Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(O)(=O)C.C=O.[CH3:10][N:11]1[C:16]2[C:17]([CH3:20])=[CH:18][NH:19][C:15]=2[C:14](=[O:21])[N:13]([CH3:22])[C:12]1=[O:23]>O>[CH3:1][N:2]([CH2:20][C:17]1[C:16]2[N:11]([CH3:10])[C:12](=[O:23])[N:13]([CH3:22])[C:14](=[O:21])[C:15]=2[NH:19][CH:18]=1)[CH3:3]
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Reactant: CNC
Agent: C=O
Solvent: CC(=O)O
Solvent: O
Product: CN(C)Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 50% dimethyl amine (0.4 mL), acetic acid (0.4 mL) and 38% formaldehyde (0.4 mL) were added, after which Intermediate 1 (0.4 g, 2.232 mmol) was added. The reaction mixture was refluxed for 10 min and then held for 20 min at 90° C. Reaction mixture was cooled to room temperature and diluted with water (25 mL). Two layers were separated. The aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water (25 mL), dried (Na2SO4) and filtered. The filtrate was evaporated to give a crude product which was recrystallised from acetonitrile to give 97 mg of the product as a white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 2.08 (s, 6H), 3.23 (s, 3H), 3.30 (s, 2H), 3.69 (s, 3H), 7.13 (s, 1H), 11.93 (br s, 1H); APCI-MS (m/z) 237.00 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:32])[CH2:16][N:17](CC2C=CC=CC=2)CC2C=CC=CC=2)=[CH:11][C:10]=1[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[NH2:17][CH2:16][CH:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:11]=1)[OH:32]
Reactant: CS(=O)(=O)Nc1cc(C(O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Temperature: 25 °C

Procedure:
To a stirred suspension of N-[2-benzyloxy-5-(2-dibenzylamino-1-hydroxy-ethyl)-phenyl]-methanesulfonamide (which was obtained in Intermediate 7)(1.03 g, 2 mmol) and 10% palladium on carbon (0.4 g) in methanol (100 mL) at room temperature was added anhydrous ammonium formate (1.26 g, 20 mmol) under a nitrogen atmosphere. The resulting mixture was refluxed for 2 hours. After cooling to room temperature the catalyst was removed by filtration through a celite pad and washed with methanol. The filtrate was evaporated under reduced pressure to give the titled compound (Leclerc, G., Bizec, J. C. J. Med. Chem., 1980, 23, 738) as a pale yellowish solid; 1 H NMR (300 MHz, DMSO-d6) δ2.62 (dd, J=12.6, 8.7 Hz, 1 H), 2.75 (dd, J=12.6, 3.7 Hz, 1 H), 2.90 (s, 3 H), 4.47 (dd, J=8.7, 3.7 Hz, 1 H), 6.84 (d, J=9.1 Hz, 1 H), 6.96 (dd, J=9.1, 2.0 Hz, 1 H), 7.16 (d, J=2.1 Hz, 1 H), 8.44 (s, 1 H); MS (ES) m/z: 246.7 (MH+); HRMS Calcd. for C9H14N2O4S(M+): 246.0674. Found: 246.0672.
Reaction SMILES: [CH3:1][C:2]([C:6]1[N:10]([CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[CH:18]=[CH:19][C:20]([S:22](Cl)(=[O:24])=[O:23])=[CH:21][C:8]=2[N:7]=1)([CH3:5])[CH2:3][CH3:4].[NH:26]1[CH:30]=[CH:29][C:28]([CH:31]=[O:32])=[CH:27]1.[H-].[Na+]>C1COCC1>[CH3:1][C:2]([C:6]1[N:10]([CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[CH:18]=[CH:19][C:20]([S:22]([N:26]3[CH:30]=[CH:29][C:28]([CH:31]=[O:32])=[CH:27]3)(=[O:24])=[O:23])=[CH:21][C:8]=2[N:7]=1)([CH3:5])[CH2:3][CH3:4]
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: O=Cc1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C=O)c3)ccc2n1CC1CCOCC1
Yield: 72.5 %

Procedure:
Following the same procedure in Example 29, using 2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (0.66 g, 1.7 mmol), 1H-pyrrole-3-carbaldehyde (0.14 g, 1.4 mmol) and sodium hydride (0.29 g, 60%, 7.2 mmol) in THF (15 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 0.45 g (71%) of a white solid as the title compound. MS (ESI) (M+H)+=443.93
Reaction SMILES: FC(F)(F)OC1C=CC(CN)=CC=1.FC1C=C(C=CC=1[N+]([O-])=O)OCC1C=CN(C)N=1.[CH3:32][N:33]1[CH:37]=[CH:36][C:35]([CH2:38][O:39][C:40]2[CH:45]=[C:44]([NH:46][CH2:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][C:55]([F:58])([F:57])[F:56])=[CH:50][CH:49]=3)[C:43]([NH2:59])=[CH:42][CH:41]=2)=[N:34]1.[CH3:60][C:61]1([CH3:69])[C@@H:66]2[C@H:62]1[C:63](=[O:68])[O:64][C:65]2=O>>[CH3:60][C:61]1([CH3:69])[C@H:66]([C:65]2[N:46]([CH2:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][C:55]([F:56])([F:57])[F:58])=[CH:50][CH:49]=3)[C:44]3[CH:45]=[C:40]([O:39][CH2:38][C:35]4[CH:36]=[CH:37][N:33]([CH3:32])[N:34]=4)[CH:41]=[CH:42][C:43]=3[N:59]=2)[C@@H:62]1[C:63]([OH:68])=[O:64]
Reactant: CC1(C)[C@@H]2C(=O)OC(=O)[C@@H]21
Reactant: Cn1ccc(COc2ccc(N)c(NCc3ccc(OC(F)(F)F)cc3)c2)n1
Agent: Cn1ccc(COc2ccc([N+](=O)[O-])c(F)c2)n1
Agent: NCc1ccc(OC(F)(F)F)cc1
Product: Cn1ccc(COc2ccc3nc([C@@H]4[C@H](C(=O)O)C4(C)C)n(Cc4ccc(OC(F)(F)F)cc4)c3c2)n1

Procedure:
The title compound was prepared using analogous conditions described for Example 1 using (4-(trifluoromethoxy)phenyl)methanamine and 3-((3-fluoro-4-nitrophenoxy)methyl)-1-methyl-1H-pyrazole in Step A then for Intermediate I using 5-((1-methyl-1H-pyrazol-3-yl)methoxy)-N1-(4-(trifluoromethoxy)benzyl)benzene-1,2-diamine and cis-6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione followed by the hydrolysis according to Example 111. MS (ESI): mass calcd. for C26H25F3N4O4, 514.18; m/z found, 515.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J=8.9, 1H), 7.33 (d, J=2.2, 1H), 7.21 (d, J=8.1, 2H), 7.09 (d, J=8.8, 2H), 7.06 (dd, J=8.9, 2.3, 1H), 6.94 (d, J=2.2, 1H), 6.31 (d, J=2.2, 1H), 5.39 (d, J=16.9, 1H), 5.31 (d, J=16.9, 1H), 5.09 (s, 2H), 3.86 (s, 3H), 2.31 (d, J=8.2, 1H), 2.04 (d, J=8.3, 1H), 1.20 (s, 3H), 0.97 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][N:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O>C1COCC1.O>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([CH2:7][OH:8])=[CH:9][CH:10]=1
Reactant: COc1ccc(C=O)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CO)cn1
Yield: 82.2 %

Procedure:
According to Scheme 16 Method A: A solution of 6-methoxynicotinaldehyde (1 eq, 2.19 mmol, 0.30 g) and LiAlH4 (0.5 eq, 1.05 mmol, 0.04 g) in THF (10 mL) was stirred for 30 min. at 0° C. and overnight at room temperature. After the addition of AcOEt, the reaction mixture was diluted with water. The organic layer washed with saturated NH4Cl solution, dried over Na2SO4, filtered and evaporated. The resulting crude residue was purified by silica gel chromatography (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/AcOEt 80/20 to afford (6-methoxypyridin-3-yl)methanol (1.80 mmol, 0.26 g, 90%) as a pale oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][C:57]=2[Cl:63])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][C:57]=2[Cl:63])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)cc2Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(Cl)cc2Cl)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.9 %

Procedure:
To a solution of 81 mg of 1H-indole-7-carboxylic acid (0.5 mmol) and 161 mg of TBTU (0.5 mmol) in 10 ml DMF, were added 0.43 ml (2.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 168 mg (0.5 mmol) of (4-tert-butyl-benzyl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine were added. After stirring for 3 h at rt, the reaction mixture was diluted with 50 ml water and extracted twice with EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; heptane/EtOAc 2:1) to give 213 mg (87%) of a light yellow oil. MS(ISP) 479.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1.CCCCCC.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:26]([NH:25][C:22]4[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=4)=[O:27])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(Nc1ccc(F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Yield: 51.2 %

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (0.89 g, 3.6 mmol) and 4-fluorophenyl isocyanate (409 μL, 3.6 mmol) in THF (20 mL) are reacted according to method C yielding 0.71 g of the product as a colorless solid after column chromatography with hexane-EtOAc.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[OH:26][CH2:27][C:28](O)=[O:29]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:27](=[O:26])[CH2:28][OH:29])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)CO
Agent: Cl
Product: O=C(CO)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (14.9 mg, 46.9%), MS (ISP) m/z=389.1 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and 2-hydroxyacetic acid.
Reaction SMILES: [C:1]([N:9]1[CH2:20][CH2:19][C:12]2[N:13]=[N:14][C:15]([NH:17][NH2:18])=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]([CH3:24])=O>C(O)(=O)C>[C:1]([N:9]1[CH2:20][CH2:19][C:12]2[N:13]=[N:14][C:15]([NH:17][N:18]=[C:22]([CH3:24])[CH3:21])=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: NNc1cc2c(nn1)CCN(C(=O)c1ccccc1)C2
Solvent: CC(=O)O
Product: CC(C)=NNc1cc2c(nn1)CCN(C(=O)c1ccccc1)C2

Procedure:
A solution of 0.5 g of 6-benzoyl-3-hydrazino-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine in 15 cc of absolute acetone, to which 4 drops of glacial acetic acid have been added, is heated on a water bath for 1 hour. The solution is concentrated in a vacuum, and the crude title compound, obtained as an oil, is crystallized with ether. The title compound has a M.P. of 185°-190° (decomp.).
Reaction SMILES: C[O:2][C:3](=[O:43])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][C@H:14]([N:16]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[C:33]=2[Cl:42])[CH2:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:15])[CH:6]=1.COC(=O)CC1C=CC=C(OC[C@H](C)CN(CC2C=CC=C(C(F)(F)F)C=2Cl)CC(C2C=CC=CC=2)C2C=CC=CC=2)C=1>>[ClH:42].[Cl:42][C:33]1[C:34]([C:38]([F:39])([F:40])[F:41])=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][N:16]([CH2:17][CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C@H:14]([CH3:15])[CH2:13][CH2:12][O:11][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:43])=[O:2])[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)Cc1cccc(OCC[C@@H](C)N(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: COC(=O)Cc1cccc(OC[C@H](C)CN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Product: C[C@H](CCOc1cccc(CC(=O)O)c1)N(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Product: Cl

Procedure:
Following the procedure of Example 44 step(e) except (R)-2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-3-methyl-propoxy}-phenyl)acetic acid methyl ester was used in step 44(e) instead of (R)-2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]-2-methyl-propoxy}-phenyl)acetic acid methyl ester the title compound was isolated to give a white solid (100 mg, 89%). MS(ESI) 596.0 (M+).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1B(O)O.Br[C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+]>O.C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:10][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:10])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20]
Reactant: Cc1ccccc1B(O)O
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccc(-c2ccccc2C)c([N+](=O)[O-])c1

Procedure:
5.46 g (4.7 mmol) of Pd(PPh3)4 are added to a well-stirred, degassed suspension of 155 g (1140 mmol) of o-tolylboronic acid, 133.4 g (474.9 mmol) of 2,5-dibromonitrobenzene and 305.3 g (1435 mmol) of potassium carbonate in a mixture of 250 ml of water and 250 ml of THF, and the mixture is heated under reflux for 20 h. After cooling, the organic phase is separated off, washed three times with 200 ml of water and once with 200 ml of saturated, aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo in a rotary evaporator. The grey residue is recrystallised from hexane. The deposited crystals are filtered off with suction, washed with a little MeOH and dried in vacuo; yield: 50.5 g, 97% of theory; purity: 99.2% according to HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[Cl:13]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+].O>CN(C)C=O>[NH2:1][C:2]1[C:7]([Cl:13])=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1
Reactant: COC(=O)c1cc(N)cc(Cl)n1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(N)c(Cl)c(Cl)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
The compound prepared in Example 404 (3.120 g) and N-chlorosuccinimide (2.456 g) were suspended in dimethyl formamide (100 mL) and stirred at 50° C. overnight. The reaction mixture was heated at 70° C. for a further 3 hours. The reaction mixture was added drop-wise to a stirred solution of 1:1 saturated aqueous sodium bicarbonate and water. The slurry was filtered and the solids dried under high vacuum to furnish the title compound (2.438 g), possessing the following physical data.
Reaction SMILES: [C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH:18]([C:22]([OH:24])=[O:23])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[K+].[C:30]([O:36][CH2:37]Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].CN(C)C=O>CCOCC>[C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH:18]([C:22]([O:24][CH2:37][O:36][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[O:23])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C(O)C1CCc2c(c3ccccc3n2C(=O)c2ccccc2)C1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCOC(=O)C1CCc2c(c3ccccc3n2C(=O)c2ccccc2)C1

Procedure:
A mixture of 12.8 g. of 9-benzoyl-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 20 g. of potassium bicarbonate, 12 ml. of chloromethyl pivalate in 50 ml. of dry dimethylformamide was stirred and heated on a steambath for two hours. The mixture was cooled and diluted with ether, the ether mixture was washed several times with water, dried over magnesium sulfate, and evaporated under reduced pressure to dryness to give 10.6 g. of the title compound; m.p. 75°-77°C. (methyl alcohol).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:25])[NH:10][C@H:11]([CH2:19]OS(C)(=O)=O)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:26]=[N+:27]=[N-:28].[Na+].O.C(OCC)(=O)C>CN(C)C=O>[C:1]1([CH2:7][O:8][C:9](=[O:25])[NH:10][C@H:11]([CH2:19][N:26]=[N+:27]=[N-:28])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)OC[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 88.5 %

Procedure:
A solution of (S)-[1-[[(methylsulphonyl)oxy]methyl]-2-phenylethyl]carbamic acid phenylmethyl ester (2.0 g, 5.5 mmol) in dimethylformamide (35 ml) was heated with sodium azide (0.43 g, 6.6 mmol) at 80° C. for 4.5 h. The reaction was then cooled and poured into iced water (100 ml) and ethyl acetate (70 ml). The aqueous phase was extracted with ethyl acetate (2×70 ml) and the combined extract was washed with water (50 ml), dried (MgSO4) and evaporated to leave an oil which was purified by flash chromatography eluting with 20% ethyl acetate in cyclohexane to give the title compound (1.51 g) as an oil, MH+ =312.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([Cl:11])[CH:5]=1)=O.[NH2:12][O:13][CH2:14][C:15]([OH:17])=[O:16].C([O-])(=O)C.[Na+]>C(O)C>[CH3:1][C:2](=[N:12][O:13][CH2:14][C:15]([OH:17])=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([Cl:11])[CH:5]=1
Reactant: NOCC(=O)O
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=NOCC(=O)O)c1ccc(Cl)c(Cl)c1

Procedure:
In the manner described in example 1, the above substance was obtained by boiling 4.73 g or 3,4-dichloroacetophenone, 2.74 g of hemihydrochloride of aminooxyacetic acid and 6.15 g of sodium acetate in 80% ethanol for one hour. After one crystallisation from a mixture of benzene and petroleum ether, the melting point was 128°-129° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][CH2:14][S:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)(=[O:17])=[O:16])[CH:10]=[CH:9][C:8]=2[NH:24][C:25]([C:27]2[N:28](COCC[Si](C)(C)C)[CH:29]=[C:30]([C:32]#[N:33])[N:31]=2)=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCO>[C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][CH2:14][S:15]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)(=[O:17])=[O:16])[CH:10]=[CH:9][C:8]=2[NH:24][C:25]([C:27]2[NH:28][CH:29]=[C:30]([C:32]#[N:33])[N:31]=2)=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(CCS(=O)(=O)N2CCOCC2)cc1C1=CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(CCS(=O)(=O)N3CCOCC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.8 %

Procedure:
A solution of 221 mg (0.367 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[2-(morpholine-4-sulfonyl)-ethyl]-phenyl}-amide (as prepared in the previous step) in CH2Cl2 (20 mL) was treated with EtOH (3 drops) and TFA (1.8 mL) and stirred at RT for 2 h. Solvents were evaporated in vacuo, and the resulting residue was chromatographed on a 25-g Varian MegaBond Elut SPE column with 50-70% EtOAc-hexane to afford 6.6 mg (4%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 8.15 (d, 1H, J=8.0 Hz), 7.96 (s, 1H), 7.20 (dd, 1H, J=8.0, 2.0 Hz), 7.12 (s, 1H, J=2.0 Hz), 5.83-5.78 (m, 1H), 3.72-3.66 (m, 4H), 3.48-3.46 (m, 1H), 3.26-3.20 (m, 4H), 3.14-3.11 (m, 1H), 3.10-3.03 (m, 2H), 2.32-2.23 (m, 4H), 1.90-1.73 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C23H27N5O4S, 470.2 (M+H). found 469.9.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([N+:11]([O-])=O)=[CH:4][N:3]=1.[H][H]>C1COCC1.[Ni]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([NH2:11])=[CH:4][N:3]=1
Reactant: [H][H]
Reactant: CCNc1nc(Cl)ncc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: CCNc1nc(Cl)ncc1N
Yield: 92 %

Procedure:
To a solution of 10.0 g (50 mmol, 1.0 eq.) of 2-chloro-N-ethyl-5-nitropyrimidin-4-amine (I-1) in 300 mL of THF was added ˜4.0 g of Raney Nickel. The solution was stirred under 1 atm. of hydrogen at room temperature for 12 h. The reaction mixture was filtered through Celite® and the pad was washed with 100 mL of THF. The solvent was removed in vacuo to provide 8.0 g (46 mmol, 92%) of 2-chloro-N4-ethylpyrimidine-4,5-diamine (I-5).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([CH:16]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([CH:16]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][CH:9]=1
Reactant: OCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=Cc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4-(5-bromo-2-chlorobenzyl)phenyl)methanol (intermediate AK) (1 g) in CH2Cl2 (10 mL), the solution of Dess-Martin periodinane (DMP) (1.22 g) CH2Cl2 (10 mL) was added dropwise. 0° C. The mixture was warmed to room temperature, and the reaction was monitored by TLC. After 1 h, CH2Cl2 was added to dilute the solution and 1 M NaOH was added to quench the reaction. The CH2Cl2 layer was separated and washed with aqueous NaHSO3 and brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography to obtain pure intermediate AL (0.62 g).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](=[S:28])[NH2:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1)=O>>[F:39][C:35]1[CH:34]=[C:33]([C:31]2[N:27]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[S:28][CH:30]=2)[CH:38]=[CH:37][CH:36]=1
Reactant: O=C(CBr)c1cccc(F)c1
Reactant: NC(=S)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)cs2)C1

Procedure:
100 mg (about 0.211 mmol) of the compound from Example 115A and 55 mg (0.253 mmol) of 2-bromo-1-(3-fluorophenyl)ethanone were reacted according to the General Method 3. Yield: 78 mg (69% of theory).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)([N:25]1C=CN=C1)=O.N>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:22])[NH2:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCCC(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCCCCCCCCC(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
A mixture of 12-tert-butoxycarbonylaminododecanoic acid (3) (202 mg, 0.64 mmol) and 1,1′-Carbonyldiimidazole (114 mg, 0.70 mmol) in anhydrous THF (6 mL) was stirred at room temperature for 1 hour. Methanolic ammonia (7 M, 3 mL, 21 mmol) was then added via syringe and the reaction mixture stirred at room temperature for 16 hours. The solvent was removed by rotary evaporation and the resulting residue was subjected to Biotage silica gel column chromatography, eluting with 5% to 36% ethyl acetate in hexanes followed by 50% ethyl acetate in dichloromethane, to give the desired amide 7 (90.0 mg, 45%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.25 (m, 14H), 1.46 (s, 9H), 1.63 (m, 4H), 2.22 (t, 2H), 3.10 (m, 2H), 4.50 (br, 1H), 5.40 (br, 2H). m/z (ESI) 337 [C17H34N2O3+Na]+.