Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2([C:27](O)=[O:28])[CH2:26][CH2:25]2)=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)[CH:10]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:52][C:53]1[CH:58]=[CH:57][C:56]([C@@H:59]([NH2:63])[CH2:60][O:61][CH3:62])=[CH:55][CH:54]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2([C:27]([NH:63][C@H:59]([C:56]3[CH:57]=[CH:58][C:53]([F:52])=[CH:54][CH:55]=3)[CH2:60][O:61][CH3:62])=[O:28])[CH2:25][CH2:26]2)=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)[CH:10]=1
Reactant: Cn1cc(-c2cc(Oc3ccc(NC(=O)C4(C(=O)O)CC4)cc3F)ccn2)cn1
Reactant: COC[C@H](N)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC[C@H](NC(=O)C1(C(=O)Nc2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(F)c2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring suspension of Example B3 (65 mg, 0.164 mmol), TBTU (79 mg, 0.246 mmol) and (R)-1-(4-fluorophenyl)-2-methoxyethanamine (40.5 mg, 0.197 mmol; prepared according to the published method: J. Med. Chem. (1999), 42(24), 4981) in DMF (2 ml) was added DIEA (0.171 ml, 0.984 mmol). The resulting clear solution was stirred at RT overnight. After stirring overnight, the reaction was diluted with satd. NaHCO3 and extracted with EtOAc (2×). The combined organics were washed with satd. NaHCO3 (1×), satd. LiCl (2×), and brine (1×), dried (MgSO4), evaporated in vacuo and purified by reverse phase chromatography. Pure fractions were pooled, treated with satd. NaHCO3 (pH 8) and extracted with EtOAc (3×). The combined organics were washed with satd. NaHCO3 (1×), brine (1×), dried (MgSO4), and evaporated to afford N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′((R)-1-(4-fluorophenyl)-2-methoxyethyl)cyclopropane-1,1-dicarboxamide as an oil. This was dissolved in 4:1 MeCN/H2O, treated with certified 0.1N HCl (1.37 ml, 1.0 eq), frozen and lyophilized to afford 63 mg (66% yield) of the HCl salt as a solid. 1H NMR (400 MHz, DMSO-d6): δ 10.64 (s, 1H), 8.49-8.48 (m, 2H), 8.44-8.42 (m, 1H), 8.18 (brs, 1H), 7.89-7.85 (m, 1H), 7.54 (brs, 1H), 7.48-7.35 (m, 4H), 7.16-7.11 (m, 2H), 6.92 (brs, 1H), 5.13-5.06 (m, 1H), 3.89 (s, 3H), 3.61-3.56 (m, 1H), 3.49-3.46 (m, 1H), 3.25 (s, 3H), 1.45-1.33 (m, 4H); MS (ESI) m/z: 516.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[C:12](=[O:23])[O:13][C:14]2[C:19]([C:20]=1[CH3:21])=[CH:18][CH:17]=[C:16]([OH:22])[CH:15]=2.[I-].[N:25]1([C:35](N2C=C[N+](C)=C2)=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[C:12](=[O:23])[O:13][C:14]2[C:19]([C:20]=1[CH3:21])=[CH:18][CH:17]=[C:16]([O:22][C:35]([N:25]1[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27][CH2:26]1)=[O:36])[CH:15]=2
Reactant: C[n+]1ccn(C(=O)N2CCCc3ccccc32)c1
Reactant: COc1ccc(OC)c(-c2c(C)c3ccc(O)cc3oc2=O)c1
Agent: [I-]
Product: COc1ccc(OC)c(-c2c(C)c3ccc(OC(=O)N4CCCc5ccccc54)cc3oc2=O)c1
Yield: 21.2 %

Procedure:
The title compound (50 mg, 21% yield, white solid) was prepared from 3-(2,5-dimethoxy-phenyl)-7-hydroxy-4-methyl-chromen-2-one (156 mg, 0.50 mmol) and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide (188 mg, 0.51 mmol).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:18][CH2:17][C:6]2([NH:10][C:9](=[O:11])[CH:8]([C:12](OC)=O)[C:7]2=[O:16])[CH2:5][CH2:4]1.[CH3:19][C:20]1(C)N[C:23](=O)[CH2:22][C:21]1=O>>[CH3:1][O:2][CH:3]1[CH2:4][CH2:5][C:6]2([NH:10][C:9](=[O:11])[CH:8]([C:12]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]2=[O:16])[CH2:17][CH2:18]1
Reactant: COC(=O)C1C(=O)NC2(CCC(OC)CC2)C1=O
Reactant: CC1(C)NC(=O)CC1=O
Product: COC1CCC2(CC1)NC(=O)C(c1ccccc1)C2=O
Yield: 90 %

Procedure:
The procedure is as in Example 1, except that 1.532 g of methyl 8-methoxy-2,4-dioxo-1-azaspiro[4.5]decane-3-carboxylate as in Example (X-2-a-1) are used instead of 5,5-dimethylpyrrolidine-2,4-dione. This gives the title compound in a yield of approximately 90% of theory.
Reaction SMILES: O=[Cr](=O)=O.C1C=CC=CN=1.C1C=CC=CN=1.N1C=CC=CC=1.[OH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH3:39])=[C:31]1[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1>ClCCl.[O-2].[O-2].[O-2].[Cr+6]>[CH:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH3:39])=[C:31]1[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)=[O:23]
Reactant: Cc1c(-c2cccnc2)n(CCCCCCO)c2ccccc12
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(-c2cccnc2)n(CCCCCC=O)c2ccccc12
Reaction time: 0.42 h

Procedure:
To a solution of Collins Reagent prepared with chromium trioxide (5.6 g) and pyridine (8.86 g, 112 mmol) in dichloromethane (150 ml) at 0°-5° under a nitrogen atmosphere is added all at once 1.8 g of 1-(6-hydroxyhexyl)-3-methyl-2-(3-pyridyl)-indole in dichloromethane (15 ml). The mixture is stirred for an additional 25 minutes, then filtered through celite. The filtrate is then passed through a silica gel column. The product is eluted from the silica gel with a 1:1 mixture of ethyl acetate:dichloromethane (500 ml). Concentration in vacuo yields the desired 1-(5-formylpentyl)-2-(3-pyridyl)-3-methylindole as a pale yellow oil; NMR (CDCl3) δ9.7 (t, 1H); IR (neat) 2710, 1720 cm-1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH2:44][CH:45]([CH3:47])[CH3:46])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH2:44][CH:45]([CH3:46])[CH3:47])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(CC(C)C)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (224 mg, 0.70 mmol) and 3-[3-(2-isobutyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K37) (247 mg, 0.70 mmol) according to the general procedure M. Obtained as an off-white solid (310 mg, 74%).
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[CH2:27][C:28](O)=[O:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[NH2:31][C@H:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][C@H:33]1[OH:41]>>[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[CH2:27][C:28](=[O:29])[NH:31][C@H:32]4[C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[CH2:34][C@H:33]4[OH:41])=[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)c4CC(=O)O)cc3)cc2)CC1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(=O)N[C@H]4c5ccccc5C[C@H]4O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 1-[4′-(4-carboxymethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and (1S,2R)-1-amino-indan-2-ol.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:7][CH:8]=1.[NH2:20][C:21]1[C:25]([C:26]#[N:27])=[C:24]([CH3:28])[NH:23][N:22]=1>>[CH3:28][C:24]1[C:25]([C:26]#[N:27])=[C:21]2[N:20]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:19])([F:18])[F:1])[CH:4]=3)[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]2[N:23]=1
Reactant: Cc1[nH]nc(N)c1C#N
Reactant: O=C(CC(=O)C(F)(F)F)c1cccc(C(F)(F)F)c1
Product: Cc1nn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc2c1C#N
Yield: 73.5 %

Procedure:
Reaction of 1-(3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (284 mg, 1.0 mmol), prepared from commercially available 3-trifluoromethyl-acetophenone according to general procedure A, and commercially available 3-amino-4-cyano-5-methyl-pyrazole (122 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light yellow solid (272 mg, 73%). MS (ISP) 371.1 [(M+H)+]; mp 215° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:13][CH2:14][NH2:15])=[CH:5][CH:4]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].Cl>N1C=CC=CC=1>[F:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1
Reactant: NCCC1CCCc2ccc(F)cc21
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NCCC1CCCc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1 eq. of the compound obtained in Step G is dissolved in 4 ml of pyridine and is cooled in an ice bath before adding 3 eq. of acetic anhydride dropwise. The reaction mixture is stirred for 5 hours at ambient temperature and is then poured into 3M HCl solution and extracted with ethyl ether. The organic phase is washed with 10% potassium carbonate solution and then with water, dried over MgSO4 and evaporated under reduced pressure. The oil obtained is precipitated from a mixture of ethyl ether/petroleum ether (1/2) and the precipitate formed is filtered off under suction and recrystallised.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:11][CH2:12]Cl)[CH2:8][CH2:9]Cl)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:28]=[CH:27][C:19]([CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].CO>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:7]1[CH2:11][CH2:12][C:20]([C:19]2[CH:27]=[CH:28][C:16]([Cl:15])=[CH:17][CH:18]=2)([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH2:9][CH2:8]1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: Clc1ccc(Cc2ccncc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccncc2)(c2ccc(Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 0.7 %

Procedure:
Under nitrogen, a solution of bis-(2-chloro-ethyl)-carbamic acid tert-butyl ester* (1.54 g, 6.36 mmol) in toluene (10 mL) was cooled in ice. 4-(4-Chloro-benzyl)-pyridine (1.30 g, 6.36 mmol) was added, followed over two minutes by sodium hexamethyldisilazide solution (10 mL, 20 mmol, 2M in THF). The mixture was stirred at 0° C. for 3.5 hours then allowed to warm to room temperature and stirred for a further 20 hours. Methanol was added then the mixture was concentrated in vacuo. The residue was taken up in ethyl acetate and washed with 1N hydrochloric acid (×3) and brine, dried (MgSO4), filtered and concentrated to afford a residue which was purified by column chromatography (SiO2), eluting with gradient of 2M methanolic ammonia in dichloromethane (1% to 5%). A second purification by column chromatography (SiO2), eluting with 50% ethyl acetate/petrol gave the title compound (16 mg, 0.7%). LCMS (PS-A2) Rt 2.65 min [M+H]+ 373. *This starting material can be made by the method described in J. Chem. Soc., Perkin Trans 1, 2000, p3444-3450
Reaction SMILES: [NH2:1][C@@H:2]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:18]3[C:13](=[C:14]([NH:19]C(=O)C)[N:15]=[CH:16][CH:17]=3)[CH2:12][O:11][C:9]=2[CH:10]=1.[OH-].[K+]>C(O)C.O>[NH2:1][C@@H:2]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:18]3[C:13](=[C:14]([NH2:19])[N:15]=[CH:16][CH:17]=3)[CH2:12][O:11][C:9]=2[CH:10]=1
Reactant: CC(=O)Nc1nccc2c1COc1cc(OC[C@@H](N)CC(C)C)ccc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C[C@H](N)COc1ccc2c(c1)OCc1c-2ccnc1N
Temperature: 70 °C
Yield: 12.8 %

Procedure:
To a stirred solution of (S)—N-(8-((2-amino-4-methylpentyl)oxy)-5H-chromeno[3,4-c]pyridin-4-yl)acetamide (20 mg, 0.056 mmol) (prepared as in Example 12, Part H) in a mixture of ethanol (10 mL) and water (2 mL) was added KOH (31.6 mg, 0.563 mmol) and the reaction was heated at 70° C. for 14 h. After completion of the reaction, the volatile organic solvent was removed under reduced pressure, water (20 mL) was added and the solution extracted with dichloromethane (2×20 mL). The combined organic extracts were washed with water (1×20 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain (S)-8-((2-amino-4-methylpentyl)oxy)-5H-chromeno[3,4-c]pyridin-4-amine (2.31 mg, 7.15 umol, 13% yield) as an off-white solid. 1H NMR (400 MHz, MeOD) δ 7.90 (d, J=5.6 Hz, 1H), 7.69 (d, J=8.7 Hz, 1H), 6.98 (d, J=5.6 Hz, 1H), 6.72 (m, 1H), 6.6 (d, J=2.5 Hz, 1H), 5.07 (s, 2H), 4.10 (m, 1H), 3.92 (m, 1H), 3.40 (m, 1H), 1.82 (m, 1H), 1.49 (m, 2H), 1.01 (m, 6H); LCMS (ESI) m/e 314.2 [(M+H)+, calcd for C18H24N3O2 314.2]; LC/MS retention time (Method C): tR=1.21 min; HPLC retention time (method A): tR=7.52 min; HPLC retention time (method B): tR=8.68 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.[NH2:54][C@H:55]([CH2:59][CH3:60])[CH2:56][C:57]#[N:58]>CN(C=O)C>[C:57]([CH2:56][C@H:55]([NH:54][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([N:12]2[C:13]([OH:14])=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[CH:10]=[N:11]2)=[N:16][CH:17]=1)[CH2:59][CH3:60])#[N:58]
Reactant: CC[C@@H](N)CC#N
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](CC#N)NC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3)c2O)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.1 %

Procedure:
Combined 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (29 mg, 0.095 mmol), EDCI (27.2 mg, 0.142 mmol), HOBT (19.2 mg, 0.142 mmol) in DMF (1 mL) and added N,N-diisopropyl ethylamine (66.0 μL, 0.379 mmol). Then (R)-3-aminopentanenitrile (13.9 mg, 0.142 mmol) was added and the reaction was stirred at room temperature for 16 hours. The reaction mixture was purified by preparative HPLC (SunFire™ C18, 5 μm, ID 30 mm×75 mm) using a gradient of 40-65% ACN (with 0.035% TFA) in water (with 0.05% TFA) to give the title compound (16.2 mg, 44%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.33 Hz, 3H) 1.67 (quin, J=7.20 Hz, 2H) 2.70-2.95 (m, 2H) 4.05-4.22 (m, 1H) 7.80 (d, J=8.34 Hz, 2H) 8.15 (br. s., 2H) 8.41-8.86 (m, 4H) 8.94 (s, 1H). MS m/z [M+H]+ 387.2.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[CH:21]([F:23])[F:22])C1C=CC=CC=1.[H][H]>[Pd].CO.[OH-].[OH-].[Pd+2]>[F:23][CH:21]([F:22])[CH:9]1[NH:8][CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(C(F)F)C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCNC(C(F)F)C1
Yield: 97.1 %

Procedure:
10% Palladium on carbon (65 mg, 0.061 mmol) was added to a solution of tert-butyl 4-benzyl-3-(difluoromethyl)piperazine-1-carboxylate (0.20 g, 0.61 mmol, racemic from Step 3) in methanol (15 mL). The suspension was stirred under an atmosphere of hydrogen provided by a balloon. When the reaction showed no progress, 20% Pd(OH)2 on charcoal (47 mg, 0.061 mmol) was added and the suspension was shaken under 50-55 psi hydrogen for 2 h. The mixture was filtered and solvent removed in vacuo to afford product as a viscous oil (140 mg, 97%). 1H NMR (300 MHz, CDCl3): δ 5.90 (td, 0.1H), 5.52-5.12 (br s, 2H), 4.25-3.96 (br s, 1H), 3.94 (d, 1H), 3.27-2.77 (m, 4H), 1.45 (s, 9H); LCMS (M-tBu+2H)+: 181.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[Mg].C(N(CC)[P:13](Cl)([O-:15])=[O:14])C.[Cl-].[NH4+]>C(OCC)C>[C:4]1([CH3:8])[CH:5]=[CH:6][CH:7]=[C:2]([P:13]([C:2]2[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=2)(=[O:14])[OH:15])[CH:3]=1
Reactant: CCN(CC)P(=O)([O-])Cl
Reactant: Cc1cccc(Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1cccc(P(=O)(O)c2cccc(C)c2)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 34.4 %

Procedure:
In 250 ml of dehydrated diethyl ether, 102.6 g (0.6 mole) of m-bromotoluene was reacted with 15.3 g (0.64 mole) of metallic magnesium to prepare a Grignard reagent. To the resulting Grignard reagent was added dropwise 57 g (0.3 mole) of N,N-diethylamidochlorophosphate at 37° to 38° C. over a period of 2 hours. After the reaction mixture was heated at reflux for 4.5. hours, 400 ml of ice-water and 150 ml of saturated aqueous ammonium chloride were added thereto to decompose the salt. After liquid separation, 400 ml of concentrated hydrochloric acid was added to the ether layer under ice-cooling, followed by heating to remove the ether by distillation. To the residue was further added 100 ml of concentrated hydrochloric acid, and a reaction was conducted at 100° to 110° C. for 5 hours. The formed oily substance was separated from the aqueous layer, and 50 ml of a 20% aqueous solution of sodium hydroxide was added thereto to form a uniform solution. The insoluble matter was removed by extraction with toluene, and 20% sulfuric acid was added to the solution to neutralize and further to make it acidic. The precipitate thus formed was collected by filtration, washed with water, and dried to obtain 27 g of a crude product. Recrystallization from methanol yielded 25.4 g (percent yield: 34%) of di-(m-tolyl)phosphinic acid as a colorless solid having a melting point of 171.5° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[N:6][C:5]2[CH:17]=[CH:18][C:19]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:20][C:4]=2[NH:3]1>[Pd]>[O:1]=[C:2]1[CH2:8][C:7]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[N:6][C:5]2[CH:17]=[CH:18][C:19]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:20][C:4]=2[NH:3]1
Reactant: N#Cc1cccc(C2=Nc3ccc(C#Cc4ccccc4)cc3NC(=O)C2)c1
Agent: [Pd]
Product: N#Cc1cccc(C2=Nc3ccc(CCc4ccccc4)cc3NC(=O)C2)c1

Procedure:
Prepared from 3-(4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile (Example 2) by catalytic hydrogenation with Pd/C according to the general procedure G (method a). Obtained as a light yellow solid (156 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[NH:11][CH:12]=[CH:13][CH:14]=2)=O)=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:16][NH2:17]>C(O)C>[NH:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[NH:17][N:16]=1
Reactant: O=C(c1ccc[nH]1)c1cccnc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: c1c[nH]c(-c2n[nH]c3ncccc23)c1
Yield: 81 %

Procedure:
A mixture of (2-chloro-pyridin-3-yl)-(1H-pyrrol-2-yl)-methanone (1 g, 4.8 mmol) and hydrazine hydrate (0.5 mL) in ethanol (15 mL) was heated to reflux for overnight. The reaction was concentrated and the residue was triturated with dichloromethane (to remove any unreacted starting material. The solid was filtered, washed wit water and dried to give 720 mg (81%) of the titled compound as a light yellow solid.
Reaction SMILES: C([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:8]=2[CH2:7][CH2:6]1)(=O)C.[Li+].[OH-]>C1COCC1>[OH:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:8]=2[CH2:7][CH2:6]1
Reactant: CC(=O)OC1CCc2c1ncnc2N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2CCC3O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a solution of tert-butyl 4-(7-acetoxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.43 g, 1.2 mmol) in THF (15 mL) was added LiOH (3M, 6 mL). The mixture was stirred at room temperature overnight. The mixture was quenched with 2N HCl (9 mL) and then extracted with DCM (3×100 mL). The organic phase was dried and concentrated. The residue was subject to chromatography on silica gel, eluted by DCM/MeOH (20:1) to afford the tert-butyl 4-(7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.37 g, 97%). 1H NMR (CDCl3, 400 MHz) δ 8.51 (m, 1H), 5.06-5.04 (m, 1H), 3.80-3.69 (m, 4H), 3.56-3.45 (m, 4H), 3.10-3.05 (m, 1H), 2.94-2.86 (m, 1H), 2.51-2.44 (m, 1H), 2.00-1.94 (m, 1H), 1.48 (s, 9H). MS (APCI+) [M+H] +321.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]([Mg]Br)([CH3:13])=[CH2:12].[NH4+].[Cl-]>C1COCC1>[CH3:13][C:11]1[NH:8][C:3]2[C:4]([CH:12]=1)=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: C=C(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc2cccc(Cl)c2[nH]1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere 42.1 g of 2-chloronitrobenzene are placed in 850 ml of THF. The mixture is cooled to −40° C. and then 1.6 1 of isopropenylmagnesium bromide at 0.5 M in THF are added dropwise. After 1 hour at −40° C. with stirring the mixture is hydrolyzed with 400 ml of saturated NH4Cl solution. The aqueous phase is extracted twice with ether. The organic phase is dried and then evaporated and the residue is chromatographed on silica, eluting with toluene. This gives 20.3 g of the expected compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2(O)[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH:10]([CH3:18])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(S(F)(F)[F:26])CC)C>ClCCl>[Cl:1][C:2]1[C:3]([C:8]2([F:26])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH:10]([CH3:18])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC1CC(O)(c2ncccc2Cl)CCC12OCCO2
Solvent: ClCCl
Product: CC1CC(F)(c2ncccc2Cl)CCC12OCCO2
Temperature: -78 °C
Reaction time: 2 h
Yield: 47.8 %

Procedure:
A solution of Example 32E (1.30 g, 4.58 mmol) in dichloromethane (100 mL) was cooled to −78° C., treated with diethylaminosulfur trifluoride (0.730 ml, 5.96 mmol) (Aldrich), and the reaction mixture was stirred at −78° C. for 2 hours. After 2 hours the reaction was partially complete and the mixture was allowed to stir for 2 additional hours. The reaction mixture was poured into dichloromethane (200 mL) and washed with saturated Na2CO3, dried over Na2SO4 and concentrated in vacuo. The material was purified on SiO2 and eluted with hexane/ethyl acetate (20%) to give a white solid (0.625 g) in 48% yield. 1H NMR (300 MHz, CDCl3) δ ppm 8.46 (dd, J=1.6, 4.7, 1H), 7.67 (dt, J=1.2C, 8.0, 1H), 7.17-7.09 (m, 1H), 4.17-3.92 (m, 4H), 2.72 (ddd, J=5.4, 10.7, 19.5, 3H), 2.57-2.50 (m, 1H), 2.25-2.15 (m, 1H), 2.06-1.94 (m, 1H), 1.83 (dd, J=6.0, 14.1, 1H), 1.08 (dd, J=6.9, 20.9, 3H). MS (DCI+) M/Z 286 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O)([O-:3])=[O:2].Br[C:14]1[S:22][C:21]2[C:20]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=4)=[CH:26][CH:25]=3)=[N:19][CH:18]=[N:17][C:16]=2[CH:15]=1>>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:27]2[CH:26]=[CH:25][C:24]([NH:23][C:20]3[C:21]4[S:22][C:14]([C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N+:1]([O-:3])=[O:2])=[CH:15][C:16]=4[N:17]=[CH:18][N:19]=3)=[CH:29][CH:28]=2)=[CH:32][CH:33]=1
Reactant: COc1ccc(Nc2ccc(Nc3ncnc4cc(Br)sc34)cc2)cc1
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Product: COc1ccc(Nc2ccc(Nc3ncnc4cc(-c5ccccc5[N+](=O)[O-])sc34)cc2)cc1

Procedure:
The title compound was prepared from 2-nitrobenzeneboronic acid and N-(6-Bromo-thieno[3,2-d]pyrimidin-4-yl)-N′-(4-methoxy-phenyl)-benzene-1,4-diamine by a procedure analogous to example 2. M.P. 228-237° C. ; LC-MS: 383.56 (MH+); HPLC RT: 6.885 minutes.