Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:21])[N:11]([C:18](Cl)=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[F:22][C:23]1[C:24](=[O:30])[NH:25][C:26](=[O:29])[NH:27][CH:28]=1.N1C=CC=CC=1>C1COCC1>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:21])[N:11]([C:18]([N:27]2[CH:28]=[C:23]([F:22])[C:24](=[O:30])[NH:25][C:26]2=[O:29])=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)Cl)c3ccccc32)[nH]1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)n3cc(F)c(=O)[nH]c3=O)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.5 %

Procedure:
To a reaction mixture of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carbonyl chloride (75 mg, 0.25 mmol), 5-fluorouracil (75 mg, 0.58 mmol), and 0.5 mL of pyridine in 2.0 mL of THF was stirred at room temperature for 1 h and filtered. The solid was then washed with THF, acetone, methanol, and ether to give 34 mg (36%) of 1-{3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carbonyl}-5-fluoro-1H-pyrimidine-2,4-dione as a light yellow solid. 1HNMR (400 MHz, DMSO-d6) δ 12.22 (d, J=4.69 Hz, 1H, CONHCO), 12.19 (s, br, 1H, NH-1′), 8.33 (d, J=6.64 Hz, 1H, H-6″), 7.92–7.94 (m, 1H, H-4), 7.74–7.76 (m, 1H, H-7), 7.71 (s, 1H, H-vinyl), 7.26–7.29 (m, 2H, H-5, 6), 6.16 (s, br, 1H, H-4′), 2.47 (s, 3H, CH3), and 2.35 (s, 3H, CH3).
Reaction SMILES: [CH3:1][S:2]([CH:5]=[CH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:8]1)(=[O:4])=[O:3]>[Pd].CO>[CH3:1][S:2]([CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:9][CH2:8]1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=CS(C)(=O)=O)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCS(C)(=O)=O)CC1
Reaction time: 8 h

Procedure:
A mixture of tert-butyl {trans-4-[2-(methylsulfonyl)vinyl]cyclohexyl}carbamate (140 mg, 0.46 mmol) and 10% of palladium on carbon (49 mg) in methanol (4 mL) was hydrogenated under balloon pressure of H2 at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated to give tert-butyl {trans-4-[2-(methylsulfonyl)ethyl]cyclohexyl}carbamate. LCMS calculated for C9H20NO2S (M-Boc+2H)+: m/z=206.1. Found: 206.1. The Boc-intermediate was treated with trifluoroacetic acid (0.2 mL, 3 mmol) in methylene chloride (0.5 mL) at room temperature for 1 h. The resulting mixture was concentrated to give the desired product as trifluoroacetic acid (TFA) salt. LCMS calculated for C9H20NO2S (M+H)+: m/z=206.1. Found: 206.1.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:55][N:56]([CH3:58])[NH2:57]>CN(C=O)C>[CH3:55][N:56]([CH3:58])[NH:57][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][N:19]=1)=[O:23]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)nc1
Reactant: CN(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NN(C)C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
To a solution of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (100 mg, 0.32 mmol) in DMF (5 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (114 mg, 0.36 mmol), N,N-diisopropyl ethyl amine (0.27 mL, 8.1 mmol) and N,N-dimethylhydrazine (21 mg, 0.35 mmol). The resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was evaporated and then diluted with water and extracted with ethyl acetate. The combined organic layers were dried, filtered and concentrated in vacuo. Concentration and purification by chromatography (silica, 0 to 5% methanol in dichloromethane) afforded the title compound (31 mg, 27%) as a white solid. MS: m/e=353.3 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][C:4]=2[N:3]=[C:2]1[SH:14])[CH:11]=[CH:10][CH:9]=[CH:8]3.[ClH:15].[Cl:16][CH2:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1>CN(C)C=O.C1(C)C=CC=CC=1>[ClH:16].[ClH:15].[NH:22]1[CH2:21][CH2:20][N:19]=[C:18]1[CH2:17][S:14][C:2]1[NH:3][C:4]2[CH:13]=[C:12]3[C:7](=[CH:6][C:5]=2[N:1]=1)[CH:8]=[CH:9][CH:10]=[CH:11]3
Reactant: ClCc1ncc[nH]1
Reactant: Sc1nc2cc3ccccc3cc2[nH]1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: c1ccc2cc3[nH]c(SCC4=NCCN4)nc3cc2c1
Temperature: 25 °C
Yield: 58.1 %

Procedure:
10.0 g 1H-Naphth[2,3-d]imidazole-2-thiol and 8.0 g of 2-chloromethylimidazole-hydrochloride were heated for 3 hours at 90° in 50 ml of dimethylformamide. The reaction mixture was cooled to room temperature and then diluted with 200 ml of toluene. The residue was suction filtered, washed well with toluene, and crystallized from 700 ml of methanol, with the addition of 300 ml of ether. 10.3 g of 2-[(2-Imidazoline-2-ylmethyl)thio]-1H-naphth[2,3-d]imidazoldihydrochloride having an m.p. of 227°-228° were obtained.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])=[CH:6][CH:5]=1.[C:18]1([C:24]2[CH:25]=[CH:26][C:27](=[O:30])[NH:28][N:29]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[Si:9]([O:8][C:7]1[CH:16]=[CH:17][C:4]([CH2:3][CH2:2][N:28]2[C:27](=[O:30])[CH:26]=[CH:25][C:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:29]2)=[CH:5][CH:6]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCBr)cc1
Reactant: O=c1ccc(-c2ccccc2)n[nH]1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CCn2nc(-c3ccccc3)ccc2=O)cc1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A mixture of (4-(2-bromoethyl)phenoxy)(tert-butyl)dimethylsilane (142 mg, 450 μmol), 6-phenyl-3(2h)-pyridazinone (116 mg, 676 μmol), and potassium carbonate (187 mg, 1351 μmol) in DMF (1.5 mL) was stirred at 40° C. for 18 h. The mixture was partioned between CH2Cl2 (20 mL) and 5% NaHCO3 (10 mL). The organic layer was dried with satd. NH4Cl and over MgSO4, and dried to a film from toluene under reduced pressure. The residue was purified on 40 g silica eluting with 0>2.5% MeOH/CH2Cl2. MS (ESI pos. ion) m/z (MH+): 407 (MH+). Calc'd exact mass for C24H30N2O2Si: 406.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2.C(N(CC)CC)C.[Cl:28][CH2:29][C:30](Cl)=[O:31].Cl>ClCCl>[Cl:28][CH2:29][C:30]([N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2)=[O:31]
Reactant: O=C(Cl)CCl
Reactant: CNCCCN1c2ccccc2CCc2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCCN1c2ccccc2CCc2ccccc21)C(=O)CCl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Dissolve 5-(3-methylaminopropyl)-10,11-dihydro-5H-dibenzo[b,f]azepine (7.0 g, 0.026 mol) and triethylamine (4 mL) in dichloromethane (100 mL) and cool with an ice-bath. Add, by dropwise addition, a solution of chloroacetyl chloride (3.23 g, 0.0286 mol) in dichloromethane (25 mL). Stir at room temperature for 12 hours, shake with dilute hydrochloric acid and dry (MgSO4). Evaporate the solvent in vacuo to give the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:32])=[C:4]([S:9]([N:12]([CH2:21][C:22]2[N:27]=[C:26]([C:28]([O:30]C)=[O:29])[CH:25]=[CH:24][CH:23]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].C1COCC1>CO>[Cl:1][C:2]1[C:3]([OH:32])=[C:4]([S:9]([N:12]([CH2:21][C:22]2[N:27]=[C:26]([C:28]([OH:30])=[O:29])[CH:25]=[CH:24][CH:23]=2)[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1cccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
A mixture of methyl 6-((3,5-dichloro-N-(4-fluorobenzyl)-2-hydroxyphenylsulfonamido)methyl)picolinate (0.185 g, 0.37 mmol), 1 N NaOH (2 mL), THF (2 mL) and MeOH (2 mL) was stirred at rt overnight. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate and 1 N HCl. The organic layer was separated, washed with brine, dried over MgSO4, filtered and the filtrate solution was concentrated to give the desired product (0.18 g, 99%) as a colorless oil. 1H NMR (CDCl3) δ 8.12 (d, J=8.0 Hz, 1H), 7.88 (t, J=8.0 Hz, 1H), 7.58 (d, J=4.0 Hz, 1H), 7.55 (d, J=4.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.06-7.03 (m, 2H), 6.93 (t, J=8.0 Hz, 2H), 4.64 (s, 2H), 4.40 (s, 2H). MS (ESI): 485.0 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[O:16][CH3:17].[CH2:18]([O:20][C:21](=[O:32])[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([CH2:29][CH2:30][CH3:31])[CH:23]=1)[CH3:19].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O>[CH2:18]([O:20][C:21](=[O:32])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=2[O:16][CH3:17])=[C:24]([CH2:29][CH2:30][CH3:31])[CH:23]=1)[CH3:19]
Reactant: CCCc1cc(C(=O)OCC)ccc1O
Reactant: COc1cccc(CCCCCCBr)c1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1cc(C(=O)OCC)ccc1OCCCCCCc1cccc(OC)c1OC
Yield: 97.2 %

Procedure:
A mixture of 1.40 g (4.8 mmol) of 1-(6-bromohexyl)-2,3-dimethoxybenzene, 1.00 g (4.8 mmol) of 4-hydroxy-3-propylbenzoic acid ethyl ester, 1.30 g (9.6 mmol) of potassium carbonate and 0.72 g (4.8 mmol) of sodium iodide in 35 mL of acetone was stirred at reflux for 47 hours. Workup and purification as described in Example 16 gave 2.0 g of 4-[6-(2,3-dimethoxyphenyl)hexyloxy]-3-propylbenzoic acid ethyl ester as an oil. The mass spectrum showed the molecular ion at m/e 428.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(=O)C1C=CC=CC=1.ClCCl.[CH2:20]([O:27][C:28](ON1C(=O)CCC1=O)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])[CH2:5][CH2:4]1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: NCC1CCNCC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=Cc1ccccc1
Product: NCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Aminomethylpiperidine (40 g, 350 mmol) and benzaldehyde (37.3 mL, 368 mmol) in toluene (600 mL) were heated to reflux under Dean Stark conditions for 2 h. The resulting reaction mixture was cooled to room temperature and 500 mL dichloromethane was added. The resulting solution was cooled to 5° C. and treated with N-(benzyloxycarbonyloxy)succinimide (91.7 g, 368 mmol). After 10 min, the cooling bath was removed and the resulting reaction mixture stirred for 1 h. The solvents were evaporated and the residue stirred with 400 mL THF and 400 mL 2M HCl for 1 h. The mixture was concentrated to remove organics and extracted with ether (3×300 mL). The aqueous phase was adjusted to pH14 with 50% NaOH and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent evaporated to give benzyl 4(aminomethyl)piperidine-1-carboxylate as an oil.
Reaction SMILES: IC1C=CC(C2NC([C@@H](N3C(=O)[C@@H](CCC(O)=O)NC3=O)C(C)C)=NC=2)=CC=1.C1(C[C@H]2NC(=O)[N:35]([C@H:39]([C:48]3[NH:49][C:50]([C:54]4[CH:59]=[CH:58][C:57]([I:60])=[CH:56][C:55]=4[F:61])=[C:51]([CH3:53])[N:52]=3)[C@H:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH3:41])C2=O)CC1.C(O[C:68]([NH:70][C@H:71]([C:75]1[CH:80]=[CH:79][C:78]([O:81][CH2:82][C:83](=[O:87])N(C)C)=[CH:77][CH:76]=1)[C:72]([OH:74])=O)=[O:69])(C)(C)C.ClN1C(=O)CCC1=O>>[F:61][C:55]1[CH:56]=[C:57]([I:60])[CH:58]=[CH:59][C:54]=1[C:50]1[NH:49][C:48]([C@@H:39]([N:35]2[C:72](=[O:74])[C@@H:71]([C:75]3[CH:76]=[CH:77][C:78]([O:81][CH2:82][CH2:83][OH:87])=[CH:79][CH:80]=3)[NH:70][C:68]2=[O:69])[C@H:40]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH3:41])=[N:52][C:51]=1[CH3:53]
Reactant: CN(C)C(=O)COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: Cc1nc([C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](CC3CC3)C2=O)[nH]c1-c1ccc(I)cc1F
Agent: CC(C)[C@@H](c1ncc(-c2ccc(I)cc2)[nH]1)N1C(=O)N[C@H](CCC(=O)O)C1=O
Agent: O=C1CCC(=O)N1Cl
Product: Cc1nc([C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](c3ccc(OCCO)cc3)C2=O)[nH]c1-c1ccc(I)cc1F

Procedure:
Prepared by the same method as described in example 1 except that (i) steps A, B and C were omitted; (ii) 1-(2-fluoro-4-iodo-phenyl)-propan-1-one (prepared as described in example 13) was used in place of 1-(2-fluoro-4-iodo-phenyl)-ethanone in step 68-D and (iii) chlorination of the 5-position of the imidazole ring with N-chlorosuccinimide in step 68-F was omitted. HR-MS: calcd for C30H28FlN4O4 [M+H+] 655.1212. Found. 655.1210.
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].BrCCC1C=CC=[C:37]([O:41]C)C=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH3:37][O:41][C:21]1[CH:20]=[C:19]([CH2:18][CH2:17][N:16]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][C:2]([CH3:1])([CH3:6])[C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: COc1cccc(CCBr)c1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: COc1cccc(CCN(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)[C@H]2CC[C@H](C)CC2)c1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 1-(2-bromo-ethyl)-3-methoxy-benzene and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[ClH:13]>>[ClH:13].[ClH:13].[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1
Reactant: COc1ccc([N+](=O)[O-])c(N)n1
Agent: Cl
Product: COc1ccc(N)c(N)n1
Temperature: 15 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To the concentrated hydrochloric acid (250 ml), 25.0 gm of 2-amino-6-methoxy-3-nitropyridine (0.147 mole) was added at room temperature. The resulting solution was cooled to 15° C. and 66.7 gm of stannous chloride dihydrate (0.294 mole) was added slowly. The reaction mass was heated to 35°–40° C. and mixed for 5–6 hrs with constant stirring. The reaction was monitored by TLC. After the reaction was over, the reaction mixture was cooled to 20° C. and stirred for one hour. The resulting mixture was filtered and dried to give 27.0 gm of 2,3-diamino-6-methoxypyridine dihydrochloride (yield=86.4%); Melting point 211 to 213° C.; HPLC purity was 99.0%.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]3[N:19]=[C:18]([NH:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)[CH:17]=[CH:16][N:15]=3)[CH:11]=2)[C:6]([CH3:32])([CH3:31])[CH2:5]1)(=O)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>CCO.Cl>[CH3:31][C:6]1([CH3:32])[C:7]2[C:12](=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([NH:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)[CH:17]=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[NH:4][CH2:5]1
Reactant: CC(=O)N1CC(C)(C)c2ccc(Nc3nccc(Nc4ccc5ncccc5c4)n3)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)CNc2cc(Nc3nccc(Nc4ccc5ncccc5c4)n3)ccc21

Procedure:
A mixture of N2-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-N4-(6-quinolinyl)-2,4-pyrimidinediamine (Example 111, 150 mg, 0.353 mmol) was dissolved in EtOH (6 mL) and 10 drops conc. HCl were added. The mixture was heated to reflux in a sealed tube for 72 h. The crude mixture was poured into EtOAc (125 mL) and sat NaHCO3 (20 mL). The organics were dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified via medium pressure liquid chromatography using linear gradient starting from 0:100 MeOH/CH2Cl2 ending with 10:90 MeOH/CH2Cl2 as the solvent system to yield the desired product as a light yellow solid. M+H—383; Calc'd for C23H22N6—382.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[CH:9]=2)[CH:4]=1.Cl.[NH+]1C=CC=CC=1>>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]3)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2)cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: Oc1ccc(-c2ccc3cc(O)ccc3c2)cc1
Yield: 97.4 %

Procedure:
2-Methoxy-6-(4-methoxyphenyl)naphthalene (5.61 g, 21.2 mmol) was added to pyridinium HCl (30 g) at 190° C. according to Method B to afford 4.88 g (98%) of a white solid: mp>220 (discolors above 200° C.); 1H NMR (DMSO-d6): δ 6.87 (2H, d, J=8.54 Hz), 7.08 (1H, dd, J=2.34 Hz, J=8.76 Hz), 7.11 (1H, d, J=2.14 Hz), 7.58 (2H, d, J=8.54 Hz), 7.65 (1H, dd, J=1.92 Hz, J=8.76 Hz), 7.71 (1H, d, J=8.54 Hz), 7.79 (1H, d, J=8.97 Hz), 7.95 (1H, s), 9.56 (1H, bs), 9.70 (1H, bs); MS (ESI) m/z 235 (M−H)−.
Reaction SMILES: NC1C=CC(F)=CC=1C(NC)=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][C:29]=1[N+:30]([O-])=O)[CH2:18][CH2:19][PH:20](=[O:26])[O:21][CH2:22][CH2:23][O:24][CH3:25]>>[NH2:30][C:29]1[CH:28]=[CH:27][C:17]([CH2:18][CH2:19][PH:20](=[O:26])[O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:16][C:15]=1[O:14][CH3:13]
Reactant: COCCO[PH](=O)CCc1ccc([N+](=O)[O-])c(OC)c1
Agent: CNC(=O)c1cc(F)ccc1N
Product: COCCO[PH](=O)CCc1ccc(N)c(OC)c1

Procedure:
The title compound was prepared according the procedure for 2-Amino-5-fluoro-N-methylbenzamide (Compound 102A) using 2-methoxyethyl (3-methoxy-4-nitrobenzyl)methylphosphinate (Compound 216B). 1H NMR (CDCl3, 400 MHz): δ=1.39 (d, J=13.64 Hz, 3 H), 3.10 (d, J=17.43 Hz, 2 H), 3.39 (s, 3 H), 3.54-3.59 (m, 2 H), 3.87 (s, 3 H), 4.09-4.14 (m, 2 H), 6.66-6.71 (m, 1 H), 6.76-6.79 (m, 1 H), 6.80 (t, J=1.89 Hz, 1 H). MS (ES+): m/z 274.11 [MH+] (TOF, polar).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[O:22]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23]1>>[O:22]1[CH:26]=[CH:25][C:24]([C:2]2[C:3]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=3)=[CH:23]1
Reactant: OB(O)c1ccoc1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(-c3ccoc3)nc2c1
Yield: 25.1 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and furan-3-yl boronic acid (48.8 mg, 0.44 mmol, 1.50 equiv) as reactants. Purification via silica gel column (dichloromethane/methanol (10:1)) yielded 23 mg (24%) of 3-(furan-3-yl)-2-phenylquinoxaline-6-carboxylic acid as a white solid.
Reaction SMILES: [CH:1]([O-:3])=[O:2].[Na+].CCN(C(C)C)C(C)C.[C:14]([O:18][C:19](=[O:31])[NH:20][C:21]1([C:24]2[CH:29]=[CH:28][C:27](I)=[CH:26][N:25]=2)[CH2:23][CH2:22]1)([CH3:17])([CH3:16])[CH3:15].[Li+].[Cl-]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:14]([O:18][C:19]([NH:20][C:21]1([C:24]2[CH:29]=[CH:28][C:27]([C:1]([OH:3])=[O:2])=[CH:26][N:25]=2)[CH2:23][CH2:22]1)=[O:31])([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C[O-]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(I)cn2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)O)cn2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 38.3 %

Procedure:
To a solution of acid anhydride (0.89 mL, 9.4 mmol) in DMF (10 mL) in a pressure tube was added sodium formate (0.96 g, 14.2 mmol) and Hunig's base (1.6 mL, 9.4 mmol). The pressure tube was sealed and the mixture allowed to stir at room temperature for 45 minutes. The tube was opened and a solution of [1-(5-iodo-pyridin-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester (1.7 g, 4.7 mmol) in DMF (3 mL) was added followed by LiCl (0.60 g, 14.2 mmol) and Pd(OAc)2 (0.11 g, 0.47 mmol). The reaction vessel was sealed and the mixture heated at 80° C. for 20 h. The reaction mixture was cooled to room temperature and the cap slowly removed allowing for gas release. The mixture was diluted with water and extracted with EtOAc (3×100 mL). The combined extracts were washed with water, 1N HCl, brine and dried with MgSO4. The mixture was filtered and concentrated to give 6-(1-tert-butoxycarbonylamino-cyclopropyl)-nicotinic acid (0.51 g, 1.8 mmol) as a yellow solid, m/z 279.6.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]2[CH2:6][CH2:7][C:4]=2[CH:3]=1.[C:10]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH2:19])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N(CCCC)CCCC)CCC.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([CH:18]=[CH:19][C:2]2[CH:9]=[CH:8][C:5]3[CH:6]=[CH:7][C:4]=3[CH:3]=2)=[CH:20][CH:21]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: C=Cc1ccc(C(C)(C)C)cc1
Reactant: Brc1ccc2c(c1)CC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Solvent: CC#N
Product: CC(C)(C)c1ccc(C=Cc2ccc3c(c2)C=C3)cc1

Procedure:
A solution of 3.0 g 4-bromobenzocyclobutane, 2.6 g 4-tert-butylstyrene, 3.0 g tri-n-butylamine, 150 mg tri-o-tolylphosphine, 36 mg palladium (II) acetate, and 10 ml acetonitrile is stirred under nitrogen at reflux for 4 hours. The reaction mixture is poured into 60 ml of 10 percent HCl. The product is isolated by filtration, dried, recrystallized from ethanol, and isolated. About 1.8 g of monomer is prepared.
Reaction SMILES: [OH-].[K+].[CH:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]#[N:20])[CH:15]=[CH:16][CH:17]=1.[BH4-].[Na+]>C(O)C.O>[Br:11][C:12]1[CH:13]=[C:14]([CH:18]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:19]#[N:20])[CH:15]=[CH:16][CH:17]=1
Reactant: N#CCc1cccc(Br)c1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CC(Cc1ccccc1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.7 %

Procedure:
A solution of 40% KOH (2.83 g in 5.0 ml of H2O) in ethanol (13 ml) was added to a solution of benzaldehyde (2.85 ml, 28.05 mmol) and 3-bromophenylacetonitrile (5 g, 25.50 mmol) in ethanol (9 ml). The reaction mixture was then stirred at room temperature for 2 hours and the precipitate was collected by suction filtration and washed with cold ethanol (6.68 g, 92%). The crude product (3.45 g, 12.14 mmol) was then dissolved in ethanol (35 ml) and heated to 65° C. Sodium borohydride (459 mg, 12.14 mmol) was added in portions and the reaction mixture was maintained at this temperature for a further 2 hours. Upon cooling, water (10 ml) was added and the solvent was removed under reduced pressure. The residue was partitioned between water (100 ml) and ethyl acetate (100 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated to afford the desired product (1.80 g, 52%), which was used without purification.