Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[CH:9]=[CH:8][CH:7]=1)=[O:4].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>CN(C=O)C>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH:12]=[CH:11]2)=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CCl)Nc1cccc2ccc(O)cc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1ccc2cccc(NC(=O)CCl)c2c1
Reaction time: 16 h

Procedure:
To a solution of the crude alcohol from Step A (50.3 mmol) in 150 mL of DMF at 0° C. was added triethylamine (15.0 mL, 108 mmol), followed by dropwise addition of methanesulfonyl chloride (6.0 mL, 77.5 mmol). After 16 hours, additional portions of triethylamine (7.0 mL, 50 mmol) and methanesulfonyl chloride (3.0 mL, 39 mmol) were added. After 4 hours, the solution was concentrated in vacuo and partitioned between EtOAc and saturated NH4Cl solution. The organic layer was extracted with saturated NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide a dark purple solid.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20]([NH2:22])=[O:21])[C:15](=[O:23])[CH2:14]2.BrC1OC(C(Cl)=O)=CC=1>S(Cl)(Cl)=O.CN(C1C=CN=CC=1)C.CN(C)C=O>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20]([NH2:22])=[O:21])[C:15](=[O:23])[CH:14]2[C:7]([C:5]1[O:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1ccc(Br)o1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: NC(=O)N1C(=O)C(C(=O)c2ccc(Br)o2)c2cc(Cl)ccc21

Procedure:
Using the procedure of Example 32, 1.91 g (10.0 mmoless) of commercially available 5-bromo-2-furancarboxylic acid was dissolved in 10 ml of thionyl chloride and heated to reflux under nitrogen for 1 hour and the acid chloride product was recovered. A 40 ml N,N-dimethylformamide solution of 1.75 g (8.3 mmoles) of 5-chloro-2-oxindole-1-carboxamide and 3.05 g (25 mmoles) of 4-(N,N-dimethylamino)pyridine was reacted with 2.09 g (10 mmoles) of 5-bromo-2-furan carbonyl chloride in 10 ml of N,N-dimethylformamide. After a reaction time of about 45 minutes, the mixture was acidified by pouring into 250 ml of 1N HC1. The product was recrystallized from acetic acid, washed with acetic acid, then hexane and dried overnight in vacuo at room temperature. The resulting product then was dried over refluxing isopropanol under high vacuum to yield 1.37 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[N+:20]([CH3:23])([O-:22])=[O:21].Cl>CO>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[CH:23]/[N+:20]([O-:22])=[O:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])/C=C/c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a mixture of 4-benzyloxybenzaldehyde (1.0 g, 4.7 mmol) and sodium methoxide (28% methanol solution, 150 μL, 0.74 mmol) and methanol (10 mL) were added nitromethane (330 μL, 6.1 mmol) and sodium methoxide (28% methanol solution, 1.0 mL, 4.9 mmol) at 0° C., which was stirred for 10 minutes at room temperature. The reaction mixture was cooled to 0° C., and 5 N aqueous hydrochloric acid solution (20 mL) was added thereto at the same temperature. The reaction mixture was then stirred for 15 minutes at room temperature. The precipitated solids were filtered to obtain the title compound (1.2 g, 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[CH2:17][CH2:16][C:15]3[CH:14]=[C:13]([C:18]([O:20]CC)=[O:19])[CH:12]=[CH:11][C:10]=3[CH2:9]2)[CH:2]=1.[ClH:23]>>[ClH:23].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[CH2:17][CH2:16][C:15]3[CH:14]=[C:13]([C:18]([OH:20])=[O:19])[CH:12]=[CH:11][C:10]=3[CH2:9]2)[CH:2]=1
Reactant: CCOC(=O)c1ccc2c(c1)CCC(Cc1cccnc1)C2
Agent: Cl
Product: O=C(O)c1ccc2c(c1)CCC(Cc1cccnc1)C2

Procedure:
1.8 g of ethyl 6-(3-pyridylmethyl)-5,6,7,8-tetrahydro-2-naphthalenecarboxylate was mixed with 50 ml of 6 normal hydrochloric acid and the mixture was heated under reflux for 4 hours. The reaction mixture was concentrated to dryness in vacuo. The residue was recrystallized from methanol to give 1.04 g of 6-(3-pyridylmethyl)-5,6,7,8-tetrahydro-2-naphthalenecarboxylic acid hydrochloride as colorless crystals with m.p. 222°-226° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[Cl:11].Cl.CN(C)CCCN=C=NCC.[CH3:24][Si:25]([CH2:28][NH2:29])([CH3:27])[CH3:26].O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:29][CH2:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[O:7])=[CH:4][C:3]=1[Cl:11]
Reactant: C[Si](C)(C)CN
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: C[Si](C)(C)CNC(=O)c1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-bromo-3-chloro-benzoic acid (commercially available) (5.0 g) in dichloromethane (30 ml) was added N-(−3-dimethylaminopropyl)-N′-ethylcarbodiimid hydrochloride (5.29 g), N,N-dimethylaminopyridine (1.19 g) and trimethylsilylmethylamine (2.85 ml). The reaction mixture was stirred at ambient temperature for 5 hours. Water and dichloromethane was added to the reaction mixture. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate and filtered through silica gel. The reaction mixture was concentrated to give 4-bromo-3-chloro-N-trimethylsilanylmethyl-benzamide (4.87 g). 1H-NMR (400 MHz, CDCl3): 7.68 (d, 1H), 7.55 (s, 1H), 7.33 (d, 1H), 5.85 (s, 1H), 2.84 (d, 2H), 0.00 (s, 9H) ppm.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[C:9]1S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])(O)=O.[OH-].[Na+]>O>[CH2:1]([N:8]1[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cnc(S)n1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: O
Product: OCc1cncn1Cc1ccccc1
Reaction time: 3 h

Procedure:
1-Benzyl-2-mercapto-5-hydroxymethyl-imidazole (7.5 g) is added in small portions to a mixture of water (18 ml) and concentrated nitric acid (7.5 g) at 35° C. The mixture is stirred for 3 hours and the pH of the reaction mixture adjusted to 9-10 with sodium hydroxide. 1-Benzyl-5-hydroxymethyl-imidazole is obtained, 3.8 g (60%), m.p. 131°-135° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[S:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Sc2ccccn2)cc1
Solvent: CC(=O)O
Product: Nc1ccc(Sc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.4 %

Procedure:
2-[(4-nitrophenylsulfanyl) pyridine (8.0 g) was dissolved in acetic acid (64 ml), and reduced iron (24 g) was added to the mixture, and then, the mixture was stirred for 16 hours at room temperature. The mixture was filtered with Celite, washed with ethyl acetate, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-(2-pyridinylsulfanyl) aniline (6.3 g).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[N+:8]([C:11]1[CH:12]=[C:13]([CH:36]=[CH:37][CH:38]=1)[CH2:14][C:15]1[C:16](=[O:35])[O:17][C:18]2[CH:28]=[C:27]([O:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])[CH:26]=[CH:25][C:19]=2[C:20]=1[CH2:21][C:22]([OH:24])=[O:23])([O-:10])=[O:9].ClCCl>CO>[CH3:1][O:23][C:22](=[O:24])[CH2:21][C:20]1[C:19]2[CH:25]=[CH:26][C:27]([O:29][C:30](=[O:34])[N:31]([CH3:32])[CH3:33])=[CH:28][C:18]=2[O:17][C:16](=[O:35])[C:15]=1[CH2:14][C:13]1[CH:36]=[CH:37][CH:38]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=1
Reactant: CN(C)C(=O)Oc1ccc2c(CC(=O)O)c(Cc3cccc([N+](=O)[O-])c3)c(=O)oc2c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Cc1c(Cc2cccc([N+](=O)[O-])c2)c(=O)oc2cc(OC(=O)N(C)C)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
Trimethylsilyl diazomethane (0.82 mL, 2.0 M in hexane) was added to a solution of {3-(3-nitrobenzyl)-7-dimethylcarbamoyloxy-2-oxo-2H-1-benzopyran-4-yl}acetic acid (compound 7f-1-1COOH) (350 mg, 0.82 mmol) in methanol (5.0 mL)/dichloromethane (8.0 mL), and the mixture was stirred at room temperature for 10 minutes. Aacetic acid (2.0 mL) was added to the reaction mixture, and the title compound (338 mg, 94%) was obtained by vacuum concentration as a pale yellow powder.
Reaction SMILES: O(Cl)Cl.CN(C)[C:6]1[CH:11]=CC=[CH:8][CH:7]=1.[C:13]1([CH3:41])[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[C:21]1[C:22]([CH3:40])=[N:23][N:24]2[C:29](=O)[C:28]([CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:27]([CH3:39])[NH:26][C:25]=12.C(=O)([O-])[O-].[K+].[K+].C(N)CCC>C(#N)C.O>[CH2:11]([C:29]1[N:24]2[N:23]=[C:22]([CH3:40])[C:21]([C:14]3[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[CH3:41])=[C:25]2[N:26]=[C:27]([CH3:39])[C:28]=1[CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:6][CH2:7][CH3:8]
Reactant: CCOC(=O)CCCc1c(C)[nH]c2c(-c3c(C)cc(C)cc3C)c(C)nn2c1=O
Reactant: CN(C)c1ccccc1
Agent: ClOCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCN
Solvent: CC#N
Product: CCCCc1c(CCCC(=O)OCC)c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn12
Temperature: 0 °C

Procedure:
Phosphoeus oxychloride (11.3 g) and N,N-dimethylaniline (3 droplets) were added to ethyl 4-(3-mesityl-2,5-dimethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)butanoate (700 mg, 1.77 mmol), followed by heating under reflux for 1.5 hours. After the reaction, it was treated with ice-water, neutralized with potassium carbonate, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated. The resulting reaction residue was dissolved in acetonitrile (5 ml) and n-butylamine (2 mL) was added, followed by heating under reflux for six hours. After the reaction, it was treated with water, and then neutralized with potassium carbonate, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (10-25% ethyl acetate/hexane), to give the title compound (2.5 g) as a yellow oil.
Reaction SMILES: [CH2:1]([N:5]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13]I)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[CH2:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([N:5]([C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([CH2:13][NH:45][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:15])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CI)C(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CNCc2ccccc2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-iodoacetyl-L-lysine (200 mg, 0.38 mmol, example 105, step B) by following the indications of general procedure H using DIEA (0.20 mL, 1.10 mmol) and benzylamine (320 mg, 2.99 mmol). The crude material was purified by preparative HPLC. The product was isolated as a solid (137 mg, 71% yield).
Reaction SMILES: [S:1]([C:5]1[C:13]2[N:12]=[N:11][NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)([OH:4])(=[O:3])=[O:2].[N+]([O-])([O-])=O.[Ag+:18]>O>[Ag:18].[Ag:18].[S:1]([C:5]1[C:13]2[N:12]=[N:11][NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)([OH:4])(=[O:3])=[O:2]
Reactant: [Ag+]
Agent: O=S(=O)(O)c1cccc2[nH]nnc12
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: [Ag]

Procedure:
An organic silver salt dispersion liquid was prepared in such a manner that 4-sulfobenzotriazole and silver nitrate were reacted together in water so as to obtain 4-sulfobenzotriazole silver, and 50 g thereof, 20 g of polyvinyl pyrolidone and 60 ml of water were dispersed by making use of a alumina ball mill.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=1[NH:37][CH:38]=[C:39]([C:45](OCC)=[O:46])[C:40]([O:42][CH2:43][CH3:44])=[O:41]>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[C:29]2[C:28]=1[NH:37][CH:38]=[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:45]2=[O:46]
Reactant: CCOC(=O)C(=CNc1cc(C(F)(F)F)ccc1Cl)C(=O)OCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2c(Cl)ccc(C(F)(F)F)c2c1=O
Temperature: 260 °C
Reaction time: 6.5 h
Yield: 62.1 %

Procedure:
A 3-neck, 1-L flask was charged with Dowtherm® (200 mL, 8 mL/g), which was degassed at 200° C. for 1 h. The solvent was heated to 260° C. and charged in portions over 10 min with diethyl 2-((2-chloro-5-(trifluoromethyl)phenylamino) methylene)malonate 14 (25 g, 0.07 mol). The resulting mixture was stirred at 260° C. for 6.5 hours (h) and the resulting ethanol byproduct removed by distillation. The mixture was allowed to slowly cool to 80° C. Hexane (150 mL) was slowly added over 30 minutes (min), followed by an additional 200 mL of hexane added in one portion. The slurry was stirred until it had reached room temperature. The solid was filtered, washed with hexane (3×150 mL), and then dried under vacuum to provide ethyl 8-chloro-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylate 15 as a tan solid (13.9 g, 65% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 8.39 (s, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 4.24 (q, J=7.1 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:3]=1.[P:12]([OH:15])([OH:14])[OH:13].P(Cl)(Cl)Cl>S1(CCCC1)(=O)=O>[CH:6]1[CH:7]=[N:2][CH:3]=[C:4]([CH2:8][C:9]([P:12]([OH:15])([OH:14])=[O:13])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH:5]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: OP(O)O
Agent: Cl
Solvent: ClP(Cl)Cl
Solvent: O=S1(=O)CCCC1
Product: O=P(O)(O)C(O)(Cc1cccnc1)P(=O)(O)O
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A suspension of 3-pyridylacetic acid hydrochloride (50 g, 0.288 mol) and phosphorous acid (35.4 g, 0.432 mol) in sulfolane (180 ml) is heated to 75° C. for 30 min. The mixture is cooled to 35-40° C. and then gradually introduced phosphorous trichloride (85.6 ml, 0.98 mol) while maintaining the temperature between 35-45° C. The mixture is heated to 63-67° C. for 3 hours whereby a thick white mass results. It is then cooled to 0-5° C. and quenched by slow addition of water (500 ml) at 0-5° C. over a period of 1 hour. The resulting clear solution is charcoalized and heated at 100° C. for 3 hrs, cooled to ambient temperature and then cooled 0-5° C. After stirring for 2 hrs at 0-5° C. the crystallized product is filtered, washed sequentially with chilled water (100 ml), rectified spirit (75 ml) and dried in air oven at 55-60° C. until loss on drying is less than 0.5% w/w. Yield 60.4 g, (70.47%), appearance: white crystalline solid, purity >99.0%.
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([N:11](CC4C=CC(OC)=CC=4)[C:12](=[O:19])[N:13]([CH3:18])[C:14]3=[O:17])=[N:9]2)=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([NH:11][C:12](=[O:19])[N:13]([CH3:18])[C:14]3=[O:17])=[N:9]2)=[CH:5][CH:6]=1
Reactant: COc1ccc(Cn2c(=O)n(C)c(=O)c3cn(Cc4ccc(-c5ccccc5)cc4)nc32)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(=O)[nH]c2nn(Cc3ccc(-c4ccccc4)cc3)cc2c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(biphenyl-4-ylmethyl)-7-(4-methoxybenzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione in CH2Cl2 (90 mL) is added TFA (10 mL) slowly at room temperature, followed by adding trifluoromethanesulfonic acid (4 mL) dropwise. After the reaction mixture is stirred at r.t. for 3 hours, solvent is removed under reduced pressure, and the obtained residue is basified by adding cold pre-diluted ammonium hydroxide (NH3 content, 7%) at 0° C. The mixture is extracted with ethyl acetate four times. The combined organic phase is washed with brine, dried over anhydrous Na2SO4, and then filtered. The filtrate is evaporated to dryness to give crude product in almost quantitative yield. MS (ESI) m/z 333.1 [M+H]+.
Reaction SMILES: CC[O:3][C:4]([C:6]1[N:16]=[CH:15][N:14]2[C:7]=1[CH2:8][N:9]([CH3:22])[C:10]([C:12]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:13]=12)=[O:11])=[O:5]>[OH-].[K+]>[F:21][C:19]1[CH:18]=[CH:17][C:13]2[N:14]3[CH:15]=[N:16][C:6]([C:4]([OH:5])=[O:3])=[C:7]3[CH2:8][N:9]([CH3:22])[C:10](=[O:11])[C:12]=2[CH:20]=1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Agent: [K+]
Agent: [OH-]
Product: CN1Cc2c(C(=O)O)ncn2-c2ccc(F)cc2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.5 %

Procedure:
Ro 15-1788 (0.82 g, 2.71 mmol) was dissolved in 80 ml of 10% methanolic KOH and the solution was stirred for 24 h at room temperature. The solvent was evaporated in vacuo and the residue was dissolved in 50 ml of distilled water. The aqueous solution was cooled to 4° C. and the pH adjusted to 6 by dropwise addition of 1M aqueous HCl. The desired product was crystallized from the solution at pH 6. The solution was left to stand at 4° C. for 10 min and filtered. The filter cake was washed with ice-cold distilled water and dried overnight in vacuo at 60° C. to give III (0.72 g, 97%); crystallization from 50% aqueous ethanol (20 ml) afforded small colorless laminae: mp 273°-274° C.; 1H-NMR (d6 -DMSO) δ 3.08 (s, 3H, NMe), 4.60 (m, 1H), 5.05 (m, 1H), 7.60-7.67 (m, 2H), 7.79 (dd, 1H, J=4.5 Hz, J=8.50 Hz), 8.29 (s, 1H); IR (KBr) 2000-3600, 3110, 1700 (broad), 1670, 1490, 1220, 890 cm-1 ; CIMS M+H=276, C13H10FN3O23 requires M+H=276. Analysis calculated for C213H10FN3O3 :C 56.73, H 3.66, and N 15.27% showed C 56.80, H 3.71, and N 15.29%.
Reaction SMILES: C([N:3](CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[C:21]([OH:23])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].ClC(OCC)=O.N>O1CCCC1>[NH2:3][C:21]([C@@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20][N:15]1[C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(N)=O
Reaction time: 0.67 h

Procedure:
Triethylamine (14.46 ml) was added to a solution of (2S)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid (18.3 g) [see Preparation 1] in tetrahydrofuran (240 ml) at −20° C. under an atmosphere of nitrogen. Ethyl chloroformate (7.52 ml) was then added to the mixture and the resulting solution was stirred for 40 mins. at −10° C. and then 0.88 aqueous ammonia solution (32 ml) added. The reaction mixture was stirred for 10 mins. after which time the solvent was removed under reduced pressure and the residue diluted with ethyl acetate and water. The organic layer was separated and dried over magnesium sulphate and the solvent was removed under reduced pressure to afford tert-butyl (2S)-2-(aminocarbonyl)-1-piperidinecarboxylate (18.65 g) as a white solid. 1H-NMR (CDCl3) δ: 6.0 (1H, bs), 5.40 (1H, bs), 4.80 (1H, s), 4.00 (1H, m), 2.85 (1H, t), 2.30 (1H, d), 1.80-1.40 (14H, m).
Reaction SMILES: [CH2:1]([N:4]([CH2:27][CH2:28][CH3:29])[C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)[CH2:2][CH3:3].[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:27]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:7]1)[CH2:28][CH3:29]
Reactant: CCCN(CCC)C1(c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCN(CCC)C1(c2ccc(C#Cc3ccc(C(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-dipropylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound 109, 51.0 mg, 0.13 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 32.0 mg (70%) of the title compound as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][OH:9].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.C([O-])(O)=O.[Na+]>Cl.C(OCC)C>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: C1=COCCC1
Reactant: OCc1ccccc1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: Brc1ccccc1COC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ten drops of concentrated hydrochloric acid were added to a mixture of 2-bromophenylmethanol (34 g, 0.18 mol) and 3,4-dihydro-2H-pyran (18 g, 0.22 mol), and the resulting mixture was stirred overnight at room temperature. The mixture was diluted with diethyl ether, and the organic phase was neutralized with a saturated NaHCO3 aqueous solution. Further, the resultant was dried over anhydrous MgSO4 and was concentrated under reduced pressure to obtain 2-(2-tetrahydro-2H-pyranoxymethyl)bromobenzene, to which dissolved in THF (450 mL) was added a 1.6 M n-BuLi solution in hexane (124 mL, 0.20 mol) at −78° C. over 40 minutes. The resulting solution was stirred for 50 minutes at −78° C., and chlorodimethylsilane (20 g, 0.22 mol) was added thereto. The mixture was warmed gradually at room temperature overnight and then was quenched with water. After evaporation of THF, the residue thereof was extracted with diethylether, and the combined organic layers were washed with brine, and then the resultant was dried over anhydrous MgSO4. The dried resultant was distilled under reduced pressure, thereby obtaining dimethyl[2-(2-tetrahydro-2H-pyranoxymethyl)phenyl]silane (5) (38 g, yield of 83%) as a colorless oil, bp: 135° C. (1.0 mmHg). 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J=7.2 Hz, 1H), 7.44 (d, J=7.2 Hz, 1H), 7.40-7.36, (m, 1H), 7.31-7.27 (m, 1H), 4.87 (d, J=12.0 Hz, 1H), 4.74 (s, 1H), 4.60 (d, J=12.0 Hz, 1H), 4.58-4.50 (m, 1H), 4.00-3.95 (m, 1H), 3.62-3.54 (m, 1H), 1.94-1.50 (m, 6H), 0.36 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 143.6, 136.5, 134.7, 129.4, 128.3, 127.0, 98.1, 69.1, 62.1, 30.6, 25.5, 19.3, −3.0, −3.1; Anal. Calcd for C14H22O2Si; C, 67.15; H, 8.86. Found: C, 67.44; H, 8.91.
Reaction SMILES: C([O:5][C:6]([C:8]1([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:43])[CH:20]([C:27]3[N:28]([C:36]4[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=4)[N:29]=[C:30]4[C:35]=3[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:14]([F:44])[CH:13]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C1COCC1.CS(C)=O>C(O)(C)C.C(O)=O>[Cl:42][C:39]1[CH:38]=[CH:37][C:36]([N:28]2[C:27]([CH:20]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:19]([NH:18][C:15]3[CH:16]=[CH:17][C:12]([O:11][C:8]4([C:6]([OH:7])=[O:5])[CH2:10][CH2:9]4)=[CH:13][C:14]=3[F:44])=[O:43])=[C:35]3[C:30]([CH2:31][CH2:32][CH2:33][CH2:34]3)=[N:29]2)=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)C1(Oc2ccc(NC(=O)C(c3c4c(nn3-c3ccc(Cl)cc3)CCCC4)C3CCCCC3)c(F)c2)CC1
Solvent: C1CCOC1
Solvent: O=CO
Solvent: CC(C)O
Product: O=C(Nc1ccc(OC2(C(=O)O)CC2)cc1F)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Yield: 100 %

Procedure:
A solution of (+)-1-(4-{2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-acetylamino}-3-fluoro-phenoxy)-cyclopropanecarboxylic acid tert-butyl ester (22 mg, 35 umol; example 21.5) in isopropanol (200 ul) and formic acid (400 ul) was stirred at 90° C. for 2 h. The mixture was poured onto ice water/brine 1/1 and extracted two times with iPrOAc. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give the title compound (20 mg, 35 umol; quant; 100% ee) as yellow foam. MS: m/e=566.3 [M+H+].