Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]N)=[CH:6][CH:5]=1.[F:12][C:13]1[CH:35]=[CH:34][C:16]([CH2:17][NH:18][C:19]([C:21]2[N:22]=[C:23]3[C:31]([C:32]#[N:33])=[CH:30][NH:29][N:24]3[C:25](=[O:28])[C:26]=2[OH:27])=[O:20])=[CH:15][CH:14]=1.FC1C=CC(CCl)=CC=1>CN(C=O)C>[F:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][NH:18][C:19]([C:21]2[N:22]=[C:23]3[C:31]([C:32]#[N:33])=[CH:30][N:29]([CH2:8][C:7]4[CH:10]=[CH:11][C:4]([F:3])=[CH:5][CH:6]=4)[N:24]3[C:25](=[O:28])[C:26]=2[OH:27])=[O:20])=[CH:34][CH:35]=1
Reactant: N#Cc1c[nH]n2c(=O)c(O)c(C(=O)NCc3ccc(F)cc3)nc12
Reactant: NCc1ccc(F)cc1
Agent: Fc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cn(Cc2ccc(F)cc2)n2c(=O)c(O)c(C(=O)NCc3ccc(F)cc3)nc12
Temperature: 90 °C
Yield: 37.5 %

Procedure:
Sodium hydride (11.0 mg, 0.367 mmol) was added in one portion to a stirred suspension of 3-Cyano-6-hydroxy-7-oxo-1,7-dihydro-pyrazolo[1,5-a]pyrimidine-5-carboxylic acid 4-fluoro-benzylamide compound with 4-fluorobenzylamine (Example 3.1) (100 mg, 0.306 mmol) in DMF (2 mL) under nitrogen at room temperature. The mixture was stirred for 30 min before p-fluorobenzyl chloride (40 μL, 0.366 mmol) was added and the mixture heated at 90° C. for 2 days. After this time, the reaction was cooled to room temperature and partitioned between ethyl acetate (10 mL) and aqueous hydrochloric acid (1M, 10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organics were washed with water (3×10 mL), brine (10 mL) and then concentrated. The residue was purified by column chromatography (95:5:1 dichloromethane:methanol:aqueous ammonia) to afford the desired product (50 mg, 36%).
Reaction SMILES: Cl.[N:2]1([C:7](=[NH:9])[NH2:8])[CH:6]=[CH:5][CH:4]=[N:3]1.OC1C(NC(=O)C(C2C=CC=CC=2)C2C=CC=CC=2)=CN=C(N2C=CC=N2)N=1.C[O-].[Na+].C([O:43][CH:44]=[C:45]([C:51](OCC)=O)[C:46]([O:48][CH2:49][CH3:50])=[O:47])C>CCO>[OH:43][C:44]1[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:51][N:8]=[C:7]([N:2]2[CH:6]=[CH:5][CH:4]=[N:3]2)[N:9]=1
Reactant: N=C(N)n1cccn1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: O=C(Nc1cnc(-n2cccn2)nc1O)C(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cnc(-n2cccn2)nc1O
Temperature: 75 °C
Yield: 60 %

Procedure:
1H-pyrazole-1-carboximidamide hydrochloride, compound 2-a from Example 2, (22.11 g, 0.15 mol) in EtOH (250 ml) was added sodium methoxide (12.3 g, 0.23 mol) and diethyl ethoxymethylenemalonate, compound 2-b from Example 2, (30 ml, 0.15 mol). The reaction was heated for about 40 min at 75° C. and then cooled to room temperature. The mixture was filtered and the solid was washed with ethanol and ether and dried under vacuum to give compound 3-a (21 g, 60%). 1H NMR (DMSO-d6, 300 MHz): δ 8.50 (m, 2H), 7.70 (s, 1H), 6.47 (m, 1H), 4.13 (m, 2H), 1.24 (m, 3H).
Reaction SMILES: [Cl-].[NH+]1C2C=CC=CC=2C=C[SiH]=1.[Cl-].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([Si:20]2([CH3:35])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:23]3[O:30][CH2:31][C:32]([CH3:34])([CH3:33])[N+:22]=3[CH2:21]2)=[CH:16][CH:15]=1.O.[BH4-].[Na+]>CO>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([Si:20]2([CH3:35])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH2:23][N:22]([C:32]([CH3:33])([CH3:34])[CH2:31][OH:30])[CH2:21]2)=[CH:18][CH:19]=1
Reactant: CC1(C)COC2=[N+]1C[Si](C)(c1ccc(Cl)cc1)c1ccccc12
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(CO)N1Cc2ccccc2[Si](C)(c2ccc(Cl)cc2)C1

Procedure:
The crude benzazasilinium chloride (34.8 g., 92 m mol) obtained in part (a) above is dissolved in 20 ml. of water and 10 ml. of methanol and the solution is added with stirring to 52.6 g. (1.38 mol) of sodium borohydride in 500 ml. of peroxide free 1,2-dimethoxyethane between 20° and 30° C. After stirring 16 hours, the reaction mixture is poured into an ice-toluene-sodium potassium tartrate-water mixture. The organic phase is washed with water, dried with sodium sulfate and concentrated to an oil. The latter is passed in chloroform through a short silica gel column. The main portion of the effluent is concentrated to yield the title product as an oil. When dissolved in acetone and upon adding 2 g. of HCl gas with cooling and addition of ethyl ether, the free base is converted into the hydrochloride salt. The resultant crystals (m.p. 197°-198° C.) are recrystallized from ethanol-acetone-ether (ca. 1:2:5) and methanol-acetone-ether (ca. 1:3:5) and then acetone to obtain the purified salt (199°-200.5° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:18](=[O:19])[O:20][CH2:21][CH3:22])=[CH:10][CH:11]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(Oc2ccc(Cl)c(Cl)c2)cc1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(Oc2ccc(Cl)c(Cl)c2)cc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
4-(3,4-Dichlorophenoxy)benzenamine (0.1 mole) and pyridine (50 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer and are cooled to about 5° C. Ethyl chloroformate (0.125 mole) is added, with stirring, at about 5° C. Stirring is continued for a period of about 30 minutes at about 5° C., then for an additional 16 hours at room temperature. The mixture is then washed with 2 portions of water (50 ml), dried and the solvent is then removed to yield the desired product ethyl [4-(3,4-dichlorophenoxy)phenyl]-carbamate.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@H:6]1[O:15][C@H:16]1[C@@H:31]([CH2:32][O:33][C@@H:34]2[O:41][C@H:40]([CH2:42][OH:43])[C@@H:38]([OH:39])[C@H:36]([OH:37])[C@H:35]2[NH:44][C:45](=[O:47])[CH3:46])[O:30][C@@H:19]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[C@H:18]([OH:48])[C@H:17]1[OH:49])(=[O:3])[CH3:2].C1C(=O)NC(=O)NC=1[C@@H]1O[C@H](COP(OP(O[C@H:73]2[O:78][C@H:77]([CH2:79][OH:80])[C@H:76]([OH:81])[C@H:75]([OH:82])[C@H:74]2[OH:83])(O)=O)(O)=O)[C@@H](O)[C@H]1O>[As](C)(C)(=O)[O-].[Na+].[Cl-].[Mn+2].[Cl-]>[C@@H:19]1([O:12][C@@H:9]2[C@@H:8]([CH2:13][OH:14])[O:7][C@@H:6]([O:15][C@H:16]3[C@@H:31]([CH2:32][O:33][C@@H:34]4[O:41][C@H:40]([CH2:42][OH:43])[C@@H:38]([O:39][C@@H:73]5[O:78][C@H:77]([CH2:79][OH:80])[C@H:76]([OH:81])[C@H:75]([OH:82])[C@H:74]5[OH:83])[C@H:36]([OH:37])[C@H:35]4[NH:44][C:45](=[O:47])[CH3:46])[O:30][C@@H:19]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[C@H:18]([OH:48])[C@H:17]3[OH:49])[C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[C@H:10]2[OH:11])[O:30][C@H:31]([CH2:32][OH:33])[C@H:16]([OH:15])[C@H:17]([OH:49])[C@H:18]1[OH:48]
Reactant: COC(=O)CCCCCO[C@@H]1O[C@H](CO[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2NC(C)=O)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2NC(C)=O)[C@H](O)[C@H]1O
Reactant: O=c1cc([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O[C@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@@H](O)[C@H]2O)[nH]c(=O)[nH]1
Agent: [Mn+2]
Agent: C[As](C)(=O)[O-]
Agent: [Cl-]
Product: COC(=O)CCCCCO[C@@H]1O[C@H](CO[C@@H]2O[C@H](CO)[C@@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2NC(C)=O)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2NC(C)=O)[C@H](O)[C@H]1O
Reaction time: 22 h

Procedure:
A solution of compound 20 of Example 20 (72 mg), UDP-galactose, (190 mg), bovine galactosyltransferase (6.25 U) and bovine serum albumin (3 mg) in 30 mM sodium cacodylate buffer (7 mL, pH 7.0) containing manganese chloride (40 umol) was incubated at 37° C. for 22 h. The reaction mixture was diluted to 20 mL and purified as described in Example 21. Yield of the product was 98 mg. The structural identity of titled compound 26 was unambiguously assigned by 1H-- and 13C-n.m.r (see Tables 4 and 5, respectively).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8](Cl)=[N:7][C:6]=12.[NH2:12][CH2:13][CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(O)(C)C.C(N(CC)CC)C>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:12][CH2:13][CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[N:7][C:6]=12
Reactant: Clc1ccn2ncc(Br)c2n1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CN(CCNc1ccn2ncc(Br)c2n1)C(=O)OC(C)(C)C
Temperature: 140 °C
Yield: 82 %

Procedure:
To 465 mg (2.00 mmol) of 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine was added tert-butyl (2-aminoethyl)(methyl)carbamate (522 mg, 3.00 mmol), 4 mL of isopropanol, and triethylamine (0.56 mL, 4.00 mmol). The resulting mixture is heated at 140° C. for 0.5 hr in the microwave. It was diluted with EtOAc, and washed with water and brine. The organic layer was dried over MgSO4, concentrated and purified on the silica gel column eluting with 20-100% EtOAc/Hex to obtain 607 mg (82%) of the desired product.
Reaction SMILES: [CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:27]#[N:28])=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)=[O:33].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:27]#[N:28])=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:31][C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=[O:33])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccc(F)cc4C#N)cc3)c2s1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccc(F)cc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]-4-fluorobiphenyl-2-carbonitrile (2 g), 2-bromo-1-(4-methoxyphenyl)ethanone (1.4 g) and N,N-dimethylformamide (19 mL) was added 60% sodium hydride (0.3 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (2.4 g, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[S:15][C:16]1[S:17][C:18]([N+:21]([O-])=O)=[CH:19][CH:20]=1.[Cl-].[NH4+].C(O)C.O>[Fe].CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[S:15][C:16]1[S:17][C:18]([NH2:21])=[CH:19][CH:20]=1
Reactant: COc1cc2nccc(Sc3ccc([N+](=O)[O-])s3)c2cc1OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: COc1cc2nccc(Sc3ccc(N)s3)c2cc1OC
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 138.5 %

Procedure:
After suspending 6,7-dimethoxy-4-(5-nitrothiophen-2-ylsulfanyl)quinoline (1.39 g, 4.00 mmol), iron (1.12 g, 20.0 mmol) and ammonium chloride (2.18 g, 40.0 mmol) in an ethanol (32 ml)-water (8 ml) mixed solvent, the suspension was heated and stirred at 80° C. for 5 minutes. After completion of the reaction, the reaction mixture was filtered with celite and washed in ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent-ethyl acetate:hexane=3:1), and the fraction containing the target substance was concentrated to obtain the title compound (1.93 g, 5.54 mmol, 55%) as yellowish-brown crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[C:4]([OH:17])[CH:3]=1.[C:18](OCC)(=[O:25])[CH2:19][C:20]([O:22]CC)=[O:21].C1CCN2C(=NCCC2)CC1>C(OCC)(=O)C>[Cl:8][C:7]1[CH:6]=[C:5]2[C:4](=[CH:3][C:2]=1[Cl:1])[O:17][C:18](=[O:25])[C:19]([C:20]([OH:22])=[O:21])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(c1ccccc1)c1cc(Cl)c(Cl)cc1O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: O=C(O)c1c(-c2ccccc2)c2cc(Cl)c(Cl)cc2oc1=O
Temperature: 170 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
A mixture of (4,5-dichloro-2-hydroxyphenyl) (phenyl)methanone (1.5 g), diethyl malonate (1.28 ml) and DBU (0.25 ml) was stirred at 170° C. for 30 minutes. The reaction mixture was dissolved in ethyl acetate (50 ml), and washed with water followed by a 1 N solution of hydrochloric acid and a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate, the solvent was distilled off under reduced presurre, and the residue was purified by a column chromatography (packing: silica gel, eluent: ethyl acetate-hexane=1:9). The resultant crude product of ethyl 6,7-dichloro-2-oxo-4-phenyl-2H-chromene-3-carboxylate was dissolved in acetic acid (10 ml) and concentrated hydrochloric acid (5 ml), and heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, and the resultant residue was dissolved in a solvent mixture of THF (10 ml) and ethyl acetate (50 ml), and then washed with water followed by a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by recrystallization from ethyl acetate to obtain the title compound (0.65 g, yield: 34%).
Reaction SMILES: [CH:1]([C:3]1[CH2:9][C:8]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:7]=2[C:6]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[N:5][N:4]=1)=[O:2].[BH4-].[Na+]>O1CCCC1.O>[OH:2][CH2:1][C:3]1[CH2:9][C:8]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:7]=2[C:6]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[N:5][N:4]=1
Reactant: O=CC1=NN=C(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(C2=NN=C(CO)Cc3ccc(Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
2.15 g (6.6 mM) of 4-formyl-8-chloro-1-(4-nitrophenyl)-5H-2,3-benzodiazepine [prepared according to Step a)] were dissolved in 88 ml of a mixture of tetrahydrofuran and water (1:1), then under ice chilling 0.12 g (3.3 mM) of sodium borohydride was added portion-wise. The reaction mixture was stirred at 25° C. for 40 minutes then it was diluted with 90 ml of water. The precipitated crystals were filtered and purified on a Kieselgel column using a mixture of benzene and ethyl acetate (1:1) as eluant.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=[CH2:15])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:15][O:25]1)=[O:16])[CH3:2]
Reactant: C=C(CCCc1ccccc1)C(=O)OCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)C1(CCCc2ccccc2)CO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
10 g of 5-phenyl-2-methylenevaleric acid ethyl ester and 18.3 g of m-chloroperbenzoic acid (85% pure) are boiled under reflux in 180 ml of methylene chloride for 40 hours. The mixture is allowed to cool; the m-chloroperbenzoic acid (which has separated out) is filtered off; the filtrate is concentrated; the residue is taken up in 40 ml of acetone; 20 ml of a saturated sodium carbonate solution are added, and the mixture is stirred at 0° C. for 1 hour. It is then diluted with 100 ml of water and extracted 3 times with 50 ml of methylene chloride each time; the organic phase is concentrated, and the residue is distilled. 8.3 g of the liquid title compound (b.p. 115° under 0.03 mm Hg) are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[C:14]3=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[N:32]1([C:2]2[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[N:23]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[C:14]4=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=[C:13]4[CH:12]=3)=[O:10])=[CH:4][CH:3]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(Nc1ccc(Cl)nc1)c1cc2ccc(C(F)(F)F)nc2n1Cc1cccc(F)c1
Reactant: C1CCNC1
Product: O=C(Nc1ccc(N2CCCC2)nc1)c1cc2ccc(C(F)(F)F)nc2n1Cc1cccc(F)c1
Yield: 64.8 %

Procedure:
According to a method similar to that described in Stage 6.2, by reacting 0.3 g (0.67 mmol) of N-[6-chloropyridin-3-yl]-6-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, described in the preceding stage, with 0.56 mL (6.68 mmol) of pyrrolidine, we obtain 0.21 g of the expected compound.
Reaction SMILES: [Cl:1][C:2]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])=[O:23])[CH2:3][N:4]1[CH:21]=[N:20][C:6]([CH2:7][C@@H:8]([C:17]([OH:19])=O)[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5]1.CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:57][C:58]([O:61][C:62](=[O:66])[C@H:63]([CH3:65])[NH2:64])([CH3:60])[CH3:59].Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:57][C:58]([O:61][C:62](=[O:66])[C@H:63]([CH3:65])[NH:64][C:17](=[O:19])[C@H:8]([CH2:7][C:6]1[N:20]=[CH:21][N:4]([CH2:3][C:2]([Cl:1])([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])=[O:23])[CH:5]=1)[NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])([CH3:60])[CH3:59]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cn(CC(Cl)(C(=O)c2ccc(Cl)cc2Cl)c2ccccc2)cn1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)[C@H](Cc1cn(CC(Cl)(C(=O)c2ccc(Cl)cc2Cl)c2ccccc2)cn1)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 89.9 %

Procedure:
To a stirred mixture of 1-[2-chloro-3-(2,4-dichlorophenyl)-3-oxo-2-phenylpropyl]-N-[(1,1-dimethylethoxy)carbonyl]-L-histidine (1.14 g), N-methylmorpholine (461 μl), 1-hydroxybenzotriazole hydrate (277 mg) and L-alanine 1,1-dimethylethyl ester hydrochloride (364 mg) in dichloromethane (30 ml) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (422 mg). The resulting mixture was stirred for 18 hours, and concentrated under reduced pressure to yield a residue which was partitioned between ethyl acetate and water. The organic phase was washed with saturated aqueous sodium hydrogen carbonate and then brine and dried over anhydrous magnesium sulphate. The solvent was removed under reduced pressure to yield a foam which was chromatographed on silica gel eluting with methanol/dichloromethane (1:24) to yield N-[1-[2-chloro-3-(2,4-dichlorophenyl)-3-oxo-2-phenylpropyl]-N-[(1,1-dimethylethoxy)carbonyl]-L-histidyl]-L-alanine 1,1-dimethylethyl ester as a white foam (1.25 g), and as a mixture of diastereoisomers, m.p. 85-90° C. (decomp), (Found: C, 55.57; H, 5.51; N, 7.86%; C33H39Cl3N4O6.H2O requires C, 55.66; H, 5.80; N, 7.87%), having the formula: ##STR35##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]([N:16]3[CH2:19][CH:18]([O:20][C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[C:23]([CH3:29])[CH:22]=4)[CH2:17]3)=[O:15])=[N:11][N:10]=2)=[CH:5][CH:4]=1.Cl.[CH3:31][C:32]1([CH2:38][OH:39])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:39][CH2:38][C:32]1([CH3:31])[CH2:37][CH2:36][N:35]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][CH:18]3[CH2:19][N:16]([C:14]([C:12]4[O:13][C:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)=[N:10][N:11]=4)=[O:15])[CH2:17]3)=[CH:22][C:23]=2[CH3:29])[CH2:34][CH2:33]1
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)c(C)c4)C3)o2)cc1
Reactant: CC1(CO)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN5CCC(C)(CO)CC5)c(C)c4)C3)o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
73C (0.12 g, 0.31 mmol) and (4-methylpiperidin-4-yl)methanol hydrochloride (0.051 g, 0.31 mmol) were mixed with DCM (3 ml). Triethylamine (0.085 ml, 0.61 mmol) and then sodium triacetoxyborohydride (0.129 g, 0.61 mmol) were added. The mixture was stirred at RT overnight and then diluted with DCM (10 ml). The mixture was washed with aqueous NaHCO3 (sat. 4 ml) and then the organic solution was filtered through a phase separator. The solvent was removed by evaporation and the residue was purified by silica gel chromatography eluting the product with 1-3% methanol in DCM where the methanol contained ammonia (2 M). The product was triturated from DCM/diethylether. There was obtained 102 mg (66%) of the title compound as a solid. 1H NMR (500 MHz, CDCl3): δ 0.95 (s, 3H), 1.32 (m, 2H), 1.53 (m, 2H), 2.30 (m, 2H), 2.34 (s, 3H), 2.53 (m, 2H), 3.38 (m, 2H), 3.42 (s, 2H), 3.89 (s, 3H), 4.32 (m, 1H), 4.63 (m, 1H), 4.72 (m, 1H), 5.04 (m, 2H), 5.10 (m, 1H), 6.55 (d, 2H), 6.59 (s, 1H), 7.03 (d, 2H), 7.19 (m, 2H), 8.10 (d, 2H), MS (APCI+) m/z 507 [M+H]+, LC purity: 98%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([CH2:14][N:15]=[N+]=[N-])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([CH2:14][NH2:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(CN=[N+]=[N-])CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(CN)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-azidomethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.97 mmol, 0.25 g) in THF (4 mL) was added triphenylphosphine (1.1 mmol, 0.3 g) and stirred for 12 h at room temperature. Water (2 mL) was added to the reaction mixture and stirred for 4 h. The reaction mixture was diluted with EtOAc (10 mL), and the organic layer was washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide 4-aminomethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[N:12]1([C:18]2[CH:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CC([O-])(C)C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:24][C:21]2[CH:20]=[CH:19][C:18]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)=[CH:23][N:22]=2)=[N:4][CH:3]=1
Reactant: Nc1ccc(N2CCOCC2)cn1
Reactant: Brc1ncc(Br)n2ccnc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: Brc1cnc(Nc2ccc(N3CCOCC3)cn2)c2nccn12

Procedure:
In the same way as described for compound 90, step 1, using 5,8-dibromo-imidazo[1,2-a]pyrazine (0.4 g, 1.45 mmol), 5-morpholin-4-yl-pyridin-2-ylamine (0.258 g, 1.23 mmol), NaOtBu (0.19 g, 2.04 mmol), Pd2dba3 (0.053 g, 0.058 mmol) and Xantphos (0.067 g, 0.116 mmol) in toluene (6 mL). After removing the solvent in vacuo, the mixture is purified by silica gel column chromatography eluting with 1:4 petroleum ether:ethyl acetate followed by 99:1 DCM:NH3 (7M in MeOH). The title compound is isolated (216.4 mg, 47%). LCMS: Rt 2.16 min (93.2%).