Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[NH2:35][C:36]1([CH3:48])[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]1>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:35][C:36]5([CH3:48])[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC1(N)CCN(C(=O)OC(C)(C)C)C1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)CCN(C(=O)OC(C)(C)C)C4)c3n2)c2ccc(F)cc21
Reaction time: 16 h
Yield: 65.2 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.32 mmol) in 6 mL of DMF were added EDCI (123 mmol, 0.64 mmol), DMAP (110 mg, 0.90 mmol) and tert-butyl 3-amino-3-methylpyrrolidine-1-carboxylate (128 mg, 0.64 mmol) in one portion at room temperature and the mixture stirred for 16 hours. The solvent was evaporated at 70° C. under reduced pressure, the residue was triturated with petroleum ether then decanted and dried to give crude tert-butyl 3-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamido)-3-methylpyrrolidine-1-carboxylate (103 mg, 65.2%) as a yellow solid which was used for the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[F:19])[CH:5]=1.[OH-].[Li+].Cl>O1CCOCC1.O>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:20])=[O:2])=[C:13]([F:19])[CH:14]=1
Reactant: COC(=O)c1cccc(COc2ccc(Br)cc2F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(COc2ccc(Br)cc2F)c1

Procedure:
A solution of 3-(4-bromo-2-fluoro-phenoxymethyl)-benzoic acid methyl ester (5.5 g, 16.22 mmol) in dioxane was treated with a solution of lithium hydroxide (1.86 g, 81.1 mmol) in water at room temperature overnight, followed by acidification with concentrated HCl and diluted with water. The precipitate was collected by filtration, washed with water, and dried to give 3-(4-bromo-2-fluoro-phenoxymethyl)-benzoic acid, 5.2 g (99%). LC-MS (ES) calculated for C14H10BrFO3, 323; found m/z 324 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1I.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][CH2:30][CH2:31][C:32]#[CH:33].[I-].[Na+].[H-].[Na+]>C(#N)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH2:31]1[C:30]2=[CH:29][C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[N:1]2[CH2:33][CH2:32]1
Reactant: C#CCCCCl
Reactant: Nc1ccncc1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: c1cc2c(cn1)cc1n2CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.2 %

Procedure:
To a solution of 4-Amino-3-iodopyridine (2.2 g, 10.00 mMol) in acetonitrile (25 ml), was added dropwise trifluoroacetic anhydride (2.53 g, 1.674 ml) at 0° C. followed by addition of potassium carbonate (4.14 g, 30 mMol). The mixture was stirred at room temperature for 10 min. To the resulting suspension was added bis(triphenylphosphine)-palladium(II)chloride (0.175 g, 0.25 mMol), copper(I)iodide (0.095 g, 0.50 mMol) and 5-chloro-1-pentyne (1.23 g, 12.00 mMol) and the mixture was heated to reflux under argon for 3 h. The mixture was cooled to room temperature and partitioned between water and ethyl acetate. The phases were separated. The organic phase was extracted with water at pH 1.00. The acidic aqueous phase was mixed with dichloromethane and the pH was raised to 10 by addition of 2N NaOH. The phases were separated and the organic phase was dried over sodium sulfate. The solvent was evaporated and the residue was taken up in acetonitrile (20 ml). To the brownish solution was added sodium iodide (3.00 g, 20 mMol) and sodium hydride (ca 55% 0.873 g, 20 mMol) and the mixture was stirred at room temperature for 2 h. The mixture was poured onto ice and partitioned between water and ethyl acetate (100 ml water 100 ml ethyl acetate). The phases were separated. The organic phase was extracted with water at pH 1.00 (5×50 ml). The combined acidic aqueous phases were mixed with dichloromethane (100 ml) and the pH was raised to 10 by addition of 2N NaOH. The phases were separated and the organic phase was dried over sodium sulfate. The solvent was evaporated and the title compound (0.81 g, 51% of theory) was obtained as a brownish solid. For analytical purposes a sample was recrystallised from t-butylmethylether to afford light brown crystals melting at 95-96° C.; Found C, 75.93; H. 6.32; N,17.80%. C10H10N2 requires: C, 75.92; H, 6.37; N, 17.71%
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][SiH:10]([Cl:12])[Cl:11].NC(N)=O.C(O)C>[Pt].C1(C)C=CC=CC=1>[CH2:1]([CH2:9][SiH:10]([Cl:12])[Cl:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: C[SiH](Cl)Cl
Agent: [Pt]
Agent: NC(N)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cl[SiH](Cl)CCCc1ccccc1
Yield: 61 %

Procedure:
Reaction between styrene and methyldichlorosilane with platinum catalyst in the presence of urea. 0.384 g Styrene and 0.435 g methyldichlorosilane were introduced into a glass tube, and an ethanol solution containing 0.255 mg urea (5.1 wt %) was added with a microsyringe. 1 mg Of a toluene solution of 0-valent platinum complex of divinylsiloxane (0.04 wt % platinum content) was added. The reaction tube was sealed with Teflon tape and a septum and placed in a 100° C. oil bath where it was heated for 20 minutes. After cooling, the tube contents were analyzed by gas chromatography revealing a styrene conversion of 64% and a phenethylmethyldichlorosilane yield of 61%. The ratio between the phenethylmethyldichlorosilane and the (α-methylbenzyl)methyldichlorosilane was 102:1.
Reaction SMILES: [OH:1][CH:2]1[C:18]([CH3:20])([CH3:19])[C:17](=[O:21])[CH:16]([CH3:22])[CH:15]([OH:23])[CH:14]([CH3:24])[CH2:13][CH2:12][CH2:11][CH:10]2[CH:8]([N:9]2[CH2:25][CH2:26][OH:27])[CH2:7][CH:6]([C:28]([CH3:36])=[CH:29][C:30]2[N:31]=[C:32]([CH3:35])[S:33][CH:34]=2)[O:5][C:4](=[O:37])[CH2:3]1.[C:38](=O)([O:49][CH2:50][CH2:51][S:52][S:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=1)[O:39]N1C2C=CC=CC=2N=N1>ClCCl.CN(C1C=CN=CC=1)C>[C:38](=[O:39])([O:49][CH2:50][CH2:51][S:52][S:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=1)[O:27][CH2:26][CH2:25][N:9]1[C@@H:8]2[C@H:10]1[CH2:11][CH2:12][CH2:13][C@H:14]([CH3:24])[C@H:15]([OH:23])[C@@H:16]([CH3:22])[C:17](=[O:21])[C:18]([CH3:19])([CH3:20])[C@@H:2]([OH:1])[CH2:3][C:4](=[O:37])[O:5][C@H:6](/[C:28](/[CH3:36])=[CH:29]/[C:30]1[N:31]=[C:32]([CH3:35])[S:33][CH:34]=1)[CH2:7]2
Reactant: O=C(OCCSSc1ccccn1)On1nnc2ccccc21
Reactant: CC(=Cc1csc(C)n1)C1CC2C(CCCC(C)C(O)C(C)C(=O)C(C)(C)C(O)CC(=O)O1)N2CCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C/C(=C\c1csc(C)n1)[C@@H]1C[C@H]2[C@@H](CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)N2CCOC(=O)OCCSSc1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-17-[2-hydroxyethyl]-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-oxa-17-azabicyclo[14.1.0]heptadecane-5,9-dione in anhydrous dichloromethane at 0° C. was added DMAP (1.2 eq.) and benzo[d][1,2,3]triazol-1-yl 2-(2-(pyridin-2-yl)disulfanyl)ethyl carbonate (1.0 eq.) in tandem. The reaction mixture was stirred at 0° C. under argon and monitored by TLC every 10 min. Additional DMAP (1.2 eq.) and Compound I (2)(1.0 eq.) were added as necessary until all of Compound G was consumed. The reaction was quenched with MeOH (1 mL) at 0° C., the solvent was removed under vacuum, and the residue was purified by chromatography (silica gel, 2.5-5% MeOH in DCM) to afford the title compound as a beige solid. Compound amounts and recoveries are listed below in Table 3. Total yield from 2.95 g of Compound G was 2.80 g (67.9%) of Compound I.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[F:14])[C:8](O)=[O:9])(=O)=O.SC1C=C(CO)C=CC=1>>[F:14][C:13]1[CH:12]=[CH:11][C:7]([CH2:8][OH:9])=[CH:6][C:5]=1[SH:2]
Reactant: O=C(O)c1ccc(F)c(S(=O)(=O)Cl)c1
Agent: OCc1cccc(S)c1
Product: OCc1ccc(F)c(S)c1

Procedure:
The required (4-Fluoro-3-mercapto-phenyl)-methanol is prepared in two steps from 3-Chlorosulfonyl-4-fluoro-benzoic acid following the procedure for the preparation of (3-Mercapto-phenyl)-methanol described in Chemistry Express, Vol 7, No. 11, pp. 865-868).
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=2)[O:12][CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=2)[O:12][CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])=[CH:27][CH:28]=1)(=[O:39])=[O:38]
Reactant: COC(=O)c1ccccc1COc1cccc(CCOc2ccc(O)cc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccccc1COc1cccc(CCOc2ccc(OS(C)(=O)=O)cc2)c1
Temperature: -20 °C
Yield: 95.5 %

Procedure:
Methyl 2-({3-[2-(4-hydroxyphenoxy)ethyl]phenoxy}methyl)benzoate (0.096 g, 0.25 mmol) was dissolved in dichloromethane (10 ml) and cooled to −20° C. Triethylamine (0.039 g, 0.38 mmol) was added drop wise and methanesulfonyl chloride (0.032 g, 0.28 mmol) was added drop wise. The ice bath was removed and the mixture was wormed to room temperature. Diethyl ether (5 ml) was added and the precipitate filtered off. The organic phase was washed with two portions of brine (5 ml) and dried (MgSO4). Removing The solvent was removed by evaporation giving 0.109 gram of methyl 2-{[3-(2-{4-[(methylsulfonyl)oxy]phenoxy}-ethyl)phenoxy]methyl}benzoate (yield 94.1%).
Reaction SMILES: CC([Si](C)(C)[O:6][C:7]1[C:8]([F:17])=[C:9]([CH2:14][C:15]#[N:16])[CH:10]=[C:11]([F:13])[CH:12]=1)(C)C.[F-].[K+].[CH3:22][O:23][CH2:24]Cl>CN(C)C=O>[F:17][C:8]1[C:7]([O:6][CH2:22][O:23][CH3:24])=[CH:12][C:11]([F:13])=[CH:10][C:9]=1[CH2:14][C:15]#[N:16]
Reactant: COCCl
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(F)cc(CC#N)c1F
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1cc(F)cc(CC#N)c1F
Temperature: 25 °C
Reaction time: 0.2 h
Yield: 95.2 %

Procedure:
(3-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}-2,5-difluorophenyl) acetonitrile (0.353 g, 1.25 mmol) was dissolved in dimethylformamide (3 mL) and potassium fluoride (0.145 g, 2.50 mmol) was added followed by chloromethyl methyl ether (0.117 mL, 1.54 mmol). The mixture was stirred at room temperature for 0.2 h and then was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford an oil which was purified by column chromatography (ethyl acetate-hexanes 1:6) to afford (2,5-difluoro-3-{[(methyloxy)methyl]oxy}phenyl)acetonitrile as a light brown solid (0.253 g, 1.19 mmol, 95% yield). 1H NMR (400 MHz, CDCl3): 7.05-6.93 (m, 1H), 6.87-6.77 (m, 1H), 5.22 (s, 2H), 3.76 (s, 2H), 3.51 (s, 3H); GCMS for C10H9NO2: 213 (M+).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][N:6]([C:10]1([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[C:18]2[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=2)[NH:12][C:11]1=[O:20])[CH:7]([CH3:9])[CH3:8])C>CO.[OH-].[K+]>[Cl:19][C:15]1[CH:14]=[C:13]2[C:18]([C:10]([N:6]([CH2:5][C:4]([OH:29])=[O:3])[CH:7]([CH3:9])[CH3:8])([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:11](=[O:20])[NH:12]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)CN(C(C)C)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)N(CC(=O)O)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Yield: 75.5 %

Procedure:
rac-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-acetic acid ethyl ester (4.5 g, 10.4 mmol) was dissolved in a mixture of MeOH and KOH aqueous solution. This mixed solution was refluxed overnight and then the solution was concentrated. The PH of water layer was adjusted to 5-6 and then the water layer was extracted with dichloromethane. The organic layer was dried, concentrated and purified by chromatography to obtain 3.2 g solid rac-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH2:23])=O)[C:9]=2[CH3:24])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]#[N:23])[C:9]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: Cc1c(C(N)=O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1c(C#N)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Added dropwise to a solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (1.57 g, 4.1 mmol) obtained in Step 1 dissolved in dimethylformamide (10 ml) at 0° C., was phosphoryl chloride (0.72 ml, 8.2 mmol). The resulting mixture was stirred for 20 minutes at 0° C. and then stirred for 1 hour at room temperature. The reaction mixture was quenched with water at 0° C., and an mixture was extracted with ethyl acetate (30 ml twice). After removing the solvent, 5-(4-chloro phenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonitrile was obtained by column chromatography as white solid (1.47 g, quantativly).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[C:20]1([CH2:26][CH2:27][NH2:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:28][CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: NCCc1ccccc1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CCCCN1C(=O)C(NCCc2ccccc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 2-phenylethanamine in a similar manner as described for e.g. Example 6 and 7. 1H NMR (500 MHz CDCl3): δ 7.58-7.52 (m, 2H), 7.50-7.42 (m, 2H), 7.30-7.20 (m, 4H), 6.88 (dd, 2H), 5.38 (t, 1H), 3.70 (t, 2H), 3.18 (dt, 2H), 2.62 (t, 2H), 1.88-1.78 (m, 2H), 1.50-1.40 (m, 2H), 0.98 (t, 2H); 13C NMR (125 MHz CDCl3): δ 159.4, 137.8, 137.5, 131.8, 130.0, 129.0, 128.9, 128.7, 127.1, 125.2, 107.2, 45.1, 40.4, 36.0, 30.4, 20.3, 13.8; Mass-Spectrum M+H+ 385.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15](OC)=[O:16])[NH:13][C@@H:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:11]1[C:25]([O:27][CH3:28])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.CO>CO>[CH2:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([CH2:15][OH:16])[NH:13][C@@H:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@H:11]1[C:25]([O:27][CH3:28])=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H]1[C@H](COCc2ccccc2)[C@@H](C(=O)OC)N[C@H]1c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1[C@H](COCc2ccccc2)[C@@H](CO)N[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 94.6 %

Procedure:
To a stirred and ice-cooled solution of (2R*,3S*,4S*,5S*)-4-benzyloxymethyl-3,5-bis(methoxycarbonyl)-2-phenylpyrrolidine (42.27 g, 0.11 mol) in anhydrous MeOH (Dojindo, 350 ml) was added NaBH4 (12.51 g, 0.33 mol) portionwise. The turbid reaction mixture was stirred with ice-cooling for 2 hours, and then at room temperature for 4.5 hours. The reaction mixture was re-cooled in the ice bath, and Hydrogen Chloride-Methanol Reagent 10 (Tokyo Kasei) was added until the mixture became acidic (pH 1-2). This was concentrated in vacuo, and the syrupy residue was basified to pH ca.10 by adding 10% NaOH aq. solution. The mixture was extracted with AcOEt (80 ml×5). The combined AcOEt extracts were washed with sat. NaCl aq. solution (×1), dried (Na2SO4), and concentrated in vacuo to give crude title compound (37.0 g, 95%) as a viscous pale yellow oil: IR νmax (film): 3330(s), 1730(vs), 1605(w), 1595(w), 1495(s), 1170(s), 750(s), 700(s) cm-1 ; 1H-NMR δ: 7.45-7.16(m, 10H), 4.58(d, J=8.3 Hz, 1H), 4.55(s, 2H), 3.85(dd, J=11.2, 4.6 Hz, 1H), 3.79(dd, J=11.2, 3.9 Hz, 1H), 3.58(dd, J=9.2, 5.3 Hz, 1H), 3,52(dd, J=9.2, 6.6 Hz, 1H), 3.35-3.25(m, 1H), 3.15(s, 3H), 3.14(dd, J=8.3, 5.7 Hz, 1H), 2.17(br.s, 2H) ppm. This was employed in the next step for salt formation without further purification.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=1[CH3:30])=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:19])[CH3:20])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=1[CH3:30]
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(CO)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a solution of N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (370 mg, 0.91 mmol) obtained in Example 20 in methanol (5 mL) was added sodium borohydride (34 mg, 0.91 mmol) at room temperature and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-hexane to obtain 290 mg (yield: 78%) of the title compound. Melting point: 274-275° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:12]([OH:14])=O.[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[CH:19]=[N:18]1)[CH3:16]>>[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][N:23]([C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:29]=2)[C:12]([CH:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[O:8][CH2:7][CH2:6]2)=[O:14])[CH:19]=[N:18]1)[CH3:16]
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Reactant: O=C(O)C1CCOc2ccc(F)cc21
Product: CCn1cc(CN(C(=O)C2CCOc3ccc(F)cc32)c2ccc(C(C)C)cc2)cn1
Yield: 67.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 6-fluorochroman-4-carboxylic acid (0.29 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-6-fluoro-N-(4-isopropylphenyl)chroman-4-carboxamide (0.42 g) was obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10]([OH:29])(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].N#N>>[C:10]([O:1][CH2:2][C:3]([CH2:8][O:9][C:10](=[O:29])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH2:6][O:7][C:10](=[O:29])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][O:5][C:10](=[O:29])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:29])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: OCC(CO)(CO)CO
Agent: N#N
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCCCC)(COC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC
Temperature: 215 °C

Procedure:
A 1000 ml round bottomed flask was charged with 598.4 g. (0.12 mol) PEG 130 pentaerythritol and 36.3 g. (0.48 mol) triple pressed stearic acid. The mass was heated to 100° C. with a N2 sparge, 1.0 g. phosphoric acid and 0.1 g hypophosphorus acid were charged. The batch was heated to 215° C. while collecting the water of reaction, and maintained until an acid value of 11.5 was reached. The finished material was a grey waxy solid.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](Br)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[CH:27][N:26]=1>>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:29]5[CH:28]=[CH:27][N:26]=[C:25]([F:24])[CH:30]=5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: OB(O)c1ccnc(F)c1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3ccnc(F)c3)ccc1-2
Yield: 30 %

Procedure:
Following the procedures for 128, 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 2-fluoropyridin-4-ylboronic acid to give 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-(2-fluoropyrid-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.60 g, 30%). MS (ESI(+): m/z 408.0 (M+H)
Reaction SMILES: [NH2:1][NH2:2].[N:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)[CH2:11][C:12](=O)[CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C1(C)C=CC=CC=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CCO>[N:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:1]=[N:2][C:12]([CH:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[O:20])[CH2:17][CH2:18]3)=[CH:11][C:10]=2[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:37])[F:39])[CH:31]=2)=[CH:7][CH:8]=1
Reactant: O=C(CC(C(=O)c1ccncc1)c1cccc(C(F)(F)F)c1)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: NN
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCC(c2cc(-c3cccc(C(F)(F)F)c3)c(-c3ccncc3)nn2)CC1
Reaction time: 4 h
Yield: 36.8 %

Procedure:
Under Ar, hydrazine (0.5 mL, 0.51 g, 15.9 mmol) was added to a solution of 34 (3.3 g) in EtOH (75 mL). After 4 h, the solution was concentrated to dryness and the residue treated with toluene (60 mL) dioxane (60 mL) and DDQ (0.8 g, 3.5 mmol). After 15 h, the reaction was concentrated to dryness. The residue was chromatographed on a Still column (50 mm) and the product eluted with 100% EtOAc to yield 1.2 g of 35.