Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH3:23])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[C:34]1[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[N:35]=1.[Na+].[Cl-]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:23])[C:34]4[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[N:35]=4)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: CNCCCCOc1ccc2c(ccn2-c2ccc(F)cc2)c1
Reactant: Cc1nccc(Cl)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nccc(N(C)CCCCOc2ccc3c(ccn3-c3ccc(F)cc3)c2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
20 mg (0.064 mmol) {4-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methylamine and 0.16 ml (0.96 mmol) N,N-diisopropyl ethyl amine in 1 ml of DMF were treated with 41 mg (0.32 mmol) 4-chloro-2-methylpyrimidine and stirred at 100° C. during 2 hours. After cooling to room temperature the mixture was treated with saturated aqueous NaCl and extracted three times with Et2O. Drying of the combined organic layers over Na2SO4, evaporation of the solvent and column chromatography on silica gel with EtOAc gave 19 mg (73%) {4-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-(2-methyl-pyrimidin-4-yl)-amine as a light yellow oil, MS: 405 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[OH-].[Na+]>Cl>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:17][CH2:16][C:11](=[O:12])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Clc1cnc(N2CCC3(CC2)OCCO3)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCN(c2ncc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
8-(5-Chloropyrimidin-2-yl)-1,4-dioxa-8-azaspiro[4.5]decane (4.2 g) is dissolved in 6 M HCl (50 mL) and stirred at r.t. for 60 h. The solution is cooled in an ice bath and 4 M NaOH (90 mL) is added in portions to make the solution strongly basic (pH ˜14). The mixture is extracted with dichloroemethane (2×200 mL) and the combined dichloromethane layers are dried over Na2SO4, filtered and concentrated to yield the title compound. LC (method 21): tR=4.21 min; Mass spectrum (APCI): m/z=212 [M+H]+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([S:10][CH3:11])[N:7]=[C:6]([OH:12])[CH:5]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[NH2:3][C:4]1[N:9]=[C:8]([S:10][CH3:11])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6](=[O:12])[CH:5]=1
Reactant: BrCc1ccccc1
Reactant: CSc1nc(N)cc(O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(N)cc(=O)n1Cc1ccccc1
Reaction time: 1.5 h

Procedure:
To a slurry of 60% NaH dispersion (1.8 g=45 mmol) in 25 ml DMF at 10° C. add dropwise a solution of 6-amino-2-methylthio-4-hydroxypyrimidine (6.3 g=40 mmol) in 150 ml DMF. When gas evolution subsides, add benzyl bromide (7.5 g=44 mmol). Stir 1.5 hr. at room temperature. Remove DMF and partition the residue between EtOAc and water. Wash the organic layer with water, dry and concentrate. Recrystallize the residue from CH3CN to give the title compound, a white solid. FAB MS: M+1=248.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14][CH2:15][OH:16])=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:24])[C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CCOS(C)(=O)=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
Methanesulfonyl chloride (2.74 mL, 35.41 mmol) was added dropwise to (S)-tert-butyl 1-(4-chlorophenyl)-3-hydroxypropylcarbamate (Intermediate 58) (9.2 g, 32.19 mmol) and triethylamine (5.38 mL, 38.63 mmol) in DCM (161 mL) at 25° C. over a period of 15 minutes under nitrogen. The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was evaporated to dryness and the residue was purified by flash silica chromatography, elution gradient 40 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (S)-3-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propyl methanesulfonate (10.03 g, 86%) as a white solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11]([F:18])[C:12]=3[O:14][CH:15]([F:17])[F:16])[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[N+:26]([O-])([O-:28])=[O:27].[K+]>S(=O)(=O)(O)O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:26]([O-:28])=[O:27])[C:10]([F:19])=[C:11]([F:18])[C:12]=3[O:14][CH:15]([F:16])[F:17])[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(F)c(F)c([N+](=O)[O-])c2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
The preparation comprises dissolving ethyl 1-cyclopropyl-6,7-difluoro-8-difluoromethoxyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (target product of embodiment 3, 1.0 g, 2.8 mmol) in concentrated sulfuric acid (10 mL), slowly adding potassium nitrate (2.0 g, 19.8 mmol), reacting for 1 h at 40° C., cooling down to room temperature, charging the reaction mixture into ice water (100 mL), stirring, filtering, treating obtained filter cake with ethanol (20 mL), refluxing for 0.5 h, cooling down to room temperature, filtering, and drying obtained filter cake to give ethyl 1-cyclopropyl-6,7-difluoro-8-difluoromethoxyl-5-nitro-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.5 g, 45.5%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6](I)=[CH:7][C:8]([F:11])=[N:9][CH:10]=1)=[N+:2]=[N-:3].[F:13][C:14]1[C:15]([C:29]2[S:33][C:32]3[C:34](B4OC(C)(C)C(C)(C)O4)=[CH:35][CH:36]=[CH:37][C:31]=3[CH:30]=2)=[N:16][C:17]([NH:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][NH:25][C:24]2=[O:28])=[N:18][CH:19]=1.C([O-])(O)=O.[Na+]>CS(C)=O.O.Cl[Pd]Cl>[N:1]([CH2:4][C:5]1[C:6]([C:34]2[C:32]3[S:33][C:29]([C:15]4[C:14]([F:13])=[CH:19][N:18]=[C:17]([NH:20][CH2:21][CH2:22][N:23]5[CH2:27][CH2:26][NH:25][C:24]5=[O:28])[N:16]=4)=[CH:30][C:31]=3[CH:37]=[CH:36][CH:35]=2)=[CH:7][C:8]([F:11])=[N:9][CH:10]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCc1cnc(F)cc1I
Reactant: CC1(C)OB(c2cccc3cc(-c4nc(NCCN5CCNC5=O)ncc4F)sc23)OC1(C)C
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCc1cnc(F)cc1-c1cccc2cc(-c3nc(NCCN4CCNC4=O)ncc3F)sc12
Temperature: 85 °C
Yield: 98.5 %

Procedure:
Combine 5-azidomethyl-2-fluoro-4-iodo-pyridine (70 mg, 0.25 mmol) and 1-(2-{5-fluoro-4-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[b]thiophen-2-yl]-pyrimidin-2-ylamino}-ethyl)-imidazolidin-2-one (100 mg, 0.21 mmol) bis(diphenylphosphino)ferrocene)dichloro palladium (8.5 mg, 0.01 mmol) and NaHCO3 (35 mg, 0.41 mmol) in DMSO (87 mL) and water (3 mL). Purge the mixture through nitrogen for 5 min twice. Heat the mixture at 85° C. for 1 hour in an oil bath. Cool to room temperature. Dilute the reaction mixture with chloroform/isopropyl alcohol 93/1), and wash with water and saturated aqueous sodium chloride. Separate the organic layer from the aqueous layer and dry over sodium sulfate. After filtration, remove the organic solvent to give a crude mixture. Purify the crude by column chromatography (10% methanol in dichloromethane) to afford the title compound (105 mg, 100%). MS (ES) m/z 508 [M+1]+.
Reaction SMILES: [Si]([N:8]1[C@H:11]([C:12]2[O:16][N:15]=[C:14]([CH3:17])[CH:13]=2)[CH2:10][C:9]1=[O:18])(C(C)(C)C)(C)C.[ClH:19].[CH3:20][CH2:21][OH:22]>>[ClH:19].[CH2:21]([O:22][C:9](=[O:18])[CH2:10][C@@H:11]([C:12]1[O:16][N:15]=[C:14]([CH3:17])[CH:13]=1)[NH2:8])[CH3:20]
Reactant: Cc1cc([C@@H]2CC(=O)N2[Si](C)(C)C(C)(C)C)on1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C[C@H](N)c1cc(C)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-tert-butyldimethylsilyl-4(S)-(3-methyl-5-isoxazolyl)-2-azetidinone (0.9 g) in EtOH (10 ml) was added HCl (16.9 mmol)/EtOH (4.2 ml) at room temperature at 0° C. The reaction mixture was stirred at room temperature for 2 hours, then evaporated in vacuo. The residue was recrystallized from diethyl ether to give 3(S)-(3-methyl-5-isoxazolyl)-β-alanine ethyl ester hydrochloride (0.67 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][CH2:19][NH2:20].Cl>O1CCOCC1>[CH3:12][N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][CH2:19][NH:20][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CN1CCCC1CCN
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCCC1CCNS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The title compound was prepared as in Example 81 with 4-chlorophenylsulfonyl chloride replacing 2-naphthalenesulfonyl chloride and with 2-(1-methyl-pyrrolidin-2-yl)-ethylamine replacing 2-pyrrolidin-1-yl-ethylamine. The hydrochloride salt was prepared by treatment with hydrogen chloride in 1,4-dioxan. 1H NMR (DMSO-d6) 8-7 (1H, br s), 7.82-7.77 (2H, m), 7.50-7.46 (2H, m), 3.10-3.01 (3H, m), 2.39 (1H, m), 2.28 (3H, s), 2.15-2.12 (1H, m), 1.82-1.42 (6H, m). Microanalysis found C 51.65 H 6.44 N 8.99. C13H19ClN2O2S requires C 51.56 H 6.32 N 9.25.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:8].C(N(CC)CC)C>C(Cl)Cl>[OH:8][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][NH:5][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: NCC(O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCC(O)c1ccccc1
Reaction time: 3 h
Yield: 34.4 %

Procedure:
A solution of acetyl chloride (10 ml, 0.146 moles) in 200 ml of methylene chloride was added under nitrogen dropwise over 45 minutes to a solution of 2-amino-1-phenylethanol (20.0 g, 0.146 moles) and triethylamine (20 ml, 0.146 moles) in 300 ml of methylene chloride at ice bath temperature. After the addition the reaction was stirred at ice bath temperature for 3 hours and overnight at room temperature. The reaction was extracted with 1N HCl. The organic layer was separated and the aqueous layer was extracted with methylene chloride and then 10% methanol-methylene chloride. The organic extracts were combined, dried (MgSO4) and the solvent removed under reduced pressure to give a solid material. Recrystallization of this solid from isopropyl alcohol gave N-(2-hydroxy-2-phenyl-ethyl)-acetamide (9.0 g, 34%) as a white solid, mp 120-122° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([O:13][CH:14]2[CH2:31][CH:30]3[CH:16]([C:17](=[O:37])[N:18]([CH3:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]4[C:27]([C:33]([OH:35])=O)([NH:28][C:29]3=[O:32])[CH2:26]4)[CH2:15]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.[CH:49]1([S:52]([NH2:55])(=[O:54])=[O:53])[CH2:51][CH2:50]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([O:13][CH:14]2[CH2:31][CH:30]3[CH:16]([C:17](=[O:37])[N:18]([CH3:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]4[C:27]([C:33]([NH:55][S:52]([CH:49]5[CH2:51][CH2:50]5)(=[O:54])=[O:53])=[O:35])([NH:28][C:29]3=[O:32])[CH2:26]4)[CH2:15]2)[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1nc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)cc(C(C)(C)C)n1
Reactant: NS(=O)(=O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)cc(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Compound 3j (120 mg, 0.233 mmol) was dissolved in DCM (10 ml). EDAC (54 mg, 0.28 mmol) was added and the reaction mixture was stirred at RT for 2.5 h. Cyclo-propanesulfonic acid amide (31 mg, 0.256 mmol) and DBU (73 μl, 0.489 mmol) were added and the reaction mixture was stirred at RT over night. 5% Citric acid was added and the organic layer was washed with brine, dried, filtered and evaporated. Purifica-tion by preparative HPLC yielded the pure title compound of (65 mg, 45%), MS (M+H)+618.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.O.[NH2:13]N.O>C(O)C>[NH2:13][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: NN
Solvent: CCO
Solvent: O
Product: NN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 42 %

Procedure:
Phthalimide powder was added to a solution of hydrazine monohydrate (28.9 mL, 462.4 mmol) in ethanol (415 mL). The resulting solution was stirred at room temperature for 2 minutes and then stirred under reflux for 8 minutes. The resulting mixture was added to icy water to precipitate solid. The resulting solid was filtered, collected, washed with a small volume of water, and then dried in vacuum. The target compound was yielded as white solid (29.5 g, 182.1 mmol, 42% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:7]2[CH:8]=[C:9]([C:12]3[S:16][C:15]([C:17]#[N:18])=[CH:14][C:13]=3[CH3:19])[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=O)[O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:21])[C:7]2[CH:8]=[C:9]([C:12]3[S:16][C:15]([C:17]#[N:18])=[CH:14][C:13]=3[CH3:19])[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[S:31])[O:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cc(C#N)sc1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Solvent: Cc1ccccc1
Product: Cc1cc(C#N)sc1-c1ccc2c(c1)C(C)(C)OC(=S)N2
Temperature: 25 °C
Yield: 51.6 %

Procedure:
To a solution of 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-4-methylthiophene-2-carbonitrile (5 g, 16.7 mmol) in anhydrous toluene was added, at room temperature under a blanket of nitrogen, Lawesson's reagent (6 g, 14.8 mmol). The reaction mixture was heated at reflux for 2 hrs, allowed to cool to room temperature, and solvent was removed in vacuo. The residue was purified by a silica gel column chromatography (THF:hexane/1:3) to yield the title compound as a yellowish solid (2.4 g, 46%): mp 211–212° C.; 1H-NMR (DMSO-d6) δ 12.3 (s, 1H), 7.88 (s, 1H), 7.46–7.52 (m, 2H), 7.16 (d, 1H, J=8.3 Hz), 2.30 (s, 3H), 1.68 (s, 6H); MS (ESI) m/z 313 [M−H]−; Anal. Calc. For C16H14N2OS2; C, 61.12; H, 4.49; N, 8.91. Found: C, 60.91; H, 4.48; N, 8.66.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(#N)C>[N:1]1([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CCOC(=O)CBr
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)Cn1ccc2ccccc21
Reaction time: 0.5 h

Procedure:
Under an atmosphere of nitrogen, a solution of indole (15.0 g, 128 mmol) in dry acetonitrile (300 mL, 0.4 M) was treated with sodium hydride (95%, 3.69 g, 153 mmol) and stirred for 30 min. Ethyl bromoacetate (17.0 mL, 153 mmol) was added in a dropwise manner over 10 min and the solution was stirred at room temperature for 16 h. After concentrating under reduced pressure, the resulting residue was dissolved in ethyl acetate and washed with sat'd. aq. NaCl. The organic extracts were dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography (50% ethyl acetate in heptane): Rf0.25 (40% ethyl acetate in heptane) 1H NMR (DMSO-d6, 300 MHz) δ 7.53 (d, J=6.3 Hz, 1H), 7.38-7.31 (m, 2H), 7.11 (br t, J=7.2 Hz, 1H), 7.02 (br t, J=7.2 Hz, 1H), 6.45-6.43 (m, 1H), 5.10 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 1.19 (t, J=7.2 Hz, 3H).
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[C:5]=1[C:12]#[N:13])([O-])=O.[F:14][C:15]([F:24])([F:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[F:14][C:15]([F:23])([F:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[C:5]=1[C:12]#[N:13]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cccc(Oc2ccccc2C(F)(F)F)c1C#N
Temperature: 50 °C
Yield: 93.2 %

Procedure:
A reaction flask equipped with a cooling tube was loaded with 8.7 g of 3-nitrophthalonitrile, 9.4 g of 2-(trifluoromethyl)phenol, 13.8 g of anhydrous potassium carbonate and 350 ml of dimethyl sulfoxide, and the temperature was raised to 50° C. with stirring under nitrogen flow. After stirring at 50° C. for three hours, the heating was stopped. The reaction liquid was cooled and added into 500 ml of water, and the precipitated crystal was collected and dried to yield 13.5 g of the intended compound.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[CH:6][N:5]=[CH:4][N:3]=1.[CH:9]1([NH2:12])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[CH:9]1([NH:12][C:2]2[C:7]([I:8])=[CH:6][N:5]=[CH:4][N:3]=2)[CH2:11][CH2:10]1
Reactant: Clc1ncncc1I
Reactant: NC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Ic1cncnc1NC1CC1
Temperature: 90 °C
Yield: 79.3 %

Procedure:
To a vial containing a solution of 4-chloro-5-iodopyrimidine (0.400 g, 1.664 mmol) in DMF (Volume: 2.67 ml) was added cyclopropanamine (0.461 ml, 6.65 mmol) followed by cesium carbonate (1.084 g, 3.33 mmol). The vial was sealed with a Teflon cap and heated at 90° C. for 3 h, then allowed to cool to room temperature. The reaction mixture was filtered through a disposable fritted funnel and the filter cake washed with EtOAc. The filtrate was diluted with H2O and the layers were separated. The organic phase was washed with H2O (2×). The combined aqueous phases were back-extracted with EtOAc (3×). All organics were combined, dried over Na2SO4, filtered, and concentrated to afford an orange residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (40 g column, 40 mL/min, 20-70% EtOAc in hexanes over 19 min, ret. T=13.5 min) gave Intermediate 108A (348 mg, 1.320 mmol, 79% yield) as a yellow solid. MS (ESI): m/z=262.0 [M+H]+ HPLC Peak ret. T=1.47 minutes was product. (HPLC conditions: Column:Luna C18 4.6×30 mm 3 u A:10:90 H2O:ACN NH4OAc/B:10:90 H2O:ACN NH4OAc; 0%-95% B in 2 min; 4 mL/min flow).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([O:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[N:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([O:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][C:32]([F:33])([F:34])[F:35])=[CH:29][CH:30]=3)[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: Cc1cc(Oc2ccc(OC(F)(F)F)cc2)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nc(C)cc(Oc3ccc(OC(F)(F)F)cc3)n2)ccc1-n1cnc(C)c1
Yield: 13 %

Procedure:
Prepared in analogy to example 81b) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 2-chloro-4-methyl-6-(4-trifluoromethoxy-phenoxy)-pyrimidine in a yield of 13%. MS ISP (m/e): 472.1 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.44 (s, 1H), 7.35-7.15 (m, 5H), 7.01 (s, 2H), 6.86 (s, 1H), 6.30 (s, 1H), 3.63 (s, 3H), 2.43 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][NH:10][C:11]([NH2:13])=[S:12])([CH3:4])([CH3:3])[CH3:2].Br[CH:16]([CH3:20])[C:17](=O)[CH3:18].CCN(C(C)C)C(C)C>C(O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][NH:10][C:11]1[S:12][C:16]([CH3:20])=[C:17]([CH3:18])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)C(C)Br
Reactant: CC(C)(C)OC(=O)NCCNC(N)=S
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(NCCNC(=O)OC(C)(C)C)sc1C

Procedure:
A solution of (2-thioureido-ethyl)-carbamic acid tert-butyl ester [CAS 331779-96-5] (3.6 g), 3-bromo-2-butanone (2.45 g), and DIPEA (5.5 ml) in ethanol (100 ml) was stirred overnight at RT and refluxed 1 hour. The mixture was concentrated. Ethyl acetate was added. Insoluble parts were filtered off and the remaining solution was extracted with brine. The organic layer was dried, evaporated and purified by flash chromatography yielding after crystallization 0.86 g of white crystals. MS (ISP): 272.2 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[C:20]4[O:25][CH2:24][O:23][C:21]4=[CH:22][C:17]=3[CH2:16][C:15]([CH3:26])=[N:14][N:13]=2)=[CH:8][CH:7]=1)=[O:4].[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>>[CH2:27]([N:29]([CH2:30][CH3:31])[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[C:20]4[O:25][CH2:24][O:23][C:21]4=[CH:22][C:17]=3[CH2:16][C:15]([CH3:26])=[N:14][N:13]=2)=[CH:8][CH:7]=1)=[O:4])[CH3:28]
Reactant: CC1=NN=C(c2ccc(NC(=O)CCl)cc2)c2cc3c(cc2C1)OCO3
Reactant: CCNCC
Product: CCN(CC)CC(=O)Nc1ccc(C2=NN=C(C)Cc3cc4c(cc32)OCO4)cc1

Procedure:
It was prepared from 1-(4-chloroacetylaminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine by using the process of Example 102, except that diethylamine was used instead of pyrrolidine, m.p.: 157°-158° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[NH:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9]1.C(N(CC)CC)C.[C:23]1(=[O:33])[O:32][C:30](=[O:31])[CH2:29][CH2:28][S:27][S:26][CH2:25][CH2:24]1>CC(C)=O>[C:23]([CH2:24][CH2:25][S:26][S:27][CH2:28][CH2:29][C:30]([N:12]1[C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9][CH:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])=[O:31])([OH:33])=[O:32]
Reactant: O=C1CCSSCCC(=O)O1
Reactant: O=C(O)[C@@H]1CSC(c2ccccc2O)N1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(O)CCSSCCC(=O)N1C(c2ccccc2O)SC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of 2.0 g of (4R)-2-hydroxyphenyl-4-thiazolidinecarboxylic acid and 1.7 ml of triethylamine in 15 ml of anhydrous acetone, 2.0 g of dithiodipropanoic anhydride is added. The resulting mixture is continuously stirred for 40 min at room temperature and extracted with ethyl acetate after addition of 50 ml of water containing a small amount of potassium carbonate. The aqueous layer is acidified with N aqueous hydrochloric acid and extracted with ethyl acetate. The second organic layer is washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residual oil is purified by column chromatography on silica gel to give crystals of the titled compound. The yield is 0.6 g (15%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:30]([O-])=O)[C:18]([NH:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH:22]([O:26][C:27](=[O:29])[CH3:28])[CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+].O>C(O)C.[Fe]>[NH2:30][C:17]1[C:18]([NH:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH:22]([O:26][C:27](=[O:29])[CH3:28])[CH2:21]2)=[C:13]2[CH:12]=[CH:11][N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=1
Reactant: CC(=O)OC1CCCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(=O)OC1CCCC(Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 80 °C

Procedure:
A mixture of Acetic acid 3-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexyl ester (trans racemic) (9.72 g, 21.2 mmol), ammonium chloride (2.26 g, 42.40 mmol), iron powder (5.92 g, 106 mmol), and water (15.0 mL) in ethanol (150 ml) was heated at 80° C. overnight. The reaction was followed by LC/MS to completion. On completion, the reaction mixture was used as is for the next step without any workup. LCMS (Method M, ESI): RT=1.90 min, m+H=428.9.