Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=O)[N:4]=[CH:3]1.[NH2:13][C@@H:14]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16]>>[NH:2]1[CH:6]=[C:5]([C:7]([CH3:12])([CH3:11])[C:8]([NH:13][C@@H:14]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:22][CH:23]=2)=[O:16])=[O:10])[N:4]=[CH:3]1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC(C)(C(=O)O)c1c[nH]cn1
Agent: Cl
Product: CC(C)(C(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1)c1c[nH]cn1
Yield: 58 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-imidazol-4-yl)-2-methylpropanoic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 213, (S)-2-(2-(1H-imidazol-4-yl)-2-methylpropanamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (93.4 mg, 58%). 1H-NMR (400 MHz, CDCl3): δ 9.30 (s, 1H), 7.52-7.46 (m, 3H), 7.37 (d, 1H), 7.33-7.22 (m, 5H), 7.03-6.98 (m, 2H), 6.95-6.88 (m, 4H), 6.82 (s, 1H), 4.73-4.68 (m, 1H), 4.58 (d, 1H), 4.47 (d, 1H), 4.08 (dd, 1H), 3.64 (dd, 1H), 1.56 (s, 3H), 1.55 (s, 3H). MS (EI) for C29H30FN4O4 found 517 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[N+:45]([O-:47])=[O:46])=[CH:30][CH:29]=2)[C@H:10]([O:48][CH2:49][C@H:50]([OH:57])[CH2:51][N:52]2[CH:56]=[CH:55][N:54]=[CH:53]2)[CH2:9]1)=O)(C)(C)C.Cl>CO>[N:52]1([CH2:51][C@@H:50]([OH:57])[CH2:49][O:48][C@H:10]2[C@H:11]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[N+:45]([O-:47])=[O:46])=[CH:30][CH:29]=3)[C@@H:12]([O:14][CH2:15][C:16]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH2:13][NH:8][CH2:9]2)[CH:56]=[CH:55][N:54]=[CH:53]1
Reactant: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H](O)Cn3ccnc3)[C@@H]2c2ccc(OCCCOc3ccccc3[N+](=O)[O-])cc2)cc2ccccc12
Agent: Cl
Solvent: CO
Product: COc1cc(CO[C@H]2CNC[C@@H](OC[C@H](O)Cn3ccnc3)[C@@H]2c2ccc(OCCCOc3ccccc3[N+](=O)[O-])cc2)cc2ccccc12

Procedure:
In analogy to the procedure described in example 1) (1) the (3S,4R,5R)-3-[(2R)-2-hydroxy-3-imidazol-1-yl-propoxy)-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl in methanol to yield the (R)-1-imidazol-1-yl-3-[(3S,4R,5R)-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidin-3-yloxy]-propan-2-ol as colorless foam; MS: 683 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([OH:9])[N:3]=1.C(O[Na])(C)=O.Br[CH:16]([CH:20]([CH3:22])[CH3:21])[CH2:17]C=O>CC#N.O>[NH2:1][C:2]1[NH:3][C:4](=[O:9])[C:5]2[C:16]([CH:20]([CH3:22])[CH3:21])=[CH:17][NH:8][C:6]=2[N:7]=1
Reactant: CC(C)C(Br)CC=O
Reactant: Nc1cc(O)nc(N)n1
Agent: CC(=O)O[Na]
Solvent: CC#N
Solvent: O
Product: CC(C)c1c[nH]c2nc(N)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
A suspension of 2,4-diamino-6-hydroxypyrimidine (6.68 g, 50 mmol), AcONa (8.3 g 100 mmol) and 3-bromo-4-methyl-pentanal (8.76 g, 50 mmol) in CH3CN (100 mL) and H2O (100 mL) was stirred at 25° C. overnight whereupon the starting materials gradually dissolved and the desired pyrrolo[2,3-d]pyrimidine precipitated. The precipitate was collected by filtration and washed with MeOH to give 2-amino-5-isopropyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (3.80 g, 40%). HPLC Rt: 4.408 min. 1H-NMR (DMSO-d6): δ 10.58 (s, 1H), 10.10 (s, 1H), 6.30 (s, 1H), 5.97 (s, 2H), 3.03 (7, 1H), 1.20 (s, 3H), 1.19 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:12][C:13]1[C:14]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:14]3[C:13]([CH3:12])=[CH:18][C:17]([CH3:19])=[CH:16][N:15]=3)[CH2:21][CH2:22]2)=[O:8])=[C:9]([CH3:11])[CH:10]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: Cc1cc(Br)ncc1C(=O)O
Product: Cc1cnc(N2CCN(C(=O)c3cnc(Br)cc3C)CC2)c(C)c1
Yield: 97.7 %

Procedure:
Using 6-bromo-4-methylnicotinic acid (500 mg) and 1-(3,5-dimethylpyridin-2-yl)piperazine (443 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (880 mg) was obtained.
Reaction SMILES: [Br:1]Br.[C:3]1([CH:10]=[CH:9][CH:8]=[C:6]([OH:7])[CH:5]=1)[OH:4]>ClCCl>[Br:1][C:5]1[C:6]([OH:7])=[CH:8][CH:9]=[CH:10][C:3]=1[OH:4]
Reactant: Oc1cccc(O)c1
Reactant: BrBr
Solvent: ClCCl
Product: Oc1cccc(O)c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromine (0.363 L) was added dropwise over 2 hours to a solution of resorcinol (250 g) in dichloromethane (3.5 L). The solution was stirred at room temperature for 18 hours at which time approximately 1 L of the dichloromethane was removed by distillation. MeOH was added and the distillation continued in this manner until all of the dichloromethane was removed and the solution contained approximately 1.5 L of MeOH. To this was added a solution of NaOH (181.5 g) and Na2SO3 (573 g) in H2O (7.5 L). The resulting mixture was stirred at ambient temperature for 1 hour. The solution was then acidified to pH=2 with concentrated HCl (75 mL) and extracted with tert-butyl methyl ether (TBME) (2×1 L). The combined organic layers were treated with activated charcoal (20 g) and filtered through Celite; the Celite was washed with an additional 500 mL of TBME. The solvent was then removed in vacuo. The resulting crude 2-bromoresorcinol was dissolved in a minimum amount of ethyl acetate and filtered through silica gel eluting with a gradient from 20% to 40% ethyl acetate in hexanes yielding 2-bromoresorcinol (122 g). m.p. 86-88°.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[N:8]=2)[CH:6]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[F:14][C:13]([F:16])([F:15])[C:11]1[CH:10]=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([NH2:27])=[N:29][CH:30]=3)[N:3]=[CH:4]2)[N:12]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)c1
Product: Nc1ccc(-c2cn(-c3nc(-c4cccc(C(F)(F)F)c4)cc(C(F)(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-iodo-imidazol-1-yl)-4-trifluoromethyl-6-(3-trifluoromethyl-phenyl)-pyrimidine (example E.16) (0.90 g, 1.86 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.491 g, 2.23 mmol) according to the general procedure VI. Obtained as a yellow solid (0.290 g, 34%). MS (ISP) 451.1 [(M+H)+]; mp 262° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[C:26]([C:28]([C:31]1[CH:32]=[C:33]([NH:37][C:38](=O)[O:39]C2C=CC=CC=2)[CH:34]=[CH:35][CH:36]=1)([CH3:30])[CH3:29])#[N:27]>C1COCC1.CN(C1C=CN=CC=1)C>[C:26]([C:28]([C:31]1[CH:32]=[C:33]([NH:37][C:38]([NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([O:18][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:20]=2)=[O:39])[CH:34]=[CH:35][CH:36]=1)([CH3:30])[CH3:29])#[N:27]
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(C#N)c1cccc(NC(=O)Oc2ccccc2)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cccc(C(C)(C)C#N)c4)c3)c2cc1OC
Yield: 54.7 %

Procedure:
Using the procedure described in Example 279a solution of 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline (103 mg, 0.3 mmol), prepared as described in Example 117B, in THF (3 ml) was added DMAP (18 mg, 0.15 mmol) and phenyl 3-(2-cyanopropan-2-yl)phenylcarbamate (92 mg, 0.33 mmol) described in Example 278A to afford 1-(3-(2-cyanopropan-2-yl)phenyl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea (86.6 mg, 55%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.66 (s, 6H), 3.78 (s, 3H), 3.98 (s, 4H), 4.34 (s, 3H), 6.95 (d, J=7.8 Hz, 1H), 7.11 (d, J=7.8 Hz, 1H), 7.26-7.41 (m, 5H), 7.58-7.66 (s, 3H), 8.54 (s, 1H), 8.90 (d, J=8.4 Hz, 2H); LC-MS (ESI) m/z 528 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.N#N.[H-].[Na+].I[CH2:19][CH3:20]>CN(C)C=O.CCOC(C)=O>[CH2:19]([CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13])[CH3:20]
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: CCI
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC1CCc2cc(OC)ccc2C1=O
Temperature: 25 °C

Procedure:
A solution of 6-methoxy-3,4-dihydro-1(2H)-naphthalenone (5.0 g, 28 mmol) in anhydrous N,N-dimethylformamide (DMF, 60 mL) was purged with N2, cooled in an ice bath, stirred, and treated with NaH (1.2 g of a 60% dispersion in mineral oil, 30 mmol). The cooling bath was removed and the mixture was stirred at room temperature for 10 minutes. The mixture was re-cooled in an ice bath, treated with iodoethane (3.35 mL, 42 mmol), and then stirred under a N2 atmosphere while gradually warming to room temperature. After stirring for 2.9 days, the mixture was diluted with EtOAc (250 mL) and washed with water (200 mL), and the aqueous phase was back-extracted with EtOAc (100 mL). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 40M (4×15 cm) silica gel column, eluting successively with 1000 mL portions of 0.2%, 1%, 2%, and 5% EtOAc in hexane. The product-containing fractions were combined and evaporated under vacuum to afford 2-ethyl-6-methoxy-3,4-dihydro-1(2H)-naphthalenone as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[CH2:24][CH2:23]2)[C:9]([N+:36]([O-:38])=[O:37])=[C:8]([CH3:39])[NH:7][C:6]=1[NH2:40])=[O:4].FC(F)(F)S(O)(=O)=[O:44].ClC1C=CC=C(C(OO)=O)C=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[CH2:24][CH2:23]2)=[O:44])[C:9]([N+:36]([O-:38])=[O:37])=[C:8]([CH3:39])[NH:7][C:6]=1[NH2:40])=[O:4]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: COC(=O)C1=C(N)NC(C)=C([N+](=O)[O-])C1c1ccccc1SCCCCN1CCN(c2ccccc2OC)CC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1=C(N)NC(C)=C([N+](=O)[O-])C1c1ccccc1S(=O)CCCCN1CCN(c2ccccc2OC)CC1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a 4-neck 500 ml round-bottom flask fitted with an addition funnel, thermometer and mechanical stirrer under a nitrogen atmosphere, was added 5.00 g of 2-amino-1,4-dihydro-4-(2-{4-[4-(2-methoxyphenyl)-1-piperazinyl]-butylthio}phenyl)-6-methyl-5-nitro-3-pyridinecarboxylic acid methyl ester and 120 ml of dichloromethane, followed by 1.73 ml of trifluoromethanesulfonic acid. The reaction mixture was cooled to -10° C. with an ice/acetone bath, and 1.88 g of 80% m-chloroperbenzoic acid in 120 ml of dichloromethane was added dropwise, maintaining -5° to -10° C. The reaction was stirred for an additional 2 hr. at -10° C. after the addition was complete. The reaction mixture was poured into conc. sodium bicarbonate, and the reaction flask was rinsed with acetone. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated to an orange oil. The product (Ex. No. 2, Table 1) was isolated after column chromatography on silica gel, eluting with 20% methanol in ethyl acetate as an orange foam, 2.8 g. 1H-NMR (CDCl3) ∂ 1.84-2.05(m,2H); 2.03-2.05(m,2H); 2.36(s,3H); 2.55(t,2H,J=7Hz); 2.71(br s,4H); 3.00-3.18(br s,6H); 3.61(s,3H); 3.85(s,3H); 5.76(s,1H); 6.70(br s,2H); 6.83-7.03(m,4H); 7.28-7.41(m,4H); 7.82-7.86(m,1H). Mass spectrum: 584 (M+1).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([C:11](=O)[CH2:12][N:13]3[CH:17]=[CH:16][N:15]=[CH:14]3)[CH:9]=[CH:10][C:4]=2[C:3]=1[CH3:19].O.NN.C(O)CO.[OH-].[K+]>O>[Br:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([CH2:11][CH2:12][N:13]3[CH:17]=[CH:16][N:15]=[CH:14]3)[CH:9]=[CH:10][C:4]=2[C:3]=1[CH3:19]
Reactant: Cc1c(Br)sc2cc(C(=O)Cn3ccnc3)ccc12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Cc1c(Br)sc2cc(CCn3ccnc3)ccc12
Temperature: 135 °C
Yield: 92.8 %

Procedure:
A mixture of 2-bromo-6-(1-imidazolyl)acetyl-3-methylbenzo[b]thiophene (0.45 g.), 99% hydrazine hydrate (0.20 g.) and ethylene glycol (5.0 ml.) was heated on a steam bath for 2 hours and then cooled. Potassium hydroxide (0.24 g.) was added and the mixture was heated at 135° C. for 1.5 hours and then cooled and poured into water. The mixture was extracted several times with ethyl acetate and the combined extracts were washed with water and dried (Na2SO4). Evaporation of the solvent gave an oil which as chromatographed on silica gel. Elution with chloroform gave a small amount of impurity followed by pure product. Evaporation of the product-containing fractions gave 2-bromo-6-[2-(1-imidazolyl)ethyl]-3-methylbenzo[b]thiophene (0.40 g.) as a thick oil which was pure enough for further reaction.
Reaction SMILES: C([O:8][C:9]1[C:13]([CH2:14][CH:15]2[S:19][C:18](=[O:20])[N:17]([CH3:21])[C:16]2=[O:22])=[CH:12][N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:10]=1)C1C=CC=CC=1.C(#N)C.I[Si](C)(C)C>O>[OH:8][C:9]1[C:13]([CH2:14][CH:15]2[S:19][C:18](=[O:20])[N:17]([CH3:21])[C:16]2=[O:22])=[CH:12][N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:10]=1
Reactant: CN1C(=O)SC(Cc2cn(-c3ccccc3)nc2OCc2ccccc2)C1=O
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: O
Product: CN1C(=O)SC(Cc2cn(-c3ccccc3)nc2O)C1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.9 %

Procedure:
To a mixture of 5-[(3-benzyloxy-1-phenyl-1H-pyrazol-4-yl)methyl]-3-methyl-1,3-thiazolidine-2,4-dione (0.30 g) and acetonitrile (10 mL) was added iodotrimethylsilane (0.46 g) at room temperature. After stirring the reaction mixture at room temperature for 15 hrs, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (2:3, v/v) to give 5-[(3-hydroxy-1-phenyl-1H-pyrazol-4-yl)methyl]-3-methyl-1,3-thiazolidine-2,4-dione as colorless crystals (0.15 g, yield 65%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 233-234° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([OH:12])[C:4]=2[N:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:20][S:21]([O:12][CH:5]1[C:4]2[N:3]=[C:2]([Br:1])[CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCCc2ccc(Br)nc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCCc2ccc(Br)nc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a cold (0° C.) stirred solution of 2-bromo-5,6,7,8-tetrahydroquinolin-8-ol (500 mg, 2.36 mmol) in dry CH2Cl2 (10 mL) was added triethylamine (0.72 mL, 5.2 mmol) followed by methanesulfonyl chloride (0.35 mL, 3.6 mmol). The resulting mixture was stirred at 0° C. for 1 h, then warmed slowly to room temperature and stirred a further 1 h. Saturated aqueous NaHCO3 (30 mL) was added and the phases were separated. The aqueous layer was extracted with CH2Cl2 (3×30 mL) and the combined organic extracts were dried (MgSO4) and concentrated to give 605 mg (88%) of 2-bromo-5,6,7,8-tetrahydroquinolin-8-yl methanesulfonate as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:30])[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:15][CH2:14]2)=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].C(O)C.[H][H]>[C].[Pd].O>[NH2:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:14][CH2:15][N:16]([C:19](=[O:30])[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:17][CH2:18]2)=[CH:9][C:3]=1[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: COc1ccc(C(=O)N2CCN(c3ccc(N)c(C=CC(=O)O)c3)CC2)cc1OC
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)N2CCN(c3ccc(N)c(CCC(=O)O)c3)CC2)cc1OC
Yield: 29.9 %

Procedure:
2-Amino-5-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]cinnamic acid (5 g) was dissolved in a mixed solvent consisting of ethanol and water. After adding 5% palladium-carbon (0.5 g), the mixture was reduced at atmospheric pressure of hydrogen gas. After absorption of theoretical amount of hydrogen gas, the catalyst was removed by filtration and the ethanol-water phase was concentrated to dryness. The residue was dissolved in chloroform and separated through silica gel column chromatography to give 1.5 g of 3-{2-amino- 5-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]phenyl}-propionic acid, m.p. 98°-101° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=[O:12])[CH:4]=[CH:3]1.S(Cl)(Cl)=O.[CH3:21]O>>[O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([O:13][CH3:21])=[O:12])[CH:4]=[CH:3]1
Reactant: O=C(O)c1cccc(-c2ccc(=O)[nH]n2)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(-c2ccc(=O)[nH]n2)c1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
12.3 g (57 mmol) of 3-(6-oxo-1,6-dihydropyridazin-3-yl)benzoic acid are dissolved in 240 ml of methanol, and 30 ml of thionyl chloride are added. The reaction mixture is stirred at 70° C. for 24 h. The reaction solution is evaporated, and the residue is digested with diethyl ether, and the residue is dried in vacuo.
Reaction SMILES: CNC(OCC)=O.[CH3:8][O:9][CH:10]1[CH:15]([CH3:16])[CH2:14][CH2:13][CH:12]([NH2:17])[CH2:11]1.C([O-])(=O)C>O1CCOCC1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:15]=1[CH3:16])[NH2:17]
Reactant: COC1CC(N)CCC1C
Agent: CC(=O)[O-]
Agent: CCOC(=O)NC
Solvent: C1COCCO1
Product: COc1cc(N)ccc1C

Procedure:
4.2 g of N-[4-(β-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl]-methyl-urethane (melting point 189°- 191°C) are suspended in 50 ml of dioxane and dissolved in 50 ml dioxane after addition of 2 g of 3-methoxy-4-methyl-cyclohexyl-amine-acetate (melting point 134° - 136° C) (obtained by hydrogenation of the nucleus of 3-methoxy-4-methylaniline at Co2O3 at 260°C and under a pressure of 250 atmospheres H2) and heated for about 1 hour to 110°C, in which process the methanol which has formed during the reaction is distilled off. After cooling, water is added and the N-[4-(β-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl]-N'-(3-methoxy-4-methylcyclohexyl)-urea precipitates in crystalline form and it is recrystallized from methanol (melting point 179° - 181° C). In analogous manner, there is obtained: from N-[4-(β-<3-trifluoromethylbenzamido>-ethyl)-benzenesulfonyl]-methylurethane (melting point 178° - 180°C)
Reaction SMILES: [Li]CCCC.[C:6]([Si:10]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]#[CH:38])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7].[CH2:39]=[O:40]>C1COCC1>[Si:10]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]#[C:38][CH2:39][OH:40])([C:6]([CH3:9])([CH3:8])[CH3:7])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=O
Reactant: C#CCCCCCCCCCCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCCCCCCCCCCCCC#CCO)(c1ccccc1)c1ccccc1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
n-BuLi (2.5 M solution in hexanes, 1.29 g, 8 mL, 20.24 mmol) was added to a stirring, −40° C. solution of tert-butyl(pentadec-14-ynyloxy)diphenylsilane (8.5 g, 18.40 mmol) in THF (175 mL) under an argon atmosphere. After 30 min, the reaction mixture was gradually warmed over 3 h to −10° C., held at this temperature for 20 min, then re-cooled to −50° C. Then, a solution of paraformaldehyde (3.05 g, 92.2 mmol) in THF (30 mL) was cannulated into the stirring reaction mixture. After 30 min, the temperature was gradually warmed over 3 h to room temperature. Following 1 h at room temperature, the reaction mixture was quenched with sat. aq. NH4Cl (10 mL), diluted with ether (100 mL), and washed with water (2×75 mL). The combined aqueous washes were back-extracted with ether (2×50 mL). The combined All of the organic extracts were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by SiO2 column chromatography using 5% EtOAc/hexanes as eluent to give 16-(tert-butyldiphenylsilyloxy)hexadec-2-yn-1-ol (6.12 g, 68%). TLC: 30% EtOAc/hexanes, Rf≈0.5; 1H NMR (CDCl3, 300 MHz) δ 7.70-7.74 (m, 4H), 7.34-7.44 (m, 6H), 4.3 (t, 2H, J=2.1 Hz), 3.65 (t, 2H, J=7.3 Hz), 2.12-2.17 (m, 2H), 1.20-1.61 (m, 22H), 1.04 (s, 9H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[Br:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(N(CC)CC)C>ClCCl.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:29][C:30]1[CH:35]=[C:34]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19]([NH:21][CH3:22])=[O:20])=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])[CH:33]=[CH:32][CH:31]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Reactant: OB(O)c1cccc(Br)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cccc(Br)c3)S(C)(=O)=O)c(C3CC3)cc12
Reaction time: 48 h
Yield: 38.7 %

Procedure:
A mixture of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxamide (500 mg, 1.24 mmol), 3-bromophenylboronic acid (1.5 g, 7.46 mmol), copper(II) acetate monohydrate (372 mg, 1.87 mmol), triethylamine (252 mg, 2.49 mmol), 4 Å molecular sieves (1 g) in dichloromethane (160 mL) was stirred for 2 days. The solid was filtered off, the filtrate was concentrated to dryness and purified by column chromatography to afford 6-(N-(3-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (270 mg, 0.48 mmol, 39% yield) as a brown solid. LCMS (m/z, ES+)=557, 559 (M+H+).