Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([CH2:13][N:14]2[C:20](=[O:21])[C@@H:19]([NH:22][C:23](=[O:35])[C@@H:24]([N:26](C)[C:27](=O)OC(C)(C)C)[CH3:25])[C@H:18]([CH3:36])[N:17]([C:37](=[O:43])[CH2:38][S:39]([CH3:42])(=[O:41])=[O:40])[C:16]3[CH:44]=[CH:45][CH:46]=[CH:47][C:15]2=3)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>Cl.O1CCOCC1.CCOCC>[ClH:1].[Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([CH2:13][N:14]2[C:20](=[O:21])[C@@H:19]([NH:22][C:23](=[O:35])[C@@H:24]([NH:26][CH3:27])[CH3:25])[C@H:18]([CH3:36])[N:17]([C:37](=[O:43])[CH2:38][S:39]([CH3:42])(=[O:40])=[O:41])[C:16]3[CH:44]=[CH:45][CH:46]=[CH:47][C:15]2=3)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1c(Cl)nc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c2ccccc21
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(C)c(Cl)nc3ccccc23)c2ccccc2N(C(=O)CS(C)(=O)=O)[C@H]1C
Reaction time: 2 h
Yield: 158.1 %

Procedure:
A rt suspension of tert-butyl(S)-1-((3S,4S)-1-((2-chloro-3-methylquinolin-4-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (61.6 mg, 89.8 μmol) in 4 M HCl in dioxane (449 μl) was stirred for 2 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((3S,4S)-1-((2-chloro-3-methylquinolin-4-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (44.2 mg, 79%) as a white solid. MS m/z 586 (MH)+.
Reaction SMILES: Br[CH2:2][C:3]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[CH2:5][CH2:4]1.[C-:14]#[N:15].[Na+].C(Cl)(Cl)Cl>CS(C)=O.[Cl-].[Na+].O>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:3]2([CH2:2][C:14]#[N:15])[CH2:5][CH2:4]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(CBr)CC2)cc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: COc1ccc(C2(CC#N)CC2)cc1

Procedure:
A crude solution of 1-(1-bromomethyl-cyclopropyl)-4-methoxybenzene (60.3 mmol) in dimethyl sulfoxide (60 mL) is treated with sodium cyanide (180.7 mmol). The reaction mixture is heated to 95 degrees Celsius overnight under nitrogen. The reaction mixture is transferred to a separatory funnel using brine (150 mL) and chloroform (300 mL). The reaction mixture is equilibrated and the aqueous layer is removed. The aqueous layer is extracted an additional two times with chloroform (2×300 mL). The combined organic extract is dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to afford [1-(4-methoxyphenyl)cyclopropyl]acetonitrile. This crude material is used in the next step (hydrolysis of the nitrile to the corresponding amide) without further purification. [Alternatively, the corresponding carboxylic acid can be obtained from this material by acid hydrolysis (e.g., using sulfuric acid).]
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:29][C:30](=O)[C:31]([CH3:34])([CH3:33])[CH3:32]>>[C:31]([C:30]1[N:26]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([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)[S:27][CH:29]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: CC(C)(C)C(=O)CBr
Product: CC(C)(C)c1csc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
100 mg (0.224 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carbothioamide (Example 53A) and 48 mg (0.269 mmol) of 1-bromo-3,3-dimethylbutan-2-one were reacted according to the General Method 3. Yield: 19 mg (17% of theory)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].O[CH2:7][CH:8]1[CH2:13][O:12][CH2:11][CH:10]([CH3:14])[O:9]1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][S:2]([CH2:7][CH:8]1[CH2:13][O:12][CH2:11][CH:10]([CH3:14])[O:9]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC1COCC(CO)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1COCC(CS(C)(=O)=O)O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
13.7 ml of methanesulphonic acid chloride are added dropwise, over a period of approximately 30 minutes, while stirring at 0° to 5° C., to a solution of 21.1 g of 2-hydroxymethyl-6-methyl-1,4-dioxan, 15.2 g of pyridine and 0.6 g of 4-dimethylaminopyridine in 80 ml of dichloromethane. After stirring for a further 18 hours at room temperature, the reaction mixture is extracted repeatedly with 1N hydrochloric acid and then washed with water until neutral. After the organic phase, which has been separated off, has been dried over sodium sulphate and the solvent has been distilled off completely, the title compound of formula ##STR55## is obtained. The 1H-proton resonance spectrum corresponds to this structure; nD22 =1.4607.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([N:14]1[CH:18]=[C:17](B(O)O)[CH:16]=[N:15]1)[CH2:10][CH:11]([CH3:13])[CH3:12].C([O-])(=O)C.[K+].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:9]([N:14]1[CH:18]=[C:17]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:16]=[N:15]1)[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)CCn1cc(B(O)O)cn1
Reactant: Brc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Product: CC(C)CCn1cc(-c2ccc(Br)cc2)cn1
Yield: 81.5 %

Procedure:
4-Bromoiodobenzene (460 mg, 1.6 mmol, 1.5 eq.), 1-isoamylpyrazole-4-boronic acid (200 mg, 1.1 mmol), potassium acetate (100 mg, 1.0 eq.), Pd(dppf)Cl2 (100 mg, 0.1 eq.), and Cs2CO3 (1 g, 3.0 eq.) in DMSO (5 mL) were heated under argon at 80° C. during 1 h. The reaction mixture was extracted from water into ether, dried Na2SO4, concentrated, and chromatographed on silica gel (0→10% EtOAc/hexanes) to give 1-isoamyl-4-(4-bromophenyl)pyrazole (263 mg, 82%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:9]=[C:10]([CH:15]([CH2:31][CH2:32][OH:33])[CH2:16][N:17]([CH3:30])[C:18]([C:20]2[C:29]3[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH:11]=[CH:12][C:13]=1[F:14].C(N(CC)CC)C.O>C(Cl)Cl.CS(C)=O>[F:7][C:8]1[CH:9]=[C:10]([CH:15]([CH2:31][CH:32]=[O:33])[CH2:16][N:17]([CH3:30])[C:18]([C:20]2[C:29]3[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: CN(CC(CCO)c1ccc(F)c(F)c1)C(=O)c1cccc2c1CCCC2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(CC(CC=O)c1ccc(F)c(F)c1)C(=O)c1cccc2c1CCCC2
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 94.6 %

Procedure:
To a stirred cooled (−78° C.) solution of oxalyl chloride (0.546 mL, 6.26 mmol) in DCM (2.55 mL) was added DMSO (0.888 mL, 12.52 mmol) in DCM (3.94). The solution was stirred at −78° C. for 5 min and a solution of N-[2-(3,4-difluorophenyl)-4-hydroxybutyl]-N-methyl-5,6,7,8-tetrahydro-1-naphthamide (1.17 g, 3.13 mmol) in DCM (6.3 mL) and DMSO (3.32 mL) was added dropwise. The solution was stirred at −78° C. for 15 min and triethylamine (2.52 mL, 18.1 mmol) was added. Stirring was continued at −78° C. for 30 min and then at room temperature for 2 h. Additional H2O and DCM (25 mL) were added, the layers separated, and the organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Purification by chromatography (silica gel; Et2O) provided the title compound (1.10 g, 95%) as a brown gum. MS m/z 372 (M+H).
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:13][C@@H:12]2[C:14](N(OC)C)=[O:15])=[CH:7][CH:6]=1>C1COCC1>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:13][C@@H:12]2[C:14](=[O:15])[CH3:1])=[CH:7][CH:6]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)[C@H]1C[C@@H]1c1ccc(F)cc1
Solvent: C1CCOC1
Product: CC(=O)[C@H]1C[C@@H]1c1ccc(F)cc1
Reaction time: 2 h

Procedure:
Methylmagnesium bromide (0.717 mL, 3M in ether, 2.150 mmol) was added dropwise to a 0° C. solution of (1S,2S)-2-(4-fluorophenyl)-N-methoxy-N-methyl cyclopropanecarboxamide (400 mg, 1.792 mmol) in THF (15 mL). After 2 h, an additional equivalent of methylmagnesium bromide (0.717 mL, 2.150 mmol) was added. The reaction was slowly quenched with sat'd ammonium chloride (2 mL). The mixture was diluted with EtOAc, washed with H2O, washed with brine, dried over magnesium sulfate, and concentrated to give (1S,2S)-1-(2-(4-fluorophenyl)cyclopropyl)ethanone as a slightly colored oil (304 mg, 95%). 1H NMR (500 MHz, CHLOROFORM-d) δ 7.12-7.04 (m, 2H), 7.03-6.95 (m, 2H), 2.53 (ddd, J=9.1, 6.5, 4.0 Hz, 1H), 2.37-2.30 (m, 3H), 2.18 (ddd, J=8.2, 5.1, 4.0 Hz, 1H), 1.67 (ddd, J=9.2, 5.1, 4.3 Hz, 1H), 1.35 (ddd, J=8.1, 6.6, 4.3 Hz, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[CH:11]=[CH:10][CH:9]=2)=[O:5])C.[OH-].[K+].CCO>>[CH:17]1([CH2:16][O:15][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:13]=2[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]3)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cc2c(OCC3CCCC3)cccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2c(OCC3CCCC3)cccc2[nH]1
Reaction time: 24 h

Procedure:
The 4-cyclopentylmethoxy-1H-indole-2-carboxylic acid ethyl ester 87 obtained above is mixed with a 2M-solution of KOH in EtOH (33.8 ml, 67.6 mmol) and stirred for 24 hours. The solvent is then evaporated and the residue is partitioned between water and ether. The water layer is acidified with HCl and extracted twice with EtOAc. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to give a white powder.
Reaction SMILES: [CH3:1][O:2][P:3](C1C=CC=CC=1)[O:4]C.CI.P([O-])[O-].[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([CH2:23][PH:3](=[O:4])[O:2][CH3:1])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COP(OC)c1ccccc1
Reactant: Cc1ccccc1
Agent: [O-]P[O-]
Solvent: CI
Product: CO[PH](=O)Cc1ccccc1
Temperature: 110 °C
Yield: 96 %

Procedure:
To a suitable vessel equipped with a stirring means, a temperature measuring means and a material addition means was charged 11 parts dimethylphenylphosphonite, 2.5 parts methyl iodide and 9 parts toluene. The resultant solution was slowly heated. The reaction is exothermic and the temperature increases to about 110° C., the reaction mixture is maintained at a temperature of about 100°-120° C., and an additional 185 parts dimethylphenylphosphonite slowly added. Additional amounts of methyl iodide, in about 1 part increments, are occasionally added during the phosphonite addition. The reaction mixture was maintained at about 110° C. for an additional hour following the addition of components. The reaction mixture was then distilled collecting the portion boiling at 148°-149° C./17 mm. (96 percent yield of methyl phenylmethylphosphinate). [Harwood and Grisley J. Am. Chem. Soc., 82, 423 (1960)]. ##STR3##
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:18]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:29]I>C1COCC1.[H-].[Na+]>[C:1]([O:5][C:6](=[O:28])[N:7]([CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([C:24]([F:25])([F:26])[F:27])[CH:18]=2)=[CH:14][CH:15]=1)[CH3:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
{2-[4-(4-Chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.1 g, 2.64 mmol, 1 eq) was dissolved in dry THF (18 ml) and NaH, 60% (316 mg, 7.92 mmol, 3 eq) was added. After 30 min, the reaction mixture was treated with methyl iodide (1.65 ml, 2.64 mmol, 10 eq) and was stirred for 3.5 h. The excess NaH was quenched by a slow addition of water, diluted with brine (40 ml) and extracted with Et2O (3×40 ml). Combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to give a product without further purification {2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethyl}-methyl-carbamic acid tert-butyl ester (1.08 g, yield=56.1%, purity=59%). [M+H]+=430.87 1H NMR (300 MHz; CDCl3) δ/ppm 1.38-1.48 (s, 9H), 2.74-2.90 (m, 4H), 3.38-3.50 (m, 2H), 6.93-7.08 (m, 3H), 7.15-7.31 (m, 3H), 7.41 (t, J=8.43 Hz, 1H)
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([NH:16][OH:17])=[CH:12][CH:11]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][C:20]=1[C:28]([F:31])([F:30])[F:29]>C(Cl)Cl>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([N:16]([OH:17])[C:13]2[CH:12]=[CH:11][C:10]([N:1]3[C:9]4[CH:8]=[CH:7][N:6]=[CH:5][C:4]=4[N:3]=[CH:2]3)=[CH:15][CH:14]=2)=[O:27])=[CH:21][C:20]=1[C:28]([F:29])([F:30])[F:31]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: ONc1ccc(-n2cnc3cnccc32)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N(O)c1ccc(-n2cnc3cnccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.4 %

Procedure:
In 5 mL of methylene chloride, 37 mg of N-(4-imidazo[4,5-c]pyridin-1-yl-phenyl)hydroxylamine obtained in Step A was dissolved, and 41 mg (1.84 mmol) of 4-chloro-3-(trifluoromethyl)phenyl isocyanate was added thereto and the mixture solution was stirred at room temperature for three hours. The reaction solution was concentrated, and then the residue was partitioned between ethyl acetate and a saturated ammonium chloride aqueous solution. The organic layer was washed with a saturated sodium chloride solution, dried and concentrated under reduced pressure. The residue was triturated with n-hexane:ethyl acetate=1:1 to obtain 12 mg (16%) of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-hydroxy-3-(4-imidazo-[4,5-c]pyridin-1-ylphenyl)urea (Table 1, Compound No. 45) as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([CH2:32][CH2:33][N:34]([CH3:62])[CH2:35][CH2:36][C:37](=O)[NH:38][C:39]3[CH:40]=[CH:41][C:42]([C:45]4[CH:50]=[C:49]([O:51][CH3:52])[C:48]([O:53][CH2:54][C:55]([F:58])([F:57])[F:56])=[C:47]([O:59][CH3:60])[CH:46]=4)=[N:43][CH:44]=3)=O)=[CH:25][N:24]=2)[CH:12]=[C:13]([O:21][CH3:22])[C:14]=1[O:15][CH2:16][C:17]([F:20])([F:19])[F:18].CO>O1CCCC1>[CH3:52][O:51][C:49]1[CH:50]=[C:45]([C:42]2[CH:41]=[CH:40][C:39]([NH:38][CH2:37][CH2:36][CH2:35][N:34]([CH3:62])[CH2:33][CH2:32][CH2:30][NH:29][C:26]3[CH:27]=[CH:28][C:23]([C:11]4[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:15][CH2:16][C:17]([F:18])([F:19])[F:20])=[C:9]([O:8][CH3:7])[CH:10]=4)=[N:24][CH:25]=3)=[CH:44][N:43]=2)[CH:46]=[C:47]([O:59][CH3:60])[C:48]=1[O:53][CH2:54][C:55]([F:56])([F:57])[F:58]
Reactant: COc1cc(-c2ccc(NC(=O)CCN(C)CCC(=O)Nc3ccc(-c4cc(OC)c(OCC(F)(F)F)c(OC)c4)nc3)cn2)cc(OC)c1OCC(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(-c2ccc(NCCCN(C)CCCNc3ccc(-c4cc(OC)c(OCC(F)(F)F)c(OC)c4)nc3)cn2)cc(OC)c1OCC(F)(F)F
Temperature: 65 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
Under nitrogen, lithium aluminum hydride (4.28 g, 113 mmol) was added to an ice-cold solution of N,N-bis[2-[N-[2-[3,5-dimethoxy-4-(2,2,2-trifluoroethoxy)phenyl]-5-pyridyl]carbamoyl]ethyl]methylamine (22.50 g, 28.3 mmol) in anhydrous tetrahydrofuran (500 mL). The ice bath was removed, and the reaction mixture was stirred at 65° C. for 1 hour. Methanol (20 mL, 490 mmol) was added to the ice-cold reaction mixture, and the ice bath was removed. Water (20 mL), diethyl ether (2 L), and anhydrous magnesium sulfate (130 g) were added, and the mixture was stirred overnight at room temperature. Insoluble materials were removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to provide N,N-bis[N-[2-[3,5-dimethoxy-4-(2,2,2-trifluoroethoxy)phenyl]-5-pyridyl]-3′-aminopropyl]methylamine as a colorless oil (20.32 mg, yield: 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]([CH:14]=O)=[CH:12][C:11]2[NH:16][N:17]=[C:18]([N:19]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:29])[C:10]=2[C:9]1=[O:30].FC(F)(F)C([NH:35]OC(C(F)(F)F)=O)=O.N1C=CC=CC=1.C1C=CC=CC=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]([C:14]#[N:35])=[CH:12][C:11]2[NH:16][N:17]=[C:18]([N:19]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:29])[C:10]=2[C:9]1=[O:30]
Reactant: O=Cc1cc2[nH]nc(N3C(=O)c4ccccc4C3=O)c2c(=O)n1-c1ccccc1Cl
Reactant: O=C(NOC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: N#Cc1cc2[nH]nc(N3C(=O)c4ccccc4C3=O)c2c(=O)n1-c1ccccc1Cl
Temperature: 25 °C
Yield: 78.6 %

Procedure:
A mixture of 5-(2-chlorophenyl)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-6-carbaldehyde obtained in Step J (260 mg), 2,2,2-trifluoro-N-(2,2,2-trifluoroacetoxyl)acetamide (140 mg), pyridine (0.100 mL) and benzene (3.10 mL) was refluxed for 1 hr, and cooled to room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (203 mg).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].C(O)C.Cl.Cl[C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1.[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[N:14]1[CH:13]=[C:12]([C:23]2[CH:24]=[CH:25][C:20]([CH:18]=[O:19])=[CH:21][CH:22]=2)[CH:17]=[N:16][CH:15]=1
Reactant: Clc1cncnc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2cncnc2)cc1
Yield: 48.7 %

Procedure:
1 M aq. Na2CO3 (20 mL) and ethanol (10 mL) were added to a solution of 5-chloropyrimidine hydrochloride (3.03 g, 20.06 mmol, prepared as described in WO 9821188), 4-formylphenylboronic acid (3.90 g, 26.01 mmol) and [1,4-bis(diphenylphosphino)butane]palladium(II) dichloride (0.60 g, 0.99 mmol) in toluene (40 mL) and the mixture was heated to reflux for 18 h. The cooled reaction mixture was diluted with ethyl acetate, washed with sat. aq. NaHCO3 and brine, dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 4:1 hexane/ethyl acetate) yielded 1.80 g (42%) of the title compound. MS 185 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[C:9]2[C:5]=1/[C:6](=[CH:17]/[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24])/[C:7](=[O:16])[NH:8]2)=[N+]=[N-].[OH-].[NH4+].[H][H]>C1COCC1.[Pt]>[NH2:1][C:4]1[C:12]([NH2:13])=[CH:11][CH:10]=[C:9]2[C:5]=1/[C:6](=[CH:17]/[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24])/[C:7](=[O:16])[NH:8]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(N=[N+]=[N-])c21
Reactant: [H][H]
Agent: [Pt]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(N)c21

Procedure:
(Z)-4-Azido-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (2.08 g, 6.37 mmol) (from Example 14) was dissolved in THF (160 mL) at r.t. Ammonium hydroxide was added (2 mL), followed by a catalytic amount of poisoned platinum on carbon (300 mg). The reaction mixture was hydrogenated in a Parr bomb under 50 psi of hydrogen for 12 h. The mixture was filtered through a cake of Celite®, the cake was washed twice with THF, and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography on Silica Gel (230-400 mesh, eluted with 75% ethyl acetate in hexanes) to yield (Z)-4,5-diamino-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 1.44 g, 84%).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[F:14][C:15]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]2[C:16]=1[C:17]1([S:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[CH2:29][CH2:28][C:27](=O)[CH2:26][CH:18]1[CH2:19][O:20]2.[NH4+].[Cl-]>O1CCCC1>[F:14][C:15]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]2[C:16]=1[C:17]1([S:31]([C:34]3[CH:35]=[CH:36][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:38][CH:39]=3)(=[O:33])=[O:32])[CH2:29][CH2:28][C:27](=[CH:5][C:3]#[N:4])[CH2:26][CH:18]1[CH2:19][O:20]2
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1CCC2(S(=O)(=O)c3ccc(C(F)(F)F)cc3)c3c(F)ccc(F)c3OCC2C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#CC=C1CCC2(S(=O)(=O)c3ccc(C(F)(F)F)cc3)c3c(F)ccc(F)c3OCC2C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. mixture of 60% NaH oil dispersion (60 mg) in tetrahydrofuran (11 mL) was added diethyl cyanomethylphosphonate (0.235 mL). After being stirred for 10 min at 0° C., 1,4-difluoro-10a-(4-trifluoromethyl-benzenesulfonyl)-6a,9,10,10a-tetrahydro-6H,7H-benzo[c]chromen-8-one (0.50 g, 1.12 mmol) was added to the resulting clear and colorless solution. After 1 h, saturated aqueous NH4Cl was added to the reaction solution. This mixture was then extracted with ethyl acetate (3×). The combined organic layers were dried over Na2SO4, filtered. and concentrated. The resulting crude residue (0.574 g) was used without further purification.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11]([CH2:15]C(O)=O)[C:12]=3[F:14])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11]([CH3:15])[C:12]=3[F:14])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)Cc1c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c2c1F
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c2c1F

Procedure:
0.5 g of the compound from Example 11 is heated to 240° C. for one hour in 5 ml of diphenyl ether. The residue remaining after distilling off the solvent consists of 0.3 g of crude product of melting point 208°-10° C. Recrystallization from ethanol gives a melting point of 226°-28°.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:36]=1O.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:33][C:36]2[CH:37]=[C:38]([CH3:41])[CH:39]=[CH:40][C:35]=2[Cl:34])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: Cc1ccc(Cl)c(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.1 %

Procedure:
Triphenylphosphine (786 mg) was added to a solution of N-tert-butoxycarbonyl-4-hydroxypiperidine (603 mg), 2-chloro-5-methylphenol (428 mg) and diethyl azodicarboxylate (522 mg) in tetrahydrofuran (10 mL) at room temperature. After stirring at room temperature for 18 hr, the reaction mixture was evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:6, v/v) to give the titled compound (489 mg) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 1.46 (s, 9H), 1.84 (m, 4H), 2.28 (s, 3H), 3.44 (m, 2H), 3.65 (ddd, J=4.0, 8.0, 12.7 Hz, 2H), 4.49 (m, 1H), 6.69 (d, J=8.0 Hz, 1H), 6.75 (s, 1H), and 7.19 (d, J=8.0 Hz, 1H).