Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[O:19]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[N:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:33](=[O:34])[CH2:32][C:29]3[CH:30]=[CH:31][C:26]([O:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:27][CH:28]=3)[N:11]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C(O)Cc1ccc(Oc2ccccc2)cc1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1ccc(Oc2ccccc2)cc1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(4-phenoxyphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ 8.31 (dd, J=7.9, 0.7, 1H), 8.03 (d, J=7.7, 1H), 8.02-7.96 (m, 1H), 7.95-7.87 (m, 1H), 7.46-7.36 (m, 4H), 7.20-7.12 (m, 1H), 7.05-6.97 (m, 4H), 3.88-3.78 (m, 4H), 3.67 (s, 2H), 3.13-3.05 (m, 4H); MS (ESI−) M/Z 455 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH:5]=[CH2:6])[CH3:2].[CH3:8][O:9][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12].[CH2:15](OC(=O)C(C)=C)[CH:16]1[O:18][CH2:17]1.[C:25]([OH:30])(=[O:29])[C:26]([CH3:28])=[CH2:27]>>[CH2:1]([O:3][C:4](=[O:7])[CH:5]=[CH2:6])[CH3:2].[C:10]([O:9][CH3:8])(=[O:14])[C:11]([CH3:13])=[CH2:12].[CH2:15]([CH:27]=[C:26]([CH3:28])[C:25]([OH:30])=[O:29])[CH:16]1[O:18][CH2:17]1
Reactant: C=C(C)C(=O)OCC1CO1
Reactant: C=C(C)C(=O)O
Agent: C=C(C)C(=O)OC
Agent: C=CC(=O)OCC
Product: CC(=CCC1CO1)C(=O)O

Procedure:
The procedure of Example 1 was repeated, a mixture of monomers containing 250 g of ethylacrylate, 185 g of methylmethacrylate, 100 g of glycidylmethacrylate, 25 g of methacrylic acid was employed.
Reaction SMILES: [CH2:1]([O:5][N:6]=[C:7]([C:13](=O)[CH2:14]Cl)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][CH2:3][CH3:4].[NH2:17][C:18]([NH2:20])=[S:19].C([O-])(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[NH2:20][C:18]1[S:19][CH:14]=[C:13]([C:7](=[N:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:17]=1
Reactant: CCCCON=C(C(=O)CCl)C(=O)OCC
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCON=C(C(=O)OCC)c1csc(N)n1
Reaction time: 0.33 h
Yield: 63.8 %

Procedure:
A solution of ethyl 2-n-butoxyimino-4-chloro-3-oxobutyrate (syn isomer, 52.1 g.), thiourea (15.9 g.), sodium acetate 3 hydrate (28.4 g.), water (130 ml.) and ethanol (180 ml.) was stirred at 40° C. for 1.25 hours. The resultant solution was adjusted to pH 6.5 with an aqueous solution of sodium carbonate under ice cooling, and stirred for 20 minutes under ice cooling. The precipitates were collected by filtration, and washed with water and diisopropyl ether in turn to give ethyl 2-(2-aminothiazol-4-yl)-2-n-butoxyiminoacetate (syn isomer, 36.1 g.), mp 126° to 128° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:13]=[C:12]([OH:14])[C:11]([OH:15])=[C:10]([N+:16]([O-:18])=[O:17])[CH:9]=1.Br[CH2:20][CH2:21]Br>CN(C=O)C.C(OCC)(=O)C>[F:7][C:8]1[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[C:11]2[O:15][CH2:21][CH2:20][O:14][C:12]=2[CH:13]=1
Reactant: O=[N+]([O-])c1cc(F)cc(O)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)cc2c1OCCO2
Reaction time: 2 h
Yield: 99 %

Procedure:
K2CO3 (15.27 g, 110.6 mmol) was added to a solution of 5-fluoro-3-nitrobenzene-1,2-diol (5 g, 28.9 mmol) in DMF (35 mL) followed by the addition of 1,2-Dibromoethane (13.63 g, 6.25 mL, 72.5 mmol) and stirring was continued at 80° C. for 2 h. Reaction mixture was diluted with ethyl acetate, washed with cold water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude, which was purified by MPLC (silica gel, Mobile Phase: ethyl acetate in n-Hexane 0 to 5% as eluant) to afford 7-fluoro-5-nitro-2,3-dihydrobenzo[b][1,4]dioxine (Int-26) (5.7 g, 85% yield) as pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.3-7.2 (1H, dd), 6.9-6.8 (1H, dd), 4.4 (4H, s) ppm.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>C(O)C.[Pd]>[NH2:11][C:9]1[C:8]([O:14][CH3:15])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[CH:10]=1
Reactant: COc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(C(=O)O)c(F)cc1N
Yield: 45.8 %

Procedure:
2-fluoro-5-methoxy-4-nitrobenzoic acid (Intermediate 12; 7.76 g, 36.1 mmol) was stirred and dissolved in ethanol (200 mL) over 5% Pd/C (770 mg) and hydrogenated at ambient temperature for 4 hours. During this time product precipitated in the reaction. DMF (20 mL) was added to give a solution. The catalyst was filtered off and washed with EtOH and the solvent evaporated. The residue was triturated with diethyl ether to yield the title compound as a dark brown solid (3.06 g, 46%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16](Cl)=[C:11]3[C:10]([I:18])=[N:9]2)=[CH:5][CH:4]=1.[F:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]2[N:45]=[CH:44][CH:43]=[CH:42][C:31]=2[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)=[O:33])[CH:25]=[CH:26][C:27]=1[OH:28].C(=O)([O-])[O-].[Cs+].[Cs+].BrC1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:28][C:27]4[CH:26]=[CH:25][C:24]([NH:29][C:30]5[N:45]=[CH:44][CH:43]=[CH:42][C:31]=5[C:32]([NH:34][C:35]5[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=5)=[O:33])=[CH:23][C:22]=4[F:21])=[C:11]3[C:10]([I:18])=[N:9]2)=[CH:5][CH:4]=1
Reactant: O=C(Nc1ccc(F)cc1)c1cccnc1Nc1ccc(O)c(F)c1
Reactant: COc1ccc(Cn2nc(I)c3c(Cl)ccnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Brc1ccccc1
Product: COc1ccc(Cn2nc(I)c3c(Oc4ccc(Nc5ncccc5C(=O)Nc5ccc(F)cc5)cc4F)ccnc32)cc1
Temperature: 160 °C
Yield: 79.4 %

Procedure:
A 100 mL sealable tube was charged with 1-(4-methoxybenzyl)-4-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (0.250 g, 0.626 mmol Example 84, Step D), 2-(3-fluoro-4-hydroxyphenylamino)-N-(4-fluorophenyl)nicotinamide (0.427 g, 1.25 mmol), cesium carbonate (0.408 g, 1.25 mmol), and 1-bromobenzene (6.26 ml, 0.626 mmol). The reaction mixture was heated to 160° C. for 18 hours. The reaction mixture was cooled to ambient temperature and concentrated. The residue was dissolved in EtOAc and washed with brine. The crude material was purified by silica gel (Biotage 40S) eluting with 4:1 Hexane/EtOAc to provide the product (0.35 g, 71%). LRMS M−1 (704.9) observed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:22]([F:25])([F:24])[F:23])=[CH:10][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][NH2:33].[Cl-].C(N(CC)CCCN=C=NCC)C.C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:22]([F:25])([F:24])[F:23])=[CH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:33][CH2:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)=[O:18])=[CH:20][CH:21]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)c1ccc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1
Reactant: NCc1ccccn1
Agent: CCN=C=NCCCN(CC)CC
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(C(=O)NCc2ccccn2)cc1
Reaction time: 72 h
Yield: 27.6 %

Procedure:
To a solution of 0.5 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)benzoic acid that was synthesized under Synthetic Example 4 and 0.21 g of 2-picolylamine in 6 mL of N,N-dimethylformamide, 0.32 g of 1-(3-(diethylamino)propyl)-3-ethylcarbodiimide chloride was added at room temperature and the mixture was stirred for 72 hours. After the completion of reaction, 20 mL of ethyl acetate and 15 mL of saturated saline were added to the reaction solution, the mixture was separated to extract an aqueous layer with 10 mL of ethyl acetate whereto an organic layer was added, the resulting mixture was washed with 10 mL of water and dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. After purification of the resulting residue using silica gel column chromatography that was eluted with ethyl acetate-hexane (5:1) to obtain 0.17 g of aimed product as resinous matter.
Reaction SMILES: B(Br)(Br)Br.C(O[C:8](=[O:27])[C:9](=[CH:14][C:15]1[CH:20]=[C:19]([O:21]C)[C:18]([O:23]C)=[CH:17][C:16]=1[O:25]C)[CH2:10][C:11]([OH:13])=[O:12])C>ClCCl>[OH:21][C:19]1[CH:20]=[C:15]2[C:16](=[CH:17][C:18]=1[OH:23])[O:25][C:8](=[O:27])[C:9]([CH2:10][C:11]([OH:13])=[O:12])=[CH:14]2
Reactant: CCOC(=O)C(=Cc1cc(OC)c(OC)cc1OC)CC(=O)O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)Cc1cc2cc(O)c(O)cc2oc1=O
Reaction time: 72 h

Procedure:
Boron tribromide (3 ml) was added to a solution of 2-(2,4,5-trimethoxy-benzylidene)-succinic acid 1-ethyl ester obtained from the previous step (a) (4 g) in dichloromethane (40 ml) at −20° C. under nitrogen atmosphere. The reaction was kept on ice for an hour and then at room temperature for three days. After water treatment , filtering and trituration with warm 2-propanol the product was filtered. Yield: 1.1 g
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[CH:9][N:10]([CH:12]([CH3:16])[CH2:13][CH:14]=O)[CH:11]=2)[CH:2]=1.[NH:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH2:18].C(=O)([O-])[O-].[Na+].[Na+]>CC(O)=O.O.CCOC(C)=O>[CH3:23][C:22]([O:21][C:19]([NH:17][NH:18][CH2:14][CH2:13][C@H:12]([N:10]1[CH:11]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]=[CH:9]1)[CH3:16])=[O:20])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(CC=O)n1cnc(-c2cccnc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: C[C@H](CCNNC(=O)OC(C)(C)C)n1cnc(-c2cccnc2)c1
Reaction time: 1 h

Procedure:
(R/S)-3-(4-pyridin-3-yl-imidazol-1-yl)-butan-1-al (11) (1 mmol) is dissolved in 10 mL HOAc and t-butyl hydrazinecarboxylate (1.1 mmol) is added. After 1 h, NaHB(OAc)3 (5 mmol) is added at 25° C. After 2 h, the reaction is poured into sodium carbonate in water and EtOAc. The water layer is removed, the organics are washed with brine, and dried over sodium sulfate. The solvent is removed in vacuo to leave the product (32).
Reaction SMILES: [CH3:1][CH:2]([OH:7])[CH:3]([OH:6])[CH2:4][CH3:5].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([O:7][CH:2]([CH:3]([O:6][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:4][CH3:5])[CH3:1])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(O)C(C)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(OS(C)(=O)=O)C(C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
Pentane-2,3-diol 1.04 g (10.0 mole) and triethylamine 2.23 g (22.0 mole) were dissolved in 40 mL of methylene chloride, and methanesulfonyl chloride 2.52 g (22.0 mole) was dropwise added thereto in a range of 0 to 5° C. and stirred at 0° C. for 30 minutes. After the raw materials were confirmed to be exhausted by gas chromatography analysis, the organic layer was washed with 20 ml of water and then 20 ml of a saturated salt solution. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was refined by column chromatography (Wako Gel C-200, hexane/ethyl acetate=2/1 eluted) to obtain 2.24 g of pentane-2,3-diyl dimethanesulfonate (pale orange liquid; novel compound) which was the targeted product (yield: 86%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[NH2:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25]>C(Cl)Cl>[OH:26][CH:23]([CH2:24][OH:25])[CH2:22][NH:21][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCC(O)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)NCC(O)CO)cc1
Reaction time: 2 h

Procedure:
A solution of 4-nitrobenzenesulfonyl chloride (Fluka, 1.00 g; 4.51 mmol) in DCM (20 mL) was treated with triethylamine (1.25 ml; 9.02 mmol) and 3-amino-1,2-propanediol (Aldrich, 518 μA; 6.77 mmol). After 2 hours, the organic solvents were evaporated in vacuo, the residue was taken up in EtOAc and extracted with a saturated NH4Cl solution. The combined organic layers were dried over MgSO4 and evaporated to dryness to give the title compound as a yellow solid.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O.O>CCOCC.C([O-])(=O)C>[Br:14][C:3]1[CH:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: O
Product: Brc1ccc2[nH]c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76989.7 %

Procedure:
32 g (0.19 mmol) of 9H-carbazole was put into a 2 L Erlenmeyer flask, and then ether acetate (1.2 L) was added thereto so that the 9H-carbazole was dissolved in the ether acetate. To this solution was added 34 g (0.19 mol) of N-bromosuccinimide (NBS), and the mixture was stirred for about 15 hours in the air at room temperature. After the stirring, water was added to the mixture so that the precipitate was dissolved in the mixture. The organic layer of this mixture was washed with water three times and then with a saturated saline solution once. Magnesium sulfate was added so that the organic layer was dried. After the drying, the mixture was subjected to gravity filtration. The obtained filtrate was condensed to give a white solid. The obtained solid was recrystallized with ether acetate/hexane to give 36 g of a white powdered solid, which was the object of the synthesis, at a yield of 67%. A synthesis scheme of Step 1 is shown in (c-1) given below.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[N:7]=[C:8]([S:10][CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[CH:14][N:13]=3)[NH:9][C:5]=2[CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:29]>C(OCC)(=O)C>[CH3:21][C:15]1[CH:14]=[N:13][C:12]([CH2:11][S+:10]([O-:29])[C:8]2[NH:7][C:6]3[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:9]=2)=[C:17]([CH3:18])[C:16]=1[O:19][CH3:20]
Reactant: COc1ccc2nc(SCc3ncc(C)c(OC)c3C)[nH]c2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Yield: 79 %

Procedure:
5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]benzimidazole (10 g; 0.0304 mole) was suspended in ethyl acetate (100 ml) and cooled below 0° C. 3-chloroperoxybenzoic acid (5.25 g; 0.0304 mole) was added in such a manner that the temperature did not exceed 5° C. After completed addition it was left to crystallize for another half an hour at a temperature below 5° C. The product formed was filtered off, washed with ethyl acetate and dried in vacuo. Crude omeprazole (8.3 g; 79.1%) was obtained.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:23]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:25]=[CH:26][CH:27]=1)=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:20][C:22]4[CH:23]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:25]=[CH:26][CH:27]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: CC(=O)Nc1cccc(C=O)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CC(=O)Nc1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with N-(3-formylphenyl)acetamide was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give N-[3-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]phenyl]acetamide.
Reaction SMILES: [H-].[K+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][CH2:15][OH:16].[CH2:17]([Sn:21]([CH2:30]I)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>O1CCCC1.CCCCCC>[CH2:17]([Sn:21]([CH2:30][O:16][CH2:15][CH2:14][CH2:13][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]=1)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:18][CH2:19][CH3:20]
Reactant: OCCCc1ccc2ccccc2c1
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)COCCCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium hydride (315 mg, 7.87 mmol) was added to a solution of 3-(2-naphthyl)propan-1-ol (1.33 g, 7.16 mmol) in tetrahydrofuran (10 ml) at room temperature under argon. After 1/2 hour, a solution of tributylstannylmethyliodide (3.09 g, 7.16 mmol) in tetrahydrofuran (2 ml) was added. After stirring at room temperature for 10 days, the mixture was diluted with hexane and washed thoroughly with water. Evaporation of the dried (magnesium sulphate) organic layer gave an oil, which was flash chromatographed on silica using 5% ethyl ether/petroleum ether. The title ether was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[NH:4][C:5]2[C:6]([N:27]=1)=[C:7]1[C:12](=[CH:13][CH:14]=2)[CH2:11][CH2:10][CH:9]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[O:8]1.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CS(C)=O>[CH2:30]([NH:37][CH2:15][CH:9]1[O:8][C:7]2[C:12](=[CH:13][CH:14]=[C:5]3[N:4]=[C:3]([C:2]([F:29])([F:28])[F:1])[NH:27][C:6]3=2)[CH2:11][CH2:10]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc4[nH]c(C(F)(F)F)nc4c3O2)cc1
Solvent: CS(C)=O
Solvent: O
Product: FC(F)(F)c1nc2ccc3c(c2[nH]1)OC(CNCc1ccccc1)CC3
Temperature: 80 °C
Reaction time: 6 h
Yield: 173.8 %

Procedure:
To a solution of toluene-4-sulfonic acid 2-trifluoromethyl-3,6,7,8-tetrahydro-9-oxa-1,3-diaza-cyclopenta[a]naphthalen-8-ylmethyl ester (213 mg, 0.5 mmol) in dimethyl sulfoxide (20 mL) was added benzylamine (268 mg, 2.5 mmol). The reaction mixture was stirred at 80° C. for 6 h, cooled to room temperature and then poured into water (20 mL), extracted with chloroform (3×30 mL) dried over anhydrous Na2SO4. Purification by chromatography (ethyl acetate) provided 314 mg (87%) of the title compound which was converted to its oxalate salt: mp 244° C.; 1H NMR (400 MHz, CDCl3): δ1.81 (m, 1H), 2.13 (m, 1H), 2.84 (m, 2H), 3.28 (m, 2H), 4.25 (d, J=13.4 Hz, 1H), 4.31 (d, J=13.4 Hz, 1H), 4.50 (m, 1H), 7.08 (d, J=8.4 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.42 (m, 3H), 7.58 (m, 2H), 13.85 (bs, 1H); IR: 3450, 3080, 2980, 1725, 1640, 1600, 1550,1080 cm−1; MS 362 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:31])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:30])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:29])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:28])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:27])[C:24](O)=[O:25])=[O:5])[CH3:2].[CH3:32][NH:33][CH3:34]>>[CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:31])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:30])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:29])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:28])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:27])[C:24]([N:33]([CH3:34])[CH3:32])=[O:25])=[O:5])[CH3:2]
Reactant: CNC
Reactant: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Product: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N(C)C

Procedure:
Starting materials: 19-ethoxycarbonyl-2,6,10,14,18-pentamethyl-2,6,10,14,18-nonadecapentaenoic acid and dimethylamine (50% aqueous dimethylamine solution)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH2:18][CH:19]4[CH2:24][C:23]([F:26])([F:25])[CH2:22][CH2:21][NH:20]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.ClC1C=C2C(C3N=C(NCC4CC(F)(F)CCN4C(OC(C)(C)C)=O)C(F)=CN=3)=CNC2=NC=1.CCN(C(C)C)C(C)C.[CH3:71][O:72][CH2:73][CH2:74][C:75](Cl)=[O:76]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH2:18][CH:19]4[CH2:24][C:23]([F:26])([F:25])[CH2:22][CH2:21][N:20]4[C:75](=[O:76])[CH2:74][CH2:73][O:72][CH3:71])[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCCC(=O)Cl
Reactant: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1NCC1CC(F)(F)CCN1
Agent: CC(C)(C)OC(=O)N1CCC(F)(F)CC1CNc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCC(=O)N1CCC(F)(F)CC1CNc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-[(4,4-difluoro-2-piperidyl)methyl]-5-fluoro-pyrimidin-4-amine, 13k, (0.086 g, 0.198 mmol) in CH2Cl2 (1 mL), DMF (0.5 mL) and iPr2NEt (0.10 mL, 0.57 mmol) was added 3-methoxypropanoyl chloride (2.43 g, 0.20 mmol). The reaction mixture was stirred at room temperature for 17 hours. All volatiles were removed at reduced pressure and the residue was purified via silica gel chromatography to give a mixture enriched in desired product, 13, which was repurified via preparatory HPLC.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([F:31])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29]C)=[O:28])[CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CCO>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[C:13]([F:31])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([OH:29])=[O:28])[CH2:24]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CN(Cc2ccc3c(F)c(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CN4CC(C(=O)O)C4)ccc3c2F)CC1
Temperature: 0 °C

Procedure:
To a solution of methyl 1-((6-((trans)-4-tert-butylcyclohexyloxy)-5-fluoronaphthalen-2-yl)methyl)azetidine-3-carboxylate 40 mg, 0.09 mmol) in EtOH (3 mL) was added aqueous NaOH (2 mL, 1%, 5.0 eq.) and refluxed for 1 h. Then the reaction was cooled to 0° C., the pH of the solution was adjusted to 6 with 1M HCl, concentrated and the residue was washed with DCM and water, dried in vacuum to give product 1-((6-((trans)-4-tert-butylcyclohexyloxy)-5-fluoronaphthalen-2-yl)methyl)azetidine-3-carboxylic acid (30 mg, 78%) as a white solid. EDI-MS (M+1)+: 414.0. HPLC: 91.27%. 1H NMR (400 MHz, CD3OD) δ 8.09-8.01 (m, 2H), 7.74-7.71 (m, 1H), 7.59-7.58 (m, 1H), 7.48 (t, 1H), 4.57 (s, 2H), 4.38-4.32 (m, 5H), 3.76-3.70 (m, 1H), 2.21-2.19 (m, 2H), 1.91-1.88 (m, 2H), 1.53-1.44 (m, 2H), 1.24-1.10 (m, 3H), 0.90 (s, 9H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.[OH:18][C:19]1[C:24]([OH:25])=[CH:23][CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27]>C1C=CC=CC=1>[OH:18][C:19]1[C:24]([O:25][CH:17]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:23][CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1cccc(O)c1O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=[N+]([O-])c1cccc(OC2CCCCO2)c1O
Reaction time: 168 h

Procedure:
0.030 g of p-toluenesulphonic acid and 17.8 g of 3,4-dihydro-2H-pyrane are added to a mixture of 29.8 g of 2,3-dihydroxy-nitrobenzene in 400 ml of absolute benzene and the solution is left to stand for 7 days at 20°. It is filtered through 15 g of a silica gel formulation (Merck silica gel 60; grain size 0.063-0.200 mm) and the silica gel is rinsed with benzene. After distilling off the benzene under reduced pressure, a reddish oil is obtained which, when crystallised from hexane, gives 2-hydroxy-3-(tetrahydropyran-2-yloxy)-nitrobenzene in the form of yellow crystals; melting point 72°-73°.