Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([CH:9]([S:17][C:18]3[NH:22][N:21]=[N:20][N:19]=3)[CH2:10][CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:7][S:8][C@H:3]12.C(N(CC)CC)C.[F:35][C:36]([F:45])([F:44])[CH2:37][S:38]([CH2:40][C:41](O)=[O:42])=[O:39]>CN(C)C=O>[F:35][C:36]([F:45])([F:44])[CH2:37][S:38]([CH2:40][C:41]([NH:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([CH:9]([S:17][C:18]3[NH:19][N:20]=[N:21][N:22]=3)[CH2:10][CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:7][S:8][C@H:3]12)=[O:42])=[O:39]
Reactant: CS(=O)(=O)NCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(O)CS(=O)CC(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CS(=O)CC(F)(F)F)[C@H]2SC1
Reaction time: 0.25 h

Procedure:
A suspension of 4.35 g (0.01 mol) of 7β-amino-3-[1-(2methanesulfonamidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 50 ml of dry dimethylformamide is treated with 2 ml of triethylamine and the mixture is stirred for 15 minutes at 25°. A slight excess of 0.01 mol of the activated ester of 2,2,2-trifluoroethylsulfinylacetic acid is added to the mixture and it is stirred an additional hour. The reaction mixture is evaporated to dryness and water and ethyl acetate are added to the residue. The layers are separated, the ethyl acetate layer is discarded, fresh ethyl acetate is added to the aqueous phase and it is acidified to pH 2.5 by addition of 6N hydrochloric acid. The mixture is filtered, the layers are separated and the aqueous phase is extracted with ethyl acetate. The combined extracts are washed with water, dried (MgSO4) and evaporated to dryness to give the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2/C=C/C(NS(C2SC=CC=2)(=O)=O)=O)[CH:3]=[CH:2]1.C([BH3-])#N.[Na+]>C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(/C=C/c1cccc2cc[nH]c12)NS(=O)(=O)c1cccs1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: c1ccc2c(c1)CCN2
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a suspension of thiophene-2-sulfonic acid ((E)-3-1H-indol-7-yl-acryloyl)-amide I-4 (120 mg, 0.39 mmol) in acetic acid (glacial, 10 mL) was added sodium cyanoborohydride (95%, 150 mg, 2.5 mmol) portion wise at rt. The mixture which resulted was allowed to heat and stir at 70° C. for 4 h. The reaction mixture was cooled to 0° C. and the reaction was quenched with the addition of water (10 mL) at 0° C. The mixture was acidified with addition of aq HCl (10%) until PH=1, which was followed by extraction of CH2Cl2/MeOH (20:1, 3×30 mL). The combined organic layers were dried (Na2SO4) and the solvent was removed under reduced pressure to provide the crude product which was purified by flash chromatography (silica gel, EtOAc/hexane,=1:5-1:1) to afford desired indoline I-18 (80 mg, 65%) as a white solid. MS(ESI−)m/z=335.2. To a stirring solution of the indoline I-18 (37 mg, 0.11 mmol) in CH2Cl2 (7 mL) was added triethylamine (21 mg, 0.22 mmol) and then 2-naphthalenesulfonyl chloride (25 mg, 0.1 mmol) at 0° C. The mixture which resulted was allowed to warm to rt and stir at rt for 24 h. The reaction mixture was cooled to 0° C. then acidified with addition of aq HCl (10%) until PH=1, which was followed by extraction of CH2Cl2/MeOH (10:1, 3×20 mL). The combined organic layers were dried (Na2SO4) and the solvent was removed under reduced pressure to provide the crude product which was purified by flash chromatography (silica gel, EtOAc/hexane,=1:5-1:1) to afford desired product P045 (12 mg, 21%) as a light yellow solid. MS(ESI−)m/z=523.5, 100%), LCMS(ESI−)>70%. 1H NMR (500 MHz, CD3OD) 2.11 (t, J=8.0 Hz, 2H), 4.08 (t, J=8.0 Hz, 2H), 6.62 (d, J=16.0 Hz, 1H), 7.01 (dd, J=7.5, 1.0 Hz, 1H) 7.11 (dd, J=5.0, 4.0 Hz, 1H), 7.19 (dd, J=7.5, 7.5 Hz, 1H), 7.36 (dd, J=8.5, 2.0 Hz, 1H), 7.60 (m, 1H), 7.67 (m, 2H), 7.73 (dd, J=5.5, 1.5 Hz, 1H), 7.79 (dd, J=3.5, 0.5 Hz, 1H), 7.87 (m, 2H), 7.93 (d, J=8.5 Hz, 1H), 8.06 (s, 1H), 8.19 (d, J=16.0 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:3]=1[CH3:18].[O:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:26]=[C:27]3[NH:33][CH2:32][C:31]4([CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[C:28]3=[N:29][CH:30]=2)[CH2:21][CH2:20]1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[CH3:18][C:3]1[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:5][C:6]2[C:11]([C:2]=1[N:33]1[C:27]3[C:28](=[N:29][CH:30]=[C:25]([N:22]4[CH2:23][CH2:24][O:19][CH2:20][CH2:21]4)[CH:26]=3)[C:31]3([CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH2:32]1)=[CH:10][CH:9]=[N:8][CH:7]=2
Reactant: c1nc2c(cc1N1CCOCC1)NCC21CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2cnccc2c1Cl
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cnccc2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y by using 4-chloro-3-methyl-2-(pyridin-2-yl)-1,7-naphthyridine (70 mg, 0.274 mmol), 6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (75 mg, 0.274 mmol), sodium tert-butoxide (52.6 mg, 0.548 mmol) and XPhos precatalyst (20 mg, 0.027 mmol) with heating in toluene (4 mL) for 2 h at 110° C. Purification by reverse phase HPLC (to 10 50% acetonitrile water) gave 1′-(3-methyl-2-(2-pyridinyl)-1,7-naphthyridin-4-yl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]-pyridine]. 1H NMR (400 MHz, chloroform-d) δ ppm 9.60 (1H, d, J=1.0 Hz), 8.75 (1H, dt, J=4.8, 1.5 Hz), 8.55 (1H, d, J=5.9 Hz), 7.92-8.01 (2H, m), 7.65 (1H, d, J=2.3 Hz), 7.51 (1H, dd, J=5.7, 1.0 Hz), 7.43 (1H, ddd, J=6.0, 4.8, 2.9 Hz), 5.84 (1H, d, J=2.3 Hz), 4.12-4.20 (2H, m), 3.93-4.05 (2H, m), 3.71-3.77 (4H, m), 3.52-3.62 (2H, m), 2.95-3.12 (4H, m), 2.47 (3H, s), 2.28-2.43 (2H, m), 1.69-1.88 (2H, m). Mass Spectrum (ESI) m/e=495.0 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:33][CH3:34])=[CH:11][C:12]([C:27]2[N:31]=[C:30]([CH3:32])[O:29][N:28]=2)=[C:13]([CH:15]([O:23]C(=O)C)[C:16](=[O:22])[NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CO.C(OCC)(=O)C>O>[CH2:1]([O:8][C:9]1[C:10]([O:33][CH3:34])=[CH:11][C:12]([C:27]2[N:31]=[C:30]([CH3:32])[O:29][N:28]=2)=[C:13]([CH:15]([OH:23])[C:16]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:22])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(-c2noc(C)n2)c(C(OC(C)=O)C(=O)NC(C)(C)C)cc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(-c2noc(C)n2)c(C(O)C(=O)NC(C)(C)C)cc1OCc1ccccc1
Yield: 100.4 %

Procedure:
A mixture of acetic acid [5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]-tert-butylcarbamoyl methyl ester (Reference example 12-1) (604 mg), a 5 mol/L aqueous solution of sodium hydroxide (1 mL) and methanol (8 mL) was stirred at room temperature for 1.5 hours. Ethyl acetate and water were added to the mixture. The separated organic layer was washed with water, an aqueous solution of sodium bicarbonate successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (552 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]3[C:29]4[CH2:30][NH:31][C:32](=[O:33])[C:28]=4[CH:27]=[CH:26]N=3)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.Cl[C:35]1C2CNC(=O)C=2C=CN=1.BrC1C=CC=C2C=1CNC2=O>>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]3[CH:35]=[CH:26][CH:27]=[C:28]4[C:29]=3[CH2:30][NH:31][C:32]4=[O:33])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:10])[F:11])[CH:7]=1
Reactant: O=C1NCc2c1ccnc2Cl
Reactant: O=C1NCc2c1ccnc2-c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1
Agent: O=C1NCc2c(Br)cccc21
Product: O=C1NCc2c1cccc2-c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1

Procedure:
The synthesis of the title compound is performed starting from 100 mg (0.25 mmol) of the product from step 3 of the compound from example 6 in a manner analogous to step 4 from example 6, whereby instead of the compound from example 22A, 4-bromo-2,3-dihydroisoindole-1-on (63 mg, 0.30 mmol) is used. This produces 64 mg (56% of theoretical yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11]C(=O)CCl)([CH3:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.NC(N)=S.C(O)(=O)C.O>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:11])([CH3:9])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(NC(=O)CCl)c1cccc(Br)c1
Agent: NC(N)=S
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(N)c1cccc(Br)c1

Procedure:
The mixture of N-[1-(3-bromo-phenyl)-1-methyl-ethyl]-2-chloro-acetamide (1.0 g, 3.5 mmol), thiourea (0.32 g, 4.2 mmol), acetic acid (1.5 mL) in ethanol (7 mL) was heated to reflux for 10 h and brought to room temperature. Water was added to the mixture until a precipitate was formed which was filtered. The filtrate was made basic pH 7-8 with 15% NaOH. The product was extracted with ethyl acetate and concentrated to afford a yellow solid. M+1=214.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:37][CH2:36][C:35]3[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=3[NH:33][C:32]2=[O:42])[CH2:27][CH2:26]1>C1COCC1>[N:10]1([C:8]([C:4]2[CH:3]=[C:2]([N:25]3[CH2:26][CH2:27][CH:28]([N:31]4[CH2:37][CH2:36][C:35]5[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=5[NH:33][C:32]4=[O:42])[CH2:29][CH2:30]3)[CH:7]=[CH:6][N:5]=2)=[O:9])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: O=C(c1cc(Cl)ccn1)N1CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(c1cc(N2CCC(N3CCc4ccccc4NC3=O)CC2)ccn1)N1CCc2ccccc21

Procedure:
110 mg (0.43 mmol) (4-chloro-pyridin-2-yl)-(2,3-dihydro-indol-1-yl)-methanone, 150 mg (1.0 mmol) potassium carbonate and 100 mg (0.41 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one in 10 mL THF were refluxed for 3 days. Then the reaction mixture was evaporated down using the rotary evaporator, taken up in 20 mL xylene and refluxed for a further 3 days. The solid was filtered off and the filtrate evaporated down i. vac. The residue was dissolved in DMF and purified by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[C:7]([C:9]([NH2:11])=O)[NH:6][N:5]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[N+:1]([C:4]1[CH:8]=[C:7]([C:9]#[N:11])[NH:6][N:5]=1)([O-:3])=[O:2]
Reactant: NC(=O)c1cc([N+](=O)[O-])n[nH]1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: N#Cc1cc([N+](=O)[O-])n[nH]1

Procedure:
3-nitro-1H-pyrazole-5-carboxamide (3.0 g, 19.2 mmol) in pyridine (30 mL) was treated with phosphorus oxychloride (5.9 g) and the resultant solution was stirred for 3 h at rt. The reaction mixture was diluted with ice, then extracted with DCM (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude 3-nitro-1H-pyrazole-5-carbonitrile, which was used directly in the next step without further purification. LC-MS (ESI) m/z 137 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH:9]([C:16]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[O:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[O:17][C:16]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)=[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccc(F)cc1)C(=O)c1ccco1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccco1
Yield: 79.3 %

Procedure:
20 g of ethyl 3-(4-fluorobenzoylamino)-3-(2-furylcarbonyl)propionate, 100 ml of chloroform and 36.8 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 15 g of ethyl 2-[2-(4-fluorophenyl)-5-(2-furyl)-4-oxazolyl]acetate are thereby obtained. Yield: 78.9%
Reaction SMILES: [NH2:1][C@@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[Br:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@@H:2]([NH:1][C:29]([NH:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([Br:21])[CH:23]=2)=[O:30])[C:3]1=[O:20]
Reactant: CN1C(=O)[C@H](N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C=Nc1cccc(Br)c1
Solvent: C1CCOC1
Product: CN1C(=O)[C@H](NC(=O)Nc2cccc(Br)c2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 3-bromophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 194°-196° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:20])[C:10](=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[O:21][CH3:22]>O>[CH2:11]([CH:10]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:5]2[C:6](=[C:7]([Cl:8])[C:2]([Cl:1])=[C:3]([O:21][CH3:22])[CH:4]=2)[C:9]1=[O:20])[CH3:12]
Reactant: CCC(=Cc1ccccc1)C(=O)c1ccc(OC)c(Cl)c1Cl
Solvent: O
Product: CCC1C(=O)c2c(cc(OC)c(Cl)c2Cl)C1c1ccccc1

Procedure:
A stirred mixture of 2,3-dichloro-4-(2-benzylidenebutyryl)anisole (55.6 g., 0.166 mole) and polyphosphoric acid (550 g.) is heated at 95°-100° C. for 6 hours than at 80°-85° C. for 16 hours, and then poured into water (2 l.) affording 2-ethyl-3-phenyl-5-methoxy-6,7-dichloro-1-indanone which melts at 114°-116° C. after recrystallization from acetic acid-water.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][NH2:25])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:25]([CH2:24][CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=1)[CH2:11]2
Reactant: COC(=O)c1c(I)cccc1CBr
Reactant: COc1ccc(CCCN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(CCCN2Cc3cccc(I)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.245 g, 0.7 mmol), 3-(4-methoxy-phenyl)-propylamine (0.132 g, 0.8 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-[3-(4-methoxy-phenyl)-propyl]-2,3-dihydro-isoindol-1-one (0.125 g, 44%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.01 (m, 2H), 2.63 (t, 2H), 3.64 (t, 2H), 3.79 (s, 3H), 4.24 (s, 2H), 6.80 (d, 2H), 7.08-7.44 (m, 4H), 7.90 (d, 1H). GC-MS: m/z 407 (M)+.
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]2[N:6]([C:9]3[CH:10]=[C:11]([NH:23][S:24]([CH:27]4[CH2:29][CH2:28]4)(=[O:26])=[O:25])[CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=4[F:22])[CH:14]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.CN(C)CC(O)=O.[NH:46]1[CH2:50][CH2:49][CH2:48][C:47]1=[O:51]>CS(C)=O.[Cu]I>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[C:13]1[CH:14]=[C:9]([N:6]2[C:5]3[CH:30]=[CH:31][C:2]([N:46]4[CH2:50][CH2:49][CH2:48][C:47]4=[O:51])=[CH:3][C:4]=3[N:8]=[CH:7]2)[CH:10]=[C:11]([NH:23][S:24]([CH:27]2[CH2:29][CH2:28]2)(=[O:25])=[O:26])[CH:12]=1
Reactant: O=S(=O)(Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(Br)ccc32)c1)C1CC1
Reactant: O=C1CCCN1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: O=C1CCCN1c1ccc2c(c1)ncn2-c1cc(NS(=O)(=O)C2CC2)cc(-c2ccc(F)cc2F)c1
Temperature: 110 °C
Yield: 90 %

Procedure:
A solution of N-(5-(5-bromo-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide (50 mg, 0.099 mmol, 1 eq.) in DMSO (2 ml) was degassed by nitrogen bubbling for 10 min. Copper(I)iodide (11.3 mg, 0.059 mmol, 0.6 eq.), K2CO3 (42 mg, 0.298 mmol, 3 eq.), N,N-dimethyl glycine HCl (11 mg, 0.079 mmol) and 2-pyrrolidone (42 mg, 0.49 mmol, 5 eq.) were added and the mixture was further degassed for 10 min and then heated to 110° C. for 16 h. The mixture was cooled to RT and diluted with ethyl acetate, filtered through a celite bed and washed with water and brine solution. The ethyl acetate layer was dried over sodium sulphate. The solvent was distilled off to afford the crude residue which was purified by preparative HPLC to afford the product in 90% yield (45 mg). 1H NMR (400 MHz, DMSO-d6): δ 8.65 (s, 1H), 7.96 (d, 1H), 7.78-7.65 (m, 3H), 7.54 (m, 2H), 7.45-7.42 (m, 2H), 7.28-7.24 (dt, 1H), 3.9 (t, 2H), 2.88-2.8 (m, 1H), 2.12-2.02 (m, 2H), 1.0 (m, 4H): LC-MS (ESI): Calculated mass: 508.54; Observed mass: 508.7 [M+H]+ (rt: 1.46 min).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].[C:13]([O:16][CH2:17][CH2:18][SH:19])(=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].CO>>[C:13]([O:16][CH2:17][CH2:18][S:19][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4])(=[O:15])[CH3:14]
Reactant: O=C(CCl)c1ccc(F)cc1F
Reactant: CC(=O)OCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)OCCSCC(=O)c1ccc(F)cc1F
Yield: 65.6 %

Procedure:
Using 2-chloro-2',4'-difluoroacetophenone (2.0 g, 0.010 mol), 2-acetoxyethanethiol (J. Chem. Soc., 1952, 817.) (1.5 g, 0.013 mol), potassium carbonate (1.8 g, 0.013 mol) and methanol (50 mol), 2-(2-acetoxyethyl)thio-2',4'-difluoroacetophenone (1.8 g, yield: 62.0%) was obtained as a colorless oil by similar procedures to Example 1.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][N:7]1[CH2:13][CH2:12][CH2:11][N:10]([CH:14]2[C:23]3[C:18](=[CH:19][C:20]([CH:24]=O)=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[CH2:9][CH2:8]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC.C1COCC1>[CH3:6][N:7]1[CH2:13][CH2:12][CH2:11][N:10]([CH:14]2[C:23]3[C:18](=[CH:19][C:20]([CH:24]=[CH2:1])=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[CH2:9][CH2:8]1
Reactant: [Li]CCCC
Reactant: CN1CCCN(C2CCCc3cc(C=O)ccc32)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cc1ccc2c(c1)CCCC2N1CCCN(C)CC1
Reaction time: 2 h

Procedure:
A dry flask under nitrogen was charged with 0.25 g (0.69 mmol) of methyltriphenyl phosphonium bromide and 2.1 ml of anhydrous THF. To this suspension at ambient temperature was added 0.30 ml (0.69 mmol) of a 2.3 M solution of n-butyllithium in hexane. This was followed by the addition of a solution of 0.18 g (0.67 mmol) of 1-methyl-4-(6-formyl-1,2,3,4-tetrahydro-1-naphthalenyl)homopiperazine in 1.4 ml THF. After two hours, analysis by 1H-NMR of a worked-up aliquot revealed the presence of the desired product (vinyl proton resonances) as well as residual aldehyde (CHO resonance). A second portion of the triphenylphosphonium ylid (0.070 mmol) was generated in 4 ml THF and added to the mixture containing the residual aldehyde. After four hours, analysis by 1H-NMR of a worked-up aliquot indicated only a trace of aldehyde. The reaction mixture was concentrated invacuo to semisolid which was treated with water and extracted several times with ether. The combined ether extract was dried (MgSO4), filtered and concentrated invacuo to a semisolid, 0.34 g. This material was triturated with hexane, filtered and the hexane was removed invacuo. The resulting residue was again titurated with hexane, filtered and concentrated invacuo to give the title compound, 0.18 g, as a yellow oil; 1H-NMR(300 Hz, CDCl3) δ 5.17-5.20 (1H, d), 5.68-5.74 (1H, d), 6.62-6.71 (1H, q).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:12])[N:10]([CH3:11])[C:6]=2[C:5]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].CS(O)(=O)=O.Cl>O1CCOCC1.C(OCC)(=O)C.C(OCC)C>[ClH:1].[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[C:7]3[CH:8]=[C:9]([CH3:12])[N:10]([CH3:11])[C:6]=3[C:5]([C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])=[CH:4][N:3]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Cc1cc2c(Cl)ncc(C(=O)N3CCOCC3)c2n1C
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc2c(Nc3cccc(Cl)c3)ncc(C(=O)N3CCOCC3)c2n1C
Temperature: 180 °C

Procedure:
A mixture of 4-chloro-1,2-dimethyl-7-(4-morpholinylcarbonyl)-1H-pyrrolo[3,2-c]pyridine (68 mg), 3-chloroaniline (0.05 ml) and methanesulfonic acid (0.03 ml) in dry 1,4-dioxan was heated under microwave conditions at 180° C. for fifteen minutes. The reaction mixture was transferred to a round bottom flask and evaporated. The residue was partitioned between ethyl acetate (10 ml) and saturated sodium bicarbonate solution and washed with saturated sodium bicarbonate solution and water. The organic layer was dried (MgSO4) and evaporated to afford a brown oil. The oil was purified by Biotage chromatography on silica gel loading the column using dichloromethane and eluting with 5% ethyl acetate/hexane (200 ml) increasing the percentage of ethyl acetate to 20%, 50% and 100% to afford a white foam. The foam was dissolved in warm ethyl acetate and treated with 1M hydrochloric acid in diethyl ether. The mixture was evaporated, the residue triturated with diethyl ether to afford a white solid which was filtered off, washed with diethyl ether and dried to afford the title compound (59 mg).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@H:11]([N:13]5[CH2:17][CH2:16][CH2:15][CH2:14][CH2:18]5)[CH2:10]4)[S:8][C:4]=3[CH:3]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: OB(O)c1cncnc1
Product: COc1ccc(-c2ccc3nc([C@H]4C[C@H](N5CCCCC5)C4)sc3c2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 44A for the product of Example 1E, and substituting 6-methoxypyridine-3-boronic acid for pyrimidine-5-boronic acid. 1H NMR (500 MHz, CDCl3) δ ppm 8.43 (d, J=2.44 Hz, 1H) 8.03 (d, J=8.54 Hz, 1H) 7.97 (d, J=1.53 Hz, 1H) 7.84 (dd, J=8.70, 2.59 Hz, 1H) 7.62 (dd, J=8.54, 1.83 Hz, 1H) 6.85 (d, J=8.54 Hz, 1H) 4.00 (s, 3H) 3.82-3.93 (m, 1H) 3.36-3.48 (m, 1H) 2.87-2.98 (m, 2H) 2.52-2.71 (m, 4H) 2.08 (s, 2H) 1.67-1.82 (m, 4H) 1.48-1.58 (m, 2H). MS: (M+H)+=380.