Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([C:22](O)=[O:23])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C[N:27](C)C=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([C:22]([NH2:27])=[O:23])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(C(=O)O)ccc1OCC2
Reactant: CN(C)C=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(C(N)=O)ccc1OCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylic acid (0.170 g, 0.000501 mol) dissolved in N,N-Dimethylformamide (7.84 mL, 0.101 mol) and treated sequentially with N,N-Diisopropylethylamine (0.524 mL, 0.00300 mol) Ammonium chloride (0.107 g, 0.00200 mol) then N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.228 g, 0.000601 mol). The reaction was stirred at r.t. overnight. The reaction was quenched with sat. sodium bicarbonate then extract with ethyl acetate (3×). The organic layers was dried (Na2SO4) and concentrated in vacuo to give 109 purified on reverse HPLC. MS: (ESI+)=339.1. 1H NMR (400 MHz, DMSO) δ 8.93 (d, J=2.2 Hz, 1H), 7.95 (s, 2H), 7.92 (s, 1H), 7.79 (dd, J=8.5, 2.2 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 5.82 (dt, J=13.2, 6.6 Hz, 1H), 4.56 (s, 4H), 1.49 (d, J=6.6 Hz, 6H)
Reaction SMILES: [CH:1]1([N:4]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:5]([C:7]2[CH:8]=[N:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[N:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Cl[C:30]1[N:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][N:31]=1>>[CH:1]1([N:4]([CH:23]2[CH2:28][CH2:27][N:26]([C:30]3[N:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][N:31]=3)[CH2:25][CH2:24]2)[C:5]([C:7]2[CH:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[N:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCc1cnc(Cl)nc1
Reactant: CS(=O)(=O)c1ccc(-c2ncc(C(=O)N(C3CCNCC3)C3CC3)cn2)cc1
Product: CCc1cnc(N2CCC(N(C(=O)c3cnc(-c4ccc(S(C)(=O)=O)cc4)nc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from 2-(4-methanesulfonyl-phenyl)-pyrimidine-5-carboxylic acid cyclopropyl-piperidin-4-yl-amide and 2-chloro-5-ethylpyrimidine following a procedure analogous to that described in Example 3. LC (method 10): tR=1.80 min; Mass spectrum (ESI+): m/z=507 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:4]=1[N+:18]([O-])=O>[Zn]>[NH2:18][C:4]1[CH:5]=[C:6]([NH:9][C:10](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(NC(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: [Zn]
Product: COc1ccc(NC(=O)c2ccccc2)cc1N
Yield: 76.4 %

Procedure:
Prepared according to the procedure described for Example 9, Step B using N-(4-methoxy-3-nitrophenyl)-benzamide (3.68 g, 13.5 mmol) and zinc dust (20 g) to give the product (2.5 g) after chromatography on silica gel in ethyl acetate/hexane and recrystallization from the same solvent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[C:13]2[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=2[N:15]=[CH:16][CH:17]=1.[H-].[Na+].[CH3:31]I.O>CC(N(C)C)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH3:31])[C:12]1[C:13]2[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=2[N:15]=[CH:16][CH:17]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Nc3ccc([N+](=O)[O-])cc3F)ccnc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(c1ccc([N+](=O)[O-])cc1F)c1ccnc2c1ccn2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 100 mg (0.25 mmol) of N-(2-fluoro-4-nitrophenyl)-1-{[2-(trimethyl-silyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-4-amine in 0.75 ml of DMA is added dropwise to a suspension of 30 mg (0.75 mmol) of sodium hydride in 0.75 ml of DMA, and the mixture is stirred at RT for 30 min. 77 μl (1.24 mmol) of methyl iodide are then slowly added dropwise, and the mixture is stirred for a further 30 min. Water is then added, and the mixture is extracted twice with dichloromethane. The combined organic phases are dried over magnesium sulfate, the solvent is removed under reduced pressure and the residue is purified by preparative HPLC.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[O:13]C(=O)C.C(OCC)C.CCCCC>C(O)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[OH:13]
Reactant: COCCCCc1ccncc1OC(C)=O
Solvent: CC(=O)O
Solvent: CCCCC
Solvent: CCOCC
Product: COCCCCc1ccncc1O
Temperature: 70 °C

Procedure:
A mixture of 39 mmol acetic acid 4-(4-methoxy-butyl)-pyridin-3-yl ester in 20 ml acetic acid is heated to 70° C. for 30 minutes. After cooling, 75 ml of diethyl ether/pentane (1:5) is added and the precipitate is collected by filtration. The title compound is obtained from the solid by re-crystallization from toluene and identified based on its Rf value.
Reaction SMILES: O.[NH3:2].[Cl:3][C:4]1[C:22]([F:23])=[CH:21][C:7]([C:8]([NH:10][C:11]2[N:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13](OC)=[O:14])=O)=[C:6]([F:24])[CH:5]=1>C(Cl)(Cl)Cl.CO>[Cl:3][C:4]1[C:22]([F:23])=[CH:21][C:7]([C:8]2[NH:2][C:13](=[O:14])[C:12]3[CH:17]=[CH:18][CH:19]=[N:20][C:11]=3[N:10]=2)=[C:6]([F:24])[CH:5]=1
Reactant: N
Reactant: COC(=O)c1cccnc1NC(=O)c1cc(F)c(Cl)cc1F
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c(-c2cc(F)c(Cl)cc2F)nc2ncccc12
Temperature: 25 °C

Procedure:
28% ammonia water was added to a chloroform-MeOH solution of methyl 2-[(4-chloro-2,5-difluorobenzoyl)amino]nicotinate and the resultant was stirred all night at room temperature to give 2-(4-chloro-2,5-difluorophenyl)pyrido[2,3-d]pyrimidine-4(3H)-one.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)C.[OH-].[K+]>CO.O.O1CCCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C2CCC(O)C2)cc1OC1CCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc([C@H]2CC[C@H](O)C2)cc1OC1CCCC1
Yield: 55.6 %

Procedure:
3-(3-Cyclopentyloxy-4-methoxyphenyl) -cyclopentan-1-ol, (predominantly cis, 160 mg, 0.58mmol) (E9) in freshly distilled tetrahydrofuran (5 ml) was stirred vigorously with diethylazodicarboxylate (96μl 0.58 mmol), triphenylphosphine (152 mg, 0.58mmol) and glacial acetic acid (35μl, 0.61 mmol) under an argon atmosphere at room temperature for 24 hr. The liquids were removed under reduced pressure, with purification by flash chromatography, eluting with 2:1 hexanes/ether, providing and trans acetate as an oil (133 mg, 72%). This oil (133 mg, 0.42 mmol) in methanol (2 ml) was treated with potassium hydroxide (89%, 52 mg 0.82 mmol) in water (0.3 ml) for 1 hr. The mixture was partitioned between ether and water, the ether was dried (potassium carbonate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with 1:1 hexanes/ether, provided the title compound as an oil (89 mg, 55.6%).
Reaction SMILES: [C:1]1([CH:7]([C:11]([OH:13])=[O:12])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:18]COCC>CN(C)C=O>[C:1]1([CH:7]([C:11]([OH:13])=[O:12])[C:8]([O:10][CH3:18])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOCC
Reactant: O=C(O)C(C(=O)O)c1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)C(C(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
Phenylmalonic acid (13.5 g, 0.07 mol) in dry ether (40 mL) was treated with thionyl chloride (8.92 g, 5.4 mL, 0.071 mol) and one drop of N,N-dimethylformamide. The mixture was heated at 40°-50° C. for 3 hours. The clear solution was evaporated under reduced pressure to remove any residual thionyl chloride. The oily residue was redissolved in dry ether (40 mL) and the solution was treated with methyl alcohol (0.075. mol, 3 mL) and refluxed for 2 hours. The reaction mixture was cooled to room temperature and washed with water. The organic layer was extracted with saturated solution of sodium bicarbonate until alkaline. The combined extracts were washed with ether and the aqueous layer acidified with 5N HCl to pH 1. The precipitated oil was extracted with CH2Cl2 (50 ml×3). The combined extracts were washed with water (50 mL×4) and dried over anhydrous MgSO4. The oily product crystallized on standing.
Reaction SMILES: Cl[C:2]([CH2:7][C:8]([F:33])([F:32])[CH2:9][C@H:10]([C@@H:12]1[C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19]([CH2:20][C@@H:21]([OH:31])[CH2:22][CH2:23]2)=[CH:18][CH2:17]3)[CH2:14][CH2:13]1)[CH3:11])([CH2:5][OH:6])[CH2:3][OH:4].[H-].[Na+]>C(COC)OC>[O:4]1[CH2:3][C:2]1([CH2:7][C:8]([F:33])([F:32])[CH2:9][C@H:10]([C@@H:12]1[C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19]([CH2:20][C@@H:21]([OH:31])[CH2:22][CH2:23]2)=[CH:18][CH2:17]3)[CH2:14][CH2:13]1)[CH3:11])[CH2:5][OH:6]
Reactant: C[C@H](CC(F)(F)CC(Cl)(CO)CO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C[C@H](CC(F)(F)CC1(CO)CO1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 38.7 %

Procedure:
The chlorodiol (11) (183 mg, 0.32 mmol) was treated with sodium hydride (18 mg, 0.75 mmol) in dimethoxyethane (18 ml) at room temperature for 6 days. The usual work-up (ether for extraction) gave a crude product, which was applied to a column of silica gel (100 g). Elution with dichloromethane provided the epoxyalcohol (12) (56 mg, 32%), glass. 1H-NMr δ: 2.92 (2H, m, 26-H2), 3.67-4.16 (3H, m, 3-H and 27-H2). MS m/z: 434 (M+ -THP OH), 416, 404, and the recovery of chlorodiol 11 (92 mg, 50%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:37]=[CH:36][C:27]([CH2:28][CH2:29][CH2:30][PH:31](=[O:35])[O:32]CC)=[CH:26][C:25]=3[O:38][CH3:39])[N:14]=2)=[CH:4][CH:3]=1.Br[Si](C)(C)C.CO>N1C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:37]=[CH:36][C:27]([CH2:28][CH2:29][CH2:30][PH:31](=[O:32])[OH:35])=[CH:26][C:25]=3[O:38][CH3:39])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CCO[PH](=O)CCCc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: c1ccncc1
Product: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCC[PH](=O)O)cc2OC)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of ethyl (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)ethylphosphinate (Compound 67C, 1.11 g, 1.76 mmol) in pyridine (15.0 mL) was cooled to 0° C. and then charged with bromotrimethylsilane (1.39 mL, 10.6 mmol). The reaction mixture was slowly warmed to rt with stirring for 72 hours. The reaction mixture was quenched with MeOH (2.3 mL, 57 mmol) and then concentrated under reduced pressure to a yellow oil. The material was dissolved in DCM (10 mL) and washed with 3N HCl (10 mL), was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to a light yellow solid. The acid layer was saturated with solid NaCl and extracted with DCM (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to a light yellow solid. Both batches of solid were combined (932.5 mg, 88%). 1H NMR (CDCl3, 400 MHz): δ=8.91 (d, J=8.3 Hz, 1H), 8.34 (s, 1H), 8.10 (q, J=4.6 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 6.89 (s, 1H), 6.82 (d, J=8.1 Hz, 1H), 3.87 (s, 3H), 3.00-3.10 (m, 5H), 1.54-1.68 (m, 2H), 1.13 (td, J=7.5, 18.3 Hz, 3H). MS (ESI): m/z 603.42/605.40 [M+H]+. UPLC: tR=1.24 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17](Cl)=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C@@H:21]1[CH2:26][O:25][CH2:24][CH2:23][NH:22]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][C@H:21]3[CH3:20])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1COCCN1
Reactant: Clc1cnc2c(n1)OCCN(Cc1ccccc1)C2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H]1COCCN1c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Temperature: 100 °C
Yield: 49.1 %

Procedure:
A suspension of 8-benzyl-3-chloro-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (208 mg), (3R)-3-methylmorpholine (115 mg), Pd2(dba)3 (21 mg), XPhos (44 mg) and sodium tert-butoxide (145 mg) in toluene (5 mL) was stirred under an argon atmosphere with heating at 100° C. for 3 hr. Water was added to the reaction mixture, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (solvent gradient: 9→50% ethyl acetate/hexane) to give the title compound (126 mg, 60%) as a pale-yellow oil.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].Br[CH2:18][CH:19]1[CH2:21][O:20]1>C1COCC1>[O:20]1[CH2:21][CH:19]1[CH2:18][N:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]1=[O:1]
Reactant: BrCC1CO1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CC2CO2)C(=O)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
tert-butyl 3-oxopiperazine-1-carboxylate (400 mg, 2 mmol) was dissolved in THF (20 mL) and cooled to 0° C. NaH (72 mg, 3 mmol) was added to the solution followed by 2-(bromomethyl)oxirane (326 mg, 2.4 mmol), and the resulting mixture was stirred at 0° C. for 16 h. The reaction mixture was quenched by addition of ice water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated. The crude product was used without further purification. (400 mg, yield 78.1%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.Cl[CH:22]([C:25]1([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[N:34]=[CH:33][CH:32]=[CH:31]3)[CH2:27][CH2:26]1)[CH:23]=O.C(N(CC)CC)C>C(O)(C)C>[N:34]1[C:35]2[C:30](=[CH:29][C:28]([C:25]3([C:22]4[N:3]5[CH:4]=[C:5]([C:8]6[CH:9]=[CH:10][C:11]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[CH:19][CH:20]=6)[CH:6]=[N:7][C:2]5=[N:1][CH:23]=4)[CH2:27][CH2:26]3)=[CH:37][CH:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cnc(N)nc2)cc1
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1
Temperature: 90 °C
Yield: 50.9 %

Procedure:
A mixture of tert-butyl 4-(2-aminopyrimidin-5-yl)benzoate (0.144 g, 0.531 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.156 g, 0.637 mmol) in isopropyl alcohol (3 mL) was heated at 90° C. overnight. The mixture was adjusted to pH=9 using triethylamine, solvent was removed and the residue was purified by chromatography on silica gel using MeOH in methylene chloride (0-5%) to afford the desired product (125 mg, 50.9%). LCMS: (M+H)=463.1.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([OH:15])=O.[Cl-].[NH4+].C([N:20](CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:20])=[O:15]
Reactant: CCN(CC)CC
Reactant: Nc1cc(-c2ccncc2)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: NC(=O)c1sc(-c2ccncc2)cc1N
Reaction time: 0.08 h
Yield: 84.4 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxylic acid (0.220 g, 1.00 mmol), ammonium chloride (0.267 g, 5.00 mmol), triethylamine (0.70 mL, 5.0 mmol) and DMF (3.0 mL) was stirred for 5 min. 1-Hydroxybenzotriazole (0.204 g, 1.50 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.286 g, 1.50 mmol) were added and stirring was continued overnight. Then, DMF (2 mL), ammonium chloride (0.267 g, 5.00 mmol), triethylamine (0.70 mL, 5.0 mmol), 1-hydroxybenzotriazole (0.204 g, 1.50 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.286 g, 1.50 mmol) were added again. After 6 h, the mixture was poured into aqueous sodium hydrogen carbonate (50 mL). Extraction with ethyl acetate-tetrahydrofuran (2:1, 2×30 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave the title compound (0.185 g, 84%) as a yellow solid:
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:34])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([Cl:33])[C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=1)([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].[OH-].[Na+].Cl>C(O)C.O1CCCC1>[C:1]([O:4][C:5]1[C:6]([CH3:34])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH:27]([Cl:33])[C:28]([OH:30])=[O:29])=[CH:24][CH:25]=1)([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CCc3c(C)c(OC(C)=O)c(C)c(C)c3O2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc(CC(Cl)C(=O)O)cc1)O2

Procedure:
0.16 g of ethyl 3-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl]-2-chloropropionate was dissolved in a mixture of 1.5 ml of 99.5% ethanol and 0.2 ml of tetrahydrofuran. 265 mg of a 9.55% w/w aqueous solution of sodium hydroxide were added dropwise, under a nitrogen stream at 0°-4° C., to the resulting mixture. The mixture was then reacted for a further 20 hours at 0°-5° C., after which it was neutralized, whilst ice-cooling, by adding 0.68 g of a 10% w/w aqueous solution of hydrochloric acid. The solvent was then distilled off under reduced pressure. The separated light reddish oil was further extracted with chloroform, and the chloroform extract was washed with water and dried over anhydrous sodium sulfate. The crude product obtained by distilling off the chloroform under reduced pressure was subjected to column chromatography through silica gel and the desired 3-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl]-2-chloropropionic acid was obtained from the fractions eluted with a 20:1 by volume mixture of benzene and 99.5% ethanol. Rf value on thin layer chromatography: 0.6 (tailing) [silica gel; developing solvent; benzene:99.5% ethanol=4:1 by volume].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])[CH:2]=1.Cl.[CH2:13](O)[CH3:14]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([O:11][CH2:13][CH3:14])=[O:10])[CH:2]=1
Reactant: CCO
Reactant: O=C(O)C=Cc1cccnc1
Agent: Cl
Product: CCOC(=O)C=Cc1cccnc1

Procedure:
To a stirred suspension of 150 g of β-(3-pyridyl)acrylic acid in 1500 ml of ethanol a slow stream of hydrogen chloride gas is bubbled for 4 to 5 hr, where all solids dissolved. Approximately 500 ml of ethanol are distilled off at atmospheric pressure, the residual solution is cooled and diluted with 1500 ml of ether with stirring. The solids are filtered, washed with ether and resuspended in ethyl acetate. The stirred suspension is neutralized with conc. aq. sodium bicarbonate. The ethyl acetate layer is separated and the aqueous layer is extracted once more with ethyl acetate. The combined organic extracts are washed with brine, dried (MgSO4), evaporated and the residual oil is distilled to give 110 g of ethyl β-(3-pyridyl)acrylate with bp 95°-100° C., 0.1 mm/Hg.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][C:3]=1[CH3:12].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH3:12]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cc(CO)ccc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
Methyl 4-bromo-3-methylbenzoate (17.0 g, 74.2 mmol) is dissolved in anhydrous THF (100 mL). The solution is cooled to 0° C. and a 2 M solution of lithium aluminum hydride in THF (40 mL) is added to the mixture. The solution is left stirring 30 min. at this temperature. A cold HCl solution is then added drop wise to the reaction mixture until dissolution of the aluminum complex. The desired product is extracted with ethyl acetate, the organic phase is washed with brine (200 mL), dried with MgSO4 and concentrated in vacuo. to provide the expected product (4-Bromo-3-methylphenyl)methanol (14.4 g, 97%) as a clear yellow oil, pure by proton NMR, and is used as such in the next step. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.40 (s, 3H) 4.61 (s, 2H) 6.89-7.10 (m, J=8.20, 1.56, 0.59 Hz, 1H) 7.23 (d, J=2.34 Hz, 1H) 7.50 (d, J=8.20 Hz, 1H)
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>O1CCCC1.O>[CH2:31]([O:30][C:28]([N:16]1[CH2:17][CH2:18][N:13]([C:11]([N:9]2[CH2:8][CH:7]([O:6][C:5]3[CH:19]=[CH:20][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:10]2)=[O:12])[CH2:14][CH2:15]1)=[O:29])[CH3:32]
Reactant: CCOC(=O)Cl
Reactant: O=C(N1CCNCC1)N1CC(Oc2ccc(F)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)N2CC(Oc3ccc(F)cc3)C2)CC1
Reaction time: 0.25 h
Yield: 71.1 %

Procedure:
A stirred mixture of 2.8 g (0.01 mole) of 1-[3-(4-fluorophenoxy)-1-azetidinylcarbonyl]piperazine and 1.4 g (0.01 mole) of potassium carbonate in 20 ml of tetrahydrofuran was treated with 1.1 g (0.01 mole) of ethyl chloroformate. After stirring for 15 minutes, a small piece of ice was added and stirring continued for 72 hr. The reaction mixture was diluted with water and the oil which separated solidified on standing. The solid residue was purified by column chromatography (silica gel; washed with chloroform and eluted with ethyl acetate) to give the product 2.5 g (71%) which was recrystallized from benzene/ligroin to yield 2.35 g (66.7%) of white crystalline product, m.p. 89°-90° C.