Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14](OC)=[O:15])([O-])=O>C(OCC)(=O)C.C1COCC1.[Pd]>[NH2:10][C:8]1[CH:9]=[C:4]2[C:5]([C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14](=[O:15])[NH:1]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(O)(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)NC(=O)C2(O)C(F)(F)F
Reaction time: 8 h
Yield: 6.2 %

Procedure:
To a solution of methyl 2-(2,4-dinitrophenyl)-3,3,3-trifluoro-2-hydroxypropanoate (1.3 g, 4.01 mmol) in ethyl acetate (18 mL) was added pH3HCl (5.2 mL) followed by 10% Pd/C (350 mg) in ethyl acetate (3 mL). The mixture was stirred overnight under an atmosphere of H2. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The crude residue obtained was partitioned between, dichloromethane (25 mL) and aqueous saturated NaHCO3 (15 mL). The organic phase was separated and the aqueous phase was extracted dichloromethane (2×25 mL). The organic phases were combined, dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography (50-100% ethyl acetate/hexanes) provided 6-amino-3-hydroxy-3-(trifluoromethyl)indolin-2-one (921 mg, 99%) To a solution of 6-amino-3-hydroxy-3-(trifluoromethyl)indolin-2-one (58 mg, 0.25 mmol) in THF (0.5 mL) at 0° C. was added BH3THF complex (1 M in THF, 1 mL, 0.95 mmol) dropwise. The mixture was stirred for 5 min at 0° C. then for 3 h at room temperature. The reaction was quenched by adding very carefully 6M HCl (3.5 mL) until no more gas release was observed. The mixture was then stirred at 80° C. for 2 h. The solvent was removed under reduce pressure and the solid residue obtained was dissolved in DMF (3 mL), filtered and purified by reverse phase HPLC (10-99% CH3CN/H2O) to provide 3-(trifluoromethyl)-1H-indol-6-amine (30 mg, 54%, TFA salt).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:15]([C:16]([OH:18])=[O:17])[CH2:14][C:13]2([CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[C:28]([O:30][C@H:31]([C:36]4[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=4[N:43]4[CH:47]=[CH:46][C:45]([CH3:48])=[N:44]4)[C:32]([F:35])([F:34])[F:33])[N:27]=[C:26](S(C)(=O)=O)[N:25]=3)[CH2:20][CH2:19]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:53]1([OH:59])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>O1CCOCC1.O>[CH2:1]([O:8][C:9]([N:11]1[CH:15]([C:16]([OH:18])=[O:17])[CH2:14][C:13]2([CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[C:28]([O:30][C@H:31]([C:36]4[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=4[N:43]4[CH:47]=[CH:46][C:45]([CH3:48])=[N:44]4)[C:32]([F:35])([F:34])[F:33])[N:27]=[C:26]([O:59][C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[N:25]=3)[CH2:20][CH2:19]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CC(C(=O)O)N(C(=O)OCc3ccccc3)C4)nc(S(C)(=O)=O)n2)C(F)(F)F)n1
Reactant: Oc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CC(C(=O)O)N(C(=O)OCc3ccccc3)C4)nc(Oc3ccccc3)n2)C(F)(F)F)n1
Temperature: 70 °C

Procedure:
To a solution of 2-((benzyloxy)carbonyl)-8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-(methylsulfonyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (300 mg, 0.393 mmol) in 1,4-dioxane (10 mL) was added phenol (74 mg, 0.79 mmol), Cs2CO3 (512 mg, 1.5 mmol), and the reaction was heated to 70° C. for 21 h. The reaction was then cooled to RT, diluted with water, acidified to pH<1 with 1 N HCl, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification on a 50 g Isco Gold RediSep reverse phase silica cartridge (H2O:HOAc: 99:1 MeOH:HOAc 99:1) provided 2-((benzyloxy)carbonyl)-8-(6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-phenoxypyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as an off-white solid.
Reaction SMILES: ClC1C(C(=O)N(CCCC)CCCC)=NN(C2C=CC(C(=O)NS(C3C=CC4C(=CC=CC=4)C=3)(=O)=O)=CC=2C(O)=O)C=1C.[Cl:44][C:45]1[C:46]([C:79](=[O:89])[N:80]([CH2:85][CH2:86][CH2:87][CH3:88])[CH2:81][CH2:82][CH2:83][CH3:84])=[N:47][N:48]([C:51]2[CH:61]=[CH:60][C:59]([C:62](=[O:78])[NH:63][S:64]([C:67]3[CH:68]=[C:69]4[C:73](=[CH:74][CH:75]=3)[N:72]([CH2:76][CH3:77])[CH2:71][CH2:70]4)(=[O:66])=[O:65])=[CH:58][C:52]=2[C:53]([O:55]CC)=[O:54])[C:49]=1[CH3:50]>>[Cl:44][C:45]1[C:46]([C:79](=[O:89])[N:80]([CH2:85][CH2:86][CH2:87][CH3:88])[CH2:81][CH2:82][CH2:83][CH3:84])=[N:47][N:48]([C:51]2[CH:61]=[CH:60][C:59]([C:62](=[O:78])[NH:63][S:64]([C:67]3[CH:68]=[C:69]4[C:73](=[CH:74][CH:75]=3)[N:72]([CH2:76][CH3:77])[CH2:71][CH2:70]4)(=[O:66])=[O:65])=[CH:58][C:52]=2[C:53]([OH:55])=[O:54])[C:49]=1[CH3:50]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4c(c3)CCN4CC)cc2C(=O)OCC)c(C)c1Cl
Agent: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)O)c(C)c1Cl
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4c(c3)CCN4CC)cc2C(=O)O)c(C)c1Cl
Yield: 33.3 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 91F, ethyl 2-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-5-(1-ethylindolin-5-ylsulfonylcarbamoyl)benzoate (180 mg, 0.27 mmol) was converted to the title compound (58 mg, 32%) after purification by preparative HPLC. 1H NMR (DMSO-d6) δ 8.41 (d, J=2.0 Hz, 1H), 8.17 (dd, J=8.3, 2.1 Hz, 1H), 7.69-7.64 (m, 2H), 7.52 (d, J=1.8 Hz, 1H), 6.83 (d, J=8.6 Hz, 1H), 3.54 (t, J=8.6 Hz, 2H), 3.28-3.24 (m, 6H), 3.00 (t, J=8.6 Hz, 2H), 2.10 (s, 3H), 1.57-1.41 (m, 4H), 1.33-1.26 (m, 2H), 1.14-1.08 (m, 5H), 0.91 (t, J=7.4 Hz, 3H), 0.75 (t, J=7.3 Hz, 3H); MS(ESI+) m/z 644.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.S(Cl)(Cl)(=O)=O.[CH3:25]O>>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:9]=2[C:10]([O:12][CH3:25])=[O:11])=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)c1cc(O)ccc1CCc1ccc(F)cc1
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)c1cc(O)ccc1CCc1ccc(F)cc1
Yield: 66 %

Procedure:
A solution of 2-(4-fluorophenethyl)-5-hydroxybenzoic acid (30 g, 115.4 mmol) in methanol (900 ml) and the stirred solution treated dropwise with sulphuryl chloride (1.6 ml, 19.6 mmol) stirred and heated at reflux for 16 hours. The mixture was evaporated to dryness, the residue dissolved in ethyl acetate (500 ml), washed with saturated aqueous NaHCO3 (×2), water and brine. After drying (MgSO4) the solution was evaporated to dryness to give a brown oil which when triturated with iso-hexane gave methyl 2-(4-fluorophenethyl)-5-hydroxybenzoate (21.02 g, 66%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:9]2[CH:22]=[CH:21][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[O:14])=[CH:11][N:10]=2)[C:6]=1[O:7]C.[CH3:23][N:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][C:25]1=[O:39]>>[OH:7][C:6]1[N:5]([C:9]2[CH:22]=[CH:21][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[O:14])=[CH:11][N:10]=2)[N:4]=[CH:3][C:2]=1[C:28]1[CH:27]=[CH:26][C:25](=[O:39])[N:24]([CH3:23])[CH:29]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Reactant: COCCCNC(=O)c1ccc(-n2ncc(Br)c2OC)nc1
Product: COCCCNC(=O)c1ccc(-n2ncc(-c3ccc(=O)n(C)c3)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 212 using 6-(4-bromo-5-methoxy-1H-pyrazol-1-yl)-N-(3-methoxypropyl)nicotinamide and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.70 (quin, J=6.7 Hz, 2H) 3.18 (s, 3H) 3.21-3.29 (m, 2H) 3.32 (t, J=6.3 Hz, 2H) 3.38 (s, 3H) 6.34 (d, J=9.3 Hz, 1H) 7.81 (dd, J=9.5, 2.4 Hz, 1H) 8.03 (s, 1H) 8.20 (d, J=1.8 Hz, 1H) 8.24 (dd, J=8.8, 2.3 Hz, 1H) 8.39 (d, J=8.6 Hz, 1H) 8.56 (t, J=5.4 Hz, 1H) 8.78 (d, J=1.8 Hz, 1H) 12.62 (br. s., 1H). MS m/z 384 [M+H]+.
Reaction SMILES: O.[OH:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]([OH:11])[C:8]([O-:10])=[O:9])=[CH:5][CH:4]=1.[Na+].[OH-].[Na+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O>[CH2:17]([O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]([OH:11])[C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: O=C([O-])C(O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(O)c1ccc(OCc2ccccc2)cc1
Yield: 68.9 %

Procedure:
A solution of 41.6 g (0.20 mol) of sodium 4-hydroxymandelate monohydrate, 9.6 g (0.24 mol) of sodium hydroxide and 27.9 g (0.22 mol) of benzyl chloride in 50 ml of water is stirred at 70° C. for 17 hours. The mixture is then diluted with 50 ml of water, and another 4.0 g (0.10 mol) of sodium hydroxide are added. The reaction mixture is refluxed for one hour, then cooled, acidified with concentrated hydrochloric acid, and the precipitated product is filtered. The residue is washed with cold water and then dried in a high vacuum, giving 35.6 g (69%) of 4-benzyloxymandelic acid, melting point 148°-155° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH:14][C:15]([C:17]3[CH:29]=[CH:28][C:20]([CH:21]=[CH:22][C:23]([O:25]CC)=[O:24])=[CH:19][CH:18]=3)=[O:16])[CH:5]=[CH:4][C:3]1=2.O.[OH-].[Li+].Cl>CO.COCCOC.O>[CH3:1][C:2]1([CH3:30])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([NH:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([CH:21]=[CH:22][C:23]([OH:25])=[O:24])=[CH:28][CH:29]=3)=[O:16])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)C=Cc1ccc(C(=O)Nc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(NC(=O)c3ccc(C=CC(=O)O)cc3)ccc21
Yield: 94.5 %

Procedure:
The above ester (109 mg, 0.269 mmol) was dissolved in methanol-DME-water (3:2:1, 4.2 ml), the solution was added with lithium hydroxide monohydrate (LiOH.H2O, 15 mg, 0.357 mmol), and the mixture was refluxed by heating for 1 hour. The mixture was cooled on ice, and then added with aqueous hydrochloric acid (1 N, 0.36 ml, 0.36 mmol), and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over anhydrous sodium sulfate, and then the solvent was evaporated. The residue was recrystallized to obtain the title compound (96 mg, 95%) as colorless prisms.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:18](Cl)(=[O:20])[CH3:19]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:18](=[O:20])[CH3:19])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Br)c1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(Br)c1
Reaction time: 1 h

Procedure:
A solution of 3-bromo-phenylamine (1.04 g, 6 mmol) was treated with DIEA (2.3 mL, 13.3 mmol) and chilled to zero degrees. Acetyl chloride (0.47 mL, 6.7 mmol) was added dropwise via syringe. Reaction was allowed to return to room temperature and stir for 1 hour. Reaction was then poured onto water and washed once. Organic phase was evaporated to beige solids (1.25 g, 98%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11](Cl)=[O:12])[C:8]([Br:14])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]([C:11]([C:22]2[CH:23]=[CH:24][C:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:20][CH:21]=2)=[O:12])[C:8]([Br:14])=[CH:7][C:3]=1[C:4]([C:22]1[CH:21]=[CH:20][C:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:24][CH:23]=1)=[O:5]
Reactant: O=C(Cl)c1cc(Br)c(C(=O)Cl)cc1Br
Reactant: CCCCCCCCCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCCCc1ccc(C(=O)c2cc(Br)c(C(=O)c3ccc(CCCCCCCCCC)cc3)cc2Br)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
Compound 7 (19.2 g, 0.059 mol) was dissolved in 100 mL of dry CH2Cl2, and aluminum chloride (16.6 g, 0.12 mol) was added. The reaction turned orange and some precipitate formed. The reaction was cooled to 0° C., and phenyldecane (45.3 g, 0.21 mol) in 50 mL of dry CH2Cl2 was added through an additional funnel. The reaction was stirred at room temperature under nitrogen overnight. The reaction was quenched carefully with 1 N HCl, extracted with CH2Cl2, and the combined organic phase was dried over MgSO4. The crude product was obtained as off-white solid and was recrystallized from acetone to give 31.8 g of pure product as white crystals at 74% yield. 1H NMR (CDCl3) δ (ppm): 0.88 (t, J=6.7 Hz, 6H), 1.26-1.32 (m, 28H), 1.62-1.67 (m, 4H), 2.69 (t, J=7.6 Hz, 4H), 7.32 (d, J=7.9 Hz, 4H), 7.58 (s, 2H), 7.76 (d, J=7.9 Hz, 4H). Mp 128-129° C.
Reaction SMILES: Cl.[C:2]([S:21][CH2:22][CH2:23][NH2:24])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:25][C:26]1[CH:27]=[C:28]2[C:32](=[C:33]([NH:35][S:36]([C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)(=[O:38])=[O:37])[CH:34]=1)[NH:31][C:30]([C:44](O)=[O:45])=[CH:29]2.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C>[CH3:25][C:26]1[CH:27]=[C:28]2[C:32](=[C:33]([NH:35][S:36]([C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)(=[O:38])=[O:37])[CH:34]=1)[NH:31][C:30]([C:44]([NH:24][CH2:23][CH2:22][S:21][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:45])=[CH:29]2
Reactant: Cc1cc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc2c1
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.1 %

Procedure:
To a mixture of 2-(tritylthio)ethylamine hydrochloride (0.77 g), triethylamine (0.31 mL) and N,N-dimethylformamide (20 mL) were added 5-methyl-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.60 g), 1H-1,2,3-benzotriazol-1-ol (0.36 g) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.45 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil was crystallized from ethyl acetate-hexane to give the title compound (1.07 g, yield 95%) as pale-yellow crystals. melting point 214-215° C.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Br:15][C:16]1[C:23]([O:24][CH2:25][CH3:26])=[C:22]([CH:27](O)[CH3:28])[CH:21]=[C:20]([Cl:30])[C:17]=1[C:18]#[N:19].C(Cl)Cl>>[Br:15][C:16]1[C:23]([O:24][CH2:25][CH3:26])=[C:22]([CH:27]([Cl:3])[CH3:28])[CH:21]=[C:20]([Cl:30])[C:17]=1[C:18]#[N:19]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCOc1c(C(C)O)cc(Cl)c(C#N)c1Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1c(C(C)Cl)cc(Cl)c(C#N)c1Br
Yield: 75.8 %

Procedure:
Cyanuric chloride (0.11 g, 0.59 mmol) was dissolved in N,N-dimethylformamide (3 mL, 40 mmol). After stirring for a few minutes, a solution of 2-bromo-6-chloro-3-ethoxy-4-(1-hydroxyethyl)benzonitrile (150 mg, 0.49 mmol) in methylene chloride (3 mL, 50 mmol) was added. The resulting mixture was stirred at room temperature overnight. The reaction was partitioned between water and dichloromethane. The organic layer was washed with sat. NaHCO3 solution, water, brine, dried over MgSO4, and concentrated. The crude product was purified by flash column chromatography, eluting a gradient of 0-30% EtOAc/Hexane to give 2-bromo-6-chloro-4-(1-chloroethyl)-3-ethoxybenzonitrile (0.12 gm, 75%) as a semisolid, LCMS calculated for C11H10BrCl2NO m/z=323.9, 320.9; found: (poor ionization).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:18])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:20]1[C:26](=[O:27])[NH:25][C:24]2[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=2[CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[O:18][CH:20]1[C:26](=[O:27])[NH:25][C:24]2[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=2[CH2:22][CH2:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Nc2ccccc2CCC1Br
Reactant: O=[N+]([O-])c1ccc(O)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1Nc2ccccc2CCC1Oc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1

Procedure:
A mixture of 3-benzyloxy-4-nitrophenol (2.45 g, 10 mmol), 3-bromo-1,3,4,5-tetrahydrobenzo[b]azepin-2-one (2.4 g, 10 mmol) and potassium carbonate (3.1 g, 23 mmol) in MeCN (10 mL) is refluxed for 10 h. Upon cooling a precipitate forms. The solid is filtered, washed with water and crystallized from EtOAc to give the title compound: mp=188-189° C.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([F:33])[CH:31]=3)[NH:26][CH:25]=2)[CH2:20][CH2:19]1)([OH:4])=[O:3].[CH3:34]O>>[CH3:34][O:3][C:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([F:33])[CH:31]=3)[NH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:4]
Reactant: CO
Reactant: O=C(O)c1ccc2[nH]cc(CCCCN3CCC(c4c[nH]c5ccc(F)cc45)CC3)c2c1
Agent: Cl
Product: COC(=O)c1ccc2[nH]cc(CCCCN3CCC(c4c[nH]c5ccc(F)cc45)CC3)c2c1

Procedure:
HCl gas is passed into a boiling solution of 2.5 g of 3-[1-(4-(5-carboxyindol-3-yl)butyl)-4-piperidyl]-5-fluoroindole in 50 ml of absolute methanol for hours. The mixture is then boiled for a further hour, is worked up in a conventional manner and gives 3-[1-(4-(5-methoxycarbonylindol-3-yl)butyl)-4-piperidyl]-5-fluoroindole.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:41][CH3:42])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]5[CH2:40][CH2:39]C[CH2:37][CH2:36]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:43][N:44]1CCNCC1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:41][CH3:42])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]5[CH2:36][CH2:37][N:44]([CH3:43])[CH2:39][CH2:40]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCN1CCCCC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCN1CCN(C)CC1
Yield: 7 %

Procedure:
The title compound was prepared as described in Example 57B by using 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea from Example 57B (200 mg, 0.37 mmol) and N-methyl piperazine (123 μL, 1.11 mmol) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(4-methylpiperazin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea (15.75 mg, 7%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.01 (s, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.52-7.43 (m, 2H), 7.34-7.26 (m, 3H), 6.49 (s, 1H), 4.20 (bs, 2H), 3.99 (s, 3H), 2.46-2.34 (m, 10H), 2.14 (s, 3H), 1.99-1.97 (m, 2H), 1.27 (s, 9H); LC-MS (ESI) m/z 606 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[C:3]=1[F:13].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:20][CH2:21][CH2:22][CH2:23]I>>[Cl:20][CH2:21][CH2:22][CH2:23][N:6]1[C:5]2[CH:11]=[CH:12][C:2]([F:1])=[C:3]([F:13])[C:4]=2[O:9][CH2:8][C:7]1=[O:10]
Reactant: ClCCCI
Reactant: O=C1COc2c(ccc(F)c2F)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C1COc2c(ccc(F)c2F)N1CCCCl
Yield: 93.2 %

Procedure:
7,8-Difluoro-4H-benzo[1,4]oxazin-3-one (81MF2082a) (0.119 g, 0.64 mmol), Cs2CO3 (0.314 g, 0.96 mmol) and 3-chloro-1-iodopropane (0.144 g, 0.70 mmol) were mixed according to GP5 giving the crude title compound (0.156 g); 1H NMR (CDCl3) δ 6.89-6.82 (m, 1H), 6.78-6.74 (m, 1H), 4.68 (s, 2H), 4.08 (t, J=7.2 Hz, 2H), 3.62 (t, J=6.4 Hz, 2H), 2.18-2.10 (m, 2H); 13C NMR (CDCl3) δ 163.5, 147.7 (q, J=245.6 Hz, J=10.4 Hz), 141.0 (q, J=249.4 Hz, J=15.7 Hz), 135.5, 126.2, 109.9 (d, J=18.4 Hz), 108.6 (q, J=7.6 Hz, J=4.2 Hz), 67.8, 42.3, 39.4, 30.0.
Reaction SMILES: [CH3:1][C:2]12[CH2:12][CH:6]3[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([CH2:13][N:14]4[CH:18]=[CH:17][CH:16]=[N:15]4)([CH2:5]3)[CH2:3]1)[CH2:9]2.[C:19]1(C)C=CC=CC=1.C([Li])CCC.CI>O1CCCC1>[CH3:11][C:8]12[CH2:7][CH:6]3[CH2:12][C:2]([CH3:1])([CH2:3][C:4]([CH2:13][N:14]4[C:18]([CH3:19])=[CH:17][CH:16]=[N:15]4)([CH2:5]3)[CH2:10]1)[CH2:9]2
Reactant: Cc1ccccc1
Reactant: CC12CC3CC(C)(C1)CC(Cn1cccn1)(C3)C2
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccnn1CC12CC3CC(C)(CC(C)(C3)C1)C2
Reaction time: 2 h

Procedure:
To a solution of EXAMPLE 32A (2.44 g) in tetrahydrofuran (25 mL)/toluene (25 mL) was added n-butyllithium (7.49 mL) at −40° C. The reaction mixture was stirred for 60 minutes when CH3I (1.873 mL) was added and the stirring was continued for 2 hours at −40° C. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over magnesium sulfate, filtered, concentrated and purified by flash chromotography (silica gel, 0%-15% ethyl acetate/hexanes).
Reaction SMILES: [C:1]1([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:18][N:17]([C:19]([C:21]4[CH:32]=[CH:31][C:24]([O:25][C@H:26]5[CH2:30][CH2:29][NH:28][CH2:27]5)=[CH:23][CH:22]=4)=[O:20])[CH2:16]3)[CH2:11][CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[CH3:40][N:41]([CH3:46])[S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[CH3:40][N:41]([CH3:46])[S:42]([N:28]1[CH2:29][CH2:30][C@H:26]([O:25][C:24]2[CH:31]=[CH:32][C:21]([C:19]([N:17]3[CH2:16][CH:15]([N:12]4[CH2:11][CH2:10][N:9]([C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[O:8])[CH2:14][CH2:13]4)[CH2:18]3)=[O:20])=[CH:22][CH:23]=2)[CH2:27]1)(=[O:44])=[O:43]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: O=C(c1ccccc1)N1CCN(C2CN(C(=O)c3ccc(O[C@H]4CCNC4)cc3)C2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)N1CC[C@H](Oc2ccc(C(=O)N3CC(N4CCN(C(=O)c5ccccc5)CC4)C3)cc2)C1
Reaction time: 3 h
Yield: 58 %

Procedure:
A solution of compound 33a (0.164 mmol) and Et3N (0.5 mL) in CH2Cl2 (2 mL) was treated with N,N-dimethylsulfamoyl chloride (26 uL, 0.246 mmol) at room temperature. The resulting mixture was stirred for 3 h, and the solvent was then removed under reduced pressure. The resultant residue was directly loaded onto a silica gel column and was purified by silica gel flash column chromatography, eluting with 5% MeOH/CH2Cl2 to give compound 439 (51.5 mg). 1H NMR (CDCl3): δ 7.61 (d, J=8.21 Hz, 2H), 7.36-7.46 (m, 5H), 6.86 (d, J=8.6 Hz, 2H), 4.98 (m, 1H), 4.31 (br. s., 1H), 4.11-4.26 (m, 2H), 4.05 (br. s., 1H), 3.87-3.96 (m, 1H), 3.84 (m, 1H), 3.70-3.79 (m, 1H), 3.66 (dd, J=11.4, 4.8 Hz, 1H), 3.39-3.58 (m, 4H), 3.21-3.26 (m, 1H), 2.82 (s, 6H), 2.42 (br. s., 4H), 2.19-2.29 (m, 2H); MS m/z (M+H+) 542.0.
Reaction SMILES: [CH3:1][C:2]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:24])[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][O:13]2)=[CH:8][CH:7]=1.C(OO)(=[O:27])C>>[O:27]1[C:19]([CH3:24])([CH2:20][CH:21]([CH3:22])[CH3:23])[CH:18]1[CH2:17][CH2:16][C:2]([CH3:1])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][O:13]2)=[CH:8][CH:7]=1
Reactant: CC(=CCOc1ccc2c(c1)OCCC2)CCC=C(C)CC(C)C
Reactant: CC(=O)OO
Product: CC(=CCOc1ccc2c(c1)OCCC2)CCC1OC1(C)CC(C)C

Procedure:
Following the procedure of Example 17, 7-(3,7,9-trimethyl-2,6-decadienyloxy)-chromane and peracetic acid are reacted to form 7-(6,7-epoxy-3,7,9-trimethyl-2-decenyloxy)-chromane, nD20 = 1.5256.