Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.[NH:24]1[CH:28]=[N:27][C:26]([SH:29])=[N:25]1.B(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:24]2[CH:28]=[N:27][C:26]([S:29][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)=[N:25]2)([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Sc1nc[nH]n1
Reactant: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: FB(F)F
Solvent: ClCCl
Product: Clc1ccc(C(Sc2ncn(C(c3ccc(Cl)cc3)(c3ccc(Cl)cc3)c3ccc(Cl)cc3)n2)(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Yield: 37.1 %

Procedure:
The procedure of Example 5(b) was followed, using 1.26 g (3.47 mmol) of tris(4-chlorophenyl)methanol, 0.52 g (5.1 mmol) of 1,2,4-triazole-3-thiol, 4.0 mL of CH2Cl2 and 1.25 mL (10 mmol) of BF3 etherate. Isolation followed by flash chromatography (75 g SiO2, 40% EtOAc-hexanes) gave 0.51 g of the title compound, followed by 0.71 g of an unstable product that turned into the title compound upon standing in solution. A 0.44 g sample of the first-eluted material was recrystallized from MeOH giving 0.18 g of (15), m.p. 219°-221° C. (dec).
Reaction SMILES: [H-].[Na+].[C:3](=[N:8][OH:9])([NH2:7])[CH2:4][CH2:5][CH3:6].[C:10]1([C:16]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:17]2[CH2:22][CH:21]([C:23](OC)=O)[CH2:20][N:19]=[CH:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[C:33]1([C:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:17]2[CH2:22][CH:21]([C:23]3[O:9][N:8]=[C:3]([CH2:4][CH2:5][CH3:6])[N:7]=3)[CH2:20][N:19]=[CH:18]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCCC(N)=NO
Reactant: COC(=O)C1CN=CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1noc(C2CN=CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)n1
Temperature: 0 °C
Reaction time: 18 h
Yield: 66.6 %

Procedure:
Prepared by a procedure similar to Example 9, where sodium hydride (60% dispersion in mineral oil 108 mg, 2.7 mmol) and butyramidoxime (276 mg, 2.7 mmol) were suspended in dry THF in an oven dried round bottom flask with stirring under nitrogen at 0° C. After 15 minutes stirring the ice bath was removed and the grey suspension refluxed 45 minutes to give a white suspension. 1-Triphenylmethyl-1,4,5,6-tetrahydro-5-methoxycarbonylpyrimidine (1.04 g, 2.7 mmol) was added, dissolved in dry THF and reflux continued 18 hours. The solvents were evaporated in vacuo and the residue was chromatographed (silica, chloroform/methanol, 9:1) to yield 1-triphenylmethyl-1,4,5,6-tetrahydro-5-(3-n-propyl-1,2,4-oxadiazol-5-yl)pyrimidine 785 mg (67%). This product was dissolved in triflouroacetic acid (2 ml), with stirring at room temperature for 24 hours. The yellow solution was then evaporated in vacuo, and the residue recrystallized from methanol/ether to yield 240 mg (43%) white crystals, mp 126°-128° C. identified by 300 MHz nmr.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[N:7]=1.[Br:17]N1C(=O)CCC1=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:17][C:9]1[CH:10]=[CH:11][C:6]([NH:5][CH2:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[Cl:1])=[N:7][C:8]=1[F:12]
Reactant: Fc1cccc(NCc2ccccc2Cl)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1nc(NCc2ccccc2Cl)ccc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To (2-chloro-benzyl)-(6-fluoro-pyridin-2-yl)-amine (16, 4.70 g, 19.8 mmol) in 100.0 mL of acetonitrile, N-bromosuccinimide (3.53 g, 19.8 mmol) in 20.0 mL of acetonitrile was added slowly at room temperature. The reaction was stirred at room temperature for 4 hours, then poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was washed with ethyl acetate in hexane to provide the desired compound (17, 5.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[NH:5]O.[N+](C1C=C2C(=CC=1)N=CN=C2)([O-])=O.[C:23]([NH:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31](=O)[NH:32][CH:33]=[N:34]2)=[CH:29][C:28]=1[N+:38]([O-:40])=[O:39])(=[O:25])[CH3:24].BrC1C=C(C=CC=1)N.Cl.N>O=P(Cl)(Cl)Cl.C(O)(C)C>[C:23]([NH:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31]([NH:5][C:4]3[CH:7]=[CH:8][CH:9]=[C:2]([Br:1])[CH:3]=3)=[N:32][CH:33]=[N:34]2)=[CH:29][C:28]=1[N+:38]([O-:40])=[O:39])(=[O:25])[CH3:24]
Reactant: ONc1cccc(Br)c1
Reactant: CC(=O)Nc1cc2nc[nH]c(=O)c2cc1[N+](=O)[O-]
Agent: Cl
Agent: N
Agent: O=[N+]([O-])c1ccc2ncncc2c1
Solvent: Nc1cccc(Br)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(C)O
Product: CC(=O)Nc1cc2ncnc(Nc3cccc(Br)c3)c2cc1[N+](=O)[O-]
Yield: 45 %

Procedure:
7-Acetamido-4-(3-bromoanilinol-6-nitroquinazoline. A solution of 7-acetamido-6-nitro-3H-quinazolin-4-one (5.00 g, 20 mmol) in POCl3 (250 mL) is heated under reflux for 2 h, the excess of POCl3 is removed under vacuum, and the residue is dissolved in CH2Cl2 and washed with aqueous Na2CO3 solution. Workup gives the crude 4-chloro derivative, which is coupled directly with 3-bromoaniline in isopropanol as above, and the resulting hydrochloride is converted directly to the free base, by treatment with aqueous NH3, to give 7-acetamido-4-(3-bromoanilino)-6-nitroquinazoline (3.60 g, 45%). 1H NMR (DMSO) δ10.56 (1H, s), 10.29 (1H, s), 9.34 (1H, s), 8.70 (1H, s), 8.19 (1H, brs), 7.97 (1H, s), 7.88 (1H, d, J=6.0 Hz), 7.43-7.35 (2H, m), 2.13 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:31]([O:33]CC)=O)=[N:4][C:5]([NH:17][CH2:18][C@H:19]2[CH2:23][CH2:22][CH2:21][N:20]2C(OC(C)(C)C)=O)=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16].C(OC([N:43]1CCC[C@@H]1CNC1N=C(C(OCC)=O)C([N+]([O-])=O)=C(NC2C=CC=CC=2OC)N=1)=O)(C)(C)C.[CH2:73]([OH:75])C>[Pd]>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:8]1[C:73](=[O:75])[NH:1][C:2]2[C:7]1=[N:6][C:5]([NH:17][CH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1)=[N:4][C:3]=2[C:31]([NH2:43])=[O:33]
Reactant: CCOC(=O)c1nc(NC[C@H]2CCCN2C(=O)OC(C)(C)C)nc(Nc2ccccc2OC)c1N
Reactant: CCO
Reactant: CCOC(=O)c1nc(NC[C@H]2CCCN2C(=O)OC(C)(C)C)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Agent: [Pd]
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(NC[C@H]3CCCN3)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
(R)-Ethyl 5-amino-2-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate. (R)-Ethyl 2-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methylamino)-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate (0.430 g, 0.802 mmol) was dissolved in ethanol (20 mL) and 10% palladium on carbon (0.086 g) were added to the flask and flushed with fresh hydrogen gas and allowed to stir at room temperature. After 16 h, the reaction was filtered through celite and the filtrate condensed under reduced pressure. The crude oil was purified using Biotage chromatography (0-100% ethyl acetate in hexanes) to afford the title compound (0.360 g, 89%). MS (ESI) m/z 487.2 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([O:17]CC)(=O)[CH2:10][C:11]([O:13]CC)=O>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:11](=[O:13])[CH2:10][C:9]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=2)=[O:17])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCOCC
Product: O=C(CC(=O)Nc1cccc(Cl)c1)Nc1cccc(Cl)c1
Temperature: 220 °C
Reaction time: 18 h

Procedure:
3-chloroaniline (5.01 g) and diethyl malonate (2.51 ml) were combined in a flask and heated to 220° C. utilizing a short path condenser with nitrogen bleed over the reaction to remove reaction ethanol. The reaction was stirred for 18 hours and then cooled to room temperature. The solid that had formed in the flask was broken up in diethyl ether 30 mL to give free flowing orange solid upon filtration and washing with ether (3.75 g). LRMS (ES+) m/z (M+H)+ 322.9.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]([CH3:11])[C:7]=1[C:8](O)=[O:9])#[N:2].[CH2:12]([SH:14])[CH3:13].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([C:3]1[N:4]=[CH:5][N:6]([CH3:11])[C:7]=1[C:8](=[O:9])[S:14][CH2:12][CH3:13])#[N:2]
Reactant: CCS
Reactant: Cn1cnc(C#N)c1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCSC(=O)c1c(C#N)ncn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
In a 1 l, three-necked flask fitted with a magnetic stirrer and a reflux condenser under inert atmosphere, 4-cyano-1-methyl-1H-imidazole-5-carboxylic acid x84 (24.5 g, 0.162 mol) and CH2Cl2 (500 ml) are stirred at room temperature. To this suspension, ethanethiol (13.2 ml, 0.178 mol) and DMAP (1.98 g, 0.016 mol) are added, followed by DCC (36.77 g, 0.178 mol) in two portions. The temperature rises to 35° C. and the mixture is stirred at room temperature for 16 h. Ethanethiol (0.0324 mol) is further added and stirring is continued overnight. The mixture is filtered and the solvent is evaporated. The residue is purified by chromatography on silicagel (Hexane/AcOEt:6/4 (v/v)) to give 29.5 g of S-ethyl 4-cyano-1-methyl-1H-imidazole-5-carbothioate x85.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[N:5].CCN(CC)CC.[CH3:13][C:14]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])[CH3:15]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:17]([O:1][CH2:2][CH2:3][C:4]#[N:5])([C:14]([CH3:16])([CH3:15])[CH3:13])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#CCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCCC#N)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxypropanenitrile (7.1 g, 0.1 mol) and DMAP (1.22 g, 0.01 mmol) in 30 mL of dry DCM at room temperature was added NEt3 (30.3 g, 0.3 mol), followed by TBDPSCl (27.5 g, 0.1 mol). A lot of white solid appeared. After stirring at room temperature overnight, the reaction mixture was quenched with sat. NH4Cl solution, extracted with DCM, dried over Na2SO4, and evaporated in vacuo. Flash chomatography (SiO2, hexane/EtOAc=100:2 to 100:5 to 100:10) gave of 3-(tert-butyldiphenylsilyloxy)propanenitrile as a white solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16].CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>ClCCl.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])[CH2:7]1
Reactant: FC(F)(F)c1ccccc1Br
Reactant: C[C@@H]1CNCCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccccc2C(F)(F)F)CCN1
Yield: 185.1 %

Procedure:
A mixture of (R)-2-methyl-piperazine (300 mg, 2.99 mmol), 2-bromo benzotrifluoride (612 mg, 2.72 mmol), tris(dibenzylidineacetone)dipalladium (0) (24.72 mg, 0.027 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (51.06 mg, 0.082 mmol) and sodium tert-butoxide (326.77 mg, 3.4 mmol) were charged to a microwave vial. Toluene (3.0 mL) was introduced under nitrogen atmosphere and the reaction mixture was irradiated at 110° C. for 30 minutes. Reaction was complete as determined by TLC. The reaction was repeated at (R)-2-methyl-piperazine (1.0 g, 9.98 mmol). Reaction mixtures were combined, diluted with dichloromethane, washed with water, saturated brine then dried over Na2SO4 and concentrated. The crude product was purified via flash column chromatography to yield (R)-3-methyl-1-(2-trifluoromethyl-phenyl)-piperazine as yellow oil (1.23 g, 39.6% yield). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.07 (d, J=6.32 Hz, 3H) 2.41-2.51 (m, 1H) 2.74-2.84 (m, 1H) 2.90-2.98 (m, 2H) 3.00-3.13 (m, 3H) 7.18-7.25 (m, 1H) 7.35 (d, J=8.08 Hz, 1H) 7.47-7.55 (m, 1H) 7.62 (d, J=7.83 Hz, 1H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[S:10]1[N:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]2[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH2:34][CH2:33][N:32](CC5C=CC=CC=5)[CH2:31][CH:30]=4)=[C:25]([F:42])[CH:24]=3)[CH2:18]2)=[N:11]1.[Cl:43]C(OC(Cl)C)=O.C(=O)([O-])N.C(Cl)C1C=CC=CC=1>ClCCl>[ClH:43].[S:10]1[N:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]2[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH:30]=4)=[C:25]([F:42])[CH:24]=3)[CH2:18]2)=[N:11]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: O=C1O[C@@H](COc2cnsn2)CN1c1ccc(C2=CCN(Cc3ccccc3)CC2)c(F)c1
Agent: NC(=O)[O-]
Solvent: ClCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Product: O=C1O[C@@H](COc2cnsn2)CN1c1ccc(C2=CCNCC2)c(F)c1
Temperature: 5 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
Diisopropylethylamine (0.39 ml, 2.24 mmol) was added dropwise to a stirred solution at 5° C. under nitrogen of 5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-(4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one (3.48 g, 7.47 mmol) in dichloromethane (60 ml), followed by 1-chloroethyl chloroforrnate (1.05 ml, 9.73 mmol). The mixture was stirred at 5° C. for 2 hours and the intermediate carbamate was freed from benzyl chloride by flash-column chromatography (silica gel. Merck 7736), eluting with a gradient of 10-30% EtOAc in isohexane. The carbamate was heated in refluxing MeOH (40 ml) for 1 hour. Solvent was evaporated and the residue triturated with ether to give 5(R)-1,2,5-thiadiazol-3-yloxymethyl-3-(3-fluoro-4-(1,2,5,6-tetrahydropyrid-4-yl)phenyl)oxazolidin-2-one hydrochloride as a solid in 82% yield MS: 376 (MH+)(free base); NMR; 2.67 (2H, s); 3.3 (2H+DMSO); 3.75 (2H, s); 4.0 (1H, m); 4.25 (1H, t); 4.7 (2H, m); 5.14 (1H, m); 6.05 (1H, s); 7.4 (2H, m): 7.55 (1H, d); 8.42 (1H, s); 9.35 (1H, bs).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:19][CH:20]=O)[C:11](=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:27][C:28](=[O:47])[N:29]([CH2:36][C:37]1[CH:46]=[CH:45][C:40]2[O:41][CH2:42][CH2:43][O:44][C:39]=2[CH:38]=1)[CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([CH3:26])([CH3:25])[CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.ClCCl>[C:23]([O:27][C:28](=[O:47])[N:29]([CH:30]1[CH2:35][CH2:34][N:33]([CH2:20][CH2:19][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][C:11]2=[O:22])[CH2:32][CH2:31]1)[CH2:36][C:37]1[CH:46]=[CH:45][C:40]2[O:41][CH2:42][CH2:43][O:44][C:39]=2[CH:38]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)cc(OCc2ccccc2)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(OCc3ccccc3)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
To 30 mL of a dichloromethane solution containing 1.20 g of (4-benzyloxy-2-oxoquinolin-1(2H)-yl)acetaldehyde, 40 mL of a dichloromethane solution containing 1.71 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 0.25 g of acetic acid were added, and stirred at room temperature for 90 min. To the reaction mixture, 1.37 g of sodium triacetoxyborohydride was added, and stirred at the same temperature for 2.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=1:1], to give 2.10 g of tert-butyl(1-(2-(4-benzyloxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([OH:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:15][C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:13](=[O:14])[CH:12]=2)=[CH:19][CH:18]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=c1cc(O)cnn1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccc(Cl)cc2)cnn1-c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 80.2 %

Procedure:
In 50 ml of N,N-dimethylformamide were dissolved 2.0 g (9.0 m mol) of 2-(4-chlorophenyl)-5-hydroxy-3(2H)-pyridazinone and 1.5 g (9.3 m mol) of p-chlorobenzyl chloride, and thereto was added 1.7 g of anhydrous potassium carbonate. The reaction mixture was heated under stirring on an oil bath at 100°-120° C. for one hour. Then, the procedure in Synthesis Example 13 were repeated to give 2.5 g of the intended compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:28]3[CH:29]=[CH:30][C:31]4[C:35]([CH:36]=3)=[N:34][N:33]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:32]=4)[CH:9]=[C:10]([CH:11]3[O:16][CH2:15][CH:14]4[CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][CH2:20][N:13]4[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1>ClCCl.FC(F)(F)C(O)=O>[CH2:37]([N:33]1[CH:32]=[C:31]2[C:35]([CH:36]=[C:28]([C:8]3[CH:9]=[C:10]([CH:11]4[O:16][CH2:15][CH:14]5[CH2:17][NH:18][CH2:19][CH2:20][N:13]5[CH2:12]4)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:29]=[CH:30]2)=[N:34]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCN2CC(c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)OCC2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnn2c(C3CN4CCNCC4CO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred solution of tert-butyl 3-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (75 mg, 0.13 mmol) in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added. The reaction was allowed to stir for 30 minutes and concentrated. The mixture was partitioned between ethyl acetate (30 mL) and pH 14 saturated aqueous NaCl (10 mL). The layers were separated and the organic phase was washed, dried (Na2SO4), and concentrated to dryness. The residue was triturated with Et2O to obtain 50 mg (80%) of the desired product. 1H-NMR (DMSO-d6) 8.53 (s, 1H), 7.90 (s, 1H), 7.78 (d, 1H), 7.57 (s, 1H), 7.35-7.28 (m, 5H), 7.11 (d, 1H), 6.70 (s, 1H), 5.64 (s, 2H), 5.11 (d, 1 H), 3.71 (dd, 1 H), 3.33-3.26 (m, 1H), 2.91 (d, 1H), 2.74-2.58 (m, 4H), 2.39 (t, 1H), 2.21-2.00 (m, 4H); LC-MS [M+H]+=481, RT=2.00 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1cccc(N)c1
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)Cc2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
A solution of 4-bromophenylacetic acid (502 mg, 2.33 mmol), m-toluidine (0.25 mL, 2.33 mmol), HOBT (350 mg, 2.59 mmol), and N-methylmorpholine (0.51 mL, 4.64 mmol) in DMF (10 mL) was treated with EDCI (496 mg, 2.59 mmol), stirred overnight at room temperature, and poured into ice water. The resulting white precipitate was collected by filtration to give 672 mg of the desired product. MS (ESI(+)) m/e 304, 306 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:31])=[C:4]([CH:26]=[CH:27][C:28]=1[C:29]#[N:30])[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([F:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[CH3:25])=[O:6].N1C=CC=CC=1.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCCC1>[C:38]([NH:1][C:2]1[C:3]([F:31])=[C:4]([CH:26]=[CH:27][C:28]=1[C:29]#[N:30])[C:5]([NH:7][C:8]1[C:9]([CH3:25])=[CH:10][C:11]([C:15]([F:24])([C:20]([F:21])([F:22])[F:23])[C:16]([F:18])([F:17])[F:19])=[CH:12][C:13]=1[CH3:14])=[O:6])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C#N)c(N)c1F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C#N)c(NC(=O)c2ccccc2)c1F
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
To a solution of 3-amino-4-cyano-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-2-fluoro-benzamide (68 mg, 0.15 mmol) (Example I12) in tetrahydrofuran (2 ml) were added pyridine (36 μl, 0.45 mmol) and benzoyl chloride (21 μl, 0.18 mmol). The reaction mixture was heated in a microwave at 140° C. for 30 minutes. The reaction mixture was allowed to cool to ambient temperature. A second portion of benzoyl chloride (21 μl, 0.18 mmol) was added and heating repeated at 140° C. for 30 minutes. The reaction mixture was allowed to cool to ambient temperature and then partitioned between sodium hydrogen carbonate (1M) and ethyl acetate. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by reverse-phase chromatography (eluent: trifluoroacetic acid/water/acetonitrile 1:4:5 to 1:1:8) to give Compound No. D15 of Table D (0.024 g, 28% yield). 1H-NMR (400 MHz, CDCl3): 2.28 (6H, s), 7.33 (2H, s), 7.45-7.96 (9H, m) ppm.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([Cl:12])=[C:10](Cl)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[CH3:14][CH:15]1[CH2:20][CH:19]([CH3:21])[CH2:18][NH:17][CH2:16]1>C(O)C>[CH2:1]([O:5][C:6]1[C:11]([Cl:12])=[C:10]([N:17]2[CH2:18][CH:19]([CH3:21])[CH2:20][CH:15]([CH3:14])[CH2:16]2)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ncnc(Cl)c1Cl
Reactant: CC1CNCC(C)C1
Solvent: CCO
Product: CC#CCOc1ncnc(N2CC(C)CC(C)C2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
Into 3 ml of ethanol was resolved 0.3 g of 4-(2-butynyloxy)-5,6-dichloropyrimidine, 0.47 g of 3,5-dimethylpiperidine (cis/trans=about 3/1) was added therein, and the mixture was stirred for 8 hours under reflux condition. The reaction mixture was cooled to near room temperature, and concentrated. Into the residue was added a saturated ammonium chloride aqueous solution, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.36 g of 4-(2-butynyloxy)-5-chloro-6-(3,5-dimethylpiperidino)pyrimidine (hereinafter, referred to as Compound (8)). Compound (8) had the cis/trans diastereomer originated two methyls on the piperidine ring. The ratio of the cis/trans diastereomer was about 3.6/1.