Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COCCOC[N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:25](=[O:33])[C:26]4[C:31]([C:18]([C:19]=23)=[N:17]1)=[CH:30][CH:29]=[CH:28][C:27]=4[NH2:32].C(N(CC)CC)C.Cl>C(Cl)Cl>[C:1]([NH:32][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:26]=1[C:25](=[O:33])[C:24]1[C:19]3[C:18]2=[N:17][NH:16][C:20]=3[CH:21]=[CH:22][CH:23]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOCn1nc2c3c(cccc31)C(=O)c1c(N)cccc1-2
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc2c1C(=O)c1cccc3[nH]nc-2c13)c1ccccc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Benzoyl chloride is added to a solution of 2-(methoxyethoxymethyl)-7-aminoanthra[1,9cd]pyrazol-6-(2H)one and triethylamine in methylene chloride at 0° C. The mixture is stirred for 16 hours, quenched with water, and extracted with ethyl acetate (×2). The combined organic layer is washed with sodium bicarbonate solution, and brine, dried and evaporated. The crude reaction mixture is then taken in aqueous 6N hydrochloric acid, and heated at 80° C. for 4 hours. After cooling, the mixture is extracted with ethyl acetate (×2), washed with brine, dried, and evaporated. The residue is chromatographed on silica gel to furnish the desired amide as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([N+:16]([O-])=O)([CH3:15])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14]>C(O)C.[Ni]>[NH2:16][C:2]([CH3:15])([CH3:1])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14]
Reactant: CC(C)(CCn1c(=O)oc2ccccc21)[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CC(C)(N)CCn1c(=O)oc2ccccc21

Procedure:
11.0 g 3-(3-methyl-3-nitro-butyl)-3H-benzoxazol-2-one from the reaction described above are dissolved in 130 mL ethanol and hydrogenated with Raney nickel as catalyst at 5 bar for 20 hours. The catalyst is filtered off and the filtrate is freed from the solvent. 10% ethanolic hydrochloric acid is added, the solvent is distilled off and the residue is stirred in an acetone/diethyl ether mixture. White solid. Yield: 6.0 g (77% over 2 steps, hydrochloride); melting range=145-147° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([NH:21][C:22]1[C:23]2[N:24]=[CH:25][N:26]([C:35]=2[N:36]=[CH:37][N:38]=1)[C@@H:27]1[O:34][C@H:31]([CH2:32][OH:33])[C@@H:29]([OH:30])[CH2:28]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CO>N1C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:33][CH2:32][C@H:31]2[O:34][C@@H:27]([N:26]3[C:35]4[N:36]=[CH:37][N:38]=[C:22]([NH:21][C:13](=[O:20])[C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[C:23]=4[N:24]=[CH:25]3)[CH2:28][C@@H:29]2[OH:30])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)c1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CO
Product: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](COC(=O)c2ccc([N+](=O)[O-])cc2)O1)c1ccccc1

Procedure:
The synthesis of this product is carried out by reacting 1 eq of p-nitrobenzoyl chloride with 6-N-benzoyldeoxyadenosine for 4 hours in pyridine. After hydrolysis of the excess reagent, partial evaporation of the pyridine, extraction and evaporation of the chloroformic phase, the product is obtained by column chromatography (elution 4% methanol).
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](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([NH2:34])[CH2:32][CH3:33]>>[CH2:32]([C:31]1[N:34]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:27][N:30]=1)[CH3:33]
Reactant: CCC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: CCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
150 mg (0.373 mmol) of the compounds from Example 44A and 66 mg (0.746 mmol) of N′-hydroxypropanimidamide were reacted according to the General Method 2. Yield: 81 mg (93% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([F:9])[C:3]=1[OH:10].Cl[CH2:12][C:13](Cl)=[O:14].C([O-])([O-])=O.[K+].[K+]>>[Br:8][C:6]1[CH:5]=[C:4]([F:9])[C:3]2[O:10][CH2:12][C:13](=[O:14])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Br)cc(F)c1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COc2c(F)cc(Br)cc2N1
Yield: 97.3 %

Procedure:
2-Amino-4-bromo-6-fluorophenol (95MF2084) (0.078 g, 0.38 mmol), 2-chloroacetyl chloride (0.048 g, 0.42 mmol) and K2CO3 (0.11 g, 0.79 mmol) were mixed according to GP1 to give the title compound as a crude (95MF44) (0.091 g)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:6][C:5]2=[O:20].[CH2:21](C([Sn])=C(CCCC)CCCC)[CH2:22]CC>CS(C)=O.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>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:20])[CH:6]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:8]2)=[CH:3][C:2]=1[CH:21]=[CH2:22]
Reactant: COc1cc2[nH]c(-c3ccccc3)cc(=O)c2cc1Br
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Product: C=Cc1cc2c(=O)cc(-c3ccccc3)[nH]c2cc1OC
Temperature: 100 °C
Yield: 79.7 %

Procedure:
To a solution of 6-bromo-7-methoxy-2-phenylquinolin-4(1H)-one (1.0 g, 3.03 mmol) in DMSO (35 mL) was added tri(n-butyl)vinyltin (1.06 mL, 3.63 mmol) and finally tetrakis(triphenylphosphine)palladium (88 mg, 0.076 mmol). The mixture was then degassed using a freeze/pump/thaw cycle (2×). The mixture was then heated to 100° C. in a sealed tube for 22 h. At this time, LC-MS revealed complete consumption of the bromoquinoline). The reaction mixture was then poured into a mixture of water (200 mL) and EtOAc (200 mL) which caused solid to crash out. The solid was filtered off, washed with CH3CN, EtOAc, DCM, and then hexanes to give 7-methoxy-2-phenyl-6-vinylquinolin-4(1H)-one as a light greenish solid (670 mg, 80%). 1H NMR (400 MHz, DMSO-d6) ppm: 11.58 (s, 1H), 8.16 (s, 1H), 7.83 (m, 2H), 7.58 (m, 3H), 7.25 (s, 1H), 6.99 (dd, J=11 Hz, 17.5 Hz, 1H), 6.28 (s, 1H), 5.85 (d, J=17.5 Hz, 1H), 5.31 (d, J=11 Hz, 1H), 3.92 (s, 3H). LRMS (CI, [M+H]) Calc'd=278.1. found=278.2.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=1)[N:13]=[C:12]([Cl:18])[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:10]2[Cl:25].CN([CH:29]=[O:30])C>C1COCC1>[Cl:18][C:12]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:10]([Cl:25])[C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]([CH:29]=[O:30])[CH:8]=2)[N:13]=1
Reactant: Cc1cc(Br)cc2c(Cl)c(-c3ccccc3)c(Cl)nc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C=O)cc2c(Cl)c(-c3ccccc3)c(Cl)nc12
Temperature: -72 °C
Reaction time: 0.5 h

Procedure:
A −71° C. solution of n-BuLi (6.14 mL, 1.59 M in hexane, 9.77 mmol) under argon was treated with a solution of 6-bromo-2,4-dichloro-8-methyl-3-phenylquinoline (3.26 g, 8.81 mmol, Intermediate 3: step a) in THF (27 mL) as an intermittent fine stream over 28 minutes. After a few minutes, DMF (1.38 mL, 17.8 mmol) was added dropwise over 2 minutes to the reddish-brown reaction, and the resulting greenish-black mixture was stirred at −72° C. for 30 minutes. The reaction was removed from the cold bath and allowed to stir under ambient conditions for 10 minutes, and was then quenched in one portion with 5 M aqueous NH4Cl (7 mL), partitioned with 4:1 EtOAc/heptane (50 mL) and 5:3 4 M aqueous NaCl/5 M aqueous NaBr (40 mL), and filtered. The filter cake was dissolved in 9:1 DCM/MeOH (15 mL), and this was combined with the clear yellow organic layer filtrate and dried (Na2SO4), filtered, and concentrated. The residue was dry load flash chromatographed with a 20% DCM/heptane to 100% DCM gradient to afford the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:12][O:13][C:14]([C:16]1([NH2:29])[CH2:27][C:26]2[C:28]3[C:22]([CH:23]=[CH:24][CH:25]=2)=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:17]1)=[O:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:12][O:13][C:14]([C:16]1([NH:29][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=2[OH:1])[CH2:27][C:26]2[C:28]3[C:22]([CH:23]=[CH:24][CH:25]=2)=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:17]1)=[O:15]
Reactant: Cc1cccc(C(=O)O)c1O
Reactant: COC(=O)C1(N)Cc2cccc3cccc(c23)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(NC(=O)c2cccc(C)c2O)Cc2cccc3cccc(c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.7 %

Procedure:
To a solution of 2-hydroxy-3-methyl-benzoic acid (1.12 g, 7.4 mmol), 2-amino-2,3-dihydro-1H-phenalene-2-carboxylic acid methyl ester (2.05 g, 7.4 mmol), HATU (3.38 g, 8.9 mmol) in anhydrous DMF (28 mL) is added DIPEA (4.89 mL, 29.6 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (300 g silica gel, gradient elution: 10%-80% EtOAc in heptane) to give the pure product (22) as white solid (353 mg, 13%).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([OH:23])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12])[CH3:6].Cl[C:26]1[N:27]=[CH:28][C:29]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])=[N:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[F:24][CH:2]([F:1])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:22]=[C:21]([CH:20]=[C:10]([C:11](=[O:12])[NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=2)[CH:9]=1)[O:23][C:26]1[N:27]=[CH:28][C:29]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])=[N:30][CH:31]=1)[CH3:6]
Reactant: CN(C)C(=O)c1cnc(Cl)cn1
Reactant: C[C@@H](COC(F)F)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@@H](COC(F)F)Oc1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Reaction time: 6 h
Yield: 36.6 %

Procedure:
A mixture of 3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-hydroxy-N-(1-methylpyrazol-3-yl)benzamide (0.1 g, 0.29 mmol), 5-chloro-N,N-dimethyl-pyrazine-2-carboxamide (66 mg, 0.35 mmol) and potassium carbonate (81 mg, 0.59 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 160° C. for 6 hours. The resulting mixture was reduced in vacuo and ethyl acetate (50 mL) added. The organics were washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and reduced in vacuo. The residue was chromatographed on silica, eluting with 10-100% ethyl acetate in isohexane to give the desired compound (52 mg).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[C:17]([CH2:19][CH2:20][C:21](=[O:37])[C:22]2[S:23][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[CH:25][CH:26]=2)[CH:16]=[CH:15][C:3]=1[O:4][CH:5]([CH2:13][CH3:14])[C:6]([O:8]C(C)(C)C)=[O:7].FC(F)(F)C(O)=O>>[Br:1][C:2]1[CH:18]=[C:17]([CH2:19][CH2:20][C:21](=[O:37])[C:22]2[S:23][C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)[CH:16]=[CH:15][C:3]=1[O:4][CH:5]([CH2:13][CH3:14])[C:6]([OH:8])=[O:7]
Reactant: CCC(Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1Br)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCC(Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1Br)C(=O)O

Procedure:
2-(2-Bromo-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-phenoxy)butanoic acid is prepared from tert-butyl 2-(2-bromo-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)butanoate according to general procedure E using 17 equivalents of trifluoroacetic acid.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[C:14]([C:26]1[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][CH:27]=1)[CH:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=1)[CH2:16][CH3:17].[Br-].[Br-].[Br-].B.O>C(Cl)Cl>[CH3:1][NH:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)=[C:15]([C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)[CH2:16][CH3:17]
Reactant: CCC(C(=CCCCCCCCCCC(=O)NC)c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: B
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: CCC(=C(CCCCCCCCCCC(=O)NC)c1ccc(O)cc1)c1ccc(O)cc1
Reaction time: 1 h
Yield: 35.3 %

Procedure:
To the above dimethoxy amide 4, (117 mg, 0.22 mmol) in CH2Cl2 (1 ml) at 0° C. was added, under argon, 1.0M borane tribromide (675 μl). The solution was stirred for 1 hour, then poured into water and extracted with ether (3x). The organic solution was washed with water, dried on magnesium sulfate, and evaporated to dryness. The residue was purified by "Flash chromatography" on silica gel (Kieselgel 60, Merck, under 0.063 mm, 30 g). Elution with mixture of hexane-ethyl acetate (4:1 v/v) gave N-butyl, N-methyl-12,13-Bis (4-hydroxyphenyl)-12-pentadecenoic amide (EM-142, compound 5 with x=10) (34 mg, 31%), colorless oil, IR vmax (neat) 3300, 1600 cm-1 ; UV γmax (log ε)=235 (4.25) nm; 1H-NMR (δ, CDCl3), 0.76 (3H, t, J=7.3 Hz, --CH2CH3 ), 0.96 (3H, t, J=7.3 Hz, N (CH2)3CH3 ), 2.05-2.20 (4H, m, CH2 --C=C--CH2 --), 2.35 (2H, t, J=7.0 Hz, --CH2CON--), 2.97 and 3.00 (3H, s, --NCH3 ), 3.29 and 3.41 (2H, 2t, J=7.3 Hz, --N--CH2 --), and 6.59-7.09 (8H, m, H--Ar) ppm; MS m/e=493 (M+). ##STR49##
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]2[CH:10]([CH2:11]2)[C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][Li].[Cl-].[NH4+]>O1CCCC1.CCOCC>[CH2:1]([N:8]1[C:13]([OH:14])([CH3:16])[CH:12]2[CH:10]([CH2:11]2)[C:9]1=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]C
Reactant: O=C1C2CC2C(=O)N1Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(O)C2CC2C(=O)N1Cc1ccccc1
Temperature: -78 °C

Procedure:
3-benzyl-3-azabicyclo[3.1.0]hexane-2,4-dione(U.S. Pat. No. 4,183,857, 1.9 gm, 9.5 mmol) was dissolved in 100 ml of tetrahydrofuran and cooled to −78° C. Methyllithium (10.5 ml of a 0.98M solution in ether, 10.2 mmol) was added dropwise. Saturated aqueous ammonium chloride was added to the cold reaction mixture; the mixture was then extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo to provide the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH2:8].CN(C)/[CH:11]=[C:12](/[C:18](=[O:27])[C:19]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][C:20]=1F)\[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>O>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:20]2[C:19](=[CH:24][C:23]([I:25])=[CH:22][CH:21]=2)[C:18](=[O:27])[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11]1
Reactant: N[C@H]1CCCC[C@@H]1N
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cn([C@H]2CCCC[C@@H]2N)c2ccc(I)cc2c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
(1S,2S)-(+)-1,2-Diaminocyclohexane (500 mg, 4.3 mmol) was added to the solution of (Z)-ethyl-3-(dimethylamino)-2-(3-iodobenzoyl)acrylate (Intermediate 24, 0.34M, 11.7 mL, 3.9 mmol) and the mixture was heated at 50° C. for 3 h. The solvent was removed in vacuo and the residue was dried in a vacuum oven for 1.5 h. The residue was then dissolved in dimethyl formamide (7 mL) and potassium carbonate powder (753 mg, 5.5 mmol) was added. The reaction was heated at 70° C. for 3 h then cooled to room temperature. Water (30 mL) was added and the suspension was extracted with 1:1 ethyl acetate:methyl tert-butyl ether (3×50 mL). The organic layers were dried over sodium sulfate, and the solvent was removed in vacuo. The residue was suspended in methyl tert-butyl ether (20 mL) and stirred at 40° C. for 1 h. The suspension was filtered and the solid dried to give 724 mg (42% yield) of ethyl 1-((1S ,2S)-2-aminocyclohexyl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate as a yellowish powder that was contaminated with about 40% bis dihydroquinoline. This material was used as is in the coupling step.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=[O:8].[CH3:10]O>>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: CO
Reactant: O=C(O)c1sccc1Br
Product: COC(=O)c1sccc1Br

Procedure:
The 3-bromothiophene-2-carboxylic acid was first protected at the carboxylic group. 3-bromothiophene-2-carboxylic acid was dissolved in methanol containing catalytic DCC. Mixture was reacted by refluxing overnight. After solvent was evaporated, the residues were applied on silica gel. Methyl 3-bromothiophene-2-carboxylate was obtained as a colorless liquid.
Reaction SMILES: O[C:2]1[C:3](=[O:22])[N:4]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[N:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH3:23]>>[NH2:23][C:2]1[C:3](=[O:22])[N:4]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[N:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=c1c(O)c([N+](=O)[O-])cnn1Cc1cccc2ccccc12
Reactant: N
Product: Nc1c([N+](=O)[O-])cnn(Cc2cccc3ccccc23)c1=O
Temperature: 130 °C

Procedure:
9.4 g (31.6 mmol) of 4-hydroxy-2-naphthalen-1-ylmethyl-5-nitro-2H-pyridazin-3-one were combined with 150 ml saturated methanolic ammonia solution and heated to 130° C. for 24 hours in a Roth bomb. The mixture was concentrated down to a volume of about 40 ml using the rotary evaporator, the product precipitated was suction filtered and recrystallised from tetrahydrofuran.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[O:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=4[NH2:29])=[CH:20][CH:21]=3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.[C:31](Cl)(=[O:33])[CH3:32]>>[CH3:30][N:2]([CH3:1])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[O:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=4[NH:29][C:31](=[O:33])[CH3:32])=[CH:20][CH:21]=3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1
Reactant: Cc1ccc(-c2ccc(C(=O)Nc3ccc(N4CCC(N(C)C)C4)cc3)o2)c(N)c1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1cc(C)ccc1-c1ccc(C(=O)Nc2ccc(N3CCC(N(C)C)C3)cc2)o1

Procedure:
5-(2-Amino-4-methylphenyl)furan-2-carboxylic acid [4-(3-dimethylamino-pyrrolidin-1-yl)-phenyl]amide was reacted with acetyl chloride by method Q. This resulted in the product with the molecular weight of 446.23 (C26H30N4O3); MS (ESI): 447 (M+H+).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([Si:7]([CH3:31])([CH3:30])[O:8][CH2:9][CH2:10][CH:11]([C:19](=[O:29])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][CH:23]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([CH3:6])[CH3:5]>CO>[CH3:6][C:4]([Si:7]([CH3:30])([CH3:31])[O:8][CH2:9][CH2:10][CH:11]([CH:19]([OH:29])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][CH:23]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])([CH3:3])[CH3:5]
Reactant: CC(C)(C)OC(=O)C(CCO[Si](C)(C)C(C)(C)C)C(=O)CCc1ccc(I)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)C(CCO[Si](C)(C)C(C)(C)C)C(O)CCc1ccc(I)cc1
Reaction time: 1.5 h
Yield: 67.7 %

Procedure:
Sodium borohydride (0.59 g, 15.6 mmol) was added portion wise to a stirred solution of 1,1-dimethylethyl 2-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-5-(4-iodophenyl)-3-oxopentanoate (7.55 g, 14.2 mmol) in methanol (100 mL) at 0° C. under nitrogen. On completion of addition stirring was continued for 1.5 h then the reaction was quenched with saturated aqueous ammonium chloride solution (100 mL). The resulting mixture was extracted with diethyl ether (3×200 mL) then the organic layers were combined, washed with brine (100 mL), dried (sodium sulfate) and the solvent evaporated. The residue was chromatographed on silica gel (25% to 50% diethyl ether: cyclohexane) to give the title compound (5.14 g, 68%) as a colourless oil which was a mixture of diastereomers. LC/MS: 4.72 min; z/e 535, calcd (M+1) 535. 1H NMR (400 MHz: CDCl3): 7.55 (2H), 6.95 (2H), 3.85-3.55 (3H), 3.30 (1H minor), 3.00 (1H major), 2.80 (1H), 2.65 (1H), 2.55 (1H major), 2.50 (1H minor), 1.95-1.65 (4H), 1.45 (9H), 0.90 (9H), 0.5 (6H).
Reaction SMILES: [CH:1]([OH:3])=O.C1CO[C:6]2([CH2:11]C[CH:9]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)O1>O>[CH2:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:9]2[CH2:8][CH2:7][CH2:6][CH2:11][C:1]2=[O:3])=[CH:17][CH:16]=1)[CH2:19][CH3:20]
Reactant: O=CO
Reactant: CCCc1ccc(C2CCC3(CC2)OCCO3)cc1
Solvent: O
Product: CCCc1ccc(C2CCCCC2=O)cc1

Procedure:
To 300 ml of formic acid (99%) was put 84 g of the 1,1-ethylenedioxy-4-(4-n-propylphenyl)cyclohexane mentioned above, and stirred under a reflux for 2 hours. After cooled, the reaction solution was added to 500 ml of water and extracted with 500 ml of ethyl acetate. Organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under a reduced pressure to obtain 65.6 g of 4-n-propylphenylcyclohexanone.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH:14]=[C:13]([C:27]([F:30])([F:29])[F:28])[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:51][C:50](Cl)=[N:49][C:48]=1[CH3:53])(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].CCCCCCC>C1(C)C=CC=CC=1.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>[C:39]([NH:43][S:44]([C:47]1[S:51][C:50]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=4)[CH:14]=[C:13]([C:27]([F:30])([F:29])[F:28])[N:12]=3)[CH:10]=2)=[N:49][C:48]=1[CH3:53])(=[O:45])=[O:46])([CH3:42])([CH3:41])[CH3:40]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(-c3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)n2)cn1
Reactant: Cc1nc(Cl)sc1S(=O)(=O)NC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: Cc1nc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)sc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Yield: 25.1 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridine (Example G.12) (0.570 g, 0.88 mmol), 2-chloro-4-methyl-thiazole-5-sulfonic acid tert-butylamide (Example H.5) (0.266 g, 0.99 mmol), tetrakis(triphenylphosphine)palladium (0.061 g, 0.046 mmol) in toluene (6 mL) was heated under reflux conditions for 16 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (130 mg, 25%). MS (ISP) 590.4 [(M+H)+]; mp 260° C.