Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:21])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1.[Cl:22][C:23]1[CH:33]=[CH:32][C:26]([CH:27]([OH:31])[C:28](O)=[O:29])=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH:27]([OH:31])[C:28]([NH:21][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[C:7]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)[CH:8]=2)=[O:29])=[CH:32][CH:33]=1
Reactant: O=C(O)C(O)c1ccc(Cl)cc1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(NC(=O)C(O)c2ccc(Cl)cc2)ccc1OCCN1CCCC1
Temperature: 50 °C
Yield: 15.1 %

Procedure:
A mixture of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (100 mg, 0.35 mmol), 4-chloromandelic acid (98 mg, 0.525 mmol), HATU (200 mg, 0.525 mmol) and triethylamine (0.5 mL) in DMF (6 mL) was heated at 50° C. overnight. The crude was purified by HPLC to provide the title compound as a semi-solid (24 mg, i 5%). 1H NMR (DMSO-d6, 400 MHz) δ 1.60-1.73 (m, 2H), 1.84-1.91 (m, 2H), 2.80-2.90 (m, 2H), 3.22-3.30 (m, 4H), 3.65 (s, 3H), 4.25 (t, J=5.05 Hz, 2H), 6.26 (d, J=1.77 Hz, 1H), 7.17 (d, J=9.09 Hz, 1H), 7.39-7.46 (m, 2H), 7.51-7.53 (m 3H), 7.67 (d, J=2.53 Hz, 1H), 7.80 (dd, J=2.78, 8.84 Hz, 1H), 9.50 (s br, 1H), 10.0 (s, 1H). Exact mass calculated for C24H27ClN4O3 454.2. found 455.4 (M+).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=2)[O:5][C:4]([CH3:21])([CH3:20])[CH2:3]1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C1COCC1>[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[O:5][C:4]([CH3:21])([CH3:20])[CH2:3][CH:2]2[NH:1][S:30]([CH3:29])(=[O:32])=[O:31])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC1(C)CC(N)c2cc(OCc3ccccc3)ccc2O1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)CC(NS(C)(=O)=O)c2cc(OCc3ccccc3)ccc2O1
Reaction time: 0.5 h

Procedure:
4.0 g (14 mmol) of 4-amino-6-benzyloxy-2,2-dimethylchroman were treated with 4.2 ml (30 mmol) of triethylamine at RT in 80 ml of THF and the mixture was stirred for 30 min, then treated with 1.95 g (1.3 ml, 17 mmol) of methanesulfonyl chloride, the temperature rising to 40° C. The mixture was then heated to reflux for 2 h, allowed to stand overnight at RT, concentrated in vac. and the residue was treated with water; 4.9 g of product, m.p. 162-165° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[N:30]1([C:35]([C:37]2[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=2[NH2:39])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH3:29][O:28][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([NH:39][C:38]2[CH:40]=[CH:41][CH:42]=[CH:43][C:37]=2[C:35]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:36])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: Nc1ccccc1C(=O)N1CCCC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)N3CCCC3)n2)c(OC)c1)OCC

Procedure:
The title product was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and the commercially available 2-(pyrrolidin-1-ylcarbonyl)aniline.MS (ES+): m/z 608.35 (100) [MH+]; HPLC: tR=1.07 min (UPLC, purity).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=1.O.[NH2:35][NH2:36]>CN(C=O)C>[CH2:31]([O:30][C:28]([CH2:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:36][N:35]=2)=[CH:22][CH:23]=1)=[O:29])[CH3:32]
Reactant: CCOC(=O)Cc1ccc(CC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)cc1
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Yield: 90.4 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(4-ethoxycarbonylmethylphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (128 mg, 0.29 mmol, prepared in Synthetic Example 26) in DMF (3 ml) was added hydrazine monohydrate (80%, 34 μl, 0.87 mmol, 3.0 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-(4-ethoxycarbonylmethylbenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (115 mg, 91%).
Reaction SMILES: N.[Na].[C:3](#[N:5])[CH3:4].[Cl:6][CH2:7][CH:8]1[CH2:12][O:11][C:10]([C:19]2[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=2[C:21](OC)=[O:22])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9]1>CCOCC>[Cl:6][CH2:7][CH:8]1[CH2:12][O:11][C:10]([C:19]2[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=2[C:21](=[O:22])[CH2:4][C:3]#[N:5])([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:9]1
Reactant: CC#N
Reactant: COC(=O)c1ccccc1C1(c2ccccc2)OCC(CCl)O1
Agent: N
Agent: [Na]
Solvent: CCOCC
Product: N#CCC(=O)c1ccccc1C1(c2ccccc2)OCC(CCl)O1

Procedure:
To a stirring solution of 75 ml of liquid ammonia was added a small piece of sodium and a few crystals of ferric nitrate. A total of 1.15 g (0.0502 mol) of sodium was added over a 20 min period, and after 5 mins a solution of 2.9 ml (0.050 mol) of acetonitrile in 10 ml of ether was added dropwise. A solution of 6.6 g (0.0198 mol) of the end product of Example 12 in 40 ml of ether was added dropwise, and after 2 hrs 100 ml of ether was added and the ammonia was allowed to evaporate. About 100 g of ice was added to the reaction, which was then acidified with acetic acid, followed by neutralization with a saturated solution of sodium bicarbonate. The water layer was separated and extracted once more with ether. The combined ether layers were washed with 100 ml of water, dried over sodium sulfate and evaporated. The oil was dissolved in 15 ml of dichloromethane and filtered through 100 g of Florisil. Elution with dichloromethane, and evaporation gave 2-[4-(chloromethyl)-2-phenyl-1,3-dioxolan-2-yl]-β-oxo-benzenepropanenitrile which was used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Mg].O(CC)CC.Br[CH2:22][CH:23]=[CH2:24]>O1CCCC1>[CH2:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH2:24][CH:23]=[CH2:22]
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: C=CCBr
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCCc1ccc(-c2ccccc2)cc1
Reaction time: 2.5 h

Procedure:
To a stirred and refluxing Grignard-complex, previously prepared starting from 89 parts of 4-(chloromethyl)-1,1'-biphenyl and 12.5 parts of magnesium in 350 parts of 1,1'-oxybisethane, is added dropwise a solution of 60 parts of 3-bromo-1-propene in 180 parts of tetrahydrofuran. Upon completion, stirring is continued for 2.50 hours at reflux temperature. The reaction mixture is cooled and poured onto water. The layers are separated and the aqueous phase is extracted with 1,1'-oxybisethane. The combined organic phases are washed with water, dried, filtered and evaporated. The residue is filtered and the filtrate is evaporated, yielding 60 parts of 4-(3-butenyl)-1,1'-biphenyl as a residue.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][C@@H:7]([NH:13]C(=O)[C@@H](O)C1C=CC=CC=1)[CH2:6]2)#[N:2].S(=O)(=O)(O)O>CCO>[NH2:13][C@H:7]1[CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[CH:4]=2)[NH:9][CH2:8]1
Reactant: N#Cc1ccc2c(c1)C[C@H](NC(=O)[C@@H](O)c1ccccc1)CN2
Agent: O=S(=O)(O)O
Solvent: CCO
Product: N#Cc1ccc2c(c1)C[C@H](N)CN2
Temperature: 25 °C
Yield: 72.8 %

Procedure:
To a solution of 1E (2.5 g, 8.14 mmol) in EtOH (25 mL) was added 15% aqueous sulfuric acid (25 mL). The resulting mixture was refluxed overnight, then cooled to RT. After removal of most of the EtOH, the mixture was diluted with water (200 mL), extracted with CH2Cl2 (3×50 mL). The aqueous layer was basified with 4N NaOH to pH=10, then extracted with CH2Cl2 (3×50 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was crystallized from EtOAc/hexane to afford the title compound (1.026 g, 73% yield),
Reaction SMILES: [CH3:1][O:2][C:3]1([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11][C:6]2(OCC[O:7]2)[CH2:5][CH2:4]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[CH3:1][O:2][C:3]1([C:13]([F:14])([F:15])[F:16])[CH2:4][CH2:5][C:6](=[O:7])[CH2:11][CH2:12]1
Reactant: COC1(C(F)(F)F)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: COC1(C(F)(F)F)CCC(=O)CC1

Procedure:
11.80 g (49.12 mmol) of 8-methoxy-8-(trifluoromethyl)-1,4-dioxaspiro[4.5]decane (Example 9A) were dissolved in 236 ml of acetone and 118 ml of water, 1.50 g (7.86 mmol) of 4-toluenesulphonic acid monohydrate were added and the mixture was heated at reflux overnight. The mixture was then poured into 1.2 l of water and the product was extracted with diethyl ether. The organic phase was washed with water, dried over sodium sulphate and concentrated under reduced pressure. The resulting residue was distilled under reduced pressure (boiling point: 106-110° C. at 40 mbar). This gave 6.86 g (71% of theory) of the title compound as a yellowish oil.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([N:5]1[CH2:12][CH2:11][C@:10]2([CH3:16])[C:13]([CH3:15])([CH3:14])[C@H:6]1[CH2:7][C:8]1[C:20](OC)=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=[CH:17][C:9]=12)=[O:4].[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([NH:35][C:20]1[C:8]2[CH2:7][C@@H:6]3[C:13]([CH3:14])([CH3:15])[C@:10]([CH3:16])([C:9]=2[CH:17]=[CH:18][C:19]=1[N+:23]([O-:25])=[O:24])[CH2:11][CH2:12][N:5]3[C:3](=[O:4])[C:2]([F:1])([F:26])[F:27])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1c([N+](=O)[O-])ccc2c1C[C@H]1N(C(=O)C(F)(F)F)CC[C@]2(C)C1(C)C
Reactant: NCc1ccccc1
Product: CC1(C)[C@H]2Cc3c(ccc([N+](=O)[O-])c3NCc3ccccc3)[C@]1(C)CCN2C(=O)C(F)(F)F
Temperature: 70 °C
Reaction time: 8 h

Procedure:
2,2,2-Trifluoro-1-[(2R,6S)-10-methoxy-6,11,11-trimethyl-9-nitro-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone (0.41 g) is combined with benzylamine (0.7 mL) and the resulting mixture is stirred at 70° C. overnight. After cooling to room temperature, the mixture is purified by HPLC on reversed phase (MeCN/H2O/F3CCO2H) to give the product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH:18]1([C:21]2[O:25][C:24]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([O:39][CH3:40])[C:33](N(OC)C)=[O:34])=[CH:28][CH:27]=3)=[N:23][N:22]=2)[CH2:20][CH2:19]1>>[CH:18]1([C:21]2[O:25][C:24]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([O:39][CH3:40])[C:33]([C:15]4[O:14][C:13]([C:5]5[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)=[CH:17][CH:16]=4)=[O:34])=[CH:28][CH:27]=3)=[N:23][N:22]=2)[CH2:19][CH2:20]1
Reactant: COc1cc(-c2ccco2)cc(OC)c1OC
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C3CC3)o2)cc1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnc(C5CC5)o4)cc3)o2)cc(OC)c1OC

Procedure:
2-(4-(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxy-1-(5-(3,4,5-trimethoxyphenyl)furan-2-yl)ethanone was prepared from 2-(3,4,5-trimethoxyphenyl)furan and 2-(4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamide according to the procedure used in Example 30. Purification by chromatography (60% EtOAc-hexanes) gave the product as a pale yellow solid (0.129 g, 42% yield). MS: m/z 491.1 [M+H]+.
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([O:13][C:14]([NH:16][C@H:17]1[CH2:23][CH2:22][S:21][C@H:20]2[CH2:24][CH2:25][CH2:26][C@@H:27]([C:28]([OH:30])=O)[N:19]2[C:18]1=[O:31])=[O:15])([CH3:12])([CH3:11])[CH3:10].C[N:33]1CCOCC1.[NH4+].[OH-]>C(Cl)Cl>[C:28]([C@H:27]1[N:19]2[C@@H:20]([S:21][CH2:22][CH2:23][C@H:17]([NH:16][C:14](=[O:15])[O:13][C:9]([CH3:11])([CH3:10])[CH3:12])[C:18]2=[O:31])[CH2:24][CH2:25][CH2:26]1)(=[O:30])[NH2:33]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)O)N2C1=O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(N)=O)N2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
Isobutyl chloroformate (31.2 mg, 0.229 mmol) was added to a solution of (4S,7S,10aS)-4-(tert-Butoxycarbonylamino)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid (75 mg, 0.22 mmol) and 4-methylmorpholine (26.4 mg, 0.261 mmol) in DCM at 0° C. After stirring for 30 min at 0° C., NH4OH was added. The ice bath was removed and the reaction mixture was stirred at rt for 30 min. The reaction mixture was concentrated and the residue was partitioned between EtOAc and aqueous 0.5 N HCl. The organic phase was isolated, washed with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to give tert-butyl (4S,7S,10aS)-7-carbamoyl-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (67 mg, 0.20 mmol, 90% yield) as an oil. Anal. Calcd. for C15H25N3O4S m/z 343.4. found: 344.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][C:10]=3[O:20][CH3:21])[NH:8][C:4]=2[CH:3]=1.[O-:24][C:25]#[N:26].[K+].C(O)(=O)C>O1CCCC1>[NH2:26][C:25]([NH:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][C:10]=3[O:20][CH3:21])[NH:8][C:4]=2[CH:3]=1)=[O:24]
Reactant: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(N)cc2[nH]1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(NC(N)=O)cc2[nH]1

Procedure:
One gram (3.0 mmol) of 5-amino-2-(2'-methoxy-4'-methanesulfonyloxy-phenyl)-benzimidazole were dissolved in 20 ml of pure tetrahydrofuran, and then 2.0 gm of potassium cyanate and 5 ml of 2M acetic acid were added successively. After the mixture refluxed for eight hours, the solvent was evaporated off in vacuo, and the residue was mixed with 10 ml of water and neutralized with 5% sodium bicarbonate solution. The crude product precipitated was subjected to suction filtration and chromatographed over 200 gm of silica gel (eluant: methylene chloride with 8% ethanol).
Reaction SMILES: F[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([N+:15]([O-])=O)[C:3]=1[NH2:18]>O=[Mn]=O.CCOC(C)=O>[CH:14]1([N:11]2[CH2:12][CH2:13][N:8]([C:7]3[CH:2]=[C:3]([NH2:18])[C:4]([NH2:15])=[CH:5][CH:6]=3)[CH2:9][CH2:10]2)[CH2:4][CH2:3][CH2:2][CH2:7]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2F)CC1
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCN(C3CCCC3)CC2)cc1N
Temperature: 120 °C
Reaction time: 2 h
Yield: 188.9 %

Procedure:
A 250 mL sealed tube was charged with benzyl alcohol 1 (1.0 g, 3.6 mmol), MnO2 (4.7 g, 54 mmol) and EtOAc (20 mL). The resulting suspension was heated to 120° C. with stirring for 2 hours. Reaction mixture filtered through Celite and washed successively with EtOAc, MeOH, and EtOH. Organics evaporated to give 936 mg (3.4 mmol, 94%) of 2 as an orange solid. 1H NMR (300 MHz, CDCl3) δ 10.01 (s, 1H), 8.64 (d, J=5.5 Hz, 1H), 8.09 (br s, 1H), 7.96 (d, J=2.75 Hz, 1H), 7.37 (d, J=2.48 Hz, 1 H), 7.29 (d, J=2.75 Hz, 1H), 7.08 (dd, J=2.47, 5.5 Hz, 1H), 6.94 (d, J=9.35 Hz, 1H), 3.08 (d, J=5.23 Hz, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH2:15][CH2:16][Cl:17])=[C:9]([O:18][CH3:19])[CH:8]=2)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].CCO>O>[Cl:17][CH2:16][CH2:15][O:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:18][CH3:19])[NH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:13]2
Reactant: COC(=O)c1cc2cc(OCCCl)c(OC)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Product: COc1cc2[nH]c(C(=O)O)cc2cc1OCCCl
Temperature: 25 °C
Yield: 94.7 %

Procedure:
A suspension of ester 17 (2.00 g, 7.05 mmol), Cs2CO3 (3.45 g, 10.6 mmol), 95% EtOH (40 mL), and water (20 mL) was heated at reflux for 8 h. After cooling to room temperature the solvent was removed in vacuo, the residue was treated with water (50 μL), and the resulting solution was acidified with 2 M HCl. The formed precipitate was isolated by filtration, washed with water (100 mL), and dried in vacuo to give 18 (1.80 g, 95%) as a beige solid. 1H NMR (300 MHz, DMSO-d6): δ=3.81 (s, 3 H, OMe), 3.93 (t, J=5.3 Hz, 2 H, 2′-H2), 4.21 (t, J=5.3 Hz, 2 H, 1′-H2), 6.91 (s, 1 H, 7-H), 6.96 (d, J=2.1 Hz, 1 H, 3-H), 7.15 (s, 1 H, 4-H), 11.44 (sbr, 1 H, NH), 12.57 (sbr, 1 H, CO2H) ppm; 13C NMR (50.3 MHz, DMSO-d6): δ=43.0 (C-2′), 55.6 (OMe), 69.5 (C-1′), 94.9 (C-7), 105.8 (C-4), 107.5 (C-3), 119.8 (C-3a), 126.8 (C-2), 133.0 (C-7a), 143.9 (C-5), 149.5 (C-6), 162.4 (C═O) ppm; MS (70 eV, EI): m/z (%)=269 (100) [M]+, 206 (58) [M-(CH2)2Cl]+; C12H12ClNO4 (269.68): calcd. C, 53.44; H, 4.49; found C, 53.54; H, 4.29.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[F:27][CH2:28][CH2:29][NH:30][C:31](=O)[O:32]C1C=CC=CC=1>>[F:27][CH2:28][CH2:29][NH:30][C:31]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:32]
Reactant: COc1cc2nccc(Oc3ccc4[nH]ccc4c3)c2cc1OC
Reactant: O=C(NCCF)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: COc1cc2nccc(Oc3ccc4c(ccn4C(=O)NCCF)c3)c2cc1OC
Yield: 18.8 %

Procedure:
4-(1H-Indol-5-yloxy)-6,7-dimethoxyquinoline (75 mg, 0.3122 mmol), sodium hydride (13 mg, 0.3278 mmol) and phenyl N-(2-fluoroethyl)carbamate (45 mg, 0.3278 mmol) were used for reaction in the same manner as Example 310, followed by extraction with ethyl acetate/tetrahydrofuran, washing with saturated saline and drying over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was adsorbed onto silica gel and subjected to silica gel column chromatography (hexane/ethyl acetate system) to obtain the title compound (24 mg, 0.0586 mmol, 18.78%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:10]=O)=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1>C(O)C>[Cl:9][C:5]1[N:4]=[C:3]([CH:10]=[N:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[C:2]([NH2:1])=[N:7][C:6]=1[Cl:8]
Reactant: Nc1nc(Cl)c(Cl)nc1C=O
Reactant: COc1ccc(N)cc1
Solvent: CCO
Product: COc1ccc(N=Cc2nc(Cl)c(Cl)nc2N)cc1

Procedure:
In a manner similar to that described in Example 9, 1.92 grams (0.01 mole) of 3-amino-5,6-dichloropyrazinaldehyde, 1.23 g (0.01 mole) of p-anisidine and 15 milliliters of ethanol were mixed together and heated at reflux temperature to obtain a 5,6-dichloro-3-[(4-methoxyphenyl)imino]methylpyrazinamine product which precipitated in the reaction mixture. The product was recovered by filtration, recrystallized from ethanol to obtain 2.14 grams of a purified product, m.p. 167°-168° C. (dec). Elemental analyses were as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:18][CH2:17][CH2:16][CH:15]=[C:14]2[C:13](=[O:19])[NH:12][C:11](=[O:20])[CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH:23]1([CH2:26]CS([O-])(=O)=O)[CH2:25][CH2:24]1.O>CN(C)C=O>[CH:23]1([CH2:26][N:12]2[C:11](=[O:20])[CH2:10][C:9]3([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[C:14](=[CH:15][CH2:16][CH2:17][CH2:18]3)[C:13]2=[O:19])[CH2:25][CH2:24]1
Reactant: COc1cccc(C23CCCC=C2C(=O)NC(=O)C3)c1
Reactant: O=S(=O)([O-])CCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(C23CCCC=C2C(=O)N(CC2CC2)C(=O)C3)c1
Reaction time: 8 h

Procedure:
4a-(m-Methoxyphenyl)-1,3-diketo-1,2,3,4,4a,5,6, 7-octahydroisoquinoline (99 g, 0.365 moles) in 1000 ml of anhydrous dimethylformamide was added dropwise to a 55% suspension of sodium hydride in mineral oil (19.8 g) in 500 ml of dimethylformamide at 70°. The reaction mixture was heated for 1 hour at 80° and then cooled to 25°. Cyclopropylmethylmesylate (59.6 g) was added and the reaction mixture heated at 70°-80° for one hour and stirred overnight. It was poured into water and extracted with ether. The residue after evaporation of the ether was chromatographed on 800 g of Florisil. The final product, after evaporative distillation at 190° (1μ), amounted to 50 g.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH:9]=2)[CH:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:3]=1.[Cl:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1>>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[C:10]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])[CH:9]=3)[CH:5]=[C:4]([C:24]([F:27])([F:25])[F:26])[N:3]=2)[CH:32]=[CH:31][N:30]=1
Reactant: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F
Reactant: OB(O)c1ccnc(Cl)c1
Product: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chloro-4-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidine (example A.39) (0.85 g, 2.0 mmol) and commercially available 2-chloro-pyridine-4-boronic acid (0.35 g, 2.22 mmol) according to the general procedure IVb. Obtained as an off-white solid (0.71 g, 70%). MS (EI) 501.1 [(M)+]; mp 138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[C@H:7]([CH2:10][C:11]([O:13]CC)=O)[CH2:8][O:9][C:4]=2[CH:3]=1.[NH3:31]>>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:16]([C:18]3[CH:19]=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[NH:23][C:22]=4[CH:28]=3)=[O:17])[C@H:7]([CH2:10][C:11]([NH2:31])=[O:13])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C[C@@H]1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Reactant: N
Product: NC(=O)C[C@@H]1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 45 h
Yield: 27.4 %

Procedure:
Ethyl {(3R)-7-chloro-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetate (Intermediate 21b, 2.00 g, 4.64 mmol) dissolved in ammonia (7 M in MeOH) (49.7 mL, 348.2 mmol) sealed and stirred at rt for 45 h. The solvent was evaporated and the residue (616 mg crude brown oil) was dissolved in DMSO and MeOH. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 10-50% ACN in H2O/ACN/FA 95/5/0.2 buffer over 20 min with a flow of 100 mL/min. The compounds were detected by UV at 253/280 nm. Pure fractions were pooled and the most of the ACN was evaporated. The residue was partitioned between EtOAc and water. The combined organic phases were concentrated in vacuo. Addition of DMSO/ACN and water a precipitate was observed. The solvents were removed in vacuo and water was added to the residue and stirred at rt over night and filtered off to give pure title compound according to LCMS. 511 mg of off white solids were isolated, yield 27.4%.