Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH2:11]([O:18][C:19]1[C:20]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[K+].O>CO>[CH2:11]([O:18][C:19]1[C:20]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)=[C:21]([CH:22]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:8][CH:9]=2)[OH:23])[CH:24]=[CH:25][CH:26]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1cccc(OCc2ccccc2)c1OCC1CC1
Reactant: Clc1cnc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OC(c1cccc(OCc2ccccc2)c1OCC1CC1)c1c[nH]c2ncc(Cl)cc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 53.6 %

Procedure:
A mixture of 5-chloro-1H-Pyrrolo[2,3-b]pyridine (4, 0.68 g, 4.46 mmol, prepared as described in Example 4), 3-benzyloxy-2-cyclopropylmethoxy-benzaldehyde (130, 1.2 g, 4.25 mmol), and potassium hydroxide (0.68 g, 11 mmol) in methanol (50 mL) was stirred at room temperature for 4 days. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was collected, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide compound as a white solid (131, 0.99 g, 54%). MS (ESI) [M+H+]+=435.21.
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([C:19]([NH2:21])=[O:20])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:8]=1)=[N+]=[N-].CO.[Cl-].[NH4+]>[Zn].O1CCCC1>[NH2:1][C:4]1[S:5][C:6]([C:19]([NH2:21])=[O:20])=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)[N:8]=1
Reactant: [N-]=[N+]=Nc1nc(-c2ccc(C(F)(F)F)cc2)c(C(N)=O)s1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1sc(N)nc1-c1ccc(C(F)(F)F)cc1
Reaction time: 1 h
Yield: 101.8 %

Procedure:
To a solution of 0.6727 g (2.147 mmole) of 2-azido-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide, 20 mL of methanol and 20 mL of tetrahydrofuran was added 1.42 g (21.8 mg-atom) of zinc and 2.84 g (53.1 mmole) of ammonium chloride. The mixture was stirred vigorously for 1 hour and then filtered through Diatomaceous earth, washing the pad with methanol and tetrahydrofuran. The filtrate was concentrated under reduced pressure and then diluted with 350 mL of ethyl acetate, washed three times with 75 mL of water, once with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give 0.6276 g of 2-amino-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (V.47) as an off-white solid.
Reaction SMILES: C(OC([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[NH:14][CH2:13][CH:12]2[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH:12]2[C:11]3([CH2:10][CH2:9][NH:8][CH2:25][CH2:24]3)[C:15](=[O:16])[NH:14][CH2:13]2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCC2c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCC(c2ccc(F)cc2)C12CCNCC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67.6 %

Procedure:
A solution of 4-(4-fluoro-phenyl)-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (46.0 g, 132 mmol) in DCM (260 mL) containing TFA (150 mL, 1.32 mol) was stirred vigorously at 0° C. for 15 min. The reaction mixture was then poured into NaOH (3 N, 200 mL) and the product extracted with DCM (3×100 mL). The combined organic extracts were then washed with water (100 mL) and brine (100 mL) and then dried over sodium sulfate. Filtration and evaporation afforded the title compound (22.14 g, 68%) as a white solid after trituration from ethyl acetate. MS: m/e=249.2 (M+H).
Reaction SMILES: Br.[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:24]C)=[C:7]([CH:23]=1)[CH2:8][C:9]1(O)[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1.O>C(O)(=O)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[O:24][C:9]3([CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)[CH2:8][C:7]=2[CH:23]=1
Reactant: COc1ccc(F)cc1CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Fc1ccc2c(c1)CC1(CCNCC1)O2
Temperature: 25 °C
Reaction time: 24 h
Yield: 38.1 %

Procedure:
Hydrobromic acid (48%, 60 mL) was added to a solution of the crude tert-butyl 4-(5-fluoro-2-methoxybenzyl)-4-hydroxypiperidine-l-carboxylate (86 g) in acetic acid (300 mL). The mixture was heated at reflux for 5 hours. Further hydrobromic acid (48%, 60 mL) was added and reflux continued for 24 hours. The mixture was cooled to room temperature, added to water (2 L) and extracted with tert.-butyl methyl ether (2×500 mL). The aqueous phase was adjusted to pH>10 by addition of 50 wt. % sodium hydroxide solution and extracted with tert.-butyl methyl ether (2L+1L). Organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The residual solid was crystallised from tetrahydrofuran/tert.-butyl methyl ether (4:1, 500 mL) to give the title compound (20 g). 1H-NMR (CD3OD, 400 MHz): δ 6.92-6.87 (m, 1H); 6.81-6.75 (m, 1H); 6.64 (dd, J=4.2, 8.7 Hz, 1H); 3.08-2.98 (m, 4H); 2.89-2.81 (m, 2H); 1.91-1.83 (m, 2H); 1.78-1.69 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:12][NH:13][O:14][CH3:15].CCN(CC)CC.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:13]([O:14][CH3:15])[CH3:12])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1Cl
Reactant: CNOC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(C)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
To a cooled mixture of 2-chloro-3-methyl-benzoic acid (1 g, 5.88 mmol), N,O-dimethylhydroxylamine (860 mg, 8.82 mmol) and Et3N (3.27 mL, 23.52 mmol) in CH2Cl2 (10 mL) was added 1-propane phosphonic acid cyclic anhydride (4.49 mL, 7.05 mmol; 50 wt % solution in EtOAc) dropwise and stirred at room temperature for 3 h. The reaction mixture was filtered, washed with CH2Cl2 (2×10 mL), evaporated to dryness and subjected to column chromatography (SiO2, 40% EtOAc-hexanes) to obtain 2-chloro-N-methoxy-3,N-dimethyl-benzamide (1.19 g) in 95% yield. ESMS m/z (relative intensity): 214 (M+H)+ (100).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[CH:12][CH:11]=2)[C:3]([O:5]C)=[O:4].[OH-].[Na+]>CO.O>[CH3:1][CH:2]([CH2:7][C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[CH:12][CH:11]=2)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a solution of methyl 2-methyl-3-{5-[3-(2-pyridylamino)propoxy]indolyl}propanoate (0.015 g, 0.04 mmol), as prepared in the preceding step, in methanol (5.0 mL) was added a solution of NaOH (0.1 g, 2.5 mmol) in H2O (0.3 mL), and the reaction was stirred at ambient temperature overnight. After evaporating the solvent in vacuo, the residue is taken up in H2O (5 mL) and acidified to pH 4–5 with 10% HCl and extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel (4% methanol in methylene chloride) to give the title compound as an oil (0.011 g, 80%). 1H-NMR (400 MHz, CDCl3) δ 7.86 (d, J=5.6 Hz, 1H), 7.50 (m, 1H), 7.26 (d, J=8.9 Hz, 1H), 7.07 (dd, J=13.1, 2.8 Hz, 2H), 6.84 (dd, J=8.9, 2.4 Hz, 1H), 6.56 (m, 2H), 6.32 (d, J=2.0 Hz, 1H), 4.38 (dd, J=14.3, 7.0 Hz, 1H), 4.07 (t, J=5.8 Hz, 2H), 4.01 (dd, J=14.3, 7.5 Hz, 1H), 3.44 (t, J=6.7 Hz, 2H), 2.92 (q, J=7.1 Hz, 1H), 2.08 (m, 2H), 1.12 (d, J=7.1 Hz, 3H). Mass spectrum (LCMS, ESI pos.) Calcd. for C20H23N3O3 354.3 (M+H); Found: 354.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[N:27]([CH3:28])[C:26](=[O:29])[CH:25]=[C:24]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[N:23]=1.C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:22]2[N:27]([CH3:28])[C:26](=[O:29])[CH:25]=[C:24]([C:30]3[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=3)[N:23]=2)[CH2:10][CH:9]1[C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCN(C(=O)OC(C)(C)C)C(c3ccc(Cl)cc3)C2)nc(-c2ccncc2)cc1=O
Yield: 94.3 %

Procedure:
A solution of 4-(tert-butoxycarbonyl)-3-(4-chlorophenyl)piperazine (330 mg, 1.1 mmol), 2-chloro-3-methyl-6-(4-pyridyl)pyrimidin-4-one (246 mg, 1.1 mmol) and triethylamine (170 μl, 1.22 mmol) in tetrahydrofuran were refluxed. Usual workup and purification by silica gel column chromatography gave 2-(1-(tert-butoxy-carbonyl)-2-(4-chlorophenyl)-piperazine-4-yl)-3-methyl-6-(4-pyridyl)pyrimidin-4-one (500 mg, 93%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([C:10](=[O:13])[CH2:11][CH3:12])[OH:9].[H-].[Na+].[CH3:16]I>CN(C)C=O.O>[CH3:16][O:9][N:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[C:10](=[O:13])[CH2:11][CH3:12]
Reactant: CCC(=O)N(O)c1ccccc1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)N(OC)c1ccccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 25 to 30° C., a solution of 22.7 g (0.127 mol) (Example 6a) of N-(2-methylphenyl)-N-propionyl-hydroxylamine in 50 ml of dimethylformamide is dripped into a stirred mixture of 3.4 g (0.14 mol) of NaH in 150 ml of dimethylformamide. After completion of gas evolution (15 mins) 18.4 g (0.13 mol) of methyl iodide is added and the mixture is stirred overnight at room temperature. The reaction mixture is then diluted with water and the aqueous phase is extracted three times with methyl tert-butyl ether. The combined organic phases are extracted with water, dried over MgSO4 and evaporated down. The residue is purified by column chromatography with mixtures of cyclohexane and ethyl acetate. There is obtained 18 g (0.081 mol{circumflex over (=)}64%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]1([CH:7]2[O:15][CH:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][O:17][CH2:18][CH2:19][NH2:20]>O>[CH3:16][O:17][CH2:18][CH2:19][NH:20][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:15]
Reactant: c1ccc(C2OC2c2ccccc2)cc1
Reactant: COCCN
Solvent: O
Product: COCCNC(c1ccccc1)C(O)c1ccccc1
Temperature: 150 °C
Yield: 80 %

Procedure:
A mixture of trans-stilbene oxide (3.93 g, 0.020 mole) and 2-methoxyethylamine (4.51 g, 0.060 mole) was heated at 125° C. for 2 hours with an oil bath. A mass spectra analysis showed no title compound was present. The mixture was heated for another 2 hours at 150° C. The mixture was poured into water (using methanol rinse) to obtain an off-white solid. NMR analysis showed the solid contained approximately 60% unreacted stilbene oxide. The mixture was added to another 4.51 g (0.060 mole) of 2-methoxy ethylamine and the mixture heated at 135° C. for 4 hours in a stainless-steel bomb. After cooling, the reaction mixture was shown by NMR analysis to contain 20% stilbene oxide and 80% of the title compound. The solid was recrystallized from toluene to give 2.92 g (54%) of a white solid, m.p. 137°-139° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C@H:16]([C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=3)=[O:44])[CH2:36][CH2:35]2)=[O:33])[CH2:15]1>O1CCCC1>[CH3:8][S:9]([O:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[O:20])[C@H:16]([C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=3)=[O:44])[CH2:36][CH2:35]2)=[O:33])[CH2:15]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCCN1CCN(C(=O)[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCN(CCOC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.5 h

Procedure:
89 μl of triethylamine and 50 μl of methanesulfonyl chloride were added, whilst ice-cooling, to a solution of 321 mg of (2S,4R)-4-hydroxy-2-{4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]-1-piperazinyl carbonyl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidine in 3.2 ml of dry tetrahydrofuran, and the resulting mixture was stirred at between 0° C. and 5° C. for 30 minutes and then at room temperature for a further 1 hour. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was mixed with an aqueous solution of sodium hydrogencarbonate; the mixture was then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, to give 345 mg of the title compound as a powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2Cl.Cl.Cl.[CH3:19][N:20]([CH3:28])[C@H:21]1[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([N:20]([CH3:28])[CH3:19])[CH2:22][CH2:23]1
Reactant: CN(C)[C@H]1CC[C@H](N)CC1
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1Cl
Agent: Cl
Product: CCC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](N(C)C)CC1

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)propan-1-one (800 mg, 2.68 mmol) was reacted with trans-N1,N1-dimethylcyclohexane-1,4-diamine dihydrochloride (692 mg, 3.21 mmol) to afford the desired product (629 mg, 58%) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 10.77 (br d, J=8.1 Hz, 1H), 9.01 (s, 1H), 8.27 (d, J=2.0 Hz, 1H), 7.84-7.68 (m, 2H), 4.05-3.89 (m, 1H), 3.08 (q, J=7.2 Hz, 2H), 2.33 (s, 6H), 2.33-2.23 (m, 2H), 2.12-1.99 (m, 2H), 1.63-1.31 (m, 4H), 1.25 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16]Br>C(Cl)(Cl)(Cl)Cl>[Br:16][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccccc1)C(Br)c1ccccc1
Yield: 99.7 %

Procedure:
196 g (l mole) of phenyl benzyl ketone were suspended in 1 liter of carbon tetrachloride. A solution of 51 ml (1 mole) of bromine in 50 ml of carbon tetrachloride were added dropwise, under irradiation (UV), at a rate such that a steady consumption of bromine took place. The solvent was then distilled off in a water pump vacuum. 274 g (quantitative yield) of ω-bromo-ω-phenyl-acetophenone of melting point 48°-50° C. were obtained.
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1/[CH:10]=[CH:11]/[C@H:12]([N:21]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20].[OH-].[Li+].Cl>O1CCOCC1.O>[CH2:29]([N:21]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])/[CH:11]=[CH:10]/[C:5]1[N:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:36])=[O:2])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)c1cccnc1/C=C/[C@@H](Cc1ccccc1F)N(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cccnc1/C=C/[C@@H](Cc1ccccc1F)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 24 h

Procedure:
To a solution of 2-[(E)-(R)-3-dibenzylamino-4-(2-fluoro-phenyl)-but-1-enyl]-nicotinic acid methyl ester (0.7 g, 1.4 mmol) in 5 mL of a 1:1 dioxane:water solution is added lithium hydroxide (0.07 g, 2.8 mmol). After stirring for 24 hours, the reaction is diluted with water and is neutralized by addition of 1N HCl. Filtration gives the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[Cl-].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][Zn+])=[CH:18][CH:17]=1>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.C1COCC1>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][CH:10]=[CH:11][N:12]=3)=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(C[Zn+])cc1
Reactant: Ic1ccc(-c2ncco2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1ccc(Cc2ccc(-c3ncco3)cc2)cc1
Reaction time: 3 h
Yield: 81.5 %

Procedure:
A Schlenk Flask was charged with tetrakis(triphenylphosphine)palladium(0) (0.42 g, 0.37 mmol), nitrogen, THF (20 ML), 2-(4-iodophenyl)oxazole (1 g, 3.7 mmol), and 4-methoxybenzyl zinc chloride (0.5 M in THF, 9.6 mL, 4.8 mmol). After 3 hours, the filtrate was concentrated. The resulting solid was treated with a mixture of ethyl acetate and a dilute aqueous ammonium chloride solution. The mixture was filtered and the organic layer was dried and concentrated. Purification on silica gel using a gradient of dichloromethane in hexane gave 0.8 g of 2-[4-[(4-methoxyphenyl)methyl]phenyl]oxazole, 1H NMR (400 MHz, CDCl3) δ 7.97 (d, 2H), 7.68 (s, 1H), 7.27 (d, 2H), 7.22 (s, 1H), 7.13 (d, 2H), 6.82 (d, 2H), 3.96 (s, 2H), 3.78 (s, 3H).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:10][CH3:11].[C:12]1(OB(O)O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>O1CCOCC1.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>[C:20]1([C:2]2[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=2[O:10][CH3:11])[C:21]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: OB(O)Oc1cccc2ccccc12
Reactant: COc1cccc(OC)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cccc(OC)c1-c1cccc2ccccc12
Yield: 78.2 %

Procedure:
To a solution of 1-bromo-2,6-dimethoxybenzene, (2.63 g, 12.1 mmol), tetrakis(triphenylphosphine)palladium (0) (0.91 g, 0.76 mol) and 1-naphthylboric acid (4.16 g, 23.9 mmol) in 1,4-dioxane (160 ml), a 2N aqueous solution of sodium hydroxide (13 ml) was added, and the mixture was heated to reflux. After cooling, the solvent was evaporated off, and the residue was dissolved in diethyl ether. The diethyl ether solution was washed with water and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated off, and the residue was purified by silica gel column chromatography (developing phase: n-hexane/ethyl acetate=5/1) to obtain 1-naphthyl-2,6-dimethoxybenzene (2.50 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]3[CH:18]=[CH:17][C:16](=[O:19])[NH:15][N:14]=3)[CH2:10][C@H:9]2[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:3]=1.[CH3:24]I>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]3[CH:18]=[CH:17][C:16](=[O:19])[N:15]([CH3:24])[N:14]=3)[CH2:10][C@H:9]2[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:3]=1
Reactant: CI
Reactant: COC(=O)[C@@H]1CN(c2ccc(=O)[nH]n2)C[C@H]1c1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CN(c2ccc(=O)n(C)n2)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
Methyl (3S,4R)-4-(4-chlorophenyl)-1-(6-oxo-1,6-dihydropyridazin-3-yl)pyrrolidine-3-carboxylate obtained in Step A of Preparation 22 was dissolved in DMF (5 ml). Cs2 CO3 (1.11 g, 3.41 mmol) was added, and methyl iodide (0.71 mL, 11.40 mmol) was added dropwise. The reaction mixture was stirred at 20-30° C. for 2 hours and concentrated in vacuo. The obtained residue was diluted with EtOAc, washed with water and purified by column chromatography (eluent: EtOAc/Hex=1/1) to give the title compound (0.55 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.[N:30]1[CH:35]=[C:34]([CH:36]=O)[CH:33]=[N:32][CH:31]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:36][C:34]4[CH:35]=[N:30][CH:31]=[N:32][CH:33]=4)[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: O=Cc1cncnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(Cc5cncnc5)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (45 mg, 0.1 mmol) and pyrimidine-5-carbaldehyde (32 mg, 0.3 mmol) in DCM (1.5 mL) was added NaBH(OAc)3 (64 mg, 0.3 mmol), followed by addition of AcOH (12 uL). After stirring at room temperature in a sealed vial for 16 h, the reaction was quenched with EtOAc (50 mL). The reaction mixture was sequentially washed with water (10 mL), brine (5 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica chromatography (0-10% MeOH in EtOAc gradient with 1% NH3 in MeOH additive) to give 5-Chloro-N2-(2-fluoro-5-methyl-4-(1-(pyrimidin-5-ylmethyl)piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as an off white solid; 1H NMR (400 MHz, CD3OD) δ 9.09 (s, 1H), 8.81 (s, 2H), 8.00 (s, 1H), 7.73 (d, J=8.4 Hz, 1H), 6.99 (d, J=13.2 Hz, 1H), 6.23 (br s, 1H), 3.65 (s, 2H), 3.03 (m, 2H), 2.76 (m, 1H), 2.27 (s, 3H), 2.25 (s, 3H), 2.25 (m, 2H), 1.80-1.68 (m, 4H); ESMS m/z 508.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5]([N:7](C=O)[NH2:8])=[NH:6])[CH3:2].[CH3:12]OCCOCCOC>>[CH2:1]([O:3][C:4]([C:5]1[N:6]=[CH:12][NH:8][N:7]=1)=[O:11])[CH3:2]
Reactant: COCCOCCOC
Reactant: CCOC(=O)C(=N)N(N)C=O
Product: CCOC(=O)c1nc[nH]n1
Yield: 85 %

Procedure:
A suspension of (N-Formylhydrazino)-imino acetic acid ethyl ester (9.62 g, 60.4 mmol) in diglyme (40 ml) was refluxed for 30 minutes. After cooling, the precipitated crystal was collected by filteration and washed with hexane to give 1H-1,2,4-triazol-3-carboxylic acid ethyl ester (7.28 g). Yield: 85%.