Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[F:1][C:2]1[S:6][C:5]([NH:7][CH2:14][C:13]2[CH:16]=[CH:17][C:10]([O:9][CH3:8])=[CH:11][CH:12]=2)=[N:4][CH:3]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1ncc(F)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CNc2ncc(F)s2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.1 %

Procedure:
To a solution of 5-fluorothiazol-2-amine (15.0 g, 127 mmol) and 4-methoxybenzaldehyde (17.3 g, 127 mmol, Spectrochem) in dichloromethane (1.0 L) was added TiCl(O-iPr)3 (66.1 g, 254 mmol, Aldrich). The mixture was stirred at room temperature for 3 h. The reaction mixture was cooled to 0° C. and NaBH(OAc)3 (108 g, 508 mmol) was added in portions and stirred at room temperature for 16 h. The reaction mixture (in portions of 200 mL) was quenched with saturated NaHCO3 solution (100 mL) and extracted with dichloromethane (2×500 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude material which was further purified by column chromatography (silica gel 100 to 200 mesh and 50 to 100% dichloromethane in hexanes) to obtain 5-fluoro-N-(4-methoxybenzyl)thiazol-2-amine (20.0 g, 45%) as brown solid. 1H NMR (400 MHz, DMSO) δ 7.84 (t, J=5.7 Hz, 1H), 7.37-7.13 (m, 2H), 6.89 (dd, J=6.4, 2.2 Hz, 2H), 6.77 (d, J=2.4 Hz, 1H), 4.28 (d, J=5.6 Hz, 2H), 3.73 (s, 3H). m/z (ESI) 239.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:23]CC3C=CC(OC)=CC=3)=[CH:8][C:9]([N:14]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[N:15]3)=[N:10]2)=[CH:5][CH:4]=1.C([O-])=O.[NH4+]>CCO.[Pd]>[OH:23][C:7]1[C:6]2[C:11](=[C:12]([CH3:13])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=[C:9]([N:14]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[N:15]2)[CH:8]=1
Reactant: COc1ccc(COc2cc(-n3ccc(C(F)(F)F)n3)nc3c(C)c(OC)ccc23)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc2c(O)cc(-n3ccc(C(F)(F)F)n3)nc2c1C
Yield: 93 %

Procedure:
A mixture of compound 234c (885 mg, 1.99 mmol), ammonium formate (629 mg, 9.98 mmol), and Pd/C (89 mg, 10% w) in EtOH (16 mL) was refluxed for 1 hr. The reaction was then filtered though celite and concentrated under reduced pressure. The residue was diluted with DCM and washed with water. Organics were dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by chromatography on silica gel (petroleum ether/EtOAc) to yield compound 236c as a white solid in 93% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 2.54 (s, 3H), 3.94 (s, 3H), 7.06 (d, J=2.48 Hz, 1H), 7.37-7.40 (m, 2H), 8.02 (d, J=9.18 Hz, 1H), 8.97 (s, 1H), 11.89 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([C:13]([CH3:15])=[O:14])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].[Si:18]([O:25][C@@H:26]([C@@H:28]1[C@@H:31](SC2C=CC=CC=2)[NH:30][C:29]1=[O:39])[CH3:27])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].[Cl-].[NH4+]>O1CCCC1>[Si:18]([O:25][C@@H:26]([C@@H:28]1[C@@H:31]([C:2]([C:13](=[O:14])[CH3:15])([C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])[CH3:1])[NH:30][C:29]1=[O:39])[CH3:27])([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:19])[CH3:20]
Reactant: CC(=O)C(C)C(=O)OCc1ccccc1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1Sc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)C(C)(C(=O)OCc1ccccc1)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.6 %

Procedure:
Benzyl 2-methylacetoacetate (825 mg, 4.00 mmole) was added to a suspension of sodium hydride (160 mg, 4.0 mmole) in tetrahydrofuran (10 ml) in a nitrogen stream, and the solution mixture was stirred for 10 min at room temperature and then admixed with cuprous bromide dimethylsulfide complex (822 mg, 5.98 mmole), followed by stirring for 1 hour, addition of (3S,4R)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-phenylthio-2-azetidinone (677 mg, 2.00 mmole) and stirring for 3 hours. The reaction solution was admixed with saturated ammonium chloride solution, and after the insoluble matters were removed by filtration, the filtrate was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous saturated sodium chloride solution three times, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (the developing solvent was a 3:1 mixture of n-hexane and ethyl acetate) to give 673 mg (77.6%) of the subject compound consisting of a diastereomer mixture (Products A and B) at a ratio of about 1:1 in the form of colorless oily matter.
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([CH2:23][C:24]([OH:26])=[O:25])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(=O)=O.[CH2:30](O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[CH2:30]([O:25][C:24](=[O:26])[CH2:23][C:21]([C:19]1[O:20][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:17][CH:18]=1)=[O:22])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OCc1ccccc1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)CC(=O)O)o1
Agent: O=C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)CC(=O)OCc2ccccc2)o1
Temperature: 25 °C

Procedure:
A mixture of 10.0 g (0.027 mole) of 2-[5-(tetradecyloxy)-2-furoyl]acetic acid, 4.4 g (0.027 mole) of N,N'-carbonyldiimidazole, and anhydrous tetrahydrofuran is stirred until the evolution of carbon dioxide stops. The mixture is cooled on an ice bath and 3.0 g (0.027 mole) of benzyl alcohol is added. The reaction is allowed to warm to room temperature and evaporated to dryness. The residue is extracted with ether-H2O. The ether layer is washed with 10% aqueous HCl, water, saturated sodium chloride, dried with sodium sulfate and evaporated to dryness affording 2-[5-(tetradecyloxy)-2-furoyl]acetic acid benzyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[Cl:14][C:15]1[CH:16]=[C:17]([S:22]([N:25]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][CH2:30][CH2:29]3)(=[O:24])=[O:23])[CH:18]=[C:19]([Cl:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>S(Cl)(Cl)=O.ClCCl.CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:31]1[C:32]3[C:28](=[CH:27][C:26]([N:25]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[S:22]([C:17]4[CH:18]=[C:19]([Cl:21])[CH:20]=[C:15]([Cl:14])[CH:16]=4)(=[O:24])=[O:23])=[CH:34][CH:33]=3)[CH2:29][CH2:30]1)=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)CN(c1ccc2c(c1)CCN2)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN(c1ccc2c(c1)CCN2C(=O)c1cc2cc(Cl)ccc2[nH]1)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
55 mg 5-chloro-1H-indol-2-carboxylic acid are dissolved in 2 ml of thionyl chloride and heated to 80° C. for 1 hour. The solvent is eliminated in vacuo and the residue is twice combined with dichloromethane and the latter is eliminated again in vacuo. The residue is taken up in 5 ml dichloromethane and the solution is added dropwise to a mixture of 100 mg tert.butyl [(3,5-dichloro-phenylsulphonyl)-(2,3-dihydro-1H-indol-5-yl)-amino]-acetate and 60 mg potassium carbonate in 2 ml dimethylformamide. The mixture is stirred for 2 hours at ambient temperature, diluted with ethyl acetate and washed with 1 N HCl and saturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 10:1 to 1:2).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[NH:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]#[N:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1](=[O:10])[N:18]=1
Reactant: N#Cc1ccc[nH]1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2ccc[nH]2)sc2ccccc12
Yield: 70.5 %

Procedure:
A mixture of methyl thiosalicylate (2.00 g, 11.8 mmol), pyrrole-2-carbonitrile (1.10 g, 11.9 mmol), triethylamine (2.00 ml, 14.3 mmol) and toluene (4.0 ml) was refluxed for 15 hrs as described in Example 1. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-ethanol to give the titled compound (1.90 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Br:24])[C:21]([F:25])=[C:20]([Br:26])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[C:47]1(=[O:57])[NH:51][C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]12.[K]>ClCCCl.CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Br:24])[C:21]([F:25])=[C:20]([Br:26])[CH:19]=3)([C:14]([F:17])([F:15])[F:16])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:51]1[C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]2[C:47]1=[O:57]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc(C2=NOC(c3cc(Br)c(F)c(Br)c3)(C(F)(F)F)C2)cc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(C2=NOC(c3cc(Br)c(F)c(Br)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3-(3-chloro-4-methylphenyl)-5-(3,5-dibromo-4-fluorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole (1.1 g) in 1,2-dichloroethane (7 mL) was added N-bromosuccinimide (0.38 g) and 2,2′-azobis(2-methylpropionitrile) (0.028 g). The mixture was heated to reflux for 3 hours and then cooled to room temperature. The resulting mixture was diluted with 1,2-dichloroethane (10 mL), washed with water (30 mL) and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a residue. The residue was dissolved in N,N-dimethylformamide (7 mL), and potassium phthalimide (0.40 g) was added. The mixture was stirred at room temperature for 15 hours. The reaction mixture was then poured into water (10 mL) and extracted with ethyl acetate (10 mL×2). The organic extracts were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the crude title compound as a pale yellow resin (0.75 g), which was used in the next step without purification.
Reaction SMILES: [CH2:1]([OH:10])[C@@H:2]([OH:9])[CH:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6].C(=O)([O-])[O-].[Ca+2].O=C(O)[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>P([O-])([O-])([O-])=O.C(O)CC.C(O)C.CO.C(O)(=O)C.C(O)=O>[CH2:5]([OH:6])[C@@H:4]([C@H:3]([C@@H:2]([CH2:1][OH:10])[OH:9])[OH:8])[OH:7]
Reactant: OC[C@@H](O)C(O)[C@H](O)CO
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: O=CO
Solvent: CCCO
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Reaction time: 6 h

Procedure:
D-arabitol was dissolved in 0.1M phosphate buffer solution(pH 6.0) to a final concentration of 5% (w/v), and 5 ml each of the solution was dispensed in a test tube. To this reaction mixture were added the bacterial cells prepared in the same manner as in Example 6 in a wet weight of about 10% (w/v) and 2% (w/v) of calcium carbonate, and a reaction with shaking was run at 30° C. After 6 hours and 10 hours from the initiation of the reaction, 5% (w/v) formic acid, acetic acid, gluconic acid, or citric acid, or 1% (v/v) methanol, ethanol, or propanol was added for further reaction. After the reaction was continued for 27 hours, the bacterial cells were removed by centrifugation and then the amount of xylitol produced was determined by HPLC. As shown in Table 3, an increase in the amount of xylitol produced was recognized by addition of various organic acids and alcohols.
Reaction SMILES: F[CH:2](F)[C:3](O)([C:8]([F:15])([F:14])[C:9]([F:13])([F:12])[CH2:10][CH3:11])C(F)(F)F.CCC(=O)C(=O)CC>>[F:12][C:9]([F:13])([C:8]([F:15])([F:14])[CH2:3][CH3:2])[CH2:10][CH3:11]
Reactant: CCC(F)(F)C(F)(F)C(O)(C(F)F)C(F)(F)F
Agent: CCC(=O)C(=O)CC
Product: CCC(F)(F)C(F)(F)CC

Procedure:
As another example, 2-difluoromethyl-1,1,1,3,3,4,4-heptafluoro-2-hexanol may be prepared by fluorinating commercially available 3,4-hexanedione to form 3,3,4,4-tetrafluorohexane which may then be dehydrogenated to form 3,3,4,4-tetrafluoro-1-hexene. CF3 may then be added to the 3,3,4,4-tetrafluoro-1-hexene to form 2-trifluoromethyl-1,3,3,4,4-pentafluorohexane which may then be dehydrogenated to form 2-trifluoromethyl-1,3,3,4,4-pentafluoro-1-hexene. The 2-trifluoromethyl-1,3,3,4,4-pentafluoro-1-hexene may then be reacted with hydrogen fluoride to form 2-trifluoromethyl-1,1,3,3,4,4-hexafluorohexane which may then be dehydrogenated to form 2-trifluoromethyl-1,1,3,3,4,4-hexafluoro-1-hexene which may then be reacted with sulfuric acid and then water to form 2-difluoromethyl-1,1,1,3,3,4,4-heptafluoro-2-hexanol.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][N:11]=2)=[CH:6][CH:5]=1.[OH-].[Na+:21]>O1CCCC1.C(O)C>[Na+:21].[C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([O-:19])=[O:2])=[CH:5][CH:6]=2)=[N:11][CH:12]=1)(=[O:18])[CH3:17]
Reactant: COC(=O)c1ccc(-c2ccc(C(C)=O)cn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)c1ccc(-c2ccc(C(=O)[O-])cc2)nc1

Procedure:
Procedure V′: To a stirring solution of 4-(5-acetyl-pyridin-2-yl)-benzoic acid methyl ester (1.0 mmol) in 1:1 tetrahydrofuran/ethanol (0.20M), add 2N sodium hydroxide and heat to reflux for three hours. After this time, concentrate the reaction in vacuo. Rinse the solid with dichloromethane and decant. The title compound, remaining as a solid, requires no further purification. MS (m/e): 242.1 (M+1)
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15]([S:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:28])=[O:27])[C:16]([C:18]4[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=4)=[CH:17][C:10]=23)[C:6]([C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)=[N:5]1)[CH3:3].[NH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1>>[CH3:3][CH:2]([N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15]([S:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:28])=[O:27])[C:16]([C:18]4[CH:25]=[CH:24][C:21]([CH2:22][N:44]5[CH2:48][CH2:47][CH2:46][CH2:45]5)=[CH:20][CH:19]=4)=[CH:17][C:10]=23)[C:6]([C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)=[N:5]1)[CH3:1]
Reactant: CC(C)n1cc(-c2ccnc3c2cc(-c2ccc(C=O)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: C1CCNC1
Product: CC(C)n1cc(-c2ccnc3c2cc(-c2ccc(CN4CCCC4)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 101 using 4-[4-[1-(1-methylethyl)-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]benzaldehyde and pyrrolidine provided the title compound. ESMS [M+H]+=647.6.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)=[C:10]([Cl:24])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([C:33]3[C:34]([CH3:40])=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=3)([C:27]3[N:31]([CH3:32])[N:30]=[N:29][CH:28]=3)[OH:26])[CH:8]=2)[N:3]=1.[NH:41]1[CH2:44][CH2:43][CH2:42]1.CN(C=O)C>CCOC(C)=O>[N:41]1([C:2]2[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:15][CH:14]=3)=[C:10]([Cl:24])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:25]([C:33]4[C:34]([CH3:40])=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=4)([C:27]4[N:31]([CH3:32])[N:30]=[N:29][CH:28]=4)[OH:26])[CH:8]=3)[N:3]=2)[CH2:44][CH2:43][CH2:42]1
Reactant: Cc1ccc(C(O)(c2ccc3nc(Cl)c(Cc4ccc(-n5cccn5)cc4)c(Cl)c3c2)c2cnnn2C)c(C)n1
Reactant: C1CNC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(O)(c2ccc3nc(N4CCC4)c(Cc4ccc(-n5cccn5)cc4)c(Cl)c3c2)c2cnnn2C)c(C)n1
Temperature: 100 °C

Procedure:
{2,4-Dichloro-3-[4-(1H-pyrazol-1-yl)benzyl]quinolin-6-yl}(2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol (198 mg, 0.347 mmol, Example 151), azetidine (70 μL, 1.04 mmol), and DMF (2 mL) were combined in a reaction tube, then sealed and heated to 100° C. and maintained at that temperature for 24 hours. The residue was taken up into EtOAc, transferred to a reparatory funnel and extracted twice with a saturated, aqueous NH4Cl solution. The organic phase was separated then dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to provide the title compound. MS (ESI): mass calcd. for C33H31ClN8O, 590.2. m/z found, 591.5 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 8.07-8.02 (m, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.64-7.56 (m, 2H), 7.38-7.31 (m, 1H), 7.08-6.99 (m, 4H), 6.98 (s, 1H), 6.88-6.77 (m, 2H), 5.89 (d, J=1.9 Hz, 1H), 4.29 (s, 2H), 4.12 (t, J=7.5 Hz, 4H), 3.93 (s, 3H), 2.47 (s, 3H), 2.34 (s, 3H), 2.31-2.18 (m, 2H).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[C:31](O)(=O)C.C=O>CO>[CH3:31][N:21]1[CH2:20][CH2:19][C:17]2[N:18]=[C:13]([NH:12][C:9]3[CH:8]=[CH:7][C:6]([C:5]4[O:1][CH:2]=[N:3][CH:4]=4)=[CH:11][CH:10]=3)[N:14]=[C:15]([NH:23][CH2:24][CH:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[C:16]=2[CH2:22]1
Reactant: CC(=O)O
Reactant: c1ncc(-c2ccc(Nc3nc4c(c(NCC5CCOCC5)n3)CNCC4)cc2)o1
Agent: C=O
Solvent: CO
Product: CN1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(NCC3CCOCC3)c2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 16.6 %

Procedure:
N2-(4-(Oxazol-5-yl)phenyl)-N4-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (134 mg, 0.33 mmol) was dissolved in methanol (3 mL). Acetic acid (0.019 mL, 0.33 mmol) was added followed by formaldehyde (0.025 mL, 0.33 mmol). The reaction mixture was stirred at room temperature for 15 minutes and MP—CNBH3 was added. The reaction was stirred overnight. The MP—CNBH3 was filtered off and the solvent was evaporated under reduced pressure. The crude was dissolved in methanol, filtered and purified by HPLC yielding 6-methyl-N2-(4-(oxazol-5-yl)phenyl)-N4-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (23.00 mg, 15.8%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH:19]([CH3:23])[CH2:20][O:21][CH3:22])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:24][CH3:25])=[C:5]([CH3:26])[O:4][N:3]=1.[N:27]#[C:28]Br>>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:24][CH3:25])=[CH:9][C:10]3[C:11]4[N:18]([CH:19]([CH3:23])[CH2:20][O:21][CH3:22])[C:28]([NH2:27])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: COCC(C)Nc1c(N)cnc2cc(-c3c(C)noc3C)c(OC)cc12
Reactant: N#CBr
Product: COCC(C)n1c(N)nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c21
Yield: 30 %

Procedure:
From 7-(3,5-dimethyl-4-isoxazolyl)-N4-[1-methyl-2-(methyloxy)ethyl]-6-(methyloxy)-3,4-quinolinediamine (for a preparation see Intermediate 17) (70 mg) and cyanogen bromide (20 mg) to give the title compound as beige solid (23 mg, 30%). LCMS (formate) Rt 0.67 min, MH+ 382
Reaction SMILES: Cl.[C:2]1([C:8](C2C=CC=CC=2)=[CH:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:26])[CH2:13][CH2:12]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([OH:35])C>>[O:35]=[C:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][CH2:12]1
Reactant: CCO
Reactant: O=C1c2ccccc2CN1C1CCN(CC=C(c2ccccc2)c2ccccc2)CC1
Agent: Cl
Product: O=C(CCN1CCC(N2Cc3ccccc3C2=O)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37 %

Procedure:
To a solution of Example 2 Part A compound (1.93 g, 8.92 mmol) in dry ethanol (15 mL) at RT was added a solution of Part B compound (1.1 g, 7.43 mmol) in dry ethanol (2 mL). The reaction was stirred at RT for 4 h. The reaction was evaporated to dryness. Ethyl ether (150 mL) was added, and the solution was washed water (2×30 mL), brine (2×30 mL) and dried over MgSO4. Purification was perfomed by flash chromatography on silica gel (150 g), loaded and eluted with 4% methanol in dichloromethane. Pure fractions were combined and evaporated to give title compound (1.0 g, 37%) as a yellowish solid.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])=[CH:14][CH:13]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[O:2]1[C:6]2[CH2:7][N:8]([C:23](=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:15]3[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=3)[CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1
Reactant: c1cc2c(o1)CNCC2
Reactant: O=C(O)CCCCCc1ccc(F)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCCCc1ccc(F)cc1)N1CCc2ccoc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.25 g (1.2 mmol) of 6-(4-fluorophenyl)hexanoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to yield the desired product.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([CH3:35])=[C:5]([C:22](=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][Br:33])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]>ClCCl.[O-2].[O-2].[Mn+4]>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:5]([C:22](=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][Br:33])=[C:4]([CH3:35])[N:3]=1
Reactant: CCOC(=O)C1=C(N)NC(C)=C(C(=O)CCCCCCCCCCBr)C1c1cccc([N+](=O)[O-])c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(=O)c1c(N)nc(C)c(C(=O)CCCCCCCCCCBr)c1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 55.6 %

Procedure:
41.9 g of ethyl 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-5-(11-bromo-1-oxo-undecyl)pyridine-3-carboxylate are dissolved in 300 ml of dichloromethane and 137 g of manganese dioxide are added. The mixture is stirred at RT for 20 h, then filtered off through Celite and the filtrate is washed with water. The oil remaining after concentration of the filtrate crystallizes on standing or is seeded. It is triturated with diisopropyl ether and filtered off with suction. 23.2 g of the title compound of m.p. 73-74° C. are obtained.