Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[O:5][CH2:6][C:7]#[N:8].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>N1C=CC=CC=1>[Cl:12][C:11]1[C:2]([NH:1][S:15]([CH3:14])(=[O:17])=[O:16])=[C:3]([CH3:13])[C:4]([O:5][CH2:6][C:7]#[N:8])=[CH:9][CH:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(OCC#N)ccc(Cl)c1N
Solvent: c1ccncc1
Product: Cc1c(OCC#N)ccc(Cl)c1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3-amino-4-chloro-2-methylphenoxy)acetonitrile (4.76 g) was dissolved in pyridine (45 mL) under an atmosphere of nitrogen and cooled in an ice bath. Methanesulfonyl chloride (2.06 mL) was added dropwise, and then the mixture was allowed to stir overnight at room temperature. The reaction mixture was evaporated to dryness under reduced pressure to afford a residue which was flash chromatographed on silica and eluted with, first ethyl acetate:hexane (1:2), then with ethyl acetate: hexane (1:1) to afford 5.36 g as an 80:20 mixture of mono and bis mesylated product, respectively. This mixture was used in the next step without any further purification.
Reaction SMILES: O[C:2]1[C:7]2=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[CH:10][N:6]2[N:5]=[C:4]([C:17]2[CH:18]=[C:19]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:20]=[N:21][CH:22]=2)[N:3]=1.CN([P+](O[N:38]1N=[N:45][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N1C=CC=CC=1CN>C1COCC1>[C:11]1([C:8]2[CH:9]=[CH:10][N:6]3[C:7]=2[C:2]([NH:38][CH2:39][C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][N:45]=2)=[N:3][C:4]([C:17]2[CH:18]=[C:19]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:20]=[N:21][CH:22]=2)=[N:5]3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: NS(=O)(=O)c1cncc(-c2nc(O)c3c(-c4ccccc4)ccn3n2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: NCc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
5-(4-Hydroxy-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide (0.150 g, 0.408 mmol) was dissolved in THF (10 mL) and BOP reagent (0.271 g, 0.612 mmol) and DIPEA (0.214 mL, 1.23 mmol) were added. The reaction mixture was stirred at room temperature for 30 min. Pyridin-2-ylmethanamine (0.0660 g, 0.612 mmol) in THF (3 mL) was added to the reaction mixture and the resulting mixture was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The aqueous layer was extracted with ethyl acetate (25×2 mL). The organic layer was dried (with anhydrous sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by CombiFlash (REDISEP®, silica gel, 40 g, 3% methanol in CH2Cl2) to afford 5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridine-3-sulfonamide (0.0400 g, 21.4%). LCMS Condition B-38: retention time 1.99 min, [M+1]=458.2. HPLC Condition B-32: retention time 7.75 min, Purity 98.90%. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.94 (d, J=4.4 Hz, 2H), 6.85 (d, J=2.8 Hz, 1H), 7.29 (dd, J=5.2 Hz, J=6.8 Hz, 1H), 7.42 (t, J=4.6 Hz, 1H), 7.46-7.50 (m, 2H), 7.52-7.56 (m, 2H), 7.60 (dd, J=2.0 Hz, J=6.8 Hz, 2H), 7.75 (s, 2H), 7.79 (dt, J=1.6 Hz, J=7.6 Hz, 1H), 7.96 (d, J=2.8 Hz, 1H), 8.39 (dd, J=0.8 Hz, J=1.6 Hz, 1H), 8.94 (t, J=2.0 Hz, 1H), 9.07 (d, J=2.4 Hz, 1H), 9.58 (d, J=2.0 Hz, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:6]=1[NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])#[N:4].S(OCC)(O[CH2:29][CH3:30])(=O)=O.O>CN(C=O)C>[C:3]([C:5]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:6]=1[N:7]([CH2:29][CH3:30])[S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])#[N:4]
Reactant: CCOS(=O)(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc([N+](=O)[O-])cc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(c1ccc([N+](=O)[O-])cc1C#N)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.4 %

Procedure:
To a suspension of sodium hydride (60%, 0.12 g (3.00 mmol)) in 3.0 ml of DMF, 2′-cyano-4′-nitro-p-toluenesulfonanilide (0.80 g (2.52 mmol)) was added with′stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, diethyl sulfate (0.40 ml (3.05 mmol)) was added dropwise and the mixture was heated at 80° C. for 2 hours and at 100° C. for 2 hours with stirring. The reaction mixture was then cooled to room temperature, poured into water and extracted with diethyl ether. The extract was washed three times with 1% aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:2) as eluent, to give 0.23 g (26%) of the title compound as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH3:13])[C:6](=[O:14])[CH2:5]2.[C:15]([O:19][C:20](=[O:26])[NH:21][CH2:22][C@H:23]1[CH2:25][O:24]1)([CH3:18])([CH3:17])[CH3:16].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C.C(OCC)(=O)C>[C:15]([O:19][C:20](=[O:26])[NH:21][CH2:22][C@H:23]([OH:24])[CH2:25][NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH3:13])[C:6](=[O:14])[CH2:5]2)([CH3:17])([CH3:16])[CH3:18]
Reactant: CCN1C(=O)Cc2cc(N)cc(F)c21
Reactant: CC(C)(C)OC(=O)NC[C@H]1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCN1C(=O)Cc2cc(NC[C@@H](O)CNC(=O)OC(C)(C)C)cc(F)c21

Procedure:
5-Amino-1-ethyl-7-fluoro-1,3-dihydro-indol-2-one (2.25 g, 11.6 mmol), (S)-oxiranylmethyl-carbamic acid tert-butyl ester (2.00 g, 11.6 mmol) and lithium trifluoromethanesulfonate (1.80 g, 11.6 mmol) in acetonitrile (12 ml) are heated at 90° C. for 20 hours. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated. Final purification by flash chromatography (70% Ethyl acetate/hexane) gives the title compound as a yellow-brown foamy solid. HPLC r.t. 3.95 min; MS for C 18H26FN3O4 m/z 368.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[Cl:30])[O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[F:31][C:32]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:33]=1[CH2:34]Br>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[Cl:30])[O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][N:14]([CH2:34][C:33]2[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:32]=2[F:31])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:11][CH:10]=1)[CH:2]=[CH2:3]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: C=CCOc1cc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)ccc1Cl
Product: C=CCOc1cc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)ccc1Cl

Procedure:
The product from Example 91D and 2,4-difluorobenzyl bromide were processed as described in Example 6B to provide the title compound. MS (ESI+) m/z 573 (M+H)+.
Reaction SMILES: [H-].[Na+].O1CCCC1.F[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26]>O>[F:15][C:13]1[CH:12]=[CH:11][C:10]([N+:16]([O-:18])=[O:17])=[C:9]([O:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[F:19])[CH:14]=1
Reactant: Oc1ccccc1F
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1Oc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
With cooling with ice, 377 mg of sodium hydride (30% liquid paraffin added) was added to a tetrahydrofuran solution of 2,4-difluoro-1-nitrobenzene (1 g), and then o-fluorophenol (775 mg) was added, and stirred at room temperature for 2 hours. Water was added, then extracted with ethyl acetate, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the entitled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:41][CH3:42])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]O)[CH:29]=[C:28]([CH2:43][CH3:44])[N:27]=1.S(Cl)([Cl:47])=O.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:41][CH3:42])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][Cl:47])[CH:29]=[C:28]([CH2:43][CH3:44])[N:27]=1
Reactant: O=S(Cl)Cl
Reactant: CCc1cc(NC(CC)CCCCCCO)nc(Cl)n1
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCc1cc(NC(CC)CCCCCCCl)nc(Cl)n1
Yield: 59.4 %

Procedure:
To a mixture of 0.9 g of dl-5-chloro-6-ethyl-4-(1-ethyl-7-hydroxyheptyl)aminopyrimidine and 0.28 g of pyridine was gradually added dropwise 0.42 g of thionyl chloride under cooling to -10° to -5° C. After dropwise addition, the mixture was heated at 60° to 70° C. for one hour and allowed to stand for cooling. The reaction mixture was neutralized with an aqueous sodium carbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting oily product was isolated through a column chromatography (Wako gel C-200, trade name, eluent; toluene:ethyl acetate=10:1) to give 0.55 g of the title compound as pale yellow oily liquid. nD22.8 1.5246.
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[NH2:14][C@H:15]([C:20]([OH:22])=[O:21])[CH2:16][C:17]([OH:19])=[O:18].C(N(CC)CC)C.O>CN(C=O)C>[C:1]([NH:14][C@H:15]([C:20]([OH:22])=[O:21])[CH2:16][C:17]([OH:19])=[O:18])(=[O:13])[CH2:2][NH:3][C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: N[C@@H](CC(=O)O)C(=O)O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)C[C@H](NC(=O)CNC(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The starting material was synthesised as follows. To a solution of hippuric acid (0.90 g, 5×10-3 moles) and L-aspartic acid dibenyzl ester (2.31 g, 5×10-3 moles) in DMF (35 ml) was added 1-hyhdroxybenzotriazole (0.73 g, 5.5×10-3 moles), triethylamine (1.4 ml, 9.7×10-3 moles) and 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide, HCl salt (1.05 g, 5.5×10-3 moles). The mixture was stirred for 4 hours at room temperature then poured into water (450 ml) and extracted twice with ethyl acetate (100 ml). The extract was washed with saturated sodium bicarbonate solution, water, 2N HCl and water. The organic phase was dried over MgSO4 and evaporated to dryness to obtain the desired starting material as a yellow oil. 1.90 g (80%)
Reaction SMILES: [F:1][C:2]([F:20])([O:10][C:11]1[CH:19]=[CH:18][C:14]([CH:15](Br)[CH3:16])=[CH:13][CH:12]=1)[CH:3]([F:9])[O:4][C:5]([F:8])([F:7])[F:6].[C:21]([N:25]1[C:30](=[O:31])[C:29]([Cl:32])=[C:28]([SH:33])[CH:27]=[N:26]1)([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCOCC>[C:21]([N:25]1[C:30](=[O:31])[C:29]([Cl:32])=[C:28]([S:33][CH:15]([CH3:16])[C:14]2[CH:18]=[CH:19][C:11]([O:10][C:2]([F:20])([F:1])[CH:3]([F:9])[O:4][C:5]([F:8])([F:7])[F:6])=[CH:12][CH:13]=2)[CH:27]=[N:26]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Reactant: CC(Br)c1ccc(OC(F)(F)C(F)OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(Sc1cnn(C(C)(C)C)c(=O)c1Cl)c1ccc(OC(F)(F)C(F)OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
1.4 g of 4-(1,1,2-trifluoro-2-trifluoromethoxy-ethoxy)-α-methyl-benzyl bromide (Example 2) and 1 g of 2-tert.-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone are added to a suspension of 0.8 g of potassium carbonate in 10 cc of dimethylformamide. The resulting reaction mixture is stirred for 1 hour at room temperature, is diluted with ether, is washed with diluted HCl and brine; the washed solution is thoroughly dehydrated, the solvent is evaporated off and the so obtained raw reaction product is chromatographed on silica gel with 9/1 hexane/ethyl acetate. 0.58 g of pure product is obtained.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][CH:12]([CH2:15][OH:16])[O:11][C:10]=2[CH:17]=1)(=[O:5])=[O:4].[C:20]1(C)[C:21]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1.[CH2:31](Cl)Cl>CN(C1C=CN=CC=1)C>[CH3:31][C:24]1[CH:25]=[CH:20][C:21]([S:26]([O:16][CH2:15][C@@H:12]2[O:11][C:10]3[CH:17]=[C:6]([S:3]([C:2]([F:1])([F:18])[F:19])(=[O:5])=[O:4])[CH:7]=[CH:8][C:9]=3[O:14][CH2:13]2)(=[O:27])=[O:28])=[CH:22][CH:23]=1
Reactant: O=S(=O)(c1ccc2c(c1)OC(CO)CO2)C(F)(F)F
Reactant: ClCCl
Reactant: Cc1ccccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(S(=O)(=O)C(F)(F)F)cc3O2)cc1
Reaction time: 18 h

Procedure:
Preparation according to Preparation 22 using [7-(trifluoromethylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (0.75 g, 2.5 mmol), toluenesulfonyl chloride (0.72 g, 3.8 mmol), TEA (0.42 ml, 3 mmol) and 4-DMAP (0.37 g, 3.0 mmol) in DCM (40 ml), stirred for 18 h. Yield 0.28 g. MS m/z (rel. intensity, 70 eV) 452 (M+, bp), 383 (41), 280 (82), 211 (80), 91 (84).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[CH2:19]([O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([C:36](O)=[O:37])=[CH:30]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[CH2:19]([O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([C:36]([N:16]1[CH2:17][CH2:18][N:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:3]([CH3:6])([CH3:4])[CH3:5])[CH2:14][CH2:15]1)=[O:37])=[CH:30]2)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: O=C(O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2cc3cc(OCc4ccccc4)ccc3[nH]2)CC1
Temperature: 25 °C
Yield: 81 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (2.0 g), 5-(benzyloxy)-1H-indole-2-carboxylic acid (2.03 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.92 g), 1-hydroxy-1H-benzotriazole monohydrate (1.53 g), triethylamine (2.79 mL), and N,N-dimethylformamide (30 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (2.6 g, 81%) as crystals.
Reaction SMILES: [CH:1]1([C:7]2[CH:30]=[CH:29][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([CH:27]=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31](Cl)(=O)C.[Sn](Cl)(Cl)(Cl)Cl.O>ClCCl>[CH:1]1([C:7]2[CH:30]=[CH:29][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](=[O:28])[CH3:31])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)Cl
Reactant: O=Cc1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
10-(4-Cyclohexylbenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carbaldehyde of Step A (3.7 g) dissolved in dichloromethane (75 mL) was treated with acetyl chloride (1.9 g) and tin (IV) chloride in dichloromethane (12.5 mL, 1N). After stirring overnight at room temperature, water was added. The organic solution was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and filtered through a short column of Magnesol® to provide the desired title compound as a pale yellow amorphous solid (1.3 g).
Reaction SMILES: [Br:1]Br.[CH:3]1([C:6]([CH:13]2[CH2:15][CH2:14]2)([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[OH:7])[CH2:5][CH2:4]1.CC([O-])=O.[Na+]>C(O)(=O)C>[Br:1][C:10]1[S:9][C:8]([C:6]([CH:3]2[CH2:5][CH2:4]2)([CH:13]2[CH2:14][CH2:15]2)[OH:7])=[N:12][CH:11]=1
Reactant: OC(c1nccs1)(C1CC1)C1CC1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: OC(c1ncc(Br)s1)(C1CC1)C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.1 %

Procedure:
Bromine (0.271 mL, 5.26 mmol) was added dropwise to a stirred mixture of the product of Step 1 (411 mg, 2.10 mmol) and NaOAc (863 mg; 10.5 mmol) in acetic acid (9.17 mL) and the mixture was stirred at room temperature for 4 h. The reaction was quenched with brine and the aqueous layer was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried (sodium sulfate), filtered, and concentrated. The residue was purified by chromatography on silica gel (0-100% ethyl acetate in hexanes) to give (5-bromo-1,3-thiazol-2-yl)(dicyclopropyl)methanol (329 mg, 1.20 mmol, 57% yield) as an off-white solid. MS APCI: [M-OH]+ m/z 255.9
Reaction SMILES: [C:1]([C:8]1([OH:16])[CH2:13][CH2:12][N:11](CN)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:17](Cl)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].[CH2:28]([N:30](CC)CC)C>C(Cl)Cl>[C:1]([C:8]1([OH:16])[CH2:9][CH2:10][N:11]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:12]([CH2:28][NH2:30])[CH2:13]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)C1(O)CCN(CN)CC1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1(O)CCN(C(=O)OCc2ccccc2)C(CN)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.), stirred solution of 4-BOC-aminomethyl-piperidin-4-ol (0.35 g, 1.52 mmol) in dried CH2Cl2 (5 mL), under N2 was slowly added CBZ-Cl (0.24 mL, 1.67 mmol), followed by triethylamine (0.42 mL, 3.04 mmol). The ice bath was removed and the reaction solution was stirred to rt in 1 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (10 CH2Cl2: 1–20 IPA: 89–10 hexane)) to give 4-BOC-aminomethyl-1-CBZ-piperidin-4-ol.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:23][S:20]([O:19][C:17]1[CH:16]=[CH:15][C:12]2[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=2[CH:18]=1)(=[O:21])=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(OS(C)(=O)=O)cc2CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc2c(c1)CCNCC2
Yield: 81 %

Procedure:
A solution of 3-(tert-butyloxycarbonyl)-7-methanesulfonyloxy-2,3,4,5-tetrahydro-1H-3-benzazepine (3.8 g, 0.011 mol), trifluoroacetic acid (3.76 g, 0.033 mol) and dichloromethane (50 ml) was heated at 50° C. for 5 h. The solvents were then evaporated in vacuo and the residue partitioned between water (200 ml) and ethyl acetate (150 ml). The aqueous layer was removed and washed with ethyl acetate (100 ml) and then basified to pH 14 with 40% sodium hydroxide. The suspension was then extracted with ethyl acetate (3×150 ml) and the combined organic layers dried (Na2SO4). The solvents were evaporated in vacuo to give the title compound (2.15 g, 80%) as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].C[Si]([C:15]#[N:16])(C)C.CCCCCC.CCOC(C)=O>CO>[OH:6][CH:5]([C:4]1[CH:7]=[CH:8][C:9]([F:10])=[C:2]([F:1])[CH:3]=1)[C:15]#[N:16]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: C[Si](C)(C)C#N
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: N#CC(O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 3,4-difluorobenzaldehyde (2.86 g, 20.0 mmol) in MeOH (20 mL)in a round bottom flask was added trimethylsilyl cyanide (4.0 mL., 30.0 mmol) at 0° C. The reaction mixture was stirred at room temperature for 10 h when TLC analysis indicated that the reaction was complete (Rf=0.4, 3:2 hexane/EtOAc). Solvent was removed in vacuo and hydroxy-(3,4-difluorophenyl)-acetonitrile was obtained as a colorless liquid (crude wt.=3.4 g). It was used in the next step without purification.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2[OH:21])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].Cl[C:23]1C(CC)=NC=C(C2CC2)N=1>>[CH:9]1([C:6]2[N:5]=[C:4]([NH:11][C@@H:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][C@@H:13]3[OH:21])[C:3]([CH2:1][CH3:2])=[N:8][CH:7]=2)[CH2:23][CH2:10]1
Reactant: CCc1ncc(C2CC2)nc1Cl
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1ncc(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3-chloro-5-cyclopropyl-2-ethylpyrazine and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.92-0.95, 1.31-1.35, 1.93, 2.59-2.70, 3.03-3.10, 3.22-3.30, 4.74, 4.91, 5.49-5.52, 7.28-7.32, 7.82; MS (ESI+) for C18H21N3O m/z 296 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH:24][CH2:25][CH:26]([O:29][N:30]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:27][OH:28]>>[OH:24][CH2:25][CH:26]([O:29]/[N:30]=[C:21](/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)\[CH3:22])[CH2:27][OH:28]
Reactant: O=C1c2ccccc2C(=O)N1OC(CO)CO
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Product: C/C(=N\OC(CO)CO)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 54 %

Procedure:
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (22.4) and 2-(aminooxy)propane-1,3-diol (intermediate B) in 54% yield using the same procedure as described in the synthesis of example 22 and example 7A. 1H-NMR (400 MHz, CD3OD), 5 ppm 9.40 (s, 1H), 8.86 (dd, 1H), 8.38 (d, 1H), 8.05 (m, 2H), 7.90 (dd, 1H), 7.56 (dd, 1H), 6.22 (s, 2H), 4.46 (t, 1H), 3.87 (d, 4H), 2.42 (s, 3H). LCMS (method B): [MH]+=394, tR=1.86 min.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[Cl:12].[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.C(N(CC)CC)C>C(O)C>[Cl:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[CH2:2][S:20][C:18]1[N:17]=[C:16]([OH:21])[CH:15]=[C:14]([CH3:13])[N:19]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: O=[N+]([O-])c1ccc(Cl)c(CBr)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2cc([N+](=O)[O-])ccc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
A mixture of 2-(bromomethyl)-1-chloro-4-nitrobenzene (1.0 g, 4.0 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (512 mg, 3.6 mmol), and triethylamine (560 μL, 4.0 mmol) in absolute ethanol (20 mL) was stirred at room temperature overnight. The product was recovered by filtration, washed with EtOH (2×15 mL) and diethyl ether (3×25 mL), and dried in vacuo, affording the title compound (1.0 g, 90% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.26 (s, 3H), 4.53 (s, 2H), 6.00 (s (br), 1H), 7.78 (d, 1H, J=8.8 Hz), 8.15 (dd, 1H, J=2.9 Hz, 8.8 Hz), 8.59 (d, 1H, J=2.7 Hz); M+ 312.