Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[Cl-].[CH2:38]([C:40]1[S:41][CH:42]=[C:43]([CH2:45][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:44]=1)[CH3:39].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:38]([C:40]1[S:41][CH:42]=[C:43](/[CH:45]=[CH:24]\[C:23]2[C:19]([O:18][CH2:17][C:16]3[CH:32]=[CH:33][C:13]([O:12][CH2:11][C:9]4[N:10]=[C:6]([C:2]5[O:1][CH:5]=[CH:4][CH:3]=5)[O:7][C:8]=4[CH3:36])=[C:14]([O:34][CH3:35])[CH:15]=3)=[N:20][N:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]=2)[N:44]=1)[CH3:39]
Reactant: CCc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc(/C=C\c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)cs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 20.4 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.60 g), [(2-ethyl-1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (0.76 g), potassium carbonate (0.25 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2, v/v) to give 4-({4-[({4-[(Z)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-2-(2-furyl)-5-methyl-1,3-oxazole as colorless crystals (0.15 g, yield 21%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 132-133° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[C:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1>O1CCOCC1.CO>[OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(-c3cccc(O)c3)cc2)S1
Solvent: C1COCCO1
Solvent: CO
Product: O=C1NC(=O)C(Cc2ccc(-c3cccc(O)c3)cc2)S1

Procedure:
In a manner similar to that of Example 1(g), starting with 3 g (10.1 mmol) of 5-(3′-hydroxybiphenyl-4-ylmethylene)thiazolidine-2,4-dione in a dioxane/methanol mixture (50/50), and after purification by chromatography on a column of silica eluted with a heptane/ethyl acetate mixture (7/3), 800 mg (27%) of the expected product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:18][CH:19]1[O:21][CH2:20]1)[CH:9]=2.[CH:29]([NH2:32])([CH3:31])[CH3:30]>CO>[OH:21][CH:19]([CH2:20][NH:32][CH:29]([CH3:31])[CH3:30])[CH2:18][O:17][C:10]1[CH:9]=[C:8]2[C:13]([C:14](=[O:16])[CH:15]=[C:6]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[CH:22]=3)[O:7]2)=[CH:12][CH:11]=1
Reactant: COc1cc(-c2cc(=O)c3ccc(OCC4CO4)cc3o2)cc(OC)c1OC
Reactant: CC(C)N
Solvent: CO
Product: COc1cc(-c2cc(=O)c3ccc(OCC(O)CNC(C)C)cc3o2)cc(OC)c1OC

Procedure:
3′,4′,5′-Trimethoxy-7-(2,3-epoxy-propoxy)-flavone, 31 (1.2 g, 3 mmol) and iso-propyl amine (0.78 mL, 9.3 mmol) in dry methanol (120 mL) were reacted in a similar manner to that described under 34 to afford 41. Yield 900 mg (65%); mp 106-107° C.; MS (FAB) 444 (M++1); IR (KBr) 3394, 1631; 1H NMR (200 MHz, CDCl3) δ 8.09 (d, J=9.5 Hz, 1H), 7.10 (s, 2H), 7.10-6.99 (m, 2H), 6.71 (s, 1H), 4.16-4.09 (m, 3H), 3.96 (s, 6H), 3.93 (s, 3H), 2.95-2.82 (m, 3H), 1.14 (d, J=6.2 Hz, 6H).
Reaction SMILES: Cl.[C:2](N)(=[NH:5])[CH2:3][CH3:4].[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][CH:10]=1>>[NH:5]=[C:2]([N:15]([C:13](=[O:14])[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:18][CH:17]=1)[NH2:16])[CH2:3][CH3:4]
Reactant: COc1ccc(C(=O)NN)cc1
Reactant: CCC(=N)N
Agent: Cl
Product: CCC(=N)N(N)C(=O)c1ccc(OC)cc1
Yield: 150.7 %

Procedure:
Prepared from 4.90 g (45 mmol) propioamidine hydrochloride and 5.00 g (30 mmol) 4-methoxy-benzoic acid hydrazide analogously to the method described for intermediate product 1a). After the ethanol has been distilled off, 10.0 g crude product is obtained that is reacted without any further purification.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[C:38]3[C:33](=[CH:34][C:35]([Cl:39])=[CH:36][CH:37]=3)[N:32]=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[C:38]3[C:33](=[CH:34][C:35]([Cl:39])=[CH:36][CH:37]=3)[N:32]=[CH:31][CH:30]=2)=[CH:26][CH:27]=1)([OH:20])=[O:19]
Reactant: N[C@@H](Cc1ccc(Oc2ccnc3cc(Cl)ccc23)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ccnc3cc(Cl)ccc23)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(7-chloro-quinolin-4-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good, yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][N:11]3[C:14](=[O:28])[N:15]([CH2:17][C:18]4[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Ca+2].[Br-:34].[Br-].[Br-].C[N+](C)(C)CC1C=CC=CC=1.C[N+](C)(C)CC1C=CC=CC=1.C[N+](C)(C)CC1C=CC=CC=1>ClC(Cl)C>[Br:34][C:9]1[C:10]2[N:11]([C:14](=[O:28])[N:15]([CH2:17][C:18]3[CH:19]=[N:20][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:22][CH:23]=3)[N:16]=2)[CH:12]=[N:13][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: [Br-]
Reactant: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2cc(-c3ccc(Cl)cc3)ncn12
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(Cl)Cl
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(Br)c(-c3ccc(Cl)cc3)ncn12
Temperature: 70 °C
Yield: 90 %

Procedure:
To a solution of 7-(4-chlorophenyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (40.5 mg, 0.10 mmol) in dichloroethane (5 mL) at room temperature under argon was added calcium carbonate (10.0 mg, 0.10 mmol) and N,N,N-trimethyl-1-phenylmethanaminium tribromide (39.0 mg, 0.10 mmol). The resulting suspension was stirred and heated at 70° C. under argon for 2 h. Analysis by HPLC/MS indicated that most of the starting material had been consumed. After the reaction mixture was cooled to room temperature, the product was purified by silica gel column chromatography eluted with ethyl acetate-dichloromethane. This provided the title compound (43.6 mg) as a solid. HPLC/MS (methanol-water with 10 mM NH4OAc): retention time=3.67 min, [M+H]+486.
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:17][OH:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:17][O:18][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:5])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)Cc1ccccc1
Temperature: 0 °C

Procedure:
500 mg (1.99 mmol) of N-Boc-L-phenylalaninol were dissolved in 5 ml DMF and cooled down to 0° C. under argon atmosphere. Then 159 mg (3.98 mmol) of a 60% suspension of sodium hydride was added in liquid paraffin. The reaction composition then was stirred until completion of gas formation and then mixed with 260 μl (2.19 mmol) of benzyl bromide. The cooling bath was removed and the reaction composition stirred for 2 hours at RT. Afterwards, the batch was evaporated, the residue absorbed in ice water and the composition extracted with dichlormethane. The organic phase was washed with saturated saline, dried over magnesium sulphate and evaporated. The residue was purified by means of a preparative HPLC. The yield was 226 mg (33% o. th.) of the title compound.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:18][CH2:19][O-:20].[Na+]>C(O)C>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:20][CH2:19][CH3:18])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC[O-]
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and sodium ethylate in ethanol there is obtained ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and therefrom with hydrochloric acid in alcohol there is obtained the hydrochloride, m.p. 158° C. (with decomposition);
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C@H:14]3[C@H:9]([CH2:10][CH2:11][NH:12][CH2:13]3)[CH2:8][C:7](=[O:15])[C:6]=2[CH:16]=1.Br[CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C@H:14]3[C@H:9]([CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH3:20])[CH2:13]3)[CH2:8][C:7](=[O:15])[C:6]=2[CH:16]=1
Reactant: O=C1C[C@H]2CCNC[C@H]2c2ccc(F)cc21
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN1CC[C@@H]2CC(=O)c3cc(F)ccc3[C@@H]2C1
Temperature: 125 °C
Yield: 63.8 %

Procedure:
A mixture of 0.29 g (1.32 mmol) of cis-8-fluoro-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one, 0.12 ml (1.39 mmol) of bromopropane, 0.2 g (1.45 mmol) of potassium carbonate and 20 ml of anhydrous DMF was heated to 125° C. for 1 hour. Subsequently, the mixture was poured into 3 ml of water and extracted once with 50 ml of ethyl acetate. The organic phase was washed once with 40 ml of saturated sodium chloride solution, dried (MgSO4) and concentrated in a vacuum. The crude product obtained was purified by column chromatography on silica gel (methylene chloride/methanol/NH4OH 9:1:0.2). There were obtained 220 mg (63%) of cis-8-fluoro-2-propyl-1,3,4,4a, 5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one as a yellow oil, which was converted with MeOH/HCl into the hydrochloride with m.p. >220°.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(O)c1cccc(Br)n1
Product: O=C(O)c1cccc(-c2ccc(Cl)cc2)n1

Procedure:
6-Bromo-pyridine-2-carboxylic acid (1 g, 4.95 mmol) was coupled to 4-chloro-phenylboronic acid (775 mg, 4.96 mmol) acid using Method F to give the title compound.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH2:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH2:11]([O:18][C:19](=[O:36])[NH:20][C@@H:21]([CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:22][S:23](Cl)(=[O:25])=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19](=[O:36])[NH:20][C@@H:21]([CH2:27][O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:22][S:23](=[O:25])(=[O:24])[NH:10][CH:7]1[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(N[C@@H](COCc1ccccc1)CS(=O)(=O)Cl)OCc1ccccc1
Reactant: CC(C)N1CCC(N)CC1
Product: CC(C)N1CCC(NS(=O)(=O)C[C@H](COCc2ccccc2)NC(=O)OCc2ccccc2)CC1

Procedure:
[(S)-1-Benzyloxymethyl-2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-carbamic acid benzyl ester was prepared by an analogous procedure as described for example 26 vi) starting from 142 mg (1.0 equiv.) 1-isopropyl-piperidin-4-ylamine and 398 mg (1.0 mmol) ((S)-1-benzyloxymethyl-2-chlorosulfonyl-ethyl)-carbamic acid benzyl ester. The product was obtained in crude form as a light yellow foam. Yield: 217 mg MS (ES+): m/e=504.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([NH:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[O:32])[C:25]=1[CH3:42])(=[O:12])=[O:11].[C:43]([O:46][CH2:47][C:48](Cl)=[O:49])(=[O:45])[CH3:44]>C(Cl)Cl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([NH:33][CH2:34][CH2:35][N:36]2[CH2:37][CH2:38][N:39]([C:48](=[O:49])[CH2:47][O:46][C:43](=[O:45])[CH3:44])[CH2:40][CH2:41]2)=[O:32])[C:25]=1[CH3:42])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)NCCN1CCNCC1
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Product: CC(=O)OCC(=O)N1CCN(CCNC(=O)Cc2c(C)[nH]c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)Cc5c(Cl)cccc5Cl)cc43)c2C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
A mixture of 2-{5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-N-(2-piperazin-1-yl-ethyl)-acetamide (300 mg, 0.475 mmol), acetoxyacetyl chloride (97 mg, 1.5 eq.) and TEA (0.5 mL) in DCM (10 mL) was stirred at rt for overnight. The precipitate was collected by vacuum filtration, washed with water and methanol to give 300 mg of acetic acid 2-{4-[2-(2-{5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetylamino)-ethyl]-piperazin-1-yl}-2-oxo-ethyl ester as a red solid.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[N:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:14]([CH3:17])([O-:16])=[O:15]>>[CH2:5]([NH:4][C:3]([S:2][CH3:1])=[CH:17][N+:14]([O-:16])=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CSC(=NCc1ccccc1)SC
Reactant: C[N+](=O)[O-]
Product: CSC(=C[N+](=O)[O-])NCc1ccccc1

Procedure:
A mixture of nitromethane (4 ml), zeolite, RE 70 Na-Y (500 mg) and benzyl carbonimidodithioic acid dimethyl ester (XI, 500 mg) was refluxed for 110 hr. It was filtered and filtrate concentrated and treated with pet. ether. The solid that separated out was filtered and characterized as compound XII.
Reaction SMILES: [F:1][C:2]([F:20])([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]CS([O-])(=O)=O.[CH3:21][NH2:22]>O1CCCC1>[F:1][C:2]([F:20])([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:22][CH3:21]
Reactant: O=S(=O)([O-])CCCCCCC(F)(F)C(F)(F)C(F)(F)F
Reactant: CN
Solvent: C1CCOC1
Product: CNCCCCCC(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.6 %

Procedure:
In a solution of 44.7 g of 6,6,7,7,8,8,8-heptafluoro-octylmethanesulfonate in 134 ml of tetrahydrofuran, 41.5 g of methylamine is condensed at −78° C. and stirred for 24 hours at room temperature in a pressurized reactor. Then, it is evaporated to the dry state in a vacuum, washed with water as well as common salt solution, dried on sodium sulfate and evaporated to the dry state in a vacuum. 34.9 g of crude 6,6,7,7,8,8,8-heptafluoro-octyl-methylamine is obtained, and after distillation, 21 g of pure 6,6,7,7,8,8,8-heptafluoro-octyl-methylamine with a boiling point of 89-93° C. at 69 mbar is obtained.
Reaction SMILES: [C:1]([O:5]C)(=O)[CH2:2][OH:3].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1>>[OH:3][CH2:2][C:1]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:5]
Reactant: Cc1ccc(N)nc1
Reactant: COC(=O)CO
Product: Cc1ccc(NC(=O)CO)nc1

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate A3, starting from methyl glycolate and 2-amino-5-picoline, 1H NMR (300 MHz, CDCl3) δ 9.24 (br s, 1H), 8.19 (d, 1H), 8.07 (d, 1H), 7.57 (dd, 1H), 5.59 (br s, 1H), 4.26 (s, 2H), 2.31 (s, 3H).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[S:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=[C:25]1[C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1>>[S:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=[C:25]1[C:33]1[CH:39]=[CH:38][C:36]([NH:37][C:1]([C:4]23[CH2:5][CH2:6][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:10][CH2:11]2)[CH2:8][CH2:9]3)=[O:3])=[CH:35][CH:34]=1
Reactant: Nc1ccc(-c2nc3ccccc3s2)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(-c4nc5ccccc5s4)cc3)(CC1)CC2
Yield: 12.7 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-(benzothiazol-2-yl)aniline (51.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-[4-(benzothiazol-2-yl)phenyl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (10.4 mg).
Reaction SMILES: [CH2:1]1CCN2C(=NCCC2)CC1.[C:12]([OH:20])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.O>[C:12]([O:20][CH3:1])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccccc1
Temperature: 90 °C

Procedure:
DBU (2.5 g, 16.4 mmol) was added to a mixture of benzoic acid (2.0 g, 16.4 mmol) in DMC (20 mL) and the resulting mixture was heated to reflux (90° C.) for 2.5 hours. The reaction mixture was cooled to ambient temperature and diluted with CH2Cl2 (50 mL) and water (40 mL). The organic layer was separated and washed in sequence with 2 M HCl (2×40 mL), saturated aqueous NaHCO3 (40 mL) and water (2×40 mL). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give methyl benzoate as an oil. The yield of the methyl benzoate as determined by HPLC was 97-98% conversion.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][C:17]1=[O:25].N1CCCCC1>C(O)C>[O:25]=[C:17]1[NH:16][C:24]2[C:19](/[C:18]/1=[CH:1]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:20][CH:21]=[CH:22][CH:23]=2
Reactant: O=C1Cc2ccccc2N1
Reactant: CCOC(=O)C=Cc1ccccc1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)CCc1ccccc1/C=C1/C(=O)Nc2ccccc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
A mixture of 1 g of ethyl 3-(2-formylphenyl)propenate, 500 mg oxindole and 0.1 mL piperidine in 5 mL of ethanol was stirred at 90° C. overnight. The mixture was evaporated and purified on a silica gel column to give 450 mg of ethyl (E)-3-[(2-oxo-1,2-dihydroindol-3-ylidenemethyl)phenyl]-propionate (M+1=322).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[S:10](=[O:12])(=[O:11])[N:9]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[CH2:8][C:7]1=[O:23].[C:30]([O:34][C:35](=[O:44])[C:36]1[CH:41]=[CH:40][C:39]([CH2:42]O)=[CH:38][CH:37]=1)([CH3:33])([CH3:32])[CH3:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:30]([O:34][C:35]([C:36]1[CH:41]=[CH:40][C:39]([CH2:42][O:20][C:18](=[O:19])[C:17]2[CH:16]=[CH:15][C:14]([CH2:13][N:9]3[CH2:8][C:7](=[O:23])[NH:6][S:10]3(=[O:11])=[O:12])=[CH:22][CH:21]=2)=[CH:38][CH:37]=1)=[O:44])([CH3:33])([CH3:31])[CH3:32]
Reactant: COc1ccc(CN2C(=O)CN(Cc3ccc(C(=O)O)cc3)S2(=O)=O)c(OC)c1
Reactant: CC(C)(C)OC(=O)c1ccc(CO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(COC(=O)c2ccc(CN3CC(=O)NS3(=O)=O)cc2)cc1
Temperature: 5 °C
Reaction time: 16 h

Procedure:
A solution of the title B compound, 4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoic acid (84 mg, 0.2 mmol) and 4-hydroxymethyl-benzoic acid t-butyl ester (42 mg, 0.2 mmol) in CH2Cl2 (3 mL) is treated with DMAP (12 mg, 0.1 mmol) and the reaction is cooled to 5° C. EDCl (39 mg, 0.2 mmol) is then added and the reaction is stirred for 16 h. The mixture is concentrated and partioned between EtOAc and 1N aqueous HCl. The organic solution is washed with saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4 and concentrated to give 4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)-benzoic acid 4-t-butoxycarbonyl-benzyl ester as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([P:16]([CH3:19])([CH3:18])=[O:17])=[CH:12][CH:11]=2)[N:3]=1.C(N(CC)CC)C.[CH3:27][C:28]1[CH:29]=[C:30]([CH:32]=[C:33]([CH3:35])[CH:34]=1)[NH2:31]>C(O)C>[Cl:8][C:6]1[N:7]=[C:2]([NH:31][C:30]2[CH:32]=[C:33]([CH3:35])[CH:34]=[C:28]([CH3:27])[CH:29]=2)[N:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([P:16]([CH3:19])([CH3:18])=[O:17])=[CH:12][CH:11]=2)[N:5]=1
Reactant: CP(C)(=O)c1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Reactant: Cc1cc(C)cc(N)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(Nc2nc(Cl)nc(Nc3ccc(P(C)(C)=O)cc3)n2)c1

Procedure:
To a solution of 4,6-dichloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 102: 0.12 mmol) in 2 mL of ethanol is added 50 μL of triethylamine and 3,5-dimethylaniline (24 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: O.[NH2:2][NH2:3].O=[C:5]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)[CH2:6][C:7]#[N:8]>C(O)C>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:12]1[CH2:11][CH2:10][CH:9]([C:5]2[CH:6]=[C:7]([NH2:8])[NH:3][N:2]=2)[CH2:14][CH2:13]1
Reactant: N#CCC(=O)C1CCN(c2ccccn2)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1cc(C2CCN(c3ccccn3)CC2)n[nH]1
Reaction time: 5 h
Yield: 89.1 %

Procedure:
Hydrazine monohydrate (0.20 mL, 4.12 mmol) was added to a solution of 3-oxo-3-[1-(pyridin-2-yl)piperidin-4-yl]propanenitrile (138 mg, 0.60 mmol) produced in Reference Example 1 in ethanol (20 mL), and the mixture was stirred for 5 hours under heating to reflux. The reaction solution was left until reaching room temperature, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elute: ethyl acetate/methanol=100/0-94/6 (gradient)] to obtain the title compound (130 mg, yield: 89%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=O)C.O.[NH2:13][NH2:14]>C(O)C>[N:7]1[CH:8]=[CH:9][CH:10]=[N:11][C:6]=1[C:4]([NH:13][NH2:14])=[O:3]
Reactant: NN
Reactant: CCOC(=O)c1ncccn1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ncccn1
Yield: 68.8 %

Procedure:
A mixture of pyrimidine-2-carboxylic acid ethyl ester (Ann. Chim., 5, 351 (1960)) (0.866 g, 5.7 mmol) and hydrazine hydrate (0.332 mL, 6.8 mmol) in ethanol (20 mL) was heated under reflux for 3 hours, then concentrated under reduced pressure. The residue was triturated with diethyl ether, collected by filtration and washed with ethyl acetate to give the title compound (0.542 g, 69%) as a yellow solid, mp 173-175° C.