Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17](Cl)=[O:18])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][NH:21][CH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([OH:33])[CH:27]=[CH:26]2.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[OH:33][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([CH2:22][N:21]([CH3:20])[C:17]([C:10]1[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=1)=[O:18])[CH:32]=[CH:31]2
Reactant: CNCc1ccc2cc(O)ccc2c1
Reactant: O=C(Cl)c1cn(Cc2ccccc2)c2ccccc12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(Cc1ccc2cc(O)ccc2c1)C(=O)c1cn(Cc2ccccc2)c2ccccc12
Reaction time: 8 h
Yield: 100 %

Procedure:
1-Benzyl-1H-indole-3-carbonyl chloride, prepared in the previous step, in 50 mL of anhydrous THF was added dropwise under nitrogen over 2 h to a mixture of 6-methylaminomethyl-naphthalen-2-ol (2.5 g, 13.37 mmol), prepared in step 1 of Example 32, and triethylamine (1.86 mL, 13.37 mmol) in 300 mL of anhydrous THF at room temperature. The reaction stirred for 17.5 h (overnight). A trace amount of solid was removed by filtration and the filtrate was concentrated under reduced pressure to give a brown oil. The oil was diluted with ethyl acetate, extracted two times with 1N HCl, dried (MgSO4) and the solvent removed under reduced pressure to give 1-benzyl-1H-indole-3-carboxylic acid (6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (5.83 g, 100%) as a brown foam, MS m/z: 421 [M+H]+.
Reaction SMILES: I[CH2:2][C:3]([F:6])([F:5])[F:4].[CH2:7]([N:10]1[C:18]2[C:13](=[N:14][C:15]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH:30]=[C:29]5[CH2:31][NH:32][CH2:33][C:28]5=[N:27]4)=[CH:22][CH:21]=3)=[C:16]([Cl:19])[CH:17]=2)[N:12]=[C:11]1[O:34][C@H:35]1[C@H:39]2[O:40][CH2:41][C@@H:42]([OH:43])[C@H:38]2[O:37][CH2:36]1)[CH:8]=[CH2:9].C(N(CC)C(C)C)(C)C.FC(F)(F)S(OCC(F)(F)F)(=O)=O>O1CCOCC1>[CH2:7]([N:10]1[C:18]2[C:13](=[N:14][C:15]([C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH:30]=[C:29]5[CH2:31][N:32]([CH2:2][C:3]([F:6])([F:5])[F:4])[CH2:33][C:28]5=[N:27]4)=[CH:24][CH:25]=3)=[C:16]([Cl:19])[CH:17]=2)[N:12]=[C:11]1[O:34][C@H:35]1[C@H:39]2[O:40][CH2:41][C@@H:42]([OH:43])[C@H:38]2[O:37][CH2:36]1)[CH:8]=[CH2:9]
Reactant: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(-n4cc5c(n4)CNC5)cc3)c(Cl)cc21
Reactant: FC(F)(F)CI
Agent: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(-n4cc5c(n4)CN(CC(F)(F)F)C5)cc3)c(Cl)cc21
Temperature: 80 °C
Reaction time: 48 h

Procedure:
2-iodo-1,1,1-trifluoroethane (12.5 μl, 0.127 mmol) was added to a stirred solution of (3R,3aR,6R,6aR)-6-[1-allyl-6-chloro-5-[4-(5,6-dihydro-4H-pyrrolo[3,4-c]pyrazol-2-yl)phenyl]imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (59.9 mg, 0.115 mmol) in dioxane (0.46 ml). The reaction mixture was a pale yellow solution that was heated to 80° C. After 2 days, N,N-diisopropylethylamine (40 μl, 0.229 mmol), 2,2,2-trifluoroethyl trifluoromethane-sulfonate (34 μl, 0.236 mmol), and additional dioxane (0.2 ml) were added to the reaction mixture. After stirring an additional 18 hours, the reaction mixture was cooled to room temperature. The reaction mixture was evaporated under reduced pressure to give a dark amber residue. The residue was purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-80% acetonitrile/water+0.05% TFA gradient followed by a 80% acetonitrile/water+0.05% TFA flush. The product fractions were combined and evaporated under reduced pressure to give the desired product as an amber residue. LC-MS: calculated for C28H26ClF3N6O4 602.17 observed m/e: 603.19 (M+H)+ (Rt 1.20/2 min)
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH2:16])[CH3:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:18][C:19](=O)[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:27]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:26][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:20]=1[C:19](=[O:18])[N:16]([CH:14]([C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=1)[CH3:15])[CH2:27]2
Reactant: CC(N)c1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)c1c(Cl)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(c1ccc(Oc2ccccc2)cc1)N1Cc2cccc(Cl)c2C1=O
Reaction time: 16 h
Yield: 33.8 %

Procedure:
A mixture of 1-(4-phenoxyphenyl)ethylamine (121 mg, 0.57 mmol), 2-bromomethyl-6-chloro-benzoic acid methyl ester (150 mg, 0.57 mmol), and K2CO3 (1 g, 7.2 mmol) in toluene (10 mL) was heated at reflux with stirring for 16 h. Workup and silica gel column chromatography using a gradient of hexanes to 30% ethyl acetate in hexanes afforded 7-chloro-2-[1-(4-phenoxyphenyl)-ethyl]-2,3-dihydroisoindol-1-one (70 mg, 34%). GC/MS gave: m/z (rel.int.) 365 (M+, 9), 363 (M+23), 350 (25), 348 (63), 211 (32), 196 (65), 168 (33), 152 (54), 141 (27), 124 (27), 115 (27), 89 (35), and 77 (100). 1H NMR (300 MHz, CDCl3): δ 1.68 (d, 3H), 3.99 (d, 1H), 4.15 (d, 1H), 5.79 (q, 1H), 6.98 (br t, 4H), 7.13 (t, 1H), 7.26-7.10 (br m, 7H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[H-].[Na+].Cl[CH2:24][O:25][CH2:26][CH3:27].ClCCl>CO>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:24][O:25][CH2:26][CH3:27])=[CH:13][CH:14]=2)=[O:7])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: CCOCCl
Reactant: O=C(Nc1ccc(O)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOCOc1ccc(NC(=O)c2ccc(Cl)c([N+](=O)[O-])c2)cc1
Temperature: 0 °C
Yield: 81 %

Procedure:
4-Chloro-N-(4-hydroxy-phenyl)-3-nitro-benzamide (14.6 g, 0.05 mol) was placed in an oven dried 2-necked 500 ml round-bottomed flask and flushed with N2. Enough Dimethoxyethane (DME, 100 ml) was added to dissolve the amide. The mixture was cooled in ice bath and sodium hydride (NaH, 50% in oil, 3.6 g total, 0.075 mol) added in small portions with vigorous stirring. An hour after addition was complete, chloromethoxy-ethane (7.13 g, 0.075 mol, commercially available) was added drop wise via a pressure-equalising dropping funnel. The reaction was followed by TLC (dichloromethane, DCM:methanol, MeOH, 95:5). The reaction mixture was poured into ice water and extracted with EtOAc (3×50 ml). The organic phase was dried (MgSO4) and evaporated under reduced pressure. The crude product was recrystallised form Hexane/ethyl acetate, 1:4. to give 81% of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=[O:6].CC1(C)C(C)(C)OB(/[CH:22]=[CH:23]/[CH2:24][O:25][CH3:26])O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[CH3:26][O:25][CH2:24]/[CH:23]=[CH:22]/[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cc(Br)cc(C(F)(F)F)c1
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC/C=C/c1cc(C=O)cc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)benzaldehyde (1 eq.) from the previous step and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1.5 eq.) in DMF (0.2 M) was added trans-bis(triphenylphosphine) palladium(II) bromide (0.05 eq.). The vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 M aq. Na2CO3 (3 eq.) was added and the resulting mixture was stirred at 100° C. for 2 h. The now black suspension was cooled to RT, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a yellow oil.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:17])[NH:11][CH2:12][CH2:13][C:14](=[NH:16])[NH2:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].[N:20]1[CH:25]=[CH:24][C:23]([C:26](=O)[CH2:27][C:28](OCC)=[O:29])=[N:22][CH:21]=1>C(O)C>[CH2:2]([O:9][C:10](=[O:17])[NH:11][CH2:12][CH2:13][C:14]1[NH:15][C:28](=[O:29])[CH:27]=[C:26]([C:23]2[CH:24]=[CH:25][N:20]=[CH:21][N:22]=2)[N:16]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Reactant: N=C(N)CCNC(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NCCc1nc(-c2ccncn2)cc(=O)[nH]1)OCc1ccccc1
Yield: 33 %

Procedure:
To a suspension of 6 g (23.3 mmol) of (2-Carbamimidoyl-ethyl)-carbamic acid benzyl ester hydrochloride (1:1) in 60 ml of ethanol were added 0.93 g (23.3 mmol) of sodium hydroxide and 4.5 g (23.3 mmol) of ethyl 3-(4-pyrimidinyl)-3-oxopropionate (prepared by analogy to the method described in patent DE2705582). The resulting mixture was stirred under reflux for 12 h. The cooled solution was evaporated to remove solvent. The resulting mixture was treated with water and the precipitate was filtered, washed with diethyl ether to afford 2.7 g (33%) of the desired compound as a brown powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[OH-:9].[Li+].[CH3:11][CH2:12][O:13][CH2:14][CH3:15]>C1COCC1>[N:1]1[CH:2]=[CH:3][C:4](/[CH:7]=[CH:11]/[C:12]([O:13][CH2:14][CH3:15])=[O:9])=[CH:5][CH:6]=1
Reactant: CCOCC
Reactant: O=Cc1ccncc1
Reactant: [OH-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccncc1

Procedure:
To a solution of 4-pyridinecarboxaldehyde (67 ml, 700 mmol) and triethyl phosphonacetate (152 ml, 770 mmol) in THF (200 ml) at room temperature was added lithium hydroxide (32.4 g, 770 mmol). After 18 hours ether (500 ml) was added and the solution was washed with sodium hydrogen carbonate, brine and concentrated to give a white solid. Yield 102.1 g (83%). NMR: 8.62 (d, 2H), 7.60 (d, 1H), 7.35 (d, 2H), 6.59 (d, 1H), 4.30 (q, 2H), 1.35 (t, 3H); m/z 178.3.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.[Na].C(=O)([O-])O>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1
Reactant: OCCCCCCl
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na]
Solvent: ClCCl
Solvent: c1ccncc1
Product: ClCCCCCOC1CCCCO1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
5-chloro-1-pentanol (12.26 g, 0.1 mol) was dissolved in dry dichloromethane (400 mL). 3,4-Dihydro-2H-pyrane (12.62 g, 0.15 mol) and pyridine toluene-4-sulphonate (1.26 g, 5 mmol) was then added and the reaction mixture was stirred magnetically in a nitrogen atmosphere at room temperature over night. Sodium-hydrogen-carbonate, saturated solution (150 mL) was added and the phases were separated. The aqueous phase was then extracted with dichloromethane (4×25 mL). The combined dichloromethane phases were washed with water (2×20 mL) and then dried (MgSO4). Dichloromethane was then distilled out on a rotary evaporator and yielded 19.6 g (95%) of a pale yellow oil. NMR indicated a pure product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.[H-].[Na+].F[B-](F)(F)F.[NH2:15][C:16]1[C:58]([Cl:59])=[CH:57][C:19]([C:20]([NH:22][C@H:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][N+]3C(C4C=CC=CC=4)=CC(C4C=CC=CC=4)=CC=3C3C=CC=CC=3)[CH2:25][C@H:24]2[O:55][CH3:56])=[O:21])=[C:18]([O:60][CH3:61])[CH:17]=1>CC1C=CC=CC=1>[NH2:15][C:16]1[C:58]([Cl:59])=[CH:57][C:19]([C:20]([NH:22][C@H:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][O:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:25][C@H:24]2[O:55][CH3:56])=[O:21])=[C:18]([O:60][CH3:61])[CH:17]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CC[n+]2c(-c3ccccc3)cc(-c3ccccc3)cc2-c2ccccc2)C[C@H]1OC
Reactant: Oc1ccncc1
Agent: F[B-](F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCOc2ccncc2)C[C@H]1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.3 %

Procedure:
A mixture of 2.36 parts of 4-pyridinol, 1.2 parts of a sodium hydride dispersion 50% and 18 parts of methylbenzene was stirred for 2 hours at room temperature. A solution of 7.1 parts of cis-1-[2-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinyl]ethyl]-2,4,6-triphenylpyridinium tetrafluoroborate in 9 parts of methylbenzene was added and stirring was continued first for 4 hours at reflux temperature and then overnight at room temperature. The whole was extracted five times with 100 parts of a hydrochloric acid solution 1N. The combined acid aqueous phases were treated with potassium hydroxide and extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified twice by column chromatography over silica gel using first a mixture of trichloromethane and methanol, saturated with ammonia, (90:10 by volume) and then a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.23 parts (28.3%) of cis-4-amino-5-chloro-2-methoxy-N-[3methoxy-1-[2-(4-pyridinyloxy)ethyl]-4piperidinyl]benzamide; mp. 212.2° C. (compound 60).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:20]([O:27][C:28]1[CH:33]=[C:32]([CH2:34]Br)[CH:31]=[CH:30][C:29]=1[N+:36]([O-:38])=[O:37])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:20]([O:27][C:28]1[CH:33]=[C:32]([CH:31]=[CH:30][C:29]=1[N+:36]([O-:38])=[O:37])[CH2:34][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C:13]1=[O:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1OCc1ccccc1
Reactant: O=C1CCCCC1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C1CCCCC1Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of diisopropylamine (0.44 mL, 3.1 mmol) in THF (5 mL) at 0° C. was added n-butyllithium (1.6 M in hexane, 1.94 mL, 3.1 mmol) dropwise and the solution is stirred for 20 min. After cooling the solution to −78° C., a solution of cyclohexanone (0.32 ml., 3.1 mmol) in THF (2 mL) is added dropwise. The solution is stirred at −78° C. for 1 h then a solution of 2-benzyloxy-4-bromomethyl-1-nitrobenzene (1.0 g, 3.1 mmol) in THF (3 mL) is added dropwise. The solution was warmed to RT and stirred for 18 h. Saturated NaHCO3 is added and the mixture is extracted with EtOAc. The organic layer is washed with water then brine and dried over MgSO4. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using a gradient of 20-33% EtOAc/hexane as eluent to give the title compound as a yellow liquid. NMR (CDCl3): δ 7.79-7.77 (d, J=8.33 Hz, 1H), 7.46-7.31 (m, 5H), 6.93 (d, J=1.51 Hz, 1H), 6.81-6.79 (dd, J=1.52 Hz, 8.34 Hz, 1 H), 5.22 (s, 2H), 3.20-3.16 (m, 1H), 2.53-2.39 (m, 2H), 2.33-2.25 (m, 1H), 2.11-2.05 (m, 1H), 1.96-1.90 (m, 1H), 1.85-1.79 (m, 1H), 1.66-1.55 (m, 2H), 1.35-1.25 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([Cl:21])[C:19]=1[Cl:20])[NH2:16]>>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[C:18]([Cl:21])[C:19]=1[Cl:20]
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1cc(Cl)c(Cl)c(Cl)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3,4,5-trichloroaniline to yield 2-[(3,4,5-trichlorophenyl)amino]phenylacetic acid.
Reaction SMILES: C([O-])(=O)C.[K+].C(Cl)Cl.CC1(C)C(C)(C)[O:13][B:12](B2OC(C)(C)C(C)(C)O2)[O:11]1.Br[C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[F:38])[N:34]=[C:33]([NH2:39])[C:32]([N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)=[CH:31]2>CN(C=O)C>[NH2:39][C:33]1[C:32]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[CH:31][C:30]2[C:35](=[CH:36][C:37]([F:38])=[C:28]([B:12]([OH:13])[OH:11])[CH:29]=2)[N:34]=1
Reactant: Nc1nc2cc(F)c(Br)cc2cc1N1CCOCC1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1nc2cc(F)c(B(O)O)cc2cc1N1CCOCC1
Temperature: 125 °C

Procedure:
A microwave vessel was charged with potassium acetate (0.34 g, 3.46 mmol), [1,1′-bis(dppf)]dichloropalladium(II) complex with CH2Cl2 (0.038 g, 0.052 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.211 g, 0.831 mmol), 6-bromo-7-fluoro-3-morpholinoquinolin-2-amine (0.226 g, 0.693 mmol), and DMF (2.2 mL). The vessel was purged with argon, sealed, and heated by microwave radiation for 30 min at 125° C. The reaction was diluted with EtOAc (10 mL), and the suspension was filtered through celite rinsing with EtOAc. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (25 mL) which had been deactivated with Et3N (2.5 mL) using 3% MeOH/DCM to afford 2-amino-7-fluoro-3-morpholinoquinolin-6-ylboronic acid.
Reaction SMILES: [IH:1].[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5](Cl)[N:4]=1>O>[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5]([I:1])[N:4]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: I
Solvent: O
Product: Nc1nc(I)c2[nH]cnc2n1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Charge 57% Hydriodic acid (10.90 kg) into a suitable vessel under nitrogen and then the solution was cooled to 0 to 10° C. Then 2-amino-6-chloropurine (0.8 kg) was charged into the solution at about 15° C. After 2 h for the completion, water (8 kg) was slowly charged to the reaction mixture at r.t. and stirred for about 0.5 h. The yellow precipitate was filtered and washed with water. The wet cake was transferred to a suitable vessel, and water (2.0 kg) and 20% NaOH aqueous solution (0.4 kg) were slowly charged to dissolve the solids at r.t. Then THF (2.14 kg) was charged into the solution and 10% HOAc (4.8 kg) was slowly charged into the solution at about 35° C. to observe slurry mixture. The resultant slurry was stirred filtered and washed with acetone (3.8). The wet cake was dried under vacuum at 70° C. to afford SPT1255C1 (1.14 kg). Yield: 90-98%. 1H NMR (400 MHz, DMSO-d6) 6.65 (s, 2H, NH2), 8.04 (s, 1H, H8)
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([N:9]([CH3:15])[CH2:10][CH:11]2[CH2:13][CH:12]2[CH3:14])[N:6]=[C:5]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])[CH:4]=1)=[O:2].[I-].[CH3:23][S+](C)C.[OH-].[K+]>C(#N)C.O.CCOC(C)=O>[CH3:21][N:16]([C:5]1[CH:4]=[C:3]([CH:1]2[CH2:23][O:2]2)[CH:8]=[C:7]([N:9]([CH3:15])[CH2:10][CH:11]2[CH2:13][CH:12]2[CH3:14])[N:6]=1)[S:17]([CH3:20])(=[O:18])=[O:19]
Reactant: C[S+](C)C
Reactant: CC1CC1CN(C)c1cc(C=O)cc(N(C)S(C)(=O)=O)n1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1CC1CN(C)c1cc(C2CO2)cc(N(C)S(C)(=O)=O)n1
Temperature: 65 °C

Procedure:
To a solution of N-(4-formyl-6-{methyl[(2-methylcyclopropyl)methyl]amino}pyridin-2-yl)-N-methylmethanesulfonamide (435 mg, 1.40 mmol) in acetonitrile (5 mL) was added 5 drops water, trimethylsulfonium iodide (342 mg, 1.68 mmol) and potassium hydroxide (188 mg, 3.35 mmol). The reaction was stirred at 65° C., sealed, for 3 h, diluted with EtOAc, washed with sat'd aq NaHCO3, brine, dried over sodium sulfate, and concentrated in vacuo to provide N-methyl-N-(6-{methyl[(2-methylcyclopropyl)methyl]amino}-4-oxiran-2-ylpyridin-2-yl)methanesulfonamide, used as is in the next step. A solution of N-methyl-N-(6-{methyl[(2-methylcyclopropyl)methyl]amino}-4-oxiran-2-ylpyridin-2-yl)methanesulfonamide (440 mg, 1.35 mmol) in EtOH (10 mL) and NH4OH (15 mL) was stirred at 60° C., sealed, for 16 h, concentrated in vacuo and purified by flash chromatography (silica, 5-15% (10% NOH/MeOH)/CH2Cl2) to provide N-(4-(2-amino-1-hydroxyethyl)-6-{methyl[(2-methylcyclopropyl)methyl]amino}pyridin-2-yl)-N-methylmethanesulfonamide as a thick oil. 1H NMR (400 MHz, CD3OD) δ 6.52 (s, 1H), 6.47 (s, 1H), 4.58 (X′ of A′B′X′, dd, J=7.6, 4.0 Hz, 2H), 3.54 (A of ABX, dd, J=14.4, 6.4 Hz, 1H), 3.35 (B of ABX, dd, J=14.4, 6.8 Hz, 1H), 3.30 (s, 3H), 3.13 (s, 3H), 3.08 (s, 3H), 3.86 (A′ of A′B′X′, dd, J=13.2, 4.0 Hz, 1H), 2.76 (B′ of A′B′X′, dd, J=13.2, 7.6 Hz, 1H), 1.02 (d, J=6.0 Hz, 3H), 0.80-0.65 (m, 2H), 0.46-0.39 (m, 1H), 0.25-0.18 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Si:12]([O:19][CH2:20][CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][C:24]=1[CH3:31])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].OS([O-])=O.[Na+].[CH3:37]C1C=CC(S(O)(=O)=O)=CC=1.O>CC(N(C)C)=O.O>[Br:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:27]([C:26]1[CH:25]=[C:24]([CH3:31])[C:23]([O:22][CH2:21][CH2:20][OH:19])=[C:30]([CH3:37])[CH:29]=1)[NH:6][C:4]2=[O:5].[Br:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:27]([C:26]1[CH:29]=[C:30]([CH3:37])[C:23]([O:22][CH2:21][CH2:20][O:19][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[C:24]([CH3:31])[CH:25]=1)[NH:6][C:4]2=[O:5]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NC(=O)c1cc(Br)ccc1N
Reactant: Cc1cc(C=O)ccc1OCCO[Si](C)(C)C(C)(C)C
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3ccc(Br)cc3c(=O)[nH]2)cc(C)c1OCCO
Product: Cc1cc(-c2nc3ccc(Br)cc3c(=O)[nH]2)cc(C)c1OCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 22 %
Yield: 10 %

Procedure:
A mixture of 2-amino-5-bromobenzamide (0.100 g, 0.465 mmol), 4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3-methylbenzaldehyde (0.143 g, 0.465 mmol), NaHSO3 (94%, 0.0515 g, 0.465 mmol), and p-TsOH.H2O (0.00885 g, 0.0465 mmol) in DMA (5.81 mL) was heated at reflux for 15 min, cooled to room temperature, the water (20 mL) was added. The precipitate was filtered, washed with water, triturated with acetone and filtered again. The crude solid was chromatographed on silica gel (CH2Cl2/CH3OH) to provide 6-bromo-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (0.0395 g, 22%) and 6-bromo-2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (0.0227 g, 10%) as white solids. Selected data for 6-bromo-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one: 1H NMR (300 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.20 (d, J=2.34 Hz, 1H), 8.01-7.80 (m, 3H), 7.66 (d, J=8.72 Hz, 1H), 4.90 (t, J=5.46 Hz, 1H), 3.85 (t, J=4.87 Hz, 2H), 3.73 (dd, J=10.06, 5.11 Hz, 2H), 2.32 (s, 6H); MS (APCI) m/z 345 [M+H]+. Selected data for 6-bromo-2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one: 1H NMR (300 MHz, DMSO-d6) δ 12.49 (s, 1H), 8.20 (d, J=2.34 Hz, 1H), 7.95 (dd, J=8.71, 2.41 Hz, 1H), 7.90 (s, 2H), 7.67 (d, J=8.72 Hz, 1H), 3.90 (m, 4H), 2.32 (s, 6H), 0.90 (s, 9H), 0.09 (s, 6H); MS (APCI) m/z 503 [M+H]+.