Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN(CC)CC>C(Cl)(Cl)Cl>[CH2:22]([N:21]([CH:18]([C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=1)[CH2:19][CH3:20])[C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCC(NCc1ccccc1)c1nn2cccc2c(=O)n1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(c1nn2cccc2c(=O)n1Cc1ccccc1)N(Cc1ccccc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.5 %

Procedure:
3-Benzyl-2-(1-benzylamino-propyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 42, 23.1 mg, 0.062 mmol) in CHCl3 (5 mL) was treated with benzoylchloride (28.8 μL, 0.248 mmol) and Et3N (23.0 μL, 0.166 mmol), then stirred for 18 h at 25° C. The mixture was concentrated under vacuum and purified by preparative HPLC using a YMC S10 ODS 20×100 mm column affording the desired compound (22 mg, 83%) as a colorless film: LC/MS 87% at 3.72 min (ESI+) 477 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[C:14]1[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N:18]=1.[CH3:21][I:22]>[N+](C)([O-])=O.COC(C)(C)C>[I-:22].[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([C:10]([F:11])([F:12])[F:13])[CH:6]=[CH:5][C:4]=1[C:14]1[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N+:18]=1[CH3:21]
Reactant: COc1c(C2=NC(C)(C)CO2)ccc(C(F)(F)F)c1C
Reactant: CI
Solvent: COC(C)(C)C
Solvent: C[N+](=O)[O-]
Product: COc1c(C2=[N+](C)C(C)(C)CO2)ccc(C(F)(F)F)c1C
Product: [I-]
Temperature: 60 °C

Procedure:
To a solution of 447 mg (1.6 mmol) 2-(2-methoxy-3-methyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole in 4 ml nitromethane was added 0.78 ml (12 mmol) methyl iodide and the mixture heated in a sealed tube to 60° C. for 18 h. The brown solution was diluted with tert-butyl methyl ether, the suspension filtered and the precipitate washed with tert-butyl methyl ether and dried. 2-(2-Methoxy-3-methyl-4-trifluoromethyl-phenyl)-3,4,4-trimethyl-4,5-dihydro-oxazol-3-ium iodide was obtained as off-white powder: MS (ISP): 302.1 (M+).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:19]1[CH:20]=[C:21]([CH:24]=[O:25])[O:22][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:19]2[CH:20]=[C:21]([CH:24]=[O:25])[O:22][CH:23]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=Cc1cc(Br)co1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=Cc1cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)co1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
A solution of 3,5-bis(trifluoromethyl)phenylboronic acid (8.84 g), 4-bromo-2-furaldehyde (5.0 g), 2M aqueous sodium carbonate solution (71.4 mL), tetrakis(triphenylphosphine)palladium(0) (1.65 g) in 1,2-dimethoxyethane (300 ml) was stirred under an argon gas atmosphere at 90° C. for 16 hr. After cooling to room temperature, the reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate 98:2-90:10) to give the title compound (7.26 g, yield 82%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.C(OC([NH:36][C@@H:37]([CH:41]([CH3:43])[CH3:42])[C:38](O)=[O:39])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCOCC>C(Cl)Cl.CO>[NH2:36][C@@H:37]([CH:41]([CH3:43])[CH3:42])[C:38]([NH:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1)=[O:39]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: CC(C)[C@H](N)C(=O)NCc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](C)c1ccc(F)cc1
Reaction time: 3 h
Yield: 26.2 %

Procedure:
A solution of (S)-3-(aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3; 0.10 g, 0.26 mmol), (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (0.06 g, 0.26 mmol), and HBTU (0.10 g, 0.26 mmol) in DCM (3 ml) was stirred at room temperature for 1 hour. The reaction was then quenched with a saturated aqueous solution of NaHCO3, and extracted with DCM (2×50 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was then passed through a silica plug. The resulting foam was placed in dioxane (4 ml) and 4 M HCl in dioxane (1 ml) was then added, and the reaction was stirred for 3 hours. The reaction was then concentrated to give a solid which was dissolved in a minimal amount of MeOH (0.5 ml) with stirring, followed by fast addition of ether (50 ml). The resulting solid was filtered, washed with ether, and dried to give the title compound (0.033 g, 26%). 1H NMR (400 MHz, CD3OD) δ 7.58 (d, J=10.7 Hz, 1H), 7.49-7.46 (m, 2H), 7.07-7.02 (m, 2H), 5.80 (s, 1H), 5.09-5.04 (m, 1H), 4.58 (dd, J=15.4, 6.8 Hz, 1H), 4.26 (dd, J=15.4, 5.2 Hz, 1H), 3.71 (d, J=6.0 Hz, 1H), 2.23-2.18 (m, 1H), 2.01-1.97 (m, 1H), 1.63 (d, J=6.8 Hz, 3H), 1.19-1.13 (m, 2H), 1.05-1.03 (m, 6H), 0.85-0.81 (m, 2H). MS: Calcd.: 483. Found: [M+H]+ 484.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]#N)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([OH:30])(C)(C)C.CC(C)([O-])C.[K+].[OH2:37]>>[CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]([OH:30])=[O:37])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)O
Reactant: O
Reactant: N#Cc1nc(NCc2ccccc2)c2c(-c3ccccc3)ccn2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(O)c1nc(NCc2ccccc2)c2c(-c3ccccc3)ccn2n1
Temperature: 95 °C
Yield: 28.3 %

Procedure:
To a stirred solution of 4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazine-2-carbonitrile (0.100 g, 0.307 mmol) dissolved in tert-butanol (15.0 mL, 157 mmol) and water (15 mL) was added potassium tert-butoxide (0.138 g, 1.23 mmol). The reaction mixture was heated in a pressure tube to 95° C. for 16 h and concentrated under reduced pressure. To the resulting residue, was added water (100 mL) and the aqueous solution was neutralized with dilute HCl to pH 7. The solid precipitated, was filtered and further purified by preparative HPLC (Condition B-74 as described in general methods) to afford 4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazine-2-carboxylic acid (30.0 mg, 28.3%). LCMS Condition B-15: retention time 1.66 min, [M+1]=345.2. HPLC Condition B-1: retention time 14.64 min, Purity 99.30%. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.71 (s, 2H), 6.29 (br s, 1H), 6.77 (d, J=2.8 Hz, 1H), 7.24-7.48 (m, 10H), 7.77 (d, J=2.8 Hz, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:19])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2].[CH2:24](N(CC)CC)[CH3:25]>CN(C=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:19])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:24][CH3:25])[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCNCC3)cc21
Solvent: CN(C)C=O
Product: CCN1CCN(c2cc3c(cc2Cl)c(=O)c(C(=O)O)cn3CC)CC1
Yield: 22 %

Procedure:
A mixture of 1-ethyl-6-chloro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1.7 g (0.005 mole), iodoethyl 1.6 g (0.01 mole), triethylamine 1.0 g (0.01 mole) and dimethylformamide (hereinafter DMF) 20 ml was heated at 90°-100° C. for 7 hours under stirring. After cooling, the reaction mixture was evaporated under vacuum. The residue was dissolved in CHCl3, washed with water, dried with anhydrous Na2SO4, and the solvent was distilled off. The residue was recrystallized from a mixed solvent of DMF and ethanol to obtain 0.4 g (22%) of 1-ethyl-6-chloro-7-(4-ethyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. Colorless needles.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[C:14]3[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CCCCCC.[C:35](OCC)(=[O:37])[CH3:36]>C(Cl)(Cl)Cl>[C:35]([C:18]1[C:13]2[O:12][CH2:11][C@@H:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[CH3:19])(=[O:37])[CH3:36]
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)[C@H](c1ccc(C(C)C)cc1)CO2
Reactant: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CC(=O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OC[C@H]2c1ccc(C(C)C)cc1
Yield: 46 %

Procedure:
Using N-((3S)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 71, the title compound was synthesized in the same manner as in Example 38. Yield: 46%. Melting point: 177-178° C. (hexane-ethyl acetate). [α]D20=−6.0° (c=0.510, chloroform).
Reaction SMILES: [OH-].[CH2:2]([N+:9](C)(C)C)[C:3]1C=CC=C[CH:4]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:18]([NH:20][CH2:21][C:22]1[NH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)=[O:19].C(#N)C=C>C(Cl)Cl>[C:2]([CH2:3][CH2:4][N:23]1[C:24]([CH3:27])=[CH:25][CH:26]=[C:22]1[CH2:21][NH:20][C:18](=[O:19])[C:17]1[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:15]([O:14][CH3:13])[CH:16]=1)#[N:9]
Reactant: COc1ccc(C(=O)NCc2ccc(C)[nH]2)cc1OC
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: ClCCl
Solvent: C=CC#N
Product: COc1ccc(C(=O)NCc2ccc(C)n2CCC#N)cc1OC
Reaction time: 0.5 h

Procedure:
3 ml of benzyltrimethyl-ammonium hydroxide (40% strength solution in methanol) are added dropwise to 5.1 g (0.019 mol) of 2-(3,4-dimethoxybenzoylamino-methyl)-5-methyl-pyrrole (compare Example 16) and 15 ml (0.23 mol) of acrylonitrile, while cooling. After 30 minutes, methylene chloride is added, the mixture is filtered, water is added, and the methylene chloride phase is separated off and concentrated. Recrystallisation from ethyl acetate gives 4.3 g of product of melting point: 175° to 176° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[C:10](=[O:29])[C:11]3[N:12]=[CH:13][N:14]([C:17]4[CH:18]=[C:19]([S:23][CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH:20]=[CH:21][CH:22]=4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.C(O)(=O)C.[OH2:41].[OH2:42].O.O.O.O.C1(=O)OOOOC(=O)C2=CC=CC=C12.[Mg]>CO.ClCCl>[C:26]([O:25][CH2:24][S:23]([C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([N:14]2[CH:13]=[N:12][C:11]3[C:10](=[O:29])[N:9]([C:30]4[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=4)[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=4)=[N:16][C:15]2=3)[CH:18]=1)(=[O:42])=[O:41])(=[O:28])[CH3:27]
Reactant: CC(=O)OCSc1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(Br)cc4)nc32)c1
Reactant: O
Agent: O=c1ooooc(=O)c2ccccc12
Agent: [Mg]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)OCS(=O)(=O)c1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(Br)cc4)nc32)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of acetic acid (3-(2-(4-bromophenyl)-1-(4-chlorophenyl)-6-oxo-1H-purin-9(6H)-yl)phenylthio)methyl acetate (3, 2.1 g, 3.6 mmol) in methanol (12 mL), dichloromethane (36 mL), magnesium monoperoxy phthalate hexahydrate (1.9 g, 3.97 mmol) is added at 0° C. The resulting solution is stirred at rt for 12 h. The reaction is quenched with the addition of saturated solution of sodium bicarbonate, and extracted with dichloromethane. The organic layer is dried over Na2SO4, concentrated. The crude product is purified by column chromatography to afford (3-(2-(4-bromophenyl)-1-(4-chlorophenyl)-6-oxo-1H-purin-9(6H)-yl)phenylsulfonyl)methyl acetate (4).
Reaction SMILES: [C:1]1([CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:18]=[N:19][NH:20][CH:21]=3)[CH:12]=2)[C:9]#[N:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N.O.[H][H]>C(O)C.[Ni]>[C:1]1([CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:18]=[N:19][NH:20][CH:21]=3)[CH:12]=2)[CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: N#CC(Cc1ccccc1)c1cccc(-c2cn[nH]c2)c1
Agent: [Ni]
Agent: N
Solvent: O
Solvent: CCO
Product: NCC(Cc1ccccc1)c1cccc(-c2cn[nH]c2)c1

Procedure:
To a solution of the product of Example 2 (70 mg, 0.256 mmol, 1.0 equiv) in ethanol (25 ml) was added concentrated ammonia (0.5 ml) and Raney Nickel (approximately 0.5 ml of the water suspension) and the reaction mixture was subjected to a hydrogen atmosphere for 17 hours. The mixture was filtered through Celite® and the mother liquor was concentrated under reduced pressure to give the title compound which was purified by preparative liquid chromatography. (LC/MS: (PS-A) Rt 1.89 [M+H]+ 278.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:11]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:28][CH:27]=2)[CH:10]([CH2:44][OH:45])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:46](Br)[CH:47]=[CH2:48]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:11]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:30][CH:31]=2)[CH:10]([CH2:44][O:45][CH2:48][CH:47]=[CH2:46])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Product: C=CCOCC1CN(C(=O)OC(C)(C)C)CC(OCc2ccc3ccccc3c2)C1c1ccc(OCCCOCc2ccccc2)cc1

Procedure:
In an analogous manner to that described in Example 13 (g), by alkylating (3SR,4RS,5RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-hydroxymethyl-5-(naphthalen-2ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester [WO 9709311, Example 148 (h)] with allylbromide there was obtained (3SR,4RS,5RS)-3-allyloxymethyl-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as a colorless solid; MS: 652 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([O:19][C@H:20]3[CH2:24][N:23]([C:25](=[O:35])[C@@H:26]([NH:31][C:32](=[O:34])O)[C:27]([CH3:30])([CH3:29])[CH3:28])[C@H:22]([C:36]([O:38][CH3:39])=[O:37])[CH2:21]3)=[CH:9][C:10]([N:14]3[CH:18]=[CH:17][CH:16]=[N:15]3)=[N:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:47]([N:51]=C=O)([CH3:50])([CH3:49])[CH3:48]>ClCCl>[CH3:39][O:38][C:36]([C@@H:22]1[CH2:21][C@@H:20]([O:19][C:8]2[C:7]3[C:12](=[CH:13][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[N:11]=[C:10]([N:14]3[CH:18]=[CH:17][CH:16]=[N:15]3)[CH:9]=2)[CH2:24][N:23]1[C:25](=[O:35])[C@@H:26]([NH:31][C:32]([NH:51][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:34])[C:27]([CH3:28])([CH3:29])[CH3:30])=[O:37]
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2cc(-n3cccn3)nc3cc(OC)ccc23)CN1C(=O)[C@@H](NC(=O)O)C(C)(C)C
Reactant: CC(C)(C)N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](Oc2cc(-n3cccn3)nc3cc(OC)ccc23)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-1-((2S,4R)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)-2-(methoxycarbonyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamic acid hydrochloride (0.165 mmol) in dichloromethane (3.0 mL) was added triethylamine (0.06 mL, 0.413 mmol) and tert-butylisocyanate (0.02 mL, 0.165 mmol) and the reaction mixture was stirred at room temperature. After 16 hours, the reaction mixture was diluted with dichloromethane and washed with 1N HCl, saturated sodium bicarbonate, and brine. The dichloromethane layer was then evaporated to dryness to give (2S,4R)-methyl-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)-pyrrolidine-2-carboxylate.
Reaction SMILES: [CH3:1][CH:2]([NH:32][CH3:33])[CH:3]1[O:8][CH:7]([O:9][CH:10]2[CH:15]([OH:16])[CH:14]([O:17][CH:18]3[O:23][CH2:22][C:21]([OH:25])([CH3:24])[CH:20]([NH:26][CH3:27])[CH:19]3[OH:28])[CH:13]([NH2:29])[CH2:12][CH:11]2[NH2:30])[CH:6]([NH2:31])[CH2:5][CH2:4]1.O.[S:35](=[O:39])(=[O:38])([OH:37])[OH:36]>CO>[CH3:1][CH:2]([NH:32][CH3:33])[CH:3]1[O:8][CH:7]([O:9][CH:10]2[CH:15]([OH:16])[CH:14]([O:17][CH:18]3[O:23][CH2:22][C:21]([OH:25])([CH3:24])[CH:20]([NH:26][CH3:27])[CH:19]3[OH:28])[CH:13]([NH2:29])[CH2:12][CH:11]2[NH2:30])[CH:6]([NH2:31])[CH2:5][CH2:4]1.[S:35]([O-:39])([O-:38])(=[O:37])=[O:36]
Reactant: O=S(=O)(O)O
Agent: CNC(C)C1CCC(N)C(OC2C(N)CC(N)C(OC3OCC(C)(O)C(NC)C3O)C2O)O1
Solvent: CO
Solvent: O
Product: O=S(=O)([O-])[O-]

Procedure:
Dissolve 5.0 gm. of 5-epigentamicin C1 in 25 ml. of water and adjust the pH of the solution to 4.5 with 1 N sulfuric acid. Pour into about 300 ml. of methanol with vigorous agitation, continue the agitation for about 10-20 minutes and filter. Wash the precipitate with methanol and dry at about 60° C in vacuo to obtain 5-epigentamicin C1 sulfate.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:14][CH2:15][Cl:16])[P:5]1(=[O:13])[NH:10][CH:9](OC)[CH2:8][CH2:7][O:6]1.[CH:17]1([NH3+:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[SH:24][CH2:25][CH2:26][S:27]([O-:30])(=[O:29])=[O:28].ClC(Cl)(Cl)C(O)=O.CCOCC>CN(C)C=O>[CH:17]1([NH3+:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[Cl:1][CH2:2][CH2:3][N:4]([CH2:14][CH2:15][Cl:16])[P:5]1(=[O:13])[NH:10][CH:9]([S:24][CH2:25][CH2:26][S:27]([O-:30])(=[O:29])=[O:28])[CH2:8][CH2:7][O:6]1
Reactant: O=S(=O)([O-])CCS
Reactant: COC1CCOP(=O)(N(CCCl)CCCl)N1
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [NH3+]C1CCCCC1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=P1(N(CCCl)CCCl)NC(SCCS(=O)(=O)[O-])CCO1
Reaction time: 20 h

Procedure:
2.9 g (10 mmol) of 2-(bis-(2-chloroethyl)-amino)-4-methoxy-tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide and 2.4 g (10 mmol) of cyclohexylammonium-2-mercaptoethanesulphonate were dissolved with some trichloroacetic acid in 10 ml of dimethylformamide and were stored at -25° C. for 20 hours. After leaving the mixture to stand for another three hours at 0° C., it was mixed with ether until clouding commenced, triturated, the crystallised material was filtered with suction after standing for 20 hours at 0° C., and was washed and dried.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:11]\[C:12](Cl)=[O:13].[OH-].[NH4+:16].CCCCCC>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:11]\[C:12]([NH2:16])=[O:13]
Reactant: O=C(Cl)/C=C1\CCc2c(F)cccc21
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCCCCC
Product: NC(=O)/C=C1\CCc2c(F)cccc21
Temperature: 0 °C
Reaction time: 18 h
Yield: 58.1 %

Procedure:
An ice cold solution of (E)-2-(4-fluoro-1-indanylidene)acetyl chloride (2.11 g, 0.01 mol) in dichloromethane (65 mL) was treated with a 30% aqueous solution of ammonium hydroxide (2.63 ml, 0.02 mol), and the mixture was stirred for 18 h. Hexane was added to the mixture, and the solids were collected by filtration to give 1.63 g of crude product. Recrystallization from acetonitrile:water mixtures gave 1.11 g (58%) of (E)-2-(4-fluoro-1-indanylidene)-acetamide as a white solid; m.p., 198-200° C.
Reaction SMILES: Cl.[N:2]1([S:8]([C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(CC)CC.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:44][S:45]([C:47]([CH3:50])([CH3:49])[CH3:48])=[O:46])([C:38]2[N:42]([CH3:43])[CH:41]=[N:40][CH:39]=2)[CH2:34][CH2:35][CH:36]=O)=[CH:29][C:28]=1[F:51])#[N:26].[BH3-]C#N.[Na+]>CO.CC(O)=O>[C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:44][S:45]([C:47]([CH3:50])([CH3:49])[CH3:48])=[O:46])([C:38]2[N:42]([CH3:43])[CH:41]=[N:40][CH:39]=2)[CH2:34][CH2:35][CH2:36][N:5]2[CH2:4][CH2:3][N:2]([S:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)(=[O:10])=[O:9])[CH2:7][CH2:6]2)=[CH:29][C:28]=1[F:51])#[N:26]
Reactant: Cn1cncc1C(CCC=O)(NS(=O)C(C)(C)C)c1ccc(C#N)c(F)c1
Reactant: O=S(=O)(c1cccc(O)c1)N1CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Cn1cncc1C(CCCN1CCN(S(=O)(=O)c2cccc(O)c2)CC1)(NS(=O)C(C)(C)C)c1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(Piperazin-1-ylsulfonyl) phenol hydrochloride (0.065 g, 0.231 mmol) was dissolved in MeOH (5 mL), neutralized with Et3N (0.032 mL, 0.231 mmol), then treated with N-[1-(4-cyano-3-fluorophenyl)-4-oxo-1-(1-methyl-1H-imidazol-5-yl)butyl]-2-methylpropane-2-sulfinamide (0.086 g, 0.220 mmol). The pH of the solution was adjusted to 5 with HOAc, then NaCNBH3 (0.021 g, 0.330 nunol) was added, and the pH was adjusted again to 5. After stirring at ambient temperature for 18 h, the reaction mixture was concentrated in vacuo, partitioned between CH2Cl2 and aqueous saturated NaHCO3 solution, the aqueous layer washed with CH2Cl2 (2×), the organic layers combined and dried (MgSO4), filtered and concentrated to give the title product. MS(M+1) 617.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.ClC[C:16](Cl)=[O:17].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[N:8]1([CH2:6][C:16]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:17])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C1CCNCC1
Product: O=C(CN1CCNCC1)N1CCCCC1

Procedure:
The title compound was prepared from 1-tert-butyloxycarbonyl-piperazine, chloroacetylchloride and piperidine in an analogous manner as described in example 21.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:18]=[C:17]([NH2:19])[C:16]([O:20][CH3:21])=[C:15]([NH2:22])[N:14]=2)=[N:6]1.C(N(CC)CC)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>CN(C=O)C>[NH2:19][C:17]1[N:18]=[C:13]([C:7]2[C:8]3[CH2:12][CH2:11][CH2:10][C:9]=3[N:5]([CH2:4][C:3]3[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=3[F:1])[N:6]=2)[N:14]=[C:15]([NH:22][C:34](=[O:36])[CH3:35])[C:16]=1[O:20][CH3:21]
Reactant: COc1c(N)nc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1N
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1c(N)nc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1NC(C)=O
Temperature: 100 °C

Procedure:
50 mg of 2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-5-methoxy pyrimidine-4,6-diamine 1-6-1 were suspended in 0.7 mL DMF. After addition of 14 mg of triethylamine (0.14 mmol, 1.0 eq.) and 14 mg of acetic anhydride (0.14 mmol, 1.0 eq.), the resulting reaction mixture was heated for three h at 100° C. For completition of reaction further 4 mg of triethylamine (0.04 mmol, 0.3 eq.) and 4 mg of acetic anhydride (0.04 mmol, 0.3 eq.) were added and the mixture was heated over night at 100° C. After cooling and dilution with water, the crude product was extracted with DCM and was purified by flash chromatography yielding 25 mg (0.063 mmol, 45%) of analytically pure target compound.