Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:45])[C:7]([O:10]/[N:11]=[C:12](/[C:32]1[N:33]=[C:34]([NH:37]C(OC(C)(C)C)=O)[S:35][CH:36]=1)\[C:13]([NH:15][C@H:16]1[C@@H:19]([CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][C:22]2=[O:26])[N:18]([S:27]([OH:30])(=[O:29])=[O:28])[C:17]1=[O:31])=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:37][C:34]1[S:35][CH:36]=[C:32](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:45])=[O:5])/[C:13](=[O:14])[NH:15][C@H:16]2[C@@H:19]([CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][C:22]3=[O:26])[N:18]([S:27]([OH:30])(=[O:28])=[O:29])[C:17]2=[O:31])[N:33]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2CN2CCCC2=O)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1CN1CCCC1=O)c1csc(N)n1)C(=O)O
Yield: 16.1 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (3S,4R)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-oxo-4-((2-oxopyrrolidin-1-yl)methyl)azetidine-1-sulfonic acid (55 mg, 0.072 mmol), DCM (720 μL) and TFA (333 μL, 4.32 mmol). The crude residue was purified by reverse phase preperative HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (6 mg, 16%) as a white solid. LCMS: Rt=0.35 min, m/z=519.0 (M+1) Method 2m_acidic; 1H NMR (400 MHz, D2O): δ 7.17 (s, 1H), 5.46 (d, J=5.8 Hz, 1H), 4.71-4.64 (m, 1H), 3.92 (dd, J=14.7, 8.7 Hz, 1H), 3.71-3.55 (m, 2H), 3.49 (dd, J=14.7, 4.1 Hz, 1H), 2.42 (td, J=8.0, 4.8 Hz, 2H), 2.08 (p, J=7.6 Hz, 2H), 1.55 (s, 3H), 1.54 (s, 3H).
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+].[CH:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)=[O:16]>O.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>[N:6]1[CH:7]=[CH:8][C:3]([C:21]2[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=2)[CH:15]=[O:16])=[CH:4][CH:5]=1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Brc1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1cccc(-c2ccncc2)c1
Temperature: 85 °C
Reaction time: 24 h
Yield: 84.9 %

Procedure:
To a solution of 4-bromopyridine hydrochloride (533.4 mg, 2.7 mmol) in water (4.0 mL) and toluene (4.8 mL) was added slowly a solution of Na2CO3 (714 mg, 6.7 mmol) in water (7.0 mL) at room temperature. The solution was then mixed with 3-formylbenzeneboronic acid (431 mg, 2.9 mmol), Pd(PPh3)4 (100 mg, 0.086 mmol). The reaction mixture was stirred at 85° C. for 24 h, and then cooled to room temperature. The reaction was worked up by extraction of the mixture with CH2Cl2 (4×5 mL). The combined organic phase was dried over anhydrous Na2SO4. The solvent was removed under vacuum, and the residue was purified by a flash chromatography (silica gel, petroleum ether/EtOAc=¼) to give product 10 (420 mg) in 85% yield; 1H NMR (300 MHz, CDCl3): 10.1 (s, 1H), 8.72-8.74 (m, 2H), 8.17 (s, 1H), 7.90-7.99 (m, 2H), 7.69 (t, J=11.4 Hz, 1H), 7.57 (d, J=6.6 Hz, 2H); 13C NMR (75 MHz CDCl3): δ191.5, 150.3, 146.5, 138.8, 136.8, 132.5, 130.1, 129.6, 127.5, 121.3; HRMS (ESI) calcd for C12H9NO (M. Hi) 184.07569; found 184.07538.
Reaction SMILES: C(O)(=O)C(O)=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2([C:30]([O:32]C)=[O:31])[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:18][CH2:17]2)[CH:12]=[CH:13][CH:14]=1.[OH-].[K+].Cl.[OH-].[Na+]>O.C(O)CO>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2([C:30]([OH:32])=[O:31])[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:20][CH2:21]2)[CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)C1(Nc2cccc(OC)c2)CCN(CCc2ccccc2)CC1
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: [K+]
Solvent: O
Solvent: OCCO
Product: COc1cccc(NC2(C(=O)O)CCN(CCc3ccccc3)CC2)c1
Temperature: 25 °C
Yield: 72.3 %

Procedure:
A mixture of 39.5 parts of methyl 4-[N-(3-methoxyphenyl)amino]-1-(2-phenylethyl)-4-piperidinecarboxylate ethanedioate, 18 parts of potassium hydroxide and 90 parts of 1,2-ethanediol is stirred and refluxed for 3 hours. The reaction mixture is cooled to room temperature, poured onto 200 parts of water and acidified with a concentrated hydrochloric acid solution. The whole is strongly alkalized with a sodium hydroxide solution and stirred vigorously for one hour. The precipitated product is filtered off, dissolved in water and the solution is neutralized with acetic acid. The product is filtered off and crystallized from N,N-dimethylformamide, yielding 27.4 parts (72.3%) of 4-[(3-methoxyphenyl)amino]-1-(2-phenylethyl)-4-piperidinecarboxylic acid; mp. 265.1° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]1[C:15]2[CH2:14][S:13][N:12]=[C:11]([NH:16]C(=O)OC(C)(C)C)[C:10]3=[N:24][N:25]([CH2:27][C:28]4[C:33]([CH3:34])=[C:32]([O:35][CH3:36])[C:31]([CH3:37])=[CH:30][N:29]=4)[N:26]=[C:8]([C:9]=23)[CH:7]=1)[CH3:2]>C(OCC)C>[CH2:1]([NH:3][CH2:4][CH2:5][C:6]1[C:15]2[CH2:14][S:13][N:12]=[C:11]([NH2:16])[C:10]3=[N:24][N:25]([CH2:27][C:28]4[C:33]([CH3:34])=[C:32]([O:35][CH3:36])[C:31]([CH3:37])=[CH:30][N:29]=4)[N:26]=[C:8]([C:9]=23)[CH:7]=1)[CH3:2]
Reactant: CCNCCc1cc2nn(Cc3ncc(C)c(OC)c3C)nc3c-2c1CSN=C3NC(=O)OC(C)(C)C
Solvent: CCOCC
Product: CCNCCc1cc2nn(Cc3ncc(C)c(OC)c3C)nc3c-2c1CSN=C3N
Yield: 32 %

Procedure:
Synthesis was performed by the same method as in Example 111 using the above tert-butyl {8-[2-(ethylamino)ethyl]-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}carbamate (17 mg), followed by trituration with diethyl ether to obtain the title compound (4.4 mg, 31%) as a solid.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][C:15]=2[CH2:25][N:26]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:27][CH3:28])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[OH-].[Li+]>>[CH2:32]([O:31][C:29]([N:26]([CH2:25][C:15]1[CH:16]=[C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:19][C:14]=1[C:8]1[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:39])=[O:3])[CH:7]=1)[CH2:27][CH3:28])=[O:30])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(NS(C)(=O)=O)cc2CN(CC)C(=O)OCc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Product: CCN(Cc1cc(NS(C)(=O)=O)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)OCc1ccccc1

Procedure:
{4′-Amino-2′-[(benzyloxycarbonyl-ethyl-amino)-methyl]-6-methoxy-biphenyl-3-yl}-acetic acid ethyl ester (0.080 g, 0.2 mmol), methanesulfonyl chloride (0.04 mL, 0.3 mmol), and triethylamine were reacted in CH2Cl2 to give {2′-[(benzyloxycarbonyl-ethyl-amino)-methyl]-4′-methanesulfonylamino-6-methoxy-biphenyl-3-yl}-acetic acid ethyl ester. {2′-[(Benzyloxycarbonyl-ethyl-amino)-methyl]-4′-methanesulfonylamino-6-methoxy-biphenyl-3-yl}-acetic acid ethyl ester (0.2 mmol) was hydrolyzed with lithium hydroxide to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][C:10]=1[F:18].[NH2:19][C:20]1[C:21]([N:29]2[CH2:34][CH2:33][CH2:32][C@H:31]([NH:35]C(=O)OC(C)(C)C)[CH2:30]2)=[C:22]2[CH2:28][CH2:27][O:26][C:23]2=[N:24][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:35][C@H:31]1[CH2:32][CH2:33][CH2:34][N:29]([C:21]2[C:20]([NH:19][C:15]([C:13]3[CH:12]=[CH:11][C:10]([F:18])=[C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[N:14]=3)=[O:17])=[CH:25][N:24]=[C:23]3[O:26][CH2:27][CH2:28][C:22]=23)[CH2:30]1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2CCO3)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N[C@H]1CCCN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCO3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
To a mixture of 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (15.0 mg, 0.0592 mmol), tert-butyl [(3S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate (19.1 mg, 0.0571 mmol) and HATU (73.6 mg, 0.194 mmol), DMF (1.50 mL) was added, followed by DIPEA (84.8 mg, 0.656 mmol). The reaction mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. DCM (2.0 mL) was added to the residue, followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.15% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (5.9 mg, 22%). LCMS calc. for C24H23F3N5O2 (M+H)+: m/z=470.2. found 470.2.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[CH3:28])[C:22](O)=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].CN.C1COCC1.C[CH2:38][N:39]=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[CH3:28])[C:22]([NH:39][CH3:38])=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared from 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid (from step 1 above) (1.5 g, 3.57 mmol) in dichloromethane (35 ml). To this mixture, 2.0 M methyl amine in THF (3.6 ml, 7.14 mmol) was added, followed, in order, by EDCI (0.67 g, 4.28 mmol), 1-hydroxybenzotriazole (0.58 g, 4.28 mmol) and triethylamine (0.99 ml, 7.14 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with NH4Cl and extracted 3 times with ethyl acetate. The combined organic layer was then washed with saturated NaHCO3 (aq.) and extracted 3 times with ethyl acetate. The organic layers were combined and washed with H2O and extracted 3 times with ethyl acetate. The organic layers were combined and dried over Na2SO4 and evaporated. The resulting residue was triturated with diethyl ether/hexane to obtain a solid, which was dried in vacuo to give a white solid (1.5 g, 72%). 1H NMR (300 MHz, CD3OD) δ 7.90 (dd, J=8.06, 1.81 Hz, 1H), 7.67 (app q, J=6.44 Hz, 1H), 7.55 (d, J=8.06 Hz, 1H), 7.13-7.06 (m, 2H), 6.74 (s, 1H), 5.40 (s, 2H), 2.93 (s, 3H), 2.13 (s, 3H), 2.04 (s, 3H); ES-MS m/z 433 (M+H). ES-HRMS m/z 433.1153 (M+H calcd for C22H20ClF2N2O3 requires 433.1125).
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11](=[O:32])[C@@H:12]([NH:24][C:25]([O:27]C(C)(C)C)=O)[CH2:13][S:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.C(Cl)(=O)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.CCCCCC>[CH3:9][C:2]([NH:10][C:11](=[O:32])[C@@H:12]([NH:24][C:25](=[O:27])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:13][S:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)([CH3:1])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(CSC[C@H](NC(=O)OC(C)(C)C)C(=O)NC(C)(C)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COc1ccc(CSC[C@H](NC(=O)c2ccccc2)C(=O)NC(C)(C)c2ccccc2)cc1
Reaction time: 1.17 h
Yield: 49.2 %

Procedure:
13.3 g of (2R)-N-(α,α-dimethylbenzyl)-2-(t-butoxycarbonylamino)-3-(p-methoxybenzylthio)propionamide (prepared as described in Preparation 6) were dissolved in 50 ml of toluene. To this solution were added 4.70 ml of triethylamine, and then 2.23 g of benzoyl chloride was added slowly to the mixture, whilst ice-cooling. The reaction solution was stirred for 70 minutes, and then ethyl acetate was added to it, after which it was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off and the resulting residue was purified by column chromatography through 210 g of silica gel. From the fraction eluted with hexane containing 30-40% v/v ethyl acetate, were obtained 4.31 g of an oily substance. This substance was dissolved in a mixture of ethyl acetate and hexane, and, after removal of crystals which had separated out (about 250 mg, melting at 189° C.), concentration of the mother liquor gave 3.61 g of the title compound as a glassy substance, [α]25 =-25.3° (C=1, CHCl3).
Reaction SMILES: C([O:9][CH2:10][C:11]1[S:12][C:13]([C:16]([O:18]CC)=[O:17])=[CH:14][N:15]=1)(=O)C1C=CC=CC=1.[OH-]>O>[OH:9][CH2:10][C:11]1[S:12][C:13]([C:16]([OH:18])=[O:17])=[CH:14][N:15]=1
Reactant: CCOC(=O)c1cnc(COC(=O)c2ccccc2)s1
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cnc(CO)s1
Temperature: 95 °C
Yield: 68.3 %

Procedure:
A mixture of 13.5 g of ethyl 2-benzoyloxymethyl-thiazole-5-carboxylate, 135 ml of water and 8 ml of postassium hydroxide was heated at 95° C with stirring for an hour and the mixture was cooled and extracted with ether. The aqueous phase was acidified and was then saturated with sodium chloride. The mixture was extracted with ethyl acetate and the organic extracts were washed with water, dried and evaporated to dryness to obtain 11,5 g of raw product. The product was chromatographed over silica gel and was eluted with a 8-2 methylene chloride-ethanol mixture containing 2% acetic acid. The 6 g of product were crystallized from a 3-1 acetone-methanol mixture to obtain 5.04 g of 2-hydroxymethyl-thiazole -5-carboxylic acid melting at 193° C.
Reaction SMILES: [Br:1]Br.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4]1>O1CCOCC1>[Br:1][C:10]1[CH:9]=[CH:8][C:7]2[O:3][CH2:4][CH2:5][C:6]=2[CH:11]=1
Reactant: BrBr
Reactant: c1ccc2c(c1)CCO2
Solvent: C1COCCO1
Product: Brc1ccc2c(c1)CCO2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
To an ice-cooled dioxane (30 ml) was slowly added liquid bromine (2.66 g) and this mixture was stirred for 30 minutes at said temperature. To the mixture was added dropwise 2,3-dihydrobenzofuran (2 g), and the resulting mixture was stirred for 3 hours at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in AcOEt (50 ml) and the solution was washed with saturated aqueous NaHCO3 solution and brine, and dried over MgSO4. The solvent was evaporated to give an orange oil as a crude product. The crude product was purified on an SiO2 column (hexane-AcOEt 20:1) to give 2.33 g of 5-bromo-2,3 dihydrobenzofuran as white crystals (yield 70.3%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH3:16][O:17][CH2:18][CH2:19][O:20][C:21](=[O:31])[C@@H:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:30][C@H:22]([C:21]([O:20][CH2:19][CH2:18][O:17][CH3:16])=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: COCCOC(=O)[C@@H](N)Cc1ccccc1
Product: COCCOC(=O)[C@H](Cc1ccccc1)Nc1nc2ccc(Cl)cc2cc1C(=O)O

Procedure:
In close analogy to the procedure described in Example 43, 2,6-dichloro-quinoline-3-carboxylic acid is reacted with (S)-2-amino-3-phenyl-propionic acid 2-methoxy-ethyl ester to provide after chromatographical separation the title compound in moderate yield.
Reaction SMILES: [CH3:1][N:2]([C@@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.[C:29]([C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([C:44]([CH3:47])([CH3:46])[CH3:45])[C:41]=1[O:42][CH3:43])[C:36](O)=[O:37])([CH3:32])([CH3:31])[CH3:30].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:44]([C:40]1[CH:39]=[C:35]([CH:34]=[C:33]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:41]=1[O:42][CH3:43])[C:36]([N:26]1[CH2:27][CH2:28][C@@H:24]([N:2]([CH3:1])[C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH2:25]1)=[O:37])([CH3:47])([CH3:46])[CH3:45]
Reactant: CN(C(=O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1)[C@@H]1CCNC1
Reactant: COc1c(C(C)(C)C)cc(C(=O)O)cc1C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1c(C(C)(C)C)cc(C(=O)N2CC[C@@H](N(C)C(=O)CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)C2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a solution of (R)-6,6-Bis-(4-fluoro-phenyl)-hexanoic acid methyl-pyrrolidin-3-yl-amide (0.78 g, 2.02 mmol) in dry CH2Cl2 (30 ml) was added 3,5-di-tert-butyl-4-methoxy benzoic acid (0.53 g, 2.02 mmol) under nitrogen. To the reaction was added EDC (0.77 g, 4.04 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate: water (10:1) (150 ml). The organic was washed with water (30 ml, 2×) and 10% NaOH (30 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:CH3OH (15:1) to give 1.1 g of desired product.
Reaction SMILES: BrC1C=CC(S(NC2C=CN=C(Cl)C=2)(=O)=O)=CC=1.[CH3:19][C@H:20]1[NH:25][C@@H:24]([CH3:26])[CH2:23][N:22]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH2:33])[CH:28]=2)[CH2:21]1.[Br:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][C:36]=1[F:45]>>[Br:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH:33][C:29]2[CH:28]=[C:27]([N:22]3[CH2:23][C@H:24]([CH3:26])[NH:25][C@H:20]([CH3:19])[CH2:21]3)[CH:32]=[CH:31][N:30]=2)(=[O:43])=[O:42])=[CH:37][C:36]=1[F:45]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Reactant: C[C@@H]1CN(c2ccnc(N)c2)C[C@H](C)N1
Agent: O=S(=O)(Nc1ccnc(Cl)c1)c1ccc(Br)cc1
Product: C[C@@H]1CN(c2ccnc(NS(=O)(=O)c3ccc(Br)c(F)c3)c2)C[C@H](C)N1

Procedure:
The title compound was prepared in a manner similar to 4-bromo-N-(2-chloro-4-pyridinyl)benzenesulfonamide (D3) using 4-[cis-3,5-dimethyl-1-piperazinyl]-2-pyridinamine (D21) and 4-bromo-3-fluorobenzenesulfonyl chloride as the starting materials. MS (ES+) m/e 443, 445 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[CH:30][N:31]2[CH2:34][C:35](O)=[O:36])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)(O)[O-].[Na+].Cl.S1C(N)=NC=N1>>[O:1]=[C:2]1[CH2:7][N:6]([C:35](=[O:36])[CH2:34][N:31]2[C:32]3[C:28](=[CH:27][CH:26]=[C:25]([C:24]([F:38])([F:23])[F:39])[CH:33]=3)[CH:29]=[CH:30]2)[CH2:5][CH2:4][N:3]1[C:8]1[CH:9]=[CH:10][C:11]([S:14]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)(=[O:16])=[O:15])=[CH:12][CH:13]=1
Reactant: O=C(O)Cn1ccc2ccc(C(F)(F)F)cc21
Reactant: O=C1CNCCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(Cn1ccc2ccc(C(F)(F)F)cc21)N1CCN(c2ccc(S(=O)(=O)Nc3nccs3)cc2)C(=O)C1
Yield: 34.5 %

Procedure:
Synthesized according to general procedure 14, method A. The reaction was set up with 4-(2-oxopiperazin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (100 mg, 0.29 mmol), 2-(6-(trifluoromethyl)-1H-indol-1-yl)acetic acid (71 mg, 0.29 mmol), HATU reagent (220 mg, 0.58 mmol), sodium bicarbonate (74 mg, 0.87 mmol), and DMF/CH2Cl2-1/1 (0.50 mL) to obtain the desired amide as a white solid (55 mg, 0.10 mmol, 34% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 7.91 (s, 1H), 7.85 (d, J=8.4 Hz, 2H), 7.75 (d, J=8.3 Hz, 1H), 7.58 (dd, J=5.1, 8.4 Hz, 2H), 7.52-7.48 (m, 1H), 7.32-7.27 (m, 2H), 6.85 (d, J=4.6 Hz, 1H), 6.61 (d, J=2.9 Hz, 1H), 5.40 (d, J=9.8 Hz, 2H), 4.49 (s, 1H), 4.22 (s, 1H), 4.01 (s, 2H), 3.81 (s, 2H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA), m/z: M+1 obs=564.4; tR=3.17 min.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[ClH:4].[CH2:5]=O.[CH2:7]1[CH2:17][C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1>O>[ClH:4].[CH3:1][NH:2][CH3:3].[ClH:4].[CH3:1][N:2]([CH2:5][CH:17]1[CH2:7][CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15]1=[O:16])[CH3:3]
Reactant: O=C1CCCc2ccccc21
Reactant: C=O
Agent: CNC
Agent: Cl
Solvent: O
Product: CN(C)CC1CCc2ccccc2C1=O

Procedure:
First, 6.83 g of a 50% by mass aqueous dimethylamine solution (dimethylamine: 75.9 mmol) was added to a 100-ml two-necked flask. Next, 8.19 g of a 35% by mass aqueous solution of hydrochloric acid (hydrochloric acid: 78.9 mmol) was added to a 100-ml dropping funnel. Subsequently, the dropping funnel was set to the two-necked flask, and then the aqueous solution of hydrochloric acid was added dropwise to the aqueous dimethylamine solution under ice-cooling. Thus, dimethylamine hydrochloride was prepared in the two-necked flask. Next, 2.78 g (92.4 mmol) of paraformaldehyde as the formaldehyde derivative and 9.0 g (61.6 mmol) of α-tetralone as the carbonyl compound were further added to the two-necked flask. Note that the volume of the mixture made of water and paraformaldehyde present in the two-necked flask was 25 mL, and the concentration of hydrochloric acid (HCl) in the mixture was 0.12 mol/L. Subsequently, a bulb condenser was set to the two-necked flask, and then the inside of the two-necked flask was replaced with nitrogen. Thereafter, the two-necked flask was immersed in an oil bath of 90° C., and heated for 4 hours with stirring. Thus, a reaction liquid was obtained. Note that the thus obtained reaction liquid was subjected to HPLC analysis for components in the reaction liquid. As a result, the conversion of α-tetralone was found to be 99%, and the yield (HPLC yield) of N,N-dimethylaminomethyl-1-tetralone hydrochloride (the Mannich base) was found to be 95%.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][CH:6]=1)[CH2:2][C:3]#[CH:4].Br[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1>C(N(CC)CC)C.C(Cl)Cl.[Cu]I.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>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:4]#[C:3][CH2:2][CH2:1][C:5]2[CH:6]=[CH:7][C:8]([CH2:11][OH:12])=[CH:9][CH:10]=2)=[N:15][CH:16]=1
Reactant: C#CCCc1ccc(CO)cc1
Reactant: Brc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCc1ccc(CCC#Cc2ccc(Br)cn2)cc1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
Under an N2 atmosphere 130 mg (0.67 mmol) CuI and 300 mg (0.42 mmol) Pd(PPh3)2Cl2 are added to a solution of 2.0 g (12.48 mmol) (4-but-3-ynyl-phenyl)-methanol and 3.2 g (13.1 mmol) 2,5-dibromopyridine in 80 mL triethylamine and the reaction mixture is stirred for 1.5 h at 50° C. The solvent is eliminated in vacuo, the residue dissolved in a little DCM and purified by chromatography on silica gel (gradient: cyc/EtOAc 4:1 to cyc/EtOAc 3:1).