Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[Si:25]([O:32][CH2:33][C:34]1[CH:35]=[C:36]([CH:50]=[CH:51][C:52]=1[CH2:53][O:54][Si:55]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56])[O:37][CH2:38][C:39]1[S:43][C:42](/[C:44](/[CH2:48][CH3:49])=[CH:45]/[CH:46]=O)=[CH:41][CH:40]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].O>ClCCl.[Zn]>[Si:25]([O:32][CH2:33][C:34]1[CH:35]=[C:36]([CH:50]=[CH:51][C:52]=1[CH2:53][O:54][Si:55]([C:58]([CH3:60])([CH3:59])[CH3:61])([CH3:56])[CH3:57])[O:37][CH2:38][C:39]1[S:43][C:42](/[C:44](/[CH2:48][CH3:49])=[CH:45]/[CH:46]=[C:20]([Br:24])[Br:21])=[CH:41][CH:40]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: BrC(Br)(Br)Br
Reactant: CC/C(=C\C=O)c1ccc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)s1
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC/C(=C\C=C(Br)Br)c1ccc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
770 mg (11.7 mmol) of zinc, 3.09 g (11.7 mmol) of triphenylphosphine and 3.9 g (11.7 mmol) of carbon tetrabromide are stirred for 30 minutes at room temperature in 150 mol of dichloromethane. A solution of 3.3 g (5.9 mmol) of (E)-3-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-2-thienyl}pent-2-enal (described in Example 7(c)) in 30 mL of dichloromethane is then added dropwise. After stirring for 1 h at room temperature the reaction medium is treated with water and extracted with dichloromethane. After purification on silica gel (eluent: 95 heptane/5 ethyl acetate), the desired product is obtained in the form of a brown oil (m=3.9 g; Y=93%).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.C[C@H]1CC[C@H](N)CC1.[Cl:22][C:23]1[CH:60]=[CH:59][C:26]([C:27]2[C:32]([C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[C:38]([C:43]5[N:47](CC)[C:46]6[CH:50]=[CH:51][C:52]([C:54](O)=O)=[CH:53][C:45]=6N=5)[CH:39]=4)[N:34]=3)=[CH:31][C:30]([O:57][CH3:58])=[CH:29][CH:28]=2)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:60]=[CH:59][C:26]([C:27]2[C:32]([C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[C:38]([C:43]5[N:47]([CH:46]6[CH2:45][CH2:53][CH:52]([CH3:54])[CH2:51][CH2:50]6)[C:2]6[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=6[N:11]=5)[CH:39]=4)[N:34]=3)=[CH:31][C:30]([O:57][CH3:58])=[CH:29][CH:28]=2)=[CH:25][CH:24]=1
Reactant: CCn1c(-c2ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c2)nc2cc(C(=O)O)ccc21
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: C[C@H]1CC[C@H](N)CC1
Product: COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCC(C)CC4)ccc3n2)c1

Procedure:
The title compound was prepared from Resin 534a and a mixture of cis and trans 4-methylcyclohexyl-amine according to the procedure described in the preparation of Compound 534.
Reaction SMILES: Cl.[F:2][C:3]([F:12])([F:11])[CH2:4][CH2:5][O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[O:44]=[C:45]1[NH:54][C:53]2[N:52]=[CH:51][C:50](/[CH:55]=[CH:56]/[C:57](O)=[O:58])=[CH:49][C:48]=2[CH2:47][CH2:46]1>CN(C)C=O.O.C(OCC)(=O)C>[O:58]=[C:57]([N:9]1[CH2:10][CH:7]([O:6][CH2:5][CH2:4][C:3]([F:2])([F:11])[F:12])[CH2:8]1)/[CH:56]=[CH:55]/[C:50]1[CH:49]=[C:48]2[C:53](=[N:52][CH:51]=1)[NH:54][C:45](=[O:44])[CH2:46][CH2:47]2
Reactant: FC(F)(F)CCOC1CNC1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCc2cc(/C=C/C(=O)N3CC(OCCC(F)(F)F)C3)cnc2N1
Reaction time: 8 h
Yield: 38.7 %

Procedure:
3-(3,3,3-Trifluoropropoxy)azetidine hydrochloride (194 mg, 0.94 mmol), EDCI (181 mg, 0.94 mmol), HOBt (128 mg, 0.94 mmol) and diisopropylethylamine (274 μL, 1.57 mmol) were successively added to a solution of (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acid hydrochloride (160 mg, 0.63 mmol) in dimethylformamide (15 mL) at room temperature. The reaction mixture was stirred overnight then diluted by addition of ethyl acetate (30 mL) and water (40 mL). The aqueous layer was separated and extracted with ethyl acetate (2×30 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×30 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using dichloromethane/methanol (98:2) as eluent. The residue was finally precipitated from methanol to afford the title product as a white solid (90 mg, 39%).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[NH:5]1)([CH3:3])[CH3:2].Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][N:27]=3)[CH2:22][CH2:21]2)=[O:19])=[C:14]([F:34])[CH:13]=1>>[CH3:32][C:31]1[C:26]([N:23]2[CH2:24][CH2:25][N:20]([C:18]([C:15]3[CH:16]=[CH:17][C:12]([N:5]4[C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][CH2:7][S:6]4(=[O:10])=[O:9])=[CH:13][C:14]=3[F:34])=[O:19])[CH2:21][CH2:22]2)=[N:27][CH:28]=[C:29]([CH3:33])[CH:30]=1
Reactant: CC(C)[C@@H]1CCS(=O)(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4[C@H](C(C)C)CCS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 16.4 %

Procedure:
Using (S)-3-isopropylisothiazolidine 1,1-dioxide (400 mg) described in Preparation Example 6 and (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (392 mg) described in Preparation Example 114 and by the reaction and treatment in the same manner as in Example 4, the title compound (78 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]([CH:26]=[O:27])[CH:23]=[N:24][CH:25]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:26]([C:22]1[CH:21]=[C:20]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[O:10][CH3:11])[CH:25]=[N:24][CH:23]=1)=[O:27]
Reactant: COc1cc(C#N)ccc1Br
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(C#N)ccc1-c1cncc(C=O)c1
Temperature: 100 °C
Yield: 100.2 %

Procedure:
A mixture of 4-bromo-3-methoxy-benzonitrile (400 mg, 1.88 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-3-carbaldehyde (440 mg, 1.88 mmol), PdCl2(PPh3)2 (108 mg, 0.15 mmol) and Na2CO3 (2M in water, 1.88 mL, 3.77 mmol) in 1,4-dioxane (8 mL) was heated at 100° C. for 1.5 h. After concentration in vacuo, the resulting residue was purified by flash column to give the title compound (449 mg, 100%) as white solid; ESI-MS m/z: 239 [M+1]+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]=[CH:10]2)=[CH:5][CH:4]=1.[CH3:13][C:14]([C:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1)=[O:15].O>C(O)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][N:9]3[CH:10]([CH2:13][C:14](=[O:15])[CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]43)[C:11]=2[CH:12]=1
Reactant: CC(=O)C1=CCCCC1
Reactant: Fc1ccc2c(c1)C=NCC2
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C1CC2c3cc(F)ccc3CCN2C2CCCCC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 19.5 g (0.1 mole) of 3,4-dihydro-7-fluoroisoquinoline hydrochloride and 18.6 g (0.15 mole) of 1-cyclohexen-1-yl methyl ketone in 22 ml of ethanol is refluxed with stirring overnight then cooled to room temperature. The solution is poured into water, whereupon a suspension of undissolved material forms, and is extracted with ether. The aqueous layer and its suspended solid are stirred and treated with ammonium hydroxide solution to pH 8.5 to 9.0. The suspended solid is broken up, collected by decantation washed with water, dissolved in methylene chloride, dried over sodium sulfate and evaporated. The remaining residue is dissolved in benzene and chromatographed on alumina and eluted with benzene. The resulting solid is triturated with hexane and dried to give 2,3,4,4a,6,7,11b, 12,13,13a-decahydro-10-fluoro-1H-dibenzo[a,f]quinolizin-13-one, M.P. 130°-136°C.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][C@H:14]1[C@H:19]([OH:20])[CH2:18][C@@H:17]2[CH2:21][C@H:15]1[C:16]2([CH3:23])[CH3:22].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Cu](I)I>[CH3:13][C@H:14]1[C@H:19]([O:20][C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:18][C@@H:17]2[CH2:21][C@H:15]1[C:16]2([CH3:22])[CH3:23]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C[C@H]1[C@H](O)C[C@@H]2C[C@H]1C2(C)C
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(O[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)cc1
Temperature: 120 °C

Procedure:
Ethyl 4-iodobenzoate (276 mg), (1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ol (154 mg), 1,10-phenanthroline (36 mg), copper iodide (19 mg) and cesium carbonate (652 mg) were combined in toluene (0.5 mL). The reaction was heated to 120° C. over 36 hours. The reaction mixture was removed from heat, allowed to cool, diluted with ethyl acetate and poured into water. The organic layer was washed thoroughly with water and brine, dried over MgSO4, filtered and concentrated under vacuum. The crude material was purified by flash chromatography eluting with 95/5 hexanes/ether.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:13][N:14]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH:37]3[CH2:39][CH2:38]3)[CH:33]=2)[CH:28]=1)[C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1)=[O:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@H:8]([C@@H:9]([CH3:12])[CH2:10][CH3:11])[CH2:13][N:14]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH:37]3[CH2:39][CH2:38]3)[CH:33]=2)[CH:28]=1)[C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1)=[O:16]
Reactant: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1ccc(F)cn1)c1ccc2cc(C3CC3)ccc2c1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@H](N)CN(C(=O)[C@@H]1C[C@H]1c1ccc(F)cn1)c1ccc2cc(C3CC3)ccc2c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of [(1S,2S)-1-({(6-cyclopropyl-naphthalen-2-yl)-[trans-2-(5-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-amino}-methyl)-2-methyl-butyl]-carbamic acid tert-butyl ester in DCM (1.5 mL) was added TFA (0.25 mL) and was stirred at room temperature for 40 mins. The reaction mixture was concentrated, dried under vacuum to afford trans-2-(5-fluoro-pyridin-2-yl)-cyclopropanecarboxylic acid ((2S,3S)-2-amino-3-methyl-pentyl)-(6-cyclopropyl-naphthalen-2-yl)-amide.TFA (14.2 mg, 18% yield in 2 steps) as a tan solid: 1H NMR (400 MHz, MeOD) δ 7.90-7.93 (d, J=12 Hz, 1H), 7.53-7.78 (m, 4H), 7.25-7.32 (m, 2H), 7.10-7.31 (m, 2H), 4.19-4.30 (m, 1H), 3.67-3.75 (m, 1H), 3.20-3.30 (m, 1H), 2.49-2.59 (m, 1H), 1.90-2.01 (m, 1H), 1.75-1.84 (m, 1H), 1.55-1.67 (m, 2H), 1.19-1.31 (m, 2H), 1.07-1.12 (m, 1H), 0.90-0.97 (m, 2H), 0.80-0.90 (m, 3H), 0.25-0.75 (m, 5H); LC/MS (ESI) m/e 446.2 [(M+H)+, calcd for C28H33FN3O 446.6].
Reaction SMILES: CC1[N:3]([C@H:8]2[CH2:12][C@@:11]([C:23]3([OH:27])[CH2:26][CH2:25][CH2:24]3)([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH:10]=[CH:9]2)C(C)=CC=1.Cl.NO.NO.O>CO>[NH2:3][C@H:8]1[CH2:12][C@@:11]([C:23]2([OH:27])[CH2:24][CH2:25][CH2:26]2)([C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[CH:10]=[CH:9]1
Reactant: Cc1ccc(C)n1[C@@H]1C=C[C@@](C(=O)OCc2ccccc2)(C2(O)CCC2)C1
Agent: Cl
Agent: NO
Solvent: CO
Solvent: O
Product: N[C@@H]1C=C[C@@](C(=O)OCc2ccccc2)(C2(O)CCC2)C1
Yield: 95.6 %

Procedure:
A mixture of 5.52 g (15.1 mmol) of benzyl (1R,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(1-hydroxycyclobutyl)cyclopent-2-ene-1-carboxylate (Preparation SRT-0229), 8.20 g (120 mmol) of hydroxylamine hydrochloride, and 7.0 mL of 50% aqueous hydroxylamine (100 mmol) in 50 mL of methanol was heated at 68 C for 8 h, then cooled. Sufficient water was added to dissolve the crystals which deposited, and the solution was concentrated under reduced pressure to remove methanol. The resulting mixture was brought to pH ˜10 with aq. NaOH and then extracted with several portions of dichloromethane. The organic phase was dried over Na2SO4 and than concentrated under reduced pressure to afford 4.15 g (96%) of the title amine as a nearly colorless oil, of sufficient purity for the subsequent reaction. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42-1.53 (m, 1H) 1.85 (dd, 1H) 1.88-2.08 (m, 4H) 2.19-2.27 (m, 1H) 2.46 (dd, J=14.5, 8.3 Hz, 1H) 3.97-4.02 (m, 1H) 4.70 (s, 1H) 5.16 (s, 2H) 5.84 (dd, J=5.6, 1.6 Hz, 1H) 5.98 (dd, J=5.6, 2.1 Hz, 1H) 7.31-7.38 (m, 5H). LC-MS ES+ 288.2
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[C:16]([O:18]CC)=[O:17])[N:12]=[CH:11][CH:10]=[N:9]2)=[O:5])C.[OH-].[K+].O>O1CCOCC1.CC(OC(C)=O)=O>[N:9]1[C:8]2[CH:7]=[C:6]3[C:4](=[O:5])[O:18][C:16](=[O:17])[C:15]3=[CH:14][C:13]=2[N:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1cc2nccnc2cc1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C1OC(=O)c2cc3nccnc3cc21
Yield: 72 %

Procedure:
11.8 g (43.0 mmol) quinoxaline-6,7-dicarboxylic acid diethyl ester and 5.0 g (86 mmol) KOH dissolved in 100 ml dioxane and 50 ml water is stirred at ambient temperature during 20 hours. After evaporation of the dioxane, the solution is made slightly acidic (pH ˜5) with HCl 2N and is extracted with methylene chloride. After evaporation of the organic phase, 6.6 g diacide is isolated. This product is directly dissolved in 25 ml acetanhydride and heated at reflux during 8 hours. Acetanhydride is evaporated and 6.2 g furo[3,4-g]quinoxaline-6,8-dione is isolated. Without purification, this material is dissolved in 50 ml methanol and heated at reflux during 1 hour. After evaporation of the solvent, the residue is crystallised in diisopropyl ether to give 6.25 g of the title compound (63%): 1H-NMR (DMSO-d6, 400 MHz): 3.73 ppm (s, 3H), 8.20 (s, 1H), 8.35 (s, 1H), 9.0 (2 s, 2H), 13.6 (s, b, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:49])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[C:40]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)=[N:39][CH:38]=[N:37]2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:49])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[C:40]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)=[N:39][CH:38]=[N:37]2)[CH:31]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2ncnc2COC2CCCCO2)c1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ncnc3COC3CCCCO3)c2)cc1Cl

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(methyl-propyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J8) (1.0 g, 3.19 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,4]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K24) (1.28 g, 3.19 mmol) according to the general procedure M. Obtained as a yellow foam (1.48 g).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](O)([C:17]1[C:25]([OH:26])=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=1)[C:5](=[O:16])[N:6]2[CH2:11]CCCC.[CH2:28]([O:35][CH2:36][CH2:37]CN1C2C(=CC=CC=2)C(O)(C2C(O)=CC3OCOC=3C=2)C1=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][CH:36]([CH3:37])[CH2:11][N:6]1[C:7]2[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=2)[CH:4]([C:17]2[C:25]([OH:26])=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=2)[C:5]1=[O:16])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C1N(CCCOCc2ccccc2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Reactant: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: CC(CN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21)OCc1ccccc1

Procedure:
Following the procedure as described in PREPARATION 1D, and making non-critical variations to replace 4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 1-[3-(benzyloxy)propyl]-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (92%): 1H NMR (300 MHz, CDCl3) δ7.42-6.95 (m, 9H), 6.56 (s, 1H), 6.24 (s, 1H), 5.86 (ABq, 1H), 5.81 (ABq, 1H), 4.99 (s, 1H), 4.42 (s, 2H), 3.91-3.76 (m, 2H), 3.46 (t, 2H), 2.03-1.93 (m, 2H); MS (ES+) m/z 418.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]([OH:16])=[O:15])[CH:8]=2)[O:3]1.[I:18]Cl.BrC1C=C(C(O)=O)C=C2C=1OC(C)(C)CC2(C)C>>[I:18][C:5]1[CH:6]=[C:7]([C:14]([OH:16])=[O:15])[CH:8]=[C:9]2[C:4]=1[O:3][C:2]([CH3:17])([CH3:1])[CH2:11][C:10]2([CH3:12])[CH3:13]
Reactant: CC1(C)CC(C)(C)c2cc(C(=O)O)ccc2O1
Reactant: ClI
Agent: CC1(C)CC(C)(C)c2cc(C(=O)O)cc(Br)c2O1
Product: CC1(C)CC(C)(C)c2cc(C(=O)O)cc(I)c2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.1 %

Procedure:
To a solution of 2,2,4,4-tetramethyl-6-chromanoic acid (66 mg, 0.28 mmol) in 0.8 ml of ACOH was added ICl (0.07 ml, 1.4 mmol). The resulting colored solution was stirred at room temperature for overnight. Following the same procedure as for the synthesis of 8-bromo-2,2,4,4-tetramethyl-6-chromanoic acid (Compound P), the reaction gave the title compound (107 mg) as white solids.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)[N:10]=[N:9][C:8]=1[C:23]([NH:25][CH:26]1[CH2:28][CH2:27]1)=[O:24])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>C(#N)C.C(OCC)(=O)C>[CH:26]1([NH:25][C:23]([C:8]2[N:9]=[N:10][N:11]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:17]=3)[C:7]=2[CH2:6][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:24])[CH2:28][CH2:27]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COS(C)(=O)=O)cc1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1.83 h
Yield: 83.4 %

Procedure:
(4-[(Cyclopropylamino)carbonyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazol-5-yl)methyl methanesulfonate (204 mg, 0.501 mmol) obtained in Example 126a), potassium carbonate (69.2 mg, 0.501 mmol, 1.0 eq.) and pyrrolidine (0.084 ml, 1.00 mmol, 2.0 eq.) were suspended in acetonitrile (4.0 ml), and the mixture was stirred at room temperature for 110 min. The reaction mixture was diluted with ethyl acetate (30 ml), washed twice with 2% aqueous sodium carbonate solution and with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a colorless oil. The oil was crystallized from ethyl acetate and diethyl ether, and the precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (160 mg, 0.418 mmol, 83.5%).
Reaction SMILES: [C:1]1(CO)[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ClC(C(CF)(CF)CF)=C[C@@H]1[C@H](C(Cl)=O)C1(C)C.C1C2CC3C(=CC=CC=3)C=2C=CC=1.[Cl:47][C:48]([C:59]([CH2:64][F:65])([CH2:62][F:63])[CH2:60][F:61])=[CH:49][C@@H:50]1[C@H:52]([C:53]([O:55][CH3:56])=[O:54])[C:51]1([CH3:58])[CH3:57]>>[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:47][C:48]([C:59]([CH2:60][F:61])([CH2:62][F:63])[CH2:64][F:65])=[CH:49][CH:50]1[CH:52]([C:53]([O:55][CH3:56])=[O:54])[C:51]1([CH3:57])[CH3:58]
Reactant: OCc1cccc2c1Cc1ccccc1-2
Reactant: COC(=O)[C@H]1[C@@H](C=C(Cl)C(CF)(CF)CF)C1(C)C
Agent: CC1(C)[C@H](C=C(Cl)C(CF)(CF)CF)[C@@H]1C(=O)Cl
Agent: c1ccc2c(c1)Cc1ccccc1-2
Product: COC(=O)C1C(C=C(Cl)C(CF)(CF)CF)C1(C)C

Procedure:
In the manner of Example I, but substituting 9H-fluorene-1-methanol and cis-3-(2-chloro-3,3,3-trifluoromethyl-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride, 9H-fluorene-1-methyl cis-3-(2-chloro-3,3,3-trifluoromethyl-1-propenyl)-2,2-dimethylcyclopropanecarboxylate was prepared.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:19]=[C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[S:17][N:16]=3)[CH:6]=[CH:5][C:4]1=2.[OH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=O>>[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:19]=[C:18]([N:20]4[CH2:21][CH2:22][N:23]([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][OH:27])[CH2:24][CH2:25]4)[S:17][N:16]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: O=CCCCCO
Reactant: CC1(C)CCC(C)(C)c2cc(-c3nsc(N4CCNCC4)n3)ccc21
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3nsc(N4CCN(CCCCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 65 mg (0.17 mmol) of 1-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,4-thiadiazol-5-yl]piperazine hydrochloride and 17 mg (0.165 mmol) of 5-hydroxypentanal.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:30][CH2:29][C@:7]2([O:11][CH2:10][C@H:9]([C:12]3[CH:17]=[C:16]([N:18]4[CH:22]=[CH:21][N:20]=[C:19]4[C:23]([F:26])([F:25])[F:24])[CH:15]=[CH:14][C:13]=3[O:27][CH3:28])[CH2:8]2)[C@@H:6]1[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[O:4].[OH-].[Na+].Cl>C(O)C.O>[F:37][C:34]1[CH:35]=[CH:36][C:31]([C@H:6]2[C@@H:5]([C:3]([OH:4])=[O:2])[CH2:30][CH2:29][C@@:7]32[O:11][CH2:10][C@H:9]([C:12]2[CH:17]=[C:16]([N:18]4[CH:22]=[CH:21][N:20]=[C:19]4[C:23]([F:26])([F:25])[F:24])[CH:15]=[CH:14][C:13]=2[O:27][CH3:28])[CH2:8]3)=[CH:32][CH:33]=1
Reactant: COC(=O)[C@H]1CC[C@@]2(C[C@@H](c3cc(-n4ccnc4C(F)(F)F)ccc3OC)CO2)[C@@H]1c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(-n2ccnc2C(F)(F)F)cc1[C@H]1CO[C@]2(CC[C@H](C(=O)O)[C@@H]2c2ccc(F)cc2)C1
Temperature: 0 °C
Yield: 103 %

Procedure:
To an ice cold solution of 40 mg (0.077 mmol) (3S,5R,6S,7S)-6-(4-fluorophenyl)-3-(2-methoxy-5-(2-trifluoromethylimidazol-1-yl)phenyl)-1-oxaspiro[4.4]nonane-7-carboxylic acid methyl ester (from Example 70) in 1.0 mL of ethanol and 0.20 mL of water was added 0.050 mL of 2.5N aqueous NaOH. The mixture was stirred at 0° C., then warmed slowly to RT overnight. After neutralizing with 0.065 mL of 2N aqueous HCl, the mixture was partitioned between 25 mL of ethyl acetate and 25 mL of brine. The layers were separated and the organic layer was dried over sodium sulfate and evaporated to give 40 mg of title compound as a colorless syrup. Mass spectrum (NH3/CI): m/z=505.0 (M+1).