Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]2)=[N:6][C:5]=1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])=[CH:27][CH:26]=1)(=[O:3])[NH2:2].[ClH:39]>O1CCOCC1>[N:33]1([C:31]([C:28]2[CH:29]=[CH:30][C:25]([NH:24][C:5]3[N:6]=[C:7]([NH:10][C@@H:11]4[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]4)[N:8]=[N:9][C:4]=3[C:1]([NH2:2])=[O:3])=[CH:26][CH:27]=2)=[O:32])[CH2:34][CH2:35][O:36][CH2:37][CH2:38]1.[ClH:39]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nnc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1nnc(N[C@@H]2CCCNC2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1

Procedure:
(R)-tert-butyl 3-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-ylamino)piperidine-1-carboxylate (74) (180 mg) was treated with 4N HCl in dioxane (30 mL) at RT for 3 h. The mixture was concentrated in vacuo to yield the title compound (75) as HCl salt in quantitative yield. MS found C20H26N8O3 as (M+H)+ 427.1, (M−H)− 425.2. UV: λ=264, 283 nm.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:16])[N:5]([CH2:7][CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH:6]=1.IC1N(CCOC2CCCCO2)C(C)=NC=1.C([Mg]Br)C.[CH3:37][Sn:38](Cl)([CH3:40])[CH3:39].[NH4+].[Cl-]>C(Cl)Cl>[CH3:16][C:4]1[N:5]([CH2:7][CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH:6]=[C:2]([Sn:38]([CH3:40])([CH3:39])[CH3:37])[N:3]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Cc1nc(I)cn1CCOC1CCCCO1
Agent: CC[Mg]Br
Agent: Cc1ncc(I)n1CCOC1CCCCO1
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1nc([Sn](C)(C)C)cn1CCOC1CCCCO1
Temperature: 10 °C
Yield: 63 %

Procedure:
To a mixture of 4-iodo-2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazole and 5-iodo-2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazole (500 mg, 1.9 mmol) in DCM (10 mL) was added ethyl magnesium bromide (0.7 ml, 3 mol/L, 2.2 mmol) at −78° C. The mixture was allowed to warm up to about 10° C. slowly. After cooled to −78° C. again, trimethyltin chloride (2.2 mL, 1 mol/L, 2.2 mmol) was added dropwise. After addition, the mixture was allowed to slowly warm up to room temperature. The reaction mixture was poured into a saturate NH4Cl solution, and extracted with DCM. The combined organic layer was washed with water twice, dried over anhydrous Na2SO4 and concentrated to give 2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(trimethylstannyl)-1H-imidazole (0.44 g, 63%) 1H NMR (CDCl3, 400 MHz): δ 6.93 (s, 1H), 4.54-4.53 (m, 1H), 4.05-4.03 (m, 2H), 3.97-3.93 (m, 1H), 3.61-3.59 (m, 2H), 3.45-3.39 (m, 1H), 2.44 (s, 3H), 1.66-1.47 (m, 6H), 0.26 (s, 9H). LC-MS, m/z 375 [M+H+], which was contaminated with some 2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-5-(trimethylstannyl)-1H-imidazole.
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:9]=[C:10]([O:14][CH3:15])[CH:11]=[CH:12][CH:13]=1.[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])[CH2:17][CH3:18]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([CH:17]([CH3:18])[C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(Br)c1
Reactant: CCC(=O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Product: COc1cccc(C(C)C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 79.1 %

Procedure:
An oven dried Schlenk tube equipped with a rubber septum was cooled under an argon purge. The septum was removed and the tube was charged with palladium acetate (2.3 mg, 0.01 mmol) and sodium t-butoxide (125 mg, 1.3 mmol). The tube was capped with the septum, purged with argon. Toluene (2 mL) was added and the mixture stirred for 1 min at room temperature. 3-Bromoanisole (0.125 mL, 1.0 mmol) and propiophenone (0.16 mL, 1.2 mmol) were added to the tube. The mixture was heated to 80° C. and stirred until the starting halide had been completely consumed, as judged by GC analysis. The mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (10 mL) and diluted with ether (20 mL). The mixture was poured into a separatory funnel and the layers were separated. The aqueous layer was extracted with ether (20 mL), the combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 190 mg (79%) of α-(3-methoxyphenyl)propiophenone. 1H NMR (CDCl3, 300 MHz) 7.93-7.90 (m, 2H), 7.45-7.14 (m, 4H), 6.85-6.68 (m, 3H), 4.61 (q, 3=6.9 Hz, 1H), 3.72 (s, 3H), 1.49 (d, 3H, J=6.9 Hz) ppm.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[N:9](OC)=O.N([O-])=O.[Na+].S(=O)(=O)(O)O>CO>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=[N:9]1
Reactant: Nc1ccccc1N
Reactant: CON=O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: c1ccc2[nH]nnc2c1
Temperature: 50 °C

Procedure:
108 g of freshly distilled 99.8% pure o-phenylenediamine were suspended in 125 ml of methanol and heated to 50° C. At this temperature, gaseous methyl nitrite, prepared from sodium nitrite solution (25% strength), methanol and sulphuric acid (48% strength), was introduced. The rate of addition was such that no off-gas left the reaction flask. As soon as the reaction mixture did not absorb any more gas (about 2 hours), a sample was removed and tested for complete conversion. This was followed by first distilling off methanol and then water from the reaction mixture. With the addition of polywax (polydiol 1550) as a lubricant, the mixture was then distilled continuously through a thin-film evaporator at 4 mbar and a heater temperature of 220° C. Benzotriazole came over at about 165° C. and 4 mbar. Such freshly distilled benzotriazole is 99.9% pure, as analyzed by gas chromatography. It has a slightly yellow colour. On standing for several weeks, the pale yellow colour fades to a palate beige colour.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[N:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)[N:14]=[C:13]([CH2:23][OH:24])[CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[N:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)[N:14]=[C:13]([CH:23]=[O:24])[CH:12]=2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1cccc(Br)c1)c1cc(CO)nn1-c1cccnc1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: O=Cc1cc(S(=O)(=O)c2cccc(Br)c2)n(-c2cccnc2F)n1
Temperature: 90 °C
Reaction time: 5 h
Yield: 75.8 %

Procedure:
{5-[(3-Bromophenyl)sulfonyl]-1-(2-fluoropyridin-3-yl)-1H-pyrazol-3-yl}methanol (371 mg) was dissolved in toluene (5 mL), manganese dioxide (626 mg) was added and the mixture was stirred at 90° C. for 5 hr. The reaction mixture was allowed to cool to room temperature, and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→3:1) to give the title compound as a colorless solid (yield 280 mg, yield 76%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([CH3:11])=[CH:7]2.C[Mg]Br.[Cl:15][C:16]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].[NH4+].[Cl-]>C1COCC1.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([CH3:11])=[C:7]2[C:18]([C:17]1[CH:21]=[CH:22][CH:23]=[C:24]([Cl:25])[C:16]=1[Cl:15])=[O:19]
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Reactant: Cc1cc2cccc(Br)c2[nH]1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1[nH]c2c(Br)cccc2c1C(=O)c1cccc(Cl)c1Cl
Temperature: -10 °C

Procedure:
10.7 g of 7-bromo-2-methyl-1H-indole are placed in 100 ml of THF and the mixture is cooled to −10° C. 22 ml of 3M methylmagnesium bromide in ether are added at this temperature. The mixture is allowed to return to AT and is then cooled to −5° C. and 13.5 g of 2,3-dichlorobenzoyl chloride, dissolved in 80 ml of THF, are added dropwise. The medium is allowed to return to AT and is then poured onto a saturated NH4Cl solution. Extraction is carried out with ether and then the organic phase is washed with a 10% NaOH solution, water and a saturated NaCl solution. It is dried and evaporated and the residue is chromatographed on silica while eluting with an AcOEt/cyclohexane (10/90, v/v) mixture. The product obtained crystallizes from ether and 5 g of the expected compound are obtained.
Reaction SMILES: NC1N(CC2C=CC(Cl)=CC=2)C2N(CC(C)N=2)C(=O)C=1N=O.S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[NH2:33][C:34]1[N:35]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=2)[C:36]2[N:37]([CH2:44][CH:45]([CH3:47])[N:46]=2)[C:38](=[O:43])[C:39]=1[NH:40][CH:41]=O>C(O)=O>[Cl:55][C:52]1[CH:53]=[CH:54][C:49]([CH2:48][N:35]2[C:34]3[NH:33][CH:41]=[N:40][C:39]=3[C:38](=[O:43])[N:37]3[CH2:44][CH:45]([CH3:47])[N:46]=[C:36]23)=[CH:50][CH:51]=1
Reactant: CC1CN2C(=O)C(NC=O)=C(N)N(Cc3ccc(Cl)cc3)C2=N1
Agent: CC1CN2C(=O)C(N=O)=C(N)N(Cc3ccc(Cl)cc3)C2=N1
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O=CO
Product: CC1CN2C(=O)c3nc[nH]c3N(Cc3ccc(Cl)cc3)C2=N1

Procedure:
The nitroso compound of Procedure 99 was reduced with sodium dithionate in formic acid according to the method of Procedure 21. The resulting 7-amino-8-[(4-chlorophenyl)methyl]-2,3-dihydro-6-formylamino-2-methylimidazo[1,2-a]pyrimidin-5(8H)-one, 185 g., (0.54 mole) was then dissolved with heating in 1 l. of 0.6N NaOH, the solution clarified by filtration, the filtrate acidified with acetic acid, and allowed to cool resulting in precipitation of the desired product, yield 71.7 g., recrystallized from ethylene glycol monomethyl ether/(iPr)2O, m.p. 259°-260.5°.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:8]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)[C:7](=[O:21])[C:6]2([CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[NH:5]1.CS(C)=O>O>[O:3]=[C:4]1[N:8]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:18])[F:19])[CH:10]=2)[C:7](=[O:21])[C:6]2([CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:5]1[CH2:23][CH2:22][CH2:6][CH2:7][OH:21]
Reactant: N#Cc1ccc(N2C(=O)NC3(CCOCC3)C2=O)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(N2C(=O)N(CCCCO)C3(CCOCC3)C2=O)cc1C(F)(F)F
Reaction time: 0.5 h
Yield: 179 %

Procedure:
55 mg of 50% sodium hydride were introduced and 340 mg of the product of Example 2 and 25 ml of dimethylsulfoxide were added dropwise over 25 minutes. Rinsing was carried out with 0,5 ml of dimethylsulfoxide and 20 minutes after the release of hydrogen had stopped, 0.41 g of 4-iodobutoxy-trimethyl-silane was added. The mixture was allowed to react for 18 hours at ambient temperature and the reaction medium was then poured into 10 ml of water. Extraction was carried out 4 times with ether and the organic phase was washed with water, then with salt water, dried and taken up in a mixture of 10 ml of methanol and 1 ml of 2N hydrochloric acid. After 30 minutes, the mixture was poured into 20 ml of saturated sodium chloride solution and extraction was carried out 3 times with chloroform, followed by drying. Purification was carried out on silica with methylene chloride-acetone 8-2 as eluant to obtain 369 mg of the expected product (friable white foam).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[S:14][CH:15]=[C:16]([CH2:18]Cl)[N:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:20]1([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[CH:24]=[N:23][N:22]=[N:21]1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[S:14][CH:15]=[C:16]([CH2:18][O:31][C:28]3[CH:29]=[CH:30][C:25]([N:20]4[CH:24]=[N:23][N:22]=[N:21]4)=[CH:26][CH:27]=3)[N:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(CCl)cs2)C1
Reactant: Oc1ccc(-n2cnnn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)C1

Procedure:
A mixture of 3-(4-Chloromethyl-thiazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (From Step 1) (775 mg, 2.56 mmol), 4-tetrazol-1-yl-phenol (415 mg, 2.56 mmol), Cs2CO3 (1.25 mg, 3.84 mmol) and KI (44 mg, 0.26 mmol) in acetonitrile (20 mL) was heated under reflux overnight. After cooling, the solid was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was purified on silica gel (EtOAc-hexanes, 1:1) to afford the desired product. 1H NMR (CDCl3): δ 8.92 (1H, s), 7.63 (2H, d), 7.27 (1H, s), 7.17 (2H, d), 5.24 (2H, s), 3.87 (1H, m), 3.79 (1H, m), 3.65 (2H, m), 3.45 (1H, m), 2.40 (1H, m), 2.23 (1H, m), 1.47 (9H, s).
Reaction SMILES: [C:1]([O:5][C:6]([C@@:9]12[CH2:18][CH2:17][CH2:16][CH2:15][C@:14]1([OH:19])[CH2:13][CH2:12][CH2:11][CH2:10]2)([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:20]=[C:21]1[O:25][C:23](=[O:24])[CH2:22]1.C(N(CC)CC)C>O1CCCC1>[C:23]([O:19][C@@:14]12[CH2:15][CH2:16][CH2:17][CH2:18][C@:9]1([C:6]([O:5][C:1](=[O:4])[CH:2]=[CH2:3])([CH3:8])[CH3:7])[CH2:10][CH2:11][CH2:12][CH2:13]2)(=[O:24])[CH2:22][C:21]([CH3:20])=[O:25]
Reactant: C=C1CC(=O)O1
Reactant: C=CC(=O)OC(C)(C)[C@]12CCCC[C@@]1(O)CCCC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)OC(C)(C)[C@]12CCCC[C@@]1(OC(=O)CC(C)=O)CCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 100 mmol of 4a-(1-acryloyloxy-1-methylethyl)-8a-hydroxy-cis-decalin prepared in the same manner as in Example 4, 110 mmol of diketene, 110 mmol of triethylamine, and 300 ml of tetrahydrofuran was stirred at room temperature for 2 hours. The resulting reaction mixture was subjected to chromatography on a silica gel to yield 8a-acetoacetyloxy-4a-(1-acryloyloxy-1-methylethyl)-cis-decalin represented by the following formula (yield: 89.1%). The conversion rate from 4a-(1-acryloyloxy-1-methylethyl)-8a-hydroxy-cis-decalin was 99%.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:11]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>CC#N>[N:11]1([C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: Clc1nc2ccccc2o1
Reactant: C1CNCCNC1
Solvent: CC#N
Product: c1ccc2oc(N3CCCNCC3)nc2c1
Yield: 38.7 %

Procedure:
In a 40 mL vial at room temperature, 2-chlorobenzo[d]oxazole (760 mg, 5 mmol) was added to a solution of homopiperazine (2 g, 20 mmol) in CH3CN. The reaction mixture gradually turned into a suspension. Upon standing for additional half an hour, solid was filtered off and the collected filtrate was directly subjected to chromatography (Isco, gradient elution, CH2Cl2 to 9:1 CH2Cl2/MeOH). 420 mg of the desired product was isolated (MS, M++H=218.1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:24][CH:25]([F:42])[O:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:32]=1>>[F:24][CH:25]([F:42])[O:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:30]=[N:29][CH:28]=1
Reactant: CC1(C)OB(c2cncc(OC(F)F)c2)OC1(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(OC(F)F)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-difluoromethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 183.1.1) to give the title compound as a white foam. (HPLC: tR 2.48 min (Method A); M+H=437 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.01 (s, 1H), 8.61-8.59 (m, 1H), 8.52-8.50 (m, 1H), 8.17-8.13 (m, 2H), 8.02-7.98 (m, 1H), 7.74-7.71 (m, 1H), 7.61-7.59 (m, 1H), 7.39 (t, 1H), 3.90 (s, 3H), 3.59 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:11]2[CH2:14][C:13](=[C:15]([C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=3)[S:16]([CH3:19])(=[O:18])=[O:17])[CH2:12]2)=[CH:6][CH:5]=1)([OH:3])=O.Cl.C[NH:37][CH:38](N=C=NCC)[CH2:39]CNC.O.OC1C2N=NNC=2C=CC=1.C(N)C>C1COCC1.C(OCC)(=O)C.C1CCCCC1.ClCCl>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([CH:10]([C:7]2[CH:6]=[CH:5][C:4]([C:1](=[O:3])[NH:37][CH2:38][CH3:39])=[CH:9][CH:8]=2)[N:11]2[CH2:14][C:13](=[C:15]([C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=3)[S:16]([CH3:19])(=[O:17])=[O:18])[CH2:12]2)=[CH:33][CH:32]=1
Reactant: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(C(=O)O)cc2)C1)c1cc(F)cc(F)c1
Reactant: CCN=C=NC(CCNC)NC
Agent: CCN
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CCNC(=O)c1ccc(C(c2ccc(Cl)cc2)N2CC(=C(c3cc(F)cc(F)c3)S(C)(=O)=O)C2)cc1
Yield: 29.7 %

Procedure:
The operation is carried out as in Example 52, starting with 1 g of (RS)-1-{(4-carboxyphenyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, 0.38 g of 1,3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride, 22 mg of hydroxybenzotriazole hydrate, 30 cm3 of dichloromethane and 0.83 cm3 of a 2 M ethylamine solution in THF, chromatographing on a silica gel column (particle size 0.04-0.06 mm, diameter 4.1 cm, height 15 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (45/55 by volume) as eluent and collecting 30 cm3 fractions. Fractions 22 to 32 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.29 g of (RS)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine is obtained in the form of a white solid [NMR spectrum in DMSO-d6, T=300K, δ in ppm (300 MHz): 1.07 (3H, t, J=6 Hz, CH3), 3.00 (3H, s, SCH3), 3.35 (2H, m, NCH2), 3.90 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.80 (1H, s, NCH), 7.15 (2H, d, J=8 Hz, 2CH arom.), 7.30 (1H, t, J=8 Hz, CH arom.), 7.35 (2H, d, J=7 Hz, 2CH arom.), 7.48 (4H, m, 4CH arom.), 7.74 (2H, d, J=7 Hz, 2CH arom.), 8.37 (1H, t, CONH)].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([SH:12])[C:6]=1[C:13]#[N:14])[CH3:2].Br[CH2:17][C:18]([NH2:20])=[O:19].[O-]CC.[Na+]>CO>[CH2:1]([O:3][C:4]([C:5]1[C:6]2[C:13]([NH2:14])=[C:17]([C:18](=[O:19])[NH2:20])[S:12][C:7]=2[N:8]=[C:9]([CH3:11])[CH:10]=1)=[O:15])[CH3:2]
Reactant: CCOC(=O)c1cc(C)nc(S)c1C#N
Reactant: NC(=O)CBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1cc(C)nc2sc(C(N)=O)c(N)c12
Temperature: 25 °C
Yield: 21 %

Procedure:
To a stirred solution of 2-cyanothioacetamide (3.52 g, 35 mmol) and ethyl 2,4-dioxovalerate (5.0 g, 32 mmol) in anhydrous EtOH (75 mL) at room temperature was added triethylamine (0.5 mL) and the reaction was stirred overnight. Filtration and washing of the precipitates with EtOH gave 3-cyano-2-mercapto-6-methyl-isonicotinic acid ethyl ester as a yellow solid (4.54 g, 64.5%). A mixture of this ester (3.54 g, 16 mmol), bromoacetamide (2.15 g, 16 mmol) and sodium ethoxide (2.18 g, 32 mmol) in MeOH was heated at reflux overnight. It was then allowed to cool to room temperature. Filtration and washing of the precipitates with EtOH provided 3-amino-2-carbamoyl-6-methyl-thieno[2,3-b]pyridine-4-carboxylic acid ethyl ester as a solid (0.94 g, 21.1%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.[CH:18]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[CH2:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:23]1[CH:24]=[CH:25][C:20]([CH:18]=[CH:19][C:2]2[CH:3]=[C:4]3[CH2:10][C@:9]4([CH:15]5[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]5)[CH2:11]4)[O:8][C:5]3=[N:6][CH:7]=2)=[CH:21][CH:22]=1
Reactant: C=Cc1ccncc1
Reactant: Brc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C(=Cc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2)c1ccncc1
Temperature: 102.5 °C
Yield: 72 %

Procedure:
(R)-(-)-5'-Bromospiro[1-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine] (295 mg, 1 mmol),4-vinylpyridine (0.135 mL, 1.25 mmol), palladium(II)acetate (7.2 mg,0.032 mmol), tri-o-tolylphosphine (38.7 mg, 0.127 mmol), and triethylamine (0.5 mL, 3.6 mmol) in anhydrous acetonitrile (0.5 mL) were combined in a heavy-walled threaded glass tube containing a magnetic stir bar, purged with argon and sealed with a Teflon plug and FETFE O-ring. The mixture was stirred and heated at 100 to 105° C. for 48 hours, cooled to room temperature, dissolved in chloroform (25 mL), washed with saturated aqueous sodium carbonate (2 mL), dried (MgSO4), and evaporated under reduced pressure. Purification by flash chromatography through silica gel (eluting with ammoniated chloroform/methanol, 95:5), followed by recrystallization from acetone afforded the title compound (230 mg, 0.72 mmol, 72%): electrospray MS (m/z, relative intensity) 320 ([MH]+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[N:24]4[N:25]=[CH:26][CH:27]=[C:28]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[C:23]4=[N:22][C:21]=3[C:35]([OH:37])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[NH2:53][C:54]1[CH:63]=[CH:62][C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[N:55]=1>O.CN(C=O)C.C(Cl)Cl>[O:32]1[CH2:31][CH2:30][N:29]([C:28]2[C:23]3[N:24]([C:20]([C:17]4[CH:16]=[CH:15][C:14]([N:11]5[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]5)=[N:19][CH:18]=4)=[C:21]([C:35](=[O:37])[NH:53][C:54]4[CH:63]=[CH:62][C:61]5[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=5)[N:55]=4)[N:22]=3)[N:25]=[CH:26][CH:27]=2)[CH2:34][CH2:33]1
Reactant: Nc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(C(=O)O)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(C(=O)Nc4ccc5ccccc5n4)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Reaction time: 0.33 h

Procedure:
Compound 20c (258 mg, 0.506 mmol) was placed in a 20 mL vial equipped with a stir bar and then DCM (4 mL) and DMF (10 μL) were added. Oxalyl chloride (66.2 μL, 0.759 mmol) was added dropwise via syringe and the reaction was stirred for 20 min. The solvent was removed under reduced pressure. The residue was dissolved in DCM (25 mL) and then DIEA (440 μL, 2.53 mmol) and 2-aminoquinoline (87.5 mg, 0.607 mmol) were added sequentially. The reaction was stirred at rt for 16 h and then poured into water (20 mL) and separated. The aqueous layer was extracted with DCM (3×10 mL) and the combined organic layers were dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude residue was chromatographed on a 12 g SiO2 pre-packed column eluting with 0-100% EtOAc/DCM to afford compound 20d. 1H-NMR (400 MHz, CDCl3) δ (ppm): 9.99 (s, 1H), 8.59-8.64 (m, 2H), 8.16 (d, J=9.0 Hz, 1H), 8.06 (d, J=5.6 Hz, 1H), 7.96 (dd, J=8.8, 2.4 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.65-7.71 (m, 1H), 7.42-7.48 (m, 1H), 6.79 (d, J=8.8 Hz, 1H), 6.15 (d, J=5.9 Hz, 1H), 4.04-4.10 (m, 4H), 3.98-4.04 (m, 4H), 3.63-3.70 (m, 4H), 3.54-3.60 (m, 4H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C34H37N9O4: 636.3 (M+H). Found: 636.4.