Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:5]([NH2:16])[CH:4]=1.[CH3:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1/[CH:23]=[CH:24]/[C:25](Cl)=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:51]([OH:56])(=[O:55])[C:52]([OH:54])=[O:53]>C(OCC)(=O)C>[C:51]([OH:56])(=[O:55])[C:52]([OH:54])=[O:53].[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[C:25](/[CH:24]=[CH:23]/[C:19]3[S:20][CH:21]=[CH:22][C:18]=3[CH3:17])=[N:16][C:5]=2[CH:4]=1
Reactant: Cc1ccsc1/C=C/C(=O)Cl
Reactant: COc1ccc(Nc2ccccn2)c(N)c1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)nc(/C=C/c1sccc1C)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-methoxy -2-amino-N-(2-pyridyl)aniline and (E)-3-(3-methyl-2-thienyl)acryloyl chloride (Sekiya, T.; Hiranuma, H.; Hata, S.; Mizogami, S.; Hanazuka, M.; Yamada, S. J. Med. Chem., 1983, 26, 411) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl MeOH/n-hexane yielded the titled compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[N:12]=[C:11]([CH2:13][OH:14])[NH:10][C:7]2=[N:8][CH:9]=1)([O-])=O.N>Cl>[NH2:1][C:4]1[CH:5]=[C:6]2[N:12]=[C:11]([CH2:13][OH:14])[NH:10][C:7]2=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1cnc2[nH]c(CO)nc2c1
Agent: Cl
Agent: N
Product: Nc1cnc2[nH]c(CO)nc2c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Stannous chloride dihydrate (1.6 g, 0.0070 mol) was added in one portion to a stirred solution of (6-Nitro-3H-imidazo[4,5-b]pyridin-2-yl)-methanol (450 mg, 0.0023 mol) in 10% aqueous hydrochloric acid (20 mL) at 50° C. The mixture was stirred at 50° C. for approx. 2 hours then allowed to cool to room temperature. The mixture was cooled further to 0° C. and then basified to ca. pH 8 using conc. NH3 solution. The aqueous layer was then filtered through Celite® to remove tin salts and the filtrate was concentrated under vacuum to leave a crude solid (380 mg; yield assumed quantitative) which was used directly in the next step (amide formation).
Reaction SMILES: [C:1]1(=[O:17])[N:5]([CH:6]([CH3:11])[CH2:7][C:8]([OH:10])=O)[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:30][C:31]1[CH:32]=[CH:33][C:34]2[N:40]=[C:39]([NH:41][NH2:42])[CH2:38][N:37]=[C:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[F:49])[C:35]=2[CH:50]=1>O1CCCC1>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]2[N:40]=[C:39]([NH:41][NH:42][C:8](=[O:10])[CH2:7][CH:6]([N:5]3[C:1](=[O:17])[C:2]4=[CH:16][CH:15]=[CH:14][CH:13]=[C:3]4[C:4]3=[O:12])[CH3:11])[CH2:38][N:37]=[C:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[F:49])[C:35]=2[CH:50]=1
Reactant: CC(CC(=O)O)N1C(=O)c2ccccc2C1=O
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(CC(=O)NNC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1)N1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 20, 3-phthalimidobutyric acid and carbonyldiimidazol are reacted in tetrahydrofuran. To this mixture is added 7-chloro-2-hydrazino-5-(o-fluorophenyl)-3H-1,4-benzodiazepine to give 3-phthalimidobutyric acid 2-[7-chloro-5-(o-fluorophenyl)-3H-1,4-benzodiazepin-2yl]hydrazide which is warmed with acetic acid to give N-[2-[8-chloro-6-(o-fluorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepin-1-yl]propyl]phthalimide
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:17])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[C:18]([OH:26])(=[O:25])[C:19]([CH2:21][C:22](O)=[O:23])=[CH2:20]>>[F:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[CH2:21][CH:19]([C:18]([OH:26])=[O:25])[CH2:20]2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Nc1ccc(OCc2cccc(F)c2)c(F)c1
Product: O=C(O)C1CC(=O)N(c2ccc(OCc3cccc(F)c3)c(F)c2)C1

Procedure:
The title compound is prepared in analogy to Example 1a) from 3-fluoro-4-(3-fluoro-benzyloxy)-phenylamine and itaconic acid. Yield: 86% of a colorless solid. MS: m/e=346.1 (M−H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9]O)=[CH:4][N:3]=1.N1C=CC=CC=1.P(Cl)(Cl)([Cl:19])=O.Cl>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][Cl:19])=[CH:4][N:3]=1
Reactant: OCc1cnc(Cl)c(Cl)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: ClCc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
To a stirred solution of 2,3-dichloro-5-hydroxymethylpyridine (4.4 g, 25 mmol) and pyridine (2.61 g, 33 mmol) in dichloromethane (75 mL) was added rapidly phosphorous oxychloride (4.91 g, 32 mmol). An exothermic reaction sufficient to boil the reaction mixture ensued. After stirring at room temperature for 2 h, 1 N HCl aqueous solution (50 mL) was carefully added to the reaction mixture and the stirring continued for 10 min. The organic phase was separated and the aqueous phase extracted with dichloromethane (50 mL). The combined organic phase was washed successively with water (25 mL), 1 N aqueous NaOH solution (25 mL) and saturated aqueous NaCl solution (25 mL), dried over anhydrous MgSO4, filtered, and concentrated to give 3.80 g of the desired 2,3-dichloro-5-chloromethylpyridine as yellow oil (77.4% yield) which solidified upon standing at room temperature. GC-MS: mass calcd for C6H5Cl2NO [M]+ 178. Found 178
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)O)=[C:7]([CH3:18])[C:6]=2[CH:19]=1.S(Cl)([Cl:22])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([Cl:22])[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[C:7]([CH3:18])[C:6]=2[CH:19]=1
Reactant: Cc1c(C(O)C2CCCCC2)oc2ccc(Cl)cc12
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1c(C(Cl)C2CCCCC2)oc2ccc(Cl)cc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution (10 mL) of (5-chloro-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methanol (518 mg) synthesized above in toluene was added thionyl chloride (163 μL), and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (553 mg, quantitative) as a pale-yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1I.[F:14][C:15]1[C:21]([F:22])=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]([F:29])=[C:18]([F:30])[C:16]=1[NH2:17].C(=O)([O-])[O-].[K+].[K+]>[Cu].[Cu]I>[CH3:1][N:2]([CH3:13])[C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:17][C:16]1[C:18]([F:30])=[C:19]([F:29])[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:21]([F:22])[C:15]=1[F:14]
Reactant: CN(C)C(=O)Cc1ccccc1I
Reactant: Nc1c(F)c(F)c(-c2ccccc2)c(F)c1F
Agent: [Cu]
Agent: [Cu]I
Agent: O=C([O-])[O-]
Product: CN(C)C(=O)Cc1ccccc1Nc1c(F)c(F)c(-c2ccccc2)c(F)c1F
Temperature: 40 °C

Procedure:
N,N-dimethyl-2-iodophenylacetamide (2.0 g, 6.9 mmol), 2,3,5,6-tetrafluoro-4-phenylaniline (3.3 g, 13.8 mmol), copper powder (219 mg, 3.4 mmol), copper(I) iodide (646 mg, 3.4 mmol) and anhydrous potassium carbonate (1.0 g, 6.9 mmol) are stirred together in 150 mL of xylenes. The reaction is heated to reflux temperature for 48 hours. While still slightly warm (40° C.) the brown suspension is filtered through a pad of Celite which in turn is rinsed with toluene (250 mL). The filtrate is evaporated by rotary evaporator and then flash chromatographed on silica gel (10–20% EtOAc/hexane) to give the title product.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([Br:7])[NH:4][N:3]=1.[CH:8]1[C:13]([F:14])=[CH:12][C:11]([F:15])=[C:10]([C:16]([CH2:18]Cl)=[O:17])[CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Br:1][C:2]1[N:6]=[C:5]([Br:7])[N:4]([CH2:18][C:16]([C:10]2[CH:9]=[CH:8][C:13]([F:14])=[CH:12][C:11]=2[F:15])=[O:17])[N:3]=1
Reactant: Brc1n[nH]c(Br)n1
Reactant: O=C(CCl)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Cn1nc(Br)nc1Br)c1ccc(F)cc1F
Yield: 86.9 %

Procedure:
First, 43.7 g of 3,5-dibromo-1H-1,2,4-triazole is introduced into 200 mL of tetrahydrofuran (THF), the resultant mixture is agitated, and 40.4 g of 2-chloro-2,4-difluoroacetophenone is further introduced thereto. Next, 36.3 g of potassium carbonate is introduced to the reaction mixture and the resultant mixture is agitated for 7 hours at room temperature. After the completion of the reaction, the reaction mixture is filtered, washed with 100 mL of tetrahydrofuran (THF), and concentrated at room temperature. Then, 437 mL of purified water is introduced so that the crystals are slurried, followed by filtering. The filtered crystals are reslurried in 175 mL of isopropanol and filtered again. The crystals are washed with 44 mL of isopropanol and dried with hot air at 50° C. to obtain 63.8 g of the title compound as a white solid (yield 87%, purity 99.2%, HPLC, detected at a wavelength of 256 nm, 18C 4.6×250 mm, mobile phase 60% ACN, flow rate 1 mL/min).
Reaction SMILES: [OH-].[Na+:2].C(O)C.CO.[CH:8]1[N:12]=[CH:11][N:10]([CH2:13][C:14]([P:20]([OH:23])([OH:22])=[O:21])([P:16]([OH:19])([OH:18])=[O:17])[OH:15])[CH:9]=1>O.CC(O)C>[CH:8]1[N:12]=[CH:11][N:10]([CH2:13][C:14]([P:16]([O-:19])([O-:18])=[O:17])([P:20]([O-:22])([OH:23])=[O:21])[OH:15])[CH:9]=1.[Na+:2].[Na+:2].[Na+:2]
Reactant: O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CO
Solvent: CCO
Product: O=P([O-])([O-])C(O)(Cn1ccnc1)P(=O)([O-])O
Temperature: 25 °C

Procedure:
A solution of sodium hydroxide (1.4 g) in a mixture of water (80% v/v)/Ethanol or Methanol or IPA (20% v/v, 10 volumes per grams of ZLD-Ac form XII) (38 ml) was added drop-wise to a suspension of Zoledronic acid form XII (5.0 g) in a mixture of water (80% v/v)/Ethanol or Methanol or IPA (20% v/v, 10 volumes per grams of ZLD-Ac) (212 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50° C. for 24 hours to give Zoledronate trisodium crystal form IX.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([N:7]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])[CH3:2].[C:24](O)(=[O:37])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>>[CH2:1]([O:3][C:4](=[O:23])[C:5]([N:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:24](=[O:37])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:18][CH:17]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)N(Cc1ccccc1)Cc1ccc(N)cc1
Reactant: CCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCC(=O)Nc1ccc(CN(Cc2ccccc2)C(=O)C(=O)OCC)cc1
Yield: 39 %

Procedure:
The same procedure as employed in the preparation of Example 5, step d using ethyl[(4-aminobenzyl)(benzyl)amino](oxo)acetate and tridecanoic acid gave the title compound as a colorless oil (39%). M−(ESI): 507.2. HPLC (Condition A), Rt: 7 min (HPLC purity-91.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8].C(N(CC)CC)C.[C:25](#[N:28])[CH:26]=[CH2:27]>Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]([C:6]1[CH:16]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[CH:27]=[CH:26][C:25]#[N:28])=[O:8]
Reactant: O=C(c1ccccc1F)c1cc(Cl)ccc1I
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Product: N#CC=Cc1ccc(Cl)cc1C(=O)c1ccccc1F

Procedure:
A solution of 5.0 g (14 mmol) of 5-chloro-2'-fluoro-2-iodobenzophenone, 2 ml (14.3 mmol) of triethylamine, 2 ml (30 mmol) of acrylonitrile and 35 mg (1.5 mmol) of palladium acetate was refluxed under an atmosphere of argon for 16 hr. The mixture was diluted with 100 ml of 1 N hydrochloric acid and the resulting precipitate was collected by filtration. The precipitate was washed with ether and air dried to give an off-white solid, mp 130°-133°.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([CH3:26])([CH3:25])[C:15]([N:17]3[CH2:22][CH:21]4[CH2:23][CH2:24][CH:18]3[CH2:19][CH2:20]4)=[O:16])[CH:12]=2)[NH:7][C:6]=1[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1)[CH3:4].[C:35]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])(=[O:38])[CH:36]=[CH2:37]>>[C:40]([O:39][C:35](=[O:38])[CH2:36][CH2:37][NH:1][CH2:2][C@H:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([CH3:26])([CH3:25])[C:15]([N:17]3[CH2:22][CH:21]4[CH2:23][CH2:24][CH:18]3[CH2:19][CH2:20]4)=[O:16])[CH:12]=2)[NH:7][C:6]=1[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1)[CH3:4])([CH3:43])([CH3:42])[CH3:41]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4CC5CCC4CC5)cc3c2[C@H](C)CN)c1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4CC5CCC4CC5)cc3c2[C@H](C)CNCCC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-2-[3-(2-amino-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-1-(2-aza-bicyclo[2.2.2]oct-2-yl)-2-methylpropan-1-one (248.6 mg in 2.1 mL absolute ethanol) was added 0.080 mL tert-butyl acrylate and the mixtureheated to 70° C. on an oil bath. After 3 hours, the mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (methylene chloride:methanol, 94:6) to give the title compound (232 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15]C)=[C:10]([Cl:17])[CH:9]=2)=[O:5])[CH3:2].B(Br)(Br)Br.C(OCC)(=O)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[C:10]([Cl:17])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OC)c(Cl)cc2[nH]1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(O)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (−78° C.) solution of 6-chloro-5-methoxy-1H-indole-2-carboxylic acid ethyl ester (example 39, step 1, 930 mg, 1.0 eq.) in dichloromethane (20 mL), was slowly added a solution of boron tribromide 1M in dichloromethane (7.33 mL, 2.0 eq.). The mixture was stirred at room temperature for 1 h, partitionned between ethyl acetate and ice water. The aqueous layer was extracted with ethyl acetate and the combined organic fractions were washed with 10% sodium bicarbonate solution and brine, dried over sodium sulfate, filtered, evaporated to dryness and purified on silica gel, eluting with a 4:1 to 3:1 gradient of cyclohexane/ethyl acetate, to yield 655 mg (74%) from the desired product as light brown solid. MS (m/e): 239.2 (M+, 35%).
Reaction SMILES: O([C:8]([NH:10][C:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C:12]=1[C:24]([O:26]CC)=O)=[O:9])C1C=CC=CC=1.C(N(CC)CC)C.Cl.[NH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>C1COCC1>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][C:11]2[NH:10][C:8](=[O:9])[N:37]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[C:24](=[O:26])[C:12]=2[CH2:13]1)=[O:18])([CH3:21])([CH3:22])[CH3:23]
Reactant: NN1CCCC1
Reactant: CCOC(=O)C1=C(NC(=O)Oc2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2[nH]c(=O)n(N3CCCC3)c(=O)c2C1
Temperature: 68 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
Under nitrogen, 1-tert-butyl 3-ethyl 4-(phenoxycarbonylamino)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (6.14 g) was dissolved in THF (50 ml) and 1-aminopyrrolidine hydrochloride (2.31 g), triethylamine (6.58 ml) and 1,8-diazabicyclo[5.4.0]und-7-ene (0.24 ml) were added, and the resultant mixture was stirred at room temperature for 2 hours. Thereafter, the reaction solution was stirred at 50° C. for 2 hours and 68° C. for 3 hours. After consumption of the raw materials was confirmed by TLC or LC/MS, to the reaction mixture 2 N sodium hydroxide solution (15.7 ml) was added at 0° C., and the resultant mixture was stirred at room temperature for two days. Thereafter, the solution was stirred at 50° C. for 3 hours and further 2 N sodium hydroxide solution (10 ml) was added at the same temperature. The reaction mixture was stirred at 68° C. for 2 hours. After the completion of the reaction was confirmed by TLC or LC/MS, the solution was cooled to room temperature, 2 N hydrochloric acid (30 ml) and a saturated ammonium chloride solution were added, the resultant mixture was extracted with ethyl acetate and dried over sodium sulfate. The solution was filtrated, concentrated and purified by silica gel chromatography to obtain desired tert-butyl-2,4-dioxo-3-(pyrrolidin-1-yl)-1,2,3,4,7,8-hexahydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate in an amount of 3.19 g (yield 60%).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[CH2:26]([N:29]=[C:30]=[O:31])[CH2:27][CH3:28].C(N(CC)CC)C.Cl>C(#N)C>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:30]([NH:29][CH2:26][CH2:27][CH3:28])=[O:31])[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: CCCN=C=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCNC(=O)NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 2 h
Yield: 55.8 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.37 g, 1.0 mmol) and propylisocyanate (0.09 mL, 1.0 mmol) in acetonitrile (10 mL), was added triethylamine (0.28 mL, 2.0 mmol) at room temperature under nitrogen. After 2 h, 1 N aq. HCl (15 mL) was added and the solids were isolated by filtration, washed with water (2×20 mL). The product was extracted with EtOAc (3×50 mL) and CH2Cl2 (3×50 mL). The organic layers were combined, concentrated and the residue was triturated in Et2O (20 mL). The product was isolated by filtration and dried in vacuo to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-propyl-urea as a white solid (0.20 g, 53% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 to 90/10 CH3CN/0.1% H3PO4 gradient over 15 mins, 5.84 min (98.91%); mp: 250-252° C.; 1H NMR (DMSO-d6) δ 0.84 (t, J=7.4 Hz, 3H, CH3), 1.22-1.59 (m, 2H, CH2), 1.85-2.10 (m, 1H, CHH), 2.25-2.47 (m, 1H, CHH), 2.60 (d, J=17.4 Hz, 1H, CHH), 2.78-3.10 (m, 3H, CH2, CHH), 4.21-4.37 (m, 3H, CH2, CHH), 4.44 (d, J=17.4 Hz, 1H, CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH), 5.99 (t, J=5.7 Hz, 1H, NH), 6.40 (t, J=5.9 Hz, 1H, NH), 7.38 (d, J=7.7 Hz, 1H, Ar), 7.45 (s, 1H, Ar), 7.67 (d, J=7.9 Hz, 1H, Ar), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 11.32, 22.49, 23.19, 31.20, 41.18, 42.92, 47.09, 51.55, 121.73, 122.83, 126.78, 130.11, 142.29, 145.55, 158.02, 167.98, 171.01, 172.86; LCMS: MH=359; Anal Calcd for C18H22N4O4: C, 60.32; H, 6.19; N, 15.63. Found: C, 60.21; H, 6.15; N, 15.51.
Reaction SMILES: [CH:1]1([C:4]([NH2:6])=[NH:5])[CH2:3][CH2:2]1.[CH:7](=[C:14]([C:17]#[N:18])[C:15]#[N:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[NH2:18][CH2:17][C:14]1[C:15]([NH2:16])=[N:5][C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#CC(C#N)=Cc1ccccc1
Reactant: N=C(N)C1CC1
Product: NCc1c(N)nc(C2CC2)nc1-c1ccccc1

Procedure:
The title compound, MS: m/e=240.1 (M+), was prepared from cyclopropanecarboxamidine and 2-benzylidene-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([F:23])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1.[NH2:24][C@@H:25]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=1)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:24][C@@H:25]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=3)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:20])=[C:16]([F:23])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: Nc1ncc(C2CCOCC2)nc1-c1ccc(C(=O)O)c(F)c1
Reactant: CC(C)(C)OC(=O)NC[C@@H](N)c1cccc(Cl)c1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC[C@@H](NC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of 4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzoic acid (35 mg, 0.110 mmol) in DMF (368 μL) was add (S)-tert-butyl (2-amino-2-(3-chlorophenyl)ethyl)carbamate (33.9 mg, 0.110 mmol), aza-HOBt (22.52 mg, 0.165 mmol), EDC (31.7 mg, 0.165 mmol), and DIEA (57.8 μL, 0.331 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed by NaHCO3, water and brine, dried over anhydrous sodium sulfate, filtered off, and concentrated in vacuo yielding crude (S)-tert-butyl (2-(4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzamido)-2-(3-chlorophenyl)ethyl)carbamate (>99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:15]=[C:14]([NH:16][C@H:17]4[C:26]5[C:21](=[C:22]([F:27])[CH:23]=[CH:24][CH:25]=5)[O:20][CH2:19][CH2:18]4)[C:13]([NH2:28])=[CH:12][N:11]=3)[C:6]=2[CH:29]=1.N[C:31](N)=[S:32]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:15]=[C:14]4[C:13]([NH:28][C:31](=[S:32])[N:16]4[C@H:17]4[C:26]5[C:21](=[C:22]([F:27])[CH:23]=[CH:24][CH:25]=5)[O:20][CH2:19][CH2:18]4)=[CH:12][N:11]=3)[C:6]=2[CH:29]=1
Reactant: Nc1cnc(-n2cnc3ccc(F)cc32)nc1N[C@@H]1CCOc2c(F)cccc21
Reactant: NC(N)=S
Solvent: CC#N
Product: Fc1ccc2ncn(-c3ncc4[nH]c(=S)n([C@@H]5CCOc6c(F)cccc65)c4n3)c2c1
Temperature: 200 °C
Yield: 14.1 %

Procedure:
In a microwave vial, to the solution of 50 mg (0.13 mmol) 2-(6-fluoro-1H-benzo[d]imidazol-1-yl)N4—((R)-8-fluorochroman-4-yl)pyrimidine-4,5-diamine (known compound, e.g. WO 2006/108103) in 0.75 mL anhydrous acetonitrile was added 24 mg (0.32 mmol) thiourea. The vial was capped and the mixture was heated in an Emrys Optimizer microwave at 200° C. for 30 minutes. The resulting red dark suspension was concentrated in vacuo, and partitioned between water and EtOAc. Extract this aqueous phase with EtOAc three more times, and the combined organic layer was concentrated in vacuo, and purified by silica gel column chromatography eluting with DCM and MeOH to yield 8 mg (14%) the titled compound as a pale yellow solid. (Note: On similar diamines, cyclization with 1,1′-thiocarbonyl-diimidazole at 0° C., then slowly warm up to room temperature was found to give improved yields.)
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[F:25][C:26]1[C:27]([O:32][CH2:33][C:34](O)=[O:35])=[N:28][CH:29]=[CH:30][CH:31]=1>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][NH:5][CH2:4][C@H:3]2[CH2:2][NH:1][C:34](=[O:35])[CH2:33][O:32][C:27]2[C:26]([F:25])=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:11][C:12]=1[F:17]
Reactant: O=C(O)COc1ncccc1F
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Product: O=C(COc1ncccc1F)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and [(3-fluoropyridin-2-yl)oxy]acetic acid, and by a method similar to that of Example 39, followed by neutralization, the title compound was obtained.