Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=1.[CH2:17](Br)[CH:18]=[CH2:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:19]([O:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=1)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: CCOC(=O)c1cc(O)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(C(=O)OCC)nc2ccccc12

Procedure:
4-Hydroxyquinaldic acid, ethyl ester (16 g), allyl bromide (22.5 g) and anhydrous potassium carbonate (30 g) in dimethylformamide (300 ml) were stirred and heated on a steam bath for 20 hours. The mixture was filtered, the filtrate was evaporated and the residue was crystallised from a mixture of ethyl acetate and light petroleum (b.p. 60°-80°) to give 4-allyloxyquinaldic acid, ethyl ester.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O.[OH:17][CH:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH3:19]>O>[CH3:19][C:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:17]
Reactant: CC(O)C1CCCCC1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)C1CCCCC1
Reaction time: 0.5 h
Yield: 64 %

Procedure:
Into a two-liter, round bottom, three-necked flask equipped with a condenser, a mechanical stirrer, thermometer and a liquid addition funnel were placed 900 ml. of water, 200 g. (0.67 mole) of technical grade sodium dichromate followed by 176 g. (1.8 mole) of concentrated sulfuric acid. The contents were cooled to 55°-60° C. and 120 g. (0.94 mole) of 1-hydroxyethylcyclohexane was added over a period of 1 hour, holding the temperature between 55°-50° C. by means of external cooling. After the alcohol had been added, the reaction mixture was allowed to stir for an additional 30 minutes and then 600 ml. of water was added and the contents heated to remove the ketone by steam distillation. When no more ketone was being steam distilled, the heat was removed, the distillate of water and ketone separated and the upper organic layer was distilled under vacuum collecting the fraction boiling at 115°-116° C. There was obtained 76 g. of ketone representing a 64% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:13])=[CH:10]2)=[CH:5][CH:4]=1.C1(=O)O[CH2:17][CH2:16][O:15]1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([O:13][CH2:17][CH2:16][OH:15])=[CH:10]2)=[CH:5][CH:4]=1
Reactant: O=C1OCCO1
Reactant: COc1ccc2ccc(O)cc2c1
Product: COc1ccc2ccc(OCCO)cc2c1

Procedure:
*Prepared from 7-methoxy-2-naphthol and ethylene carbonat according to the procedure of Example 134, step 1, in WO 00/76984. The reaction mixture was refluxed for 2 h. Pure 2-(7-methoxy-naphthalen-2-yloxy)ethanol was obtained after column chromatography on silica gel using n-hexane/ethyl acetate (6:4) as eluent.
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[F:9][C:10]([F:46])([F:45])[C:11]1[CH:12]=[C:13]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:14][N:15]([C:32]1[N:33]=[N:34][N:35]([CH3:37])[N:36]=1)[C@H:16]1[CH2:22][CH2:21][CH2:20][NH:19][C:18]2[CH:23]=[C:24]([C:28]([F:31])([F:30])[F:29])[C:25]([CH3:27])=[CH:26][C:17]1=2.N1C=CC=CC=1>C(Cl)Cl>[F:45][C:10]([F:9])([F:46])[C:11]1[CH:12]=[C:13]([CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:40]=1)[CH2:14][N:15]([C:32]1[N:33]=[N:34][N:35]([CH3:37])[N:36]=1)[C@H:16]1[CH2:22][CH2:21][CH2:20][N:19]([C:4](=[O:5])[CH:3]([CH2:7][CH3:8])[CH2:1][CH3:2])[C:18]2[CH:23]=[C:24]([C:28]([F:29])([F:30])[F:31])[C:25]([CH3:27])=[CH:26][C:17]1=2
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: CCC(CC)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(CC)C(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2cc(C)c(C(F)(F)F)cc21
Reaction time: 1 h
Yield: 106.7 %

Procedure:
Add 2-ethyl-butyryl chloride (0.014 g, 0.108 mmol) dropwise under an atmosphere of nitrogen to a 0° C. cooled solution of (S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine (Example 3, Step 18) (0.060 g, 0.108 mmol) and pyridine (0.010 g, 0.108 mmol) in methylene chloride (5 mL). After stirring for 1 h, wash the reaction with saturated aqueous sodium bicarbonate solution (10 mL), 2N aqueous hydrogen chloride solution (10 mL), and brine (10 mL). Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to afford the title compound as a colorless gum (0.075 g, 98%). 1H NMR (CDCl3, 300 MHz) δ 0.71-2.16 (m, 16H), 2.34-2.43 (m, 1H), 2.43 (s, 3H), 2.50-2.41 (m, 1H), 4.14 (s, 3H), 4.25-4.67 (m, 2H), 6.89 (bs, 1H), 7.43 (s, 1H), 7.75 (s, 2H), 7.85 (s, 1H); ESI MS m/z 651 [C29H31F9N6O+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:4]=1.Br.[OH-].[Na+]>C(O)(=O)C.O>[C:10]1([NH:9][C:5]2[NH:4][C:3](=[O:2])[CH:8]=[CH:7][N:6]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccnc(Nc2ccccc2)n1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=c1ccnc(Nc2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
To a solution of 4-methoxy-N-phenylpyrimidin-2-amine (0.632 g, 3.14 mmol) in acetic acid (20 mL) was added HBr (2.132 ml, 18.84 mmol; 48 wt % in H2O). The reaction mixture was heated at a temperature ranging from about 90° C. to about 95° C. for 3 hours. The reaction mixture was cooled to room temperature and diluted with H2O. The pH of the reaction mixture was adjusted to about 5 to about 6 with 6M aqueous NaOH which resulted in the formation of a solid precipitate. The solid was filtered, washed with H2O, collected and dried under vacuum to yield the desired product (0.553 g, 94%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 10.74 (br s, 1H), 8.81 (br s, 1H), 7.76 (s, 1H), 7.60 (d, 2H), 7.31 (t, 2H), 7.02 (t, 1H), 5.81 (s, 1H). LRMS (ESI pos) m/e 188 (M+1).
Reaction SMILES: C(CCC1C(CCCCCCOC2C=C(C3C=CC(F)=C(F)C=3)C=C(C(=O)N(C)C)C=2)=CC=CC=1OCCCC(O)=O)(O)=O.C([O:47][C:48](=[O:102])[CH2:49][CH2:50][CH2:51][O:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][O:65][C:66]2[CH:71]=[C:70]([C:72](=[O:85])[NH:73][CH2:74][C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=3[O:81][CH:82]([F:84])[F:83])[CH:69]=[C:68]([C:86]3[CH:94]=[CH:93][C:89]4[O:90][CH2:91][O:92][C:88]=4[CH:87]=3)[CH:67]=2)[C:54]=1[CH2:95][CH2:96][C:97]([O:99]CC)=[O:98])C.[OH-].[Na+]>C1COCC1.CCO>[O:90]1[C:89]2[CH:93]=[CH:94][C:86]([C:68]3[CH:67]=[C:66]([CH:71]=[C:70]([C:72](=[O:85])[NH:73][CH2:74][C:75]4[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=4[O:81][CH:82]([F:83])[F:84])[CH:69]=3)[O:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][C:55]3[C:54]([CH2:95][CH2:96][C:97]([OH:99])=[O:98])=[C:53]([CH:58]=[CH:57][CH:56]=3)[O:52][CH2:51][CH2:50][CH2:49][C:48]([OH:102])=[O:47])=[CH:87][C:88]=2[O:92][CH2:91]1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)NCc3ccccc3OC(F)F)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Agent: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)c(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)NCc3ccccc3OC(F)F)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)O
Yield: 86.9 %

Procedure:
The title compound was prepared by the same method as 4-{2-(2-carboxy-ethyl)-3-[6-(5-dimethylcarbamoyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid starting from 4-[3-{6-[3-benzo[1,3]dioxol-5-yl-5-(2-difluoromethoxy-benzylcarbamoyl)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (167 mg, 0.2 mmol) and 1.0 N aqueous NaOH (5 mL) in THF (5 mL) and EtOH (5 mL) to afford 4-[3-{6-[3-benzo[1,3]dioxol-5-yl-5-(2-difluoromethoxy-benzyl carbamoyl)-phenoxy]-hexyl}-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (130 mg, 87%) as a white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:18])[NH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C=O)C>[CH2:25]([N:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]1=[O:18])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=c1[nH]cc(-c2cccc(Cl)c2)c2ncccc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cccnc2c(-c2cccc(Cl)c2)cn1Cc1ccccc1
Temperature: 21 °C
Reaction time: 8 h
Yield: 55820.2 %

Procedure:
To a suspension of 8-(3-chlorophenyl)-1,6-naphthyridin-5-one (200 mg, 0.78 mmoles) and potassium carbonate (130 mg, 0.93 mmoles) in 10 ml DMF was added dropwise benzyl bromide (0.14 ml, 1.2 mmoles) under an atmosphere of nitrogen and stirred overnight at 21° C. The reaction mixture was poured into 100 ml water and after stirring for one hour the white precipitate was collected and dried. Crystallization from methanol gave 151 grams (56% yield) of the desired 6-benzyl-8-(3-chlorophenyl)-1,6-naphthyridin-5-one as a white solid. Characteristic analytical data are as follows: mp 148.8°-150° C.; TLC in 1:4 EtOAc/Hex; 1H NMR (CDCl3, 300 MHz) δ5.28 (s, 2H), 7.30-7.55 (m, 10H), 8.78 (dd, 1H, J=8.1, 1.9), 8.94 (dd, 1H, J=4.5, 1.9); 13C NMR (75 MHz, CDCl3 ) δ154.31, 151.66, 136.97, 136.84, 136.17, 134.30, 134.13, 130.02, 129.51, 129.05, 128.23, 128.07, 127.77, 122.10, 122.01,119.86, 52.04; IR (KBr) vmax 1645, 1612, 1589, 1552, 1483, 1460, 1439, 1417, 1369, 1304, 1294, 1197, 1170, 790, 744, 729, 713, 702, 692, 599 cm-1 ; mass spectrum (EI), m/e 346. Anal. (C21H15ClN2O) Calcd.: C, 72.73; H, 4.36; N, 8.08. Found: C, 72.61; H, 4.35; N, 8.14.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([S:8]([N:10]1[CH2:13][CH2:12][CH2:11]1)=[O:9])([CH3:7])[CH3:6])[CH3:2].ClC1C=CC=C(C(OO)=[O:23])C=1>ClCCl>[CH2:1]([O:3][C:4](=[O:14])[C:5]([S:8]([N:10]1[CH2:11][CH2:12][CH2:13]1)(=[O:23])=[O:9])([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)S(=O)N1CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)S(=O)(=O)N1CCC1
Reaction time: 2 h

Procedure:
To a solution of 2-(azetidine-1-sulfinyl)-2-methyl-propionic acid ethyl ester (4.62 g, 21 mmol) in dichloromethane (100 mL) at room temperature is added meta-chloroperbenzoic acid (5.46 g, 32 mmol). The reaction is stirred for 1 h before Ambersep 900-OH resin (2.9 g) is introduced. The suspension is shaken for 2 h and then filtered. The filtrate is concentrated under reduced pressure and the residue is re-dissolved in dichloromethane (50 mL), washed with a saturated solution of sodium bicarbonate (50 mL) and the solvent is concentrated under reduced pressure to provide the title compound as an orange oil. This oil is used without further purification, m/z 236 [M+H+].
Reaction SMILES: [CH:1]1([Ru:6][CH:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:16](O)([CH3:19])([CH3:18])[CH3:17]>O>[C:16]([Ru:6]([CH:1]1[CH:2]=[CH:3][CH:4]=[CH:5]1)[CH:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)O
Reactant: C1=CC([Ru]C2C=CC=C2)C=C1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(C)(C)[Ru](C1C=CC=C1)C1C=CC=C1
Temperature: 120 °C
Yield: 20 %

Procedure:
8.0 g of bis(cyclopentadienyl)ruthenium, 3.0 g of aluminum chloride, and 80 g of polyphosphoric acid were mixed. The mixed solution was heated to 100° C. under a nitrogen atmosphere, to which 3.0 g of tert-butyl alcohol was added dropwise over 30 minutes, and then the mixture was heated to 120° C. to carry out the reaction for 4 hours. After the reaction, hot water was added to the solution to remove polyphosphoric acid, and then distillation treatment gave 2.0 g of tert-butylcyclopentadienyl(cyclopentadienyl)ruthenium. Five lots of tert-butylcyclopentadienyl(cyclopentadienyl)ruthenium were prepared by this preparing method, and subjected to film production as described later.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:23][N:22]([C:24](=O)[CH2:25][CH3:26])[CH2:21]3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(OCC)(=O)C>C1COCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:21][N:22]([CH2:24][CH2:25][CH3:26])[CH2:23]3)=[CH:16][CH:15]=2)(=[O:11])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCC(=O)N1CC(c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cc2)C1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cc2)C1
Yield: 67.1 %

Procedure:
Following the same procedure as described in Example 46.6, 4-isopropyl-N-[4-(1-propionyl-azetidin-3-yl)-phenyl]-benzenesulfonamide (140 mg, 0.36 mmol) in THF (18 ml) was then treated with 1M BH3. THF (3.6 ml). The crude material was chromatographied (ethyl acetate) to afford the title compound (90 mg, 67%) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N-:10]=[N+:11]=[N-:12].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]1[NH:12][N:11]=[N:10][N:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1Br
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccccc1-c1nnn[nH]1
Temperature: 100 °C
Yield: 73.5 %

Procedure:
A mixture of 2-bromobenzonitrile (10.0 g, 0.055 mol), sodium azide (3.9 g, 0.060 mol), ammonium chloride (3.2 g, 0.060 mol), and DMF (90 mL) was heated at 100° C. for 18 h. The mixture was concentrated, taken up in water, and made basic (pH 9) with 1N KOH. The aqueous mixture was extracted with ether (discarded) and acidified with 2N HCl. The precipitate was collected by filtration to give 9.1 g (73%) of product as an off-white solid, mp 179°-181° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][CH2:5][C:4](=[O:7])[CH:3]=1.[Cl-].[Ca+2].[Cl-].O=[CH:12][C:13]1[CH:21]=[CH:20][C:18]([OH:19])=[C:15]([O:16][CH3:17])[CH:14]=1.B(OC(CC)C)(OC(CC)C)OC(CC)C>ClCCl.C(N)CCC.CCCCCC.C(O)(=O)C>[OH:19][C:18]1[CH:20]=[CH:21][C:13]([CH:12]=[C:5]2[C:4](=[O:7])[CH:3]=[C:2]([CH3:1])[O:6]2)=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1cc(C=O)ccc1O
Reactant: CC1=CC(=O)CO1
Agent: CCC(C)OB(OC(C)CC)OC(C)CC
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(C=C2OC(C)=CC2=O)ccc1O
Temperature: 2.5 °C
Yield: 73 %

Procedure:
5-methyl-furan-3-one (2, 7.0 g g, 0.071 mol) was dissolved in dichloromethane (40 mL) and taken in a 3-necked 500 mL round bottomed flask fitted with a mechanical agitator and calcium chloride guard tube. Vanillin (3b, 9.0 g, 0.059 mol) dissolved in dichloromethane (40 mL) was added. The mixture was cooled to 0-5° C. with stirring. Tri-sec-butyl borate (15.0 g, 0.065 mol) was added and stirred for 2 h. The color of the reaction mixture turned yellow. n-Butyl amine (2 drops) was added and the reaction mixture allowed to warm to room temp. on its own and stirred at room temp. overnight. The yellow color of the reaction mixture intensified. This mixture was poured into 5% aq. acetic acid solution (120 mL) preheated to 60° C. with stirring. This was stirred for 30 min., and then allowed to settle down. The dichloromethane layer was isolated and concentrated under reduced pressure to get a red color thick liquid. Hexane (80 mL) was added to this gummy material and stirred overnight. A yellow color solid crystallized out. This was filtered, dried in vacuo at 110° C. to get pure 2-(4-hydroxy-3-methoxy-benzylidene)-5-methyl-furan-3-one (4b, 10.0 g, 61% yield) as pale yellow powder, m.p. 167.5°-170.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][O:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]([C:26]1[CH:27]=[C:28](OB(O)O)[CH:29]=[CH:30][CH:31]=1)=[O:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][O:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:30]4[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=4)[C:24]([O:23][CH3:22])=[O:25])[CH2:17]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CO[C@@H]1CCCNC1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Product: COC(=O)c1cccc(N2CCC[C@@H](OCc3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Yield: 40.1 %

Procedure:
Using (R)-3-[[2-(4-chlorophenyl)-4-methylthiazol-5-yl]methoxy]piperidine (294 mg, 0.911 mmol) and 3-(methoxycarbonyl)phenylboric acid (328 mg, 1.82 mmol), the same procedure was followed as in Example 2 to give 167 mg (40%) of the desired compound as a colorless oil.
Reaction SMILES: N1C=CN=C1.[CH3:6][CH:7]([O:9][C:10]1[C:11]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29]CC3C=CC=CC=3)=[CH:23][C:12]=2[S:13][C:14]=1[C:15]([NH:17][C:18]1[NH:22][N:21]=[N:20][N:19]=1)=[O:16])[CH3:8]>[Pd].C(O)(=O)C>[CH3:8][CH:7]([O:9][C:10]1[C:11]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([OH:29])=[CH:23][C:12]=2[S:13][C:14]=1[C:15]([NH:17][C:18]1[NH:22][N:21]=[N:20][N:19]=1)=[O:16])[CH3:6]
Reactant: COc1cc2c(OC(C)C)c(C(=O)Nc3nnn[nH]3)sc2cc1OCc1ccccc1
Agent: [Pd]
Agent: c1c[nH]cn1
Solvent: CC(=O)O
Product: COc1cc2c(OC(C)C)c(C(=O)Nc3nnn[nH]3)sc2cc1O
Reaction time: 33 h
Yield: 28.6 %

Procedure:
A slurry of 3-(1-methylethoxy)-5-methoxy-6-(phenylmethoxy)-N-1H-tetrazol-5-yl-benzo[b]thiophene-2-carboxamide imidazole salt (1.55 g, 3 mmoles) and 20% palladium on carbon (0.5 g) in acetic acid (250 mls) is shaken under hydrogen (50 psig) in a Parr apparatus at 40° C. After 19 hours an additional 0.5 g of catalyst and acetic acid (250 mls) are added and shaking continued at 50° C. for 33 hours. The catalyst is filtered from the cooled mixture and rinsed with acetic acid. The filtrate is stripped of solvent under reduced pressure to leave the crystalline product. Recrystallization from methanol gave the pure 3-(1-methylethoxy)-5-methoxy-6-hydroxy-N-1H-tetrazol-5-yl-benzo[b]thiophene-2-carboxamide (0.3 g): mp=245° C. (dec).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:28]([F:29])=[C:27]([NH2:30])[C:9]2[C:10](=[O:26])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:24])[CH2:22]Cl)=[C:16]([F:25])[CH:15]=3)[O:13][C:8]=2[C:7]=1[F:31])(=[O:3])[CH3:2].Cl.[CH3:33][NH:34][CH3:35].C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[C:28]([F:29])=[C:27]([NH2:30])[C:9]2[C:10](=[O:26])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:24])[CH2:22][N:34]([CH3:35])[CH3:33])=[C:16]([F:25])[CH:15]=3)[O:13][C:8]=2[C:7]=1[F:31])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)CCl)c(F)c3)oc2c1F
Reactant: CNC
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)CN(C)C)c(F)c3)oc2c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of 7-(acetoxymethyl)-5-amino-2-[4-(chloroacetamido)-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one (2.02 g, 4.44 mmol) in dimethylformamide (50 mL) were added dimethylamine hydrochloride (1.81 g, 22.2 mmol) and diisopropylethylamine (3.90 mL, 22.4 mmol), and the mixture was stirred at room temperature for 2 hours. Water was added thereto, and the crystals precipitated were collected by filtration to afford compound 1f (1.97 g, 96%).
Reaction SMILES: C(C1(NC([C@@H]2C[C@@H](S(C3C=CC=CC=3C(F)(F)F)(=O)=O)CN2C2N(C3C=CC=CC=3)N=C(C)C=2)=O)CC1)#N.COC([C@H]1C[C@@H](S(C2C=CC=CC=2C(F)(F)F)(=O)=O)CN1C(=O)CC(=O)C)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.Cl.C1(NN)CCC1.[CH3:96][O:97][C:98]([C@H:100]1[CH2:104][C@@H:103]([S:105]([C:108]2[CH:113]=[CH:112][CH:111]=[CH:110][C:109]=2[C:114]([F:117])([F:116])[F:115])(=[O:107])=[O:106])[CH2:102][N:101]1[C:118]1[N:119]([CH:124]2[CH2:127][CH2:126][CH2:125]2)[N:120]=[C:121]([CH3:123])[CH:122]=1)=[O:99]>>[CH3:96][O:97][C:98]([C@@H:100]1[CH2:104][C@@H:103]([S:105]([C:108]2[CH:113]=[CH:112][CH:111]=[CH:110][C:109]=2[C:114]([F:117])([F:115])[F:116])(=[O:107])=[O:106])[CH2:102][N:101]1[C:118]1[N:119]([CH:124]2[CH2:127][CH2:126][CH2:125]2)[N:120]=[C:121]([CH3:123])[CH:122]=1)=[O:99]
Reactant: COC(=O)[C@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1C1CCC1
Agent: COC(=O)[C@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)CC(C)=O
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(-c2ccccc2)n1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1C1CCC1

Procedure:
In analogy to the procedure described in example 308d, a mixture of (2S,4R)-1-(3-oxo-butyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192 f) and of (2R,4R)-1-(3-oxo-butyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with Lawesson's reagent (CAS Reg. No. 19172-47-5) and cyclobutylhydrazine hydrochloride (CAS Reg. No. 158001-21-9) to give a mixture of the title compound and (2R,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester as white solid. MS (ESI): m/z=472.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([N+:15]([O-])=O)=[C:13]([F:18])[CH:12]=[C:11]([O:19][CH3:20])[C:10]=2[F:21])=[C:4]([F:22])[CH:3]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([NH2:15])=[C:13]([F:18])[CH:12]=[C:11]([O:19][CH3:20])[C:10]=2[F:21])=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc(F)c([N+](=O)[O-])c(Nc2ccc(Br)cc2F)c1F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(F)c(N)c(Nc2ccc(Br)cc2F)c1F
Temperature: 70 °C
Yield: 78.6 %

Procedure:
A suspension of (4-bromo-2-fluoro-phenyl)-(2,5-difluoro-3-methoxy-6-nitro-phenyl)-amine (Intermediate 16, 0.850 g, 2.2 mmol) in ethanol (13 mL) was stirred at 70° C. to obtain a clear solution. To this hot solution, was added a freshly prepared solution of Na2S2O4 (1.2 g, 6.7 mmol) in water (2.4 mL) and stirred the reaction mixture at 90° C. for 1 h. The progress of reaction was monitored by TLC. After completion, the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water, and the organic phase was dried over anhydrous Na2SO4 and concentrated to yield N2-(4-bromo-2-fluoro-phenyl)-3,6-difluoro-4-methoxy-benzene-1,2-diamine as a brown solid (600 mg). 1H-NMR (400 MHz, CDCl3): δ 3.61 (2H, bs), 3.82 (3H, s), 5.40 (1H, bs), 6.37 (1H, t), 6.68-6.73 (1H, m), 7.06 (1H, d, J=8.4), 7.24 (1H, d, J=14).
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[CH:18]([CH3:32])[C:19]([C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27](=[O:29])[N:26]([CH3:30])[C:25]=2[CH:31]=1)=[O:20].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[CH:18]([CH3:32])[C:19]([C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27](=[O:29])[N:26]([CH3:30])[C:25]=2[CH:31]=1)([OH:20])[C:2]([F:4])([F:3])[F:1]
Reactant: COc1ccc(Cl)c(C(C)C(=O)c2ccc3oc(=O)n(C)c3c2)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cl)c(C(C)C(O)(c2ccc3oc(=O)n(C)c3c2)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
Trifluoromethyltrimethylsilane (2M in THF, 0.80 mL) was added at 0° C. to a solution of 5-[2-(2-chloro-5-methoxy-phenyl)-propionyl]-3-methyl-3H-benzooxazol-2-one (312 mg, obtained in Example 192, step 2) in THF (20 mL) followed by the addition of tetrabutylammonium fluoride trihydrate (253 mg). Stirring was continued for 72 hours at r.t. The reaction mixture was poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, heptane:ethyl acetate=7:3 to 6:4) to give the title compound as a orange amorphous foam (43 mg, 14%). MS (neg. ion, m/e)=414.3 [(M−H)−].