Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH2:16]([O:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>CC(C)=O>[CH2:16]([O:22][CH2:23][CH2:24][CH2:25][NH:26][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCOCCCN
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCOCCCNC(c1ccccc1)C(O)c1ccccc1
Temperature: 140 °C
Reaction time: 44 h
Yield: 33.8 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mol) and 3-hexyloxypropylamine (1.75 g, 0.011 mol) was heated at 140° C. for 6 hours. After standing at ambient temperature for 44 hours, the reaction mixture was dissolved in acetone (10 mL) and the solution poured into water (150 mL). The light brown oil that separated from solution solidified on standing for 1 hour. The solid was collected and dried on absorbent paper for 18 hours. The solid was then triturated in isooctane (soluble) and the solution chilled to obtain a solid that was collected, washed with cold isooctane, and dried under ambient conditions to obtain 1.20 g (34%) of the product; mp 67°-69° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9]C2.[CH3:24][O:25][CH2:26][C:27](Cl)=[O:28].C(OCC)(=[O:32])C>C(=O)([O-])O.[Na+]>[CH3:24][O:25][CH2:26][C:27]([NH:23][C:21]1[CH:20]=[CH:19][C:17]2[N:18]=[C:13]([NH:12][CH:10]3[C:11]4[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=4[O:32][CH2:9]3)[O:14][CH2:15][C:16]=2[CH:22]=1)=[O:28]
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CC2
Reactant: CCOC(C)=O
Reactant: COCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COCC(=O)Nc1ccc2c(c1)COC(NC1COc3cccc(OC)c31)=N2
Temperature: 23 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
To a solution of rac-N2-(7-methoxy-indan-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 10) (100 mg, 0.321 mmol) in ethyl acetate (5 ml) and sat. sodium hydrogen carbonate-sol. at 0° C. was added methoxyacetyl chloride (35 ul, 0.385 mmol) and the mixture was stirred at 23° C. for 16 h. Diluted with ethyl acetate, washed with water, dried the organic layer over sodium sulfate. After filtration, the solvent was removed in vacuum and the crude product was triturated with diethyl ether to give the title compound as a white solid (90 mg, 73%), MS (ISP) m/e=384.2 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@H:7]2[CH2:8][C@H:5]([C:6]2([CH3:10])[CH3:9])[C:4](=[O:11])[O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:9][C:6]1([CH3:10])[C:7](=[C:2]([CH3:1])[CH3:12])[CH2:8][C@H:5]1[C:4]([OH:11])=[O:3]
Reactant: CC1(C)OC(=O)[C@@H]2C[C@H]1C2(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)=C1C[C@@H](C(=O)O)C1(C)C
Yield: 78.1 %

Procedure:
A solution of 3.68 g (21.9 mmol) of 4a in 60 mL of benzene with 416 mg (2.19 mmol) of p-toluenesulfonic acid monohydrate was heated in an oil bath at 100-110° C. for 24 h. A mini Dean-Stark trap was used for azeotropic distillation. Benzene was evaporated on a rotary evaporator, and the residue was treated with 2N aqueous Na2CO3 solution. The basic aqueous solution was washed with ether, then acidified to pH 2 with hydrochloric acid, and again extracted with ether. The combined ether extracts were washed with water, brine, dried, and concentrated to give 2.87 g (17.1 mmol, 78% yield) of 5a as clear oil after chromatography (silica gel, eluted with 20% to 25% of ethyl acetate in hexanes). Optical purity: 79% ee (after methylation); [α]24D−22.0 (c 0.1, MeOH); 1H NMR (CDCl3): δ 1.19 (3H, s), 1.37 (3H, s), 1.48 (3H, s), 1.58 (3H, s), 2.55 (1H, m), 2.81 (2H, m); 13C NMR (C6D6): δ 183.49, 135.57, 123.27, 47.47, 45.09, 28.15, 25.94, 22.09, 19.51, 18.52; EI-MS m/z (%): 168 [M]+ (38), 153 (38), 135 (8), 125 (21), 123 (27), 107 (59), 93 (29), 81 (100), 67 (30), 53 (16), 41 (25); HREIMS: obsd. 168.1152, calcd. for C10H16O2 (M+): 168.1150.
Reaction SMILES: Cl.Cl.[OH:3][C@H:4]1[C@@H:9]([CH3:10])[CH2:8][CH2:7][N:6]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH:16]([CH3:20])[C:15]2=[O:21])[CH2:5]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)[CH:26]=[CH:27][C:28](O)=[O:29].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:22][C:23]1[CH:24]=[C:25](/[CH:26]=[CH:27]/[C:28]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][N:6]3[CH2:7][CH2:8][C@H:9]([CH3:10])[C@H:4]([OH:3])[CH2:5]3)[C:15](=[O:21])[CH:16]2[CH3:20])=[O:29])[CH:31]=[CH:32][CH:33]=1
Reactant: CC1NCCN(CCCN2CC[C@H](C)[C@H](O)C2)C1=O
Reactant: O=C(O)C=Cc1cccc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1C(=O)N(CCCN2CC[C@H](C)[C@H](O)C2)CCN1C(=O)/C=C/c1cccc(Cl)c1
Reaction time: 1 h

Procedure:
To a solution of crude 1-[3-((3S,4S)-3-hydroxy-4-methyl-piperidin-1-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride (example 41; 0.03 g, 0.1 mmol) in N,N-dimethylformamide (0.8 ml) was added 3-chloro-cinnamic acid (0.02 g, 0.1 mmol), triethylamine (0.05 ml, 0.4 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (0.04 g, 0.1 mmol) and the reaction shaken for 1 h, after which time the reaction mixture was directly purified by preparative HPLC. This afforded the titled product as a colorless gum. MS (ISP)=434.3 (M+H)+.
Reaction SMILES: [ClH:1].O[CH2:3][C:4]1[CH:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:11]2[C:6](=[C:7]([O:23][CH3:24])[CH:8]=[CH:9][CH:10]=2)[N:5]=1.S(Cl)([Cl:27])=O.[OH-].[Na+]>CN(C=O)C>[ClH:27].[Cl:1][CH2:3][C:4]1[CH:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:11]2[C:6](=[C:7]([O:23][CH3:24])[CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: COc1cccc2c(NCc3ccccc3C)cc(CO)nc12
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cccc2c(NCc3ccccc3C)cc(CCl)nc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2 5 g (=7.2 mmol) of 2-hydroxymethyl-8-methoxy-4-(2-methylbenzylamino)quinoline hydrochloride, 5.3 ml of thionyl chloride and 2 drops of DMF was stirred at room temperature for 90 minutes. The mixture was poured onto ice, made alkaline with 1 N NaOH and extracted with ethyl acetate. The crude product after the organic phase had been dried with Na2SO4 and the solvent had been stripped off was converted into the hydrochloride with methanolic hydrochloric acid. 2.48 g of 2-chloromethyl-8-methoxy-4-(2-methylbenzylamino)quinoline hydrochloride were obtained.
Reaction SMILES: [CH:1]1([C:6]#[C:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[C:10]([F:18])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-]>CO>[CH:1]1([C:6]#[C:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:18])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C#CC2CCCC2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(C#CC2CCCC2)cc1F

Procedure:
Methyl 4-(cyclopentylethynyl)-2-fluorobenzoate was dissolved in 10 mL of MeOH and 10 mL of 2N LiOH and the mixture was refluxed overnight. The MeOH was removed under vacuum and the basic layer was washed with EtOAC, acidified, and re-extracted with EtOAC. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated under vacuum to give the desired product (645 mg) as a beige solid. m/z=233 (M+1).
Reaction SMILES: [C:1]([CH2:4][CH2:5][N:6]([CH2:50][CH3:51])[CH2:7][CH2:8][NH:9][C:10]([C@:12]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:43])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]2[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1)=[O:11])([OH:3])=[O:2].I[CH2:53]CC>>[C:1]([CH2:4][CH2:5][N:6]([CH2:50][CH2:51][CH3:53])[CH2:7][CH2:8][NH:9][C:10]([C@:12]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:43])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]2[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1)=[O:11])([OH:3])=[O:2]
Reactant: CCCI
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CC)CCC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CCC)CCC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-((2-carboxyethyl)(ethyl)amino)ethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (example 89). using 1-iodopropane as alkylating reagent. The product was isolated as a white solid (10 mg, 49%). LCMS: m/e 715.50 (M+H)+, 2.08 min (method 1). 1H NMR (500 MHz, Acetic Acid-d4) δ ppm 8.03 (d, J=7.93 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.37 (d, J=4.58 Hz, 1H), 4.78 (s, 1H), 4.65 (s, 1H), 3.88-3.72 (m, 2H), 3.55 (t, J=7.02 Hz, 2H), 3.44 (q, J=6.51 Hz, 2H), 3.32-3.21 (m, 2H), 3.13 (td, J=11.22, 3.51 Hz, 1H), 2.97 (t, J=6.71 Hz, 2H), 2.55 (td, J=12.13, 3.81 Hz, 1H), 2.25-2.13 (m, 2H), 1.75 (s, 3H), 2.04-1.10 (m, 21H), 1.08 (s, 3H), 1.07 (s, 3H), 1.06 (s, 3H), 1.03 (t, J=5 Hz, 2H), 1.01 (s, 3H), 0.99 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:44][C@@H:45]([CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=1[C:65]([F:68])([F:67])[F:66])[CH2:46][N:47]1[C:55](=[O:56])[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:48]1=[O:57]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:44][C@@H:45]([CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:68])([F:66])[F:67])[CH2:46][N:47]2[C:55](=[O:56])[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:48]2=[O:57])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O)c1ccc(Br)cn1
Reaction time: 16 h

Procedure:
To a solution of 5-bromo-2-pyridinecarboxylic acid (97 mg, 2.6 mmol), PyBrOP (269 mg, 0.578 mmol) and diisopropylethyl amine (419 uL, 2.41 mmol) in DCM (5 mL) at 25° C. was added 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (168 mg, 0.481 mmol)[prepared in preparation 3]. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fraction were dried (Na2SO4), concentrated and used directly without further purification: LC-MS (ES) m/z=435 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:50])[N:11]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[N:26](COCC[Si](C)(C)C)[C:27]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:29]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:50])[N:11]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[NH:29][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:27]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:26]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCN(CCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)n1COCC[Si](C)(C)C)C(=O)Nc1ccc(F)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCN(CCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(=O)Nc1ccc(F)cc1F
Yield: 53.2 %

Procedure:
Part D. To a solution of N'-(2,4-difluorophenyl)-N-[6-(4,5 -diphenyl-1-[(trimethylsilyl)ethoxymethyl]-1H-imidazol-2-yl)hexyl]-N-heptylurea (0.60 g, 0.000853 mol) in dry tetrahydrofuran (10 mL) under a nitrogen atmosphere, tetrabutylammonium fluoride (1M in tetrahydrofuran, 3.41 mL) was added and the reaction mixture was heated to reflux 7 hours. The reaction mixture was cooled, poured into water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The product was purified by flash chromatography on silica gel (75 mL) eluting hexane:ethyl acetate (60:40 v:v) to give the title compound as a colorless glass (0.26 g, 0.000454 mol). 1H NMR (CDCl3) δ 9.5-9.0(bs,1H), 7.87 (m,1H), 7.5-7.2(m,10H), 6.83-6.7(m,2H), 6.4(d,1H), 3.28(m,4H), 2.67(t,2H), 1.75-1.26(m,18H), 0.88(t,3H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH2:18]3)=[CH:11][CH:10]=2)[C:5]([C:28]2[CH:47]=[CH:46][C:31]([O:32][C@H:33]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]([O:36]CC)=[O:35])=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.[OH-].[K+].Cl>C1COCC1.CO>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH:17]3[CH2:18][CH2:19][CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:21][CH2:22]3)=[CH:13][CH:14]=2)[C:5]([C:28]2[CH:29]=[CH:30][C:31]([O:32][C@H:33]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]([OH:36])=[O:35])=[CH:46][CH:47]=2)=[CH:4][CH:3]=1
Reactant: CCCCCC1CCC(COc2ccc(CCn3c(C)ccc3-c3ccc(O[C@H](Cc4ccccc4)C(=O)OCC)cc3)cc2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCC1CCC(COc2ccc(CCn3c(C)ccc3-c3ccc(O[C@H](Cc4ccccc4)C(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a mixed solution of ethyl (2R)-2-[4-(5-methyl-1-{2-[4-(4-pentylcyclohexylmethoxy)phenyl]ethyl}-1H-pyrrol-2-yl)phenoxy]-3-phenylpropanoate (550 mg, 0.865 mmol) in THF (20 ml) and methanol (10 ml) was added 1N aqueous potassium hydroxide solution (15 ml, 15 mmol) and the mixture was stirred for 1 hour at room temperature. The reaction solution was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate anhydride, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the object compound as an oily substance. 342 mg (yield: 65.0%)
Reaction SMILES: [CH:1]1[C:6](CC(N)=O)=[CH:5][CH:4]=[C:3]([OH:11])[CH:2]=1.Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])([O-])=O.[K+].[K+].C[N:28]([CH:30]=[O:31])C>O>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13][O:11][C:3]1[CH:4]=[CH:5][C:6]([C:30]([NH2:28])=[O:31])=[CH:1][CH:2]=1)[CH3:20]
Reactant: CCOC(=O)CCCBr
Reactant: CN(C)C=O
Reactant: NC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)CCCOc1ccc(C(N)=O)cc1
Yield: 60 %

Procedure:
A mixture of p-hydroxyphenylacetamide (3.8 g), ethyl 4-bromobutyrate (3.6 ml) and K2CO3 (3.45 g) was stirred for 12 hr in DMF (30 ml). The mixture was diluted with water (100 ml); the solid was filtered and air dried. Crystallization of the solid from ethanol gave 4 g (60%) of the title compound as white crystals; mp 144.5°-145.5°.
Reaction SMILES: [N+:1]([C:4]1[C:47]([F:48])=[C:46]([F:49])[C:7]([O:8][C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([C:17]3[C:22]([F:23])=[C:21]([F:24])[C:20]([O:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([O:34]CC5C=CC=CC=5)=[O:33])=[CH:28][CH:27]=4)=[C:19]([F:42])[C:18]=3[F:43])=[C:11]([F:44])[C:10]=2[F:45])=[C:6]([F:50])[C:5]=1[OH:51])([O-])=O.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[C:47]([F:48])=[C:46]([F:49])[C:7]([O:8][C:9]2[C:10]([F:45])=[C:11]([F:44])[C:12]([C:17]3[C:22]([F:23])=[C:21]([F:24])[C:20]([O:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([OH:34])=[O:33])=[CH:28][CH:27]=4)=[C:19]([F:42])[C:18]=3[F:43])=[C:13]([F:16])[C:14]=2[F:15])=[C:6]([F:50])[C:5]=1[OH:51]
Reactant: O=C(OCc1ccccc1)c1ccc(Oc2c(F)c(F)c(-c3c(F)c(F)c(Oc4c(F)c(O)c([N+](=O)[O-])c(F)c4F)c(F)c3F)c(F)c2F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1c(O)c(F)c(Oc2c(F)c(F)c(-c3c(F)c(F)c(Oc4ccc(C(=O)O)cc4)c(F)c3F)c(F)c2F)c(F)c1F
Reaction time: 72 h
Yield: 93 %

Procedure:
50 g of 4-(4-nitro-3-hydroxy-2,5,6-trifluoro-phenoxy)-4'-(4-benzyloxycarbonylphenoxy)octafluoro-biphenyl prepared as described in Example 5 (0.069 mol) are dissolved in 600 ml of a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1:1), and 5 g of Pd/C (palladium/carbon) are added to the solution. The mixture is then hydrogenated at room temperature in an autoclave with vigorous stirring using hydrogen at a pressure of 1 bar; after 3 days, the reaction is terminated. The orange solution is evaporated to half in a rotary evaporator and left to stand overnight at room temperature, during which the reaction product precipitates out in crystalline form. The reaction product is then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 93%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([S:13]([NH2:16])(=[O:15])=[O:14])[S:10][N:9]=2)=[CH:4][CH:3]=1.C[C:18](C)(C)[C:19]([O-:22])([O-])[O-].[CH3:25]CCCC>>[CH3:25][O:22][C:19](=[N:16][S:13]([C:11]1[S:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[N:12]=1)(=[O:15])=[O:14])[CH3:18]
Reactant: NS(=O)(=O)c1nc(-c2ccc(O)cc2)ns1
Reactant: CC(C)(C)C([O-])([O-])[O-]
Reactant: CCCCC
Product: COC(C)=NS(=O)(=O)c1nc(-c2ccc(O)cc2)ns1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
A mixture of 3.0 g of 3-(4-hydroxyphenyl)-1,2,4-thiadiazole-5-sulfonamide and 20 ml of trimethylorthoacetate was stirred at room temperature for 42 hours. Pentane (25 ml) was added and stirring continued overnight. The precipitated solid was triturated with benzene and collected to give 2.4 g of powder, m.p. 190°-192°.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].Cl.[CH2:23]([N:30]([CH3:38])[CH2:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(NC(C)C)(C)C>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:35]3[CH2:34][CH2:33][CH:32]([CH2:31][N:30]([CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH3:38])[CH2:37][CH2:36]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: CN(Cc1ccccc1)CC1CCNCC1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: Cl
Solvent: CC(C)NC(C)C
Product: CN(Cc1ccccc1)CC1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and benzyl-methyl-piperidin-4-ylmethyl-amine, hydrochloride, 5 equivalent of diisopropylamine was added, praeparative HPLC (Method C) (56%, colourless crystals). HPLC-MS m/z=500.2 (M+1), Rt: 3.18 min.
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:26]1[CH:30]=[C:29]([C:31]2[C:32]3[CH:39]=[CH:38][N:37](COCC[Si](C)(C)C)[C:33]=3[N:34]=[CH:35][N:36]=2)[CH:28]=[N:27]1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[F:22])=[O:13])[CH2:8][CH:7]1[CH:23]([F:25])[F:24])#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH2:3][CH:4]([N:26]1[CH:30]=[C:29]([C:31]2[C:32]3[CH:39]=[CH:38][NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH:28]=[N:27]1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[F:22])=[O:13])[CH2:8][CH:7]1[CH:23]([F:24])[F:25])#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCN(C(=O)c5ccc(C#N)cc5F)CC4C(F)F)c3)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCC(CN1CCN(C(=O)c2ccc(C#N)cc2F)CC1C(F)F)n1cc(-c2ncnc3[nH]ccc23)cn1

Procedure:
4-{[4-{3-cyano-2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-3-(difluoromethyl)piperazin-1-yl]carbonyl}-3-fluorobenzonitrile (27 mg, 0.041 mmol; Peak 3 from Step 8) was stirred in a 1:1 mixture of TFA:DCM (4 mL) for 1 h. Solvent was removed in vacuo. The residue was dissolved in methanol (1.9 mL), and 0.2 mL of ammonium hydroxide aqueous solution was added. Preparative HPLC-MS (C18, eluting with a gradient of H2O/MeCN containing 0.15% NH4OH) afforded purified product (7.7 mg, 35%). 1H NMR (400 MHz, DMSO-d6, rotamers): δ 12.13 (br s, 1H), 8.82 (s, 0.55H), 8.81 (s, 0.45H), 8.68 (s, 0.45H), 8.68 (s, 0.55H), 8.38 (s, 0.45H), 8.37 (s, 0.55H), 8.01 (dd, 0.45H), 7.96 (dd, 0.55H), 7.81 (dd, 0.45H), 7.76 (br d, 0.55H), 7.65-7.57 (m, 2H), 6.97 (d, 1H), 6.24 (br t, 1H), 4.91 (ddd, 1H), 4.25 (d, 0.55H), 4.05 (br m, 0.45H), 3.53-2.33 (m, 10H); 19F NMR (400 MHz, DMSO-d6): −114.10 to −115.21 (m, 1F), −123.22 to −125.01 (m, 2F); LCMS (M+H)+: 534.2.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([OH:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[H-].[Na+].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][CH3:27]>CN(C)C=O.O>[CH3:7][N:6]1[C:2]([NH2:1])=[C:3]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:4]([O:8][CH2:27][CH2:26][O:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:19]=2)=[N:5]1
Reactant: Cc1ccc(-c2c(O)nn(C)c2N)cc1
Reactant: CCOc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(OCCOc3ccccc3)nn(C)c2N)cc1
Reaction time: 2 h
Yield: 25.1 %

Procedure:
To 5-amino-1-methyl-4-(4-methylphenyl)-1H-pyrazol-3-ol (Preparation 3a) (50 mg) in dimethylformamide (2 ml) at room temperature was added sodium hydride (60% dispersion in oil, 10 mg) and bromophenetole (49.5 mg). The mixture was stirred for 2 hrs. The reaction was diluted with water (10 ml) and extracted with ethyl acetate (10 ml). The organic fraction was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10 g) eluted with ether to yield the title compound as a white solid (20 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:33]=[CH:34][C:35]2[C:36]([CH:40]=1)=[N:37][O:38][N:39]=2>>[N:39]1[O:38][N:37]=[C:36]2[CH:40]=[C:32]([CH2:31][O:1][C:2]3[CH:3]=[C:4]([C:8]4[C:17]5[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=5)[N:11]=[CH:10][C:9]=4[C:22]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[O:23])[CH:5]=[CH:6][CH:7]=3)[CH:33]=[CH:34][C:35]=12
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: BrCc1ccc2nonc2c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccc3nonc3c2)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 5-Bromomethyl-benzo[1,2,5]oxadiazole following the procedure of Example 478: MS (ESI) m/z 526; MS (ESI) m/z 524; HRMS: calcd for C30H18F3N3O3+H+, 526.13730; found (ESI, [M+H]+), 526.1356.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]=[O:12])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](CC=O)C(=O)OC(C)(C)C

Procedure:
To a solution of tert-Butyl N-(tert-butoxycarbonyl)-L-homoserinate (1.00 g, 3.63 mmol) in dichloromethane (50 mL) was added at r.t. pyridine (0.88 mL, 10.9 mmol) and Dess-Martin-periodinane (2.31 g, 5.45 mmol). After 90 min the reaction mixture was diluted with ethyl acetate (40 mL), washed with 10% sodium thiosulphate solution (30 mL), saturated sodium bicarbonate solution (40 mL), and brine (40 mL). The combined aqueous layers were extracted with ethyl acetate (50 mL) and the combined organic layers were dried over sodium sulphate and concentrated under reduced pressure.