Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18]C)[C:7]([O:16]C)=[N:8]2.[CH3:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(CC)CC)C>>[BrH:1].[O:16]=[C:7]1[C:6](=[O:18])[NH:5][C:4]2[C:9](=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:3]=2[CH2:2][N:24]2[CH2:25][CH2:26][CH:21]([CH3:20])[CH2:22][CH2:23]2)[NH:8]1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CBr)c2nc1OC
Reactant: CC1CCNCC1
Solvent: CCN(CC)CC
Product: Br
Product: CC1CCN(Cc2cc([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c23)CC1

Procedure:
100 mg (0.304 mmol) of 5-bromomethyl-2,3-dimethoxy-7-nitro-quinoxaline, 0.04 ml (1.1 equiv.) of 4-methyl-piperidine and 0.05 ml (1.2 equiv.) of triethylamine are stirred at reflux for 20 hours. The mixture is concentrated by evaporation and the residue is extracted with ethyl acetate and a 5% sodium carbonate solution. The combined organic phases are dried over magnesium sulfate and concentrated by evaporation.
Reaction SMILES: O=C1N2C3C=CC(N4CCOCC4=O)=CC=3OC[C@@H]2[C@@H](CCS([O-])(=O)=O)O1.O([CH2:36][C@H:37]1[C@@H:45]2[N:40]([C:41]3[CH:49]=[CH:48][C:47]([N:50]4[CH2:55][CH2:54][O:53][CH2:52][C:51]4=[O:56])=[CH:46][C:42]=3[O:43][CH2:44]2)[C:39](=[O:57])[O:38]1)[Si](C(C)(C)C)(C)C.[K].[C:59]1(=[O:69])[NH:63][C:62](=[O:64])[C:61]2=[CH:65][CH:66]=[CH:67][CH:68]=[C:60]12>>[O:57]=[C:39]1[N:40]2[C:41]3[CH:49]=[CH:48][C:47]([N:50]4[CH2:55][CH2:54][O:53][CH2:52][C:51]4=[O:56])=[CH:46][C:42]=3[O:43][CH2:44][C@@H:45]2[C@H:37]([CH2:36][N:63]2[C:59](=[O:69])[C:60]3[C:61](=[CH:65][CH:66]=[CH:67][CH:68]=3)[C:62]2=[O:64])[O:38]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@H]12
Agent: O=C1COCCN1c1ccc2c(c1)OC[C@@H]1[C@@H](CCS(=O)(=O)[O-])OC(=O)N21
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1C[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@H]12
Yield: 82.1 %

Procedure:
Using compound ((3R,3 aR)-1-oxo-7-(3-oxomorpholin-4-yl)-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-3-yl)methylmethanesulfonate (2.98 g, 7.48 mmol) prepared above in (a) and phthalimide potassium (2.08 g, 11.22 mmol) as starting materials, preparation following the method as described in Example 1 (d) afforded white solid 2.76 g, yield: 82.1%.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.CN(C)C=O.[H-].[Na+].[CH3:16][O:17][CH2:18]Cl>O>[CH3:16][O:17][CH2:18][O:7][C:6]1[CH:5]=[CH:4][C:3]([Br:8])=[CH:2][CH:1]=1
Reactant: COCCl
Reactant: Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(Br)cc1
Temperature: 30 °C
Yield: 79.1 %

Procedure:
Into a reactor, 40 g of p-bromophenol and 200 ml of DMF (dimethylformamide) were charged, to which 10 g of a 60% NaH (sodium hydride) were gradually added to give a solution. To the solution, 18 g of methoxymethyl chloride were added dropwise with stirring at a temperature of 30° C. or lower, and reacted overnight at room temperature to give a reaction solution. The reaction solution was poured into water, extracted with benzene, washed with water, dried over sodium sulfate anhydride, and thereafter the solvent was evaporated and the residue was distilled under reduced pressure to give 38.4 g (Y., 79.3%) of 4-bromopheny methoxymethyl ether.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([CH3:12])[CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:11][CH3:13])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1cc([N+](=O)[O-])c(F)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of 4-fluoro-2-methyl-5-nitrophenol (0.5 g) in N,N-dimethylformamide (5 mL) were added potassium carbonate (0.44 g) and iodomethane (0.46 g), and this mixture was stirred at room temperature overnight. To this reaction mixture was added water and the precipitated solid was collected by filtration, and washed with water and n-hexane to give the title compound (0.44 g).
Reaction SMILES: [Na].C(OCC)(=O)[CH2:3][C:4](OCC)=[O:5].[Cl:13][C:14]1[C:22]2[O:21][C:20]([CH3:24])([CH3:23])[CH2:19][C:18]=2[C:17]([CH3:25])=[C:16]([CH3:26])[C:15]=1[CH:27]=[CH:28][C:29](=[O:31])[CH3:30].O>CO>[Cl:13][C:14]1[C:22]2[O:21][C:20]([CH3:23])([CH3:24])[CH2:19][C:18]=2[C:17]([CH3:25])=[C:16]([CH3:26])[C:15]=1[CH:27]1[CH2:3][C:4](=[O:5])[CH:30]=[C:29]([OH:31])[CH2:28]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)C=Cc1c(C)c(C)c2c(c1Cl)OC(C)(C)C2
Agent: [Na]
Solvent: O
Solvent: CO
Product: Cc1c(C)c(C2CC(=O)C=C(O)C2)c(Cl)c2c1CC(C)(C)O2
Temperature: 25 °C

Procedure:
To a solution of 1.0 g of sodium in 30 ml of absolute methanol was added 6.5 ml of diethyl malonate and 10 g of the 4-(7-chloro-2,3-dihydro-2,2,4,5-tetramethyl-benzofuran-6-yl)-3-buten-2-one in 20 ml of absolute methanol, and refluxed for 4 hours. The reaction mixture was added 100 ml of water and concentrated under reduced pressure and then added 17 g of 20% aqueous solution of sodium hydroxide. After refluxing 1 hour, the reaction mixture was cooled to room temperature and washed with benzene. Concentrated hydrochloric acid was added dropwise into the aqueous layer until the bubble of carbon dioxide ceased. And then, solid was dissolved in ethyl acetate and washed with water. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford 11.8 g of 5-(7-chloro-2,3-dihydro-2,2,4,5-tetramethylbenzofuran-6-yl)-3-hydroxycyclohex-2-en-1-one.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:16])=[C:4]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[CH:14]N=2)=O)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-:18].[K+].[K+].Br[CH2:24][CH:25](OCC)OCC>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:16]=[C:9]([C:11]([N:12]1[CH2:13][CH2:14][CH2:25][CH2:24]1)=[O:18])[NH:8]2
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Br)cccc1NC(=O)c1ncc[nH]1
Reactant: CCOC(CBr)OCC
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1cc2c(Br)cccc2[nH]1)N1CCCC1
Temperature: 25 °C
Reaction time: 18.25 h
Yield: 67 %

Procedure:
Step 2 A solution of N-(3-bromo-2-methylphenyl)-1H-imidazole-2-carboxamide (0.70 g, 2.499 mmol) in DMF (12.5 mL) was treated with potassium carbonate (0.794 g, 5.75 mmol) and 2-bromo-1,1-diethoxyethane (0.395 mL, 2.62 and the mixture was stirred at rt. After 18.25 h, the mixture was diluted with EtOAc, filtered to remove some tan solid, and washed sequentially with 1 M hydrochloric acid and NaHCO3 (aq), and dried and concentrated to provide (4-bromo-1H-indol-2-yl)(pyrrolidin-1-yl)methanone as a tan solid (205 mg, 67%). 1H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1 H) 7.46 (d, J=7.9 Hz, 1 H) 7.27 (d, J=7.5 Hz, 1 H) 7.06-7.17 (m, 1 H) 6.82 (s, 1 H) 3.85 (t, J=6.8 Hz, 2 H) 3.55 (t, J=6.8 Hz, 2 H) 1.93-2.04 (m, 2 H) 1.81-1.92 (m, 2 H). Mass spectrum m/z 293, 295 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[O:17]1[CH:21]=[CH:20][CH2:19][CH2:18]1>O.C1COCC1>[Cl:2][C:3]1[C:4]([O:11][CH2:12][C:13]([F:15])([F:14])[F:16])=[C:5]([NH:9][N:10]=[CH:21][CH2:20][CH2:19][CH2:18][OH:17])[CH:6]=[CH:7][CH:8]=1
Reactant: NNc1cccc(Cl)c1OCC(F)(F)F
Reactant: C1=COCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: OCCCC=NNc1cccc(Cl)c1OCC(F)(F)F
Reaction time: 3 h

Procedure:
The 3-chloro-2-(2,2,2-trifluoroethoxy)phenylhydrazine hydrochloride (13.3 g, 48 mmol) was dissolved in H2O (133 mL) and THF (133 mL). Dihydrofuran (3.75 mL, 48 mmol) was added in one portion, and the reaction mixture was stirred for 3 hours. After this time, the organic layer was separated and the aqueous layer extracted with Et2O (250 mL). The combined organic layers were washed with brine (250 mL), dried (MgSO4), and concentrated to afford 14 g (98%) of a 3:1 mixture of E:Z isomers of 4-[3-chloro-2-(2,2,2-trifluoroethoxy)phenylhydrazono]-1-butanol as an orange oil which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[I:17].Br[CH2:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][O:1][C:2]1[C:3]([I:17])=[CH:4][C:5]([C:9](=[O:10])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:7]=1[I:8])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C(c1ccccc1)c1cc(I)c(O)c(I)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(COc1c(I)cc(C(=O)c2ccccc2)cc1I)OCc1ccccc1
Reaction time: 15 h
Yield: 37.8 %

Procedure:
To a solution of (4-hydroxy-3,5-diiodophenyl)-phenyl-methanone (as prepared in Example 6, 2.25 g, 5.0 mmol) and benzyl 2-bromoacetate (1.71 g, 7.5 mmol) in 50 mL DMF was added cesium carbonate (4.1 g, 13 mmol). The resulting suspension was stirred for 15 hours, then the reaction mixture was poured into ˜150 mL 1 M HCl. A pale oil formed, and the supernatant was removed by decantation. The oil was crystallized from hot isopropanol, yielding the title compound as colorless crystals (1.13 g, 38%). 1H NMR (400 MHz, CDCl3): δ 8.18 (s, 2H), 7.77-7.74 (m, 2H), 7.63 (tt, J=7.4, 1.2 Hz, 1H), 7.54-7.50 (m, 2 H), 7.45-7.35 (m, 5H), 5.33 (s, 2H), 4.71 (s, 2H). TLC (4:1 Hex:EtOAc), Rf 0.52. LRMS (EI+) calc'd for [C22H16I2O4+H] 598.9, found 598.8.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][O:39][CH:40]([O:44][CH3:45])[CH2:41][NH:42][CH3:43]>>[CH3:38][O:39][CH:40]([O:44][CH3:45])[CH2:41][N:42]([CH3:43])[C:21]1[N:20]=[C:19]([O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:29]=[C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH:31]=[C:2]([F:1])[CH:3]=3)=[CH:9][CH:10]=2)[CH:24]=[CH:23][N:22]=1
Reactant: CNCC(OC)OC
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: COC(CN(C)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1)OC

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and (2,2-dimethoxy-ethyl)-methylamine according to conditions described in general procedure C. Mp: 92-94° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.84-3.6 (m, 11 H), 3.28 (m, 4 H), 3.77 (m, 4 H), 4.5 (s, 1 H), 6.26-6.24 (m, 1 H), 7.04 (d, J=12.0 Hz, 1 H), 7.26 (d, J=9.1Hz, 1 H), 7.47-7.65 (m, 5 H), 7.82 (m, 1 H), 7.99-8.01 (m, 1 H), 8.29 (m, 1 H), 10.45 (s, 1 H).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34].C(OCC)(=O)C>CN(C=O)C>[CH3:34][CH:33]([CH3:35])[CH2:32][CH2:31][CH2:30][CH2:29][N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: CC(C)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CCCCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 50 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 1-bromo-5-methylhexane (0.199 g, 1.05 mmol) in DMF (5.3 mL). Heat at 50° C. overnight, then increase the temperature to 80° C. for 3.5 hours. Cool die reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1× 30 mL), brine (1× 30 mL), dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 382.2 (M+H)+, HRMS calcd for C23H31N3O2 382.2492 (M+H)+, found 382.2495, time 0.46 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=12.4 min, 97.7% purity.
Reaction SMILES: [NH2:1][C@H:2]([CH3:18])[C@@H:3]([OH:17])[CH2:4][N:5]([CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[CH3:6].[CH3:19][N:20]1[C:24]([C:25]2[CH:26]=[C:27]([NH:31][C:32](=O)[O:33]C3C=CC=CC=3)[CH:28]=[CH:29][CH:30]=2)=[N:23][N:22]=[N:21]1>C(#N)C>[F:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][N:5]([CH3:6])[CH2:4][C@H:3]([OH:17])[C@H:2]([NH:1][C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([C:24]3[N:20]([CH3:19])[N:21]=[N:22][N:23]=3)[CH:26]=2)=[O:33])[CH3:18])=[CH:15][CH:14]=1
Reactant: Cn1nnnc1-c1cccc(NC(=O)Oc2ccccc2)c1
Reactant: C[C@@H](N)[C@@H](O)CN(C)CCCc1ccc(F)cc1
Solvent: CC#N
Product: C[C@@H](NC(=O)Nc1cccc(-c2nnnn2C)c1)[C@@H](O)CN(C)CCCc1ccc(F)cc1
Yield: 3.7 %

Procedure:
The product of Step g (186 mg, 7.3 mmol, 1 eq.), phenyl 3-(1-methyl-1H-tetraazol-5-yl)phenylcarbamate (220 mg, 7.3 mmol, 1 eq.) and acetonitrile (10 mL) were mixed at 25° C. under N2 overnight. Worked up by stripping off the solvents then purifying the residue over silica gel in 1:1 Hexanes/EtOAc to 100% EtOAc to 4:1 EtOAc/MeOH. Obtained 123 mg of an amorphous solid. NMR (300 MHz, CDCl3) δ 7.88 (s, 1H); 7.60 (d, 1H, J=7 Hz); 7.42 (t, 1H, J=7 Hz); 7.30 (d, 1H, J=7 Hz); 7.20-7.00 (m, 2H); 6.91 (t, 2H, J=7 hz); 4.17 (s, 3H); 3.97 (m, 1H); 3.80 (m, 1H); 2.70-2.40 (m, 6H); 2.34 (s, 3H); 1.90-1.70 (m, 2H); 1.18 (d, 3H, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:32])([CH3:31])[CH2:12][C:13]([OH:30])([C:26]([F:29])([F:28])[F:27])[CH2:14][C:15]2[NH:23][C:22]3[C:17](=[N:18][C:19]([C:24]#N)=[CH:20][CH:21]=3)[CH:16]=2)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[CH:33]([Mg]Cl)([CH3:35])[CH3:34].C1C[O:41]CC1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:32])([CH3:31])[CH2:12][C:13]([OH:30])([C:26]([F:28])([F:29])[F:27])[CH2:14][C:15]2[NH:23][C:22]3[C:17](=[N:18][C:19]([C:24](=[O:41])[CH:33]([CH3:35])[CH3:34])=[CH:20][CH:21]=3)[CH:16]=2)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: CC(C)(CC(O)(Cc1cc2nc(C#N)ccc2[nH]1)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Reactant: C1CCOC1
Reactant: CC(C)[Mg]Cl
Product: CC(C)C(=O)c1ccc2[nH]c(CC(O)(CC(C)(C)c3cc(Cl)cc4c3OCC4)C(F)(F)F)cc2n1
Temperature: 75 °C
Yield: 70 %

Procedure:
2-[4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (50 mg, 0.11 mmol) was dissolved in 3 mL of THF. Isopropyl magnesium chloride (2 M in THF, 0.15 mL, 0.3 mmol) was added, followed by CuBr (7 mg, 0.05 mmol). The reaction was stirred at reflux (75° C.) for 30 minutes. The mixture was cooled to room temperature. The reaction was quenched with 1 mL of water, followed by 3 drops of concentrated HCl. The mixture was stirred for 10 minutes, and neutralized with saturated sodium carbonate solution until the pH was 8. The reaction mixture was extracted with ethyl acetate and washed with brine. The solvent was removed in vacuo. The residue was purified by preparative HPLC (medium polar condition) to give the title compound (39 mg, 70% yield).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:12]#[C:13][Br:14]>>[BrH:14].[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]=[C:13]1[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCNCc1ccccc1
Reactant: N#CBr
Product: Br
Product: NC1=NCCN1Cc1ccccc1
Yield: 93 %

Procedure:
Reaction of N-benzylethylenediamine (15.02 g, 0.10 mol) with cyanogen bromide (10.6 g, 0.10 mol) as described in the preparation of intermediate 6 gave 23.82 g (93% yield) of the title product as white crystals; mp 202-204° C. (ethanol). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 3.48-3.56 (4H, m, 2×CH2), 4.57 (2H, m, NCH2), 7.30-7.44 (5H, m, aromatics), 7.92 and 8.18 (broad s, NH). Anal. Calcd for ClOH13N3.HBr: C, 46.89, H 5.50; N, 16.40. Found: C, 47.03; H, 5.49; N, 16.24.
Reaction SMILES: [N:1]#[C:2][NH2:3].[N:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[C:5]=[S:6].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([F:34])[CH:28]=1)=[O:26]>>[NH2:1][C:2]1[N:3]=[C:5]([NH:4][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:14][CH2:15][N:16]([CH2:19][CH:20]4[CH2:22][CH2:21]4)[CH2:17][CH2:18]3)=[CH:11][CH:12]=2)[S:6][C:24]=1[C:25]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([F:34])[CH:28]=1)=[O:26]
Reactant: O=C(CBr)c1ccc(O)c(F)c1
Reactant: S=C=Nc1ccc(N2CCN(CC3CC3)CC2)cc1
Reactant: N#CN
Product: Nc1nc(Nc2ccc(N3CCN(CC4CC4)CC3)cc2)sc1C(=O)c1ccc(O)c(F)c1

Procedure:
This compound was prepared from cyanamide, 1-(4-isothiocyanatophenyl)-4-cyclopropylmethylpiperazine (of Example 14G) and 2-bromo-1-(3-fluoro-4-hydroxyphenyl)ethanone (of Example 14M) following the procedure used in Example 24. Mass spectrum (ES) MH+=468.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([OH:17])=[O:16])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:18][C:19]1[NH:20][CH:21]=[CH:22][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CC(N(C)C)=O>[ClH:8].[Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([OH:17])=[O:16])=[N:4][C:5]([N:20]2[CH:21]=[CH:22][N:23]=[C:19]2[CH3:18])=[N:6][CH:7]=1
Reactant: Cc1ncc[nH]1
Reactant: O=C(O)C1COCCN1c1nc(Cl)ncc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1nccn1-c1ncc(Br)c(N2CCOCC2C(=O)O)n1
Product: Cl
Temperature: 120 °C
Reaction time: 48 h
Yield: 40.9 %

Procedure:
A mixture of 4-(5-bromo-2-chloropyrimidin-4-yl)morpholine-3-carboxylic acid (PREPARATION x30, 1 g, 3.12 mmol), 2-methyl-1H-imidazole (0.54 g, 6.55 mmol) and Cs2CO3 (4 g, 12 mmol) in DMA (20 mL) was stirred at 120° C. for 2 days. Water was added and the mixture was concentrated, resulting in precipitation of solids. The solids were collected to give an HCl salt of the title compound as an off-white solid (0.47 g, 45%). 1H NMR (400 MHz, CD3OD) δ 2.95 (s, 3H), 3.96-3.61 (m, 4H), 4.42-4.38 (m, 2H), 5.17-5.15 (m, 1H), 7.50 (d, J=2.0 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 8.59 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C13H14BrN5O3, 368. found, 368.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][Si](C(C)(C)C)(C)C)=[CH:9][C:8]=1[OH:21])=O)[CH3:2].Cl[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34])=[O:26].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH2:1]([O:3][C:4]([C:5]1[C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=2[O:21][C:24]=1[C:25](=[O:26])[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34])=[O:22])[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1O
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(O)ccc12
Temperature: 90 °C
Reaction time: 16 h
Yield: 36.1 %

Procedure:
To a solution of [4-(tert-Butyl-dimethyl-silanyloxy)-2-hydroxy-phenyl]-oxo-acetic acid ethyl ester from step 2 (2.0 g, 6.16 mmol) and 2-chloro-1-(2,4-dichlorophenyl)ethanone (1.65 g, 7.4 mmol, 1.2 eq) in anhydrous N,N-dimethylformamide (100 mL) was added potassium carbonate (1.7 g, 12.3 mmol, 2 eq). The reaction mixture was stirred at 90° C. for 16 h. The mixture was cooled to room temperature then poured into ethyl acetate (100 mL) and water (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). Combined the organic layer was washed by water (2×100 mL), dried over Na2SO4, filtrated, and evaporated in vacuo. The residue was purified by column chromatography eluted with 20% EtOAc/hexane then 50% EtOAc/hexane solution to afford an yellow solid (843 mg, 36%) as product. 1H-NMR (CD3CN): δ 7.79 (d, J=8.0 Hz, 1H), 7.64 (d, 1.9 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.47(dd, J=2.3, 8.3 Hz, 1H), 7.06 (d, J=2.3 Hz, 1H), 7.0 (dd, J=2.3, 8.0 Hz, 1H), 4.11(q, 2H), 1.21(t, 3H).; LC-MS (MH+=379/381).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:54]1[CH2:59][CH2:58][N:57]([CH2:60][CH2:61][O:62][CH2:63][CH2:64]O)[CH2:56][CH2:55]1>C(Cl)Cl>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:64][CH2:63][O:62][CH2:61][CH2:60][N:57]4[CH2:58][CH2:59][O:54][CH2:55][CH2:56]4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: OCCOCCN1CCOCC1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCOCCN1CCOCC1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
Diethyl azodicarboxylate (209 mg, 1.2 mmol) was added dropwise to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6 methoxyquinazoline (128 mg, 0.4 mmol), (prepared as described for the starting material in Example 2), triphenylphosphine (314 mg, 1.2 mmol) and 2-(2-morpholinoethoxy)ethanol (97 mg, 0.56 mmol) in methylene chloride (4 ml) under nitrogen. The mixture was stirs for 1 hour at ambient temperature, triphenylphosphine (105 mg, 0.4 mmol), 2-(2-morpholinoethoxy)ethanol (49 mg, 0.28 mmol) and diethyl azodicarboxylate (70 mg, 0.4 mmol) were added. The mixture was stirred for 1 hour at ambient temperature and was purified by pouring directly onto a silica column eluting with methylene chloride/acetonitrile/methanol (6/3/1). The purified product was triturated with ether, collected by filtration and dissolved in methylene chloride. 2M Ethereal hydrogen chloride (0.5 ml) was added and the resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-morpholinoethoxy)ethoxy)quinazoline hydrochloride (100 mg, 45%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]([O:15][C:16]([NH:18][CH:19]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:20]([O:22][C@@H:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1)=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].CCOCC>CCOC(C)=O>[Cl-:1].[C:11]([O:15][C:16]([NH:18][CH:19]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:20]([O:22][C@@H:23]1[CH:28]2[CH2:29][CH2:30][N+:25]([CH2:2][C:3](=[O:4])[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)([CH2:26][CH2:27]2)[CH2:24]1)=[O:21])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: O=C(CCl)c1ccccc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1C[N+]2(CC(=O)c3ccccc3)CCC1CC2)c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.8 %

Procedure:
2-Chloro-1-phenylethanone (30.0 mg, 0.19 mmol) was added to a solution of (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-phenylacetate (C1) (70.0 mg, 0.19 mmol) in EtOAc (2 ml). The reaction was stirred at RT for 24 hours. Then Et2O (1 ml) was added, and the reaction was sonicated. The solid was collected by suction filtration to obtain (3R)-3-(2-(tert-butoxycarbonylamino)-2-phenylacetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane chloride (54.6 mg; 55% yield).