Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][C:7]([NH2:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:11]([C:17]([C:19]([F:22])([F:21])[F:20])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[CH:1]1([NH:6][C:7]2[O:8][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:17]([C:19]([F:20])([F:22])[F:21])[N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)NC1CCCC1
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Product: CCOC(=O)c1oc(NC2CCCC2)nc1C(F)(F)F
Yield: 34.2 %

Procedure:
By the procedure of Example 4, 7.68 g (60 mmol) of cyclopentyl urea was reacted with 10.9 g (50 mmol) of ethyl 2-chloro-4,4,4-trifluoroacetoacetate at 140°-150° C. for 18 hours. The product was separated and then recrystallized from methylcyclohexane to yield 5.0 g of a white solid product (m.p.=41°-42° C.) identified in Table I.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C.O[CH2:37][CH2:38][N:39]1[CH:44]=[CH:43][C:42]2[CH:45]=[CH:46][O:47][C:41]=2[C:40]1=[O:48].[N+:49]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[S:58]([NH:61][CH2:62][CH2:63][CH2:64][O:65][CH:66]1[CH2:71][CH2:70][CH2:69][CH2:68][O:67]1)(=[O:60])=[O:59])([O-:51])=[O:50]>O1CCCC1>[N+:49]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[S:58]([N:61]([CH2:37][CH2:38][N:39]1[CH:44]=[CH:43][C:42]2[CH:45]=[CH:46][O:47][C:41]=2[C:40]1=[O:48])[CH2:62][CH2:63][CH2:64][O:65][CH:66]1[CH2:71][CH2:70][CH2:69][CH2:68][O:67]1)(=[O:59])=[O:60])([O-:51])=[O:50]
Reactant: O=c1c2occc2ccn1CCO
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCCOC1CCCCO1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1c2occc2ccn1CCN(CCCOC1CCCCO1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 56.6 %

Procedure:
Triphenylphosphine (393 mg, 1.5 mmol) and azodicarboxylic acid di-tert-butyl ester (345 mg, 1.5 mmol) were added to a tetrahydrofuran (THF) solution (10 ml) of 6-(2-hydroxyethyl)-6H-furo[2,3-c]pyridin-7-one (179 mg, 1.0 mmol) and 2-nitro-N-[3-(tetrahydropyran-2-yloxy)propyl]benzenesulfonamide (413 mg, 1.2 mmol), and stirred overnight. The resulting reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1→0:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 286 mg (yield: 57%) of 2-nitro-N-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]-N-[3-(tetrahydropyran-2-yloxy)propyl]benzenesulfonamide as a white amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]2[CH3:15])=[CH:4][C:3]=1Br.[CH3:17][N:18]1CCCC1=O>>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]2[CH3:15])=[CH:4][C:3]=1[C:17]#[N:18]
Reactant: Cc1cn(-c2cc(C)c(N)c(Br)c2)c(C)n1
Reactant: CN1CCCC1=O
Product: Cc1cn(-c2cc(C)c(N)c(C#N)c2)c(C)n1

Procedure:
A mixture of 1-(4-amino-3-bromo-5-methylphenyl)-2,4-dimethylimidazole (17.3 g) and cuprous cyanide (17.9 g) was heated and stirred at 150° in N-methylpyrrolidone (50 cm3) for 6 hours. The cooled mixture was partitioned between ammonia solution (200 cm3 ; S.G. 0.880) and chloroform (200 cm3). The aqueous phase was extracted further with chloroform (2×100 cm3), and the combined and dried (MgSO4) organic phases were evaporated in vacuo to give an oil, which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]), eluting with dichloromethane:methanol, 19:1. Combination and evaporation of the appropriate fractions gave an oil which was triturated with ether to give a solid (10.05 g). A small portion of this material was recrystallised from ethyl acetate-methanol to afford the title compound, m.p. 214°-217°.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Br:30])[CH:25]=2)[CH:19]=[CH:18][C:17]=1[S:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1>>[Br:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][O:22][C:20]1[CH:19]=[CH:18][C:17]([S:31][C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:21]=1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: Nc1cc(OCc2cccc(Br)c2)ccc1Sc1ccc(O)cc1
Product: CCCc1ccc2c(Nc3cc(OCc4cccc(Br)c4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 2g (62 mg, 0.30 mmol) was reacted with 4-[2-Amino-4-(3-bromo-benzyloxy)-phenylsulfanyl]-phenol (120 mg, 0.30 mmol) for 48 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (86 mg, 41%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J=7.73 Hz, 3H) 1.85 (dt, J=7.73 Hz, 2H) 3.00 (dd, J=7.72 Hz, 2H) 5.15 (s, 2H) 6.27 (d, J=7.35 Hz, 1H) 6.66 (d, J=8.82 Hz, 2H) 7.07-7.69 (m, 7H) 7.65 (s, 1H) 7.83 (d, J=8.82 Hz, 1H) 8.41 (d, J=6.99 Hz, 1H) 9.03 (d, J=8.82 Hz, 1H) 9.81 (s, 1H) 11.05 (br s, 1H) 14.43 (br s, 1H); MS (ESI+) m/z 572, 574 (M+H−TFA)+; (ESI−) m/z 570-572 (M−H−TFA)−.
Reaction SMILES: [OH:1][C@@H:2]([C@H:17]([OH:32])[C@H:18]([OH:31])[C@@H:19]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:25])[CH2:20][OH:21])[C:3]([NH:5][C@H:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:7][C:8]([OH:10])=[O:9])=[O:4].[OH-].[Na+].Cl[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>>[CH2:39]([O:38][C:36]([NH:25][C@H:24]([C:23]([NH:22][C@@H:19]([CH2:20][OH:21])[C@@H:18]([OH:31])[C@@H:17]([OH:32])[C@H:2]([OH:1])[C:3]([NH:5][C@H:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:7][C:8]([OH:10])=[O:9])=[O:4])=[O:30])[CH2:26][CH:27]([CH3:28])[CH3:29])=[O:37])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of (S)-3-[(2S,3R,4R,5S)-2,3,4,6-tetrahydroxy-5-(L-leucyl)aminohexanoyl]amino-3-phenylpropionic acid (Compound 3) (2.28 g) and 0.2N aqueous sodium hydroxide solution (25 ml) were added benzyl chloroformate (0.714 ml) and 1N aqueous sodium hydroxide solution at 0° C. After stirring at room temperature for 3 hours, the mixture was washed with diethylether and acidified with 1N hydrochloric acid (20 ml). The aqueous solution was extracted with ethyl acetate and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Removal of the organic solvent gave a residue, which was recrystallized from diethylether-hexane to afford the title compound(1.51 g)
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:20][CH:21]=[CH2:22])[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][Br:19])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Br:19][CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][O:10][CH2:9][C@H:8]([NH2:7])[CH2:20][CH:21]=[CH2:22]
Reactant: C=CC[C@H](COCc1ccccc1CBr)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC[C@@H](N)COCc1ccccc1CBr
Yield: 96.4 %

Procedure:
A solution of compound 18j (2.8 g, 7.3 mmol) in TFA/DCM (25 mL, v/v=1/4) was stirred at rt for 1 hr. The mixture was concentrated under reduced pressure to give compound 18k (2.0 g, 98% yield), which was used without purification. LCMS (m/z): 285.1 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].N>C(O)C.O1CCCC1.[Ni]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=2)(=[O:13])=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(C#N)cc2)CC1
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(CN)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
[Step 2] To a mixture of 1-(4-cyanobenzenesulfonyl)piperidine-4-carboxylic acid ethyl ester (1.36 g) in ethanol (84 ml) and tetrahydrofuran (14 ml) was added 28% aqueous ammonia (3 ml) and then Raney nickel (500 mg) was added. Under a hydrogen pressure (0.5 Mpa), the mixture was stirred at room temperature for 2 hrs., and undesired substances were removed by filtration. The filtrate was concentrated under reduced pressure to give 1-(4-aminomethylbenzenesulfonyl)piperidine-4-carboxylic acid ethyl ester (1.05 g, 77%).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:2]1.[Br:16][C:17]1[C:18](F)=[C:19]2[C:25]([NH:26][C:27]([CH:29]3[CH2:31][CH2:30]3)=[O:28])=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1>CCCCO>[Br:16][C:17]1[C:18]([N:1]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:2]2)=[C:19]2[C:25]([NH:26][C:27]([CH:29]3[CH2:30][CH2:31]3)=[O:28])=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCNC1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CC1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@H]1CCCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CC4)c23)C1
Yield: 9 %

Procedure:
(S)-tert-Butyl azepan-3-ylcarbamate (431 mg, 2.01 mmol; commercially available or Moon, Sung-Hwan, et al. “An Efficient Conversion of Chiral α-Amino Acids to Enantiomerically Pure 3-Amino Cyclic Amines.” Synthetic Communications. Vol. 28, No. 21 (1998): pp. 3919-3926) was added to N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (200 mg, 0.671 mmol) in n-BuOH (3 mL), and the reaction was heated for 18 hours to 160° C. in a sealed tube. After concentration, the residue was purified by chromatography (SP4, 25M, water/ACN 100/0→0/100, 40CV) to yield (S)-tert-butyl 1-(5-bromo-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)azepan-3-ylcarbamate (30 mg, 9% yield) as a solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH2:21][CH3:22])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:23])[C:4]=1[CH2:24][CH2:25][C:26]([OH:28])=O)[CH3:2].C[CH2:30][N:31](C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CN>CN(C=O)C.C1COCC1>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH2:21][CH3:22])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:23])[C:4]=1[CH2:24][CH2:25][C:26]([NH:31][CH3:30])=[O:28])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCc1cc(-c2nc(-c3cc(C)c(CCC(=O)O)c(CC)c3)no2)cc(C)n1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCc1cc(-c2nc(-c3cc(C)c(CCC(=O)NC)c(CC)c3)no2)cc(C)n1
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of 3-{2-ethyl-4-[5-(2-ethyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-propionic acid (26 mg, 69 μmol) and DIPEA (27 mg, 207 μmol) in DMF (3 mL) is added PyBOP (40 mg, 76 μmol) at 0° C. The mixture is stirred for 15 min at 0° C. before methylamine (2.4 mg, 76 μmol, 38 μL of a 2 M solution in THF) is added. Stirring is continued for 1 h at 0° C. The reaction is quenched with water (2 mL), and the mixture is diluted with sat. aq. NaHCO3 solution. The mixture is extracted twice with ether. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates with heptane:EA 1:4 to give 3-{2-ethyl-4-[5-(2-ethyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-N-methyl-propionamide (21 mg) as a white solid; LC-MS: tR=0.90 min; [M+1]+=393.45; 1H NMR δ 1.32 (t, J=7.5 Hz, 3 H), 1.40 (t, J=7.8 Hz, 3 H), 2.34-2.41 (m, 2 H), 2.45 (s, 3 H), 2.69 (s, 3 H), 2.77 (q, J=7.5 Hz, 2 H), 2.85 (d, J=4.8 Hz, 3 H), 2.95 (q, J=7.8 Hz, 2 H), 3.07-3.13 (m, 2H), 5.41 (s br, 1 H), 7.76 (s, 2 H), 7.84 (s, 1 H), 7.86 (s, 1 H).
Reaction SMILES: [CH3:1][N:2]([C:14]([NH:16][C@H:17]([C:21]([OH:23])=O)[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:3][C:4]1[N:5]=[C:6]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[S:7][CH:8]=1.[NH2:24][C@@H:25]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:26][C@H:27]([OH:46])[C@@H:28]([NH:36][C:37]([O:39][CH2:40][C:41]1[O:45][N:44]=[CH:43][CH:42]=1)=[O:38])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:1][N:2]([C:14]([NH:16][C@H:17]([C:21]([NH:24][C@@H:25]([CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[CH2:26][C@H:27]([OH:46])[C@@H:28]([NH:36][C:37]([O:39][CH2:40][C:41]1[O:45][N:44]=[CH:43][CH:42]=1)=[O:38])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:23])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH2:3][C:4]1[N:5]=[C:6]([N:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)[S:7][CH:8]=1
Reactant: CC(C)[C@H](NC(=O)N(C)Cc1csc(N2CCCC2)n1)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccno1
Product: CC(C)[C@H](NC(=O)N(C)Cc1csc(N2CCCC2)n1)C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccno1

Procedure:
Using the procedure of Example 1U, but replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine with N-((N-methyl-N-((2-(1-pyrrolidinyl)-4-thiazolyl)methyl)amino)carbonyl)-L-valine and replacing (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-5-amino-2-(N-((5-isoxazolyl)methoxy-carbonyl)amino)-1,6-diphenyl-3-hydroxyhexane provided, after purification by silica gel chromatography using 2% methanol in chloroform, the desired compound (Rf 0.30, 4% methanol in chloroform).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](O)=[N:13][C:12]([C:19]([F:22])([F:21])[F:20])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(Cl)([Cl:31])=O)C=CC=CC=1.C(=O)(O)[O-].[Na+].C>CCCCCC.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([Cl:31])=[N:13][C:12]([C:19]([F:22])([F:21])[F:20])=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: Oc1nc(C(F)(F)F)nc2c1CCN(Cc1ccccc1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: FC(F)(F)c1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 29.6 g (95.7 mmol) of 7-benzyl-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol (prepared essentially as described in Step A, above) and 53 mL of phenylphosphonic dichloride in a 250-mL round bottom flask was heated at 150° C. After 2 h, the reaction was judged to be complete by TLC analysis. The mixture was cooled to ambient temperature and poured onto 400 g of ice, transferring with about 500 mL of ethyl acetate. The aqueous layer was neutralized with solid sodium bicarbonate and the layers separated. The aqueous layer was extracted with two portions of ethyl acetate. The combined organics were washed sequentially with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated to give a brown solid. The solid was boiled in 2 L of hexane with charcoal, filtered, and concentrated in vacuo to give the title compound as a yellow solid. LC-MS 328 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:19](OC)=[O:20])=[C:7]([CH3:18])[N:8]2[C:17]=1[CH2:16][C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:9]2)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>ClCCl.C(OCC)C>[OH:20][CH2:19][C:6]1[C:5]([CH2:3][OH:2])=[C:17]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N:8]2[C:7]=1[CH3:18]
Reactant: COC(=O)c1c(C(=O)OC)c2n(c1C)Cc1ccccc1C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1c(CO)c(CO)c2n1Cc1ccccc1C2
Reaction time: 2 h

Procedure:
A solution of 3-methyl-5,10-dihydropyrrolo[1,2-b]-isoquinoline-1,2-dicarboxylic acid dimethyl ester (2.39 g, 8 mmol) in anhydrous dichloromethane (20 mL) was added dropwise into a stirred suspension of LiAlH4 (0.69 g, 18.4 mmol) in anhydrous diethyl ether (30 mL) at 10-15° C. The reaction mixture was further stirred for 2 hours after the addition was completed. The mixture was cooled in an ice bath and the excess hydride was destroyed by the sequential addition of water (1.2 mL), 15% aqueous NaOH (1.2 mL), and water (3.6 mL) at 0° C. The mixture was filtered, and the inorganic solid was removed by filtration, washed with hot THF (300 mL). The combined filtrate and washings was evaporated in vacuo to dryness. The solid residue was recrystallized from dichloromethane/ether to give (2-hydroxymethyl-3-methyl-5,10-dihydropyrrolo[1,2-b]isoquinolin-1-yl)methanol (DA-1107), 1.47 g (76.2%); mp 99-101° C.; 1H NMR (DMSO-d6) δ 2.22 (3H, s, Me), 3.96 (2H, s, CH2), 4.34 and 4.39 (each 3H, brs, CH2 and exchangeable, OH), 4.93 (2H, s, CH2), 7.26 and 7.34 (each 2H, brs, 4×ArH); m/z 243.0 (M+H)+ Anal. Calcld. for C15H17NO2.0.1H2O): C, 73.50; H, 7.07; N, 5.71. Found: C, 73.42; H, 6.97; N, 5.71.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12]
Reactant: Brc1nccs1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(Oc2nccs2)c1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
In a sealed tube, combine 2-bromo-thiazole (2.0 ml, 22.2 mmol), 3-hydroxy-benzaldehyde (1.8 g, 15.0 mmol) and potassium carbonate (2.1 g, 15.0 mmol) in dimethylformamide (20 ml). Heat to 100° C. After 48 hours, cool, pour into water (150 ml), and extract with ether. Combine the organic layers and wash sequentially with distilled water and brine and then dry (Na2SO4), filter, and concentrate to give a residue. Chromatograph the residue eluting with 9:1 hexane:EtOAc to give the title compound.
Reaction SMILES: [B:1]([F:4])([F:3])[F:2].[C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([N+:18]([O-:20])=[O:19])=[CH:10][C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]1=2)#[N:6].C(O)(=[O:27])C>ClC1C=CC=CC=1>[C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([N+:18]([O-:20])=[O:19])=[CH:10][C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]1=2)(=[O:27])[NH2:6].[B:1]([F:4])([F:3])[F:2]
Reactant: N#CN1c2ccccc2C=C([N+](=O)[O-])c2ccccc21
Reactant: CC(=O)O
Agent: FB(F)F
Solvent: Clc1ccccc1
Product: NC(=O)N1c2ccccc2C=C([N+](=O)[O-])c2ccccc21

Procedure:
25 ml of a solution of 15% by weight of BF3 in acetic acid are allowed to flow rapidly into a suspension of 13.1 g (0.05 mole) of 5-cyano-10-nitro-5H-dibenz[b,f]azepine in 130 ml of chlorobenzene, while stirring, and a clear brownish solution is obtained of which the temperature increases to 35°. The crystallisation, which begins after a few minutes, is completed by stirring for one hour in an ice-bath. Suction-filtering is carried out, followed by washing with chlorobenzene and drying in vacuo at 40°, resulting in 19.2 of 5-carbamoyl-10-nitro-5H-dibenz[b,f]azepine in the form of a BF3 adduct. To liberate the end product the BF3 adduct is made into a slurry with 150 ml of water, stirred for 15 hours, suction-filtered and washed neutral with water. After drying, 5-carbamoyl-10-nitro-5H-dibenz[b,f]azepine, which is identical to the product obtained according to Example 21, is obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:4]1[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1sc(=O)[nH]c1C
Product: CCOC(=O)c1sc(Cl)nc1C
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
A mixture of ethyl 4-methyl-2-oxo-2,3-dihydro-1,3-thiazole-5-carboxylate (0.57 g, 3.05 mmol) and POCl3 (5 mL) was heated at 120° C. for 18 h. Upon cooling, the mixture was concentrated. Water (15 mL) was slowly added and stirred for 10 min. The mixture was extracted with Et2O (3×15 mL). The combined organics were dried with MgSO4 and concentrated. The crude material was purified by chromatography (EtOAc/hexanes) to give the title compound as a white solid (0.54 g, 86%). 1H NMR (400 MHz, CDCl3) δ 4.32 (q, J=7.1 Hz, 2H), 2.68 (s, 3H), 1.35 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]([CH2:14][NH:15][C:16](=[O:26])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:4][N:3]=1.[C-]#N.[K+].[N:30]12CCN(CC1)C[CH2:31]2>CS(C)=O.O>[C:31]([C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]([CH2:14][NH:15][C:16](=[O:26])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:4][N:3]=1)#[N:30]
Reactant: COc1ccc(CC(=O)NCc2cnc(Cl)nc2NCC(C)(C)C)cc1
Reactant: C1CN2CCN1CC2
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CC(=O)NCc2cnc(C#N)nc2NCC(C)(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of 0.036 g (0.096 mmol) of N-[2-chloro-4-(2,2-dimethyl-propylamino)-pyrimidin-5-ylmethyl]-2-(4-methoxy-phenyl)acetamide, 0.013 g (0.192 mmol) of KCN and 0.011 g (0.096 mmol) of 1.4-diazabicyclo[2.2.2]octan in 1 ml of DMSO/H2O (85:15) is stirred for 45 minutes at 60° C. The reaction mixture is cooled to r.t. and subjected to preparative HPLC. N-[2-cyano-4-(2,2-dimethyl-propylamino)-pyrimidin-5-ylmethyl]-2-(4-methoxy-phenyl)-acetamide is obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([OH:17])=O)[CH2:11][CH:10]1[CH:12]([F:14])[F:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:30]1([S:33]([NH2:36])(=[O:35])=[O:34])[CH2:32][CH2:31]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH:30]1([S:33]([NH:36][C:15]([C:9]2([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:11][CH:10]2[CH:12]([F:13])[F:14])=[O:17])(=[O:35])=[O:34])[CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1C(F)F
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(C(=O)NS(=O)(=O)C2CC2)CC1C(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.6 %

Procedure:
A mixture of 1-(tert-butoxycarbonylamino)-2-(difluoromethyl)cyclopropanecarboxylic acid (975 mg, 3.88 mmol) and CDI (755 mg, 4.66 mmol) in tetrahydrofuran (10 mL) was heated at reflux for 1 h. It was then cooled to rt and then cyclopropanesulfonamide (564 mg, 4.66 mmol) was added, followed by DBU (0.702 mL, 4.66 mmol). This mixture was stirred at rt for 18 h. It was then concentrated in vacuo, diluted with water and adjusted to pH=4 using 1 N HCl. The acidic solution was extracted with EtOAc, washed with water (5×15 mL), dried (MgSO4), and concentrated in vacuo to yield 1.6 g of the crude product as a white solid. Recrystallization from hexane/EtOAc gave 1.15 g (84%) of tert-butyl 1-(cyclopropylsulfonylcarbamoyl)-2-(difluoromethyl)cyclopropylcarbamate as a white solid. LC-MS, MS m/z 377 (M+1+Na).
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@@H:10]([O:11][CH3:12])[C@H:9]([CH3:13])[O:8][C@@H:7]([O:14][C:15](=[O:42])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:27]=[CH:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([O:34][C:35]([F:41])([F:40])[C:36]([F:39])([F:38])[F:37])=[CH:30][CH:29]=4)[N:24]=3)=[CH:19][CH:18]=2)[C@@H:6]1[O:43][CH3:44])[CH2:2][CH3:3].I[CH2:46][CH3:47]>>[CH2:1]([O:4][C@@H:5]1[C@@H:10]([O:11][CH3:12])[C@H:9]([CH3:13])[O:8][C@@H:7]([O:14][C:15](=[O:42])[N:16]([CH2:46][CH3:47])[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:27]=[CH:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([O:34][C:35]([F:41])([F:40])[C:36]([F:38])([F:37])[F:39])=[CH:30][CH:29]=4)[N:24]=3)=[CH:19][CH:18]=2)[C@@H:6]1[O:43][CH3:44])[CH2:2][CH3:3]
Reactant: CCI
Reactant: CCCO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](OC(=O)Nc2ccc(-c3ncn(-c4ccc(OC(F)(F)C(F)(F)F)cc4)n3)cc2)[C@@H]1OC
Product: CCCO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](OC(=O)N(CC)c2ccc(-c3ncn(-c4ccc(OC(F)(F)C(F)(F)F)cc4)n3)cc2)[C@@H]1OC

Procedure:
Compound 207 was N-ethylated as in Example 82, using iodoethane instead of iodomethane, to give Compound 253. 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.22 (d, J=68 Hz, 2H), 7.83 (d, J=8.8 Hz, 2H), 7.41 (d, J=9 Hz, 2H), 7.39 (d, J=8.6 Hz, 2H), 6.17 (s, 1H), 3.8 (q, J=7.5 Hz, 2H), 3.60-3.30 (m, 11H), 3.10 (br s, 1H), 1.38 (d, J=6.0 Hz, 3H), 1.20 (t, J=7.5 Hz, 3H); MS 659.12 ([M+H]30).