Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.Cl.[NH:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]4[CH:22]=N[CH:24]=[CH:25][CH:26]=4)=[CH:20][C:15]=3[CH2:14][N:13]([C:27](=[O:32])[C:28](F)(F)F)[CH:12]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:11]2)[N:6]=[CH:5]1.N1C=C(C=O)N=[CH:41]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(O)(=O)C>[ClH:1].[C:27]([N:13]1[CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:22]=[CH:41][CH:24]=[CH:25][CH:26]=3)[CH:18]=[CH:17][C:16]=2[N:10]([CH2:9][C:7]2[N:6]=[CH:5][NH:4][CH:8]=2)[CH2:11][C@H:12]1[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)(=[O:32])[CH3:28]
Reactant: O=Cc1c[nH]cn1
Reactant: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(=O)N1Cc2cc(-c3ccccc3)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.9 %

Procedure:
A solution of 115 mg (0.29 mmol) of Compound B in 2.5 mL of dichloroethane and 2.5 mL of glacial acetic acid was treated with 69 mg (0.71 mmol) of 4-imidazole-carboxaldehyde, 3A sieves and stirred at rt for 18 hrs. The mixture was treated with 122 mg (0.58 mmol) of sodium triacetoxyborohydride in one portion and stirred at rt for 30 min and filtered. The filtrate was partitioned between 100 mL of ethyl acetate and 100 mL of 1 N sodium hydroxide. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo. The oil was purified by reverse phase preparative HPLC (gradient of aq methanol with 0.1% TFA). The yellow foam was evaporated 3× from methanolic hydrogen chloride. The foam was dissolved in water and lyophilyzed to afford 30 mg (22%) of Compound C as a yellow lyophilate. MS: (M+H)+ =480.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[N:15])=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[N:15])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccccc1-c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
A solution of 5.59 g of 4'-methyl-2-cyanobiphenyl, 29 mmol of N-bromosuccinimide, 0.9 mmol of benzoylperoxide and 500 mL of carbon tetrachloride was refluxed for 3 hours. After cooling to room temperature, the resulting suspension was filtered and then concentrated in vacuo to provide the crude 4'-bromomethyl-2-cyanobiphenyl. The product was recrystallized from ether to yield 4.7 g of product; m.p. 114.5°-120.0°. NMR (200 MHz, CDCl3) δ 7.82-7.37 (m, 8H); 4.50 (s, 2H). Anal. Calcd. for C14H10BrN: C, 61.79, H, 3.70; N, 5.15. Found: C, 62.15; H, 3.45; N, 4.98.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15].[F:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[N:31]=[C:30]([CH2:32]O)[CH:29]=[CH:28][CH:27]=2)=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([O:16][CH2:32][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([O:25][C:24]2[CH:34]=[CH:35][C:21]([F:20])=[CH:22][CH:23]=2)[N:31]=1)=[O:15]
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Reactant: OCc1cccc(Oc2ccc(F)cc2)n1
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)OCc1cccc(Oc2ccc(F)cc2)n1

Procedure:
The acid chloride of 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid is reacted with [6-(4-fluorophenoxy)-2-pyridyl]methanol using the procedure of Example 1 to give [6-(4-fluorophenoxy)-2-pyridyl]methyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[Cl:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9]>CC(C)=O>[Cl:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([N:3]=[C:2]=[S:1])=[O:9]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Product: O=C(N=C=S)c1cccnc1Cl

Procedure:
1.891 g (12.0 mmol) of 2-chloronicotinic acid, 15 ml of thionyl chloride and two droplets of DMF were heated under reflux for 2 hours. The reaction mixture was allowed to cool, and then concentrated under reduced pressure. 2-Chloronicotinoyl chloride thus obtained was then dissolved in 10 ml of acetone. 770 mg of ammonium thiocyanate was it then dissolved in 15 ml of acetone with stirring. To the solution thus obtained was then added dropwise the acetone solution of 2-chloronicotinoyl chloride in 5 minutes. The mixture was then stirred. The mixture was then stirred over a 40° C. oil bath for 5 minutes. The insoluble matters thus precipitated were then removed by filtration to obtain an acetone solution of 2-chloronicotinoyl isothiocyanate. To the solution thus obtained was then added dropwise a mixture of 2.151 g of N-ethyl-3,4-ethylenedioxyaniline and 10 ml of acetone with stirring at room temperature in 5 minutes. The reaction mixture was stirred at room temperature for 16 hours, and then poured into about 1,000 ml of ice-water. The resulting crystal was collected by filtration, washed with water, and then dried under reduced pressure. The resulting product was then recrystallized from ethanol to obtain 2.18 g of 2-[N-(2,3-dihydro-1,4-benzodioxan-6-yl]-N-ethylamino-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[NH2:27][C:28]1[S:29][C:30]([C:33](O)=[O:34])=[CH:31][N:32]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:27][C:28]1[S:29][C:30]([C:33]([NH:13][C:10]2[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]3[CH:6]=[CH:5][C:4]([O:17][CH2:18][CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[C:3]([O:2][CH3:1])[C:12]=3[N:11]=2)=[O:34])=[CH:31][N:32]=1
Reactant: Nc1ncc(C(=O)O)s1
Reactant: COc1c(OCCCN2CCOCC2)ccc2c1N=C(N)N1CCN=C21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(OCCCN2CCOCC2)ccc2c1N=C(NC(=O)c1cnc(N)s1)N1CCN=C21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (250 mg, 0.70 mol) was dissolved in DMF (4 mL), and 2-amino-1,3-thiazole-5-carboxylic acid (110 mg, 0.76 mmol) was added. PYBOP (543 mg, 1.04 mmol) and diisopropylethylamine (0.61 mL, 3.50 mmol) were subsequently added, and the mixture was stirred at room temperature overnight. The desired product was isolated via HPLC to give the title compound (80.0 mg, 24%): HPLC MS RT=1.03 min, MH+=486.3; 1H NMR (MeOH-d4+2 drops TFA-d) δ: 7.90 (1H, d), 7.79 (1H, d), 7.50-7.60 (2H, m), 3.70 (2H, m), 3.30 (2H, d), 3.20 (2H, q), 2.10 (2H, s), 1.35 (10H, m).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11](Br)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[O:21]=[C:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CN1CCCC1=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11]([N:25]4[CH2:26][CH2:27][C:22](=[O:21])[CH2:23][CH2:24]4)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C1CCNCC1
Reactant: Cc1c(F)c(Br)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CN1CCCC1=O
Product: Cc1c(F)c(N2CCC(=O)CC2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 90 °C
Yield: 37.6 %

Procedure:
To a solution of 1-cyclopropyl-6-fluoro-7-bromo-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.58 g) in N-methyl-2-pyrrolidone (5 ml) is added 4-oxopiperidine (0.64 g) and the mixture is heated at 90° C. for 20 minutes The solvent is distilled off under reduced pressure To the resulting residue is added ethanol and the precipitated crystals are filtered to give 1-cyclopropyl-6-fluoro-7-(4-oxo-1-piperidinyl)-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (230 mg).
Reaction SMILES: O.S(=O)(=O)(O)O.[F:7][C:8]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][C:9]=1[NH2:10].[C:16]1([C:22](O)([CH3:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[F:7][C:8]1[CH:14]=[CH:13][C:12]([S:15][C:22]([CH3:24])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:23])=[CH:11][C:9]=1[NH2:10]
Reactant: CC(C)(O)c1ccccc1
Reactant: Nc1cc(S)ccc1F
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Sc1ccc(F)c(N)c1)c1ccccc1
Temperature: 0 °C
Yield: 45.9 %

Procedure:
To a mixture of water (10 mL) and concentrated sulfuric acid (10 mL) were added 2-fluoro-5-mercaptoaniline (1.85 g) and a solution of 2-phenyl-2-propanol (1.76 g) in tetrahydrofuran (10 mL) successively at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=6/1−3/1) to give the title compound (1.55 g).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:31]2[CH2:43][CH2:42][N:34]3[C:35]4[CH2:36][CH2:37][CH2:38][CH2:39][C:40]=4[CH:41]=[C:33]3[C:32]2=[O:44])=[N:8][CH:9]=[CH:10][C:11]=1C1C=C(NC2C=C3CN(C)CCN3N=2)C(=O)N(C)C=1)(=[O:3])[CH3:2].Br[C:46]1[CH:47]=[C:48]([NH:54][C:55]2[CH:60]=[CH:59][C:58]([N:61]3[CH2:66][C@@H:65]([CH3:67])[N:64]([CH:68]4[CH2:71][O:70][CH2:69]4)[CH2:63][C@@H:62]3[CH3:72])=[CH:57][N:56]=2)[C:49](=[O:53])[N:50]([CH3:52])[CH:51]=1.C(OCC1C(N2CCN3C4CCCCC=4C=C3C2=O)=NC=CC=1B1OC(C)(C)C(C)(C)O1)(=O)C>>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:31]2[CH2:43][CH2:42][N:34]3[C:35]4[CH2:36][CH2:37][CH2:38][CH2:39][C:40]=4[CH:41]=[C:33]3[C:32]2=[O:44])=[N:8][CH:9]=[CH:10][C:11]=1[C:46]1[CH:47]=[C:48]([NH:54][C:55]2[CH:60]=[CH:59][C:58]([N:61]3[CH2:66][C@@H:65]([CH3:67])[N:64]([CH:68]4[CH2:71][O:70][CH2:69]4)[CH2:63][C@@H:62]3[CH3:72])=[CH:57][N:56]=2)[C:49](=[O:53])[N:50]([CH3:52])[CH:51]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: C[C@@H]1CN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Agent: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4C[C@@H](C)N(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 41 %

Procedure:
Following the procedures as described for compound 113j, reaction of 122e (723 mg, 1.62 mmol) and 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113i (613 mg, 1.62 mmol) afforded 122f as a yellow solid (464 mg, 41%). LCMS: [M+H]+ 707
Reaction SMILES: [OH-].[K+].[N:3]1[C:12]2[C:7](=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Br[CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1>C(O)C>[N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:15][CH2:16][O:17][C:18]3[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: Oc1ccc2ncccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=Cc1ccc(OCCOc2ccc3ncccc3c2)cc1
Temperature: -5 °C
Yield: 43.8 %

Procedure:
To a solution of potassium hydroxide (0.67 g, 9.80 mmol) in ethanol (30 ml) is added 6-quinolinol (1.42 g, 9.80 mmol) and 4-(2-bromoethoxy)benzaldehyde (2.25 g, 9.80 mmol). Then the mixture is heated to reflux for 8 hours. After cooled to −5° C., the precipitate is collected by filtration, washed with water, and dried under vacuum to give the title product (1.26 g, 44%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[I:15](O)(O)(O)(O)(O)=O.II.S(=O)(=O)(O)O>O.C(O)(=O)C>[I:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: [O-][I+](O)(O)(O)(O)O
Reactant: CCc1ccc(-c2ccccc2)cc1
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCc1ccc(-c2ccc(I)cc2)cc1
Temperature: 70 °C

Procedure:
25.0 g (137 mmol) of 4-ethylbiphenyl, 7.23 g (27.4 mmol) of orthoperiodic acid, 13.9 g (54.9 mmol) of iodine, 133 ml of acetic acid, 27 ml of water and 4.1 ml of sulfuric acid were placed in a 500 ml three-necked flask with a mechanical stirrer and bulb-shaped cooler. This was heated to 70° C. in a water bath, and subjected to the reaction for 2 hours. The product was cooled down to the ambient temperature. To this was added 300 ml of water, which was subjected to the extraction with chloroform. The resultant chloroform phase was washed with sodium thiosulfate and water in this order. To this was added sodium sulfate, and the dehydration was carried out. After the filtration was carried out, the chloroform was distilled away in an evaporator to obtain a light yellow solid. The resultant solid was recrystallized in the presence of ethanol to obtain a white crystal. The yield of the compound was 71%. Its melting point was 145-149° C. The IR chart is shown in FIG. 24.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][OH:18])[C:10]2[C:5](=CC=CC=2)[CH:4]=[CH:3][CH:2]=1.[Mg].Br[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[C:24]1([C:27]2[C:11]([C:1]3[CH:10]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:12]([CH2:17][OH:18])[CH:13]=[CH:14][C:15]=2[CH3:16])[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=1
Reactant: OCc1ccccc1-c1cccc2ccccc12
Reactant: Cc1ccc(Br)cc1
Agent: O=C(c1ccccc1)c1ccccc1
Agent: [Mg]
Product: Cc1ccc(CO)c(-c2ccccc2)c1-c1ccccc1

Procedure:
With the same method as for Compound 13, a Grignard reagent was prepared from magnesium (Wako Pure Chemical Industries, Ltd.) and p-bromotoluene (Wako Pure Chemical Industries, Ltd.), and benzophenone (Wako Pure Chemical Industries, Ltd.) was allowed to react with the reagent, to thereby obtain the title compound. m.p. 68-71° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:12]2[CH2:14][CH2:13]2)[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.[O-:15][CH2:16][CH3:17].[Na+].O>C(O)C>[CH:12]1([C:4]2[C:5]3[N:6]([C:8]([NH2:11])=[N:9][N:10]=3)[N:7]=[C:2]([O:15][CH2:16][CH3:17])[CH:3]=2)[CH2:14][CH2:13]1
Reactant: CC[O-]
Reactant: Nc1nnc2c(C3CC3)cc(Cl)nn12
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1cc(C2CC2)c2nnc(N)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 113 %

Procedure:
6-Chloro-8-cyclopropyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.010, 77 mg) was initially charged in ethanol (10 ml) while stirring at RT and admixed with sodium ethoxide (67 mg). After stirring for 4.5 h, the mixture was left to stand overnight and then the solvent was drawn off. The residue was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 91 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([O:13][Si](C)(C)C(C)(C)C(C)C)[C:5]=1[CH2:23][S:24][CH2:25][C@H:26]([NH:33][C:34]#[N:35])[C:27]1[O:31][N:30]=[C:29]([CH3:32])[N:28]=1.[OH:37][CH2:38][C:39](=O)[CH3:40]>O1CCCC1.[OH-].[Na+].O>[CH3:1][O:2][C:3](=[O:36])[C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([OH:13])[C:5]=1[CH2:23][S:24][CH2:25][C@@H:26]([C:27]1[O:31][N:30]=[C:29]([CH3:32])[N:28]=1)[NH:33][C:34]1[O:37][CH:38]=[C:39]([CH3:40])[N:35]=1
Reactant: COC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1CSC[C@H](NC#N)c1nc(C)no1
Reactant: CC(=O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(C)c(OC)cc(O)c1CSC[C@H](Nc1nc(C)co1)c1nc(C)no1
Temperature: 40 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 260 mg of (R)-3-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-2-[2-cyanoamino-2-(3-methyl-1,2,4-oxadiazol-5-yl)-ethylsulfanylmethyl]-5-methoxy-6-methyl-benzoic acid methyl ester in 50 ml of tetrahydrofuran were added 0.1 ml of 25% aqueous hydroxyacetone and 0.09 ml of IN sodium hydroxide solution. The suspension was stirred for 12 h at 40° C. After cooling, the mixture was diluted with 100 ml water and subsequently extracted with 200 ml ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel using ethyl acetate/hexane (1:1, v/v) as eluent, and the purified product was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 1 to yield (R)-3-hydroxy-5-methoxy-6-methyl-2-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(4-methyl-oxazol-2-ylamino)-ethylsulfanylmethyl]-benzoic acid methyl ester as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[I-].C[N+]1C=CN([C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)C=1.C(N(CC)CC)C>C(#N)C>[F:10][C:8]([F:9])([F:11])[C:5]1[CH:6]=[CH:7][C:2]([O:1][C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:3][CH:4]=1
Reactant: Oc1ccc(C(F)(F)F)cn1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C(=O)Oc1ccc(C(F)(F)F)cn1)c1ccccc1
Yield: 66.4 %

Procedure:
A solution of 2-hydroxy-5-(trifluoromethyl)pyridine (0.49 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (15:85)) yielding the title compound (0.59 g, 66% yield) as a white solid.
Reaction SMILES: [CH:1]1([C:4](=[O:18])[CH:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[ClH:19]>>[Cl:19][CH2:3][CH2:2][CH2:1][C:4](=[O:18])[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cl
Reactant: O=C(C1CC1)C(c1ccccc1)c1ccccc1
Product: O=C(CCCCl)C(c1ccccc1)c1ccccc1

Procedure:
A mixture of 16 parts of 1-cyclopropyl-2,2-diphenylethanone and 300 parts of hydrochloric acid were stirred and refluxed for 4 hours. The reaction mixture was cooled and extracted with 2,2'-oxybispropane. The extract was washed with water and with a diluted sodium hydrogen carbonate solution, dried, filtered and evaporated, yielding 17 parts of 5-chloro-1,1-diphenyl-2-pentanone as a residue. (intermediate 3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: NCCN1CCOCC1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCCN1CCOCC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (100 mg, 0.28 mmol) and 4-(2-aminoethyl) morpholine (42 mg, 0.32 mmol). The title compound was obtained as a solid (49 mg, 38% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, m), 8.83 (1H, m), 8.43 (1H, s), 4.02 (4H, m), 3.31 (2H, m), 2.45 (2H, m), 2.38 (4H, m). MS m/z: 463.06, 465.05 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CCC(C(O)=O)CC1.C([O:38][C:39](=[O:50])[CH2:40][CH2:41][C@H:42]([NH:46]C(O)=O)[C:43](O)=[O:44])(C)(C)C>>[NH2:46][C@H:42]([C:43](=[O:44])[NH:24][C:21]1[CH:22]=[N:23][C:18]([O:17][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[O:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:16][CH2:15]3)=[CH:19][CH:20]=1)[CH2:41][CH2:40][C:39]([OH:50])=[O:38]
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)O)C(=O)O
Agent: O=C(O)C1CCNCC1
Product: N[C@@H](CCC(=O)O)C(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1

Procedure:
(S)-4-Amino-4-[6-(2-phenylchroman-6-yloxy)pyridin-3-ylcarbamoyl]butyric acid was prepared as described for piperidine-4-carboxylic acid [6-(2-phenyl-chroman-6-yloxy)pyridine-3-yl]amine in Example 19 a) and b) but replacing N-(tert-butoxycarbonyl)isonipecotic acid with (S)-2-carboxyaminopentanedioic acid 5-tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][CH3:19])=[CH:4][C:5]2[CH:9](O)[CH:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[S:7][C:6]=2[C:16]=1[Cl:17].B(F)(F)F.CCOCC.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([O:18][CH3:19])=[CH:4][C:5]2[CH:9]=[C:8]([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)[S:7][C:6]=2[C:16]=1[Cl:17]
Reactant: COc1cc2c(c(Cl)c1Cl)SC(C1CCCC1)C2O
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1cc2cc(C3CCCC3)sc2c(Cl)c1Cl
Reaction time: 8 h
Yield: 76.3 %

Procedure:
A mixture of 2.5 g of 6,7-dichloro-2-cyclopentyl-2,3-dihydro-3-hydroxy-5-methoxybenzo[b]thiophene and 10 ml of glacial acetic acid containing 5 ml of boron trifluoride etherate is warmed on a steam bath for 15 minutes and allowed to stand overnight. The mixture is poured into a chilled solution of dilute sodium hydroxide and the organic material is extracted into ether. Washing with water, followed by drying over anhydrous magnesium sulfate and evaporation in vacuo, gives 2.0 g of wax-like crystals. Recrystallization from ether-hexane gives 1.8 g of 6,7-dichloro-2-cyclopentyl-5-methoxybenzo-[b]thiophene as fine needles, mp 59.5°-60°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[Si:11]([CH3:14])([CH3:13])[CH3:12]>>[CH3:12][Si:11]([CH3:14])([CH3:13])[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: Cc1cc(C)cc(Br)c1
Product: Cc1cc(C)cc([Si](C)(C)C)c1

Procedure:
In the same manner as described in preparation 1, 5-bromo-m-xylene was allowed to react with chlorotrimethylsilane, and afforded TSIX. The yield and properties of product are summarized in Table 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:10])[CH:4]=1.C([N:13](CC)CC)C.C(OC(=O)C)(=O)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:8][CH:9]=1)[NH:7][N:13]=[CH:10]2
Reactant: CCN(CC)CC
Reactant: COc1ccc(N)c(C)c1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COc1ccc2[nH]ncc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4-methoxy-2-methylaniline (2 ml) in dichloromethane (10 ml) was treated with triethylamine (3.27 ml). The mixture was cooled to 0° C. then treated with acetic anhydride (2.38 ml), then stirred at ambient temperature for 1 hour, then cooled to 0° C. when a pink solid precipitated. This solid was filtered, then washed with cold dichloromethane and then dissolved in acetic acid (55 ml) and concentrated hydrochloric acid (20 ml). This solution was cooled to −5° C., then treated with a solution of sodium nitrite (2.68 g) in water (20 ml), then stirred at that temperature for 1 hour and then treated with water (100 ml). This mixture was stirred vigorously at 0° C. for 10 minutes after which a yellow solid precipitated. This solid was filtered, then washed with water and then dissolved in toluene (13 ml). This solution was heated to 80° C. for 1.5 hours, then cooled and then washed with aqueous 1N sodium carbonate solution. The organic phase was extracted three times with aqueous 2N hydrochloric acid and the acid extracts chilled and then made alkaline by addition of aqueous 5N sodium hydroxide solution. The aqueous layers were extracted three times with ethyl acetate and the combined organic layers were dried over magnesium sulfate and then evaporated to yield 5-methoxy-1H-indazole (0.410 g) as a yellow solid. LC-MS (METHOD B): RT=1.32 minutes; 149 (M+H)+.