Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:62])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:61])[C:48]([NH:56][C:57]([O:59][CH3:60])=[O:58])([C:50]6[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=6)C)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:63]([O:67]C(N1CCCC1C(O)=O)=O)(C)(C)C.COC(NC(C1C=CC=CC=1)C(O)=O)=O.COC(NC(C1C=CC=CC=1)(C)C(O)=O)=O>>[CH3:1][O:2][C:3](=[O:62])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH:45]([O:67][CH3:63])[CH2:44][N:43]6[C:47](=[O:61])[CH:48]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]6[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=6)=[N:40][CH:41]=5)=[CH:35][CH:36]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(C)(NC(=O)OC)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Agent: COC(=O)NC(C(=O)O)c1ccccc1
Agent: COC(=O)NC(C)(C(=O)O)c1ccccc1
Product: COC(=O)NC(C(=O)N1CC(OC)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1

Procedure:
[1-(2-{5-[6-(4-{2-[4-Methoxy-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester was prepared following the procedure for [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester, substituting 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester for Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and Methoxycarbonylamino-phenyl-acetic acid for 2-Methoxycarbonylamino-2-phenyl-propionic acid. LCMS-ESI+: calc'd for C48H52N8O7: 852.40 (M+); Found: 853.43 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([C:13]([C:16]1[CH:17]=[C:18]([CH:33]=[CH:34][CH:35]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([OH:32])[CH:23]=1)=[O:20])([CH3:15])[CH3:14])#[N:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:11]([C:13]([C:16]1[CH:17]=[C:18]([CH:33]=[CH:34][CH:35]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[C:24]([O:32][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH:23]=1)=[O:20])([CH3:15])[CH3:14])#[N:12]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C(F)(F)F)c(O)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C(F)(F)F)c(Oc3ccc([N+](=O)[O-])cn3)c2)c1
Temperature: 80 °C
Reaction time: 20 h
Yield: 66.3 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (2.00 g, 5.74 mmol) and 3-(1-cyano-1-methylethyl)-N-[3-hydroxy-4-(trifluoromethyl)phenyl]benzamide (955 mg, 6.02 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (1.18 g, 8.61 mmol), and the mixture was stirred at 80° C. for 20 hr. After the reaction mixture was cooled to room temperature, water (150 mL) was added, and the mixture was twice extracted with ethyl acetate/hexane (75 mL/75 mL). The combined organic layer was washed with saturated brine (150 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→30/70). The obtained solution was concentrated under reduced pressure to give the title compound (1.79 g, 66%) as a yellow amorphous substance.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH2:15][NH:16][CH3:17].[CH2:18]([O:25][C:26]([NH:28][C@@H:29]([C:31](O)=[O:32])[CH3:30])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC2N(O)N=NC=2C=1.O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH2:15][NH:16][CH2:17][C:31](=[O:32])[C@@H:29]([CH3:30])[NH:28][C:26]([O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:27]
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1F
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)CNCc1cc(C(=O)OC(C)(C)C)ccc1F
Reaction time: 16 h
Yield: 73.3 %

Procedure:
To a stirred solution of tert-butyl 4-fluoro-3-(methylaminomethyl)benzoate (2.42 g, 10.1 mmole) in DMF (75 mL) was added N-(benzyloxycarbonyl)-D-alanine (2.45 g, 11 mmole) and HOBt H2O (1.5 g, 11 mmole), followed by DCC (2.4 g, 11.6 mmole). The reaction was stirred for 16 h then was concentrated to dryness. Purification by flash chromatography on silica gel (30% EtOAc/hexanes) gave the title compound (3.29 g, 73%) as a clear oil: 1H NMR (300 MHz, CDCl3) mixture of amide rotamers δ 7.90-7.95 (m, 1 H), 7.81 (dd, 1 H), 7.31-7.32 (m, 5 H), 7.08 (t, 1 H), 5.72 & 5.83 (2 d, J=7.8 Hz, 1 H), 5.11 (s, 2 H), 4.89 (d, J=15.3 Hz, 1 H), 4.72-4.77 (m, 1 H), 4.47 (d, J=15.3 Hz 2.92 & 3.05 (2s, 3 H), 1.56(s, 9 H), 1.37 & 1.40(2 d, J =6.8Hz, 3 H).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:13][C@H:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[CH2:11][C@@H:10]1[C@H:23]1[O:27]C(C)(C)[N:25]([C:30](=[O:32])[CH3:31])[C@H:24]1[CH2:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[C:36]([F:41])[CH:35]=1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[F:41][C:36]1[CH:35]=[C:34]([CH:39]=[C:38]([F:40])[CH:37]=1)[CH2:33][C@H:24]([NH:25][C:30](=[O:32])[CH3:31])[C@H:23]([OH:27])[C@H:10]1[CH2:11][C@@H:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[CH2:13][NH:9]1
Reactant: COc1ccccc1O[C@@H]1C[C@H]([C@H]2OC(C)(C)N(C(C)=O)[C@H]2Cc2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccccc1O[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(C)=O)C1
Reaction time: 1 h
Yield: 100 %

Procedure:
Add 4M hydrogen chloride in dioxane (3 mL) to (2R,4R)-2-[(4S,5S)-3-acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-(2-methoxy-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.061 g, 0.21 mmol). Stir 1 h and concentrate to give the title compound as a foam (0.05 g, 100%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[N:14]=[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:12]=2[CH3:28])[CH:3]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[NH:63]1[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][C:4]3[CH:3]=[C:2]([N:63]4[CH2:68][CH2:67][O:66][CH2:65][CH2:64]4)[CH:9]=[CH:8][C:5]=3[C:6]#[N:7])=[C:12]([CH3:28])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Oc1cc(Br)ccc1C#N
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Oc1cc(N2CCOCC2)ccc1C#N

Procedure:
Prepared according to general Procedure H using 4-bromo-2-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yloxy)benzonitrile (70 mg, 0.16 mmol), tris(dibenzylideneacetone)dipalladium(0) (7.4 mg, 0.008 mmol), X-Phos (7.7 mg, 0.016 mmol), morpholine (28 mg, 0.32 mmol) and sodium tert-butoxide (31 mg, 0.32 mmol) in toluene (6.9 mL) and heating at reflux for 2 h. After purification 2-((7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)oxy)-4-(4-morpholinyl)benzonitrile was obtained. 1H NMR (400 MHz, chloroform-d) δ ppm 8.68-8.78 (1H, m), 7.86-7.95 (3H, m), 7.82 (1H, dd, J=10.0, 2.5 Hz), 7.57 (1H, d, J=8.6 Hz), 7.41 (1H, ddd, J=6.7, 4.6, 2.3 Hz), 7.30-7.36 (1H, m), 6.56 (1H, dd, J=9.0, 2.3 Hz), 5.83 (1H, d, J=2.3 Hz), 3.69 (4H, dd, J=6.1, 3.7 Hz), 2.90-3.10 (4H, m), 2.30-2.46 (3H, s). Mass Spectrum (ESI) m/e=441.0 (M+1).
Reaction SMILES: [C:1](=O)([O-:58])[O:2][CH:3]([C@](C)(CI)C(=O)[C@H](CC(C)C)NC(=O)[C@H](CC1C=CC=CC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC1C=CC=CC=1)NC(=O)CN1CCOCC1)[C:4]#[CH:5].C(O)C#C.[CH3:64][S:65]([O:68][CH2:69][C@:70]([OH:120])([CH3:119])[C:71](=[O:118])[C@H:72]([CH2:114][CH:115]([CH3:117])[CH3:116])[NH:73][C:74](=[O:113])[C@H:75]([CH2:106][C:107]1[CH:112]=[CH:111][CH:110]=[CH:109][CH:108]=1)[NH:76][C:77](=[O:105])[C@H:78]([CH2:101][CH:102]([CH3:104])[CH3:103])[NH:79][C:80](=[O:100])[C@H:81]([CH2:92][CH2:93][C:94]1[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=1)[NH:82][C:83](=[O:91])[CH2:84][N:85]1[CH2:90][CH2:89][O:88][CH2:87][CH2:86]1)(=[O:67])=[O:66]>>[CH3:64][S:65]([O:68][CH2:69][C:70]([CH3:119])([O:120][C:1]([O:2][CH2:3][C:4]#[CH:5])=[O:58])[C:71](=[O:118])[C@H:72]([CH2:114][CH:115]([CH3:116])[CH3:117])[NH:73][C:74](=[O:113])[C@H:75]([CH2:106][C:107]1[CH:112]=[CH:111][CH:110]=[CH:109][CH:108]=1)[NH:76][C:77](=[O:105])[C@H:78]([CH2:101][CH:102]([CH3:104])[CH3:103])[NH:79][C:80](=[O:100])[C@H:81]([CH2:92][CH2:93][C:94]1[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=1)[NH:82][C:83](=[O:91])[CH2:84][N:85]1[CH2:86][CH2:87][O:88][CH2:89][CH2:90]1)(=[O:66])=[O:67]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)[C@](C)(O)COS(C)(=O)=O
Reactant: C#CC(OC(=O)[O-])[C@](C)(CI)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1
Agent: C#CCO
Product: C#CCOC(=O)OC(C)(COS(C)(=O)=O)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1

Procedure:
Prepared according to the procedure for (4S,7S,10S,13S,15S)-10-benzyl-16-iodo-7,13-diisobutyl-15-methyl-1-morpholino-2,5,8,11,14-pentaoxo-4-phenethyl-3,6,9,12-tetraazahexadecan-15-ylprop-2-yn-1-yl carbonate, except using propargyl alcohol and (4S,7S,10S,13S,15R)-10-benzyl-15-hydroxy-7,13-diisobutyl-15-methyl-1-morpholino-2,5,8,11,14-pentaoxo-4-phenethyl-3,6,9,12-tetraazahexadecan-16-yl methanesulfonate.
Reaction SMILES: [OH-].[Na+].S(O[CH2:8][C:9]([NH2:12])([CH3:11])[CH3:10])(O)(=O)=O.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>O>[CH3:10][C:9]([NH2:12])([CH3:11])[CH2:8][S:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(N)COS(=O)(=O)O
Reactant: Sc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(N)CSc1ccccc1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
In 5 ml of water was dissolved 0.20 g (5 mmol) of sodium hydroxide, followed by adding thereto 0.85 g (5 mmol) of 2-amino-2-methylpropyl hydrogensulfate and 0.66 g (6 mmol) of thiophenol, and the resulting mixture was stirred at 80° C. for 8 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and acidified with 6N hydrochloric acid. The aqueous layer was washed with ethyl acetate and made basic with an aqueous sodium hydroxide solution, and the desired compound was extracted three times with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby 0.52 g of 2-methyl-1-phenylthio-2-propylamine was obtained (yield: 57%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[CH3:14].[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25]Br>O1CCCC1.O>[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25][CH:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[CH3:14]
Reactant: Clc1ccccc1CCBr
Reactant: CCc1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: CC(CCc1ccccc1Cl)c1ccncc1
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 58.8 %

Procedure:
In a 200-ml flask, 0.94g (9.35 mmol) of diisopropyl amine and 15 ml of tetrahydrofuran were placed and cooled to -50° C. Then 6.5 ml (10.3 mmol) of n-butyl lithium (15% n-hexane solution) was added thereto under nitrogen atmosphere. The resulting mixture was stirred for 10 minutes, and a solution of 1.0 g (9.35 mmol) of 4-ethylpyridine dissolved in tetrahydrofuran was added dropwise. After stirring for 30 minutes at -50° C., the reaction temperature was gradually raised up to -10° C., which was kept for 30 minutes, and lowered again to -50° C. A solution of 2.05 g (9.35 mmol) of 2-chlorophenethyl bromide dissolved in tetrahydrofuran was added dropwise to the reaction mixture, and after stirring for 30 minutes at -50° C., the temperature was raised up to room temperature. Subsequently, water was added, tetrahydrofuran was distilled away under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, then dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure, to obtain an oil. Said oil was purified by silica gel column chromatography, to obtain 1.35 g of the desired compound (yield: 58.2%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[N:14]=[CH:13][N:12]([CH2:15][C:16]([OH:18])=O)[N:11]=2)=[O:8])=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1>C1COCC1>[CH3:19][N:20]1[CH2:21][CH2:22][CH:23]([N:26]2[CH2:31][CH2:30][N:29]([C:16](=[O:18])[CH2:15][N:12]3[CH:13]=[N:14][C:10]([NH:9][C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:8])=[N:11]3)[CH2:28][CH2:27]2)[CH2:24][CH2:25]1
Reactant: O=C(O)Cn1cnc(NC(=O)c2ccc(Cl)s2)n1
Reactant: CN1CCC(N2CCNCC2)CC1
Solvent: C1CCOC1
Product: CN1CCC(N2CCN(C(=O)Cn3cnc(NC(=O)c4ccc(Cl)s4)n3)CC2)CC1

Procedure:
Using general method A, using THF instead of DMF as solvent, {3-[(5-chloro-thiophene-2-carbonyl)-amino]-[1,2,4]triazol-1-yl}-acetic acid (example 61.3) was reacted with 1-(N-methyl-4-piperidyl)-piperazine to give 5-chloro-thiophene-2-carboxylic acid (1-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-1H-[1,2,4]triazol-3-yl)-amide. Off-white solid. MS 452.3 ([M+H]+)
Reaction SMILES: FC(F)C1N2N=C(N3CCNCC3)C=CC2=NN=1.[F:19][CH:20]([F:48])[C:21]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][C:22]=1[CH2:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[CH:32][C:33]3[N:34]([C:36]([C:39](F)([F:41])[F:40])=[N:37][N:38]=3)[N:35]=2)[CH2:26][CH2:25]1>>[F:41][CH:39]([F:40])[C:36]1[N:34]2[N:35]=[C:30]([N:27]3[CH2:26][CH2:25][N:24]([CH2:23][C:22]4[CH:43]=[C:44]([F:47])[CH:45]=[CH:46][C:21]=4[CH:20]([F:19])[F:48])[CH2:29][CH2:28]3)[CH:31]=[CH:32][C:33]2=[N:38][N:37]=1
Reactant: Fc1ccc(C(F)F)c(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1
Agent: FC(F)c1nnc2ccc(N3CCNCC3)nn12
Product: Fc1ccc(C(F)F)c(CN2CCN(c3ccc4nnc(C(F)F)n4n3)CC2)c1
Yield: 58 %

Procedure:
Obtained in 58% yield by General Synthetic Method 5, starting from 3-(difluoromethyl)-6-(piperazin-1-yl)-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Examples 248-263, preparation of starting materials) and 2-difluoromethyl-5-fluorobenzaldehyde (obtained as described in Example 779, preparation of starting materials).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][O:5][C:4]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[C:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[C:19]([CH:26]=O)=[CH:18]1.[ClH:28]>C(O)C>[ClH:28].[NH:17]1[C:25]2=[N:24][CH:23]=[CH:22][CH:21]=[C:20]2[C:19]([CH:26]=[C:6]2[O:5][C:4]([N:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)=[C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]2=[O:1])=[CH:18]1
Reactant: CCOC(=O)C1=C(N2CCCC2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=C(N2CCCC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 61 %

Procedure:
To a solution of ethyl 4-oxo-2-pyrrolidinyl-4,5-dihydrofuran-3-carboxylate (0.034 g, 0.15 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.022 g, 0.15 mmol) in ethanol (1.0 mL), 2M hydrochloric acid in ethanol (0.16 mL, 0.32 mmol) was added at ambient temperature. The mixture was refluxed for 3 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.038 g, y. 61%).
Reaction SMILES: CS(C)=O.[N+:5](/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=1)([O-:7])=[O:6].C(O)(=O)C.[BH4-].[Na+]>O>[N+:5]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=1)([O-:7])=[O:6]
Reactant: O=[N+]([O-])/C=C/c1cccc(Oc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1cccc(Oc2ccccc2)c1
Reaction time: 0.05 h
Yield: 68.1 %

Procedure:
To a dimethyl sulfoxide (30.0 mL) solution of 1-((E)-2-nitro-vinyl)-3-phenoxy-benzene (3.60 g, 14.9 mmol) described in Manufacturing Example 64-1-1 and acetic acid (3.00 mL) was added sodium borohydride (902 mg, 23.8 mmol) at room temperature while cooling appropriately under nitrogen atmosphere, which was stirred for 3 minutes. Water was then added dropwise at room temperature while cooling appropriately. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduce pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:5) to obtain the title compound (2.47 g, 68.1%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](=[O:7])[CH2:3][CH:2]=1.[N+:8]([O-])([OH:10])=[O:9].S(=O)(=O)(O)O>>[OH:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: O=C1C=CN=CC1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cnccc1O
Temperature: 100 °C

Procedure:
4-Hydroxy-3-nitropyridine was prepared by addition of 4-pyridone (50 g, 0.532M) to a mixture of fuming nitric acid and sulfuric acid. The resulting solution was heated for 1 hour at 100° C. The solution was cooled and poured into 500 mL of ice water and the desired product was obtained as a solid. (mp. 280° C.)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9](Cl)[C:8]([Cl:13])=[C:7]([Cl:14])[N:6]=1)=[O:4].[F-:15].[Cs+]>CC#N.CCOC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([F:15])[C:8]([Cl:13])=[C:7]([Cl:14])[N:6]=1)=[O:4]
Reactant: [F-]
Reactant: COC(=O)c1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(Cl)c(Cl)c(F)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3,4,5,6-tetrachloropyridine-2-carboxylic acid methyl ester (1.00 equivalent) in MeCN is added CsF (1.00 equivalent) at room temperature. The resulting mixture is refluxed with stirring for 16 hours. The reaction mixture is cooled to room temperature and diluted with EtOAc and water. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product that is purified by flash column chromatography as necessary.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[C:12]([C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[C:12]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:7][C:6]2[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=2)=[CH:26][CH:25]=1)#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCCCCC#Cc1ccc(C=O)cc1
Product: CCCCCCCCCCC#Cc1ccc(CNc2ccc(C(F)(F)F)cc2)cc1
Yield: 42 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-(trifluoromethyl)aniline and 4-dodec-1-ynylbenzaldehyde gave the title compound as a pale yellow oil (42%). 1H NMR (CDCl3, 300 MHz) δ 7.40-7.23 (m, 8H), 4.35 (s, 2H), 2.40 (m, 2H), 1.62-1.27 (m, 16H), 0.88 (t, 3H, J=6.8 Hz). HPLC (Condition A), Rt: 7.0 min (HPLC purity: 99.4%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:14]3([CH2:17][N:16]([C:18](OC(C)(C)C)=[O:19])[CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[CH2:40][N:41]=C=O.C(N(CC)CC)C>ClCCl.C(#N)C>[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[CH2:40][NH:41][C:18]([N:16]1[CH2:15][C:14]2([N:11]([S:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)(=[O:9])=[O:10])[CH2:12][CH2:13]2)[CH2:17]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CC2(CCN2S(=O)(=O)c2ccc(F)cc2)C1
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NCc1ccc(Cl)cc1Cl)N1CC2(CCN2S(=O)(=O)c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a solution of tert-butyl 1-(4-fluorophenylsulfonyl)-1,6-diazaspiro[3.3]heptane-6-carboxylate (452 mg, 1.27 mmol) in dichloromethane (8 mL) was added trifluoroacetic acid (489 μl, 6.34 mmol). After 2 h at ambient temperature, another amount of trifluoroacetic acid was added (300 μl, 3.89 mmol). The reaction mixture was stirred for 1.5 h at ambient temperature and concentrated under reduced pressure. The residue was partitioned in toluene (10 mL) and then concentrated, this procedure was repeated twice to give the unpurified amine (540 mg), which was used directly in the next step without further purification. To a solution of the obtained 1-(4-fluorophenylsulfonyl)-1,6-diazaspiro[3.3]heptanes in acetonitrile (10 mL) was added 2,4-dichloro-1-(isocyanatomethyl)benzene (216 μl, 1.47 mmol) followed by triethylamine (294 μl, 2.11 mmol) and the mixture was stirred for 1 h at ambient temperature. The solvent was evaporated in vacuo and the resulting solid was purified by chromatography (SiO2; heptane:ethyl acetate 1:4 to dichloromethane/methanol/ammonia 95:4.5:0.5) to give the titled compound (530 mg, 91%) as colorless solid. HRMS (EI): 457.0431 (exact mass calculated for C19H17Cl2FN3O3S ([M]+)=457.0430).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=1[F:34]>>[F:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([F:34])[C:27]=1[O:26][CH2:25][CH2:24][CH2:23][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: Fc1cccc(F)c1OCCCBr
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3c(F)cccc3F)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.820 g of 2-(3-bromopropoxy)-1,3-difluorobenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.70 (1:1 EtOAc-heptane); Rt=5.26.