Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S([O:26][C@@H:27]([CH2:29][C@H:30](O)[CH3:31])[CH3:28])(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C>[C:3]1([C:9]2[CH:10]=[CH:11][C:12]([O:15][C@H:30]([CH2:29][C@@H:27]([OH:26])[CH3:28])[CH3:31])=[CH:13][CH:14]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)O[C@H](C)C[C@@H](C)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](O)C[C@H](C)Oc1ccc(-c2ccccc2)cc1
Reaction time: 3 h

Procedure:
0.26 g of 55% sodium hydride was mixed with 5 ml of DMF and 0.85 g of 4-phenylphenol was added dropwise thereto. After the completion of the reaction, 1.42 g of optically active (R,R)-2,4-pentanediol monotosylate in 5 ml of DMF was added dropwise thereto. After reacting at 90° C. for three hours, the reaction mixture was treated in a conventional manner. Then it was purified by silica gel column chromatography with the use of a mixture of n-hexane with ethyl acetate (7/3) as a developing solvent. Thus 0.77 g of optically active (S,S)-2-(4'-phenylphenoxy)pentan-4-ol was obtained. Separately, 0.08 g of 55% sodium hydride was mixed with 3 ml of DMF and a solution of 0.49 g of 5-n-decylpyrimidine in 3 of DMF was added dropwise thereto. Then a solution of 0.71 g of the (S,S)-2-(4'-phenylphenoxy)pentane-4-ol tosylate obtained above in 3 ml of DMF was added dropwise thereto and the obtained mixture was stirred at 90° C. for five hours. After cooling, the reaction mixture was poured into 100 ml of ice/water, extracted with ethyl ether, dried and freed of the solvent. The residue was then purified by silica gel column chromatography with the use of a mixture of n-hexane with ethyl acetate (8/2) as a developing solvent. Thus 0.82 g of optically active (s,S)-2-(4'-phenylphenoxy)-4-[4'-(5"-dicylpyrimidin-2"-yl)phenoxy]pentane was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([Br:11])=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([Br:11])=[N:8][C:7]=1[CH2:12][Br:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)c1sc(Br)nc1CBr
Yield: 98.8 %

Procedure:
2-Bromo-4-methyl-thiazole-5-carboxylic acid ethyl ester (17 g, 68.0 mmol, purchased from Ryan Scientific), N-bromosuccinimide (12.7 g, 71.4 mmol), and benzoyl peroxide (1.65 g, 6.8 mmol) were suspended in 222 mL of benzene and heated at reflux temperature for 16 h. The reaction mixture was cooled and diluted with ethyl acetate. The reaction mixture was washed successively with saturated bicarbonate solution, brine, saturated ammonium chloride solution, and brine. The organic solvent was dried, filtered, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-20% ethyl acetate in hexanes to produce 22.1 g of a light yellow solid. 1H NMR (CDCl3, 200 MHz): δ=4.88 (s, 2H), 4.37 (q, 2H, J=7.0 Hz), and 1.39 (t, 3H, J=7.0 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[C:16]1([N:22]2[CH:26]=[N:25][C:24]([NH2:27])=[N:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:15][C:13]1[N:12]=[CH:11][N:10]([C:5]2[CH:4]=[CH:3][C:2]([NH:27][C:24]3[N:25]=[CH:26][N:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:23]=3)=[CH:9][C:6]=2[C:7]#[N:8])[CH:14]=1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Nc1ncn(-c2ccccc2)n1
Product: Cc1cn(-c2ccc(Nc3ncn(-c4ccccc4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-phenyl-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a brownish solid (Yield=64%). MS ISP (m/e): 340.4 (100) [(M+H)+].
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3I)[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:35][C:36]1[C:41]([CH:42]([CH3:44])[CH3:43])=[CH:40][C:39](B(O)O)=[C:38]([O:48][CH3:49])[CH:37]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>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.CCO>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3[C:39]3[CH:40]=[C:41]([CH:42]([CH3:44])[CH3:43])[C:36]([F:35])=[CH:37][C:38]=3[O:48][CH3:49])[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(OC(F)(F)F)ccc1I
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C

Procedure:
In a microwave tube were placed (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one (41.6 mg, 0.0679 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (18 mg, 0.085 mmol), DME (305 μL), EtOH (100 μL), and 1M aqueous Na2CO3 (140 μL, 0.140 mmol). The mixture was degassed with N2. Next, Pd(PPh3)4 (4 mg, 3.4×10−3 mmol) was added and the mixture was degassed again with N2. The tube was sealed and irradiated in a microwave for 10 minutes at 150° C. and 200 W. The reaction was then cooled to room temperature, diluted with EtOAc (40 mL), and washed with water and brine (15 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (2 to 15% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethoxy)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.24 (15% EtOAc/hexanes). LCMS=654.3 (M+1)+. 1H NMR (CDCl3, 500 MHz, rotamers present) δ 7.85 (s, 1H), 7.69 (s, 2H), 7.21-7.30 (m, 4H), 6.95-7.00 (m, 1H), 6.65-6.68 (m, 1H), 5.59 (d, J=8.0 Hz), 5.41 (d, J=8.0 Hz), 4.74-4.81 (m, 1H), 3.75-4.09 (m, 5H), 3.19 (m, 1H), 1.16-1.27 (m, 6H), 0.51 (d, J=6.7 Hz), 0.36 (d, J=6.6 Hz).
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23]CC2C=CC([N+]([O-])=O)=CC=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]2[CH2:54][CH2:53][C@H:52]([N:55](C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C:56]([NH2:58])=[NH:57])[CH2:51]2)=[O:49])[CH2:43]1>>[NH:55]([C@H:52]1[CH2:53][CH2:54][N:50]([C:48]([C@@H:44]2[CH2:43][C@H:42]([S:41][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([OH:23])=[O:22])[CH2:46][N:45]2[CH3:47])=[O:49])[CH2:51]1)[C:56]([NH2:58])=[NH:57]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: CN1C[C@@H](S)C[C@H]1C(=O)N1CC[C@H](N(C(=N)N)C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](NC(=N)N)C4)N(C)C3)[C@H](C)[C@H]12

Procedure:
A procedure similar to that described in Example 101 was repeated, but using 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (prepared as described in preparation 123) and (2S,4S)-4-mercapto-1-methyl-2-[(3S)-3-(4-nitrobenzyloxycarbonylguanidino)pyrrolidin-1-ylcarbonyl]pyrrolidine (prepared as described in Preparation 99) as starting materials, in relative proportions similar to those used in that Example, to obtain the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH:11]([O:12][C:13](=[O:15])[CH3:14])[CH:10]([O:16][C:17](=[O:19])[CH3:18])[CH:9]([O:20][C:21](=[O:23])[CH3:22])[CH:8]([O:24][C:25]2[CH:29]=[CH:28][S:27][C:26]=2[CH:30]=O)[O:7]1)(=[O:3])[CH3:2].[C:32](=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][CH2:5][CH:6]1[CH:11]([O:12][C:13](=[O:15])[CH3:14])[CH:10]([O:16][C:17](=[O:19])[CH3:18])[CH:9]([O:20][C:21](=[O:23])[CH3:22])[CH:8]([O:24][C:25]2[CH:29]=[CH:28][S:27][C:26]=2[CH:30]=[CH2:32])[O:7]1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)OCC1OC(Oc2ccsc2C=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1sccc1OC1OC(COC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O

Procedure:
3.30 g of 3,4,5-triacetoxy-6-(2-formyl-thiophen-3-yloxy)-tetrahydropyran-2-ylmethyl actate were dissolved in 60 ml of dioxane. 6.43 g of methyltriphenylphosphonium bromide, 5.37 g of potassium carbonate and 0.25 ml of water were added, and the solution was refluxed for 4 h. The solution was concentrated and purified by column filtration. 2.89 g of the product with the molecular weight: 456.47 (C20H24O10S), MS (ESI): 479.10 (M+Na+); 474.10 (M+NH4+) were obtained.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[CH:6]=1)[CH2:3][OH:4].[OH-].[Na+].[Cl:15][CH2:16][C:17](Cl)=[O:18]>C(Cl)Cl>[Cl:15][CH2:16][C:17]([NH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[CH:6]=1)[CH2:3][OH:4])=[O:18]
Reactant: NC(CO)c1ccc(F)c(F)c1
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCl)NC(CO)c1ccc(F)c(F)c1
Reaction time: 0.25 h

Procedure:
To a solution of 2-amino-2-(3,4-difluorophenyl)-ethanol 2.6 g, 15.0 mmol) in CH2Cl2 (15 mL) and 20% (by wt.) NaOH (15 mL) was added a solution of chloroacetyl chloride (1.32 mL, 16.5 mmol) in 15 mL of CH2Cl2 at −10° C. dropwise under argon atmosphere. After the addition was complete, the reaction mixture was stirred for 15 min and then it was transferred to a separatory funnel. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic extracts were washed with a solution containing 10 mL of brine and 5 drops of concentrated HCl. The organic layer was dried over MgSO4, filtered and the solvent was removed in vacuo to give a white solid. It was further purified with flash column chromatography on silica gel with 1:1 hexane/EtOAc followed by EtOAc as the eluting system. 2-Chloro-N-[1-(3,4-difluoro-phenyl)-2-hydroxy-ethyl]-acetamide was obtained as a white solid (2.6 g, 69.5% yield).
Reaction SMILES: [ClH:1].[CH2:2]([NH:4][C:5](=[O:30])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:29])[C@H:12]([CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:28])[NH2:27])[NH:13][C:14](=[O:21])[C@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[NH2:16])[CH3:3].[CH2:31]([O:38][C:39]([NH:41][C@@H:42]([C:50](O)=[O:51])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[ClH:1].[CH2:2]([NH:4][C:5](=[O:30])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:29])[C@H:12]([CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:27])[NH2:28])[NH:13][C:14](=[O:21])[C@H:15]([CH2:17][CH:18]([CH3:19])[CH3:20])[NH:16][C:50](=[O:51])[C@@H:42]([CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[NH:41][C:39]([O:38][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:40])[CH3:3]
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 23 °C
Reaction time: 72 h

Procedure:
A mixture of the above product g), 900 mg. of Nα -benzyloxycarbonyl-D-phenylalanine [cf. Yajima and Kubo, J. Am. Chem. Soc., 87, 2039 (1965)] and 400 mg. of 1-hydroxybenztriazole is dissolved in 40 ml. of dimethylformamide and then cooled and treated with 700 mg. of dicyclohexylcarbodiimide. The reaction is stirred at 23° C. for three days, filtered and the filtrate evaporated at 50° C. and under reduced pressure. The residue is obtained solid by repeated precipitation from methanol by ether and by ethyl acetate and ether; liquifies 130°-135° C.; [α]D23 -69° (c 1.02, methanol); ultraviolet in methanol λmax 258 E11 5.8.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[N:22]3[CH:23]=[CH:24][N:25]=[C:26](Cl)[C:21]3=[C:20]([I:28])[N:19]=2)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:30]>CC(O)C>[CH2:1]([O:8][C:9](=[O:29])[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[N:22]3[CH:23]=[CH:24][N:25]=[C:26]([NH2:30])[C:21]3=[C:20]([I:28])[N:19]=2)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC[C@H]1CC[C@H](c2nc(I)c3c(Cl)nccn32)CC1)OCc1ccccc1
Reactant: N
Solvent: CC(C)O
Product: Nc1nccn2c1c(I)nc2[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Temperature: 110 °C

Procedure:
A solution of benzyl{[trans-4-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methyl}carbamate (1.70 g, 0.00324 mol) in IPA (30 mL) was cooled to −78° C., treated with a stream of ammonia gas over 3 min. and then heated at 110° C. in a Parr vessel overnight. The reaction solution was concentrated in vacuo and residue washed with water to afford 1.37 g of desired product. 1H NMR (400 MHz, CDCl3): δ=1.08-1.17 (m, 2H), 1.88 (m, 1H), 1.71-1.81 (m, 2H), 1.91-1.94 (m, 2H), 2.00-2.04 (m, 2H), 2.90 (m, 1H), 3.13 (t, J=6.4 Hz, 2H), 4.86 (br, 1H), 5.11 (s, 2H), 5.76 (br, 2H), 7.00 (d, J=5.2 Hz, 1H), 7.22 (d, J=5.2 Hz, 1H), 7.31-7.37 (m, 5H). MS (ES+): m/z 5.7.36 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:21][C:20]2[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: COC(=O)c1cn(Cc2ccc([N+](=O)[O-])cc2)c2ccccc12

Procedure:
1-(4-Nitro-benzyl)-1H-indole-3-carboxylic acid methyl ester (I13220-11) was prepared from 1H-indole-3-carboxylic acid methyl ester and 4-nitrobenzyl bromide followed the procedure of Example 3 Step 1 as a yellow powder: 1H NMR (DMSO-d6) δ 3.83 (s, 3H), 5.70 (s, 2H), 7.23 (ddd, J=9.9, 4.6, 0.8 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 7.50 (ddd, J=9.9, 4.6, 0.8 Hz, 1H), 8.05 (ddd, J=9.9, 4.6, 0.8 Hz, 1H), 8.19 (d, J=8.8 Hz, 2H), 8.40 (s, 1H); MS (ESI) m/z 311 (MH+), 309 ([M−H]−).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:7][C:8]1([CH2:21][NH2:22])[C:13]2[NH:14][C:15]3[C:20]([C:12]=2[CH2:11][CH2:10][O:9]1)=[CH:19][CH:18]=[CH:17][CH:16]=3.C(N(CC)CC)C>O1CCCC1>[CH3:7][C:8]1([CH2:21][NH:22][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[C:13]2[NH:14][C:15]3[C:20]([C:12]=2[CH2:11][CH2:10][O:9]1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: CCCC(=O)Cl
Reactant: CC1(CN)OCCc2c1[nH]c1ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)NCC1(C)OCCc2c1[nH]c1ccccc21
Yield: 94.4 %

Procedure:
Butanoyl chloride (5.3 g) is added to a stirring mixture at 0° C. of 1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indole-1-methanamine (10.0 g, described in Example 3), triethylamine (5 g) and dry tetrahydrofuran (400 ml). The temperature is allowed to rise to room temperature, the reaction mixture is filtered, and the filtrate is evaporated to give the title compound (12.5 g): ir(CHCl3) 3420, 3250, 2855 and 1660 cm-1 ; nmr(CDCl3) δ0.75(t), 1.57(s), 1.62(m), 2.08(t), 2.87(m), 3.91(t), 4.10(t), 6.12(s), 7.0-7.7(m) and 9.86(s)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)[CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11].[C:24]1([CH3:42])[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=[C:32]([C:38]([F:41])([F:40])[F:39])[N:31]=2)[CH:25]=1>C(#N)C.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]([NH:37][CH2:36][C:35]2[C:30]([C:26]3[CH:25]=[C:24]([CH3:42])[CH:29]=[CH:28][CH:27]=3)=[N:31][C:32]([C:38]([F:41])([F:39])[F:40])=[CH:33][CH:34]=2)=[O:23])[CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][S:10]([CH3:13])(=[O:11])=[O:12]
Reactant: Cc1cc(NC(=O)Oc2ccccc2)ccc1CNS(C)(=O)=O
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)Nc2ccc(CNS(C)(=O)=O)c(C)c2)c1
Temperature: 50 °C
Reaction time: 15 h
Yield: 87.9 %

Procedure:
To a stirred solution of phenyl 3-methyl-4-(methylsulfonamidomethyl)-phenylcarbamate (46 mg, 0.137 mmol) and (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (36 mg, 0.137 mmol) in acetonitrile were added 4-dimethylaminopyridine (17 mg, 0.137 mmol). The reaction mixture was stirred for 15 h at 50° C. The mixture dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. N-(2-Methyl-4-(3-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)ureido)benzyl)methanesulfonamide (example 81) (61 mg) was obtained as 88% yield.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([Cl:52])=[C:34]([N:36]2[CH2:45][C:44]3[C:39](=[N:40][C:41]([S:46]([CH3:49])(=[O:48])=[O:47])=[N:42][CH:43]=3)[N:38]([CH3:50])[C:37]2=[O:51])[CH:35]=1>O1CCCC1.ClCCl>[Cl:52][C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:11]3[CH:12]=[CH:13][C:8]([CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:9][CH:10]=3)=[CH:19][CH:18]=2)=[O:21])=[CH:35][C:34]=1[N:36]1[CH2:45][C:44]2[C:39](=[N:40][C:41]([S:46]([CH3:49])(=[O:47])=[O:48])=[N:42][CH:43]=2)[N:38]([CH3:50])[C:37]1=[O:51]
Reactant: CN1C(=O)N(c2cc(N)ccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Reactant: O=C(O)c1ccc(-c2ccc(CN3CCOCC3)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1C(=O)N(c2cc(NC(=O)c3ccc(-c4ccc(CN5CCOCC5)cc4)cc3)ccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
300 mg of 4′-Morpholin-4-ylmethyl-biphenyl-4-carboxylic acid in 15 ml dry tetrahydrofuran (THF) were treated dropwise with 129 mg oxalyl chloride under cooling with ice. The mixture was subsequently stirred for 20 min at room temperature (RT) before a suspension of 200 mg aniline derivative from example d in 5 ml dichloromethane was added slowly. The mixture was stirred over night and then diluted with 50 ml dichloromethane. Precipitate was filtered off and the filtrate was washed several times with conc. aqueous sodium carbonate solution. The organic phase was dried, evaporated and purified by flash chromatography on silica, using a gradient from dichloromethane to dichloromethane/methanol (60/1) to dichloromethane/methanol/concentrated ammonia (60/1/0.2).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.[C:10]([C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])#[CH:11]>>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[C:11]#[C:10][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: C#C[C@H]1CCCN1C(=O)OC(C)(C)C
Reactant: Nc1ccc(Br)cc1I
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C#Cc1cc(Br)ccc1N
Yield: 89 %

Procedure:
(R)-tert-butyl 2-((2-amino-5-bromophenyl)ethynyl)pyrrolidine-1-carboxylate (4.32 g) was prepared via Sonogashira coupling according to the general procedure described in Example 156, Step 1, from 4-bromo-2-iodoaniline (3.96 g, 13.29 mmol) and (R)-tert-butyl 2-ethynylpyrrolidine-1-carboxylate (3.25 g, 16.64 mmol) in 89% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]([NH:9][S@@](C(C)(C)C)=O)[CH3:8].[ClH:16].O1CCOCC1>CO>[ClH:16].[ClH:16].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]([NH2:9])[CH3:8]
Reactant: C[C@@H](N[S@](=O)C(C)(C)C)c1ccccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H](N)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-2-methyl-propane-2-sulfinic acid ((R)-1-pyridin-2-yl-ethyl)-amide (1.10 g, 4.86 mmol) in MeOH (12 mL) was added 4.0 M hydrogen chloride in dioxane (3.04 mL, 12.1 mmol). The reaction mixture was stirred at room temperature for 30 min then concentrated and dried under high vacuum to afford 1.0 g of (R)-1-pyridin-2-yl-ethylamine dihydrochloride as a light yellow solid. 1H NMR (METHANOL-d4, 300 MHz): δ (ppm) 8.80 (t, J=3.8 Hz, 1H), 8.32 (tdd, J=7.9, 4.5, 1.7 Hz, 1H), 7.88 (dd, J=7.9, 4.5 Hz, 1H), 7.72-7.83 (m, 1H), 4.78 (qd, J=6.9, 4.5 Hz, 1H), 1.73 (dd, J=6.9, 4.5 Hz, 3H). Assume 82% ee based on 10:1 dr of the starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16](O)[CH3:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15].P(Br)(Br)[Br:20].O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]([Br:20])[CH3:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15]
Reactant: BrP(Br)Br
Reactant: CC(O)c1ccc(CC2CCCCC2=O)c(Cl)c1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccc(CC2CCCCC2=O)c(Cl)c1
Reaction time: 1 h

Procedure:
Forty (40) grams of 1-[3-chloro-4-(2-oxocyclohexane-1-yl methyl)phenyl]ethanol were dissolved in 300 ml of carbon tetrachloride and then incorporated dropwise with 44.7 g of phosphorus tribromide at a temperature of -15° to -10° C., after which the whole was stirred at said temperature for 30 minutes, withdrawn from the ice bath and then further stirred for one hour. After the completion of the reaction, the reaction mixture was water washed, dried and then freed of the solvent at a reduced pressure to obtain a residue. The residue was adhered to a silica gel-packed column and then eluted with isopropyl ether-hexane (1/2), after which the eluate was freed of the solvent thereby to obtain 46.5 g of 1-[3-chloro-4-(2-oxocyclohexane-1-yl methyl)phenyl]ethylbromide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:11](OC(=O)C)(=[O:13])[CH3:12].S(=O)(=O)(O)O>O>[C:11]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[C:7]#[N:8])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1cc(Cl)ccc1O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc(Cl)cc1C#N
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
5-Chloro-2-hydroxybenzonitrile (39.25 g, 0.25 mol) and acetic anhydride (40 ml) were combined, to which 0.5 ml of concentrated sulfuric acid was added. The reaction mixture was stirred at 60° C. for 10 minutes, followed by the addition of water. Subsequent to extraction with ethyl acetate, the organic layer was washed with 1 N aqueous solution of sodium hydroxide and a saturated aquous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, whereby 45 g of 2-acetoxy-5-chlorobenzonitrile were obtained as a brown solid (yield: 92%). It was provided for immediate use in the next step.