Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[C:46]([C:50]1[CH:68]=[CH:67][C:53]([CH2:54][NH:55][CH2:56][CH2:57][CH:58]([C:63]([F:66])([F:65])[F:64])[C:59]([F:62])([F:61])[F:60])=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:51]=[CH:52][C:53]([CH2:54][N:55]([CH2:56][CH2:57][CH:58]([C:63]([F:64])([F:65])[F:66])[C:59]([F:60])([F:61])[F:62])[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:67][CH:68]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)c1ccc(CNCCC(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCC(C(F)(F)F)C(F)(F)F)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67.7 %

Procedure:
To a solution of 80 mg (0.41 mmol) 5-chloro-1H-indole-7-carboxylic acid and 128 mg of TBTU (0.41 mmol) in 6 ml DMF, were added 0.42 ml (2.45 mmol) of N,N-diisopropyl-ethyl amine. After stirring for 5 min at rt, 155 mg (0.41 mmol) (4-tert-butyl-benzyl)-(4,4,4-trifluoro-3-trifluoromethyl-butyl)-amine hydrochloride was added. After stirring for 17 h at rt, the reaction mixture was diluted with 60 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; diethylether/heptane 1:1; then 8 g silicagel DCM/heptane 70:30 to 90:10) to give 144 mg white foam (66%). MS (EI) 518.1 (M)+.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[NH:4][CH:3]=1.[Cl-].[NH4+]>CO.[Zn]>[F:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[NH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc2[nH]cc(F)c2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1ccc2[nH]cc(F)c2c1
Yield: 49.9 %

Procedure:
Add zinc powder (387 mg, 5 mmol) portionwise to a solution of 3-fluoro-5-nitro-1H-indole (360 mg, 2 mmol) in methanol (10 mL). Then add dropwise 15.5% ammonium chloride solution (10 mL, 20 mmol), stir the reaction at ambient temperature for 5 hrs. Filter, dilute the filtrate with water (50 mL), extract with ethyl acetate (50 mL×2), wash with brine (50 mL×2), dry over anhydrous sodium sulfate. Concentrate under reduced pressure to give the crude product. Purify by flash chromatography (silica gel, EtOAc:PE=1:3) to yield the title compound (150 mg, 50%). MS: (M+1): 151.2.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:25]=[C:24]2[C:11]([O:12][C:13](=[O:30])[C:14]3[C:23]2=[CH:22][CH:21]=[C:20]2[C:15]=3[N:16]([CH3:29])[C:17](=[O:28])[C:18]([CH3:27])([CH3:26])[NH:19]2)=[CH:10][CH:9]=1.C(OCC)(=O)C.O>O1CCCC1.[Cl-].[Na+].O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([OH:12])=[C:24]([C:23]2[C:14]([CH2:13][OH:30])=[C:15]3[C:20]([NH:19][C:18]([CH3:26])([CH3:27])[C:17](=[O:28])[N:16]3[CH3:29])=[CH:21][CH:22]=2)[CH:25]=1
Reactant: CN1C(=O)C(C)(C)Nc2ccc3c(c21)c(=O)oc1ccc(Cl)cc13
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1C(=O)C(C)(C)Nc2ccc(-c3cc(Cl)ccc3O)c(CO)c21
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 68.5 %

Procedure:
Lithium aluminium hydride (442 mg, 11.7 mmol) was suspended in anhydrous tetrahydrofuran (10 mL) under nitrogen atmosphere. An anhydrous tetrahydrofuran solution (40 mL) of 9-chloro-2,2,4-trimethyl-1,4-dihydro-2H-6-oxa-1,4-diazachrysen-3,5-dione (Reference Compound No. 11-1, 1:99 g, 5.81 mmol) was added dropwise thereto at −10° C. and stirred for 10 minutes at the same temperature. After ethyl acetate (1 mL) and water (1 mL) were added thereto successively, ethyl acetate (300 mL) and saturated brine (300 mL) were added and partitioned. The organic layer was washed with saturated brine (150 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (1.38 g) as a pale yellow solid. (Yield 69%)
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:6]([C:13]([CH3:23])=[CH:14][CH:15]=[CH:16][C:17]([CH3:22])=[CH:18][C:19]([O-:21])=[O:20])[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[CH:1]([C:4]1[C:5]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:6]([C:13]([CH3:23])=[CH:14][CH:15]=[CH:16][C:17]([CH3:22])=[CH:18][C:19]([OH:21])=[O:20])[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCCCCCCOc1c(C(C)=CC=CC(C)=CC(=O)[O-])cc(C(C)C)cc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCOc1c(C(C)=CC=CC(C)=CC(=O)O)cc(C(C)C)cc1C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.9 %

Procedure:
A solution of the crude ethyl-(2E, 4E, 6E)-7-(3,5-diisopropyl-2-n-heptyloxyphenyl)-3-methylocta-2,4,6-trienoate (500 mg, 1.10 mmol) in methanol (5 mL) was hydrolyzed with NaOH (1 mL of 5N aqueous solution) at reflux temperature. After 10 min, the mixture was cooled to room temperature and acidified with a 20% aqueous HCl solution. The solution was concentrated and the aqueous residue was extracted with EtOAc (2×10 mL). The EtOAc layer was washed with water (2×5 mL) and brine (5 mL), dried (MgSO4), filtered and concentrated. The major product (highest running spot by TLC) was isolated by preparative TLC (20% EtOAC-80% hexanes) to give (2E, 4E, 6E)-7-(3,5-diisopropyl-2-n-heptyloxyphenyl)-3-methylocta-2,4,6-trienoic acid (146) 220 mg (47%): TLC (10% MeOH-90% CHCl3) Rf=0.6; 1H NMR (CDCl3) δ 7.04(m, 1H, olefinic), 7.01(s, 1H, ArH ), 6.84(s, 1H, ArH ), 6.35(d, J=11.0 Hz, 1H, olefinic), 6.30(d, J=15.0 Hz, 1H, olefinic), 5.79(s, 1H, olefinic), 3.65(t, J=7.4 Hz, 2H, OCH2), 3.32(m, 1H, CH), 2.84(m, 1H, CH), 2.37(s, 3H, CH3), 2.19(s, 3H, CH3), 1.66(m, 2H, CH2), 1.31(m, 8H, 4CH2), 1.27(d, J=14.0 Hz, 6H, 2CH3), 1.24(d, J=14.0 Hz, 6H, 2CH3), 0.89(t, J=7.5 Hz, 3H, CH3).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](Cl)=[CH:7][N:6]=1)=[O:4].CCN(C(C)C)C(C)C.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(N2CCCCC2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.2 %

Procedure:
To a solution of 5-chloro-pyrazine-2-carboxylic acid methyl ester (Preparation 41, 85 g, 492 mmol) in DMF (365 mL) was added DIPEA (129 mL, 738 mmol) and piperidine (58.4 mL, 591 mmol) and the resulting solution was stirred at room temperature for 18 hours. The reaction mixture was poured onto water (4 L) and the resulting precipitate was collected by filtration to give the title compound as a white solid (85.12 g) in a 78% yield.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[C:34]2[N:33]=[C:32](N)[N:31]=[C:23]([NH:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:22]=2[N:21]=[CH:20]1)(=O)C.[F:36][B-](F)(F)F.[H+].N([O-])=O.[Na+]>C1COCC1>[F:36][C:32]1[N:31]=[C:23]([NH:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:22]2[N:21]=[CH:20][N:19]([C:34]=2[N:33]=1)[C@@H:6]1[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: F[B-](F)(F)F
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NN4CCCCC4)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CCCCC4)nc(F)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.3 h

Procedure:
The above 2',3',5'-tri-O-acetyl-N-(1-piperidinyl)adenosine (1.33 g, 2.7 mmol) was dissolved in THF (50 ml) and the temperature of the solution was held between -10° C. and -20° C. Fluoroboric acid (48%, 100 ml) was added followed by an aqueous solution of sodium nitrite (0.75 g/ml, 1.5 ml). Addition of three identical amounts of sodium nitrite was continued at 0.3 hour intervals, after which TLC investigation (on a neutralised sample) indicated that the starting material was consumed [rf 0.47 (SiO2, ethyl acetate/methanol (90/10))]. The pH of the reaction mixture was adjusted to ca. 6 with 50% sodium hydroxide solution with cooling to below 0° C. and the now red reaction mixture was diluted with water (250 ml). The solution was extracted with chloroform (2×100 ml) and the combined extracts were dried (MgSO4). The residue on evaporation (containing 2',3',5'-tri-O-acetyl-2-fluoro-N-(1-piperidinyl)adenosine was treated with methanolic ammonia (150 ml) (previously saturated at -10° C.) and stirred at room temperature for 72 hours. The reaction mixture was evaporated and the resultant residue was purified by column chromatography on silica gel eluting with dichloromethane/methanol (0-10%) to provide the title compound (0.093 g) as a white solid, after washing with ethyl acetate. M.p. 197°-199° C.; 1H NMR (400 MHz, Me2SO-d6) δ3.57, 3.65 (2H, ABX, H-5'a and H-5'b), 3.92 (1H, q, H-4'), 4.12 (1H, m, H-3'), 4.50 (1H, q, H-2'), 5.80 (1H, d, H-1'), 8.35 (1H, s, H-8). HPLC retention time 10.12 (gradient elution, 5-25% acetonitrile/0.1M pH 3.3 ammonium sulphate buffer: 214 nm detector): 100% purity.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C@:17]3([C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[C@H:20]([C:30]([OH:32])=O)[NH:19][C@H:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65]1[CH:71]=[C:70]([S:72]([N:75]2[CH2:80][CH2:79][O:78][CH2:77][CH2:76]2)(=[O:74])=[O:73])[CH:69]=[CH:68][C:66]=1[NH2:67]>>[CH3:63][O:64][C:65]1[CH:71]=[C:70]([S:72]([N:75]2[CH2:80][CH2:79][O:78][CH2:77][CH2:76]2)(=[O:73])=[O:74])[CH:69]=[CH:68][C:66]=1[NH:67][C:30]([C@@H:20]1[NH:19][C@@H:18]([CH2:33][C:34]([CH3:35])([CH3:36])[CH3:37])[C@:17]2([C:12]3[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)[NH:15][C:16]2=[O:38])[C@H:21]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[F:29])=[O:32]
Reactant: COc1cc(S(=O)(=O)N2CCOCC2)ccc1N
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(S(=O)(=O)N2CCOCC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Yield: 16 %

Procedure:
In a manner similar to the method described in Example 5, chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 136 (0.3 g, 0.52 mmol), was reacted with diisopropylethylamine (0.34 g, 2.6 mmol), diphenylphosphinic chloride (0.37 g, 1.6 mmol), then reacted with 2-methoxy-4-(morpholinosulfonyl)aniline (Matrix) (0.16 g, 0.59 mmol) to give chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [2-methoxy-4-(morpholine-4-sulfonyl)-phenyl]-amide as a white solid (Yield 0.06 g, 17%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.Br[CH2:20][C:21]1[CH:25]=[CH:24][S:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][N:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:20][C:21]3[CH:25]=[CH:24][S:23][CH:22]=3)=[CH:3][C:4]2=[O:18])=[CH:11][CH:12]=1
Reactant: BrCc1ccsc1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccsc2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 582 mg (2.37 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) in 10 mL DMF is added 0.70 g (3.95 mmol) 3-bromomethyl-thiophene and 1.64 g (11.9 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT, filtered and is directly transferred to a reverse HPLC for purification (Zorbax stable bond C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:20]([C:21]([OH:23])=[O:22])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:29]O>>[CH2:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH:20]([C:21]([O:23][CH3:29])=[O:22])[N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C(O)C1Cc2ccccc2CN1C(=O)OCc1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1Cc2ccccc2CN1C(=O)OCc1ccccc1

Procedure:
Step-1: A mixture of 2-((benzyloxy)carbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (2 g, 6.42 mmol) and conc. sulfuric acid (0.45 mL) in methanol was refluxed overnight. The reaction mixture was concentrated, neutralized with aq. sodium bicarbonate and extracted with DCM. The DCM layer was washed with brine, dried over anhydrous sodium sulfate and evaporated to afford 2-benzyl 3-methyl 3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate. MS (ES+): m/z 348.12 [M+Na]+
Reaction SMILES: C(C(CC)CNCC1SC(C2C=C3C(=C(C(N)=O)C=2)NC=C3C2CCN(S(CC)(=O)=O)CC2)=CC=1)C.[CH:37]([C:39]1[S:43][C:42]([B:44]([OH:46])[OH:45])=[CH:41][CH:40]=1)=O.[CH3:47][O:48][CH2:49][CH2:50][CH2:51][NH2:52].[BH3-]C#N.[Na+]>>[CH3:47][O:48][CH2:49][CH2:50][CH2:51][NH:52][CH2:37][C:39]1[S:43][C:42]([B:44]([OH:46])[OH:45])=[CH:41][CH:40]=1
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: COCCCN
Agent: CCC(CC)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COCCCNCc1ccc(B(O)O)s1
Yield: 40.9 %

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [3-(methyloxy)propyl]amine (29 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[3-(methyloxy)propyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[3-(methyloxy)propyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The crude product was purified once on an Agilent MDAP using the procedure shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide to give 7.6 mg of the title compound (9%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[C:4]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]3[NH:21][C:22]([CH3:27])=[C:23]([Cl:26])[C:24]=3[Cl:25])=[O:19])[CH2:13][CH2:12]2)[N:3]=1.[NH3:28]>CO>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:28])=[O:10])[CH:5]=[C:4]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]3[NH:21][C:22]([CH3:27])=[C:23]([Cl:26])[C:24]=3[Cl:25])=[O:19])[CH2:13][CH2:12]2)[N:3]=1
Reactant: N
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc(Cl)n3)CC2)c(Cl)c1Cl
Solvent: CO
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)nc(Cl)n3)CC2)c(Cl)c1Cl

Procedure:
Title compound was synthesized by an analogous method to Example 8 by coupling 2-chloro-6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)pyrimidine-4-carboxylic acid (Example 32) with 2 M ammonia in MeOH.
Reaction SMILES: C(S[C:4](=[O:20])[CH:5]([CH:11]1[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12]1)C(SCC)=O)C>C1C=CC=CC=1.[Ni]>[O:14]1[C:13]2([CH2:18][CH2:19][CH:11]([CH2:5][CH2:4][OH:20])[CH2:12]2)[O:17][CH2:16][CH2:15]1
Reactant: CCSC(=O)C(C(=O)SCC)C1CCC2(C1)OCCO2
Agent: [Ni]
Solvent: c1ccccc1
Product: OCCC1CCC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.2 %

Procedure:
To a solution Raney-Ni (250 mL) in benzene (100 mL) was added a solution of 2-(1,4-dioxa-spiro[4.4]non-7-yl)-dithiomalonic acid di-S-ethyl ester (28.7 g, 90 mmol) in benzene (600 mL). The mixture was stirred for 16 h at room temperature under nitrogen. The mixture was filtered to remove Raney-Ni and the filtrate was concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 5% ethyl acetate/pentane) afforded 2-(1,4-dioxa-spiro[4.4]non-7-yl)-ethanol (7 g, 45%).
Reaction SMILES: C1(C2CCC(=O)C(C(=S)NC3C=CC=CC=3)C2)CCCCC1.C(NN)C#C.[CH:28]1([CH:34]2[CH2:42][CH2:41][C:40]3[C:36](=[C:37]([NH:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[N:38]([C:43]#CC)[N:39]=3)[CH2:35]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(NN)C=C.C1(C2CCC3C(=C(NC4C=CC=CC=4)N(C=CC)N=3)C2)CCCCC1>>[CH:28]1([CH:34]2[CH2:42][CH2:41][C:40]3[C:36](=[C:37]([NH:46][C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)[N:38]([CH3:43])[N:39]=3)[CH2:35]2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CC#Cn1nc2c(c1Nc1ccccc1)CC(C1CCCCC1)CC2
Agent: C#CCNN
Agent: C=CCNN
Agent: CC=Cn1nc2c(c1Nc1ccccc1)CC(C1CCCCC1)CC2
Product: Cn1nc2c(c1Nc1ccccc1)CC(C1CCCCC1)CC2

Procedure:
In a similar manner starting from 6.9 g of 4-cyclohexyl 2-phenylthiocarbamoyl cyclohexanone and from 1.68 g propargylhydrazine, 4.10 g of 5-cyclohexyl 3-phenylamino 2-propynyl 4,5,6,7-tetrahydroindazole are obtained. In a similar manner starting from 6.9 g 4-cyclohexyl 2-phenylthiocarbamoyl cyclohexanone and 1.70 g allylhydrazine, 5.4 g of 5-cyclohexyl 3-phenylamino 2-propenyl 4,5,6,7-tetrahydro indazole are obtained.
Reaction SMILES: [C-:1]#[N:2].[Na+].[F:4][C:5]1[CH:6]=[C:7]([C:10]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)[CH2:8]Cl>CS(C)=O>[F:4][C:5]1[CH:6]=[C:7]([CH2:8][C:1]#[N:2])[C:10]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1
Reactant: Fc1ccc(Sc2ccccc2)c(CCl)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1cc(F)ccc1Sc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
18.6 g of sodium cyanide in 222 ml of dimethyl sulphoxide are treated at 50° C with 74 g of 3-fluoro-6-(phenylthio)-benzyl chloride in 75 ml of dimethyl sulphoxide in one portion. The resulting dark solution is stirred at 45°-50° C for 1 hour, subsequently poured on to 1500 ml of ice-water and extracted with ether. The organic phase is washed three times with 500 ml of water each time, dried over sodium sulphate and evaporated. There is obtained 3-fluoro-6-(phenylthio)-phenylacetonitrile as a reddish oil.
Reaction SMILES: [O-:1][Si:2]([O-:4])=[O:3].[Na+:5].[Na+].[OH2:7]>>[Si:2]([OH:7])([OH:4])([OH:1])[OH:3].[O-:3][Si:2]([O-:4])=[O:1].[Na+:5].[Na+:5]
Reactant: O
Agent: O=[Si]([O-])[O-]
Agent: [Na+]
Product: O[Si](O)(O)O

Procedure:
Since the supplying mechanisms 3' and 3" are provided in the paths of the pipes 6' and 6", respectively, the acidic reactant and the water are delivered into the mixing container 2 by the operation of these supplying mechanisms. As the supplying mechanism, a switching valve or a supplying pump can be employed, for instance. Then, the water glass is added into the acidic reactant in the mixing container 2, and the non-alkaline aqueous solution of silicic acid is prepared by mixing these two materials. The water glass, as was described before, is jetted into the acidic reactant aqueous solution from a jetting device 7 through the material container 1 and the pipe 6 by the operation of the supplying machanism 3. The jetting device 7 is formed by providing jetting apertures 8 in the end portion or the side wall of the pipe 6. The jetting apertures 8 are holes or nozzles opened towards the inside of the mixing container 2, and are adapted to provide jet streams of water glass. If the jet pressure is set to 0.5-30 kg/cm2, and preferably several kg/cm2 by controlling the supplying mechanism 3, it is sufficiently possible to allow the water glass to be added into and mixed with the acidic reactant aqueous solution. However, it is obvious that sufficient mixing of these material can be achieved by use of an agitator 9 operating at high speed with jetting.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([CH3:40])([OH:39])[CH3:38])[CH:28]=[CH:29][CH:30]=2)[CH:12]=[CH:13][C:14]=1[O:15][Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:39][C:37]([CH3:40])([CH3:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]=[CH:31][C:27]1[CH:26]=[C:25]([CH:24]=[CH:23][C:11]2[CH:10]=[C:9]([OH:8])[C:14]([OH:15])=[CH:13][CH:12]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(O)CCCCC=Cc1cccc(C=Cc2ccc(O[Si](C)(C)C(C)(C)C)c(O[Si](C)(C)C(C)(C)C)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(O)CCCCC=Cc1cccc(C=Cc2ccc(O)c(O)c2)c1

Procedure:
In a manner similar to Example 3(i), by reacting 166 mg (0.286 mmol) of 8-(3-{2-[3,4-bis-(tert-butyldimethylsilanyloxy)phenyl]vinyl}phenyl)-2-methyloct-7-en-2-ol with 0.63 ml of tetrabutylammonium fluoride 1M/THF, after purification on a silica column (ethyl acetate 45-heptane 55), white crystals (m=65 mg; Y=64%) are obtained. m.p.=116-8° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:11](=[O:19])[NH:12][C:13]4[N:14]([N:16]=[CH:17][N:18]=4)[C:15]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].[Na].[CH3:21]I>COCCOCCOC>[CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:11](=[O:19])[N:12]([CH3:21])[C:13]4[N:14]([N:16]=[CH:17][N:18]=4)[C:15]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: CI
Reactant: CCn1ncc2c1ncc1c(=O)[nH]c3ncnn3c12
Agent: [Na]
Solvent: COCCOCCOC
Product: CCn1ncc2c1ncc1c(=O)n(C)c3ncnn3c12
Reaction time: 0.5 h

Procedure:
2.6 g. of 8-ethyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one (0.01 mol.) are treated with 0.3 g. of sodium in 50 ml. of diethyleneglycol dimethyl ether at reflux temperature with stirring for 30 minutes. After this time, the temperature is lowered to 60° and 3 g. of methyl iodide are added. Stirring and heating is continued for 12 hours. The precipitate of sodium iodide is filtered off and the solvent distilled from the mother liquor. The remaining 8ethyl-4-methyl-4Hpyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin5(8H)-one is recrystallized from butanol, yield 2 g. (75%); m.p. 208°-210°.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](Cl)=[O:8])[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][OH:22].C(N(CC)CC)C.O>O1CCCC1>[OH:22][CH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][C:7]([C:5]1[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:8]
Reactant: Cn1cc(C(=O)Cl)c(C(F)(F)F)n1
Reactant: Nc1ccccc1CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1cc(C(=O)Nc2ccccc2CO)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.6 %

Procedure:
A solution of 34.5 g (0.16 mols) 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl chloride in 50 ml tetrahydrofuran is added dropwise at room temperature to a solution of 20.0 g (0.16 mols) 2-aminophenylmethanol and 36 ml (0.26 mols) triethylamine in 250 ml tetrahydrofuran. After the exotherm has subsided, the reaction is refluxed for 6 hours, then stirred at room temperature for another 48 hours. The reaction mixture is added to about 250 ml water, extracted with ethyl acetate, washed with 2 N hydrochloric acid gewaschen, dried over magnesium sulfate and concentrated tinder vacuum. Column chromatography (gradient cyclohexane/ethyl acetate) yielded 33.8 g (69% theoretical yield) of N-[2-(hydroxymethyl)phenyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide [logP (pH 2.3)=1.55].