Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([O:22][C:23]1[CH:27]=[CH:26][O:25][N:24]=1)[CH2:20]N)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cl:28][CH2:29][CH2:30][CH2:31][S:32]([NH:35]CC(OC)CSCCCCCCCCCCCCCCCC)(=[O:34])=[O:33]>>[Cl:28][CH2:29][CH2:30][CH2:31][S:32]([NH:35][CH:18]([S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:19]([O:22][C:23]1[CH:27]=[CH:26][O:25][N:24]=1)[CH3:20])(=[O:34])=[O:33]
Reactant: CCCCCCCCCCCCCCCCSCC(CN)Oc1ccon1
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Product: CCCCCCCCCCCCCCCCSC(NS(=O)(=O)CCCCl)C(C)Oc1ccon1

Procedure:
3-Hexadecylthio-2-(3-isoxazolyloxy)propylamine IVJ1 is allowed to react and worked up by the same procedure as described in (4). The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:11]1[CH:12]=[CH:13][C:14]([C:21]#[N:22])=[C:15]([CH:20]=1)[C:16](OC)=[O:17])([CH3:10])([CH3:9])[CH3:8].[OH-].[Na+]>CCOCC>[NH2:22][CH2:21][C:14]1[CH:13]=[CH:12][C:11]([C:7]([CH3:8])([CH3:10])[CH3:9])=[CH:20][C:15]=1[CH2:16][OH:17]
Reactant: COC(=O)c1cc(C(C)(C)C)ccc1C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)c1ccc(CN)c(CO)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 256.9 %

Procedure:
Lithium aluminium hydride (105 mg) was supended in ether (3 ml) and the suspension was cooled to 0° C. To the suspension was added dropwise a solution of the compound 13-6 (140 mg) prepared by Step 2 in ether (4 ml) and the mixture was refluxed for 2 hours. After the completion of the reaction, the reaction mixture was basified with 5 N aqueous sodium hydroxide solution, followed by adding aqueous Rochel solution thereto and then stirring for 1 hour. Then, the resulting mixture was extracted with ether (50 ml×3) and concentrated under reduced pressure to yield the compound 13-7 (320 mg, 90%). The following Step 4 was proceeded using the compound 13-7 which was not purified
Reaction SMILES: [C:1]([O:5][C:6]1[C:11]([F:12])=[C:10](F)[N:9]=[C:8]([F:14])[C:7]=1[CH3:15])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[C:1]([O:5][C:6]1[C:11]([F:12])=[C:10]([N:23]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:9]=[C:8]([F:14])[C:7]=1[CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(F)nc(F)c(F)c1OC(C)(C)C
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CCO
Product: Cc1c(F)nc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1OC(C)(C)C

Procedure:
4-t-Butoxy-2,5,6-trifluoro-3-methylpyridine from Step 253c above is reacted with dibenzylamine in ethanol at reflux temperature. Solvent is removed, and the residue is dissolved in methylene chloride and washed with water. The product is purified by column chromatography.
Reaction SMILES: Cl.[N:2]1([CH:7]2[CH2:22][C:11]3[C:12]4[NH:13][C:14](=[O:21])[C:15](=[O:20])[NH:16][C:17]=4[CH:18]=[CH:19][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[N+:23]([O-])([OH:25])=[O:24]>FC(F)(F)C(O)=O>[N+:23]([C:19]1[C:10]2[CH2:9][CH2:8][CH:7]([N:2]3[CH2:6][CH2:5][CH2:4][CH2:3]3)[CH2:22][C:11]=2[C:12]2[NH:13][C:14](=[O:21])[C:15](=[O:20])[NH:16][C:17]=2[CH:18]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]c2ccc3c(c2[nH]c1=O)CC(N1CCCC1)CC3
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2cc([N+](=O)[O-])c3c(c2[nH]c1=O)CC(N1CCCC1)CC3
Reaction time: 2 h

Procedure:
A mixture of 9-pyrrolidin-1-yl-1,4,7,8,9,10-hexahydrobenzo[f]quinoxaline-2,3-dione hydrochloride (35 mg) in trifluoroacetic acid (2 mL) was cooled in an ice bath and treated with 0.5 mL fuming nitric acid. After 2 h at room temperature, the solvent was evaporated and the residue suspended in acetone:water, and the resulting solid collected by filtration (35 mg). Calc'd for C16H18N4O4.HCl: C, 52.39; H, 5.22; H, 15.27; found: C, 42.95; H, 4.69; N, 16.28. MS M+1 (331).
Reaction SMILES: N[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]([CH:35](OC)OC)[CH2:10][CH2:11][CH2:12][C:13]2[CH:34]=[CH:33][C:16]([C:17]([NH:19][C@H:20]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:18])=[CH:15][CH:14]=2)=[C:4]([NH2:40])[N:3]=1.Cl.[NH3:42]>C(O)C.O>[NH2:42][C:2]1[N:7]=[C:6]([NH2:8])[C:5]2[C:9]([CH2:10][CH2:11][CH2:12][C:13]3[CH:34]=[CH:33][C:16]([C:17]([NH:19][C@H:20]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:18])=[CH:15][CH:14]=3)=[CH:35][NH:40][C:4]=2[N:3]=1
Reactant: N
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCCC(c2c(N)nc(N)nc2N)C(OC)OC)cc1)C(=O)OCC
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCCc2c[nH]c3nc(N)nc(N)c23)cc1)C(=O)OCC
Temperature: 25 °C

Procedure:
To a suspension of the product of Example 17 (100 mg) in ethyl alcohol (2.0 ml), ethyl alcohol containing 20% (w/w) of hydrogen chloride (2.0 ml) and water (0.02 ml) were added and the mixture was heated at room temperature for 2 hours. The reaction mixture was diluted with water (10 ml), and neutralized by adding aqueous ammonia thereto, followed by removing solvent therefrom by distillation under reduced pressure. The resulting residue was purified by column chromatography (15 g of silica gel; dichloromethane separated from conc. ammonia→dichloromethane separated from conc. ammonia-ethanol=40:1→30:1) to give the subject compound (68 mg).
Reaction SMILES: [Si]([C:8]1[S:9][C:10]([CH2:37][CH2:38][CH3:39])=[C:11]([CH2:13][C@H:14]2[C@@H:18]([CH2:19][O:20][Si](C(C)(C)C)(C)C)[O:17][C:16]([CH3:29])([CH3:28])[N:15]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:12]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:20][CH2:19][C@H:18]1[O:17][C:16]([CH3:29])([CH3:28])[N:15]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[C@H:14]1[CH2:13][C:11]1[N:12]=[CH:8][S:9][C:10]=1[CH2:37][CH2:38][CH3:39]
Reactant: CCCc1sc([Si](C)(C)C(C)(C)C)nc1C[C@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)N1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCc1scnc1C[C@H]1[C@@H](CO)OC(C)(C)N1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
(4S,5S)-Tert-butyl 4-((2-(tert-butyldimethylsilyl)-5-propylthiazol-4-yl)methyl)-5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate was dissolved in THF (3 mL) and cooled to 0° C. when TBAF (0.808 ml, 0.808 mmol) was added. The reaction was stirred one hour before being quenched with saturated ammonium chloride. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine and dried over sodium sulfate to afford the title compound.
Reaction SMILES: [C:1]([CH2:8][CH2:9][CH2:10][NH:11][NH2:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1F)[C:24]#[N:25]>CN(C=O)C>[C:1]([CH2:8][CH2:9][CH2:10][N:11]([NH2:12])[C:28]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=1[Cl:20])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)CCCNN
Reactant: N#Cc1ccc(F)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)CCCN(N)c1ccc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
3.49 g (20 mmol) 3-Boc-amino-propylamine in 5 ml DMF are combined with 2.75 ml (25 mmol) NMM. After the addition of 3.11 g (20 mmol) 3-chloro-4-fluoro-benzonitrile the mixture is stirred for 3.5 hours at ambient temperature under a nitrogen atmosphere, heated to 105° C. for 20 minutes and extracted with ethyl acetate. The combined organic phases are washed with water and sat. sodium chloride solution, dried over magnesium sulphate and evaporated down i. vac. The residue is further reacted without any more purification.
Reaction SMILES: Br[CH:2]([CH3:6])[C:3](=[O:5])[CH3:4].[I-].[K+].[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O.O>[O:15]([CH:2]([CH3:6])[C:3](=[O:5])[CH3:4])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1ccccc1
Reactant: CC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CC(=O)C(C)Oc1ccccc1

Procedure:
A mixture of 3-bromobutan-2-one (75.5 g.) and finely-powdered potassium iodide (1 g.) in ethyl methyl ketone (50 ml.) was added dropwise, over 25 minutes, to a stirred, refluxing mixture of phenol (47 g.) and dry potassium carbonate (82 g.) in ethyl methyl ketone (100 ml.) Stirring and refluxing were continued for a total of 5 hours and the mixture was cooled, poured into water (cs. 500 ml.) and extracted with ether. The ether extract was washed exhaustively with 5N-sodium hydroxide, dried over anhydrous sodium sulphate and evaporated. The residue was distilled to give pure 3-phenoxybutan-2-one, b.p. 110°-112°/14 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15](=[O:19])[NH:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:20]([CH3:23])=[N:21][O:22][C:11]=3[CH2:10][N:9]=2)=[CH:4][CH:3]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)#[N:25]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15](=[O:19])[N:16]([C:29]4[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[CH:27][CH:28]=4)[CH:17]=[CH:18][C:13]=3[C:12]3[C:20]([CH3:23])=[N:21][O:22][C:11]=3[CH2:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1noc2c1-c1cc[nH]c(=O)c1C(c1ccc(Cl)cc1)=NC2
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: Cc1noc2c1-c1ccn(-c3ccc(C#N)cc3)c(=O)c1C(c1ccc(Cl)cc1)=NC2
Temperature: 40 °C
Yield: 82.1 %

Procedure:
6-(4-Chlorophenyl)-1-methyl-4H-isoxazolo[4,5-e]pyrido[3,4-c]azepin-7(8H)-one (0.025 g, 0.077 mmol), 4-cyanophenylboronic acid (0.023 g, 0.153 mmol), copper(II) acetate (0.035 g, 0.192 mmol) and pyridine (1 mL) were charged into a vial equipped with a stir bar. The reaction was heated to 40° C. for 3 h in an open vial (to allow contact with air) before silica gel was added. Then the pyridine was removed under vacuum. The dry silica gel was packed and the adsorbed product was purified by flash chromatography (hexane/EtOAc 19:1 to 4:6) to give 4-(6-(4-chlorophenyl)-1-methyl-7-oxo-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-8(7H)-yl)benzonitrile as an off-white solid (0.027 g). 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J=6.87 Hz, 1H), 8.02 (td, J=2.10, 8.24 Hz, 2H), 7.66 (td, J=2.10, 8.70 Hz, 2H), 7.49 (td, J=2.10, 8.47 Hz, 2H), 7.35 (td, J=2.30, 8.70 Hz, 2H), 6.84 (d, J=7.32 Hz, 1H), 5.26 (d, J=13.28 Hz, 1H), 4.18 (d, J=13.05 Hz, 1H), 2.56 (s, 3H); LC/MS m/z 427 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([OH:30])([C:28]#[CH:29])[CH3:27])[N:21]=1>>[F:19][C:3]1[C:2]([C:29]#[C:28][C:26]([OH:30])([C:22]2[N:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[CH3:27])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#CC(C)(O)c1cccnn1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1cccnn1
Yield: 9 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(pyridazin-3-yl)but-3-yn-2-ol to give the titled compound as a brown solid (26 mg, 9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:15])[CH2:11][C:12]([OH:14])=O.C1C=CC2N(O)N=NC=2C=1.[F:26][C:27]1[CH:28]=[C:29]([NH2:56])[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]2[CH:40]=[C:41]([C:43]3[N:44]=[CH:45][N:46]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:47]=3)[S:42][C:35]=12.C(Cl)CCl>CN(C=O)C>[F:26][C:27]1[CH:28]=[C:29]([NH:56][C:12](=[O:14])[CH2:11][C:10]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[O:15])[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]2[CH:40]=[C:41]([C:43]3[N:44]=[CH:45][N:46]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:54])([CH3:53])[CH3:55])[CH:47]=3)[S:42][C:35]=12
Reactant: C[Si](C)(C)CCOCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: COc1ccccc1NC(=O)CC(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4cn(COCC[Si](C)(C)C)cn4)sc23)c(F)c1
Reaction time: 0.17 h
Yield: 58.4 %

Procedure:
To a solution of the acid 27 (59 mg, 2 eq, 0.28 mmol) and HOBT (19 mg, 1 eq, 0.14 mmol) in DMF (3 ml) was added amine 104 (64 mg, 0.14 mmol) and the reaction mixture was stirred for 10 mins. EDC (54 mg, 2 eq, 0.28 mmol) was added and the reaction mixture was stirred at RT overnight. The solvents were removed and the residue was partitioned between EtOAc and water. The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by column chromatography (20% acetone in hexane to 100% acetone) afforded title compound 105 (53 mg, 58% yield). MS (m/z): 648.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[CH3:11][C:12]([CH3:14])=O.N1CCCC1>CO>[CH3:11][C:12]1([CH3:14])[CH2:9][C:8](=[O:10])[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[O:1]1
Reactant: CC(=O)c1ccccc1O
Reactant: CC(C)=O
Solvent: CO
Solvent: C1CCNC1
Product: CC1(C)CC(=O)c2ccccc2O1

Procedure:
A solution of 2′-hydroxyacetophenone (5.0 mL), acetone (4.7 mL), and pyrrolidine (5.4 mL) in 150 mL of methanol was stirred for 66 hours. The mixture was concentrated and treated with aqueous HCl (pH<1). The acidic layer was extracted twice with ethyl ether, which was dried and concentrated to provide 2,2-dimethylchroman-4-one. The 2,2-dimethylchroman-4-one was dissolved in 300 mL of methanol and treated with ammonium acetate (65 g) and sodium cyanoborohydride (2.5 g) for 24 hours. The resulting mixture was concentrated to 100 mL and diluted with 300 mL water. Concentrated HCl was carefully added until the pH was less than 1 and the acidic mixture was extracted with ethyl ether. The acidic phase was made basic with KOH and then extracted twice with ethyl ether. The basic extracts were dried and concentrated to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].[F:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:8][C:6]1[C:5]([F:9])=[CH:4][C:3]([OH:10])=[C:2]([N:1]=[CH:14][C:13]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:12]=2[F:11])[CH:7]=1
Reactant: O=Cc1ccc(F)cc1F
Reactant: Nc1cc(Br)c(F)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Oc1cc(F)c(Br)cc1N=Cc1ccc(F)cc1F
Temperature: 25 °C

Procedure:
A solution of 2-amino-4-bromo-5-fluorophenol (10.1 g, 49 mmol), 2,4-difluorobenzaldehyde (5.36 mL, 49 mmol) and p-toluenesulfonic acid (100 mg, 0.52 mmol) in toluene (250 mL) was heated to reflux in a Dean-Stark apparatus for 0.5 h and then allowed to cool to ambient temperature. After adding triethylamine (1 mL) the reaction mixture was concentrated under reduced pressure to give the crude compound which was used without further purification. (16.1 g, 99%). 1H-NMR (400 MHz, CDCl3) 6.83 (d, J=10.2, 1H), 6.93 (m, 1H), 7.01 (m, 1H), 7.49 (d, J=7.6, 1H), 8.13 (m, 1H), 8.85 (s, 1H).
Reaction SMILES: [OH:1][CH:2]([CH3:31])[CH:3]([N:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH:7]=[N:6]1)[CH3:4].[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([N:20]2[CH2:19][CH2:18][N:17]([C:14]3[CH:13]=[CH:12][C:11]([N:8]4[CH:7]=[N:6][N:5]([CH:3]([CH3:4])[CH:2]([O:1][S:38]([C:35]5[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=5)(=[O:40])=[O:39])[CH3:31])[C:9]4=[O:10])=[CH:16][CH:15]=3)[CH2:22][CH2:21]2)=[CH:28][CH:27]=1
Reactant: COc1ccc(N2CCN(c3ccc(-n4cnn(C(C)C(C)O)c4=O)cc3)CC2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCN(c3ccc(-n4cnn(C(C)C(C)OS(=O)(=O)c5ccc(C)cc5)c4=O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of [S-(R*,S*)]-2,4-dihydro-2-(2-hydroxy-1-methylpropyl)4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (0.01 mol), p-toluene-sulfonyl chloride (0.012 mol), triethylamine (2 g) and dimethylaminopyridine (0.5 g) in CH2Cl2 (100 ml) was stirred at room temperature for 4 days. The mixture was taken up in CH2Cl2 and purified by column chromatography over silica gel (eluent: CH2Cl2 100%). The pure fractions were collected and the solvent was evaporated. The residue was triturated in methylisobutyl keton, filtered off and dried, yielding 4.6 g (79%) [S-(R*,S*)]-2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2-[1-methyl-2-[[(4-methylphenyl)sulfonyl]oxy]propyl]-3H-1,2,4-triazol-3-one (interm. 134).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][OH:19])[CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[NH:26]([C:27]([O:19][CH2:18][CH2:17][C:13]1[CH:12]=[C:11]([CH2:10][CH:4]([O:3][CH2:1][CH3:2])[C:5]([OH:7])=[O:6])[CH:16]=[CH:15][CH:14]=1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)C(Cc1cccc(CCO)c1)OCC
Product: CCOC(Cc1cccc(CCOC(=O)Nc2ccccc2)c1)C(=O)O

Procedure:
Using ethyl 2-ethoxy-3-[3-(2-hydroxyethyl)phenyl]propanoate and phenylisocyanate, the title compound was obtained in the same manner as described in Example 160b).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH:6](Br)[C:7](=O)[CH3:8])[CH3:2].C(N(CC)CC)C.[C:19]([SiH2:23][O:24][C:25]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:26]1[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1)([CH3:22])([CH3:21])[CH3:20]>C(O)(C)C>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]1[N:30]2[CH:31]=[C:26]([C:25]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[O:24][SiH2:23][C:19]([CH3:22])([CH3:20])[CH3:21])[CH:27]=[CH:28][C:29]2=[N:32][C:7]=1[CH3:8])[CH3:2]
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1ccc(N)nc1
Reactant: CCOC(=O)CC(Br)C(C)=O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCOC(=O)Cc1c(C)nc2ccc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cn12
Yield: 55 %

Procedure:
3-Bromo-4-oxo-pentanoic acid ethyl ester (1.77 g, 7.86 mmol, 2.0 equiv) and triethylamine (1.10 ml, 7.86 mmol, 2.0 equiv) are added to a solution of 5-(tert-butyl-diphenyl-silanyloxymethyl)-pyridin-2-ylamine in iso-propanol (10 ml). The reaction mixture is heated to reflux for 5 hours. After cooling, volatiles are removed in vacuo. The residue is taken up with water and EtOAc. The aqueous phase is extracted three times with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (hexane/AcOEt 1:1 to 1:4) affords the title compound (1.10 g, 55%). MS (ES+): 487 (M+H)+.
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=CN=3)CC3CC(CC(C3)C1)C2.[C:25]12([CH2:35][O:36][C:37]3[C:45]([CH:46]4[CH2:48][C:47]4([F:50])[F:49])=[CH:44][C:40]([C:41](O)=[O:42])=[C:39]([F:51])[CH:38]=3)[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2.COCCS(N)(=O)=O.[CH:60]1([S:63]([NH2:66])(=[O:65])=[O:64])[CH2:62][CH2:61]1>>[C:25]12([CH2:35][O:36][C:37]3[C:45]([CH:46]4[CH2:48][C:47]4([F:50])[F:49])=[CH:44][C:40]([C:41]([NH:66][S:63]([CH:60]4[CH2:62][CH2:61]4)(=[O:65])=[O:64])=[O:42])=[C:39]([F:51])[CH:38]=3)[CH2:32][CH:31]3[CH2:33][CH:27]([CH2:28][CH:29]([CH2:30]3)[CH2:34]1)[CH2:26]2
Reactant: O=C(O)c1cc(C2CC2(F)F)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: NS(=O)(=O)C1CC1
Agent: COCCS(N)(=O)=O
Agent: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2(F)F)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Yield: 43 %

Procedure:
Following the procedure as described in Example 271 and making variations as required to replace 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with 4-(adamantan-1-ylmethoxy)-5-(2,2-difluorocyclopropyl)-2-fluorobenzoic acid and to replace 2-methoxyethanesulfonamide with cyclopropylsulfonamide. Purification by silica gel column chromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gave the title compound as a colorless solid (0.055 g, 43%): 1H NMR (300 MHz, DMSO-d6) δ 11.86 (br s, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.00 (d, J=13.0 Hz, 1H), 3.70-3.56 (m, 2H), 3.10-2.99 (m, 1H), 2.84-2.71 (m, 1H), 2.04-1.85 (m, 5H), 1.76-1.55 (m, 12H), 1.14-1.02 (m, 4H); MS (ES+) m/z 484.1 (M+1).
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH2:7]([OH:10])[C:8]#[CH:9]>C(NC(C)C)(C)C.[Cu]I>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:9]#[C:8][CH2:7][OH:10]
Reactant: Ic1cccs1
Reactant: C#CCO
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: OCC#Cc1cccs1
Yield: 72.4 %

Procedure:
To a suspension of tetrakis (triphenylphosphine)palladium (300 mg, 0.25 mmol) and copper (I) iodide (100 mg, 0.50 mmol) in diisopropylamine (100 ml) under nitrogen was added 2-iodothiophene (6.3 g, 30 mmol). After stirring 1.5 h at room temperature a solution of propargyl alcohol (3.0 g, 33 mmol) in diisopropylamine (50 ml) was added. After 16 h at room temperature the mixture was filtered and concentrated in vacuo. The residue was submitted to flash chromatography using dichloromethane as eluent to give 3.0 g (73%) of 3-(2-thienyl)-2-propyn-1-ol as a crude product.
Reaction SMILES: S([O-])([O-])(=O)=O.[Zn+2:6].[NH2:7][C@H:8]([C:16]([OH:18])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[NH2:7][C@H:8]([C:16]([O-:18])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Zn+2:6].[NH2:7][C@H:8]([C:16]([O-:18])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Zn+2]
Product: N[C@@H](Cc1ccccc1)C(=O)[O-]

Procedure:
26.5 g of zinc sulfate (0.17 M) is added to 1l of fermented broth of phenylalanine (27 g/l, 0.16 M) from which the microorganisms have been removed. The mixture is stirred slowly to completely dissolve the zinc sulfate. Ammonia water is gradually added to the dissolved solution to maintain the pH of 7.5 and then zinc phenylalaninate crystals are obtained (crystal wt: 32.4 g, purity: 99.2%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:14])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-])=O.O.O.[Sn](Cl)Cl.CN(C=O)C.C([O-])(O)=O.[Na+]>CCOC(C)=O>[F:13][C:10]([F:11])([F:12])[C:8]1[CH:9]=[C:4]([NH2:1])[C:5]([NH2:14])=[N:6][CH:7]=1
Reactant: Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(C(F)(F)F)cnc1N
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-nitro-5-trifluoromethyl-pyridin-2-ylamine from step (a) above (1.2 g, 5.59 mmol), tin (II) chloride dihydrate (3.9 g, 17.3 mmol, Aldrich), and DMF (19 mL) was heated to 60° C. for 4 h. The reaction mixture was cooled to room temperature and NaHCO3 (150 mL) was added. The mixture was stirred for 0.5 h, diluted with EtOAc (300 mL), stirred for 0.5 h and filtered. The organic layer was separated and the aqueous layer was extracted with EtOAc (2×300 mL). The combined organic extracts were dried over MgSO4 and filtered. The solvent was removed in vacuo to give the title compound, which was used in the next step without additional purification. MS (ESI, positive ion) m/z: 178 (M+1).