Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Li]CCCC.[F:18][C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][CH:30]=1)[C:22](N(OC)C)=[O:23].Cl>C1COCC1.O>[F:18][C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][CH:30]=1)[C:22]([C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:23]
Reactant: CON(C)C(=O)c1cccc(F)c1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cccc(F)c2)c(C(=O)O)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
A −78° C. solution of 2-bromo-5-methoxybenzoic acid (26.0 g, 112.5 mmol) in THF (100 mL) was treated with n-BuLi (1.6 M in hexane) (140 mL, 225 mmol) and stirred at −78° C. for 1 h. 3-fluoro-N-methoxy-N-methylbenzamide (15.3 g, 83.8 mmol) in THF (40 mL) was added dropwise then warmed to rt for 16 h. The reaction mixture was diluted with water (100 mL), acidified with 5N HCl (25 mL) and extracted with EtOAc (3×200 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain 2-(3-fluorobenzoyl)-5-methoxybenzoic acid (21.0 g, 68%) (274.83 [M+H]); 1H NMR: (400 MHz, DMSO) δ: 3.89 (s, 3H), 7.26-7.29 (m, 1H), 7.37-7.45 (m, 4H), 7.50-7.55 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](N)[N:6]=[CH:5]2.C(O[N+]([O-])=O)(C)(C)C.C([O-])(O)=O.[Na+].[Cl:26]CCCl>>[Cl:26][C:7]1[N:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: Nc1ncc2cc(Cl)ccc2n1
Reactant: ClCCCl
Agent: CC(C)(C)O[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1ccc2nc(Cl)ncc2c1
Temperature: 60 °C
Yield: 20 %

Procedure:
To a suspension of 6-chloro-quinazolin-2-ylamine (110) (2.8 g, 15.8 mmol) and SbCl3 (7.2 g, 32 mmol) in 1,2-dichloroethane (100 mL) was added tert-butylnitrate (6.2 ml, 52 mmol) and heated at 60° C. for 3 h under nitrogen atmosphere. To the mixture was added aqueous saturated NaHCO3 and the mixture was filtered off and filtrate was extracted with CHCl3. The organic layer was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by silica gel column chromatography, using CHCl3/EtOAc (9:1, v/v) as eluent to give 2,6-dichloro-quinazoline (111) (0.65 g, 3.12 mmol, 20% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5]([Cl:16])=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=[O:19].[Na].O.[CH2:23](I)[CH3:24]>CN(C)C=O>[NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5]([Cl:16])=[CH:4][C:3]=1[CH2:17][C:18]([O:20][CH2:23][CH3:24])=[O:19]
Reactant: Nc1c(CC(=O)O)cc(Cl)cc1C(=O)c1ccccc1
Reactant: CCI
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cc(Cl)cc(C(=O)c2ccccc2)c1N
Reaction time: 2 h
Yield: 4.7 %

Procedure:
A solution of 3.12 g (0.1 mole) of 2-amino-3-benzoyl-5-chlorobenzeneacetic acid, sodium salt.1/2 H2O in 250 ml of dry dimethylformamide was treated with 44 g of ethyl iodide (0.3 mole) under nitrogen and stirred for 2 hours. The resulting solution was then added to one liter of water and extracted several times with ethyl ether. The combined ether layers were washed with water, dried over sodium sulfate, filtered and stripped to yield a solid yellow residue. This residue was recrystallized from ethyl alcohol, yielding 1.5 g of the title compound as yellow needles, m.p. 80°-82° C.
Reaction SMILES: CN(C)[CH:3]=[CH:4][CH:5]=[O:6].P(Cl)(Cl)(Cl)=O.[CH3:13][C:14]1([CH3:33])[CH2:23][CH2:22][C:21]2[C:16]3=[C:17]([C:24]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[CH:25][N:15]13)[CH:18]=[CH:19][CH:20]=2.[OH-].[Na+]>C(#N)C.O>[CH3:13][C:14]1([CH3:33])[CH2:23][CH2:22][C:21]2[C:16]3=[C:17]([C:24]([C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)=[C:25](/[CH:3]=[CH:4]/[CH:5]=[O:6])[N:15]13)[CH:18]=[CH:19][CH:20]=2
Reactant: CN(C)C=CC=O
Reactant: CC1(C)CCc2cccc3c(-c4ccc(F)cc4)cn1c23
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC1(C)CCc2cccc3c(-c4ccc(F)cc4)c(/C=C/C=O)n1c23
Temperature: 25 °C
Yield: 70.4 %

Procedure:
A solution of 3-dimethylaminoacrylaldehyde (3.68 g) in dry acetonitrile (10 ml) was slowly added over a 30-minute period to a solution of phosphorus oxychloride (6.07 g) in dry acetonitrile (10 ml) with stirring at 0°-10° C. under nitrogen. A solution of 5,6-dihydro-4,4-dimethyl-1-(4-fluorophenyl)-4H-pyrrolo[3,2,1-ij]quinoline (3.70 g) in dry acetonitrile (9 ml) was slowly added to the reaction mixture at the same temperature. The reaction mixture was refluxed for 7 l hours under nitrogen, cooled to room temperature and slowly poured into a cold solution of sodium hydroxide (6.34 g) in water (130 ml) with stirring. The reaction mixture was extracted twice with toluene. The extracts were combined, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on a silica gel column eluting with a mixture of n-hexane and ethyl acetate (5:1, V/V). The fractions containing the object compound were collected and evaporated under reduced pressure. The residual oil was triturated with n-hexane to give yellow crystals of (E)-3-[5,6-dihydro-4,4-dimethyl-1-(4-fluorophenyl)-4H-pyrrolo[3,2,1-ij]quinolin-2-yl]acrylaldehyde (3.11 g).
Reaction SMILES: C([O:8][C:9](=[O:40])[C@@H:10]1[CH2:14][C@@H:13]([OH:15])[CH2:12][N:11]1[C:16]([C@H:18]1[NH:30][C:29](=[O:31])[CH:28]([CH2:32][S:33]C(=O)C(C)(C)C)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][S:20][CH2:19]1)=[O:17])C1C=CC=CC=1.O.[OH-].[Li+].Cl>>[SH:33][CH2:32][CH:28]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][S:20][CH2:19][C@@H:18]([C:16]([N:11]2[CH2:12][C@H:13]([OH:15])[CH2:14][C@H:10]2[C:9]([OH:40])=[O:8])=[O:17])[NH:30][C:29]1=[O:31]
Reactant: CC(C)(C)C(=O)SCC1CCCCCCCSC[C@@H](C(=O)N2C[C@H](O)C[C@H]2C(=O)OCc2ccccc2)NC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C1N[C@H](C(=O)N2C[C@H](O)C[C@H]2C(=O)O)CSCCCCCCCC1CS
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Trans-N-[(3R)-6-(pivaloylthiomethyl)-5-oxo-1-thia-4-azacyclotridecan-3-yl-carbonyl]-4-hydroxy-L-proline benzyl ester (0.30 g, 0.05 mmol) is dissolved in nitrogen degassed tetrahydrofuran (1 ml) and water (0.5 ml). Lithium hydroxide monohydrate (0.006 g, 0.15 mmol) is added and the mixture is stirred at room temperature for 2.5 hours. The mixture is poured into 1N hydrochloric acid and extracted with ethyl acetate (2×10 ml). The combined organic layers are dried (MgSO4) and the solvent is evaporated. The product is triturated from diethyl ether to give trans N-[[(3R)-6-mercaptomethyl-5-oxo-1-thia-4-azacyclotridecan-3-yl]-carbonyl]-4-hydroxy-L-proline, m.p. 124°-130° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH:10][O:11][CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[Br:18]Br>O.CC(O)=O>[NH2:1][C:2]1[C:3]([C:8]([NH:10][O:11][CH3:12])=[O:9])=[N:4][C:5]([Br:18])=[CH:6][CH:7]=1
Reactant: CONC(=O)c1ncccc1N
Reactant: BrBr
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CONC(=O)c1nc(Br)ccc1N
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
A suspension of 3-amino-N-methoxypyridine-2-carboxamide (Compound 46E, 0.275 g, 1.64 mmol) in H2O (4.5 mL) was treated with a drop of Sulfuric acid and 0.6 mL of AcOH. After about 10 min of vigorous stirring, a solution of Bromine (84.7 uL, 1.64 mmol) in 0.4 mL of AcOH was cautiously added. After an additional 15-20 min of stirring the texture of the reaction mixture/suspension changed to become a more coarse orange ppt. This material was collected by filtration and dried to afford 240 mg of the title compound as an orange solid (59%). 1H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 6.91 (br. s., 2H), 3.66 (s, 3H); MS (ESI): m/z=245.98, 247.98 [M+H]+; UPLC: tR=0.67 min (UPLC-TOF: polar—2 min)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9](=[O:11])[CH3:10].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:27]1([CH2:33][S:34][CH:35]([C:39](O)=[O:40])[C:36](O)=[O:37])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[O:11][C:36](=[O:37])[C:35]([S:34][CH2:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:39]([OH:40])[CH:10]=1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: CC(=O)c1c(C)cccc1C
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1cc(O)c(SCc2ccccc2)c(=O)o1

Procedure:
The title compound was prepared by Method A using 2',6'-dimethyl acetophenone (0.785 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. 140-143° C.; 1H NMR (400 MHz, DMSO-d6) δ2.15 (s, 6 H), 3.99 (s, 2 H), 6.12 (s, 1 H), 7.22 (m, 8H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:10][CH:9]=2)[C:4]1=[O:23].C(N(C(C)C)C(C)C)C.C[N:34](C)[CH:35]=[O:36]>>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:6][CH2:7][C@@H:3]([NH:2][C:35]([NH2:34])=[O:36])[C:4]2=[O:23])=[CH:13][CH:12]=1
Reactant: N[C@@H]1CCN(c2ccc(OCc3cccc(F)c3)cc2)C1=O
Reactant: CN(C)C=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)N[C@@H]1CCN(c2ccc(OCc3cccc(F)c3)cc2)C1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 250 mg (0.7 mmol) of (R)-3-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride and 294 mg (2.2 mmol) of N-ethyl-diisopropylamine in 2 ml of N,N-dimethylformamide is cooled to 0° C. and treated with 267 mg (2.2 mol) of trimethylisocyanate. The reaction mixture is left to warm to RT and stirring is continued for 2 days. For the working-up, the suspension is evaporated under reduced pressure. The crude product is triturated in water, then the recovered solid material triturated a second time in a mixture of ethyl acetate and a saturated solution of sodium hydrogencarbonate. The remaining solid is collected on a filter funnel to give, after drying under high vacuum, 155 mg (61% of theory) of (R)-{1-[4-(3-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidin-3-yl}-urea as a white solid; MS: m/e=344 (M+H)+.
Reaction SMILES: [Si:1]([O:18][C@H:19]([C@H:22]1[O:26][C:25](=[O:27])[CH2:24][CH2:23]1)[CH2:20][CH3:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[Si:1]([O:18][C@H:19]([C@H:22]1[O:26][C:25](=[O:27])[C@H:24]([CH3:28])[CH2:23]1)[CH2:20][CH3:21])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CC[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H]1CCC(=O)O1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H]1C[C@@H](C)C(=O)O1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a solution of (5S)-5-[(1S)-1-[tert-butyl(diphenyl)silyl]oxypropyl]tetrahydrofuran-2-one (Compound 28e-S, 3.0 g, 7.8 mmol) in THF (60 mL) at −78° C. was added lithium diisopropylamide (2M in THF, 5.9 mL, 11.8 mmol) dropwise. After addition, the reaction was stirred at −78° C. for 1 hour. To the mixture was added iodomethane (5.5 g, 39 mmol) and the mixture was stirred at −78° C. for another 1 hour. The mixture was quenched with saturated NH4Cl solution (40 mL), extracted with EtOAc (100 mL) twice. The organic layers were combined, washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:20 to 1:10 EtOAc in petroleum ether) to afford 2.7 g of (3R,5S)-5-[(1S)-1-[tert-butyl(diphenyl)silyl]oxypropyl]-3-methyl-tetrahydrofuran-2-one (compound 28f) as a colourless oil. (Refer to Tetrahedron. 1997, 53, 6281-6294).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([OH:26])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C@:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([OH:26])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:23])[F:24])[CH2:9]1
Reactant: OC(Cc1ccccc1C(F)(F)F)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: O[C@@](Cc1ccccc1C(F)(F)F)(c1ccccc1)[C@H]1CNCCO1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
To a solution of 1-(4-Benzyl-morpholin-2-yl)-1-phenyl-2-(2-trifluoromethyl-phenyl)-ethanol (352 mg, 1 equiv.) in ethanol (15 mL) at room temperature under nitrogen atmosphere was added ammonium formate (507 mg g, 10 equiv.) followed by addition of palladium on charcoal (10%, 355 mg.). The reaction mixture was heated to reflux for 1 hour, cooled to room temperature and then filtered through Celite. All volatiles were evaporated under vacuum to give 265 mg of the title compound as white solid (94%). The enantiomeric mixture was resolved using chiral HPLC, to give the title compound as a single enantiomer. 1H NMR (300 MHz, CDCl3) δ: 2.25-2.30 (m, 1H), 2.56-2.64 (m, 1H), 2.75-2.87 (m, 2H), 3.18 (d, 1H, J=14.88 Hz), 3.71-3.81 (m, 2H), 3.89 (d, 1H, J=14.88 Hz), 4.02-4.05 (m, 1H), 6.83-6.86 (m, 1H), 7.09-7.34 (m, 7H), 7.53-7.55 (m, 1H) ppm. LCMS (12 minute method) [M+H]+=352 @ Rt 4.73 min. single peak.
Reaction SMILES: C([O:8][P:9](=[O:53])([O:45]CC1C=CC=CC=1)[O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[C:18]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([C:31]4[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][N:32]=4)=[CH:28][CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:17]=[CH:16][C:15]=1[C:41]([CH3:44])([CH3:43])[CH3:42])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:41]([C:15]1[CH:16]=[CH:17][C:18]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([C:31]4[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][N:32]=4)=[CH:28][CH:29]=3)[N:24]=[CH:23][N:22]=2)=[CH:19][C:14]=1[O:13][CH2:12][CH2:11][O:10][P:9](=[O:8])([OH:53])[OH:45])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)c1ccc(Nc2ncnc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1OCCOP(=O)(OCc1ccccc1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1ccc(Nc2ncnc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1OCCOP(=O)(O)O

Procedure:
Hydrogenate a mixture of phosphoric acid 2-{2-tert-butyl-5-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-ylamino]-phenoxy}-ethyl ester dibenzyl ester (65 mg) and 10% Pd/C (60 mg) in methanol under 1 atmosphere of hydrogen for 12 hours. Filter the mixture through Celite and evaporate to dryness to give the title compound. MS 563 (M+1).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([Cl:15])=[C:7]([O:16][CH2:17][C:18]#[CH:19])[N:6]=1>>[Cl:15][C:8]1[C:7]([O:16][CH2:17][C:18]#[CH:19])=[N:6][C:5]([NH:2][NH2:3])=[C:10]([C:11]([F:14])([F:13])[F:12])[CH:9]=1
Reactant: NN
Reactant: C#CCOc1nc(Cl)c(C(F)(F)F)cc1Cl
Solvent: O
Product: C#CCOc1nc(NN)c(C(F)(F)F)cc1Cl

Procedure:
Starting from 7.8 g (0.155 mol) of hydrazine hydrate and 20 g (0.074 mol) of 2, 5-dichloro-6-propargyloxy-3-trifluoromethylpyridine, 11.0 g (56% of theory) of the title compound were obtained as a colorless powder of m.p. 98°-102° C. (Table II, No. 2.036) under the conditions of Example III.4.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]2[C:6](=[CH:7][N:8]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:9]=2)[CH:5]=1)([O-])=O.[Cl-].[NH4+]>[Fe].C(O)C.O>[N:15]1([CH2:14][CH2:13][N:8]2[CH:7]=[C:6]3[C:10]([CH:11]=[CH:12][C:4]([NH2:1])=[CH:5]3)=[N:9]2)[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: O=[N+]([O-])c1ccc2nn(CCN3CCCC3)cc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2nn(CCN3CCCC3)cc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 5-Nitro-2-(2-pyrrolidin-1-yl-ethyl)-2H-indazole (0.250 g, 0.961 mmol), iron powder (0.536 g, 9.60 mmol) and ammonium chloride (0.0257 g, 0.480 mmol) in a 4:1 ethanol/H2O solution was heated to reflux for 3 hours and then cooled to room temperature. The solvent was removed under vacuo and the residue stirred in triethylamine/ethyl acetate (1/4, 30 mL) for 15 minutes and then filtered through a plug of silica gel. After rinsing with triethylamine/ethyl acetate (1/4), the filtrate was concentrated unde vacuo to provide the title product. 1H NMR (300 MHz, DMSO-d6) ppm 1.79 (s, 4H), 2.48 (m, 4H), 2.88 (s, 2H), 3.26 (m, 2H), 4.58 (m, 2H), 6.57 (m, 1H), 6.76 (m, 1H), 7.34 (m, 1H), 7.96 (s, 1H); MS (DCI/NH3) m/z 231 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3[CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH:15]=3)[N:6]2[N:5]=[CH:4][N:3]=1>CC(O)=O.[Pt](=O)=O>[NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(N)ncnn23)C1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3c(N)ncnn23)C1
Reaction time: 16 h
Yield: 93.3 %

Procedure:
A suspension of platinum(IV) oxide (2.1 g, 9.5 mmol) and tert-butyl 3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (11.4 g, 37.8 mmol) in AcOH (150 mL) was stirred for 16 h under a H2 atmosphere. The reaction was purged with N2 and filtered through Celite®, washing with AcOH. After removal of solvent in vacuo, the residue was dissolved in THF:EtOAc and washed with saturated, aqueous sodium carbonate solution. The organic layer was dried and concentrated in vacuo to provide the desired product as a dark solid (10.7 g, 93%). MS: LC/MS (+esi): m/z=304.1 [MH]+; LC/MS rt=2.74 min.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[C:6]1([S:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([S:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])[CH2:17][CH2:16]2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ClCC1CO1
Reactant: O=S(=O)(c1ccccc1)N1CCNCC1
Product: O=S(=O)(c1ccccc1)N1CCN(CC(O)CCl)CC1
Yield: 98.7 %

Procedure:
Epichlorohydrin (0.5 g) and 3.7 g of 1-benzenesulfonylpiperazine were reacted and worked up in the same way as in Referential Example 1 to give 1.7 g of 1-benzenesulfonyl-4-(3-chloro-2-hydroxypropyl)piperazine as a colorless powdery crystal having a melting point of 136 to 137° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]([C:19]#[C:20][CH:21]([O:25]CC)[O:22]CC)=[CH:4][N:3]=1.[CH3:28][CH2:29][CH2:30]C[N+](CCCC)(CCCC)CCCC.[F-].OOS([O-])=O.[K+]>C1COCC1.CN(C=O)C.C(OCC)(=O)C.C(O)(=O)C.O.O>[C:14]([O:13][C:12]([NH:11][CH2:10][CH:9]([N:8]1[C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=2[CH:19]=[C:20]1[C:21]([OH:22])=[O:25])[CH:29]([CH3:30])[CH3:28])=[O:18])([CH3:15])([CH3:16])[CH3:17]
Reactant: CCOC(C#Cc1cnc(Cl)nc1NCCNC(=O)OC(C)(C)C)OCC
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])OO
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)C(CNC(=O)OC(C)(C)C)n1c(C(=O)O)cc2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution tert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]ethyl]carbamate in THF was added TBAF and the contents refluxed for 3 hrs. Ethyl acetate and water was then added and the organic layer separated, dried with magnesium sulfate and then concentrated under vacuum. To this crude reaction was added acetic acid/water (9:1) and then contents stirred for 12 hrs at room temperature. After concentration under vacuum, sat NaHCO3 and ethyl acetate was then added. The organic layer was separated, dried and then concentrated under vacuum. The crude reaction product thus obtained was dissolved in DMF, oxone was then added and the contents stirred for 3 hrs. After addition of ethyl acetate, the reaction mixture was filtered through CELITE™ and concentrated under vacuum. Column chromatography of the crude product over silica gel using hexane/ethyl acetate (0-100%) afforded 7-[1-[(tert-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid. 1H NMR (600 MHz, DMSO-d6) δ ppm 0.85 (d, J=7.03 Hz, 3H) 0.97 (d, J=6.73 Hz, 3H) 1.52 (s, 9H) 1.99-2.23 (m, 1H) 3.98 (dd, J=14.05, 3.51 Hz, 1H) 4.47-4.71 (m, 2H) 7.47 (s, 1H) 9.17 (s, 1H). LCMS (ESI) 383 (M+H).
Reaction SMILES: C(O[C:4](=[O:21])[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:8][N:9]([CH3:11])C)C.C(N)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[CH3:15][O:14][C:12]([C:6]1[CH:7]=[CH:8][N:9]([CH2:11][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:4](=[O:21])[C:5]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:13]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C(C(=O)OCC)=C(C=CN(C)C)C(=O)OC
Solvent: CO
Product: CCOC(=O)c1c(C(=O)OC)ccn(Cc2ccccc2)c1=O
Temperature: 25 °C
Yield: 77.9 %

Procedure:
A mixture of 5-dimethylamino-2-ethoxycarbonyl-3-methoxycarbonyl-penta-2,4-dienoic acid ethyl ester (5 g, 16.7 mmol) and benzylamine (1.9 mL, 17.6 mmol) in MeOH (30 mL) was refluxed for 5 h. The mixture was cooled to r.t., concentrated in vacuo, and taken up in ether. The solution was washed with 1 M HCl and water, and then dried over MgSO4. Evaporation of the solvent in vacuo afforded 4.1 g of the title compound as a dark brown oil. 1H NMR (CDCl3, 200 MHz): δ=7.20-7.40 (m, 6H), 6.56 (d, 1H, J=7.0 Hz), 5.15 (s, 2H), 4.42 (q, 2H, J=7.4 Hz), 3.88 (s, 3H), 1.40 (t, 3H, J=7.0 Hz).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[N:13]=[CH:12]3)[N:4]=1.[OH-].[Na+]>Cl>[CH3:18][N:14]1[C:15]2[C:11](=[CH:10][C:9]([C:5]3[N:4]=[C:3]([OH:2])[CH:8]=[CH:7][N:6]=3)=[CH:17][CH:16]=2)[CH:12]=[N:13]1
Reactant: COc1ccnc(-c2ccc3c(cnn3C)c2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1ncc2cc(-c3nccc(O)n3)ccc21
Temperature: 85 °C

Procedure:
5-(4-methoxypyrimidin-2-yl)-1-methyl-1H-indazole (30.2 mg, 0.126 mmol) was suspended in hydrochloric acid (1.25 mL of a 2N solution) and heated at 85° C. for 14 h, cooled, and neutralized by dropwise addition of NaOH (2N solution). The mixture was extracted six times with 1:1 chloroform/isopropanol and the combined organic layers were dried over Na2SO4 and concentrated to provide the crude product which was used without further purification. LCMS-ESI+: calc'd for C12H11N4O: 227.1 (M+H+); Found: 227.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[C:12](O)(=[O:14])[CH3:13]>[Fe]>[F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[NH:8][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: [Fe]
Product: CC(=O)Nc1ccc(O)cc1F
Temperature: 25 °C
Yield: 64 %

Procedure:
373.3 mg of iron powder were added to a solution of 300 mg of 3-fluoro-4-nitrophenol [prepared as described in step (c) above] in 6 ml of glacial acetic acid. The resulting mixture was stirred under reflux for 6 hours, after which it was allowed to cool to room temperature. Ice-water was then added to the reaction mixture and the solvent was removed by evaporation under reduced pressure. Ethyl acetate was added to the residue and the resulting solution was washed with water and then dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting residue was purified by column chromatography through silica gel using a mixture of hexane and ethyl acetate as the eluent, initially using a 2:1 by volume mixture of the two solvents and then changing to a 1:1 by volume mixture, to give 206.8 mg (yield 64%) of the title compound as a brown solid.