Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:28])[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[N:3]=1.[NH2:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([NH2:36])[CH2:32][CH2:31]1>>[ClH:1].[ClH:1].[NH2:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([NH:36][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:3]=2)[CH2:32][CH2:31]1
Reactant: O=C(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1ccc(F)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Product: Cl
Product: N[C@H]1CC[C@H](Nc2nc(NCCNC(=O)c3ccc(F)cc3)c3ncn(C4CCCC4)c3n2)CC1
Temperature: 140 °C

Procedure:
247 mg of the product obtained in Stage 1 above and 350 mg of trans-1,4-diaminocyclohexane are mixed together and the reaction medium is heated to 140° C. for 6 hours. After evaporating the solvent, chromatography on silica is carried out (eluent methylene chloride/methanol/ammonium hydroxide 85/15/1.5) followed by taking up in an ethanolic solution of hydrochloric acid, leaving to crystallize, separating, drying under reduced pressure and 130 mg of expected product is recovered.
Reaction SMILES: CCN(CC)CC.F[B-](F)(F)F.[N:13]1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=[N:14]1.[C:30]([O:34][C:35]([N:37]1[CH2:44][CH2:43][C@:42]2([CH3:47])[C@H:45]([CH3:46])[C@H:38]1[CH2:39][C:40]1[CH:51]=[CH:50][C:49]([C:52](O)=[O:53])=[CH:48][C:41]=12)=[O:36])([CH3:33])([CH3:32])[CH3:31].O.NN>CN(C)C=O.O>[C:30]([O:34][C:35]([N:37]1[CH2:44][CH2:43][C@:42]2([CH3:47])[C@H:45]([CH3:46])[C@H:38]1[CH2:39][C:40]1[CH:51]=[CH:50][C:49]([C:52]([NH:13][NH2:14])=[O:53])=[CH:48][C:41]=12)=[O:36])([CH3:32])([CH3:31])[CH3:33]
Reactant: C[C@@H]1[C@H]2Cc3ccc(C(=O)O)cc3[C@]1(C)CCN2C(=O)OC(C)(C)C
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: NN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@@H]1[C@H]2Cc3ccc(C(=O)NN)cc3[C@]1(C)CCN2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NEt3 (1.7 mL) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (3.9 g) are added in turn to a solution of (2R,6R,11S)-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3,8-dicarboxylic acid 3-tertbutyl ester (4.2 g) in dimethylformamide (10 mL). The resulting solution is stirred at ambient temperature for 30 min, before hydrazine hydrate (3 mL) is added. The solution is stirred further at room temperature for 1 h and then water (30 mL) is added. The resulting mixture is extracted with ethyl acetate and the combined organic extracts are washed with 1 M aqueous NaOH solution, water, and brine. After drying (MgSO4), the solvent is evaporated and the residue is purified by chromatography on silica gel (cyclohexane/EtOAc 1:4->0:1) to give the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1.I[CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][O:29]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:25])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)[CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][O:29]1
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: ICC1CCCO1
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCO1)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 43.9 %

Procedure:
A solution of diisopropylamine (0.59 mL, 4.51 mmol) in tetrahydrofuran (30 mL) was cooled to −78° C. under an argon atmosphere and then was treated with a 2.5M solution of n-butyllithium in hexanes (1.8 mL, 4.51 mmol). The reaction mixture was stirred at −78° C. for 15 min, after which time, a solution of (3,4-dichloro-phenyl)-acetic acid methyl ester (825 mg, 3.76 mmol) in tetrahydrofuran (3 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL) was slowly added via a cannula. The bright yellow solution was allowed to stir at −78° C. for 1 h, after which time, a solution of 2-iodomethyl-tetrahydro-furan (798 mg, 3.76 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.5 mL) was added via a cannula. The reaction mixture was stirred at −78° C. for 1 h and then allowed to warm to 25° C., where it was stirred for 14 h. The reaction mixture was then quenched by the addition of a saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 90/10 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-(tetrahydro-furan-2-yl)-propionic acid methyl ester (501 mg, 44%) as a colorless oil: EI-HRMS m/e calcd for C14H16Cl2O3 (M+) 302.0477, found 302.0464.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH2:22])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:23][N:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH:22][C:29]([C:25]4[N:24]([CH3:23])[CH:28]=[CH:27][N:26]=4)=[O:30])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ccnc1C(=O)O
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccnc1C(=O)Nc1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
To a mixture of (R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Example 6, Step A; 40 mg, 0.13 mmol, prepared as described in a previous example), 1-methyl-1H-imidazole-2-carboxylic acid (34 mg, 0.27 mmol), and HATU (102 mg, 0.27 mmol) was added 1.0 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.07 mL, 0.4 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred for 10 minutes. The reaction mixture was diluted with EtOAc (15 mL), washed with water and brine (5 mL each), concentrated, and purified by reverse-phase column chromatography, eluting with 5 to 65% acetonitrile/water to yield the final product as a yellowish solid (37 mg, 68% yield). MS (apci) m/z=406.2 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][C:11]1[C:14](=[O:38])[N:15]([CH2:24][C:25]([NH:27][CH:28]([CH:35]([CH3:37])[CH3:36])[C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])=[O:26])[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:17][C:10]2=1)=[O:4].C1(C)C=CC=CC=1.ClC(Cl)C(O)=O.C(OCC)(=O)C>CS(C)=O>[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][C:11]1[C:14](=[O:38])[N:15]([CH2:24][C:25]([NH:27][CH:28]([CH:35]([CH3:36])[CH3:37])[C:29](=[O:34])[C:30]([F:32])([F:33])[F:31])=[O:26])[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:17][C:10]2=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cccc2c1[nH]c1c(=O)n(CC(=O)NC(C(=O)C(F)(F)F)C(C)C)c(-c3ccccc3)cc12
Agent: O=C(O)C(Cl)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)cc2c([nH]c3c(C(=O)O)cccc32)c1=O)C(=O)C(F)(F)F
Reaction time: 2 h

Procedure:
2-(8-Methoxycarbonyl-1-oxo-3-phenyl-1,2-dihydropyrido[3,4-b]-indol-2-yl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide. To a solution of the product from Example 3.a. (0.1 g) in dimethyl sulfoxide (1 mL) and toluene (1 mL) was added 1-(3-dimethyl- aminopropyl)-3-ethylcarbodiimide hydrochloride (0.34 g) and dichloroacetic acid (0.06 mL), and the resulting solution was allowed to stir for 2 hours. The mixture was poured into ethyl acetate, washed (1N hydrochloric acid, H2O), dried and evaporated. The resulting material was chromatographed, with ether as the eluent, give the ketone (0.90 g) as a white solid; TLC: Rf =0.65, methanol:dichloromethane (2:98); MS: m/z=528(M+1).
Reaction SMILES: [F:1][C:2]1(F)[C:7]([N:8]2[CH2:13][CH2:12][C:11]([F:16])([CH2:14][OH:15])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH2:3]1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>ClCCl>[F:16][C:11]1([CH2:14][O:15][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([N:17]3[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]3=[O:27])=[CH:3][C:2]=2[F:1])[CH2:9][CH2:10]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)NC[C@H]1CN(C2=CC=C(N3CCC(F)(CO)CC3)C(F)(F)C2)C(=O)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(F)(COS(C)(=O)=O)CC3)c(F)c2)C(=O)O1
Yield: 75 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[3-fluoro-4-(4-fluoro-4-hydroxymethyl-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.76 mmol) with methanesulfonyl chloride (0.91 mmol) in dichloromethane (10 ml) at 10° C. in presence of triethylamine (1.3 mmol) followed by purification by using silica gel column chromatography in 75% yield. M.P. 182-183° C. and MS (M+1)=462 (MH+, 100%) M.F.=C19H25F2N3O6S.
Reaction SMILES: CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:32][O:33][C:34]1[CH:39]=[C:38]([CH3:40])[C:37]([S:41]([N:44]2[CH2:49][CH2:48][CH2:47][CH2:46][C@H:45]2[CH2:50][O:51][CH2:52][C:53]([OH:55])=O)(=[O:43])=[O:42])=[C:36]([CH3:56])[CH:35]=1.[N:57]1[CH:62]=[CH:61][C:60]([C:63]2([O:76][CH2:77][CH2:78][N:79]3[CH2:83][CH2:82][CH2:81][CH2:80]3)[CH2:68][CH2:67][N:66](C(OC(C)(C)C)=O)[CH2:65][CH2:64]2)=[CH:59][CH:58]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:32][O:33][C:34]1[CH:39]=[C:38]([CH3:40])[C:37]([S:41]([N:44]2[CH2:49][CH2:48][CH2:47][CH2:46][C@H:45]2[CH2:50][O:51][CH2:52][C:53]([N:66]2[CH2:67][CH2:68][C:63]([C:60]3[CH:59]=[CH:58][N:57]=[CH:62][CH:61]=3)([O:76][CH2:77][CH2:78][N:79]3[CH2:83][CH2:82][CH2:81][CH2:80]3)[CH2:64][CH2:65]2)=[O:55])(=[O:43])=[O:42])=[C:36]([CH3:56])[CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCN2CCCC2)(c2ccncc2)CC1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)O)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)N2CCC(OCCN3CCCC3)(c3ccncc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
DIPEA (4 eq.), EDCl (1.2 eq.) and HOBt (1 eq.) were added to a solution of (S)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid [acid D] (0.65 mmol) in methylene chloride (5 ml). tert-Butyl 4-(pyridin-4-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)piperidine-1-carboxylate [amine J] (0.78 mmol) [Boc-deprotected in the presence of TFA (10-13 eq.) in methylene chloride (see e.g. stage (iii)/amine H)] and DIPEA (2 eq.) were added dropwise in methylene chloride (3 ml) to the reaction mixture, while cooling with ice, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride and washed with saturated ammonium chloride solution, saturated sodium chloride solution, saturated sodium bicarbonate solution and finally with sat. sodium chloride solution again. The organic phase was dried over sodium sulfate and concentrated to dryness on a rotary evaporator. The crude product was purified by means of column chromatography (silica gel, methanol/methylene chloride) to obtain the desired product. Yield: 36%. MS, Rt=2.6 min, m/z=629.4 [MH]+
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][NH:5][S:6]([C:9]1[C:10]2[CH:11]=[CH:12][N:13]=[CH:14][C:15]=2[CH:16]=[CH:17][CH:18]=1)(=[O:8])=[O:7].S(O)(O)(=O)=O.CS[C:32](=[NH:34])[NH2:33].C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH:1]([CH2:2][CH:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][NH:5][S:6]([C:9]1[C:10]2[CH:11]=[CH:12][N:13]=[CH:14][C:15]=2[CH:16]=[CH:17][CH:18]=1)(=[O:8])=[O:7])[C:32]([NH2:34])=[NH:33]
Reactant: NCC(CNS(=O)(=O)c1cccc2cnccc12)c1ccccc1
Reactant: CSC(=N)N
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CO
Product: N=C(N)NCC(CNS(=O)(=O)c1cccc2cnccc12)c1ccccc1
Yield: 85.9 %

Procedure:
In 30 ml of a 60% methanol/water solution (volume ratio) was dissolved 2 g of N-(3-amino-2-phenypropyl)-5-isoquinolinesulfonamide obtained Referential example 2, 2.05 g of S-methylisothiourea sulfate and 1.67 g of potassium carbonate, and the mixed solution was heated at reflux for two hours. After the reflux, the methanol was distilled therefrom under reduced pressure and the white crystalline residue the obtained was separated by filtration under reduced pressure. The residue was recrystallized from methanol to give 1.93 g of N-(3-guanidino-2-phenylpropyl)-5-isoquinolinesulfonamide, i.e., Compound (31) in a yield of 86%.
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:57][C@H:58]1[CH2:63][CH2:62][N:61]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:60][C@H:59]1[F:71]>CN(C)C=O.ClCCl>[C:67]([O:66][C:64]([N:61]1[CH2:62][CH2:63][C@H:58]([NH:57][C:18]([C@@H:13]2[CH2:12][CH2:11][C@@H:10]3[CH2:17][N:14]2[C:15](=[O:16])[N:9]3[O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:20])[C@H:59]([F:71])[CH2:60]1)=[O:65])([CH3:70])([CH3:68])[CH3:69]
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](F)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)[C@H](F)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (2.108 g, 7.63 mmol) in anhydrous dimethylformamide (15 mL) was added BOP (4.05 g, 9.15 mmol) and the resulting mixture was stirred at room temperature under nitrogen for 5 minutes. Diisopropyl ethyl amine (2.66 mL, 15.26 mmol) was then added followed by a solution of tert-butyl (3R,4S)-4-amino-3-fluoropiperidine-1-carboxylate (1.665 g, 7.63 mmol) in 20 mL of dichloromethane. The resulting solution was stirred at room temperature under nitrogen for 2 hours then concentrated under vacuum and the residue partitioned between ethyl acetate and water. The aqueous layer was washed twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified via silica gel flash chromatography (Isco Combiflash apparatus—120 g silica gel, 80 mL/min, 254 nM, 0% to 100% EtOAc/hexane over 6 column volumes then 100% EtOAc for 9 column volumes; title compound eluted at 100% EtOAc). Fractions containing pure title compound were collected and concentrated in vacuo to give a tan solid. Fractions containing impure product were also collected and repurified by HPLC (30×100 mm Sunfire column, 5 microns, 35 mL/min, 10% to 100% CH3CN+0.1% TFA/water+0.1% TFA over 15 min.; title compound eluted at 70% CH3CN+0.1% TEA). Fractions containing pure product were combined and concentrated in vacuo. The resulting aqueous residue was then extracted with ethyl acetate. The organic layer was collected and dried over magnesium sulfate. Concentration in vacuo gave a white solid which was combined with the material isolated from silica gel chromatography to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1>O.C(O)(=O)C.[Fe]>[NH2:9][C:5]1[CH:6]=[C:7]([Cl:8])[C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cnc(Cl)c(Cl)c1
Yield: 70 %

Procedure:
The procedure of Koch and Schnatterer, Synthesis,1990, 499-501 was followed. To 2-hydroxy-5-nitropyridine (70.0 g, 0.5 mol) in 12 N hydrochloric acid was added dropwise a solution of potassium chlorate (21.4 g, 0.18 mol) in H2O (300 mL) at a rate such that the temperature remained ≦60° C. The mixture was allowed to stir for a further 30 minutes at ca. 50° C., then allowed to cool to ambient temperature, then was further cooled in an ice bath. The yellow solid was collected by filtration, washed with cold H2O, and dried under vacuum at 50° C. to afford 3-chloro-2-hydroxy-5-nitropyridine (72.4 g, 83%) as a yellow powder. To phosphorus oxychloride (37.4 mL, 0.4 mol) at 0° C. was added quinoline (23.6 mL, 0.2 mol), followed by 3-chloro-2-hydroxy-5-nitropyridine (70 g, 0.4 mol) from above. The mixture was heated at 120° C. for 2.5 hours, during which time it became a dark liquid. After cooling to 100° C., H2O (150 mL) was added cautiously, and the mixture was cooled to 0° C. The precipitated solid was collected by filtration, washed with cold H2O, and dried under vacuum at 50° C. to afford 2,3-dichloro-5-nitropyridine (68.6 g, 89%). To 2,3-dichloro-5-nitropyridine (68.5 g, 0.39 mol) in a mixture of H2O (800 mL) and acetic acid (160 mL) were added bits of metallic iron with stirring until the starting material was consumed (TLC analysis). The mixture was filtered, and the filter cake was washed repeatedly with EtOAc. The aqueous filtrate was extracted with EtOAc and the organic fractions were combined and concentrated. The residue was chromatographed (silica gel; MeOH: CHCl3, 0.5:99.5 to 1:99) to afford the title compound (44.5 g, 70%) as a light orange powder: MS (CI/NH3) m/z 163 and 165 (M+H+), 180 and 182 (M+NH4)+.
Reaction SMILES: [N+](C(S(C1C=CC(C)=CC=1)(=O)=O)([C:5]1[C@:22]2(C)[C@H:8]([C@H:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12](=[CH:13][C:14](=[O:24])[CH:15]=[CH:16]2)[CH2:11][CH2:10]3)[CH2:7][CH:6]=1)C)#[C-].C([O:37][CH2:38][CH3:39])C.[CH2:40](Cl)Cl>>[CH3:40][C:38](=[O:37])[C:39]1[C@:22]2([CH3:5])[C@H:8]([C@H:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12](=[CH:13][C:14](=[O:24])[CH:15]=[CH:16]2)[CH2:11][CH2:10]3)[CH2:7][CH:6]=1
Reactant: CCOCC
Reactant: ClCCl
Reactant: [C-]#[N+]C(C)(C1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C)S(=O)(=O)c1ccc(C)cc1
Product: CC(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C

Procedure:
The compound prepared in Example 9a (450 mg) was hydrolized in methylenechloride (15 ml) and diethylether (30 ml) at 20° C. for two minutes. The product obtained was purified by filtration over alumina. Yield 235 mg (75%). Crystallization from methanol gave the title product, m.p. 200°-204° C. (dec.) (alpha)22 +134 (CHCl3, c 1.00).
Reaction SMILES: [H-].[Na+].[NH2:3][CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7].[H][H].[Cl:12][C:13]1[CH:24]=[C:23]([F:25])[C:22]([N:26]=[C:27]=[O:28])=[CH:21][C:14]=1[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16]>CN(C)C=O.C(O)(=O)C.O>[NH2:7][C:6]1[N:26]([C:22]2[C:23]([F:25])=[CH:24][C:13]([Cl:12])=[C:14]([CH:21]=2)[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[C:27](=[O:28])[N:9]=[CH:8][C:5]=1[C:4]#[N:3]
Reactant: CC(C)OC(=O)c1cc(N=C=O)c(F)cc1Cl
Reactant: [H][H]
Reactant: N#CC(C#N)=CN
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1cc(-n2c(N)c(C#N)cnc2=O)c(F)cc1Cl
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
To 0.71 g of a 55% sodium hydride dispersion in 25 ml of dimethylformamide are introduced 1.52 g of 3-amino-2-cyanoacrylonitril, and the mixture is stirred for 30 minutes at 30° C. After completion of the hydrogen evolution the mixture is treated with 4.20 g of isopropyl 2-chloro-4-fluoro-5-isocyanatobenzoate, during which the temperature rises to 30° C. The reaction mixture is then stirred for a further 2 hours at room temperature and poured into water, and the aqueous mixture is acidified with acetic acid and extracted twice with 100 ml of ethyl acetate. The organic phase is washed with water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is dissolved in 50 ml of methylene chloride and crystallization induced by addition of diethyl ether and cooling to 0° C. Isopropyl 5-[6-amino-5-cyano-2-oxo-1(2H)-pyrimidinyl]-2-chloro-4-fluorobenzoate, m.p. 212°-213° C., is obtained.
Reaction SMILES: [CH:1]12[C:9](=[O:10])[O:8][C:6](=O)[CH:3]([CH2:4][CH2:5]1)[CH2:2]2.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH2:18][CH2:17]1.C(Cl)Cl.C1(C)C(C)=CC=CC=1>O>[Cl:28][C:24]1[CH:23]=[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:6](=[O:8])[CH:3]4[CH2:2][CH:1]([CH2:5][CH2:4]4)[C:9]3=[O:10])[CH2:21][CH2:20]2)[CH:27]=[CH:26][CH:25]=1
Reactant: NCCCCN1CCN(c2cccc(Cl)c2)CC1
Reactant: O=C1OC(=O)C2CCC1C2
Solvent: O
Solvent: Cc1ccccc1C
Solvent: ClCCl
Product: O=C1C2CCC(C2)C(=O)N1CCCCN1CCN(c2cccc(Cl)c2)CC1

Procedure:
1,3-Cyclopentane dicarboxylic anhydride (2.2 g., 15 mmole) and 4.0 g. (15 mmole) of 1-(4-aminobutyl)-4-(3-chlorophenyl)piperazine were combined in 300 ml. of methylene chloride and stirred for 30 minutes at room temperature. The solvent was replaced with xylene and the mixture was refluxed for 48 hours with water removal via a Dean-Stark trap. The solvent was removed in vacuum and the residue filtered through 75 g. of silica gel with 2% ethanol/chloroform as eluent. The product was concentrated in vacuum and crystallized from 50 ml. of isopropanol with addition of 4N isopropanolic HCl. Recrystallization from ethanol gave 1.6 g. of the title compound as the hydrochloride, quarter hydrate; m.p. 199°-202° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]2=[CH:4][C:3]=1[CH3:13].[ClH:14].[CH3:15][NH:16][CH3:17].[CH2:18]=O.Cl>C(O)C>[ClH:14].[CH3:15][N:16]([CH2:18][CH:10]1[CH2:9][CH2:8][C:6]2[C:5](=[CH:4][C:3]([CH3:13])=[C:2]([CH3:1])[CH:7]=2)[C:11]1=[O:12])[CH3:17]
Reactant: CNC
Reactant: Cc1cc2c(cc1C)C(=O)CCC2
Reactant: C=O
Agent: Cl
Solvent: CCO
Product: Cc1cc2c(cc1C)C(=O)C(CN(C)C)CC2
Yield: 74.8 %

Procedure:
A mixture of 10.0 g of 6,7-dimethyl-α-tetralone, 6.0 g of dimethyl amine hydrochloride, 2.2 g of paraformaldehyde, and 12 ml of 95% ethanol containing .15 ml of concentrated hydrogen chloride is heated on a steam bath for 3 hours. After the mixture has been heating for a short time, an additional 20 ml of 95% ethanol is added. The mixture is cooled, yielding a crystalline mass that is washed with absolute ethanol to give 11.5 g of the title compound, melting point 204°-205° C.
Reaction SMILES: FC(F)(F)C([O:5][C:6]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][C:16]([Cl:21])=[C:15](Cl)[N:14]=2)[CH2:8][CH2:7]1)=O.[B:25]1([OH:35])[C:29]2[CH:30]=[CH:31][C:32]([OH:34])=[CH:33][C:28]=2[CH2:27][O:26]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CS(C)=O.CCOC(C)=O>[Cl:21][C:16]1[C:15]([O:34][C:32]2[CH:31]=[CH:30][C:29]3[B:25]([OH:35])[O:26][CH2:27][C:28]=3[CH:33]=2)=[N:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][C:6](=[O:5])[CH2:8][CH3:7])=[C:18]([CH:17]=1)[C:19]#[N:20]
Reactant: N#Cc1cc(Cl)c(Cl)nc1OCCCC1(OC(=O)C(F)(F)F)CC1
Reactant: OB1OCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCC(=O)CCCOc1nc(Oc2ccc3c(c2)COB3O)c(Cl)cc1C#N
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a mixture of compound 1-(3-(5,6-dichloro-3-cyanopyridin-2-yloxy)propyl)cyclopropyl 2,2,2-trifluoroacetate (0.87 g, 2.3 mmol) and benzo[c][1,2]oxaborole-1,5(3H)-diol (0.36 g, 2.4 mmol) in DMSO was added Cs2CO3 (0.89 g, 2.7 mmol) at room temperature and the resulting mixture was stirred at 40° C. overnight. The mixture was then poured into cold water, diluted with EtOAc, the organic phase was separated and the aqueous phase was further extracted twice with EtOAc. The combined organic layers were washed with brine twice, dried over Na2SO4 and concentrated, the residue was purified by Prep-HPLC (column: Luna 300×50.0 mm, 10μ; liquid phase: [A-H2O; B—CH3CN] B %:35%-62%, 23 min) to give the product D233 (105 mg) and D234 (112 mg), total yield 24%.