Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[CH:9][C:10](=O)[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:4][CH:3]=1.Cl.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][NH2:28].N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]2[N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[Cl:20])[N:28]=[C:10]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:9]2)[N:7]=1
Reactant: O=C(C=Cc1cccc(Br)n1)C(F)(F)C(F)(F)F
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2cccc(Br)n2)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 11 %

Procedure:
1-(6-Bromo-pyridin-2-yl)-4,4,5,5,5-pentafluoro-pent-1-en-3-one (100.0 mg, 0.3 mmol) prepared in Step 3, 2-chlorophenylhydrazine hydrochloride (55.0 mg, 0.3 mmol), and piperidine (60.0 uL, 0.6 mmol) were added to ethanol (3.0 mL). The reaction mixture was stirred at 60° C. for 2 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The mixture was washed with distilled water, dried on anhydrous magnesium sulfate, and concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[OH:18])=[C:15]3[C:10]([CH:11]=[C:12]([F:26])[C:13]([F:25])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.C[O:28][C:29]([C:31]1([O:34][C:35]2[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=2)[CH2:33][CH2:32]1)=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([CH:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[O:18][C:38]3[CH:39]=[CH:40][C:35]([O:34][C:31]4([C:29]([OH:30])=[O:28])[CH2:33][CH2:32]4)=[CH:36][CH:37]=3)=[C:15]3[C:10]([CH:11]=[C:12]([F:26])[C:13]([F:25])=[CH:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1(Oc2ccc(O)cc2)CC1
Reactant: OC(c1c2cc(F)c(F)cc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O)C1(Oc2ccc(OC(c3c4cc(F)c(F)cc4nn3-c3ccc(Cl)cc3)C3CCCCC3)cc2)CC1

Procedure:
In analogy to the procedure described in example 29.2, [rac]-[2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-cyclohexyl-methanol (example 24.4) was reacted with 1-(4-hydroxy-phenoxy)-cyclopropanecarboxylic acid methyl ester (Hazeldine, Stuart T.; Polin, Lisa; Kushner, Juiwanna; White, Kathryn; Corbett, Thomas H.; Horwitz, Jerome P. Bioorganic & Medicinal Chemistry (2005), 13(12), 3910-3920) in the presence of tri-phenylphosphine and di-tert-butyl azodicarboxylate in THF to give the title compound as white solid. MS: m/e=567.4 [M+H4].
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:15]=[C:16]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[N:18][CH:19]=1.[CH:28](OC)=[O:29].C([O-])(O)=O.[Na+]>O1CCCC1.CC(C)=O.CCCCCC>[Cl:13][C:14]1[C:15]([CH:28]=[O:29])=[C:16]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:17]=[N:18][CH:19]=1
Reactant: COC=O
Reactant: Clc1cncc(OCc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: CC(C)=O
Product: O=Cc1c(Cl)cncc1OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
To a stirred solution of diisopropylamine (4.5 mL, 31.78 mmol) in anhydrous tetrahydrofuran (20 mL) under nitrogen atmosphere at −5° C. was added dropwise n-BuLi in hexanes (2.5 M solution, 12.8 mL, 31.78 mmol) maintaining internal temperature of the reaction mixture below 0° C. The reaction mixture was stirred at −10° C. for 10 minutes, then at 0° C. for 30 minutes. This was cooled to −78° C. and a solution of Example 236A (5.8 g, 26.5 mmol) in anhydrous tetrahydrofuran (30 mL) was added slowly. Stirring at −78° C. was continued for 1 hour. Then the reaction was quenched with dropwise addition of methyl formate (5 mL, 79.5 mmol) in anhydrous THF (15 mL) and stirred at −78° C. for 3.5 hours. Internal temperature of the reaction mixture was maintained at or below −74° C. throughout the reaction. After 3.5 hours, the reaction mixture was poured into an ice cold saturated aqueous solution of NaHCO3 (200 mL) and stirred for 15 minutes. The mixture was partitioned with ethyl acetate (250 mL), organic layer was separated and washed with brine (2×60 mL). The dried (MgSO4) organic layer was concentrated under reduced pressure to obtain the crude product (8.5 g). The title compound was obtained in 75% yield (4.2 g) by flash chromatography on silica gel eluting with 6% acetone-hexane.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]2[C:10]([CH3:14])=[C:11]([CH3:13])[N:12]=[C:6]2[C:5]=1[NH:15]C(=O)C(C)(C)C)(=[O:3])[CH3:2].S(=O)(=O)(O)O.C(Cl)Cl.[OH-].[Na+]>CO>[C:1]([C:4]1[CH:9]=[CH:8][N:7]2[C:10]([CH3:14])=[C:11]([CH3:13])[N:12]=[C:6]2[C:5]=1[NH2:15])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccn2c(C)c(C)nc2c1NC(=O)C(C)(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1ccn2c(C)c(C)nc2c1N
Temperature: 0 °C
Yield: 39.6 %

Procedure:
A cooled solution of 80.4 g of 7-acetyl-2,3-dimethyl-8-pivaloylaminoimidazo[1,2-a]pyridine in 720 ml of methanol is treated with 496 ml of concentrated sulfuric acid and heated at reflux for 2.5 hours. It is then poured onto 1 l of ice water, 400 ml of methylene chloride are added and the mixture is adjusted to pH 7 with 10 N sodium hydroxide solution with cooling. After phase separation, the aqueous phase is again extracted twice with 300 ml of methylene chloride each time, the organic phases are collectively washed with 1 l of water, dried over sodium sulfate and the solvent is stripped off in vacuo. The solid residue is purified on silica gel (eluent: ethyl acetate). 22.5 g of the title compound of m.p. 195-97° C. (diethyl ether) are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]2[N:10]=[CH:11][N:12]([CH2:13][CH3:14])[C:4]=2[CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[Cl:22].[F-].[Cs+]>COCCOC.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:13]([N:12]1[C:4]2[CH:3]=[C:2]([C:19]3[CH:18]=[CH:17][C:16]([Cl:15])=[C:21]([Cl:22])[CH:20]=3)[N:7]=[C:6]([C:8]#[N:9])[C:5]=2[N:10]=[CH:11]1)[CH3:14]
Reactant: CCn1cnc2c(C#N)nc(Cl)cc21
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: CCn1cnc2c(C#N)nc(-c3ccc(Cl)c(Cl)c3)cc21
Temperature: 80 °C
Yield: 46.5 %

Procedure:
Tetrakis(triphenylphosphine)palladium (15 mg) was added under a nitrogen atmosphere to a mixture of 6-chloro-1-ethyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (42 mg), 3,4-dichloro-phenylboronic acid (152 mg) and cesium fluoride (100 mg) in DME (2mL) and methanol (1 mL). The mixture was heated at 80° C. for 24 hours then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by using preparative LC/MS (eluent: A: NH4HCO3 10 mM/B: CH3CN). to afford the title compound (30 mg) as a white solid. 1H NMR (CDCl3) δ: 8.20-8.15 (m, 2H); 7.94 (d, J=8 Hz, 1H); 7.91 (s, 1H); 7.58 (d, J=8 Hz, 1H); 4.37 (q, J=7 Hz, 2H); 1.65 (t, J=7 Hz, 3H). MS m/z: 317/ 319 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:43])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:39])([C:33]3[O:34][C:35]([CH3:38])=[CH:36][CH:37]=3)[CH3:32])[NH:17][CH:16]2[C:40](O)=[O:41])[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:49][C@@H:48]([CH2:50][CH2:51][NH2:52])[CH2:47][O:46]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:49][C@H:48]([CH2:47][OH:46])[CH2:50][CH2:51][NH:52][C:40]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:43])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:39])([C:33]2[O:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[CH3:32])[NH:17]1)=[O:41]
Reactant: Cc1ccc(C(C)(C)CC2NC(C(=O)O)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)o1
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(C(C)(C)CC2NC(C(=O)NCC[C@H](O)CO)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)o1
Yield: 27.7 %

Procedure:
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-methyl-2-(5-methyl-furan-2-yl)-propyl]-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 125c (0.6 g, 0.93 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.4 g, 2.8 mmol), HATU (0.6 g, 1.7 mmol) and iPr2NEt (0.8 mL, 4.6 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-methyl-2-(5-methyl-furan-2-yl)-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.16 g, 29%).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([CH2:13][CH:14]([C:34]([OH:36])=O)[C:15]([C@H:20]2[CH2:25][CH2:24][C@@H:23]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:22][CH2:21]2)(O)C(O)=O)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:39]([O:42]C(=O)C)(=[O:41])C>>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C:14]2[C:34](=[O:36])[O:42][C:39](=[O:41])[C:15]=2[C@H:20]2[CH2:25][CH2:24][C@@H:23]([O:26][Si:27]([C:30]([CH3:32])([CH3:31])[CH3:33])([CH3:29])[CH3:28])[CH2:22][CH2:21]2)=[CH:37][CH:38]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(C(=O)O)C(O)(C(=O)O)[C@H]2CC[C@@H](O[Si](C)(C)C(C)(C)C)CC2)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC2=C([C@H]3CC[C@@H](O[Si](C)(C)C(C)(C)C)CC3)C(=O)OC2=O)cc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
3-(4-((tert-Butyldimethylsilyl)oxy)benzyl)-2-(cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2-hydroxysuccinic acid (90 mg, 0.16 mmol) was dissolved in acetic anhydride (2.0 ml), and the mixture was stirred at 120° C. for 18 hr. The mixture was allowed to cool, excess acetic anhydride was concentrated under reduced pressure, and the residue was chromatographed on silica gel column (hexane:ethyl acetate=94:6) to give the title compound as a yellow oil (60 mg, yield 70%).
Reaction SMILES: [NH2:1][C@H:2]([C:13](O)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.S(C)C>C1COCC1>[NH2:1][C@@H:2]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)[CH2:13][OH:14]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Solvent: C1CCOC1
Solvent: CSC
Product: N[C@H](CO)Cc1c[nH]c2ccccc12
Temperature: 70 °C
Yield: 92 %

Procedure:
To a stirred solution of (S)-tryptophan (4.0 g, 20.0 mmol) in THF (100 mL) at 0° C. was slowly added BH3.Me2S complex (5.9 mL, 10M solution in THF, 59.0 mmol). The reaction mixture was heated to 70° C. for 16 h and, after cooling, the excess borane was quenched by the addition of MeOH (10 mL) at 0° C. The reaction mixture was then concentrated in vacuo and the resultant white solid was dissolved in EtOAc (100 mL) and washed with aqueous 20% NaOH solution (2×70 mL). The organic layer was then extracted into aqueous 2M HCl (2×100 mL). The combined acidic aqueous layers were basified to pH 14 (addition of solid NaOH) and were re-extracted with EtOAc (2×150 mL). The combined organic fractions were washed with brine (70 mL), dried over MgSO4, filtered and concentrated in vacuo to give the title compound (3.5 g, 92%) as a white solid that required no further purification. δH (CD3OD) 7.46 (1H, d, J 7.9 Hz), 7.21 (1H, d, J 8.0 Hz), 6.96 (3H, m), 3.79 (1H, dd, J 11.3 and 3.6 Hz), 3.54 (1H, dd, J 11.2 and 6.2 Hz), 3.05 (1H, m), 2.80 (1H, m), 2.61 (1H, m). Exchangeable protons were not observed.
Reaction SMILES: BrC1C=CC(S(O[CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)(=O)=O)=CC=1.[I-:21].[Na+]>CC(C)=O>[CH:15]1([O:14][CH2:13][CH2:12][I:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: [I-]
Reactant: O=S(=O)(OCCOC1CCCCC1)c1ccc(Br)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCOC1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.6 %

Procedure:
To a solution of 2-cyclohexyloxyethyl 4-bromobenzenesulfonate (Preparation 86, 120 mg, 0.3 mmol) in acetone (5 ml) was added sodium iodide (90 mg, 0.6 mmol) and the reaction mixture was left to stir at room temperature for 18 h. A further equivalent of sodium iodide was added and the reaction mixture was stirred at room temperature for a further 18 h after which time the reaction mixture was heated to 80° C. for 5 h. The resulting precipitate was filtered and the filtrate was diluted with water (100 ml) and extracted with dichloromethane (100 ml). The extract was washed with brine (100 ml), dried (MgSO4) and concentrated in vacuo to give the title compound as a colourless oil (50 mg, 60%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C@H:12]2[CH2:14][C@H:13]2[C:15]([OH:17])=O)[O:9][N:8]=1.Cl.[Cl:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[Cl:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:23][N:24]1[CH2:25][CH2:26][CH:27]([NH:30][C:15]([C@@H:13]2[CH2:14][C@@H:12]2[C:10]2[O:9][N:8]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[N:11]=2)=[O:17])[CH2:28][CH2:29]1
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: O=C(O)[C@@H]1C[C@@H]1c1nc(-c2ccccn2)no1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1)[C@@H]1C[C@@H]1c1nc(-c2ccccn2)no1
Reaction time: 24 h
Yield: 19 %

Procedure:
Cis-2-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]cyclopropanecarboxylic acid (0.139 g) and N,N′-carbonyldiimidazole (0.110 g) in dichloromethane was stirred under nitrogen for 1 hour. 1-(3,4-dichlorobenzyl)-4-piperidinamine hydrochloride (0.198 g), and triethylamine (0.121 g) was then added and allowed to stir for 24 hours under nitrogen. Saturated sodium hydrogen carbonate was added to the reaction with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave an oil. This oil was purified by RPHPLC (75%-5%, 0.1% ammonium acetate/acetonitrile). The solvent was removed under reduced pressure to leave Cis-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]cyclopropanecarboxamide (0.054 g) as a white solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>C1C=CC=CC=1>[CH3:15][N:16]([CH:18]=[C:4]([C:3](=[O:10])[C:2]([F:11])([F:12])[F:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:17]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: COC(OC)N(C)C
Solvent: c1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)C(F)(F)F
Yield: 64.9 %

Procedure:
Ethyl 4,4,4-trifluoroacetoacetate (18.5 g, 77.34 mmol) and N,N-Dimethylformamide dimethyl acetal (9.21 g, 77.34 mmol) were dissolved in benzene (10 mL). The mixture was heated under reflux for 1 h. The solvent was evaporated and distilled with a Kugelrohr apparatus to give 12 g of ethyl 2-((dimethylamino)methylene)-4,4,4-trifluoro-3-oxobutanoate (yield 65%).
Reaction SMILES: [NH2:1][C:2]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH2:7]1)([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:17][O:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([C:2]1([CH3:5])[CH2:3][O:4][C:26](=[O:28])[NH:1]1)[CH2:15][CH2:14]2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc2c(c1)CCC(C(C)(N)CO)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CCC(C1(C)COC(=O)N1)C2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 54.1 %

Procedure:
To 25 grams of 2-amino-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propan-1-ol in 575 mL of dichloromethane was added 45 g of triethylamine. The mixture was cooled to 0° C., and kept below 5° C. while 21 g of triphosgene in dichloromethane was added dropwise. The mixture was stirred at 20-25° C. for 1.5 hrs. The reaction was followed by HPLC until the starting material disappeared. The mixture was concentrated under reduced pressure, 375 mL ethyl acetate was added to the residue. It was washed with water (50 mL×2), dried, decolorized with carbon, and concentrated and dried to afford 10 g of 4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-4-methyloxazolidin-2-one, M=261, purity 97%.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:20])[CH2:18][CH2:17][CH2:16][CH:15]([CH3:19])[CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30]>>[CH3:20][C:13]1([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:25]4[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=4)[N:3]=3)[NH:8][CH:9]=2)=[O:12])[CH2:18][CH2:17][CH2:16][CH:15]([CH3:19])[CH2:14]1
Reactant: CC1CCCC(C)(C(=O)c2c[nH]c3ncc(Br)nc23)C1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCCC(C)C4)c3n2)cc(OC)c1OC

Procedure:
(1,3-Dimethyl-cyclohexyl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1,3-dimethyl-cyclohexyl)-methanone and 3,4,5-trimethoxybenzeneboronic acid following general procedures as described in these Examples. MP 229-231° C., M+H=424.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[N+:11]([O-:13])=[O:12])=[CH:5][C:4]=1[O:14][CH3:15].C[Si](C)(C)[O:18][C:19]([CH:21]=[CH2:22])=[CH2:20].C1(C)C=CC=CC=1.Cl>C(OCC)(=O)C>[CH3:15][O:14][C:4]1[CH:5]=[C:6]([CH:9]2[CH:10]([N+:11]([O-:13])=[O:12])[CH2:22][CH2:21][C:19](=[O:18])[CH2:20]2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(/C=C/[N+](=O)[O-])cc1OC
Reactant: C=CC(=C)O[Si](C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(C2CC(=O)CCC2[N+](=O)[O-])cc1OC
Temperature: 140 °C
Reaction time: 48 h

Procedure:
90.0 g of 3,4-dimethoxy-w-nitrostyrene (compound G2), 90 ml of 2-trimethylsilyloxy-1,3-butadiene and 180 ml of abs. Toluene are put in an autoclave, where the mixture is stirred at 140° C. for 2 days and then cooled. After addition of 1000 ml of ethyl acetate, 300 ml of a 2 N solution of hydrochloric acid are dropped under stirring. The phases are separated and the aqueous layer is extracted three times with dichloromethane. The combined organic extracts are washed with saturated sodium hydrogen-carbonate solution, dried over magnesium sulfate and the solvents are removed under reduced pressure to give 150 g of the crude title compound. Further purification is carried out by chromatography on silica gel using petroleum ether/ethyl acetate in the ratio 1/1 as eluent to give 81.5 g (67% of theory) of the pure title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:15][CH2:14][CH2:13][CH2:12][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: ClCCCBr
Reactant: CC(C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)c1ccc(OCCCCl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
A mixture of 27.4 g (0.2 mole) of p-isopropylphenol, 63 g (0.4 mole) of 1-bromo-3-chloropropane and 82.9 g (0.6 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 24 hr. The reaction mixture was cooled, filtered and filtrate concentrated. The residue was dissolved in 200 ml of benzene and treated with potassium hydroxide pellets to remove excess starting phenol. The mixture was stirred in ambient temperature for 0.5 hr, filtered through Celite® and the filtrate concentrated to give 36.4 g (87% yield) of the title compound as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.Cl[C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.C(OCC)(=O)C>[N:11]1[CH:12]=[CH:13][CH:14]=[N:15][C:10]=1[N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1
Reactant: OCC1CCNCC1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: OCC1CCN(c2ncccn2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a solution of 4-piperidinemethanol (1.00 g) in dimethyl sulfoxide (28.9 mL), 2-chloropyrimidine (994 mg) and potassium carbonate (2.40 g) were added and the mixture was stirred at 100° C. for three hours. After cooling the reaction mixture to room temperature, water was added to it and extraction was conducted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and after removing the desiccant by filtration, the filtrate was concentrated under reduced pressure to give [1-([pyrimidin-2-yl)piperidin-4-yl]methanol as a colorless oil (1.50 g).
Reaction SMILES: C([O:3][C:4]1[C:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:6][CH:7]=[CH:8][C:9]=1[CH:10]([CH3:12])[CH3:11])=O.[OH-].[K+]>C(O)C>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:5]2[C:4]([OH:3])=[C:9]([CH:10]([CH3:11])[CH3:12])[CH:8]=[CH:7][CH:6]=2)=[CH:18][CH:17]=1
Reactant: CC(C)c1cccc(-c2ccc(F)cc2)c1OC=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1cccc(-c2ccc(F)cc2)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.6 %

Procedure:
To a solution of 4'-fluoro-3-(1-methylethyl)[1,1'-biphenyl]-2-ol formate (2 g) in ethanol (5 mL) was added a 10% solution of potassium hydroxide in ethanol (10 mL) and the reaction mixture was stirred at room temperature for 1 hour. The reaction was concentrated in vacuo, and the residue was partitioned between dichloromethane (20 mL) and 1N hydrochloric acid (20 mL). The separated aqueous layer was extracted with dichloromethane (2×20 mL), then the combined organic layers were washed with water, dried (MgSO4) and evaporated to furnish 1.9 g of 4'-fluoro-3-(1-methylethyl) [1,1'-biphenyl]-2-ol as a oil which solidified on standing. A small sample was sublimed to give the analytical specimen, mp 41°-43° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH2:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.CCN(CC)CC.[CH2:20]([S:22](Cl)(=[O:24])=[O:23])[CH3:21]>C(Cl)Cl>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][S:22]([CH2:20][CH3:21])(=[O:24])=[O:23])[C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: NC1CCCc2c(Br)cncc21
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)NC1CCCc2c(Br)cncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of (rac)-4-bromo-5,6,7,8-tetrahydro-isoquinolin-8-ylamine (intermediate A-2 [D]) (227 mg, 1 mmol) and Et3N (152 mg, 1.5 mmol) in DCM (5 mL) was added ethanesulfonyl chloride (193 mg, 1.5 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 hr before it was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water and the organic layer was dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give a crude product (302 mg, 95% yield). MS: 319.0 (M+H)+.