Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH4+:2].[Cl:3][C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=O>>[Cl:3][C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6]#[N:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: [NH4+]
Agent: [Cl-]
Product: N#Cc1ccc(Cl)cc1Cl
Temperature: 230 °C
Yield: 699.5 %

Procedure:
The reaction was performed as in Example 1. The following reactants were charged to the reactor: 2,4-DCBTC (132.8 g, 0.5 mol), ammonium chloride (28.1 g, 1.05 eq), and 2,4-dichlorobenzoyl chloride (13.3 g). The mixture was heated at 230° C. for 14 h. Distillation of the reaction mixture gave pure 2,4-dichlorobenzonitrile (2,4-DCBN) (76.4 g, 89% yield, melting point: 59°-60° C.).
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([NH:25][C:26]([NH:28][C:29](=[O:37])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[S:27])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1.Cl.[CH3:39][NH:40][CH3:41].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:39][N:40]([CH3:41])[CH:17]1[CH2:18][CH2:19][N:14]([C:12]([NH:11][C:7]2[CH:6]=[C:5]([O:4][C:3]3[CH:21]=[CH:22][C:23]([NH:25][C:26]([NH:28][C:29](=[O:37])[CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[S:27])=[CH:24][C:2]=3[F:1])[CH:10]=[CH:9][N:8]=2)=[O:13])[CH2:15][CH2:16]1
Reactant: CNC
Reactant: O=C1CCN(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)ccn2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)C1CCN(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)ccn2)CC1
Reaction time: 8 h
Yield: 56.8 %

Procedure:
To a solution of 4-{2-fluoro-4-[3-(2-phenylacetyl)thioureido]phenoxy}-2-[(4-oxopiperidin-1-yl)carbonylamino]pyridine (38 mg) in dichloromethane (2.0 ml) were added dimethylamine HCl (15 mg) and sodium triacetoxyborohydride (40 mg) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under a reduced pressure to give a residue, which was dried in vacuum to provide the titled compound (22.8 mg, 57%) as white powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]([F:34])([F:33])[O:22][C:23]1[CH:24]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:14]=[C:15]([NH:19][S:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([O:22][C:21]([F:20])([F:33])[F:34])[CH:24]=3)(=[O:31])=[O:30])[CH:16]=[CH:17][CH:18]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(OC(F)(F)F)c1
Reactant: Nc1cccc([C@@H]2CCN(Cc3ccccc3)C2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1cccc([C@@H]2CCN(Cc3ccccc3)C2)c1)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
(S)-1-Benzyl-3-(3-amino-phenyl)-pyrrolidine (0.4 g, 1.59 mmol) and commercially available 3-trifluoromethoxy-benzene sulfonylchloride (0.39 g, 1.5 mmol) were dissolved in 30 ml tetrahydrofurane. 0.66 ml of triethylamine (3.75 mmol) were added and the mixture was stirred for 16 h at room temperature. The solvent was evaporated under reduced pressure and the residue was treated with water/diethylether. After adjusting the aqueous phase to alkaline pH with 1 N aqueous NaOH, the aqueous layer was extracted with diethylether and the combined organic layers dried over magnesium sulfate, filtered and evaporated. The product was purified via silica gel chromatography using an Isco Companion semi-automated chromatography system to yield 0.512 g of the desired compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][C:17]3[C:23](=[O:24])[N:22]([CH2:25][CH3:26])[CH2:21][CH2:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:25]([N:22]1[CH2:21][CH2:20][C:18]2[N:19]=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:15]=[CH:16][C:17]=2[C:23]1=[O:24])[CH3:26]
Reactant: [H][H]
Reactant: CCN1CCc2nc(N3CCN(Cc4ccccc4)CC3)ncc2C1=O
Agent: [Pd]
Solvent: CCO
Product: CCN1CCc2nc(N3CCNCC3)ncc2C1=O
Yield: 96.1 %

Procedure:
Dissolved in 20 ml of ethanol was 0.70 g of 2-(4-benzylpiperazino)-6-ethyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (Referential Example 38), followed by an addition of 10% Pd-C. The resultant mixture was stirred at 60° C. for 4 hours in a hydrogen atmosphere. After allowing the reaction mixture to cool down, the catalyst was filtered off and the filtrate was concentrated to obtained 0.50 g of 6-ethyl-5-oxo-2-piperazino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine as crystals (yield: 96%). The crystals were purified by their immersion in ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:23]=2[C:24]([NH2:26])=[O:25])[C:18]([Cl:32])=[CH:17][N:16]=1>>[Cl:32][C:18]1[C:19]([NH:21][C:22]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:23]=2[C:24]([NH2:26])=[O:25])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: NC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Product: NC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3)ncc1Cl

Procedure:
Title compound was prepared from 8-Amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-benzamide in an analogous manner to Example 1221d. Title compound isolated as a moss green solid (86 mg, 69%). HPLC purity 90%, LCMS 443.03 (M+H), HNMR (DMSO) 9.92 (bs, 1H), 9.82 (bs, 1H), 9.32 (s, 1H), 8.30 (d, J=1.9 Hz, 1H), 8.03 (s, 1H), 7.71 (s, 1H), 7.54 (s, 1H), 7.47-7.38 (m, 3H), 7.15-7.13 (m, 1H), 6.99-6.90 (m, 2H). 2.60-2.56 (m, 2H), 2.07-2.03 (m, 4H).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[Cl:10][C:11]1[C:12]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)=[N:13][NH:14][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:6]([O:5][C:3]([CH2:2][N:14]1[CH:15]=[C:11]([Cl:10])[C:12]([C:16]2[CH:17]=[C:18]([Cl:23])[CH:19]=[C:20]([Cl:22])[CH:21]=2)=[N:13]1)=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: Clc1cc(Cl)cc(-c2n[nH]cc2Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Cn1cc(Cl)c(-c2cc(Cl)cc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94 %

Procedure:
A solution of 5.00 g (0.033 mol) of t-butyl chloroacetate in 30 ml of DMF is run, dropwise and at room temperature, into a mixture of 7.62 g (0.030 mol) of 4-chloro-3-(3,5-dichlorophenyl)pyrazole and 5.60 g (0.040 mol) of K2CO3. The reaction mixture is stirred for 12 h at room temperature, diluted with 200 ml of H2O and extracted with ether. After drying the organic phase and concentration under vacuum, the residue is triturated with 20 ml of heptane, filtered and dried. We obtain 10.20 g of 1-t-butoxycarbonylmethyl-4-chloro-3-(3,5-dichlorophenyl)pyrazole, melting at 86° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:30]=[C:31]([C:35]2[C:36]([O:41][CH3:42])=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:32]=[CH:33][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:33]4[CH:34]=[CH:29][CH:30]=[C:31]([C:35]5[C:36]([O:41][CH3:42])=[N:37][CH:38]=[CH:39][CH:40]=5)[CH:32]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: COc1ncccc1-c1cccc(Br)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccnc5OC)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-(3-bromo-phenyl)-2-methoxy-pyridine.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]([O:32][CH3:33])[CH:26]([CH3:31])[CH2:27][CH2:28][CH2:29][CH3:30])[CH:12]=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1.[H][H]>[C].[Pd].CO.C(OCC)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][CH:25]([O:32][CH3:33])[CH:26]([CH3:31])[CH2:27][CH2:28][CH2:29][CH3:30])[CH:12]=[CH:13][C:14]=1[OH:15]
Reactant: [H][H]
Reactant: CCCCC(C)C(C=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)OC
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCC(C)C(CCc1ccc(O)c(O)c1)OC
Yield: 98.4 %

Procedure:
Using 0.1 g of 10% palladium-carbon as catalyst, 560 mg of 1-(3,4-dibenzyloxyphenyl)-3-methoxy-4-methyl-1-octene was catalytically reduced in a mixture of 5 ml of methanol and 5 ml of ethyl acetate until the absorption of hydrogen stopped. Thereafter, the catalyst was filtered off and the filtrate was concentrated under reduced perssure to provide 330 mg of oily 1-(3,4-dihydroxyphenyl)-3-methoxy-4-methyl-octane.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[NH:10][N:11]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[CH:13]=2)[C:3]=1[N+:17]([O-])=O.C(OC([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([NH2:36])[CH:34]=2)[C:29](=[O:37])[NH:28]1)=O)(C)(C)C.C(N(C(C)C)CC)(C)C>C1COCC1>[NH2:17][C:3]1[C:2]([NH:36][C:33]2[CH:34]=[C:35]3[C:30]([C:29](=[O:37])[NH:28][NH:27]3)=[CH:31][CH:32]=2)=[N:7][CH:6]=[N:5][C:4]=1[NH:8][C:9]1[NH:10][N:11]=[C:12]([CH:14]2[CH2:16][CH2:15]2)[CH:13]=1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Nc1cc(C2CC2)n[nH]1
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2ccc(N)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1c(Nc2ccc3c(=O)[nH][nH]c3c2)ncnc1Nc1cc(C2CC2)n[nH]1
Temperature: 25 °C
Reaction time: 14 h
Yield: 33.6 %

Procedure:
To a solution of (6-chloro-5-nitro-pyrimidin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (50 mg, 0.18 mmol) in anhydrous THF (2 mL) was added 6-amino-3-oxo-2,3-dihydro-indazole-1-carboxylic acid tert-butyl ester (67 mg, 0.27 mmol) and diisopropylethylamine (23 mg, 0.18 mmol). The mixture was stirred at RT for 14 hrs and the solvents were removed under vacuum. The residue was dissolved in CH2Cl2 (3 mL) and treated with TFA (2 mL) at RT for 2 hrs. After removal of the solvents via evaporation, the residue was reduced by hydrogen (50 psi) in MeOH (10 mL) in the presence of Pd/C (10%, 50 mg) for 3 hrs. The solution was filtered via celite, the filtrate was evaporated under vacuum, and the residue was purified by HPLC to give the desired product as white solid (22 mg). NMR (500 MHz, DMSO-d6) δ11.16 (br, 1H), 9.92 (br, 1H), 8.98 (s, 1H), 8.27 (s, 1H), 7.67 (s, 1H), 7.55 (d, 1H), 7.08 (d, 1H), 5.95 (s, 1H), 2.00 (m, 1H), 1.06 (m, 2H), 0.81 (m, 2H) ppm. MS (ES+): m/e=364.3 (M+H); LC/Method A/2.45 min.
Reaction SMILES: C(Br)C1C=CC=CC=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH2:16]([NH:23][C:24]([C:26]1[S:30][C:29]([N:31]2[CH2:35][CH2:34][NH:33][C:32]2=[O:36])=[N:28][C:27]=1[CH3:37])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([NH:23][C:24]([C:26]1[S:30][C:29]([N:31]2[CH2:35][CH2:34][N:33]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:32]2=[O:36])=[N:28][C:27]=1[CH3:37])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1nc(N2CCNC2=O)sc1C(=O)NCc1ccccc1
Agent: BrCc1ccccc1
Product: CCOC(=O)CN1CCN(c2nc(C)c(C(=O)NCc3ccccc3)s2)C1=O
Yield: 38 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with ethyl bromoacetate to react with N-benzyl-4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a white solid in 38% yield: 1H NMR (300 MHz, CDCl3) δ 7.39-7.27 (m, 5H), 5.87 (t, J=5.4 Hz, 1H), 4.57 (d, J=5.4 Hz, 2H), 4.27-4.13 (m, 4H), 4.08 (s, 2H), 3.76-3.68 (m, 2H), 2.63 (s, 3H), 1.29 (t, J=7.1 Hz, 3H); MS (ES+) m/z 403.2 (M+1).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]1([S:11]([N:14]2[C:22]3[C:17](=[C:18]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OC(=O)C)(=O)C>[N+:1]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[N:14]([S:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)(=[O:12])=[O:13])[CH:15]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)OC(=O)Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)Cc1cccc2c1c([N+](=O)[O-])cn2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To acetic anhydride (5 mL) at 0° C. was added 90% nitric acid (0.183 mL, 3.90 mmol) and the resulting mixture was aged for 10 min, then added dropwise to a solution of tert-butyl [1-(phenylsulfonyl)-1H-indol-4-yl]acetate from Step B (1.00 g, 2.69 mmol) in acetic anhydride (5 mL) at −78° C. The reaction mixture was stirred at −78° C. for 6 h, then aged at −20° C. for 16 h, then quenched with H2O and extracted with EtOAc (2×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 70:30, to give the title compound. MS: m/z=361 (M−C4H7).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([CH3:10])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:30])=[C:4]([CH3:10])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)ccc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(Br)ccc1CBr
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of (4-bromo-2-methyl-phenyl)-methanol (Intermediate 133, 319.0 mg, 1.58 mmol) and triphenylphosphine (466.0 mg, 1.74 mmol) in 5 mL CH2C12 was cooled to 0° C. and N-bromosuccinimide (309.0 mg, 1.74 mmol) was added in 5 portions over 20 minutes. The solution was warmed to 25° C. and stirred for 17 hours. The reaction was quenched by the addition of dilute aqueous NaHCO3. The resulting mixture was extracted with Et2O and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (Na2SO4) and concentrated under reduced pressure. The title compound, 350.0 mg (84%), was isolated by column chromatography (2-3% EtOAc-hexanes) as a colorless oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:20][C:21]1[C:30]([CH2:31][CH2:32][CH3:33])=[C:29]2[C:24]([CH2:25][CH2:26][CH:27]([C:34]([O:36][CH3:37])=[O:35])[O:28]2)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:38](C1NC=CN=1)(=[O:40])[CH3:39].S([O-])(O)(=O)=O.[K+]>O1CCCC1>[C:38]([C:27]1([C:34]([O:36][CH3:37])=[O:35])[CH2:26][CH2:25][C:24]2[C:29](=[C:30]([CH2:31][CH2:32][CH3:33])[C:21]([O:20][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:22][CH:23]=2)[O:28]1)(=[O:40])[CH3:39]
Reactant: CC(=O)c1ncc[nH]1
Reactant: CCCc1c(OCc2ccccc2)ccc2c1OC(C(=O)OC)CC2
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCc1c(OCc2ccccc2)ccc2c1OC(C(C)=O)(C(=O)OC)CC2
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 63.3 %

Procedure:
A 100 ml 3 neck roundbottom flask was fitted with a magnetic stirring bar, dropping funnel, serum cap, and gas inlet tube, flushed with argon and flame dried. 1.11 g or 1.54 ml (11 mmole) of diisopropylamine and 30 ml dry tetrahydrofuran were added. After cooling to -20° C., 6.43 ml of 1.71M n-butyl lithium (11 mmole) was added dropwise via syringe. The solution was stirred 15 minutes at -10° C. and then cooled to -70° C. 3.40 g (10 mmole) of the product of Example 22 in 20 ml tetrahydrofuran at -70° C. was added dropwise over a period of half hour. After stirring one additional hour at -70° C., 1.27 g (11.5 mmole) of acetylimidazole in 10 ml tetrahydrofuran was added and the reaction mixture allowed to warm slowly to -10° C. 0.5M potassium hydrogen sulfate solution was added until the pH reached 2.0, the layers were separated and 100 ml ethyl acetate was added. The organic layer was washed with 0.5M potassium hydrogen carbonate, twice with water and then dried with anhydrous magnesium sulfate. After filtration, the ethyl acetate was removed by rotary evaporation and the residual oil purified by high pressure liquid chromatography (10% ethyl acetate-hexane) to give 2.42 g (63%) of the title compound as an oil. Calc: C, 72.22; H, 6.85; Found: C, 72.43; H, 6.86.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[OH-].[Na+].O.Cl[C:10]1[N:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[N:11]=1>CC(C)=O>[Cl:17][C:12]1[CH:13]=[C:14]([Cl:16])[N:15]=[C:10]([NH:4][C:3]([NH2:5])=[NH:2])[N:11]=1
Reactant: N=C(N)N
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: N=C(N)Nc1nc(Cl)cc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.7 %

Procedure:
A solution of 141.8 g (1.48 mole) of guanidine hydrochloride, 59.3 g (1.48 m) of sodium hydroxide and 709 ml of water was added to a solution of 183.4 g (0.74 m) of 2,4,6-trichloropyrimidine in 2127 ml of acetone causing a mild exothermic reaction. After stirring for 1 hour at room temperature, a mixture of solid and oil had formed. Refrigeration caused complete crystallization. The crystals were filtered, then suspended in 1200 ml of water and stirred for 1 hour, filtered, washed with water, then acetone and air dried to give 53.0 g (35%) of 4,6-dichloro-2-guanidinopyrimidine, mp>360°.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([S:14][CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:19][NH2:20]>>[CH3:19][NH:20][C:16](=[O:18])[CH2:15][S:14][CH:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CN
Reactant: CCCC(SCC(=O)O)c1ccc2c(c1)OCO2
Product: CCCC(SCC(=O)NC)c1ccc2c(c1)OCO2

Procedure:
2.5 g of the title compound was prepared from 2.7 g of [{1-(1,3-benzodioxol-5-yl)butyl}thio]acetic acid by using a 40% aqueous solution of methylamine as a colorless oil according to the same procedure as that described in Example 27.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH3:6].Br[C:8]1[N:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Br:31])[C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:17][CH:18]=2)=[N:11][N:12]=1>C(Cl)(Cl)Cl>[Br:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[N:9]1[C:10]([C:13]2[CH:18]=[N:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[N:11][N:12]=[C:8]1[N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH3:6]
Reactant: Brc1ccccc1-n1c(Br)nnc1-c1ccc(-c2ccccc2)nc1
Reactant: CNCCOC
Solvent: ClC(Cl)Cl
Product: COCCN(C)c1nnc(-c2ccc(-c3ccccc3)nc2)n1-c1ccccc1Br
Temperature: 200 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
In a sealed tube, N-(2-methoxyethyl)methylamine (3 ml) was added to 5-[5-bromo-4-(2-bromophenyl)-4H-1,2,4-triazol-3-yl]-2-phenylpyridine (1.0 g) prepared in the Production Example 3, and stirred at 180° C. for 13 hours and at 200° C. for 24 hours. After the reaction solution was cooled to ambient temperature, chloroform was added to the solution, which was then washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resulting residue was washed with ethyl acetate, to afford the entitled compound as white solid (711 mg, 70%). The physico-chemical values are as follows.
Reaction SMILES: C(OC(N1CCC([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([N+:25]([O-:27])=[O:26])=[CH:17][N:16]=2)CC1)=O)(C)(C)C.[C:28](O)([C:30](F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[N+:25]([C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([O:14][N:16]2[CH2:30][CH2:28][CH2:23][CH2:24][CH2:15]2)=[N:16][CH:17]=1)([O-:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncc([N+](=O)[O-])c3ccccc23)CC1
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc(ON2CCCCC2)c2ccccc12
Temperature: 22 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a cold solution of 4-(4-nitro-isoquinoline-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (9.68 g, 25.9 mmol, 0° C.) in DCM (100 mL) add TFA (80 mL). Stir at 22° C. for 2 hours, then remove solvent under reduced pressure. Dissolve residue in DCM and treat with 1 N sodium hydroxide to pH˜14. Isolate the aqueous phase and extract twice with DCM. Combine the organic phases and dry with anhydrous sodium sulfate. Removal of the solvent gives (4-nitro-isoquinoline-1-yloxy)-piperidine (7.06 g, 99% yield, ES+ (m/z) 274.3 [M+H]).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][CH:10]([CH2:11]3)[N:9]3[C:5](=[N:6][C:7]([C:17]([NH2:19])=[O:18])=[CH:8]3)[C:4]=2[CH:3]=1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C@:26]([OH:30])([C:28]#[CH:29])[CH3:27])[N:22]=1>>[OH:30][C@:26]([C:23]1[N:22]=[C:21]([CH3:20])[O:25][N:24]=1)([CH3:27])[C:28]#[C:29][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][CH:10]([CH2:11]3)[N:9]3[C:5](=[N:6][C:7]([C:17]([NH2:19])=[O:18])=[CH:8]3)[C:4]=2[CH:3]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1C1CC2C1
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Product: Cc1nc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)cn2C2CC3C2)no1

Procedure:
9-Bromo-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7(12),8,10-pentaene-4-carboxamide (0.15 g) was reacted with (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol similar to as described in Procedure G to afford 24.2 mg of 9-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-yn-1-yl]-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7(12),8,10-pentaene-4-carboxamide following reverse phase hplc purification. MS (Q1) 390.1 (M)+. 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 7.84 (s, 1H), 7.52 (s, 1H), 7.30 (s, 2H), 7.09 (s, 1H), 6.72 (s, 1H), 4.98-4.88 (m, 1H), 3.78-3.68 (m, 1H), 3.15-3.02 (m, 2H), 2.62 (s, 3H), 1.85 (s, 3H), 1.66 (d, J=11.9 Hz, 2H).
Reaction SMILES: [Br:1]/[CH:2]=[CH:3]\[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:14][C:15]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[Br:1]/[CH:2]=[CH:3]\[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[C:15]=2[CH3:14])=[CH:8][CH:7]=1
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: O=Cc1ccc(OC/C=C\Br)cc1
Product: Cc1c(NCc2ccc(OC/C=C\Br)cc2)cccc1[N+](=O)[O-]

Procedure:
The product from Example 57A and 2-methyl-3-nitroaniline were processed as described in Example 6A to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=[O:20])=[CH:15][CH:14]=2)=[CH:11][CH:10]=[N:9]1.[C:22]1([CH3:31])[CH:27]=[CH:26][C:25]([CH2:28]C#N)=[CH:24][CH:23]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]3=[N:19][O:20][C:31]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[C:15]3[CH:14]=2)=[CH:11][CH:10]=[N:9]1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccccc2F)cc1
Reactant: Cc1ccc(CC#N)cc1
Product: Cc1ccc(-c2onc3ccc(-c4ccnn4-c4ccccc4F)cc23)cc1

Procedure:
The title compound, light green solid (92 mg, 71%), MS (ISP) m/z=370.1 [(M+H)−], mp 173° C., was prepared in accordance with the general method of example 1 from 1-(2-fluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate B) (100 mg, 353 μmol) and commercially available 2-(p-tolyl)-acetonitrile.