Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].CCN(C(C)C)C(C)C.[CH3:14][C:15]([C:19]1[N:23]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:22]2[CH:31]=[CH:32][C:33]([S:35]([N:38]3[CH:42]=[C:41]([C:43]([OH:45])=O)[CH:40]=[N:39]3)(=[O:37])=[O:36])=[CH:34][C:21]=2[N:20]=1)([CH3:18])[CH2:16][CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:14][C:15]([C:19]1[N:23]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:22]2[CH:31]=[CH:32][C:33]([S:35]([N:38]3[CH:42]=[C:41]([C:43]([NH:4][CH2:2][CH3:3])=[O:45])[CH:40]=[N:39]3)(=[O:37])=[O:36])=[CH:34][C:21]=2[N:20]=1)([CH3:18])[CH2:16][CH3:17]
Reactant: CCN
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1cnn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)CC)n3CC2CCOCC2)c1
Yield: 60.4 %

Procedure:
Following the same procedure in Example 24, Step A, using ethylamine hydrochloride (29 mg, 0.36 mmol), DIPEA (104 uL, 77 mg, 0.59 mmol), 1-{[2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (0.18 mmol) and HATU (109 mg, 0.29 mmol) in DMF (3 mL). The crude product was purified by MPLC using Hex/EtOAc (1:4) on silica gel to give 53 mg (61%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.77 (t, J=7.42 Hz, 3 H), 1.15 (t, J=7.32 Hz, 3 H), 1.39-1.57 (m, 4 H), 1.58 (s, 6 H), 1.94 (q, J=7.68 Hz, 2 H), 2.19-2.37 (m, 1 H), 3.24-3.40 (m, 4 H), 3.83-3.94 (m, 2 H), 4.41 (d, J=7.23 Hz, 2 H), 7.92 (d, J=8.8 Hz, 1 H), 7.99 (dd, J=8.8, 1.4 Hz, 1 H), 8.04 (s, 1 H), 8.34 (d, J=1.17 Hz, 1 H), 8.74 (s, 1 H); MS (ESI) (M+H)+=488.0; Anal. Calcd for C24H33N5O4S+0.9 TFA+0.3H2O (595.65): C, 52.02; H, 5.84; N, 11.76. Found: C, 52.01; H, 5.66; N, 11.91.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]3[CH:13]=[C:14]([N:18](C(=O)CC(C)(C)C)[C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:9]=[N:8][C:7]=12)#[N:2].F[C:30](F)(F)[C:31]([OH:33])=[O:32]>ClCCl>[C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]3[CH:13]=[C:14]([N:18]([CH2:30][C:31]([OH:33])=[O:32])[C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:9]=[N:8][C:7]=12)#[N:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)N(C(=O)CC(C)(C)C)c1cccc(-c2ccnc3c(C#N)cnn23)c1
Solvent: ClCCl
Product: CC(=O)N(CC(=O)O)c1cccc(-c2ccnc3c(C#N)cnn23)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-tert-butylacetylacetamide 4 (9.0 g, 0.023 mol) in dichloromethane (200 ml) was added trifluoroacetic acid (60 ml). The reaction mixture was stirred at room temperature for four hours. The solution was concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using chloroform/methanol (9/1). 5.5 g of Hapten-A was obtained as a foamy solid. NMR13C: 172.7, 172.2, 153.1, 151.6, 147.6, 147.2, 143.7, 131.56, 131.2, 131.0, 129.8, 112.9, 110.4, 84.1, 51.6, 29.5 and 22.6
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([F:29])=[C:14]([C:16]2[CH:25]=[C:24](B(O)O)[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([F:29])=[C:14]([C:16]2[CH:25]=[C:24]([C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=3)[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH:15]=1
Reactant: OB(O)c1cc(-c2cc(Cl)ccc2F)nc2ncccc12
Reactant: Nc1ccc(Br)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Nc1ccc(-c2cc(-c3cc(Cl)ccc3F)nc3ncccc23)cn1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A slurry of 352 mg (2.04 mmol) 2-amino-5-bromo-pyridine, 678 mg (2.24 mmol) 2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid and 1.33 g (4.07 mmol) cesium carbonate in 10 ml dioxane and 2 ml water was heated to 80° C. under nitrogen. Then 118 mg (0.10 mmol) tetrakis-(triphenylphosphine)-palladium(0) were added and the reaction mixture was stirred for 1 hour at 100° C. The reaction mixture was cooled to room temperature and water and dichloromethane were added. The resulting precipitate was filtered off, washed with water and dried in vacuo yielding 5-[2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-pyridin-2-ylamine as brown crystals; HPLC-MS: 1.43 min, [M+H] 351.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]=[C:6]([NH:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1I)[C:7]([F:10])([F:9])[F:8])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])(O)=O.[Na+].CCOC(C)=O.O>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:3][C:4]([C:5]1[C:13]2[C:12](=[CH:17][C:16]([O:18][CH3:19])=[CH:15][CH:14]=2)[NH:11][C:6]=1[C:7]([F:10])([F:9])[F:8])=[O:21])[CH3:2]
Reactant: CCOC(=O)C=C(Nc1cc(OC)ccc1I)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C(F)(F)F)[nH]c2cc(OC)ccc12
Temperature: 120 °C
Yield: 63 %

Procedure:
A mixture of 4,4,4-trifluoro-3-(2-iodo-5-methoxy-phenylamino)-but-2-enoic acid ethyl ester 76c (0.5 g, 1.2 mmole), Pd(OAc)2 (22.4 mg, 0.1 mmole), PPh3 (52.5 mg, 0.2 mmole) and NaHCO3 (505 mg, 6 mmole) in 5 ml DMF was heated at 120° C. under argon for 24 hours and cooled to room temperature. The mixture was poured into EtOAc/water and washed with brine. The organic layer was dried over Na2SO4 and concentrated under rot vap. The residue was purified by column chromatography to give 217 mg product (63% yield). 1H NMR (300 MHz, CD3OD) δ8.00 (1H, d, J=9.0 Hz), 6.96 (1H, d, J=2.0 Hz), 6.90 (1H, dd, J=2.0, 9.0 Hz), 4.37 (2H, m), 3.84 (3H, s), 1.40 (3H, m).
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1)[CH3:2].[OH-].[Na+].Br[CH2:15][CH2:16][CH2:17][Cl:18]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.CC1C=CC=CC=1>[Cl:18][CH2:17][CH2:16][CH2:15][N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=[C:3]1[CH2:1][CH3:2]
Reactant: ClCCCBr
Reactant: CCc1nc2ccccc2[nH]1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCc1nc2ccccc2n1CCCCl
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 29.2 parts of 2-ethyl-1H-benzimidazole, 5 parts of N,N,N-triethylbenzenemethanaminium chloride and 300 parts of a sodium hydroxide solution 60% are added 60 parts of 1-bromo-3-chloropropane. The whole is heated to about 65° C. and stirring is continued for 30 minutes at this temperature. Methylbenzene is added and the whole is poured onto water. The organic phase is separated, dried, filtered and evaporated. The residue is purified twice by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1-(3-chloropropyl)-2-ethyl-1H-benzimidazole as a residue.
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13](I)[CH2:12]1.Cl[C:19]1[S:23][N:22]=[C:21]([S:24][CH3:25])[N:20]=1>[Zn].O1CCCC1>[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:19]2[S:23][N:22]=[C:21]([S:24][CH3:25])[N:20]=2)[CH2:12]1
Reactant: CSc1nsc(Cl)n1
Reactant: CC1CCCC(I)C1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CSc1nsc(C2CCCC(C)C2)n1
Temperature: 65 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
1.31 g of zinc foil (99.998%) and 190 mg of 1,2-dibromoethane was added into 2 ml of tetrahydrofurane under nitrogen atmosphere and the mixture was heated in an oil bath at 65° C. for 1 minute. After cooling to room temperature, 0.1 ml of trimethylsilyl chloride, 2.14 g of 3-methylcyclohexyl iodide and 10 ml of tetrahydrofuran were added to the mixture, and the mixture was exposed to ultrasonic wave in a water bath for 4 hours. Further, 1.31 g of 5-chloro-3-methylthio-1,2,4-thiadiazole, 390 mg of {1,1′-bis(diphenylphosphino)ferrocene} dichloro palladium(II) dichloromethane complex and 10 ml of tetrahydrofuran were added in the mixture, and the reaction mixture was stirred for 3.5 days at room temperature. The reaction mixture was concentrated, and the residue subjected to silica gel column chromatography to give 790 mg of 5-(3-methylcyclohexyl)-3-methylthio-1,2,4-thiadiazole.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21](C1C=CC(B(O)O)=CC=1)=[O:22]>>[CH:21]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)=[CH:6][CH:5]=1)=[O:22]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: O=Cc1ccc(-c2[nH]c3cccc4c3c2CCNC4=O)cc1

Procedure:
In a manner similar to that described above for Compound 12, the tricyclic bromide (168 mg, 0.63 mmol) and 4-formylbenzeneboronic acid (142 mg, 0.95 mmol) were coupled to yield 2-(4-formylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one, 141 mg (77%), as a yellow solid. mp 238-240° C. (dec.); 1H NMR (300 MHz, d6-DMSO) δ3.12 (m, 2H), 3.42 (m, 2H), 7.28 (t, 1H, J=7.6 Hz), 7.59 (d, 1H, J=7.6 Hz), 7.62 (d, 1H, J=7.6 Hz), 7.88 (d of ABq, 2H, J=7.7 Hz), 8.05 (d of ABq, 2H, J=7.7 Hz), 8.11 (br t, 1H), 10.07 (s, 1H), 11.75 (br s, 1H); HRMS (FAB, MH+) Calcd for C18H15N2O2: 291.1134, Found: 291.1132.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[CH:11]/[C:12]1[C:13]([O:29]CC2C=CC=CC=2)=[N:14][C:15]([CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:16]([CH2:18][CH3:19])[CH:17]=1>O1CCCC1.CO.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][C:12]1[C:13](=[O:29])[NH:14][C:15]([CH2:20][O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:16]([CH2:18][CH3:19])[CH:17]=1
Reactant: CCc1cc(/C=C/c2nc3ccccc3o2)c(OCc2ccccc2)nc1COCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(CCc2nc3ccccc3o2)c(=O)[nH]c1COCc1ccccc1
Reaction time: 20 h

Procedure:
A solution of cis/trans 3-[2-(benzoxazol-2-yl)ethenyl]-5-ethyl-6-benzyloxymethyl-2-benzyloxypyridine (1.40 g, 2.94 mmol) in dry tetrahydrofuran (20 mL) and methanol (15 mL) containing 10% Pd on charcoal (215 mg) as a catalyst was hydrogenated at atmospheric pressure for 20 hours. The catalyst was filtered off and the solution evaporated to give a white residue. This residue was triturated with diethyl ether to give pure product with m.p. of 140°-142° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([OH:31])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:40][C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:42])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 14.5 g 4-{(S)-4-tert-butoxycarbonyl-2-[(5-hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 110 ml DMF were added 4.5 ml benzyl bromoacetate and 17.8 g cesium carbonate. After stirring at RT for 12 h the solution was reduced to a volume of 50 ml, diluted with 400 ml ethyl acetate and extracted with aqueous LiCl (4% w/w). The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica eluting with a gradient of n-heptane/ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[C:21]#[N:22])=[CH:4][C:5](=[O:13])[N:6]([CH:8]([CH3:12])[C:9]([OH:11])=O)[CH:7]=1.[F:23][C:24]([F:36])([F:35])[C:25]1[NH:29][C:28]2[CH:30]=[C:31]([NH2:34])[CH:32]=[CH:33][C:27]=2[N:26]=1>>[Cl:1][C:2]1[C:3]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[C:21]#[N:22])=[CH:4][C:5](=[O:13])[N:6]([CH:8]([CH3:12])[C:9]([NH:34][C:31]2[CH:32]=[CH:33][C:27]3[N:26]=[C:25]([C:24]([F:36])([F:35])[F:23])[NH:29][C:28]=3[CH:30]=2)=[O:11])[CH:7]=1
Reactant: CC(C(=O)O)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Nc1ccc2nc(C(F)(F)F)[nH]c2c1
Product: CC(C(=O)Nc1ccc2nc(C(F)(F)F)[nH]c2c1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
68 mg (purity 94%, 0.20 mmol) of 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) (Example 12.1D) and 44 mg (0.22 mmol) of 2-(trifluoromethyl)-1H-benzimidazole-6-amine were reacted according to General Method 1. Yield: 63 mg (60% of theory)
Reaction SMILES: C([O:3][C:4](=[O:36])[CH:5]=[CH:6][CH:7]([N:18]([CH3:35])[C:19](=[O:34])[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1)[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)C.[OH-].[Li+]>O1CCCC1.CO.O>[CH3:35][N:18]([CH:7]([CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[CH:6]=[CH:5][C:4]([OH:36])=[O:3])[C:19](=[O:34])[C:20]1[CH:21]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1
Reactant: CCOC(=O)C=CC(Cc1c[nH]c2ccccc12)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C=CC(=O)O)Cc1c[nH]c2ccccc12

Procedure:
A solution of 8.5 g of 4-[N-methyl-N-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(1H-indol-3-yl)-pent-2-enoic acid ethyl ester and 1.2 g of lithium hydroxide in 70 ml of tetrahydrofuran/methanol/water=2/2/1 is stirred at room temperature for 16 hours and then concentrated by evaporation. The residue is dissolved in 150 ml of water with heating to 50°, extracted with ether at 20°, acidified to pH=2 with 0.1N hydrochloric acid and extracted three times with ether. The combined organic phases originating from the extraction of the acidic aqueous phase are washed with water and saturated NaCl solution, dried (magnesium sulfate) and concentrated by evaporation. In this way the title compound is obtained in the form of a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:3]=1.O.[NH2:24][NH2:25]>N1C=CC=CC=1.O>[Cl:1][C:2]1[N:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[C:6]([NH:24][NH2:25])[N:7]=1
Reactant: NN
Reactant: Clc1ccc(-c2nc(Cl)nc(Cl)c2-c2ccc(Cl)cc2)cc1
Solvent: O
Solvent: c1ccncc1
Product: NNc1nc(Cl)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
2,4-Dichloro-5,6-bis(4-chlorophenyl)pyrimidine (1.8 g, 4.86 mmol) was dissolved in pyridine (5 mL) and hydrazine monohydrate (0.26 mL, 5.36 mmol) was added. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was then diluted with water (10 mL) and extracted with EtOAc (10 mL×2). The combined organic extracts were washed with water, followed by saturated aqueous NaCl, dried (MgSO4), and concentrated at reduced pressure to obtain 1.7 g of the title compound, as a mixture with its regioisomer, as a yellow solid. HPLC/MS: title compound retention time=3.261 min, [M+H]30 =365; regioisomer retention time 3.385 min.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[C:13](=[O:20])[CH2:12][CH2:11]2.[CH:21]1([CH2:26][CH2:27][C:28](Cl)=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22]1>ClC(Cl)C>[N+:17]([C:16]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][C:13]2=[O:20])=[CH:9][C:8]=1[NH:7][C:28](=[O:29])[CH2:27][CH2:26][CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)([O-:19])=[O:18]
Reactant: O=C(Cl)CCC1CCCC1
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)CC2
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: O=C(CCC1CCCC1)Nc1cc2c(cc1[N+](=O)[O-])C(=O)CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.2 %

Procedure:
Pyridine (0.1 g, 1.3 mmol) was added to a suspension of 5-amino-6-nitro-indan-1-one (0.19 g, 1 mmol) in 15 ml of anhydrous dichloroethane followed by the addition of 3-cyclopentylpropionyl chloride (0.193 mg, 1.2 mmol) at room temperature under argon. The mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure and the residue was purified by column (hexane/EtOAc, 5:1) to give a yellow solid (0.26 g, 83%). 1H-NMR (DMSO-d6): δ 10.47 (s, 1H, NH, exchangeable with D2O), 8.06 (s, 1H), 7.87 (s, 1H), 3.15 (m, 2H), 2.69 (m, 2H), 2.38 (t, 2H, J=7.8 Hz), 1.74 (m, 2H), 1.59-1.46 (m, 7H), 1.08 (m, 2H). MS: 317 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][C@H:4]1[CH2:6][NH:5]1.C(N(CC)CC)C.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>CCOCC>[CH3:1][CH:2]([CH3:7])[CH2:3][CH:4]1[CH2:6][N@@:5]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)C[C@H]1CN1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)CC1CN1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 90.5 %

Procedure:
A solution of 24.3 g of (S)-2-(2-methylpropyl)aziridine [Bull. Chem. Soc. (Japan) 35, 1004 (1962).] in 500 ml of ether is treated with 34.2 ml of triethylamine and cooled in ice. While stirring rapidly 40.4 ml (a 10% excess) of benzyl chloroformate is added dropwise over a 30 minute period. After stirring for one hour at 0°, the triethylamine, hydrochloride is filtered off and the ether removed under reduced pressure. The residue is distilled under reduced pressure. After a forerun of benzyl chloride, the product distills at 105°-122°/0.6 mm. There is obtained 51.66 g (90.5% yield) of (S)-2-(2-methylpropyl)-1-aziridinecarboxylic acid, phenylmethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH2:30]=O>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:19][CH2:20][N:21]([CH3:30])[CH2:22][CH2:23]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: C=O
Reactant: O=C(NC(COCC1CCNCC1)c1ccccn1)c1ccc2c(Cl)c[nH]c2c1
Product: CN1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccn2)CC1

Procedure:
Using alkylation method B, 3-chloro-N-[1-(2-pyridinyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (30 mg, 0.07 mmol) and paraformaldehyde (15 mg, 0.12 mmol) afforded, after purification (SiO2: 10% isopropylamine in DCM), 20 mg (65%) of the title compound.
Reaction SMILES: Cl.[NH2:2][OH:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:32]=O)[CH:17]=3)[C:12]2=[O:34])=[CH:7][CH:6]=1.C([O-])(=O)C.[Na+]>C(O)C.ClCCl>[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:32]=[N:2][OH:3])[CH:17]=3)[C:12]2=[O:34])=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)CCCCc1cc2cc(C=O)ccc2c(=O)n1-c1ccc(F)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)CCCCc1cc2cc(C=NO)ccc2c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
Hydroxylamine hydrochloride (314 mg, 4.52 mmol) was added to a stirred, room temperature mixture of tert-butyl 5-(2-(4-fluorophenyl)-6-formyl-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (638 mg, 1.507 mmol) and sodium acetate (742 mg, 9.04 mmol) in ethanol (10 mL), and the mixture was stirred at room temperature for 1 h. The mixture was diluted with dichloromethane (60 mL), washed with brine (saturated, 1×30 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to give tert-butyl 5-(2-(4-fluorophenyl)-6-((hydroxyimino)methyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (658 mg, 1.501 mmol) as a white solid.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]=2)=[CH:8]1)(C)(C)C.Cl.[Cl:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][C:34]([F:38])([F:37])[CH2:33][CH2:32]1>>[ClH:28].[F:37][C:34]1([F:38])[CH2:35][CH2:36][N:31]([CH2:30][CH2:29][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]4[CH:24]=[CH:25][S:26][C:20]=4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH2:32][CH2:33]1
Reactant: CC(C)(C)ON=c1cc(-c2cc3sccc3cn2)oc2ccc(O)cc12
Reactant: FC1(F)CCN(CCCl)CC1
Agent: Cl
Product: ON=c1cc(-c2cc3sccc3cn2)oc2ccc(OCCN3CCC(F)(F)CC3)cc12

Procedure:
6-[2-(4,4-Difluoro-piperidin-1-yl)-ethoxy]-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one oxime, hydrochloride was prepared in 28% overall yield using the method described in example 127, starting from 6-Hydroxy-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one O-tert-butyl-oxime (example 127B) and 1-(2-Chloro-ethyl)-4,4-difluoro-piperidine hydrochloride.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[CH3:8][N:9]([CH3:38])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH:29][C:30]1[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][C:31]=1[CH3:37])=[N:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1.C(N(CC)C(C)C)(C)C.C(#N)C>CCCCCC.CO>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH3:1])[N:19]=[CH:18][N:17]=[C:16]2[NH:15][C:14]([NH:13][CH2:12][CH2:11][CH2:10][N:9]([CH3:8])[CH3:38])=[N:29][C:30]1[C:31]([CH3:37])=[CH:32][CH:33]=[CH:34][C:35]=1[CH3:36]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1cc2c(N=C(NCCCN(C)C)Nc3c(C)cccc3C)ncnc2cc1O
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(NC(=Nc3c(C)cccc3C)NCCCN(C)C)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
An aliquot (0.15 ml) of a 2M solution of trimethylsilyldiazomethane in hexane was added to a mixture of N-(3-dimethylaminopropyl)-N′-(2,6-dimethylphenyl)-N″-(7-hydroxy-6-methoxyquinazolin-4-yl)guanidine (0.1 g), N,N-diisopropylethylamine (0.06 ml), acetonitrile (1.8 ml) and methanol (0.2 ml). The resultant reaction mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a 2M solution of ammonia gas in methanol as eluent. There was obtained the title compound (0.059 g); NMR Spectrum: (DMSOd6, 100° C.) 1.78 (m, 2H), 2.06 (s, 6H), 2.3 (s, 6H), 2.38 (t, 2H), 3.6 (q, 2H), 3.81 (s, 3H), 3.93 (s, 3H), 7.11 (s, 1H), 7.2 (s, 3H), 7.66 (s, 1H), 8.47 (s, 1H), 10.9 (br s, 1H); Mass Spectrum: M+H+ 473.