Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:12])[CH:2]([OH:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+].Cl[CH2:16][C:17]([O-])=[O:18].[Na+].O>C(OCC)C>[CH2:3]([CH:2]1[O:11][C:17](=[O:18])[CH2:16][O:12][CH2:1]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC(O)CO
Reactant: O=C([O-])CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCC1COCC(=O)O1
Temperature: 55 °C
Reaction time: 1.75 h
Yield: 63 %

Procedure:
Powdered decane-1,2-diol (0.25 moles) is stirred at room temperature and very well powdered sodium hydroxide (0.25 moles) is added in portions. Gentle heating of the mixture to 55° C. gives a viscous yellow paste. Sodium chloroacetate (0.25 moles) is now added in portions over 10 minutes. The white mobile paste produced is stirred at 70°-60° C. for 1.75 h. After cooling to 20° C., 100 ml of petroleum ether is added followed by water. After separation of phases (aided by acetone) the aqueous phase is run off and acidified to pH 1.5 using 98% sulphuric acid. The oil produced is taken up into 2×375 ml diethyl ether which is then dried and evaporated to leave the title product as a clear oil (63%).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])[CH3:3].CN(C1C=CC=CN=1)C.[C:41](O)(=[O:47])[CH2:42][CH2:43][C:44]([OH:46])=[O:45].O>N1C=CC=CC=1>[CH3:29][O:28][C:26]1[CH:27]=[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([NH:13][C:6]3[CH:5]=[C:4]([CH:2]([O:1][C:41](=[O:47])[CH2:42][CH2:43][C:44]([OH:46])=[O:45])[CH3:3])[C:9]([CH3:10])=[N:8][C:7]=3[O:11][CH3:12])=[O:15])[CH2:17][CH2:18]2)[CH:23]=[C:24]([O:30][CH3:31])[CH:25]=1
Reactant: O=C(O)CCC(=O)O
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C(C)O)c(C)nc3OC)CC2)c1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C(C)OC(=O)CCC(=O)O)c(C)nc3OC)CC2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
1-{[5-(1-Hydroxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl}-4-(3,5-dimethoxyphenyl)piperazine(107 mg, 0.25 mmol) and dimethylaminopyridine(3 mg, 0.025 mmol) were dissolved in pyridine and anhydrous succinic acid(50 mg, 0.5 mmol) was added. The mixture was stirred at room temperature for 5 hrs. Distilled water was added into the above mixture. The above solution was extracted with CH2Cl2 and the organic phase washed with 1N-HCl and then concentrated under the reduced pressure to remove the solvent. The concentrate was purified by column chromatography(dichloromethane:methanol=20:1) to obtain the titled compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[F:23][C:24]1[CH:25]=[C:26]([C:31]2[S:35][C:34]([CH3:36])=[N:33][C:32]=2[C:37](O)=[O:38])[CH:27]=[CH:28][C:29]=1[F:30]>>[F:23][C:24]1[CH:25]=[C:26]([C:31]2[S:35][C:34]([CH3:36])=[N:33][C:32]=2[C:37]([N:6]2[CH2:5][C@H:4]3[C@H:8]([CH2:9][CH:2]([CH3:1])[CH2:3]3)[C@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])=[O:38])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)c(F)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2ccc(F)c(F)c2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(3,4-difluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[O:8][CH:9]=1)=O.[NH:14]1[CH2:18][CH2:17][NH:16][C:15]1=[S:19].C(O)C>C(O)(=O)C>[BrH:1].[O:8]1[CH:9]=[C:5]([C:3]2[N:16]3[CH2:17][CH2:18][N:14]=[C:15]3[S:19][CH:2]=2)[C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]1=2
Reactant: O=C(CBr)c1coc2ccccc12
Reactant: S=C1NCCN1
Solvent: CCO
Solvent: CC(=O)O
Product: Br
Product: C1=C(c2coc3ccccc23)N2CCN=C2S1
Temperature: 25 °C
Yield: 56.4 %

Procedure:
A mixture of 3-(2-bromoacetyl)benzo[b]furan (36.9 g), 2-imidazolidinethione (15.75 g), ethanol (600 ml) and acetic acid (400 ml) was heated under reflux for 21 hours then allowed to cool to ambient temperature. The resulting solid was collected by filtration, washed with ether (500 ml), and dissolved in hot methanol (500 ml). Charcoal (2 g) was added and the hot mixture was stirred for a few minutes, then filtered and allowed to cool to ambient temperature. The resulting solid was collected by filtration, ground to a fine powder, and dried in vacuo at 80° C. to give 3-(benzo[b]furan-3-yl)-5,6-dihydroimidazo[2,1-b]thiazole monohydrobromide 0.7 hydrate as an off-white solid (28.1 g), m.p. 251°-254.50C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:23]=[CH:22][C:11]3[CH:12]([NH:15][C:16]([C:18]4([NH2:21])[CH2:20][CH2:19]4)=[O:17])[CH2:13][O:14][C:10]=3[CH:9]=2)[CH:7]=1.[N:31]1[CH:36]=[CH:35][C:34]([C:37](O)=[O:38])=[CH:33][N:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:23]=[CH:22][C:11]3[CH:12]([NH:15][C:16]([C:18]4([NH:21][C:37]([C:34]5[CH:35]=[CH:36][N:31]=[N:32][CH:33]=5)=[O:38])[CH2:20][CH2:19]4)=[O:17])[CH2:13][O:14][C:10]=3[CH:9]=2)[CH:7]=1
Reactant: O=C(O)c1ccnnc1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)OCC3NC(=O)C2(N)CC2)no1
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)OCC3NC(=O)C2(NC(=O)c3ccnnc3)CC2)no1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-6-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-2,3-dihydro-benzofuran-3-yl}-amide (example 45) has been coupled with pyridazine-4-carboxylic acid to yield the title compound as yellow solid. MS: 535.1 (MH+, 1Cl).
Reaction SMILES: [CH:1](O)=[O:2].[NH2:4][C:5]1[C:6](=[O:21])[NH:7][CH:8]=[C:9]([CH3:20])[C:10]=1[S:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1>C(OCC)=O>[CH:1]([NH:4][C:5]1[C:6](=[O:21])[NH:7][CH:8]=[C:9]([CH3:20])[C:10]=1[S:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1)=[O:2]
Reactant: Cc1cc(C)cc(Sc2c(C)c[nH]c(=O)c2N)c1
Reactant: O=CO
Solvent: CCOC=O
Product: Cc1cc(C)cc(Sc2c(C)c[nH]c(=O)c2NC=O)c1
Yield: 58 %

Procedure:
Formic acid (2 ml) was added to a solution of amine 8a (0.10 g, 0.4 mmole) in ethyl formate (previously distilled over calcium hydride) (8 ml). The mixture was heated under reflux for 12 hours. After evaporation of the volatile substances, the residue was washed twice with ethanol and once with ethyl acetate. It was purified by column chromatography using a mixture of dichloromethane and ethanol (95:5) as eluant and, at the end, ethyl acetate, to give compound 11a (0.06 g, 58%) in the form of a white powder: melting point 221-222° C.; NMR-1H (DMSO-d6) δ 11.96 (1H, s, NH-1), 8.28 (1H, s, NH-3) 7.23 (1H, s, H-6), 6.88 (1H, d, H-4'), 6.78 (2H, s, H-2' and 6'), 2.23 (6H, s, CH3 -3' and 5'), 1.85 (3H, s, CH3 -5). Anal. C15H16N2O2S (C, H, N, S).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:13]=[C:12](Cl)[C:11]2[CH2:15][CH2:16][CH2:17][C:10]=2[N:9]=1>C(O)C>[Cl:7][C:8]1[N:13]=[C:12]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[C:11]2[CH2:15][CH2:16][CH2:17][C:10]=2[N:9]=1
Reactant: Clc1nc(Cl)c2c(n1)CCC2
Reactant: C1COCCN1
Solvent: CCO
Product: Clc1nc2c(c(N3CCOCC3)n1)CCC2
Reaction time: 13 h
Yield: 85 %

Procedure:
Morpholine (0.32 mL, 3.7 mmol) was added to a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopentapyrimidine (0.5 g, 2.65 mmol) in anhydrous ethanol (5 mL) and stirred at a temperature in the range of 65° C. to 85° C. for 10 to 16 hours. Thereafter, the mixture was concentrated under reduced pressure and the crude was diluted with anhydrous ether. After standing at a temperature in the range of 5° C. to 10° C. for 2 hours, the precipitated solid was filtered and washed with ether. The solid was recrystallized from ethyl acetate to afford the title compound as a pale yellow solid (0.54 g, 86% yield).
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[C:26]([N:35]2[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41]C(=O)OC(C)(C)C)[CH2:36]2)=[C:27]2[CH2:33][CH2:32][C:31](=[O:34])[C:28]2=[N:29][CH:30]=1)=[O:23])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[C:26]([N:35]2[CH2:40][CH2:39][CH2:38][C@H:37]([NH2:41])[CH2:36]2)=[C:27]2[CH2:33][CH2:32][C:31](=[O:34])[C:28]2=[N:29][CH:30]=1)=[O:23]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1)CCC2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(c1N1CCC[C@H](N)C1)CCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
A solution of tert-butyl {(3S)-1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-7-oxo-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate (2.0 mg, 0.0029 mmol) in DCM (0.009 mL) was treated with TFA (0.01 mL, 0.1 mmol). The reaction mixture was stirred at room temperature for 1 h, concentrated and then diluted with MeOH and neutralized with NH4OH. After filtration, the crude was purified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the title compound as white powder (1.3 mg, 92%). LCMS calc. for C23H23F2N6O2S (M+H)+: m/z=485.2. Found: 485.1.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.[F:26][C:27]([F:39])([F:38])[C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.[CH2:40]([NH:42][CH2:43][CH2:44][OH:45])[CH3:41]>>[CH2:40]([N:42]([CH2:43][CH2:44][OH:45])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C@H:6]1[CH2:5][CH2:4][C@H:3]([N:2]([CH3:1])[S:34]([C:31]2[CH:32]=[CH:33][C:28]([C:27]([F:39])([F:38])[F:26])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH2:8][CH2:7]1)[CH3:41]
Reactant: CCNCCO
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CN[C@H]1CC[C@H](CCCCCOS(C)(=O)=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCN(CCO)CCCCC[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to examples 29.10 and 29.11, trans-Methansulfonic acid 5-(4-methyl amino-cyclohexyl)-pentyl ester.Trifluoroacetic acid salt and 4-(trifluoromethyl)benzenesulphonyl chloride were reacted, followed by treatment with 2-ethylamino-ethanol to yield trans-N-(4-{5-[Ethyl-(2-hydroxy-ethyl)-amino]-pentyl}-cyclohexyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide, MS: 479 (MH+).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:12]=2)=[O:10])[CH3:7])[CH2:3]1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C(Cl)Cl>[F:29][C:25]1[CH:24]=[C:23]2[C:28]([C:20]([C:17]3[N:18]=[C:19]4[C:11]([C:9]([NH:8][CH:6]([C@@H:4]5[CH2:3][C@H:2]([O:1][S:47]([CH3:46])(=[O:49])=[O:48])[CH2:5]5)[CH3:7])=[O:10])=[CH:12][N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[C:14]4=[N:15][CH:16]=3)=[N:21][N:22]2[CH3:30])=[CH:27][CH:26]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@@H](O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@@H](OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a partial suspension of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(cis-3-hydroxy-cyclobutyl)-ethyl]-amide (100 mg, 0.19 mmol) in CH2Cl2 (3 mL) at 0° C. was added triethylamine (39 μL, 0.28 mmol) followed by methanesulfonyl chloride (16 μL, 0.21 mmol). The reaction mixture was stirred at 0° C. for 1 h then quenched with water and extracted with CH2Cl2. The organics were dried over MgSO4 and concentrated to give methanesulfonic acid cis-3-(1-{[2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-ethyl)-cyclobutyl ester as an off-white foam which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([C:9]2[C:10]([CH3:18])=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:21][N:22]([CH:24](OC)OC)[CH3:23]>CN(C=O)C>[CH3:21][N:22]([CH3:24])[CH:23]=[CH:18][C:10]1[C:9]([C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=2)=[CH:14][CH:13]=[CH:12][C:11]=1[N+:15]([O-:17])=[O:16]
Reactant: COC(OC)N(C)C
Reactant: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2C)cc1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2C=CN(C)C)cc1
Yield: 91.9 %

Procedure:
A solution of 97.9 g (0.36 mole) of 3-(4-methoxybenzoyl)-2-methylnitrobenzene and 191 ml (1.45 mole) of DMF dimethyl acetal in 400 ml of DMF was heated under reflux for about nineteen hours and the reaction mixture then taken to dryness in vacuo to give 108 g of 2-(2-dimethylaminoethenyl)-3-(4-methoxybenzoyl)nitrobenzene as a red oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[CH2:23][C@H:12]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=4[CH2:23][C@H:12]23)=[O:8])=[CH:9][CH:10]=1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: Nc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1ccc(C(=O)N2CCC[C@@H]3c4ccccc4C[C@@H]32)cc1
Yield: 70 %

Procedure:
The title compound is prepared from 4-amino-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 70% of theory; LC (method 4): tR=1.77 min; Mass spectrum (ESI+): m/z=293 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:6](O)=[O:7].S(Cl)([Cl:25])=O>ClC(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:6]([Cl:25])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(CCCBr)(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Product: O=C(Cl)C(CCCBr)(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
To a stirred solution of 29.5 parts of α-(3-bromopropyl)-4-fluoro-α-(4-fluorophenyl)benzeneacetic acid in 300 parts of trichloromethane were added 28.8 parts of thionyl chloride and the whole was stirred and refluxed for 3 hours. The reaction mixture was evaporated, yielding 30 parts of α-(3-bromopropyl)-4-fluoro-α-(4-fluorophenyl)benzeneacetyl chloride as a residue (intermediate 17).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]=[C:9]([CH2:13][C:14](O)=[O:15])[C:10]([OH:12])=[O:11].[OH-].[Na+]>O>[CH:1]1([N:7]2[C:14](=[O:15])[CH2:13][CH:9]([C:10]([OH:12])=[O:11])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: C=C(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CC(=O)N(C2CCCCC2)C1
Temperature: 110 °C
Yield: 58.1 %

Procedure:
A mixture of cyclohexanamine (3.70 mL; 31.94 mmol) and 2-methylenesuccinic acid (5.04 g; 41.62 mmol) in water (10 mL) was heated in a sealed tube at 110° C. for 21 hours. After cooling to room temperature, 6N NaOH (10 mL) was added and the resulting precipitate was filtered off. The filtrate was acidified with 6N hydrochloric acid to pH 1 and the resulting precipitate was filtered, washed with water, and dried to yield 3.92 g (58%) of 1-cyclohexyl-5-oxopyrrolidine-3-carboxylic acid as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[C:16]([F:18])[C:13]([C:14]#[N:15])=[C:12]([F:19])[CH:11]=2)=[N:6]1)[CH3:4].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:30]=[C:29]([C:31](O)=[O:32])[NH:28][N:27]=2)[CH:21]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:14]([C:13]1[C:16]([F:18])=[CH:17][C:10]([C:7]2[CH:8]=[CH:9][N:5]([C@@H:3]([CH3:4])[CH2:2][NH:1][C:31]([C:29]3[NH:28][N:27]=[C:26]([C:22]4[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=4)[CH:30]=3)=[O:32])[N:6]=2)=[CH:11][C:12]=1[F:19])#[N:15]
Reactant: O=C(O)c1cc(-c2cccnc2)n[nH]1
Reactant: C[C@@H](CN)n1ccc(-c2cc(F)c(C#N)c(F)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](CNC(=O)c1cc(-c2cccnc2)n[nH]1)n1ccc(-c2cc(F)c(C#N)c(F)c2)n1

Procedure:
The title compound was synthesized from (S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile (0.277 g, 1.06 mmol), 3-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid (0.2 g, 1.06 mmol), HOBt (0.17 g, 1.27 mmol), DIPEA (0.22 mL, 1.27 mmol) and EDCI (0.243 g, 1.27 mmol) using DCM as the solvent using the method of Example 34(d). Yield 0.13 g. 1H NMR (400 MHz; d6-DMSO): δ 1.50 (d, 3H), 3.66 (m, 2H), 4.72 (m, 1H), 7.00 (d, 1H), 7.20 (s, 1H), 7.48 (m, 1H), 7.78 (m, 2H), 7.93 (d, 1H), 8.13 (m, 1H), 8.55 (dd, 1H), 8.97 (s, 1H).
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:34])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([Cl:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:22][CH:21]=1)([CH3:17])[CH2:9][CH2:8]2)(=O)C.[O-]CC.[Na+].Cl>C(O)C.O1CCCC1>[Cl:33][CH:27]([CH2:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][C:10]2([CH3:17])[CH2:9][CH2:8][C:7]3[C:12](=[C:13]([CH3:16])[C:14]([CH3:15])=[C:5]([OH:4])[C:6]=3[CH3:34])[O:11]2)=[CH:25][CH:24]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CCc3c(C)c(OC(C)=O)c(C)c(C)c3O2)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)cc1

Procedure:
0.48 g of ethyl 3-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl]-2-chloropropionate was dissolved in a mixture of 3 ml of absolute ethanol and 2 ml of dry tetrahydrofuran. An ethanolic solution of sodium ethoxide (prepared by dissolving 49.0 mg sodium in 2 ml of absolute ethanol) was added dropwise, under a nitrogen stream at 10°-13° C., to the resulting solution. The mixture was then reacted for 21 hours at 0°-5° C., after which 0.22 g of concentrated hydrochloric acid dissolved in 99.5% ethanol was added dropwise, with ice-cooling. The solvent was then distilled off from the reaction mixture under reduced pressure; the separated light reddish oil was extracted with chloroform; and the extract was washed with water and then dried over anhydrous sodium sulfate. The crude product obtained by distilling the chloroform off from the extract under reduced pressure was subjected to silica gel column chromatography, and the desired ethyl 2-chloro-3-[4-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-ylmethoxy)phenyl]propionate was obtained from the fractions eluted with benzene. Rf value on thin layer chromatography: 0.60 [silica gel; developing solvent; benzene:ethyl acetate=10:1 by volume].
Reaction SMILES: NO.[C:3]([C:6]1[CH:35]=[CH:34][C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])=[CH:14][CH:13]=2)=[C:8]([CH2:36][CH2:37][CH3:38])[C:7]=1[OH:39])(=[O:5])[CH3:4].[N:40]1C=CC=CC=1.Cl[C:47]([O:49]CC(CC)CCCC)=[O:48]>C(O)C.Cl.CO.O>[C:3]([C:6]1[CH:35]=[CH:34][C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[C:19]3[CH:20]=[C:21]([C:22]4[NH:40][C:47](=[O:48])[O:49][N:23]=4)[CH:24]=[CH:25][CH:26]=3)=[CH:14][CH:13]=2)=[C:8]([CH2:36][CH2:37][CH3:38])[C:7]=1[OH:39])(=[O:5])[CH3:4]
Reactant: CCCCC(CC)COC(=O)Cl
Reactant: c1ccncc1
Reactant: CCCc1c(OCc2ccc(C(OC3CCCCO3)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Agent: Cl
Agent: NO
Solvent: CO
Solvent: CCO
Solvent: O
Product: CCCc1c(OCc2ccc(C(OC3CCCCO3)c3cccc(-c4noc(=O)[nH]4)c3)cc2)ccc(C(C)=O)c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 2.1 %

Procedure:
Add hydroxylamine (50% solution in water, 0.128 mL, 2.09 mmol) to a solution of 3-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile (950 mg, 1.90 mmol) in ethanol (20 mL) and stir. Heat the solution to reflux for 3 hours. Cool the reaction to ambient temperature and concentrate to dryness. Dissolve the resulting residue in tetrahydrofuran (20 mL) and cool to 0° C. Add pyridine (226 mg, 2.85 mmol) and 2-ethylhexyl chloroformate (403 mg, 2.09 mmol) and stir. After 30 minutes, add water (50 mL) and extract with ethyl acetate. Combine the organic extracts, dry with sodium sulfate, filter and concentrate to dryness. Dissolve the resulting residue in xylenes (20 mL) and heat to 130° C. After 4 hours, cool to ambient temperature and concentrate under reduced pressure to dryness. Purify the resulting residue by flash chromatography eluting with acetone:acetic acid:hexanes (25%:1%:74%) to give a white solid. Dissolve the solid in a solution of 1% aqueous hydrochloric acid:methanol, and stir. After 1 hour, concentrate under reduced pressure to dryness. Purify the resulting residue by reverse phase chromatography eluting with methanol:acetic acid:water to yield the title compound as a white solid (22 mg, 2.4%): 1H NMR (DMSO-d6) δ 0.86 (t, 3H), 1.48 (sextet, 2H), 2.56 (m, 5H), 5.21 (s, 2H), 5.79 (d, 1H), 6.11 (d, 1H), 6.70 (d, 1H), 7.41 (m, 4H), 7.49 (t, 1H), 7.63 (m, 2H), 7.79 (d, 1H), 7.89 (s, 1H), 12.83 (s, 1H), 12.96 (bs, 1H); MS (esi negative) m/z (rel intensity) 473 (100).
Reaction SMILES: [H-].[Na+].C[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=O.[C:12]([C:16]([CH3:18])=[O:17])([CH3:15])([CH3:14])[CH3:13]>COCCOC>[CH3:11][O:10][CH2:8][CH2:7][CH2:6][C:5](=[O:4])[CH2:18][C:16](=[O:17])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(=O)C(C)(C)C
Reactant: COCCCC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COCCCC(=O)CC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14 %

Procedure:
1.8 mol of sodium hydride was added to the solvent ethylene glycol dimethyl ether, and 1 mol of methyl 4-methoxybutanoate was added thereto and stirred at room temperature for 10 minutes. Then, 1.2 mol of t-butylmethylketone was added to the solution which was then stirred at 92° C. for 19 hours. Then, the solution was cooled to room temperature and quenched in 36% hydrochloric acid, after which water and dimethylether were added to and mixed with the solution, and water was removed therefrom. The resulting organic material was washed with 1 wt % sodium hydroxide and then with saturated saline and concentrated, and the residue was fractionated, thereby obtaining the intermediate 8-methoxy-2,2-dimethyloctan-3,5-dione at a yield of 14%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2=[N:6][Se:7][N:8]=[C:4]2[CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>OS(O)(=O)=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2=[N:6][Se:7][N:8]=[C:4]2[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Clc1ccc2n[se]nc2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1c(Cl)ccc2n[se]nc12
Temperature: 0 °C

Procedure:
A solution of 5-chloro-2,1,3-benzoselenadiazole from Step A (800 mg, 1.80 mmol) in conc. H2SO4 (12 mL) was cooled to 0° C. and 90% HNO3 (0.8 mL) was added. After 30 min the reaction was cooled to 0° C. and diluted with H2O (10 mL). The solid was filtered off and washed with cold H2O to yield the title compound. MS: m/z=264 (M+1).