Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[C:13]([CH3:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=2[CH3:18])=[CH:5][CH:4]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:18][C:9]1[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[C:13]([CH3:14])[C:8]=1[O:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:20]([C:26]([C:25]2[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=2)=[O:27])[CH:19]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-(4-methoxy-phenoxy)-3,5-dimethyl-nitrobenzene (2.7 g, 10 mmol) and p-fluorobenzoyl chloride (4.0 g, 3.0 mL, 25 mmol) in methylene chloride (10 mL) was added titanium tetrachloride (1M in methylene chloride, 50 mL, 50 mmol). The reaction mixture was stirred at room temperature for 3 d, poured into ice (100 g), and stirred 1 h. The organic layer was separated and the aqueous layer was extracted with methylene chloride (3×50 mL). The combined organic extracts were washed with 5% sodium carbonate (200 mL), brine (150 mL), dried and concentrated. The residue was triturated with ether-petroleum ether. The solid was collected by filtration to give the title compoud of Step A (2.1 g) as a tan solid. MS (APCI−) Calc.: 395.2, Found: 394.2 (M−1).
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C([Li])CCC.[C:24]([N:34]1[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]1)([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>O1CCCC1>[C:28]1([CH2:27][O:26][C:24]([N:34]2[CH2:35][CH2:36][C:37]([OH:40])([C:15]3[CH:16]=[CH:17][C:12]([NH:11][C:1]([O:3][CH2:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[O:2])=[CH:13][CH:14]=3)[CH2:38][CH2:39]2)=[O:25])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Nc1ccc(Br)cc1)OCc1ccccc1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C2(O)CCN(C(=O)OCc3ccccc3)CC2)cc1)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(carbobenzyloxy)-4-bromaniline (5.00 g) in dry tetrahydrofuran (80 mL) at -78° C. under N2 is added n-butyllithium (21.4 mL, 1.6 M in hexanes) dropwise over five minutes. The resulting yellow solution is stirred at -78° C. for 30 minutes and is then treated with a solution of N-(carbobenzyloxy)-4-piperidone (3.99 g) in dry tetrahydrofuran (17 mL). The reaction mixture is stirred for three hours, during which the reaction temperature is allowed to rise to 0° C. and is quenched with saturated aqueous ammonium chloride (30 mL). The mixture is then diluted with water (100 mL), the layers are separated, the aqueous phase is extracted with diethyl ether, and the combined organic phase is washed with saline (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is chromato-graphed on silica gel (230-400 mesh, 350 g), eluting with ethyl acetate/hexane (25/75), and those fractions with an Rf =0.38 by TLC (ethyl acetate/hexane, 50/50) are pooled and concentrated under reduced pressure to give the title compound, mp 156° C.-158° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(C[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3Cl)C=2N=1)(C)(C)C.C1(C2CCNC2)C=CC=CC=1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH:24]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: c1ccc(C2CCNC2)cc1
Product: CC(C)(C)c1nc(N2CCC(c3ccccc3)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-phenylpyrrolidine. MS(m/e): 447.4 (MH+).
Reaction SMILES: [CH:1]([NH:5][C:6](=[O:18])[NH:7][C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12]C)=O)([CH2:3][CH3:4])[CH3:2]>S(=O)(=O)(O)O>[CH:1]([NH:5][C:6]1[O:18][C:10](=[O:12])[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[N:7]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)NC(=O)Nc1ccccc1C(=O)OC
Agent: O=S(=O)(O)O
Product: CCC(C)Nc1nc2ccccc2c(=O)o1
Reaction time: 2 h

Procedure:
Methyl 2-(3-sec-butyl-ureido)benzoate (90 mg) was dissolved in 2 ml of concentrated sulfuric acid. The solution was stirred for 21/2 hours and poured onto ice. The ice-quenched mixture was rapidly neutralized with saturated sodium bicarbonate solution. The resulting white precipitate was filtered, dried and recrystallized from ether and petroleum ether, to yield 2-sec-butylamino-4H-3,1-benzoxazin-4-one, m.p. 122°-123° C.; 'H NMR (delta CDCl3): 1.0 (t, 3H, CH3CH2); 1.3 (d, 3H, CH3CH); 1.6 (m, 2H, CH2); 4.0 (m, 1H, CH--N); 7.2, 7.6 8.0 (3m, 4H, ArH). The infrared spectrum of this compound showed maxima at 3290, 1740, 1635 and 1600 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:14][NH:15][C:16]([O:18]CC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][NH:15][C:16]2=[O:18])=[CH:4][CH:3]=1
Reactant: CCOC(=O)NC=C(C(=O)OCC)c1ccc(Cl)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)c1c[nH]c(=O)c2cc(Cl)ccc12
Yield: 60.4 %

Procedure:
Then, 13.7 g of ethyl p-chlorophenyl-(α-ethoxycarbonylaminomethylene)acetate was added to 50 ml of diphenyl ether and the mixture was heated at reflux for 3 hours. After cooling, benzene and petroleum ether were added to the reaction mixture, and the precipitated crystals were filtered and recrystallized from a mixture of dimethylformamide and ethanol to obtain 7 g of 7-chloro-4-ethoxycarbonyl-1(2H)-isoquinolone having a melting point of 243° C. as colorless prisms.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C:24]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>C(#N)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C:24]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])=[CH:23][N:22]=[C:21]([O:7][C:6]3[CH:1]=[CH:2][C:3]([CH3:8])=[CH:4][CH:5]=3)[N:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(-c2nc(S(C)(=O)=O)ncc2C(=O)N2CCOCC2)cc1OC
Reactant: Cc1ccc(O)cc1
Solvent: CC#N
Product: COc1ccc(-c2nc(Oc3ccc(C)cc3)ncc2C(=O)N2CCOCC2)cc1OC
Temperature: 65 °C
Yield: 75 %

Procedure:
Acetonitrile (10 ml) potassium carbonate (0.5 g), paracresol (2.7 g) and the pyrimidine obtained in Example 432 (1 g) are placed in a reactor together with 3 drops of TDA--1[tris(3,6-dioxaheptyl)amine] as catalyst. The mixture in heated to 65° C. for one hour, and the solvent in evaporated. The mixture in taken up in water and extracted with ether, dried over MgSO4 and evaporated. A white solid in obtained in a yield of 75%, m.p. 152° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH:5]=[CH:4][CH:3]=1.[N+:18]([CH3:21])([O-:20])=[O:19].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([O:8][CH2:9][C:10]2[CH:17]=[CH:16][C:13](/[CH:14]=[CH:21]/[N+:18]([O-:20])=[O:19])=[CH:12][CH:11]=2)[N:7]=1
Reactant: Cc1cccc(OCc2ccc(C=O)cc2)n1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1cccc(OCc2ccc(/C=C/[N+](=O)[O-])cc2)n1
Temperature: 110 °C
Reaction time: 3 h
Yield: 110 %

Procedure:
To a solution of 4-(6-methyl-pyridin-2-yloxymethyl)-benzaldehyde (4.19 g, 18.5 mmol) described in Manufacturing Example 3-1-2 in acetic acid (30 mL) were added nitromethane (5.65 g, 92.6 mmol) and ammonium acetate (2.85 g, 37.0 mmol) under nitrogen atmosphere, which was stirred for 3 hours at 110° C. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure to obtain the title compound (5.50 g) as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14]C(N)=O>ClC1C=CC=CC=1Cl.P(O)(O)O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:14])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: NC(N)=O
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: OP(O)O
Solvent: Clc1ccccc1Cl
Product: NC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
100 g (0.5 mol) of 4-chloro-3-nitrobenzoic acid, 36 g (0.6 mol) of urea and 0.5 g of phosphorous acid are heated in 250 ml of 1,2-dichlorobenzene with stirring at from 165° to 178° C. for 8 h. After cooling to 25° C. the solid is filtered off with suction and washed with 50 ml of 1,2-dichlorobenzene. The filter cake is introduced into 250 ml of water, and the mixture is adjusted to a pH of 12 using aqueous sodium hydroxide solution and subjected to steam distillation. Subsequently the solid is filtered off with suction and dried at 100° C. 89.7 g of 4-chloro-3-nitrobenzamide are obtained having a melting point of from 146° to 149° C. This corresponds to a yield of 90.2% of theory. By acidification of the aqueous mother liquor to pH 2, 4.9 g of 4-chloro-3-nitrobenzoic acid (4.9% of theory) are obtained, which can be employed again in a subsequent batch.
Reaction SMILES: [CH2:1]([C:8]1[N:13]([CH2:14]C(O)=O)[C:12](=[O:18])[C:11]([NH:19][C:20](=[O:29])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:34]([NH:36][C@H:37]([C:46](=[O:57])[CH2:47][O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[Cl:56])[CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])=[O:35])C=C>>[CH2:1]([C:8]1[N:13]([CH2:14][C:34]([NH:36][CH:37]([C:46](=[O:57])[CH2:47][O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[Cl:56])[CH2:38][C:39]([OH:41])=[O:40])=[O:35])[C:12](=[O:18])[C:11]([NH:19][C:20](=[O:29])[CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCOC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)COCc1ccccc1Cl
Reactant: O=C(O)Cn1c(Cc2ccccc2)ccc(NC(=O)CCc2ccccc2)c1=O
Product: O=C(O)CC(NC(=O)Cn1c(Cc2ccccc2)ccc(NC(=O)CCc2ccccc2)c1=O)C(=O)COCc1ccccc1Cl

Procedure:
N-2-(6-Benzyl-1,2-dihydro-2-oxo-3-(3-phenylpropionyl)amino-1-pyridyl)acetyl-3-amino-5-(2-chlorobenzyloxy)-4-oxo-pentanoic acid (90) was prepared from 52b and (3S)t-butyl N-(allyloxycarbonyl)-3-amino-5-(2-chlorophenylmethoxyl)-4-oxo-pentanoate (prepared by a similar method as 82) to give a white solid: 1H NMR(DMSO-d6) δ 9.2(s, 1H), 8.75(d, 1H), 7.7-7.1(m, 14H), 6.4(d, 1H), 4.65(d, 6H), 4.56(s, 1H), 4.6-4.35(dd, 1H), 3.9(s, 2H), 2.9-2.6(m, 6H) ##STR155##
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[CH:6][CH:5]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O.[BH4-].[Na+]>CO>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH:1][CH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[CH:6][CH:5]=1
Reactant: NCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Reactant: COc1ccccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1CNCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Yield: 85.4 %

Procedure:
Add three-angstrom molecular sieves to a stirred solution of 6-[4-(2-amino-ethyl)-phenoxy]-nicotinamide (0.1000 g, 0.3887 mmol) (compound of example 33), 2-methoxybenzaldehyde (0.047 mL, 0.39 mmol), and methanol (5 mL). Agitate the reaction for 18 h on a platform shaker at room temperature. Add sodium borohydride and agitate for 1 h at room temperature. Filter to remove the molecular sieves and load the reaction mixture directly onto a 10 g prepacked SCX cartridge. Flush with methanol (150 mL) and elute the product off the SCX cartridge with 2 M ammonia in methanol (50 mL). Concentrate on a rotary evaporator to give 0.1253 g (85%) of 6-{4-[2-(2-methoxy-benzylamino)-ethyl]-phenoxy}-nicotinamide: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 4.14 minutes, Purity: 97.9%; mass spectrum (ion spray): m/z=378.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[OH-].[K+].Cl[CH2:15][CH:16]([OH:20])[CH2:17][CH2:18][Cl:19]>O.C(O)(C)C>[Cl:19][CH2:18][CH2:17][CH:16]([OH:20])[CH2:15][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: OC(CCl)CCCl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: OC(CCCl)COc1cccc(C(F)(F)F)c1
Temperature: 65 °C

Procedure:
To a mixture of 0.5 mole (75 g.) of m-trifluoromethylphenol, 1 mole (56 g.) of potassium hydroxide, 100 ml. of water and 400 ml. of isopropanol was added 0.6 mole (84 g.) of 1,4-dichloro-2-butanol with stirring at temperature below 55° C. The resulting reaction mixture was heated at 65° C. for 20 hr., mixed with 2 liters of water, and extracted with 400 ml. of isopropyl ether. The ether extract was washed with 0.5N sodium hydroxide and then with water, dried over sodium sulfate and distilled under reduced pressure. The distillate which was collected at 120°-124° C./0.01 mm. solidified at room temperature and melted at 50°-52° C.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.Cl[C:16]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:16]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:1][C@@H:2]2[C@@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)=[CH:30][CH:29]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)[C@@H](O)C1
Solvent: c1ccncc1
Product: COc1ccc(C(O[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 64.7 %

Procedure:
To a solution of (3S,4S)-tert-butyl 3,4-dihydroxypyrrolidine-1-carboxylate (2.79 g, 13.7 mmol) in anhydrous pyridine (144 mL) was added 4,4′-(chloro(phenyl)methylene)bis(methoxybenzene) (5.43 g 15.2 mmol) and the resulting mixture stirred at ambient temperature for 4 days. The reaction was quenched with methanol (10 mL) and concentrated under reduced pressure. The residue was stirred in diethyl ether (150 mL) and the solid which precipitated was collected by filtration. The filtrate was concentrated under reduced pressure and purified by column chromatography (Biotage, 40M; 1% methanol:dichloromethane) to afford (3S,4S)-tert-butyl 3-(bis(4-methoxyphenyl)(phenyl)methoxy)-4-hydroxypyrrolidine-1-carboxylate (4.48 g, 65%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25]C([O-])=O.Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH2:25][C:24]([O:30][CH2:31][CH3:32])=[O:29])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccnc(F)c1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
To a solution of 2-fluoro-4-pyridinecarboxylic acid (10 g, 70.9 mmol) in tetrahydrofuran (150 ml) was added 1,1′-carbonylbis-1H-imidazole (12.7 g, 78.0 mmol), and the mixture was heated under reflux for 30 min. The reaction solution was cooled and monoethyl malonate magnesium salt (11.2 g, 39.0 mmol) was added. The mixture was stirred at room temperature for 30 min. 1N Hydrochloric acid (200 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from hexane to give ethyl 3-(2-fluoro-4-pyridyl)-3-oxopropionate (7.32 g, 49%).
Reaction SMILES: [CH3:1][N:2]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1)[C:3](=[O:19])[CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1.[OH-].[Na+]>C1COCC1>[CH3:1][N:2]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)[C:3](=[O:19])[CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:15])([CH3:16])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1
Reactant: COC(=O)c1ccc(N(C)C(=O)Cc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C(=O)Cc1ccc2c(c1)C(C)(C)CCC2(C)C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.8 g (4.6 mmol) of the ester obtained above in (a), 100 ml of 2N methanolic sodium hydroxide and 50 ml of THF are introduced into a round-bottomed flask. The mixture is stirred at room temperature for one hour and evaporated to dryness, the residue is taken up with water, the mixture is extracted with ethyl ether and the aqueous phase is separated after settling has taken place. The aqueous phase is acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl ether and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated. 1.6 g (94%) of the expected acid, having a melting point of 192°-193° C., are collected.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:22](=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:19]=3)[CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH:22]([OH:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:19]=3)[CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1ccc2c(c1)CC(CNS(=O)(=O)c1ccc(Cl)cc1)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(O)c1ccc2c(c1)CC(CNS(=O)(=O)c1ccc(Cl)cc1)C2
Reaction time: 2 h
Yield: 97.5 %

Procedure:
4.46 g of ethyl 3-[2-[(4-chlorophenyl)sulfonylaminomethyl]indan-5-yl]-3-oxopropionate obtained in Step 1 of Example 46 was dissolved in 60 ml of ethanol, to which 193 mg of sodium borohydride was added under ice-cooling, followed by stirring for 2 hours at the same temperature. Subsequently, the solvent was distilled off under reduced pressure. The residue was added with ethyl acetate, washed with water and dried. The solvent was removed under reduced pressure. The residue was recrystallized from a solvent mixture of ethyl acetate and isopropyl ether to obtain 4.37 g of colorless crystals. Yield: 99%
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[OH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C>CN(C=O)C>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([N:16]2[CH2:17][CH2:18][CH:13]([OH:12])[CH2:14][CH2:15]2)=[N:3][CH:4]=1)=[O:7]
Reactant: OC1CCNCC1
Reactant: COC(=O)c1ccc(Cl)nc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(N2CCC(O)CC2)nc1
Temperature: 80 °C
Yield: 86.1 %

Procedure:
To a solution of methyl 6-chloronicotinate (890 mg, 1.00 equiv; 5.03 mmol) in dry DMF (30 mL) is added 4-hydroxypiperidine (1.5 equiv; 7.55 mmol; 778.95 mg) and triethylamine (1.05 mL; 1.5 equiv; 7.55 mmol). The system is flushed with N2 and heated at 80° C. for 4.5 h. The reaction is allowed to reach room temperature and is diluted with water/EtOAc. The aqueous layer is extracted with ethyl acetate (3×). The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue is purified via chromatography eluting with hexane/EtOAc 2:1 to 1:2 to yield an orange solid. The solid is triturated with hexane/EtOAc 4:1 and filtered to provide the title compound (1.023 g, 86%) as a white solid. ES/MS m/z 237.0 (M+1)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH:22]=O)[CH:7]=1)[CH3:2].[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:27]([NH2:34])[C@@H:26]1[OH:35]>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22][NH:34][C@H:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:25][C@H:26]2[OH:35])[CH:7]=1)[CH3:2]
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2C=O)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN[C@H]2c3ccccc3C[C@H]2O)c1

Procedure:
Prepared according to the procedure described in Example 45, Step 3, using the following starting materials: [3-(4-bromo-2-formyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and (1S,2R)-(−)-cis-1-amino-2-indanol.
Reaction SMILES: C1(S([CH2:10][CH2:11][CH2:12][CH:13]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=O)(=O)=O)C=CC=CC=1.C1(S)C=CC=CC=1.C(Cl)C(Cl)Cl.C(OO)(=O)C.OS([O-])=O.[Na+].[OH-].[Na+]>O>[C:13]12[CH2:12][CH2:11][CH:10]=[C:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=2
Reactant: O=C1CCCCCCCCCCC1CCCS(=O)(=O)c1ccccc1
Agent: CC(=O)OO
Agent: O=S([O-])O
Agent: Sc1ccccc1
Solvent: O
Solvent: ClCC(Cl)Cl
Product: C1=C2CCC=C2CCCCCCCCC1
Yield: 91 %

Procedure:
2-(3-Phenylsulfonyl-prop-1-yl)-cyclododecanone used hereinabove (Examples 1 and 2) as starting material was prepared as follows: 222 g (1 mole) of 2-allyl-cyclododecanone-Helv. 54, 2889 (1971)--in admixture with 132 g (1.2 mole) of thiophenol and 3.0 g of α,α'-azoisobutyronitrile were heated at 100° for 10 hours, an additional amount of 6.0 g of α,α'-azoisobutyronitrile being added over this period, portionwise, to the reaction mixture. After dilution with an excess amount of trichloroethane and cooling in an ice-bath, 376 ml (2.6 mole) of 40% peracetic acid were progressively added to the reaction mixture, under good stirring (reaction temperature: 25°-30°). After treatment with an excess amount of an aqueous solution of NaHSO3 (elimination of peroxides), a 10% solution of NaOH in water was added thereto until pH 8-9 (temperature ca. 10°). After extraction with methylene chloride (2×300 ml), successive washings with water and brine, drying over Na2SO4, evaporation and crystallization of the crude residue in a CH2Cl2 /diethyl ether/petrol ether mixture, there were finally isolated 332 g (91% yield) of the desired compound, m.p. 97°-102°.