Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@:2]1([C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C:25](=[CH:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[C:3](=[O:11])[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[Cl:31][C:32]1[CH:33]=[C:34]([N:38]=[C:39]=[O:40])[CH:35]=[CH:36][CH:37]=1.O>CN(C=O)C>[OH:1][C@:2]1([C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C:25](=[CH:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[C:3](=[O:11])[CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C:39]([NH:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([Cl:31])[CH:33]=2)=[O:40])[CH2:9][CH2:10]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CN1CCNCC1
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CN1CCN(C(=O)Nc2cccc(Cl)c2)CC1
Reaction time: 1 h

Procedure:
17α-Hydroxy-21-(1-piperazinyl)pregna-4,9(11) -diene-3,20-dione (EXAMPLE 6A, 5.00 g) is treated in DMF (20 ml) with m-chlorophenyliso-cyanate (1.84 g) for 3 days. The mixture is poured into water (200 ml). After 1 hr, the liquid is decanted. The solid is dissolved in methylene chloride and is extracted with aqueous sodium bicarbonate. The phases are separated and the organic phase is dried over sodium sulfate and concentrated. The concentrate is chromatographed on silica gel (3% methanol in methylene chloride to 4%) to give the title compound which is crystallized from hot ethyl acetate.
Reaction SMILES: [CH3:1][N:2]([CH3:50])[CH2:3][CH2:4][CH2:5][NH:6][CH2:7][C@:8]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:43])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[CH:42]=[CH:41][C:33]([C:34]([O:36]C(C)(C)C)=[O:35])=[CH:32][CH:31]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:50][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][NH:6][CH2:7][C@:8]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:43])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:41][CH:42]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(CNCCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.1 %

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(dimethylamino)propylamino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (114 mg, 0.167 mmol) in DCM (1 ml) was added TFA (0.4 ml, 5.19 mmol). The mixture was stirred at rt for 5 h and was concentrated under reduced pressure. The residue was purified by prep HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure to afford the title compound as a white solid (77 mg, 0.122 mmol, 73.3% yield). LCMS: m/e 629.6 (M−H)−, 2.22 min (method 6). 1H NMR (500 MHz, Acetic acid) δ ppm 8.03 (d, J=8.24 Hz, 2H) 7.30 (d, J=8.24 Hz, 2H), 5.37 (d, J=4.58 Hz, 1H), 4.79 (s, 1H), 4.68 (s, 1H), 3.32-3.44 (m, 3H), 3.25-3.32 (m, 2H), 2.96 (d, J=13.12 Hz, 1H), 2.89-2.94 (m, 6H), 2.49-2.58 (m, 1H), 2.30-2.38 (m, J=8.09, 7.86, 7.74, 7.74 Hz, 2H), 1.75 (s, 3H), 1.19 (s, 3H), 1.13-2.23 (m, 22H), 1.09 (s, 3H), 1.08 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30]O>>[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:21])([CH3:22])[C:6]=2[CH:23]=1
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: COCCOCCO
Product: COCCOCCOc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and 2-(2-methoxyethoxy)ethanol.
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)=[CH:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C=CC2NC=C3C(=O)N(C4C=C[C:44]([O:47]C)=CC=4)N=C3C=2C=1>>[CH3:44][O:47][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]5)=[CH:17][C:18]=4[C:9]3=[N:8]2)=[CH:2][CH:3]=1
Reactant: COc1ccc(-n2nc3c4cc(N)ccc4[nH]cc-3c2=O)cc1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)cc3c-2nn1-c1ccccc1
Product: COc1ccc(-n2nc3c4cc(N5CCNCC5)ccc4[nH]cc-3c2=O)cc1

Procedure:
The title compound was prepared following the procedure for 7a using 6c. 1H-NMR (DMSO-d6) δ (ppm): 3.25 (4H, br), 3.50 (4H, br), 3.75 (3H, s), 7.00 (1H, d, J=9.06 Hz), 7.40 (1H, m), 7.48 (1H, br), 7.68 (1H, d, J=9.06 Hz), 7.92 (1H, d, J=8.79 Hz), 8.05 (2H, d, J=8.79 Hz), 8.56 (1H, br), 9.12 (1H, br). m/z 376.4 (MH+).
Reaction SMILES: [C:1]1(=[O:23])[N:5]([O:6][CH2:7][C:8]2([CH:17]=[CH:16][CH:15]=[CH:14][CH2:13]2)C(OC)=O)C(=O)C2=CC=CC=C12.O.NN>CO>[CH2:7]1[C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[C:1](=[O:23])[NH:5][O:6]1
Reactant: COC(=O)C1(CON2C(=O)c3ccccc3C2=O)C=CC=CC1
Agent: NN
Solvent: CO
Solvent: O
Product: O=C1NOCc2ccccc21
Yield: 21.4 %

Procedure:
This reaction was run in the same manner as Example 6, Part B, using 52.5 grams (0.169 mole) of methyl 1-(phthalimidooxymethyl)benzoate and 17.0 grams (0.34 mole) of hydrazine hydrate in 800 ml of methanol to give 5.4 grams of 1H-2,3-benzoxazin-4(3H)-one; m.p. 123°-125° C.
Reaction SMILES: [Br:1][C:2]1[C:3]2[O:11][CH:10]=[CH:9][C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1.[CH3:12]I.[NH4+].[Cl-]>CN(C=O)C>[Br:1][C:2]1[C:3]2[O:11][CH:10]=[CH:9][C:4]=2[C:5](=[O:8])[N:6]([CH3:12])[CH:7]=1
Reactant: O=c1[nH]cc(Br)c2occc12
Reactant: CI
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cn1cc(Br)c2occc2c1=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 7-bromo-5H-furo[3,2-c]pyridin-4-one (250 mg, 1.17 mmol) in DMF (5 mL) cooled to 0° C. was added HNa (56 mg, 1.4 mmol, 60% dispersion in mineral oil) in three portions. After stirring at room temperature for 45 min, MeI (87 μl, 1.4 mmol) was added drop wise over five minutes. The reaction was allowed to warm up to rt stirred for 2 h. It was then cooled to 0° C. followed by addition of sat. aq. NH4Cl (5 mL) drop wise. The resulting mixture was extracted with EtOAc (3×5 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound. LCMS: 227.9 (M+H)+
Reaction SMILES: [C:1]([C:5]1[C:10](=[O:11])[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7](=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23])[CH3:18].B(F)(F)F.CCOCC>O1CCCC1>[C:1]([C:5]1[C:10](=[O:11])[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7](=[N:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([O:19][CH2:17][CH3:18])[CH:21]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cccc(N)c1
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOc1cccc(N=C2C=C(C(C)(C)C)C(=O)C(C(C)(C)C)=C2)c1
Yield: 2.7 %

Procedure:
A mixture of 22.0 g (0.10 mole) of 3,5-di-tertiary-butyl-p-benzoquinone, 15.1 g (0.11 mole) of m-ethoxyaniline, 125 ml of tetrahydrofuran and 1 ml of boron trifluoride etherate was heated at reflux for about 40 hours. The reaction mixture was evaporated to give an oil which was partitioned between hexane and 10% hydrochloric acid. The hexane phase was dried by filtering through Whatman IPS phase separation filter paper, then evaporated to give a solid. This solid was triturated with hexane, collected, rinsed with hexane, air dried and then recrystallized from ethanol to give a red solid. 1.0 g of this red solid was recrystallized from ethanol to give 0.9 g of red-orange crystalline 2,6-di-tertiary-butyl-4-(3'-ethoxyphenylimino)-2,5-cyclohexadiene-1-one, m.p. 105°-107° C. Calculated for C22H29NO2 : % C, 77.8; % H, 8.6; % N, 4.1; Found: % C, 77.4; % H, 8.5; % H, 3.9.
Reaction SMILES: O[CH:2]([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[O:27][C@H:26]([CH3:33])[CH2:25]2)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][C@H:5]1[CH2:20]O.S(Cl)(Cl)=O.[CH2:38]([NH2:41])[CH:39]=[CH2:40].[I-].[Na+]>C(OCC)(=O)C>[CH2:38]([N:41]1[CH:2]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[C:28](=[O:32])[O:27][C@H:26]([CH3:33])[CH2:25]3)[CH2:3][N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:6][C@H:5]2[CH2:20]1)[CH:39]=[CH2:40]
Reactant: C[C@@H]1Cc2cc(C(O)CN3CCN(C(=O)OCc4ccccc4)C[C@H]3CO)ccc2C(=O)O1
Reactant: C=CCN
Agent: [I-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: C=CCN1C[C@@H]2CN(C(=O)OCc3ccccc3)CCN2CC1c1ccc2c(c1)C[C@@H](C)OC2=O
Temperature: 90 °C

Procedure:
A solution of (3S)-benzyl 4-(2-hydroxy-2-((R)-3-methyl-1-oxoisochroman-6-yl)ethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (2.07 g, 4.55 mmol) in thionyl chloride (30.0 mL, 411 mmol) was heated at reflux for 1 h. After removing the volatiles, the residue was dissolved in N,N-dimethylformamide (20 mL) and treated with allylamine (1.879 mL, 25.05 mmol) at 0° C. The resulting solution was treated with sodium iodide (0.0680 g, 0.455 mmol) and heated at 90° C. for 1 h. The solution was diluted in ethyl acetate (300 mL) and was washed with saturated sodium bicarbonate three times, dried over sodium sulphate concentrated and the residue was purified on Biotage using 40-100% ethyl acetate/hexane to give the title compound: LC/MS: (M+1)+: 476.14.
Reaction SMILES: [Cl:1][C:2]1([C:14]([OH:16])=O)[N:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][NH:3]1.C(N(CC)CC)C.N1C(F)=NC(F)=NC=1[F:26]>ClCCl>[Cl:1][C:2]1([C:14]([F:26])=[O:16])[N:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][NH:3]1
Reactant: O=C(O)C1(Cl)N=C(NC2CCCC2)C=CN1
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(F)C1(Cl)N=C(NC2CCCC2)C=CN1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
To a suspension of 5.24 (21.68 mmol) of the product prepared in step 3.1 in 140 mL of dichloromethane are added 3.02 mL (21.68 mmol) of triethylamine and then 2.75 mL (35.52 mmol) of cyanuric fluoride. The mixture is stirred at room temperature for 4 hours and the solution is diluted with 150 mL of dichloromethane. The organic phase is washed three times with 200 mL of ice-cold aqueous NaHCO3, dried over MgSO4, filtered and concentrated under vacuum. 5.2 g of the expected product are obtained in the form of an orange solid. Yield=98%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[OH:16].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28]>C1COCC1.O>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([C:27]([F:29])([F:28])[F:30])[CH:20]=2)=[O:26])=[C:3]([OH:16])[CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1O
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(OCc2ccccc2)cc1O
Reaction time: 1.25 h

Procedure:
To a solution of 1.00 g (4.6 mMol) 2-amino-5-benzyloxy-phenol [preparation see: WO 03/045925; page 146] in 15 ml THF, a solution of 1.1 g (5.0 mMol) 4-chloro-3-trifluoromethyl-phenylisocyanate in 15 ml THF is added dropwise. After 75 min at rt, the reaction mixture is diluted in water and EtOAc, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Trituration from hexane gives the crystalline title compound: m.p.: 182-184° C.; HPLC: tRet=17.5.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][C:25](O)=[O:26])=[CH:5][C:4]=2[N:3]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[NH:49]1[CH2:54][CH2:53][S:52](=[O:56])(=[O:55])[CH2:51][CH2:50]1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]([CH2:15][C:16]([CH3:17])([OH:19])[CH3:18])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][C:25]([N:49]3[CH2:54][CH2:53][S:52](=[O:56])(=[O:55])[CH2:51][CH2:50]3)=[O:26])=[CH:5][C:4]=2[N:3]=1
Reactant: COCc1nc2c(N)nc3cc(CCC(=O)O)ccc3c2n1CC(C)(C)O
Reactant: O=S1(=O)CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Product: COCc1nc2c(N)nc3cc(CCC(=O)N4CCS(=O)(=O)CC4)ccc3c2n1CC(C)(C)O
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
3-[4-Amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanoic acid (1.25 g, 3.30 mmol), anhydrous pyridine (75 mL) and 1-hydroxybenzotriazole (892 mg, 6.60 mmol) were combined and the reaction was stirred for 30 minutes. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (1.27 g, 6.60 mmol) was added and the reaction mixture was stirred for an additional 15 minutes. Thiomorpholine 1,1-dioxide (895 mg, 6.60 mmol) was added in one portion. After stirring for 18 hours the solution was concentrated under reduced pressure and the residual foam was dissolved in chloroform (50 mL) and washed with 1% aqueous sodium carbonate (2×25 mL). The combined aqueous washes were extracted with chloroform. The combined organic fractions were concentrated under reduced pressure and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient; 0-25% CMA over 1500 mL, followed by 25-30% CMA over 500 mL, finally 30% CMA over 1000 mL). The resulting material was subjected to a second chromatography purification using a HORIZON HPFC system (silica cartridge, eluting with CMA:chloroform gradient; 0-25% CMA over 1500 mL, followed by 25-30% CMA over 500 mL) followed by recrystallization from acetonitrile to provide 1.07 g of 1-[4-amino-7-[3-(1,1-dioxidothiomorpholin-4-yl)-3-oxopropyl]-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white solid, mp 190-192° C.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[CH:30]=[C:29]([C:34]([O:36]CC4C=CC=CC=4)=[O:35])[CH:28]=[CH:27]5)[CH:14]=[CH:15][C:16]=3[CH2:17][CH2:18][CH2:19][O:20][C:21](=[O:23])[CH3:22])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>O1CCOCC1.[Pd]>[C:1]12([C:11]3[CH:12]=[C:13]([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[CH:30]=[C:29]([C:34]([OH:36])=[O:35])[CH:28]=[CH:27]5)[CH:14]=[CH:15][C:16]=3[CH2:17][CH2:18][CH2:19][O:20][C:21](=[O:23])[CH3:22])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CC(=O)OCCCc1ccc(-c2ccc3cc(C(=O)OCc4ccccc4)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Agent: [Pd]
Solvent: C1COCCO1
Product: CC(=O)OCCCc1ccc(-c2ccc3cc(C(=O)O)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
1.77 g (3.1 mmol) of the diester obtained in Example 44, in solution in 50 ml of dioxane, are hydrogenated in the presence of 530 mg of palladium on carbon (10%) at 50° C., under a hydrogen pressure of 7 bar. After the same treatment as in Example 5 followed by a recrystallization from ethyl acetate, 1.13 g (83%) of the expected product are isolated, which product melts at 260° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1>CC(C)=O.O>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:1]=[N+:2]=[N-:3])(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
Sodium azide (2.7 g, 42 mmol) was added to a cold (0-4° C.) stirred solution of (4-methyl-benzenesulfonyl chloride (8 g, 42 mmol) in acetone:water (1:1, 240 mL) and continued stirring at 0° C. for 2 hr. Concentrated the reaction mixture to get the residue. The residue was extracted with diethyl ether and the organic phase was dried Na2SO4 and concentrated under reduced pressure to afford 7.3 g (88.2% yield) of 4-methyl-benzenesulfonyl azide.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:11]=[C:10]([O:12][CH:13]([F:15])[F:14])[N:9]([CH3:16])[N:8]=2)[N:5]=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].S(Cl)([Cl:23])(=O)=O>C(Cl)Cl>[NH2:1][C:2]1[N:6]([C:7]2[C:11]([Cl:23])=[C:10]([O:12][CH:13]([F:14])[F:15])[N:9]([CH3:16])[N:8]=2)[N:5]=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: Cn1nc(-n2ncc([N+](=O)[O-])c2N)cc1OC(F)F
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: Cn1nc(-n2ncc([N+](=O)[O-])c2N)c(Cl)c1OC(F)F
Reaction time: 0.17 h

Procedure:
1.5 g (5.5 mmole) 5-Amino-4-nitro-1-(1-methyl-5-difluoromethoxy-3-pyrazolyl)pyrazole in 30 ml methylene chloride was treated with 0.74 g (5.5 mmole) sulfuryl chloride and the mixture stirred for 10 minute sat room temperature. It was then concentrated and the residue was recrystallised from diisopropyl ether/ethyl acetate. The mother liquor was concentrated and chromatographed (SiO2 /hexane/ethyl acetate 3:1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:17]3)=[O:15])[C:10]([CH3:26])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][CH:28]([CH3:31])[C:29]#[CH:30]>>[CH2:22]([N:21]([CH2:24][CH3:25])[CH:18]1[CH2:19][CH2:20][N:16]([C:14]([C:11]2[C:10]([CH3:26])=[N:9][N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:30]#[C:29][CH:28]([CH3:31])[CH3:27])[CH:3]=3)[C:12]=2[CH3:13])=[O:15])[CH2:17]1)[CH3:23]
Reactant: CCN(CC)C1CCN(C(=O)c2c(C)nn(-c3cccc(Br)c3)c2C)C1
Reactant: C#CC(C)C
Product: CCN(CC)C1CCN(C(=O)c2c(C)nn(-c3cccc(C#CC(C)C)c3)c2C)C1

Procedure:
In analogy to the procedure described in Example 31F], [1-(3-bromo-phenyl)-3,5-dimethyl-1H-pyrazol-4-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone (1 eq) (Example 28A]) and 3-methyl-1-butyne (1.2 eq) gave the title compound in 90% yield yellow viscous oil. MS: 407.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]([O:10][C:11]2[CH:16]=CC=C[CH:12]=2)=[O:9])[CH:4]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:3]=1.[CH3:28]C(C)([O-])C.[K+].CCOC(C)=O>C1COCC1>[C:11]([O:10][C:8]([N:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:9])([CH3:12])([CH3:16])[CH3:28]
Reactant: CCCCCCCCCCCC1C=C(Cl)C=CN1C(=O)Oc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCC1C=C(Cl)C=CN1C(=O)OC(C)(C)C
Temperature: -42 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
To a stirred solution of the 4-Chloro-1-(phenoxycarbonyl)-2-n-undecyl-1,2-dihydropyridine (5.31 g, 13.62 mmol) in 157 ml of THF at −42° C. was added dropwise over 15 minutes a 11.0M solution of potassium t-butoxide (54.5 ml, 54.5 mmol). The resulting orange solution was stirred for 1 h at −42° C. The cooling bath was removed, and the reaction mixture was allowed to stir for 20 min while being slowly warmed to room temperature. Water (40 ml) and ether (80 ml) were added and the aqueous phase was extracted twice with ether. The combined organic extracts were washed with cold 1.0 N NaOH (2×35 ml), and brine. The organic phase was dried over MgSO4, filtered through Celite, and concentrated by evaporation to give the crude product. Column chromatography with 5% EtOAc in hexanes afforded 3.5 g (83%) of the product as a colorless oil which was homogeneous by TLC analysis. 1H NMR (300 MHz) d 6.92-6.61 (pair of br d, 1H), 5.53 (pair of br d, 1H), 5.55 (br s, 1H), 5.25-5.11 (pair of br d, 1H), 4.82-4.63 (br m, 1H), 1.53 (s, 9H), 1.24 (br s, 20H), 0.83 (t, 3H); 13C NMR (75 MHz) 152.6 (s), 151.8 (s), 127.7 (s), 127.5 (s), 117.8 (s), 117.4 (s), 106.6 (s), 106.2 (s), 81.7 (s), 54.1 (s), 53.2 (s), 34.3 (s), 33.8 (s), 31.9 (s), 29.7 (s), 29.6 (s), 29.5 (s), 29.3 (s), 28.1 (s), 24.3 (s), 22.7 (s), 14.1 (s) ppm; FT-IR 2954, 2926, 2855, 1717, 1633, 1369, 1390, 1171, 1145, 1129, 1054 cm−1.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:51])[C@@H:20]([NH:36][C:37](=[O:50])[C@@H:38]([NH:42][C:43](OC(C)(C)C)=[O:44])[CH:39]([CH3:41])[CH3:40])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH:23]=3)[NH:14]2)=[O:12])[CH:4]=1)=[CH2:2].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(N(CC)C(C)C)(C)C>ClCCl>[CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:51])[C@@H:20]([NH:36][C:37](=[O:50])[C@@H:38]([NH:42][CH:43]=[O:44])[CH:39]([CH3:41])[CH3:40])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][Si:29]([C:32]([CH3:33])([CH3:34])[CH3:35])([CH3:31])[CH3:30])[CH:23]=3)[NH:14]2)=[O:12])[CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccnc(COC(=O)[C@@H]2CCCN(C(=O)[C@H](Cc3cccc(O[Si](C)(C)C(C)(C)C)c3)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)N2)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=Cc1ccnc(COC(=O)[C@@H]2CCCN(C(=O)[C@H](Cc3cccc(O[Si](C)(C)C(C)(C)C)c3)NC(=O)[C@@H](NC=O)C(C)C)N2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of (S)-1-{(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 4-vinyl-pyridin-2-ylmethyl ester (377 mg, 0.52 mmol) in dichloromethane (10 mL) was stirred at 0° C. under nitrogen. Trimethylsilyl trifluoromethanesulfonate (173 mg, 0.14 mL, 0.78 mmol) was added and the reaction mixture was stirred at 0° C. for 1 hour. N,N-Diisopropylethylamine (268 mg, 0.36 mL, 2.08 mmol) was added and the reaction mixture was warmed to room temperature. The solvent was evaporated to afford (S)-1-[(S)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-((S)-2-formylamino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 4-vinyl-pyridin-2-ylmethyl ester (0.52 mmol), which was used crude in the next step. LCMS (m/z) 624 [M+H], Tr=4.30 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[C:11]2[CH:12]=[C:13]([N:16]3[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[NH:18][C:17]3=[O:27])[CH:14]=[CH:15][C:10]=2[S:9][N:8]=1.[C:28](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:28][N:18]1[C:19]([C:23]([F:26])([F:25])[F:24])=[CH:20][C:21](=[O:22])[N:16]([C:13]2[CH:14]=[CH:15][C:10]3[S:9][N:8]=[C:7]([C:3]4[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=4)[C:11]=3[CH:12]=2)[C:17]1=[O:27]
Reactant: O=C([O-])[O-]
Reactant: Cn1cccc1-c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cccc1-c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 0 °C
Yield: 21.5 %

Procedure:
To a mixture of 3-[3-(1-methylpyrrol-2-yl)-1,2-benzisothiazol-5-yl]-6-(trifluoromethyl)uracil(1.35 g, 3.44 mmol), dry dimethylformamide and potassium carbonate (0.710 g, 5.14 mmol) is added iodomethane (0.730 g, 5.14 mmol). The resultant mixture is stirred overnight at room temperature and poured into ice water. Filtration and drying affords the title compound as a pink foam (0.300 g, 21.4%) which is identified by NMR spectral analysis.