Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH2:6]1)=[O:4].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=2)[N:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:33][C:29]1[CH:28]=[C:27]2[C:32]([C:23]([NH:1][CH2:2][C:3]([N:5]3[CH2:9][CH2:8][CH:7]([N:10]4[CH2:11][CH2:12][CH:13]([C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH2:14][CH2:15]4)[CH2:6]3)=[O:4])=[N:24][CH:25]=[N:26]2)=[CH:31][CH:30]=1
Reactant: Clc1ccc2c(Cl)ncnc2c1
Reactant: NCC(=O)N1CCC(N2CCC(c3ccccc3)CC2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: O=C(CNc1ncnc2cc(Cl)ccc12)N1CCC(N2CCC(c3ccccc3)CC2)C1
Yield: 58.9 %

Procedure:
A solution of 2-amino-1-[3-(4-phenylpiperidin-1-yl)pyrrolidin-1-yl]ethanone (preparation #9) (0.108 g, 0.377 mmol), 4,7-dichloroquinazoline (0.075 g, 0.377 mmol) and DIEA (0.1 mL, 0.565 mmol) in n-butanol was heated in a microwave (CEM Explorer, maximum power 300 W) at about 120° C. for about 20 min. The solvent was removed in vacuo and the residue was purified by preparative RP-HPLC (20% to 50% acetonitrile/0.05M aqueous ammonium acetate, buffered to pH 4.5, over 30 min at 81 mL/min; λ=254 nm; Microsorb C18, 100 Å, 5 μm, 250×46 mm column) to yield 2-(7-chloroquinazolin-4-ylamino)-1-[3-(4-phenylpiperidin-1-yl)pyrrolidin-1-yl]ethanone (0.100 g, 0.222 mmol) as a yellow solid. RP-HPLC (Table 1, Method a) Rt 1.77 min; m/z: (M+H)+ 450.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH:14](O)[C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[N:11]([CH2:21][C:22]([N:24]2[C:32]3[CH:31]=[C:30]([C:33]([F:38])([F:37])[CH2:34][CH2:35][CH3:36])[N:29]=[CH:28][C:27]=3[C:26]([CH3:40])([CH3:39])[CH2:25]2)=[O:23])[CH2:10][C@H:9]1[CH3:41])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS([Cl:53])(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH:14]([Cl:53])[C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[N:11]([CH2:21][C:22]([N:24]2[C:32]3[CH:31]=[C:30]([C:33]([F:38])([F:37])[CH2:34][CH2:35][CH3:36])[N:29]=[CH:28][C:27]=3[C:26]([CH3:40])([CH3:39])[CH2:25]2)=[O:23])[CH2:10][C@H:9]1[CH3:41])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC(F)(F)c1cc2c(cn1)C(C)(C)CN2C(=O)CN1C[C@@H](C)N(C(=O)OC(C)(C)C)C[C@@H]1C(O)c1nccs1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(F)(F)c1cc2c(cn1)C(C)(C)CN2C(=O)CN1C[C@@H](C)N(C(=O)OC(C)(C)C)C[C@@H]1C(Cl)c1nccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
To (2R,5R)-4-{2-[6-(1,1-difluoro-butyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl]-2-oxo-ethyl}-5-(hydroxy-thiazol-2-yl-methyl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.076 g, 0.13 mmol) and triethylamine (36 μL, 0.3 mmol) in DCM (0.6 mL) cooled with an ice bath under nitrogen was added methanesulfonyl chloride (12 μL, 0.2 mmol). The reaction was stirred at this temperature for 1 h and then warmed room temperature for 18 h. Saturated aqueous sodium bicarbonate was added and the mixture extracted with EtOAc. The combined organics were washed with brine, dried with sodium sulfate, filtered and concentrated. Chromatography (silica gel, gradient elution, 0-100%, EtOAc in petrol 40-60) gave the title compound (0.03 g). MS: [M+H]+=612.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[C:15]1([C:24]([O-])=[O:25])([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>ClCCl>[Cl:2][C:3]1[CH:14]=[C:13]2[C:6](=[CH:5][CH:4]=1)[NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH:12][C:24]([C:15]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16]1)=[O:25]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CCOC(=O)C1(C(=O)[O-])CCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)CCC1

Procedure:
23.1 g of 5-chlorotryptamine hydrochloride, 17.3 g of monoethyl cyclobutanedicarboxylate, 36 ml of diisopropylethylamine and 33.7 g of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate are stirred for 20 hours at ambient temperature in 200 ml of dichloromethane. After washing with water, drying over sodium sulphate and filtering off the organic phase over Celite, evaporation under reduced pressure enables the expected product to be isolated.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[O:12])=[CH:4][C:3]=2[O:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1COCC1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[O:12])=[CH:4][C:3]=2[O:2]1
Reactant: BrCc1ccccc1
Reactant: CC(C)c1ccc(S(=O)(=O)NC(=O)Cc2ccc3c(c2)OCO3)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1ccc(S(=O)(=O)NC(=O)C(Cc2ccccc2)c2ccc3c(c2)OCO3)cc1
Temperature: -78 °C
Yield: 64.3 %

Procedure:
A solution of 0.228 g (0.63 mmol) of the product of Example 1 was dissolved in 0.5 mL of anhydrous THF in an oven dried 25 mL round bottom flask and was magnetically stirred at -78° C. under a nitrogen atmosphere. A solution of lithium bis(trimethylsilyl)amide (1.89 mL; 1.0M; 1.89 mmol) was slowly added and the resulting yellow solution was stirred at -78° C. for 1 hour. At this point 150 μL (1.26 mmol) of benzyl bromide was added via syringe, the dry ice-acetone bath was removed, the reaction mixture was allowed to warm to room temperature and was stirred an additional 2 hours. The mixture was then partitioned between EtOAc and 10% aqueous NaHSO4 and extracted. The organic layer was separated, washed once with water, once with saturated brine, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with CHCl3 -MeOH--NH4OH (92:8:0.5). Evaporation of the purified fractions and drying in vacuo afforded 0.183 g (64%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>O1CCCC1>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1ncnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (15.3 g, 99.6 mmol) in tetrahydrofuran (200 mL) was added NaH (60% dispersion in mineral oil, 4.20 g, 105 mmol) at 0° C. The resulting solution was stirred for 1 hour at 0° C. and then SEMCl (16.6 g, 100 mmol) was added dropwise. After stirring for an additional 5 hours at 25° C., the reaction was quenched by addition of 250 mL of water/ice, and extracted with ethyl acetate (×2). The organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. The reaction was purified by chromatography using silica gel, eluting with 50% EtOAc/petroleum ether. The product was collected and concentrated in vacuo to afford 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine as a light yellow oil. LRMS (PSI) calc'd for C12H19N3ClOSi [M+H]+: 284. found 284.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:19][S:20]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([N:29]([C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:32][CH:31]=2)[NH2:30])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Reactant: CS(=O)(=O)c1ccc(C(=O)NN)cc1
Product: Cc1c(N[C@@H](C(=O)N(N)C(=O)c2ccc(S(C)(=O)=O)cc2)[C@H](C)O)ccc(C#N)c1Cl
Yield: 83.2 %

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (813 mg, 3.0 mmol) and 4-(methylsulfonyl)benzohydrazide (648 mg, 3.0 mmol) were coupled in a procedure analogous to that described for the preparation of intermediate 3b. The crude product was recrystallized from hotchloroform (100 mL to yield product as a white solid (1.16 g, 82%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.83 (br s, 2H), 8.14 (AA′XX′, J=8.5 Hz, 2H), 8.06 (AA′XX′, J=8.5 Hz, 2H), 7.53 (d, J=8.6 Hz, 1H), 6.70 (d, J=8.7 Hz, 1H), 5.57 (d, J=7.0 Hz, 1H), 4.40 (m, 1H), 4.14 (dd, J=3.4, 6.9 Hz, 1H), 3.19 (s, 3H), 2.90 (br s, 1H), 2.36 (s, 3H), 1.36 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.C[O-].[Na+].[C:13](OCC)(=[O:15])C.O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:15][CH3:13])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)c1
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(Cl)nc(Cl)c1
Reaction time: 12 h

Procedure:
To a solution of 2,4,6-trichloropyridine (4.5 g) in methanol was added sodium methoxide (25% in methanol, 6.8 mL) at room temperature. The mixture was stirred for 12 h then poured into ethyl acetate/water and separated. The organic layer was washed with water, brine and dried over magnesium sulfate. Upon evaporating, the residue was purified by crystallization (100% hexanes) to give title compound as solid (3.1 g).
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN1CCCC1=O.O>[CH2:22]([NH:29][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:5]=[CH:4][N:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: COCCOc1ccnc(F)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COCCOc1ccnc(NCc2ccccc2)c1[N+](=O)[O-]

Procedure:
2.32 g of 2-fluoro-4-(2-methoxyethoxy)-3-nitropyridine (starting material J3), 4.44 g of potassium carbonate and 1.11 ml of benzylamine in 25 ml of N-methylpyrrolidone are stirred at room temperature for 5 hours. The mixture is diluted with water and then extracted twice with diethylether. The combined ether phases are washed with with water and brine and are then concentrated in vacuo. The residue is chromatographed on silica gel (ethyl acetate/petroleum ether 1:2). Concentration of the pure fractions and drying in vacuo gives 2.0 g of the title compound as a yellow oil, which crystallizes on standing (m.p. 81–83° C.). The mass spectrum shows the molecular peak MH+ at 304.0 Da.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[O:3]1.[CH3:17][C:18]([CH3:23])=[CH:19][C:20](Cl)=[O:21].O>C1COCC1>[CH3:17][C:18]([CH3:23])=[CH:19][C:20]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)[CH:10]=1)=[O:21]
Reactant: CC(C)=CC(=O)Cl
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=CC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.0 g, 0.00456 mol) in THF (5 mL) at 0° C., were added TEA (0.552 g, 0.000547 mol) and dimethylacryloyl chloride (0.648 g, 0.00456 mol) and stirred for 15 mins at 0° C. The reaction was poured into water (200 mL) and extracted with EtOAc (300 mL×2). The combined extracts was washed with brine (200 mL), dried over sodium sulphate, and concentrated under vacuum to afford 3-methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)but-2-enamide (0.7 g, Yield: 51%).
Reaction SMILES: C([O:4][C:5]1[C:10]2[CH:11]=[C:12]([CH3:14])[S:13][C:9]=2[CH:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.ClCCl>[CH2:18]([O:17][C:15]([C:7]1[CH:6]=[C:5]([OH:4])[C:10]2[CH:11]=[C:12]([CH3:14])[S:13][C:9]=2[CH:8]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)c1cc(OC(C)=O)c2cc(C)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cc(O)c2cc(C)sc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
Ethyl 4-(acetyloxy)-2-methyl-1-benzothiophene-6-carboxylate was dissolved in absolute ethanol (200 mL). Potassium carbonate (7 g, 50 mmol) was added. The reaction mixture was stirred for 3 h at 60° C. and diluted with 200 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 100 mL of dichloromethane. The combined solutions were washed by 200 mL of a 10% aqueous solution of citric acid and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (150×100 mm) with hexane/ethyl acetate mixture, 2:1 as eluent to give 5.5 g (23 mmol, 79%) of 4-Hydroxy-2-methyl-1-benzothiophene-6-carboxylate ethyl ester as a cream solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[N:8][OH:9])[NH2:7])=[CH:4][CH:3]=1.[CH3:12][C:13]1[S:14][C:15]([C:22]([O-])=O)=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1>>[CH3:12][C:13]1[S:14][C:15]([C:22]2[O:9][N:8]=[C:6]([C:5]3[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:7]=2)=[C:16]([C:18]([F:21])([F:19])[F:20])[N:17]=1
Reactant: Cc1nc(C(F)(F)F)c(C(=O)[O-])s1
Reactant: NC(=NO)c1ccc(Cl)cc1
Product: Cc1nc(C(F)(F)F)c(-c2nc(-c3ccc(Cl)cc3)no2)s1

Procedure:
The title compound was prepared from 4-chlorobenzamidoxime and 2-methyl-4-trifluoromethyl-thiazole-5-carboxylate similar to Example 16 as a light orange solid. 1H NMR (CDCl3): 8.08 (dd, J=8.52, 2.20 Hz, 1H), 7.50 (dd, J=8.51, 2.13 Hz, 1H), 2.85 (s, 3H).
Reaction SMILES: C(OC([NH:8][C@H:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[NH:12][C@@H:11]([C:21]([OH:23])=[O:22])[CH2:10]1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[ClH:19].[NH2:8][C@H:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[NH:12][C@@H:11]([C:21]([OH:23])=[O:22])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 177.1 %

Procedure:
To a solution of cis-4-tertiary-butyloxycarbonylamino-2-carboxy-5,7-dichloro-1,2,3,4-tetrahydroquinoline (100 mg, 0.277 mmol) in ethyl acetate (5 ml) was added hydrogen chloride in ethyl acetate (5 ml of an approx. 5M solution) and the resulting mixture was stirred at room temperature for 2.5 h. The solvent was removed in vacuo and the residue was triturated with ethyl acetate. The solid was collected by filtration to give the title compound (0.073 g, m.p. 176°-178 g°C.); δ (360 MHz, D2O) 2.42 (1H, m, CHACHBHCCHD), 2.67 (1H, dm, J=15.6 Hz, CHACHBHCCHD 4.27 (1H, dd, J=6.6 and 1.7 Hz, CHACHBHCCHD), 4.90 (1H, dd, J=5.6 and 1.4 Hz, CHACHBHCCHD), 6.77 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.88 (1H, d, J=2.0 Hz, 6-H or 8-H); m/e (FAB) 261 (M+1); Found: C, 40.17; H, 3.79; N, 9.23. C10H10Cl2N2O3.HCl requires C, 40.36; H, 3.73; N, 9.41%.
Reaction SMILES: [CH3:1]N1C2C(=CC=C(N)C=2)CC1.[N+:12]([C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][CH2:20][NH:21]2)=[CH:17][CH:16]=1)([O-:14])=[O:13].CI.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][N:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:23]=2)[CH2:19][CH2:20]1
Reactant: CN1CCc2ccc(N)cc21
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN1CCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
1-Methyl-2,3-dihydro-1H-indol-6-ylamine. 6-Nitroindoline (2 mmol) was combined with methyl iodide (2.2 mmol), n-Bu4I (7.4 mg, 0.020 mmol), and K2CO3 (350 mg, 2.5 mmol) in acetone (10 mL). The mixture was stirred at 25° C. for 16 h. The mixture was partitioned between CH2Cl2 and satd. aq. NaHCO3 (20 mL), and the organic layer was dried and concentrated. Purification by silica gel chromatography provided 1-methyl-6-nitroindoline (300 mg, 84%). To a solution of 1-methyl-6-nitroindoline (194 mg, 1.15 mmol) in MeOH (2 mL) was added FeCl3.6H2O (3 mg), Me2NNH2 (0.80 mL, 11 mmol), and charcoal (25 mg). The mixture was heated at reflux for 4 h. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated to provide the desired compound in quantitative yield. Step B. (1-Benzyl-piperidin-4-yl)-(1-methyl-2,3-dihydro-1H-indol-6-yl)-amine. The product from Step A (161 mg, 1.1 mmol) was converted to the desired compound as in Example 2, Step B. Step C. The title compound (80 mg, 35%) was prepared as in Example 2, Step C. 1H NMR (500 MHz, CDCl3): 7.63 (d, J=15.5 Hz, 1H), 7.30-7.25 (m, 10H), 7.02 (d, J=7.4 Hz, 1H), 6.38-6.36 (d, J=8.8 Hz, 1H), 6.25 (d, J=15.5 Hz, 1H), 6.14 (s, 1H), 4.73-4.68 (m, 1H), 3.46-3.34 (m, 4H), 3.02-2.86 (m, 4H), 2.73 (s, 3H), 2.17-2.12 (m, 2H), 1.86-1.77 (m, 2H), 1.61-1.51 (m, 2H). MS: exact mass calculated for C30H33N3O, 451.26; m/z found, 452.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17]O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][Cl:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: ClCCCc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
3-(4-Benzyloxyphenyl)propanol produced in Example 193-(1) (1.5 g) was dissolved in toluene (30 ml). To the solution were added thionyl chloride (0.88 g) and pyridine (0.1 ml). The mixture was stirred for 2 hours at 80° C. The reaction mixture was cooled, to which was added saturated sodium hydrogencarbonate to cause decomposition, followed by extraction with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to leave 3-(4-benzyloxyphenyl)propyl chloride (1.3 g) as a colorless crystalline product. m.p.: 34-35° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[C:10]([N:12]3[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[NH:14][C:13]3=[O:20])[CH:9]=[CH:8][C:5]=2[C:6]#[N:7])[CH2:3][CH2:2]1.[Br:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[CH2:29]Br>>[Br:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[CH2:29][N:14]1[C:15]([CH3:18])([CH3:19])[C:16](=[O:17])[N:12]([C:10]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH:1]3[CH2:2][CH2:3]3)[CH:11]=2)[C:13]1=[O:20]
Reactant: Fc1ccc(CBr)c(Br)c1
Reactant: CC1(C)NC(=O)N(c2ccc(C#N)c(C3CC3)c2)C1=O
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C3CC3)c2)C(=O)N1Cc1ccc(F)cc1Br

Procedure:
Under conditions as described for the preparation of 1.2, compound 158.1 was reacted with 2-bromo-1-bromomethyl-4-fluorobenzene and afforded 158.2. Molecular weight 455.06 (C22H19BrFN3O2); retention time Rt=2.15 min. [B]; MS (ESI): 456.02 (MH+).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:6]([NH2:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[F:15][C:16]([F:21])([F:20])[C:17](=N)N>C(O)C>[F:15][C:16]([F:21])([F:20])[C:17]1[NH:1][CH:2]2[CH2:3][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH:6]2[N:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@@H](N)C1
Reactant: N=C(N)C(F)(F)F
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2N=C(C(F)(F)F)NC2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the product from Step C (250 mg) in ethanol (5 mL) was added 2,2,2-trifluoroethanimidamide (180 mg) and the reaction mixture heated to reflux. After 2 h, the mixture was cooled to ambient temperature and the solvent evaporated in vacuo and used without further purification. LC/MS 224.2 (14+1-56).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[C:25]1([S:31]([C:34]2[CH:39]=[CH:38][C:37](CO)=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[C:25]1([S:31]([C:34]2[CH:39]=[CH:38][C:37]([CH2:20][Cl:24])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(CO)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1ccc(CCl)cc1
Temperature: 100 °C
Yield: 101.6 %

Procedure:
Triphenylphosphine (5.98 g, 22.8 mmol), carbon tetrachloride (9 mL, 93 mmol), (4-benzenesulfonyl-phenyl)-methanol (2.83 g, 11.4 mmol) and tetrahydrofuran (42 mL) were combined and heated at 100° C. for 4 hours. The reaction mixture was cooled to room temperature, then partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase was dried over MgSO4, filtered, and concentrated to give the crude product as an oily solid. A solution of this crude product and dichloromethane was evaporated over silica gel, and the resulting silica gel supported crude product was loaded onto an Analogix SuperFlash™ column. Flash chromatography (15%-35% ethyl acetate in hexanes) afforded 3.09 g (100%) of 4-(benzenesulfonyl)benzyl chloride as a white, crystalline solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.89-8.04 (m, 4 H), 7.53-7.75 (m, 5 H), 4.81 (s, 2 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([CH3:14])[NH:11][CH:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=1.CC1(C)CCCC(C)(C)N1>CN(C=O)C>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([N:11]2[CH:12]([CH3:14])[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH:10]2[CH3:15])=[N:18][CH:19]=1)#[N:22]
Reactant: CC1CN(C(=O)OC(C)(C)C)CC(C)N1
Reactant: N#Cc1ccc(Br)nc1
Agent: CC1(C)CCCC(C)(C)N1
Solvent: CN(C)C=O
Product: CC1CN(C(=O)OC(C)(C)C)CC(C)N1c1ccc(C#N)cn1
Temperature: 150 °C
Yield: 34.5 %

Procedure:
The compound 3,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (250 mg, 1.1 mmol) was dissolved in dry DMF (1 mL) taken in a shield tube. To the reaction mixture was added 6-bromonicotinonitrile (210 mg, 1.1 mmol) followed by 2,2,6,6-tetramethyl piperidine (0.16 g, 1.1 mmol) and the mixture was heated to 150° C. for 5 h. Reaction mixture was cooled to room temperature. The product was extracted with EtOAc and the organic layer was washed with H2O and brine. Solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 20-25% EtOAc in petroleum ether) to afford tert-butyl 4-(5-cyanopyridin-2-yl)-3,5-dimethylpiperazine-1-carboxylate (0.12 g, yield 33%). 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=2.3 Hz, 1H), 7.64 (dd, J=9.0 Hz, J=2.3 Hz, 1H), 6.53 (d, J=9.0 Hz, 1H), 4.48 (m, 2H), 4.13-4.00 (m, 2H), 3.16-3.06 (m, 2H), 1.51 (s, 9H), 1.27 (s, 3H), 1.25 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[N+:13]([O-])([OH:15])=[O:14]>>[Br:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Product: O=Cc1cc(Br)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 7 %

Procedure:
To ice cold conc. sulphuric acid (360 mL) was added fuming nitric acid (180 mL) dropwise followed by (ii) (60 g, 0.26 mol) dropwise over 15 min. The reaction mixture was stirred for 10 min and then allowed to warm to RT. After 30 min, the reaction mixture was heated at 45° C. for 2 h and then at 50° C. for 3 h and then allowed to cool to RT. The reaction mixture was then poured carefully over ice-water and the organics were extracted into chloroform (500 mL). The volatiles were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography eluting with EtOAc:n-hexane (gradient elution from 5% to 30% v/v) to give (iii) (5.1 g, 7%).