 ml) was heated at reflux for 30 minutes. The solvent was removed by evaporation and the residue was triturated with isopropanol. The resulting solid was collected by filtration, washed with isopropanol and dried under vacuum to give 4-(3-hydroxy4-methylanilino)-7-(2-methoxyethoxy)quinazoline hydrochloride (428 mg, 74%).
Reaction SMILES: [Na].[O-]CC.[Na+].[CH2:6]([O:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]([CH:28]([CH3:30])[CH3:29])=[CH:16][C:15]=1[C:31](=[O:33])[CH3:32])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:34](OCC)(=[O:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36]>C(O)C>[CH2:38]([O:37][C:35](=[O:36])[C:34]([OH:40])=[CH:32][C:31]([C:15]1[CH:16]=[C:17]([CH:28]([CH3:30])[CH3:29])[C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:19][C:14]=1[O:13][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:33])[CH3:39]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cc(C(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(O)=CC(=O)c1cc(C(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Sodium (2.8 eq) was added to ethanol under nitrogen at room temperature and stirred for 25 minutes to generate sodium ethoxide. 1-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-ethanone (1 eq) was dissolved in further ethanol and added to the sodium ethoxide solution. Diethyl oxalate (1.64 eq) was added and the reaction mixture heated to reflux for 4 hours. The mixture was allowed to cool to room temperature and enough 1MHCl (aq) was added to acidify the reaction mixture, which was then concentrated in vacuo. The resulting gum was partitioned between dichloromethane and brine, and the organic phase was dried over MgSO4, filtered and evaporated in vacuo to give 4-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid ethyl ester as a yellow gum.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[CH3:8][N:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH2:18][CH2:19]Br)=[CH:17][C:12]=2[O:11][C:10]1=[O:21]>O1CCOCC1>[CH3:8][N:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])=[CH:17][C:12]=2[O:11][C:10]1=[O:21]
Reactant: Cn1c(=O)oc2cc(CCBr)ccc21
Reactant: CCCNCCC
Solvent: C1COCCO1
Product: CCCN(CCC)CCc1ccc2c(c1)oc(=O)n2C

Procedure:
2.02 g (0.02 mol) of N,N-dipropylamine and 2.56 g (0.01 mol) of 3-methyl-6-(2-bromoethyl)-benzoxazolinone, dissolved beforehand in 30 cm3 of dioxane, were introduced into a 100 cm3 flask with a ground glass neck, fitted with a reflux condenser, and the mixture was then heated under reflux for seventy-two hours, with stirring. After cooling, the reaction mixture was filtered and the filtrate was then evaporated in a water-bath, in vacuo. The residue was then taken up in 30 cm3 of diethylether, the solution was filtered, the filtrate was washed with water and dried over calcium chloride, and a stream of hydrogen chloride was then bubbled. The precipitate formed was filtered off and then recrystallised from ethylacetate, and this gave 2.23 g of the title compound, in the form of the hydrochloride, having a melting point of 150°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[C:4](=[O:15])[C:3]=1[CH:16]=[N:17]O.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[C:4](=[O:15])[C:3]=1[C:16]#[N:17]
Reactant: Cc1ccccc1-n1ccc(Cl)c(C=NO)c1=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1ccccc1-n1ccc(Cl)c(C#N)c1=O
Temperature: 90 °C
Yield: 53.2 %

Procedure:
To a solution of 4-chloro-3-((hydroxyimino)methyl)-1-(2-methylphenyl)pyridin-2(1H)-one obtained in Step C (6.36 g) in acetonitrile (60 mL) was added phosphorus oxychloride (2.93 mL) at room temperature. The reaction mixture was heated at 90° C. for 1 hr, cooled to room temperature, and poured into ice water. The resulting solid was collected by filtration to give the title compound (3.15 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:19]=3[NH:18][CH:17]=[CH:16]4)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.[CH3:30][O:31][C:32](=[O:56])[C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[CH:35][C:34]=1[NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+].Cl>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].C(#N)C.C1COCC1>[CH3:30][O:31][C:32](=[O:56])[C:33]1[CH:38]=[C:37]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:12]=[CH:13][CH:14]=[C:15]5[C:19]=4[NH:18][CH:17]=[CH:16]5)=[CH:9][N:8]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[C:5]3=[N:6][CH:7]=2)[CH:36]=[CH:35][C:34]=1[NH:48][C:49]([O:51][C:52]([CH3:54])([CH3:53])[CH3:55])=[O:50]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cccc4cc[nH]c34)c3cc(Br)cnc32)cc1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: Cl
Solvent: CC#N
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1cc(-c2cnc3c(c2)c(-c2cccc4cc[nH]c24)cn3S(=O)(=O)c2ccc(C)cc2)ccc1NC(=O)OC(C)(C)C
Yield: 55.9 %

Procedure:
To a mixture of 5-bromo-3-(1H-indol-7-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (802 mg, 1.7 mmol) and 2-tert-butoxycarbonylamino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (641 mg, 1.7 mmol) in a 20 mL microwave reaction flask was added THF (6 mL), acetonitrile (6 mL) and sodium carbonate (6 mL, 1 N aqueous solution, 6 mmol). The mixture was purged with nitrogen for 1 minute. Dichloro[1,1′-bis(diphenylphoshino)ferrocene]palladium(II) dichloromethane adduct (122 mg, 170 μmol) was added and the purging continued for another minute. The flask was sealed and irradiated in a microwave reactor to 70° C. for 15 minutes. Saturated sodium chloride (15 mL) was added and the pH was adjusted to 7 using hydrochloric acid (1 N). The resulting mixture was extracted with ethyl acetate (10 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel using a gradient of methanol in dichloromethane to afford 2-tert-butoxycarbonylamino-5-[3-(1H-indol-7-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid methyl ester as a yellow solid (605 mg, 56% yield). MS: m/z 637 (M+H+).