Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:10][N:11]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[CH:13]=2)[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][N:3]=1.C(OC([N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([NH2:39])[CH:37]=2)[C:32](=[O:40])[NH:31]1)=O)(C)(C)C.CO>C(O)CCC>[CH:14]1([C:12]2[CH:13]=[C:9]([NH:8][C:6]3[C:5]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][N:3]=[C:2]([NH:39][C:36]4[CH:37]=[C:38]5[C:33]([C:32](=[O:40])[NH:31][NH:30]5)=[CH:34][CH:35]=4)[N:7]=3)[NH:10][N:11]=2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2ccc(N)cc21
Reactant: Clc1ncc(-c2ccccc2)c(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CO
Solvent: CCCCO
Product: O=c1[nH][nH]c2cc(Nc3ncc(-c4ccccc4)c(Nc4cc(C5CC5)n[nH]4)n3)ccc12
Temperature: 95 °C
Reaction time: 12 h

Procedure:
To ((2-Chloro-5-phenyl-pyrimidin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (75 mg, 0.241 mmol), was added 6-Amino-3-oxo-2,3-dihydro-indazole-1-carboxylic acid tert-butyl ester (180 mg, 0.72 mmol) in n-butanol and the solution was heated to 95° C. in a sealed tube. After 12 hr, the solution was concentrated and the title compound was isolated by preparative HPLC as a white solid (5.2 mg, 5% yield) HNMR (500 MHz, MeOH d-6). □17.82–7.80 (2H, m), 7.59–7.50 (6H, m), 7.19–7.17 (1H, m), 6.08 (1H, s), 2.65 (1H, m), 0.91–0.89 (2H, m), 0.45 (2H, m); LCMS m/e: 1.9 min, 425.1 (M+H), 423.1 (M−H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:26])[NH:17][C:18]([CH3:25])([CH3:24])[CH2:19][S:20](Cl)(=[O:22])=[O:21])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:27]([N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1)([CH3:29])[CH3:28]>>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:26])[NH:17][C:18]([CH3:25])([CH3:24])[CH2:19][S:20](=[O:22])(=[O:21])[NH:36][CH:33]3[CH2:34][CH2:35][N:30]([CH:27]([CH3:29])[CH3:28])[CH2:31][CH2:32]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)N1CCC(N)CC1
Reactant: CC(C)(CS(=O)(=O)Cl)NC(=O)OCC1c2ccccc2-c2ccccc21
Product: CC(C)N1CCC(NS(=O)(=O)CC(C)(C)NC(=O)OCC2c3ccccc3-c3ccccc32)CC1

Procedure:
[2-(1-Isopropyl-piperidin-4-ylsulfamoyl)-1,1-dimethyl-ethyl]-carbamic acid 9H-fluoren-9-ylmethyl ester was prepared by an analogous procedure as described in example 26 vi) starting from 479 mg (1.2 mmol) (2-chlorosulfonyl-1,1-dimethyl-ethyl)-carbamic acid 9H-fluoren-9-ylmethyl ester and 208 mg (1.2 equiv.) 1-isopropyl-piperidin-4-ylamine. The product was obtained in crude form as light yellow foam. Yield: 678 mg MS (ES+): m/e=500.
Reaction SMILES: [H-].[Al+3].[H-].[H-].[CH3:5][C:6]([CH2:14][CH2:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:7][CH2:8][CH2:9][C:10](OC)=[O:11].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:5][C:6]([CH2:14][CH2:15][CH2:16][CH:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:7][CH2:8][CH2:9][CH2:10][OH:11]
Reactant: COC(=O)CCC=C(C)CCCC(C)CCCC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(=CCCCO)CCCC(C)CCCC(C)C
Temperature: 50 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
Under a nitrogen atmosphere, 16.8 g (443 mmol) of ithium aluminum hydride was added little by little at 0° C. to a solution of 50.0 g (177 mmol) of methyl 5,9,13-trimethyltetradec-4-enoate in dry tetrahydrofuran (440 mL). After being stirred at 50° C. for 4 hours, the reaction mixture was cooled on ice, followed by careful addition of saturated sodium sulfate aqueous solution until the resulting gray suspension turned white. Sodium sulfate was added to the solution at room temperature for drying. After filtration, the filtrate was concentrated to obtain 45 g of the title compound (100% yield) as a slightly yellow transparent liquid. The results of NMR analysis of the obtained compound are as shown below.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH:10]([CH3:12])[CH3:11])[N:6]=[C:5]([NH:13][CH2:14][CH2:15][OH:16])[N:4]=1.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26]>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH:10]([CH3:12])[CH3:11])[N:6]=[C:5]([NH:13][CH2:14][CH2:15][O:16][C:25](=[O:26])[NH:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[F:17])[N:4]=1
Reactant: COc1nc(NCCO)nc(NC(C)C)n1
Reactant: O=C=Nc1ccccc1F
Solvent: CCN(CC)CC
Product: COc1nc(NCCOC(=O)Nc2ccccc2F)nc(NC(C)C)n1

Procedure:
A solution of 5 g of 2-methoxy-4-isopropylamino-6-(2-hydroxyethylamino)-s-triazine, 3.0 g o-fluorophenyl isocyanate and 10 drops triethylamine was stirred at 25° C. for about 2 days. The reaction mixture was filtered to give the product. The melting point and elemental analysis on the product are tabulated in Table I.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:9]C.Br>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[OH:9]
Reactant: COc1cc(N)ccc1Cl
Agent: Br
Solvent: CC(=O)O
Product: Nc1ccc(Cl)c(O)c1

Procedure:
4.35 Moles (688 grams) of 2-chloro-5-amino anisole are introduced into 3.44 liters of hydrobromic acid (d = 1.49) to which has been added 1.38 liters of acetic acid.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4].[Cl:13][C:14]1[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=1>C(O)C>[Cl:13][C:14]1[C:19]([O:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=2)=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: Clc1nccnc1Cl
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])c1cccc(Oc2nccnc2Cl)c1
Yield: 46 %

Procedure:
In a 250-ml single-necked, round-bottomed flask containing a solution of 3.0 g (75 mmol) of sodium hydroxide in 100 ml of absolute ethanol was added 9.28 g (67 mmol) of 3-nitrophenol at which point the solution turned dark red. To the dark red solution, 10.0 g (66 mmol) of 2,3-dichloropyrazine was added and the resulting solution refluxed for 162 hours. The reaction mixture was cooled and concentrated. Upon pouring the concentrate into approximately 300 ml of water, an off-white solid precipitated which was collected by filtration. Recrystallization from absolute ethanol gave the product, 2-chloro-3-(3-nitrophenoxy)pyrazine, (46% yield) as white needles, mp 119°-121° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C12CC(CC1)C=C2.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]>CC(N(C)C)=O.CCOCC.O>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCCBr
Reactant: Cc1ccc2cc[nH]c2c1
Agent: C1=CC2CCC1C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: COC(=O)CCCc1cc2ccc(C)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.2 %

Procedure:
A round bottom flask was charged with 42 (1.76 g, 13.4 mmol), norbornene (2.53 g, 26.9 mmol), K2CO3 (3.71 g, 26.9 mmol), and PdCl2(CH3CN)2 (0.35 g, 1.34 mmol). A solution of water in DMA (0.5 M, 10 mL) was then added. The reaction mixture was evacuated, back filled with argon three times, and then added with methyl 4-bromobutyrate (4.7 mL, 26.0 mmol). The reaction mixture was placed in a preheated oil bath at 70° C., and the mixture was stirred vigorously for 16 h under N2. The reaction was cooled to rt, diluted with ether, and filtered. The filtrate was concentrated in vacuo at 60° C. to remove ether and most of DMA. The residue was purified by flash column chromatography eluting with a linear gradient ranging from 0 to 40% EtOAc-hexanes to provide 0.72 g (23%) of product 48 as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 1.98-2.07 (m, 2H), 2.40 (t, J=7 Hz, 2H), 2.43 (s, 3H), 2.80 (t, J=7 Hz, 1H), 3.66 (s, 3H), 6.18-6.19 (m, 1H), 6.91 (d, J=8 Hz, 1H), 7.09 (s, 1H), 7.40 (d, J=8 Hz, 1H), 7.90 (brs, 1H). LC-MS (CI): m/z 232.1 [(M+H)+ C14H17NO2 requires 231.13].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@@H:16]3[O:17]C(C)(C)[O:19][C@@H:15]3[C@@H:14]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])[O:13]2)=[C:5]([NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:4]=1.C(N(CC)CC)C.[C:49]1([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:54]=[CH:53][C:52]([S:55](Cl)(=[O:57])=[O:56])=[CH:51][CH:50]=1>ClCCl>[C:49]1([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:54]=[CH:53][C:52]([S:55]([NH:1][CH2:2][C:3]2[N:11]=[C:10]3[C:6]([N:7]=[CH:8][N:9]3[C@@H:12]3[O:13][C@H:14]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])[C@@H:15]([OH:19])[C@H:16]3[OH:17])=[C:5]([NH:27][CH2:28][CH:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:4]=2)(=[O:57])=[O:56])=[CH:51][CH:50]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)c4ccc(-c5ccccc5)cc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
A solution of (3aS,4S,6R,6aR)-6-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-2,2-dimethyltetrahydrofuro[3,4-][1,3]dioxole4-carboxamide (Preparation 10) (140 mg, 0.25 mmol) and triethylamine (0.05 ml, 0.36 mmol) in anhydrous dichloromethane (1 ml) was treated with a solution of [1,1′-biphenyl]-4-sulfonyl chloride (J. Pharm. Sci., 1964, 53, 73) (71 mg, 0.28 mmol) in anhydrous dichloromethane (1 ml). The mixture was stirred at room temperature for 18 hours during which time the solvent was allowed to evaporate off freely. The residue was dissolved in ethanol (1 ml), treated with hydrochloric acid (1M, 1 ml) and heated at 60° C. for 15 hours. The solvent was removed under reduced pressure and the residue was azeotroped with ethanol (×2). The residue was then purified by column chromatography on silica gel eluting with a gradient system of dichloromethane: methanol (95:5 by volume) gradually changing to dichloromethane:methanol (90:10 by volume) to give a solid which was triturated with diethyl ether, diluted with pentane, filtered and dried to afford the title compound as a solid (110 mg).
Reaction SMILES: [C:1]([O:7]CC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH3:10][Si:11](C(O)C)([CH3:13])[CH3:12]>C1(C)C=CC=CC=1>[C:1]([O:7][Si:11]([CH3:13])([CH3:12])[CH3:10])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(O)[Si](C)(C)C
Reactant: CCOC(=O)CC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)O[Si](C)(C)C
Yield: 82.5 %

Procedure:
A solution of ethyl acetoacetate (2.60 g. 20 mmol; Aldrich) and trimethylsilylethanol (2.51 g, 21.1 mmol, Fluka) in toluene (100 ml) was heated and slowly distilled at 80°-100° with a Vigreaux column (1.7 cm×7 cm), removing most of the solvent over a period of 10 h. The residue was distilled under a reduced pressure with a Vigreaux column (1.7 cm×7 cm to obtain 3.34 g (16.5 mmol, yield 82.7%) of the title compound as a colourless oil: Rf 0.32 (20% ETOAc/Hex); bp 85°-88° C. (0.3 Torr); ir (neat) max : 1740 (ketone) and 1720 (ester) cm-1 ; 1Hmr (CDCl3) : 0.07 (9H, s, SiMe3), 1.00 (2H, `t` J=8 Hz, SiCH2), 1.93 (0.45H, s, MeC(OH)=), 2.28 (2.55H, s, MeCO), 3.12 (0.15H, s, OH of the enol form), 3.43 (1.7H, s, COCH2), 4.2 (2H, `t` J=8 Hz, CO2CH2), and 4.95 (0.15H, s, vinyl proton of the enol form) ppm;
Reaction SMILES: C([O:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:19])[CH3:18])=[CH:12][CH:11]=1)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[C:23]([O:22][C:20]([C:17]([CH3:19])([O:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]([OH:27])=[O:8])=[CH:15][CH:14]=1)[CH3:18])=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(1-tert-Butoxycarbonyl-1-methyl-ethoxy)-benzoic acid benzyl ester (2.75 g, 7.42 mmol) was dissolved in EtOAc and Pd/C (10% Pd, ca. 100 mg) was added. The reaction vessel was evacuated and connected to a hydrogen line. After 3 h stirring at r.t. under H2 atmosphere the catalyst was filtered off and the filtrate was evaporated. The crude product was used in the next step without further purification (2.0 g, 96.1%). 1H NMR (500 MHz, CDCl3): δ 7.99 (d, 2H), 6.84 (d, 2H), 1.62 (s, 6H), 1.41 (s, 9H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[Cl:14])(=[O:3])[CH3:2].[C:15]([O:19][C:20]([CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27](=[O:41])[CH:28]([NH:30]C(=O)C1C=CC(N)=C(Cl)C=1)[CH3:29])=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27](=[O:41])[CH:28]([NH:30][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[C:6]([Cl:14])[CH:7]=1)[CH3:29])=[O:21])([CH3:17])([CH3:16])[CH3:18]
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1Cl
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)OC(C)(C)C
Product: CC(=O)Nc1ccc(C(=O)NC(C)C(=O)N2CCCC2C(=O)OC(C)(C)C)cc1Cl
Yield: 77 %

Procedure:
Prepared from 95 and 4-acetylamino-3-chlorobenzoic acid according to the method used for 96a to afford the title compound as a white solid (9.18 g, 77% yield). 1H-NMR (500 MHz, CD3OD) δ 1.30-1.62 (m, 12H), 1.85-2.16 (m, 3H), 2.16-2.44 (m, 1H), 2.27 (s, 3H), 3.47-3.83 (m, 2H), 4.34-4.54 (m, 1H), 4.89 (m, 1H), 7.27-7.39 (m, 1H), 7.59-7.71 (m, 2H), 7.83-7.97 (m, 1H), 8.47 (d, 1H). Analytical HPLC 9.43 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]#[N:22])=[C:4]([SH:23])[N:3]=1.C(=O)(O)[O-].[Na+].Cl.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36]Cl.O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=2)[N:3]=1
Reactant: ClCc1ccccn1
Reactant: COCCOc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc(-c2c(C#N)c(N)nc(SCc3ccccn3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanyl-pyridine-3,5-dicarbonitrile are dissolved in 1 ml of DMF. 103 mg (1.23 mmol) of sodium bicarbonate and 75.4 mg (0.46 mmol) of 2-picolyl chloride hydrochloride are then added. The suspension is shaken at RT overnight, and water is added. The precipitate is filtered off with suction, washed with ethanol and diethyl ether and dried at 40° C. under reduced pressure. This gives 104 mg (81% of theory) of product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].C(O)(=O)C.[CH3:22][C:23]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:24]=1[NH2:25]>C(O)C>[CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=[N:25][C:24]2[C:26]([CH3:31])=[CH:27][C:28]([CH3:30])=[CH:29][C:23]=2[CH3:22])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CC1=C(C)C(c2ccccc2C=O)C(C)=C1C
Solvent: CCO
Solvent: CC(=O)O
Product: CC1=C(C)C(c2ccccc2C=Nc2c(C)cc(C)cc2C)C(C)=C1C
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a solution of 2-(2,3,4,5-tetramethylcyclopentadienyl)benzaldehyde (10.0 mmol) in ethanol (30.0 mL) were added dropwise acetic acid (1.0 mmol) and 2,4,6-trimethylaniline (10.5 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature. After disappearance of the aldehyde was confirmed by gas chromatography, the solvent was distilled off under reduced pressure to give N-[2-(2,3,4,5-tetramethylcyclopentadienyl)phenylmethylene]-N-(2,4,6-trimethylphenyl)amine (3.43 g, yield 100%).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([NH2:16])[CH3:15]>O>[C:1]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:16][CH2:14][CH3:15])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccccc1C(=O)Cl
Reactant: CCN
Solvent: O
Product: CCNC(=O)c1ccccc1C(C)(C)C

Procedure:
2-tert-butyl-N-ethylbenzamide was prepared from 2-tert-butylbenzoyl chloride, prepared in Example 186, and 70% ethylamine in water according to the method of step b of Example 248.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.Cl[CH2:21][CH2:22][CH2:23][C:24]1([CH3:29])[O:28][CH2:27][CH2:26][O:25]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:21][CH2:22][CH2:23][C:24]3([CH3:29])[O:28][CH2:27][CH2:26][O:25]3)[C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: CC1(CCCCl)OCCO1
Solvent: CN(C)C=O
Product: CC1(CCCN2C(=O)CN=C(c3ccccc3)c3cc(Cl)ccc32)OCCO1
Temperature: 100 °C

Procedure:
A solution of 54.2 g. of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one in 500 ml. of dimethylformamide is treated under an atmosphere of argon at 0° C. with 32.8 g. of potassium tertiary butylate and the mixture is then stirred in an ice-bath for 30 minutes. Then, at 10°-15° C. there is added a solution of 66 g. of 2-(3-chloropropyl)-2-methyl-1,3-dioxolan in 100 ml. of dimethylformamide, the mixture is stirred at 20°-25° C. for 30 minutes and subsequently heated to 100° C. for 30 minutes. The mixture is cooled and poured on to 2.5 liters of ice-water. The separated oily product is extracted with methylene chloride and the organic phase washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated to dryness. The residue crystallizes upon trituration with ether, and there is obtained 7-chloro-1,3-dihydro-1-[3-(2-methyl-1,3 -dioxolan-2-yl)propyl]-5-phenyl-2H-1,4-benzodiazepin-2-one having a melting point of 152°-153° C. Recrystallization from ethanol does not increase the melting point.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[C:15](=[O:16])[N:7]2[CH2:8][CH:9]=[CH:10][CH:11]([C:12]([OH:14])=[O:13])[N:6]2[C:5]1=[O:17].ClCCl.S(=O)(=O)(O)O.[CH2:26]=[C:27]([CH3:29])[CH3:28]>O1CCOCC1.O>[Cl:1][CH2:2][CH2:3][N:4]1[C:15](=[O:16])[N:7]2[CH2:8][CH:9]=[CH:10][CH:11]([C:12]([O:14][C:27]([CH3:29])([CH3:28])[CH3:26])=[O:13])[N:6]2[C:5]1=[O:17]
Reactant: C=C(C)C
Reactant: O=C(O)C1C=CCn2c(=O)n(CCCl)c(=O)n21
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)C1C=CCn2c(=O)n(CCCl)c(=O)n21
Temperature: 25 °C
Reaction time: 96 h

Procedure:
0.1 mol of 2-(2-chloroethyl)-2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylic acid was dissolved in 500 ml of dioxan or dichloromethane. 12 ml of concentrated sulphuric acid were added and the mixture was then treated with 500 ml of isobutene. After stirring at room temperature for 4 days, the mixture was diluted with water and extracted with ether. The ether extracts were washed with 10% sodium carbonate solution, dried over magnesium sulphate and evaporated to give tert.butyl 2-(2-chloroethyl)-2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylate of melting point 87°-88° C.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.[O:17]=[C:18]1[C:27]2([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:26][C:25]2[C:20](=[N:21][CH:22]=[C:23](/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36])[CH:24]=2)[NH:19]1>ClCCCl>[CH3:1][N:30]1[CH2:31][CH2:32][C:27]2([CH2:26][C:25]3[C:20](=[N:21][CH:22]=[C:23](/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36])[CH:24]=3)[NH:19][C:18]2=[O:17])[CH2:28][CH2:29]1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CC1(CCNCC1)C(=O)N2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCC2(CC1)Cc1cc(/C=C/C(=O)O)cnc1NC2=O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Sodium triacetoxyborohydride (671 mg, 3.17 mmol) and paraformaldehyde (95 mg, 3.17 mmol) were successively added to a suspension of (E)-3-(2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylic acid (455 mg, 1.58 mmol) in 1,2-dichloroethane (40 mL) at room temperature. The reaction mixture was then heated to 70° C. and stirred for 2 hours. The reaction mixture was cooled to room temperature, the precipitated product filtered and washed with H2O (50 mL) and MeOH (3×50 mL) and dried. The title product was obtained as a white solid (319 mg, 66%, py 74.1%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:12]2[S:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[C:10]=1[Cl:11])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:25][C:26]([N:28]2[CH2:29][CH2:30][N:31]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:32][CH2:33]2)=[O:27])[N:8]=[C:9]([C:12]2[S:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[C:10]=1[Cl:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]nc(-c2ccc(Cl)s2)c1Cl
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Cl)c(-c2ccc(Cl)s2)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 4-Chloro-5-(5-chloro-thiophen-2-yl)-2H-pyrazole-3-carboxylic acid ethyl ester, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3) afforded the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): 7.46-7.48 (m, 1H), 6.94-7.1 (m, 2H), 6.84-6.92 (m, 3H), 5.4 (s, 2H), 4.34-4.4 (q, 2H), 3.62-3.81 (m, 4H), 3.04-3.24 (m, 4H), 1.36-1.44 (m, 3H). MS (ES) M+H) expected=511.41, found 511.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:15][C:16]([O:18]C(C)(C)C)=O)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=1.C(O)(C(F)(F)F)=O.FC1C=C(CC(O)=O)C=CC=1C1C=CN=C(F)C=1.[NH2:48][C:49]1[N:54]=[CH:53][C:52]([N:55]2[CH2:60][CH2:59][N:58]([C:61](=[O:63])[CH3:62])[CH2:57][CH2:56]2)=[CH:51][CH:50]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C=O)C>[C:61]([N:58]1[CH2:57][CH2:56][N:55]([C:52]2[CH:51]=[CH:50][C:49]([NH:48][C:16](=[O:18])[CH2:15][C:4]3[CH:5]=[CH:6][C:7]([C:8]4[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=4)=[C:2]([F:1])[CH:3]=3)=[N:54][CH:53]=2)[CH2:60][CH2:59]1)(=[O:63])[CH3:62]
Reactant: CC(C)(C)OC(=O)Cc1ccc(-c2ccnc(F)c2)c(F)c1
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)Cc1ccc(-c2ccnc(F)c2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(F)c4)c(F)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of tert-butyl 2-(3-fluoro-4-(2-fluoropyridin-4-yl)phenyl)acetate 207-5 (100 mg, 0.33 mmol) and TFA (0.5 mL) in DCM (3 mL) was stirred at room temperature for 5 hours. The solvents were evaporated to dryness under high vacuum. The crude product, 2-(3-fluoro-4-(2-fluoropyridin-4-yl)phenyl)acetic acid 207-6 (50 mg, 0.20 mmol), was dissolved in DMF (2 mL), 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone (53 mg, 0.24 mmol) and DIEA (174 uL, 1.0 mmol) were added to the solution before O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (114 mg, 0.30 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(3-fluoro-4-(2-fluoropyridin-4-yl)phenyl)acetamide 207. MS m/z 452.2 (M+1); 1H NMR 400 MHz (MeOD) δ 8.21 (d, 1H), 7.96 (d, 1H), 7.88 (d, 1H), 7.57-7.51 (m, 1H), 7.48-7.45 (m, 1H), 7.37 (dd, 1H), 7.30-7.21 (m, 3H), 3.75 (s, 2H), 3.68 (t, 2H), 3.63 (t, 2H), 3.14 (t, 2H), 3.09 (t, 2H, J=5.2 Hz), 2.09 (s, 3H).