Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([CH2:21][C:22](O)=[O:23])[C:6](=[O:25])[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:4]=1[CH3:36])#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:61][CH2:62][CH2:63][OH:64].C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:18])=[O:19])[N:7]([CH2:21][C:22]([NH:61][CH2:62][CH2:63][OH:64])=[O:23])[C:6](=[O:25])[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:27]=2)[C:4]=1[CH3:36])#[N:2]
Reactant: NCCO
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)O)C(=O)N1c1cccc(C(F)(F)F)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: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)NCCO)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 81.9 %

Procedure:
The reaction was carried out under argon. 2-[(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]acetic acid (45 mg, 87 μmol; Example 21) was initially charged in DMF (1.5 ml), HATU (165 mg, 434 μmol, 5 eq.) was added at 0° C. and the mixture was stirred for 20 min. 2-Aminoethanol (26.5 mg, 434 μmol, 5 eq.) and N,N-diisopropylethylamine (56 mg, 434 μmol, 5 eq.) were then added, and the mixture was stirred at RT for 16 h until complete conversion had been achieved (HPLC control). The reaction mixture was then concentrated under reduced pressure, and the crude product was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a colorless solid (40 mg, 82% of theory).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([NH:15][C:16]([C:18]2[C:19]3[C:33]([CH3:34])=[N:32][N:31]([CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][O:36]4)[C:20]=3[N:21]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])([CH3:14])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH3:14][C:11]1([NH:15][C:16]([C:18]2[C:19]3[C:33]([CH3:34])=[N:32][N:31]([CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][O:36]4)[C:20]=3[N:21]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=3)[CH:23]=2)=[O:17])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C(=O)NC3(C)CCN(Cc4ccccc4)CC3)c12
Agent: [Pd]
Solvent: CO
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C(=O)NC3(C)CCNCC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of 6-(4-hydroxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (1-benzyl-4-methyl-piperidin-4-yl)-amide (136 mg) in methanol (2 mL) was added palladium (10% on charcoal, 27 mg). Argon was purged through the mixture, then the mixture was saturated with hydrogen and stirred at r.t. overnight. The catalyst was filtered off, the residue was concentrated in vacuo, the residue was re-dissolved in fresh methanol (2 mL) and fresh palladium (10% on charcoal, 27 mg) was added. The mixture was again stirred at r.t. for 1 week. The catalyst was filtered off, the residue was concentrated in vacuo to give 75 mg (66%) of the title compound.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[C:12]([CH3:14])([CH3:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([Cl:15])[CH:10]=2)[C:5]1=O.O.[NH2:20][CH2:21][C@H:22]([OH:24])[CH3:23]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:15][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:16][CH3:17])[C:5]1[N:20]([CH2:21][C@H:22]([OH:24])[CH3:23])[CH:2]=[CH:3][C:4]=1[C:12]2([CH3:14])[CH3:13]
Reactant: COc1cc2c(cc1Cl)C(C)(C)C(CC=O)C2=O
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1Cl)C(C)(C)c1ccn(C[C@@H](C)O)c1-2
Reaction time: 0.75 h
Yield: 91.5 %

Procedure:
A solution of 6.67 g of (RS)-2-(2-oxoethyl)-5-chloro-6-methoxy-3,3-dimethyl-1-indanone and 150 mg of p-toluenesulfonic acid in 200 ml of anhydrous toluene was heated on a water separator. A solution of 7.51 g of (R)-1-amino-2-propanol in 40 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 40 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/hexane 1:1). 7.0 g (92%) of (R)-1-(6-chloro-7-methoxy-4,4-dimethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: CC1CCCN(C)C1(C)C.[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=1.CN(C)[CH:23]=[O:24]>O1CCCC1.C([Li])CCC>[Cl:11][C:12]1[CH:20]=[C:19]([CH:23]=[O:24])[C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CN(C)C=O
Agent: CC1CCCN(C)C1(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc(Cl)ncc1C(=O)O
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 53.19 %

Procedure:
To a stirred solution of tetramethylpiperidine (6.89 mL, 40.8 mM) in dry tetrahydrofuran (20 mL), n-butyl lithium (36.5 mL, 1.12 mL, 40.8 mM) was added drop wise at −78° C. for 15 min. The reaction mixture was stirred at −78° C. for 30 min and at −50° C. for 30 min. 6-Chloro nicotinic acid (1.6 g, 10.2 mM) dissolved in dry tetrahydrofuran (10 mL) was added dropwise to the above reaction mixture for 15 min at −78° C. The reaction mixture was stirred at −78° C. for 30 min and at −50° C. for 30 min. Dry dimethyl formamide (5 mL) was added dropwise at −78° C. for 5 min. The reaction mixture was stirred at −78° C. for 30 min and at −50° C. for 30 min. After the completion of the reaction, reaction mixture was quenched with 2N hydrochloric (30 mL) extracted with ethyl acetate (2×150 mL). Organic layer dried over anhydrous MgSO4, then concentrated. The concentrate was subjected to column chromatography, and the product was eluted with 15% ethyl acetate in petroleum ether to get 1.01 g (53.19%) of the title compound. MS (APCI): 186 (M+H+) for C7H4ClNO3; NMR CD3OD): δ 6.18 (s, 1H), δ 7.75 (s, 1H), δ 8.74 (s, 1H).
Reaction SMILES: [Mg].II.[CH3:4][S:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Cl)=[CH:8][CH:7]=1.C(Cl)C1C=CC=CC=1.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[C:28](=O)[CH:27]([CH3:33])[CH2:26]2>CCOCC>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH:28]([CH2:10][C:9]1[CH:12]=[CH:13][C:6]([S:5][CH3:4])=[CH:7][CH:8]=1)[C:27]([CH3:33])=[CH:26]2
Reactant: CC1Cc2cc(F)ccc2C1=O
Reactant: CSc1ccc(CCl)cc1
Agent: II
Agent: [Mg]
Solvent: ClCc1ccccc1
Solvent: CCOCC
Product: CSc1ccc(CC2C(C)=Cc3cc(F)ccc32)cc1
Reaction time: 0.08 h

Procedure:
13.44 Grams (0.56 mole) of magnesium turnings are placed in a dried flask under N2 with 125 ml. of ether and a crystal of iodine. Six ml. of 65 ml. solution of 24.2 g. (0.14 mole) of p-methylthiobenzyl chloride in ether is added. After 3 to 5 minutes of stirring the iodine color disappears and the reaction begins. After aging for 5 minutes, the rest of the benzyl chloride is added dropwise over 45 minutes. It is rinsed in with 10 ml. of ether and the reaction aged for 2 hours with stirring. 21 Grams (0.128 mole) of 5-fluoro-2-methyl-1-indanone dissolved in 50 ml. of ether is added dropwise over 30 minutes. After aging for 1 hour, the milky supernatent mixture is decanted from the magnesium into 100 ml. of acetic acid. The flask and residual magnesium are rinsed into the acid solution with 4 × 50 ml. of benzene. Two hundred ml. of water are added, the layers are separated and the organic layer is washed with 5 × 200 ml. water. It is stripped to dryness after drying over Na2SO4. The crude reaction product is crystallized from hexane to give pure 5-fluoro-2-methyl-1-(p-methylthiobenzyl)-indene, melting point 58°-59°C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][O:8][NH2:9])=[CH:4][CH:3]=1.[C:10]([C:13]1[C:14](=[O:29])[CH2:15][CH:16]([CH:23]2[CH2:28][CH2:27][CH2:26][S:25][CH2:24]2)[CH2:17][C:18]=1[O:19][C:20](=[O:22])[CH3:21])(=O)[CH3:11]>C(O)C>[C:20]([O:19][C:18]1[CH2:17][CH:16]([CH:23]2[CH2:28][CH2:27][CH2:26][S:25][CH2:24]2)[CH2:15][C:14](=[O:29])[C:13]=1[C:10](=[N:9][O:8][CH2:7][C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:11])(=[O:22])[CH3:21]
Reactant: CC(=O)OC1=C(C(C)=O)C(=O)CC(C2CCCSC2)C1
Reactant: NOCc1ccc(Cl)s1
Solvent: CCO
Product: CC(=O)OC1=C(C(C)=NOCc2ccc(Cl)s2)C(=O)CC(C2CCCSC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.34 g (2.0 mmol) of (5-chlorothien-2-yl)methoxyamine is added to a stirred solution of 0.59 g (2.0 mmol) of 2-acetyl-3-acetyloxy-5-(tetrahydro-2H-thiopyran-3-yl)cyclohex-2-en-1-one in 10 ml of absolute ethanol. After stirring overnight at room temperature, the reaction mixture is concentrated under reduced pressure. The resulting residue is diluted with 25 ml of dichloromethane and washed twice with 10 ml of saturated sodium chloride solution. The washed extract is then dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The product can then be purified by column chromatography employing tetrahydrofuran-hexane (1:2 by volume) as eluent to afford the title compound.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:17]([C:19]1[CH:23]=[CH:22][S:21][CH:20]=1)=[O:18])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[C:2]1([C:1]2[O:18][C:17]([C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)=[C:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccccc1)C(=O)c1ccsc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nc(-c2ccccc2)oc1-c1ccsc1
Yield: 78.4 %

Procedure:
5.8 g of ethyl 3-benzoylamino-3-(3-thienylcarbonyl)propionate, 30 ml of dimethylformamide and 3.8 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 4.3 g of ethyl 2-[2-phenyl-5-(3-thienyl)-4-oxazolyl]acetate are thereby obtained.
Reaction SMILES: COC1C=CC(C[O:8][CH2:9][CH2:10][C:11]([CH2:13][O:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH2:12])=CC=1.C(Cl)Cl.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O>[OH:8][CH2:9][CH2:10][C:11]([CH2:13][O:14][C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH2:12]
Reactant: C=C(CCOCc1ccc(OC)cc1)COC(=O)c1ccccc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: C=C(CCO)COC(=O)c1ccccc1

Procedure:
Combine 4-(p-methoxybenzyloxy)-2-benzoyloxymethylbut-1-ene (1.08 g, 3.30 mmol) with methylene chloride (10 mL) and water (0.5 mL) and stir rapidly. Add 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.826 gm, 3.64 mmol). After 0.25 hours filter the reaction mixture and rinse the filter cake with methylene chloride (20 mL) and concentrate the filtrate in vacuo. Chromatograph on silica gel eluting with 1/9 ethyl acetate/hexane to give the title compound as an oil. Rf =0.28; silica gel, 1/9 ethyl acetate/hexane.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][C:15]3[NH:14][C:13](=O)[CH:12]=[CH:11][C:10]=3[C:9](=[O:18])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:13]1[CH:12]=[CH:11][C:10]2[C:9](=[O:18])[CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:16][C:15]=2[N:14]=1
Reactant: O=C1CC(c2ccccc2)Cc2[nH]c(=O)ccc21
Reactant: O=P(Cl)(Cl)Cl
Product: O=C1CC(c2ccccc2)Cc2nc(Cl)ccc21

Procedure:
In analogy to (Shanazarov, A. K.; Kuzovkin, V. A.; Chistjakov, V. V.; Granik, V. G. Khim. Geterotsikl. Soedin. 1991, (1) 86-92) 7-phenyl-7,8-dihydro-1H,6H-quinoline-2,5-dione was treated with phosphoryl chloride (POCl3) to give after chromatographical separation the title compound as a colorless solid.
Reaction SMILES: [C:1]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][C:10]([OH:12])=O)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C([O-])(=O)C.[Mg+2].C([O-])(=O)C.C(OC(=O)C)(=O)C>C(OCC)(=O)C>[C:1]([NH:7][C@@H:8]1[C:13](=[O:14])[O:15][C:10](=[O:12])[CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)O
Agent: CC(=O)[O-]
Agent: [Mg+2]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)N[C@H]1CC(=O)OC1=O
Temperature: 55 °C

Procedure:
21.72 parts of N-acetoacetyl-L-aspartic acid, 0.14 parts of magnesium acetate, and 9.5 parts by volume of acetic anhydride were mixed with 200 parts by volume of ethyl acetate and heated at 55±2° C. under argon for 24 hours.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18](=[O:28])[C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([C:26]#[N:27])[CH:20]=2)[C:12]=1[F:29])[CH2:9][CH3:10])(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:18](=[O:28])[C:13]2[C:14]([Cl:17])=[CH:15][CH:16]=[C:11]([C@H:8]([NH2:7])[CH2:9][CH3:10])[C:12]=2[F:29])=[CH:20][C:21]=1[C:26]#[N:27]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(N)c(C#N)c2)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2ccc(N)c(C#N)c2)c1F
Reaction time: 60 h
Yield: 93.3 %

Procedure:
Step 4 To a solution of {(R)-1-[3-(4-amino-3-cyano-benzoyl)-4-chloro-2-fluoro-phenyl]-propyl}-carbamic acid tert-butyl ester (66 mg, 0.15 mmol) in DCM (2 mL) was added 4M HCl in dioxane (0.19 mL, 0.76 mmol, 5 eq.) and the reaction mixture was stirred for 60 hours. The mixture was partitioned between DCM (10 mL) and water (10 mL) made basic with 5M NaOH. The aqueous phase was extracted with further DCM (10 mL) and then the combined organics were dried (MgSO4), filtered and concentrated to give 2-Amino-5-[3-((R)-1-amino-propyl)-6-chloro-2-fluoro-benzoyl]-benzonitrile (46 mg, 0.14 mmol) as a viscous gum.
Reaction SMILES: C([O:4][C@H:5]([CH2:10]Br)[CH2:6][C:7]([OH:9])=[O:8])(=O)C.[CH:12]([NH:15][CH:16]([CH3:18])[CH3:17])([CH3:14])[CH3:13]>O>[CH:12]([NH:15][CH:16]([CH3:18])[CH3:17])([CH3:14])[CH3:13].[O:4]1[CH2:10][C@@H:5]1[CH2:6][C:7]([OH:9])=[O:8]
Reactant: CC(=O)O[C@H](CBr)CC(=O)O
Solvent: O
Solvent: CC(C)NC(C)C
Product: O=C(O)C[C@H]1CO1
Reaction time: 2 h

Procedure:
To a 2 l of three-necked flask equipped with thermometer pH meter and mechanical stirrer were charged distilled water (1 l), (S)-3-acetoxy-4-bromobutyric acid (90 g, 0.4 mol) and diisopropylamine (121 g, 1.2 mol). The reaction mixture was stirred at 0˜5° C. for 2 hours to afford (S)-3,4-epoxybutyric acid diisopropylamine salt. Over 99% of conversion was detected by NMR.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][N:2]=1.C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Cl:15][CH2:16][C:17]([NH:7][C:4]1[CH:5]=[CH:6][N:1]=[N:2][CH:3]=1)=[O:18]
Reactant: Nc1ccnnc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccnnc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
A solution of pyridazin-4-ylamine (1.0 g) in dry dichloromethane (10 mL) under nitrogen was cooled to 0° C. in an ice bath. Triethylamine (1.6 mL) was added, followed by slow addition of chloroacetyl chloride (0.92 mL). On completion of the addition the ice bath was removed and the reaction mixture was allowed to reach room temperature and stirred for 2 hours. The reaction mixture was diluted with water (25 mL) and dichloromethane (30 mL) A solid was filtered off and washed with pentane, water and more pentane to give the sub-titled compound (0.87 g, 48%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:24][CH:25]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH2:26][N+:27]([O-])=O)=[O:23])[N:9]=2)=[CH:4][CH:3]=1.[In].Cl>C1COCC1>[ClH:1].[NH2:27][CH2:26][CH:25]([NH:24][C:22](=[O:23])[CH2:21][N:10]1[C:11](=[O:20])[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:18])([F:16])[F:17])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:9]1)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:37])[F:39])[CH:31]=1
Reactant: O=C(Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)NC(C[N+](=O)[O-])c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [In]
Solvent: C1CCOC1
Product: NCC(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Of the compound from Example 1, 45 mg (77 μmol) and 40 mg (348 μmol) of indium powder were admixed in 0.5 ml of THF with 42 μl of conc. hydrochloric acid, and the mixture was stirred at RT for 2 h. Then the mixture was purified by preparative HPLC (Method 10). The product-containing fractions were admixed with 2 ml of 1N hydrochloric acid and concentrated on a rotary evaporator. Drying in an HV gave 21 mg (46% of theory) of the title compound as a diastereomer mixture.
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:12][CH2:11][C:10]3([CH2:21][CH2:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:22]([O:24][CH3:25])=[O:23])[CH:18]=4)[CH2:13]3)[C:9]2=[O:26])=CC=1>CC#N.O>[O:26]=[C:9]1[C:10]2([CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22]([O:24][CH3:25])=[O:23])[CH:18]=3)[CH2:13]2)[CH2:11][CH2:12][NH:8]1
Reactant: COC(=O)c1ccc2c(c1)CCC1(CCN(Cc3ccc(OC)cc3)C1=O)C2
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc2c(c1)CCC1(CCNC1=O)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (±)-methyl 1′-(4-methoxybenzyl)-2′-oxo-3,4-dihydro-1H-spiro[naphthalene-2,3′-pyrrolidine]-6-carboxylate from Step E (270 mg, 0.712 mmol) in CH3CN (9 mL) was added dropwise a solution of ceric ammonium nitrate (1.95 g, 3.56 mmol) in H2O (9 mL). The resulting mixture was stirred at ambient temperature for 18 h, then at 50° C. for 4 h, then allowed to cool. The CH3CN was removed under reduced pressure, and the residual mixture was partitioned between dilute aqueous NaHCO3 (100 mL) and EtOAc (200 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with EtOAc to give the title compound. MS: m/z=260 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([NH:6][CH3:7])=[O:5].[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([N+]([O-])=O)[C:14]=1[C:15]#[N:16])([O-:12])=[O:11]>>[C:15]([C:14]1[C:13]([N+:10]([O-:12])=[O:11])=[CH:20][CH:19]=[CH:18][C:17]=1[O:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([NH:6][CH3:7])=[O:5])#[N:16]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CNC(=O)C(C)(C)CO
Product: CNC(=O)C(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Yield: 77 %

Procedure:
Prepared as in Example 197c from 3-hydroxy-N,2,2-trimethylpropanamide (Example 202d) and 2,6-dinitrobenzonitrile in 77% yield as a pale yellow solid. MS 378 (MH+).
Reaction SMILES: [F:1][CH:2]([F:35])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH:21]3[CH2:24][N:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:22]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:5]=2[N:4]=1.[H-].[Na+].I[CH3:39].O>CN(C=O)C>[F:35][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]([CH3:39])[CH:21]3[CH2:22][N:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:24]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:5]=2[N:4]=1
Reactant: CI
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CN(S(C)(=O)=O)C2)nc(N2CCOCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(C)C2CN(S(C)(=O)=O)C2)n1
Temperature: 20 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-3-azetidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine (Example 28) (170 mg, 0.33 mmol) in DMF (4 mL) at 0° C. was added NaH (24 mg, 1.0 mmol). The mixture was stirred for 30 min at this temperature and iodomethane (0.3 mL, excess) was added. The resulting mixture was allowed to warm to 20° C. and stirred for 2 hrs. Water was added and the resulting precipitate was filtered, washed with water, and dried. Recrystallization from CH2Cl2/MeOH gave 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[1-(methylsulfonyl)-3-azetidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine (156 mg, 89% yield): mp (CH2Cl2/MeOH) 242-244° C.; 1H NMR (DMSO-d6) δ7.97-7.60 (m, 2H), 7.42 (t, J=8.1 Hz, 1H), 6.96 (d, J=7.9 Hz, 1H), 5.50 and 5.26 (2m, 1H), 4.17-4.12 (m, 4H), 3.98 (s, 3H), 3.81 (m, 4H), 3.71-3.69 (m, 4H), 3.24 (s, 3H), 3.09 (s, 3H); Anal. Calcd. for C21H26F2N8O4S: C, 48.1; H, 5.0; N, 21.3. Found: C, 48.0; H, 5.0; N, 21.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH2:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[N+](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([CH3:10])[N:5]=[C:6]([CH:8]2[CH2:9][CH:13]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1cc(Cl)nc(C)n1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC1c1cc(Cl)nc(C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-chloro-2-methyl-6-vinylpyrimidine (4-1, 15.0 g, 97 mmol 1.0 eq) in Toluene (300 mL) was heated to 100° C. under a nitrogen atmosphere. A solution of ethyl diazoacetate (30.2 mL, 291 mmol, 3.0 eq) was added as a solution in toluene (100 mL) over 1.5 hours. Heating was continued for 2 hours. The reaction mixture was allowed to cool to room temperature and concentrated to dryness. The residue was partitioned between saturated sodium bicarbonate solution (1 L) and ethyl acetate (1 L). The organic layer was separated, dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified by silica gel column chromatography (0-100% ethyl acetate in hexanes) to give ethyl 2-(6-chloro-2-methylpyrimidin-4-yl)cyclopropanecarboxylate (4-2) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:20]([OH:22])=O)=[CH:11][C:12]3[N:16]([CH3:17])[CH:15]=[N:14][C:13]=3[C:18]=2[Cl:19])=[C:4]([Cl:23])[CH:3]=1.[CH:24]([O:26][CH2:27][CH2:28][O:29][NH2:30])=[CH2:25].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>CCOC(C)=O.CN(C)C=O>[CH:24]([O:26][CH2:27][CH2:28][O:29][NH:30][C:20]([C:10]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[Cl:23])=[C:18]([Cl:19])[C:13]2[N:14]=[CH:15][N:16]([CH3:17])[C:12]=2[CH:11]=1)=[O:22])=[CH2:25]
Reactant: C=COCCON
Reactant: Cn1cnc2c(Cl)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1cc2c(ncn2C)c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5-carboxylic acid 10ff (32 mg, 0.077 mmol), O-(2-vinyloxy-ethyl) -hydroxylamine (0.010 mL, 0.092 mmol), HOBt (13 mg, 0.093 mmol), triethylamine (0.011 mL, 0.077 mmol) and EDCl (19 mg, 0.10 mmol) are dissolved into dimethylformamide (1.0 mL) and allowed to stir under a nitrogen atmosphere at room temperature for 24 hours. The reaction mixture is diluted with EtOAc, washed with water (3×), 10% potassium carbonate (2×), saturated ammonium chloride, brine, dried (Na2SO4), and concentrated under reduced pressure to give 39 mg of 85% pure material. MS APCI (−) m/z 497, 501 *M−, Br pattern) detected.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)(Cl)=O.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[C:21]([C:28](O)=O)=[C:22]2[CH2:27][CH2:26][CH2:25][N:23]2[N:24]=1>>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[C:21]([C:28]2[O:8][C:7]3[C:2]([N:1]=2)=[N:3][CH:4]=[CH:5][CH:6]=3)=[C:22]2[CH2:27][CH2:26][CH2:25][N:23]2[N:24]=1
Reactant: Nc1ncccc1O
Reactant: O=C(O)c1c(-c2ccccn2)nn2c1CCC2
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(-c2nn3c(c2-c2nc4ncccc4o2)CCC3)nc1
Yield: 22.2 %

Procedure:
In a similar fashion to Example 8, react 2-amino-3-hydroxypyridine (Fluka; 144 mg, 1.3 mmol) and phosphorous oxychloride (4.4 mL) with 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid (Preparation 3; 250 mg, 1.1 mmol) to provide the title compound (74 mg, 22%) as a tan solid. Mp 182-184° C. MS ESI+ m/e 304 (M+1). 1H NMR (CDCl3) δ 8.75 (m, 1H), 8.52 (m, 1H), 8.12 (m, 1H), 7.84 (m, 1H), 7.69 (m, 1H), 7.32 (m, 1H), 7.15 (m, 1H), 4.31 (m, 2H), 7.37 (m, 2H), 2.75 (m, 2H). HPLC: 98.3%, Rt=13.95 min. TLC (SiO2): Rf0.4 (1:3 [80:18:2 chloroform/methanol/concentrated aqueous ammonium hydroxide]/dichloromethane).