Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH:25]=O)=[CH:19][CH:18]=2)[S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]([C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH2:25][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:21][CH:22]=2)[S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=CCCc1ccc(N(Cc2ccc(O)cc2)S(=O)(=O)c2ccccc2)cc1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)N(Cc1ccc(O)cc1)c1ccc(CCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of N-(4-hydroxy-benzyl)-N-[4-(3-oxo-propyl)-phenyl]-benzenesulfonamide (0.093 g, 0.24 mmol) in 1.5 mL methylene chloride was added pyrrolidine (0.034 g, 0.47 mmol) and NaB(OAc)3H (0.092 g, 0.44 mmol). The reaction mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with methylene chloride. The organic layer was dried (magnesium sulfate) and concentrated. Medium pressure chromatography (10% methanol/methylene chloride) afforded 0.053 g (50%) of the title compound. MS 451.1 (M+1)+
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][NH:5][C:6]([NH:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:29])=[N:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:20])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[CH:10][N:9]=1.[CH3:31][Si](C=[N+]=[N-])(C)C>>[CH3:19][O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][C:14]=1[O:20][CH3:31])[N:11]=[CH:10][N:9]=[C:8]2[NH:7][C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:30])=[N:21][C:22]1[C:23]([CH3:29])=[CH:24][CH:25]=[CH:26][C:27]=1[CH3:28]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1cc2c(N=C(NCCN(C)C)Nc3c(C)cccc3C)ncnc2cc1O
Product: COc1cc2ncnc(NC(=Nc3c(C)cccc3C)NCCN(C)C)c2cc1OC
Yield: 63 %

Procedure:
Using an analogous procedure to that described in Example 11, N-(2-dimethylaminoethyl)-N′-(2,6-dimethylphenyl)-N″-(7-hydroxy-6-methoxyquinazolin-4-yl)guanidine was reacted with trimethylsilyldiazomethane to give the title compound in 63% yield; NMR Spectrum: (DMSOd6, 100° C.) 2.21 (s, 6H), 2.24 (s, 6H), 2.54 (t, 2H), 3.57 (q, 2H), 3.75 (s, 3H), 3.9 (s, 3H), 7.08 (s, 1H), 7.17 (s, 3H), 7.58 (s, 1H), 8.43 (s, 1H), 10.8 (br s, 1H); Mass Spectrum: M+H+ 423.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)=[O:6].[K].CC(C)([O-])C>CN(C)C=O>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])=[CH:10][CH:11]=1)#[N:16]
Reactant: N#Cc1ccc(CNC(=O)NCCCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN2CCNC2=O)cc1

Procedure:
To a solution of 20.0 g (84.1 mMol) of 1-(2-chloroethyl)-3-[(4-cyanophenyl)methyl]-urea in 200 ml of anhydrous dimethylformamide were added, in batches and at ambient temperature, 11.2 g (99.8 mMol) of potassium-tert.butoxide and the mixture was then stirred for 2 hours at +40° C. The reaction mixture was evaporated down in vacuo, the residue remaining was distributed between water and ethyl acetate, the organic phase was dried over sodium sulphate, clarified over activated charcoal and evaporated down in vacuo once more. The residue was triturated with tert.butyl-methylether, suction filtered and dried in a vacuum dryer. 3.0 g (18% of theory) of colourless crystals were obtained, Mp. 117-118° C.
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[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[CH2:40]([N:47]1[CH2:50][C:49]([C:54]([OH:56])=[O:55])([C:51]([OH:53])=[O:52])[CH2:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:40]([N:47]1[CH2:48][C:49]([C:51]([OH:53])=[O:52])([C:54]([OH:56])=[O:55])[CH2:50]1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1.[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[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:54]([C:49]2([C:51]([NH:28][C:27]3[CH:29]=[CH:30][C:24]([F:23])=[CH:25][CH:26]=3)=[O:52])[CH2:50][N:47]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:48]2)=[O:55])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Nc1ccc(F)cc1
Agent: O=C(O)C1(C(=O)O)CN(Cc2ccccc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CN(Cc5ccccc5)C4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 23.5 %

Procedure:
1-Benzyl-azetidine-3,3-dicarboxylic acid was prepared by following the literature procedure (Miller, R. A.; et al. Syn. Comm. 2003, 33, 3347). To a solution of 4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylamine (4.2 mmol, 1 equiv.) and 4-fluoroaniline (4.2 mmol, 1 equiv.) in DMF (20 mL) was charged with DIEA (12.6 mmol, 3 equiv) and a solution of 1-benzyl-azetidine-3,3-dicarboxylic acid (4.2 mmol, 1 equiv.) in DMF (10 mL). The reaction mixture was allowed to stir at RT and monitored by LCMS. The reaction was complete in 6 h. The reaction mixture was diluted with ethyl acetate and washed with 10% LiCl (3×), brine (3×), dried with sodium sulfate, filtered and the solvent was reduced in vacuo. The crude product was purified by silica gel chromatography eluting with 2% of MeOH in EtOAc. The fractions containing the desired product were further purified using preparative HPLC to give ′N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)-1-(phenylmethyl)azetidine-3,3-dicarboxamide (300 mg, 12% yield) as a white solid. 1HNMR (DMSO-d6): 10.0 (s, 1H), 9.90 (s, 1H), 8.45 (d, 1H), 7.80 (d, 2H), 7.70 (m, 2H), 7.50 (s, 1H), 7.40 (s, 1H), 7.48-7.15 (m, 9H), 3.95 (s, 6H), 3.70 (s, 4H), 3.60 (s, 2H). LCMS (POS): 607.2 (M+H).
Reaction SMILES: [Na].[OH:2][C:3]([CH:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])=[CH:4][N+:5]([O-:7])=[O:6].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].O>C1COCC1>[CH2:29]([O:28][C:26]([CH2:25][O:2][C:3]([CH:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])=[CH:4][N+:5]([O-:7])=[O:6])=[O:27])[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: COc1ccccc1OC(C(O)=C[N+](=O)[O-])c1ccccc1
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)COC(=C[N+](=O)[O-])C(Oc1ccccc1OC)c1ccccc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
To 3.23 g of 2-hydroxy-3-phenyl-3-(2-methoxy-phenoxy)-1-nitropropene sodium salt dissolved in 50 ml of anhydrous THF there was added at 0° C. 16.7 g of ethyl bromoacetate. After 2 hours at 0° C. the mixture was stirred at room temperature for 48 hours. The mixture was poured into water and extracted with ethyl acetate. The organic extracts were washed with water, dried over Na2SO4 and concentrated to dryness. The residue was separated by column chromatography on silica gel (mobile phase:ethyl acetate/cyclohexane 1/1), to obtain 2.70 g of 2-ethoxycarbonylmethyloxy-3-phenyl-3-(2-methoxy-phenoxy)-1-nitropropene (oil). Yield 70%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[CH2:29][O:28][CH2:27][CH2:26][C:11]=3[N:12]([C:14](N[C@@H](C(C)(C)C)C(NC)=O)=[O:15])[N:13]=2)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:30][C:31]1[S:32][CH:33]=[C:34]([C:36]([CH3:39])([CH3:38])[CH3:37])[N:35]=1>>[C:36]([C:34]1[N:35]=[C:31]([NH:30][C:14]([N:12]2[C:11]3[CH2:26][CH2:27][O:28][CH2:29][C:10]=3[C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)=[N:13]2)=[O:15])[S:32][CH:33]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)c1csc(N)n1
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(C)(C)C
Product: CC(C)(C)c1csc(NC(=O)n2nc(-c3ccc(F)c(F)c3)c3c2CCOC3)n1

Procedure:
Compound 56 was prepared according to the procedure described for the synthesis of compound 28 by replacing tert-leucine methylamide with 2-amino-4-tert-butylthiazole. LCMS (+ESI) m/z=419.2 [M+H]+.
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][CH:7]([C:20]([CH3:22])=[CH2:21])[CH2:8][CH2:9]/[C:10](/[CH3:19])=[CH:11]/[CH2:12][CH2:13][C:14]([CH3:18])=[CH:15][CH2:16][OH:17])([CH3:4])([CH3:3])[CH3:2]>ClCCl.[O-2].[O-2].[Mn+4]>[C:1]([Si:5]([CH3:23])([CH3:24])[O:6][CH:7]([C:20]([CH3:22])=[CH2:21])[CH2:8][CH2:9]/[C:10](/[CH3:19])=[CH:11]/[CH2:12][CH2:13][C:14]([CH3:18])=[CH:15][CH:16]=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)C(CC/C(C)=C/CCC(C)=CCO)O[Si](C)(C)C(C)(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: C=C(C)C(CC/C(C)=C/CCC(C)=CC=O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10.58 g of (6E)-10-(tert.-butyldimethylsiloxy)-3,7,11-trimethyl-2,6,11-dodecatrien-1-ol are added dropwise at 0° to a suspension of 110 g of manganese dioxide (precipitated, active) in 220 ml of dichloromethane and the mixture is stirred at room temperature for 2 hours. After filtration over Hyflo the filtrate is concentrated and oily residue is chromatographed on silica gel with hexane-ethyl acetate-triethylamine 90:10:0.1. There is obtained (6E)-10-(tert.-butyldimethylsiloxy)-3,7,11-trimethyl-2,6,11-dodecatrienal as a yellowish oil. NMR (80 MHz, CDCl3): 10.1 (d, J=8, H-C(1)); 6.0 (d, J=8, H-C(2)); 5.2 (m, H-C(6)); 5.0-4.8 (m, 2H-C(12)); 4.1 (t, J=6.5, H-C(10)); 2.4-1.4 (m, 4CH2, 3CH3); 0.95 (s, SiC(CH3)3); 0.1 and 0.05 (2s, Si(CH3)2).
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][C@H:7]([C:15]([OH:17])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:5])[CH3:4].Cl.[CH3:19][O:20][C:21](=[O:31])[CH:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH2:23]>>[C:3]([NH:6][C@H:7]([C:15]([OH:17])=[O:16])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:5])[CH3:4].[CH3:19][O:20][C:21](=[O:31])[C@@H:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH2:23]
Reactant: COC(=O)C(N)Cc1ccccc1
Agent: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Product: COC(=O)[C@H](N)Cc1ccccc1

Procedure:
To 310 parts by volume of an aqueous 0.5N sodium hydroxide solution, heated to about 70°, is added, successively, 17.7 parts of N-acetyl-L-phenylalanine and 33.3 parts of DL-phenylalanine methyl ester hydrochloride. A precipitate forms and upon cooling and filtering, the salt of N-acetyl-L-phenylalanine and D-phenylalanine methyl ester is obtained. Recrystallization from hot water affords the pure salt exhibiting an [α]D in 0.5% water of about +32.2°.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:14])[C:6]([CH3:13])=[C:7]([OH:12])[CH:8]=2)[O:3]1.C1N2CN3CN(C2)CN1C3.[C:26](O)(C(F)(F)F)=[O:27]>C(O)(=O)C>[OH:12][C:7]1[C:6]([CH3:13])=[C:5]([CH3:14])[C:4]2[O:3][C:2]([CH3:15])([CH3:1])[CH2:11][CH2:10][C:9]=2[C:8]=1[CH:26]=[O:27]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1c(O)cc2c(c1C)OC(C)(C)CC2
Agent: C1N2CN3CN1CN(C2)C3
Solvent: CC(=O)O
Product: Cc1c(C)c2c(c(C=O)c1O)CCC(C)(C)O2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2,2,7,8-Tetramethylchroman-6-ol (2.0 g, 9.7 mmol) and hexamethylene tetramine (680 mg, 4.05 mmol) were weighed into a 20-mL scintillation vial, after which TFA (640 μL) and acetic acid (6.4 mL) were added. The vial was sealed, and the resulting mixture heated to 100° C. for 90 min, during which time a deep red color developed. The mixture was then concentrated to a red oil at 55° C. in vacuo. The darkly-colored residue was stirred in a biphasic mixture of 50 mL ethylacetate (EtOAc) and 50 mL 1 M aqueous sodium bicarbonate for 1 hr. At this time, the organic layer was removed, and successively washed with 1 M aqueous sodium bicarbonate (2×50 mL), 1 M aqueous citric acid (2×50 mL), and brine (50 mL). The residual organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to 2.1 g yellow oil. Crude purification was accomplished by silica gel chromatography (gradient elution 0→10% EtOAc/Heptane) to obtain 1.0 g 6-hydroxy-2,2,7,8-tetramethylchroman-5-carbaldehyde product, which was immediately dissolved in DMF (88 mL) and treated with MOMCl (670 μL, 8.8 mmol) and Di-isopropyl ethyl amine (DiPEA) (2.2 mL, 13.2 mmol). The reaction mixture was heated to 50° C. for 2 hr and then subsequently diluted in EtOAc (75 mL). The organics were washed successively with 1 M aqueous sodium bicarbonate, 1 M aqueous citric acid, and brine (25 mL each), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (gradient elution 0→15% EtOAc/Heptane) afforded the 6-(methoxymethoxy)-2,2,7,8-tetramethylchroman-5-carbaldehyde (920 mg) as a colorless oil. 1H NMR (CDCl3, 400 MHz) 10.4 (s, 1H), 4.93 (s, 2H), 3.56 (s, 3H), 3.06 (t, 2H), 2.18 (s, 3H), 2.13 (s, 3H), 1.72 (t, 2H), 1.28 (s, 6H) ppm.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.Br[C:7]1[CH:8]=[C:9]2[C:15]3([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH2:14][N:13]([C:28]3[C:29]4[C@H:36]([CH3:37])[CH2:35][CH2:34][C:30]=4[N:31]=[CH:32][N:33]=3)[C:10]2=[CH:11][CH:12]=1>C1COCC1.CCOC(C)=O.[Zn+2].[Br-].[Br-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([C:7]2[CH:8]=[C:9]3[C:15]4([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17][CH2:16]4)[CH2:14][N:13]([C:28]4[C:29]5[C@H:36]([CH3:37])[CH2:35][CH2:34][C:30]=5[N:31]=[CH:32][N:33]=4)[C:10]3=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Br)ccc43)c21
Reactant: Br[Mg]C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(C5CC5)ccc43)c21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
To a stirred suspension of ZnBr2 (41 mg, 0.18 mmol) in THF (0.5 mL) was added dropwise a 0.5 M solution of cyclopropylmagnesium bromide in THF (0.36 mL, 0.18 mmol) at about −78° C. under nitrogen. After being stirred at about −78° C. for about 30 min, the resulting solution was allowed to warm to about 0° C. A solution of (R)-tert-butyl 5-bromo-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (38 mg, 0.076 mmol) and Pd(PPh3)4 (4.4 mg, 0.0038 mmol) in THF (0.3 mL) was added. The resulting mixture was heated to about 60° C. overnight. After cooling, the mixture was diluted with EtOAc, washed with water and brine, dried and concentrated. The residue was purified by reverse phase preparative HPLC to give (R)-tert-butyl 5-cyclopropyl-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (20 mg, 57%). LCMS (APCI+) m/z 461 [M+H]+; Rt=3.24 min.
Reaction SMILES: [C:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]([C:10]([F:12])([F:13])[F:11])[N:8]([CH2:21][C:22]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:28][CH2:29]2)=[O:23])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: CC(C)(C)c1cc(C(F)(F)F)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(C(F)(F)F)n(CC(=O)N2CCN(c3ccc(F)cc3)CC2)n1

Procedure:
Protocol T was followed using 5-tert-Butyl-3-trifluoromethyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3); 6.92–7.08 (t, 2H), 6.82–6.88 (dd, 2H), 6.52 (s, 1H), 5.08 (s, 2H), 3.70–3.80 (m, 2H), 3.58–3.68 (m, 2H), 3.05–3.15 (m, 4H), 1.3 (s, 9H). 13C NMR (400 MHz, CDCl3): 164, 161.2, 158.2, 156.4, 147.2, 118.4, 118.2, 115.8, 115.4, 108.2, 54, 50.6, 50.2, 45, 44, 30.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([NH:26][C:27]3C=C(O)[C:30]([Cl:34])=[CH:29][C:28]=3[F:35])=[CH:21][N:22]=[N:23]2)=[CH:18][C:17]=1[O:36][CH3:37])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:5]([O:4][C:1]1[C:30]([Cl:34])=[CH:29][C:28]([F:35])=[C:27]([CH:2]=1)[NH:26][C:20]1[C:19]2[C:24](=[CH:25][C:16]([O:15][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[C:17]([O:36][CH3:37])[CH:18]=2)[N:23]=[N:22][CH:21]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(Nc3cc(O)c(Cl)cc3F)cnnc2cc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1cc2c(Nc3cc(OC(C)=O)c(Cl)cc3F)cnnc2cc1OCc1ccccc1
Temperature: 110 °C

Procedure:
Acetic anhydride (920 μl, 9.7 mmol) and 4-dimethylaminopyridine (80 mg, 0.65 mmol) were added to a suspension of 7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxycinnoline (3 g, 6.5 mmol), (prepared as described in Example 6), in pyridine (50 ml). After heating at 110° C. for 25 minutes, the solid was filtered off, washed with water and ether and dried under vacuum. The solid was suspended in 2M ethereal hydrogen chloride and the volatiles removed by evaporation to give 4-(5-acetoxy-4-chloro-2-fluoroanilino)-7-benzyloxy-6-methoxycinnoline as the hydrochloride salt (yellow solid, 3.1 g, 94%).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][N:6]1[C:11](=[O:12])[N:10]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[C:9](=[O:21])[C:8]([CH3:22])=[N:7]1.Cl>O1CCCC1>[CH3:22][C:8]1[C:9](=[O:21])[N:10]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[C:11](=[O:12])[N:6]([CH2:5][CH2:4][CH:3]=[O:2])[N:7]=1
Reactant: COC(CCn1nc(C)c(=O)n(C(=O)c2ccccc2)c1=O)OC
Agent: Cl
Solvent: C1CCOC1
Product: Cc1nn(CCC=O)c(=O)n(C(=O)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2-[3,3-bis(methyloxy)propyl]-6-methyl-4-(phenylcarbonyl)-1,2,4-triazine-3,5(2H,4H)-dione (P3, 92 mg, 0.276 mmol) in Tetrahydrofuran (THF) (2.3 mL), 1N hydrochloric acid aqueous solution (0.690 mL, 0.690 mmol) was added and the mixture was stirred at rt for 2.5 hours. The reaction was then quenched with water and extracted with AcOEt. Organic phase was washed with water and NaHCO3 saturated solution, dried over Na2SO4 and evaporated under reduced pressure affording 3-[6-methyl-3,5-dioxo-4-(phenylcarbonyl)-4,5-dihydro-1,2,4-triazin-2(3H)-yl]propanal as a crude product that was used for next step without purification.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[Br:13][CH2:14][C@H:15]1[C:24]2[C:19](=[C:20]([O:26][CH3:27])[C:21]([CH3:25])=[CH:22][CH:23]=2)[CH2:18][C@@H:17]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[O:16]1>CN1C(=O)CCC1>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:31]2[CH2:32][CH2:33][CH:28]([C@@H:17]3[CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=4[O:26][CH3:27])[C@H:15]([CH2:14][Br:13])[O:16]3)[CH2:29][CH2:30]2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COc1c(C)ccc2c1C[C@@H](C1CCNCC1)O[C@H]2CBr
Solvent: CN1CCCC1=O
Product: COc1c(C)ccc2c1C[C@@H](C1CCN(Cc3ccc(C(F)(F)F)cc3)CC1)O[C@H]2CBr
Reaction time: 4 h

Procedure:
Add 4-trifluoromethylbenzyl bromide (7.2 g) and NMP (20 mL) to REM bound (1R,3S)-4-(1-bromomethyl-5-methoxy-6-methyl-isochroman-3-yl)-piperidine (2.0 g 0.78 mmol/g of loading) in a 50 mL shaking vessel. Shake the reaction mixture at room temperature overnight, filter and wash three times each with NMP, dichloromethane, methanol, and dichloromethane. To this resin add of dichloromethane (18.6 mL) and of DIEA (1.4 mL). Shake the resulting mixture at room temperature overnight, filter and wash the resin twice each with dichloromethane, methanol, and dichloromethane. Combine the filtrates concentrate and add Amberlite IRA-67 (2.0 g) with of dichloromethane (20 mL). Shake the resulting mixture at room temperature for 4 hours, filter and wash twice each with dichloromethane, methanol, and dichloromethane. Combine the filtrates and concentrate to yield the title compound. CIMS 512.1 (MH+), tR (min)=3.52.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[NH:7][N:6]=[C:5]([NH2:8])[CH:4]=1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([Cl:19])=[CH:14][N:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO>[Cl:11][C:12]1[N:17]=[C:16]([NH:8][C:5]2[CH:4]=[C:3]([C:2]([F:10])([F:9])[F:1])[NH:7][N:6]=2)[C:15]([Cl:19])=[CH:14][N:13]=1
Reactant: Nc1cc(C(F)(F)F)[nH]n1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: FC(F)(F)c1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 5-(trifluoromethyl)-1H-pyrazol-3-amine (500 mg, 3.3 mmol), 2,4,5-trichloropyrimidine (607 mg, 3.3 mmol) and sodium carbonate (525 mg, 5 mmol) in anhydrous EtOH (10 mL) was stirred at rt. After one day, LCMS showed the reaction was not complete. Additional 2,4,5-trichloropyrimidine (0.15 mL) and sodium carbonate (525 mg) were added and the reaction continued for two more days. The solvent was evaporated, and the residue was extracted with DCM (3×20 mL). The combined DCM layers were washed with brine (10 mL), dried over Na2SO4 and evaporated. The crude product was purified by silica chromatography (0-50% EtOAc in hexanes gradient) to give 2,5-Dichloro-N-(5-(trifluoromethyl)-1H-pyrazol-3-yl)pyrimidin-4-amine as a light tan colored solid; ESMS m/z 297.9 (MAI).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:22][CH2:21][C:9]3([CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]3)[CH2:8]2)=[CH:3][CH:2]=1.[ClH:23].CO>>[ClH:23].[ClH:23].[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:22][CH2:21][C:9]3([CH2:10][CH2:11][NH:12][CH2:13]3)[CH2:8]2)=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccncc3)C2)C1
Agent: Cl
Solvent: CO
Product: c1cc(N2CCC3(CCNC3)C2)ccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 7-(pyridin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (2.208 mmol, 1 eq) was heated at the boiling temperature with hydrogen chloride in methanol (1.25 M, 6 eq) for 30 min. The methanol was concentrated in vacuo, the residue was dissolved in analytical grade ethanol (5 ml), and analytical grade acetone (25 ml) was added. The mixture was stirred at 0° C. for 30 min and a pale precipitate precipitated out. This was filtered out, washed with diethyl ether and dried under a high vacuum to obtain the desired product. Yield: 0.55 g (90%)
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[F:10][C:11]([F:21])([F:20])[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br.C([O-])([O-])=O.[Na+].[Na+]>>[OH:1][C@H:2]1[CH2:6][N:5]([CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([C:11]([F:21])([F:20])[F:10])[CH:13]=2)[C@@H:4]([C:7]([O:9][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([C:11]([F:10])([F:20])[F:21])[CH:13]=2)=[O:8])[CH2:3]1
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(OCc1cccc(C(F)(F)F)c1)[C@H]1C[C@@H](O)CN1Cc1cccc(C(F)(F)F)c1

Procedure:
The title compound (D8) (1.02 g) was prepared according to the general procedure for substituted benzyl amines preparation starting from cis-4-Hydroxy-D-proline (4.0 g; available from Aldrich#H5877) and 3-(Trifluoromethyl)benzyl bromide (9.37 ml). (Na2CO3: 2.5 eq; Reaction time: 24 hrs; 60° C.).