Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:4][CH:3]=1.Br[CH:35]1[CH2:37][CH2:36]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[CH:35]1([O:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:13](=[O:14])[C:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([C:22]5[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=5)=[CH:18][CH:17]=4)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]3[CH3:33])=[CH:6][CH:7]=2)[CH2:37][CH2:36]1
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc(C)n(-c2ccc(OC3CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of 4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and bromocyclopropane (1.8 mL) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.5 g), and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.097 g, 9%).
Reaction SMILES: COC(C1SC(N)=C(C#N)C=1C1C=CC(C(C)(C)C)=CC=1)=O.[CH2:23]([O:25][C:26]([C:28]1[S:29][C:30]([N:42]=[N+]=[N-])=[C:31]([C:40]#[N:41])[C:32]=1[C:33]1[CH:38]=[CH:37][C:36]([I:39])=[CH:35][CH:34]=1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1[S:29][C:30]([NH2:42])=[C:31]([C:40]#[N:41])[C:32]=1[C:33]1[CH:38]=[CH:37][C:36]([I:39])=[CH:35][CH:34]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1sc(N=[N+]=[N-])c(C#N)c1-c1ccc(I)cc1
Agent: COC(=O)c1sc(N)c(C#N)c1-c1ccc(C(C)(C)C)cc1
Product: CCOC(=O)c1sc(N)c(C#N)c1-c1ccc(I)cc1

Procedure:
Using a method substantially in accordance with the method of example 5-amino-3-(4-tert-butyl-phenyl)-4-cyano-thiophene-2-carboxylic acid methyl ester starting with the compound 5-azido-4-cyano-3-(4-iodo-phenyl)-thiophene-2-carboxylic acid ethyl ester gives the title compound.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[N:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].[CH:25]([C:28]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:37])[CH3:36])[C:29]=1[NH2:30])([CH3:27])[CH3:26]>C(O)C>[C:1]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[N:22]=[C:21]([CH:23]=[N:30][C:29]2[C:31]([CH:35]([CH3:36])[CH3:37])=[CH:32][CH:33]=[CH:34][C:28]=2[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CC(C)(C)NCc1ccc2ccccc2c1-c1cccc(C=O)n1
Solvent: CCO
Product: CC(C)c1cccc(C(C)C)c1N=Cc1cccc(-c2c(CNC(C)(C)C)ccc3ccccc23)n1

Procedure:
A mixture of 4.80 g (15.0 mmol) of 6-{2-[(tert-butylamino)methyl]-1-naphthyl}pyridine-2-carbaldehyde and 2.70 g (15.0 mmol) of 2,6-diisopropylaniline in 50 ml of dry ethanol was refluxed overnight. The resulting mixture was evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um; eluent: dichloromethane-methanol-triethylamine=100:10:1, vol.). Yield 5.50 g (76%) of orange oil which crystallized at room temperature. Anal. calc. for C33H39N3: C, 82.97; H, 8.23; N, 8.80. Found: C, 83.10; H, 8.41; N, 8.68. 1H NMR (CDCl3): 8.41 (m, 1H, 3-H in Py), 8.38 (s, 1H, CH═N), 8.00 (m, 1H, 4-H in Py), 7.91 (d, J=8.6 Hz, 4-H in naphthyl), 7.88 (m, 1H, 8-H in naphthyl), 7.66 (d, J=8.6 Hz, 3-H in naphthyl), 7.56 (m, 1H, 5-H in Py), 7.37-7.47 (m, 3H, 5,6,7-H in naphthyl), 7.10-7.18 (m, 3H, 3,4,5-H in Ph), 3.60 (m, 2H, CH2N), 3.02 (sept, J=6.8 Hz, 2H, CHMe2), 1.18 (d, J=6.8 Hz, 6H, CHMeMe′), 1.19 (d, J=6.8 Hz, 6H, CHMeMe′), 0.95 (s, 9H, tBu).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:23])=[C:4]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=3)[C:9]2=O)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>CO.C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:23])=[C:4]([N:8]2[CH2:9][C:10]3[C:15](=[CH:14][C:13]([C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:12][CH:11]=3)[C:16]2=[O:17])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1N1C(=O)c2ccc(C(C)(C)C)cc2C1=O
Agent: CC[SiH](CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Cc1c(Br)cccc1N1Cc2ccc(C(C)(C)C)cc2C1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 13.9 %

Procedure:
A suspension of 2-(3-bromo-2-methylphenyl)-5-tert-butylisoindoline-1,3-dione (Intermediate 3-2, 1.0 g, 2.69 mmol) in methanol (20 mL) was treated with sodium borohydride (203 mg, 5.37 mmol) and stirred at rt. After a few minutes, additional sodium borohydride (203 mg, 5.37 mmol) was added. After 40 min, the mixture was concentrated, and the residue was dissolved in DCM, washed with water and brine, and dried and concentrated to provide a white solid. This material was dissolved in DCM (10 mL) and treated with TFA (10 mL) and stirred for a few minutes at rt, then was treated with triethylsilane (6.40 mL, 40.1 mmol) and stirred at rt for 2.5 h. The mixture was concentrated and the residue was dissolved in DCM, washed with NaHCO3 (aq) and water. The organic phase was dried and concentrated. The residue was purified by column chromatography (eluting with hexane-EtOAc) to provide 2-(3-bromo-2-methylphenyl)-6-tert-butylisoindolin-1-one (Intermediate 4-3, 134 mg, 28%). 1H NMR (400 MHz, chloroform-d) δ 7.99 (1H, d, J=1.32 Hz), 7.68 (1H, dd, J=7.91, 1.76 Hz), 7.60 (1H, dd, J=7.69, 1.10 Hz), 7.45 (1H, d, J=7.91 Hz), 7.19-7.23 (1H, m), 7.15 (1H, t, J=7.69 Hz), 4.68 (2H, s), 2.31 (3H, s), 1.39 (9H, s). Mass spectrum m/z 358, 360 (M+H)+. Also isolated was 2-(3-bromo-2-methylphenyl)-5-tert-butylisoindolin-1-one (Intermediate 4-4, 250 mg, 52%). 1H NMR (400 MHz, chloroform-d) δ 7.88 (1H, d, J=7.91 Hz), 7.59 (2H, dd, J=8.13, 2.86 Hz), 7.53 (1H, s), 7.20-7.23 (1H, m), 7.12-7.17 (1H, m), 4.69 (2H, s), 2.31 (3H, s), 1.40 (9H, s). Mass spectrum m/z 358, 260 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:12])=[C:8]([CH:11]=1)[CH:9]=O)[CH3:2].[NH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:12])=[C:8]([CH:11]=1)/[CH:9]=[N:13]/[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)[CH3:2]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCOc1ccc(F)c(C=O)c1
Solvent: Cc1ccccc1
Product: CCOc1ccc(F)c(/C=N/c2ccc(C#N)cc2)c1
Yield: 72.5 %

Procedure:
A mixture of 53.1 (600 mg, 3.6 mmol) and 4-aminobenzonitrile (421 mg, 3.6 mmol) in toluene (50 mL) was refluxed in a Dean-stark apparatus for 4 h. The reaction mixture was the concentrated and the resulted solid was washed with hexane to obtained Intermediate 53.2 (700 mg, 80%). 1H NMR (CDCl3) δ 1.42 (t, 3H), 4.08 (q, 2H), 7.05 (m, 2H), 7.27 (d, J=8 Hz, 2H), 7.70 (d, J=8 Hz, 2H), 8.69 (s, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]([NH2:7])=[S:6])(=[NH:3])[NH2:2].[Cl:8][CH:9]([CH:15]=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(O)C>[ClH:8].[NH:4]([C:5]1[S:6][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][N:7]=1)[C:1]([NH2:2])=[NH:3]
Reactant: N=C(N)NC(N)=S
Reactant: CCOC(=O)C(Cl)C=O
Solvent: CCO
Product: CCOC(=O)c1cnc(NC(=N)N)s1
Product: Cl
Yield: 41.5 %

Procedure:
A solution of amidinothiourea (117 g; 0.99 mole) and ethyl chloro-α-formylacetate (150 g; 1.0 mole) in 3.5 liters of absolute ethanol was stirred at ambient temperature for 18 hours and then heated at reflux temperature for 1 hour. At this time additional ethyl chloro-α-formylacetate (20.0 g; 0.13 mole) was added and 1 hour later another 20.0 g of ethyl chloro-α-formylacetate was added. After 2 hours of additional heating at reflux temperature, the reaction mixture was evaporated under reduced pressure and the residue triturated with 1.5 liters of acetone and filtered to give 103 g of product. Recrystallization from 2-propanol yielded the title compound, mp 204°-206°.
Reaction SMILES: F[S:2]([CH2:5][CH2:6][N:7]([CH2:15][CH3:16])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1)(=[O:4])=[O:3].[OH-:17].[K+:18]>O>[K:18][CH:5]([S:2]([OH:17])(=[O:4])=[O:3])[CH2:6][N:7]([CH2:15][CH3:16])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1
Reactant: CCN(CCS(=O)(=O)F)c1cccc(C)c1
Reactant: [K+]
Reactant: [OH-]
Solvent: O
Product: CCN(CC([K])S(=O)(=O)O)c1cccc(C)c1

Procedure:
N-(2-Fluorosulfonylethyl)-N-ethyl-m-toluidine (24.5 g, 0.1 m) is stirred in water (200 ml) and potassium hydroxide (10 g) for 1-3 hours at room temperature or until thin-layer chromatography shows the reaction to be complete. The product is not isolated but is used as an aqueous solution in the coupling reaction.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([CH3:21])=[N:11][C:12]([O:16][CH2:17][C:18]([OH:20])=O)=[N:13][C:14]=1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([N:29]1[CH2:34][CH2:33][CH:32]([NH:35][CH:36]2[CH2:38][CH2:37]2)[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:29]1[CH2:30][CH2:31][CH:32]([N:35]([CH:36]2[CH2:37][CH2:38]2)[C:18](=[O:20])[CH2:17][O:16][C:12]2[N:13]=[C:14]([CH3:15])[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[C:10]([CH3:21])[N:11]=2)[CH2:33][CH2:34]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: c1ccc(CN2CCC(NC3CC3)CC2)cc1
Reactant: Cc1nc(OCC(=O)O)nc(C)c1NC(=O)OC(C)(C)C
Product: Cc1nc(OCC(=O)N(C2CC2)C2CCN(Cc3ccccc3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 9 and 1-benzyl-N-cyclopropylpiperidine-4-amine in the same manner as in Example 49.
Reaction SMILES: ClC1N=C(C)N([CH2:8][C:9]2[S:24][C:12]3[N:13]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:14](=[O:19])[N:15]([CH3:18])[C:16](=[O:17])[C:11]=3[C:10]=2[C:25]([N:27]([O:29][CH3:30])[CH3:28])=[O:26])C=1Cl.[O:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[NH:34][C:33]1=[O:41]>>[CH3:30][O:29][N:27]([CH3:28])[C:25]([C:10]1[C:11]2[C:16](=[O:17])[N:15]([CH3:18])[C:14](=[O:19])[N:13]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:12]=2[S:24][C:9]=1[CH2:8][N:34]1[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:32][C:33]1=[O:41])=[O:26]
Reactant: O=c1[nH]c2ccccc2o1
Reactant: CON(C)C(=O)c1c(Cn2c(C)nc(Cl)c2Cl)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Product: CON(C)C(=O)c1c(Cn2c(=O)oc3ccccc32)sc2c1c(=O)n(C)c(=O)n2CC(C)C

Procedure:
The subtitle compound was synthesised by the method of example 1 c) using the product of example 1 part b) and benzoxazolone. The product was isolated by SiO2 chromatography eluting with ethyl acetate/i-hexane (3:2), followed by recrystallisation with diethyl ether to so give the sub-title compound.
Reaction SMILES: [CH2:1]([C@@H:5]1C[C@@H]([C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CCO[Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)OC1=O)[CH:2]=CC.[CH2:44]([NH:48][C:49](=[O:91])[C@H:50]([CH2:87][CH:88]=[CH:89][CH3:90])[CH2:51][C@H:52]([OH:86])[C@@H:53]([NH:78][C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[CH2:54][C:55]([CH3:77])([CH3:76])[CH2:56][CH2:57][O:58][Si:59]([C:72]([CH3:75])([CH3:74])[CH3:73])([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH2:45][CH2:46][CH3:47].C(NC(=O)[C@H](CC(C)=C)C[C@@H]1OC(C)(C=C=O)N(OC(C)(C)C)[C@H]1CC(C)(C)CCOCC1C=CC=CC=1)CCC>>[CH2:44]([NH:48][C:49](=[O:91])[C@H:50]([CH2:87][CH:88]=[CH:89][CH3:90])[CH2:51][C@@H:52]1[O:86][C:1]([CH3:5])([CH3:2])[N:78]([C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[C@H:53]1[CH2:54][C:55]([CH3:76])([CH3:77])[CH2:56][CH2:57][O:58][Si:59]([C:72]([CH3:74])([CH3:73])[CH3:75])([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)[CH2:45][CH2:46][CH3:47]
Reactant: CC=CC[C@H](C[C@H](O)[C@H](CC(C)(C)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OC(C)(C)C)C(=O)NCCCC
Reactant: CC=CC[C@@H]1C[C@@H]([C@H](CC(C)(C)CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)NC(=O)OC(C)(C)C)OC1=O
Agent: C=C(C)C[C@H](C[C@@H]1OC(C)(C=C=O)N(OC(C)(C)C)[C@H]1CC(C)(C)CCOCc1ccccc1)C(=O)NCCCC
Product: CC=CC[C@H](C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)NCCCC

Procedure:
Starting from 472 mg of 3(R)-but-2-enyl-5(S)-[5-tert-butyl-diphenylsilyloxy-1(S)-tert-butoxycarbonylamino-3,3-dimethyl-pentyl]-2-oxo-tetrahydrofuran via 2(R)-but-2-enyl-9-tert-butyldiphenylsilyloxy-5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7,7-dimethyl-nonanoic acid (N-butyl)amide (Rf (A)=0.64; FAB-MS: (M+H)+ =681) analogously to Examples 74b and 74c): Rf (B)=0.71; FAB-MS: (M+H)+ =721.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)C(C)C)(C)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl.O>[CH3:13][C:3]1[C:2]([O:1][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1cccc(O)c1C
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cccc(OS(C)(=O)=O)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
To a cooled (0° C.) solution of ethyl 3-hydroxy-2-methylbenzoate (116a, 2.4 g, 13 mmol) and N,N-diisopropylethylamine (5.8 mL, 33 mmol) in dichloromethane (50 mL) was added drop wise methanesulfonyl chloride (1.4 mL, 17 mmol). The reaction mixture was stirred at 0° C. for 30 minutes then diluted with water (20 mL) and extracted with dichloromethane (2×25 mL). The combined organic extracts were dried over magnesium sulfate, concentrated under vacuum, and purified by column chromatography (30% EtOAc/Heptane) to give ethyl 2-methyl-3-[(methylsulfonyl)oxy]benzoate (116b, 3.0 g, 88% yield) as a yellow oil.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](Cl)=[O:9].ClC1C(C(F)(F)F)=C[N:15]=C2NC=C(N)C=12>N1C=CC=CC=1>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH2:15])=[O:9]
Reactant: Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Product: NC(=O)c1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 224.8 %

Procedure:
Picolinoyl chloride hydrochloride (270 mg, 1.53 mmol) was added to 4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-amine (240 mg, 1.02 mmol, Example 11, step G) in pyridine (5 mL). The reaction was stirred at 0° C. for 10 minutes, and then the pyridine was removed. THF (5 mL) and 2N LiOH (3 mL) were added and stirred for 20 minutes. The THF was removed, and water (20 mL) was added. The solid formed was collected by filtration and dried to give N-(4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2, 3-1)]pyridin-3-yl)picolinamide (280 mg, 79% yield) as a solid.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:11]1[O:12][CH:13]=[C:14]([CH2:16][C:17]#[N:18])[N:15]=1)([CH3:10])([CH3:9])[CH3:8].[Cl:19][C:20]1[C:24]([C:25](Cl)=[O:26])=[C:23]([Cl:28])[N:22]([CH3:29])[N:21]=1>C1COCC1>[C:7]([C:11]1[O:12][CH:13]=[C:14]([C:16](=[C:25]([C:24]2[C:20]([Cl:19])=[N:21][N:22]([CH3:29])[C:23]=2[Cl:28])[OH:26])[C:17]#[N:18])[N:15]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1nc(CC#N)co1
Reactant: Cn1nc(Cl)c(C(=O)Cl)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1nc(Cl)c(C(O)=C(C#N)c2coc(C(C)(C)C)n2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
2.87 g of potassium tert-butoxide was suspended in 20 ml of THF, and a solution of 2.00 g of 2-tert-butyl-4-cyanomethyloxazole and 2.37 g of 3,5-dichloro-1-methylpyrazole-4-carbonyl chloride as dissolved in 10 ml of THF was dropwise added thereto with cooling with ice, and then stirred overnight at room temperature. The reaction mixture was poured into ice water, extracted with ethyl acetate, and washed with a small amount of water. After the resulting product was dried with anhydrous sodium sulfate, the solvent was evaporated out under reduced pressure. The residual product was purified through column chromatography (silica gel; n-hexane:ethyl acetate=4:1) to obtain 3.26 g of the intended compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[OH:21][C@@H:22]([CH2:40][OH:41])[CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[C:32]([O:38][CH3:39])[CH:31]=2)[CH2:26][CH2:25]1>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([CH:27]4[CH2:26][CH2:25][N:24]([CH2:23][C@@H:22]([OH:21])[CH2:40][OH:41])[CH2:29][CH2:28]4)=[CH:31][C:32]=3[O:38][CH3:39])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc(C2CCN(C[C@@H](O)CO)CC2)ccc1C=O
Product: COc1cc(C2CCN(C[C@@H](O)CO)CC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 9.8 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (63.4 mg, 0.216 mmol) and 4-[1-((R)-2,3-Dihydroxy-propyl)-piperidin-4-yl]-2-methoxy-benzaldehyde (69.6 mg, 0.469 mmol) were reacted to produce 12 mg (10%) of the title compound. mp: 209-211° C., 1H NMR (300 MHz, CDCl3): 10.67 (s, 1H), 8.35 (d, J=8 Hz, 1H), 8.04 (s, 1H), 7.04 (d, J=8 Hz, 1H), 6.94 (s, 1H), 6.39-6.35 (m, 3H), 5.51 (d, J=8 Hz, 1H), 5.19 (t, J=8 Hz, 1H), 5.07 (s, 1H), 4.08 (s, 3H), 3.89 (m, 1H), 3.19 (s, 2H), 2.98 (d, 1H), 2.91 (s, 1H), 2.88 (d, J=8 Hz, 1H), 2.62 (m, 1H), 2.46-2.22 (m, 5H). MS: 567 (M+H), HPLC: 1.83 min (G method).
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])(C)(C)C.[CH3:20][N:21]([CH3:32])[S:22]([C:25]1[CH:26]=[N:27][CH:28]=[C:29](Br)[CH:30]=1)(=[O:24])=[O:23]>>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:19])=[C:10]([C:17]#[C:18][C:29]2[CH:28]=[N:27][CH:26]=[C:25]([S:22]([N:21]([CH3:32])[CH3:20])(=[O:23])=[O:24])[CH:30]=2)[CH:11]=1)#[N:16]
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Reactant: CN(C)S(=O)(=O)c1cncc(Br)c1
Product: CN(C)S(=O)(=O)c1cncc(C#Cc2cc(C#N)ccc2OCC(=O)O)c1

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-cyano-2-ethynyl phenoxy)acetate (Intermediate 46) and 5-bromo-pyridine-3-sulfonic acid dimethylamide (Intermediate 32), the title compound was obtained as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH:13]=O)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[CH2:17]([NH2:22])[CH2:18][CH2:19][CH2:20][CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCOC(C)=O>ClCCCl>[C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][NH:22][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCCCCN
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCCCCNCc1cncn1Cc1ccc(C#N)cc1
Reaction time: 120 h

Procedure:
To a solution of the aldehyde 6 (132 mg) in 3 mL of 1,2-dichloroethane at 0° C. was added 4Å powdered molecular sieves (300 mg), n-pentylamine (0.217 mL), and sodium triacetoxyborohydride (260 mg). After five days, the reaction was poured into EtOAc and washed with water, sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the amine 7 as a brown oil which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[O:26]=[C:27]1[NH:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]1>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([N:32]4[CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:28][C:27]4=[O:26])=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Product: CN1CCN(c2cc(N3CCc4ccc(N5CCN(C(=O)OC(C)(C)C)CC5=O)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 14 starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and tert-butyl 3-oxopiperazine-1-carboxylate (Aldrich, Cat. No. 641057). LCMS (M+H)+: m/z=523.2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br.[O:8]([C:15]([CH3:20])([CH3:19])[C:16]([Cl:18])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCO.O.C1COCC1>[ClH:18].[O:8]([C:15]([CH3:20])([CH3:19])[C:16]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(Oc1ccccc1)C(=O)Cl
Reactant: C1CNCCN1
Agent: Br
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(Oc1ccccc1)C(=O)N1CCNCC1
Product: Cl
Reaction time: 3 h

Procedure:
To a solution of 17.2 g of anhydrous piperazine in 50 ml of EtOH 95% and 22 ml of H2O, 3.37 g of HBr 48% are dropped in about 10' and thereafter, in about 40' and at room temperature, a solution of 9.93 g of 2-phenoxy-2-methylpropionyl chloride (prepared according to: Bull. Soc. Chim. Fr. 1956, 776-783) in 70 ml of THF. The suspension is stirred 2 h at the same temperature and 3 h under reflux, diluted with 130 ml of THF, cooled, and the piperazine salts precipitated are filtered away. The filtered is evaporated to dryness, the residue is resuspended with 120 ml of H2O and 35 ml HCl 2N and extracted with Et2O; the aqueous phase is treated with 40 ml NaOH conc. and extracted with Et2O (4×50 ml). The ethere-phase, dried, is treated with HCl in Et2 O about 3N and the precipitate is collected by filtration and crystallized from EtOH giving 5.98 g (42%) of the wanted compound; m.p.: 236°-238° C.
Reaction SMILES: [C:1]([NH:3][C:4](=[O:7])[O:5][CH3:6])#[N:2].[C:8]1(N)[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].C(O)(=O)C>O>[N:2]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:1]=1[NH:3][C:4]([O:5][CH3:6])=[O:7]
Reactant: Nc1ccccc1N
Reactant: COC(=O)NC#N
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2ccccc2[nH]1
Temperature: 50 °C
Yield: 72 %

Procedure:
A solution of 5.0 parts of the salt of methyl cyanocarbamate with o-phenylenediamine and 1.5 parts of acetic acid in 25 parts of water is refluxed for 30 minutes. The solution is cooled to 50° C. and filtered. The product is washed with water and dried in vacuo at 95° C. This procedure gives 3.3 parts (72% yield) of 2-benzimidazolecarbamic acid, methyl ester.
Reaction SMILES: CS(O[CH:6]([C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(=O)=O.[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([CH:9]2[CH2:8][CH2:7][CH:6]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)[N:33]2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: Nc1ccccc1
Reactant: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Product: O=[N+]([O-])c1ccc(C2CCC(c3ccc([N+](=O)[O-])cc3)N2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of the product from Example 1C (50 mg, 0.102 mmol) and aniline (0.2 ml, 2.19 mmol) were stirred at rt for 48 h. The mixture was partitioned between 1N aq. HCl and ethyl acetate, and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-50% ethyl acetate in hexanes. The title compound was obtained as a yellow solid (19 mg, 48%).