Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:17][C:18]=3[O:23][CH:24]([CH3:26])[CH3:25])[N:13]=2)=[CH:7][C:6]=1[CH3:31].[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.O>CN(C=O)C>[CH3:31][C:6]1[CH:7]=[C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:17][C:18]=3[O:23][CH:24]([CH3:26])[CH3:25])[N:13]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[O:4][CH2:3][CH2:2][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: Cc1cc(-c2nc3cc(OC(C)C)cc(OC(C)C)c3c(=O)[nH]2)cc(C)c1OCCBr
Reactant: C1CCNC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3cc(OC(C)C)cc(OC(C)C)c3c(=O)[nH]2)cc(C)c1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-diisopropoxy-3H-quinazolin-4-one (0.39 g, 0.79 mmol) in DMF (10 mL) was added pyrrolidine (0.45 g, 6.37 mmol). The reaction mixture was stirred at room temperature for 4 hours. Then, water was added and product was extracted with ethyl acetate (2×200 mL). The combined organic phase was washed with water, then brine, and dried over anhydrous Na2SO4. Solvent was evaporated to give the title compound as a white solid. Yield: 0.32 g (83%). MP 65-68° C. 1H NMR (400 MHz, CDCl3): δ 9.05 (br s, 1H), 7.63 (s, 2H), 6.78 (s, 1H), 6.42 (s, 1H), 4.70 (m, 1H), 4.63 (m, 1H), 3.94 (m, 2H), 2.94 (m, 2H), 2.64 (br s, 4H), 2.38 (s, 6H), 1.84 (m, 4H), 1.46 (m, 3H), 1.42 (m, 3H). MS (ES) m/z: 480.29 (M+1).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:7])[CH:4]([CH3:6])[CH3:5].[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH:30]2[CH2:32][CH2:31]2)[C:17](=[O:29])[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[O:28][CH:27]=[N:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)#N>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH:30]1([N:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:8]3[O:1][N:2]=[C:3]([CH:4]([CH3:6])[CH3:5])[N:7]=3)[CH2:11][CH2:12]2)[C:17](=[O:29])[C:18]2[CH:19]=[CH:20][C:21]([C:24]3[O:28][CH:27]=[N:26][CH:25]=3)=[CH:22][CH:23]=2)[CH2:32][CH2:31]1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: CC(C)C(=N)NO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)n1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A 0.5 M solution of zinc chloride in tetrahydrofuran (5.20 mL) is added dropwise at room temperature to a mixture of N-hydroxy-isobutyramidine (266 mg) and N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide (600 mg) in ethyl acetate (25 mL). The reaction mixture is stirred at 50° C. for 3 h and cooled to room temperature. The precipitate is filtered off and heated to 100° C. for 2 h in a mixture of ethanol (10 mL) and glacial acetic acid (5 mL). The solvents are evaporated and the residue is chromatographed on silica gel [ethyl acetate/cyclohexane/methanol 9:9:2] to give the title compound. LC (method 6): tR=1.66 min; Mass spectrum (ESI+): m/z=422 [M+H]+.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]=12)=[O:10].[CH2:20]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:32][C:31]([CH3:33])=[N:30][C:29]=2[C:34](O)=[O:35])=[CH:24][CH:23]=1)[CH3:21]>>[CH2:20]([C:22]1[CH:23]=[CH:24][C:25]([C:28]2[S:32][C:31]([CH3:33])=[N:30][C:29]=2[C:34]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=23)=[O:10])=[O:35])=[CH:26][CH:27]=1)[CH3:21]
Reactant: CCc1ccc(-c2sc(C)nc2C(=O)O)cc1
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)c1cccc2occc12
Product: CCc1ccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3occc23)cc1

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 5-(4-ethyl-phenyl)-2-methyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=0.93 min; [M+H]+=486.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([S:18](CCC(OC)=O)(=[O:20])=[O:19])[CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CO.C[O-].[Na+:31]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([S:18]([O-:20])=[O:19])[CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[Na+:31]
Reactant: COC(=O)CCS(=O)(=O)c1cnc2cc(-c3ccc(F)cc3)ccc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=S([O-])c1cnc2cc(-c3ccc(F)cc3)ccc2c1
Reaction time: 1 h
Yield: 60.1 %

Procedure:
Methyl 3-{[7-(4-fluorophenyl)quinolin-3-yl]sulfonyl}propanoate (4.23 g, 11.3 mmol) was dissolved/suspended in hot tetrahydrofuran (240 mL). Methanol (60 mL) was added and the mixture allowed to cool to about 30° C., at which point sodium methoxide (0.91 g, 17 mmol) was added and the resulting mixture stirred for 1 hour. The solid present was collected under suction, washed with tetrahydrofuran and dried in vacuo to afford a first crop of sodium 7-(4-fluorophenyl)quinoline-3-sulfinate (2.1 g). The filtrate was concentrated and the residue triturated with tetrahydrofuran. The solid was collected under suction, washed successively with small volumes of tetrahydrofuran, ice-cold water then tetrahydrofuran, and dried in vacuo to give a second crop of product (0.87 g). The combined yield of the title product was 2.97 g (85%). 1H NMR (500 MHz, CD3OD) δ 9.13 (1H, d, J 1.9 Hz), 8.52 (1H, d, J 1.6 Hz), 8.24 (1H, s), 8.11 (1H, d, J 8.5 Hz), 7.94 (1H, dd, J 1.7, 8.5 Hz), 7.84-7.82 (2H, m), 7.26 (2H, t, J 8.7 Hz).
Reaction SMILES: [C:1]([CH:4]1[CH2:11][C:7]2=[CH:8][S:9][CH:10]=[C:6]2[CH2:5]1)([OH:3])=[O:2].[CH3:12]OC(OC)(C)C.S(=O)(=O)(O)O>CO>[C:1]([CH:4]1[CH2:11][C:7]2=[CH:8][S:9][CH:10]=[C:6]2[CH2:5]1)([O:3][CH3:12])=[O:2]
Reactant: O=C(O)C1Cc2cscc2C1
Reactant: COC(C)(C)OC
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C1Cc2cscc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dissolve 5-(carboxy)-2,4,5,6-tetrahydro-cyclopenta[c]thiophene (3.95 g, 23.5 mmol) in methanol (60 mL) and treat with dimethoxypropane (5.8 mL, 47mmol) and sulfuric acid (0.8 mL). Stir at room temperature for 1 day. Evaporate the solvent in vacuo, dilute with methylene chloride (75 mL) andwash with saturated sodium hydrogen carbonate (35 mL). Extract the aqueous phase with methylene chloride (30 mL), wash combined organics with brine (30 mL) and dry (Na2SO4). Evaporate the solvent in vacuo and pass through a plug of silica gel to give 5-(carbomethoxy)-2,4,5,6-tetrahydro-cyclopenta[c]thiophene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:40]=[CH:39][C:18]([O:19][C:20]2[CH:25]=[C:24]([NH:26][C:27]([N:29]3[CH2:34][CH2:33][CH:32]([CH2:35][N:36]([CH3:38])[CH3:37])[CH2:31][CH2:30]3)=[O:28])[N:23]=[CH:22][N:21]=2)=[C:17]([F:41])[CH:16]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[CH3:38][N:36]([CH2:35][CH:32]1[CH2:33][CH2:34][N:29]([C:27]([NH:26][C:24]2[CH:25]=[C:20]([O:19][C:18]3[CH:39]=[CH:40][C:15]([NH:14][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[S:13])=[CH:16][C:17]=3[F:41])[N:21]=[CH:22][N:23]=2)=[O:28])[CH2:30][CH2:31]1)[CH3:37]
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)CC1
Reaction time: 2 h
Yield: 40 %

Procedure:
After adding a solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.2 M, 3.0 ml) to a solution of 4-(4-amino-2-fluorophenoxy)-6-{[4-(dimethylaminomethyl)piperidin-1-yl]carbonylamino}pyrimidine (118 mg) and (+)-10-camphorsulfonic acid (70.6 mg) in ethanol (3.0 ml) at room temperature, the mixture was stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:heptane=4:1) to provide the title compound (70.0 mg, 40%) as white powder.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[N:18]=[C:17](O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:22])=O.[OH-].[Na+]>>[Cl:22][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:6]2[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)[N:18]=1
Reactant: CC(C)c1csc(-c2nc(O)c3ccccc3n2)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1csc(-c2nc(Cl)c3ccccc3n2)n1
Temperature: 100 °C

Procedure:
Compound 50 (100 mg, 0.37 mmol) was added to phosphorous oxychloride (2 mL) and heated to 100° C. for 2 h. The reaction mixture was then poured on ice with vigorous stirring and made basic with NaOH (aq). The resulting slurry was extracted with ether (3×20 mL) and the combined organic phases were dried (MgSO4) and filtered. Removal of the solvent in vacuo afforded the title compound in quantitative yield. LC/MS>95%, m/z (ESI+)=290 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6](CC)[C:5]2(O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.N[OH:24]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N+:6]([O-:24])=[C:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCN1C(=O)Nc2ccc(Cl)cc2C1(O)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)[n+]1[O-]
Yield: 85 %

Procedure:
A stirred mixture of 12.11 g (0.04 mole) of 6-chloro-3-ethyl-3,4-dihydro-4-hydroxy-4-phenyl-2(1H)quinazolinone and 8.34 g (0.12 mole) of hydroxylamine hydrochloride in 200 ml ethanol was refluxed for 3 days and then cooled. The solid portion of the reaction mixture was collected on a filter, washed with ethanol, and dried to give 9.27 g (85%) of 6-chloro-4-phenyl-2(1H)quinazolinone 3-oxide as yellow crystals, mp 267°-269°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8](Br)=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:12]([Cu])#[N:13].N>CN(C=O)C.CO>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:12]#[N:13])=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Fc1ccc(Br)c2[nH]ccc12
Reactant: N#C[Cu]
Agent: N
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1ccc(F)c2cc[nH]c12
Temperature: 25 °C
Yield: 69.1 %

Procedure:
Intermediate 1 was prepared according to procedures described in Wallace, O. B. et al. PCT int. appl. WO0204440, and as described in Steps A-D below. Step A A mixture of 4-fluoro-7-bromoindole (600 mg, 2.8 mmol) and CuCN (1.004 g, 11.2 mmol) in DMF (4 ml) was refluxed for 16 hours. After cooling to room temperature, the reaction mixture was poured into a solution of ammonia in MeOH (30 ml, sat.) and the residue removed by filtration. The filtrate was added to a mixture of water (20 ml)/ammonia (20 ml, sat. aq.) and extracted with EtOAc/Ether (1/1) until TLC analysis showed no product in the aqueous phase. The combined organic extracts were washed with brine (2×200 ml) and water (200 ml), dried (MgSO4); evaporation in vacuo gave 4-fluoro-7-cyanoindole as a tan yellow solid (310 mg, 69%). Step B To a solution of KOH (13.04 g, 0.232 mol) in 14% H2O/EtOH (50 ml) was added 4-fluoro-7-cyanoindole (900 mg, 5.60 mmol). The resulting mixture was refluxed for 12 hours, slowly cooled to room temperature, and concentrated in vacuo to about 30 ml. The residue was acidified to pH 2 with HCl (˜5.5 N aq.). The precipitate was filtered, washed with excess of water, and dried under high vacuum to afford 4-fluoro-7-carboxyindole as a white solid (100% conversion). The material was used without further purification. Step C To a suspension of 4-fluoro-7-carboxyindole in a mixture of MeOH (18 ml)/PhH (62 ml) was added (trimethylsilyl)diazomethane (8.8 ml, 17.6 mmol, 2 M in hexane). The resulting mixture was stirred at room temperature for 30 min., quenched with excess acetic acid and evaporated in vacuo. The crude oily material was purified by flash chromatography using a gradient elution (Hexane to 10% EtOAc/Hexane) to afford 4-fluoro-7-carbomethoxy indole as a white solid (1.04 g, 83% two steps). Step D
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([N:17]4C=CN=C4)=[O:16])=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1.N.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([NH2:17])=[O:16])=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1
Reactant: CN1Cc2c(C(=O)n3ccnc3)ncn2-c2ccc(F)cc2C1=O
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2c(C(N)=O)ncn2-c2ccc(F)cc2C1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
15 g (46.1 mmol) of 1-[[8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl]carbonyl]imidazole are suspended in 75 ml of N,N-dimethylformamide, whereupon the suspension is treated with 7.8 ml (102 mmol) of a 25 percent aqueous ammonia solution, the mixture is stirred at room temperature for 0.75 hour and then poured into 300 ml of water. The product is filtered off under suction after 1 hour, rinsed with water and dried at 85° in a vacuum drying oven. There is obtained 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide of melting point 272°-273°.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[C:14](=[O:32])[CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C([O-])(=[O:35])C.[K+]>CN(C=O)C>[C:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][N:15]2[CH2:16][CH2:17][N:12]([S:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][OH:35])=[CH:8][CH:7]=3)(=[O:11])=[O:10])[CH2:13][C:14]2=[O:32])[CH2:20][CH2:21]1)=[O:26])([CH3:30])([CH3:29])[CH3:31]
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(CBr)cc3)CC2=O)CC1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(CO)cc3)CC2=O)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 80.4 %

Procedure:
To a solution of 4-[4-(bromomethyl)benzenesulfonyl]-1-[1-(tert-butoxycarbonyl)-4-piperidylmethyl]-2-piperazinone (2.85 g) in DMF (30 ml) was added potassium acetate (1.58 g), and the mixture was stirred at 60° C. for 4 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added ethyl acetate. The mixture was washed with water and saturated brine, dried and concentrated, and the residue was dissolved in methanol (50 ml). To the solution was added sodium methoxide (28% methanol solution, 290 mg), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added ethyl acetate. The mixture was washed with water and saturated brine, dried (MgSO4) and concentrated. The residual crystals were washed with ether to give colorless crystals of 1-[1-(tert-butoxycarbonyl)-4-piperidylmethyl]-4-[4-(hydroxymethyl)benzenesulfonyl]-2-piperazinone (2.02 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[F:13][C:14]1[CH:19]=[C:18](B(O)O)[CH:17]=[CH:16][N:15]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC(O)CC.CC([O-])=O.CC([O-])=O.[Pd+2].CS(C)=O>[F:13][C:14]1[CH:19]=[C:18]([C:2]2[C:3]([CH3:12])=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][N:7]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Cc1cc(CC(=O)O)cnc1Cl
Reactant: OB(O)c1ccnc(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCC(C)O
Solvent: CS(C)=O
Product: Cc1cc(CC(=O)O)cnc1-c1ccnc(F)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a reaction vial was added 2-(6-chloro-5-methylpyridin-3-yl)acetic acid 74-4 (185 mg, 1 mmol), 2-fluoropyridin-4-ylboronic acid 193-1 (220 mg, 1.5 mmol), Pd(OAc)2 (12 mg, 0.05 mmol), S-Phos (41 mg, 0.1 mmol) and K3PO4 (636 mg, 3 mmol) in 1 mL 2-butanol. The reaction was heated to 100° C. and stirred for 2 hours. The reaction was cooled down to room temperature and then diluted to DMSO. The reaction mixture was filtered and the filtrate was purified by reverse-phase HPLC to give 2-(2′-fluoro-3-methyl-2,4′-bipyridin-5-yl)acetic acid 193-2 as white solid. MS m/z 247.2 (M+1).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:27])=[CH:6][C:7]([O:22][CH2:23][CH:24]2[CH2:26][CH2:25]2)=[C:8]([C:10]2[C:11]3[NH:18][CH:17]=[C:16]([C:19]([OH:21])=O)[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:9]=1)(=[O:3])[CH3:2].[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35](=[O:37])[CH3:36])[CH2:31][CH2:30]1>>[C:35]([N:32]1[CH2:33][CH2:34][CH:29]([NH:28][C:19]([C:16]2[C:12]3[N:13]=[CH:14][N:15]=[C:10]([C:8]4[CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[C:5]([CH3:27])=[CH:6][C:7]=4[O:22][CH2:23][CH:24]4[CH2:25][CH2:26]4)[C:11]=3[NH:18][CH:17]=2)=[O:21])[CH2:30][CH2:31]1)(=[O:37])[CH3:36]
Reactant: CC(=O)c1cc(-c2ncnc3c(C(=O)O)c[nH]c23)c(OCC2CC2)cc1C
Reactant: CC(=O)N1CCC(N)CC1
Product: CC(=O)c1cc(-c2ncnc3c(C(=O)NC4CCN(C(C)=O)CC4)c[nH]c23)c(OCC2CC2)cc1C

Procedure:
Starting from 4-(5-acetyl-2-cyclopropylmethoxy-4-methyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A82) and 1-(4-amino-piperidin-1-yl)-ethanone (A191) the title compound is obtained as colorless solid.
Reaction SMILES: N#N.[C:3]([O:9][C:10]1([C:13]2[N:14]=[C:15]([CH2:18]OS(C)(=O)=O)[O:16][CH:17]=2)[CH2:12][CH2:11]1)(=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[N+:24]([C:27]1[CH:31]=[N:30][NH:29][N:28]=1)([O-:26])=[O:25].CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.O>[C:3]([O:9][C:10]1([C:13]2[N:14]=[C:15]([CH2:18][N:29]3[N:28]=[C:27]([N+:24]([O-:26])=[O:25])[CH:31]=[N:30]3)[O:16][CH:17]=2)[CH2:11][CH2:12]1)(=[O:8])[C:4]([CH3:5])([CH3:6])[CH3:7]
Reactant: O=[N+]([O-])c1cn[nH]n1
Reactant: CC(C)(C)C(=O)OC1(c2coc(COS(C)(=O)=O)n2)CC1
Agent: N#N
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OC1(c2coc(Cn3ncc([N+](=O)[O-])n3)n2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(2-(((methylsulfonyl)oxy)methyl)oxazol-4-yl)cyclopropyl pivalate (400 mg, 1.26 mmol) in DMF (3.0 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (T. E. Eagles et al. Organic preparations and procedures 2 (2), 117-119, 1970; P. N. Neuman J. Heterocycl. Chem. 8, 51-56, 1971) (1.80 g of a 8% solution in DMF, 1.26 mmol) in DMF (3.0 mL) pre-treated for 30 min with DIPEA (0.43 mL, 2.53 mmol) and the reaction mixture was stirred overnight at 50° C. Water (20 mL), followed by EA (20 mL) were added. The layers were separated and the org. layer was washed with water (3×10 mL), dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (7:3 hept-EA) gave the title compound as a yellow oil: TLC: rf (7:3 hept-EA)=0.34. LC-MS-conditions 06: tR=0.91 min, [M+H]+=336.22.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=1)[CH2:15][CH:12]1[CH2:13][CH2:14]1)=[O:6]
Reactant: O=C(O)c1c(F)cccc1Cl
Reactant: NCC(CC1CC1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(CC1CC1)c1ccc(C(F)(F)F)nc1)c1c(F)cccc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-6-fluorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=401.1, tR (minutes, Method G)=2.88. [α]D20=−25.9 (c=0.81 mg/mL,CHCl3)
Reaction SMILES: [F:1][C:2](F)=[C:3]([CH2:18][CH3:19])[C:4]([C:6]1[C:7]([CH3:17])=[CH:8][C:9]([CH3:16])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12])=O.O.[NH2:22][NH2:23].FC(F)(F)C(O)=O>C1COCC1.O>[CH2:18]([C:3]1[C:2]([F:1])=[N:22][NH:23][C:4]=1[C:6]1[C:7]([CH3:17])=[CH:8][C:9]([CH3:16])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12])[CH3:19]
Reactant: CCC(C(=O)c1cc(C(=O)OC)c(C)cc1C)=C(F)F
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCc1c(F)n[nH]c1-c1cc(C(=O)OC)c(C)cc1C
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 52.5 %

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of methyl 5-(2-(difluoromethylene)butanoyl)-2,4-dimethylbenzoate (compound 255.3, 175 mg, 0.62 mmol) in THF (100 mL). At room temperature, hydrazine hydrate (120 μL, 2.48 mmol) was added followed by trifluoroacetic acid (144 μL, 1.88 mmol), then the solution was stirred at 50° C. for 1.5 h. The reaction was cooled to room temperature, carefully diluted with water and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by a silica gel column with ethyl acetate/hexane (1:10) as eluent to obtain the title compound as a yellow oil (90 mg, 53%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([F:21])=[C:8]2[O:12][C:11]([N:13]([CH3:15])[CH3:14])=[N:10][C:9]2=[C:16]([C:19]#[N:20])[C:17]=1[CH3:18])=[CH2:5])C.O.[Br:23]N1C(=O)CCC1=O>O1CCCC1>[Br:23][CH2:3][C:4]([C:6]1[C:7]([F:21])=[C:8]2[O:12][C:11]([N:13]([CH3:15])[CH3:14])=[N:10][C:9]2=[C:16]([C:19]#[N:20])[C:17]=1[CH3:18])=[O:5]
Reactant: C=C(OCC)c1c(C)c(C#N)c2nc(N(C)C)oc2c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)CBr)c(F)c2oc(N(C)C)nc2c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
6-(1-Ethoxyvinyl)-2-(dimethylamino)-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-169) (0.51 g, 1.76 mmol) was dissolved in tetrahydrofuran (10 ml), then water (1.0 ml), N-bromosuccinimide (0.30 g, 1.69 g) were added. After stirring at room temperature for 30 minutes, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane to dichloromethane:methanol=100:1) to obtain a pale brown solid (0.60 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:28]([Cl:29])=[CH:27][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:20]([O:22]C(C)(C)C)=O)[CH2:14]2)=[O:7])=[C:4]([O:30][CH3:31])[CH:3]=1.[NH2:32][C:33]1[C:41]([Cl:42])=[CH:40][C:36](C(O)=O)=[C:35]([O:43][CH3:44])[CH:34]=1>>[NH2:32][C:33]1[C:41]([Cl:42])=[CH:40][C:36]([C:20]([NH:19][CH2:18][CH:15]2[CH2:16][CH2:17][N:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:27]=[C:28]([Cl:29])[C:2]([NH2:1])=[CH:3][C:4]=3[O:30][CH3:31])[CH2:14]2)=[O:22])=[C:35]([O:43][CH3:44])[CH:34]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCCCCN1CCC(CNC(=O)OC(C)(C)C)C1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)C1

Procedure:
4-Amino-N-(4-(3-tert-butoxycarbonylaminomethylpyrrolidin-1-yl)-butyl)-5-chloro-2-methoxybenzamide (1.35 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.60 g) to give 4-amino-N-(1-(4-(4-amino-5-chloro-2-methoxybenzoylamino)butyl)pyrrolidin-3-ylmethyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1)=[O:4].[Cl:12][C:13]1[NH:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1>>[CH3:11][C:7]1[N:6]=[C:5]([C:3](=[O:4])[CH2:2][N:14]2[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=[C:13]2[Cl:12])[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cccc(C(=O)CBr)n1
Reactant: Clc1nc2ccccc2[nH]1
Product: Cc1cccc(C(=O)Cn2c(Cl)nc3ccccc32)n1
Yield: 55.2 %

Procedure:
In a manner analogous to Example 28 steps a)→d) 2-bromoacetyl-6-methylpyridine (11.4 g) was reacted with 2-chlorobenzimidazole (8.2 g) to give 1-[2-(6-methylpyrid-2-yl)-2-oxoethyl]-2-chlorobenzimidazole (8.4 g). This wasreacted with thiourea, then NH4OH to give 1-[2-(6methylpyrid-2-yl)-2-oxoethyl]-2-mercaptobenzimidazole (6.9 g); which compound was reduced with NaBH4 to give 1-[2-hydroxy-2-(6-methylpyrid-2-yl]-2-mercaptobenzimidazole (5.0 g.) Treatment of this with polyphosphoric acid gave the title compound (2.1 g.) m.p. 79°-81° C.