Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]2O)=[CH:4][CH:3]=1.BrC1C=CC(O[C@@H]2CCCC[C@H]2O)=CC=1.[CH3:31][CH:32]([S:34]([NH2:37])(=[O:36])=[O:35])[CH3:33]>>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]2[NH:37][S:34]([CH:32]([CH3:33])[CH3:31])(=[O:36])=[O:35])=[CH:4][CH:3]=1
Reactant: O[C@H]1CCCC[C@@H]1Oc1ccc(Br)cc1
Reactant: CC(C)S(N)(=O)=O
Agent: O[C@@H]1CCCC[C@H]1Oc1ccc(Br)cc1
Product: CC(C)S(=O)(=O)N[C@H]1CCCC[C@H]1Oc1ccc(Br)cc1

Procedure:
The title compound of Step 7 was prepared according to the general procedure for the synthesis of cis-N-[2-(4-bromophenoxy)cyclopentyl]propane-2-sulfonamide in Example 5, except that (1S,2R)-2-(4-bromophenoxy)cyclohexanamine was used in place of cis-2-(4-bromophenoxy)cyclopentan-amine, and the product purification was carried out using a gradient of 0% to 1% methanol in dichloromethane. N-[(1S,2R)-2-(4-bromophenoxy)cyclohexyl]propane-2-sulfonamide was obtained as a white foam. Yield: 1.67 g, 4.44 mmol, 75%. 1H NMR (400 MHz, CDCl3) δ 1.36 (d, J=6.9 Hz, 3H), 1.37 (d, J=6.9 Hz, 3H), 1.37-1.48 (m, 4H), 1.77-1.88 (m, 3H), 2.06 (m, 1H), 3.12 (septet, J=6.8 Hz, 1H), 3.54 (m, 1H), 4.48 (d, J=9.5 Hz, 1H), 4.54 (m, 1H), 6.84 (d, J=9.0 Hz, 2H), 7.39 (d, J=9.0 Hz, 2H). The enantiomer of N-[(1S,2R)-2-(4-bromophenoxy)cyclohexyl]propane-2-sulfonamide was prepared using similar chemistry to that described above in this Step 7, but employing (1S,2S)-2-(4-bromophenoxy)cyclohexanol as starting material instead of (1R,2R)-2-(4-bromophenoxy)cyclohexanol. The absolute stereochemistry of the enantiomer of N-(1S,2R)-2-(4-bromophenoxy)cyclohexyl]propane-2-sulfonamide was established via X-ray crystallography.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:9][CH2:10][O-:11].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH2:10][CH3:9])=[N:6][CH:7]=1
Reactant: CC[O-]
Reactant: Clc1ncc(Br)cn1
Agent: [Na+]
Solvent: CCO
Product: CCOc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
5-Bromo-2-chloro-pyrimidine (5.0 g, 25 mmol) is dissolved in ethanol (55 mL) and sodium ethylate (1.81 g, 26.6 mmol) is added in portions. The reaction mixture is stirred for 15 hours at ambient temperature. When the reaction is complete, the solvent is evaporated off, water (200 mL) is added, and then the reaction mixture is extracted with dichloromethane (2×100 mL). The organic phase is dried over Na2SO4, and then evaporated to dryness to yield 5-bromo-2-ethoxy-pyrimidine.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][CH:13]=[CH:12][C:11]=2[CH:15]=1.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].O>C1COCC1>[CH2:25]([Sn:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:21][CH2:22][CH2:23][CH3:24])[C:13]1[O:14][C:10]2[CH:9]=[CH:8][C:7]([F:6])=[CH:15][C:11]=2[CH:12]=1)[CH2:26][CH2:27][CH3:28]
Reactant: Fc1ccc2occc2c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cc2cc(F)ccc2o1
Temperature: 25 °C
Yield: 22.5 %

Procedure:
Butyllithium (1.5 mL, 2.4 mmol, 1.6 M) was added at −75° C. to a solution of 5-fluorobenzofuran (0.3 g, 2.2 mmol) in THF (10 mL). Tributyltin chloride (0.98 g, 1 mL) was added at −75° C. and the mixture was allowed to warm to 25° C. over a period of 2 hours. Water (25 mL) was added and the aqueous layer was extracted with diethyl ether (2×25 mL). The combined organic extracts were dried over Na2SO4 and concentrated. Silica gel chromatography (pentane) provided tributyl-(5-fluorobenzofuran-2-yl)-stannane (210 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.O>[Zn].C(O)(=O)C>[NH2:9][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:16][C:6]=1[C:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:8]
Reactant: Brc1ccc2noc(-c3ccccc3)c2c1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(Br)cc1C(=O)c1ccccc1
Temperature: 80 °C
Yield: 98.2 %

Procedure:
5-Bromo-3-phenyl-2,1-benzisoxazole (7.5 g, 28.6 m mol), water (14.6 ml), and zinc dust (9.3 g, 143 m mol) were combined. Acetic acid (8.6 ml, 143 m mol) was added and the mixture was stirred and heated at 80° C. for 90 minutes. After cooling to room temperature, both the liquid and solid portion of the reaction were extracted with methylene chloride. The combined methylene chloride solutions was washed once with sodium hydroxide solution (10%) and several times with water. Drying (sodium sulfate) and evaporation yielded the desired product (7.42 g) of mp. 92°-102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[O:18][C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=3[F:27])=[C:15]3[C:10]([CH:11]=[C:12]([F:35])[C:13]([F:34])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[N-:36]=[N+:37]=[N-:38].[Na+].Cl.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[O:18][C:19]3[CH:26]=[CH:25][C:22]([C:23]4[NH:38][N:37]=[N:36][N:24]=4)=[CH:21][C:20]=3[F:27])=[C:15]3[C:10]([CH:11]=[C:12]([F:35])[C:13]([F:34])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(OC(c2c3cc(F)c(F)cc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Fc1cc2nn(-c3ccc(Cl)cc3)c(C(Oc3ccc(-c4nnn[nH]4)cc3F)C3CCCCC3)c2cc1F

Procedure:
In analogy to the procedure described in example 31, [rac]-4-{[2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-cyclohexyl-methoxy}-3-fluoro-benzonitrile (example 35) was reacted with sodium azide in the presence of triethylamine hydrochloride in DMF to obtain the title compound as yellow solid. MS: m/e=539.2 [M+H+].
Reaction SMILES: Br[C:2]1[S:19][C:5]2[CH2:6][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C@H:9]([CH3:11])[O:10][C:4]=2[C:3]=1[CH:20]([CH3:22])[CH3:21].[CH3:23]B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:11][C@H:9]1[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]2[S:19][C:2]([CH3:23])=[C:3]([CH:20]([CH3:22])[CH3:21])[C:4]=2[O:10]1
Reactant: CB(O)O
Reactant: CC(C)c1c(Br)sc2c1O[C@@H](C)CN(C(=O)OC(C)(C)C)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1sc2c(c1C(C)C)O[C@@H](C)CN(C(=O)OC(C)(C)C)C2
Yield: 92.9 %

Procedure:
A solution of tert-butyl (2S)-7-bromo-2-methyl-8-(1-methylethyl)-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (400 mg), methylboronic acid (245 mg), potassium phosphate (870 mg), tetrakis(triphenylphosphine)palladium (118 mg) and DME (6 mL) was stirred at 80° C. for 16 hr, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 3→7% ethyl acetate/hexane) to give the title compound (310 mg, 93%) as a solid.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>C1COCC1>[C:1]([Cl:12])(=[O:9])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccncc1
Solvent: C1CCOC1
Product: O=C(Cl)c1ccncc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Isonicotinic acid N (15 g, 121.8 mmol, obtained from Aldrich Chemical Co.) was added to about 100 mL of thionyl chloride and the reaction mixture was stirred for about 17 h at about 25° C. After this period, excess SOCl2 was removed under reduced pressure to provide a white solid. About 400 mL of THF was added to the resulting solid and the solvent was removed under reduced pressure to provide isonicotinic acid chloride as a white powder. The white powder was dissolved in about 400 mL of THF. The solution was cooled to about 0° C. and 4-trifluoromethyl-aniline (21.6 g, 134.0 mmol, 1.1 eq., obtained from Aldrich Chemical Co.) and sodium bicarbonate (30 g, 365.4 mmol, 3.0 eq.) were added. The reaction mixture was stirred for about 5 min at about 0° C., warmed to about 25° C. over about 30 min, then heated to about 65° C. and kept at that temperature for about 1 h. After this period, the reaction mixture was cooled to about 25° C. and the THF was removed under reduced pressure. The residue was suspended in about 800 mL of ethyl acetate and washed with about 600 mL of aqueous 3N HCl. Separate aqueous and organic layers formed. The layers were separated and the aqueous layer was extracted three times with about 600 mL of ethyl acetate per extraction. The organic layer was combined with the post-extraction ethyl acetate aliquots. The combination was dried with Na2SO4 and the solvent was removed under reduced pressure to provide 32 g of the Compound of Formula O as a white solid (99% yield).
Reaction SMILES: [CH3:1][C:2]([OH:22])([CH3:21])[CH2:3][N:4]([CH3:20])[CH2:5][CH2:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH3:30][Si:31](Cl)([CH3:33])[CH3:32]>C(Cl)Cl>[CH3:21][C:2]([O:22][Si:31]([CH3:33])([CH3:32])[CH3:30])([CH3:1])[CH2:3][N:4]([CH3:20])[CH2:5][CH2:6][CH:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(CCC(c1ccccc1)c1ccccc1)CC(C)(C)O
Reactant: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCC(c1ccccc1)c1ccccc1)CC(C)(C)O[Si](C)(C)C
Temperature: 12.5 °C

Procedure:
2,N-Dimethyl-N-(3,3-diphenylpropyl)-1-amino-2-propanol (5.0 gm) is dissolved in methylene chloride (25 ml) at 25-30° C., triethylamine (2.5 gm) is added and then the contents are cooled to 10-15° C. under N2 atmosphere. Trimethylsilyl chloride (2.5 gm) is slowly added to the reaction mass while maintaining the temperature 10-15° C., the mass temperature is raised to 25-30° C. and maintained for 2 hours at the same temperature to give the reaction mass of 2,N-dimethyl-2-(trimethylsilyloxy)-N-(3,3-diphenylpropyl)-1-propanamine.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][C:12](O)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.C(Cl)(=O)C([Cl:24])=O.CN(C)C=O>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]([CH2:11][C:12]([Cl:24])=[O:13])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)C[C@H](CC(=O)O)c1ccc2c(c1)OCO2
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](CC(=O)Cl)c1ccc2c(c1)OCO2
Reaction time: 24 h

Procedure:
(S)-3-(1,3-benzodioxol-5-yl)-5-ethoxy-5-oxopentanoic acid (2.01, 7.2 mmol) was dissolved in methylene chloride (50 mL) at O° C. under argon. An excess of oxalyl chloride (3 mL) was added along with a drop of dimethylformamide (catalyst). The reaction mixture was stirred 24 hours and concentrated to a crude brown oil. Yield=2.23 g (>100%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([NH2:39])=[N:31][CH:30]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:39][C:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:29]([C:2]2[N:3]=[C:4]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:5]3[S:10][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[CH:8][C:6]=3[N:7]=2)=[CH:30][N:31]=1
Reactant: CC1(C)OB(c2cnc(N)c3ccccc23)OC1(C)C
Reactant: CC(C)(O)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(O)c1cc2nc(-c3cnc(N)c4ccccc34)nc(N3CCOCC3)c2s1
Temperature: 140 °C
Yield: 5.6 %

Procedure:
To a solution of 2-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-ol (63 mg, 0.20 mmol) in acetonitrile (3.6 ml) in a microwave reaction vessel was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-amine (110 mg, 0.40 mmol), Bis(triphenylphosphine)palladium(II) chloride (7.02 mg, 0.010 mmol) and 1M sodium carbonate in water (0.60 ml). The reaction vessel was sealed and heated in the microwave at 140° C. for 20 minutes. LC-MS of the reaction mixture showed no more starting material. The solvent was evaporated and the resulting oil was purified on silica gel (0 to 20% of 2N NH3 in MeOH/DCM). The resulting oil was further purified by reversed phase HPLC to give 141 as an off-white solid (4.7 mg, 6%) 1H NMR (DMSO d6, 400 MHz) 9.02 (d, 1H, J=8.4 Hz), 8.26 (s, 1H), 8.26 (d, 1H, J=8.4 Hz), 7.67 (t, 1H, J=7.6 Hz), 7.50 (t, 1H, J=7.6)m 7.33 (s, 1H), 7.11 (s, 2H), 5.84 (s, 1H), 3.98-3.94 (m, 4H), 3.81-3.78 (m, 4H), 1.61 (m, 6H). LCMS m/z: 422 (MH+)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[N:8]/[OH:9].ClN1[C:15](=[O:16])[CH2:14][CH2:13]C1=O.C(O)C#C.C(N(CC)CC)C>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:13]=[C:14]([CH2:15][OH:16])[O:9][N:8]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O/N=C/c1ccccn1
Agent: C#CCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OCc1cc(-c2ccccn2)no1
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
A solution of (E)-picolinaldehyde oxime (4 g) in N,N-dimethylformamide (20 mL) was treated with N-chlorosuccinimide (4.81 g) at 0° C., in portions. The mixture was stirred at 60° C. for 2 hours. The mixture was then cooled to 0° C. and treated with prop-2-yn-1-ol (7.59 mL) through a syringe. A solution of triethylamine (5.02 mL) in N,N-dimethylformamide (4 mL) was added slowly (30 minutes). The resulting mixture was stirred at 0° C. for 1 hour, and then at room temperature for 18 hs. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was separated, dried and evaporated in vacuo to a yellow oil and purified by column chromatography on silica gel (2-10% methanol in dichloromethane) to obtain the title compound (4.25 g) having the following physical data.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]2[O:10][C:11]3[C:16]([C@@:17]4([CH2:22][CH2:21][O:20][C:19]([NH2:23])=[N:18]4)[C:4]=2[CH:3]=1)=[CH:15][C:14]([NH2:24])=[CH:13][CH:12]=3.[O:25]1[CH2:30][CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.O.C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[O:25]1[CH2:26][CH:27]=[C:28]([C:2]2[N:7]=[C:6]([O:8][CH3:9])[C:5]3[O:10][C:11]4[C:16]([C@@:17]5([CH2:22][CH2:21][O:20][C:19]([NH2:23])=[N:18]5)[C:4]=3[CH:3]=2)=[CH:15][C:14]([NH2:24])=[CH:13][CH:12]=4)[CH2:29][CH2:30]1
Reactant: COc1nc(Cl)cc2c1Oc1ccc(N)cc1[C@@]21CCOC(N)=N1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1nc(C2=CCOCC2)cc2c1Oc1ccc(N)cc1[C@@]21CCOC(N)=N1
Yield: 79.7 %

Procedure:
A mixture of (S)-3-chloro-1-methoxy-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.183 g, 0.528 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.222 g, 1.055 mmol), 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (0.019 g, 0.026 mmol) and potassium phosphate tribasic (0.336 g, 1.583 mmol) in dioxane/water (21 mL) was heated in microwave at 130° C. for 40 min. The mixture was poured into water and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-5% 2M NH3 MeOH/DCM to afford a yellow solid as (S)-3-(3,6-dihydro-2H-pyran-4-yl)-1-methoxy-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.166 g, 0.421 mmol, 80% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].S(C1C=CC(C)=CC=1)(OO[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:18][C:17]([F:20])([F:19])[CH2:16][CH2:15][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: Cc1ccc(S(=O)(=O)OOCCC(F)(F)F)cc1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=Cc1cccc(OCCC(F)(F)F)c1
Yield: 47.7 %

Procedure:
Combine 3-hydroxybenzaldehyde (130.2 g, 1.066 mol), 3,3,3-trifluoropropoxy tosylate (143 g, 0.533 mol), potassium carbonate (147.35 g, 1,066 mol) and absolute ethanol (1430 mL) in a three-necked round-bottomed flask equipped with a reflux condenser and a magnetic stirred and reflux for 4 h under argon atmosphere. Concentrate the reaction mixture under reduced pressure. Pour the concentrated mixture over 1N sodium hydroxide (2145 mL), stir for 30 min and extract with dichloromethane (2145 mL). Decant the organic layer wash with 1N sodium hydroxide (2145 mL). After separation, wash the organic layer successively twice by 1 L water (pH aqueous phase=7), dry over 30 g magnesium sulfate, evaporate the dichloromethane organic layer to dryness under reduced pressure to yield 55.4 g of the title compound (0.254 mol, 47.6% yield) as a slightly yellow oily material.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=3[F:24])=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:25][CH3:26].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][S:35]([CH3:34])(=[O:37])=[O:36])=[C:7]([O:25][CH3:26])[CH:8]=3)[N:13]=[CH:12][N:11]=2)=[C:18]([F:24])[CH:19]=1
Reactant: COc1cc2c(Oc3ccc(Br)cc3F)ncnc2cc1OCCCN
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc(Br)cc3F)ncnc2cc1OCCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.1 %

Procedure:
A solution of 7-(3-aminopropoxy)-4-(4-bromo-2-fluorophenoxy)-6-methoxyquinazoline (2.71 g, 6.4 mmol) and triethylamine (1.1 ml, 0.80 g, 7.9 mmol) in dichloromethane (15 ml) was treated with a solution of methanesulphonyl chloride (0.53 ml, 0.79 g, 6.9 mmol) in dichloromethane (10 ml) and stirred at ambient temperature, under nitrogen for 18 hours. The dichloromethane was then removed by evaporation and THF (4 ml) added. The resulting solution was treated with saturated aqueous sodium hydrogen carbonate solution (to pH 8), stirred vigorously for 30 minutes and the precipitate filtered, washed with water and dried to give 4-(4-bromo-2-fluorophenoxy)-6-methoxy-7-(3-(N-methylsulphonylamino)propoxy)quinazoline (2.98 g, 93%).
Reaction SMILES: [Si:1]([C:8]1[S:9][C:10]([C:13]2([OH:19])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:11][N:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O=[C:21]1[CH2:24][CH:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:22]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[Si:1]([C:8]1[S:9][C:10]([C:13]2([OH:19])[CH2:18][CH2:17][N:16]([CH:21]3[CH2:24][CH:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:22]3)[CH2:15][CH2:14]2)=[CH:11][N:12]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)c1ncc(C2(O)CCNCC2)s1
Reactant: CC(C)(C)OC(=O)NC1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CC(N2CCC(O)(c3cnc([Si](C)(C)C(C)(C)C)s3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 8 mL vial, was placed a solution of 4-(2-(tert-butyldimethylsilyl)thiazol-5-yl)piperidin-4-ol (as prepared in the previous step) (80 mg, 0.27 mmol, 1.00 equiv) in dichloromethane (1 mL), tert-butyl 3-oxocyclobutylcarbamate (as prepared in Step B, 128.8 mg, 0.70 mmol, 1.00 equiv) and NaBH(OAc)3 (273 mg, 1.29 mmol, 3.00 equiv). The reaction mixture was stirred for 2 h at room temperature. The reaction was then quenched by the addition of 4 ml, of H2O. The resulting solution was extracted with 3×5 mL of DCM. The combined organic layers washed with 2×5 mL of brine, dried (Na2SO4), and concentrated under vacuum. The title compound was obtained as a yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH2:10][CH:11]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12][CH3:13])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:25]([O:27][CH:28]([O:31][CH2:32][CH3:33])[C:29]#[CH:30])[CH3:26].ClC1N=C(NCCNC(=O)OC(C)(C)C)C(C#CC(OCC)OCC)=CN=1>>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][CH2:10][CH:11]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12][CH3:13])[C:2]([C:30]#[C:29][CH:28]([O:31][CH2:32][CH3:33])[O:27][CH2:25][CH3:26])=[CH:7][N:6]=1
Reactant: C#CC(OCC)OCC
Reactant: CCC(CNc1nc(Cl)ncc1Br)NC(=O)OCc1ccccc1
Agent: CCOC(C#Cc1cnc(Cl)nc1NCCNC(=O)OC(C)(C)C)OCC
Product: CCOC(C#Cc1cnc(Cl)nc1NCC(CC)NC(=O)OCc1ccccc1)OCC

Procedure:
benzyl N-[1-[[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]methyl]propyl]carbamate is prepared by treating benzyl N-[1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]propyl]-carbamate with 3,3-diethoxyprop-1-yne in the presence of a catalyst such as Pddba using similar experimental conditions as described for the synthesis of tert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4 yl]amino]ethyl]carbamate LCMS (ESI) (M+H) 461.
Reaction SMILES: [CH2:1]([O:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH3:2].[H-].[Na+].[CH3:14]I.O>CN(C=O)C>[CH2:1]([O:3][N:4]([CH3:14])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH3:2]
Reactant: CI
Reactant: CCONC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCON(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.8 %

Procedure:
A solution of tert-butyl ethoxycarbamate (XCIII, 2.48 g, 15.38 mmol) in DMF (10 mL) was added dropwise to the suspension of 60% sodium hydride (0.66 g, 16.92 mmol) in DMF (5 mL) at 0° C. After 30 min. methyl iodide (1.95 mL, 31.32 mmol) in DMF (10 mL) was added, and the reaction mixture was stirred at room temperature for 24 h. Water (100 mL) was added and the product was extracted with ethyl acetate (3×50 mL), dried over Na2SO4, and concentrated in vacuo to yield tert-butyl ethoxy(methyl)carbamate (XCIV, 2.34 g, 87%). 400 MHz 1H NMR (DMSO-d6, ppm) 3.81 (2H, q, J=7.0 Hz), 3.00 (3H, s), 1.41 (9H, s), 1.12 (3H, t, J=7.0 Hz).