Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[OH:19].Cl[CH2:21][C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH:14]1([C:7]2([CH3:13])[CH2:6][C:5]3[C:9](=[C:10]([Cl:11])[C:2]([Cl:1])=[C:3]([O:19][CH2:21][C:22]#[N:23])[CH:4]=3)[C:8]2=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C2CCCC2)Cc2cc(OCC#N)c(Cl)c(Cl)c2C1=O
Yield: 83.8 %

Procedure:
A mixture of 6,7-dichloro-2-cyclopentyl-5-hydroxy-2-methyl-2,3-dihydro-1H-inden-1-one (9.0 g, 30 mmole), chloroacetonitrile (2.5 g, 33 mmole), potassium carbonate (4.15 g), and potassium iodide (0.5 g) in acetone (150 ml) was stirred at reflux for 19 hours. Concentration to dryness in vacuo yielded an oil that crystallized upon trituration with water. Recrystallization from benzene-cyclohexane (ca. 1:3 by volume) gave the title compound (8.5 g), m.p. 129°-131°.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[NH:8][CH2:7][CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>CS(C)=O>[Cl:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[N:8]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=3)[CH2:7][CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: Cc1nc(Cl)nc2c1NCC1COCCN21
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1nc(Cl)nc2c1N(Cc1ccc(S(C)(=O)=O)cc1)CC1COCCN21
Temperature: 25 °C
Reaction time: 48 h
Yield: 21 %

Procedure:
To a round-bottom flask was added 2-chloro-4-methyl-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x20, 264 mg, 1.097 mmol) in DMSO (8.6 mL). Sodium tert-butoxide (126 mg, 1.316 mmol) was then added, followed by 1-(bromomethyl)-4-(methylsulfonyl)benzene (287 mg, 1.152 mmol). The reaction mixture was stirred for 2 days at room temperature. The mixture was subsequently filtered and the filtrate was purified by preparatory HPLC using a gradient of 5-60% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). The fractions were collected and concentrated in vacuo to give the title compound as a yellow solid (94 mg, 21%). ESI-MS m/z [M+H]+ calc'd for C18H21ClN4O3S, 409.1. found 409.6.
Reaction SMILES: [C:1]([C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]([NH:12][C@H:13]([C@@H:17]([OH:19])[CH3:18])[C:14]([OH:16])=O)=[CH:5][CH:4]=1)#[N:2].[C:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=[O:27])=[CH:24][CH:23]=1)#[N:21].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>C1COCC1>[C:20]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH:28][NH:29][C:14](=[O:16])[C@H:13]([NH:12][C:6]2[C:7]3[CH:11]=[CH:10][S:9][C:8]=3[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[C@@H:17]([OH:19])[CH3:18])=[O:27])=[CH:30][CH:31]=1)#[N:21]
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)O
Reactant: N#Cc1ccc(C(=O)NN)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: C1CCOC1
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)NNC(=O)c1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
To a mixture of (2R,3S)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoic acid (0.66 g, 2.39 mmol), 4-cyanobenzhydrazide (390 mg, 2.42 mmol), HOBt (327 mg, 2.42 mmol) in THF (40 mL) was added EDC (696 mg, 3.63 mmol) and Et3N (0.56 mL, 4.02 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min., then at room temperature overnight. The reaction was quenched by adding water and extracted with EtOAc (400 mL). The EtOAc extracts were washed with water, brine and dried over Na2SO4. Removal of the solvent and purification of the residue gave the title compound 4-cyano-N′-((2R,3S)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoyl)benzohydrazide (0.68 g, 68%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.09 (d, J=2.6 Hz, 2H), 7.93 (d, J=8.6 Hz, 2H), 7.81 (d, J=5.7 Hz, 1H), 7.73 (d, J=5.7 Hz, 1H), 7.67 (d, J=8.2 Hz, 1H), 6.68 (d, J=8.2 Hz, 1H), 6.21 (d, J=7.2 Hz, 1H), 4.42 (m, 1H), 4.25 (dd, J=3.9, 7.2 Hz, 1H), 1.39 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1>C(O)(=O)C.[Zn]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1ccnn1C
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(N)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a solution of 5-(2-methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (7.95 g, 34.1 mmol) in acetic acid (250 mL) was added zinc dust (11.7 g, 179 mmol) in portions under cooling in an ice bath over a period of 10 minutes. After stirring for 30 min at room temperature, solids were filtered of through celite. Filtrate was concentrated and residue was purified by SiO2 column chromatography (Eluent: methylene chloride/methanol 20: 1) to give 4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (4.34 g, 21.4 mmol, 62%) as an oil. LCMS m/z (%)=204 (M+H). 1H NMR (400 MHz, CDCl3) δ: 7.51 (d, J=1.8 Hz, 1H), 6.83 (d, J=8.7 Hz, 1H), 6.76 (dd, J=2.8, 8.7 Hz, 1H), 6.62 (d, J=2.8 Hz, 1H), 6.22 (d, J=1.8 Hz, 1H), 3.74 (s, 3H), 3.73 (s, 3H), 3.24-3.55 (broad s, 2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([OH:42])[CH:38]=3)[CH:33]=2)[CH2:27][CH2:26]1)=[O:24])[CH3:21].[CH:43]12[CH2:49][CH:46]([CH:47]=[CH:48]1)[CH2:45][CH:44]2O.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(OC(=O)C)C>[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([O:42][CH:48]4[CH2:47][CH:46]5[CH2:49][CH:43]4[CH:44]=[CH:45]5)[CH:38]=3)[CH:33]=2)[CH2:27][CH2:26]1)=[O:24])[CH3:21]
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(O)ccc3c2)CC1
Reactant: OC1CC2C=CC1C2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(Cc2ccc3cc(OC4CC5C=CC4C5)ccc3c2)CC1
Yield: 8 %

Procedure:
Triphenylphosphine was added to a solution of 1-(6-Hydroxy-naphthalen-2-ylmethyl)-piperidine-4-carboxylic acid ethyl ester (0.4319 g, 0.001378 mol) and bicyclo[2.2.1]hept-5-en-2-ol (0.243 g, 0.00220 mol) in toluene (0.881 mL, 0.00827 mol) and the mixture was stirred for several minutes. Diisopropyl azodicarboxylate (0.434 mL, 0.00220 mol) was then added dropwise and the mixture was stirred at room temperature for 72 hours. The reaction mixture was then diluted in ethylacetate and washed with water, then brine. The organic phase was dried over MgSO4, filtered, concentrated under reduced pressure and purified by flash chromatography (0-40% EtOAc in heptanes) to give the title compound in 8% yield. ESI-MS (M+H+): 406.2.
Reaction SMILES: C([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)(=O)C.[C:17]([O:20]O)(=[O:19])[CH3:18]>C(O)(=O)C>[C:17]([O:20][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:15][CH:16]=1)(=[O:19])[CH3:18]
Reactant: COC(=O)C(C)Oc1ccc(C(C)=O)cc1
Reactant: CC(=O)OO
Solvent: CC(=O)O
Product: COC(=O)C(C)Oc1ccc(OC(C)=O)cc1
Temperature: 58 °C
Yield: 83.8 %

Procedure:
Methyl 2-(4-acetylphenoxy)propanoate (22.4 g, 100.0 mL) is dissolved in acetic acid (100 mL). Purified peracetic acid (19%, 58.0 g, 145.0 mmol) is dropwise added to the reaction at 58° C. and 60 mmHgA. The reaction is refluxed for 10 hours at 58° C. and 60 mm HgA whereupon the reaction is analyzed by GLC. The reaction is cooled to room temperature and concentrated under reduced pressure to give pure methyl 2-(4-acetoxyphenoxy)propanoate (20.13 g) (yield 84%):b.p 96-98° C. at 0.15 mm HgA, IR(neat) 1757.8 (vs); 1H NMR (CDC13) delta 1.58 (d, J=6.9 Hz, 3H), 2.23 (s, 3H), 3.72 (s, 3H), 4.70 (q, J=6.9 Hz, 3H), 6.84 and 6.96 (dd, J=9.2 Hz, 4H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[N:18][NH:19]2)=[CH:15][CH:14]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:19]1[C:20]2[C:16](=[CH:15][CH:14]=[C:13]([NH:12][C:2]3[N:3]=[C:4]([NH2:11])[C:5]4[CH:10]=[CH:9][NH:8][C:6]=4[N:7]=3)[CH:21]=2)[CH:17]=[N:18]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: Nc1nc(Cl)nc2[nH]ccc12
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: Nc1nc(Nc2ccc3cn[nH]c3c2)nc2[nH]ccc12
Temperature: 115 °C
Yield: 12.8 %

Procedure:
To a mixture of 2-chloro-7H-pyrrolo[2,3-d]pyrimidine-4-amine (0.06 g, 0.353 mmol) in nBuOH (0.7 mL) was added 6-aminoindazole (0.094 g, 0.70 mmol) and TMSCl (0.023 mL, 0.175 mmol). After heating at 115° C. for 8 h, it was cooled and purified by prep HPLC to give N2-(1H-indazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2,4-diamine (0.012 g, MS calcd for C13H11N7 265.3, found 266.1; UV 216.9, 308.0 nm).
Reaction SMILES: ClC1C=C(Cl)C=CC=1N1N=C(C(O)=O)C2C3CCC(C4C3=CC=CC=4)C1=2.[CH:27]12[CH2:39][CH2:38][CH:34]([C:35](=[O:37])[CH2:36]1)[C:33]1[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=1.C[Si](C)(C)N[Si](C)(C)C.[Li]CCCC.[C:54](OCC)(=[O:60])[C:55]([O:57][CH2:58][CH3:59])=[O:56]>>[O:60]=[C:54]([CH:36]1[C:35](=[O:37])[CH:34]2[CH2:38][CH2:39][CH:27]1[C:28]1[C:33]2=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:55]([O:57][CH2:58][CH3:59])=[O:56]
Reactant: O=C1CC2CCC1c1ccccc12
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C(O)c1nn(-c2ccc(Cl)cc2Cl)c2c1C1CCC2c2ccccc21
Agent: [Li]CCCC
Product: CCOC(=O)C(=O)C1C(=O)C2CCC1c1ccccc12

Procedure:
The title product was prepared by a procedure similar to that described for step 1 of intermediate 1. From tricyclo[6.2.2.02,7]dodeca-2,4,6-trien-9-one [prepared by one of the methods available in the art of organic synthesis, e.g., as described in Hales et. al. Tetrahedron, 1995, 51, 7777-7790] (2.5 g, 14.53 mmol), hexamethyldisilazane (4.9 ml, 23.2 mmol), 2.34M n-BuLi (10 ml, 23.4 mmol) and diethyl oxalate (3.18 ml, 21.18 mmol) the desired product was obtained (2.3 g, 63%).
Reaction SMILES: C[C@@]12[C@@H](C(NC3C=C(C(F)(F)F)C=CC=3C(F)(F)F)=O)CC[C@H]1[C@@H]1CC[C@H]3NC(=O)C=C[C@]3(C)[C@H]1CC2.[O:38]=[C:39]1[CH2:56][CH2:55][C@@:54]2([CH3:57])[C:41]([CH2:42][CH2:43][C@@H:44]3[C@@H:53]2[CH2:52][CH2:51][C@@:49]2([CH3:50])[C@H:45]3[CH2:46][CH2:47][C@@H:48]2[C:58]([OH:60])=O)=[CH:40]1.S(Cl)([Cl:63])=O>N1C=CC=CC=1>[O:38]=[C:39]1[CH2:56][CH2:55][C@@:54]2([CH3:57])[C:41]([CH2:42][CH2:43][C@@H:44]3[C@@H:53]2[CH2:52][CH2:51][C@@:49]2([CH3:50])[C@H:45]3[CH2:46][CH2:47][C@@H:48]2[C:58]([Cl:63])=[O:60])=[CH:40]1
Reactant: O=S(Cl)Cl
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Agent: C[C@]12C=CC(=O)N[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)Nc3cc(C(F)(F)F)ccc3C(F)(F)F)CC[C@@H]12
Solvent: c1ccncc1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Cl

Procedure:
U.S. Pat. No. 5,565,467 disclosed Dutasteride and process for preparation. According to U.S. Pat. No. '467, Dutasteride may be prepared by reacting 3-oxo-4-androstene-17β-carboxylic acid (II) with thionyl chloride in presence of pyridine to produce 3-oxo-4-androstene-17β-carboxylic acid chloride (IIa), which is further reacted with 2,5-bis(trifluoromethyl)aniline (III) to produce 17β-N-[2,5-bis(trifluoromethyl)-phenyl]carbomoyl-1-androst-4-en-3-one (IV). Oxidation of 17β-N-[2,5-bis(trifluoromethyl)phenyl]carbomoyl-1-androst-4-en-3-one (IV) by treating with aqueous sodium permanganate and sodium periodate under basic conditions produce 17β-N-[2,5-bis(trifluoromethyl)phenyl]carbamoyl-5-oxo-A-nor-3,5-secoandrostan-3-oic acid (V), which is further treated with ammonia in ethylene glycol, followed by hydrogenation to produce 17β-N-[2,5-bis(trifluoromethyl)phenyl]carbamoyl-4-aza-5α-androstan-3-one (VI). Dehydrogenating a compound (VI) using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and bis(trimethylsilyl)trifluoroacetamide in dry dioxane to produce Dutasteride (I).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][CH2:24][CH2:25][CH3:26])[N:14]([CH2:15][C:16]([CH3:22])([CH3:21])[C:17]([O:19]C)=O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[OH-].[K+].C(Cl)(=O)C(Cl)=O.[NH3:35]>CO>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][CH2:24][CH2:25][CH3:26])[N:14]([CH2:15][C:16]([CH3:21])([CH3:22])[C:17]([NH2:35])=[O:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: N
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)C(=O)OC
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)C(N)=O
Reaction time: 8 h

Procedure:
A modification of the methods described in Part C of Example 60 was used to treat methyl 3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanoate (7.6 g, 21 mmol) with potassium hydroxide (44 mL of 0.5 M); additional potassium hydroxide (22 mL) was added after refluxing for four hours. After the reaction was heated at reflux for five days, additional potassium hydroxide (11 mL) was added, and the reaction was heated for four more hours. After the reaction with oxalyl chloride (3.7 mL, 42 mmol) was stirred overnight, additional oxalyl chloride (1.0 mL) was added, and then the reaction was stirred for two hours. After the addition of ammonia in methanol (35 mL), the reaction was stirred for one hour and then concentrated. The residue was stirred with saturated aqueous sodium bicarbonate for 30 minutes, isolated by filtration, and recrystallized three times from methanol/water. During the first recrystallization, a solution in methanol was filtered through a 20 micron filter prior to the addition of water. The resulting crystals were dried overnight in a vacuum oven at 70° C. to provide 1.60 g of 3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanamide as light tan crystals, mp 231-233° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[N:12]([C:14]2[CH:15]=[C:16]([N:20]3[S:24](=[O:26])(=[O:25])[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:22](=[O:35])[CH2:21]3)[CH:17]=[CH:18][CH:19]=2)[CH:13]=1.[Cl:52][C:53]1[N:54]=[N:55][C:56](Cl)=[CH:57][CH:58]=1>>[Cl:52][C:53]1[N:54]=[N:55][C:56]([C:40]2[CH:41]=[CH:42][C:37]([CH2:36][C:11]3[N:12]([C:14]4[CH:15]=[C:16]([N:20]5[S:24](=[O:25])(=[O:26])[N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:33])[CH3:34])[C:22](=[O:35])[CH2:21]5)[CH:17]=[CH:18][CH:19]=4)[CH:13]=[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[N:10]=3)=[CH:38][CH:39]=2)=[CH:57][CH:58]=1
Reactant: CC1(C)OB(c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3cccc(N4CC(=O)N(COCC[Si](C)(C)C)S4(=O)=O)c3)cc2)OC1(C)C
Reactant: Clc1ccc(Cl)nn1
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Cl)nn4)cc3)c2)S1(=O)=O

Procedure:
5-(3-{4-(2,4-Dichloro-phenyl)-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-imidazol-1-yl}-phenyl)-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (385 mg, 0.5 mmol) was treated as described in general procedure G using 3,6-dichloropyridazine (149 mg, 1 mmol) to give 5-{3-[2-[4-(6-chloro-pyridazin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH2:7]Br.[C-:11]#[N:12].[K+]>O1CCOCC1.O.C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH2:7][C:11]#[N:12])[CH:9]=1
Reactant: [C-]#N
Reactant: Fc1ccc(Br)cc1CBr
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: N#CCc1cc(Br)ccc1F
Temperature: 25 °C

Procedure:
5-Bromo-2-fluorobenzyl bromide (8.0 g, 0.03 mole) was dissolved in 1,4-Dioxane (60 mL) and added to a solution of KCN (2.04 g, 0.031 mole) in H2O (20 mL) and ethanol (20 mL). The resulting mixture was heated under reflux for 5 h. After cooling to rt, the product was extracted with ether (200 mL), washed with brine, dried over MgSO4, concentrated, and crystallized from ether/hexane to give 5-bromo-2-fluorophenylacetonitrile as a white crystalline material (5.6 g, 88%): mp 55-58° C.; 1H NMR (DMSO-d6) δ4.07 (s, 2H), 7.29(t, 1H,J=9.23 Hz), 7.60-7.69(m, 2H); MS(EI) M+. m/z 213 ; Anal. Calc. For C8H5Br2FN: C, 44.89, H, 2.35, N, 6.54. Found: C, 44.90, H, 2.24, N, 6.43.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:15])[C:16]4[O:17][C:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[N:19][N:20]=4)=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1nnc(-c2ccccc2)o1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4nnc(-c5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 28, Step 1, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(5-phenyl-[1,3,4]oxadiazol-2-yl)-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23]([O:25]CC)=O)[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:25])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:28])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNC1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCCC2)no1
Temperature: 60 °C
Yield: 112.9 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (300 mg, 0.76 mmol) in ethanol (4 ml) was treated dropwise with pyrrolidine (0.63 ml, 7.60 mmol) and the resulting solution was heated at 60° C. for 9 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane:ethyl acetate (4:1) to afford the title compound as a pale yellow oil (360 mg).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[C:22]4[N:26]([CH:27]=3)[C:25]3[CH:28]=[CH:29][C:30]([CH2:32][CH2:33][C:34]([N:36]5[CH2:41][CH2:40][N:39]([CH2:42][CH3:43])[CH2:38][CH2:37]5)=O)=[CH:31][C:24]=3[S:23]4)=[CH:16][CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(C)C>C1COCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[N:21]=[C:22]4[N:26]([CH:27]=3)[C:25]3[CH:28]=[CH:29][C:30]([CH2:32][CH2:33][CH2:34][N:36]5[CH2:41][CH2:40][N:39]([CH2:42][CH3:43])[CH2:38][CH2:37]5)=[CH:31][C:24]=3[S:23]4)=[CH:18][CH:19]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN1CCN(C(=O)CCc2ccc3c(c2)sc2nc(-c4ccc(NC(=O)Nc5cc(C(C)(C)C)on5)cc4)cn23)CC1
Solvent: CSC
Solvent: C1CCOC1
Product: CCN1CCN(CCCc2ccc3c(c2)sc2nc(-c4ccc(NC(=O)Nc5cc(C(C)(C)C)on5)cc4)cn23)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of N-(5-tert-butyl-isoxazol-3-yl)-N′-(4-{7-[3-(4-ethyl-piperazin-1-yl)-3-oxo-propyl]imidazo[2,1-b][1,3]benzothiazol-2-yl}phenyl)urea from Example 12A (0.17 g, 0.28 mmol) in THF (10 mL) at room temperature was added 2.0 M solution of BH3/Me2S in THF (1 mL). The mixture was heated to reflux for 4 hours. The reaction was quenched by dropwise addition of 10% HCl solution and stirred at room temperature for 15 min. The mixture was basified with saturated NaHCO3 solution and was extracted with dichloromethane. The combined organic extracts were dried over MgSO4 and concentrated. The crude product was purified by Flash chromatography with silica gel using a 30-100% hexane/ethyl acetate gradient followed by a 0-20% methanol/ethyl acetate gradient. The appropriate fractions were collected, combined, and concentrated to give free base, N-(5-tert-butyl-isoxazol-3-yl)-N′-(4-{7-[3-(4-ethyl-piperazin-1-yl)propyl]imidazo[2,1-b][1,3]benzothiazol-2-yl}phenyl)urea. The free base was dissolved in dichloromethane (about 1 mL) and methanol (a few drops). To this solution was added dropwise a 1.0 M solution of HCl/ether (1.3 equivalents) and a precipitate was formed. After evaporation of the solvents, the residue was taken up in ether, filtered, and washed with ether to give the product as a white solid (0.011 g, 6%). 1H NMR (DMSO-d6) δ 9.6 (s, 1H), 9.07 (s, 1H), 8.69 (s, 1H), 7.92 (m, 2H), 7.78 (d, 2H), 7.54 (d, 2H), 7.48 (d, 1H), 6.53 (s, 1H), 3.50 (4H, overlapping with solvent), 3.22 (m, 6H), 2.75 (m, 4H), 2.10 (m, 2H), 1.30 (s, 9H), 1.24 (t, 3H); LC-MS: ESI 586 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C@H:7]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:24])=[N-]>CO>[C:1]([O:5][C:6](=[O:21])[C@H:7]([CH2:16][CH2:17][C:18]([O:20][CH3:24])=[O:19])[NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Reactant: C=[N+]=[N-]
Solvent: CO
Product: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
2.3 g of N-tert.butyloxycarbonyl-L-glutamic acid 1-tert.-butyl ester (7.58 mmol) are dissolved in 80 ml of methanol and a freshly prepared diazomethane solution (23 mmol of Diazald®) is added dropwise at room temperature. After one hour, the solvent is removed under vacuum. The compound is purified using chromatography on silica gel. (column: 18.5*4 cm, DCM/MeOH=99/1, Rf=0.99).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd]>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Product: Nc1ccc(CN2CCN(Cc3ccccc3)CC2)cc1

Procedure:
Prepared analogously to Example Id by catalytic hydrogenation of 1.3 g (4.2 mmol) of 4-(4-benzylpiperazinomethyl)-nitrobenzene over palladium/charcoal.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([O:19][C:20](=[O:29])[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23](Br)[CH:22]=1)[CH3:18]>[Cu]I>[CH2:17]([O:19][C:20](=[O:29])[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([N:7]2[C:8]([NH2:10])=[CH:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6]2)[CH:22]=1)[CH3:18]
Reactant: CCOC(=O)c1cc(Cl)cc(Br)c1
Reactant: CC(C)(C)c1cc(N)[nH]n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cc(Cl)cc(-n2nc(C(C)(C)C)cc2N)c1
Yield: 19.2 %

Procedure:
3-(Tert-butyl)-1H-pyrazol-5-amine (1.10 g, 7.90 mmol), potassium carbonate (2.29 g, 16.6 mmol), and copper (I) iodide (75.0 mg, 1.58 mmol) were weighed into a microwave vial and purged with argon. 3-Bromo-5-chloro-benzoic acid ethyl ester (2.50 g, 9.49 mmol) was then added, followed by trans-N,N′-dimethylcyclohexane-diamine (225 mg, 1.58 mmol) and the reaction vessel purged with argon. The reagents were then solvated with toluene (8 mL), and then degassed with argon, sealed and subjected to microwave irradiation (135° C., 6 h). The reaction mixture was filtered through Celite, concentrated in vacuo and purified by FCC, eluting with 0-10% EtOAc/cyclohexane, to afford the title compound (489 mg, 19%). LCMS (Method 3) Rt 4.26 min, 322.1 [MH+].