Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18](O)=[O:19])=[CH:15][CH:16]=2)[N:11]([S:21]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[O:31][CH3:32])(=[O:23])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl-].[CH2:41]([O:43][C:44](=[O:52])[C:45]1[CH:50]=[CH:49][C:48]([NH2:51])=[CH:47][CH:46]=1)[CH3:42]>CC(C)=O.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18](=[O:19])[NH:51][C:48]3[CH:49]=[CH:50][C:45]([C:44]([O:43][CH2:41][CH3:42])=[O:52])=[CH:46][CH:47]=3)=[CH:15][CH:16]=2)[N:11]([S:21]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[O:31][CH3:32])(=[O:23])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)c2ccc(C(=O)O)cc21
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCN3C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-quinoxaline-1,6-dicarboxylic acid 1-tert-butyl ester (100 mg, 0.21 mmol) in acetone (30 mL) and tetrahydrofuran (10 mL) was treated with triethylamine (21 mg, 0.21 mmol) and stirred at room temperature 1 hour. A solution of cianuric chloride (46 mg, 0.25 mmol) in tetrahydrofurane (2 mL) was added dropwise over a period of 1 hour. The reaction mixture was stirred at room temperature for 2 hours, then 4-amino-benzoic acid ethyl ester (51 mg, 0.31 mmol) and a further aliquot of triethylamine (42 mg, 0.42 mmol) were added. The reaction mixture was stirred at room temperature for 48 hours, the solvents were then removed. The residue was purified by flash chromatography, to yield 4-(5-chloro-2-methoxy-benzenesulfonyl)-6-(4-ethoxycarbonyl-phenylcarbamoyl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester as a light yellow solid, 100 mg (77%), δH (300 MHz; CDCl3) 8.01-8.08 (4H, m), 7.94 (1H, d), 7.73-7.77 (3H, m), 7.48 (1H, dd), 6.82 (1H, d), 4.38 (2H, q), 3.89 (2H, m), 3.64 (2H, m), 3.47 (3H, s), 1.48 (9H, s), 1.40 (3H, t).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15]([O:16][CH3:17])=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([N+:18]([O-])=O)[CH:7]=1.[Cl-].[NH4+]>O.CO.[Fe]>[NH2:18][C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])[C:15]([O:16][CH3:17])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc(OC)c(OCCCCl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(OC)c(OCCCCl)cc1N
Yield: 90 %

Procedure:
JP-A-2001-519788 describes a process for preparing a 5-alkoxy-4-halogenoalkoxyanthranilic acid compound from a 5-alkoxy-4-halogenoalkoxy-2-nitrobenzoic acid compound. For example, methyl 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoate is reacted with a very excessive amount of iron and ammonium chloride in a mixture of water and methanol, to give methyl 2-amino-4-(3-chloropropoxy)-5-methoxybenzoate (i.e., ethyl 4-(3-chloropropoxy)-5-methoxyanthranilate) in 90% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]([CH3:11])=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[C:34]([CH3:35])=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][C:25]=1[CH3:36].N1C=CC=CC=1>C1COCC1.C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:23][C:24]2[C:25]([CH3:36])=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][C:34]=2[CH3:35])=[O:10])[C:5]([CH3:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)nc1C(=O)O
Reactant: CCOC(=O)c1cc(C)c(N)c(C)c1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C)c(NC(=O)c2nc(Cl)ccc2C)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
To a solution of 6-chloro-3-methyl-pyridine-2-carboxylic acid (465 mg, 2.71 mmol) in THF (5 ml), CH2Cl2 (5 ml) and DMF (0.01 ml, 129.33 moles) is added dropwise oxalyl chloride (0.3 ml, 3.46 mmoles) at 0° C. and reaction mixture is slowly allowed to warm to ambient temperature. After 2 hours, the solvent is removed under reduced pressure and the residue. To the residue CH2Cl2 (20 ml) is added and reaction mixture is cooled to 0° C., then ethyl 4-amino-3,5-dimethyl-benzoate (520 mg, 2.69 mmol) is added followed by N,N-dimethylpyridin-4-amine (15 mg, 122.78 moles) and Pyridine (0.66 ml, 8.16 mmoles). The cooling bath is removed and the clear yellow solution is allowed to warm to ambient temperature. After 1 hour, the solvent is removed and the reaction mixture is diluted with ethyl acetate and washed with 0.5N HCl, saturated solution of sodium bicarbonate, and brine. The organic layers are combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by flash chromatography (silica gel) using 0-50% ethyl acetate in hexanes to give the title compound as a solid (790 mg, 84%). Mass spectrum (m/z): 347.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=2[CH2:16][OH:17])=[O:7])=[CH:4][CH:3]=1.N#N.C(OC(B)OC(C)C)(C)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([OH:7])[C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=2[CH2:16][OH:17])=[CH:18][CH:19]=1
Reactant: N#Cc1ccc(C(=O)c2ccc(F)cc2)c(CO)c1
Agent: BC(OC(C)C)OC(C)C
Agent: N#N
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C(O)c2ccc(F)cc2)c(CO)c1
Temperature: -80 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
145 mg of 4-(4-fluorobenzoyl)-3-hydroxymethyl-benzonitrile (0.56 mmol, 1.0 eq.) and 100 mg of 1S,2R—N-methylephedrine 99% (0.56 mmol, 1.0 eq.) are dissolved in a two-necked round bottomed flask in 3 mL of toluene under an inert atmosphere (N2). At room temperature, 160 μL of diisopropoxymethyl borane (0.59 mmol, 1.05 eq.) is added. The reaction mixture is brought to 70° C. and stirred at this temperature for 30 minutes. The solvent is gently removed under reduced pressure within 15 minutes. 3 mL of toluene is added and the reaction mixture is cooled to −80° C. 800 μL (2 eq.) of a 1.3M solution of dimethylaminopropyl magnesium chloride in THF is slowly added (duration: 2 minutes). Stirring is continued for 10 minutes at −80° C. HPLC control indicated a conversion of >90%. The ratio of S-diol (4-[(S)-4-dimethylamino-1-(4-fluorophenyl)-1-hydroxy-butyl]-3-hydroxymethyl-benzonitrile) to R-diol (4-[(R)-4-dimethylamino-1-(4-fluorophenyl)-1-hydroxy-butyl]-3-hydroxymethyl-benzonitrile) is 71.6:28.4 (enantiomeric excess=43.2%). About 10% of 4-[(4-fluorophenyl)-hydroxy-methyl]-3-hydroxymethyl-benzonitrile are formed as a byproduct.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(O)C.COCCOC.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1Br
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: O=Cc1ccccc1-c1ccc(Cl)cc1
Temperature: 75 °C
Reaction time: 20 h
Yield: 70.9 %

Procedure:
To a solution of 2-bromobenzaldehyde (18.0 g, 97.0 mmol) and 4-chloro-phenylboronic acid (19.0 g, 122 mmol) in a 1:1 mixture of ethanol/DME (400 mL) is added a solution of potassium carbonate (26.9 g, 195 mmol) in water (100 mL), and the reaction mixture is purged with nitrogen for 30 minutes. Tetrakis(triphenyl-phosphine)palladium (5.62 g, 4.86 mmol) is then added, and the reaction is purged again with nitrogen for 20 minutes. The pale yellow-green solution is heated to 75° C. and stirred for 20 hours. The reaction is then cooled to room temperature, diluted with ethyl acetate (200 mL), and filtered through a ZAPCAP filter. The filtrate is washed with brine (400 mL) and the aqueous layer is back-extracted with ethyl acetate (2×200 mL). The combined organic layers are dried over MgSO4 and concentrated to afford an orange oily solid. This crude material is purified via flash chromatography on silica gel (0-20% EtOAd heptanes) to afford the title compound (14.9 g, 71% yield). 1H NMR (400 MHz, CDCl3) δ 10.0 (s, 1H), 8.05 (d, J=7.5 Hz, 1H), 7.68 (t, J=6.2 Hz, 1H), 7.54 (t, J=7.4 Hz, 1H), 7.49 (d, J=9.4 Hz, 2H), 7.45 (d, J=9.1 Hz, 1H), 7.34 (d, J=8.5 Hz, 2H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]=[CH:13][NH:12][C:11]2=O>C1(C)C=CC=CC=1>[Cl:3][C:11]1[C:10]2[C:15](=[CH:16][C:17]([O:18][CH3:19])=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[CH:13][N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Cl)c2cc1OC
Temperature: 120 °C
Reaction time: 6.5 h
Yield: 105.6 %

Procedure:
Toluene (100 ml) and phosphorus oxychloride (7.4 g, 48.6 mmol) were added to 6,7-dimethoxy-4-quinazolone (10.0 g, 48.5 mmol), and the mixture was stirred at 120° C. for 6.5 hr. The reaction solution was cooled to room temperature, was then filtered, was washed with toluene (100 ml, 50 ml), and was dried to give 11.5 g (yield 91%) of the target product.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1.[F:25][B-](F)(F)F.F[B-](F)(F)F.F[N+]1C=CC=CC=1C1C=CC=C[N+]=1F.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[F:25][C:12]1[CH:13]=[C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:3][CH:2]2[OH:1])[CH:9]=[CH:10][C:11]=1[OH:14]
Reactant: F[B-](F)(F)F
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(O)cc2)C(O)C1
Agent: F[n+]1ccccc1-c1cccc[n+]1F
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: O=C(OCc1ccccc1)N1CCC(c2ccc(O)c(F)c2)C(O)C1

Procedure:
A solution of 0.581 g of benzyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate in 5 ml of acetonitrile is admixed with 0.320 g of N,N′-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) and the suspension is subsequently heated at reflux over 15 hours. The reaction mixture is poured onto 10 ml of saturated aqueous sodium thiosulphate solution and the mixture is extracted with 2×50 ml of ethyl acetate. The combined organic phases are washed with 10 ml each of 0.5 M HCl and brine, dried over sodium sulphate and concentrated. The title compound is obtained as a colourless solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.33 (2:1 EtOAc-heptane); Rt=3.80.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:9][C:7](=O)[CH2:6][C:4](=[O:5])[CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Pd].C(O)(C)C>[CH3:1][C:2]1([CH3:10])[CH2:9][CH2:7][CH2:6][C:4](=[O:5])[CH2:3]1
Reactant: CC1(C)CC(=O)CC(=O)C1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: CC1(C)CCCC(=O)C1
Reaction time: 0.17 h

Procedure:
41 g of 5% Pd/C E 101 N/D were placed in a 2 L glass-steel autoclave with glass-liner. 385 g of dimedone (2.75 mol), 663 g (850 mL) of isopropanol and 15.3 g (88 mmol) of p-toluene sulfonic acid were added. The glass-liner was closed and stirring was started with 500 rpm. The autoclave was flushed three times with 5 bara N2. The stirrer was turned off. The autoclave was then pressurized with 5 bara H2 for 10 minutes for pressure check. The pressure was released.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[C:16]([OH:23])[CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13]2)=[O:10])=[CH:4][CH:3]=1.C(Cl)(=[O:26])C.N1C=CC=CC=1>ClCCl>[C:21]([OH:22])(=[O:26])[CH3:20].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[C:16]([OH:23])[CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13]2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Agent: O=C(Nc1ccc(Cl)cc1)Nn1cnc2c(O)cccc2c1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O
Reaction time: 8 h

Procedure:
A mixture of 1-(p-chlorophenyl)-3-(3,4-dihydro-8-hydroxy-4-oxo-3-quinazolinyl)urea (0.66 g, 2.00 mmol) in dichloromethane is treated with acetyl chloride (0.155 mL, 2.11 mmol) and pyridine (0.165 mL, 2.04 mmol), stirred overnight, washed sequentially with 5% hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous MgSO4 and concentrated in vacuo to obtain a solid. The solid is washed with dichloromethane and dried to give the title product as a white solid, 0.30 g, mp 216°-218° C., which is identified by 1HNMR spectral analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:13])[CH:12]=1.[Li]CCCC.CN([CH:22]=[O:23])C.[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:13])[C:12]=1[CH:22]=[O:23]
Reactant: Cn1cc(-c2ccccc2F)nn1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1nnc(-c2ccccc2F)c1C=O
Temperature: -75 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a solution of 4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazole (1.44 g, 8.1 mmol) in THF (41 mL) was added n-BuLi (1.6 M in hexane, 6.10 mL, 9.8 mmol) dropwise at −75° C. under Argon. The resulted orange solution was stirred at −75° C. for 1 h, then DMF (0.82 mL, 10.6 mmol) was added dropwise at −75° C. and the reaction mixture was allowed to warm up to room temperature over 1 h. The mixture was then poured into saturated ammonium chloride solution and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 50% ethyl acetate in heptane) afforded the title compound (1.45 g, 87%) as an off white solid. MS: m/e=206.0 [M]+.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([C:19]3[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=3)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)C.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][NH:38][CH:39]=2)O1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH:37]1[CH:36]=[C:35]([C:22]2[CH:21]=[CH:20][C:19]([C:13]3([C:10]4[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:26])=[CH:12][CH:11]=4)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:24][CH:23]=2)[CH:39]=[N:38]1
Reactant: CCOC(=O)COc1ccc(C2(c3ccc(Br)cc3)CCNCC2)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(O)COc1ccc(C2(c3ccc(-c4cn[nH]c4)cc3)CCNCC2)cc1
Temperature: 80 °C
Yield: 5 %

Procedure:
{4-[4-(4-bromo-phenyl)-piperidin-4-yl]-phenoxy}-acetic acid ethyl ester was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1, but using tetrakis(triphenylphosphine) palladium (0) as the catalyst and heating at 80° C. for 30 minutes, to yield a mixture of the title compounds. On work up the basic aqueous extract was neutralised with hydrochloric acid and extracted with ethyl acetate (×2), then these organic extracts were combined and washed with brine, dried (MgSO4), filtered and concentrated to give a crude product that was recrystallised from water to afford (4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenoxy)-acetic acid (12 mg, 5%); LCMS (PS-A3) Rt 5.33 min [M+H]+378. 1H NMR (DMSO-d6) δ 2.22-2.26 (4H, m), 2.67-2.71 (4H, m), 4.65 (2H, s) 6.67 (2H, d), 7.11 (2H, d), 7.24 (2H, d), 7.46 (2H, d), 7.96 (2H, br.s).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-])=O)=[N:12][CH:13]=2)[CH2:4][CH2:3]1>[Pd].CO>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CN1CC=C(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCC(c2ccc(N)nc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.9 %

Procedure:
A 250-mL single-neck round-bottomed flask was purged with nitrogen and charged with 232b (2.0 g, 9.0 mmol), 10% palladium on carbon (50% wet, 200 mg), and methanol (40 mL). The flask was evacuated, charged with hydrogen gas, and stirred under hydrogen at room temperature for 12 h. The hydrogen was then evacuated and nitrogen was charged to the flask. The catalyst was removed by filtration through a pad of CELITE® and the filtrate was concentrated under reduced pressure to afford 232c (1.6 g, 92.5%), which was used directly in the next step without further purification. MS-ESI: [M+H]+ 192
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[CH3:13][O:14][C:15](=[O:21])[CH2:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1.ClC(Cl)C>[CH3:13][O:14][C:15](=[O:21])[CH2:16][S:17](=[O:19])(=[O:18])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([C:9]([F:10])([F:11])[F:12])[CH:4]=1
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: COC(=O)CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: COC(=O)CS(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1

Procedure:
Analogously to the instructions for example 7, 5 g (27.64 mmol) of 4-fluoro-3-(trifluoromethyl)-aniline in 25 ml of dry pyridine is reacted with 4.82 g (27.4 mmol) of chlorosulfonyl acetic acid methyl ester in 100 ml of dry dichloroethane. After crystallization from ether/hexane, 7.35 g=84.35% of the theoretical yield is obtained. Melting point 111°-112° C.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].CCOCC>CN(C=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:20]
Reactant: CCOC(=O)CBr
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 89.8 %

Procedure:
To a solution of thiophenol (1 mL, 9.7 mmol) in DMF (20 mL) is added potassium carbonate (1.51 g, 10.9 mmol) and ethyl bromoacetate (1.17 mL, 10.6 mmol), and the mixture is stirred at RT for 25 min. Et2O is added, and the mixture is washed with water, brine, then dried (MgSO4), and filtered. The filtrate is evaporated, and the residue is vacuum distilled (130-140° C.) to give 1.71 g of the product 400. 1H NMR (CDCl3) δ 7.41 (d, 2H), 7.33-7.2 (m, 4H), 4.16 (q, 2H), 3.63 (s, 2H), 1.22 (t, 3H); MS: m/z 196 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([CH:9]=1)[NH:7][CH3:8].O.NN>CO.[Ni]>[Br:1][C:2]1[CH:9]=[C:6]([NH:7][CH3:8])[C:5]([NH2:10])=[CH:4][CH:3]=1
Reactant: CNc1cc(Br)ccc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CNc1cc(Br)ccc1N
Temperature: 80 °C

Procedure:
5-bromo-N-methyl-2-nitroaniline (1.5 g) was dissolved in methanol (60 mL) by heating to 80° C. Hydrazine hydrate was added (3.2 mL) followed by Raney Nickel (50% slurry in water, 6 drops) and the reaction mixture was heated to reflux for 1 hour. The reaction mixture was filtered through Celite® and concentrated under reduced pressure, providing 5-bromo-N1-methylbenzene-1,2-diamine as an amber oil. This product was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Br:19])=[O:11].[NH2:24][C@@H:25]([CH3:44])[CH2:26][O:27][C:28]1[CH:43]=[CH:42][C:31]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=[CH:30][CH:29]=1.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([NH:24][C@@H:25]([CH3:44])[CH2:26][O:27][C:28]2[CH:43]=[CH:42][C:31]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[O:33])=[CH:30][CH:29]=2)=[O:23])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Br:19])=[O:11]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Br
Reactant: C[C@H](N)COc1ccc(C(=O)OCc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)N[C@@H](C)COc2ccc(C(=O)OCc3ccccc3)cc2)ccc1NC(=O)Nc1ccccc1Br
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of 3-methoxy-4-[N′-(2-bromophenyl)ureido]phenylacetic acid (480 mg, 1.27 mmol), benzyl (S)-4-(2-amino-1-propoxy)benzoate (361 mg, 1.27 mmol), EDC(hydrochloride) (364 mg, 1.90 mmol), HOBt (256 mg, 1.89 mmol), and 4-DMAP (31 mg, 0.25 mmol) in DMF (8 mL) was stirred at room temp. overnight. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3 to 5% MeOH in CHCl3 as eluent to give 476 mg (58%) benzyl (S)-4-[2-[3-methoxy-4-[N′-(2-bromophenyl)ureido]phenylacetylamino]-1-propoxy]benzoate as a brown solid. 1H-NMR (CDCl3) δ1.25-1.28 (m, 3 H), 3.51 (s, 2 H), 3.74 (s, 3 H), 3.95-3.97 (m, 2 H), 4.36-4.39 (m, 1 H), 5.33 (s, 2 H), 6.75-6.94 (m, 5 H), 7.26-7.70 (m, 8 H), 7.99-8.26 (m, 5 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9]Br)[CH:3]=1.[C-:11]#[N:12].[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[CH2:9][C:11]#[N:12]
Reactant: [C-]#N
Reactant: Cc1cc(Br)cc(CBr)c1
Agent: [K+]
Solvent: CCO
Product: Cc1cc(Br)cc(CC#N)c1
Temperature: 25 °C
Yield: 39.5 %

Procedure:
To a stirred solution of 1-bromo-3-(bromomethyl)-5-methylbenzene (6.56 kg, 0.1515 M) in ethanol (20 L) were added potassium cyanide (2.38 kg, 36.55 mol) and distilled water (10 L) in this order. The mixture was refluxed for 3 hours. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate (30 L) and brine (20 L). The organic layer was dried with magnesium sulfate (2 kg) and concentrated under reduced pressure to give a brown-colored oil. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate/hexane, 1:9) to afford 3-bromo-5-methylbenzyl cyanide (2.06 kg, 9.81 mol, 39%) as a pale brown oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].F[C:8]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[CH:12][CH:11]=[C:10]([N+:21]([O-])=O)[C:9]=1[NH2:24].[BH4-].[Na+].[OH-].[Na+]>O.C1COCC1>[CH:20]1([N:17]2[CH2:18][CH2:19][N:14]([C:13]3[CH:8]=[C:9]([NH2:24])[C:10]([NH2:21])=[CH:11][CH:12]=3)[CH2:15][CH2:16]2)[CH2:10][CH2:9][CH2:8][CH2:13]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2F)CC1
Agent: [Al+3]
Agent: [BH4-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(N2CCN(C3CCCC3)CC2)cc1N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A flame dried 500 mL three necked round bottom flask purged with N2 was charged with LAH (3.0 g, 75.0 mmol) and dry THF (240 mL). The resulting suspension was cooled to 0° C. and t-butyl ester 1 (20.7 g, 60 mmol) was slowly added while keeping the internal reaction temperature under 5° C. Reaction stirred at 0° C. for 2 hr followed by stirring at RT for overnight. NaBH4 (2.27 g, 60 mmol) was added and stirred for an additional hour at rt. After the reaction was judged complete, the stirred reduction mixture was treated with successive dropwise addition of 3 mL H2O, 3 mL NaOH, and 9 mL H2O. Reaction mixture filtered through Celite, washed with ethyl acetate and methanol, and evaporated. Crude product absorbed onto silica gel and chromatographed using 97:3 CH2Cl2/MeOH to give 2 as an orange solid. 1H NMR (300 MHz, CDCl3) δ 8.40 (d, J=5.5 Hz, 1H), 8.05 (br s, 1H), 7.96 (d, J=2.75 Hz, 1H), 7.29 (d, J=2.75 Hz, 1H), 6.92 (d, J=9.35 Hz, 1H), 6.75 (m, 2H), 4.68 (s, 2H), 3.07 (d, J=5.23 Hz, 3H).