Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([C:9]2[O:10][C:11]3[C:18]([CH2:19][CH2:20][CH3:21])=[CH:17][C:16]([Cl:22])=[C:15]([OH:23])[C:12]=3[C:13]=2[CH3:14])=O)=[CH:5][CH:4]=1.NN.[OH-].[K+]>C(O)CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:9]2[O:10][C:11]3[C:18]([CH2:19][CH2:20][CH3:21])=[CH:17][C:16]([Cl:22])=[C:15]([OH:23])[C:12]=3[C:13]=2[CH3:14])=[CH:24][CH:25]=1
Reactant: CCCc1cc(Cl)c(O)c2c(C)c(C(=O)c3ccc(OC)cc3)oc12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CCCc1cc(Cl)c(O)c2c(C)c(Cc3ccc(OC)cc3)oc12
Yield: 54.5 %

Procedure:
A solution of 2-(p-methoxybenzoyl)-3-methyl-4-hydroxy-5-chloro-7-propylbenzofuran (90 mg; 0.25 mmole), hydrazine (80 μl) and potassium hydroxide (98 mg) in ethylene glycol (2 mL) was heated at 145° C. for a period of 5 hours. The reaction mixture was cooled, poured in water, and extracted with ether. The organic phase was washed with 20% citric acid, with brine, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel using 20% ethylacetate in hexane as eluent to yield 47 mg (50%) of 2-(p-methoxybenzyl)-3-methyl-4hydroxy-5-chloro-7-propylbenzofuran.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.Cl.[CH3:26][O:27][C:28]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[CH2:35][NH:34][CH2:33]2)=[O:29].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:26][O:27][C:28]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[CH2:35][N:34]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:33]2)=[O:29]
Reactant: COC(=O)c1ccc2c(c1)CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c1F)C2
Yield: 9.6 %

Procedure:
170 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 109 mg of 5-methoxycarbonylisoindoline hydrochloride, 228 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 24 mg of the target compound.
Reaction SMILES: [SH2:1].[CH3:2][C:3]1([C:20]#[N:21])[CH2:7][CH2:6][C:5]([CH2:18][CH3:19])([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[O:4]1>N(CCO)(CCO)CCO.C(O)C>[CH2:18]([C:5]1([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[O:4][C:3]([CH3:2])([C:20](=[S:1])[NH2:21])[CH2:7][CH2:6]1)[CH3:19]
Reactant: CCC1(COCc2ccccc2Cl)CCC(C)(C#N)O1
Reactant: S
Solvent: CCO
Solvent: OCCN(CCO)CCO
Product: CCC1(COCc2ccccc2Cl)CCC(C)(C(N)=S)O1
Reaction time: 6 h

Procedure:
Excess hydrogen sulfide was condensed into a stainless steel bomb containing 2.94 g of the chromatographically purified trans-nitrile, tetrahydro-2-methyl-5-ethyl-5-[(2-chlorophenylmethoxy)methyl]-2-furancarbonitrile, (ca>9:1 trans-cis by proton NMR), 10 ml ethanol, and 0.15 g triethanolamine catalyst. The sealed bomb was kept at 55±3° C. for 6 hours during which time the internal pressure rose to 350 psi. After cooling, the reaction mixture was concentrated on a rotary evaporator. The residue was purified by dry column chromatography on silica gel using 96.4 hexane:tetrahydrofuran as eluent. The white cyrstalline desired product weighed 1.10 g, mp 78°-80° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)[CH2:7][CH2:6]2.[H][H].[ClH:25]>C(O)C.O.[Pd]>[ClH:25].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)N(c1ccc([N+](=O)[O-])cc1)CC2
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc2c(cc1OC)N(c1ccc(N)cc1)CC2
Yield: 84.9 %

Procedure:
5,6-Dimethoxy-1-(4-nitrophenyl)-indoline was hyrogenated overnight with Pd (5%) on carbon in ethanol/water (8:2) in a shaking “duck”. When the uptake of hydrogen had come to an end, 10% hydrochloric acid was added, the catalyst was filtered off and the remainder was concentrated to dryness. The residue was dried in vacuo at 45° C. The product 4-(5,6-dimethoxyindolinyl)-phenylamine hydrochloride was obtained in a yield of 84.9% (melting point: 143-145° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.[CH3:26][N:27]([CH3:33])[CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>C(OCC)(=O)C.CO>[CH3:26][N:27]([CH3:33])[CH:28]1[CH2:32][CH2:31][N:30]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]3[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:29]1
Reactant: CN(C)C1CCNC1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(N3CCC(N(C)C)C3)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 44 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-fluoro-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 24] and 3-(dimethylamino)pyrrolidine according to the procedure of example 25, except that the reaction time was of 16 h and that ethyl acetate/methanol (9:1) was used. Yield: 44%; MS: m/z=446 (M+H).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][C:13]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[C:14]=1[C:15](O)=[O:16]>>[CH3:12][C:13]1[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:19]=[C:18]([C:26]([F:27])([F:28])[F:29])[C:14]=1[C:15]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:16]
Reactant: Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, white solid, MS: m/e=409.3 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-methyl-4,6-bis-trifluoromethyl-benzoic acid (CAS 895580-37-7).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O.[OH-].[NH4+]>C(O)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:1]=[C:2]3[N:6]([CH:8]=2)[CH:5]=[CH:4][S:3]3)=[CH:12][CH:13]=1
Reactant: Nc1nccs1
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Fc1ccc(-c2cn3ccsc3n2)cc1
Reaction time: 16 h
Yield: 86 %

Procedure:
To a mixture of 2-aminothiazole (23.7 g, 0.23 mol) and 2-bromo-4′-fluoroacetophenone (alternatively named: 2-bromo-1-(4-fluorophenyl)-ethanone) (50 g, 0.23 mol) is added absolute ethanol (600 ml). The reaction is allowed to reflux with vigorous stirring for 16 hours. The reaction mixture is reduced to half its original volume in vacuo. The remaining liquid is poured onto ice and the solution made basic by the addition of ammonium hydroxide solution (30%). The resulting fine solid is filtered and washed with water. The dark yellow solid so obtained is dried in a vacuum oven at 50° C. to provide 6-(4-fluorophenyl)-imidazo[2,1-b]thiazole (43.0 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[CH2:12]([Li])[CH2:13][CH2:14]C.CC1(C)CCCC(C)(C)N1>>[CH2:14]([C:7]1[C:2]([Cl:1])=[N:3][C:4]([O:10][CH3:11])=[N:5][C:6]=1[O:8][CH3:9])[CH:13]=[CH2:12]
Reactant: COc1cc(Cl)nc(OC)n1
Reactant: [Li]CCCC
Agent: CC1(C)CCCC(C)(C)N1
Product: C=CCc1c(Cl)nc(OC)nc1OC

Procedure:
Synthesis of 2,4-dichloro-7-aryl-6,7-dihydro-5H-cyclopenta[d]pyrimidines 33 could also be performed according to the pathway described on Scheme 9. 4-Chloro-2,6-dimethoxypyrimidine 40 could be deprotonated with a strong base, such as n-butyllithium or 2,2,6,6-tetramethylpiperidine, and quenched with allyl bromide to give 5-allyl-4-chloro-2,6-dimethoxypyrimidine 41. Nencka, R.; Votruba, I.; H{hacek over (r)}ebabecký, H.; Jansa, P.; Tlou{hacek over (s)}t'ová, E.; Horská, K.; Masojídková, M.; Holý, A. J. Med. Chem. 2007, 50, 6016-6023. The latter compound can react with α-styrylborinic acids in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium, to provide compounds of formula 42 which can undergo ring closure olefin metathesis under Grubbs conditions to form 2,4-dimethoxy-7-aryl-5H-cyclopenta[d]pyrimidines 43. Grubbs, R. H. Handbook of Metathesis, 2003, First Edition, Wiley-VCH. The double bond in compounds 43 can be reduced to give 2,4-dimethoxy-7-aryl-6,7-dihydro-5H-cyclopenta[d]pyrimidines 44, which upon acid-catalyzed hydrolysis, followed by chlorination with phosphorus oxychloride afford intermediates 33.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([Cl:19])=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:11][C:12]1[N:17]=[C:16]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:15]([Cl:19])=[CH:14][N:13]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: COc1cccc(CN)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(CNc2nc(Cl)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a solution of 3-methoxybenzylamine (0.75 g, 5.4 mmol) and 2,4,5-trichloropyrimidine (1.1 g, 6.0 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (2.3 g, 16 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water. Ethyl acetate (“EtOAc”) was added and the layers were separated. The aqueous layer was extracted with EtOAc once. The combined organic layers were washed with water and brine successively, then dried (Na2SO4), filtered, and concentrated. The crude product was purified by silica gel column chromatography to give the desired product as a white powder (1.43 g, 92%). LCMS for C12H12ClN3O (M+H)+: m/z=284.0, 286.0.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8].Cl.[O:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:10]1[CH2:14][CH2:13][N:12]=[C:11]1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8])=[CH:17][CH:16]=1
Reactant: N#CCCCCCBr
Reactant: Oc1ccc(-c2ncco2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCCCCOc1ccc(C2=NCCO2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
A mixture of 6-bromohexanenitrile, 12 parts of 4-(2-oxazolyl)phenol monohydrochloride, 16.6 parts of potassium carbonate and 282 parts of N,N-dimethylformamide was stirred overnight at 60° C. After cooling, the reaction mixture was poured into water and the product was extracted with methylbenzene. The extract was washed with water, dried, filtered and evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 3.2 parts (20.6%) of 6-[4-(4,5-dihydro-2-oxazolyl)phenoxy]hexanenitrile (int. 107).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([O:22]CC)=[O:21])[CH2:16][C@H:15]1[NH:25][C:26]([C:28]1[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=1)=[O:27])=[O:12])=[CH:5]2.C(O)C.[OH-].[Na+].Cl>O1CCCC1>[C:20]([C@H:17]1[CH2:18][CH2:19][C@@H:14]([NH:13][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[O:12])[C@H:15]([NH:25][C:26]([C:28]2[S:29][C:30]3[CH2:31][N:32]([CH3:37])[CH2:33][CH2:34][C:35]=3[N:36]=2)=[O:27])[CH2:16]1)([OH:22])=[O:21]
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)O)CC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reaction time: 12 h
Yield: 78.4 %

Procedure:
(1R,2R,4S)—N1-[(5-Chloroindol-2-yl)carbonyl]-4-ethoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexane-diamine (1.6 g) was suspended in a mixed solvent of ethanol (20 ml) and tetrahydrofuran (15 ml), and a 1N aqueous solution (5.9 ml) of sodium hydroxide was added at room temperature to stir the mixture for 12 hours at the same temperature. After adding 1N hydrochloric acid (5.9 ml), the solvent was distilled off under reduced pressure, and the residue was washed with water and ether to obtain the title compound (1.19 g) as a colorless solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:15][CH2:14][CH2:13][CH2:12][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10]
Reactant: ClCCCBr
Reactant: O=C1Cc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1Cc2ccccc2N1CCCCl

Procedure:
Oxindole (2.00 g, 0.0150 mol), 1-bromo-3-chloropropane (2.97 mL, 0.03 mol), and potassium carbonate (4.15 g, 0.03 mol) in acetonitrile (40 mL) were heated at reflux for 20 hours. The mixture was evaporated, diluted with ethyl acetate, washed with 2M aqueous hydrochloric acid and brine, dried (MgSO4), and evaporated. The residue was purified by Biotage flash column chromatography (30% ethyl acetate/hexanes) to give product as an oil which solidified on standing (1.57 g, 50%); MS for C11H12ClNO m/z 210 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[C:7]1(C)[CH:12]=CC(S(O)(=O)=O)=C[CH:8]=1>C(OC(C)=O)C.Cl.COC(OC)(C)C>[CH3:8][C:7]1([CH3:12])[O:6][CH:3]([CH2:2][NH2:1])[CH2:4][O:5]1
Reactant: NCC(O)CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: COC(C)(C)OC
Solvent: CCOC(C)=O
Product: CC1(C)OCC(CN)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 533.6 %

Procedure:
3-Aminopropane-1,2-diol (400 mg, 4.4 mmol) was dissolved in EtOAc—HCl (20 mL). And the reaction mixture was stirred at r.t. for 30 min. The reaction mixture was concentrated in vacuo to get to the white solid. The white solid was added in 2,2-dimethoxy-propane (10 mL) and toluene-4-sulfonic acid (86 mg, 0.5 mmol) was added into the mixture. The reaction mixture was stirred at 60 for 12 h. The reaction mixture was concentrated in vacuo, washed by acetone to give (2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (350 mg, yield: 46%). 1HNMR (DMSO-d6, 400 MHz): δ8.08 (s, 2H), 4.32 (s, 1H), 4.05 (q, J=4.8 Hz, 1H), 3.73 (t, J=6.4 Hz, 1H), 3.00-2.78 (m, 2H), 1.37 (s, 3H), 1.28 (s, 3H)
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:27])[CH2:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]23[CH2:26][CH:21]4[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]4)[CH2:18]2)[CH2:24]3)=[CH:13][CH:12]=1)C>C(O)C.O1CCCC1>[C:17]12([C:14]3[CH:13]=[CH:12][C:11]([S:10][CH2:9][CH2:8][CH2:7][C:6]([OH:27])=[O:5])=[CH:16][CH:15]=3)[CH2:18][CH:19]3[CH2:25][CH:23]([CH2:22][CH:21]([CH2:20]3)[CH2:26]1)[CH2:24]2
Reactant: CCOC(=O)CCCSc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCCSc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reaction time: 72 h

Procedure:
100 ml of 2 N sodium hydroxide solution are added to a solution of 6 g of crude 4-[4-(1-adamantyl)-phenylthio]-butyric acid ethyl ester in 300 ml of ethanol and 100 ml of tetrahydrofurane and the mixture is left to stand for 3 days at about 25° C with exclusion of air. The reaction solution is then evaporated in vacuo to a volume of about 100 ml and partitioned between 3 times 200 ml of methylene chloride and 200 ml of 2 N hydrochloric acid. The organic phases are washed until neutral, dried over sodium sulphate and evaporated in vacuo. Crystallisation of the evaporation residue from benzene/petroleum ether gives 4-[4-(1-adamantyl)-phenylthio]-butyric acid of melting point 136°-138° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][N:10]=1)=[O:5])C.O.[OH-].[Li+]>CO.O>[CH2:11]([C:8]1[O:7][C:6]([C:4]([OH:5])=[O:3])=[N:10][CH:9]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1ncc(Cc2ccccc2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ncc(Cc2ccccc2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-Benzyl-oxazole-2-carboxylic acid ethyl ester (0.95 g, 3.5 mmol) and lithiumhydroxide-hydrate (0.73 g, 17.5 mmol) in 20 mL MeOH and 10 mL water was stirred at room temperature for 2 h. The mixture was evaporated in vacuo, extracted with hexane and the aq. layer was acidified with 1 N aq. HCl. After extraction with ethyl acetate, the organic layer was dried over MgSO4, and evaporated to yield the crude product which was used in the next step without further purification. LCMS (method A) RtA=1.350 min; [M+H]+=203.9.
Reaction SMILES: C1C=CC=CC=1.[C:7]([Cl:10])(Cl)=[O:8].C([N:18]1[CH2:22][CH2:21][CH:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[CH2:19]1)C1C=CC=CC=1>O1CCCC1>[Cl:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[O:23][CH:20]1[CH2:21][CH2:22][N:18]([C:7]([Cl:10])=[O:8])[CH2:19]1
Reactant: O=C(Cl)Cl
Reactant: Clc1cccc(OC2CCN(Cc3ccccc3)C2)c1
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: O=C(Cl)N1CCC(Oc2cccc(Cl)c2)C1
Yield: 8.1 %

Procedure:
A benzene solution of 450 ml of 2M phosgene (0.9 mole) was cooled to 10° C. and while stirring, 210 g (0.81 mole) of 1-benzyl-3-(3-chlorophenoxy)pyrrolidine in 210 ml of tetrahydrofuran was added over a 31/2 hr period. The reaction mixture was allowed to stir overnight and then filtered to remove the hydrochloric acid salt of unreacted starting material. The filtrate was evaporated to give a dark colored oil which was triturated with three 500 ml portions of 30/60 petroleum ether decanting off the petroleum ether each time from the oil residue. The petroleum ether layers were cooled and the oils which separated were combined to give 17 g of pure title product as an oil. After washing with more petroleum ether, the oil (203 g) residue contained about 17% benzyl chloride by NMR analysis. Yield of contained product in both portions was 88%.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C@@H:10](O)[CH3:11])=[CH:2]1.C1C=CC(P([N:27]=[N+:28]=[N-:29])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C@H:10]([N:27]=[N+:28]=[N-:29])[CH3:11])=[CH:2]1
Reactant: C[C@H](O)c1csc2ccccc12
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@H](N=[N+]=[N-])c1csc2ccccc12
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
The process was carried out with reference to a method of Thompson, et al. (J. Org. Chem. 1993, 58, 5886). Under an argon atmosphere, a mixture of 5.50 g of (1S)-1-(1-benzothiene-3-yl)ethanol and 7.98 g of DPPA was dissolved in toluene, and 5.54 mL of DBU was then added thereto in an ice bath. After stirring for 30 min under ice-cooling, it was further stirred at room temperature for 15 hours. The reaction mixture was washed with water and 1 M hydrochloric acid in this order, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 5.86 g of (1R)-1-(1-benzothiene-3-yl)ethylazide as a colorless oily substance. EI: 203
Reaction SMILES: [NH2:1][C@H:2]([C:22]1[C:23]([CH3:32])=[C:24]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:31])[O:26][CH2:25]2)[CH2:3][N:4]1[CH2:21][CH2:20][C:7]2([C:11](=[O:12])[N:10]([C:13]3[CH2:14][O:15][C:16](=[O:19])[C:17]=3[CH3:18])[CH2:9][CH2:8]2)[CH2:6][CH2:5]1.C(N(CC)CC)C.Cl[C:41]([O:43][CH3:44])=[O:42]>ClCCl>[CH3:32][C:23]1[C:24]2[CH2:25][O:26][C:27](=[O:31])[C:28]=2[CH:29]=[CH:30][C:22]=1[C@@H:2]([NH:1][C:41](=[O:42])[O:43][CH3:44])[CH2:3][N:4]1[CH2:5][CH2:6][C:7]2([C:11](=[O:12])[N:10]([C:13]3[CH2:14][O:15][C:16](=[O:19])[C:17]=3[CH3:18])[CH2:9][CH2:8]2)[CH2:20][CH2:21]1
Reactant: COC(=O)Cl
Reactant: CC1=C(N2CCC3(CCN(C[C@H](N)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@@H](CN1CCC2(CC1)CCN(C1=C(C)C(=O)OC1)C2=O)c1ccc2c(c1C)COC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-8-(2-amino-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (Example 62) (35 mg, 0.08 mmol) and triethylamine (17 μL, 0.12 mmol) in dichloromethane (2 mL) was added methyl chloroformate (11 mg, 0.12 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stir for 2 h. TLC indicated half of starting material remained. The reaction mixture was re-cooled to 0° C. and triethylamine (17 μL, 0.12 mmol) was added thereto, followed by methyl chloroformate (11 mg, 0.12 mmol). The reaction mixture was allowed to warm to room temperature and stirred for another 2 h. TLC showed the reaction was complete. The resulting mixture was concentrated in vacuo. The residue was taken up into small amount of DCM and purified by preparative TLC (dichloromethane: methanol=15:1) to afford the title compound. MS-ESI (m/z): 498 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[CH3:7].I.[PH2](O)=O.C=O.[C:14](O)(=O)[CH3:15]>>[CH3:5][C:4]1[NH:3][C:2]([CH3:1])=[C:6]([CH3:7])[C:14]=1[CH3:15]
Reactant: Cc1cc[nH]c1C
Reactant: CC(=O)O
Agent: C=O
Agent: I
Agent: O=[PH2]O
Product: Cc1[nH]c(C)c(C)c1C
Yield: 51 %

Procedure:
As in Example 58, using 2,3-dimethyl-pyrrole (2 g), acetic acid (50 ml), hydriodic acid (50 ml), hypophosphorous acid (5 ml) and paraformaldehyde (1.2 g). Yield 51%, m.p. 105°-107°. Anal. Found: C, 77.81; H, 10.32; N, 11.45.
Reaction SMILES: [F:1][CH:2]([F:17])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[NH:8][C:7](=O)[CH2:6][O:5][CH2:4]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1COCC1>[F:1][CH:2]([F:17])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[NH:8][C:7](=[S:27])[CH2:6][O:5][CH2:4]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1COCC(c2ccccc2F)(C(F)F)N1
Solvent: C1CCOC1
Product: Fc1ccccc1C1(C(F)F)COCC(=S)N1
Temperature: 68 °C
Yield: 195 %

Procedure:
A mixture of 5-difluoromethyl-5-(2-fluoro-phenyl)-morpholin-3-one (141 g, 575 mmol) and Lawesson's reagent (132 g, 316 mmol) in 1400 ml of THF was heated at 68° C. for 1 h, cooled down and then evaporated. The residue was dissolved in 1 L DCM and filtered over 2 Kg silica gel with 10 L DCM to give 161 g of the title compound in the form of a greenish resin that slowly crystallized. The compound was used without further purification.
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[Cl:5][C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[N:10][C:11]=1[Cl:12].[OH-].[Na+]>O1CCOCC1.O>[Cl:5][C:6]1[CH:7]=[C:8]([O:13][CH:2]([F:4])[F:3])[CH:9]=[N:10][C:11]=1[Cl:12]
Reactant: FC(F)Cl
Reactant: Oc1cnc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)Oc1cnc(Cl)c(Cl)c1

Procedure:
Chlorodifluoromethane was passed at 50° C. into a mixture of 32.8 g (0.2 mol) of 5,6-dichloro-3-pyridinol in 200 ml of 1,4-dioxane and 40 g (1 mol) of sodium hydroxide in 100 ml of water until starting material was no longer present. The further procedure was then carried out as described in Example 1.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[CH3:20][C:2]1([CH3:1])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([C:22]([F:33])([F:32])[F:21])[CH:28]=3)[CH:9]=2)[C:4](=[O:19])[CH2:3]1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: CC1(C)CC(=O)c2ccc(-c3cccc(C(F)(F)F)c3)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 3-trifluoromethylphenyl boronic acid according to the procedure described in example 21. MS m/z 305; HRMS: calcd for C18H15F3O+H+, 305.11478; found (ESI, [M+H]+), 305.1142.