Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH:11][CH2:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1.C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>Br.O>[OH2:11].[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1.[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Nc1ncccc1CO
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ncccc1CSc1nc2ccccc2[nH]1
Temperature: 25 °C

Procedure:
A mixture of 9.6 g (63 mmole) of 2-mercaptobenzimidazole and 7.7 g (62 mmole) of 3-hydroxymethyl-2-pyridinamine was dissolved in 60 ml of 48% aqueous hydrobromic acid and 60 ml of acetic acid and heated to reflux. After being cooled to room temperature, the mixture was poured into water and make alkaline with potassium carbonate. The oil that separated solidified upon addition of diethyl ether to the aqueous mixture. The solid was collected by filtration, washed with portions of diethyl ether and water, and air dried to yield 12.4 g of analytically pure 3-[(1H-benzimidazol-2-ylthio)methyl]-2-pyridinamine hemihydrate, as confirmed by the nmr and infrared spectra and by elemental analysis. [Calcd. for C13H12N4S.1/2H2O: C, 58.84; H, 4.93; N, 21.11; S, 12.08. Found: C, 59.06; H, 4.48; N, 20.82; S, 12.16.]A mixture of 4.0 g (15 mmole) of 3-[(1H-benzimidazol-2-ylthio)methyl]-2-pyridinamine hemihydrate, 1.9 ml (ca. 18 mmole) of 50% aqueous chloroacetaldehyde, and 1.5 g (18 mmole) of sodium bicarbonate in 25 ml of ethanol was stirred at room temperature. After three days the mixture was filtered and the filtrate was concentrated in vacuo. Trituration of the residue from the filtrate with a mixture of water and dichloromethane induced crystallization. The solid was collected, washed sequentially with water and dichloromethane, and air dried to yield 3.0 g of the title compound. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]3[C:18](=[C:19]([F:21])[CH:20]=2)[N:17]([CH3:22])[C:16](=[O:23])[CH2:15][CH2:14]3)[CH2:6]1)=O.[CH3:24][NH2:25]>CO>[CH3:24][NH:25][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]3[C:18](=[C:19]([F:21])[CH:20]=2)[N:17]([CH3:22])[C:16](=[O:23])[CH2:15][CH2:14]3)[CH2:6]1)=[O:2]
Reactant: COC(=O)[C@H]1CN(c2cc(F)c3c(c2)CCC(=O)N3C)C(=O)O1
Reactant: CN
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2cc(F)c3c(c2)CCC(=O)N3C)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
3-(8-Fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-5-oxazolidinecarboxylic acid methyl ester (EXAMPLE 82, Step 5, 0.300 g, 9.31 mmol) is dissolved in 2M methylamine in methanol solution (8 ml) and stirred overnight at room temperature. The resulting precipitate is filtered, washed with methanol, and dried under vacuum to give the title compound as a white solid (0.145 g, 48%), mp 264-5° C.; 1H NMR (300 MHz, CDCl3) δ 2.47-2.52 (m, 2H), 2.64 (d, 3H), 2.84-2.89 (m, 2H), 3.27 (d, 3H), 4.00 (dd, 1H), 4.24 (t, 1H), 5.06 (dd, 1H), 7.26 (s, 1H), 7.46 (dd, 1H), 8.39 (d, 1H); MS for C15H16FN3O4 m/z 322 (M+H)+.
Reaction SMILES: I[C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: O=C(c1ccc(I)cc1)N1Cc2cccn2Cc2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-c2ccccn2)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 120 °C
Yield: 81.6 %

Procedure:
To a solution of 2.0 g of 10,11-dihydro-10-(4-iodobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 4.39 g of 2-[(tri-n-butyl)stannyl]pyridine in 30 ml of toluene under nitrogen is added 0.2 g of tetrakis(triphenylphosphine)palladium and the mixture heated to 120° C. for 16 hours. The toluene is evaporated in vacuo and the oily residue diluted with 50 ml of chloroform and washed with water, dried (Na2SO4), filtered through diatomaceous earth and evaporated in vacuo to give a residue which is columned on silica gel by elution with 7:1 to 1:1 ethyl acetate:hexane to give 1.44 g of the desired product as a solid, m.p. 170°-172° C.; M+H=366.1; M+Na=388.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[N:12]=[C:11]([C:21]([OH:23])=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28]O>S(Cl)(Cl)=O>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[N:12]=[C:11]([C:21]([O:23][CH2:28][CH2:27][CH2:26][N:25]([CH3:30])[CH3:24])=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1
Reactant: CN(C)CCCO
Solvent: O=S(Cl)Cl
Product: CN(C)CCCOC(=O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1

Procedure:
Treatment of 4-benzyloxy-5,7-dichloroquinoline-2-carboxylic acid (1 g, Example 33b) with thionyl chloride (10 ml) followed by 3-dimethylamino- 1-propanol (1.1 ml) as described in Example 33c gave 3-dimethylaminopropyl 4-benzyloxy-5,7-dichloroquinoline-2-carboxylate (0.52 g). δ (360 MHz, DMSO-d6) 1.93 (2H, m, CO2CH2CH2), 2.20 (6H, s, (CH3)2), 2.44 (2H, t, CH2N), 4.40 (2H, t, CO2CH2), 5.50 (2H s, OCH2), 7.34 (3H, m, m,p-ArH), 7.58 (2H, d, 2 ArH), 7.72 (1H, s, 3-H), 7.88 (1H, d, 6-H) and 8.14 (1H, d, 8-H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[CH:14]([C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21])[C:15]([CH3:19])([CH2:17]Br)[S:16][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:20]([O:22][CH2:23][C:24]([Cl:26])([Cl:27])[Cl:25])=[O:21])=[C:15]([CH3:17])[CH2:19][S:16][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Yield: 73.9 %

Procedure:
A mixture of 2,2,2-trichloroethyl 6-(2-phenylacetamido)-2-methyl-2-bromomethylpenam-3-carboxylate (0.54 g.), chloroform (5 cc) and pyridine (0.16 g.) was heated under reflux for 2.5 hours. The reaction mixture was washed with water, dried over magnesium sulfate and then concentrated. The residue was crystallized from ether to yield crystals (0.34 g.) of 2,2,2-trichloroethyl 7-(2-phenylacetamido)-3-methyl-3-cephem-4-carboxylate, m.p. 161° - 162° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:14]([O:21][CH2:22][CH2:23]Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O1CCCC1>[CH2:14]([O:21][CH2:22][CH2:23][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCCOCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCOCc1ccccc1)C(=O)OCC
Temperature: 0 °C
Yield: 90.4 %

Procedure:
506 mg (60% in oil, 13 mmol equivalents) of sodium hydride was added to 5.0 mL of tetrahydrofuran, and the mixture was cooled to about 0° C. in an ice bath. 3.2 mL (20.7 mmol equivalents) of diethyl malonate was added thereto (solution A). 2.3 g (10.7 mmol equivalents) of 2-benzyloxy-1-bromoethane was dissolved in 3.0 mL of tetrahydrofuran, this was added dropwise to solution A over 10 minutes, and the mixture was refluxed while heating overnight. After completion of the reaction, a 0.5 mol/L aqueous solution of hydrochloric acid was added dropwise to the reaction liquid, and the mixture was extracted three times with diethyl ether. The combined diethyl ether layers were washed with brine, then dried with anhydrous magnesium sulfate, and subsequently concentrated under vacuum, and the obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=20/1) to give 2.85 g (9.67 mmol equivalents) of diethyl 2-(2-benzyloxyethyl)malonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.C([Li])CCC.[O:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:17]2([OH:20])[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)=[N:6][CH:7]=1
Reactant: Brc1cnc(I)nc1
Reactant: O=C1CCOCC1
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: OC1(c2ncc(Br)cn2)CCOCC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 41.9 %

Procedure:
5-Bromo-2-iodopyrimidine (2 g, 7.02 mmol) was dissolved in dry toluene (30 mL) and cooled to −78° C. under N2. n-Butyllithium (2.5M solution in hexanes, 2.95 mL) was added dropwise, and the reaction mixture was aged for 15 minutes prior to dropwise addition of tetrahydro-4H-pyran-4-one (0.77 g, 7.72 mmol). The reaction was stirred at −78° C. for 30 minutes, then allowed to warm to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried over magnesium sulphate and filtered, then the solvent was removed under reduced pressure. The resulting crude orange oil (1.91 g) was absorbed onto a 50 g KP-Sil column, and eluted with 10-100% ethyl acetate in heptanes on a Biotage Isolera 4, to afford the title compound (762 mg, 42%) as a yellow oil. δH (500 MHz, CDCl3) 8.79 (s, 2H), 4.24 (s, 1H), 3.99-3.89 (m, 4H), 2.37 (td, J 12.3, 11.6, 6.3 Hz, 2H), 1.54 (dd, J 13.6, 2.0 Hz, 2H).
Reaction SMILES: [CH2:1]([S:5][C:6]1[C:11]([CH2:12]O)=[CH:10][CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].O=S(Cl)[Cl:16]>CC#N>[CH2:1]([S:5][C:6]1[C:11]([CH2:12][Cl:16])=[CH:10][CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCSc1ncccc1CO
Reactant: O=S(Cl)Cl
Solvent: CC#N
Product: CCCCSc1ncccc1CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
(2-Butylsulfanyl-pyridin-3-yl)-methanol (0.85 g, 4.3 mmol) obtained in Step B was dissolved in CH3CN (20 mL). SOCl2(0.63 mL, 8.6 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure to remove the solvent and then added with EtOAc. The organic layer was washed with water, dried with MgSO4, and concentrated under reduced pressure to obtain the title compound (0.77 g, 82%).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(#N)C>[Cl:17][C:6]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]2)=[C:2]([C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)[CH:3]=[N:4][CH:5]=1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: NC(=O)C1CCN(c2c(Cl)cncc2-c2cccnc2)CC1
Yield: 25.1 %

Procedure:
General procedure D was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (24 mg, 0.088 mmol), pyridin-3-yl boronic acid (12 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile (1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 10:1) to furnish the title compound as a white solid (7 mg, 25%), LC-MS (ESI, 3.5 min) Rt 1.06 min, m/z 317 (100%, [M+H]+); m/z (ESI) C16H18ClN4O requires 317.1164 found [M+H]+ 317.1161.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]2[N:19]([CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=2)[CH:20]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(Cl)ccc2n1
Yield: 53 %

Procedure:
As described for Example 1, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (140 mg, 0.5 mmol) was converted, using 2-amino-5-chloropyridine instead of 2-aminopyridine, to the title compound (82 mg, 53%) which was obtained as a yellow gum. MS: m/e=310.3[M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:12][CH:11]2[CH2:13][CH:14]=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[OH-:16].[Na+]>CCO.O.[N+]([O-])([O-])=O.[Ag+]>[F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:12][CH:11]2[CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C2CC2CC=O)cc1F
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C2CC2CC(=O)O)cc1F
Reaction time: 3 h
Yield: 79.6 %

Procedure:
[2-(3-Fluoro-4-methoxy-phenyl)-cyclopropyl]-acetaldehyde (0.088 g, 0.42 mmol) obtained in Step C was dissolved in EtOH (2 mL). AgNO3(0.143 g, 0.84 mmol) dissolved in water (0.26 mL) and NaOH (0.067 g, 1.69 mmol) dissolved in water (0.26 mL) was added thereto in turn, and the mixture was stirred for 3 hours. After the termination of the reaction, the reactant was filtered by using celite to remove solid material, and 1N HCl aqueous solution was added to adjust the pH of the solution to 2. The organic layer obtained by the extraction with EtOAc was separated, dried with MgSO4, and concentrated under reduced pressure to obtain the title compound (0.075 g, 79%).
Reaction SMILES: O[CH2:2][C@H:3]([NH:5]C(=O)OC(C)(C)C)[CH3:4].[Cl:13][C:14]1[CH:34]=[CH:33][CH:32]=[CH:31][C:15]=1[CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]([O-:30])=[O:29])(=[O:21])=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[NH2:5][C@H:3]([CH3:4])[CH2:2][N:18]([CH2:17][CH2:16][C:15]1[CH:31]=[CH:32][CH:33]=[CH:34][C:14]=1[Cl:13])[S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]([O-:30])=[O:29])(=[O:21])=[O:20]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCc1ccccc1Cl
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](N)CN(CCc1ccccc1Cl)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 22.6 %

Procedure:
740 mg of (R)-tert-butyl 1-hydroxypropan-2-ylcarbamate was dissolved in 30 mL of tetrahydrofuran in a nitrogen atmosphere, and 1.44 g of N-(2-chlorophenethyl)-2-nitrobenzenesulfonamide and 3.3 g of triphenylphosphine were added thereto. 2.5 mL of diisopropyl azodicarboxylate was added thereto at 0° C., and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue (intermediate) was dissolved in 20 mL of dichloromethane. To the solution, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was neutralized with a saturated aqueous solution of sodium bicarbonate, followed by extraction with dichloromethane (30 mL×3). The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain 380 mg of the title compound as a pale yellow oil (23%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]([NH2:14])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1.Cl>[F:16][C:2]([F:1])([F:15])[CH:3]([NH:14][S:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:25])=[O:24])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1
Reactant: NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(NC(Cc1c[nH]c2ccccc12)C(F)(F)F)c1ccccc1
Temperature: 45 °C
Reaction time: 18 h
Yield: 66.4 %

Procedure:
A mixture of 40 mg (0.18 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethylamine and 30 μL (0.23 mmol) of benzenesulfonyl chloride in 1 mL of pyridine was warmed at 45° C. The reaction was monitored by TLC (ethyl acetate-hexanes (25:75)) indicating a new less polar product compared to amine. The mixture stirred for 18 hours at 45° C. and over the weekend at room temperature. The mixture was diluted with 7 mL of 1 N aqueous HCl and extracted with three 7 mL portions of ethyl acetate. The combined organic layers were washed with three 5 mL portions of 1 N aqueous HCl, 5 mL of brine, and three 5 mL portions of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was adsorbed onto silica gel and chromatographed on silica gel using dichloromethane-hexanes (gradient 50-100%). The material from the column solidified from ether-hexanes to afford 44 mg (68%) of the title compound as an white solid, m.p. 121° C.-123° C., MS: m/z 367.08 (M−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]2[CH2:33][O:34][CH2:35][CH:29]2[CH2:28]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH:30]5[CH2:33][O:34][CH2:35][CH:29]5[CH2:28]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: BrCCCN1CCC2COCC2C1
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCC2COCC2C1
Temperature: 80 °C
Yield: 23.3 %

Procedure:
A mixture of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (140 mg, 0.44 mmol, 1 eq), 5-(3-bromopropyl)octahydrofuro[3,4-c]pyridine (90 mg, 0.44 mmol, 1 eq) and K2CO3 (135 mg, 0.98 mmol, 2 eq) in DMF (10 mL) was heated at 80° C. overnight under N2 and cooled to rt. To this, 50 mL of CH2Cl2 was added. The mixture was washed with brine (20 mL×3) and water (20 mL×2). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (20:1 (v/v) CH2Cl2/MeOH) to afford the title compound as a yellow solid (50 mg, 25.00%), HPLC: 96.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 487.1 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.76-1.77 (1H, m), 2.24-2.48 (3H, m), 2.50-2.64 (2H, m), 2.68-2.71 (2H, m), 2.73-2.75 (2H, m), 2.96-3.03 (3H, m), 3.07-3.12 (1H, m), 3.61-3.90 (2H, m), 4.24-4.27 (2H, m), 7.06-7.10 (1H, m), 7.16 (1H, s), 7.76-7.82 (1H, m), 7.82 (1H, s), 8.09-8.11 (1H, m), 8.59 (1H, s) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]3[CH2:19][CH2:20][O:21][CH2:22][CH:23]=3)=[C:13](Cl)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]([Sn](CCCC)(CCCC)CCCC)=[CH2:25]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]2[C:15](=[CH:14][C:13]([CH:24]=[CH2:25])=[C:12]([C:18]3[CH2:19][CH2:20][O:21][CH2:22][CH:23]=3)[CH:11]=2)[CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(C3=CCOCC3)cc2C1
Product: C=Cc1cc2c(cc1C1=CCOCC1)CN(C(=O)OC(C)(C)C)C2

Procedure:
Prepared in analogy to Example A54(a) from 5-chloro-6-(3,6-dihydro-2H-pyran-4-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A61(a)) and vinyltributylstannane. White solid. MS (m/e): 272.4 ([M+H-Me2C═CH2]+, 100%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@@H:5]1[N:10]([C:11](=[O:33])[C@@H:12]([NH:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:9][CH2:8][N:7]([CH2:34][C:35]([OH:37])=[O:36])[C:6]1=[O:38].C([O-])(O)=O.[Na+].[ClH:44].O=C1N([O:55][C:56](=O)[C:57]2[CH:62]=[CH:61][C:60]([NH:63][C:64]([NH2:66])=[NH:65])=[CH:59][CH:58]=2)C(=O)C2C1C1CC2C=C1.Cl>O1CCOCC1>[ClH:44].[CH2:26]([O:25][C:23]([NH:22][C@@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:11]([N:10]1[CH2:9][CH2:8][N:7]([CH2:34][C:35]([OH:37])=[O:36])[C:6](=[O:38])[C@@H:5]1[CH2:4][CH2:3][CH2:2][NH:1][C:56](=[O:55])[C:57]1[CH:58]=[CH:59][C:60]([NH:63][C:64]([NH2:66])=[NH:65])=[CH:61][CH:62]=1)=[O:33])=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N=C(N)Nc1ccc(C(=O)ON2C(=O)C3C4C=CC(C4)C3C2=O)cc1
Reactant: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)N2CCN(CC(=O)O)C(=O)[C@@H]2CCCN)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)N2CCN(CC(=O)O)C(=O)[C@@H]2CCCNC(=O)c2ccc(NC(=N)N)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
In 50 ml of a 50% aqueous solution of dioxane was dissolved 0.5 g of (S,S)-3-(3-aminopropyl)-4-[2-benzyloxycarbonylamino-3-(4-methoxyphenyl)propionyl1-2-oxopiperazine-1-acetic acid produced in Reference Example 35. To the solution was added 0.24 g of NaHCO3, to which was then added 0.377 g of 4-guanidinobenzoic acid 3,5-dioxo-4-azatricyclo[5,2,1,0 2,6)deca-8-en-4-yl ester hydrochloride. The mixture was stirred for two hours at room temperature. The pH of the reaction mixture was adjusted to 3 with 1N-HCl, followed by distilling off dioxane. The residue was purified by means of a column chromatography (eluting with H2O→10% aqueous solution of CH3CN→a 20% aqueous solution of CH3CN→a 50% aqueous solution of CH3CN) to afford 0.43 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][CH2:8][CH3:9])=[CH:5][NH:4][N:3]=1.O1CCCC1.C(=O)(O)[O-].[Na+].[F:20][C:21]([F:31])([F:30])[CH2:22][CH2:23][S:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>O>[Cl:1][C:2]1[C:6]([N:7]([CH2:8][CH3:9])[C:27](=[O:28])[CH2:26][CH2:25][S:24][CH2:23][CH2:22][C:21]([F:31])([F:30])[F:20])=[CH:5][NH:4][N:3]=1
Reactant: CCNc1c[nH]nc1Cl
Reactant: O=C(Cl)CCSCCC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(C(=O)CCSCCC(F)(F)F)c1c[nH]nc1Cl
Temperature: 5 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
A 500-mL 3-neck flask was charged with 3-chloro-N-ethyl-1H-pyrazol-4-amine (3.25 g, 22.3 mmol), tetrahydrofuran (80 mL) and water (80 mL). The resulting suspension was cooled to 5° C. and sodium bicarbonate (3.75 g, 44.6 mmol) was added, followed by dropwise addition of 3-((3,3,3-trifluoropropyl)thio)propanoyl chloride (5.42 g, 24.56 mmol) at <5° C. The reaction mixture was stirred at <10° C. for 3 hours. The reaction mixture was poured into water (100 mL) and the mixture was extracted with dichloromethane (150 mL×3). The combined organics were washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure to afford crude product as a light brown oil, which was purified by flash column chromatography using 0-5% methanol/dichloromethane as eluent. The fractions containing pure product were concentrated to give the desired product as a white solid (3.60 g, 48%): mp 67-68° C.; 1H NMR (400 MHz, CDCl3) δ 11.55 (bs, 1H), 7.65 (s, 1H), 3.73-3.68 (dd, J1=7.2, J2=14.0, 2H), 2.86-2.82 (t, J=7.2, 2H), 2.67-2.63 (t, J=8.0, 2H), 2.45-2.30 (m, 4H), 1.16-1.12 (t, J=7.2, 3H); 13C NMR (101 MHz, CDCl3) δ 171.87, 137.89, 128.40, 125.97 (q, J=277.4 Hz), 120.81, 44.01, 34.31 (q, J=27.3 Hz), 33.97, 27.30, 24.08 (q, J=3.4 Hz), 12.77; ESIMS m/z 330 ([M+H]+).