Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].Cl.Cl.[CH:22]12[CH2:29][CH2:28][CH:25]([NH:26][CH2:27]1)[CH2:24][NH:23]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:22]12[CH2:29][CH2:28][CH:25]([NH:26][CH2:27]1)[CH2:24][N:23]2[C:10]1[C:11]([F:13])=[C:12]2[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]2[CH2:1][CH3:2])=[CH:8][C:9]=1[F:15]
Reactant: C1CC2CNC1CN2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4CCC3CN4)c(F)c21
Yield: 62.4 %

Procedure:
A solution of 0.81 g (3.0 mmole) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.74 g (4.0 mmole) of 2,5-diazabicyclo[2.2.2]octane dihydrochloride [P. A. Sturm et al., J. Med. Chem., 17, 481 (1974)], 1.65 ml (11 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 40 ml of acetonitrile was stirred at room temperature for 25 hours and heated under reflux for two hours. The reaction mixture was filtered and the solid was washed with methanol to give 0.68 g of the title compound, mp 255°-257°.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=3)[CH2:13][CH:12]([C:27](O)=[O:28])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:31]=[C:32]([C:34]1[CH:39]=[N:38][CH:37]=[CH:36][N:35]=1)[NH2:33]>>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:24])[F:25])[CH:17]=3)[CH2:13][CH:12]([C:27]3[O:28][N:33]=[C:32]([C:34]4[CH:39]=[N:38][CH:37]=[CH:36][N:35]=4)[N:31]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:7]1
Reactant: NC(=NO)c1cnccn1
Reactant: O=C(O)C1CC(c2cccc(OC(F)(F)F)c2)CN(C(=O)N2CCC(O)CC2)C1
Product: O=C(N1CCC(O)CC1)N1CC(c2cccc(OC(F)(F)F)c2)CC(c2nc(-c3cnccn3)no2)C1

Procedure:
60 mg (0.14 mmol) of the compound from Example 194A and 30 mg (0.22 mmol) of N′-hydroxypyrazin-2-carboximidamide were reacted according to the General Method 2. Yield: 36 mg (48% of theory)
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].C([O-])(=O)C.[K+].C(N(CC)CC)C.[CH3:20][C@@H:21]([CH2:25][CH2:26][CH:27]=[C:28](C)[CH3:29])[CH2:22]C=O>O>[C:5]([O:4][CH:1]=[CH:2][C@@H:28]([CH3:29])[CH2:27][CH2:26][CH:25]=[C:21]([CH3:22])[CH3:20])(=[O:7])[CH3:6]
Reactant: CC(C)=CCC[C@H](C)CC=O
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)OC=C[C@@H](C)CCC=C(C)C
Temperature: 120 °C

Procedure:
A 50 mL round-bottom-flask equipped with a condenser was charged with acetic anhydride (6.1 mL, 64.8 mmol), potassium acetate (0.51 g, 5.18 mmol) and triethylamine (4.5 mL, 32.4 mmol). To the stirred mixture was (S)-3,7-dimethyloct-6-enal (5.0 g, 32.4 mmol) slowly. The reaction mixture was heated to 120° C. for 7.5 hours. After cooling to room temperature, the reaction mixture was poured into water (25 mL) and then extracted with toluene (10 mL). The organic layer was washed with saturated aqueous sodium carbonate (25 mL×2) and brine (25 mL). The material was transferred to a 50 ml round-bottom-flask and the separatory funnel was washed with toluene (1 mL). The solution of the title compound in toluene (11 ml) (15.7 g) was used directly for the next step. Mass spectrum (ESI +ve) m/z 187 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([N:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)=[O:32])=[CH:28][CH:29]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2ccc(-c3ccc(-c4nc(-c5ccc(Cl)c(Cl)c5)cs4)cc3C(=O)O)cc2)CC1
Yield: 74.1 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 1-methylpiperazine (available from Aldrich Chemical Company, Inc.; 62 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(4-methyl-piperazine-1-carbonyl)-biphenyl-2-carboxylic acid (86 mg, 75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.20 (br s, 1H), 9.97 (br s, 1H), 8.47 (s, 1H), 8.39 (s, 1H), 8.34 (s, 1H), 8.26 (d, J=8.3 Hz, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.48-7.57 (m, 4H), 3.25-3.44 (m, 8H), 2.81 (br s, 3H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][C:23]([O:25]CC)=[O:24])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:28]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[OH-].[Li+]>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][C:23]([OH:25])=[O:24])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:28]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Agent: [Li+]
Agent: [OH-]
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(CC(=O)O)cc1OCC2

Procedure:
ethyl 2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetate and lithium hydroxide were reacted to give 336. M/z 354.1, calc. 353.15
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[O:9][CH:6]1OC)(=[O:3])[CH3:2].C(OC(C)C)(C)C.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O.[C:40]([O-:43])(=[O:42])[CH3:41].[Na+].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:40]([O:43][CH:6]1[O:9][C@@H:10]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:5]1[O:4][C:1](=[O:3])[CH3:2])(=[O:42])[CH3:41]
Reactant: CC(=O)[O-]
Reactant: COC1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC[C@@H]1OC(OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 0 °C
Yield: 126.5 %

Procedure:
A 100-ml four-necked flask was subjected to nitrogen substitution. 11.32 g (corresponding to 40 mmol of L-ribose) of the 2,3,5-tri-O-acetyl-1-O-methyl-L-ribofuranose obtained in Example B1(1) and 20 ml of diisopropyl ether were added to the flask. The flask was maintained at a temperature of 0±5° C. in an ice bath, and 8.17 g (2.0 equivalents) of acetic anhydride was added thereto. While stirring in an ice bath, 3.2 g (0.8 equivalents) of concentrated sulfuric acid was added dropwise thereto at an internal temperature of 0±5° C. The mixture was stirred in an ice bath for 3.5 hours, and the reaction product was then maintained at 5° C. or lower in a refrigerator overnight. While stirring in an ice bath, 7.87 g of sodium acetate was added to the reaction product, and the obtained mixture was then stirred in an ice bath for 30 minutes. 120 ml of ethyl acetate and a saturated sodium bicarbonate aqueous solution were added to the reaction solution at room temperature until the aqueous layer was neutralized, followed by liquid separation. The aqueous layer was extracted with 120 ml of ethyl acetate, and organic layers were gathered. The gathered layers were washed with 120 ml of a saturated sodium bicarbonate aqueous solution and then with 120 ml of a saturated sodium chloride aqueous solution 2 times. The organic layer was dried over anhydrous sodium sulfate, and the drying agent was then removed by filtration, concentrated under reduced pressure. Thus, 16.10 g of crude 1,2,3,5-tetra-O-acetyl-L-ribofuranose was obtained in the form of yellow oil. The obtained compound was analyzed by HPLC. As a result, it was found that the crude product contained 9.76 g of 1,2,3,5-tetra-O-acetyl-L-ribofuranose, that the ratio of α-/β-anomers was 7/93, and that the total reaction yield of the β-anomer from L-ribose was 72%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[CH:13]=[CH:14][C:15]4[O:19][C:18]([CH2:20][OH:21])=[CH:17][C:16]=4[CH:22]=3)=[N:9]2)=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[CH:13]=[CH:14][C:15]4[O:19][C:18]([CH:20]=[O:21])=[CH:17][C:16]=4[CH:22]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: OCc1cc2cc(-c3ccc4ccc(Cl)cc4n3)ccc2o1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1cc2cc(-c3ccc4ccc(Cl)cc4n3)ccc2o1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85318.9 %

Procedure:
A mixture of 7-chloro-2-(2-hydroxymethylbenzofuran-5-yl)quinoline (767.9 mg) and manganese (IV) oxide (5.01 g) in chloroform (80 ml) was stirred for 5 hours at ambient temperature. The resulting mixture was filtered and the filtrate was concentrated in reduced pressure to give 7-chloro-2-(2-formylbenzofuran-5-yl)quinoline (650.9 g).
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:2]1.[CH:19](=O)[CH2:20][CH2:21][CH3:22].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[CH2:19]([N:9]1[CH2:10][CH2:11][C:6]2([CH2:1][CH2:2][N:3]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4][CH2:5]2)[CH2:7][CH2:8]1)[CH2:20][CH2:21][CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)CC1
Reactant: CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CCCCN1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (150 mg, 0.59 mmol) was dissolved in 10 ml of absolute dichloromethane and admixed with butyraldehyde (52 μl, 1 eq.). With ice bath cooling, 17 μl of glacial acetic acid (0.5 eq.) and sodium triacetoxyborohydride (137 mg, 1.1 eq.) were added. The mixture was stirred at RT for 16 h. Owing to incomplete reaction, butyraldehyde (52 μl, 1 eq.), glacial acetic acid (17 μl, 0.5 eq.) and sodium triacetoxyborohydride (137 mg, 1.1 eq.) were again added. After stirring at RT for a further 4 h, a little water was added and the reaction mixture was washed with saturated NH4Cl solution. The organic phase was dried over MgSO4 and freed from the solvent under reduced pressure. The product was obtained as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([N+:14]([O-])=O)=[CH:9][C:8]=2[F:17])([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH2:14])=[CH:9][C:8]=2[F:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2cc([N+](=O)[O-])cc(F)c2[nH]1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)c1cc2cc(N)cc(F)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.4 %

Procedure:
To a solution of 2-tert-butyl-7-fluoro-5-nitro-1H-indole (2.0 g, 8.5 mmol) in MeOH (20 mL) was added Ni (0.3 g) under nitrogen atmosphere. The reaction mixture was stirred under hydrogen atmosphere (1 atm) at room temperature overnight. The catalyst was filtered off through the celite pad and the filtrate was evaporated under vacuum. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 100:1) to give 2-tert-butyl-7-fluoro-1H-indol-5-amine (550 mg, 24%). 1H NMR (300 MHz, CDCl3) δ 7.87 (brs, 1H), 6.64 (d, J=1.5 Hz, 1H), 6.37 (dd, J=1.8, 12.3 Hz, 1H), 6.11 (dd, J=2.4, 3.6 Hz, 1H), 1.39 (s, 9H). MS (ESI) m/z (M+H+) 207.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1([OH:20])[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22].Cl>C1COCC1>[CH2:13]([N:10]1[CH2:11][CH2:12][C:7]2([O:20][C:21](=[O:22])[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:6]2)[CH2:8][CH2:9]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)NCC1(O)CCN(Cc2ccccc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)N1CC2(CCN(Cc3ccccc3)CC2)OC1=O
Yield: 76.7 %

Procedure:
A mixture of (tert-butyl)(1-benzyl-4-hydroxypiperidin-4-ylmethyl)amine (11.9 g, 43 mmol), 1,1'-carbonyldiimidazole (8.4 g, 52 mmol) and THF (150 mL) was heated 3.5 hours at reflux. The mixture was cooled, poured into dilute hydrochloric acid and then washed with methylene chloride (2× 200 mL). The combined washes were extracted with dilute hydrochloric acid and the combined. aqueous layers were treated with sodium hydroxide and extracted with methylene chloride. The extract was dried (Na2 SO4) and concentrated and the residue was recrystallized from heptane to give 8-benzyl-3-tert-butyl-3,8-diaza-1-oxaspiro[4.5]decane-2-one (9.98 g, 33 mmol), m.p. 110°-112° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]2[C:13](=[O:14])[CH:12]=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.[Br:15][C:16]1[C:23]([O:24][CH2:25][CH3:26])=[C:22]([CH:27](Cl)[CH3:28])[CH:21]=[C:20]([Cl:30])[C:17]=1[C:18]#[N:19]>CN(C)C=O.C(Cl)Cl>[NH2:3][C:4]1[C:5]2[C:13](=[O:14])[CH:12]=[CH:11][N:10]([CH:27]([C:22]3[CH:21]=[C:20]([Cl:30])[C:17]([C:18]#[N:19])=[C:16]([Br:15])[C:23]=3[O:24][CH2:25][CH3:26])[CH3:28])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: Nc1ncnc2[nH]ccc(=O)c12
Reactant: CCOc1c(C(C)Cl)cc(Cl)c(C#N)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1c(C(C)n2ccc(=O)c3c(N)ncnc32)cc(Cl)c(C#N)c1Br
Reaction time: 0.17 h
Yield: 50 %

Procedure:
Sodium hydride (16 mg, 0.41 mmol) was added to a mixture of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (36 mg, 0.22 mmol) in N,N-dimethylformamide (3 mL, 40 mmol) and was stirred for 10 minutes. 2-Bromo-6-chloro-4-(1-chloroethyl)-3-ethoxybenzonitrile (Example 43, step 4) (60 mg, 0.2 mmol in N,N-dimethylformamide (2 mL) was added and the reaction was stirred at 50° C. overnight. The mixture was diluted with methylene chloride, washed with sat'd NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The product was purified by FCC eluting with CH2Cl2/MeOH (0-10%), to give 4-[1-(4-amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-2-bromo-6-chloro-3-ethoxybenzonitrile (0.04 g, 50%) as a solid, LCMS calculated for C18H15BrClN5O2 (M+H)+: m/z=450.0, 448.0; found: 450.0, 448.0.
Reaction SMILES: [F:1][CH:2]([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[CH:30]=[CH:29][C:22]4[N:23](CO)[C:24](=[O:26])[O:25][C:21]=4[CH:20]=3)=[CH:13][N:12]=2)=[CH:6][CH:5]=1>CO.O>[F:31][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[N:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[CH:30]=[CH:29][C:22]4[NH:23][C:24](=[O:26])[O:25][C:21]=4[CH:20]=3)=[CH:13][N:12]=2)=[CH:8][CH:9]=1
Reactant: O=c1oc2cc(OCc3cnc(Nc4ccc(OC(F)F)cc4)nc3)ccc2n1CO
Solvent: CO
Solvent: O
Product: O=c1[nH]c2ccc(OCc3cnc(Nc4ccc(OC(F)F)cc4)nc3)cc2o1
Yield: 86.5 %

Procedure:
6-((2-((4-(difluoromethoxy)phenyl)amino)pyrimidin-5-yl)methoxy)-3-(hydroxymethyl)benzo[d]oxazol-2(3H)-one (0.011 g, 0.026 mmol) was dissolved in a mixture of methanol (2 mL) and water (2 mL). The reaction mixture was sonicated for 15 min. Solvent was concentrated and the residue was lyophilized to give 6-((2-((4-(difluoromethoxy)phenyl)amino)pyrimidin-5-yl)methoxy)benzo[d]oxazol-2(3H)-one as a white solid (0.009 g, 87% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.99 (s, 2H) 6.82 (dd, J=8.53, 2.26 Hz, 1H) 6.94-7.32 (m, 5H) 7.79 (s, 2H) 8.59 (br. s., 2H) 9.84 (s, 1H) 11.42-11.50 (m, 1H). LCMS: R.T.=0.84 min; [M+H]+=401.0.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:17](Br)=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)=O>O.O1CCOCC1>[CH2:1]([NH:8][C:9]1[C:17]([C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(O)c1cnc(NCc2ccccc2)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=CO
Solvent: O
Product: O=C(O)c1cnc(NCc2ccccc2)c(-c2ccc(Cl)cc2)c1
Temperature: 85 °C
Yield: 38.3 %

Procedure:
A mixture of 77 mg (0.25 mmol) 6-benzylamino-5-bromo-nicotinic acid, 58 mg (0.375 mmol) 4-chlorophenyl boronic acid, 9.1 mg 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium (II) dichloromethane complex 1:1 and 0.38 mL 2N Na2CO3 aq. in 0.5 mL water and 2 mL dioxane was heated to 85° C. for 20 h. Formic acid was added, filtered and the mixture was purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/HCOOH. The combined product fractions were evaporated to yield 32.4 mg (38%) of the title compound. MS (m/e): 337.3 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[C:11]3[CH:22]=[C:23]([C:25]([O:27]C)=[O:26])[S:24][C:10]=3[C:9]=2[CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:4][CH:3]=1.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[C:11]3[CH:22]=[C:23]([C:25]([OH:27])=[O:26])[S:24][C:10]=3[C:9]=2[CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(Cl)cc1)n2CC(=O)N1CCOCC1
Agent: BrB(Br)Br
Product: O=C(O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(Cl)cc1)n2CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.15 h
Yield: 47 %

Procedure:
A solution (0.1 M) of methyl 5-(4-chlorophenyl)-6-cyclohexyl-4-(2-morpholin-4-yl-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate was treated with BBr3 (4 eq.) and the mixture was stirred at RT. After 1 h an additional quantity of BBr3 (2 eq.) was added and the mixture was stirred at RT for 1 h, then quenched with aqueous HCl (1 N) and extracted with AcOEt. The combined organic phase was dried and solvent was evaporated under reduced pressure to give a residue which was purified by RP-HPLC (Conditions: Waters X-TERRA MS C18, 10 micron, 19×150 mm; flow: 20 mL/min; Gradient: A: H2O+0.05% TFA; B: MeCN+0.05% TFA; 90% A isocratic for 2 min then linear to 10% A in 9 min) to afford the title compound (47%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]1[NH:7][CH2:8][CH2:9][N:10]=1.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[C:16]1([NH:22][C:23]([N:10]2[CH2:9][CH2:8][N:7]=[C:6]2[CH2:5][O:4][C:3]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:2]=2[CH3:1])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1cccc(OCC2=NCCN2)c1C
Solvent: ClCCl
Product: Cc1cccc(OCC2=NCCN2C(=O)Nc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(2,3-dimethylphenoxymethyl)-2-imidazoline (20.4 g; 1.0 moles) in methylene chloride (300 ml) was cooled to -65° C. and a solution of phenylisocyanate (11.9 g; 1.0 moles) in methylene chloride (300 ml) added dropwise during 30 minutes. The reaction mixture was then allowed to warm to ambient temperature and left to stand for 2 hours, when a precipitate had formed. The reaction mixture was evaporated under reduced pressure and the residue recrystallised from acetone to give 1-N-phenylcarbamoyl-2-(2,3-dimethylphenoxymethyl)-2-imidazoline, m.p. 150°-152° C.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[CH:26]1([CH2:29][NH:30]N)[CH2:28][CH2:27]1.CCN(CC)CC.Cl>CO>[CH:26]1([CH2:29][N:30]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH2:28][CH2:27]1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: NNCC1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1CC1CC1
Temperature: 25 °C
Yield: 43.7 %

Procedure:
A solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (675 mg, 2 mmol), cyclopropylmethylhydrazine hydrochloride (490 mg, 4 mmol), and Et3N (0.558 mL, 4 mmol) in MeOH (20 mL) was refluxed for 2 h. After cooling to room temperature, the reaction mixture was poured into 1 M HCl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from hexane/AcOEt to give the title compound (315 mg, 44% yield) as a pale yellow solid: mp 155-157° C.; 1H NMR (300 MHz, CDCl3): δ ppm 0.35-0.44 (2H, m), 0.45-0.57 (2H, m), 1.24-1.40 (1H, m), 4.37 (2H, d, J=6.8 Hz), 6.76 (1H, d, J=7.9 Hz), 7.37 (1H, d, J=1.9 Hz), 7.61 (1H, d, J=1.9 Hz), 7.68-7.74 (2H, m), 7.78-7.83 (1H, m), 7.94 (1H, s), 8.28 (1H, d, J=7.9 Hz). Anal. Calcd for C18H15F3N4O: C, 60.00; H, 4.20; N, 15.55. Found: C, 60.07; H, 4.24; N, 15.56.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:16]([O-])=O)=[C:5]([C:12]([O:14][CH3:15])=[O:13])[S:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].Cl.[Cl-].[NH4+]>CO.[Fe]>[NH2:16][C:4]1[C:3]([O:2][CH3:1])=[C:7]([C:8]([O:10][CH3:11])=[O:9])[S:6][C:5]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1sc(C(=O)OC)c([N+](=O)[O-])c1OC
Agent: [Fe]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: COC(=O)c1sc(C(=O)OC)c(OC)c1N
Temperature: 70 °C
Yield: 81 %

Procedure:
To a solution of methyl 4-methoxy-5-(methoxycarbonyl)-3-nitrothiophene-2-carboxylate (0.9 g, 3.27 mmol) in methanol (20 mL) was added conc. Hydrochloric acid (0.3 mL). To the above solution was added iron powder (0.91 g, 16.36 mmol) followed by an aqueous solution of ammonium chloride (0.87 g, 16.3 mmol, water: 5 mL) at rt. The reaction mixture was stirred and warmed to 70° C. for 1 h and was then allowed to cool to rt. The solution was filtered and basified with saturated sodium bicarbonate solution. The solution was extracted with ethyl acetate (4×100 mL). The combined organic layer was washed with brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent to give the product as a pale yellow color solid (0.65 g, 81%), mp 120-124° C. NMR (400 MHz, CDCl3): δ 5.39 (2H, br s), 4.01 (3H, s), 3.87 (3H, s), 3.85 (3H, s); LC-MS (positive ion mode): m/z 246 (M+H)+.