Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:25])([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH2:3]1.[CH:26]1([CH2:29][NH:30][C:31](=[O:42])[NH:32][C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[CH2:28][CH2:27]1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[CH:26]1([CH2:29][NH:30][C:31]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([C:37]([N:7]3[C@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]4[CH:11]=[CH:12][C:13]([C:16]([OH:25])([C:21]([F:24])([F:23])[F:22])[C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=4)[CH2:3][C@@H:2]3[CH3:1])=[O:38])=[CH:40][CH:41]=2)=[O:42])[CH2:28][CH2:27]1
Reactant: C[C@@H]1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)C[C@H](C)N1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)C[C@H](C)N1C(=O)c1ccc(NC(=O)NCC2CC2)cc1
Temperature: 25 °C
Yield: 1.9 %

Procedure:
2-(4-((-3,5-cis-Dimethylpiperazin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (0.27 mmol, 0.1 g), 4-(3-(cyclopropylmethyl)ureido)benzoic acid (0.27 mmol, 0.063 g) and triethylamine (0.81 mmol, 0.113 mL, 0.082 g) were combined in dichloromethane and stirred at room temperature. 1-Propanephosphonic acid cyclic anhydride (0.405 mmol, 0.241 mL, 0.258 g; 50% solution in ethyl acetate) was added and the reaction allowed to stir for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by acidic preparative HPLC to afford the desired compound (3 mg). MS (ESI) m/z 587.3 [M+H]+
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[OH-].[Na+].C(=O)=[O:14]>>[NH:8]1[C:4]2[N:5]=[CH:6][CH:7]=[C:2]([OH:14])[C:3]=2[CH:10]=[CH:9]1
Reactant: Clc1ccnc2[nH]ccc12
Reactant: O=C=O
Agent: [Na+]
Agent: [OH-]
Product: Oc1ccnc2[nH]ccc12
Temperature: 180 °C

Procedure:
4-Chloro-1H-pyrrolo-[2,3-b]pyridine [80 g, Reference Example 64] was treated with 10% aqueous sodium hydroxide solution (330 g) and heated to 180° C. for 8 hours in a parr bomb with magnetic stirring. The reaction mixture was cooled to room temperature and excess sodium hydroxide was neutralized with a large excess of solid carbon dioxide pellets. Undissolved starting material was removed by filtration and the filtrate was concentrated in vacuo. The residue was extracted with hot methanol (3×1000 mL). The combined methanol extracts were concentrated and the residue purified by flash column chromatography on silica gel eluting with a mixture of dichloromethane and methanol (9:1 v:v to 4:1 v:v) to afford the title compound as a solid (63 g). TLC: RF=0.32 (dichloromethane/methanol 4/1).
Reaction SMILES: CS[C:3]1[N:8]2[C:9]([CH3:12])=[N:10][CH:11]=[C:7]2[CH:6]=[C:5]([S:13][CH3:14])[N:4]=1.C[O-].[Na+].Cl.C(=O)(O)[O-:20].[Na+]>O.CO>[CH3:12][CH:9]1[N:8]2[C:3](=[O:20])[N:4]=[C:5]([S:13][CH3:14])[CH:6]=[C:7]2[CH:11]=[N:10]1
Reactant: CSc1cc2cnc(C)n2c(SC)n1
Reactant: O=C([O-])O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CSc1cc2n(c(=O)n1)C(C)N=C2
Temperature: 0 °C

Procedure:
To a solution of 4.8 g (21.3 mmole) of 5,7-bis(methylthio)-3-methylimidazo[1,5-c]pyrimidine in 10 ml of water and 90 ml of methanol was added 5.0 g (23.1 mmole) of 25% sodium methoxide in methanol. The mixture was heated at reflux for 16 hours, poured into 400 ml of an ice-water mixture, and acidified with 3 ml of concentrated hydrochloric acid. The mixture was basified with solid sodium bicarbonate, and the precipitate was separated by filtration. The solid was washed with water and dried to provide 3-methyl-7-methylthioimidazo[1,5-c]pyrimidin-5-one, m.p. 221°-222° C. Analysis: Calculated for C8H9N3OS; %C, 49.2; %H, 4.7; %N, 21.5; Found; %C, 48.9; %H, 4.6; %N, 21.6.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[NH:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]1>C(#N)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]2[NH:13][C:1](=[O:2])[N:21]([CH:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:26][CH2:27]3)[C:15]=2[CH:16]=1
Reactant: CCOC(=O)N1CCC(Nc2cc(Cl)ccc2N)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CCOC(=O)N1CCC(n2c(=O)[nH]c3ccc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 61.8 %

Procedure:
1,1′-Carbonyldiimidazole (15.7 g, 97 mmol) was added portionwise over 10 minutes to a stirred solution of D6 (18.0 g, 60 mmol) in acetonitrile (300 mL). The reaction mixture was stirred at room temperature for 6 hours and the resulting precipitate was collected by filtration to give the title compound (12.0 g, 62% yield) as a violet solid that was used without further purification. (Rf: 0.2 (ethyl acetate))
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:8]([NH:10][C@H:11]([C:19]([NH:21][C@H:22]([C:28]([NH:30][C@H:31]([C:35]([NH:37][C@H:38]([C:47]([OH:49])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1)=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[CH2:23][CH2:24][C:25](=[O:27])[OH:26])=[O:20])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:18])[NH2:17])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[C:60]([OH:63])(=[O:62])[CH3:61]>O>[NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:19]([NH:21][C@H:22]([C:28]([NH:30][C@H:31]([C:35]([NH:37][C@H:38]([C:47]([O:49][CH3:60])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1)=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[CH2:23][CH2:24][C:25](=[O:27])[OH:26])=[O:20])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:18])[NH2:17])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH3:61][C:60]([OH:63])=[O:62]
Reactant: CC(C)[C@H](NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCCCN)NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCCCN)C(C)C

Procedure:
800 mg (approx. 0.88 mmole) of Z-Lys-Arg-Glu-Val-Tyr-Ome acetate are subjected to catalytic hydrogenation in 90 percent strength acetic acid and the product is worked up analogously to Example 25 I. Yield 680 mg (93%), [α]D22 =-31.6° (c=1, in water).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][NH:11]1.Cl[CH2:16][CH:17]1[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH:17]1([CH2:16][N:9]([C:10]2[NH:14][CH2:13][CH2:12][N:11]=2)[C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:19][CH2:18]1
Reactant: ClCC1CC1
Reactant: Clc1cccc(Cl)c1N=C1NCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1cccc(Cl)c1N(CC1CC1)C1=NCCN1
Yield: 10.6 %

Procedure:
A mixture consisting of 6.9 gm (0.03 mol) of 2-(2,6-dichlorophenyl-imino)-imidazolidine, 2.9 gm (110% of stoichiometrically required amount) or chloromethyl-cyclopropane, 4 gm of sodium carbonate and 50 ml of absolute toluene was refluxed for 32 hours, while stirring. Thereafter, the reaction solution was evaporated to dryness in vacuo, and the residue was dissolved in about 1N hydrochloric acid. The resulting acidic solution was extracted several times with ether, and the ethereal extracts were discarded. The acidic aqueous phase was then fractionally extrated with ether at stepwisely increasing pH-values (alkalization with dilute sodium hydroxide), and the thin-layer chromatographically pure fractions were combined, dried over magnesium sulfate and evaporated in vacuo, yielding as the residue 0.9 gm (10.6% of theory) of the compound of the formula ##STR7## which had a melting point of 126°-129° C.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=1)[NH2:3].CN(C)/[CH:14]=[CH:15]/[C:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=1)=O>>[CH3:25][N:24]([CH3:26])[C:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:2]([C:4]3[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=3)[N:3]=[CH:14][CH:15]=2)=[CH:19][CH:20]=1
Reactant: CN(C)/C=C/C(=O)c1ccc(N(C)C)cc1
Reactant: N#Cc1ccnc(NN)c1
Agent: Cl
Product: CN(C)c1ccc(-c2ccnn2-c2cc(C#N)ccn2)cc1
Yield: 69 %

Procedure:
The title compound was prepared in 69% yield from 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3) and (2E)-3-(dimethylamino)-1-[4-(dimethylamino)phenyl]prop-2-en-1-one according to the procedure for the preparation of Example 46, part B.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-])=O)[CH:11]=1)[NH:8][C:7](=[O:15])[CH:6]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:5]2.C(N(C(C)C)CC)(C)C.CN1[CH2:38][CH2:37][CH2:36][C:35]1=[O:39]>[Pd]>[O:15]=[C:7]1[CH:6]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:5][C:4]2[C:9](=[C:10]([N:12]3[CH2:38][CH2:37][CH2:36][C:35]3=[O:39])[CH:11]=[CH:2][CH:3]=2)[NH:8]1
Reactant: CC(C)(C)OC(=O)NC1Cc2cc(Br)cc([N+](=O)[O-])c2NC1=O
Reactant: CN1CCCC1=O
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1Cc2cccc(N3CCCC3=O)c2NC1=O
Temperature: 53 °C
Reaction time: 4 h

Procedure:
tert-Butyl 6-bromo-8-nitro-2-oxo-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (200 g) was suspended in N-methylpyrrolidone (520 mL), and diisopropylethylamine (136.6 g) and 10% Pd—C (water content: 52.5%) (12.6 g) were added thereto. The reactor was washed with N-methylpyrrolidone (200 mL), and the wash liquid was combined with the mixture. The resultant mixture was purged with hydrogen three times, and the mixture was stirred vigorously for four hours while maintaining the internal temperature at 50-56° C. (formation of Compound A). The resultant mixture was cooled to 25° C., and the mixture was filtered through Celite. The filtered solid was washed with N-methylpyrrolidone (20 mL) three times. The filtrate was cooled to 8° C., and 4-chlorobutyryl chloride (80.3 g) was added dropwise thereto, followed by stirring at 14-17° C. for 20 minutes (formation of Compound B). To the resultant mixture was added dropwise 25% aqueous sodium hydroxide solution (265.2 g) over 12 minutes, and the mixture was stirred for 1.5 hours (formation of Compound C). Water (720 mL) was added to the resultant mixture, and stirring was continued for one hour. The formed precipitates were recovered through vacuum filtration, and the thus-recovered residue was washed three times with water (200 mL), whereby the title compound (154 g) (water content: 14%) was yielded as a powdery compound.
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]1[N:10]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:9]=[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:7]=1.O>CS(C)=O>[C:17]1([C:8]2[N:7]=[C:6]([CH2:5][C:1]#[N:2])[N:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[N:9]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [C-]#N
Reactant: BrCc1nc(-c2ccccc2)nn1-c1cccnc1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1nc(-c2ccccc2)nn1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of potassium cyanide (30.7 mg, 472 μmol) and 3-(5-(bromomethyl)-3-phenyl-1H-1,2,4-triazol-1-yl)pyridine (124 mg, 393 μmol) in DMSO (3 mL) was stirred at RT for 2 h. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (2×25 mL). The combined organic phase was washed with water and brine, dried, filtrated and evaporated. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as light brown solid (47 mg with 80% purity, 180 μmol, 36.6%).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].[NH2:6][C:7]1[C:16]2[N:17]=[C:18]([CH2:28]Cl)[N:19]([CH2:20][C:21]3([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1>CN(C=O)C>[C:1]([O:4][CH2:28][C:18]1[N:19]([CH2:20][C:21]2([OH:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:6])[C:16]=2[N:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: Nc1nc2ccccc2c2c1nc(CCl)n2CC1(O)CCCCC1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1nc2c(N)nc3ccccc3c2n1CC1(O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium acetate (0.28 g, 2.89 mmol) was added to a solution of 1-{[4-amino-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol (0.83 g, 2.41 mmol) in DMF (10 mL). The reaction mixture was stirred at ambient temperature overnight and then concentrated under reduced pressure to provide crude [4-amino-1-(1-hydroxycyclohexylmethyl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][C:7]=2[N:6]=[C:5]([NH:12][C:13](=[N:17][S:18]([C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])(=[O:20])=[O:19])SCC)[N:4]=1.CC(C)=[O:33]>>[CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][C:7]=2[N:6]=[C:5]([NH:12][C:13]([NH:17][S:18]([C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])(=[O:20])=[O:19])=[O:33])[N:4]=1
Reactant: CC(C)=O
Reactant: CCSC(=NS(=O)(=O)c1ccccc1C(=O)OC)Nc1nc2c(c(OC)n1)CCC2
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc2c(c(OC)n1)CCC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 3.2 g of methyl 2-[[1-(6,7-dihydro-4-methoxy-5H-cyclopentapyrimidin-2-ylamino)-1-(ethylthio)methylene]aminosulfonyl]benzoate in 75 ml of acetone is treated with 3.0 g of mercuric oxide and stirred at room temperature for 3 days. The mercury salts are removed by filtration and the solvent is evaporated to yield the solid product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[O:11]1[CH2:16][CH2:15][CH:14](O)[CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)=[C:4]([F:10])[CH:3]=1
Reactant: OC1CCOCC1
Reactant: Oc1c(F)cc(Br)cc1F
Product: Fc1cc(Br)cc(F)c1OC1CCOCC1

Procedure:
The title compound was prepared from 4-bromo-2,6-difluorophenol and tetrahydro-4H-pyran-4-ol in analogy to Example 9c): MS (EI): 292 and 294 M+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12](F)[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:3]=1[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].[CH2:18]([NH2:20])[CH3:19]>C1COCC1>[Cl:1][C:2]1[CH:13]=[C:12]([NH:20][CH2:18][CH3:19])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:3]=1[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5]
Reactant: CCN
Reactant: O=C(NC1CC1)c1cc([N+](=O)[O-])c(F)cc1Cl
Solvent: C1CCOC1
Product: CCNc1cc(Cl)c(C(=O)NC2CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.17 g (8.40 mmol) of 2-chloro-N-cyclopropyl-4-fluoro-5-nitrobenzamide were initially charged in 100 ml of THF, 12 ml of a 2 molar solution of ethylamine in THF (16.79 mmol) were added and the mixture was stirred in a closed ampoule at room temperature for 18 hours. The reaction mixture was poured onto water, the organic solvents were distilled off and the residue obtained was filtered off with suction. Yield: 2.10 g (81% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[OH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][C:11]=1[C:26](OCC)=[O:27]>C1(C)C=CC=CC=1>[OH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:12][C:11]=1[C:26]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1)=[O:27]
Reactant: CCOC(=O)C1=C(O)c2ccccc2N(c2ccccc2)C1
Reactant: Cc1cccc(N)n1
Solvent: Cc1ccccc1
Product: Cc1cccc(NC(=O)C2=C(O)c3ccccc3N(c3ccccc3)C2)n1
Yield: 43.8 %

Procedure:
A solution of 5.49 g of 2-amino-6-methylpyridine and 10.0 g of 1,2-dihydro-4-hydroxy-1-phenyl-3-quinolinecarboxylic acid, ethyl ester in 250 ml of toluene was refluxed overnight in a soxhlet apparatus containing 10 g of 4 Å molecular sieves. Evaporation of the volatiles afforded a residue which was purified by means of high pressure liquid chromatography (silica gel: 2% ethyl acetate-dichloromethane). The resultant solution was degassed and evaporated. Recrystallization of the residue from diethyl ether yielded 5.30 g (43%) of 1,2-dihydro-4-hydroxy-N-(6-methyl-2-pyridyl)-1-phenyl-3-quinolinecarboxamide, m.p. 74°-77° C.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[CH3:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=1[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=1.ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]1[N:29]=[C:28]([C:27]2[CH:30]=[CH:31][C:24]([CH3:23])=[C:25]([O:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:41])([F:42])[F:40])=[CH:35][N:34]=3)[CH:26]=2)[N:2]([CH3:1])[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2ccccc2Cl)cc1
Reactant: Cc1ccc(C#N)cc1Oc1ccc(C(F)(F)F)cn1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(-c2nc(-c3ccccc3Cl)nn2C)cc1Oc1ccc(C(F)(F)F)cn1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-benzohydrazonoyl chloride (1.1 g), 4-methyl-3-(5-trifluoromethylpyridine-2-yloxy)benzonitrile (1.00 g), anhydrous iron (III) chloride (0.60 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.50 g of desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([C:21]([O:23][CH3:24])=[O:22])[C:19]=1[CH3:20])[O:5][CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1.O=[C:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:28][CH2:27]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:35]([O:34][C:33]([NH:32][CH:29]1[CH2:30][CH2:31][CH:26]([NH:1][C:2]2[CH:3]=[C:4]([CH:17]=[C:18]([C:21]([O:23][CH3:24])=[O:22])[C:19]=2[CH3:20])[O:5][CH:6]2[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]2)[CH2:27][CH2:28]1)=[O:39])([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)c1cc(OC2CN(C(=O)OC(C)(C)C)C2)cc(N)c1C
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COC(=O)c1cc(OC2CN(C(=O)OC(C)(C)C)C2)cc(NC2CCC(NC(=O)OC(C)(C)C)CC2)c1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.2 %

Procedure:
To a stirred solution of tert-butyl 3-(3-amino-5-(methoxycarbonyl)-4-methylphenoxy)azetidine-1-carboxylate (0.90 g, 2.67 mmol) and tert-butyl (4-oxocyclohexyl)carbamate (0.741 g, 3.47 mmol) in dichloroethane (10 mL) was added acetic acid (0.96 g, 16.1 mmol) and the mixture stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydride (1.7 g, 8.0 mmol) was added at 0° C. and the reaction stirred at room temperature for 2 h. On completion, the reaction was quenched with aqueous sodium bicarbonate, the organic phase separated and the aqueous phase extracted with dichloromethane. The combined organic layers were washed with water, dried, concentrated under reduced pressure and the crude material purified by column chromatography to afford the title compound (0.9 g, 63%) as a mixture of cis/trans isomers.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[N:5]=1.[F:11][C:12]([F:16])([F:15])[CH2:13][OH:14]>CN(C)C=O>[Br:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:14][CH2:13][C:12]([F:16])([F:15])[F:11])[N:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1cccc(Br)n1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.93 g, 23 mmol) was added to a solution of 2,6-dibromopyridine (5 g, 21 mmol) in N,N-dimethylformamide (10 mL) and the mixture was allowed to stir for 10 minutes. 2,2,2-Trifluoroethanol (2.53 g, 25.2 mmol) was then added and the mixture was heated at 60° C. for 90 minutes. The reaction mixture was then partitioned between water and ethyl acetate and the layers were separated. The organic layer was washed with a further volume of water, dried over magnesium sulfate and concentrated in vacuo to give a liquid residue. Purification of the liquid by column chromatography on silica gel, eluting with petroleum ether (60-80):dichloromethane, 99:1, afforded the title compound as a white liquid in 80% yield, 4.3 g.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:27]([O:31][C:32](=[O:44])[NH:33][CH2:34][CH:35]([NH2:43])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:44])[NH:33][CH2:34][CH:35]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1)[NH:43][C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CN1CCN(c2nccn3c(-c4ccnc(S(C)(=O)=O)n4)cnc23)CC1
Reactant: CC(C)(C)OC(=O)NCC(N)c1cccc(Cl)c1
Product: CN1CCN(c2nccn3c(-c4ccnc(NC(CNC(=O)OC(C)(C)C)c5cccc(Cl)c5)n4)cnc23)CC1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of 3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 46 supra) (210 mg, 0.563 mmol) and [2-amino-2-(3-chloro-phenyl)-ethyl]-carbamic acid tert-butyl ester (from Example 78 supra) (611 mg, 2.25 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 10:1 to 4:1) to afford crude (2-(3-chloro-phenyl)-2-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-ethyl)-carbamic acid tert-butyl ester. (Yield 150 mg). LC-MS: [M+H]+ 564.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1)=[CH2:2].[F:11][C:12]([F:20])([F:19])[C:13]([C:15]([F:18])([F:17])[F:16])=[O:14]>OS(O)(=O)=O>[F:11][C:12]([F:20])([F:19])[C:13]([C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=1)([OH:14])[C:15]([F:18])([F:17])[F:16]
Reactant: C=Cc1ccc([Mg]Br)cc1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: O=S(=O)(O)O
Product: C=Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 0.25 h

Procedure:
The title compound was prepared by a modification of the procedure of Przybilla, described in German Patent No. DE4207261A1 (Sep. 9, 1993), herein incorporated by reference. The (4-vinylphenyl)magnesium bromide solution of Example 1 was cooled to −40 to −30° C. using a dry ice/acetone bath. Subsequently, hexafluoroacetone was introduced below the surface until an excess was achieved (weight added 62 g, 373.45 mmol). The reaction mixture was stirred in the cooling bath for 15 min, then placed in an ice-bath for an additional 15 min, and finally poured into cold 1N H2SO4 (1000 mL). The aqueous solution was extracted with ether, and the combined extracts were washed with brine, dried (Na2SO4), and concentrated to provide 101.60 g of a pale yellow oil. This material was purified by vacuum distillation to provide 52.43 g (73%) of a colorless oil: bp 55-6° C. (1.3 mm); 1H NMR (CDCl3) δ 7.69 (d, 2ArH), 7.50 (d, 2ArH), 6.75 (dd, CH═), 5.84 (dd, ═CHH), 5.36 (dd, ═CHH), 3.73 (s, OH),+9% THF.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][Br:7].B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][Br:7]
Reactant: COc1ccccc1CCBr
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccccc1CCBr
Temperature: 25 °C

Procedure:
To a solution of 2-methoxyphenethyl bromide (1.07 g, 4.98 mmol) in 5 ml of CH2Cl2 was added BBr3 (9.5 ml, 1.0 M in CH2Cl2) at -78° C. and it was allowed to warm to rt over 1.5 h. The reaction mixture was poured into CH2Cl2 and was washed with brine, dried to afford 2-hydroxy phenethyl bromide (quantitative).