Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21]S(C(C)(C)C)=O)[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Cl>CO.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:21])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)S(=O)NC(CCc1ccc(C(F)(F)F)cc1)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC(CCc1ccc(C(F)(F)F)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 157.6 %

Procedure:
To a solution of 210 mg (0.5 mmol) 2-Methyl-propane-2-sulfinic acid [1-(4-chloro-phenyl)-3-(4-trifluoromethyl-phenyl)-propyl]-amide in methanol (0.5 mL) was added a 4M HCl solution in dioxane (0.5 mLl) at room temperature under argon. The mixture was stirred at room temperature for 30 minutes. The solvent was removed in vacuo. The solid was stirred in ether, filtered and dried to provide 138 mg (78%) of the title compound as white solid. MS (m/e): 313.9 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:7][CH:6]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].Cl>CCOC(C)=O.C(#N)C>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:13]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:12][CH2:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:2])=[O:18])=[CH:6][CH:7]=2)=[CH:26][CH:25]=1)[CH2:28][CH2:29][CH3:30]
Reactant: COC(=O)Cc1ccc(CCNS(C)(=O)=O)cc1
Reactant: CCCCc1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCc1ccc(CN(CCc2ccc(CC(=O)O)cc2)S(C)(=O)=O)cc1

Procedure:
A mixture of [4-[2-methanesulfonylamino-ethyl]-phenyl]-acetic acid methyl ester (38 mg, 0.14 mmol), 1-bromomethyl-4-butylbenzene (35 mg, 0.15 mmol), K2CO3 (25 mg, 0.182 mmol) and acetonitrile was heated at reflux for 1 h. Aqueous HCl (2 mL, 1N) and EtOAc (30 mL) were added to the reaction. The organic solution was dried with MgSO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography (30% EtOAc/hexanes) to afford the title compound of Step A. 1H NMR (400 MHz, CDCl3) δ 7.28-7.05 (m, 8H), 4.37 (s, 2H), 3.65 (s, 3H), 3.58 (s, 2H), 3.26 (t, 2H), 2.77 (t, 2H), 2.69 (s, 3H), 2.60 (t, 2H), 1.59 (m, 2H), 1.37 (m, 2H), 0.94 (t, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][C:5]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1.[N:19]#CBr>C(Cl)(Cl)Cl>[C:18]([N:2]([CH2:3][CH2:4][C:5]1([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[CH2:6][CH2:7][CH2:8][CH2:9]1)[CH3:1])#[N:19]
Reactant: COc1ccc(C2(CCN(C)C)CCCC2)cc1
Reactant: N#CBr
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2(CCN(C)C#N)CCCC2)cc1

Procedure:
By following the manipulative procedure outlined above in Example 12, a solution of 5.43 g of 1-(2-dimethylaminoethyl)-1-(4-methoxyphenyl)cyclopentane (the free base of Example 46) in chloroform is added to a stirred solution of 2.57 g of cyanogen bromide in chloroform to give an oil. The oil is dissolved in chlorofrom, subjected to column chromatography with a silica gel column and eluted with ether to produce an orange oil of 1-(N-cyano-N-methylaminoethyl)-1-(4-methoxyphenyl)cyclopentane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[CH:10][C:11]([CH:12]([CH3:14])[CH3:13])=[C:4]2[N:3]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCO>[CH2:15]([NH:22][C:6]1[N:5]2[N:9]=[CH:10][C:11]([CH:12]([CH3:14])[CH3:13])=[C:4]2[N:3]=[C:2]([Cl:1])[CH:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)c1cnn2c(Cl)cc(Cl)nc12
Reactant: NCc1ccccc1
Solvent: CCO
Product: CC(C)c1cnn2c(NCc3ccccc3)cc(Cl)nc12
Temperature: 25 °C

Procedure:
5,7-dichloro-3-isopropylpyrazolo[1,5-α]pyrimidine (500 mg, 2.17 mmol) and benzyl amine (0.52 mL, 4.78 mmol) in EtOH (20 mL) were refluxed for about 3 hours. The reaction mixture was then cooled to ambient temperature and concentrated in vacuo. The remaining residue was purified by flash chromatography on silica (methanol/ethyl acetate) to yield N-benzyl-5-chloro-3-isopropylpyrazolo[1,5-α]pyrimidin-7-amine as a white solid in analytically pure form (630 mg, 97%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.CCN(C(C)C)C(C)C.[F:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[NH2:29]>O1CCCC1>[F:25][C:26]1[CH:27]=[C:28]([NH:29][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:8][CH:9]=2)[CH:30]=[CH:31][C:32]=1[N:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: O=C(Cl)c1ccc(-c2ccccn2)cc1
Reactant: Nc1ccc(N2CCCCC2)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc(N2CCCCC2)c(F)c1)c1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Pyrid-2-yl)benzoyl chloride (1.37 mmol, prepared as described in Example 1B, and DIEA (1.2 mL, 6.9 mmol) in tetrahydrofuran (5 mL) were treated with the product from Example 10B (260 mg, 1.34 mmol). The mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was taken up in ethyl acetate (50 mL), washed with H2O (3×15 mL) and brine (15 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with 3:2 hexanes:ethyl acetate to provide the title compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.72 (d, J=4.7 Hz, 1H), 8.25 (d, J=8.2 Hz, 2H), 8.05–8.10 (m, 3H), 7.94 (td, J=7.8 Hz, 1.7 Hz, 1H), 7.70 (dd, J=14.9 Hz, 2.4 Hz, 1H), 7.40–7.50 (m, 2H), 7.04 (t, J=9.4 Hz, 1H), 2.92–2.96 (m, 4H), 1.62–1.69 (m, 4H), 1.52–1.56 (m, 2H); MS (ESI+) m/z 376 (M+H)+.
Reaction SMILES: C([N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8])=C.[NH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=O>>[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[C:13](#[N:9])[CH2:12][CH2:11][C:10]#[N:3]
Reactant: C=CN1CCCC1=O
Agent: O=C1CCCN1
Product: N#CCCC#N

Procedure:
The distillation residue, 59.1 grams, is dissolved in 16.2 grams water and mixed with 60 grams toluene. While stirring, carbon dioxide is then passed through the mixture until the pH is approximately 13.2. The potassium pyrrolidonate remaining in the residue has then been converted into pyrrolidone and potassium carbonate. The supernatant toluene layer is separated off. The remaining mixture is then extracted four times, each time with 60 grams toluene. After evaporating the toluene from the combined toluene layers, 54 grams of 98.8% pure pyrrolidone is obtained which is suitable for conversion into, for instance, N-vinyl pyrrolidone. If desired, this pyrrolidone can be recirculated to the section where the reaction mixture obtained in the preparation of pyrrolidone from succinonitrile is worked up.
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[C:8]([F:11])[C:5]([C:6]#[N:7])=[C:4]([F:12])[C:3]=1[F:13].C[Al](C)C.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C@@:26]([OH:52])([CH2:46][N:47]1[CH:51]=[N:50][CH:49]=[N:48]1)[C@H:27]([S:29][C@@H:30]1[CH2:35][O:34][C@@H:33]([C:36]2[CH:45]=[CH:44][C:39]([C:40](OC)=[O:41])=[CH:38][CH:37]=2)[O:32][CH2:31]1)[CH3:28]>>[C:6]([C:5]1[C:4]([F:12])=[C:3]([F:13])[C:2]([NH:1][C:40](=[O:41])[C:39]2[CH:44]=[CH:45][C:36]([C@H:33]3[O:32][CH2:31][C@H:30]([S:29][C@H:27]([CH3:28])[C@:26]([C:20]4[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=4[F:18])([OH:52])[CH2:46][N:47]4[CH:51]=[N:50][CH:49]=[N:48]4)[CH2:35][O:34]3)=[CH:37][CH:38]=2)=[C:9]([F:10])[C:8]=1[F:11])#[N:7]
Reactant: COC(=O)c1ccc([C@H]2OC[C@H](S[C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CO2)cc1
Reactant: N#Cc1c(F)c(F)c(N)c(F)c1F
Agent: C[Al](C)C
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3c(F)c(F)c(C#N)c(F)c3F)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(4), a reaction was carried out using commercially available 4-amino-2,3,5,6-tetrafluorobenzonitrile (227 mg, 1.2 mmol), trimethylaluminium (1.1 ml, 1.07M n-hexane solution, 1.2 mmol) and methyl 4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzoate (150 mg, 0.30 mmol), obtained in Example 12(1), and the reaction mixture was treated using a similar procedure to that described in Example 3(4) to afford the title compound (84 mg, yield 42%) as a colorless oil which was recrystallized from ethyl acetate-hexane to give white powdery crystals.
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.[C:11]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br)#[N:12]>>[CH2:9]([O:8][P:1]([CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([C:11]#[N:12])[CH:14]=1)(=[O:2])[O:5][CH2:6][CH3:7])[CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: N#Cc1cccc(CBr)c1
Product: CCOP(=O)(Cc1cccc(C#N)c1)OCC
Temperature: 140 °C
Yield: 83 %

Procedure:
A stirrd mixture of triethyl phosphite (0.500 g, 2.95 mmol) and 3-cyanobenzyl bromide (0.609 g, 2.95 mmol) was refluxed at 140° C. under argon for 2 h and the resulting volatiles were removed at room temperature in vacuo to afford the tided intermediate as a colorless oil (0.62 g, 84%). 1H-NMR (400 MHz, CDCl3) δ 7.7-7.5 (m, 3H), 7.44 (t, J=7.8 Hz, 1H), 4.06 (p, J=7.6 Hz, 4H), 3.17 (d J=21.8 Hz, 2H), 1.27 (t, J=7.1 Hz, 6H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.CC(=CC)C.Cl([O-])=[O:18].[Na+].Cl>CC(O)(C)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:18])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a stirred solution of benzo[d][1,3]dioxole-5-carbaldehyde (254a, 2 g, 13.3 mmol), Na2H2PO4 (6.38 g, 53.2 mmol), and 2-methyl-2-butene (9.85 mL, 93.1 mmol) in t-BuOH (41 mL) and water (17 mL) was added sodium chlorite (7.19 g, 79.9 mmol). The resulting reaction mixture was stirred for 2 hours at room temperature. Water (100 mL) and 1M HCl (25 mL) were added and the mixture was extracted with EtOAc (2×50 mL). The organic phase was separated, dried with sodium sulfate and evaporated under reduced pressure. The resulting solid was triturated with EtOAc (20 mL) to yield the title compound 255a as a white solid (1.9 g, 86% yield). 1H NMR: (DMSO) δ 12.72 (br s, 1H), 7.53-7.50 (m, 1H), 7.34-7.32 (m, 1H), 6.99-6.95 (m, 1H), 6.10 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[CH2:17][NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.OO.C(=O)([O-])[O-:30].[K+].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[CH2:17][NH:18][CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH2:11])=[O:30])=[CH:12][CH:13]=1
Reactant: N#Cc1ccc(Oc2ccc(CNCCc3ccccc3)c(Cl)c2)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3ccccc3)c(Cl)c2)cc1

Procedure:
The compound of step 1 above is subject to hydrolysis using hydrogen peroxide and potassium carbonate. The details of the hydrolysis procedure to form the amide form nitrile have been described exhaustively elsewhere in this document. Electrospray MS M+1 ion=381. 1H-NMR (CDCl3, 200 MHz): 7.92-7.85 (m, 2H), 7.39 (d, 1H, J=8.3 Hz), 7.30-7.12 (m, 5H), 7.06-6.91 (m, 4H), 3.84 (s, 2H), 2.83 (s, 4H).
Reaction SMILES: Cl[C:2]1[C:6]2[N:7]([C:17](=[O:34])[CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:21][CH2:20]3)[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[C:5]=2[N:4]([CH3:35])[CH:3]=1.C(#N)C>C(O)=O.CN(C)C=O.[Pd]>[CH2:32]([N:29]([CH2:30][CH3:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH:22]1[CH2:23][CH2:24][N:19]([CH2:18][C:17]([N:7]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[C:5]3[N:4]([CH3:35])[CH:3]=[CH:2][C:6]2=3)=[O:34])[CH2:20][CH2:21]1)[CH3:33]
Reactant: CCN(CC)CCCCC1CCN(CC(=O)N2c3ccccc3NC(=O)c3c2c(Cl)cn3C)CC1
Agent: [Pd]
Solvent: CC#N
Solvent: O=CO
Solvent: CN(C)C=O
Product: CCN(CC)CCCCC1CCN(CC(=O)N2c3ccccc3NC(=O)c3c2ccn3C)CC1

Procedure:
4.715 g (9.7 millimol) of 3-chloro-4-[[4-[4-(diethylamino)-butyl]-1-piperidinyl]acetyl ]-1-methyl-1,4,9,10-tetrahydropyr rolo[3,2-b][1,5]benzodiazepin- 10-one were dissolved in a mixture of 5 ml of 85% formic acid and 25 ml of dimethylformamide and after the addition of 0.5 g of 10% palladium/activated charcoal the mixture was refluxed for 3 hours. 7.0 ml of formic acid were added, the mixture was refluxed for a further 6 hours and then, after the addition of a further 4.0 ml of formic acid and 0.8 g of 10% palladium/activated charcoal, the mixture was finally refluxed for a further 8 hours. The mixture was filtered while hot, the filtrate was evaporated down in vacuo and the residue was purified by column chromatography (silica gel; dichloromethane/ethyl acetate/methanol/conc. ammonia 3.5:1.5:0.46:0.06 v/v). 1.45 g (33% of theory) of colourless crystals were obtained, m.p. 196°-198° C. (acetonitrile), which were found according to thin layer chromatography and IR, UV and 1H-NMR spectra, to be identical to a preparation obtained according to Example 39.
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]1(=[O:22])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19](O)=[O:20])=[N:11][NH:10]1.C(N(CC)CC)C.[BH4-].[Na+].Cl>C1COCC1.CCOC(C)=O.[Cl-].[Na+].O.O>[OH:20][CH2:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:22])[NH:10][N:11]=1
Reactant: O=C(O)c1n[nH]c(=O)c2ccccc12
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(CO)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
With the exclusion of moisture, a solution of 155 ml (1.19 mol) isobutyl chloroformate in 620 ml THF is added dropwise to a suspension of 207 g (1.089 mol) phthalazin-1 (2H)-one-4-carboxylic acid in 6 l THF and 166 ml (1.188 mol) triethylamine at about 10° C. After stirring for 3 h at RT, the mixture is filtered and the residue washed with 0.5 l THF. The yellow filtrate is cooled to 15° C., then 93 g (2.46 mol) sodium borohydride is added and the suspension stirred for about 8 h at RT. To complete the reduction, another 10 g sodium borohydride is added and the mixture heated for 5 h to 40° C. Then 0.5 l water and finally 0.5 l of 5 N HCl are added dropwise at 15° C. and the turbid solution is stirred for 30 min. The reaction mixture is diluted with 3 l EtOAc and 2 l semisaturated brine, the aqueous phase is separated off and extracted 3 times with 2 l EtOAc. The organic phases are washed twice each time with semisaturated brine and brine, dried (Na2SO4) and concentrated by evaporation. Stirring in water at 90° C., cooling and filtration yield the title compound; m.p. 199-201° C.; 1H-NMR (DMSO-d6) 12.52 (s, HN), 8.25 (d, 1H), 8.11 (d, 1H), 7.9 (m, 2H), 5.49 (t, HO), 4.68 (d, 2H); FAB-MS (M+H)+=177.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]=12.[OH-].[Na+].[N+:18]([O-])([OH:20])=[O:19]>S(=O)(=O)(O)O>[Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([N+:18]([O-:20])=[O:19])=[C:9]([CH3:11])[N:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]=12
Reactant: O=[N+]([O-])O
Reactant: Cc1cc2cnnc(Cl)c2n1CC(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1c([N+](=O)[O-])c2cnnc(Cl)c2n1CC(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
16.0 g (71.5 mmol) of 7-chloro-1-isobutyl-2-methylpyrrolo[2,3-d]pyridazine are dissolved in portions at 0° C. with vigorous stirring in a mixture of 100 ml of fuming nitric acid and 50 ml of conc. sulfuric acid. The solution is stirred at room temperature for a further 4 h and subsequently introduced into 400 ml of ice-water. The mixture is then neutralized with 10 N sodium hydroxide solution and extracted with 3×250 ml of ethyl acetate. The organic extracts are dried over magnesium sulfate and concentrated. After crystallization from diisopropyl ether/ethyl acetate, 15.9 g (82%) of the title compound are isolated. M.p.: 96° C. (dec.).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=O)[C:2]([O:4][CH2:5][CH3:6])=[O:3].C(OC[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.[O-]CC.[Na+].Cl>C1(C)C=CC=CC=1>[CH2:18]([O:17][C:15](=[O:16])[CH:1]([O:8][CH2:9][CH3:10])[C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH3:19]
Reactant: CCOCC(=O)OCC
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(OCC)C(=O)OCC
Temperature: 75 °C
Yield: 93.7 %

Procedure:
A mixture of diethyl oxalate (39.23 ml, 1.12 eq.) and ethyl ethoxyacetate (34.95 ml, 1 eq.) was added dropwise to a slurry of sodium ethoxide (18.64 g, 1.07 eq.) in toluene (100 ml) at 45-50° C. After dropping, the resulting solution was heated to 70-80° C. for 2 hrs and poured into 70 ml of 14% HCl with cooling. The resultant mixture was extracted with EA and the combined organic layers were washed with brine and dried in vacuo to give 55.86 g (93.7%) of a product.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]([C:9]1[S:10][C:11]([Br:14])=[CH:12][CH:13]=1)=[O:8])(=[O:3])[CH3:2].[BH4-].[Na+].C([O-])([O-])=O.[Na+].[Na+].O>C1COCC1>[C:1]([O:4][CH2:5][CH2:6][CH:7]([C:9]1[S:10][C:11]([Br:14])=[CH:12][CH:13]=1)[OH:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC(=O)c1ccc(Br)s1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OCCC(O)c1ccc(Br)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A mixture of 3-(5-bromothiophen-2-yl)-3-oxopropyl acetate (2.4 g, 8.8 mmol, 1 eq) in THF (150 ml) was stirred at 0° C., and NaBH4 (401.2 mg, 10.6 mmol, 2 eq) was added slowly and the reaction was stirred at 23° C. After 1 hour, Na2CO3.H2O was added. After 30 min the mixture was filtered and extracted with EtOAc (3×50 ml). The combined organic phases were washed (brine), dried (Na2SO4), filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography (PE/EtOAc=5:1 as eluant) to give 3-(5-bromothiophen-2-yl)-3-hydroxypropyl acetate (1.92 g, 78.2%) as white solid. LC-MS (m/z)=279.1 [M+H]+
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27]([Si:31]([CH3:42])([CH3:41])[O:32][CH2:33][CH2:34][N:35]1[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([Si:31]([CH3:42])([CH3:41])[O:32][CH2:33][CH2:34][N:35]1[CH:39]=[CH:38][C:37]([NH:40][C:8](=[O:9])[CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:36]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3c(F)cccc3F)cc2=O)n1
Yield: 52 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 47) and 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (Intermediate 3) afforded N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as a white solid (840.3 mg, 52%); ES+-HRMS m/e calcd for C29H39N5O4SiF2 [M+H+] 588.2812 found 588.2817. 1H NMR (300 MHz, DMSO-d6) δ ppm −0.07 (s, 6H), 0.80 (s, 9H), 1.08 (br s, 2H), 1.22-1.79 (m, 7H), 1.83-2.03 (m, 1H), 2.17-2.34 (m, 1H), 3.85 (t, J=5.1 Hz, 2H), 4.06 (t, J=5.1 Hz, 2H), 5.46 (dd, J=10.7, 4.4 Hz, 1H), 6.03 (d, J=2.7 Hz, 1H), 6.36 (d, J=2.1 Hz, 1H), 7.32-7.51 (m, 3H), 7.53 (d, J=2.1 Hz, 1H), 8.28 (d, J=2.7 Hz, 1H), 10.84 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:5][CH:6]([N:8]1[C:21]2[CH:20]=[C:19]([C:22](=[S:24])[NH2:23])[CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:7])[CH3:4])[CH3:2].[CH2:25](N)[CH2:26][CH2:27][CH3:28].S>C(O)C>[CH2:25]([NH:23][C:22]([C:19]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH:6]([CH3:7])[CH2:5][N:3]([CH2:1][CH3:2])[CH3:4])[C:21]=2[CH:20]=1)=[S:24])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCN
Reactant: CCN(C)CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Agent: S
Solvent: CCO
Product: CCCCNC(=S)c1ccc2c(c1)N(C(C)CN(C)CC)c1ccccc1S2
Temperature: 100 °C

Procedure:
A mixture of 10-[(2RS)-1-(N-ethyl-N-methylamino)-2-propyl]-2-phenothiazinecarbothioamide (2.1 g) and butylamine (8.5 cc) in absolute ethanol (30 cc) is saturated with hydrogen sulphide and heated for 16 hours to a temperature in the region of 100° C. After being cooled, the orange solution obtained is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual brown oil is purified by chromatography on a column (height: 4 cm; diameter: 3 cm) of silica gel (0.2-0.063 mm), eluting successively with methylene chloride (2 liters) and with a mixture (90:10 by volume) (1 liter) of methylene chloride and methanol and collecting 60-cc fractions. Fractions 36 to 39 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual orange oil (1.8 g) is again purified by chromatography on a column (height: 25 cm; diameter: 4 cm) of silica gel (0.04-0.063 cm) under a slight excess pressure of nitrogen (40 kPa), eluting with a mixture (75:25 by volume) (1 liter) of ethyl acetate and cyclohexane and collecting 60-cc fractions. Fractions 5 to 12 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. N-Butyl-10-[(2RS)-1-(N-ethyl-N-methylamino)-2-propyl]-2-phenothiazinecarbothioamide (1.25 g) is thereby obtained in the form of a yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[C:39]2[C:38](=[O:40])[N:37]([CH3:41])[CH2:36][C:35]=2[C:34]([C:42]([OH:44])=[O:43])=[CH:33][CH:32]=1>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][C:31]3[C:39]4[C:38](=[O:40])[N:37]([CH3:41])[CH2:36][C:35]=4[C:34]([C:42]([OH:44])=[O:43])=[CH:33][CH:32]=3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH3:29])[CH:15]=1)([O:22][CH2:23][CH3:24])=[O:25])[CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CN1Cc2c(C(=O)O)ccc(N)c2C1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C(=O)O)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared using the procedure from Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and Compound 128A. MS (ES+): m/z 624.19 (100) [MH+]; HPLC: tR=1.07 min (UPLC, purity).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[C:20]([C:24]1[NH:28][N:27]=[C:26]([NH2:29])[CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[NH:28][N:27]=[C:26]([NH:29][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])[CH:25]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1cc(N)n[nH]1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)Nc3cc(C(C)(C)C)[nH]n3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and (5-tert-butyl-1H-pyrazol-3-yl)-amine to afford the title compound. MS: m/e=380 (M+H).