Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:23][CH2:24][C@@H:25]([OH:27])[CH3:26]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17]([NH:23][CH2:24][C@@H:25]([OH:27])[CH3:26])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[C@H](O)CN
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Solvent: C1CCOC1
Product: C[C@H](O)CNc1cc2c(Nc3ccc(F)c(Cl)c3)c(C#N)cnc2cn1
Temperature: 140 °C
Yield: 17.5 %

Procedure:
Following the procedure described above in Example 51, 4-(3-Chloro-4-fluoro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile (0.10 g, 0.32 mmol) was reacted with (S)-1-amino-2-propanol (0.47 g, 6.32 mmol) in 2 mL of THF. The reaction mixture was heated up in a sealed vial in a microwave reactor at 140° C. for 40 min. The crude product was purified by preparative HPLC and lyophilized to give a yellow solid (20.8 mg, 17.7% yield): 1H NMR (400 MHz, DMSO-D6) δ ppm 0.93 (d, J=6.32 Hz, 3 H) 2.96-3.03 (m, 2 H) 3.68 (s, 1 H) 4.58 (s, 1 H) 6.46 (m, 1 H) 6.80 (s, 1 H) 7.06-7.17 (m, 1 H) 7.21-7.33 (m, 1 H) 7.33-7.47 (m, 1 H) 8.05 (s, 1 H) 8.62 (s, 1 H) 9.44 (s, 1 H); HRMS (ESI+) calcd for C18H15ClFN5O 372.10219, found (MH+) 372.1019.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([CH2:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[O:13])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[C:21]1([Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOCC.[NH4+].[Cl-]>O1CCCC1>[CH:1]1([CH2:4][N:5]2[CH2:6][CH2:7][CH:8]([CH2:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[OH:13])[CH2:9][CH2:10]2)[CH2:3][CH2:2]1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C(CC1CCN(CC2CC2)CC1)c1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(CC1CCN(CC2CC2)CC1)(c1ccccc1)c1ccc(F)cc1

Procedure:
1-(Cyclopropylmethyl)-4-(2'-(4"-fluorophenyl)-2'-oxoethyl)piperidine (Example 429, 1.0 g, 3.6 mmol) was mixed with dry tetrahydrofuran (10 mL). A solution of phenyl magnesium bromide in ether (3.0 M, 3 mL, 9 mmol) was added with stirring. The reaction mixture was stirred for 24 h; poured onto a saturated NH4Cl solution and extracted with ethyl acetate three times. The combined organic layers were dried over magnesium sulfate and filtered. Solvent was removed in vacuo. Trituration with ether-hexanes (1:9) and filtration afforded the title compound, a solid, which was dried in vacuo (0.9 g). mp 115°-116° C.; Anal. : Calcd for C23H28FNO: C, 77.36, H, 7.90, N, 3.92, F, 5.32; Found: C, 77.47, 77.41, H, 8.00, 7.92, N, 3.42, 3.52, F, 5.09.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[S:13][CH:14]=[CH:15][C:8]=2[C:7]=1O)=[O:5])[CH3:2].[O-]CC.[Na+].C(OC(C1C(Cl)=C2C=CSC2=NC=1[Cl:32])=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[S:13][CH:14]=[CH:15][C:8]=2[C:7]=1[Cl:32])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)nc2sccc2c1Cl
Reactant: CCOC(=O)c1c(O)c2ccsc2[nH]c1=O
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)c1c(Cl)c2ccsc2[nH]c1=O

Procedure:
A preferred intermediate in the preparation of compounds of structure (III) is 4-chloro-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester, depicted by formula (42) below. To prepare this intermediate, methyl-2-amino-thiophene-3-carboxylate was reacted with ethylmalonyl chloride to yield intermediate 2-(2-ethoxycarbonyl-acetylamino)-thiophene-3-carboxylic acid methyl ester, depicted by formula (39). This intermediate was converted to 4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester, depicted by formula (40), by reacting it with sodium ethoxide, and then converting it into 4,6-dichloro-thieno[2,3-b]pyrdine-5-carboxylic acid ethyl ester, depicted by formula (41). Hydrolysis of 4,6-dichloro-thieno[2,3-b]pyrdine-5-carboxylic acid ethyl ester, depicted by formula (41), yielded 4-chloro-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester, depicted by formula (42), as shown in Scheme 20.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[N:26]1([CH2:32][CH2:33][NH:34][S:35]([C:38]2[S:39][C:40](Cl)=[CH:41][CH:42]=2)(=[O:37])=[O:36])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[N:26]1([CH2:32][CH2:33][NH:34][S:35]([C:38]2[S:39][C:40]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)=[N:8][C:7]=34)=[CH:41][CH:42]=2)(=[O:36])=[O:37])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: O=S(=O)(NCCN1CCOCC1)c1ccc(Cl)s1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=S(=O)(NCCN1CCOCC1)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and 5-chloro-thiophene-2-sulfonic acid (2-morpholin-4-yl-ethyl)-amide (example B.38) (155 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (51 mg, 16%). MS (ISP) 630.1 [(M+H)+]; mp 219° C.
Reaction SMILES: [O:1]=[C:2]([O:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:30]=1[CH2:31][CH2:32][CH2:33]2)[CH:3]1[O:8][CH2:7][CH2:6][N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:4]1.[Cl-].[NH4+].F[C:41](F)(F)C(O)=O.C(=O)([O-])O.[Na+]>O.O1CCCC1>[OH:1][C:2]([O:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:30]=1[CH2:31][CH2:32][CH2:33]2)([CH:3]1[O:8][CH2:7][CH2:6][NH:5][CH2:4]1)[CH3:41]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(Oc1cccc2c1CCC2)C1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCO1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(Oc1cccc2c1CCC2)C1CNCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 50 ml. of anhydrous tetrahydrofuran was added 1g. (0.04 atom) of magnesium and then methyl bromide was added dropwise to the mixture at 5°-10° C. to provide a Grignard reagent. Then, a solution prepared by dissolving 2 g. (0.004 mole) of 2-(1-oxo-4-indanyloxymethyl)-4-triphenylmethyl morpholine in 20 ml. of anhydrous tetrahydrofuran was added dropwise to the reagent at 5°-10° C. Then, the mixture was stirred for 3 hours at room temperature and the solvent was distilled off under reduced pressure. The residue formed was mixed with saturated aqueous ammonium chloride solution and the mixture was extracted with chloroform. The extract obtained was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue formed was dissolved in 20 ml. off trifluoroacetic acid under ice-cooling and 20 ml. of water was immediately added to the solution followed by stirring for 15 minutes at 5°-10° C. The reaction mixture was neutralized with sodium hydrogencarbonate and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Thereafter, the residue formed was subjected to a silica gel column chromatography (diameter 3 cm., height 7 cm.) and from the fraction recovered therefrom using a 8 : 2 mixture of chloroform and methanol 820 mg. of sticky 2-(1-hydroxy-1-methyl-4-indanyloxymethyl)morpholine was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=[C:5]2[CH:4]=[CH:3]1.F[C:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[C:17]([F:22])[N:16]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.N1C=CC=CC=1>[F:22][C:17]1[N:16]=[C:15]2[O:13][C:11]([C:9]3[CH:10]=[C:5]4[CH:4]=[CH:3][N:2]([CH3:1])[C:6]4=[N:7][CH:8]=3)=[N:21][C:20]2=[CH:19][CH:18]=1
Reactant: Cn1ccc2cc(C(=O)O)cnc21
Reactant: Nc1ccc(F)nc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1ccc2cc(-c3nc4ccc(F)nc4o3)cnc21
Temperature: 150 °C
Yield: 12.9 %

Procedure:
To a suspension of 1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (68 mg, 0.38 mmol) in CH2Cl2 (2 mL) was added 1-chloro-N,N-2-trimethylpropenylamine (50 μL, 0.38 mmol). Following formation of the resulting acid chloride, the reaction mixture was concentrated affording a residue that was dissolved in pyridine (2 mL) before 2,6-difluoro-pyridin-3-ylamine (50 mg, 0.38 mmol) was added in one portion. After an additional 30 minutes the reaction mixture was concentrated to dryness affording a residue, to which was added DMF (2 mL) and K2CO3 (53 mg, 0.38 mmol). The resulting mixture was heated by microwave to 150° C. for 10 min, after which the resulting mixture was filtered and concentrated. The resulting residue was purified by reverse phase chromatography affording 5-fluoro-2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-oxazolo[5,4-b]pyridine (13.1 mg, 0.049 mmol, 13% yield). ES MS (M+H+)=269; 1H NMR δ (ppm)(DMSO-d6): 9.07 (1H, d, J=2.12 Hz), 8.75 (1H, d, J=2.13 Hz), 8.42 (1H, t, J=7.74 Hz), 7.70 (1H, d, J=3.52 Hz), 7.29 (1H, d, J=8.41 Hz), 6.69 (1H, d, J=3.52 Hz), 3.89 (3H, s); HRMS m/z 269.0831 (C14H9FN4O+H+ requires 269.0833).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1.OC1C=CC(O)=CC=1C(=O)C.[Br:31]C1C=C(C=CC=1)C=O>>[Br:31][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: O=C1CC(c2cccc(F)c2)Oc2ccc(O)cc21
Agent: CC(=O)c1cc(O)ccc1O
Product: O=C1CC(c2cccc(Br)c2)Oc2ccc(O)cc21

Procedure:
2-(3-Bromophenyl)-6-hydroxychroman-4-one was prepared as described for 2-(3-fluorophenyl)-6-hydroxychroman-4one in Example 9(a) starting from 3.0 g of 2′,5′-dihydroxyacetophenone and 2.3 ml of 3-bromobenzaldehyde. The product was recrystallised from acetic acid. 1H NMR (300 MHz, d6-DMSO) δ: 9.41 (s, 1H), 7.50 (m, 1H), 7.59-7.53 (m, 2H), 7.39 (m, 1H), 7.12 (d, 1H, J 2.9 Hz), 7.05 (dd, 1H, J 8.8, 2.9 Hz), 6.98 (d, 1H, J 8.8 Hz), 5.57 (dd, 1H, J 13.0, 2.9 Hz), 3.12 (dd, 1H, J −16.9, 13.0 Hz), 2.81 (dd, 1H, J −16.9, 2.9 Hz).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:42]=[CH:41][C:40]([N:43]3[C:47](=[O:48])[N:46]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[CH:45]=[N:44]3)=[CH:39][CH:38]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9]([CH2:11][CH2:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:37]3[CH:38]=[CH:39][C:40]([N:43]4[C:47](=[O:48])[N:46]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[CH:45]=[N:44]4)=[CH:41][CH:42]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: Brc1cnc(N2CCOCC2)c2nc(CCc3ccc4ccccc4n3)cn12
Reactant: CC1(C)OB(c2ccc(-n3ncn(COCC[Si](C)(C)C)c3=O)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cnn(-c2ccc(-c3cnc(N4CCOCC4)c4nc(CCc5ccc6ccccc6n5)cn34)cc2)c1=O
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A mixture of compound 3a (102 mg, 0.233 mmol), compound 84d (97.1 mg, 0.233 mmol, PdCl2(dppf)-DCM (5.7 mg, 0.0070 mmol), and Ar-degassed aqueous 2M Na2CO3 (0.582 mL, 1.16 mmol) in Argon-degassed 1,4-dioxane (4 mL) was further degassed with Argon for 3 min and then stirred at 90° C. for 5 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure to a brown oil which was purified by flash column chromatography on silica gel (40-100% EtOAc-DCM, followed by 100% EtOAc) to afford compound 84e as a crystalline white solid. Mass spectrum (LCMS, ESI pos.): Calcd. for C35H40N8O3Si, 649.3 (M+H). found 649.6.
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[N:3]=1.Cl[CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:33][C:32]1[O:31][C:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[N:29][C:28]=1[CH2:27][O:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[N:3]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CCOC(=O)c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1OCc1nc(-c2ccccc2)oc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A mixture of ethyl 3-hydroxy-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (4.07 g), 4-chloromethyl-5-methyl-2-phenyloxazole (2.58 g), potassium carbonate (1.73 g) and N,N-dimethylformamide (30 ml) was stirred at 80° C. for 8 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (5.86 g, yield: 96%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 96–97° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:42][C:43]#[C:44][C:45]([CH3:55])([O:47][Si:48]([CH2:53][CH3:54])([CH2:51][CH3:52])[CH2:49][CH3:50])[CH3:46]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:42][C:43]#[C:44][C:45]([CH3:46])([O:47][Si:48]([CH2:53][CH3:54])([CH2:51][CH3:52])[CH2:49][CH3:50])[CH3:55])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC[Si](CC)(CC)OC(C)(C)C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)C#CCO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 92.8 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5(10 μl) and 1-bromo-4-methyl-4-triethylsilyloxy-2-pentyne (109 mg, 0.375 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) to give the title compound as a colorless oil (76.4 mg, 93%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:12][CH2:13]1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of (trans-4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester (7.0 g, 33 mmol) in CH2Cl2 (165 mL) was charged with pyridine (13 mL, 79 mmol) and methanesulfonylchloride (6.4 mL, 82 mmol). The reaction was stirred at RT for 14 h and concentrated in vacuo. The residue was dissolved in EtOAc and the resulting solution was washed successively with water (2×) and brine (1×) before being dried (MgSO4), filtered, and concentrated in vacuo to afford methanesulfonic acid trans-4-tert-butoxycarbonylamino-cyclohexyl ester (9.3 g, 96% yield). MS found: (M+H)+=294.2.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17]([CH2:33][C:34]([OH:36])=[O:35])=[C:18]([CH3:32])[C:19]2=[CH:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:31])=[O:30])=[CH:25][CH:24]=2)=[CH:15][C:14]=1[O:37][CH3:38]>CC(C)=O>[F:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17]([CH2:33][C:34]([OH:36])=[O:35])=[C:18]([CH3:32])[C:19]2=[CH:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:31])(=[O:9])=[O:30])=[CH:25][CH:24]=2)=[CH:15][C:14]=1[O:37][CH3:38]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc2c(cc1F)C(=Cc1ccc(S(C)=O)cc1)C(C)=C2CC(=O)O
Solvent: CC(C)=O
Product: COc1cc2c(cc1F)C(=Cc1ccc(S(C)(=O)=O)cc1)C(C)=C2CC(=O)O

Procedure:
6-Fluoro-5-methoxy-2-methyl-1-(ρ-methylsulfonylbenzylidene)-3-indenyl acetic acid is prepared according to the procedure of Example 7 by the addition of 1.0 mole of m-chloroperbenzoic acid per mole of 6-fluoro-5-methoxy-2-methyl-1-(ρ-methylsulfinylbenzylidene)-3-indenyl acetic acid in an acetone solution.
Reaction SMILES: O=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1([Cl:15])[CH2:11][CH:10]1[C:12]([NH2:14])=[O:13]>C1(C)C=CC=CC=1>[Cl:8][C:9]1([Cl:15])[CH2:11][CH:10]1[C:12]([NH:14]/[C:2](=[CH:6]\[CH3:7])/[C:3]([OH:5])=[O:4])=[O:13]
Reactant: NC(=O)C1CC1(Cl)Cl
Reactant: CCC(=O)C(=O)O
Solvent: Cc1ccccc1
Product: C/C=C(\NC(=O)C1CC1(Cl)Cl)C(=O)O
Yield: 17.8 %

Procedure:
A mixture of 1.53 g (15 mmoles) of 2-ketobutyric acid, 1.54 g (10 mmoles) of 2,2-dichlorocyclopropanecarboxamide and 10 ml of toluene was heated under reflux for 12 hrs. with removal of H2O by a modified Dean-Stark trap containing molecular sieves (4A). An additional 0.7 g of 2-ketobutyric acid was added and the reaction mixture was heated under reflux for an additional 12 hrs. The mixture was cooled, diluted with 20 ml of toluene and extracted with saturated sodium bicaronate (3×10 ml). The extracts were combined, washed with ether and acidified to pH 3 (pH meter) with concentrated hydrochloric acid. A gum precipitated which soon solidified. It was filtered, washed with water, dried and recrystallized from nitromethane to give 423 mg of Z-2-(2,2-dichlorocyclopropanecarboxamido)-2-butenoic acid, m.p. 188°-189.5° C. The NMR spectrum was in accord with the desired structure.
Reaction SMILES: C(=O)([O-])N.C[O:6][C:7](=[O:24])[CH2:8][C:9]1[C:10]([CH3:23])=[N:11][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:13]=1[CH3:14].C(N(C(C)C)CC)(C)C.Cl[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]>ClCCl>[CH2:38]([O:37][C:35]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:12]2[C:13]([CH3:14])=[C:9]([CH2:8][C:7]([OH:6])=[O:24])[C:10]([CH3:23])=[N:11]2)=[CH:17][CH:18]=1)=[O:36])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(N)cc2)c1C
Reactant: O=C(Cl)OCc1ccccc1
Agent: NC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(Cc2ccc(NC(=O)OCc3ccccc3)cc2)c(C)c1CC(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Carbamate formation: To a solution of [1-(4-amino-benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-acetic acid methyl ester (intermediate 1.1.3, 70 mg, 0.26 mmol) in dichloromethane (1 mL) was added diisopropylethylamine (55 μL, 0.32 mmol) and benzyl chloroformate (55 μL, 0.39 mmol). The reaction mixture was stirred for 18 h at room temperature. The reaction mixture was filtered over Alox B, eluting with 10% methanol in dichloromethane. Saponification: After removing the volatiles under reduced pressure, the remaining residue was dissolved, in methanol (1 mL) and treated with aqueous NaOH solution (4 M, 0.2 mL). The mixture was neutralized with aqueous HCl and purified via preparative reversed phase HPLC (gradient of methanol in water+0.1% NH3).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][N:7]([CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[C:28]1[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[CH:31]=[CH:30][C:29]=1[O:37][CH3:38])[C:8]1[N:9]=[N:10][N:11]([CH2:13][CH2:14][S:15][CH3:16])[N:12]=1.ClC1C=CC=C(C(OO)=[O:56])C=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[F:45][C:42]([F:43])([F:44])[C:40]1[CH:39]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:46])[F:47])[CH:41]=1)[CH2:6][N:7]([CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[C:28]1[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[CH:31]=[CH:30][C:29]=1[O:37][CH3:38])[C:8]1[N:9]=[N:10][N:11]([CH2:13][CH2:14][S:15]([CH3:16])=[O:56])[N:12]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCSC)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCS(C)=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.8 %

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-[2-(2-methylsulfanyl-ethyl)-2H-tetrazol-5-yl]-amine (270 mg) is dissolved in chloroform (3 ml), and thereto is added m-chloroperbenzoic acid (168 mg), and the mixture is stirred at room temperature for 3 hours. To the reaction solution is added a saturated aqueous sodium bicarbonate solution and the mixture is extracted with ethyl acetate, and the organic layer is washed with a brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=40:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-[2-(2-methanesulfinyl-ethyl)-2H-tetrazol-5-yl]-amine (157 mg). MS (m/z): 708 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]([CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[C:9]1=[O:26].[ClH:27].O1CCOCC1>C(OCC)(=O)C>[ClH:27].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]([CH:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)[C:9]1=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccn(-c3ccccc3F)c2=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=c1n(-c2ccccc2F)ccn1C1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
tert-Butyl 4-(3-(2-fluorophenyl)-2-oxo-2,3-dihydroimidazol-1-yl)piperidine-1-carboxylate (215 mg, 594.9 μmol) was dissolved in ethyl acetate (4.0 mL). 4N Hydrogen chloride in 1,4-dioxane (5.0 mL, 20.0 mmol) was added to the mixture. Reaction stirred at room temperature for 18 hours. The material was concentrated by roto-vap. Residue was triturated in diethyl ether. Solids were filtered off and washed with diethyl ether. Solids were collected and dried in vacuo. Title compound was obtained as tan solid in 46% yield. MS (M+H)+=262.0.