Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH3+:14])[CH2:10][CH2:9]1.[F:15][C:16]([F:28])([F:27])[C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.OS([O-])(=O)=O.[K+].CC(OC)(C)C>[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([NH:14][S:23]([C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:27])[F:28])=[CH:22][CH:21]=2)(=[O:25])=[O:24])[CH2:12][CH2:13]1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: [NH3+][C@H]1CC[C@H](CCCCCBr)CC1
Agent: O=S(=O)([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: COC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(N[C@H]1CC[C@H](CCCCCBr)CC1)c1ccc(C(F)(F)F)cc1
Reaction time: 1.5 h

Procedure:
A solution of 1.0 g (3.04 mmol) of trans-4-(5-Bromo-pentyl)-cyclohexylammonium bromide in 12 ml CH2Cl2 was first cooled at 0° C., treated with 0.8 g (3.27 mmol) 4-(trifluoromethyl)benzenesulfonylchloride and then with 1.2 ml (7.01 mmol; 2.3 equivalents) of Hünig's base (during 30 min). After total 1.5 h at 0° C., the mixture was dissolved in aqueous 10% KHSO4/TBME (3×). The organic phases were washed with aqueous saturated NaHCO3 and aqueous 10% NaCl, dried over Na2SO4 and evaporated to give 1.38 g crude product which was crystallized (CH2Cl2/hexane) to give 1.26 g (91%) of pure trans-N-[4-(5-Bromo-pentyl)-cyclohexyl]-4-trifluoromethyl-benzenesulfonamide, MS: 454 (M−H−, 1Br).
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH:11]([Mg]Br)=[CH2:12]>C1COCC1>[CH:11]([CH:1]([C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[OH:10])=[CH2:12]
Reactant: COc1ccc(C=O)cc1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)c1ccc(OC)cc1
Reaction time: 12 h

Procedure:
p-anisaldehyde (136 mg) was mixed with THF (4 ml) and further mixed with vinylmagnesium bromide (1 N solution) (4 mL), followed by stirring for 12 hours to obtain the title compound (195 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1>>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:19][CH:20]=1)#[N:25]
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Reactant: N#Cc1ccc(CBr)cc1
Product: N#Cc1ccc(CN(c2ccc(C#N)cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[(4-cyanophenyl)amino]pyrimidine and α-bromo-p-tolunitrile
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][C:16]1[CH:21]=[C:20]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31]([NH:33][C@H:34]4[CH2:39][NH:38][C@H:37]([C:40]([O:42][CH3:43])=[O:41])[CH2:36][CH2:35]4)=[O:32])[CH:29]=3)[NH:24][N:23]=2)[CH:19]=[CH:18][N:17]=1.[F:44][C:45]1[CH:52]=[CH:51][CH:50]=[C:49]([O:53][CH3:54])[C:46]=1[CH:47]=O>CO>[F:44][C:45]1[CH:52]=[CH:51][CH:50]=[C:49]([O:53][CH3:54])[C:46]=1[CH2:47][N:38]1[CH2:39][C@H:34]([NH:33][C:31]([C:28]2[CH:29]=[C:30]3[C:25](=[CH:26][CH:27]=2)[NH:24][N:23]=[C:22]3[C:20]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:15])[CH:21]=2)=[O:32])[CH2:35][CH2:36][C@H:37]1[C:40]([O:42][CH3:43])=[O:41]
Reactant: COC(=O)[C@@H]1CC[C@@H](NC(=O)c2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)CN1
Reactant: COc1cccc(F)c1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H]1CC[C@@H](NC(=O)c2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)CN1Cc1c(F)cccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
SODIUM TRIACETOXYBOROHYDRIDE (6.46 g, 30.5 mmol) was added to a stirred mixture of (2S,5R)-methyl 5-(3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamido)-piperidine-2-carboxylate (2 g, 5 mmol) and 2-Fluoro-6-Methoxy-Benzaldehyde (4.70 g, 30.5 mmol) in MeOH (100 ml) and the mixture was stirred at room temperature for overnight. The reaction LCMS gave M+H at 532. The reaction was rotovap to dryness and the residue was purified by column chromatography on silica gel Biotage 40M, eluting with 5% MeOH/NH3(2M)CH2Cl2 to give desired product as a brown solid (2 g, 3.76 mmol, 74.0% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[C:10](OC)[C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1.C(O)C.C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:25][C:22]1[CH:23]=[CH:24][C:2]([CH3:1])=[C:3]([CH:21]=1)[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1
Reactant: COc1cc2c(Nc3cc([N+](=O)[O-])ccc3C)ncnc2c(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2ncnc(Nc3cc(N)ccc3C)c2cc1OC
Reaction time: 18 h

Procedure:
Using similar procedures to those described in the last paragraph of the portion of Example 2 which is concerned with the preparation of starting materials, a solution of 4-(2-methyl-5-nitroanilino)-6,7,8-trimethoxyquinazoline in a 30:3:1 mixture of ethanol, acetic acid and water was reduced at 90° C. during 18 hours. Solid sodium carbonate was added after cooling. The filtrate was triturated with diethyl ether and the resultant residue was purified by column chromatography eluting with 2.5% methanol in ethyl acetate to give 4-(5-amino-2-methylanilino)-6,7-dimethoxyquinazoline; NMR: (CDCl3) 2.73 (s, 3H), 3.95 (s, 3H), 4.04 (s, 3H), 4.14 (s, 3H), 6.9 (s, 1H), 7.21 (m, 2H), 7.64 (s, 1H), 7.96 (d, 1H), 8.50 (s, 1H), 8.72 (s, 1H); Mass: M+H+ 341.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:25])[CH:7]([CH2:12][C:13]([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10].[Cl-].[Na+]>O.O1CCCC1.CO>[CH2:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:23][CH2:24][N:15]1[C:13](=[O:14])[CH2:12][CH:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:6]([OH:25])=[O:5]
Reactant: COC(=O)C(CC(=O)N1CCc2ccccc2C1)CC(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)CC(CC(=O)N1CCc2ccccc2C1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 12 %

Procedure:
A solution of lithium hydroxide monohydrate (0.01452 g, 0.3461 mmol) in water (1.5 ml) was added drop-wise over 1 minute to a solution of 2-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]-4-methyl-pentanoic acid methyl ester (0.035 g, 0.1154 mmol) in tetrahydrofuran:methanol 2:1 (9 ml) at 0° C. The mixture was stirred at ambient temperature for 16 hours then poured into saturated aqueous sodium chloride solution (10 ml). The aqueous layer was extracted with diethyl ether (2×10 ml) which was discarded. The aqueous layer was acidified with 1M hydrochloric acid to pH (1˜2), then the product was extracted into dichloromethane (3×10 ml). The combined dichloromethane layers were washed with water (2×10 ml), saturated aqueous sodium chloride solution (2×10 ml) then dried (Na2SO4) and the solvents removed in vacuo to leave 2-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]-4-methyl-pentanoic acid as a colourless oil (4.0 mg, 12%). TLC (main spot, Rf=0.2, methanol:dichloromethane 1:10), analytical HPLC Rt=13.297 min. HPLC-MS (290.2 [M+1]+, 312.2 [M+Na]+, 601.3 [2M+Na]+).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]3[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=3)(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[K+].C(OCC)(=O)C.Cl>O.CC(C)=O>[OH:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([NH:24][C:25]3[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=3)(=[O:23])=[O:22])=[CH:19][CH:20]=2)=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Nc3ncccc3C)cc2)ccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Cc1cccnc1NS(=O)(=O)c1ccc(C#Cc2ccc(O)c(C(=O)O)c2)cc1

Procedure:
Ethyl 2-hydroxy-5-[[4-[(3-methyl-2-pyridinylamino)sulfonyl]phenyl]ethynyl]benzoate (15.5 g, 35 mmol) was refluxed in potassium hydroxide (10 g, 0.15 mol) in water (100 ml) for 1 h. After cooling to ca 70° C., ethyl acetate (50 ml) was added and hydrochloric acid was added to reach pH 7-8. Cooling during stirring and then filtration gave a solid that was dissolved in acetone (100 ml) and water (100 ml). The solution was acidified at ca 50° C. and cooled, filtered and washed with water. Yield 8.0 g (56%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:37]=[CH:36][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25](OCC)=[O:26])[C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:21]2)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([O:14][C:15]1[CH:37]=[CH:36][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][OH:26])[C:22]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[N:21]2)=[CH:17][CH:16]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 267.7 %

Procedure:
Lithium aluminium hydride (884 mg) was added to a solution of ethyl 1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazole-4-carboxylate (9.61 g) in tetrahydrofuran (50 ml) at 0° C., and the mixture was stirred at 0° C. for one hour. After adding water, the reaction mixture was stirred at room temperature for one hour. After the precipitate was removed by filtration, the filtrate was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The crystals obtained were collected by filtration to yield [1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazol-4-yl]methanol (23.10 g, yield: 97%). This was recrystallized from ethyl acetate-hexane. Melting point: 88–89° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][N+:9]([O-])=[CH:8][CH:7]=1.C([O-])(=[O:20])C.[K+].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>C(O)(=O)C>[F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:20])[CH:7]=1
Reactant: CC(=O)[O-]
Reactant: [O-][n+]1ccc(OCc2ccc(F)cc2F)cc1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [K+]
Solvent: CC(=O)O
Product: O=c1cc(OCc2ccc(F)cc2F)cc[nH]1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
4-[(2,4-difluorobenzyl)oxy]pyridine 1-oxide (from Step 1) (30.0 g, 0.127 mol), anhydrous potassium acetate (25 g, 0.25 mol), acetic anydride (25 g, 0.25 mol), and 10 ml acetic acid were combined in a 250-ml round-bottomed flask with overhead stirring and heated to 130° C. for 4 hours. The mixture was concentrated under vacuum, the solids dissolved in 95 ml acetonitrile; 5 ml water, filtered through charcoal and poured into 600 ml ice with stirring. The mixture was allowed to stand overnight at room temperature, then 9.62 g (30%) product collected by filtration as a medium brown solid (adequate for the next step without purification). 1H-NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 7.59 (quartet, J=9.91 Hz, 1H), 7.29 (t, J=10.36 Hz, 1H), 7.21 (d, J=8.20 Hz, 1H), 7.11 (t, J=8.48 Hz, 1H), 5.83 (m, 2H), 5.02 (s, 2H). 19F-NMR (400 MHz, DMSO-d6) δ −109.57 (quintet, J=7.66 Hz, 1F)-113.88 (quartet, J=8.93 Hz, 1F). LC/MS tr=4.29 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 254 nm, at 50° C.) ES-MS m/z 238 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[N:34]=[C:35]=[O:36]>>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[NH:34][C:35](=[O:36])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C=Nc1c(F)cccc1F
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4c(F)cccc4F)cc3)cc2C1=O

Procedure:
The compound of example 19 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 2,6-difluorophenyl isocyanate. The compound of example 19 was used directly without isolation for the preparation of compound of example 20.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:32][CH2:33][CH:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[OH:35]>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:32][CH2:33][CH:34]([OH:35])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:29])=[CH:23][CH:24]=1
Reactant: O=C(COc1ccc(Cl)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: NCC(O)c1ccccc1
Product: O=C(NCC(O)c1ccccc1)c1ccc2n1Cc1ccccc1N(C(=O)COc1ccc(Cl)cc1)C2

Procedure:
The title compound was synthesized from 2,2,2-trichloro-1-{10-[(4-chlorophenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 67 (0.3 mmol) and 2-amino-1-phenylethanol (2.2 eq.) in the manner of Example 68, m.p. 157-158° C. MS [(−)ESI, m/z]: 514.3 [M−H]−
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[N:12][C:13]#[N:14])[CH3:2].C([O-])C.[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[N:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]2=[N:12][C:13]=1[NH2:14])=[O:15])[CH3:2]
Reactant: CCOC(=O)CN1CCCCC1=NC#N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(N)nc2n1CCCC2
Yield: 57.8 %

Procedure:
Compound D (16.05 g, 76.7 mmol) was added to a solution of sodium ethanolate (5.20 g, 76.7 mmol, 1.0 eq.) in ethanol (500 mL) and the resulting reaction mixture was heated for 30 minutes under reflux. The solvent was removed under vacuum and the untreated product was purified by means of column chromatography (hydromatrix as the adsorbent, SiO2, DCM/3% MeOH→DCM/5% MeOH). 9.27 g of the desired product E were obtained. The columns were washed with methanol, the solvent was removed under vacuum and the residue was recrystallised by heptane in order to obtain a further 3.26 g of the desired product 2-amino-5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridine-3-carboxylic-acid ethyl ester (E). In total, 12.53 g (78%) of the desired product 2-amino-5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridine-3-carboxylic-acid ethyl ester (E) were obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([OH:37])=O)=[CH:31][CH:30]=2)[CH:12]=[C:13]([Cl:28])[C:14]=1[CH2:15][C@@H:16]1[CH2:20][CH2:19][N:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:17]1=[O:27].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[F:51][C:52]([F:60])([F:59])[CH:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C(OCC)(=O)C>[Cl:8][C:9]1[CH:10]=[C:11]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([N:56]3[CH2:57][CH2:58][CH:53]([C:52]([F:60])([F:59])[F:51])[CH2:54][CH2:55]3)=[O:37])=[CH:33][CH:34]=2)[CH:12]=[C:13]([Cl:28])[C:14]=1[CH2:15][C@@H:16]1[CH2:20][CH2:19][N:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:17]1=[O:27]
Reactant: FC(F)(F)C1CCNCC1
Reactant: O=C(O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCOCC4)C3=O)c(Cl)c2)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCOCC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Treat a mixture of (R)-3′,5′-dichloro-4′-(1-morpholin-4-yl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carboxylic acid trifluoro acetate (0.16 g, 0.28 mmol) in CH2Cl2 (10 mL) with 1,1′-carbonyldiimidazole (0.092 g, 0.57 mmol), 4-trifluoromethylpiperidine hydrochloride (0.081 g, 0.43 mmol) and diisopropylethylamine (0.110 g, 0.86 mmol) and stir for 12 hours at room temperature. Load the mixture on silica gel column and flash with 50% ethyl acetate in hexanes to 100% ethyl acetate to afford 0.081 g of a mixture of the title compound and impurity. Re-purify via reverse phase HPLC to afford 0.055 g (34%) of the title compound. MS (m/z): 584 (M+).
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=[O:35])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:22](=[O:34])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[CH:16][CH:15]=1.CC(O)=O.C(Cl)Cl>CCCCCCC.CCOC(C)=O.[Zn]>[F:33][C:30]([F:31])([F:32])[C:27]1[CH:26]=[CH:25][C:24]([CH2:23][C:22]([O:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([S:13][CH2:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[C:5]([OH:35])=[O:4])=[CH:15][CH:16]=2)=[O:34])=[CH:29][CH:28]=1
Reactant: O=C(Cc1ccc(C(F)(F)F)cc1)OCc1ccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)cc1
Agent: [Zn]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(Cc1ccc(C(F)(F)F)cc1)OCc1ccc(SCc2ccccc2C(=O)O)cc1
Yield: 68.9 %

Procedure:
The titled compound was prepared according to the method described for example 1 above from 2-{4-[2-(4-trifluoromethyl-phenyl)-acetoxymethyl]phenylsulfanylmethyl}benzoic acid 2,2,2-trichloro-ethyl ester (112 mg, 0.189 mmol), zinc (247 mg, 3.79 mmol), HOAc, 97% (1.08 mL, 18.9 mmol) and DCM (9 mL). The crude was submitted to flash chromatography using heptane and EtOAc (70/30-60/40) as eluent to give the titled compound (60 mg, 69%) as a solid; 1H NMR (400 MHz, CDCl3): δ 3.72 (s, 2H), 4.57 (s, 2H), 5.09 (s, 2H), 7.18 (d, 2H), 7.24-7.30 (m, 3H), 7.31-7.46 (m, 4H), 7.48 (d, 2H), 8.05 (d, 1H); Mass spectrum: M−H+ 459.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:29][CH3:30])=[C:23]([O:26][CH2:27][CH3:28])[CH:24]=2)[N:19]=[CH:18][N:17]=1>C1COCC1.C(OCC)(=O)C>[CH2:27]([O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:29][CH3:30])[N:19]=[CH:18][N:17]=[C:16]2[O:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[NH2:7])[CH3:28]
Reactant: Nc1cccc(O)c1
Reactant: CCOc1cc2c(Cl)ncnc2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc2c(Oc3cccc(N)c3)ncnc2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a stirred suspension of cesium carbonate (3.60 g, 11.06 mmol) in THF (50 mL) was added 3-aminophenol (0.91 g, 8.38 mmol). After stirring for 30 minutes at rt, 4-chloro-6-ethoxy-7-methoxyquinazoline described in Example 11A (2.00 g, 8.38 mmol) was added and the reaction mixture was heated at 50° C. for 15 h. The reaction mixture was cooled to rt and diluted with ethyl acetate. The solution was washed with aqueous 1 M NaOH solution, then brine, and dried over MgSO4. Filtration and concentrated under reduced pressure, gave a solid that was triturated with ethyl acetate. Filtration and drying afforded 3-(6-ethoxy-7-methoxyquinazolin-4-yloxy)aniline (1.30 g, 50%) as a cream solid, which did not require further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.48 (s, 1H), 7.36 (s, 1H), 7.08 (dd, J=8, 8 Hz, 1H), 6.36-6.49 (m, 3H), 5.30 (brs, 2H), 4.21 (q, J=7 Hz, 2H), 3.98 (s, 3H), 1.41 (t, J=7 Hz, 3H); LC-MS (ESI) m/z 312 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[N:10]=[C:9]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[O:13])[CH:8]=[CH:7][N:6]=1.Br[CH2:25][C:26]([O:28][CH3:29])=[O:27].C(=O)(O)[O-].[Na+]>CS(C)=O.O>[CH3:29][O:28][C:26](=[O:27])[CH2:25][CH:11]([C:9]1[CH:8]=[CH:7][N:6]=[C:5]([S:4][CH3:3])[N:10]=1)[C:12](=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=1
Reactant: CSc1nccc(CC(=O)c2cccc(C(F)(F)F)c2)n1
Reactant: COC(=O)CBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CC(C(=O)c1cccc(C(F)(F)F)c1)c1ccnc(SC)n1
Reaction time: 0.5 h

Procedure:
Sodium hydride (95%, 1.78 g, 83 mmol) and dimethyl sulfoxide (DMSO) (150 mL) were combined under argon in a 3-neck 1L round bottom flask. A solution of Compound 3 in DMSO (50 mL) was added dropwise over 0.75 h using an addition funnel. After stirring an additional 0.5 h, methyl bromoacetate (7.9 mL, 83 mmol) in DMSO (50 mL) was added dropwise. After 18 h, the contents of the reaction flask were poured into water. Saturated sodium bicarbonate was added and the resulting solution was extracted several times with ethyl acetate. The combined organic extracts were washed successively with water and brine. The organic layer was dried with anhydrous sodium sulfate then concentrated in vacuo to give an oil. Purification by flash column chromatography (hexane:ethyl acetate 70:30) afforded Compound 4 as an oil: 24.6 g (64 mmol, 100%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O1CCCC1.O.C(OCC)(=O)C>[CH2:23]([O:22][C:20]([NH:5][C:4]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc([N+](=O)[O-])cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc([N+](=O)[O-])cc1NC(=O)OCc1ccccc1
Reaction time: 12 h
Yield: 86 %

Procedure:
To a stirred solution of 2-methoxy-5-nitroaniline (5.0 g, 30 mmol) and potassium carbonate (12 g, 90 mmol) in tetrahydrofuran (200 mL) and water (100 mL) was added benzyl chloroformate (6.1 g, 36 mmol). After 12 h, the mixture was diluted with ethyl acetate (200 mL) and the layers were separated. The organic phase was washed twice with 1 N aqueous hydrochloric acid, once with saturated aqueous sodium chloride solution, twice with saturated aqueous sodium bicarbonate solution, twice with saturated aqueous sodium chloride solution, dried (magnesium sulfate), filtered, and concentrated in vacuo. The resulting solid was suspended in diethyl ether and after sonication, the solid was filtered, washed with diethyl ether, and dried in vacuo to give 7.8 g (86%) of the title compound as a light yellow solid.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1.C(O)(=O)CC>Br>[CH2:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:18][NH:10]1
Reactant: Cc1ccc(S(=O)(=O)N2Cc3ccccc3C2)cc1
Agent: Br
Solvent: Oc1ccccc1
Solvent: CCC(=O)O
Product: c1ccc2c(c1)CNC2
Temperature: 25 °C
Yield: 62.6 %

Procedure:
A solution of 12.0 g (0.044 mol) of 2-(p-tolylsulfonyl) isoindoline, 12.0 g (0.13 mol) of phenol, 90 ml of 48% HBr, and 15 ml (0.201 mol) of propionic acid was refluxed for two hours. The mixture was cooled to room temperature, triturated with diethyl ether, and then added to a solution of 75 gm of sodium hydroxide in 200 ml of cold water. This mixture was extracted with diethyl ether and the combined ether extracts were washed with water. The organic phase was dried over magnesium sulfate, concentrated in vacuo and kugelrohr distilled to give 3.28 g (61%) of a white solid, m.p. 118°-127° C. NMR (CDCl3) δ 2.2 (1H,s), 4.0 (4H, s), 6.95 (4H, s)