Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([NH:14][CH:15]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:16]([NH:23][C:24]([NH:26][C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([O-:32])=[O:31])=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[OH-].[Li+].O>CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([NH:14][CH:15]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:16]([NH:23][C:24]([NH:26][C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([OH:32])=[O:31])=[O:25])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)NC(c2ccccc2)C(NC(=O)Nc2cccc(C(=O)[O-])c2)c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=O)NC(c2ccccc2)C(NC(=O)Nc2cccc(C(=O)O)c2)c2ccccc2)cc1
Temperature: 50 °C

Procedure:
To a solution of ethyl (-)-[S-(R*,R*)]-3-[[[[2-[[[[(4-methylphenyl)sulfonyl]amino]carbonyl]-amino]-1,2-diphenylethyl]amino]carbonyl]amino]benzoate (0.1 g, 0.17 mmol), in MeOH (5 mL) is added lithium hydroxide monohydrate (0.006 g, 0.17 mmol) followed by water to the cloud point. The resulting mixture is warmed to 50° C. for 4 hours. The solvent is removed in vacuo and the residue partitioned between water and diethyl ether. The layers are separated and the aqueous layer is acidified to pH=2 with 2 M HCl. The resulting solid is filtered and dried in vacuo at 114° C. for 5 hours, mp 185°-189° C. IR (KBr): 3383, 1699, 1558, 699 cm-1. NMR (DMSO-d6): δ2.31 (s, 3H), 4.87-5.04 (m, 2H), 6.84-7.72 (m, 19H), 8.07 (s, 1H), 8.77 (s, 1H), 10.65 (br s, 1H), 12.87 (br s, 1H). Analysis calculated for C30H28N4O6S.1.63H2O: C, 59.86; H, 5.23; N, 9.31. Found: C, 59.85; H, 4.96; N, 9.35. [α]D25 =-3.7° (c=1, DMF).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([Br:7])[N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCCC1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CCOC(C)=O.O>[Br:7][C:5]1[N:6]=[C:2]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[S:3][C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1sc(Br)nc1Br
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1sc(N2CCOCC2)nc1Br
Temperature: 90 °C
Reaction time: 4 h
Yield: 81.1 %

Procedure:
In a sealable reaction vessel, to a suspension of ethyl 2,4-dibromo-1,3-thiazole-5-carboxylate (2.90 g, 9.21 mmol, prepared as in WO 2005026149) and cesium carbonate (9.00 g, 27.6 mmol) in tetrahydrofuran (24.3 mL, 299 mmol) was added morpholine (0.883 mL, 10.1 mmol), at which point the vessel was sealed and the mixture was heated with stirring at 90° C. for 4 hours. Reaction mixture was diluted with EtOAc and water and transferred to a separatory funnel. Layers were separated, and the organic layer was washed with water, dried over Na2SO4, filtered, and concentrated in vacuo. Residue was subjected to column chromatography (gradient elution, 0 to 50% EA in hexanes) to afford ethyl 4-bromo-2-morpholin-4-yl-1,3-thiazole-5-carboxylate (2.4 g, yield 81%) as a white solid. LC/MS: (FA) ES+ 321, 323; 1H NMR (300 MHz, CDCl3) δ 4.30 (dd, J77.1, 7.1, 2H), 3.82-3.75 (m, 4H), 3.58-3.50 (m, 4H), 1.34 (dd, J=7.1, 7.1, 3H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[F:34])[C:28](Cl)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[F:24][C:25]1[CH:26]=[C:27]([C:28]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[C:7]3[CH2:17][CH2:18][CH3:19])[N:16]=2)[CH:31]=[CH:32][C:33]=1[F:34]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2ccc(F)c(F)c2)n1
Temperature: 150 °C
Yield: 48 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.050 g, 0.154 mmol) in anhydrous acetonitrile (2.0 mL) under N2, was added 3,4-difluorobenzoyl chloride (0.121 g, 0.177 mmol) and N,N-diisopropylethylamine (0.50 mL, 5.21 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.033 g (48% yield) of pure product: MS (ES) m/z 446 (M+).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10](Cl)(=[O:12])=[O:11])[S:7][C:6]=2[CH:14]=1.[ClH:15].[NH2:16][C@H:17]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[O:31][C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[C:18]1=[O:32]>>[O:31]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH2:22][N:19]1[CH2:20][CH2:21][C@H:17]([NH:16][S:10]([C:8]2[S:7][C:6]3[CH:14]=[C:2]([Cl:15])[CH:3]=[CH:4][C:5]=3[CH:9]=2)(=[O:12])=[O:11])[C:18]1=[O:32]
Reactant: N[C@H]1CCN(Cc2cc3ncccc3o2)C1=O
Reactant: Cl
Reactant: O=S(=O)(Cl)c1cc2ccc(F)cc2s1
Product: O=C1[C@@H](NS(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1Cc1cc2ncccc2o1

Procedure:
The title compound is prepared as described in EXAMPLE 1, Part K using 6-fluoro-benzo[b]thiophene-2-sulfonyl chloride and 3-(S)-amino-1-(furo[3,2-b]pyridin-2-ylmethyl)-pyrrolidin-2-one hydrochloride as starting material. The crude product is purified by column chromatography eluting with 66% EtOAc/CH2Cl2 to provide the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][CH2:11][C@H:10]([OH:12])[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(COC[C@@H]2CO2)cc1
Reactant: NCc1ccccc1
Product: O[C@@H](CNCc1ccccc1)COCc1ccccc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Benzyl-(S)-(+)-glycidyl ether (3.28 g) was dissolved in benzylamine (15 ml) and the mixture was stirred at room temperature for 4 days. Excess benzylamine was removed by evaporation in vacuo and the resulted residue was purified with a silica gel column chromatography (eluting solvent: chloroform to chloroform/methanol=9/1) to give (2S)-1-(benzylamino)-3-(benzyloxy)propane-2-ol (4.50 g) as a colorless oil.
Reaction SMILES: [N+:1]([O-])([OH:3])=[O:2].C1(O)C=CC(C)=C(C)C=1.[N+:14]([C:17]1[C:22]([CH3:23])=[C:21]([CH3:24])[CH:20]=[CH:19][C:18]=1[OH:25])([O-:16])=[O:15].[N+](C1(C)C=CC(O)=CC1C)([O-])=O>ClCCl>[N+:14]([C:17]1[C:22]([CH3:23])=[C:21]([CH3:24])[CH:20]=[C:19]([N+:1]([O-:3])=[O:2])[C:18]=1[OH:25])([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(O)c([N+](=O)[O-])c1C
Agent: CC1C=C(O)C=CC1(C)[N+](=O)[O-]
Agent: Cc1ccc(O)cc1C
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1C
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A mixture of 630 grams (5 moles/ of a 50% aqueous nitric acid and 400 ml dichloromethane were introduced in a two liter flask fitted with a stirrer, a reflex condenser, a dropping funnel and a thermometer. To this stirred mixture was added dropwise a solution of 245 g (2 moles) 3,4-xylenol in 400 ml dichloromethane, during two hours, maintaining the temperature at 20°-25° C. After another hour stirring at the same temperature the reaction mixture was heated to reflux (about 40° C.) until the starting product and the two intermediate products (2-nitro-3,4-xylenol and 4-nitro-3,4-xylenol) have disappeared (followed by GC analysis). This occurs in about three hours. The mixture was cooled to ambient temperature and allowed to separate in two phases. The lower organic phase was separated from the aqueous acidic layer and washed twice with water. Water (400 ml) was added to the organic phase and dichloromethane was removed by distillation. The slurry of the dinitro compound in water was cooled and filtered and dried at 70° C. A product of 93.7%. 2,6-dinitro-3,4-xylenol pure was obtained which was 74.5% of the theoretical yield. After crystallization from ethyl alcohol it has a melting point of 124°-125° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=1)[C:4]([O:6][CH3:7])=[O:5].[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl.C(N(CC)CC)C>[C:24]([NH:2][CH:3]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=1)[C:4]([O:6][CH3:7])=[O:5])(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCc1ccc(CCC(N)C(=O)OC)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCc1ccc(CCC(NC(C)=O)C(=O)OC)cc1
Temperature: 25 °C

Procedure:
To a solution of methyl 2-amino-4-(4-octylphenyl)butyrate hydrochloride (16 g) in methylene chloride (300 ml), triethylamine (16 ml) and acetyl chloride (3.8 ml) were added and the mixture was stirred at room temperature for an hour. Then, methylene chloride (500 ml) was further added to the mixture, the whole mixture was washed with a dilute hydrochloric acid, an aqueous sodium hydrogencarbonate solution and a saturated brine in order and dried over magnesium sulfate. The solvent was distilled away under reduced pressure and the residue was purified by silica gel chromatography (eluent; hexane-ethyl acetate=1:2) to give the subject compound (11 g). MS: 348(M++1).
Reaction SMILES: [Na].[OH:2][CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=[O:6].O1CCOCC1.[C:23]([O:26]C(=O)C)(=[O:25])[CH3:24]>O>[C:23]([OH:26])(=[O:25])[CH3:24].[OH:2][CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=1)=[O:6]
Reactant: CC(=O)OC(C)=O
Agent: O=C(C=CO)c1cccc(C(F)(F)F)c1
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)O

Procedure:
A suspension of 12.0 g. of 3-hydroxy-3'-(trifluoromethyl)acrylophenone sodium salt in 75 ml. of dioxane and 10 ml. of acetic anhydride is stirred at room temperature for 2 hours and then poured into water. The precipitate is collected by filtration, dissolved in methylene chloride and then passed through a hydrous magnesium silicate column and crystallized from methylene chloride-hexane to give the desired product, m.p. 55°-57° C.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3OC(C)=[C:37]([CH:39]([CH3:41])[CH3:40])[N:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH:43]1([NH:49][CH:50]=O)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1.[CH:52]1(N)CCCCC1>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:49]([CH:43]4[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]4)[C:50]([CH3:52])=[C:37]([CH:39]([CH3:40])[CH3:41])[N:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: NC1CCCCC1
Reactant: O=CNC1CCCCC1
Reactant: CCCc1nc2c(C)cc(-c3nc(C(C)C)c(C)o3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Product: CCCc1nc2c(C)cc(-c3nc(C(C)C)c(C)n3C3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 146 from tert.butyl 4'-[[2-n-propyl-4-methyl-6-(4-isopropyl-5-methyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and N-cyclohexyl-formamide/cyclohexylamine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2O)[N:7]=1)=[O:5])[CH3:2].[C:21](=[O:24])([O-])[O-].[K+].[K+].[I-].[K+].[Cl:29][C:30]1[CH:37]=[CH:36][C:33](CBr)=[CH:32][CH:31]=1>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH:12]([O:24][CH2:21][C:33]2[CH:36]=[CH:37][C:30]([Cl:29])=[CH:31][CH:32]=2)[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][CH:14]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: Clc1ccc(CBr)cc1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc(C)n(Cc2cc(Cl)ccc2O)n1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C)n(C(OCc2ccc(Cl)cc2)c2cccc(Cl)c2)n1
Temperature: 100 °C
Yield: 66.8 %

Procedure:
To a solution of 1-(5-Chloro-2-hydroxy-benzyl)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester 2 (0.6 g, 2.0 mmol) in DMF (5 mL) were added potassium carbonate (0.84 g, 6.1 mmol), potassium iodide (0.34 g, 2.0 mmol) and 4-chlorobenzylbromide (0.38 g, 2.2 mmol). The resulting mixture was heated at 100° C. overnight. The mixture was poured into water (20 mL) and extracted with Et2O (3×15 mL). The organic layers were combined, washed with brine (30 mL), dried (Na2SO4) and the volatiles were removed in vacuo to give 0.56 g (71%) of 1-(2-Benzyloxy-5-chloro-benzyl)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester 3 as a white solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[C:12]2[C:19]([CH3:20])=[CH:18][S:17][C:13]=2[N:14]=[CH:15][N:16]=1.[H-].[Na+].[CH3:23]I.O>CN(C)C=O>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[N:10]([C:11]1[C:12]2[C:19]([CH3:20])=[CH:18][S:17][C:13]=2[N:14]=[CH:15][N:16]=1)[CH3:23]
Reactant: Cc1csc2ncnc(NC3Cc4ccccc4C3)c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1csc2ncnc(N(C)C3Cc4ccccc4C3)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
A compound of the above Production Example 190, 4-(2-indanylamino)-5-methylthieno[2,3-d]pyrimidine (29 mg, 0.10 mmol), was dissolved in dry dimethylformamide (0.5 ml), to which sodium hydride (4.4 mg, 0.11 mmol) was added. After the mixture was stirred at room temperature for 10 minutes, methyl iodide (7.0 μl, 0.11 mmol) was added to the reaction mixture, which was further stirred at room temperature for 30 minutes. Water was added to the reaction mixture, which was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (20 mg, 0.070 mmol) having the following physical properties:
Reaction SMILES: CC([Si](C)(C)[O:6][CH:7]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C:16]2([C:27]2[CH:31]=[CH:30][O:29][CH:28]=2)O)[CH2:8]1)(C)C.Cl.C(Cl)Cl>O1CCOCC1>[O:29]1[CH:30]=[CH:31][C:27]([C:16]2[C@:17]3([CH2:19][CH2:20][C@H:21]4[C@@H:12]([CH2:11][CH:10]=[C:9]5[C@:22]4([CH3:25])[CH2:23][CH2:24][C@H:7]([OH:6])[CH2:8]5)[C@@H:13]3[CH2:14][CH:15]=2)[CH3:18])=[CH:28]1
Reactant: CC(C)(C)[Si](C)(C)OC1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC2(O)c2ccoc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3ccoc3)=CC[C@@H]12
Yield: 58.4 %

Procedure:
Combine (3β,17β)-3β,17β)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-17-(3-furanyl)-androst-5-en-17-ol (2.50 g, 5.31 mmol) prepared as in Scheme III, step B above, with 4N hydrogen chloride in 1,4-dioxane (35 mL) under an atmosphere of nitrogen. Stir the reaction for 40 minutes at room temperature and then dilute the reaction with methylene chloride (150 mL). Wash the organic layer with water (35 mL), saturated sodium bicarbonate (2×50 mL), brine (30 mL), dry over anhydrous magnesium sulfate, filter and concentrate under vacuum. Purify the residue by flash chromatography (ethyl acetate/hexane, 3:7, silica gel) to provide 1.05 g of product as a white solid. Recrystallize a portion of the product from aqueous acetone and dry under high vacuum over refluxing ethanol for 4 hours to provide the title compound as a white crystallize solid, Rf =0.43 (ethyl acetate/hexane, 35:65, silica gel), mp 186°-189° C.; 1H NMR (CDCl3) δ7.47 (broad singlet, 1H), 7.36 (t, 1H, J=1.7 Hz), 6.48 (dd, 1H, J=0.8, 1.8 Hz), 5.83 (dd, 1H, J=1.9, 3.2 Hz), 5.41-5.37 (m, 1H), 3.60-3.48 (m, 1H), 1.07 (s, 3H), 0.96 (s, 3H); MS (CI/CH4) m/z (rel. intensity) 339 (MH+, 68), 338 (55), 337 (28), 321 (100); HRMS C23H31O2 (MH+) calcd 339.2324, observed 339.2304.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[F:32][C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=1B(O)O>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:32][C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=1[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: Cc1ccc(B(O)O)c(F)c1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc(C)cc1F
Yield: 68.3 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.08 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 mg; 0.025 mmol), N,N-diisopropylethylamine (0.173 mL; 1 mmol) and 2-fluoro-4-methylphenylboronic acid (0.077 g; 0.5 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 0.067 g (67%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]([N:18]1[CH2:22][CH:21]([OH:23])[CH:20]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH2:26][CH2:25]2)[CH2:19]1)=[O:17].[C:38](OC(=O)C)(=[O:40])[CH3:39]>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([C:16]([N:18]2[CH2:22][CH:21]([OH:23])[CH:20]([N:24]3[CH2:25][CH2:26][N:27]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=4)[CH2:28][CH2:29]3)[CH2:19]2)=[O:17])=[C:9]([NH:8][C:38](=[O:40])[CH3:39])[CH:14]=1
Reactant: Nc1cc(Cl)ccc1C(=O)N1CC(O)C(N2CCN(Cc3ccc(Cl)cc3)CC2)C1
Reactant: CC(=O)OC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(Cl)ccc1C(=O)N1CC(O)C(N2CCN(Cc3ccc(Cl)cc3)CC2)C1
Reaction time: 1 h
Yield: 10.6 %

Procedure:
A mixture of (3R,4R; 3S,4S)-(2-Amino-4-chloro-phenyl)-{3-[4-(4-chloro-benzyl)-piperazin-1-yl]4-hydroxy-pyrrolidin-1-yl}-methanone trifluoroacetate (22 mg, 0.05 mmol) was dissolved in DMF and acetic anhydride (20 uL, 0.2 mmol) was added. The reaction mixture was shaken for 1 h and directly used for LC-MS purification, to yield 3.2 mg of the title compound as the trifluoroacetate salt. ESIMS ([M+H]+): 491.2 (100).
Reaction SMILES: [OH-:1].[Na+].C(C[CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:8][CH2:7]1)#N.[CH2:16]([OH:18])[CH3:17]>>[C:16]([CH2:17][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:8][CH2:7]1)([OH:1])=[O:18]
Reactant: N#CCC1COc2ccccc2C1
Reactant: CCO
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)CC1COc2ccccc2C1
Yield: 96 %

Procedure:
50 ml of 2N sodium hydroxide solution are added to a solution of 7.8 g (45 mmol) of 3-cyanomethylchroman in 150 ml of ethanol and the whole is boiled under reflux for 16 hours. After cooling, the reaction mixture is concentrated by evaporation in vacuo. The residue is dissolved in water and extracted with diethyl ether. The aqueous phase is acidified with hydrochloric acid (36% strength) and extracted by shaking with dichloromethane. The combined dichloromethane extracts are dried over sodium sulphate and concentrated by evaporation in vacuo. 8.3 g (96%) of 3-carboxymethylchroman are obtained in the form of colourless crystals which melt at 106°-107°.
Reaction SMILES: [NH2:1][OH:2].[C:3]([C:5]1[CH:32]=[CH:31][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:22]=[C:23]([O:25][C@@H:26]([CH3:30])[CH2:27][O:28][CH3:29])[CH:24]=2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])=[CH:7][CH:6]=1)#[N:4]>C(O)C>[OH:2][NH:1][C:3](=[NH:4])[C:5]1[CH:32]=[CH:31][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:22]=[C:23]([O:25][C@@H:26]([CH3:30])[CH2:27][O:28][CH3:29])[CH:24]=2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])=[CH:7][CH:6]=1
Reactant: NO
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C#N)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Solvent: CCO
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=N)NO)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Hydroxylamine (50% w/w solution, 1 mL) was added to absolution of 3-(4-cyanophenoxy)-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (300 mg, 0.74 mmol) in ethanol (3 mL) and the reaction mixture allowed to stir at RT for 18 hours. The volatiles were removed in vacuo to give the desired compound as a colourless foam (325 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[NH:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([C:20]([OH:22])=O)[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:34]=[CH:33][C:28]2[NH:29][C:30](=[O:32])[O:31][C:27]=2[CH:26]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[O:32]=[C:30]1[NH:29][C:28]2[CH:33]=[CH:34][C:25]([NH:24][C:20]([C:18]3[CH:17]=[CH:16][C:14]4[N:15]=[C:11]([NH:10][C:9]([NH:8][C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)=[O:23])[S:12][C:13]=4[CH:19]=3)=[O:22])=[CH:26][C:27]=2[O:31]1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Reactant: O=C(Nc1ccc(Cl)cc1)Nc1nc2ccc(C(=O)O)cc2s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)Nc1nc2ccc(C(=O)Nc3ccc4[nH]c(=O)oc4c3)cc2s1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
Starting material 35 (300 mg, 45% content, 0.4 mmol) and 6-Amino-3H-benzooxazol-2-one (30, 58 mg, 0.4 mmol) were dissolved in 2 ml of dry DMF. Then EDCI (96 mg, 0.5 mmol) and HOBt (76 mg, 0.5 mmol) were added. The reaction was stirred at ambient temperature over night. It was then purred into water and the resulting precipitate was filtered. The isolated precipitate was then stirred in 100 ml warm methanol and the non-soluble crystals filtered and washed with methanol. Thereby the desired product 36 (130 mg, 0.271 mmol, 70%) could be isolated.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].C(Cl)Cl.[NH2:16][C:17]1[S:29][C:28]2[CH2:27][C@@H:26]3[C@H:21]([CH2:22][C@@H:23]([C:31]([N:33]([CH2:42][CH2:43][CH3:44])[C:34]([NH:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])=[O:35])=[O:32])[CH2:24][N:25]3[CH3:30])[CH2:20][C:19]=2[C:18]=1[C:45]#[N:46].[CH3:47][OH:48]>CN(C)C1C=CN=CC=1>[C:45]([C:18]1[C:19]2[CH2:20][C@@H:21]3[C@@H:26]([CH2:27][C:28]=2[S:29][C:17]=1[NH:16][C:1](=[O:2])[O:48][CH3:47])[N:25]([CH3:30])[CH2:24][C@H:23]([C:31]([N:33]([C:34](=[O:35])[NH:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])[CH2:42][CH2:43][CH3:44])=[O:32])[CH2:22]3)#[N:46]
Reactant: CO
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCN(C(=O)NCCN(C)C)C(=O)[C@@H]1C[C@@H]2Cc3c(sc(N)c3C#N)C[C@H]2N(C)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCN(C(=O)NCCN(C)C)C(=O)[C@@H]1C[C@@H]2Cc3c(sc(NC(=O)OC)c3C#N)C[C@H]2N(C)C1
Temperature: 25 °C

Procedure:
To a mixture of 1,1′-carbonyldiimidazole (13 mg) and methylene chloride (1 mL) was added 4-dimethylaminopyridine (8 mg), followed by 1-{[(4aR*,6R*,8aR*)-2-amino-3-cyano-8-methyl-4H,4aH,5H,6H,7H,8H,8aH,9H-thieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea (example 1-15) (30 mg) while stirring under ice bath cooling, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added 1,1′-carbonyldiimidazole (13 mg), followed by 4-dimethylaminopyridine (8 mg) and warmed to room temperature and stirred for 1 hour. To the reaction mixture was added 1,1′-carbonyldiimidazole (50 mg), followed by 4-dimethylaminopyridine (32 mg) while stirring at room temperature and stirred at the same temperature for 12 hours. To the reaction mixture was added methanol (0.003 mL) while stirring at room temperature and stirred at the same temperature for 1 hour. The mixture was purified by aminopropyl silica gel column chromatography (eluent: 0%-10% methanol/methylene chloride, gradient elution) to give the title compound (18 mg). The structure was illustrated in Table 11.