Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:37]=[CH:36][C:16]([CH2:17][N:18]([CH2:30][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26]C)=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].CCOC(C)=O>CCO>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:37]=[CH:36][C:16]([CH2:17][N:18]([CH2:30][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([OH:26])=[O:25])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(CCC(C)(C)C)c3ccc(F)c(C(=O)OC)c3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCc1ccc(C#Cc2ccc(CN(CCC(C)(C)C)c3ccc(F)c(C(=O)O)c3)cc2)cc1
Temperature: 65 °C
Yield: 85.8 %

Procedure:
Methyl 5-[{4-[(4-butylphenyl)ethynyl]benzyl}(3,3-dimethylbutyl)amino]-2-fluorobenzoate (541 mg; 1.08 mmol) was dissolved in 10 mL of EtOH and sodium hydroxide (649.63 μl; 5.00 M, 3.25 mmol) was added. The reaction mixture was stirred at 65° C. for 2h30. The reaction mixture was allowed to cool down and EtOAc (50 mL) was added. The organic layer was washed three times with HCl (1M), dried over MgSO4, filtered and concentrated under reduced pressure to afford 450 mg (86%) of the title compound as a yellow solid. HPLC, Rt: 5.97 min (purity: 98.9%); LC/MS M+(ESI): 486.2, M−(ESI)=484.0; 1H NMR (CDCl3) δ: 7.44 (m, 4H), 7.32 (m, 1H), 7.20 (d, J=9.8 Hz, 2H,), 7.14 (d, J=8.3 Hz, 2H), 6.97 (m, 1H), 6.91-6.75 (m, 1H), 4.48 (s, 2H), 3.42 (m, 2H), 2.60 (t, J=7.7 Hz, 2H), 1.65-1.46 (m, 4H), 1.40-1.28 (m, 2H), 0.99-0.87 (m, 12H).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([CH:17]([NH:23][C:24]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:48])[CH2:33][CH2:34][CH:35]4[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]4)[CH2:27]3)=[O:25])[CH2:18][C:19]([O:21]C)=[O:20])[CH:14]=[N:15][CH:16]=2)=[CH:7][CH:6]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>CO>[C:44]([O:43][C:41]([N:38]1[CH2:39][CH2:40][CH:35]([CH2:34][CH2:33][C:32]([N:28]2[CH2:29][CH2:30][CH2:31][C@@H:26]([C:24]([NH:23][CH:17]([C:13]3[CH:14]=[N:15][CH:16]=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][F:1])=[CH:6][CH:7]=4)[CH:12]=3)[CH2:18][C:19]([OH:21])=[O:20])=[O:25])[CH2:27]2)=[O:48])[CH2:36][CH2:37]1)=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccc(OCCF)cc2)c1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)NC(CC(=O)O)c3cncc(-c4ccc(OCCF)cc4)c3)C2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
76 mg (0.11 mmol) tert-butyl 4-(3-{(3R)-3-[(1-{5-[4-(2-fluoroethoxy)phenyl]pyridin-3-yl}-3-methoxy-3-oxopropyl)carbamoyl]piperidin-1-yl}-3-oxopropyl)piperidine-1-carboxylate were dissolved in 14 ml methanol. 358.5 mg (1.14 mmol) barium hydroxide octahydrate were added. The mixture was stirred at room temperature for 20 hours and then concentrated to give 3-({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]carbonyl}amino)-3-{5-[4-(2-fluoroethoxy)phenyl]pyridin-3-yl}propanoic acid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([N+:15]([O-])=O)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]N(C=O)C>>[O:1]([C:8]1[CH:9]=[C:10]2[C:11]([CH:14]=[CH:18][NH:15]2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(Oc2ccccc2)cc1[N+](=O)[O-]
Reactant: CN(C)C=O
Product: c1ccc(Oc2ccc3cc[nH]c3c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine 4-phenoxy-1-methyl-2-nitro-benzene (6 g, 26.2 mmol) and DMF dimethylacetal (15.6 g, 131 mmol) in 60 mL dry DMF and heat at 170° C. for 16 hours. Cool to room temperature and concentrate to dryness. Dissolve residue in 50 mL EtOAc and hydrogenate with 2 g 5% Pd/C and hydrogen for 3 hours at atmospheric pressure. Filter through celite and concentrate to an oil. Purify by chromatography using Hex/EtoAC to obtain a tan solid: ISMS 210 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br.Br[CH2:26][C:27]([C:29]1[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][N:30]=1)=[O:28]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:26]=1[C:27]([C:29]1[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][N:30]=1)=[O:28]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: Cc1cnc(C(=O)CBr)c(C)c1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2ncc(C)cc2C)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(penylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 2-bromoacetyl-3,5-dimethylpyridine hydrobromide*.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)=[O:8].Cl[CH2:27][O:28][C:29]([N:31]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:30]>>[CH2:36]([O:35][C:33]([CH2:32][N:31]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:29]([O:28][CH2:27][O:25][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:11]=1)=[O:8])=[O:30])=[O:34])[CH3:37]
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Reactant: CCOC(=O)CN(CC(=O)OCC)C(=O)OCCl
Product: CCOC(=O)CN(CC(=O)OCC)C(=O)OCOc1ccc(Cl)cc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 38.6 %

Procedure:
Using 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide 1 sodium salt (compound of Example 43(1)) and diethyl N-[(chloromethoxy)carbonyl]iminodiacetate as the raw materials, the same operation as the Example 98 gave the title compound.
Reaction SMILES: [CH2:1]1[O:16][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24]>C(O)(C)C>[CH2:23]([NH:24][CH2:1][CH:2]([OH:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][CH2:1][CH:2]([OH:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: NCCCCCCN
Reactant: CCCCCCCCCCCCCC1CO1
Solvent: CC(C)O
Product: CCCCCCCCCCCCCC(O)CNCCCCCCNCC(O)CCCCCCCCCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-pentadecene oxide (81.7 g.) and hexamethylenediamine (21 g.) and recrystallization of the resulting product (74.3 g.) from isopropyl alcohol gave N,N'-(1,6-hexylene)-bis[2-hydroxypentadecylamine] (I: R = CH3 (CH2)12, R' = H, X = (CH2)6, Z = H) (m.p. 117.4°-124.0° C.).
Reaction SMILES: O[CH2:2][C:3]#[N:4].[CH2:5]([NH2:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>CO>[CH2:5]([NH:17][CH2:2][C:3]#[N:4])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCN
Reactant: N#CCO
Solvent: CO
Product: CCCCCCCCCCCCNCC#N
Reaction time: 16 h

Procedure:
In a flask of 500 ml provided with a magnetic stirrer, 4.56 gr of hydroxyacetonitrile (0.08 mol) were mixed at room temperature with 16.3 gr of dodecylamine (0.088 mol) in 250 ml of methanol. The mixture was allowed to stand for 16 hours at room temperature and methanol was evaporated. The obtained liquid was distilled under 10-2 mm Hg. The fraction distilling between 106° and 116° crystallizes after cooling.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[S:7][C:6]=2[CH:11]=1.[C:12]([O:16][CH2:17][CH2:18][N:19]=[C:20]=[O:21])(=[O:15])[CH2:13][CH3:14]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C(C(C)=O)C>[C:12]([O:16][CH2:17][CH2:18][NH:19][C:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[S:7][C:6]=2[CH:11]=1)=[O:21])(=[O:15])[CH2:13][CH3:14]
Reactant: O=c1oc2ccc(O)cc2s1
Reactant: CCC(=O)OCCN=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCC(C)=O
Product: CCC(=O)OCCNC(=O)Oc1ccc2oc(=O)sc2c1
Reaction time: 12.5 h

Procedure:
5-hydroxy-1,3-benzoxathiol-2-one (16.8 grams) was mixed with 2-(isocyanato)ethyl propionate (15.0 grams) and 10 drops of dibutyltin dilaurate in 200 milliliters of methyl ethyl ketone. The resulting solution was heated at reflux temperature for four hours and fifteen minutes, after which the solvent was removed by evaporation in vacuo, leaving a brown, viscous oil which crystallized upon standing at room temperature for 10 to 15 hours. The crude product was twice recrystallized from toluene. The purified compound, 5-[2-(propionyloxy)ethylcarbamoyloxy]-1,3-benzoxathiol-2-one, was a white, fibrous crystalline substance with a melting point of 78°-79° C. Elemental analysis calculated for C13H13NO6S (percent): carbon--50.15; hydrogen--4.21; nitrogen--4.50. Found: carbon--50.4; hydrogen--4.27; nitrogen--4.45.
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][NH:13][CH2:14][C:7]=3[C:6]=2[C:5]([Br:15])=[CH:4][CH:3]=1.[C:16](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:14][C:7]=3[C:6]=2[C:5]([Br:15])=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1ccc(Br)c2c3c([nH]c12)CCNC3
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Brc1ccc(Br)c2c3c([nH]c12)CCN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C3
Temperature: 25 °C
Yield: 114.3 %

Procedure:
A suspension of 6,9-dibromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (700 mg, 2.121 mmol) in dichloromethane (10 mL) was stirred on an ice-water bath and treated with TEA (0.591 mL, 4.24 mmol), DMAP (25.9 mg, 0.212 mmol) and trityl chloride (1.183 g, 4.24 mmol). The mixture was allowed to warmed to room temperature and stirred for 71 h. The solution was concentrated under vacuum and the residue was subjected to column chromatography on silica gel (120 g), eluting with EtOAc-hexane (gradient from 5:95 to 50:50) to provide the desired product as a yellow glassy foam (1.388 g) contaminated with a trityl derivative (probably trityl chloride or triphenylmethanol), estimated purity 75% (estimated yield of desired product 82%). This material was used without further purification. LCMS m/z 243.2 (trityl cation), 329, 331, 333 (M+H-trityl)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][CH3:11])[N:5]=[C:4]([NH2:12])[CH:3]=1.[C:13](Cl)([CH3:15])=[O:14]>N1C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][CH3:11])[N:5]=[C:4]([NH:12][C:13](=[O:14])[CH3:15])[CH:3]=1
Reactant: CCc1nc(N)cc(N)c1C#N
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CCc1nc(NC(C)=O)cc(N)c1C#N
Yield: 68 %

Procedure:
The 4,6-diamino nicotinonitrile from Example 101A (35 mg, 0.22 mmol) was dissolved in 0.5 mL of anhydrous pyridine. AcCl was then dropped in until the TLC shows the starting material was completely consumed (appr. 150 μL of AcCl used). Water was then added, the light-yellow precipitate was collected through filtration and dried in vacuum oven to provide the titled compound (30 mg, 68% yield). 1H NMR (300 MHz, DMSO-d6) δ 10.28 (s, 1H), 7.39 (s, 1H), 6.82 (s, 2H), 2.66 (q, J=7.5 Hz, 2H), 2.06 (s, 3H), 1.19 (t, J=7.5 Hz, 3H). MS (ESI) m/e 205 (M+H)+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:8])=[CH:4][CH:3]=1.[Cl:17][CH:18]([Cl:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@H:23]([OH:34])[C:24]1[CH:29]=[CH:28][C:27]([Sn](C)(C)C)=[CH:26][CH:25]=1)=[O:20]>>[Cl:17][CH:18]([Cl:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@@H:23]([C:24]1[CH:25]=[CH:26][C:27]([C:2]2[S:6][C:5]([CH:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:8])=[CH:4][CH:3]=2)=[CH:28][CH:29]=1)[OH:34])=[O:20]
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Br)s1
Product: CC(NC(=O)OC(C)(C)C)c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1
Yield: 30.8 %

Procedure:
The compound is prepared from tert-butyl (1-(5-bromothiophen-2-yl)ethyl)-carbamate (138 mg, 0.45 mmol) and 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethylstannyl)phenyl)propan-2-yl)acetamide (200 mg, 0.45 mmol) in a manner analogous to Example 74, Step 2 to give the title compound (70 mg): 1H-NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 1.57 (d, J=6.8 Hz, 3H), 2.68 (bs, 1H), 4.25-4.38 (m, 1H), 4.42-4.48 (m, 0.5H), 4.53-4.60 (m, 1H), 4.65-4.72 (m, 0.5H), 4.77-4.89 (m, 1H), 4.98-5.09 (m, 1H) 5.11 (d, J=4.0 Hz, 1H), 5.87 (s, 1H), 6.90 (d, J=3.5 Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 7.14 (d, J=3.8 Hz, 1H), 7.37 (d, J=8.1 Hz, 2H), 7.55 (m, 2H).
Reaction SMILES: [Na].Cl.[NH2:3][C:4]([NH2:6])=[NH:5].Cl.Cl[C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][N:21]=2)[CH:12]=1)=[O:10]>CO>[C:20]1([N:13]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:19]3[C:11]([C:9]([NH:5][C:4]([NH2:6])=[NH:3])=[O:10])=[CH:12]2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][N:21]=1
Reactant: O=C(Cl)c1cn(-c2nccc3ccccc23)c2ncccc12
Reactant: N=C(N)N
Agent: Cl
Agent: [Na]
Solvent: CO
Product: N=C(N)NC(=O)c1cn(-c2nccc3ccccc23)c2ncccc12

Procedure:
0.397 g (17.28 mmol) of sodium (washed beforehand in toluene) was gradually added to 40 cm3 of methanol at a temperature in the region of 20° C. under an argon atmosphere. After dissolving with stirring, 1.685 g (17.28 mmol) of guanidine hydrochloride were added and the mixture was stirred at a temperature in the region of 20° C. for 1 h 30. The reaction mixture was filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue was subsequently taken up in a mixture of 70 cm3 of tetrahydrofuran and 70 cm3 of dichloromethane under an argon atmosphere at a temperature in the region of 20° C. and then 3.46 mmol of 3-chlorocarbonyl-1-(isoquinolin-1-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride were added thereto with stirring. After stirring at a temperature in the region of 20° C. for 15 h, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa). The solid residue was taken up in 100 cm3 of water and stirred for 2 h, and then the insoluble material was filtered off. The solid was dried and then triturated in 20 cm3 of cyclohexane. The solid was filtered off and then dried at a temperature in the region of 20° C. under reduced pressure (2.7 kPa) and 0.784 g of N-[1-(isoquinolin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine was thus obtained in the form of a light yellow solid melting at 250° C. 1H N.M.R. spectrum (300 MHz, (CD3)2SO, δ in ppm): 7.31 (dd, J=8 and 5 Hz, 1H), 7.58 (broad d, J=8.5 Hz, 1H), 7.66 (ddd, J=8.5, 7.5 and 1 Hz, 1H), 7.89 (ddd, J=8.5, 7.5 and 1 Hz, 1H), 8.09 (d, J=5.5 Hz, 1H), from 8.10 to 8.25 (mt, 2H), 8.29 (s, 1H), 8.56 (d, J=5.5 Hz, 1H), 8.90 (dd, J=8 and 1.5 Hz, 1H).
Reaction SMILES: CI.[CH2:3]([S:5]([C:8]1[C:9]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:30][CH3:31])([O:28][CH3:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6])[CH3:4].[C:32](=O)([O-])[O-].[K+].[K+].CC(C)=O>O.CN(C=O)C>[CH2:3]([S:5]([C:8]1[C:9]([C:14]([N:16]([CH3:32])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:28][CH3:29])([O:30][CH3:31])[C:24]([F:25])([F:27])[F:26])=[CH:19][CH:18]=2)=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:6])=[O:7])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCS(=O)(=O)c1cccnc1C(=O)Nc1ccc(C(OC)(OC)C(F)(F)F)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: CCS(=O)(=O)c1cccnc1C(=O)N(C)c1ccc(C(OC)(OC)C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 104.9 %

Procedure:
1.0 g of methyl iodide was added to a mixture of 0.12 g of 3-ethylsulfonyl-N-[4-(2,2,2-trifluoro-1,1-dimethoxyethyl)phenyl]picolinamide (Compound of Present Invention 42), 0.15 g of potassium carbonate, 2 mL of acetone and 2 mL of DMF, and the mixture was stirred at 80° C. for 3 hours. Water was added to the reaction mixture cooled to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.13 g of 3-ethylsulfonyl-N-methyl-N-[4-(2,2,2-trifluoro-1,1-dimethoxyethyl)phenyl]picolinamide (hereinafter, referred to as Compound of Present Invention 43).
Reaction SMILES: [Se](=O)=[O:2].[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([CH3:15])=[N:12]2)=[CH:7][CH:6]=1>O1CCOCC1>[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([CH:15]=[O:2])=[N:12]2)=[CH:7][CH:6]=1
Reactant: Cc1ccc2ccc(Br)cc2n1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=Cc1ccc2ccc(Br)cc2n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 124.8 %

Procedure:
Selenium dioxide (1.6 g, 14 mmol, 1.3 eq) was suspended in dioxan (50 mL) and was heated to 60° C. At this temperature 7-bromoquinaldine (2.5 g, 11.2 mmol) was introduced and the mixture was left at 80° C. for 3 hours. After cooling the mixture to room temperature, the crude slurry was filtered on celite, eluted with dioxan and concentrated under reduced pressure. The product was obtained pure as a brown solid (3.3 g, >98%) that was used without furter purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:49][O:50][CH:51]([O:54][CH3:55])[CH2:52][NH2:53]>CN(C=O)C>[CH3:49][O:50][CH:51]([O:54][CH3:55])[CH2:52][NH:53][C:13](=[O:15])[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:17])[CH3:16]
Reactant: COC(CN)OC
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(CNC(=O)C(C)(C)NC(=O)OCc1ccccc1)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-(benzyloxycarbonylamino)-2-methylpropanoic acid (20 g, 0.084 mol), HATU (CAN 148893-10-1, 41.56 g, 0.11 mol) and N-methylmorpholine (CAN 109-02-4, 25.54 g, 0.253 mol) in DMF (400 mL) was stirred at room temperature for 10 min. 2,2-Dimethoxyethanamine (CAN 22483-09-6, 9.75 g, 0.093 mol) was added and the mixture was stirred overnight. After evaporation of solvents, the residue was diluted with methylene chloride (500 mL) and saturated sodium bicarbonate solution (500 mL). After being separated, the organic layer was washed with 5 N citric acid solution (500 mL), brine (500 mL) and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure left a yellow oil (27 g, 99%) which was used in the next reaction step without further purification. 1H NMR (300 MHz, CDCl3): δ 7.36-7.33 (m, 5H), 6.44-6.38 (b, 1H), 5.31 (s, 1H), 5.09 (s, 2H), 4.34-4.33 (m, 1H), 3.40-3.37 (m, 8H), 2.06-2.03 (m, 6H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:22])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][CH:20]=1)[O:17][C:12]1([CH2:16][CH2:15][NH:14][CH2:13]1)[CH2:11][C:10]2=[O:21].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C([O-])(O)=O.[Na+]>[CH3:2][O:3][C:4](=[O:22])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][CH:20]=1)[O:17][C:12]1([CH2:16][CH2:15][N:14]([CH2:28][C:27]3[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=3)[CH2:13]1)[CH2:11][C:10]2=[O:21]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCNC1)O2
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccc(F)cc3)C1)O2
Yield: 98.7 %

Procedure:
A suspension of Intermediate 1 (250 mg, 0.77 mmol) in aqueous 10% NaHCO3 solution was extracted with DCM (3×10 ml). The organic phase was dried over Na2SO4 and evaporated. The resulting solid was dissolved in DCM (10 ml), treated with 4-fluoro-benzaldehyde (0.090 ml, 0.85 mmol) and NaBH(OAc)3 (245 mg, 1.15 mmol) as described in Example 2, Step A, to give (±)-(E)-3-[1′-(4-fluoro-benzyl)-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester (300 mg, 0.76 mmol, 99%) as a light brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([Cl:30])[N:25]=2)[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][N:16]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([Cl:30])[N:25]=2)[CH:19]=1)[S:32]([CH3:31])(=[O:34])=[O:33])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCNCc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CS(=O)(=O)Cl
Product: CC(C)(C)OC(=O)N1CCCCC1CCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O

Procedure:
Intermediate 57 was coupled with methanesulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 509.
Reaction SMILES: [NH2:1][C:2]1[C:17]([OH:18])=[CH:16][C:15]([Br:19])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:5].[CH:20]([N:23]1[CH2:28][CH2:27][CH:26]([C:29](O)=[O:30])[CH2:25][CH2:24]1)([CH3:22])[CH3:21].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C.O.C(N(CC)CC)C>[ClH:13].[Br:19][C:15]1[CH:16]=[C:17]([OH:18])[C:2]([NH:1][C:29]([CH:26]2[CH2:27][CH2:28][N:23]([CH:20]([CH3:22])[CH3:21])[CH2:24][CH2:25]2)=[O:30])=[C:3]([C:4](=[O:5])[NH:6][C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=2)[CH:14]=1
Reactant: Nc1c(O)cc(Br)cc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(C)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)N1CCC(C(=O)Nc2c(O)cc(Br)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 72.7 %

Procedure:
2-Amino-5-bromo-N-(5-chloro-2-pyridyl)-3-hydroxybenzamide (2.39 g) and 1.32 g of 1-isopropylpiperidine-4-carboxylic acid were dissolved in 35 ml of N,N-dimethylformamide, then 2.02 g of 1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride, 1.42 g of 1-hydroxybenzotriazole and 1.46 ml of triethylamine were added thereto and the mixture was stirred at room temperature for 22 hours. To the reaction solution were added 105 ml of water and 105 ml of ethyl acetate, the mixture was stirred at room temperature for 3 hours and the resulting precipitate was filtered, washed with ethyl acetate and water and dried in vacuo. The resulting solid was suspended in 60 ml of ethanol, 5 ml of 1N hydrochloric acid were added thereto and the mixture was stirred at room temperature for 30 hours. The resulting precipitate was filtered, washed with ethanol and dried in vacuo to give 1.35 g of 4′-bromo-2′-[(5-chloro-2-pyridyl)carbamoyl]-6′-hydroxy-1-isopropylpiperidine-4-carboxanilide hydrochloride.