Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[C:8]([O:10][CH3:11])=O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.[F:25][C:26]1[C:31]([F:32])=C(O)[CH:29]=[CH:28][C:27]=1[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37]>>[F:25][C:26]1[C:31]([F:32])=[C:11]([O:10][CH2:8][C:4]2[N:5]([C:19]3[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)[CH:6]=[CH:7][C:3]=2[C:2]([F:13])([F:12])[F:1])[CH:29]=[CH:28][C:27]=1[CH2:34][CH2:35][C:36]([OH:38])=[O:37]
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)c1[nH]ccc1C(F)(F)F
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1F
Product: COc1ccc(-n2ccc(C(F)(F)F)c2COc2ccc(CCC(=O)O)c(F)c2F)cc1

Procedure:
The title compound was prepared by (a) reacting the product prepared in Step B of Example 1 and 4-methoxyphenylboronic acid according to the procedure described in Example 1, Step C, (b) then reacting the resulting product according to the procedure in Example 1, Step D, and (c) then reacting the resulting product with ethyl 3-(2,3-difluoro-4-hydroxyphenyl)propanoate according to the procedure described in Example 1, Steps E and F.
Reaction SMILES: C([O:3][C:4](=O)[CH:5](O)[CH:6]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[C:7](=O)[CH2:8][CH2:9][CH2:10][CH3:11])C.O.[NH2:30][NH2:31]>C(O)(=O)C>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([C:6]2[C:7]([CH2:8][CH2:9][CH2:10][CH3:11])=[N:31][NH:30][C:4](=[O:3])[CH:5]=2)=[CH:14][CH:15]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCCCC(=O)C(c1ccc(OCc2ccccc2)cc1)C(O)C(=O)OCC
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CCCCc1n[nH]c(=O)cc1-c1ccc(OCc2ccccc2)cc1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 3-(4-benzyloxy-phenyl)-2-hydroxy-4-oxo-octanoic acid ethyl ester (28.08 mmol, 10.8 g) and hydrazine hydrate (15 mL) in acetic acid (45 mL) was stirred at 120° C. for 4 h. The reaction mixture was concentrated under reduced pressure and to the residue was added water (200 mL). This was extracted with DCM (3×200 mL), and the combined organic layer was dried and concentrated under reduced pressure. The resultant residue was purified by flash silica gel column chromatography eluting with 50% ethyl acetate in hexanes to afford 5-(4-benzyloxy-phenyl)-6-butyl-2H-pyridazin-3-one.
Reaction SMILES: NC1C=CC(C2C=C(C)C=CC=2S(C2C=CC(C)=CC=2C2C=CC(N)=C([N+]([O-])=O)C=2)=O)=CC=1[N+]([O-])=O.[Br:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([S:50]([C:52]3[CH:57]=[CH:56][C:55]([Cl:58])=[C:54]([N+:59]([O-])=O)[CH:53]=3)=[O:51])=[CH:46][CH:45]=2)=[CH:40][CH:39]=1>>[Br:37][C:38]1[CH:39]=[CH:40][C:41]([C:44]2[CH:45]=[CH:46][C:47]([S:50]([C:52]3[CH:57]=[CH:56][C:55]([Cl:58])=[C:54]([NH2:59])[CH:53]=3)=[O:51])=[CH:48][CH:49]=2)=[CH:42][CH:43]=1
Reactant: O=[N+]([O-])c1cc(S(=O)c2ccc(-c3ccc(Br)cc3)cc2)ccc1Cl
Agent: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Product: Nc1cc(S(=O)c2ccc(-c3ccc(Br)cc3)cc2)ccc1Cl
Yield: 88 %

Procedure:
Following the procedure described in Example 2 but using as a starting material instead of (4-amino-3-nitrophenyl)-4-methylphenyl sulfoxide a corresponding amount of 1-(4-bromophenyl)-4-(4-chloro-3-nitrophenylsulfinyl)benzene, the title compound is obtained.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[CH3:10][C:11]1[C:12]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[N:13][C:14]([Cl:18])=[N:15][C:16]=1[CH3:17]>CN(C)C=O>[ClH:18].[CH3:10][C:11]1[C:12]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[N:13][C:14]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=2[CH3:9])=[N:15][C:16]=1[CH3:17]
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2)c1C
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Nc1nc(C)c(C)c(N2CCc3ccccc3C2)n1
Product: Cl
Yield: 40.4 %

Procedure:
After 4-fluoro-2-methylaniline(0.8 ml, 7 mmol) was added to a mixture solution of 5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloropyrimidine(1.0 g, 3.6 mmol) and dimethylformamide(10 ml), 0.58 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][C:26]=1[C:34]([F:37])([F:36])[F:35]>>[CH3:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][CH2:2][C@H:3]2[N:8]([C:9]([C:11]3[N:12]=[C:13]([CH3:23])[S:14][C:15]=3[C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[O:10])[CH2:7][C@H:6]3[C@@H:4]2[CH2:5]3)=[O:30])=[CH:27][C:26]=1[C:34]([F:35])([F:36])[F:37]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: Cc1ccc(C(=O)O)cc1C(F)(F)F
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2ccc(C)c(C(F)(F)F)c2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-Methyl-3-trifluoromethyl-benzoic acid. LC-MS (basic): tR=1.00 min; [M+H]+=514.1.
Reaction SMILES: C([O:3][C:4]([C:6]1([OH:19])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[H-].[Na+].I[CH3:23].O[Li].O>CN(C=O)C.O>[C:15]([O:14][C:12]([N:9]1[CH2:8][CH2:7][C:6]([O:19][CH3:23])([C:4]([OH:3])=[O:5])[CH2:11][CH2:10]1)=[O:13])([CH3:16])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C1(O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CI
Agent: [H-]
Agent: [Li]O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.415 g (1.52 mmol) 4-Hydroxy-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester, 68 mg (1.97 mmol) NaH (55% in oil) and 0.3 g (2.12 mmol) iodomethane in 10 mL DMF was stirred for 2 h at room temperature. Water was added and the mixture was concentrated to dryness. The residue was dissolved in THF and water and 0.254 g (6 mmol) LiOH.H2O wad added and the mixture was stirred for 16 h at room temperature. After evaporation the residue was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid to yield after evaporation of the product containing fractions 49.7 mg (13%) of the title compound as white solid. MS (m/e): 258.1 [(M−H)].
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[O:26]1[CH2:31][CH2:30][CH:29](O)[CH2:28][CH2:27]1.OCCC1CCN(C(OC(C)(C)C)=O)CC1>>[O:26]1[CH2:31][CH2:30][CH:29]([O:1][C:2]2[C:7]3[C:8]([O:11][CH2:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[N:9][O:10][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(O)c23)CC1
Reactant: OC1CCOCC1
Agent: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Product: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(OC4CCOCC4)c23)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 2 of EXAMPLE 7 using tert-butyl 4-{[(4-hydroxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidine-1-carboxylate (EXAMPLE 17, step 2) and tetrahydro-2H-pyran-4-ol instead of 4-(benzyloxy)-1,2-benzisoxazol-3-ol and tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]([CH:17]1[C:25]2[C:20](=[CH:21][C:22]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)=[O:16].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>O1CCCC1>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][C:17]1([C:15]([O:14][CH3:13])=[O:16])[C:25]2[C:20](=[CH:21][C:22]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)[CH3:38]
Reactant: CCOC(=O)CBr
Reactant: COC(=O)C1CCc2cc(C3CCCCC3)ccc21
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC1(C(=O)OC)CCc2cc(C3CCCCC3)ccc21
Temperature: -20 °C

Procedure:
23.6 ml of butyl-lithium (20% strength in hexane) are slowly added dropwise to a solution of 7.6 g of diisopropylamine (absolute) in 80 ml of absolute tetrahydrofurane at -10° to -15°C under a dry nitrogen atmosphere, whilst stirring, and 15 minutes after completion of the addition a solution of 15.5 g of 5-cyclohexyl-1-indanecarboxylic acid methyl ester in 40 ml of absolute tetrahydrofurane is added. The reaction solution is cooled to -20°C and a solution of 16.5 g of ethyl bromoacetate in 40 ml of absolute tetrahydrofurane is rapidly added dropwise. In the course thereof, the temperature rises to 0°C. The reaction solution is partitioned between three times 200 ml of methylene chloride and three times 200 ml of 2 N hydrochloric acid. The combined organic phases are washed with water, dried over sodium sulphate and evaporated in vacuo. Distillation of the evaporation residue in a high vacuum yields 1-methoxycarbonyl-5-cyclohexyl-1-indaneacetic acid ethyl ester in the fraction boiling at 140°-142°C/0.04 mm Hg.
Reaction SMILES: [H-].[Na+].[C:3](#[N:5])[CH3:4].[F:6][C:7]([F:19])([F:18])[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11](OC)=[O:12].C(O)(C)C>O1CCCC1>[O:12]=[C:11]([C:10]1[CH:15]=[CH:16][CH:17]=[C:8]([C:7]([F:6])([F:18])[F:19])[CH:9]=1)[CH2:4][C:3]#[N:5]
Reactant: CC#N
Reactant: COC(=O)c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: N#CCC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
To a suspension of 7.6 g of sodium hydride (60% dispersion in oil) in 200 mL of tetrahydrofuran under a nitrogen atmosphere was added dropwise at room temperature a solution consisting of 7.8 g of acetonitrile and 38.8 g of methyl 3-(trifluoromethyl)benzoate in 50 mL of tetrahydrofuran. Following addition, the suspension was stirred 1 h at ambient temperature, refluxed about 5 h, and then cooled to room temperature. Isopropyl alcohol (20 mL) was added dropwise at room temperature. After stirring about 15 min, the solvent was removed in vacuo, and about 200 mL of water was added to the residue. The aqueous suspension was washed with 3×50 mL diethyl ether and then acidified with concentrated hydrochloric acid to form a solid. The solid was isolated by filtration, washed 2×100 mL with water and then dissolved in methylene chloride. The organic solution was dried (MgSO4), filtered and concentrated to give 30.0 g of the title compound of Step A as a white solid melting at 51-55° C. 1H NMR (CDCl3): δ 8.1-8.2 (m,2H), 7.95 (d,1H), 7.7 (m,1H), 4.15 (s,2H); IR (mineral oil) 1704.1 cm-1.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:11]2[CH:16]=[C:15]([CH3:17])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:11]3[CH:16]=[C:15]([CH3:17])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Reactant: Cc1ncc[nH]1
Product: Cc1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-methyl-4-(3,4-methylene dioxybenzylamino)-thieno-[2,3-d]-pyrimidine yields 2-(2-methylimidazol-1-yl)-6-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C([C:4]1[C:9]([CH3:10])=[CH:8][C:7]([CH:11]2[O:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:6][C:5]=1[CH3:17])C=C.[OH2:18].[CH3:19][C:20]([CH3:22])=[O:21]>C(O)(C)(C)C.C(Cl)Cl.O=[Os](=O)(=O)=O>[O:12]1[CH2:13][CH2:14][CH2:15][O:16][CH:11]1[C:7]1[CH:8]=[C:9]([CH3:10])[C:4]([CH2:19][CH:20]([OH:21])[CH2:22][OH:18])=[C:5]([CH3:17])[CH:6]=1
Reactant: C=CCc1c(C)cc(C2OCCCO2)cc1C
Reactant: O
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: Cc1cc(C2OCCCO2)cc(C)c1CC(O)CO
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 2-(4-allyl-3,5-dimethyl-phenyl)-[1,3]dioxane (790 mg, 3.4 mmol) in acetone (10 mL) is treated with OsO4 (1 mL of a 2.5% solution in tert.butanol), NMO hydrate (551 mg, 4.08 mmol) and water (0.5 mL). The mixture is stirred at rt for 2.5 h before it is diluted with DCM, washed with 10% aq. citric acid solution (2×50 mL), dried over MgSO4, filtered and evaporated. The product is crystallized from DCM/heptane to give 3-(4-[1,3]dioxan-2-yl-2,6-dimethyl-phenyl)-propane-1,2-diol (335 mg) as a grey powder; 1H NMR (CDCl3): δ 7.15 (s, 2H), 5.42 8 s, 1H), 4.26 (dd, J=4.6, 10.6 Hz, 2H), 3.98 (dt, Jd=1.8 Hz, Jt=12.3 Hz, 2H), 3.92-3.81 (m, 2H), 3.66 (dd, J=2.9, 11.1 Hz, 1H), 3.55 (dd, J=7.0 11.1 Hz, 1H), 2.88 (dd, J=8.8, 14.1 Hz, 1H), 2.74 (dd, J=5.3, 13.5 Hz, 1H), 2.34 (s, 6H), 2.30-2.14 (m, 2H), 1.90 (s br, 2H).
Reaction SMILES: C1(C[O:8][C:9](=[O:59])[CH2:10][N:11]([CH2:48][C:49](=[O:58])[O:50]CC2C=CC=CC=2)[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:14]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:13]=2)C=CC=CC=1.[H][H]>[Pd].C1COCC1.C(OCC)(=O)C>[C:9]([CH2:10][N:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:14]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:13]=1)[CH2:48][C:49]([OH:58])=[O:50])([OH:59])=[O:8]
Reactant: CCCCCCCCCCCCCCOc1ccc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)cc1OCCCCCCCCCCCCCC
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(N(CC(=O)O)CC(=O)O)cc1OCCCCCCCCCCCCCC
Yield: 56 %

Procedure:
A mixture of N-[2-oxo-2-(phenylmethoxy)ethyl]-N-[3,4-bis(tetradecyloxy)phenyl]glycine phenylmethyl ester and 0.5 g of 10% palladium on carbon in 40 ml of THF and 20 ml of ethyl acetate was stirred in a hydrogen atmosphere at room temperature for 2.5 hours when uptake ceased. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to a solid which was triturated with hexane and filtered to give 1.4 g (56% yield, mp 89°-93°) of pure N-(carboxymethyl)-N-[3,4-bis(tetradecyloxy)phenyl]glycine.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([S:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:21])=O.[NH2:22][C:23]([NH2:25])=[S:24]>CCO>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([S:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:22]=[C:23]([NH2:25])[S:24][CH:2]=3)=[C:6]([CH3:21])[CH:7]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(Sc2cc(C)c(C(=O)CBr)c(C)c2)cc1
Reactant: NC(N)=S
Solvent: CCO
Product: COc1ccc(Sc2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Yield: 89.7 %

Procedure:
A reaction mixture containing 2-bromo-1-(4-(4-methoxyphenylthio)-2,6-dimethylphenyl)ethanone (1.06 g, 2.9 mmol, 1.0 equiv) and thiourea (221.5 mg, 2.9 mmol, 1.0 equiv) in EtOH (20.0 mL) was heated at reflux for 16 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 (30 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (5.0% EtOAc in hexanes as eluant) to provide 4-(4-(4-methoxyphenylthio)-2,6-dimethylphenyl)thiazol-2-amine (890.9 mg, 2.6 mmol) as yellow solids in 90% yield: 1H NMR (DMSO-d6, 500 MHz) δ 7.40 (d, J=8.7 Hz, 2 H), 7.00 (d, J=8.7 Hz, 2 H), 6.86-6.87 (m, 4 H), 6.33 (s, 1 H), 3.78 (s, 3 H), 2.03 (s, 6 H); ESI-MS m/z 343.9 (M+H)+.
Reaction SMILES: [CH:1]1([N:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:30]1(NC2CCCCC2)CCCCC1.COC(=O)CN(S(C1SC(N)=NC=1)(=O)=O)C>>[CH:24]1([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([N:18]([CH2:19][C:20]([OH:22])=[O:21])[CH3:30])(=[O:16])=[O:17])=[CH:13][N:14]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: O=C(O)CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: COC(=O)CN(C)S(=O)(=O)c1cnc(N)s1
Product: CN(CC(=O)O)S(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1

Procedure:
Prepared in a similar manner to [2-(3,3-dicyclohexyl-ureido)-thiazole-5-sulfonylamino]-acetic acid via dicyclohexylamine and [(2-amino-thiazole-5-sulfonyl)-methyl-amino]-acetic acid methyl ester to give the title compound.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:24])=[N:5]1)([CH3:3])[CH3:2].[CH2:25]1[C@@H:29]([C:30]([NH2:32])=[O:31])[NH:28][CH2:27][C@H:26]1[F:33].Cl>>[F:33][C@@H:26]1[CH2:27][N:28]([C:21]2[N:20]=[CH:19][C:16]3[C:17]4[N:11]([CH:10]=[C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[C:6]([CH3:24])[N:7]=5)[N:18]=4)[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[C@H:29]([C:30]([NH2:32])=[O:31])[CH2:25]1
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(O)cc2OCC3)n(C(C)C)n1
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1
Agent: Cl
Product: Cc1nc(-c2cn3c(n2)-c2cnc(N4C[C@@H](F)C[C@H]4C(N)=O)cc2OCC3)n(C(C)C)n1
Yield: 42 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol and 4-cis-fluoro-L-prolinamide hydrochloride with added TEA (2.5 eq.), were reacted and the crude product recrystallised from IMS/DCM to give 382 as a white solid (68 mg, 42%). LCMS: RT=2.58 min, [M+H]+ 441. 1H NMR 400 MHz (DMSO-d6) δ: 9.04 (1 H, s), 7.76 (1 H, s), 7.10 (1 H, s), 6.91 (1 H, s), 5.95 (1 H, s), 5.87-5.80 (1 H, m), 5.42 (1 H, s), 5.29 (1 H, s), 4.49-4.36 (5 H, m), 3.74-3.73 (2 H, m), 2.46-2.45 (1 H, m), 2.20 (3 H, s), 1.40 (6 H, dd, J=6.59, 3.37 Hz)
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.[C:6]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[F:17][C:18]([F:25])([F:24])[CH2:19][CH2:20][C:21](Cl)=[O:22].Cl>C(OCC)C.C(O)C>[CH2:15]([O:14][C:6](=[O:13])[CH:7]([C:21](=[O:22])[CH2:20][CH2:19][C:18]([F:25])([F:24])[F:17])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:16]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)CCC(F)(F)F
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)C(C(=O)CCC(F)(F)F)C(=O)OCC
Temperature: 55 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
0.1 ml of carbon tetrachloride was added to a mixture of 20.35 g of magnesium(turnings) and 148 ml of ethanol and then heated at 55° C. A mixed solution of 197 ml of ethanol, 700 ml of diethyl ether and 168 g of diethyl malonate was added to the reaction mixture over 1 hour. Two hours later the reaction solution was cooled to -5° C. and 112 g of 4,4,4-trifluorobutyryl chloride was added to the solution under an atmosphere of nitrogen, then the resultant reaction mixture was left at an ambient temperature for 1 hour. Then the mixture was allowed to react further 12 hours. After completion of the reaction, the reaction solution was poured into a 5% hydrochloric acid solution and extracted three times with diethyl ether. The ether layers were combined and washed twice with brine and dried over anhydrous magnesium sulfate. The filtered ether solution was evaporated under reduced pressure. The obtained residue was distilled under reduced pressure to yield 179 g of the desired 4,4,4-trifluorobutyrylmalonic acid diethyl ester in a yield of 90%. (b.p. 125°-134° C., 15 mmHg)
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH:16]([CH3:18])[C:15](=[O:19])[C:14]([CH3:20])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:21][CH2:22][O:23][CH3:24])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].[Li+].[CH3:26]C([N-]C(C)C)C.IC>C1COCC1>[CH2:1]([C:5]12[CH2:17][C:16]([CH3:26])([CH3:18])[C:15](=[O:19])[C:14]([CH3:20])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:21][CH2:22][O:23][CH3:24])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)[N-]C(C)C
Reactant: CCCCC12Cc3cc(OCOC)ccc3C1=C(C)C(=O)C(C)C2
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCCCC12Cc3cc(OCOC)ccc3C1=C(C)C(=O)C(C)(C)C2
Temperature: -78 °C

Procedure:
A solution of (2SR,9aSR)-9a-butyl-2,4-dimethyl-7-methoxymethoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (39 mg, 0.12 mmol) in anhydrous THF (1.0 mL) was cooled in an ice bath, stirred under a nitrogen atmosphere, and treated with 0.4M LDA in THF (0.39 mL, 0.16 mmol). After stirring at 0° C. for 30 minutes, the yellow solution was cooled to −78° C. and treated with iodomethane (0.037 mL, 0.6 mmol). The resulting mixture was allowed to gradually warm to room temperature, then stirred at room temperature overnight. Workup as described in Example 18, step 2, afforded a crude product which was purified by PLC on a 0.1×20×20 cm silica gel GF plate, using 10:1 hexanes-EtOAc as developing solvent. The band at Rf 0.18-0.24 afforded 9a-butyl-7-methoxymethoxy-2,2,4-trimethyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (28 mg) as an oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].Cl[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=1.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1>CN(C=O)C>[F:18][C:2]([F:1])([F:17])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([O:16][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=3)[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(N1CCc2ccc(O)cc2CC1)C(F)(F)F
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCN(C(=O)C(F)(F)F)CC3)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
Add 2,2,2-trifluoro-1-(7-hydroxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)ethanone (0.750 g, 2.89 mmol), 6-chloronicotinamide (0.377 g, 2.41 mmol) and K2CO3 (0.833 g, 6.03 mmol) to a round bottom equipped with a Dean-Stark trap. Add toluene (6 mL) and DMF (18 mL). Heat at reflux for two hours. Cool the reaction mixture to 100° C. and stir overnight. Remove the toluene and DMF as an azeotrope with xylenes. Suspend the solid in 5% methanol/ethyl acetate (100 mL) and filter. Wash the filter cake with ethyl acetate. Concentrate the filtrate, then purify by flash chromatography, eluting with 40% ethyl acetate in dichloromethane to give the title compound (0.312 g, 34.0%):