Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:8](=[O:24])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([CH:22]=[O:23])[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)(=[O:32])C.S(=O)(O)[O-].[Na+].ClCCl>N1C=CC=CC=1>[CH:1]1([N:7]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:8](=[O:24])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([C:22]([OH:32])=[O:23])[CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)CN(C(=O)CCCOc1ccc([N+](=O)[O-])c(C=O)c1)C1CCCCC1
Reactant: CCOC(C)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CN(C(=O)CCCOc1ccc([N+](=O)[O-])c(C(=O)O)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(N-cyclohexyl-4-(3-formyl-4-nitrophenyl)oxybutyramidyl)acetate (3.5 g) in dry pyridine (20 ml) under a blanket of nitrogen was added solid tetra-N-butylammonium permanganate portionwise over 1 hour. The reaction was stirred at room temperature for 1 hour and was then poured into ethyl acetate/6M hydrogen chloride (100 ml each). Solid sodium bisulfite was added to decolorize the solution and the layers were separated. The aqueous layer was washed with ethyl acetate (2×50 ml). The combined organic layers were washed with 1M HCl (3×50 ml) and brine (2×50 ml), dried, filtered and evaporated to give a syrup which foamed at high vacuum from dichloromethane to yield methyl 2-(N-cyclohexyl-4-(3-carboxy-4-nitrophenyl)oxybutyramidyl)acetate.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:22])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([OH:3])=O.F[C:24]1[C:29](O)=[C:28](F)[C:27](F)=[C:26](F)[C:25]=1F.Cl.C([N:38]=C=NCCCN(C)C)C>C(Cl)Cl>[CH:24]1([NH:38][C:1]([C:4]2[CH:5]=[C:6]([NH:10][C:11](=[O:22])[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=3)[CH:7]=[CH:8][CH:9]=2)=[O:3])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(CC(=O)Nc2cccc(C(=O)O)c2)ccc1O
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Solvent: ClCCl
Product: COc1cc(CC(=O)Nc2cccc(C(=O)NC3CCCCC3)c2)ccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
A mixture of N-(3-carboxyphenyl)-4-hydroxy-3-methoxyphenylacetamide (500 mg), pentafluorophenol (305 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (320 mg) and methylene chloride (10 ml) is stirred at 25° C. for 18 hours. The reaction solution is washed with water, and the solvent is evaporated under reduced pressure. To the residue are added ethyl acetate (10 ml) and cyclohexylamine (174 mg), and the mixture is heated with stirring at 60° C. for 18 hours. The solvent is evaporated and the residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the desired compound (600 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:25])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]#[N:41])[CH:35]=1)=[O:33])C>>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:25][C:30](=[O:29])[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]#[N:41])[CH:35]=1)=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1cccc(C#N)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
Prepared from (3-amino-4′-trifluoromethoxy-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G27) and 3-(3-cyano-phenyl)-3-oxo-propionic acid ethyl ester (Pol. J. Chem. 1978, 25) according to the general procedure K. Obtained as a brown semisolid (94 mg).
Reaction SMILES: [BH4-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([C@@H:10]2[C@@H:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:14]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[O:32][CH3:33])[C:13](=[O:34])[C:12]([CH3:39])([C:35](OC)=[O:36])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1>C1COCC1.CCOCC>[Cl:3][C:4]1[CH:5]=[C:6]([C@@H:10]2[C@@H:15]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:14]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[O:32][CH3:33])[C:13](=[O:34])[C:12]([CH2:35][OH:36])([CH3:39])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(Cc2ccc(OC)cc2OC)C1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)C(C)(CO)C[C@H](c3cccc(Cl)c3)[C@H]2c2ccc(Cl)cc2)c(OC)c1

Procedure:
2M lithium borohydride (1.078 mL, 2.157 mmol) was added to a solution of (5R,6S)-methyl 5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxopiperidine-3-carboxylate (Example 88, Step A) (1.17 g, 2.157 mmol) in anhydrous THF (21.57 mL) and anhydrous ether (20 mL) at 0° C. under nitrogen. The reaction was quenched after 58 hours with the addition of sat. aq. NH4Cl and the layers were separated. The aqueous layer was extracted with EtOAc twice and the organics were pooled, washed with sat. aq. NaCl solution, dried (MgSO4), filtered and concentrated in vacuo to provide a colorless oil. Purification using a 80 g SiO2 column and eluting with 35 to 65% EtOAc/hexanes provided the title compound as a ˜30:1 mixture of isomers.
Reaction SMILES: [OH:1][C:2]1[C@:6]([CH:8]([CH3:10])[CH3:9])([CH3:7])[NH:5][C:4](=[O:11])[CH:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH3:30]>>[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]([CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[C:4](=[O:11])[NH:5][C@@:6]([CH:8]([CH3:9])[CH3:10])([CH3:7])[C:2]=1[OH:1])=[C:24]2[CH3:30]
Reactant: Cc1c[nH]c2ccc(F)cc12
Reactant: O=Cc1ccccc1
Reactant: CC(C)[C@@]1(C)NC(=O)C=C1O
Product: Cc1c(C(C2=C(O)[C@@](C)(C(C)C)NC2=O)c2ccccc2)[nH]c2ccc(F)cc12

Procedure:
Using general procedure D, (R)-4-hydroxy-5-isopropyl-5-methyl-1,5-dihydro-pyrrol-2-one (Example E) was reacted with benzaldehyde and 5-fluoro-3-methyl-1H-indole to give the title compound as a pale yellow solid. MS: 393.1 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.CC[N:25]=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.N>ClCCl.CO>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([NH2:25])=[O:11])[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cc(Nc2ncccc2C(=O)O)n(-c2ccccc2)n1
Agent: N
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cc(Nc2ncccc2C(N)=O)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.6 %

Procedure:
To a solution of 2-[(3-methyl-1-phenyl-1H-pyrazol-5-yl)amino]nicotinic acid (40 mg, 0.14 mmol), EDCI (52 mg, 0.27 mmol), HOAT (37 mg, 0.27 mmol), and triethylamine (0.06 mL, 0.41 mmol) in dichloromethane (4 mL) was added ammonia (7 N) in methanol (0.2 mL). The reaction mixture was stirred at rt for 16 h. The organic layer was washed with water, dried over MgSO4, and subsequently concentrated under reduced pressure. The product was purified on a silica gel preparative plate (1000 microns) with EtOAc/hexane (2:1, v/v) to obtain the product as a white solid (22 mg, 55%). 1H NMR (400 MHz, DMSO-d6) δ 2.2 (s, 3H), 6.63 (s, 1H), 6.89 (m, 1H), 7.38 (m, 1H), 7.50 (m, 4H), 7.71 (s, 1H), 8.15 (d, 1H), 8.24 (s, 1H), 8.33 (d, 1H), 11.56 (s, 1H); ES-MS m/z 294.1 (MH+); HPLC RT (min) 2.02.
Reaction SMILES: [CH2:1]([Si:3]([C:8]#[CH:9])([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.Cl[C:18]1[C:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:21]=[CH:20][N:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:8]([Si:3]([C:6]#[C:7][C:18]1[C:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:21]=[CH:20][N:19]=1)([CH2:4][CH3:5])[CH2:1][CH3:2])[CH3:9]
Reactant: COC(=O)Cc1cccnc1Cl
Reactant: C#C[Si](CC)(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[Si](C#Cc1ncccc1CC(=O)OC)(CC)CC
Temperature: 90 °C

Procedure:
A solution of triethylsilyl acetylene (0.579 mL, 3.23 mmol) in degassed DMF (3 mL) and triethylamine (0.901 mL, 6.47 mmol) were added to a mixture of methyl 2-(2-chloropyridin-3-yl)acetate (I118) (0.200 g, 1.08 mmol), Pd(PPh3)2Cl2 (75.6 mg, 0.108 mmol), Cu(I)I (30.8 mg, 0.162 mmol) and triphenylphosphine (42.4 mg, 0.162 mmol) in degassed DMF (4 mL) and the resulting mixture was heated at 90° C. for 20 hours. The cooled mixture was diluted with EtOAc and passed through a plug of celite, washing with ethyl acetate (100 mL). Water (75 mL) was added to the filtrate and the layers separated. The aqueous layer was extracted with EtOAc (2×75 mL). The combined organic extracts were washed with brine (100 mL) and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give a dark brown residue. The residue was purified by column chromatography on silica gel (0-50% EtOAc in cyclohexane) to yield the title compound (I119) (0.353 g) as a brown oil which was used without further purification; 1H NMR (400 MHz, CDCl3) δ 8.50 (dd, J=4.8, 1.6 Hz, 1H), 7.62 (dd, J=7.8, 1.6 Hz, 1H), 7.22 (dd, J=7.8, 4.8 Hz, 1H), 3.86 (s, 2H), 3.70 (s, 3H), 1.05 (t, J=7.9 Hz, 9H), 0.75-0.67 (m, 6H). LCMS Method C: rt 6.55 min; m/z 290 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[N:3]=[N:4][C:5]([CH2:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]([CH3:9])[C:7]=2[CH3:8])=[CH:20][CH:19]=1
Reactant: Cc1c(Cl)nnc(Cc2ccncc2)c1C
Reactant: Nc1ccc(Cl)cc1
Product: Cc1c(Cc2ccncc2)nnc(Nc2ccc(Cl)cc2)c1C
Temperature: 25 °C

Procedure:
A solution of 0.070 g 3-chloro-4,5-dimethyl-6-(pyridin-4-yl)methylpyridazine and 0.153 g para-chloroaniline is heated in a sealed tube for 20 h to 130° C. After cooling to RT, the solution is concentrated by evaporation, the residue diluted with 100 ml CH2Cl2 and then extracted with 100 ml sat. aqueous NaHCO3 solution. The organic phase is dried over MgSO4, concentrated by evaporation, and the residue purified by flash chromatography (FC) on silica gel in Ch2Cl2/methanol 19/1. The title compound is obtained: m.p. 196-199° C. 1H-NMR (250 MHz, CDCl3): δ=8.45 (s, wide, 2H); 7.55 (d, 2H); 7.25 (d, 2H); 7.10 (d, 2H); 6.20 (s, wide, 1H); 4.25 (s, 2H); 2.15 (s, 3H); 2.10 (s, 3H). ES-MS 325, 327 (M+H for 35Cl and 37Cl).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3]1.[CH2:18](O)[CH2:19][OH:20]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:20]1[C:2]2([CH2:6][CH2:5][N:4]([S:7]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=3)(=[O:9])=[O:8])[CH2:3]2)[O:1][CH2:18][CH2:19]1
Reactant: N#Cc1ccc(S(=O)(=O)N2CCC(=O)C2)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(S(=O)(=O)N2CCC3(C2)OCCO3)cc1
Temperature: 25 °C
Yield: 95.4 %

Procedure:
4-[(3-oxo-1-pyrrolidinyl)sulfonyl]benzonitrile 23b (11.6 g, 46.3 mmol) was suspended in toluene (110 ml) and stirred at room temp. Ethylene glycol (6.2 ml, 6.9 g, 111 mmol) and para-toluene sulphonic acid monohydrate (100 mg, 0.53 mmol) were added. The reaction mixture was heated to reflux under Dean-Stark conditions and monitored by water collection and TLC (5% methanol in DCM). If necessary for the completion of the reaction (typically within 3h), further portions of p-TSA were added. When complete the reaction mixture was washed with saturated sodium bicarbonate solution (55 ml) and water (2×55 ml). The organic layer was filtered through cotton wool and then concentrated in vacuo to approximately 50 ml or until precipitation started. Hexane (150 ml) was added and the suspension stirred at 0-5° C. for 10-20 min, filtered and washed with hexane (2×50 ml). The residue was air dried to yield 13.0 g (96%) ketal 4-(1,4-dioxa-7-azaspiro[4.4]non-7-ylsulfonyl)benzonitrile 23c.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].Br[CH2:9][CH2:10][OH:11].[N:12]1[CH:17]=[CH:16][CH:15]=[N:14][C:13]=1[NH2:18].C(N(CC)CC)C>C(Cl)Cl>[O:7]=[C:6]1[N:5]([S:2]([NH:18][C:13]2[N:14]=[CH:15][CH:16]=[CH:17][N:12]=2)(=[O:4])=[O:3])[CH2:9][CH2:10][O:11]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Nc1ncccn1
Reactant: OCCBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1OCCN1S(=O)(=O)Nc1ncccn1
Reaction time: 2.5 h
Yield: 36.3 %

Procedure:
In a 200-mL round-bottom flask was charged with DCM (50 mL) and chlorosulfonyl isocyanate (0.913 ml, 10.51 mmol). The flask was cooled in an ice-bath for 20 min, then 2-bromoethanol (0.745 ml, 10.51 mmol) was added dropwise. The mixture was stirred for 2.5 h, then a solution of pyrimidin-2-amine (1.00 g, 10.51 mmol) and triethylamine (4.40 ml, 31.5 mmol) in DCM (30 mL) was added dropwise via an addition funnel over 10 min. When the addition was complete, the cooling bath was removed, and the mixture was stirred for 2 days. The mixture was washed with 2 N aq. HCl, and the aq. layer was extracted with DCM. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The mixture was taken up in a mixture of DCM and EtOAc, then filtered and dried under a stream of nitrogen to give 2-oxo-N-(pyrimidin-2-yl)oxazolidine-3-sulfonamide (0.930 g, 3.81 mmol, 36.2) as a cream-colored solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.98 (br. s, 1H), 8.66 (s, 2H), 7.13 (t, J=5.0 Hz, 1H), 4.44-4.18 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]1[NH:15][C:14]([C:16]2([CH3:20])[CH2:19][O:18][CH2:17]2)=[N:13][C:12]=1[CH3:21].CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.Cl.[NH:40]1[CH2:45][CH2:44][CH:43]([C:46]2[CH:53]=[CH:52][C:49]([C:50]#[N:51])=[CH:48][CH:47]=2)[CH2:42][CH2:41]1.Cl.N1CC(C2C=CC(C#N)=CC=2)C1>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:40]2[CH2:45][CH2:44][CH:43]([C:46]3[CH:53]=[CH:52][C:49]([C:50]#[N:51])=[CH:48][CH:47]=3)[CH2:42][CH2:41]2)=[O:8])=[CH:4][C:3]=1[C:11]1[NH:15][C:14]([C:16]2([CH3:20])[CH2:19][O:18][CH2:17]2)=[N:13][C:12]=1[CH3:21]
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2(C)COC2)nc1C
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cl
Agent: N#Cc1ccc(C2CNC2)cc1
Product: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1-c1[nH]c(C2(C)COC2)nc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5, except 4-methyl-3-(4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazol-5-yl)benzoic acid (compound 177.2) was used in place of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 455 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 11.78 (br, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 7.40-7.23 (m, 3H), 4.92 (t, J=6.0 Hz, 5.2 Hz, 2H), 4.78-4.52 (m, 1H), 4.43 (t, J=5.2 Hz, 4.8 Hz, 2H), 3.91-3.71 (m, 1H), 3.24-3.08 (m, 1H), 2.98-2.88 (m, 2H), 2.34 and 2.25 (2 singlets, CH3, 3H), 2.16 and 2.03 (2 singlets, amide rotamers, CH3, 3H), 1.91-1.59 (m, 4H), 1.69 and 1.68 (2 singlets, CH3, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10]2)=[O:8])=[CH:3][CH:2]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:24][Cl:25]>C(OCC)(=O)C>[Cl-:25].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:24][N+:1]2[CH:2]=[CH:3][C:4]([C:7]([N:9]3[CH2:18][CH2:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH2:10]3)=[O:8])=[CH:5][CH:6]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(CCl)cc1OC
Reactant: O=C(c1ccncc1)N1CCc2ccccc2C1
Solvent: CCOC(C)=O
Product: COc1ccc(C[n+]2ccc(C(=O)N3CCc4ccccc4C3)cc2)cc1OC
Product: [Cl-]

Procedure:
A mixture of 4.76 g (20 mmol) of 2-[(4-pyridyl)-carbonyl]-1,2,3,4-tetrahydroisoquinoline, 4.5 g (24 mmol) of 3,4-dimethoxybenzyl chloride and 200 ml of ethyl acetate is heated under reflux for 20 h. The mixture obtained is allowed to cool, and the precipitate is separated off by filtration and washed with ether. 6.6 g of salt are collected, this being used without further purification in the following stage.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([NH:19][NH2:20])=[S:18])[CH:12]=1.Cl.C([O:25][C:26](=N)[CH2:27][CH2:28]O)C>N1C=CC=CC=1.CCOC(C)=O>[CH3:8][O:9][C:10](=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[S:18][C:28]([CH2:27][CH2:26][OH:25])=[N:20][N:19]=2)[CH:12]=1
Reactant: COC(=O)c1cccc(C(=S)NN)c1
Reactant: CCOC(=N)CCO
Agent: Cl
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2nnc(CCO)s2)c1
Temperature: 100 °C
Yield: 100.9 %

Procedure:
A mixture of 3-hydrazinothiocarbonyl-benzoic acid methyl ester trifluoroacetate (0.45 g) and 3-hydroxy-propionimidic acid ethyl ester hydrochloride (0.35 g) in pyridine (5 mL) was heated to 100° C. for 1.5 h. The mixture was diluted with AcOEt and washed with IN HCl and with brine. The organic layer was dried and evaporated and the residual oil was chromatography on silica gel using AcOEt/hexane (1:1) as eluent to give 3-[5-(2-hydroxy-ethyl)-[1,3,4]thiadiazol-2-yl]-benzoic acid methyl ester (0.37 g) as a white solid, MS (ISP) 265.3 [(M+H)+].
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([CH:22]2[CH2:24][CH2:23]2)[C:6]2[C:12]([C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])=[C:11]([F:21])[CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:3].[NH2:25][C:26]1[C:31]([C:32]#[N:33])=[C:30](Cl)[N:29]=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>CC(O)C.CO>[NH2:25][C:26]1[C:31]([C:32]#[N:33])=[C:30]([NH:1][C@H:2]([C:4]2[N:5]([CH:22]3[CH2:23][CH2:24]3)[C:6]3[C:12]([C:13]([N:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)=[O:14])=[C:11]([F:21])[CH:10]=[CH:9][C:7]=3[N:8]=2)[CH3:3])[N:29]=[CH:28][N:27]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1nc2ccc(F)c(C(=O)N3CCOCC3)c2n1C1CC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(C(=O)N3CCOCC3)c2n1C1CC1
Temperature: 90 °C
Yield: 41.6 %

Procedure:
A mixture of [2-((S)-1-aminoethyl)-3-cyclopropyl-5-fluoro-3H-benzoimidazol-4-yl]-morpholin-4-yl-methanone (106 mg, 0.32 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (54 mg, 0.35 mmol) and DIPEA (170 μL, 0.98 mmol) in IPA (1 mL) was heated at 90° C. in a sealed vial for 17 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) followed by trituration with EtOAc to afford 401 as a white solid (60 mg, 31%). LCMS (Method K): RT 2.81 min [M+H]+ 451.06. 1H NMR (CDCl3, 400 MHz): δ 8.18 (1H, s), 7.71-7.65 (1H, m), 7.05-6.97 (1H, m), 6.47-6.40 (0.7H, m), 6.15-6.05 (0.3H, m), 5.98-5.88 (1H, m), 5.38-5.31 (2H, m), 4.22-4.14 (1H, m), 3.93-3.72 (4H, m), 3.69-3.52 (2H, m), 3.44-3.33 (2H, m), 1.73 (1H, d, J=6.78 Hz), 1.65 (2H, d, J=6.76 Hz), 1.43-1.24 (2H, m), 1.11-0.93 (1H, m), 0.86-0.69 (1H, m)
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][N:16]2[C:22](=[O:23])[C:21]3[C:24]([CH3:33])=[C:25]([O:29][CH:30]([CH3:32])[CH3:31])[CH:26]=[C:27](Br)[C:20]=3[O:19][CH2:18][CH2:17]2)=[C:13]([CH3:34])[CH:12]=[C:11]([CH3:35])[N:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.[CH3:43][N:44](C)C(=O)C>O>[CH3:34][C:13]1[CH:12]=[C:11]([CH3:35])[NH:10][C:9](=[O:8])[C:14]=1[CH2:15][N:16]1[C:22](=[O:23])[C:21]2[C:24]([CH3:33])=[C:25]([O:29][CH:30]([CH3:32])[CH3:31])[CH:26]=[C:27]([C:43]#[N:44])[C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: Cc1cc(C)c(CN2CCOc3c(Br)cc(OC(C)C)c(C)c3C2=O)c(OCc2ccccc2)n1
Reactant: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(C)c(CN2CCOc3c(C#N)cc(OC(C)C)c(C)c3C2=O)c(=O)[nH]1
Temperature: 120 °C
Yield: 19 %

Procedure:
To a solution of 4-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-9-bromo-7-isopropoxy-6-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (116 g, 98 mg, 0.18 mmol) in N,N-dimethylacetamide (2 mL) was added cuprous cyanide (50 mg, 0.55 mmol). The reaction mixture was heated at 120° C. in a sealed tube for 20 hours, cooled to room temperature then additional cuprous cyanide (25 mg, 0.26 mmol) was added and the reaction was heated at 150° C. in a sealed tube for 5 hours. The reaction was cooled to room temperature, diluted with water (5 mL) and extracted with methyl tert-butyl ether (2×5 mL). The combined organic layers were washed with brine (5 mL), dried over magnesium sulfate and concentrated under vacuum. The crude residue was taken up in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL, 2 mmol) and stirred at room temperature overnight then concentrated under vacuum. The residue was purified by reverse phase HPLC to provide the title compound (Example 116, 13 mg, 19% yield). 1H NMR (700 MHz, DMSO-d6) δ 7.47 (s, 1H), 5.93 (br. s., 1H), 4.58-4.69 (m, 3H), 4.12 (br. s., 2H), 2.19 (d, J=12.91 Hz, 6H), 2.14 (s, 3H), 1.26 (d, J=6.02 Hz, 6H): MS 396 [M+H].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[S:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.C(N(CC)CC)C>C(Cl)Cl.O>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]([N:15]2[CH2:16][CH2:17][S:13][CH2:14]2)=[O:8])[CH:10]=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: C1CSCN1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccc([N+](=O)[O-])c1)N1CCSC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a stirred solution of 3-nitrobenzoyl chloride (5.00 g, 26.9 mmol) in DCM (50 ml), thiazolidine (3.60 g, 40.4 mmol) was added at 0° C. Triethylamine, (7.51 ml, 53.9 mmol) was added dropwise into the reaction mixture over 5 min and the reaction mixture was stirred at RT for 1 hr. Reaction mixture was diluted with cold water. Organic phase was separated and aq. phase was extracted using DCM (3×10.0 ml). Combined organic layer was washed with brine (100 ml), dried over sodium sulphate and the solvent was evaporated under vacuum to afford the title compound (5.0 gm).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:15][C:16]1[CH:21]=[C:20](Cl)[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24]>CN(C)P(N(C)C)(N(C)C)=O.O>[CH3:3][C:4]([C:20]1[CH:19]=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[C:16]([Cl:15])[CH:21]=1)([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])c(Cl)c1
Reaction time: 7 h

Procedure:
The starting material can also be prepared as follows: 4.8 g 50% sodium hydride in mineral oil are added to 100 ml hexamethylphosphoramide while stirring under nitrogen. Hereupon 17.1 g diethyl α-methylmalonate are added and the mixture slowly heated to 100°. The solution of 19.2 g 2,4-dichloro-nitrobenzene in 20 ml hexamethylphosphoramide is added dropwise during 1/2 hour and the temperature kept at 100° for 7 hours. After cooling, the mixture is diluted with water, concentrated in vacuo, the residue taken up in water and extracted with benzene. The extract is washed with water, dried, filtered, evaporated, the residue distilled and the fraction boiling at 147°-148°/0.25 mm Hg collected, to yield the diethyl α-methyl-α-(3-chloro-4-nitrophenyl)-malonate. (The analogously prepared diethyl α-ethyl-α-(3-chloro-4-nitrophenyl)-malonate boils at 170°-174°/1 mm Hg.)