Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:17])=O>>[CH3:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([Cl:17])=[O:6]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: O=S(Cl)Cl
Agent: Cl
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)Cl

Procedure:
Part A. A 1-L flask equipped with a reflux condenser and a nitrogen sweep to an HCl gas scrubber was charged with 2-methyl-5-nitrobenzoic acid (200 g, 1.10 mol). The reaction vessel was cooled in an ice bath and thionyl chloride (307 mL, 4.20 mol) was added in one portion. The ice bath was removed, and the reaction mixture was refluxed overnight. The excess thionyl chloride and the SO2 and HCl reaction side-products were removed by vacuum distillation to afford 2-methyl-5-nitrobenzoyl chloride as a solid residue, which was used without further purification. This material was immediately dissolved in methylene chloride (100 mL) and added dropwise with stirring to a commercial 40% dimethylamine solution (500 mL, 4.45 mol) which was maintained at 0° to 12° by periodic immersion in a dry ice-acetone bath. After complete addition, the reaction mixture was stirred for 30 minutes at room temperature. The reaction mixture was diluted with water and extracted with methylene chloride. The combined organic extracts were washed with water, dried, and concentrated. The resulting material was distilled under vacuum to afford 5-nitro-N,N,2-trimethylbenzamide (189.9 g, 0.91 mol, 83% yield) as a solid: mp 98°-99°; bp 156°-170° (0.5 torr); MS m/e 209(M+ +H); 1H NMR(CDCl3) δ 8.00-8.17(m,2H), 7.40(d,J=8 Hz,1H), 3.17(s,3H), 2.88 (s,3H), 2.41(s,3H). Anal. Calcd for C10H12N2O3 : C,57.69; H,5.81; N,13.45. Found: C,57.72; H,5.84; N,13.49.
Reaction SMILES: S(Cl)(Cl)(=O)=O.[F:6][C:7]1[C:15]2C=C[S:12][C:11]=2[C:10]([C:16]#[N:17])=[CH:9][CH:8]=1.[Cl:18][CH2:19][CH2:20][Cl:21]>>[Cl:18][CH:19]1[S:12][C:11]2[C:10]([C:16]#[N:17])=[CH:9][CH:8]=[C:7]([F:6])[C:15]=2[CH:20]1[Cl:21]
Reactant: N#Cc1ccc(F)c2ccsc12
Reactant: ClCCCl
Solvent: O=S(=O)(Cl)Cl
Product: N#Cc1ccc(F)c2c1SC(Cl)C2Cl
Temperature: 60 °C

Procedure:
Sulfuryl chloride (3.0 mL, 37.0 mmol) was added to a solution of 4-fluorobenzo[b]thiophene-7-carbonitrile (1.05 g, 5.93 mmol) in 1,2-dichloroethane (30 mL) at room temperature. The mixture was heated at 60° C. for 24 h and then the solvent was removed and the residue mixed with saturated aq. NaHCO3 solution and extracted with 10% EtOAc in hexanes. These extracts were then washed with saturated aq. NaHCO3 solution, water, brine and dried over Na2SO4. Concentration gave the crude 2,3-dichloro-4-fluoro-2,3-dihydrobenzo[b]thiophene-7-carbonitrile as a brown solid (1.57 g). 1H NMR (400 MHz, CDCl3, δ in ppm) 7.68 (dd, J=4.7, 8.6 Hz, 1H), 7.03 (t, J=8.2 Hz, 1H), 5.82 (s, 1H), 5.74 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[OH:15].[C:16](OCC)(OCC)(OCC)[CH3:17]>>[C:8]([C:6]1[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]2[O:15][C:16]([CH3:17])=[N:1][C:2]=2[CH:7]=1)([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1cc(N)c(O)c([N+](=O)[O-])c1
Reactant: CCOC(C)(OCC)OCC
Product: Cc1nc2cc(C(C)(C)C)cc([N+](=O)[O-])c2o1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2-Amino-4-tert-butyl-6-nitrophenol was dissolved in triethyl orthoacetate (10 mL). The reaction mixture was stirred overnight at 100° C. Evaporation of volatiles in vacuo afforded 5-tert-butyl-2-methyl-7-nitrobenzoxazole (110 mg).
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:10]2[N:14]=[C:13]([NH:15]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:12][N:11]=2)[C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[NH2:15][C:13]1[S:12][N:11]=[C:10]([C:6](=[N:5][O:4][CH:1]2[CH2:3][CH2:2]2)[C:7]([OH:9])=[O:8])[N:14]=1
Reactant: O=C(O)C(=NOC1CC1)c1nsc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(C(=NOC2CC2)C(=O)O)ns1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-cyclopropyloxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer)(1 g) in anisole (2 ml) was added trifluoroacetic acid (8 ml) under ice-cooling. After stirring for 2 hours at ambient temperature, the mixture was concentrated in vacuo. The residue was poured into ice-water (50 ml). The mixture was adjusted to pH 7 with saturated aqueous solution of sodium bicarbonate and an insoluble material was filtered off. After washing with a mixture of ethyl acetate and tetrahydrofuran, the filtrate was adjusted to pH 2 with 6N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, concentrated in vacuo, and triturated with diisopropyl ether to give 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(cyclopropyloxyimino)acetic acid (syn isomer) as a crystal. The physical data of this compound were identical to those of the compound prepared in Preparation 48.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[C:14](=[O:32])[CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C([O-])(=[O:35])C.[K+]>CN(C=O)C>[C:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][N:15]2[CH2:16][CH2:17][N:12]([S:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][OH:35])=[CH:8][CH:7]=3)(=[O:11])=[O:10])[CH2:13][C:14]2=[O:32])[CH2:20][CH2:21]1)=[O:26])([CH3:30])([CH3:29])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(CBr)cc3)CC2=O)CC1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(CO)cc3)CC2=O)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 80.4 %

Procedure:
To a solution of 4-[4-(bromomethyl)benzenesulfonyl]-1-[1-(tert-butoxycarbonyl)-4-piperidylmethyl]-2-piperazinone (2.85 g) in DMF (30 ml) was added potassium acetate (1.58 g), and the mixture was stirred at 60° C. for 4 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added ethyl acetate. The mixture was washed with water and saturated brine, dried and concentrated, and the residue was dissolved in methanol (50 ml). To the solution was added sodium methoxide (28% methanol solution, 290 mg), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added ethyl acetate. The mixture was washed with water and saturated brine, dried (MgSO4) and concentrated. The residual crystals were washed with ether to give colorless crystals of 1-[1-(tert-butoxycarbonyl)-4-piperidylmethyl]-4-[4-(hydroxymethyl)benzenesulfonyl]-2-piperazinone (2.02 g).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[OH:8])=[O:4].[N-:19]=[N+:20]=[N-:21].[Na+]>>[N:19]([CH2:2][C:3]([NH:5][CH2:6][CH:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[OH:8])=[O:4])=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(OC)c(C(O)CNC(=O)CCl)c1
Agent: [Na+]
Product: COc1ccc(OC)c(C(O)CNC(=O)CN=[N+]=[N-])c1

Procedure:
The synthesis of Midodrine HCl consists of reacting the key intermediate (2) with chloroacetyl chloride to afford 2-chloro-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide (3). The reaction of (3) with sodium azide will provide 2-azido-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide (4) which is subsequently subjected to hydrogenation to afford Midodrine base (6).
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[C:13]2[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:16]([N:18]2[CH2:23][CH2:22][C:21]3([CH2:32][C:31](=[O:33])[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:34]5[NH:38][N:37]=[N:36][N:35]=5)[CH:29]=4)[O:24]3)[CH2:20][CH2:19]2)=[O:17])[CH:5]=1.[CH3:39]I>CN(C=O)C>[CH3:2][O:3][C:4]1[C:13]2[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:16]([N:18]2[CH2:23][CH2:22][C:21]3([CH2:32][C:31](=[O:33])[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:34]5[N:38]([CH3:39])[N:37]=[N:36][N:35]=5)[CH:29]=4)[O:24]3)[CH2:20][CH2:19]2)=[O:17])[CH:5]=1
Reactant: CI
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)nc2c(OC)cccc12
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnnn4C)ccc2O3)nc2c(OC)cccc12
Temperature: 25 °C
Reaction time: 13 h

Procedure:
The sodium salt (15.7 mg) obtained in Example 18 was dissolved in 0.3 mL of DMF, 0.009 mL of methyl iodide was added to it, and the mixture was stirred at room temperature for 13 hours. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate, washed with water and saturated brine in order, then dried over sodium sulfate, and concentrated. The residue was purified through silica gel chromatography (chloroform/methanol=10/1) to obtain 1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(1-methyltetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one (this is referred to as 1-isomer) and 1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(2-methyltetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one (this is referred to as 2-isomer) both as colorless powders. 1-Isomer: 1H-NMR (CDCl3) δ: 8.20 (1H, d, J=2.3 Hz), 8.05 (1H, dd, J=8.5, 2.3 Hz), 7.78 (1H, d, J=8.4 Hz), 7.48 (1H, dd, J=8.4, 7.9 Hz), 7.25 (1H, d, J=8.5 Hz), 7.20 (1H, s), 7.09 (1H, d, J=7.9 Hz), 4.67-4.57 (1H, m), 4.29-4.18 (1H, m), 4.22 (3H, s), 4.09 (3H, s), 4.04 (3H, s), 3.69-3.58 (1H, m), 3.46-3.33 (1H, m), 2.91 (1H, d, J=16.8 Hz), 2.84 (1H, d, J=16.8 Hz), 2.30-2.20 (1H, m), 2.16-1.88 (3H, m). MS [M+H]+=515.2-Isomer: 1H-NMR (CDCl3) δ: 8.65 (1H, d, J=2.3 Hz), 8.29 (1H, dd, J=8.7, 2.3 Hz), 7.77 (1H, d, J=8.5 Hz), 7.47 (1H, dd, J=8.5, 7.6 Hz), 7.19 (1H, s), 7.15 (1H, d, J=8.7 Hz), 7.08 (1H, d, J=7.6 Hz), 4.65-4.54 (1H, m), 4.39 (3H, s), 4.23-4.13 (1H, m), 4.08 (3H, s), 4.03 (3H, s), 3.69-3.57 (1H, m), 3.46-3.33 (1H, m), 2.88 (1H, d, J=16.7 Hz), 2.80 (1H, d, J=16.7 Hz), 2.28-2.19 (1H, m), 2.15-2.05 (1H, m), 2.01-1.85 (2H, m). MS [M+H]+=515.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]=[C:15]([OH:18])[C:14](=[O:19])[C:13]=2[CH:20]=1.O1CCC[CH2:22]1.[H-].[Na+].CI>O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]=[C:15]([O:18][CH3:22])[C:14](=[O:19])[C:13]=2[CH:20]=1
Reactant: O=c1c(O)coc2ccc(OCCCCCCCl)cc12
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1coc2ccc(OCCCCCCCl)cc2c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5'-(6-chlorohexoxy)-2'-hydroxyacetophenone (32 g) and benzaldehyde (12 g) was dissolved in 250 mL of ethanol. A solution of 24 g of sodium hydroxide dissolved in 40 mL of water was added. This mixture was allowed to stand at room temperature for 6 hours. A solution of 8 g of sodium hydroxide dissolved in 40 mL of water was added, the solution was cooled to 15°-20° C., and then 20 mL of hydrogen peroxide (30% solution) was added and the solution was allowed to warm to room temperature and was stirred overnight. Then the solution's pH was adjusted to 3 using hydrochloric acid. The yellow precipitate was collected by vacuum filtration and washed with water, ethanol, and ether to give 16 g of 6-(6-chlorohexoxy)-3-hydroxy-4H- 1-benzopyran-4-one. Next, 10 g of 6-(6-chlorohexoxy)-3-hydroxy-4H-1-benzopyran-4-one was dissolved in100 mL of tetrahydrofuran. Then 800 mg of sodium hydride was added followed by 8.3 mL of methyl iodide and the resulting solution was stirred at room temperature for 48 hours. The reaction was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water and then with brine. After drying over sodium sulfate, the solvent was removed to give 8 g of 6-(6- chlorohexoxy)-3-methoxy-4H-1-benzopyran-4-one.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].Cl.[NH2:33][CH2:34][CH2:35][N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38].C[O-].[Na+]>CCO>[CH3:40][S:37]([N:36]([CH3:41])[CH2:35][CH2:34][NH:33][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4])(=[O:39])=[O:38]
Reactant: CN(CCN)S(C)(=O)=O
Reactant: COC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CN(CCNC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O)S(C)(=O)=O
Temperature: 140 °C
Yield: 67.8 %

Procedure:
A mixture of 1-benzyl-8-cyano-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (25 mg, 0.061 mmol), N-(2-amino-ethyl)-N-methyl-methanesulfonamide HCl salt (57 mg, 0.30 mmol), and NaOMe (16 mg, 0.30 mmol) in EtOH (3 mL) was heated at 140° C. for 6 h in a microwave reactor. Solvent was evaporated in vacuo, and the residue was partitioned between EtOAc and 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (0-3% MeOH/CH2Cl2) to give 22 mg of the title compound as a light yellow solid. MS: (+) m/z 532.11 (M+1).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]#[N:11])[C:7](Cl)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH:13]1[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14]1>CC#N>[C:1]([C:4]1[N:9]=[C:8]([C:10]#[N:11])[C:7]([N:13]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: O[C@H]1CCNC1
Reactant: CC(=O)c1ccc(Cl)c(C#N)n1
Solvent: CC#N
Product: CC(=O)c1ccc(N2CC[C@H](O)C2)c(C#N)n1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 57.3 %

Procedure:
6-Acetyl-3-chloro-pyridine-2-carbonitrile (64) (1.80 g, 9.97 mmol) was dissolved in MeCN (19 mL). (S)-3-Pyrrolidinol (884 μL, 10.9 mmol) and TEA (4.16 mL, 29.8 mmol) were added and the mixture stirred at 100° C. in the microwave for 20 minutes. The solvent was evaporated in vacuo and the crude material dissolved in EtOAc (100 mL). The solution was washed with 1:1 saturated brine solution-H2O (100 mL), saturated brine solution (100 mL), then dried (MgSO4), filtered and the solvent evaporated in vacuo. The crude product was purified by flash chromatography (Biotage SP1, 50 g SNAP cartridge) eluting with 6:4 isohexane-EtOAc→8:2 EtOAc-isohexane to yield the title compound as a yellow solid (1.32 g, 64%); LCMS, Rt=2.04 min (MeOH-FA method), m/z 232 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[C:8]2=[N:9][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:11][N:12]=[C:7]2[NH:6][CH2:5][C:4]1=[O:22])[CH3:2].Br[C:24]1[C:25]([CH3:41])=[N:26][C:27]([C:30]2[N:34]=[CH:33][N:32]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)[N:31]=2)=[CH:28][CH:29]=1.C(=O)([O-])O.[K+].O1CCCC1>Cl[Pd]Cl.O>[CH2:1]([N:3]1[C:8]2=[N:9][C:10]([C:24]3[C:25]([CH3:41])=[N:26][C:27]([C:30]4[N:34]=[CH:33][N:32]([CH:35]5[CH2:40][CH2:39][CH2:38][CH2:37][O:36]5)[N:31]=4)=[CH:28][CH:29]=3)=[CH:11][N:12]=[C:7]2[NH:6][CH2:5][C:4]1=[O:22])[CH3:2]
Reactant: CCN1C(=O)CNc2ncc(B3OC(C)(C)C(C)(C)O3)nc21
Reactant: Cc1nc(-c2ncn(C3CCCCO3)n2)ccc1Br
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCN1C(=O)CNc2ncc(-c3ccc(-c4ncn(C5CCCCO5)n4)nc3C)nc21
Temperature: 55 °C

Procedure:
A portion of 1-ethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1 equiv), 3-bromo-2-methyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridine (0.95 equiv), potassium hydrogen carbonate (2.3 equiv), and PdCl2 Amphos2 (0.001 equiv) were treated with a mixture of tetrahydrofuran and water, and the reaction mixture was heated to 55° C. The reaction mixture was cooled and the organic layer was treated with activated carbon at ambient temperature and filtered. The filtrate was distilled to 70% of its original volume, cooled, treated with water, seeded, and treated with additional water. The solids were filtered and washed with tetrahydrofuran/water and dried to obtain 1-ethyl-7-(2-methyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one as a solid.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH2:16])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1.Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]3[O:31][C:32]([C:35]([F:38])([F:37])[F:36])=[N:33][N:34]=3)[CH:28]=2)[N:23]=[CH:22][N:21]=1>>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([C:30]6[O:31][C:32]([C:35]([F:38])([F:36])[F:37])=[N:33][N:34]=6)[CH:28]=5)[N:23]=[CH:22][N:21]=4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(cnn2Cc2ccc(F)cc2)c1
Reactant: FC(F)(F)c1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Product: Fc1ccc(Cn2ncc3cc(Nc4ncnc5ccc(-c6nnc(C(F)(F)F)o6)cc45)ccc32)cc1

Procedure:
The title compound was prepared according to Procedure A from 1-(4-fluoro-benzyl)-1H-indazol-5-ylamine and 4-chloro-6-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)-quinazoline; δH [2H6]DMSO 11.91(1H, bs), 9.55(1H, s), 8.91(1H, s), 8.69(1H, dd), 8.23(1H, s), 8.14(2H, m), 7.88(1H, d), 7.69(1H, dd), 7.36(2H, m), 7.18 (2H, dd), 5.71(2H, s); m/z (M+1+) 506
Reaction SMILES: Cl[CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[CH:6]=1)[OH:4].C1(C)C=CC=CC=1.[OH-].[Na+]>O>[F:12][C:7]1[CH:6]=[C:5]([C@H:3]2[CH2:2][O:4]2)[CH:10]=[CH:9][C:8]=1[F:11]
Reactant: O[C@H](CCl)c1ccc(F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccc([C@H]2CO2)cc1F
Temperature: 40 °C
Yield: 96 %

Procedure:
A mixture of (1S)-2-chloro-1-(3,4-difluorophenyl)-1-ethanol (net 11.47 g, 59.5 mmol), toluene (25.23 g), sodium hydroxide (2.53 g, 1.06 molar equivalents) and water (24.25 g) was stirred and heated at 40° C. for 1 hour. The organic layer was separated, washed with water, and concentrated under reduced pressure. (2S)-2-(3,4-difluorophenyl)oxirane was obtained as resultant concentrate (net 8.94 g, yield: 96%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1)[CH3:2].[N:15]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][NH2:15])[CH:8]=1)[CH3:2]
Reactant: O=N[O-]
Reactant: CCOC(=O)CCc1cccc(N)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCc1cccc(NN)c1
Reaction time: 1 h

Procedure:
To a solution of 3-(3-amino-phenyl)-propionic acid ethyl ester (14 g, 72.5 mmol) in concentrated HCl (200 mL) was added an aqueous solution (10 mL) of NaNO2 (5 g, 72.5 mmol) at 0° C. and the resulting mixture was stirred for 1 h. A solution of SnCl2.2H2O (33 g, 145-mmol) in concentrated HCl (150 mL) was then added at 0° C. The reaction solution was stirred for an additional 2 h at RT. The precipitate was filtered and washed with ethanol and ether to give 3-(3-hydrazino-phenyl)-propionic acid ethyl ester as a white solid, which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26](O)=[O:27])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([O:31][C:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]([N:37]2[CH2:36][CH2:35][N:34]([C:32]([O:31][CH2:29][CH3:30])=[O:33])[CH2:39][CH2:38]2)=[O:27])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Product: CCOC(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCCN(C(=O)OC(C)(C)C)CC4)ccc3[nH]2)CC1

Procedure:
The title compound was synthesized in analogy to example 47a), from 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1H-indole-2-carboxylic acid and 4-ethoxycarbonylpiperazine. Off-white solid. MS (m/z): 505.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:11][CH2:10][CH2:9][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cccc(CCO)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(CCOS(=O)(=O)c2ccc(C)cc2)n1

Procedure:
A solution of 2-(6-methoxypyridin-2-yl)ethanol (0.23 g, 1.50 mmol), 4-dimethylaminopyridine (0.028 g, 0.23 mmol), triethylamine (0.63 mL, 4.50 mmol) and p-toluenesulfonyl chloride (0.34 g, 1.80 mmol) in dry dichloromethane (5 mL) was stirred at rt over night. The solvent was removed in vacuo. Ethyl acetate and water were added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (Na2SO4) and concentrated. The product was purified by flash chromatography (SiO2; heptane/EtOAc, gradient 0-100%). Yield: 0.18 g (38%).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[O:8][CH:9]=[CH:10][N:11]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:1][CH2:2][C:3]([NH:6][C:7]1[O:8][CH:9]=[CH:10][N:11]=1)=[O:4]
Reactant: Nc1ncco1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CBr)Nc1ncco1
Reaction time: 16 h

Procedure:
A solution of bromoacetyl bromide (0.44 mL) in dry CHCl3 (5 mL) was added dropwise to a suspension of 2-amino-1,3-oxazole (0.39 g) and triethylamine (0.96 mL) in dry CHCI3 (92 mL) at room temperature. The brown mixture was allowed to stir for 16 h, then quenched with H2O (2 mL) and stirred for 20 mins before concentrating under reduced pressure to a light brown solid. The crude product was purified by silica gel chromatography eluting with 1-3% MeOH/dichloromethane to give the title compound (0.56 g) as an off-white solid.
Reaction SMILES: [CH3:1][CH:2]([C:6](=O)[CH3:7])[C:3](=O)[CH3:4].[NH2:9][C:10]([NH2:12])=[O:11]>C(O)C.Cl>[OH:11][C:10]1[N:12]=[C:6]([CH3:7])[C:2]([CH3:1])=[C:3]([CH3:4])[N:9]=1
Reactant: CC(=O)C(C)C(C)=O
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: Cc1nc(O)nc(C)c1C

Procedure:
To 3.65 g (32 mmol) of 3-methyl-2,4-pentanedione in ethanol (15 ml) was added urea (1.92 g; 32 mmol) followed by 3 drops concentrated HCl. This mixture was refluxed under N2 overnight (12 hours). Upon cooling a solid separated which was filtered off and washed with cold ethanol and ethyl ether. Drying on the pad gave an off-white tlc pure solid. NMR (d6 -DMSO, δ from TMS): 1.94(S, 5-CH3), 2.22(S, 4, 6 -CH3S), 5.47 (br S, OH). Mass spectroscopy showed M+ at m/e 138.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:22](=[O:24])[CH3:23])[C:14]4[C:19]([C:20]=3[CH:21]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)O1.[Br:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29](Br)[CH:28]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:26][C:27]1[CH:28]=[C:29]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]([C:22](=[O:24])[CH3:23])[C:14]4[C:19]([C:11]=3[CH:10]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:30]=[CH:31][CH:32]=1
Reactant: CC(=O)n1c2ccccc2c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: Brc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)n1c2ccccc2c2cc(-c3cccc(Br)c3)ccc21
Temperature: 25 °C
Yield: 23 %

Procedure:
A mixture solution of 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazol-9-yl)ethanone (10.00 g, 29.8 mmol), 1,3-dibromobenzene (17.59 g, 74.6 mmol), Pd(PPh3)4 (0.689 g, 0.597 mmol) and K2CO3 (12.37 g, 89 mmol) in toluene (100 mL) and water (20 mL) was refluxed under N2 overnight. After cooling to room temperature, the organic phase was isolated and the solvent was evaporated. The residue was purified by column chromatography on silica gel with hexane/DCM (1/1, v/v) as eluent to yield 1-(3-(3-bromophenyl)-9H-carbazol-9-yl)ethanone (2.5 g, 23%) as a white solid.