Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].OO.C([C@H]1COC(=O)N1[C:18](=[O:38])[C@@H:19]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=1)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)C1C=CC=CC=1.S(S([O-])=O)([O-])=[O:40].[Na+].[Na+]>CO.O1CCCC1.O>[OH:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][C@H:19]([O:28][C:29]2[CH:30]=[CH:31][C:32]([CH:35]([CH3:36])[CH3:37])=[CH:33][CH:34]=2)[C:18]([OH:38])=[O:40])=[CH:26][CH:25]=1
Reactant: CC(C)c1ccc(O[C@@H](Cc2ccc(O)cc2)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Reactant: O=S([O-])S(=O)[O-]
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1ccc(O[C@@H](Cc2ccc(O)cc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.6 %

Procedure:
A mixture of aqueous lithium hydroxide solution (1N, 57.0 ml) and aqueous hydrogen peroxide solution (31%, 6.34 ml) was added dropwise to a suspension of (S)-4-benzyl-3-[(S)-3-(4-hydroxyphenyl)-2-(4-isopropylphenoxy)propionyl]oxazolidine-2-one (10.6 g), which is the product of Reference example 29(d), in a mixture of methanol (140 ml) and tetrahydrofuran (15 ml). After the mixture was stirred at ambient temperature for 6 hours, a solution of sodium dithionite (10.1 g) in water (50 ml) was added to the reaction mixture and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure. Aqueous sodium hydroxide solution (1N) was added to the residue to make it basic. The solution was washed with dichloromethane and partitioned between aqueous hydrogen chloride solution and ethyl acetate. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was crystallized from hexane to afford (S)-3-(4-hydroxyphenyl)-2-(4-isopropylphenoxy)propionic acid (6.00 g) as a white powder. Oxalyl chloride (5.50 ml) and N,N-dimethylformamide (5 drops) were added to a suspension of this carboxylic acid (4.43 g) in dichloromethane (100 ml) at ambient temperature. The mixture was stirred for 1 hour. At the end of this time the reaction mixture was concentrated under reduced pressure. The residue was azeotropically distilled off using toluene to remove excess reagent. 2-Trimethylsilylethanol (9.06 ml) was added to a solution of the residue in dichloromethane (50 ml). This mixture was stirred at ambient temperature for 15 hours. Triethylamine (4.40 ml) and 4-N,N-dimethylaminopyridine (155 mg) were added to the mixture. This mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the layers were separated. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified via chromatography on a silica gel column using hexane/ethyl acetate=5/1-4/1 as the eluant to afford the desired compound (5.30 g) as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[CH:15]=[CH:14][C:5]=1[O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])([O-])=O.CO>C(OCC)(=O)C.C(N(CC)CC)C>[NH2:1][C:4]1[CH:17]=[C:16]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[CH:15]=[CH:14][C:5]=1[O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cccs2)cc1[N+](=O)[O-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cccs2)cc1N
Yield: 41 %

Procedure:
Following the same procedure described for Example 48, step 3 (scheme 36) but substituting compound 171 for compound 299 and using ethyl acetate and triethylamine as a solvent instead methanol, the title compound 300 was obtained in 41% yield over two steps. MS: calc: 305.5; found: 306.1 (M+H).
Reaction SMILES: [CH3:1][S:2]([C:5]([CH3:11])([CH3:10])[CH2:6][C:7]([OH:9])=[O:8])(=[O:4])=[O:3].I[CH2:13]C>>[CH2:1]([S:2]([C:5]([CH3:11])([CH3:10])[CH2:6][C:7]([OH:9])=[O:8])(=[O:3])=[O:4])[CH3:13]
Reactant: CCI
Reactant: CC(C)(CC(=O)O)S(C)(=O)=O
Product: CCS(=O)(=O)C(C)(C)CC(=O)O

Procedure:
The starting material 3-(ethanesulfonyl)-3-methylbutyric acid was prepared in a manner analogous to that described for the preparation of 3-(methanesulfonyl)-3-methylbutyric acid, the starting material usedfor Example 95, using iodoethane in place of iodomethane.
Reaction SMILES: [SH2]=N.[CH2:3]([NH:5][C:6](C1C=CC=CC=1C(O)=O)=[O:7])[CH3:4].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.O>CC(C)=O>[C:18]1([NH:17][C:6]([NH:5][CH2:3][CH3:4])=[O:7])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCNC(=O)c1ccccc1C(=O)O
Reactant: Nc1ccccc1
Agent: N=[SH2]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: CCNC(=O)Nc1ccccc1
Yield: 79 %

Procedure:
5.08 g ethylcarbamoyl-benzoic acid sulfimide was reacted with 1.86 g aniline and 2.8 ml triethylamine in 20 ml of a 1:1 mixture of water and acetone, as described in example 1. 2.59 g 1-phenyl-3-ethylurea was obtained, melting at 99°-100° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>ClCCl>[CH3:23][S:20]([O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:22])=[O:21]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cccc(OS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 55.2 %

Procedure:
To a stirred solution of ethyl 3-hydroxybenzoate (3.32 g, 20 mmol) in dichloromethane (20 mL) cooled to 0° C. was added triethylamine (4.17 mL, 30 mmol). To this was added mesyl chloride (1.94 mL, 25 mmol) dropwise over 15 min. The reaction was stirred at 0° C. for 15 min then quenched with water and the phases separated. The aqueous layer was extracted with dichloromethane and the combined organics were dried over MgSO4 and concentrated in vacuo. The crude material was purified via the Biotage SP4 (silica-packed 25+M; 0-50% EtOAc/hexanes) to provide the title compound as a white solid (2.698 g, 55%). 1H NMR (300 MHz, CDCl3) δ: 7.98 (m, 1H), 7.89 (s, 1H), 7.47 (m, 2H), 4.35 (q, J=7.0 Hz, 2H), 3.16 (s, 3H), 1.37 (t, J=7.0 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 165.3, 149.3, 132.9, 130.3, 128.7, 126.9, 123.2, 61.8, 37.8, 14.5 ppm. IR (neat, cm−1): 1721, 1384, 1369, 1268, 1194, 1168, 1098, 936, 840, 798.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C:11]([CH:25]=[O:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1.[CH3:27][Mg]Br>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C:11]([CH:25]([OH:26])[CH3:27])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1
Reactant: C[Mg]Br
Reactant: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC1(C=O)c1ccccc1
Solvent: C1CCOC1
Product: CC(O)C1(c2ccccc2)C=C(c2cc(F)ccc2F)CN1C(=O)N(C)C
Reaction time: 1 h

Procedure:
To a suspension of 75 mg (0.21 mmol) of aldehyde 3-1 in THF at −78° C. was added 80 μL (0.25 mmol) of methyl magnesium bromide solution (3M in Et2O). After stirring 1 h at that temperature, an additional 80 μL of the Grignard reagent was added and stirring was continued for 1 h more. The reaction was quenched with saturated NH4Cl, partitioned between brine and EtOAc, the organic phase washed with brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography on silica gel with EtOAc/hexanes to provide 5-1 as a white solid. Data for 5-1: 1HNMR (500 MHz, CDCl3) δ 7.6 (m, 2H), 7.4-7.2 (m, 3H), 7.1-6.9 (m, 3H), 6.5 (s, 1H), 5.05 (m, 1H), 4.8 (m, 1H), 4.6 (m, 1H), 4.35 (m, 1H), 2.8 (s, 6H), 1.4 (m, 3H) ppm. HRMS (ES) calc'd M+H for C21H22F2N2O2: 373.1722. Found: 373.1713.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:17](=[O:19])[CH3:18])=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[Br:20]Br.C(OCC)(=O)C>C(O)(=O)C>[Br:20][CH2:18][C:17]([C:9]1[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=2)=[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]2[N:10]=1)=[O:19]
Reactant: CC(=O)c1nn2ccccc2c1-c1ccnc(F)c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(CBr)c1nn2ccccc2c1-c1ccnc(F)c1
Temperature: 80 °C
Yield: 63 %

Procedure:
To a solution of 1-[3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-2-yl]ethanone (580 mg, 2.27 mmol) in acetic acid (20 mL) was added bromine (0.12 mL, 2.27 mmol). After heating at 80° C. for 30 minutes, the solution was cooled to room temperature. Ethyl acetate was added to dilute the reaction mixture. The mixture was washed with water (×3), brine and dried over magnesium sulfate. Filtration and concentration, followed by recrystallization from ethyl acetate gave 2-bromo-1-[3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-2-yl]ethanone (478 mg, 64%) as a yellow solid. 1H NMR (CDCl3): δ 8.51 (d, 1H), 8.27 (d, 1H), 7.65 (d, 1H), 7.33 (m, 2H), 7.10 (s, 1H), 7.06 (t, 1H), 4.76 (s, 2H). MS m/334 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:9][C:5]=2[CH:4]=1.[C-:18]#[N:19].[Na+]>CN(C)C=O>[C:10]1([C:8]2[O:9][C:5]3[CH:4]=[C:3]([CH2:2][C:18]#[N:19])[CH:17]=[CH:16][C:6]=3[N:7]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [C-]#N
Reactant: BrCc1ccc2nc(-c3ccccc3)oc2c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1ccc2nc(-c3ccccc3)oc2c1

Procedure:
A mixture of 6-bromomethyl-2-phenylbenzoxazole (40 gm) and sodium cyanide (7.4 gm) in dry dimethylformamide (800 ml) was heated on a steam bath for 3 hr. The mixture was filtered and the filtrate was evaporated to dryness. The solid was recrystallised to give 2-phenyl-6-benzoxazolylacetonitrile as white crystals, m.p. 144°C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:9]=2)[S:4][C:3]=1[C:16]([O:18]CC)=[O:17].[OH-].[K+]>C(O)C.O>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:9]=2)[S:4][C:3]=1[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)c1sc2ncc(-c3ccco3)nc2c1N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1c(C(=O)O)sc2ncc(-c3ccco3)nc12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A suspension of ethyl 7-amino-2-(furan-2-yl)thieno[2,3-b]pyrazine-6-carboxylate 58 (100 mg, 0.346 mmol) and potassium hydroxide (97 mg, 1.728 mmol) in ethanol (5 mL) and water (1 mL) was stirred at 70° C. for 1 h. Quenched in ice cold citric acid solution. The resulting precipitate was collected, washed with water and dried to 7-amino-2-(furan-2-yl)thieno[2,3-b]pyrazine-6-carboxylic acid 59 (66 mg, 73.1%). (m/z)=262 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:48]=[CH:47][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].C[Si]([N:53]=[N+:54]=[N-:55])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[NH:53]1[C:1]([C:3]2[CH:4]=[CH:5][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][C:40]([C:43]([F:44])([F:45])[F:46])=[CH:39][CH:38]=4)=[CH:33][CH:32]=3)[CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=3)=[CH:47][CH:48]=2)=[N:2][N:55]=[N:54]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)Cc2ccc(C#N)cc2)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)Cc2ccc(-c3nnn[nH]3)cc2)cc1
Temperature: 80 °C

Procedure:
A solution of 295 mg (0.53 mmol) of methyl 4-[(4E)-3-(4-cyanobenzyl)-5-(2-{[4′-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)pent-4-en-1-yl]benzoate in 20 ml of toluene is mixed with 1.33 ml (9.99 mmol) of trimethylsilyl azide and 249 mg (1 mmol) of di-n-butyltin oxide and heated at 80° C. for 12 hours. After cooling to room temperature, the mixture is washed with saturated sodium bicarbonate solution. The organic phase is separated off, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate is concentrated to dryness. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: dichloromethane→dichloromethane/methanol 10:1). 387 mg (0.56 mmol, 64% of theory) of a white foam are obtained.
Reaction SMILES: [O:1]1CCC[O:3][CH:2]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](O)([CH:31]=[CH2:32])[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1.Cl>CC(C)=O.O>[F:29][C:27]([F:28])([F:30])[C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:20]=1)[CH2:16][O:15][CH2:14][C:13]1([CH:31]=[CH2:32])[C:8]2[C:7](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]([OH:1])[O:3]1
Reactant: C=CC(O)(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1C1OCCCO1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: C=CC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(2-(1,3-dioxan-2-yl)phenyl)-1-(3,5-bis(trifluoromethyl)benzyloxy)but-3-en-2-ol (800 mg, 1.68 mmol) in acetone (20 mL) and water (1 mL) was added concentrated hydrochloric acid (0.2 mL) at room temperature. The resulting reaction was stirred at room temperature for 2 h. The reaction was quenched by addition of saturated sodium bicarbonate, and concentrated to remove most of the acetone. The mixture was poured into diethyl ether, washed with water, then brine, dried over magnesium sulfate, and concentrated. Column chromatography (25%-->50% EtOAc/Hex) gave 475 mg (68%) as a colorless oil. Mass spec.: 401.32 (M-OH)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:18][CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]2[N:3]=1.[NH2:25][C:26]1[C:27]([Cl:51])=[C:28]([N:34]2[CH2:43][CH2:42][C@@H:41]3[C@H:36]([O:37][CH2:38][CH2:39][N:40]3[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:35]2)[CH:29]=[C:30]([C:32]#[N:33])[CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[Cl:51][C:27]1[C:26]([NH:25][C:2]2[N:7]=[C:6]([N:8]([CH2:18][CH3:19])[CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:5]3=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]3[N:3]=2)=[CH:31][C:30]([C:32]#[N:33])=[CH:29][C:28]=1[N:34]1[CH2:43][CH2:42][C@@H:41]2[C@H:36]([O:37][CH2:38][CH2:39][N:40]2[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H]2CN(c3cc(C#N)cc(N)c3Cl)CC[C@H]21
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Cl)nn2c(C#N)cnc12
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H]4[C@@H](C3)OCCN4C(=O)OC(C)(C)C)c2Cl)nn2c(C#N)cnc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 43.3 %

Procedure:
2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 10) (85.0 mg, 0.248 mmol), (+/−)-(4aR,8aR)-tert-butyl 6-(3-amino-2-chloro-5-cyanophenyl)octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (97.0 mg, 0.248 mmol), DPPF (9.62 mg, 0.017 mmol), Cs2CO3 (137 mg, 0.422 mmol), Xantphos (14.35 mg, 0.025 mmol), Palladium(II)Acetate (16.7 mg, 0.074 mmol) and 1,4-dioxane (2 ml) were combined in a microwave vial. The vial was evacuated and backfilled with Nitrogen (3×). The reaction stirred at 100° C. for 3 hr. The reaction mixture cooled to 25° C., diluted with EtOAc, washed with brine and dried (Na2SO4). The solvents were removed and the material purified on silica gel 25% EtOAc in DCM to afford (+/−)-(4aR,8aR)-tert-butyl 6-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (75 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[OH:32]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:32][C:26]3[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=3[F:24])=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: Oc1cc(F)ccc1F
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2cc(Oc3cc(F)ccc3F)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (200 mg, 0.613 mmol) and 2,5-difluorophenol were reacted as starting materials at 150° C. for 24 hours and post-treatment was then conducted, whereby the title compound was obtained as a colorless crystalline powder (235.5 mg, 91.5%). Melting point: 174.4-175.2° C. (chloroform-hexane).
Reaction SMILES: CN(C)/C=[CH:4]/[C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1.C1C[O:22]CC1.O>>[N+:15]([C:14]1[C:5]([CH:4]=[O:22])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-:17])=[O:16]
Reactant: C1CCOC1
Reactant: CN(C)/C=C/c1ccc2cccnc2c1[N+](=O)[O-]
Solvent: O
Product: O=Cc1ccc2cccnc2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
NalO4 (11.71 g, 54.76 mmol) was added portionwise to a solution of dimethyl-[(E)-2-(8-nitro-quinolin-7-yl)-vinyl]-amine (Intermediate 203) (4.44 g, 18.3 mmol) in THF/water (1:1, 70 ml). The mixture was stirred at room temperature for 16 h. The insoluble material was removed by filtration and washed with EtOAc (60 ml). The combined organic phases were washed with sat. sodium bicarbonate solution, brine, dried (Na2SO4) and concentrated in vacuo to give the title compound (3.24 g, 71%).
Reaction SMILES: [Li].[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[Br-].[OH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:28][CH:27]=1>C(O)C>[OH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:13]/[C:12]2[CH:15]=[CH:16][C:9]([O:8][CH:3]3[CH2:4][CH2:5][CH2:6][CH2:7][O:2]3)=[CH:10][CH:11]=2)=[CH:28][CH:27]=1
Reactant: O=Cc1ccc(OC2CCCCO2)cc1
Reactant: OCCCCCCOc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]
Solvent: CCO
Product: OCCCCCCOc1ccc(/C=C/c2ccc(OC3CCCCO3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.1 %

Procedure:
0.23 g of lithium was dissolved in 150 ml of ethanol. Then 6.2 g of 4-(tetrahydropyran-2-yloxy)benzaldehyde (H) was added. The solution was cooled in an ice-water bath and 16.5 g of 4-(6-hydroxyhexyloxy)phenylmethyltriphenylphosphonium bromide (I) was added. After stirring for 2 hours at room temperature, a white precipitate was obtained. 3.34 g of (E)-4-(6-hydroxyhexyloxy)-4′-(tetrahydropyran-2-yloxy)stilbene (J, 31%) was obtained after collection by filtration and two washings with 150 ml of ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[S:17][C:18]([CH:21]=[O:22])=[CH:19][N:20]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[C:23]1([Li])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN1C(=O)N(C)CCC1.O1CCCC1.C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[S:17][C:18]([CH:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[OH:22])=[CH:19][N:20]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(Nc2ncc(C=O)s2)ccc1-n1cnc(C)c1
Reactant: [Li]c1ccccc1
Solvent: CN1CCCN(C)C1=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(Nc2ncc(C(O)c3ccccc3)s2)ccc1-n1cnc(C)c1
Temperature: 0 °C

Procedure:
To a solution of 100 mg (0.32 mmol) 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazole-5-carbaldehyde in DMPU (1 ml) and tetrahydrofurane (2 ml) was added slowly 0.67 ml (1.27 mmol) 1.9 M phenyl lithium solution in diethyl ether at −72° C. under nitrogen. The reaction was warmed to 0° C. over 40 minutes. The solvent was evaporated under reduced pressure. The residue was partitioned between in ethyl acetate and 1N aqueous NaOH solution. The aqueous layer was extracted once with ethyl acetate. The combined organic layers were washed twice with water, dried over sodium sulphate, filtered and the solvent was evaporated under reduced pressure. The residue was purified on silica gel with methylene chloride/methanol 9/1 yielding 39 mg (22%) {2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-5-yl}-phenyl-methanol as a yellow oil. MS ISP (m/e): 393.0 (100) (M+H)+. 1H NMR (CDCl3, 250 MHz): δ (ppm)=7.56 (s, 1H), 7.47-6.84 (m, 11H), 5.99 (s, 1H), 3.79 (s, 3H), 2.28 (s, 3H).
Reaction SMILES: C(OC([O:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:23][CH:22]3[CH:20]([CH:21]3[N:24]([C:36](=[O:44])[CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])[CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[CH2:19]2)=[N:16][CH:17]=1)=[O:11])C)C(C)C.Cl.O1CCOCC1>C(Cl)Cl>[OH:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:23][CH:22]3[CH:20]([CH:21]3[N:24]([C:36](=[O:44])[CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])[CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[CH2:19]2)=[N:16][CH:17]=1)=[O:11]
Reactant: CCN(CC)CCC(=O)N(Cc1ccc2ccccc2c1)C1C2CN(c3ncc(C(=O)NOC(C)OCC(C)C)cn3)CC21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCN(CC)CCC(=O)N(Cc1ccc2ccccc2c1)C1C2CN(c3ncc(C(=O)NO)cn3)CC21
Yield: 56.7 %

Procedure:
N-(1-Isobutoxyethoxy) 2-{6-[(3-diethylaminopropionyl)naphthalen-2-ylmethyl-amino]-3-azabicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide (199 mg, 0.33 mmol) was dissolved in DCM (3 ml) and treated with a solution of 4M HCl in dioxane (0.5 ml, 2 mmol). The resulting precipitate was filtered and dried to give the title compound as a white solid (94 mg, 57%). LCMS purity 98%, m/z 475 [M+H]+, 1H NMR (300 MHz, CD3OD) δ: 1.39 (6H, t, J=7.2 Hz), 2.26 (2H, br s), 2.77 (1H, s), 3.37 (4H, m), 3.55 (2H, d, J=10.5 Hz), 3.81 (4H, br s), 3.93 (2H, d, J=10.5 Hz), 4.71 (2H, br s), 7.61 (2H, m), 7.76 (1H, d, J=8.4 Hz), 7.95-8.04 (3H, m), 8.20 (1H, s), 8.71 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CCN(C(C)C)C(C)C.[F:34][C:35]([F:50])([F:49])[C:36]([NH:38][CH:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42][NH:41][CH2:40]1)=[O:37]>CN(C=O)C.CCOC(C)=O>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH2:10][C:11]([N:41]2[CH2:40][CH:39]([NH:38][C:36](=[O:37])[C:35]([F:50])([F:34])[F:49])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42]2)=[O:13])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C(NC1CNCc2ccccc21)C(F)(F)F
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CNc1cc(Cl)cc(Cl)c1)N1Cc2ccccc2C(NC(=O)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
To a solution of 2-(3,5-dichlorophenylamino)acetic acid (0.332 g, 1.5 mmol) in DMF (10 mL) was added HOBt (0.30 g, 2.2 mmol) EDCI: HCl (0.434 g, 2.2 mmol), DIEA (0.39 g, 3.0 mmol) and 2,2,2-trifluoro-N-(1,2,3,4-tetrahydroisoquinolin-4-yl)acetamide (370 mg, 1.5 mmol) at 0° C. The reaction mixture was warmed to rt and stirred overnight. After the reaction was shown to be complete as indicated by TLC the reaction mixture was diluted with EtOAc (50 mL), and washed with water (20 mL×3). The EtOAc layer was concentrated in vacuo to give crude reaction mixture which was purified by column chromatography (silica gel, gradient MeOH in CH2Cl2) to give (0.45 g, 74%) of the titled intermediate. 1H NMR (DMSO-d6, 400 MHz): δ 7.56 (s, 1H), 7.37-7.21 (m, 4H), 6.74 (d, J=11.6 Hz, 2H), 6.61 (s, 1H), 6.4-6.2 (m, 1H), 5.20-5.06 (m, 1H), 4.85 (t, J=16.4 Hz, 1H), 4.60 (d, J=16.8 Hz, 1H), 4.58 (d, J=17.6, 1 H), 4.12-4.03 (m, 1H), 3.9-3.8 (m, 1H), 3.58-3.39 (m, 1H). LCMS: M/z: (M+1):446